CA1063108A - Azetidinone derivatives and process for preparation thereof - Google Patents

Abstract

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REMPLACEMENT
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Description

DEMANDES OU BREVETS VOLUMINEUX
. s LA PRÉSENTE PARTIE DE CETTE DEMANDE OU CE BREVET
COMP5:~END PLUS D'UN TOME.

CECI EST LE TOME / DE
_ NOTE: Pour les tomes additionels, veuillez contacter le Bureau canadien des brevets ~31 ~ -JUMBO APPLICATIC)NS/PATENTS

THAN ONE VOLUME

THIS IS Vl)LUNIE / OF ~Z

NOTE: Fo~ additional volumes please contact the Canadian Patent Office .

.

.

.

, ~ 3108 The present invention is based on the success of identi-fication of the chemical structure of FR-1923 substance.
That is, FR-1923 substance is a known antibiotic isolated from the fermentation broth of a strain of the genus Nocardia deposited with the American Type Culture Collection under ATCC 21806, the details of which are described for example, in German Patent Specification ~o. 2,242,699.
In said prior literature, the FR-1.923 substance is defined by the various physico-chemical properties without any disclosure of its chemical structure.
As a result of extensive investigations, the inventors of the present invention have succeeded in identificating-the chemical structure of the FR-1923 substance and assign-ing the following chemical structure and name to said sub-stance.

I 2CH2O ~ CCONH ~
COOH ~OH J~ H~OH
COOH
FR-1923 substance l-(~-Carboxy-4-hydroxybenzyl)-3- E 2-~4-(3-amino-3-carboxy-propoxy)phenyl~-2-hydroxyiminoacetamido~-2-azetidinone.
The above new discovery and knowledge gave the inventors of the present invention the possibility of studying some chemical modifications of FR-1923 substance for the first time. Then, based on such facts, the inventors have been ,~,~;, - .
~J~

- - - . . . .. . :

1~31~8 making a study of said modification so that they have just succeeded in synthesizing a lot of novel and unique modified compounds derived from FR-1923 substance and the related compounds.
Only for the purpose of ilLustrating the state of the arts, the known compound derived from penicillins and the relevant literatures are mentioned as follows.

-O-CH2CON ~ (U.S.P~ 3487,072) ~2 CH

-O-C-CO~H
I ~ (Journal of Organic Chemistry.

NO2 ~H3 o ~ H Vol.38, p. 940-943, 1973) CH3CONH ~ IH3 ~ ~-CH - CH (Tetrahedron, Vol.23, O I I p.4769, 1967) ~CH2CO~H ~ fH3 ~-O ~ ~ -CH - CH (Tetrahedron, Vol.23, p~4769,1967) -CO~H ~ CH3 ~ ~`

~ -CII CH ~Tetrahedron, Vol.23, . .
O I \ p.4769, 1967) The present invention relates to azetidinone derivatives. ~ .

More particularly, it relates to novel azetidinone derivatives ~ ~

::
. ~ 1 ::.: . . , :
. .; .

~;3:~(1 8 having antimicrobial activities and to process for pre-paration thereof.
Accordingly, it is an object of the present invention to provide azetidinone derivatives having antimicrobial activities.
Another object o~ the present invention is to provide a process for preparation of the aze~idinone derivatives.
The azetidinone derivatives of the present invention comprise a new and novel chemical structure which has never been expected to the skilled in the arts.
The azetidinone derivatives of the present invention are repxesented by the following general formula (I) , 1 1 ¦
~ -A (I) wherein Rl is amino or acylamino A is hydrogen, - saturated or unsaturated normal aliphatic hydrocarbon residue which is substituted by at least one substituent of carboxy or its derivative, cyano, hydroxy and amino, - saturated-branched aliphatic hydrocarbon residue which is substituted by at least one substituent of carboxy or its derivative, cyano, hydroxy and/or amino, - unsaturated-branched aliphatic hydrocarbon residue which is substituted by at least one substituent of carboxy or its derivative, cyano hydroxy and/or amino, or - aliphatic-hydrocarbon residue which is substituted by aryl whose ring may be substituted by one or more l~S3:108 substituents selected from hydroxy, amino, nitro, alkyl, alkoxy, aralkoxy, alkylthio, halogen and sulfo;
provided that when Rl is 2-[4-(3-amino-3-carboxypropoxy)-phenyl]-2-hydroxyiminoacetamido, A is hydrogen, saturated or unsaturated normal aliphatic hydrocarbon residue which is substituted by at least one substituent of carboxy or its derivative, cyano, hydroxy and/or amino, saturated branched-aliphatic hydrocarbon residue which is substituted by at.least one substituent of carboxy or its derivative, cyano, hydroxy and/or amino, unsaturated branched-aliphatic hydrocarbon residue which is substituted by at least one substituent of carboxy or its derivative, cyano, hydroxy and/or amino, or aliphatic-hydrocarbon residue which is substituted by .
aryl whose ring may be substituted~by one or more ~ ~
substituents selected from amino, nitro, alkyl, alkoxy, ~ ~.
aralkoxy, alkylthio, halogen and sulfo, when Rl is acetamido, benzoylamino or phenylacetamido, A is hydrogen, saturated or unsaturated normal aliphatic hydrocarbon residue which is substituted by at least one substituent of carboxy or its derivative, cyano, hydroxy and/or amino, unsaturated branched-aliphatic hydrocarbon residue which is substituted by at least one substituent of carboxy or its derivative, cyano, hydroxy and/or amino, or aliphatic-hydrocarbon residue which is substituted by aryl whose ring may be substituted by one or more sub-stituents selected from hydroxy, amino, nitro, alkyl, alkoxy, aralkoxy, alkylthio, halogen, and sulfo, ~1 ~631~3 when Rl is 2-(2-nitrophenoxy)acetamido or 2-(2-nitro phenoxy)-2-methylpropionamido, A is - saturated or unsaturated normal aliphatic hydrocarbon residue which is substituted by at least one sub-stituent of carboxy or its derivative, cyano, hydroxy and/or amino, -- saturated branched-aliphatic hydrocarbon residue which is substituted by at least one substituent of carboxy ~0 or its derivative, cyano, hydroxy and/or amino, - unsaturated branched-aliphatic hydrocarbon residue which is substituted by at least one substituent of carboxy or its derivative, cyano, hydroxy,and/or amino, or - aliphatic-hydrocarbon residue which is substituted by aryl whose ring may be substituted by one or more substituents selected from hydroxy, amino, nitro, alkyl, alkoxy, aralkoxy, alkylthio, halogen, and sulfo;
According to the present invention, the azetidinone derivatives (I) can be prepared by various methods, which are illustrated collectively by tne following scheme for convenience`ts sake.

.. ..
~1) Process 1:

~H2 ~ 1 N-A > ~ A

(II) (I)

(2) Process 2: .

Rl~H 1 " . ._ > 0 ~ N A

(III) (I") l~S33~ 8 ( 3) Process 3:
L I NH
0~ N A ~ --A

(I') (I:l) ( 4) Process 4:

Rl ~ 1~
N--Y~ IH
( IV) ( III ) ( 5 ) Process 5:
HOOCfH( CH2 ) 2 ~ ~--f--CO~H
R2 ~OH ~-fH~-OH (V~
COOH

2 2 ~ e I I ~
2 O ~-CH~-OH (VI ) COOH

1~631~8 (6) Process 6:
HoocfH(cH2)2o- ~ aC-CONH ~
R3 R4 ~ -CH- ~ -OH (VII) COOH

HooccH(cH2)2o- ~ CHCONHI ~
R3 R5 o ~ -fH- ~ -OH (VIII) COOH
(7) Process 7:
HOOCfH(CH2)2o_ ~ C-CO~H ~
~H2 R6 R7 O~ - ~-ICH- ~ -OH (IX) COOH

HOOCCH(CH2)2o_ ~ -C-CO ~ I .
8 Rg Rlo ~ -CH- ~ OH (X) COOH

(8) Process 8: `
Xl-Alcol~H _--I Rll-AiCNE~
O ~ ¦ ~ :~ N-CIH~ ~ -OH
COOH COOH
(XI) (XII) (9) Process 9:
R12--NH~ 1 X2 R ' ~H X2 ~-fH ~ -OR13 - ~ ~ CH ~ OR
COOH k COOH \X
(XIII) (XIV~

iO8 (10) Process 10:

R14_NH ~ R14--NH~ X
-CH- ~ -OH~ ~ -CH- ~ OH

(XV) (XVI) (11) Process 11: `
Rl5-~HcONH n Rl5 cHcONH~
R16 o~-fH~OH~ R17 ,LN-CH4~0H
COOH COOH
(XVII) (XVIII) (12) Process 12:
Rl8--CHCONH nRl8--CHCONH
S ~ -fH ~ OH > 5~0 o ~ N~CH ~ OH
Rlg COOH Rlg COOH
(XIX) (X~) , ... .
(13) Process 13:
HooccH(cH2 ) 20~fHCONHl~ .
R22 ~H2 ~ N-fH ~ -OH (XXI) COOH

HooccH(cH2)2o ~ CHCONH ~
R22 NHR21 ~ N-fH ~ OH (XXII) COOH

. : -- 8 - ~ :

. . ~: ~ , . ~ .

1~63108 (14) Process 14:
IH(cH2)2 ~ ~-CO ~ l NH2 H O ~ ~-ICH- ~ OH (XXIII) COOH

HoocfH(cH2)2o ~C-CON~
R23 ~OH N-CH- ~ -OH (XXIV) COOH

(15) Process 15:
R24-co~H I ¦ R25-co~H
O ~ I ~ ~ ~ -C`H- ~ -OH
OOH C'OOH
(XXV) (XXVI) (16) Process 16:

R26 C~O-A2-CO~Hrl O ~ N-fH ~ OH (XXVII) COOH

X5 ~ ~
R2 6--C~--A2 -c`( ~I~ ' N-R~7 O ~ ~-fH- ~ -OH (XXVIII) COOH

1~3108 (17) Process 17:
HoocfH(cH2)2o- ~ CHCO ~
R28 ~H2 o~ -~ ICH- ~ -OH (XXIX) COOH

HOOCfH(cH2)2o ~ -CHCO~H ~

R28 R29 J--N-CH~-OH (XXX) COOH

(18) Process 18:
HooccH(cH2)2o- ~ C-CONH l l ~2 R30 R31 ~ ~ fH ~ -OH (XXXI) COOH

HOOCCH(CH2)20 ~ ~ -CONH ~
~ 3 R30 R31 ~ N-fH ~ -OH (XXXII) ::

1~3~ 8 (19) Process 19:
HooccH(cH2)2o ~ C-CONH
R34 R35 R36 F ~-CH ~ OH (XXXIII) COO~I

R41OOCcH(cH2)O ~ -C-CONH ~
R34 R37 R38 ~ I ~ 40 (XXXIV) (20) Process 20:
R42 -5-A3-CONHcHco~H ~
~~CH ~ OH (XXXV) ~ COOH

R42-~-A3-CO~HcHcO ~
O ~ O~ ~ -CH ~ OH (XXXVI) COOH

1~3108 (21) PrOCeSS 21:
HOOCCH(CH2)0 - ~ ICI CO~HI ~
~H2 O ~ ~-CH- ~ -OH (XXXVII) COOH

HOOCCH(CH2)20 ~ -~-CO ~
OH d ~ ~-CH ~ OH (XXXVIII) OOH
(22) PrOCeSS 22: -_A4_Co~Hl~
~-CH ~ H (XXXIX) R43-NH-A4-co~
-CH ~ -OH (X~XX) COOH

(23) Process 23: .
R4~_CONH ~ R44 CONH
CIH_ ~ -OH~ ~H ~ OR46 (W~I ) (XX~CII ) (24) Process 24:

~ f ~ I ~

(XXXXII:C ) (XXXXIV) 1~3108 (25) Process 25: , R49 n R50~
~ N-A ~ o ~
(XXXXV)(XXXXVI) (26) Process 26:

R51~R52Tl N-A > ~ N-A
(XXXXVII) (XXXXVIII) (27) Process 27:
R51 ~ R53 r ~ N-A~ ~ N-A
(XXXXVII)(XXXXrX) (28) Process 28:
R54 ~ R51 ~
O ~ N-A ~ ~ N-A
(XXXXXII) (XXXXVII) (29) Process 29:
R5 ~ 56 ~
N-A ` ~ ~ N-A
(XXXXXIII) (a) (XXXXXIV) OHC ~ -~OCH2Co~H ~
N-lH- ~ OH (XXXXXV) (b) OOH
R57 CH2 ~ -CH2c ~
N-CIH ~ -OH (XXXXXVI) COOH

(30) Process 30:

CIHCO~H ~
~H ~ -CH- ~ -OH (XXXXXVII) ~CO~ -~ECOCE~X6 HCO ~
NIH o ~ N-fH ~ -OH (XXXXX VIII) --CO-~NHCOCH21~

`
(31) Process 31:
H2N-C-NHCON ~ ~61 f NHcoNH~
NH N-CH- ~ -OH NH o ~ N~CH ~ ~OH

(XXXXX) (XXXXXI) With regard to the process as illustrated above, it is to be u~derstood t:hat the Process 1 and Process 2 are fundamental process and the remaining Processes are alter-native ones.
The defi.nitions of the symbols used in the above formulae are menti.oned in the foll~wing. -' ' ..

- 14 - :

1~63:3L08 Rl is as defined above;
A is as defined above;
A' is as defined in the symbol "A" excepting hydrogen, Rl' is acylamino;
Y is alkyl whose first carbon is substituted by protected amino, protected hydroxy, 02~alo or esterified oxalo;
R2 is amino or acylamino R3 is amino or acylamino;
R4 is oxo or hydroxyimino;
R5 is amino or hydroxy:
R6 and R7 are combined to form oxo or hydroxyimino, or R6 is hydrogen, and R7 is amino or hydroxy;
R8 is acylamino;
Rg and Rlo are combined to form oxo or hydroxyimino, or Rg is hydrogen and Rlo is amino, hydroxy, acylamino or acyloxy;
Xl is acid residue, Al is bivalent aliphatic hydrocarbon radical;
Rll is residue of nucleophile;
R12 is acyl having protected amino, protected hydroxy or protected carboxy function~s).;
R12 is acyl having amino, hydroxy or carboxy function(s);
R13 is hydrogen or alkyl, X2 is hydrogen or halogen;
R14 is acyl;
X3 is hydrogen or halogen;
X4 is halogen;
R15 is hydrogen, alkyl, aryl, aralkyl, aryloxy, heterocyclic group or heterocyclic alkyl;
R16 is amino or hydrocarbon residue having amino;

1~31(~8 R17 is acylamino or acylamino-substituted-hydrocarbon residue;
R18 is hydrogen or aryl;
Rlg is alkyl, ~-arylcarbamoylalkyl or aryl;
R20 is amino or acylamino;
R21 is aryl substituted by at least one substituent of nitro and esterified carboxy;
R22 is arylamino whose aryl ring is substituted by at least one substituent of nitro and esterified carboxy R23 is mono-or di-alkylamino;
R24 is nitroaryl;
R25 is aminoaryl;
R26 is hydrogen or aryl;
X5 i3 hydrogen or halogen;

A2 is bivalent aliphatic hydrocarbon radical;
R27 is hydroxy, alkoxy or alkanoylamino;
R28 is acylamino;
R29 is acylamino;
R30 and R31 are combined to form oxo or hydroxyimino, or R30 is hydrogen and R31 is hydroxy;
- R32 and R33 are hydrogen or alkyl, R34 is acylamino;
R35 and R36 are combined to form oxo or hydroxyimino, or R35 is hydrogen and R36 is acylamino or hydroxy;
R37 and R38 are combined to form oxo, hydroxyimino, alkoxyimino, or substituted alkoxyimino or, R37 is hydrogen and R38 is acylamino, hydroxy, alkoxy or substituted alkoxy;

- ~6 - \
C36~ 8 R39 is alkyl or substituted alkyl;
R40 is hydrogen, alkyl or substituted alkyl;
R41 is alkyl or substituted alkyl;
R42 is alkyl, aryl or aralky~.;
A3 is alkylene;
A4 is bivalent aliphatic hydrocarbon radical;
R43 is aryl, substituted by at least one substituent of nitro and esterified carboxy or aromatic heterccyclic group;
R44 is aralkyl;
R45 is alkyl, R46 is hydrogen or alkyl;
R47 is carboxy or its derivative;
R48 is a protected amino;
R49 is an acylamino having carboxy or its reactive derivative;
R50 is an acylamino having carbazoyl, N-(hydroxyalkyl)-carbamoyl or N-aralkylcarbamoyl;
R51 is an acylamino having amino, R52 is an acylamino having esterified carboxyalkylamino;
R53 is an acylamino having alkenoylamino substituted by esterified carboxy;
R54 is an acylamino having nitro or azido;
R55 is an acylamino having one group selected from formyl, alkanoyl and aroyl, R56 is an acylamino having hydroxyalkyl or hydroxyaralkyl;
R57 is aralkylamino;
X6 is halogen;
R58, R59 and R60 are each alkyl, and R61 is aralkanoylamino;
Examples of the definitions for the above symbols are illustrated below, respectively.

1~6310B

With respect to the compounds (I), (I"), (III), (IV), (XXXXIII), and (XXXXIV):
An acyl moiety in the acylamino for Rl may include an aliphatic acyl, an aromatic acyl, a heterocyclic acyl and an aliphatic acyl whose aliphatic moiety is substituted by aromatic group or heterocyclic group. Examples of such acyl are illustrated in the following;
An aliphatic moiety in said aliphatic acyl may include saturated or unsaturated acyclic or cyclic hydrocarbon residue, in which the acyclic hydrocarbon residue may be branched and partially cyclized. Suitable examples of said acyclic or alicyclic hydrocarbon residue (hereinafter referred to aliphatic-hydrocarbon residue) are mentioned in more concrete as follows.
- alkyl (e.g., methyl, ethyl, propyl, butyl, isobutyl, pentyl, neopentyl, octyl, undecyl, tridecyl, pentadecyl, cyclohexylmethyl, cyclohexylethyl, bornanyl, etc.);
- alkenyl (e.g., vinyl, propenyl, isopropenyl, 3-methylbutenyl, butenyl, 2-methylpropenyl, pentenyl, octadecenyl, 3-cyclohexenylmethyl, etc.);
- alkynyl (e.g., ethynyl, 2-propynyl, etc.);
- cycloalkyl (e.g., cyclopropyl, cyclopentyl, cyclohexyl, idanyl, bornyl, adamantyl, etc.), and - cycloalkenyl (e.g., l-cyclopenten-l-yl, 2-cyclopenten-l-yl, 3-cyclohexene-1-yl, bornenyl etc.).

A suitable aromatic group in said aromatic acyl may include aryl such as phenyl, tolyl, naphthyl and the like.

A heterocyclic group in said heterocYclic acyl may include monocyclic or polycyclic heterocyclic group con-taining at least one hetero-atom selected from oxygen, - 18 _ . . .
., j , ~ . . .

1~363108 sulfur, nitrogen and the like. Suitable examples of said heterocyclic group are mentioned in more concrete as follows.
- a 3-to 8- membered monocyclic heterocyclic group containing at least one sulfur atom (e.g., thienyl dihydrothiopyranyl, etc.);
- a 3-to 8- membered monocyclic heterocyclic group con-taining at least one oxygen atom (e.g., oxiranyî, furyl, dihydrofuryl, pyranyl, dihydropyranyl, tetrahydropyranyl, dioxanyl, etc.);
- a 3-to 8- membered monocyclic heterocyclic group containing at least one nitrogen atom (e.g., aziridinyl, azetidinyl, pyrrolyl, 2-or 3H-pyrrolyl, 2 or 3 pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolidinyl, pyraæolyl, pyridyl, pyrimidyl, pyrazinyl, piperidinyl, pyridazinyl, tetrazolyl, etc.);
- a 3-to 8- membered monocyclic heterocyclic group containing at least o~Q oxygen atom and at least one nitrogen atom (e.g., oxazolyl, isoxazolyl, oxadiazolyl, sydnonyl, etc.) - a 3-to 8- membered monocyclic heterocyclic group containing at least one sulfur atom and at least one nitrogen atom (e.g., thiazolyl, isothiazolyl, thiadiazolyl, etc.);
- a polycyclic heterocyclic group containing at least one sulfur atom (e.g., benzene-fused heterocyclic group such as benzothienyl, benzothiopyranyl, etc.);

.
- .

~i~&i3108 - a polycycle heterocyclic group containing at least one nitrogen atom ~e.g., indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinoyl, dihydroisoquinolyl, quinazolyl, 1 or 2H-indazolyl, 1 or 2H-benzotriazolyl, purinyl, carbazolyl, etc.);
- a polycyclic heterocyclic group containing at least one oxygen atom and at least one nitrogen atom (e.
g., benzoxazolyl, benzoxadiazolyl, etc.), and - a polycyclic heterocyclic group containing at least one sulfur atom and at least one nitrogen atom (e.
g., benzothiazolyl, benzothiadiazolyl, etc~).
An aliphatic moiety in said aliphatic acyl whose aliphatic moiety is substituted by aromatic group or heterocyclic group is intended to mean the same meaning as defined in the above explanation of the aliphatic moiety in the aliphatic acyl, and include the same suitable examples thereof as stated in more concrete above. And in the same manner, each of the aromatic group and an heterocyclic group also is intended to mean the same meaning as defined in the --above explanation of the aromatic group in the aromatic acyl and of the heterocyclic group in the heterocyclic acyl as well, and include tha same suitable examples thereof as stated in more concrete above, respectively.

The optional carbon atom of the aliphatic acyl as defined above may be replaced and/or interrupted by one or more radicals selected from a bivalent aromatic radical, a bivalent heterocyclic radical, -0., -N=, -S-, -S0-, -~2-' -and -NH- whose hydrogen atom may be replaced by alkyl or aryl.

~` ` ` '' ~ ~ , , ` `'. ` ' 1~31~3 Each of the aliphatic moiety, aromatic group and heterocyclic group in the aliphatic acylamino, the aromatic acylamino, the heterocyclic acylamino and the aliphatic acylamino whose aliphatic moiety i.s substituted by aromatic group or heterocyclic group as defined above may optionally be substituted by one or more substituents selected from halogen, nitro, amino, carboxy, esterifiedcarboxy, hydroxy, -N3, -CN, -NHNH2, =0, =NH, =S, sulfo and =NOH whose hydrogen atom may be replaced by alkyl or aralkyl, and the said heterocyclic group in the foregoing acylamino group may optionally be substituted by alkyl and~or an aromatic group.

- 21 - :

- . : . . ~ , . ; .

' ~G~3:1 08 Particularly suitable examples of the aforementioned acylamino for Rl may be illustrated as follows.

alkanoylamino;
alkenoylamino;
aroylamino;
heterocycle carbonylamino;
alkanoylamino substituted by~ aryl or heterocyclic group;
alkenoylamino substituted by aryl or heterocyclic group;
alkanoyl or alkenoyl amino, whose optional carbon chain(s) is interrupted by bivalent-aromatic radical and~or bivalent heterocyclic radical;
alkanoyl or alkenoyl amino substituted by aryl and~or heterocyclic group, in which an optional carbon chain(s) of the acyclic hydrocarbon moiety is interrupted by bivalent-aromatic radical and~or bivalent-heterocyclic radical;
alkanoyl or alkenoyl amino substituted by aryl and~'or heterocyclic group, in which an optional carbon chain(s) of the acyclic hydrocarbon moiety is interrupted by one or more radicals selected from -o-, -~=. -S-, -S-, -SO2-, and -NH- whose hydrogen atom may be replaced by alkyl or aryl, alkanoyl or alkenoyl amino substituted by aryl and~or . .
heterocyclic group, in which an optional carbon chain(s) of the acyclic hydrocarbon moiety is interrupted by .. ~ - . . .

310~3 aromatic radical and~or bivalent heterocyclic radical, and further is interrupted by one or more radicals selected from -0-, -N=, -S-;-S~-, -S02-, and -NH-whose hydrogen atom may be replaced by alkyl or aryl;
- alkanoyl or alkenoyl amino whose optional carbon chain is interrupted by one or more radicals selected from -O-, -N=, -S-, -~S-, -S02-, and -NH- whose hydrogen atom may be replaced $y alkyl or aryl;
- alkanoyl or alkenoyl amino whose optional carbon chain is interrupted by bivalent-aromatic radical and~or bivalent heterocyclic radical and further interrupted by one or more radicals selected from -o-, -~=, -S-, -~S-, -S02-, and -~H- whose hydrogen atom may be replaced by alkyl or aryl;
- aroylamino or heterocycle carbonylamino, in which the bond between the ring ànd the carbonyl is interrupted by one or more radicals selected from -0-, -N=, -S-, -~S-, -SO2-, and -NH-, whose hydrogen atom may be `r8placed by alkyl or aryl: .
- alkanoyl or alkenoyl amino substituted by cycloalkyl, aryl and~or heterocyclic group, in which the bond between such ring and the acyclic hydrocarbon moiety is interrupted by one or more radicals selected from -O-, -N=, -S-, -~S-, S02, and -NH-, whose hydrogen atom may be replaced by alkyl or aryl;
- alkanoyl or alkenoyl amino substituted by cycloalkyl, aryl and~or heterocyclic group, in which each of the bond between the ring and the acyclic hydrocarbon moiety and an optional carbon chain of the acyclic hydrocarbon moiety is interrupted by bivalent-aromatic 1~363;~8 .radical and~or bivalent heterocyclic radical, and/or one or more radicals selected from -O-, -N=, -S-, -g-, -S02- and -~H-, whose hydrogen atom may be replaced by alkyl or aryl, - aroylamino or heterocycle carbonylamino in which the bond between the ring and the carbonyl is interrupted by one or more bivalent-aromatic radical andJor bivalent-heterocyclic radical;
- alkanoyl or alkenoyl amino substituted by aryl and~or heterocyclic group, in which the bond between the ring and the acyclic hydrocarbon moiety are interrupted by bivalent aromatic radical and/or bivalent-heterocyclic radical, and further one or more radicals selected from -O-, -N=, -S~ -, -S02- and -NH-, whose hydrogen atom may be replaced by alkyl or aryl, and - alkanoyl or alkenoyl amino substituted by aryl and/or heterocyclic group, in which the bond between the ring and the acyclic hydrocarbon moiety is interrupted by one or more bivalent-aromatic radicals and~or bivalent-heterocyclic radicals, . .

An optional carbon atom of above defined acylamino group may be substitutecl by ona or more substituents selected from halogen, nitro, amino, carboxy, esterified carboxy, hydroxy, -N3, -CN, -NH~H2, =O, =NH, =S, sulfo, =NOH whose hydrogen atom may be replaced by alkyl or aralkyl, and the heterocyclic group in the foregoing acylamino group may optionally be substituted by alkyl..
More particularly suitable examples of the acylamino for Rl may be illustrated as follows.

1~63~08 alkanoylamino, in which an optional carbon chain is interrupted by one phenylene and further optional carbon atoms are substituted by one halogen and one oxo;
phenylalkanoylamino, in which an optional carbon atom may be substituted by one substituent selected from amino, carboxy, esterified carboxy, hydroxy, halogen, nitro, sulfo, oxo, hydroxyimino and benzyloxyimino;
naphthylalkanoylamino;
dihydropyranylalkanoylamino, in which an optional carbon atom is substituted by one hy.droxy;
morpholinoalkanoylamino: :
thienylalkanoylamino in which an optional carbon atom may be substituted by one substituent selected -from amino, hydroxy, oxo and hydroxyimino;
furylalkanoylamino:
tetrazolylalkanoylamino;
indolylalkanoylamino, in which an optional carbon atom is substituted by one amino;
diphenylalkanoylamino;
alkanoylamino substituted by phenyl and thienyl;

3-alkyl-1,2,5-oxadiazol-4-yl-alkanoylamino;
phenylalkenoylamino;
phenylalkanoylamino, in which an optional carbon chain of the alkane moiety is interrupted by one phenylene;
phenylalkanoylamino, in which an optional carbon chain of the alkane moiety is interrupted by one or two bivalent raclicals selected from -0-, -N=, -S-, -NH-, - 25 _ ~31~8 -N- and -~-, and further an optional carbon atom(s) of the group thus defined may be substituted by one to four substituents selected from amino, carboxy, esterified carboxy, halogen, oxo and =~H;
- thienylalkanoylamino, in which an optional carbon chain(s) of the alkane moiety is interrupted by one to two bivalent radicals selected from -O-, -S- and -NH-, and further an optional carbon atom(s) of the group thus defined is substituted by one to four substituents selected from amino, carboxy, halogen and oxo, - dihydropyranylalkanoylamino, in which an optional carbon chain of the alkane moiety is interrupted by -~H-and an optional carbon atom o the group thus defined is substituted by halogen;
- diphenylalkanoylamino, in which an optional carbon ` ;~
chain(s) of the alkane moiety is interrupted by one to three bivalent radicals selected from -O-, -N= and -NH-, and . - -:~
further an optional carbon atom(s) of the group thus :~
defined may be substituted by one or two substituents selected from carboxy, hydroxy and oxo;
- alkanoylamino substituted by phenyl and thienyl, in which an optional carbon chain(s) of the alkane moiety is ~`
interrupted by one to two bivalent radicals selected from -O-, -~= and -~H-, and further an optional carbon ` `
atom(s) of the group thus defined may be substituted by one to five substituents selected from amino, halogen, oxo and thioxo;
- alkanoylamino substituted by phenyl and indolyl, in which an opt:ional carbon chain(s) of the alkane moiety is interrupt:ed by one -O- and one -NH-, and further an 1~31~)8 optional carbon atom of the group thus defined is substituted by one oxo;
- alkanoylamino substituted by phenyl and benzo[d]-isoxazolyl, in which an optional carbon chain(s) of the alkane moiety is interrupted by one -o- and one -NH-, and further an optional carbon atom of the group thus defined is substituted by one oxo;
- phenylalkanoylamino, in which an optional carbon chain(s) of the alkane moiety is interrupted by one or two bivalent radicals selected from phenylene, 2-oxo-azetidin-1,3-diyl, 1,3,4-thiadiazol-1,5-diyl and 1,3-oxazolidin-3,4-diyl and one to four bivalent radicals selected from -0~ =, -S-, -NH- and -~-, and further an optional atom(s) of the group thus defined may be substituted by one to six substituents selected from amino, halogen, hydroxy, esterified carboxy, oxo, hydroxyimino, benzyloxyimino and hydrazino, - thienylalkanoylamino, in which an optional carbon chain(s) of the alkane moiety is interrupted by one phenylene, and two bivalent radicals selected from -0- and -~H- and further an optional carbon atom(s) of the group thus defined is substituted by carboxy, oxo and hydroxyimino, - benzo~c]pyrrolidinylalkanoylamino, in which an optional carbon chain of the alkane moiety is inter-rupted by o:ne phenylene and one -0-, and further optional ca:rbon atoms of the group thus defined are substituted by four substituents selected from amino, carboxy, hydroxy, esterified carboxy, oxo, hydroxyimino and methoxyimino:

1~S,3:108 .~
- diphenylalkanoylamino, in which optional carbon chains of the alkane moiety are interrupted by one phenylene and one -O- and one -~H-, and further an optional carbon atom(s) of the group thus defined is substituted by two to four substituents selected from amino, halogen, nitro, oxo and hydroxyimino;
- alkanoylamino substituted by phenyl and furyl, in which optional carbon chains of the alkane moiety are interrupted by one phenylene and one -~H- and one -O-, ` 10 and further an optional carbon atom(s) of the group thus defined is substituted by three substituents selected from halogen and oxo;
- alkanoylamino, in which an optional carbon chain(s) is interrupted by one or two bivalent radicals selected from -O-, -S-, -NH-, -S02- and -~-, and further an optional carbon atom(s) of the group thus defined may be substituted by one to two substituents selected from amino, azido, carboxy, hydroxy, oxo, thioxo and =~H;
- alkenoylamino, whose optional carbon chain is interrupted by one -S-;
- alkanoylamino, in which an optional carbon chain(s) is interrupted by one or two phenylenes and one to five bivalent radicals selected from -O-, -N=, -S-, -~H- and -N- , and further an optional carbon atom(s) of the group thus defined may be substituted by one to seven substituents selected from amino, carboxy, hydroxy, halogen, azido,~sulfo, esterified carboxy, oxo, thioxo, hydroxyimino and methoxyimino;
- alkanoylamino, in which an optional carbon chain is . interrupted by one 1,3,4-thiadiazol-2,5-diyl and one ~3108 or two bivalent radicals selected from -S- and -~H-, and further an optional carbon atom(s) of the group thus defined is substituted by one or six substituents selected from amino, hydroxy and oxo;
- alkenoylamino, in which an optional carbon chain is interrupted by one phenylene and one or two bivalent radicals selected from -o- and -~H-, and further an optional carbon atom(s) of the group thus defined is substituted by one or three substituents selected from carboxy, esterified carboxy, nitro, oxo and hydroxyimino, - 1,2-oxazolidinylcarbonylamino, in which the bond between the 1,2-oxazolidinyl and the carbonyl is interrupted by -NH-, and further an optional carbon atom of the group thus defined is substituted by one oxo;
- bicyclot2,2,1~heptylalkanoylamino, in which the bond between the bicyclo~2,2,1]heptyl and the alkane moiety is interrupted by one -0-, and further an optional carbon atom(s) of the bicyclo[2,2,1]heptane ring is substituted by three alkyl;
- phenylalkanoylàmino, in which the bond between the phenyl and the alkane moiety is interrupted by one or two bivalent radicals selected from -0-, -S-, -~H- and -S02-, and further an optional carbon atom of the group thus defined may be substituted by one substituent selected from halogen and nitro;
- naphthylalkc~noylamino, in which the bond between the naphthyl and the alkane moiety is interrupted by one bivalent radical selected from -0- and -NH-;
- pyridylalkanoylamino, in which the bond between the 1~;3108 pyridyl and the alkane moiety is interrupted by one _o_;
1,3,4-thiadiazolylalkanoylarnino, in which the bond between the 1,3,4-thiadiazolyl and the alkane moiety is interrupted by one -S-;
lH-1,2,3-benzotriazolylalkanoylamino, in which the bond between the lH-1,2,3-benzotriazolyl and the alkane moiety is interrupted by one -0-;
pyridyl-l-oxidealkanoylamino, in which the bond between the pyridyl-l-oxide and the alkane moiety is interrupted by one -S-;
diphenylalkanoylamino, in which the bond between the one or two phenyl and the alkane moiety is interrupted by one or two bivalent radicals selected from -o-, -S-, -~H- and -S02-, and further an optional carbon atom(s) of the group thus defined is substituted by one or two substituents selected from nitro, carboxy, halogen, hydroxy and oxo;
àlkanoylamino substituted by phenyl and naphthyl, in which the bond between the naphthyl and the alkane moiety is interrupted-by one -0-;
alkanoylamino substituted by phenyl and pyrimidinyl, in which the bond between the pyrimidinyl and the alkane moiety is interrupted by -S-, and further an optional carbon atom(s) of the group thus defined is substituted by one amino and one hydroxy;

- - ~ . . . . . .

1~3;~08 - alkanoylamino substituted by bicycloC2,2,1]heptyl and phenyl, in which the bond between the bicyclor2,2,1~-heptyl and the alkane moiety is interrupted by one -O-and an optional carbon chain of the alkane moiety is ` interrupted by one -NH-, ancl further an optional carbon atom of the alkane moiety is substituted by oxo and optional carbon atoms of the bicyclo~2,2,1]-heptane ring are substituted by three alkyl, - diphenylalkanoylamino, in which the bond between one of the diphenyl and the alkane moiety is interrupted by one of two bivalent radicals selected from -O-, -~H-, -S-, -~-, S02- and -~- and an optional carbon chain of the alkane moiety is interrupted by one or two bivalent radicals selected from -~H- and -S-, and further an optional carbon atom(s) of the group thus defined is substituted by one to three substituents selected from carboxy, esterified carboxy, halogen, nitro and oxo: .
- alkanoylamino substituted by 9H-purinyl and phenyl, in which the bond between the 9H-purinyl and the alkane moiety is interrupted by one.-S- and an optional carbon chain of the alkane moiety is interrupted by one -NH-, and further an optional carbon atom of the group thus defined is substituted by one oxo;
- alkanoylamino substituted by phenyl and thienyl, in which the bond between the phenyl and the alkane moiety is interrupl:ed by one bivalent radical selected from -O- and -~H- and an optional carbon chain of the alkane moiety is interrupted by one -~H-, and further optional carbon atoms of the group thus de~ined are ~3108 substituted by three substituents selected from esterified carboxy, halogen, nitro and oxo, - alkanoylamino substituted by phenyl and pyridyl-l-oxide, in which the bond between the pyridyl-l-oxide and the alkane moiety is interrupted by one -S- and an optional carbon chain of the alkane moiety is interrupted by one -NH-, and further an optional carbon atom of the group thus defined is substituted by oxo;
- alkanoylamino substituted by naphthyl and phenyl, in which the bond between the naphthyl and the alkane moiety is interrupted by one bivalent radical selected from -O- and -NH- and an optional carbon chain of the alkane moiety is interrupted by one or two bivalent radicals selected from -o-, -S-, -~H- and -~-, and further an optional carbon atom of the group thus defined is substituted by oxo;
- alkanoylamino substituted by phenyl and pyrimidinyl, in which the bond between the pyrimidinyl and the alkane moiety is interrupted by one -S- and an optional carbon chain of the alkane moiety is interrupted by one -~H-, and further opt:ional carbon atoms of the group thus :.
defined are substituted by one amino, one hydroxy and one oxo:
- triphenylalkanoylamino, in which the bond between the one or two phenyls and the alkane moiety is interrupted by one or two bivalent radicals selected from -O- and -NH- and an optional carbon chain of the alkane moiety is interrupted by one -NH-, and further an optional ,-carbon atom(s) of the group thus defined is substituted by one or tw~ substituents selected from halogen and oxo;

3 ~08 - alkanoylamino substituted by naphthyl and diphenyl, in . which the bond between the naphthyl and the alkane '` moiety is interrupted by one -O- and an optional carbon chain of the alkane moiety is interrupted by one -NH-, and further an optional carbon atom of the group thus .. , defined is substituted by o:xo;
- alkanoylamino substituted by dinaphthyl and phenyl, in which the bond between the two naphthyl and the alkane moiety is interrupted by one -O- and an optional carbon chain of the alkane moiety is interrupted by one -~H-, and further an optional carbon atom of the group thus defined is substituted by oxo;
- phenylalkanoylamino, in which the bond between the phenyl and the alkane moiety is interrupted by one bivalent radical selected from -0-, -NH- and -S- and optional carbon chains of the alkane moiety are interrupted by one phenylene and onè to three bivalent radicals selected from -0- and -NH-, and further an optional carbon atom(s) of the group thus defined is substituted by one to five substituents selected from carboxy, esterified carboxy, halogen, nitro, oxo, thioxo and hydroxyimino;
- naphthylalkanoylamino, in which the bond between the naphthyl and the alkane moiety is interrupted by one -NH- and optional carbon chains of the alkane moiety are interrupted by one phenylene and three bivalent radicals selected from -0- and -~H-, and further optional carbon atoms of the group thus defined are substituted by one carboxy, one oxo and one thioxo, - alkanoylami:no substutued by pyridyl and phenyl, in ~ 31~8 . which the bond between the pyridyl and the alkane moiety is interrupted by one -S- and the optional carbon chains of the alkane moiety are interrupted by two phenylenes and three bivalent radicals selected from -0- and -~H-, and further optional carbon atoms of the group thus defined are substituted by four substituents selected from halogen and oxo.
- alkanoylamino substituted by phenyl and benzo[c]-pyrrolidinyl, in which the bond between the phenyl and the alkane moiety is interrupted by one -NH- and an optional carbon chain(s) of the alkane moiety is interrupted by one phenylene and one -0-, and further optional carbon atoms of the group thus defined are substituted by five substituents selected from carboxy, esterified carboxy, nitro and oxo, - diphenylalkanoylamino, in which the bond between the one or two phenyls and the alkane moiety is interrupted by one or two -~H- and an optional carbon chain(s) of the alkane moiety is interrupted by one phenylene and one to three bivalent radicals selected from -0- and -~H-, and further an optional carbon atom(s) of the group ;-thus defined is `substituted by one to five substituents selected from carboxy, nitro, esterified carboxy, oxo and thioxo;, -- dinaphthyla:Lkanoylamino, in which the bonds between the two naphthy:L and the alkane moiety are interrupted by one -NH- and optional carbon chains of the alkane moiety are interrupted by one phenylene and three bivalent raclicals selected from -0- and -N~I-, and further opti.onal carbon atoms of the group thus -~ 3108 defined are substituted by three substituents selected - from carboxy and thioxo;
- alkanoylamino substituted by phenyl and thienyl, in which the bond between the thienyl and the alkane moiety is interrupted by one tetrazol-1,5-diyl and an optional carbon chain of the alkane moiety is inter-rupted by one -~H-, and further an optional carbon atom of the group thus defined is substituted by one oxo;
- phenylalkanoylamino, in which the bond between the phenyl and the alkene moiety is interrupted by one -O-and an optional carbon chain of the alkane moiety is interrupted by one -NH-, and further the optional carbon atoms of the group thus defined are substituted by one halogen, one nitro and one oxo:
- diphenylalkanoylamino, in which the bond between the phenyl and the àlkane moiety is interrupted by one phenylene and one -O- and an optional carbon chain of the alkane moiety is interrupted by one -NH-, and ~0 further an optional carbon atom of the group thus defined is substituted by one oxo;
- diphenylalkanoylamino, in which the bond between the phenyl and the alkane moiety is interrupted by one isoxazol-3,'~-diyl which is substituted by one alkyl and an optional carbon chain of the alkane moiety is interrupted by one -NH-, and further an optional carbon atom of the group thus defined is substituted by one oxo;
- benzamido, in which the bond between the phenyl and the carbonyl is interrupted by isoxazol-3,~-diyl which is substituted by one alkyl, and further an optional carbon atom of-the group thus defined is substituted by halog~n, - phenylalkanoylamino, in which the bond between the phenyl and the alkane moiety is interrupted by one bivalent radical selected f~om phenylene and i 1,3,5-oxadiazol-2,4-diyl and one or two bivalent radicals selected from -O-, -NH- and -S02-, and further - the optional carbon atom of the group thus defined may be substituted by one carboxy and one hydroxy;
- phenylalkanoylamino, in which the bond between the phenyl and the alkane moiety is interrupted by one

4,5-dihydro-1,2,4 -oxadiazol-3,4-diyl, and an optional carbon atom of the group thus defined is substituted by one oxo: ;
- thienylalkanoylamino, in which the bond between ~ ~ `
the thienyl and the alkane moiety is interrupted by ~ ;
lH-tetrazol-1,5-diyl.

With respect to the compounds (I), (I'), (II), (XXXXV), (XXXXVI), (XXXXVII), (XXXXVIII), (XXXXIX), (XXXXXII), (XXXXXIII), and (XXXXXIV):
Suitable examples of saturated or unsaturated normal (or branched) aliphatic hydrocarbon moiety in the definition for "A" may include alkyl which may be branc~ed (e.g., methyl, ethyl, propyl, butyl, pentyl, isopropyl, l-methylpropyl, isobutyl, tert-butyl, methylbutyl, methylpentyl, ethylpropyl, ethylbutyl, neopentyl, dimethylbutyl, etc.) and alkenyl, which may be branched, (e.g., l-propenyl, allyl, l-butenyl, l-pentenyl, isopropenyl, methylpropenyl, methylbutenyl, methylpentenyl, ethylpropenyl, ethylbutenyl, dimethylpropenyl, dimethylbutenyl, etc.).

_ 36 _ 1~i3:108 The aliphatic hydrocarbon moiety in "aliphatic hydro-carbon residue which is substituted by one or more substituents selected from hydroxy, amino, nitro, alkyl, alkoxy, aralkoxy, alkylthio, halogen and sulfo" in the definition "A" may be substituted by at least one subst;.tuent of carboxy or its derivative, cyano, hydroxy and amino.
Suitable examples of the derivative of carboxy in saturated or unsaturated normal (or branched) aliphatic hydrocarbon residue which is substituted by at least one substituent of carboxy or the derivative of carboxy, cyano, hydroxy,and amino may lnclude an ester, an acid amide and a salt, and are exemplified as follows.
(a) Ester:
Esters are conventional ones, including silyl esters, aliphatic esters and esters containing an aromatic or a hetero-cyclic ring.
The suitable silyl esters may be illustrated by examples of tri(lower)alkylsilyl (e.g., trimethylsilyl, triethylsilyl, etc.) esters, etc.
The suitable aliphatic esters may include saturated or unsaturated acyclic or cyclic aliphatic esters which may be branched or which may contain a cyclic ring, such as aliphatic esters, for example, alkyl (e.g., methyl, - 37 _ ethyl, propyl, isopropyl, l-cyclopropylethyl, butyl, tert-butyl, octyl, nonyl, undecyl, etc.) esters; alkenyl (e.g., vinyl, l-propenyl, allyl, 3-buten~yl, etc.) esters, alkynyl (e.g., 3-butynyl, 4-pentynyl, etc.) esters: cycloalkyl (e.g., cyclopentyl, cyclohexyl, cycloheptyl, etc.) esters, etc., and aliphatic esters containing at least one heteroatom of nitrogen, sulfur and oxygen ato~, for example, lower a~koxyalkyl (e.g., methoxymethyl, ethoxyethyl, methoxyethyl, etc.) esters;
lower alkanoyloxyalkyl (e.g., acetoxymethyl, propionyloxymethyl, pivaloyloxymethyl, etc.) esters; alkylthioalkyl (e.g., methylthiomethyl, ethylthioethyl, methylthiopropyl, etc.) esters; dialkylamino (e.g., dimethylamino, diethylamino, dipropylamino, etc.) esters; alkylideneamino (e.g., ethylideneamino, propylidenèamino, isopropylideneamino, etc.) esters: lower alkylsulfinyl(lower)alkyl (e.g., methyl-sulfinylmethyl, ethylsulfinylmethyl, etc.) esters, etc.
The suitable esters containing an aromatic ring may include, for example, aryl (e.g., phenyl, xylyl, tolyl, naphthyl, indanyl, dihydroanthryl, etc.) esters; aralkyl (e.g., -~
benzyl, phenethyl, etc.) esters; aryloxyalkyl (e.g., phenoxy-methyl, phenoxyethyl, phenoxypropyl, etc.) esters; arylthio-alkyl (e.g., phenylthiomethyl, phenylthioethyl, phenylthiopropyl, etc.) esters; arylsulfinylalkyl (e-.g., phenylsulfinylmethyl, phenylsulfinylethyl, etc.) esters; aryloxyalkyl (e.g., benzoylmethyl, toluoylethyl ! etc.) esters; aryloylamino (e.g., phthalimido, etc.) esters; etc.;
The suitable esters containing an heterocyclic ring may include, for lexample, heterocyclic esters, heterocyclic-alkyl esters, etc.; in which the suitable heterocyclic ester may include, for example, saturated or unsaturated, condensed - 38 _ 1~31~8 ` or uncondensed 3 to 8-membered heterocyclic group containing 1 to 4 hetero-atom(s) such as an oxygen, sulfur and nitrogen atom (e.g., pyridyl, piperidino, 2-pyridon-1-yl, tetrahydro-pyranyl, quinolyl, pyrazolyl, etc.) esters; etc., and the suitable heterocyclicalkyl esters may include, for example, saturated or unsaturated, condensed or uncondensed 3 to 8-membered heterocyclic containing 1 to 4 heteroatom~s) such as an oxygen, sulfur and nitrogen atom (e.g., pyridyl, piperidino, 2-pyridon-1-yl, tetrahydropyranyl, quinolyl, pyrazolyl, etc.)-substituted-alkyl (e.g., methyl, ethyl, propyl, etc.) esters, etc.: `
The silyl esters, the aliphatic esters and the esters containing an aromatic or heterocyclic ring as mentioned above may have 1 to 10 appropriate substituent(s) such as lower alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, etc.), lower cycloalkyl (e.g., cyclopropyl, cyclohexyl, etc.), lower alkoxy (e.g., methoxy, ethoxy, propoxy,isopropoxy, butoxy, tert-butoxy, etc.), lower alkylthio (e.g., methylthio, ethylthio, propylthio, etc.), lower alkylsulfinyl (e.g., methylsulfinyl, ethylsulfinyl, propylsulfinyl, etc.), lower alkanesulfonyl (e.g., methanesulfonyl, ethanesulfonyl, etc.), phenylazo, halogen (e.g., chlorine, bromine, fluorine, etc.), cyano! nitro, etc., examples of which are illustrated by mono (or di or tri)halo(lower)alkyl (e.g., chloromethyl, bromomethyl, di-chloromethyl, 2,2,2-trichloroethyl, 2,2,2-tribromoethyl, etc.) esters, cyano(lower)alkyl (e.g., cyano methyl, cyanoethyl, etc.) esters, mono (or di or tri or tetra or penta)halophenyl (e.g., 4-chlorophenyl, 3,5-dibromophenyl, ~,4,5 -trichlorophenyl, 2,4,6-trichlorophenyl, pentachlorophenyl, etc.) esters, lower .. .

1~i3:108 alkanesulfonylphenyl (e.g., 4-methanesul~onylphenyl, 2-ethane-sulfonylphenyl, etc.) esters, 2-(or 3 or 4-)phenylazophenyl esters, mono(or di or tri)nitrophenyl (e.g., 4-nitrophenyl, 2,4-dinitrophenyl, 3,4,5-trinitrophenyl, etc.) esters, mono-(or di or tri or tetra or penta)halophenyl(lower)alkyl (e.g., 2-chlorobenzyl, 2,4-dibromobenzyl, 3,4,5-trichlorobenzyl, pentachlorobenzyl, etc.) esters, mono(or di or tri)nitrophenyl-(lower)alkyl (e.g., 2-nitrobenzyl, 2,4-dinitrobenzyl, 3,4,5-trinitrobenzyl, etc.~ esters, mono(or di or tri) (lower)-alkoxyphenyl(lower)alkyl (e.g., 2-methoxybenzyl, 3, 4-dimethoxybenzyl, 3,4,5-trimethoxybenzyl, etc.) esters, hydroxy and di(lower)alkylphenyl(lower)alkyl (e.g., 3,~-dimethyl-4-hydroxybenzyl, 3,5-ditert-butyl-4-hydroxybenzyl, etc.) esters, etc.
(b) Acid amide:
The suitable acid amides may include, for example, N-unsubstituted acid amide, N-lower alkyl acid amide (e.g.r N-methyl acid amide, ~-ethyl acid amide, etc.), N,N-di(lower)alkyl acid amide (e.g., N,N-dimethyl acid amide, N,N-diethyl acid amide, ~-methyl-N-ethyl acid amide, etc.), N-phënyl acid amide, or an acid amide with pyrazol`e, imidazole, 4-lower alkylimidazole (e.g., 4-methylimidazole, 4-ethylimidazole, etc.), etc.
(c) Salt:
Suitable salts may include salt with inorganic base (e.g., sodium salt, potassium salt, magnesium salt, ammonium salt, etc.), and organic base (e.g. dicyclohexylamine salt, pyridine salt, eth~nolamine salt, etc.).

1~31C~I~

With respect to the compound (IV):
Suitable examples of alkyl in the definition for "Y" may include those of "the alkyl which may be branched" as mentioned above.
Suitable examples of protected group in the protected amino or the protected hydroxy in the definition for "Y"
may include a conventional acyl such as conventional alkanoyl (e.g., formyl, acetyl, etc.), conventional haloalkanoyl (e.g., dichloroacetyl, trifluoroacetyl, etc.), conventional aroyl (e.g., benzoyl, etc.), conventional alkoxycarbonyl (e.g., ethoxycarbonyl, tert-butoxycarbonyl, adamantyloxy-carbonyl, etc.), conventional haloalkoxycarbonyl (e.g., trichloroethoxycarbonyl, etc.), conventional substituted or unsubstituted aralkoxycarbonyl (e.g., benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, etc.) and the like.
The protected groups as illustrated above are to be referred to a group attached to the terminal amino or hydroxy function in the acyl amino for Rl, and, for convenience sake to explain the present invention, the term "protected"
group is ;3108 also referred, with the same meaning as explained above, to a group attached to the other terminal functional group i.e.
carboxy group hereinafter used in the specification.
With respect to the compound (I'):
Suitable examples of acyl in the acylamino for Rl' may include the same examples as illustrated for the acyl in the definition for Rl.
With respect to the compound (I"):
Suitable examples of groups for "A"' may include the same examples as illustrated for the groups in the definition for "A" excepting hydrogen.
With respect to the compounds (V), (VI),(VII), (VIII), (X), (XXI), (XXIX), (XXX), (XXXIII) and (XXXIV):
A suitable acyl moiety in the acylamino for R2, R3, R8 Rlo' R20' R22~ R28~ R29~ R34~ R36 and R38 may inclucle the same aliphatic acyl, aromatic acyl, heterocyclic acyl` and aliphatic acyl whose aliphatic moiety is substituted by aromatic group or heterocyclic group as illus;trated for the acyl in the acylamino for Rl.
Suitable examples of the above acyl may be:
alkanoyl or cycloalkanoyl (e.g., formyl, acetyl, propionyl, butyryl, isobutyryl, pivaloyl, cyclohexanecarbonyl, etc.), aralkanoyl (e.g., phenyacetyl, phenylpropionyl, naphthylacetyl, etc.); heterocyclic alkanoyl (e.g., thienylacetyl, tetrazolyl-acetyl, furylacetyl, thiadiazolylacetyl, thiazolylacetyl, morpholinoacetyl, piperazinoacetyl, benzothiazolylacetyl, thienylpropionyl, etc.), aroyl (e.g., benzoyl, toluoyl, xyloyl, naphthoyl, phthaloyl, etc.) heterocyclic carbonyl (e.g., thenoyi, furoyl, prolyl; nicotinbyl, isonicotinoyl, benzodioxanecarbonyl, etc.) or cycloalkylalkanoyl (e.g.
cyclopentylacetyl, cyclohexylacetyl, etc.).
In the above examples, the optional bond of the alkylene moiety, the bond between the carbonyl and the aliphatic, aromatic or heterocyclic group, and/or the bond between the alkylene and the cycloalkyl, aryl or heterocyclic group may be interrupted by a bivalent radical -0-, -S- or -~H-. Suitable examples of such acyl may be alkoxycarbonyl (e.g., methoxycarbo~yl, ethoxy-carbonyl, propoxycarbonyl, tert-butoxycarbonyl, etc.); cyclo-alkoxycarbonyl (e.g. cyclopropoxycarbonyl, cyclohexyloxycarbonyl, bornyloxycarbonyl, adamantyloxycarbonyl, etc.); aralkoxycarbonyl (e.g., benzyloxycarbonyl, phenethyloxycarbonyl, etc.); hetero-cyclic alkoxycarbonyl (e.g., furfuryloxycarbonyl, pyrrolidinyl-methoxycarbonyl, pyridylmethoxycarbonyl, etc.); aryloxycarbonyl (.e.g., phenoxycarbonyl, naphthoxycarbonyl, etc.); alkoxythio-carbonyl (e.g., methoxythiocarbonyl, ethoxythiocarbonyl, propoxy-thiocarbonyl, etc.); alkoxyalkanolyl (e.g., methoxyacètyl, ethoxy-propionyl, etc.); cycloalkoxyalkanoyl (e.g., cyclohexyloxyacetyl, bornyloxyacetyl, adamantyloxyacetyl, etc.): alkylthioalkanoyl (e.g., methylthioacetyl, ethylthioacetyl, isopropylthioacetyl, butylthioacetyl, etc.); arylthioalkanoly (e.g., phenylthioacetyl, etc.); hèterocyclicthioalkanoyl (e.g., thienylthioacetyl, thienylthiopropionyl, thiazolylthioacetyl, thiadiazolylthio-acetyl, oxazolylthioacetyl, oxadiazolylthioacetyl, triazolyl-thioacetyl, tetrazolylthioacetyl, benzothiazolylthioacetyl, etc.): ~-alkylcarbamoly (e.g., N-methylcarbamoyl, N-ethyl-carbamoyl, etc.); N-arylcarbamoyl (e.g., N-phenylcarbamoyl, N-naphthylcarbamoyl, etc.); N-alkylthiocarbamoyl (e.g., N-methylthiocarbamoyl, N-ethylthiocarbamoyl, etc.), N-arylthio-carbamoyl (e.g., N-phenylthiocarbamoyl, etc.) and the like.
The optional carbon atom of said acyl group may be sub-stituted by one or more suitable substituents such as a halogen atom (e.g., chlorine, bromine, etc.),-nitro or formyl.

1~3:1 0~3 .~
With respect to the compound (XI):
Suitable examples of acid residue in Xl may include an acid residue of an inorganic acid (e.g.; hydrochloric, hydrobromic, hydroiodic, sulfuric acid, etc.), an organic acid such as organic sulfonic acid (e.g., methanesulfonic, benzenesulfonic or toluenesulfonic acid), an organic carbamic acid (e.g., dimethylcarbamic or diethyl-carbamic acid, etc.).
Suitable examples of bivalent aliphatic hydrocarbon radical in the definition,for "Al" may include alkylene or alkylidene (e.g., methylene, ethylene, trimethylene, propylene, pentylidine, hexamethylene, etc.), in which the optional carbon atom may be replaced by at least one radical selected from -~H-, -0-, and - ~ - and further may be substituted by oxo, aryl such as phenyl, naphthyl, etc. or heterocyclic group such as thienyl With respect to the compound (~II):
Suitable~examples of residue of nucleophile in the definition for Rll may include substituted or unsubstituted alkylthio (e.g., methylthio, ethylthio, propylthio, isopropylthio, etc.);
alkenylthio (e.g., vinylthio, propenylthio, isopropenylthio, butenylthio, etc.); alkynylthio (e.g., 2-propynylthio, etc.):
arylthio (e.g., phenylthio, naphthylthio, etc.);
substituted or unsubstituted aralkylthio (e.g., benzyl-thio, phenethylthio, phenylpropylthio, phenylbutylthio, etc.), in which the optional carbon atom of said alkyl moiety may be replaced by at le,ast one radical selected from -0-, -NH- and further may be su]bstituted by oxo;

substituted or unsubstituted heterocyclicthio (e.g., morpholinylthio, thiadiazolylthio, oxadiazolylthio, triazolyl-thio, pyrimidinylthio, oxazolylthio, tetrazolylthio, purinyl-thio, pyridin-l-oxide-2-ylthio, 5-methyl-1,3,4-thiadiazolyl-thio, 5-ethyl-1,3,4-thiadiazolylt;hio, l-methyltetrazolylthio, 2-aminothiazolylthio, l-methyltriazolylthio, etc.), substituted or unsubstituted aryloxy (e.g., pllenoxy, tolyloxy, chloro-phenoxy, biphenylyloxy, naphthoxy, methoxyphenoxy, phenoxyphenoxy, vinylphenoxy, propenylphenoxy, acetylphenoxy, benzoylphenyloxy, benzoylnaphthoxy, etc.);
substituted or unsubstituted arylamino (e.g., anilino, N-methylanilino, naphthylamino, etc.);
substituted or unsubstituted aralkylamino (e.g., benzylamino ~-methylbenzylamino, phenethylamino, naphthylamino, etc.).
In the above, the residue of nucleophile may be substi-tuted by at least one substituent selected from carboxy, esterified carboxy (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, etc.), halogen (e.g., bromine, chlorine, etc.), nitro, formyl amino, hydroxy, protected amino or protected hydroxy and the like.
With respect to compounds (XIII) and (XIV): -Suitable examples of acyl moiety in an acyl having protected amino, protected hydroxy and /or pxotected carboxy for R12 may include the same examples as defined and illustrated for the acyl in the acylamino for Rl.
Suitable exampl-e of acyl moiety of an acyl having amino, hydroxy or carboxy function in R ! 12 may include the same examples as defined and illustrated for the acyl in the 31~8 acylamino for Rl.
- Suitable examples of alkyl in the definition for R13 may include methyl, ethyl, propyl and the like, Suitable halogen in the definition for X2 may include bromine, chlorine and the like.
With respect to compounds (XV) and (XVI):
Suitable examples of acyl for R14 may include the same examples as defined and illustrated for the acyl in the acylamino for Rl, and more particularly aroyl (e.g., benzoyl, naphthoyl, etc.), aralkanoyl (e.g., phenylacetyl, phenylpropionyl, etc.):
heterocyclic alkanoyl such as thienylalkanoyl (e.g., thienyl-acetyl, thienylpropionyl, thienylbutyryl, etc.), an alkoxy-aralkanoyl, in which the optional carbon atom is substituted by at least one substituant selected from hydroxyimino, carboxy, amino, protected amino and the like, the examples of which are illustrated as follows.
2-~4-(3-carboxy-3-acetamidopropoxy)phenyl]-2-hydroxyimino-acetyl, 2-[4-{3-carboxy-3-(3-phenylureido)propoxy~phenyl]-2-hydroxy-iminoacetyl, 2-r4-{3-(2,2,2-trifluoroacetamido)-3-carboxypropoxy~phenyl~-2- '~'~
hydroxyiminoacetyl, etc.
Suitable examples of halogen for X3 and X4 may be the same as illustrated for the halogen for X2.
With respect to the compounds (XVII) and (XVIII):
Suitable examples for the definition for R15 are as follows:
aryl (e.g., phenyl, naphthyl, etc~);
alkyl (e . g., methyl, ethyl, propyl, etc.);
aralkyl (e.g., benzyl, phenylpropyl, etc.);
aryloxy (e.g., phenoxy, naphthoxy, etc.);

t~
1~3 ~ (1 8 heterocyclic group (e.g., thienyl, pyranyl, 5,6-di-hydro-2H-pyranyl, isobenzofuranyl, indolyl, etc.);
heterocyclicalkyl (e.g., thienylmethyl, thienylpropyl, furylmethyl, furylethyl, furylpropyl, indolylethyl, thiadiazolylmethyl, thiadiazolylethyl, oxazolylmethyl, etc.).
Suitable examples of hydrocarbon residue having amino in the definition for R16 may include aminoalkyl (e.g., amino-methyl, aminoethyl, aminopropyl,` etc.), and aminoaryl (e.g., aminophenyl, aminonaphthyl, etc.), and the like.
Suitable examples for the definition for R17 are as follows:
Hydrocarbon gro-lp in acylamino-sbustituted-hydrocar-bon residue for R17 may include alkyl (e.g., methyl,`ethyl, propyl, butyl, pentyl, hexyl, etc.): alkenyl (e.g., vinyl, propenyl, isopropenyl, etc.); aryl (e.g., phenyl, naphthyl, etc.);
aralkyl (e.g., benzyl, phenetyl, phenylpropyl, phenylbutyl, etc.), and the optional carbon atom of said hydrocarbon group may be substituted by at least one substituent selected-from halogen (e.g., bromine, chlorine,- etc.), hydroxy, carboxy, and the like, and further the optional carbon atom of said hydro-carbon group may be replaced by at least one bivalent radical selected from oxygen, nitrogen, sulfur, imino, carbonyl, thio- ;
carbonyl and carbamoyl. "
And, suitablè examples of acyl in acylamino and acyl-amino-substituted-hydrocarbon residue for R17 are the same as defined and illustrated for the acyl in the acylamino for Rl.
With respect to compounds (XrX) and (XX):
Suitable examples of aryI for R18 may be the same as mentioned above.

31~3 Suitable examples of alkyl and aryl for Rlg may~be the same as mentioned above.
Suitable examples of N-arylcarbamoylalkyl for Rlg may include N-phenylcarbamoylmethyl, ~-phenylcarbamoylethyl, N-naphthylcarbamoylmethyl, N-naphthylcarbamoylethyl, and the like.
With respect to the compound (XXII):
Suitable examples of "aryl substituted by at least one sub-stituent of nitro and esterified carboxy" for R21 may include p-nitrophenyl, 2,4-dinitrophenyl, 2-nitro-4-methoxycarbonyl-phenyl and the like, and suitable examples of substituted aryl moiety in arylamino whose aryl ring is substituted by at least one substituent of nitro and esterified carboxy for R22 may be the same as illustrated for the definition for R21.
With respect to the compound (XXIV) Suitable examples of mono- or di-alkylamino for R23 may include mono-~lkylamino such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, etc. and dialkyl-amino such as dimethylamino diethylamino, etc., and the optional carbon atom of said mono- or di-alkylamino may be substituted by esterified carboxy such alkoxycarbonyl (e.g. methoxy-carbonyl, ethoxycarbonyl, etc.), and the liXe.
With respect to the compound (XXV): -Suitable examples of nitroaryl for R24 may include mono- or di-nitrophenyl, mono or dinitronaphthyl, and the like.
With respect to the compound (XXVI):
Suitable examples of aminoaryl for R25 may include mono or diaminophenyl, mono or diaminonaphthyl and the like.
With respect to compounds (XXVII) and (XXVIII):
Suitable examples of aryl for R26 may include phenyl and 3~08 naphthyl and the like.
A suitable example of alkylene for "A2" is the same as illustrated in the definition for "Al".

Suitable examples of halogen atom for X5 may include bromine, chlorine and the like.
` Suitable examples of alkoxy for R27 may include methoxy, ethoxy, propoxy, etc., whose alkyl moiety may be substituted by suitable substituent such as carboxy, esterified carboxy and the like, for example, carboxymethoxy, methoxycarbonyl-methoxy, etc.
Suitable examples of alkanoylamino for R27 may includeformamido, acetamido, propionamido, etc.), whose alkyl moiety may be substituted by ammonio radical (e.g., ~,N,N-trimethyl-ammonio, N,~,N-triethylammonio or pyridinio, etc.) which bears an anion such as chloro, bromo, iodo, sulfoxy, methylsulfoxy, ethylsulfoxy-, formyloxy or p-toluenesulfonyloxy, and the like.

~i3108 With respect to the compound (XXXII):
A suitable example of alkyl for R32 and R33 is the same as i~lustrated for the alkyl for R13.
With respect to the compounds (XXXIII) and (XX~IV):

.;
.
A suitable example of alkyl for R39. R40 and R41 and alkyl moiety in alkoxy and acyloxyalkoxy for R38 is the same as illustrated for the alkyl for R13.
Suitable examples o~ acyl moiety in acyloxyalkoxy for R38 is a conventional alkanoyl (e.g. acetyl, propionyl, butyryl, isobutyryl, pivaloyl, etc.), etc. as illustrated for the protected group for Y.
Suitable examples of substituted-alkyl in the definitions for R39 and R41 may include acyloxyalkyl such as alk~noyloXy-alkyl (e.g., acetoxymethyl, acetoxyethyl, acetoxypropyl, propionyloxymethyl, propionyloxyethyl, butyryloxymethyl, pi~aloyloxymethyl, etc.) and haloalkyl such as monohaloalkyl (e.g., fluoromethyl, chloromethyl, bromomethyl, chloroethyl, bro ethyl, chloropro~yl, bromopropyl, etc.), dihaloalkyl (e.g.-dichloroethyl, 2,3-dichloropropyl, etc.) and tri-haloalkyl (e.g. trichloromethyl, etc.), and the like.
With respect to the compounds (XXXV) and (XXXVI):
Suitable aryl in the definition for R42 may include aryl which may be substituted by suitable substituent such as carboxy, etc., the examples of which are phenyl, carboxyphenyl, tolyl, naphthyl and the like.
A suitable example of-alkylene for "A3" may include methylene, ethylene, propylene, etc.).
With respect to the compounds (xxxrx) and (XXXX):

1~3:~8 Suitable examples of aryl substituted by at least one substituent of nitro and esterified carboxy for R43 are the same as illustrated for the same group for R21.
Suitable examples of aromatic heterocyclic group for R43 may include the same as illustrated in the explanation of the heterocyclic group for Rl of the compound (1~, and the more particular examples thereof are pyridyl, pyridyl-l-oxide, pyrimidynyl, oxadiazolyl, etc., which may be substituted by an aryl such as phenyl, tolyl, naphthyl and the like.
With respect to the compounds (XXXXI) and (XXXXII):
Suitable examplès of aralkyl for R44 are the same as illustrated for R15.
Suitable examples of alkyl for R45 and R46 are the same as illustrated for R13.
With respect to the compounds (XXXXIII) and (XXXXIV):
Suitable examples of "carboxy or its derivative" for R47 are the same as illustrated in the explanation for "A", i.e. that of "carboxy or its derivative".
Suitable examples of protected group in the protected ~ -amino for R48 may include the same as illustrated in the explanation for Y.
With respect to the compounds (xxxxv? . (XXXXVI), (XXXXVII), (XXXXVIII~, (XXXXIX), (XXXXKII), (XXXXXIII? and (XXXXXIV):
Suitable examples of acyl moiety in the acylamino group in the definition for R49~ R50, R51, R52, R53~ 54, 55 56 m~y include the same as illustrated in the explanation of an acyl iety in th~e acylamino for Rl.
Suitable examples of "carboxy or its reactive derivative"
moiety in the definition for R49 are the same as illustrated -in explanation of "A", i.e. that of "carboxy or its derivative".
Suitable examples of "N-(hydroxyalkyl)carbamoyl" moiety 1~3~8 :;
in the definition for R49 may include N-(hydroxymethyl)carbamoyl, N-(hydroxyethyl)carbamoyl, N-(hydroxypropyl)carbamoyl, etc.
Suitable examples of "~-aralkylcarbamoyll' moiety in the definition for R49 may include N-benzylcarbamoyl, ~-phenethyl-carbamoyl, etc., in which aryl moiety may be substituted by suitable substituent(s).
Suitable examples of the ester in "esterified carboxy-alkylamino" moiety in the definition for R52 may include the same as illustrated in the explanation for l'A", i.e. that of "ester", and more particularly are methoxyethylamino, ethoxy-ethylamino, propoxymethylamino and the like.
Suitable examples of "alkenyl substituted by esterified carboxy" in the definition for R53 may include an alkoxycarbonyl alkenyl such as methoxycarbonylvinyl, methoxycarbonylpropenyl, ethoxycarbonylvinyl, methoxycarbonyl-l-methylvinyl, ethoxy-carbonyl-2-propenyl, etc., and further examples of the ester in "esterified carboxy" moiety may include the same as illustrated in the explanation for "A", i.e. that of "ester".
Suitable examples of alkanoyl in the definition for R55 may include the same as illustrated in the explanation of an acyl moiety in the acylamino for Rl Suitable examples of aroyl moiety in the definition for R55 may include the same as illustrated in the explanation of acyl moiety in the acylamino for Rl.
Suitable examples of alkyl moiety in the definition for R56 is the same as illustrated for R13.
Suitable examples of ~-hydroxy aralkyl moiety in the definition for R56 may include ~-hydroxybenzyl, l-hydroxy-l-(l-naphthyl)methyl, etc.
With respect to the compound (XXXXXVI):

- 5 2 -10~i3 1 08 Suitable examples of aralkyl moiety in aralkylamino for R57 may include the same as illustrated for R15.
With respect to the compounds (XXXXXVI) and (XXXXXVII):
Suitable examples of halogen for X6 may include the same as illustrated in the definition for X2.
Suitable examples of alkyl for R58, R59 and R60 are the same as illustrated for R13.
With respect to the compound (XXXXXI):
Suitable exa~ples of aralkanoyl moiety in aralkanoylamino for R61 may include the same as illustrated in the explanation of the acyl moiety in the acylamino for Rl.

1~3~

The processes of the present invention are explained in details hereinafter.
In the present invention, as key starting compounds, there are employed FR-1923 substance and 1-substituted-3-amino-2-azetidinone (a) which can be derived from FR-1923 substance; and l-substituted-3-amino-2-azetidinone (b) and 3-amino-2-azetidinone (c) which can be derived from 3-acylamino-2-azetidinone.
Such starting compounds can be prepared, for example, by processes as shown in the following scheme.

~ H2 ..
I HCH2CH2~3CI co~
COOH ~OH ~ -CH ~ -OH

COOH

FR-1923 substance ¦ Deacylation H2N~
-ICH ~ -OH (a) COOH

- . . . . . .

lQ~i3108 .
~H

~` N2 CH3 ~ NH

.. / \ Deacylation ¦ A' - X

-o-C-C0 ~ H2 ~

N02 CH3 ~ -A' ~ (c) Deacylation n ~ -A' (b) wherein X is an acid residue and A' is as defined above.

(1) Process 1 : (II) >(I) In this process, the object compound (I) can be prepared by reacting the compound (II) or its reactive derivative at the amino with an acylating agent.

As acylating agents to be used in the present reaction, there may be exemplified an organic carboxylic acid, an organic sulfonic acid and the corresponding thio-, or imido-acid, and more particularly, an aliphatic acid;
an aromatic or heterocyclic carboxylic acid, and the corresponding sulfonic acid, carbamic acid, carbonic acid .~ ;
and thio-acid, ancl their reactive derivative.
As the reactive derivatives, there may be exemplified - ~ i . : . . ~ .

1~3:~08 an acid anhydride, an activated amide, anactivated ester, an isocyanate and an isothiocyanate, etc.
Examples of such reactive derivatives are illustrated by an acid azide;
an mixed acid anhydride with an acid such as dialkyl-phosphoric acid, phenylphosphoric acid, diphanylphosphoric acid, dibenzylphosphoric acid, ha:Logenated phosphoric acid, dialkylphosphoraus acid, sulfurous acid, thiosulfuric acid, hydrohalogenic acid (e.g., hydrochloric acid, hydrobromic acid, etc.), sulfuric acid, monoalkyl car~onic acid, aliphatic carboxylic acid (e.g., acetic acid, pivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutyric acid or trichloroacetic acid), aromatic carboxylic acid (e.g., benzoic acid), or symmetrical acid anhydride; ~ ~
- an acid amide with pyrazole; imidazole, 4-substituted imidazole, dimethylpyrazole,~triazole or tetrazole,`and an ester (e.g., cyanomethyl ester, methoxymethyl ester, vinyl ester, propargyl ester, p-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, methanesulfonyiphenyl ester, phenylazophenyl ester, phenyl thioester, p-nitrophenyl tXioester, p-cresyl thioester, carboxymethyl thioester, pyranyl ester,'pyridyl ester, ` piperidyl ester, 8-quinolyl thioester, or ester with N,N-dimethylhydroxylamine, l-hydroxy-2-(lH)-pyridone, N-hydroxysuccinimide or N-hydroxyphthalimide) and the like.
The above reactive derivatives`are selected according to the kind of the acid to bè used. In the reaction, when free acid is used as an acylating agent, the reaction may be preferably conducted in the presence of a condensing agent 3~ such an N,N'-dicyclohexylcarbodiimide, N-cyclohexyl-nt-morpho-. . .

1~3:10~

linoethylcarbodiimide, N-cyclohexyl-N'-(4-diethylamino-cyclohexy~carbodiimide, ~,N'-diethylcarbodiimide, N,N'-diisopropylcarbodiimide, N-ethyi-N'-(3-dimethylaminopropyl)-` carbodiimide, N,N'-carbonyldi-(2-methylimidazole), pentamethyleneketene-N-cyclohexylimido, diphenylketene-N-cyclohexylimine, alkoxyacetylene, l-alkoxyl-l-chlorocethylene, trialkyl phosphite, ethyl polyphosphate, isopropyl polyphosphate, phosphorus oxychloride, phosphorus trichloride, thionyichloride, oxalyl chloride, triphenylphosphine, 2-ethyl-7-hydroxy-benzisoxazolium salt, 2-ethyl-5-(m-sulfophenyl)isoxazolum hydroxide(chloromethylene)-dimethylammonium chloride, 2,2,4,4,-

6,6-hexachloro-2,2,4,4,6,6-hexahydro-1,3,5,2,4,6-triaza-triphosphorine, or a mixed condensing agent such as triphenylphosphine ànd a carbon tetrahalide (e.g.; carbon tetrachloride, carbon tetrabromide, etc.) and the like.
The example of an acyl group to be introduced into the amino group in the compound (I) by the above acylating agent may b~ a dehydroxylated group of an aliphatic, aromatic and heterocyclic carboxylic acid, and the corresponding sulfonic acid, carbonic acid, carbamic acid and thio acid, etc., and more particular acyl group may be the same acyl group as illustrated in the explanation of the acyl group in the acylamino group for Rl.
As the reactive derivative at the amino at the 3rd position of the compound (II), there may be exemplified Shiff's base, salt with acid (e.g. hydrochloric acid) and the conventional reactive derivative.
The acylation in the present process is conducted in a conventional manner known s~illed in the art, for example, the acylation of 6-aminopenicillanic acid or 7-cephalosporanic ,: ~ , - . .

~0~31~3 acid to provide the corresponding 6-acylamino penicillin or !` 7-acylaminocephalosporin compounds.
That is, the present reaction is conducted by reacting the compound (II) or its reactive derivative at the amino with an acylating agent usually in a solvent which does not give bad influence to the reaction, for example. water, acetone, dioxane, acetonitrile, chloroform, methylene chloride, dichloroethane, tetrahydrofuran, ethyl acetate, dimethylformamide, pyridine, etc., and the hydrophilic solvent as mentioned above can be used in a mixture with water.
The present reaction can also be carried out in the presence of a base such as inorganic base (e.g., alkali metal bicarbonate, etc.) and an organic base such as trialkylamine (e.g., trimethylamine, triethylamine, tributylamine, etc.), N-methylmorpholine, N-methylpiperidine, ~,N-dialkylaniline (e.g., N,N-dimethylaniline, ~,N-diethylaniline, etc.), ~,N-dialkylbenzylamine (e.g., N,~-diethylbenzylamine, etc.), pyridine, picoline, lutidine, l,5-diazabicyclo~4,3,0]non-5-ene, 1,4-diazabicyclor2,2,2]octane, 1,8-diazabicyclo~5, 4,Q]undecene-7, etc.
In the present reaction, a liquid base or liquid condensing agent also can be used as a solvent for the rèaction.
There is no limitation to the present reaction tempera-ture, and the present reaction can be preferably carried out under cooling or at ambient temperature.

- 5~ -1~;3~B

(2) Process 2: (III) ~ (I") In this process, the object compound (I") can be pre-pared by reacting the compound (III~ with a reagent of the formula: A'-X' wherein A' is as defined above and X' is an acid residue.
In the reagent of the formula: A'-X, examples of the definitions for A' are the same as illustrated in the expla-nation of the definitions for A excepting hydrogen.
As examples o~ the acid residue for X, there may be exemplified an acid residue of an inorganic acid (e.g. hydrochloric acid, hydrobronic acid, hydroiodic acid, sulfuric acid, etc.);
an acid residue of an organic acid such as organic sulfate (e.g. methyl sulfate, ethyl sulfate, etc.), organic sulfonic acid (e.g. methane sulfonic acid, benzene sulfonic acid, to~uene sulfonic acid, etc.) and organic carbamic acid (e.g.
dimethylcarbamic acid, diethylcarbamic acid, etc.) and the like.
The reaction is usually conducted in a solvent. Suitable examples of the solvents are water, acetone, dioxane, aceto-nitrile, methylene chloride, chloroform,dichloroethane, tetrahydrofuran, ethyl acetate, dimethyl-formamide, pyridine, etc., among which hydrophilic solvent can be used in a mixture with water. Any other solvent which does not give bad influence to the reaction also may be used.
There is no limitation to the reaction temperature, and the reaction ls usually conducted at ambient temperature or under cooling.
In case that the compound (I") thus produced has the derivative of carboxy or the protected carboxy as substituent, the compound (I") may be subjected to elimination reaction, ~ 31~l!8 , whereby said derivative of carboxy or protected group is converted into the corresponding carboxy group, whose reaction is also included within the scope of the present invention.
The elimination reaction is conducted by a conventional method, that is substantially the same methods as those explained in the elimination reaction for the hereinafter ; mentioned Process 3, e.g. solvolysis, reduction, etc.

10f~3;108 (3) Process 3: (I') ~(II) In this process, the object compound (II) can be prepared by eliminating the acyl group of compound (~!) in ` a conventional manner.
A suitable method to be used in the elimination reaction of the acyl moiety in acylamino may include solvolysis such as hydrolysis using an acid or a base; hydrazinolysis and reduction such as chemical reduction or catalytic reduction and combined method comprising iminohalogenation, imino-etherification and solvolysis.
In the above reaction, suitable examples of reagents to be used are as follows.
For solvolysis:
Solvolysis is conducted in the presence of an acid or base.
Suitable acids are an inorganic acid (e.g. hydrochloric acid, sulfuric acid, etc.), an organic acid (e.g., formic acid, acetic acid, trifluoroacetic acid, propionic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.), an acidic ion exchange resine and the like.
Suitable bases are an inorganic base such as a hydroxide, carbonate or bicarbonate of an alkali metal (e.g., sodium, potassium, etc.), an alkaline earth metal (e.g. magnesium, calcium, etc.), and the like, an organic base such as an alkoxide of the above metal, a tertiary amine such as tri-alkylamine (e.g., trimethylamine, triethylamine, etc.), a disubs~ituted arylamine (e.g., N,N-dimethylamine, etc.) or a heterocyclic amine (e.g., N-methylmorpholine, N-methyl-piperidine, N,N-dimethylpiperazine, pyridine, etc.), a basic ion exchange resine and the like.

1~;3:~8 ' For reduction:
Reduction is conducted with a conventional chemical reducing agent or by conventional catalytic reduction.
Suitable reducing agents are a metal (e.g., tin, zinc, iron, etc.) or a combination ofmetallic compound (e.g., chromium chloride, chromi~m acetate, etc.) and an organic or an inorganic acid (e.g., acetic acid, propionic acid, hydrochloric acid, etc.).
Suitable catalysts used in catalytic reduction are conventional ones such as platinum catalysts (e.g., platinum plate, spongy platinum, platinum black, colloidal platinum, platinum oxide or platinum wire), palladium catalysts (e.g., spongy palladium, palladium black, palladium oxide, palladium on carbon, colloidal palladium, palladium on barium sulfate or palladium on barium carbonate), nickel catalysts (e.g. reduced nickel, nickel oxide or Raney nickel), cobalt catalysts (e.g., reduced cobalt or Raney cobalt), iron catalysts (e.g., reduced iron or Raney iron) copper catalysts (e.g., reduced copper, Raney copper or Ullman copper), or other con-ventional catalysts.
For combined method:
Iminohalogenation, iminoetherification, and solvolysisare conducted with a conventional iminohalogenating agent and conventional iminoetherizing agent, and then by conventional solvolysis:
Suitable iminohalogenating agents are a phosphorus compound such as p]hosphorus trichloride, phosphorus penta-chloride, phosphorus tribromide, phosphorus pentabromide, phosphorus oxychloride, and their reaction equivalents such as thionyl chloride, phosgen, etc.

"'`
Suitable iminoetherifying agents used in the reaction with the resultant product in the foregoing iminohalogenation of the acylamino compound (I') are an alcohol such as an alkanol (e.g., methanol, ethanol, propanol, isopropanol, butanol, tert-butanol, etc.) or the corresponding alkanol having alkoxy (e.g. methoxy, ethoxy, propoxy, isopropoxy, buthoxy, etc.) as substituent(s) at the alkyl moiety thereof, and an alkoxide of such metal as mentioned above (e.g., sodium alkoxide, potassium alkoxide, calcium alkoxide, barium alkoxide, etc.), each of which is derived from said alcohol.
Thus obtained reaction product is, if necessary, solvolyzed in a conventional manner.
The elimination reactions, i.e. solvolysis, hydrazinoly-sis, reduction and combined method comprising iminohalogenation, iminoetherification and solvolysis are conventional ones employed for the elimination of acyl group in acylamino group of penicillin and cephalosporin compounds, and said reactions may be conducted in the similar conditions to that of the elimination reaction in the penicillin and cephalosporin cases.
For example, the iminohalogenation and iminoetherifi-cation reactions are preferably conducted at ambient temperature or unqer cooling, and the solvolysis proceeds simply pouring the reaction mixture to water or a mixture of~a hydrophilic solvent such as alcohol (e.g. methanol, ethanol, etc.) and water, and if necessary, with addition of an acid or base as exem~lified above thereto.
The object compound (II) prepared in the above elinina-tion reaction is also used as a key intermediate for the compound (I) of the present: invention. That is, the introduction of an acyl group different from that of the compound (I t ) to l-substituted-3-a~lino-2-azetizinone (II) can produce a new l-substituted-3-acylamino-2-azetizinone (I) having different antimicrobial activity spectrum from that of the compound (I').

:: -~ 31~8 .
(4) Process 4: (IV) > (III) The object compound (III) can be prepared by subjecting the compound (IV) to degradative elimination reaction.
Suitable methods to be used in this elimination reaction are a conventional solvolysis such as hydrolysis (e.g., an acidic or a basic hydrolysis.) and a reduction (e.g., chemical or catalytic, reduction.), which may be optionally selected depending on a kind of a starting compound (IV).
Solvolysis such as hydrolysis is conducted preferably in the presence of an acid or a base in a conventional manner, the examples of which are the same as those illustrated in the explanation of Process 3 and to be referred to them.
Suitable examples of reducing agents for chemical reduct~
ion and catalysts for catalytic reduction are also the same as those illustrated in the explanation of Process`3, and to be referred to them.
The degradative reduction is usually conducted by red-ucing the compound (IV) with a reducing agent in a solvent in a conventional manner. The reaction conditions, for example, the solvent to be used and the reduction temperature are selected in accordance with the reduction method used and~or thè kind of the co~pounds (IV) and~or (III). Generally, in the catalytic reduction method, it is preferable to employ a solvent such as methanol, ethanol, propanol, isopropanol, ethyl acetate or the like. In the method using a combination of a metalIic compound and an acid, said acid is generally used as a solvent, but if necessary, there is employed a solvent such as water, acetone and the like.

The reaction temperature is not especially limited, and the reaction i,s usually conducted under cooling, at 3i~8 temperature or at an elevated temperature.
The object compound (III) as prepared above is also used as a key intermediate for the compound (I') of the present invention.

(5) Process 5: (V) ~(VI) In this process, the object compound (VI) is prepared by hydrolyzing the compound (V) or its derivative at carboxy.
Examples of the derivative of carboxy of the starting compound is the same as illustrated in the explanation for the "A" of compound (I).
The hydrolysis is conducted in a conventional manner.
That is, a suitable method to be used in this hydrolysis is conducted in the presence of an acid or base ! example of which is the same one as that illustrated in the hydrolysis in the explanation for Process 3.
Though there is no limitation to the reaction temperatu~e, it may be suitably selected according to the hydrolyzing condition to be used in the reaction, and the reaction is preferably conducted at ambient temperature or at somewhat elevated temperature in accordance with the kind of the solvent of other reagent used.

~ ' ; ; ' ' , ~ ` '; !

1~3108 (6) Process 6 : (VII) ~(VIII) In this process, the object compound (VIII) can be prepared by reducing the compound (VII) or its derivative at carboxy.
Examples of the derivat;.ve at carboxy of the starting compound (VII) are the same as those illustrated in the explanation for "A" of the compound (I).
In this reduction, the reaction is conducted by a conventional method such as a catalytic reduction; a reduction using a combination of a metal such as iron, tin or zinc and an acid such as an inorganic acid (hydrochloric acid, sulfuric acid or the like) or an organic acid (acetic acid or the like):
a combination of an alloy (e.g., sodium amalgam, aluminum amalgan, etc.) a metal (e.g., zinc, tin, iron, etc.), or a salt thereof (e.g., zinc chloride, stannous chloride, ferric or ferrous chloride, etc.) and water, an alkali solution or an alcohol (e.g., methanol, ethanol, propanol,or butanol); a hydrazine compound (e.g., phenyl hydrazine or hydrazine); a combination of titanium chloride and hydrochloric acid; an alkali borohydride such as sodium borohydride, and potassium borohydride; diborane; or an electrolytic reduction.
Suitable examples of catalysts for the catalytic reduction are the same one as those illustra~ed in the explan-ation of the catalyst for Process 3.
The reaction conditions for this reduction, for example, the solvent to be used and the reaction temperature may optionally be selected in accordance with the reduction method to be used. In general, it is preferable to employ a solvent such as water, an alcohol as mentioned above, dioxane, acetonitrile, tetrahydrofuran, dimethylformamide, - .
. , ~ .

1~3i(~8 pyridine and the like, and further the acid as mentioned above may also used as a solvent.
The reaction temperature is not especially limited, and the reaction is usually conducted under cooling, at ambient temperature or at an elevated temperature.

(7) Process 7: (IX)~ (X) In this process, the object compound (X) can be pre-pared by reacting the compound (IX) or its derivative at carboxy with an acylating agent.
Examples of the derivative at carboxy of the starting compound are the same as those illustrated in the explanation for "A" of the compound (I).
As acylating agents in the present reaction, there may ~e exemplified the same examples as those illustrated in the explanation of the acylating agents for Process 1.
The reaction conditions, for example, the solvent to be used and the reaction temperature are also substantially the same as those explained in the acylation for Process 1.
The present acylation may include, within its scope, the case that when the starting compound (IX) has group(s) of free hydroxy and hydroxyimino, it (they) is also occasionally acylated.

, 1~3ial8 - (8) Process 8: (XI) --~(XII) In this process, the object compound (XII) can be pre-pared by reacting the compound (XI) or its reactive derivative at carboxy with a nucleophile of the formula: Rll-H wherein R
is residue of nucleophile, or its salt.
The nuclèophile of the formula: Rll-H wherein Rll is as defined above to be used as a reagent may include an amine such as a primary and secondary amine, a thiol compound and a hydroxy compound, respectively.
Examples of the residue of nucleophile are aliphatic hydrocarbon amino (e.g., alkylamino, alkenylamino, etc.), di-aliphatic hydrocarbon amino (e.g. di-alkylamino, etc.), aromatic amino (phenylamino, tolylamino, naphthylamino, etc.), heterocyclic amino (thienylamino, thiadiazolylthio, triazol-thio, etc.), and aliphatic hydrocarbon substituted by such aromatic or heterocyclic group; and aliphatic hydrocarbon thio(or oxy), aromatic thio (or oxy), h~terocyclic thio (or oxy), and aliphatic hydrocarbon thio (or oxy),substituted by such aromatic or heterocyclic group; in which aliphatic hydrocarbon moiety may be saturated or unsaturated and branched or partially cyclized, and such aliphatic hydrocarbon moiety, aromatic ring and heterocyclic ring may be substituted by at least one possible substituent.
Suitable examples of aliphatic hydrocarbon residue, aromatic group, a heterocyclic group, aliphatic hydrocarbon residue substituted by aromatic or heterocyclic group may include the same ones as illustrated in the explanation of the definitions for Rl.
More suitable examples of the residue of nucleophile are illustrated in the explanàtion for the compound (XII).

.. . . .

1~i3~ 8 .:

In the present process, there may be employed the nucleophile for above thiol or phenolic hydroxy compound in a form of a salt such as an alkali metal (e.g., sodium, potassium, etc.) salt and an alkaline earth metal (e.g., magnesium, calcium, etc.) salt. In the case that the thiol compound has a free amino as subst:ituent, said amino substituted thiol compound may be employed in the form of the salt of amino with an acid such as an inorganic acid (e.g., hydrochloric acid, hydrobromic acid, etc.) and an organic acid (formic acid, p-toluenesulfonic acid, etc.).
The reaction is usually conducted in an solvent.
Suitable examples of the solvents includs any solvent which does not give bad influence to the reaction, and are water, acetone, methanol, ethanol, tetrahydrofuran, dioxane, dimethylformamide, methylene chloride, chloroform, carbon tetrachloride, etc., in which a hydrophilic solvent may be employed in a mixture with water, The present reaction is preferably conducted in the presence of a base such as an alkalimetal hydroxide (e.g., sodium hydroxide, potassium hydroxide, etc.), an alkaline earth metal hydroxide (e.g., magnesium hydroxide, calcium hydroxide, etc.), an alkali metal carbonate (e.g., sodium carbonate, etc.), an alkaline earth metal carbonate (e.g., calcium carbonate, etc.), an alkaline metal alkoxide (e.g., sodium alkoxide, potassium alXoxide, etc.), an alkaline earth metal alkox:ide (e.g., calcium alkoxide, barium alkoxide, etc.), c~n organic amine (e.g. trimethylamine, etc.), a basic ionexchanqe resine, etc.
There is no limitation to the present reaction tem-perature, and the reaction is usually carried out undercooling, at ambient temperature or at an elevated temperature.

- 69 _ : . . .. ~ .

lOS3:108 : ~9) Process 9 : (XIII) ~(XIV) In this process, the object co~pound (XIV) can be pre-pared by removing the protected group at the terminal amino, hydroxy and/or carboxy group in the acylamino group at the 3rd position of the compound (XIII) or its derivative at carboxy.
Examples of protected groups at the terminal amino, hydroxy and carboxy are the same as those illustrated in the explanation of a protected group for the compound (IV), including the examples of ester of the carboxy group (i.e., esterified carboxy) as illustrated in the explanation of the derivative of carboxy for the compound (I).
Suitable methods to be used in the present reaction are conventional ones, including a conventional solvolysis, a convention reduction, a conventional method using a heavy metal and the like, which are selected depending on a kind of a starting compound (XIII).
A solvolysis and reduction may be conducted in substan-tially the same manner illustrated in the explanation of the degradative elimination process for Process 4.
Suitable examples of heavy metal in the method using a heavy metal are copper, zinc, etc.
Although there is no specific limitation to the reaction temperature and a preferable temperature are employed ; -~
depending on a kind of the protecting group to be removed and the method to be used, the reaction is usually carried out under cooling, at ambient temperature or at somewhat elevated temperature. :: .
By the present reaction, the protected group at the terminal amino, hydroxy and~or carboxy group in the acylamino group at the 3rd position of the starting compound (XIII) are `~
:`:

31~8 removed to provide the corresponding free amino, hydroxy and/or carboxy, respectively, and when the derivative at carboxy in : the substituent at the 1st position of the starting compound ~ (XIII) are the ester, said ester is also converted into the `~ corresponding free carboxy, which is also included within the scope of the present process.

31~8 (10) Process 10 : (XV) ~ (XVI) In this process, the object compound (~VI) can be pre-pared by reacting the compound (XV) or its derivative at carboxy with a halogenating agent.
Examples of the derivative at carboxy of the starting compound (XV ? are the same as those illustrated in the explanationfor the compound (II).
Suitable examples of halogenating agents may include halogen such as chlorine bromine, etc.; hypohalogenous acid or its alkyl ester such as hypochlorous acid, tert-butyl-hypochlorite, e~c., N-halamide such as ~-bromoacetamide, N-iodoacetamide, ~-bromosu~cinamide, N-chlorosuccinimide, N-chlorophthalimide, etc.; a cuprous halogenide such as cuprous chloride, cuprous bromide, etc.; and, pyridinium hydrobromide perbromide, dioxan dibromide, etc., and the like.
The reaction is uqually carried out in an inert solvent.
A suitable solvent to be used in this reaction may include any solvent which does not deleteriously influence the reaction, for example, water, methanol, ethanol, acetic acid, chloroform, methylene chloride, carbon tetrachloride, dioxan, acetonitrile, tetrahydrofuran, dimethylformamide and the like.
There is no limitation to the present reaction temperature, and the reaction is usually conducted under cooling, at ambient temperature or at somewhat elevated temperature .

1~31~

(11) Process 11: (XVII) ~ (XVIII) In t~s process, the object compound (XVIII) can be prepared by reacting the compound (XVII) or its derivative at carboxy with an acylating agent. The derivative at carboxy of the starting compound (XVII) are the same as those illustrated in the explanation of the compound (I).
Acylating agents to be used in the present reaction may include the same example as those illustrated in the explanation of the acylating agents for Process 1.
The acylation of the present process is conducted in a conventional manner, and the reaction conditions, for example, the solvent to be used and the reaction temperature are substantially the same as those explained in the acylation for Process 1.
(12) Process 12: (XIX) ~ (XX) In this process, the object compound (XX) can be pre-pared by oxidizing the compound (XIX) or its derivative at carboxy.`
The derivative at carboxy of the starting compound (XIX) are the same as those illustrated in the explanation for the compound (I).
Oxidation in the present reaction is conducted in a conventional manner with a conventional oxidizing agent which can oxidize a -S- group into -S- group.
Suitable examples of the oxidizing agent are inorganic peracid or its salt (e.g., periodic acid persulfuric acid, etc. or the sodium or potassium salt thereof); an organic peracid or its salt (e.g., perbenzoic acid, m~chloroperbenzoic 1~31~8 acid, performic acid, peracetic acid, chloroperacetic acid, trifluoroperacetic acid, etc. or the sodium or potassium salt thereof etc.); ozone, hydrogen peroxide, urea-hydrogen peroxide and the like.
The present reaction is preferably conducted in the presence of a compound comprising a Group Vb or Vlb metal in the Periodic Table, for example, tungstic acid, molybdic acid, vanadic acid, etc. or their salt with an alkali metal (e.g., sodium, potassium, etc.), an alkaline earth metal (e.g., calcium, magnesium, etc.) or ammonium, etc.,` or vanadium pentoxide.
The present oxidation is usually conducted in a solvent such as water, acetic acid, chloroform, methylene chloride, alcohol (e.g., methanol, ethanol, etc.), tetrahydro-furan, dioxan, dimethylformamide or any other solvent which does not give bad influence to the present reaction.
There is no particular limitation to the reaction temperature, and the present reaction is usually conducted at ambient temperature or under cooling.

:

1~31~8 (13) Process 13: (XII) > (XXII) In this process, the o~ject compound (XXII) can be prepared by reacting the compound (XXI) or its derivative at carboxy with an aryl halide of the formula; R'-X', wherein R' is aryl substituted by at least one substituent nitro and esterified carboxy and X' is halogen.
The derivative at carboxy of the starting compound (XXI) is the same as those illustrated in the explanation for the compound (I).
Suitable examples of aryl in the aryl substituted by at least one sub~tituent of nitro and esterified carboxy for R' are the same as illustrated in the explanation of the definitions of R21 and R22 for the compound (XXII), and suitable examples of halogen are chlorine, bromine, etc. Further, examples of the ester in the esterified carboxy may include the same as those illustrated in the explanation of the ester for the definition of ~ for the compound (I).
The present reaction is usually conducted in a solvent such as water, methanol, ethanol, propanol, tetrahydrofuran, dioxane, acetone, N,N-dimethylformamide, methylenechloride, chloro~orm, carbon tetrachloride or any other solvent which does not give bad influence to the present reaction.
The present reaction is preferably conducted in a base such as an inorganic or an organic base, for example, alkali metal hydroxide (e.gO, sodium hydroxide, potassium hydroxide, etc.), an alkaline earth metal hydroxide (e.g., magnesium hydroxide, calcium hydroxide, etc.), an alkali metal carbonate (e.g., sodium carbonate, etc.), an alkaline earth metal carbonate .
(e.g., calcium carbonàte, etc.), an alkali metal alkoxide (e.g., sodium alkoxide, potassium alkoxide, etc.), an alkaline _ 75 -1C~i3~

metal alkoxide (e.g., calcium alkoxide, ~arium alkoxide, etc.), an organic amine (e.g., trimethylamine, etc.), a basic ion exchange resin, etc.
There is no particular limitation to the reaction temperature, and the present reaction is usually conducted under cooling, at ambient temperature or at an elevated temperatùre.
(14) Process 14: (XXIII) > (XXIV) In this process, the object compound (xxrv) can be pre-pared by reacting the compound (X~III) or its derivative at carboxy with a carbonyl compound of the formula: R""C-0 wherein R"' and R"" are same or dif~erent hydrogen, alkyl or aralkyl, or its acetal or ketal, and then reducing the resulting product.
The derivative at carboxy of the starting compound (XXIII) are the same as those illustrated in the explanation of the derivative of carboxy for "A" with respect to the compound (I).
Exampleq of alkyl in a carbonyl compound are methyl, ethyl propyl, butyl, ii~obutyl, pentyl, etc. which may be sub-stituted by at least one ~ubstituent of carboxy, alkoxy, carbonyl, and halogen (chlorine, bromine, etc.), and examples of aralkyl are benzyl, phenethyl, phenylpropyl, naphthylmethyl, etc. whose aryl moiety may be ~ubstituted at least one substituent of the above sub~tituent~ Suitable examples of the carbonyl compound may include an aldehyde such as alkane aldehyde (e.g., formaldehyde, acetaldehyde, propionaldehyde, butylaldehyde, isobutylaldehyde, valeraldehyde, etc.) and aralkane aldehyde (e.g., benzaldehyde), and a ketone (e.g., acetone, methylethyl-ketone, diethylket:one, methylpropylketone, methylphenylketone, methyltolylketone, etc.).
The re~ulting product which i~ produced by reacting the 1~310l3 compound (XXIII) or its derivative at carboxy with the carbonyl compound can be subjected to the following reduction with isolation or without isolation thereof.
In the following react:ion, the reduction is conducted in a conventional manner including the substantially same methods and reaction condition (solvent, t:emperature, etc.) as illustrated in the explanation of the reduction for Process 6.
The first step of this reaction is usually conducted in an inert solvent which does not give bad influence to the reaction such as water, dioxane, methanol, ethanol, ~,N-dimethylformamide or the like. The carbonyl compound in liquid may be also used as a solvent.
There is no particular limitation to the reaction temperature, which is selected depending on a kind of the carbonyl compound to be used and the reducing agent to be u~ed, and the reaction is usually conducted under cooling or at ambient or somewhat elevated temperature.
In this reaction, in the course of the reaction or poqt-treatment, the derivative at carboxy may be converted into the corre~ponding carboxy, -C- may be converted into -CH-NOH ~H2 - by reduction, and the substituent, halogen may be converted into hydrogen by dehalogènation. The cases as above are included within the scope of the present invention.

~ 3iO8 (15) Process 15: (XXV) ~ (XXVI) In this process, the compound (XXVI) can be prepared by reducing the compound (XXV) or its derivative a~
carboxy.
Examples of the derivative at carboxy of the starting compound (XXV) are the same as those illustrated in the explanation for the compound (I).
In this reaction, the reduction is conducted in a conventional manner, and examples of the reducing agents and the reduction conditions are substantially the same as illustrated in the explanation of the reduction for Process 6.
t16) Process 16: (XXVII) > (XXVIII) In this process, the compound (XXVIII~ can be prepared by reacting the compound (XXVII) or its derivative at carboKy with an amine compound of the formula: R27-~H2 wherein R27 is as defined above.
Examples of the derivative at carboxy of the starting compound (XXVII) may include same ones as illustrated in t~e explanation for the compound (I).
Examples of alkoxy group and alkanoyl moiety in the alXanoylamino in the definitions for R27 in the amine compound are the same as illustrated in the above explanation for the compound (XXVII).
In the reaction, the amine compound (R27-NH2) may be used in the form of its salt with an acid such as inorganic salt (e.g. hydrochloric acid, sulfuric acid, etc.) and organic acid ~e.g. formic acid, acetic acid, etc.), and in this case the react:ion may be preferably conducted under ~-i31~8 alkaline condition, for example, in the presence of alkali metal (e.g., sodium hydroxide, potassium hydroxide), alkaline ` earth metal (e.~., calcium hydroxide, etc.) and the like.
The reaction is usually conducted in an inert solvent Suitable examples of the solvent are water and an hydrophilic solvent such as methanol, ethanol, propanol, and ~,N-dimethyl formamide, and any other solvent which does not give bad influence to the present reaction.
There is no particular limitation to the reaction temperature, and the present reaction is usually conducted under cooling at ambient temperature or at somewhat elevated temperature.
(17) Process 17: (XXIX) ~ (XXX) In this process, the object compound (XXX) can be pre-p æ ed by acylating the compound (XXIX) or its derivative at carboxy with an acylating agent.
Examples of the derivative at carboxy of the startin~
compound are the same as those illustrated in the explanation for the compound (I).
Examples of acylating agent and acyl group in acyl-amino for R29 may include the examples as illustrated in the explanation for Process 1.
The acylation reaction of the present conditions, for example, the solvent and the reaction temperature, are also the same.
This process is conducted in a conventional manner, and may be conducted in sub~tantially the same conditions (e.g., solvent, reaction temperature, etc.) as those mentioned in the explanation for Process 1.

1~31(~8 (1~) Process 18: (XXXI) ~ (XXXII) In this process, the object compound (XXXII) can be prepared by reacting ~he compound (XXXI) or its derivative at carboxy with a hydroxyalkane sulfonic acid of the ormula:
~O-C-S03H or the salt thereof, wherein R32 and R33 are as defined above.
Examples of the derivative at carboxy of the starting compound (XXXI) are the same as those illustrated in the explanation for the compound (I).
Examples of alkyl in the definitions of R32 and R33 for the above reagent, hydroxyalkane sulfonic acid, are illustrated in the explanation for the compound (XXXII), As an example of the salts of said hydroxyalkane sulfonic acid, there may be illustrated an salt with metal such as aIkali metal (e.g., sodium, potassium, etc.), alkaline earth metal (e.g. calcium, magnesium, etc.) and the like.
The hydroxyalkane~ulfonic acid to be used as a reagent can be prepared by reacting a carbonyl compound of the formula .
R32~ R33 (wherein R32 and R33 are as defined above) with sulfurous acid or the salt thereof (e.g. alkali or alkaline earth metal). Then, the object compound (XXXII) may be also prepared by reacting the compound (XXXI) with the above carbonyl compound and thereafter with the sulfurous acid or the salt thereof, the case of which is incluAed within the scope of the present process.
The reaction is usually conducted in a solventO As example of the ~uitable ~olvent~, there may be illustrated water hydrophilic solvent such as;methanol, ethanol, propanol, ~0~3iO8 tetrahydrofuran, dioxane, N,N-dimethylformamide, etc., and the mixture thereof, and any other solvent which does not give bad influence to the present reaction.
There is no particular limitation to the reaction temperature, and the present reaction is usually conducted under cooling, at ambient temperature or at an elevated temperature.
In the course of the reaction, amino group of the compound (XXXI) may react with the hydroxyalkanesulfonic acid to be converted into the corresponding di-substituted amino group ~-~ ~ -S03H)2 or the salt thereof], the case of which is also included within the scope of the present process.
When the hydroxy alkanesulfonic acid is used as a reagent, the reaction is preferably conducted in the presence of alkali or alkaline earth metal.

~ , . . .

i3:~08 (19) Process 19: (XXXIII) -- ~(XXXIV) In this process, the compound (XXXIV) having esterified carboxy group (-COOR39 and -COOR41 wherein R39 and R41 are a - group which is derived from an esterifying agent) can be pre-` pared by reacting the compound (XXXIII) with a conventional esterifying agent.
Examples of esterified carboxy of the object compound may include the same as illustrated in the explanation of the ester for the derivative of carboxy for the compound (I) including silyl ester, aliphatic ester, ester containing aromatic or heterocyclic ring.
Esterifying agent may include any conventional agent which can esterify a carboxy group to provide an esterified carboxy group.
Suitable esterifying agents may include a halide com-pound such as alkyl halide (e.g., methyliodide, ethylbromide, ethyliodide, propylbromide, etc.), an alkenyl or alkynyl halide (e.g., allylbromide, methallylbromide, propynyl-bromide, etc.~; substituted alkylhalide such as alkanoyloxy alkylhalide (e.g., acetoxymethylchloride, acetoxyethylchloride acetoxypropylbromide, etc.), aroylalkylhalide (e.g., phenacyl bromide, etc.), an aralkylhalide (e.g., benzylchloride, phenethylchloride) and the like.
a dialkyl sulfate (e.g., dimethyl sulfate, diethyl sulfate, dipropyl sulfate, etc.);
an alkyl sulfonate (è.g., methyl benzenesulfonate, methyl p-toluenesulfonate, ethyl 4-bromobenzenesulfonate, etc.):
a haloformate such as alkyl haloformate (e.g., methyl chloroformate, ethyl chloroformate, propyl chloroformate, etc.), alkenyl or alkynyl haloformate (e.g., allyl chloroformate, 31~8 propynyl chloroformate, etc.), a diazoalkane (e.g., diazomethane, diazoethane, etc.) and;
a hydroxy compound such as alcohol, for example, an alkanol (e.g., methanol, ethanol, propanol, 2-chloroethanol, 2,2,2-trichloroethanol, butanol, l-cyclopropylethanol, etc.), a cycloalkanol (e.g., cyclopropanol, cyclopentanol, cyclohexanol, borneol, adamantanol, etc.) and an aralkanol (e.g., benzyl-alcohol, diphenylmethanol, phenethylalcohol, etc.), and the like.
In case that the hydroxy compound is used as an esterifying agent in this process, the reaction may be pre-ferably conducted in the presence of a condensing agent such as those illustrated in the explanation of the condensing agent for Process 1.
In the course of the present reaction, hydrogen atom in the hydroxy group of the starting compound (XXXIII) may be replaced by a group which is derived from an esterifying agent, that is the said hydroxy group may be, for example, alkylated, aralkylated, etc. Such cases as mentioned above are included within the scope of the present process.
The reaction is usually conducted in a solvent such as water, dioxane, acetone, pyridene, ~-N-dimethylformamide, ether, and the like.
There is no particular limitation to the reaction temperature, and the reaction is usually conducted under cooling at ambient temperature or an elevated temperature.

(20) Process 20: (XXXV)____~(XXXVI) In this process, the object compound (XXXVI) can be 1~63108 .. .

prepared by oxidizing the compound (XXXV) or its derivative at carboxy. Examples of the derivative at carboxy of the start-ing compound (XXXV) are the same as those illustrated in the explanation for the compound (I).
The present oxidation are conducted in a conventional manner.
As examples of the oxidizing agents, there may be employed such examples as illustrated for the oxidizing agents for Process 12.
The reaction of the present process also are conducted under substantially same conditions (e.g. solvent, reaction temperature, etc.) as mentioned in the explanation of Process 12.

(21) Process 21: (XXXVII)_-~(XXXVIII) .:
In this process, the object compound (XXXVIII) can be prepared by reacting the compound (XXXVII) or its derivative .-at carboxy with a diazotizating agent and then solvolyzing the resultant diazonium salt.
~ . ~
The examples of derivative at carboxy of the starting compound (XXXVII) are the same as those illustrated in the explanation of the derivative of carboxy for "A" with respect to the compound (I).
Suitable examples of diazotizating agent to be used in the reaction may include dinitrogen trioxide; nitrous acid or its derivative such as alkyl ester (e.g., methyl nitrite, ethyl nitrite, amyl nitrite, etc.), alkali metal salt (e.g., sodium nitrite, potassium nitrite, etc.); and mixed anhydride (e.g., nitrosyl chloride, nitrosyl bormide, nitrosylsulfuric acid, nitrosylacetic acid, etc.).

:. , ~ . .,:

1~3iOI~

The diazatization is usually conducted in a solvent such as water, methanol, ethanol, ~,~-dimethylformamide, dimethylsulfoxide or any other solvent which does not give bad influence to the reaction.
The resulting diazonium salt which is produced by reacting the compound (XXXVII) or its derivative at carboxy with a diazotizating agent is solvolyzed by treating the reaction mixture per se or the isolated diazonium salt under acidic condition in the presence of an acid such as an inorganic acid (e.g., hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, etc.) and an organic acid (e.g., formic acid, acetic acid, propionic acid, butiric acid, p-toluenesulfonic acid, etc.).
There is no limitation to the present reaction temp-erature and the reaction is usually carried out under cooling, at ambient temperature, or at an elevated temperature.
In the present reaction, the amino group in the start-ing compoùnd (XXXVII) is first diazotiæated and then the result-ing diazonium salt is solvolyzed to the corresponding hydroxy -group. Then, depending upon a kind of the diazotizating agent to be used, the object compound (XXXVIII) or its deri-vative at carboxy can be prepared by one step by diazotizat-ing the compound (XXXVII) or its derivative at carboxy, under acidic condition, i.e. in an acidic solvent selected from a liquid inorganic or organic acid as stated above and a mixture of the inorganic or organic acid and the solvent as mentioned above, whereby the object compound (XXXVIII) are obtained without any specific solvolysis treatment.

3:1~8 ~22) Process 22: (XXXrX) )(XXXX) - In this process, the ob]ect compound (XXXX) can be prepared by reacting the compound (XXXIX) or its derivative at carboxy with an aryl halide of the formula: R"X' wherein R" is aryl which may be substituted by at least one substituent of nitro, esterified carboxy and heterocyclic group, and X' is . halogen.
Examples of the derivative at carboxy of the starting compound (XXXIX) are the same as those illustrated in the ~ `
explanation for the compound (I).
Suitable examples of aryl in the aryl which may be substituted by at least one substituent of nitro, esterified carboxy and heterocyclic group for R43 are the same as those illustrated in the explanation for Process 13 (to be referred to the explanation of the compound (XXII)).
Further, examples of the ester in the esterified - carboxy may include the same as those illustrated in the ex-planation of the ester for the definition of A for the compound (I). Examples of the heterocyclic group are illustrated in the explanation for the compound (XXXIX).
The reaction is conducted under substantially the same conditions (solvent, reaction temperature, etc.) as those explained in the explanation of the reaction for the Process 13.

1~3~ 8 (23) Process 23: (XXXXI)~ (XXXXII) In this reaction, the object compound (XXXXII) can be prepared by reacting the compound (XXXXI) with an alkylating agent.
Suitable alkylating agents may include, for example, alkanol (e.g., methanol, ethanol, propanol, isopropyl alcohol, butanol, etc.), diazoalkane (e.g." diazomethane, diazoethane, etc.), dialkyl sulfate (e.g., dimethyl sulfate, diethyl sulfate, dipropyl sulfate, etc.), alkyl tosylate (e.g., methyl tosylate, ethyl tosylate, etc.) and the like.
The present reaction is usually conducted in a solvent such as methanol, ethanol, acetone, ether, dimethylformamide and any other solvent which does not give bad influence to the reaction.
In case that diazoalkane, dialkyl sulfate or alkyl tosylate is used as an alkylating agent in the present reaction, both of carboxy and hydroxy groups of the compound (XXXXI) are usually alkylated, but in case that alkanol is used as an alkylating àgent, carboxy group of the compound (XXXXI) is selectively alkylated.
When dialkyl sulfate, alkyl tosylate is employed as an alkylating agent in the present reaction, the reaction may be preferably conducted in the presence of a base such as an inorganic base (e.g., sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, etc.) and an organic base (e.g., tri-methylamine, triethylamine, pyridine, picoline, etc.), and when alkanol is employed as an alkylating agent in the present reaction, the reaction is preferably conducted in the presence of a conventional condensing agent such as 1-(4-i31CI1~3 chlorobenzenesulfonyloxy)-6-chloro-lH-benzotriazole.
There is no particular limitation to the present reaction temperature, and it may be suitably selected in accordance with kinds of the compound (XXXXI) and, an alkylat-ing agent to be used. For example, when diazoalkane is employed in the present reaction, the reaction may proceed under cooling or at ambient temperature.
(24) Process 24: (XXXXIII) ~ (XXXXIV) In this process, the object compound (XXXXIV) can be prepared by subjecting the compound (XXXXIII) to elimination reaction of the protective group of amino. The present elimination reaction is conducted in a conventional manner, that is under substantially the similar conditions as those described in the elimination reaction of the protected group of amino of the compound (XIII) in Process 9.
Examples of the protected group may include the same as those illustrated in the explanation with respect to the compound (I~).
In this reaction, in case that the starting compound (XXXXIII) has the other protected amino, protected hydroxy and~
or protected carboxy group, suchiprotected group may be eliminated in the reaction to be converted into the correspond-ing amino, hydroxy and~or carboxy group, whose reaction is also included within the scope of the present process.

.. . ,: . - - .; :. .- : -.
1~i3108 (25) Process 25: (XXXXV) ,' (XXXXVI) In this process, the object compound (XXXXVI) can be prepared by reacting the compound (XXXXV) with a reagent selected from hydrazide, hydroxyalkylamine and aralkylamine or the salt thereof.
Suitable examples of hydroxyalkylamine may include hydroxyethylamine, hydroxypropylamine and the like, and suitable examples of aralkylamine may include benzylamine, phenethylamine and the like.
Suitable examples of the salts of hydrazide, hydroxy-alkylamine or aralkylamine may include an organic acid salt (e.g., acetate, maleate, tartrate, benzenesulfonate, toluenesulfonate, etc.) and an inorganic acid salt (e.g., hydrochloride, sulfate, phosphate, etc.).
The present reaction can be conducted under substan-tially the similar conditions as those described in the explana-tion of the acylation of the compound (II) in Process 1.

3:108 (26) Process 26: (XXXXVII) ~ (XXXXVIII) In this process, the object compound (XXXXVIII) can be prepared by reacting the compound (XXXXVII~ with an esterified alkene carboxylic acid.
Examples of alkene moiety in the esterified alkene carboxylic acid may include alkenyl which may be branched, such as alkyl, l-propenyl, l-butenyl, l-pentenyl, isopropenyl, methylpropenyl, methylbutenyl, methylpentenyl, ethylpropenyl, ethylbutenyl, etc., and examples of ester moiety therein may include a non-reactive ester in the ester as illustrated in the explanation o~ the ester with respect to the compound (I), (I') and (II).
The present reaction is usually conducted in a solvent which does not give bad influence to the reaction such as water, methanol, ethanol, acetone, chloroform, dimethylformamide and the like.
The present reaction can be preferably conducted in the presence of a base such as an inorganic base (e.g., sodium hydroxide, potassium hydroxide~ sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, etc.) and an organic base (e.g., trimethylamine, triethylamine, pyridine, picoline, etc.).
There is no particular limitation to the present re-action temperature, and the reaction may proceed under cooling or warming.

-- 90 _ ~S3101~

(27) Process 27: (XXXXVII) ~ (xxxxrx) The object compound (XXXXIX) can be prepared by re-acting the compound (XXXXVII) or its salt with an esterified aliphatic hydrocarbon carbonyl acetic acid or its salt.
Examples of aliphatic hydrocarbon moiety in the esteri-fied aliphatic hydrocarbon carbonyl acetic acid may include the same as those illustrated in the explanation of that in the acyl for the compound (I). Suitable example of the esterified aliphatic hydrocarbon carbonyl acetic acid is esterified alkanoylacetic acid such as esterified acetyl. propionyl, butyryl acetic acid, etc. Examples of ester moiety in esterified aliphatic hydrocarbon carbonyl acetic acid may include a non-reactive ester in the ester as illustrated in the explanation of the ester with respect to the compound (I), (I') and (II).
Suitable salt of the compound (XXXXVII) may include an organic acid salt (e.g., acetate, maleate, tartrate, benzene-sulfonate, toluenesulfonate, etc.) and an inorganic acid salt (e.g., hydrochloride, sulfate, phosphate, etc.), and a suitable salt of an alkanoylacetic acid ester may include an inorganic base salt (e.g. sodium salt, potassium salt, calcium salt, magnesium salt, etc.).
The present reaction can be conducted with or without solvent. Suitable solvents may include methanol, ethanol, propanol, ether, acetone, benzene, toluene and any other solvent which does not give bad influence to the reaction.
The present reaction can be preferably conducted in the presence of a base such as an inorganic base (e.g., sodium hydroxide, potassium hydroxide, sodium carbonate. potassium carbonate, sodium bicarbonate, potassium bicarbonate, etc.) ~063iQ8 ~ and an organic base (e.g., trimethylamine, triethylamine, - pyridine, picoline, etc.).
There is no particular limitation to the present re-action temperature, and the present reaction are usually con-ducted under warming or heating.
Thus obtained object compound (XXXX~X) may include an isomer of the compound (xxxxrx) wh~erein R53 is replaced by an ` acylamino having alkylidenamino substituted by esterified carboxy.

(28) Process 28: (XXXXXII) )(XXXXVII) In this process, the object compound (XXXXVII) can be prepared by reducing the compound (XXXXXII).
The reduction is conducted in a conventional manner in which nitro and azido group can be reduced to amino group, including the reduction method as described in the reduction for Process 15.
Suitable reduction applicable for the reaction may include a chemical reduction using a metal (e.g., tin, zinc, iron, etc.) and an acid (e.g., acetic acid, hydrochloric acid, etc.) or a catalyic reduction in the presence of a metallic catalyst such as palladium carbon, Raney-nickel.
platinum oxide and other conventional catalysts.
The reaction is conducted in a solvent such a methanol, ethanol, propanol and the like.
There is no particular limitation to the present re-action temperature, and it may suitably be selected in accord-ance with kinds of the compound (XXXXXII) and reduction methods.

1~i3101~
;`
(29)-(a) Process 29-(a): (XXXXXIII)-- ~(XXXXXIV) In this process, the object compound (XXXXXIV) can be prepared by reducing the compound (XXXXXIII).
The reduction is conducted in a conventional ~nanner.
Suitable reduction applicable for the present reaction may }be, for example, reduction using an alkali metal borohydride (e.g., sodium borohydride, lithium borohydride, etc.).
The present reaction is usually conducted in a solvent which does not give bad influence to the reaction such as water, methanol, ethanol, chloroform, benzene, toluene and the like.
There is no particular limitation to the present re-action temperature, and it may be suitably selected in accord-ance with kinds of the compound (XXXXXIII) and reduction methods.

(29)-(b) Process 29-(b): (XXXXXV) ~(XXXXXVI) In this process, the object compound (XXXXXVI) can be prepared by reacting the compound (XXXXXV) or its derivative at carboxy with an aralkylamine under reductive condition.
Suitable examples of aralkylamine are benzylamine, phenethylamine and the like, whose benzene ring may be sub-stituted by at least one suitable substituent.
Examples of the derivative ~t carboxy of the starting compound (X~nCrV) are the same as illustrated in the explanation of th~e derivative of carboxy for "A" with respect to the compound (I).
The pre3ent reaction is conducted under reductive con-ditions, that is ]by reacting the starting compound (XXXXXV) with an aralkylam:ine in the presence of a conventional reducing agent or by reacting the starting compound (XXXXXV) 1Cl ~;3108 with an aralkylamine and then reducing the resulting product with a conventional reducing agent.
Suitable examples of the reducing agents are, an alkali metal borohydride (e.g., sodium borohydride, potassium borohydride, etc.), and other conventional reducing agent and methods as illustrated in Process 6 can be used.
In case that the reaction is conducted by reacting the compound (XXXXXV) with an aralkylamine and then reducing the resulting product, the reaction of the compound (XXXXXV) with an aralkylamine can be preferably conducted in the presence of base such as an inorganic base (e.g., sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate. etc.) and an organic base (e.g., trimethylamine, triethylamine, pyridine, picoline, etc.).
The present reaction is usually carried out in a solvent which does not give bad influence to the reaction such as methanol, ethanol, chloroform, benzene, toluene and the like.
There is no particular limitation to the present reaction temperature, and it may be suitably selected in accordance with kinds of the compound (XXXXXV), aralkylamine and reduction conditions or reduction methods.

(~0)- Process 30: (XXXXXVII) )(XXXXXVIII) In this process, the object compound (XXXXXVIII) can be prepared by reacting the compound (XXXXXVII) or its derivative at car~xy with a trialkylamine.
Examples of the derivative at carboxy are the same as illustrated in the explanation of the derivative of carboxy ~ i31~8 s- 95 .
for "A" with respect to the Compound (I).
Suitable trialkylamines may include trimethylamine, triethylamine~ triporpylamine and the like.
The present reaction is usually conducted in a solvent which does not give bad influence to the reaction such as methanol, ethanol, acetone, ether~ dimethylformamide and the like.
There is no particular limitation to the present .
reaction temperature 3 and the reaction is usually conducted at ambient temperature or under warming.

(31) Process 31: (XXXXX) ~ (XXXXXI) In this process, the object compound (XXXXXI) can be prepared by reacting the compound (XXXXX) or its derivative ~t at carboxy ~Yith an acylating agent.
The derivative at carboxy of the starting compound (XXXXX) are the same as illustrated in the explanation of the derivative of carboxy for "A" ~Yith respect to the compound (I).
The acylation is conducted in a conventional manner, : -and the reaction is conducted under substantially the same condition (solvent, reaction temperature, e~c.) as illustrated in the acylation for Process 1.
Examples of acylating agents may include the same as illustration in the explanation of the acvlating agent for Process 1.

=~~ ..
_ --~
~ : :

, . . .
- , ,~ ; ., , . . ~ ~ , , -, , 10~310~ s- 96 According to kinds of the reactions to be used in the afore-mentioned Processes, the carboxy group may be converted into the corresponding derlvative at carboxy and/or the derivative at carboxy may be converted into the correspond-ing free carboxy group in the course of the reaction of the starting compounds or the post treatment of the reaction mixtures or the object compounds. In the same manner, protected group~s) of ~he protected carboxy, protected amino and/or protected hydroxy, may be converted into the corres-ponding carboxy, ami~o and/or hydroxy group~s)l respectively.
Such cases of the reactions as mentioned above also includ w~ nthe scope of the Processes as concerned in the present invention.

/

/ `

. ..

, ~S

~0 '.
. . `

,. ~ . ~ ~ ;. .

:~0~3108 s~ 97 The object compounds (I~ of the present invention have antimicrobial activities against various pathogenic micro-organisms and may be useful for treatment of diseases inected by such microorganisms in human being and animals.
With regard to the representative object compounds of ` the present invention, their antimicrobial activities against pathogenic microorganisms are illustrated as M.I.C(Minimum In-hibitory Concentration) value determined in a conventional manner as followed. ~n the following~ ~I.I.C. value is shown as ~-microgram per ml.
~` An object compound of Example 39, Pseudomonas aeruginosa (3) ; an object compound of Example 519 Bacillus subtilis (12.5); an object compound of Example 112~ Escherichia coli (60), Proteus vulgaris (<3)9 Staphylococcus aureus (60);
`15 an object compound of Example 157, Bacillus subtilis ~7.5), - Staphylococcus aureus ~7~5)s an object compound of Example 1589 , . .
Bacillus subtilis ~80), StaphYlococcus aureus ~80); an object compound of Example 1619 Escherichia coli ~16)9 Pr~teus vulgaris ~8), Staphylococcus aureus ~8); an object compound of Example 291, E~cherichia coli ~1.6)9 Proteus vulgaris ~25); an object compound of Example 300~ Pseudomonas aeruginosa (15J9 Escherichia coli ~60); an object compound o~ Example 400~ Pseudomonas aeruginosa ~32), Escherichia coli ~16); an object compound of Examp:!e 409, Escherichia coli ~60)9 Proteus vulgaris ~<3), Staphylococcus aureus ~60)~ an object compound of Example 469, Baci lus subt lis (60), Escherichia coli ~4), ~ y~coccus aureus (4); an object compou~d of Example 489, Pseudomonas aeruginosa (15), Escherichia _oli ~3.9), Proteus vulgaris (60)~ an object compound of Example 507 9 Pseudomonas aeruginosa (6~3), Proteus _ul~.aris (25); an object compound of Example 503, Pseudomonas aer ~inosa :

~C~6i3108 ~, (6.3), Proteus vulqaris (25); an object compound of example 508, Pseudomonas aeru~inosa (6.3),Proteus vulqaris (25), Staph~lococcus aureus (1~6); an object compound of Example 511, Bacillus subtilis (6), Escherichia coli (30), Staphylo-coccus aureus (60).

`~ 10~310~ s - 99 , As previously mentioned, the cor,lpounds produced by the ~- processes according to the invention are new. The new com~ounds may be particularly represented by the follo~ing formula.

~, R
`,! . a\
N- CH - C~
Rb~ 1 1 2 J -Aa , in ~hich (1) Ra and Rb are each hydrogen, (2) Ra is hydrogen and i ~ is hydrocarbon sulfonyl . ~---~-~; (such as arene sulfonyl, etc.), (3) Ra and Rb together form a bivalent acyl group derived from a dicarboxylic acid (e.g., phthalic acid, etc.), (4) Ra is hydrogen and Rb is an acyl group as mentioned in the explanation of an acyl group for Rl, and more particularly an acyl group selected from the following groups:-Rl -CH~CII ) O ~ C -CO- ; wherein Pb Rb Rb , ,, n is an integer O - 4 Rbl is hydrogen; or carboxy or its derivative (e.g., the salt, the ester, etc.), Rb is hydroxy;
halogen; r azido;
amino;

~ 3108 aliphatic radical-amino such as alkylamino, alkenylamino, cycloalkylamino, etc.;
arylamino;
acylamino such as aliphatic acylamino (e.g., alkanoylamino, etc.), aliphatic radical-oxy(thiocarbonyl)amino le.g., a1koxy(thiocarbonyl)amino, etc.], aryloxy-aliphatic acylamino (e.g., aryloxyalkanoylamino, etc.), aryl-aliphatic acylamino (e.g., aralkanoylamino, etc.), i~
aryloxy-aliphatic acylamino (e.g., aryloxyalkanoylamino), heterocyclic-aliphatic acylamino (e.g., heterocyclic alkanoylamino, etc.), aroylamino, etc.;
substituted ureido such as N'-arylureido, etc.;
su~stituted thioureido such as Nl'-arylthioureido, etc.; or arylthio.

.

--) UD

. . .. : . .

S - 1 () ]
3~8 Rb is hydrogen;
hydroxy;
amino;

arylamino;
acylamino such as aliphatic acylamino (e.g., alkanoylamino, etc.), aliphatic radical-oxy(thiocarbc)nyljamino [e.g., alkoxy(thiocarbonyl)amino, etc.], aroylamino, etc.;
substituted ureido such as N'-arylureido, etc.; or substituted thioureido such às N'-arylthioureido, etc.
Rb is hydrogen, or Rb and Rb together form oxo;
hydroxyimino; or substituted hydroxyimino such as alkoxyimino, etc., in which the aliphatic hydrocarbon moiety may be subst:ituted by at least one suitable substituent of carboxy or its derivative (e.g., the salt, the ester, etc.), halogen, sulfo, and the aryl and heterocyclic ring may be substituted by at least one suitable substituent of nitro, halogen c:arboxy or its derivative (e.g., the salt, the ester, etc.).
'~

~31~8 ., ` (ii) X~6_ C--CO-Rb , in which Rb is oxo;
hYdroxyimino; or substituted hydroxyimino s~ch as àliphatic radical-oxyimino (e.g., alkoxyimino, etc.), aryl-aliphatic radical-oxyimino - (e.g., aralkoxyimino, etc.).
is cyano; _~
aliphatic radical such as alkyl, etc.;
aryl;
heterocyclic rad.ical;
aliphatic radical-amino such as alkylamino, etc.;
aryl-aliphatic radical-amino such as aralkylamino, etc.; or aliphatic radical-oxy such as alkoxy, etc., in which the aliphatic moiety may be substituted by at least one suitable substituent such as hydroxy~, carboxy or its derivative (e.g., the salt, the ester, etc.) and ` 1()~ `~

' S - 103 the aryl and heterocyclic ring may be substituted by at least one suitable substituent such as hydroxy, aliphatic radical-oxy (e.g., alkoxy, alkenyloxy, etc.) which may have carboxy or its derivative, aryl-aliphatic radical-oxy(e.~., aralkoxy, etc.).

(iii) R7- CO- : wherein Rb is aryl;
aryloxy.î
aryl-aliphatic radical-oxy sueh as aralkyloxy, etc.;
arylamino;
heterocyclic radical;
guanidino; or substituted guanidino such as acylguanidino (e.g., 3-aralkanoylguanidino, etc.), ete, in-which aryl and heterocyclie radieal may be - substituted at least one suitable substituent sueh as nitro, halogen, aliphatie radical (e.g., alkyl, etc.), aliphatic radical-oxy ~e.g., alkoxy), etc.

~~3 1~3~8 s- 104 (iv~ Rb _(C~2)n - CH - (CH2)n CO- : wherein n2 and n3 are each an inte~er of 0 - 4, Rb is hydrogen;
aliphatic radicaL
such as alkyl;
aryl;
substituted oxy such as aryloxy, etc.;
heterocyclic radical; or N-substituted carbamoyl such as N-arylcarbàmoyl, etc., in which the aryl and heterocyclic radical may be substituted by at least one suitable substituent (e.g., hydroxy, etc.).
Rb is hydrogen;
amino;
azido;
halogen;
" hydroxy;
carboxy or its derivative (e.g., the salt, the ester, etc.);
s~lfo;
- substituted sulfo such as arylsulfo, etc.;
aliphatic radical ~ such as a:Lkyl, alkenyl, etc., which may be substituted by at least one suitable substituent selected from amino, protected amino, azido, halogen, hydroxy, carboxy or its derivative ~e.g., the salt, the ester, etc.), sulfo, acyl (e.g., aroyl), ~,N-disubstituted amino (e.g., N-alky:L-N-arylamino alkyl, etc.), aryl, substituted aryl, heterocyclic radical, substituted heterocyclic radical, and the like;

aryl which may be substituted by at least one suitable substituent selected from hydroxy, nitro, carboxy, halogen, substituted sulfonamido re.g., aromatic ring sulfonamido (e.g., benzenesulfonamide, etc.) which may have at least one substituent (e.g., carboxy, hydroxy, etc.)~ and the like, heterocyclic radical which may be substituted by at least one suitable substituent selected from aliphatic radical, aryl, heterocyclic radical, , acylamino and the like re.g., heterocyclic radical, alkyl-heterocyclic radical, aryl-heterocyclic radical, heterocyclic-heterocyclic radical, heterocyclic-aliphatic acyl (e.g., heterocyclic-alkanoyl, etc.) amino-heterocyclic radical, - , ~ . - . .

3:~0i~
arylaliphatic acyl (e.g. aralkanoyl, etc.) amino-heterocyclic radical in which aryl and heterocyclic ring may have at least one suitable substituent (e.g. oxo, halogen, etc.),` etc.];

.. .
acyl such as aroyl, etc;
I

aliphatic radical-oxy such as alkoxy, cycloalkyloxy, etc.
which may be substituted by at least one suitable substituent;

aryloxy whose aryl ring may be substituent by at least one substituent selected from nitro, halogen, acyl (e.g., formyl, alkanoyl, etc.), acylamino (e.g., alkanoylamino, etc.), `
aryl, aryl-aliphatic radical (e.g., aralkylamino, etc.), and aliphatic radical ~e.g., alkyl, alkenyl, etc~) which may be substituted by at least one suitable substituent [e.g., carboxy or its derivative (the salt, the ester, etc.), amino, hydroxy, ni~ro, hydroxyimino, substituted hydroxyimino such as aliphatic radical-oxyimino .. . . ~ .

l~S3:10B
(e.g., alkoxyimino, etc.), which may be sub~tituted by carboYy, etc., (N-halo-N,N,N-trialiphatic radicalammonio)-aliphatic acylhydrazono (e.g., (N-halo-N,N,N~trialkylan~lonio)-alk~noylhy~razono, etc.), aliphatic radical-thio-aliphatic acylamino (e.g., alkylthioalkanoylamino, etc.) in which aliphatic-thio moiety may be substituted by at least one suijtable substituent (e.g., amino, carboxy, etc.), etc,] and the like;

heterocyclic-oxy;

aliphatic radical-thio which may be substituted by at least one suitable substituent selected from amino, carboxy, acyl,acylamino, and the like, le^g., alkylthio, alkenylthio, ~ ;
acylamino-aliphatic radical thio -(e.g., aroylalkanoylamino-alkylthio, etc.) acyl-aliphatic radical-thio (e.g.,-aroyl-alkylthio, N-arylcarbamoyl- ;~
alkylthio etc.) which may have at least one suitable substituent (e.g., halogen, nitro, etc.)~;

.
aliphatic radical-sulfinyl ;~

which may be substituted by at least one suitable substituent selected from substituted carbamoyl and the like, (e.g., alkylsulfinyl, .

,.

1 ~ S 31 O 8 S - 108 N-arylcarbamoylalkylsulfinyl, etc.);

.
arylthio which may be substituted by at least one suitable substituent selected ~rom carboxy and the like;

.
heterocyclic-thio which may be substituted by at least one suitable substituent of amino, hydroxy, amino aliphatic radical, acylamino-aliphàtic radica~ and the like, -le.g., heterocyclic-thio, aminoalkyl-heterocyclic-thio, alkanoylaminoalkyl-heterocyclic thio, etc.), which may have at least one suitable substituent (e.~., hydroxy, etc.);

arylamino which may be substituted by at least one suitable substituent;

heterocyclic-amino which may be substituted by at least one suitable substituent selected from oxo, aryl, etc.
(e.g., oxo-substituted heterocyclic amino, aryl-heterocyclic amino, etc.);

mono- or di- substituted amino such as ~ I O ~ -. .

10~3iOB s- 109 aliphatic radical-amino (e.g., alkylamino, etc.), N-aliphatic radical -N-protected- amino (e.g., N-alkyl-N-protected carboxy amino, etc.~, N-substituted-N-axylamino [e.g., N-aliphatic radical-N-arylamino (e.g., N-alkyl-N-arylamino, etc.)], N-acyl-N-arylamino (e.g., N-alkanoyl-N-arylamino, etc.), N-aliphatic radical-N-arylamino (e.g., N-alkyl-N-arylamino, etc in which aliphatic hydrocarbon moiety may have at least one suitable substituent (e.g., azido, carboxy, etc.) N-substituted sulfonyl-N-arylamino (e.g., N-alkanesulfonyl-N-arylamino, etc.];

acylamino selected from:-, aliphatic acylamino (e.g., alkanoylar.lino, etc.) which may be substituted by at least one suitable substituent (e.g., halogen, amino, etc.);

aliphatic radical-ox~-aliphatic acylamino (e.g., cycloalkyloxyalkanoyl, etc.) w~hich may be substituted by at least one suitable substituent;

..

1~3~8 s - llo aliphatic radical-thio-aliphatic acylamino te-~-, alkylthioalkanoylamino, etc.) in which aliphatic hydrocarbon moiety may be substituted by at least one suitable substituent (e.g., amino, halogen, carboxy, etc.);

aryl-aliphatic acylamino in which aryl ring may be substituted by at least one suitable substituent selected from aliphatic radical oxy, aryloxy,~etc.
(e.g., alkoxy-aralkanoylamino, aryloxy aralkanoylamino, etc.) in which aliphatic hydrocarbon moiety and aryl ring may have at least one suitable substituent [e.g., halogen, arylaliphatic radical-oxyimino (e.g., aralkoxyimino, etc.), arylamino, amino, hydroxy, etc.];

arylamino-aliphatic acylamino ~e.g., arylaminoalkanoylamino, etc.) in which aryl ring and aliphatic hydrocarbon moiety may be substituted by at least one suitable substituent (e.g., halogen, carboxy, amino);

aryloxy-aliphatic acylamino whose aryl ring may be substituted by ~1 1 V --. .

~ ;310~3 s~

a substituent selected from aliphatic radical (e.g., alkyl, etc.), aryl, arylaliphatic radical (e.g., aralkyl, etc.), heterocyclic radical, aryl (e.g., aliphatic acyl, substituted-aroyl, heterocyclic-carbonyl, etc.) arylaliphatic radical-amino-aliphatic ;`
radical (e.g;, aralkylaminoalkyl, etc.) and the like, [e.g., aryloxyalkanoylamino which may be substituted by at least one suitable substituent (e.g., halogen, nitro, carboxy, formyl, carbazoyl, etc.);

alkyl-aryloxyalkanoylamino which may be substituted by at least one suitable substituent (e.g., hydroxy, etc.);
aryl-aryloxyalkanoylamino;

aralkyl-aryloxyalkanoylamino which may be substituent by at least one suitable substituent (e.g., hydroxyimino, halogen, etc.);

Eormyl-aryloxyalkanoylamino;
alkanoyl-aryloxyalkanoylamino;

aroyl-aryloxyalkanoylan~ino _ll I

i310B s- 112 which may be substituted by at least one suitable substituent (e.g., nitro, amino, -halogen, etc.);
alkylthioalkanoylaminoaroyl-aryloxy-alkanoylamino which may be substituted by at least one suitable substituent (e.g., halogen, amino, carboxy, etc.);
alkylthioalkylaminoaroyl-aryloxyalkanoylamino which may be substituted by at least one suitable substituent (e.g., amino, halogen, etc.);
(N-halo-N,N,N-trialkylammoni~) alkanoylaminoaroyl-aryloxyalkanoylamino which may be substituted by at least one suitable substituent (e.g., halogen, etc.);
heterocyclic-carbonyl-aryloxyalkanoylamino which may be substituted by at least one suitable substituent (e.g., halogen, etc.);

aralkylaminoalkyl-aryloxyalkanoylamino which may be substituted by at least one suitable substituent (e.g., alkoxy, carboxy-alkoxy, carboxy, etc.);

heterocyclic-aryloxyalkanoylamino in which heterocyclic ring may be substituted by at least one suitable substituent (e.g., alkyl, aryl, substituted (e.g., halo) aryl, etc.) and alkane moiety may be substituted by at least one suitable substituent (e.g., halogen, amino, etc.), 1~631~8 S - 113 diaryloxy~aliphatic acylamino (e.g., diaryloxyalkanoylamino, etc.) in which aliphatic: hydrocarbon moiety May be substituted by at least one suitable substituent (e.g., halogen, amino, etc.);

.

arylthio-aliphatic acyl amino ~e.g., arylthioalkanoyl amino, etc!) which may be substituted by at least one suitable substituent (e.g., carboxy, etc.);

heterocyclic-aliphatic acylamino in which heterocyclic radical may have at lèast one suitable substituent [e.g., aliphatic radical (e.gO, alkyl, etc.), aryl which may have substituent (e.g., halogen, etc.), etc.] and aliphatic hydrocarbon moiety may have at least one suitable substituent (e.g., halogen, amino, etc.);

heterocyclic-heterocyclic-aliphatic acylamino (e.g., heterocyclic-heterocyclic-alkanoyl, etc.);

heterocyclicthio-aliphatic acyl amino (e.g., heterocyclicthioalkanoyl amino, etc.) which may be substituted by at least one -ll3~

y~, .

lC~S310~1 s- ll,l suitable substituent [e.g., hydroxy, amino, aliphatic radical (alkyl) which may have at least one suitable substituent (e.g., amino, etc.)];

.
acylamino-aliphatic acylamino [e.g., arylaliphatic acylamino-aliphatic acylamino (e.g., aralkanoylamino-alkanoylami~o, etc.) in which aliphatic hydrocarbon moiety and/or aryl ring may be substituted by at least one suitable substituent (e.g., amino, halogen, carboxy, etc.);

substituted sulfinyl-aliphatic acylamino ~e.g;, arylsulfinylalkanoylamino, etc.) which may be substituted by at least one suitable substituent (e.g., carboxy, etc.);

substituted sulfo-aliphatic acylamino (e.g., arylsulfoalkanoylamino, etc.);

N,N-disubstituted amino-aliphatic acylamino (e.g., (N-aryl-N-arylsulfonylamino)-alkanoylamino, etc.)i substituted glyoxyloylamino (e.g., arylglyoxyloylamino, etc.);
' ` ' substituted-oxalylamino (e.g., alkoxalylamino, aralkylaminooxalylamino, etc.);

J~ ' . ' : ' ~S3~0~ s- 115 N-substituted carbamoyl (e.g., N-arylcarbamoyl, etc.);

guanidinocarbonylamino;

substitùted sulfonamido [~e.g., aromatic ring sulfonamido (e.g., benzenesulfonamido, etc.)~
aliphatic hydrocarbon sulfonamido (e.g., alkane sulfonamid~, etc.) which may have at least one suitable substituent (e.g., hydroxy,'carboxy, halogen, etc.);

substituted ureido [e.g., acyl ureido (e.g., N'-aroylureido, etc.), etc.];

substituted aminoxy such as acylaminoxy [e.g., aliphatic acylaminoxy which may be substituted by aryloxy (e.g., aryloxyalkanoylaminoxy, etc.)], alkylidenaminoxy which may be substituted by aryl, heterocyclic radical, (e.g., alkylidenaminoxy, heterocyclic-alkylidenaminoxy, aralkylidenaminoxy, etc.), which may have at least one suitable' substituent (e.g., carboxy, or its derivative alkoxy, etc.), - 1 )5`

' ' , . - `-. ~ ':- ''' .. .' `: . ' 10~3108 s - 116 in which, the aryl and heterocyclic rin~ may be additionally substituted by at least one suitable substituent selected from carboxy or its derivative (e.g., the salt, the ester, etc.), amino or protected amino, hydroxy or protected hydroxy, halogen, nitro, oxo, carbazyl, acyl [e.g., alkanoyl (e.g., formyl, alkanoyl~ etc.)etc.], aliphatic radical (e.g., alkyl, etc.), aliphatic radical-oxy (e.g., alkoxy, etc.), aryl, aryl-aliphatic radical (e.g., aralkyl, etc.),l acylamino (e.g., alkanoylamino, etc.) and the like, and the aliphatic moiety or radical may comprise 1 - 8 carbon atoms, preferably 1 - 4 carbon atoms and may be additionally substituted by at least one suitable substituent selected from carboxy or its derivative (the salt, the ester, etc.) amino or protected amino, azido, nitro, halogen, hydroxy, sulfo, and the like.

Further, in the above definition, heterocyclic radical is mentioned in the above explanation, and particularly is intended to mean mono-aliphatic or aromatic heterocyclic radical, which may be 5 - 7 membered heterocycle containing at least one hetero atom selected from oxygen, nitrogen and sulfur, and poly-aliphatic or aromatic hetexocyclic radical, for example, benzene-fused heterocyclic radical, heterocycle-fused aryl, radical, hèterocycle-fused heterocyclic radical and the like, in which the heterocycle may be 5 - 7 membered heterocycle containing at least one heteroatom selected from oxygen, nitrogen and sulfur.

~~11 .

ii31C~8 .~; - 11 (;a ~a is - ~ - Aci , wl~er~in Aà is llydrocJen, Aa is hyArogell;
aliphatic radical (e.9. alkyl, al];enyl, cycloal~yl, etc); or aryl which may be substituted by at least one suitable substituent selected from hydroxy or protected hydroxy, amino or pl-OteC ~ed am;no, nitro, halogen, alipllatic radical, aliphatic radical - oxy (e.g. alkoxy, etc.), aliphatic radical - thio (e.g. alkylthio, etc.) and the lik~, or ~a and A?i togetller form : aliphatic radical methylene (e.g. alkylidene, etc.) or cycloalkadienylidene, and Aa is carboxy or its derivative (e.g. the salt, the ester, azido, etc.) cyano, amino or protected aMino or hydroxy or protected hydroxy.

.

~ 3~-1~3108 s - 117 The object compounds (I) of the present invention may be formulated for a~ministration in any convenient way by analogy with other antibiotic.

Thus, the composition of present :invention can be used in the form of pharmaceutical preparat:ion, for examples, in solid, semisolid or liquid form, which contains the active object compound (I) of the present invention in admixtuFe ~ith a pharmaceutical organic or inorganic carrier or excipient suitable for external or inorganic carrier or excipient suitable for external or parenteral applications. The active ingredient may be compounded, for example, with usual carriers for tablets, peletts, capsules, suppositories, solutions, emulsions, aqueous suspensions, and other form suitable for use. The carriers ~Yhich can be used are glucose, lactose, gum acacia, gelatin, mannitol, starch paste, magnesium trisilicate, talc, corn starch, keratinl colloidal silica, potato starch, urea and other carriers suitable for use in manufacturing preparations, in solid, semisolid, or liquid form, and in addition auxiliary, stabilizing, thickening and coloring agents and perfumes. The compositions of the present invention can also contain preserving or bacteriostatic agents thereby keeping the active ingredient in the desired preparations stable in activity. rrhe active objecting compound (I) of the present invention is included in the composition of the present invention in an amount sufficient to produce the desired therapeutic eifect upon the bacterially infected process or condition. ~hile the dosage or therapeutically effective quantity of the compound (I) of the present invention varies from and also -11 'i - - ~.

.

~ S - 118 t~3~

depends upon the age and cond~tion of each individual patient to be treated, a daily dose of about 0.5-5 g, preferably 1-2 g/day of the active ingredient is generally given for treating diseases a~ainst ~hich the,compoulld (I) of the present invention are useful.

The following examples are given for the purpose of illustrating the present invention.

10~i310~ s- 119 Example 1 3-Amino~ -carbo~y-~l-hydro~yben7yl)-2-azetidinone (hereinafter referred to 3-aminollc~acillanic acid) ~0. 94 n.) was suspended in w~qter ~10 ml.)9 whercafter to the suspension was added sodium bicarbonate ~0.~0 g.). To ~he solution was added acetone ~10 ml.) and thcn thc solution was cooled to -7C, whereafter acetone ~5 ml.! containing 2-phenylacetyl chloride ~0.80 g.) was added to the solution. ~The reaction mi~ture was stirred at the same temperature for 2 hrs, and then thc acetone was distilled off unde.r reduced pressure.
The remaining aqueous layer was ~ashed Wit]l ether~ and then adjusted to pH 2 with 10% hydrochloric acid9 whereafter twice extractions were carried out with ethyl acetate ~15 ml.).
The extracts obtained were combined, and washed with water znd a sodium chloride-saturated_ aqueous solution9 respectively, whereafter it was dried over anhydrous magnesium sulfate.
The solvent was distilled off from the extract and the residue obtained was treated with a small amount of a mi~ture of ethyl acetate and ether to give 3-(2-phenylacetamido~- -lactacillanic acid ~Q.53 g.). Mp 134 to 1~1C.
~.:' . ' .
The following compounds were obtained in substantially `the similar manner as described above.

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E - ll `, S - 129 Example 57 -, N-Phenylglycyl chloride hydrochloride (49~
mg.) was suspelld2d in me~hylene chloride ~10 ml.), and the suspension ~as cooled to -15C. To the suspension were added all at once a solution prepared by dissolving 3-aminolactacillanic acid ~i7~ mg.) and, ~O-bis~tri-methylsilyl)acetamide ~2.03 g.) in methylene chloride ~17 ml.). The mixture ~as stirred for 1 hour~ keepin~
the reaction temperature of the mixture at 0 to -10C, and then stirred for 1.5 hrs. aftcr removing the cooling bath. The methylene chloride ~as distilled off fxom the reaction mixture, and the residue obtained was dissolved in ethyl acetate. The solution ~as washed with water and a sodium chloride-saturated-aqueous solution respectively, and dried. The solvent was distilled off from the solution, and to the residue was added a small amount of acetone to give crystals of 3-~N-phenylglycin-amido)lactacillanic acid ~116 mg.). Mp 194 to 194 . 5C .
The filtra~e was allowed to stand under cooling to give crystals of the same object compound ~60 mg.). Mp 193 to 194.5C. Total yield ~as 176 mg.
' ' ; ~ :.
The following compounds were obtained in substantially the similar manner as described above.

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, _ 10~3108 E - 17 Example ~3 f~ mixture of N~N-dimet:ilylforamide (320 mg.~
and thionyl chloride (780 mg.) was heated for 30 minutes at 40 to 5nc, alld ~he excess oE the tllionyl ch:loriclc was distillcd off from the mixture~ and the residue obtained was suspcnded in methylene chloride ~10 ml.) To the suspension was added !I-hydroxypllenylglyoxylic acid (370 mg.) under cooling at -15 to -20C9 and the mixture ~as stirred for 15 minutes~ After the reaction temperature of the mixture was elevated to -5 to -10C, - the mixture was stirred for 10 minutes to obtain a clear solution containing -~-hydroxyphenylglyoxyloyl chloride.
Subsequently, the solution was cooled to -45 to -50C, and to the solution was added dropwise a solution of triethylamine (4~0 m~.) and methylene chloride ~2 ml.) during 5 minutcs, and then the reaction mixture was stirred for 30 minutes. A solution, prepared by sub-jecting 3-aminolac~acillanic acid (470 mg.) and ~,0-bis~trimethylsilyl)acetamide (1.2 g.) to a dissolution in dried methylene chloride (10 ml.) at room temperature for l hour while stirring ~as added all at once to the solution9 keeping the tem~erature at -~5 to -50C. The reaction mixture was stirred for 30 minutes, and then stirred for 1.5 hrs., elevating the reaction temperature to room temperature slow,ly after removing the cooling bath.
The methylene chloride was distilled off from the reaction mixture 9 and the residue obtained was dissolved in 5%
sodium bicarbonate aqueous solution (20 ml.). The 3~ solution ~las washed with ethyl acetate (10 ml.) twice, -13~ -10~3iO8 E ~ 18 and ethyl acetate (50 ml.) was added to ~he solution~
~rhereafter ~he aqueous layer was adjusted to pll 1 with 5~ hydrochloric acid ~hile shal~ing cnough. Thc et]lyl acetate layer was separated owt, and the aqueous layer ~as e~tracted with ethyl acetate ~20 ml.~ twice. The ethyl acetate layers were combined, ~ashed with a sodium chloride-saturatèd a~ueous solution and dried over anhydrous magnesium sulfate~ The solvent was distilled off from the solution to give crude crystals of 3~ -hydroxyphenylglyoxyloylamino~lactacillanic acid (460 mg.~. This product (76Q mg.) prepared by tlle same manner as mentioned above was dissolved in ethyl acetate ~3 ml.) J and the solution was subjected to column chromatography using silica-gel. The fractions containing the object compound were collected by eluting -~
with ethyl acetate. The residue, obtained by distilling off the solvent from the eluate, was dissolved in acetone, and then an acetone solution of sodium 2-ethylhexanate was added to the solution to give the solution of the sodium salt of the object compound> and then the acetone was distilled off from the solution. The residue was powdered by adding ether, and the powder was collected by filtration and washed with acetone to give 3-(4-hydroxyphenylglyoxyloylamino)lactacillanic acid sodium salt ~17Q mg.). Mp 220 to 225C. The ollowing compounds were obtained in substantially the similar manner described above.
R
~ N-A
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10~3108 Ex~mple 89 Sodium bicarbonate (0.453 g.) was dissolved in water (10 ml.), and the solution was cooled to 5C.
To the solution was added 3-aminolactacillanic acid (0.427 g.), and then acetone (10 ml.) was added to the solution. To the solution was added dropwise an acetone (5 ml.) solution of butyric acid anhydride (0.38 g.) for 5 minutes. Sodium bicarbonate (0.04 g.) was added to the reaction mixture and then stirred for 1.5 hrs. at 5C. The acetone was distilled off from the reaction mixture, and the aqueous layer was washed with ether, and then adjusted to pH 1 to 2 with l~/o hydro-chloric acid. The aqueous layer was extracted with ethyl acetate (30 ml.) twice respectively. The extracts were combined, washed with water (50 ml.) and then washed with a sodium chloride-saturated-aqueous solution, and dried over anhydrous magnesium sulfate.
The solvent was concentrated to give crystals of 3-butyramidolactacillanic acid (112 mg.). Mp 178 to 178.5C (dec.).
Example 90 ` Pivaloyl chloride (0.350 g.) was dissolved in methylene chloride (15 ml.), and to the solution was added a solution prepared by dissolving 4-methoxyphenyl-glyoxylic acid (0.520 g.) and triethylamine (0.290 g.) in methylene chloride (10 ml.). The mixed solution was reacted for 1 hour to prepare a mixed acid anhydride solution with 4-methoxyphenylglyoxylic acid and pivalic 1~;310l~
acid. On the other hand, N,O-bis(trimethylsilyl)acetamide (2.3 g.) was added to a suspension prepared by suspending 3-aminolactacillanic acid (0.680 g.) in methylene chloride (10 ml), and the suspension was stirred for 1 hour at ambient temperature. To the solution obtained was added the mixed acid anhydride solution obtained above, and the reaction mixture was reactled for 2 hrs., keeping the reaction temperature at -10 to -15C. The methylene chloride was distilled off from the reaction mixture, and the residue obtained was dissolved in ethyl acetate.
The solution was washed with 5% hydrochloric acid and a sodium chloride-saturated-aqueou~ solution, respectively, and then dried over anhydrous magnesium sulfate. The solvent was distilled off from the solution, and diisopropyl ether (about 30 ml.) was added to the residue, and then the mixture was stirred for 1 hour. The pre- -cipi~ating material obtained was collected by filtration to give the powder (1.14 g.). This powder was dissolved in ethyl acetate (30 ml.), and the solution was treated wi~h an activated carbon ~0.11 g.) and filtered. The filtrate was concentrated to the volume of about 2 ml., and crystals were obtained by scrubbing the wall of the vessel containing the solution, The crystals were collected by filtration and recrystallized from a small amount of ethyl acetate to give crystals of 3-(4-methoxy-phenylglyoxyloylamino)lactacillanic acid (0.16 g.).
mp 178 to 181C (dlec.). The following compounds were obtained in substantially the similar manner as described above.

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Example 109 3-Aminolactacillanic acid (O.944 g.) was suspended in dried methylene chloride (60 ml.), and to the suspension were added N,O-bis(trimethylsilyl)acetamide (7.0 g.) and N,N-dimethylformamide (0.7 ml.), whereafter the mixture was stirred for 2 hrs. at ambient temperature.
On the other hand, to a dried methylene chloride (30 ml.) solution of ethyl chloroformate (0.523 g.) was added dropwise a dried methylene chloride (30 ml.) solution of N-benzyloxycarbonyl-2-(2-thienyl)glycine (1.40 g.) and triethylamine (0.485 g.) during 7 minutes under cooling at -5 to ~0 e, and then the mixture was stirred at the same temperature for 20 minutes to prepare a mixed acid anhydride solution. To this solution was added dropwise the solution obtained above during 20 minutes, and then the reaction mixture was stirred for 3 hrs. at the same temperature, and the reaction temperature was slowly elevated to room temperature during 2 hrs. while stirring.
The reaction mixture was washed with diluted hydrochloric acid and water, respectively, and then dried. The solution was concentra~ed to give crystals of 3-[2-(2-thienyl)-N- -benzyloxycarbonylglycinamido]lactacillanic acid (1.40 g.).
I.R~ absorption spectrum, ~ cm 1 (liquid film) : 1730, 1710, 1650 The following compound was obtained in substantially the similar manner as described above.

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1~i3:1 08 Example 111 2-(4-Methoxyphenyl)-2-methoxyiminoacetic acid (500 mg.) and N,N'-dicyclohexylcarbodi:imide (495 mg.) were dissolved in a mixture of chloroform (9 ml.) and dioxane (3 ml.), and the solution was stirred for 1.5 hrs. under ice-cooling. To the solution was added all at once a solution, prepared by dissolving 3-aminolactacillanic acid (472 mg.) and N,0-bis(trimethylsilyl)acetamide (1.22 g.) in chloroform (10 ml.), and then the reaction mixture was stirred for 4 hrs.
at ambient temperature. The solvent was distilled off from the reaction mixture, and to the residue were added a sodium bicarbonate aqueous solution and ethyl acetate. After stirring the mixture, the aqueous layer was separated out, adjusted to pH 1 to 2 with 10% hydrochloric acid and then extracted with ethyl acetate. The extract was washed with water and then dried. The solvent was distilled off from the extract, and ether was added to the residue to give crude crystals. The crystals were collected by filtration and washed with ether to give crystals of 3-E2-(4-methoxyphenyl)-2-methoxyiminoacetamido]lactacillanic acid (150 mg.).
Mp 157 to 161 C (dec.).
The following compound was obtained in substantially the similar manner as described above.

R ~
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(I) `

.~J ~i310~ S_ 1~7 ~ ~1 \ . : ' ~ o o o ~0~3;~0~3 ExampLe lL3 3-Aminolactacillanic acid (0.472 g.) was suspended in methylene chloride (10 ~L.), and to the suspension was added N,0-bis-(trimethylsilyl)acetamide (1.22 g.) at ambient tempera-ture, and then-the solution was cooled to -15C. To the solu-tion was added dropwise during 25 minutes a methylene chloride (10 ~L.) solution of triethyl-amn~onium salt of acid anhydride (935 mg.) prepared from 2-phenyl-2-sulfoacetic acid and ethyl chloroformate, and the reaction mixture was stirred for 1 hour at the same temperature and further for 1.5 hrs. at ambient temperature. Water (50 ml.) was added to the reaction mixture and then the aqueous layer was separated out. The aqueous layer was washed with ethyl acetate and adjusted to p~ 5 to 6 with an aqueous solution of sodium bicarbonate, and then the solution was filtered. The filtrate was concentrated, and the residue obtained was adsorbed on a column packed with nonionic adsorption resin, AmberLite XAD-4 (trade mark, maker: Rohm and Haas Co., Ltd.) (20 ml.), which had been treated in advance with methanol, and the object compound was eluted with water. The eluate was concentrated under reduced pressure, and ethanol was added to the eluate, whereafter the solvent was distilled off from the eluate under reduced pressure. Ethanol was added to the residue to give crystals. The crystals were collected by filtration to give crystals of 3-(2-phenyl-2-sulfoacetamido)-lactacillanic acid disodium salt (120 mg.~. Further, the fil-trate was concentrated, and the oily material obtained was treated with acetone to give powdery crystals of 3-~2-phenyl-2-sulfoacetamido)lactacillanic acid disodium salt (0.45 g.). Mp 144 to 152C.
The fol;Lowing compounds were obtained in substantially the similar manner as described above.

(I) N-A

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lC3~31Q8 F.-32 Example 116 2-~Benzo[d]iso.~azol-3-yl)-N-ben~yloxycarbonylglycine t (652 mg.~ and triethylamine (202 mP.~ were dissolved in dried tetrahydrofuran (8 ml.). To the solutioll was added 6-chloro-1-(4-chlorobenzenesulfonyloxy)benzotriazole (690 mg.) ~hile stirring under ice-cooling and then the solution was stirred at the s~me ~emperature for 3 hrs. Keeping the solution under ice-cooling, 2 solution9 prepared by dissolving 3-aminolactacillanic acid (~l72 mg.) and triethylamine (202 mg.) in a mixed solution of acetone and water (1 : 1) (10 ml.) 9 ` `, was added to the solution. The reaction mixture ~as stirred for 1 hour, and then the solvent was distilled off from the reaction mixture. To the residue obtained was added water (20 ml.), wllereafter ethyl acetate was added to the solution and then the solution was acidified by adding dropwise lN
hydrochloric acid while shaking. Ethyl acetate layer was separated out, wllereafter the aqueous layer was subjected to extraction witll ethyl acetate and the ethyl acetate extracts ~ere combined. The extract was l~ashed with water and then dried over anhydrous magnesium sulfate. The solvent was distilled off from the solution to obtain the residue ~1.2 g.).
The residue was subjected to column chromatography using silica-gel and elution was conducted with ethyl acet~te cont?.ining 10~ methanol ~500 ml.) to obtain the fr~ctions containing the object compound. The residue obtained by concentrating the eluate was trea-ted with ether to give crystals of 3-[2-(benzo[d]isoxazol-3-yl)-N-benzyloxycarbonyl-glycinamido]lact2cillanic acid ~180 mg.). Mp lS9 to 168C.
The following compound was obtained in substantially the similar manner as aescribcd above.
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1~3:~8 Example 118 3-Aminolactacillanic acid (0.472 g.) was suspended in water (20 ml.), and to the suspension was added sodium bicarbonate (0.420 g.). Acetone (20 ml.) was added to the solution, and the solution was cooled at 0 to 5C~ To the solution was added dropwise an acetone (2 ml.) solution containing phenyl isocyanate (0.286 g.), and then the solution was stirred for 2.5 hrs. at the same temperature. The acetone was distilled off from the reaction mixture, and -~
then the residue obtained was filtered to remove insoluble materials.
The aqueous solution obtained was washed with ethyl acetate, and then adjusted to pH 1 with 10% hydrochloric acid, whereafter, extraction was conducted with ethyl acetate.
The ethyl acetate layer obtained was washed with water and then dried over anhydrous magnesium sulfate. The solvent was distilled off from the solution to give the crystalline residue. The residue was washed with diisopropyl ether and collected by filtration to give crystals of 3-(~'-phenyl-ureido)lactacillanic acid (0.470 g.). Mp 167 to 172C.

Example 119 Guanidinocarbohydrazide dihydrochloride (0.38 g.) was dissolved in water (2 ml.), and to the solution was added sodium nitrite (0,.1~ g.) under cooling at 0 to 5C, and then the solution was stirred for lS minutes to prepare a solution of guanidinocarbonylazide. On the other hand, 3-amino-lactacillanic acid (0.240 g.) was suspended in water (7 ml.), and to the suspension was added sodium bicarbonate (0.170 g.).
The aqueous solution was cooled to 0 to 5C, and to the - ~ ~
.

1~311~3 ` solution was added dropwise the solution of guanidinocarbonyl-` azide prepared above during 10 minutes, and then the reaction mixture was stirred for 2 hrs. The reaction mixture was washed with ethyl acetate (10 ml.) and concentrated until the remaining solution became transparent, and then the ethyl acetate saturated in the aqueous layer was distilled off completely to precipitate crystals. The solution containing the crystals was allowed to stand for a while and the crystals were collected by filtration to give crystals of 3-(guanidinocarbonamido)lactacillanic acid (0.15 g.).
Mp 206 to 210C.
Example 120 A solution containing 2-phenyl-N-(2,2,2-trichloro-ethoxycarbonyl)glycine (1.42 g.) and thionyl chloride (15 ml.) was heated for 1 hour under reflux. The excess of the thionyl chloride was distilled off from the solution under reduced pressure, and the residue obtained was dissolved in acetone~
To the solution was added dropwise a solution containing 3-aminolactacillanic acid (1,0 g.), sodium bicarbonate (0.9 g.), water (40 ml.) and acetone (40 ml.) under cooling at 0 to 5C.
The acetone was distilled off from the reaction mixture under reduced pre~sure, and the remaining solution was washed with ethyl acetate. me solution was adjusted to pH 1 to 2 with 10% hydrochloric acid, and then extracted with ethyl acetate.
The ethyl acetate layer was separated out and dried over anhydrous magne~ium ~ulfate. The solvent was distilled off from the ethyl acetate solution, and the residue (2.1 g.) obtained was dissolved in ether. The ether solution was concentrated to give a residue. The residue was wa3hed with - 153 _ , . ' . : .

1~i31~l~
diisopropyl ether to give crystals of 3-[2-phenyl-N-(2,2,2-` trichloroethoxyc æbonyl)glycinamido]lactacillanic acid (1.69 g.). Mp 130 to 132C (dec.).
The following compounds were obtained in substantially the simil r manner as described above.
R ~
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(I) - 154 _ ~i3~ 3 s- 155 : ! .;

l ~ N ~ ~ . ..
, ~ 1 5~5 ---~ 1~;310~1 ê s 156 . ~ .~
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i3108 Example_131 3-Aminolactacillanic acid (700 mg.) was suspended in dried methylene chloride (15 ml.), and to the suspension was added ~,O-bis(trimethylsilyl)acetamide (3.6 g.), and then the mixture was stirred for 3 hrs. The solution was cooled to -50 to -40C, and to the solution was added all at once 2-(2-pyridylQxy)acetyl chloride hydrochloride (630 mg.), and the reaction mixture was stirred for 20 minutes at the same temperature. Elevating slowly the reaction temperature to -10C during 40 minutes, the reaction mixture was stirred for 1 hour at the same temperature and further for 1 hour under ice-cooling. me methylene chloride was distilled off from the reaction mixture, and to the residue wa~ added a solution containing 5% sodium bicarbonate aqueous solution (25 ml.) and ethyl acetate (30 ml.). The aqueous layer was separated out, and then washed with ethyl acetate. The aqueous layer was adjusted to pH 3 with 10% hydrochloric acid under ice-cooling, and then the aqueous solution was extracted with ethyl acetate. The ethyl acetate layer was separated out, and the remaining aqueous layer was adjusted to pH 1 to 2 with lQ% h~drochloric acid, and then the aqueous solution was extracted with ethyl acetate several times. These ethyl acetate layers and the ethyl acetate layer obtained above were combined, and the solution was washed with a sodium chloride-saturated-aqueous solution, and then dried over anhydrous magnesium sulfate. The solvent was distilled off from the ethyl acetate solution, and the residue (330 mg.) obtained was powdered with ether. The powder was washed with acetone to give crystals of 3-[2-(2-pyridyloxy)acetamido]lactacillanic acid (130 mg.). Mp 192.5 to 193C (dec.).

1~3108 Example 132 A mixture of N,N-dimethylformamide (292 mg.) and - thionyl chloride (710 mg.) was heated for 30 minutes at 50C.
The excess of the thionyl chlc~ride was distilled off from the mixture to give a residue. The residue was washed with ether.
Methylene chloride (7 ml.) was adcled to the residue and then the solution was cooled to 0 to 5C, whereafter a solution prepared by dissolving 2-(5,6-dihydro-2H-pyran-3-yl)glycolic acid (455 mg.) in methylene chloride (5 ml.), was added dro~
wise to the solution. To the reaction mixture was added dropwise a methylene chloride (5 ml,) solution of triethyl-amine (600 mg.) during 10 minutes under cooling at -50C, and the solution was stirred for 30 minutes at the same temperature. The ~olution was added all at once to a mixture of 3-aminolactacillanic acid~(472 mg.), N,0-bis(trimethyl-silyl)acetamide (1.22 g.) and methylene chloride (10 ml), which had been stirred for 2 hrs. at room temperature previously.
The reaction mixture was stirred for 2 hrs. at -50C, and further stirred for 2 hrs., elevating slowly the reaction temperature to 0C. The solvènt was distilled off from the reaction mixture, and to the remaining solution were added a sodium bicarbonate aqueous solution and ethyl acetate. The aqueous layer obtained was adjusted to pH 1 to 2 with lO~o hydrochloric acid, and then the solution was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate, and then the solvent was distilled off from the extract to give crystals of 3-[2-(5,6_ dihydro-2H-pyran-3-yl)glycolamido~lactacillanic acid (80 mg.).
I.R. absorption spectrum, v cm 1 (Nujol) : 1740, 1685, 1660.

3:108 Example_133 To the solution o~ methylene chloride (10 ml.) containing ethyl chloroformate (216 mg.) was added dropwise a mi~ture of 2-(2-bromoacetamido)-2-p]lenylacetic acid ~576 mg.), S triethylamine (200 mg.), N,N-dimethylbenzylamine (one drop) and methylene chloride (8 ml.) under cooling at -30C, and then the reaction mixture was stirred for 30 minutes at the same temperature. ~ mi~ture of 3-aminolactacillanic acid (~72 mg.)9 N,0-bis(trimethylsilyl)acetamide (1.2 g.)9methylene chloride (10 ml.) and N,N-dimethylforamide (1 ml.), which had been stirred for a while at room temperature and cooled to OC was added all at once to the reaction mixture, keeping the temperature of the reaction mixture at -30C. The reaction mixture was stirred for 2 hrs. at -25C and then stirred for 1 hour, elevatin~ slol~ly the reaction temperature to 0C.
The reaction mixture was concentrated, and to the residue obtained were added ethyl acetate and water. ~nd then the mixture was adjusted to p~l 1 to 2 with 10~ hydrochloric acid.
The ethyl acetate layer was separa~ed out, washed with water, dried over anhydrous magnesium sulfate and then concentrated.
The residue obtained was washed with diisopropyl ether, and then powdered with ethyl acetate to give 3-[2-~2-bromoacet-amido)-2-phenylacetamido]lactacillanic acid (400 mg.).
Further, the same compound (188 mg.) was recovered from the mother liquor. Total yield was 588 mg. Mp 156 to 161C
(dec.).
The following compounds were obtailled in substantially the similar manner as described above.
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1~3i~8 Example 1~1 A mixture of N-phenylimiclinodiacetic acid (537 mg.), N,N'-dicyclohexylcarbodiimide ~495 mg.~, chloroform (9 ml.) and dioxane (3 ml.) was stirred for 1.5 hrs. under ice-cooling.
The insoluble materials were filtered off from the solution, and to the filtrate was added all at once a mixture of 3-aminolactacillanic acid (~72 mg.), methylene chloride (10 ml.) and N,0-bis(trimethylsïlyl)acetamide ~1.2 g.), and then the reaction mixture was stirred for ~ hrs. at room temperature The solvent was distilled off from the reaction mixture, and the residue was dissolved in ethyl acetate a and to the solution was added a sodium bicarbonate aqueous soiution. The mixture was adjusted to pH 4.0 with 10~. hydrochloric ~cid, and the ethyl acetate layer was separated out. The remaing a~ueous layer was adjusted to pH 1 to 3 with lO~o hydrochloric acid, and the aqueous solution was extracted with ethyl acetate.
The ethyl acetate layers were combined, washed with water and dried, and then the solvent was distilled off from the solution to give crystals of 3-(N-carboxymethyl-N-phenylglycinamido)-lactacillanic acid (260 mg.). ~lp 142.5 to 145C ~dec.).

Example 142 A solution, prepared by dissolving 2- E4- (3~
bromopropoxy)phenyl]acetic acid (300 mg.) and thionyl chloride (300 mg.) in chloroform (2 ml.), was heated for 2 hrs. under reflux. The solvent and the excess of the thionyl chloride were distilled off from the solution and the residue obtained was dissolved in dried acetone (1 ml.). The solution was added dropwise to a solution, prepared by dissolving 3-amino-lactacillanic acid (240 mg.) and sodium bicarbonate (210 mg.) . .

1~63~0~

in a mixture of water (10 ml.) and acetone (10 ml.), under cooling at 0 to 5C while stirring. The reaction mixture was stirred for 45 minutes at the same temperature. The acetone was distilled off from the reaction mixture, and to the remaining aqueous layer was added ethyl acetàte (30 ml.).
The mixture was adjusted to p~l 1 with 10~ hydrochloric acid.
The ethyl acetate layer was separated out, and then the aqueous layer was extracted with ethyl acetate (20 ml.). The ethyl acetate layers were combined and washed with a sodium chloride-saturated-aqueous solution, and then dried over anhydrous magnesium sulfate. The solvent was distilled off from the solution, and the residue (510 mg.) obtained was washed with ether to give crystals o~ 3-[2-{~-(3-bromopropoxy)-phenyl}acetamido]lactacillanic acid (420 mg.). Mp 120 to lS 123C (dec.).

The following compounds were obtained in substantially the similar manner as aescribed above.

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1~31~3 Example 148 A mixture of 3-aminolactacillanic acid (472 mg.), N,0-bis(trimethylsilyl)acetamide (1.2 g.), methylene chloride (10 ml.) and N,N-dimethylformamide (1 ml.) was stirred for 1 hour at room temperature. The solution was cooled to 0 to 5C, and to the qolution was addecl dropwise a methylene chloride (3 ml.) solution containing hexadecanoyl chloride (548 mg.), whereafter the reaction mixture was reacted for 1.5 hrs. at the same temperature and further for 30 minutes at ambient temperature. The reaction mixture was concentrated, and to the remaining solution were added ethyl acetate and water, and then the mixture was adjusted to pH 1 to 2 with 10% hydrochloric acid. The èthyl acetate separated out was washed with water and then dried over anhydrous magnesium ~ulfate. The solution was concentrated to give crude 3-hexadecanoylaminolactacillanic acid (0.~5 g.). Furthermore, the product (600 mg.) was subjected to column chromatography uAing silica gel and elution was conducted with ethyl acetate.
The solvent was distilled off from the eluate to give the purified object compound (110 mg.). l~p 157 to 161C (dec.).
Exam~le 149 To a solution of 2-~N-(2-thenyliden)aminoc~y]-2-phenylacetic acid (400 mg.~, triethyl amine (155 mg.) and tetrahydrofuran (10 ml.) wa~ added dropwise a solution,;
prepared by di~solving pivaloyl chloride (1~34 mg.) in tetrahydrofuran (3 ml.), during 5 minutes under cooling at -2 to 0C, and the mixture was stirred far 30 minutes.
The solution was aclded all at once to a solution of 3-aminc~
lactacillanic acid (320 mg.), ~,0-bis(trimethylsilyl)-' '., ' ~,~

': :

~3:~08 acetamide (825 n~.) and methylene chloride (10 ml.) under cooling at -30C ~ and the reaction mixture was reacted for 2,5 hrs., elevating slowly the reaction temperature to 10C.
The solvent was distilled off from the reaction mixture, and to the remaining solution were added a sodium bicarbonate aqueous solution and ethyl acetate. The aqueous layer separated out waq adjusted to pH 1 to 2 with 10~/o hydrochloric acid and then extracted with ethyl acetate. The extract was washed with water and dried, and then the solvent was 10 distilled off from the solution to give residues ( 300 mg.).
The residues were dissolved in acetone and then sodium 2-ethylhexanate was added to the solution to give crystals of 3- r2-~N-(2-thenyliden)aminooXy~-2--phenylacetamido]lactacillanic acid sodium salt (160 mg.).
I.R. absorption spectrum, Vcm~l (~ujol): 1730, 1650, 1600.
Example 150 3-Aminolactacillanic acid (355 mg.), N, ~bis~(tri-methylsilyl)acetamide (0.92g.) and N,N-dimethylformamide 20 (0.23 ml.) were added to methylene chloride (7 ml.), and the solution was stirred for 2 hrs. at room temperature.
On the other hand, 2-(2-nitrophenoxy)-2-phenoxyacetic acid (380 ~ .), triethylamine (132 mg.) and N,N-dimethylbenzyl-amine (2 drops) were dissolved in methylene chloride (10 ml.), and the solution was cooled, to -30Co To the solution was added dropwise ethyl chloroformate (141 mg.), and the mixture was stirred for 40 minutes at the same temperature. To this solution was added the solution prepared above quickly, and the reaction mixture was stirred for 5.5 hrs. at -40 to -20C.

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1~i3:1~8 The solvent was distilled off from the reaction mixture under reduced pressure, and into the residue were poured ethyl acetate and a sodium bicarbonate aqueous solution. The aqueous layer separated out was adjusted to pH 1 to 2 with 10~/o hydrochloric acid, and then the mixture was extracted with ethyl acetate.
The extract was washed with a sodium bicarbonate-saturated-aqueous ~olution and dried over anhydrous magnesium sulfate, and then the solvent was distilled off from the solution.
The residue (540 mg.) obtained was dissolved in a small amount of acetone and sodium 2-ethylhexanate was added to the solution.
To the solution was added ether, and the precipitating crystals were collected by filtration and washed with a mixed solvent of ether and acetone to give crystals of 3-~2-(2-nitrophenoxy)-2-phenoxyacetamido]lactacillanic acid sodium salt (380 mg.). Mp 169 to 172C (dec.).
The following compounds were obtained in substantially the similar manner as described above.

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Example 175 2- [4-~3-(4-Nitrophenylthio)propoxy~phenyl]acetic acid (260 mg.~ and thionyl chloride (300 rr~.) were dissolved in chloroform (10 ml.), and the solution was heated for 2 hrs.
under reflux. The chloroform and the excess of the thionyl chloride were distilled off from the reaction mixture under reduced pressure, and the residue abtained was dissolved in acetone (1 ml.). The acetone solution was added dropwise to a solution of 3-aminolactacillanic acid (180 mg.), sodium bicarbonate (160 mg.), water (5 ml.) and acetone (5 ml.) under cooling at 0 to 5C, and then the reaction mixture was stirred for 45 minutes at the same temperature. The acetone was distilled off from the reaction mixture under reduced pressure, and into the residue obtained was poured ethyl acetate (40 ml.), and then the solution vas adjusted to pH 1 with 10% hydrochloric acid. The ethyl acetate layer was separated out, and the remaining aqueous layer was extracted with ethyl acetate (20 ml.). The ethyl acetate layers were conibined, washed with a sodium chloride aqueous solution and 20 dried over anhydrous magne~ium sulfate. The solvent was distilled off frQm the solution to give crystals of 3-[2-[4-~3-(4-nitrophenylthio)propoxy~phenyl]acetamido]lactacillanic acid (400 mg.). Mp 142 to 146C (dec.).
Example 176 A dried tetrahydrofuran solution (10 snl.) containing 2- [2-(2-naphthoxy)acetamidoc~xy]-2-phenylacetic acid (351 mg.) and triethylamine (101 mg.) was cooled to -10C, and to the solution was added dropwise a dried tetrahydrofuran solution (5 ml.) containing pivaloyl chloride (120 mg.), and the -- 173 _ ~0~31al8 mixture was stirred for 1 hour at the same temperature. The solution was cooled to -30C, and to the solution was added all at once a dried methylene chloride (5 ml.) containing 3-amino-lactacillanic acid (236 mg.) and N,O-bis(trimethylsilyl)-acetamide (600 mg.), and the reaction mixture was stirred for 1 hour at -10C and for 1 hour at 0C. The solvent was diqtilled off from the reaction mi~:ture under reduced pressure, and into the residue was poured a sodium bicarbonate-saturated-aqueous qolution. The aqueous solution was washed with ethyl acetate, adjusted to pH 1 to 2 with 1~% hydrochloric acid and then extracted with ethyl acetate. The extract was washed with water and a sodium chloride-saturated-aqueous solution, ' respectively, and then dried over anhydrous magnesium sulfate.
The solvent was diQtilled off from the solution, and the residue obtained was powdered with ether to give crystals of 3-[2-~2-(2-naphthoxy)acetamidooxy~-2-phenylacetamido]-lactacillanic acid (340 mg.). Mp 109 to 112C (dec.).
Example 177 2-[2-Oxo-3-(2-phenylacetamido)-1-azetidinyl]-3-methyLbutyric acid (455 mg.), triethylamine (151 mg.) and N,N-dimethyLbenzylamine (2 drops) were added to methylene chloride (10 ml.), and the solution was cooled to -30C. The solution was added dropwise a methylene chloride (5 ml.) solution containing ethyl chloroformate (163 mg.). The solutio~ was cooled to -40C, and to the qolution was added all at once a solution, prepared by dissolving 3-aminolactacillanic acid (389 mg.), N,O-bi~(trimethylsilyl)acetamide (1.0 g.) and N,N-dimethylformamide (0.25 ml.) in methylene chloride (10 ml.) and then by stirring the solution for 3 hrs. at room - 174 _ ~ i31~8 temperature. The reaction mixture was reacted for 1.5 hrs.
under stirring. The solvent was distilled off from the reaction mixture, and to the residue were added ethyl acetate and a sodium bicarbonate aqueous solution, and then the aqueous layer was separated out. The aqueous layer obtained was adjusted to pH 1 to 2 with l~-hydrochloric acid, and extraction was carried out by adding ethyl acetate to the solution. The ethyl acetate layer was separated out, and the remaining aqueous layer was also extracted with ethyl acetate. These ethyl acetate layers were combined, washed with a sodium chloride-saturated-aqueous solution and dried over anhydrous magnesium sulfate. The solvent was distilled off from the solution, and the powder (480-mg.) obtained was washed with ether to give crystals of 4-[2 ~ 2-Qxo-3-(2-phenylacetamido)-1-azetidinyl~-3-methylbutyramido]lactaci~lanic acid (359 mg.).
Mp 160 to 164C (dec.).
The following compounds were obtained in substantially the similar manner as described above.

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3~ 8 Example 188 2-Methyl-5,6-dihydro-1,4-oxathiin-3-carboxylic acid (0.320 g.) was dissolved in chloroform (10 ml.). To the solution was added a dried methylene chloride solution (5 ml.) containing thionyl chloride (7 ml.), and the mixture was heated for 4 hrs. under reflux, and then concentrated to give a solution of an acid chloride of a 2-methyl-5,6-dihydro-1,4-oxathiin-3-carboxylic acid. On the other hand, 3-amino-lactacillanic acid (0.236 g.) was suspended in dried methylene chloride (20 ml.), and ~,0-bis(trimethylsilyl)acetamide (1.50 g.) was added to the suspension, and then the mixture was stirred for 4 hrs. at ambient temperature. To the solution obtained was added dropwise the acid chloride solution prepared above under cooling to -5 to 0C, and the mixture was stirred for 2 hrs. at the same temperature, and further stirred for 50 hrs. at ambient temperature. The reaction mixture wa~ concentrated under reduced pressure to give a residue. Ethyl acetate and a sodium bicarbonate aqueous solution were poured into the residue and the mixture was stirred enough, whereafter the aqueous layer was separated out.
The aqueous layer was washed with ether, and adjusted to pH 1 to 2 with diluted hydrochloric acid, and then the solution was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate.
The solven~ was distilled off from the solution to give a powder. Hot ethyl acetate (5 ml.) was added to the powder, and an insoluble material in the mixture was collected by filtration to give crudè 3-(2-methyl-5,6-dihydro-1,4-oxathiin-3-carbonylamino)lactacillanic acid (240 mg.).
This product was recrystallized from acetone to give the . ,. , ~ -~S31C~8 purified object compound (172 mg.). Mp 172.5 to 175.0C
(dec.).
Example 189 3-Aminolactacillanic acid (0.708 g.) was suspended in dried methylene chloride (20 ml.). To the suspension was added ~,O-bis(trimethylsilyl)acetamide (2.0 g.), and the mixture was stirred for a while to dissolve it. On the other hand, ~-[4-(3-benzyloxycarbonyl-5-oxo-1,3-oxazolidin-4-yl)butyryl]succinimide (1.212 g.) was dissolved in dioxane (15 ml.), and the solution was cooled to 0 to 5C. To the solution was added dropwise the solution obtained above, and the mixture wa~ stirred for 6 hrs. at the same temperature.
The reaction mixture was concentrated under reduced pressure to give a residue, and 5% sodium bicarbonate aqueous solution and ethyl acetate were added to the residue. The aqueous layer was separated out and washed with ethyl acetate twice.
The aqueous ~olution was adjusted to pH 1 to 2 with diluted hydrochloric acid and then extracted with ethyl acetate.
The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off from the solution, and the oily material (0.470 g.) obtained was subjected to column chromatography using silica gel (l0 g.).
An elution was conducted with a mixture of ethyl acetate and methanol (volume ratio, 50 : 1), and the fractions containing the object compound were collected. These fractions were combined, and the solvent was distilled off from the solution t;o give 3-r4-(3-benzyloxycarbonyl-5-oxo-1,3-oxazolidin-4-yl)-butyramido~lactacillanic acid (0.100 g.).
I.~. albsorption spectrum, ~ cm~l (~ujol) : 1730, 1720, 1700-1680, 1650.

Si3:~L08 Example 190 3-Aminolactacillanic acid ~472 mg.), 2-(2-propionyl-phenoxy)acetic acid (458 mg.), and ethyl chloroformate (238 mg.) was treated in substantially the s:imilar manner as described in Example 109 to give 3-[2-(2-propionylphenoxy)acetamido]-lactacillanic acid (40 mg.). Mp 114 to 118C ~dec.).
Example 191 3-Aminolactacillanic acid (0.236 g.), 2-[4-~4-chloro-N-(2,2,2-trichloroethoxycarbonyl)anilinomethyl~-phenoxy]-2-methylpropionic acid (0.610 g.) and thionyl chloride (7 ml.) were treated in substantially the similar manner as described in Example 120 to give 3-[2-[4-~4-chloro-N-(2,2,2-trichloroethoxycarbonyl)anilinomethyl}-phenoxy]-2-methylpropionamido]lactacillanic acid (450 mg.), Mp 76 to 82C (dec.).

1~i3108 Example 192 ~ Methoxycarbonyl-2-methyl-1-propenyl)-3-phenoxyacetamido-2-azetidinone (1.0 g.) was dissolved in methylene chloride (40 ml.). To t:he solution was added N,N-dimethylaniline (0.55 g.), ancl the solution was cooled to -35 to -30C. Phosphorus pent~chloride (0.94 g~) was added to the solution all at once under stirring, and then the reaction mixture was stirred for 1.5 hrs. at the same temperature. Methanol (0.9 g.) was added to the reaction mixture, and then the solution was stirred for an hour at the same temperature. Elevating the reaction temperature to 0 to 5C, water (0.6 ml.) was added to the solution, and the solution was stirred for an hour. The reaction mixture was extracted with water three times (total volume: 10 ml.), and these aqueous extracts were combined and adjusted to about pH 7 with sodium bicarbonate. The aqueous solution was washed with ethyl acetate (10 ml.) and ethyl acetate (5 ml.) respectively.
The aqueousilayer was salted out with sodium chloride and then extracted with chloroform (8 ml.) seven times. These chloroform extracts were combined and dried over anhydrous magnesium sulfate, and the solvent was dis-tilled off from the solution to give crystals of 3-amino-1-(1-methoxycar~onyl-2-methyl-1-propenyl)-2-azetidinone (0.34 g.).
A part of this product was treated with p-toluen sulfonic acid in a conventional manner to give p-toluensulfonic acid salt of an object compound. Mp 169 to 171~C (dec.).
Example 193 l-(l-Carboxy-2-methylpropyl)-3-phenylacetamido-1~63 1 ~8 2-azetidinone (1.52 g.) and N,N-dimethylaniline (2.15 g.) were suspended in methylene chloride (12 ml.), and to the suspension was added trimethylsilyl chloride (0.88 g.).
The solution was stirred for 30 minutes at ambienttemperature and cooled to -50C. Phosphorus pentachloride (1.1 g.) was added to the solution and the solution was stirred for 2 hrs. (the reaction temperature wais elevated to about -30C.
during the stirring.) The solution was cooled to -50C, and n-butyl alcohol (1.85 g.) was added to the solution, and then the solution was stirred for 2 hrs. (in this time, the reaction temperature was elevated to about -30C). The solution was cooled again to -50C, and a solution prapared by dissolving sodium bicarbonate (1.3 g) in water (15 ml.) was added to the solution (in this time, the reaction tempera-ture was elevated to about -25C, and the solution indicated about pH 3). The solution was adjusted to pH 4 with sodium bicarbonate, and then the aqueous layer was separated out and washed with ether. The solution was evaporated to dryness under reduced pressure, ~eeping the temperature of the solution under 25C. To the residue obtained was added isopropyl alcohol (15 ml.), and the mixture was filtered to ~btain an insoluble material and a filtrate. The filtrate was evaporated to dryness under reduced pre~sure. This operation was repeated twice to give colorles~ powdery 3-amino-1-(1-carboxy-2-methylpropyl)-2-azetidinone (0.3 g.). These in~oluble materials in isopropyl alcohol obtained above were combined and dissolved in a small amQunt of water, and the solution was adjusted to pH 2.5 with l~-hydrochloric acid. The aqueous solution was evapo-rated to dryness under reduced pressure at 25C, and the - 183 _ 31(3 ~
residue obtained was treated with isopropyl alcohol in the similar manner a~ described above to recover an object compound (0.13 g.). Total yield was 0.43 g. This product was treated in a conventional manner to give its salt of D-camphor-10-sulfonic acid, and the salt was recrystallized from a mixture of acetone and ether to give D-camphor-10-sulfonic acid salt of the object compound. Mp 178 to 183C.
Exa~E~e 194 - 3-[2-~4-(3-Benzamido-3-carboxypropoxy)phenyl~-2-(3-phenylthioureido)acetamido]lactacillanic acid (7.2 g.) was dissolved in acetic acid (20 ml.), and to the solution was added dropwise concentrated hydrochloric acid (2 ml.) under cooling while stirring. The reaction mixture was ~tirred ~or 1.5 hrs. and poured into a mixture of ice-water (50 ml.) and ethyl acetate (50 ml~).
The mixture was separated into an ethyl acetate layer and an aqueous layer. The ethyl acetatè layer was extracted with ice-water (20 ml.). This aqueous layer and the aqueous layer obtained above were combined, and washed with ethyl acetate (20 ml~. To the aqueous layer was added a weak basic anion-exchange resin, Amberlite IR-45 (OH type) (trademark, maker: Rohm and Haas Co. Ltd.,) (60 ml.), and the mixture was stirred under ice-cooling, and then filtered.
The resin was washed with ice-water (10 ml.), and then the washing and the filtrate were combined, and concentrated under reduced pre~sure to obtain a residue. Methanol was added to the residue, and then the residue was collected by filtration. The residue was washed with acetone to give 3-aminolactacillanic acid. (0.59 g.). Mp 203 to 206C (dec.).

- 184 _ ~3:1~8 I.R. absorption spectrum, cm 1 (~ujol) : 1763, 174 N.M.R. absorption spectrum, ppm (D20+NaOD) : 2.89 (lH, d,d, J=3Hz, 6Hz) 3.79 (lH, t, J=6Hz) 4.22 (IM, d,d, J=3Hz, 6Hz) 5.26 (~, s) 6.91 (2H, d, J=9Hz) 7.23 (2H, d, J=9Hz) Example 195 3-(2-Phenylacetamido)lactacillanic acid was treated in substantially the similar manner as described in Example 193 to give 3-amino-lactacillanic acid, which was identified by comparing an I.R. absorption spectrum, a N.M.R. absorption spectrum and a melting point with an authentic sample.
Example 196 3-[2-[4-~3-(3-Phenylthioureido)-3-carboxypropoxy3-phenyl]-2-(3-phenylthioureido)acetamido]lactacillanic acid (1.44 g.) was suspended in water (10 ml.), and to the suspension was added anhydrous potassium carbonate (0.56 g.).
The solution (pH 9) was stirred for 27 hrs. at 30C, and then was filtered. Filtrate was diluted by adding ethanol (50 ml.) and the solution was allowed to stand under ice-cooling to give à precipitate. The precipitate was filtered off, and the filtrate was concentrated under reduced presRure to give a residue. The residue was adjusted - 185 _ 1~3~Q8 to pH 2 with 5% hydrochloric acid, and then washed with ethyl acetate. The solution was acljusted to pH 7.5 with sodium carbonate, and then evaporated to dryness under reduced pressure to obtain the powcler (0.75 g.).
Water (7 ml) was added to the powder, and an insoluble material in the water was collecteal by filtration and washed with water to give 3-aminolactacillanic acid (40 mg.).
The filtrate and the washing were combined, and the combined solution was treated with an activated carbon to give crùde crystals of 3-aminolactacillanic acid (123 mg.).
These object compounds were combined and suspended in 30~O
aqueous methanol solution. The suspension was stirred for an hour, and, then filtered to give the purified crystals of 3-aminolactacillanic acid (133 mg.), which was identified by com~
paring an I.R. absorption spectrum, a N.M.R. absorption spectrum and a melting point with an authentic sample.
Example 197 3-[2-~-{3-(3-Phenylthioureido)-3-carboxypropoxy~-phenyl]-2-(3-phenylthioureido)acetamido]lactacillanic acid (0.36 g.) was dissolved in methanol (3 ml.), and concentrated hydrochloric acid (0.1 ml.) wa~ added to the solution under ice-cooling, and then the reaction mixture was stirred for 30 minutes.
Sodium bicarbonate (0.08 g.) was added to the reactionimixture, and the solution ~las stirred for 10 minutes. Ice-water (10 ml.) was poured into the solution, and the solution was filtered to remove precipitating crystals. ~he filtrate was washed with ethyl acetate! (10 ml.) and evaporated to dryness under reduced pressure. Methanol wa~ added to the residue to give crystals and the crystals were collected by 31~8 filtration to give 3-aminolactacillanic acid (10 mg.). The mother liquor was concentrated to recover an object compound (80 mg.), which wa~ identified by comparing an I.R. absorption spectrum, a ~.M.R. absorption spectrum, and a melting point with an authentic sample.
Example 198 3-[2-[4-~3-(3-Phenylthioureido)-3-carboxypropoxy~-phenyl]-2-(3-phenylthioureido)acetamido]lactacillanic acid (0.50 g.) was dissolved in 2,2,2-trifluoroacetic acid (4 ml.), and the solution was stirred for an hour under ice-cooling.
The reaction mixture was poured into ice-water (about 10 ml.), and the solution was washed with ethyl acetate (10 ml.) twice.
The aqueous solution was adjusted to pH 4 with a weak basic anion-exchange resin, Amberlite IR-45 (OH type) (trade mark maker, Rohm and Haas Co. Ltd.,) (9.5 ml.), and the resin was filtered off from the mixture, and then the filtrate was concentrated to give residues. Methanol was added to the residueq to give cry~tals, which were collected by filtration to give 3-amino-lactacillanic acid (30 mg.). This product was identified by comparing an I.R. absorption spectrum; a ~.M.R.
absorption spectrum, and a melting point with an authentic sample O
Exa~le 199 3-[2-~4-(3-Acetamido-3-carboxypropoxy)phenyl~-2-(3-phenylthioureido)acetamido]lactacillanic acid (0.67 g.`) was dissolved in acetic acid (6.7 ml.), and to the solution was added all at once concentrated hydrochloric acid (0.15 ml.) under water-cooling while stirring, and then the reaction - 187 _ 1~i3108 mixture was stirred for an hour. The reaction mixture was treated in substantially the similar manner as described in Example 198 to give 3-aminolactacillanic acid (90 mg.), which was identified by comparing an I.R. absorption spectrum and a ~.M.R. absorption spectrum with an authentic sample.
Example 200 3-[2-~4-[3-Carboxy-3 ~ ~-ethoxy(thiocarbonyl)-aminopropoxy}]phenyl]-2-~N-ethoxy(thiocarbonyl)amino~aceta~ido]-lactacillanic acid was treated in substantially the similarmanner as described in Example 199 to give 3-aminolactacillanic acid.
Exa~ple 201 3-[2-[4-~3-(3-Phenylthioureido)-3-carboxypropoxy~-phenyl]-2-(3-phenylthioureido)acetamido]lactacillanic acid (2.28 g.) waq dissolved in ace-tic acid (6 ml.), and to the solution was added dropwise a mixture of concentrated hydrochloric acid (0.45 ml.) and acetic acid (6 ml.) during 15 minutes under water-cooling while stirring. Furthermore, the reaction mixture was stirred ~or 15 minùtes, and;ethyl acetate (25 ml.) and water (25 ml.) were added to the reaction mixture, whereafter the mixture was stirred. The ethyl acetate layer separated out was extracted with water (10 ml.).
Thi~ extract and the aqueous layer obtained above were com~
bined, and the combined aqueous solutïon was washed with ethyl acetate and adjusted to pH 3.4 with a weak basic anion-exchange resin, Amberlite I.R. -45 (OH type) (trade mark, maker: Rohm and Haas Co., Ltd.) (15 ml.). The resin was ~ 31~8 filtered off from the mixture, and the filtrate was con-centrated under reduced pressure to give residues.
Methanol was added to the residues to give crystals, which were collected by filtration to give 3-aminolactacillanic acid (0.25 g.). This product was identified by comparing an I.R. absorption spectrum, a N.M.R. absorption spectrum, and a melting point with an authent:ic sample.
Example 202 3-[2-{4-(3-Benzamido-3-carboxypropoxy)phenyl ~ 2-~2-nitro-4-methoxycarbonylanilino)acetamido]lactacillanic acid (1.54 g.) was dissolved in a mixture of water (10 ml.) and methanol (20 ml.), and to the ~olution~was added 1~
palladium carbon (500 mg.) as a catalyst. The solution was stirred for 2 hrs. in hydrogen atmosphere under increased pressure using a middle-pressure reduction apparatus at ambient temperature, After the reaction was completed, the catalyst wa~ filtered off, and the m~thanol was distilled off from the filtrate under reduced pre~sure. The remaining solution was washed with ethyl acetate and cooled. Acetone was added to the solution to give precipitating crystals, which were collected by filtration to give 3-aminolactacillanic acid (83 mg.). Furthermore, the mother li~uor was evaporated to dryness under reduced pressure, and the residue obtained was washed with methanol to give crystals. The crystals were collected by filtration to give an o~ject compound (50 mg.). Total yield was 123 mg. This product was identi-fied by comparing an I.R. absorption spectrum and a ~.M.R.
absorption spectrum with an authentic ~ample.

1~i31(1 8 Example 203 3-[2-C4-~3-(2-Nitro-4-methoxycarbonylanilino)-3-carboxypropoxy}phenyl~-2-t2-nitro-4-methoxycarbonylanilino)-acetamido]lactacillanic acid was trleated in substantially the similar manner as described in Example 202 to give 3-aminolactacillanic acid.

Example 204 3-[2-{4-(3-Acetamido-3-carboxypropoxy)phenyl~-2-~3-(1-naphthyl)thioureido}acetamido]lactacillanic acid (2.5 g.) was dissolved in acetic acid (10 ml.), and to the solution was added concentrated hydrochloric acid (0.56 ml.) under water-cooling while stirring. The reaction mixture was stirred for 30 minutes, and then poured into a mixture of ice-water (10 ml.) and ethyl acetate (20 ml.), and the aqueous layer was separated out~ The remaining ethyl acetate layer was extracted with ice-water (10 ml.~. The aqueous layers were combined and washed with ethyl acetate (10 ml.).
A weak basic anion-exchange resin, Amberlite IR-4S (OH type) (trade mark, maker Rohm and Haas Co., Ltd.~ (15 ml.) was added to the solution, and then the mixture (pH 3.4) was stirred for S minutes. The resin was filtered off from the mixture and washed with ice-water (5 ml.). The filtrate and the washing were combined and concentrated to give residues.
The residues were washed with methanol to give crystals. The crystals were collected by filtration to give 3-amino-lactacillanic acid (149 mg.). Furthermore, the mother liquor was concentrated, and the residue obtained was washed with methanol to recover an object compound (80 mg.). Total yield `~`
was 229 mg. This product was identified by comparing an I.R.

1~ii3:~8 absorption spectrum and a N.M.R. absorption spectrum with an authentic sample.

Example 205 3-[2-~4-[3-Carboxy-3-~3-(1-naphthyl)thioureido~-propoxy]phenyl]-2-{3-(1-naphthyl)thioureido}acetamido]-lactacillanic acid (2.6 g.) was reacted in substantially the similar manner as described in Example 204 to give 3-aminolactacillanic acid ~190 mg.), which was identified by comparing an I~Ro absorption spectrum and a melting point with an authentic sample.

~ . . ,, . :.

-~31~8 Example 206 3-(2-Phenylacetamido)-2-azetidinone (816 mg.) and benzyl 2-bromo-2-phenylacetate (1.2~ g.) were dissolved in N,N-dimethylformamide (20 ml.), ancl to the solution was added sodium hydride (50~O oily) (210 mg.) in nitrogen atmosphere under ice-cooling while stirring, and then the reaction mix-ture wal3 stirred for an hour at the! same temperature. Ethyl acetate (150 ml.) was added to t~e reaction mixture, and the solution was washed with water, a sodium bicarbonate-saturated-aqueous solution and water respectively, and the mixturedried over anhydrous magnesium sulfate. The solution was evaporated to dryness under reduced pressure to give the yellow oily material (1.7 g.?. The material was subjected to column chromatography using silica.gel (developer : ~
chloroform to give two isomers of l-(~-benæyloxycarbonylbenzyl)-3-(2-phenyl)acetamido-2-azetidinone. Yield of the isomer A
is 26 mg. and of the isomer B is 65 mg.
Physical con~3tant of isomer A:
Oil - Mass spectrum, m/`e = 428 (M+) I.R. absorption '3pectrum, ~ cm 1 (CHC13) : 1760, 1740 (shoulder), 1678.

N.M.R. absorption spectrum, ~ppm (CDC13) : 3.46 (2H, m), 3.55 t2H, s), 4.96 (lH, m), 5.15 (2H, s), 5.61 (lH, q), 6.37 (lH, d, J=8Hz), 6.90 - 7.60 (15H, m).
Phy~3ical constant of i30mer B:
Mp: 96 to 98C.

1~i3108 Mass spectrum, mJe = 428 ~M~) I.R. absorption spectrum ~ cm 1 (Nujol) : 1750, 1732, 1680 N.M.R. absorption spectrum:
~ppm (CDC13) : 3.03 (IH[, d,d, J=3Hz), 3.53 (2H, s), 3.85 (lH,d,d, J=5Hz, 5 Hz), 4.88 (lH,m), 5.17 (2FI,s), 5.62 (lH,s), 6.05 (lEt,d, J=8Hz), 7.00 - 7.60 (15H, m).
The following compounds were obtained in sub-stantially the ~imilar manner as described above.

~-A' (I ) i31~3 s- 194 ~ ,~ ~ ~ ~ ~ ' E ' 13 . Z ` r~ ~D N

U E o ~ E E ~ 1` E _ ~ ~1 ` E _ ~ 1~ N '~1 Q. C~ ~:1 C~ ~ O U-)~ O 05~
1~ I t ~ n~ ~
c~ ~::D ~D
O ~ N ~ o g . *~ ~o~
*c~-~. ~ 8 _ , _ . _ ........... . . . _ o~ o o X . ~ . . ...... _ - ~ lcll~

I~ ~r ~ r~ 9i O ~ O C~o~
1~ ~ ~ ~ ~ ~9 CO ~ l ~ . ,~ ~
. ~r ~ . . ~ ~ u~ In 00 ~r ~; I ~ ~ o ~J r~
. ~ . ~ ~ , ,t , .
_ _ tn _ -- E~ D l l _ H
~: m ~n ~ m ~ u~ ~ ~r ~ m 1`
h ~1 ~1 h ~ ~ _ _ _ o ~1 h ~1 ,1 . E~ ~ E~ ~ mX ~ E~ ~
,~ u~ ,u~ ,~ n ,~ ~1 . . ~
~ ~
O ~D
~, o ~:C o ~ ~ .
l #C.~ C C~ ' . .

_1 ,1 ~1 ~ ~ ' ~`I . ~ . ~ ~1 ~1 ~
... ~ _ ._ l : - .. ~

310B s- 196 C~ -,_ _ ~_ E~

5~

. . ~ .
.q C`~ ~

~.--~ ~, ~ ` ''"' ''.
. , ~ .5:~: .~C) '"'` "" '' ' :1: ~ . R o o R ~ 5 o ~D ~D R ~ô R
~ O ~ ~ :

æ ~:
. _ .

~, l ~ .
. . ' _ .
.

~ . . . .

~ S310B

Example 217 3-(2-Phenylacetamido)-2-azetidinone (610 mg.), methyl 2-bromo-2-(3-nitrophenyl)acetate (900 mg.) and anhydrous potassium carbonate (460 mg.) were added to ethyl methyl ketone (60 ml.), and the solution was heated for 8 hrs. under reflux while stirring. The reaction mixture was cooled and then poured into ice-water, whereafter the mixture was extracted with ethyl acetate. The extract was washed with a sodium chloride-saturated-agueous solution, and then dried over anhydrous magnesium sulfate. The solution was evaporated to dryness, and the oily residue obtained was subjected to column chromatography. The fractions, eluted with a mixture of chloroform and methanol (100:~), was subjected to thin layer chromatography using silica.gel ~ developer : a mixed solvent of chloroform and methanol (40:1)] to give a mixture of two isomers of l-(~-methoxycarbonyl-3-nitrobenzyl)-3-(2-phenyl-acetamido)-2-azetidinone (7.5 mg.).
I.R. absorption spectrum, ~ cm 1 (CHC13) : 1765, 1745, 1680.

Exam~le 218 3-(2-Phenylacetamido)-2-azetidinone (612 mg.) and methyl 2-bromo-2-(4-methylthiophenyl)acetate (825 mg.) were dissolved in N,N-dimethylformamide (20 ml.). Keeping a temperature of the solution at 20 to 30C, a benzene (20 ml.) solution of sodium N,N-bis(trimethylsilyl)amine (546 mg.) was added to the solution during an hour in nitrogen atmosphere, and the reaction mixture was stirred ~or 15 minutes at the same temperature. Ethyl acetate (150 ml.) was added to the re~lction mixture, and the ethyl acetate 1~3~C1 8 layer was washed with wàter, a sodium bicarbonate-saturated-aqueous solution and water respectively, and then dried over anhydrous magnesium sulfate. The solvent was distilled off from the solution to give the oily residue (1.2 g). The residue was subjected to column chromatography using silica.
gel (developer : chloroform) to give two isomers of 1~
methoxycarbonyl-4-methylthiobenzyl)-3-phenylacetamido-2-azetidinone. Yield of the isomer A: 10 mg, mp 115 to 117C
(dec.): Yield of the isomer B: 43.5 mg, mp 157 to 159C
(dec.). -Example 219 3-(2-Phenylacetamido)-2-azetidinone (408 mg.) and 2-chloroacetonitrile (152 mg.) was dissolved in N,N-dimethylformamide (15 ml~), and to the solution was added sodium hydride (5~% oily) (105 mg.) under stirring àt ambient temperature, whereafter the reaction mixture was stirred for an hour at room temperature, and ethyl acetate (100 ml.) was added to the reaction mixture. The ethyl acetate layer was washed with water and dried over anhydrous magnesium sulfate, and then the solvent was distilled off from the solution under reduced pressure. The oily residue (0.25 g.) obtained was subjected to column chromatography using silica.gel.
l-Cyanomethyl-3-(2--phenylacetamido)-2-azetidinone (56.3 mg.) was obtained from fractions eluted with chloroform. Mp 108 to 109C (dec.).

Example 220 2-(2-Phenoxyacetamido)-2-azetidinone (154 mg.) was dissolved in N,N-dimethylformamide (1.75 ml.), and 10f~31~B

to the solution was added all at once thallium ethoxide (174.6 mg.), and then the mixture was stirred for 10 minutes at ambient temperature. To the reaction mixture was added dropwise a solution, prepared by dissolving ethyl 2-bromo-2-(4-ethoxycarbonyloxyphenyl)acetate (232 mg.) in N,N-dimethylformamide (0~6 ml.), was aclded to the reaction mix-ture and then the reaction mixture was stirred for 2 hrs. at ambient temperature. The reaction mixture was filtered to give insoluble materials and a filtrate. The insoluble materials were washed with ethyl acetate. The filtrate and the washing were combined and diluted with ethyl acetate.
The solution was washed with water and dried over anhydrous magnesium sulfate. The solution was concentrated under re-duced pressure to give the yellow oily residue, which was subjected to column chromatography using silica.gel. Oil of l-(~-ethoxycarbonyl-4-ethoxycarbonyloxybenzyl)-3-(2-phenoxy-acetamido)-2-azetidinone was obtained from fractions eluted with benzene.
I.R. absorption spectrum;
~ cm 1 (liquid film) : 1760, 1740 (shoulder), 1675.

Example 221 A isomer B of l-(~-benzyloxycarbonylbenzyl)-3-(2-phenylacetamido)-2-azetidinone (63 mg.) obtained in Example 206 was dissolved in isopropyl alcohol (12 ml.), and to the solution was added 10% palladium.carbon (10 mg.).
The mixture was reacted in hydrogen atmosphere at ordinary temperature and ordinary atm. until the absorption of hydrogen ~as was completed. The catalyst was filtered off, and the solvent was distilled off from the filtrate, and 1~3~08 then ether was added to the residue obtained to give crystals of l-(~-carboxybenzyl)-3-(2-phenyl-acetamido)-2-a2etidinone (27 mg.), which was recrystalliz~d from a mixture of methanol and ether to give the purified object compound. Mp 174 to 175C
(dec.).

Example 222 l-Carboxymethyl-3-(2-phenylacetamido)-2-azetidinone was obtained by treating l-Benzyloxycarbonylmethyl-3-(2-phenylacetamido)-2-azetidinone in substantially the similar manner as described in Example 221. Mp 144 to 145C.

Example 223 3-(2-Phenylacetamido)-2-azetidinone (750 mg.) and benzyl 2-bromo-2-(4-benzyloxyphenyl)acetate (1.51 g.) was added to anhydrous N,N-dimethylformamide (10 ml.), and dis-solved in it by warming for a while. The solution was cooled in an ice-water bath, and to the solution was added all at once sodium hydride (50% oily) (178 mg.) under stir-ring. After removing the cooling bath, the reaction mixture W2S stirred for 30 minutes to which ethyl acetate was added.
The reaction mixture was filtered and the filtrate was washed with water, 2% hydrochloric acid and water respectively, and then dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure to give an oily material (1.98 g.), which was subjected to colurnn chromatography using silica-gel (40 g.). The fractions, eluted with a mixture of benzene and chloroform were subjected ,-to thin layer chrornatography using silica-gel, and the thin layer was developeci with a mixture of chloro~orm and acetone i3:1~8 to give two isomers of l~ benzyloxycarbonyl-4-benzyloxy-benzyl)-3-(2-phenylacetamido)-2-azetidinone. The isomer A was recrystallized from a mixture of chloroform and ether, yield: 90 mg. Mp: 129 to 130C (dec.). The isomer B is oily materiaL yield: 120 mg. The isomer A (90 mg.) obtained above was dissolved in methanol (7 lml.), and to the solution was added 10% palladium carbon (30 lmg.). The mixture was reacted in hydrogen atmosphere at ordinary temperature and ordinary atm. until the absorption of hydrogen gas was completed. The catalyst was filtered off from the reaction mixture, and the filtrate was concentrated under reduced pressure. The residue obtained was crystallized from a mixture of ethyl acetate and ether to give crystals of 3-(2-phenylacetamido)lactacillanic acid. The product was identified by comparing an I.R. absorption spectrum and a .M.R. absorption spectrum and a melting point with an authentic sample synthesized by another method from 3-aminolactacillanic acid.

Example 224 0 3-(2-Phenylacetamido)-2-azetidinone (300 mg.) and benzyl 2-bromo-2-t4-benzyloxyphenyl)acetate (604 mg.) were dissolved in anhydrous ~,~-dimethylformamide (4 ml.) under warming. The solution was cooled in a cooling bath, to which was added all at once sodium hydride (50% oily) (71 mg.), and then the reaction mixture was stirred for a while. After removing the cooling bath, the reaction mix-ture was stirred for 30 minutes, whereafter ethyl acetate was added thereto. The reaction mixture was filtered and then the filtrate was washed with water, 2% hydrochloric acid _ 201 -.
.. . . ..

1~i3 1 ~8 and water respectively, and then dried over anhydrous mag-nesium sulfate. The solution was concentrated to give an oily residue (727 mg.), which was subject to column chromatography using silica-gel (15 g.). Elution was carried out with a mixture of benzene and chloroform to obtain an oily material (255 mg.). A part of this material (200 mg.) was dissolved in methanol (14 ml.), and to the solution was added 10%
palladium~carbon (60 mg.). The mi~ture was reacted in hydrogen atmosphere at ordinary temperature and ordinary atm.
until the absorption of hydrogen gas was completed. The catalyst was filtered off from the reaction mixtuxe, and the filtrate was concentrated under reduced pressure. The residue obtained was crystallized from a mixture of ethyl acetate and ether to give 3-(2-phenylacetamido)lactacillanic acid.
I.R. absorption spectrum, ~ cm~l (~ujol) : 1745, 1690, 1650.

The following compounds were obtained in substantially the similar manner as described above.

0~ ~ ]~ ~ , O

(III) (I") 1- r ~>3~L08 s 203 U~ _ ~î~D ~îo .
W c~ O ~9 O u~ I~ I~ ~r ~ -ær. ~ æ

;

~ ~ n ., . , ~

i~i3~ s 204 ,, ~ E ~ N E -I E ~ ~

_ - , _ _ _ .. . . .,,' ~ ~ u ~ 8 ~ z o ~ n ~ ~
o~ '~ I ~o) L ~ N , ~ N ¦ N

1~;31C! ~3 '` 1~ 1 1 ~ ~ 5-205 F~l N O ~1 ~ .
,~ ~r ~1 ~ ' . . , 3~OJB

Example 239 A crude product (157 mg.) without separation and purification thereof, obtained by the reacting ethyl 3-(2-phenoxyacetamido~-2-azetidinone and ethyl 2-bromo-2-(4-ethoxycarbonyloxyphenyl)acetate in the same manner as des-cribed in Example 220 similarly, was dissolved in ethanol (3 ml.). lN Sodium hydroxide aqueous solution (1.0 ml.) was added to the solution under cooling in ice-water bath and then the solution was stirred for 30 minutes after re-moving the cooling bath. The reaction mixture was concentra-ted under reduced pressure, and water was added to the residue obtained. The aqueous solution was washed with ethyl acetate and then the aqueous layer was adjusted to pH 1 to 2 with lN hydrochloric acid, whereafter was extracted with ethyl acetate. The extract was washed with a sodium chloride-saturated-aqueous solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off from the solution under reduced pressure to give residues, which were washed with ether to give 3-(2-phenoxyacetamido)lactacillanic acid.
I.R. absorption spectrum;
~cm~l (~ujol) : 1745, 1690, 1660 The corresponding 3-acylamino-2-azetidinone was treated in substantially the similar manner as described above, and the following compounds were obtained.

O ~aH O~-z ) ' ~-a~

(III) (I") 1 _ _ - ?n7 ~G~ O .. .. ' ..
;~ ~ ~Z~ Z~ Z~ ,~ .ô~r ~ .
c~ 0~ 0 ~~ ~ ~ O ~ _ ~ u~
. !~8 ~ ~:
~ ~ , ~ .. .

u~ = =. o~
..-~,, gD~U aW ~ 3~ ~
.-o ~ ~ ~'~ ~ Ul .. ' , ' ~ ~, ' " " ~ `

1~3~

~ - T ~ o ~ ~
~ ~ ~ o ~ o ~ ~ o , ~
~a~ ~u~ . ~ ~

.. .

i ' ~ : ` ` ' b ,~:

;, 1~3~0~3 s- 209 ~ r . .~ o P; ~

_ __ ~ .
OZ_ 3: ~ .
'.~ ~ : ~ 1,. i, . k ~ . ~ ..~ ~ ~ ~
. . . _ . . t ~
Cl-31C~ s 210 _' .
~ ~o C~ ~ o ~î o ' ,1 . `~

IY ~ ~ N C V I _ : ~

. _ _ I ~ ' _ 3' .
~ O I N ~

~lV

3~

The 3-acylamino-2-azetidinone (m) shown in the following table was treated in substantially the similar manner as described in Example 224 to give the compound (I") shown in the following table.
.

NN ~ ~ ~ N-Z~ N-A' (II) (I") ', -all .

1C1~3~ 3 s- 212 ~ t .... .
- ~-13 ~ 310B :~

10~31al8 The 3-acylamino-2-azetidinone (III) shown in the following table was treated in substantially the similar manner as described in Example 239 to give the compound (I") shown in the following table.

> ~ ~ ~ Z ~ ~ ~ -A' (III) (I") i~ S - 215 ~' ~

- ~1 5- 10~;3~0B
. .. .... .. . . . .. ..

l~S31Q~3 s 216 ~ ~_ N N ~ ~) I~

~1 N O N . ~ r-l .
. ,.

. . __ , _.

. `~

= : . = ~ ~ '.'''' : ~ . . ~' .- `'''.
. . ._ ~' I ~ o I '~

~ o_O~ ~\ ~ 9N

. . .__ ,, . . . ____._, ~ _ _ . .. __ . _ .. _ .. .. .. . ... . _ . --- -- . --- -- . _ _ .. _ _ _ _ _ ~ . _ . _ . _ . . _ _ _ _ . _ . _ .. _ ...

~i3108 o~ ~ --;~ ,, _ , ~' _ .__ ` _ _ '''' . . ` 1`'''`" " `' ~ ' ' ~
: ': : : =
`-,~

8 8 ~ ~ ~ d _ .. .
:
l O , ~ ~ r~ _ ,.~

`: 10~310B s 218 ~o ~'~ \

¦ m~ o ¦ ~ o ~ 8~
'~

b ;~

, .

1~3~08 The 3-acylamino-2-azetidinone (III) was treated in substantially the si~ilar manner as described in Example 239 to give the compound (I") shown in the following table.

R ~

(III) (I") ~ .

31~3~ s 220 ~ ,, ~

¦ ~ N

.~ ~ ~ ~_ ~~ ~

^ 1~ l I I~1 ; ~D~

O _ H

~1 ~ ~ : ' : :
~ ~0~-~
~ ~ _ _ N

_ ~ 8 m m m ~ m ~ m ~;~ o 1l oZ m c~ o I ~-D ¦ ~D ~ D
r N N

o-`` 163 ~i31~8 Example 291 3-[2-~4-(3-Amino-3-carboxypropoxy)phenyl~-2-hydroxy-iminoacetamido]lactacillanic acid ~1.0 g.) was dissolved in 1.5% sodium bicarbonate aqueous solution (20 ml.), and to the solution was added sodium hydrogen sulfite (1.0 g.), and then the mixture was heated for 3 hrs. at 80C. The reaction mixture was adjusted to pH 3 with 10% hydrochloric acid, and the mixture was concentrated to a volume of about 10 ml. and the concentrate was adjusted to pH 3 with 10~ hydrochloric acid again to give crystals of 3-[4-(3-amino-3-carboxypropoxy)-phenylglyoxyloylamino]lactacillanic acid (0.57 g.).
Mp 216C (dec.).
Example 292 3-t2-14-(3-Acetamido-3-carboxypropoxy)phenyl~-2-hydroxyiminoacetamido]lactacillanic acid was treated in substantially the similar manner as described in Example 291 to give crystals of 3-~4-(3-acetamido-3-carboxypropoxy)phenyl-glyoxyloylamino]lactacillanic acid. Mp 96 to 102C ~dec.).
Example 293 3-r2-~4-(3-carboxy-3-phthalimidopropoxy)phenyl~-2-hydroxyiminoacetamido]lactacillanic acid (4.2 g.) was dissolved in methanol (40 ml.). A solution, prepared by dissolving sodium hydrogen sulfite (4.2 g.) in water (80 ml.), was added to the solution, and the mixed solution was heated for 3.5 hrs.
under reflux. Subsequently, the reaction mixture was concentrated to a volume of about 30 ml., and the concentrate was adjusted to pE[ 2.0 with lOYo hydrochloric acid under ice-cooling, and then the solution was extracted with ethyl _ 221 -acetate. The extract was washed with water and dried, and then the solvent was distilled off from the extract to give 3-~4-~3-carboxy-3-phthalimidopropoxy)phenylglyoxyloylamino]-lactacillanic acid (2.1 g.). Mp 115 to 120C (dec.).
Example 294 3-~2-~4-î3-Carboxy-3-(3-E~henylureido)propoxy~phenyl]-2-hydroxyiminoacetamido]lactacillanic acid was treated in substantially the similar manner as described in Example 293 to give 3-~4-~3-carboxy-3-(3-phenylureido)propoxy~phenyl-glyoxyloylamino]lactacillanic acid. Mp 100 to 106C (dec.).

.
- ~ .

1~i3108 Example 295 3-~2-¦4-(3-Amino-3-carboxypropoxy)phenyl~-2-hydroxy-iminoacetamido]lactacillanic acid (0.5 g.) was suspended in an aqueous solution (10 ml.) of a~monium acetate (1.93 g.), and 28% ammonia water (0.3 ml.) and zinc powder (0.435 g.) were added to the solution, whereafter the mixture was stirred for 24 hrs. at ambient temperature. The reaction mixture was adjusted to pH 4 with lN-hydrochloric acid, and hydrogen sul~ide gas was introduced into the solution, and then the insoluble material was filtered off. The filtrate was concentrated under reduced pressure to give a residue, and the residue was dissolved in water (10 ml.), and then to the solution was added ethanol (200 ml.). The forming precipitate was collected by filtration, and dried to give 3-[2-~4-(3-amino-3-carboxypropoxy)phenyl~glycinamido]lactacillanic acid (420 mg.). Mp 206 to 208C (dec.).

Example 296 N,N-Dimethylformamide (0.5 ml.), formic acid (0.5 ml.) and zinc powder (1.0 g) were added to a solution containing 3-~2-~4-(3-phthalimido-3-carboxypropoxy)phenyl~-2-hydroxyimino-acetamido]lactacillanic acid (1.00 g.), methanol (8 ml.) and water (2 ml.), and the mixture was stirred for 4 hrs. The zinc powder was filtered off from the reaction mixture, and hydrogen sulfide was introduced into the filtrate, and then the insoluble material was filtered off. The filtrate was concentrated under reduced pressure, to give a residue which was powdered with acetone to give 3-[2-~4-(3-phthalimido-3-carboxypropoxy)phenyl~glycinamido]lactacillanic acid (0.68 g.).
Mp 215 to 219C (dec!).

.

_ 223 -1~63;~08 Example 297 10% Palladium carbon (0,,6 g.) was added to a solution containing 3-[2-¦4-~3-acetamido-3--carboxypropoxy)phenyll-2-hydroxyiminoacetamido]lactacillanic acid (1.85 g.), sodium bicarbonate (0.6 g.) and water (20 ml.). The mixture was subjected to absorption of a calculated volume of hydrogen gas at ordinary temperature and ordinary atm. The catalyst was filtered off from the reaction mixture, and the filtrate was adjusted to pH 3 with lO~o hydrochloric acid under ice-cooling, and then treated with an activated carbon. The aqueous solution obtained was crystallized from acetone (150 ml.) under ice-cooling. The crystals were collected by filtration, ~nd washed with water (10 ml.) and acetone, respectively to give 3-~2-¦4-(3-acetamido-3-carboxypropoxy)phenyl~glycinamido]-lactacillanic acid (0.38 g.). Futhermore, the washing obtained above was crystallized from acetone (10 ml.) under ice-cooling, and the crystals were washed with acetone, and then collected by filtration to recover an object compound (0.32 g.). Total yield was 0.70 g. Mp 198 to 204C (dec.).

Example 298 10% Palladium carbon (3 g.) was added to a solution of 3-~2-i4-(3-benzamido-3-carboxypropoxy)phenyl~-2-hydroxyimino-acetamido]lactacillanic acid (10.0 g.), sodium bicarbonate (2.79 g.) and wat~er (70 ml.), and the mixture was subjected to a catalytic reduction for 5 hrs. under shaking enough under 3 atm at ordinary temperature. After the reaction, the catalyst was filtered off from the reaction mixture, and the filtrate was adjusted to pH 3.0 with lO~o hydrochloric acid under ice-cooling to give crystals of 3-[2~4-(3-benzamido-3-lOS3;~08 carboxypropoxy)phenyllglycinamido]lactacillanic acid (7.8 g~).
Futher~ore, an object compound (0.4 g.) was recovered from the mother liquor. Total yield was 8.2 g. Mp 171 to 176C (dec.).

Exam~le 299 3-~4-(3-Carboxy-3-phthal:imidopropoxy)phenylglyoxyloyl-amino]lactacillanic acid (1.10 g.) was suspended in water (11 ml.), and to the suspension was added sodium bicarbonate (0.40 g.) to dissolve it. To the solution was added sodium borohydride (0.03 g.) under ice-cooling, and the mixture was stirred for 4 hrs. at the same temperature. The reaction mixture was adjusted to pH 2 with 10% hydrochloric acid to give crystals of 3-[2-~4-(3-carboxy-3-phthalimidopropoxy)-phenyl~-2-hydroxyacetamido]lactacillanic acid (0.91 g.).
Mp 160 to 163~C (dec.).

Example 300 Acetic acid anhydride (20 ml.) was added to a suspen-sion, prepared by suspending 3-~2-~4-(3-amino-3-carboxypropoxy)-phenyl~-2-hydroxyiminoacetamido]lactacillanic acid (10 g.) in methanol (150 ml.), and the mixture was stirred for 4.5 hrs.
The reaction mixture was concentrated under reduced pressure to give a residue, to which was added toluene. The solution was concentrated under reduced pressure again to give a residue which was powdered by adding ethyl acetate to give 3- r 2- î 4-(3-acetamido-3-carboxypropoxy)phenyl~_2-hydroxyimino-acetamido~lactacillanic acid (10.3 g.). Mp 90 to 93~C (dec.).

Example 301 Acetic acid anhydride (6 ml,) was added to a methanol _ 225 -1~3108 suspension (60 ml.) of 3-[4-(3-amino-3-carboxypropoxy)phenyl-glyoxyloylamino]lactacillanic acid (3.0 g.) under ice-cooling, and the mixture was stirred for 1 hour at the same temperature, and further stirred for 4 hrs. at ambient temperature. The reaction mixture was concentrated under reduced pressure, and the concentrate was powdered with ether to give 3-~4-(3-acetamido-3-carboxypropoxy)phenylglyoxyloylamino]lactacillanic acid (2.26 g.). Mp 96 to 102C (dec.).
Example 302 3-~ 4-t3-Amino-3-carboxypropoxy)phenyl~glycinamido]
lactacillanic acid was treated in substantially the similar manner as described in Example 301 to give 3-[2-~4-(3-acetamido-3-carboxypropoxy)phenyl~-N-acetylglycinamido~lactacillanic acid.
I.R. absorption spectrum, y cm~l (~ujol) : 1735, 1650.

Example 303 3-[2-~4-(3-Amino-3-carboxypropoxy)phenyl~-2-hydroxyiminoacetamido]lactacillanic acid (0.50 g.) was suspended in dried methylene chloride (20 ml.). To the suspension was added N,O-bis(trimethylsilyl)acetamide (1.50 g.), and the mixture was stirred for 2 hrs. at ambient temperature, and then heated for 10 minutes under reflux. The reaction solution was cooled to 0 to 5C/ and triethylamine (0.12 g.) and 2,2,2-trifluoro-acetic acid anhydride (0.27 g.) were added to the solution, and then the reaction solution was stirred for 1 hour. The methylene chloride was distilled off from the reaction mixture to give a residue which was dissolved in ethyl acetate (20 ml.~.
The solution was washed with 2% hydrochloric acid five times, _ 226 -.

1~310i3 with water twice and with a sodium chloride-saturated-aqueous solution once, respectively, and then dried over anhydrous magnesium sulfate. The solvent was distilled off from the solution, and benzene was added to the residue to give powdery crystals of 3-~2-~4-~3-carboxy-3-(2,2,2-trifluoroacetamido)-propoxy7phenyl]-2-hydroxyiminoacetamido]lactacillanic acid (0.41 g.). Mp 143 to 147C (dec.).

Example 304 ~,O-Bis(trimethylsilyl)acetamide (15 ml.) was added to a suspension, prepared by suspending 3-~4-(3-amino-3-carboxypropoxy)phenylglyoxyloylamino]lactacillanic acid (4.0 g~) in dried methylene chloride (80 ml.), and the mixture was stirred for 2 hrs. to dissolve the starting material completely.
To the solution was added triethylamine (0.88 g.) under ice-cooling, and then a solution, prepared by dissolving 2,2,2-trifluoroacetic acid anhydride (1.9 g.) in methylene chloride (5 ml.), was added dropwise to the solution during 30 minutes.
The reaction mixture was stirred for 1.5 hrs. at the same temperature, and then the methylene chloride was distilled off from the reaction mixture under reduced pressure, whereafter the residue was poured into a mixture of ice-water (50 ml.) and ethyl acetate (100 ml.). The ethyl acetate layer separated out was dried over anhydrous magnesium sulfate, and then the solvent was distilled off to give a residue to which was added benzene to give powdery crystals of 3-~4-~3-carboxy-3-(2,2,2-trifluoroacetamido)propoxy7phenylglyoxyloylamino]-lactacillanic acid (3.0 g.).
I.R. absorpt:ion spectrum, cm 1 (~ujol) : 1730, 1680.

-Example 305 3-[2-~4-~3-Amino-3-carboxypropoxy)phenyl~-2-hydroxy-iminoacetamido]lactacillanic acid (20.0 g.) was suspended in a mixture of water (200 ml.) and acetone (200 ml.), followed by adding sodium bicarbonate (6.8 g.) to dissolve it. Benzoyl chloride (6.7 g.) was added dropwise to the solution under ice cooling, keeping the solution in pH 8Ø The reaction mixture was stirred for 4 hrs. and the acetone was distilled off from the reaction mixture. The remaining aqueous solution was washed with ethyl acetate, and ethyl acetate (400 ml) was added to the solution. The mixture was adjusted to pH 2.0 with lOYo hydrochloric acid under cooling and then the ethyl acetate layer was separated out, and washed with water and with a sodium chloride-saturated-aqueous solution, respectively, and dried. The ethyl acetate was distilled off from the solution to give a residue, followed by suspending in water (200 ml.). lN-Sodium hydroxide aqueous solution (160 ml.) was added to the suspension, and the solution was stirred for 2 hrs. Ethyl acetate (400 ml.) was added to the solution, and the mixture was adjusted to pH 2.0 with lOYo hydrochloric acid under ice-cooling. The ethyl acetate layer separated out was washed with water and dried. The solvent was distilled off from the solution to give the powder (21.6 g.) which was crystallized from a mixture of acetone and benzene to give crystals of 3-r2-~4-~3-benzamido-3-carboxypropoxy)phenyl~-2-hydroxyiminoacetamido]lactacillanic acid (10.4 g.). Mp 170 to 172C (dec.).

Example 306 3-r4-(3--Amino-3-carboxypropoxy)phenylglyoxylaylamino]-~3~0~il lactacillanic acid (970 mg.) was suspended in water (10 ml.), and the suspension was adjusted to pH 8 to 9 with lN-sodium hydroxide aqueous solution under ice-cooling. An acetone solution (10 ml.~ of phenyl isocyanate (360 mg.) was added dropwise to the solution, keeping the solution at pH 8 to 9 during adding dropwise. The solution was stirred for an hour, and the diphenylurea produced as a by-product was filtered off from the solution. The filtrate was adjustèd to pH 1 to 2 with lOYo hydrochloric acid and then extracted with ethyl acetate. The extract was washed with a sodium chloride-saturated-aqueous solution, and dried over anhydrous magnesium sulfate, whereafter the solvent was distilled off from the solution to give crystals of 3-[4-~3-carboxy-3-(3-phenylureido)propoxy~phenylglyoxyloylamino]lactacillanic acid (1.33 g.). Mp 100 to 106C (dec.).
Example 307 3-~2-~4-(3-Amino-3-carboxypropoxy)phenyl~glycinamido]-lactacillanic acid (250 mg.) was suspended in water ~ ml.), and the suspension was adjusted to pH 8 with lN-sodium hydroxide aqueous solution to dissolve it under ice-cooling.
A dried acetone solution (2 ml.) of phenyl isocyanate (150 mg.) was added to the solution under cooling, keeping the solution in pH 8 to 9 during the addition. The solution was stirred for an hour under ice-cooling, and then adjusted to p~ 2 with 10% hydrochloric acid to give a precipitate. The precipitate was collected by filtration and washed with water, and then dissolved in a sod:ium bicarbonate aqueous solution. Insoluble materials were filtered off, and the filtrate was adjusted to pH 1 to 2 with 10% hydrochloric acid to give crystals which 1~i3~08 were collected by filtration, washed with water and then dried on phosphorus pentachloride to give crystals of 3-C2-L4-~3-carboxy-3-(3-phenylureido)propoxy~phenyl]-2-(3-phenylureido)-acetamido]lactacillanic acid (0.35 g.). Mp 170 to 172C
(dec.).
Example 308 A suspension of 3-[2-~4-~3-amino-3-carboxypropoxy)-phenyl~-2-hydroxyiminoacetamido]lac-tacillanic acid (10 g.), water (100 ml.) and acetone (30 ml.) was adjusted to pH 8 to

9 with lN-sodium hydroxide aqueous solution under ice-cooling.
To the solution-was added dropwise an acetone solution (5 ml.) of phenyl isocyanate (2.9 g.) at the same temperature, and the mixture was stirred for an hour. The acetone was distilled off from the reaction mixture under reduced pressure, and the remaining solution was adjusted to pH 2 with 10%
hydrochloric acid, and extracted with ethyl acetate. The extract was washed with diluted hydrochloric acid and water, respectively, and dried. The ethyl acetate was distilled off from the solution to give a residue which was crystallized from ether (100 ml.) to give crystals of 3-C2-C4-~3-car~oxy-3-(3-phenylureido)propoxy~phenyl]-2-hydroxyiminoacetamido]-lactacillanic acid (10.3 g.). Mp 135 to 139C (dec.).
Example 309 An acetone solution (5 ml.) containing ethyl phthalimido-formate (0.60 g.) was added dropwise to a solution containing 3-~2~4-(3-amino-3-car~oxypropoxy)phenyl~-2-hydroxyimino-acetamido~lactaciIlanic acid (0.94 g.), 10% a dipotassium hydrogenphosphate aqueous solution (20 ml.) and acetone (10 ml.), ---, l~S3~08 and the mixture was stirred for 2 hrs., keeping the mixture in pH 8. The acetone was distilled off from the reaction mixture under reduced pressure, and the remaining solution was adjusted to pH 2 with diluted hydrochloric acid, and then extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The ethyl acetate was distilled off from the solution to give residue, which was crystallized from an eth~nol aqueous solution to give crystals of 3-~2-~4-(3-carboxy-3-phthalimidopropoxy)-phenyl~-2-hydroxyiminoacetamido]lactacillanic acid (0.69 g.).
Mp 160 to 165C (dec.).
Example 310 3-[2-~4-(3-Amino-3-carboxypropoxy)phenyl~glycolamido]-lactacillanic acid was treated in substantially the similar manner as described in Example 309 to give crystals of 3-[2-~4-(3-carboxy-3-phthalimidopropoxy)phenyl~glycolamido]-lactacillanic acid. Mp 160 to 163C (dec.).
Example 311 3-L4-(3-Amino-3-carboxypropoxy)phenylglyoxyloylamino]-lactacillanic acid was treated in substantially the similarmanner as described in Example 309 to give crystals of 3-[4-(3-carboxy-3-phthalimidopropoxy)phenylglyoxyloylamino]-lactacillanic acid. Mp 216C (dec.).
Example 312 Phenyl isothiocyanate (320 mg.) was added to a 50%
pyridine aqueous solution (6 ml.) of 3-[2-~4-(3-amino-3-carboxypropoxy)phenyl~glycinamido]lactacillanic acid (250 mg.) 1~3108 at 40C under stirring. The mixture was stirred for an hour, keeping the mixture in pH 8 to 9 with a sodium bicarbonate-saturated-aqueous solution. The reaction mixture was washed with ether, and the aqueous layer 1was separated out, and then adjusted to pH 1 to 2 with 10% hydrochloric acid under cooling to give crystals of 3-[2-[4-~3-carhoxy-3-(3-phenylthioureido)-propoxy~phenyl]-2-(3-phenylthioureido)acetamido]lactacillanic acid (250 mg.). Mp 190 to 195C (dec.).
Example 313 3-[2-~4-(3-Amino-3-carboxypropoxy)phenyl~glycinamido]-lactacillanic acid (2.0 g.) was suspended in a 50% pyridine aqueous solution (20 ml.), and the suspension was adjusted to pH 8.6 with l~-sodium hydroxide aqueous solution to dissolve it. To the solution was added l-naphthyl isothiocyanate (1.94 g.), and the mixture was stirred for 4 hrs. The reaction mixture was washed with ether and adjusted to pH 2.0 with 10%
hydrochloric acid under cooling to give a precipitate. The precipitate was collected by filtration and washed with water.
The precipitate was dissolved in a sodium bicarbonate-saturated-aqueous solution, and 10% hydrochloric acid was added to the solution to give crystals of 3-~2-L4-r3-carboxy-3-~3-(1-naphthyl)-thioureido~propoxy~phenyl]-2-~3-(1-naphthyl)thioureido~-acetamido~lactacillanic acid (2.7 g.). Mp 169 to 173C (dec.).
Example 314 3-[-~4-(3-Amino-3-carboxypropoxy)phenyl~glycinamido]-lactacillanic acid (480 mg.) was suspended in water (10 ml.), and to the suspens:ion was added LN-potassium hydroxide aqueous solution ~5 ml.) under ice-cooling, while stirring.

An acetone (5 ml.) solution of 0-ethyl-S-methyl dithiocarbonate (0.72 g.) was added to the solution, and then the mixture was stirred for 5 hrs. at ambient temperature. The reac~ion mixture was washed with ether, and the remaining aqueous layer was separated out. The aqueous solution was adjusted to pH 1 to 2 with loYo hydrochloric acid and extracted with ethyl acetate, and then the extract was washed with water and dried. The solvent was distilled off from the solution to give 3-~2-r4-~3-carboxy-3-ethoxy(thiocarbonyl)aminopropoxy~-phenyl~-2-ethoxy(thiocarbonyl)aminoacetamido]lactacillanic acid (230 mg.). Mp 112 to 119C (dec.).
Example 315 3-[2-~4-(3-Amino-3-carboxypropoxy)phenyl~-2-hydroxyiminoacetamido]lactacillanic acid (1.0 g.) was dissolved in a mixture of 0.1~-sodium hydroxide aqueous solution (40 ml.) and acetone (15 ml.). To the solution were added dropwise an acetone (5 ml,) solution containing 2-(4-chloro-2-nitrophenoxy)acetyl chloride (550 mg.) and 0.1~-sodium hydroxide aqu-eoùs solution (40 ml.) at the same time under ice-cooling, while stirring. The mixture (pH 9.2 to 9.4) was stirred for 40 minutes at the same temperature, and further stirred for 40 minutes at ambient temperature. The reaction mixture was washed with ethyl acetate, and then ethyl acetate was added to the aqueous layer, whereafter the mixture was adjusted to pH 2 with 10% hydrochloric acid. The ethyl acetate layer was separated out, washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off from the solution to give a residue which was washed with ether several times. The residue was dissolved in ethyl _ 233 -31~8 acetate under warming, and an insoluble material was filtered off and then to the solution was added chloroform to give a powder which was collected by filtration to give 3-~2-~4-~3-~2-(4-chloro-2-nitrophenoxy)acetamido~-3-carboxypropoxy]phenyl]-2-hydroxyiminoacetamido]lactacillanic acid (150 mg.).
Furthermore, an object compound (30 mg.) was obtained from the mother liquor. Total yield was 180 mg. Mp 145 to 150C (dec.).

Example 316 An acetone (4 ml.) solution containirg 2-(2-thienyl)-acetyl chloride (352 mg.) was added dropwise to a solution containing 3-~2-~4-(3-amino-3-carboxypropoxy)phenyl~-2-hydroxyimino~cetamido]lactacillanic acid (1.0 g.), sodium bicarbonate (504 mg.), water (30 ml.) and acetone (10 ml.) under ice-cooling, while stirring, keeping the solution in pH 8. The mixture was stirred for 40 minutes at the same temperature, and further stirred for 30 minutes ambient temperature. The reaction mixture was washed with ethyl acetate, and then ethyl acetate was added to the solution, whereafter the mixture was adjusted to pH 2 with 10% hydrochloric acid. The ethyl acetate layer was separated out, and the remaining aqueous layer was extracted with ethyl acetate.
These ethyl acetate layers were combined and washed with a sodium chloride-saturated-aqueous solution, and then dried over anhydrous magnesium sulfate. The solvent was distilled off from the solution, and the residue (740 mg.) obtained was added to 0.1~-sod:ium hydroxide aqueous solution (30 ml.).
The solution (pH '3.4) was stir`red for an hour at ambient temperature, and washed with ethyl acetate, and to the .- .

lOS3108 solution was added ethyl acetate. The mixture was adjusted to pH 2 by adding 10% hydrochloric acid and then treated in the similar manner as described above to give a residue (450 mg.). The residue was dissolved in a mixture of acetone and n-hexane, and the solution was treated with activated carbon, followed by filtration. The ~iltrate was concentrated to give a residue which was washed with ether several times and with n-hexane once to give 3-[2-~4-[3-carboxy-3-~2-(2-thienyl)acetamido~ propoxy]phenyl]-2-hydroxy-iminoacetamido]lactacillanic acid (400 mg.), mp 145 to 150C
(dec.).

Exa~ple 317 An acetone (25 ml.) solution eontaining ~-ethoxy-carbonyloxycarbonyl-~-toluenesulfonic acid triethylamine salt (3.1 g.) and an aqueous solution (10 ml.) of sodium bicarbonate (756 mg.) were added dropwise to a solution containing 3-[2-~4-(3-amino-3-carboxypropoxy)phenyl~-2-hydroxyiminoacetamido]-lactacillanic acid (2.0 g.), sodium bicarbonate (756 mg.), water (35 ml.) and acetone (15 ml.) during 15 minutes under ice-cooiing. The reaction mixture (pH 7.6) was stirred for 30 minutes at the same temperature, and further stirred for 30 minutes at ambient temperature. The acetone was distilled off from the reaction mixture, and the remaining solution was adjusted to pH 3 with 10% hydrochloric acid, whereafter the solution was washed with ethyl acetate. The ethyl acetate layer was separated out, and the remaining aqueous solution was adjusted to pH 1 with lOYo hydrochloric acid, and extracted with n-butyl alcohol. The extract obtained was washed with 1~3:i~08 5% hydrochloric acid once and with a sodium chloride-saturated-aqueous solution once, respectively, and dried over anhydrous magnesium sulfate. The extract was adjusted to pH 6 with an acetone (21 ml.) solution containing sodium 2-ethylhexanate (11 mg.) to give a powder which was collected by filtration.
The powder was washed with acetone to give the colorless powder (2.3 g.). A part of the po~der (1.0 g.) was dissolved in water (3 ml.), and the solution was adjusted to pH 3 with

10% hydrochloric acid, and then washed with ethyl acetate, whereafter the solution was subjected to column chr~matography using a nonionic adsorption resin, Amberlite XAD-2 (trade mark, maker: Rohm and Haas Co. Ltd.,), and the compound eluted with water was lyophillized to give 3-[2-~4-~3-carboxy-3-(2-phenyl-2-sulfoacetamido)propoxy~phenyl]-2-hydroxyiminoacetamido]-lactacillanic acid sodium salt (350 mg.). Furthermore, an object compound (480 mg.) was recovered from the fractions, eluted with water containing methanol (20%) and methanolO
Total yield was 830 mg. Mp 244 to 250C (dec~).

Example 318 Potassium carbonate ~0.127 g.) and water (3 ml.) were added to an acetone solution (3 ml.) containing N-methylaniline (0.200 g.), and the solution was stirred at 25 to 28C. To the solution was added dropwise a mixture (4 ml.) of acetone and water (1:1) containing 3-(2-bromoacetamido)lactacillanic acid (0.321 g.) and sodium bicarbonate (0.067 g.), and the reaction mixture was re-acted for 17 hrs. at the same temperature. The acetone was distilled off from the reaction mixture under reduced pres-sure, and the remaining aqueous layer was washed with ethyl acetate. The aqueous layer was adjusted to pH 3 with diluted hydrochloric acid, and then extracted with ethyl acetate. The extract was washed with water, dried and then concentrated. The residue obtained was crystallized from methanol to give crystals of 3-(N-methyl-N-phenylglycinamido)-lactacillanic acid (0.208 g.). Mp 198 to 199C (dec.).
Th~ following compounds were obtained in substantial-ly the similar manner as described above.

~ Rll--A~ C~H
(Nucleophile) ~
N-CH ~ OH ~ ~ , N-CH- ~ OH

COOH COOH

(XI) (XII) o ~ u~ S-238 ~ _ ~

6 = ~ ' 'L
. .
~ - . - :

3;~08 Example 323 Morpholine (0.262 g.) was dissolved in a mixture (5 ml.) of acetone and water (1:1), and to the solution was added potassium carbonate ~0.180 gO). The solution was cooled to 10C, and to the solution was added dropwise a mixture (S ml.) of acetone and water (1:1) containing 3-(2-bromoacetamido)lactacillanic acid (0.464 g.) and sodium bicarbonate (0.110 g.). The reaction mixture was reacted for 5 hrs., keeping the reaction temperature at 10 to 20C.
The acetone was distilled off from the reaction mixture under reduced pressure, and the remaining aqueous solution was washed with ethyl acetate. The aqueous solution was adjusted to ~H 1 to 2 with diluted hydrochloric acid and washed with ethyl acetate. The aqueous solution was adjusted to pH 4.5 to 4.8 with sodium bicarbonate, and the solution was concentrated under reduced pressure, and then the residue was extracted with methanol. The extract was concentrated to give an oily material which was dissolved in a small amount of methanol. Acetone was added to the solution, which was filtered. The filtrate was concentrated to give an oily material (0.38 g.) which was subjected to column chromatography using a nonionic adsorption resin, Amberlite XAD-2 (trade mark, maker;
Rohm and Haas Co., ~td.) (35 ml.). Isolation and purification were carried out. Fractions eluted with water were collected and the water was distilled off from the eluate to give crystals of 3-(2-morpholinoacetamido)lactacillanic acid (0.38 g.).
Mp 201 to 203C (dec.).

Example 324 A mixture containing 3-[2-(2-bromoacetamido)-2-l~S3~08 phenylacetamido]lactacillanic acicl (196 mg.) 2-mercaptobenzoic acid (62 mg.) and 0.1~-sodium hydroxide aqueous solution (12 ml.) was stirred for an hour at ambient temperature~
The reaction mixture (pH 6.8 to 7.~) was adjusted to pH 3 with lN-hydrochloric acid (0.4 ml.) and washed with ether and then further adjusted to pH 1 to 2 with lN-hydrochloric acid. The solution was extracted with ethyl acetate and the extract was washed with water and dried over anhydrous magnesium sulfate. The solution was concentrated to a volume of about 4 ml. under reduced pressure to give crystals which were washed with ether to give crystals of 3-[2-~2-(2-carboxyphenylthio)acetamido~-2-phenylacetamido]-lactacillanic acid (125 mg.). Furthermore, an object compound (50 mg.) was recovered from the filtrate. Total yield was 175 mg.
Mp 143 to 146C (dec.).
The following compounds were obtained in substantial-ly the similar manner as described above. -XlAlCONH Rl-lAlC~H
~ ~ucleophile ~ ~-CH- ~ -OH > ~ ~-fH - ~-OH ~
COOH COOH

(XI) (XII) _ 240 -10~310B s 2~1 ô . ._ . .
u~ ~ In~ r~
o U~ i`~ C~ ~ Ln H 1~ ~ ___ ._ ¦ x ¦ " ¦ E C a I ~ I ¦ I I
. ~ , _ ~.' '' ~ ~ ~ ~

u ~ g D ~ ~ ~ ~
. . _ ~ X I N -- _ : ~

~' ._ C~ ~C P~ 1: : . _ .
l U- --- _ ._ ' :-E ~, ~ ~ ~ .

1~ti31V8 s- 242 . . . __ ' ,.... ..

.. . __ . ' ' ' = : = =
. .. __ . . ~ ~ . . A
~ , 1~i3108 s- 2~3 N U~

~'1 }"i ~ ~

. ~ , _ l ~' _ ., ~ , I . r~ . -.

--~13-1~3101~
Example 340 3-(2-Bromo-2-phenylacetamido)lactacillanic acid (86 mg.) and cysteine hydrochloride (one hydrate) (35 mg.) were suspended in water (3 ml.), and to the suspension was added LN-sodium hydroxide aqueous solution (0.4 ml.) under ice-cooling, while stirring. The solution was reacted for about 3 hrs. and then the mixture was adjusted to pH 8, followed by being reacted for 2 hrs. The reaction mixture was adjusted to about pH 2 with LN-hydrochloric acid and then filtered. The filtrate was adjusted to pH 8 to 9 with a sodium bicarbonate aqueous solution, and then concentrated to give a residue which was subjected to column chromatography using a nonionic adsorption resin, Amberlite XAD-2 (trade mark, maker, Rohm and Haas Co., Ltd.) (20 ml.) which had been washed previously with methanol and water. The fractions, obtained by being eluted with water, were collected, and the eluate was evaporated to give crystals of 3-~2-(2-amino-2-carboxyethylthio)-2-phenylacetamido]lactacillanic acid disodium salt of carboxy group (20 mg.). Mp 211 to 216C
(dec.).

Example 341 3-(2-Bromo-2-phenylacetamido)lactacillanic acid (150 mg.) and 2-aminoethanethiol (35 mg.) were treated in substantially the similar manner as described in Example 340 to give crystals of 3-~2-(2-aminoethylthio)-2-phenylacetamido]-lactacillanic acid sodium salt (54 mg.). Mp 171 to 173C
(dec.).

~0~3iO8 Example 342 A mixture of 3-(2-bromoacetamido)lactacillanic acid ~107 mg.), water (3 ml.) and LN-potassium hydroxide aqueous solution (0.6 ml.) was added dropwise to a solution containing cysteine hydrochloride (38 mg.), water (3 ml.) and 1~-potassium hydroxide aqueous solution (0.9 ml.) under ice-cooling while stirring, and then the solution was reacted for an hour at the same temperature. The reaction mixture was adjusted to about pH 4 with l~-hydrochloric acid (0.9 ml.), and con-centrated under reduced pressure to give a residue which wasdissolved in methanol. The solution was subjected to column chromatography using a nonionic adsorption resin, Amberlite XAD-2 (trade mark, maker, Rohm and Haas Co., Ltd.). Fractions eluted with water were collected, and evaporated to give crystals of 3-~2-(2-amino-2-carboxyethylthio)acetamido]-lactacillanic acid (95 mg.). Mp 105 to 110C (dec.).
The following compounds were obtained in substantially the similar manner as described above.

Xl-Al-CONH RllA~CO~H
~ucleophile _~
~-fH- ~ -OH ~ ~-CH- ~ -OH

COOH
COOH

(XI) (XII) l~ - l ~ . . ~ ~ r . .

1s~

.. . ~ l .
. . . ~ .
,.. . ~ . ~. . .

l~S3~8 Example 348 Sodium pyridine-l-oxide-2-thiolate (60 mg.) was added to a mixture of 3-[2-(2-bromoacetamido)-2-phenylacetamido]-lactacillanic acid (200 mg.) and O.IN-sodium hydroxide aqueous solution (4 ml.) under ice-cooling, and the mixture was stirred for 30 minutes. Ethyl acetate was added to the reaction mixture, and the solution was adjusted to pH 1 to 2 with 10% hydrochloric acid to give a precipitate which was collected by decantation. The precipitate was dried and washed with acetone to give 3-[2-~2-(pyridyl-1-oxide-2-thio)acetamido~-2-phenylacetamido]lactacillanic acid (82 mg.). Furthermore, the acetone washing was concentrated to give a residue which was washed with diisopropyl ether to recover an object compound (33 mg.). Total yield was 115 mg. Mp 160 to 164C (dec.).

Example 349 3-(2-~romoacetamido)lactacillanic acid (285 mg.) and sodium pyridine-l-oxide-2-thiolate (120 mg.) were treated in substantially the similar manner as described in Example 348 to give 3-~2-(pyridyl-1-oxide-2-thio)acetamido]lactacillanic acid (250 mgO). Mp 221 to 225C (dec.).

Example 350 8-Mercapto-9H-purine (76 mg.) was added to a mixture o~f 3-r2-phenyl-2-(2-phenylsulfoacetamido)acetamido]lactacillanic acid (285 mg.) and O.lN-sodium hydroxide aqueous solution (10 ml.) under ice-cooling. After the reaction temperature was elevated to ambient temperature, the reaction mixture was stirred for 3 hrs. To the reaction mixture was added LN-hydrochloric acid (O.5 ml.) to give a precipitate which ` ~
1~i3~0~3 `
was collected by filtration. The precipitate was washed with water and dried to give 3-[2-phenyl-2-12-(9H-purin-8-yl-thio)-acetamido¦acetamido]lactacillanic acid (120 mg.~ Mp 192 to 197C (dec.).
Exam~le 351 Sodium hydride (50% oily) (9.6 mg.) and phenol (19 mg.) were added to anhydrous N,N-dimethylformamide (2 ml.) and the mixture was stirred for 30 minutes, and then ice-cooled. To the solution was added all at once 3-~2-phenyl-2-(2-bromoacetamido)acetamido]lactacillanic acid (50 mg.), and the reaction mixture was s-tirred for an hour at the same temperature and further stirred for an hour at ambient tem-perature. Ether (10 ml.) was added to the reaction mixture to give a precipitate which was collected by filtration.
The precipitate was dissolved in a small amount of water, and the solution was adjusted to pH 1 with 10% hydrochloric acid, and then extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and then the solvent was distilled off from the solution. The residue was powdered with ether, and collected by filtration and washed with ether sufficiently to give 3-~2-phenyl-2-(2-phenoxyacetamido)acetamido]lactacillanic acid (lO mg.).
I.R. absorption spectru~, ;~
~ cm 1 (~ujol) : 1740, 1720, 1~50.
' "

1~i310~3 The following compounds were obtained in substantially the similar manner as described above.

XlAlCONH RllAlCNH
~ucleophile C~ COOH ~ ~ -CH- ~ -OH
COOH
(XI) (XII) ~' 2~9 -.` lO~;~lOB s 2~0 I l~r~ r~
~^

i 'I ~i b ~æ g D ~D ~ ~ æ æ 0~

~ ~ 1~

~
3 ~

_ . ~

lO~alos ~ s - 252 10~3~08 Example 362 3-[2-~2-[2-{4-(2-Chloroacetamido)ben%oyl}-4-chlorophenoxy]acetamido]-2-phenylacetamido]~actacillanic acid (150 mg~) and pyridine-2-thiol (25 mg~) was treated in substantially the similar manner as described in Example 324 to give 3-[2-[2-[2-[4-{2-~pyridin-2-yl-thio)acetamido}-benzoyl]-4-chlorophenoxy]acetamido]-2-phenylacetamido]-lactacillanic acid ~120 mg.). ~Ip 109-114C ~dec.) The following compounds were obtained in substantially the similar manner as described in Example 342.

-CONH ~ -CONH
h Nucleophile ~- N-CH- ~ OH - -- 7 ,~--N-CH- ~ OH
COO~I COO~l ' ~I) ~ II) .;

~ ,_ ~ S-253 ~ H ~ U ~ ~
' ~

~o ~ 3-~ ~

, 3} L ~ ~ :

_ ~3~ i3~

~OS3~08 s - 254 -Example 365 10~ Palladium carbon ~25 mg) was added to a methanol solution (10 ml.) of 3-(6-benzyloxycarbonylaminohexanamido)-lactacillanic acid (220 mg.), and a theoretical volume of hydrogen gas was introduced to the mixture in 2 hrs. at ordinary temperature and ordinary atmosphere. The reaction mixture was subjected to filtration, and the filtrate was concentrated under reduced pressure. The residue was pulver~
i7ed with acetone, washed with acetone and subjected to filtration to give 3-(6-aminohexanamido)lactacillanic acid (100 mg.). hlp 118 to 122C (dec.).
The following compounds were prepared in substantial-ly the similar manner as described above.

~2-~H R12-- o~N-CH~_oRl3 o F ~ 13 COOH COOH

` `

~63108 ~= ~ b . Z 1`~ . Zl~
--~ ~ ~ `-a ~ ~ _ _ ~ ¦ r' (~ E l ¦
E n l l I I ~
N ~ N ~ O O-- â

~ ~ ~D ~ CO ~0 ~ ' .. . - I . ' .

1~3~0B s- 256 T~ ~ r T
~ ~ ~ ~ ~ O
. . .. `,, . =

a ou 0 ~=~ tt~=~

~ "c~ ~ ~0~

g D gD gD gD ~D gD ~
. . _ .
~ . _ ~ , .

.. , ...... ~

_ ~ 31(~8_ s 2 ~7 ~9 ~ o U~
~D ~1 l ~ ~1 . __ . ~ --- .

r . . m m~ m '.' = ` -- = ' ' ': `

~ '' ~ ~` ~ ~ ~ .'' "
._ ... ..
~ ~ 1` O ~
.. _ ' ' . ` ~
- ~ . ...

o ~-~ 1~631~8 s 258 ,~ Z

11~ I . ~ .
H
., \ ' . = \ ,'.
\ '"

Z~

. \ :., \ ' , . .

l .

. . . ~

Si3108 Example 383 3-[2-(2-Thienyl)-~-(2,2,2-trichloroethoxycarbonyl)-glycinamido]lactacillanic acid (0.250 g.) was dissolved in a 90YO acetic acid aqueous solution (13 ml.), and the solution was cooled to 10C. To the solution, was added gradually zinc powder (1.20 g.) in 50 minutes~ and the mixture was subjected to reaction for an hour at the same temperature.
To the reaction mixture, was added zinc powder (0.50 g.) in 30 minutes, and then the mixture was subjected to further reaction for 2 hrs. The zinc powder was removed by filtration, and hydrogen sulfide gas was introduced to the filtrate, and then the precipitate was removed by filtration. The filtrate was washed with ethyl acetate, and the remaining aqueous layer was concentrated. The residue was crystallized from a mixture of methanol and ether to give 3- r 2-(2-thienyl)glycinamido]lactacillanic acid (35 mg.). Furthermore, the ethyl acetate layer was extracted with water, and the aqueous layer was concentrated to recover the same compound (15 mg.). Total yield was 50 mg. Mp 184 to 189C (dec.).
The following compounds were prepared in sub-stantially the similar manner as described above.

H~oR13 ~ -CH~oR13 COOH COOH
(XIII) ~ (xrv) ,' - -.

10~3:10B
-`` ! s - 260_~ ~

~ ; ~
_~O-- . ~

31~8 Example 386 -Carboxy-3,5-dibromo-4-hydroxybenzyl)-3-r2-[4-~3-carboxy-3-(2,2,2-trifluoroacetamido)propoxy~phenyl~-2-hydroxyiminoacetamido]-2-azetidinone (Q.50 g.) was suspended in water (3 ml.), and IN-sodium hydroxide aqueous solution (3 ml) was added to said suspension, and then the solution was stirred for 30 minutes. The reaction mixture was adjusted to pH 3 with 10% hydrochloric acid under ice-cooling. The precipitated crystals were collected by filtration, and the crystals were dissolved in a small amount of a sodium bicar-bonate aqueous solution, and then the solution was treated with activated carbon. After the treatment, the solution was adjusted to pH 4 with lOYo hydrochloric acid under ice-cooling, and the precipitate was collected by filtration to give 1-- (~-carboxy-3,5-dibromo-4-hydroxybenzyl)-3-~2-~4-~Lamino-3-carboxypropoxy)phenyl~-2-hydroxyiminoacetamido]-2-azetidinone (40 mg.). Furthermore, the same compound (60 mg.) was recovered from the mother liquor. Total yield was 100 mg.
Mp 190 to 194C (dec.).

Example 387 10% Palladium-carbon ~25 mg.) was added to a methanol solution (15 ml.) of 3-~2-(4-benzyloxycarbonyloxy-phenyl)acetamido]lactacillanic acid (230 mg.), and a theoretical volume of hydrogen gas was added to said mixture in 2 hrs. at ordinary temperature and ordinary atmosphere. The reaction mixture was subjected to filtration and the filtrate was concentrated under reduced pressurè, and then the resiclue was crystallized from a mixture of acetone and ethyl acetate. The crystals were collected by _ 261 -. ~ . , :
1~3108 filtration and washed with ethyl acetate to give 3-[2-(4-hydroxyphenyl)acetamido]lactacillanic acid (90 mg.). Mp 171 to 176C (dec.).

Example 388 A solution consisting of 3-(2-ethoxycarbonyl-2-phenylacetamido)lactacillanic acid (213 mg.), ethanol (5 ml.) and l~-sodium hydroxide aqueous solution (1.4 ml.) was subjected to reaction at ambient temperature for 1.25 hrs.
After the reaction, the reaction mixture was cooled and adjusted to pH 1 by adding l~-hydrochloric acid (1.4 ml.).
Then, the mixture was adjusted to pH 6 to 7 by adding lN-sodium hydroxide aqueous solution, and concentrated. The re-sidue was dissolved in water, and the solution was adjusted to pH 1 to 2 with LN-hydrochloric acid, and then washed with ethyl acetate. The remaining aqueous layer was adjusted to pH 6 with LN-sodium hydroxide aqueous solution, and con-centrated. For the purpose of isolation and purification`, the residue was subjected to column chromatography using a nonionic adsorption resin, Amberlite XAD-2 (trade mark, maker: -Rohm and Haas Co. Ltd.,) (30 ml.) which was washed in advance with methanol and water. The fractions eluted with water were collected, and the water was distilled off from the eluate to give 3-(2-carboxy-2-phenylacetamido)lactacillanic acid, disodium salt of the carboxy group (159 mg.). Mp 209 to 214C (dec.).

..... .

10~310B

The following compounds were prepared in substantially the similar manner as described above.

R12- ~H R12 ~

~-CH-I~)-OR 3~-CH--~\--OR
COOH COONa (XIII) tXIV) ... ..

.~ .
~3~0~3 .
-- ~i.LI ' - . ` . . ` .

1063~0B

Example 391 3-[2-i2-(2-Ethoxycarbonylphenoxy)acetamido~-2-phenylacetamido]lactacillanic acid (170 mg.) was dissolved in LN-sodium hydroxide aqueous solution (0.9 ml.), and the solution was stirred at ambient temperature for 3.5 hrs. Water (about 10 ml.) was added to the reaction mixture.
The mixture was adjusted to pH 1 with 10~/o hydrochloric acid and extracted with ethyl acetate. The extract was washed twice with a sodium chloride aqueous solution and dried over anhydrous magnesium sulfate. The solvent was dis-tilled off from the ethyl acetate solution, and the residue was crystallized from diisopropyl ether to give 3-[2-~2-(2-carboxyphenoxy)acetamido~-2-phenylacetamido]lactacillanic acid (120 mg.). Mp 130`to 135C (dec.).
The following compounds were prepared in substantiai-ly the similar manner as described above.
~`': ` .

R12- NH R12- NH . .

o I ~ 13 > O ~ ~~CH~ ~ ~OR
COOH . COOH `

(XIII) (XIV) i31(;~8 ~ W _ ¦ n ----- _ i ~

~, ~

8 s 267 . ~ ' P
o o _ _ . :,, .

n ~ 1 4 ~ D

. _ _ ._ ., I ~ 1__ 1 a 1~3108 S- 26~
~ -` ~ __ _l ~D O ~ Ir) 00 ~ ,1 ~ ~ ~ o I ,1 ~D= Z U .

N--U O ( P~

uN m u u~ o~ :: ~ .
~o ~

. _ : ~_ 2 - . ~.
O o ~ _ ~D= Z u o . .
_ O U U ~ U

u u ll o o ~ m :~ o o ~ ~:
C~ ~: u~ C~ C~ ' ..
m~ ~

o' ___ ~o o ~r .' . . ~ ~ ~ .' 1~3:10~3 s- 269 ~ , ~ o 8~, ~D o ~.' .

-~l,S~

18~3108 Example 410 ~ -MethoxycarbOnyl-4-methOXybenzyl)-3-~2-C4-~3-methoxycarbonyl-3-(2,2,2-trifluoroacetamido)propoxy~phenyl]-2-methoxyiminoacetamido]-2-azetidinone (0.19 g.) was dissolved in acetone (2 ml.). lN-Sodium hydroxide aqueous solution (0.9 ml.) was added to the solution at ambien~ temperature, and the mixture was stirred for 5 minutes. The acetone was distilled off from the reaction mixture, and the remaining solution was adjusted to pH 3 with 10% hydrochloric acid.
The separated oily material was isolated by decantation, washed with acetone and water, and then pulverized with àcetonitrile to give l-(~-carboxy-4-methoxybenzyl)-3-~2-~4-(3-amino-3-carboxypropoxy)phenyl1-2-methoxyiminoacetamido]-2-azetidinone (0.02 g.). Mp 170 to 176~C (dec.).

Exam~le 411 3-~2-[4-~4-Chloro-~-~2,2,2-trichloroethoxycarbonyl)-anilinomethyl~phenoxy]-2-methyl-propionamido]lactacillanic acid (320 mg.) was treated in substantially the similar manner as described in Example 365 to give 3-r2-~4-(4-chloro`anilino-methyl)phenoxy¦-2-methylpropionamido]lactaciIlanic acid (110 mg.). Mp 130 to-136C (dec.).

Example 412 Sodium methylate (15 mg.) and absolute methanol (20 ml.) were added to 1-methoxalyl-3-(2-phenoxyacetamido)-2-azetidinone (1.1 g.), and the mixture was heated under reflux for 30 minutes. The solvent was distilled off from the reaction mixture under reduced pressure, and the residue was dissolved in acetone, and then the insoluble material .

~L~S310~
was filtered off. The filtrate was concentrated and allowed to stand cool, and then the precipitated crystals were col-lected by filtration. The crystals were washed with acetone and dried to give 3-(2-phenoxyacetamido)-2-azetidinone (456 mg.). Furthermore, the same compo~md (109 mg.) was recovered from the mother liquor. Total yie~d was 565 mg. Mp 153 to 155C.

Example 413 l-Methoxalyl-3-benzyloxycarkonylamino-2-azetidinone (240 mg.) was dissolved in methanol (10 ml.), and sodium methylate (6 mg.) was added to said solution, and then the mixture was heated under reflux for 45 minutes.
The meth~nol was distilled off from the reaction mixture, and the residue was washed with ether to give crude 3-benzyloxycarbonylamino-2-azetidinone (126 mg.). Furthermore, this product was recrystallized from acetone to give the purified compound (50 mg.). And, the purified same compound (54 mg.) was recovered from the mother liquor. Total yield was 104 mg. Mp 164 to 165C.

Example 414 ~ -Acetoxy-2-methylpropyl)-3-(2-phenylacetamido)-2-azetidinone (13.8 g.) was dissolved in a solution of methanol (100 ml.) and water (100 ml.). Potassium carbonate (6 g.) and sodium borohydride (1.65 g.) were added to said solution under ice-cooling, and the mixture was subjected to reaction at 20C for an hour. The precipitated crystals were collected by filtration, washed with water and dried to give 3-(2-phenylacetamido)-2-azetidinone (5.15 g.).

. . ~ . - : .-1~S;3108 Furthermore, the same compound (1.35 g.) was recovered from the filtrate. Total yield was 6.5 g~ Mp 191 to 193C.

Example 415 1-~1-(2,2,2-Trichloroethoxycarbonylamino)-2-methylpropyl]-3-(2-phenylacetamido)-2-azetidinone ~1.13 g.) was dissolved in a 9~/O acetic acicl aqueous solution (20 ml.), and the solution was cooled to 5C. Zinc powder (1.62 g.) was added dropwise to said solution in 5 minutes, and the mixture was stirred for 30 minutes. Furthermore, zinc powder (1.62 g.) was added to said mixture, and the mixture was stirred for 2 days. The reaction mixture was neutralizèd with a sodium bicarbonate aqueous solution, and extracted with methylene chlor`ide. The extract was washed with water-and dried over anhydrous magnesium sulfate, and then the solvent was distilled off from the solution. The residue (0.65 g.) was subjected to preparative thin layer chromato-graphy using silica-gel ~developing solvent: a mixed solvent of ethyl acetate,; ethyl methyl ketone, water and formic acid (volume ratio 5:3:1:1)], isolated and purified to give 3-(2-phenylacetamido)-2-azetidinone (0.3 g.). Mp 190 to 192C.

- . - - , ~

10~310~3 .
Example 416 ~ Methoxycarbonyl-4-hydroxybenzyl)-3-C2-(2-thienyl)acetamido]-2-azetidinone (0.18 g.) was dissolved in a solution consisting of sodium kx~rate buffer (pH 7.8)(3 ml.), methanol (5 ml.) and acetone (3 m].), and the solution was cooled to -5C. A methanol (0.5 ~.) solution containing tert-butyl hypochlorite (0.10 g.) was added to said solution three times every 15 minutes, and the mixture wa~ stirred for 30 minutes. The solvent was distilled off from the reaction mixture, and the remaining solution was adjusted to pH 2 with lOYo hydrochloric acid, and then extracted with ethyl acetate. The extract was separated out, washed`with water and a sodium chloride-saturated-aqueous solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off from the ethyl acetate solution, and the residue (0.22 g.) was subjected to column chromatography using silica.gel ~10 g.).
The fractions eluted with chloroform were collected, and the chloroform was distilled off from the eluate to give 1-(~-methoxycarbonyl-3,5-dichloro-4-hydroxybenzyl)-3-C2-(2-thienyl)acetamido]-2-azetidinone (50 mg.).
I.R. absorption spectrum, Y cm 1 (liquid film) : 3270, 1760, 1755, 1665.

Example 417 Chloroform (1.5 ml.) was added to a solution of l-(~-methoxycarbonyl-4-hydroxybenzyl)-3-(2-phenylacetamido)-2-azetidinone (184 mg.) dissolved in dioxane (2 ml.), and a chloroform (0.5 ml.) solution containing bromine (184 mg.) was added dropwise to said mixt`ure in 5 minutes under ice-cooling. After addition of ethyl acetate (80 ml.) to said -1~310~3 reaction mixture, the ethyl acetate layer was separated out, washed with water and dried over anhydrous magnesium sulfate, This solution was concentrated, and the residue was dissolved in a small amount o acetone. The " solution was subjected to preparative thin layer chromatography using silica-gel ~developing solvent; a mixture of chloroform and methanol (5:0.3)] for isolation and purification. The product thus obtained was recrystallized from a mixture of ethyl acetate and acetone to give l-(~-methoxycarbonyl-3-bromo-4-hydroxybenzyl)-3-(2-phenylacetamido)-2-azetidinone (18 mg.). Mp 151 to 153C (dec.).

Example 418 A methanol solution (1 ml.) of bromine (352 mg.) was rapidly added dropwise to a solution (5 ml.) of 3-(2-phenylacetamido)lactacillanic acid (354 mg.) and sodium acetate (246 mg.) dissolved in absolute methanol with stirring under ice-cooling. The methanol was distilled off from the reaction mixture under reduced pre,ssure. After addition of a mixture of ethyl acetate and water to the residue, the ethyl acetate layer was separated out and washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off from the solution, and the residue (590 mg.) as the yellow orange oily material was dissolved in a small amount of ethyl acetate, and the'solution was subjected to column chromato-graphy using silica-gel (7 g.). The fractions, eluted with a mixed solvent of ethyl acetate and acetone, were collected, and the solvent was distilled off from the eluate. The residue thus obtained was further subjected to preparative thin layer chromatogra,phy using silica gel for isolation and l~S310~

purification. The fractions, eluted with a mixture of ethyl - acetate and acetic acid (5:1), were collected, and the solvent was distilled off from the eluate, and then the residue was pulverized with chloroform. This powder was recrystallized from a mixture of chloroform and acetone to give 1~
carboxy-3,5-dibromo-4-hydroxybenzyl)-3-(2-phenylacetamido)-2-azetidinone (157 mg.). Furthermore, the same compound (26 mg.) was recovered from the mother liquor. Total yield was 183 mg. Mp 161 to 162C (dec.).

ExamPle 419 3-~2-~4-~3-Carboxy-3-(2,2,2-trifluoroacetamido)-propoxy~phenyl]-2-hydroxyiminoacetamido]lactacillanic acid (1.77 g.) was dissolved in methanol (20 ml.). After addition of sodium acetate (1.03 g.) to said solution, the mixture was cooled to -5C and a methanol solution ~5 ml.) of bromine (1.06 g.) was added dropwise thereto in lS minutes. The reaction mixture was subjected to reaction for 15 minutes, and the mathanol was distilled off from the reaction mixture, and then the residue was added to a mixture of ethyL acetate (20 ml.) and water (20 ml.). After adjusting the mixture to pH 2 with 2% hydrochloric acid, the ethyl acetate layer was separated out and washed with a sodium thiosulfate aqueous solution, water and a sodium chloride-saturated-aqueous solution respectively, and then dried over anhydrous magnesium sulfate. The ethyl acetate solution was con-centrated, and the residue (2.56 g.) thus obtained was subjected to precipitation repeatedly twice with a mixture of benzene and acetone to give l-(~-carboxy-3,5-dibromo-4-hydroxybenzyl)-3-[2-[4-~3-carboxy-3-(2,2,2-trifluoroacetamido)-_ 275 -: - , ..

1~i3iO8 propoxy~phenyl]-2-hydroxyiminoacetamido]-2-azetidinone (1.16 g.) I.R. absorption spectrum:
~ cm 1 (liquid film) : 1720 (broad), 1650.

Example 420 3-Glycinamidolactacillanic acid (100 mg.) suspended in water (5 ml.) was dissolved by adding sodium bicarbonate (70 mg.). The solution was cooled to 0 to 5C, and a solution of 2-(4-chloro-2-nitrophenoxy)acetyl chloride (100 mg.) dissolved in acetone (5 ml.) was added dropwise thereto.
The mixture was allowed to react at the same temperature for 2 hrs. The acetone was distilled off from the reaction mixture under reduced pressure, and the remaining solution was adjusted to pH 1 to 2 by adding diluted hydrochloric acid and then extracted with ethyl acetate. The extract-was washed with water and dried, and the solvent was distilled off. The oily residue was washed with ether, dissolved in a small amount of methanol, and then ether was added to the solution.
The precipitated powder was collected by filtration and dried to give 3_~2_J2-(4-chloro-2-nitrophenoxy)acetamido3acetamido]-lactacillanic acid (82 mg.). Mp 149 to 153C (dec.~.
The following compounds were prepared in substantially the similar manner as described above.

Rl-5CHCONHr ACylating agentR15 IcHcoNH
R16 O N-CH- ~ -OH ~ R17 o ~ ~~CH~ ~ -OH
- COOH COOH

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ExamDle 469 ` 3-(2-Phenylglycinamido)lactacillanic acid as a starting material and 2-~4-chloro-2-(~-acetoxyiminobenzyl)phenoxy]acetyl chloride as an acylating agent were treated in substantially the similar manner as described in Example 420 to give 3-[2-[2- ~-chloro-2-(~-hydroxyiminoberlzyl)phenoxy~acetamido~-2-phenylacetamido]lactacillanic àcid, in which the protective group (i.e. acetyl) on the hydroxyimino group of the starting matarial was eliminated. Mp 171 to 176C (dec.).

Example 470 A suspension of 3-(2-Phenylglycinamido)lactacillanic acid (200 mg.) in a solution consisting of methylene chloride (10 ml.), N,N-dimethylformamide (1 ml.) and ~,0-bis(trimethyl-silyl)acetamide (1 ml.), was stirred at ambient temperature for an hour. 2-Anilino-2-phenylacetyl chloride hydrochloride (1~0 mg.) was added to the reaction mixture under ice-cooling, and the mixture was stirred at the same temperature for an hour for dissolution. Furthermore, the reaction mixture was stirred at ambient temperature for an hour and then concentrated-under reduced pressure. After addition of ethyl acetate and water to the residue, the ethyl acetate layer was separated out and extracted with a sodium bicarbonate aqueous solution.
After adjusting the aqueous layer to p~ 1 to 2 with -lN-hydrochloric acid, it was extracted with ethyl acetate and the extract thus obtained was washed with water and dried over anhydrous magnesium sulfate. After solvent was distilled off, ether waQ added to the reqidue thus obtained and then the mixture was stirred for an hour. The separated powder was collected by filtration to give 3-~2-phenyl-2-(2-anilino-2-- \
1~63108 phenylacetamido)acetamido]lactacillanic acid (89 mg.).
Mp 158 to 161C ~dec.).

Example 471 A mixture of N,N-dimethylformamide (50 mg.) and thionyl chloride (200 mg.) was stirred at 40 to 50C. for 30 minutes. After the excess of the thionyl chloride was distilled off, the residue was dissolved in methylene chloride (5 ml.), and then the solution was cooled to -10 to -5C.
2-[5-(2-Thienyl)tetra`zol-l-yl]acetic acid (114 mg.) was added to-this-solution at once and dissolved by adding ~,N-dimethyl-formamide (2 drops), and then the mixture was-stirred for 15 minutes. This solution was-cooled to -60 to -50C, and a methylene chloride (2 ml.) solution of triethylamine (65 mg.) was added thereto, and then the mixture was stirred at the same temperature for 30 minutes. To the solution cooled to -60 to -50C, there was added at once a solution which had been prepared in advance by stirring a suspension consisting of 3-(2-phenylglycinamido)lactacillanic acid (200 mg.), N,0-bis(trimethylsilyl)acetamide (430 mg.), methylene chloride (10 ml.) and N,N-dimethylformamide (1 ml.) at the same temperature for an hour. The reaction mixture was stirred for 30 minutes at the same temperature and for an hour at -20 to -10C and further for an hour at -10 to 0C. The solvent was distilled off from the reaction mixture to leave the residue, to which ethyl ac~_tate and a sodium bicarbonate aqueous solution were added. The aqueous layer was separated out, adjusted to pH 4 with 10% hydrochloric acid and then extracted with ethyl acetate. The ethyl acetate layer was separated out, washed with water, dried over anhydrous magnesium sulfate and then l~S31C~8 the solvent was distilled off. The residue (70 mg.) thus obtained was washed with ether to give crude 3-[2-phenyl-2-~2-~5-(2-thienyl)tetrazol-1-yl~acetamido~acetamido]lacta-cillanic acid (60 mg.). Furthermore, the product was dissolved in ethyl acetate, and ether was added to the solution to precipitate crystals. The crystals were collected by filtration to give the purified product (30 mg.). Mp 170 to 174C (dec.).

Example 472 2-Phenylglycolic acid, instead of the 2-~5-(2-thienyl)-tetrazol-l-yl3acetic acid, was treated in substantially the similar manner as described in Example 471 to give 3-r2-(2-hydroxy-2-phenylacetamido)-2-phenylacetamido~lactacillanic acid. Mp 90 to 93C (dec.).

Example 473 Acetone (5 ml.) was added to an aqueous solution (5 ~1~) of 3-C2-(2-thienyl)glycinamido]lactacillanic acid (0.358 g.) and sodium bicarbonate (0.185 g.),and the solution was cooled to 0 to 5C. To the solution, there was added dropwise a dried acetone (5 ml.) solution of 2-(4-chloro-2-nitrophenoxy)acètyl chloride (0.230 g.), and the mixture was allowed to react at the same temperature for 2 hrs. After the acetone was distilled off from the reaction mixture under reduced pressure, the remaining aqueous layer was washed with ethyl acetate, ad~usted to pH 1 to 2 with diluted hydrochloric acid and then extracted with ethyl acetate. The extract was washed with water and dried, and the solvent was distilled off to give the residue (0.34-g.). The residue was dissolved .... . . ~

1~i3108 in methanol (2 ml.), and to the solution, there was added an acetone (1 ml.) solution of sodium 2-ethylhexanate (0.88 g.) and then ether (15 ml.). The prec:ipitated powder was collected and washed three times with ether to give sodium salt of 3-~2-~2-(4-chloro-2-nitrophenoxy)acetamido~-2-(2-thienyl)acetamido]
lactacillanic acid (0.140 g.). Mp 187 to 190C (dec.).
The following compounds were prepared in substantially the similar manner as described above.

'Rl--5CHCONH R15-CHCONH
R16 ~ Acylating agent R17 ~
O~ - N-CH- ~ -OH ~ O~ - ~-CH- ~ OH
COOH COONa (XVII) (XVIII) -, ~ ~ ~ g D gD g~
.. t, _ ~ _. _ _~ .'~

= = = = = .
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1~31Ci 8 Example 481 Sodium nitrite (140 mg.) was little by little added to a solution of guanidinocarbohydrazide dihydrochloride (380 mg.) dissolved in water (3 m]L.) under cooling at 0 to 5C, and the mixture was stirred for 10 minutes to provide a solution of guanidinocarbonylazide. On the other hand, 3-(2-phenylglycinamido)lactacillanic acid (220 mg.) and sodium bicarbonate (150 mg.) were dissolved in a mixture of water (8 ml.) and acetone (4 ml.), and the solution was stirred at 0 to 5C for 15 minutes. After removal of the insoluble material by filtration from said solution, the solùtion as prepared above was added dropwise to the filtrate in`5 minutes and then the mixture was stirred at 0 to 5C for 2 hrs, while the reaction mixture was kept at pH 7.5 to 8.0 by adding 5% sodium bicarbonate aqueous solution. The precipitated crystals in the reaction mixture were collected by filtration to give 3-(2-guanidinocarbonylamino-2-phenylacetamido)-lactaciallanic acid (20 mg.). Furthermore, the filtrate was concentrated to a volume of about 5 ml. to precipitate crystals, which were collected by filtration to recover the same compound (60 mg.). Total yield was 80 mg. Mp 198 to 202C (dec.).

Example 482 3-t2-(2-Thienyl)glycinamido]lactacillanic acid (375 mg.) suspended in water (5 ml.) was dissolved by adding potassium carbona,te (104 mg.) (the nature of the solution indicated about pH 9). To said solution, there was added a - solution (10 ml.) of acetone and water (1 : 1) and then was added dropwise a dried acetone (5 ml.) solution of benzoyl 3~B

isothiocyanate (163 mg.) with stirring at ambient temperature.
The mixture was stirred for 3 hrs. (during that time, the reaction mixture was kept at pH 8.5 by adding a solution of potassium carbonate (104 mg.) in water (7 ml.)).
The acetone was distilled off from the reaction mixture. The aqueous residue was washed with et'hyl acetate, ad,justed to pH
1 to 2 with diluted hydrochloric acid and extracted with ethyl acetate. The extract was washed with water and dried, and t~e solvent was distilled off. The oily residue (469 mg.) was chromatographed on silica.gel ~7 g.) and eluted with a mixture of ethyl acetate and methanol to give 3-[2-(3-benzoylthioureido)-2-(2-thienyl)acetamido]lactacillanic acid (97 mg.) Mp 124 to 129C (dec.).

Example 483 85% 3-Chloroperbenzoic acid (50 mg.) was added to a solution of 3-(2-methylthio-2-phenylacetamido)-lactacillanic acid (100 mg`.) diss,olved in methanol (5 ml.) under ice-cooling, and the mixture was allowed to react with -stirring at the same temperature for an hour. The reaction mixture was concentrated under reduced pressure, and the residue wàs washed with chlbroform to give 3-(2-methylsulfinyl-2-phenylacetamido)lactacillanic acid (86 mg.).
I.R. absorption spectrum, ' ~ cm 1 (Nujol) : 1740, 1720, 1665, 1020.

Example 484 85% Chloroperbenzoic acid (61 mg.) was added to a solution of 3-C2-{N-(2-naphthyl)carbamoylmethylthio~-2-phenylacetamido]lactacillanic acid (171 mg.) dissolved in - .. . . , ~ . . . .

~L~i3iLOi~3 acetone (7 ml.) under ice-cooling, and the mixture was allowed to react with stirring at the same temperature for an hour. The reaction mixture was concentrated, and the residue was crystallized from chloroform to give 3-C2-~-(2-naphthyl)carbamoylmethylsulfinyl~-2-phenylacetamido]-lactacillanic acid (134-mg.). Mp 151 to 155C (dec.).

Example 485 3-C2-~4-(3-Amino-3-carboxypropoxy)phenyl~-glycinamidollactacillanic acid (1.00 g.) was dissolved in an aqueous solution (20 ml.) of sodium bicarbonate ~0.66 g.), and acetone (10 ml.) was added thereto. After the solution was ice-cooled, an acetone solution (5 ml.) of 2,4-dinitro-l-fluorobenzene (0.75 g.) was added dropwise thereto with stirring, and then the mixtùre was stirred at the same temperature for30 minutes and further at ambient temperature for 5 hours. The reaction mixture was washed with ethyl acetate and was adjusted to pH 2 with 10% hydrochloric acid, and then extracted with ethyl acetate. The ethyl acetate layer was separated, and the solvent was distilled aff under reduced pressure. The residue was pulverized with ether to give 3-t2-C4-~3-carboxy-3-(2,4-dinitroanilino)propoxy~-phenyl]-2-(2,4-dinitroanilino)acetamido]lactacillanic acid (1.50 g.).
I.R. absorptlon spectrum, ~ cm 1 (Nujol) : 1735, 1700 (shoulder), 1520, 1340.

Example 486 3-[2-~4-(3-Amino-3-carboxypropoxy)phenyl~-glycinamido]lactacillanic acid (0.49 g.) and sodium 1~;310B

bicarbonate (0.49 g.) were dissolved in water (10 ml~), and methanol (5 ml.) was added to the solution. To the solution, there was added dropwise a methanol solution (7 ml.) of methyl 4-fluoro-3-nitrobenzoate ~0.80 g.), and the mixture was allowed to react at ambient te~perature for 17 hrs.
and further at 50C for 4 hours. After cooling the reaction mixture for a while, the precipitat:e was removed by filtra-tion. The methanol was distilled off from the filtrate under reduced pressure, and the aqueous residue was washed with 10` ether, adjusted to pH 3 with LN-hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was separated and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was pulverized with benzene to give 3-[2-~4-~3-carboxy-3-(4-methoxycarbonyl~2-nitroanilino)propoxy~phenyl]-2-(4-methoxycarbonyl-2-nitroanilino)acetamido]lactacillanic acid (0.86 g.). Mp lS0 to 155C (dec.).

Example 487 3-~2-~4-(3-Benzamido-3-carboxypropoxy)phenyl~-glycinamido]lactacillanic acid (8.9 g.) and sodium bicarbonate - (5.4 g.) was dissolved in water (100 ml.), and methanol (100 ml.) and methyl 4-fluoro-3-nitrobenzoate (4.5 g.) was added thereto. The mixture was allowed to react with stirring at 40 to 50C for 4 hrs. The-methanol was distilled off from the reaction mixture under reduced pressure, and the residue was washed with ethyl acetate, adjusted to pH 2 with 10% hydrochloric acid and extracted with ethyl acetate.
The extract was wa~3hed with diluted hydrochloric acid and water,-and dried. The solvent was distilled off from the .
:
3~C~8 ethyl acetate layer under reduced pressure, and the residue was pulverized with ether and collected by filtration to give 3-[2-~4-(3-benzamido-3-carboxypropoxy)phenyl~-2-(4-methoxycarbonyl-2-nitroanilino)acetamido~lactacillanic acid (9.23 g.).
I.R. absorption spectrum, ~ cm~l (~ujol) : 1730, 1620, 1528, 1352.

Example 488 3-[2-~4-(3-Carboxy-3-phthalimindopropoxy)phenyl~-glycinamido]lactacillanic acid (0.68 g.) was dissolved in an aqueous solution (10 ml.) of sodium bicarbonate (0.40 g.).
To the solution, there was added methanol (10 ml.) and then methyl 4-fluoro-3-nitrobenzoate (0.30 g.), and the mixture was allowed to react at 50C under stirring for 3 hrs.
The methanol was distilled off from the reaction mixture, and the aqueous residue was washed with ethyl acetate, adjusted to pH 2 with lOYo hydrochloric acid and then extract-ed with ethyl acetate. The ethyl acetate layer was separated and dried over anhydrous magnesium sulfate. The solvent was ~distilled off from the ethyl acetate layer under reduced pressure, and the residue was pulverized with ether to give 3-[2-~4-(3-carboxy-3-phthalimindopropoxy)phenyl~-2-(4-methoxycarbonyl-2-nitroanilino)acetamido~lacta~illanic acid (0.53 g.). Mp 1S5 to 160C (dec.).

Example 489 Sodium salt of 3-~2-~4-(3-amino-3-carboxypropoxy)-phenyl~-2-hydroxyiminoacetamido]lactacillanic acid (0.50 g.) was dissolved in water (10 ml.). Acetone (2 ml.) was added _ 295 -~3 ~ ~8 to the solution, and a~ter stirring the solution for a while sodium borohydride (0.30 g.) was added little by little thereto, and then the mixture was stirred for 3 hrs. Acetone (2 ml.) was added to the reaction mixture, and the solution was adjusted to pH 3 with 10% hydrochloric acid. The pre-cipitated crystals were collected by filtration to give 3-[2-[4-~3-carboxy-3-(~-isopropylami~o)propoxy~phenyl]-2-hydroxyiminoacetamido]lactacillanic acid (0.05 g.). Further-more, the mother liquor was concentrated to nearly half of its orginal volume, and the precipitated crystals were collected by filtration to recover the same product (0.17 g.)~
Total yield was 0.22 g. Mp 193 to 194C (dec.).

Example 490 3-C2-~4-(3-Amino-3-carboxypropoxy)phenyl~-2-hydroxyiminoacetamido]lactacillanic acid as a starting material and methyl 2-formylacetate as a carbonyl compound were treated,in sub~tantially the similar manner as de-scribed in Example 489 to give 3-~2- r 4-~3-carboxy-3- ~-(2-methoxycarbonylethyl)amino~propoxy]phenyl]-2-hydroxy-iminoacetamido]lactacillanic acid. Mp 175 to 179C ~dec.).

Example_491 Sodium salt of 3~[2-~4-(3-amino-3-carboxypropoxy)-phenyl~-2-hydroxyiminoacetamido]lactacillanic acid (0.50 g.) was dissolved in water (10 ml.), 30YO formaldehyde aqueous solution (1 ml.) was added thereto under ice-cooling.
The mixture was stirred for a while, and sodium borohydride (0.15 g.) was added gradually thereto. After stirring the mixture for 30 minutes, it was adjusted to pH 3 with 10%

r - ~
1~6,310~3 hydrochloric acid under ice-cooling. The precipitated crystals were collected by filtration, washed with water and acetone, and dried at 40C under reduced pressure to give 3-[2-[4-13-carboxy-3-(N,N--dimethylamino)propoxy~-phenyl]-2-hydroxyiminoacetamido~lactacillanic acid (0.28 g.).
Mp 193 to 194C (dec.).

Example 492 3-(4-Nitrobenzamido)lactacillanic acid (235 mg.) was dissolved in methanol (20 ml.), and pal-ladium carbon (40 mg.) as a catalyst was added thereto.
The mixture was shaken in a stream of hydrogen at ambient temperature under ordinary atmosphere, while a calculated volume (44 ml.) of hydrogen was absorbed in about an hour.
The catalyst was removed by filtration from the reaction mixture, and the filtrate was evaporated to dryness under reduce pressure. The residue was treated with ether and collected by filtration to give 3-(4-aminobenæamido)-lactacillanic acid (200 mg.). Mp 190 to 194C (dec.).

Example 493 3-(3-5-Dinitrobenzamido)lactacillanic acid ~210 mg.) was dissolved in methanol (20 ml.), and palladium carbon (40 mg.) as a catalyst was added thereto. The mixture was shaken in a stream of hydrogen at ambient temperature under ordinary atmosphere, while a calculated volume (70 ml.) of hydrogen was absorbed in 2 hrs. The catalyst was removed - by filtration from the reaction mixture, and the filtrate was evaporated to dryness under reduced pressure. The residue was washe~ with ether and dissolved in acetone.

1~63108 After the acetone solution was filtered, ethyl acetate was added to the filtrate, and then the solution was concentrated.
The concentrate was filtered, and the filtrate was evaporated ; to dryness under reduced pressure. The residue was treated with ether and collected by filtration to give 3-(3,5-diaminobenzamido)lactacillanic acid ~60 mg.). Mp-116 to 121C (dec.).

Example 494 3-[2-(4-Formylphenoxy)acetamido]lactacillanic acid (20Q mg.) was added to a solution of hydroxylamine hydrochloride (70 mg.) dissolved in water (1 ml.) and LN-sodium hydroxide aqueous solution (1.5 ml.), and the mixture was stirred at ambient temperature for 30 minutes. Ethyl ~-acetate was added to the reaction mixture and-L~-hydrochloric acid (1.5 ml.) was added thereto. The mixture was shaken and the ethyl acetate layer was separated. The layer was washed with water and dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The residue (190 mg.) was allowed to crysta-llize. A mixed solvent of ethyl-acetate ` and chloroform (1:1) was added to the residue to precipitate crystals, and the solution was stirred at ambient temperature for an hour. The crystals were collected by filtration to give 3-[2-(4-hydroxyiminomethylphenoxy)acetamido]lactacillanic acid (130 mg.). Mp 150 to 155C (dec.).

Example 495 3-~2-(4-Formylphenoxy)acetamido]lactacillanic acid (200 mg.) was added to a solution consisting`of 2-aminooxyacetic acid 1/-2 hydrochloride (66 mg.) and 31Ci 8 I~-sodium hydroxide aquecus solution (1.5 ml.), and the mixture was stirred at ambient temperature for 2 hrs. The reaction mixture was adjusted to pH 2 with IN-hydrochloric acid, and then extracted with ethyl acetate. The ethyl acetate layer was separated, washe~d with water and dried over anhydrous magnesium sulfate. After the solvent was distilled off from the extract, ether was added to the residue--and then the mixture was stirred at ambient temperature for 2 hrs.
The precipitated crystals were collected by filtration, and the crystals (150 mg.) was washed with ethyl acetate to give 3-~2-(4-carboxymethoxyiminomethylphenoxy)acetamido]-lactacillanic acid`(llO mg.). Mp 144 to 147C (dec.).

Example 496 3-~2-(4-Formylphenoxy)-2-phenylacetamido]lactacillanic acid (237 mg.) was added to a solution consisting of 2-aminooxyacetic acid 1/2 hydrochloride (106 mg.) and lN-sodium hydroxide aqueous solution (1.8 ml.), and the mixture was stirred at ambient temperature for 2 hrs. The reaction mixture was adjusted to pH 1 to 2 with lO~o hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was separated, washed with water and dried over anhydrous magnesium sulfate. After the solvent was distilled off from the extract-, the residue was-washed with diisopropyl ether and collected by filtration to give 3-C2-(4-carboxymethoxy-iminomethylphenoxy)-2-phenylacetamido]lactacillanic acid (190 mg.). Mp 117 to 121C (dec.).

Example 497 , 3-[2-(4-Formylphenoxy)acetamido~lactacillanic acid i~6310B

(200 mg.) was added to a solution of lN-sodium hydroxide aqueous solution (5 ml.) and N-(carbazoylmethyl)-N,N,N-trimethylammonium chloride (90 mgO), and the mixture was stirred at ambient temperature for 2 hrs. Further, N-(carbazoylmethyl)-N,N,N-trimethylammonium chloride (90 mg.) was added to this solution, and the mixture was allowed to stand overnight. To the reaction mixture, there were added IN-hydrochloric ac~d (0.5 ml.)-and acetic acid (100 mg.), and then the solution was washed with ethyl acetate clnd ether. The aqeuous layer was separated, and the organic solvent saturated in th'e layer was completely distilled off under reduced pressure. The residue was chromatographed on a nonionic adsorption resin, Amberlite XA~-2 (50 ml.) (trade mark, maker, Rohm and Haas Co., Ltd.). Elution was conducted with water and then methanol, and the fractions containing an objective compound, which can~be eluted with methanol, were collected. ~The fractions combined together was`concentrated. The-residue was washed with ethanol and collected by filtration to give N-[3-[4-CN-~ -carboxy-4-hydroxybenzyl)-2-oxo-3-azetidinyl~carbamoylmethoxy]-benzylidene]carbazoylmethyl]-~,N"N-trimethylammonium chlori~e (188 mg.). Mp 199 to 205C (dec.).

Example 498 A solution of hydroxylamine hydrochloride (35 mg.) in water was added to 0.lN-sodium hydroxide aqueous solution (5 ml.) of 3-[2-~'2-(2-benzoyl--4-chlorophenoxy)acetamido~-2-phenylacetamido]lactacillanic acid (160 mg.). The solution was adjusted to pH 6.0 to 6.2 by adding a small amount of hydroxylamine hydrochloride and stirred for 10 minutes.

_ 300 -DEMAI\IDES OU BREVETS VOL~JMII~IEUX

LA PRÉSENTE PARTIE DE CETTE~ DEMANDE OU CE BREVET
COMPREND PLUS D'UN TOME.

CECI EST LE TOME / DE ~/

NOTE: Pour les tomes additionels, veuille~ contacter le Bureau canadien des brevets ~06~/~``
_ _ JUMBO APPLICATIONS/PATENTS

THIS SECTION OF THE APPLICATION/PATENT CONTAINS MORE
THAN ONE YOLUME

THIS IS VOLUME ~ OF Z

NOTE: For additilDnal vo1umes p1easQ contact the Canadian Patent O~fice .

. . . ^ ~ . , . ~

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. ~

Claims (108)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A process for preparing an azetidinone derivative of the formula (I):

(I) wherein R1 is amino or acylamino, and A is hydrogen, or a group of the formula:

or in which RU is hydrogen and RV is hydrogen or alkyl containing up to 6 carbon atoms, or RU and RV are linked together to form alkylidene containing up to 6 carbon atoms, RW is carboxy or its derivative, or cyano, R?, R? and R? are same or different group selected from hydrogen, hydroxy, amino, benzyloxycarbonylamino, nitro, alkyl containing up to 6 carbon atoms, alkoxy containing up to 6 carbon atoms, benzyloxy, ethoxycarbonyloxy, alkylthio containing up to 6 carbon atoms and halogen, and RX is carboxy or its derivative, provided that, when A is hydrogen, or a group of the formula:

in which RU, RV,and RW are each as defined above, R1 is amino;
phenylalkanoylamino whose alkyl moiety contains up to 6 carbon atoms;
phenoxyalkanoylamino whose alkyl moiety contains up to 6 carbon atoms; or phenylalkoxycarbonylamino whose alkyl moiety contains up to 6 carbon atoms;
which comprises (i) reacting a compound of the formula;

(II) wherein A is as defined above, with an acylating agent to give a compound of the formula:

(III) wherein R? is acylamino and A is as defined above, provided that, when A is hydrogen, or a group of the formula:

in which RU, RV and RW are each as defined above, R? is phenylalkanoylamino whose alkyl moiety contains up to 6 carbon atoms:
phenoxyalkanoylamino whose alkyl moiety contains up to 6 carbon atoms; or phenylalkoxycarbonylamino whose alkyl moiety contains up to 6 carbon atoms; or (ii) eliminating the acyl group of a compound of the formula:

(IV) wherein R? is acylamino, and AX is hydrogen or a group of of the formula:

or in which R? is carboxy or its derivative, and RUand RV, are each as defined above; provided that, when AX is a group of the formula:

in which RU, RV and R? are each as defined above, R? is phenylalkanoylamino whose alkyl moiety contains up to 6 carbon atoms; or phenoxyalkanoylamino whose alkyl moiety contains up to 6 carbon atoms;
to give a compound of the formula:

(V) wherein AX is as defined above; or (iii) reacting a compound of the formula:

(VI) wherein R? is as defined above, with an N-substituting agent of the formula:
AY - X1 (VII) wherein AY is a group of the formula:

or in which R? is hydrogen or alkyl containing up to 6 carbon atoms; R?, R?, R?, R? and RX are each as defined above, and X1 is halogen, to give a compound of the formula:

(VIII) wherein R? and AY are each as defined above, provided that, when AY is a group of the formula:

in which R? and R? are each as defined above, R? is phenyl-alkanoylamino whose alkyl moiety contains up to 6 carbon atoms;
or (iv) subjecting a compound of the formula:

(IX) wherein R? is phenylalkanoylamino whose alkyl moiety contains up to 6 carbon atoms; phenoxyalkanoylamino whose alkyl moiety contains up to 6 carbon atoms, or phenylalkoxycarbonylamino whose alkyl moiety contains up to 6 carbon atoms, and Y is oxalo, esterified oxalo or alkyl whose first carbon is sub-stituted by protected amino or protected hydroxy, to an elimination reaction to give a compound of the formula:

(X) wherein R? is as defined above; or (v) subjecting a compound of the formula:

(XI) wherein R12 is acyl having protected amino, protected hydroxy or protected carboxy function, R13 is hydrogen or alkyl contain-ing up to 6 carbon atoms, and X2 is hydrogen or halogen, to a removal reaction of a protective group in protected amino, protected hydroxy or protected carboxy, to give a compound of the formula:

(XII) wherein R?2 is acyl having an amino, hydroxy or carboxy function, and R13 and X2 are each as defined above; or (vi) hydrolysing a compound of the formula:

(XIII) wherein R2 is amino or acylamino, to give a compound of the formula:

(XIV) wherein R2 is as defined above; or (vii) reducing a compound of the formula:

(XV) wherein R3is amino or acylamino, and R4 is oxo or hydroxyimino, to give a compound of the formula:

(XVI) wherein R3 is as defined above and R5 is hydroxy or amino;
or (viii) reacting a compound of the formula:

(XVII) wherein R6 and R7 are combined to form oxo or hydroxyimino, or R6 is hydrogen, and R7 is amino or hydroxy, with an acylating agent to give a compound of the formula:

(XVIII) wherein R8 is acylamino, and R9 and R10 are combined to form oxo or hydroxyimino or R9 is hydrogen and R10 is amino, hydroxy, acylamino or acyloxy; or (ix) reacting a compound of the formula:

(XIX) wherein X1 is acid residue, and A1 is bivalent aliphatic hydrocarbon radical, with a nucleophile of the formula:
R11 - H (XX) wherein R11 is a residue of nucleophile, to give a compound of the formula:

(XXI) wherein R11 and A1 are each as defined above, or (x) reacting a compound of the formula:

(XXII) Wherein R14 is acyl, with a halogenating agent to give a compound of the formula:

wherein R18 and R19 are each as defined above; or (xiii) reacting a compound of the formula:

(XXVIII) wherein R20 is amino or acylamino, with an aryl halide of the formula:
R21 - X (XXIX) wherein R21 is aryl substituted by at least one substituent selected from nitro and esterified carboxy and X is halogen, to give a compound of the formula:

(XXX) wherein R22 is arylamino whose aryl ring is substituted by at least one substituent selected from nitro and esterified carboxy, or acylamino and R21 is as defined above; or (xiv) reacting a compound of the formula:

(XXXI) with a carbonyl compound of the formula:

(XXXII) wherein R''' and R'''' which may be the same or different are selected from hydrogen and alkyl, or its acetal or ketal, and reducing the resultant product to give a compound of the formula:

(XXXIII) (XXIII) wherein R14 is as defined above, X3 is hydrogen or halogen and X4 is halogen; or (xi) reacting a compound of the formula:

(XXIV) herein R15 is hydrogen, alkyl, aryl, aralkyl, aryloxy, heterocyclic group or heterocyclic alkyl, and R16 is amino or hydrocarbon residue having amino; with an acylating agent to give a compound of the formula:

(XXV) wherein R17 is acylamino or acylamino-substituted-hydrocarbon residue; or (xii) oxidizing a compound of the formula:

(XXVI) wherein R18 is hydrogen or aryl, and R19 is alkyl, N-aryl-carbamoylalkyl or aryl, to give a compound of the formula:

(XXVII) wherein R23 is mono- or di- alkylamino; or (xv) reducing a compound of the formula:

(XXXIV) wherein R24 is nitroaryl, to give a compound of the formula:

(XXXV) wherein R25 is aminoaryl; or (xvi) reacting a compound of the formula:

(XXXVI) wherein R26 is hydrogen or aryl; X5 is hydrogen or halogen;
and A2 is a bivalent aliphatic hydrocarbon radical with an amine compound of the formula:
R27 - NH2 (XXXVII) wherein R27 is hydroxy, alkoxy or amino, to give a compound of the formula:

(XXXVIII) wherein R26, R27, A2 and X5 are each as defined above; or (xvii) reacting a compound of the formula:

(XXXIX) wherein R28 is acylamino, with an acylating agent to give a compound of the formula:
(XL) wherein R28 and R29 are each acylamino; or (xviii) reacting a compound of the formula:
(XLI) wherein R30 and R31 are combined to form oxo or hydroxyimino, or R30 is hydrogen and R31 is hydroxy, with a hydroxyalkane-sulfonic acid of the formula:

(XLII) wherein R32 and R33 are hydrogen or alkyl, to give a compound of the formula:
(XLIII) wherein R30, R31, R32 and R33 are each as defined above; or (xix) reacting a compound of the formula:
(XLIV) wherein R34 is acylamino, and R35 and R36 are combined to form oxo or hydroxyimino, or R35 is hydrogen and R36 is acylamino or hydroxy; with an esterifying agent to give a compound of the formula:
(XLV) wherein R34 is as defined above, R37 and R38 are combined to form oxo, hydroxyimino, alkoxyimino, or substituted alkoxy-imino or, R37 is hydrogen and R38 is acylamino, hydroxy, alkoxy or substituted alkoxy, R39 is alkyl or substituted alkyl, R40 is hydrogen, alkyl or substituted alkyl, and R41 is alkyl or substituted alkyl, or (xx) oxidizing a compound of the formula:
(XLVI) wherein R42 is alkyl, aryl or aralkyl, and A3 is alkylene, to give a compound of the formula:

(XLVII) wherein R42 and A3 are each as defined above; or (xxi) reacting a compound of the formula:
(XLVIII) with a diazotizating agent and then solvolyzing the resulting diazonium salt, to give a compound of the formula:

(IL) (xxii) reacting a compound of the formula:

(L) wherein A4 is bivalent aliphatic hydrocarbon radical; with an aryl halide of the formula:
R43 - X (LI) wherein R43 is aryl, substituted by at least one substituent of nitro and esterified carboxy or aromatic heterocyclic group, and X is halogen, to give a compound of the formula:

(LII) wherein R43 and A4 are each as defined above: or (xxiii) reacting a compound of the formula:

(LIII) wherein R44 is aralkyl, with an alkylating agent to give a compound of the formula:

(LIV) wherein R44 is as defined above, R45 is is alkyl, and R46 is hydrogen or alkyl; or (xxiv) subjecting a compound of the formula:

(LV) wherein R62 is phenylalkanoylamino, R47 is carboxy or its derivative, and R48 is a protected amino; to elimination reaction of the protective group of amino to give a compound of the formula:
(LVI) wherein R62 is as defined above:
(xxv) reacting a compound of the formula:

(LVII) wherein R63 is phenoxyalkanoyl bearing phenoxycarbonyl or alkoxyalkyl with a compound selected from hydrazine and aralkylamine to give a compound of the formula:
(LVIII) wherein R64 is phenoxyalkanoyl bearing hydrazono or N-aralkyloxamoyl; or (xxvi) reacting a compound of the formula:
(LIX) with an esterified alkenecarboxylic acid to give a compound of the formula:
(LX) wherein R65 is esterified carboxyalkyl; or (xxvii) reacting a compound of the formula:

(LXI) with an ester of alkanoylacetic acid to give a compound of the formula:
(LXII) wherein R66 is 1-alkyl-2-esterified carboxyvinyl; or (xxviii) reducing a compound of the formula:

(LXIII) wherein R67 is nitrobenzoyl- and halo- disubstituted phenoxyalkanoylamino, or azidoalkoxyphenyl, and R68 is hydrogen or phenyl, to give a compound of the formula:

(LXIV) wherein R68 is as defined above, and R69 is aminobenzoyl-and halo- disubstituted phenoxyalkanoylamino, or amino-alkoxyphenyl; or (xix) reducing a compound of the formula:
(LXV) wherein R70 is hydrogen or phenyl, and R71 is formylphenoxy, formylphenoxyalkanoylamino or phenylglyoxyloylamino, to give a compound of the formula:

(LXVI) wherein R70 is as defined above, and R72 is hydroxyphenyl, hydroxyphenoxyalkanoylamino or 2-phenylglycoloylamino; or (xxx) reacting a compound of the formula:
(LXVII) with an aralkylamine under reductive condition to give a compound of the formula:

(LXVIII) wherein R57 is aralkylamino; or (xxxi) reacting a compound of the formula:
(LXIX) wherein X6 is halogen, with trialkylamine to give a compound of the formula:
(LXX) wherein X6 is as defined above, and R58, R59 and R60 are each alkyl; or (xxxii) reacting a compound of the formula:

(LXXI) with an aralkanoylating agent to give a compound of the formula:

(LXXII) wherein R61 is aralkanoylamino.

2. A process according to claim 1 which comprises reacting said compound of formula (II); with an acylating agent to give said compound of formula (III).

3. A process according to claim 2, wherein R? is phenyl-acetamido and A is hydrogen or a group of the formula:
-CH2COOH, -CH2COOC2H5, , , -CH2CN, , , , or , , , , ,

4. A process according to claim 2, wherein R? is phenoxyacetamido and A is a group of the formula:

5. A process according to claim 2, wherein R? is 2-(2-thienyl)acetamido, and A is a group of the formula:

6. A process according to claim 2, wherein R? is 2-phenylacetamido, 2-phenoxyacetamido, 2-acetamido-2-[4-(3-acetamido-3-methoxycarbonylpropoxy)phenyl]acetamido, 2-[4-(3-acetamido-3-methoxycarbonylpropoxy)phenyl]-2-methoxy-iminoacetamido or 2-[4-(3-phthalimido-3-methoxycarbonyl-propoxy)phenyl]-2-methoxyiminoacetamido, and A is a group of the formula:

7. A process according to claim 2, wherein R? is acylamino, and A is a group of the formula:

8. A process according to claim 2, wherein A is a group of the formula:

, and R? is 2-phenylacetamido, 2-bromobutyramido, 2-phenyl-N-benzyloxycarbonylglycinamido, 2-phenyl-2-methylthioacetamido, 2-phenyl-2-bromoacetamido, 2-phenyl-2-(2-chlorophenoxy)acetamido, 2-phenyl-N-benzenesulfonylglycinamido, 2-phenyl-2-methoxy-acetamido, 2-phenyl-2-(4-formylphenoxy)acetamido, 2-phenyl-2-(2-naphthoxy)acetamido, 2-(3-methyl-1,2,5-oxadiazol-4-yl)aceta-mido, 2-(4-benzyloxycarbonyloxyphenyl)acetamido, 3-phenyl-3-benzyloxycarbonylaminopropionamido, 2-(1-naphthyl)acetamido, 6-benzyloxycarbonylaminohexanamido, 2-(2-thienyl)acetamido, 3-carboxypropionamido, 2-(4-chloroacetylphenyl)acetamido, 2-(2-furyl)acetamido, ethoxalylamino, N-methanesulfonyl-N-phenylglycinamido, 2-methoxyacetamido, N-methanesulfonyl-glycinamido, 2-(4-biphenylyloxy)acetamido, 2-(2-naphthoxy)-acetamido, 2-phenoxyacetamido, 2-(2-formylphenoxy)acetamido, 2-[4-(2-nitrovinyl)phenoxy]acetamido, 2-[4-(2-methoxycarbonyl -2-benzyloxycarbonylaminoethyl)phenoxy]acetamido, 2-[4-(1-methoxycarbonyl-1-benzyloxycarbonylaminomethyl)phenoxy]acetamido, 2-(4-formylphenoxy)acetamido, N-(4-chlorobenzenesulfonyl)-glycinamido, 2-allylthioacetamido, 2-methylthioacetamido, 2-(4-nitrophenoxy)acetamido, 2-azidoacetamido, 2-bromoacetamido, 2-[4-(2-ethoxycarbonylvinyl)phenoxy]acetamido, 2-chloroacetamido, 2-phenylthioacetamido, cinnamoylamino, 4-(2-phenoxyacetamido)-benzamido, 3,5-dinitrobenzamido, 4-nitrobenzamido, 4-methoxy-benzamido, 3-(2-chlorophenyl)-5-methylisoxazole-4-carboxamido, 2,2-dichloroacetamido, 2,2-diphenylacetamido, benzenesulfonamido, phenoxycarbonylamino, 2-(2-thienyl)-N-(2,2,2-trichloroethoxy-carbonyl)glycinamido, 2-anilinoacetamido, 2-cyano-2-hydroxy-iminoacetamido, 2-(1H-tetrazol-1-yl)acetamido, glycinamido, 2-morpholinoacetamido, N-methyl-N-phenylglycinamido, 2,2-dimethylpropionamido, 2-phenylglycinamido, 3-amino-3-phenyl-propionamido, 4-aminobenzamido, N-phenyl-2-phenylglycinamido, N-benzyl-N-methylglycinamido, 2-(1-naphthylamino)acetamido, 3-(3-oxo-4-isoxazolidinyl)ureido, 4-hydroxyphenylglyoxyloyl-amino, 2-(2-thienyl)glycoloylamino, 2-thienylglyoxyloylamino, pyruvolylamino, 4-methoxycarbonylmethoxyphenylglyoxyloylamino, 4-allyloxyphenylglyoxyloylamino, butyramido, 4-methoxyphenyl-glyoxyloylamino, 2-(2-thienyl)-2-(3-phenylpropionamido)acetamido, 2-(4-hydroxyphenyl)-N-benzyloxycarbonylglycinamido, 2-(4-hydroxyphenyl)acetamido, 3-benzoylpropionamido, 2-(4-hydroxy-methyl(phenoxy)acetamido, 2-(4-chloro-2-nitrophenoxyacetamido)-acetamido, 2-(4-hydroxyiminomethylphenoxy)acetamido, N-phenyl-N-azidoacetylglycinamido, 2-(pyridin-1-oxide-2-ylthio)-acetamido, 2-(1,3,4-thiadiazol-2-ylthio)acetamido, 2-(4-ethoxybenzylideneaminooxy)acetamido, 2-(1-benzotriazolyloxy)-acetamido, N-benzyloxycarbonylglycinamido, 2-[5-(2-thienyl)-1H-tetrazol-1-yl]acetamido, 3-methylthioacryloylamino, 2-(2-thienyl)-N-benzyloxycarbonylglycinamido, N-methyl-N-benzyloxy-carbonylglycinamido, 2-methoxyimino-2-(4-methoxyphenyl)acetamido, 2-(2-thienyl)-2-[2-(4-chloro-2-nitrophenoxy)acetamido]acetamido, 2-phenyl-2-sulfoacetamido, 2-phenylglycoloylamino, phthalimido, 2-(3-benzisoxazolyl)-N-benzyloxycarbonylglycinamido, 3-(3-indolyl)-2-benzyloxycarbonylaminopropionamido, 3-phenylureido, guanidinocarbonamido, 2-phenyl-N-(2,2,2-trichloroethoxycarbonyl)-glycinamido, 2-(4-nitrophenyl)acetamido, 2-(bornyloxy)acetamido, 2-phenyl-2-(2-thienyl)acetamido, 2-carboxy-2-phenylacetamido, 2-(2-nitrophenoxy)acetamido, 2-(2-pyridyloxy)acetamido, 2-(5,6-dihydro-2H-pyran-3-yl)glycoloylamino, 2-phenyl-2-(2-bromoacetamido)acetamido, 2-(.alpha.-ethoxycarbonylbenzylideneamino-oxy)acetamido, 2-phenyl-2-(N-phenylcarbamoyl)acetamido, 2-ethoxycarbonyl-2-phenylacetamido, 2-(5,6-dihydro-2H-pyran-3-yl)-N-chloroacetylglycinamido, 2-methanesulfinyl-2-phenylaceta-mido, 2-[2-(4-chloro-2-nitrophenoxy)acetamido]-2-phenylaceta-mido, 2-(2-thienyl)-N-bromoacetylglycinamido, N-carboxy-methyl-N-phenylglycinamido, 2-[4-(3-bromopropoxy)phenyl]acetami-do, 2-benzenesulfonyloxyacetamido, 2-[4-(3-azidopropoxy)phenyl]-acetamido, 2-(3-phenyl-5-oxo-4,5-dihydro-1,2,4-oxadiazol-4-yl)acetamido, 2-[4-(3-benzyloxycarbonylaminopropyl)phenoxy]-acetamido, 2-phenyl-2-(3-phenyl-1,2,4-oxadiazol-5-ylamino)-acetamido, palmitoylamino, 2-phenyl-2-(2-thenilideneaminooxy)-acetamido, 2-phenoxy-2-(2-nitrophenoxy)acetamido, 2-phenyl-2-phenylglyoyloylamino)acetamido, 2-phenyl-2-[N- 2-(2-phenyl-acetamido)ethyl carbamoyl]acetamido, 2-phenacylthioacetamido, 2-phenyl-2-(6-benzyloxycarbonylaminohexanamido)acetamido, 2-phenyl-2-[2-(2-thienyl)acetamido]acetamido, 2-phenyl-2-[2-(pyridin-1-oxide-2-ylthio)acetamido]acetamido, 2-phenyl-2-[2-phenyl-2-(2-chlorophenoxy)acetamido]acetamido, 2-phenyl-2-[3-(2-chlorophenyl-5-methylisorazole-4-carboxamido]acetamido, 2-phenyl-2-[2-{2-(4-chloro-2-nitrophenoxy)acetamido}-ethyl-thio]acetamido, 2-phenyl-2-(2-bornyloxyacetamido)acetamido, 2-phenyl-2-[2-(4-chloro-2-benzoylphenoxy)acetamido]acetamido, 2-phenyl-2-[2-(2-ethoxycarbonylphenoxy)acetamido]acetamido, 2-(N-phenylcarbamoyl)-2-(2-phenylacetamido)acetamido, 2-phenoxy-2-(2-acetamidophenoxy)acetamido, 2-(2-thienyl)-2-[2-phenyl-N-(2,2,2-trichloroethoxycarbonyl)glycinamido]acetamido, 2-phenyl-N-ethoxalylglycinamido, 2-phenyl-2-[N-(N-benzyloxamoyl)-amino]acetamido, 2-phenyl-2-(2-phenoxyacetamido)acetamido, 2-phenyl-2-(2-benzenesulfonyloxyacetamido)acetamido, 2-phenyl-2-[2-(2-formylphenoxy)acetamido]acetamido, 2-phenyl-2-[2-(2-propionylphenoxy)acetamido]acetamido, 2-phenyl-2-[2-(4-benzoylphenoxy)acetamido]acetamido, 2-phenyl-2-[2-(2-biphenylyl-oxy)acetamido]acetamido, 2-phenyl-2-[2-(2-phenoxycarbonyl-phenoxy)acetamido]acetamido, 2-[4-{3-(4-nitrophenylthio)propoxy}
phenyl]acetamido, 2-phenyl-2-[2-(2-naphthoxy)acetamidooxy]aceta-mido, 3-methyl-2-[2-oxo-3-(2-phenylacetamido)-1-azetidinyl]-butyramido, 2-phenyl-2-[2-(2-phenoxycarbonylphenylthio)aceta-mido]acetamido, 2-phenyl-2-(N-phenyl-N-benzenesulfonylglycin-amido)-acetamido, 2-phenyl-2-[2-{4-chloro-2-(4-nitrobenzoyl)-phenoxy}acetamido]acetamido, 2-phenyl-2-(2,2-diphenoxyacetamido)-acetamido, 2-phenyl-2-[2-phenyl-2-(2-naphthoxy)acetamido]aceta-mido, 2-phenyl-2-[2,2-di(1-naphthoxy)acetamido]acetamido, 2-phenyl-2-[2-{5-(2-thienyl)-1H-tetrazol-1-yl}acetamido]-acetamido, 2-phenyl-2-[2-[4-chloro-2-{4-(2-bromoacetamido)-benzoyl}-phenoxy]acetamido]acetamido, 2-phenyl-2-[2-(4-methoxyphenyl)-2-benzyloxyiminoacetamido]acetamido, 2-phenyl-2-[2-{4-chloro-2-(2-furoyl)phenoxy}-acetamido]acetamido, 2-methyl-5,6-dihydro-1,3-oxathiin-3-carboxamido, 4-(3-benzyloxy-carbonyl-5-oxo-4-oxazolidinyl)-butyramido, 2-(2-propionyl-phenoxy)acetamido, 2-methyl-2-[4-{N-(2,2,2-trichloroethoxycar-bonyl)-4-chloroanilinomethyl}phenoxy]propionamido, 2-hydroxy-imino-2-(4-benzyloxyphenyl)acetamido, 2-hydroxyimino-2-phenylacetamido or 2-hydroxyimino-2-(2-thienyl)acetamido.

9. A process according to claim 1(ii), which comprises eliminating the acyl group of said compound of formula (IV), to give said compound of formula (V).

10. A process according to claim 9, wherein Ax is a group of the formula:

, and R? is 2-phenylacetamido, 2-(3-phenylthioureido)-2-[4-(3-carboxy-3-benzamidopropoxy)phenyl]acetamido, 2-(3-phenylthio-ureido)-2-[4-{3-carboxy-3-(3-phenylthioureido)propoxy}phenyl]-acetamido, 2-(3-phenylthioureido)-2-[4-(3-carboxy-3-acetamido-propoxy)phenyl]acetamido, 2-ethoxy(thiocarbonyl)amino-2-[4-{3-carboxy-3-ethoxy(thiocarbonyl)aminopropoxy}phenyl]
acetamido, 2-(4-methoxycarbonyl-2-nitroanilino)-2-[4-(3-carboxy-3-benzamidopropoxy)phenyl]acetamido, 2-(4-methoxycarbonyl-2-nitroanilino)-2-[4-{3-carboxy-3-(4-methoxycarbonyl-2-nitro-anilino)propoxy}phenyl]acetamido, 2-[3-(1-naphthyl)thioureido]-2-[4-(3-carboxy-3-acetamidopropoxy)phenyl]acetamido, or 2-[3-(1-naphthyl)thioureido]-2-[4-[3-carboxy-3-{3-(1-naphthyl) thioureido}propoxy]phenyl]acetamido.

11. A process according to claim 9, wherein R? is 2-phenylacetamido, and Ax is a group of the formula:

12. A process according to claim 9, wherein R? is 2-phenoxyacetamido, and Ax is a group of the formula:

13. A process according to claim 1 (iii), which comprises reacting said compound of the formula (VI) with said N-substituting agent of the formula (VII) to give said compound of formula (VIII).

14. A process according to claim 13, wherein R? is 2-phenylacetamido, X1 is bromo, and AY is a group of the formula:

-CH2COOH, -CH2COOC2H5, , -CH2CN, , , , , , or

15. A process according to claim 13, wherein R? is 2-phenoxyacetamido, X1 is bromo, and AY is a group of the formula:

16. A process according to claim 13, wherein R? is 2-phenylacetamido, 2-phenoxyacetamido or 2-methoxyimino-2-[4-(3-methoxycarbonyl-3-phthalimido-propoxy)phenyl]acetamido, X1 is bromo, and AY is a group of the formula:

17. A process according to claim 13, wherein X1 is bromo, AY is a group of the formula:

, and R? is 2-phenylacetamido, 2-(1-naphthyl)acetamido, 2-(4-hydroxyphenyl)acetamido, butyramido, 2-methoxyacetamido, 2-(4-biphenylyloxy)acetamido, 4-methoxybenzamido, 2,2-dimethyl-propionamido, phthalimido, 2-morpholinoacetamido, 2-phenyl-2-methoxyacetamido, 3-carboxypropionamido, N-phenyl-N-methyl-glycinamido, 2-(2-furyl)acetamido, 2-(2-naphthoxy)acetamido, 2-phenoxyacetamido, 2-phenyl-2-(2-chlorophenoxy)acetamido, 2-(3-methyl-1,2,5-oxadiazoi-4-yl)acetamido, 2-(2-thienyl)-acetamido, 3-benzoylpropionamido, 2-thienylglyoxyloylamino, pyruvoylamino, 4-methoxyphenylglyoxy-loylamino, N-phenyl-N-methanesulfonylglycinamido, 2-(1H-tetrazol-1-yl)acetamido, 2-allylthioacetamido, 2-methylthio-acetamido, 2-(4-nitrophenoxy)acetamido, 2-(1,3,4-thiadiazol-2-ylthio)acetamido, 2-(4-ethoxybenzylideneaminooxy)acetamido, 2-(1-benzotriazolyloxy)acetamido, cinnamoylamino, 3,5-di-nitrobenzamido, 4-nitrobenzamido, 3-(2-chlorophenyl)-5-methylisoxazole-4-carboxamido, 4-allyloxyphenylglyoxyloylamino, 2,2-diphenylacetamido, 2-phenyl-2-(2-naphthyl)acetamido, 2-[5-(2-thienyl)-1H-tetrazol-1-yl)acetamido, 2-phenyl-2-methyl-thioacetamido, palmitoylamino, 2-(bornyloxy)acetamido, 2-phenyl-2-(2-bornyloxyacetamido)acetamido, 2-phenyl-2-[2-(2-ethoxycarbonylphenoxy)acetamido]acetamido, 2-phenyl-2-(N-phenylcarbamoyl)acetamido, 2-phenyl-2-ethoxycarbonylacetamido, 2-phenyl-2-N-[2-(2-phenylacetamido)ethyl]carbamoylacetamido, 2-(2-pyridyloxy)acetamido, 2-phenyl-2-[2-(2-thienyl)acetamido]-acetamido, 2-phenyl-2-[2-(4-chloro-2-nitrophenoxy)acetamido]-acetamido, 2-phenyl-2-[2-phenyl-2-(2-chlorophenoxy)acetamido]-acetamido, 2-phenyl-2-[3-(2-chlorophenyl)-5-methylisorazole-4-carboxamido]acetamido, 2-phenacylthioacetamido, 2-(4-nitrophenyl)acetamido, 2-phenyl-2-[2-(4-chloro-2-benzoyl-phenoxy)acetamido]acetamido, 2-phenyl-2-phenylglyoxyloyl-aminoacetamido, 2-(2-thienyl)-2-phenylacetamido, 2-(2-thienyl)-2-[2-(4-chloro-2-nitrophenoxy)acetamido]acetamido, 2-(2-nitrophenoxy)acetamido, 2-phenoxy-2-(2-nitrophenoxy)acetamido, 2-phenyl-2-carboxyacetamido, 2-phenyl-2-(2-thenylidene-aminooxy)acetamido, 2-phenyl-2-[2-{2-(4-chloro-2-nitrophenoxy)-acetamido}ethylthio]acetamido, 2-[4-{3-(4-nitrophenylthio)pro-poxy}phenyl]acetamido, 2-phenyl-2-[N-(2-naphthyl) carbamoyl-methylthio]acetamido, or 3-methyl-2-[2-oxo-3-(2-phenylacetamido)-1-azetidinyl]butyramido.

18. A process according to claim 1 (iv) which comprises subjecting said compound of formula (IX) to an elimination reaction to give said compound of formula (X).

19. A process according to claim 18, wherein R? is 2-phenoxyacetamido or benzyloxycarbonyl, and Y is methoxalyl.

20. A process according to claim 18, wherein R? is 2-phenylacetamido and Y is 1-methoxycarbonyl-2-methylpropyl or 1-(2,2,2-trichloroethoxycarbonylamino)-2-methylpropyl.

21. A process according to claim 1 (v), which comprises subjecting said compound of formula(XI) to a removal reaction of a protective group in protected amino, protected hydroxy or protected carboxy, to give said compound of formula (XII).

22. A process according to claim 21, wherein R12 is 2-hydroxyimino-2-[4-{3-carboxy-3-(2,2,2-trifluoroacetamido)-propoxy}phenyl]acetyl, R?2 is 2-hydroxyimino-2-[4-(3-carboxy-3-aminopropoxy)-phenyl]acetyl, X2 is bromo, and R13 is hydrogen.

23. A process according to claim 21, wherein R12 is 2-methoxyimino-2-[4-{3-methoxycarbonyl-3-(2,2,2-trifluoro-acetamido)propoxy}phenyl]acetyl, R?2 is 2-methoxyimino-2-[4-(3-carboxy-3-aminopropoxy)-phenyl]acetyl, X2 is hydrogen, and R13 is methyl.

24. A process according to claim 21, wherein X2 is hydrogen, R13 is hydrogen, and R12 is 6-benzyloxycarbonyl-aminohexanoyl, N-benzyloxycarbonylglycyl, 2-phenyl-N-benzyloxy-carbonylglycyl, 2-(4-hydroxyphenyl)-N-benzyloxycarbonylglycyl, 3-phenyl-3-benzyloxycarbonylaminopropionyl, 2-benzyloxy-carbonylamino-3-(3-indolyl)propionyl, N-methyl-N-benzyloxy-carbonylglycyl, 2-[4-(1-carboxy-1-benzyloxycarbonylaminomethyl)-phenoxy]acetyl, 2-[4-(3-benzyloxycarbonylaminopropyl)phenoxy]-acetyl, 2-phenyl-2-(6-benzyloxycarbonylaminohexamido)acetyl, 2-phenyl-2-[2-{4-chloro-2-(4-benzyloxycarbonylaminobenzoyl)-phenoxy}acetamido]acetyl, 2-phenyl-2-[2-(2-benzyloxycarbonyl-aminomethyl-1,3,4-thiadiazol-5-ylthio)acetamido]acetyl, 2-phenyl-2-[2-[4-chloro-2-[4-{2-(2-benzyloxycarbonylaminoethylthio)-acetamido}benzoyl]phenoxy]acetamido]acetyl, 4-benzyloxy-carbonylaminobenzoyl, 2-(2-benzyloxycarbonylaminomethyl-1,3,4-thiadiazol-5-ylthio)acetyl, 2-(2-benzyloxycarbonylamino-ethylthio)acetyl,2-[4-(3-benzyloxycarbonylaminopropoxy)-phenyl]acetyl, 2-(2-thienyl)-N-(2,2,2-trichloroethoxycarbonyl)-glycyl, 2-(2-thienyl)-2-[2-phenyl-N-(2,2,2-trichloroethoxy-carbonyl)glycinamido]acetyl, 2-phenyl-N-(2,2,2-trichloro-ethoxycarbonyl)glycyl, 2-(4-benzyloxycarbonyloxyphenyl)-acetyl, 2-phenyl-2-ethoxycarbonylacetyl, 3-methoxycarbonyl-propionyl, 4-acetoxyphenylglyoxyloyl, 2-phenyl-2-[2-(2-ethoxycarbonylphenoxy)acetamido]ac tyl, 4-methoxycarbonyl-methoxyphenylglyoxyloyl, 2-(4-methoxycarbonylmethoxyimino-methylphenoxy)acetyl, 2-phenyl-2-(4-methoxycarbonylmethoxy-iminomethylphenoxy)acetyl, 2-phenyl-2-[2-(2-methoxycarbonyl-phenylthio)acetamidoacetyl, 2-[4-(4-hydroxy-3-methoxycarbonyl-benzenesulfonamido)-phenyl]acetyl, 2-phenyl-2-[2-(2-methoxy-carbonylbenzenesulfinyl)-acetamido]acetyl, 2-phenyl-2-(4-hydroxy-3-methoxycarbonylbenzenesulfonamido)acetyl, 2-phenyl-2-[2-[2-{4-(2-methoxycarbonylmethylthioacetamido)-benzoyl}-4-chlorophenoxy]acetamido]acetyl, 2-hydroxyimino-2-[4-{3-(2-methoxycarbonylethylamino)-3-carboxy}phenyl]-acetyl, 2-[4-(2-ethoxycarbonylvinyl)phenoxy]acetyl, 2-(.alpha.-ethoxycarbonylbenzylideneaminooxy)acetyl, 2-phenyl-2-(2-ethoxycarbonylphenylthio)acetyl, 2-phenyl-O-acetylglycoloyl, 2-(2-thienyl)-O-acetylglycoloyl, 2-(5,6-dihydro-2H-pyran-3-yl)-O-acetylglycoloyl, 2-[4-(4-acetoxy-3-carboxybenzenesulfon-amido)phenyl]acetyl, 2-phenyl-2-(4-acetoxy-3-carboxybenzene-sulfonamido)acetyl, 2-phenyl-2-(2-phenyl-O-acetylglycololyl-amino)acetyl, 2-methyl-2-[4-{N-(2,2,2-trichloroethoxycarbonyl)-4-chloroanilinomethyl}phenoxy]propionyl, 4-(3-benzyloxy-carbonyl-5-oxo-4-oxazolidinyl)butyryl, 2-[4-(1-methoxycarbonyl-1-benzyloxycarbonylaminomethyl)phenoxy]acetyl, 2-[4-(2-methoxycarbonyl-2-benzyloxycarbonylaminoethyl)phenoxy]acetyl, or 2-[4-(1-methoxycarbonyl-1-benzyloxycarbonylaminomethyl)-phenoxy]acetyl, and R?2 is 6-aminohexanoyl, glycyl, 2-phenylglycyl, 2-(4-hydroxyphenyl)glycyl, 3-phenyl-3-amino-propionyl, 2-amino-3-(3-indolyl)propionyl, N-methylglycyl, 2-[4-(1-carboxy-1-aminomethyl)phenoxy]acetyl, 2-[4-(3-aminopropyl)phenoxy]acetyl, 2-phenyl-2-(6-aminohexanamido)-acetyl, 2-phenyl-2-[2-{4-chloro-2-(4-aminobenzoyl)phenoxy}-acetamido]acetyl, 2-phenyl-2-[2-(2-aminomethyl-1,3,4-thia-diazol-5-yl-thio)acetamido]acetyl, 2-phenyl-2-[2-[4-chloro-2-[4-{2-(2-aminoethylthio)acetamido}benzoyl]phenoxy]acetamido]-acetyl, 4-aminobenzoyl, 2-(2-aminomethyl-1,3,4-thiadiazol-5-ylthio)acetyl, 2-(2-aminoethylthio)acetyl, 2-[4-(3-amino-propoxy)phenyl]acetyl, 2-(2-thienyl)glycyl, 2-(2-thienyl)-2-(2-phenylglycinamido)acetyl, 2-(4-hydroxyphenyl)acetyl, 2-phenyl-2-carboxyacetyl, 3-carboxypropionyl, 4-hydroxyphenyl-glycoloyl, 2-phenyl-2-[2-(2-carboxyphenoxy)acetamido]acetyl, 4-carboxymethoxyphenylglyoxyloyl, 2-(4-carboxymethoxyimino-methylphenoxy)acetyl, 2-phenyl-2-(4-carboxymethoxyimino-methylphenoxy)acetyl, 2-phenyl-2-[2-(2-carboxyphenylthio)-acetamido]acetyl, 2-[4-(4-hydroxy-3-carboxybenzenesulfonamido)-phenyl]acetyl, 2-phenyl-2-[2-(2-carboxybenzenesulfinyl)-acetamido]acetyl, 2-phenyl-2-(4-hydroxy-3-carboxybenzene sulfonamido)acetyl, 2-phenyl-2-[2-[2-{4-(2-carboxymethyl-thioacetamido)-benzoyl}-4-chlorophenoxy]acetamido]acetyl, 2-hydroxyimino-2-[4-{3-(2-carboxyethylamino)-3-carboxy}phenyl]-acetyl, 2-[4-(2-carboxyvinyl)phenoxy]acetyl, 2-(.alpha.-carboxy-benzylideneaminooxy)acetyl, 2-phenyl-2-(2-carboxyphenylthio)-acetyl, 2-phenylglycoloyl, 2-(2-thienyl)glycoloyl, 2-(5,6-di-hydro-2H-pyran-3-yl)glycoloyl, 2-[4-(4-hydroxy-3-carboxy-benezenesulfonamido)-phenyl]acetyl, 2-phenyl-2-(4-hydroxy-3-carboxybenzenesulfonamido)acetyl, 2-phenyl-2-(2-phenylglycol-oylamino)acetyl, 2-methyl-2-[4-(4-chloroanilinomethyl)phenoxy]-propionyl, 4-amino-4-carboxybutyryl, 2-[4-(1-methoxycarbonyl-1-aminomethyl)phenoxy]acetyl, 2-[4-(2-carboxy-2-benzyloxy-carbonylaminoethyl)phenoxy]acetyl, or 2-[4-(1-carboxy-1-benzyloxycarbonylaminomethyl)phenoxy]acetyl.

25. An azetidinone derivative of the formula:

wherein R1 and A are as defined in claim 1, whenever prepared by the process of claim 1 or by an obvious chemical equivalent.

26. An azetidinone derivative of formula (III), as defined in claim 2, whenever prepared by the process of claim 2 or by an obvious chemical equivalent thereof.

27. An azetidinone derivative of formula (III), as defined in claim 3, whenever prepared by the process of claim 3 or by an obvious chemical equivalent thereof.

28. An azetidinone derivative of formula (III), as defined in claim 4, whenever prepared by the process of claim 4 or by an obvious chemical equivalent thereof.

29. An azetidinone derivative of formula (III), as defined in claim 5, whenever prepared by the process of claim 5 or by an obvious chemical equivalent thereof.

30. An azetidinone derivative of formula (III), as defined in claim 6, whenever prepared by the process of claim 6 or by an obvious chemical equivalent thereof.

31. An azetidinone derivative of formula (III), as defined in claim 7, whenever prepared by the process of claim 7 or by an obvious chemical equivalent thereof.

32. An azetidinone derivative of formula (III), as defined in claim 8, whenever prepared by the process of claim 8 or by an obvious chemical equivalent thereof.

33. An azetidinone derivative of formula (V), as defined in claim 9, whenever prepared by the process of claim 9 or by an obvious chemical equivalent thereof.

34. An azetidinone derivative of formula (V), as defined in claim 10, whenever prepared by the process of claim 10 or by an obvious chemical equivalent thereof.

35. An azetidinone derivative of formula (V), as defined in claim 11, whenever prepared by the process of claim 11 or by an obvious chemical equivalent thereof.

36. An azetidinone derivative of formula (V), as defined in claim 12, whenever prepared by the process of claim 12 or by an obvious chemical equivalent thereof.

37. An azetidinone derivative of formula (VIII), as defined in claim 13, whenever prepared by the process of claim 13 or by an obvious chemical equivalent thereof.

38. An azetidinone derivative of formula (VIII), as defined in claim 14, whenever prepared by the process of claim 14 or by an obvious chemical equivalent thereof.

39. An azetidinone derivative of formula (VIII), as defined in claim 15, whenever prepared by the process of claim 15 or by an obvious chemical equivalent thereof.

40. An azetidinone derivative of formula (VIII), as defined in claim 16, whenever prepared by the process of claim 16 or by an obvious chemical equivalent thereof.

41. An azetidinone derivative of formula (VIII), as defined in claim 17, whenever prepared by the process of claim 17 or by an obvious chemical equivalent thereof.

42. An azetidinone derivative of formula (X), as defined in claim 18, whenever prepared by the process of claim 18 or by an obvious chemical equivalent thereof.

43. An azetidinone derivative of formula (X), as defined in claim 19, whenever prepared by the process of claim 19 or by an obvious chemical equivalent thereof.

44. An azetidinone derivative of formula (X), as defined in claim 20, whenever prepared by the process of claim 20 or by an obvious chemical equivalent thereof.

45. An azetidinone derivative of formula (XII), as defined in claim 21, whenever prepared by the process of claim 21 or by an obvious chemical equivalent thereof,

46. An azetidinone derivative of formula (XII), as defined in claim 22, whenever prepared by the process of claim 22 or by an obvious chemical equivalent thereof.

47. An azetidinone derivative of formula (XII), as defined in claim 23, whenever prepared by the process of claim 23 or by an obvious chemical equivalent thereof.

48. An azetidinone derivative of formula (XII), as defined in claim 24, whenever prepared by the process of claim 24 or by an obvious chemical equivalent thereof.

49. A process for preparing a compound of the formula:
I

wherein R1 is amino or acylamino, and R2' is hydrogen, or a group of the formula:
or in which R4' is hydrogen, alkyl, or phenyl which may be substituted by at least one substituent selected from hydroxy, substituted or unsubstituted aralkoxy and acyloxy R5 is carboxy or its derivative, substituted or unsubstituted alkoxycarbonylamino, acyloxy or alkyl bearing carboxy or its derivative, R? is carboxy or its derivative, R6 is hydrogen or alkyl, and R? is alkyl, or substituted or unsubstituted aryl, provided that, ? , when R2' is hydrogen, then R1 is amino;
? , when R2' is a group of the formula:

wherein R? is as defined above, then R1 is phenylglyoxyloylamino, 2-(2-furyl)glycoloylamino, bromopyruvoylamino, 2-(2-thienyl)-2-(2-azidoacetamido)acetamido, 2-benzyloxyimino-2-(4-methoxyphenyl)acetamido, 2-benzoyloxyimino-2-[4-(3-tert-butoxycarbonylamino-3-methoxycarbonylpropoxy)phenyl]acetamido, 2-[2-(2,2,2-trichloroethoxycarbonylaminomethyl)-phenoxy]acetamido, 2-[2- N-(2,2,2-trichloroethoxycarbonyl)-2-(carboxymethoxy)benzylaminomethyl phenoxy]acetamido, 2-benzyloxyimino-2-phenylacetamido, 4-(3-tert-butoxycarbonylamino-3-methoxy-carbonylpropoxy)phenylglyoxyloylamino, orotoylamino, 2-methoxyimino-2-[2-(2,2,2-trifluoroacetamido)-4-thiazolyl]acetamido, 4-(3-tert-butoxycarbonylamino-3-methoxycarbonyl-propoxy)-3-chlorophenylglyoxyloylamino, 4-(3-methoxycarbonylpropoxy)phenylglyoxyloylamino, 3-(3-tert-butoxycarbonylamino-3-methoxycarbonyl-propoxy)phenylglyoxyloylamino, 4-(3-phthalimidopropoxy)phenylglyoxyloylamino, N-[N-(2-nitrophenyl)oxamoyl]-2-phenylglycinamido, 2-[2-?2-(4-chloro-2-nitrophenoxy)acetamidomethyl?-phenoxy]acetamido, 2-[2-(2-bromoacetamidomethyl)phenoxy]acetamido, N-(N-benzyloxamoyl)amino, 2-[4-(3-amino-3-carboxypropoxy)phenyl]-2-(5-chlorosalicyloylamino)acetamido, 2-[4-(3-amino-3-carboxypropoxy)phenyl]-2-(3-phenylureido)acetamido.
2-[4-(3-amino-3-carboxypropoxy)phenyl]-2-(2-oxo-1-imidazolidinelcarboxamido)acetamido, 3-(3-amino-3-carboxypropoxy)phenylglyoxyloylamino, 2-[4-(3-amino-3-carboxypropoxy)-3-chlorophenyl]-2-hydroxyiminoacetamido, 4-(3-amino-3-carboxypropoxy)-3-chlorophenyl-glyoxyloylamino, 2-[4-(3-amino-3-carboxypropoxy)phenyl]-2-hydrazono-acetamido, 2-[4-?3-carboxy-3-(2-phenylglycinamido)propoxy?phenyl]-2-hydroxyiminoacetamido, 2-[4-(3-carboxy-3-glycinamidopropoxy)phenyl]-2-hydroxyiminoacetamido, 2-(2-aminoethoxyimino)-2-[4-(3-amino-3-carboxy-propoxy)phenyl]acetamido, 2-[2-(2-carboxymethoxybenzylaminolllethyl)phenoxy]-acetamido, 2-(2-aminomethylphenoxy)acetamido, 2-methoxyimino-2-(2-amino-4-thiazolyl)acetamido, 4-(3-aminopropoxy)phenylglyoxyloylamino, 2-[4-(3-amino-3-carboxypropoxy)phenyl]-2-(carboxy-methoxyimino)acetamido, 4-(3-tert-butoxycarbonylamino-3-carboxypropoxy)-phenylglyoxyloylamino, 3-(3-tert-butoxycarbonylamino-3-carboxypropoxy)-phenylglyoxyloylamino, 4-(3-carboxypropoxy)phenylglyoxyloylamino, 4-(3-tert-butoxycarbonylamino-3-carboxypropoxy)-3-chlorophenylglyoxyloylamino, 2-[4-(3-tert-butoxycarbonylamino-3-carboxypropoxy)-phenyl]-2-(5-chlorosalicyloylamino)acetamido, 2-[4-(3-tert-butoxycarbonylamino-3-carboxypropoxy)-phenyl]-2-(2-oxo-1-imidazolidinecarboxamido)-acetamido, 2-benzamido-2-[4-(3-tert-butoxycarbonylamino-3-carboxypropoxy)phenyl]acetamido, 2-[4-(3-tert-butoxycarbonylamino-3-carboxypropoxy)-phenyl]-2-(3-phenylureido)acetamido, 2-(2-aminoacetamido)-2-(2-thienyl)acetamido, N-[N-(2-hydroxyethyl)oxamoyl]amino, (2-amino-2-carboxyethylthio)pyruvoylamino, 2-[4-(3-amino-3-carboxypropoxy)phenyl]-2-(2-phenylacetamido)acetamido, 2-[4-(3-tert-butoxycarbonylamino-3-carboxypropoxy)-phenyl]-2-hydroxyiminoacetamido, 2-[4-(3-amino-3-carboxypropoxy)phenyl]glycoloylamino, 2-hydroxyimino-2-(4-hydroxyphenyl)acetamido, 2-[4-(3-amino-3-methoxycarbonylpropoxy)phenyl]-2-hydroxyiminoacetamido, 2-[4-(3-tert-butoxycarbonylamino-3-carboxypropoxy)-phenyl]glycinamido, 2-[4-(3-tert-butoxycarbonylamino-3-carboxypropoxy)-3-chlorophenyl]-2-hydroxyiminoacetamido, 2-[3-(3-amino-3-carboxypropoxy)phenyl]-2-hydroxy-iminoacetamido, 2-[4-(3-carboxypropoxy)phenyl]-2-hydroxyiminoacetamido, 2-[4-(3-amino-3-carboxypropoxy)phenyl]-2-methoxy-iminoacetamido, 2-[4-(3-amino-3-carboxypropoxy)phenyl]-2-(2-ethoxycarbonylethoxyimino)acetamido, 2-[4-(3-amino-3-carboxypropoxy)phenyl]-2-(2-tert-butoxycarbonylaminoethoxyimino)acetamido, 2-[4-(3-amino-3-carboxypropoxy)phenyl]-2-benzyloxy-iminoacetamido, 2-[4-(3-tert-butoxycarbonylamino-3-carboxypropoxy)-phenyl]-2-hydrazonoacetamido, 2-[4-(3-amino-3-carboxypropoxy)phenyl]-2-semi-carbazonoacetamido, 2-[4-(3-amino-3-carboxypropoxy)phenyl]-2-thio-semicarbazonoacetamido, 2-[4-?3-(2-chloroacetamido)-3-carboxypropoxy?phenyl]-2-hydroxyiminoacetamido, 2-[4-?3-(2-phthalimidoacetamido)-3-carboxypropoxy?-phenyl]-2-hydroxyiminoacetamido, 2-[4-?3-(3-amidinoureido)-3-carboxypropoxy)phenyl]-2-hydroxyiminoacetamido, 2-[4-?3-(2-tert-butoxycarbonylaminoacetamido)-3-carboxypropoxy?phenyl]-2-hydroxyiminoacetamido, 2-(4-hydroxyphenyl)-N-tert-butoxycarbonylglycinamido, 2-[4-(3-carboxy-3-formamidopropoxy)phenyl]-2-hydroxy-iminoacetamido, 2-[4-{3-(2-phenyl-2-tert-butoxycarbonylamino-acetamido-3-carboxypropoxy}phenyl]-2-hydroxyimino-acetamido, 2-(.alpha.-iminobenzylamino)acetamido, 2-[4-(3-tritylamino-3-carboxypropoxy)phenyl]-2-hydroxyiminoacetamido;
2-[4-(3-tert-butoxycarbonylamino-3-methoxycarbonyl-propoxy)phenyl]-2-(5-chlorosalicyloylamino)acetamido, 2-[4-(3-tert-butoxycarbonylamino-3-methoxycarbonyl-propoxy)phenyl]-2-(2-oxo-1-imidazolindinecarboxamido)-acetamido, 2-benzamido-2-[4-(3-tert-butoxycarbonylamino-3-methoxycarbonylpropoxy)phenyl]acetamido, 2-[4-(3-tert-butoxycarbonylamino-3-methoxycarbonyl-propoxy)phenyl]-2-(3-phenylureido)acetamido, 2-(2-thienyl)-2-[N-(2,2,2-trichloroethoxycarbonyl-glycinamido]-acetamido, N-[N-(2-acetoxyethyl)oxamoyl]amino, (2-tert-butoxycarbonylamino-2-methoxycarbonyl)-ethylthiopyruvoylamino, 2-[4-(3-tert-butoxycarbonylamino-3-methoxycarbonyl-propoxy)phenyl]-2-(2-phenylacetamido)acetamido, 2-[4-(3-tert-butoxycarbonylamino-3-methoxycarbonyl-propoxy)phenyl]-2-benzoyloxyiminoacetamido, 4-(3-amino-3-carboxypropoxy)phenylglyoxyloylamino, 2-[4-(3-amino-3-carboxypropoxy)phenyl]-2-hydroxyimino-acetamido, 2-[4-{3-(3-phenylureido)-3-carboxypropoxy}phenyl]-2-hydroxyiminoacetamido, 2-[4-(3-acetamido-3-carboxypropoxy)phenyl]-2-hydroxyiminoacetamido, 2-(2-thienyl)-2-hydroxyiminoacetamido, 2-(4-methoxyphenyl)-2-methoxyiminoacetamido, 2-phenyl-2-benzyloxyiminoacetamido or 2-(4-methoxyphenyl)-2-benzyloxyiminoacetamido, ? when R2' is a group of the formula:

or wherein R? is as defined above, then R1 is amino, phthalimido, phenylacetamido or a group of the formula:

, or wherein RA is carboxy, protected carboxy or protected amino, RB is hydrogen, amino, protected amino, N-protected or unprotected glycinamido, N-protected or unprotected arylglycinamido, alkanoylamino whose alkane moiety may be sub-stituted by at least one suitable substituent, arylureido, amidinoureido, or aralkylamino, RC is hydrogen or halogen, RD is oxo, hydroxyimino, or alkoxyimino whose alkane moiety may be substi-tuted by at least one suitable substituent, RG is carboxy or protected carboxy, RH is amino or protected amino, RI is hydroxy, amino, aralkanoylamino, aroylamino whose aryl moiety may be substituted by at least one suitable substituent, 5-membered heterocyclecarboxamido which contains at least one hetero-atom selected from oxygen, nitrogen and sulfur atoms and may be substituted by at least one suitable substituent, or arylureido, RL is hydrogen, hydroxy.or alkoxy, and RM is hydroxyimino, alkoxyimino, aralkoxyimino, or aroyloxyimino;
and ? when R2 is a group of the formula:

or wherein R? is as defined above, then R1 is phthalimido, phenylacetamido, or a group of the formula:
, or RK-CONH-wherein RE is a 5-membered heterocyclic group containing at least one hetero-atom selected from nitrogen, oxygen, and sulfur atoms, RF is hydrogen, hydroxy, amino, protected amino, alkanoylamino whose alkane moiety may be sub-stituted by at least one suitable substituent, or aryloxyalkanoylamino whose aryl moiety may be substituted by at least one suitable substituent, RK is aralkoxy;
6-membered heterocyclic group which contains at least one nitrogen atom, and may be substi-tuted by at least one suitable substituent N-(hydroxyalkyl)carbamoyl, N-aralkylcarbamoyl, aryloxyalkyl, or .alpha.-iminoaralkylaminoalkyl, and RA, RB, RC and RD are each as defined above.

? when R2' is a group of the formula:

wherein R? is as defined above, then R1 is amino or 2-(2-thienyl)acetamido, which comprises (1) reacting a compound of the formula:

wherein R? is a group of the formula:

or in which R? is phenyl which may be substituted by at least one substituent selected from hydroxy, substituted or unsubstituted aralkoxy, and acyloxy; or alkyl, R? is alkyl, or substituted or unsubstituted aryl and R5, R? and R6 are each as defined above, with an acylating agent to give a compound of the formula:

wherein R? is acylamino and .

R? is as defined above;

(2) subjecting a compound of the formula:
wherein R? is acylamino of which acylmoiety bears at least one functional group selected from protected amino, protected hydroxy and protected carboxy, and R? is a group of the formula:

or in which R? is phenyl which may be substituted by at least one substituent selected from hydroxy, substituted or unsubstituted aralkoxy and acyloxy, R? and R? are each alkyl and R5 and R? are each as defined above, to removal reaction of amino, hydroxy and/or carboxy protective group(s) in protected amino, protected hydroxy and protected carboxy groups to give a compound of the formula:

R? is acylamino whose acyl moiety bears at least one functional group selected from amino, hydroxy and carboxy, and R? is as defined above.

(3) subjecting a compound of the formula:

wherein R? is phthalimido or aralkoxycarbonylamino and R? is hydrogen or a group of the formula:

or or in which R5, R?, R?, and R? are each as defined above, to cleavage reaction of amido linkage to give a compound of the formula:

wherein R? is as defined above;

(4) reacting a compound of the formula:

wherein Ra is alkoxy having at least one substituent selected from amino, protected amino, carboxy and protected carboxy, Rb is oxo or hydroxyimino, R8 is hydroxy, or substituted or unsubstituted aralkoxy, and R5 is as defined above, with a reducing agent to give a compound of the formula:

wherein Rc is hydroxy or amino and Ra, R? and R8 are each as defined above, (5) reacting a compound of the formula:

wherein Rd is substituted or unsubstituted aryl, or substituted or unsubstituted heterocyclic group, R? is a group of the formula:

or in which R? is phenyl which may have at least one sub-stituent selected from hydroxy and substituted or unsubstituted aralkoxy, naphthyl:
substituted or unsubstituted aralkyl;

substituted or unsubstituted hetero-cyclic group; or substituted or unsubstituted aryl thioalkyl, R? is alkyl;
substituted or unsubstituted hereto-cyclic-thioalkyl; or substituted or unsubstituted arylthio, and R5, R? and R6 are each as defined above, and R3 is as defined above, with an amino compound of the formula:
Re - NH2 wherein Re is hydroxy, amino, substituted or unsubstituted alkoxy, substituted or unsubstituted aralkoxy, ureido or thioureido, or its salt to give a compound of the formula:

wherein Rd, Re, R? and R3 are each as defined above;

(6) reacting a compound of the formula:

wherein Rf is phenyl which may be substituted by alkoxy having at least one functional group selected from amino, protected amino, carboxy and protected carboxy; or substituted or unsubstituted heterocyclic group, Rg and Rh are each hydrogen, or are combined together to form oxo, hydroxyimino or acyloxyimino, and R? is as defined above, with an acylating agent of the formula:

wherein R9 is acyl, or its reactive derivative, to give a compound of the formula:

wherein Rf, Rg, Rh, R? and R9 are each as defined above;

(7) reacting a compound of the formula:

wherein R? is carboxy or its derivative and R? is as defined above, with an acylating agent to give a compound of the formula:

wherein Ri is acyl selected from haloalkanoyl, N-protected glycyl, N-protected-2-(substituted or unsubstituted aryl)-glycyl and N-(amidino)carbamoyl, and R? and R? are each as defined above;

(8) subjecting a compound of the formula:

wherein R10 is protected amino and Ra and R? are each as defined above, to removal reaction of amino protective group in protected amino to give a compound of the formula:

wherein Ra and R? are each as defined above;

(9) reacting a compound of the formula:

wherein Rj is substituted or unsubstituted aryl, A is alkylene and R? is as defined above, with a reducing agent to give a compound of the formula:

wherein Rj, A and R5 are each as defined above;

(10) reacting a compound of the formula:

wherein R? and R? are each as defined above, with an aralkylating agent of the formula:

wherein R11 is substituted or unsubstituted aralkyl and:
X is an acid residue, to give a compound of the formula:

wherein R?, R?, and R11 are each as defined above;
(11) reacting a compound of the formula:

wherein Ra and R? are each as defined above, with an aralkylating agent of the formula:

wherein R11 and X are each as defined above, to give a compound of the formula:

wherein Ra, R? and R11 are each as defined above;
(12) reacting a compound of the formula:

wherein R? is acylamino, R? is a group of the formula:

or in which R13 is hydrogen, hydroxy, or substituted or unsubstituted aralkoxy and R?, R? and R? are each as defined above, and R12 is alkyl, benzene-fused heterocyclic-thio or a group of the formula:

in which R?, R?, R? and R? are each as defined with a desulfurating agent to give a compound of the formula:

wherein R? and R? are each as defined above;

(13) subjecting a compound of the formula:

wherein R? is acylamino, R? is alkyl and R? is as defined above, or its reactive derivative to dehydrating intramolecular cyclization to give a compound of the formula:

wherein R?, R? and R? are each as defined above;
(14) reacting a compound of the formula:

wherein R?, R? and R? are each as defined above, with hydrazoic acid or its reactive derivative;
subjecting the resultant compound of the formula:

wherein R? and R? are each as defined above, to thermal degradation;
and then reacting thus obtained compound of the formula:

wherein R? and R? are each as defined above, with an alcohol of the formula:

wherein R14 is substituted or unsubstituted alkyl, to give a compound of the formula:

wherein R?, R? and R14 are each as defined above; and (15) reacting a compound of the formula:

wherein R? and R? are each as defined above, with a lead compound of the formula:
Pb(CR15)4 wherein R15 is acyl, to give a compound of the formula:

wherein R?, R? and R? are each as defined above.

50. A process according to claim 49, which comprises reacting a compound of the formula:

with an acylating agent to give a compound of the formula:

(IA) wherein R? is phenylglyoxyloylamino, 2-(2-furyl)glycoloylamino, bromopyruvolylamino, 2-(2-thienyl)-2-(2-azidoacetamido)-acetamido, 2-benzyloxyimino-2-(4-methoxyphenyl)-acetamido, 2-benzoyl-oxyimino-2-[4-(3-tert-butoxy-carbonylamino-3-methoxycarbonylpropoxy)phenyl]acetamido, 2-[2-(2,2,2-trichloroethoxycarbonylaminomethyl)-phenoxy]acetamido, 2-[2-{N-(2,2,2-trichloroethoxy-carbonyl)-2-(carboxymethoxy)-benzylaminomethyl}-phenoxy]acetamido, 2-benzyloxyimino-2-phenylacetamido, 4-(3-tert-butoxycarbonylamino-3-methoxycarbonylpropoxy)-phenylglyoxyloylamino, orotoylamino, 2-methoxy-imino-2-[2-(2,2,2-trifluoroacetamido)-4-thiazolyl]-acetamiclo, 4-(3-tert-butoxycarbonylamino-3-methoxy-carbonylpropoxy)-3-chlorophenylglyoxyloylamino, 4-(3-methoxycarbonylpropoxy)phenylglyoxyloylamino, 3-(3-tert-butoxycarbonylamino-3-methoxycarbonyl-propoxy)phenylglyoxyloylamino, 4-(3-phthalimido-propoxy)phenylglyoxyloylamino, N-[N-(2-nitrophenyl)-oxamoyl]-2-phenylglycinamido, 2-[2-{2-(4-chloro-2-nitrophenoxy)acetamidomethyl}phenoxy]acetamido, 2-[2-(2-bromoacetamidomethyl)phenoxy]acetamido, N-(N-benzyloxamoyl)amino, 2-[4-(3-tert-butoxycarbonyl-amino-3-methoxycarbonylpropoxy)phenyl]-2-(5-chloro-salicyloylamino)-acetamido, 2-[4-(3-tert-butoxy-carbonylamino-3-methoxycarbonylpropoxy)phenyl]-2-(2-oxo-1-imidazolidinecarboxamido)-acetamido, 2-benzamido-2-[4-(3-tert-butoxycarbonylamino-3-methoxycarbonylpropoxy)phenyl]acetamido, 2-[4-(3-tert-butoxycarbonylamino-3-methoxycarbonylpropoxy)-phenyl]-2-(3-phenylureido)acetamido, 2-(2-thienyl)-2-[N-(2,2,2-trichloroethoxycarbonylglycinamido]aceta-mido, N-[N-(2-acetoxyethyl)oxamoyl]amino, (2-tert-butoxycarbonylamino-2-methoxycarbonyl)ethylthio-pyruvoylamino, 2-[4-(3-tert-butoxycarbonylamino-3-methoxycarbonylpropoxy)phenyl]-2-(2-phenylacetamido)-acetamido, 2-[4-(3-tert-butoxycarbonylamino-3-methoxy-carbonylpropoxy)phenyl]-2-benzoyloxyiminoacetamido, 2-hydroxyimino-2-(4-hydroxyphenyl)acetamido or 2-(4-hydroxyphenyl)-N-tert-butoxycarbonylgiycinamido.

51. A process according to claim 49, which comprises-reacting a compound of the formula:

wherein R? is a group of the formula:

or in which R4' is phenyl which may be substituted by acyloxy, R6 is hydrogen, R? is substituted or unsubstituted aryl and R5 and R? are each as defined in claim 49, provided that when R4' is phenyl, then R5 is alkyl bearing carboxy or its derivative, with an acylating agent to give a compound of the formula:

(IB) wherein R? is as defined above and R? is acylamino.

52. A process according to claim 51, wherein R? is 2-phenylacetamido, 2-[4-(3-acetamido-3-methoxycarbonylpropoxy)-phenyl]-2-acetoxyiminoacetamido or 2-phenyl-2-hydroxyimino-acetamido, and R? is a group of the formula:
, , , or .

53. A process according to claim 49, which comprises subjecting a compound of the formula:

wherein R5 is carboxy or methoxycarbonyl and R? is 4-(3-tert-butoxycarbonylamino-3-carboxypropoxy)phenylglyoxyloylamino, 2-[4-(3-tert-butoxycarbonylamino-3-carboxypropoxy)phenyl]-2-(5-chlorosalicyloylamino)acetamido, 2-[4-(3-tert-butoxy-carbonylamino-3-carboxypropoxy)phenyl]-2-(3-phenylureido)-acetamido, 2-[4-(3-tert-butoxycarbonylamino-3-carboxypropoxy)-phenyl]-2-(2-oxo-1-imidazolidinecarboxamido)acetamido, 3-(3-tert-butoxycarbonylamino-3-carboxypropoxy)phenylglyoxyloyl-amino, 2-[4-(3-tert-butoxycarbonylamino-3-carboxypropoxy)-3-chlorophenyl]-2-hydroxyiminoacetamido, 4-(3-tert-butoxycarbonyl-amino-3-carboxypropoxy)-3-chlorophenylglyoxyloylamino, 2-[4-(3-tert-butoxycarbonylamino-3-carboxypropoxy)phenyl]-2-hydrazonoacetamido, 2-[4-{3-(N-tert-butoxycarbonyl-2-phenyl-glycinamido)-3-carboxypropoxy}phenyl]-2-hydroxyiminoacetamido, 2-[4-{3-(N-tert-butoxycarbonylglycinamido)-3-carboxypropoxy}-phenyl]-2-hydroxyiminoacetamido, 2-[4-(3-tert-butoxycarbonyl-amino-3-carboxypropoxy)phenyl]-2-(2-tert-butoxycarbonylamino-ethoxyimino)-acetamido, 2-[2-{2-carboxymethoxy-N-(2,2,2-tri-chloroethoxycarbonyl)benzylaminomethyl}phenoxy]acetamido, 2-[2-(2,2,2-trichloroethoxycarbonylaminomethyl)phenoxy]-acetamido, 2-methoxyimino-2-[2-(2,2,2-trifluoroacetamido)-4-thiazolyl]acetamido, 4-(3-phthalimidopropoxy)phenylglyoxyloyl-amino, 2-[4-(3-N-phthalimidoglycinamido-3-carboxypropoxy)phenyl]-2-hydroxyiminoacetamido, 2-(2-thienyl)-2-(2,2,2-trichloroethoxy-carbonylglycinamido)acetamido, N'-(2-acetoxyethyl)oxamoylamino, (2-tert-butoxycarbonylamino-2-methoxycarbonyl)ethylthio-pyruvoylamino, 2-[4-(3-tert-butoxycarbonylamino-3-methoxy-carbonylpropoxy)phlenyl]-2-phenylacetamidoacetamido or 2-[4-(3-tert-butoxycarbonylamino-3-methoxycarbonylpropoxy)-phenyl]-2-hydroxyiminoacetamido, to removal reaction of amino, hydroxy and/or carboxy protective group(s) in protected amino, protected hydroxy and carboxy groups to give a compound of the formula (IC) wherein R5 is as defined above, and R? is 4-(3-amino-3-carboxypropoxy)phenylglyoxyloyl-amino, 2-[4-(3-amino-3-carboxypropoxy)phenyl]-2-(5-chlorosalicyloylamino)acetamido, 2-[4-(3-amino-3-carboxypropoxy)phenyl]-2-(3-phenylureido)acetamido, 2-[4-(3-amino-3-carboxypropoxy)phenyl]-2-(2-oxo-1-imidazolidinecarboxamido)acetamido, 3-(3-amino-3-carboxypropoxy)phenylglyoxyloylamino, 2-[4-(3-amino-3-carboxypropoxy)-3-chlorophenyl]-2-hydroxyimino-acetamido, 4-(3-amino-3-carboxypropoxy)-3-chloro-phenylglyoxyloylamino, 2-[4-(3-amino-3-carboxypropoxy)-phenyl]-2-hydrazonoacetamido, 2-[4-(3-carboxy-3-(2-phenylglycinamidopropoxy)phenyl]-2-hydroxyiminoaceta-mido, 2-[4-(3-carboxy-3-glycinamidopropoxy)phenyl]-2-hydroxyiminoacetamido, 2-(2-aminoethoxyimino)-2-[4-(3-amino-3-carboxypropoxy)phenyl]-acetamido, 2-[2-(2-carboxymethoxybenzylaminomethyl)-phenoxy]acetamido, 2-(2-aminomethylphenoxy)acetamido, 2-methoxyimino-2-(2-amino-4-thiazolyl)acetamido, 4-(3-aminopropoxy)-phenylglycoxyloylamino, 2-(2-aminoacetamido)-2-(2-thienyl)acetamido, N-[N-(2-hydroxyethyl)oxamoyl]-amino, (2-amino-2-carboxyethylthio)pyruvoylamino, 2-[4-(3-amino-3-carboxypropoxy)phenyl]-2-(2-phenyl-acetamido)-acetamido or 2-[4-(3-amino-3-methoxy-carbonylpropoxy)-phenyl]-2-hydroxyiminoacetamido.

54. A process according to claim 49, which comprises subjecting a compound of the formula:

wherein R? is 4-(3-tert-butoxycarbonylamino-3-carboxypropoxy)-phenylglyoxyloylamino, 2-[4-(3-tert-butoxycarbonyl-amino-3-carboxypropoxy)phenyl]-2-hydroxyiminoacetamido or 2-[4-(3-tert-butoxycarbonylamino-3-carboxypropoxy)-phenyl]-2-hydroxyacetamido, to removal reaction of amino protective group in protected amino to give a compound of the formula:

(ID) wherein R? is 4-(3-amino-3-carboxypropoxy)phenylglyoxyloyl-amino, 2-[4-(3-amino-3-carboxypropoxy)phenyl]-2-hydroxyiminoacetamido or 2-[4-(3-amino-3-carboxy-propoxy)phenyl]-2-hydroxyacetamido.

55. A process according to claim 49, which comprises subjecting a compound of the formula:

wherein R? is phenyl substituted by acyloxy and R? and R5 are each as defined in claim 49, to removal reaction of amino protective group in protected amino to give a compound of the formula:

(IE) wherein R? is as defined above and R? and R5 are each as defined in claim 49.

56. A process according to claim 55, wherein R? is 4-[3-tert-butoxycarbonylamino-3-carboxypropoxy]-phenylgly-oxyloylamino or 2-[4-(3-tritylamino-3-carboxypropoxy)phenyl]
-2-hydroxyiminoacetamido, R? is 4-(3-amino-3-carboxypropoxy)phenylglyoxyloylamino or 2-[4-(3-amino-3-carboxypropoxy)phenyl]-2-hydroxyiminoacetamido, R? is 4-benzoyloxyphenyl, 4-carbamoyloxyphenyl or 4-benzyloxy-carbonyloxyphenyl and R5 is carboxy.

57. A process according to claim 49, which comprises subjecting a compound of the formula:

wherein R? is 2-[4-(3-amino-3-carboxypropoxy)phenyl]-2-(ethoxy-carbonylmethoxyimino)acetamido, 4-(3-tert-butoxy, carbonylamino-3-methoxycarbonylpropoxy)phenylglyoxy-loylamino, 3-(3-tert-butoxycarbonylamino-3-methoxy-carbonylpropoxy)phenylglyoxyloylamino, 4-(3-methoxy-carbonylpropoxy)phenylglyoxyloylamino, 4-(3-tert-butoxycarbonylamino-3-methoxycarbonylpropoxy)-3-chlorophenylglyoxyloylamino, 2-[4-(3-tert-butoxy-carbonylamino-3-methoxycarbonylpropoxy)phenyl]-2-(5-chlorosalicyloylamino)acetamido, 2-[4-(3-tert-butoxycarbonylamino-3-methoxycarbonylpropoxy)phenyl]-2-(2-oxo-1-imidazolidinecarboxamido)acetamido, 2-[4-(3-tert-butoxycarbonylamino-3-methoxycarbonyl-propoxy)phenyl]-2-benzamidoacetamido, 2-[4-(3-tert-butoxycarbonylamino-3-methoxycarbonylpropoxy)phenyl]-2-(3-phenylureido)acetamido or 2-[4-(3-tert-butoxy-carbonylamino-3-methoxycarbonylpropoxy)phenyl]-2-benzoyloxyiminoacetamido, to removal reaction of carboxy protective group in protected carboxy to give a compound of the formula:

(IF) wherein R? is 2-[4-(3-amino-3-carboxypropoxy)phenyl]-2-carboxymethoxyimino)acetamido, 4-(3-tert-butoxy-carbonylamino-3-carboxypropoxy)phenylglyoxyloyl-amino, 3-(3-tert-butoxycarbonylamino-3-carboxypropoxy)-phenylglyoxyloylamino, 4-(3-carboxypropoxy)phenyl-glyoxyloylamino, 4-(3-tert-butoxycarbonylamino-3-carboxypropoxy)-3-chlorophenylglyoxyloylamino, 2-[4-(3-tert-butoxycarbonylamino-3-carboxypropoxy) phenyl]-2-(5-chlorosalicyloylamino)acetamido, 2-[4-(3-tert-butoxycarbonylamino-3-carboxypropoxy)phenyl]
-2-(2-oxo-1-imidazolidinecarboxyamido)acetamido, 2-[4-(3-tert-butoxycarbonylamino-3-carboxypropoxy)phenyl]
-2-benzamidoacetamido, 2-[4-(3-tert-butoxycarbonyl amino-3-carboxypropoxy)phenyl]-2-(3-phenylureido)acet-amido or 2-[4-(3-tert-butoxycarbonylamino-3-carboxy-propoxy)phenyl]-2-hydroxyiminoacetamido.

58. A process according to claim 49, which comprises subjecting a compound of the formula:

where R? is phthalimido or benzyloxycarbonylamino and R? is hydrogen or a group of the formula , , -CH2COOCH2C6H5 or in which R5 is carboxy or methoxycarbonyl, to cleavage reaction of amido linkage to give a compound of the formula:

(IG) wherein R? is as defined above.

59. A process according to claim 49, which comprises reacting a compound of the formula:

wherein Ra is 3-amino-3-carboxypropoxy or 3-tert-butoxycarbonyl-amino-3-carboxypropoxy and Rb is oxo or hydrooxyimino, with a reducing agent to give a compound of the formula:

(IH) wherein Rc is hydroxy or amino and Ra is as defined above.

60. A process according to claim 49, which comprises reacting a compound of the formula:

with a reducing agent to give a compound of the formula (IJ)

61. A process according to claim 49, which comprises reacting a compound of the formula:
wherein Rd is 4-(3-amino-3-carboxypropoxy)phenyl, 4-(3-tert-butoxycarbonylamino-3-carboxypropoxy)-3-chlorophenyl, 3-(3-amino-3-carboxypropoxy)phenyl, 4-(3-carboxypropoxy)phenyl, 4-[3-(3-phenylureido)-3-carboxypropoxy] phenyl, 4-(3-acetamido-3-carboxypropoxy)phenyl, 4-(3-tert-butoxycarbonylamino-3-carboxypropoxy)phenyl, 4-(3-amino-3-carboxypropoxy)-3-chloro-phenyl, 2-thienyl or 4-hydroxyphenyl, with hydroxylamine or its salt to give a compound of the formula:
(IK) wherein Rd is as defined above.

62. A process according to claim 49, which comprises reacting a compound of the formula:

wherein Rd is 4-(3-amino-3-carboxypropoxy)phenyl, 4-methoxy-phenyl or 2-amino-4-thiazolyl, with methoxylamine or its salt to give a compound of the formula:
(IL) wherein Rd is as defined above.

63. A process according to claim 49, which comprises reacting a compound of the formula:
with an amino compound of the formula:
Re-NH2 wherein Re is ethoxycarbonylmethoxy, benzyloxy, ureido or thioureido, or its salt to give a compound of the formula:
(IM) wherein Re is as defined above.

64. A process according to claim 49, which comprises reacting a compound of the formula:
with an amino compound of the formula:

Re-NH2 wherein Re is 2-(tert-butoxycarbonylamino)ethoxy or amino, or its salt to give a compound of the formula:
(IN)

65. A process according to claim 49, which comprises reacting a compound of the formula:
wherein Rd is phenyl or 4-methoxyphenyl, with benzyloxylamine or its salt to give a compound of the formula:
(IO) wherein Rd is as defined above.

66. A process according to claim 49, which comprises reacting a compound of the formula:

wherein RA is carboxy or protected carboxy;
RB is amino or protected amino; and R? is a group of the formula:

or in which R? is phenyl which may have at least one substituent selected from substituted or unsubstituted aralkoxy, R6 and R? are each alkyl and R? is as defined in claim 49, with hydroxylamine or its salt to give a compound of the formula:

(IP) wherein RA, RB and R? are each as defined above.

67. A process according to claim 66, wherein RA is carboxy, RB is tert-butoxycarbonylamino and R? is a group of the formula:

68. A process according to claim 49, which comprises reacting a compound of the formula:

wherein Rf, Rg, Rh and R? are each as defined in claim 49, with an acylating agent of the formula:

wherein R9 is acyl, or its reactive derivative to give a compound of the formula:

(IQ) wherein R9 is as defined above and Rf, Rg, Rh and R? are each as defined in claim 49.

69. A process according to claim 68, wherein Rf is 2-thienyl, 4-(3-tert-butoxycarbonylamino-3-carboxy-propoxy)-phenyl or 4-(3-tritylamino-3-carboxypropoxy)phenyl, Rg and Rh are each hydrogen or Rg and Rh are combined together to form oxo or hydroxyimino, R5a is carboxy and R9 is benzoyl, benzyloxycarbonyl, N-(2,2,2-trichloroacetyl)-carbamoyl or 2-phenylacetyl.

70. A process according to claim 49, which comprises reacting a compound of the formula:
with an acylating agent to give a compound of the formula:
(IR) wherein Ri is 2-chloroacetyl, 2-phthalimidoacetyl, 3-amidino-carbamoyl, 2-tert-butoxycarbonylaminoacetamido, 2-phenyl-2-tert-butoxycarbonylaminoacetamido or formyl.

71. A process according to claim 49, which comprises subjecting a compound of the formula:

wherein R10 is protected amino and Ra and R? are each as defined in claim 49, to removal reaction of amino protective group in protected amino to give a compound of the formula:

(IS) wherein Ra and R? are each as defined in claim 49.

72. A process according to claim 71, wherein Ra is 4-(3-tert-butoxycarbonylamino-3-carboxypropoxy), R? is carboxy and R10 is 2,2,2-trichloroacetylamino.

73. A process according to claim 49, which comprises reacting a compound of the formula:
wherein Rj is phenyl and A is methylene, with a reducing agent to give a compound of the formula:

(IT) wherein Rj and A are each as defined above.

74. A process according to claim 49, which comprises reacting a compound of the formula:
with trityl chloride to give a compound of the formula:
(IU)

75. A process according to claim 49, which comprises reacting a compound of the formula:
wherein RA and RB are each as defined in claim 49, with aral-kylating agent to give a compound of the formula:
(IV) wherein RA and RB are each as defined in claim 49, and R" is substituted or unsubstituted aralkyl.

76. A process according to claim 75, wherein RA is carboxy, RB is tert-butoxycarbonylamino and R" is benzyl.

77. A process according to claim 49, which comprises reacting a compound of the formula:

with Raney Nickel to give a compound of the formula:

(IW)

78. A process according to claim 49, which comprises reacting a compound of the formula:
wherein R? is phthalimido or phenylacetamido, with Raney Nickel to give a compound of the formula:

(IX)

79. A compound of formula (IA) as defined in claim 50, whenever prepared by the process of claim 50 or by an obvious chemical equivalent thereof.

80. A compound of formula (IB) as defined in claim 51, whenever prepared by the process of claim 51 or by an obvious chemical equivalent thereof.

81. A compound of formula (IB) as defined in claim 52, whenever prepared by the process of claim 52 or by an obvious chemical equivalent thereof.

82. A compound of formula (IC) as defined in claim 53, whenever prepared by the process of claim 53 or by an obvious chemical equivalent thereof.

83. A compound of formula (ID) as defined in claim 54, whenever prepared by the process of claim 54 or by an obvious chemical equivalent thereof.

84. A compound of formula (IE) as defined in claim 55, whenever prepared by the process of claim 55 or by an obvious chemical equivalent thereof.

85. A compound of formula (IE) as defined in claim 56, whenever prepared by the process of claim 56 or by an obvious chemical equivalent thereof.

86. A compound of formula (IF) as defined in claim 57, whenever prepared by the process of claim 57 or by an obvious chemical equivalent thereof.

87. A compound of formula (IG) as defined in claim 58, whenever prepared by the process of claim 58 or by an obvious chemical equivalent thereof.

88. A compound of formula (IH) as defined in claim 59, whenever prepared by the process of claim 59 or by an obvious chemical equivalent thereof.

89. A compound of formula (IJ) as defined in claim 60, whenever prepared by the process of claim 60 or by an obvious chemical equivalent thereof.

90. A compound of formula (IK) as defined in claim 61, whenever prepared by the process of claim 61 or by an obvious chemical equivalent thereof.

91. A compound of formula (IL) as defined in claim 62, whenever prepared by the process of claim 62 or by an obvious chemical equivalent thereof.

92. A compound of formula (IM) as defined in claim 63, whenever prepared by the process of claim 63 or by an obvious chemical equivalent thereof.

93. A compound of formula (IN) as defined in claim 64, whenever prepared by the process of claim 64 or by an obvious chemical equivalent thereof.

94. A compound of formula (IO) as defined in claim 65, whenever prepared by the process of claim 65 or by an obvious chemical equivalent thereof.

95. A compound of formula (IP) as defined in claim 66, whenever prepared by the process of claim 66 or by an obvious chemical equivalent thereof.

96. A compound of formula (IP) as defined in claim 67, whenever prepared by the process of claim 67 or by an obvious chemical equivalent thereof.

97. A compound of formula (IQ) as defined in claim 68, whenever prepared by the process of claim 68 or by an obvious chemical equivalent thereof.

98. A compound of formula (IQ) as defined in claim 69, whenever prepared by the process of claim 69 or by an obvious chemical equivalent thereof.

99. A compound of formula (IR) as defined in claim 70, whenever prepared by the process of claim 70 or by an obvious chemical equivalent thereof.

100. A compound of formula (IS) as defined in claim 71, whenever prepared by the process of claim 71 or by an obvious chemical equivalent thereof.

101. A compound of formula (IS) as defined in claim 72, whenever prepared by the process of claim 72 or by an obvious chemical equivalent thereof.

102. A compound of formula (IT) as defined in claim 73, whenever prepared by the process of claim 73 or by an obvious chemical equivalent thereof.

103. A compound of formula (IU) as defined in claim 74, whenever prepared by the process of claim 74 or by an obvious chemical equivalent thereof.

104. A compound of formula (IV) as defined in claim 75, whenever prepared by the process of claim 75 or by an obvious chemical equivalent thereof.

105. A compound of formula (IV) as defined in claim 76, whenever prepared by the process of claim 76 or by an obvious chemical equivalent thereof.

106. A compound of formula (IW) as defined in claim 77, whenever prepared by the process of claim 77 or by an obvious chemical equivalent thereof.

107. A compound of formula (IX) as defined in claim 78, whenever prepared by the process of claim 78 or by an obvious chemical equivalent thereof.

108. A compound of formula (I) as defined in claim 49, whenever prepared by the process of claim 49 or by an obvious chemical equivalent thereof.