DESC:The following specification particularly describes the invention and the manner in which it is to be performed.
PROCESSES FOR THE PREPARATION OF DIMETHYL FUMARATE.

INTRODUCTION
Aspects of the present application relate to processes for the preparation of dimethyl fumarate or its crystalline form with uniform particle size distribution.
The drug compound having the adopted name “Dimethyl fumarate” has chemical name: dimethyl (E) butane-1,4-dioate and can be represented by structural formula (I) as below.

Dimethyl fumarate have been shown to activate the Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway in vitro and in vivo in animals and humans. Dimethyl fumarate is approved for the treatment of patients with relapsing forms of multiple sclerosis and is available in the market under the brand name TECFIDERA™ in the United States and Europe in the form of a hard gelatin delayed-release capsules for oral administration, containing 120 mg or 240 mg of dimethyl fumarate.
Various methods are reported for the synthesis of dimethyl fumarate in the art such as isomerization of corresponding maleate esters or esterification of fumaric acid. Isomerization of maleate esters can be carried out in the presence of suitable reagents such as triphenylphosphine, PhSeSePh, PhSSPh, Al2O3, triethylamine, Co(OAc)2 and Aminals.
Esterification of fumaric acid is the widely explored method for the synthesis of dimethyl fumarate. Suitable catalysts that are used in esterification method include suitable acids such as sulfuric acid, sulfonic acid or its derivatives, hydrogen halides; Boron trifluoride-etherate complex; trialkyloxonium salts; acyl chloride; Organo-phosphorus reagents; FeCl3; and SOCl2. Alternatively, esterification methods using other methylation agents such as diazomethane has been employed.
The processes for the preparation of dimethyl fumarate described in the literature do not describe or emphasize on the techniques to obtain dimethyl fumarate with desired particle sizes or particle size distribution. There remains a need to provide economically and industrially viable process, which avoids lengthy procedures for the preparation of dimethyl fumarate with desired particle size and other attributes to use it directly to prepare pharmaceutical formulations.

SUMMARY
An aspect of the present application provides a process for preparing dimethyl fumarate with uniform particle size distribution, which comprises:
a) providing a mixture of dimethyl fumarate and a suitable solvent or mixture thereof;
b) milling the reaction mixture of step a) under suitable milling conditions;
c) subjecting the mixture of step a) or b) to ultra sound sonication and
d) recovering dimethyl fumarate with uniform particle size distribution.

BRIEF DESCRIPTION OF THE DRAWING
Figure 1 is an illustrative X-ray powder diffraction pattern of dimethyl fumarate prepared by the method of Example No 6.

DETAILED DESCRIPTION
Aspects of the present application provide processes for the preparation of dimethyl fumarate or its crystalline form with uniform particle size distribution, which are suitable for consistent handling for drug product processing.

In an aspect, the present application provides a process for preparing dimethyl fumarate with uniform particle size distribution, which comprises:
a) providing a mixture of dimethyl fumarate and a suitable solvent or mixture thereof;
b) milling the reaction mixture of step a) under suitable milling conditions;
c) subjecting the mixture of step a) or b) to ultra sound sonication and
d) recovering dimethyl fumarate with uniform particle size distribution.

Starting material, dimethyl fumarate that is used in step a) of this aspect can be prepared by any methods known in art or according to the procedures described in the present application. Dimethyl fumarate can optionally be purified prior to using in step a).
Step a) of this aspect can be carried out by providing a mixture of dimethyl fumarate and a suitable solvent or mixture thereof. In embodiments, the mixture can be provided by combining Dimethyl fumarate with a suitable solvent or mixture of solvents.
In embodiments, the combined mixture of Dimethyl fumarate and solvent of step a) forms a homogeneous (or) heterogeneous mass such as a solution (or) suspension, slurry. In preferred embodiment, the combined mixture of Dimethyl fumarate and solvent of step a) forms a heterogeneous mass.
In embodiments, mixture of dimethyl fumarate and suitable solvent can be provided by directly taking the mixture from the synthetic reaction mass containing dimethyl fumarate and a solvent.
In an embodiment, suitable solvent that can be used includes, but not limited to: C1-C6 alcohols, C3-C6 ketones, C5-C8 aliphatic or aromatic hydrocarbons, C3-C6 esters, aliphatic or cyclic C2-C6 ethers, C2-C6 nitriles, halogenated hydrocarbons, water or mixtures thereof. In preferred embodiment, suitable solvent can be an alcohol solvent such as methanol, ethanol, isopropyl alcohol or the like.
In embodiments, dimethyl fumarate can be combined with a suitable solvent at a suitable temperature of about 25°C to reflux temperature of the solvent used.
In embodiments, the combined mixture of dimethyl fumarate and solvent of step a) can optionally be cooled to a suitable temperature before proceeding to step b).
In embodiments, the combined mixture of dimethyl fumarate and solvent of step a) can optionally be cooled to a suitable temperature before proceeding to step b). In embodiments, the combined mixture of Dimethyl fumarate and solvent of step a) can be cooled to about -80°C to 0°C. In embodiments, the combined mixture of dimethyl fumarate and inert solvent of step a) can be cooled in single step or in multiple steps.
Step b) of this aspect can be carried out by optionally milling the reaction mixture of step a) under suitable milling conditions. In an embodiment, the reaction mixture of step a) can be milled using techniques known in art or according to the procedures described in the present application.
In an embodiment, milling of step b) can be carried out by wet milling. It is a known fact that dimethyl fumarate sublimates even at relatively lower temperatures leading to loss of dimethyl fumarate while processing and even during long-term storage. The superiority of wet milling over other milling techniques lies as to the fine fractions generated during milling remain in the suspension with a significant reduction of material loss; dust formation can be avoided; operations such as product feeding or dosing are comparatively easier than a dry process. Further specific to Dimethyl fumarate, its direct contact may lead to skin and mucosal membrane irritations, which can be avoided with wet milling method unlike dry milling.
In embodiments, milling of step b) can be carried on by subjecting the reaction mixture of step a) in the form of heterogeneous suspension or slurry under suitable wet milling conditions.
In embodiment, milling of step b) can be carried out under suitable milling conditions. Suitable conditions for milling may include, but not limited to temperature, speed, feed rate and pressure. Depending upon the milling equipment used the conditions for milling may be optimized to obtain desired product.
In embodiments, step b) can be carried out using a rotar stator wet mill under controlled milling conditions such as controlled temperature, controlled milling speed and feed rate of the mixture of dimethyl fumarate and suitable solvent.
In embodiments, the milling speed may be fixed or it can be increased or decreased incrementally based on the particle size requirement and nature of the input material such as agglomerates, fragile particles, low density solids etc. In embodiment, the milling speed can be increased steps wise starting from a minimum speed of about 10000 RPM of the mill to a maximum speed about 30000 RPM.
In embodiments, the temperature at which milling is carried out can be controlled by an external source such that there are no drastic temperature increase or decrease due to changing milling parameters and no agglomeration of particles takes place. In embodiments suitable temperature can be at about -80°C to 0°C.
In embodiments, the mixture of dimethyl fumarate and the suitable solvent of step a) can be fed into the mill at controlled rate. In embodiment, mixture of step a) can be fed at a rate of about 500 mL / minute to about 2000 mL/ minute.
The reaction mixture of step b) can be subjected to sonication in an ultra sound flow cell or the mixture of step a) can be directly subjected to sonication.
In embodiments, step c) of this aspect can be carried out by subjecting the mixture of step b) or step a) to ultra sound sonication in a flow cell at suitable amplitude. In embodiments, the amplitude for sonication can be fixed or can be increased or decreased step wise. In embodiments, sonication can be carried out by increasing the amplitude step wise starting from minimum amplitude of about 40 to a maximum amplitude of about 100.
In embodiments, sonication can be carried out at a suitable temperature of about -80°C to 10°C. In embodiments, sonication can be carried out at constant temperature and controlling the raise in temperature during sonication.
In embodiments, sonication can be carried out for time sufficient to attain the uniformity of the Dimethyl fumarate particles, which are suitable for consistent handling for drug product processing. In embodiments, sonication can be carried out for atleast 5 minutes or more.
In an embodiment, the combined mixture of dimethyl fumarate and inert solvent can be circulated through a closed loop systems connecting a reactor, a wet mill and a flow cell or connecting a reactor and a flow cell or connecting a reactor and a wet mill. These closed systems can be operated at suitable conditions such as controlled temperature, milling parameters, sonication amplitude or according to the conditions described in this aspect.
Step d) of this aspect can be carried out by employing any of the techniques known in the art to obtain uniform particle size distribution of dimethyl fumarate. Techniques for the isolation of Dimethyl fumarate include, but not limited to: decantation, filtration by gravity or suction, centrifugation, and the like, and optionally washing with a solvent.
The Dimethyl fumarate recovered by the process of this aspect can be subjected to drying at suitable temperatures, such as about 25°C to 35°C and suitable pressures, using drying equipment known in the art, such as air dryer, vacuum dryer, fluidized bed dryer, spin flash dryer, flash dryer, and the like. Drying can be carried out for times sufficient to achieve desired quality of product.
In embodiments, dimethyl fumarate that is used in step a) of this aspect can be prepared according to a process, comprising the steps of
1) reacting fumaric acid with methanol in the presence of a suitable catalyst
2) re-crystallizing the product of step a) in a suitable solvent.
This process can be schematically illustrated as in Scheme-I.

The individual steps of the process are described herein below.
Fumaric acid is commercially available or can be prepared according to any of the processes known in art. The Fumaric acid can be purified by techniques known in art like column chromatography, fractional distillation, acid-base treatment, slurring or re-crystallization, before using.
Step 1) can be carried out by reacting Fumaric acid with methanol in presence of a suitable catalyst.
In embodiments, step 1) can be carried out by reacting Fumaric acid with methanol optionally in presence of an inert solvent. Suitable inert solvent is a solvent that does not interfere in the esterification of Fumaric acid with methanol and include, but not limited to ketones such as acetone, methyl ethyl ketone; hydrocarbons such as dichloromethane; esters such as ethyl acetate, isopropyl acetate; water or mixtures thereof. In preferred embodiments, Fumaric acid can be reacted with methanol alone, where it acts as both solvent as well as methylating agent.
In embodiments, step 1) can be carried out, by reacting Fumaric acid with methanol in the mole ratio of 1:1 to 1:12 respectively.
In embodiments, Fumaric acid can be reacted with methanol in presence of a suitable catalyst. Suitable catalyst can include, but not limited to acid catalyst such as hydrochloric acid; sulfuric acid; alkyl or aryl sulfonic acids like as methane sulfonic acid, toluene sulfonic acid; reactive acid derivatives such as acid chlorides like acetyl chloride, acetyl bromide; a alkoxonium salts such as trimethyloxonium tetraborohyride, trimethyloxonium tetraborohyride; a metal halide such as ferric chloride; a organo phosphorus reagents; thionyl chloride or the like.
In embodiments, the catalyst can be in concentrated or diluted form such as aqueous or organic solution, gaseous phase or a salt containing the catalyst. In an embodiment, alcoholic hydrochloric acid such as methanolic hydrochloric acid can be used as catalyst.
In embodiments, the reaction between Fumaric acid and the methanolic hydrochloric acid can be carried out in the volume ratio of 1:1 to 1:6 respectively.
In embodiments, the reaction of the Fumaric acid and methanol can be carried out at temperatures ranging from about 30ºC to reflux temperature of the solvent.
In embodiments, the reaction between Fumaric acid and methanol can be carried out for time sufficient for the formation of Dimethyl fumarate. Preferably reaction can be carried out in about 1 to about 10 hours or longer. In embodiments, the reaction can be carried out for sufficient time till no traces of Fumaric acid and mono methyl fumarate.
In embodiments, the reaction mixture can be cooled to suitable temperature of about 0°C to 35°C after the completion of the reaction.
In embodiments, dimethyl fumarate obtained by the process of step 1) can be isolated by employing any of the techniques known to a person skilled in art. Techniques for the isolation of dimethyl fumarate include, but not limited to: decantation, filtration by gravity or suction, centrifugation, and the like, and optionally washing with a solvent.
In embodiments, dimethyl fumarate obtained by the process of step 1) can be dried at suitable drying conditions known in the art or the wet compound can be used without drying. In embodiments, drying can be carried out at temperatures and times sufficient to achieve desired quality of product.
Step 2) can be carried out by re-crystallizing the product of step 1) by employing a suitable technique known in the art or according to any of the procedures described in the present application.
In an embodiment, re-crystallizing the product of step 1) can be carried out by providing a solution of dimethyl fumarate in a suitable solvent and recovering dimethyl fumarate.
Suitable solvent that can be used include, but are not limited to C1-C6 alcohols, C3-C6 ketones, C3-C6 esters, C2-C6 nitriles, halogenated hydrocarbons, water or mixtures thereof. In preferred embodiment, suitable solvent can be an alcohol solvent such as methanol, ethanol, isopropyl alcohol or the like.
In embodiments, solution of dimethyl fumarate can be obtained directly from the reaction mixture containing dimethyl fumarate or by dissolving dimethyl fumarate in a suitable solvent.
In embodiments, solution of dimethyl fumarate can be obtained by heating a mixture of dimethyl fumarate and a suitable solvent at a suitable temperature of about 25°C to boiling point of the solvent. In embodiments, the solution of step a) can be treated with de-colorizing agent such as charcoal and / or filtered to make it particle free solution before proceeding to next step.
Recovering dimethyl fumarate from the solution can be carried out by employing any of the techniques known to a person skilled in art that include, but not limited to: cooling the reaction mixture, removal of solvent, contacting the reaction mixture with an anti-solvent, etc., or combination of techniques thereof.
Recovering dimethyl fumarate from the solution can be carried out by cooling to a suitable temperature of about -10°C to 35°C. Cooling can be carried out gradually in a single step or in multiple steps with controlled cooling rate.
Recovering dimethyl fumarate from the solution can be carried out by removal of solvent which can include, but not limited to: evaporation of solvent under atmospheric pressure or under reduced pressure / vacuum, spray drying, freeze drying and the like.
Recovering dimethyl fumarate from the solution can be carried out by contacting the solution containing dimethyl fumarate with a suitable anti-solvent. Anti-solvent is a solvent in which dimethyl fumarate has low solubility. Anti-solvent can be contacted either by addition of anti-solvent to the solution or by addition of solution to the anti-solvent either in a single lot or in multiple lots.
Anti-solvent can be contacted with the reaction mixture for sufficient time and suitable temperature.
In embodiments, dimethyl fumarate can be isolated by employing any of the techniques known to a person skilled in art. Techniques for the isolation of Dimethyl fumarate include, but not limited to: decantation, filtration by gravity or suction, centrifugation, and the like, and optionally washing with a solvent.
The Dimethyl fumarate isolated by any process described in the present application can be subjected to drying at suitable temperatures, such as about 25°C to 35°C and suitable pressures, using drying equipment known in the art, such as air dryer, vacuum dryer, fluidized bed dryer, spin flash dryer, flash dryer, and the like. Drying can be carried out at temperatures and times sufficient to achieve desired quality of product.
Dimethyl fumarate obtained according to processes of the present application can be a crystalline Dimethyl fumarate and characterized by XRPD 2theta peaks at 10.8°, 21.8°, 23.9° and 27.2° ± 0.2 or substantially same as the X-ray diffraction pattern depicted in figure 1 or substantially same as the crystalline form disclosed in Acta Crystallographica, Section E: Structure Reports Online (2004), 60(5), page: 917-918.
In another aspect the present application provides dimethyl fumarate with particle size of less than about 150 microns or less than about 100 microns. In embodiments, the present application provides dimethyl fumarate with d(0.5) of less than about 50 microns or less than about 30 microns. In embodiments, the present application provides dimethyl fumarate with d(0.9) of less than about 100 microns or less than about 50 microns.
In another aspect the present application provides dimethyl fumarate with a chemical purity of greater than about 99%, or greater than about 99.5%, or greater than about 99.9%, as determined using high performance liquid chromatography (HPLC). In embodiments, the present application provides dimethyl fumarate containing single maximum impurity less than about 0.1%, or less than about 0.05 %, or less than about 0.01%, as determined using high performance liquid chromatography (HPLC).
In another aspect, the present application provides pharmaceutical compositions containing a therapeutically effective amount of Dimethyl fumarate prepared according to any of the process described in the present application, together with one or more pharmaceutically acceptable excipients.
Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the application in any manner. Variations of the described procedures, as will be apparent to those skilled in the art, are intended to be within the scope of the present application.
Definitions
The term "about" when used in the present invention preceding a number and
referring to it, is meant to designate any value which lies within the range of ±10%,
preferably within a range of ±5%, more preferably within a range of ±2%, still more
preferably within a range of ±1 % of its value. For example "about 10" should be
construed as meaning within the range of 9 to 11 , preferably within the range of 9.5
to 10.5, more preferably within the range of 9.8 to 10.2, and still more preferably
within the range of 9.9 to 10.1 .
An “inert solvent” is a solvent that does not react with the reactants or reagent s under conditions that cause the chemical reaction indicated to take place.
The term “uniform particle size” or “uniform particle size distribution” when used in the present invention refers to the sample of dimethyl fumarate wherein the major portion of the particles of a given sample have similar particle diameter or the diameter of all the particles of the given sample is within a narrow range as measured by methods known for particle size measurement which include but not limited to laser technique using instruments such as Malvern mastersizer; sieve analysis or the like.
An “alcohol” is an organic compound containing a carbon bound to a hydroxyl group. “C1-C6 alcohols” include, but are not limited to, methanol, ethanol, 2-nitroethanol,2-fluoroethanol, 2,2,2-trifluoroethanol, hexafluoroisopropyl alcohol, ethylene glycol, 1-propanol, 2-propanol (isopropyl alcohol), 2-methoxyethanol, 1-butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, phenol, glycerol, or the like.
An “aliphatic hydrocarbon” is a liquid hydrocarbon compound, which may be linear, branched, or cyclic and may be saturated or have as many as two double bonds. A liquid hydrocarbon compound that contains a six-carbon group having three double bonds in a ring is called“aromatic.” Examples of “C5-C8aliphatic or aromatic hydrocarbons” include, but are not limited to, n-pentane, isopentane, neopentane, n-hexane, isohexane, 3-methylpentane, 2,3-dimethylbutane, neohexane, n-heptane, isoheptane, 3-methylhexane, neoheptane, 2,3-dimethylpentane, 2,4-dimethylpentane, 3,3-dimethylpentane, 3-ethylpentane, 2,2,3-trimethylbutane, n-octane, isooctane, 3-methylheptane, neooctane, cyclohexane, methylcyclohexane, cycloheptane, benzene, toluene, ethylbenzene, m-xylene, o-xylene, p-xylene, trimethylbenzene, chlorobenzene, fluorobenzene, trifluorotoluene, anisole, or any mixtures thereof.
An “ester” is an organic compound containing a carboxyl group -(C=O)-O- bonded to two other carbon atoms. “C3-C6esters” include, but are not limited to, ethyl acetate, n-propyl acetate, n-butyl acetate, isobutyl acetate, t-butyl acetate, ethyl formate, methyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate, or the like.
An “ether” is an organic compound containing an oxygen atom –O- bonded to two other carbon atoms. “C2-C6 ethers” include, but are not limited to, diethyl ether, diisopropyl ether, methyl t-butyl ether, glyme, diglyme, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, dibutyl ether, dimethylfuran, 2-methoxyethanol, 2-ethoxyethanol, anisole, or the like.
A “halogenated hydrocarbon” is an organic compound containing a carbon bound to a halogen. Halogenated hydrocarbons include, but are not limited to, dichloromethane, 1,2-dichloroethane, trichloroethylene, perchloroethylene, 1,1,1-trichloroethane, 1,1,2-trichloroethane, chloroform, carbon tetrachloride, or the like.
A “ketone” is an organic compound containing a carbonyl group -(C=O)- bonded to two other carbon atoms. “C3-C6 ketones” include, but are not limited to, acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone, ketones, or the like.
A “nitrile” is an organic compound containing a cyano -(C=N) bonded to another carbon atom. “C2-C6Nitriles” include, but are not limited to, acetonitrile, propionitrile, butanenitrile, or the like.

Preparation of Dimethyl fumarate

Preparation-A: Fumaric acid (1160 g), methanol (3000 mL) and concentrated sulfuric acid (10 ml) were added in a flask and the heated to 75°C. Stirred the reaction mixture at the same temperature for 10 hours and cooled to 30°C. Filtered the product and washed with methanol to obtain the title compound. Yield: 1224 g

Preparation-B: Fumaric acid (1.45 g), methanol (20 mL) and concentrated sulfuric acid (0.5 mL) were added in a flask and the heated to reflux. Stirred the reaction mixture at the reflux for 1 hour and cooled to 0°C. The reaction mixture was neutralized with saturated sodium carbonate and extracted with dichloromethane. The organic layer was separated and evaporated under vacuum and purified the crude product by Silica gel chromatography with dichloromethane as eluent to obtain the title compound. Yield: 1.63 g

Preparation-C: Fumaric acid (50 g), methanolic hydrochloride (100 mL) and methanol (300 mL) were added in a flask and heated to 62°C and stirred at the same temperature for 2.5 hours. Cooled the reaction mixture to 28°C and stirred at the same temperature for 4 hours. Cooled the reaction mixture to 0°C and stirred at the same temperature for 1.5 hours. Filtered the product and washed with methanol (100 mL). Wet compound was taken in a flask and added methanol (750 mL). The reaction mixture was heated to 62°C and stirred at same temperature for 15 min and cooled to 30°C in 1hour 15 min and further cooled to -5°C in 45 min. The reaction mixture was stirred at -5°C for 1.5 hours and filtered the product and washed with methanol (50 mL). Wet compound was dried under vacuum at 25°C for 8 hours to obtain the title compound. Yield: 53.0 g, Purity by HPLC: 99.99%

Preparation-D: Fumaric acid (50 g), methanolic hydrochloride (100 mL) and methanol (300 mL) were added in a flask and heated to 61°C and stirred at the same temperature for 2.5 hours. Cooled the reaction mixture to 28°C and stirred at the same temperature for 4 hours. Cooled the reaction mixture to 0°C and stirred at the same temperature for 1 hour. Filtered the product and washed with methanol (100 mL). Wet compound was taken in a flask and added methanol (750 mL). The reaction mixture was heated to 62°C and stirred at same temperature for 17 min and cooled to 30°C in 1hour 10 min and further cooled to -5°C in 40 min. The reaction mixture was stirred at -5°C for 2 hours and filtered the product and washed with methanol (50 mL). Wet compound was dried under vacuum at 25°C for 7.5 hours to obtain the title compound. Yield: 52.7 g, Purity by HPLC: 99.99%

Preparation-E: Fumaric acid (50 g), methanol (400 mL) and acetyl chloride (14.6 g) were added in a flask and heated to 70°C and stirred at the same temperature for 12 hours. Cooled the reaction mixture to 28°C and stirred at the same temperature for 1 hour. Filtered the reaction mixture and wet compound was dried under vacuum at 25°C for 2 hours. Dried compound (45 g) was dissolved in methanol (540 mL) at 55°C and the clear solution was filtered to make it particle free solution. The reaction mixture was cooled to 28°C and then further cooled to 15°C. The reaction mixture was stirred at same temperature for 2 hours and filtered the product. Wet compound was dried under vacuum at 28°C for 3 hours to obtain the title compound. Yield: 33.2 g, Purity by HPLC: 99.97%

Preparation-F: Fumaric acid (50 g), methanolic hydrochloride (80 mL) and methanol (300 mL) were added in a flask and heated to 62°C and stirred at the same temperature for 2.5 hours. Cooled the reaction mixture to 28°C and stirred at the same temperature for 4 hours. Cooled the reaction mixture to 0°C and stirred at the same temperature for 1 hour. Filtered the product and washed with methanol (100 mL). Wet compound was taken in a flask and added methanol (750 mL). The reaction mixture was heated to 62°C and stirred at same temperature for 15 min and cooled to 30°C in 1hour 10 min and further cooled to -5°C in 40 min. The reaction mixture was stirred at -5°C for 1 hour 40 minutes and filtered the product and washed with methanol (50 mL). Wet compound was dried under vacuum at 25°C for 7.5 hours to obtain the title compound. Yield: 53.0 g, Purity by HPLC: 99.99%

EXAMPLES

Example-1: Dimethyl fumarate (10 g) was dissolved in methanol (150 mL) at 65°C. This clear solution was cooled to 40°C and transferred into a pre-cooled flask at 5°C. The reaction mass was subjected to sonication at 8°C for 20 minutes and filtered the reaction mass. The solid was dried under vacuum at 30°C for 2 hours to obtain title compound. Yield: 7.67 g; Particle size distribution: D(10): 13 microns, D(50): 27 microns and D(90): 58 microns.

Example-2: Dimethyl fumarate (10 g) was dissolved in methanol (150 mL) at 65°C. This clear solution was cooled to 40°C and transferred into a pre-cooled flask at 5°C. The reaction mass was subjected to sonication at 8°C for 10 minutes and filtered the reaction mass to obtain title compound. The solid was dried under vacuum to obtain title compound. Yield: 8.1 g;
Particle size distribution: D(10): 17 microns, D(50): 36 microns and D(90): 65 microns.

Example-3: A mixture of dimethyl fumarate (150 g) and methanol (2250 mL) was heated to 45°C for complete dissolution. Wet milling was started by circulating it through a wet mill at 18000 RPM with liquid flow rate of 1100 mL / minute and cooling it simultaneously. After 30 minutes of milling, wet mill parameters were changed to 24000 RPM with liquid flow rate of 1650 mL / minute at 21°C. After 30 minutes of milling, the liquid flow rate was changed to 2000 mL / minute at 16°C. After 40 minutes, milling was stopped at 15°C and the reaction mass was cooled to 5°C. Solid was filtered at 5°C to obtain 39 g of wet dimethyl fumarate. Particle size distribution: D(10): 16.52 microns, D(50): 50.08 microns and D(90): 118.28 microns.

Example-4: A mixture of dimethyl fumarate (240 g) and methanol (2000 mL) was taken in a reactor at 25°C. A circulatory loop was set up connecting the reactor and wet mill. The reaction mass was circulated from reactor to the wet mill and back into the reactor. The reaction mass was circulated continuously through this loop under controlled temperature conditions. Wet milling was started at -2°C with 12000 RPM and at liquid flow rate of 900 mL/ min and after 10 min the wet mill parameters were changed to 15000 RPM and liquid flow rate of 1000 mL/ minutes. After 30 minutes, wet mill parameters were changed to 24000 RPM and liquid flow rate of 1200 mL/ min at -5°C. After 30 minutes, wet milling was stopped and the solid was recovered by filtration at -3°C ad dried under vacuum to obtain 131 g of dimethyl fumarate. Particle size distribution: D(90): 103 microns.

Example-5: A mixture of dimethyl fumarate (250 g) and methanol (2500 mL) was taken into a reactor. A circulatory loop was set up connecting the reactor, wet mill and ultrasound flow cell and the reaction mass was circulated from reactor to the wet mill followed by ultra sound flow cell and back into the reactor. The reaction mass was circulated continuously through this loop under controlled temperature conditions. This closed loop system was cooled to -8°C and wet milling was started at -20°C with 18000 RPM and at liquid flow rate of 1200 mL/ min and ultra sound flow cell with 70 Amp and after 15 min the wet mill parameters were changed to 21000 RPM. After 30 minutes, parameters were changed to 24000 RPM in wet mill and ultra sound flow cell with 90 Amp at -5°C. After 20 minutes, wet milling and ultra sound flow cell were stopped and the solid was recovered to obtain 170 g of dimethyl fumarate. Particle size distribution: D(10): 6.963 microns, D(50): 17.57 microns and D(90): 37.78 microns

Example-6: A mixture of dimethyl fumarate (120 g) and methanol (1.1 L) was taken into a reactor and cooled to -32°C. The mixture of dimethyl fumarate and methanol was circulated through ultra sound flow cell with amplitude of 70 and back into the reactor. Every 10 minutes the amplitude of ultra sound flow cell was increased by 5 units and the temperature is maintained. Maximum amplitude of 90 is attained and continued for 20 minutes at that condition. Later, amplitude is increased to 95 and continued for 10 minutes and then decreased the amplitude to minimum. The reaction mass was filtered and dried to obtain 77.2 g of dimethyl fumarate. Particle size distribution: D(10): 7.08 microns, D(50): 21.15 microns and D(90): 64.25 microns.
,CLAIMS:CLAIMS:
We Claim:
1. A process for the preparation of dimethyl fumarate with uniform particle size distribution, which comprises the steps of:
a) providing a mixture of dimethyl fumarate and a suitable solvent or mixture thereof;
b) milling the reaction mixture of step a);
c) subjecting the mixture of step a) or b) to ultra sound sonication and
d) recovering dimethyl fumarate with uniform particle size distribution.

2. The process of claim 1, wherein a suitable solvent at step a) may be selected from the group comprising of methanol, ethanol, isopropyl alcohol, n-propanol, n-butanol, Sec. butanol, Tert. Butanol or mixtures thereof.

3. The process of claim 1, wherein milling at step b) may be carried out through wet milling.

4. The process of claim 1, wherein ultra sound sonication at step c) may be carried out in an ultra sound flow cell.

5. The process of claim 1, wherein the mixture of dimethyl fumarate and inert solvent may be circulated through a closed loop connecting a reactor with a wet mill and / or an ultra sound flow cell.

6. The process of claim 1, wherein dimethyl fumarate that is used in step a) may be obtained according to a process comprising the step of reacting fumaric acid with methanol in the presence of a catalyst.

7. The process of claim 6, wherein the catalyst may be selected from the group comprising of acid catalyst such as hydrochloric acid; sulfuric acid; alkyl or aryl sulfonic acids like as methane sulfonic acid, toluene sulfonic acid; reactive acid derivatives such as acid chlorides like acetyl chloride, acetyl bromide; a alkoxonium salts such as trimethyloxonium tetraborohyride, trimethyloxonium tetraborohyride; a metal halide such as ferric chloride; a Organo phosphorus reagents; thionyl chloride or the like.