CA1250284A - Antibacterial epimeric azahomoerythromycin a derivative and production thereof - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE
Disclosed are antibacterial 4"-epi-9-deoxo-9a-methyl-9a-aza--9a-homoerythromycin A and pharmaceutically acceptable salts thereof. The antibacterial compound may be prepared by (a) methyl-ation of 4"-epi-deoxo-9a-aza-9a-homoerythromycin A, (b) N-deoxy-genation of 4"-epi-9-deoxo-9a-methyl-9a-aza-9a-homoerythromycin A 3'-N-oxide or (c) hydrogenation of 4"-deoxy-4"-oxo-9-deoxo-9a-methyl-9a-aza-9a-homoerythromycin A. The antibacterial compound and its pharmaceutically acceptable salts can be formulated in pharmaceutical compositions and may be used in the treatment of bacterial infections in mammals.

Description

~l2S~;12~
-l- 72222-57D

This is a divisional application of Ser. No. 440,924 filed November lO, l983.
The present invention relates to antibacterial 4"-epi-9-de-oxo~9a-methyl-9a-aza-9a-homoerythromycin A and pharmaceutically-acceptable salts thereof and their production processes.
More speci~ically, the present invention is concerned with compounds of the formula:
zl (C113)2N(-~)n z ~ ~C113 R O~ ~

0( ~11 110 ~ 3 ~ Yl O ' ,~'//~y C,13 OC113 (wherein (V) Rl=H,2 and zl together = O, R2=~1, Y=~1, Yl=OH and n=0;

l z zl ~ R2=11 Y=11, Yl=oll and n=O;
(VII) Rl=benzyloxycarbonyl, Z=Zl=11, R2=~, Y and Y
together =O and n=O;

(VIII) Rl=benzyloxycarbonyl, Z=Z =T1, R2=(C2-C3)alkanoyl, Y and yl -together =O; n=0;

:12S~284 -la- 72222-57~

(VIIa) R =methyl, Z=Z =H, R =H, Y and Y together = O and n=O;
VIIIa) Rl=methyl, Z=Z =H, R =(C2-C3)alkanoyl, Y and yl together =O and n=O, (IX) R =benzyloxycarbonyl, Z=Z =H, R =(C2-C3)alkanoyl, Y=OH, Yl=H and n=O;
l OH Z Zl=H R2=H Y=H, Yl=OH and n=l; or (XI) Rl=methyl, Z=Zl=H, R2=H, Y=H, Yl=OH and n-l).
These compounds can be derived from erythromycin A and are useful directly or indirectly for the preparation of antibacterial 4"-epi-9-deoxo-9a-methyl-9a-aza-9a-homoerythromycin A which will be described in more detail infra.
The present invention is also concerned with a process for the production of those intermediates. This process comprises one or more of the following:
(a) a Beckman rearran~ement of 4"-epi-erythromycin A

oxime of the formula:
( 3)2 0~ "~ o ~\C113 Cliz~\ `~ \~ ~ '/ o """ ~o C113 C~13 O 12" ~ 011 / '//

- lZ51;~213~
- .Lb - i;'222-57 D

~o give 4~'-e~!i-9a-a~a-9a-homoerYthromYcin A (i.e., compound V);
(1~) reduction of the amide carbonyl in saicl produced 4"-epi-9a-aza-9a-homoerythromycin A (i.e., compound V) in-to its dihydro derivative 4'~-epi-9-deoxo-9a-aza-9a-homoerythromycin A
(i.e., compound VI);
(c) acylating 9-deoxo-9a-aza-9a-homoerythromycin A
of the ~ormula:

C1-13 ~cH3)~N

3 ~ 3 ~ \
HO t t ~ 10 ~ "" Cll C~ 13 3 ~ C1-13 C1112 \l~C~,I /1/""~;O~Cll~, C133 o~
" ", 01 1 with a limited excess of acetic or propionic anhydride in a reaction inert solvent at 0-30C to form 2'-0-(C2-C3)alkanoyl-9-deoxo-9a-aza-9a-homoerythromycin A; and reacting said

2'-0-(C2-C3)alkanoyl-9-deoxo-9a-aza-9a-homoerythromycin A Wit}

carbobenzoxy chloride in the presence oE a base in a reaction inert solvent a-t 0-50C to form 2'-0-(C2-C3)alkanoyl-9-deoxo-9a-benzyloxycarbonyl-9a-aza-9a-homoerythromycin A (i.e. compound IX);

- ~z5~89L

- lc - 72222-57 (d) oxidizing said produced 2'-O-(C2-C3)alkanoyl-9-deoxo-9a-benzyloxycarbonyl-9a-aza-9a-homoerythromycin A (i.e., compound IX) with oxalyl chloride and dimethylsulfoxide at -40 to -80C, followed by treatment with triethylamine, to -orm 2'-(C2-C3)alkanoyl-9a-benzyloxycarbonyl-9-deoxo-4"-deoxy-4"-oxo-9a-aza-9a-homoerythromycin A (i.e., compound VIII);
(e) solvolyzing said produced 2'-O-(C2-C3)alkanoyl-9-deoxo-9a-benzyloxycarbonyl-4"deoxy-4"-oxo-9a-aza-9a-homoerythromycin A (i.e., compound VIII) in methanol at 0-100C., lC to form 9a-benzyloxycarbonyl-9-deoxo-4"-deoxy-4"-oxo-9a-aza-9a-homoerythromycin A (i.e., compound VII);
(f) hydrogenation of said produced 9a-benzyloxycarbonyl-9-deoxo-4ll-deoxy-4ll-oxo-9a-aza-9a-homoerythromycin A (i.e., compound VII) over a Raney nickel catalyst in a reaction inert solvent at 20-100C to give 4"-epi-9-deoxo-9a-aza-9a-homoerythrom-ycin A (i.e., compound VI);
(g) oxidation of 2'-O-(C2-C3)alkanoyl-9-deoxo-9a-methyl-9a-aza-9a-homoerythromycin A of the formula:

~2S~28~
_ ld _ 72222-57 P

C113 ~ 3)2N
- (c2-c3)all~anylo~ l /~\ '~
¦ 61~` 3 0 / ~ 0 1 C11 CH3 ~ I/o/~ t 3 CE12 ~ C11 CH3 OC1-1~

~ith trifuloroacetic anhydride and dimethylsulfoxide at -40C.
to -80C., followed by treatment with triethylamine, to form 2'-O-(C2-C3)alkanoyl-4"-deoxy-4"-oxo-9-deoxo-9a-methyl-9a-aza-9a-homoerythromycin A (i.e., compound VIIIa);
~ h) solvolysis of said produced 2'-O-tC2-C3)alkanoyl-4'-deoxy-4''-oxo-9-deoxo-ga-methyl-ga-aza-ga-homoerythromycin A
(i.e., compound VIIIa) to form 4~l-deDxy-4ll-oxo-9-deoxo-9a-meth ~a-a~a-9a-homoerythromycin A (i.e. ! compound VIIa);
(i) oxidizing said produced 4"-epi-9-deoxo-9a-aza-9a-homoerythromycin A (i.e., compound VI) with E12O2 to give 4"-epi-9-deoxo-9a-hydroxy-9a-aza-9a-homoerythromycin A

3'-N-oxide (i.e., compound X); or ~25~28~
- le - 72222-57 ~

(j) methylating and dehydroxylating said produced

4"-epi-9-deoxo-9a-hydroxy-9a-aza-9a-homoerythromycin A 3'-N-oxide (i.e., compound X) with methyl iodide in the presence of a solvent-insoluable base to give 4"-epi-9-deoxo-9a-methyl-9a-a~a-9a-homoerythromycin A 3'-N-oxide (i.e., compound XI).

-lf- 72222-57 Erythromycin A is a well-known macrolide antibiotic, having the formula (I), which has found extensive clinical use.

CH3 N (CH3)2 3 J ~ 3 ~ CH3 CH3 ~, 13 3 ~ CH3 CH3 o$ ~ CH3 CH3 'OCH3 (I) 4-Epi-9-deoxo-9a-methyl-9a-aza-9a-homoerythromycin A
4"-epimer of the previously reported erythromycin A derivative of the formula (II), the ~,CH3 N ( CH3) 2 ~ HO, R-N9a 7~ ~' 3 4~

HO ~ lHo ~ " ~ ~ CH3 HO ~ 2 ~ CH3 CH2"~3~ o~" ~ ,oH3 CH "'OCH
(II) R=methyl (III) R=hydrogen -2- 72222-57 ~

subject of Belgian Patent 892,357, as well as United States Patent No. 4,474,768. In that Belgian patent, the compound of the for-mula (II~ is named as the N-methyl derivative of "ll-aza-10-deoxo-10-dihydroerythromycin A", a name coined earlier by Kobrehel et al., United States Patent 4,32~,334 for the precursor compound of the formula (III). For the latter ring expanded (homo), aza ~nitro-gen substituted for carbon) erythromycin A derivative, we prefer the name 9-deoxo-9a-aza-9a-homoerythromycin A. That compound could also be named as a 10-aza-14-hexadecanolide derivative.
Certain of novel intermediates are likewise 4"-epimers of previously known compounds. Thus 4"-epi-9-deoxo-9a-aza-9a-hom-erythromycin A is the 4"-epimer of the above compound of the formula (III); and 4"-epi-erythromycin A oxime is the 4"-epimer of the erythromycin A oxime of Djokic et al., United States Patent 3,478,014.
The present invention provides the antibacterial compound 4"-epi-9-deoxo-9a-methyl-9a-aza-9a-homoerythromycin A, of the formula (IV) described hereinunder or a pharmaceutically-accep-table salt thereof which is useful in pharmaceutical compositions and in method of the treatment of bacterial infections in mammals.
The present invention also provides a process for the pre-paration of 4"-epi-9-deoxo-9a-methyl-9a-aza-9a-homoerythromycin A or a pharmaceutically acceptable salt thereof which is char-acterized by:
(a) methylation of 4"-epi-deoxo-9a-aza-9a-homoerythromycin A with formaldehyde in the presence of a reducing agent selected from formic acid, sodium cyanoborohydride, or hydrogen and a nobel metal catalyst in a reaction-inert solvent at 20-100C;

~Z5C~:284 -2a- 72222-57 (b) N-deoxygenation of 4"-epi-9-deoxo-9a-methyl-9a-aza-9a-homoerythromycin A 3'-N-oxide with hydrogen over a noble metal or Raney nicke~ catalyst in a reaction-inert solvent at 20-100C;
or (c) hydrogenation of 4"-deoxy-4"oxo-9-deoxo-9a-methyl-9a-aza-9a-homoerythromycin A over a noble metal or Raney nickel catalyst in a reaction inert so~vent at 20-100C.

l~S4~8~ `

zl ~H33 ( H3)~

~0 ~ ~o` ~ CH3 H ~ 3 (IV) R=methyl, Z=Zl=hydrogen (V) R=hydrogen, Z and zl together=o~cygen (VI) R=Z=Zl=hydrogen S The therapeutie compound (IV) shows a relative1y broad spectrum o~ antibacterial acti~ity which includes erythromycin ~ susceptible organisms and, in addition, fully incorporates the major respi-ratory pathogen Hemo~'nilus influenzae. Its high oral a~sor~tion and extraordinarily long half-liCe in ivo renders compound (IV) of especial value in the oral treatment Oc suscep~ible bacterial infections in mammals.
The following novel intermediates are useful in the synthesis of 4"-epi-9-deo.~o-9a-methyl-9a-aza-9a-homoerythromycin A (IV):
(a) A compound selected from the group consisting of 4"-epi-9a-aza-9a-homoerythromycin A and the 9-deo~.o derivative thereof, of the above formulae tV) and (VI), respectively.
~ b) 4n-Epi-erytilromycin A ocime.
(c) A compound selected ~rom the sroup consisting of 9a-benzylo~ycarbonyl-9-deo.Yo-~"-deo~Yy-4"-o~o-9a-aza-9a-homoerythromycin ~, of the ormula ~VII); 9-125~ 4 deoxo-4"-deoxy-4"-oxo-9a-methyl-9a-aza-9a-homoery~llro-mycin A, of the formula (VIIa); and the corre~pon~ing 2'-O-(C2-C3)alkanoyl derivatives thereof of the formulae (VIII) and (VIIIa). Acetyl is the preferred value of 2'-O-~C2-C3)alkanoyl.

~CH3 N(CH3)2 Rl_N ~ R O" ~

HO"~ ~ HO~ " ` CH3 HO~I
CH ~ '~'SxcH3 (YII) Rl=benzyloxycarbonyl, R2=H
(VIII) Rl=benzyloxycarbonyl, R2=(C2-C3)alkanoyl (VIIa) Rl=methyl, R2=H
(VIIIa) Rl=methyl, R2=(C2-C3)alkanoyl (d) ~ compound selected from the group consisting of the 2'-0-acetyl- and the 2'-0-propionyl-9-deoxo-9a-benzoyloxycarbonyl-9a-aza-9a-homoerythromycin A, of the formula (IX). The 2'-0-acetyl derivative is of particu-lar value.

1 ~ R20 ~, HO ,~J HO)~ ~O` I~olCH3 CH~ cH3 ~CH 3 ~X

(IX) Rl=benzyloxycarbonyl, R2=(C2-C3)alkanoyl ~2~8~

and (e) A comFound selected from the grG~
consistin~ o- ~"-e~i-9-deoxo-9a-hydro~-9~-aZ~-9~ omo-ervthromycin A 3'-~-o.cide and 4"-epi-9-deo~o-~-methvl-92-aza-9a-homoerythromycin A 3'-M-o~ide, o~ the formulae (,~ and (,YI), -es?ectively ~3~ 3 ~3 ~ ~, OH

(~) R3=hyaroxy tXI) R3=methyl The antibacterial compound ~o 4"-epi-9-deoxo-92-methyl-9a-aza-9a-homo-erythromycin A (IV), is readily prep~ed by a nu~er o~ routes from erythrom~,~cin .~. These rou.es, which variously proceed ~ia novel and known com~ounds as intermediates, involve intrinsic transforma~ions as lS follows:
(A) C-4" epimeri~2tion;
(B) ring e:cpansion, with introduction of 9a-nitrogen;
(C) removal of the 9-o:co group; and (D) 9a-M-methylation;
together with any optional or necess2r~ introductior.
and re.moval o~ protecting groups. Prererred are or.e o-the other of the following sequences of transfor~2tions:

lZ~

(~)(3)(C)(D), (3)(A)(C)(D) or (~)(C)(D)(~). T~e various interme~iates and final product are isolate~
by standard manipulative methods (e.g., e.Ytraction, precipitation, evaporation, chromatography, crys~al-lization).
(A)!B)(C)(D) The overational se~uence (A)(B)(C)(D) involves initial conversion of erythromycin A (I) to 4"-epi-erythromycin A, according to the method of Sciavolino et al. (su ra). The latter is then converted, in virtually quantitative yield, to 4"-epi-erythromycin ocime by reaction with hydroxyla.nine or preferabl~,. a hydro~ylamine salt such as the hydrochloride. Vnder ~resently discovered, preferred conditions, at least one molar equivalent, usually an excess, e.g., 10-30 esuivalents, of the hydro~ylamine is employed; in an e.~ccess of a weakly 'oasic, tertiary amine (preferably py-idine) as solvent; at a temperature in the range 0-50, conveniently at ambient temperature.
The resulting 4"-epi-erythromycin ocime is re-arranged to the 4"-epi-9a-aza-9a-homo derivative ('J) via a Bechman rearrangement. The preferred conditions employ an e~cess (e.g., 3-~l ~olar equivalents) of an organic sulfonyl chloride, preferably methane sulfonyl chloride, which is reacted with the oxime (as free base or as an acid salt) in a mi.cture oE a lower ~etone (e.g., metnyl ethyl ketorle, acetone) and water con-taining a large molar eccess of sodium bicarbonate, at a temperature of 0-50C., preferably at 0-30C.
The C-9 amide carbonyl of (V) is then conveniently reduced to the correspollding dihydro derivative, i.e., 4"-epi-9-dedco-9a-aza-9a-homoerythromycill ~ (VI) by reduction with sodium boro'nydride (preferabl~ in e.ccess to force the reaction to completion in a reasonable time period, but with at least t~o equivalents). The reduction is carried out in a suita`~le protic solvent, such as a lower al'~anol (preferably methanol) at 0-50 _7_ ~25~æ8~

(preferably at or below 38). Excess NaBH4 is care-fully decomposed by quenching the reaction in dilute aqueous acid.
Final methylation to yield the compound (IV) is accomplished by reductive methylation, using form-aldehyde in the presence of a reducing agent, such as hydrogen and a noble metal catalyst, sodium cyanobor-hydride, or, preferably, formic acid. The reaction is pre~erably carried out with at least one equivalent each of formaldehyde and forrnic acid in a reaction inert solvent at 20-100C. The preferred solvent is chloroform. In this solvent, reactants are conveniently combined at ambient temperature and then heated at reflux to force the reaction to completion.
Alternatively, methylation of (~I) to (IV) is accomplished by oxidatively protecting the dimethyl-amino group as its M-oxide (simultaneously forming the 9a-N-hydroxy derivative), methylating with methyl iodide, with (at least in part) simultaneous 3a-N-deoxygenation, and reduction of the resulting 9a-methyl-3"-N-o~ide. Oxidation of (VI) is readily accomplished by reaction with hydrogen peroxide, generally in excess of the minimum necessar~ two molar equivalents, in a reacti~n inert solvent at 10-50C., conveniently at ambient temperature. In this manner 9a-hydroxy-3'-N-oxide (X) is formed. The latter is methylated and deoxygenated to (~I) with methyl iodide conveniently in a reaction inert solvent (e~g., methylene chloride) at 0-50C. (conveniently at ambient temperature), preferably in the presence of a solvent insoluble base which will neutralize formed acid (e.g., HI when methyl iodide is the methylating agent). With methylene chloride as solvent, an excess of potassium carbonate is the base of choice. Thus the e::cess base and formed sodium iodide are completely remo~ed ~
simple filtration prior to isolation of the 9a~methyl-3'-N-oxide (~I). Finally, removal of the 3'-~-o~ide group is readily accomplished by hydrogenation over a noble metal or Raney nickel catalyst. In this hydro-genation, temperature and pressure are not critical, e.g., suitably 0-100C. and a pressure which ranges from subatmospheric to lO0 atmospheres or more. Most convenient are ambient temperature and moderate pres-sures, e.g., 2-8 atmospheres. Suitable noble metal catalysts include palladium rhodium and platinum, of the suppor~ed or non-supported type, well known in the art of catalytic hydrogenation. The preferred catalysts are palladium supported on carbon and Raney nickel.
tB)(~)(C)(D) The operational sequence (B)(A)(C)(D) involves initial conversion of erythromycin A (I) to 9-deoxo-9a-aza-9a-homoerythromycin (III), via erythromycin A
oxime and 9a-aza-9a-homoerythromycin, according to the method of Kobrehel et al. (supra). In this connection, the novel process, described above for 4"-epi-erythromycin A oxime, is advantageously employed for the preparation of the intermedia.e erythromycin A oxime.
The 2'-hydroxy group of compound (III) is first protected in the form of its acetate or propionate ester. Acylation is selectively accomplished by reacting compound (III) with a limited excess of acetic or propionic anhydride in a reaction inert solvent (e.g., methylene chloride) at 0-30C. (con-veniently ambient temperature). The limited excess of anhydride is used to compensate for reagent consumed in side reactions, e.g., undesired acylation of other groups, particularly the 9a-nitrogen.

~2Sl3~
g mhe resulting 2'-(C2-C3)alkanoyl derivati~s is then protected on 9a-nitrogen with a benzyloxycar'~onyl group. Thus compound (IX) is formed by reactivn of the above 2'-ester with carbobenzoxy chloride, in a re-action inert solvent in the presence of a base.
Particularly well suited are Schotten-Baumann con-ditions, i.e., reaction of the 2'-ester with the acid chloride under aqueous, alkaline conditions, e.g., aqueous tetrahydrofuran, maintaining the pH 7.5-8.5 with dilute NaOH as the acid chloride is added and as the reaction proceeds. Temperature is not critical, but will generally be in the range 0-50C., conveniently ambient.
The C-4" hydroxyl compound (IX) is then oxidized to C-4"-oxo compound (VIII) by the action of oxalyl chloride/ dimethylsulfoxide at low temperature t-40 to -80C.) in a reaction inert solvent (e.g., methylene chloride), followed by treatment of the cold reaction mixture with an excess of a tertiary amine (e.g., triethylamine). The alkanoate ester protecting group is removed by solvolysis, preferably by contact with excess methanol at 0-100C. thereby forming compound (VII~.
Hydrogenation over Raney nickel catalyst, using conditions as described above, converts compound (VII) tc 4"-epi-9-deoxo~9a-aza-9a-homoerythromycin ~ (VI).
The latter is converted to the 3a-N-methyl derivative (IV) according to one of alternative methods as de-scribed above.
(B)(C)(D)(A) This operational sequence involves initial conversion of erythromycin A to the above compound of the formula (II) according to my above cited co-pending application, using methods detailed in the Preparati~n section below. C-4" epimerization is then accomplished according to the steps and methods described above. The Z'-hydroxy group is prot~cted by acylation, the 4"-hydroxy group is oxidized to the 4"-oxo group, preferably substituting trifluoroacetic anhydride for oxalyl chloride; the protecting acyl group is rernoved; and the 4"-oxo group catalytlcally hydrogenated to the desired 4"-epimeric hydroxy group. In this case, the preferred catalyst is Raney nickel.
Since compound (IV) of the present invention contains two basic nitrogen atoms, pharmaceutically acceptable mono and di acid addition salts are formed ~y contacting the free base (IV), respectively, with substantially one equivalent of the acid or with at least two equivalents of the acid. Salts are generally formed by combining the reagents in a reaction inert solvent; i~ the salt does not precipitate directly, it is isolated by concentration and/or addition of a non-solvent. Suitable pharmaceutically acceptable acid addition salts include, but are not restricted to those with HCl, HBr, HNO3, H2SO4, HO2CCH2CH2CO2H, cls and trans-Ho2ccHcHco2H~ CH3SO3H and p-CH3C6H4SO3H-The antibacterial activity of the compound of the formula (IV) is demonstrated by measuring its minimum inhibitory concentrations (~IC's) in mcg./ml. against a variety of microorganisms in brain heart infusion (BHI) broth. Generally twelve 2 fold dilutions of the test compound are employed, with initial concentration of the test drug being in the range of 50 to 200 mcg./ml. The susceptibility (MIC) of the test organism is accepted as the lowest concentra-tion of compound capable of producing complete inhibition of growth as judged by the naked eye. A comparison of the activity of 4"-epi-9-deoxo-9a-methyl-9a-aza-9a-homoerythromycin A (IV) with that of an erythromycin ~ control is shown in replicate in the Table I.

5~8~

TABLE I
In vitro Activity o~ Compound (IV) .
Replicate MIC Va_ues _ _ Day l_ Day 2 A B A B
Staph. aur. 0050.05 0.200.05 0.39 - 0520.10 0.2~0.10 0.39 4003.12 3.126.25 12.5 Staph. epi 1110.05 0.10O.OS 0.20 Strep. faec. 006 0.781.56 0.78 0.78 Strep. pyoq. 203 0.0250.025 0.025 0.025 Strep. pneumo. 012 0.0250.025 0.025 0.025 E. Coli 125(a) 6.25(a) 6.25 129(a~ 1.56(a) 6.25 266~a) 3.12(a) 6.25 4703.12 0.783.12 0.78 Kleb. pn. oog~a) 12.5 (a) - 12.5 - 031(a) 12.5(a) 12.5 Xleb. oxy. 024(a) 12.5(a) 12.5 Past. mult. 0011.56 0.101.56 0. IO
Serr. mar. 017(a) 50 (a) 50 Neiss. sic. 0001.56 0.203.12 0.39 Ent. aerog. 040(a) 12.5(a) 12.5 Ent. cloac. 009(a) 25 (a) 25 Prov. strua. 013 (a) 50 (a) 50 H. influ. 0123.12 0.391.56 0.39 0366.25 0.393.12 0.39 03~6.25 0.393.12 0.78 ~s~æ~

TA~LE I (Cont.) In vitro Activity of Compound (IV) Replicate MIC Values . . _ Day 1 Day 2 .
A B A B
~. influ. 042 1.56 0.39 1.56 0.39 _ 051 3.12 0.39 3.12 0.78 073 3.12 0.39 3.12 0.78 078 1.56 0.39 1.56 0.39 081 3.12 0.39 ~.12 0.78 (a) greater than 50 A Erythromycin A control B Compound (IV) Additionally, compound (IV) is tested ln vivo by the well-kr.o-~n mouse protection test, or by a micro-biological (bioassay) determination of serum levels in a variety of mammals (e.g., mouse, rat, dog). Using rats as the test species, compound (IV) has been shown to be exceptionally well absorbed after oral dosage, providing exceptionally high and long lasting serum levels.
For the treatment of systemic infections in animals, including man, caused by susceptible micro-organisms, compound (IV) is dosed at a level o~ 2.5-100 mg./kg. per day, preferably 5-50 mg./kg./day, in divided doses, or preferably by a single daily dose.
Variation in dosage will be made depending upon the individual and upon the susceptibility of the micro-organism. These compounds are dosed orally or paren-terally, the preferred route being oral. The sus-ceptibility of microorganisms isolated in the clinics is routinely tested in clinical la~oratories by the - lZS~

well-known disc-plate method. Compound (IV) is ger.erally the compound of choice when it shows a relatively large zone of inhibition against the bacteria causing the infection to be treated.
Preparation of optimal dosage forms will be by methods well known in the pharmaceutical art. For oral administration, the compounds are formulated alone or in combination with pharmaceutical carriers such as inert solid diluents, aqueous solutions or various non-to~ic organic solvents in suc:h dosage forms as gelatin capsules, tablets, powders, lozenges, syrups and the like. Such carriers include water, ethanol, benzyl alcohol; glycerin, propylene glycol, vege~able oils, lactose, starches, talc, gelatins, gums and other well known carriers. The parenteral dosage forms required 'or the above systemic use are dissolved or suspended in a pharmaceutically-acceptable carrier such as water, saline, sesame oil and the like. Agents which improve the suspendability and dispersion qualities can also be added.
For the topical treatment of superficial infections in animals, including man, caused by susceptible micro-organisms, the compound (IV) is formulated by methods well known in the phar~acist's art into lotions, ointments, creams, salves, gels, or the like at con-centrations in the range 5-200 mg./cc. of the dosage form, preferably in ~he range 10-100 mg./cc. The dosage form is applied at the site of infection ad libitum, generally at least once a day.
The present invention is illustrated by the following examples. However, it should be understood that the invention is not limited to the specific details of these e~amples. Unless otherwise specified, ~LZ5~

all operations were carried out at ambient tem?era~ure;
all solvent stripping was carried out in vacuo f~om a bath at 40 or less; all listed temperatues are in degrees Centigrade; all thin layer chromatography ttlc) was carried out on commercial silica gel plates (using the eluant indicated in parentheses); and all solvent ratios are by volume. THF is used ~or tetrahydrofuran, and DMSO is used for dimethylsulfoxide.

~Z5~

EX~P~E 1 4"-Epi-erythromycin A Oxime [Oxime of 4"-Epimer o~ tI)]
4"-Epi-erythromycin A (50 g., 0.0646 mole) was dissolved in 265 ml. pyridine. Hydroxylamine hydro-chloride (112.2 g., 1.615 mole) was added and the slurry stirred 16 hours. The reaction mixture was stripped to a thicX slurry, diluted with 300 ml. iso-propanol, stirred well and filtered with 3 x 100 ml.
isopropanol for wash. The filtrate and washes were combined, stripped to a water-soluble foam, and tri-turated with ether to yield crude title product as the hydrochloride salt (100 g.). The latter was purified by distributing between CH2C12 and aqueous NaHC03 adjusted to pH 9.5 with dilute NaOH. The aqueous layer was separated and washed with ethyl acetate and then ether. All organic layers were com-bined, dried (Na2S04) and stripped to yield title product as a white foam, 59.5 g.; tlc Rf 0.5 (60:10:1 CH2C12:CH30H:conc. NH40H); lHnmr (CDC13)delta 2.31 [6H, s, (CH3)2N-], 3.32 (3H, s, cladinose CH30-).

125~

4"-Epi~9a-aza-9a-homoerythromycin A (V) Title product of the preceding E~:ample (59.2 g., 0.0787 mole) was dissolved in 400 ml. acetone. A
slurry of NaHCO3 (60 g.) in 225 ml. H2O was added.
Methanesulfonyl chloride (36.3 g., 24.5 ml.) in 50 ml.
acetone was added portionwise over 10 minutes, while maintaining the temperature :Less than 30 by means of a cooling bath. The mixture was stirred 4.5 hours, lQ stri2ped of acetone, CH2C12 t400 ml.) added to the aqueous residue, and the pH adjusted to 5.6 with 6N
HCl. The aqueous layer was separated, washed with two additional portions o~ CH2C12 and then adjusted to pH
9.5 with 6~ NaOH. The basic solution was extracted 2 x fresh CH2C12, 1 x ethyl acetate and 1 x ether. The basic organic e~tracts were combined, dried (Na2SO4) and stripped to yield title product as an ivory foam, 41 g.; tlc Rf 0.4 ~60:10:1 CH2C12: cH3oH:conc NH40H);
Hnmr (CDC13)delta 2.27 [6H, s, (CH3)2N-J, 3.29 (3H, s, cladinose CH O-); 13Cnmr [CDC13, (CH3)4 Si internal standard] ppm 177.24 (lactone C=O), 163.53 (amide C=O), 102.29 and 95.24 (C-3, C-5), 40.22 [(CH3)2N-].

.

~z56):284 2'-O-Acetyl-9-deo~o-9a-aza-9a-homoerythromycin A
_ [2'-O-Acetate of _ III)]
9-Deoxo-9a-aza-9a-homoerythromycin A (10 g., 0.0136 molei (III); U.S. Patent 4,328,334) was dis-solved in 150 ml. of CH2C12. Acetic anhydride (1.39 g., 1.28 ml., 0.0136 mole1 was added and the mi~ture stirred 3 hours. The acetylation was monitored by tlc;
to force the reaction to completion, 0.25 ml. acetic anhydride and then 0.5 ml. acetic anhydride were added, wi~h additional stirring ror 1.5 and 1 hour respectively.
The reaction mixture was diluted with H2O and the pH
adjusted to 11 with dilute NaOH. The organic layer was - separated, dried (NaSO4), and stripped to a foam, 11.5 - 15 g. The foam (10 g.) was chromatographed on 300 S-silica gel with 9:1 CH2C12:CH30H as eluant and tlc monitoring. A less polar impurity (3.6 g.) was eluted, followed by purified title product, isolated as a white foam, 2 g.; tlc Rf 0.2 (90:10:1 CH2C12:CH3OH:
conc. NH4QH); lHnmr (CDC13)delta 2.02 (3H, s, C-2' -O-C-CH3), 2.26 t6H, s, (CH3)2N-], 3.35 (3H, s, cladinose CH30-).
By the same method, ubstituting propionic anhydride for acetic anhydride, the corresponding 2'-O-propionyl derivative is prepared;

lZSQ2~4 2'-O-Acetyl-9-deoxo-9a-benzyloxycar~onyl-9a-aza-9a-homoerythromycin A [(IX~, R =acetyl]
Title product of the preceding Example (1.7 g., 0.00219-mole) was dissolved in 70 ml. 5:2 THF:H2O.
The pH was adjusted to 8 with dilute NaOH. Carbobenzoxy chloride (0.51 g., 0.427 ml., 0.003 mole) was added and the mixture stirred for 2 hollrs with further addition of dilute NaOH as necessary to maintain pH 8. Since tlc indicated reaction incomplete, more carbobenzoxy chloride (0.3 ml.) was added, and reaction continued for 3 hours, still maintaining pH 8. The reaction was quencned with copious H2O and ethyl acetate, the pH was adjusted to 9.6, and the aqueous layer washed with CH2C12. The organic layers were combined, d ied (~a2SO4) and stripped to a foam, 2.4 g. The ~oam was chromatographed on 85 g. silica gel, eluting with 170:10:1 CH2C12: CH3OH:conc. NH4OH. Pure fractions were combined, stripped to a foam, taken up in CH2C12 and concentrated until title product crystallized, 1.2 g.; m.p. 122; tlc Rf 0.4 (90:10:1 CH2C12:CH3OH:conc.
NH~OH); lHnmr (CDC13)delta 2.00 (3H, s, C-2' -O-C-CH3), 27 [6H, s, (CH3)2N-], 3.35 t3H, s, cladinose CH30-);
~ Cnmr [CDC13, (CH3)g Si internal standard] ppm 176~31 (lactone C=O), 169.36 (C-2' ester C=O), 157.10 (carba-mate C=O); 137.0, 127.55 and 127.92 (aromatic ring);
40~6 [(cH3)2N-]~
By the same method, the 2'-O-propionyl derivative of the preceding E~ample is converted to the corres-ponding 2'-O-propionyl-9a-benzylo~ycarbonyl derivative.

~LZ5~289~

. .
2'-O-Acetyl-9a-benzyloxycarbonyl-9-deoxo-4"-deoxy-4"-oxo-9a-aza~9a-homoerythroMycin r ( VIII), R =acetyl]
Oxalyl chloride (4.37 g , 3.0 ml., 0.0344 mole) was dissolved in 25 ml. CH2C}2 and cooled to -60.
DMSO (6.70 g., 6.09 ml., 0.0~56 mole) in 3 ml. CH2C12 was added. ~fter holding the mixture at -60 for 10 minutes, title product of the preceding Example (502 g., 0.00572 mole1 in 16 ml. CH2C12 was added at the same temperature. ~fter a further 25 minutes at -o0, triethvlamine (17.3 g., 23.9 ml., 0.172 mole) was added and the mi~ture warmed to room temperature, diluted with 50 ml. H2O and excess ~laHCO3. The organic 1, layer was separated, dried (Na2SO4) and stripped to yield title product as a tacky foam, 6.8 g.; tlc Rf 2 2 CH2OH:conc~ NH4OH); lH
delta 2.05 (3H, s, C-2' -O-C-CH3), 2.25 ~6H, s, (CH3)2N-], 3.32 (3H, s, cladinose CH30-), 7.37 (5~, s, aromatic p~otons), MS: major peaks at m/e 536 and 51 ~N-benzyloxycarbonyl aglycone ion (minus both sugars via cleavage at C-l", C-5)], 200 (base peak, desos-amine-derived fragment), 125 (neutral sugar-derived fragment). This intermediate is preferably used immediately in the next step.
In like manner, the corresponding 2'-O-propionyl-~"-oxo derivative is prepared from the 2'-O-propionyl compound of the preceding Example.

9a-Benzyloxycarbonyl-9-deoxo-4"-deox~
oxo-9a-aza-9a-homoerythromycin A (VII) _ Title product of the preceding Example, 1.0 g. was stirred in 25 ml. methanol for 65 hours, then stripped to a foam. The foam was taken up in CH2C12, washed with saturated NaHC03, and restripped to a second foam.
The second foam was chromatographed on 20 g. silica gel using 13:1 CH2C12:CH30H as eluant. Clean product fractions were combined and stripped to yield purified title product as a foam, 336 mg.; tlc Rf 0.4 (90:10:1 c~2cl2:cH3o~:conc. NH40H; 13Cnmr [CDC13, (CH3)4 Si internal standard] ppm 210.87 (C-4" C=0~, 176.03 (lactone C=0), 157.41 (carbamate C=0); 136.31, 128.2 lS and 128.0 (aromatic ring); 104.15 and 96.83 (C-3, C-5).
Alternatively, title product of the preceding Example (6 g.) was stirred 16 hours, then refluxed for 4 hours and stripped to yield title product as a tacky foam, 6.2 g., which tlc (Rf and eluant as above) indicated of sufficient purity to be used directly in the next step.
In li]ce manner, the same title product is prepared by solvolysis of the 2'-0-propionyl ester of the preceding Example.

12SO,~!34 4"-Epi-9-deoxo-9a-aza-9a-homoerythrom~cin A (VI) Method A
Title product of Example 2 (40 g.) was dissolved 600 ml. CH30H. NaBH4 (45 g.) was added over 45 minutes maintaining temperature less than 38. The reaction mixture was stirred 64 hours, then stripped to a thick slurry containing excess borohydride and ~oron ester complex of product. The latter was distri~uted between 500 ml. each CH2C12 and H2O, and the following sequence was repeated 3 times: The pH was adjusted with stir-ring to constant pH 2.5 wit~ dilute HCl; the mixture was stirred vigorously 25 minutes; and the H2O layer was separated, combined with 500 ml. fresh CH2C12, adjusted to pH 9.5 with dilute NaOH and the CH2C12 layer separated. The pH 9.5 CH2C12 layer was combined with 500 ml. fresh H2O for repetition of the sequence.
On the third pass, the pH 9.5 CH2C12 layer was dried (Na2SO4) and stripped to yield crude title product as a foam, 34 g., which was crystallized from 150 ml. hot isopropyl ether, cooled and diluted with 300 ml. of pentane, affordin7 purified title product, 25.8 g.;
~hite crystals; tlc Rf 0.5 (9:1 CHC13:diethylamine); Rf 0.1 t90 10:1 C~2C12:CH3OH:conc. NH40H), mp 170-180;
Hnmr (CDC13) delta 2i26 [6H, s, (CH3)2N-], 3.29 (3H, s, cladinose CH30-); Cnmr [CDC13, (CH3)4 Si internal standard] ppm 179.44 (lactone C=O), 103.57 and 96.70 (C-3, C-5); 41.50 [(CH3)2-N-].
Method B
Unchromatographed title product of the preceding Example (6.2 g.) was dissolved in 200 ml. ethanol and hydrosenated over 12.5 g. Rane~ Ni at 50 psig for lB

zso~

EXAMPLE 7 (Cont.) hours. The reaction mixture was filtered, charged with 20 g. fresh Raney Ni and hydrogenation continued 4 hours. Filtration and fresh catalyst recharge were repeated, and hydrogenation continued for a further 16 hours. Filtration and stripping of the filtrate gave crude title product as a white foam. The latter was distributed between CH2C12 and saturated NaHC03, and the organic layer separated, dried (~a2So4) and strip-ped to yield title product as a second white foam, 3.6 g., crystallized as a~ove to yield purified title ~roduct, 955 mg., having physical properties identical - with product prepared by Method A.

4"-Epi-9-deoxo-9a-hydroxy-9a-a~a-9a-homo-erythromycin A 3'-N-Oxide (X) Stirrin~ under N2, title product of the preceding Example (3.0 g.) was dissolved in 15 ml. of 1:1 THF:
CH30H. Thirty percent H202 (5 ml.) was added. After-20 0.5 hour, additional 30~ H202 (2.5 ml.) was added.
After a further 0.5 hour, the reaction mixture was cautiously poured into 1:1 CH2C12:H20 containing excess Na2S03 (exothermic). The pH was 9. The aqueous layer was washed with fresh CH2C12 and then ethyl acetate.
25 The organic layers were combined, dried (Na2S04) and stripped to yield title product, 2.7 g., tlc Rf 0.15 (60:10:1 CH2C12 CH30H:conc. NH40H~; Hnmr (cDcl3)delta 3-21 [6H, s, (CH3)2N 0], 3.38 (3H, s, cladinose CH30-); MS: major peaks at m/e 576 (ion from desosamine 30 fragmentation at C-5), 418 (N-hydroxyaglycone ion-minus both sugars). Both peaks diagnostic for -N-OH moiety with aglycone.

~z~2~4 4"-Epi-9-deoxo-9a-methyl-9a-aza-9a-homoerythrom~cin A
3'-N-O~ide (XI) Title product of the preceding Example (2.6 g., 0.0034 mole) was dissolved in 100 ml. CH2C12. With strong agitation, K2CO3 ~37.5 g., 0O271 mole) and then CH3I (19.3 g., 8.5 ml. 0.136 mole) were added and the mixture stirred 20 hours. Filtration and stripping gave title product as a foam, 2.9 g.; tlc Rf 0.3 ~60:10:1 C~2C12:CH3OH:conc. N~40H), R~ 0.15 (90:10:1 CH2C12:CH30H:conc. NH40H).
Title product prepared in this manner (2.8 g.) was further purified by chromatography on 85 g. silica gel using 90:10:1 CH2C12:CH3OH:conc. NH40H as eluant;
- 15 thereby removing minor, more polar impurities. Re-covery:0.87 g; lHnmr (CDC13)delta 2.32 (3H, s, aglycone CH3-lN-), 3.20 [6H, s, (CH3)2M-~0], 3.37 (3H, s, cladinose CH3O-) - E,YAMP~E 10 4"-Epi-9-deo~o-9a-methyl-9a-aza-9a-homoerythromycin A (IV) Method A
.
Title p-oduct of Example 7 (0.706 g., 0.96 mmole) was dissolved in 20 ml. CHC13. Formaldehyde (37~, 0.078 ml.) and then formic acid (0.03 ml.) ~Jere added and the mixture stirred 4 hours, then refluxed 7 hours.
The reaction mixture was cooled, added to 30 ml. H2O
and adjusted to pH 9 with 6N NaOH. The organic layer was separated, dried (Na2SO4) and stripped to yield title product as a white foam, 0.7 g.; crystallized from hot ethanol/H2O, 302 mg., mp 153; recrystallized from hot ethanol/H2O, 246 mg.; mp 155; tlc Rf 0.55 EXA~IPLE 10 (Cont.) (60:10:1 CH2C12:CH30H:conc. NH40~), Rf 0.6 (9:1 CHC13:
diethylamine); l~nmr (CDC13)delta 2.29 [9H, broadened s, aglycone N-CH3 and desosamine (CH3)2N-], 3.31 (3H, s, cladinose CH30-); 1 C~mr (CDC13, CDC13 internal standard) ppm 178.89 (lactone C=O), 102.63 znd 95.15 (C-3, C-5~, 40.38 [(CH3)2N-]; MS: major peaks at m/e 590 (N-methyl aglycone-desosamine ion vla cladinose cleavage at C-l"), 416 EN-methyl aglycone ion (minus both sugars via cleavage at C-l", C-5)~, 158 (base pe~, desosamine-derived fragment).
Method B
Unchromatographed title product of the preceding Example (0.242 g.) and 10% Pd/C (0.4 g.) were combined in 15 ml. 95~ ethanol and the mixture hydrosenated at 50 psig for 1 hour. Catalyst was recovered by filtration and the filtrate evaporated to yield title product as a white foam, 160 mg., crystallized from ether/pentane, 124 mg., recrystallized from ethanol/H2O, 95 mg., having physical properties identical with title product by Method A.
Method C
.
Chromatographically purified title product of the preceding E~æmple (319 mg.) and Raney nickel ~1.5 g., 50~ water-wet) were combined in 20 ml. ethanol and hydrogenated at 50 psig for 1.5 hours. Catalyst was removed by filtration and the mother liquor evaporated to dryness to yield 205 mg. title product, identical in physical properties with title product by ~ethod A.

12SO;2~4 2'-O-Acetyl-9-deoxo-9a-methyl-9a-aza-9a-homoerythromycin A
Title product oE Preparation 5 (2.5 g., 3.34 mmoles) was stirred with acetic anhydride (0.339 ml., 3.60 mmoles) in 30 ml. CH2C12 for 4 hours. The reaction mixture was stripped and the residue dis-solved in 50 ml. ethyl acetate, combined with 50 ml.
H2O and the pH adjusted to 9.5 with lN NaOH. The aqueous layer was separated and washed with 20 ml.
fresh ethyl acetate. The organic layers were combined, dried (~aSO4), stripped, dissolved in 30 ml. CHC13 and restripped to yield title product as a dry solid, 2.82 g., lHnmr/CDC13 includes delta 3.31 (C4i'-OCH3), 2.28 (N-CH3), 2.25 ~N-(CH3)2] and 2.0 (2'-OCOCH3).

2'-O-Acetyl-4"-deoxy-4"-oxo-9-deoxo-9a-methyl-9a-aza-9a-homoerythromycin ~ (VIIIa) Title product of the preceding Example (2.5 g., 3.2 mmoles) and DMSO (0.38 ml., 5.23 mmoles) were dissolved in 90 ml. CH2C12 and cooled to -70C.
Maintaining a temperature less than -50C., tri~luoro-acetic anhydride (0.72 ml., 4.95 mmoles) was added by syringe and the mixture stirred 50 minutes at -60.
Triethylamine (1.54 ml., 11 mmoles~ was added by syringe, maintaining less than -50 during addition.
The mixture was then warmed to 0, diluted with H2O
and the pH adjusted to 9.5 with dilute NaOH. The organic layer was separated, dried (NaSO4) to yield title product as a foam, 2.5 g. The foam was ~lash chromatographed on silica gel with 10:1 CHC13:CH30H as eluant, monitoring by tlc and collecting 3 fractions.
Cleanest product fraction 1, i.7 g., was dissolved in CHC13, diluted with H2O, adjusted to 2H 4 with dilute ~~ ' l2soæ~

EXAMPLE 12 (Cont.) HCl, and the aqueous layer separated, diluted with fresh CHC13, adjusted to pH 8 with dilute NaO~ and the organic layer separated. The last aqueous layer was extracted with three portions of fresh CHC13. The last ~our organic layers were co~bined, backwashed with H20, dried (Wa2So4) and stripped to yield puri~ied title product, 0.98 g.; tlc R 0.7 (S:l:O.l CHC13:
CH30H:NH40H); lHnmr (CDC13) includes delta (ppm): 2.05 (s, 3H, COCH3), 2.26 [s, 6H, N(CH3)2], 2.33 (d, 3H, NCH3) and 3.33 (d, 3H, OCH3).
EXAI~PLE 13 4"-Deoxy-4"-oxo-9-deoxo-9a-methyl~9a-aza-9a-homoerYthromycin A (VIIa) ..
Title product of the preceding Example (0.93 g.) was dissolved in methanol. ~fter 20 minutes the mixture was stripped to yield present title product, 0.74 g.; ms 746.4, 588.4, 573.4, 413.3, 158.1, 125.1;
lHnmr (CDC13) includes delta (ppm): 5.5 (t, lH, Cl"-H), 4.6 (q, lH, C5"-H), 3.35 (s, 3H, OCH3), 2.38 (s, 3H, NCH3), 2.30 [s, 6H, N(CH3)2].

:~25~8~

4"-Epi-9-deoxo-9a-methyl-9a-aza 9a-homoerythromycin ~ (IV) Title product of the preceding Example (0.25 g.) and 250 mg. of Raney nickel were combined in 20 ml.
ethanol and hydrogenated under 50 psig for 4 hours.
The catalyst was removed by filtration and the ~il-trate stripped to an oil which crystallized on standing.
Title product was recovered by trituration with iso-propyl ether and filtration, 0.13 g., identical inproperties with the product of Example 10.

125~

4"-Epi-erythromycin A
A suspension of 100 g~ of Raney nic~el sludge in 1 liter of absolute ethanol containing 100 g. of 4"-deoxy-4"-o~oerythromycin A (U.S. 4,510,220) was shaken in a hydrogen atmosphere overnight at room temperature at 50 psig. The spent catalyst was filtered over diatomaceous earth and the filtrate concentrated in vacuo to 300 ml. Water (700 ml.) was added to the concentrated filtrate and the resulting milky solution warmed on a steam bath. A small amount of ethanol was added to prevent gumming of the product as it precipi-tated from solution. After stirring for 2 hours at room temperature the product was filtered and dried, lS 57.6 g., and the filtrate concentrated in vacuo to the haze point. The mixture was allowed to stir for one hour and was filtered and dried, 21.4 g.
The resulting crops were combined, m.p. 141-144C. The lHnmr spectrum (CDC13) showed a~sorption at 3.3 (3H, s), 2.3 (6H, s) and 1.4 (3H, s) ppm.

12~ 8`~

Erythromycin A Oxime Hydrochloride Under N2, erythromycin A (500 g., 0.681 mole) was dissolved in pyridine (2.787 Ry., 2.850 L, 35.29 mole). Hydroxylamine hydrocilloride (1.1~3 Kg., 17.02 mole) was added and the mixture stirred for 22 hours, then stripped to a thick slurry and filtered with iso-propanol wash. The combined filtrate and wash was restripped to a thick, waxy MaSS, which crystallized by trituration with 2 L of water, 615 g., (slightly water wet, used in the next step without thorough drying);
tlc Rf 0.45 (60:10:1 CH2C12:CH3OH conc. NH40~).
By the same procedure, 5 g. of erythromycin A was converted to dried title product, 4.5 g., at least 95%
pure by 13Cnmr. Recrystallization of 1 g. from 10 ml.
methanol and 30 ml. isopropyl ether gave 725 mg.; mp 187 (dec.) ~literature mp 188-191, Massey et al., Tetrahedron Letters, pp. 157~160, 1970]; 13Cnmr [DMSO-d~, (CH3)4 Si internal standard] ppm 174.35 (lactone C=O), 168.78 (C=N-), 101.0 and 95.46 (C-3, C-5).

9a-Aza-9a-homoerythromycin A
By the procedure o Example 2 , with gas evolution noted on addition of the bicarbonate, slightly water wet, title product of the preceding Preparation (615 g., estimated to be 506 g., 0.613 mole on a dry basis was converted to crystalline title product, 416 g.;
Cnmr ~CDC13, CDC13 internal standard] ppm 177 54 (lactone C=O), 163.76 (amide C=O), 102.28 and 94.20 (C-3, C-5), 40.13 [(CH3)2N-].

--` lZ502:B~

9-Deoxo-9a-aza-9a-homoerythromycin A
sy reduction with NaBH4 according to the method of Kobrehel et al. (supra), title product of the preceding preparation was converted to present title product.

9-Deoxo-9a-methyl-9a-aza-9a-homoerythromycin A
By the procedure of Example 10 above, title product of the preceding Preparation (21.1 g., 0.0287 moles) was converted to present title product, initially isolated as a white foam, crystallized from hot ethanol/
H2O, 18.0 g., mp 136C.

Claims (13)

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

1. The compound 4"-epi-9-deoxo-9a-methyl-9a-aza-9a-homoery-thromycin A or a pharmaceutically acceptable mono- or di-acid addition salt thereof.

2. A process for the preparation of 4"-epi-9-deoxo-9a-methyl-9a-aza-9a-homoerythromycin A or a pharmaceutically acceptable salt thereof which is characterized by:
(a) methylation of 4"-epi-deoxo-9a-aza-9a-homoerythromycin A with formaldehyde in the presence of a reducing agent selected from formic acid, sodium cyanoborohydride, or hydrogen and a noble metal catalyst in a reaction-inert solvent at 20-100°C;
(b) N-deoxygenation of 4"-epi-9-deoxo-9a-methyl-9a-aza-9a-homoerythromycin A 3'-N-oxide with hydrogen over a noble metal or Raney nicket catalyst in a reaction-inert solvent at 20-100°C; or (c) hydrogenation of 4"-deoxy-4"-oxo-9-deoxo-9a-methyl-9a-aza-9a-homoerythromycin A over a noble metal or Raney nickel catalyst in a reaction inert solvent at 20-100°C.

3. A process of claim 2, wherein the 4"-epi-9-deoxo-9a-aza-9a-homoerythromycin A is prepared by reduetion of 4"-epi-9a-aza-9a-homoerythromycin A with excess NaBH4 in a protic solvent at 0-50°C.

4 A process of claim 2, wherein the 4"-epi-9-deoxo-9a-methyl-9a-aza-9a-homoerythromycin A 3"-N-oxide is prepared by methylation and dehydroxylation of 4"-epi-9-deoxo-9a-hydroxy-9a-aza-9a-homoerythromycin A 3'-N-oxide with excess methyl iodide and K2CO3 in a reaction inert solvent at 0-50°C.

5. A process of claim 2, wherein the 4"-deoxy-4"-oxo-9-deoxo-9a-methyl-9a-aza-9a-homoerythromycin A is prepared by the steps of:

(a) oxidation of 2'-O-(C2-C3)alkanoyl-9-deoxo-9a-methyl-9a-aza-9a-homoerythromycin A with trifluoro-acetic anhydride and dimethylsulfoxide at -40°C. to -80°C., followed by treatment with triethylamine, to form 2'-O-(C2-C3)alkanoyl-4"-deoxy-4"-oxo-9-deoxo-9a-methyl-9a-aza-9a-homoerythromycin A; and (b) solvolysis of said 2'-O-(C2-C3)alkanoyl-4"-oxo derivative in methanol at 0-100°C.

6. A process of claim 4 wherein the 4"-epi-9-deoxo-9a-hydroxy-9a-aza-9a-homoerythromycin A 3'-N-oxide is prepared by oxidation of 4"-epi-9-deoxo-9a-aza-9a-homoerythromycin A with H2O2 in a reaction inert solvent at 10-50°C, which in turn is prepared by reduction of 4"-epi-9a-aza-9a-homoerythromycin A with excess NaBH4 in a protic solvent at 0-50°C.

7. A process of claim 3 or claim 6 wherein 4"-epi-9a-aza-9a-homoerythromycin A is prepared by re-arrangement of 4"-epi-erythromycin A oxime in the presence of an excess of an organic sulfonyl chloride in an aqueous lower ketone solvent containing a large excess of NaHCO3 at 0-50°C.

8. A process of claim 2 wherein the 4"-epi-9-deoxo-9a-aza-9a-homoerythromycin A is prepared by hydrogenation of 9a-benzyloxycarbonyl-9-deoxo-4"-deoxy-4"-oxo-9a-aza-9a-homoerythromycin A over a Raney nickel catalyst in a reaction inert solvent at 20-100°C.

9. A process of claim 8 wherein the 9a-benzyloxycarbonyl-9-deoxo-4"-deoxoy-4"-oxo-9a-aza-9a-homoerythromycin A is prepared by the steps of:

(a) acylating 9-deoxo-9a-aza-9a-homoerythromycin A with a limited excess of acetic or propionic anhydride in a reaction inert solvent at 0-30°C
to form 2'-O-(C2-C3)alkanoyl-9-deoxo-9a-aza-9a-homoerythromycin A;
(b) reacting said 2'-O-(C2-C3)alkanoyl-9-deoxo-9a-aza-9a-homo-erythromycin A with carbobenzoxy chloride in the presence of a base in a reaction inert solvent at 0-50°C to form 2'-O-(C2-C3)alkanoyl-9-deoxo-9a-benzyloxycarbonyl-9a-aza-9a-homoerythromycin A;
(c) oxidizing said 2'-O-(C2-C3)alkanoyl-9-deoxo-9a-benzyloxycarbonyl-9a-aza-9a-homoerythromycin A with oxalyl chloride and dimethylsulfoxide at -40° to -80°C, followed by treatment with triethylamine, to form 2'-(C2-C3) alkanoyl-9a-benzyloxycarbonyl-9-deoxo-4"-deoxy-4"-oxo-9a-aza-9a-homoerythromy-cin A; and (d) solvolyzing said 2'-O-(C2-C3)alkanoyl -9-deoxo-9a-benzyloxy-carbonyl-4"-deoxy-4"-oxo-9a-aza-9a-homoerythromycin in methanol at 0-100°C.

10. A pharmaceutical composition comprising an antibiotic effective amount of 4"-epi-9-deoxo-9a-methyl-9a-aza-9a-homoerythromycin A or a pharmaceutically acceptable mono-or di-acid addition salt thereof in admixture with a pharmaceutically acceptable carrier.

11. A composition according to claim 10, which is in a dosage unit form.

12. A composition according to claim 11, which contains 5 to 50 mg/kg/day of the said compound.

13. The compound according to claim 1, which is in the free amine form.