Process for the synthesis of dimethyl fumarate

Abstract

The present invention describes an improved process for the industrial scale production of dimethyl fumarate. The process involves a one-pot ring opening reaction of maleic anhydride to monomethyl maleate and isomerization into the corresponding monomethyl fumarate in presence of a Lewis acid. Finally the mono methyl fumarate was converted into the dimethyl fumarate by an acid catalyzed esterification reaction.

Claims

1. A improved process for the preparation of dimethyl fumarate comprising: (i) a ring opening reaction of maleic anhydride using methanol to obtain monomethyl maleate, followed by Lewis acid catalyzed isomerization of the monomethyl maleate to obtain monomethyl fumarate; (ii) conversion of monomethyl fumarate into dimethyl fumarate by an acid chloride mediated esterification, characterized in that the acid chloride mediated esterification comprises the following steps: a. dissolving monomethyl fumarate obtained in step (i) in methanol; b. adding thionyl chloride to the solution obtained in step (a); c. heating the reaction mixture obtained in step (b) at 60-65 C. for 10-12 hours; and d. isolating dimethyl fumarate; wherein the acid chloride mediated esterification is carried out in the absence of base and avoids separate formation of crude monomethyl fumaryl chloride.

2. The process according to claim 1, wherein the Lewis acid employed in step (i) is selected from the group consisting of AlCl.sub.3, ZnCl.sub.2, SnCl.sub.4 and TiCl.sub.4.

3. The process according to claim 1, wherein the step (i) is completed without isolation of the intermediary monomethyl maleate.

Description

DETAILED DESCRIPTION OF THE INVENTION

(1) The invention relates to a process for the synthesis of dimethyl fumarate of formula I, which comprises a one pot ring opening reaction of maleic anhydride using methanol to obtain monomethyl maleate followed by the Lewis acid catalyzed isomerization of the intermediate to the monomethyl fumarate.

(2) ##STR00003##

(3) The ring opening of the maleic anhydride with methanol can be carried out at 25 to 60 C. and the quantity of methanol can be used ranging from 0.5 to 2 equivalents.

(4) In another aspect of the invention, the catalyst used for the isomerization of monomethyl maleate to monomethyl fumarate is a Lewis acid. The Lewis acid, which can be employed is AlCl.sub.3, ZnCl.sub.2, SnCl.sub.4, TiCl.sub.4 or the like. The quantity of Lewis acid used for the isomerization may be varied from catalytic to stoichiometric amount. The temperature of the reaction may be varied from 25 to 100 C.

(5) ##STR00004##

(6) In yet another aspect of the invention, the monomethyl fumarate is converted in to the dimethyl fumarate by converting it to its acid chloride in an organic solvent. The reagent used for the acid chloride conversion is selected from the group comprising of thionyl chloride, oxalyl chloride, pivoloyl chloride or the like. The solvent used for the conversion of acid chloride is selected from the group consisting of alcohols like methanol, propanol, butanol or the like, hydrocarbons like CH.sub.2Cl.sub.2, Toluene, Hexane or the like, ethers like THF, MTBE or the like. The acid chloride is isolated and later quenched into methanol which generates the dimethylfumarate. The temperature of the reaction may vary between 25 to 100 C.

(7) The process is particularly advantageous that there is no formation of dimethyl sulfate impurity which is genotoxic and has to be controlled in the API in the prior art processes.

(8) The dimethyl fumarate obtained by this process is completely synthetic and avoids the use of fumaric acid starting material which could be obtained from non-synthetic sources.

(9) The process of the invention is illustrated in the following Scheme.

(10) ##STR00005##

(11) In conclusion, the authors have disclosed an improved industrial scale process for the synthesis of dimethyl fumarate.

(12) Preparation of Monomethyl Fumarate

(13) 100 g of Maleic anhydride was dissolved in 0.4 L, of methanol and the reaction mass was stirred for 3-4 hrs at 45-50 C. To the reaction mass, 150 ml of ethyl acetate was added and 10.0 g of anhydrous aluminum chloride was added at 45-50 C. for 10-20 min and maintained the reaction mass for 4-5 hrs at 70-75 C. After completion of reaction, the reaction mixture was maintained for 60-80 minutes at 5-10 C. and filtered. The solid obtained was washed with chilled ethyl acetate and dried. 80% of the product was isolated after purification.

(14) Preparation of Monomethyl Fumarate

(15) 100 g of Maleic anhydride was dissolved in 0.4 L, of methanol and stirred the reaction mass for 3-4 hrs at 45-50 C. To the reaction mass, 10.0 g of anhydrous aluminum chloride was added at 45-50 C. for 10-20 min and 150 ml of toluene was added and maintained the reaction mass for 4-5 hrs at 70-75 C. After completion of reaction, the reaction mixture was maintained for 60-80 minutes at 5-10 C. and filtered. The solid obtained was washed with chilled toluene and dried. 80% of the product was isolated after purification.

(16) Preparation of Dimethyl Fumarate

(17) 100 g of Monomethyl fumarate was dissolved in 500 ml of methanol and cooled to 10 C. 15 ml of thionyl chloride was slowly added to the reaction mass for 40-60 min and the reaction mass was heated to 60-65 C. and maintained for 10-12 h. After completion of the reaction the product was isolated and purified in methanol and water to yield 80 g of dimethyl fumarate with required spec.