JP2006507289A5

JP2006507289A5 -

Info

Publication number: JP2006507289A5
Application number: JP2004547902A
Authority: JP
Filing date: 2003-10-23
Publication date: 2006-12-21

Description

本発明の方法で調整された（I）のクロロメチルセフェム誘導体は、式（II）のセファロスポリン系抗生物質の調整に有用であり、当該クロロメチルセフェム誘導体を中間体として、式（II）のセファロスポリン系抗生物質を製造することができる。

ここで、Ｒ_４は、カルボン酸イオンまたはＣＯＯＲ_ｄを表す。なお、Ｒ_ｄは、水素原子、エステル、または塩形成可能な対イオンを表す。Ｒ_６は、Ｈ、ＣＨ_３、ＣＲ^ａＲ^ｂＣＯＯＲ^ｃを表す。なお、Ｒ^ａおよびＲ^ｂは、それぞれ独立に水素原子またはメチル基を示し、Ｒ^ｃは、水素原子または炭素数１〜６のアルキル基を示し、Ｒ_５は、ＣＨ_３、ＣＨ_２ＯＣＨ_３、ＣＨ_２ＯＣＯＣＨ_３、ＣＨ＝ＣＨ_２、または、

を表す。 Chloromethyl cephem derivative of adjusted by the method (I) of the present invention is it practical to adjust the cephalosporin antibiotics of Formula (II), the chloromethyl cephem derivatives as intermediates of formula (II ) Cephalosporin antibiotics.

Here, R ₄ represents a carboxylate ion or COOR _d . R _d represents a hydrogen atom, an ester, or a counter ion capable of forming a salt. R ₆ represents H, CH ₃ , CR ^a R ^b COOR ^c . R ^a and R ^b each independently represent a hydrogen atom or a methyl group, R ^c represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, R ₅ represents CH ₃ , CH ₂ OCH ₃ , _{_{CH 2 OCOCH 3, CH = CH}} 2, or,

Represents.

Claims

An improved process for the preparation of a chloromethyl cephem derivative of formula (I) comprising:

(Wherein R ₁ is a carboxy protecting group, that is, a substituted methyl group that can be easily deprotected, for example, t-butyl group, diphenylmethyl group, 4-methoxybenzyl group, 2-methoxybenzyl group, 2-chlorobenzyl group) R ₂ represents hydrogen, an alkyl group having 1 to 4 carbon atoms, a substituted or unsubstituted phenyl group, or a substituted or unsubstituted phenoxy group.
The method
(I) converting the compound of formula (V) to the compound of formula (VI);

(Here, R ₈ represents a substituted or unsubstituted alkyl group or aryl group having 1 to 6 carbon atoms. In addition, arylsulfinic acid or 1 to 6 carbon atoms at a temperature in the range of 25 ° C. to 40 ° C. Metal salts of sulfinic acids, bases and solvents to which alkyl groups have been added are used, and improvements are made by adding metal salts of aryl sulfinic acids at a pH in the range of 4.0 to 8.0.)
(Ii) chlorinating the compound of formula (VI) with a chlorinating agent in the presence of a base and a solvent at a temperature ranging from 15 ° C to 40 ° C to produce a compound of formula (VII); ,

(Here, R ₈ represents a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms or an aryl group, and other symbols are the same as those described above.)
(Iii) A step of producing a chloromethylcephem derivative of the formula (I) by cyclizing the compound of the formula (VII) with a base in a solvent at a temperature in the range of −60 ° C. to + 50 ° C. When,
Have

The metal salt of arylsulfinic acid used in step (i) is copper (II) p-toluenesulfinate, copper (II) benzenesulfinate, sodium toluenesulfinate, silver (II) p-toluenesulfinate, benzenesulfine 2. A process according to claim 1, selected from acid silver (II).

The process according to claim 1, wherein the solvent used in step (i) is selected from acetone, THF, dioxane, acetonitrile and alcohols such as methanol, ethanol and isopropanol in the presence or absence of water. .

The method according to claim 1, wherein the addition of arylsulfinic acid or a metal salt of sulfinic acid to which an alkyl group having 1 to 6 carbon atoms has been added in step (i) is preferably carried out in the range of pH 5-7.

The process according to claim 1, wherein the base used in step (i) is selected from ammonia, calcium carbonate, sodium bicarbonate, sodium carbonate, potassium carbonate, potassium bicarbonate, diisopropylethylamine, triethylamine.

The chlorinating agent used in step (ii) is chlorine gas, HOCl, Cl in the presence or absence of a solvent. _２2 O, CH _３3 2. A method according to claim 1 selected from OCl.

The method of claim 6, wherein the chlorinating agent is selected from dioxane, carbon tetrachloride, ethyl acetate, acetonitrile, diglyme, dimethylformamide, dimethylacetamide, tetrahydrofuran, methylene chloride, butyl acetate, diphenyl ether, toluene, or mixtures thereof. .

The solvent used in step (ii) is selected from dioxane, carbon tetrachloride, ethyl acetate, acetonitrile, diglyme, dimethylformamide, dimethylacetamide, tetrahydrofuran, methylene chloride, butyl acetate, diphenyl ether, toluene, or mixtures thereof. Item 2. The method according to Item 1.

The cyclization in step (iii) is selected from ammonia and ammonium salts such as ammonium carbonate, ammonium acetate, and organic amines such as N, N-diisopropylamine, N, N-diethylamine, methylamine, triethylamine. The method according to claim 1, which is carried out using a base.

The solvent used in step (iii) is selected from 1-methylpyrrolidone-2-one (NMP), DMF, acetonitrile, N, N-dimethylacetamide, dimethylacetamide, ethyl acetate, dioxane, THF, methylene dichloride, The method of claim 1.

A method for producing a compound of formula (II), wherein the compound of formula (I) obtained by the production method according to claim 1 is used as an intermediate .

(Wherein, _{R 4} represents a carboxylic acid ion or COOR _d. Note, _{R d} is .R ₆ _{is H,} CH 3 represents a hydrogen atom, an ester or a salt formable counterion,, ^CR a R ^b COOR ^c , wherein R ^a and R ^b each independently represent a hydrogen atom or a methyl group, R ^c represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and R ₅ represents CH ₃ , CH ₂ OCH ₃ , CH ₂ OCOCH ₃ , CH═CH ₂ , or

Represents. )