WO2003091230A1 - Process for the preparation of 4-methyl-thiazole-5-carbaldehyde intermediate - Google Patents

Process for the preparation of 4-methyl-thiazole-5-carbaldehyde intermediate Download PDF

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Publication number
WO2003091230A1
WO2003091230A1 PCT/IB2002/005270 IB0205270W WO03091230A1 WO 2003091230 A1 WO2003091230 A1 WO 2003091230A1 IB 0205270 W IB0205270 W IB 0205270W WO 03091230 A1 WO03091230 A1 WO 03091230A1
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Prior art keywords
thiazole
methyl
formula
preparation
formyl
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Application number
PCT/IB2002/005270
Other languages
French (fr)
Inventor
Pandurang Balwant Deshpande
Parven Kumar Luthra
Rajesh Vyas
Ramakrishna Kamma
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Orchid Chemicals & Pharmaceuticals Limited
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Priority to JP2003587790A priority Critical patent/JP2005526112A/en
Priority to CA002483482A priority patent/CA2483482A1/en
Priority to AU2002367890A priority patent/AU2002367890A1/en
Publication of WO2003091230A1 publication Critical patent/WO2003091230A1/en

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    • 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
    • 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

Definitions

  • the present invention provides a process for the preparation of thiazole derivative.
  • the present invention relates to a process for the preparation of 4- methyl-5-formyl-thiazole of the formula (I).
  • Harrington et al J. Chem. Soc, (1939) 443-446) described a process for the preparation of 4-methyl-5-formyl-thiazole of the formula (I), starting from ethyl 4- methylthiazole-5-carboxylate which was converted through the amide to the nitrile, which in turn was converted to the aldehyde.
  • the process involves the preparation of the nitrile compound by using POCl 3 , which is highly corrosive, hazardous and difficult to handle in large scales.
  • Yokoyama et al (Stud. Surf. Sci. Catal., (1994), 90, 47-58) reports a process for the direct hydrogenation of aromatic carboxylic acid to the corresponding aldehydes.
  • the catalyst used is modified zirconia.
  • EP patent number 0 343 640 claims a process for the preparation of heterocyclic aldehyde from the corresponding carboxylic acid and its derivatives using a catalyst consisting of an oxide of Zinc, Yitrium, lanthanides or Group 4A elements.
  • the oxides of these metals are prepared at very high temperature such as 200 to 900°C.
  • Methyl 4- methylthiazole-5-carboxylate was hydrogenated using an oxide catalyst composed of chromium, zirconium to produce 4-methylthiazole-5-carboxaldehyde also at very high temperature ranging from 200 to 700°C, which makes the process industrially non- workable.
  • JP 45036908 discloses a process for the preparation of 4-methyl-5-hydroxymethyl thiazoles from 4-methyl-5-(ethoxycarbonyl) thiazoles using LiAlH and diethylether.
  • the process suffers the following disadvantages :
  • the reducing agent, LiAlH 4 cannot be handled in the large operations as it is an hazardous reagent.
  • This problem has been overcome by the use of sodium borohydride, in the presence of A1C1 3 in the present invention as the rate of evolution of hydrogen in the process is controllable and hence, the reaction as a whole is easy to handle.
  • the main objective of the present invention is to provide a process for the preparation of 4-methyl-5-formyl-thiazole of the formula (I), which is useful as an intermediate in the preparation of Cefditoren.
  • Another objective of the present invention is to provide a process for the preparation of 4-methyl-5-formyl-thiazole of the formula (I), which is commercially viable, high yielding, and with high purity of the product.
  • the present invention relates to a process for the preparation of 4-methyl-5-formyl- thiazole of the formula (I)
  • a process for the preparation of 4-methyl-5-hydroxymethyl thiazole of the formula (IV), which comprises reducing the thiazole ester of the formula (III), wherein R represents (C - C )alkyl group such as methyl, ethyl, n-propyl, iso-propyl, tert-butyl to 4-methyl-5- hydroxymethyl thiazole of the formula (IN), using sodium borohydride, in the presence of A1C1 3 and a solvent, at a temperature in the range of -20 °C to 90 °C.
  • the reaction scheme described above is as shown below.
  • the oxidizing agent is selected from pyridinium chlorochromate (PCC), NaOCl and KBr, in presence of TEMPO (2,2,6,6- tetramethyl-1-piperidinyloxy free radical) or Jones reagent (CrO 3 /H 2 SO 4 ) in the presence of a solvent selected from dichloromethane or ethylacetate.
  • the oxidizing agent is preferably selected from pyridinium chlorochromate or NaOCl . and KBr in presence of TEMPO.
  • reduction is carried out in a solvent selected from ethylene glycol dimethyl ether (monoglyme), THF or diethylene glycol dimethyl ether (diglyme).
  • a solvent selected from ethylene glycol dimethyl ether (monoglyme), THF or diethylene glycol dimethyl ether (diglyme).
  • reaction mixture was concentrated at 50-60 °C to remove organic solvents from it and cooled the reaction mixture to 5 °C.
  • the pH of the reaction mixture was adjusted with sodium hydroxide solution at 5-15 °C up to 12.5 and heated to 45 °C.
  • the reaction mixture was extracted with THF (4 x 250 ml). Combined THF layers were collected and treated with charcoal at 45 °C. THF layer was distilled of at 50 °C to yield the title compound (55 - 60 g), (purity by HPLC : 97-98%).
  • Example 3 Example 3:

Abstract

The present invention provides a process for the preparation of 4-methyl-5-formyl-thiazole of the formula (I), which comprises reducing the thiazole ester of the formula (III) to thiazole alcohol of the formula (IV), using a sodium borohydride in the presence of AlCl3 in a solvent and oxidising the thiazole alcohol of the formula (IV) to obtain 4-methyl-5-formyl-thiazole of the formula (I) using an oxidizing agent.

Description

PROCESS FOR THE PREPARATION OF 4-METHYL-THIAZOLE-5-CARBALDEHYDE INTERMEDIATE
The present invention provides a process for the preparation of thiazole derivative.
More particularly, the present invention relates to a process for the preparation of 4- methyl-5-formyl-thiazole of the formula (I).
Figure imgf000002_0001
4-Methyl-5-formyl-thiazole of the formula (I) is useful as a key intermediate in the preparation of Cefditoren pivoxil of the formula (II), which is well known as an antibiotic.
Figure imgf000002_0002
Background Art
Harrington et al (J. Chem. Soc, (1939) 443-446) described a process for the preparation of 4-methyl-5-formyl-thiazole of the formula (I), starting from ethyl 4- methylthiazole-5-carboxylate which was converted through the amide to the nitrile, which in turn was converted to the aldehyde. The process involves the preparation of the nitrile compound by using POCl3 , which is highly corrosive, hazardous and difficult to handle in large scales. Yokoyama et al (Stud. Surf. Sci. Catal., (1994), 90, 47-58) reports a process for the direct hydrogenation of aromatic carboxylic acid to the corresponding aldehydes. The catalyst used is modified zirconia.
EP patent number 0 343 640 claims a process for the preparation of heterocyclic aldehyde from the corresponding carboxylic acid and its derivatives using a catalyst consisting of an oxide of Zinc, Yitrium, lanthanides or Group 4A elements. The oxides of these metals are prepared at very high temperature such as 200 to 900°C. Methyl 4- methylthiazole-5-carboxylate was hydrogenated using an oxide catalyst composed of chromium, zirconium to produce 4-methylthiazole-5-carboxaldehyde also at very high temperature ranging from 200 to 700°C, which makes the process industrially non- workable. JP 45036908 discloses a process for the preparation of 4-methyl-5-hydroxymethyl thiazoles from 4-methyl-5-(ethoxycarbonyl) thiazoles using LiAlH and diethylether. The process suffers the following disadvantages : The reducing agent, LiAlH4 cannot be handled in the large operations as it is an hazardous reagent. This problem has been overcome by the use of sodium borohydride, in the presence of A1C13 in the present invention as the rate of evolution of hydrogen in the process is controllable and hence, the reaction as a whole is easy to handle.
To overcome the problems associated in the preparation of 4-methyl-5-formyl- thiazole of the formula (I), we focussed our research to develop a process, which uses non- hazardous materials, industrially workable at ambient temperature and safe to use.
Objective of the Invention The main objective of the present invention is to provide a process for the preparation of 4-methyl-5-formyl-thiazole of the formula (I), which is useful as an intermediate in the preparation of Cefditoren. Another objective of the present invention is to provide a process for the preparation of 4-methyl-5-formyl-thiazole of the formula (I), which is commercially viable, high yielding, and with high purity of the product.
Summary of the Invention The present invention relates to a process for the preparation of 4-methyl-5-formyl- thiazole of the formula (I)
Figure imgf000003_0001
which comprises oxidising the 4-methyl-5-hydroxymethyl thiazole of the formula (IN) to 4-methyl-5-formyl-thiazole of the formula (I), using an oxidizing agent at a temperature in the range of -10 °C to 50 °C, in the presence of a solvent.
In another embodiment of the present invention, there is a provided a process for the preparation of 4-methyl-5-hydroxymethyl thiazole of the formula (IV), which comprises reducing the thiazole ester of the formula (III), wherein R represents (C - C )alkyl group such as methyl, ethyl, n-propyl, iso-propyl, tert-butyl to 4-methyl-5- hydroxymethyl thiazole of the formula (IN), using sodium borohydride, in the presence of A1C13 and a solvent, at a temperature in the range of -20 °C to 90 °C. The reaction scheme described above is as shown below.
Figure imgf000004_0001
(III) (IV) (I)
Detailed Description of the Invention
In another embodiment of the present invention, the oxidizing agent is selected from pyridinium chlorochromate (PCC), NaOCl and KBr, in presence of TEMPO (2,2,6,6- tetramethyl-1-piperidinyloxy free radical) or Jones reagent (CrO3/H2SO4) in the presence of a solvent selected from dichloromethane or ethylacetate. In still another embodiment of the present invention, the oxidizing agent is preferably selected from pyridinium chlorochromate or NaOCl . and KBr in presence of TEMPO.
In another embodiment of the present invention, reduction is carried out in a solvent selected from ethylene glycol dimethyl ether (monoglyme), THF or diethylene glycol dimethyl ether (diglyme).
The present invention is exemplified by the following examples, which are provided for illustration only and should not be construed to limit the scope of the invention.
Example 1: Preparation of 4-methyl-5-hydroxymethyl-thiazole (IV)
Monoglyme (200 ml) was charged and cooled to -10 °C. To this NaBH4 (44.0g) was charged in one lot at -10 °C and stirred for 15 minutes. A1C13 (50.0g) was slowly added for 1 hour at -10 to +5 °C, stirred for 30 min at 0 °C. Then 4-methyl-thiazole-5-carboxylic acid ethyl ester (III) (100.0 g) was added for 1 hour at 0-15 °C. The reaction mixture was stirred at 15-25 °C for 4 hours and the progress of reaction was monitored by HPLC. The reaction mixture was poured into mixture of ice (500 g) and cone. HC1 (200 ml) and stirred for 30 minutes. The reaction mixture was concentrated at 50-60 °C to remove organic solvents from it and cooled the reaction mixture to 5 °C. The pH of the reaction mixture was adjusted with sodium hydroxide solution at 5-15 °C up to 12.5 and heated to 45 °C. The reaction mixture was extracted with THF (4 x 250 ml). Combined THF layers were collected and treated with charcoal at 45 °C. THF layer was distilled of at 50 °C to yield the title compound (55 - 60 g), (purity by HPLC : 97-98%). Example 2: Preparation of 4-methyl-5-hydroxymethyl-thiazole (TV)
Monoglyme (200 ml) was charged and cooled to -10 °C. To this NaBH4 (40.0 g) was charged in one lot at -10 °C and stirred for 15 minutes. A1C13 (47. Og) was slowly added for 1 hour at -10 to +5 °C, stirred for 30 min at 0 °C. Then 4-methyl-thiazole-5-carboxylic acid methyl ester (III) (100.0 g) was added for 1 hour at 0-15 °C. The reaction mixture was stirred at 15-25 °C for 4 hours and the progress of reaction was monitored by HPLC. The reaction mixture was poured into mixture of ice (500 g) and cone. HC1 (200 ml) and stirred for 30 minutes. The reaction mixture was concentrated at 50-60 °C to remove organic solvents from it and cooled the reaction mixture to 5 °C. The pH of the reaction mixture was adjusted with sodium hydroxide solution at 5-15 °C up to 12.5 and heated to 45 °C. The reaction mixture was extracted with THF (4 x 250 ml). Combined THF layers were collected and treated with charcoal at 45 °C. THF layer was distilled of at 50 °C to yield the title compound (55 - 60 g), (purity by HPLC : 97-98%). Example 3:
Preparation of 4-methyl-5-formyl-thiazole (I) 4-Methyl-5-hydroxymethyl-thiazole (50 gm (0.38 mole)) was added to dichloromethane (300 ml) and stirred for 5 minutes. To this solution, sodium bicarbonate solution (17 g in 250 ml of water) was added at 30-32°C and stirred the solution for 5-10 minutes at 30- 32°C. The reaction mass was cooled to 0°C and KBr solution (6 g in 10 ml of water) and TEMPO (0.285 g, 0.0018 mole) was added in single lot. To this sodium hypochlorite solution (450 ml of 12.5% w/v) was added in 1 hour at 0-2°C temperature. The reaction mass was stirred at 0-2°C and the progress of reaction was monitored by HPLC. After completion of reaction, the organic layer was separated. The aqueous layer was extracted with dichloromethane (2 x 125 ml). Dichloromethane layer was collected and washed with alkaline solution (80 ml) followed by brine (125 ml). The dichloromethane layer was dried over Na2SO and filtered. The dichloromethane layer was evaporated under reduced pressure to get 4-methyl-5-formyl-l,3-thiazole (36-38g), (purity by HPLC : 97- 98%). Example 4:
Preparation of 4-methyl-5-formyl-thiazole (I) PCC (102 g) was charged to dichloromethane (400 ml) under stirring. This mixture was cooled to 15-18°C. 4-Methyl-5-hydroxymethyl-thiazole (50.0g), dissolved in dichloro- methane (100 ml) was added to the above mixture in 1 hour at 15-25°C with vigorous stirring. The reaction mixture was stirred at 25-30°C. The progress of the reaction was monitored by HPLC. The solution was decanted from the reaction mixture to separate the inorganic residue. The inorganic residue was extracted with dichloromethane (200 ml). All the dichloromethane washings were pooled and concentrated to half, which was diluted with of IPE (400 ml). The combined organic layer was washed with water, dried over Na2SO4. The solvent was distilled off at 40°C under reduced pressure to get the title compound (30 g), ( purity by HPLC : >99%).

Claims

Claims
1. A process for the preparation of 4-methyl-5-formyl-thiazole of the formula (I)
Figure imgf000007_0001
which comprises, oxidising 4-methyl-5-hydroxymethyl thiazole of the formula (IN),
Figure imgf000007_0002
using an oxidizing agent at a temperature in the range of -10 °C to 50 °C, in the presence of a solvent.
2. The process according to claim 1, wherein the oxidizing agent is selected from pyridinium chlorochromate, ΝaOCl and KBr, in presence of TEMPO or Jones reagent (CrO3/H2SO4). '
3. The process according to claim 1, wherein the solvent used is selected from dichloromethane or ethylacetate.
4. A process for the preparation of 4-methyl-5-hydroxymethyl thiazole of the formula
(IN) used in claim 1, which comprises reducing the thiazole ester of the formula
(III)
Figure imgf000007_0003
wherein R represents (d-C^alkyl group to 4-methyl-5-hydroxymethyl-thiazole of the formula (IN),
Ν^S
(IV)
Me CH2OH
using sodium borohydride, in the presence of A1C1 , at a temperature in the range of -20°C to 90°C, in presence of a solvent.
5. The process according to claim 4, wherein the solvent used is selected from monoglyme, THF or diglyme. A process for the preparation of cefditoren pivoxil of the formula (II),
Figure imgf000008_0001
using 4-methyl-5-formyl thiazole of the formula (I) prepared by a process as claimed in any of the proceeding claims.
PCT/IB2002/005270 2002-04-26 2002-12-10 Process for the preparation of 4-methyl-thiazole-5-carbaldehyde intermediate WO2003091230A1 (en)

Priority Applications (3)

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JP2003587790A JP2005526112A (en) 2002-04-26 2002-12-10 Method for preparing 4-methyl-thiazole-5-carbaldehyde intermediate.
CA002483482A CA2483482A1 (en) 2002-04-26 2002-12-10 Process for the preparation of 4-methyl-thiazole-5-carbaldehyde intermediate
AU2002367890A AU2002367890A1 (en) 2002-04-26 2002-12-10 Process for the preparation of 4-methyl-thiazole-5-carbaldehyde intermediate

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005016936A2 (en) * 2003-08-14 2005-02-24 Ranbaxy Laboratories Limited Process for selective preparation of z-isomer of cefditoren and pharmaceutically acceptable salts and esters thereof
WO2005100330A1 (en) * 2004-04-13 2005-10-27 Ranbaxy Laboratories Limited Preparation of intermediate for 3-[2-(4-methylthiazole-5-yl)vinyl] cephalosporins

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997024359A1 (en) * 1995-12-28 1997-07-10 Il-Dong Pharm. Co., Ltd. Novel cephalosporin derivatives and processes for the preparation thereof
WO2000015634A2 (en) * 1998-09-11 2000-03-23 Warner-Lambert Company Hiv protease inhibitors

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997024359A1 (en) * 1995-12-28 1997-07-10 Il-Dong Pharm. Co., Ltd. Novel cephalosporin derivatives and processes for the preparation thereof
WO2000015634A2 (en) * 1998-09-11 2000-03-23 Warner-Lambert Company Hiv protease inhibitors

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
CHEMISCHE BERICHTE (1985), 118(10), 4099-130 *
DATABASE CA [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; OEHLER, ELISABETH ET AL: "Dialkyl (1,2-epoxy-3-oxoalkyl)phosphonates as synthons for heterocyclic carbonyl compounds: synthesis of acyl-substituted thiazoles, indolizines, imidazo[1,2-a]pyridines, and imidazo[1,2-a]pyrimidines", XP002234397, retrieved from STN Database accession no. 104:109580 *
KERNAG C A ET AL: "Mild and Convenient Oxidation of Aromatic Heterocyclic Primary Alcohols by 4-Acetylamino-2,2,6,6-tetramethylpiperidine-1-oxoammonium Perchlorate", TETRAHEDRON LETTERS, ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM, NL, vol. 40, no. 9, 26 February 1999 (1999-02-26), pages 1635 - 1636, XP004157153, ISSN: 0040-4039 *
R L WHITE ET AL: "Thiamin Biosythesis in Yeast. Origin of the Five-Carbon Unit of the Thiazole Moiety", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, vol. 104, no. 18, pages 4934 - 4943, XP002234396 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005016936A2 (en) * 2003-08-14 2005-02-24 Ranbaxy Laboratories Limited Process for selective preparation of z-isomer of cefditoren and pharmaceutically acceptable salts and esters thereof
WO2005016936A3 (en) * 2003-08-14 2005-08-11 Ranbaxy Lab Ltd Process for selective preparation of z-isomer of cefditoren and pharmaceutically acceptable salts and esters thereof
WO2005100330A1 (en) * 2004-04-13 2005-10-27 Ranbaxy Laboratories Limited Preparation of intermediate for 3-[2-(4-methylthiazole-5-yl)vinyl] cephalosporins

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