WO2017013672A1 - Process for the preparation of pharmaceutical grade dimethyl fumarate - Google Patents

Process for the preparation of pharmaceutical grade dimethyl fumarate Download PDF

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Publication number
WO2017013672A1
WO2017013672A1 PCT/IN2015/050122 IN2015050122W WO2017013672A1 WO 2017013672 A1 WO2017013672 A1 WO 2017013672A1 IN 2015050122 W IN2015050122 W IN 2015050122W WO 2017013672 A1 WO2017013672 A1 WO 2017013672A1
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Prior art keywords
dimethyl fumarate
formula
aqueous
preparation
methanol
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PCT/IN2015/050122
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French (fr)
Inventor
Naga Vasantha Srinivasu VUPPALAPATI
Srinivasa Krishna Murthy Konduri
Prabhakar VANGA
Pulla Reddy Muddasani
Bhujanga Rao Adibhatla Kali Satya
Venkaiah Chowdary Nannapaneni
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Natco Pharma Ltd
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Publication of WO2017013672A1 publication Critical patent/WO2017013672A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/08—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with the hydroxy or O-metal group of organic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/48—Separation; Purification; Stabilisation; Use of additives
    • C07C67/52—Separation; Purification; Stabilisation; Use of additives by change in the physical state, e.g. crystallisation

Definitions

  • the present invention relates to an improved process for the preparation of pharmaceutical grade dimethyl fumarate (DMF) of formula (1).
  • DMF dimethyl fumarate
  • the chemical name of dimethyl fumarate is dimethyl (E)-butenedioate.
  • Dimethyl fumarate is a white crystalline solid.
  • FAE fumaric acid esters
  • Dimethyl fumarate is the methyl ester of fumaric acid.
  • Dimethyl fumarate is chemically known as dimethyl (E) butenedioate and structurally represented as below.
  • Dimethyl fumarate is marketed under the brand name of TECFIDERA ® It is indicated for the treatment of patients with relapsing forms of multiple sclerosis.
  • dimethyl fumarate is prepared by esterifying fumaric acid with methanol in the presence of sulfuric acid as catalyst.
  • dimethyl fumarate is prepared from fumaric acid, methanol in the presence of C2-C 4 -alkanoyl halide as catalyst.
  • the main aspect of the present invention is to provide an improved process for the preparation of dimethyl fumarate of formula (1), which comprises simple, safe, economical, and commercially viable process which surpasses the above mentioned disadvantages.
  • Another aspect of the present invention is to provide an improved process for the preparation of dimethyl fumarate of formula (1), by using readily and cheaply available raw materials in the process.
  • Still another aspect of the present invention is to provide an improved process for the preparation of dimethyl fumarate of formula (1), by avoiding multiple purifications and adopting commercially feasible single purification method in the process.
  • another aspect of the present invention is to provide a process for the preparation of dimethyl fumarate by reacting fumaric acid with methanol in the presence of aqueous hydrochloric acid or methanolic HC1.
  • yet another aspect of the present invention is to provide an improved process for the preparation of dimethyl fumarate of formula (1), which produces pharmaceutically acceptable grade dimethyl fumarate of formula (1) having more than 99.9% HPLC purity.
  • Still another aspect of the present invention is to provide an improved process for the preparation of dimethyl fumarate of formula (1), which produces dimethyl fumarate of formula (1) free from genotoxic impurities.
  • fumaric acid of formula (3) (prepared from maleic anhydride using literature process, CS243823), is reacted with methanol in the presence of catalysts like aqueous hydrochloric acid or anhydrous methanolic HC1 preferably aqueous hydrochloric acid at temperatures ranging from 20-75° C and preferably at 60-70° C for 4-5 hours. Later the reaction mixture is cooled to 0-20° C preferably to 0-5° C and filtered. Thereafter, the wet product is suspended in water and the pH of the product mixture is adjusted to neutral pH using aq.
  • catalysts like aqueous hydrochloric acid or anhydrous methanolic HC1 preferably aqueous hydrochloric acid at temperatures ranging from 20-75° C and preferably at 60-70° C for 4-5 hours.
  • the reaction mixture is cooled to 0-20° C preferably to 0-5° C and filtered. Thereafter, the wet product is suspended in water and the pH of the product mixture is adjusted
  • aqueous sodium bicarbonate selected from aqueous sodium bicarbonate, aqueous sodium carbonate, aqueous potassium bicarbonate or aqueous potassium carbonate preferably aqueous sodium bicarbonate and filtered at 20-35° C preferably at 25-30° C to get dimethyl fumarate having > 99.8% HPLC purity.
  • the product is crystallized from 5-70% aqueous methanol preferably 50% aqueous methanol to get pharmaceutical grade dimethyl fumarate of formula (1) having HPLC purity of dimethyl fumarate obtained by present process is >99.95% having monomethyl fumarate impurity at 0.01-0.02% level and genotoxic impurity, maleic anhydride, at less than 0.9 ppm level (Limit of maleic anhydride as per ICH guidelines is NMT 3.125 ppm). Particle size distribution of dimethyl fumarate obtained by present process is as given below, d 90 is 350-500 micron, d50 is 200-250 micron and d 10 is 80-120 microns.
  • the present invention provides an improved process for the preparation of dimethyl fumarate of formula (1),
  • the acid catalyst employed in step (ii) is selected from aqueous hydrochloric acid or methanolic HC1, preferably, aqueous hydrochloric acid.
  • the reaction temperature employed for the conversion of fumaric acid of formula (3) to dimethyl fumarate of formula (1) is 20-75° C, preferably, 60-70°C.
  • the temperature at which crude dimethyl fumarate of formula (1) isolated in step (ii) is between 0-20° C, preferably, 0-5° C.
  • the pH at which dimethyl fumarate isolated in step (ii) is between 6.5-8.0, preferably, 7.0-7.5.
  • the base employed for pH adjustment in step (ii) is selected from aqueous sodium bicarbonate, aqueous sodium carbonate, aqueous potassium bicarbonate or aqueous potassium carbonate, preferably, aqueous sodium bicarbonate.
  • the temperature at which technical grade dimethyl fumarate of formula (1) isolated in step (ii) is between 20-35° C, preferably, 25-30° C.
  • HPLC purity of the isolated product of formula (1) is >99.8%.
  • the solvent employed to dissolve technical grade dimethyl fumarate of formula (1) in step (iii) is selected from 5-70% aqueous methanol, preferably, about 50% aqueous methanol. Yield of dimethyl fumarate is > 82% and HPLC purity is above 99.95% having monomethyl fumarate impurity at 0.01-0.02% level, genotoxic impurity, maleic anhydride, at 0.9 ppm level, particle size distribution of dimethyl fumarate obtained by present process is d90 is 350-500 micron, d50 is 200-250 micron and d 10 is 80-120 microns.
  • Example- 1 Preparation of fumaric acid of formula (3) from maleic anhydride of formula (2):
  • Example-2 Preparation of dimethyl fumarate of formula (1) from fumaric acid of formula (3):
  • Example-3 Preparation of dimethyl fumarate of formula (1) from fumaric acid of formula (3):
  • Example-4 Purification of technical grade dimethyl fumarate of formula (1)

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The present invention relates to a process for the preparation of dimethyl fumarate of formula (1) from fumaric acid of formula (3). The present process is simple, cost effective and feasible in large scale production. Dimethyl fumarate obtained by the present process is free of geno toxic impurities.

Description

PROCESS FOR THE PREPARATION OF PHARMACEUTICAL GRADE
DIMETHYL FUMARATE
FIELD OF THE INVENTION:
The present invention relates to an improved process for the preparation of pharmaceutical grade dimethyl fumarate (DMF) of formula (1). The chemical name of dimethyl fumarate is dimethyl (E)-butenedioate. Dimethyl fumarate is a white crystalline solid.
Figure imgf000002_0001
(1)
BACKGROUND OF THE INVENTION:
The medical use of fumaric acid esters (FAE) was first described in 1959 by the German chemist W. Schweckendiek who reported on successful internal and external treatment of his own psoriasis. Today, FAE are the most frequently prescribed medication for systemic treatment of psoriasis in Germany. FAE were also found to be effective in other conditions, including necrobiosis lipoidica, granuloma annulare, sarcoidosis, alopecia areata, cheilitis granulomatosa, recurrent oral aphthae, pityriasis rubra pilaris, annular elastolytic giant-cell granuloma or non-infectious chronic uveitis.
Dimethyl fumarate is the methyl ester of fumaric acid. Dimethyl fumarate is chemically known as dimethyl (E) butenedioate and structurally represented as below.
Figure imgf000002_0002
Dimethyl fumarate
Dimethyl fumarate is marketed under the brand name of TECFIDERA® It is indicated for the treatment of patients with relapsing forms of multiple sclerosis.
Conversion of dialkyl maleate to dialkyl fumarate by heating around 100° C in presence of catalysts like phosphorus oxychloride, thionyl chloride or phosphorus trichloride is disclosed in US2764609 patent. In another patent application US 20020002306, process for the preparation of dimethyl fumarate using heterogeneous group VIII catalyst is disclosed.
In another patent application WO201270923, dimethyl fumarate is prepared by esterifying fumaric acid with methanol in the presence of sulfuric acid as catalyst.
In another patent application WO2014203231, dimethyl fumarate is prepared from fumaric acid, methanol in the presence of C2-C4-alkanoyl halide as catalyst.
However, in spite of having the choice of variety of methods for preparation of dimethyl fumarate of formula (1), there is still a need to develop commercially viable process for large scale operations since, in general, the processes reported for preparation of dimethyl fumarate of formula (1) have the following disadvantages:
1. The processes cited above, require toxic reagents like thionyl chloride, phosphorous oxychloride, etc.
2. Removal of genotoxic impurities like dimethyl sulphate to the acceptable level from the drug substance requires several crystallizations.
SUMMARY OF THE INVENTION:
Keeping in view of the drawbacks associated with the processes disclosed in the literature for the preparation of dimethyl fumarate of formula (1) we aimed at developing a simple and economically viable process for commercial production of dimethyl fumarate of formula (1).
Accordingly, the main aspect of the present invention is to provide an improved process for the preparation of dimethyl fumarate of formula (1), which comprises simple, safe, economical, and commercially viable process which surpasses the above mentioned disadvantages.
Accordingly, another aspect of the present invention is to provide an improved process for the preparation of dimethyl fumarate of formula (1), by using readily and cheaply available raw materials in the process.
Accordingly, still another aspect of the present invention is to provide an improved process for the preparation of dimethyl fumarate of formula (1), by avoiding multiple purifications and adopting commercially feasible single purification method in the process.
Accordingly, another aspect of the present invention is to provide a process for the preparation of dimethyl fumarate by reacting fumaric acid with methanol in the presence of aqueous hydrochloric acid or methanolic HC1.
Accordingly, yet another aspect of the present invention is to provide an improved process for the preparation of dimethyl fumarate of formula (1), which produces pharmaceutically acceptable grade dimethyl fumarate of formula (1) having more than 99.9% HPLC purity.
Accordingly, still another aspect of the present invention is to provide an improved process for the preparation of dimethyl fumarate of formula (1), which produces dimethyl fumarate of formula (1) free from genotoxic impurities.
The resent invention is shown in scheme- 1.
Figure imgf000004_0001
Scheme- 1
DETAILED DESCRIPTION OF THE INVENTION:
Accordingly, in the present invention, fumaric acid of formula (3) (prepared from maleic anhydride using literature process, CS243823), is reacted with methanol in the presence of catalysts like aqueous hydrochloric acid or anhydrous methanolic HC1 preferably aqueous hydrochloric acid at temperatures ranging from 20-75° C and preferably at 60-70° C for 4-5 hours. Later the reaction mixture is cooled to 0-20° C preferably to 0-5° C and filtered. Thereafter, the wet product is suspended in water and the pH of the product mixture is adjusted to neutral pH using aq. base selected from aqueous sodium bicarbonate, aqueous sodium carbonate, aqueous potassium bicarbonate or aqueous potassium carbonate preferably aqueous sodium bicarbonate and filtered at 20-35° C preferably at 25-30° C to get dimethyl fumarate having > 99.8% HPLC purity. The product is crystallized from 5-70% aqueous methanol preferably 50% aqueous methanol to get pharmaceutical grade dimethyl fumarate of formula (1) having HPLC purity of dimethyl fumarate obtained by present process is >99.95% having monomethyl fumarate impurity at 0.01-0.02% level and genotoxic impurity, maleic anhydride, at less than 0.9 ppm level (Limit of maleic anhydride as per ICH guidelines is NMT 3.125 ppm). Particle size distribution of dimethyl fumarate obtained by present process is as given below, d 90 is 350-500 micron, d50 is 200-250 micron and d 10 is 80-120 microns.
Accordingly, the present invention provides an improved process for the preparation of dimethyl fumarate of formula (1),
Figure imgf000005_0001
(1)
which comprises :- i) reaction of maleic anhydride of formula (2)
Figure imgf000005_0002
(2)
with water in the presence of thiourea to get fumaric acid of formula (3),
o
Figure imgf000005_0003
(3)
ii) esterification of compound of formula (3) with methanol in the presence of an acid catalyst to get technical grade of dimethyl fumarate of formula (1),
o
Figure imgf000005_0004
(1)
iii) recrystallization of technical grade dimethyl fumarate of formula (1) from aqueous methanol to et pharmaceutical grade compound of formula (1).
Figure imgf000005_0005
(1)
In a preferred embodiment of the present invention:-
The acid catalyst employed in step (ii) is selected from aqueous hydrochloric acid or methanolic HC1, preferably, aqueous hydrochloric acid. In step (ii) the reaction temperature employed for the conversion of fumaric acid of formula (3) to dimethyl fumarate of formula (1) is 20-75° C, preferably, 60-70°C.
The temperature at which crude dimethyl fumarate of formula (1) isolated in step (ii) is between 0-20° C, preferably, 0-5° C.
The pH at which dimethyl fumarate isolated in step (ii) is between 6.5-8.0, preferably, 7.0-7.5. The base employed for pH adjustment in step (ii) is selected from aqueous sodium bicarbonate, aqueous sodium carbonate, aqueous potassium bicarbonate or aqueous potassium carbonate, preferably, aqueous sodium bicarbonate.
The temperature at which technical grade dimethyl fumarate of formula (1) isolated in step (ii) is between 20-35° C, preferably, 25-30° C. HPLC purity of the isolated product of formula (1) is >99.8%.
The solvent employed to dissolve technical grade dimethyl fumarate of formula (1) in step (iii) is selected from 5-70% aqueous methanol, preferably, about 50% aqueous methanol. Yield of dimethyl fumarate is > 82% and HPLC purity is above 99.95% having monomethyl fumarate impurity at 0.01-0.02% level, genotoxic impurity, maleic anhydride, at 0.9 ppm level, particle size distribution of dimethyl fumarate obtained by present process is d90 is 350-500 micron, d50 is 200-250 micron and d 10 is 80-120 microns.
Advantages of the present process:
• Present process avoids anhydrous reaction conditions.
• Dimethyl fumarate produced is free from genotoxic impurities.
• Present process is feasible on large scale production.
• Present process is cost effective.
• No metal catalysts required in the present process
• Easy to scale-up the process on commercial scale
• Raw materials used in the process are commercially available
Brief Description of drawings:
• Figs-1: XRD pattern of dimethyl fumarate prepared as per present invention.
• Figs-2: DSC of dimethyl fumarate prepared as per present invention.
The following examples are provided for illustration purpose only and are not intended to limit the scope of invention. Example- 1: Preparation of fumaric acid of formula (3) from maleic anhydride of formula (2):
Into a 3L, 4-necked RB flask, 1.25 L of water and 250 g of maleic anhydride were charged at 25-35 0 C and stirred the reaction mixture at 25-30° C for complete dissolution. After dissolution, 7.5g of thiourea was charged and maintained the reaction mixture at 25-30°C for 8-9h under stirring. After completion of reaction, resulting product was filtered and washed with 750 ml water, suck dried for 30 min, and dried at 50-55°C to get 247.5 g (83.6%) of fumaric acid of formula (3) as white crystalline powder.
HPLC purity: >99.0%
Example-2: Preparation of dimethyl fumarate of formula (1) from fumaric acid of formula (3):
Into a 2L, 4-necked RB flask, 200 g of fumaric acid was reacted with methanol (800 ml) in the presence of concentrated hydrochloric acid (40 ml) at reflux temperature for about 5 hours. After completion of reaction, reaction mixture cooled to 0-5° C and filtered. Later, the wet cake was suspended in 800 ml of water and adjusted the pH to 7.0-7.5. The resulting product was filtered and dried at 25-30° C to get 210.5g (84.8%) technical grade white crystalline dimethyl fumarate. HPLC purity: >99.8%
Example-3: Preparation of dimethyl fumarate of formula (1) from fumaric acid of formula (3):
Into a 500 mL, 4-necked RB flask, 25 g of fumaric acid and methanolic HC1 (192 ml) were charged and reacted at reflux temperature for about 12-14 hours. After completion of reaction, cooled the reaction mixture to 0-5° C and filtered. Later, the wet cake was suspended in 800 ml of water and adjusted the pH to 7.0-7.5. The resulting product was filtered and dried at 25- 30° C to get 24.0 g (77.0%) of technical grade white crystalline dimethyl fumarate.
HPLC purity: >99.8%
Example-4: Purification of technical grade dimethyl fumarate of formula (1)
Into a 5L, 4-necked RB flask equipped with reflux condenser, thermometer socket, 1.40 L of methanol, 1.40 L of water and 175.0 g of technical grade dimethyl fumarate were charged. The reaction mixture was heated to reflux temperature to dissolve completely. After complete dissolution, filtered and the solution cooled the filtrate to 0-5° C. The product was filtered and dried at 25-30° C under vacuum to get 134.6 g (87.8%) of pharmaceutical grade dimethyl fumarate. HPLC purity: >99.95%

Claims

We Claim :-
1. An improved process for the preparation of dimethyl fumarate comprising the steps of:
i) esterification of fumaric acid of formula (3) with methanol in the presence of an acid catalyst to get technical grade dimethyl fumarate of formula (1),
o o
Figure imgf000009_0001
(1)
(3)
ii) recrystallization of dimethyl fumarate of formula (1) from aqueous methanol to get ure compound of formula (1).
Figure imgf000009_0002
(1)
2. An improved process for the preparation of dimethyl fumarate of formula (1) as claimed in claim 1, wherein in step (i)
(a) The acid catalyst employed for the esterification of fumaric acid of formula (3) with methanol is selected from aqueous hydrochloric acid or methanolic HC1, preferably aqueous hydrochloric acid.
(b) The reaction temperature employed for the conversion of fumaric acid of formula (3) to dimethyl fumarate of formula (1) is 20-75° C, preferably 60-70°C.
(c) The temperature at which crude dimethyl fumarate of formula (1) isolated is between 0-20° C, preferably 0-5° C.
(d) The pH at which dimethyl fumarate isolated is between 6.5-8.0, preferably 7.0-7.5.
(e) The base employed for pH adjustment is selected from aqueous sodium bicarbonate, aqueous sodium carbonate, aqueous potassium bicarbonate or aqueous potassium carbonate, preferably aqueous sodium bicarbonate.
(f) The temperature at which technical grade dimethyl fumarate of formula (1) isolated is between 20-35° C, preferably 25-30° C.
3. An improved proces s for the preparation of dimethyl fumarate of formula ( 1 ) as claimed in claims 1 & 2, wherein in step (ii)
a) The solvent employed to dissolve technical grade dimethyl fumarate of formula (1) is selected from 5-70% aqueous methanol preferably, 50% aqueous methanol. b) Dimethyl fumarate prepared according to present process is having a peak in DSC at 105-108°C.
4. Dimethyl fumarate, which is free of genotoxic impurity maleic anhydride.
PCT/IN2015/050122 2015-07-23 2015-09-25 Process for the preparation of pharmaceutical grade dimethyl fumarate WO2017013672A1 (en)

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IN3795/CHE/2015 2015-07-23

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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2764609A (en) 1953-07-24 1956-09-25 Monsanto Chemicals Isomerization of dialkyl maleates to dialkyl fumarates
CN1103398A (en) * 1993-11-30 1995-06-07 张治明 Process for producing dimethyl fumarate with cis-butanedioic anhydride
US20020002306A1 (en) 2000-02-15 2002-01-03 Yasushi Kadowaki Method for producing fumaric acid esters
WO2012070923A1 (en) 2010-11-26 2012-05-31 Mimos Berhad A method and a system to ensure a secured online transaction for a debit card
WO2012170923A1 (en) * 2011-06-08 2012-12-13 Biogen Idec Ma Inc. Process for preparing high purity and crystalline dimethyl fumarate
WO2014203231A2 (en) 2014-01-24 2014-12-24 Shilpa Medicare Limited Process for preparation of dimethyl-(e)-butenedioate
WO2016001093A1 (en) * 2014-07-03 2016-01-07 Synthon B.V. Process for making microcrystalline dimethyl fumarate

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2764609A (en) 1953-07-24 1956-09-25 Monsanto Chemicals Isomerization of dialkyl maleates to dialkyl fumarates
CN1103398A (en) * 1993-11-30 1995-06-07 张治明 Process for producing dimethyl fumarate with cis-butanedioic anhydride
US20020002306A1 (en) 2000-02-15 2002-01-03 Yasushi Kadowaki Method for producing fumaric acid esters
WO2012070923A1 (en) 2010-11-26 2012-05-31 Mimos Berhad A method and a system to ensure a secured online transaction for a debit card
WO2012170923A1 (en) * 2011-06-08 2012-12-13 Biogen Idec Ma Inc. Process for preparing high purity and crystalline dimethyl fumarate
WO2014203231A2 (en) 2014-01-24 2014-12-24 Shilpa Medicare Limited Process for preparation of dimethyl-(e)-butenedioate
WO2016001093A1 (en) * 2014-07-03 2016-01-07 Synthon B.V. Process for making microcrystalline dimethyl fumarate

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