FIELD OF THE INVENTION
The present invention relates to a process for the preparation of Dimethyl fumarate by using phosphorous acid or phosphoric acid. Further, the present invention relates to purification of dimethyl fumarate in methanol.
BACKGROUND OF THE INVENTION
Fumaric acid is an intermediate in the citric acid cycle that is hydrated by the enzyme fumarase to maleic acid. The use of fumaric acid for the treatment of psoriasis was introduced in 1959.
Fumaric acid has also been shown to impede the growth of Ehrlich solid tumor cells in mice. Kuroda, K., et al, Cancer Res. 36:1900-1903 (1976).
Later, the derivative of fumaric acid, Dimethyl Fumarate, was approved by the FDA in 2013 for the treatment of Multiple Sclerosis. Biogen Idec marketed dimethyl fumarate as Tecfidera®. Dimethyl fumarate chemically described as dimethyl-(E)-butenedioate, and
represented as structure of formula I:
O
H V—O
H3C \ ( CH3
O—X H
O
Formula I
In the 1980's, more standardized oral preparations of fumaric acid esters were developed, containing dimethylfumarate and monoethyl fumarate as the main components. After oral uptake, dimethyl fumarate is rapidly hydrolyzed to mono methyl fumarate.
The biological half-life of methyl hydrogen fumarate is 36 hours with 30% being bound by serum proteins. Schilling, S., et al, Clin. Exp. Immunol 145:101-107(2006).

U.S. Patent No. 2,764,609 discloses dialkyl fumarate and process from dialkyl maleate. U.S. Patent No. 4,851,439 discloses fumaric acid derivatives in the form of prodrugs.
Various prior arts, US 4,959,389, US 5,424,332, US 5,451,667 US 6,277,882, US 6,355,676, US 6,359,003, US 6,858,750, discloses monoalkyl ester, calcium, magnesium, zinc and iron salts of fumaric acid and their pharmaceutical uses.
PCT publication No. WO 2012/170923 A1 and CN 103848739 disclose a method for the preparation of dimethylfumarate by reacting the fumaric acid with methanol in the presence of sulfuric acid. However, this process leads to the formation of dimethyl sulphate, which is a known genotoxic impurity.
Various other prior arts, WO2015/044853, WO 2014/203231, WO 2015/140811, US Publication No 2002/0002306, CN 101318901, CN 1103398, CN 102757346, IP.COM Journal IPCOM000242958D, discloses different processes for Dimethyl fumarate. However, these processesfaces one or the other problems, for example, use of expensive reagents, conducting reactions in longer hours, formation of genotoxic impurities, which leads to lower yield and purity.
The impurity, Dimethyl sulphate, which is forming in the prior art processes, is a known mutagenic, and thus, genotoxic compound (Tan et al., J. Toxicol. Environ. Health 1983, , 11, 373-380). Further, regulatory authorities have set strict guidelines for the amount of genotoxic impurities contained in drug substance (Robinson, Org. Proc. Res. Dev. 2010, 14: 946-959).
Therefore, the inventors of the present invention developed a process for dimethyl-(E)-butenedioate, which is an efficient, cost-effective, industrially scalable and overcomes the drawbacks of various prior art processes.
SUMMARY OF INVENTION
In an embodiment, the present invention provides a process for the preparation of dimethyl fumarate of formula I:

O
H y—O
H3C y ( CH3
O—X H
O
(I)
which comprises reacting fumaric acid with methanol in the presence of phosphorous acid-or phosphoric acid.
In another embodiment, the present invention provides a process for the preparation of dimethyl fumarate, which comprises:
a) providing a solution of Fumaric acid in methanol;
b) adding phosphorous acid or phosphoric acid to the reaction mixture of step (a);
c) heating the reaction mixture to an elevated temperature;
d) isolating dimethyl fumarate with purity greater than 99.5%.
In another embodiment, the present invention provides a process for the purification of
dimethyl fumarate, which comprises:
i) providing solution of dimethyl fumarate in methanol;
ii) heating the reaction mixture to an elevated temperature
iii) isolating the dimethyl fumarate with purity greater than 99.95% by HPLC.
DETAILED DESCRIPTION OF INVENTION
In an embodiment, the present invention provides a process for the preparation of dimethyl fumarate of formula I:
O
H V—O
H3C y y CH3
O—^ H
O
(I)
which comprises reacting fumaric acid with methanol in the presence of phosphorous acid or phosphoric acid.

The phosphorous acids are coupling agents and is selected from ortho phosphoric acid, phosphorous acid, meta phosphoric acid, or pyro phosphoric acid. The coupling agent can be solid or liquid. The amount of coupling agent that may be utilized in the reaction may be molar excess compared with that of the fumaric acid. It may be present in an amount of about 0.2 to about 4.0 moles per mole of the Fumaric acid or 0.5 to 3 moles per mole of fumaric acid. Commercially available liquid phosphorous acid contains relatively high moisture content, so the water may be removed from the liquid phosphorous acid before to use as coupling agent.
The inventors of the present invention found that the use of phosphorous acid as coupling agent provides dimethyl fumarate with higher purity and avoids formation of toxic impurities like dimethyl sulphate and chloromethane, which are the main toxic impurities formed in the prior art processes.
The fumaric acid may be added to methanol to provide a solution. The amount of methanol used for the reaction may range from 1 to 15 volumes per gram of Fumaric acid or 3 to 10 volumes per gram of Fumaric acid. The reaction mixture is heated to elevated temperature or the fumaric acid is added to the hot methanol. The temperature per the reaction is from 25 to 65 ◦C. The reaction mixture may be refluxed for a period of 1 to 10 hours or more to complete the reaction.
If desired, the solution may be treated with charcoal or filtered to remove the undissolved particles and coloured impurities. The undissolved particles and impurities may be removed suitably by filtration, centrifugation, and other techniques. The solution may be filtered by passing through paper, glass fiber, or other membrane material, or a clarifying agent such as celite. Depending upon the equipment used and the concentration and temperature of the solut ion, the filtration apparatus may need to be preheated to avoid premature precipitation.
The reaction mixture is subjected for cooling may be in controlled manner. The cooling temperature is in the range from about 0 to about 35 ◦C. The reaction mixture may be stirred at the same temperature for a period of about 1 hour to 3 hours or more to enhance the pr ecipitat ion.

The obtained precipitation may be separated by the techniques known in the art. One skilled in the art may appreciate that there are many ways to separate the solids from heterogeneous mixtures. For example, it may be separated by using any techniques such as filtration by gravity or by suction, centrifugation, decantation, and the like. After separation, the solid may optionally be washed with suitable solvent.
The solid thus obtained may be dried. Drying may be suitably carried out in a tray dryer, vacuum oven, air oven, fluidized bed drier, spin flash dryer, flash dryer and the like. The drying may be carried out at temperature of about 30 ◦C to about 70 ◦C, and preferably at about 35◦C, optionally under reduced pressure. The drying may be carried out for any time period necessary for obtaining the product with desired purity, such as from about 1 to about 5 hours, or longer.
The obtained dimethyl fumarate of the present invention has purity greater than 99.9% by HPLC.
In an embodiment, the present invention provides a process for the preparation of dimethyl fumarate, which comprises:
a) providing a solution of Fumaric acid in methanol;
b) adding phosphorous acid or phosphoric acid to the reaction mixture of step (a);
c) heating the reaction mixture to an elevated temperature;
d) isolating dimethyl fumarate with purity greater than 99.9%.
The solut ion of fumaric acid is formed by the dissolut ion of fumaric acid in methanol at a temperature of 25 to 70 ◦C, preferably at 25 to 35 ◦C. Phosphorous acid or ortho-phosphoric acid is added to the solution of step (a), which is then heated to elevated temperature i.e. about 40 ◦C to reflux temperature. The obtained reaction solution is refluxed for a period of 8 to 10 hours.
After completion of the reaction, the reaction solution is subjected for solid isolation using suitable techniques such as cooling, distillation, anti-solvent and the like. The reaction solution is cooled to room temperature i.e. 25 to 35 ◦C or further cooled to 0◦C to initiate precipitation. The obtained reaction mixture is stirred at the lower temperature for a period of

1 to 3 hours to enhance the precipitation. The obtained suspension is filtered and then dried to afford dimethyl fumarate with purity greater than 99.9% by HPLC.
The present invention also provides a process for the purification of dimethyl fumarate, which comprises treating dimethyl fumarate with an organic solvent(s) and recovering the crystalline solid.
The organic solvent may be selected from C1-C4 alcoholic solvent, for example, methanol, ethanol, n-propanol and 2-propanol, 1-butanol, 2-butanol or mixture thereof. Dimethyl fumarate is mixed in alcoholic solvent at a temperature of 25 to 35◦C. The reaction mixture is then heated to reflux temperature to get a clear solution. The clear solution may be then filtered to remove particles. The reaction mixture is slowly cooled to RT and then further to a temperature of 0-15°C. The obtained reaction mixture is further maintained for a period of 1 to 3 hours. The solid material obtained is filtered and suck dried at room temperature for a period of 30 minutes to 1 hour. The resultant solid is dried till to get the desired dried material.
In another embodiment, the present invention provides a process for the purification of
dimethyl fumarate, which comprises:
i) providing solution of dimethyl fumarate in methanol;
ii) heating the reaction mixture to an elevated temperature
iii) isolating the dimethyl fumarate with purity greater than 99.95% by HPLC.
The solution of dimethyl fumarate is providing by the dissolution of dimethyl fumarate in methanol at a temperature of about 25 to reflux temperature. The solution can be prepared at reflux temperature or it can be taken from the previous step where the dimethyl fumarate is in the solution form. The dimethyl fumarate used for the dissolution can be in any polymorphic form, for example, it can be crystalline or amorphous.
The solution is subjected for isolation of solid by using suitable techniques such as re-crystallization, anti-solvent technique, distillation and the like. The isolation may be by re-crystallization i.e. cooling the solution from reflux temperature to room temperature i.e. 25 to

35 C The reaction mixture may be further cooled till 0 C to enhance the crystallization of dimethyl fumarate.
The obtained suspension or solid is recovered by using known techniques such as filtration, decantation, and the like. The solid may be further washed with methanol and then dried.
The dimethyl fumarate obtained from the present invention has purity greater than 99.95% by HPLC and can be used directly for the preparation of pharmaceutical composition.
Certain specific embodiments of the present invention will be explained in more detail with reference to the following examples, which are provided by way of illustration only and should not be construed as limiting the scope of the invention in any manner.
EXAMPLE
Example 1: Preparation of Dimethyl Fumarate
Methanol (25 ml) was charged to fumaric acid (5 gm). Solid orthophosphoric acid (12.66 gm) was charged to the reaction mixture at room temperature (25 to 35 C) and heated to reflux. The reaction mixture was refluxed for 8-10 hours. After completion of reaction, the reaction
' f
mixture was cooled to 10-15 C. T he solid was iltered and washed with methanol and then dried to get the solid. HPLC Purity: 99.76%
Example 2: Preparation of Dimethyl fumarate
The water was removed from the orthophosphoric acid (85-88% solution) using dean stark apparatus. Methanol (500 ml) was charged to fumaric acid (100 gm). Liquid ortho¬phosphoric acid (254 gm) was charged to the reaction mixture at room temperature and then heated to reflux. The reaction mixture was refluxed for 8-10 hours. After completion of reaction, the reaction mixture was cooled to 10-15 ◦C. The solid was filtered and washed with methanol. HPLC Purity of Wet material: 99.98%
Example 3: Purification of dimethyl fumarate

Methanol (500 ml) was charged to wet solid obtained in example 2 and then heated to reflux. The reaction mass was refluxed to get clear solution. The reaction mixture was cooled slowly 10-15 C The obtained suspension was filtered and washed with methanol. The solid was dried at 35 ◦C. Yield: 97 gm HPLC Purity 100%
Example 4: Preparation of Dimethyl fumarate
Methanol (100 ml) was charged to fumaric acid (20 gm) phosphorous acid (42.38 gm) was
charged to the reaction mixture at room temperature (25 to 35◦C) and heated to reflux. The
reaction mixture was refluxed for 8-10 hours. The reaction mixture was cooled to 10-15◦C.
The solid was filtered and washed with methanol and then dried to get the solid.
HPLC purity: 99.92%

We Claims:
1. A process for the preparation of dimethyl fumarate of formula I:
O
H V—O
H3C y ( CH3
O—