KR790001446B1 - Process for preparing 2,3-low alkylene penam-3-carboxlic acid derivatives - Google Patents

Abstract

2,3-lower alkylene penam-3-carboxylic acid deriv. (I; R1 = amino, subst. amino, R2 = carboxy, protected carboxy, R3 = lower alkyl, R4 = lower alkylene, X = S, SO), useful as bactericidal and pharmaceutical intermediate was prepd. Thus, II (Y=acid residue) was reacted with several kinds of base (e.g. alkali metal, alkali earth metal, metal salts, amines, tertiary ammonium hydroxide) to give I.

Description

Method for preparing 2,3-lower alkylene phenam-3-carboxylic acid derivative

The present invention relates to 2,3-lower alkylene phenam-3-carboxylic acid derivatives. It relates to novel 2,3-lower alkylene phenam-3-carboxylic acid derivatives which have an antibacterial action, which are useful as intermediates and which are pharmaceutical preparations.

Another object of the present invention is to provide an antimicrobial agent, 2,3-lower alkylene phenam-3-carboxylic acid derivative, which is gram-positive, such as staphylococcus or bacillus, and 3-cefe-4-carboxylic acid derivative, which is an antimicrobial agent. To provide an intermediate. The 2,3-lower alkylene phenam-3-carboxylic acid derivatives are new compounds with new and useful chemical structures that were unpredictable by the prior art, such as the following structural formula (I).

In the above formula

R ¹ is amino, substituted amino

R ² is carboxy, protected carboxy

R ³ is lower alkyl

R ⁴ is lower alkylene

According to the present invention, the 2,3-lower alkylene phenam-3-carboxylic acid derivative is prepared by a number of methods.

The basic manufacturing method which becomes (II)-(I) was illustrated collectively.

In the above formula

R ¹ is amino, substituted amino

R ² is carboxy, protective carboxy

R ³ is lower alkyl

R ⁴ is lower alkylene

R ⁵ and R ⁶ are each aryl, substituted aryl

R ⁷ is acyl

Y is the residue of the acid

R ^1a is protected amino

R ^1b and R ^{1b '} are each acylamino

R ^1c is acylamino with a protective amino group

R ^1d is an acylamino having an amino group

R ^1e is acylamino with a protective hydroxy

R ^1f is acylamino with hydroxy

R ^2a is a protective carboxyl group.

Benzyl-2-acetoxy methyl-2-methyl-6 of methyl-2-acetoxy ethyl-2-methyl-6- (2-phenoxy acetamido) phenam-3-carboxylate in starting material (II) -(2-phenoxy acetamido) penam-3-carboxylate is prepared according to U.S. Patent No. 3466275 and other starting materials are corresponding 2-oxo-3-amino (or substituted amino) -4-substituted amino ( Or by reacting a substituted thio) -substituted thio-1-acetidine-a- (1-alkylvinyl) acetic acid or a derivative thereof in carboxy with a corresponding catalyst capable of introducing residues of acids such as hydrogen chloride. Are manufactured.

As used herein, “substituted amino” in R ¹ refers to hydrazino, mono (di)-(lower) alkylamino, mono (di)-(lower) alkenyl amino, lower alkylideneamino, mono (lower) alkyl It refers to an appropriately substituted amino group, such as an amino group substituted by an amino protecting group in addition to the idenamino, 1-substituted or unsubstituted arylimino-1-acylthio methylamino, acylamino and acyl groups.

In the above-mentioned moderately substituted amino group, a lower alkyl group suitable for mono (di) lower alkylamino means methyl, ethyl, propofyl, isopurophyll, butyl, etc., and a lower alkenyl group suitable for mono (di) lower alkenyl amine Aryl, 2-butenyl, etc., and suitable alkylidene among lower alkylidene amino refers to ethylidene, furophylidene, butylidene and the like, and suitable egg among lower (lower) alkylidene (lower) 1) Ilkylidene means benzylidene, phenethylidene and the like, and suitable acyl groups in the acylamino group mean carbamoyl, aliphatic acyl groups and acyl groups containing aromatic or heterocyclic rings. Let me explain. Suitable aliphatic acyl groups include lower and higher aliphatic acyl groups, such as lower alkanoyls (formyl, acetyl, furopionyl, butyryl, isobutyryl, valeryl, isovaleryl, oxalyl, succinyl, Pivaloyl), higher alkanoyl (octanoyl, lauroyl, palmiroyl, etc.), lower alkenoyl (acryloyl, crotonoyl, etc.), lower alkinoyl (such as propinoyl), lower Higher cycloalkanecarbonyl (cyclopentane carbonyl, cyclohexanecarbonyl, cycloheptane carbonyl, etc.), lower or higher cycloalkyl (lower) alkanoyl (cyclopentyl acetyl, cyclohexylacetyl, cycloheptylacetyl, cycloheptylacetyl, Cyclohexylfulopionyl, cycloheptylfulopionyl, etc.), lower and higher cycloalkadienecarbonyl (such as dihydro benzoyl), lower and higher cycloalkadienyl (lower) alkanoyl (dihydroxy phenyl acetyl, dihydride) Saturated or unsaturated lower or higher alkanoyl groups containing side chains or cyclic rings such as phenyl phenylpropionyl, and the like and lower alkoxy (lower) alkanoyls (methoxy acetyl, epoxy acetyl, methoxy furo) Pioneyl, etc.), lower alkylthio (lower) alkanoyl (methylthio acetyl, ethylthio acetyl, methylthio puropionyl, etc.), lower alkenylthio (lower) alkanoyl (allylthio acetyl, allylthio furopionyl, etc.) ), Lower or higher cycloalkylthio (lower) alkanoyl (cyclopentylthio acetyl, cyclohexylthio furopionyl, cycloheptylthio acetyl, etc.), lower or higher cycloalkoxy (lower) alkanoyl (cyclopentyl oxyacetyl, cyclo Hexyloxy furopionyl, etc.), lower and higher cycloalkanedenyl oxy (lower) alkanoyls (such as dihydroxy pentoxy acetyl, dihydro phenoxy furopionyl, etc.), lower and high Lower cycloalkanedienylthio (lower) alkanoyl (dihydro phenylthio acetyl, dihydro phenylthio propionyl, etc.) Lower alkoxycarbonyl (methoxy carbonyl, ethoxy carbonyl, propoxycarbonyl, 1-cyclo Propofyl-ethoxycarbonyl, isopuroxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, etc., lower and higher cycloalkyloxycarbonyl (cyclopentyl oxycarbonyl, cyclohexyloxy carbonyl, Cycloheptyloxycarbonyl and the like), lower and higher cyclo alkanedenyl oxycarbonyl (such as dihydrophenoxy carbonyl) and the like, containing oxygen or sulfur atoms and containing lower or higher aliphatic acyl groups.

Suitable acyl groups containing aromatic rings such as benzene and naputalin, for example, are arline carbamoyl (such as phenylcarbamoyl), aryl oils (benzoyl, toluoyl, nafutoyl, α-methyl nafutoyl, phthaloyl, Benzenesulfonyl, tetrahydronaphthoyl, indancarbonyl, etc.), al (lower) alkanoyl (phenyl acetyl, phenylfulopionyl, phenylbutyryl, tolylacetyl, xylylacetyl, naphthylacetyl, tetrahydrona And the carbon atoms of the alkyl groups in the above-mentioned al (lower) alkanoyl groups include aryl oxy (lower) alkanoyls (phenoxyacetyl, phenoxyfulopionyl, phenoxybutyryl, Xyloxyoxyacetyl, etc.), aryloxy carbonyl (phenoxycarbonyl, xylyloxycarbonyl, naphthyloxycarbonyl, indanyloxy carbonyl, etc.), al (lower) alkoxy carbonyl (benzyloxycarbonyl, Phenethyloxycarbonyl Etc.), arylthio (lower) alkanoyl (phenylthioacetyl, phenylthiofulopionyl, etc.), arylglyoxyloyl (phenylglyoxyloyl), etc. may be replaced by oxygen, a sulfur atom or a carbonyl group.

Suitable acyl groups containing heterocyclic rings include heterocyclic carbonyls or heterocyclic lower alkanoyls, and for heterocyclic carbonyls or heterocyclic lower alkanoyls, heterocyclic rings may be saturated or unsaturated monocyclic or polycyclic. That is to say, containing at least one hetero atom such as oxygen, sulfur or nitrogen atoms, for example as follows. That is, unsaturated 3-8 position heterocyclic compound containing one sulfur atom (thienyl, etc.), unsaturated cyclic heterocyclic compound containing one sulfur atom (benzothienyl, etc.), unsaturated 3-8 containing one oxygen atom Stomach heteromonic ring (furyl, 2 (4) pyranyl, 5,6-dihydro-2H-pyran-3-yl, etc.), unsaturated 3-8 position heteromonic ring containing 1-4 nitrogen atoms Rollyl, 2 (3) H-pyrrolyl, 2 (3) -pyrrolidinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, 1H-tetrazolyl, 2H-tetrazolyl, etc.) , Saturated 3-8 position heteromonic ring containing 1-2 nitrogen atoms (pyrrolidinyl, imidazolidinyl, piperidino, piperadinyl, etc.), unsaturated condensed complex containing 1-3 nitrogen atoms Cyclic (indolyl, isoindoleyl, indolinyl benzimidazolyl, quinolyl, isoquinolyl, 1 (2) H-indazolyl, 1 (2) H-bentriazolyl), 1-3 nitrogens Unsaturated 3-8 position containing atoms and one oxygen atom Cyclic (oxazolyl, isoxoxazolyl, oxdiazolyl, etc.), saturated 3-8 position double-cyclic cyclic rings (such as sidnoyl) containing 1-2 oxygen atoms and 1-2 nitrogen atoms, sulfur and 1-3 Unsaturated 3-8 position heteromonic ring containing nitrogen atom (thiazolyl, thiadiazole etc.), unsaturated condensed heterocyclic ring containing 1 oxygen atom and 1-2 nitrogen atoms (benzoxazolyl, benzoxadiaza Zolyl et al.), Unsaturated condensed heterocyclic (such as benzothiazolyl benzothiadiazolyl) containing one sulfur atom and 1-2 nitrogen atoms, and the carbon source of the lower alkyl group in the heterocyclic lower alkanoyl as described above. The substituent may be replaced by one oxygen atom or one sulfur atom, such as heterocyclic lower alkoxycarbonyl, heterocyclic oxycarbonyl, heterocyclic oxy (lower) alkanoyl and heterocyclic-thio- (lower) alkanoyl. Furthermore, carbamoyl, aliphatic acyl as described above, and acyl groups containing aromatic or heterocyclic rings, lower alkyl (methyl, ethyl, furophyll, isopurophil, etc.), lower alkenyl (1-furophenyl, alline, etc.) , Lower and higher cyclic alkyls (cyclic fluoropropyl, cyclic pentyl, cyclic hexyl, cyclic heptyl, etc.), lower alkoxy (methoxy, ethoxy, furoxy, isopuroxy, etc.), lower alkyl thio (methylthio, ethylthio, etc.) ), Aryl (phenyl, cysyl, tolyl, indanyl, etc.), al (lower) alkyl (benzyl, phenethyl, etc.), halogen (chlorine, bromine, fluorine, etc.), halophenyl (chloro phenyl, bromo phenyl, etc.) , Halophenoxy (chloro phenoxy, bromo phenoxy, etc.), cyano lower alkylsulfinyl (methylsulfinyl, ethylsulfinyl, etc.), lower alkensulfonyl (methanesulfonyl, ethanesulfonyl, etc.), lower alkoxy Carbonyl (lower alkoxy (methoxy carbonyl methoxy, ethoxy carbonyl ethoxy, 1-cyclic prorophyl ethoxy, car Carbonyl ethoxy, tert-butoxycarbonyl methoxy), nitro, sulfo, amino, azido, mercapto, carboxy, hydroxy, hydroxyamino, mono (di) methylamino (mono (di) ethylamino , Mono (di) furophylamino, mono (di) isopurophyl amino, etc.).

As described above, when the acyl group has a functional group such as amino, hydroxy mercapto, carboxy, or the like, the functional group may be protected with a suitable protecting group. Suitable protecting groups for amino groups include trityl, 2-nitrophenylthio, 2,4-dinitrophenylthio, 2-hydroxybenzylidene, 2-hydroxy-5-chlorobenzylidene, 2-hydroxy-1- Naphthyl methylene, 3-hydroxy-4-pyridylmethylene, 1-methoxycarbonyl-2-furofilidene, 1-ethoxycarbonyl-2-furofilidene, 3-ethoxycarbonyl-2- Butylidene, 1-acetyl-2-furopylidene, 1-benzoyl-2-furopyridene, 1- [N- (2-methoxyphenyl) carbamoim] -2-furophilidene, 1- [ N- (4-methoxyphenyl) carbamoyl] -2-furophilidene, 2-ethoxycarbonyl cyclohexylidene, 2-ethoxycarbonylcyclo pentidene, 2-acetylcyclohexylidene, 3,3-dimethyl-5-oxo-cyclohexylidene, of which the 1-methoxycarbonyl-2-furopylidene and 2-ethoxycarbonyl cyclohexylidene groups are 1-methoxycarbonyl-1- Fufen-2-yl and 2-ethoxycarbonyl-1-cyclohexenyl groups may be substituted with each other), mono ( ) Includes one of the non-acyl such as silyl or acyl group, conventional protecting groups, such as other groups. Suitable protecting groups for hydroxy or mercapto groups are usually used, for example, acyl or other groups other than acyl groups such as benzyl, trityl, methoxymethyl, 2-nitro phenylthio, 2,4-dinitrophenylthio and the like. It includes any one of the protecting groups. And suitable protecting groups for the carboxyl groups are, for example, lower alkyl esters (methyl ester, ethyl ester, fluoropropyl ester, butyl SL, 1-cyclofuropropyl ethyl ester, tertiary butyl ester, etc.), mono (di, tri) halo ( Lower) alkyl esters (chlor methyl ester, 2,2,2-trichlor ethyl ester, 3,3-dibromo furophil ester, etc.), aryl esters (phenyl ester, nitrophenyl ester, nitrophenyl ester, indanyl ester) Al (lower) alkyl ester (benzyl ester, diphenyl methyl ester, triphenyl methyl ester, P-nitrobenzyl ester, P-bromo benzyl ester, etc.), tri (lower) alkyl silyl ester (triethyl silyl ester, etc.) And triethylsilyl ester, etc.). Furthermore, as the protective amino group other than the acyl group described above with respect to "substituted amino", it is explained in the same manner as described in the protecting group for the amino group in the acyl group. Particularly suitable examples of acyl groups are listed as follows.

(1) lower alkoxy carbonyl (methoxycarbonyl, ethoxycarbonyl, furoxyoxylyl, 1-cyclofurophylethoxy carbonyl, tert-butoxycarbonyl, etc.)

(2) lower alkylthio (lower) alkanoyl (2-methylthio acetyl, 2-methylthiobutyryl, 2-ethylthiobutyryl, 3-ethylthiofulopionyl, etc.)

(3) lower alkenylthio (lower) alkanoyl (2-allylthio acetyl, 3-arylthio propionyl, etc.)

(4) cyano (lower) alkanoyl (2-cyano acetyl, 3-cyano furopionyl, 4-cyanobutyryl, etc.)

(5) phenyl (lower) alkanoyl (2-phenylacetyl, 3-phenylpropionyl, 4-phenylbutyryl, etc.)

(6) phenoxy (lower) alkanoyl (2-phenoxyacetyl, 3-phenoxyfulopionyl, 4-phenoxybutyl)

(7) phenyl carbamoyl

(8) phenyl glyoxyloyl

(9) phenylthio carbonyl

(10) lower alkanoyl substituted with phenyl and amino (phenylglycyl, 3-amino-3-phenyl furopionyl, etc.)

(11) lower alkanoyl substituted with phenyl and hydroxy (2-hydroxy-2-phenylacetyl, 2-hydroxy-3-phenylfulopionyl, etc.)

(12) lower alkanoyl substituted with phenyl and lower alkoxy carbonyl amino (N-methoxy carbonylphenyl glycyl, N-ethoxy carbonylphenyl glycyl, N- (1-cyclofurophylethoxy) -carbon Carbonylphenyl glycyl, N-tertbutoxy carbonylphenyl glycyl, 2- (1-cyclofurophylethoxy) carbonylamino-3-phenylfuro piionyl, etc.)

(13) lower alkanoyl substituted with phenyl and trihalo (lower) alkoxy carbonylamino (N-trichloroethoxy carbonyl phenylglycidyl, 3-trichloro ethoxycarbonyl amino-3-phenylfuropy O'Neill, N-tribromo ethoxy carbonyl-phenylglycidyl, etc.)

(14) lower alkanoyl substituted with phenyl and lower alkanoyloxy (2-formyloxy-2-phenylacetyl, 2-acetoxy-2-phenylacetyl, 3-propionyloxy-3-phenylfuropionyl Etc)

(15) lower alkanoyl substituted with phenyl and semicarbazono (2-phenyl-2-semicarbazonoacetyl, 2-semicarbazono-3-phenylfulopionyl, etc.)

(16) halophenylthio carbamoyl (2- (3 or 4) -chlorophenylthio-carbamoyl, 2- (or 3 or 4) -chlorophenylthio carbamoyl-2- (3 or 4)- Bromophenylthio carbamoyl, etc.)

(17) Putaroyl

(18) lower alkanoylaminobenzenesulfonyl (2- (3 or 4) acetamidobenzenesulfonyl, 2- (3 or 4) -propionamidobenzenesulfonyl, etc.)

(19) lower alkanoyl (2-phenyl-2- [2- (3 or 4) chlorophenoxy] acetyl, 2-phenyl-2 [2- (3 or 4) bromo substituted with phenyl and halophenoxy Phenoxy] acetyl, etc.)

(20) halophenyl (lower) alkanoyl (2- [2- (3 or 4) chlorophenyl acetyl, 2- [2- (3 or 4) bromophenyl] acetyl, 3- [2- (3 or 4) chlorophenyl] propionyl, etc.)

(21) phenyl (lower) alkoxy carbonyl (benzyloxycarbonyl, phenethyloxy carbonyl, etc.)

(22) lower alkanoyl (2-amino-2- [2- (3 or 4) hydroxyphenyl] acetyl, 2-amino-3- [2- (3 or 4) hydroxy substituted with hydroxyphenyl and amino Oxyphenyl) propionyl, etc.)

(23) lower alkanoyl (2-methoxycarbonyl amino-2- [2- (3 or 4) hydroxyphenyl] acetyl, 2- (1-cyclofuro) substituted with hydroxyphenyl and lower alkoxy carbonyl amino Philethoxy) carbonylamino-2- [2- (3 or 4) hydroxyphenyl] acetyl, 2-tert-butoxycarbonylamino-2- [2- (3 or 4) hydroxyphenyl] acetyl and the like )

(24) lower alkanoyls substituted with phenyl and sulfo (2-phenyl-2-sulfoacetyl, 3-phenyl-3-sulfofulopionyl, etc.)

(25) lower alkanoyl (2-amino-2- [2- (3 or 4) -methoxyphenyl] acetyl, 2-amino-3- [2- (3 or 4) substituted with lower alkoxyphenyl and amino -Methoxyphenyl] acetyl, etc.)

(26) lower alkanoyl (2-methoxycarbonyl amino-2 [2- (3 or 4) methoxyphenyl] acetyl, 2- (1-cyclofurophyll) substituted with lower alkoxyphenyl and lower alkoxy carbonyl amino Ethoxy) carbonyl amino-2- [2- (3 or 4) methoxyphenyl] acetyl, 2-tert-butoxy carbonylamino-2- [2- (3 or 4 methoxyphenyl] acetyl, etc.)

(27) lower alkanoyl substituted with lower alkylthiophenyl and amino (2-amino-2- [2- (3 or 4) methylthiophenyl] acetyl, 2-amino-3- [2- (3 or 4) Ethylthiophenyl] propionyl, etc.)

(28) lower alkanoyl (2-methoxycarbonylamino-2- [2- (3 or 4) methylthiophenyl] acetyl, 2 (1-cyclopropyl) substituted with lower alkylthiophenyl and lower alkoxy carbonylamido Ethoxy) carbonyl amino-2- [2- (3 or 4) methylthiophenyl] acetyl, 2-tertbutoxy carbonylamino-2- [2- (3 or 4) methylthiophenyl] acetyl, 2 Tert-butoxycarbonylamino-3- [2- (3 or 4) ethylthiophenyl] propionyl, etc.)

(29) lower alkylsulfinylphenyl and lower alkanoyl substituted with amino (2-amino-2- [2- (3 or 4) methylsulfinylphenyl] acetyl, 2-amino-3- [2- (3 or 4) ethylsulfinylphenyl] propionyl, etc.)

(30) lower alkanoyl (2-methoxycarbonylamino-2- [2- (3 or 4) methylsulfinylphenyl] acetyl, 2 (1-) substituted with lower alkylsulfinylphenyl and lower alkoxycarbonylamino Cyclofurophylethoxy) carbonylamino-3- [2- (3 or 4) ethylsulfinylphenyl] propionyl, 2-tertbutoxycarbonylamino-2- [2- (3 or 4)- Methylsulfinyl] acetyl, etc.)

(31) lower alkoxycarbonyl (lower) alkoxy phenyl and lower substituted alkanoyl (2-amino-2- [2- (3 or 4) methoxy carbonylmethoxyphenyl] acetyl, 2-amino-3 -[2- (3 or 4) puroxycarbonyl methoxyphenyl furopionyl, 2-amino-2- (3 or 4) tert-butoxycarbonylmethoxyphenyl] acetyl, etc.)

(32) lower alkanoyl (2-methoxy carbonylamino-2- [2- (3 or 4) methoxy carbonylmethoxyphenyl substituted with lower alkoxycarbonyl (lower) alkoxyphenyl and lower alkoxy carbonyl amino) ] Acetyl, 2- (1-cyclofurophylethoxy) carbonyl-3- [2- (3 or 4) ethoxy carbonylmethoxyphenyl] propionyl, 2-tertbutoxy carbonylamino-2 -[2- (3 or 4) tert-butoxycarbonyl-methoxy phenyl] acetyl etc.)

(33) lower alkanoyl substituted with phenyl and thiadiazolylthio (lower) alkanoylamino (N- (1,3,4-thiadiazol-2-yl) thioacetyl phenylglycinyl, 2- [3 -(1,3,4-thiadiazol-2-yl) thiofulopionyl] amino-3-phenyl furopionyl and the like)

(34) lower alkanoyl substituted with phenyl and indanyloxycarbonyl (2-phenyl-2-indanyloxycarbonylacetyl, 3-phenyl-2-indanyloxycarbonylpropionyl, etc.)

(35) lower alkanoyl substituted with dihydrophenyl and amino (2-amino-2 (2,5-dihydrophenyl) acetyl, 2-amino-3- (2,5-dihydrophenyl) furopionyl, etc. )

(36) lower alkanoyl (2-methoxycarbonylamino-2- (2,5-dihydrophenyl) acetyl, 2- (1-cyclofurophylethoxy) substituted with dihydrophenyl and lower alkoxycarbonylamino ) -Carbonylamino-2- (2,5-dihydrophenyl) acetyl, 2-tert-butoxycarbonylamino-2- (2,5-dihydrophenyl) -acetyl, 2-tert-butoxycar Carbonylamino-3- (2,5-dihydrophenyl) propionyl, etc.)

(37) 3-halophenyl-5-lower alkylisoxazol-4-ylcarbonyl (3- [2- (3 or 4) chlorophenyl] -5-methylisoxazol-4-ylcarbonyl, 3 -[2- (3 or 4) bromophenyl] -5-ethylisoxazol-4-ylcarbonyl, etc.)

(38) thienyl (lower) alkanoyl (2- (2-thienyl) acetyl, 3- (2-thienyl) propionyl, etc.)

(39) lower alkanoyl substituted with thienyl and amino (2-amino-2- (2-thienyl) acetyl, 2-amino-3- (2-thienyl) furopionyl, etc.)

(40) lower alkanoyl (2-methoxycarbonylamino-2- (2-thienyl) acetyl, 2- (1-shinolophylethoxy) carbonyl amino substituted with thienyl and lower alkoxycarbonyl amino 2- (2-thienyl) acetyl, 2-tert-butoxycarbonylamino-2- (2-thienyl) acetyl, 2-tert-butoxycarbonylamino-3- (2-thienyl) furo Thionyl, etc.)

(41) Tetrazolyl (lower) alkanoyl (2- (1H-tetrazol-1-yl) acetyl, 3- (1H-tetrazol-1-yl) furiononyl, 4- (1H-tetrazol-1 Butylyl, etc.)

(42) thiadiazolyl (lower) alkanoyl (2-1,2,5-thiadiazol-3-yl) acetyl, 2- (1,3,4-thiadiazol-2-yl) acetyl, 3 -(1,2,5-thiadiazol-3-yl) furopionyl, etc.)

(43) thiadiazolylthio (lower) alkanoyl (2- (1,3,4-thiadiazol-2-ylthio) acetyl, 2- (1,2,5-thiadiazol-3-ylthio ) Acetyl, 3- (1,3,4-thiadiazol-2-ylthio) propionyl, etc.)

(44) halobenzotriazolyl (lower) alkanoyl (2- [4- (5,6 or 7) chloro-1H-benzotriazol-1-yl acetyl, 2- [4 (5,6 or 7 bromo -1H-benzotriazol-1-yl] acetyl, 3- [4- (5,6 or 7) fluoro-2H-benzotriazol-2-yl] furopionyl, etc.)

(45) lower alkylthiadiazolyloxy (lower) alkanoyl (2- (5-methyl-1,3,4-thiadiazol-2-yloxy) acetyl 2- (4-methyl-1,2,5 -Thiadiazol-3-yloxy) acetyl, 2- (5-ethyl-1,3,4-thiadiazol-yloxy) propionyl and the like)

(46) lower alkanoyl substituted with dihydropyranyl and amino (2-amino-2- (5,6-dihydro-2H-pyran-3-yl) acetyl, 2-amino 3- (5,6- Dihydro-2-pyran-3-yl) propionyl, etc.)

(47) lower alkanoyl (2-methoxycarbonylamino-2- (5,6-dihydro-2H-pyran-3-yl) acetyl, 2- (substituted with dihydro pitanyl and lower alkoxy benzoylamino) 1-cyclofurophilethoxy) carbonylamino-2- (5,6-dihydro-2H-pyran-3-yl) acetyl, 2-tertbutoxycarbonylamino-2- (5,6 -Dihydro-2H-pyran-3-yl) acetyl, 2-tertbutoxycarbonylamino-3- (5,6-dihydro-2H-pyran-3-yl) furopionyl, etc.)

(48) cydnonyl (lower) alkanoyl (2- (sidnon-3-yl) acetyl, 3- (sidnon-3-yl) furopionyl, etc.)

(49) phenyl (lower) alkoxycarbonyl (benzyloxycarbonyl, phenethyloxycarbonyl, etc.)

In acylamino having a protective amino group for R ^1a and R ^1c , the term “protecting amino” includes amino and acylamino groups substituted by an amino protecting group other than an acyl group as described above.

For acylamino with a protective hydroxy, the term “protective hydroxy” includes hydroxy protected by the same conventional protecting group for hydroxy as described above.

^Acylamino with protected amino for R ^1b , R ^'x , R ^c , acylamino with amino for R ^1d , acylamino with protective hydroxy for R ^1e and acyl with hydroxy for R ^1f The term "acylamino" for amino includes the same acylamino as described above.

The term "protective carboxyl group" for R ² and R ^2a includes esters, acidamides, acid anhydrides, salts and the like. Suitable esters include silyl esters, aliphatic esters and esters containing aromatic or heterocyclic rings. Suitable silyl esters are described, for example, with tri (lower) alkylsilyl (trimethylsilyl, triethylsilyl, etc.) esters and the like.

Suitable aliphatic esters include lower alkyl (methyl, ethyl, furophyll, isoprofil, 1-cyclofurophyll, ethyl, butyl, tertiary butyl, etc.) esters, higher alkyl (octyl, nonyl, undecyl, etc.) esters, lower al Kenyl (vinyl, 1-furophenyl, allyl, 3-butenyl, etc.) ester, lower alkynyl (3-butynyl, 4-pentynyl, etc.) ester, lower or higher cycloalkyl (cyclopentyl, cyclohexyl, cycloheptyl) Etc.) Saturated or unsaturated higher or lower alkyl esters having side chain or cyclic rings such as ester, etc., and lower alkoxy (lower) alkyl (methoxymethyl, ethoxyethyl, methoxyethyl, etc.) ester, lower alkylthio (lower) ) Alkyl (methylthiomethyl, ethylthioethyl, methylthiofurophyll, etc.) ester, di (lower) alkylamino (dimethylamino, dimethylamino, difurophylamino, etc.) ester, lower alkylideneamino (ethylideneamino , Furophyldeniamino, isopurophilidenamino, etc.) Saturated or unsaturated lower or higher aliphatic esters containing nitrogen, sulfur or oxygen, such as esters, lower alkylsulphenyl (lower) alkyl (methylsulphenylmethyl, ethylsulphenylmethyl, etc.) esters and the like. Suitable esters containing aromatic rings include, for example, aryl (phenyl, xylyl, tolyl, naphthyl, indanyl, dihydroantryl, etc.) esters, al (lower) alkyl (benzyl, phenethyl, etc.) esters, allyloxy ( Lower) alkyl (phenoxymethyl, phenoxyethyl, phenoxyfurophyll, etc.) esterarylthio (lower alkyl (phenylthiomethyl, phenylthioethyl, phenylthiofurophyll, etc.) ester, alkylsulphenyl (lower) alkyl (phenyl) Sulfenylmethyl, phenylsulfonylethyl and the like), aryloil (lower) alkyl (benzoylmethyl, toluurylethyl and the like), aryloil amino (such as phthalimido) ester and the like.

Suitable esters containing heterocyclic rings include, for example, heterocyclic esters, heterocyclic lower alkyl esters, and the like, and suitable heterocyclic esters are saturated or containing 1-4 heterofactors such as oxygen, sulfur and nitrogen. Unsaturated, condensed or non-condensed 3-8 position heterocyclic (pyridyl, piperidino, 2-pyridin-1-yl, tetrahydropyranyl, quinolyl, pyrazolyl, etc.) esters, and suitable heterocyclic Lower alkyl esters are saturated, unsaturated, condensed or uncondensed 3-8 heterocyclic (pyridyl, piperidino, 2-pyridone-1-yl) containing 1-4 heteroatoms such as oxygen, sulfur and nitrogen atoms. Tetrahydropyranyl, quinolyl, pyrazolyl, etc.) di-substituted lower alkyl (methyl, ethyl, furophil, etc.) ester. Silyl esters, aliphatic esters and esters containing an aromatic or heterocyclic ring as described above are those having 1 to 10 substituents as appropriate. Lower alkyl (methyl, ethyl, furophyll, isofurophyll, butyl, tertiary butyl, etc.), lower alkoxy (methoxy, ethoxy, puroxy, isopuroxy, butoxy, tertiary butoxy, etc.), lower Alkylthio (methylthio, ethylthio, furophylthio, etc.), lower alkylsulfinyl (methylsulfinyl, ethylsulfinyl furophylsulfinyl, etc.), lower alkanesulfonyl (methanesulfonyl, ethanesulfonyl, etc.), phenyl Azo, halogen (chlorine, bromine, fluorine, etc.) cyano, nitro, etc., for example, mono (di, tri) halo (lower) alkyl (chloromethyl, bromomethyl, dichloromethyl, 2,2,2-trichloro Ethyl, 2,2,2-tribromoethyl, etc.) ester, cyano (lower) alkyl (cyanomethyl, cyanoethyl, etc.) ester, mono (di, tri, tetra or penta) halophenyl (4-chloro Phenyl, 3,5-dibromophenyl, 2,4,5-trichlorophenyl, 2,4,6-trichlorophenyl, pentachlorophenyl, etc. ester, lower alkanesulfonylphenyl (4-methanesulfonylphenyl , 2-ethane Phenyl, etc.), 2- (3 or 4) phenyl azophenyl ester, mono (di, tri) nitrophenyl (4-nitrophenyl, 2,4-dinitrophenyl, 3,4,5-trinitrophenyl, etc.) Esters, mono (di, tri, tetra or penta) halophenyl (lower) alkyl (2-chlorobenzyl, 2,4-dibromobenzyl, 3,4,5-triclobenzyl, pentachlorobenzyl, etc.) esters, mono (Di, tri) nitrophenyl (lower) alkyl (2-nitrobenzyl, 2,4-dinitrobenzyl, 3,4,5-trinitrobenzyl, etc.) ester, mono (di, tri) (lower) alkoxyphenyl (lower) ) Alkyl (2-methoxybenzyl, 3,4,5-trinitrobenzyl, etc.) ester, mono (di, tri) (lower) alkoxyphenyl (lower) alkyl (2-methoxybenzyl, 3,4-dimethoxybenzyl , 3,4,5-trimethoxybenzyl and the like) Esters, hydroxy and di (lower) alkylphenyl (lower) alkyl (3,5-dimethyl-4-hydroxybenzyl, 3,5-ditertbutyl) 4-hydroxybenzyl, etc.).

Suitable acidamides are, for example, N-lower alkyl acid amides (N-methyl acid amide, N-ethyl acid amide, etc.) NN-di (lower) alkyl acid amides (NN-dimethyl acid amide, NN-diethyl acid amide) , N-methyl-N-ethyl acid amide, etc.), N-phenyl acid amide, or acid amide (4-methylimidazole, 4-ethyl with pyrazole, imidazole, 4-lower alkylimidazole) Midazole and the like).

Suitable acid anhydrides include, for example, di (lower) alkyl phosphates (dimethyl phosphate, diethyl phosphate, etc.), dibenzyl phosphate, phosphate halides (phosphate chloride, bromide phosphate, etc.), di (lower) alkyl phosphites (dimethyl phosphite). Diethyl phosphite, etc.), sulfurous acid, thiosulfate, sulfuric acid, lower alkyl carbonates (methyl carbonate, ethyl carbonate, etc.), hydrazic acid, hydrohalonic acid (hydrochloric acid, bromic acid, etc.), saturated or unsaturated Lower aliphatic carboxylic acids (fibaric acid, pentanoic acid, isopentanoic acid, 2-ethyl) butanoic acid, crotonic acid, gylic acid, propionic acid, etc.), saturated or unsaturated halo (lower) aliphatic carboxyl Acids (chloroacetic acid, 3-chloro-2-pentenoic acid, 3-bromo-2-burenoic acid, etc.), substituted lower aliphatic carboxylic acids (phenylacetic acid, phenoxyacetic acid, furanacetic acid, thiophenic acid, etc. ), Aromatic carboxylic acids (such as benzoic acid), or symmetric acid Such as water is included.

Suitable acid salts include salts such as metals (sodium, carium, magnesium) and organic amines (methylamine, diethylamine, triethylamineaniline, pyridine, picoline, NN-dibenzylethylenediamine, etc.). do.

The term "lower alkyl" in R ³ is either red, branched, or cyclic, having one to six carbon atoms, such as methyl, ethyl, propofyl, isoprophyl, butyl, tert-butyl, cyclohexyl, etc. Means to have.

"Lower alkylene" in R ⁴ means alkylene having 1-3 carbon atoms, for example methylene, ethylene, furopropylene, etc.

Means a halo-phenyl, such as such as chlorophenyl, tolyl, - R ⁵ and R ⁶ "aryl" is phenyl, refers to or putil, "substituted aryl" in R ⁵ and R ⁶ term 2 (3 or 4).

The term "acyl" is the same as above

The term "acid residue" in Y is given by removing one hydrogen atom from an acid such as halogen (chlorine, bromine, fluorine, etc.), acyloxy (methylsulfonyloxy, benzenesulfonyloxy, toluenesulfonyloxy) Means a flag.

Salts such as pyridine, picoline NN-dibenzylethylenediamine, and the like.

The term "lower alkyl" in R ³ refers to a side chain having 1 to 6 carbon atoms, or cyclic, such as methyl, ethyl, propofyl, isofurophyll, butyl, tertiary butyl, cyclohexyl, etc. It means to have

"Lower alkylene" in R ⁴ means alkylene having 1-3 carbon atoms, for example methylene, ethylene, furopropylene, etc.

Means a halo-phenyl, such as such as chlorophenyl, tolyl, - R ⁵ and R ⁶ "aryl" is phenyl, refers to or putil, "substituted aryl" in R ⁵ and R ⁶ term 2 (3 or 4).

The term "acyl" is the same as above

The term "acid residue" in Y is given by removing one hydrogen atom from an acid such as halogen (chlorine, bromine, fluorine, etc.), acyloxy (methanesulfonyloxy, benzenesulfonyloxy, toluenesulfonyloxy), etc. Means a flag.

As used herein, the term "lower" means a 1-6 carbon atom chain and the term "advanced" means a 7-16 carbon atom chain and may be branched or cyclic.

Compound [I] of the present invention can be prepared by reacting starting material [II] with a base.

Suitable bases for use in the present invention include, for example, inorganic bases such as alkali metals (lithium, sodium, carium, etc.), alkaline earth metals (magnesium, calcium, etc.), corresponding hydride leads, lower alkoxides (methoxide, Ethoxide, furoxide, butoxide, tertiary butoxide, etc.), hydroxides, carbonates, bicarbonates, amides, methylphenylamides, diisopurophyllamides, and the like such as butyl, phenyl or triphenylmethyl Metal salts and primary amines (methylamine, ethylamine, furophilamine, tertiary butylamine, etc.), secondary amines (dimethylamine, diethylamine, diisofurophylamine, etc.), tertiary amines ( Trimethylamine, Triethylamine, Trifufilamine, Triisofurofilamine, Tributylamine, Dimethylbenzylamine, Triphenethylamine, Pyridine, Picoline, α-Picoline, N-methylpiperidine, N -Methylmorpholine, NN'-dimethylpiperazine, 1,5-diazabicycline [4,3,0] non-5-ene, 1,4 diazabicyclo [2,2,2] octane, 1,8-diazabicyclo [5,4,0] undecene-7, etc.) Organic bases such as quaternary ammonium hydroxide compounds and the like.

This reaction is usually carried out using equimoles of starting material and base in a solvent. When the base used in the present invention is a liquid, it can also be used as a solvent. The reaction proceeds well with or without solvent but with solvent. The solvent used in the present invention does not adversely affect the reaction, for example, dimethylformamide, dimethylsulfoxide, hexamethylphosphoamide, tetramethylurethane, tetrahydrofuran, methylene chloridedioxane, glyme, Diglyme, acetonitrile, acetone, phosphate buffer and the like.

In the present reaction, the reaction temperature is not particularly limited and is good under normal conditions such as ambient temperature.

The present invention includes a protective carboxyl group in which the carboxyl group is a protective carboxyl group and a protective carboxyl group in which the protective carboxyl group is different, or a free carboxyl group during the post-treatment reaction or the present reaction. When target (I) is used in the next process, it is isolated or purified or otherwise just used.

기로 되게 하는 조건하에서 수행된다.Target object (1b) is produced by oxidizing compound (1a). This oxidation reaction is -S-group

It is carried out under conditions that make it crosswise.

Oxidation in this reaction is halogen (chlorine, bromine, etc.), halogen compounds (isocyuroyl chloride, phenyl iododichloride, etc.), ozone, inorganic peracids (periodic acid, persulfate, etc.), organic peracids (perbenzoic acid, m- Chloro perbenzoic acid, pericic acid, peracetic acid, chloroperacetic acid, trifluoroperacetic acid, and the like), metal salts of inorganic or organic peracids, and an oxidizing agent such as hydrogen peroxide.

The reaction is, for example, metals of the fifth or sixth group of the periodic table such as tungstenic acid, molybdic acid, vanadic acid, or alkali metals (sodium, carium, etc.), alkaline earth metals (calcium, magnesium, etc.), these It is preferable to carry out in the presence of a compound containing an ammonium salt or vanadium pentoxide.

This oxidation is usually carried out in the presence of chloroform, methylene chloride, lower alcohols (methanol, ethanol, etc.), pyridine, water, tetrahydrofuran, dimethylformamide, dioxane, acetic acid or other solvents that do not adversely affect the reaction. do. The reaction temperature is not particularly limited and usually proceeds at ambient temperature or under cooling.

The present invention includes a carboxyl group as a protective carboxyl group and a protective carboxyl group as another protective carboxyl group or free carboxyl group during the present reaction or post-treatment reaction in the process.

기로 될수 있는 조건하에서 실시한다.The target object 1a is prepared by reducing the target object 1b.

Carry out under conditions that can be used.

Reduction in this reaction is either stannous chloride or metal thiosulfate (sodiumthio sulfate, cardium thiosulfate, etc.), or acid chloride, and a combination of the above mentioned stannous chloride or metal sulfate, or phosphoris trichloride, phosph It is carried out by a conventional method using forless pentachloride, silicon trichloride and the like and the method described in Japanese Patent No. 21,111.

The reaction is also carried out in a solvent which does not adversely affect the reaction, such as dimethylformamide, acetonitrile, acetoacetic acid ester, tetrahydrofuran, chloroform, methylene chloride, dioxane and the like. There is no particular limitation on the reaction temperature, and the reaction temperature may be appropriately selected depending on compound (1b) and the reduction method used in the present reaction.

The present invention includes changing the carboxyl group to a protective carboxyl group and changing the protective carboxyl group or a free carboxyl group during the present reaction or post-treatment reaction in the production process. The target (1d) is prepared by removing the amino protecting group from the compound (1c), and the target (1h) is prepared by removing the amino protecting group from the compound (1g).

This removal reaction proceeds by conventional methods such as hydrolysis with acid, treatment with hydrazine, reduction and the like. These methods can be chosen arbitrarily depending on the protecting group to be removed. When the protecting group is an acyl group, it is treated with an aminohalogenating agent and then with an imino esterifying agent, and if necessary, hydrolyzed and then removed. The removal reaction by acid is benzyloxycarbonyl, substituted benzyloxycarbonyl, adamantyloxycarbonyl, alkoxycarbonyl substituted alkoxycarbonyl, aralkyloxycarbonyl, trityl, substituted phenylthio, substituted aralkylidene It is one of the most common methods used to remove protecting groups such as substituted alkylidene, substituted cycloalkylidene and the like. Suitable acids are formic acid, trifluoroacetic acid, bezelsulfonic acid, p-toluenesulfonic acid and the like, and most suitable acids are acids which are easily distilled off under reduced pressure such as formic acid and trifluoroacetic acid. The appropriate acid for the reaction is chosen by the protecting group to be removed and other factors.

When the removal reaction is induced by an acid, it proceeds under the problem of a solvent such as a hydrophilic organic solvent, water, or a mixed solvent thereof. Removal reactions with hydrazine are commonly used to remove things such as, for example, phthalate oil. The reduction is generally used to remove such things as trichloro ethoxycarbonyl, benzyloxycarbonyl, substituted benzyloxycarbonyl, 2-pyridylmethoxycarbonyl and the like.

Reductions that can be applied to the removal reaction of the present invention include, for example, metals (tin, zinc, iron, etc.), combinations of metal compounds (chromium chloride, chromium acetate, etc.), and organic or inorganic acids (acetic acid, propionic acid, hydrochloric acid, etc.). ), And the catalytic reduction is carried out under a metal catalyst. Metal catalysts in catalytic reduction include lane-nickel, platinum oxide palladium carbon, and other known catalysts.

The protecting group, ie trifluoro acetyl, is usually removed by reaction with water in the presence or absence of a base, and halogen-substituted alkoxycarbonyl and 8-quinolyl oxycarbonyl are usually removed by treatment with heavy metals such as copper, zinc and the like. .

When the protecting group is acyl, the acyl is reacted with an iminohalogenating agent followed by reaction with an iminoetherating agent and hydrolysis if necessary. Suitable iminohalogenating agents are, for example, phosphorus trichloride, phosphorus pentachloride, phosphorus triphosphate, phosphorus pentachloride, phosphorus oxychloride, thionyl chloride, phosgene and the like. In imino halogenation, the reaction temperature is not particularly limited and is sufficiently performed at ambient temperature or under cooled temperature. Suitable imino etherification agents to react with the product after reacting in the imino halogenation reaction are alkanols (metholol, ethanol, furanolol, isofuropanol, butanol, tert-butanol, etc.), or alkoxy as substituents at these alkyl groups. (Methoxy, ethoxy, furoxy, isopuroxy, butoxy, etc.) and alkali metal alkoxides (sodium alkoxide, carium alkoxide, etc.), or alkaline earth metal alkoxides (calcium alkoxide, barium alkoxide, etc.) derived from the above-mentioned alcohols, respectively. And corresponding alkanols with metal alkoxides). The reaction temperature of the imino etherification reaction is not particularly limited and is sufficiently performed at ambient temperature or under cooling. If necessary, the reaction product is hydrolyzed. Hydrolysis can be performed sufficiently by adding the reaction mixture to water or a mixture of water and a hydrophilic solvent such as methanol and ethanol. In this hydrolysis, water preferably contains a base such as an alkali metal carbonate or trialkylamine, or an acid such as dilute hydrochloric acid or acetic acid. If the protecting group is acyl, this acyl group can be removed by the above-mentioned hydrolysis or by other conventional hydrolysis. The reaction temperature is not limited and may be appropriately selected according to the protecting group for amino or the above-described elimination reaction, and the present reaction is preferably carried out under cooling or slightly warm mild conditions.

The present invention also includes a case where the protective carboxyl group is changed to another protective carboxyl group or an organic carboxyl group during the reaction or post-treatment step in the step.

The present invention also provides that when the compound (1 g) is at least one protective carboxyl, protective hydroxy, and a protective mercapto group of the acylamino group at the 6th position of the penam ring during the reaction in the production process, the above-mentioned groups may be corresponding free groups. Included. The obtained compounds (1d) and (1h) can be changed to these acid addition salts as desired if desired.

The target product (1e) can be prepared by reacting an acylating agent with compound (1d) and salts thereof. Suitable salts of compound (1d) include those such as organic acid salts (acetates, maleate salts, tartarate salts, benzenesulfonate salts, toluenesulfonate salts, etc.) and inorganic acid salts (hydrochloride salts, sulfate salts, phosphate salts and the like).

Acylating agents in this reaction are aliphatic, aromatic, and heterocyclic carboxylic acids with the corresponding sulfonic acids, ester carbonates, carbamic acids and thio acids and reactive derivatives of these acids. Reactive derivatives include acid anhydrides, active amides, active esters, isocyanates and isothiocyanates, for example, acid azide, dialkyl phosphoric acid, phenyl phosphate diphenyl phosphate, dibenzyl phosphate, halogen phosphate, dialkyl phosphate, Sulfurous acid, thiosulfate, hydrohalogenic acid (hydrochloric acid), sulfuric acid, monoalkyl carbonate, aliphatic carboxylic acid (acetic acid, pivaric acid, pentanoic acid, isopentanoic acid, 2-ethylbutyric acid, trichloroacetic acid), aromatic Acid anhydrides or symmetric acid anhydrides mixed with acids such as carboxylic acids (benzoic acid), and acid amides with pyrazoles, imidazoles, 4-substituted imidazoles, dimethylpyrazoles, triazoles, tetrazole, and esters ( Cyanomethyl ester, methoxy methyl ester, vinyl ester, propargyl ester, p-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, methanesulfo Phenyl ester, phenyl ester, phenyl azo phenyl ester, phenyl thio ester, p-nitro phenyl thioester, p-crissul thio ester, carboxymethyl thio ester, pyranyl ester, pyridyl ester, piperidyl ester, 8-qui Norylthioester or N, N-dimethylhydroxylamine, 1-hydroxy-2- (1H) -pyridone, N-hydroxysuccinimide, or ester of N-hydroxyfutalimide). The reaction derivatives described above are determined according to the type of acid used.

When free acid was used in the acylation reaction, NN'-dicyclo hexylcarbodiimide, N-cyclohexyl-N morpholinoethylcarbodiimide, N-cyclohexyl-N '-(4-diethylamino Cyclhexyl carbodiimide, NN'-diethylcarbodiimide, NN'-diisopurophylcarbodiimide, N-ethyl-N '-(3-dimethylaminofurophyll) carbodiimide, NN'-carbo Nyldi- (2-methylimidazole), pentamethyleneketene-N-cyclohexylimide, diphenylketene-N-cyclohexylimine, alkoxyacetylene, 1-alkoxy-1-chloroethylene, trialkylphosphite, ethyl Polyphosphate, isoprophyll polyphosphate, phosphorus oxychloride, phosphorus chloride, thionyl chloride, oxaryl chloride, triphenylphosphine, 2-ethyl-7-hydroxybenzisoxazolium salt, 2-ethyl- 5- (m-sulfophenyl) -isoxazolium hydroxide intramolecular salt, (chloromethylene) -di Tylammonium chloride 2,2,4,4,6,6-hexachloro-2,2,4,4,6,6-hexahydro-1,3,5,2,4,6-triazatrifoss It is more effective to add a condensing agent such as porin or a mixed condensing agent such as triphenylphosphine and tetrahalocyclic carbon (carbon tetrachloride, tetrafluorocarbon, etc.) or halogen (chlorine, bromine, etc.). Examples of the acyl group introduced by the amino group of compound (1d) refer to a group in which the hydroxyl group is removed from aliphatic, aromatic and heterocyclic carboxylic acids and their corresponding sulfonic acid carbonates, carbamic acid and thio acid, and the like, in more detail. Is the same acyl group as described for the acyl group in the acylamino group for R 'The acylation reaction is usually water, acetone, dioxane acetonitrile, chloroform, methylene chloride, ethanedichloride, tetrahydrofuran, ethyl acetate, Dimethylformamide, pyridine, etc. The hydrophilic solvent described above may be used as a mixed solvent with water, and the acylation reaction may be carried out with inorganic bases (such as alkali metal carbonates) and organic bases (trialkylamines). , NN-dialkylamine, NN-dialkylbenzylamine, pyridine, 1,5-diazabicyclo [4,3,0] non-5-ene, 1,4-diazabicyclo [2,2,2] Octane, 1,8-diazacyclo [5,4,0 undecene-7 and the like).

In this reaction, a liquid base or a liquid condensing agent can be used as the solvent.

The reaction temperature in this reaction is not limited and is cooled or carried out at ambient temperature.

The present invention includes the case where the protected carboxyl group in the present or post-treatment reaction is another protected carboxyl group or changed to a free carboxyl group.

The desired compound (1f) can be prepared by reacting compound (1e) with an iminohalogenating agent, an imino etherifying agent, followed by reaction with an acylating agent and, if necessary, by hydrolysis. Suitable imino halogenating agents include phosphorus trichloride, phosphorus pentachloride, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, thionyl chloride, phosgene and the like. In the imino halogenation reaction, the reaction temperature is not limited and proceeds sufficiently at ambient temperature or at a cooled temperature. Suitable imino etherification agents which will react with the reaction product after reaction in the imino halogen reaction are alkanols (methol, ethanol, furanol, isopuranol, butanol, tert-butanol, etc.) or alkoxy (as a substituent on the alkyl group). Corresponding alkanols with methoxy, ethoxy, furoxy, isopuroxy, butoxy and the like, and alkali metal alkoxides (sodium alkoxides, carium alkoxides, etc.) or alkali earth metal alkoxides (calcium alkoxides, barium) derived from the alcohols Alkoxide, etc.), and in the imino etherification, the reaction temperature is not limited and is sufficiently performed at ambient temperature or cooling.

This acylation reaction is carried out under the same conditions as described for the acylation reaction of compound (1d). The reaction product obtained is hydrolyzed if necessary. The hydrolysis proceeds sufficiently by injecting the reaction mixture into water or a mixture of water and a hydrophilic solvent such as methanol or ethanol. In this hydrolysis, water preferably contains a base such as an alkali metal carbonate, trialkylamine, and an acid such as dilute hydrochloric acid or acetic acid.

In this reaction, the acylamino group R ^1b in compound (1e) is changed to another acylamino group R ^1b'x in compound (1f).

The target (Ij) can be prepared by removing the protecting group of hydroxy from the compound (Ii). This removal reaction is carried out by a conventional method using an acid or a base, reduction or the like. These methods are chosen depending on the type of protecting group to be removed. Acid-removing reactions include benzyloxycarbonyl, substituted benzyloxycarbonyl, alkoxycarbonyl, substituted alkoxycarbonyl, adamantyloxycarbonyl, trityl, substituted phenylthio, substituted aralkylidene and substituted alkyl. It is one of the most common methods used to remove protecting groups such as den, substituted cycloalkylidene and the like.

Suitable acids are for example formic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like and most suitable acids are acids which are easily removed by evaporation under reduced pressure such as formic acid, trifluoroacetic acid.

The acid suitable for the reaction depends on the protecting group to be removed and other factors. The removal reaction with acid is carried out under hydrophilic organic solvent, water, or a mixed solvent thereof. Base removal reactions are used to remove acyl groups. Suitable bases are, for example, inorganic bases such as alkali metals (such as sodium carium), alkaline earth metals (magnesium, calcium, etc.) and alkaline earth metals (magnesium, calcium, etc.), inorganic acids such as hydroxides or carbonates thereof, or hydrocarbonates thereof. Base and trialkylamine (triethylamine, methylamine, triethylamine, etc.), picoline, N-methylpyrrolidine, N-methylmorpholine, 1,5-diazabicyclo [4,3,0] non- Organic bases such as 5-ene, 1,4-diazacyclo [2,2,2] octane, 1,8-imazacyclo [5,4,0] undecene-7 and the like. Removal reactions as salts are sometimes carried out in the presence of water, hydrophilic solvents or mixed solvents thereof. Reduction is generally used to remove trichloroethoxycarbonyl, benzyloxycarbonyl, 2-pyridylmethoxycarbonyl and the like. The reduction used in the elimination reaction of the present invention is a combination of a metal (tin, zinc, iron, etc.) or a metal compound (such as chromium chloride, dichromate, etc.) and an organic or inorganic acid (acetic acid, propionic acid, hydrochloric acid, etc.). Reduction by means of reusing the reaction proceeds under a metal catalyst for catalytic reduction. Metal catalysts for catalytic reduction include, for example, Raney-Nickel, platinum oxide, palladium carbon and other known catalysts.

The protecting group, trifluoroacetyl, is usually removed by treatment, of course, in the presence or absence of a base. And halogen substituted alkoxycarbonyl and 8-quinolyloxycarbonyl are usually removed by treatment with heavy metals such as copper, zinc and the like. When the protecting group is trifluoroacetyl, it is removed by treatment in the presence of water or base. When the protecting group is halogen-substituted alkoxycarbonyl or 8-quinolyloxycarbonyl, it is removed by treatment with heavy metals such as copper and lead. When the protecting group is an acyl group, the acyl can be removed by hydrolysis or other conventional hydrolysis as described above.

The reaction temperature is not particularly limited and is selected according to the protecting group and the removal method for hydroxy, and the reaction proceeds more effectively under mild conditions such as cooling or under slight heating.

The present invention also includes a case where the protective carboxyl group is changed to another protective carboxyl group or free carboxyl group in the present reaction or post-treatment method in the production process. The present invention also encompasses the conversion of the aforementioned groups to the corresponding free groups during the reaction when compound (Ii) has one or more protective amino, protective carboxy and / or protective mercapto groups in the acylamino group at the sixth position of the penam ring. .

Target (II) can be manufactured by removing a protective carboxyl group from compound (Ik).

All known methods in this removal reaction are used for this removal reaction and conventional methods, for example reduction, hydrolysis, etc., are used to remove the protective carboxyl groups. When protecting groups are active esters, activated amides or acid anhydrides, they can be removed by hydrolysis methods under suitable conditions of contact with water.

Reduction can be applied to remove 2-iodoethylester, 2,2,3-trichloroethylester, benzylester and the like. The removal reaction as an acid is p-methoxybenzyl ester, tertiary butyl ester, tertiary pentyl ester triester, diphenylmethyl ester, bis (methoxyphenyl) methyl ester, 3,4-dimethoxybenzyl ester, 1-cyclo It is used to remove protecting groups, such as propyl propylene. The removal reaction as an anhydrous basic catalyst can be used to remove protecting groups such as ethynyl and 4-hydroxy-3,5-di (tri-butyl) -benzyl ester.

Reductions applied to the elimination reaction of the present invention include, for example, metals (zinc, zinc amalgam, etc.) or chromium salt compounds thereof (chromium monochloride, primary chromium acetate) and organic or inorganic acids (acetic acid, propionic acid, hydrochloric acid). And combinations thereof under the metal reduction catalyst. Metal catalysts for catalytic reduction are, for example, platinum catalysts (platinum wire, platinum sponge, platinum black, platinum colloid), and palladium catalysts (paradium sponge, palladium black, palladium oxide, palladium sulfate, palladium carbonate, palladium carbonate, palladium palladium, palladium Colloids, etc.) Nickel catalysts (reduced nickel, nickel oxide, raninickel, urushibaranic, etc.), and suitable acids in the removal reaction are formic acid, trihaloacetic acid (trichloroacetic acid, trifluoroacetic acid, etc.) hydrochloric acid, hydrofluoric acid, p- Fluenesulfonic acid, trifluoromethanesulfonic acid, mixed acids of hydrochloric acid and acetic acid, and the like. Suitable base anhydride catalysts in the removal reaction include sodium thiophenorate. [(CH ₃ ) ₂ LiCu].

In the present reaction, when the protecting group is removed by treatment with water or liquid acid, the present reaction is performed without a solvent. Any solvent that does not adversely affect the reaction in the reaction, for example, dimethylformamide, methylene chloride, chloroform, tetrahydrofuran, acetone can be used. The reaction temperature is not particularly limited and may be appropriately selected depending on the starting compound and the removal reaction actually applied.

The present invention also includes the case where the protective carboxy, hydroxy, mercapto or amino groups contained in the starting material can be changed to free carboxy, hydroxy, mercapto or amino groups in the post-treatment or in situ processing of the reaction, respectively. do. Thus, compound (II) can be converted into a preferable metal (sodium, carium) salt or these unbase salt.

Target object (In) can be manufactured by making semicarbazide and these bases react with compound (Im).

Suitable salts of semicarbazide include those such as inorganic acid salts (hydrochlorides, sulfates, etc.) and organic acid salts (acetates, maleates, tartarates, etc.). This reaction is usually carried out in a solvent which does not adversely affect the reaction, such as methanol, ethanol, ethanol, water, acetonitrile, ether, chloroform, formamide, benzene and the like.

This reaction is preferably carried out in the presence of a base. Suitable bases are, for example, inorganic bases such as alkali metals (lithium, sodium, carium) and alkali metals (magnesium, calcium, etc.), the corresponding hydrides, amides, alkoxides (methoxide, ethoxide, furoxide, Tert-butoxide, etc.), hydroxides, carbonates, bicarbonates, acetates, etc., and third-amids (trimethylamine, triethylamine, trifurophylamine, triisofurophylamine, tributylamine, dimethylbenzylamine, tri Phenethylamine, pyriridine, pyridine, α-picoline, N-methylpiperidine, N-methylmorpholine, NN'-dimethylpiperazine, 1,5-diazabicyclo [4,3,0] non- Organic compounds such as 5-ene, 1,4-diazabicyclo [2,2,2] octane, 1,8-diazabicyclo [5,4,0] undensen-7, etc.) and quaternary ammonium hydroxide compounds Base. There is no restriction | limiting in particular in reaction temperature, This reaction is normally performed by heating to the vicinity of the boiling point of the solvent used for this reaction.

This reaction also includes a step of subjecting the protective carboxyl group to another free carboxyl group during the post-treatment or the present reaction in the process.

The target product (I _p ) can be prepared by reacting an acylating agent with reduced compound (I _D ).

기로 변환하는 즉 화합물(I_a)이 화합물(I_b)을 환원시킴으로 제조되는 것과 동일한 조건하에서 진행된다.This acylation reaction

Conversion to a group, ie compound (I _a ) proceeds under the same conditions as prepared by reducing compound (I _b ).

Suitable acylating agents are the same as those used for the acylation reaction in compound (I _e ).

This reaction is better performed by using acid halides as acylating agents. The present invention is usually carried out in the presence of a solvent which does not adversely affect the present reaction, such as dimethylformamide acetonitrile, acetoacetic acetate, tetrahydrofuran, chloroform, methylene chloride, dioxane and the like.

The reaction temperature is not particularly limited and the reaction temperature is selected according to the compound (I _o ) and also according to the acylating agent or the reaction method used.

In the present reaction and post-treatment of the present invention, a step of changing a carboxyl group to a protective carboxyl group and a protective carboxyl group to another protective carboxyl group, free carboxyl group or free carboxyl group is also included.

The object (I) of the present invention has an antimicrobial effect against various pathogens and is useful for the treatment of diseases transmitted by such pathogens in humans and animals.

Regarding the representative object of the present invention, the antimicrobial effect is described in the following reference.

The MIC values (mcg / ml) of Staphylococcus 209-PJC-1 and Bacillus ATCC6633 of the target (I) are as follows.

Evaluation method of antimicrobial effect in vitro

In vitro, the antimicrobial effect was assessed by two superimposed agar plate dilution methods as described below.

Tryty case-soybean juice (10 ⁶ viable cells / ml) was cultured on one day and night of each test strain on the Platinum Ring, and on a HI-agar containing a certain concentration of antibiotics. After incubation at 37 ° C. for 20 hours, the minimum inhibitory concentration (MIC) was expressed in mcg / ml.

(1) 2-methyl-2,3-methylene-6-phenylglyciylaminophenam-3-carboxylic acid (fo: staphylococcus liver: bacilli)

Four: 25 liver: 1.56

(2) NN'- of 2-methyl-2,3-methylene-6- [3- (2-chlorophenyl) -5-methylisoxazole-4-carboxamido] phena-3-carboxylic acid Dibenzylethylenediamine salt

Four: 50 liver: 12.5

(3) 2-methyl-2,3-methylene-6- [2- (2-thienyl) acet amido] penam-3-carboxylic acid

Four: 12.5 liver: 1.56

(4) NN'-dibenzyl ethylenediamine salt of 2-methyl-2,3-methylene-6 [-2- (2-chlorophenoxy) -2-phenylacetamido] phenam-3-carboxylic acid

Four: 1.56 Inter: 1.56

(5) Sodium 2-methyl-2,3-methylene-6 [2- (1,3,4-thiadiazol-2-ylthio) -acet imido] penam-3-carboxylate

Four: 12.5 liver: 3.13

(6) Sodium 2-methyl-2,3-methylene-6- (2-methylthio acetamido) penam-3-carboxylate

Four: 12.5 liver: 3.13

(7) Sodium 2-methyl-2,3-methylene-6- (2-formyloxy-2-phenylacetamido) -penam-3-carboxylate

Four: 12.5 liver: 1.56

(8) 2-methyl 2,3-methylene-6-phenylthio carbonyl aminophenam-3-carboxylic acid

Four: 200 Liver: 100

(9) Sodium 2-methyl 2,3-methylene-6- (2-hydroxy-2-phenylacet amido) penam-3-carboxylate

Four: 12.5 liver: 3.13

(10) -NN'-dibenzylethylenediamine salt of 2-methyl-2,3-methylene-6-phthalimidophenam-3-carboxylic acid

Four: 200 Liver: 50

(11) 2-Methyl-2,3-methylene-6- (2-phenyl-2-semicarbazono) -acetamidophenam-3-carboxylic acid

Four: 50 liver: 3.13

(12) NN'-dibenzylethylenediamine salt of 2-methyl-2,3-methylene-6- (1-cyclofurophylethoxy) carbonylaminophenam-3-carboxylic acid

Four: 6.25 Inter: 6.26

(13) 2-methyl-2,3-methylene-6- (2-phenylacetamido) phenam-3-carboxylic acid

Four: 25 liver: 3.13

(14) 2-Methyl-2,3-methylene-6- [2- (1H-tetrazol-1-yl) acetamino] -phenam-3-carboxylic acid

Four: 50 liver: 12.5

Object (I) of the present invention is also useful for preparing antimicrobial compounds and major intermediates thereof, such as, for example, 2-lower alkyl-7-acyl amino-3-cepem-4-carboxylic acid derivatives.

Compound (I) of the present invention is formulated for administration in a convenient way by analogy with other antibiotics.

The preparation of compound (I) is used in a solid, semi-solid or liquid form by mixing a compound (I) with a pharmaceutical or inorganic excipient or additive suitable for external or injectable use. For example, the active ingredient is mixed with conventional excipients to formulate into tablets, pills, capsules, suppositories, solutions, suspensions, emulsions and other suitable formulations for use. The additives used are starch, taxose, acacia gum, gelatin, mannitol, starch paste, magnesium trisilicate, talc, corn starch, keratin, colloidal silica, potato starch, urine, etc. Formulations in semi-solid liquid form may contain adjuvant, stabilizer and colorant.

In addition, the preparation of the present invention may contain a preservative and a preservative so that the active ingredient of the desired preparation is not deteriorated in effect.

The active ingredient (I) contains an amount that can have a sufficient antimicrobial effect on the preparation, and the active ingredient content of the preparation varies depending on the conditions and ages for the treatment of each patient, but is usually 0.5-5 g daily. Preferably 1-2 g / 1 day of active ingredient is generally administered to treat diseases in which target compound (i) is useful.

Although the present invention has been described in general, but in order to make it more understandable, the following specific examples have been given, which are not intended to be limiting unless the invention is specifically described or described.

[reaction]

Example 1

5.16 g of 2,2,2-trichloroethyl-2-bromomethyl-2-methyl-6- (2-phenylacetamido) phenam-3-carboxylate-1-β-oxide in 50 ml of dimethylformamide To a solution of 1,8-diazabicyclo (5,4,0) undecene-71.67 g in 5 ml of dimethylformamide was added at -45 -50 ° C. After stirring the mixture at −50 ° C. for 3 hours, the jade is removed and stirred until the internal temperature rises to 0-10 ° C. The mixture obtained is poured into an ice-cold solution of ethyl acetate and hydrochloric acid, the ethyl acetate layer is separated, and the aqueous solution is extracted with ethyl acetate. The combined ethyl acetate layers were washed with water and then dried over magnesium sulfate. After treatment with activated charcoal, the solvent was removed and the residue obtained was washed with ether, and colorless crystals of 2,2,2-trichloroethyl-2-methyl-2,3-methylene-6- (2-phenylacetamido) penam- 3.64 g of 3-carboxylate-1-β-oxide are obtained (melting point 148 ° -148.5 ° C).

Analysis: C ₁₈ H ₁₇ N ₂ 0 ₄ SCl ₃

Calculated Value: C, 45.06, C, 3.57, N, 5.84, Cl, 22.17, S, 6.68

Theoretic: C, 44.82, H, 3.50, N, 5.72, Cl, 22.71, S, 7.04

The results obtained by treatment as in Example (1) under various conditions are shown in Table (1) below.

TABLE 1

Example 2

0.08 g of sodium carbonate was dissolved in 5 ml of dried dimethylformimide, 2,2,2-trichloroethyl 2-bromomethyl-2-methyl-6- (2-phenylacetamido) -phenam-3-carboxylate- It is added to a solution of 0.56 g of 1-α-oxide and stirred for 5 hours at room temperature. The mixed solution is poured into ice water, acidified with phosphoric acid and extracted with ethyl acetate. The ethyl acetate extract is washed sequentially with water, saturated aqueous sodium bicarbonate solution and water, and then dried over magnesium sulfate. The residue obtained by removing the solvent under reduced pressure was purified by column chromatography on silica gel using chloroform as the developing solvent. Crystallization of the purified product with ethers afforded colorless needles of 2,2,2-trichloroethyl-2-methyl-2,3-methylene-6- (2-phenylacetamido) penam-3-carboxylate-1. 130 mg of -α-oxide are obtained (melting point: 142-143).

Analysis: C ₁₈ H ₁₇ N ₂ 0 ₅ SCl ₃

Calculated Value: C, 45.06, H, 3.57, N, 5.83, S, 6.68, Cl, 22.17

Experimental Value: C, 44.92, H, 3.42, N, 5.81, S, 6.35, Cl, 22.03

Example 3

To a suspension of 14.4 g of 2,2,2-trichloroethyl-2-bromomethyl-2-methyl-6-aminophenam-3-carboxylate-1-β-oxide hydrochloride in 100 ml of dimethylformamide A solution of 1.8-diazabicyclo [5,4,0] decene-7 (9.13 g) in 5 ml of dimethylformamide is added dropwise while cooling at -50 -50 ° C for at least 10 minutes and then stirred for 3 hours. The mixture obtained after the reaction was poured into a solution of 500 ml of ethyl acetate and 300 ml of ice water, and the ethyl acetate layer was separated, washed twice with water and with saturated aqueous sodium chloride solution, and the extract was dried over magnesium sulfate.

After treatment with activated carbon, the mixture was concentrated under reduced pressure, and the residue was dissolved in 70 ml of ethyl acetate. A solution of 5.7 g of 2-toluenesulfonic acid monohydrate in 50 ml of ethyl acetate was added to the solution and the precipitated crystals were collected by filtration. The crystals were recrystallized from methanol to obtain 2,2,2-trichloroethyl-2-methyl-2,3-methylene-6-aminophenam-3-carboxylate-1-β-oxidetoluenesulfonate 13. Og is obtained (melting point 176-179 ° C.).

Analysis: C ₁₇ H ₁₉ N ₂ 0 ₇ SCl ₃

Calculated Value: C, 38.24, H, 3.59, N, 5.25, S, 12.01

Experimental Value: C, 38.11, H, 3.51, N, 5.25, S, 11.80

Example 4

To a solution of 1.08 g of 2,2,2-trichloroethyl-2-methyl-2-bromomethyl-6- (2-phenylacet amido) phenam-3-carboxylate in 10 ml of dimethylformamide, 1.8-diazabicyclo [5,4,0] undecene-7 (360 mg) is added while cooling at 60 ° C. and stirred at the same temperature for 1 hour.

The internal temperature of the reaction mixture was raised to -10 ° C.

The mixture is washed sequentially with ethyl acetate, dilute phosphoric acid, water, saturated aqueous sodium bicarbonate solution and water, treated with activated charcoal and dried over magnesium sulfate. The residue obtained after removing the solvent was purified by column chromatography on silica gel using chloroform as a developing solvent.

360 mg of 2,2,2-trichlorethyl-2-methyl-2,3-methylene-6- (2-phenylacetamido) phenam-3-carboxylate is obtained (melting point: 140 ° -143 ° C).

Example 5

2,2,2-trichloroethyl-2-bromomethyl-2-methyl-6- [2-4,2,5-thiadizol-3-yl) aceramido) in 6 ml of dimethylformamide) 1,8-diazabicyclo [5,4,0] undecene in 2 ml of dimethylformamide with cooling and stirring at a solution of 0.57 g of phenam-3-carboxylate-1-β-oxide at -45-50 ° C A solution of -7 (0.617 g) was added dropwise over 15 hours, and the reaction temperature was gradually raised to -15 ° C over 1.5 hours. After the reaction, the mixture was poured into a mixture of 15 ml of ethyl acetate, 15 ml of cold water, and 1 ml of 10% hydrochloric acid, and extracted with ethyl acetate. The extract is washed twice with 10 ml of 3% hydrochloric acid, twice with 10 ml of saturated aqueous sodium chloride solution and then dried over magnesium sulfate.

After drying, the solution was treated with activated carbon, the solvent was distilled off, and the obtained rubbery material was triturated with a mixture of ether and n-hexane to give 2,2,2-trichloroethyl-2-methyl-2,3- 0.31 g of methylene-6- [2- (1,2,5-thiadiazol-3-yl) -acetamido] phenam-3-carboxylate-1-β-oxide is obtained.

Infrared absorption spectrum (new sol)

3,350, 1,790, 1,747, 1680 cm ^-1

Example 6

2,2,2-trichloroethyl-2-bromomethyl-2-methyl-6- (2-methylthioacetamido) phenam-3-carboxylate-1-β-oxide in 5 ml of dimethylformaamide To 0.53 g of solution was cooled at -50 DEG C, and while stirring, a solution of 1,8-diazabicyclo undecene-7 (0.17 g) in 2 ml of dimethylformamide was added dropwise at least 3 minutes. The reaction temperature is gradually raised to -10 ° C over 2 hours. A mixture of 30 ml of ethyl acetate, 30 ml of cold water and 1 ml of 10% hydrochloric acid is added immediately to the reaction mixture, the solution is sufficiently stirred, treated with activated charcoal, and the ethyl acetate layer is separated. The ethyl acetate layer was washed twice with 20 ml of 3% hydrochloric acid, washed twice with 20 ml of saturated aqueous sodium chloride solution in turn, dried over magnesium sulfate, the solvent was distilled off and treated with activated charcoal, and the obtained residue was obtained as a mixture of ether and n-hexane. After washing, 0.33 g of 2,2,2-trichlorethyl-2-methyl-2,3-methylene-6- (2-methylthioacetamido) penam-3-carboxylate-1-β-oxide Get (Melting point: 169-170 ℃)

Example 7

2,2,2-trichloroethyl-2-bromomethyl-2-methyl-6- (2-phenoxyacetamido) penam-3-carboxylate-1-β- in 60 ml of anhydrous dimethylformamide To a solution of 5.58 g of oxide, 1,8-diazabicyclo [5,4,0] undecene-7 (1.78 g) was added dropwise for 5 minutes with cooling and stirring at -455 to -50 ° C, and the mixture was 3.7 hours. Stir while. After the reaction was completed, the reaction mixture was poured into a mixture of 100 ml of ethyl acetate and 100 ml of cold water, the ethyl acetate layer was separated, and the aqueous layer was extracted twice with ethyl acetate.

The combined extracts were washed sequentially with dilute hydrochloric acid, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution and then dried over magnesium sulfate. After drying, the solution is treated with activated carbon and the solvent is removed. The obtained oily substance was purified by column chromatography on silica gel using chloroform as a developing solvent, and purified by oil chromatography in 2,2,2-trichlorethyl-2-methyl-2,3-methylene-6- (2-phenoxy Cyacetamido) penam-3-carboxylate-1-β-oxide 3.Og is obtained.

Infrared absorption spectrum (chloroform)

3,350, 1,800, 1,750, 1,687 cm ^-1

The following compounds were obtained using the same method described above in Examples (1)-(7).

(1) 2,2,2-trichloroethyl-2-methyl-2,3-methylene-6- [2- (1-tetrazol-1-yl) acetamido] penam-3-carboxylate ( Melting Point: 133-137 ℃)

(2) 2,2,2-trichlorethyl-2-ethyl-2,3-methylene-6- (2-thienyl) acetamido-fel am-3- carboxylate (melting point: 141-145 ° C) )

(3) 2,2,2-trichloroethyl-2-methyl-2,3-methylene-6- (3-phenylurate) phenam-3-carboxylate (melting point: 153.5-155 ° C)

(4) 2,2,2-trichloroethyl-2-methyl-2,3-methylene-6- [2-phenyl-2- (2-chlorophenoxy) acetamido] penam-3-carboxylate , oil

(5) 2,2,2-trichloroethyl-2-methyl-2,3-methylene-6- (2-phenyl-2-formyloxyacetamido) penam-3-carboxylate, oil

(6) 2,2,2-trichloroethyl-2-methyl-2,3-methylene-6- [2- (1,3,4-thiadiazol-2-ylthio) acetamido] penam- 3-carboxylate, oil

(7) 2,2,2-trichloroethyl-2-methyl-2,3-methylene-6- [2- (5-chloro-1-benzotriazol-1-yl) acetamido] penam-3 Carboxylate (melting point: 164-166 ° C)

(8) 2,2,2-trichloroethyl-2-methyl-2,3-methylene-6- (2-methylthioacetamido) phenam-3-carboxylate, oil

(9) 2,2,2-trichloroethyl-2-methyl-2,3-methylene-6- (1-cyclopropylethoxy) carbonylaminophenam-2-carboxylate, oil

(10) 2,2,2-trichlorethyl-2-methyl-2,3-methylene-6- [N- (1-cyclopropylethoxy) carbonylphenylglycidyl] aminophenam-3-carboxyl Late, amorphous

(11) 2,2,2-trichloroethyl-2-methyl-2,3-methylene-6- [3- (2-chlorophenyl) -5-ethylisoxazole-4-carbonamido) penam -3-carboxylate, foam

(12) 2,2,2-trichloroethyl-2-methyl-2,3-methylene-6-phenylglyoxysilamido penam-3-carboxylate (melting point 132-133 ° C)

(13) 2,2,2-trichloroethyl-2-methyl-2,3-methylene-6- (phenylthio) carbonylamino phenam-3-carboxylate (melting point: 121 ° C)

(14) 2,2,2-trichloroethyl-2-methyl-2,3-methylene-6- (4-acetamido benzenesulfonamide) penam-3-carboxylate (melting point: 193-198 ° C) )

(15) 2-methyl-2,3-methylene-6- (2-phenylacetamido) phenam-3-carboxylic acid (melting point: 112-118 ° C: decomposition)

(16) 2-Methyl-2,3-methylene-6- [2- (1-tetrazol-1-yl) -acetamido] phenam-3-carboxylic acid (melting point: 167-170 ° C: decomposition)

(17) 2-methyl-2,3-methylene-6- [2- (2-thienyl) acetamido] penam-3-carboxylic acid (melting point: 106-108 ° C: decomposition)

(18) 2-methyl-2,3-methylene-6- (3-phenylureido) phenam-3-carboxylic acid (melting point: 108-110 ° C: decomposition)

(19) N, N'-dibenzyl ethylenediamine of 2-methyl-2,3-methylene-6- [2-phenyl-2- (2-chlorophenoxy) acetamido] phenam-3-carboxylic acid Salt (melting point: 107-110 ° C: decomposition)

(20) 2-methyl-2,3-methylene-6- (2-phenyl-2-phenyloxy acetamido) phenam-3-carboxylic acid, oil

(21) Natrium salt of 2-methyl-2,3-methylene-6- [2- (1,3,4-thiadiazol-2-ylthio) acetamido] phena-3-carboxylic acid ( Melting Point: 171-177 ℃)

(22) Natrium salt of 2-methyl-2,3-methylene-6- (2-methylthioacetamido) phenam-3-3-carboxylic acid (melting point: 178-181 ° C: decomposition)

(23) N, N'-dibenzylethylenediamine salt of 2-methyl-2,3-methylene-6- (1-cyclopropylethoxy) carbonylaminophenam-3-carboxylic acid, (melting point: 148- 149.5 ℃ Decomposition)

(24) 2-Methyl-2,3-methylene-6- [N- (1-cyclopropylethoxy) carbonylphenylglycyl] -aminophenam-3-carboxylic acid, amorphous

(25) 2-methyl-2,3-methylene-6- [3- (2-chlorophenyl) -5-methylisoxazole-4-carbonamido] N, N of phenam-3-carboxylic acid '-Dibenzylethylenediamine salt (melting point: 97-100 ° C: decomposition)

(26) Natrium salt of 2-methyl-2,3-methylene-6- (2-hydroxy-2-phenylacetamido) phenam-3-carboxylic acid (melting point: 180-190 ° C: decomposition)

(27) 2-methyl-2,3-methylene-6- (2-phenyl-2-carbamoylhydrazonoacetamido) phenam-3-carboxylic acid (melting point: 198-199 ° C: decomposition)

(28) 2-Methyl-2,3-methylene-6- [1- (4-chlorophenyl) imino-1-acetylthiomethyl] aminophenam-3-carboxylic acid (melting point: 147-150 ° C: decomposition) )

(29) 2-methyl-2,3-methylene-6- (phenylthio) carbonylaminophenam-3-carboxylic acid, (melting point: 116-119 ° C: decomposition)

(30) 2-Methyl-2,3-methylene-6- (4-acetamido benzenesulfonamido) penam-3-carboxylic acid (melting point: 230 ° C: decomposition)

(31) 2,2,2-trichloroethyl-2-methyl-2,3-methylene-6- [2- (1H-tetrazol-1-yl) acetamido] penam-3-carboxylate- 1-β-oxide (melting point: 189-192 ° C: decomposition)

(32) 2,2,2-trichloroethyl-2-methyl-2,3-methylene-6- [2- (2-thienyl) acetamido] phenam-3-carboxylate-1-oxide ( Melting Point: 118.5-122 ℃: Decomposition)

(33) 2,2,2-trichloroethyl-2-methyl-2,3-methylene- (3-phenylureido) phenam-3-carboxylate-1-β-oxide (melting point: 167.5-169.5 ° C) )

(34) 2,2,2-trichloroethyl-2-methyl-2,3-methylene-6- [2-phenyl- (2-chlorophenoxy) acetamido] penam-3-carboxylate-1 Oxides, oils

(35) 2,2,2-trichloroethyl-2-methyl2,3-methylene-6- (2-phenyl-2-phenyloxyacetamido) penam-3-carboxytate-1-β-oxide (Melting point: 151.5-153.5 ° C)

(36) 2,2,2-trichloroethyl-2-methyl-2,3-methylene-6- [2- (1,3,4-thiadiazol-2-ylthio) acetamido] penam- 3-carboxylate-1-β-oxide, oil

(37) 2,2,2-trichloroethyl-2-methyl-2,3-methylene-6- [2- (5-chloro-1H-benzotriazol-1-yl) acetamido] penam-3 -Carboxytate-1-β-oxide (melting point: 145-149 ° C: decomposition)

(38) 2,2,2-trichloroethyl-2-methyl-2,3-methylene-6- (2-methylthioacetama) penam-3-carboxytate-1-β-oxide (melting point: 177 ℃)

(39) 2,2,2-trichloroethyl-2-methyl-2,3-methylene-6- [3- (4-chlorophenyl) thiouteido] penam-3-carboxylate-1-β Oxide (melting point: 180-190 ° C: decomposition)

(40) 2,2,2-trichloroethyl-2-methyl-2,3-methylene-6- (1-cyclopropylethoxy) -carbonylaminophenam-3-carboxylate-1-β-oxide , oil

(41) 2,2,2-trichloroethyl-2-methyl-2,3-methylene-6- [N- (1-cyclopropylethoxy) -carbonylphenylglycine] amino penam-3-carboxylate -1-β-oxide, foam

(42) 2,2,2-trichloroethyl-2-methyl-2,3-methylene-6- [3- (2-chlorophenyl) -5-methylisoxazole-4-carbonamido] penam -3-carboxylate-1-β-oxide, amorphous

(43) 2,2,2-trichloroethyl-2-methyl-2,3-methylene-6-phenylglyoxylamidophenam-3-carboxylate-1-β-oxide (melting point: 175-176 ° C) : Disassemble)

(44) Tylenediamine salt in N, N'-dibenzyl of 2-methyl-2,3-methylene-6-phthalimido penam-3-carboxylic acid (melting point: 181-182 ° C: decomposition)

(45) 2,2,2-trichloroethyl-2-methyl2,3-methylene-6- (phenylthio) -carbonylamino phenam-3-carboxylate-1-β-oxide (melting point: 171.5- 172.5 ℃)

(46) 2,2,2-trichloroethyl-2-methyl-2,3-methylene-6- (4-acetamido benzenesulfonamido) penam-3-carboxylate-1-β-oxide ( Melting Point: 149-153 ℃)

(47) 2-Methyl-2,3-methylene-6-aminophenam-3-carboxylic acid (melting point: 200 ° C: decomposition)

(48) 2-Methyl-2,3-methylene-6- (2-phenylglycyl) aminophenam-3-carboxylic acid (melting point: 200-202 ° C: decomposition)

(49) 2,2,2-trichloroethyl-2-methyl-2,3-methylene-6- (2-phenyl-2-carbamohydrazonoacetamido) penam-3-carboxylate (melting point) : 200-201 ℃: Decomposition)

(50) 2,2,2-trichloroethyl-2-methyl-2,3-methylene-6- [1- (4-chlorophenyl) imino-1-acetylthiomethyl] aminophenam-3-carboxyl Late, amorphous

(51) Methyl-2-methyl-2,3-methylene-6- (2-phenoxyacetamido) phenam-3-carboxylate-1-β-oxide (melting point: 133-137 ° C: decomposition)

[reaction]

Example 1

A solution of 1.88 g of 2-methyl-2,3-methylene-6- [N- (1-cyclopropylethoxy) carbonyl-2-phenylglycyl] aminophenam-3-carboxylic acid in 10 ml of formic acid was added for 1 hour. Is stirred at room temperature and the solvent is removed under reduced pressure at room temperature. The residue is triturated by adding ether and filtered. The powder was added to a mixture of 10 ml of acetonitrile and 1 ml of water. The precipitates were collected by filtration, washed with acetonitrile and dried. -0.89 g of carboxylic acids (melting point: 200-202 ° C: decomposition) are obtained.

Analysis: C ₁₆ H ₁₇ N ₃ 0 ₄ S 1/2 H ₂ O

Calculated Value: C, 54.01 H, 5.08 N, 11.80 S, 9.01

Experimental Value: C, 54.09 H, 4.80 N, 11.46 S, 9.24

Infrared absorption spectrum (new sol)

3,350, 1,780, 1,694, 1,520cm ^-1

2-Methyl-2,3-methylene-6- (N- (1-cyclofurophylethoxy) carbonyl-2-phenylglyciyl] in the above-described example] 2-instead of amino phenam-3-carboxylic acid The same result is obtained when using methyl-2,3-methylene-6- [N- (3-butoxycarbonyl) -2-phenylglycyl] aminophenam-3-carboxylic acid.

[reaction]

Example 1

1 N to pH 7-8 in a solution of 1.1 g of 2-methyl-2,3-methylene-6- (2-phenyl-2-formyloxyacetamido) penam-3-carboxylic acid in 10 ml of methanol and 7 ml of water. An aqueous solution of potassium hydroxide is added dropwise and stirred at room temperature for 10 hours. After completion of the reaction, methanol was distilled off under reduced pressure, and the remaining solution was made acidic by adding 1N hydrochloric acid, and then extracted with ethyl acetate. The solvent was removed under reduced pressure, and powdered by addition of N-hexane, 0.4 g of 2-methyl-2,3-methylene-6- (2-phenyl-2-hydroxyacetamido) phenam-3-carboxylic acid was added. Get

Infrared Absorption Spectrum (Film)

1,785, 1,720, 1,660 cm ^-1

[reaction]

Example 1

2,2,2- in a mixture of 3 ml of dimethylformamide and 1 ml of acetic acid

0.7 g of zinc powder was added to a solution of 517 mg of trichloroethyl-2-methyl-2,3-methylene-6- (2-phenylacetamide) phenam-3-carboxylate under ice-cooling and stirred at the same temperature for 1 hour. The zinc powder is then filtered off and washed twice with 2 ml of dimethyl formamide. The filtrates are combined as washes and the combined solution is poured into a cooled, mixed solution of ethyl acetate and water, extracted with ethyl acetate and the extract is washed with water and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and thus, 390 mg of the obtained crystalline substance was washed with ether and dried to give 2-methyl-2,3-methylene-6- (2-phenylacetamide) phenam-3- carboxylic acid as colorless crystals. Get 310 mg. (Melting point 112-118 ° C: decomposition)

Infrared absorption spectrum (new sol)

3,300, 1,763, 1,722, 1,665 cm ^-1

Example 2

2,2,2-trichloroethyl-2-methyl-2,3-methylene-6 [2- (1H-tetrazol-1-yl) acetamido] in a mixture of 5 ml of dimethyl formamide and 1.5 ml of acetic acid To a solution of 0.91 g of phen-3--3-carboxylate, 1.2 g of zinc powder is added under ice-cooling, and the mixture is stirred for 1 hour. After the reaction was completed, the reaction mixture was added to a mixture of 2% hydrochloric acid saturated with 30 ml of sodium chloride and 50 ml of ethyl acetate, extracted, and the aqueous layer was further extracted with 10 ml of ethyl acetate.

The combined ethyl acetate layers were washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was crystallized by adding a small amount of ethyl acetate, and the crystals were collected by filtration. 0.45 g of, 3-methylene-6- [2- (1H-tetrazol-1-yl) acetamido] phenam-3-carboxylic acid is obtained.

(Melting point 167-170 ° C: decomposition)

Infrared absorption spectrum (new sol)

3,250, 1,775, 1,740, 1,700 cm ^-1

Example 3

2,2,2-trichloroethyl-2-methyl-2,3-methylene-6- [2- (2-thienyl) acet amido) penam- in a mixture of 7.5 ml of dimethyl formamide and 1.75 ml of acetic acid To a 1.4 g solution of 3-carboxylate, 1.8 g of zinc powder is added under ice-cooling, and the mixture is stirred for 1 hour. After the reaction was completed, the reaction mixture was worked up in the same manner as described above in Example (1) to give 2-methyl-2,3-methylene-6- [2 (2-thienyl) acetamido] phen-3 -0.8 carboxylic acids are obtained. (Melting point 106-108 ℃ decomposition)

Infrared absorption spectrum (new sol)

3,350, 1,765, 1,720cm ^-1

Example 4

2.3 ml of acetic acid in a solution of 1.12 g of 2,2,2-trichloromethyl-2-methyl-2,3-methylene-6- (3-phenylureido) phenam-3-capoxylate in 7.5 ml of dimethyl formamide 1.8 g of zinc powder was added under ice cooling, the mixture was stirred for 1 hour. After completion of the reaction, the reaction mixture was worked up in the same manner as described in Synthesis Example 1, and ethyl acetate was distilled off to remove a small amount of the residue. Crystallization by addition of acetonitrile yields 0.72 g of colorless crystals of 2-methyl-2,3-methylene-6- (3-phenylureido) phenam-3-carboxic acid. (Melting point 108-110 ° C).

Infrared Absorption Spectrum (Newsol)

3,350, 3,300, 1,765, 1,710, 1,665 cm ^-1

Example 5

2,2,2-Trichloroethyl-2-methyl-2,3-methylene-6- [2-phenyl-2- (2-chlorophenoxy) acetami in a mixture of 5 ml of dimethyl formamide and 1.5 ml of acetic acid 1.2 g of zinc powder was added to a solution of phenam-3-carboxylate 1.18 under ice-cooling, the mixture was stirred for 1.5 hours, and after the reaction was completed, the reaction mixture was worked up in the same manner as described in Example (1). The obtained residue was dissolved in 2 ml of methanol, and a solution of 0.20 g of N, N'-dibenzylethylenediaminediacelate in 10 ml of water was added to the solution. The crystals obtained in this way were dissolved in methanol and reprecipitated as water to give 2-methyl-2,3-methylene-6- [2-phenyl-2- (2-chlorophenoxy) acetamido) phenam-3- N, N'-dibenzylethylenediamine salt of 0.55 g of carboxylic acid is obtained. (Melting point 107-110 ° C)

Infrared absorption spectrum (new sol)

1,785 1,690 cm ^-1

Example 6

1.52 g of 2,2,2-trichloroethyl-2-methyl-2,3-methylene-6- (2-phenyl-2-phenyloxyacetamido) penam-3-carboxylate in 7.5 ml of dimethyl formamide To the solution of was added 2.3 ml of acetic acid, 1.8 g of zinc powder was added under ice-cooling and the mixture was stirred for 1 hour. After completion of the reaction, the reaction mixture was worked up in the same manner as described in Example (1) and distilled with ethyl acetate. 1.1 g of 2-methyl-2,3-methylene-6- (2-phenyl-2-portyloxyacetamido) phenam-3- carboxylic acid in oily form is obtained.

Infrared Absorption Spectrum (Film)

1,785, 1,720 cm ^-1

Example 7

2,2,2-trichloroethyl-2-methyl-2,3-methylene-6- [2- (1,3,4-thiadiazole-2) in a mixture of 12.5 ml of dimethyl formamide and 3.8 ml of acetic acid -Ylthio) acetamido] To a solution of 2.5 g of penam-3-carboxylate, 3 g of zinc powder was added under ice-cooling. When the reaction was completed after stirring for 1 hour, the oily material obtained by working up in the same manner as in Example (1) and distilling with ethyl acetate was used as a sodium salt by a conventional method. Sodium-2-methyl-2, 0.6 g (melting point 171-177 ° C: decomposition) of 3-methylene-6- [2- (1,3,4-thiadiazol-2-ylthio) acetamido] phenam-3-carboxylate is obtained. Infrared absorption spectrum (new sol)

1,790, 1,670, 1,590cm ^-1

Example 8

2,2,2-trichloroethyl-2-methyl-2,3-methylene-6- (2-methylthioacet amido) penam-3-carboxyl in a mixed solution of 5 ml of dimethyl formamide and 1.5 ml of acetic acid 1.2 g of zinc powder is added to 0.9 g of the late solution under ice-cooling, followed by stirring for 1 hour. After the reaction was completed, the zinc powder was filtered off, and the filtrate was poured into a mixture of 20 ml of ice water containing 20 ml of ethyl acetate and 2 ml of 10% hydrochloric acid. The ethyl acetate layer is separated and the aqueous layer is further extracted with 10 ml of ethyl acetate. The combined ethyl acetate layers are washed sequentially with water and saturated aqueous sodium chloride solution and dried over magnesium sulfate. When the residue obtained by removing the solvent after drying was used as a sodium salt by a conventional method, sodium 2-methyl-2,3-methylene-6- (2-methylthio acetamido) penam-carboxylate 0.63 g (melting point 178) -181 ° C: decomposition) is obtained.

Infrared Absorption Spectrum (KBr Tablet)

1,775, 1,665, 1,610cm ^-1

Example 9

A solution of 1.78 g of 2,2,2-trichloroethyl-2-methyl-2,3-methylene-6- (1-cyclofurophylethoxy) carbonyl amino phenam-3-carboxylate in 10 ml of dimethyl formamide 3 ml of acetic acid and 2.4 g of zinc powder are added to the mixture, and the mixture is stirred for 1 hour. The zinc powder is filtered off, washed with dimethyl formamide and the wash and filtrate are poured into a mixture of ethyl acetate and ice water. The solution was adjusted to pH 2 with 10% hydrochloric acid and extracted. The extract was washed with water, brought to pH 7 with sodium bicarbonate, then acidified with 10% hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, and the solvent was removed under reduced pressure to obtain amorphous carboxylic acid 840. The acid was dissolved in methanol, NN'-dibenzylethylene diaminediacelate aqueous solution was added to this solution, and after precipitation, it was collected by filtration, dried and 2-methyl-2,3-methylene-6- (1-cyclofuro). The NN'-dibenzylethylenediamine salt (melting point 148-1 49.5 degreeC: decomposition | disassembly) of piethoxy) -carbonyl aminophenam-3-carboxylic acid is obtained.

Infrared absorption spectrum (new sol)

3,210, 1,770, 1,715, 1,605 cm ^-1

Example 10

2,2,2-trichloroethyl-2-methyl-2,3-methylene-6- [N- (1-cyclofurophylethoxy) carbonylphenylglycyl] amino penam-3-carboxylate 3.66 g Was treated in a similar manner to the method of Example (9) above and the reaction mixture was filtered. The filtrate is poured into a mixture of ethyl acetate and ice-cold 2% hydrochloric acid and extracted to separate the ethyl acetate layer. The extract was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, and then the solvent was removed. Then, amorphous 2-methyl-2,3-methylene-6N-[-(1-cyclofurophylethoxy) carbonylphenylglycile] aminophen 3.04 g of dark-3-carboxylic acid is obtained.

Infrared Absorption Spectrum (Newsle)

3,290, 1,790, 1,720, 1,710, 1670 cm ^-1

Example 11

2,2,2-trichloroethyl-2-methyl2,3-methylene-6- [3- (2-chlorophenyl) -5-methylisoxazole-4-carboxamido "penam-3-carboxyl 2 g of rate was treated in a similar manner to Example (10) above and 2-methyl-2,3-methyl-6-3- (2-enechlorophenyl) -5-methylisoxazole-4-carboxamido 1.31 g of penam-3-carboxylic acid are obtained. This carboxylic acid was converted to the N, N'-dibenzylethylenediamine salt with NN'-dibenzylethylenediaminediacetate, resulting in 2-methyl-2,3-methylene-6- [3- (2-chlorophenyl) -5-methylisoxazole-4-carboxamido] The N, N'-dibenzylethylenediamine salt of phenam-3-carboxylic acid is obtained. (Melting point, 97-100 ° C .: decomposition)

Infrared absorption spectrum (new sol)

3,400, 1,785, 1,670, 1,603, 1,510cm ^-1

Example 12

2.3 ml of acetic acid and zinc were ice-cooled in a solution of 2,2,2-trichloroethyl-2-methyl-2,3-methylene-6-phenylglycilamamidophenam-3-carboxylate 1.44 in 10 ml of dimethyl formamide. 2.25 g of powder is added and stirred for 1 hour. After the completion of the reaction, the zinc powder is filtered off and the filtrate is added to a mixed solution of ethyl acetate and dilute hydrochloric acid.

After extraction, the extract is extracted with aqueous sodium bicarbonate solution, made acidic with hydrochloric acid, extracted with ethyl acetate, washed with water and dried over magnesium sulfate. After drying, the solvent is distilled off under reduced pressure to obtain 790 mg of amorphous 2-methyl-2,3-methylene-6-phenylglyoxyl amidophenam-3-carboxylic acid. 346 mg of this compound was dissolved in 1 ml of acetone, an acetone solution containing 138 mg of sodium-2-ethylhexaneate was added to the solution, and ether was added to the resulting precipitate, which was collected by filtration and washed with ether. 250 mg of (3-Methylene-2-hydroxy-2-phenylacet amido penam-3-carboxylate (melting point 180-190 ° C: decomposition) are obtained.

Infrared Absorption Spectrum (KBr Tablet)

3,400, 1,770, 1,670, 1,605 cm ^-1

Example 13

560 mg of 2,2,2-trichloroethyl-2-methyl-2,3methyl-6- [2-phenyl-2-carbamoylhydrozono acetamido) phen-3--3-carboxylate in 3 ml of dimethyl formamide To the solution of 0.8 ml of acetic acid and 0.75 g of zinc powder were added under ice-cooling, and stirred for 1.5 hours. The zinc powder was removed by filtration, washed with dimethyl formamide, the filtrate and the washing solution were combined, poured into ice water and the filtrate was adjusted to pH 2 with 10% hydrochloric acid. The precipitated crystals were filtered and washed with ethyl acetate Dissolved in. The insoluble matter was filtered off and the filtrate was acidified with 10% hydrochloric acid to give 2-methyl-2,3-methylene-6- (2-phenyl-2-carbamoyl hydranozoacetamido) penam-3-carr 270 mg of acid (melting point 198-199 ° C .: decomposition) are obtained.

Infrared absorption spectrum (new sol)

3,260, 1,763, 1,710, 1,692, 1,650cm ^-1

Example 14

2 ml of acetic acid was added 2,2,2-trichloroethyl-2-methyl-2,3-methylene-6- [1- (4-chlorophenyl) imino-1-acetyl thiomethyl] aminophenam-3-carboxyl 1.05 g of the rate was added to a solution dissolved in 5 ml of dimethyl formamide.

2 g of zinc powder was added thereto at -5 to 8 ° C., stirred for 1 hour at the same temperature. After the reaction was completed, the zinc powder was filtered off, poured into a cooled mixture of ethyl acetate and hydrochloric acid, and extracted. The extract is washed with water and dried over magnesium sulfate, and then the solvent is distilled off under reduced pressure. 770 mg of the obtained amorphous compound was crystallized by adding acetonitrile. The crystals were washed with acetonitrile and the crystals obtained by washing with water were combined to form 2-methyl-2,3-methylene-6- [1- (4-chlorophenyl) imino-1- Acetylthio methyl] 510 mg of amino penam-3-carboxylic acid (melting point 147-150 ° C .: decomposition) are obtained.

Infrared absorption spectrum (new sol)

3,120, 1,802, 1,703, 1,683 cm ^-1

Example 15

2,2,2-trichloroethyl-2-methyl-2,3-methylene-6- (phenylthio) carbonylamino penam-3-carboxylate 1.04 in a mixed solution of 7 ml of dimethyl formamide and 2.2 ml of acetic acid 1.8 g of zinc powder was added to the solution of g under ice-cooling and stirred for 1.5 hours. After the completion of the reaction, the zinc powder was filtered off, and the filtrate was poured into a mixture of 30 ml of ice water containing 30 ml of ethyl acetate and 2 ml of 2% hydrochloric acid. After extraction, the aqueous layer was further extracted with 10 ml of ethyl acetate, and the combined extracts were washed sequentially with water and saturated aqueous sodium chloride solution, dried over magnesium sulfate, and the solvent was removed under reduced pressure. The obtained residue was crystallized by adding a small amount of acetonitrile to obtain 0.48 g of 2-methyl-2,3-methylene-6- (phenylthio) carbonylaminophenam-3-carboxylic acid (melting point 116-119 ° C: decomposition). .

Analysis: C ₁₅ H ₁₄ N ₂ O ₄ S ₂

Calculated C: 51.42 H: 4.03 N: 7.73

Experimental value C: 51.16 H: 3.94 N: 8.02

Example 16

2,2,2-trichloroethyl-2-methyl-2,3-methylene-6- (4-acetamidobenzenesulfonamido) phenam-3-carboxylate 1.09 g, acetic acid 1.5 ml and zinc powder 1.2 g was crystallized using the residue ethyl acetate obtained by treating in a similar manner as in Example (1) above to 2-methyl-2,3-methylene-6- (4-acetamido benzene sulfone amido) penam- 0.5 g (melting point 230 ° C .: decomposition) of 3-carboxylic acid is obtained.

Example 17

2,2,2-trichloroethyl-2-methyl2,3-methylene-6- [2- (5-chlorobenzotriazol-1-yl) acetamide in a mixture of 5 ml of dimethyl formamide and 1.5 ml of acetic acid 1.2 g of zinc powder is added to a solution of 1.04 g of penam-3-carboxylate under ice-cooling.

After the reaction was completed, the zinc powder was filtered, and the filtrate was poured into a mixed solution of 20 ml of ice water containing 20 ml of 10% hydrochloric acid and 20 ml of ethyl acetate, followed by extraction. The ethyl acetate layer is washed sequentially with water and saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was removed from the reduced pressure, the residue was dissolved in a small amount of acetone, and then converted into its sodium salt by addition of an acetone solution of sodium ethyl hexanate to give sodium-2-methyl-2,3-methylene-6- [2 0.43 g of-(5-chlorobenzotriazol-1-yl) acetamido) phenam-3-carboxylate (melting point 230 ° C: decomposition) is obtained.

The following compounds were produced using the same method as in 17 in Example 1.

(1) NN'-dibenzylethylenediamine salt of 2-methyl-2,3-methylene-6-phthalimido penam-3-carboxylic acid (melting point 181-182 °: decomposition)

(2) 2-methyl-2,3-methylene-6-aminophenam-3-carboxylic acid melting point 200 deg.

(3) 2-methyl-2,3-methylene-6- (2-phenylglycyl) amino phenam-3-carboxylic acid (melting point 200-202 ° C. decomposition)

Claims (1)

A method for preparing a new compound of formula (I) by reacting a compound of formula (II) with a base.

In the above formula R ¹ is amino or substituted amino R ² is carboxy or protective carboxy R ³ is lower alkyl R ⁴ is lower alkylene

Y is a residue of the acid.