FORM 2 THE PATENTS ACT 1970
(39 OF 1970)
COMPLETE SPECIFICATION
(SECTION 10)
IMPROVED PROCESS FOR THE PREPARATION OF
DIMETHYL FUMARATE
UNICHEM LABORATORIES LIMITED
A COMPANY REGISTERED UNDER THE INDIAN COMPANY
ACT, 1956, HAVING ITS REGISTERED OFFICE LOCATED AT
UNICHEM BHAVAN, PRABHAT ESTATE, OFF.S.V.ROAD,
JOGESWARI(W) MUMBAI-400102, MAHARASHTRA, INDIA
The following specification particularly describes the invention and the manner in which it is to be performed

IMPROVED PROCESS FOR THE PREPARATION OF DIMETHYL
FUMARATE
TECHNICAL FIELD
The present invention relates to an improved process to prepare Dimethyl fumarate of Formula I.
BACKGROUND OF THE INVENTION
Dimethyl fumarate or BG-12 , is an oral Nrf2 pathway activator used for the treatment of relapsing forms of multiple sclerosis and is chemically described as dimethyl (E) butenedioate of Formulae-I.
Dimethyl fumarate was first approved by US FDA on 27 of March 2013, under the brand name Tecfidera, developed and marketed by Biogen Idee Inc.
Dimethyl fumarate is an achiral trans-butane diester and has limited aqueous solubility (3-4 mg/ml) but possesses higher solubility in methanol (30 mg/ml).
There are several synthetic processes available in the literature for the synthesis of Dimethyl Fumarate.

US patent application 2009/0112016 disclosed a process for the esterification of Fumaric acid (Formula-II) using sulfonated resin catalysts to reduce byproduct formation. The inventor disclosed that the catalyst is useful for any catalyzed esterification process that suffers from side reaction. Sulfonated resin is an expensive catalyst. Disclosure in the application is silent about the process and the yield of ester.
US patent application 2002/0002306 disclosed a process for the preparation of Dimethyl fumarate of (Formula-I) by isomerization of a dimethyl maleate by using heterogeneous group VIII catalyst which is readily separable and non-corrosive. Heterogeneous catalyst used in this invention are RuC12 (PPh3)3, RhCl (CO) (PPh3)2, or RuClH (CO) (PPh3)3. These catalysts used are very expensive. The reaction takes place at very high temperature of about 140°C.
US patent application 2014/0200363 disclosed a process for the preparation of
Dimethyl Fumarate fro m Fumaric acid using sulphuric acid and methanol under
refluxing condition. The yield of the Dimethyl fumarate produced in this process is
73%. Dimethyl sulphate is formed during the process and is very difficult to remove
from the final drug substance. To obtain the dimethyl fumarate according to this
invention fumaric acid was charged in a jacketed reactor equipped with stirrer and
reflux condenser, followed by methanol .The slurry was stirred under ambient
temperature and sulfuric acid was added. The reaction mixture was then heated to
65°C and held at that temperature for approximately 3 hours. The reaction solution

was then cooled to <20°C in 3-8 hours during which the product precipitated. The
main drawback of this invention is production of dimethyl sulphate impurity which is
toxic. Presence of toxic impurity mandates more purification reactions and impacts
efficiency.

US patent application 2009/0155866 disclosed a esterification method of fumaric
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acid by the treatment of fumaric acid with an alcohol in the presence of a mineral acid

such as sulfuric acid or dry hydrogen chloride. While the choice of alcohol will be determined by the type of ester or di ester desired however no example is given. Use of dry HC1 is normally discouraged as it is corrosive and damages reactors and metal parts in the vicinity. Difficulties are also known in purging HC1 gas or dry HC1 into methanol. The process may also result into formation of undesirable impurity. It is silent on the yields obtained
The abstract of "Chemical evolution of citric acid cycle: Sunlight and Ultraviolet photolysis of cycle intermediates" by Waddl et al, "Origin of life and evolution of biosphere, Vol 19, Issue 6, Page 603-7 Journal 1989" mentions about conversion of Carboxylic acid residue to methyl esters (2% HC1 in Methanol, 2 hrs and reflux). However when the article was accessed, it is silent about conversion of fumaric acid into its methyl ester. It describes the process of conversions of acids into other acids by photolysis. The article does not provide any hint, direction or motivation or description to use aquous HC1 to esterify fumaric acid or teach any process to do so. Prior art teaches purification of dimethyl fumarate by methanol washings. The yields reported after methanol washes are low.
The processes taught by prior art have several drawbacks namely use of expensive reagents, difficulty in handling reagents, giving lower yields, longer duration of corrosive reactions, production of toxic impurities and less user friendly. There is a urgent and pressing need for simple, energy economical, cheaper, easily scalable and plant friendly process for the preparation of Dimethyl Fumarate (Formula-I), particularly an improved process that will consistently produce ICH quality of Dimethyl Fumarate with higher yield which is free of dimethyl sulphate impurity.
In the present esterification reaction, water is one of the products along with the ester. Hence formation and or use of water in the reaction will propagate backward reaction. Use of water will retard the forward reaction i.e. it will retard formation of ester.

Presence of water hence will result into lower yields and or slow conversion. Person skilled in the art would understand this and would never opt for using aqueous HC1.
OBJECT OF THE INVENTION
The object of the present invention is to provide an improved process for the synthesis of ICH quality Dimethyl Fumarate (Formula-1) with better overall yield and which is free of dimethyl sulphate impurity.
Another object of the present invention is to provide process which increases the throughput in industrial scale of Dimethyl Fumarate, by improving carbon efficiency and reducing the volume of solvent involved in the process.
Yet another object of the present invention is to provide the process for the synthesis of Dimethyl Fumarate (Formula-I), with minimum impurity formation.
SUMMARY OF THE INVENTION
The present invention relates to an improved process for the preparation of Dimethyl Fumarate of Formula (I)
comprising reaction between Fumaric acid and aqueous hydrochloric acid in methanol at suitable temperature followed by purification of obtained product.
The present invention relates to an improved process for the preparation of Dimethyl Fumarate of Formula (I)

comprising,
a) Contacting Fumaric acid and methanol, optionally under stirring, to prepare the solution,
b) Contacting aqueous Hydrochloric acid with the solution obtained in step a) to obtain reaction mass,
c) Maintaining the temperature of the reaction mass obtained in step b) in the range of 20-60°C for 30 minutes to 24 hours, with optional stirring,
d) Lowering the temperature of the reaction mass obtained in step c) to about -10°C to 20°C while optionally stirring to obtain the compound of the Formula-
e) Separating the compound of Formula-I obtained in Step d),
f) Optionally washing the compound of the Formula-I obtained in step e) with suitable solvent to obtain washed compound of Formula-I,
g) Optionally drying the washed compound of Formula-I obtained in step f).
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides an improved and efficient, process to produce ICH quality Dimethyl Fumarate of Formula-I comprising a reaction between Fumaric acid and aqueous hydrochloric acid in methanol as indicated in Scheme-1.

(Formula-II) (Formula-Ill) (Formula-I)
Scheme-1
The present invention relates to an improved process for the preparation of Dimethyl Fumarate of formula (I). The process comprising,
a) Contacting Fumaric acid and methanol, optionally under stirring, to prepare the solution,
b) Contacting aqueous Hydrochloric acid with the solution obtained in step a) to obtain reaction mass,
c) Maintaining the temperature of the reaction mass obtained in step b) in the range of 20-60°C for 30 minutes to 24 hours, with optional stirring,
d) Lowering the temperature of the reaction mass obtained in step c) to about -10°C to 20°C while optionally stirring to obtain the compound of the Formula-
e) Separating the compound of Formula-I obtained in Step d),
f) Optionally washing the compound of the Formula-I obtained in step e) with suitable solvent to obtain washed compound of Formula-I,
g) Optionally drying the washed compound of Formula-I obtained in step f).
Novelty of the reaction resides in using aqueous Hydrochloric acid. Inventive step of the invention also resides in use of aqueous Hydrochloric acid. As mentioned in the foregone text, water is one of the products of the esterification reaction. Therefore by use of water in the reaction will discourage.forward reaction which will result into lower yield or will retard forward reaction. Albeit the laws of chemical reaction support this view, surprisingly it was found that use of aqueous Hydrochloric acid provides good esterification, good yield and quick conversion.
Aqueous hydrochloric acid used in the present invention is obtained from commercial source and used in amount sufficient to catalyze the reaction. Aqueous hydrochloric

acid having normality 11.3 N gives satisfactory results. The fumaric acid and aqueous hydrochloric are added in a ratio of fumaric acid: aqueous hydrochloric acid in a range from 1:0.54 to 1:0.81. Preferred molar ratio according to present.invention is 1:0.67.
Suitable temperature according to present invention refers to the temperature at which the esterification reaction takes place. The reaction conditions include reacting fumaric acid and aqueous hydrochloric acid in methanol at a temperature range from about 20-3 0°C, preferably at a temperature range of 30-40°C, more preferably at a temperature range of 40-50°C, most preferable temperature range being 50-60°C. Surprisingly it was noticed that at higher temperature range i.e. about 50°C to about 60°C, reaction rate is appreciably fast.
The duration of reaction may vary from 30 minutes to 24 hours depending upon the temperature. Formation of dimethyl ester takes place in short period, as short as about 30 minutes. Formation and completion of reaction and the yield of the product depends on the temperature attained and duration for which it is maintained. As mentioned here before, in the temperature range of about 50°C to about 60°C, reaction rate is appreciably fast. Reaction takes place even at lower temperatures, as low as from about 20°C to about 30°C. If the reaction is carried out for inadequate time, the product may contain the impurity of Monomethyl fumarate. Reaction can be monitored adequately by TLC. Embodiment mentioned hereafter shows one of the best modes of performing the invention. Maintaining suitable temperature and maintaining it for suitable time is critical for good yields of good quality,.
Duration of reaction according to present invention may vary from a time period of 30 minutes to 6 hours or for the time period of 6 hours to 12 hours or for the time period of 12 hours to 18 hours or for the time period of 18 hours to 24 hours, more

preferably from 6 to 12 hours. As illustrated in a preferred embodiment duration of 6 to 10 hours provides good results.
On lowering of temperature, dimethyl fumarate precipitates out from the reaction mass. Temperature may be lowered to about -10 to about 20°C. Preferred tempreture to precipitate out dimethyl fumarate according to present invention is 0-10°C. Although lowering temperature below 0 C or above 10 C can provide the product, these temperatures exhibit some temperature specific phenomenon which may impact on yield or cost of the product.
Separation of the product obtained after the completion of esteriflcation reaction can be done by any process known in prior art such as filtration.
After the completion of esteriflcation process, obtained product is purified and crystallized by using suitable solvent selected from water, alcoholic solvent, ester solvents, ether solvents, hydrocarbon solvent, amine solvent, ketone solvent, halogenated solvents or a mixture thereof. Alcoholic solvents according to the present invention may include but not limited to methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, isopentanol, or benzylalcohol. Ester solvents according to present invention may include but not limited to methyl acetate, ethyl formate, ethyl acetate, isopropyl acetate, isobutyl acetate or propyl acetate. Ketone solvents according to present invention may include but not limited to acetone, methyl ethyl ketone or methyl isobutyl ketone. Ether solvents according to present invention may include but not limited to diethyl ether, isopropyl ether , t-butyl methyl ether ,anisole or 1,4-dioxane. Hydrocarbon solvents according to present invention may include but not limited to cumene, heptane, toluene, p-xylene, methyl cyclohexane, or isooctane. Halogenated solvents according to present invention may include but not limited to dichloromethane, Carbon tetrachloride. Preferable solvents according to present invention are halogenated solvents and more preferably dichloromethane.

Washing of the final product according to present invention involves washing of organic layer of dimethyl fumarate obtained in purification process, by Sodium bicarbonate solution and water. Depending upon the extent of purity required, the washings can be repeated. The invention is capable of producing ICH quality of material when adequate washings are given. Preferred embodiment, teaches the method and the process to produce ICH quality of Dimethyl Fumarate.
Minimum impurity refers to quantitative criteria for impurities as described by ICH guidelines.
Solvent used in the reaction can be recycled. Esterification reactions as described by present invention results into more than 90% yield which is well above the yield described in prior art process. The product obtained is free of dimethyl sulphate impurity.
In the similar manner dialkyl esters of fumaric acid can be prepared using different straight or branched chain alcohols having C1 to C5 carbon atoms.
Improved and efficient reaction or process is to be inferred as reaction or process resulting in high yield with ICH quality material. It also means a process where the product requires lesser number of purification processes or runs.
EXAMPLE-1:
Preparation of Dimethyl fumarate from Fumaric acid using aqueous
hydrochloric acid:
Charged (25g) Fumaric acid and methanol (150 ml) under stirring. Charged aqueous HC1 (15 ml, 35%). Stirred the reaction mass for next 6-10 hrs at 50°C to 55°C. Reaction was monitored on TLC. Reaction mass was chilled to 0-5°C and stittered for

30 min at 0-5°C. Filtered and washed the compound of Formula-I with chilled methanol. Dried the material in air oven at 40-50°C. Dry Weight of solid 28 g (Yield 90%).
Purification of Dimethyl fumarate:
Charged (25g) dimethyl fumarate (Formula-I) and dichloromethane (175 ml) under stirring. Wash the MDC layer with 25 ml 5% Sodium bicarbonate solution and 25 ml of water. Filtered the MDC layer and distilled out under vacuum. Charged methanol (100 ml), chilled to 5-10°C, centrifuged and washed the compound of Formula-I with chilled methanol (25ml). Dried the material in air oven at 40-50°C. Dry Weight of solid 21 g (Yield 84%).
Example-2:
Preparation of Dimethyl fumarate from Fumaric acid using aqueous
hydrochloric acid:
Charged (50g) Fumaric acid and methanol (200 ml) under stirring. Charged aqueous HC1 (25 ml, 35%). Stirred the reaction mass for next 6-10 hrs at 50°C to 55°C. Reaction was monitored on TLC. Reaction mass was chilled to 5°C -10°C and stirred for 30 min. Filtered and washed the compound of Formula-I with chilled methanol. Dried the material in air oven at 40-50°C. Dry Weight of solid 59.1 g (Yield 95.32%).
Purification of Dimethyl fumarate:
Charged (59g) dimethyl fumarate (Formula-I) and dichloromethane (470 ml) under
stirring. Wash with 50ml 5% Sodium bicarbonate solution and then with 50 ml
Water. Distilled out the dichloromethane atmospherically and charge 200 ml of
Methanol chilled to 5°C-10°C and stirred for 30 min. Filtered and washed with chilled
methanol. Dried the product in air oven at 40-50°C.
Dry Weight of solid 52.3 g (Yield 88.49%).

We Claim:
1. An improved process for the preparation of Dimethyl Fumarate of Formula (I) comprises, Reacting
a) Fumaric acid (Formula-II) and
b) Methanol
c) In presence of aqueous hydrochloric acid at suitable temperature.

2. The process as claimed in claim 1, wherein the reaction is carried out at a temperature range of 20-60°C.
3. The process as claimed in claim 2, where in the reaction is carried out at a temperature range of 20-30°C, preferably at a temperature range of 30-40°C, more preferably at a temperature range of 40-50°C, most preferable temperature range being 50-60°C.
4. The process as claimed in claim 3, wherein the reaction is carried out at a temperature range of 50-60°C.
5. The process as claimed in claim 1, wherein the reaction is carried out for a time period of 30 minutes to 24 hours.

6. The process as claimed in claim 5, wherein the reaction is carried out for a time period of 30 minutes to 6 hours or for the time period of 6 hours to 12 hours or for the time period of 12 hours to 18 hours or for the time period of 18 hours to 24 hours, more preferably from 6 to 12 hours.
7. An improved process to prepare Dimethyl Fumarate of Formula (I) comprising,

a) Contacting Fumaric acid and methanol, optionally under stirring, to prepare the solution,
b) Contacting aqueous Hydrochloric acid with the solution obtained in step a) to obtain reaction mass,
c) Maintaining the temperature of the reaction mass obtained in step b) in the range of 20-60°C for 30 minutes to 24 hours, with optional stirring,
d) Lowering the temperature of the reaction mass obtained in step c) to about -10°C to 20°C while optionally stirring to obtain the compound of the Formula-I.
e) Separating the compound of Formula-I obtained in Step d),
f) Optionally washing the compound of the Formula-I obtained in step e) with suitable solvent to obtain washed compound of Formula-I,
g) Optionally drying the washed compound of Formula-I obtained in step f).

8. The process as claimed in claim 7, wherein the reaction is carried out at a tempreture range of 20 to 30°C or 30 to 40°C or 40 to 50°C or 50 to 60°C, more preferably at 50 to 60°C.
9. The process as claimed in claim 7, wherein the reaction is carried out for a time period of 30 minutes to 6 hours or for the time period of 6 hours to 12 hours or for the time period of 12 hours to 18 hours or for the time period of 18 hours to 24 hours, more preferably from 6 to 12 hours.