PL145972B1 - Method of obtaining cephalosporin - Google Patents

Description

The patent description was published: 89 04 15 145972 Int. Cl.4 C07D 501/56 Inventor, Patent Possessor: Toyama Chemical Co., Ltd., Tokyo (Japan) A method of producing a cephalosporin (The rnzedimioite of the invention is a method of producing a cephalosporin. Previously stated. that a cephalosporin of general formula 1 or a salt thereof is a very useful compound (Kokai Published Japanese Patent Application No. 9069 | 2 / 8i2i, No. 9310i85y © 4 and No. 119,399 (3/84 and Published Japanese Patent Application No. 41911) (85 and 66044815). Generally, the methods disclosed in the above-mentioned Japanese publications are shown in Schemes 3, 4 and a. Thus, known methods consist in the preparation of a cephalosporin by aylation of a 7-aminoinocephalosporin derivative with a thiazole compound or its reactive derivative. preparation of eephalosporin by closing the ring of the 7- [chloromethyl-carbonyl- (saturated oxyimino) / carbonylamino] -cephalisporin derivative using a thiourea or preparation treatment of a cephalosporin by oxidation of the 7 - [: 2-substituted thiazol-4-yl-loxylamido] -cephalosparin derivative. As a result of an intensive search for a new process for the preparation of a compound of general formula I, in which R1 is a lower alkyl group, possibly a optionally substituted carboxyl group or a protected carboxyl group; R2 is hydrogen or a carboxyl protecting group; Rl is a substituted or unsubstituted heterocyclic group attached to the exomethyl group at the 3-position of the cephem ring on the carbon-nitrogen linkage; it has been found that the useful compound of formula I or a salt thereof is easily obtained by the method described below, which is the subject of the invention. Contrary to the known methods of aylation, ring closure; or oximation, the method according to the invention comprises the dehydration * of the 4-i-hydroxytiazoline compound. The present invention thus provides a novel process for the preparation of a useful cephalasiporin of formula I or a salt thereof, which is easy and highly efficient on an industrial scale. According to the invention, a process for the preparation of the cephalosporin of formula I, wherein R1, R2 and R8 are as defined above. is that the compound of formula II or its salt, in which R1, R2 and R3 are as defined above, is dehydrated and, if necessary, the protecting group is removed, the carboxyl group is protected or the compound is converted into a salt. The compound of general formula II and its salts are new compounds and useful in the preparation of a cephalosporin of general formula I or a salt thereof. The structural feature of the compound of general formula II and its salts used in the process according to the invention is the presence of a group of formula II. general 3, in which R1 has the meaning given above. The cephalosporin syn isomer represented by the above formula and its salt has a wide range of antimicrobial activity and more it demonstrates an excellent antimicrobial activity against Gram-positive and Gram-negative bacteria, and is stable against mactaimase produced by, fibric &lt; RTI ID = 0.0 &gt;. &lt; / RTI &gt; Thus, the compound exerts an excellent therapeutic effect in human and animal cholera when administered intravenously. "In", unless otherwise stated, the alkyl group is straightforward. or branched C 1-4 alkyl group such as (methyl, ethyl, n-propyl, isopropyl, n-butyl, isotoutyl, tertiary-ibutyl, tert-butyl, pentyl, hexisyl, heptyl, octyl) , dodecyl and similar; an alkenyl group is a Ca-10-afflkene group such as vinyl, allyl, isophenyl pentenyl, 2-pentenyl, buiteoyl and the like; an aryoyl group is e.g. benzyl, phenethyl, 4- -methylbenzyl, naphthiomethyl, or the like; the aicyl group is a C1-12-iacyl group such as acetifluoro, prapionyl, butyryl, pivaloyl, pentebokatrtoonyl, cyclohexainecarbonyl, ibenzodl, naphthyllhloro, chlorophyll or halogen; bromine or iodine the first group "represents a group of 1-6 carbon atoms. Thus, terms such as alkyl, alkenyl, aryl, arylalkyl, acyl, and the like, s, represented in various names throughout this description, are unless otherwise stated. In each formula, R 1 represents a lower alkyl group, an optionally substituted carboxyl group or a protected carboxyl group, and R 1 represents a hydrogen atom or a carboxyl protecting group. The groups protecting the carboxyl group include those which are routinely used in penicillin and icephaospebrin chemistry, for example, such as an ester-forming group that can be removed by catalytic hydrogenation, chemical reduction or hyttrrolysis in mild weather conditions. ; an ester-forming group that is easily hydrolysed in a living organism; or an organosilyl, organophosphorus, tinorganicine group, which groups can be easily removed by treating the compound with water or alcohol; or other well-known ester-forming groups. - - Preferred protecting groups are as follows: (a) alkyl groups, for example C1-4alkyl; (these) substituted lower alkyl groups, wherein at least one of the substituents is a halogen atom or a nitro, acyl, alkoxy, keto, cyanogen, hydroxyl, digital alkali, aryl, alkyl tdol, alkylsulfinyl group, alkylsulfonyl, alkoxycarbonyl, S-alkyl-2-keto-1,3-idioxoliyl-4,1-indanylate, 2-indanyl, fuiryl, pyridyl, 4'-imild4-zolyl, phthalimic-dbwa, succinimide, azathidine lh-pyrrolidinyl, piperidine, morfloline, thio-morpholine, N-lower alkyl, pyrrolidinyl, pyraziolyl, thiazolyl, isothiazolyl, ox- siazolyl, isoxazolyl, thiadiazolyl, thio-morpholine, oxenazolyl thiazolyl, oxirazolyl thiazolyl thiazolyl , benzoifu 15 972 4 yl, benzothienyl, benzooxazolyl, benzothiiazolyloyl, coumarinylLowa, 2y5-dimethylpyrrolidinyl, 1,4,4,5-6-fourax) hydrogenpyridinyl, 4-methylpiperidinyl, 2,6-dipiperidinyl 4- 5 - (S-methyl ^^ irolanyl), 4i (2-pyrrolinyl ", N-me. tylopiperydynylowa, lf, 34enzlad, ioksioiLanylowa, alkylamine, dwualkiloatminowa, acylooksylowia, acyl diethylamino, dwualkifloaminokarbonylowa, alkoxy karbonyloaminiowa, ailkenylooksylowa, 10 arylooksylo- important, aralkoxy, cykioalkoksylowa, cycloalkyl, cycloalkenyl nyilooksylowa, heterocykliooksylowa, alkoxycarbonyl nylooksylowa, aikenylooksykarboinylooksylowa, macaws - Jlooksykarbonylooksylowa, aryloaikoksykartoanyloo- j polycarboxylic acids heterocyMooksykaffibonylooksylowa, 15 nylooksykanbonylowa alkenyl, aralkoxycarbonyl, and "ryilioóksykarbonylowa, cykloalkiMooksykarbonylowa, cykloalkenyloctaykatfboinyllowa, heterocyklooksykar- bonylowa alkiloainilinowa or substituted or alkiloainilinowa dhiorowca atom, a lower alkyl group of 20 or lower Iowa aikoksyiowa (c) cycloalkyl groups, alkyl groups substituted by lower alkyl group or (2,2-diisoalkyl-yl, 3-diocolyl-4-methyl groups; and (id) alkenyl groups; and (e) alkynyl groups; (i) the phenyl group and the phenyl group are substituted therein Na in which at least one substituent is the group given in (b); or an aryl group such as that of formula IV in which "Y1" represents a group of the formula —CH = CH — O—, —CH = CH — S—, —CH2CH2iS—, —CH = N — CH = N—, ^ CH = CH- ^ CH-CH ^, ^ CO-CH = CH — CO— or • - ^ CO — CO — CH = CK—, or its substituted cnodine, in which subscribers are groups given in (b) under 35, or a group of formula 5 in which "Y2" is a lower aUcilene group, such as a group of formula - (CH21 / 3) or - ^ ICH. ^^ -, or a substituted derivative thereof, wherein the substituents are the groups defined in i (b) above; (G) arylalkyl such as benzyl or substituted benzyl in which at least one substituent is selected from (to) above; and (h) a heterocyclic group or a substituted 45-1beterocyclic group in which at least one of the substituents is selected from (to) above; (i) iindanyl or phthalMyl groups, or substituted derivatives thereof, wherein the substituents are methyl or halogen; a tetrahydroonaphthyl group or a substituted derivative thereof, wherein the substituents are methyl or halogen; trityl, cholesteryl, bicyclo [4A'O!) decyl and the like; 55 (ij) a lower alkyl group, a substituted phthalidylidene group or substituted derivatives thereof, in which the names are halogen or a lower alkyl group. The carboxyl protecting groups given above are typical examples, but other protecting groups described in US Pat. US No. 3,490,909; 3 5r7i3 21910 and 3 6410 (118 'and in German patents No. 2 3i0a'M <4 and B3J3T7lOSu 65 of the above groups protecting the carboxy-75 Iowa group more preferred such as diphenylmethyl, 6-lower aMOo-Slnket ^ salkyl, acyloxyallkylpwa, acylthioalkyl, phthadiidyl, indanyl, phenyl, substituted or unsubstituted lower phthalidylene alkyl group, or groups that are easily deselected in a living organism, such as groups of formulas 6, 7 and 8, in which R4 is unsubstituted or unsubstituted alkyl, alkenyl, aryl, aralkyl, aliicyclic or heteaxcyclic group; R5 is a hydrogen aitome or a substituted or unsubstituted alkyl, alkenyl, aryl, arylalkyl, acyclic or heterocyclic group; alkyl, cycloalkyl, aryl or heterocyclic, or a group of the formula - (CH2) aCOOR5, where R * has the annotations given above or and n is 0, 1 or 2; and m is a number * 0, 1 or 2. More specifically, a 5-lower alkyl-24-ceto-1 -3H-dioxy group may be used, such as 5-methyl-3-keito-3-gooxaM-5-ethyl-2-keto-1 , 3-diokisoilyl-4H-methyl, 5-propyl-n2-ketoHly-3Kiiyloxediyl-4-methyl and the like; acyloxyalkyl group such as acetoxymethyl, pivaloyloxymeityl, ppopionyloxymethyl, butyryloxymethyl, isobutyryloxymethyl, valeryloxyimatyl, 1-aceitoxyethyl, 1-acetoxymethyl, 1-acetoxy-pyroxy-phenyl-like-pivaloyl-like-pivaloyl-like; acylthioalkyl group, such as acetyltrioniethyl, pivaloylthiomethyl, benzoylthiomethyl, pnc ^oioibenzoyl / otdontyl group * 1-acetyluioeityl, ilpivaliftthioethyl, 1-benzoylthioethyl and the like / ethylthioethyl and the like; an alkoxymethyl group such as methoxymethyl, I ethoxymethyl, propoxymethyl, isopropoxymethyl, n-butoxymethyl and similar alkoxycarbonyloxyalkyl groups such as methoxycarbonyloxymethyl, ethoxycarbonyloxymethyl, ethoxycarbonyloxymethyl, isopropoxymethyl, propoxymethyl , H1-tibutoxytaarbonyl'0ok6ymethyl, l ^ irriet1xxycayrtbonyaooxyethyl, l ^ ethoxy-caribonyloxyethyl, l-propoxycarbonyloxy-ethyl, l-ichoprotoxycnar ^^ 1- -III-ra.-buix) lxyloxy! -butoxy-kaitbonyloxyethyl and the like; an alpha-carbonylmethyl group such as methoxycarbonylmethyl, ethoxycarbonylmethyl and the like; phtalddyl group; an indanyl group; a phthalidylene alkyl group such as 2-itfitailddyliMeno / ethyl, 2- (5-fluoroiftalMylidene) ethyl, 2i-tftaiLMylidene / eltyl, 2h / 6nrne1x) xyiflMyilii ^^ and the like; etc. In each formula, R * represents a substituted or unsubstituted heterocyclic group attached to the 3-exomethylene group at the 3-position of the cethem ring via a carbon-nitrogen bond. The heterocyclic group can be, for example, a tetrazolyl, traazolal, pyrazinyl, paridazinyl and pyrimidinyl group, and a group of formula 9 where W is a bivalent group forming a 5- or 6-membered ring together with an adjacent nitrogen 'atom and a sulphonyl group such as for example, a 5- or 6-membered heterocyclic group containing one or more carbon atoms, such as 1,1-dioxide, 1,6-thiiadiazines, 1,1-isotliaisolidine dioxide, and lower. 5 More precisely, it can (it be the lH / 1,2,3,4-tetrazolyl group /, 1- / 1,2,3-tinazoQyl /, 2- / 1,2,3,4-tetrazoldyl-oc- wa, l-Zil ^^^ triiazolyl /, B- ^ lv2, M-triiazolyl /, r- / l, 2,3HMazoldJowa /, 1-71,2,4-triiazolyl /,, 4- / 1,2, 4-triazolyl /, 2,3-tetrahydro-pyridazinyl /, 2,3-dithiohydropyridazinyl, 3,6-tetrahydropyridazinyl, 3,6-tetrahydropyridazinyl, 6-keto-1,6-dihydropyridazinyl, 2-cato-1, 2-dihydro-pyrazinyl, 6-keto, l, 16-dihydropyrimidinyl, 2-keto-11, 2-dihydro-L-rimidinyl, l ', 2,6-thia 1,1- "2-iisothiiiazolidinyl dioxide and the like. heterocyclic atoms can be halogen, nitro, alkyl, aryl, alkyl, aryl, alkenyl, hydroxyl, alkoxy, cyan, amine, r alkylamino, dialkylamino, acylamino, acyl, acyloxyalkyl, acylalkyl, acylalkyl, acylalkoxy adkisycarbonyl, alkoxycarbonylalkyl, carbamyl, amdioalkyl, N-alkylaminoalkyl, hydroxyalkyl, hydroxyimdnoalkyl alkoxyalkyl, carboxyalkyl, sulfoalkyl, sulfone, sulfamylalkyl, isulfamylcarbamylalkyl, carbamylalkenyl, N-hydroxyalkylalkyl and the like. The above heterocyclic groups may be one or more subscribed. From the above substituents, the hydroxyl, amino and carboxyl groups may be protected with a suitable protective group, usually used. Removable groups such as acyl groups, e.g., benzyloxycarbonyl, 4-nitroibenzyloxy-carbonyl, 4-: bTomobenzyloxycarbonyl, 4- -methoxybenzyloxycarbonyl, 3,4-dimethoxy-4-phenzyloxy-isyloxy [beta] -tbenzyl-sycaribonyl, 4-.M-non-thoxyyphenylazo (benzyloxy-carbonyl, tert-butoxycarbonyl, ¦-1), 1-di: methylpropoxy caribonyl, bonyl, 'isopropoxycarbonyloxy, 2,2-carbonyl! 2-trichloroethoxycarbonyl, 2,2,2-ttromoethoxycarbonyl, 2-furfuryloxycarbonyl, 1-ada ^ a ^ yl ^ xycarbonyl, 1-cyclicsLopropylethoxycarbonyl, S-quinolyloxycarbonyl, dlorhylmethyl acetyl, benzodl, and fluoroacetyl-like; sulfonyl group, mp. methanesulfonyl, ethanesulfonyl and the like; an arylsulfonyl group, eg, phenylsulfonyl, thaluenesulfonyl, and podolbne; benzyl group; diphenylmethyl; trate group; an iinethoxymethyl group; a tetrahydropyranyl group; a tetrahydrofuranyl group; 2-niitrotphenylthiiol group; 2,4 ^ uunitrophenyl group (thiol and the like. In addition, to the protecting groups, the amino group includes all 60 groups usually used for this purpose, such as easily removable acyl groups, rip, ^ ^ Httri <5HJor1C ^ caribonyl toxic, 2.2, 2-tribromymethoxycarbonyl, benzyloxycarbonyl, p-toluenesilphonyl, 4-nitrobenzyloxycarbonyl, 4-bronTobenzyloolpycarbonyl, acetyl, 65 (mono-, di-, tri-chloroacetyl-7-tyl) amyloolkBycarbonyl, H-tert-butoxycarbonyl, 4-nontoxybenzyloxy-carbonyl, 3,4-dimethoxybenzyl'Ooxycarbonyl, 4- (phenylazo) -benzyloxycarbonyl, 4- (4-rmethaxyphenylazo / berizyloxycarbonyl) -2-methoxycarbgonyl, 2-furyloxycarbonyl, diphenylmethoxycarbonyl, 1,1-dimethylpropoxycarbonyl, isopropoxycarbonyl, yl-cyclopropylethoxycarbonyl, phthaloyl, succinyl, alkoxycarbonyl; easily removable groups, tax identification number. trityl, 2-nitrophenylthio, 2,4-diniltao enylthiol, 2-hydroxybenzylidene, 2-hydroxy-5-cVorobenzylidene, 2-hydroxy-1-, naphthylimethylene, 3-hydroxy-4- pyridylmethylene, 1-methoxycarboyl-2-pro) pylidene, 3-ethoxycarbonyl-2-ibutylidene, 1-ethoxycarbonyl-2-propylidene, 1-acetyl-2-propyiidene, il'-benzoyl-2-n-propyliidene, 1- [N- - (2-methoxyphenyl) carbaimyl] -2- | propylitdein, 1- - [iN- (4-meth.tolkisyphenyl) cairbamyl] -2-propylidene, 2-ethoxycarbonylcycloihexylideine, 2-ethoxycarbonylcyclopentylidene, 2-ethoxycarbonyleyklopentylidene, 2-ethoxycarbonylyclopentylidene, 2-acetyldehyde 3,3-di-ethyl-15'-ketocyclohexyl idene, 4-nitrhylpyrphyrrolidine and the like; and di- or trialkylsilyl and others. The groups protecting the carboxyl group are those given for R1. The hydroxyl group and the amino group may be protected by the protecting groups present in R3 and the carboxyl group by the protective group R1. The salts of the compounds of general formula 1 and 2 may be salts with basic groups or groups acidic salts, which are well known in the chemistry of penicillins and cephalosporins. Salts with basic groups may be, for example, salts with inorganic acids, such as. such as hydrogen chloride, hydrogen bromide, hydrogen iolide, nitric acid, sulfuric acid, and the like, and the salts with organic acids may be salts with acids such as oxalic acid, succinic acid, formic acid, trichloroacetic acid, trifluoroacetic acid and the like, or Sols with sulfonic acids, such as methanasulfionic acid, ethanesulfonic acid, benzenesulfonic acid, toluene-2-sulfonic acid, toluene-4-suilonic acid, imesitylBnosulfonic acid, / ^^^ triple ^^ tylobenzeniosulfioic / and the like. The salts with an acid group can be, for example, salts with alkali metals such as sodium, potassium and the like; alkaline earth metal salts such as calcium, magnesium and the like; ammonium salts; and salts with nitrogen-containing organic bases such as triethylamino, trimethylamine, aniline, N, N-dimethylalilinja, pyridine, dicyclohexylamine and the like. The invention also relates to all optical isomers, e.g., optical isomers. occurring due to the presence of an asymmetric carbon atom in the 4-position of the thiazoline ring and the like, crystalline forms and hydrates of Bvdazides (syn isomers) of general formulas 1 and 2 and their salts. 1 or a salt thereof is obtained. by subjecting a compound of formula II or a salt thereof to a dehydration reaction. The reactions are preferably carried out in a solvent. Any solvent that does not adversely affect the reaction can be used, for example, water, methanol, ethanol, acetone, acetonitrile, mtromethane, methyl acetate, ethyl acetate, chloroform, methylene chloride, tetrahydrofuran, N, N- -ojviimethylformamide, N, N-dimethylacitimide, etc., or mixtures thereof. The reactions are preferably carried out in the presence of an acid. These can be a protic acid, such as hydrogen chloride, hydrogen bromide, sulfuric acid, "formic acid, acetic acid," trifluoroacetic acid, p-toluenesulfonic acid, mesitylen sulfonic acid. and W like; Lewis acid such as boron trifluoride, aluminum chloride, zinc chloride and the like; complexes with Lewis acids, for example, a complex of boron trifluoride with ethyl ether, etc. Quantity; The acid used, although not critical, is preferably from 0.1 to 0.1 to 0.15 moles per mole of the compound of formula II or salt thereof. In addition, if a non-aqueous solvent is used, then a suitable dehydrating agent, such as, for example, anhydrous magnesium sulfate, molecular sieve or the like, may be added to the reaction system. The reactions are usually carried out at 0-410 ° C for 10 minutes to 48 hours. The resulting compound of the general formula I or its salt can be isolated and separated by known processes. The compound of general formula I in which R2 is a carboxyl protecting group, or a salt thereof, can easily be converted into a compound of general formula I in which R2 is a hydrogen atom, or a salt thereof using known methods. In addition, the compound of general formula I, in which R2 is a hydrogen atom, or a salt thereof, can easily be converted into a compound of general formula I, in which R2 is a carboxyl protecting group, or a salt thereof. The starting material of general formula 2 is described below. This compound can be prepared readily as shown in Schemes 1 and 2. In the compound formulas of these Schemes, R7l is an optionally substituted alkyl, aralkyl or aryl group. , X is halogen, the bond means that the compound is syn or anti-lyisomer or a mixture thereof, and R1, R2 and R8 have the meaning given above. If R7 is and a substituted alkyl, aralkyl or aryl group, then their substituents are the groups listed for the heterocyclic groups of R8. Some of these substituents may be protected with the protecting groups of hydroxyl or amino groups mentioned in the discussion of R8, and the carboxyl group with protecting groups listed in the discussion of R1. The salts of the compounds of general formulas 10, 11 and 10 are analogous to the salts of the compounds of general formulas [1] and [2], (a) preparation of thicloesters of formulas 16 and IB 65 The thiolester of general formula 16 can be obtained from diectene by the method described in the Bulletin of Chemistry Society of. Japan, 42, 1312 (2-IL32H <196I9) or the like. A compound of general formula 118- can be prepared by reacting 4Krhalogen-3'-ketobutyryl halide (Formula 19) prepared by reacting diketene with a halogen such as chlorine , bromine or the like [J. Chem. .Soc, 97, 1067 (1910M, with thiol. Reactions are conducted without or in a solvent, in the consistency of an acid-binding agent, for example an inorganic base such as carbonate or an alkali metal hydrocarbonate; an organic base such as such as froyalkylamine, pyridine, N, N-dimethylaminopyridine etc .; or in the presence of an acid scavenger such as propylene oxide or the like. hours. The reaction is usually carried out in a solvent inert to the course of the reaction. such as water, acetic acid, benzene, methanol, ethanol, tetrahydro rhodium: urain, and the like. Preferred examples of nitrosating agents are nitric acid and its derivatives, e.g., nitrosyl halide such as nitrosyl chloride, nitrosyl bromide etc, alkali metal nitrate such as sodium nitrate, potassium nitrate and the like; nitrous acid alkyl esters; such as butyl nitrite, pentyl nitrite and the like. When the alkali metal salts of nitrous acid are used as nitrosating agents, the reactions are preferably carried out in the presence of an inorganic or organic acid such as hydrogen chloride, sulfuric acid, formic acid, acetic and the like. When an alkyl nitrite is used as the nitrite agent, the reactions are preferably carried out in the presence of a strong base such as an alkali metal alkoxide. The reactions are usually carried out at reduced, room or elevated temperatures for 10 'minutes to 10' hours. (C) Alkylation In order to obtain a compound of formula I (4 or formula 113 from a compound of formula 15 or 17, the latter compounds are subjected to an alkylation reaction. , at a temperature of -20 ° C to 0 ° C and takes place from 5 minutes to 1.0 hours. Any solvent not interfering with the reaction may be used, for example, tetrahydrofuran, dioxane, methanol, ethanol, ol ilonoform, methylene chloride, ethyl acetate, butyl acetate, N, NH dimethylformamide, NRN-dimethylacetamide, water and mixtures thereof. For example, a lower alkyl halide such as methyl iodide, methyl bromide, iodide is used as the alkylating agent. ethyl bromide, ethyl bromide and the like, and dimethyl sulfate, diethyl sulfate, dibachomethane, diazoitane, tert-butyl chloroacetoacetate, methyl p-4-olenesulfonate and the like. If an alkylating agent other than cLazomethane or diazoethane is used, the reactions are carried out. usually in the presence of an alkali metal carbonate such as sodium carbonate, carbonate, potassium carbonate and the like, an alkali metal hydroxide such as sodium hydroxide, potassium hydroxide and the like; triethylamine, pyridine, N, N-dimethylaniline and the like. and (id) Halogenation. Compound j in general formula 113 is obtained by reacting a compound of formula 10 and general formula 114 with a halogenating agent. A halogen such as bromine, chlorine or the like is used as the halogenating agent; sulfuryl halide such as sulfuryl chloride; hypochlorous acid or a salt thereof such as hypochlorous acid or hypobromic acid; hypochlorite such as sodium hypochlorite and the like; N-chloroimide such as N-phormosuccinimide, N-chloro, rosuccinimide, N-bromophthalimide. or similar; perbromide such as pyridinium perbromide hydrobromide, 2-carboxyethyltriphenylyphosphonium perbromide and the like. The reactions are usually performed in a solvent that does not interfere with the reaction, for example halogenated hydrogen such as methylene chloride, chloroform, etc .; an organic acid such as acetic acid, propioic acid, and podolbne; an ether such as tetrahydrofuran. (e) The preparation of a thiazoline derivative of the general formula or its salt (ring closure reaction). A thiazoline derivative of formula 10 or a salt thereof is prepared by reacting a compound of formula 13 with a thiourea. In particular, it is possible to selectively obtain a thiazoline derivative (syn isomer) of general formula 10 or a salt thereof, in crystalline form, by reacting a compound of general formula 0.13 with thiourea in the solvents given below and under the following conditions. acet ethyl acetate, acetone, dioxane, tetrahydrofuran, acetonitrile, acetic acid, methylene chloride, chlorinated fluorine, benzene or 12-dimethyloxyethane, or mixtures thereof. The reactions are usually carried out at a temperature of about -4 D ° C to 30 ° C, preferably -30 ° C to 20 ° C, for usually 30 minutes to 5 hours, preferably 301 minutes to 3 hours. of the general formula 13 is the syn isomer, then it is sufficient that the amount of thiuria to be used is mole per mole of syn isomer. If, on the other hand, the compound of formula 13 is a mixture of syn and anti isomers, then the amount of thiourea is corrected depending on the ratio of the number of isomers of the compound of formula 13. In this case, the obtained compound (syn isomer) of formula 10 selectively crystallizes and exudes from the reaction mixture, and the unreacted anta isomer of the compound of formula 113 can be returned to the system. For this purpose, acid is added to the remaining anti-isomer. such as dry hydrogen chloride or dry hydrogen bromide to carry out its isomerization to the syn isomer. As a result, when the ring closure reaction is repeated, only the syn isomer is isolated. Only the isomer and syn can be easily produced in this way. The termination of the reaction can be easily determined by routine methods such as thin layer dhromatography, etc. The identity of the compound as a thiazide compound 10 15 20 25 30 .35 45 45 50 55 6011 U5 972 12 confirms. On the second sitron, published Japanese Patent Application No. 172t264V! 63 describes a method for producing a tlazol compound of formula 20, in which R1, R4 and the bond are as defined herein by reacting such starting compounds , that is, the compound of general formula 13, with thiourea. However, under the conditions used in the present process, the desired sterile thiazoline (syn isomer) can be selectively prepared without the preparation of the above thiazole. an acid halide of general formula Ii or a salt thereof. A compound of general formula II or a salt thereof can easily be obtained by reacting a compound of general formula 10 or a salt thereof with a halogenating agent which is usually it converts the thiol ester to an acid halide, preferably chloride, bromide or the like. These reactions are usually carried out in a solvent. Any solvent that does not adversely affect the reaction can be used, for example, methylene chloride, chloroform, ethylene chloride, ethyl acetate, or a mixture of these. several equivalents for one equivalent of a compound of general formula III or a salt thereof. The reactions are generally carried out at -30 ° C to 30 ° C for 5 minutes to 5 hours, preferably 16 minutes to 2 hours. (g) Preparation of a compound of general formula II or a salt thereof (acylation) A compound of general formula II or a salt thereof can be obtained by reacting a compound of formula I (1 or a salt thereof with a compound of general formula 12 ktb of its salt, usually carried out by in a suitable solvent without or in the presence of a base. Any solvent not detrimental to the reaction may be used, for example, water, acetone, dioxane, acetonitrile; chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, acetate methyl, ethyl acetate, N, N-dimethylformamide, N, N-dimethylacetamid, 1,2-dimethoxyethane, dimethylsulfoxide, sulfolate, etc., or mixtures thereof. such as an alkali metal hydroxide, hydrocarbonate or carbonate, or alkali metal acetate; a tertiary amine such as triethylamine, trimethylamine, trimethylamine, pyridine, N-methylpiperidine, N4ne-ithiomorpholine, lutidine, collidine and the like; such as -dicyclohexylamine, diethylamine and the like. A compound of the general formula (12) or the salt thereof can be readily prepared, e.g. by subjecting 7-aminoephalosporanic acid to the usual 3-position conversion reaction (Japanese Kokai Application No. 906 (9121/182, 03086/841, 9®m / M and 19G09GI / 84 and Japanese Patent Application No. 11J3665 / 83, No. [1HI433J13i / 83 and the like) and then, if necessary, to the carboxyl group at the 4-position. In addition, the compound of general formula IIfi or a salt thereof may be used in a reactive and hydrated form at the amino group. These are reactive substances frequently used in acylation, such as, for example, silyl derivatives, phosphorus derivatives and tin derivatives which are obtained by the reaction of a compound of general formula I {3 or. its salts, respectively with a silyl compound such as bis (trimethylsilyl) acetamide, trimethylsilylacetamlide, trimethylsilyl chloride, etc. a phosphorus compound such as a compound of formula II, formula 22, formula 213, formula (OH2CH2O) 2, PCI, formula (CH1GH1PCl and the like) or a tin compound such as a compound of formula fC2Hgl2 SamCl or the like. The amount of the compound of formula 11 or its salt to be used is not strictly defined, but is usually about 0.8-h2 moles, preferably fl1.0–1.5 moles per mole of the compound of formula 11 or the like. formula 10 or a salt thereof. The reactions are carried out at temperatures from -60 ° C to 50 ° C, preferably from - <3-5 ° C to 25 ° C, for 10 minutes to 10 hours. v 20 Compounds obtained in the above reactions can be isolated and separated; by known methods or may be steel in the following study without isolation. The invention is illustrated by the following Examples. Examples 1-8 relate to the preparation of substrates. Example I. (1) In IW ml of N, N-dimethylformamidium were dissolved 20 .0 g. S-methyl ester of 2-hydroxyismino-3 (-ketothioate) acid, 10.1 g. 30 g of potassium carbonate and 2 (2.4 g of tert-butyl chloroacetate, at a temperature of 0- <5 ° C. The reaction is carried out for 3 hours and then the mixture is added to a mixture of 40 (0 ml of ethyl acetate and 200 ml of water. The organic layer is then separated, washed with 20 ml of water, 200 ml of 1N hydrochloric acid and 200 ml of saturated sodium chloride solution, then dried over anhydrous magnesium sulfate. The solvent is evaporated off under reduced pressure and 100 ml of diisiopropyl ether are added to the residue. The precipitated crystalline precipitate is filtered off to obtain 14.4 g (4B%). 2-tert-butoxycarbonylmethoxyimaine-3-ketothioma-S-methyl ester words with a melting point of 715 ° C-7.7 ° C. IR spectrum of Kbr / 45 ohms: y 1700, 1664. C = 0.1 / 7.312. PMR / CDCl3 spectrum (:: 1 J50 / s, 9H, 3 C / CH, a, 2.39 / s, 3H, -Olth, 2.46 (1s, 3H, -CHa), 4.03 (s, 2) H, --H2CH2OW. v (2) To 6O1 ml of tertifluoroacetic acid, cooled to 0.150-5 ° C, was added over 10 minutes, 10.0 g of 2-111-butoxycarbonylmethic acid, S-methyl ester. Everything was left to rest for 1 hour at 0 &lt; 5 &lt; 0 &gt; C and then the solvent was evaporated under reduced pressure. 50 ml of diisopropyl ether were added to the residue and the crystalline precipitate was filtered off. 7.2 g of • (90.5%) ester were obtained. Sn-methylic acid of α-carboxymethoxyimino-3-ke1xthiiom, with a temperature of 1514-h1I5.70C. • IR / KBr / cm1 spectrum: y C = 0.13l4, 1700, lGOO. PMR / DMSO spectrum ^ d6 / <3: 2.36 (te 3H, --CH3 /, 2.45 / s, 3H, - CHif, 4.815 / s, BH, —OGH.jOO- ^ L. Example II. (ID To 300 ml of vial, 38.0 g of sodium nitrite 55 and 66.1 g of 3-ketoitilbutyric acid S-methyl ester were added, followed by propionion with stirring at 5-8 ° C for 30 minutes, 2110 ml of 4N sulfuric acid After incubation, the mixture was post-flushed at this temperature for 30 minutes, then poured into 5KX0 ml of ethyl acetate. The organic layer was separated, washed with 500 ml of water and dried over anhydrous. magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dropped in 651 ml of an aqueous solution of 110 g of sodium carbonate, and then 150 ml of methanol was added. EO of the solution was added dropwise at H? -20 ° O 715, 7 g of dimethyl sliaircizain and allowed to stand at this temperature for 2 hours. Then, the reaction mixture was poured into 1 liter of ethyl acetate, the organic layer was separated, washed with 50 ml of water and dried over anhydrous magnesium sulfate. under reduced pressure and the residue was distilled under cold evaporation. O-triamine G 0.4 g (6.8i.9P / 0.1) mixture; syn and 'anrtai isomers of 2-methoxyimino-3l-ketoitiiomaisilic acid S-methyl ester. boiling point 80 - ^ mPC / 0.2 m k) Pa. - Miteszanine was separated and chromatographed on a silica gel {Wako Silica Gel. C-2010), using a mixture of n-hexane and benzene for the elution. The 2- (syn () -methylxy! Ta.butyric acid S-methyl ester and the <2- (anti / -me- v toxyunimcH3-keitoite acid S-methyl ester) in the form of oily products were obtained. 2- / syn / -metaxyimino- ^ -ketoltolyoinasylic acid methyl IR spectrum / film / om- *: y C = 0 1720, 1690, H67KK PMR spectrum / CDCls / d: 12.42 / s, 3jH /, ^, 48 (s, 31H), t4.14 / s, < 3 (H) .Sn-methyl ester: 2- (an1n1) -methoxByimino- -3Mketotonobutyric IR spectrum / µm / cm "1:? C = 0 1750, 1680. PMR / CDCV $ spectrum:% 4tt- / s, 3H /, 2.42 M, 3) H /, 4 ^ 16 / s, & HJ. <2) For a solution of 10.0 g mliesisiainin of the syn and anthi ester S- isomers 2-methotoshiimino-, -3-keitothiimino-acid methyl acid in 160 ml. of 4-dioxane, 210.1 g of pardridinium pertaomide hydrobromide was added and the whole was left for 4 hours at room temperature. reduced pressure and 100 ml of ethyl acetate and HO10 ml of water were added to the residue. The organic layer was separated, washed successively with 1.0O ml of 5 vegio, 1100 ml of water and 10 0 ml of a saturated aqueous sodium chloride solution. After drying with anhydrous magnesium sulfate, the solvent was evaporated to give 11.6 g. (60.0%) of a mixture of syn and antimethyl 4-broimethyl-2Hmethyl isomers. and purified by chromatography on a silica gel column (IWako Silica Gel C 2 200i), eluting with a mixture of n-hexane and benzene. -2-45 972 - / anti / -netoxyimino-3-Hkeitothio! Butyl in the pores of oily products. S ^ methyl ester, 4-ibromo-2- / syn / -methoxyimino-3-ketoteinobutyric acid 5 Wddimo IR / film / cm "1: y C — O IflOft '1665. PMR spectrum / CDCls / <5: 2 ^ 52 / s, 3H, —SCH3 /, 4.2.1 / s, 3IH, ^ OCHa /, 4 ^ 42 (s, 2H, BrCH 2). Wildmo 1! * C-NiMR (CDC13A5: 1H ', 30') -SGEty, 29.76 (BrCH2W, 64.97 (4). /, 105.60. (Group of formula 25), 1186.96 f-C = Of.'4-Biromo-2- methyl ester (anti) - [methoxyimino-e'-ketothiomasyl ester Wildlmo IR / film / cni- !: y C = 0.17201, 1655. PMR (CDCl3) spectrum: 2.411 (s, 3H, 4CH3), 4, Z1 15 (s, 3 H, 4 OCH 3), 4.23 (s, 2H, DrCH2 - K). A similar method is a mixture of syn isomers and antis-methyl ester of 4-nbromo-2-k, arboxymyetoxyimino-34-cetotic-naphthylic acid. Melting point 11.0Hl] 14PC. 20 Spectrum m / KBr / cm ~ i: y C = 0 1724, 1652. PlMRyU ^ yESO-de '/ 8: 2,! 50' 7s, 3H, ^ SCH3 /, Aftl / s, 2H, BrCH2CO ^ / , 4.93. 7s, 2H, —OCH2CO— /, 9.27 (bs, 1H, 100OH)., Ponialdto, by reaction and the above S-methyl ester of 44-Dromo-2-14 carboxyimethoxyimino-3-ke- (thiomassyl) with diphenyldiazomethane, used in the usual manner, the products obtained, after separation of the products on a column, SL-methyl ester of 4-bromo-i3-keto-2- (syin) -diphenyl), L-methoxy-carbonylethoxyiiminthioniasilegio, having a foaming temperature of 87- 99 ° C. IR spectrum / KBr / ohm-i: y C — O, 1.7150, 17-14, 16SI0, 11660. PMR spectrum / CIDC13A5: 2.4 µg / s, 3iHf ^ SCH ^, 4.08 35 / s, 21H, BrCH2CO— /, 4y, 7. (s, 2iH, ^ OCH2CO), 6.95 / s, 1 ml. Example III. (! 1 () and (! I) To the mozzoline, 25.4 g of B4-methyl-S-methyl ester 4-rtKnomo-2r-, (tsyn / jmethio-40oxyimino-S-ketothioimasi) in 200 ml of ethyl acetate was added for 1 hour at a temperature of 6H- (20 ° C, 7.6 g of thiourea. The reaction was carried out for one hour at this temperature, and then the precipitated crystalline precipitate was filtered off to obtain 30.2 g (9dV5l °). / o () 2- (2-amino-4 ^ hydrolkBy- ^ -) tóazeoinyl ^ 4 - / - 2- / syin ^^ Spectrum iR / KEr / cm "1: y C = 0 1670 (Ii) Repeating the above reaction and using 50 ml of ethyl acetate, as above, acetone, dioxane, tetrahydrofurari, acetanitrile, acetic acid, methylene chloride, chloroform, benzene or II. 2H-dimethyxyethane, ipadolbne endings were obtained. (Lily) Using the method given in (i), we obtained 2- / 2-aimiino-4-hydimxy-2-thia phenyl-onethoxycerbonyl natomethoxy! Mi) S-methyl ester hydrobromide. / on-i; y C = 0 176K), li7) 4K, 116610. and (2) For chilled ice With a suspension of 8.0 g of 2- (2-amino-, -4-hydroxy-2-thiazolium-, -4-hydroxy-2-thiazolium-, -thio-acetic) acid S-methyl ester in a mixture of 200 ml of ethyl acetate iv, 100 ml of water, 4 ° C was added 0 g of sodium bicarbonate. Everything was mixed for 5 mabut, then. The organic layer was separated, washed with 100 ml of water and dried over anhydrous magnesium sulfate. The solvents are evaporated off under reduced pressure and 310 ml of benzene are added to the residue. The crystalline precipitate was filtered off to give 5.5.2 g (86.71% / ol) of 2- (2-amino-4-hydroxy-2-thiazolmyl-4 (-2- (syn) -methyl) acid ester. ^^ notioacetic acid with a melting point of 127'-130 ° C. IR spectrum / KBr / cm- *: y C = 0 16140, PMR spectrum / DMiSO ^ d6 / (3: 2y36 / s, 3H, - ^ SCHy, 3, 21.3.84 (ABq, 2H, J = 11.2 Hz), group of formula 27), 3.78 (s, 3H, -OCH3), 6.16 (bs, 1HNH2A Wiidmo 13 C-NMR (DMSO) d © M: Itt ^ 10 (- ^ SCH3), 43.51 (C-5), © 2.119 (-OCH3), 11012.43 (C-4), H57.34 (group of formula 24), 161, 85 / C-2 /, il / 90 |,! 26 / (group 10 in the formula mi. Mass visimo / m / e /: 260 7M ++ 11 /. UV spectrum / tanoil /: yLmax 23l2i / iS / / *? - 8167). 2- (2-AirninTO-4H-hydroxy-Hfe- (syr-diphenylmethoxy-acetic acid) -s-methyl ester, mp 1140-d) 4120C. IR spectrum (KBr / cm "1: y) was obtained in a similar manner. C = 0 11728,16512 PMRADMSO spectrum, d * (S: 2.36 / s, 3H, -SCHj), 3JH8, 3.717 (ABq, 2H, J = 12Hz, group of formula 27), 4.79f , 2H /, —OCH2 ^ GO— /, '6jl7 / bs, UH, ^ OH /, a84 te,' 3H, —NH2, - ^ CH py of 'formula 26 /. (Example IV. (1) To' a solution of 50.8 g of a mixture of syn and anti isomers of 4-baxvno-2-metholoyl acid S-methyl ester in 40101 or ethyl acetate was added at H5M20'0 for 30 minutes to an additional 7.6 g of thiomonocyte. Reactions were carried out at this temperature for one hour, after which the resulting crystalline precipitate was filtered off and washed with 50 ml of ethyl acetate. 31.4 g (47.5lD / o) of the 2- (2-amino acid) S-methyl ester biohydride were obtained. The IR spectrum was identical to that of the compound obtained in the example. 111 (1) (i). (2) The slurry of (II) was washed with 2 × 300 ml of water and dried over anhydrous magnesium sulfate, then 5.0 g of dry hydrogen chloride was introduced while cooling with ice, and all was left in the water. for 5 hours at room temperature The reaction mixture was washed with 2 x 300 ml of water The organic layer was dried over anhydrous magnesium sulfate and 3.9 g of thiourea was added over 30 minutes at 15 to 20 ° C. The steel precipitate was washed by filtration with 20 ml of ethyl acetate to obtain 110.1 g (l5.3 l%) of the bromohydride of the S-methyl ester of the 2-γ-amino-4-hydroxy-2-thiaizolinyl-acid. 4 (I1) The IR spectrum was identical to that of the compound obtained in the example IHJ (1 {) (i). Example V. (I1) For a solution of 50.0 g of a mixture of syn and anlti isomers 4-bromo-2-methoxyimino-3-ketothiobutyric acid SH-methyl ester in 250 ml of acetone was added at a temperature from - ^ 25 ° C to - ^ 2 PC in one hour 7.5 g of thiourea. It was further charged at the same temperature for two hours, and the finally precipitated crystalline precipitate was filtered off and washed with 50 ml of acetone. 30.9 g (47.5 (% a) of 2- (2-amino-1-hydrofcsy-2-thiiazolinyl-4- (2- (syn)) methoxy-imiinoacetic acid, S-methyl ester hydrobromide were obtained. 5 IR spectrum / KBr / cm "i: γ C = 0.1650. (2) The filtrate from (ii) was put under reduced pressure and the residue was dissolved in 2010 ml of ethyl acetate, washed with 200 ml of water and dried over anhydrous. With magnesium sulfate, 2 to 10 g of dry hydrogen chloride were introduced into the solution at 0-5 ° C, left at room temperature for 5 hours, washed with 2 × 100 ml of water and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. under pressure, and the residue was dissolved in 120 ml of acetone, and then 30.0 g of thiourea was added at a temperature of -12.15 ° to -20PC in 1 hour. Reactions were carried out at the same temperature for two hours, after which a crystalline precipitate was formed. The precipitate was filtered off and washed with 2 µl of acetone to give 10 µl "g (1.55.5") of the 2- (2-amino-4-h) S-methyl ester bromohydride. ydiroxy-2-thiazolinyl-acetic. IR / KBr / cni- * spectrum; y C = 0 16150. (3) 2- () 2-'a! mino-4-hydroxy-! 2-thiazolinyl 4j (-2-) syin / -im © to- xyiminothioO'Ctic acid baromide @o obtained in (1) and (2) were treated the same as in example 111 (2,) d to give 2- (2-iamino-4--halidroxy-2-halo-2-azolinyl) acid S-methyl ester 4 - / - 2 - (syn) -metholxyimine-thioacetic acid, mp 127-130 ° C. The physical properties (IR, CSF, 13C-NMR and UV) were identical to those of the compound of the example IUjOa). Example VI. To a solution of 20.0 g of 2- (12-amino-4 -I-hydroxy-2-thiazolinyl-4- (-2-syn) -methoxydimino-thioacetic acid bromohydride in HOO ml. of anhydrous methylene chloride was instilled at 0 ° -5 ° C. for 110 minutes with 100 ml of anhydrous methylene chloride containing BFI g of chlorine. The mixture was left at the same temperature for 30 minutes, after which the resulting crystalline precipitate was filtered off and washed with 2 × 20 ml of anhydrous methylene chloride. There were obtained 14.6 g (715.7% C) of 2- (2-amino-, 4-hydroxy-2-thiazolylnyl-4-2- (syn) -methoxyiminoacetic acid chloride hydrobromide, m.p. 120i — iH2E ° C (decomposed). 50 IR spectrum (KBr / cm "1: γC-O If7.180. Using ethyl acetate in place of anhydrous methylene chloride) was prepared in the same manner with 2- (2-tazol-4) -j2- / syn acid chlorohydride. N-diphenylethoxycarbonyl-methoxyiminoacetic acid melting point ilyl (8Ml (20 ° C (decomposed). IR spectrum / IKJBr / cm "*: y C = 0 1 (716 (4, 1740, 1642. Example VII. For chilled - to a temperature of O1 to 5 ° C of a suspension of 20.0 g of 2- (2-amino-4-hydroxy-2-thiazolioyl-4 (-2) syn) -ineitoxyimethyl ester 60 g hydrobromide in 2O0 ml and anhydrous chloride methylene was added dropwise over 20 minutes to 10.6 g of bromine The mixture was left at the same temperature for 30 minutes, then the precipitated crystalline sediment was filtered off and washed with 2 × 20 ml of anhydrous methylene chloride. The obtained Mfi g (T1j4P / *) 2- ^ 12-amino ^ -hyctoxy-2 - ta) aizolinyl-H4 - / - 2- (syn) -methoxyiminooic acid bromide hydrobromide, mp 88 ° C (decomposed IR / KBr ^ cm &quot; 1 spectrum: / C = 018118. & Example VIII. (1) To a solution cooled to -30 ° C, 4.1 g of pivaloyloxy-methyl ester of 7-aimimim-3- (5-methyl-ill213), 4-tetrazolyl-methyl-cephem-3 -cariboclsyl-4 in a mixture of <32 nor ethyl acetate and 8 ml of N, N-dimethyl ethamide, 3.50 g of 2- (2-amffino-i4H-hydroxy-α- "thiazolyinyl-4) acid chloride hydrohydride were added. 2- - (syn) -methioxyiminooctiO (weigo and reactions were carried out for two hours at -3.10 ° C to -20 ° C. The reaction mixture was poured into a mixture of 50 ml of ethyl acetate and 110 ml of a saturated solution of Aqueous sodium bicarbonate. The organic layer was separated, washed with 50 ml of water and dried with anhydrous magnesium sulfate. The Indk solution was evaporated in vacuo, and 50 μm of ethyl ester was added to the residue. the precipitate was filtered off to obtain 4.8 g (78i, 4J%) of 7- [12- (2Haimiino-4-hyidroixy-β-thiaEOilinyl-4 (-2f- / syn) / 4-methoxyiminoacetaimido) pivaloyloxyimethyl ester / -S - / 5 -methyl- - | ls2.34- (tetrazoMl-2-toethyl-4-, m.p. 85-87 ° C (decomposition). IR spectrum / KBr / cm- *: y C = O 17 [mu] l (0i, 117510., 1670 PMR spectrum / CDCl3 / <5: \ m / s, 9H, -C / CH3 / 3 /, 2.50 [mu] s, 3tl, group of formula 29 /, 3.29 (s, 2H, NC2-H), 3.30, Table 1 Compound of Formula 21 R1 R * R "Melting point (° G) IR / KBr / cm" 1: y C = 0 IPMR / CDClj (8: - CH $ ggroup of formula 1, group 1, 20 (s, 9H, -C (OH3) 3), 1.58 (d, 3H, J = 7 Hz, group of formula 37). 2.55 (s, 3H, group of formula 11785, 29), 3 $ 5 (bs, 2H, C2-H), 3.09-? 3.59, 3.77-? 4.28 104! 1750 |, (m, 2H, group of formula 27), 3.97 (s, 3H, -OCIty, 11670 4.91 ^ 5 ^ 16 to, 1H, C6 ^ H), 5.63 (bs, 2iH, group of formula 30 ') /, 5.75 ^ 6.011 to, UH, C7-H), 6.71 ^ 7.24 to, UH, group of formula 38 (-CHt group of formula -CH2OOOC), formula 33 xt (CH *), 1070H1, 213 / s, 9H, 3.61, 3.75-h4.29 to, 2H, group of formula 27 /, 3.91 / s, 3 H, - OCH 1, 4 # 5, -6.5, 8 is, 3 H, group of formula 30; C6-iH), 5.57-1'40 to, 3H, C7-H, 5OCHaO-, s ^ 1H, group of formula 30). - CH8 group 0 group of formula 34 of formula 32 1215- ^ 1 ( 30 (decomposed) M80, 1725, 1660 2.47 (2s, 3H, group 20), 3.26 (bs, 2H, C12H), 3.1 (3R-3.57, 3.76-4.20 '(Im, 2H, group of formula 27), 4.86- 5.00 (1H, m, C6-H), 3.88 (s, 3H, -OCH,). 5.39.5, TIU / AB, q, 2H, J = 15iHzf group of formula 30, 5.72-6J0 (Im, 1'H, C7-H), 6.96 (s, 1H, -CH) C§Hj - / .- CH, group of formula 34 gi group of formula 3j5 160 dem) 1 (780, 1720, 1682, 1640 1 ^ 22 (t, 3H, J = 7Hz, -CHaGH * /, 3.4L) bs, &lt; 2H, CH2H /, 3.11 (O ^ 3.519, 3.70M4.30i / m7aH, group formula 27 /, 3.60 ^ 4.20 to, 2iH, -GH2PH5), 3.85 (s, 3H, -OCH8), 4.4 [beta] 4.95 (ABq, 2H7j = H5iHz, group of formula 30), 4.90- ^ 5.25 to, -1H, C8-H), 5.65- € A <5 Au, 1'H, C7-H), 6.24, 6.4) 4 (ABq, 2H, J = 5Kz, group of formula 40), 6% 6 / s, 1H, -CH (im, I110H, 2, groups of formula 26) group 0 group formula 36 group 0 group formula 34 formula 32 1 <03 ^ 1 0.15 (decomposed), 1780, 1730 1674 x2 2, 42 (s, 3H, group of formula 29), 3.0D-? 3.5I1, 3.6 Or- 4; 1.5 (m, 2H, Gruipa 27), 4.70 (s, 2H, -OOH2CO-), 4., '96 -? 5.30 to, 1H, C6-H), 5, (55 (bs, 2H, group of formula 30), 5.90i-j6.20 to, liH, CH), 6.87 (s, UH, -OH, 20H, 4 groups of formula 26) . (spectrum made in DMSO-dj / xj) Oxalate, 7-α! mino-i3- (5-chloro-X) oxalate, ipdialoyl ester and oxalyimitoyl ester of 7-α! mino-i3- (5-chloro-X) were used as the starting compound} Methylene chloride anhydrous was used as a mixture of ethyl acetate and N, iN-triethylacetal as acid binding agent 145 972 19 4.07 or 4J18-3.43, 4.07 or 4.13 (ABq, 2H, J = 1.2 Hz, group of formula 27), 3.93 Vis, 3H , —OGEty, 5/30 / i / 12iH, d, J = 5Hz, C6-H /, 5.05 / d, 1 »/ 2H, J = 5Hz, C 5.53, 5.67 / ABq, 2H , J = ill5Hz, group of formula 30 / ,. 5.713kh6.0 (3 to, 3H, C7-A - OCH2CO-I. UV spectrum (ethanol): ≤ max 260 / e = 9075 / .. The compounds shown in Table 1 were obtained in a similar manner, repeating the previously described reactions and using 2- (2-amimo-4-hydroxy-2-thialzoiinyl-4 /- ^. ^ g acid bromide phorohydride instead of 2- (2-amino-4 ^ hydroxy-2-thiazolinyl chloride ibromide) ) o-4 / ^^ -liminoacetic acid, the pivaloyloolk-methyl ester of 7- [2 / - # - amino-4-hydroxy-2-thiazO-4l / -2- / syn / H-metolxyitala © -U2.3 was obtained , 4-tetrazolyl-2-toe-4, m.p. 8 ° -87 ° C (from decomposition. Example IX. In BO ml of acetonitrile containing 0.1 ml of concentrated sulfuric acid, 6.12 g of 7- [2-β-2-amino-4-hydro-2-thia-methoxyiminoacetamido] -3- (5-methyl-2-methyl-2-amino-4-amino-4-amino-4-amino-4-hydroxyiminoacetamido] -3- (5-methyl-2-amino-3Hcarbon) ester and the remainder was brought to room temperature for 5 hours, the solvent was evaporated under reduced pressure and 100 ml of ethyl acetate and 100 ml of water were evaporated, then the pH was adjusted to 6.0. The organic layer was separated, washed with 100 ml of water and dried over magnesium anhydrous sulfate. The solvent is evaporated off under reduced pressure, and 30 ml of diethyl ether are added to the residue. The precipitated crystalline precipitate was filtered off to obtain 5.613 g (94.8%) of 7- [2- (12-amino-thiazolyl-4] - -2- (syn) -methaxyl (manoaicetamido] - '3H) pivaloyl ester ester. (15H-methyl-1,2, - A4, tetrazonyl- {2) -methyl-cei-emo-3 *, m.p. 127- (lf28.10G (decomposed). IR spectrum / KBr / am-i; y C = C 17fl0 " 11743,1676 PMR spectrum (DMSO-d6A5: 1.115 / s, 9H, -C (Cttty,), 2.43 s, 3H, group of formula 2 (9 /, 3-, 47 (bs, 2H, C2H)) , 3, i8K (s, 3H, -OCHj), & fl & d, 1H, J = 5Hz, C6-H), 6.55 (bs, 2H, group of formula 30), 5.63-6 ^ 98) m, 3H, 20, C7, H, -OCHiO-, 6.69 (s, 1H, group of formula 41), 7.14 (fos, 2H, NH2-), 9, '5 | 8 (d, UH, J = 8Hz, -CONH - /. Wiidmo UV / ethanol /: Xmax 235 fe = 1: 91394 / i 260 te = mmi. formula 1 R * R * R * Melting point / ° C / IR / KBr / cm-1: y C = 0 —CR * • -OHOCOC / CHJ / 3CH3 group of formula 32 107 ^ 100 (decomposed) 11080, ar7mo , 16715 -CH, &lt; 3 &gt; CHgOOOOCH5 (s group of formula 33 &lt; M &lt; &gt; —CH, -OH group of formula 34, groupa, and formula 32 10 B, UOG f (with decomposition) 177/8, 1117120, Jiaaa Tempera-1 IR / KBr / R * R * R * top-1: alternate J 0 th C = 0 PMR / DMSO 4 d 6/3: 2 CH 8 group of formula 34 166-167 1730, 117120, 11080, 11640 lyl 8 / t, OH, J = 7Hz, -CH2CH, /, 3.5 | 5 / fos, 2H, C2 ^ H /, 3, ^ 5 / q, 2H, J = 7Hz ~ CH2CH $ /, 3.90 te, 3H, -OCH3 /, 4.411, 5.012 / ABq , "iS; J = 16 Hz, group of formula 30), 5.26 (d, 1H, J = 5 (Hz, Ce-H), 6.06 (dd, UH, J = 5 Hz and 8 Hz, C7-H), 6 R 52, 6.65 (AlBq, 2H, J = 6 IHz, group of formula 40), 6.88 (s, liH, group of formula 41 '), 7.017 (s, 1H, -GH 7 R 15-7) ^ 84 is, 10H, 2 groups of formula 26 /, 9.81 / d, 1H, J = ^ 8Hz, -CONH-A group of L1 / 1 — and K115 of formula 36 group ° group ° (from decomposition 34 of formula 32 dem} 1780, 1728, 1 (682 2.412 / s, 3H, group taken 29 /, 3.36 / bs, 2H, CVH /, 485 / s, 2IH, -OCHCO- /, 5V23 / Id, 1H , J = 5Hz, C &lt; -H &gt;, I5 | y5i3 (fos, 2IH, group of formula W, 5.07 (dd, UH, J = ^ 5Hz, li 8Hz, C7-H), 6.80 / s , 1H), 6.8 (s, 1H), 6.94 (1s, 1 (H), 7.02-7.68 (m, 20JH, 4 groups of formula 26), A, 7Bi / d, 1H, J = 8Hz, group of formula 26 /. Xi Dehydration reactions were carried out in ethyl acetate using p-toluenesulfonic acid in a rinomolam amount with an S-substituted acid ester of 7- [2-y! 2-amino-4 -: hy) dDnoxy-12-thiijai ^^ taniido] methyl-cephemo-caaciphoxylic-4.21 145 972 Table 3 Compound of formula 42 TR * R »Melting temperature (i (° C) IR / KBr / cm -1: y C = 0 PMiRyiDMSO-idft): &quot; CH &quot; group of formula 35 165-R517 and (with decomposition!) V, Z1 / t, 3H, J = 7Hz, -OHgCH &quot;, 3.612 (bs, 2H) , C2-H /, 3.7 & 11.7715, (q, 2H, J = 7Hz, -CH2CHa), 3.96 (s, '3H, -OGH3), 4.414, 5.12 ltf-10 MaBq, EIH, J = 11.5ez, group of formula 307.5, ^ 11 (d, 1H, J = 6iHz, S C6-H), 5.813 (dd, 1 (H, J '= ISHz, and 8Hz, C7-H), 5 [gamma] 86 (bs, 3H, 1630 [deg.] NH3), 6.71 (bs, 2H, group of formula 4101), 6.06 (s, 1H, group of formula 4I19, -90 (d, UH, J = 8Hz, -CQiNH - (.- CHsGOOH group of formula 312, ill23-1 ^ 5 (decomposed) (1794, itrao,: 1) 6715 2.46 (s, 3H, group of formula '29), 3.42 (bs, 2H, C2- ^ H), 4.6 * 1 ytb & "2H, -OOH ^ CO-A 5.16 (d, 1H, J = 5Hz, C6-H), 5.66 / bs, 2IH , group of formula 3W, 5.810 (dd, 1'H, J = 6Hz and 8Hz, C7-H), group of formula 4yl), 7.65 Jlbs, 3H, 1NH3), 9.53 (jd, 1H, J = 8 Hz, -GONH - /. When the above reaction was carried out for 24 hours at room temperature without the addition of concentrated salic acid, the 7- [2- (2-amdiumnotliaizolyl-4 - / -) acid pi-dihydroxymethyl ester was obtained. l2h / synV-methoksyiiini! noac ^^^ -l, 2,3,4-iteltrazolyl-2 / -methyl-4, m.p. 27-1j28 ° C (with decomposition). (I2) Solution 1.46 g of diphenylmethyl ester 7- [2-amino-thiaizoloyl- 4 / -2- / isyin / -metokBy- andimlmoacetairmdo] ^^ taietylOHoei EmiO-3HcarfbokBylic-4 in a mixture of 7 ml of trifluoroacetic acid and 3.5 ml of anistol, left at room temperature for 2 hours, the solvent was then evaporated under reduced pressure For the remainder, 10 ml of diethyl ether are added. The precipitated crystalline precipitate was filtered off and washed with ethyl ether to give 1.7 g (911%) of 7- [2- (2i-aaniinoite] acid trifluoroethane, ^ ^ - yiS'yin) -melbimiinoaicetaimido] -3-. / 5 ^^ ymethyl-cephemio-34-carboxylic-4 with a melting point of II | 2S-1J215 ° C (decomposed). IR spectrum / KBr. / Cm "1: y C = 0 ir7190, 120-1 (636. V W the compounds shown in Table 3, Example X, were obtained in a similar manner. For a solution of 6.112 g of 7- [2-yi-2-ajmino-4H-hydroxy-2r-thiazoliinyl44- (isyin) - -3n / 5.- Methyl-1,2,3,4-4-Hcambokisyl-4-etrazole in 69 ml of positive ethyl ootaine and 2b412 g of mesitylenesilonic acid dihydrate and the rest of it at room temperature for 5 hours. © 10 (©) mesylene sulfonyl pivaloric oxymethyl ester of 7- [2r (2-aa ^ ijnoiJia, zolyl-4i (-2-) syin) -methoxy-iminoaretaoriido} H3- (5-methyl &lt; 25 &gt; yimethyl) ce! Femo -8) -carboxy-4, m.p. 2H8? H2 120 ° C (with decomposition). IR spectrum / 1KBr / cm "*: y C = 0 1 (7-2, 1/7415, 10810 ;. PL PL PL PL PL

Claims (3)

1. Claims 30 • '¦, - 1. A process for the preparation of a cephalosporin of general formula I or a salt thereof wherein R1 is a lower alkyl group, an optionally substituted carboxyl group or a substituted protected carboxyl group; R2 is a hydrogen atom or a carboxyl protecting group; and R8 is a substituted or orb unsubstituted heterocyclic group attached to the exo-methylene group at the 3-position of the cephem ring by a carbon-nitrogen linkage, characterized in that the compound of general formula II or a salt thereof, in which R1, R2 and R8 are the meaning given above is subjected to a dehydration reaction and, optionally, after completion of the reaction, the group is removed. The carboxyl group is protected or the carboxyl group is protected or converts the product to a salt. 2. Way according to personalities. A compound according to claim 1, characterized in that the compound of formula II is used, in which R250 is acyloxyalkyl group, and the other symbols have the meaning given in claim 1. 1. 31 Siposób wefdlug claim. The method of claim 1, wherein the compound of formula is used 2. where R8 is substituted with orb and unsubstituted with 55 l, 3, 4-tetrazolyl or lj2i, 4-triazolyl. Joined to the exomethylene group at the 3-position of the ceifium ring by a carbon bond, nitrogen, and the symbols are have the meaning given in claim 1.145 972 DR ^ rr \ r \ o2 X0R WZdR 1 COOR '(syn isomer) JO1 WZOR U OH H2N- ^ .N- C-CONH- N 0 ^ "NY ^ CH2R3 ~~ 1 COOR2 (syn isomer) WZdR 2 - CH (CH2) mORZt R5 FORMULA 6 -CH (CH2) mCOOR! R6. WZdR 8 y WZdR 5-CHOCOOR ^ WZdR 7 OH H2N- ^, N- ¦C-CO- II N \ OR1 (syn isomer) WZdR 3 V -NW WZdR 9 CH3COCH2COSR7 WZdR 15 I nitrosation CH3COC-COSR7 (J WZdR 15 | \) HI alkylation CH3COC-COSR7 ¦ (and wzdR u ^ ORl halogenation halogenation \ XCH2C0CH2C0X] 'R7SCH2 WZOR2 WZOR2 WZOR2 WZOR2 WZOR2 WZOR2 WZOR2 17 'alkylation XCH2COC-COSR' l0Rl SCHEME 1 N FORMULA 13 "S.145 972 S NH2CNH2 OH H2N S- ^ N C-COSR7 1 vi OR (halogen syn isomer I UWt-U- Q | J not JH-C- H2N cox WZdR 10 or its sol 'S- * N (syn jj ^ 1 isomer) FORMULA 11 or its sdl acylation H2Ni-rs, s! I ^ "N-fSCH2RJ C00R2 FORMULA 12 or its sol OH J FORMULA ^ sJ (io ^ UnY ^ ch2r ^ OR1 C00R2 (syn isomer) MODEL 2 or its sdl SCHEME 2 s NW WZCfR 20 CH3-I — Ox MODEL 22 PCI r-0s WZdR 21 \ / PCl NO 'WZdR 2 "3 WZdR 26 —CS- II O WZdR 28 .N- WZdR 27 N —CH3 N WZdR 29 - C - II N V PATTERN 24 —C- II N WZ0R 25 iSg = L — CH2- PATTERN 3.0 -CH0C0C (CH3) 3 CH3 WZdR 31 145 972 • n; , N = N 01- PATTERN 32 er PATTERN 33 —CH - l ~ CH3 PATTERN 38 W WZCfR 39 -CH- ^ Q PATTERN 34 W -NN CH2CH3 WZCiR 35 WZCfR, 1.0 NXH PATTERN 41 -ch2cooch-KW MODEL 36 - CH - I. CHj WZC5R 37 N — jpC — CONH —r-Y'S \ CF3COOH.H2l ^ J | J 0JI 1C (¥, 3 COOH (syn isomer) WZCfR U2 H2N-Tr O 5-N ¦CH2FT COOR or its sol R ^ YC- COOH II N. ^ OR or its reactive derivative acylation H2N- Ns 0 ^ Ny ^ CH2RJ T *? COOR2 SCHEME 3145 972 S ^ XCH? COCCONH-Trr, II n ^ -N- ^ ru p3 + H-, NCRJ NO 7 CH2R - u OR1 or its salt COOR2 N. H2N ~ ^ SU | j J_N X.CH, R- Nn. 0 T 2 OR 'COOR SCHEME U N- ^ ir0000 ^ "!: h 0 <^ - N ^ -CH2R- COOR2 or its sol H2NOR 'or its sol N. 2 sJ l; c ^ V "Ch2r3 W COOR' SCHEME 5 EN EN EN EN EN