FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13]
1. Title of the invention: "An improved process for the preparation of Dimethyl
Fumarate"
2. Macleods Pharmaceuticals Ltd., an Indian Company, having its Registered Office at 304 - Atlanta Arcade, Opp. Leela Hotel, Marol Church Road, Andheri (East), Mumbai - 400 059, Maharashtra, India.
3. The following specification describes the invention.

FIELD OF THE INVENTION
The present invention relates to the improved process to prepare pure, crystalline dimethyl fumarate containing no genotoxic impurities.
BACKGROUND OF THE INVENTION
Dimethyl fumarate is used in many chemical industries as well as in the pharmaceutical industries. However use of dimethyl fumarate in the pharmaceutical industries as a drug needs to be manufactured with devoid of any genotoxic impurities. U.S. Patent no. 4,851, 439 discloses fumaric acid derivatives in the form of pro-drugs. U.S. Patent no. 5,424,332 discloses calcium, magnesium, zinc and iron salts of fumaric acid monoalkyl esters. U.S. Patent no. 5,451,667 discloses derivatives of fumaric acid for the treatment of cryptogenically -caused diseases. U.S. Patent no. 6,355,676 discloses the use of salts of fumaric acid monoalkyl esters optionally in admixture with a dialkyl fumarate for the treatment of psoriatic arthritis, neurodermatitis and enteritis regional is Crohn. U.S. Patent no. 6,355,003 discloses the use of fumaric acid monoalkyl esters for transplantation medicines. U.S. Patent no. 6,858,750 discloses the use of pharmaceutical composition of fumaric acid derivatives for the treatment of mitochondrial diseases. U.S. Patent no. 7, 320,999 discloses the use of dialkyl fumarates for the therapy of autoimmune diseases.
Genotoxic impurity is the prime concern in the manufacture of pharmaceutical grade product. Thus there is a significant interest in the manufacture and regulation of pharmaceuticals regarding the generation, analysis and controlling of genotoxic impurities.
OBJECT OF THE INVENTION
The object of the present invention is to provide a scalable industrial process for the synthesis of highly pure dimethyl fumarate crystal form I in which there is no formation of genotoxic impurity with economical advantage.
SUMMARY OF THE INVENTION
Dimethyl sulfate is the genotoxic impurity as described in US20140200636. The present invention manufactures dimethyl fumarate which is devoid of dimethyl sufate impurity.

Z.physik.chem. (1928), l(Abt.B), 205-38 discloses process to prepare dimethyl fumarate from dimethyl maleate by bromination reaction. Bulletin of the Chemical Society of Japan (1942), 17,417-19 describes the isomeriastion of dimethyl maleate in presence of catalyst to produce dimethyl fumarate. Huaxue Shiji (1993), 15 (6), 374-376 describes the process in which ferric chloride is used as a catalyst for the esterification reaction of fumaric acid instead of sulfuric acid.
JP0322795S describes esterification of maleic acid, maleic anhydride, fumaric acid with methanol in. presence of mehane sulfonic acid.
Huagong Shikan (2005),19(4), 1.8-19 discloses process to prepare dimethyl fumarate by the reaction of fumaric acid with methanol in the presence of conc.Sulfuric acid catalyst, but silent about genotoxic impurity dimethyl sulfate.
U.S. Patent Appl. no. 2009/0112016 discloses the use of sulfonated resin catalyst in esterification reactions to reduce by-product formation.
U.S. Patent Appl. no. 2002/0002306 discloses a method of producing dimethyl fumarate containing no catalytic residue by use of a heterogeneous Group VIII catalyst which is readily separable and non-corrosive.
U.S. Patent Appl. no. 2014/200363 discloses a method of producing dimethyl fumarate containing no more than trace amounts of dimethyl sulfate.
Yunnan Daxue xuebao, Ziran Kexueban , vol 16, Issue 2, pg 139-41, Journal 1994, discloses the preparation of dimethyl fumarate from fumaric acid using methanol with different catalysts such as Sulfuric acid, Phosphoric acid, Polyphosphoric acid, Amberlite IR-120, Amberlite IRC-50, and solid acid such as Fe203 , di(p-nitrophenyl) phosphate. The article is silent about the removal of genotoxic impurity.
The present invention describes the process wherein there is no formation of genotoxic impurity and hence preparing the product which is highly pure and pharmaceutical grade product and existing as crystal form I, with particle size ranges from about 5 μm to about 300 μm.
BRIEF DESCRIPTION OF THE INVENTION
The methods provided are exemplary and are not intended to limit the scope of the claimed
embodiments.
In one embodiment, the present invention provides a method for preparing dimethyl fumarate, which
comprises: reacting fumaric acid with methanol in presence of acid catalyst such as polyphosphoric

acid, hydrochloric acid and mixture there of to obtain product mixture comprising dimethyl fumarate
containing no genotoxic impurities.
Further the invention provides method for preparing dimethyl fumarate having particle size in the
range of 5 urn to about 300 μm.
In one embodiment, the present invention provides a method for the preparation of dimethyl fumarate
of crystal form I, wherein the crystal form is characterized by peaks expressed in 29° at approximately
10.96, 22.01, 24,17 and 27.39 ± 0.2°, which comprises:
In one embodiment, the method further comprises recrystallizing the dimethyl fumarate using an
organic solvent.
In one embodiment, the organic solvent is selected from the group consisting of acetone, anisole,
benzyl alcohol, 1- butanol, 2-butanol, tert-butanol, butyl acetate, cumene, dichloromethane, diethyl
ether, 1,4- dioxane, DMF, DMSO, ethyl acetate, ethanol, ethylene glycol, ethyl formate, water,
heptane, isobutyl acetate, isopropyl ether, isopropyl acetate, isooctane, acetonitrile, MEK, methanol,
methyl acetate, methyl cyclohexane, M1BK, nitrobenzene, NMP, o-xylene, 1-octanol, isopentanol,
propyl acetate, l-propanol, isopropanol, pyridine, MTBE, tetrahydrofuran, triethylamine,
trifluorotoluene, toluene, p-xylene and mixtures thereof.
In one embodiment, the present invention provides crystal form I of dimethyl fumarate which is
prepared by a method of the present invention.
A pharmaceutical composition comprising dimethyl fumarate prepared by the method of the present
invention, having crystal form I, wherein the particle size ranges from about 5 μm to about 300 pm.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a process for the preparation of highly pure and crystalline dimethyl
fumarate by esterifying fumaric acid with methanol in presence of an acid catalyst. It has been
discovered that this process produces high purity crystalline dimethyl fumarate containing no
genotoxic impurities.
The present invention also provides a process for the preparation of highly pure and crystalline
dimethyl fumarate with a particle size from 5 μm to 300pm
The process of the present invention includes in various embodiments, reacting fumaric acid with
methanol in the presence of poly phosphoric acid.
The esterification of fumaric acid leading to dimethyl fumarate is illustrated in scheme-1.


I he reaction, which is initially heterogeneous, due to limited rumaric acid solubility in methanol, gradually becomes a homogenous reaction upon heating to the reaction temperature. An excess amount of methanol is generally used in the reaction. The volume can range from a ratio of 2.0 to 10.0 times with respect to fumaric acid. Preferably 5.0 volumes of methanol are used in the reaction. Monomethyl fumarate is formed rather quickly from the starting material, fumaric acid. The time required to reach the equilibrium level for monomethyl fumarate and the product dimethyl fumarate, depends on the amount of poly phosphoric acid (catalyst) used. The catalyst molar equivalents used in the reaction can range from a ratio of 0.5 to 3.0 times with respect to fumaric acid. Preferably 1.0 molar equivalents of catalyst are used in the reaction. Higher reaction temperatures are preferred to improve the solubility of fumaric acid in methanol and to improve the rate of reaction. The reaction conditions include reacting at a temperature from about 25°C to 70°C. Preferably reaction temperatures from 55° to 60°C are used in the reaction. The reaction can proceed for any length of time necessary to achieve conversion of fumaric acid to dimethyl fumarate. The reaction proceeds for about 1.0 to about 24.0 hours. Preferably the reaction proceeds for about 6.0 hours. The crude products are isolated by cooling the reaction mass to a temperature from about -15°C to 20°C and filtered. Preferably the reaction mass is cooled to temperature from -5°C to 0°C.
Highly pure and crystalline dimethyl fumarate can be prepared by recrystallization in a suitable solvent selected from the group consisting of acetone, anisole, benzyl alcohol, 1- butanol, 2-butanol, tert-

butanol, butyl acetate, dichloromethane, diethyl ether, DMF, DMSO, ethyl acetate, ethanol, ethylene glycol, ethyl formate, water, heptane, isobutyl acetate, isopropyl ether, isopropyl acetate, isooctane, acetonitrile, MEK, methanol, methyl acetate, methylcyclohexane, M1BK, propyl acetate, 1-propanol, 2-propanol, p-xylene or mixtures thereof at a temperature suitable for dissolution of crude dimethyl fumarate. Preferably, methanol is used as the solvent. The dissolution, which is initially heterogeneous, due to limited dimethyl fumarate solubility in methanol, gradually becomes a homogenous reaction upon heating to the reaction temperature 65°C to 70°C. An excess amount of methanol is generally used in the reaction. The volume can range from a ratio of 3.0 to 10.0 times with respect to crude dimethyl fumarate. Preferably 5.0 volumes of methanol are used for dissolution. High temperatures are preferred for dissolution of crude dimethyl fumarate in methanol. The dissolution conditions include a temperature from about 25°C to 75°C. Preferably temperatures from 65°C to 70°C are used for dissolution. The final products are isolated by cooling the solution to a temperature from about -15°C to 20°C and filtered. Preferably, the solution is cooled to temperature from -5°C to 0°C. The wet solids are dried using conventional methods known in the art. Dimethyl fumarate is dried at a temperature of about 10°C to about 50°C under vacuum. Preferably, it is dried at a temperature of about 25°C to 30°C under vacuum. Further to aid drying, the material is sifted through 20 to 60 mesh sieve. Preferably, it is sifted through 40 mesh sieve.
Dimethyl fumarate obtained are of crystal form I, the crystal form is further characterized by peaks expressed in 28° at approximately 10.96, 22.01, 24.17 and 27.39 ± 0.2°.
After completion of drying, the dimethyl fumarate is processed further to obtain the desired particle size using conventional methods known in the art. The particles are reduced in size to produce particles of a suitable size for consistent handling for drug product processing. Dimethyl fumarate is processed by jet milling to reduce to particle size from 5 μm to 300 μm.
The compound can be formulated into pharmaceutical composition that can be administered using conventional means known in the art. The amount of Dimethyl fumarate or combination thereof administered will also vary, as those recognized by those skilled in the art, dependent on route of administration, excipients usage and the possibility of co-usage with other therapeutic treatments including use of other therapeutic agents.

EXAMPLE-1
The invention is exemplified herein for the purpose of illustration only. Preparation of Dimethyl fumarate
To 3 solution of poly phosphoric acid (1.69 kg) in methanol (10.0 Its) is charged fumaric acid (2.0 kg) and heated to 55°C to 60°C and maintained for 6 hrs. The reaction mass is cooled to 0°C to -5°C, filtered and washed with chilled methanol (2.0 Its). Wet material obtained is charged alongwith methanol (10.0 Its) and is heated to 65°C to 70°C, filtered through hyflo and washed with hot methanol (2.0 Its). The clear filtrate obtained is stirred at 0°C to -5°C for 3 hrs, during which the product precipitated, filtered and washed with chilled methanol (2.0 Its). The wet cake is dried under vacuum at 25°C to 30°C to yield dimethyl fumarate (2.15 kg). Dimethyl fumarate product obtained had residual methanol well below the 1CH limit (3000 ppm). Dimethyl fumarate product obtained had particle size ranging from about 5um to about 300 urn. Dimethyl fumarate product obtained had crystal form I which showed characteristic peaks expressed in 20° at approximately 10.96, 22.01, 24.17 and 27.39 ± 0.2°.
EXAMPLE-2
To a methanolic HC1 (5.87 Its), charged fumaric acid (2.0 kg) and methanol (4.13 Its) and heated to 55°C to 60°C and maintained for 2 hrs. The reaction mass is cooled to 0°C to -5°C, filtered and washed with chilled methanol (2.0 Its). Wet material obtained is charged along with methanol (10.0 Its) and is heated to 65°C to 70°C, filtered through hyflow and washed with hot methanol (2.0 Its). The clear filtrate obtained is stirred at 0°C to -5°C for 3 hrs, during which the product precipitated, filtered and washed with chilled methanol (2.0 Its). The wet cake is dried under vacuum at 25°C to 30°C to yield dimethyl fumarate (2.15 kg). Dimethyl fumarate product obtained had residual methanol well below the fCH limit (3000 ppm). Dimethyl fumarate product obtained had particle size ranging from about 5 urn to about 300um. Dimethyl fumarate product obtained had crystal form I which showed characteristic peaks expressed in 20° at approximately 10.96, 22.01, 24.17 and 27.39 ± 0.2°.

CLAIMS:
We claim.
1. A method for the preparation of dimethyl fumarate, which comprises:
reacting fumaric acid with methanol in presence of acid catalysts such as polyphosphoric acid, hydrochloric acid or mixture thereof.
2. A method for the preparation of dimethyl fumarate with no genotoxic impurities,
which comprises:
reacting fumaric acid with methanol in presence of acid catalysts such as polyphosphoric acid,
hydrochloric acid or mixture thereof.
3. Dimethyl fumarate as prepared in claim 1 and claim 2 contains no genotoxic impurities.
4. Dimethyl fumarate as prepared in claim land claim 2 is reduced to the particle size in the range from 5 μm to 300 μm.
5. Dimethyl fumarate as prepared in claim 1 and claim 2 is of crystal form I and is characterized by peaks expressed in 20° at 10.96, 22.01, 24.17 and 27.39 ± 0.2°.
6. Dimethyl fumarate as prepared in claim 1 and claim 2 is recrystallised from the organic solvents, wherein the organic solvent is selected from the group consisting of acetone, anisole, benzyl alcohol, 1- butanol, 2-butanol, tert-butanol, butyl acetate, cumene, dichloromethane, diethyl ether, 1, DMSO, ethyl acetate, ethanol, ethylene glycol, heptane, isobutyl acetate, isopropyl ether, isopropyl acetate, isooctane, acetonitrile, MEK, methanol, methyl acetate, methylcyclohexane, MIBK, o-xylene, isopentanol, propyl acetate, 1-propanol, 2-propanol, MTBE, tetrahydrofuran, toluene, p-xylene or mixtures thereof.

7. A pharmaceutical composition comprising Dimethyl fumarate prepared by the method of claim 1 and claim 2, where in Dimethyl fumarate is crystal form I and particle size ranges from 5 μm to 300 μm.