KR20050018667A - Process for the preparation of 4-methyl-thiazole-5-carbaldehyde intermediate - Google Patents

Abstract

The present invention provides a method for preparing 4-methyl-5-formyl-thiazole of formula 1 by reducing the thiazole ester of formula 3 with thiazole alcohol of formula 4.

Formula 1

Description

Process for preparing 4-methyl-thiazole-5-carbaldehyde intermediate {PROCESS FOR THE PREPARATION OF 4-METHYL-THIAZOLE-5-CARBALDEHYDE INTERMEDIATE}

The present invention relates to a process for the preparation of thiazole derivatives, and more particularly to a process for the preparation of 4-methyl-5-formyl-thiazole of formula (I).

Formula I

4-Methyl-5-formyl-thiazole of formula (I) is useful as a key intermediate in the preparation of ceftitorene fibosyl of formula (2), well known as antibiotic.

Formula 2

Harrington, J. Chem. Soc., (1939) 443-446, starting with ethyl-4-methylthiazole-5-carboxylate, which is converted to nitrile via an amide, and subsequently converted to aldehyde, to 4-methyl- Although a method for preparing 5-formyl-thiazole has been described, the process involves preparing a nitrile compound by using POCl ₃ , which is very corrosive, dangerous and difficult to handle in large quantities.

Yokoyama, Stud. Snuf. Sci. Catal., (1994), 90, 47-58, report on the direct hydrogenation of aromatic carboxylic acids with their corresponding aldehydes. The catalyst used at this time is modified zirconia.

Heterocyclic aldehydes are also prepared from the corresponding carboxylic acids and derivatives thereof in European Patent 0 343 640 using a catalyst consisting of zinc, yttrium, lanthanides or oxides of elements of the 4A group. How to do this is described. Oxides of the metals are prepared at very high temperatures such as 200 to 900 ° C. To prepare 4-methylthiazole-5-carboaldehyde, methyl-4-methylthiazole-5-carboxylate was also prepared at 200 using an oxide of a catalytic compound of chromium, zirconium. It is industrially inefficient because of hydrogenation at very high temperatures of 700 ° C.

In addition, Japanese Patent No. 45036908 discloses a process for preparing ₄ -methyl-5-hydroxymethylthiazole from 4-methyl-5- (ethoxycarbonyl) thiazole using LiAlH ₄ and diethylether. have. The process suffers from the following disadvantages.

The reducing agent, LiAlH _4, is a dangerous reagent and therefore cannot be processed in large quantities of operation. This problem can be overcome by the use of NaBH ₄ (Sodium Borohidride) in the presence of AlCl ₃ . Since the yield of oxygen in the process can be controlled, the reaction can be controlled in its entirety.

In order to overcome the problems associated with the preparation of 4-methyl-5-formyl-thiazole of formula (1) as discussed above, our study is a process that uses materials that are not dangerous and industrially available and safe to use at environmental temperatures. Focused on developing

Purpose of the Invention

It is a primary object of the present invention to provide a process for the preparation of 4-methyl-5-formyl-thiazole of formula 1 which is useful as an intermediate in the preparation of Cefditoren.

It is a further object of the present invention to provide a process for the preparation of commercially available high yield, high purity 4-methyl-5-formyl-thiazole of formula (1).

Summary of the Invention

The present invention is a method for preparing 4-methyl-5-formyl-thiazole of the formula (1)

Formula 1

4-methyl-5-formyl- of formula 1 comprising oxidizing 4-methyl-5-hydroxymethyl thiazole of formula 4 in the presence of a solvent using a oxidizing agent at a temperature in the range of -10 to + 50 ° C. It relates to a process for preparing thiazole.

Further, in another embodiment of the present invention, the thiazole ester of formula 3 wherein R is methyl, ethyl, n-propyl, t- attached to 4-methyl-5-hydroxy-methyl-thiazole of formula _4- (C1-C4) alkyl group, such as butyl), in the presence of a solvent with NaBH ₄ in the presence of AlCl ₃ at a temperature in the range of -20 to 90 ° C. Provided is a method for preparing methyl-5-hydroxymethyl thiazole.

The reaction structure described above is as shown below.

Detailed description of the invention

In one embodiment of the present invention, the oxidizing agent is a solvent selected from dichloromethane or ethyl acetate, TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy free radical) or Jones reagent (CrO3 / H 2 SO 4) is selected from pyridium chlorochloromate (PCC), NaOCl and KBr.

In this case, the oxidant is preferably selected from pyridinium chlorochloromate or NaOCl and KBr in the presence of TEMPO.

In another embodiment of the invention, the reduction is carried out in a solvent selected from reduced ethylene glycol dimethyl ether (monoglyme), THF or diethylene glycol dimethyl ether (diglyme).

The following examples are provided for illustrative purposes and do not limit the claimed invention.

Example 1.

Preparation of 4-methyl-5-hydroxymethyl-thiazole (Formula 4).

Monoglyme (200 ml) was charged and cooled to -10 ° C, and NaBH ₄ (44.0 g) was added thereto and stirred at -10 for 15 minutes. AlCl ₃ (50.0 g) was added slowly at −10 to + 5 ° C. for 1 hour and stirred at 0 ° C. for 30 minutes. Then 4-methyl-thiazole-5-carboxylic acid ethyl ester (Formula 3) (100.0 g) was added at 0-10 ° C. for 1 hour. The reaction mixture was stirred at 15-25 ° C. for 4 hours and the reaction progress was observed by HPLC. The reaction mixture was poured into a mixture of ice (500 g) and concentrated hydrochloric acid (200 ml) and stirred for 30 minutes. The reaction mixture was concentrated at 50-60 ° C. to remove organic solvent and then cooled to 5 ° C. The pH of the reaction was adjusted to 12.5 with NAOH solution at 5-15 ° C. and heated to 45 ° C. The reaction was extracted with THF (4 × 250 ml). The mixed THF layers were collected and treated with charcoal at 45 ° C. The THF layer was diluted at 50 ° C. to yield the whole compound (55-60 g) (purity by HPLC: 97-98%).

Example 2

Preparation of 4-methyl-5-hydroxymethyl-thiazole (Formula 4).

Monoglyme (200 ml) was charged and cooled to -10 ° C, where NaBH ₄ (40.0 g) was added at a time and stirred at -10 for 15 minutes. AlCl ₃ (47.0 g) was slowly added at −10 to + 5 ° C. for 1 hour and stirred at 0 ° C. for 30 minutes. Then 4-methyl-thiazole-5-carboxylic acid ethyl ester (Formula 3) (100.0 g) was added at 0-10 ° C. for 1 hour. The reaction mixture was stirred at 15-25 ° C. for 4 hours and the reaction progress was observed by HPLC. The reaction mixture was poured into a mixture of ice (500 g) and concentrated hydrochloric acid (200 ml) and stirred for 30 minutes. The reaction mixture was concentrated at 50-60 ° C. to remove organic solvent and then cooled to 5 ° C. The pH of the reaction was adjusted to 12.5 with NAOH solution at 5-15 ° C. and heated to 45 ° C. The reaction was extracted with THF (4 × 250 ml). The mixed THF layers were collected and treated with charcoal at 45 ° C. The THF layer was diluted at 50 ° C. to yield the whole compound (55-60 g) (purity by HPLC: 97-98%).

Example 3.

Preparation of 4-methyl-5-formyl-thiazole (Formula 1).

4-Methyl-5-hydroxymethyl-thiazole (50 gm (0.38 mole)) was added to dichloromethane (300 ml) and stirred for 5 minutes. To this solution, a NaCO ₂ (17 g in 250 ml of purified water) solution was added at 30-32 ° C. and the solution was stirred at 30-32 ° C. for 5-10 minutes. The reaction was cooled to 0 ° C. and KBr (6 g in 10 ml of purified water) solution and TEMPO (0.285 g, 0.0018 mole) were added at once. After 1 hour, a sodium chloride solution (450 ml of 12.5% w / v) was added thereto at a temperature of 0-2 ° C. The reaction was stirred at 0-2 [deg.] C. and the progress of the reaction was observed by HPLC.

After the reaction was completed, the organic layer was separated. The aqueous layer was extracted with dichloromethane (2X125 ml). After collecting the dichloromethane layer followed by Dublin (125ml) and washed with an alkaline solution (80ml). The dichloromethane layer was dried over sodium sulfate and filtered. The dichloromethane layer was evaporated under reduced pressure to yield 4-methyl-5-formyl-1,3-thiazole (36-38 g) (HPLC purity: 97-98%).

Example 4.

Preparation of 4-methyl-5-formyl-thiazole (Formula 1).

Dichloromethane (400 ml) was charged with PCC (12 g) with stirring and cooled to 15-18 ° C. 4-methyl-5-hydroxymethyl-thiazole (50.0 g), dissolved in dichloromethane (100 ml), was added to the mixture for 1 hour with vigorous stirring at 15-25 ° C. The reaction mixture was stirred at 25-30 ° C. The course of the reaction was observed by HPLC. The inorganic residue was separated by gently decanting the solution from the reaction mixture. The inorganic residue was extracted with dichloromethane (200 ml). All dichloromethane washes were combined, concentrated in half, and diluted with IPE (400 ml). The mixed organic layer was washed with water and dried over sodium sulfate. The solvent was distilled off under reduced pressure at 40 ° C. to obtain the title compound (30 g) (HPLC purity over 99%).

Claims (6)

In the method for preparing 4-methyl-5-formyl-thiazole of the formula (1), Formula 1 4-Methyl-5-hydroxymethyl thiazole of Formula 4 Formula 4 Oxidizing in the presence of a solvent at a temperature in the range of -10 to + 50 ° C. using an oxidizing agent. The method of claim 1, wherein the oxidizing agent is selected from pyridium chlorochloromate, NaOCl and KBr in the presence of TEMPO or Jones reagent (CrO3 / H2SO4). . The method of claim 1, wherein the solvent used is selected from dichloromethane or ethyl acetate. In the method for preparing 4-methyl-5-hydroxymethyl thiazole of Chemical Formula 4 used in claim 1, 4-methyl-5-hydroxymethyl thiazole of formula (4) comprising reducing the thiazole ester of formula (3) in the presence of a solvent with NaBH4 in the presence of AlCl3 at a temperature ranging from -20 to 90 ° C Manufacturing method. Formula 3 (Wherein R represents a (C1-C4) alkyl group attached to 4-methyl-5-hydroxy-methyl-thiazole of formula (4).) Formula 4 The method of claim 4, wherein the solvent used is selected from monoglyme, THF, or diglyme. A method for preparing ceftitorene fibosyl represented by the following Chemical Formula 2, wherein 4-methyl-5-formyl-thiazole of Chemical Formula 1 prepared by the method according to claim 1 is used. Formula 2