SE505256C2 - New 7-amino cephalosporin derivatives with a quaternary ammonio group and process for the preparation thereof - Google Patents

Abstract

7-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-(substituted)-iminoacetamido]-3 -[3-(quaternaryammonio)-1 - propen-1-yl]-3-cephem-4-carboxylates of the formula in which R<1> and R<2> are as defined herein and is a quaternary ammonio group as defined herein, and salts, solvates, hydrates and esters thereof, are potent antibacterial agents. Processes for their preparation and intermediates in such processes are described.

Description

505 256 alkynyl, optionally substituted cycloalkyl, cycloalkenyl or an O- or S-containing 5-membered heterocyclic ring, which is substituted by oxo groups; R 3 is hydrogen or alkyl; R 4 is hydrogen, acyloxyalkyl, acylthioalkyl, optionally substituted pyridinioalkyl, optionally substituted heterocyclyltioalkyl, alkyl, halogen, hydroxy or optionally substituted thiazolioalkyl; and R 5 is carboxy or protected carboxy; with the proviso that R 5 is CO- when R 4 is optionally substituted pyridinioalkyl or optionally substituted thiazolioalkyl; and the dashed line indicates either single or double bond.

European Patent Application 13,762, published August 6, 1980, is consistent and has a similar description.

U.S. Patents 4,381,299 (issued April 26, 1983), 4,331,665 (issued May 25, 1982) and 4,332,798 (issued June 1, 1982), each based on parent applications to U.S. Patent 4,390,534, have similar descriptions. nings.

B) European Patent Application 62 321, published October 13, 1982, discloses cephem compounds of the formula al '-cous ____' ä ä ni à fi z f / '0 \\ wherein R 1 is amino or protected amino; R 2 is an optionally substituted lower aliphatic hydrocarbon group or cycloalkenyl; and the group of the formula f \ 1 \ "4i (3 If 505 256 is an optionally substituted beterocyclic cation group containing more than one nitrogen atom; and pharmaceutically acceptable salts thereof. Compounds of the formula s nl-å ä; š are also disclosed as intermediates). -coua- fl- T p S ¿R2 67 - N ll / \\ '~ \ I 4 caz N \ ® /. 3 __ wherein R1 and R2 have the meanings given above, R4 is a protected carboxyl group and X- is a acid group.

C) European Patent Application 74,653, published March 23, 1983, discloses cephem compounds of the formula C009 - '1 wherein R is amino or protected amino; R 2 is an optionally substituted lower aliphatic hydrocarbon group, cyclo (lower alkyl) or cyclo (lower alkenyl); R 3 is lower alkylamino, N-protected (lower alkyl) amino, di (lower alkyl) amino, sulfo (lower alkylamino, hydroxy- (lower alkyl) amino, N-protected hydroxy (lower alkyl) amino, acyloxy (lower alkyl), (lower alkoxy) (lower alkoxy) (lower alkyl), d1 (lower alkyl) amino (lower alkyl), (lower alkyl) - thio (lower alkyl), (lower alkyl) thio, lower alkoxy (lower alkoxy) (lower alkoxy), hydroxy (lower alkoxy), acyl lower alkyl), hydroxy (lower alkyl) thio, di (lower alkyl) amino (lower 505 256 alkyl) thio, N-containing unsaturated 5-membered heterocyclic group, N-containing unsaturated 5- articulated heterocyclylthio or N-containing unsaturated 5- or 6-membered heterocyclylthio (lower alkyl), which may be substituted by appropriate substituents: and R 4 is hydrogen or lower alkyl; is a salt thereof.

D) U.S. Patent 4,332,800, issued June 1, 1982, discloses, inter alia, compounds of the formula V -CONH S 'Lock / N ai 32 æjjQ-c fl ï see wherein R 1 is amino or protected amino; R 2 is lower alkyl and X is hydrogen or carbamoyl.

E) European Patent Application 47 977, published March 24, 1§82, discloses cephem compounds of the formula (0) f, m Am- r- fi -coua_-fs z-az) / '_' / 0 _ cnzn: we In which m is 0 or 1; Am is optionally substituted amino; T is a thiadiazolyl group (attached to the other groups via two of its carbon atoms); R 2 is hydrogen, optionally substituted alkyl, cycloalkyl or optionally substituted carbamoyl; and R 1 is an optionally substituted thiazolio, optionally substituted pyrazolio, tri (lower alkyl) ammonio or pyridinio group of the formula R b R wherein Ra is substituted lower alkyl [the substituent is cycloalkyl, phenyl, hydroxy, alkoxy, halogen, cyano, carbamoyl, carboxyl or sulfq], lower alkenyl or carboxy-substituted lower alkenyl, lower alkylthio or carboxy-substituted lower alkylthio, amino or monosubstituted amino substituent is lower alkyl, lower alkanoyl or aminobenzenesulfonyl], di (lower alkyl) amino, substituted carbamoyl [substituent is lower alkyl, hydroxy (lower alkyl), lower alkoxy, hydroxy or cyano], di (lower alkyl) - carbamoyl, thiocarbamoyl, cycloalkyl, phenyl, hydroxy, lower alkoxy, halogen, (lower alkoxy) carbonyl, lower alkanoyloxy, lower alkanoyl, carboxyl, sulfo, cyano, nitro or hydroxysulfo (lower alkyl); R b is hydrogen or carbamoyl or has the same meaning as Ra; and R c is hydrogen or has the same meaning as Ra; and salts thereof.

Although European Patent Application 25,017, published March 11, 1981, is not formally related to the above-mentioned European Patent Application, it has a similar description.

F) European Patent Application 30 630, published June 24, 1981, discloses 3-vinyl cephem compounds of the formula 1 S 'a - A-cona-uI / g N 2 \ ca-cn2 R 505 256 wherein R1 is a optionally protected amino-substituted heterocyclic group, which may also contain halogen, or a group of formula 3 R SO 2 BN wherein R 3 is lower alkyl; R 2 is carboxy or protected carboxy; and A is lower alkylene, which may contain a substituent consisting of amino, protected amino, hydroxy, oo or a group of the formula = N ~ OR 4, where R 4 is hydrogen, cyclo (lower alkenyl), lower alkynyl, lower alkenyl [ optionally substituted with carboxy or protected carboxyl, lower alkyl - [optionally protected with one or more carboxy, protected carboxy, amino, protected amino, cyano, phosphono, protected phosphono or a heterocyclic group, which in turn may be substituted]; and salts thereof.

This application specifically discloses compounds of the formula ^ com / an / „um I = s / \ on 'ä * / C008 -cn wherein OR4 is methoxy, carboxymethoxy, tert-butoxycarbonylmethoxy or 1-tert-butoxycarbonylethoxy.

G) British Patent 1,399,086, published June 25, 1975, contains a generic disclosure comprising a very large number of cephalopods. with the formula * fi iíïïïf C008 505 256 possible meanings for R3, the application only exemplifies compounds in which R3 is hydrogen, chlorine or vinyl.

I) U.S. Patent 4,307,233, granted December 22, 1981, discloses, inter alia, 3-vinylcephalosporin derivative of the formula S cona-à /. wherein Rs i.a. may be alkyl, vinyl, cyanomethyl or a protecting group such as 2-methoxyprop-2-yl and R 3 and R 4 are alkyl groups (optionally substituted with hydroxy, alkoxy, amino, alkylamino or dialkylamino) or phenyl groups or R 3 and R 4 together with the nitrogen atom to which they are attached may form a saturated heterocyclic ring having an S or 6 member, optionally containing another heteroatom, which is N, O or S, and optionally substituted with an alkyl group. The compounds are useful as intermediates in the preparation of 3-thiovinylcephalosporin derivative. There is no disclosure or suggestion of an S-amino-1,2,4-thiadiazol-3-yl group in place of the 2-amino-thiazol-4-yl substituent or of a ¿quaternary ammonio-substituted propenyl group as 3-substituent. Published British Patent Application 2,051,062 is consistent and has a similar description.

J) European patent application 53 S37, which was published on 9 June 1982, reveals i.a. 3-vinylcephalosporin derivatives of the formula 505 256 _ l \ E, áoun j n få? \ r se / fJ '/ 2 2' / ° \ ° § ° „S Rs Rs _c ,, _ N /“: “a wherein R: and R: are the same or different and are hydrogen or alkyl or together form an alkylene group containing 2 or 3 carbon atoms, R 1 is an acid protecting group, R 2 is an acid protecting group such as an ester, R 3 and R 4 are the same or different and are hydrogen, alkyl (optionally substituted with hydroxy, alkoxy, amino, alkylamino or dialkylamino) or phenyl or R 3 and R 4 together with the nitrogen atom to which they are attached form a saturated 5 or 6 membered heterocyclic ring, optionally containing another heteroatom, which is N, O or S, and optionally substituted with an alkyl group. The compounds are useful as intermediates in the preparation of 3-thiovinylcephalosporin derivatives. There is no disclosure or indication of a 5-amino-1,2,4-thiadiazol-3-yl group in place of the 2-aminothiazol-4-yl substituent or of an Equaternary ammonio-substituted propenyl group as 3 -substituent.

U.S. Patent 4,423,214 conforms thereto and has a similar description.

K) European Patent Application 53 074, published June 2, 1982, generically discloses a large number of 3-vinyl cephalosporin derivatives of the formula 505 256 wherein R ° 1a (1 one of several embodiments) may be ° CO ° N š_ / Ls: \ ° R n: 5 wherein RS i.a. may be hydrogen, alkyl, vinyl, cyanomethyl, an oxime protecting group such as trityl, etc. or a group of the formula '-c-coon ° R 5 wherein R 6 and R 8 are the same or different and may be hydrogen, alkyl or together an alkylene group having 2 or 3 carbon atoms and Res is hydrogen or an acid protecting group; R ° 2a is hydrogen or an acid protecting group such as methoxymethyl; Ro (in one of several embodiments) may be a methyl group substituted with a 5- or 6-membered aromatic heterocyclic ring containing a single heteroatom, such as 2- or 3-pyridiyl, 2- or 3-thienyl or 2 - or 3-furyl; and R 3 is a group of the formula R 4 SO 2 O - wherein R 6 may be alkyl, trihalomethyl or optionally substituted phenyl.

These compounds are stated to be intermediates in the preparation of compounds wherein the 3-substituent is a group of the formula RO -cH = c-s1i '11 505 256 which are stated to have antibacterial activity.

Although this patent includes the possibility that R 0 is a methyl group substituted with an N-containing heterocyclic ring, both in the intermediates and the end products (and thus gives a heterocyclyl-substituted propenyl group), it only teaches that the heterocyclic ring is attached via a of their carbon atoms. Thus, there is no hint of a quaternary ammonio-substituted propenyl group. The reference exemplifies Ro in the intermediates and end products only as methyl. Furthermore, in both the intermediates and the final product, the propenyl group must contain a second substituent (-O3SR4 and -SR, respectively). There is also no disclosure or indication of a 5-amino-1,2,4-thiadiazol-3-yl group instead of the 2-aminothiazol-4-yl substituent.

L) European Patent Application 53 538, published on 9 June 1982, discloses, inter alia: 3-vinylcephalosporin intermediates of formula (0) z 0 c as: / Å Å å: s “_” / 52 !! s OR o // 'UHQ coon wherein n is 0 or 1, R 5 is hydrogen, alkyl, vinyl, cyanomethyl or an oxime protecting group and R 3 is halogen. There is no disclosure or suggestion of an S-amino-1,2,4-thiadiazol-3-yl group instead of the 2-aminothiazol-4-yl substituent and no disclosure or suggestion of a 3-halo 1-propen-1-yl substituent in the 3-position. 12 505 256 Full description The present application relates to novel cephalosporin derivatives, which are potent antibacterial agents. More particularly, the invention relates to compounds of the formula N * Q Z I - '| 'u j e lmL s J! Wherein R 1 is hydrogen or a conventional amino protecting group, R 2 is hydrogen, a straight or branched chain alkyl group containing 1 to 4 carbon atoms, a cycloalkyl or cycloalkenyl ring containing 3 to 6 carbon atoms or a group of the formula R4 R4 | 3 | _ 3 coon Rs Rs X η -f-COOH r R5 wherein R 3 is hydrogen, lower alkyl or carboxyl, X is halogen, hydroxy or lower alkoxy and R 4 and R 5 are each independently hydrogen , methyl or ethyl or R 4 and R 5 together with the carbon atom to which they are attached may be a cycloalkylidene ring containing 3-5 carbon atoms and GD -NEEQ is a ¿quaternary ammonio group: and non-toxic pharmaceutically acceptable salts and physiologically hydrolysable esters thereof. The scope of the invention also includes solvates (including hydrates) of the compounds of formula I, as well as the tautomeric forms of the compounds of formula I, for example the 2-iminothiazolin-4-yl-moiety of 2-aminothiazol-4-yl the group.

In another aspect, this invention relates to a process for the preparation of the compounds of formula I and certain intermediates in their preparation.

As shown in the structural formula, the compounds of formula I have a "sight" or "Z" configuration with respect to the alkoxyimino group, because the compounds are geometric isomers, some amount of the "anti" isomer may also be present. The invention includes compounds of formula I which contain at least 90% of the "syn" isomer The compounds of formula I are preferably "syn" isomers which are substantially free of the corresponding "anti" isomers.

In addition to geometric isomers, which are possible with respect to the alkoxyimino group, the compounds of formula I (and the intermediates of formulas VIII and IX) also form geometric (cis and trans) isomers around the double bond of the propenyl group. Both the cis ("Z") and trans ("E") isomers of these compounds fall particularly within the scope of this invention.

The non-toxic pharmaceutically acceptable salts of the compounds of formula I include salts with mineral acids such as hydrochloric acid, hydrobromic acid, phosphoric acid and sulfuric acid or with organic carboxylic acids or sulfonic acids such as acetic acid, trifluoroacetic acid, citric acid, formic acid, maleic acid, maleic acid, maleic acid, maleic acid tartaric acid, fumaric acid, mandelic acid, ascorbic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and other acids known and used in the pancillic and cephalosporin fields. The preparation of these acid addition salts is carried out by conventional techniques. Examples of physiologically hydrolyzable esters of the compounds of formula I include indanyl, phthalidyl, methoxymethyl, acetoxymethyl, pivaloyloxymethyl, glycyloxymethyl, phenylglycyloxymethyl and S-methyl-2-oxo-1,3-oxo dioxolen-4-ylmethyl esters and other physiologically hydrolysable esters which are known and used in the field of penicillin and cephalosporin. Such esters are prepared by conventional techniques known in the art.

The compounds of formula I, wherein R 1 is hydrogen, show high antibacterial activity against various gram-positive and gram-negative bacteria and are useful in the treatment of bacterial infections in animals, including humans. The compounds of formula I may be formulated for parenteral use in a conventional manner using known pharmaceutical carriers and excipients and may be presented in unit dosage form or in multi-dose 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 may also be in the form of a dry powder for reconstitution for use, for example with sterile pyrogen-free water.

The compounds of formula I may also be formulated as suppositories using conventional suppository bases, such as cocoa butter or other glycerides. The compounds of this invention may, if desired, be administered in combination: with other antibiotics such as penicillins or other cephalosporins. When the compositions are in unit dosage form, they preferably contain from about 50 to about 1500 mg of the active ingredient of formula II. The dosage of the compounds of formula I depends on such factors as the weight and age of the patient as well as on the particular nature and severity of the disease and is determined by the physician. However, the dosage for the treatment of an adult is usually in the range of about 500 to 5000 mg per day, 505 256 depending on the frequency and mode of administration. For intramuscular or intravenous administration to an adult, a total dose of from about 750 to about 3000 mg per day is usually sufficient, in divided doses, although higher daily doses of some of the compounds may be desirable in the case of Pseudomonas infections. .

The quaternary ammonio group of the formula G -DEEQ may be acyclic, cyclic or a combination thereof and may contain one or more additional heteroatoms consisting of nitrogen, sulfur and oxygen.

An example of an acyclic quaternary ammonio group is a group of the formula wherein R 6, R 7 and R 8 may be the same or different and may be, for example, lower alkyl or substituted lower alkyl, in which the substituents are, for example, halogen, amino with the proviso that the amino group may not be present on the end-carbon atom, hydroxy with the proviso that the hydroxy group may not be present on the end-carbon atom, lower alkoxy with the proviso that the alkoxy group may not be present on the mono-carbon atom, lower alkylthio, lower alkylamino, di- (lower alkyl) amino , carbamoyl, lower alkenyl, phenyl (lower alkyl), phenyl or substituted phenyl (wherein the substituents may be, for example, halogen, hydroxy, amino, lower alkylamino, di (lower alkyl) amino, acylamino, lower alkyl, lower alkylthio, lower alkoxy or similar). 16 505 256 Examples of cyclic Equaternary ammonio groups are completely unsaturated monocyclic heterocyclic ring systems and bicyclic heterocyclic ring systems, where at least one N-containing ring is completely unsaturated. Suitable cyclic quaternary fist; ammonium ring systems include, for example, those of the formulas 9 9 ~ 9 g, / *, fra / f ä? “. net w _ .. 10 = - ~ 10. '-' R R _? ('43 -N -N'N "" 'N 9 l + ~ “° - | - + -« °. I g fl- R s: * ÄR10: * <\ R10 S RIU Rs Rs' ““ ß 10. "HI 1 ° u * f * w W 0 310 @) \\ 5 // -S 9 g1 ° \ n”. N ”.

/ I, / N a CB | ® -u / '. I i / íL. s 1: 9 310 çu / nnk - o 9 i 17 'SUS 256 and iixnmae, var: 1: 9 and n "a: 111m ene: substances are for example hydrogen, halogen, amino, lower alkyl, lower alkenyl, lower alkylthio , carboxy, hydroxy, lower alkoxy, (lower alkoxy) (lower alkyl), halo (lower alkyl), hydroxy- (lower alkyl), amino (lower alkyl), (lower alkyl) amino (lower alkyl), d1 (lower alkyl) ) amino (lower alkyl), lower alkylamino, di (lower alkyl) amino, carboxy (lower alkyl), carboxy (lower alkyl) amino, carboxy (lower alkyl) thio, carbamoyl, N- (lower alkyl) carbamoyl, formylamino, acylamino , acyloxy, phenyl, pyridyl, amidino, guanidino and the like. Then the structure of the heterocyclic ring so allow? R 9 and R 10 may together be an alkylene group containing 3-5 carbon atoms, for example propylene.

Examples of combined acyclic / cyclic equatorial ammonio groups include, for example, those of the formula _ 6 1; ~ @ / \ | 12 9 12 -g n, -n -a-R, m 'En Rn / \ / * n / \ / s 12 312 -ai: f 9 ~ f ç'. o - ä! s N n / "\ __ J n / \ _ J '-u N- (lower) alkyl, - /\_./ 3, / all 18 505 256 and the like, wherein R 11 is, for example, lower alkyl, (lower alkoxy) (lower alkyl), hydroxy lower alkyl) with the proviso that hydroxy can not be present on the end-carbon atom, carboxy (lower alkyl), amino lower alkyl) with the proviso that amino can not be present on a d-carbon atom lower alkenyl, halo ( lower alkyl), allyl and the like and R 12 are, for example, hydrogen, hydroxy, halogen, lower alkyl, hydroxy (lower alkyl), (lower alkoxy) (lower alkyl), halo (lower alkyl), amino (lower alkyl), lower alkoxy, lower alkylthio, lower alkenyl, amino, lower alkylamino, di (lower alkyl) amino, acylamino, acyloxy, carbamoyl, amidino (lower alkyl), phenyl, pyridyl, amidino, guanidino and the like.

Preferred quaternary ammonio groups are those of the formulas wherein R 1, R 2 and B 15 are the same or different and are lower alkyl, lower alkenyl, amino (lower alkyl) with the proviso that amino may not be present on the end carbon atom or hydroxy (lower alkyl) with the proviso that the hydroxy group may not be present on one if the carbon atom 1116 is hydrogen, lower alkyl, lower alkoxy, lower alkylthio, amino, lower alkylamino, di (lower alkylamino, formylamino, lower alkanoyl) amino, carboxy, hydroxy, carboxy (lower alkyl), carbox1 (lower alkyl) thio, hydroxy (lower alkyl), halo (lower alkyl), amino (lower alkyl), (lower alkoxy) (lower alkyl), carbamoyl or N- (lower alkyl) carbamoyl or R 16 may represent a divalent alkylene group having 3-5 carbon atoms; R 17 is lower alkyl, (lower alkoxy) (lower alkyl), halo (lower alkyl), allyl, hydroxy (lower alkyl) with the proviso that the hydroxy group is not present on the GC carbon atom, amino (lower alkyl) with the proviso that the amino group is not present on the carbon atom n or? phenyl (lower alkyl); R 18 is hydrogen, lower alkyl, lower alkoxy, (lower alkoxy) (lower alkyl), lower alkylthio, amino, lower alkylamino, di (lower alkyl) amino, carboxy, hydroxy, carboxy (lower alkyl), hydroxy (lower alkyl), amino (lower alkyl), formylamino, lower alkanoylamino, carbamoyl or N- (lower alkyl) carbamoyl; n is an integer from 1 to 3; Z is CH 2 or, when n is 2, Z may also be S, O or N-R 19, where R is hydrogen or lower alkyl; and n 2 ° and n 'are the same or different and are hydrogen, lower alkyl, lower alkoxy, lower alkylthio, amino, lower alkylamino, di (lower alkyl) amino, carboxy, hydroxy, hydroxy (lower alkyl), amino (lower alkyl) , (lower alkox1) (lower alkyl), carboxy (lower alkyl), carboxy (lower alkyl) amino, lower alkanoylamino, carboxy (lower alkanoyl) amino, carbamoyl or N- (lower alkyl) carbamoyl.

Particularly preferred quaternary ammonio groups are N- (lower alkyl) pyrrolidin10 (and especially N-methylpyrrolidinio), tri (lower alkyl) ammonio (and especially trimethyl- mmM, W fi üMM, mmw fl Mmm, mm fl mm @ W fi mm, carbamoylpyridinio, amino (lower alkyl) pyridinio, carboxypyridinio, hydroxy (lower alkyl) pyridinio, N- (lower alkyl) -carbamoylpyridinio, lower alkylenepyridinio, 2-methylthiazolo and z-amino-s-: lazolos .s-cycpyralinlo 505 256 In the compounds of formula I are especially preferred values for R 2 lower alkyl (and especially methyl), cycloalkyl having 3-5 carbon atoms, 1-carboxycycloalk-1-yl having 3-S carbon atoms, allyl, propargyl and carboxy (lower alkyl) (and especially 2-carboxyprop-2-yl) The most preferred compounds of the invention are 1) 2) 3) 4)) 6) 7) 8) 9)) 7- [2- (5-amino-1,2,4 -thiadiazol-3-yl) -2-methylimino-acetamide] -3- [3- (trimethylammonio) -1-propen-1-yl] -3-cephem-4-carboxylate, 7-12- (5-amino- 2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- [3- (1-methylpyrrolidinio) -1-propen-1-yl] -3-cephem- 4-Carboxylate, 7- [2- (S-amino-1,2,4-thiadiazol-3-yl) -2-methoxyimino-acetamide] -3- [ε-pyridinio-1-propen-1-yl] - 3-Cephem-4-carboxylate, 7-1β- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamide] -3- [3- (3-aminopyridinio) -1 -propen-1-yl] -3-cephem-4-carboxylate, 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamide] -3- [3 - (3-formylaminopyridinio) -1-propen-1-yl] -3-cephem-4-carboxylate, 7-12- (S-amino-1,2,4-thiadiazol-3-yl) -2-methoxyimino-acetamide ] -3- [§- (3-aminomethylpyridinio) -1-propen-1-yl] -3-cephem-4-carboxylate, 7- [2- (5-amino-1,2,4-thiadiazole-3- yl) -2-methoxyiminoacetamido] -3- [§- (3-carbamoylpyridinio) -1-propen-1-yl] -3-cephem-4-carboxylate, 7- [2- (5-amino-1, 2,4-thiadiazol-3-yl) -2-methoxyiminoacetamide] -3- [3- (4-carbamoylpyridinio) -1-propen-1-yl] -3-cephem-4-carboxylate, 7- [2 - (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamide] -3- [3- (2-methylthiazolio) -1-propen-1-yl] -3-cephem 4-carboxylate, 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamide] -3- [3- (2-amino-5-thiazolol, 5- q] pyridinio) - 1-propen-1-yl7-3-cephem-4-carboxylate, 11) 12) 13) 14)) 16) 17) 18) 19)) 21) 22) 21 505 256 7- [2- (5-amino -1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido [7- [3- (4-hydroxymethylpyridinio) -1-propen-1-yl] -3-cephem-4-carboxylate, 7- 12- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- [§- (3-hydroxymethylpyridinio) -1-propen-1-yl] -3-cephem -4-carboxylate, 7-12- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamide] -3- [α-k4- (N-methylcarbamoyl] pyridinio) -1-propylene -1-yl] -3-cephem-4-carboxylate, 7-17- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamide] -3- [3- (2 , 3-propylenepyridinio) -1-propen-1-yl] -3-cephem-4-carboxylate, 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-ethoxyimino- acetamide] -3- [3- (4-carbamoylpyridinio) -1-propen-1-yl] -3-cephem-4-carboxylate, 7- [2- (5-amino-1,2,4-thiadiazole-3 -yl) -2-cyclopentyloxy-iminoacetamide] -3- [§- (4-carbamoylpyridinio) -1-propen-1-yl] -3-cephem-4-carboxylate, 7- [Q- (5-amino- 1,2,4-thiadiazol-3-yl) -2-allyloxyiminoacetamide] -3- [§- (4-carbamoylpyridinio) -1-propen-1-yl] -3-cephem -4-carboxylate, 7-12- (s-amino-1,2,4-thiaziaz-3-yl) -2-propargyloxy-iminoacetamide] -3- [3- (4-carbamoylpyridinio) -1-propeno- 1-yl] -3-cephem-4-carboxylate, 7-1β- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamide] -3- [3- (4 -carboxypyridinio) -1-propen-1-yl] -3-cephem-4-carboxylate, 7- (2- (5-amino-1,2,4-thiadiazol-3-yl) -2-ethoxyliminoacetamide] -3 - [3- (4-Carboxypyridinio) -2-propen-1-yl] -3-cephem-4-carboxylate, 7-12- (S-amino-1,2,4-thiadiazol-3-yl) -2 methoxyiminoacetamide] -3- [3- (3-carboxymethylpyridinio) -1-propen-1-yl] -3-cephem-4-carboxylate and 7- [2- (5-amino-1,2,4- thiadiazol-3-yl) -2-methoxyiminoacetamyl] -3-la- (4-carboxymethylthiopyrimino) -1-propen-1-yl] -3-cephem-4-carboxylate. 22 505 256 The numbering system used in the present context for the various reactants, intermediates and final products is as follows: Arabic numeral Letter (if applicable) (1 if applicable) [Roman numeral] - The Roman numeral »indicates whether the compound is a final product (I) or an intermediate or other reactant (all other Roman numerals). The Arabic numerals_ and letters are not used in cases where the overarching class (family) of associations is meant.

The Arabic numeral indicates the special meaning of the substituent R2. If the particular R 2 group in question contains a carboxyl group which is protected by a conventional carboxyl protecting group, a prime sign (') after the Arabic numeral is used to indicate this fact. If the carboxyl group is unprotected, no prime sign is used. A prime sign is also used with the generic R 2 substituent (ie R 2 ') when generically referring to an R 2 group which contains a protected carboxyl group.

The letter at the end of the association number refers to the special meaning of the quaternary ammonio group (9 -NšQ For convenience, the Arabic numerals and letters attributed to some of the preferred R2 groups and quaternary ammonio groups are given below.

'Ai-abisk' number ~ 1: 2 1 = methyl 2 = ethyl 3 = allyl 4 = '_ propargyl = cyclopentyl Letter ABCDEFGHIJKLMNOPQ 23 sus 256 9 -fl ë-ï 1-methylpyrrolidinio pyridinio 2-amino-S-thiazololï.SQ] 3-pyridinio trimethylammonio aminopyridinio 3-formylaminopyridinio 3-karbamoylpyridinio 4-karbamoylpyridinio 3-aminometylpyridinio 2-metyltiazolio- 3-hydroximetylpyridinio hydroximetylpyridinio 4-4- (N-methylcarbamoyl) pyridinio-4 karboxipyridinio 2,3-propylenpyridinio 3-karboximetylpyridinio 4-karboximetyltiopyridinio In the preliminary evaluation of the compounds of this invention, the values of the minimum inhibitory concentration (MIC) of the compounds were determined by the dual agar series dilution method in Mueller-Hinton agar for 32 strains of test organisms in six groups. The geometric mean values of the MIX values determined in these experiments are given in Table 1. 24 505 256 Table 1 ° l 'Pre-Conf. Geometric mean of MIK (pa / ml) nina v1a áubbe -. No. binding 40 +) - 10 40 +) - 10 (0 -) - 10 40 -) - 10 40-I-11 40 -) - 111 (51 (5) (5) (5) (5) (J) 1-10 0 / z-1/1 0.20 0.10 - 0.05 0.15 0.23 2.4 1-11 0 / 2-1 / 1 0.19 0.35 0.029 0.05 0.11 1.4 1-10 - 0 0.20 0.40- 0.010 0.044 0.11, 1.0 1-10 0 / z-1/4 0.35 0.00 0.05 0.11 0.35 3.5 1-1c 0 0.10 0.20 0.0011 0.033 0.001 3.0 1-10 0 / z-1/1 0.01 1.4 0.10 0.20 0.40 2.4 1-10 0 / 2-10 / 1 0.30 0.53 0.05 0.010 0.20 1.3- 1-10 _ 0 0.20 0.40 0.0094 0.029 0.10 1.4 1-10 0 0.15 0.40 0.0094 0.033 0.099 1.2 1-10 0 0.20 0.35 0.0094 0.093 '0.10 1.1 1-10 0 0.20 0.40 0.013 0.043 0.10 0.91 1-11 0 0.00 1.0 0.10 0.20 0.09 3.1 1-10 0 0.11 0.35 0.025 0.010 0.15 1.0 T 1-10 0 0.35 0.00 0.029 0.044 0.20 3: 5 1-10 0 0.20 0.01 0.029 0.000 0.15 2.0 _ 1-10 _ 0 0.35 0.10 0.029 0.10 0.11 2.3 1-10 0 / z-1/1 1.2 1.0 0.013 0.000 0.30 5.1 1-10 0 0.11 0.35 0.029 0.033 0.11 14 1-20 0 0.20 0.40 0.014 0.051 0.15 1: 4 1-za 0 1.2 2.1 0.010 0.11 0.05 4.1 1-20 2 '1.4 3.1 0.044 0.15 0.09 10 1-30 0 0.29 0.40 0.051 0.10 0.52 1.9 "1-40 0 0.20 0.40 0.000 0.11 0.00 2.0 1-5 0 0 0.13 0.40 0.20 0.40 2.1 4.2 1-10 0 0.0 1.0 0.01: 0.001 0.34 14 1-10 0 0.1 0.92 0.0095 0.044 0.23 14 zs 505 256 (G +) - Ia (GH-Ib (G -) - Ia Penicillin-sensitive §¿ aureus (5 strains) Penicillin-reslstent §¿ aureus (5 strains) Cephalotin-sensitive §¿ ~ ggl¿ (2 strains), §l¿ gneumoniae (1 strain) and g§¿ mirabilis (2 strains) Cephalotin-resistant §¿ ggli (3 strains) and §l¿ Eneumoniae (2 strains)! ¿'Morganii (1 strain), §n§¿ cloacae (2 strains) and §g¿¿ marcescens (2 strains) (G -) - III §§¿ aeruginosa (7 strains) _,. (G -) - Ib (G -) - II Table 2 below provides the protective dose (PDSO) of mice for a number of the compounds of formula I with respect to selected microorganisms. Table 3 gives the blood levels of various compounds of formula I when intramuscularly administering the test compounds to mice at a dosage of 20 mg / kg. ¶¿Bè11.2 PDSO (mg / kg) .. .. .V. ' §¿; aureus "§. Coli 'P..aer fi ginosa Compound No. * Smith' Juhl A9 43A I-18 0.44 0.028 7.7 I-1B 0.65 0.072 ET I-1C 0.22 0.013 ET I-1G 0.96 0.021 5.92 I-1H 0.39 0.015 3.9 I-1J 0.35 0.029 ET I-1K 0.53 ET BT I-1M 0.96 ET ET I-1N 2.0 ET ET I ~ 10 0,26 0,17 ET 1-2N 5,0 ET ET ET == ej testad 27. 505 256/5 z »= - ~ I. n. Fl g fl 5 RR: O // Fu / C fl g fi l COOCEÜIÜ: Na ! e: KI C521 cooca (rn) 2 P (Ph) 3 P (Pl fl s Conn- s _ V z íf * Q v: N rN / QS '\ ° * 2 o // az »mn 3 COXÜ (P51: base fw °° "“ "_ fs ~ ns / \ ° R2 ÄF- n / fl iPfPh) 3 'Ox fi (PXÛZ lClClizCim 505 256» M CONH' / s VIII I cs-cacnzcz. ooca (Ph 7 2 ° Na: eller KI N - i? com: / s ß š N 2 / fl "/ H2 S \ ° R _ c / ca-cncazz '': x oocnmz), an '\ R | Qz-: N (secondary amin) X1 (tert- '' _ S iår; (7 K com I n amir fi n * S) 0112 I ÅF ”/ a-cacnz-u / - coocnum), \ n '' xi” TS, e - / '6 a T cava- Ås Ba § \ oa2: f ngn - _xn J s-cacaz-EQ oqcn (va) z 29 505 256 avblockering N '---- con -___ 5' ÅÅÃÅ 8 1 - ngn 5 OR: á-n / Q -cscaz -Nggb qgå Reaction Scheme 1a shows two alternative ways to go from compound IX to compound XII. The direct route, which utilizes a tertiary amine (XI), is applicable to the preparation of all compounds of formula I. The indirect route, via compound X, utilizes a secondary amine as a reactant and is quaternized in subsequent steps. The secondary amine RR'NH, may be acyclic (eg dimethylamine) or cyclic (eg pyrrolidine) and this indirect process is therefore suitable for the preparation of compounds of formula I, wherein the 'quaternary ammonio group is acyclic or' mixed 'acyclic / cyclic. This indirect route is not suitable for the preparation of compounds of formula I, wherein the quaternary nitrogen is in a completely unsaturated heterocyclic ring (for example pyridinio, thiazolio, 2-amino-S-thiazolo [α, 5-quipyridinio and the like). åèakfiànssehèma 1b 11 e g ... 505 256 ® '“'" s nu fl / cxzcl. _ ooc acw, NaI eller KI s.

Qcn-m- fl l / _ 04 "- N / az: XIV coocnmz), Punnï *» mn 3 9 C00CB (Ph) 2 bas: Q »* f xv: ca-v (Pb) 3 'ooc acw, 31 505 256 C1C fl2 C8O Genus-f s. Xvn Ä-N / n-cacazci oocnmn, _ 'Q- Girard reagent T or HCl Hzn - w / Ä xvzn 0 / - N / ca-cacazcl coocxumnz as in Scheme 1§ I VIII Reaction Scheme 1b is a variation of Reaction Scheme 1a in that the 7-amino group 1 of the starting material (II) is protected as a Schiff base during most of the reaction steps and the desired 7-side chain acid is added later during the synthesis. same.

(J5 32 2556 - Reaction scheme 1c CBICH-CH2Cl CO0CH (Ph) 2 Q§I or KI ca = N Ö s ¿7__Ji \\ 1 ;; J \\ cn = ca-cuzï C00CH (Ph) 2 (second year amine) XX C00CB (Ph) 2 Qf fl- * P-rs N XXI ¿ár_ 1 'coocn (Pn) 2 yö <âï;: 3 >> - en-n í "s GÅV-N \\ 1 ;; J \ * cn- cncnz-a1: 3 \ _ RI / XVII XIX QEEN XI (tertiary "amine) aa 595 256 ® 0 cn-cacnz-naq XXII 9 cco N'¿CYler1ng mad III mf :ämm I / s N \.

S / ORZ / Year-N 1, / CD ° ca-caca -some 6 2 coo I Ill N 2 21 Reaction Scheme 1c is a further variation of Reaction Scheme 1b. In Reaction Schemes 1a and 1b, the quaternization of the 3-side chain is the last step, while in Reaction Scheme 1c the last step is an acylation of the 7-amino group. The relationship between reaction schemes 1a, 1b and 1c is shown in the following flow chart. Quaternization Ib <7-N-acylation 1c Compound I a: s 1 Q o "" "° qnö S05 256 In Reaction Schemes 1a, 1b and 1c the benzhydryl group has been shown as the preferred carboxyl protecting group. by the person skilled in the art that other carboxyl protecting groups, which are well known in the art, can be used.The acylating acid III can be used in the form of a derivative such as its acid halide, activated ester, mixed acid anhydride, etc., all of which are well known in the art.We prefer to use The acylating acid III may also have its amino group protected with any of the common amino protecting groups, for example N-trityl, N-formyl or the like. The base used for the conversion of the phosphonium iodide (VI or XV ) to obtain the phosphorylidene (VII or XVI) may be NaOH, Na 2 CO 3, IRA-410 (OH -) resin, IRA (CO 3 -) resin} or the like or a mixture thereof.

The chloroacetaldehyde used for the conversion of phosphorylene liden VII to 3-chloropropenyl-3-cephem compound VIII (or compound XVI to compound XVII) may be the commercially available 40-50% aqueous solution, a distilled solution (for example 70%) or the anhydrous aldehyde.

We have found that compound VIII, prepared from compound VII (Scheme 1a), typically had a Z: E ratio of about 2: 1 at the propenyl double bond. Compound VIII, prepared from compound XVIII (Scheme 1b), on the other hand, was typically almost exclusively the Z-isomer. The difference may not lie in the route used but in the conditions used in the Wittig reaction (VII to VIII or XVI to XVII).

We have also found that the use of a suitable silyl reagent, such as N, O-bis (trimethylsilyl) acetamide, in the Wittig reaction (VII to VIII in Scheme 1a and XVI to XVII in Scheme 1b) caused an improvement in the yields of and the purity of VIII and XVII. The reaction is preferably carried out with 2-5 equivalents of the silyl reagent. When the chloropropylene cephem compound (VIII) was reacted with NaI in acetone to give the iodopropenyl cephem compound (IX), the double bond in the propenyl group was isomerized from Z to E during the iodination. A short reaction period maintained confi- 37; ses 256 Reakthmuæxâænn 2 n. fi com: s IN ~, 'N _ gym / L s / \ ° R2 / cn-cn-caz: * nu' 'oocn mn, II -fi coma - f _ N n .__ / XXIV gÄm / L g / N \ 2 o; ca-ca-caz: coocu (vn) 2 RLAW W ”ß u __u _ 8 / \ ° R2 04 / n-ca-cnznsq coocaum), Reduction gt: CONB -_- (sp _ O COOCH (Pl fl z 38 505 256 Abbiækermg ug _ S JL-I ä com: -1 / I azu S \ on2 '_ N / Q. 0/1 n-caznaq m9 Reaction Scheme 2, which is given in schematic summary form above, is similar to Reaction Scheme 1a except that compound XXIII (equivalent to compound IX in Reaction Scheme 1a) is converted to its S-oxide before quaternization.

Compound XXV is then reduced and the remainder of Reaction Scheme 2 is as Reaction Scheme 1a. In Reaction Scheme 2, it is preferred to protect the amino group on the 7-side chain with a known amino protecting group, such as the trityl group.

The acylating acids of formula III in the present context are either known compounds or can be easily prepared by published methods. European Patent 7,470, published October 12, 1983 (application published February 6, 1980), exemplifies the preparation of compounds of formula III, wherein R 2 is methyl, ethyl, propyl and isopropyl. U.S. Patent 4,390,534, to which reference is made in our prior art description, illustrates the preparation of a variety of compounds of formula III, wherein R 2 is, for example, cyclopentyl, 2-cyclopenten-1-yl, allyl, 2-propynyl, 1- tert. butyloxycarbonyl-1-methylethyl, 1-tert. butyloxycarbonyl-1-cyclopentyl, 1-ethoxycarbonyl-1-methylethyl, tert. butyloxycarbonylmethyl, 1-tert. butyloxy-x carbonyl-2-methylpropyl, trityl and the like. Compound II herein (7-amino-3-chloromethyl-3-cephem-4-carboxylate), which was used as a starting material in Reaction Schemes 1a, 1b and 1c, is a known compound.

The tertiary amines of formula XI (and the secondary amines RR'NH) used in the preparation of the quaternary ammonio compounds of this invention are either known compounds or can be readily prepared by those skilled in the art. Many of the amines are commercially available.

The present invention also relates to a process for the preparation of compounds of the formula cm 1 - T / S low -N / cm 2 wherein R 1 is hydrogen or a conventional amino protecting group, R 2 is hydrogen a straight or branched chain alkyl group having 1-4 carbon atoms , a cycloalkyl or cycloalkenyl ring having 3-6 carbon atoms or a group of the formula R4 COOH I 3 '= 3 -C-CH = CH-R, -ï-CCR, or is -Q -C-COOH r wherein R 3 is hydrogen, lower alkyl or carboxyl, X is halogen, hydroxy or lower alkoxy and R 4 and R 5 are each independently hydrogen, methyl or ethyl or R 4 and R 5 together are teddaaleolate to which they may be attached. 256 cycloalkylidene ring having 3-5 carbon atoms and wherein 9 -N ::: Q is a quaternary ammonio group: And non-toxic pharmaceutically acceptable salts and physiologically hydrolysable esters thereof, which process involves reacting a compound of formula o I! s -Tc-coma - f \ 2 '/ / l \ B23 "S' / N OR 0 cnfc fi cazz coosl wherein R2 'has the same meaning as R2 or is a group of the formula cooal R * elkn' IX 5 where X, R4 and R 5 have the meanings given above, B 1 is a conventional carboxyl protecting group, B2 is hydrogen or a conventional amino protecting group, Z is chlorine, bromine or iodine and m is 0 or 1, with a tertiary amine QÉEEN (or in turn with a secondary amine RR'NH and a compound of formula R "Z) and, if m is 1, reduces the sulfoxide in a conventional manner and then removes all blocking groups by conventional methods.

The present invention also relates to a process for the preparation of compounds of formula 41 505 256 | JJ ka, 9. a-ca-cs: -nggq m? Wherein R is hydrogen or a conventional amino protecting group, R 2 is hydrogen a straight or branched chain alkyl group having 1 to 4 carbon atoms, a cycloalkyl or cycloalkenyl ring having 3 to 6 carbon atoms or a group of the formula R 3 II 3 COOH - ('| IšCH = CH-R p -ÉÉEC -íC-R, or RRX ¥ 4 -? ŠCOOH: R - wherein R 3 is hydrogen, lower alkyl or carboxyl, X is halogen, hydroxy or lower alkoxy and R 4 and R 5 are each independently hydrogen , methyl or ethyl or R4 and R5 together with the carbon atom to which they are attached may be a cycloalkylidene ring having 3-5 carbon atoms and CD -NEEEQ is a quaternary ammonio group, and non-toxic pharmaceutically acceptable salts and physiologically hydrolysable esters thereof, which process comprises acylates a compound of formula 42 505 256 s' - "2" "" "'(//"' "/ ~ 0 CHICHCH2-NEEQ C00 XXII with an acid of formula C - C008 vrf: i 2 Å / N \ 2 HN s ° R n: or with an acylating derivative of said acid, wherein R has the same meaning as R 2 or is a group of the formula cooal n or wherein X, R 4 and R 5 have the meanings given above, B 1 is a conventional carboxyl protecting group and B 2 is hydrogen or a conventional amino protecting group.

The reactions are carried out in an anhydrous organic solvent such as dimethyl sulfoxide, hexamethylphosphoramide, methylene chloride, chloroform, ethyl ether, hexane, ethyl acetate, tetrahydrofuran, acetonitrile and the like or mixtures of such solvents. The reactions are conveniently carried out at a temperature of from about -10 ° C to about + 50 ° C; we normally prefer to carry out the reactions at room temperature. During the quaternization step, at least one mole of the tertiary amine should be used per mole of compound IX, XIV] XXIII or XXIV; we normally prefer to utilize from about 25% to 100% excess of the tertiary amine.

Carboxyl protecting groups suitable for use as B1 in the above reactions are well known to those skilled in the art and include aralkyl groups such as benzyl, p-methoxybenzyl, p-nitrobenzyl and diphenylmethyl (benzhydryl); alkyl groups such as t-butyl haloalkyl groups such as 2,2,2-trichloroethyl, and other carboxyl protecting groups described in the literature, for example in British Patent 1 399 086. We prefer to use carboxyl protecting groups which can be easily removed by treatment with acid. Particularly preferred carboxyl protecting groups are the benzhydryl and t-butyl groups.

Amino protecting groups suitable for use as B2 are also well known in the art and include the trityl group and acyl groups such as chloroacetyl, formyl and trichloroethoxycarbonyl. Amino protecting groups which can be easily removed by treatment with acid, for example the trityl group, are preferred.

When the cephalosporin core is used in the form of the 1-oxide (m = 1), 1-oxides are prepared by known methods such as oxidation with m-chloroperbenzoic acid, peracetic acid, sodium tungstate, etc. The 1-oxide can then be reduced by known methods, e.g. reduction of the corresponding alkoxysulfonium salt with iodide ion in aqueous medium. The alkoxysulfonium salt itself can be easily prepared by treating the 1-oxide with, for example, acetyl chloride.

In another aspect, this invention relates to novel intermediates of the formula 44 505 256 '1Tâ-coNa-fs az "S j * \ oa2 Ä / o cn-cacazz coon XXVIII wherein Z is chlorine, bromine or iodine, R 2 is hydrogen, a straight or branched chain alkyl group having 1 to 4 carbon atoms, a cycloalkyl or cycloalkenyl ring having 3 to 6 carbon atoms or a group "of the formula - F E COOH -c-cH = cH-R3. -c-cc-R3, or Is s RRX? 4 -? - COOH Rs wherein R 3 is hydrogen, lower alkyl or carboxyl, X is halogen, hydroxy or lower alkoxy and R 4 and R 5 are each independently hydrogen, methyl or ethyl or R 4 and R 5 together with the carbon atom to which they are attached may be a cycloalkylidene ring having 3-5 carbon atoms, and salts and esters thereof. Compounds also included are those of formula XXVIII, wherein the amino and / or carboxyl groups are protected by conventional amino protecting and carboxyl protecting groups, respectively.

In yet another aspect, this invention relates to novel intermediates of the formula 454's E24 CH = N ---- T / I FN '325 // / ca-cacazz 0 COOR22 XXIX wherein R22 is hydrogen or a conventional carboxyl protecting group and now, 1124 and 1:25 are the same or different and are hydrogen, hydroxy, lower alkyl or lower alkoxy, or a salt, solvate, hydrate or ester thereof.

In yet another aspect, this invention relates to novel intermediates of the formula "f-" f j / -w / -. e ca-cn-caz-usq CCKDCD XXII wherein -qi-š-IQ is a quaternary ammonio group or a salt, ester, solvate or hydrate thereof.

The terms "acylamino" and "acyloxy" as used herein mean an acylated amino or acylated hydroxy group, where the acyl moiety is lower alkanoyl (e.g. formyl, acetyl, propionyl, butyryl, isobutyryl, isovaleryl, etc.), aroyl (e.g. benzoyl, etc. .), lower alkanesulfonyl (e.g. mesyl, ethanesulfonyl, etc.) or arylsulfonyl (e.g. benzenesulfonyl, tosyl, etc.). The terms 'lower alkyl', 'lower alkoxy' and 'lower alkylthio' (or the like) mean straight or branched chain alkyl, alkoxy and alkylthio groups (or the like) having 1-6 carbon atoms. Likewise, the terms "lower alkenyl" and "lower alkynyl" refer to alkenyl and alkynyl groups having 2 to 6 carbon atoms, respectively.

The invention is further illustrated by the following exemplary embodiments.

Example 1 JNL coma - ï / Q uzu _, _ Q sß '\ OCHB OÄ n: ß u-ca-cuz / -rzo en, I-LA * Z / EI1 / 1 7- [2- (s-amino -1,2,4-E1aa1a '= a1-H3-yl) -z-methoxylaminoacetamyl-3- [3- (1-methylpyrrolidinio) -1-propen-1-yl] -3-cephem-4-carboxy-' lat (I-1A) 'To a solution of 150 mg (0.21 mol) of diphenylmethyl-7- [ε- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamide] -3 - (3-Iodo-1-propen-1-yl) -3-cephem-4-carboxylate (IX-1) (Z / E = 2/1) in 2 ml of ethyl acetate was added a solution of 36 mg (0.42 mol) 1-methylpyrrolidine in 1 ml of ethyl acetate in one portion with stirring. The mixture was stirred for 15 minutes and diluted with 10 ml of isopropyl ether to give a precipitate which was collected by filtration. A mixture of the solid (130 mg), 1 ml of formic acid and 0.1 ml of concentrated HCl was stirred at room temperature. After 1 hour, the reaction mixture was concentrated under reduced pressure, diluted with 20 ml of water and filtered. The aqueous solution was passed through a reverse phase column (filling from a cartridge of PrepPAK-5001018, 100 ml), eluting with water and 10% CH 3 OH. The desired fractions were collected and concentrated in vacuo to a small volume and lyophilized to give 13 mg (12%) of the title compound (I-1A) (Z / E = 1/1), m.p. exceeding 280 ° C (decomposition). m nä: cm * 3400, fl so, 1660, 1610.

Uv: barrel buffer (PH 7) nm m "y 236 (372), 285 (322). Max 1 cm -H nun;: D2 ° 2.31 ma, m, Nf-"), 3.12 (311, s , N-cn3), 3.6 (514, PPN _ H _ m, ZTH a) ys, 2_H) '4.1 d, Jë8, C§2N), 4.2 (3H, s, OCH3), 5 36 (1H, d, J = 4.5, 6-H), 5.95 (3H, m, 7-H & 3-CH = C§), 6.66 (1 / 2H, d, J = 10,3-CH cis), 7.0) 1/28, d, J = 16,3-CH trans). coNa - fi / s V '\ 0ca3 Å_N / ca: ca-cn2? © - cooe I-18 en 48 505 256 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamide] -3-ε-pyridinio-1-progen-1-glz-3-cephem-1-carboxylate (I-13) A mixture of 716 mg (1 mmol) of diphenylmethyl-7- [2- (5 -amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamide] -3- (3-iodo-1-propen-1-yl) -3-cephem-4-carboxylate (IX-1) ( E) and 158 mg (2 mmol) of pyridine in 1 ml of dimethyl sulfoxide (DMSO) were stirred for 1 hour at room temperature. To the mixture was added 20 ml of ethyl acetate to precipitate 620 mg of a solid, which was added to 6 ml of formic acid containing 60 mg of sodium sulfite. The mixture was stirred for 40 minutes at 40 DEG C. and concentrated to dryness. The residue was dissolved in 40 ml of water and some insoluble matter was removed. The aqueous phase was applied to a reverse phase column (PrepPAK-500 / C18, 100 ml) and eluted with 300 ml of water and 800 ml of a 5% aqueous solution of methanol and the eluate was monitored by UV (254 nm) and HPLC. The fractions (SS-aqueous methanol) containing the desired product were combined, concentrated to a small volume and lyophilized to give 40 mg (8%) of the title compound (I-18) with a m.p. exceeding 200 ° C (decomposition).

In = 0: 2: cm -1 aaso, 1160, 1660, 1eoo. ¿Phosphate buffer (pä 7) hm (E18 max I cm) 240 (352), 258 (366), 267. (279), 290 (469).

UV: nux = c: 5g * "" 5 ° '° sa, 74 (za, br-S, 2-H). 4.20 (an, s, øcg3),, 92 (1a, a, a = 4 , s, 7-H) .s, 1s (1n, m, 3-ca = cg), 1, o4 (1a, a, a = 1s, 3-en trans), 8.2 (23, m, Py -H3'5), 8.62 (18, m, Py- n4>. 8.91 (za, m, Py-azls). 49 505 256 Ü Q s / \ ocg3 04 "": ß ca-ca- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamide] -3- [3-pyridinio-1-propene-1] -yl] -3-cephem-4-carboxylate EI-13) 937 mg (1.5 mmol) diphenylmethyl-8- [7- (5-amino-1,2,4-thiadiazol-3-yl) - 2-Methoxyiminoacetamide] -3- (3-chloro-1-propen-1-yl) -3-cephem-4-carboxylate (VIII-1) (Z) was added to a stirred solution of 237 mg (3 mmol) pyridine in 3 ml of DMSO containing 11 mg (0.07S mmol) of NaI. The mixture was diluted with ml of ethyl acetate to separate the precipitate, which was then collected by filtration, washed with 10 ml of ethyl acetate and dried to give 350 mg of the pyridine. The precipitate was treated with 3.4 ml of formic acid containing 34 mg of sodium bisulfite for 30 minutes at 40 ° C. After removal of the formic acid, The residue was obtained by reverse phase column chromatography (filling from a cartridge PrepPAK-500 / C18, 100 ml) by eluting with a% aqueous solution of methanol. The fractions containing the desired product were combined on the basis of HPLC analysis, evaporated under reduced pressure and lyophilized to give 41 mg (5.5%) of the title compound (I-18) (Z-18). E = 4/1). M.p. exceeding 200 ° C (decomposition). 50 505 256 road; cm-1 ssoo, 1160, 1660, 1600. Äfoafat buffer (pH 7) max) 237 (386), 250 (377), 258 (369), 265 (347), 280 (311). nm (E} §cm 8 ° 2 ° ppm 3.45 & 3.76 (value 1H, d, J = 16, 2-H), 4.18 (3H, s, OCH 3), 5.34 (38, m, CH = CB-CH 2 G 6 -H), 92 (1H, d, J = 4.5, 7-H), 6.58 (4 / SH, d, J = 11, 3-CH cis) 7.03 (1 / SH, d, J = 16, 3-CH trans), 8.12 (ZH, m, Py-H3 '5), 8.56 (1H, m, Py-H4), 8 , 82 (ZH, m, Py-H).

NMR: 216 Exemgel 4 S 1 / w I Är-N af 'G) J CHICHCII - I wa 2' L 'I si' NH CONH 2 I-IC * E 7- [2- (5-amino-1,2 , 4-thiadiazol-3-yl) -2-methoxyiminoacet- fl r fi dyl-εfef + - '= f fi1 ê = ° 1 ° ß »Sfvmffêêivßë fl fmmveff 1-y;] - 3-cephem-4-carboxylate' (I-1c) A stirred solution of 714 mg (1 mmol) of diphenylmethyl-7- [7- (S-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamide] 3- (3-iodo-1- propen-1-yl) -3-cephem-4-carboxylate (IX-1) (E-isomer), 2-aminothiazolo [1, Sq] pyridine (prepared by the method of T. Takahashl et al., Pharm. Bull (Japan), 2, 34 (1964)) and 1 ml of dry solution were incubated for 1 hour at room temperature, 20 ml of ethyl acetate were added to the reaction mixture to give 710 mg of a yellow powder, 7 ml of formic acid and 70 mg of sodium bisulfite was added to the powder (700 mg) and the mixture was stirred for 30 minutes at 40-45 ° C.

After evaporation, the residue was triturated with 40 ml of water.

Insoluble material was filtered off and the filtrate was chromatographed on a reverse phase column (PrepPAK-500 / C18, 100 ml) with water and 10% methanol as eluent. The fractions containing the desired product were combined and the solvent was removed under reduced pressure. Lyophilization gave the desired product (I-1C) as a colorless amorphous powder of the E-isomer. Yield 110 mg (19%). M.p. exceeding 200 ° C (decompositionâ. m = cm * 3300, 1760, 1660, 1630, 16oo. _ asphalt buffer (pH 7) 1% uv. Išax mm (21 cm) 245 (499), 265 (266). mm = s ::: ° 'd6 * ° z ° 3.66 (an, s, ocg3), 4.96 (m, a, .n 4.5, 6-11), 5.2 (zu, m, cnæn- cgz),, 57 (m, m, a-cmcg), s, 96 (1u, m, 1-11), 1.16 (111, d, J = 16I s-cn trans), 8.36 & 8 , 45 (each 1H, d, J = 7, Py-H), 8.92 (1H, s, Py-H).

S I J! n Conn I / I, _ uZNL s \ ocn3 n / cn-ca-cszg (cn3) 6669 3 I'19 * Z / EI 1/1 505 256 52 7- [2- (5-amino-1,2, 4-Thiadiazol-3-yl) -2-methoxyiminoacetamide] -3- (3-trimethylammonio-1-propen-1-yl) -3-cephem-4-carboxylate (I-1D) To a solution of 490 mg (0.68 mmol) diphenylmethyl-7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamide] 3- (3-iodo-1-propen-1-yl) -3-cephem-4-carboxylate (IX-1) (Z / E = 2/1) in 14 ml of ethyl acetate was added 13.6 ml of a 0.1 M trimethylamine solution in ether in one portion. The mixture was stirred for 10 minutes and evaporated to dryness and the residue was triturated with 20 ml of ether. The resulting solid (490 mg) was added to 0.2 ml of trifluoroacetic acid, which contained one drop of anisole. After stirring for 1.5 hours, the mixture was evaporated to dryness under reduced pressure and the residual oil was triturated with 20 ml of ether. The resulting precipitate was collected by filtration and dissolved in 20 ml of water. Some insoluble matter was removed and the aqueous solution was eluted on a C18 reverse phase column (filling from a cartridge PrepPAK-S00 / C18, Waters, 30 ml) using water as eluent. Fractions containing the desired compound were combined and concentrated to a small volume and lyophilized to give 30 mg (9.2%) of the title compound (I-1D) (Z / E = 1/1) as a colorless amorphous powder with a m.p. exceeding 150 ° C (decomposition).

IR UV = sooo; cm71 3330, 1710, 1670, 16os.

NEX _: D20 ppm phosphate buffer (pH 7) 1% nm (E1 cm) 236 (389), 287 (343). 3.45 & 3.7 (1H, d, J = 16, 23), 3.81 (1H, s, GD z-H), 4.1 d 'J = 8 | s 'd' J = 4 | 5 | m 'i d, 7.05 (1 / 2H, d, j = 16, 3-CH trans). s: 505 256 1-12 t: 7- [α- (S-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamide] -3- [3- (3-aminopyridinio) - 1-propen-1-yl] -3-cephem-4-carboxylate (I-1E) 716 mg (1 mmol) diphenylmethyl- 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) ) -2-Methoxyiminoacetamide] -3- (3-iodo-1-propen-1-yl) -3-cephem-4-carboxylate (IX-1) (E) was added to a stirred solution of 188 mg (2 mmol) 3-aminopyridine in 1 ml DMSO. The mixture was stirred for 1 hour and diluted with 20 ml of ethyl acetate.

The resulting precipitate was collected by filtration, washed with ethyl acetate and dried to give 520 mg of a yellow powder. A mixture of 500 mg of the powder, 5 ml of formic acid and 50 mg of sodium bisulfite was stirred for 30 minutes at 40 ° C. The mixture was concentrated in vacuo, dissolved in 40 ml of water and filtered to remove insoluble matter. The aqueous solution was chromatographed on a reverse phase column (filling of PrepPAK-500 / C18, 100 ml) with a 7.5% aqueous solution of methanol. The fractions containing the desired compound were evaporated and lyophilized to give the title compound (I-1E) (7 mg, 1.4%), m.p. exceeding 185 ° C (decomposition. ss. 505 256 the resulting precipitate was taken up by filtration, washed with 10 ml of ether and dried. The quaternized salt was dissolved in 3 ml of formic acid containing 0.3 ml of concentrated HCl and stirred for 1.5 hours. The mixture was concentrated to dryness under reduced pressure. The residue was dissolved in 110 ml of 2% HCl and filtered. The aqueous layer was chromatographed on a reverse phase column (PrepPAK-500 / C18, 100 ml). After washing with 500 ml of water, the column was eluted with A 5% aqueous solution of methanol The fractions containing the title compound were combined, concentrated in vacuo and lyophilized to give 15 mg (4.2%) of the title compound (I-1E). ) (Z / E = 1/1) as a colorless amorphous powder, mp exceeding 160 ° C (decomposition).

KBr -1 IR: vmax Cm 3400, 1765, 1675, 1620, 1600. uv = lfæfatlmffert (PH 7) mn (Elgcm) 244 (434). 287 (333). max mm = 8 ° "s ° 'ds * ° 2 ° 3.73 (za, m), 4.14: (33, s, ocus), s, 3s ppm (3H, m, en a. czwcn-cgz ), 6.9 (za, m, 7-11 a 3-ca = c_g), 6.6 (1/211, d, J = 11, 3-cn cis), 7, os (vad, J = 1s , 3, cn m, PY_HJ, 6) I 914 m 'mkengg 1 su (([13, nzu s / \ oca3 oåpu / cn-cacazc-: DÖ cocf) 3 S6 505 256 7- (2- (5-amino -1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamide] -3- [3- (3-formylaminopyridinio) -1-propen-1-yl] -3-cephem-4-carboxylate (I -1F).

A mixture of 716 mg (1 mmol) of diphenylmethyl-7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamide] -3- (3-iodo-1-propylene) 1-yl) -3-cephem-4-carboxylate (IX-1) (E) and 244 mg (2 mmol) of 3-formylaminopyridine (prepared by the method of N. Enomoto 3E_§l., Bull.

Chem. Soc. Japan, 22, 2665 (1972)) in 2 ml of DMSO was stirred at room temperature for 1 hour and poured into 200 ml of ethyl acetate.

The precipitate was collected by filtration, washed well with ethyl acetate and dried. A mixture of 500 g of the quaternized salt and SO mg of sodium bisulfite in 5 ml of HCOOH was stirred for 80 minutes at 40-50 ° C and evaporated to dryness in vacuo. The residue was dissolved in water (40 ml), neutralized with sodium bicarbonate and filtered to remove insoluble matter. The clear filtrate was chromatographed on a reverse phase column, PrepPAK-500 / C18 (100 ml) with water and 5% methanol, 10% methane, 20% methanol and 30% methanol. The fractions containing the desired compound were combined, concentrated in vacuo and lyophilized to give 16 mg (2.9%) of the title compound (I-1F) (E) as a tan powder. M.p. exceeding 170 ° C (decomposition).

In = 1: 2: cm ° 1 344o (br), 1760, 1610, 1s2o (br), 1590. uv = J-fåïfatlmffert (PH "mn (sPcm) 21a (428), 248 (362), 290 (4749 una. 6 “2 ° * Na“ °° 3 3.68 (za, br, 2-H), 4.15 (sn, s, ocn3), PP ”5.91 (1n, a, J = 4 , s, 1-a), s, 2s (1a, m, cmcg-cnz) 6.98 (m, a, J = 16, a-cn trans), 8.8-7.9 (4H, m , Py-H), 9,38 (1n, br, uncgo). S? 505 256 Example 9 u U: ouu ~ r's dlL ~ § \\ I _ GD cows: 32); 5 / ocg: N z ClillC fl C fl z- C 1-6 I-16 0: 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamide] -3- [3- (3- carbamoylpyridinio) -1-propen-1-yl] -3-cephem-4-carboxylate (I-1G) To a solution of 716 mg (1 mmol) of aphenylmethyl- 7- [ε- (s-amino-1,2, 4-Thiadiazol-3-yl) -2-methoxyiminoacetamide] -3- (3-iodo-1-propen-1-yl) -3-cephem-4-carboxylate (IX-1) (E) in 2 ml of DMSO was added 244 mg (2 mmol) of nicotinamide and the mixture was stirred for 1.5 hours at ambient temperature and poured into 200 ml of ethyl acetate with stirring, the resulting precipitate was collected by filtration, the quaternized salt (500 mg) was dissolved in 5 ml of HCOOH in nä In the presence of 50 mg of sodium bisulfite and the mixture was heated for 40 minutes at 40-50 ° C with stirring and evaporated to dryness. The residue was dissolved in 40 ml of water and an insoluble solid was filtered off and washed with a small amount of water. The filtrate and washings were combined and chromatographed on a reverse phase column, PrepPAK-S00 / C18 (100 ml). After elution with water and in turn a 5 S aqueous solution, 10% 201% aqueous solution of methanol, the fractions containing the desired material were combined, concentrated in vacuo and lyophilized to give 21 mg ( 3.8%) of the title compound (I-1G) (E) as a yellow powder. M.p. exceeding 175 ° C (decomposition). 505 256 IR NMR: PPN Example 10 I-1H 1- [2- (s-amino-3- [Eph (4-carbamoylpyridinio) -1-p] epenemylate (1-111) phosphate buffer (pH 7) mn 8 ° z ° * “a“ °° 3 3,68 (za, br, zm, fi ---- CONH NÄL. N \ æ1l3 U! UI Jåíucnnf * aa-xocbr), 1160, 1570, 1600. 8 cm) 235 ( 326), 274 (Sk, 405), 290 (446). 4.15 (3H, s, OCH 3), 32 (1H, d, J = 4.5, 6-H), 5.45 (1H, a, J = 7, clwcn-cgz), 5.88 ( m, d, a = 4.5, 7-H), 6.15 (1H, dt, J = 16 & 7, 3-CH = CI_i_), 7.00 HH, d, J = 16, 3-CH trans), 8.23 (1H, m, Py-H5), 9.03 (ZH, m, Py-H4 & 6), 9.34 (1H, s, Py-H2).

J * \.

Q 1 '/ ca-cacaz-C009 r' (*, 1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamidyl-1-yl] -3-α-cephem-4-carb- To a stirred solution of 716 mg (1 mmol) of diphenylmethyl-7- [2- (5-amino-1,2,4 3- (3-iodo-1-propene-2 ml of dry DMSO) the mixture was stirred 1-thiadiazole-silyl) -2-methoxyiminoacetamide ] - 1-yl) -3-cephem-4-carboxylate (IX-1) (E) test 244 mg (2 mmol) isonicotinamide. Mix for 1 hour at room temperature and poured there. 7- [2- (S-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamide] -3- [§- (3- aminomethylpyridinio) -1-propen-1-yl7-3-cephem-4-carboxylate (I-11) A mixture of 716 mg (1 mmol) of diphenylmethyl-7- [2- (5-amino-1,2,4- thiadiazol-3-yl) -2-methoxyiminoacetamide] -3- (3-iodo-1-propen-1-yl) -3-cephem-4-carboxylate (IX-1) (E) and 516 mg (2 mmol) 3- (t-Butyloxycarbonylaminomethyl) -pyridine in 2 ml DMSO was stirred for 30 minutes at ambient temperature. The mixture was poured into 200 ml of ethyl acetate and the precipitate was collected by filtration, washed well with ethyl acetate and dried. A mixture of the quaternized salt (500 mg) and 50 mg of sodium bisulfite in 5 ml of HCOOH was stirred for 80 minutes at 40-50 ° C and evaporated to dryness under reduced pressure. The remaining solid was dissolved in 40 ml of water and the mixture was neutralized with sodium bicarbonate. Insoluble material was filtered off and the filtrate was chromatographed on a reverse phase column (filling from a PrepPAK-500 / C18 cartridge, 100 ml), eluting successively with a 5%, 20% and 30% aqueous solution of methanol. The fractions ° containing the desired compound were combined, evaporated and lyophilized to give 10 mg (1.8%) of the title compound (I-11) (E) as a tan powder. in = fi âí cm'1 33ao (br), 1760, 1sso (sk), 1s2o (sx). uv = Iš§: fàtb “ff ° rt (PH 7) (n} * cm) zas (sk, zso), zss (310). nun = c ° 2 ° * "“ “°° a 3,68 (zu, br, 2-H), 4,16 (aa. s, ocn3), PP” 6,98 (1a, a, J = 1s , 3-ca trans), a, os (18, m, Py-H5), 8.50 (13, m, Py-H4), a, so (zu, m, Py-n2'6). 256 Exemgel 12 H fouc-α / β "zymic chain J'- N co ] -3- [E- (4-Carbamoylpyridinio) -1-propen-1-yl] -3-cephem-4-carboxylate 11-1H) A mixture of 4.1 g (5.7 mmol) of diphenylmethyl-7 - [2- (5-amino-1) 2,4-thiadiazol-3-yl) -2-methoxyiminoacetamide] 7- (3-iodo-1-propen-1-yl) -3-cephem-4-carboxylate ( IX-1) E-isomer) and 1.4 g (11 mmol) of isonicotinamide in 6 ml of dry DMSO were stirred for 2 hours at room temperature under TLC monitoring (silica gel plate, CHCl 3: CH 3 OH = 3: 1).

The reaction mixture was diluted with 100 ml of ethyl acetate to separate a yellow gum, which was treated with f0fml formic acid and 390 mg of sodium bisulfite at 4S ° C for 30 minutes.

The resulting solution was concentrated to dryness. The residue was dissolved in 100 ml of water and insoluble matter was removed by filtration. The combination of filtrate and water wash was applied to the top of a column containing reverse phase filling (PrepPAK-500 / C18, 120 ml).

The column was eluted with water. The eluate was collected in 300 ml fractions and monitored by UV (254 nm) and HPLC (Lichrosorb RP-18, 4 x 300 mm, 0.01 M ammonium phosphate buffer; pH 7.2 containing 20% methanol). Fractions no. 4 and S were combined and concentrated to a small volume. Lyophilization gave 250 mg (8.1%) of the title compound I-1H, m.p. exceeding 180 ° C (decomposition). Spectra showed that the product was identical to that obtained according to Example 10.

Preparation of the hydrochloride - To a suspension of 98 mg (0.18 mmol) of compound I-18 in 1 ml of methanol was added 0.1 ml of 19% hydrochloric acid, and the mixture was stirred for 5 minutes. To the resulting yellow solution was added 100 ml of acetone to form a precipitate, which was collected by filtration, washed with 2 x 10 ml of acetone and dried in vacuo to give the hydrochloride salt of I-1H as a colorless powder. Yield 88 mg (79%). M.p. exceeding 190 ° C (decomposition).

KB! -1 Is: vmax cm 3300, 1770, 1680, 1620. _ phosphate buffer (pH 7) 1% UV _ Åhax nm (E1 cm) 227 (385), 286 (374). nun = § ° 2 ° 2.32 (1n, S, acetone-H), 3.79 (za, br-s, PP ”2-H), 4.17 an, s, ocn3), 5.34 ( 1n, d, J = 4, s, su), 5.49 (za, d, J = 7, cfhcn-cgz). 5.93 (111, a, a = 4, s, 1-H), 6.28 (1n, at, J = 1s 4 7, 3-cn = cg), 7.15 (1n; a, J fi1s, 3-cg), s, 43 to 9.1 (each 2H, d, J = 7, Py-H).

. N - ïr fi conn T 'JL \ 2-11 / * Q - nzn søf ocns of ca-cncaz- C009 ,, 3, _T¿¶_ sa 505 256 7-12- (5-amino-1,2,4 -thiadiazol-3-yl) -2-methoxyiminoacetamide-7- [3- (2-methylthiazolio) -1-propen-1-yl] -3-cephem-4-carbogylate (I-1J) r111 a mixture of 714 mg (1 mmol) alphenylmethyl- 7- [ε- (5-amino-1,2,4-thiadiazol-3-yl) -2-methiminoacetamide] -3- (3-iodo-1-propen-1-yl) -3-cephem-4-carboxylate (IX-1) (E) and 198 mg (2 mmol) of 2-methylthiazole [prepared by the method of RP Kurkjy, EV Brown, J. Am.

Chem. Soc., 11, 5778 (1952L] in 10 ml of dry CH 2 Cl 2. A§Br 4 (purity 90%, 217 ng, 1 nnoI1 was added at -zo ° C. The mixture was stirred for 30 minutes at room temperature and filtered.

The precipitate was extracted with 3 x 20 mL of 10% CH 3 OH-CHCl 3.

The combined extracts were washed with brine (2 x 5 ml), dried over magnesium sulphate and evaporated to dryness to give a yellow residue, which was triturated with isopropyl ether and filtered to give 350 mg of the quaternized product. A mixture of this solid, 35 mg of sodium bisulfite and 3.5 ml of formic acid was stirred for 30 minutes at 0 ° C. The mixture was concentrated to remove the formic acid and the residue was diluted with 40 ml of water. Some insoluble matter was removed by filtration. The filtrate was applied to a reverse phase column (PrepPAR-500 / C18, 100 ml). The column was eluted with 200 ml of water, 400 ml of a 5% aqueous solution of methanol and 300 ml of a 10% aqueous solution of methanol in turn. The fractions containing the desired product were pooled by HPLC analysis (Lichrosorb RP-18, 4 x 300 mm, 0.01 M ammonium phosphate buffer pH 7.2 containing 20% methanol). The combined solution was concentrated to a small volume and lyophilized to give 40 mg (7.7%) of the title compound (I-1J) (E). M.p. exceeding 19500 (decomposition). '64 505 256 m = v22: auf' saoo, 1760, 1sso, 1soo. (421). man = Glššgwusæds .3, os (an, s,: 1 am1-cg3), 3,74 (za, br-sy s; (18, d 'J = 4ysy 631 m; - Gps d) J = 16' trans ) | 8.04 G 8.23 (each 1H, d, J = 4, f thiazole-Q).

Example 14 S ”TE CONR-íf || N - es aznf§s / kan: / CHsCHC> 81P 82 ° a CV I-IL 'E' 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxy] iminoacet- = m1d§7-? f13- <4 + h ¥ fi f ° * 1 @@ fYlP ¥ r1ê4 fl49> f1-P # ° Penf1- ¥ L7f? - cefem fi decarboxylate '(1-1L). "' ''“ '' En mixture of 1.07 g (1.5 mmol) of diphenyl-7- [E- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamide] -3- (3-iodo-1 -propen-1-yl) -3-cephem-4-carboxylate (IX-1) (E-isomer) | 818 mg (7.5 mmol) of 4-hydroxymethylpyridine 1 4.5 ml of CH 3 CN and 3 ml of methanol were stirred at room temperature After removal of the solvents by evaporation, the residual oil was triturated with isopropyl ether, collected by filtration and washed with 10 ml of a 3: 1 mixture of isopropyl ether and ss 505 256 methanol to give 1.28 g of the A solution of the quaternized ester (1.25 g) and 600 mg of sodium bisulphite in 10 ml of 85 S HCOOB was stirred for 1 hour at room temperature under a nitrogen atmosphere. -ig HCOOH omr the mixture was stirred under the same conditions for another 1 hour. Toluene was added and the reaction mixture was azeotroped under reduced pressure. The residue was triturated with acetone to give 1.17 g of the crude formate of the title T compound. A suspension of this compound (1.15 g) in 100 ml of water was filtered to remove insoluble matter, which was washed with 2 x 10 ml of water. The filtrate and washings were combined and subjected to reverse phase column chromatography. The column, which was filled with the filling from a (prepPAK-500 / C18 cartridge (Waters) 60 ml), was developed successively with water, 5% methanol and 10% methanol. The fractions containing the desired compound were combined, concentrated under reduced pressure and precipitated by the addition of acetone to give 100 mg of the title compound (I-1L) as a pale yellow powder. To a suspension of the powder (90 mg) in 9 ml of methanol was added 0.5 ml of 1N HCl in methanol, and the mixture was stirred at room temperature and concentrated in vacuo. To the concentrate was added isopropanol to precipitate 77 mg of the hydrochloride of the title compound as a pale yellow powder.

M.p. exceeding 190 ° C (decomposition). rn = road; cm'1, 1775, 1670, 1635, 1s3o.

UV - phosphate buffer (pH 7) * max nn te), 230 (zzsoo). 264 (sn, 16300) una 8D2 ° ppm 3.83 (23, br. 2-CH), 4.17 (3H, s, OCH3), .06 (zu, s, 2) gzon), 5.36 ( 1n, d, J = 4, s Hz, 6-H), 5.41 (zn, d, J = 7 Hz, cH = cH-cgz). , 94 (1n, a, a = 4, s az, 1-a), s, 36_11n, at, 66 505 256 J = 1s and 7 az, cuægcnz), 7.13 (m, a, J-1s Hz , C§ = CH-CH2), 8.08 and 8.83 (each ZH, d, ag? Hz; Py-n) o Example 15 fm \ s Conny “ÄÄca-: caCHENO-CONH; 1- [1- (5-Amino-1,2,4-thiadiazol-3-yl) -2-ethoxyiminoacetamide] -3-13- (4-carbamoylpyridinio) -1-propylene -1-yl] -3-cephem-4-carboxylate (I-23) To a solution of 200 mg of 7-amino-3- [3- (4-carbamoylpyridinio) -1-propylene-3- yl] -3-cephem-4-carboxylate hydrochloride (E-isomer) in 5 ml of a 50% aqueous solution of acetone was added portionwise 190 mg of 2-ethoxyimino-2- (5-amino-1,2,4- thiadiazol-3-yl) acetyl chloride hydrochloride (prepared by the procedure described in Japanese Patent Application Laid-Open (Kokai) 57-24389 (2/8/82)) and the mixture was adjusted to pH § 5- 7.0 with 2 N sodium carbonate (about 1 ml).

The reaction mixture was stirred at 10 ° C for 1 hour, acidified to pH 2 with 1 N hydrochloric acid and evaporated in vacuo. the residue was filtered and the filtrate, chromatographed on a column of BP-20, which was eluted successively with 500 ml of water and a 25% aqueous solution of isopropanol.

The fractions containing the desired product were combined and evaporated under reduced pressure. The oily residue was treated with 20 ml of isopropanol to give 263 mg (93%) of the title compound (I-23). 67 505 256 M.p. 170 ° C (dec.).

To a stirred suspension of 225 mg (0.40 mmol) of the above zwitterion in 10 ml of methanol was added 1 ml of 1 N hydrochloric acid in methanol, and the mixture was stirred for 30 minutes at room temperature. The solution was filtered and concentrated under reduced pressure. To the residue was added 15 ml of isopropyl alcohol, and the resulting precipitate was collected by filtration and dried in vacuo to give the title compound as its hydrochloride.

Yield 146 mg (57%). M.p. 160 ° C (decomposition). Estimated purity 65%.

In = road: cm'1, 3330, 1780, 1680, 1620.

UV: ligate buffer (pH 7) nm (¿), 227 (223O0) '288 (zzaoo). nun = c ° 2 ° 1.44 (sn, t, J = 7 az, ocaz-c§3). 3.74 (zu, PP ”br. S, 2-H), 4.45 (zu, q, J = 7 Hz, ocgz-cn3), s, 36 (1a, a, J = 41s nz, 6- H), 5.46 (zu, d, af? Az, 3-cn = cs-cgz), 5.92 (13, a, J = 4, s Hz, 7-H1, 6.2o (1n, m , 3-cu = cg), 1.04 (1n, a, J = 16 Hz, 3-c§ = cn), s, 43 (za, a, J = 7 Hz, .Py-HA), 9, (Za, a, a = 7 az, Py-aa). Nxegggl 16 '7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetavidsi-Bffêf < This example shows the preparation of compound I-18 via the final step of Reaction Scheme 1a or 1b, where the intermediate is used to evaporate the carbon dioxide carboxylate (I * 1H2 (E-isomer). benzhydryl-7 - [[- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamide] -3- [3- (4-carbamoylpyridinio) -1-propen-1-yl] - 3-Cephem-4-carboxylate formate (XXVII-1H) 68 505 256 is isolated.

A. Benzhydryl 7 - [[- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamide] 3- [3- (4-carbamoyl-1-pyridinio) -1-propylene] 1-yl] -3-cephem-4-carboxylate-formate (E isomer) zxxyrx-1u) V A solution of 34 g (758 purity) XII-1H (fa = fa, E-isomer) in 200 ml of a 1: 1 mixture of acetone and methanol was applied to a column of Amberlite. IRA-410 (formate form 340 ml). The column was eluted with the same solvent system.

The first fraction (1 liter) was evaporated to about 100 ml by volume and the brown residue was triturated with 400 ml of isopropyl ether. The resulting powder was collected by filtration and dried in vacuo to give 299 (75% purity by HPLC) of the title compound XXVII-1H (E-isomer) as a brown powder, m.p. exceeding 150 ° C (decomposition).

KBr -1 IR: Q cm max 3300, 1780, 1680, 1630, 1600. uv = Aâšïn nm (E '*) 282 (186).

NHR: Jshaton-de / CH 3 OH-d4 (1 / I? ¿, ° (3H 'S' OCE3), 5.26, (1H, d, J = 4.5 H2, 6-H), 5.43 ( 2H, d, J = 7 az, cgzrf), 5.99 (m, d, J = 4.5 Hz, 7-H), 6.5 (1H, m, 3-CH = C§), 6, 92 (1H, s, C§Ph2), 7.1 (1H, d, J = 16 Hz, 3 * C§), 7.35 (1on, m, vn-g), s, 3s (1a, S , gcoo), 8.46 & 9.12 (28 each, d, J = 8 Ez, Py-H).

B. 7-Ia- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- [3- (4-carbamoyl] -1-pyridinio) -1-propen-1-yl ] -3 cephem-4-carbogylate (I-1H) (E-isomer) ~ ï A mixture of 29 g (75% purity) XXVII-1H (E-isomer) from 69 505 256 step A and 290 ml 85% formic acid stirred for 2 hours at room temperature. Evaporation of the mixture gave a brown oil, which was triturated with 500 ml of acetone. The powder was collected by filtration, washed with 2 x 100 ml of acetone and dried in vacuo to give 24 g (508 purity by HPLC) of the title compound as a crude product. The brown solid was treated twice with 1 liter and 0 ml. The aqueous extracts were combined and applied to a column filled with Diaion HP = 20 (1.5 L). The column was washed with 8 l of water and eluted with 5 l of 3% methanol. The fraction containing the desired product was evaporated to about 30 ml, the concentrate was treated with 200 ml of acetone to give a precipitate, which was collected by filtration and dried in vacuo to give 10.1 g (8S% purity) of the title compound. To a suspension of this product in 100 ml of methanol was added 1 N HCl in 55 ml of methanol at room temperature and the mixture was stirred for 30 minutes. The resulting clear solution was filtered to remove insoluble matter. material, co was concentrated to about 50 ml of the volume and precipitated with 200 ml of isopropanol. The resulting powder was collected, washed with 50 ml of isopropanol and dried in vacuo to give 10.5 g (858 purity) of the title compound I-18 (E-isomer) (HCl salt), m.p. exceeding 180 ° C (decomposition). Pale yellow powder. z-nšempg '1 i 11 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacet-wi-ël-ßfßf <4f1 = ## b @ m °> r1PY ¥ 1 @ # fl1 P> -f1-P = F ° P = f = f1- ¥ U - = - oefem-4-carboxylate (I-1H) (B-isomer) "''“ This example shows the preparation of compound I-1H via the final steps of Reaction Scheme 1a or 1b, isolating the intermediate XXVII-1H (formate) gI 50 505 256 A solution of 27.6 g (38, 5 mmol) of IX-1 (E-isomer) and 22.8 g g (187 mmol) of isonicotinamide in a mixture of 120 ml of CH 3 CN and 100 ml of methanol were stirred for 1 hour at room temperature under a nitrogen atmosphere After trituration of the organic solvents, the oily residue was triturated with isopropyl ether to give 50.5 g of a mixture of the quaternized salt and isonicotinamide A solution of the mixture (SO 3 9) and 16 g of sodium bisulfite in 160 ml of 85 8 HCOOH was stirred for 40 minutes at room temperature and then for 1 hour at 40 ° C under nitrogen.

The mixture was evaporated in vacuo. The residual oil was mixed with 50 ml of toluene, azeotroped and triturated with 400 ml of acetone to give 27.8 g of the title compound as a crude product.

This material was treated twice with 2 N HCl (1 L and 0.5 L). The acid extracts were combined and applied to a column of HP-20 resin (1.5 L). The column was eluted with 9 l of water and 10 l of 30% methanol. The fractions containing the desired compound were combined and concentrated to give a yellow oil, which was triturated with 300 ml of acetone to give 9.35 g of the zwitterionic form of the title compound; To a suspension of the product (9.3 g) in 180 ml of methanol was added 1 N HCl in methanol (55 ml) to obtain a clear solution. The solution was concentrated to about 100 ml and diluted with isopropanol to precipitate 9.50 g (purity 75%) of the title compound I-1H (B-isomer) as its hydrochloride. Pale yellow amorphous powder with a snp. exceeding 195 ° C (decomposition) .. new- 1 'ia 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamino] -phosphine + Pf ° Pe: = * 1 + YV-2-f cefene fl á fl carboxylate (I-18) (E-isomer) 'This example shows the preparation of the compound I-1H 71 505 256 via the last step (7-N-acylation) in reaction scheme 1c.

To an ice-cooled suspension of 5.0 g (12.6 mmolJ of the 7-amino-cephem hydrochloride XXII-H (E-isomer) in 100 ml of an SO 8 -8 aqueous solution of acetone was added sodium bicarbonate in small portions. to the cold neutralized solution (pH about 7) was added 4.0 g (15.6 mmol) of 2- (5-amino-1,2,4-thiadiazol-3-yl) to the cold neutralized solution. -2-methoxyiminoacetyl chloride hydrochloride in small portions over a period of 1 hour and the pH of the reaction mixture was kept in the range of 6.8-7.5 by addition as needed for sodium bicarbonate.

The reaction was also monitored by tlc. After all compound XXII-H had been consumed, the mixture was acidified to pH 3 by the addition of 2 N hydrochloric acid. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was diluted with 400 ml of acetone to separate the precipitate, which was collected by filtration to give 9.59 g of the title compound as a crude product in the form of a light yellow powder.

Estimated purity 40% by HPLC. A suspension of the crude product (9.5 g) in 150 ml of 2 N hydrochloric acid was filtered and the filtrate was adsorbed on a column of 500 ml of HP-20 resin. After washing with 1.5 L of water, the column was eluted with a 25% aqueous solution of isopropyl alcohol and the eluate was collected in 100 ml fractions. The desired fractions were pooled, acidified with 10 ml of 2 N hydrochloric acid and concentrated. The residual oil was triturated with 200 ml of isopropyl alcohol and the precipitate was collected by filtration. After drying over phosphorus pentoxide, 18 g of the hydrochloride of the title compound X-18 (E-isomer) were obtained as a yellow amorphous powder. M.p. exceeding 190 ° C (decomposition). Estimated purity 75%. Purification and Crystallization of Compound I-1H (E-isomer) Compound I-1H hydrochloride obtained in Example 16 was a pale yellow amorphous powder having a purity of 85%.

Process 16 g of the hydrochloride having a purity of 85% were dissolved in 20 ml of water and filtered through a pad of celite. The amber: colored filtrate (pH 2) was passed through a reverse phase column (fill from a prepPAK-500 / C18 cartridge, Waters; 120 ml), which was eluted with water. The eluate was collected in 120 ml fractions under HPLC monitoring. Fractions 3-5 were combined and concentrated in about 10 ml and precipitated with 100 ml of acetone to give 3.3 g of the zwitterionic form of I-18 (pale yellow amorphous powder; estimated purity 95%). To a suspension of the powder with a purity of 95% (3.2 g) in 32 ml of methanol was added 1 N HCl in 18 ml of methanol and the mixture was stirred at room temperature until a clear solution was obtained. The solution was filtered and the filtrate was concentrated to about 10 ml. To the concentrate was added 100 ml of isopropanol to separate a pale yellow precipitate, which was collected by filtration, washed with 5 ml of isopropanol and dried to give 2.6 g of the HCl salt (amorphous powder; estimated purity 95%).

A solution of the hydrochloride with a purity of 95% (1 g) in 4 ml of water was adjusted to pH 6.5 with 200 mg of sodium hydrogen carbonate and stirred for 30 minutes. The crystals which separated with stirring were collected by filtration, washed with 2 x 5 ml of water and dried in vacuo to give 710 mg of I-1H (zwitterionic form) which was bleached under reduced pressure to obtain 170 mg (80% recovery) of pale yellow prisms of I-18 (zwitterionic form) with a m.p. exceeding 185 ° C (decomposition), which was identical to that obtained by Method 1 (which could be shown by IR, UV and NHR).

The crystalline zwitterionic form of compound I-1H was sparingly soluble in water (6 mg / ml in saline at 23 ° C).

Exemggl 20 S NF - íTï @ \ CONB --- T 8203 'n G / "- n 1' _- 32 * s / N OCR: 0 / Gå CB-CB-Cßz I-1! * E 7- [ α- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamide] -3- [3- (3-hydroxymethylpyridinio) -1-propenyl] -3-cephem-4-carboxylate (I -1K) (E-isomer) A. Diphenylmethyl-7- [7- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamide] -3- [3- (3 -hydroxymethylpyridinio) -1-propenyl-3-cephem-4-carboxylate iodide (E-isomer) - (XII-HK) + For a solution of 1.79 g (2.5 mmol) of IX-1 (E -isomer) in 2.5 ml of methanol and 7.5 ml of CH 3 CN was added 545 mg (5 mmol) of 3-hydroxymethylpyridine and the mixture was stirred for 3 hours at room temperature. The reaction mixture was poured into 100 ml of ethyl acetate with vigorous stirring. The resulting precipitate was collected by filtration, washed with a small volume of ethyl acetate and dried to give 2.06 g (100%) of the title compound XII-1K as a brown powder. M.p. 170-180 ° C (dec.). 505 256 (nar) 1 = m'1 1vao, 1725, 1615, 1515, 1530, 1355, 1225, 1o4o, vso, voo.

IR: mamax A (c a ou) 1 n 121 * 1 290 (196). max 25 m 1 cm 2 NMR δ (DMSO + D 2 O) in ppm 3.7 (ZH, br.s, 2-H), 3.91 (3H, s, OCH 3), 4.70 (2H, s, Py-C§2- ou), 5.28 (zu, m, cuz-N *), 5.23 (1H, d, J = 5HZ, 6-H), 5.90 (1H, Ö, J = 5Hz, 7-H), 6.34 (1H, m, - 3-CH = C§); P6.86 (1H, d, J = 16 Hz, 3-CH), 6.89 (1H, S, CHPh2) | 7.35 (TUH, m, Ph "H) and 7.9" 8.9 (Å: m: Py-H).

B. 7- [2- (5-Amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamide] -3- [3- (3-hydroxymethylpyridinio) fipropenyl] -3-cephem-4 Carboxylate (I-1K) (E-isomer) A mixture of 2.0 g (2.4 mmol) of XII-1K (E-isomer) and 1 g of sodium bisulfite in 10 ml of 85% HCOOH was stirred. 2 hours at room temperature. The reaction mixture was concentrated to about 5 ml under reduced pressure. The oily residue was poured into 100 ml of acetone with vigorous stirring.

The precipitate was collected by filtration, washed with a small amount of acetone and dried to obtain 1.1 g of a brown powder, which was purified by column chromatography (using the filling from a PrepPAK-S00 / C18 cartridge (Waters)) to obtaining 283 mg (22%) of I-1K as an amorphous powder. The powder was crystallized from 48 sulfuric acid and acetone to give 144 mg of the title compound I-1K as colorless needles. m.p. 155-1sa ° C (sonar eel). 1 1775, 1saosn, 1sso, 1630, 1225, 1045, 850.

IR: λ (KBr) in cm -1 + 76 505 256 1% UV 1 cm 1 (phosphate buffer, pH 7) 1 nm (λ max 1 236.5 (233) 275 sh, (280), 292.5 (330) .

NMR: δ (D 2 O) δ ppm 3.75 (28, s, 2-H), 4.18 (3H, s, OCH 3), 4.97 (za, S, Py-cgzone), 5.35 (1H , a, J = 4az, 6-H), 5.43 (za, a, J = 6, suz, cnz-N *), 5.92 (1n, a, J = 4az, 7-H), 6 , 16 (1H, at, J = 16nz, J = 6, snz, 3-cn = cg-), 6.91 (1n, d, J = 16uz, 3-ca), 6.13 (1n, dd, J = sHz, J = 6Hz, vy-H), 3.60 (1H, d, J = a, nz, py = H), a, s4 (1n, a, J = 6az, Py-H), 8 90 (1H, s, Py-H).

Example 21 s _ NI ü coun F ”_ Ä LN / fN / '3 Q 8 N 5, / \\ ° cg3 0 / cncn-cn¿- ouacaz 2 cooe _ 1-in * B _ 7- [2- ( 5-Amino-1,2,4-thiadiazol-3-yl) -2- (Z) -methoxyiminoacetamide] -3- [3- (4-N-methylcarbamycylpyridinyl-1-propenyl] -3-cephem-4-carboxylate (I-1M) (E-isomer) A mixture of 450 mg (0.62 mmol) of diphenyl-7- [E- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamide] -3- (3-iodo-1-propenyl) -3-cephem-4-carboxylate (IX-1) (B-isomer) and 215 mg (1.58 mmol) of 4-N-methylcarbamoylpyridine [ prepared by the method of M. Samejima, Yakugaku Zasshi, QQ, 1706 (1960) J in 2 ml of acetonitrile was stirred for 5 hours at room temperature under a nitrogen atmosphere, the mixture was evaporated under reduced pressure and the residue triturated with ether to give 530 mg of the quaternary A mixture of the solid material and 150 mg of sodium bisulfite 71 505 256 in 2 ml of 85 S-formic acid was stirred for 4 hours and then heated for 30 minutes at 40 ° C. The mixture was evaporated under reduced pressure. triturated with acetone and the crude product was collected by filtration. The crude product was chromatographed on a column of HP-20 (1.5 x 18 cm) and the column was eluted with water and a 30% aqueous solution of methanol. The methanolic eluate was evaporated under reduced pressure and the residue was lyophilized to give 140 mg of an amorphous powder which was further purified by HPLC (column: Lichrosorb RP-18, solvent:% methanol) and the eluate from HPLC was lyophilized to give 60 mg (18 %) of the title I-1M. M.p. 180-183 ° C (dec.). Estimated purity: 80%. 1 m = v (mar) 1 cm '1760, 1660, 1600. ma! UV: λmax (phosphate buffer, pH 7) in nm (C) 230 (22100), 286 (22100).

NMR: MDZO) δ ppm 3.08 (3H, s, CONHCg3), 3.72 (2H, s, 2-H), 4.16 (33, s, OCHB), 5.35 (1H, d, J = 4.5Hz), 6-H), 5.95 (1H, d, J = 4.5Hz, 7-H), 7.00 (1H, d, J = 16Hz, 3-CH), 8.35 (2H, d, J-6Hz, pyridine-H), 9.05 (2H, d, J = 16Hz, pyridine-H).

Exeæel 22 lill J ”com; . Q nzu s bena C009 cs-ca-cnz-Q-coon I-1H * E / 2 I 7 / I 78 505 256 7- (2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamide] -3- [3- (4-carboxypyridinio) -1-propenyl] -3-cephem-4-carboxylate (I-1N) To a stirred suspension of 340 mg (2.8 mmol) of isonicotine acid in 3.5 ml of dry DMF was added 0.7 ml (2.8 mmol) of N, O-bis- (trimethylsilyl) acetamide under a nitrogen atmosphere To the resulting clear solution was added 720 mg (1 mmol) of diphenylmethyl. - [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamide] 3- (3-iodo-1-propenyl) -3-cephem-4-carboxylate (IX-1 (E-isomer) in one portion and the red solution was stirred for 1.5 hours - at room temperature The reaction mixture was added dropwise to a stirred saturated sodium chloride solution (SO ml) containing 150 mg of sodium thiosulphate, the yellow precipitate was collected by filtration. was washed with water and dried to give 722 mg of a pale yellow powder, the powder (700 mg) and sodium bisulfite (70 mg) were dissolved in 5 ml of 85% formic acid and the solution was allowed to stand for 1.5 hours. d room temperature. The mixture was suspended in 50 ml of toluene and concentrated. The residue was triturated with 70 ml of acetone and the precipitate was isolated by filtration to give 421 mg of a yellow powder. This crude powder (400 mg) was suspended in 2 ml of water and to the suspension was added sodium bicarbonate. The resulting dark solution was adsorbed on a column containing SO ml filling from a PrepPAK / C18 cartridge (Water's System 500) and the column was eluted with 200 ml of water. The eluate was fractionated into ten "fractions (20 ml each) and the desired fractions (fractions Nos. 4-7) were combined, acidified to pH 3 with 2N hydrochloric acid and concentrated. The residue was triturated with 30 ml of acetone and the precipitate was collected by filtration to obtain of 201 mg (37%) of the title compound I-1N as a yellow powder.

E / 2 = 7/1; 80% purity. M.p. exceeding 189 ° C (decomposition). 79 505 256 n:: vmx (xsr) 1 om "1710, 1sss, 1soo.

UV: Ämax (phosphate buffer, pH 7 = 1 nm (å) 227 (22S00), 290 (22100).

NHR: δ D 2 O + NaHCO 3) in ppm 3.7 (28, br.s), 4.15 (BH, s), 32 (1H, d, J = 4H 2), 5.39 (2H, d, J = 6H2), 6.14 (18, dt, J = 15.5 and GHz), 7.03 (18, Ö, J = 15.5Hz), 8.31 (ZH, d, J = 7Hz), δ 94 (2H, d, _J = 7Hz).

Example 23 Com: --- (ss / N n; -2- (Z) -Methoxyimino-acetamide] -3- [3- (2,3-cyclopentenopyridinio) fipropenyl] -3-cephem-4-carboxylate (I-10) ~ (E-isomer) of 450 mg (0.62 mmol) of diphenylmethyl- 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamide] -3- (3-iodo-1-propenyl) -3-Cephem-4-carboxylate (IX-1) (E-isomer) and 217 mg (1.83 mmol) of 2,3-cyclopentenopyridine in 2 ml of acetonitrile were stirred under a nitrogen atmosphere for 4 hours at room temperature. the mixture with ether to give 560 mg of the atequaternary salt A mixture of the solid and 2 ml of 85% formic acid was stirred for 3 hours under nitrogen at room temperature and then heated for 30 minutes at 40 ° C. The mixture was evaporated under reduced pressure and trituration of the residue gave 391 mg of crude product, which was purified by chromatography on a column of 80 505 256 HP-20 (1.5 x 18 cm). and an 8-g aqueous solution of methanol. Evaporation of the methanolic eluate under reduced pressure, followed by freeze-drying gave 160 mg of an amorphous powder, which: was further reconstituted by HPLC (column: Lichrosorb, solvent: 10% methanol). The eluate from HPLC was lyophilized to give 50 mg (15%) of the title product I-10. M.p. exceeding 190 ° C (decomposition). Estimated purity: 75%.

IR = u (kbr) 1 cm -1 nes, 1670, 1eoo. max max: UV max (phosphate buffer, pH 7) in nm (E) 235 (2000O), 283 (25000).

NMR: δ (D 2 O + NaHCO 3) δ ppm 2.2-2.6 (2H, m, -CH 2 -), 3.1- 3.6 m 'fs', 33 d 'J = 4fsnzf 5190 d' J = 4p5Hz | 6.75 (18, d, J = 16Hz, 3-CH), 7'65-8 | 2 m 'Example 24 Jm gi mgiís 52 "5 / ° / ca-cn-cn 9 I 2 008 I-28 ís a1 505 256 7- [2- (5-amino-1,2,4-thiazolazol-3-yl) -2- (z) -ethoxyiminoacetamide] -3- [3- (4-carboxypyridinio) -1-propenyl] -3-cephem-4-carboxylate (1-ZN, E-isomer) and 7-α- (s-amino-1,2,4-ciadiazol-3-yl) -2- (z) -ethoxy] amino-acetamide ] -3- [3- (4-Carboxypyridinio) -1-propenyl] -3-cephem-4-carboxylate (I-2N, Z-isomer) To a cooled mixture of 1.0 ml (4.12 mmol) of BSA and To 506 mg (4.12 mmol) of isonicotinic acid was added 1.0 g (1.37 mmol) of IX-2 (from Preparative Example 21) and the mixture was stirred for 2 hours at room temperature under nitrogen. The mixture was poured into 20 ml of 10% Na 2 S 2 O 3 To precipitate 1.3 g of the quaternary salt, which was collected by filtration, washed with water and dried, a mixture of the solid and 0.3 g of sodium bisulfite in ml of 98% formic acid was heated for 1 hour at 40 °. C and evaporated under reduced pressure, the residue was triturated with acetone and filtered to give of 900 mg of crude product (E-propenyl isomer: Z-propenyl isomer = 2: 1). Separation of the isomers was performed by HPLC (column: Lichrosorb, solvent, 15% methanol). The fast moving fractions from HPLC were collected, evaporated under reduced pressure and lyophilized to give 44 mg (yield 6%) of the E-propenyl isomer of I-2N. The slower fractions gave 32 mg yield (4%) of the Z-propenyl isomer of I-2N in a similar procedure.

I-2N, E-isomer m.p. > zoo ° c 1söna.) -1 u txnræ 1 cm 1765, 1sso, 1620, 1380.

IR UV νmax (water 1 nm (8) 228 (22200), 291 (23600). 82 505 256 una = Stnzo) 1 ppm 1.45 (sa, c, J = saz, ca2cg3), 3.72 (23, s, 2-H), 4.45 (28, q, CQZCHB),, 40 (1n, a, a = 4nz, 6-a). 5.90 (13, d, J = 4n =, 7-H), 7.05 (1n, a, J = 15az, 3-CH), 8.30 (ZH, d, J = 6Hz, Py-H ), 8.95 '(2H, a, J = snz, Py-H).

I-ZN, Z-isome; mp => 20 ° C (Sun.) IR; Qmax (KBr) and Ciif1-v1760; "1660 (sk), 1620, 1370.

UV: Åmax (phosphate buffer, pH 7) in nm (¿) 225 (22400), 275 (Sh, 16000). nun = Stbzo) 1 ppm 1.45 (35, c, J = 7uz, cn2c§3), 3.50 (1u, a, J = 17nz, 2-H), 3.15 (1a, a, J = 17nz, 2-H), 5.38 (1n, a, J = 4az, 6-H), 5.55 (1a, a, J = 4nz, 7-H), 5.52 (1n, a, J = 11nz, 3-ca), 8.35 (zu, a, J = enz, Py-H), 8.92 (2H, d, J = 6Hz, Py-H).

Exegggl 25 41.8 M1. ~. . , 828 S / N \ 9 94'- / ç8-CB-C82- © .'ç0p | g2 _08: -CHIC82 C005) "I-38 * E aa 505 256 7-12- (amino-1,2,5 -thiadiazol-3-yl) -2- (propen-3-yloxyimino) -acetamide] -3- [3- (4-carbamoylpyridinio) -1-propenyl] -3-cephem-4-carboxylate (I-3H) ( E-isomer) To a solution of 35 mg (0.08 mol) of 7-amino-3- [3- (4-carbamoylpyridinio) -1- (E) -propenyl] -3-cephem-4-carboxylate hydrochloride in 2 ml of a 50% aqueous solution of acetone was added 52 mg of 2- [β-amino-1,2,4-thiadiazol-3-yl)] - 2- (propen-3-yloxy-imino) Acetyl chloride hydrochloride (from Preparation Example) and the mixture were adjusted to pH 6.5-7.0 with 2N sodium carbonate, the mixture was stirred for 1 hour at room temperature, acidified to pH 2 with 1N hydrochloric acid and concentrated under The residue was chromatographed on a column of HP-20 resin, eluting with 300 ml of water and% CH 3 OH-H 2 O. The fractions containing the product were combined and evaporated under reduced pressure. The residue, 73 mg, was purified on a column of reverse phase carrier, which was removed ur and PrepPAK-S00 / C18 column (Waters, 30 ml). The column was eluted successively with water, 5% methanol, 10% methanol and 20% methanol. The fractions containing the product were combined and lyophilized to give 26 mg (62%) of the title product I-3H. M.p. 160 ° C (decomposition). 1 in = v (xßr) 1 cm "34oo, 1765, 1sso, 1sos, 1400. max Ä (barrel buffer, pH 7) in nm ¶6) 226 (24600), 288 UV max (22800).

NHR: δ (D 2 O) in ppm 3.75 (ZH, s, 2-H), 5.41 (1H, d, J = 5Hz, sH), s, so (4a, m, cnzu * a ca = cg2 ), V, 98 (1H, d, J = 5Hz, 7-H), 6.20 (1H, m, 3-CH = C§), 7.09 (1H, Ö, J = 17H2, 3-CH ), 8.59 (2H, d, J = 7H2, Py-H), 9.16 (2H, d, J = 7Hz, Py-H). w 32 "/ l1 ~ s / l! ÉL \ ïa then 84 505 256 Example 26 C088- s.

I-_ N f n. G / \ n? - [5-Amino-1,2,4-thiadiazol-3-yl) -2-propargyloxyimino-acetamide] -3- [3- (4-carbamoylpyridinio) -1-propenyl] f3-cephem-4-carboxylate (I-4H) (E-isomer) To a solution of 86 mg (0.19 mmol) 7-amino-3- [3- (4-carbamoylpyridinio) -1- (E) - propenyl] -3-cephem-4-carboxylate hydrochloride (XXII-H) in 2 ml of a 50% aqueous solution of acetone was added 63 mg of 2-propargyloxyimino-2- (5-amino-1,2,4-thiaziazole -3-yl) -acecylchlorohydrochloria (from Preparative Example 26). The suspension was maintained at pH 6.5-7.0 with 2N sodium carbonate and stirred for 1 hour at room temperature. The reaction mixture was acidified to pH 2 with 1N hydrochloric acid and concentrated in vacuo. The residue was diluted with 30 ml of water, neutralized with sodium bicarbonate and filtered. The filtrate was transferred to the top of a column packed with reverse phase support (30 ml) taken from a PrepPAK-500/18 cartridge (Waters). The column was eluted sequentially with water, 5% methanol, 10% methanol and 20% methanol. The fractions containing the product were combined and lyophilized to give 13 mg (12%) of the title product I-4H. Estimated purity 70%.

M.p. 160 ° C. 1 In = 0 (nar) 1 cm -1 3400, 2120, 11ss, 1sao, 1610. måX 2-5 »as 505 256 (phosphate buffer, pH 7) 1 nm (E) 229 (24000) 288 (21200).

UV: lmax man = unzo) 1 ppm 3.78 (za, s, zu), 5.15 (za, d, J = 1nz, -cgz-cšcn), 5.40 (m, d, J = snz, m.p., 50 (zu, m, cg-N), 5.98 (m, d, J = 5nz, 7-11), 6.20 (m, m, 3-cn = cg), 7.05 ( m, d, J = 17az, a-cg), 0.50 (za, d, J = 7nz, Py-m, 9.16 (zu, d, J = 7az, Py-u).

Exegggl 27 - Û / cH-Ca-CaENÖ- comaz de-x-sn * z 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-cyclopentyloxyimino-acetamido] - 3- [3- (4-Carbamoylpyridinio) -1-propenyl] -phosphine-4-carboxylate (I-SH) (E-isomer) To a stirred solution of 139 mg (0.31 mmol of 7-amino-3- [ 3- (4-Carbamoylpyridinio) -1-propenyl] -3-cephem-4-carboxylate hydrochloride in 3.5 ml of a 50% aqueous solution in an ice-cold bath was added portionwise 120 mg 10.44 mmol) 2- (5-amino-1,2,4-thiadiazol-3-yl) -2-cyclopentyloxyiminoacetyl chloride hydrochloride (from Preparative Example 27). The mixture was adjusted to pH 6.5-7.0 with 2N sodium carbonate (0.9 ml) and stirred for 1 hour at 10 ° C. The reaction mixture was acidified to pH 2 with 1N HCl and evaporated under reduced pressure. The residue was chromatographed on a column of HP-20 resin (20 ml) and eluted successively with 300 ml of water and 30% CH 3 OH-H 2 O. The fractions containing the product were combined and concentrated in vacuo. The residue was treated with 60 ml of acetone to give 111 mg (83%) of the title compound I-SH. 86 505 256 M.p. 160 ° C (dec.). Estimated: unit 70%. 1 xn = v¿ax (nar) cm 'sann, 1170, 1sao, 1605, 1s3o.

UV: substance (phosphate buffer, pH 7) 1 nm (5) 224 (23300), 286 124600). una = 6 (nuso-ds) 1 ppm 1.70 (sa, br.s, H- (]). 4.68 (1u, n sms, w), s, os nu, a, J = sHz, o 6-H), 5.30 (zu, m, cn 2 N *), 5.67 (1n, dd, J = 5Hz & 7Hz, 7-H), 6.20 (1H, m, 3-cn = c§ >, 7, oa (1n, a, J = 1vn =, 3-ca), 8.34 (za, d, J = 7nz, Py-H), 9.11 (zu, d, J = 7Hz, Py -H), 9.38 (1H, d, J = 7Hz, 7-NH). __ Exemggl 28 CBZCOOH s u --- T- couu- ... W / '. UznJLs / I' ocu, ä'- [1- (5-Amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamide] 3- [3- (3-carboxymethylpyridinio) -1fp; 9psny;] - Qfcçfepfdfkatt-_ggylate (I-1P) (E-isomer) '""' '' '* “A. Diphenylmethyl1-7- [2- (S-amino-1,2,4- thiazolazol-3-yl) -2-methoxyimipoacetamide] -3- [3- (3-cycloxyethylpyrethyl) or propylene; 1-3-cephem-4-carboxylate (XII-TP-type dipid, 'E-isomer) To a suspension of 0.89 g (5 mmol) of 3-carboxymethylpyridine hydrochloride in 10 ml of CH 2 Cl 2 was added 4.97 ml (18 mmol) of 505 256.

N, O-bis (trimethylsilyl) acetamide and the mixture was stirred at room temperature until a clear solution was obtained. To the solution was added 1.79 g (2.5 mol) of IX-1 and the mixture was allowed to stand at room temperature. After 3 hours, 3 ml of methanol was added to the cooled mixture, and the solution was evaporated in vacuo to give an oil, which was triturated with ethyl acetate to give 2.28 g of the title compound XII-1P as a brown powder. M.p. 161 ° C (dec.).

In = vma¿ '(xsr> 1 cm'1 1780, 1720, 1s7s; f1s3o, 1530, 1385, 1225, 1045, vss, voo.

UV: δ 1% max (C 2 H 5 OH) 1 nm (E1 cm) 295 (188).

1 H NMR: δ (DMSO + D 2 O) in ppm 3.70 (2H, br.S, 2-H), 3.90 (SH, S, OCH 3 & Py-CH 2 CO), 5.25 (3H, m, - cnzu * 2 6-H), 5.92 (1u, d, J = 4, snz, 7-H), 6.35 (1a, m; 3-cn = cg-), 6.90 (1n, a J = 1eaz, 3-ca), 6.92 (1n, S, cnpnzx; 7.35 (1on, m, Ph-H), 8.8-9.0 (4n, m, o B. 7- [2- (5-Amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamide] -3- [3- (3-carboxymethylpyridiniol] propylphenyl] -3-cephem-4-carboxylate (I-1P isomer® A mixture of 2.28 g of XII-1P (iodide) and 1.1 g of sodium bisulfite in 10 ml of 85% HCOOH was stirred for 2 hours at room temperature. The reaction mixture was concentrated to about 5 ml under The oily residue was triturated with 100 ml of acetone to give 1.22 g of crude product, which was purified by column chromatography (HP-20, 420 ml) to give 533 mg of the title compound I-1P (38 % starting from IX-1) as a pale yellow amorphous powder, mp 165 ° C (dec.) 505 256 xx = wax (s) 1 cm -1 111o, 1s1o, 1600, 1530, 1325, 1140. 1040. uv = Amax (phosphate buffer, pa s, 2r 1 nm (a} * cm; 234 (314), 277 sk (sso fi, 290 (402).

NMR = guao + NaHco3) δ ppm 3.78 (za, s, 2-H), 3.92 (za,: S, d 'sLg4 (zu, a, J = e, snz, -cnz-N *) .97 (1H, d, J = 4Hz, 7-H), 6.20 (1n, at, J = 1s 2s, snz, 3-cu = cg), 7108 (1H |; 1 'd, J = 16Hzy 8.11 (18, dd, J = 8 & 7Hz, Py-H5), 8 | 53 d 'J = 8Hzy (1H. D, J = 7az, Py-H6), 8.86 (1a, s, Py-H2).

Exeggel 29 s NF - IT-E CONH; J:;: 1 / I L u. Q nzn sf '\\ ocn3' I ca-ca-ca2-n¿ï: Éš} -s.ca2c °° g coåa ": -19 fz 7-1? - (S-amino-1,2,4- thiadiazol-3-yl) -2-methoxyiminoacetamide] -3-13- (4-carboxymethylthiopyl; diphenyl) -1β-piperidine-3-cephem-4-carboxylate (I + 1Q) (E-isomer) "Diphenylmethyl-7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyminoacetamide] -3-13- (4-carboxymethylthiophyridinio) -1-propenyl] -3-cephalomethyl- To a suspension of 0.888 g (5 mmol) of 4-carboxymethylthiopyridine in 10 ml of CH 2 Cl 2 was added 5 ml of (2 mmol CH 2 Cl 2). 18 mmol) of N, O-bis (trimethylsilyl) -acetamide and the mixture was stirred at room temperature until a clear solution was obtained, to which 1.79 g (2.5 mmol) of IX-1 (E- isomer) and the mixture was allowed to stand at room temperature After 3 hours, 3 ml of methanol was added to the cold mixture and the solution was evaporated in vacuo to give an oily residue, which was triturated with ethyl acetate to give 2.43 g of the isomer. the title compound XII-1Q (iodide) as a tan to powder: M.p. 155 ° C (dec.). 1 In = 9 (xßr) 1 cm '1780, 1720, 1670, 1625, 1525, max 1385, 1225, 1115, 1040, 755, 700.. 1% Uv) max (czusou) 1 nm (E1 cm) 312 (299). (sn, S, ocn3), 5.07 (zu, m, cnz-n *), 5.23 (1a, a, J = snz, sn), 5.90 (1n, a, J_snz ,, 7- n), 6.29 (1n, m, 3-ca = cg), 6.81 (1n, a, J = 1snz, 3-ca), 6.91 (18, s, CHPh2), 7.35 ( 10H, m, Ph-H), 7.88 & 8.58 (each 2H, d, J = 6Hz, Py-H).

B. 7- [2- (5-Amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamide] -3- [3- (4-carboxymethylthiopyridiniol-1-propenyl] -3-cephem -4-Carboxylate (I-Ig) (E-isomer) A mixture of 2.43 g of XII-10 (iodide) and 1.1 g of sodium bisulfite in 10 ml of 85% HCOOH was stirred for 2 hours at room temperature. The reaction mixture was concentrated to about 5 ml under reduced pressure. The oily residue was triturated with 100 ml of acetone, filtered and dried to give 1.39 g of crude product, which was purified by column chromatography 90 505 256 (HP-20, 20 ml) to to give 577 mg of the title compound I-10 (398 starting from IX-1) as a pale yellow amorphous powder (mp 188 ° C ice decomposition). 1 In = vmax (nar) 1 cm '1765, 1610, 1625, 1530, 1380, 1110, 1oas. s uv = Amax (phosphate buffer, pa 6.2) 1 nm (E: cm) 234 (4591, 310 (678).

NHR f S (D 2 O + NaHCO 3) in ppm 3.79 (2H, br.s, 2-H), 4.10 (2H, s, S-CH 2), 4.23 (3H, s, OCH 3), δ , 25 (2H, d, J = 6.5Hz, cuz-N * 1, 5.39 (1H, a, J = 4, oz, 6 ~ H), 5.97 (1H, d, J = 4Hz, 7-H), 6.18 (1H, dt, J = 15.5Hz and 6.5Hz, 3-c11 = c_r_1_), 7.05 (111, d, J = 15.5 H2, 3-CH), 7.84 & 8.55 (each 28, d, J = 7Hz, Py-H).

N ^ cows r's “Ä: ng. à s »f" ocg ¿¿"" "« ”'ca-ca-c Sá? 2 3 ° ¿9 så \ ._. c -: '13 'E / 2.' 7/1 7- [2- (5-Amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -β-β-WW γ-PYrN11 Carboxylate-sulfate (I-1A, sulphate) -A Diphenylmethyl- 7- [2- (5-amino-1; 2,4-thiadiazol-3-yl) -2-methoxyiminoacetamide] -3- [3- (1-methylpyrrolidinyl) f1-grogenygz-3-cephem -4-Carboxylate (XII-1A, iodide) To a cold solution of 21.5 g (30 mmol) of diphenylmethyl 7- [2- (5-amino-1,2,4-thiadiazole-3) -yl) -2-methoxyiminoacetamide (3- (3-iodo-propenyl) -3-cephem-4-carboxylate (IX-1) (from Preparative Example 14) in 300 ml of ethyl acetate was added dropwise a solution of 2.55 g (30 mol) of 1-methylpyrrolidine in 30 ml of ethyl acetate for 1 hour at -5 to 0 ° C with stirring.

After stirring for an additional 10 minutes, the resulting precipitate was collected by filtration and washed with 200 ml of chloroform to give 23.0 g (9S, 8%) of the title compound (IX-1A, iodide), m.p. exceeding 175 ° C (decomposition).

In = 0 (xßry 1 cm'1 3300, 1780, 1730, 1685, 1615.

IBEX uv 1 (czonson) 1 nm (E1 * Cm) 218 (435)) 295 (188).

IIIBX B. Diphenylmethyl-7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamide] -3f [3- (1-methylpyrrolidinio] -1-propenyl] -3-cephem-4 Carboxylate (XII-1A; chloride) 23 g (28.7 mmol) of the compound XII-1A (iodide) were dissolved in 230 ml of a 1: 1: mixture of acetone and methanol and applied to a column of M -410 (chloride form, 230 ml), which was pretreated with the same mixed solvent, the column was developed with the solvent and the fractions containing the desired compound were combined and concentrated to an oily residue, which was triturated with 300 ml of ethyl acetate to give 17.9 g (87.7%) of the title compound (XII-1A, chloride) with a melting point of 190 DEG C. (decomposition) 1 In = 0 (xßr) 1 cm @ 3, 3300, 1100, 1600 , 1620. 1 tczasou) 1 nm 1: 1 * 1 220 (369), 290 (2321.

UV max 1 cm 92 505 256 c 7- [2- (s-amino-1, z, pheniazole-α-yn -z-mecaxiimino- & Cetamino]] 3'3 ° (1-methylpyrrolidinio) -1-propenyl] - 3-cephem-4-carboxylate sulphate (I-1A, sulphate A mixture of 17.8 g (25 mmol) of compound XII-1A (chloride) in 178 ml of 85% formic acid was stirred for 2 hours at room temperature under a nitrogen atmosphere. The mixture was evaporated in vacuo and the residue was triturated with acetone to give 9.80 g of crude I-1 A. Concentration of the filtrate and acetone washings gave an additional 2.95 g of crude I-1 A. Two batches of the crude material were combined and extracted with 1 L and 0 L, respectively. The combined extracts were adsorbed on a 1.5 L column of Diaion HP-20 resin, which was eluted with water and a 30% aqueous solution of methanol. The desired fractions were collected and evaporated in vacuo. vacuum to an oily residue, which was triturated with 200 ml of isopropanol and 200 ml of acetone in order to obtain 7.09 g of a light yellow powder, this material (6.80 g) was dissolved in 20 ml of water and then subjected to column chromatography over the filling from a PrepPAK-500 / C18 column (90 ml) using water and an 8-aqueous solution of methanol as eluent. The eluate was collected in 20 ml fractions under HPLC monitoring. j fl olonn, Nucleocil SSC-ODS-262, 8 x 100 mm; mobile phase, 0.018 phosphate buffer (pH 7.2) / CH 3 OH = 90:10; detection, UV (254 nmL]. Fractions 4-10 were combined, evaporated under reduced pressure and lyophilized to give 2.28 g of a yellow powder (E / 2 = 7/1, 70% purity) (batch 1). 11-85 were worked up in the same manner as described above to give 3.27 g of a yellow powder (E / Z = 5/1, 70% purity) (batch 2), a batch of batch 1 (1.0 g) The column was eluted successively with water and a 5% aqueous solution of methanol. The eluate containing the desired compound was concentrated and lyophilized to give the residue purified by chromatography on the filling from a PrepPAK-500 / C18 cartridge (90 ml). 93,505,256 obtaining 638 mg (E / Z = 7/1, 80% purity) of a yellow powder Another portion of batch 1 (1.14 g) was worked up in the same manner to give 880 mg ( E / 2 = 7/1, 80% purity) of a yellow powder, the two purified samples were combined and a portion (1.45 g) was dissolved in ml of 1N sulfuric acid, the solution was diluted with 315 mg of acetone with stirring. beast The solution was collected by filtration to give 1.48 g of the title compound (I-1A, sulfate) (E / Z = 7/1, 80% purity) with a m.p. exceeding 185 ° C (decomposition). -f: - 1: ne = »max (xsr1 1 cm '33so, 3ooo, 1765, 1615, 1630, 1535, 1390, 1115. uv = lmåx (phosphate buffer, pn 7 1 1 nm (61 236 1199001, 291.5 1225001.

H nun = ¿(o2o + Nanco31 1 ppm 2.36 (4n, br., - N: | 1, 3.15 (sn, S, ca: N 1, 3.62 (sa, brl, 2-H and an: | 1, 3.63 (1a, br., 2-H1, 4.13 (zu, d, J = suz, ca2Nï1, 4.22 (33, s, ocna),, 39 (1n, d, J = 4.5nz, 6-H1, 5.96 (13, a, J = 4.5Hz, 7-H) .6.00 (1H, m, 3-cn = cg1, 6.67 (1 / BH, d , J = 10Hz, 3-ca, cis), 7.04 (7 / sa, d, J = 16Hz, 3-CH, trans). 94 505 256 Exemggl 31 'S f com: l / JL J r-Ü Q 523 5 OCR: when CBICH-C32-N (CB3) 3 6669 I-in * E / 2 '10/1 7- [2- (5-amino-1,2,4-thiadiazol-3-yl ) -2-Methoxyiminoacetamide] -2- [3-trimethylammonio-1-propenyl] -3-cephem-4-carboxylate (I-1D) A. Diphenylmethyl 7- [2- (5-amino-1,2) , 4-thiadiazol-3-yl) -2-methoxyiminoacetamide] -3- (3-trimethylammonio-1-quenyl) -3-cephem-4-carboxylate (XII-1D, iodide) To a solution of 13.0 g ( 19 mmol) diphenylmethyl-7- [1- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamide] 3- (3-iodopropenyl) -3-cephem-4-carboxyate (IX -1, from Preparative Example 10) In 38 ml of dry ethyl acetate was added 1.75 ml (19.1 mmol) of 1.1N trimethylamine in ethyl acetate at -S ° C and the mixture stirred for 1 hour at -S ° C. The resulting precipitate was filtered off, washed well with CHCl 3 and dried to give 12.5 g (88%) of the title compound (XII-1D) as the iodide. 1 m = v (nar) 1 cm 'ssoo, 1165, 1720, 1665. ma !! UV λmax (C2E50H) 1 nm (8) 300 (18400).

B. Diphenylmethyl-7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2- m -1 fi ° X11m1 fl ° a ° = * am4 fl @? - 3 f fl3 ft ¥ # m§ # Y = mm @ fl1 ° -1 fPr9P @ vYl1-3-cephem ¥ 4-carbogylate '(XII-ïD,' chloride) C \ "'' at 12.5 g of the iodide XII-1D was dissolved in 60 ml of methanol-acetone 256 (1: 1) and allowed to pass a column of ion exchange resin (IRA-410 (Cl_), 125 ml) The column was eluted with 300 ml of methanol-acetone (1: 1) and the eluate was evaporated in vacuo and triturated with 300 ml isopropyl ether to give 10.4 g (91%) of the quaternary salt (XII-1D, chloride). 1 u (man 1 cm '3300, 1165, 1110, 1665.

IR max uv xmaxxcznson) 1 mn u.): Se nswo).

C. 7-Z- (S-amino-1,2L5-thiadiazol-3-yl) -2-methoxyiminoacetamide] -3- [3-trimethylammonio-1-propenyl] -3-cephem-4-carboxylate ( I-1D, sulfate, E-isomer) A solution of 10.4 g (16.0 mmol) of XII-1D (chloride) in 20.8 ml of 85% formic acid was allowed to stand for 3 hours at room temperature and concentrated in vacuo. The residue was treated with 210 ml of isopropanol and the precipitate was filtered off. The solid (10.1 g) was triturated with 210 ml of water and neutralized with sodium bicarbonate. The suspension was filtered off and the filtrate was chromatographed on a column of HP-20 (300 ml), which was eluted successively with 1000 ml of water, 200 ml of 10% methanol and 150 ml of 30% methanol.

The fractions containing the desired product were combined and concentrated under reduced pressure. The residue was purified by reverse phase chromatography. The column was packed with the filling from a PrepPAK-S00 / C18 column, (Waters, 200 ml). Elution in turn with 600 ml of water and 200 ml of 30% methanol, followed by concentration of the fractions containing the desired product, gave 2.0 g (18%) of the title compound. A solution of the zwitterionic product (1.5 g) in 5 ml of 1N sulfuric acid was added portionwise to 300 ml of acetone and the resulting precipitate was filtered and dried. The yield of I-1D sulfate was 1.42 g (80%). The E / Z ratio was approximately 10/1 based on HPLC. n Q 96 505 256 rn = vmax (nar) 1 cm'1 saao, 1165, 1665. uv = lmax rføsfatbuffert, pa 7), 1 nm (e) 237 (19soo), 293 (22400). nn = 8 (n2o) 1 ppm 3.25 (en, S, N * -CH3), 3.94 (za, s, 2-H), 4.14 (zu, a, J = 7Hz, cn2N *) , 4.23 (an, s, o-cn3). 5.42 (1a, a, J = 4, snz, 6-H), e, oo (1n, a, J = 4, snz, 1-H), 6.23 (1n, a-1 ;, a = 1 1 1sn =, 3-ca = cg), 7.23 f (1n, a, J = 1sHz, 3-ca).

Example 32 s IIÃÉ - 11-ä CONH:; [I: ïï, 'I /. G, / "\ 82" s ,, N \\ ° ca3 _ ca-ca-ca, - &<; g:> - cows: c I-IB * E 7- [Q- (5-amino-1, 2,4-thiadiazol-3-yl) -2-methoxyiminoacetamide] -3- [3- (4-carbamoylpyridinio) -1-propenyl] -3-cephem-carboxylate (1-1H, E-isomer) To a mixture of 397 mg (1 mmol) of 7-amino-3- [3- (4-carbamoylpyridinio) -1- (E) -propenyl] -3-cephem-4-carboxylic acid hydrochloride (XXII-H ) and 168 mg (2 mmol) of sodium bicarbonate in aqueous DMF (3.5 ml of water and 7} 5 ml of DMF) were added 479 mg (1.5 mmol) of benzotriazol-1-yl-2- (5-amino-1,2 , 4-thiadiazol-3-yl) -2-methoxyiminoacetate (from Preparative Example 28) The mixture was stirred for 3.5 hours at room temperature.The reaction mixture was adjusted to pH 3-4 with 3N HCl and diluted with 200 ml of acetone to obtain of a precipitate which was collected by filtration The crude product was dissolved in a small volume of aqueous THF and the solution was adjusted to pH 6.8 with sodium bicarbonate, treated with decolorizing carbon, concentrated to about 1 ml and added to crystalline seed crystals. llin I-13. After stirring overnight, the crystalline precipitate was collected by filtration to give the title compound I-18 (zwitterionic form). Yield 83 mg '(16%). M.p. exceeding 185 ° C (decomposition). Physical / chemical data for this product were identical to those for the compound of Example 10.

Preparation Example 1 Diphenylmethyl 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamide] -3-chloromethyl-3-cephem-4-caroboxylate (IV-1) To a stirred suspension of 2.1 g (10 mmol) of 2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetic acid (III-1) in 50 ml of dry CH 2 Cl 2 was added 2.09 (10 mmol) PCl5 at -30 ° C and the mixture was stirred for 20 minutes at from -15 to -20 ° C.

To the above acid chloride solution was added a solution of 4.5 g (10 mmol) of diphenylmethyl 7-amino-3-chloromethyl-3-cephem-4-carboxylate hydrochloride (II) in 50 ml of CH 2 Cl 2, containing 10 g (so mmol ) n, o-51s- (crmethyls11y1) acetam1a, at -3o ° c.

After stirring for 1 h at -10 ° C, the mixture was concentrated to remove CH 2 Cl 2 and diluted with 200 mL of ethyl acetate.

The mixture was washed successively with 2 x 40 ml of a 10% aqueous solution of sodium bicarbonate, 2 x 20 ml of water and 10 ml of brine and dried over magnesium sulphate. The solvent was evaporated in vacuo and the resulting oily residue (10 g) was dissolved in 20 ml of CHCl 3 and chromatographed on a silica gel column (Wako-gel C-200, 100 g containing 10 ml of 1 / 1.5 M phosphate buffer pH 7) using 1 - 3% ethanol-CBCI3. The fractions containing the title compound were evaporated to give 5.7 g (95%) of IV-1 as a yellow amorphous powder. M.p. exceeding 140 ° C (decomposition). 98 505 256 In = vx fi r cm "3300, 1700, 1120, 1600, 1620. uv lššg fi nm (0) 245 (1000), 200 (9900). Nun = 8gg: ° 'ds 3,53 (za, Aßq, 2- u), 3.94 (an, s, ocg3), 4.42 (zu, S, a-cnz), s, 22 (1n, a, J = 4, s, sH), 5.92 <1n, aa, a = 4, s 2 s, 1-a), 6.93 (1H, s. cgvhz), 7.36 (100), m, Ph-H), 0.1 (29. br-S, NH 2), 9.58 (1H, d, J = 6, 7-NH).

Preparation Example 2 Diphenylmethyl 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamide] -3-β-dimethyl-3-cephem-4ecarboxylate (V-1) A mixture of 5.7 g (9.5 mmol) of IV-1 from Preparative Example 1 and 4.3 g (29 mmol) of NaI in 50 ml of dry acetone were stirred for 5 minutes at room temperature. The mixture was concentrated under reduced pressure and the resulting oil was shaken with a mixture of 100 ml of ethyl acetate and 10 ml of water. The organic layer was separated and washed successively with 10% (w / v) sodium thiosulfate and brine. After drying, the ethyl acetate was removed in vacuo to give 6.1 g (93%) of the title compound (V-1) as a yellow amorphous powder having a melting point exceeding 120 ° C (dec.).

Ia = road; cm'1 3300, 1700, 1725, 1ss0, 1620. uv = Ä fi âgn nm (0) 245 (17000), 202 412000). nun = 6§ :: ° '° s 3,72 (za, Anq, 2-n). 3.94 (an, S, ocn3), 4.23 (za, S, 3-cnz), 5.21 (13, a, a = 4, s, sn), s, s9 (1a, aa, J = 4, s 0s, 1-H), 6.94 (1n, S, cgvnz), 1.35 (10a, m, Ph-s), 0.12 (28, br-s, NH 2), 9 , 65 (13, d, J = 6, 7-NH). 99 505 256 Preparation Example 3 Diphenylmethyl-7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamide] -3-triphenylphosphoniomethyl-3-cephem-4-carboxylate iodide (VI-1 A mixture of 690 mg (1 mmol) of V-1 from Preparative Example 2 and 786 mg (3 mmol) of triphenylphosphine in 20 ml of ethyl acetate was stirred at room temperature overnight, the precipitated solid was washed twice. 10 ml of ethyl acetate and dried to give 950 mg (1008) of the phosphoniomiodide VI-1 mp 186 ° C (dec.).

IR: ÉÉ; cm'1 3300, 1700, 1710, 1600, 1610. ston Uv = Amax mm (5) 268 115000), 275 113000), 300 17300). | 34 d] J = 4 | 5 | 519 m, 6.3 (8); 7 | 3 m] Ph-H) y 7 | 8 m 'una = $ E :: °' ds 3,52 (zu, br-e, zu), 3,94 (au, e, ocg3), Preparation Example 4 Diphenylmethyl 7- [α- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxymine fl ° = ° <fl t = m1 ° 7-3-f (t-phenylphenylphenylic acid-4-carboxylate) A mixture of 952 mg (1 mmol) of VI-1 from Preparative Example 3, such as mg medium (RA-410 10n 'form) a 4 ml 1u sodium hydroxide in 10 ml CH 2 Cl 2 was stirred. The mixture was filtered and the separated organic layer was dried over magnesium sulfate and concentrated under reduced pressure, the resulting oil was triturated with ethyl acetate and the resulting yellow precipitate was collected by filtration to give 740 mg (90%). ) of the title compound VII-1, m.p., exceeding 1 ° C (temperature) 100 505 256 In 3 V33: cm'1 max 3400, 1760, 1630. uv = lššgnnm 161 266 1120001, 216 1100001, 304 123000 ).

Preparation Example 5 Diphenylmethyl-7- [7- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamide] -3- (3-chloro-1-propen-1-yl) - To a solution of 6.9 g (8.4 mmol) of VII-from Preparative Example 4 was added 3 g of magnesium sulfate and 810 mg (8.4 mmol) of 3-cephem-4-carboxylate (VIII-1). The mixture was stirred for 1.5 hours at room temperature and then filtered.The filtrate was eluted on silica gel (Wakogel C-200, 100 g containing ml 1 / 1.5 M phosphate buffer) using CHCl 3 and CHCl 3 containing methanol. containing the desired product (0.5-1% methanol-CHCl 3) was evaporated in vacuo to give 1.6 g (30%) of the title compound VIII-1 as a yellow amorphous powder, which was a mixture of the Z and E isomers with respect to the chloropropenyl group (Z / E = 2/1 according to NMR), mp exceeding 130 ° C (decomposition).

In = våg: cm'1 3300, 1700, 1125, 1660, 1620. uv = lâšga max (6) 240 120000), 206 112000). nun =; ::: ° 'd6 * ° 2 ° 3.56 3 3.3 cm, 2-31, 3.94 (an, S, ocnz). 4.16 10, J = v, s, cgzci), 5.26 (1n, a, J = 4, s, 6-n), s, a1 (1n, a, a = 4, s, 1-31 , 6,20 (2 / su, a, a = 11, 3-eg cis-H1, 6,12 (1 / sa, a, a = 16, 3-eg trans-a1, 6,61 (2 / 3n , s, cgphz), 6.92 (1/33, s, cgrhz), 1.4 110a, m, Ph-a) 101 505 256 Example Preparation 6 Diphenylmethyl-7-benzylideneamino-3- [Triphenylphosphoranylidene) methyl 2-cephem-4-carboxylate (XVI) To a solution of 60 g (70 mmol) of diphenylmethyl-7-benzylideneamino-3-lithriphenylphosphonio) methyl] -3-cephem-4-carboxylate iodide (XV) [ prepared by the method of Japanese Patent Application Laid-Open (Kokai) 56-86187 (7/31 / 81L] in 350 ml of CH 2 Cl 2 was added 140 ml of 1N sodium hydride and one as g: mbefrite Ina-uu (crf form) at s ° c. The mixture was stirred for 1 hour at 5 ° C and filtered, the organic layer was separated, dried over magnesium sulphate, concentrated to a volume of about 100 ml and precipitated with 500 ml of ethyl acetate.The resulting yellow solid was collected by filtration and dried in vacuum to give 48 g (94%) of it in the title compound XVI with a m.p. of 195-198 ° C (dec.).

Br -1 m. vâaxcm 1770, 1620.

Preparation Example 7 Dife fl vlme fi vl-V-be fl svli fi s fl ami fl êfßf Ufkl flfifl fwavsfë-ï fw. To a stirred solution of 2.9 g (4 mmol) of XVI from Preparative Example 6 in a mixture of 40 ml of CH 2 Cl 2 and ml of water was added 3-cephem-4-carboxylate (XVII). 800 mg anhydrous chloroacetaldehyde at room temperature. To the mixture was added an additional 800 mg of chloroacetaldehyde in three portions over a period of 1 hour while maintaining the pH of the mixture between 6 and 9 by adding 1N sodium hydroxide. After 15 minutes, the aqueous layer was removed and the organic layer was dried over magnesium sulfate. Evaporation of the solvent gave a red oil which was dissolved in 80 ml of a 1: 2 mixture of ethyl acetate and isopropyl ether. The solution was washed successively with 10 ml of a saturated aqueous solution of sodium hydrogencarbonate and 10 ml of water. After drying over magnesium sulphate, removal of the solvent gave 3.3 g of a yellow oil. A solution of the oil in 50 ml of CH 2 Cl 2 was filtered off using silica gel (12 g, Wakogel C-200) containing 1 / 1.5 M phosphate buffer (1.2 ml, pH 6.4) and the silica gel was washed with 50 ml of CH 2 Cl 2. The filtrate and washings were combined and evaporated to dryness. The residue was triturated with n-hexane to give 1.7 g (80%) of the title compound (XVII) as a yellow polyer. NMR spectrum showed that the chloropropenyl group had Z-configuration. M.p. exceeding 50 ° C (decomposition).

KB! -1 IR = umaxcm 3400, 1775, 1720, 1630. uv = ššg š nm (5) 253 (1100o), 258 (11000), 265 (100o), 273 (8300), 281 (7000), 290 (6300). nun = 6g: fi ° 'ds 3.63 (zu, br-S, 2-ny; 4.0 (zu, m, cgz-cl),, 42 (zu, m, sn 4 3-ca = cg) , 5.72 (1n, a, J = 4, s, 1-ax, 6.21 (1n, a, J = 11, 3-ca), 6.05 (1n, S, cgvnzæ, 4,33- (10a, m, Ph-H).

Preparation of anhydrous gracetaldehyde Anhydrous calcium chloride was added to a cooled solution of 50 ml of a 50% aqueous solution of chloroacetaldehyde with stirring in order to separate it into two layers.

The chloroacetaldehyde hydrate layer (1) (the upper layer) was separated and diluted with 100 ml of CHCl 3, mixed with 20 g of magnesium sulphate, heated to reflux for 5 minutes and filtered. The solvent and water were removed azeotropically (b.p. S6-64 ° C) (2) and the residue was distilled to give anhydrous chloroacetaldehyde (3), boiling point 10-a2 ° c / 160 mm. 103 505 256 In = vflåšmcfff11vzo. (1) R.P. Xurkjy, E. V. Brown, J. Amer. Chem. Soc., 11, S778 (1952). (2) S. Trippett, D. M. Walker, J. Chem. Soc., 1961 1266. (3) H. 0. House, V. K. Jones, G. A. Frank, J. Org, Chem., 22, 3327 (1964).

Preparation Example 8 Diphenylmethyl-7-amino-3- (3-chloro-1-propen-1-yl) -3-cephem-4-carboxylate (RVIII) A solution of 180 mg (0.34 mmol) of XVII from Preparation Example 7 in 10 ml of ethyl acetate was added to a solution of 251 mg (1.5 mmol) of Girard reagent T [Ycarboxymethyl) -trimethylammonium chloride hydrazine] in 10 ml of CH 3 OH containing 0.25 ml of acetic acid at 5 ° C. After stirring for 30 minutes at ° C, the mixture was concentrated to remove the methanol and 20 ml of ethyl acetate was then added. The ethyl acetate solution was washed successively with 2 x 5 ml of water, ml of a saturated aqueous solution of sodium hydrogencarbonate and ml of brine, and dried over magnesium sulfate. Evaporation of the solvent gave 145 mg (97%) of the title compound XVIII (Z-isomer) as a yellow powder. M.p. exceeding 100 ° C (decomposition).

KB: -1 IR: Vmax cm 3400, 1770, 1720. uv l š šg fi nm (E) 252 (3700), zss (saoo), zso (4000), 274 (4000) l 285 (4000). 104 505,256 Preparation Example 9 N-phenylmecyl-7- [7- (S-amino-1,2,4-thiaziaz-3-yl) -z-methoxy-1-iminoacetamide] -3- (3-chloro-1-propen-1-yl) - 3-Cephem-4-carboxylate (VIII-1) A mixture of 10.1 g (50 mmol) of 2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetic acid (III -1) and 10 ,! 9 (50 mmol) Pcls 110 ml of dry cazclz are stirred at -7: 111 -1s ° C for 2 hours. The clear solution was poured into 500 ml of n-hexane to obtain a precipitate. The organic sieve was discarded by decantation and the remaining solid was triturated with 100 ml of n-hexane. The yellow precipitate was collected by filtration and dried in vacuo to give 12.5 g (99%) of the acid chloride, m.p. of 80 ° C (decomposition).

IR: ν 2 cm 1 1770. mg (0.1 mmol) of the acid chloride was added to a solution of 44 mg (0.1 mmol) of XVIII (Z-isomer) from Preparative Example 8 in 5 ml of dry CH2Cl2 at room temperature while stirring. After 30 minutes, the mixture was concentrated under reduced pressure and diluted with 20 ml of ethyl acetate and 5 ml of a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was washed with 5 ml of a saturated aqueous solution of sodium hydrogencarbonate, 5 ml of brine, 5 ml of hydrochloric acid and 5 ml of brine. The solvent was dried over magnesium sulfate and the solution was evaporated to dryness to give the product as a yellow foam. The foam was purified by silica gel column chromatography (Wakogel C-200, 1 g containing 0.1 ml 1 / 1.5 M phosphate buffer pH 6.4) eluting with a 100: 1 mixture of CH 2 Cl 2 and methanol to give 31 mg (50 %) of the title compound VIII-1 (2-isomer) as a yellow powder. M.p. exceeding 150 ° C (decomposition). . "\ 105 505 256 IR path; cm" 3400, 1775, 1720, 1675, 1630. uv =) fi :: “um ts) 240 (17ooo). 230 (1oooo1. Man = 6 ° "s ° 'ds 3.6 (za, m, 2-H), 3.92 (aa, s, o-cn3), ppm 4.0 (zu, m, cg2c11, 5.27 (za, m, 6-H a 3-cH = cg), 5.33 (1a, aa, J = 4, sa 10, 7-H1, 6.25 11n, a, J = 11, 3 -eg), 6.83 11a, S, cgphz), 7.33 (10H, m, Ph-H), 8.0 (2H, br-s. nn2>, 9.57 <1n, a, a = 1o, 7-nn).

Preparation Example 10 Diphenylmethyl-7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamide] -3- (3-iodo-1-propen-1-yl) - 3-cephem-4-carhoxylate (Ix-1) “A solution of 480 mg (0.77 mmol) of VIII-1 from Preparative Example S (Z / E = 2/1) in 10 ml of dry acetone containing 346 mg ( 2.3 mmol) Nal was stirred for 30 minutes at ambient temperature. The reaction mixture was evaporated under reduced pressure. The resulting oil was partitioned between 50 ml of ethyl acetate and 10 ml of water. The upper layer was washed successively with 10 ml of a 10 S (w / v) aqueous solution of sodium thiosulfate and 10 ml of brine and dried over magnesium sulfate. Evaporation of the solvent gave 540 mg (98%) of the title compound IX-1 (Z / E = 1/1) as a reddish amorphous solid, m.p. exceeding 120 ° C (decomposition).

VKBI cm-1 3300, 1780, 1720, 1680, 1620.

IR max uv = fi šga cm'1 1 :) 24o (21ooo1, 290 (12ooo). Nun =; ° "S ° '° 2 ° 3.67 (za, m, 2-H), 5.29 (1a, a, J = 4, s, ppm 6-H), 5.95 (18, d, J = 4.5, 7-H), 6.27 (1 / 2H, d, J = 11, 3-CH cis), 6.72 (1 / 2H, d, J = 16, 3fCH trans), 6.87 & 6.96 (each 1/23, S, C§Ph2), 7.4 (10H, m, Ph 106 505 256 Preparation Example 11 01 Phenylmyl-1- [2-15-amino-1,2,4-thiaziazol-3-yl) -2-methoxy-1-aminoacetamido] -3- (3-iodine -1-propen-1-yl) -3-cephem-4-carboxylate (Ix-1) 4 A mixture of 5.6 g (9 mmol) of VIII-1 (Z-isomer) from Preparative Example 9 and 4 g (27 mmol) NaI in 100 ml of dry acetone was stirred for 1.5 hours at room temperature, the mixture was evaporated and the residual oil was diluted with 90 ml of ethyl acetate.The ethyl acetate layer was washed with 10 ml of a 1% (w / v) aqueous solution of sodium thiosulfate and 10 ml of water Removal of the solvent dried over magnesium sulphate, crude oil, which solidified by trituration with isopropyl ether Filtration of the precipitate gave 4.3 g (67%) of the title compound. an IX-1 as an E-isomer. M.p. exceeding 165 ° C (decomposition).

In = väg: cm'1 3400, 1700, 1725, 1580, 1510. uv ššg fl nm (5) 240 118000), 291 (11000í. Nun =: ° "S ° 'de * ° 2 ° 3,90 (au, S, ocn3), 5.25 (10, m, 5-a), ppm 5.95 (1H, m, 7-H), 6.72 (d, J = 16, 3-CH trans) | s] Preparation Example 12 Benzhydryl 7-amino-3- [3-chloro-1-propen-1-yl] -} - cephem-4-carboxylate (2-isomer) (XVIII) Compound XVIII is the common intermediate used in Reaction Schemes 1b and 1c. 108 505 256 r -1 in. egg: om 1770, 1620. uv =: gšclz mn (e) 254 1230cc). 389 (zzooo). mm =: mms 2.56 1. 3.16 (zu, Aag), s, oo (m, a, J = 4 az), ppm 5.23 (1H, d, J = 4 Hz), 5.47 (1H, d, J = 22 Hz), 6 | 95 5)] 7 | 2-7 | 8 m) | 5.0 C. Benzhydryl 7-amino-3- [chloro-1-propen-1-yl] -3-cephem-4-carboxylate hydrochloride (Z-isomer) (XVIII hydrochloride) To an aqueous solution of 214 g (0.294 mol) of XVI and 40 ml (0.15 mol) of N, O-bis- (trimethylsilyl) acetamide in 2.9 l of dry CH 2 Cl 2 were added dropwise with stirring 93 g (0.59 mol) of a 50% solution of chloroacetaldehyde in CHCl 3 over a period of 15 minutes. After allowing the mixture to stand for 30 minutes, it was concentrated to dryness.

To the residual oil was added 1.5 L of CH 2 Cl 2, 99 g (0.59 mol) of Girard Reagent T and 300 ml of a 10% aqueous solution of hydrochloric acid, and the mixture was stirred for 1 hour at room temperature. The organic layer was washed with 200 ml of water and with 200 ml of a saturated sodium chloride solution, dried over magnesium sulfate, treated with 5 g of charcoal and filtered. The filtrate was cooled to -10 ° C and treated with 300 ml of 1N hydrochloric acid in methanol. The mixture was stirred for 30 minutes at room temperature and concentrated to a volume of about 300 ml. The concentrate was diluted with 400 ml of ethyl acetate and added to seed crystals of XVIII hydrochloride. After 2 hours, the separated crystals were collected by filtration, washed with 200 ml of ethyl acetate and dried in vacuo to give 74 g (53%) of the title compound XVIII as its hydrochloride, m.p. exceeding 185 ° C (decomposition).

Pale yellow needles. m: _ vä; cm "2830, 1730, 1120. 109 505 256 vv = Aâšga um (ey zas (asoo). 6 3.73 (38, br, S, 2-H), 3.97 (2H, m, C§2C1) , ppm 5.22 (1H, d, J = 4.5 Hz, 6-H), 5.37 (18, d, J = 4, 5 Hz, 7-H), 5.77 (18, m, 3-CH = C§), 6.45 (1H, d, J = 11H2, 3-CE), 6.88 (1H, S, C§Ph2), 7133 br's' Ph-g).

Analysis calculated for C 23 H 21 N 2 O 3 SCl · HCl: C, 57.87; H, 4.65; N, 5.87; S, 6.72; Cl, 14.85.

Found: C, 57.62; H, 4.53; N, 5.70; S, 6.64; Cl, 14.89.

Preparation Example 13 Benzhydryl-7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamide] -3- [3-chloro-1-propen-1-yl] -3 -cephem fi4-carboxylate (Z-isomer) (VIII-1) To a stirred solution of 20 g (42 mmol) of XVIII (2-isomer) in 420 ml of CH2Cl2 containing 34 ml (125 mmol) of N, O-bis- trimethylsilyl) acetamide was added 15.2 g (59 mmol) of 2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetyl chloride hydrochloride in 3 portions over a period of 30 minutes at from : 111 ° C. The mixture was stirred for 5 minutes at 0 ° C and concentrated under reduced pressure. The residual brown oil was dissolved in 420 ml of ethyl acetate and the solution was washed successively with 3 x 15 ml of a saturated aqueous solution of sodium hydrogencarbonate, 15 ml of a saturated aqueous solution of sodium chloride, 15 ml of 8 8 g of hydrochloric acid and 15 ml of a saturated aqueous sodium chloride solution and concentrated to a volume of about 50 ml. To the concentrate was added 200 ml of n-heptane to obtain 28.5 g (90% purity) of the title compound VIII-1 (Z-isomer) as a colorless powder. M.p. exceeding 1S0 ° C (decomposition). 110 505 256 In = \ §: § 6m'1 3400, 1100, 1130, 1600, 1620. uv = Aššg fl um (6) 240 (2000p1,2a3 (1z00o). Nun =; a °° t ° “'d6 3 , 6 (zu, m, 2-H), 3.96 (au, s, ocgsa, ppm 4.0 (za, m, cg2c1), s, 3z (10, 0, a = 4, s H2, 6 -a), s, 62 (10, m, 3-ca-eg), 6.03 (1n, a, J = 4, s az, 1-0), 6.32 (10, a, J = 11 Hz, 3-ca), 6.87 (1H, s, cgphz), 7.33 (10H, br, s, Ph-H)., In Preparation Example 14 Benzhydryl-7- [2- (5-amino) -1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamide] -3- [3-iodo-1-propen-1-yl] -3-cephem-1-carboxylate (E-isomer ) (IX-1) A mixture of 28.5 g (90% purity) of VIII-1 (Z-isomer) and 19 g of sodium iodide in 420 ml of dry acetone was stirred for 10 minutes at room temperature and allowed to stand for 2 hours at + 5 ° C.

The mixture was concentrated under reduced pressure. To the residue were added 420 ml of ethyl acetate and 30 ml of a 10% (w / v) aqueous solution of sodium thiosulfate, and the mixture was shaken. The organic layer was washed with 30 ml of water, dried over magnesium sulfate and evaporated to a volume of about 50 ml. The concentrate was diluted with 200 ml of n-heptane to give 30.6 g (95% purity) of the title compound IX-1 (E-isomer) as a yellow powder, m.p. exceeding 120 ° C (decomposition).

In = vxßí cm ° '3400, 1100, 1725, 1600, 1620. _ ston uv. : bax nm (6) 306 (1s000). nun = 5a °° t ° “° d6 3.11 (zu, m, 2-n), 3.91 (3a, S, oc§3), ppm 4.0 (23, d, J = 8 Hz, C§2I), 5.26 (TH, d, J = 4 | 5 Hz dd, J = 4 | 5 G 111 505 256 8 Hz, second-row double J = 4, S Hz with D20, 7-H), 6 , 32 (1H, dt, J = 15 G 8 Hz, 3-CH = C§), 6.79 (1H, d, J = 15 Hz, 3-Cg), 6.98 (1H, s, C§ Ph2), 7.35 (108, m, Ph-H), 7.63 (2H, br, s, disappeared with D 2 O, N § 2), 8.52 (1H, d, J = 8 Hz, disappeared with D20, 7-Ng).

Preparation Example 15 Benzhydryl-7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamide] -3- [3- (4-carbamoyl-1-pyridinio) -1 -propen-1-yl7-3-cephem-4-carbogylate iodide (E-isomer) (XII-1H) «To a suspension of 30.5 g of IX-1 (E-isomer) and 26 g (212 mmol) isonicotinamide and 120 ml of CH 3 CN were added to 100 ml of CHBOH until the mixture was clear. The solution was stirred for 2 hours under a nitrogen atmosphere at room temperature and concentrated to about 100 ml under reduced pressure. The remaining semi-solid was triturated with 200 ml of isopropyl ether. The solvent was removed by decantation and the remaining yellow powder was washed with 120 ml of a 3: 1 mixture of isopropyl ether and methanol. The powder was collected by filtration and dried in vacuo to give 36 g (758 purity estimated by HPLC) of the title compound XII-18 (E-isomer) as a pale yellow powder, m.p. exceeding 150 ° C (decomposition) .. 'Kßr -1 IR: V Cm max 3300, 1780, 1720, 1680, 1620. uv = 3: 3 ”nm (z} * cm) 252 (170). nnn. = & ° "s ° 'd6 3.72 (za, m, 2-a), 3.90 (sn, S, ocg3), ppm 5.25 (sa, m, sa a cg2n *), 5 , 9 (1n, aa, J = 4.5 Q 8 Hz, changed to a doublet: J = 4.5 Hz at D 2 O addition, 7-H), 6.35 (1H, m, 3-cn = cg) , 5.89 (1n, S, cgphz), 5.9 (1a, S, J = 1s az, 3-eg), 1.35 (1on, m, vn-a), 112 505 256 8.06 ( 2H, br, s, disappeared at D20, N§2), 3.21 (ZH, br, s, disappeared at D20 - addition, NH2), 8.36 I 9.07 (2H, d, J = 6 each Hz, Py-H), 9.57 (1H, d, J = 8 Hz, disappeared at D 2 O - addition, 7-NH).

Preparation Example 16 Benzhydryl-7-benzylideneamino-3- {3-chloro-1-propen-1-yl] -3-cephem-4-carboxylate (XVII) (Z-isomer) To an ice-cooled mixture of 13.4 g (28 mmol) ) of the crystalline 7-amino-cephem intermediate XVIII (Z-isomer) and 3.3 g (31 mmol) of benzaldehyde in 150 ml of ethyl acetate were added dropwise 56 ml (28 mmol) of 0.5N sodium hydroxide over a period of 20 minutes. minutes to keep the temperature of the reaction mixture below 10 ° C. The mixture was stirred under cooling for a further 15 minutes and the organic layer was separated, washed with 2 x 100 ml of a saturated aqueous solution of sodium bicarbonate and dried over magnesium sulphate.

To the dried solution was added a small amount of charcoal and the mixture was filtered. The filtrate was concentrated to dryness. The residual oil was dissolved in 50 ml of carbon tetrachloride and concentrated again. This procedure was repeated three times and the mixture was monitored by reverse phase TLC to confirm that all of the starting 7-amino-cephalosporin had been converted to the Schiff base.

Removal of the solvent in vacuo gave 16.45 g of the title compound XVII (Z-isomer) as a pale yellow powder (estimated purity 85%) with a m.p. of 74 ° c '(sönaerae1n1ng). The product is used in 1 subsequent step without purification.

In = wave: em'1 1180, 1125, 1635.

Aggšclz nu (s' *) 251 (400).

UV 1 cm now = °°° 13 s, 1s (1a, a, J = 11 az). ppm -f 113 505 256 Preparation Example 17 Benzhydryl-7-benzylideneamino-3- [§- (4-carbamoyl-1-pyridinio) -1-propen-1-ylZ-3-cephem-4-carbogylate iodide (XXI-H ) (E-isomer) To a cooled mixture of 16.4 g of the 3-chloropropenylcephem compound XVII (Z-isomer) in 5 ml of acetone was added dropwise a solution of 6.3 g (42 mmol) of sodium iodide in 30 ml of acetone under 10 minutes of nitrogen atmosphere and the mixture was stirred at room temperature. The reaction was monitored by feeding uv-ebedrione prion ratio ¿h1 * (zss nm) / 1 cm E1% cm (320 nmL] When this ratio reached a value below 1.30 (after 45 minutes) the mixture was diluted with 400 ml of carbon tetrachloride and allowed to stand. at room temperature, when the ratio reached a value below 1.10 (after 3 rhymes), the mixture was concentrated to half its volume, the concentrate was treated with a small amount of charcoal and diatomaceous earth and filtered, and the filter cake was washed with 100 ml of a 1: 1 mixture. To the combined solution of filtrate and washing liquids was added a solution of 3.5 g (28.7 mmol) of isonicotinamide in 20 ml of dimethylformamide and the mixture was concentrated under reduced pressure, the concentrate was allowed to stand for 1.5 hours at room temperature and washed with 3 x 100 ml of isopropyl ether The remaining brown semi-solid was dissolved in 50 ml of methylene chloride and the solution was added dropwise with stirring to 1.5 l of ethyl acetate. was taken up by filtration and washed with 200 ml of ethyl acetate. After drying over phosphorus pentoxide in vacuo, 17 g of the title compound XXI-H (E-isomer) were obtained. Yellow amorphous powder. M.p. 150-155 ° C (dec.). Estimated purity 80% according to NHR. m3 rn = i em 1715, 1725, 1690, 1635. uv lå: C12 um (n} * cm) zss (sas) 293 (ass). 114 505 256 mm = J ° "s ° 'ds a, 4-s, a (za, un), 5.25 (za, ma), 5.41 ppm (18, d, J = 4 Hz), 5 73 (1B, d, J = 4 Hz), 6.93 un, s), 5.97 (m, a, J = 1s az), 7.3-1.5 (1511, br. S), a, 4o (zu, a, a = s, s az), 9.15 (za, a, a = s, 5 m).

Preparation Example 18 7-Amino-3- [3- (4-carbamoyl-1-pyridinio) -1-propen-1-yl] -3-cephem-4-carboxylate (XXII-H) (E-isomer) To a suspension of 17 g of the quaternized cephem compound XXI-H in 25 ml of 85% formic acid were added dropwise ml of concentrated hydrochloric acid and the mixture was stirred for 1.5 hours at room temperature and treated with a small amount of charcoal. The mixture was filtered and washed with 85% formic acid. The filtrate was combined with the washings and poured into 1 L of acetone with stirring. The resulting precipitate was collected by filtration to give 9.52 g of a yellow crude product. To a suspension of the raw material (9.5 g) in 50 ml of water was added a small amount of charcoal and the mixture was filtered. The filtrate was added dropwise with stirring to 700 ml of isopropyl alcohol. The resulting precipitate was collected by filtration, washed with a small amount of methanol (30 ml) and dried to give 7.58 g of the title compound XXII-H (E-isomer) as the hydrochloride. Light yellow powder. Estimated purity 85% according to UV. M.p. 173-188 ° C (dec.). n = vfâg; cm * 1795, 1680, 1620, 1575, 1540.

UV xphosphate buffer (pH 7) nm (E1%) 294 (457). max 1 cm 115 505 256 una = c ° 2 ° * °° 1 3.52 (za, 5), 5.11 (15, a, J-5 az), ppm 5.33 (28, d, J = 7 Hz), 5.43 (1H, d, J = 5 az), 5.31 (1n, at, a = 1s and 1 az), 1.23 (1u, a, a = 1s az), a, 34 (za, a, a = 1 az), 9, oo (za, a, a = v az).

Preparation Example 19 2- (5-Amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetyl chloride hydrochloride (III-1-9,9m gyrachloride hydrochloride A. 2-cyano-2-methoxyiminoacetamide To a stirred mixture of 252 g (3 moles) of cyanoacetamide and 414 g (6 moles) of sodium nitrite in 600 ml of water, 371 ml (10 moles) of acetic acid were added at 5-10 ° C for 1.5 hours. 5 hours and was adjusted to pH 8.5 with 6N sodium hydroxide, to the mixture was added 1 ml (6 ml) of ethyl sulfate via 15 DEG-20 DEG C. and the mixture was stirred for 1.5 hours at 45 DEG C. The reaction mixture was adjusted to a temperature of with a sodium nyaroxia and allowed to stand at s ° c 'overnight to separate the precipitate, which was collected by filtration, washed with cold water and air dried to give 292 g (177%) of the title compound as brown needles with and m.p. of 170-172 ° C.

KB: -1 IR Vmax cm 3400, 3180, 1720 (sh), 1715, 1690, 1615, 1570. uv AF 3 um 1 :) 238.5 (3290), zsa (sk, 3810). now:; 8 ° "S ° 'ds 4.20 (an, s, ocn3), 7.35 (zu, br. N52). Ppm Analysis calculated for C 15 H 5 N 3 O 2: C, 37.80; H, 3.97; N 33.06%: = c, 31.43; n, 3.75; N, 32.51. 116 505 256 B. 2-Methoxyiminopropanedinitrile A stirred mixture of 88.9 g (0.7 mol) of 2-cyano -2-methoxyiminoacetamide, 70 g of sodium chloride and 97 ml (1.05 mol) of phosphorus oxychloride in 350 ml of dry 1,2-dichloroethane were refluxed for 16 hours, the insoluble material was filtered off through a dicalite pad and washed with dichloroethane. and the washings were combined and poured with stirring into 1.5 l of ice water to decompose the excess phosphorus oxychloride, the organic phase was washed with 500 ml of sodium bicarbonate, 3 x 500 ml of water and 50 ml of a saturated sodium chloride solution and dried over The filtrate was distilled under reduced pressure to obtain 61.5 9 (81%) of the title compound, which was boiled at 62 ° C / 24 mm Hg. (Literature boiling point 47-4 ° C / 12 mm Hg). ).

IR = viscous film cm -1 3002, 2960, 2245, 2020, 1530, 1455; 1oao. nun = ¿°°° 13 4.3s (sn, s, ocn3).

PP "of C. 2-cyano-2-methoxyiminoacetamidinium acetate To a solution of 28.4 g (0.53 mol) of ammonium chloride in 355 ml of a 28% aqueous solution of ammonia and 180 ml of ethanol was added dropwise a solution of 58 .0 g (0.3 mol) of 2-methoxyiminopropanedinitrile in 120 ml of methanol at -15 to -10 ° C for a period of 30 minutes with stirring. The mixture was stirred at -10 ° C overnight and then at ambient temperature (20-2S ° C) for one day. The reaction mixture was partitioned between 350 ml of water and 350 ml of CH 2 Cl 2 and the aqueous phase was saturated with sodium chloride and extracted again with 300 ml of CH 2 Cl 2. The organic extracts were combined, dried over magnesium sulphate and evaporated in vacuo. A solution of the residue in 1.6 l of ethyl acetate was adjusted to pH 3-4 with acetic acid to precipitate the title compound as crystals, which were taken up by filtration and washed with ethyl acetate.

Yield 67.6 9 (69%). M.p. 152-4 ° C (decomposition vapor). [Iitature value: m.p. 150-1S5 ° C (dec.

: R = wave: cm'1 3160, zsoo, zsso, 2235, zooo, 1665, 1sss, 1495, 1415. uv = zššg fl nm (a) 243 (ssoo), zss (sk, ssao),: os (sk, 1400).

NMR δ SDM 50-ds 1.88 (311, s, cgzcoon), 4.15 (311, s, ocn3), ppm 7.60 (4H, br.).

Analysis calculated for C 4 H 6 N 4 O · CH 3 COOH: C, 38.71; H, 5.41; N, 30.09 Found: C, 38.71; H, 5.59; N, 29.51.

D. 2- (5-Amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetonitrile To a suspension of 125 g (0.672 mol) of 2-cyano-2-methoxyiminoacetamidinium acetate in 1,25 To methanol was added dropwise 234 ml (1 mol) of crystalline thiamine at -10 ° C, then 41.6 ml (0.806 mol) of bromine for 20 minutes at -15 to -10 ° C and the mixture was stirred for 20 minutes. To the mixture was added dropwise a solution of 78.3 g (0.806 mol) of KSCN in 550 ml of methanol for 1 hour at -15 to -10 ° C.

After stirring at 0-5 ° C for 1 hour, the mixture was poured into 12 l of ice water to form a crystalline precipitate, which was collected by filtration, washed with water and air dried to give 120 g (98%) of the title compound. Association. M.p. 263-5 ° C (dec.).

M.p. for the compound prepared is about 60 ° C higher than the m.p. as stated in the literature (Japanese Published Patent Application Kokai S7-158769; 210-1 $ ° C (decomposition)) but our spectral and microanalysis data are consistent with the structure. 118 505 256 In = scale: cm "3435, 3260, 3120, 2960, 2245, 0020, 1630, 1s4s, 14ss, 141s.

UV 1:22 ”nm (4) 240 (13300), 310 (3470).

Nan = 8 ° “s ° 'd6 4.21 (sn, s, ocn3). 8.30 (sat, br. Nnz).

PPN Analysis calculated for CSHSNSOS: C, 32.78; H, 2.75; N, 38.23; S, 17.50.

Found: C, 32.76; H, 2.51; N, 30.02; A, 17.50. 1 E. 2- (S-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetic acid (III-1) A mixture of 18.3 g (0.1 mol) of 2- (S -amino-1,2,4-thiadiazol-3-yl-2-methoxyiminoacetonitrile) in 250 ml of 4N sodium hydroxide was heated for 3 hours at 50-55 ° C with stirring.

The reaction mixture was adjusted to pH 1 with phosphoric acid and washed with 100 ml of ethyl acetate, saturated with sodium chloride and extracted three times with a mixture of ethyl acetate and tetrahydrofuran (3: 1, 2 x 300 ml and 1 x 200 ml). The extracts were combined, dried over magnesium sulfate and concentrated under reduced pressure. The residue was triturated with isopropyl ether to give pale yellow crystals of the title acid. Yield 16.8 g (83%). M.p. 184-185 ° C (dec.). (Literature value; (Japanese published patent application Kokai sv-1ss1s9; m.p. 100-1a2 ° c (dec.)).

KBr -1 IR: Vmax Cm 3460, 3260, 3140, 1725, 1620, 1605) 1545.

UV egg: nm (2) 234 (13200), zss (sk, 3620). 119 505 256 F. 2- (5-Amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetyl chloride hydrochloride To a suspension of 40.4 g (0.2 mol) of 2- (S -amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetic acid (III + 1) in 400 ml of dry CH 2 Cl 2 was added 41.6 g (0.2 mol) of PCl 5 in one portion at -50 ° C. The slurry was stirred for 4 hours via -zo-cin -s ° C and poured into 2 l of a 2: 1 mixture of n-heptane and isopropyl ether. The yellow precipitate was collected by filtration, washed with the same solvent mixture and dried over potassium hydroxide under reduced pressure to give 46.0 g (90%) of the title acid chloride.

IR = vfnäfl cm ”1775.

Preparation Example 20 com: I / N - RZNJLSJ u \ cf-n / ca-ca-csz-ci Än, COCB (Ph) 2 VIII ~ 2 Ål Diphenylmethyl-7- [2- (5-amino-1,2 , 4-thiadiazol-3-yl) -2- (Z) -ethoxyiminoacetamide] -3-13-chloro-1-propenyl] [3-cephem-C 1-4 carboxylate (VIII-2,2-Z isomer) To a mixture of 2,3 ml (9 mmol) of N, O-bis (trimethylsilyllacetamide and 1.338 g (2.8 mmol) of 7-amino-3- [3-chloro-1- (2) -propen-1-yl] -3-cephem 4-Carboxylate hydrochloride (XVIII: from Preparation Example 12) in 10 ml of methylene chloride was added 800 mg (2.95 mmol) of 2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (Z Ethoxyiminoacetyl chloride hydrochloride portionwise with stirring at -10 DEG C. and the mixture was allowed to stand for 2 hours at 0 DEG C. The mixture was diluted with 200 ml of ethyl acetate, washed with water and evaporated under reduced pressure. with isopropyl ether gave the title product VIII-2 as an amorphous powder. Yield 1.10 g (ess). mp exceeding 100 ° C (ssnaeraelninq). mu (nar) 1 cm -1 1aa3o, 1780, 1120, 1690, 13ao, 1220. ma !! uv = Ämax (cznsou) 1 mn (a) zas 111000). nun = s (DM 50 -d) 1 ppm 1.26 (3H, t, J = 7nz, cazcga), 4.25 (2H, q, J = 7Hz, C§2CH 3), 5.90 (1H; - dd J = 4 to 8Hz, 7-H), 6.26 (13, d, J = 11Hz, 3-CH), 6.85 (1H, s, cHPh2); 9.53 (1H, d, J = 8nz, 7-NH).

Preparation Example 21 a 'ß com: / s (1' H. '. - I: s, _ \ ?. 0 / 1'- / ca-cn-cnz-x czns coocnma), Diphenylmethyl-7- [2- ( 5-Amino-1,2,4-thiadiazol-3-yl) -2- (Z) -ethoxyiminoacetamide] -3-13-iodo-1-propenyl] -3-cephem-4-carboxylate (IX-2 A mixture of 1.90 g (3 mmol) of VIII-2 (from Preparative Example 20) and 1.4 g (9 mmol) of sodium iodide in 20 ml of acetone was stirred for 10 minutes at room temperature and then allowed to stand for 3 hours at 5 ° C. C. The mixture was evaporated under reduced pressure, diluted with 100 ml of ethyl acetate, washed with S-sodium sodium thiosulphate and water and evaporated under reduced pressure. Trituration of the residue with isopropyl ether gave 1.82 g (84%) of the title product IX-2 as a light brown amorphous powder. 1 In = 0¿ax (nar) 1 cm '3290, 1170, 1120, 1670, 1530, 1310, 1220. uv. =: Max (c2H50H> 1 nm 1n} * cm1 304 1109).

Preparation Example 22 - <::: >> 'CHIN "1“ "1 / Vs. fa oy-J '/. ca-cn-cnz? [ONE, COOCH (Ph) 2 Diphenylmethyl-7-benzylideneamino-3- (TE) -3- (4-carbamoyl-pyridinio) -1-propenyl] -3-cephem-4-carboxylate (XXI-H-iodide) (E4 isomer) To a cooled solution of 42.8 g (90 mmol) of the 3-chloropropenyl cephem compound (XVII, Z isomer) (from Preparative Example 16) in 80 ml of dry DMF was added 20 g (120 mmol) of XI in one portion and the mixture was stirred at room temperature. The reaction was monitored by the UV absorption ratio (1:% c- (255 nm) / E:% cm (320)). When the ratio was less than 1.10 (after 45 minutes), the mixture was diluted with 800 ml of methylene chloride, treated with 4 g of activated carbon and filtered. The filter cake was washed with 100 mL of CH 2 Cl 2. To the combination of filtrate and washings was added 14.64 g of isonicotinamide and the mixture was concentrated under reduced pressure. The concentrate was kept for 1.5 hours at room temperature and washed with 600 ml of a 1: 1 mixture of toluene and n-heptane. The remaining brown semi-solid was dissolved in 100 ml of CH 2 Cl 2 and the solution was added dropwise to 3 l of ethyl acetate with vigorous stirring. After drying over P2 O5 in vacuo, 57.37 g (88%) of the title quaternary product XXI-H were obtained as the iodide. Yellow amorphous powder. M.p. 150-1S5 ° C (dec.). This product was identical to that obtained by iodination with NaI (Preparation Example 17).

Preparation Example 23 s acin2N --- I / _ _ ._- N '04 / cu-cn-cnz-ci coocn (Ph) 2 xylI1_ * z Diphenylmethyl-7-amino-3- (3-chloro-1- propenyl) -3-cephem-4-carboxylate hydrochloride (Z-isomer) (XVIII, hydrochloride) A 25% solution of 69 g (0.22 mmol) of chloroacetaldehyde in CHCl 3 was added to a solution of 80 g (0, 11 mol) XVI in 1.1 l of CH 2 Cl 2 containing 16.2 ml (0.06 mol) of N, O-bis- (trimethylsilyl) acetamide at -10 ° C in one portion and the mixture was allowed to stand overnight at 5 ° C. The mixture was concentrated to about 0.3 L, diluted with a mixed solution: ethyl acetate and isopropyl ether (1/2, 0.6 L), treated with silica gel (Wakogel C-100, 60 g) and filtered. through a dicalite pad. The filter cake was washed with the same solvent system (0.2 l). The combination of filtrate and washings was concentrated to about 0.2 L, treated with Girard reagent T (60 g, 0.26 mol) and 220 ml of 4N HCl and added with some seed crystals. of XVIII hydrochloride. After stirring for 3 hours, the resulting crystals were collected by filtration, washed with 0.5 L of water and 0.5 L of ethyl acetate and dried in vacuo to give 37 g (70%) of the title XVIII-123 SUS 256 hydrochloride. with a m.p. at> 185 ° C (dec.). The pale yellow needle bone product was identical to that obtained in Preparation Example 12.

Preparation Example 2 4 s-cgl-azn - fs .- N "da / I CBICB-CB: -C1 'CO00CH (Ph) 2 Y XVIII * Z Diphenylmethyl-7-amino-3- (3-chloro-1- propenyl) -3-cephem-4-carboxylate hydrochloride (Z-isomer) (XVIII, hydrochloride To a solution of 628 mg (2 mmol) of chloroacetaldehyde (25% solution in CHCl 3) in 10 ml of CH 2 Cl 2 was added 0.135 ml (0 .5 mmol) of N, O-bis (trimethylsilyl) acetamide and 728 mg (1 mmol) of XVI successively at 5 ° C. The mixture was allowed to stand overnight at 5 ° C. The mixture was evaporated and diluted with a mixture of ethyl acetate and isopropyl ether (1/2, 0 ml). Insoluble material was removed by filtration and the filtrate was concentrated to about 5 ml.

The concentrate was treated with 2 ml of 4N HCl, added with seed crystals of XVIII hydrochloride and stirred for 1 hour at room temperature. The crystals were collected by filtration, washed with 10 ml of ethyl acetate and 10 ml of water and dried in vacuo to give 384 mg (80%) of the title XVIII hydrochloride. of> 18S ° C (dec.). Pale yellow needles. This product was identical to that obtained in Preparation Example 12. 124 505 256 Preparation Example 25 2- (S-amino-1,2,4-thiadiazol-3-yl) -2- (propen-3-yloxyimino) -acetyl chloride hydrochloride (III-3 as its acid chloride hydrochloride) A. Methyl 2- (5-t-butoxycarbonylamino-1,2,4-thiadiazol-3-yl) -2- (propen-3-yloxyimino) acetate A mixture of 685 mg (3.37 mmol) of N- (propen-3-yloxy) -phthalimide prepared by the method of E.

Grochosaki & J. Jurczak, Synthesis 1976 682] and 175 mg (3.35 mmol) of hydrazine hydrate in 5 ml of ethanol were stirred for 1 hour at room temperature. The resulting precipitate was filtered off and the filtrate and washings were combined. To the solution was added 967 mg (3.37 mmol) of methyl 2- (5-t-butoxycarbonylamino-1,2,4-thiadiazol-3-yl) -2-oxoacetate and the mixture was allowed to stand for 1 hour. at room temperature and concentrated by means of rotary evaporators. The residue was purified by silica gel chromatography. The column was eluted with n-hexane / ethyl acetate (4: 1) and the fractions containing the main product were combined and evaporated under reduced pressure. yield 514 mg (46%). m.p. as-ss ° c. 1 In = Q (nar) 1 em '3100, 1745, 1710, 1610; ma !! uv) hax (cznsoa) 1 nm te) 223 (9700), 242 410000). nun =; (cnc13) 1 ppm 1.55 (sn. s. soc-H). 4.4u (zu, a, J = sHz, o-c fl z). 5.21 (za, m, c§2 = cn), S190 m; -cë = CH2, | brus' NH).

B. 2- (5-t-Butoxycarbonylamino-1,2,4-thiadiazol-3-yl) -2-prophen-3-yloxyimino) acetic acid1) A solution of 770 mg (2.3 mmol methyl-2- (5 mmol) -t-butoxycarbonyl-125 505 256 amino-1,2,4-thiadiazol-3-yl) -2- (propen-3-yloxyimino) acetate and 3.5 ml of a ZN sodium hydroxide solution (7.0 mmol) in ml The reaction mixture was concentrated in vacuo and diluted with 10 ml of a 1: 1 mixture of ethyl acetate and water, the aqueous layer was separated, acidified to pH 2 with 6N hydrochloric acid and extracted with 2 x 10 ml of ethyl acetate. over magnesium sulphate and concentrated by means of a rotary evaporator to give 596 mg (81%) of the title compound, mp 134-135 ° C (literature value1): mp 135-136 ° C.

(Nujol) i cm * 3150, 1745, 1710, 1sso.

IR: νmax UV: λmax (C 2 H 5 OH) in nm (E) 223 (11000), 242 (11300).

J = SHZ | I mp cgfcn), 6.0 (m, m, cycnz). 1) I. Csendes, et al., J. Antibiotics, §§, 1020 (1983).

C. 2- (5-Amino-1,2,4-thiadiazol-3-yl) -2- (propylene-3-phyloxy-imino) -acetic acid '(III-3) 1) A solution of 570 mg (1, 74 mmol) 2- (5-t-butoxycarbonylamino-1,2,4-thiadiazol-3-yl) -2- (propen-3-yloxyimino) acetic acid in 6 ml of trifluoroacetic acid was allowed to stand for 1 hour at room temperature. the temperature of the giving. Evaporation followed by trituration with 30 ml of isopropyl ether gave 376 mg (95%) of the title compound. M.p. 109 ° C (dec.). 1 In = * max (uujol) -1 cm -1 3180, 1710, 1545, 1460. uv = xmax (cznson) 1 nm (s) 245 (nsoo). nun =: wusø-as) 1 ppm 4.77 (za, a, J = saz, o-cnz), s, 2o (zu, m, cg = ca), 6.0 (m, m, cgæaz). 126 505 256 1) Japan Kokai S7-112396 (7/13/82, Fujisawa) Brit. apply. 7935533 (10/12/79).

D. 2- (S-Amino-1,2,4-thiadiazol-3-yl) -2- (propen-3-yloxyimino) -acetyl chloride hydrochloride A solution of 350 mg (1.1 S4 mmol) of III -3 and 410 mg (1.97 mmol) of phosphorus pentachloride in 5 ml of dichloromethane were stirred for 1 hour at 25 ° C. The reaction mixture was poured into 60 ml of n-hexane and the precipitate was filtered off. Yield 323 mg. 1765

IR: Q (Nuiol) in cm-1 max. Preparation Example 26 2- (5-Amino-1,2,4-thiadiazol-3-yl) -2-propargyloquinoaminoacetyl chloride hydrochloride (III-4 as its acid chloride hydrochloride) A. Methyl -2- (5-t-butoxycarbonylamino-1,2,4-thiadiazol-3-yl) -2-propargyloxyiminoacetate A 1H A. A suspension of 870 mg (4.32 mmol) of N-propargyloxyphthalimide1) and 200 mg (4 .0 mmol) of hydrazine hydrate in 5 ml of ethanol were stirred for 1 hour at 25 ° C and filtered. To the combination of filtrate and washings was added 1.0 g (3.86 mmol) of methyl 2- (St-butoxycarbonylamino-1,2,4-thiadiazol-3-yl) -2-oxoacetate. The solution was allowed to stand for 1 hour and concentrated under reduced pressure. Purification by silica gel chromatography, followed by evaporation, gave 319 mg (27%) of the title product, m.p. 72-75 ° C. 2) 1 IR: Vmax (Kßr) 1 cm-3200, 2380, 1745, 1710, 1610.

UV: axHax (C 2 H 5 OH) 1 nm (8) 235 112200). _? Sum-do) in ppm 1.56 (911, s. Soc-n), 3.55 (111, t, J = 2Hz, cacn), 4.85 (za, d, J = 2nz, 127 505 256 1 ) Commercially available, Aldrich. 2) I. Csendes et al., J. Antibiotics gg, 1020 (1983).

B. 2- (St-Butoxycarbonylamino-1,2,4-thiadiazol-3-yl) -2-propargyloxyiminoacetic acid A solution of 490 mg (1.4 mmol) of methyl 2- (5-t-butoxycarbonylamino-1) , 2,4-thiadiazol-3-yl) -2-propargyloxyiminoacetate and 2.2 ml of a 2N aqueous solution of sodium hydroxide (4.4 mmol) in 14 ml of methanol were refluxed for 30 minutes. The reaction mixture was concentrated under reduced pressure, and a 1: 1 mixture of ethyl acetate and water was added to the solution. The separated aqueous layer was acidified to pH 2 with 6N hydrochloric acid and extracted with 2 x 10 ml of ethyl acetate.

Drying over magnesium sulphate, followed by evaporation of the organic layer, gave 149 mg (89%) of the title product, m.p. 135 ° C (dec.). 1 In = vhax (uujoly 1 cm '3350, 1720, 1s1o, 1sso. Üv 5 lmax (cznson) 1 nm (e) 233 (11soo). Ë J = 2Hz | d; J = 2Hzp Cgzcšßfn: 9: 0 (1fl l S: NH).

C. 2- (5-Amino-1,2,4-thiadiazol-3-yl) -2-propargyloxyiminoacetic acid (III ¥ 4) 3) '' A solution of 410 mg (1.26 mol) 2- ( 5-t-Butoxycarbonylamino-1,2,4-thiadiazol-3-yl) -2-propargyloxyiminoacetic acid 1 ml of trifluoroacetic acid was allowed to stand for 1 hour at 25 ° C. Evaporation followed by trituration of the residue with 25 ml of isopropyl ether gave 204 mg (72%) of the title compound. M.p. 156-158 ° C (dec.). 128 505 256 xn 1 qaax (uujol) 1 cm "ssoo, 2480, 1730, 1610. uv =: max 1c2n5ou> 1 mm 1 :) 234 112000). Nun 1 g (nnso-a6) 1 ppm 3,52 (1a , 1, a = 2nz, <: asacu), 4, ss (2111 d 'J = 2Hz | (za, br.s, Nnz). 2 3) Japan Kokai 57-112396 (7/13/82, Fujisawa) British Application 7935538 (10/12/79). 2- D. 2- (5-amino-1,2,4-thiadiazol-3-yl) -2-propargyloxyiminoacetyl chloride hydrochloride A mixture of 175 mg (0.07 mol) of III-4 and 182 mg (0.88 mmol) of phosphorus pentachloride in 2 ml of dichloromethane were stirred for 1 hour at -5 ° C. The reaction mixture was poured into 30 ml of n-hexane and the precipitate was filtered off. 34%). 1 xx = Q (nujol) 1 cm -1 1170. male Preparation Example 27 2- (5-Amino-1,2,4-thiadiazol-3-yl) -2-cyclopentyloxyiminoacetyl chloride hydrochloride (IIIQS as its acid chloride hydrochloride) '' “A. Methyl-2- (5-t-butoxycarbonylamino-1,2-§-thiaoia; o1 * 3-yl) -2-cyclopentyloxyiminoacetate A suspension of 860 mg (3.7 mmol) ) N- (cyclopentyloxy) - phthalinyl) and 1ase mg (3.1 mmol molar nyarazine): 1 s ml ethanol was stirred for 1 hour at ambient temperature and was filtered. The filtrate and washings were combined and added to 1.06 g (3.7 mmol) of methyl 2- (5-t-butoxycarbonylamino-1,2,4-thiadiazol-3-yl) -2-oxoacetate). The solution was allowed to stand for 1 hour at room temperature and concentrated in vacuo. The residue was purified by silica gel column chromatography. Elution with a 4: 1 mixture of n-hexane and ethyl acetate, followed by evaporation, gave the title product in a yield of 906 mg (81%) and with amp. 115-11a ° c. 1 In = vmax (xsr) 1 cm 3200, 1745, 1710, 1sso. uv = lhax (cznson) 1 nm te) 217 (1800), 252 (7600).

NMR: δ (CDCl 3) δ ppm 1.51 (9H, s, BOC-H), 1.60 (8H, br.s, - HG), 3.88 (gu, s, 00143). 4.90 '3 (1n, br.s,) <:] 1, 8.70, (1n, br.s, O NH). 1) U.S. Pat. Patent 3,971,778 (7/27/76; Glaxo), Brit. apply. 49255 (10/25/72). 2) I. Csendes et al., J. Antibiotics åâ, 1020 (1983).

B. 2- (5-t-butoxycarbonylamino-1,2,4-thiadiazol-3-phyl) 2-cyclopentyloxyiminoacetic acid A solution of 500 mg (1.34 mmol) of methyl 2- (5-t-butoxycarbonylamino-1,2) 4-thiadiazol-3-yl) -2-cyclopentyloxyiminoacetate and 2 ml of a 2N sodium hydroxide solution (4 mmol) in 15 ml of methanol were refluxed for 30 minutes. The reaction mixture was evaporated and 10 ml of a 1: 1 mixture of ethyl acetate and water was added to the solution. The aqueous layer was separated, acidified to pH 2 with GN hydrochloric acid and extracted with 2 x 10 ml of ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure to give 377 mg (78%) of the title compound, m.p. 1ss ° c (sönaeraelning). 130 505 256 0 (xxx) 1 cm "3100, 1110, 1ss0.

IR IBEX UV: axHax (C 2 H 5 OH) 1 nm (E) 238 (13300). una =; (0Mso) 1 ppm 1.51 (sa, s, soc-a), 1.70 (su, br.s, H 0- <2] 1, 4.02 110. m.> <11 O C. 2- (5-Amino-1,2,4-thiadiazol-3-yl) -2-cyclopentyloxyimino-acetic acid (III-5, Z-isomer) 3) I hd 1 'A solution of 348 mg (0, 97 mmol of 2- (5-t-butoxycarbonylamino-1,2,4-thiadiazol-3-yl) -2-cyclopentyloxyiminoacetic acid in 2 ml of trifluoroacetic acid were allowed to stand for 1 hour at room temperature.The reaction mixture was concentrated under reduced pressure. with 5 ml of isopropyl ether and 10 ml of hexane to give 215 mg (86%) of the title compound, mp 162-165 ° C (dec.) (literature value 3): mp 160-165 ° C (dec.) . 1 in = umax (uujo11 1 cm '3290, 3200, 1110, 1615, 1600. uv 3 lmax tczason) 1 nm 12) 238 113300). m), 8.22 (2H, S). 3) Japan Kokai 57-158769 (9/30/82, Fujisawa) Brit. apply. 0101134 (3 / s / 01). 0. 2-15-amino-1,2,4-thiaziazol-3-yl) (2-cyclopaptyl) x1-iminoacetyl chloride hydrochloride "A solution of 190 mg (0.74 mmol) of III-5 and 219 mg ( 1.0 mm / h) phosphorus pentachloride in 5 ml of dichloromethane was stirred for 1 hour at room temperature The reaction mixture was poured into 50 ml of n-hexane The resulting precipitate was collected by filtration Yield 122 mg (60%) 1 rn = Q (uuj ° 1) 1 cm -1 1160. max Preparation Example 28 Benzotriazol-1-yl-2- (S-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetate A mixture of 2.7 g (20 mmol) 1-Hydroxybenzotriazole and 4.12 g (20 mmol) of dicyclohexylcarbodiimide in 65 ml of DMF were stirred at room temperature After 15 minutes, 4.04 g (20 mmol) of III-1 were added to the stirred mixture at 6 ° C and the stirring was continued. The reaction mixture was filtered to remove the insoluble urea and the filter cake was washed with a small volume of DMF, the filtrate and the washing liquids were combined and poured into 800 ml of ice water. whereby 5.24 g (82%) of the title compound were obtained as a light gray powder. M.p. 189-192 ° C (dec.).

In = omax (Kax) 1 = m'1 1815, 1620, 1540, 1415, 1090, 1oso, 1oos, 945, ass, 740. uv = Anax 1c2H5oH1 1 nm 1z} * cm) 246 (sec), zassk 1228) .

Claims (3)

505 256 m PATENT REQUIREMENTS Compounds of the formula 'zu-f s xxx: JP' cn-cs-cafnšo coca 9 wherein, -N = -_ IQ is a quaternary ammonio group of the formula 9 a "'É-wefu' Ii-lit l -) '. Wherein b13, B14 and B15 are the same or different and are lower alkyl, lower alkenyl, amino (lower alkyl) with the proviso that amino may not be present on the α-carbon atom, or hydroxy (lower alkyl) with the proviso that the hydroxy group may not be present on an α-carbon atom; B16 is hydrogen, lower alkyl, lower alkoxy, lower alkylthio, amino, lower alkylamino, di (lower alkydamino, formylamino, lower alkanoylamino, carboxy, hydroxy , carboxy (lower alkyl), carboxy (lower alkyl) thio, hydroxy (lower alkyl), halo (lower alkyl), amino (lower alkyl), (lower alkoxy) (lower alkyl), carbamoyl or N- (lower alkyl) carbamoy1 or E16 is a divalent alkylene group with 3-5 carbon atoms; E17 is lower alkyl, (lower alkoxy) (lower alkyl), halo (lower alkyl), allyl, hydroxy (33 505 256 (lower alkyl) with the proviso that hydroxy the group may not be present on the α-carbon atom, amino (lower alkyl) with the proviso that the amino group may not be present on the α-carbon atom, or phenyl (lower alkyl); 1:18 is hydrogen, lower alkyl, lower äneeri, (lower äneexnaägre älkyn, (lower älkyntie, amino, (lower alkyl) amino, di (lower alkyDamino, carboxy, hydroxy, carboxy-lower alkyl), hydroxy (lower alkyl), amino-lower alkyl ), formylamino, (lower alkanoyl) -amino, carbamoyl or N- (lower alkyl) carbamoyl; n is an integer from 1 to 3; Z is CH 2 or, when n is 2, Z may also be S, O or N- Rlg, where B19 is hydrogen or lower alkyl; and B20 and B21 are the same or different and are hydrogen, lower alkyl, lower alkoxy, (lower alkylthio, amino, lower alkylamino, lower alkylamino, carboxy, hydroxy, hydroxy (lower alkyl), amino-lower alkyl), (lower alkoxy) (lower alkyl), carboxy-lower alkyl), carboxy-lower alkyhamino, (lower alkanoyDamino, carboxy-lower alkanoyl) -amino, carbamoyl or N- (lower alkylcarbamoyl); and salts, esters, solvates and hydrates thereof. Compounds according to Claim 1, characterized in that the group 'N - N = - "- Q is 1-methylpyrrolidinio, pyridinio, Z nopyridinio, β-carbamoylpyridinio, 4-carbamoylpyridinio, β-aminomethylpyridinio, 2-methylthiazolio, 3-hydroxymethylpyridinio, fl1-hydroxymethylpyridinio, 4- (N-methyl-carbamoyl) pyridinio, 4-propenio-3-pyrino -carboxymethyl-pyridinio or 4-carboxymethylthiopyridinio. A process for the preparation of compounds of formula XI -r - rmj / '_13 C11-CI-'CBZQISO 0 m9 sus zsel we Q 10 wherein -NIZ Q is a quaternary ammonium group having the meaning given in claim 1,> or a salt, ester, solvate or hydrate thereof, characterized in that reacting a compound of formula I -®_m I with a compound of formula II s: zum-r 'pr-fl / cazci II coastal, to obtain a compound of the formula III sa III o "I" coocs m), then the compound of the formula III reacts with sodium iodide or potassium iodide to give a compound of the formula IV Crr-g, ma, IV then the compound of the formula IV reacts with triphenylphosphine or reacts the compound of formula III with triphenylphos fi n to give a compound of formula V F55 '505 256 O *' * ° fl / gm), V ma, then the compound of formula V is reacted with a base to give a compound of formula VI Ü e »CÜ, a VI Én (m, then the compound of formula VI reacts with CICHZCHO to give a compound then the compound of formula VII reacts with sodium iodide or potassium iodide to give a compound of formula VIII -u --- r's 4 o -cnzx VIII ooocnttu, then the compound of formula VIII reacts with a secondary amine R HN <, where R and R 'are each methyl or together form pyrrolidine, RI to give a compound of formula IX 505 256 mk s. then the compound IX reacts with R "Y, where R" is a tertiary amine Q: N and Y is chlorine, bromine or iodine, to give a compound of formula X cooca m), or reacting compound VIII with a tertiary amine QšN, to give compound X, then treating compound X with Girard's reagent T or HCl to give compound XI and, if desired, converting the free acid to a salt, ester , solvate or hydrate thereof.