DESC:FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003

COMPLETE SPECIFICATION
(See section 10 and rule 13)

“PROCESS FOR PREPARATION OF DIROXIMEL FUMARATE”

Glenmark Pharmaceuticals Limited;
an Indian Company, registered under the Indian company’s Act 1957 and having its registered office at
Glenmark House,
HDO- Corporate Bldg, Wing-A,
B. D. Sawant Marg, Chakala,
Andheri (East), Mumbai- 400 099

The following specification particularly describes the invention and the manner in which it is to be performed.
FIELD OF THE INVENTION
[0001] The present invention relates to a process for the preparation of diroximel fumarate. The present invention relates to amorphous solid dispersion comprising diroximel fumarate or salt thereof together with at least one pharmaceutically acceptable carrier and process for its preparation.
BACKGROUND OF THE INVENTION
[0002] Diroximel fumarate, also known as 2-(2, 5-dioxopyrrolidin-1-yl) ethyl methyl fumarate, is represented by the structure of formula I.
I
[0003] Diroximel fumarate is indicated for the treatment of patients with relapsing forms of multiple sclerosis (MS).
SUMMARY OF THE INVENTION
[0004] The present invention provides a process for the preparation of diroximel fumarate, a compound of formula I, the process comprising:
(a) reacting maleic anhydride with methanol to give monomethyl maleate, a compound of formula IV;
IV
(b) reacting monomethyl maleate, the compound of formula IV with thionyl chloride to give monomethyl fumarate, a compound of formula II; and
II III
(c) reacting monomethyl fumarate, the compound of formula II with a compound of formula III to give diroximel fumarate, the compound of formula I.
[0005] In another embodiment, the present invention provides a process for the
preparation of an amorphous solid dispersion of diroximel fumarate or salt thereof together with at least one pharmaceutically acceptable carrier, the process comprising:
(a) providing a solution or mixture of diroximel fumarate or salt thereof together with at least one pharmaceutically acceptable carrier in a solvent; and
(b) obtaining the amorphous solid dispersion of diroximel fumarate or salt thereof together with at least one pharmaceutically acceptable carrier from the solution or mixture of step (a).
BRIEF DESCRIPTION OF THE DRAWINGS
[0006] Figure 1 is a characteristic XRPD of crystalline diroximel fumarate as obtained in Example 3.
[0007] Figure 2 is a DSC thermogram of crystalline diroximel fumarate as obtained in Example 3.
[0008] Figure 3 is a characteristic XRPD of amorphous solid dispersion comprising diroximel fumarate and polyvinyl pyrrolidone as obtained in Example 4.
[0009] Figure 4 is a characteristic XRPD of amorphous solid dispersion comprising diroximel fumarate and hydroxypropyl methylcellulose phthalate as obtained in Example 5.
[0010] Figure 5 is a characteristic XRPD of amorphous solid dispersion comprising diroximel fumarate and hydroxypropyl methylcellulose phthalate as obtained in Example 6.
[0011] Figure 6 is a characteristic XRPD of crystalline diroximel fumarate as obtained in Example 11.
DETAILED DESCRIPTION OF THE INVENTION
[0012] The present invention provides a process for the preparation of diroximel fumarate, a compound of formula I, the process comprising:
(a) reacting maleic anhydride with methanol to give monomethyl maleate, a compound of formula IV;
IV
(b) reacting monomethyl maleate, the compound of formula IV with thionyl chloride to give monomethyl fumarate, a compound of formula II; and
II III
(c) reacting monomethyl fumarate, the compound of formula II with a compound of formula III to give diroximel fumarate, the compound of formula I.
[0013] In the present application, the term “room temperature” means a temperature of about 25°C to about 30°C.
[0014] In (a) of the process for the preparation of diroximel fumarate, maleic anhydride is reacted with methanol to give monomethyl maleate, the compound of formula IV.
[0015] In one embodiment, the reaction of maleic anhydride with methanol occurs in the presence of a solvent.
[0016] In one embodiment, the solvent is selected from the group consisting of hydrocarbons, ethers, halogenated hydrocarbons, esters, nitriles, and mixtures thereof.
[0017] In one embodiment, the solvent is selected from the group consisting of hydrocarbons such as toluene, xylene, chlorobenzene, heptane, hexane, cyclohexane and the like; ethers such as dimethyl ether, diethyl ether, diisopropyl ether, tert-butyl methyl ether, dibutyl ether, dimethoxyethane, diethoxyethane, tetrahydrofuran, dioxane and the like; halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, ethylene dichloride, and the like; esters such as methyl acetate, ethyl acetate, n-propyl acetate, tert-butyl acetate and the like; nitriles such as acetonitrile, benzonitrile and the like; and mixtures thereof.
[0018] In one embodiment, the reaction of maleic anhydride with methanol occurs in the presence of a solvent, wherein the solvent is toluene.
[0019] In one embodiment, the reaction of maleic anhydride with methanol occurs in the absence of a solvent.
[0020] In one embodiment, the molar ratio of maleic anhydride to methanol is in the range of about 1 to 0.70 to about 1 to 4.
[0021] In one embodiment, the molar ratio of maleic anhydride to methanol is in the range of about 1 to 0.70 to about 1 to 3.
[0022] In one embodiment, the molar ratio of maleic anhydride to methanol is in the range of about 1 to 0.70 to about 1 to 2.5.
[0023] In one embodiment, the molar ratio of maleic anhydride to methanol is in the range of about 1 to 0.70 to about 1 to 2.
[0024] In one embodiment, the molar ratio of maleic anhydride to methanol is in the range of about 1 to 0.70, about 1 to 0.75, about 1 to 0.80, about 1 to 0.85, about 1 to 0.90, about 1 to 0.95, about 1 to 1, about 1 to 1.05, about 1 to 1.1, about 1 to 1.15, about 1 to 1.2, about 1 to 1.25, about 1 to 1.3, about 1 to 1.35, about 1 to 1.4, about 1 to 1.45, about 1 to 1.5, about 1 to 1.55, about 1 to 1.6, about 1 to 1.65, about 1 to 1.7, about 1 to 1.75, about 1 to 1.8, about 1 to 1.85, about 1 to 1.9, about 1 to 1.95, about 1 to 2, about 1 to 2.05, about 1 to 2.1, about 1 to 2.15, about 1 to 2.2, about 1 to 2.25, about 1 to 2.3, about 1 to 2.35, about 1 to 2.4, about 1 to 2.45, about 1 to 2.5, about 1 to 2.6, about 1 to 2.7, about 1 to 2.8, about 1 to 2.9, about 1 to 3, about 1 to 4.
[0025] In one embodiment, the molar ratio of maleic anhydride to methanol is in the range of about 1 to 1 to about 1 to 4.
[0026] In one embodiment, the molar ratio of maleic anhydride to methanol is in the range of about 1 to 3.
[0027] In one embodiment, the molar ratio of maleic anhydride to methanol is in the range of about 1 to 2.
[0028] In one embodiment, the reaction of maleic anhydride with methanol occurs at a temperature of about 20°C to about 100°C.
[0029] In one embodiment, the reaction of maleic anhydride with methanol occurs at a temperature of about 20°C to about 100°C, about 25°C to about 80°C, about 30°C to about 80°C, about 40°C to about 75°C, about 45°C to about 70°C, about 50°C to about 70°C, about 50°C to about 65°C.
[0030] In one embodiment, the reaction of maleic anhydride with methanol occurs at a temperature of about 40°C to about 75°C.
[0031] In one embodiment, the reaction of maleic anhydride with methanol occurs at a temperature of about 50°C to about 70°C.
[0032] In one embodiment, the reaction of maleic anhydride with methanol occurs over a period of about 1 hour to about 12 hours.
[0033] In one embodiment, the reaction of maleic anhydride with methanol occurs over a period of about 1 hour to about 6 hours.
[0034] In one embodiment, the reaction of maleic anhydride with methanol occurs over a period of about 1 hour to about 4 hours.
[0035] In one embodiment, monomethyl maleate, the compound of formula IV obtained in step (a) is isolated.
[0036] In one embodiment, the compound of formula IV obtained in step (a) is isolated by removing the solvent.
[0037] In one embodiment, removal of solvent may be accomplished by substantially complete evaporation of the solvent. The solvent may be completely evaporated in, for example, a rotavapor, a vacuum paddle dryer or in a conventional reactor under vacuum above about 720mm Hg.
[0038] In (b) of the process for the preparation of diroximel fumarate, monomethyl maleate, the compound of formula IV is reacted with thionyl chloride to give monomethyl fumarate, the compound of formula II.
[0039] In one embodiment, the compound of formula IV obtained in step (a) is isolated and then reacted with thionyl chloride.
[0040] In one embodiment, the reaction of the compound of formula IV with thionyl chloride occurs in the presence of a solvent.
[0041] In one embodiment, the solvent is selected from the group consisting of hydrocarbons, ethers, halogenated hydrocarbons, esters, nitriles, and mixtures thereof.
[0042] In one embodiment, the solvent is selected from the group consisting of hydrocarbons such as toluene, xylene, chlorobenzene, heptane, hexane, cyclohexane and the like; ethers such as dimethyl ether, diethyl ether, diisopropyl ether, tert-butyl methyl ether, dibutyl ether, dimethoxyethane, diethoxyethane, tetrahydrofuran, dioxane and the like; halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, ethylene dichloride, and the like; esters such as methyl acetate, ethyl acetate, n-propyl acetate, tert-butyl acetate and the like; nitriles such as acetonitrile, benzonitrile and the like; and mixtures thereof.
[0043] In one embodiment, the reaction of the compound of formula IV with thionyl chloride occurs in the presence of a solvent, wherein the solvent is toluene.
[0044] In one embodiment, the molar ratio of the compound of formula IV to thionyl chloride is in the range of about 1 to 0.01 to about 1 to 1.
[0045] In one embodiment, the molar ratio of the compound of formula IV to thionyl chloride is in the range of about 1 to 0.01, about 1 to 0.015, about 1 to 0.02, about 1 to 0.025, about 1 to 0.03, about 1 to 0.035, about 1 to 0.04, about 1 to 0.045, about 1 to 0.05, about 1 to 0.055, about 1 to 0.06, about 1 to 0.065, about 1 to 0.07, about 1 to 0.075, about 1 to 0.08, about 1 to 0.085, about 1 to 0.09, about 1 to 0.095, about 1 to 0.10, about 1 to 0.15, about 1 to 0.20, about 1 to 0.25, about 1 to 0.30, about 1 to 0.35, about 1 to 0.40, about 1 to 0.45, about 1 to 0.50, about 1 to 0.55, about 1 to 0.60, about 1 to 0.65, about 1 to 0.70, about 1 to 0.75, about 1 to 0.80, about 1 to 0.85, about 1 to 0.90, about 1 to 0.95, about 1 to 0.10, about 1 to 0.15, about 1 to 0.20, about 1 to 0.25, about 1 to 0.30, about 1 to 0.35, about 1 to 0.40, about 1 to 0.45, about 1 to 0.50, about 1 to 0.55, about 1 to 0.60, about 1 to 0.65, about 1 to 0.70, about 1 to 0.75, about 1 to 0.80, about 1 to 0.85, about 1 to 0.90, about 1 to 0.95, about 1 to 1.
[0046] In one embodiment, the molar ratio of the compound of formula IV to thionyl chloride is in the range of about 1 to 0.01 to about 1 to 0.1.
[0047] In one embodiment, the reaction of the compound of formula IV with thionyl chloride occurs at a temperature of about 50°C to about 100°C.
[0048] In one embodiment, the reaction of the compound of formula IV with thionyl chloride occurs at a temperature of about 50°C to about 100°C, about 60°C to about 100°C, about 60°C to about 90°C, about 70°C to about 90°C, about 75°C to about 90°C.
[0049] In one embodiment, the reaction of the compound of formula IV with thionyl chloride occurs at a temperature of about 70°C to about 100°C.
[0050] In one embodiment, the reaction of the compound of formula IV with thionyl chloride occurs at a temperature of about 75°C to about 95°C.
[0051] In one embodiment, the reaction of the compound of formula IV with thionyl chloride occurs at a temperature of about 80°C to about 90°C.
[0052] In one embodiment, the reaction of the compound of formula IV with thionyl chloride occurs over a period of about 1 hour to about 24 hours.
[0053] In one embodiment, the reaction of the compound of formula IV with thionyl chloride occurs over a period of about 1 hour to about 12 hours.
[0054] In one embodiment, the reaction of the compound of formula IV with thionyl chloride occurs over a period of about 1 hour to about 8 hours.
[0055] In one embodiment, the reaction of the compound of formula IV with thionyl chloride occurs over a period of about 1 hour to about 6 hours.
[0056] In one embodiment, monomethyl fumarate, the compound of formula II obtained in step (b) is isolated by crystallization from a solvent selected from ethyl acetate, toluene, methanol, water, or mixtures thereof.
[0057] In one embodiment, monomethyl fumarate, the compound of formula II obtained in step (b) is in a purity of at least 99.0% and wherein the level of fumaric acid is less than 0.15%.
[0058] In one embodiment, monomethyl fumarate, the compound of formula II obtained in step (b) is in a purity of at least 99.0% and wherein the level of fumaric acid is less than 0.10%.
[0059] In one embodiment, monomethyl fumarate, the compound of formula II obtained in step (b) is in a purity of at least 99.0% and wherein the level of fumaric acid is less than 0.05%.
[0060] In one embodiment, monomethyl fumarate, the compound of formula II obtained in step (b) is in a purity of at least 99.0% and wherein the level of monomethyl maleate or dimethyl maleate or dimethyl fumarate is less than 0.15%.
[0061] In one embodiment, monomethyl fumarate, the compound of formula II obtained in step (b) is in a purity of at least 99.0% and wherein the level of monomethyl maleate or dimethyl maleate or dimethyl fumarate is less than 0.10%.
[0062] In (c) of the process for the preparation of diroximel fumarate, monomethyl fumarate, the compound of formula II is reacted with the compound of formula III to give diroximel fumarate.
[0063] In one embodiment, monomethyl fumarate, the compound of formula II obtained in step (b) in a purity of at least 99.0% with the level of fumaric acid or dimethyl fumarate less than 0.15%, is reacted with the compound of formula III to give diroximel fumarate.
[0064] In one embodiment, the reaction of the compound of formula II with the compound of formula III occurs in the presence of a solvent.
[0065] In one embodiment, the solvent is selected from the group consisting of halogenated hydrocarbons, ethers, hydrocarbons, esters, nitriles, amides, sulfoxides, and mixtures thereof.
[0066] In one embodiment, the solvent is selected from the group consisting of halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, and the like; ethers such as dimethyl ether, diethyl ether, diisopropyl ether, tert-butyl methyl ether, dibutyl ether, dimethoxyethane, diethoxyethane, tetrahydrofuran, dioxane and the like; hydrocarbons such as toluene, xylene, chlorobenzene, heptane, hexane, cyclohexane and the like; esters such as methyl acetate, ethyl acetate, n-propyl acetate, tert-butyl acetate and the like; nitriles such as acetonitrile, benzonitrile and the like; amides such as dimethylformamide, dimethyl acetamide and the like; sulfoxides such as dimethyl sulfoxide; and mixtures thereof.
[0067] In one embodiment, the reaction of the compound of formula II with the compound of formula III occurs in the presence of a solvent, wherein the solvent is dichloromethane.
[0068] In one embodiment, the reaction of the compound of formula II with the compound of formula III occurs in the presence of a coupling agent selected from the group consisting of TsCl (p-toluenesulfonyl chloride), HBTU (N,N,N',N'-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate), EDCI (N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride), HOBt (hydroxybenzotriazole hydrate), COMU ((1-cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate), TBTU (O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate), TATU (O-(7-azabenzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate), Oxyma (ethyl (hydroxyimino)cyanoacetate), PyBOP ((benzotriazol-1-yloxy) tripyrrolidinophosphonium hexafluorophosphate), HOTT (S-(1-oxido-2-pyridyl)-N,N,N',N'-tetramethylthiuronium hexafluorophosphate), FDPP (pentafluorophenyl diphenylphosphinate), T3P (propylphosphonic anhydride), DMTMM (4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium tetrafluoroborate), PyOxim ([ethyl cyano(hydroxyimino)acetato-O2]tri-1-pyrrolidinylphosphonium hexafluorophosphate), TSTU (N,N,N,N-tetramethyl-O-(N-succinimidyl)uronium tetrafluoroborate), TDBTU (O-(3,4-dihydro-4-oxo-1,2,3-benzotriazin-3-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate), TPTU (O-(2-oxo-1 (2H)pyridyl)-N,N,N',N'-tetramethyluronium tetrafluoroborate), TOTU (O-[(ethoxycarbonyl)cyanomethylenamino]-N,N,N',N'-tetramethyluronium tetrafluoroborate), IIDQ (isobutyl 1,2-dihydro-2-isobutoxy-1-quinolinecarboxylate), PyCIU (chlorodipyrrolidinocarbenium hexafluorophosphate), DCC (dicyclohexylcarbodiimide), DIC (diisopropylcarbodiimide), TOTT (N,N,N',N'-tetramethyl-S-(1-oxido-2-pyridyl)thiouronium tetrafluoroborate), EEDQ (N-Ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline), HDMC (N-[(5-Chloro-3-oxido-1H-benzotriazol-1-yl)-4-morpholinylmethylene]-N-methylmethanaminium hexafluorophosphate), HCTU (2-(6-chloro-1H-benzotriazole-1-yl)-1,1,3,3-tetramethylaminium hexafluorophosphate), DEPBT (3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one), PyOxim (ethyl cyano(hydroxyimino)acetato-O2]tri-1-pyrrolidinylphosphonium hexafluorophosphate), PyAOP ((7-azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate), PyBOP (benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate), BOP (benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate), HOOBt (hydroxy-3,4-dihydro-4-oxo-1,2,3-benzotriazine), HOSu (N-hydroxysuccinimide), HOAt (1-hydroxy-7-azabenzotriazole), TFFH (tetramethylfluoroformamidinium hexafluorophosphate), and mixtures thereof.
[0069] In one embodiment, the reaction of the compound of formula II with the compound of formula III occurs in the presence of a coupling agent, wherein the coupling agent is TsCl.
[0070] In one embodiment, the reaction of the compound of formula II with the compound of formula III occurs in the presence of a base selected from organic base or inorganic base.
[0071] The organic base includes but is not limited to diisopropylethylamine, trimethylamine, tributylamine, triphenylamine, pyridine, lutidine (2,6-dimethylpyridine), collidine (2,4,6-trimethylpyridine), imidazole, DMAP (4-(dimethylamino)pyridine), DABCO (1,4-diazabicyclo[2.2.2]octane), DBU (1,8-diazabicyclo[5.4.0]undec-7-ene), DBN (1,5-diazabicyclo[4.3.0]non-5-ene), N,N,N',N'-tetramethyl-1,8-naphthalenediamine, oxyma (ethyl cyanohydroxyiminoacetate), or mixtures thereof.
[0072] The inorganic base includes but is not limited to lithium carbonate, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, or mixtures thereof.
[0073] In one embodiment, the reaction of the compound of formula II with the compound of formula III occurs in the presence of a base selected from the group consisting of diisopropylethylamine, trimethylamine, triethylamine, tributylamine, triphenylamine, pyridine, lutidine (2,6-dimethylpyridine), collidine (2,4,6-trimethylpyridine), imidazole, DMAP (4-(dimethylamino)pyridine), DABCO (1,4-diazabicyclo[2.2.2]octane), DBU (1,8-diazabicyclo[5.4.0]undec-7-ene), DBN (1,5-diazabicyclo[4.3.0]non-5-ene), N,N,N',N'-tetramethyl-1,8-naphthalenediamine, lithium carbonate, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, and mixtures thereof.
[0074] In one embodiment, the reaction of the compound of formula II with the compound of formula III occurs in the presence of a base, wherein the coupling agent is DMAP, sodium carbonate, or mixtures thereof.
[0075] In one embodiment, the diroximel fumarate obtained in step (c) is isolated from a solvent selected from the group consisting of esters such as methyl acetate, ethyl acetate, n-propyl acetate, tert-butyl acetate and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; nitriles such as acetonitrile and the like; water; and mixtures thereof.
[0076] In one embodiment, the diroximel fumarate is obtained in a purity of =99.0% and wherein the level of impurity A is less than 0.15%.
A
[0077] The presence of fumaric acid impurity in monomethyl fumarate, the compound of formula II, leads to the formation of impurity A in step (c) of the preparation of diroximel fumarate.
[0078] In one embodiment, monomethyl fumarate, the compound of formula II obtained in step (b) in a purity of at least 99.0% with the level of fumaric acid less than 0.15%, is reacted with the compound of formula III to give diroximel fumarate in a purity of =99.0% with the level of impurity A less than 0.15%.
[0079] In one embodiment, the diroximel fumarate is obtained in a purity of =99.0% and wherein the level of impurity is less than 0.10%.
[0080] In one embodiment, the diroximel fumarate is obtained in a purity of =99.0% and wherein the level of impurity A is less than 0.05%.
[0081] In one embodiment, the diroximel fumarate is obtained in a purity of =99.5% and wherein the level of impurity A is less than 0.15%.
[0082] In one embodiment, the diroximel fumarate is obtained in a purity of =99.0% and wherein the level of impurity B is less than 0.15%.
B
[0083] In one embodiment, the diroximel fumarate is obtained in a purity of =99.0% and wherein the level of fumaric acid or dimethyl fumarate is less than 0.15%.
[0084] In one embodiment, the diroximel fumarate is obtained in a purity of =99.0% and wherein the level of compound of III or monomethyl fumarate is less than 0.15%.
[0085] In one embodiment, the diroximel fumarate is obtained in a purity of =99.0% and wherein the level of impurity C or impurity D or impurity E or impurity F is less than 0.15%.
C D
E F
[0086] The present invention provides diroximel fumarate obtained by above process, as analyzed by chemical purity using high performance liquid chromatography (HPLC) with the conditions described below: Reagents and Solvents: Perchloric acid (AR grade), Pentane-1-sulfonic acid Na salt (AR grade), Methanol (Gradient Grade), Water (Milli Q or equivalent), Acetonitrile (Gradient Grade); Chromatographic Conditions:
Apparatus: A High Performance Liquid Chromatograph equipped with quaternary gradient pumps, variable wavelength UV detector attached with data recorder and integrator software; Column: Zorbax SB C8 250 X 4.6 mm, 5µ; Column temperature: 40°C; Sample Cooler temperature: 10°C; Mobile phase A = Buffer: Methanol (980:20, V/V); Buffer: Add 1.0 mL perchloric acid and 0.4 g of Pentane-1-sulfonic acid Na salt in 1000 mL of water; Mobile Phase B: Buffer: Methanol (500:500, V/V)
Time (min.) % Mobile Phase A % Mobile Phase B
0.01 100 00
07 100 00
65 45 55
90 10 90
109 10 90
111 100 00
120 100 00

Diluent: Water: Acetonitrile (980:20, V/V); Flow Rate: 1.0 mL/minute; Detection: UV 210 nm; Injection Volume: 40µL; Run time: 120 minutes; Needle wash: Acetonitrile (100%); The retention time of diroximel fumarate is about 58.0 minutes under these conditions.
[0087] In one embodiment, the compound of formula III is prepared by reacting succinimide with ethylene carbonate.
[0088] In one embodiment, the compound of formula III is prepared by reacting succinimide with ethylene carbonate in the presence of a base.
[0089] In one embodiment, the reaction of succinimide with ethylene carbonate occurs in the presence of a base selected from the group consisting of diisopropylethylamine, trimethylamine, triethylamine, tributylamine, triphenylamine, pyridine, DMAP (4-(dimethylamino)pyridine), and mixtures thereof.
[0090] In one embodiment, the compound of formula III is isolated.
[0091] In one embodiment, the compound of formula III is isolated by removing the solvent.
[0092] In one embodiment, the compound of formula III is isolated as a residue.
[0093] In one embodiment, the compound of formula III is not isolated.
[0094] In one embodiment, the compound of formula III is dissolved in a solvent selected from the group consisting of halogenated hydrocarbons, ethers, hydrocarbons, esters, nitriles, amides, sulfoxides, and mixtures thereof.
[0095] In one embodiment, the compound of formula III dissolved in a solvent is reacted with the compound of formula II to give diroximel fumarate.
[0096] In one embodiment, the present invention provides an amorphous solid dispersion comprising diroximel fumarate or salt thereof together with at least one pharmaceutically acceptable carrier.
[0097] In one embodiment, the pharmaceutically acceptable carrier is selected from a group consisting of one or more of a povidone, meglumine, gum, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose-acetate succinate, hydroxypropyl methylcellulose phthalate, hydroxypropyl ethyl cellulose, microcrystalline cellulose, cyclodextrin, gelatin, hypromellose phthalate, lactose, polyhydric alcohol, polyethylene glycol, polyethylene oxide, polyoxyalkylene derivative, methacrylic acid copolymer, polyvinyl alcohol, polyvinyl pyrrolidone, propylene glycol derivative, fatty acid, fatty alcohols, or esters of fatty acids.
[0098] In one embodiment, the present invention provides an amorphous solid dispersion comprising diroximel fumarate with polyvinyl pyrrolidone.
[0099] In one embodiment, the present invention provides an amorphous solid dispersion comprising diroximel fumarate with hydroxypropyl methylcellulose phthalate.
[0100] In one embodiment, the present invention provides a process for the preparation of an amorphous solid dispersion of diroximel fumarate or salt thereof together with at least one pharmaceutically acceptable carrier, the process comprising:
(a) providing a solution or mixture of diroximel fumarate or salt thereof together with at least one pharmaceutically acceptable carrier in a solvent; and
(b) obtaining the amorphous solid dispersion of diroximel fumarate or salt thereof together with at least one pharmaceutically acceptable carrier from the solution or mixture of step (a).
[0101] In one embodiment, the step (a) of providing a solution or mixture of diroximel fumarate or salt thereof for the preparation of amorphous solid dispersion, involves mixing with at least one pharmaceutically acceptable carrier as described herein above with a suitable solvent.
[0102] In one embodiment, the solvent is selected from the group consisting of ethers, ketones, esters, halogenated hydrocarbons, amides, alcohols, water, and mixtures thereof.
[0103] In one embodiment, the solvent is selected from the group consisting of ethers such as such as dimethyl ether, diethyl ether, diisopropyl ether, tert-butyl methyl ether, dibutyl ether, dimethoxyethane, diethoxyethane, tetrahydrofuran, dioxane and the like; ketones such as acetone, methyl isobutyl ketone, ethyl methyl ketone and the like; esters such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, tert-butyl acetate and the like; halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform and the like; amides such as dimethylformamide, dimethyl acetamide and the like; alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 1-pentanol and the like; water; and mixtures thereof.
[0104] In one embodiment, the step (b) of obtaining the amorphous solid dispersion comprises:
(i) removing the solvent from the solution or mixture obtained in (a); or
(ii) treating the solution of step (a) with an anti-solvent to form a mixture and optionally, cooling and stirring the obtained mixture.
[0105] In one embodiment, the removal of solvent in (b)(i) may be carried out by solvent distillation, concentration, spray drying, fluid bed drying, lyophilization, flash drying, spin flash drying, or thin-film drying.
[0106] In one embodiment, removal of solvent in (b)(i) may be carried out by spray drying.
[0107] In one embodiment, removal of solvent in (b)(i) may be carried out by solvent distillation, preferably under vacuum.
[0108] In one embodiment, the anti-solvent used in (b)(ii) is a solvent which on addition to the solution of step (a) causes precipitation of amorphous solid dispersion of diroximel fumarate with at least one pharmaceutically acceptable carrier.
[0109] In one embodiment, the anti-solvent is selected from the group consisting of ethers, ketones, esters, halogenated hydrocarbons, amides, alcohols, water and mixtures thereof.
[0110] The examples that follow are provided to enable one skilled in the art to practice the invention and are merely illustrative of the invention. The examples should not be read as limiting the scope of the invention as defined in the features and advantages.

EXAMPLES

[0111] EXAMPLE 1: Preparation of monomethyl fumarate
Maleic anhydride (20g) was added in toluene (40mL) and methanol (13.05g) by maintaining temperature at about 42°C to about 55°C. The reaction mixture was maintained at about 50°C to about 60°C for about 2h. The solvent was distilled out and the reaction mixture was stripped out with toluene. To the obtained residue, toluene (80mL) was added, followed by thionyl chloride (2.43g). The reaction mixture was maintained at about 80°C to about 90°C for about 2h. The reaction mixture was cooled to about 20°C to about 30°C, stirred for about 1h and filtered. The solid was washed with toluene and dried under vacuum at about 60°C for about 6h.
HPLC Purity: 99.01%; Fumaric acid content in monomethyl fumarate: 0.09%
A mixture of the obtained solid in ethyl acetate (60mL) was heated to about 70°C to about 80°C for about 30min and then cooled to about 5°C to about 10°C, stirred for about 2h and filtered. The solid obtained was recrystallized with ethyl acetate and dried. Yield: 16.5g; HPLC purity 99.96%; Fumaric acid content in monomethyl fumarate: 0.04%

[0112] EXAMPLE 2: Preparation of 1-(2-hydroxyethyl)-2,5-pyrrolidinedione
A mixture of ethylene carbonate (10g), succinimide (10.06g) and triethylamine (2g) was heated at about 90°C to about 100°C for about 6h. Traces of triethylamine were distilled out. Ethyl acetate and cyclohexane were added to the reaction mixture. The reaction mixture was stirred and filtered. The solid obtained was dried.
Yield: 11g; HPLC Purity: 98.97%

[0113] EXAMPLE 3: Preparation of diroximel fumarate
To a mixture of monomethyl fumarate (12g), 1-(2-hydroxyethyl)-2,5-pyrrolidinedione (17.1g) and DMAP (0.6g) in dichloromethane (120mL), cooled to about below 10°C, EDC.HCl (18.4g) was added. The reaction mixture was stirred and heated to about 20°C to about 30°C for about 150min. Water was added to the reaction mixture and the two layers were separated. The organic layer was washed with sodium bicarbonate solution followed with dilute hydrochloric acid solution. The organic layer was concentrated and the solid obtained was crystallized in ethyl acetate. Yield: 16.5g
HPLC Purity: 100%; Impurity A content in diroximel fumarate: Not detected
A mixture of diroximel fumarate (7g) in acetone (35mL) was heated to about 40°C to about 45°C and filtered through micron filter. The filtrate was concentrated and the solid obtained was crystallized with ethyl acetate. The solid obtained was dried in VTD under vacuum NLT 650 mmHg at about 50°C to about 55°C. Yield: 5.85g
HPLC Purity: 100%; Impurity A content in diroximel fumarate: Not detected
XRPD table of crystalline diroximel fumarate:
Pos. [°2Th.] d-spacing [Å] Rel. Int. [%] Pos. [°2Th.] d-spacing [Å] Rel. Int. [%]
7.01 12.59 4.70 28.63 3.11 2.18
11.58 7.64 3.09 29.56 3.01 0.59
12.01 7.36 0.30 30.69 2.91 5.09
13.41 6.60 47.09 31.12 2.87 4.27
13.67 6.47 8.88 31.84 2.80 1.89
14.42 6.14 0.63 32.19 2.77 1.16
16.04 5.52 1.52 33.60 2.66 4.34
16.65 5.32 3.70 34.17 2.62 5.55
17.99 4.92 34.10 34.77 2.57 1.69
18.36 4.83 1.75 35.07 2.55 2.23
19.26 4.60 0.53 35.71 2.51 1.49
19.73 4.49 0.54 36.60 2.45 0.56
21.02 4.22 20.56 38.23 2.35 2.41
21.95 4.04 7.72 40.01 2.25 0.94
22.08 4.02 5.52 40.45 2.22 1.85
22.86 3.88 18.69 41.59 2.16 1.03
23.05 3.85 30.92 42.37 2.13 2.13
23.73 3.74 4.18 42.97 2.10 2.44
24.22 3.67 13.38 43.28 2.08 4.76
24.41 3.64 15.20 43.68 2.07 1.20
25.43 3.49 7.25 44.90 2.01 1.14
26.87 3.31 10.16 45.31 1.99 1.19
27.12 3.28 16.16 46.38 1.95 1.99
27.38 3.25 100.00 48.62 1.87 1.27
27.95 3.18 1.82 49.29 1.84 0.19

[0114] COMPARATIVE EXAMPLE 1: Preparation of monomethyl fumarate (using acetyl chloride)
To a mixture of maleic anhydride (10g) in toluene (40mL), methanol (4.46g) was added. The reaction mixture was stirred at about 60°C to about 65°C for about 2h. The reaction mixture was concentrated under vacuum at about below 60°C and degassed under vacuum at about 50°C to about 60°C for about 1h. The reaction mixture was cooled to about 20°C to about 30°C and toluene (50mL) was added to it. Acetyl chloride (0.45g) was added to the reaction mixture which was heated to about 80°C to about 85°C for about 5h. The reaction mixture was cooled to about 20°C to about 30°C, stirred for about 1h and filtered. The solid was washed with toluene and dried under vacuum at about 60°C for about 6h. Yield: 10.1g; HPLC Purity: 97.32%; Fumaric acid content in monomethyl fumarate: 2.35%
A mixture of the obtained solid (4g) in ethyl acetate (20mL) was heated at about 65°C to about 75°C for about 1h. The reaction mixture was cooled to about 5°C to about 10°C and stirred for about 2h. The solid obtained was filtered, washed with ethyl acetate and dried under vacuum at about 40°C to about 45°C for about 12h. Yield: 3.22g; HPLC Purity: 99.49%; Fumaric acid content in monomethyl fumarate: 0.51%

[0115] EXAMPLE 4: Preparation of amorphous solid dispersion of diroximel fumarate with polyvinyl pyrrolidone (PVP K90)
Diroximel fumarate (1g) and polyvinyl pyrrolidone K90 (6g) were dissolved in methanol (80mL). The solution was stirred at about room temperature for about 15-20 minutes. The solution was filtered for particle free solution. The solvent was removed from the obtained solution by spray dryer. The solid obtained was dried in air tray dryer (ATD) at about 40°C for about 30 minutes. Yield: 85%
Spray drying parameters: Carrier nitrogen flow 2.0kg/cm2, inlet temperature 48°C, outlet temperature 75°C, feed rate 16rpm, aspirator 1700rpm and vacuum 250mm Hg.

[0116] EXAMPLE 5: Preparation of amorphous solid dispersion of diroximel fumarate with hydroxypropyl methylcellulose phthalate (HPMC-Phthalate)
Diroximel fumarate (0.25g) and hydroxypropyl methylcellulose phthalate (1.5g) were dissolved in methanol and dichloromethane (1:1v/v) solvent mixture (50mL). The solution was stirred at about room temperature for about 15-20 minutes. The solution was filtered for particle free solution. The obtained clear solution was distilled off under high vacuum at about 50°C using rotavapour. The solid obtained was dried on rotavapour at about 50°C for about 30 minutes. Yield: 90%

[0117] EXAMPLE 6: Preparation of amorphous solid dispersion of diroximel fumarate with hydroxypropyl methylcellulose phthalate (HPMC-Phthalate)
Diroximel fumarate (0.25g) and hydroxypropyl methylcellulose phthalate (0.75g) were dissolved in methanol and dichloromethane (1:1v/v) solvent mixture (50mL). The solution was stirred at about room temperature for about 15-20 minutes. The solution was filtered for particle free solution. The obtained clear solution was distilled off under high vacuum at about 50°C using rotavapour. The solid obtained was dried on rotavapour at about 50°C for about 30 minutes. Yield: 85%

[0118] EXAMPLE 7: Preparation of diroximel fumarate
A mixture of ethylene carbonate (47.38g), succinimide (49.5g) and triethylamine (10.11g) was heated at about 85°C to about 95°C for about 6h. The reaction mixture was cooled to about 50°C to about 60°C and concentrated. To the obtained residue, dichloromethane (150mL) was added (solution of 1-(2-hydroxyethyl)-2,5-pyrrolidinedione in dichloromethane). To a mixture of monomethyl fumarate (50g) in dichloromethane (350mL), was added sodium carbonate (52.96g), DMAP (2.5g) followed by the solution of 1-(2-hydroxyethyl)-2,5-pyrrolidinedione in dichloromethane. The reaction mixture was stirred for about 10min and p-toluenesulfonyl chloride (80.60g) was lot wise added to it. The reaction mixture was stirred for about 2h. Water was added to the reaction mixture and the two layers were separated. The organic layer was washed with water, dilute hydrochloric acid solution followed by water. The organic layer was concentrated under vacuum and degassed. To the obtained solid, ethyl acetate was added and the reaction mixture was heated to about 60°C to about 70°C. The reaction mixture was cooled to about 5°C to about 10°C and stirred it for about 3h. The reaction mixture was filtered, washed with ethyl acetate and dried. The solid was crystallized in ethyl acetate-methanol mixture. Yield: 60.9g; HPLC Purity: 100%
A mixture of diroximel fumarate (50g) in ethyl acetate (325mL) was heated at about 45°C to about 55°C for about 30min and filtered through micron filter. The filtrate was concentrated under vacuum up to about 150mL to about 160mL. The mixture was heated to about 60°C to about 70°C and stirred for 30min. The mixture was cooled to about 10°C to about 15°C and stirred for about 3h. The solid obtained was filtered, washed with ethyl acetate and dried under vacuum. Yield: 44g; HPLC Purity: 100%

[0119] EXAMPLE 8: Preparation of diroximel fumarate
To a mixture of monomethyl fumarate (17.26g) and 1-(2-hydroxyethyl)-2,5-pyrrolidinedione (20g) in toluene (200mL) was added p-toluenesulfonic acid (2g). The reaction mixture was heated to about 110°C to about 115°C. The water was removed azeotropically for about 12h. The reaction mixture was cooled to about 20°C to about 30°C. Water was added to the reaction mixture. The reaction mixture was stirred, filtered and washed with water. The solid obtained was dried at about 45°C to about 50°C. Yield: 10g

[0120] EXAMPLE 9: Preparation of impurity B
To a mixture of 1-(2-hydroxyethyl)-2,5-pyrrolidinedione (50g) in acetone (150mL), was added maleic anhydride (34.93g) followed by triethylamine (1.45g). The reaction mixture was heated to about 40°C to about 45°C for about 6h. The reaction mixture was cooled, filtered and washed with acetone. The solid was dried to give 52g of (2Z)-4-[2-(2,5-dioxopyrrolidin-1-yl)ethoxy]-4-oxobut-2-enoic acid.
To a mixture of (2Z)-4-[2-(2,5-dioxopyrrolidin-1-yl)ethoxy]-4-oxobut-2-enoic acid (10g) in dichloromethane (120mL), was added triethylamine (6.93mL). The reaction mixture was cooled to about 0°C to about 5°C. Methyl chloroformate (3.92g) was slowly added to the reaction mixture followed by DMAP (0.5g). The reaction mixture was stirred for about 60min. Water was added to the reaction mixture and the two layers were separated. The organic layer was concentrated under reduced pressure to give impurity B.

[0121] EXAMPLE 10: Preparation of diroximel fumarate
A mixture of ethylene carbonate (9.4g), succinimide (9.9g) and triethylamine (2g) was heated at about 80°C to about 85°C for about 12h. After the reaction was completed, the reaction mixture was cooled to about 60°C to about 65°C and concentrated under vacuum NLT 650 mmHg at about below 65°C for about 30min to obtain residue. To the obtained residue, dichloromethane (4mL) was added (solution of 1-(2-hydroxyethyl)-2,5-pyrrolidinedione in dichloromethane).
A mixture of monomethyl fumarate (1.2g) and sodium carbonate (1.05g) was stirred at about 20°C to about 30°C temperature for about 10min to about 15min. To this mixture, solution of 1-(2-hydroxyethyl)-2,5-pyrrolidinedione in dichloromethane and dimethyl amino pyridine (0.5g) was added at about 20°C to about 30°C temperature. To this reaction mixture, p-toluenesulfonyl chloride (16.1g) was added slowly at about 20°C to about 30°C temperature and stirred at about same temperature for about 2h. The reaction mixture was charged water at about 20°C to about 30°C temperature and stirred for about 30min. The two layers were separated and the organic layer was washed with dil. HCl solution. Activated carbon was added to the organic layer, the resulting solution was stirred for about 30min and was filtered through hyflo with dichloromethane washing. The filtrate was concentrated under vacuum at about 45°C and toluene was added to the obtained residue. The resulting mixture was stirred at about 70°C to about 80°C temperature for about 1h. The resulting mixture was cooled to about 20°C to about 30°C temperature and stirred at about the same temperature for about 2h. The resulting mixture was filtered, washed with toluene and dried under vacuum. Yield: 1.45g

[0122] EXAMPLE 11: Preparation of diroximel fumarate
A mixture of diroximel fumarate (1g) in acetone (4.5mL) was stirred to about 40°C to about 50°C temperature for about 30min. The resulting mixture was filtered through micron filter and washed with acetone (5mL). The filtrate was concentrated under vacuum. To the obtained residue, acetone (2mL) and DM water (8mL) was added at about below 35°C temperature. The resulting mixture was stirred at about 55°C to about 65°C temperature for about 30min. The resulting mixture was cooled to about 25°C to about 35°C temperature and stirred at about same temperature for about 3h. The resulting mixture was filtered and washed with DM water. The solid obtained was dried in VTD under vacuum NLT 650 mmHg at about 50°C to about 55°C temperature for about 6h. Yield: 0.8g.
XRPD table of crystalline diroximel fumarate:
Pos. [°2Th.] d-spacing [Å] Rel. Int. [%] Pos. [°2Th.] d-spacing [Å] Rel. Int. [%]
6.96 12.69 4.42 27.20 3.27 33.74
11.53 7.66 4.82 27.38 3.25 100.00
12.05 7.34 0.41 28.41 3.13 0.75
13.13 6.73 4.18 28.84 3.09 0.40
13.35 6.63 67.08 30.17 2.95 0.52
13.60 6.51 12.16 30.40 2.93 2.11
16.14 5.48 0.33 30.61 2.91 3.07
16.51 5.36 1.05 31.07 2.87 2.45
17.73 5.00 5.62 31.72 2.81 0.91
17.92 4.94 26.65 32.10 2.78 0.48
18.29 4.84 0.95 33.47 2.67 1.85
19.63 4.52 0.17 34.06 2.62 0.65
20.70 4.29 1.80 34.66 2.58 0.69
20.96 4.23 18.63 34.89 2.56 0.67
22.00 4.03 2.00 35.04 2.55 1.57
22.75 3.90 3.15 35.29 2.54 0.53
22.95 3.87 10.16 35.63 2.51 1.35
23.76 3.74 1.83 35.92 2.49 1.11
24.03 3.70 4.79 36.47 2.46 0.21
24.19 3.67 12.73 36.97 2.42 0.16
24.35 3.65 18.72 38.17 2.35 2.40
24.69 3.60 0.72 39.92 2.25 0.25
25.38 3.50 0.53 41.41 2.17 0.55
26.65 3.34 5.76 41.58 2.17 0.70
26.87 3.31 15.97 42.26 2.13 0.71
,CLAIMS:WE CLAIM

1] A process for the preparation of diroximel fumarate, a compound of formula I,
I
the process comprising:
(a) reacting maleic anhydride with methanol to give monomethyl maleate, a compound of formula IV;
IV
(b) reacting monomethyl maleate, the compound of formula IV with thionyl chloride to give monomethyl fumarate, a compound of formula II; and
II
(c) reacting monomethyl fumarate, the compound of formula II with a compound of formula III,
III
to give diroximel fumarate, the compound of formula I.

2] The process as claimed in claim 1, wherein in step (a), the molar ratio of maleic anhydride to methanol is in the range of about 1 to 0.70 to about 1 to 4 and wherein the reaction of maleic anhydride with methanol occurs at a temperature of about 20°C to about 100°C.

3] The process as claimed in claim 1, wherein the compound of formula IV obtained in step (a) is isolated and then reacted with thionyl chloride.

4] The process as claimed in claim 1, wherein in step (b), the molar ratio of the compound of formula IV to thionyl chloride is in the range of about 1 to 0.01 to about 1 to 1 and wherein the reaction of the compound of formula IV with thionyl chloride occurs at a temperature of about 50°C to about 100°C.

5] The process as claimed in claim 1, wherein the compound of formula II obtained in step (b) is in a purity of at least 99.0% and wherein the level of fumaric acid is less than 0.15%, as determined by HPLC.

6] The process as claimed in claim 1, wherein the reaction of the compound of formula II with the compound of formula III occurs in the presence of a coupling agent selected from the group consisting of TsCl, HBTU, EDCI, HOBt, COMU, TBTU, TATU, Oxyma, PyBOP, HOTT, FDPP, T3P, DMTMM, PyOxim, TSTU, TDBTU, TPTU, TOTU, IIDQ, PyCIU, and mixtures thereof.

7] The process as claimed in claim 1, wherein the reaction of the compound of formula II with the compound of formula III occurs in the presence of a base selected from the group consisting of diisopropylethylamine, trimethylamine, triethylamine, tributylamine, triphenylamine, pyridine, lutidine, collidine, imidazole, DMAP, DABCO, DBU, DBN, N,N,N',N'-tetramethyl-1,8-naphthalenediamine, lithium carbonate, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, and mixtures thereof.

8] The process as claimed in claim 1, wherein the diroximel fumarate obtained in step (c) is isolated from a solvent selected from the group consisting of esters, ketones, nitriles, water, and mixtures thereof.

9] The process as claimed in claim 1, wherein the diroximel fumarate is obtained in a purity of =99.0% and wherein the level of impurity A is less than 0.15%, as determined by HPLC,
A.

10] A process for the preparation of an amorphous solid dispersion of diroximel fumarate or salt thereof together with at least one pharmaceutically acceptable carrier, the process comprising:
(a) providing a solution or mixture of diroximel fumarate or salt thereof together with at least one pharmaceutically acceptable carrier in a solvent; and
(b) obtaining the amorphous solid dispersion of diroximel fumarate or salt thereof together with at least one pharmaceutically acceptable carrier from the solution or mixture of step (a).

Dated this 14th day of September, 2020

(Signed)___________________________________
DR. VARSHA SADEKAR
DEPUTY GENERAL MANAGER-IPM
GLENMARK LIFE SCIENCES LIMITED