WO2014203231A2 - Process for preparation of dimethyl-(e)-butenedioate - Google Patents

Process for preparation of dimethyl-(e)-butenedioate Download PDF

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Publication number
WO2014203231A2
WO2014203231A2 PCT/IB2014/065440 IB2014065440W WO2014203231A2 WO 2014203231 A2 WO2014203231 A2 WO 2014203231A2 IB 2014065440 W IB2014065440 W IB 2014065440W WO 2014203231 A2 WO2014203231 A2 WO 2014203231A2
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WO
WIPO (PCT)
Prior art keywords
dimethyl
butenedioate
reaction mixture
preparation
temperature
Prior art date
Application number
PCT/IB2014/065440
Other languages
English (en)
French (fr)
Other versions
WO2014203231A3 (en
Inventor
Rafiuddin DR.
Bhagat Raj PIPAL
Ravindra Reddy UMMADI
Akshay Kant CHATURVEDI
Original Assignee
Shilpa Medicare Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Shilpa Medicare Limited filed Critical Shilpa Medicare Limited
Priority to US15/110,104 priority Critical patent/US20160326087A1/en
Priority to EP14812977.8A priority patent/EP3097075A4/en
Publication of WO2014203231A2 publication Critical patent/WO2014203231A2/en
Publication of WO2014203231A3 publication Critical patent/WO2014203231A3/en

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Classifications

    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the present invention relates to a process for preparation of dimethyl-(E)-butenedioate (I).
  • the process for preparation of dimethyl-(E)-butenedioate (I) comprises reaction of Fumaric acid with methanol in the presence of C 2 -C4 alkanoyl halide as coupling catalyst.
  • Dimethyl-(E)-butenedioate (I) is generally also known as Dimethyl Fumarate and is available commercially as TECDIFERA ® , for the treatment of patients with relapsing forms of multiple sclerosis.
  • Dimethyl-(E)-butenedioate is a white to off-white powder that is highly soluble in water with a molecular mass of 144.13
  • Fumaric acid is an intermediate in the citric acid cycle that is hydrated by the enzyme fumarase to maleic acid.
  • the use of fumaric acid for the treatment of psoriasis was introduced in 1959.
  • Earlier known derivatives of fumaric acid like dihydroxy fumaric acid, fumaramide, and fumaronitrile, suffered from problem of insufficient resorbtion, due to which high doses were to be utilized leading to high toxicity and serious side effects.
  • Kadowaki, Yasushi; et al. in U.S. Patent Appl. No. 2002/0002306 disclosed a method of producing dimethyl fumarate containing no catalyst residue by use of a heterogenous Group VIII catalyst.
  • inventors of the present application provide a process for preparation of dimethyl- (E)-butenedioate, which is amenable to scale up at industrial level and solves purity/ compliance related issues of the end product.
  • the process of preparation of dimethyl-(E)-butenedioate (I) comprises the steps of- a) providing a solution of Fumaric acid in methanol at room temperature;
  • step f) optionally, treating the solid material obtained in step e) with an organic solvent or a mixture thereof, and recovering the crystalline solid.
  • crystalline dimethyl-(E)-butenedioate (I) prepared according to the process of the present invention is having HPLC purity greater than 99.95% (by HPLC) and is characterized by Monomethyl Fumarate content of 0.01% or less.
  • the present invention relates to crystalline dimethyl-(E)-butenedioate (I), characterized by X-ray powder diffraction pattern- having at least five 20° peaks selected from the XRPD peak set of 9.82, 10.88, 17.44, 19.81 , 23.71, 23.97, 26.17, 33.26 and 41.26 ⁇ 0.1 °; or substantially according to Fig-1 and DSC isotherm comprising at least one endothermic peak ranging between- a. Peak -1- Between 100 to 110 °C; or
  • Fig. 1 is illustration of X-ray powder diffraction ("XRPD") pattern of dimethyl-(E)- butenedioate (I) obtained in Example 1.
  • XRPD X-ray powder diffraction
  • Fig. 2 is illustration of Differential Scanning Calorimetry ("DSC") curve of dimethyl-(E)- butenedioate (I) obtained in Example 1.
  • DSC Differential Scanning Calorimetry
  • embodiments of the present invention relate to a process for the preparation of dimethyl-(E)-butenedioate (I),
  • step f) optionally, treating the solid material obtained in step e) with an organic solvent or a mixture thereof, and recovering the crystalline solid.
  • Step a) comprises providing a solution of Fumaric acid in methanol at room temperature, wherein solution of Fumaric acid is provided in 5-10 volumes of methanol (in mL) w.r.t. weight of Fumaric acid (in g).
  • solution of Fumaric acid is provided in 5-10 volumes of methanol (in mL) w.r.t. weight of Fumaric acid (in g).
  • 50 g Fumaric acid was provided as solution in 400 mL methanol.
  • Step b) comprises adding coupling catalyst C 2 -C4 alkanoyl halide to the reaction mixture, wherein C 2 -C4 alkanoyl halide is added in catalytic amount ranging from 0.35-0.5 moles per 1 mole of Fumaric acid used in step a).
  • C 2 -C4 alkanoyl halide is selected from acetyl chloride or acetyl bromide.
  • Step c) comprises raising the temperature of reaction mixture up to a range of 50-75 °C;
  • the reaction mixture obtained from step b) is heated to temperature ranging from 50-75 °C; preferably up to 60-70 °C.
  • the raised reaction temperature is maintained for time duration of 5- 15 hrs depending upon the progress of the reaction as is intermittently checked by HPLC.
  • Step d) comprises cooling the reaction mixture to room temperature, wherein cooling is performed in controlled manner of not more than 1 °C/ minute.
  • the cooled reaction mass is further subjected to stirring for time duration varying from 1 to 3 hours.
  • Step e) comprises isolating the solid material, wherein the solid material separated in step d) is filtered by any method known to person having skill in the art. The solid material is then dried at room temperature for time duration ranging from 1-3 hours.
  • Step f) comprises optionally treating the solid material obtained in step e) with an organic solvent or a mixture thereof and recovering the crystalline solid.
  • Solid material obtained in step e) is optionally treated with an organic solvent or a mixture thereof.
  • the said organic solvent may be selected from C1-C3 alcoholic solvent for e.g. methanol, ethanol or «-propanol.
  • Solid material obtained in step e) is dissolved in 8-15 volume C1-C3 alcoholic solvent.
  • the reaction mixture is then heated to get a clear solution. Heating is preferably performed to a temperature of 50-60 °C.
  • the clear solution is then filtered through celite bed to get a particle free solution, which is again heated if required, to get clear solution. Under continuous stirring the reaction mixture is slowly cooled to RT and then further to a temperature of 0-15 °C, wherein it is maintained for time duration of 1-3 hours.
  • the solid material obtained above is filtered and suck dried at room temperature for time ranging from 30 mins to 1 hour. Further drying may be performed under reduced pressure conditions. Reduced pressure conditions may be suitably utilized by person skilled in the art in order to obtain the dried material. In one particular embodiment of the current application, further drying was performed under vacuum. This drying may be performed for time ranging from 2 to 4 hrs depending upon compliance to the product characteristics of dimethyl-(E)- butenedioate (I).
  • Process of isolating dimethyl- (E)-butenedioate (I) may further comprise processes but not limited to conventional processes including scrapping and if required filtering from slurry which may be carried out at room temperature for the suitable durations.
  • the process related impurities that appear in the impurity profile of dimethyl-(E)-butenedioate (I) may be substantially removed by the process of the present invention resulting in the formation of pure dimethyl-(E)-butenedioate (I) in a crystalline form.
  • the merit of the process according to the present invention resides in that - product obtained after drying is highly pure and very stable and can be suitably stored for prolonged durations.
  • Substantially pure dimethyl- (E)-butenedioate (I) obtained according to the process of the present invention results in the final API purity by HPLC of more than 99.95 % w/w.
  • the final API is characterized by Monomethyl Fu mar ate content of 0.01 % or less.
  • the crystalline dimethyl-(E)-butenedioate (I), obtained according to the process of the present invention is characterized by X-ray powder diffraction pattern substantially according to Fig- 1 and DSC isotherm comprising at least one endothermic peak ranging between- a. Peak -1- Between 100 to 110 °C; or
  • the crystalline dimethyl-(E)-butenedioate (I), obtained according to the process of the present invention is further characterized by moisture content of less than 0.3 % w/w (Karl Fischer Analysis) and TGA weight loss of less than 0.5 % w/w, up to temperature of 120 °C.
  • the crystalline dimethyl-(E)-butenedioate (I), prepared according to the process of the present invention is consistently obtained with particle size, wherein D90 is greater than 250 ⁇ .
  • dimethyl-(E)-butenedioate (I) described herein were analyzed by XRPD on a Bruker AXS D8 Advance Diffractometer using X-ray source - Cu Ka radiation using the wavelength 1.5418 A and lynx Eye detector. DSC was done on a Perkin Elmer Pyris 7.0 instrument. Illustrative example of analytical data for dimethyl-(E)-butenedioate (I) obtained in the examples is set forth in the Figs. 1 & 2.
  • Example-01 Process for preparation of dimethyl-(E)-butenedioate (I).
  • the reaction mixture was further cooled to -15° C under stirring and maintained at this temperature for 2 hours.
  • the solid material obtained was filtered and suck dried for 30 mins at RT.
  • the solid material was then further dried under vacuum at room temperature for three hours, to obtain 33.2 g dimethyl-(E)-butenedioate (I) in a crystalline form having the XRPD diffractogram and DSC thermogram as shown in Fig. 1 and 2 respectively.
  • the crystalline dimethyl-(E)-butenedioate (I) obtained by this process was designated as Form- SD.
  • Example-02 Process for preparation of dimethyl-(E)-butenedioate (I).
  • the reaction mixture was further cooled to -10° C under stirring and maintained at this temperature for 2 hours.
  • the solid material obtained was filtered and suck dried for 30 mins at RT.
  • the solid material was then further dried under vacuum at room temperature for three hours, to obtain 26.1 g dimethyl-(E)-butenedioate (I) in a crystalline form having the XRPD diffractogram and DSC thermogram according to Fig. 1 and 2 respectively.
  • Example-03 Process for preparation of dimethyl-(E)-butenedioate (I).
  • the crystalline dimethyl-(E)-butenedioate (I) obtained by this process was designated as Form- SD.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
PCT/IB2014/065440 2014-01-24 2014-10-18 Process for preparation of dimethyl-(e)-butenedioate WO2014203231A2 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
US15/110,104 US20160326087A1 (en) 2014-01-24 2014-10-18 Process for preparation of dimethyl-(e)-butenedioate
EP14812977.8A EP3097075A4 (en) 2014-01-24 2014-10-18 Process for preparation of dimethyl-(e)-butenedioate

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN0308/CHE/2014 2014-01-24
IN308CH2014 IN2014CH00308A (enrdf_load_stackoverflow) 2014-01-24 2014-10-18

Publications (2)

Publication Number Publication Date
WO2014203231A2 true WO2014203231A2 (en) 2014-12-24
WO2014203231A3 WO2014203231A3 (en) 2015-07-30

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2014/065440 WO2014203231A2 (en) 2014-01-24 2014-10-18 Process for preparation of dimethyl-(e)-butenedioate

Country Status (3)

Country Link
EP (1) EP3097075A4 (enrdf_load_stackoverflow)
IN (1) IN2014CH00308A (enrdf_load_stackoverflow)
WO (1) WO2014203231A2 (enrdf_load_stackoverflow)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017013672A1 (en) 2015-07-23 2017-01-26 Natco Pharma Ltd Process for the preparation of pharmaceutical grade dimethyl fumarate

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3078302A (en) * 1958-09-25 1963-02-19 Monsanto Chemicals Production of dialkyl fumarates
US3905943A (en) * 1973-04-16 1975-09-16 Koppers Co Inc Preparation of fumarates
PL2718257T3 (pl) * 2011-06-08 2018-04-30 Biogen Ma Inc. Sposób przygotowywania dimetylofumaranu krystalicznego o wysokiej czystości
CN102766050A (zh) * 2012-08-10 2012-11-07 太仓市运通化工厂 一种富马酸二甲酯的合成方法

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017013672A1 (en) 2015-07-23 2017-01-26 Natco Pharma Ltd Process for the preparation of pharmaceutical grade dimethyl fumarate

Also Published As

Publication number Publication date
EP3097075A2 (en) 2016-11-30
EP3097075A4 (en) 2017-06-21
WO2014203231A3 (en) 2015-07-30
IN2014CH00308A (enrdf_load_stackoverflow) 2015-07-31

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