WO2005100330A1 - Preparation of intermediate for 3-[2-(4-methylthiazole-5-yl)vinyl] cephalosporins - Google Patents

Preparation of intermediate for 3-[2-(4-methylthiazole-5-yl)vinyl] cephalosporins Download PDF

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WO2005100330A1
WO2005100330A1 PCT/IB2005/000972 IB2005000972W WO2005100330A1 WO 2005100330 A1 WO2005100330 A1 WO 2005100330A1 IB 2005000972 W IB2005000972 W IB 2005000972W WO 2005100330 A1 WO2005100330 A1 WO 2005100330A1
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formula
compound
hydrogen
protecting group
amino protecting
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Yatendra Kumar
Mohan Prasad
Kaptan Singh
Ashok Prasad
Santosh Richhariya
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Ranbaxy Laboratories Limited
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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
    • C07D277/22—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 only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/24—Radicals substituted by oxygen atoms
    • 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 the preparation of 4-methylthiazol-5- carboxaldehyde of Formula I, and use thereof as an intermediate in prepara-tion of 3-[2-(4- methylthiazole-5-yl)vinyl] cephalosporins.
  • Cephalosporin antibiotics belonging to the class of 3-[2-(4-methyltt ⁇ iazole-5- yi)vinyl] cephalosporins have a broad spectrum of antimicrobial activity.
  • Cefditoren pivoxil which belongs to this class, is highly active not only against a variety of gram- positive and gram-negative bacteria but also against some resistant strains of bacteria. 4- Methylthiazol-5-carboxaldehyde (Formula I)
  • FORMULA I is an intermediate in synthesis of 3-[2-(4-methylthiazole-5-yl)vinyl] cephalosporins such as Cefditoren pivoxil of Formula II,
  • FORMULA A wherein R is methyl and is hydrogen.
  • This compound is a third-generation cephalosporin derivative developed with the aim of producing active cephalosporins with potent and broad-spectrum activity (see EP 175 610).
  • Cefditoren pivoxil is active not only against a variety of gram-positive and gram-negative bacteria but also against some resistant strains of bacteria.
  • EP 343 640 describes a process of preparation of heterocyclic aldehydes, which comprises hydrogenating the corresponding heterocyclic carboxylic acid with molecular hydrogen in the presence of catalyst containing an oxide of at least one element selected from zirconium, yttrium, zinc, cerium, titanium and hafnium.
  • 6,277,871 describes preparation of inliibitors of protein isoprenyl transferases wherein a process for the preparation of 4-methylthiazole-5-carboxaldehyde has been disclosed.
  • the process follows Swern oxidation of 2-hydroxymethyl-4-methyl- thiazole in anhydrous methylene chloride and oxalyl chloride under N 2 atmosphere in anhydrous DMSO at -70 to -80°C.
  • the product is obtained in 87% yield.
  • the reaction requires lower temperature of about -70°C and therefore it is not commercially feasible.
  • the intermediate 4-methyl-5-hydroxymethylthiazole has been prepared by reduction of ethyl 4-methylthiazole-5-carboxylate using sodium borohydride and calcium chloride in ethanol in 48 hours.
  • US Patent Appl. No. 2003/0204095 describes a process for preparation of 4- methylthiazole-5-carboxaldehyde from 4-methyl-5-hydroxymethylthiazole using 2,2,6,6- tetramethyl- 1 -pyperidinyloxy free radical (TEMPO) in presence of potassium bromide, sodium carbonate, sodium hypochlorite and methylene chloride at 0-2°C and also using pyridinium chlorochromate in presence of methylene chloride at 15-30°C.
  • TEMPO 2,2,6,6- tetramethyl- 1 -pyperidinyloxy free radical
  • FORMULA III is carried out in presence of an oxidizing agent, for example, manganese dioxide at relatively high temperature, the reaction proceeds efficiently and gives yields of about 80% of 4-methylthiazol-5-carboxaldehyde.
  • the purity of the 4-methylthiazol-5- carboxaldehyde obtained is in excess of 99%, as determined, for example, by HPLC.
  • the intermediate 4-methyl-5-hydroxymethylthiazole can be prepared by reduction of Ci. 3 alkyl ester of 4-methylthiazole-5-carboxylic acid using lithium aluminium hydride in 2 to 3 hours in excellent yield and purity.
  • Detailed Description of the Invention Inn one aspect, herein is provided an efficient oxidative preparation of 4- methylthiazole-5-carboxaldehyde of Formula I,
  • the reaction can be carried out in presence of an inert organic solvent at a temperature of about 50-150°C. After completion of the reaction (as monitored, for example, by TLC or by HPLC), the reaction mass can be filtered to remove the catalyst and the solution obtained can be cooled suitably to precipitate the product. The product can then be filtered and dried to obtain 4-methylthiazole-5-carboxaldehyde as light yellowish solid having purity in excess of 99% (as determined, for example, by HPLC).
  • the inert organic solvent can be selected from, for example, aromatic hydrocarbons, such as benzene, toluene, xylene, substituted toluenes, substituted xylenes or substituted benzenes; chlorinated hydrocarbons, such as chloroform, or ethylene chloride; ethers, such as tetrahydrofuran, 1,4-dioxane, or diisopropyl ether; aliphatic hydrocarbons, such as hexane, heptane or petroleum ether; cylohexane; ketones, such as acetone, diisobutyl ketone, methyl ethyl ketone, or methyl isobutyl ketone; polar aprotic solvents, such as dimethylacetamide, dimethylformamide or dimethylsulphoxide; or mixtures thereof.
  • aromatic hydrocarbons such as benzene, toluene, xylene, substituted
  • R 5 is an esterifying residue selected from C ⁇ - 3 alkyl, with lithium aluminium hydride.
  • the reaction of 4-methylthiazole-5-caboxylate of Formula IV with lithium aluminium hydride can be carried out in the presence of an organic solvent, such as, for example, tetrahydrofuran, di ethyl ether, 1,4-dioxane, cyclohexane, hexane, heptane, toluene, benzene, xylene or mixtures thereof, at a temperature of about -50 to about 40°C.
  • the reaction mass can be quenched with water and the entire mass filtered to remove inorganic residue.
  • aqueous layer can be extracted with a solvent capable of substantially dissolving the compound of Formula III.
  • the product of Formula III can be obtained having purity in excess of 99% (as determined, for example, by HPLC).
  • a process for the preparation of 4- methylthiazol-5-carboxaldehyde of Formula I wherein the process comprises a) reacting a compound of Formula IV (wherein R 5 is an esterifying residue selected from C ⁇ - 3 alkyl) with lithium aluminium hydride to get compound of Formula III, b) oxidizing the compound of Formula III with an oxidizing agent (for example, manganese dioxide), and c) isolating the compound of Formula I.
  • an oxidizing agent for example, manganese dioxide
  • R is hydrogen, esterified residue or a metal cation capable of forming a salt
  • Ri and R are independently selected from hydrogen, amino protecting group or combine together form a divalent amino protecting group, an optionally substituted amino acid residue or a group of Formula A
  • R 3 is a optionally substituted lower alkyl (wherein the substituents groups are selected from carboxyl, hydroxy, aryl, heterocyclic containing one or more heteroatoms or halo) and 4 is hydrogen or amino protecting group, wherein the process comprises a) oxidizing a compound of Formula III
  • R is a hydrogen atom, esterifying residue or a metal cation capable of forming a salt and Ri and R 2 are independently hydrogen, a monovalent amino protecting group or together form a divalent amino protecting group or a group of Formula A
  • R 3 is an optionally substituted lower alkyl wherein the substituents groups are selected from, for example, carboxyl, hydroxy, aryl, heterocyclic containing one or more heteroatoms or halo; and R 4 is hydrogen or amino protecting group, Y is absent or oxygen or sulphur, n is an integer 2, 3 or 4 and R 6 is selected from Ci to C 7 straight or branch chain alkyl, alkenyl, alkynyl or C 6 to Cio cycloalkyl, aryl or aralkyl, and c) isolating the compound of Formula II.
  • the compound of Formula I can be prepared by the oxidation of compound of Formula III using, for example, manganese dioxide as described above.
  • the isolated product can be treated with a compound of Formula V wherein R, R l5 R 2 , R 3 , R4, Y, n and R 6 are as defined above in presence of an organic solvent at a temperature of about -50 to about 35°C. After completion of the reaction, it can be quenched by addition of water, followed by washing of organic layer with sodium bisulphite solution to eliminate aldehydic and related impurities generated during reaction.
  • the compound of Formula II can then be isolated from the organic layer by suitable method of isolation, which includes evaporation of organic solvent to get the product, precipitation of the product from the organic solvent by addition of anti-solvent and the like.
  • the organic solvent can be selected from, for example, chlorinated hydrocarbons, such as chloroform or methylene chloride; lower alkanols, such as methanol, ethanol, n- propanol, isopropanol or n-butanol; ethers, such as tetrahydrofuran, diethyl ether, or 1,4- dioxane; esters, such as ethyl acetate, n-butyl acetate, isopropyl acetate, or the like, or ketones, such as acetone, or ethyl methyl ketone; or mixtures thereof.
  • Chlorinated hydrocarbons containing lower alkanols can be used as a solvent mixture, for example.
  • R is hydrogen, esterified residue or a metal cation capable of forming a salt
  • Ri and R 2 are independently selected from hydrogen, an amino protecting group or combine together form a divalent amino protecting group, or a group of Formula A
  • R 3 is a optionally substituted lower alkyl (wherein the substituents groups are selected from carboxyl, hydroxy, aryl, heterocyclic containing one or more heteroatoms or halo) and R 4 is hydrogen or amino protecting group; wherein the process comprises a) treating a compound of Formula IV
  • FORMULA I c reacting compound of Formula I with an ylide of Formula V, FORMULA V wherein, R is a hydrogen atom, esterifying residue or a metal cation capable of forming a salt and Ri and R 2 are independently hydrogen, monovalent amino protecting group or together form a divalent amino protecting group or a group of Formula A
  • R 3 is a optionally substituted lower alkyl wherein the substituents groups are selected from carboxyl, hydroxy, aryl, heterocyclic containing one or more heteroatoms or halo and R- t is hydrogen or amino protecting group; Y is absent or oxygen or sulphur, n is an integer 2, 3 or 4 and R 6 is selected from Ci to C straight or branch chain alkyl, alkenyl, alkynyl or C 6 to do cycloalkyl, aryl or aralkyl, and d) isolating the compound of Formula II.
  • the compound of Formula III can be prepared by reducing the compound of Formula IV with, for example, lithium aluminium hydride as described above.
  • Example 1 Preparation of 4-Methyl-5-hydroxymethylthiazole To a stirred mixture of lithium aluminum hydride (0.25 g) in THF (100 ml) at 5- 10°C was added 4-methyl thiazole-5-caboxylic acid methyl ester (10 g) over a period of 30 minutes. The reaction mixture was stirred at 10- 15°C for 2 to 3 hours. Progress of reaction was monitored by TLC.
  • Example 2 Preparation of 4-Methylthiazolyl-5-carboxaldehyde To a stirred mixture of 4-methyl-5-hydroxymethylthiazole (10 g ) in toluene (100 ml) at 55-60°C was added manganese dioxide (50 g ) in one lot. The reaction mixture was stirred at 55-60°C for 8 to 10 hours. Progress of reaction was monitored by TLC. After completion of the reaction, manganese dioxide was filtered over celite bed and washed with toluene. Filtrate was cooled below minus 20°C to get solid.
  • Example 3 Preparation of Cefditoren acid, sodium salt Step a) Preparation of 7-Amino-3-[2-(4-methylthiazol-5-yl)vinyI]-3-cepheme-4- carboxylic acid 1 , 1 -diphenylmethyl 7-(phenylacetamido)-3-[(triphenylphoshoranylidene)methyl]- 3-cepheme-4-carboxylate (16 g) was mixed with methylene chloride (120 ml) and 1- propanol (40 ml) followed by addition of 4-methylthiazol-5-carboxaldehyde (8 g). The resultant heterogeneous mixture was stirred at 20 to 25°C for 20 to 22 hours.
  • reaction mixture was sequentially washed with 3% sodium bisulfite (100 ml) and water (100 ml).
  • the organic layer was concentrated under reduced pressure to get an oily residue of 1,1, -diphenylmethyl 7- (phenylacetamido)-3-[2-(4-methylthiazol-5-yl)vinyl]-3-cepheme-4-carboxylate.
  • phenol 60 ml was added to the residue to get a clear solution. This solution was stirred at 40 to 50° C for 10 to 12 hours and n-butyl acetate (150 ml) was added to the reaction mass followed by cooling to 5 to 10°C.
  • the organic portion was extracted with sodium bicarbonate solution (0.17 Molar, 2 x 150 ml).
  • the aqueous layer was washed with n-butyl acetate (2 x 150 ml) to remove traces of phenol.
  • Pen-G amidase 8 g wet
  • the pH of the reaction mixture was intermittently adjusted to 7.5 to 7.7 by slow addition of 5% sodium carbonate solution.
  • enzyme was filtered and washed with deionized water. The filtrate was treated with activated carbon and then filtered at 30-35°C.
  • the filtrate was cooled to 20-25°C and to it was added dilute HC1 (2 M) to adjust the pH to 3.0 to 3.5 in order to affect complete precipitation of title compound.
  • the product was filtered and sequentially washed with water and acetone and finally dried under vacuum to get 5.5 g of off-white title compound.
  • Step b) Preparation of Cefditoren acid, sodium salt
  • Triethylamine (2.3 ml) was added slowly at 0-5 °C over 15 to 20 minutes. The mixture was stirred at 0-5 °C for 2-3 hours. The reaction was quenched by addition of dichloromethane followed by layer separation.
  • the aqueous layer was diluted with acetone to 50 ml.
  • Sodium 2- ethylhexanoate (3.3 g, 19.8 mmol) was added to the aqueous acetone solution at 20-25°C.

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

Abstract

The present invention relates to the preparation of 4-methylthiazol-5-carboxaldehyde of Formula I, and use thereof as an intermediate in preparation of 3-[2-(4-methylthiazole-5-yl)vinyl] cephalosporins.

Description

PREPARATION OF INTERMEDIATE FOR 3-[2-(4-METHYLTHIAZOLE-5-YL)VINYL] CEPHALOSPORINS
Field of the invention The present invention relates to the preparation of 4-methylthiazol-5- carboxaldehyde of Formula I, and use thereof as an intermediate in prepara-tion of 3-[2-(4- methylthiazole-5-yl)vinyl] cephalosporins. Background of the Invention Cephalosporin antibiotics belonging to the class of 3-[2-(4-methylttιiazole-5- yi)vinyl] cephalosporins have a broad spectrum of antimicrobial activity. Cefditoren pivoxil, which belongs to this class, is highly active not only against a variety of gram- positive and gram-negative bacteria but also against some resistant strains of bacteria. 4- Methylthiazol-5-carboxaldehyde (Formula I)
Figure imgf000002_0001
FORMULA I is an intermediate in synthesis of 3-[2-(4-methylthiazole-5-yl)vinyl] cephalosporins such as Cefditoren pivoxil of Formula II,
Figure imgf000002_0002
FORMULA II wherein R is pivaloxyniethyl group, one of the R] and R2 is hydrogen and other is a group of Formula A
Figure imgf000003_0001
FORMULA A wherein R is methyl and is hydrogen. This compound is a third-generation cephalosporin derivative developed with the aim of producing active cephalosporins with potent and broad-spectrum activity (see EP 175 610). Cefditoren pivoxil is active not only against a variety of gram-positive and gram-negative bacteria but also against some resistant strains of bacteria. EP 343 640 describes a process of preparation of heterocyclic aldehydes, which comprises hydrogenating the corresponding heterocyclic carboxylic acid with molecular hydrogen in the presence of catalyst containing an oxide of at least one element selected from zirconium, yttrium, zinc, cerium, titanium and hafnium. High-pressure hydrogenation with molecular hydrogen requires a specially designed pressure vessel. The catalysts described in the patent are costly and recovery after the completion of reaction can be doubtful. An oxidative degradation of 5-(/3-hydroxyethyl)-4-methylthiazole using pyridinium dichromate in methylene chloride at room temperature to get 4-methylthiazol-5- carboxaldehyde is reported by White et al in JACS, 104, No. 18, 4934-4943 (1982). However, the reaction time is 24 hours and the work-up involves vacuum distillation of ethereal extract to get the desired product. The yield is only 52%. U.S. Patent No. 6,277,871 describes preparation of inliibitors of protein isoprenyl transferases wherein a process for the preparation of 4-methylthiazole-5-carboxaldehyde has been disclosed. The process follows Swern oxidation of 2-hydroxymethyl-4-methyl- thiazole in anhydrous methylene chloride and oxalyl chloride under N2 atmosphere in anhydrous DMSO at -70 to -80°C. The product is obtained in 87% yield. The reaction requires lower temperature of about -70°C and therefore it is not commercially feasible. The intermediate 4-methyl-5-hydroxymethylthiazole has been prepared by reduction of ethyl 4-methylthiazole-5-carboxylate using sodium borohydride and calcium chloride in ethanol in 48 hours. US Patent Appl. No. 2003/0204095 describes a process for preparation of 4- methylthiazole-5-carboxaldehyde from 4-methyl-5-hydroxymethylthiazole using 2,2,6,6- tetramethyl- 1 -pyperidinyloxy free radical (TEMPO) in presence of potassium bromide, sodium carbonate, sodium hypochlorite and methylene chloride at 0-2°C and also using pyridinium chlorochromate in presence of methylene chloride at 15-30°C. Both these processes use costly catalysts and reagents and gives yield of about 60-70%. The intermediate 4-methyl-5-hydroxymethylthiazole has been prepared by reduction of methyl or ethyl ester of 4-methylthiazole-5-carboxylic using sodium borohydride and aluminium chloride in monoglyme. Summary of the Invention While attempting the synthesis of 4-methylthiazol-5-carboxaldehyde, the present inventors have found that when oxidation of 5-hydroxymethyl-4-methylthiazole of Formula III
Figure imgf000004_0001
FORMULA III is carried out in presence of an oxidizing agent, for example, manganese dioxide at relatively high temperature, the reaction proceeds efficiently and gives yields of about 80% of 4-methylthiazol-5-carboxaldehyde. The purity of the 4-methylthiazol-5- carboxaldehyde obtained is in excess of 99%, as determined, for example, by HPLC. The intermediate 4-methyl-5-hydroxymethylthiazole can be prepared by reduction of Ci.3 alkyl ester of 4-methylthiazole-5-carboxylic acid using lithium aluminium hydride in 2 to 3 hours in excellent yield and purity. Detailed Description of the Invention Inn one aspect, herein is provided an efficient oxidative preparation of 4- methylthiazole-5-carboxaldehyde of Formula I,
Figure imgf000005_0001
FORMULA I wherein the process comprises oxidizing 5-hydroxymethyl-4-methylthiazole of Formula III with manganese dioxide. ι
Figure imgf000005_0002
FORMULA III The reaction can be carried out in presence of an inert organic solvent at a temperature of about 50-150°C. After completion of the reaction (as monitored, for example, by TLC or by HPLC), the reaction mass can be filtered to remove the catalyst and the solution obtained can be cooled suitably to precipitate the product. The product can then be filtered and dried to obtain 4-methylthiazole-5-carboxaldehyde as light yellowish solid having purity in excess of 99% (as determined, for example, by HPLC). The inert organic solvent can be selected from, for example, aromatic hydrocarbons, such as benzene, toluene, xylene, substituted toluenes, substituted xylenes or substituted benzenes; chlorinated hydrocarbons, such as chloroform, or ethylene chloride; ethers, such as tetrahydrofuran, 1,4-dioxane, or diisopropyl ether; aliphatic hydrocarbons, such as hexane, heptane or petroleum ether; cylohexane; ketones, such as acetone, diisobutyl ketone, methyl ethyl ketone, or methyl isobutyl ketone; polar aprotic solvents, such as dimethylacetamide, dimethylformamide or dimethylsulphoxide; or mixtures thereof. In another aspect, herein is provided a process for preparation of 5-hydroxymethyl- 4-methylthiazole of Formula III,
Figure imgf000006_0001
FORMULA III wherein the process comprises treating 4-methylthiazole-5-caboxylate of Formula IN
Figure imgf000006_0002
FORMULA IV wherein R5 is an esterifying residue selected from Cι-3 alkyl, with lithium aluminium hydride. The reaction of 4-methylthiazole-5-caboxylate of Formula IV with lithium aluminium hydride can be carried out in the presence of an organic solvent, such as, for example, tetrahydrofuran, di ethyl ether, 1,4-dioxane, cyclohexane, hexane, heptane, toluene, benzene, xylene or mixtures thereof, at a temperature of about -50 to about 40°C. After conversion of the starting material, the reaction mass can be quenched with water and the entire mass filtered to remove inorganic residue. The aqueous layer can be extracted with a solvent capable of substantially dissolving the compound of Formula III. After recovering the solvent from the organic layer, the product of Formula III can be obtained having purity in excess of 99% (as determined, for example, by HPLC). In another aspect, herein is provided a process for the preparation of 4- methylthiazol-5-carboxaldehyde of Formula I wherein the process comprises a) reacting a compound of Formula IV (wherein R5 is an esterifying residue selected from Cι-3 alkyl) with lithium aluminium hydride to get compound of Formula III, b) oxidizing the compound of Formula III with an oxidizing agent (for example, manganese dioxide), and c) isolating the compound of Formula I. In yet another aspect, herein is provided a process for the preparation of compound of Formula II;
Figure imgf000007_0001
FORMULA II wherein R is hydrogen, esterified residue or a metal cation capable of forming a salt; Ri and R are independently selected from hydrogen, amino protecting group or combine together form a divalent amino protecting group, an optionally substituted amino acid residue or a group of Formula A
Figure imgf000007_0002
FORMULA A wherein R3 is a optionally substituted lower alkyl (wherein the substituents groups are selected from carboxyl, hydroxy, aryl, heterocyclic containing one or more heteroatoms or halo) and 4 is hydrogen or amino protecting group, wherein the process comprises a) oxidizing a compound of Formula III
Figure imgf000007_0003
FORMULA III with an oxidizing agent (for example, manganese dioxide) to get a compound of Formula I,
Figure imgf000008_0001
FORMULA I b) reacting the compound of Formula I with an ylide of Formula V,
Figure imgf000008_0002
FORMULA V wherein, R is a hydrogen atom, esterifying residue or a metal cation capable of forming a salt and Ri and R2 are independently hydrogen, a monovalent amino protecting group or together form a divalent amino protecting group or a group of Formula A
Figure imgf000008_0003
FORMULA A wherein R3 is an optionally substituted lower alkyl wherein the substituents groups are selected from, for example, carboxyl, hydroxy, aryl, heterocyclic containing one or more heteroatoms or halo; and R4 is hydrogen or amino protecting group, Y is absent or oxygen or sulphur, n is an integer 2, 3 or 4 and R6 is selected from Ci to C7 straight or branch chain alkyl, alkenyl, alkynyl or C6 to Cio cycloalkyl, aryl or aralkyl, and c) isolating the compound of Formula II. The compound of Formula I can be prepared by the oxidation of compound of Formula III using, for example, manganese dioxide as described above. The isolated product can be treated with a compound of Formula V wherein R, Rl5 R2, R3, R4, Y, n and R6 are as defined above in presence of an organic solvent at a temperature of about -50 to about 35°C. After completion of the reaction, it can be quenched by addition of water, followed by washing of organic layer with sodium bisulphite solution to eliminate aldehydic and related impurities generated during reaction. The compound of Formula II can then be isolated from the organic layer by suitable method of isolation, which includes evaporation of organic solvent to get the product, precipitation of the product from the organic solvent by addition of anti-solvent and the like. The organic solvent can be selected from, for example, chlorinated hydrocarbons, such as chloroform or methylene chloride; lower alkanols, such as methanol, ethanol, n- propanol, isopropanol or n-butanol; ethers, such as tetrahydrofuran, diethyl ether, or 1,4- dioxane; esters, such as ethyl acetate, n-butyl acetate, isopropyl acetate, or the like, or ketones, such as acetone, or ethyl methyl ketone; or mixtures thereof. Chlorinated hydrocarbons containing lower alkanols can be used as a solvent mixture, for example. In still a further aspect, herein is provided a process for the preparation of compound of Formula II;
Figure imgf000009_0001
FORMULA II wherein R is hydrogen, esterified residue or a metal cation capable of forming a salt; Ri and R2 are independently selected from hydrogen, an amino protecting group or combine together form a divalent amino protecting group, or a group of Formula A
Figure imgf000010_0001
FORMULA A wherein R3 is a optionally substituted lower alkyl (wherein the substituents groups are selected from carboxyl, hydroxy, aryl, heterocyclic containing one or more heteroatoms or halo) and R4 is hydrogen or amino protecting group; wherein the process comprises a) treating a compound of Formula IV
Figure imgf000010_0002
FORMULA IV with lithium aluminium hydride to get compound of Formula III,
Figure imgf000010_0003
FORMULA III b) oxidizing the compound of Formula III to get a compound of Formula I,
Figure imgf000010_0004
FORMULA I c) reacting compound of Formula I with an ylide of Formula V,
Figure imgf000011_0001
FORMULA V wherein, R is a hydrogen atom, esterifying residue or a metal cation capable of forming a salt and Ri and R2 are independently hydrogen, monovalent amino protecting group or together form a divalent amino protecting group or a group of Formula A
Figure imgf000011_0002
FORMULA A wherein R3 is a optionally substituted lower alkyl wherein the substituents groups are selected from carboxyl, hydroxy, aryl, heterocyclic containing one or more heteroatoms or halo and R-t is hydrogen or amino protecting group; Y is absent or oxygen or sulphur, n is an integer 2, 3 or 4 and R6 is selected from Ci to C straight or branch chain alkyl, alkenyl, alkynyl or C6 to do cycloalkyl, aryl or aralkyl, and d) isolating the compound of Formula II. The compound of Formula III can be prepared by reducing the compound of Formula IV with, for example, lithium aluminium hydride as described above. The compound of Formula III obtained can then be converted to a compound of Formula II by a process as described above. While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are within the scope of the present invention. Example 1: Preparation of 4-Methyl-5-hydroxymethylthiazole To a stirred mixture of lithium aluminum hydride (0.25 g) in THF (100 ml) at 5- 10°C was added 4-methyl thiazole-5-caboxylic acid methyl ester (10 g) over a period of 30 minutes. The reaction mixture was stirred at 10- 15°C for 2 to 3 hours. Progress of reaction was monitored by TLC. After completion, the reaction was quenched by adding a aqueous solution of sodium sulfate. The resultant inorganic solids were filtered and the cake was washed with ethyl acetate. Filtrate was concentrated under reduced pressure to get a pale yellow solid (7.5 g), providing an HPLC Purity (% area) of more than 99%. 1H-NMR (300MHz): 2.36 (s, 3H), 3.98 (s broad, 1H), 4.79 (s, 2H), 8.58 (s, 1H). Example 2: Preparation of 4-Methylthiazolyl-5-carboxaldehyde To a stirred mixture of 4-methyl-5-hydroxymethylthiazole (10 g ) in toluene (100 ml) at 55-60°C was added manganese dioxide (50 g ) in one lot. The reaction mixture was stirred at 55-60°C for 8 to 10 hours. Progress of reaction was monitored by TLC. After completion of the reaction, manganese dioxide was filtered over celite bed and washed with toluene. Filtrate was cooled below minus 20°C to get solid. The solid was filtered, and dried to get 7.0 g 4-methylthiazole-5-carboxaldehyde as a light yellowish solid, with an HPLC Purity (% area) of more than 99%. 1H-NMR (300MHz): 2.80 (s, 3H), 8.99 (s, 1H) 10.15 (s, 1H).
Example 3: Preparation of Cefditoren acid, sodium salt Step a) Preparation of 7-Amino-3-[2-(4-methylthiazol-5-yl)vinyI]-3-cepheme-4- carboxylic acid 1 , 1 -diphenylmethyl 7-(phenylacetamido)-3-[(triphenylphoshoranylidene)methyl]- 3-cepheme-4-carboxylate (16 g) was mixed with methylene chloride (120 ml) and 1- propanol (40 ml) followed by addition of 4-methylthiazol-5-carboxaldehyde (8 g). The resultant heterogeneous mixture was stirred at 20 to 25°C for 20 to 22 hours. Progress of reaction was monitored by HPLC. After completion, reaction mixture was sequentially washed with 3% sodium bisulfite (100 ml) and water (100 ml). The organic layer was concentrated under reduced pressure to get an oily residue of 1,1, -diphenylmethyl 7- (phenylacetamido)-3-[2-(4-methylthiazol-5-yl)vinyl]-3-cepheme-4-carboxylate. To this oily residue was added phenol (60 ml) was added to the residue to get a clear solution. This solution was stirred at 40 to 50° C for 10 to 12 hours and n-butyl acetate (150 ml) was added to the reaction mass followed by cooling to 5 to 10°C. The organic portion was extracted with sodium bicarbonate solution (0.17 Molar, 2 x 150 ml). The aqueous layer was washed with n-butyl acetate (2 x 150 ml) to remove traces of phenol. To the aqueous layer was added Pen-G amidase (8 g wet) at 20 to 25°C. The pH of the reaction mixture was intermittently adjusted to 7.5 to 7.7 by slow addition of 5% sodium carbonate solution. After completion of reaction, enzyme was filtered and washed with deionized water. The filtrate was treated with activated carbon and then filtered at 30-35°C. The filtrate was cooled to 20-25°C and to it was added dilute HC1 (2 M) to adjust the pH to 3.0 to 3.5 in order to affect complete precipitation of title compound. The product was filtered and sequentially washed with water and acetone and finally dried under vacuum to get 5.5 g of off-white title compound.
Step b) Preparation of Cefditoren acid, sodium salt A suspension of the product obtained in Step a) (5.0 g, 15.4 mmol) and 2- methoxyimino-2-(2-amino thiazol-4-yl)acetic acid, S-2-benzothiazole ester (6.7 g, 18.6 mmol) in aqueous tetrahydrofuran (60 ml) was stirred at 0 to 5°C. Triethylamine (2.3 ml) was added slowly at 0-5 °C over 15 to 20 minutes. The mixture was stirred at 0-5 °C for 2-3 hours. The reaction was quenched by addition of dichloromethane followed by layer separation. The aqueous layer was diluted with acetone to 50 ml. Sodium 2- ethylhexanoate (3.3 g, 19.8 mmol) was added to the aqueous acetone solution at 20-25°C. After stirring the mixture for sufficient time for crystallization of the sodium salt of Cefditoren, acetone was added (50 ml) slowly to the reaction mass in order to effect crystallization. Filtered the crystallized product under suction and washed with acetone (2 x 10 ml). The product was vacuum dried to get 6.5 g of off-white title compound (Yield = 75%).

Claims

We Claim: 1. A method of preparing 4-methylthiazole-5-carboxaldehyde of Formula I,
Figure imgf000014_0001
FORMULA I the process comprising oxidizing 5-hydroxymethyl-4-methylthiazole of Formula III.
Figure imgf000014_0002
FORMULA III
2. The process of claim 1 , wherein the oxidation is carried out in presence of an inert organic solvent.
3. The process of claim 1, wherein the oxidation is carried out at a temperature of about 50- 150°C. 4. The process of claim 2, wherein the inert organic solvent is selected from benzene, toluene, xylene, substituted toluenes, substituted xylenes, substituted benzenes, chloroform, ethylene chloride, tetrahydrofuran, 1,
4-dioxane, diisopropyl ether, hexane, heptane, petroleum ether; cyclohexane, acetone, diisobutyl ketone, methyl ethyl ketone, methyl isobutyl ketone, dimethylacetamide, dimethylformamide and dimethylsulphoxide.
5. The process of claim 1 , wherein the product of Fonnula I is obtained in purity of 99% or greater.
6. A process for the preparation of 5-hydroxymethyl-4-methylthiazole of Formula III,
Figure imgf000015_0001
FORMULA III the process comprising treating 4-methylthiazole-5-caboxylate of Formula IV
Figure imgf000015_0002
FORMULA IV wherein R5 is an esterifying residue selected from Cι-3 alkyl, with lithium aluminium hydride.
7. The process of claim 6, carried out in presence of an organic solvent.
8. The process of claim 7, wherein the organic solvent is selected from tetrahydrofuran, diethyl ether, 1,4-dioxane, cyclohexane, hexane, heptane, toluene, benzene, and xylene.
9. The process of claim 6, wherein the product of Formula III is obtained in purity of 99% or greater.
10. A process for the preparation of 4-methylthiazol-5 -carboxaldehyde of Formula I,
Figure imgf000015_0003
FORMULA I the process comprising: a) reacting a compound of Formula IN
Figure imgf000016_0001
FORMULA IV wherein R5 is an esterifying residue selected from Cι- alkyl with lithium aluminium hydride to get compound of Formula III,
Figure imgf000016_0002
FORMULA III b) oxidizing the compound of Formula III, and c) isolating the compound of Formula I.
11. A process for the preparation of a compound of Formula II;
Figure imgf000016_0003
FORMULA II wherein R is hydrogen, esterified residue or a metal cation capable of forming a salt; Ri and R2 are independently selected from hydrogen, amino protecting group or combine together form a divalent amino protecting group, an optionally substituted amino acid residue or a group of Formula A
Figure imgf000017_0001
FORMULA A wherein R is a optionally substituted lower alkyl wherein the substituents groups are selected from carboxyl, hydroxy, aryl, heterocyclic containing one or more heteroatoms or halo and R is hydrogen or amino protecting group, the process comprising: a) oxidizing a compound of Formula III
Figure imgf000017_0002
FORMULA III to get a compound of Formula I,
Figure imgf000017_0003
FORMULA I b) reacting the compound of Formula I with an ylide of Formula V,
Figure imgf000017_0004
FORMULA V wherein, R is a hydrogen atom, esterifying residue or a metal cation capable of forming a salt and i and R2 are independently hydrogen, monovalent amino protecting group or together form a divalent amino protecting group or a group of Formula A
Figure imgf000018_0001
wherein R3 is a optionally substituted lower alkyl wherein the substituents groups are selected from carboxyl, hydroxy, aryl, heterocyclic containing one or more heteroatoms or halo; R is defined as above, Y is absent or oxygen or sulphur, n is an integer 2, 3 or 4 and R6 is selected from Ci to C7 straight or branch chain alkyl, alkenyl, alkynyl or C6 to C10 cycloalkyl, aryl or aralkyl, and c) isolating the compound of Formula II.
12. The process of claim 11 , further comprising washing the reaction mass of step b) with sodium bisulphite.
13. The process of claim 11 , wherein the compound of Fonnula II is
Figure imgf000018_0002
FORMULA II wherein R is hydrogen, esterified residue or a metal cation capable of forming a salt; Ri and R2 are hydrogen or amino protecting group or combine together form a divalent amino protecting group.
14. The process of claim 11 , wherein the compound of Formula II is
Figure imgf000019_0001
FORMULA II wherein R is hydrogen, esterified residue or a metal cation capable of forming a salt; one of Ri and R2 is hydrogen, and other is a group of Fonnula A
Figure imgf000019_0002
FORMULA A wherein R3 is methyl and is hydrogen.
15. A process for the preparation of a compound of Formula II;
Figure imgf000019_0003
FORMULA II wherein R is hydrogen, esterified residue or a metal cation capable of forming a salt; Ri and R2 are independently selected from hydrogen, amino protecting group or combine together form a divalent amino protecting group, or a group of Formula A
Figure imgf000020_0001
FORMULA A wherein R3 is a optionally substituted lower alkyl wherein the substituents groups are selected from carboxyl, hydroxy, aryl, heterocyclic containing one or more heteroatoms or halo, and R4 is hydrogen or amino protecting group, the process comprising :0 a) treating the compound of Formula IV
Figure imgf000020_0002
FORMULA IV with lithium aluminium hydride to get compound of Formula III,
Figure imgf000020_0003
FORMULA III b) oxidizing the compound of Formula III to get a compound of Formula I,
Figure imgf000020_0004
FORMULA I c) reacting the compound of Formula I with an ylide of Formula V,
Figure imgf000021_0001
FORMULA V wherein, R is a hydrogen atom, esterifying residue or a metal cation capable of forming a salt and Ri and R2 are independently hydrogen, monovalent amino protecting group or together form a divalent amino protecting group or a group of Formula A
Figure imgf000021_0002
FORMULA A wherein R3 is a optionally substituted lower alkyl wherein the substituents groups are selected from carboxyl, hydroxy, aryl, heterocyclic containing one or more heteroatoms or halo, R is as defined above; Y is absent or oxygen or sulphur, n is an integer 2, 3 or 4 and R6 is selected from Ci to C7 straight or branch chain alkyl, alkenyl, alkynyl or C6 to Cio cycloalkyl, aryl or aralkyl, and isolating the compound of Formula II.
PCT/IB2005/000972 2004-04-13 2005-04-13 Preparation of intermediate for 3-[2-(4-methylthiazole-5-yl)vinyl] cephalosporins WO2005100330A1 (en)

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CN100360511C (en) * 2006-01-24 2008-01-09 浙江工业大学 Method for synthesizing 4-methyl-5-methyol thiazole
CN103030604A (en) * 2011-10-10 2013-04-10 上海医药工业研究院 Preparation method of 4-alkyl-5-formoxyl thiazole or 5-formoxyl thiazole
US8445476B2 (en) 2007-10-25 2013-05-21 Achaogen, Inc. Carbacephem β-lactam antibiotics

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CN100360511C (en) * 2006-01-24 2008-01-09 浙江工业大学 Method for synthesizing 4-methyl-5-methyol thiazole
US8445476B2 (en) 2007-10-25 2013-05-21 Achaogen, Inc. Carbacephem β-lactam antibiotics
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