KR800001528B1 - Preparing process for cepham intermediate - Google Patents

Abstract

Cephems. (I; A,B = H or amino substitution product; X = hydroxy or carboxyl substitution product; R = H or thiol sub stitution product) were manufd. by oxidative clevage of unsatd. bond of compd. (II). Thus, α- [4-acetylthio-3-phthalimido-2-oxo-azetidin-1-yl -α-isoprophenyl acetic acid and Me were mixed, cooled and added with excess ozone to give intermidiate, which was extracted to give α -[4-acetylthio -3 -phthalimido -2 -oxoazetidin -1 -yl -α-acetyl acetic acid.

Description

Method for preparing intermediate of cefem ring

The present invention relates to a process for the preparation of the following structural formula (I) which is an intermediate of a cefme ring.

Wherein A and B are each hydrogen or amino substituents, X is hydroxy or carboxy substituents and R is hydrogen or thiol substituents.

In detail, the present invention can prepare the compound of formula (I) by oxidizing the unsaturated bond of the compound of formula (II).

Wherein A, B, X and R are as described above.

3-Hydroxy-3-cefem compounds are useful cefem compounds (e.g., recently developed 3-methoxy-7- (a-phenylglycineamido) -3-cefe-4-carboxylic acid, 3-chloro- Synthesis of 7- (α-phenylglycineamido) -3-cepem-4-carboxylic acid, 3-bromo-7- (2-thienylacetamido) -3-cepem-4-carboxylic acid) Useful intermediates.

In the above structural formula, the ABN group is an amino group or a substituted amino group. The substituted amino groups are acylamino, hydrocarbylamino, hydrocarbylideneamino, silylamino, sulfenylamino or cephalosporins or common protecting groups containing up to 20 carbon atoms in the penicillin chemistry field.

Representative examples of the acyl group in the acylamino group include acyl carbonate (e.g., alkoxycarbonyl, aralkoxycarbonyl or aryloxycarbonyl), acyl sulfate, acyl phosphate (e.g., dialkoxyphosphinyl, dialkoxythiophosphonyl or alkoxy). Inorganic acyl groups such as aminophosphoryl), and organic acyl groups such as alkanoyl, cycloalkanoyl, aralkanoyl, aroyl, alkylsulfonyl, arylsulfonyl or alkylphosphonyl. These groups may, if possible, contain heteroatoms in their backbone, or for example halogen (eg fluorine, chlorine or bromine), nitrogen groups (eg amino, hydrazino, azido, alkylamino, Allylamino, acylamino, alkylideneamino, asimamino, amino or nitro), oxygen groups (e.g. hydroxy, alkoxy, aralkoxy, aryloxy, acyloxy or oxo), sulfur groups (e.g. metcapto, alkylthio, ar Alkylthio, arylthio, acylthio, thioxo, sulfo, sulfonyl, sulfinyl, alkoxy-sulfonyl, or acyloxysulfinyl), carbon groups (e.g. alkyl, alkenyl, aralkyl, aryl, carboxy, car) It may be unsaturated or substituted by broalkoxy, carbamoyl, alkanoyl, aroyl, aminoalkyl, aralkanoyl or cyano), or by popularity (eg phosphor or phosphoroyl). A and B are also contemplated as forming the diacyl groups of polybasic acids (eg, phthaloyl, pyridine-2,3-dicarbonyl, maleoyl or succinoyl).

More suitable groups of the acyl groups are acyl groups of the penicillin side chain (e.g., phenylacetyl, phenoxyacetyl, heptanoyl) or groups suitable for the antimicrobial effect of the final product (e.g., hydrogen, N-tertoxy-2-phenylglycineami). Figure, α- (1-carbomethoxy-1-isopropen-2-yl) amino-α-phenylglycyl, 4-phenyl-2,2-dimethyl-5-oxo-1,3-imidazoli Din-1-yl, α-diphenylmethoxycarbonyl-α-phenylacetamido).

The hydrocarbon group represented by A and / or B can be easily removed aliphatic hydrocarbon group containing 1 to 20 carbon atoms (e.g., alkyl, alkenyl, aralkyl or other aliphatic hydrocarbon group) or easily removed. Mono-cyclic aromatic hydrocarbon groups (eg phenyl or pyrimidyl). These groups may contain a hetero atom in its skeleton when necessary, or may be unsaturated or substituted by a substituent (for example, a halogen atom or a nitrogen group, an oxygen group, a sulfur group, a carbon group or a popularity).

A and B together form a divalent hydrocarbon group (e.g., alkylene, aralkylene, alkylidene, aralkylidene, α-halo- or alkoxy-aralkylidene, diarylmethylidene or cycloalkylidene). It may be considered that this may contain a hetero atom in its skeleton when necessary, and may be substituted or unsaturated by the above-described substituents.

When the A group is an acyl group and the B group is a hydrocarbon group, they may be bonded together with the nitrogen atom bonded to the 7 position of the cefe ring to form a ring (eg, 4-oxo-3-amidazolidinyl ring).

Silyl groups (eg, trialkylsilyl) and sulfenyl groups (eg, phenylsulphenyl or 0-nitro phenylsulphenyl), which may be represented by A and / or B, are common aminoprotecting groups.

Representative acyl groups for A and B in the formula (I) include the following groups.

1) alkanoyl groups containing 1 to 5 carbon atoms, 2) haloalkanoyl groups containing 2 to 5 carbon atoms, 3) azidoacetyl groups, 4) cyanoacetyl groups, and 5) Acyl represented,

Wherein Q and Q 'are each hydrogen or methyl,

Ar is a monocyclic heterocyclic aromatic group containing 1-4 hetero atoms selected from phenyl, dihydrophenyl or nitrogen, oxygen and / or antigens, which is an alkyl or alkoxy group containing 1 to 3 carbon atoms; And optionally substituted by an inert group such as chlorine, bromine, iodine, fluorine, trifluoromethyl, hydroxy, cyano, aminomethyl, amino or nitro group.)

6) acyl group represented by the following formula,

(Wherein G is oxygen or sulfur and Ar, Q and Q 'are as described above).

7) acyl group represented by the following formula,

Wherein Ar is as described above, and T is i, amino, ammonium, benzyloxycarbonyl, an alkoxycarbonyl group containing 1 to 4 carbon atoms, cyclopenyloxycarbonyl, cyclohexyloxycarbonyl, Benzhydryloxycarbonyl, cyclopropylmethoxycarbonyl, methanesulfonylethoxycarbonyl, methanesulfonylcarbonyl, triphenylmethyl, 2,2,2-trichloroethoxycarbonyl, guanidylcarba Moyl, optionally substituted ureidocarbonyl group containing 3-methanesulfonylimidazolidon-1-yl carbonyl, alkanoyl group containing 1 to 5 carbon atoms, pyroncarbonyl, thiopyronecarbonyl, pyridone Carbonyl, ortho-or heterocyclic monocyclic aromatic acyl groups optionally substituted by hydroxy, lower alkanoyloxy containing 1 to 3 carbon atoms, halogen, trifluoromethyl or amino containing 1 to 3 carbon atoms Alkyl group Or a hydroxyalkyl group containing 1 to 3 carbon atoms, or a conventional amino-protecting group such as a phthalamido or enamine form derived from acetoacetate, acetylacetone, acetoacetamide or acetoacetonitrile Containing amino groups, ii) hydroxy or acyloxy, carbamoyloxy containing 1-7 carbon atoms, or aralkyloxy containing 7-12 carbon atoms, iii) carboxyl or containing 2-7 carbon atoms Alkoxycarbonyl, indanyloxycarbonyl, phenoxycarbonyl, or a) azido, cyano, carbamoyl, alkoxysulfonyl, sulfo, or alkoxysulfonyl.)

8) 2-sidone-3-alkanoyl containing 3 to 5 carbon atoms

9) (2- or 4-pyridone-1-yl) acetyl.

10) 5-aminoadipoyl, aroyl or 5-aminoadipoyl groups protected from amino groups by alkanoyls containing 1 to 10 carbon atoms, chloroalkanoyls containing 1 to 5 carbon atoms or 2 to 10 carbon atoms 5-aminoadifoyl groups, 2,2,2-trichloroethyl, trialkylsilyl, alkyl containing 1 to 6 carbon atoms, nitrobenzyl, protected at the carboxyl group by alkoxycarbonyl or benzhydryl containing carbon atoms Or methoxybenzyl

11) acyl group represented by the following formula,

Wherein L is a readily removable hydrocarbon group containing 1 to 8 carbon atoms (e.g., 2,2,2-trichloroethyl, isobornyl, tert-butyl, 1-methylcyclohexyl , 2-alkoxy tertbutyl, benzyl, P-nitrobenzyl or P-ethoxybenzyl.)

Optionally, A and B together represent a diacyl group derived from a polybasic carboxylic acid containing 4 to 12 carbon atoms, an alkylidene group containing 1 to 6 carbon atoms, or an arylmethyl containing 7 to 9 carbon atoms It may represent a leaden group.

In the above, examples of the Ar group include furyl, thienyl, pyryl, oxazolyl, isoxazolyl, oxdiazolyl, oxatriazolyl, thiazolyl, isothiazolyl, thiadiazolyl, tithiazolyl, pyrazolyl, imidazolyl , Triazolyl, tetrazolyl, phenyl, pyridyl, pyrimidyl, lyrazinyl, pyridazinyl, triazinyl and dihydrophenyl, each of which is halogen, an alkyl group containing 1 to 3 carbon atoms, hydroxy , May be optionally substituted with aminomethyl or an alkoxy group containing 1 to 3 carbon atoms.

The carboxy protecting group represented by X contains up to 20 carbon atoms, an alkoxy group containing 1 to 8 carbon atoms (e.g. methoxy, ethoxy or tert-butoxy), aralkoxy containing 7 to 20 carbon atoms Groups (eg benzyloxy, methoxybenzyloxy, nitrobenzyloxy, diphenylmethoxy or trityloxy), mono- or bi-cyclic aryloxy groups (eg phenoxy or naphthyloxy), or organic metals Oxy (e.g. trimethylstannicoxy or trimethylsilyloxy), an organic or muralyloxy group containing up to eight carbon atoms or a metal oxy group of groups I, II or III of the periodic table (e.g. sodium oxy , An oxygen group such as potassium oxy or magnesio dioxy), and X is selected from a nitrogen group such as forming a sulfur group, an amido, hydrazide, azide group, etc., which forms a thiol ester, a thiocarboxyl group, or the like. Or the other or a carboxy-protecting group may be selected from.

These groups may contain heteroatoms in the nucleus, if possible, and may be unsaturated or substituted by substituents as mentioned above (strict nitrogen groups, oxygen groups, sulfur groups, carbon groups or popular or halogens). . Groups which form haloalkyl esters containing 1 to 5 carbon atoms as appropriate among the carboxyl protecting groups X, acylalkyl ester groups containing 2 to 10 carbon atoms, alkoxyalkyl- or aminoalkyl esters containing 2 to 8 carbon atoms Groups, alkoxyalkyl- or aminoalkyl ester groups containing 2 to 8 carbon atoms, aryl esters or aralkyl ester groups containing 7 to 20 carbon atoms, ester groups having oximes containing 2 to 10 carbon atoms, 1 N-alkoxyamide groups containing ˜5 carbon atoms, imide groups with saccharin, imide groups with phthalimide, N, N-diisobutylhydrazide, metal salts, or alkyls containing 1 to 6 carbon atoms Amine salts, or groups that actually correspond to these groups (wherein the specific number of carbon atoms is the same as for X groups).

Antimicrobially preferred carboxy-protecting groups X are acyloxymethyl esters, phenacyl esters, benzaldooximes, N, N-dimethylaminomethyl esters, alkali metal salts, alkaline earth metal salts, acylated alkaline earth metal salts and others which actually correspond to these groups. And those that form groups of. Preferred carboxyprotecting group X includes tertiary butoxybenzyloxy, benzhydryloxy, P-nitrobenzyloxy, P-methoxybenzyloxy, 2,2,2-trichloroethoxy and alkali metal-oxy groups.

Thiol substituent R means groups that can be easily removed without adversely affecting other parts of the molecule before or during the cyclization reaction. Examples thereof include acyl groups, for example tert-butoxycarbonyl, carbobenzoxyl, cyclopropylmethoxycarbonyl, cyclopropylethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2- Methanesulfonylethoxycarbonyl:

1-alkoxy or acyloxyalkyl groups containing 2 to 10 carbon atoms (eg methoxymethyl, ethoxymethyl, acetoxymethyl, 1-benzoyloxyethyl), mono- or dicyclic aromatic thio groups (eg thia And groups such as diazolylthio, thiazolylthio, benzothiazolylthio, phenylthio, 0-nitrophenylthio and naphthylthio).

The process of the present invention is the oxidation separation of unsaturated bonds represented by the following scheme.

Wherein A, B, R and X are as described above.

The method of the present invention obtains the desired compound by oxidatively separating the starting materials at unsaturation in the α-position substituent.

Oxidative separation reaction to form a glycol group using ozone-oxidation, ie, osmium tetraoxide, hydrogen, peroxide-osmium tetroxide, sodium chlorate-osmium tetroxide, permanganate, and then to separate the glycol; Another oxidative separation reaction is carried out according to a conventional method under conditions in which other parts of the molecule are not adversely affected.

In particular, the ozone oxidation reaction involves less side reactions and is preferably performed under mild reaction conditions. The ozonation reaction introduces an amount of ozone sufficient to make an ozonate into a solution of the starting material and then treats the produced ozonate with a reducing agent that can reductively separate the produced ozonate. Particularly preferred solvents include alkanes, haloalkanes, ethers, alkano esters, alkanoic acids, alcohols, aromatic hydrocarbons, in particular chloroalkane solvents and mixed solvents with alcohols (eg methanol, ethanol).

Reducing agents include metals and acids (such as zinc and acetic acid, iron and hydrochloric acid), sulfur dioxide or sulfite (such as sodium sulfite and potassium hydrogen sulfite), trivalent phosphite compounds (such as phosphite esters and phosphites), ferrocyanide, Sulfides (dialkylsulfides, eg dimethylsulfides, aromatic sulfides, eg diphenylsulfides, dibenzylsulfides), hydrogen (in the presence of la-nickel, platinum, palladium, etc.), borohydrides or complexes thereof (sodium Borohydride and the like), aluminum hydride complexes (such as lithium aluminum hydride), hydrazine and other reducing agents. The formation of the ozone cargo can be carried out at -80 ° C or higher than room temperature, but the effect of ozone at high temperatures is high, and side reactions can be suppressed. Excess ozone can be removed from the reaction medium by introducing oxygen, nitrogen, air or the like into the reaction mixture. The reducing agent may be added to the reaction mixture containing the ozonate itself but may be added after the reaction mixture has been properly concentrated. The reaction with the reducing agent can be carried out under conventional conditions suitable for the reagents used and the like.

Instead of the ozonation reaction described above, the target compound can be obtained by subjecting the ozonate to hydrolysis, oxidation, and pyrolysis.

Example 1

To a solution of methyl α- [4-acetylthio-3-phthalimido-2-oxoazetidin-1-yl] -α-isopropenyl acetate (200 mg) in methylene chloride (10 ml) was excess at −5 ° C. Introduced ozone. After the gas at the outlet produced potassium iodide branching, the reaction mixture was concentrated to 2 ml, then mixed with a solution of sodium borohydride (50 mg) in methanol (10 ml) and stirred for 30 minutes. The reaction mixture was concentrated, dissolved in methylene chloride, washed with water, dehydrated and evaporated. The residue was recrystallized from a mixture of methylene chloride and ether to give methyl α- [4-acetylthio-3-phthalimido-2-oxoazetidin-1-yl] -α- (1-hydroxyethylidene ) Acetate (157 mg) was obtained. Yield: 78%, m.p. 178 ~ 183 ℃

Example 2

Excess in a solution of α- [4-acetylthio-3-phthalimido-2-oxo-azetidin-1-yl] -α-isopropenyl acetate (100 mg) dissolved in methanol (10 ml) at 0 ° C. Ozone was introduced. After the gas at the outlet produced potassium iodide starch, the reaction mixture bubbled with sulfur dioxide gas. The reaction mixture was concentrated, and the obtained residue was extracted with methylene chloride sodium hydrogen chloride. The extract was washed with water, dehydrated and evaporated to afford α- [4-acetylthio-3-phthalimido-2-oxoazetidin-1-yl] -α-acetyl acetate (64 mg). Yield 63% foamy.

Example 3

2,2,2-trichloroethyl α- [4- (2-benzothiazolyl) dithio-3-phenoxyacetamido-2- dissolved in a mixture with methylene chloride (70 ml) and methanol (18 ml) Ozone was introduced into the stirred solution of oxoazetidin-1-yl] -α-isopropenyl acetate (1.76 g) while cooling with dry ice acetone until the solution appeared pale blue. After introducing nitrogen gas, the solution was treated with sulfur dioxide gas and concentrated until the solution of the reaction mixture became pale yellow (about 30 seconds). The resulting residue was extracted with methylene chloride, washed with brine, dehydrated and then concentrated to give a powdered residue (1.35 g). This residue was purified by silica gel (30 g) chromatography to give 2,2,2-trichloroethyl α- [4- (2-benzothiazolyl) dithio-3-phenoxyacetamido-2-oxoazeti Din-1-yl] -α (1-hydroxyethylidene) acetate (1.09 g: yield: 62.0%; mp 130-131 DEG C) and 2,2,2-trichloroethyl α- [4- (2 -Benzothiazolyl) dithio-3-phenoxyacetamido-2-oxoazetidin-1-yl] -α- (1,1-dimethoxyethyl) acetate (0.30 g, yield: 15.6%) Got it.

Example 4

Of α- [4-substituted (R ² ) thio-3-substituted amino (R ¹ ) -2-oxoazetidin-1-yl] -α-isopropenyl-acetate ester (R ³ ) dissolved in a solvent Ozone was introduced into the solution under ice cooling. After the gas made potassium iodide starch blue at the outlet, the introduction of ozone was stopped and nitrogen gas was introduced to remove excess ozone. A reducing agent is added to the reaction mixture and allowed to react for 10-30 minutes. After reduction, the solvent is evaporated and the residue is crystallized or the reaction mixture is filtered through a silica gel layer and the filtrate is evaporated to α- [4. -Substituted thio-3-substituted amino-2-oxoazetidin-1-yl] -α- (1-hydroxyethylidene) acetate ester was obtained. The reaction conditions are shown in Table I, and the physical properties of the product are shown in Table II.

TABLE 1

TABLE II

Example 5

In a similar manner to that of Example 4, 4-substituted thio-3-substituted amino-2-oxo-α- (1-hydroxyethylidene or acetyl) azetidine-1-acetic acid ester Prepared from isopropenyl azetidine derivatives.

(1) P-methoxybenzyl α- [4- (2-methyl-1,3,4-thiadiazol-5-yl) dithio-3- (3-thienylacetamido) -2-jade Pediatric zetidin-1-yl] -α- (1-hydroxyethylidene) acetate

(2) 2,2,2-trichloroethyl α- [4- (0-nitrophenyl) dithio-3- (2,2,2-trichloroethoxycarbonamide) -2-oxoazetidine -1-yl] -α- (1-hydroxyethylidene) acetate

(3) diphenylmethyl α- [4-cyclopropylmethoxycarbonylthio-3-tert-butoxycarbonamido-2-oxoazetidin-1-yl] -α- (1-hydroxy Ethylidene) acetate

(4) 2,2,2-trichloroethyl α- [4-acetylthio-3- (n-tert-butoxycarbonamido-α-phenylglycineamido) -2-oxoazetidine-1- Il] -α- (1-hydroxyethylidene) -acetate.

(5) P-bromophenacyl α- [4- (benzothiazol-2-yl) dithio-3- (2,2-dimethyl-3-nitroso-4-phenyl-5-oxoimidazolidine -1-yl) 2-oxoazetidin-1-yl] -α- (1-hydroxyethylidene) acetate.

(6) P-nitrobenzyl α- [4- (1,2,3-thiadiazol-5-yl) dithio-3- (0-nitrobenzylideneamino) -2-oxoazetidine-1 -Yl] -α- (1-hydroxyethylidene) -acetate.

(7) Methyl α- [4-benzylthiodio-3- (2,6-dimethoxybenzoylamino) -2-oxoazetidin-1-yl] -α- (1-hydroxyethylidene) acetate .

(8) ethyl α- [4-acetylthio-3-cyanoacetamido-2-oxoazetidin-1-yl] -α- (1-hydroxyethylidene) acetate.

(9) Acetoxymethyl [4-acetylthio3- (α-indanyloxycarbonyl-α-phenylacetamido) -2-oxoazetidin-1-yl] -α- (1-hydroxye Tilidene) acetate and

(10) disodium α- [4-pyrididithio-3- (α-sulfo-α-phenylacetamido) -2-oxoazetidin-1-yl] -α- (1-hydroxye Tilidene) acetate.

Claims (1)

A method for preparing an intermediate of the cefe ring compound of formula (I), wherein the unsaturated bond of the compound of formula (II) is subjected to oxidative cleavage.

Wherein A and B are each hydrogen or amino substituent, X is hydroxy or carboxy substituent, and R is hydrogen or thiol substituent.