CA1225954A - Process for the preparation of cephem compounds - Google Patents

Abstract

Abstract of the disclosure:

Process for the preparation of cephem compounds Process for the preparation of 7-amino-cephalos-poranic acid derivatives of the formula

Description

L2Z595~

The invention relates to a process for the pre-~ parat;on of 7-amino-cephalosporanic acid derivatives of ; the general formula I

l (I) o ,~ ~ CH 7,A
co2e S- wherein R1 ~denotes hydrogen or methoxy and A denotes a pyridlnium rad7cal 0 N ~ , ~hich can be monosubstituted or polysubstituted by identical or different substituents;from the group ~10 ~ compr;sing opt;onally subst;tuted C;-C6-alkyl, it `bei~ng possible for two alkyl groups in the ortho-; ~ pos;tion also to be llnked to form an optionally ~ subststuted di- to deca-methylene ring, in which ; ~ one ring carbon atom can be replaced by a hetero-atom and wh;ch can furthermore also contain one or two double bonds, optionally substituted C2-C6-alkenyl, C2-C6-alk;nyl and C3-C7-cycloalkyl and :
C3-C7-cycloalkyl-methyl, it being possible for the ring also to be subst;tuted in the last two sub-stituents; C4-C7-cycloalkenyl, optionally substi-tuted C1-C6-alkoxy, C2-C6-alkenyloxy and C2-C6-` alkinyloxy, halogenr trifluoromethyl and hydroxyl, .. .
~r~
~4 .

,~ ~LrZ2~;i9~i4 and optionally substituted phenyl, benzy1 and heteroaryL, and where;n, furthermore, A denotes a quinol;nium ~ or an isoquinol;-n;um - ~ ~ rad;caL, each of which can also be monosubstituted or polysubstituted by identi-cal or different substituents from the group com-prising opt;onally substituted C1-C6-alkyl, C1-C6-alkoxy, halogen, trifLuoromethyl and hydroxyl.
The present invention particularly relates to com-pounds in wh;ch A denotes a pyr;d;nium rad;cal - ~ , which can be monosubstituted or polysubstituted by iden-ticai or different substituents from the group compris-; ;ng C1-C6-alkyl, which can be monosubstituted or poly-~ s~u~bsti~tuted~by hydroxyl or sulfo; and C1-C6-alkoxy and h;ydroxy-C1-C6-aLkoxy, it being possible ~or two alkyl gr;oups also ~o be~linked to form an optiona~lly substitu-~ted di~-`to de~ca-m~ethylene ring, in which one ring carbon ; atom can be replaced by a heteroatom and which can fur-:
thermore~also contain one or two double bonds, C2-C6-alkenyl, which can be substituted by hydroxyl, C2-C6-alkinYl~
C3-C7-cycLoalkyl and C3-C7-cycloaLkyl-methyl, it being poss;bLe for the ring also to be subst;tuted by hydroxyl or halogen in these two substituents, C4-C7-cycloalkenyl, C1-C6-alkoxy~ which can be substituted by hydroxyl, C~-C6-alkenyloxy and c2-c6-alk;nYloxy, halogen, ~r;fluoromethyl and hydroxyl, and phenyl, benzyl ..

.
' Z2S~3$~

or heteroaryl, wh;ch can also be subst;tuted by halo~en, or in which A denotes a qu;nol;n;u~ or ;soquinolinium rad;cal, each of which can also be monosubstituted or polysubstituted by identical or different substituents from the group compris;ng C1-C6-alkyl, wh;ch can be sub-st;tuted by hydroxyl, and c1-C6-alkoxy, halogen, tr;flu-oromethy~ and hydroxyl.
- ~ossible optional substituents of the di- to deca-methylene ring mentioned under A, in which one ring car-bon atom can be replaced by a heteroatom and which can furthermore also contain one or two double bonds, are, ;n ; part;cular, the follow;ng substituents, wh;ch may occur singly or in combinat;on, but preferably singly: C1-C6-; alkyl, C1-C4-alkoxy, hydroxymethyl, halogen, hydroxyl, oxo and exome~thylene.
These substituents can occur on the above rings fused ont~o the pyridinium rad;cal, ;ndependently of whe-t~her the particular ring is saturated, unsaturated or also ;nterrupted by a heteroatorn.
The ring fused onto the pyridinium radical can contain two to ten r;ng members Sd;- to deca-methylene), but preferably three to five ring members, and thus is, for example, a cyclopenteno, cyclohexeno or cyclohepteno ring. lf such a fused-on ring contains a double bond, examples which may be mentioned are the dehydrocyclopen-tadieno, dehydrocyclohexadieno and dehydrocycloheptadieno r;ng. If one carbon atom ;n such a r;ng is replaced by a heteroatom, poss;ble heteroatoms are, ;n particular~ oxy-:
~ gen or sulFur. Examples wh1ch may be mentioned of fused-on .

2~i954 r;ngs wh;ch contain an oxygen atom and two or one doubLe bond are furo, pyrano, dihydrofuro and dihydropyrano;
examples of fused-on rings containing a sulfur atom and t~o or one double bond are thieno, thiopyrano, dihydro-thieno and dihydropyrano. Of the fused-on rings contain-;ng a~heteroatom, those rings wh;ch contain only one double bond are particularly suitable for subst;tution, especially by the abovementioned substituents.
The following substituents are examples of parti-cularLy pre~erred substituents:
A: a quinolinium or an ;soquinolinium radical, each of ~h;ch can also be monosubstituted or polysubstituted -, by identical or d;fferent substituents from the group i compri~slng C1-C6~alkyl, such as, for exampLe, methyl, .
ethyl and propyl, preferably methyl, methoxy, hydroxyl, halogen and tr;fluoromethyl, or a pyridinium radical, ~hich can be~monosubstituted or polysubstituted, pre-ferabLy mono-, di- or tr;-substituted, in particular ~ mono- or~ di-s~ubstituted, for example by C1-C4-alkyl, such as, in particular, methyl, ethyl, propyl, isopro-pyl, n-butyl, sec.-butyl, tert.-butyl, dim~thyl, tri-methyl, methyl and etbyl, methyl and propyl, methyL
and isopropyl or ethyl and ethyl; or hydroxy-C1-C4-~ alkyl, such as, i~n particular, hydroxymethyl, hydroxy-ethyl, hydroxypropyl, hydroxyisopropyl, hydroxybutyl, hydroxy-sec.-butyl or hydroxy tert.-butyL~ it also be~
;ng possible, for example, for the alkyl radical to carry two or three hydroxyl groups; C3-C4-alkenyl, such as, ;n part;cular, allyl~ 2-methallyl and buten-.
~ ' ,.

;9~;4 -- 6 --3-yl, which can also be substituted by hydroxyl, such as, in part;cular, hydroxyallyl and hydroxybutenyl;
C3-aLkinyl, such as, in particular, propargyl~ C3-C6-cycloalkyl or C3-C6-cycLoalkyl-methyl, the carbon num-ber relat;ng to the cycloalkyl part, such as, in par-ticular, cyclopropyl, cyclobutyl, cyclopentyl, cyclo hexyl and cyclopentylmethyl, it be;ng possible for the r;ngs also to be subst;tuted, for example by hydroxyl, such as, in particular, 1-hydroxy-cyclopentyl and 1-hydroxy-cyclohexyl, or by halogen, preferably chlorine;
C5-C6-cycloalkenyl, such as, ;n particular, cyclo-penten-1-yl and cyclohexen-1-yl;
C1-C6-alkoxy, such as, in particular, methoxy and eth-oxy;
halogen, such as, in particular, 3-fluoro, 3-chloro,

3-bromo or 3-iodo; hydroxyl, in particular 3-hydroxyl;
tr;fluoromethyl, in part;cular 3-~rifluoromethyl; phe-nyl and benzyl, which can also be subst;tuted, for ex-ample by halogen, in particular chlorine, such as, for example, 4-chlorobenzyl; or Z'-th;enyl or 3'-thienyl.
If A is a pyridinium radical which is substitu-ted by two alkyl groups linked to form a di- to deca methylene ring which can ;n turn be monosubstituted or polysubst;tuted, preferably monosubstituted, and can con-ta;n one or two double bonds, the following fused~on ringsystems are very particularly suitable here:
cyclobuteno, cyclopenteno, hydroxycyclopenteno, oxocyclo-penteno, hydroxymethylcyclopenteno, exomethylenecyclopen-teno, carboxycyclopenteno and carbamoylcyclopenteno, , ` ~2~:;95 cyclohexeno, hydroxycyclohexeno, oxocyclohexeno, hydroxy-methyl-cyclohexeno, exomethylene-cyclohexeno, carboxycyclo-hexeno and carbamoylcyclohexeno, cyclohepteno, hydroxy-, oxo-, hydroxymethyl-, exomethyl-ene- and carboxy~cyclohepteno and carbamoylcyclohepteno;
and dehydro-cyclopenteno, dehydro-cyclohexeno and dehydro-cyc lohepteno.
If a ring carbon atom in the abovement;oned fused-on ring systems is replaced by a heteroatom, in particu-lar oxygen, the foliowing ring systems are particularlysultable: furoC2,3-b]pyridine, furo~3,2-b3pyridine, furo-C2,3-c~pyridine, furo~3,2-c]pyridine, thieno~2,3-b]pyrid-;ne, th;eno~3,2-b]pyrid;ne, th;eno~2,3-c3pyridine, thieno-C3,2-c3pyridine, thieno~3,4-b3pyr;d;ne and th;eno~3~4~c3-pyrid;ne.
The process according to the ;nvention for thepreparat;on of compounds of the formula I comprises reac-ting a compound of the general formula II, or salts thereof, R3CONIl = ,~S
~:H2R ~II) COO~ .
wherein R1 denotes hydrogen or methoxy, R2 denotes a group which can be replaced by the base corresponding to the radicals A of formula I, ~. 7 and in which RJC0 represents an acyl radical, for example a formyl radical or an acyl radical which is generally known from cephaLosporin and peni-~` `f' '' ' ' - 1~259S4 . - 8 -cill;n chem;stry, with the base on which the radical A defined above in for-mul:a I is based, to form the compound of the general for-mula III
~R1 R3CoN~I~5~
5 ~ o ~ ~ ( I I I ) in ~hich ~ A, R1 and R3 have the abovement;oned meaning, and then spl;tt;ng off the acyl radical by general chemi-cal or enzymatic methods known from cephalosporin and :
penicillin chemistry, to form the compound I.
: Particularly su;table radicals R2 are acyLoxy : radicaLs of lower aliphatic carboxylic acids, preferablywith 1 tD 4 carbon atoms, such as, for example, acetoxy or propionyloxy, in particular acetoxy, which can opt;on-; 15 ally be substituted, such as, for example, chloroacetoxy or acet~o~acetoxy. Other ~roups are aLso suitable for R2, such as, for example, carbamoyloxy.
In the acyl radicals R3Co-, R3 denotes hydrogen or the group R4-~CH2)n-, in which n = O or 1 and R4 denotes ` 20 a C~-C1û-alkyl radical, preferably a C1-C4-alkyl rad;-caL, whlch can be monosubstituted or polysubstituted by identi~cal or different substituents from the group com-`pr;sing optionally substituted carbocyclic or heterocyc~
I;c aryl, such as, for example, phenyl and thienyl, opti-.
onally substituted aryloxy or heteroaryloxy, such as~ for example, phenyloxy, optionalLy substituted arylthio or :. ~l225954 _ 9 _ heteroarylthio~ such as, for example, phenylthio and imi~
dazolylthio, C3-C6-cycloalkyl and C4-C~-cycloalkenyl, op~
tionally subst;tuted c1-c6-alkoxY, opt;onally subst;tu-ted Cl-c6-alky~thio~ cyano, haLogen, trifluoromethyl, sul-fo, hydroxyl, amino and carboxyl, it being possible forhydroxyl, am;no and carboxyl groups also to be protected or blocked, for example the group , 2 3 ' CO01~
;n which Z represents optionally substituted arylcarbonyl, such as, for example, phenylcarbonyl or heteroarylcarbonyl, such as, for example, th;en-2-yl-carbonyl, opt;onally sub-stituted C1-C4-alkoxycarbonyl or the group ; -CH=C(C02C2H5)~, opt;onally subst;tuted C1-C6-alkyl-sul-fonyl or opt;onally subst;tuted phenylsulfonyl, such as, for example, 4-methyl-phenylsulfonyl or 4-chloro-phenyl-sulfonyl, or R4 denotes an opt;onally substituted car-bocycl;c or heterocyclic aryl radical, such as, for ex-ample,~phenyl, th;enyl or furyl.
R3 furthermore denotes the group R4-C~
~oR5 wherein RS denotes hydrogen or an opt;onally subst;tu-ted C1-C6-alkyl rad;cal and R4 has the above mening, or R3 denotes the rad;cal R6CO-~C,- , in which R6 de-oR5C1-C6-alkyl~
Particularly preferred starting compounds are those in which the acyl radicals R3Co- denote a thienyl-acetyl or phenylacetyl radical whictl can be split off ~225~5 - 10 ~
enzymatically by means of pen;c;llin G am;dohydrolase.
Start;ng compounds wh;ch are readily access;ble preparat-ively and are thus inexpensive and in which R3Co- can be, for example, thienylacetyl~ phenylacetyl or phenoxyacetyl S are also preferred. The radicals of the natural product cephatosporin C and blocked and protected derivatives thereof, of the formula Z-NH-CH~CH2)3 CO-, in wh;ch COOH

Z has the abovementioned meaningy are furthermore parti-cularly preferred. The startiny compounds are thus known from the literature or can eas;ly be prepared by proces-ses which ire known from the literature.
The react;on of compounds of the general formula II w;th the bases which correspond to the radicals A ;n the general formula I can be carried out in water or in ~a mixture of water and a readily water-m;scible organ;c solvent, such as, for example, acetone, d;oxane, aceto-~nitrile, d;methylformam;de, dimethylsulfoxide or ethanol.

::
The reac~t;ion temperature ;s ;n general in the range from about 10~to about 100C, and is preferably between 20 and 80C. The base ComponQnt is added in amounts between approximately equimolar amounts and up to a 5-fold excess.
Replacement of the radical R2 is facilitated by the pre-sence of neutral salt ;ons, preferably of iodide or thio-cyanate ions, ln the reaction medium. In particular, about 10 to about 30 equivalents of potassium iodide~
sodium iodide, potassium thiocyanate or sodium thiocyanate are added. The reaction is advantageously carried out close to ~he neutral po;nt, preferably at a pH value in the ~ ~ . . . . .
, f` ~ 9S4 range from about 5 to about 8~
The react;on can also preferabLy be carried out ;n non-aqueous solut;on ;n the presence of tr;-C1-C4-alkyl-. iodosilane, such as, for example, trimethyl- or triethyl-;odos;lane. The react;on of compounds of the general for-mula II with pyr;d;ne bases ;s known. Thus, for example, it is reported in the literature tEuro~pean Patent 60,144) that 3-iodomethyl-cephalosporin deriva~ives, for example compounds wh;ch correspond to those of the formula I, 1û ~here A - I, react with pyridine bases to give the corre-spond;ng pyridinium compounds. Such iodoalkyl compounds can generally be prepared from esters, for example acet-ates, wlth trimethyliodosilane (J. Amer. Chem. Soc. 99, 968, 1977; and Angew. Chem;e 91, 648, 1979)~ a reaction wh;ch has~subsequently been applled to cephalosporins (European Patent 34,924, U.S. Patent 4,266,049, Tetra~
hedron Letters 1981, 3915 and European Patent 70,706).
According to the two-stage process described in European~Patent 60,144, for example, the acetates corre 2a sponding to those of the forwuLa II (R2=OCOCH3) are first converted into the 3-iodomethylcompounds, and these are ;solated and then reacted with the desired pyridine bases.
Purification by chromatography is necessary to isolate the end products, and the maximum yield of pure end product is below 10% o~ theory. Even in a var;ant described in European Patent 70,706, Example 5, in which the 3-iodo-methyl compounds are not isolated, after reaction with pyridine, the title compound, besides several components~
can be identified only by chromato~raphy.

2S9S~

It is surprising that the yields of end products of the formula I are ;ncreased up to more than ten-fold ~hen the nucleoph;l;c replacement react;on ;s carried out from the start ;n the presence of an excess of the corre-sponding bases on which the radical A in formula I is based,i.e. a tr;-C1-C4-alkyl;odos;lane, preferably trimethyl-iodos;lane~ after addition of the base to the react;on mixture.
The process ;s carr;ed out by a procedure in which the base corresponding to the rad;cal A ;s added to a solut;on or suspension of the compound II ;n a suitable solvent, followed by tr;methyliodosilane. It is also poss;ble, for example, for a reaction mixture of iodine and~hexamethyldisilane, which have first been reacted at temperatures between about 60 and 1Z0C in a manner known from the L;terature, tr;methyl;odos;lane being formed, to be used instead of trimethyliodosilane. In-stead of trimethyliodosilane, triethyl;odosilane which has been prepared in a manner which is known from ~he literature can also be used with the same good results.
The reaction ;s carried out at temperatures between about -S and ~100C, preferably between +10 and t80C.
Examples of su;table inert aprotic solvents are chlorinated hydrocarbons, such as methylene chloride~
chloroform, d;chloroethane, trichloroethane and carbon tetrachlor;de, or lower alkyl-n;tr;les, such as aceton;t-rile or propion;trile, or fr;gens; ;n part;cular, methyl-ene chlor;de ;s an outstand;ng solvent.
At least the stoichiometric arnount up to a twenty-' ' .

- ~.2Z595~

fold excess of the base corresponding to the radical A is added, and the react;on ;s preferably carr;ed out with amounts such that the quant;ty of hydrogen ;od;de l;ber-ated ;s bonded and at least 1 mole, preferably 2-5 moles, of the base are still ava;lable for the replacement reac-tion~
Since, besides the group R2 to be replaced in the start;ng compound II, other funct;onal groups present, such as the am;no, carboxyl or am;de group, react w;th trimethyl~iodos;lane, the latter ;s added ;n at least a four-fald up to a twenty-fold excess, preferably in a f;ve- to ten-fold excess.
Carboxyl and N-am;no groups ;n the compound II
i can also be pres;lylated by add;t;on of a silylating `15 agent,~such as, for example, b;strimethyls;lylacetam;de, bistr;met~hylsilyltr;fluoroacetamide, trimethylchloros;l-i ane~, hexamethyldisilazane or bistrimethylsilylurea, eitherin the absence of or in the presence of a base, preferably ;the desired bsse on wh;ch the group A ;s based, in the amount descr;bed above. At least the stoichiometr;c amount or an excess of tr;methyl;odos;lane, preferably a two-~ :
fold up to a ten-fold excess, is then added~
If the base on wh;ch the radical A in formula I
;s based contains funct;onal groups, such as, for example, hydroxyl groups and the l;ke, these are preferably pre-silylated with one of the abovementioned silylat;ng agents and then used ;n tl1e react;on.
The reaction products of the formula III can be isolated from the aqueous phase obtained by adding watcr . ' .

5~354 or aqueous mineral ac;ds, for example d;lute HCl, HBr, HI
or H2S04~ in the customary manner, for example by freeze-dry;ng the aqueous phase, chromatography and the l;ke~
The polar reaction products are preferably precipitated from the aqueous soLut;on in the form of a sparingly sol~
uble salt, for example a hydr;od;de salt.
~ he acyl group R C0 in the result;ng compounds of the generaL formula III iS then split off by generally known chemical methods - for example by hydrolysis with d;lute mineral ac;ds, such as, for example, hydrochlor;c acid or sulfuric acid, or by imide chlorides - or enzym-at;c methods, such as are described, for example, ;n 6erman Offenlegun~sschr1ft 3,019,838.
If imide chloride splitting is used, the compound 15 :~III ;s reacted with, for example, phosphorus pentachloride, the imide chlor;de formed is converted into the imino-ether by~addition of an alcohol and this ether is then ~split~by~hydrolysis~or alcoholysis. The reaction is ad-vantageously carried out in the presence of a silylating agent, such as trimethyLchlorosiLane. After hydrolysis of the reaction mixture by addition of water, the compound of the general formula I formed is isolated from the aqueous p;hase in the customary manner, for example by freeze-drylng or chromatography over silica gel or the like~ The~rea~ction products are preferably isolated from the reaction solution directly as spar;ngly soluble salts, for exampLe a hydrochloride or hydr;od;de~
If enzymatic splitting is used, for example, the acyl radical in compounds of the formula III in which X~i9S4 R3co denotes C6H5CH2CO- or ~ ~ c~ CO_ is spljt off with fixed penicillin G am;dohydrolase. The reaction is carried out ;n aqueous solut;on at a temperature of about 25-40C, preferably 35-37C, and a pH value of about 6.5-8.0, preferably 7~2-7.8. The pH value ;s kept con-stant-by addition of 1 N NaOH. When the react;on has ended, the f;xed enzyme ;s separated off by filtration.
The react;on products of the formula I thus ob-tained are ;solated from the aqueous phase ;n the custom-ary manner, for example by freeze-drying, chromatography or precip;tation in the form of a spar;ngly soluble salt.
The compounds of the formula I according to the ~;nvent;on are starting substances for the preparation of numerous h;ghly act;ve ant;b;ot;cs of the general formula 1~5 III' ~ R1 R CO-l~H ~--~S ~

o) ~ ~ 2 C2 ( I I I ' ) in wh;ch, for example, R1 denotes hydrogen or methoxy and `~' R3 CO denotes, ;n part;cular, a 2-(aminoheterocyclyl)~2-~ oxy;m;noacetyl radical, for example the 2-~2-aminothia-zolyl~-2-oxyimino-acetyl radical, which are described in German Patent Applications corresponding to German Offen legungsschrift 3,118,732, P 32 07 840.4, P 32 47 614.0 and P 32 47 613.2~
~` The following embodiment examples for the com-pounds which can be prepared by the process according to the invention serve to further illustrate the invention, .
'' ' .~ 2S9~L

but do not restrict it thereto.
Preparation of the starting materials Example 1 3-[(2 3-C clo enteno 1- ; erid;n;o)methYl]-7-(2~th;enyl)~
,~ Y P _P P
acetalnido)-ceph-3-em-4 carboxylate Variant a A mixture of 150 g (0036 mole).of sod;um 7-t2 thienylacetamido)-cephalosporinate ~cephalothin), 680 g (7 moles) of potasslum thiocyanate, 66.5 g (65 rnl, 0.56 mole) of 2,3-cyclopentenopyr;dine, 150 mL of water and 30 g of 85 per cent strength phosphoric acid ;s stirred at 66-68C for 4 hours. During this time, the pH value drops from 6.6 to pH 6Ø The yellow-colored viscous solution is diluted with 3 liters of water and extracted wlth ~our 400 ml por~ions of methylene chloride. 110 ml of 18 per cent strength hydrochloric acid are then added dropwise at 5-10C in the course of 30 mlnutes, wh;le cooling and stirring, whereupon a voluminous precipitate forms. The mixture is left in an ice-bath for 2 hours and the precipitate is filtered off with suction, washed w;th three 500 ml portions of water and dried in vacuo.
~-~ Yield: 130 g (0.245 mole) of light yellow-colored crys-tflls (68X of theory) of decomposition point 156-1 58C.

C22H21N34S2 x HSCN x H20 Calculated C 51.86 H 4.54 N 10052 S 18.06 H20 3.38%
Found C 51.8 H 4.3 N 10.2 S 18.0 H20 2.9 %
IR (KBr): 1775 ~lactam C0); and 2040 cm 1 (SCN) H-NMR (CF3C02D): S = 2.3-2.8 (m, 2H, cyclopentene H);

2S~3~;4 3.15-3.95 (m, 6H, 4 cyclopentene H
and SCH2); 4.06 ts, 2H, CH2CO);
5.2-6.2 (m, 4H, CH2Py and 2 lactam H); 6.8-7.4 (m, 3H, th;o-phene) and 7.65-8.70 ppm ~m, 3H, PY).
Varlant b 3.96 9 (10 mmol) of 7-(2-thienylacetamido)-cepha-losporanic acid are dissolved in 90 ml of methylene chlor-ide, and 10.2 9 (10 ml, 86 mmol~ of Z,3-cyclopentenopyri-dine are added. 14 g (10 ml, 70 mmcl) of trimethyliodo-silane are then added dropw;se, while stirring and cool-;ng, and the solution ;s heated under reflux for 2 hours.
It is cooled to -15C, 25 ml of 2 N hydrochlor;c acid ~: ~
are added and the organic phase is separated off. The aqueous phase is adjusted to pH 6.0 by addition of sod;um ~bi~carbonate and ;s chromatographed over sllica gel (Grace, ~ : : : ~ ~ . : :
` 0.1 mm) us;n`g acetone:water (3:1). After freeze-drying the pro~duct fractlons, the t;tle compound ;s obtained ;n 20~ the for~m~of a l;ght yellow amorphous solid. ~
Yield; 3.2 g (70.5% of theory) ~, IR (KBr):~ 1775 cm~1 (lactam C0) ~MR `(CF3C02D): ~ - 2 .3-2.8 (m, 2H, cyclopentene H);
3.1-3.~5 (m, 6H, 4 cyclopentene H
and SCH2); 4.09 (s, 2H, CH2C0);
5.2-6.2S ~m, 4H, CH2Py and 2 lactam H);
6.8-7.4 (m, 3H, thiophene); and 7.65-8.85 ppm ~m, 3H, Py).
'` ', :
' " ' ' .

: ' S9~;4 ~ 18 -Example 2 3-C~2,3-Cyclopenteno-1-pyr;d;n;o)methyl~-7-phenylacetam-ido-ce h-3-em-4-carboxylate P
Vari ant a The t;tle compound is obta;ned from 14.l~ g of sod;urn 7-phenyLacetamido-cephalospor;nate, ~8 g of pot-assium thiocyanate, 6.5 ml of 2,3-cyclopentenopyridine, 15 ml of water and 3.4 g of 85 ~er cent strength phospho-ric acid analogously to Example 1a. The react;on m;xture is diluted with 120 ml of acetone and chromatographed over 500 9 of silica gel (Grace, 0.1 mm) using acetone:water (8:1) and then acetone:water (2:1). After freeze-drying, the product fractlons give 7a5 g (48% of theory) of a light grey-colored amorphous solid.
15 IR tKBr): 1770 cm 1 (lactam C0) H-NMR (CF3C02D~: S = 2.25-2.85 (m, 2H, cyclopentene H);
3.1-3.75 (m, 6H, 4 cyclopentene H
and SCH2); 3.87 (s, 2H, CH2C0);
3.2-6.25 (m, 4H, CH2Py and 2 lac- ;
tam H); 7.38 (s, 5H, phenyl); and `~`~ 7.6-8.7 ppm (m, 3H, Py).
~~ Variant b The title compound is obtained from 3.9 g of 7-phenylacetam;do-cephalosporinate, 10 ml of 2,3-cyclopen-tenodpyridine and 10 ml of trimethyliodosilane ;n 90 mlof methylene chloride analogously to Example 1b. After the hydrolys;s, the rnixture is chromatographed as above, over silica gel using acetone:water (3:1).
Yield: 2.4 g (53.5%) of an arnorphous solid.

~L22~;9~i4 The compound is identicaL in all its properties to that of Example 2a.

Examp le 3 ,. 3-~(2r3-~enteno-1-pyridlnio)lnethyl]-7~phenoxy-acetam;do~ceph-3-em-4-carboxylate Var;ant a The title compound is obtained~ from 21.4 g oF
sodium 7-phenoxyacetam;do-cephalosporinate, 95 g of pot-ass;um thiocyanate, 9 ml of 2,3-cyclopentenopyr;dine and 1.5 g of 85 per cent strength H3P04 in 21 ml of water ana-logously to Example 1a. After dilution with acetone, the m;xture is chromatographed over 600 g of silica gel using acetone:water (8-1) and then using acetone:water (2:1).
The product fractions are freeze-dried. 11.9 g (51% of theory) of a colorless amorphous sol;d are obta;ned.
IR; ~KBr)~: 1770 cm 1 (la~ctam C0) H-NMR ~CF3C02D): ~ = 2.25-2.85 ~m, 2H, cyclopentene H);
3.15-3.9 (m, 6H, cyclopentene H and SCH2); 4.~31 (s,. 2H, CH2CO); 5.25-6.20 (m, 4H, CH2Py and 2 lactam H);
: ;, 6.8-7.5 ~m, 5 phenyl H); and 7.65-8.7 ppm (m, 3H, Py).
Var;ant b The t;tle compound is obtained from 2.5 g of 7-- 25 phenoxyacetamido-cephalospor;nate, S ml of 2,3~cyclopen-tenopyridine and 5 ml of trimethyliodosilane ;n 45 ml of methylene chlor;de analogously to Example 1b. After the hydrolysis, the aqueous phase is chromatographed over silica gel using acetone:water (3:1~ After freeze-drylng, 25g5 the product ~ractions give 1.8 g (61.5% of theory) of a brown;sh-colored amorphous solid. The compound ;s iden-ticaL in all its properties to that of Example 3a.
Example _ 7-(D~5 B_ zam;do-5-carboxypentane-am;do)-3-rt2,3-cyclo~
Denteno-1-DYridinio)methyl]ceoh~3-em 4-carboxylate Variant a A solution of 5.2 g (10 mmol) of 7-tD-5-benzamido~
5-carboxypentane-amido)-cephalosporinate, 11.9 g (11~7 ml, 0.1 mole) of 2,3~cyclopentenopyridine, 66 g (0.4 mole) of potassium iodide and 30 mg of ascorbic acid in 75 ml of water and 25 ml of acetone is heated at 66-68C for 4 hours. After cooling, the mixture is diluted wi~h 500 ml of acetone and chromatographed over 300 g of s;lica gel.
15 ~The sa~ts are eluted w;th acetone:water (7:1) and the title~compound is eluted w~ith acetone:water t2:1). After ~freeze-drying of the product fractions, 3.2 g (55% of theory) of a colorless amorphous solid are ob~ained~
IR (KBr): 1770 cm 1 (lactam C0) 1H-NMR (CF3C02D): ~ = 1.8-3.9 (m, 15H, 6 cyclopentene H, SCH2 and pentane H); 4.8-602 (m~
4H, CH2Py and 2 lactam H); and 7.3-8.7 ppm (m, 8H, Py and phenyl)0 Var;ant b 5.1 g ~4 ml, 28 mmol) of trimethyliodosilane are added all at once to a mixture of 2.1 g (4 mmol) of 7- -~
(D-5-benzamido-5~carboxypentane aMido)-cephalospor;nate,

4.06 g (4 ml, 34 mmol) of 2,3-cyclopentenopyridine and - 40 rnl of methylene chloride, wh1le cooling~ The mixture - ~ ~Z2~i9~4 ....~. - 21 - -;s heated under reflux for 2 hours, cooled and hydrolyzed by add;t;on of 5 ml of 2 N HCl. The aqueous phase ;s separated off, adjusted to pH 6 with sodium bicarbonate and chromatographed over 150 g of sil;ca geL using ace tone:water (5:1) and then acetone:water (2:1~. After ~ freeze-drying, the produc~ fracti~ons give 1.9 g (47~5X of ; a light yellow amorphous solid. The compound is ;dent;-cal in all its properties to that described above.
Example 5 7-tD-5-(4-Chlorobenzamido)~5-carboxypentane-amido)-3-~(2,3-cyc~lopenteno-1-pyrid;nio)methyl]-ceph-3-em-4-car-boxylate Variant a ~The title compound is obtained as an amorphous solid 1n 48% yield analogously to Example 4a from 5.5 g t10 mmol) of 7-CD-5-(4 chlorobenzamido)-5-carboxypentane-amido~-c~ephalosporinate, 11.9 9 (0.1 mole) of 2,3-c-yclo--penten~opyridine, 66 g (0.4 mole) of potassium iodide and 30 mg of ascorbic acid in 100 ml of water:acetone (3:1).
.
20 IR (~Br): 1770 cm 1 (lactam C0) H-NMR (CF3C02D): ~ = 1.9-2.9 (m, 8H, (CH2)3 and 2 cyclo-pentene H); 3.1-3.8 (m, 7~, lt cyclo-pentene H, SCH2 and CH); 4.9-6.3 (m, 4H, CH2Py and 2 lactam H); and 7.3-8.7 ppm tm, 7H, phenyl and Py).
Variant b The title compound is obtained as an amorphous sol;d analogously to Example 4b from 7-CD-5-~4-chlorobenz-amido)-5-carboxypentane-arnido]-cephalosporinate, (Z.Z g), .. .

.

-' ~ 2259S4 2,3-cyclopentenopyr;d;ne ~4.06 9) and tr;methyliodosilane (5.1 g) ;n methylene chlor;de (40 ml), after chrorna-tography. Yield: 51X of theory.
The compound is identical in all its propert;es S to ehat described above.
The compounds of the following ~xamples 6~12 are obtained from the correspond;ng cephalosporin derivatives and 2,3-cycLopentenopyr;d;ne analogously to Example 4, var;ant a ~replacement in water) or 4, variant b (tri-methyliodosilane method).Example 6 7-(D-5-benzenesulfonamido)-5-carboxypentane-am;do)-3-~(2,3-cyclopenteno-1-pyr;dinio~methyl]-ceph-3-em-4-car-boxylate Yield according to variant a. 45%, according to variant b: 5ZX
.

1H-NMR (CF3C02D): ~ = 1.6-4.4 (m, 15H, 6 cyclopentene H, - 7 pentane H and SCH2); 5.15-6.2 (m, 4H, CHzPy and 2 lactam H); and 7.4-8.65 ppm tm~ 8H~ phenyl and Py).
Example 7 7 CD-5-(4-MethylbenzenesuLfonamido)-5-carboxy-pentane-amidoJ-3-~t2,3-cyclopenteno-1-pyridinio)methyl]-ceph-3-em~4-carboxylate Yield according to variant a: 38%
H-NMR tD6-DMS0): ~ = 1.2-4.1 tm~ 18H with s at 2.36-CH3, 6 cyclopentene H, 7 pentane H and CH2S); 4.8~507 t4H, CH2 Py and 2 lactam H); and 7.2-9.4 ppm (~H, .

~22~;95~

3 Py H, 4 phenyl H and 2NH).

7-~D-5~(4-chlorobenzenesulfonam;do)-5~carboxypentane am;do~3-(2,3-cyclopenteno-1-pyridinio)methyl-ceph-3-em 4-carboxylate ~ rield according to variant a: 48%, accord;ng to variant ; b: 55%
H-NMR (CF3C02D): ~ = 1.6-4.4 ~m, 15H~ 6 cyclopentene H, 7 pentane H and SCH2); 5.1-6.25 (m, 4H, CH2Py and 2 lactam H); and 7.4-8.7 ppm (m, 7H, phenyl and Py) Example 9 7-(D-S-Am;no~5-carboxy pentane-am;do-3-(2,3-cyclopenteno-1-pyridinio)methyl-ceph-3-em-4-carboxylate Yield (accord;ng to var;ant a): 19%
H-NMR (D2~0): ~ = 1.6-2.7 (m~ 8H, (CH2)3 and 2 cyclopentene H): 2.9-3.9 (m, 7H, 4 cyclopentene M; SCH2 and CH N); 5.9 5.95 (m, 4H, CH2Py and 2 lactam H); and 7~6-8.7 ppm (m, 3H, Py) Example 10 `- 7-(P-5-tert.-Butyloxycarbonylamino-5-carboxypentane-amido)-3-t2,3-cyclopenteno-1-pyr;d;nio)methyl-ceph-3-em 4-car-boxylate Yield according to variant a: 15% of theory H-NMR (D6-DMS0): ~ = 1.2-1.9 ~rn, 15H, ~CH2)3 and C(CH3)3); 1.9-2.4 ~rn, 2 cyclo-pentene H); 2.7-4.0 tln, 7H~ CHN, SCH2 and 4 cyclopentene H); 4.~~

.

22S9~;A

5~7 (m, 4H, CHzPy and 2 lactam H);

6.0-6.3 (NH); 7.7-8.9 (m, 3H, Py):
and 9.1-9.4 ppm (NH) Example 11

7-~(D-5-Carboxy-5-~2,2-diethoxycarbonyl)v;nylamino-pen-tane-amido]-3-(2 3-cycLopenteno-1-pyridinio~methyl-ceph-3-em-4-carboxylate Yield accord;ng to variant a: 14X Of theory 1H-NMR ~D6-DMSO~: ~ = 1.0-1.4 (t, 6H, ethyl), 1.4-1.8 (m, 6H, (CHz)3); 1.9-2.4 tm, Z
cyclopentene H); Z.8-4.3 (m, 11H, 4 cyclopentene H), CHNH, SCH2 and 4 ethyl); 4.7-5.7 (4H~ CHzPy and 2 lactam H); and 7.6-9.8 ppm ~6H, 3 Py H, vinyl H~ 2 NH) Example 12 7-t2 Acetyl-2-sYn-methoxyimino-acetam;do)-3-~2~3-cyclo-penteno-1-pyridin;o)methyl-ceph-3-em-4-carboxylate Yield according to variant a: 18% of theory ~ZO 1H-NMR (CF3C02D): ~ = 2.3-2.9 (m with s at 2n49~ 5H~
CH3CO and 2 cyclopentene H); 3.1-~`~` . 3~ (m, 6H, SCH2 and 4 cyclopen-tene H) 4~26 (s~ 3H~ NOCH3), 5.1-6.Z ~m, 4H~ CH2Py and 2 lactam H~;
and 7~6-8.7 ppm (m, 3H, Py) The compounds sho~n below, which correspond to the general formula .

12;~9S4 C6115CO~ C13 (CH2) 3CONH~
~C~I2A

and ;n which A denotes the subst;tuent shown ;n the second column of TabLe 1, are obtained ana~ogously to Example 4b (trimethyliodosilane method).
Table 1 Ex- A Yield 1H-NMR (CF3C02D): ~(ppm) ample _ ~ of th.
13 ~ ~ 38 1.7-3.9 (m, 9H, SCH2, 7 pentane -~ ~ H) 4.8-6.4 (m, 4H, CH2Py and 2 lactam H); 7.4-9.2 (m, 10H, Py ' and phenyl) ~ ' .
14 ~ ~ 22 1.7-3.9 (m, 9H, SCH2 and 7 pen-tane H): 4.8-6.3 (m, 4H, CH2Py \> and 2 lactam H) 7~3-8.6 (m, 10H, \~/ phenyl and quinoline) 8.9-9.4 (m, 2 quinoline H) 26 1.8-3.1 (m, 7H, pentane); 3.39 ~ ~ and 3.82 (AB, J = 19~1Z, SCH2);
4.8-6.3 (m, 4H, CH2Py and 2 lac-\~/ tam H); 7.3-8.7 (m, 11H, ohenyl and ;soquinoline); 9.5-9.85 (m, 1 isoquinoline H) `` lZ2~i954 Ex- A Yield 1H-NMR (Cf3C02D): ~ ~ppm) ample % of th _ ........... __ _ 16 ~ 32 1.6-4.1 (m, 17H, 8 cyclohexene H, 7 pentane H and SCH2), 4.9-6.4 (m, 4H, CH2Py and 2 lactam -~ ~ H); 7.3-9.0 ~m, 8H, phenyl and . Py) : _ 17 35 1.7-3.0 (m, 7H, pentane); 2.76 (s, 3H, CH3); 3.65 and 3.73 ~ C~33 (AB, J = 19 Hz, SCH2); 4.7-6.3 I ~ (m, 4H, CH2Py and 2 lactam H);
7.3-8.9 (m, 9H, phenyl and Py) . ' _ 18 62 1.8-2.9 (m, 7 pentane H); 3.42 . C~T~5 and 3.76 (AB, J = 19 Hz, SCH2);
4.9-6.4 (m, 4H, CH2Py and 2 lactam H); 7.3-9.25 (m, 14H, : ~ phenyl and Py) :
.

~ .
.

The compounds shown beLow, wh;ch correspond to the general formula ~L C~2CO~il ~S
L~L--C~I2A

CO ~

and ;n which A denotes the substituent shown in the sec-ond column of Table 2, are obtained analogously to Example 1b (trimethyliodosilane method).
Table 2 Ex- A ¦Yield 1H-NMR (CF3C02D): ~ (ppm ampl~ ¦% of th.
19 ~ 84 2.66 (s, 3H, CH3); 3.40 and C~ 3.72 (AB, J = 19 Hzf 2H, SCH2);
4.06 (s, 2H, CH2C0); 5~05~6.40 : : ~ (m, 4H, CH2Py and 2 lactam H);
. ~ ~ ~ 6.8-7.4 (m, 3H, thiopene), 7.95-: : ~ 9.20 (m, 4H, Py) __ _ ~
3.38 and 3.72 (AB, J = 19 Hz, C ~ SCH2); 4.10-(s, 2H, CH2C0);
~._ . 4.9-6.3 (m, 4H, CH2Py and 2 lac-C~ tam H); 6.9-7.3 (m, 3H, thio-~ ~ pene); 7.66 (s, 5H, phenyl);
: : 8.0-9.4 (m, 4H, Py) "
.

.
~.

^ ~LZZ~ii954 Ex- A ¦Yield 1H-NMR (CF3C02D): ~ (ppm) ampl~e '~ of th.
- 21 ~ 35 1.7-2.4 (m, 4H, cyclohexene H);
2.8-3.8 (m, 6H, 4 cycLohexene H), -~ ~ SCH2); 4.05 (s, 2H, CH2C0);
5.15-6.25 (m, 4H, CH2Py and . 2 lactam H); 6.8-7.5 (m, 3H, ¦ th;opene); 7.6-8~8 (m, 3H, Py) . . _ ~
; 22 ~ 38 3.40 and 3.78 (AB, J = 19 Hz, 2H, SCH2); 4.08 (s, 2H, CH2CO);
5.15-6.35 (m, 4H, CH2Py and 2 lactam H); 6.8-7.4 (m, 3H
thiopene); 7.9-8.8 (m, 6H, isoqu;noline H); 9.5-9.8 (m, 1 soqu;noline H) .. . . __ . ..... ~
23 Ci ~ 28 3.42 and 3n75 (AB, ~ = 19 Hz, ~1 ~ SCH2); 4.06 (s, 2H, CH2C0);
5.26-6.42 (m, 4H, CH2Py and 2 lactam H); 6.8-7.4 (m, 3H, .
thiopene); 8.0-9.2 (m, 5H, Py) : ~

~ 2~;9S4 The compounds shown below, whir,h correspond to the general formula and in wh;ch R1 and R3 deno'ce the substi'cuents given in Table 3, are obta;ned analogously to Example 1b (tri-methyliodosilane method).
.
Table 3 Ex- R1 R3 Yield l1H-NMR (CF3COZD): ~(PPm) ample % of th.
_ 24 H ~ ~ 28 2.1-2.9 (m, SH, CH3-S~H - s;ng. at 2.33 and N 2 2 cyclopentene H); 3.1-3.9 (m, 6H, SCH2 and 4 cyclopentene H); 4.03 (S, 2H, CH2CO); 5.15-6.25 (m, 4H, CH2Py and 2 lactam H); 7.3-8.7 ~ I r (m, SH, Py and imidazole) H CNCH2- 32 2.1-2.9 (m, 2 cyclopen-tene H); 3.1-3.8 (m, 6H, -!
. SCH2 and 4 cyclopentene H);
3.88 (S, 2H, CH2CO3; 5.2-6.25 (m, 4H, CH2PY and 2 lactam H); 7.65-8.7 (m, 3H, PY) - - - - -: : :

2sgs~ ~

Ex- R1 R3 Yield 1N-NMR (CF3C02D): ~S(PPm) ample X of th.
26 H ~ 68 2.2-2.9 ~m, Z cyclopen-~ 11 tene H); 3.15-3.85 (m, 6H, N SCH2 and 4 cyclopentene H);
OC}13 5.2-6.Z5 (rn, 4H, CH2Py . . and 2 lactam H); 6.60;
6.98 and 7.57 (one . furan H each); 7.6-8.7 . . . ~m, 3H, Py) _ 27OCH3 ~ I 65 2.2-2.9 (m, 2 cyclopen-CO tene H); 2.9-3.8 (m, 6H, SCH2 and 4 cyclopentene . H); 3.70 (s, 3H, OCH3);
4.10 (s, 2H, CH2CO);
5.25-6.20 (m, 4H, CH2Py . and 2 lactam H); 6.7-7.45 (m, 3 thiopene H);
~ : ~ ~.65-8.7 tm, 3H, Py) ' , .

.
` -~ 2~s4 End products Example 1 7-Am;no-3-C2,3-cyclopenteno-1-pyr;d;n;o)methyl]~ceph~3~
em-4 carboxylate a) Chem;caL spl;ttin~
- 5~6 ml (44 mmol) of N,N-d;rnethylan;l;ne and 2.8 ml ~22.2 rnmol~ of trimethylchlorosilane are added to a stir-red suspension of 5~6 g (10.5 mmol) of 3-C(2,3~cyclopen-teno-1-pyr;d;n;o)methyl~-7-(2-thienylacetam;do~-ceph-3-ern-4-carboxylate hydro~hiocyanate salt (Example 1) in 40 ml of dry methylene chloride. When the temperature is in-creased slightly to 27C, a clear solution is formed.
After the mixture has been stirred at room temperature for 1 hour, it is cooled to -40C and 4.6 g (22.2 mmol) of PCl5 are added all at once, whereupon the tempera-ture r;ses to -25C. The dark brown solution is stir-red at -30C for 1 hour and is then poured into a solu-- t~on, cooled to -40C, of 9 ml of ;sobutanol in 18 rnl of methy;lene chloride. A precipitate formsO After the mixture has been left to stand overnight in a refriyera-; tor, the precip;tate is f;ltered off w;th suction and washed with methylene chloride. The rnoist crude product is immed;ately dissolved in 15 ml of methanol of -5C, and 80 ml of methylene chloride:ether ~1:1) are added drop-wise~ After stlrring at -10C for 2 hours, the precipi-tate formed is filtered off ~ith suction, washed with acetone and dried over PzO5 in vacuo.
Yield: 3c3 g (78% of theory) of Light brown crystals.

16H17N33S x 2 HCl .

2~g~4 Calculated: C 47.41 H 4.97 Cl 17.49 N 10.37X
Found: C 46.2 H 5.6 Cl 16.6 N 9.8%
IR (Ksr): 1785 cm -1 (lactam CO) 1H-NMR(CF3C02D): ~ = 2~55-2.95 ~m, 2H cyclopentene H);
3.15-3.95 (mf 6H, 4 cyclopen-tene H and S-CHz); 5~53 (s, 2H, lactam H); 5.55 and 6.03 (AB,J - 15 Hz, 2H~ CH2Py), 7.65-8.70 ppm (m, 3H, Py).
10 b) Enzymatic splitting 106 y (0.2 mole) of 3-C(2,3-cyclopenteno~1-pyri~
d;n;o)methyl~-7-(2-th;enyl-acetamido)-ceph~3-em 4-car-boxylate hydrothiocyanate salt (Example 1) are suspended ;n 6CO ml of water, a solution of 150 ml of Amberl;te LA-2 .
(Rohm and~Haas) in 800 ml of ethylacetate are added and ; the mixture ;s stirred in an ice-bath for half an hour.
The phases are sPparated and the aqueous solution is ex-tracted~w;th two 50 ml portions of LA-2 (acetate forrn) in 150 ml of methyl isobutyl ketone and the extract is also washed with four 100 ml portions of methylene chloride.
The aqueous phase is made up to a volume of 500 ml and adjusted to pH 7 with NaHC03 tO.2 g). 100 9 of fixed pen;c;llin G am;nohydrolase enzyme are added and the mix-ture is stirred at 37C and pH 7.1. The pH value is ; 25 kept constant by dropwise addition of 1N NaOH. After 2 hours, 90 per cent conversion is achieved (thin layer chromatography system: acetone/H20 - 5:1, silica ~el plates)~
The fixed enzyme is filtered off and washed with three 100 ml portions of water and the aqueous phases are brought ~ 122~954 to pH 6 ~ith 2N HCL and freeze-dried. The amorphous lyoph;l;sate ;s stirred w;th 250 ml of methanol, a small amount of unsoluble mater;al is filtered off and 300 ml of 15 percent strength alcoholic hydrochloric acid and S then 1 l;ter of ether are added to the f;ltrate. After 2 hours at 0C, this precipitate is filtered off with suction, washed with ether:methanol ~4:1~ and dried in vacuo.
Yield: 61 g of colorless product (75% of theory). The com-pound is identical ;n all its properties to that descr;bed above in Example 1a.
The compounds of the general formula I l;sted inthe following Table 4 are obtained from the corresponding 2-thienylacetamido-cephalosporine der;vat;ves analogously 15 to Example 1 (method a: chemical spl;tting; method b: en-zymatic splitting).

:

Table 4 Ex- A ¦Method Yield ~ 1H-NMR(CF3C02D): ~(ppm) ; ample 1- ~ of th~
2 ~ ¦ a(b)72 1.7-2.4 (m, 4H, cyclo- 3 . ~ hexene H); 2.7-3~95 (m, (69) 6H, 4 cyclohexene H and . ~ SCH2); 5~35-6.25 (m, 4H, CH2Py and 2 lactam _ _ H), 7.75-8 65 (m, 3H, Py) .
,' .

-- ~X2~;95~

Ex- A Method Yield 1H-NMR(CF3C02D): ~(ppm) ample % of th.
.
3 ~_~ 3 a (b) 81 2.69 (s, 3H, CH3);
(78) 3.66 (s, 2H, SCH2);
5.25 6.39 (m, 4H, CH2Py and 2 lactam H);
7.83-9.03 (m, 4 Py H) ... _ .. ___ 4 ~ a (b) 77 3.4-3.9 (AB, 2H, SCH2);
~ (75) 5.2-6.4 ~m, 4H, CH2Py -~ 9 and 2 lactam H); 7.9-

8.8 (m, 5 q~;nol;ne H);
8.85-9.2 (mJ2 qu;no-l;ne H) _~ .. .. ~ _ ~ a (b) 80 3.5-4.0 (AB, 2H, SCH2);
-N ~ ~ J 5.1-6.6 (m, 4H, CH2Py (74) and 2 lactam H); 7.9-8.8 (m, 6 ;soqu;noline H); 9.8-9.95 (bs, 1 ;so-qu;nol;ne H) . _ ~. _ :
: ~ :

::

:

:` :

-` ~L225!9S4 Example 6 7-Amino-3-(2,3-cyclopenteno-1-pyrid;n;o)methyl-ceph-3-em-4-carboxylate -3 9 (5.2 mmole) of 7-(D-5-benzamido-5-carboxypen-S tanamido)-3-(2,3-cyclopenteno-1-pyridinio)methyl-ceph-3 em-4-carboxylate (Starting Example 4) are suspended in 20 ml of methylene chloride. After addition of 3.9 ml (31.2 mmole) of N,N-dimethylaniline and 3.9 ml (31.Z mmole) of trimethylchlorosilane, the mixture is stirred at room temperature for 1 hour. The clear solu~ion is cooled to 40C and 6.2 g (30 mmole) of PCl5 are added~ The solu-tion ;s stirred at -30 for 1 hour and is then poured, all at once, into a solution, cooled to -40C, of 4.1 ml of isobutanol in lO ml of methylene chloride. The mix-ture ;s left at 0 for 1 hour and the solvent is thenremoved in a rotary vacuum evaporator. The res;due is d;ssolved in 5 g of ;ce-water and the solution is brought to pH 6 by addition of NaHC03O It is chromatographed over~a silica gel column using acetone:~ater (2:1). The product fract;ons are fre~eze-dried.
Y;eid: 0.83 g (48% of theory) H-NMR ~CF3C02D): ~ ~= 2.2-2.9 (m, 2H, cyclopentene H); 3.15-3.93 (m, 6H, 4 cyclopen-tene H and SCH2); 5.25 6.35 (m, 4H, CH2Py and 2 lactam H); 7.65-8.0 (m, 1H, Py); 8.23-8~7 ppm (m, 2H, PY) ~he compound of Example 6 is obtained from the . ' .

benzenesulfonamido compounds o~ startlng Examples 6, 7 and 8, ;n a manner analogous to that descr;bed ;n Example 6.
Y;eld: 55% from the compound of starting Example 6 62% from the compound of starting Example 7 58% from the compound of start;ng Example 8 The compound obtained in each case is ;dent;cal in all its properties to that describe~d above in Example 6.
Example 6 a) 3-~(2,3-Cyclopenteno-1 pyridin;o)methyl]-7-for--~ mylamino-ceph-3-em-4-carboxylate hydriodide 24 g (0.08 mole) of anhydrous 7-formyl-am;no cephalosporanlc acid are suspended in 400 ml of dr;ed methylene chloride, and 46~8 ml (0~4 mole) of cyclopen-tenopyr;~dlne are added at room temperature. 45.6 ml (0.32 mole) of trimethylsilyl iodlde are added dropwise to the clear solution, ~Ihile stirriny and wi.h exclusion of mo;sture, and the m;xture is heated under refLux for two hours. Tbe reaction mixture is then cooled to 0C, 2ûO ml of water are added and tl1e mixture is neutralized w;th about 400 ml of saturated sodium bicarbonate solutlon ~pH 6). The phases are separated and the organ;c phase ;s extracted by shaking with 80 ml of water. The comb;ned aqueous phases are extracted with three 200 ml portions ; of methylene chloride and separated off, residues of methylene chloride are removed from the aqueous phase in vacuo and the aqueous phase is clar;fied with 4 g of -~ act;ve charcoal. The filtered a~ueous solution is brought to a pH value of about 1~5 with 200 ml of 1N HI and is then concentrated to about 100 ml in vacuo on a rotary , -- ~i7 --evaporator The prec;pitate is filtered off with suction, ~Jashed w;th acetone and dr;ed ;n vacuo over P20 Yield: 24.1 9 (59.6% of theory) cl7ti17N304XHIXH20 (505 3) Calculated: C 40.41 H 3.99 I 25.11 N 8.32 S 6.35 H20 3.56X
Found: C 40.1 H 4.1 I Z3O7 N 8.2 S ~.4 H20 4.2%
H-NMR (CF3)C02)D: aS = 2.3-2.8 ~m, 2H, cyclopen tene H); 3.15-3.~5 (m, 6H, 4 cyclopentene H and SCH2); 5.25-6.30 (m, 4H, CH2Py and Z lac-tam H~; 7.65-8 75 tm, 4H, HC0 and 3 Py H) b) 7~-hmino-3-~(Z,3-cyclopenteno-1~pyr;din;o)methyl]-ceph 3-em-~-carboxylate , 15 D;hydrochloride 20.2 g (0.04 mole~ of the product of Stage a are suspended ;n 200 ml of 2N hydrochloric acid. The suspen-s;on ;s warmed to ~60C, a cLear solution be;ng formed, and the soLution ;~5 lef~ at th;s temperature for a fur~
20 ther S~ minutes. It is concent~rated to a volume of about 40 ml on a rotary vacuum evaporator. After addit;on of 120 ml of acetone, the dihydrochloride of the title com-pound precipitates as crystals. The crystals are filtered otf witl1 suction, washed with acetone and dried in vacuo over P205.
Y;eld: 15.4 g ~B6% of theory~, decomposition 167C
C16H17N303S x 2 HCl x H20 (422~4) Calculated: C 45.5 H 5.0 Cl 160~ N 9.9 H20 4.3%

Found: C 44~0 H 4~8 Cl 15.2 N 9~6 H20 3O3%

~ .
The N.~R spectrum is identical in all its proper-t;es to that of Example 1a.
-Monohydr;od;de and monohydrochloride . 0.422 g (1 mmole) of the above dihydrochloride is dissolved ;n 2 ml of water at room temperature. 84 mg of sodium b;carbonate and 0.05 ml ~about 0.4 mmole) of 57 per cent hydriodic acid are added. The mo.nohydriodide preci-p;tates from the clear solut;on as crystal. The crystals are f;ltered off w;th suct;on~ washed with a l;ttle water 10 and dried in vacuo over H2S04.
Yield 0-2 y C16H17N33S x HI x H20 (4773) Calculated: C 1~0.26 H 4.22 I 26.59 N 8.80%
Found: ~C 40.7 H 4.2 I 25.0 N 8.9%
The monochloride is obtained from the mother ~l;qor by adding~acetone until crystaLlization starts.
The crystallization of 200 mg from acetone: water (6:1) gives 130 mg of pure monochloride monohydrate.

16H17N33S x HCl x H20 (385.9) Calculated: C 49.80 H 5.22 Cl 9.18 N 10.89 S 8.31%
.
Found: C 50.1 H 5.6 Cl 8.8 N 10.9 S 8.9%

.

~, .
~ ' :` ' .

, . .

Claims (5)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for the preparation of a 7-amino-cepha-losporanic acid derivative of the formula I

wherein R1 denotes hydrogen or methoxy and A denotes a pyridinium radical , which can be monosubstituted or polysubstituted by iden-tical or different substituents from the group comprising optionally substituted C1-C6-alkyl, it being possible for two alkyl groups in the or-tho-position also to be linked to form an optio-nally substituted di- to deca-methylene ring, in which one ring carbon atom can be replaced by a heteroatom and which can furthermore also con-tain one or two double bonds, optionally substi-tuted C2-C6-alkenyl, C2-C6-alkinyl and C3-C7-cycloalkyl and C3-C7-cycloalkyl-methyl, it being possible for the ring also to be substi-tuted in the last two substituents; C4-C7-cyclo-alkenyl, optionally substituted C1-C6-alkoxy, C2-C6-alkenyloxy and C2-C6-alkinyloxy, halo-gen, trifluoromethyl and hydroxyl, and optionally substituted phenyl, benzyl and heteroaryl, and wherein, furthermore, A denotes a quinolinium or an isoquinoli- nium radical, each of which can also be monosubstituted or polysubstituted by identi-cal or different substituents from the group com-prising optionally substituted C1-C6-alkyl, C1-C6-alkoxy, halogen, trifluoromethyl and hydroxyl, which comprises reacting a compound of the general formula II, or salts thereof, (II) in which R1 denotes hydrogen or methoxy, R2 denotes a group which can be replaced by the base corresponding to the radicals A of formula I, and in which R3Co- represents an acyl radical, with the base on which the radical A defined above in for-mula I is based, to form the compound of the general for-mula II

(III) in which A, R1 and R3 have the abovementioned meaning, and then splitting off the acyl radical by general chemi-cal or enzymatic methods known from cephalosporin and penicillin chemistry, to form the compound I.

2. A process as claimed in claim 1, wherein the radi-cal R3Co- is a formyl radical or an acyl radical known from cephalosporin and penicillin chemistry.

3. The process as claimed in claim 2, wherein the radical R3Co- is a thienylacetyl, phenylacetyl or phen-oxyacetyl radical or the radical NH2-(CH2)3CO-the functional groups of which can be protected.

4. The process as claimed in claim 1, wherein the reaction with the base corresponding to the substituent A is carried out in the presence of a tri-C1-C4-alkyliodosilane.

5. The process as claimed in claim 4, wherein the tri-C1-C4-alkyliodosilane is trimethyl- or triethyl-iodosilane.