JPS5932474B2 - Method for producing 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 COR_, 1R_.

R_1-x-N□ -ZO(I) (In the formula, R_1 and kl are groups obtained by removing the carbonyl group from mutually different acyl groups, R_2 is OH from alcohol
is removed, R_3 is an alkyl group, X is -5- or s-, and ZO is an anion liberated upon acylation).
- 7-acylamino-2(or 3)-cephem-4-carboxylic acids or their The present invention relates to a method for producing 7-acylamino-2 (or 3)-cephem-4-carboxylic acids, which comprises obtaining derivatives at the carboxy group.

Raw material of this invention, 2 (or 3)-Cefm-4-
Carboxylic acids 1) or their derivatives at the carboxy group are new substances, for example the corresponding 2-alkyl-
6-acylamino-2,3-methylenepenam-3-carboxylic acid or its derivatives at the carboxy group or their 1-oxide compounds are treated with a Lewis acid to form the corresponding 2-alkyl-J-[acylamino-2 (or 3)- After preparing cefem-4-caphonic acid or its derivative at the carboxy group or its 1-oxide compound, it is treated with an iminohalogenating agent and then an iminoetherifying agent, and then an acylating agent corresponding to the reaction product It can be produced by reacting with In the definition of the above formula, the acyl group defined as a group in which a carbonyl group is removed from mutually different acyl groups in R1 and k1 means all aliphatic acyl, acyl containing an aromatic ring, or acyl containing a heterocycle. death,
Specifically, the following are exemplified.

Aliphatic acyl is saturated or unsaturated alkanoyl, which may have a side chain or be cyclic, such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, bivaloyl, acryloyl, crotonoyl, 2-methyl. Acryloyl, cyclopentylcarbonyl, cyclohexylcarbonyl,
Cycloheptylcarbonyl, cyclopentylacetyl,
Cyclohexylacetyl, cyclohebutylacetyl (:′
,.

SS'': Insertion;.Gozu;?)ζ!E!6-cycloheptatrienylacetyl, dihydrophenylacetyl, etc., and these saturated or unsaturated alkanoyls are interrupted by an oxygen atom or a sulfur atom. Examples of such groups include methoxyacetyl, methylthioacetyl, 2-propenylthioacetyl, cyclohexylthioacetyl, cyclohexyloxyacetyl, dihydrophenoxyacetyl, dihydrophenylthioacetyl, etc. Acyl containing aromatic rings include aroyl such as benzoyl, toluoyl, naphthol, α-methylnaphthol, and tetrahydronaphthol, and aralkanoyl such as phenylacetyl, phenylpropionyl, phenylbutyryl, tolylacetyl, xylylacetyl, naphthylacetyl, and tetrahydronaphthylacetyl. In addition, the carbon atom of the alkyl part of this aralkanoyl may be replaced with an oxygen atom or a sulfur atom, such groups include, for example, phenoxyacetyl, phenylthioacetyl, 2-phenoxy Examples include propionyl and 2-phenoxybutyryl.

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, benzothiadiazolyl, 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, imbutyryl, ≦leryl, isovaleryl, pivaloyl, acryloyl, crotonoyl, 2-methylacryloyl, etc. having a group such as N-alkyl heterocyclic substituted amino as a substituent, for example 1H (or 2H)- Tetrazolylacetyl, thienyl acetyl, thienylpropionyl, furyl acetyl, piperazinyl acetyl, pyrrolidinyl acetyl, pyrrolidinylpropionyl, benzothiazolylacetyl,
oxazolyl acetyl, benzoxazolyl acetyl,
Examples of such groups include 4-pyridylthioacetyl, and the carbon atom of the alkyl moiety of the alkanoyl having this heterocycle as a substituent may be replaced with an oxygen atom or a sulfur atom. Examples of such a group include pyridylmethoxy, Examples include acetyl, 2-furylmethoxyacetyl, 8-quinolylmethoxyacetyl, and the like.

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, drill, aralkyl such as benzyl, phenethyl, amino, mercapto, nitro , halogens such as chloro, fluoro, bromine, carboxy, sulfo, hydroxy, hydroxyamino, mono(or di)methylamino, mono(or di)ethylamine, mono(or di)propylamino,
A mono(or di)alkylamino group such as mono(or di)isopropylamino, a mono(or di)alkylamino group such as mono(or di)phenylamino, mono(or di)tolylamino, etc.
Or mono(or di)aralkylamino such as di)arylamino, mono(or di)benzylamino, mono(or di)phenethylamino, etc., and further includes aliphatic acyl and aromatic having such substituents. Examples of acyl or acyl containing a heterocycle include chloroacetyl, 2-chloropropionyl, trifluoroacetyl, aminoadiboyl, α-aminophenyl acetyl, α-hydroxyphenylacetyl, p-hydroxyphenylacetyl, 2-amino -2-(5,6-dihydro-2H-pyran-3-yl)acetyl, 2-amino-
2-(p-hydroxyphenyl)acetyl, 2,6-dimethoxybenzoyl, 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, when there is a free amino group, hydroxy group, mercapto group, carboxy group, sulfo group, etc. in such an acyl group, such amino group, hydroxy group, mercapto group, carboxy group, sulfo group, etc. is protected. The scope of the present invention also includes cases where the compound is protected with a group.

Here, the protecting group for the amino group includes all groups that can be normally used as an amino protecting group, such as trichloroethoxycarbonyl, tribromoethoxycarbonyl, benzyloxycarbonyl, p-toluenesulfonyl, p-nitrobenzyloxycarbonyl, O -bromopencyloxycarbonyl, 0-nitrophenylsulfenyl, chloroacetyl, trifluoroacetyl, formyl, vinyloxycarbonyl, tertiary butoxycarbonyl, p-methoxybenzyloxycarbonyl, 3,4-
Dimethoxybenzyloxycarbonyl, 4-(phenylazo)benzyloxycarbonyl, 4-(methoxyphenylazo)benzyloxycarbonyl, pyridine-1-
Oxide-2-methoxycarbonyl, 2-pyridylmethoxycarbonyl, 2-furyloxycarbonyl, diphenylmethoxycarbonyl, 1,1-dimethylpropoxycarbonyl, isopropoxycarbonyl, 1-cyclopropylethoxycarbonyl, 2-cyano-1,1 -dimethylethoxycarbonyl, putarol, succinyl,
Examples include acyl groups that are easily eliminated such as 1-adamantyloxycarbonyl, 8-quinolyloxycarbonyl, and isobornyloxycarbonyl, and 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, 1-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, 2-ethoxycarbonylcyclopentylidene, 2
-acetylcyclohexylidene, 3,3-dimethyl-5
- Easily eliminated groups such as oxocyclohexylidene (for example, 1-methoxycarbonyl-2-propylidene is sometimes expressed as 1-methoxycarbonyl or 1-propen-2-yl, and for example, 2-ethoxycarbonyl (cyclohexylidene is sometimes expressed as 2-ethoxycarbonyl-1-cyclohexenyl), and protecting groups for amino groups other than acyl groups such as di- or trialkylsilyl, and for protecting hydroxy and mercapto groups. Groups include all groups that can normally be used as protective groups for hydroxy and mercapto groups, such as formyl, acetyl, benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 4-methoxybenzyloxy Carbonyl, 3,4-dimethoxybenzyloxycarbonyl, 4-(phenylazo)benzyloxycarbonyl, 4-(4-methoxyphenylazo)benzyloxycarbonyl, tertiary butoxycarbonyl, 1,1-dimethylpropoxycarbonyl, isopropoxy Carbonyl, diphenylmethoxycarbonyl, 2-pyridylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2,2,2tribromoethoxycarbonyl, 3-
In addition to easily eliminated acyl groups such as iodopropoxycarbonyl, 2-furfuryloxycarbonyl, 1-adamantyloxycarbonyl, 1-cyclopropylethoxycarbonyl, 3-quinolyloxycarbonyl, and trifluoroacetyl, benzyl, trityl, and methoxymethyl ,
Examples include groups such as 2-nitrophenylthio and 2,4-dinitrophenylthio, and examples of the carboxyl group-protecting group include all groups that can be used as ordinary carboxy group-protecting groups. The ester moiety is methyl, ethyl, propyl, isopropyl, tertiary butyl, butyl, benzyl, diphenylmethyl, triphenylmethyl,
p-Nitrobenzyl, p-methoxybenzyl, benzoylmethyl, acetylmethyl, p-nitrobenzoylmethyl, 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-putenyl, succinimidomethyl, 1-cyclopropylethyl, 3,5-ditert-butyl-4-hydroxybenzyl, methylsulfenylmethyl, phenylsulfenylmethyl, methylthiomethyl, phenylthiomethyl, dimethyl Aminomethyl, pyridine-1-oxide
2-methyl, quinoline-1-oxide-2-methyl, methylsulfinylmethyl, di(p-methoxyphenyl)
Esters such as methyl, 2-cyano-1,1-dimethylethyl and the like, as well as silyl compounds such as dimethyldichlorosilane as described in JP-A-46-7073 and Dutch Publication No. 7105259; For example, the case where a carboxyl group is protected with a nonmetallic compound such as titanium tetrachloride is exemplified as described in Publication No. 2062925. In addition, examples of the group from which 0H is removed from the alcohol represented by R2 include alkanols such as methanol, ethanol, propanol, isopropanol, butanol, alanools such as benzyl alcohol and phenethyl alcohol, or those that have an adverse effect on this reaction. Examples include residues obtained by removing the hydroxyl group from alcohols, including those having substituents such as alkoxy groups such as methoxy, ethoxy, and propoxy. Further, examples of the alkyl group in R3 include methyl, ethyl, propyl, and the like.

Further, as the derivatives in the carboxy group of the compounds of the formulas (1) to (11), the derivatives in the acyl group are 5
For example, the following derivatives of the carboxy group may be exemplified, including derivatives derived by the reaction of a silyl compound or a nonmetallic compound with a carboxylic acid as exemplified in the protecting group of the carboxy group. can. (a) Ester: Here, ester includes all active esters and inactive esters, for example, the ester moiety is methyl, ethyl, pukapyl, isopropyl, butyl, tertiary
butyl, cyclohexyl, cycloheptyl, vinyl,
1-propenyl, 2-propenyl, 1,1-dimethyl-
2-propenyl, 3-butenyl, 1,1 dimethyl-2-
Saturated or unsaturated alkyl such as propynyl, aryl such as phenyl, xylyl, tolyl, naphthyl, aralkyl such as benzyl, phenethyl, etc.; Methoxymethyl, ethoxymethyl, methylthioethyl, methoxymethyl, dimethylaminoethyl, diethylaminoethyl, phenoxymethyl, phenylthiomethyl, methylsulfenylmethyl, phenylsulfenylmethyl, benzoyl, replaced with an oxygen atom or carbonyl, etc. Methyl, toluoylmethyl, etc., and these above-mentioned groups may further contain suitable substituents, such as halogens such as cyano, nitro, fluoro, quail, bromine, alkoxys such as methoxy, ethoxy, propoxy, alkanesulfole, pheazo, etc. Chloromethyl, bromomethyl, trichloroethyl, cyanomethyl, 2-cyano-1●1-dimethylethyl, p-nitrophenyl, 2● having one or more
4●5-Trichlorophenyl, 2●4,6-trichlorophenyl, pentachlorophenyl, p-methanesulfonylphenyl, 4-(ph40enylazo)phenyl, 2
●4-dinitrophenyl, p-chlorobenzyl, 0-nitrobenzyl, p-methoxybenzyl, p-nitrobenzyl, 3,4,5-trimethoxybenzyl, bis(p-
methoxyphenyl)methyl, pentachlorobenzyl, trichlorobenzyl, 3●5-ditert-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
: Strive 7. γ2goτ゛:,Go几); , tertiary butylethynyldimethylamine, tertiary butylethynyldiethylamine, ethylethynyldiethylamine, 2-ethyl-5(3-sulfophenyl)isoxazolium hydroxide inner salt, 1, 5, 9, 9, 10- Pentachlor-9,10-dihydroanthracene, 9,9,10-trichlor-9,
10-dihydroanthracene-1, 8, 9, 10, 10
-Esters with halogeno-9,10-dihydroanthracene derivatives such as pentachlor-9,10-dihydroanthracene.

・) Amide: Here, the amide includes acid amide,
Including all N-mono-substituted acid amides and N-N-disubstituted acid amides, such as N-alkyl acid amides such as N-methyl acid amide and N-ethylic acid amide, N-phenyl acid amide, N-phenyl acid amide,
-N-dimethylamide, N-N-diethylamide,
Acid amides with N-N-dialkyl acid amides such as N-ethyl-N-methyl acid amide, pyrazoles, imidazoles, 4-substituted imidazoles, etc. are useful.

The anion liberated upon acylation represented by Ze is an anion liberated from the acylating agent represented by the general formula R'1C0Z (wherein k1 has the same meaning as above).

That is, Ze is an anion liberated upon acylation from an acylating agent which is a free carboxylic acid corresponding to RCOZ or a reactive derivative at its carboxy group. Here, examples of reactive derivatives of the carboxy group include acid anhydrides, amides, esters, etc.
Particularly frequently used are paic acid chloride, acid azide,
Dialkyl phosphoric acid mixed anhydride, diphenyl phosphoric acid mixed anhydride, dibenzyl phosphoric acid mixed anhydride, halogenated phosphoric acid mixed anhydride, dialkyl phosphorous acid mixed anhydride, sulfite mixed anhydride,
Thiosulfuric acid mixed anhydride, sulfuric acid mixed anhydride, alkyl carbonic acid mixed anhydride, aliphatic carboxylic acid (e.g. pivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutanoic acid) mixed anhydride, aromatic carboxylic acid (e.g. benzoic acid) Acid anhydrides such as mixed anhydrides and symmetrical acid anhydrides, imidazole, 4
Acid amides, cyanomethyl esters, methoxymethyl esters, vinyl esters, 1-methoxy vinyl esters, 1-ethoxy vinyl esters, with monosubstituted imidazoles, dimethylpyrazoles, triazoles, tetrazoles, etc.
propargyl ester, p-nitrophenyl ester,
trichlorophenyl ester, pentachlorophenyl ester, methanesulfonyl phenyl ester, phenyl azophenyl ester, phenyl thioester, p-nitrophenyl thioester, p-cresyl thioester, carboxymethyl thioester, pyranyl ester,
Pyridyl ester, piperidyl ester, 8-quinolylthioester, N-N-dimethylhydroxylamine,
Examples include esters such as esters with 1-hydroxy-2(1H)pyridone, N-hydroxysuccinimide, or N-hydroxyphthalimide. The reaction of this invention is carried out by hydrolyzing 2 (or 3)-cephem-4-carboxylic acids (1) or derivatives thereof at the carboxy group.

The hydrolysis reaction proceeds just by contacting with water, but
An alkali metal hydrogencarbonate, a base such as a trialkylamine, or an acid such as dilute hydrochloric acid or acetic acid may be added to the water in advance. Although the temperature of this reaction is not particularly limited, it often proceeds sufficiently under mild conditions around room temperature. The reaction product is isolated and collected by conventional methods. In the reaction of this invention, when a carboxyl group is converted into a derivative of a carboxyl group during the reaction or during post-treatment of the reaction, cases where a carboxyl group is converted into a derivative of a carboxyl group or other derivatives or a carboxyl group are also included in the scope of this invention. .

The 7-acylamino-2(or 3)-cephem-4-carboxylic acids m or its derivatives at the carboxy group obtained by this invention are new substances, have antibacterial activity, are useful as medicines, and have other antibacterial properties. Useful as an intermediate for manufacturing substances.

Next, the present invention will be explained with reference to Examples 6. Example 1 2-Methyl-Jyoroi2-phenylacetamide)-3-
1.127 2,2,2-trichloroethyl ester of Cefem-4-carboxylic acid was added to 20 ml of anhydrous dichloromethane.
of pyridine and cooled to -15°C.
．． Next, 0.6167 phosphorus pentachloride was added, and the mixture was stirred at the same temperature for 20 minutes, and then further stirred at room temperature for 2 hours.

Add 5 ml of anhydrous methanol to this solution while cooling to -15°C again.
was added, and after stirring at the same temperature for 1 hour, dimethylaniline 2.
27 Next, a solution of 0.427 2-thienylacetyl chloride dissolved in 5 ml of anhydrous dichloromethane was added dropwise, and the resulting solution was stirred at the same temperature for 2.5 hours.
% hydrochloric acid, water, 5% aqueous sodium bicarbonate solution, and water in this order, and then dried. After drying, the solution is concentrated and the resulting oil is crystallized by adding ether to give Mpl6l~1
62-C (decomposition) of 2-(2-thienyl)acetamido}-3-cephem-4-carboxylic acid 2,2,2-trichloroethyl ester of 750% is obtained. Infrared absorption spectrum (nujiol) 330011795, 1748, 1675, 1630C
T! L-1 nuclear magnetic resonance 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, .d0fd, .J-8, 4Hz) 3.
29 (1H, .d, .J-6Hz) 2.67-3.03
(3H,.m) The following compound is obtained in the same manner.

(1) 2-methyl-Jyo2-(3-F-rophenyl)
Acetamide}-3-cephem-4-carboxylic acid 2.
2,2-trichloroethyl ester {Mpl44-14
4.5℃ (decomposition)} (2) 2-methyl-Jyoro2-(
2,2,2- of 1,2,5-thia 5diazol-3-yl)acetamide}-3-cephem-4-carboxylic acid
Trichloroethyl ester {Mpl8O~185℃ (decomposition)} (3) 2-Methyl-2-phenoxyacetoacetate 10mido)-3-cepheme-4-carboxylic acid methyl ester (oil) (4) 2- Methyl-Jyo-i2-
2,2,2-trichloroethyl ester of (phenoxyacetamide)-3-cephem-4-carboxylic acid (Mpl
5ll8~120℃) (5) 2-Methyl-JYoN-
(1-cyclopropylethoxy)carbonylphenylglycyl}amino-3-cephem-4-carboxylic acid (Mp
l68~169℃) 20(
6) 2-methyl-Jio2-(1H-tetrazole-
1-yl)acetamide}-3-cepheme-4-carboxylic acid {Mp2O2~203℃ (decomposition)} (7) 2-methyl-Jyoro2-(2-thienyl)acetamide}-3-
Cefem-4-carboxylic acid 25 {Mpl75℃ (decomposition)
}(8) 2-Methyl-2-phenylthioacetamide)-3-cephem-4-carboxylic acid {Mpl68
~171℃ (decomposition)} (9) 2-methyl-Jyoro2-(3-chlorophenylene)
30L) Acetamide}-3-Cefem-4-carboxylic acid {Mpl73-174℃ (decomposition)}AO) 2-Methyl-JYo3-(N-tert-butoxycarbonylamino)-3-(2-thienyl ) Propionamide}-3-cephem-4-cal 35phonic acid {Mpl67-170℃
(Decomposition)} aυ 2-methyl-JYo-i2-cyanoacetamide) 3-cephem-4-carboxylic acid (Mpl62~
166゜c)02) 2-Methyl-Jyo-o2-(1.3
・4-thia 40diazol-2-ylthio)acetamide}-3-cephem-4-carboxylic acid (Mpl97~
199℃) 03) 2-Methyl-JYoN-tertiary-butoxycarbonyl-2-thienylglycyl}amino-3-cephem-4-carboxylic acid (powder) 4) 2-Methyl-J
io2-(5-methyl-1,3,4-thiadiazol-2-yloxy)acetamide}-3-cephem-4
-Carboxylic acid (Mpll3~116℃) 52-methyl-
3-(2-chlorophenyl)-5-methyl-isoxazol-4-yl}carboxamide-3-cephem-4-carboxylic acid (Mp2O2-203℃) 6) 2
-Methyl-JYo-i2-methylthioacetamide)-3-
Cefem-4-carboxylic acid {Mpl8l~183°C (decomposition)} 7) 2-Methyl-Jyoroi2-allyl (Ally
l) Thioacetamide)-3-cephem-4-carboxylic acid (Mpl2l~123°C) 8) 2-Methyl-Jyoro
i2-azido-2-phenylacetamide)-3-cephem-4-carboxylic acid (Mp 65-68°C) 9) 2-
Methyl 2-JYoN-tert-butoxycarbonyl-2-
(4-hydroxyphenyl)-D glycyl}amino-3
-2,2,2-trichloroethyl ester of Cefem-4-carboxylic acid {Mpl3O~135°C (decomposition)}! 0
) 2-Methyl-Jio2-(3-pyridyl)acetamide}-3-cephem-4-carboxylic acid {Mpl47~
149℃ (decomposition)}1) 2-Methyl-JYoN-13
butoxycarbonyl-2-(2●5-dihydrophenyl)glycyl}amino-3-cephem-4-carboxylic acid {Mpl26-13FC (decomposition)}2) 2-methyl-
2-(4-hydroxyphenyl)-D-glycyl}amino-3-cephem-4-carboxylic acid (powder) 3) 2-methyl-
oN-tertiary-butoxycarbonyl-2-(4-methylthiophenyl)glycyl}amino-3-cephem-4-carboxylic acid (MpllO~120°C) 4) 2-methyl-
JyoroN-tert-butoxycarbonyl-2-(4-methoxyphenyl)glycyl}amino-3-cephem-4-
Carboxylic acid {Mp8l~86℃ (decomposition)}]) 2-Methyl-JYoN-tertiary butquine carbonyl-2-(4
-methylthiophenyl)glycyl}amino-3-sej
2,2,2-trichloroethyl ester of G-4-carboxylic acid (Mpll5-120℃) C26) 2-Methyl-JYoN-tertiary-butoxycarl 5-bonyl-2-(4-methoxyphenyl)glycyl }
2,2,2- of amino-3-cephem-4-carboxylic acid
Trichloroethyl ester {Mp92-95℃ (decomposition)
}(27) 2-methyl-JYoN-tertiary-butoxycarl 10bonyl-2-(2,5-dihydrophenyl)glycyl}amino-3-cephem-4-carboxylic acid 2.
2,2-trichloroethyl ester {MplO4~11
1℃ (decomposition)} (28) 2-Methyl-JYoN-(1
-cyclopropyl 15-ethoxy)carbonyl-2-(
2,2,2 of 5,6-dihydro2H-pyran-3-yl)glycyl}amino-3-cephem-4-carboxylic acid
-Trichloroethyl ester {Mpll8~120℃(
decomposition)} X(29) 2-
Methyl-Jyo-N-tertiary-butoxycarbonyl-2-(
4-tert-butoxycarbonylmethoxyphenyl)glycyl}amino-3-cephem-4-carboxylic acid 2,2
・2-Trichloroethyl ester (powder)
25 (30) 2-methyl-Jyo-oN-(1.3
・4-thiadiazol-2-yl)thiomethylcarbonyl2-phenylglycyl}amino-3-cephem-4-
2,2,2-trichloroethyl ester of carboxylic acid {
Mpl48~1500C (decomposition)}3θ(302-methyl-JYo-N-tertiary-butoxycarbonyl-2-(4-
Methylsulfinyl phenyl)glycyl}amino-3-
2,2●2-trichloroethyl ester of cefem-4-carboxylic acid (Mpll5-125℃)
35(1) 2-Methyl-2-isonicotinoyloxy-2-phenylacetamide)-3-cephem-4-carboxylic acid (Mp2l7-219°C) (33)
2-Methyl-Jyo-i2-isonicotinoyloxy-2-
phenylacetamide)-3-ceph 2,2,2-trichloroethyl ester of 4-carboxylic acid {Mp
lOO~115℃ (decomposition)}C34) 2-Methyl-J
Yoiro2-(5-indanyl)oxycarbonyl-2-
2,2,2-trichloroethyl ester of 1-3-cephem-4-carboxylic acid (Mpl6
5-170℃)? 2-Methyl-JYoN-(1.3.
4-thiadiazol-2-yl)thiomethylcarbonyl-2-phenylglycyl}amino-3-cephem-4-
Carboxylic acid {Mpl43-145℃ (decomposition)}: 6)
2-Methyl-JYoN-tertiary-butoxycarbonyl-2
-(4-tert-butoxycarbonylmethoxyphenyl)
Glycyl}amino-3-cephem-4-carboxylic acid (powder) (7) 2-methyl-JYoN-(1-cyclopropylethoxy)carbonyl-2-(5,6-dihydro-2
H-pyran-3-yl)glycyl}amino-3-cephem-4-carboxylic acid (Mpl95-197°C) 8)
2-Methyl-JYo2-(1,2,5-thiadiazol-3-yl)acetamide}-3cephem-4-carboxylic acid {Mpl88-19 ``C (decomposition)}

Claims (1)

[Claims] 1 General formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ 2 (or 3)-cephem represented by a group, R_3 is an alkyl group, -4-Carboxylic acids or their derivatives at the carboxy group are hydrolyzed to produce 7-acylamino represented by the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (wherein R'_1, R_3 and X have the same meanings as before) -2 (or 3) -Cefm-
A method for producing 7-acylamino-2(or 3)-cephem-4-carboxylic acids, which comprises obtaining 4-carboxylic acids or derivatives thereof at the carboxy group.