WO2016046836A2

WO2016046836A2 - A novel process for preparation of ethyl 2-(4-hydroxy-3-nitrophenyl)-4-methyl-5-thiazolecarboxylate

Info

Publication number: WO2016046836A2
Application number: PCT/IN2015/000362
Authority: WO
Inventors: Ravi Ashwin SHROFF; Mahesh Laxmikant PATIL; Mangesh Namdeo PRABHU; Harishchandra Lalji BARAI
Original assignee: Excel Industries Ltd.
Priority date: 2014-09-25
Filing date: 2015-09-16
Publication date: 2016-03-31
Also published as: WO2016046836A3

Abstract

A novel process for preparation of ethyl 2-(4-hydroxy-3-nitrophenyl)-4-methyl-5-thiazolecarboxylate is disclosed. The process involves reaction of ethyl 2-(4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate with metal nitrate in presence of acid chloride and N,N-Dimethylformamide to produce title compound with improved yield and economics than that reported in the prior art.

Description

A NOVEL PROCESS FOR PREPARATION OF

ETHYL 2-(4-HYDROXY-3-NITROPHENYL)-4-METHYL-5- TH IAZO LEC ARBOXYLATE

FIELD OF INVENTION

The present invention relates to a novel process for preparation of ethyl 2-(4-hydroxy-3-nitrophenyl)-4-methyl-5-thiazolecarboxylate, a key intermediate for Febuxostat API. More particularly, the present invention relates to a novel process of for preparation of ethyl 2- (4- hydroxy-3-nitrophenyl)-4-methyl-5-thiazolecarboxylate by reaction of ethyl 2-(4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate with metal nitrate in presence of acid chloride and N,N- Dimethylformamide(DMF) .

BACKGROUND AND PRIOR ART

Ethyl 2-(4-hydroxy-3-nitrophenyl)-4-methyl-5-thiazolecarboxylate is an intermediate for preparation of Febuxostat which is a xanthine oxidase inhibitor used in treatment of gout.

US5614520 discloses a method for preparation of ethyl 2-(4-hydroxy- 3-nitrophenyl)-4-methyl-5-thiazolecarboxylate. The method involves reaction of 4-hydroxy-3-nitrobenzaldehyde with hydroxylamine hydrochloride and sodium formate to obtain 4-hydroxy-3- nitrobenzonitrile, which is reacted with thioacetamide to get 4- hydroxy- 3-nitrobenzthioamide, which was further reacted with ethyl 2-chloroacetoacetate to obtain ethyl 2-(4-hydroxy-3-nitrophenyl)-4- methyl-5-thiazolecarboxylate in 37% overall yield. The raw material 4-hydroxy-3-nitrobenzaldehyde used in this method is costly and the yield is very low. There is a need for a process for preparation of title compound with improved yield and better economics.

OBJECTS OF INVENTION

An object of invention is to provide a process for preparation of ethyl 2-(4-hydroxy-3-nitrophenyl)-4-methyl-5-thiazolecarboxylate with improved yield and economics.

Another object of invention is to provide a process for preparation of ethyl 2-(4-hydroxy-3-nitrophenyl)-4-methyl-5-thiazolecarboxylate by reaction of ethyl 2-(4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate with metal nitrate in presence of acid chloride and DMF.

DETAILED DESCRIPTION OF INVENTION

Process for preparation of ethyl 2-(4-hydroxy-3-nitrophenyl)-4- methyl- 5-thiazolecarboxylate comprises reaction of ethyl-2-(4- hydroxyphenyl)- 4- methyl- 5-thiazolecarboxylate with metal nitrate in presence of acid chloride and DMF.

Ethyl 2-(4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate required for the synthesis of title compound [ethyl 2-(4-hydroxy-3-nitrophenyl)- 4-methyl- 5-thiazolecarboxylate] is prepared by conventional method, particularly, by reaction of 4-cyanophenol with diethyldithiophosphoric acid to obtain 4-hydroxybenzamide, which was reacted with ethyl 2-chloroacetoacetate to give ethyl 2-(4- hydr oxyphenyl)- 4-methy 1- 5-thiazolecarboxylate .

Preferred acid chloride used for preparation of title compound as per present invention is POC . Other acid chlorides such as SOCb, oxalyl chloride, cyanuric chloride, isocyanuric chloride etc. can also be used.

Nitrates used in the invented process include metal nitrates, preferred nitrates are alkali metal nitrates.

Preferred solvent used in the process is acetonitrile and N,N- dimethylformamide(DMF) as given in the examples.

EXAMPLE- 1 (preparation of 4-hydroxythiobenzamide)

0.23 moles of diethyldithiophosphoric acid was added to 1.66 moles of water followed by addition of 0.21 moles of 4-cyanophenol. The reaction mixture was heated to 50°C and was maintained at this temperature with stirring for 3 hrs. The reaction mass was then cooled to 25-30°C. 100 ml of dichloromethane was added to the mixture and it was maintained at 25-30°C for 30 min. It was then filtered and the solid product was washed with saturated sodium carbonate solution followed by 70 ml water. It was dried at 75oC to obtain 4-hydroxythiobenzamide in 87,5% yield. EXAMPLE-2

(preparation of ethyl 2-(4-hydroxyphenyl)-4-methyl-5- thiazolecarboxylate)

0.26 moles of 4-hydroxythiobenzamide suspended in 180 ml of ethanol was taken in the reactor. 0.29 Moles of ethyl-2- chloroacetoacetate was added. The reaction mixture was then heated to 65-70°C and maintained at this temperature for 3 hrs. Ethanol was distilled off and 300 ml water was added to the reaction mass. It was then cooled to 25-30°C and maintained at this temperature for 30 min. The solid obtained was filtered and washed with 70 ml water. The product was dried at 80oC to obtain ethyl 2- (4- hydroxyphenyl)- 4- methyl- 5-thiazolecarboxylate with 98% yield.

EXAMPLE- 3 (present invention)

1.0 Mole of ethyl 2-(4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate prepared as given in Example -2 was added to 280 ml of acetonitrile in a reactor. 0.5 Mole copper(II) nitrate was added to the mixture. Temperature was maintained at 25-30°C. In another flask, 1.3 moles of DMF was taken and was cooled to 5- 10°C. 1.3 Moles of POC was added to DMF, maintaining the temperature 5- 10°C. DMF-POCI3 mixture was added drop wise with stirring to the reaction mixture in the reactor maintaining temperature of the reaction mixture below 45°C. The mixture was stirred further for 30 min. After completion of the reaction, 100 ml water and 260 ml chloroform were added to the reaction mixture. The mixture was stirred and organic and aqueous layers were allowed to separate. The organic layer was washed with 200 ml of 5% sodium bicarbonate solution and the solvent was removed by distillation under reduced pressure to obtain ethyl 2-(4-hydroxy-3-nitrophenyl)-4-methyl-5-thiazolecarboxylate with 94% yield and 91% purity.

EXAMPLE-4 (present invention)

0.38 Moles of ethyl 2-(4-hydroxyphenyl)-4-methyl-5- thiazolecarboxylate prepared as given in Example- 2 was added to 3 moles of N,N-dimethylformamide. 0.42 Moles of sodium nitrate was added with stirring to the mixture. The reaction mass was then cooled to 0-5°C. 0.45 Moles of POCb was added dropwise with stirring to the reaction mixture maintaining the temperature 0-5°C. The reaction mass was brought to ambient temperature and was stirred for 60 min at ambient temperature. . It was then cooled to 10°C. 1.0 L water was added to the mixture maintaining the temperature below 20°C and it was stirred for 30 min at 20°C. Solid obtained was filtered, washed with water and dried at 60°C under reduced pressure to obtain ethyl 2-(4-hydroxy-3-nitrophenyl)-4- methyl-5-thiazolecarboxylate with 81% yield and 93% purity.

EXAMPLE- 5 (present invention)

Process as given in Example-4 was repeated except that potassium nitrate was used in place of sodium nitrate. Ethyl 2 -(4 -hydroxy- 3- nitrophenyl)-4-methyl-5-thiazolecarboxylate was obtained with 82% yield and 92% purity.

Claims

WE CLAIM:

1. A process for preparation of ethyl 2-(4-hydroxy-3-nitrophenyl)-4- methyl-5-thiazolecarboxylate by reaction of ethyl 2-(4- hydroxyphenyl)- 4- methyl- 5-thiazolecarboxylate with metal nitrate in presence of acid chloride and Ν,Ν-Dimethylformarnide.

2. A process as claimed in claim 1, wherein said metal nitrate is selected from sodium nitrate, potassium nitrate and copper(II) nitrate.

3. A process as claimed in claim 1 , wherein said acid chloride is POCl₃.