CA1213882A - Cephalosporins - Google Patents

Abstract

Abstract of the Disclosure Disclosed are novel cephalosporin derivatives of the formula I

wherein R1 is hydrogen or a conventional amino-protecting group, and R2 is a straight or branched alkyl group containing from 1 to 4 carbon atoms, allyl, 2-butenyl or 3-butenyl, or is a group

Description

~Z~3~38%
~ j J ~%
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C~EMLCAL C~?~P~U~S

~ummary of the Invention This inventioll relates to novel cepnalosporin derivatives of tne formula N C - CR - N

wherein Kl is hydrogen or a conventional amino-protecting group, a~
K2 is a straight or branched alkyl group containing from l to 4 carbon atoms, allyl, 2-butenyl or 3-butenyl, or is a group COO~

wherein K3 and K4 each are independently hydrogen, rnethyl or ethyl, or K3 and K4, taken together with the carbon atom to which they are attached, may be a cycloalkylidene ring containing from ~ to 5 carbon atoms, and nontoxic pharmaceutically acceptable salts, physiologically hydrolyzable esters and solvates thereof. Processes fo~ their preparation are also described.

;

~escription of the Prior Art U.K. Patent Specification No. 1,399,086 contains a gene,ic disclosure encompassing a vast number of cephalosporins of the formu~

R-C-CO-NH

OR COO13 "

wherein K is nydrogen or an organic group, Ka is an etherifying monovalent organic group linked to the oxygen through a carbon atom, is ~ S or S~0, and P is an organic group. However, the

2-aminothiazol-4-yl group is not identified as an R substituent and there is no suggestion that P may be N-methylpyrrolidiniummethyl ~or any other fully saturated nitrogen-containing ring whicll is attached to the 3-methyl moiety via its nitrogen atom and which contains an additional substituent ~n its nitrogen atom). U.S. Patent 3,971,778 and its divisionals ~os. 4,024,133, 4,024,137, 4,064,346 4,033,9~0, 4,079,178, 4,091,209, 4,092,477 and 4,093,803 have similar disclosures.

U.~. 4,278,793 contains a generic disclosure encompassing a vast number of cephalosporin derivatives of the f,ormula NI~ X ~

~; \OR2 N ~' ~3~8Z

in which the variables Kl, R27 R3, K4, X and h incliJd.e generic de~initions of the corresponding substituents of th~ COI~;PrJUndS OL
Formula I claimed herein. ~owever, in the 2~ columns of dofini~ is of the various substituent groups, the 7~ page lsng table of structural formulae and the 225 examples, there is no disclosure tna A may be N-methylpyrrolidiniummethyl (or any other fully saturated nitrogen-containing heterocyclic ring) which is attached to ~he

3-methyl moiety via its nitrogen atom and which contains an additional substituent on its nitrogen atom. United Kingdom Patent ~pecification No. 1,604,971 is concordant thereto and has a substantially identical disclosure. Published United Kingdom Patent Application No. 2,023,3n, A, although apparently not formally related, contains the same broad generic disclosure but exemplifies A only as hydrogen.

West German UL~ 2,805,655 discloses 7-[2-~2-aminothiazol-~-yl) -2-(syn~methoxyiminoacetamidoJcephalosporin acid derivatives of the formula ~1N ~ S

--CONH ~

3 ~ ~ R2 COOR

in which RlNH is an optionally protected amino group, R2 is halogen or an optionally substituted hydroxyl, thiol or amino group, and CUOR is an optionally esterified carboxyl group. It is also disclosed that, when ~2 is an amino group, it may be disubstituted and the substituents, taken together with the N atom~ may form inter alia a pyrrolidino group. However, there is no disclosure of an N-methyl-pyrrolidiniummethyl group (or of any other ~uate-fnar~
ammonium group) and substituent ~2 cannot be connected to tne 3-position via a methylene group.

U.S. Patent No. 4,278,671 discloses 7-[2-(2-aminothiazol-1-'-yl, -2-(syn)-methoxyiminoacetamido]cephalosporin derivatives of the rO~

R2NH ~ , S
ICl - CONH ~

,~

in which K2NH is an optionally protected amino group and R3 is hydrogen or "the residue of a nucleophilic compound". The term "the residue of a nucleophilic compound" is broadly defined and it is then stated that K3 "may alternatively be a quaternary ammonium group".
Pyridinium, variously substituted pyridinium, quinolinium~ picolinium and lutidinium are disclosed as quaternary ammonium groups. There is no suggestion that the quaternary ammonium group may consist of a fully saturated nitrogen-containing heterocyclic ring system which is bound via its nitrogen atom and which contains an additional substituent on its nitrogen atom. United ~ingdom Patent Specification No. 1,581,854 is concordant thereto and has a substantially identical disclosure. ~ther patents to the same patentee9 which are not formally related but which have similar disclosures, include U.S.
Patent 4,098,888 and its divisionals U.S. Patents 4,203,899, 4,205,180 and 4,298,606, and United Kingdom Patent Specification No. 1,535,281.

- 4 U.S. Patent No. 4,168,309 discloses cephalosporin deriJati~J-s ~I
he formula R-C- -NH~

C H

O (CH2)m-~- (cH2~ncooH
Rb wherein R is phenyl, thienyl or f~ryl; R and ~b are independently hydrogen, alkyl, cycloalkyl, phenyl, naphthyl, thienyl, furyl, carboxy, alkoxycarbonyl or cyano, or Ra and ~b, taken together with the carbon atom to which they are attached, form a cycloalkylidene or cycloalkenylidene ring; m and n are each O or 1 such that the sum of m and n is O or l; and ~1, together with the nitrogen atom to which it is attached, is broadly defined but may not inter alia be a saturated 5-membered ring. The co]npound having the .
formula 1~ ~ CP3Coo~3 \ IH3 OOH /
O-C-COO~ c~3 1~3 is exemplified in ~xample 5 thereof. United Kingdom Patent - Specification No. 1,591,439 is concordant thereto and has a substantially identical disclosure. There is no suggestion in this patent that the ~ substituent may be the 2-aminothiazol-4-yl moiety ur that the imino substituent not contain a carboxyl group.

~3~
Cornplete Disclos~re This invention relates to cephalosporin derivatives of ho .or"~ La ~ S
~ fi _ NH ~

S oR2 ~ H ~HN3 ~ I

wherein ~1 is hydrogen or a conventional amino-protecting group, ana is a straight or branched chain alkyl group containing from 1 to 4 carbon atoms, allyl, 2-butenyl or 3-butenyl, or is a group COOH
wherein K3 and K4 each are independently hydrogen, methyl or ethyl, or K and ~ , taken together with the carbon atom to which they are attached7 may be a cycloalkylidene ring containing from 3 tG

5 carbon atoms, and nontoxic pharmaceutically acceptable salts and physiologically hydrolyzable esters thereof. Also included within tn-scope of this invention are the solvates (including hydrates) of the compounds of Formula I, as ~ell as the tautomeric forms of the compounds of Formula I, e.g. the 2-iminothiazolin-4-yl form of the 2-aminothiazol-4-yl moiety.

As shown in the structural formula, the compounds of Formula 1 have the "syn" or "Z" configuration with respect to the alkoxyimino (or alkenyloxyimino) group or the carboxy-substituted alkoxyimino gr~up. ~ecause the compounds are geometric isomers, some of the "anti" isomer may also be present. This invention comprises compoun~ls of Formula I containing at least 9~ of the "syn" isomer. PreferaL,ly the compounds of Formula I are "syn" isomers which are essentially free of the corresponding "anti" isomers.

~ g~ q~

The pharmaceutically acceptable salts of the c~jm~ounds ~if r~ .qu I include the inorganic base salts such as the al.~ali metal ^al~s ~e.g. the sodium and potassium salts3 and the all~aline ealth m ta~
salts (e.g. the calcium salts), ammonium salts, organic 3ase salts (e.g. with triethylamine, procaine, phenethylbenzylamine, dibenzylethylenediamine and other organic bases which have be n }se~
in the penicillin and cephalosporin art), and the acid addition sal s (e.g. the salts with hydrochloric, hydrobromic, formic, nitric, sulfuric, methanesulfonic, phosphoric, acetic or trifluoroacetic acid) and other acids which have been used in the penicillin and cephalo-sporin art. rhe physiologically hydrolyzable esters include the acyloxyalkyl esters, e.g. (lower)alkanoyl(lswer)alkyl esters such as acetoxymethyl, acetoxyethyl, pivaloyloxymethyl and the like. The h~s~
salts and the esters may be formed with either of the carboxyl group, of the compounds of Formula I.

The compounds of Formula I in which Rl is hydrogen exhibit hish antibacterial activity against various Gram positive and Gram negative bacteria, and are useful in the treatment of bacterial infections in animals, including man. The compounds of Formula I may be formulated for parenteral use in a conventional manner utilizing known pharmaceutical carriers and excipients, and may.be presented in unit dosage form or in multi-disage containers. The compositions may be in the form of solutions, suspensions or emulsions in oily or aqueous vehicles, and may contain conventional dispersing, suspending or stabilizing agents. The compositions Inay also be in the form of a dry powder for reconstitution before use~ e.g. with sterile, pyrogen-free water. The compounds of Formula I may also be formulated as suppositories utilizing conventional suppository bases such as cocoa butter or other glycerides. rhe compounds of this invention may, if desired, be administered in combination with other antibiotics such as penicillins or other cephalosporins.

~ hen provided in unit dosage forms the compositions will preferably contain from about 50 to about 1500 mg of the active ingredient of Formula I. The dosage for adult human treatment preferabl-y be in the range of from about 5(Jr~ to a-lout ~(J~ m ~er ~a), depending on the frequency and route of administration. /"Jen administered intramuscularly or intravenously to an a~ult hu.iar., a total dosage o~ from about 750 to about 3000 mg per day, in ~iiid_d doses, normally will be sufficient, although higher daily dos_, of some of the compounds may be desirable in the case of Pseudomonas infections.

The preferred compounds of Formula I are those in which ~1 is hydrogen and R2 is methyl or ethyl or R3 and X4 each are independently hydrogen or methyl. In the most preferred compounds, R2 is Inethyl or ~3 and ~4 each are methyl. In the primary evaluation of the compounds of this invention, the Minimum Inhibitory Concentrations (MIC'sJ of the compounds and two reference compounds (cefotaxime and ceftazidime) were determined by the two-fold serial agar dilution method in Mueller-Hinton agar against 32 strains of test organisms in six groups. The geometric means of the MIC's determinea in this test are shown in Tables 1 and 4.

3 ~ CH20eCII3 COOH
(Cefotaxime; Comparison Compound) N ~C - CONH ~ ~
3 ~ 3 H263N 3 COOH
(Ceftazidime; Comparison Compounds) 2 5 ~ R CH ~ N ~ I

(Test Compounds) ~%~

It may be seen that all of the test compounds were more acti-~JP ~haq, cefotaxime against the (G-)-II and (G-)-III groups of tes~ o~,an~s~
with the most preferred Compound Ia being markedly more active. .~11 of the test compounds were more active than ceftazidime agains~ ~he (G+)-Ia and lG~)-Ib groups of test organisms, with the most prefeired Compound Ia being markedly more active than ceftazidime against all groups of test organisms except (G-)-III, which has somewhat more susceptible to ceftazidime.

The absorption of the most preferred Compound Ia and of reference compounds (cefotaxime and ceftazidime) were determined in mice following a single intramuscular injection of the test compound (dissolved in p.lM phosphate buffer; pH 7) at a dosage of 20 mg/kg.
~lood samples were collected from ~he orbital sinuses into heparinized capillary tubes and assayed in Mueller-Hinton medium using Morganella Morganii A9695 as the test organism. The blood levels at various time intervals, the half-life Yalues (tl/2) and ~he areas under the curve (~UC) are shown in Table 2.

Tests to identify organisms resistant to the preferred compound o~ Formula Ia~ cefotaxime and ceftazidime were also conducted. The MIC's of these ~hree compounds against 240 strains of ~nterobacteriaceae were determined in Mueller-Hinton medium, and an MIC of equal to or greater than 8 for at least one of the test compounds was arbitrarily taken as indicating a resistant organism.
~f the 240 strains, Z7 were found to be resistant -to at least one of the test compounds. The results, showing 3 organisms resistant to Compound Ia, 15 organisms resistant to ceftazidime and 18 organisms resistant to cefotaxime, are given in Table 3.

3~

Table 1 _ ,~ . . .. __ H _ C~
. _- ~ L~
~ _ ~
~ _ H ~ O t~J 'r ~ ~D -r( ~ U
_ -- O ~ ~ ~
. t~ U~ `-- h . ~ Q~
_ Q~ ~rl h H _ r~ ~ . " 3 o ~
~ ~ o ~ ~ ~ o ~ o q, E ~ ~ ~ ~

H - ¦ ~ ¦ _ ~; .1~ S
O H In r` u~ o I _ ~ ~ 1~ 1`
_ ~n o o rl ~ o o u~
~ I _ . . ..... .. ~ m ~
a) ~ o c~ c~ o o o . . ~ ~ _ V ~ ~ h h 115 ~ _ - tn u~
~ :1 --- -- N '1 ~1 O I -- r~ D N 1~ U~
Q) ~ ~ . . . . ~ ~ ~ -~
C~ ~ r ) ~; ~ r~ N t`J 3 :~ V O fi _ ~ ~ ~ 3 ~ 5~
I~ W U~
.
H h N ~ ~ C~ O ~-1 ua I IJ ~ . - 1~ a _ u~ ~1 ~1 ~ ,~ n ~ ~J tll ~ h U~ E~
~ t~ C: '~ ~0 .~
_ ._ . ___ ~ rl .~J ~-- ~-1 a1 ~1 ~ ~ O h X
~1 V W E E~
R. _' ~ 3;
O ~ r' PJ P
.... " .. O
l~ o ~ U3'~ E A

E~ ~ 11 1I X ~ ~ H
O t~J N t~ H 1~( H H H H
t ~ ~ 15 ~ IILI + + I ~ I
_ ~ ~ V ~ V
_ ~ ~

~ --E

. ~V

~ o a~
~ ~ ~o~ ~
.V _ ~ O ,~D~
V ~ V _ ._ ~ ~ ~ ~ U~ D~
a~ u~ ~ u~ ~. .
A ~: E~ ~
E~ ~ l E~ _ ~- ~

_ ._ _ ~ S~V ~

V
: ~ o r~ _~ ~ In ,~ . _ ~ ~ ~. ~ ~
: ~ ~

O ~ ~. R -- O O
lS~ ::~ .~ -- . q) ~ J~ ~) o .,. g) ~
E~ E~ E ~ QJ
~ ~ ~ ~ r~
.~ ~ ~ ~
._ ~ ~ U ~ ~ O

~3~

Table 3 Resistance (MIC = >8 ~g/ml~ to One or More Test Cor,pouh~s ~..ong 240 S~rains of Enterobacteriaceae in ~ueller-~inton ~lediu~

¦ Geometric ~5ean ~SIC l~g7ml) OrganismNo. of ~ .
:Strains ¦ Ia Ceftazidi~e ¦ Cefo.ax~m~
Escherichia c~li 1 0.25 32 8 Escherichia coli 1 4 0.~ 8 Klebsiella pneumoniae 1 2 16 O.13 ~terobacter aerogenes 3 0.25 32 13 ~terobacker aerogenes 1 4 8 32 ~terobacter cloacae 1 0.13 4 ~terobacter cloacae 3 0.5 40 50 -nterobacter cloacae 3 1.6 >63 >63 ~terobacter cloacae 1 ~32 >63 >63 itrobacter freundii 2 0.35 45 32 itrobacter , species 1 0.03 ~63 32 roteus ~_ , vulgaris ! 1 O ~6 8 5Organella morganii 1 0.06 32 32 erratia marcescens I 1 1 1 16 Serratia . ..
r~arcescens ¦ 1 2 ............. 8 16 ~3~

Table 3 - cont.

_ Geometric ~lean ~-SIC (~g/ml) Organisml~o. of I __ Strains Ia Ceftazidime ~ Cefo'a~ime Serratia marcescens 2 2.8 2 11 Serratia marcescens 1 4 8 63 Serratia marcescens 1 8 16 8 Serra'cia marcescens 32 >63 >63 ~otal Number of Resistant Strains 27 15 18 38~

3 ~ 3 1 (Test Compound) Tabie 4 Geometric Mean of MIC (mcg/mL) Compound Test Compound Organisms Ie Cefotaxime(a) Ceftazidime~a) (G+)-Ia (5 strains) 14 1.0 5.1 (G+)-Ib (5) 33 2.2 12 (G-)-Ia (5) 0.066 0.015 0,070 (G-)-Ib (6) 0.79 0.35 1.7 (G-)-II (5) 1.2 4.1 2.6 (G-)-III (6) 4.0 22 1.8 ~G+)-Ia : Penicillin-sensitive S. aureus (5 strains) (G+)-Ib : Penicillin-resistant S. aureus (5 strains) (G-)-Ia : Cephalothin-sensitive E. coli (2 strains), ~I.
pneumoniae (1 strain) and Pr. mirabilis (2 strains) (G-)-Ib : Cephalothin-Iesistant E. coli (3 strains) and ~1.
pneumoniae (3 strains) (G-)-lI : Pr. ~ ani (1 strain)g Ent. cloacae (2 strains) and Ser. Marcescens (2 strains) (G-)-III : Ps. aeruginosa (6 strains) (a) Mean of five experiments ~3~

lt may be seen that compound Ie was more active tha~ refotaxime against the (G-)-II group of test organisms and mar~edl~J mor active than cefotaxime against the (~ I group of t~st orGanisms ~P~.
aeruginosa3. It was more active than ceftazidir~e against al~ 5rou~s of Gram-negative test organisms except (G-)-III (Ps. aerusino,a~, which was somewhat more susceptible to ceftazidime.

In another aspect, this invention relates to processes for the preparation of the compounds of Formula I. There are two basic procedures for converting a readily available starting cephalospori~
to another cephalosporin having di~ferent substituents on the 7- an~
3-positions. ~ne may first remove the 7-substituent and replace it with the desired 7-substituent, and then insert tlle desired 3-substituent. Alternatively, one may first insert the desired 3-substituent and subsequently exchange the 7-substituent. The compounds of Formula I may be prepared by either procedure and botn are included within the scope of this invention, but it is preferred to insert the desired 7-substituent first and then insert the desired 3-substituent. The pre~erred procedure is shown below in Reaction Scheme 1 while the alternative procedure is shown in Reaction Scheme 2. The abbreviation "Tr" represents the trityl (triphenylmethyl) group, which is a preferred amino-protecting group. The abbreviation "Ph" represents the phenyl group. Thus, the -CH(Ph)2 moiety is ~he benzhydryl group, which is a preferred carboxyl-protecting group.
Reaction Sçhemes 3 and 4 show the preparation of Compound (Ie) in which ~1 is hydrogen and R3 and R4 are each methyl.

~3~

Reaction Scheme 1 COOC2}15 II
TrHN 5 OH

¦ R2X

N ~ ~--C OOC H I I I

TrHN S R

¦ OH

N ~ Ç-COOH
IV
Trl~N ~ / ~oR2 F~ CH Cl CoocH (Ph~ 2 ~%~88~

TrHN 1~\OR2 ~ ~ Z VI
COOC1~ (Ph) 2 ¦NaI

~C~ CONH ~a~ VII

COOCH (Ph3 ;2 1. 1~3~ N

2 . d ebl ock Il N~ ~ ~ `

Reaction Scheme 2 Phcl~2coNH~ S ~ ~JIII

d~--CH20H

COOCH (Ph) 2 PCl~;
pyr idine Phcl~2coNHT~ ~ IX
~HzC
COO(::H (Ph) 2 NaI

PhCH2CONH~ S ~ X

COOCH (Ph)2 :.
..3C-N~

PhCH2CON;~ CH2 ~ X}
OocH(ph)2 deacylation H2~
2 ~ XII

OOC H ( Ph 3 2 3 V

CONH ~ 3 X I I I

TrH~ S R ~ 2 ~OOCH (Ph~

debl ocl;
~ ~' N~ CONH

2 S \oR2 ~D ~ CH2~

Reaction Scheme ~j~ C-rO~H H2 TrHN S \ O CH
COOC~Ph) H3C~CH3 2 cOOc(CH3)3 IIIa' V

\l) dicycloh~yl/ 1~ bis~trime~hyl-\ carbodiimide (DCC) / silyl)ace.amide BSA~
\2) V
\ / 2) IIIa + PC15 C C0~8 ~ ~ ~ 1 H3C CH3 COOCH(Ph)2 ~O~C(C~3)3 ¦ NaI

~38~

3 ~ 3 C~XH (~ 2 COOC (Cl~3) 3 N ~ C CONH ¦ ~ ~

Trli,~li S \l ~ 2 10 VIIa H3CCI CH3 COOCH ( Ph ) ;~
COOC ( CH3 ) 3 deb10ck ~ ~ S
N-- ~ C CONH--_~ ~

~2N~S~ ~0 ~ ] ~H -N~ Ie 3 ¢' 3 Coo~3 Reaction Sche~ne 4 PhC~l~CoNH~ VIII

--~CH2oH
COOCH (Ph)2 pyridine ,. ~ ~

388~
- PhC1~2CON~ S ~ IX

N~.~--CH2Cl COC~CH ( Ph ) 2 NaI

Phcll2coNH~--~ S ~ X

d~N~c~l2 I
COOCH ( Ph ) 2 H3c-N~

PhCH2CN~L_cl~_~? XI

OOCH (Ph) deaeylation 88~

j CH2--~1 XII

ooCH(Ph)2 lIla' DCC

TrBN~ CH2 N/~ VIIa H3C~CH3 OOCH ~ Ph ) 2~
looc (CH3) 3 CB3 deblock N~C--CONH 7~ Ie H3C CH 3 co~3 CoO~I C1~3 Although the above Keaction Schemes show prefer-red multi-~ _p procedures for the preparation of the compounds of Formula I, i~
be appreciated that other starting materials and procedures may bD
utilized to prepare the intermediates used in the key s~ep of eac.
Keaction Scheme. Thus, the key step in Keaction Scheme 1 is ~he reaction of Compound VII with N-methylpyrrolidine. Compound VII may itself be prepared by other procedures. Similarly, the key step in Keaction Scheme 2 is the acylation of Compound XII with Compound I~:.
Both compounds XII and IV may be prepared by other prosedures.

The key step in Reaction Scheme 3 is the reaction of Compound ~I
with N-methylpyrrolidine. Compound VIa may itself be prepared by other procedures Similarly, the key step in reaction Scheme 4 is the acylation of Compound XII with Compound IIIa. Both Compounds XII and IIIa'may be prepared by other procedures.

The present invention provides a process for the preparation of compounds of the formula N C - ~ - NH
2 ~ ~ o~2 ~ ~ H ~ ~ I

wherein K2 is a straight or branched chain alkyl group containing from 1 to 4 carbon atoms, allyl, 2-butenyl or 3-butenyl, or is a group COOH

3~

wherein ~ and K each are independently hydrogen, met~yl or etnyl, or R3 and K4, taken together with the carbon atom to "~JhiCh:
they are attached, may be a cycloalkylidene ring containing ,rom 3 o 5 carbon atoms, and nontoxic pharmaceutically acceptable salts, physiologically hydrolyzable esters and solvates theresf whirh proress comprises reacting a compound of the formula B2HN~
COOB
in which ~2 is as defined above, Bl is a conventional carboxyl-protecting group and B2 is a conventional amino-protecting group, with N-methylpyrrolidine to produce a compound of the formula o B2~
COOB

and subsequently removing all protecting groups by conventional means or which comprises reacting a compound of the formula B~IIN~\10 ~H I XIVa R3-~-R~ COOB
COOB

in which ~3 and ~4 are as defined above, ~1 and B3 are conventional carboxyl-protecting groups and ~2 is a con;/entiorlal amino-protecting group, with N-methylpyrrolidine to produce a comp~un~
of the formula N C--l~ NH~ ~ ~3 2 ~1~ N~ ~H -N~
R3-~ R4 CO~B ~3 ~OOB

and subsequently removing all protecting groups by conventional means The reaction is carried out in a non-aqueous organic solvent such a methylene chloride, chloroform, ethyl ether, hexane ethyl acetate, tetrahydro~uran, acetonitrile and the like, or mixtures of such solvents. The reaction is conveniently carried out at a temperature of from about -10C to about +50C; we normally prefer to conduct tne reaction at room temperature. At least one mole of N-methylpyrroli-dine should be used per mole of Compound XIV or XIVa; we normally prefer to utilize from about 50~ to 100~ excess of N-methylpyrrolidine.

Carboxyl-protecting groups suitable for use as Bl and B3 in the above reaction are well-known to those skilled in the art and include aralkyl groups such as benzyl, p-methoxybenzyl, p-nitrobenzyl and dipehnylmethyl (benezhydryl); alkyl groups such as t-butyl;
haloalXyl groups such as 2,2,2-trichloroethyl, and other carboxyl-protecting groups described in the literature, e.g. in U.K.
Patent 1,399,086. he pre~er to utilize carboxyl-protecting groups which are readily removed by treatment with acid. Particularly preferred carboxyl-protecting groups are the benzhydryl and t-butyl moities.

Amino-protecting groups suitable for use a5 ~ ~re alio well-known in the art, and include the trityl grotJp an~l acJl groups such as chloroacetyl. Amino-protecting groups whicn a-re re~dill removed by treatment with acid, e.g. the trityl group, are pref-rre The present invention also provides a process for .he prepara~ion of compounds of the formula 2 5 \oR2 F~ N~ I

wherein K2 is a s~raight or branched chain alkyl group containing from 1 to 4 carbon atoms, allyl, 2-butenyl or 3-butenyl, or is a group R3 C~-R4 COOH

wherein R3 and R4 each are independently hydrogen, methyl or ethyl, or ~3 and K4, taken together with the carbon atom to which they are attached, may be a cycloalkylidene ring containing from 3 to 5 carbon atoms, and nontoxic pharmaceutically acceptable salts, physiologically hydroly~able esters and solvates thereof, which process comprises acylating a compound of the formula 2N~ ~ ~3 C~3 il388%

or an N-silyl derivative thereof, in l-lhich ~ is i~ydrogen or a conv~ntional carboxyl-protec~ing group, with an acylating deri~atiie of ~1 acid of the forlnl)la N C-COOH
JI~

B2HN S bR

wherein ~2 is a conventional amino-protecting group and R2 is as defined above, to produce a compound of the form~la o~2 ~. ~7~ ~
COOB

and subsequently removing all protecting groups or acylating compound XVI or an N-Silyl derivative thereof with an acylating derivative of an acid of the forrnula N ~ CU-COOH

R3-C-R4 XVIIa ~herein ~2 is a conventional amino-protecting group, B3 is a conventional carboxyl-protecting group and R3 and R4 each are independently hydrogen, methyl or ethyl, or R3 and R4, ta~en together with the carbon atom to which they are attached, may be a cycloalkenylidene ring containing from 3 to 5 carbon atoms, to produce a compound of the formula O S
C~ J----Nlir~

B H S \O o~ \~H -N~ XV~
R3-C-P~'l COOBl (~H/
COQB

~3~8~

and subsequently removing all protecting ~roups.

The acylating derivatives of ~he acid of FGr,nula X~II or X~1IIa include the acid halides (and particularly the acid chlorids), m~ed acid anhydrides (such as the acid anhydrides formed with piv~l$c aci~
or a haloformate such as ethyl chloroformate), and actiYated e~ er~
(such as may be formed with ~-hydroxybenztriazole in the presence of a condensing agent such as dicyclohexylcarbodiimide). The acylation ma~
also be effected by use of the free acid of Formula XVII or ~VIIa in the presence of a condensing agent such as dicyclohexylcarbodiimide, carbonyldiimidazole or an isoxazolium salt. As used herein, the term "acylating derivative" of the acid of Formula XVlI or XVIIa includes Ihe free acid itself in the presence of a condensing agent sucn as described above. The preferred acylating derivative of the acid of Formula XVlI or XVIIa is the acid chloride, preferably used in the presence of an acid Dinding agent (and particularly a tertiary amine acid binding agent such as triethylamine, dimethylaniline or pyridine).

When the acylation is conducted with an acid halide it is possible to utilize an aqueous reaction medium, but a non-aqueous medium is preferred. When acid anhydrides, activated esters, or the free acid in the presence of a condensing agent, are used for the acylation, the reaction medium should be non-aqueous. Particularly preferred solvents for the acylation reaction are halogenated hydrocarbons such as methylene chloride and chloroform, but tertiary amides such as dimethylacetamide or dimethylformamide may be utilized, as well as other conventional solvents such as tetrahydrofuran, acetonitrile and the like.

The acylation reaction may be conducted at a temperature of from about -50C to about ~50C. However, it is preferably conducted at or below room temperature and most preferably from about -30C to about 0C. It is usually preferred to acylate the compound of Formula X~I

with about a stoichiometric amount of the acylating a~nt of F~jr~J~l~
XVII or XVIIa, although a srnall excess (e.g. 5-25~J of the acylatin, agent may be utilized.

It is preferable that the compound of Formula XVI by zcylaied ~, the form of its N-silyl derivative (when utilizing a non-aqueolis reaction medium). This is conveniently done in situ by simply a~dirg a suitable silylating agent (e.g.N,O-bistrimethylsilylaceta~ide~ to the solution of compound XVI prior to the addition of the acylatins agent of Formula XVII or XVIIa. We prefer to utilize about 3 moles o' silylating agent per mole of Compound XVI although this is not critical. The silyl compound is readily removed after acylation by the addition of water.

The acylating acids of Formula XVII or XVIIa including carboxy'-and amino protected derivatives thereof, are known in the art or may be prepared by known procedures. This, (Z)-2-(2-t-butoxycarbonylprop-2 -oxyimino)-2-(2-tritylamino-thiazol-4-yl)acetic acid (IIIa) was prepared by the general procedure described in U.S. Patent 4,258,041 and United Kingdom Patent Application No. 2,025,398. The melting point reported therein was 152-156C (decomp.) but, in our hands this compound melted at 174-175C decomp.) Preparation No. 1 N ~ CO~C2H5 III
TrHN S OR

~thY~ 2-Methoxyimino-2-(2-tritylaminothiazol-4-yl)acetate (IIIa) A mixture of ethyl (Z)-2-hydroxyimino-2-(2-tritylamino-thia701-4-yl) acetate (II) (5.00 g, 10.9 mmoles), CH3I (2.04 mL, 32.8 mmoles) and K2CU3 (4.54 g, 32.8 mmoles) in dry dimethyl-sulfoxide ~13~Z

(D~S~) (100 mL) was stirred at room temperature orernigh, an~ ~he poured into water (250 mL). The precipitate whizh formed "ai collected by filtration, washed with water and dried to gi~e h.e compound (5.15 g, quantitative yield). Mp. 115~C ~dec.) NMR : ~CDCl3 ppm 1.32 (3H, t), 3.98 (3H, s), 4.30 ~2H, ~),

6.42 ~lH, s), 7.2 (lH, m), 7.25 (15H, s'.

Compounds IIIb, IIIc and IIId were prepared by the general procedure set forth above, but replacing the methyl iodide with the appropriate iodide.

Literature (1) Compound ~ Yield (~) Mp ~C) Mp (C) IIIa methyl 100 115 (dec.)ca. 120 (dec.) IIIb ethyl 67 97-98 *
IIIc isopropyl 26 51-55~ *
IIId allyl * * *

* The ester was hydrolyzed without isolation (l)Tetrahedrom, 34, 2233 (1978) Preparation No. 2 N ~ ~ COO~I IV
TrHN S OP~

(Z)-2-Methoxyimino-2-(2-trity1aminothiazol-4-yl)ace~ic acid (I~!a) The ethyl ester lIIa prepared in Preparation o. 1 ~'~,00 g, 12.7 mmoles) in ethanol ( 120 mL) was treated with 2,!; ~al~rl ~12,7 m~j a~ r50-temperature overnight. The reaction mixture was adjusted to p~ 8 ~y the addition of powdered dry ice and the solvent was ev~porat_d un~er reduced pressure. The residue was dissolved in water (100 mLJ anA tl,_ solution was acidified with lN ~Cl to pH 2 and then extracted ~,;i n ethyl acetate (3 x 50 mL). The combined extracts were washed with a saturated aqueous NaCl solution, dried and evaporated. The residue was crystallized from ethyl acetate-hexane to afford 5.56 g (yield 98~) of the title product. Mp. 13B-143C (dec.).

C~C13 ppm 3.89 (311, s), 6.52 (1~, s), 7.2 (15H, s).

Compounds IVb, IVc and IVd were prepared by the general procedure set forth above.

Literature (1) Compound ~2 Yield (~)Mp (C,dec.) Mp (C dec.) IVa methyl 98138-143 ca. 140 IVb ethyl 85140-145 not reported IVc isopropyl 85166-169 ca. 170 IIId allyl 66170-178 ca. 170 ~1) retrahedrom, 34, 2233 (1978) Preparation No. 3 y_ryl 3-~ydroxymethyl-7-phenylacetamido-3-cephem-4-carbox-late (VIII) 38~

To a stirred suspension of phosphate buffer ~p~ 7, 162~ ~D~j and wheat bran (20 g, dry) at room temperature was added

7-phenylacetamidocephalosporanic acid sodium 5alt ~5 ~m, 12.1 .~olesi in one portion. The progress of the reaction was monitored ~y h~LC
until the hydrolysis was complete (5 hours~. The suspension "as filtered to remove the wheat bran and the filtrate was cooled to 5-10C for extractive esterification. To the cooled solution was added methylene chloride (32 mL) followed by a 0.5J~ solution of diphenyldiazomethane in methylene chloride (2~ mL). The p.~ ,;as th~n adjusted to 3.0 with 28~ phosphoric acid. After 1 hour the reaction mixture was allowed to rise to 20C. Heptane (56 mL) was slowly a~de~
and the resulting crystalline title product was recovered by filtration. Yield of the ~itle product was 3.0 gm ~50~).

Preparation No. 4 Benzhydryl 7-Amino-3-chloromethyl-3-cephem-4-carboxylate (V) To a slurry of PC15 (8.3 g, 40 mmoles) in CH2C12 (100 mL) was added pyridine (3.2 g, 40 mmoles) and the mixture was stirred for 20 minutes at 20C. To the mixture was added benzhydryl 3-hydroxymethyl-7-phenylacetamido-3-cephem-4-carboxylate prepared in Preparation No. 3 (5.1 g, 10 mmoles) with stirring at -40C, in one portion. The mixture was stirred at -10C for 15 minutes and allowed to stand at -10C to -15C for 7 hours. To the cooled solution (-20C) was added propane-1,3-diol ~10 mL) and the mixture was allowed to stand at 20C for 16 hours and then at room temperature for 20 minutes with stirring. The resulting solution was washed with ice-water (2 x 20 mL) and saturated aqueous NaCl (10 mL), dried ov~r MgS~4 and concentrated in vacuo. The gummy residue (12 g) was dissolved in a mixture of C~C13 and n-hexane (2:1), and subjected to chromatography using a silica gel column (200 g) and the same solvent as eluant. Fractions containing the title compound were evaporated in vacuo and the residue triturated with n-hexane to give the title product (2.1 g, 51~), melting at ~110C (dec.).

~31 3i~8~

IK : vK~r 3~00, 2800, 178~, 1725 cm UV ~tUH 265 nm (El' 160).
max lcm NMK DMso-d6 + C~C13 3.69 (2H, s), ~-43 (2H~ s), 5.0g ( PP J = 4.5Hz), 5.24 (lH, d, J = 4.5Hz), 6.87 (1~, s), 7.3 (10, m).

~xample 1 7-[(Z)-2-Methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-~(1-meth~l-1-pyrrolidinium)methyl]-3-cephem-4-carboxylate (Ia) A. Benzhydryl 3-Chloromethyl-7-[(Z)-2-methoxyimino-2-(2-tritYlamin thia~ol-4-Yl~acetamido]-3-cephem-4-carboxylate (VIa') Benzhydryl 7-amino-3-chloromethyl-3-cephem-4-carboxylate prepared in Preparation No. ~ (2.29 g, 5.52 mmoles) in CH3CN (57 mL) was treated with bis(trimethylsilyl)acetamide (~SA, 4.09 mL, 16.6 mmoles) at room temperature for 50 minutes to give a clear solution.
To the solution was added an acid chloride solution, which was prepared from (Z)-2-methoxyimino-2-(2-tritylaminothiazol-4-yl)acetic acid (IVa) (2.04 g, 4.60 mmoles) and PC15 (1.15 g, 5.52 mmoles) in methylene chloride (20 mL). The mixture was stirred at room temperature for 30 minutes, poured into çold water (200 mL) and extracted with ethyl acetate (3 x 100 mL). The combined extracts here washed with aqueous NaCl, dried and evaporated. The residual syrup (~
g) was chromatographed on a silica gel (150 g) column by eluting with 10:1 and 3:1 mixtures of toluene and ethyl acetate successively. The fractions containing the desired compound were combined and evaporated to afford 2.61 g (68~) of VIa' as an amorphous powder.

%

NMK : ~ 3 3.50 (2H, s), 4.02 (3~, s), 4.33 ~2~1, -,), 4.g8 (1~, d), 5.~7 (lH, q), 6.65 ~ sj, 6.90 (1~; s), 7.3 (25H, m).

~ enzhydryl 3-Iodomethyl-7-~(Z)-2-methoxyimino-2-(2-trit-jiamino-thiazol-4-yl)acetamido]-3-cephem-4-carboxylate (VIla') A mixture of the 3-chloromethyl derivative (VIa') (1.50 g, 1.7 mmoles) and NaI (1.34 g, 8.93 mmoles) in methyl ethyl ketone (30 mL~
was stirred at room temperature for 1 hour. After evaporation of the solvent the residue was dissolved in ethyl acetate (100 mL) and wasned with water, aqueous Na2S2O3 and aqueous ~aCl9 dried and evaporated to give the title compound VIIa' (1.47 g, 8~) as an amorpnous powder.

Nl~lR ~ CDC13 ppm 3 55 (2H, A~q), 4.00 (3H, s), ~.25 (2H, s), 4.~7 (lH, d), 5.80 (lH, q), 6.65 (lH, s~, 6.90 (1~, s)~ 7.3 (25H, m).

C. 7-[(Z)-2-Methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-t(l-methYl-l-pyrrolidinium)methyl]-3-cephem-4-carboxylate (Ia) A mixture of VIIa' (4.5 g, 4.83 mmoles) and N-methylpyrrolidine (0.65 mL, 6.28 Inmoles) in C~2C12 (45 mL) was stirred at room temperature for 20 minutes. ~ther (300 mL) was added to the mixture to separate the quaternary salt of the blocked cephalosporin, which was collected by filtration and treated with 90~ trifluoroacetic acid (TFA) (40 mL) at room temperature for 1 hour. The mixture was then evaporated under reduced pressure below 20C. The residue was triturated with ether to give the TFA salt of Ia (2.40 g), which was dissolved in methanol (5 mL) and treated with 1~ solution of sodium-2-e~hylhexoate (S~H) in ethyl acetate (8 mL) at room temperature for 30 minutes. After the addition of ethyl acetate (100 mL), the precipitate (1.94 g) formed was collected by filtration. HPLC

~3~

analysis showed that the crude product was 7~ pure witn a 1:~ r~
~he ~3 isomer to ~he ~2 isomer. Purification o tne prodsu_~ ~y ~PLC was repeated three times (Lichrosorb*R~-18, 8 x 30~mm, elu,e~
with S~ aqueous CH3~H or O.OlM ammonium phosphate buffer (pH 7.2~
containing 5~ C~3~H to give 35 mg ~1.5~) of the title product as a colorless powder. Estimated purity (by HPLC) 90%. Mp. 150~C (dec.~.

IR : v r cm 1 1770, 1660, 1620.
max UV phosphate buffer, pH 7 nm(~) 235 (16200), 258 ~15400)-max N~R :~2 ppm 2.31 (4H, m), 3.08 (3H, s), 3.53 (4H, m~,-4.09 (3H, s), 5~43 (lH, d, J = 4.8 Hz), 5.93 (lH, d), 7.08 (lH, s).

Example 2 7-[(~)-2-MethoxYimino-2-(2-amino~hiazol-4-yl)acetamido]-3-[(1-methyl--PyrrolidiniuTn)methyl]-3-cephem-4-carboxylate (Ia) To a stirred solution of 20.4 g ~21.9 mmoles) of VIIa' in 150 ~L
of dry methylene chloride was added 2.42 g (28.5 mmoles) of l-methylpyrrolidine in one portion at room temperature. The mixture ~as stirred for 5 minutes and poured into 1000 mL of ether with vigorous stirring to fsrm a precipitate, which was filtered, washed with ether (5 x 30 mL) and dried in vacuo to give 19~3 g of tlle blocked product as a pale yellow powder.
K : vKBr cm 1 3400, 1780 (s), 1740, 1675, 1530.
max LC : solvent ethanol-CHC13 (1:3), Kf=0.30 ~Rf=0.95 for VlIa').

Trade Mark ~3~

The solid was dissolved in 185 mL of triflur(J~cetic arid--,iater (99:1), stirred for 1 hour at room temperature and concentra,ed So 30 mL below lU~. The concentrate was poured into 1000 mL of et,-.er with vigorous stirring to form a precipitate, which was filtered, washed with ether (5 x 40 mL) and dried under vacuum to yield l(j.~ O
of pale yellow powder. The powder was dissolved in 20 mL of mstna,o and the solution was filtered. To the filtrate was added 4~ mL of 0.8M SE~I in ethyl acetate. The resultant suspension was poured to 4l-Jrj mL of ethyl acetate and filtered to give 8.08 g of a solid which was a mixture of the title compound and the corresponding ~ iso"mer (~3/a2 = 1:8) as shown by ~PLC analysis (Lichrosorb ~P-18, 10-1 methanol in O.OlM phosphate ouffer, pH 7). A second run fro~ 28.9 (31.0 mmoles) of VIIa' gave 16.0 ~ of the crude product (~3/~2 =
1:8). lsolation of the ~esired ~3 isomer from the combined crude product (2~.08 ~) by usin~ preparative HPLC (System 500, waters ~ssociates, PrepPA~ 50~/C18, 5-10~ CH3~l) afforded 769 mg of ~ompound Ia.

Example 3 7-[(~)-2-Methoxyimino-2-(2-(2-aminothiazol-4-yl)acetamido]-3-~(1-methyl-l-pyrrolidinium)methyl]-3-cephem-4-carboxylate (Ia) A series of experiments were conducted to determine the effect or solvent, amount of solvent and reaction time on the yield of Compour.C
Ia and the ~3/~2 ratio in the reaction product. The general procedure was as ~`ollows:

To a suspension of the 3-iodomethyl derivative VIIa' (~ mg, 0.048 mmole) in the indicated amount of the indicated solvent was added a solution of ~-methylpyrrolidine (0.01 mL, 0.097 mmole) in ether (0.1 mL) and the mixture was stirred at room temperature for the indirated period. The reaction mixture was diluted with ether (~ mL) and the resulting precipitate was collec~ed by filtration and mixe~

~L3~

with 90~ TFA. The mixture was stirred for one nour and e~ap,ra, ~ ~o dryness under reduced pressure below 20C to give the product Tne ratio of ~ /Q2 in the product was determined by ~PLC ~Lichrssor~
RP-18; mobile phase, 0.01 M ammonium phosphate buffer (pH 7.2) containing 15% CH3UH; retention time, ~ 3 6.60 minutes, 2 5.56 minutes). Yield of the product and the ratio of ~3/~2 isomers for each experiment are given below.

Ratio of VIIa' (in gms.) to Reaction Experi- Solvent Time Yield ~atio ment No. ~olvent (in mE) (l~in.) ~ 3/A Z

1 G~2C12 1:20 15 73 1/~
2 CH2C12-~ther (1/10) 1:100 15 25 4jl 3 Ethyl acetate Ether (1/10) 1:100 15 27 ~/1 4 Ethyl acetate-Ether (1/10) 1:100 60 64 2/1 Ether 1:100 15 31 6/1 6 Ether 1:100 60 62 3/1 7 Ether 1:60 15 55 3.5/1

8 Ether 1:60 60 82 1/l Example 4 7-[(Z)-2-Ethoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-[(1-methyl-'-pyrrolidinium)methyl]-3-cephem-4-carboxylate (Ib) A. ~enzhydrYl 3-Chloromethyl-7-[(Z)-2-ethoxyimino-2-(2-tritylamino-thiazol-4-Yl)acetamido]-3-cephem-4-carboxylate (VIbJ

121~3B8Z

To a solution of (Z)-2-ethoxyimino-2-~2-trit~la~inot'rliazo~
acetic acid (lVb) (1.095 g, 2.4 mmoles) in dichloro~ethane .2fj ,~L~ was added phosphorus pentachloride r500 mg). hfter stirring for 1 Jlou-r ~t room temperature, the mixture was added in one portion to an ice-cooled sol~tion of Compound V (1.083 g, 2.4 mmoles) and ~ J~.
in dichloromethane (20 mL). After stirring for ~.5 hour tne reaction mixture was poured into 10~ aqueous NaHC~3 (200 mL) and extracted with CHC13 (100 mL). The extract was washed with water, dried o~;er MgSO4, and evaporated under reduced pressure.

The residue was chromatographed on a silica gel column. Elution with CHC13 gave VIb as an amorphous powder, 1.76 g (86~).

NMR ~C~C13 ppm 1.40 (3H, t, CH2CH3~, 3.53 (2H, ABq, 2-CH2~, 4.37 (2H, s, -CH2Cl), 4.60 (2H, q, -CH2CH3), 4.90 (lH, d, 6-H), 5.89 (lH, d, 7-H), 6.88 (lH, s), thiazole-H), 6.91 (lH, s, benzhydryl-CH.) . Diphenylmethyl 7-[(Z)-2-Ethoxyimino-2-(2-tritylaminothiazol-1-yl) acetamido]-3-iodomethyl-3-cephem-4-carboxylate (VIIb) A mixture of VIb (1.07 g, 1.25 mmoles) and NaI (562 mg, 2.75 mmoles) in acetone (20 mL) was stirred for 1 hour. The mixture was filtered and the filtrate was poured into water and extracted with ethyl acetate. The organic layer was washed successively with 5 aqueous Na2S2~3, water and saturated aqueous NaCl, dried over MgSU4 and evaporated to give 1.04 g (89~) of Compound VIIb.

NM~ ~ CUC13 ppm 3.55 (2H, q, 2-CH2), 4.27 (2H, s, CH2-I), 5.02 (lH, d, 6-H), 5.87 (lH, d3 7-H), 6.68 (lH, s, thiazole ring H), 6.93 (lH, s, benzhydryl-CH).

- 3.

C. 7-[(Z)-2-Ethoxyimino-2-~2-aminothiazol-4-yl)acetamido]-3-~methyl-l-pyrrolidinium)methyl]-3-cephem-4-carboxylate ~Ib) A mixture VIIb (333 mg, 0.35 mmole) and N-methylpyrrolidine ~'0 mg, 0.7 mmole in CH2C12 (5 mL) was stirred for 0.5 nour at room temperature and then evaporated in vacuo. ~he residue was ~;ashed '~Ji, n ether and dissolved in 90~ aqueous TFA. After standing for 0.5 ho-~r at room temperature the mixture was concentrated under reduced pressure. Ether was added to the concentrate to separate the quaternized product, which was collected by filtration and dissolved in a small a;nount of methanol. The solution was chromatographed Oil an HP-2- column (40 mL). Elution with 30~ aqueous CH30H followed by lyophilization afforded 0.062 g of a mixture of thea 2 and~ 3 isomer (~2 ~3 = 5:l). The mixture was purified by HPLC
(Lichrosorb ~P-18, 8 x 300 mml 15% methanol) and the desired ~3 isomer (Ib) was isolated as pale yellow powder, 4.9 mg (2.7~).

UV : phosphate buffer, Ph 7 nm(E) 235 (15000), 258 (14000) max NMK ~D2~ ppm 1.43 (3H, t), 2.33 (4H, m), 3010 (3H, s, 3.64 (4H, m), 4.36 (2H, q), 5.44 (lH, d), 5~95 (lH, d), 7.08 (lH, s).

Example 5 7-L(Z)-2-(2-Propoxyimino)-2-(2-aminothiazol-4-yl)acetamido]-3-[(l-methyl-l-pyrrolidinium)methyl]-3-cephem 4-carboxylate (Ic) A. ~iphenylmethyl 3-Chloromethyl-7-[(Z~-2-(2-propoxyimino)-2-(2-tritylaminothiazol-4-yl)acetamido]-3-cephem-4-carboxylate (VIc) ~388~
A mixture of (Z)-2-(2-propoxyiminoJ-2-(2-tritylamino-tf3iazol-~acetic acid (IVc) (707) mg, 1.5 mmoles) and phos~horus pentachlori~_ (344 mg, 1.65 mmoles) in dichloromethane (14 mL~ was stirre~ at roo,-m temperature for 1 hour and poured into a solution of Cormpound V ~677 mg, 1.5 mmoles) and ~A (1.1 mL, 4.5 mmoles) in dichlorometrl~ne ~15 mLJ. The reaction mixture was stirred at room temperature for 30 minutes, diluted with ethyl acetate (2~0 mL), and water (3 x lorJ mL), dried over sodium sulfate and evaporated to give 1.4 g (10~) of Compound VIc.

IK : K~rcm~l 3360~ 3020, 3060, 2960, 1785, 1725, 1680, 1~20, max 1500, 1450, 1375, 1300, 1250, 1160, 1090, 1~60, 1010, 990, 840, 740, 700.

UV : Et~Hnm() 240 (24600), 260 (2070 max NI~R : ~CDC13 ppm 1.35 (6H, d, J=6~z), 3.50 (2H, s), 4.35 2H, s), 4.58 (lH, m, J=6Hz), 5.00 (lH, d, J=4.5Hz)l S.91 (lH, d-d, J=4.5 ~ 9Hz;
d by D2O, J=4.5Hz), 6.68 (lH, s), 6.88 ~lH, s), 7.25 (25H, s).

. ~iphenylmethyl 3-Iodomethyl-7-[(2)-2-(2-propoxyimino)-2-(2-tritylaminothiazol-4-Ylacetamido]-3-cephem-4-carboxylate (VIIc) A mixture of Compound VIc (S00 mg, 0.55 mmole) and sodium iodide (248 mg, 1.66 mmoles) in acetone (10 mL) was stirred at room temperature for 50 minutes. After evaporation, the residue was dissolved in ethyl acetate (15 mL), washed successively with 10~
aqueous sodium thiosulfate (10 mL), water (10 mL) and aqueous ~aCl (10 mL), dried over sodium sulfate and evaporated to yield 494 mg (~0~) of the title compound (VIIc)o ~2~ 132 I~ : K~rcm~l 3360, 3040, 3020, 296~U, 17~5, 172~J, 16~
max 1600, 1520, 15~0, 1450, 1370, 13~)0, 123~, ~ , 1115, 1080, 990, 900, 8~, 7~rJ, 7 UV EtUH nm( E) 240 (24900), 260 (1940 max ~MR : ~C~C13 ppm 1.30 (6H, d, J=6HzJ9 3.37 ~ 3.70 (lH eac'n, d, J=16Hz), 4.22 (2H, s), 4.55 (lH, m, J=6Hz), 4.95 (lH, d, J=4.5Hz), 5.83 (lH, d-d, J=4.5 ~ 9Hz; d by ~2)' 6.66 (lH, s), 6.87 (lH, sJ, 7.25 (25H, s).

C 7-[(Z)-2-(2-Propoxyimino)-2-(2-aminothiazol-4-yl~acetAmido]-3-~(l-methyl-l-pyrrolidinium)methyl]-3-cephem-4-carboxylate ~Ic) A mixture of the Compound VIIc (545 mg, 0.55 mmole) and l-methylpyrrolidine (70 mg, 0,82 mmole) in dichloromethane (10 mL) ~as stirred at room temperature for 30 minutes and diluted with ether (100 mL). The resulting precipitate was collected by filtration. A
solution of the precipitate in 90~ TFA (4.5 mL) was stirred at room temperature for 30 minutes and evaporated in vacuo. The residue was triturated with ether to give 317 mg of the crude product, which was chromatographed on an HP-20 column (50 mL), eluted with water (500 ~L) and 30~ CH3~H (500 mL). Ihe 30~ CH3~H eluate was concentrated and lyophilized to yield 109 mg of a mixture of the Q2 and Q3 isomers r,Q2/Q3 = 6/1), 100 mg of which was purified by HPLC (Lichrosorb RP-18, 15~ MeOH) to give 5 mg (3~) of the desired title Compound Ic.

UV ~pll 7 buffer nm( ) 236 (15100), 252 (14600)-max NMK : ~2~ppm 1.42 (6H, d, J=6Hz), 2.33 (4H, s), 3.1Q (3H, s), 3.65 (4H, s), 3.83 ~ 4.23 (lH each, d, J=17Hz), 5.45 (lH, d, J=4.5Hz), 5.95 (lH, d, J=4.5Hz)~ 7.05 (lH, s).

3~

Example 6 7-[(Z)-2-Allyloxyimino-2-(2-aminothiazol-4-yl)acetamido3-3- ! ~ et~J1 l_Pyrrolidinium)methyl]-3-cephem-4-carboxylate (Id~

A. Benzhydryl 7-[(Z)-2-Allyloxyimino-2-(2-tritylaminothiazol-4-yl) acetamido]-3-chloromethyl-3-cephem-4-carboxylate (VId) To a suspension of Compound V (1.35 g, 3 mmoles) in methylene chloride (20 mL) was added BSA (1.1 mL, 4.5 mmoles)7 and the mixture was stirred for 30 minutes at room temperature to become a clezr solution. A mixture of (Z)-2-allyloxyimino-2-(2-tritylaminothiazol-4-yl)acetic acid (IVd) (1.40 g, 3.0 mmoles) and phosphorus pentachloride (690 mg, 3.3 mmolesJ in methylene chloride (20 mL) was stirred for 15 minutes at room temperature and poured in one portion into the solution of the trimethylsilylated Compound V. The mixture was stirred for 2~ minutes at room temperature and diluted with ethyl acetate (200 mL), washed with aqueous sodium bicarbonate and water, dried and evaporated under reduced pressure. The oily residue was purified by silica gel column chromatography (Wako-gel, C-200, 30 g).
The column was eluted with chloroform and the fractions containing the desired product were combined. Evaporation under reduced pressure afforded the title compound (VId) as an amorphous powder, yield 2.32 g (89~). Mp. 100-115C (dec.).

IK KBrcm~l 3990, 1790, 1730, 1680, 1530, 1380, 1250, max 1160, 1020.

NMR : ~C~C13 ppm 3 50 (2H, 2-H), 4.32 (2H, s, 3-CH2), 4.6-6.1 (7H, m, CH2CH=CH2 and 6,7-H), 6.70 (lH, s, thiazole-H), 6.90 (lH, s, Ph2CH), 7.1-7.6 (30H, m, phenyl protons).

* trade mark.

, nal. Calc'd. for C48H40N505S2C1.1/3CH513: C, 64.05; H, ~.45;
N, 7.73; ~, 7-~Cl, 7~82.
Found: C, 64.13, 53.9~;
H, 4.61, 4.64;
N~ 7.50, 7.30;
S, 6.85, 6.85;
Cl, 7.55, 7.46.

~. Benzhydryl 7-[(~)-2-Allyloxyimino-2-(tritylaminothiazol)-4-yl) acetamido]-3-iodomethyl-3-cephem-4-carboxylate ~VIId) A mixture of Compound VId (2.30 g, 2.65 mmoles) and sodium iodide (2 g, 13.3 mmoles) in acetone (15 mL) was stirred for 1 hour at room temperature and then evaporated under reduced pressure. A solution Or the oily residue in ethyl acetate (200 mL) was washed with 10~ sodiu,.
thiosulfate and water, evaporated under reduced pressure to afford Compound VIId as an amorphous powder, which was used in the next Ste?
without further purification. Yield 2.52 g (99~).

C. 7-L(Z)-2-Allyloxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-~(1-methyl-l-pyrrolidinium)methyl]-3-cephem-4-carboxylate (Id) A mixture of Compound VIId (478 mg, 0.5 mmole) and N-methyl-pyrrolidine (0.05 mL~ O.S mmole) in methylene chloride (5 mL) was stirred for 20 minutes at room temperature and diluted with ether (50 mL) to precipitate the quaternized product (yield 500 mg). A mixtur_ of the quaternized product and TFA (2 mL) was allowed to stand at room temperature ~or 1.5 hours and diluted with ether to precipitate the crude TFA salt of the product (yield 265 mg), which was chromatographed on a column o~ ~P-20 (1.8 x 18 cm). The colulnn was eluted with water and 30~ aqueous methanol. The methanolic eluate was evaporated under reduced pressure and the residue was freeze-dried to give an amorphous powder (yield 124 mg), which contained the desired ~%~3~

product (17~) and the cor-resporldin~ 2 isomer (~3~). Ine mixf~
was purified by HPLC (Lichrosorb ~P-18; 0.~ H4H2P~ ~p,-3 7):CH30H=85:15). The eluate was acidified to pH 3 trith dilufe HdC~
and chromatographed on a column of HP-20 (1.8 x 1~ cm). TJhG CO1Um?~
was eluted with water and then with 30~ aqueous methanol. Tne methanolic eluate was evaporated under reduced pressure and the residue was freeze-dried to afford the title compound (Id) as an amorphous powder (yield 13 mg, 5.1~). Mp. 155C (dec).

IK : V K~r cln 1 3600-2800, 1770, 1670, 1610, 1530, 1200.
max UV : ~pH 7 buffer nm(~) 235 (16600), 253 (15600).
max NM~ ~D2U ppm 2.1-2.5 (4H, m, pyrrolidine-H), 3.10 ~3H, s, +

NCH3), 3.4-3.8 (4H, m, pyrrolidine-H), 5.95 (lH, d, 4Hz, -H), 7.10 (lH, s, thiazole-H).

Example 7 7-[2-(2-Aminothiazol-4-yl)-(~-2-(2-carboxyProp-2-oxyimino)-acetamid -3-[(1-methyl-1-pyrrolidinium)methyl]-3-cephem-4-carboxylate (Ie) A. ~enzhydryl 3-Chloromethyl-7-[(Z)-2-(2-t-butoxycarbonylprop-2-oxyimino-2-(2-tritylaminotlliazol-4-yl)acetamido]-3-cephem-4-carboxylate (Va!

~z~
Procedure 1 A mixture of (Z)-2-(2-t-butoxycarbonylprop-2-oxyiinino)-2-~2-tritylaminothiazol-4-yl)acetic acid (IIIa') (1.94 g, 3.6 mmoles~ D~;
(742 mg, 3.6 mmoles) and N-hydroxybenztriazole (486 mg, 3.6 r.~moles) in tetrahydrofuran (THF) (45 mL) was stirred at room temperature for 4 minutes, during which dicyclohexylurea separated. The dicyclohexylurea was removed by filtration and the filtrate ,was mixe~
with V (1.5 g, 3.6 mmoles). The mixture was stirred overnight at roo.
temperature and then evaporated in vacuo. The residual oil was dissolved in CHC13 (20 mL), washed with saturated aqueous NaHCO3 and saturated aqueous NaCl, dried over MgSO4 and evaporated to dryness. The residue (3.9 g) was dissolved in n-hexane:CHC13 (1:2) and passed through a silica gel column (40 g) using the same solvent system. Fractions containing the title compound were evaporated in vacuo to give 1.3 g ~39~) of Va melting at >100C (dec.).

I~ : vKBr cm 1 3990, 1790, 1715, 1690.
max UV : ~tOH nm 240 (El~ 280), 265 (EI~ 190).
max 1 cm 1 cm NM~ :~CDC13 ppm 1.45 (9H, s), 1.63 ~ 1.66 (6H, each s), 3.49 (2H, broad s), 4.34 (2H, s), 4.96 (lH, d, J=4.5Hz), 5.90 (lH, d-d, J=4.5 ~ 7.5), 6.66 (lH, s), 6.86 (lH, s), 7.0-7.5 (25H, m), 8.23 (lH, d, J=7.5Hz).

Procedure 2 A solution of V (1.86 g, 4.49 mmoles) in CH3CN (46.5 mL) was treated with BSA (3.33 mL~ 13.5 mmoles) at room temperature for 5U
minutes to give a clear solution. To the solution was added an acià

chloride solution which had been prepared from IIIa' (2.55 g, 4 49 mmoles) and PC15 (1.12 g, 5.38 mmoies) in methylene chlo,ide '.~fj mL). The mixture was stirred at room temperature for 3~ minu eS~"
poured into cold water (100 mL) and extracted with ethyl ac't~5 ~3 50 mL). The combined extracts were washed with aqueous IYaCl, dried and evaporated. The residual syrup (5 g) was chromatograpned 5Q a silica gel (100 g) column by eluting with 10:1 mixture of toluene and ethyl acetate. The fractions containing the desired compound were combined and evaporated to afford 2.84 g (65~) of Va.

. Benzhydryl 7-[(Z)-2.-(2-t-~utoxycarbonylprop-1-oxyimino)-2-(2-tritylaminothiazol-4-yl)acetamido]-3-iodomethyl-3-cephem-4-carboxylate (VIa) A mixture of Va (500 mg, 0.53 mmole) and NaI (240 mg, 1.6 mmoles~
in acetone (3 mL) was stirred for 2 hours at room temperature and then evaporated in vacuo. To the residue were added CH2C12 (20 mL) and water (10 mL). The organic layer was washed with 10~ s/v sodium thiosulfate (5 mL) and aqueous NaCl (5 mL), dried over MgS04 and evaporated to dryness to give 540 mg (90~,) of VIa as an amorphous powder melting at 106C (dec.).

IK ~Br cm~l 3350, 1790, 1690.
max UV : ~Et~H nm 240 (El~ 270), 265 (El~ 190).
max 1 cm 1 cm NM~ : ~C~C13 ppm 1.44 (9H, s), 1.65 (6H, s), 3.54 (lH, 4.28 (ZH, s), 4.98 (lH, d, J=4.5Hz), 5.85 (lH, d-d, J=4.5 ~ 7.5Hz), 6.70 (lH, s), 6.90 (lH, s), 7.1-7.5 (25H, m).

- ~7 C. 7-L2-~2-Aminothiazol-4-yl)-(/)-2-(2-car~Joxj~pf?~-2-o~ noj acetamido]-3-[(1-methyl-1-pyrrolidinium)rnethyl~-3-cepne~i-4-carboxylate (Ie) A mix~ure of the iodomethyl derivative VIa (538 mg, 5 ~1 mmole~
and N-methylpyrrolidine (0.07~ mL, 0.076 mmole) in CH2Cl2 (10 mL) was allowed to stand at room temperature for 30 minutes and the diluted with ether (80 mL). The precipitate which formed was collected by filtration and washed with ether to give 420 mg of the quaternized product, which was deblocked with 90-~ trifluoroacetic acid (TFA) (4.2 mLJ at room temperature for 1 hour. The reaction nixture was then evaporated to dryness. To the residue was added either to give crude TFA salt of Ia (245 mg, quantitative), which ~ias a 1:4 mixture of the ~3 and ~2 isomers. The crude was subjected to HPLC purification [Lichrosorb ~P-18, 4 x 300 mm, eluted with 9.01 ammonium phosphate buffer (pH 7.0) containing 10~ CH3~H]. The fractlon containing the desired product was collected and evaporated to a small volume. The concentrate was adjusted to pH ca. 2 by adding 1 ~ HCl and passed through an IIP-20 column (2 x 15 cm) to remove th-inorganic salt. The column was washed with H20 (lO00 mL) and eluted with 30~ CH3~H. The eluant was evaporated and lyophilized to a~ford 21 mg (10~) of the title product (Ie) as a colorless powder. ,~p.
160~C (dec.).

IR vK~r cm 1 3400, 1775, 1610.
max UV : phosphate buffer, pH 7 nm(~) 237 (15700), 257 (155500) max NMR : ~D20 ppm 1.65 (6H, 5)7 2.3 (4H9 m), 3.09 (3H, s), 3.6 (4H, m)> 4.0 (2H, m), 5.44 (lH, d, J=~.8H ), 5.94 (lH, d), 7.15 (lH~ s).

- ~8 -~xample ~

The general procedure o~ Example 7 is follo~t;ed 5xcept that t~'le (Z)-2-(2-t-butoxycarbonylprop-2-oxyimino)-2-(2-tritylamino~hiazol-~-yl, acetic acid is replaced by an equimolar amsunt o~

(Z)-2-(t-butoxycarbonylmethoxyimino)-2-(2-tritylaminothiazol-4-y~ace acid, (Z)-2-(1-t-butoxycarbonylethoxyimino)-2-(2-tritylaminothiazol-4-yl) acetic acid, (ZJ-2-(2-t-butoxycarbonylbut-2-oxyimino)-2-(2-tritylaminothiazol-4-yl-acetic acid, (Z)-2-(3-t-butoxycarbonylpent-3-oxyimino)-1-(2-tritylaminothiazol-4-yl~acetic acid, (Z)-2-~1-t-butoxycarbonylcycloprop-1-oxyimino)-2-(2-tritylaminothiazoi-4-yl)acetic acid, (Z)-2-(1-t-butoxycarbonylcyclobut-1-oxyimino)-2-(2-tritylaminothiazol-4-yl)acetic acid and (Z)-2-(1-t-butoxycarbonylcyclopent-1-oxyimino)-2-(2-tritylaminothiazol--yl)acetic acid; respectively, and there is thereby produced 7-[2 (2-aminothiazol-4-yl)-(Z)-2-~carboxymethoxyimino)acetamido]-3-l(l-methyl-l-pyrrolidinium)methylJ-3-cephem-~-carboxylate, 7-[2-(2-aminothiazol-4-yl)-(Z)-2-(1-carboxyethoxyimino)acetamido]-3-[(l-methyl-l-pyrrolidinium)methyl]-3-cephem-4-carboxylate, ~3i~Z

7-[2-(2-aminothiazol-4-yl)-(Z)-2-(Z-carboxybut-2-oxyirlinoj-arefami~o~-3-[(1-methyl-1-pyrrolidiniumJmethyl]-3-cephem-4-carboxylate, 7-~2-(2-aminothiazol-4-yl)-(Z)-2-t3-carboxypent-3-oxyimino~-acetami~o'-3-[(1-methyl-1-pyrrolidinium)methyl]-3-cephem-4-carboxylate, 7-[2-(2-aminothiazol-4-yl)-(Z)-2-(1-carboxycycloprop-1-oxyimino)-ace-tamido]-3-[(1-methyl-1-pyrrolidinium)methyl]-3-cephem-4-carboxylate, 7-[2-(2-aminothiazol-4-yl)-(Z)-2-(1-carboxycyclobut-1-oxyimino)ace-tamido]--3-[(1-methyl-1-pyrrolidinium)methyl]-3-cephem-4-carboxylate and 7-[2-(2-aminothiazol-4-yl)-(Z)-2-(1-carboxycyclopent-1-oxyi;llino) acetamido]-3-[(1-methyl-1-pyrrolidinium)methyl]-3-cephem-4-carboxy-late, respectively.

Claims (16)

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 compounds of the formula wherein R1 is hydrogen or a conventional amino-protecting group used in the cephalosporins art, and R2 is a straight or branched chain alkyl group containing from 1 to 4 carbon atoms, allyl, 2-butenyl or 3-butenyl, or is a group wherein R3 and R4 each are independently hydrogen, methyl or ethyl, or R3 and R4, taken together with the carbon atom to which they are attached, may be a cycloalkylidene ring con-taining from 3 to 5 carbon atoms, or a nontoxic pharmaceutically acceptable salt, physiologically hydrolyzable esters or solvate thereof, which comprises either:
acylating a compound of the formula XVI

or an N-silyl derivative thereof, in which B1 is hydrogen or a conventional-protecting group, with an acylating derivative of an acid of the formulae or XVII XVIIa wherein B2 is a conventional amino-protecting group used in the cephalosporins art, B3 is a conventional carboxyl-protecting group and R3 and R4 are as defined above, to produce a compound of the formulae XV

or XVa and subsequently removing all protecting groups; or:
reacting a compound of the formulae XIV

or XIVa wherein R2, R3 and R4 are as defined above, B1 and B3 are conventional carboxyl-protecting groups, B2 is a conventional amino-protecting group used in the cephalosporins art, with N-methylpyrrolidine to produce a compound of the formulae XV

or XVa and subsequently removing all protecting groups by conventional means.

2. A process for the preparation of compounds of the formula I

wherein R1 is hydrogen or a conventional amino-protecting group used in the cephalosporins art, and R2 is a straight or branched chain alkyl group containing from 1 to 4 carbon atoms, allyl, 2-butenyl or 3-butenyl, or is a group wherein R3 and R4 each are independently hydrogen, methyl or ethyl, or R3 and R4, taken together with the carbon atom to which they are attached, may be a cycloalkylidene ring con-taining from 3 to 5 carbon atoms, or a nontoxic pharmaceutically acceptable salt, physiologically hydrolyzable esters or solvate thereof, which comprises acylating a compound of the formula XVI

or an N-silyl derivative thereof, in which B1 is hydrogen or a conventional-protecting group, with an acylating derivative of an acid of the formulae XVII or XVIIa wherein B2 is a conventional amino-protecting group used in the cephalosporins art, B3 is a conventional carboxyl-protecting group and R3 and R4 are as defined above, to produce a compound of the formulae XV

or XVa and subsequently removing all protecting groups.

3. A process for the preparation of compounds of the formula I

wherein R2 is a straight or branched chain alkyl group containing from 1 to 4 carbon atoms, allyl, 2-butenyl or 3-butenyl, or is a group wherein R3 and R4 each are independently hydrogen, methyl or ethyl, or R3 and R4, taken together with the carbon atom to which they are attached, may be a cycloalkylidene ring containing from 3 to 5 carbon atoms, and nontoxic pharma-ceutically acceptable salts, physiologically hydrolyzable esters and solvates thereof, which process comprises reacting a compound of the formulae XIV

or XIVa wherein R2, R3 and R4 are as defined above, B1 and B3 are conventional carboxyl-protecting groups, B2 is a conventional amino-protecting group used in the cephalosporins art, with N-methylpyrrolidine to produce a compound of the formulae XV

or XVa and subsequently removing all protecting groups by con-ventional means.

4. The process of claim 2 or 3, for the preparation of 7-[2-(2-aminothiazol-4-yl)-(Z)-2-(2-carboxyprop-2-oxyimino)-acetamido]-3-[(1-methyl-l-pyrrolidinium)methyl]-3-cephem-4-carboxylate (Ie) or a nontoxic pharmaceutically acceptable salt, physiologically hydrolyzable ester or solvate thereof, which comprises reacting a mixture of benzhydryl 7-amino-3-chloromethyl-3-cephem-4-carboxylate,(Z)-2-(2-t-butoxycarbonyl-prop-2-oxyimino)-2-(2-tritylaminothiazol-4-yl) acetic acid, dicyclohexylcarbodiimide,N-hydroxybenztriazole in an organic solvent to give benzhydryl 3-chloromethyl-7-[(Z)-2-(2-t-butoxycarbonylprop-2- oxyimino)-2-(2-tritylaminothiazol-4-yl) acetamido]-3-cephem-4-carboxylate (If) or alternatively reacting a mixture of benzhydryl 7-amino-3-chloromethyl-3-cephem-4-carboxylate and bis(trimethylsilyl)acetamide with an acid chloride of (Z)-2-(2-t-butoxycarbonylprop-2-oxyimino)-2-(2-tritylaminothiazol-4-yl)acetic acid to give (If), then reacting (If) with iodide salt to give benzhydryl 7-[(Z)-2-(2-t butoxycarbonylprop-2-oxyimino)-2-(2-tritylaminothiazol-4-yl) acetamido]-3-iodomethyl-3-cephem-4-carboxylate (Ig), then further reacting (Ig) with N-methylpyrrolidine in an organic solvent to give (Ih), and finally deblocking (Ih) to give the title compound (Ie), melting at 160°C ldec) and/or if desired optionally converting (Ie) to its nontoxic pharmaceuti-cally acceptable salts, physiologically hydrolyzable esters and solvates thereof.

5. The process of claim 2 or 3, for the preparation of compounds of the formula I

wherein R1 is hydrogen and R2 is methyl, ethyl, isopropyl, or allyl, or a nontoxic pharmaceutically acceptable salt or solvate thereof, which comprises reacting a mixture of benzhydryl 7-amino-3-chloromethyl-3-cephem-4-carboxylate and bis(trimethylsilyl) acetamide with an acid chloride of (Z)-2-methoxyimino-2-(2-tritylaminothiazol-4-yl) acetic acid or (Z)-2-ethoxyimino-2-(2-tritylamino-thiazol-4-yl) acetic acid or (Z)-2-(2-propoxyimino)-2-(2-tritylamino-thiazol-4-yl) acetic acid or (Z)-2-allyloxyimino-2-(2-tritylaminothiazol-4-yl) acetic acid to give the corresponding condensed derivative containing 2-methoxyimino or 2-ethoxyimino or 2-propoxyimino or 2-allyloxyimino group, then reacting said condensed deri-vative with iodide salt to give the corresponding 3-iodomethyl derivative, then further reacting said 3-iodiomethyl derivative with N-methyl-pyrrolidine in an organic solvent or a mixture of organic solvents to give the corresponding pyrrolidinium derivative and finally deblocking said pyrrolidinium derivative to give 7-[(Z)-2-methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-[(1-methyl-1-pyrrolidinium)-methyl]-3-cephem-4-carboxylate, or 7-[(Z)-2-ethoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-[(1-methyl-l-pyrrolidinium)-methyl]-3-cephem-4-carboxylate, or 7-[(Z)-2-(2-propoxyimino)-2-(2-aminothiazol-4-yl)acetamido]
-3-(1-methyl-1-pyrrolidinium)methyl]-3-cephem-4-carboxylate, or 7-[(Z)-2-allyloxyimino-2-(2-aminothiazol-4-yl)acetamido, -3-[(1-methyl-1-pyrrolidinium)methyl]-3-cephem-4-carboxylate, and/or if desired converting said deblocked derivatives to nontoxic pharmaceutically acceptable salt or solvate thereof.

6. The process of claim 1, wherein R2 is a methyl group.

7. The process of claim 1, wherein R2 is an ethyl group.

8. The process of claim 1, wherein R2 is a propyl group.

9. The process of claim 1, wherein R2 is allyl.

10. The process of claim 1, wherein R2 is a group wherein R3 and R4 are methyl.

11. A compound of the formula I

wherein R1 is hydrogen or a conventional amino-protecting group used in the cephalosporins art, and R2 is a straight or branched chain alkyl group containing from l to 4 carbon atoms, allyl, 2-butenyl or 3-butenyl or is a group wherein R3 and R4 each are independently hydrogen, methyl or ethyl, or R3 and R4, taken together with the carbon atom to which they are attached, may be a cycloalkylidene ring con-taining from 3 to 5 carbon atoms, or a nontoxic pharmaceuti-cally acceptable salt, physiologically hydrolyzable esters or solvate thereof, whenever prepared by the process of claim 1 ox by an obvious chemical equivalent thereof.

12. The compound of claim 11, which is 7-[(Z)-2-methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-[(1-methyl -1-pyrrolidinium)-methyl]-3-cephem-4-carboxylate, or a nontoxic pharmaceutically acceptable salt or solvate thereof, whenever prepared by the process of claim 6 or by an obvious chemical equivalent thereof.

13. The compound of claim 11, which is 7-[(Z)-2-ethoxylimino-2-(2-aminothiazol-4-yl)acetamido]-3-(1-metnyl-1-pyrrolidinium)-methyl]-3-cephem-4-carboxylate, or a nontoxic pharmaceutically acceptable salt or solvate thereof, whenever prepared by the process of claim 7 or by an obvious chemical equivalent thereof.

14. The compound of claim 11 which is 7-[(Z)-2-(2-propoxyimino)-2-(2-aminothiazol-4-yl)acetamido]-3-(1-methyl -1-pyrrolidinium)methyl]-3-cephem-4-carboxylate, or a nontoxic pharmaceutically acceptable salt or solvate thereof, whenever prepared by the process of claim 8 or by an obvious chemical equivalent thereof.

15. The compound of claim 11 which is 7-[(Z)-2-Ally-loxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(1-methyl-1-pyrrolidinium)methyl]-3-cephem-4-carboxylate, or a nontoxic pharmaceutically acceptable salt or solvate thereof, whenever prepared by the process of claim 9 or by an obvious chemical equivalent thereof.

16. The compound of claim 1 which is 7-[2-(2-amino-thiazol-4-yl)-(Z)-2-(2-carboxyprop-2-oxyimino)acetamido]-3-[(1-methyl-l-pyrrolidinium)methyl]-3-cephem-4-carboxylate or a nontoxic pharmaceutically acceptable salt, physiologically hydrolyzable ester or solvate thereof, whenever prepared by the process of claim 10 or by an obvious chemical equivalent thereof.