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WO2001098309A1 - Procede de preparation de composes de cepheme - Google Patents

Procede de preparation de composes de cepheme Download PDF

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Publication number
WO2001098309A1
WO2001098309A1 PCT/JP2001/005163 JP0105163W WO0198309A1 WO 2001098309 A1 WO2001098309 A1 WO 2001098309A1 JP 0105163 W JP0105163 W JP 0105163W WO 0198309 A1 WO0198309 A1 WO 0198309A1
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WO
WIPO (PCT)
Prior art keywords
ester
salt
compound
group
reaction
Prior art date
Application number
PCT/JP2001/005163
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English (en)
Japanese (ja)
Inventor
Katsuhiko Shinozaki
Masaru Hayashi
Masato Kitayama
Original Assignee
Fujisawa Pharmaceutical Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Fujisawa Pharmaceutical Co., Ltd. filed Critical Fujisawa Pharmaceutical Co., Ltd.
Priority to AU2001274541A priority Critical patent/AU2001274541A1/en
Publication of WO2001098309A1 publication Critical patent/WO2001098309A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/587—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with aliphatic hydrocarbon radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms, said aliphatic radicals being substituted in the alpha-position to the ring by a hetero atom, e.g. with m >= 0, Z being a singly or a doubly bound hetero atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring

Definitions

  • the present invention relates to a method for producing 7- [2- (2-aminothiazol-4-yl) -12-lower alkoxycarbonylmethoxyiminoacetamide] -3-3-cebum compound or a salt thereof.
  • the present invention provides a compound represented by the following general formula: 7- [2_ (2-amino'thiazo-l-yl-4_yl) _2-lower alkoxycarbonyl methoxyiminoacetamide] -3-cepum compound or Of the salt thereof from the corresponding 7-amino-3-cebum compound or a salt thereof and 2- (2-aminothiazo-1-yl-4-yl) -12-lower alkoxycarbonylmethoxymethoxyminacetyl halide or a salt thereof It relates to a novel production method with high yield.
  • an object of the present invention is to provide 7- [2- (2-aminothiazolyl-14-yl) 1-2-lower alkoxycarbonylmethoxyiminoacetate.
  • A.Mid It is an object of the present invention to provide a novel industrial production method of 1-3-cepum compound (I) or a salt thereof.
  • the inventors of the present invention have proposed various processes for the industrial production of 7-C2- (2-aminothiazol-4-yl) -12-alkoxycarbonylmethoxyiminoacetamide] -13-cephum compounds.
  • the method was studied diligently, and as a result, 2- (2-aminothiazo-l- 4-yl) -l-l-alkoxycarbonylmethyoxy misoacetyl halide or its acid addition salt was separated in a stable form.
  • the production method of the present invention has the following formula:
  • Suitable salts of the raw material compound (II) and the target compound (I) include common salts used in the field of cephalosporin and venicillin, and salts with inorganic bases, for example, sodium Salts, alkali metal salts such as potassium salts, for example, alkaline earth metal salts such as calcium salts and magnesium salts; salts with organic bases, for example, triethylamine salts, pyridine salts, picoline salts, Organic amine salts such as ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N, N'-dibenzylethylenediamine salt and the like; for example, hydrochloride, hydrobromide, Inorganic acid addition salts such as sulfates and phosphates; for example, formate, acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonic acid Salts, salts with bases or acid addition salts such as organic carboxy
  • the production method of the present invention is represented by the following reaction formula.
  • Starting compound 2 _ (2-aminothiazolyl 4-yl) 12-lower alkoxycarbonylmethoxyiminoacetyl halide (III) contains novel compounds, which are represented by the following reaction formulas. It can be manufactured by a method.
  • lower unless indicated otherwise, shall mean a group having 1 to 6, preferably 1 to 4 carbon atoms.
  • Suitable "lower alkyl groups” include lower alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isoptyl, tertiary butyl, pentyl, neopentyl, tertiary pentyl and hexyl.
  • Suitable "protected carboxy groups” include the commonly used esterified carboxy groups at the 3- or 4-position in penicillin or cephalosporin compounds.
  • Suitable "ester moieties" of the "esterified carboxy group” include, for example, methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, tertiary butyl ester, pentyl ester, tertiary ester Lower alkyl esters such as lower-pentyl ester and hexyl ester; lower alkenyl esters such as vinyl ester and aryl ester; lower alkynyl esters such as ethynyl ester and propynyl ester; for example, methoxymethyl ester, ethoxymethyl ester and isopropoxymethyl Lower alkoxy (lower) alkyl esters such as esters, 1-methoxyl ester, 1-ethoxyl ester, etc., for example, methylthiomethyl ester, ethylthio Methyl ester Lower alkylthio (low
  • Halo (lower) alkyl C-ster, for example, acetomethyl ester, propionyloxymethyl ester, ptyryloxymethyl ester, isobutyryloxymethyl ester, noryloxymethyl ester, vivaloyloxy Lower alkanoyloxy (lower) alkyl esters such as methyl ester, hexanoyloxymethyl ester, 2-acetoxyl ester, 2-propionyloxetyl ester, 1-acetooxypropyl ester
  • lower alkanesulfonyl (lower) alkyl esters such as methyl mesyl ester and 2-mesyl ethyl ester, for example, benzyl ester, 4-methoxybenzinole estenole, 4-nitropentinole estenole, fenethino lenestenole
  • Suitable substituents such as benzhydryl ester, trityl ester, bis (methoxyphenyl) methyl ester, 3,4-dimethoxybenzyl ester, 4-hydroxy_3,5-ditert-butylbenzyl ester Al (lower) alkyl esters which may have one or more substituents such as mono (or di or tri) phenyl (lower) alkyl esters which may have one or more, for example, phenyl esters, Ril ester, tertiary butyl phenyl ester, xylyl ester
  • Aryl esters which may have one or more suitable
  • Suitable "organic groups” include those commonly used in the 3-position of cephalosporin compounds, such as aliphatic, aromatic and heterocyclic groups such as methyl, ethyl, propyl, isopropyl, butyl, isoptyl, tertiary Lower alkyl groups such as tert-butyl, pentyl, neopentyl, tertiary pentyl, and hexyl;
  • Aryl groups such as, for example, phenyl, tolyl, xylyl, cumenyl, naphthyl;
  • heterocyclic thiomethyl groups such as furylthiomethyl, thiazolylthiomethyl, thiadiazolylthiomethyl, tetrazolylthiomethyl, etc .;
  • heterocyclic methyl group having a quaternary nitrogen atom such as a 1-lower alkylpyrrolidiniomethyl such as -methyl-12-rubamoyloxymethylpyrrolidiniomethyl.
  • Suitable "halogen” includes chlorine, bromine, iodine and the like.
  • R 2 and R 3 are as follows.
  • R 1 is, for example, a lower alkenyl group such as vinyl; or a heterocyclic thiomethyl group, preferably a 5-membered aromatic heterocyclic ring containing one io atom and one or two nitrogen atoms such as 1,2,4-thiadiazolyl. Group;
  • R 2 is a carboxy group or an esterified carboxy group, preferably a tri (lower) alkylsilyloxycarbonyl group, preferably a tri (-) alkyl group such as trimethylsilyloxycarbonyl. Kirsilyloxycarbonyl group;
  • R 3 is a lower alkyl group, preferably Mel one C 4 alkyl group such as methyl.
  • the compound (I) or a salt thereof can be obtained by converting the compound (II) or a reactive derivative thereof at the amino group or a salt thereof to a 2- (2-aminothiazolyl-1-4-yl) -12-alkoxycarbonyl It can be produced by reacting with toximino acetyl halide (III) or a salt thereof.
  • Suitable reactive derivatives at the amino group of compound (II) include compounds (II) and silyl compounds such as bis (trimethylsilyl) acetamide and mono (trimethylsilyl) acetamide. Examples include silyl derivatives generated by the reaction.
  • Suitable salts of the compound (II) include salts as exemplified for the compound (I).
  • the reaction is usually carried out with common solvents such as water, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N, N-dimethylformamide, pyridine.
  • solvents such as water, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N, N-dimethylformamide, pyridine.
  • solvents such as water, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N, N-dimethylformamide, pyridine.
  • the reaction can be carried out in any other organic solvent that does not adversely affect the reaction.
  • These conventional solvents may be used as
  • the reaction involves inorganic or organic bases such as alkali metal bicarbonates, tri (lower) alkylamines, pyridines, N- (lower) alkylmorpholines, N, N-di (lower) alkylbenzylamines, etc. It may be done with or without it.
  • inorganic or organic bases such as alkali metal bicarbonates, tri (lower) alkylamines, pyridines, N- (lower) alkylmorpholines, N, N-di (lower) alkylbenzylamines, etc. It may be done with or without it.
  • the reaction temperature is not particularly limited, but the reaction is usually performed under cooling or at room temperature. Is performed.
  • the compound (III) or a salt thereof used in this reaction is isolated in a stable form for the first time by the inventors of the present invention, whereby the reaction proceeds in high yield, and the step of recovering by-products is reduced. It is very convenient because it is not needed, and the amount of reactants can be easily controlled under the best conditions.
  • Starting compound (III) or a salt thereof can be produced by reacting compound (Ilia) with a halogenating agent.
  • a preferred salt of compound (III) is a salt with a base
  • a preferred salt of compound (Ilia) is a salt with a base or an acid addition salt as exemplified for compound (I).
  • Compound (Ilia) can be produced by the method described in the production method described later or by a conventional method.
  • Suitable halogenating agents used in this reaction include conventional ones capable of converting carboxylic acids such as phosphorus pentachloride, phosphorus oxychloride, thionyl chloride, and phosgene into acid halides.
  • the reaction is usually carried out in a conventional solvent such as methylene chloride, chloroform, and the like, but the reaction can be carried out in any other solvent that does not adversely influence the reaction.
  • the reaction temperature is not particularly limited, but the reaction is usually performed under cooling or at room temperature.
  • Acid addition salts such as the hydrochloride salt of compound (III) can be isolated in stable crystalline form and are particularly preferred for the reaction of the present invention.
  • the present invention will be described with reference to examples.
  • 2-Phosphorus pentachloride (58.Og) was added to a dichloromethane (350 ml) solution of 2- (2-aminothiazoyl 4-yl) -1-2-methoxycarbonylmethoxyaminoacetic acid (syn isomer) (68.8 g). Continue stirring at 25-30 ° C for 60 minutes. Diisopropyl ether (1240 ⁇ 1) is added to the reaction solution over 60 minutes.
  • Example 3 7-Amino_3-vinyl-1-3-fuemu-4-carboxylic acid (30. Og) and 1 [, N-bistrimethylsilylurea (54.2 g) are suspended in dichloromethane (450 ml) for 90 minutes. Reflux to silylate and dissolve. Cool the reaction mixture to -20 ° C, add 2- (2-aminothiazole-41-yl)-2-methoxycarbonylmethoxyamino acetyl chloride hydrochloride (cin isomer) and react for 30 minutes I do.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Cephalosporin Compounds (AREA)
  • Thiazole And Isothizaole Compounds (AREA)

Abstract

L'invention concerne un nouveau procédé industriel de préparation de composés 7-[2-(2-amino-thiazol-4-yl)-2-inférieur-alkoxycarbonylméthoxyiminoacétamido]-3-céphème représentés par la formule générale (I) ou des sels de ces derniers, formule dans laquelle R1 est un groupe organique, R2 est du carboxyle ou du carboxyle protégé, et R3 est un alkyle inférieur. Ledit procédé consiste à faire réagir un composé 7-amino-3-céphème représenté par la formule générale (II), un dérivé réactif de celui-ci obtenu par modification du groupe amino, ou un sel de celui-ci, avec un composé représenté par la formule générale (III) ou un sel de celui-ci, X étant halogéno.
PCT/JP2001/005163 2000-06-21 2001-06-15 Procede de preparation de composes de cepheme WO2001098309A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2001274541A AU2001274541A1 (en) 2000-06-21 2001-06-15 Process for the preparation of cephem compounds

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2000-185513 2000-06-21
JP2000185513A JP2004149412A (ja) 2000-06-21 2000-06-21 ７−［２−（２−アミノチアゾール−４−イル）−２−低級アルコキシカルボニルメトキシイミノアセトアミド］−３−セフェム化合物の製造法

Publications (1)

Publication Number Publication Date
WO2001098309A1 true WO2001098309A1 (fr) 2001-12-27

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2001/005163 WO2001098309A1 (fr) 2000-06-21 2001-06-15 Procede de preparation de composes de cepheme

Country Status (4)

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JP (1) JP2004149412A (fr)
AR (1) AR028744A1 (fr)
AU (1) AU2001274541A1 (fr)
WO (1) WO2001098309A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1268488A1 (fr) * 2000-03-20 2003-01-02 Hanmi Fine Chemicals Co., Ltd. Procede de preparation de derives de cephalosporine utilisant un nouveau compose de thiazole
US6800755B2 (en) * 2002-10-24 2004-10-05 Orchid Chemicals And Pharmaceuticals Limited Process for the preparation of cefixime
CN105061470A (zh) * 2015-08-18 2015-11-18 齐鲁安替（临邑）制药有限公司 一种头孢噻肟酸的一锅式合成方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2146332A (en) * 1983-09-12 1985-04-17 Biochemie Gmbh 2-Oxoimino acetic acid amides and their use in producing cephalosporin antibiotics
JPH02790A (ja) * 1988-01-07 1990-01-05 Fujisawa Pharmaceut Co Ltd ７―［２―（２―アミノチアゾール―４―イル）―２―ヒドロキシイミノアセトアミド］―３―セフェム化合物の製造法
US6277996B1 (en) * 2000-03-06 2001-08-21 Hanmi Fine Chemicals Co., Ltd. Thiazole compound and a process thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2146332A (en) * 1983-09-12 1985-04-17 Biochemie Gmbh 2-Oxoimino acetic acid amides and their use in producing cephalosporin antibiotics
JPH02790A (ja) * 1988-01-07 1990-01-05 Fujisawa Pharmaceut Co Ltd ７―［２―（２―アミノチアゾール―４―イル）―２―ヒドロキシイミノアセトアミド］―３―セフェム化合物の製造法
US6277996B1 (en) * 2000-03-06 2001-08-21 Hanmi Fine Chemicals Co., Ltd. Thiazole compound and a process thereof

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1268488A1 (fr) * 2000-03-20 2003-01-02 Hanmi Fine Chemicals Co., Ltd. Procede de preparation de derives de cephalosporine utilisant un nouveau compose de thiazole
EP1268488A4 (fr) * 2000-03-20 2004-02-04 Hanmi Fine Chemicals Co Ltd Procede de preparation de derives de cephalosporine utilisant un nouveau compose de thiazole
US6800755B2 (en) * 2002-10-24 2004-10-05 Orchid Chemicals And Pharmaceuticals Limited Process for the preparation of cefixime
CN105061470A (zh) * 2015-08-18 2015-11-18 齐鲁安替（临邑）制药有限公司 一种头孢噻肟酸的一锅式合成方法

Also Published As

Publication number Publication date
JP2004149412A (ja) 2004-05-27
AR028744A1 (es) 2003-05-21
AU2001274541A1 (en) 2002-01-02

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