KR790001542B1 - Process for preparing 2,3-low alkylene penam-3-carbox-vlic acid derivatives - Google Patents

Abstract

The title compds. I (R2 = carboxyl or protected carboxyl, R3 = lower alkyl, R4 = lower alkylene, X = S, SO) were prepd. by removing the protecting group from II (Rla = protected aminoacyl, R2,R3,R4,X = given). II in HCOH was stirred for 1.5hr at room temp. 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 are particularly antimicrobial, useful as intermediates, and become pharmaceutical preparations.

Another object of the present invention is an intermediate between 2,3-lower alkylene phenam-3-carboxylic acid derivatives, which are effective antibacterial agents for the improvement of pictures such as staphylococci and bacilli, and 3-cepam-4-carboxylic acid derivatives, which are antibacterial agents. To provide a substance.

The 2,3-loweralkylene phenam-3-carboxylic acid derivatives are new compounds with new and useful chemical structures that were not predictable by conventional techniques, such as the following structural formula (I).

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,

이다.X is -S-,

to be.

According to the present invention, the 2,3-lower alkylene phenam-3-carboxylic acid derivatives are prepared by various methods, and the general formulas of the preparation methods (II)-(I) are collectively illustrated as follows. .

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

이며X is -S-,

And

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.

Methyl-2-acetoxymethyl-2-methyl-6- (2-tenoxyacetamide) phenam-3-carboxylate and benzyl-2-acetoxy methyl-2-methyl-6 in starting material (II) -(2-phenoxyacetamido) phenam-3-carboxylate is prepared according to U.S. Patent 3, 466, 275 and other starting materials are corresponding 2-oxo-3-amino (or substituted amino) -4- Reacts with substituted amino (or substituted thio) -substituted thio-1-acetidine-α- (1-alkyl vinyl) acetates or their derivatives in carboxy and corresponding condensing agents which may introduce residues such as hydrogen chloride It is prepared by making.

As used herein, “substituted amino” in R ¹ refers to hydrazino, mono (di)-(lower) alkylamino, mono (di)-(lower) alkenylamino, loweralkylideneamino, al (lower) alkyl By edenamino, 1-substituted or unsubstituted arylamino-1-acylthiomethylamino, acylamino, acyl groups rather than appropriately substituted amino groups such as amino groups substituted by other aminoprotecting groups.

Suitable lower alkyl groups in the mono (di) lower alkylamino in the above-mentioned appropriately substituted amino group mean methyl, ethyl, propofyl, isofurophyll, butyl and the like, and suitable lower alkenyl groups in the mono (di) lower alkenylamine Aryl, 2-butenyl, and the like, and suitable alkylidene in alkylideneamino refers to ethylidene, furophylidene, butylidene and the like, and suitable egg (lower) in al (lower) alkylidene. Alkylidene means benzylidene, phenethylidene and the like, and the appropriate acyl group among acylamino groups means carbamoyl, aliphatic acyl groups and acyl groups containing aromatic or heterocyclic groups. I will explain.

Suitable aliphatic acyl groups are, for example, lower alkanoyls (formyl, acetyl, furopionyl, butyryl, isobutyryl, valeryl, isovaleryl, oxaryl, succinyl, vivaroyl, etc.) Noil (octanoyl, lauroyl, palmitoyl, etc.), lower alkenoyl (acryloyl, crotonoyl, etc.), lower alkinoyl (such as propinoyl), lower or higher cycloalkencarbonyl (cyclopentene carbon) Carbonyl, cyclohexane carbonyl, cyclohaptencarbonyl, etc.), lower and higher cycloalkyl (lower) alkanoyls (cyclopentyl acetyl, cyclohexylacetyl, cycloheptylacetyl, cyclohexyl furopionyl, cycloheptyl furopionyl, etc.) Lower and higher aliphatic acyl groups such as lower and higher cycloalkadiene carbonyl (such as dihydrobenzoyl) and lower and higher cycloalkadieenyl (lower) alkanoyls (such as dihydrophenylacetyl and dihydrophenylfuropionyl). , And Higher alkoxy (lower) alkanoyl (methoxyacetyl, ethoxyacetyl, methoxy furopionyl, etc.), lower alkylthio (lower) alkanoyl (methylthioacetyl, ethylthio acetyl, methylthiofulopionyl); Etc.), lower alkenylthio (lower) alkanoyl (such as arylthioacetyl, arylthio furopionyl), lower or higher cycloalkylthio (lower) alkanoyl (cyclopentylthio acetyl, cyclohexylthio furopionyl, cyclo) Heptylthio acetyl, etc.), lower and higher cycloalkoxy (lower) alkanoin (cyclopentyloxyacetyl, cyclohexyloxylfulopionyl, etc.), lower and higher cycloalkenedenyloxy (lower) alkanoyl (dihydrophenoxy Acetyl, dihydrophenoxyfulopionyl, etc.), lower and higher cycloalkenedenyl thio (lower) alkanoyls (dihydrophenyl thioacetyl, dihydrophenylthio furiononyl, etc.), lower alkoxycarbonyl (methok Carbonyl, ethoxycarbonyl, propoxycarbonyl, 1-cyclofurophyll-ethoxycarbonyl, isopuroxycarbonyl, butoxycarbonyl, tertbutoxycarbonyl, etc.), lower and higher cycloalkyloxy Side chains and cyclic rings such as carbonyl (cyclopentyloxycarbonyl, cyclooxyxyloxyl carbonyl, cycloheptyl oxylcarbonyl, etc.), lower and higher cycloalkenedenyloxy carbonyl (dihydropentoxycarbonyl, etc.) Containing saturated or unsaturated lower or higher alkanoyl groups.

Suitable acyl groups containing aromatic rings, such as benzene and naphthalene, are for example arylcarbamoyl (such as phenyl carbamoyl), aryl oils (benzoyl, toluoyl, nafutoyl, α-methylnafutoyl, putaroyl, Benzenesulfonyl, tetrahydronafutoyl, indancarbonyl, etc.), al (lower) alkanoyl (phenylacetyl, phenylfulopionyl, phenylbutyryl, tolylacetyl, xylylacetyl, naphthylacetel, tetrahydronaphthyl Acetyl, indanylacetyl, etc.), and carbon atoms of the alkyl group in the above-mentioned al (lower) alkanoyl group include allyloxy (lower) alkanoyl (phenoxyacetyl, tenoxyfulopionyl, phenoxybutyryl) , Xyloxyoxyacetyl, etc.), aryloxycarbonyl (phenoxycarbonyl, xyloxycarbonyl, naphthyloxycarbonyl, indanyloxycarbonyl, etc.), al (lower) alkoxycarbonyl (benzyloxycarbonyl , Phenethyloxycarbonyl, etc.), arylthio You may replace with lower oxygen, a sulfur atom, or carbonyl like (lower) alkanoyl (phenylthioacetyl, phenylthio furiononyl, etc.), arylglyoxyloyl (panylglyoxyloyl, etc.).

Suitable acyl groups containing a heterocyclic ring include heterocyclic carbonyl or heterocyclic lower alkanoyl, and for heterocyclic carbonyl or heterocyclic lower alkanoyl, the heterocyclic ring refers to a saturated or unsaturated monocyclic or polycyclic ring; , Containing at least one heteroatom such as oxygen, sulfur or nitrogen atoms, for example: That is, unsaturated 3-8 gasocyclic ring containing sulfur atom (thienyl etc.), unsaturated condensation heterocyclic ring containing sulfur atom (benzothienyl etc.), unsaturated 3-8 gasocyclic heterocyclic ring containing oxygen atom (Furyl, 2 (4) pyranyl, 5, 6-dihydro-2H-pyran-3-yl, etc.), unsaturated 3-8 stomach heterocyclic containing 1-4 modifying atom (pyrrolyl, 2 (3) H-pyrrolyl , 2 (3) -pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, 1H-tetrazolyl, 2H-tetrazolyl, etc.), containing 1-2 nitrogen atoms One saturated 3-8 gasocyclic ring (pyrrolidinyl, imidazolidinyl, piperidino, piperidinyl, etc.), unsaturated condensed heterocyclic ring containing 1-3 nitrogen atoms (indolyl, isoindoleyl, benzyl) Imidazolyl, quinolyl, isoquinolyl, 1 (2) H-indazolyl, 1 (2) H-benzotriazolyl, etc.), unsaturated 3-8 stomach heterocycle containing 1-3 nitrogen and oxygen atoms Formulas (oxazolyl, isoxoxazolyl, oxadiazolyl, etc.), 1-2 Unsaturated 3-8 gasocyclic ring containing oxygen atoms and 1-2 nitrogen atoms (such as sidnoyl), unsaturated 3-8 gasocyclic ring containing sulfur and 1-3 nitrogen atoms (thiazolyl, thiadia) Jolyl, etc.), unsaturated condensed heterocyclic ring containing oxygen and 1-2 nitrogen atoms (benzoxazolyl, benzoxadiazolyl, etc.), unsaturated condensed heterocyclic ring containing sulfur and 1-2 nitrogen atoms ( Benzothiazolyl, benzothiadiazolyl, etc.), and as described above, the carbon atom of the lower alkyl group in the heterocyclic lower alkanoyl is heterocyclic lower alkoxycarbonyl, heterocyclic oxycarbonyl, heterocyclic oxy (lower) alkanoyl And oxygen atoms such as heterocyclic-thio- (lower) alkanoyl or sulfur atoms.

Furthermore, carbamoyl, aliphatic acyl as described above, and acyl groups containing aromatic or heterocyclic rings, lower alkyl (methyl, ethyl, furophyll, isofurophyll, etc.), lower alkenyl (1-furophenyl, allyl, etc.) Lower and higher cyclic alkyl (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 (chlorophenyl, bromophenyl, etc.) , Halophenoxy (chlorooxy, bromophenoxy, etc.), cyano, lower alkylsulfinyl (methylsulfinyl, ethylsulfinyl, etc.), lower alkensulfonyl (methanesulfonyl, ethanesulfonyl, etc.), lower Alkoxycarbonyl (lower) alkoxy (methoxycarbonylmethoxy, ethoxycarbonylethoxy, 1-cyclic furopropylethoxy carbonylmethoxy, tert-butoxide Cycarbonylmethoxy, etc.), nitro, sulfo, amino (azido, melcapto, carboxy, hydroxy, hydroxyamino, mono (di) alkylamino (mono (di) methylamino, mono (di) ethylamino, mono (Di) furophyllamino, mono (di) isofurophylamino, etc.).

As described above, when the acyl group has a functional group such as amino, hydroxymelcapto, carboxy, or the like, the functional group may be protected with an appropriate protecting group. Suitable protecting groups for amino groups are trityl, 2-nitrophenylthio, 2, 4-dinitrophenylthio, 2-hydroxybenzylidene, 2-hydroxy, 5-chlorobenzylidene, 2-hydroxy-1 Naphthylmethylene, 3-hydroxy-4-pyridylmethylene, 1-methoxycarbonyl-2-furopylidene, 1-ethoxycarbonyl-2-furopylidene, 3-ethoxycarbonyl-2 -Butylidene, 1-acetyl-2-furopylidene, 1-benzoyl-2-furopyridene, 1-benzoyl-2-furopylidene, 1- [N- (2-methoxyphenyl) carbamoyl] 2-furopilidene, 1- [N- (4-methoxyphenyl) carbamoyl] -2-furophilidene, 2-ethoxycarbonylcyclohexylidene, 2-ethoxycarbonylcyclopentyli Den, 2-acetylcyclohexylidene, 3, 3-dimethyl-5-oxo-cyclohexylidene, of which 1-methoxycarbonyl-2-furopylidene and 2-ethoxycarbonyl cyclohexylidene Groups replace 1-methoxycarbonyl-1-furopan-2-yl and 2-ethoxycarbonyl-1-cyclohexenyl groups with one another Turning good). It includes any of the conventional protecting groups such as other acyl groups or other groups than acyl groups such as monodisyryl and the like.

Suitable protecting groups for hydroxy or melcapto groups are hydroxy for other or acyl groups than acyl groups such as, for example, benzyl, trityl, methoxymethyl, 2-nitrophenylthio, 2, 4-dinitrophenylthio, etc. Or a conventional protecting group for a melcapto group. And suitable protecting groups for carboxyl groups are, for example, lower alkyl esters (methyl ester, ethyl ester, fluoropropyl ester, butyl ester, 1-cyclofurophil ethyl ester, tertiary butyl ester, etc.), mono (di, tri) halo ( Lower) alkyl esters (chloromethyl ester, 2, 2, 2-trichloroethyl ester, 3, 3-dibromo furopropyl ester, etc.), aryl esters (phenyl ester, nitrophenyl ester, indanyl ester, etc.) (Lower) alkyl ester (benzyl ester, diphenyl methyl ester, triphenyl methyl ester, P-nitrobenzyl ester, P-bromobenzyl ester, etc.), tri (lower) alkyl silyl ester (trimethyl silyl ester, triethyl silyl ester) Etc.) and any one of protecting groups.

Furthermore, for protecting amino groups other than the acyl groups described above of "substituted amino", they are described in the same manner as described for the protecting groups for amino groups in the acyl.

In particular, suitable examples of acyl groups are as follows.

(1) lower alkoxycarbonyl (methoxycarbonyl, ethoxycarbonyl, furoxycarbonyl, 1-cyclofurophylethoxycarbonyl, tertiary butoxycarbonyl, etc.)

(2) lower alkylthio (lower) alkanoyl (2-methylthioacetyl, 2-methylthiobutyryl, 2-ethylthioacetyl, 3-methylthiofulopionyl, etc.)

(3) lower alkenylthio (lower) alkanoyl (2-allylthioacetyl, 3-arylthiofulopionyl, etc.)

(4) cyano (lower) alkanoyl (2-cyanoacetyl, 3-cyanopropionyl, 4-cyanobutyryl, etc.)

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

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

(7) phenylcarbamoyl

(8) phenylglyoxyloyl

(9) phenylthiocarbonyl

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

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

(12) lower alkanoyl substituted with phenyl and lower alkoxycarbonylamino (N-methoxycarbonylphenylglysil, N-ethoxycarbonylphenylglysil, N- (1-cyclofurophylethoxy) carbonyl Phenylglycyl, N-tertiary butoxycarbonylphenylglysil, 2- (1-cyclofurophylethoxy) carbonylamino-3-phenylfulopionyl, etc.)

(13) lower alkanoyl substituted with phenyl and trihalo (lower) alkoxycarbonylamino (N-trichloroethoxycarbonylphenylglycyl, 3-trichloroethoxycarbonylamino-3-phenylfuropionyl , N-tribromoethoxycarbonylphenyl glycyl, 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) halophenylthiocarbamoyl (2- (3 or 4) -chlorophenylthiocarbamoyl, 2 (3 or 4) -chlorophenylthiocarbamoyl, 2- (3 or 4) -bromophenyl Thiocarbamoyl, etc.)

(17) Putaroyl

(18) lower alkanoylaminobenzenesulfonyl (2- (3 or 4) acet amidobenzenesulfonyl, 2 (3 or 4) propionylaminobenzenesulfonyl, etc.)

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

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

(21) Phenyl (lower) alkoxycarbonyl (benzyloxycarbonyl, phenethyloxycarbonyl, 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)

(23) lower alkanoyl (2-methoxycarbonylamino-2- [2- (3 or 4) hydroxyphenyl] acetyl, 2- (1-cyclofuro) substituted with hydroxylphenyl and lower alkoxycarbonylamino Philethoxy) carbonylamino-2- [2- (3 or 4) hydroxyphenyl] acetyl, 2-tertiary butoxycarbonylamino-2- [2- (3 or 4) hydroxyphenyl] acetyl, etc. )

(24) lower alkanoyls substituted with phenyl and sulfo (2-phenyl-2-sulfoacetyl, 3-phenyl-3-sulfopurionyl, 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-methoxycarbonylamino-2- [2- (3 or 4) methoxyphenyl] acetyl, 2- (1-cyclofuro) substituted with lower alkoxyphenyl and lower alkoxycarbonylamino Philethoxy) carbonylamino-2- [2- (3 or 4) methoxyphenyl] acetyl, 2-tertiary butoxycarbonylamino-2- [2- (3 or 4methoxyphenyl] acetyl, etc.)

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

(28) lower alkanoyl (2-methoxycarbonylamino-2- [2- (3 or 4) methylthiophenyl] acetyl, 2 (1-cyclofuro) substituted with lower alkylthiophenyl and lower alkoxycarbonylamino Philethoxy) carbonylamino-2- [2- (3 or 4) methylthiophenyl] acetyl, 2-third carbonylamino-2- [2- (3 or 4) methylthiophenyl] acetyl, 2- Tertiary 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) ethylsulfinylphenylfuropionyl] acetyl, etc.)

(31) lower alkoxycarbonyl (lower) alkoxyphenyl and lower substituted alkanoyl (2-amino-2- [2- (3 or 4) methoxycarbonylmethoxyphenyl] acetyl, 2-amino-3 -[2- (3 or 4) furooxycarbonylmethoxyphenyl] propionyl, 2-amino-2- [2- (3 or 4) tertiary butoxycarbonylmethoxyphenyl) acetyl, etc.)

(32) lower alkanoyl (2-methoxycarbonylamino-2- [2- (3 or 4) methoxycarbonylmethoxyphenyl substituted with lower alkoxycarbonyl (lower) alkoxyphenyl and lower alkoxycarbonylamino) ] Acetyl, 2- (1cyclofurophylethoxy) carbonyl-3- [2- (3 or 4) ethoxycarbonylmethoxyphenyl] propionyl, 2-tert-butoxycarbonylamino-2- [2- (3 or 4) tert-butoxycarbonylmethoxyphenyl] acetyl, etc.)

(33) lower alkanoyl substituted with phenyl and thiadiazolylthio (lower) alkanoylamino (N- (1, 3, 4-thiadiazol-2-yl) thioacetylphenylglycyl, 2- [3- (1,3,4-thiadiazol-2-yl) thiofulopionyl] amino-3-phenylfulopionyl, etc.)

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

(35) lower alkanoyl (2-amino-2 (2, 5-dihydrophenyl) acetyl, 2-amino-3- (2, 5-dihydrophenyl) fulopionyl substituted with dihydrophenyl and amino Etc)

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

(37) 3-halophenyl-5-lower alkali isoxazol-4-ylcarbonyl (3- [2- (3 or 4) bromophenyl] -5-ethylisoxazol-4-ylcarbonyl and the like )

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

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

(40) lower alkanoyl (2-methoxycarbonylamino-2- (2-thienyl) acetyl, 2- (1-cyclofurophylethoxy) carbonylamino substituted with thienyl and lower alkoxycarbonylamino 2- (2-thienyl) acetyl, 2-tertiary butoxycarbonylamino-2- (2-thienyl) acetyl, 2-tert-butoxycarbonylamino-3- (2-thienyl) furo Fionyl)

(41) terrazolyl (lower) alkanoyl (2- (1H-tetrazol-1-yl) acetyl, 3- (1H-tetrazol-1-yl) fulopionyl, 4- (1H-tetrazol- 1-day) butyryl)

(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) propionyl and the like)

(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] propionyl

(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-2-yloxy) propionyl, etc.)

(46) dihydropyranyl and lower substituted alkanoyl (2-amino-2- (5, 6-hydro-2H-pyrano-3-yl) acetyl, 2-amino-3- (5, 6) Dihydro-2H-pyran-3-yl) propionyl)

(47) lower alkanoyl (2-methoxycarbonylamino-2- (5, 6-dihydro-2H-pyran-3-yl) acetyl, 2- (substituted with dihydropyranyl and lower alkoxybenzoylamino) 1-cyclofurophilethoxy) carbonylamino-2- (5, 6-dihydro-2H-pyran-3-yl) acetyl, 2-tertiary butoxycarbonylamino-2- (5, 6-di Hydro-2H-pyran-3-yl) propionyl)

(48) sidnoyl (lower) alkanoyl (2- (sidon-3- yl) acetyl, 3- (sidnon-3- yl) propionyl)

(49) In acylamino having a protective amino group for phenyl (lower) alkoxycarbonyl (benzyloxycarbonyl, phenethyloxycarbonyl, etc.) R ^1a and R ^1c , the term "protecting amino" is as defined above. Amino groups and acylamino groups substituted by other amino protecting groups than the actual groups are included. For acylamino having a protective hydroxy, the term “protective hydroxy” includes hydroxy protected by the same conventional protecting group for hydroxy as described above.

R^1b, R^{1b '}, R^1cAcylamino with protected amino for, R^1dAcylamino with amino for R^1eAcylamino and R with protective hydroxy for^1fFor acylamino having a hydroxy for "acylamino" includes the same acylamino as described above.

The term "protective carboxyl group" for R ² and R ^2a includes esters, acid amides, 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, fusoyl, isoprophyl, 1-cyclofurophyll, ethyl, butyl, tertiary bunyl, etc.) esters, higher alkyl (octyl, nonyl, undecyl, etc.) esters, lower Alkenyl (vinyl, 1-furophenyl, allyl, 3-butenyl, etc.) ester, lower alkynyl (3-butynyl, 4-pentynyl, etc.) ester, lower or higher cycloalkyl (cyclophenyl, cyclohexyl, cyclo Saturated or unsaturated higher or lower alkyl esters having side chains or cyclic rings such as heptyl), such as heptyl, etc .; lower alkoxy (lower) alkyls (methoxyketyl, ethoxyethyl, methoxyethyl, etc.), lower alkylthio (Lower) alkyl (methylthiomethyl, ethylthioenyl, methylthiofurofil, etc.) ester, di (lower) alkylamino (dimethylamino, diethylamino, difurophylamino, etc.) ester, lower alkylideneamino ( Ethyl idenamino, furophyldeniamino, isofurofilideneamino, etc.), lower grade Alkylsulphenyl (lower) alkyl (methylsulphenylmethyl, ethylsulphenylethyl, etc.) ester and the like and saturated or unsaturated lower or higher aliphatic esters containing sulfur nitrogen or oxygen.

Suitable esters containing aromatic rings include, for example, aryl (phenyl, xylyl, tolyl, naphthyl, indanyl, dihydroantryl, etc.) esters, al (lower) alkyl (benzyl, phenenyl, etc.) esters, allyloxy (Lower) alkyl (phenoxymethyl, phenoxyethyl, phenoxyfurophyll, etc.) ester, arylthio (lower) alkyl (phenylthiomethyl, phenylthiophenyl, thiofurophyll, etc.) ester, alkylsulphenyl (lower) alkyl (Phenyl sulfenyl methyl, phenyl sulfenyl ethyl, etc.), aryl aryl (lower) alkyl (benzoyl ethyl, toluuryl ethyl, etc.), aryl oyl 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 include 1-4-1-yl such as oxygen, sulfur and nitrogen, tetrahydropyranyl And quinolyl, pyrazolyl) esters, and suitable heterocyclic lower alkyl esters are saturated, unsaturated, condensed or non-condensed 3-8 position heterocyclic compounds containing 1-4 heteroatoms such as oxygen, sulfur and nitrogen atoms. (Pyridyl, piperidino, 2-pyridone-1-yl, tetrahydropyranyl, quinolyl, pyrazolyl, etc.). 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 (metal, 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.), Phenylazo, halogen (chlorine, bromine, fluorine, etc.), cyano, nitro, etc., for example, mono (di, tri) halo (lower) alkyl (chloromethyl bromomethyl, dichlormethyl, 2, 2, 2- Trichloroethyl, 2, 2, 2-tribromoethyl, etc.) ester, cyano (lower) alkyl (cyanomethyl, cyanoethyl, etc.), ester, mono (di, tri, datra or penta) halophenyl (4-chlorophenyl), 3,5-dibromophenyl, 2, 4, 5-trichlorophenyl, 2, 4, 6-trichlorophenylpentachlorophenyl, etc., ester, lower alkanesulfonylphenyl (4-methane Sulfonylphenyl, 2-ethalsulfo Phenyl), 2- (3 or 4) phenyl azophenyl ester, mono (di, tri) nitrophenyl (4-nitrophenyl, 2, 4-dinitrophenyl, 3, 4, 5-trinitrophenyl, etc.) , Mono (di, tri, tetra or penta (halophenyl (lower) alkyl (2-chlorobenzyl, 2,4-dibromobenzyl, 3, 4, 5-trichlorobenzyl, pentachlorobenzyl, etc.) (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-dimethoxybenzyl, 3, 4, 5-trimethoxybenzyl, etc.) ester, hydroxy and di (lower) alkylphenyl (lower) alkyl (3, 5-di Menyl-4-hydroxybenzyl, 3,4-tert-butyl-4-hydroxybenzyl, and the like.

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-fetylic acid amide, or acid amide (4-methylimidazole, 4-enylimida) with pyrazole, imidazole, 4-lower alkylimidazole And so on).

Suitable acid anhydrides include, for example, di (lower) alkyl salts (dimethyl phosphate, diethyl phosphate, etc.), dibenzyl phosphate, phosphate halides (phosphate chloride, bromide phosphate, etc.), di (lower) alkyl phosphites (dimenyl phosphate). Pits, diethylphosphite, etc.), sulfurous acid, thiosulfate, sulfuric acid, lower alkyl carbonate (mate), hydrazonic acid, hydrohalogen (acid salt, bromic acid, etc.), saturated or unsaturated lower aliphatic carboxylic acid (Pibaric acid, pentanoic acid, isopentanoic acid, 2-ethylbutanoic acid; crotonic acid (gilic acid, propionic acid, etc.), saturated or unsaturated halo (lower) aliphatic carboxylic acid (chloroacetic acid, 3 -Chloro-2-pentenoic acid, 3-bromo-2-butenoic acid, etc.), substituted lower aliphatic carboxylic acids (phenylacetic acid, phenoxyacetic acid, furanacetic acid, thiophenic acid, etc.), aromatic carboxylic acid (Benzoic acid, etc.), or symmetric acid anhydrides.

Suitable acid salts are salts such as metals (sodium, potassium, magnesium, etc.) and organic amines (methylamine, diethylamine, triethylamine, aniline, pyridine, picoline, NN'-dibenzylethylenediamine, etc.). This includes.

The term "lower alkyl" in R ³ refers to any of straight, branched, or cyclic chains having 1 to 6 carbon atoms, such as methyl, ethyl, propofyl, isofurophyll, butyl, tertiary butyl, cyclohexyl, etc. It means to have one.

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

R ⁵ and R ⁶ "aryl" is phenyl, "substituted aryl" refers to or in putil, R ⁵ and R ⁶ The term 2- (3 or 4), - means halophenyl such as chlorophenyl, tolyl, etc. .

The term "acyl" is the same as above

The term “residue of acid” in Y means a group given by removing hydrogen, such as halogeno (chlorine, bromine, fluorine, etc.), acyloxy (ethanesulfonyloxy, benzenesulfonyloxy, toluenesulfonyloxy) and the like.

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. It can be prepared by reacting the starting material (II) of the compound (I) of the present invention with a base.

Suitable bases for use in the present invention are, for example, alkali metals (titanium, sodium, potassium, etc.), inorganic bases such as alkali earth metals (magnesium, calium, etc.), hydrides substituted, lower alkoxides (methoxide, Ethoxide, furoxide, butoxide, tertiary butoxide, etc.), hydroxides, carbonates, bicarbonates, amides, enylphenylamides, diisoprophyllamides, and butyl, phenyl or triphenylmethyl The above-mentioned metal salts of the present invention also include primary amines (metal amines, ethyl amines, propofyl amines, tertiary butyl amines, etc.), secondary amines (dimethyl amine, diethyl amine, diisofurophyl amine, etc.), and third Tertiary amines (trimethylamine, triethylamine, trifurophylamine, triisofurophylamine, tributalamine, dimethylbenzylamine, tripenethylamine, pyriridine, picoline, α-picoline, N-ethylpiperi Dean, N-ethylmorpholine, NN'-di Tilpiperazine, 1,5-diazanecyclo [4, 3,0] non-5-ene, 1,4-diazabicyclo [2, 2, 2] octane, 1,8-diazabicyclo [5, 4, 0] undecene-7, etc.), and quaternary ammonium hydroxide compounds. The reaction proceeds using equimolar amounts of starting material and base in a form 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, tetramenylurea, tetrahydrofuran, methylene chloridedioxane, call time , Diglyme, acetonitrile, acetone, phosphate buffer, and the like. The reaction temperature in this reaction 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 in the pretreatment reaction or the present reaction of the present reaction. When the target (I) is used in the next process, it is isolated, purified or otherwise used.

기로 되게하는 조건하에서 수행된다. 본 반응에서 산화는 할로겐(염소, 브롬등), 할로겐화합물(이소시안우로일클로라이드, 페닐요오디클로라이드등), 온존, 무기과산(과요도산, 과황산등), 유기과산(과안식향산, M-클로로과안식향산, 과개미산, 과초산, 클로로과초산, 트리후로로과초산등), 무기나 유기과산의 금속염, 그리고 과산화수소등과 같은 산화제를 사용하는 공지의 방법에 의하여 진행된다.Target object (Ib) is manufactured by oxidizing compound (Ia). 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 (isocyanuroyl chloride, phenyliodichloride, etc.), warm zone, inorganic peracids (periodic acid, persulfate, etc.), organic peracids (perbenzoic acid, M- Chloroperbenzoic acid, pericic acid, peracetic acid, chloroperacetic acid, trifluoroperacetic acid, and the like), a metal salt of an inorganic or organic peracid, and an oxidizing agent such as hydrogen peroxide.

The reaction is a periodic table such as, for example, tungstenic acid, molybdate, vanadic acid, alkali metals (sodium, potassium, etc.), alkaline earth metals (calcium, magnesium, etc.), their ammonium salts, or vanadium pentoxide. Better in the presence of elemental compounds of Group Vb or Group VIb.

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

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

를기로 되게하는 조건하에서 진행된다. 본 반응에서 환원은 제일 클로라이드 또는 금속티오설페이트(소디움티오설페이트, 포타시움티오설페이트 등), 또는 산클로라이드, 상술한 제일클로라이드나 금속설페이트의 조합물, 또는 포스포터스트티클로라이드, 포스포터스펜클로라이드, 시리콘트리클로라이드등의 방법이나 일본특허 제 21111 호에 기술된 방법등 통상의 방법에 의하여 수행된다.When the target (Ia) is prepared by reducing the target (Ib), the reduction reaction is -S-

Proceeds under the condition that makes it to be. Reduction in this reaction is the first chloride or metal thiosulfate (sodium thiosulfate, potassium thiosulfate, etc.), or an acid chloride, a combination of the above-mentioned first chloride or metal sulfate, or phosphorus thichloride, phosphorus pen chloride, siri It is carried out by a conventional method such as a method such as corn trichloride or the method described in Japanese Patent No. 21111.

The reaction is also carried out in a solvent which does not adversely affect the reaction, such as dimethylformamide, acetonitrile, acetoacetic acetate, 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 the compound (Ib) and the reduction method used in the present reaction.

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

The target (Id) is prepared by removing the amino protecting group from the compound (Ic) and the target (Ih) is prepared by removing the amino protecting group from the compound (Ig).

This removal reaction proceeds by conventional methods such as hydrolysis hydrazine using acid and treatment, 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, the imino halogenating agent is reacted to imino esterify and, if necessary, hydrolyzed to remove it. The reactions brought about by the acid include benzyloxycarbonyl, substituted benzyloxy carbonyl, adamantyloxycarbonyl, alkoxycarbonyl, substituted alkoxycarbonyl, araloxycarbonyl, 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, benzenesulfonic 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 acid, it proceeds in the presence of a solvent such as 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 trichloroethoxycarbonyl, benzyloxycarbonyl, substituted benzyloxycarbonyl, 2-pyridylmethyloxycarbonyl and the like.

The present invention can be applied to the reduction reaction, for example, metals (stone, lead, iron, etc.), combinations of metal compounds (chromium chloride, chromium acetate, etc.) and organic or inorganic acids (acetic acid, propionic acid, hydrochloric acid, etc.). ), And reduction of the catalyst is carried out under a metal catalyst. Metal catalysts for catalytic reduction include Tani-Nickel, Platinum Oxide, Palladium Carbon and other known catalysts. The protecting group, ie trifluoroacetyl, is removed by reaction with water 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, etc. . When the protecting group is acyl, the acyl is reacted with an iminohalogenating agent to iminoethylate and, if necessary, hydrolyzed.

Suitable iminohalogenating agents include, for example, phosphorus trichloride, phosphorus pentachloride, phosphorus triphosphate, phosphorus pentachloride, phosphorus oxychloride, thionyl chloride, phosgene and the like. In iminohalogenation, the reaction temperature is not particularly limited and is sufficiently performed at ambient temperature or under cooled temperature. The iminoetherification agent that results in the progress of the iminohalogen reaction is alkanol (methol, ethanol, furanolol, isofuropanol, butanol, tert-butanol, etc.), or alkoxy (methoxy as a substituent in the alkyl group). , Ethoxy, furoxy, isopuroxy, butoxy and the like, and alkali metal alkoxides (sodium alkoxide, potassium potassium side, etc.), or alkali metal oxides (calcium alkoxide, barium alkoxide, etc.) derived from the alkoxy mentioned above. Corresponding alkanols having the same metal alkoxide.

The reaction temperature 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 a reaction mixture to water or a mixture of water and a hydrophilic solvent such as ethanol and ethanol. In this hydrolysis, water preferably contains a base such as an alkali metal bicarbonate 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 may be appropriately selected according to the protecting group for amino or the above-described elimination reaction, and the present reaction may be performed under suitable conditions such as cooling or slightly warming.

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

The present invention also relates to the free groups corresponding to the above-mentioned groups when the compound (Ig) is one or more protective carboxyl, protective hydroxy, and hexameraccapto groups in the acylamino group at the 6th position of the phenam ring in the preparation process. It also includes. The obtained compound (Id) and (Ih) can be converted into these desired acid addition salts if necessary. The target substance (Ie) can be produced by reacting an acylating agent with compound (Id) and salts thereof. Suitable salts of compound (Id) include those such as organic acid salts (acetates, maleates, tartarate salts, benzelsulfonate salts, toluene sulfonate salts, etc.) and inorganic acid salts (hydrochloride salts, sulfate salts, phosphate salts, etc.). Acylating agent in this reaction refers to the sulfonic acid, carboxylic acid ester, carbamic acid and thio acid and corresponding reactive derivatives of aliphatic, aromatic, and heterocyclic carboxylic acids.

Reactive derivatives include acid anhydrides, active amides, active esters, isocyanates and isothiocyanates, for example, acid azide, dialkyl phosphate, diphenyl phosphate, dibenzyl phosphate, halogen phosphate, dialkyl phosphite, and sulfuric acid. , Thiosulfate, hydrohalogenic acid (hydrochloric acid), sulfuric acid, monoalkyl carbonate, aliphatic carboxylic acid (acetic acid, pivaric acid, pentanoic acid, isopentanoic acid, 2-ethyl lac acid, trichloroacetic acid) Mixed acid anhydrides or symmetric acid anhydrides with acids such as acids (benzoic acid) and pyrazoles, imidazoles, 4-substituted imidazoles, dimethylpyrazoles, triazoles, acid amides with tetrazole, and esters (Cyano methyl ester, methoxy methyl ester, vinyl ester, furparzyl ester, P-nitrophenyl ester, 2, 4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, methanesulfonylphenyl Tel, phenyl azophenyl ester, tenyl thioester, P-nitrophenyl thioester, P-crysyl thio ester, carboxyethyl thio ester, pyridyl ester, pyridyl ester, piperidyl ester, 8-quinolyl thioester, Or N, N-dimethylhydroxylamine, 1-hydroxy-2- (1H) -pyridone), N-hydroxysuccinate or ester of N-hydroxyfutalamide).

The reaction derivatives described above are determined according to the type of acid used. When free acid is used in the acylation reaction, NN'-dicyclohexylcarbodiimide, N-cyclohexyl-N'-morpholinoethylcarbodiimide, N-cyclohexyl-N '-(4-diethylamino Cyclohexyl) carbodiimide, NN'-diethylcarbodiimide, NN'-diisofurophyllcarbodiimide, N-ethyl-N '-(3-dimethylaminofurophyll) carbodiimide, NN'-carbox Carbonyl, di- (2-methylimidazole), pentamethyleneketene-N-cyclohexylimide, dimethylketene-N-cyclohexylimine, alkoxyacetylene, 1-alkoxy-1-chloroethylene, trialkylphosphite, Ethylpolyphosphate, isofurophyllpolyphosphate, phosphorus oxychloride, phosphorus chloride, thionyl chloride, oxyl chloride, triphenylphosphine, 2-ethyl--7-hydroxybenzisoxazolium salt, 2-ethyl -5- (M-sulfophenyl) -isoxazolium hydroxide molecular salt, (chloromethylene ) -Dimethylammonium chloride-2, 2, 4, 4, 6, 6-hexachloro-2, 2, 4, 4, 6, 6-hexahydro-1, 3, 5, 2, 4, 6-tree It is more effective to add condensing agents such as azatriphosphorine or mixed condensing agents such as triphenylphosphine and carbon tetrahalide (carbon tetrachloride, carbon tetrabromide, etc.) or halogens (chlorine, bromine, etc.). .

Examples of the acyl group introduced into the amino group of compound (Id) by the acylating agent described above include aliphatic, aromatic and heterocyclic carboxylic acids and their corresponding sulfonic acids (dehydrating from carboxylic acid esters, carbamic acid and thio acids). Oxylated groups, moreover, acyl groups are the same acyl groups as described for the acyl groups in the acylamino groups for R 'Acylation reactions are usually water, acetone, dioxane, acetonitrile, chloroform, ethylene chloride, ethanedichloride, Tetrahydrofuran proceeds under a solvent which does not adversely affect the present reaction, such as ethyl acetate, dimethylformamide, pyridine, and the like, and the above-mentioned hydrofill solvent may also be used as a mixed solvent with water.

In addition, the acylation reaction is carried out for inorganic bases (alkali metal bicarbonate, etc.) and organic bases (trialkylamine, NN-dialkylamine, NN-dialkylbenzylamine, pyridine, 1,5-diazabicyclo [4, 3,0] non-5-one, 1,4-diazabicyclo [2, 2, 2] octane, 1,8-diazabicyclo [5, 4, 0] undecene-7, etc.) It is better to perform in the presence.

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 in the present reaction or pretreatment reaction is another protected carboxyl group or changed to a free carboxyl group. The desired compound (If) can be prepared by reacting compound (Ie) with an iminohalogenating agent, an iminoethering agent, and then an acylating agent, if necessary, by hydrolysis.

Suitable iminohalogenating agents include phosphorus trichloride, phosphorus pentachloride, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, thionyl chloride, phosgene and the like. In the iminohalogenation reaction, the reaction temperature is not limited and proceeds sufficiently at ambient temperature or at a cooled temperature. Suitable iminoetherification agents for which the iminohalogen reaction is completed are alkanols (methol, ethanol, furopanol, isofuropanol, butanol, tertiary butanol, etc.) or alkoxy (methoxy.ethoxy, furo) as substituents on alkyl groups. Corresponding alkanols with foxy, isopuroxy, butoxy and the like, and metals derived from such alcohols as alkali metal alkoxides (sodium alkoxides, potassium alkoxides, etc.) and alkoxytometal alkoxides (calcium alkoxides, barium alkoxides, etc.) It refers to an alkoxide. In iminoetherification, 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 compound (Id). The obtained reaction product 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 and ethanol. In this hydrolysis, water preferably contains a base such as alkali metal bicarbonate, trialkylamine, and an acid such as dilute hydrochloric acid or acetic acid.

In this reaction, the acylamino group R ^1b in the compound (Ie) is changed to another acylamino group R ^{1b '} in the compound (If). Target (Ij) can be prepared by removing the protecting group of hydroxy from compound (Ii). This removal reaction is carried out by conventional methods such as acid, base or reduction. These methods are chosen according to the type of protecting group to be removed. Removal reaction with acid is benzyloxycarbonyl, substituted benzyloxycarbonyl, alkoxycarbonyl, substituted alkoxycarbonyl, araloxycarbonyl, adamantyloxycarbonyl, trityl, substituted phenylthio, substituted aralkylidene It is one of the most common methods used to remove such things as substituted aral ardene substituted cycloalkyl ide.

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 and trifluoroacetic acid. The acid suitable for the reaction depends on the protecting group or other factors to be removed. When the acid is removed, the acid is carried out under hydrophilic organic solvent, water, or a mixed solvent thereof. The removal reaction as a base is used to remove acyl groups. Suitable bases are, for example, alkali metals (sodium, potassium, etc.), inorganic bases, hydroxides or carbonates, or bicarbonates thereof and the like, and trialkylamines (trimentylamine, triethylamine, etc.), Picoline, N-methylpyrrolidine, N-methylmorpholine, 1,5-diazabicyclo [4, 3,0] non-5-ene, 1,4-diazacyclo [2, 2, 2] octane And organic bases such as 1,8-diazacyclo [5, 4, 0] undecene-7 and the like. Removal reactions with salts are sometimes carried out in the presence of water or hydropyrin solvents or mixed solvents thereof. Reduction is generally used to remove from trichloroethoxycarbonyl, benzyloxycarbonyl, substituted benzyloxycarbonyl, 2-pyridylmethoxycarbonyl and the like. The reduction used in the removal reaction of the present invention is a combination of a metal (stone, zinc, iron, etc.) or a metal compound (chromose chloride, chromose acetate, etc.) and an organic or inorganic acid (acetic acid, propionic acid, hydrochloric acid, etc.). It refers to the reduction made by using a reaction which proceeds under a metal catalyst for catalytic reduction. Metal catalysts for catalytic reduction include, for example, Raney-nickel, platinum oxide, paradiopcarboxylic acid and other known catalysts. The protecting group, trifluoroacetyl, is usually removed by treatment with water in the presence or absence of a base. Halogen-substituted alkoxycarbonyl or 8-quinolyloxycarbonyl is 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 with water or water in the presence of a base. When the protecting group is halogen-substituted alkoxycarbonyl or 8-quinolyloxycarbonyl, it is removed by treatment with heavy metals such as copper and tin. 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 suitable conditions such as cooling or slight warming. This invention also includes the case where it changes into a protective carboxyl group, another protective carboxyl group, or free carboxyl group in this reaction or a post-treatment method in a manufacturing process.

The present invention also relates to converting the aforementioned groups into the corresponding free groups during the reaction when compound (Ii) has a protective melcapto group in the acylamino group at the 6th position of one or more of the protective amino, protective carboxy and phenam rings. Include it. Target (II) can be prepared by removing the protective carboxyl group from compound (Ik).

All known methods in this removal reaction are used in this removal reaction and conventional methods are used to remove the protective carboxyl groups, for example reduction, hydrolysis and the like can be applied. When protecting groups are active esters, activated amides or acid anhydrides they are hydrolyzed under suitable conditions in contact with water. Reduction can be applied to remove 2-iodoethylester, 2, 2, 2-trichloroethylester, benzylester and the like. The removal reaction as an acid was P-methoxybenzyl ester, tertiary butyl ester, trityl ester, diphenyl methyl ester, bis (methoxyphenyl) methyl ester, 3, 4-dimethoxybenzyl ester, 1-cyclofuropropyl ethyl It is used to remove protecting groups such as esters. Reductions applied to the elimination reactions of the present invention are, for example, metals (zinc, zinc amalgam, etc.), chromium salt compounds (chromose chloride, chromose acetate, etc.) and organic or inorganic acids (acetic acid, propionic acid, Hydrochloric acid) and the reduction carried out under a metal reduction catalyst.

Catalytic reduction metal catalysts include, for example, platinum catalysts (platinum wire, platinum sponges, platinum bumps, platinum colloids), palladium catalysts (paradium sponges, palladium humps, palladium oxides, palladium sulfate, palladium carbonate, palladium on charcoal, and silica Gel-like palladium, palladium colloid, etc.) Nickel catalysts (reducing nickel, nickel oxide, Raney-nickel, urushibaranic, etc.) and suitable acids in the removal reaction are formic acid, trihaloacetic acid (trichloroacetic acid, trifluoroacetic acid, etc.). Hydrochloric acid, hydrofluoric acid, P-toluenesulfonic 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].

The reaction is carried out without solvent when the protecting group is removed by treatment with water or liquid acid in the reaction. In this reaction, any solvent such as dimethyl fluoromide, methylene chloride, chlorofulom, tetrahydrofuran, acetone, etc., which does not adversely affect the reaction can be used. The reaction temperature is not particularly limited and may be appropriately selected depending on the starting material and the removal reaction actually applied.

The present invention also includes the case where the protective carboxy, hydroxy, melcapto or amino group contained in the starting material is changed to free carboxyhydroxy melcapto or amino group in the pretreatment or original process of the reaction, respectively. In this way, compound (II) can be converted into a desired metal (sodium, fortisium) salt or organic base salt. The target product (In) can be prepared by reacting compound (Im) with semicarbazide or salts thereof.

Suitable salts of semicarbazide include such as inorganic acid salts (hydrochloride, selphenyl copper) and organic acid salts (acetate maleate, tartarate, etc.). Usually the reaction is carried out in solvents that do not adversely affect the reaction, ie methanol, ethanol, water, acetonitrile, edel, chlorofulom, fluoromide, benzene and the like.

The reaction proceeds better in the presence of a base. Suitable bases include, for example, inorganic bases such as alkali metals (lithium, sodium, potassium, etc.) and (alkaline metal magnesium, calcium, etc.), corresponding hydrides, amides, alkoxides, methoxides (ethoxides, furo) Oxides, butoxides, tertiary butoxides, etc.), hydroxides, carbonates, bicarbonate acetates, and the like and tertiary amines (trimethylamine, triethylamine, trifurophylamine, triisofurophylamine). , Tributylamine, dimethylbenzeneamine, tripenethylamine, pyriridine, pyridine, α-picoline, N-methylpiperidine, N-methylolpine, NN-dimethylpiperazine, 1,5-diazabicyclo [ Organic such as 4, 3, 0] non-5-ene, 1, 4-diazabicyclo [2, 2, 2] octane, 1,8-diazabicyclo [5, 4, 0] undensene-7) and the like Base. The reaction temperature is not particularly limited and the reaction is usually carried out under heating which is heated at the boiling point of the solvent used in the reaction.

기가-S-기로 변환하는 즉 화합물(Ⅰa)이 화합물(Ⅰb)을 환원시킴으로 제조되는 것과 동일한 조건하에서 진행된다. 적당한 아실화제는 화합물(Ⅰe)에서 아실화 반응에 사용된 것과 동일한 것이다.This reaction also includes a step of subjecting the protective carboxyl group to another protective carboxyl group or free carboxyl group during the post-treatment or the present reaction in the step. The desired compound (Ip) can be prepared by reacting compound (Io) with an acylating agent under reaction conditions. This acylation reaction

The conversion proceeds under the same conditions as those prepared by the conversion to the giga-S-group, ie compound (Ia) is reduced by compound (Ib). Suitable acylating agents are the same as those used for the acylation reaction in compound (Ie).

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 acid ester, tetrahydrofuran, chloroformum, methylene chloride, dioxane and the like.

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

The present invention also includes a step of changing a carboxyl group to a protective carboxyl group and a protective carboxyl group to another protective carboxyl or organic carboxyl group in the present reaction and pretreatment of the present invention.

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 aureus 209-PJC-1 and each bacterium ATCC 6633 of the target (I) are as follows.

Evaluation method of antimicrobial effect in vitro

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

Each test strain was cultured in tripty case-soybean juice (10 ⁶ viable cells / ml) for one night and one night, and arranged on HI-agor containing a certain concentration of antibiotics. After 20 hours of incubation, the minimum stopping concentration (MIC) was expressed in mcg / ml.

(1) 2-methyl-2, 3-methylene-6-phenylglycosylaminophenam-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-carbox amido] phenam-3-carboxylic acid Dibenzylethylenediamine

Four: 50 liver: 12.5

(3) 2-methyl-2, 3-methylene-6- [2- (2-thienyl) acetamido] phenam-3-carboxylic acid

Four: 12.5 liver: 1.56

(4) NN'-dibenzylethylene diamine salt of 2-methyl-2, 3-methylene-6- [2- (2-chlorophenoxy) -2-phenyl acetamido] 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) -acetamido] phenam-3-carboxylate

Four: 12.5 liver: 3.13

(6) Sodium 2-methyl-2, 3-methylene-6- (2-methylthio acetamido) phenam-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-phenylthiocarbonyl aminophenam-3-carboxylic acid

Four: 200 Liver: 100

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

Four: 12.5 liver: 3.13

(10) -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-seicarbazono) -acetamidophenam-3-carboxylic acid

Four: 50 liver: 3.13

(12) N, N'-dibenzylethylenediamine salt of 2-methyl-2, 3-methylene-6- (1-cyclofurophylethoxy) carbonylamido penam-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) acetate] -phenam-3-carboxylic acid

Four: 50 liver: 12.5

Object (I) of the present invention is also useful for preparing major intermediates of antimicrobial compounds such as, for example, 2-lower alkyn-7-acylamino-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. Formulation of compound (I) is used in the form of a solid, semi-solid or liquid by mixing the compound (I) with a pharmaceutical or inorganic excipient or additive suitable for external use or content. For example, the active ingredient is mixed with excipients to formulate into tablets, pills, capsules, suppositories, solutions, suspensions, emulsions and other suitable formulations for use. The additives used are starch, lactose, acacia gum, gelatin, mannitol, starch paste, manesium trisilicate, talc corn starch, keratin, colloidal silica, potato starch, urea and other suitable additives for formulating solids, semis It may contain adjuvant, stabilizer, coloring agent in formulating in solid and liquid form.

In addition, the preparation of the present invention may contain a preservative and preservative so that the effective 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 content of the active ingredient of the preparation varies depending on the conditions and ages for the treatment of each patient. Preferably 1-2 g / l of the active ingredient is generally administered to treat diseases in which the target compound (I) is useful.

Although the present invention has been generally described so far, but in order to make it more understandable, the following specific embodiments have been given, which are described or described in detail, and are not intended to be limiting unless otherwise indicated.

[reaction]

Example 1

A solution of 840 mg of 2-methyl-2, 3-methylene-6- (1-cyclopropylethoxy) -carbonyl aminophenam-3-carboxylic acid in 5 ml of formic acid is stirred at room temperature for 1.5 hours. After the reaction, formic acid is distilled off under reduced pressure. The residue was washed with ether, and acetonitrile containing water was crystallized. The crystals were collected by filtration to give 380 mg of 2-methyl-2, 3-methylene-6-aminophenam-3-carboxylic acid. .

(Decomposition of melting point 200 ℃)

Infrared absorption spectrum (new sol)

1, 788, 1, 608 cm ^-1

Example 2

0.12 g of pyridine in a solution of 10 ml of dried benzene in 0.46 g of 2, 2, 2-trichloroethyl-2-methyl-2, 3-methylene-6- (2-phenylacet amido) phenam-3-carboxylate And 0.30 g of phosphorus contaminant are added sequentially and the mixture is stirred at room temperature for 2 hours. 1 ml of methanol of anhydride is added to the solution while cooling at −10 ° C. and the solution is stirred for 2 hours. To the solution is added 5 ml of water at −10 ° C. and further stirred for 10 minutes.

After the reaction is complete, the aqueous layer is completely separated from the reaction mixture, adjusted to pH 8-9 with aqueous sodium bicarbonate solution and extracted with ethyl acetate. The extract is dried over manganese, the solvent is distilled off under reduced pressure, and the residue is washed with a small amount of petroleum ether and dissolved in a small amount of ethyl acetate. A solution of P-toluenesulfonic acid monohydrate of ethyl acetate was added to the solution, and the precipitate was collected by filtration and dried to give 2, 2, 2-trichloro ethyl-2-methyl-2, 3-methylene-6-aminophen 25 mg of dark-3-carboxylate-P-toluenesulfonate are obtained.

(Decomposition of melting point 179 ~ 180 ℃)

Infrared absorption spectrum (nusol)

1, 800, 1, 755 cm ^-1

Example 3

960 mg of 2, 2, 2-trichloroethyl-2-methyl-2, 3-methylene-6- (2-phenylacetamino) phenam-3-carboxylate-1-β-oxide in 10 ml of dried dichloromethane To the solution, 370 mg of dimethylaniline and 620 mg of phosphorus contaminant are sequentially added while cooling at -40 ° C, and the mixture is stirred at -30'-40 ° C for 2 hours and further stirred at -10 ~ -20 ° C for 30 minutes. The solution is cooled at -30 to -40 [deg.] C. and 0.7 ml of anhydrous methanolol is added dropwise to the solution and then the mixture is stirred at -20 to -30 [deg.] C. for 2 hours. 0.7 ml of water is added to the reaction mixture and the solution is stirred for 1 hour under ice-cooling. 5-6 ml of water are added to the mixture, the aqueous layer is separated, neutralized with sodium bicarbonate and extracted with ethyl acetate.

The extract is washed with water, dried over forget-me-not and the solvent is distilled off under reduced pressure.

The oily residue is washed with a small amount of petroleum ether, dissolved in a small amount of ethyl acetate, and then a solution of 120 mg of P-toluenesulfonic acid monohydrate in 5 ml of ethyl acetate is added to the solution. The precipitate was collected by filtration and fractionated from acetone to give 2, 2, 2-trichloroethyl-2-methyl-2, 3-methylene-6-aminophenam-3-carboxylate-1-β-oxide-P 60 mg of toluenesulfonate is obtained.

(Decomposition of melting point 176 ~ 179 ℃)

Infrared absorption spectrum (nusol)

1, 800, 1, 745 cm ^-1

Example 4

Carbon phase 1.5 in a solution of 0.8 g of 2, 2, 2-trichloroethyl-2-methyl-2, 3-methylene-6- (2-benzyloxycarboxyamido) phenam-3-carboxylate in 70 ml of tetrahydrofuran g of 10% palladium was added and the starting material was catalytically reduced for 3 hours at room temperature. After the reaction was completed, the reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was dissolved in 2 ml of ethyl acetate. To this solution was added a solution of ethyl acetate P-toluenesulfonic acid, and the precipitated crystals were collected by filtration, washed with ether and dried to give 2, 2, 2-trichloroethyl-2-methyl-2, 3-methylene- 0.43 g of 6-aminophenam-3-carboxylate-P-toluenesulfonate is obtained.

(Decomposition of melting 179 ~ 180 ℃)

2, 2, 2-trichloroethyl-2-methyl-2, 3-methylene-6-aminophenam-3-carboxylate-P-toluenesalfonate (melting point 179-180 DEG C decomposition) is shown in Example (2). It is obtained according to the same method in (4).

Each of the following compounds is used as starting material.

(a) 2, 2, 2-trichloroethyl-2-methyl-2, 3-methylene-6- [2 (1H-tetrazol-1-yl) acetamido] penam-3-carboxylate (melting point 133 ~ 137 ℃)

(b) 2, 2, 2-trichloroethyl-2-methyl-2, 3-methylene-6- [2- (2-thienyl) -acetamido] penam-3-carboxylate (melting point 144- 145 ℃)

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

(d) 2, 2, 2-trichloro ethyl-2-methyl-2, 3-methylene-6- (2-phenyl-2-formyloxyacetamido) phenam-3-carboxylate (oil)

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

(f) 2, 2, 2-trichloroethyl-2-methyl-2, 3-methylene-6- [2- (5-chloro-1H-benzotriazol-1-yl) acetamido] penam-3 -Carboxylate (melting point: 164 ~ 166 ℃)

(g) 2, 2, 2-trichloroethyl-2-methyl-2, 3-methylene-6- (2-methylthio acetamido] phenam-3-carboxylate (oil)

(h) 2, 2, 2-trichloro ethyl-2-methyl-2, 3-methylene-6- [N- (1-cyclopropylethoxy) carbonylphenylglycyl] aminophenam-3-carboxylate (Amorphous)

(i) 2, 2, 2-trichloroethyl-2-methyl-2, 3-methylene-6- [3- (2-chlorophenyl) -5-methylisoxazole-4-carboxamido] penam- 3-carboxylate (foam)

(j) 2, 2, 2-trichloroethyl-2-methyl-2, 3-methylene-6- [2-phenyl-2-semicarbazono acetamido] penam-3-carboxylate (melting point 200 ~ 201 ℃ decomposition)

(k) 2, 2, 2-trichloroethyl-2-methyl-2, 3-methylene-6-2- (1H-tetrazol-1-yl) acetamidophenam-3-carboxylate-1- β-oxide (melting point 189 ~ 192 ℃ decomposition)

(l) 2, 2, 2-trichloro ethyl-2-methyl-2, 3-methylene-6- [2- (2-thienyl) -acetamido] penam-3-carboxylate-1-β Oxide (melting point: 118.5 ~ 122 ℃)

(m) 2, 2, 2-trichloroethyl-2-methyl-2, 3-methylene-6- [2-phenyl-2- (2-chlorophenoxy) acetamido] phenam-3-carboxylate -1-β-oxide (oil)

(n) 2, 2, 2-trichloroethyl-2-methyl-2, 3-methylene-6- (2-phenyl-2-formyloxyacetamido) penam-3-carboxylate-1-β Oxide (melting point 151.5 ~ 153.5 ℃ decomposition)

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

(p) 2, 2, 2-trichloroethyl-2-methyl-2, 3-methylene-6- [2- (5-chloro-lH-benzotriazol-1-yl) -acetamido] penam- 3-carboxylate-1-β-oxide (melting point 145 ~ 149 ℃ decomposition)

(q) 2, 2, 2-trichloroethyl-2-methyl-2, 3-methylene-6- (2-methylthio acetamide) penam-3-carboxylate-1-β-oxide (melting point 177 ℃ decomposition)

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

(s) 2, 2, 2-trichloro ethyl-2-methyl-2, 3-methylene-6- [N- (1-cyclopropylethoxy) carbonylphenylglycyl] aminophenam-3-carboxylate -1-β-oxide (bubble type)

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

Claims (1)

Method for preparing a new compound of the following general formula (Id) by removing the amino protecting group from the compound of the following general formula (Ic)

In the above formula R ² is carboxy or protective carboxy R ³ is lower alkyl R ⁴ is lower alkylene X is -S-,

ego R ^1a is a protective amino.