JPS5932472B2 - Method for producing 2-alkyl-7-acylamino-2 (or 3)-cephem-4-carboxylic acids - Google Patents

Description

[Detailed description of the invention] This invention is based on the general formula H’N□R”.

I, (wherein R1 is an alkyl group, X is -5- or -5-
, the dotted line means 2 or 3-cephem, respectively).
Cefem-4-carboxylic acids, esters at their carboxy groups, reactive derivatives at their amino groups, or salts thereof are treated with an acylating agent to form the general formula (wherein R1, X and dotted lines have the same meanings as before,
R2 means an acylamino group) [2-alkyl J] [2-alkyl J] consisting of obtaining acylamino-2 (or 3)-cephem-4-carboxylic acids or esters or salts thereof at the carboxy group thereof; Me[acylamino-1 2 (or 3)-cephem 4]
-Relates to a method for producing carboxylic acids.

The raw material of this invention is a new substance, for example, by reacting a Lewis acid with 2-alkyl-6-amino-2,3-methylenepenam-3-carboxylic acid or its 1-oxide or an ester at the carboxy group thereof. can be manufactured. In the definition of the above formula,
Examples of the alkyl group for R1 include methyl, ethyl, propyl, butyl, and the like.

In addition, esters at the carboxy group of 2-alkyl-J-amino-2 (or 3)-cephem-4-carboxylic acids (1) include both active esters and inactive esters, for example, when the ester moiety is methyl, ethyl ,
Propyl, isopropyl, butyl, tertiary butyl, cyclohexyl, cycloheptyl, vinyl, 1-propenyl, 2-propenyl, 1,1-dimethyl-2-propenyl,
Saturated or unsaturated alkyl such as 3-butenyl and 1,1-dimethyl-2-propynyl, aryl such as phenyl, xylyl, tolyl, naphthyl, aralkyl such as benzyl and phenethyl, and alkyl of the above saturated or unsaturated alkyl and aralkyl. The carbon atom in the part is a sulfur atom,
Methoxymethyl, ethoxymethyl, methylthioethyl, methylthiomethyl, dimethylaminoethyl, diethylaminoethyl, phenoxymethyl, phenylthiomethyl, methylsulfenylmethyl, phenylsulfenylmethyl, replaced with nitrogen atom, oxygen atom or carbonyl, etc. , benzoylmethyl, toluoylmethyl, etc. Furthermore, these above-mentioned groups can be substituted with suitable substituents, such as halogens such as cyano, nitro, fluoro, chloro, bromo, alkoxys such as methoxy, ethoxy, propoxy, alkanesulfonyl, phenylazo, etc. chloromethyl, bromomethyl, trichloroethyl, cyanomethyl, 2-cyano-1,1-dimethylethyl, P-
Nitrophenyl, 2,4,5-trichlorophenyl, 2
・4,6-trichlorophenyl, pentachlorophenyl, P-methanesulfonylphenyl, 4-(phenylazo)phenyl, 2,4 dinitrophenyl, P-chlorobenzyl, 0-nitrobenzyl, P-methoxybenzyl, P-
nitrobenzyl, 3,4,5-trimethoxybenzyl,
Bis(P-methoxyphenyl)methyl, pentachlorobenzyl, trichlorobenzyl, 3.5 ditertiary butyl-
4-Hydroxybenzyl, P-nitrophenylthiomethyl, P-chlorophenylthiomethyl, P-nitrobenzoylmethyl, P-chlorobenzoylmethyl, etc., other substituted or unsubstituted thioalcohols, N-hydroxysuccinimide, N-hydroxyphthalimide , tetrahydropyranol, 1-cyclopropylethanol, 1-phenyl-3-methyl-5-pyrazolone, 3-hydroxypyridine, 2-hydroxymethylpyridine-1-oxide, 1-hydroxypiperidine, 1-hydroxy-2(1
H)-Pyridone, dimethylhydroxylamine, diethylhydroxylamine, glycolamide, 8-hydroxyquinoline, oxime, 2-hydroxymethylquinoline-1-oxide, methoxyacetylene, ethoxyacetylene, tertiary butylethynyldimethylamine, tertiary
butylethynyldiethylamine, ethylethynyldiethylamine, 2-ethyl-5-(3-sulfophenyl)
Isoxazolium hydroxide inner salt, 1, 5, 9
9, 9,10-pentachlor-9,10-dihydroanthracene, 9,9,10-trichlor-9,10-dihydroanthracene, 1,8,9,10,10-pentachlor-9,10-dihydroanthracene, etc.・10・1
Esters with 0-trihalogeno-9,10-dihydroanthracene derivatives, etc.

Examples of salts of 2-alkyl-J-amino-2 (or 3)-cephem-4-carboxylic acids (1) or esters thereof at the carboxy group include acetate, maleate, tartrate, benzenesulfonate. , organic acid salts such as toluenesulfonate, and inorganic acid salts such as hydrochloride, sulfate, and phosphate.

Examples of the acylating agent used in this reaction include aliphatic carboxylic acids, aromatic carboxylic acids, heterocyclic carboxylic acids, similar sulfonic acids, thio acids, etc., and reactive derivatives of these acids. It will be done.

Examples of reactive derivatives include acid anhydrides, active amides, active esters, isocyanates, thioisocyanates, and specific examples include acid azides, dialkylphosphoric mixed anhydrides, phenylphosphoric mixed anhydrides, and diphenylphosphoric mixed anhydrides. , dibenzyl phosphoric acid mixed anhydride, halogenated phosphoric acid mixed anhydride, dialkyl phosphorous acid mixed anhydride, sulfite mixed anhydride, thiosulfuric acid mixed anhydride, hydrohalic acid mixed anhydride (e.g. acid chloride), sulfuric acid mixed anhydride, Alkyl carbonic acid mixed anhydrides, aliphatic carboxylic acid (e.g. acetic acid, pivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutanoic acid, trichloroacetic acid) mixed anhydrides, aromatic carboxylic acid (e.g. benzoic acid) mixed anhydrides, symmetrical Acid anhydrides such as acid anhydrides, acid amides with pyrazoles, imidazoles, 4-substituted imidazoles, dimethylpyrazoles, triazoles, tetrazoles, etc., hydrazides (carried out in the presence of oxidizing agents), cyanomethyl esters, methoxymethyl esters, vinyl ester, propargyl ester, P-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, methanesulfonylphenyl ester, phenylazophenyl ester, phenylthioester, P-nitro Phenyl thioester, P-cresyl thioester, carboxymethyl thioester, pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolyl thioester, N-N-dimethylhydroxylamine, 1-hydroxy-2-(1H) pyridone, N- Examples include esters such as esters with hydroxysuccinimide or N-hydroxyphthalimide, and these are appropriately selected depending on the type of acid used. If a free acid is used as the acylating agent in this reaction, examples include N-N-dicyclohexylcarbodiimide, N-cyclohexyl-N'-morpholinoethylcarbodiimide, N-cyclohexyl-N! -(4-diethylaminocyclohexyl)carbodiimide, N-merdiethylcarbodiimide, N-N7-diisopropylcarbodiimide, N-ethyl-N''-(3-dimethylaminopropyl)carbodiimide, N-N'-monocarbonyldi(2
-methylimidazole), pentamethyleneketene-N cyclohexylimine, diphenylketene-N cyclohexylimine, alkoxyacetylene, 1-alkoxy-
1-chloroethylene, phosphorous acid trialkyl ester, polyphosphoric acid ethyl ester, polyphosphoric acid isopropyl ester, phosphorus oxychloride, phosphorus trichloride, thionyl chloride, oxalyl chloride, triphenylbosine, 2-ethyl
[Hydroxybenzisoxazolium salt, 2-ethyl-
5(m-sulfophenyl)isoxazolium hydroxide inner salt, (chloromethylene)dimethylammonium chloride, 2,2,4,4,6,6-hexachloro-2,2,4,4,6,6- Hexahitorow 1, 3, 5
- Adding a condensing agent such as 2,4,6-triazatriphosphorine, or a combination of triphenylphosphine and a carbon tetrahalide such as carbon tetrachloride or carbon tetrabromide, or a halogen such as chlorine or bromine. Preferably, the reaction is carried out.

This reaction also reacts with 2-alkyl-J[amino-2 (or 3)cephem-4-carboxylic acids (1) or their esters at the carboxyl group, such as phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, and halophosphate esters. , a halophosphorous ester, etc. may be activated in advance to activate the amino group to form a reactive derivative thereof, and then the reaction may be carried out. The acyl group introduced into the amino group by the above-mentioned acylating agent means all aliphatic acyl, acyl containing an aromatic ring, and acyl containing a heterocycle, and specifically, the following are exemplified. Ru.

The aliphatic acyl is saturated or unsaturated alkynoyl and may have a side chain or be cyclic, such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, acryloyl, crotonoyl, 2 -methyl acryloyl, cyclopentyl carbonyl, cyclohexyl carbonyl,
Examples include cycloheptylcarbonyl, succinyl, cyclopentylacetyl, cyclohexylacetyl, cycloheptylacetyl, cyclohexylpropionyl, cycloheptylpropionyl, dihydrobenzoyl, 2,4,6-cycloheptatrienylacetyl, dihydrophenylacetyl, etc. Saturated or unsaturated alkanoyl may be interrupted with oxygen or sulfur atoms; such groups include, for example, methoxyacetyl, methylthioacetyl, 2-propenylthioacetyl,
Cyclohexylthioacetyl, cyclohexyloxyacetyl, dihydrophenoxyacetyl, dihydrophenylthioacetyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, tertiary butoxycarbonyl, cyclopentyloxycarbonyl, cyclohexyloxycarbonyl, dihydrophenoxy Examples include carbonyl, cycloheptyloxycarbonyl, and the like. Examples of acyls containing aromatic rings include benzoyl, toluoyl, naphthol, α-methylnaphthol, putarol, and tetrahydronaphthol; arylsulfonyls such as benzenesulfonyl and tosyl; and phenylacetyl, phenylpropionyl, phenylbutyryl, tolylacetyl, and It includes aralkanoyl such as silylacetyl, naphthylacetyl, and tetrahydronaphthylacetyl, and the carbon atom of the alkyl part of this aralkanoyl may be replaced with an oxygen atom or a sulfur atom. Examples of such a group include phenoxy Examples include acetyl, phenylthioacetyl, benzyloxycarbonyl, xylyloxycarbonyl, naphthoxycarbonyl, phenoxycarbonyl, 2-phenoxypropionyl, 2-phenoxybutyryl, and the like.

Furthermore, acyl containing a heterocycle includes saturated or unsaturated heteromonocyclic or heteropolycyclic residues containing at least one or more oxygen atom, sulfur atom, nitrogen atom, or other heteroatoms, such as thienyl, benzothienyl, furyl, etc. , pyranyl, 5,6 dihydro 2H-pyranyl, isobenzofuranyl, chromenyl, xanthenyl, 2H-pyrrolyl, 3H-pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, isoindolyl, indolyl, intazolyl, quinolyl, Isoquinolyl, isoxazolyl, isothiazolyl, oxadiazolyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, piperidinyl, piperazinyl, diazolyl, triazolyl, oxazolyl, thiazolyl,
Thiadiazolyl, tetrazolyl, benzoxazolyl,
Heterocyclic carbonyl containing a heterocycle such as benzoxadiazolyl, benzothiazolyl, benzthiadiazolyl, benzotriazolyl, benzimidazolyl, cydononyl, and the above heterocycle or heterocycle-substituted oxy or heterocycle-substituted thio or heterocycle-substituted amino or Alkanoyl such as acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, acryloyl, crotonoyl, 2-methylacryloyl having a group such as N-alkyl heterocyclic substituted amino as a substituent, such as 1H (or 2H)-tetrazolyl Examples include ruacetyl, thienylacetyl, thienylpropionyl, furylacetyl, piperazinyl acetyl, pyrrolidinylacetyl, pyrrolidinylpropionyl, benzothiazolylacetyl, oxazolyl acetyl, benzoxazolyl acetyl, etc. The carbon atom of the alkyl part of the alkanoyl having a heterocycle as a substituent may be replaced with an oxygen atom or a sulfur atom, and examples of such groups include pyridylmethoxycarbonyl, 2furyloxycarbonyl, 8-quinolyloxycarbonyl. etc.

Furthermore, these aliphatic acyls, acyls containing an aromatic ring, or acyls containing a heterocycle may have one or more suitable substituents at any position thereof, and such substituents include methyl, ethyl, propyl, isopropyl, 1-propenyl, 2-propenyl, cyclopropyl,
Alkyl such as cyclopentyl, cyclohexyl, cycloheptyl, alkoxy such as methoxy, ethoxy, propoxy, isopropoxy, alkylthio such as methylthio, ethylthio, aryl such as phenyl, xylyl, tolyl, aralkyl such as benzyl, phenethyl, amino, mercapto, nitro, Halogens such as azide, chloro, fluoro, brome, carboxy, sulfo, hydroxy, hydroxyamino, mono(or di)methylamino, mono(
or a mono(or di)alkylamino group such as di)ethylamino, mono(or di)propylamino, mono(or di)isopropylamino, mono(or di)alkylamino group such as mono(or di)phenylamino, mono(or di)tolylamino, etc. Examples include mono(or di)aralkylamino such as di)arylamino, mono(or di)benzylamino, mono(or di)phenethylamino, and further aliphatic acyl having such a substituent,
As aromatic-containing acyl or heterocyclic-containing acyl,
For example, trichloroethoxycarbonyl, tribromoethoxycarbonyl, 1-cyclopropylethoxycarbonyl, chloroacetyl, 2-chloropropionyl, trifluoroacetyl, aminoadipoyl, α-aminophenyl acetyl, carbamoyl, phenylcarbamoyl, α
-Hydroxyphenylacetyl, P-nitrobenzyloxycarbonyl, 0-bromopenzyloxycarbonyl, O-nitrobenzyloxycarbonyl, Pmethoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, P-hydroxyphenylacetyl,
2-amino-2-(5,6-dihydro-2H-pyran-3-yl)acetyl, 2-amino-2-(P-hydroxyphenyl)acetyl, 2,6-dimethoxybenzoyl, P-acetamidobenzenesulfonyl, 3 -Phenyl 5
-Methyl-4-oxazolylcarbonyl, 3(2-chlorophenyl)-5-methyl-4-oxazolylcarbonyl, 3-(2,6-dichlorophenyl)-5-methyl-
4-oxazolylcarbonyl, 3-(2-chloro-6-
(fluorophenyl)-5-methyl-4-oxazolylcarbonyl and the like.

In addition, if there is a free amino group, hydroxy group, mercapto group, carboxy group, sulfo group, etc. in such an acyl group, such an amino group, hydroxy group, mercapto group, carboxy group, sulfo group, etc. The scope of the present invention also includes cases where the compound is protected with a protecting group.

Here, the protecting group for the amino group includes all groups that can be normally used as amino protecting groups, such as trichloroethoxycarbonyl, tribromoethoxycarbonyl, benzyloxycarbonyl, P-toluenesulfonyl, P-nitrobenzyloxycarbonyl, O -bromobenzyloxycarbonyl, O-nitrophenylsulfenyl, chloroacetyl, trifluoroacetyl, formyl, α-picolinyl, vinyloxycarbonyl, tertiary butoxycarbonyl, P-methoxybenzyloxycarbonyl, 3,4 dimethoxybenzyloxy carbonyl,
4-(phenylazo)benzyloxycarbonyl, 4(
methoxyphenylazo)benzyloxycarbonyl, pyridine-1-oxide-2-methoxycarbonyl, 2
-pyridylmethoxycarbonyl, 2-furyloxycarbonyl, diphenylmethoxycarbonyl, 1,1-dimethylpropoxycarbonyl, isopropoxycarbonyl, 1-cyclopropylethoxycarbonyl, 2-cyano-1,1dimethylethoxycarbonyl, putalol, succinyl, Examples include acyl groups such as 1-adamantyloxycarbonyl, 8-quinolineoxycarbonyl, isobornyloxycarbonyl, and 9-fluorenylmethoxycarbonyl; further examples include trityl, 2-nitrophenylthio, 2,4- Dinitrophenylthio, benzylidene, 4-nitrobenzylidene, 2-hydroxybenzylidene, 2-hydroxy-5-chlorobenzylidene, 2-
Hydroxy-1-naphthylmethylene, 3-hydroxy-
4-pyridylmethylene, l-methoxycarbonyl-2-
Propylidene, 1-ethoxycarbonyl-2-propylidene, 3-ethoxycarbonyl-2-butylidene, 1-acetyl-2-propylidene, 1-benzoyl-2-propylidene, 1{N-(2-methoxyphenyl)carbamoyl}2- Propylidene, 1-{N-(4-methoxyphenyl)carbamoyl}-2-propylidene, 2-ethoxycarbonylcyclohexylidene, 2ethoxycarbonylcyclopentylidene, 2acetylcyclohexylidene, 3,3-dimethyl 5-oxo Easily eliminated groups such as cyclohexylidene (among these, for example, 1-methoxycarbonyl-2-propylidene is sometimes expressed as 1-methoxycarbonyl-1-propen-2-yl, and for example, 2-ethoxycarbonylcyclohexylidene) (Dene is sometimes expressed as 2-ethoxycarbonyl 1-cyclohexenyl), and protecting groups for amino groups other than acyl groups such as di- or trialkylsilyl, and protecting groups for hydroxy groups and mercapto groups include It includes all groups that can normally be used as protecting groups for hydroxy and mercapto groups, such as formyl, acetyl, benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 4-
Methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 4-(phenylazo)benzyloxycarbonyl, 4-(4-methoxyphenylazo)benzyloxycarbonyl, tertiary butoxycarbonyl, 1,1-dimethylpropoxycarbonyl , isopropoxycarbonyl, diphenylmethoxycarbonyl 2-pyridylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2,2,2-tribromoethoxycarbonyl, 3-iodopropoxycarbonyl,
In addition to acyl groups such as 2-furfuryloxycarboxyl, 1-adamantyloxycarbonyl, 1-cyclopropylethoxycarbonyl, 3-quinolyloxycarbonyl, and trifluoroacetyl, benzyl, trityl, methoxymethyl, and 2-nitrophenyl Examples include groups such as ruthio, 2,4-dinitrophenylthio, etc. Protecting groups for kyleboxyl groups include all groups that can be used as ordinary protecting groups for carboxyl groups, such as methyl, Ethyl, propyl, isopropyl, tertiary butyl, butyl, benzyl, diphenylmethyl, triphenylmethyl, P-nitrobenzyl, P-methoxybenzyl, benzoylmethyl, acetylmethyl, Pnitrobenzoylmethyl, P-bromobenzoylmethyl, P- methanesulfonylbenzoylmethyl, phthalimidomethyl,
Trichloroethyl, tribromoethyl, 1,1-dimethyl-2-propynyl, acetoxymethyl, propionyloxymethyl, pivaloyloxymethyl, 1,1-dimethylpropyl, 1,1-dimethyl-2-propenyl, 3
-Methyl-3-butenyl, succinimidomethyl, 1-
Cyclopropylethyl, 3,5-ditertiary butyl-4-
Hydroxybenzyl, methylsulfenylmethyl, phenylsulfenylmethyl, methylthiomethyl, phenylthiomethyl, dimethylaminomethyl, pyridine-1-oxide-2methyl, quinoline-1-oxide-2-
Esters such as methyl, methylsulfinylmethyl, di(P-methoxyphenyl)methyl, 2-cyano-1,1-dimethylethyl, etc., as well as those described in JP-A No. 467,073 and Dutch Publication No. 7105259 For example, the carboxyl group is protected with a silyl compound such as dimethyldichlorosilane, which is described in German Patent Publication No. 2062925, or a nonmetallic compound such as titanium tetrachloride, which is described in DE 2062925. This reaction is usually carried out in a solvent. Water is used as a solvent.
Acetone, dioxane, acetonitrile, chloroform, dichloromethane, dichloroethane, tetrahydrofuran, ethyl acetate, dimethylformamide, pyridine or other common organic solvents that do not participate in the reaction,
Among these, hydrophilic solvents can also be used in combination with water. This reaction also works with alkali metal carbonates, trimethylamine, triethylamine, tributylamine, N
-Trialkylamines such as methylmorpholine, N-methylpiperidine, N-N-dialkylaniline, N-N-
Dialkylbenzylamine, pyridine, picoline, lutidine, 1,5-diazabicyclo[4,3,O]non-5
It can be carried out in the presence of a base such as -ene, 1,4-diazabicyclo[2,2,2]octane, 1,8diazabicyclo[5,4,O]undecene-7, and among the bases or the above-mentioned condensing agents. Liquid ones can also be used as solvents.

Although the reaction temperature is not particularly limited, it is usually carried out under cooling or at room temperature. In this reaction, cases where a carboxyl group is converted into its ester during the reaction or post-treatment of the reaction, cases where an ester in a carboxyl group is converted into a free carboxyl group, etc. are all included within the scope of the present invention.

In addition, in this reaction, 2-alkyl J me[amino-2(
or 3) -Cefem-4 carboxylic acids (1) or esters at their carboxy groups or reactive derivatives at their amino groups or salts thereof at the 2-position of the 2-cephem, 3-cephem and 3-cephem forms. The stereoisomers can be used alone or in a mixture, but the target compound may be obtained in which they are rearranged during the reaction or post-treatment. Included in the range. If a mixture of these isomers is produced in this reaction, each can be isolated by conventional methods such as recrystallization, if necessary. The 2-alkyl-J-methyl-acylamino-2(or 3)-cephem-4-carboxylic acids () or their esters at the carboxy group obtained by this invention have antibacterial activity, are useful as pharmaceuticals, and are useful for other antibacterial agents. It is useful as an intermediate for producing chemical substances.

Next, the present invention will be explained with reference to examples.

Example 1 0.677 chloroformic acid ethyl ester was dissolved in 15 m' of anhydrous dichloromethane, and N-(1
-cyclopropylethoxycarbonyl) phenylglycine 1.637, triethylamine 0.607 and dimethylbenzylamine 2 drops in 10 ml of anhydrous dichloromethane
Add the solution dissolved in the mixture dropwise and stir for 1 hour.

Afterwards, the solution was cooled to -10 to -15°C, and 2,2 of 2-methyl-J-[amino-3-cephem-4-carboxylic acid] was added to the solution.
・2-Trichloroethyl ester hydrochloride 2,27 and triethylamine 0.557 were dissolved in anhydrous dichloromethane 2
A solution dissolved in 0ml was added dropwise over 10 minutes, and then stirred at the same temperature for 2.5 hours. After the reaction, the reaction solution is washed successively with water, 2% hydrochloric acid, saturated aqueous sodium bicarbonate solution, and saturated aqueous sodium chloride solution, and dried over magnesium sulfate. After drying, the solvent was distilled off under reduced pressure, and isopropyl ether was added to the residue to form a powder, which was collected and dried to give Mpl6.
2,2,2-trichloroethyl ester of 2-methyl-JYoN-(1-cyclopropylethoxy)carbonylphenylglycyl}amino-3-cephem-4-carboxylic acid at 5-167.5°C3. Obtain 0y (91%). Infrared absorption spectrum (′;<diol) 3300, 17
95, 1745, 1710, 1675? -1 nuclear magnetic resonance absorption spectrum (CDCl3, τ) 9.94-9.00
(5H,.m) 8.77 (3H.d.J-7Hz) 8.57 (3H,.d,.J-7.5Hz) 6.44 (
1H,. m)5.

74 (1H, .m) 5.12 (2H, .s) 5.07 (1H, .d, .J=4Hz) 4.60 (1H, .d, .J-7Hz) 4.00 (1H, .dd, .J=4Hz) 3.32(1
H. d. ．． J-6Hz) 2.65 (5H,.s) Example 2 1.207 pivalic acid chloride was dissolved in anhydrous dichloromethane 2
A solution of 1.08 y of tetrazole acetic acid, 0.96 y of triethylamine and 2 drops of dimethylbenzylamine dissolved in 10 ml of anhydrous dichloromethane was added dropwise to this solution over 10 minutes while cooling to -10°C. Stir for an hour.

Next, a solution of 3.05 y of hydrochloride of 2,2,2-trichloroethyl ester of 2-methyl-J-amino-3-cephem-4-carboxylic acid and 0.87 y of triethylamine dissolved in 20 ml of anhydrous dichloromethane was dissolved over a period of 10 minutes. Add dropwise and stir for 3 hours. After the reaction, the reaction solution was mixed with water, 5%
Wash with hydrochloric acid, saturated aqueous sodium bicarbonate solution, and saturated aqueous sodium chloride solution in this order, and dry with magnesium sulfate. After drying, the solvent was distilled off, and the resulting residue was washed with ether and collected to give 2-methyl-J with an Mpl of 68 to 170°C.
Colorless crystals of 2,2,2-trichloroethyl ester of io2(1H-tetrazol-1-yl)acetamido}-3-cephem-4-carboxylic acid 2.347 (64%)
). Infrared absorption spectrum (KBr tablet method) 1785, 174011700c1n-1 nuclear magnetic resonance absorption spectrum (D6-dimethylsulfoxide, τ)
8.

55 (3H, .d, .J-7.5Hz)6.

00 (1H,.m) 4.94 (2H.s) 4.84 (1H.d,.J-5Hz) 4.64 (2H,.s) 4.10 (1H.dd,.J-5. 0Hz18.0Hz
) 3.22 (1H.d,.J=6Hz) 0.34 (1H.
、． s) 0.13 (1H.d.J-8Hz) Example 3 Hydrochloride of 2,2,2-trichloroethyl ester of 2-methyl-J-[amino-3-cephem-4-carboxylic acid 3,
07 was suspended in 50 mj of anhydrous dichloromethane and heated to -15°C.
While cooling, add 0.72y of triethylamine and 1.97y of dimethylaniline and dissolve.

While cooling and stirring at the same temperature, a solution of 2.0 y of (2-thienyl)acetyl chloride dissolved in 10 ml of anhydrous dichloromethane was added dropwise, and the mixture was stirred at the same temperature for 1.5 hours. After the reaction, the reaction solution is washed with 5% hydrochloric acid, water, 5% aqueous sodium bicarbonate solution, then water, and dried. After drying, the solvent was distilled off, ether was added to the residue to dissolve it, and the mixture was allowed to cool. After collecting a lot of precipitated crystals, it was dried to give a Mpl of 6L to 162℃ (decomposition).
-Methyl-JYo2-(2-thienyl)acetamide}
3.27 crystals of 2,2,2-trichloroethyl ester of -3-cephem-4-carboxylic acid are obtained. Infrared absorption spectrum (nujiol) 330011795, 1748, 1675, 1630?
-1 nuclear magnetic resonance absorption spectrum (CDCl3, τ)8.
50 (3H.d.J-7Hz) 6.26 (1H..m) 6.15 (2H..s) 5.12 (2H..s) 5.02 (1H.d.J-4Hz) 4 .05 (1H, .dd, .J-4.8Hz) 3.29
(1H.d,.J-6Hz) 3.03~2.67 (3H.d,.J-6Hz)
、． m) Example 4 Hydrochloride of 2,2,2-trichloroethyl ester of 2-methyl-J[amino-3-cephem-4-carboxylic acid3.
0y was suspended in 50 ml of anhydrous dichloromethane and heated to -15°C.
While cooling, 0.727 g of triethylamine and 1.97 g of dimethylaniline were added and dissolved.

Then, a solution prepared by dissolving 2.27 g of phenylthioacetyl chloride in 10 ml of anhydrous dichloromethane was added dropwise to this solution while stirring, and the mixture was stirred at the same temperature for 1.5 hours.

After the reaction, the reaction solution is washed successively with 5% hydrochloric acid, water, 5% aqueous sodium bicarbonate solution, and water, and dried. After drying, the solvent was distilled off, ether was added to the residue, and the precipitated crystals were collected and dried to give 2-methyl-J at a temperature of Mpl4O~142°C.
3.40y of 2,2,2-trichloroethyl ester of 2-phenylthioacetamide)-3-cephem-4-carboxylic acid is obtained. Infrared absorption spectrum (nujiol) 3270, 1798, 1738, 167216230f
! L-1 Nuclear magnetic resonance absorption spectrum (CDCl3, τ)8,55
(3H,.d,.J-7Hz) 6.37 (2H,.s) 6.35 (1H.m) 5.17 (2H,.s) 5.08 (1H.d.J-4Hz) 4 .12 (1H.dd.J-4Hz, 8Hz) 3.37
(1H.d.J=6Hz) 2.78 (6H,.m) Example 5 2.2y of benzyl acid ester was dissolved in 10ml of anhydrous dichloromethane, and while cooling to -15°C, 2.2y was added to this solution. -Methyl-J-amino-3-cephem-4-carboxylic acid 2,2,2-trichloroethyl ester hydrochloride 3
．． A solution prepared by dissolving 0.727 of triethylamine and 1.9 y of dimethylaniline in 50 ml of anhydrous dichloromethane was added dropwise over 1.5 hours, and then stirred at the same temperature for 1 hour.

After the reaction, the reaction solution is washed successively with 5% hydrochloric acid, water, 5% aqueous sodium bicarbonate solution, and water, and dried. After drying, the solvent was distilled off, the residue was dissolved in ethanol, and the precipitated crystals were collected and dried to give 2-methyl-J-[benzyloxycarboxamide-13-cephem-4-carboxylic acid] with an Mpl of 43 to 144°C. Crystals 3.27 of 2,2,2-trichloroethyl ester of are obtained. Infrared absorption spectrum (nujiol) 334011797, 1733, 1721, 1630?
-1 nuclear magnetic resonance absorption spectrum (D6-dimethylsulfoxide, τ) 8.50 (3H.d.J-7Hz) 6.08 (1H, .m) 4.93 (2H, .s) 4.85 (2H,.s) 4.85 (1H,.d,.J-4Hz) 4.30 (1H,.dd,.J-4Hz18Hz)3.
23(1H,.d,.J-6Hz)2.62(5H,.
s) Example 6 330η of chloroformic acid isobutyl ester was dissolved in 10 ml of anhydrous dichloromethane and cooled to -15 to -10°C.
To this solution, a solution of 795 ~ 3-(N-tert-butoxycarbonylamino)-3-(2-thienyl)propionic acid and 240 η of triethylamine dissolved in 10 ml of dichloromethane was added dropwise over about 20 minutes, and then the same solution was added dropwise over a period of about 20 minutes. A solution of mixed acid anhydride is prepared by stirring at temperature for 1 hour.

Hydrochloride of 2,2,2-trichloroethyl ester of 2-methyl-J-amino-3-cephem-4-carboxylic acid 7
A solution prepared by dissolving 60m9 of triethylamine in dichloromethane and adding 160m of triethylamine and 50η of dimethylaniline to this solution was added to the above acid anhydride solution at -15 to -10°C, kept at the same temperature for 3 hours, and then heated to room temperature. Stir for 3 hours.

After the reaction, dichloromethane was distilled off and the residue was dissolved in ethyl acetate.
After dissolving in 50ml, the solution is washed with 5% hydrochloric acid (20ml), 15% sodium bicarbonate aqueous solution, and saturated sodium chloride aqueous solution in this order, and dried over magnesium sulfate. After drying, the solvent was distilled off under reduced pressure to give 2-methyl-J with an Mpl of 88 to 192°C.
Yoiro o3-(N tertiary butoxycarbonylamino)-3
-(2thienyl)propionamide}-3-cephem-4-carboxylic acid 2,2,2-trichloroethyl ester 1.17y (94%) is obtained. Infrared absorption spectrum (nujiol) 3325, 1770J1730, 1680, 1650?
-1 nuclear magnetic resonance absorption spectrum (D6-dimethylsulfoxide, τ) 8.62 (9H18) 8.70-8.46 (3H) 7.24 (2H, .d, .J-7Hz) 6.24 ~5.85 (1H, .m) 4.91 (2H, .s) 5.00 ~ 4.80 (1H) 4.2 (1H.m) 3.23 (1H, .d, .J-6Hz ) 3.14-2.60 (4H) 1.10 (1H, .d, .J-6Hz) Example 7 2-2-2 of 2-methyl-J-amino-3-cephem-4-carboxylic acid -Trichloroethyl ester hydrochloride 3
．． 82y was suspended in 80ml of anhydrous dichloromethane, and to this was added 0.9y of triethylamine and 0.9y of dimethylaniline.
．． A solution of 157 dissolved in 20 ml of dichloromethane is added under ice-cooling with stirring, then 0.857 y of cyanoacetic acid and 2.25 y of synchlohexylcarbodiimide are added, and the mixture is stirred for 1 hour under ice-cooling.

Next, 50 ml of 5% hydrochloric acid was added, and after stirring for 30 minutes, the organic layer was separated, washed successively with 5% hydrochloric acid, a saturated aqueous sodium bicarbonate solution, and a saturated aqueous sodium chloride solution, and then dried over magnesium sulfate. After drying, when the solvent is distilled off,
Mpl6O ~ 165℃ (decomposition) 2-methyl-J Yoroi2
3.57 (85.5%) of colorless powder of 2,2,2-trichloroethyl ester of -cyanoacetamide)-3-cephem-4-carboxylic acid is obtained. Infrared absorption spectrum (nujiol) 3310, 225011773, 1735, 1665,
1630cTL-1 nuclear magnetic resonance absorption spectrum (CDC
l3, τ) 8.46 (3H..d,.J-7Hz)6.
48 (2H.s) 6.30 (1H,.m) 5.10 (2H.s) 4.99 (1H.d.J-5Hz) 4.06 (1H,.dd.J-5Hz, 9Hz) 3.2
7 (1H.d.J-6Hz) Example 8 Hydrochloride of 2,2,2-trichloroethyl ester of 2-methyl-J-amino-3-cephem-4carboxylic acid3.
82y was suspended in 30ml of dichloromethane, 0.9y of triethylamine and 0.17y of dimethylaniline were added and dissolved, and 1.2y of phenyl isocyanate was added under stirring under ice cooling.
After adding, stir for 5 hours.

Next, 10% hydrochloric acid was added to the reaction solution, stirred for 10 minutes, filtered, and the dichloromethane layer was separated from the resulting solution, washed with a saturated aqueous sodium bicarbonate solution, then a saturated aqueous sodium chloride solution, and dried over magnesium sulfate. After drying, the solvent was distilled off to give 2-methyl-
4.2y of 2,2,2-trichloroethyl ester of phenylureido-3-cephem-4-carboxylic acid is obtained. Infrared absorption spectrum 3320, 1786, 1742? -1 Nuclear magnetic resonance absorption spectrum (CDCl3, τ) 8.54
(3H.d.J=7Hz) 6.45 (1H.m) 5.15 (2H,.s) 5.05 (1H.d.J-4.2Hz) 4.02 (1H,.dd,. J-9Hz, 4.2Hz)
3.60 (1H.d.J-9Hz) 3.8 (5H,.m
) 3.32 (1H, .d, .J-5.5Hz) 2.38 (
IH. s) Example 9 Hydrochloride of 2,2,2-trichloroethyl ester of 2-methyl-J-amino-3-cephem-4-carboxylic acid 3
．． 827 was suspended in 80 m' of anhydrous dichloromethane, and to this was added 0.97 m of triethylamine and 0.9 m of dimethylaniline.
．． A solution of 15y dissolved in 20 ml of dichloromethane is added to the mixture under ice cooling and stirring to dissolve.

To this solution, 1.8 y of (1,3,4-thiadiazol-12-ylthio)acetic acid and 2.25 ml of synchlohexylcarbodiimide are added while stirring under ice cooling, and the mixture is stirred for 1 hour under ice cooling. Next, 50 ml of 5% hydrochloric acid is added to the reaction solution, and after stirring for 30 minutes, the organic layer is separated, washed with 5% hydrochloric acid, a saturated aqueous sodium bicarbonate solution, and a saturated aqueous sodium chloride solution in this order, and dried over magnesium sulfate. After drying, when the solvent is distilled off, 2-methyl-7{
2-(1,3,4-thiadiazole-2-ylthio)acetamide}-3-sej-4-carboxylic acid 2,2
・Pale and colored powder of 2-trichloroethyl ester 4.5
7 (90%). Nuclear magnetic resonance absorption spectrum (CD
Cl3, τ) 8.52 (3H.d,.J-7Hz)6.
25 (1H.m) 5.82 (2H) 5.12 (2H,.s) 5.01 (1H,.d..J-5Hz) 4.04 (1H..dd,.J-5Hz19Hz)3 ．．
26(1H,.d,.J=6Hz)1.73(1H,.
d,. J-9Hz) 0.90 (1H,.s) Example 10 {N-tert-butoxycarbonyl-2-(2-thienyl)
}Glycine 930TI! 9 to 15 m of anhydrous dichloromethane
Next, 360η of triethylamine was added to form a solution, and a solution of 400η of pivalic acid chloride dissolved in 1 ml of dichloromethane was added dropwise to this solution while stirring and cooling to -10 to 15°C, and the mixture was stirred at the same temperature for 2 hours to mix. Prepare a solution of acid anhydride.

Add 2-methyl-J-amino-3-ceph-4 to this solution.
- Suspend the hydrochloride of 2,2,2-trichloroethyl ester of carboxylic acid in 10 ml of dichloromethane, then add 0.647 g of 2,6-lutidine while stirring on ice and stir for several minutes to dissolve, then -10°C. The solution prepared by cooling to 100° C. was added all at once, and the mixture was stirred at −15° C. for 1.5 hours and at room temperature for 0.5 hours. After the reaction, the reaction solution was concentrated under reduced pressure, and ethyl acetate and 2-3% sulfuric acid were added to the residue to extract the ethyl acetate layer, which was then washed with water, a saturated aqueous sodium bicarbonate solution, and water in that order, and dried over magnesium sulfate. do. After drying, the solvent was distilled off under reduced pressure, and a mixture of ether and petroleum ether was added to the residue to form a powder, which was collected and dried to give 2-methyl-J-Yo-I-N-tertiary-butoxycarbonyl-2-thienylglyceride. syl)amino-3-cephem-4-carboxylic acid 2,2
- Obtain 1.77y of 2-trichloroethyl ester. Infrared absorption spectrum (nujiol) 3320, 1790,
17401171011690, 168011632c
m-1 nuclear magnetic resonance absorption spectrum (CDCl3, τ)6
．． 6-6.1 (1H, .m) 5.12 (2H, .s) 5.06 (d) } (1H.J-5Hz) 5.

02(d) 4.37 (1H.s) 4,6-3.9 (2H,.m) 3.32 (1H.d.J-6Hz) 3.2-2.5 (3H,.m) Example 11 (5-methyl-1,3,4-thiadiazol-2-yloxy)acetic acid 3.13y and triethylamine 1.80
7 was dissolved in 50 ml of anhydrous dichloromethane, and cooled to -15°C. To this solution was added dropwise a solution of 2.0 y of pivalic acid chloride dissolved in 5 me of dichloromethane, and then stirred at the same temperature for 2 hours to dissolve the mixed acid anhydride. Prepare the solution.

Add to this solution 2-methyl
- Suspend 5.757 ml of hydrochloride of 2,2,2-trichloroethyl ester of carboxylic acid in 40 ml of dichloromethane, add 2.0 y of 2,6-lutidine to this solution under ice cooling,
Stir for 10 to 20 minutes, cool to -15°C after dissolution, add the prepared solution all at once, stir at the same temperature for 1.5 hours, and then stir at room temperature for 30 minutes. After the reaction, the reaction solution was mixed with 5% sulfuric acid, water,
Wash sequentially with saturated aqueous sodium hydrogen carbonate solution and water, and dry with magnesium sulfate. After drying, the solvent was distilled off under reduced pressure to yield colorless, amorphous 2-methyl-Jio2-(5-methyl-1,3,4-thiadiazole!2-yloxy)acetamido}-3-cepheme-4-carvone. Acid 2.2
・2-Trichloroethyl ester 7.23y (96%)
get. Infrared absorption spectrum (chloroform) 3420, 1790, 1740, 1700, 1635 (
1-1 Nuclear magnetic resonance absorption spectrum (CDCl3, τ)8
．． 46 (3H.d.J-7Hz) 7.38 (3H,.s
) 6,5~6.0(1H,.m) 5.10(2H,.s) 4.95(1H,.d..J-4.5Hz) 4.90(
2H,. s) 3.97 (1H.dd,.J-4.5Hz
18.5Hz)3.26(1H,.d,.J-5.5H
z) 2.37 (1H,.d,.J-8.5Hz) Example 12 Adding 5 ml of thionyl chloride to 12 {3-(2-chlorophenyl)-5-methylisoxazol-4-yl}carboxylic acid 855TI19 After heating under reflux for 2 hours, thionyl chloride was distilled off under reduced pressure.
3-(2-chlorophenyl)-5-methylisoxazol-4-yl)carboxylic acid chloride is dissolved in 3-4 ml of anhydrous dichloromethane.

Add this solution to 2-methyl-J-amino-3-ceph-4
- 1.15y of hydrochloride of 2,2,2-trichloroethyl ester of carboxylic acid is suspended in 10mj of dichloromethane, 250η of triethylamine and 0
．． 647 was added and dissolved, added dropwise to the ice-cooled solution, and then stirred for 1 hour under ice-cooling.

After the reaction, the reaction solution was concentrated under reduced pressure, ethyl acetate and 2% sulfuric acid were added to the residue, and extracted with ethyl acetate. The extract was washed with water, a saturated aqueous sodium bicarbonate solution, and water in that order, and dried over magnesium sulfate. do. After drying, the solvent was distilled off under reduced pressure to obtain amorphous 2-methyl-(2-chlorophenyl)-5-methylisoxazol-4-yl}carpoxamide-3-cepheme-4-carboxylic acid. 2・2
- Obtain 1.82y of 2-trichloroethyl ester. Infrared absorption spectrum (nujiol) 334011790117401167511 Nuclear magnetic resonance absorption spectrum (CDCl3, τ) 8,52 (3H.
d,. J-7.5Hz) 7.22 (3H, .s) 6.40 (1H, .m) 5.11 (2H, .s) 5.10 (1H, .d) 4.1~3.9 ( 2H.m) 3.32 (1H,.d,.J-6Hz) 2.7 to 2.5 (4H,.m) Example 13 0.427 methylthioacetic acid to 5ml of thionyl chloride
After standing at room temperature for 40 minutes and at 40-50°C for 5 minutes, thionyl chloride was distilled off under reduced pressure, and 5 ml of benzene was added to the residue, which was further distilled off under reduced pressure to obtain 0.477% of methylthioacetyl chloride. obtain.

Methylthioacetyl chloride produced in this manner 0.
Suspend 0.7647 of 2-methyl-J■■2-trichloroethyl ester hydrochloride in 8 ml of dichloromethane, cool to -30°C, and add 0.187 of triethylamine.
was added to a solution prepared by adding 0.2667 dimethylaniline dissolved in 2 ml of dichloromethane and a solution of 0.2667 dimethylaniline in 2 ml of dichloromethane at -30°C, stirred at the same temperature for 30 minutes, and then gradually raised the temperature while stirring. After 1 hour, the temperature is -10°C. After the reaction, the reaction solution was diluted with 5% hydrochloric acid,
Wash with water, saturated aqueous sodium bicarbonate solution, and saturated brine in this order, and dry with magnesium sulfate. After drying, the solvent was distilled off and the obtained crystal 0.817 was recrystallized from ethanol to give 2-
0.627 (71.7%) of 2,2,2-trichloroethyl ester of methyl Jio(2-methylthio)acetamide}-3cephem-4-carboxylic acid is obtained. Infrared absorption spectrum (nujiol) 332011780, 1732, 1668 礪-1 nuclear magnetic resonance absorption spectrum (CDCl3, τ) 8.47 (3H
．． d. J-8Hz) 7.83 (3H..s) 6.75 (2H.s) 6.27 (1H..m) 5.10 (2H..s) 4.92 (1H.d) 4.0 (1H,.dd..J-5Hz110Hz)3.
27 (1H.d.J-6Hz) 2.40 (1H.d.
．． J-10Hz) Elemental analysis: Cl3Hl, N2O4S2
Cl3 calculated value: C36. OO. H3.49, N6.46
Experimental values: C36.23, H3.45, N6.4l Example 0.7647 of the hydrochloride of 2,2,2-trichloroethyl ester of 142-methyl-J[amino-13-cephem-4-carboxylic acid] was anhydrous. It was suspended in 8 ml of dichloromethane, and a solution of 0.187 triethylamine dissolved in 2 m' of dichloromethane was added dropwise to this solution at -30°C, and then a solution of 0.277 dimethylaniline dissolved in 2 m' of dichloromethane was added dropwise at the same temperature.

Add 0.528 ml of Allyl thioacetic acid to this solution.
Allylthioacetyl chloride 0.52 was prepared by adding 7 to 5 ml of thionyl chloride, leaving it for 20 minutes at room temperature and 5 minutes at 50°C, then distilling off thionyl chloride under reduced pressure, and then adding a small amount of benzene and distilling off under reduced pressure.
A solution of 0.4527 of 77 dissolved in dichloromethane 3me was added dropwise at -30°C over 5 minutes, and then -
Stir at 20°C for 1 hour. After the reaction, the reaction solution is washed twice with 5% hydrochloric acid, once with water, twice with a saturated aqueous sodium bicarbonate solution, and once with a saturated aqueous sodium chloride solution, and then dried over magnesium sulfate. After drying, the solvent was distilled off, and the residue (0.82y) was recrystallized from a mixture of ether and isopropyl ether to give 2-methyl-Jyo-i2 with an Mp of 96°C.
0.717 (76.6%) of 2●2.2-trichloroethyl ester of -Allyl thioacetamide)-3-cephem-4-carboxylic acid is obtained. Infrared absorption spectrum (nujiol) 33001180011745, 1670cTn-1 nuclear magnetic resonance absorption spectrum (CDCl3, τ) 8.47 (
3H. d,. J-7.5Hz)6.80(2H,.d.
．． J-6Hz) 6.78 (2H,.s) 6.5-6.0 (1H,.m) 5.10 (2H.s) 4.97 (1H..d,.J-5Hz) 5, 0-3.8 (4H.m) 3.24 (1H..d,.J-6Hz) 2.47 (1H,.br0add,.J-9Hz) Elemental analysis: Cl5Hl7N2O2S2Cl3 Calculated value: C39
．． l9, H3.73, N6. O9, Sl3.95 Experimental values: C39, O8, H3.63, N6. lOlSl3.9
7 Example 15 0.8647 (2-formyloxy)phenylacetic acid was dissolved in 15 ml of tetrahydrofuran, and -20
While cooling to ℃ and stirring, add 0.0% of synchhexylcarbodiimide.
A solution of 997 dissolved in 5 ml of tetrahydrofuran was added dropwise, followed by stirring at the same temperature for 30 minutes.

Next, 1.537 ml of 2-methyl-J■■2-trichloroethyl ester hydrochloride was added to this solution in dichloromethane 2.
0ml plus 0.4y of triethylamine at -20°C
The solution prepared by adding is added dropwise at -20°C, and then the temperature is gradually raised while stirring, and after 1.5 hours it is brought to 0°C. After further stirring at O℃ for 1.5 hours, the precipitate was removed, and the precipitate was concentrated to dryness under reduced pressure. A small amount of ethyl acetate was added to the residue to remove insoluble matter, and then the precipitate was concentrated to 5% After sequentially washing with hydrochloric acid, water, saturated aqueous sodium bicarbonate solution, and saturated aqueous sodium chloride solution, drying with magnesium sulfate. After drying, it is filtered through about 27 ml of silica gel, the solvent is distilled off, and ether is added to form a powder, which is filtered and dried.
2-methyl-2-formyloxy-2-phenylacetamide)-3-cepheme-4 at pl42-147°C
-2,2,2-trichloroethyl ester of carboxylic acid 1,72y (87.5%) is obtained. Infrared absorption spectrum 335011797, 1745, 173011690 (
1-JMo V1-1 nuclear magnetic resonance absorption spectrum (CDCl3
, τ) 8.50 (1H, .d, .J-7Hz) 6.7~
6.1 (1H,.m) 5.13 (2H,.s) 5.03 (1H,.d..J-5Hz) 4.08 (1H..dd,.J-5Hz18Hz)3.
74 (1H..d..J-1Hz) 3.32 (1H,.
d,. J-6Hz) 2.85-2.35 (5H..m) 1.82 (1H..d.J-1Hz) Example 16 2-Methyl-J-[amino-3-cephem-4-carboxylic acid] 2,2,2-trichloroethyl ester hydrochloride 1
．． 927 in tetrahydrofuran while cooling to -10°C.
Add 1.02y of triethylamine to the solution suspended in Me.
Add and stir vigorously.

Then, to this was added 20 m of tetrahydrofuran containing 5.5 mmol of chloroformic acid 1-cyclopropylethyl ester.
1 solution was added dropwise over about 10 minutes, and then stirred at the same temperature for 1.5 hours. After the reaction is completed, the reaction solution is filtered, and the filtered solution is concentrated at room temperature or below. The residue was dissolved in 30 ml of ethyl acetate, washed successively with 5% hydrochloric acid, an aqueous sodium bicarbonate solution, and a saturated aqueous sodium chloride solution, dried over magnesium sulfate, and then the solvent was distilled off. Add a small amount of isopropyl ether to the residue, powder it, take it out and dry it to obtain Mp.
2,2,2-trichloroethyl ester of 2-methyl-1-cyclopropylethoxy)carboxamide-3-cephem-4-carboxylic acid at 181 to 183°C1.
Get 47. Infrared absorption spectrum 3250, 1780, 173011690? -1 nuclear magnetic resonance absorption spectrum (CDCl3, τ) 9.94-9.
00(5H,.m)8.75(3H,.d..J-6H
z) 8.52 (3H,.d,.J-7Hz) 6.30 (1H..m) 5.79 (1H.m) 5.14 (2H..s) 5.05 (1H..d ,.J-4.5Hz)54.30
(1H,.dd.J-4.5Hz, 8Hz) 3.32(
1H,. d. ．． J-6Hz) The following compound is obtained in the same manner.

(1) 2,2,2-trichloroethyl ester of 2-methyl-2-phenylacetamide-3-cephem-4-carboxylic acid (Mpl75-178°C)). )
2-methyl-2-phenylacetamide)-2
-2,2,2-trichloroethyl ester of cefem-4-carboxylic acid (Mpl36-137℃) 2,2,2-trichloroethyl ester {Mpl44-144.5℃ (decomposition)}1) 2-Methyl-Jio2-(1,2,5-thiadiazol-3-yl)acetamide}-3Cefem-4 -2,2,2-trichloroethyl ester of carboxylic acid {Mpl8O~185℃ (decomposition)}-)) 2-methyl-2-phenoxyacetamide)-3-cepheme-methyl ester of 4-carboxylic acid (oily) 3)
2-Methyl-JYo-i2-phenoxyacetamide)-3
-2,2,2-trichloroethyl ester of cefem-4-carboxylic acid (Mpll8-120°C) 1) 2-Methyl-2-phenylacetamide)
-2 of 1-oxide of 3-cephem-4-carboxylic acid
・2,2-trichloroethyl ester (Mpl73-1
75℃)',) 2-Methyl-JYoN-(1-cyclopropylethoxy)carbonylphenylglycyl}amino-3-cephem-4-carboxylic acid (Mpl68-16
9℃))) 2-Methyl-Jio2-(1H-tetrazol-1-yl)acetamide}-3-cepheme 4-carboxylic acid {Mp2O2~203℃ (decomposition)}0) 2-
Methyl-JYo2-(2-thienyl)acetamide}-
3-Cefem-4-carboxylic acid {Mpl75℃ (decomposition)
}02-Methyl-J[benzyloxycarboxamide-3-cephem-4-carboxylic acid {Mpl67-169℃
(Decomposition)}2) 2-Methyl-JYo-i2-phenylthioacetamide)-3-cephem-4-carboxylic acid {Mp
l68-17FC (decomposition)}

Claims (1)

[Claims] 1 General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R_1 is an alkyl group, X is -S- or ▲ Numerical formula,
Chemical formulas, tables, etc. are available.
Amino-2-(or 3)-cephem-4-carboxylic acids or their esters at the carboxy group, or their reactive derivatives at the amino group, or their salts are treated with an acylating agent to form the general formula ▲ mathematical formula, chemical formula, or table. 2-alkyl- represented by ▼ (in the formula, R_1, X and the dotted line have the same meanings as before, and R_2 means an acylamino group)
2-Alkyl-7-acylamino-2(or 3)-cephem- characterized by obtaining 7-acylamino-2(or 3)-cephem-4-carboxylic acids or esters at their carboxy group or salts thereof
Method for producing 4-carboxylic acids.