FIELD OF INVENTION
The invention relates to an improved process for the preparation of Monomethyl fumarate of compound of Formula-I.

BACK GROUND OF THE INVENTION
Monomethyl fumarate is chemically known as (2E)-4-Methoxy-4-oxobut-2-enoic acid, which has been identified as a nicotinic acid receptor agonist in vitro. Monomethyl fumarate and prodrugs of monomethyl fumarate are useful for treating neurodegenerative, inflammatory, and autoimmune diseases including multiple sclerosis, psoriasis, irritable bowel disorder, ulcerative' colitis, arthritis, chronic obstructive pulmonary disease, asthma, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis.
US 4,515,974 A of Bayer discloses preparation of monomethyl fumarate via isomerization of monomethyl maleate using cis-trans catalysts like acetyl chloride, benzenesulphochloride, titanium tetrachloride, boron trifluoride etc.
JP 60181047 of Kokai Tokkyo Koho discloses preparation of monomethyl fumarate via isomerization of monomethyl maleate in the presence of quaternary ammonium bromide and organic peroxide.
DE 1165586 of Walter schweckendiek discloses preparation of monomethyl fumarate via isomerization of monomethyl maleate using oxalyl chloride as a catalyst.
JP 03294245 of Kokai Tokkyo Koho discloses preparation of monomethyl fumarate via isomerization of monomethyl maleate in the presence of aq. NaBr and aq. K2S2O8.
Journal of Organic Chemistry (1958), 23, 1559-60 discloses preparation of monomethyl fumarate via isomerization of monomethyl maleate using thiourea as a catalyst.

Organic Preparations and Procedure International (1983), 15 (4), 233-8, discloses preparation of monomethyl fumarate via isomerization of monomethyl maleate using HCI, AlCb or phthaloyl chloride as a catalyst.
To prepare monomethyl fumarate (MMF) or prodrugs of monomethyl fumarate for human pharmaceutical use, it is desirable to start with relatively pure MMF. The methods reported for the synthesis of monomethyl fumarate obtained by isomerization of the monomethyl maleate using different catalyst such as fumaryl chloride, thiourea. HCI, AICI3 etc. However aforementioned methods for the preparation of MMF result in .MMF contaminated with various impurities and needed many purifications to get rid of those impurities, there by obtained over all yields are very low.
The present inventors have repeated the process for preparing monomethyl fumarate by known prior art catalyst such as AICI3, fumaryl chloride, thiourea, HCI. However it has been observed that isolation of monomethyl fumarate requires tedious workup procedures and there by yields of monomethyl fumarate are low yield and low purity. Hence the reported procedures are not suitable for the commercial scale production of monomethyl fumarate.
In order to overcome the problems associated with prior art, there is a need to develop an efficient and cost effective method for the commercial scale production of monomethyl fumarate.
OBJECTIVES OF THE INVENTION
The objective of the present invention is to provide an efficient and industrially viable process for the preparation of monomethyl fumarate.
Another objective of the present invention is to provide process for preparing monomethyl fumarate having a high yield, purity and commercially viable process.

SUMMARY OF THE INVENTION
The present invention provides an improved process for the preparation of monomethyl fumarate of compound of Formula-1,

which comprises:
(i) reacting maleic anhydride with methanol to obtain monomethyl maleate. followed by addition of catalyst for isomerization of the monomethyl maleate to obtain monomethyl fumarate; and
(ii) optionally purifying the obtained monomethyl fumarate. wherein the catalyst is Boron tribromide (BBo).
DETAILED DESCRIPTION OF THE INVENTION
The invention relates to a process for the synthesis of monomethyl fumarate of compound Formula-1, which comprises reacting maleic anhydride with methanol to obtain monomethyl maleate, followed by the addition of catalyst for isomerization of the monomethyl maleate to obtain monomethyl fumarate

The ring opening of the maleic anhydride with methanol can be carried out at 25°C to 60°C. In another aspect of the invention, the catalyst used for the isomerization of monomethyl maleate to monomethyl fumarate is Boron tribromide. The quantity of ■ Boron tribromide used for the isomerization is varied from catalytic to stoichiometric amount. The temperature of the reaction is in the range from 25°C to 100°C. ■
In yet another aspect of the present invention, the process for the synthesis of
monomethyl fumarate is carried out by not isolating monomethyl maleate as an
NT nFFTTF r w P M M A T 11 , 1 ^ . ^ ^ ., -, „ . „ „

intermediate and hence avoiding the use of large quantities of solvents at a commercial scale.
In yet another aspect of the present invention, purification of monomethyl fumarate, by dissolving MMF crude in an organic solvent(s). Solvent is selected from the group comprising of halogenated solvents, alcohols, ketonic solvents, ethers, esters, hydrocarbons, nitriles, polar aprotic solvents.
In another aspect of present invention, the solvent through out the patent specification, halogenated solvents are selected from the group comprising of dichloromethane (MDC), ethylene dichloride (EDC), chloroform and the like; alcohols are selected from the group comprising of methanol, ethanol, isopropanol, butanol and the like; ketonic solvents are selected from the group comprising of acetone, methyl isobutyl ketone, dimethylformarnide and the like; ethers are selected from the group comprising of tetrahydrofuran (THF), 2-methyltetrahydrofurari (MeTHF), diethyl ether, isopropyl ether, methyl isobutylether, methyl t-Butyl ether (MTBE), dioxane and the like; esters are selected from the group comprising of ethyl acetate, isopropyl acetate and the like; hydrocarbons are selected from the group comprising of toluene, xylene and the like; nitriles are selected from the group comprising of acetonitrile, propionitrile, butyronitrile, acrylonitrile, Potassium cyanide and the like; Polar aprotic solvents are selected from the group comprising of dimethylformarnide (DMF), dimethylacetamide (DMA), acetonitrile, dimethylsulfoxide (DMSO) and the like.
The monomethyl 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.
The process of the present invention is illustrated in the following scheme:


Example-1
Preparation of Monomcthyl Fumaratc:
100 g of Maleic anhydride was dissolved in 85 ml of toluene and 65 ml of methanol and the reaction mass was stirred for 5-6 hrs at 50-55°C. After completion of the reaction, the reaction mixture was cooled to 25-30°C. To the reaction mass Boron tribromide was added at 25-30°C and maintained the reaction mass until the completion of the reaction. Further toluene was added to the reaction mixture, maintained for 2-3 hrs at 20-25°C, filtered and the solid thus obtained was washed with toluene and dried.
ExampIe-2:
Purification of Monomcthyl Fumaratc:
lOOgm of Monomethyl Fumarate crude was dissolved in 1200 ml of acetone, stirred for 30 min at 50-55°C; filtered the reaction mass on hi-flow bed and partially distilled out the acetone. The reaction mass was stirred for 1 hr at 0-5°C, filtered and dried.