JP3195960B2 - Method for producing 3-hydroxycephem derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a method for producing a 3-hydroxycephem derivative.

[0002]

BACKGROUND OF THE INVENTION Conventional technology and its problems

[0003]

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Wherein R ¹ is an amino group or a protected amino group, R ² is a hydrogen atom or a carboxylic acid protecting group, and R ³ is a hydrogen atom or a hydroxyl protecting group. As a method for producing the 3-hydroxycephem derivative represented by the following formula, for example, a method described in JP-B-62-5919 is known.

However, this method is a method for producing a 3-hydroxycephem derivative by a ring-closing reaction using a base. Therefore, in the above method, in addition to the target 3-cephem derivative represented by the general formula (2), General formula

[0006]

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[Wherein R ¹ , R ² and R ³ are as defined above. Cannot be avoided as a by-product of the 2-cephem compound represented by the formula: Therefore, in order to separate the mixture and obtain only the desired 3-cephem compound, purification by silica gel column chromatography or the like is required. It has a drawback. For this reason, there are disadvantages that industrial implementation is difficult and that the yield of the desired 3-cephem compound is low.

[0008]

DISCLOSURE OF THE INVENTION The object of the present invention is to provide an industrially advantageous compound of the above general formula (III) which is free from the drawbacks of the above-mentioned conventional method, is safe and easy to operate, has a high yield and a high purity. An object of the present invention is to provide a method capable of producing the 3-hydroxycephem derivative represented by 2).

That is, the present invention provides a compound represented by the general formula

[0010]

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Wherein R ¹ , R ² and R ³ are as defined above.
Ar represents an aryl group which may have a substituent, and X represents a halogen atom. Reacting a halogenated β-lactam compound represented by the following formula with a metal iodide or an iodine salt of an ammonium compound to obtain a 3-hydroxycephem derivative represented by the above general formula (2). The present invention relates to a method for producing a derivative.

In the present invention, the halogenated β-lactam compound of the general formula (1) used as a starting material is, for example,

[0013]

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Wherein Ar, R ¹ , R ² and X are as defined above. ] Is produced by ozone oxidation of a β-lactam compound represented by the following formula:

Each group shown in the present specification is more specifically as follows.

Examples of the aryl group which may have a substituent represented by Ar include a phenyl group and a naphthyl group. Examples of the type of the substituent which may be substituted on the phenyl group or the naphthyl group represented by Ar include, for example, a halogen atom (eg, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom), a C _1-4 straight-chain or A branched alkoxy group (eg, methoxy group, ethoxy group, etc.), a C _1-4 straight-chain or branched alkylthio group (eg, methylthio group,
An ethylthio group), a C _1-4 linear or branched alkyl group (eg, methyl group, ethyl group, etc.), an amino group, and a C _1-4 linear or branched alkyl group as a substituent. An amino group having one or two (eg, a methylamino group,
Acyloxy groups (for example, phenylcarbonyloxy group, acetyloxy group) represented by a hydroxyl group, R ⁴ COO— (R ⁴ is a phenyl group, a tolyl group, or a C _1-4 linear or branched alkyl group) Group), R
An acyl group (eg, phenylcarbonyl group, acetyl group, etc.), nitro group, cyano group, phenyl group, etc. represented by ⁴ CO- (R ⁴ is the same as above) can be exemplified. These substituents are 1 to 5, particularly 1, 2 or 3, when the aryl group represented by Ar is a phenyl group, and 1 to 7, particularly when the aryl represented by Ar is a naphthyl group. One, two or three, the same or different types may be substituted.

The protected amino group represented by R ¹ includes Protective Group in Organic
Synthesis (Protective Groups in Organic Synthesi)
s, Theodora W. Greene, hereinafter simply referred to as "Document I", Chapter 7 (pp. 218-287), phenoxyacetamide, p-methylphenoxyacetamide, p-methoxy. Phenoxyacetamide, p-chlorophenoxyacetamide, p-bromophenoxyacetamide, phenylacetamide, p
-Methylphenylacetamide, p-methoxyphenylacetamide, p-chlorophenylacetamide, p-
Bromophenylacetamide, phenylmonochloroacetamide, phenyldichloroacetamide, phenylhydroxyacetamide, phenylacetamide, phenylacetoxyacetamide, α-oxophenylacetamide, benzamide, p-methylbenzamide, p-
Methoxybenzamide, p-chlorobenzamide, p-
Examples thereof include bromobenzamide, phenylglycylamide, phenylglycylamide in which an amino group is protected, p-hydroxyphenylglycylamide, and p-hydroxyphenylglycylamide in which one or both of an amino group and a hydroxyl group are protected. . Phenylglycylamide and p
Examples of the protecting group for the amino group of -hydroxyphenylglycylamido include the above-mentioned Reference I, Chapter 7, Chapters 218 to 287.
Page)). Examples of the hydroxyl-protecting group of p-hydroxyphenylglycylamido include various groups described in Chapter 2 of the above-mentioned Document I (pages 10 to 72).

Examples of the protecting group for the carboxylic acid represented by R ² include various groups described in Chapter 5 of the above-mentioned Reference I (pages 152 to 192), a benzyl group, a p-methoxybenzyl group, Examples thereof include a p-nitrobenzyl group, a diphenylmethyl group, a trichloroethyl group, and a tert-butyl group.

The hydroxyl-protecting group represented by R ³ includes
In addition to the various groups described in Chapter 2 (pages 10 to 72) of Document I, methyl, ethyl, isopropyl, tert-butyl, benzyl, p-methylbenzyl, and p-methyl Examples include a methoxybenzyl group, a diphenylmethyl group, a trimethylsilyl group, a tert-butyldimethylsilyl group, a triethylsilyl group, a phenyldimethylsilyl group, and an acetyl group.

Examples of the halogen atom represented by X include a chlorine atom, a bromine atom and an iodine atom.

Among the compounds of the general formula (1), those in which R ³ represents a hydrogen atom can be obtained, for example, by reacting a β-lactam derivative represented by the above general formula (4) with ozone to form an exomethylene group of the derivative. Manufactured by oxidative cleavage.

This ozone oxidation reaction is carried out by reacting a β-lactam derivative represented by the general formula (4) with ozone in a suitable solvent, and the resulting peroxide such as ozonide is reduced. To produce a compound of the general formula (1) in which R ³ represents a hydrogen atom.

The reaction conditions for the ozone oxidation reaction include:
For example, The Chemical Society of Japan, “New Experimental Chemistry Course” Vol. 15, No. 5
The conditions described on pages 93 to 603 can be applied.

Specifically, this reaction is performed in a suitable solvent. Such solvents include, for example, methanol,
Alcohols such as ethanol, propanol, isopropanol, butanol, tert-butanol, and lower grades such as methyl formate, ethyl formate, propyl formate, butyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, methyl propionate, and ethyl propionate Lower alkyl esters of carboxylic acids, ketones such as acetone, methyl ethyl ketone, methyl propyl ketone, methyl butyl ketone, methyl isobutyl ketone, diethyl ketone, diethyl ether, ethyl propyl ether, ethyl butyl ether, dipropyl ether, diisopropyl ether, dibutyl ether , Ethers such as methyl cellosolve and dimethoxyethane, cyclic ethers such as tetrahydrofuran and dioxane, acetonitrile, propionitrile, butyronitrile , Toluene, xylene, chlorobenzene, substituted or unsubstituted aromatic hydrocarbons such as anisole, dichloromethane, chloroform, dichloroethane, trichloroethane, dibromoethane, propylene dichloride , Carbon tetrachloride, halogenated hydrocarbons such as fluorocarbons, pentane, hexane, heptane, aliphatic hydrocarbons such as octane, cyclopentane,
Examples thereof include cycloalkanes such as cyclohexane, cycloheptane and cyclooctane; amides such as dimethylformamide and dimethylacetamide; and dimethylsulfoxide. These may be used alone or as a mixture of two or more. Further, these organic solvents may contain water as necessary. Such a solvent is generally used in an amount of about 10 to 200 l per kg of the compound of the general formula (4),
Preferably, about 20 to 100 l is used.

The reaction temperature of the above reaction is usually -78 to 0 ° C.
Degree, preferably about -60 to -25 ° C.

The amount of ozone used in the above reaction is usually 1 equivalent to the starting compound (4), but if necessary, it is preferable to pass ozone until the starting compound (4) is consumed. When the use amount of ozone exceeds 1 equivalent, it is preferable to drive off excess ozone by passing dry nitrogen into the reaction mixture, and then perform post-treatment.

When the peroxide such as ozonide generated by the above reaction is reductively decomposed by a reducing agent used in a usual organic reaction, the desired compound of the general formula (1) is produced. Here, as the reducing agent, for example, platinum,
Examples include catalytic hydrogenation using a catalyst such as palladium, nickel, and rhodium, phosphites, trivalent phosphorus compounds such as triphenylphosphine, and dimethyl sulfide.

The thus-obtained compound of the general formula (1) in which R ³ is a hydrogen atom can have a keto-enol type tautomerism.

Formula (1) wherein R ³ is a hydroxyl-protecting group
The compound represented by is produced by protecting the hydroxyl group in the compound obtained as described above (the compound of the general formula (1) in which R ³ represents a hydrogen atom) according to a known method. As the reaction conditions for protecting the hydroxyl group, for example, various conditions described in the above-mentioned Document I, Chapter 2 (pages 10 to 72) can be applied.

The compound of the present invention obtained in each of the above steps is isolated and purified from the reaction mixture by a conventional isolation and purification means, for example, filtration, recrystallization, column chromatography, preparative thin-layer chromatography and the like.

In the reaction of the present invention, the starting compound (1) is reacted with an iodide salt of a metal iodide or an ammonium compound in an organic solvent to give the desired 3-hydroxycephem of the above general formula (2). A derivative is produced.

As the organic solvent used in the above reaction of the present invention, conventionally known organic solvents can be widely used as long as they dissolve the compound of the general formula (1) and are inert under the conditions of the reaction. Alcohols such as methanol, ethanol, propanol, isopropanol, butanol, tert-butanol, methyl formate, ethyl formate, propyl formate, butyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, methyl propionate, ethyl propionate, etc. Lower alkyl esters of lower carboxylic acids of
Ketones such as acetone, methyl ethyl ketone, methyl propyl ketone, methyl butyl ketone, methyl isobutyl ketone, diethyl ketone, diethyl ether, ethyl propyl ether, ethyl butyl ether, dipropyl ether, diisopropyl ether, dibutyl ether, methyl cellosolve, dimethoxyethane, etc. Ethers, tetrahydrofuran, cyclic ethers such as dioxane, acetonitrile, propionitrile, butyronitrile, isobutyronitrile, nitriles such as valeronitrile, benzene, toluene, xylene, chlorobenzene,
Substituted or unsubstituted aromatic hydrocarbons such as anisole, dichloromethane, chloroform, dichloroethane,
Halogenated hydrocarbons such as trichloroethane, dibromoethane, propylene dichloride, carbon tetrachloride, and fluorocarbons; aliphatic hydrocarbons such as pentane, hexane, heptane, and octane; cyclopentane, cyclohexane, cycloheptane, and cyclooctane such as cyclooctane Examples thereof include alkanes, amides such as dimethylformamide and dimethylacetamide, and dimethylsulfoxide. These may be used alone or as a mixture of two or more. Further, these organic solvents may contain water as necessary. Such a solvent contains 1 kg of the compound of the general formula (1).
0.5 to 200 l, preferably 1 to 50
It is preferable to use about l.

Examples of the metal iodide used in the above reaction include alkali metal salts such as lithium iodide, sodium iodide and potassium iodide, and alkaline earth metal salts such as magnesium iodide, calcium iodide and barium iodide. And the like. Examples of the iodine salt of an ammonium compound include, for example, ammonium iodide, methyl ammonium iodide, ethyl ammonium iodide, propyl ammonium iodide, isopropyl ammonium iodide, butyl ammonium iodide,
Ammonium salts derived from substituted or unsubstituted alkyl or substituted or unsubstituted aryl primary amines such as sec-butylammonium iodide, tert-butylammonium iodide, benzylammonium iodide, and anilinium iodide, dimethyl iodide Ammonium, diethyl ammonium iodide, dipropyl ammonium iodide, diisopropyl ammonium iodide, dibutyl ammonium iodide, di iodide
sec-butylammonium, ditert-butylammonium iodide, dibenzylammonium iodide, N-methylanilinium iodide, pyrrolidinium iodide, 2-pyrrolinium iodide, 2-imidazolinium iodide, piperidinium iodide,
Ammonium salts derived from substituted or unsubstituted alkyls such as indolinium iodide, substituted or unsubstituted aryl or substituted or unsubstituted heterocyclic secondary amines, trimethylammonium iodide, triethylammonium iodide, iodine Tripropylammonium iodide, tributylammonium iodide, benzyldiethylammonium iodide, N, N-dimethylanilinium iodide, pyridinium iodide, imidazolium iodide, pyrazolium iodide, benzimidazolium iodide, N, N iodide Substituted or unsubstituted alkyl such as dimethylcyclohexylammonium,
Ammonium salts derived from substituted or unsubstituted aryl or substituted or unsubstituted heterocyclic tertiary amines, tetramethylammonium iodide, tetraethylammonium iodide, tetrapropylammonium iodide, tetrabutylammonium iodide, iodine Substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted, such as benzyltrimethylammonium iodide, 1-methylpyridinium iodide, 3-methylthiazolium iodide, and 3-ethylbenzothiazolium iodide And the like. The amount of the metal iodide or the iodine salt of an ammonium compound to be used is generally 0.1 to 10 moles, preferably about 0.9 to 5 moles, per mole of Compound (1).

The reaction temperature of the above reaction varies depending on the starting compound, the organic solvent used, and the like, and cannot be determined unconditionally, but is usually about -20 to 100 ° C, preferably about 0 to 80 ° C.

In this reaction, an inorganic reducing agent may be present in the reaction system. Such inorganic reducing agents include, for example, dithionites such as sodium, potassium, and magnesium; sulfites such as sodium, potassium, calcium, and ammonium; bisulfites such as sodium, potassium, and calcium; sodium, potassium, and ammonium. Such as pyrosulfites, thiosulfates such as sodium, potassium, magnesium and iron; disulfites such as sodium; hypophosphites such as sodium, potassium, calcium, ammonium and aluminum; sodium phosphite; phosphonic acid Sodium hydrogen, sodium diphosphite, sodium hypophosphate and the like. The amount of the inorganic reducing agent to be used is generally 0.1 to 10 times mol, preferably about 0.5 to 5 times mol, relative to compound (1).

After completion of the above reaction, the desired 3-hydroxycephem derivative (2) can be isolated in a substantially pure form, for example, by performing a normal extraction operation. If further purification is necessary, conventional purification means such as recrystallization and column chromatography may be employed.

[0037]

According to the present invention, the halogenated β- of the general formula (1)
When a lactam compound is used, the 3-hydroxycephem derivative of the general formula (2) can be produced by a safe and simple operation, in a high yield and a high purity, by an industrially advantageous method.

[0038]

The present invention will be further clarified with reference to the following examples.

[0039]

Example 1 R ¹ is a phenylacetamide group and R ² is p
201 mg of a compound of the general formula (1) in which -methoxybenzyl group, R ³ is a hydrogen atom, Ar is a phenyl group and X is a chlorine atom (hereinafter referred to as “compound (1a)”) were dissolved in 5 ml of tetrahydrofuran. To this, 48 mg of sodium iodide and 85 mg of sodium thiosulfate pentahydrate were added, and the mixture was reacted with stirring at room temperature for 5 hours while protecting from light. Water was added to the reaction solution thus obtained, and extracted with ethyl acetate. The organic layer is separated, washed with water, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. A general formula in which R ¹ is a phenylacetamide group, R ² is a p-methoxybenzyl group, and R ³ is a hydrogen atom. Compound (2) (hereinafter referred to as “compound (2)
a) ") in 95% yield.

The spectral data of the obtained compound completely coincided with that of the separately synthesized compound.

[0041]

EXAMPLE 2 Compound (1a) (500 mg) was added to acetone (25 ml).
Was dissolved. To this, 295 mg of potassium iodide was added and reacted under reflux for 1 hour. The reaction solution thus obtained was concentrated under reduced pressure, redissolved in ethyl acetate, and washed with an aqueous solution of sodium thiosulfate. The organic layer was separated, dried over magnesium sulfate, and concentrated under reduced pressure to give compound (2)
a) was obtained in 90% yield.

[0042]

Examples 3 to 9 The types and solvents of metal iodides are shown in Table 1 below.
Compound (2a) was obtained by treating in the same manner as in Example 2 except for changing as shown in (2). The results are shown in Table 1.

[0043]

[Table 1]

[0044]

Example 10 A compound of the general formula (1) wherein R ¹ is a phenylacetamide group, R ² is a diphenylmethyl group, R ³ is a hydrogen atom, Ar is a phenyl group and X is a chlorine atom (hereinafter referred to as “compound (1b) ") And treated in the same manner as in Example 1 to obtain a compound represented by the general formula (2) wherein R ¹ is a phenylacetamide group, R ² is a diphenylmethyl group, and R ³ is a hydrogen atom.
(Hereinafter referred to as “compound (2b)”) was obtained in a yield of 93%.

The spectral data of the obtained compound was completely identical to that of the separately synthesized compound.

[0046]

Example 11 A compound of the general formula (1) wherein R ¹ is a phenylacetamide group, R ² is a p-methoxybenzyl group, R ³ is a hydrogen atom, Ar is a phenyl group and X is an iodine atom (hereinafter referred to as “compound ( 1c) ") to give the compound (2a) in a yield of 94%.

[0047]

Example 12 A compound of the general formula (1) wherein R ¹ is a phenylacetamide group, R ² is a diphenylmethyl group, R ³ is a hydrogen atom, Ar is a phenyl group and X is an iodine atom (hereinafter referred to as “compound (1d) ") To give compound (2b) in 93% yield.

──────────────────────────────────────────────────続 き Continued on the front page (72) Inventor Michio Sasaoka 463 Otsuka Chemical, Kagasuno, Kawauchi Town, Tokushima City, Tokushima Prefecture (72) Inventor Takashi Joi 463 Otsuka Chemical, Kasuno, Kawauchi Town, Tokushima City, Tokushima Prefecture Inside the Tokushima Research Laboratories Co., Ltd. (72) Inventor Yutaka Kameyama 463 Otsuka Chemical Co., Ltd., Kagasuno, Kawauchi-cho, Tokushima City, Tokushima Prefecture (56) References JP-A-61-257991 (JP, A) CHEMISTRY LETTERS (1990) , (10), pages 1867-1868 (58) Fields investigated (Int. Cl. ⁷ , DB name) C07D 501/00-501/62 CA (STN) REGISTRY (STN)

Claims (1)

(57) [Claims] 1. A compound of the general formula [Wherein Ar is an aryl group which may have a substituent, R
¹ is an amino group or a protected amino group, R ² is a hydrogen atom or a carboxylic acid protecting group, R ³ is a hydrogen atom or a hydroxyl protecting group, and X is a halogen atom. Is reacted with a metal iodide or an iodine salt of an ammonium compound to obtain a compound represented by the general formula: Wherein R ¹ , R ² and R ³ are the same as above. ] A method for producing a 3-hydroxycephem derivative, characterized by obtaining a 3-hydroxycephem derivative represented by the following formula: