SE470260B - Intermediates for cepholosporins - Google Patents

Description

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 C 0 O- 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 RI -CONB --_ L.

N 2 / _ '0 \\ o: i °° 9 \ æ2_n \ ä, 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 \ I \ _.¶ () I \ I f; å »23 Ä7o zeo is an optionally substituted heterocyclic cation group containing more than one nitrogen atom; and pharmaceutically acceptable salts thereof. Compounds of the formula sn are also disclosed as intermediates: -ÄÄ-í-cona- * í / N u S R2 Ö? - * Ü //, \\: §2 ~ \ 34 auf-riga 'I wherein R1 and R2 have above given meaning, R4 is a protected carboxyl group and X- is an acid group.

C) European Patent Application 74 653, published March 23, 1983, discloses cephem compounds of the formula 3 l S 1 Äïç-c-coua-f-I / 3 n å; ) _- ug- cnïu / R cooe _ 4 n: o ”wherein R 1 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 alkyl) amino, hydroxy- (lower alkyl) amino, N-protected hydroxy (lower alkyl) amino, acyloxy (lower alkyl) ), (lower alkoxy) (lower alkoxy) (lower alkyl), di (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 470 260 alkyl) thio, N-containing unsaturated S-membered heterocyclic group, N-containing unsaturated 5-membered heterocyclylthio or N-containing unsaturated 5- or 6-membered heterocyclylthiol lower alkyl), which may be substituted by suitable substituents; and * R is hydrogen or lower alkyl; is a salt thereof. i D) U.S. Patent 4,332,800, issued June 1, 1982, discloses, inter alia, compounds of the formula nl__åsl fl àl-: Icomzñíëïcå _ I 009 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 on 24 March 1§82, discloses cephem compounds of the formula (mn å "mr- fi- cona- fi L, // / °. C112: m? 1 wherein n 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 470 26G thiazolio-. , optionally substituted pyrazolio, tri (lower alkyl) ammonio or pyridinio group of the formula R 1 wherein R e 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 [the substituent is lower alkyl, lower alkanoyl or aminobenzenesulfonyl, di (lower alkyl) amino, substituted carbamoyl [the substituent is lower a alkyl, hydroxy (lower alkyl), lower alkoxy, hydroxy or cyanoq], di (lower alkyl) -carbamoyl, thiocarbamoyl, cycloalkyl, phenyl, hydroxy, lower alkoxy, halogen, (lower alkoxy) carbonyl, lower alkanoyloxy, lower alkanoyl, carboxyl , sulfo, cyano, nitro or hydroxy sulfo (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 July 24, 1981, discloses 3-vinyl cephem compounds of the formula S aï- a-cona- fi \ _ / 6 'z \ cn-cn¿a 470 260 wherein R1 is an optionally protected amino-substituted heterocyclic group | which may also contain halogen, or a group of the formula fi soznn 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 "-1 alkenyl), lower alkynyl, lower alkenyl [optionally substituted with carboxy or protected carboxy, 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 α \ "CON1-H N / X !! H \ ° 2 S1 / RÅ da wherein OR4 is methoxy, carboxymethoxy, tert-butoxycarbonylmethoxy or 1-tert-butoxycarbonylethoxy.

G) British Patent 1,399,086, published June 25, 1975, contains a generic description comprising a very large number of the formula a- fi ïo-na 1/3 Q 'on' Ä'- / oon ': 470 260 wherein R is hydrogen or an organic group, Ra is an etherifying monovalent organic group, which is attached to the oxygen via a carbon atom, B is> S or) S -90 and P is an organic group.

According to that embodiment, P can b1.a. be a vinyl group of the formula -CH = C / \ 4 ..

R wherein R 3 and R 4 may independently be hydrogen, nitrile, lower alkoxycarbonyl or a substituted or unsubstituted aliphatic, cycloaliphatic, araliphatic or aromatic group. However, the 5-amino-1,2,4-thiadiazol-3-yl group is not identified as a possible R-substituent and there is no disclosure or indication that P may be a quaternary ammonio-substituted propenyl group. U.S. Patents 3,971,778 and the U.S. Patent 4,024,133, 4,024,137, 4,064,346, 4,033,950, 4,079,178, 4,091,209, 4,092,477 and 4,093,803 are similar; nings.

H) European Patent Application 88 385, published September 14, 1983, discloses compounds of the formula aL-i-coua-q-r s 0112 6: - '4 / 33a wherein R 1 is unsubstituted thiadiazolyl; R 2 is carboxy (lower alkyl) or protected carboxy (lower alkyl); R 3 is hydrogen, halogen or lower alkenyl; and R 4 is carboxy or protected carboxy. Although 1-propenyl is stated as one of the 470,260 possible meanings for R3, the application only exemplifies compounds in which Ra 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 N ac conz _es "s, .Ål Ä / = az s: _ \ ° Rs ° // cn-ca-n <: ¿coon wherein Rs may be, inter alia, 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 is 1: 4 in common with the nitrogen element. bonded 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 derivatives. There is no disclosure or suggestion of an -amino-1,2,4-thiadiazol-3-yl group instead of the 2-amino-thiazol-4-yl substituent or of a ¿quaternary ammonio-substituted propenyl group Published British Patent Application 2,051,062 is consistent with and has a similar description. vning.

J) European Patent Application 53 537, published on 9 June 1982, discloses, inter alia: 3-vinylcephalosporin derivatives with iormeln liva 260. _ s. § \ __'_ - _- coun-FJ - (/ Q H2 so !! CHICE-Näa X5 RS coon: 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 3 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. only as intermediates in the preparation of 3-thiovinyl-cephalosporin derivatives, there is no disclosure or indication of a 5-amino-1,2,4-thiadiazol-3-yl group in place of 2-aminothiazol The 4-yl substituent or about a Lquaternary ammonio-substituted propenyl group as the 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-vinylcephalosporin derivatives of the formula R'1.-NH-, 70 260 wherein R ° 1¿ (in one of several embodiments) may be wherein Rs.a. may be hydrogen, alkyl, vinyl, cyanomethyl, an oxime protecting group such as trityl, etc. or a group of the formula -C-c-COOR 5 19 / \ nb5 'wherein Ras and Rbs 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 0 is hydrogen or an acid protecting group such as methoxymethyl; R 0 (in one of several embodiments) may be a methyl group substituted with an S- 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 formula 2a R 4 SO 2 O - wherein R 3 may be alkyl, trihalomethyl or optionally substituted phenyl.

These compounds are stated to be intermediate products in the preparation of compounds wherein the 3-substituent is a group of formula 11 - 470 260 which are said to have antibacterial activity.

Although this patent includes the possibility that R 0 is a methyl group PP which is 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 bound via one of its carbon atoms. Thus, there is no indication of a Lquaternary ammonio-substituted propenyl group. The reference exemplifies the Ro 1 intermediates and end products only as methyl. Furthermore, in both the intermediates and the final product, the propenyl group must contain a second substituent (-O 3 SR and -SR, respectively). There is also no disclosure or indication of an s-amino-1,2,4-thiaziaz-3-yl group 1 instead of the 2-aminothiazol-4-yl substituent.

L) European patent application 53 S38, published on 9 June 1982, reveals, inter alia: 3-vinylcephalosporin intermediates of formula m, 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 a 5-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. 12 470 260 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 S g CON8 - 'elm s, 032 J: a-cn-cnz-uo' C '_' _ »wherein R 1 is hydrogen or a conventional amino-protecting group, R 2 is hydrogen, a straight-chain or branched chain alkyl group containing a 1-4 carbon atoms, a cycloalkyl or cycloalkenyl ring containing 3-6 carbon atoms or a group of the formula R 4 R 4 I 3 I __ 3 COOH -C-CH = CH-R, -CC =: CR, or I5 R 5 R 4 is 4 -f-COOH 1 R 5 are: 23 a: be, iagre any-i anar xarboxyl, x is hauogan, 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 G-NEEQ is a quaternary ammonio group, and non-toxic pharmaceutically acceptable salts and physiologically hydrolysable esters thereof. Also included within the scope of the invention are solvates (including hydrate) 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 form of 2-aminothiazole-4- yl 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 "sight" or "Z" configurations with respect to the alkoxyimino group. Because the compounds are geometric isomers, some amount of the "anti" isomer may also be present. This invention includes compounds of formula I which contain at least 90% of the "syn" isomer. Preferably, the compounds of formula I are "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 field of penicillin and cephalosporin. The preparation of these acid addition salts is carried out by conventional techniques. Examples of physiologically hydrolysable esters of the compounds of formula I include indanyl-phthalidylmine methoxymethyl and acetoxymethyl-q-pivaloyloxymethyln glycyloxymethylene phenylglycyloxymethyl- and 5-methyl-2-oxo-1-methyl-dioxol-1-3-oxo-1-methyl other physiologically hydrolyzable esters known and used in the penicillin and cephalosporin regions. 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 I. 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 mermaid is usually in the range of about 500 to 5000 mg per day, 1s __ 470 260 depending on the frequency and mode of administration. When administered intramuscularly or intravenously 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 Q -EEEQ 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 enol-carbonate hydroxide with the proviso that the hydroxy group may not be present on the encyclo 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 the like). 16 -tb \ l CD N) O \ CJ 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 hub; ammonia ring systems include, for example, those with the forms æ / n, æwn, ._ 'cân / s. -nn ~ ø 9 ® ..); ___._ 1 -N-à 'N _ ""' _ N m + \ 'R9 II ¶ "_' R9 v I ï-Rs c sXalg XR” s Rio RB 9 __ -uP - val n 9 'l O m' _ __, 1! ü, 819 59 '\ ~ 5 // S _9 1110 \ Rs c Río I N-' fê ”Û -u / '. I i jL« SR, n çn / N 1 '¿7o 260 90 and the like, wherein R and R 1 are the same or different and 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), di (lower alkyl) amino (lower alkyl), lower alkylamino, di (lower alkyl) lower alkyl) amino, carboxy (lower alkyl), carboxylic lower alkyl) amino, carboxy (lower alkyl) thio, carbamoyl, N- (lower alkyl) carbamyl, formylamino, acylamino, acyloxy, phenyl, pyridyl, amidino, guanidino and the like. the structure of the heterocyclic ring so allowed, R 9 and R 10 together may be an alkylene group containing 3-S carbon atoms, for example propylene.

Examples of combined acyclic / cyclic 'quaternary ammonio groups include, for example, those of formula e? R 0 I / \ __ / 1 / R -I> - = - 18 60 7Ü PO and the like. wherein R "is, for example, lower alkyl, (lower alkoxy lower alkyl), hydroxy lower alkyl) with the proviso that hydroxy may not be present on the end-carbon atom, carboxy (lower alkyl), amino lower alkyl) with the proviso that anino can not present on a d-carbon atom, lower alkenyl, lower alkyl) 1 allyl and the like and B12 is, for example, hydrogen, hydroxy, halogen, lower alkyl, hydroxy (lower alkyl) (lower alkoxy) (lower alkyl), lower alkyl), amino lower alkyl), lower alkoxy, lower alkylthio, lower alkenyl, amino, lower alkylamino, di (lower alkyl) amino, acylamino, acyloxy, carbamoyl, lower amino-alkyl), phenyl, pyridyl, amidino, guanidino and the like.

Preferred quaternary ammonio groups are those of the formulas 'Ris _ __' I r 16 Qšmu 'E -j-g' RIS s E17 æ are; wherein R 1, R 2 and R 3 are the same or different and are lower alkyl, lower alkenyl, lower amino alkyl) with the proviso that amino may not be present on the lower carbon atom or hydroxy lower alkyl) with the proviso that the hydroxy group may not be present on an o: carbon atom n 'is hydrogen, lower alkyl, an alkoxy, lower alkynio, amino, lower alkylamino, di (lower alkyhamino, formylamino, 19,470,260 (lower alkanoyl) amino, carboxy, hydroxy. carboxy (lower alkyl), carboxy (lower alkyl) tic, 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: lower alkyl, lower alkoxy (lower azoxy, mm (lower alkyl), allyl, hydroxy (lower alkyl) with the proviso that the hydroxy group does not exist on the GG-carbonate amino (lower alkyl) with the proviso that the amino group does not exist on the u-carbon atom or: phenyl (lower alkyl); R18 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 or, when n is 2, Z may also be S, O or N-R 19, where R is hydrogen or lower alkyl; and R 20 and R 21 are the same or different and are hydrogen, lower alkyl, lower alkoxy, lower alkyltic, amino, lower alkylamino, di (lower alkyl) amino, carboxy, hydroxy, hydroxy (lower alkyl), amino (lower alkyl) | (lower alkoxy) (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), tr1 (lower alkyl) ammonio (and especially trimethylamino), pyridiniol, aminopyridinio, formylaminopyridinio, carbamoylpyridinio, carbamoylpyridinio , carboxy-pyridinio, hydroxy (lower alkyl) pyridinio, N- (lower alkyl) -carhamcylpyridinio, lower alkylene-pyridinio, 2-methylthiazolio and 2-amino-5-thiazolo [α, 5-q] pyridinio. In the compounds of formula I, especially preferred values for R 2 are lower alkyl (and especially methyl), cycloalkyl having 3-5 carbon atoms, 1-carboxycycloalk-1-yl having 3-5 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- Methoxyiminoacetamide [7- [3- (trimethylammonio) -1-propen-1-yl] -3-cephem-4-carboxylate, 7- [2- (5-amino-α, 2,4-thiadiazole-3- yl) -2-methoxyiminoacetamide] -3- [3- (1-methylpyrrolidinio) -1-propen-1-yl] -3-cephem-4-carboxylate, 7- [2- (5-amino-1,2, 4-thiadiazol-3-yl) -2-methoxyimino: acetamido] -3- [3-pyridinio-1-propen-1-yl] -3-cephem-4-carboxylate, 7- [2- (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-propenyl] -yl] -3-cephem -4-carboxylate, 7-12- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamide] -3- [1- (3-aminomethylpyridinio) -1-propeno- 1 * yl7-3-cephem-4-carboxylate, 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamide] -3- [§- (3- carbamoylpyridinio) -1-propen-1-yl] -3-cephem-4-carboxylate, 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) - 2-Methoxyimino-acetamide] -3- [3- (4-carbamoylpyridinio) -1-propen-1-yl] -3-cephem-4-carboxylate, 7-α2- (5-amino-1,2,4- thiadiazol-3-yl) -2-methoxyiminoacetamide [7- [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 - 470 260 7- [2- (5-amino-1,2,4- thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- [3- (4-hydroxymethylpyridinio) -1-propen-1-yl] -3-cephem-4-carboxylate, 7- [2- (5- amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- [§- (3-hydroxymethylpyridinio) -1-propen-1-yl] -3-cephem-4-carboxylate, 7- [2- (S-amino-1,2,4-thiadiazol-3-yl) -2-methoxy] aminoacetamide] -3- [α-κ4- (N-methylcarbamoyl) pyridinio) -1-propene-1 -yL7-3-cephem-4-carboxylate, 7- (2- (s-amino-1,2,4-thiazole-1-3-yl) -2-methoxy] -mino-acetamide] 7- [3- (2, 3-propylenepyridinio) -1-propen-1-yl] -3-cephem-4-carboxylate, 7- [E- (5-amino-1,2,4-thiadiazol-3-yl) -2-ethoxyimino- acetam idq] -3- [3- (4-carbamoylpyridinio) -1-propen-1-yl] -3-cephem-4-carboxylate, 7-12- (5-amino-1,2,4-thiadiazol-3-yl) -2-cyclopentyloxy-iminoacetamide [7- [3- (4-carbamoylpyridinio) -1-propen-1-yl] -3-cephem-4-carboxylate, 7- [Y- (5-amino-1,2, 4-thiadiazol-3-yl) -2-allyloxyiminoacetamide] -3- [α- (4-carbamoylpyridinio) -1-propen-1-yl] -3-cephem-4-carboxylate, δ 7-12- ( S-amino-1,2,4-thiadiazal-3-yl) -2-propargyloxy-iminoacetamide] -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- (4-carboxypyridinio) -1-propen-1-yl] 3-Cephem-4-carboxylate, 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-ethoxyiminoacetamide] -3- [3- (4-carboxypyridinio-2-propene) -1-yl] -3-cephem-4-carboxylate, 7- [β- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamide] -3- [3- ( 3-carboxymethylpyridinio) -1-propen-1-yl;] - 3-cephem-4-carboxylate and 7- [2- (S-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetate] amideq] -3- [§- (4-carboxymethylthiopyridinio) -1-propen-1-yl] -3-cephem-4-carboxylate. 22 470 260 The numbering system used in the present context for the various reactants, intermediates and final products is as follows: Arabic numeral Letter (1 case) (if applicable) [commercial number] - The Roman numeral indicates whether the compound is an end product ( I) or an intermediate or other reactant (all other Roman numerals). The Arabic numerals_ and the letters are not used in such 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 f 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 character is also used with the generic R 2 substituent (ie, R 2 ') when generically referring to an R 2 groupPPv containing a protected carboxyl group.

The letter at the end of the association number refers to the special meaning of the quaternary ammonio group ê> -nšQ For convenience, the Arabic numerals and letters attributed to some of the preferred R2 groups and quaternary ammonio groups are given below. sniabísk 'number ~ az 1 = methyl 2 = ethyl 3 = allyl 4 =' _ propargyl = cyclopentyl Letter A. (> w CJ Z: zt * w G4 H: n cm w gg Q; ry N 23 570 260 0 -na-L 1-methylpyrrolidinio pyridinio 2-amino-5-thiazolo [2,2-q] -pyridinio trimethylammonio 3 -aminopyridinio-3-formylaminopyridinio-3-carbamoylpyridinio-4-carbamoylpyridinio-3-aminomethylpyridinio-2-methylthiazolio-3-hydroxymethylpyridinio-4-hydroxymethylpyridinio of the compounds of this invention, the values of the minimum inhibitory concentration (MIC) of the compounds were determined by the double agar series dilution method in Mueller-Hinton agar with respect to 32 strains of test organisms in six groups. determined in these experiments are given in Table 1. '' 24 470 260 202211 1 '“Before .. gonfyn Geometric mean of MIX (pa / ml) ning at double - - no binaning 40 +) - 12 40 +) - 12 (0 -1-10 40-1-Ib 40-1-11 40-1-111 461 451. (51 cs »<5) 411 1-12 2 / 2-1 / 1 0.26 0.10 - 0.05 0.15 0.23 2.4 1-11 2 / 2-1 / 1 0.13 0.35 0.029 0.05 0.11 1.4 1-12 - 2 0.20 0.40- 0.016 0.044 0.11, 1.6 1-12 2 / 2-1 / 4 0.35 0.00 0.05 0.11 0.35 3.5 1-1c 2 0.10 0.20 0.0011 0.033 0.001 3.0 1-10 2 / z-1/1 0.61 1.4 0.10 0.26 0.46 2.4 1-12 2 / z- 10/1 0.30 0.53 0.05 0.016 0.26 1.3 1-12 _ 2 0.20 0.40 0.0094 0.029 0.10 1.4 1-12 2 0.15 0.40 0.0094 0.033 0.099 1.2 1-10 2 0.20 0.35 0.0094 0.033 '0.10 1.4 1-12 2 0.20 0.40 0.013 0.043 0.10 0.91 1-11 2 0.00 1.6 0.10 0.20 0.69 3.1 1-10 2 0.11 0.35 0.025 0.016 0.15 156 t 1-1: 2 0.35 0.00 0.029 0.044 0.20 3: 5 1-12 2 0.26 0.61 0.029 0.000 0.15 2.6 _ 1-12 _ 2 0.35 0.10 0.029 0.10 0.11 2.3 1-12 2 / z-1/1 1.2 1.6 0.013 0.066 0.30 5.1 1-10 2 0.11 0.35 0.029 0.033 0.11 14 1-22 2 0.20 0.40 0.014 0.051 0.15 1: 4 1-22 2 1.2 2.1 0.016 0.11 0.35 4.1 1-22 2 '1.4 3.1 0.044 0.15 0.69 10 1-32 2 0.23 0.40 0.051 0.10 0.52 1: 9': -42 2 0.26 0.46 0.056 0.11 0.60 2.6 1-52 2 0.13 0.40 0.20 0.46 2.1 4: 2 1-12 2 0.0 1.6 0.013 0.001 0.34 14 1-10 2 0. 1 0.92 0.0095 0.044 0.23 14 (G +) - Ia (G +) ~ Ib (G -) - Ia (G -) - Ib (G -) - II (G -) - III .f Table 2 1170 260: Penicillin-sensitive §¿ aureus (5 strains) Penicillin-resistant §¿ aureus (5 strains) Cephalotin-sensitive §¿ ~ col1 (2 strains), gl; gneumoniae (1 strain) and §¿¿ mirabilis (2 strains) Cephalotin-resistant §¿ coli (3 strains) and §l¿ Bneumoniae (2 strains) §¿'morganii (1 strain), Ent. cloacae (2 strains) and Ser. marcescens (2 tribes) Ps. aeruginosa (7 strains) __ below provides the protective dose (PD50) 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 during intramuscular administration of the test compounds to mice at a dose of 20 mg / kg. 'i-abën' á Pnso (mg / kg) .. _. ._. ' S..aureus "E.Icoli 'P..aern'inosa Compound' No." šhith 'Üfuhl' I-1B 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-13 0.39 0.015 3.9 I-1J 0.35 0.029 BT I-1K 0.53 ET ET 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 == not tested 26 470 260 gbell 3 cmax T1 / 2 AUC Compound No. (ßglml) lmlgl (Eg hr / ml) I-18 17 21 11 I-1C 21 32 18 I-1D 20 19 11 I-18 23 16 14 I-1J 19 16 9.7 I-1K 24 14 14 I-1! 20 23 14 I-1N 24 = '19 18 I-10 28 32 17 I-2N 22 20 12 I-3H 19 47 25 I-4H 27 22 16 I-SH 22 32 18 In another aspect, this invention relates to processes for the preparation of the compounds of formula I. The preferred The procedures are set forth in Reaction Schemes 1a, 1b and 1c below, while an alternative procedure is shown in Reaction Scheme 2. The abbreviation "Ph" denotes the phenyl group, thus the -CH (Ph) 2 group is the benzhydryl group, which is a preferred carboxyl protecting group. When R 2 contains a carboxyl group, it is desirable to protect the carboxyl group with a conventional carboxyl protecting group such as the t-butyl group. Y denotes chlorine, bromine or iodine. Éeaktlonsschema'1a fl = ~ \ _ | / ° II o // fn / cazc: C00C8 (Ph) 2 a-: fl -cooa In nzu-ßs / “\ ° R¿” N v 27 f-ÄWÛ 260 I s '7T * “* °°“ ““ ~ f WL ~ / ggn s \ n2 (lr-n cnzcl coocama, Na! Oz KI _ s 1; 5' ä pewa -__? I A / 2214 S \ ° R2 o // r- caz: coocs (Ph) 2 P m ”av rum), r-'N, f '13 OR: o // ngr (vn) 3 cooca (m 2 °°“ “" ““' 1 ” s = ° w 32 base S CONH- 'fi VII / N \ ° R2 car-_ z 3' Own (Pl fl z lClC fl zC H0 470 260: om t / s | vu: á fl- Bfc fl cuàcl Oxg 'na: eller x: nc com : / sj Éà fl; n, S \ ° R2 _ / cs-cscazz '' ¶ '_ n oocnmn, f * \ R. (secondary amin) -. - CON fl-' ñ s azufá s) OR: á'- / kcnca $ u <1 <COæB (Pb) 2 R 'nV cona-T s 19 Å \ K / P- / 9 / u sf' on: of s-cscnz-rc-: Q '_52 m' oqcazvna, QÉW XI (tartar;; amine fi 29 470 260 unblocking Ä \ ü .cows I / s azN S), \ OR2 N .ZH CH 9 a CR2_NÉQ DO 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 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 / oyclic. 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-5-thiazolo [1,5-c] pyridinio and the like). àèanèèia fi sgenèm n »II _ gm so 4-78 260 s 04-” / cnzcl oocawh), NaI or KI O cu-n - q / Q s / -N / XIV 'O! H2: rum) coocxuvrnz 3 mm, Qc fl- »fß æ xv 04" ”f az fl rn), coocnum), ba: Ga» ß N xv: / a-rtrn), 'ooc nam, 3' 479 260 CICHZCBO ® ° “ '“~ F °. XVII Ä" "" / u-cacnzci oocnlrn), __ - _.

Girard reagent T or HCl S. a rw-r 2 xvzzz oå- "/ cn-cncnzcl COOCH (Pb) 2 1 \ few !!: nn š 2 Kon: _ _ VIII as in Scheme 1a Reaction Scheme 1b is a variation of Reaction Scheme 1a in that the 7-amino group in 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 in the synthesis, otherwise the general procedure is the same 32 Reaction Scheme 1c C00CH (Ph) 2 gg! Or KI Qc fl qq -... j / s /; _ / Q cn = ca-cnzz cooca (Pn) ¿n az: 'a (secondary amine) Qæ-N - rs / COOCH (Ph ) zi ”y S ÖWf-f ß r-Ü __ xx: 60 ICHCH2-§š == Q CO9C fl (Ph) 2 ,, R -cncnz-n \\ \ _ RI / XVII XIX QEEN XI (tertiät" 'amin ) 33 4-79 260 S aza- j / Å / nu 0 ca-cacaz-nsq m6 N 'fi ° Y1er1ng meg _ III mc: own / 5 JL t! 4. ' In H2 'g \ oR2 //' _ 'N / ® ° ca-cacnz-NEQ C009 In 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. 34 -_ 470 260 - s - | - ~ -cous' i f * ä / Ga ”s S2 !! 3 \ 0g2 9 C fl ztl: v coocnu-n), nu o in coocamn, hn: / coocncrn), ° ”min vm -: mn massan), Kvaterniserixxg Kvatemise-rixzg 1. 'Avblodærm 1, Avz fl ækering Ib <7-N- acylation n:, IQ Compound I o -W-'Q .m6 _ 470 260 In Reaction Schemes 1a, 1b and 1c, the benzhydryl group has been shown as the preferred carboxyl protecting group. It will be appreciated by those skilled in the art that other carboxyl protecting groups, which are well known in the art, may 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 it in the form of its acid chloride. 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, Nazcos, RA-no (ouï resin, IRA (CO 3) resin or the like or a mixture thereof.

The chloroacetaldehyde used for the conversion of phosphorylidene 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-S 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 largely maintained the configuration of the parent compound VIII, while a long reaction period primarily gave the E isomer of compound IX. However, an excessively long reaction time at high temperature gives compound IX of low purity. We have found that about 10 minutes: via zs ° c and 2 hours: at 5 ° C gives pure IX in good yield. Using Reaction Scheme 1c, we have found that upon iodination of compound XIV with NaI, a purer compound is obtained if the acetone solution is diluted with CCl 4, when the iodination is substantially complete, and the isomerization portion of the reaction is carried out in the acetone-CCl 4 mixture. When iodination of the chloropropenylcephem compound (XVII) to the iodopropenylcephem compound (XIX) was carried out with KI in DMF, the isomerization of the double bond from Z to E took place as fast as the iodination took place. The whole reaction was completed within 45 minutes at room temperature to give pure XIX without dilution with CCl 4 during the course of the reaction.

Compound XII was normally deblocked without purification and the final product (I) was purified by reverse phase column chromatography using a glass column containing the filler removed from a Waters! Associates Prep- PAK-S00 / C18 cartridge. 37 370 260 9 næmtkns: àem2 _l, S n .f ä com: f | _ I 'L {N R1_s / \ ° R2 J- / s-cu-cuz: N ) 2 2 of-a / n-ca-cnznzq coocn (bn) 2 E.

Reduction XXIII XXVI 470 260 38 H Avbiæmrng N ______ __ S 1 :? ä com: -1 / I: zu S \ oa2 '_ n / æ. Α-cazna-Q C009 Reaction Scheme 2, shown 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 prior to 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 procedures. 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 I 390 S34, 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-n 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 the person 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 formula II from MIn-f RIE "s" z N / a-cn-ca fi gao 'cooe wherein R 1 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 1: 4 1: 4 coon - -ca = cn-n3,- 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 dedexylolate to to which they are attached may be a FI 40 ÄÉ ~ 7Û 260 cycloalkylidene ring having 3-5 carbon atoms and wherein G> -NEEEQ is a quaternary ammonio group, and non-toxic pharmaceutically acceptable salts and physiologically hydrolysable esters thereof, which process involves reacting a ning with the formula - (0) ß / sv \\ ä conz 1 _ sam / Ls) \ on2 '/ / 0 cafczacazz coosl wherein R2' has sam a meaning as R 2 or is a group of the formula 1 R 4 "or I -c-coosl C008 X 5 where X, R 4 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 on conventional method and then removes all blocking groups by conventional methods.

The present invention also relates to a process for the preparation of compounds of the formula 41 wherein the R1 is hydrogen or a conventional amino-protecting group, R2 is hydrogen and a straight-chain group. or branched chain alkyl group reaching 1-4 carbon atoms, a cycloalkyl or cycloalkenyl ring having 3-6 carbon atoms or a group of the formula R4: '24 coon -Å-cnæn-RÉ ', -c-cëc-R3, ene; F 'phase x 4 -f-coon.

R 5 - 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 with 3-S carbon atoms and 9 -N EQ is a quaternary ammonio group, and non-toxic pharmaceutically acceptable salts and physiologically hydrolysable esters thereof, which process involves acylating a compound of the formula 42 ss' zw fi- 'I fr' / ~ ._ C90 9 -: if with an acid of the formula NTI- fi- LCOQH Ä NN \ 2 I BZHN s / ° R n: or with an acylating derivative of said acid, wherein R2 'has the same meaning as R2 or is a group of the formula coosl a or wherein X, RA and R 5 have the meanings given above, B1 is a conventional carboxyl protecting group and B2 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 prefer 43 ävo 260 normally 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-butylr-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. for example, 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 α 444 en-cncazz xxvzrz wherein Z is chlorine, bromine or 10, 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 f F4 n4 coon -c-cH = cH-R3, -g-cT-: c-Rïs, enar Is s R nx R4 -è-coon Rs wherein R3 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 formula 45 wherein R 22 is hydrogen or a conventional carboxyl protecting group and R 23, R 24 and R 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 / r- "f en ca-ca Er? - o 2" Q coca XXII wherein $: kÉEEQ is a quaternary ammonio group, or a salt, ester, solvate or hydrate thereof .

The terms "acylamino" and "acyloxy" in the present context refer to an acylated amino or acylated hydroxy group, where the acyl radical is lower alkanoyl (for example formyl, acetyl, propionyl, butyryl, isobutyryl, isovaleryl, etc.). aroyl (for example benzoyl, etc.). lower alkanesulfonyl (e.g. nesyl, ethanesulfonyl, etc.) or arylsulfonyl (e.g. benzenesulfonyl, tosyl, etc.). The terms 'lower alkyl', 'lower alkoxy' and 'lower alkylthio' (or the like) refer to straight or branched chain alkyl, alkoxy and alkylthio groups (or the like) having 1 to 6 carbon atoms. Likewise, the terms 'lower alkenylph' and 'lower alkynyl' refer to alkenyl and alkynyl groups having 2 to 6 carbon atoms, respectively.

The invention is further illustrated by the following working examples.

Exemgel 1 N-l-u c conz? s JL '/ IN | å \ “gaten-cs QNG HZN S Oc fi a Q t 2- 009 / ena I-1A * Z / E11 / 1 7- [2- (5-amino-1,2,4-thiadiarol- 3-yl) -2-methoxyiminoacetamide or 3- [3- (1-methylpyrrolidinio) -1-propen-1-yl] -3-cephem-4-carboxylate (Im '' 't' To a solution of 150 mg (0.21 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 / B = 2/1) in 2 ml of ethyl acetate, a solution of 36 mg (0.42 mmol) of 1-methylpyrrolidine in 1 ml of ethyl acetate was added in one portion over 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. 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-S00fC18, 100 ml), eluting with water and 10% CHBOB. 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 2ao ° c (sunburn). m nä ”en” 3400, 1160, 1660, 1610. uv: Psfatbuffert (PH 7) mn 12 "* 1 236 (312), zag (322). max 1 cm -ßn NMR:: D2 ° 2,31 (411 , m, f "), 3,12 (314, s, n-cn3), 3,6 (53, \ _ .. ppm _ gm) &) ¶ s' Ö, J58, C§2N), 4, 2 (3H, S, OCHB), 5.36 (1H, Ö, J-: Jys / ym] 7 "'H & 3" CH = CÉ) [d | J = 10 | 7 | ° d 'J = 16 | 3-CH trans). 'ßåemggl 2- "C com: / s Vu | * |: l! \ N' 6 82 V ocas f- / cn-ca-cnz- / \ C009 _ I-18 en 470 260 48 7- [2- ( 5-Amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamidyl-3- (Q-pyridinio-1-propyl-1H-2β-cephem-6-carbogylate (I-13) A mixture of 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) and 158 mg (2 mol) 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 give 620 mg of a solid, which was added to 6 ml of formic acid containing 60 mg of sodium bisulphite, the mixture was stirred for 30 minutes at 40 ° 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-S00 / 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. ions (5% 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-1B) with a m.p. exceeding 200 ° C (decomposition).

IR: UV NHR: KB! V ma !! xphosphate buffer (pH 7) mi !! n 'on ° * "" S °' ds 3.74 (za, br-S, Ill -1 Cl 3350, 1760, 1660, 1600. 1% I cm) 240 (352), 258 (366), 267 ( 279), 290 (469). Nm (E 2 -H), 4.20 (38, s, 0C§3), 92 (1H, d, J = 4.5, 7-H), 6.15 (1H, m, 3-CH = C§), 7.04 (TH, G, J = 16, 3-CH trano), 8.2 (2H, m, Py-83.5), 8.62 ( 13, m, Py- a4), 8.97 (za, m, vy-nzls), fmia, 49 470 260 I-IB tz IE, 4/1 I- [2- (5-amino-1,2, 4-thiadiazol-3-yl) -2-methoxyiminoacetamide] -3-13-pyridinio-1-propen-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) of pyridine in 3 ml of DMSO containing 11 mg (0.075 mmol) of Nal. The mixture was diluted with ml of ethyl acetate to The precipitate was separated, which was then collected by filtration, washed with 10 ml of ethyl acetate and dried to give 350 mg of the blocked product.The precipitate was treated with 3.4 ml of formic acid containing 34 mg of sodium bisu Let stand for 30 minutes at 40 ° C. After removal of the formic acid: the residue was reconciled 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-1B) (Z-1B). E = 4/1). M.p. exceeding 200 ° C (decomposition). 50 47Û 26Û l za = väg: cn "'saoo, 1160, 1660, 1soo. Uv. §Â :: f ° tb“ ff ° * t (PH 7) nm (z} * cm1 231 (sas), zso ( 311), 258 (369), 265 (347), 280 (311) .nun = & ° 2 ° 3.45 & 3.16 (each 1n, a, J = 1s, 2-n), 4.18 PP ”(An, s, ocns), 5.34 (311, m, crucn-cnz a. 6-11),, 92 (m, a, J = 4, s, 7-11), 6.58 (4 /sn,a.a, J = 11, 3-CH cis), 7.03 (1 / SH, d, J = 16, 3-CH trans), 8.12 - (zu, m, Py-n3,5 ), apss (1u, m, Py-n4), s, az (2H, m, Py-H216).

Exemgel 4 S Ní -] Ä ~ ¶ CONB --- T 'N g æ _ H “Ls / \ ocii3 å'- N / cH-cucnz- I g 2 cx fi a | IHL N82 - I-IC * E 7-12- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacet-awê A stirred solution of 714 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-isomer), 2-aminothiazolo [3,5-q] pyridine (prepared by the method of T. Takahashi g§ Gl., Pharm. Bull- (Japan), 2, 34 (1954) and 1 ml of dry DMSO were kept for 1 hour at room temperature 4. To the reaction mixture was added 20 ml of ethyl acetate to obtain 710 mg of a yellow powder. 7 ml of formic acid and 70 mg of sodium bisulfite were added to the powder (700 mg) and the mixture was stirred for 30 minutes at 40-45 °.

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 (dec. n: = cm * asoo, 1760, 1660, 1630, 1600. uv = llfåftfatlwffeft (PH 7) nm (z fi cm) 245 (499), 265 (266). mm = sggâ ° 'de * ° z ° 3.66 (an, s, ocgs) 4.96 un, a, J = 4.5, sm, 5.2 (za, m, cmcn-cgz),, 51 (m, m, s -cnæg), 5.96 ma, m, vm, 7.16 ma, a, J = 16I a-én trans). 8.36 & 8.45 (each 1H, d, J = 7, Py- n), 6.92 na, s, py-a). àxémgèiš nl I CONB; 1 :: - [IIS: L E! * e ~ nzn s \ 0cg3 n / ca-ca-cnz-rucas), cooe MD * z / n - 1/1 52 - 470 260 7- [2- (5-amino-1,2,4-thiadiazole- 3-yl) -2-methoxyiminoacetamide] -3- (3-trimethylamino-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-500 / 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). m = sm'1 33: o-, 117ø, 1670, mos. uv = äf ° $ fatb “ff ° '* (PH 7) sm (s1 *) 236 (ass). zsv (3431. max 1 cm mm s. s ° 2 ° 3.45 a 3.7 (m, a, a = 1s, m, 3.81 (m, s, PPW 65 zm, 4.1 (za, a, a = a, -cgzun 4.21 (an, s, oca3), 5.39 (m, a, a = 4, s, sa), 5.95 (za, m, s-cuæg s. vm , 6,61 (1/211, a, asn, s, -cn sis), 1, os (1/211, a, j = 1s, s-cn trans). 53 _ .470 268 Exempgl 6 N 3- Con - ifs I "H2 flznil fl / Camino C I-13 in 7- [α- (5-amino-1,2,4-ciaiazol-3-yl) -2-methoxyimino] acetamide] -3- [3 - (3-aminopyridinio) -1-propen-1-yl] -3-cephem-4-carboxylate (I-1E) 716 mg (1 mmol) of diphenylmethyl-7 - [? - (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 188 ml (2 mmol) of 3-aminopyridine in 1 ml of 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 S20 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 8 g 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 (dec. 470 26O n: en "3400, nes, 1675. mo, 1soo. phosphate buffer (pH 7) nm (E18 max 1 cm) 246 (403), 290 (468). mm = 6 ° 2 ° 3.72. (Zu, m, 2-11), 4.14 (an, s, ocns), 5.35 PP ”(an, m, sn a cnæa-cgz), 5.9 ma, a, a = 4, s, 7-H), 6.1 (1H, m, 3-CH = C§), 7.05 (1H, d, J = 16, 3-CH, trans), 8, 1 (13, m, Py-H5), 8.54 (1H, br-s, Py-H6), 8.68 (1H, m, Py-H4), 9.4 (1H, m, Py-H2 ).

Treatment of IX-1 (716 mg, 1 mmol) with 324 mg (2 mmol) of 3-t-butoxycarbonylaminopyridine by a procedure similar to that described above gave 12 mg (2.3%) of I-1EJ. -¶ - couu ---_ r's wL / "\ f” f '<+> \ / ,:> ““ = H, S ocaa cncncaz-n _ _ coc fi _ I-18 oz / 2 Q 1/1 7 - (2- (5-Amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacet-β-β-β-β-β-sf11 == ° -1-P ¥ 1f1d% == 19> f? -P ¥ ° P @ fl f? - ¥ lJfê-s <ï = fsw- a-karmxyla fi (I-mf '"" -f__ A bmaning of soo mg (0.7 m1) aiphenylmethyl-v- [z- (s- amino-1,2,4-thiadiazl-3-yl) -2-methoxyiminoacetamide] 3- (3-iodo-1-propen-1-yl) -3-cephem-4-carboxylate (IX-1) ( Z / E = 2/1) and 66 mg (0.7 mmol) of 3-aminopyridine in 1 ml of dimethyl sulfoxide were stirred for 20 minutes at room temperature, the mixture was diluted with 10 ml of ethyl acetate and 10 ml of ether and ss - 470 260 den. The precipitate obtained was collected 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 at room temperature. n was concentrated to dryness under reduced pressure. The residue was dissolved in 10 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. M.p. exceeding 16000 (decomposition) Ä In = 0: 2: cm'1 34oo, 1765, 1675, 1620, 16oo. uv = Aââïfatbuffert (PH 7) mn (zfcm) 244 (434). 281 (333). una = & ° ”S ° 'd6 * ° 2 ° 3,73 (zu, m), 444133, s, ocns), s, 3s PP” (an, m, 6-11 a Cmos-egg), 6, 0 (zn, m, 7-11 a. A-cnæg), 6.6 (1/214, d, J = 11, s-cn cis), 7.05 (Hmm, J = 16, 3, cn trans ), 8.08 (18, m, Py-H5), 8.6 128, m, Py-H4'6), 9.4 (15, m, Py-H2). Érempgl 8 t fl com: L | LN i ® mæcao nus / \ ocx-1 04'- / cn-cacnz-Ö 56 _ 470 260 7-13- (5-amina-1, z, 4-tlaalazoi-3- yi) -2-Methoxyniminoacidamide] -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 g§¿¿l., Bull.

Chem. Soc. Japan, go, 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 50 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% methamide, 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).

Ia = wave; = m'1 344o (br), 1160, 1670, 1s2o (br), 1590. uv = charge buffer (PH 7) nm (n} * cm) 218 taza), 248 (362), 290 (414). & ° 2 ° * “a“ °° s 3, sa (za, br, 2-n), 4,15 (sa, 8, oca3), PP ”s, 91_ (1n, a, J = 4, s , 1-H), 6.25 (13, m, cn = cg-cnz), 6.96 (1n, a, a = 1s, 3-ca trans), 8.8-7.9 (48, m , Py-H), 9.38 (m, br, Nncgo). sv - 470 260 Exegggl 9 ul U fl \\: ons r's Conn:: gul s / ocaa J_ "f cu: cnca2§ © - c I-lG f: __ ___ 7- [Q- (5-amino-1, 2,4-thiadiazole-3-91) -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-1-β- (s-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamide] -3- (3-iodo-1-propylene) 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 The precipitate obtained was collected by filtration The quaternized salt (500 mg) was dissolved in 5 ml of HCOOH 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 the washing liquid were combined and chromatographed on a rever phase column, PrepPAK-500 / C18 (100 ml). After elution with water and in turn an 8% aqueous solution, 10% 20L% aqueous solution of methanol, the fractions containing the desired material were combined, concentrated in vacuo and lyophilized to give 21 mg (3.8 mg). %) of the title compound (I-1G) (E) as a yellow powder. M.p. exceeding 175 ° C (decomposition). 58 _ 4-70 260: n: våíucfí 's34o (br), mo, mo, 1600. osfatbuffert (pH 73 “1% uv. Hfl” um (m1 om) zss (szs), 214 (sk, (os) , 290 (446). Man = 8 ° z ° * “a“ °° sa, ss (zu, br, zm, 4,15 (an, s, ocua), PP "5,32 (m, a, a = 4, s, sn), 5.45 (m, d, 01:71 d | J: 415 '7-41); d-tp &7; f' d, trans), 8.23 (1H, m , Py-H5), 9,03 m] S 'Exemggl 10 u ~ fi com: / s “JL u" \ L' Û f \ H2 s, oc á'- / cn-cxcnz-: Q-connz. C 1-11: * B 7-12- (5-Amino-1,2,4-thiadiazol-3-yl) -2-methoxy] aminoacetamide [7-B] [(4-carbamoylpyridipio) -1-prepen-1-yl] -§ to a stirred solution of 716 mq (1 mmol) of diphenylmethyl- 7- [2- (5-amino-1,2,4-thiadiazole) (Eyl) -2-methoxyiminoacetamide] 3- (3-iodo-1-propen-1-yl) -3-cephem-4-carboxylate (IX-1) (E) 1 2 ml of dry DMO was added 244 mg (2 mmol The mixture was stirred for 1 hour at room temperature and then poured into 200 ml of ethyl acetate. The precipitate obtained was collected by filtration, washed well with ethyl acetate and dried. The first mixture of the quaternized material (400 mg) and 40 mg of sodium bisulfite in 4 ml of HCOOH was heated for 1 hour at 40-50 ° C and evaporated to dryness under reduced pressure. The solid raw material was dissolved in 40 ml of water. After filtration of insoluble material, the filtrate was chromatographed on a reverse phase column (filling of PrepPAK / C18, 100 ml) using water and an S%, 10%, 20% and 30% aqueous solution of methanol as eluent. The fractions containing the desired compound were combined, evaporated and lyophilized to give 21 mg (3.8%) of the title compound (I-1H) (E) as a pale yellow powder. M.p. exceeding 180 ° C (decomposition) m = v12: cmq 3340 (br), 1760, 1670, 1600. uv 6 Affaffat buffer (PH "mn (Efcm) 222 (362, zss (452). mm =: Dzwua fl ws 3.66 ( zu, br, 2-H), 4.1s (an, s, ocna), PP ”5.33 (1n, ° a, 'J = 4, s, 6-11), 5.46 (zu, a , J = 7, CH = CH-Cgz), 5.90 (1H, Ö, J = 4.5, vn), 6.11 un, at, J = 16 a 1, a-cnæg), 7.02 nu, a, J = 16, a-cn trans »0,43 a 9,09 (vardera 2H, d, J = 7, Py-H). àxèm '' i ii nf ä coun / s cnznaz 1 n,. \ ¿,.: Zu s) 00:13 f ”/ cn-cacaz-u / \ c _.

I-II tg 470 260 7- [2- (5-amino-1} 2,4-thiadiazol-3-yl) -2-methoxyiminoacetamide] 7- [3- (3-aminomethylpyridinio) -1-propene- 1-yl] -3-cephem-4-carboxylate (I-11) A mixture of 716 mg (1 mmol) of diphenylmethyl-7- [2- (S-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) of 3- (t-butyloxycarbonylaminomethyl) ) - pyridine in 2ml 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 filtered off; and the filtrate was chromatographed on a reverse phase column (filling from a PrepPAK-S00 / 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.

IR ~ §: § = m'1 a3aø (b :). 1160, 1sso (sx), 1szo (sk). '1 av: §§§§fatb “ff °” t' PH 77 (E1 * cm) zas (sk, zso), zss (svor. Nun = s ° 2 ° * “a“ °° 3 3,68 ( zu, br, 2-H), 4.16 (sn, S, oca3), PP ”s, 9a. (1a, a, a = 1s, 3-ca trans), s, os (18, m, Py -H5), 8.50 (1H, m, Py-84), s, ao (za, m, Py-n2,6). 61 _ 4.70 260 Example 12 a: conu- s ._ nf 9 i ll ' H1 "S 00113 J / cn-cacuz-G-counzcooÖ I-la 'f: _'- 7- [α- (5-amino # 1,2,4-thiadiazol-3-yl) -2-methoxyiminoacet- amidq] -3- [3- (4-carbamoylpyridinio) -1-propen-1-yl] -3-cephem-4-carboxylate 11-1H) A mixture of 4.1 g (5.7 mmol) of aphenylmexyl .yl-N- [z- (s-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 OB = 3: 1).

The reaction mixture was diluted with 100 ml of ethyl acetate to separate a yellow gum, which was treated with 10 ml of formic acid and 390 mg of sodium bisulfite at 45 ° 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 HLC (Lichrosorb RP-18, 4 x 300 mn, 0.01 M ammonium phosphate buffer pH 7.2 containing 20% methanol). Fractions no. 4 and 5 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 10% 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 19 ° C (solar eclipse).

: R = vKBr cm'1 saoo, 1770, 1680, 1620. max _ phosphate buffer (pH 7) 1% UV _ Åmax nm (E1 cm) 227 (385), 286 (374).

NHR: & D2 ° 2.32 (1H, s, acetone-H), 3.79 (2H, br-s, PP ”2-H), 4.17 aa, S, ocn3). 5.34 (1n, a, J = 4, s, 6-H), 5.49 (2H, d, J = 7, CH = CH-C§2), 5.93 (1H, d, J = 4.5, 7-H), 6.28 (1H, dt, J = 16 G 7, 3-CH = C§), 7.15 (1H, d, J fi16, 3-Cg), 8.43 & 9.1 (each ZH, d, J = 7, Py-H). a -c coun if 'd¿' _ 'N' I ca: cncs ;? ' n C009 H3, fl- sj _ I-IJ * E ss - 470 260 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamide] 7- [3- - (2-methylthiazolio) -1-propen-1-yl] -3-olefin-4-carboxylate (I-1J) To a mixture of 714 mg (1 mmol) of diphenylmethyl-7- [2- (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 nv xurkiy, sv Brown, J. Am.

Chem. Soc., 11, 5778 (1952L] in 10 ml of dry CH 2 Cl 2. A§BF 4 (purity 90%, 217 mg, 1 mmol) was added at -20 ° 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 40 ° 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 (PrepPAK-500 / C18, 100 ml). The roller was eluted with 200 ml of water, 400 ml of a 5 t aqueous solution of methanol and 300 ml of an 8 t 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 195 ° C (decomposition). 470 269 Ia = ¶: §§ = mf1 asoo, 1vso, 1sso, 1soo. av _ lšgífatbuffert (pä 7) um (Eztcm) 238 (442), 292 (421). nun. & gš§ * ° ”S ° 'ds; 3, os (aa, 8, ciazal-cg3), 3.74 (za, br'sy S | (1H | d' J = 4 | 5 | 7-H) I 611 m '. “3-CH = CI¶_) | 618 d 'J: 16y transø' 8.04 & 8.23 (each 1H, d, J = 4, f- thiazolf fl).

Example 14 STU fi conzin "IN - 9 32N / \ S / kan: / CHICIiC_32- n2 ° 8 CCKšD '1-: L * s - 7-lä- (5-amino-1,2,4-thiadiazole-3 -yl) -2-methoxyiminoacet- MiL fl QY-ëfß- <4-h ¥ ° f ° = r = 1ff = e fifl1 = ¥ = o1ê% fl% 9> f? -1.> ¥ ° 1. = e == f ? - ¥ 1.Jf -? »~ Cefem * 4 * carboxy1at '(1-1L).'“ '' '' "A mixture of 1, o1 g (1.5 mmol) a1pheny1-1-1â- (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), 818 mg (7.5 mmol) of 4-hydroxymethylpyridine in 4.5 ml of CH 3 CN and 3 ml of methanol were stirred at room temperature for 1 hour under a nitrogen atmosphere. 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 - f47Û 260 methanol to obtain 1.28 g of the quaternized cefen ester as a yellow powder. A solution of the quaternized ester (1.25 g) and 600 mg of sodium bisulfite in 10 ml of 85% HCOOB was stirred for 1 hour at room temperature under a nitrogen atmosphere. After adding 5 ml of 85% HCOOH, the mixture was stirred under the same conditions for a further 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 compound. A suspension of this compound (1.1S 9) in 100 nl 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).

In = nä: cn fl, 1115, 1670, 1635, 1sso.

UV - phosphate buffer (pH 7) '* max mn (e). zao (zzsoo). 264 (sn, 16300) nun: 8 ° 2 ° ppm 3.83 (2H, br. 2-CH), 4.17 (3H, s, OCH 3), .06 (za, s, 5.36 nu, a, J = 4, s Hz, 6-11), 5.41 (2H, d, J = 1 Hz, cnæn-cgzh .94 (111, d, J = 4, s az, 7-11) ), 6.36 __ (1a, ae, 66 70 260 J = 16 and 7 Hz, CH = C§çH2), 7.13 (1H, d, J = 16 Hz; and (each za) d] J = 7 Hz, Py-H).

Example 15 u - coua af's JL k ”/ cazcncaç / \ own 323 5 Odz fl s Ä 069 2 __ 2 7 1-21: '' E 7- [ä- (5-amino-1,2,4-thiadiazole- 3-yl) -2-ethoxyiminoacetamide Q7- 3- [3- (Q-carbamoylpyridinio) -1-propen-1-yl] [3-cephem-4-carboxylate '(Ifi2H) a solution of 200 mg of 7-amino-3- [3- (4-carbamoylpyridinio) -1-propenyl] -3-cephem-4-carboxylate hydrochloride (E-isomer) in 5 ml of a SO% aqueous solution of acetone was added portionwise to 190 mg of 2-ethoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetyl chloride hydrochloride (prepared by the method described in the published Japanese patent application (Kokai) S7-24389 (2/8/82)) and the mixture was adjusted to pH §, S-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 was chromatographed on a column of BB-20, which was eluted successively with 500 ml of water and a 25 S 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). of _ 470 260 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. 16 ° C (Sunday pitch). Estimated purity 65%.

IR = vxßf cm -1, 3330, 1780, 1sso, 1620. maX uv =) š :: fatb (ffert (PH 7) nm te), 227 <223oo), zsa (zzaoo). man = & ° z ° 1.44 (3n, t, J = 1 az, ocnz-cg3), 3.14 (zu, PP ”br. s, 2-H), 4.45 (zu, q, J = 7 az, ocgz-cu3), 36 (1H, d, J = 415 Hz, 6-H), 5.46 (2H, d, ai? Hz, 3-cH = cn-cgz), 5.92 (1n, a, J = 4, s az, 7-n), 6.20 «1n, m, 3-cn = cg), 1.04 (1n, a, J = 16 Hz, 3-c§ = cH), 8.43 (za, d, J = 7 Hz, .Py-HA), 9.10 (2H, d, J = 7 Hz, Py-HB). sxenggi 16 '7-lä- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacet-allyl-SfsfH + 1 = 3rb = 13 ° 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 give the cfene-β-carboxylate β-carboxylate. benzhydryl-7- [§- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamide] -3-13- (4-carbamoylpyridinio) -1-propen-1-yl] -3- cephem-4-carboxylate-formate (XXVII-1H)

G 2450 insulated.

A. Benzhydryl-7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamide] -3- [3- (4-carbamoyl-1-pyridinio) -1-propylene -1-yl7-3-cephem-4-carboxylate-formate (Eisomer) (xxy-1H) '- In a mixture of 34 g (high purity) xxx-1u (J9 = fe-a-isamerium in 200 ml of a 1 : 1 mixture of acetone and methanol was applied to a column of Anberlite IRA - HO (formate form 340 ml), eluting 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 29 g (75% purity by HPLC) of the title compound XXVII-1H (E-isomer) as a brown powder, m.p. exceeding 150 ° C (decomposition).

KB: -1 IRäQ Cm max 3300, 1780, 1680, 1630, 1600. uv = Aššgn nn (s1 *) zsz (186). ppm δ, oc§3), 5.26, (13, d, q = 4, s az, 6-H), 5.43 (za, a, J = 7 Hz, cg2u *), 5.99 ( 1n, a, J = 4.5 Hz, 7-H), 6.5 (1n, m, 3-cn = o§), 6.92 (1n, s, cgrnz), 7.1 (1n, a , a = 1s az, 3 + çg), 7.35 (1on, m, Phfg). 8.36 (1a, s, gcoo), 8.46 & 9.12 (2H each, d, J = 8 Hz, Py-H) o B. 7-low- (S-amino-1,2,4 -thiadiazol-3-yl) -2-methoxyiminoacetamido] (f-43- (4-chlorobamoyl) -yridinio) -1-propen-1-yl] -3-ephem> 4'-carboxylic acid (1-1n A mixture of 29 g (75% purity) XXVII-13 (E-isomer) from 69: 4'.70 260 step A and 290 ml of 85 l of formic acid was 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 (§ (50% purity according to HPLC) of the title compound as a crude product, the brown solid was treated twice with 1 liter and 0.5 liters of 2-N HCl 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 30% 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 evaporated in vacuo to give 10.1 g (85% 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, k was concentrated to about 50 ml 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 (85% purity) of the title compound I-1H (E-isomer) (HCl salt), m.p. . exceeding 180 ° C (decomposition). Pale yellow powder.

Example 17 7- [2- (5-Amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamyl] -phelic-lipophilic-lipid-β-β-β? cephem-4-carboxylate '(1-1H) (E-isomer) "i'i'" This example shows the preparation of compound I-18 via the final steps of Reaction Scheme 1a or 1b, where intermediate XXVII-18 (formate) E ¿470 26Û A solution of 27.6 9 (38, S mol) of IX-1 (E-isomer) and 22.8 9 (187 mmol) of isonicotinamide in a mixture of 120 ml of CB3CN and 100 ml of methanol was stirred 1 After evaporation 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 (50.3 g). 9) and 16 g of sodium bisulfite in 160 ml of 85% HCOOH were 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 (S5 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-13 (S-isomer) as its hydrochloride. Pale yellow amorphous powder with a m.p. exceeding 195 ° C (decomposition) .- smgggl'ia 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetam- [4]? fbam ° Y ¥ PY ¥ 1 ° ¥ P1 °) '? fP = ° P? ¥ * 1fY% Z ° 3T ._ cefen fi iécarboxylate (I-18) (E-isomer)' '' '' This example shows the preparation of the compound I-18 71 - 470 260 via the final step (7-N-acylation) in Reaction Scheme 1c.

To an ice-cold suspension of 5.0 g (12.6 mmol) of the 7-amino-cephem hydrochloride XXII-H (E-isomer) in 100 ml of an aqueous solution of acetone was added sodium bicarbonate in small portions. The mixture pH was monitored by a pH meter during the reaction. 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) -2-methoxyiminoacetyl chloride hydrochloride in small amounts. 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-1H (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-U-I 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 scale colored filtrate (pH 2) was passed through a reverse phase column (filling from a prepPAK-SOO / Cw 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-1H (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) as pale yellow prisms. M.p. exceeding 185 ° C (decomposition).

Microanalysis showed that the compound was present as the trihydrate.

IR = 0: 2; cm'1, 1730, 1695, 1000, 1630, 1610. uv = zšgífatbuffeft (PH 73mm te) 221 1220001, 290 123000). snusa-a6 + n2o ppm '3.45 (zu, br, S, 2-a), 3.9 (aa, s, ocg31, 4.99 (1fl, a, J = 4, s Hz, s-H1 , 5.10 (za, 0, J = 7 az, cg2n *>, «s, e1 (10, a, a = 4, s Hz, 7-H), 5.8 (1n, dt, _ J = 1s 3 7 sz, 3-ca-cg1, 6.93 (1n, a, J = 1s az, 3-qgä, 8.18 & 8.89 (each 2H, d, J = 7 Hz, -Py- H1 .

NMR: Analysis calculated for C 21 H 20 N 8 O 6 S 2 -3H 2 O: C, 42.14; H, 4.38 N, 18.72; S, 10.71.

Found: C, 42.41: H, 4.35; N, 18.86: S, 11.00.

* Column, Lichrosorb RP-18, 4 x 300 mm: Mobile phase, 0.01 M phosphate buffer (pH 7.2) / CH 3 OH = 85/15: Detection, UV (254 nm).

Method 2 When crystalline I-1H had been obtained by Method 1, it was possible to obtain the crystalline zwitterionic form of I-1H directly from the crude I-1H hydrochloride by adding a few crystals of pure I * 1H as seed crystals.

A solution of the hydrochloride having a purity of 85% (250 mg) in 1 ml of water was treated with charcoal. The solution was adjusted to pH 6.5 with 60 mg of sodium bicarbonate and decolorized with charcoal. The filtrate was added to seed crystals obtained from Method 1 and stirred overnight at room temperature. The separated crystals were collected by filtration, washed with 2 x 2 ml of water and dried under reduced pressure to obtain 170 mg (80% recovery) of pale yellow prisms of I-1H (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).

Exegggl 20 S NI. I CUNE 8203 I i I - o H * S / u Ia: 2 or "/ ca-cs-cnf '009 \ I-IK * E 7-lä- (S-amino-1,2,4-thiadiazole-3 -yl) -2-methoxyiminoacetamide] -3- [3- (3-hydroxymethylpyridinio) -1-propenyl] -phosphine-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-cephemylcarborylate iodide 13 -isomer1_ (xx-Ii 11 :) To a solution of 1.79 g (2.5 mmol) of IX-1 (E-isomer) in 2.5 nl of methanol and 7.5 ml of CH 3 CN was added 545 mg (5 mmol) 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 precipitate obtained was filtered off, washed with a small volume of ethyl acetate and dried to give 2.06 g (1008) of the title compound XII-1K as a brown powder, mp 170-180 ° C (dec.) vs - 470 260 IR: vmax (Kßr) 1 cm-1 1780, 1725, 1675, 1615, 1530, 1385, 1225 , 1040, 750, 700. 1% UV.1max (C ZHSOH) 1 nm 1? cm) 290 (196).

NMR: δ (DMSO + D 2 O) in ppm 3.7 (28, br.s, 2-H), 3.91 (3H, δ, ocu 3), 4.10 (za, s, Py-cg 2 -one) , s, 2s (za, m, cnz-n *), 5.23 (1n, a, J = suz, 6-H1, 5.90 (1a, a, J = snz, 7-H), 6, 34 (1n, m, - 3-cu = c§);> s, as (1n, a, J = 1s az, 3-ca), 6.89 (1H, s, cnphz), 1.35 (1oa , m, rn-H), 7.9-8.9 (4n, m, Py-H).

B. 7- [2- (5-Amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamide] -3- [3- (3-Nydroxymethylpyridinio) f] propyl] -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 give 1.1 g of a brown powder, which was purified by column chromatography (using the filling from a PrepPAK; 500 / C18 cartridge (Waters)) to obtaining 283 mg (22%) of I-1K as an amorphous powder. The powder was crystallized from 4N sulfuric acid and acetone to give 144 mg of the title compound I-1K as colorless needles. m.p. 1ss-1sa ° c (sönaerae1n1ng>.

In = X (xßr) 1 cm'1 1175, 1saosn, 1650, 1sao, 1225, 1045, 850. “ma 470 260 uv =: max (fosfaebuffert, pa 1) 1 um (n} * cm) 236,5 ( zas) 275 sh, (zaor, 292.5 (330).

NHR 2 š (D2Û) i. PPI !! 3:75 (23: s: 2 "H) | 4:18 (311: 3: ÜCH3) | 4.91 (za, S, Py-cgzoa), s, ss (1n, a, a = 4az, sH ), 5.43 (za, a, J = s, snz, cuz-n *), 5.92 (1a, a. A = 4az, 7-H), 6.18 (1n, at, J = 1snz , J = e, snz, 3-cn = cg-), 6.97 (1a, a, J = 1snz, 3-cn); 8.13 (1a, d ~ d, J = 8Hz, J = 6Hz, Py-H), 8.60 (13, d, J = 8, Hz, Py = H), 8.84 (1H, d, J = 6Hz, Py-H), 8.90 (1u, S, vy -HRS).

Example 21 3 - ^ CONB l 1-13 'E 7- (2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (Z) -methoxyiminoacetanide] -3- [3 - (4-N-methylcarbamoylpyridiniol-1-propenyl] -3-cephem-4-carboxylate (I-18) (E-isomer) "" "'' A mixture of 450 mg (0.62 mmol) of diphenyl-7- [2- (5 -amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- (3-iodo-1-propenyl) -3-cephem-4-carboxylate (IX-1) (E-isomer) and 215 mg (1.8 mmol) of 4-N-methylcarbamoylpyridine [prepared by the method of H. Samejima, Yakugaku Zasshi, QQ, 1706 (1960)). 2 ml of acetonitrile were stirred for 5 hours at room temperature under a nitrogen atmosphere. reduced pressure and the residue was triturated with ether to give 530 mg of the quaternary salt A mixture of the solid and 150 mg of sodium bisulfite 77 - 470 260 1 2 ml 85 1-l of formic acid was stirred for 4 hours and then heated for 30 minutes at 40 ° C. The mixture was evaporated under reduced pressure, the residue was 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 product I-1M indicated in the title. M.p. 180-183 ° C (dec.). Estimated purity: 80%. m = u (xsr) in cm ° 1 1760, 1660, 1600. maX UV: Ämax (phosphate buffer, pH 7) in nm (C) 230 (22100), 286 (22100).

NHR: 30320) in ppm 3.08 (3H, s, CONfiCg3), 3.72 (2H, s, 2-H), 4.16 (3H, s, OCHB), 5.35 (18, 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 (23, d, J = 16Hz, pyridine-H).

Example 22 CHICH-CB2-00! coca CORE ”- J - I-18 * B / 2 I 7 / I .ps 7G 260 7-12- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamide] - 3- [3- (4-Carboxypyridinio) -1-propenyl] -3-cephem-4-carboxylate (I-1N) W To a stirred suspension of 340 mg (2.8 mmol) of isonicotinic acid in 3.5 nl dry DNF 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-7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamide] -3- (3-iodine). -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 (50 ml) containing 150 mg of sodium thiosulphate. The yellow precipitate was collected by filtration, 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 at 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 50 ml of 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 / Z = 7/1; 80% purity. M.p. exceeding 189 ° C (decomposition). i 19 _ 4.70 260 1 IR = 1 x (mar) 1 om '1710, 1665, 1600. m3 UV: lmax (phosphate buffer, pH 7 = i nn (2) 227 (22S00), 290 (22100).

NMR - (D 2 O + NaHCO 3) δ ppm 3.7 (28, br.s), 4.15 (35, s), 32 (1H, d, J = 4Hz) δ 5.39 (2H, d, J = 6Hz), 6.14 (1H, dt, J = 15.5 and GHz), 7.03 (15, d, J = 1S, 5Hz), 8.31 (2H, d, J = 7Hz), δ 94 (2H, d, _J = 7Hz).

Exemgel 23 N fi: com: l / s JL "* 0 _1122: s / N u: JF" / nice-ca: - c 1-10 * s 7- [2- (5-amino-1,2,4 -thiadiazol-3-yl) -2- (Z) -methylsiminoacetamide] -3- [3- (2,3-cyclopentenopyridinic) f] propylene-3-cephem-4-carboxylate (I-10) * (E- isomer) '' '' A mixture of 450 mg (0.62 mmol) diphenylmethyl- 7- [2- (S-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. After evaporation under reduced pressure, the mixture was triturated with ether to give 560 mg of the quaternary 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 80 470 269 HP-20 (1.5 x 18 cm). The column was eluted with water and a 30% 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 purified 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%. 1 In = vw! (kbr) 1 cm '1165, 1610, 1600. _.

UV:) max (f0SfätbuffeIt, PH 7) i Hm (E) 235 (20000), 233 (ZSÛÛO).

NMR = δ (n 2 O + ua fl co 3) δ ppm 2.2-2.6 (ZH, m, -CH 2 -h 3.1- 3 | 6 m; -CH 2 -)] s '5133 d' J = 4ysnzf 6-H) | 5190 d; J = áysaz | 7-H)] d; 7165-812 ml Exemggl 24 lmïïís 52 "5 / ° / ca-cn-caç I 2 008 C235 C009 I-23 ís 31 f_ 470 260 7-L? - (5-amino-1,2,4-thiadiazole-3 -yl) -2- (2) -ethoxy] amino-acetamide] -3- [3- (4-carboxypyridinio) -1-propenyl] -3-cephem-4-carboxylate (1-ZN, E-isomer) Odh 1- 13- (s-amino-1,2,4-thiaziazol-3-yl) -2- (z) -ethoxy] amino-acetamide] -3- [3- (4-carboxypyridinio) -1-propenyl] -3-cephem To a cooled mixture of 1.0 mL (4.12 mmol) of BSA and 506 mg (4.12 mmol) of isonicotinic acid was added 1.0 g of a 4-carboxylate (I-2N, Z-isomer). (1.37 mmol) 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 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-ZN. The slower fractions gave 32 mg yield (4%) of the Z-propenyl isomer of I-ZN in a similar procedure.

I-2N, E-isomer m.p. > 2oo ° c xsöna.) -1 ax (nar) 1 cm 11ss, 1660, 1620, 1380.

IR um UV) max (water in nm (C) 228 (22200), 291 (23600) 4-70 260 NMR: I-2N, Z-ismer M.p .: IR UV: NMR: Exegggl 25> 20 ° C (sol ) wmax (mr) 1 ¿fi-1 _-, 11 so; ° 1sso (sk1, 1620, ma. 82 _ 80:20) 1 ppm 1,45 (an, t, nam, ca2cg3), 3,12 (zu, s, 2-14), 4.45 (zu, q, cg2ca3),, 40 (m, d, Juaz, sn), 5.90 (m, d, J = 4Hz, 7-H), 7.05 (15, d, J = 1 $ Hz, s-cn), 8.30 (za, a, J = 6nz, Py-n), 8.95 (za, d, a = snz, ry-a). Λmax (phosphate buffer, pH 7) in nm (E) 225 (22400), 275 (sh, 16000). 80:20) in ppm 1.4s (an, t, J fl nz, cn2cg3), 3.50 (m, d, J = 17Hz, 2-H), 3.75 (1H, G, J = 17Hz, 2-H), 5.38 (1H, d, J = 4Hz, 6-H), 5.25 (1H, G J = 4Hz, 7-H), 6.62 (1H, d, J = 11Hz, 3-CH), 8.35 (2H, d, J = 6Hz, Py-H), 8.92 (2H, d, J = 6H2, Py-E). cum: 'fsi 04 FI / 9 ca: ca-cn2? w @ -' cona, _ uz-ca-caz coo - z-: nf: aa _ 470 260 7-Å? - (amino-1,2,5 -thiadiazol-3-yl) -2- (propen-3-yloxyimino) -acetanide] -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-hydro chloride in 2 ml of a 50% aqueous solution of acetone was added S2 mg 2- [β-amino-1,2,4-thiadiazol-3-yl) J-2- (propen-3-yloxyimino) acetyl chloride hydrochloride (from Preparation Example) and the mixture was 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 reduced pressure. The residue was chromatographed on a column of HP-20 resin, which was eluted 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 reverse phase support column taken from a 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).

X (KBI) and cm_1 3400, 1765, 1680, 1605, 1400.

IR: Vma uv = zmax x phosphate buffer, pa 7) 1 nm ge) 226 (24soo),: as (zzsoo). nun = c (n2o) 1 ppm 3.15 (za, S, 2-ax, s, 41 (1a, a, _J¿saz, 6-H), 5.50 (4n, m, cnzu * a ca = cg2), _, 98 (13, d, J = snz, 7-H), 6.20 (1a, m, 3-CH = C§), 7.09 (1H, Ä, J = 17H2, 3- CH), 8.50 (za, d, J = 7nz, Py-H), 9.16 (zu, d, J = 7Hz, Py-H). »S H 84 470 260 Example 26 - 1:03 tg 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-propargyloxyiminoacetanido] -3- [3- (4-carbamoylpyridinio) -1-propenyl] [3] cephem-4-carboxylate ( I-4H) (E-isomer) "To a solution of 86 mg (0.19 mmol) of 7-amino-3- [3- (4-carbanoylpyridinio) -1- (E) -propenyl] -3-cephemyl- 4-Carboxylate hydrochloride (XXII-H) in 2 ml of a 50% aqueous solution of acetone was added 63 mg of 2-propargyloxyimino-2- (S-amino-1,2,4-thiadiazol-3-yl] -acetyl chloride- hydrochloride (from Preparative Example 26) The suspension was maintained at pH 6.5-7.0 with 2NL sodium carbonate and stirred for 1 hour at room temperature. The reaction mixture was acidified to pH 2 with 18 hydrochloric acid and concentrated in vacuo. The residue was diluted with 30 ml of water. , was neutralized with sodium bicarbonate and filtered es. 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 successively 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. 1 ° C. 1 0 (KBr) i cm 'IR: 3400, 2120, 1765, 1680, 1610. Ä: F ° °° "“ "'“ |: nd dzw sz ”Lac-ECB jN eg n-ca-cazçßcomz as _ 470 260 UV: Ämax (phosphate buffer, pH 7) 1 nm (E) 229 (24000) 288 121200).

NHR 2 i 81 2 "H) | d; J = 1Bzy -cgz-cssaca). 5.40 (1a, a, J = snz, sa); .50 (211. m. Cg-NÜ. 5.98 (m, a, a = saz, vm. 5.20 nu. m. ß-crecg), nos nu, d; J = 17Hz | 3-cg) | d; J = 7Hz | Py-H) | d 'J = 7azj Py- H) o Exegggl 27 _ S N -: BJ- fi “* -_-- 'CONH --- 1 / I | N 1 ¿@ law / Ls ï j'- oogcn cn-caz n / _ \ gong: 1-8 * E 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-cyclopentyloxyaminoacetamide] -3- [3- (4-carbamoylpyridinio) -1-progenyl] 4-Carboxylate (1-SH) (E-isomer) - To a stirred solution of 139 mg (0.31 mmol of 7-amino-3- [§- (4-carbamoylpyridinio) -1-propenyl] -3- cephem-4-carboxylate hydrochloride 1 3.5 ml of a 50 g aqueous solution in an ice-cold bath were added portionwise 120 mg (0.44 mmol) of 2- (5-amino-1,2,4-thiadiazole-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 100 DEG C. The reaction mixture was adjusted to pH 2 with 1N HCl and evaporated under reduced pressure, the residue was chromatographed on eluent n 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. as 470 260 M.p. 160 ° C (decomposition). Estimated purity 70%. n: = vmx (nar) cm ”3400, 1110, 1600, 1605, 1530.

UV: ihax (phosphate buffer, pH 7) 1 nm (6) 224 (23300), - 206 124600). man = aumso-aö) 1 ppm 1.10 (an, nns, aC]), 4.60 un, H nns, m), 5.05 nu, a, J = saz, nr- O å: sx), 5.30 (an, m, cnzrfü. 5.57 un, d-dy J = 5Hz & 7Hz | 7_H) ym '3-CH = C§) | d 'J = 17Hzy 3-CH), 8134 d] J = 7Hz | Py-H), d, J = 7HZ, PY_H) | d] J = 7Hz | Exemggl 28 / uL-n- conz-TS i Q cazcoon s) j ”/ a-cn-cn2-1 _0069 I-1? 'E AND; Bz fl 7-12- (S-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamide-3- [3- (3-carboxymethylpyridinio) -1β-phenyl] -phosphylphosphate-alkylate I-TP) (E-isomer) '' 0 '""' '"' '' A. Diphenylmethyl- 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyimipoacetamide] ] -3-13- (3-k§r§px§pe§ylpyr§§iq; o} f17 propeny¶Z; §-cefem-4-carboxylate (XII-TP¿¿19dïd, 'E * isomer) Till 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 470 260 N, O-bis (trimethylsilyl) acetamide and the mixture was stirred at room temperature until 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 were 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, mp 161 ° C (dec.).

In = vma¿- (xsr) 1 em'1 1780, 17zo, 1s1s; = 1s3o, 1sao, 1385, 1225, 1045, vss, voo. 1% 1 cm) 295 (188).

UV: λmax (C 2 H 5 OH) in nm (E - NMR = δ (DM 50 + D 2 O) in ppm 3.70 (2H, br.s, 2-H), 3.90 (SH, S, ocna and Py-cazco) , 5.25 (sa, m, -cazu * a 6-H), 5.92 (13, a, J = 4, snz, 1-H), 6.35 (1a, m; 3-ca = cg -1, 6.9 δ (1n, d, J = 1snz, 3-ca), 6.92 (1n, s, cnpnzz; 7.35 (10H, m, Ph-H), 8.8-9.0 (48, m, Py-H).

B. 7-12- (5-Amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamide] -3- [3- (3-carboxymethylpyridiniol] propyl] 3-cephem-4-carboxylate (I- 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 The oily residue was triturated with 100 ml of acetone to give 1.22 g of crude product, which was purified by column chromatography (BP-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.) 08 4-70 260 0 x (nar) 1 cm -1 1110, 1670, 1600, 1530, 1385, IR ma 11407 1040. 1% 1 cm) 234 (374), lm (phosphate buffer, pa 6.21 1 mn (s ä 277 sk (390), 290 (402).

NHR 50:20 + NaHco3) 1 ppm 3.78 (211, s, zH), 3.92 (211,, Py-cazco), 4.22 (311, s, ocn3), 5.40 (111, d , J = 4Hz, 6-11), .51 (211, d, 0 = 6.511z, -cnz-u fi,, 97 (111, d, J = 4x1z, 7-11), 6.20 (111, dt , J = 16 a. 6,582, 3-c11 = c¿1_), 7.08 un; d, J = 16Hz, s-ca), '8,11 (111, dd, J = 8 1 7112, Py- Hs), 8.53 (m, d, J = 8Hz, Py-H4), 8.82 (18, d, J = 7Hz, Py-H6), 8.86 (1H, s, Py-H2).

Exemggl 29 _ c sena 'fs 11211 s / oca,: f cn-ca-cnz-u s-cazcoon cooe _ 1-10 * z _ 7- [2- (5-amino-1,2,4-thiadiazol- 3-yl) -2-methoxyiminoacetamide] -3- [α- (4-carboxymethyltypropyl; 1β) p] -1gp; qpegy; Z-37 cephem-4-carboxylate (fi1 g) (E-isomeric "A. Diphenylmethyl-7-Z1- (S-amino-1,2,4-thiadiazol-3-yl) -z-methyliminoadecamide-3- [3- (hydroxymethyl-pyridinyl) -1-propenyl] -3-propyl §Çmf§-Kdr§qxy} a§_ (¥; If1Q¿ iodide, 'E-isomer 7' ~ '"' X '" "se - 470 260 To a suspension of 0.88 g (S mmol) 4- carboxymethylthiopyridine in 10 ml of CH 2 Cl 2 was added 5 ml (18 mmol N, O-bis (trimethylsilyl) -acetamide and the mixture was stirred at room temperature until a clear solution was obtained. .5 mmol) 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 title compound XII-10Q (iodine) d) as a tan powder: m.p. 155 ° C (dec.). 1 IR 1 »max (ner) 1 cm '1730, 1120, 1670, 1625, 1525, 13ss, 1225, 1113, 1o4o, vss, voo. uv - 1 (cn ou) 1 nm 131% 1 312 1299) 'max 2 5 1 cm' NMR (nnso-axis + D 2 O) 1 ppm 3.10 12n, br.s, 2-H) ._ 3.93 ( 38, s, OCHB), 5.07 (2H, m, cnz-n *), 5.23 (1n, a, J = snz, 6-H), 5.90 11n, a, J_snz, _7-H ), 6.29 (1n, m, 3-ca = c§) f 6.87 (1n, a, J = 1saz, 3-ca), 6.91 (15, s, C fl æhz), 7.35 ( 108, m, Ph-B), 7.88 & 8.58 (vardera za, a, J = saz, Py-n).

B. 7-12- (5-Amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamide [7- [3- (4-carboxymethylthiopyridinyl] propyl] -3-cephem-4-carboxylate (1-1Q) (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 70 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 to give 470 260 (HP-20, 20 ml) to give 577 g. mg of the title compound I-1Q (39% starting from IX-1) as a pale yellow amorphous powder, mp 188 ° C (dec.) 1 In = vmax (nar) 1 cm -1 1165, 1670, 1625, 1ssø, 1ssø, 1110, 1oas. Uv = Amax (føsfatbuffert, pa 6,21 1 nn (s} * cm) 234 (4591, 310 (sve).

NHR: -8 (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 31, 5 , 25 (za, a, J = e, sHz, cnz-N *), 5.39 (1n, a, J = 4, oz, 6-H), 5.97 (1H, d, J = 4Hz , 7-H), 6.18 (1H, dt, J = 15.5Hz & s, suz, 3-cn = çg), 7.05 (1H, a, J = 15.5Hz, 3-CH) , 7.84 & 8.55 (each 2H, d, J = 7Hz, Py-H).

Exegggl 30 _ ut 'fâ cow: r ”s _ 1 3' aZnLs / N \ ° cg3 OÄ-u / ca-cn-âzë-æn '- .me \ - - I-1; «S / ze- 1/1 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamino] -β-G-β1 - =. '= ¥ -1P ¥ r_ = ° ¥ 14.1n% 9> f1.-1.> ¥ ° P <. = Fl ¥% Jfê- ° @ f§ = f = -êf carboxylate fl sulfate (I-TA,' suIfatY " A. Diphenylmethyl- 7- [7- (5-amino-1,4,4-thiadiazol-3-yl) -2-methoxyiminoacetamide] -3- (1-methylpyrrolidinyl) f1-green; z -3-cephem-4-carboxylate (XII-1A, iodide) 91 - To a cold solution of 21.5 g (30 mmol) of diphenylmethyl 7-L2- (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 g (30 mmol) of 1-methylpyrrolidine in 30 ml of ethyl acetate for 1 hour at -S 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 (95.8%) of the title compound (IX-1A, iodide), m.p. exceeding 175 ° C (decomposition). 1: R = v (xßr) 1 cm '3300, 178o, 1730, 1885, 1615. max vv =) max (c2u5on) 1 nm (8} * cm) 218 1435), 298 (188).

B. Diphenylmethyl-7- [7- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamide] -3- [3- (1-methylpyrrolidinio) -17-gene; Z-3-cephem-4- carboxylate (fx11-1A, clo.) 23 g (28.7 mmol) of compound XII-1A (iodide) were dissolved in 230 nl of a 1: 1: mixture of acetone and methanol and applied to a column of Anberlíe: IRA-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 (xx). : -1A, xioria) with an amp. Of 190 ° C (sßnaerae1n1ng). (Nar) 1 = m'1 3380, 1780, 1880, 1820.

IR V ma !! (c a ou) 1 nm 181 *) 220 (369), zso (282). x 2 5 UV 1 at 11 !! 8. 92 DEG-470 DEG C. 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamide] -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 oily residue was triturated with acetou to give 9.80 g of crude I-1 A. Concentration of the filtrate and acetone washes 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 0.5 l of 2N hydrochloric acid, 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 ions were collected and evaporated in vacuo 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) dissolved in 20 ml of water and then subjected to column chromatography on the filling from a PrepPAK-500 / C18 column (90 ml) using water and a 10% aqueous solution of methanol as eluent. The eluate was collected in 20 ml fractions under HPLC monitoring. zkøiom, uucleoaii ssc-ons-zsz, a x 100 m; mobile phase, 0.01M phosphate buffer (pH 7.2) / CHBOH = 90:10: detection, UV (254 ml). Fractions 4-10 were combined, evaporated under reduced pressure and lyophilized to give 2.28 g of a yellow powder (E / Z = 7/1, 70% purity) (batch 1) Fractions 11-85 were worked up in the same manner as described above to obtain 3.27 g of a yellow powder (E / Z = 5/1, 70% purity) (batch 2) A portion of batch 1 (1.0 g) was purified by chromatography on the filling from a PrepPAK-500 / C18 cartridge (90 ml), the column was eluted successively with water and an S 5 -g aqueous solution of methanol The eluate containing the desired compound was concentrated and lyophilized for EQ a ss-47Û 260 to give 638 mg (E / Z = 7/1, 80% purity) of a yellow powder. 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 1 ml of 1N sulfuric acid The mixture was diluted with 315 mg of acetone with stirring. The creamy precipitate was collected by filtration to give 1.48 g of the title compound (I-1A, sulphate) (E / Z = 7/1, 80% purity), m.p. exceeding 185 ° C (decomposition).

IR ': νmax (KBr) in cm -1 3380, 3000, 1765, 1675, 1630, 1535, 1390, 1115. (phosphate buffer, pH 7) in nm (5) 236 (19900), 291.5 (22500).

1 H NMR: δ (D 2 O + NaHCO 3) δ ppm 2.36 MH, br ), 3.15 UV: 1max), 3.62 (5H, al-brl | zH -N (3H, s, CH: N), 3.83 (1n, br., 2-ny, 4.13 ( za, a, J = anz, cnznï), 4.22 (au, S, ocas), s, s9 (1n, a, J = 4, sn =, su), 5.96 (1a, a, a = 4, saz, 1-H), s, oo (13, m, 3-ca = cg), 6.67 (1 / sa, a, J = 1on =, 3-cn, cis), 1.04 ( 1 / su, a, J = 16Hz, 3-CH, trans). 94 _ 47Û 260 Exegggl 31 3 'S --- cows l J * Jïíl- ß ~ \ 1' _ 323 5 003 Cop C fl llC fl- C fl z N ( GHz) 3 I-ID * B / 2 '10/1 7-12- (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-trimethylamnonio-1--propenyl) -3-cephem-4-carboxylate (XII-1D, iodide) To a solution of 13.0 g (19 mmol) of diphenylmethyl-7- [7- (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 dry ethyl acetate was added 1.75 ml (19.1 mmol) of 1.1N trimethylamine in ethyl acetate at -5 ° C and the mixture was stirred for 1 hour at -5 ° 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.

In = um (man 1 cm ”asoo, 1765, mo, 1665.

UV λmax (C 2 H 5 OH) 1 nm (8) 300 (18400).

B. Diphenylmethyl-7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2- ~ ° t ° X11m ¥ fl ° a °° * = w # fl @ Z-3? fäft ¥% m§ # v1ëm @ 9n1? -1fP ¥? P @ vY ¥> - 3ëcefemf4-carboxylate '(XII-TD,' k1drid) C \ ”12.5 g of iodide XII-1D was dissolved in 60 ml of methanol- acetone ss _ Ã70 260 (1: 1) and passed through 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 of isopropyl ether to give 10.4 g (91%) of the quaternary salt (XII-1D, chloride). .

IR OO -1 »max (nar) 1 cm ssoo, 1765, 1110, 1665. vv => max1C2H50H) 1 nm (a) 298 (1s1oo).

C. 7-12- (5-Amino-1,2,5-thiadiazol-3-yl) -2-methoxyiminoacetamide] -3-13-trimethylammonio-1-propenyl] -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 fi roduct 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-500 / 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 2.52 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. 96 470 260 IR 1 max (KBI) in cm 3380, 1765, 1665. 'å Amax (phosphine buffer, pa 7), 1 nm ta) 237 (1ssoo), 293 (224oo). nn = 8 (nzo) in ppm 3.25 (911, s, rf-cna), 3.94 (211, s, 2-H), 4.14 (za, a, J = 7nz, cn2n *), 4.23 (an, s, o-cn3), 5.42 (m, d, J = 4.5az, 6-H), 6.00 (1n, a, J = 4, sHz, 7-H) , 6.23 (1n, at ;, J = 7 3 16nz, 3-cH = c§), 7.23 sf (1n, a, J = 16az, 3-ca).

Exemggl 32 lïšï-11-E CONB S. <9 Ban s / N \ ° c83 „cs-cn-caz-NO-connz c 1-in-fn 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2- methoxyiminoacetamide] -3- [3- (4-carbameylpyridinio) -1-propenylzyl] -phosphonyl carboxylate (I-1H, E isomer) '* = ""' 'now a mixture of 397 ng (1 nunon 7-anno- 3- [3- (4-Carbanoylpyridinio) -1- (E) -propenyl] -3-cephem-4-carboxylic acid hydrochloride (XXII-H) and 168 ml (2 mmol) of sodium bicarbonate in aqueous DNF (3.5 ml water and 7.5 ml DHF) was added 479 mg (1.5 mmol) of benzotriazol-1-yl-2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetate (from the preparation 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 give a precipitate which was collected by filtration.The crude product was dissolved in a small volume of aqueous THF The solution was adjusted to pH 6.8 with sodium bicarbonate, treated with decolorizing charcoal, concentrated to about 1 ml and added to crystalline crystalline crystals. 1H. After stirring overnight, the crystalline precipitate was collected by filtration to give the title compound I-1H (zwitterionic form). Yield 83 mg '(16%). M.p. exceeding 18S ° C (decomposition). Physical / chemical data for this product were identical to those for the compound of Example 10.

Preparation Example 1 Defenylmethyl 7- [2- (5-amino-1,2,4-thiadiol-dyl] -2-methomino-iminoacetamide-3-chloromethyl-3-cephem-4-caroboxylate (IV-1) To a stirred suspension of 2 To 1 g (10 mmol) of 2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetic acid (III-1) in a dry mixture was added 2.09 g (10 mmol) of Pcls. at -3 ° C and the mixture was stirred for 20 minutes at -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 ) u, o-51s- (trimethylsilylsacetamide, at -ao ° 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 hydrogencarbonate, 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% methanol-CHCl 3. 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 In = 0: 2: = m "3300, 1190, 1120, 1600, 1620. uv = I š šg fl nm (6) 245 (1000), 200 (9900). & G :: ° 'd6 3,53 (za, Asq, 2-n), 9.94 (sa, s, Ocg3), 4.42 (ZH, S, 3-C82), 5.22 (18, å, J = 4.5, 6-H), 5, 92 (1H, å-d, J = 4.5 & 6, 7-H), 6.93 HH: S: Ceph2): 7.36 ÜÜÜ), m, Ph "H), 8.1 (23: bI (S | NH 2), 9.58 (1H, d, J = 6, 7-NH).

Preparation Example 2 NMR Diphenylmethyl 7- [7- (5-amino-1,2,4-thiadiazol-3-yl) methoxyiminoacetamide gz-3-iodomethyl-3-cephem-4 * carboxylate (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 quenched 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, m.p. 120 ° C (dec.). in = wave; cm'1 3300, 1700, 1125, 1600, 1620. uv = Aššgn nn (6) 245 (17000), 202 112000). nun = 8g :: ° 'd6 3.72 (za, Asq, 2-n), 3.94 (sa, S, oca3), 4.23 (za, S, 3-cnz), s, 21 (1a , a, J = 4, s, 6-a), 5.09 (10, aa, J = 4, s 0 6, 7-n), 6.94 110, 8, cgphz), 1.35 (10n , m, Ph-n), 0.12 (zu, br-S, NH 2), 9.65 (1n, a, 0 = 6, 7-un). 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 precipitating solid was collected, washed with ethyl acetate (2 x 10 ml) and dried to give 950 mg (1008) -f of the phosphoniomiodide VI-1. M.p. 186 ° C (dec.).

In = väg: em'1 3300, 1780, 1710, 1880, 1610. uv = zâšg fl nm (8) 268 (1sooo), 275 (13ooo), zoo (7300). una = 6g :: P'd8 3,52 (za, br-s, 2n¿¿ 3,94 (aa, s, oc§3),, 34 (18, a, J = 4, s, 6-a ), 5,9 (1n, m, 7-H), 613 5) 7 | 3 m 'Ph-H)] 7,8 m'c Preparation Example 4 Diphenylmethyl-7 - [? - (5-amino-1 , 2,4-thiadiazol-3-yl) -2-methoxy-m1 = ° = ° e * am1ë8-7-3-fft fl fevyë fi ë ë ë ë ßrliêe fl? Wetßflïfßfsešsm-4-carboxylate (VII-11 '' '' '' A mixture of 952 mg ( 1 mmol) of VI-1 from Preparative Example 3, so mg mg-medium Ina-440 (on 'form) a 4 ml 1u sodium hydroxide in 10 ml CH 2 Cl 2 was stirred for 1 hour at room temperature The mixture was filtered and the separated organic layer 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. exceeding 18o ° c (sönaerae1n1ng). _ 1š 100 470 260 IR II 1: 2: = m'1 s4oo, 11so, 1630. nm (5) 268 (12000), 276 (10000): 384 (23000). ntoš Uv lmax Preparation Example 5 Diphenylmethyl -7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamide] -3- (3-chloro-1-propen-1-yl) -3-cephem To a solution of 6.9 g (8.4 mmol) of VII-Preparation Example 4 was added 3 g of magnesium sulfate and 810 mg (8.4 mmol) of 40% strength sodium chloride (VIII-1). chloroacetaldehyde. 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. The fractions containing the desired product (0.5-1% methanol-CHCl 3) were 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 NHR). M.p. exceeding 130 ° C (decomposition).

Br -1 IR: VK om max 3300, 1780, 1725, 1680, 1620. uv = lâšga max (si 240 (zoooo), zss (12ooo). Nun =; :: â ° '° s * ”2 ° 3, 56 1 3.8 (m, 2-3), 3.94 (sn, 8, ocn3), 4.16 (a, J = 1, s, cg2c1), 5.26 (1n, a, J = 4 , s, sa), s, a1 (1n, a, a = 4, s, 1-3), s, 2e (2 / sn, a, a = 11, 3-eg cis-H). (1/38, d, J = 16, 3-Cg trans-H), §, 81 (2/33, s, cgrhz), 6.92 (1 / sn, s. CgPh2), 7.4 (1oa , d, Phenyl 470 260 Preparation Example 6 Diphenylmethyl-7-benzylideneamino-3- [Ytriphenylphosphoranylidene) ethylethyl; 3-cephem-4-carboxylate (XVI) To a solution of 60 g (70 mmol) of diphenylmethyl -7-Benzylideneamino-3- [Ytrifhenylphosphonio) methyl] -3-cephem-4-carboxylate iodide (XV) [prepared by the process of Japanese Patent Application Laid-Open (Kokai) 56-86187 (7/31 / 81L] in 350 ml of CH 2 Cl 2 were added to 140 ml of 1N sodium hydroxide and ss gznnxænne: an-41o mon 'form) via s ° c. The mixture was allowed to stand for 1 hour at 5 ° C and filtered. The organic layer was separated, dried over magnesium sulfate, 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 vacuo to give 48 g (94%) of the title compound xvz, m.p. of 195-19s ° c (sonar unit).

Br -1 IR. vâaxcm 1770, 1620.

Preparation Example 7 Dife fl rlmetvl-Yfbe fl svli fl s fl awê fl sfßf .ßfklês-ï fPFQPsv-ï fr !! 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 1-cephem-4-carboxylate (XVII). water was added 800 mg of 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 S0 ° C (decomposition).

In = uâ :: cm'1 3400, 1775, 1720, 1630. uv = Jšâg fi nn (s) 253 (11ooo), zss (11ooo), 265 (1oooo), 273 (8300), 281 (7000), 290 ( 6300). nun = 6g: â ° '° s 3.63 (za, br-s. 2-n); 4.0 (zu, m, cgz-c1),, 42 (zu, m, sn a 3-ca = cg), s, 12 (1n, a, a = 4, s, 1-ny, s, 21 (1a, a, a = 11, 3-ca), 6.85 (1a, s, cgrnz), 4.33 ~ (1ou, n, 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. 56-64 ° C) (2) and the residue was distilled to give anhydrous chloroacetaldehyde (3), b.p. 10-a2 ° c / vso etc. 103 _ _41o 260 za = vâåš “en" 1120. (1) RP Kurkjy, EV Brown, J. Amer. Chem. Soc., 1¿, 5778 (1952). (2) S. Trippett, DM Walker, J. Chem. Soc., 1961 1266. (3) H. 0. House, VK Jones, GA 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 Preparative Example 7 in 10 ml of ethyl acetate was added to a solution of 251 mg (1.5 mmol) Girard reagent T [1-carboxymethyl) -trimethylammonium chloride hydrazine] in 10 ml CH 3 OH containing n, 2s ml acetic acid via s ° c. after stirring for aa minutes via ° C, the mixture was concentrated to remove methanol and 20 ml ethyl acetate The ethyl acetate solution was washed successively with 2 x 5 ml of water, ml of a saturated aqueous solution of sodium hydrogencarbonate and 5 ml of brine and dried over magnesium sulphate. Evaporation of the solvent gave 145 mg (97%) of the - the rich compound XVIII (Z-iso more) as a yellow powder. M.p. exceeding 100 ° C (decomposition). : m = road: en "3400, 1110, 1120. vv = lay” nn te) 252 (3100), zsa (saoo). zso (4000). 214 (4ooo) 1: as (aoooi. 104 470 260 Preparation example 9 Diphenylmethyl-7- [2- (S-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamide] -3- (3-chloro-1-propen-1-yl) -3- cephem-4-carbogylate (VIII-111) A mixture of 10.1 g (SO mmol) 2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetic acid (III-1) and 10 .mu.g (50 .mu.l) Pcis of 110 ml of dry cnzciz are stirred via -1 to -1s ° C for 2 hours. The clear solution was poured into 500 ml of n-hexane to obtain a precipitate. The organic layer was discarded. by decantation and the residual 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. C (decomposition).

IR: λ :: ¿° 1 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 1 5 ml 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 S-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 H phosphate buffer pH 6.4) eluting with a 100: 1 mixture of CH 2 Cl 2 and methanol to give 31 mg (50 g). %) of the title compound VIII-1 (2-isomer) as a yellow powder. M.p. exceeding 1S0 ° C (decomposition). .- \ 10s _ 470 260 Ia vå; cm'1 3400, 1116, 1120, 1616, 1630.

CO uv = lššgn um (6) 240 111000), 260 110000). nun = ¿° ”S ° 'd6 3.6 (zu, m, 2-H1, 3.92 136, s, 0-ca3), ppm 4.0 (ZH, m, C§2Cl), 5.27 (2H, m, 6-HI 3-cn = cg1, 5.63 (1a, aa, a = 4, s 0 10, 1-n), 6.23 (1a, a, J = 11, 3-eg ), 6.83 11n, S, cgpn21, 1.33 (10n, m, Ph-H1, 3.0 (za, br-S, N32), 9.57 (111, d, J = 10, 1- Preparation Example 10 Diphenylmethyl-7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamide] -3- (3-iodo-1-propene-1 -yl) -3-cephem-4-carboxylate (IX-1) "A solution of 480 mg (0.77 mmol) of VIII-1 from Preparative Example 5 (Z / E = 2/1) in 10 ml of dry acetone containing 346 mg (2.3 mmol) of NaI 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 thiosulphate and 10 ml of brine and dried over magnesium sulphate Evaporation of the solvent gave 540 mg (98%) of the title compound IX-1 (Z / E = 1 / 1) as a reddish amorphous solid with a m.p. exceeding 120 ° C (decomposition). vxßr cm'1 3300, 1100, 1120, 1600, 1620.

IR max uv = add "cm'1 (6) 240 (21oo0), 290 (12000). nun =; ° “S ° '° z ° 3.61 (za, m, 2-a). 5.23 116, a, J = 4, s, ppm 6-H), 5.95 (1H, d, J = 4.5, 7-H), 6.27 (1 / 2H, Q, J = 11, 3-CH cis), 6.72 (1/23, d, J = 16, 3fCH trans), 6.87 I 6.96 (each 1 / za, S, cgvhz), 1.4 (10n, m, vn-H). 106 476 260 Preparation Example 11 N-phenylmethyl- 7- [α- (s-amino-1,2,4-aminoazol-3-yl) -2-methoxy-iminoacetamide] -3- (3-iodo-1-propylene) 1-yl) -3-cephem-4-carboxylate (Ix-1) A mixture of 5.69 (9 mmol) VIII-1 (Z-isomer) from Preparative Example 9 and 4 g (27 mmol) of 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% (w / v) aqueous solution of sodium thiosulfate and 10 ml of water. Removal of the solvent dried over magnesium sulfate gave a yellow oil which solidified by trituration with isopropyl ether. Filtration of the precipitate gave 4.3 g (67%) of the title compound IX-1 as E-isomer. M.p. exceeding 165 ° C (decomposition).

In = v fifi š cm "s4oo, 1780, 1725, 1sao, 1610. uv =: äga nu (sa 240 11aooo), 291 (11oooí. Nun =: °“ S ° 'âs * ° 2 ° 3,90 (sn, S , oca3), s, zs (1n, m, 6-a), ppm m; 7-B) '(d) 3:16; trans) y S; m; Ph-H) o Preparation Example 12 Be fl shv fl fvl-V- ê minê-ß-fßfkhr? fv ¥ evs = v1fvlí fl f ° sšefflf4f carboxylate (Z-isomer) '(XVIIIï ""' '"Compound XVIII is the common intermediate used in reaction schemes 1b and 1c. 101 _ 479 260 A. Benzhydryl. -benzylideneamino-3-triphenylphosphoniomethyl-3-cephem-4-carboxylate chloride (XV) To a suspension of 200 g (0.44 mol) of benzhydryl-7-amino-3-chloromethyl-3-cephem-4-carboxylate hydrochloride (II hydrochloride To 940 ml of CH 2 Cl 2 was added 440 ml of 1N sodium hydroxide at room temperature, the mixture was shaken for 10 minutes and the organic layer was separated, to the organic layer was added 75 g of magnesium sulfate and S1 g (0.48 mol) of benzaldehyde The reaction mixture was filtered and the insoluble matter was washed with 200 ml of CH 2 Cl 2. and washings were added with 126 g (0.48 mol) of triphenylphosphine. The mixture was concentrated to a volume of about 400 ml and allowed to stand for 4 days. The resulting viscous oil was diluted with 1 L of ethyl acetate and triturated to separate the title compound XV as a pale yellow crystalline powder, which was collected by filtration and dried in vacuo. yield 322 g (96%). mp, 1ss-190 ° C (sanerization).

IR 0: 2: = m / l 1180, 172o, 1690. uv = lâgšclz nm (8): so (241oo).

B. Benzhydryl 7-benzylideneamino-3- [Ethriphenylphosphoranylidene] methylz-3-cephem-4-carboxylate '(XVI) -' '' '' A mixture of 322 g (0.42 mpl) XV and 252 ml of SN sodium carbonate 1 1.6'L CH 2 Cl 2 was stirred vigorously for 15 minutes at room temperature. The organic layer was separated, dried over magnesium sulfate and concentrated to a volume of about 500 ml. The concentrate was added to 1 L of acetone with stirring to give a light yellow crystalline powder, which was collected by filtration to give 237 g (vase) of xv1, m.p. of 195-19a ° C (dec.). 108 470 260 in 0: 2: am'1 1770, 1620. uv = say: mn (s) 254 123000), 369 122000). man =; °°° 13 2.66 a. 3.16 (za, Aaq), 5.00 nu, a, J = 4 az), ppm d; J = 4 az) y d; 32) '6195 s) | 712-718 and's).

C. Benzhydryl-7-amino-3-Chloro-1-propen-1-yl] -3-cephem-4-carboxylate hydrochloride (Z-isomer) (XVIII hydrochloride) To the brine-liquefied carbonate solution of 2194 (0.294 mol) 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 for 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 g 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. za: _ våg: auf * 2330, 1760, 1720. * x 109 _ 470 260 uv = 12:25 nm (e) zas (saoo). nun = 6 ° "S ° 'ds 3.73 (sa, br, 8, 2-ap, 3.91 (zu, m, cgzciy, ppm s, 2z (1a, a, a = 4, s az, 6 -n), 5.31 (1a, a, J = 4.5 Hz, 7-11), 5.77 (m, m, s-caæg), 6.45 (1a, a, J = 11az, 3 -eg), s, sa (1a, 8, cgpnz), 7.33 <1on, br, S, en-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; r 'Cl, 14.85.

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

Fllnllêt! Preparation Example 13 Benzhydryl-7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamide] -3- [3-chloro-1-propen-1-yl] -3-cephemophen4 -carnoxylate (Z-isomer) (VIII-1) - To a stirred solution of 20 g (42 mmol) of XVIII (Z-isomer) in 420 ml of CH 2 Cl 2 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 o ° c. The slurry was stirred for a few 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 10% 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 (908 purity) of the title compound VIII-1 (Z-isomer) as a colorless powder. M.p. exceeding 1S0 ° C (decomposition). 110 470 260 IR ~ §§§ cm'1 3400, 17so, 11gg¿ 1sao, 1620. uv = lay ”nu 1 :) 24o (zooop), zaa (1zooo). nun = s “°° t °” 'ds a, s (zu, m, 2-n), 3.95 (aa, 8, ocgs), ppm 4.0 (za, m, çgzci), s, s2 (1n, a, a = 4, s H2, 6-H), 5.62 (1H, N, 3 (CH1Q§), 6.03 (1n, a, J = 4, s az, 1-a) , 6.32 (1n, a, J = 11 az, 3-ca), 6.87 (1a, s, cgphz), 1.33 (1on, br, 8, vn-H). Preparation Example 14 Benzhydryl-7- [2- (S-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamide] -3- [3-iodo-1-propene-1 -yl] -3-cephem-4-carboxylate (E-isomer) (IX-1) A mixture of 28.5 9 (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 (9S% purity) of the title compound IX-1 (E-isomer) as a yellow powder, m.p. exceeding 120 ° C (decomposition).

In = wave: = m ° '3400, 1180, 1125, 1sao, 1620.

UV ston liax nm (s) 306 (15000). una = ¿a ° et ° “'ds 3.71 (za, m, 2-n), 3.91 (sn, s, ocg3), ppm (go d; J = 8 Hz; d' a = 4, s Hz sa), s.os (1n, aa, J = 4, sa 111 _ 470 260 8 Hz, changed to double J = 4.5 Hz with D 2 O, 7-H), 6.32 (1H, dt, J = 15 to 8 Hz, 3-CH = C§), 6.79 (1H, d, J = 15 Hz, 3-CH), 6.98 (1H, s, C§Ph2), 7.35 (10H , m, Ph-H), 7.63 (2H, br, s, disappeared with D 2 O, Ngz), 8.52 (1H, d, J = 8 Hz, disappeared with D 2 O, 7-NH).

Preparation Example 15 Benzhydryl- 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamide] -3- [3- (4-carbamoyl-1-pyridinio) -1 -propene-1phyl] -3- gep-4-carboxylate iodide (E-isggr) (XII-1H) 9 "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 CH 3 OH 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. and the residual 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- 1H (E-isomer) as a light yellow powder with a melting point exceeding 150 ° C (decomposition) .. IR = ve 01171 3300, 1780, 1720, 1630, 1620. uv = 3: 2 ” um (s: * cm1 zaz (17o). nun = & ° "S ° 'd6 3.72 (za, m, 2-a), 3.90 (sn, s, ocg3), ppm s, 2s (an, m, 6-H ac§2u *) , 5.9 (1n, ad, J = 4.5 Q 8 Hz, changed to a doublet J = 4.5 Hz at D 2 O addition, 7-H), 6.35 (18, m, 3-cn = cg ), 6.89 (1n, s, cgphz), 6.9 (1n, s, J = 1s az, 3-cg), 7.35 (1on, m, vn-H), 112 478 260 8.06 (28, br, s, disappeared at D20, Ngz), 8.21 (28, br, s, disappeared at D20 - addition, N82), 8.36 & 9.07 (each 23, d, J = 6 Hz , Py-H), 9.57 (1H, d, J = 8 Bz, disappeared at D 2 O - addition, 7-NH).

Preparation Example 16 Benzhydryl-7-benzylideneamino-3-13-chloro-1-propen-1-yl] -3-cephem-4-carboxylate (XVII) (Z-isomer) To an ice-cold 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. 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 (dec.). The product was used in subsequent steps without purification.

Ia = våg: em'1 1180, 1725, 1635. uv = - Agššclz nn (s} * cm) zsv (400). nun = ° ”° 1z 6.18 (1a, a, J = 11 az). ppm 11: _ 4.70 260 Preparation Example 17 Benzhydryl-7-benzylideneamino-31 [§- (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 ml. minutes under a nitrogen atmosphere and the mixture was stirred at room temperature. The reaction was monitored by measuring the UV absorption ratio [11% (255 nm) / 1 cm E1 * cm (szo nmyy. When this product was at a temperature 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 hours), the mixture was concentrated to half its volume. The concentrate was treated with a small amount of charcoal and diatomaceous earth and filtered. Filter cake edge washes with 100 ml of a 1: 1 mixture of methylene chloride and carbon tetrachloride. To the combined solution of filtrate and washings was added a solution of 3.5 g (28.7 mmol) of isonicotinamide in 20 nl 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. The resulting precipitate was collected 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. Mp: 150-155 ° C (dec.). Estimated purity 80% according to NHR.

IR wave; cm'1 1175, 1725, 1690, 1635. uv = xâgšclz nm (s} * cm) zss (sas) 298 (255). 114 470 260 nan z J ° “5 ° '° s 3,4-a, s (za, ba), s, zs (za, bn), 5.41 ppm (m, a, a = 4 az), 5.73 (1a, a, a = 4 az), 6.93 (1a, s), 6.91 nu, a, a = 1s az), 1.3-1, s (1sa, br. S) , 8.40 (za, a, a = s, s az), 9.15 (za, a, a = s, s az).

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 Uquaternized cephem compound XXI-H in 25 ml of 85% formic acid was 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 obtain 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.).

IR: Road; cm.1 1795, 1680, 1620, 1575, 1540.; phosphate buffer (pH 7) nm (E1%) max 1 cm 294 (451).

UV: 115 470 260 KJ nun = c ”2 ° * °° 1 a, ez (za, S), 5.11 (1a, a, J-5 az), ppm 5.33 (23, d, J = 7 Hz), 5.43 (18, d, JIS az), 6.31 (1n, am, a = 1s 1 1 az), 1.23 <1a, a, a = 1s az), s, a4 ( zu, a, a-1 az), 9, oo (za, a, a = 1 az).

Preparation Example 19 2- (5-Amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetyl chloride hydrochloride (III-1 - ppm its acid chloride hydrochloride ..- A. 2-cyano-2-methoxyiminoacetamide Till a stirred mixture of 252 g (3 moles) of cyanoacetamide and 414 g (6 moles) of sodium nitrite in 600 ml of water was added to 371 ml (10 moles) of acetic acid at s-100 ° C for 1.5 hours. The mixture was stirred for a further 1.5 hours and adjusted to pH 8.5 with 6N sodium hydroxide, 568 ml (6 moles) of dimethyl sulphate were added to the mixture at 15-20 ° C and the mixture was stirred for 1.5 hours at 45 ° C. A matrix hyaroma was allowed to stand at 5 ° C overnight to separate the precipitate, which was collected by filtration, washed with cold water and air dried to give 292 g (77%) of the title compound as brown needles with a melting point of 170-172 ° C.

IR: Road: cm -1 3400, 3180, 1720 (sh), 1715, 1690, 1615, 1570. uv = agg: mm (e) 238.5 (8290), zea (sk, savo). nun == 6D “s ° 'ds 4,20 (sn, s, ocn3), 1, ss (zu, br. naz).

PPM Analysis calculated for C 4 H 5 N 3 O 2: C, 37.80; H, 3.97; N, 33.06. Found: C, 37.43; H, 3.75; N, 32.51. 116 470 260 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 (1.0S mol) of phosphorus oxychloride in 350 ml of dry 1 , 2-dichloroethane was boiled for 16 hours. The insoluble material was filtered off through a dicalite pad and washed with dichloroethane. The filtrate and washings were combined and poured with stirring into 1.5 liters 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 magnesium sulphate. The filtrate was distilled under reduced pressure to give 61.5 g (81%) of the title compound, which boiled at 62 ° C / 24 mm Hg. (Literature value boiling point: 47-4a ° c / 12 mm Hg).

In = všššskefilm cm'1 sozo, zeso, 2245, zozo, 1sso, 1455; 1080. mm = 6 ° D ° 13 4.35 (an, s, oca3).

PPM ___ 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 g (0.53 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 (20-25 ° 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 g (69%). M.p. 152-4 ° C (decomposition steam). [Literature value: amp. 150-155 ° C (dec.

In = path: cm "a1eo, zeoo, zsso, zzas, zooo, 1ses, 1sss, 1495, 1415. uv = 3: 3” nm (s) 243 (ssoo1,: ss (sk, s3ao1, sos (sk, ' 14øo). _: Snuso fl iß 1.88 (BH, s, cg3ceon), 4.15 (an, s, ocn3), ppm “7.60 (4H, bra).

Analysis calculated for C 4 H 6 N 4 O · CH 3 COH: 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-methoxyimino-acetonitrile - To a suspension of 125 g (0.672 mol) of 2-cyano-2-methoxy-iminoacetamidinium acetate in 1,25 To methanol was added dropwise 234 ml of 11.68 mol) of triethylamine via -100 ° C and 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) xscu 1 sso m1 methanol unaer 1 hour via -1s t111 -1o ° 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; 210-1S ° C (decomposition)) but our spectral and microanalysis data are consistent with the structure. 118 - 470 260 IR path: 60 "* 3435, 3260, 3120, 2960, 2245, 2020, 1630, 1546, 14ss, 1415. zE * ° H nn (61 248 1133001, 310 13470).

UV ma !! una = 8 ° “s ° 'd6 4.21 (an, 6, ocn31, 8.30 (za, br. NH2).

PPm 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; f '' A, 17.50.

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- (5- 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 nl). The extracts were combined, dried over magnesium sulphate and concentrated under reduced pressure. The residue was triturated with isopropyl ether to give pale yellow crystals of the title acid. Yield 16.6 g (6331. mp. 164-1as ° c (sanaarae1n1ng1.) Literature value; (Japanese published patent application-Kokai s1-1sa769; mp. 160-1s2 ° c 1sanaerae1n1ng11.

In = road; em'1 3460, 3260, 3140, 1125, 1620, 1605; 1545. uv = egg: um 12) 234 113200), zsa (sk, 3620). 119 - (470 260 F. 2- (S-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetyl chloride hydrochloride To a suspension of 40.4 g (0.2 mol) 2- (S-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetic acid (III + ä) 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 ° The mixture is stirred for 4 hours at -50 DEG C. and poured into 2 liters 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 was dried over potassium hydroxide under reduced pressure to give 46.0 g (90%) of the title acid chloride.

IR = vfåâffl om * 1775.

Preparation Example 20 i:: ns cozm - j / Û: f u / ca-ca-cnz-ci coocntrn), VIII-2 Q! Biphenylmethyl-7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (Z) -ethoxyiminoacetamide] -3-13-chloro-1-propenyl] -3-cephem-§- Carboxylate (VIII-2,2-Z isomer) To a mixture of 2.3 ml (9 mmol) of N, O-bis (triethylsilyl) acetamide and 1,338 g (2.8 mmol) of 7-amino-3- [§-chloro-1- (Z) -propen-1-yl] -3-cephem-4-carboxylate hydrochloride (XVIII: from Preparation Example 12) In 10 ml of methylene chloride was added 800 mg (2.9S mmol) of 2- ( 5-Amino-1,2,4-thiadiazol-3-yl) -2- (Z) -ethoxyiminoacetyl chloride hydrochloride portionwise with stirring at -10 ° C and the mixture was allowed to stand for 2 hours at 0 ° C. The mixture was diluted with 200 ml of ethyl acetate, washed with water and evaporated under reduced pressure. Trituration of the residue with isopropyl ether gave the title product VIII-2 as an amorphous powder. Yield 1.70 g (95%). M.p. exceeding 150 ° C (decomposition).

IR: Vmx (KBr) in cm-13330, 1780, 1720, 1690, 1380, 1220.

UV (C 2 H 5 OH) 1 nm (6) 285 111000). Λmax NMR OO § (DM 50-ds) δ ppm 1.26 (3H, t, J = 7Hz, cH2cg3), 4.25 (28, q, J = 7Hz, C§2CH3), 5.90 (1H, - dd, J = 4 to 8Hz, 7-H), 6.26 (1H, d, J = 11Hz, 3-cH), 6.85 (1H, s, cHPh2); 9.53 (m, a, a = szgz, v-Nn).

Preparation Example 21 i m., Lf "J" of own car: Diphenylmethyl-7-Z2- (S-amino-1,2,4-thiadiazol-3-yl) -2- (Z) -ethoxyiminoacetamide] -3- [3-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) 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. The mixture was evaporated under reduced pressure, diluted with 100 ml of ethyl acetate, washed with% sodium thiosulfate and water and evaporated under reduced pressure. Trituration of the residue with ispropyl propyl ether gave 1.82 g (84%) of the title product IX-2 as a light brown amorphous powder. 1 3290, mo, 1120, 1610, 1sao, 1370, 1220.

IR: vmax (kar) 1 and UV: Ä 1: max (cznso fl) i nn (E, cm) 304 (199).

Preparation Example 22 1 '(Cyclone (C 1-4 -Cn-cn-2-®-cona2coconium), Diphenylmethyl-7-benzylideneamino-3- [YE) -3- (4-carbamoyl-pyridinio) -1-propenyl ] -3-cephem-4-carboxylate (XXI-H-iodide) (Eeisomer) To a cooled solution of 42.8 g (90 mmol) of the 3-chloropropenyl cephem compound (XVII, 2-isomer) (from Preparative Example 16 ) in 80 ml of dry DMF was added 20 g (120 mmol) of KI in one portion and the mixture was stirred at room temperature. The reaction was monitored by the UV absorption ratio t fi cm (255 ml / 212 m (32011.) 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 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- The remaining brown semi-solid was dissolved in 100 ml of CH 2 Cl 2 and the solution was added dropwise to 70 l of ethyl acetate with vigorous stirring. After drying over P 2 O 5 in vacuo, 57.37 g (88%) of the quaternary solution were obtained. The title XXI-H as the iodide is a yellow amorphous powder, mp 150-1SS ° C (dec.) This product was identical to that obtained by iodination with NaI (Preparation Example 17).

Preparation Example 23 Acin2n - (off) CHCH-C1a-Clococ (ma), XVIII_ * Z Diphenylmethyl-7-amino-3- (3-chloro-1-propenyl) -3-cephem-4- carboxylate hydrochloride (Z-isomer) (XVIII, hydrochloride) A 25% solution of 699 (0.22 mmol) of chloroacetaldehyde in CHCl 3 was added to a solution of 80 g (0.11 mol) of XVI in 1.1 l 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 ° C. , 3 l, diluted with a mixed solution, ethyl acetate and isopropyl ether (1/2, 0.6 l), treated with silica gel (fl acogel C-100, 60 g) and filtered through a dicalite pad. 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 crystals obtained 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 hydrochloride of m.p. at> 185 ° C (dec.). The pale yellow needles product was identical to that obtained in Preparation Example 12.

Preparation Example 24 (N) -Na-aza--fu * (f- (ca-ca-cnz-ci-cocycline), f 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 mol) of N , 0-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, 10 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 BCI, 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> 185 ° C (dec.). Pale yellow needles. This product was identical to that obtained in Preparation Example 12. Preparation Example 2- 2- (5-Amino-1,2,4-thiadiazol-3-yl) -2- (propen-3-yloxyimino) - acetyl chloride hydrochloride (III-3 as its acid chloride hydrochloride) A. Ethyl 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 a rotary evaporator. 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. 83-86 ° C. 1 3100; 1745, 1710, 1610; IR: λ (KBr) 1 cm -1 (UV) 5ax (C 2 H 5 OH) 1 nm (G) 223 (9700), 242 (10000).

J = SHZ | m; 5,190 m; 'C§ = CHZ) I bros | NH). p. zI (su-butoxycarbonynmino-1, z. 4-1-1,1aaalazol-s-yl) -z- (propen-3-yloxyimino) acetic acid1) A solution of 770 mg (2.3 mmol methyl-2- ( 5-t-butoxycarbonyl-125 - 471] 260 amino-1,2,1-thiadiazol-y-yl) -2- (propen-3-yloxyimino) acetate and 3.5 ml of a 2N sodium hydroxide solution (7.0 mmol 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 SN hydrochloric acid and extracted with 2 x 10 ml of ethyl acetate. The ethyl acetate solution was dried over magnesium sulphate and concentrated on a rotary evaporator to give 596 mg (81%) of the title compound, mp 134-135 ° C (literature fi: mp 1ss-136 ° c. M = v ( Nujol) i cmq 3150, 1745, 1710, 1sso. Ma !! Uv) max (cznsou) i mn (e) 223 moon), 242 (11300).

NMR: 61132430-56) in ppm 1.55 (9H, S, BGC-H), 4.77 (Z1-I, δ, J = 5Hz | m] cgfcu), 6.0 (m, m, cgfcnz) . 1) I. Csendes, et al., J. Antibiotics, 32, 1020 (1983).

C. 2- (5-Amino-1,2,4-thiadiazol-3-yl) -2- (propylene-γ-yloxy-imino) -acetic acid (III-3) 1) A solution of 570 mg (1.74 mmol) Z- (St-butoxycarbonylamino-1 JA-thiadiazol-B-yl) -2- (propen-3-yloxyimino) acetic acid in 6 ml of trifluoroacetic acid was allowed to stand for 1 hour at ambient temperature. Evaporation followed by trituration with 30 ml of isopropyl ether gave 376 mg (95%) of the title compound. M.p. 109 ° C (dec.). rn = * max (union -1 cm * 3160, mo, 1545, 1460.

Uv = xmax (czuson) and nm (S) 245 (13500). (zu, m, cg = ca), 6.0 (m, m .. cgænz). w 126 470 260 1) Japan Kokai 57-112396 (7/13/82. Fujisawa) Brit. apply. 7935533 (10/12/79).

D. 2- (5-Amino-1,2,4-thiadiazol-3-yl) -2- (propen-3-yloxyimino) -acetyl chloride gydochloride 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. 1 In = u (nu-lol) icm '1765. ma !! Preparation Example 26 2- (5-Amino-1,2,4-thiadiazol-3-yl) -2-propargyloquinoaminoacetyl chloride hydrochloride (III-4 as its acid chloride hydrochloride) A. Ethyl 2- (5-t-butoxycarbonylamino -1.2, Phthiadiazol-4-yl) -2-pregpargyloxyiminoacetate 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 was 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- (5-t-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. 72-7 ° C. 1 n: = »max (mr) 1 cm 'szoo, 2330, 1745, 1110, 1610.

Uv = imax (cazone) 1 nm (a) 235 (12200). _? J = 2Hz, CEECH), 4.85 (23, d, J = 2Hz, noise) 127 _ 470 260 1) Commercially available, Aldrich. 2) I. Csendes et al., J. Antibiotics gg, 1020 (1983).

B. 2- (5-t-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 ZN aqueous solution of sodium hydroxide (4.4 mol) 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.).

In - vhax (uujel) 1 em'1 ssso, 1120, 1670, 1sso. fi v- * x max (C 2 H 5 OH) in nm (6) 233 (11S00). ë J = 2Hzy d; J = 2HZ | cgzcsscn), 9.0 (1n, e, un).

C. 2- (5-Amino-1,2,4-thiadiazol-3-yl] -2-progargyloxyiminoacetic acid (III14) 31 'A solution of 410 mg (1.26 mmol) of 2- (5-t-butoxycarbonyl amino-1,2,4-thiadiazol-3-yl) -2-propargyloxyiminoacetic acid 1 cm 3 trifluoroacetic acid flex for 1 hour via 2 ° C. Evaporation followed by trituration of the residue with 25 ml of isopropyl ether gave 204 mg (72 %) of the title compound, mp 156-1ss ° c (eönaeraelninga. 128 470 260 1 saoo, z4so, 17aø, 1610.

IR = »max (Nujol) 1 cm 'uv = ahax cczasoaa 1 um 1 :) 234 (12ooo).

NHR δ (DMSO-d 6) in ppm 3.52 (111, t, J = 2Hz, CECH), 4.86 (zap d; J = 2Hz | (2H, br.s, NH 2). 3) Japan Kokai 57 -112396 (7/13/82, Fujisawa) Brit. apply. 7935538 (10/12/79).

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 was stirred for 1 hour at -5 ° C. The reaction mixture was poured into 30 ml of n-hexane and the precipitate was filtered off. Yield 65 mg (34%). 1 IR: Qmax (Nujol) in cm-1770.

Preparation Example 27 2- (5-Amino-1,2,4-thiadiazol-3-yl) -2-cyclopentyloxyiminoacetyl chloride hydrochloride (IIIe5 as its acid chloride hydro- _ .K. _ _..... Chloride) Ethyl 2- (5-t-butoxycarbonylamino-1,2,4-thiadia; ol-3-yl) -2-cyclopentyloxyiminoacetate A suspension of 860 mg (3.7 mmol) N- (Cyclopentyloxy) -phthalinide1) and 185 mg (3.7 mmol) of hydrazine hydrate in 5 ml of ethanol were stirred for 1 hour at ambient temperature and 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 Ir-15129 - 470 260 n-hexane and ethyl acetate, followed by evaporation, gave the title product in a yield of 906 mg (81%) and m.p. 115-118 ° C. n: = vmax (man 1 cm * azoo, 1745, mo, 1sso. uv x (czason) 1 mn (s) 217 usoo), 252 (vanor. Äl fi a.

NHR: δ (CDCl 3) in ppm 1.51 (9H, s, BOC-H), 1.60 (8H, br.s, .HU) r 3188 (still: 'Sr ÛCH 3) I 4:90 H i (m, bra, X]), sno, ma, bus, 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 §§, 1020 (1983).

B. 2-15-t-butoxycarbonylamino-1,2,4-thiadiagol-3phyl) (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 6N 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. 185 ° C (dec.). 130 470 260 1 IR 3160, 1710, 1550.

OO Qmax (KBr) and cm-UV S lhax (CZHSOHI 1 Dm (2) 238 1133001.

NMR i s; noise; H H - {:]), 4.32 (1n, m, oxy] 11 ° C. 2- (S-amino-1,2,4-thiadiazol-3-yl) -2-cyclopentylo] iminoacetic acid (III- S, Z-isomer) 3) - "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 was obtained stand for 1 hour at room temperature The reaction mixture was concentrated under reduced pressure The residue was triturated with 5 ml of isopropyl ether and 10 ml of hexane to give 215 mg (86%) of the title compound, mp 162-165 ° C. (decomposition) (litteraturvärde3): m.p. 160-1es ° c (sönaerae1n1ng)). AQ (nujo1) 1 cm'1 3290, szoo, 1110, 1615, 1soo.

IR: max uv = lhax (cznson) 1 um (s): as (13:00).

NHR: δ (DMSO-d 6) in ppm 1.17-2.10 (88, m) f 4.60-4.98 (1Hf m), 8.22 (2H, S). 3) Japan Kokai 57-158769 (9/30/82. Fujisawa) Brit. apply. a1o71a4 (3/6/81). D. 2- (5-Amino-1,2,4-thiadiazol-3-yl) -2-cyclopentylogiminoacetyl chloride hydrochloride 5 - A solution of 190 mg (0.74 mmol) of III-5 and 219 mg (1.0 mol) of 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 131 - 4.70 260 by filtration. Yield 122 mg (60%).

Q 1 uujol) 1 cm -1 1750. max Preparation Example 28 IR Benzotriazol-1-yl-2- (S-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetate A mixture of 2.7 g ( 20 mmol) of 1-hydroxybenzotriazole and 4.12 gf (20 mmol) of dicyclohexylcarbodiimide in 65 ml of DM? was stirred at room temperature. After 15 minutes, 4.04 g (20 mmol) of III-1 was added to the stirred mixture at 6 ° C and stirring was continued for 3 hours. 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 washings were combined and poured into 800 ml of ice water. The precipitate was collected by filtration to give 5.24 g (82%) of the title compound as a light gray powder. M.p. 589-192 ° C (dec.). (xßr) 1 cm'1 1815, 1e2u, 1s4o, 1415, 1ø9o, 1oeo, 1oos, 945, ass, 740.

IR: Omax uv = imax (c2n5on1 1 nm (z} * cm1 246 (sec), zeask (2281).

Claims (5)

5 10 15 20 25 30 35 in <1 CJ RJ O \ CD 132 BBIEHIEBAIL Compounds of the formula in _ gï4 ca-u s _ nu: aäå 3 1 / '53323 conz: wherein Ra * is hydrogen or a conventional carboxyl protecting group and Ra'. R = “and R = 5 are the same or different and are hydrogen, hydroxy, lower alkyl or lower alkoxy and Z is chlorine, bromine or iodine; and salts, esters, solvates and hydrates thereof. Compounds according to claim 1, characterized in that R == is a benzhydryl group and that Z is chlorine or iodine. Compounds according to claim 2, characterized in that R ° ', Ra * and Ra * are hydrogen. The compounds benzydryl-7-benzylideneamino-3- [3-chloro-1-propen-1-yl] -3-cephem-4-carboxylate and benzhydryl-7-benzylidenamino-3- (3-iodo-1-propene -1-yl] -3-cephem-4-carboxylate according to claim 1. A process for the preparation of compounds of formula VIII wherein R22 is hydrogen or a conventional carboxyl protecting group and Raa, R = "and Rfs are the same or different and are hydrogen, hydroxy, lower alkyl or lower alkoxy and Z is chlorine, bromine or iodine, or a salt, solvate, hydrate or ester thereof, characterized in that the reaction a compound of formula II .za in "cno n _ las wherein R = °, R" "and R °° have the meanings given above, with a compound of formula III H28 III II, CIQC1 coon" wherein R fifl is a conventional carboxyl protecting group. to obtain a compound of formula IV vs now cam_1__r n .ß \ 4 CD ßâ Ü \ CD 134 then the compound of formula IV converts with sodium iodide or potassium iodide to obtain a compound of formula V u "n" w - " Then the compound of formula V reacts with triphenylphosphine to give a compound of formula VI k (_ 15 n "GB's * ev: 25 I / 534m), if" '. Or reacting the compound of formula IV with triphenylphosphine to give a compound of formula VI, then reacting the compound of formula VI with a base to give a compound of formula VII. then the compound of formula VII is reacted with ZCH = CHO, where Z is chlorine, bromine or iodine, to give a compound of formula VIII 35 135 aa "cas 5 u Mßcuzl vm ock" and finally, if desired, in a conventional manner removes the carboxyl protecting group R °° to give the corresponding free acid and converts said free acid to a salt or an ester thereof.