DESC:Field of the Invention:
The present application relates to a process for the preparation of Siponimod
hemifumareate salt and intermediates thereof, which is represented by the following
5 structural formula-I.
10 Background of the Invention:
Siponimod, with the chemical name of l-(4-(l-((E)-4-cyclohexyl-3-tri-fluoro-methyl benzyl
oxy -imino)-ethyl)-2-ethyl-benzyl)-azetidine-3 -carboxylic acid, selective sphingosine-1 -
phosphate receptor modulator for the therapy of secondary progressive multiple sclerosis.
Siponimod fumaric acid as 2:1 co-crystal was approved by USFDA with the brand
15 name of MAYZENT on Mar 26, 2019 for the treatment relapsing forms of multiple sclerosis
(MS), to include clinically isolated syndrome, relapsing-remitting disease, and active
secondary progressive disease, in adults.
Siponimod base, its synthetic process and its pharmaceutical compositions are reported in
20 US patent No. 7939519 B2 (US '519). The process described in US '519 is schematically
represented below scheme-1.
US patent No. 8173634 B2 (US '634) describes crystalline polymorphic form A of
siponimod base and pharmaceutical compositions thereof.
25
3
Reaction scheme-1:
Siponimod hemifumarate salt and its pharmaceutical compositions are reported in
US patent application No. 20150175536 A1 (US„536).
The US„536 application also describes various 5 crystalline forms (Form-A, B, C, D
and E) of Siponimod hemifumarate salt and their pharmaceutical compositions.
There are various processes reported for the preparation of siponimod and salts
thereof, using different solvents and reagents.
Based on draw backs in the prior art processes, there is a need for providing an
10 improved process for the preparation of siponimod and salts thereof, which involves simple
experimental procedures, well suited to industrial production, which avoids the use of
4
column chromatography purification, and which affords high pure siponimod fumaric acid salts. The present invention provides an improved process for preparation of siponimod fumaric acid salt and intermediates thereof, which is efficient, industrially viable and cost effective. 5
Brief Description :
The first aspect of the present invention is to provide a process for the preparation of the compound of formula-I.
The second aspect of the present invention is to provide a process for the preparation of the compound of formula-2. 10
Detailed Description:
As used herein the term “suitable solvent” used in the present invention refers to “hydrocarbon solvents” such as n-hexane, n-heptane, cyclohexane, petether, toluene, pentane, cycloheptane, methyl cyclohexane, m-, o-, or p-xylene and the like; “ether solvents” such as dimethoxymethane, tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, furan, diethyl ether, ethylene 15 glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, anisole, t-butyl methyl ether, 1,2-dimethoxy ethane and the like; “ester solvents” such as methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate and the like; “polar-aprotic solvents such as dimethylacetamide (DMA), dimethylformamide (DMF), dimethylsulfoxide (DMSO), N-20 methylpyrrolidone (NMP) and the like; “chlorinated hydrocarbon solvents” such as dichloromethane, dichloroethane, chloroform, carbontetra chloride and the like; “ketone solvents” such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; “nitrile solvents” such as acetonitrile, propionitrile, isobutyronitrile and the like; “alcoholic solvents” such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, 2-25 nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 2-methoxyethanol, l,2-ethoxyethanol, diethylene glycol, 1, 2, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, or glycerol and the like; “polar solvents” such as water or mixtures thereof.
30
5
As used herein the present invention the term “suitable base” refers to inorganic or organic base. Inorganic base refers to “alkali metal carbonates” such as sodium carbonate, potassium carbonate, lithium carbonate and the like; “alkali metal bicarbonates” such as sodium bicarbonate, potassium bicarbonate and the like; “alkali metal hydroxides” such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; “alkali metal alkoxides” 5 such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert.butoxide, potassium tert-butoxide, lithium tert-butoxide and the like; alkali metal hydrides such as sodium hydride, potassium hydride, lithium hydride and the like; alkali metal amides such as sodium amide, potassium amide, lithium amide and the like; and organic bases such as like dimethylamine, diethylamine, diisopropyl amine, diisopropyl 10 ethylamine, diisobutylamine, triethylamine, pyridine, piperidine, 4-dimethyl amino pyridine (DMAP), N-methyl morpholine (NMM), or mixtures thereof.
The term “reducing” agent used in the present invention refers suitable reducing reagents are selected from lithium aluminium hydride, lithium tri-tert-butoxyaluminum 15 hydride, lithium triethylborohydride, potassium triethylborohydride, lithium borohydride, potassium boro hydride, sodium borohydride, BF3 etherate solution, Pd/C, Ray-nickel;
The term “protecting” agent / group (PG) used in the present invention refers to a suitable protecting reagents that are selected selected from di-tert-butyl dicarbonate, chlorobenzyl formate, benzoylchloride, benzylbromide, benzylchloride, acetylchloride, fluorenyl 20 methyloxy carbonyl chloride; The term “phase transfer catalyst (PTC)” used in the present invention refers are selected from triethylbenzyl ammonium chloride, tetrabutyl ammonium bromide, tetrabutyl ammonium chloride, tetrabutyl ammonium acetate, methyl tributyl ammonium chloride, tetrabutyl ammonium hydroxide, tributylbenzylammonium chloride;
25
The first aspect of the present invention provides a process for the preparation of compound of formula-I,
6
Comprising of:
a) Reacting 5 the compound of formula-2 or [2A]
with compound-1,
10 Formula-1
using suitable reagent, solvent to provide compound of formula-3,
15 Formula-3
7
b) oxidizing the compound of formula-3 with a suitable reagent, solvent to provide
compound of formula-4,
Formula-4
5
c) reacting the compound obtained in step-b) with compound of formula-5, in presence of
suitable reagent, solvent, base to provide compound of formula-6,
10 Formula-6
d) optionally purifying the compound obtained in step-c) with suitable solvent to provide
compound formula-I.
Wherein in step-a), b), c) and d) the suitable solvent is selected from hydrocarbon
15 solvents, chlorinated hydrocarbons solvents, ether solvents, nitrile solvents, ketone solvents,
ester solvents, polar aprotic solvents, alcoholic solvents, water or any mixture thereof;
Where is in step-a) the suitable reagents are selected from aq.HCl, HCl (g), HBr, trifluoro
acetic acid, an organic base such as triethylamine, diisopropyl ethylamine, diisopropyl amine
or an inorganic base and mixture thereof.
20 wherein in step-b) suitable reagents manganese dioxide, 2,2,6,6-Tetramethyl piperidinyloxy
(TEMPO), 2-iodoxybenzoic acid (IBX), sodium hypochlorite, inorganic base and mixture
thereof;
8
wherein in step-c) the suitable reagent is selected from sodium borohydride, sodium cyano
borohydride, sodium triacetoxy borohydride, potassium triethylborohydride, lithium boro
hydride, potassium borohydride and mixture thereof. fumaric acid, an organic base and
fumaric acid;
5 wherein in step-d) suitable solvent is selected from chlorinated hydrocarbons solvents, ether
solvents, nitrile solvent, ketone solvents, ester solvents, alcohol solvents, polar aprotic
solvents, or water any mixture thereof; suitable temperature 0-100°C.
The preferred embodiment of the present invention provides a process for the
preparation of compound of formula-I,
10
Comprising of:
a)Reacting the compound of formula-2b
with compound-1,
15
[1]
using HCl and triethylamine in methanol to provide compound of formula-3,
9
Formula-3
b)oxidizing the compound of formula-3 with manganese dioxide in n-heptane to provide
5 compound of formula-4,
Formula-4
c)reacting the compound obtained in step-b) with azitidine carboxylic acid the compound of
10 formula-5, in presence of sodium triacetoxy borohydride in methanol to provide siponimod,
in-situ treating with fumaric acid in methanol to provide compound of formula-6,
Formula-6
d) purifying the compound obtained in step-c) with dimethylsulfoxide, ethyl acetate and
15 water to provide compound formula-I.
The other aspect of the present invention in step-a) treating the compound of
formula-2A with suitable acid and further reacting in-situ with compound of formula- 1 to
obtain compound of formula -3.
The other aspect of the present invention in step-a) involves treating the compound of
20 formula-2A with suitable acid and the isolating compound of formula-2A, was further
10
reacting with compound of formula- 1 to obtained compound of formula -3. Optionally the
compound of formula-2A isolated as organic acid addition salt or inorganic acid addition salt.
The other aspect of the invention is isolation of compound of formula-2b and 2c has
more advantage in terms of isolation, solubility and deprotection of imine group over the
5 prior art related compounds.
[2b] [2c]
The other aspect of the present invention involves in-situ reaction of siponimod
10 obtained in step-c) treating with fumaric acid to obtain siponimod hemifumaric acid.
The other aspect of the present invention involves a process for purification of the
compound of formula-I
Comprising of,
a) Suspending siponimod hemifumarate in a suitable solvent,
15 b) adding anti solvent to the compound obtained in step-a) to provide solid compound,
c) isolating the compound obtained in step-b) to get the pure compound of formula-I.
Suitable solvent is selected from chlorinated hydrocarbons solvents, ether solvents, nitrile
solvent, ketone solvents, ester solvents, alcohol solvents, polar aprotic solvents, or water any
mixture thereof; suitable temperature 0-100°C.
20
The preferred embodiment of the present invention involves a process for purification of
the compound of formula-I
Comprising of,
a)Suspending siponimod hemifumarate in dimethyl sulfoxide and ethyl acetate,
25 b)adding purified water to the solution obtained in step-a) to provide solid compound,
c)isolating the compound obtained in step-b) to get the pure compound of formula-I.
11
The present invention described as follows in a schematic representation:
As present invention used compound-5 1 in the preparation of siponimod, various
processes for compound of formula-1 are known in the art in US793519B2 and ACS
Medicinal Chemistry Letters, 4, 3, 333-337, 2013.
The second aspect of the present invention provides a process for the preparation of
compound of formula-2A or its acid addition salts, which is a key starting compound for the
10 preparation of siponimod.
12
The present invention described as follows in a schematic representation:
Scheme-2:
5 Scheme-3:
Compound of formula-11;
10
The present invention used a compound of formula-2 in the preparation of siponimod,
various processes are known in the art for the preparation compound of formula-2. There are
13
various processes are reported in the art for the preparation of compound of formula--10.
The process for the preparation of siponimod hemifumarate developed by the present inventors produces highly pure with good yield. All the related substances and residual solvents are controlled well within the limits as suggested by ICH guidelines and most of the related substances are controlled in non-detectable levels. 5
The compound of formula-I produced by the process of the present invention is
having purity of greater than 99.5%, preferably greater than 99.7%, more preferably greater than 99.9% by HPLC.
The process described in the present invention was demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not 10 be construed as limitation of the scope of the invention.
Examples:
Example-1: Preparation of compound of formula-7b. (propan-2-one o-4-chloro-3-(trifluoro methyl)benzyl oxime)
A round bottom flask was charged with compound of formula--6 ( 1 eq) propan--2--one oxime 15 (1.2 eq) in dry DMF (25 mL) followed by potassium tert --butoxide (1.2 eq) and the reaction mixture was heated to 50--60 °C and stirred for 3 hr. The reaction mixture was quenched with water (250 mL) and extracted with ethyl acetate (200 mL) and separated the layers. The aqueous layer was further extracted with EtOAc (100 mL), the combined organic layer was washed with brine and dried over anhydrous Na2SO4 and concentration to get the title 20 compound.
Yield: 20 g
Example-2: Preparation of compound of formula-2b (propan-2-one-o-4-cyclohexyl-3-(tri fluoromethyl)benzyl oxime)
A round bottom flask was charged with ZnCl2 (1.25 eq), NMP (150 mL) and heated to 100oC 25 and the resulting solution was allowed to cool to 25-35°C. Cyclo hexyl magnesium chloride (1.01 eq) was slowly added to the reaction mixture and stirred at 80oC for 2 hr. The reaction mixture was cooled, added compound of formula- 7B (1 eq) and Pd(PBut3)2 (catalyst 0.01 %) was flushed with argon and the mixture was then heated to 140°C -150°C and stirred for 1 h. Cooled the reaction mixture, partitioned between aqueous HCl (70 mL) and ethyl acetate 30
14
(100 mL) The aqueous layer was extracted with ethyl acetate, the combined organic layer was washed with brine and dried over sodium sulphate and concentrated to get the title product.
Yield: 25.5 g
Example-3: Preparation of compound of formula-2A as HCl salt ( o-(4-cyclohexyl-3-5 (trifluoro methyl) benzyl)hydroxylamine hydrochloride salt)
A round bottom flask was charged with propan-2-one-o-4-cyclohexyl-3-(trifluoro methyl) benzyl oxime) compound of formula-2b (100 g) in methanolic HCl (250 mL) and stirred at 50--55°C for 1 hr . The reaction mixture was cooled and evaporated the solvent . The resulting solution was stirred for 30 min, filtered the obtained solid and dried to get the title 10 compound.
Yield: 78.5 g
Example-4: Preparation of compound of formula-3.
A round bottom flask was charged with propan-2-one-o-4-cyclohexyl-3-(trifluoromethyl) benzyl oxime compound of formula-2b (100 g), methanol (500 mL) and Conc. HCl (45 mL) 15 stirred for 1.5 hr at 25--35°C. The reaction mixture was cooled, adjusted the pH upto 4.0 using triethylamine (68.6 mL) and stirred for 10 min. To the reaction mixture a solution of compound--3 (50 g) in methanol (200 mL) was added and stirred for 20 hr at 35--45°C. The reaction mixture was evaporated, charged with ethyl acetate (700 mL), water (300 mL) stirred for 30 min. The both layer were separated, the organic layer was washed with sodium 20 bicarbonate solution, brine solution and evaporated the solvent and dried to get the title compound.
Yield: 108. 2 g
Example-5: Preparation of compound of formula-4
A round bottom flask was charged with compound of formula--3 (100 g), heptane (500 mL) 25 and manganese dioxide (100.2 g) and stirred at 45-55° C for 7 hr. Charged second lot of manganese dioxide (100 .2 g) to the reaction mixture and stirred for 7 hr at 45-55°C. Charged the same quantities of manganese dioxide in lot-3 and lot-4 and stirred for 7 h at 45-55°C. Cooled the reaction mixture to 20-30°C, filtrated through celite bed, washed with heptane ( 200 mL), the filtrate solution was dried and evaporated to dryness to get crude compound. 30
15
The crude compound was suspended in a mixture of isopropanol (150 mL), water (4.5 mL) at 55--65°C stirred for 1 hr. Cooled the solution to 5--15°C, stirred for 30 min and filtered the obtained solid, washed with isopropanol (50 mL) and dried for 13 hr at 50--60°C, to get the title compound.
Yield: 91.5 g. 5
Example-6: Preparation of compound of formula-6.
A round bottom flask was charged with compound of formula--4 (100 g), compound of formula--5 (33.47 g) in methanol (1733 mL) and stirred for 30 min at 25--35°C. Cooled the reaction to 5--10°C, added sodium triacetoxy borohydride (94.7 g) in portion wise in about 2 10 hr and stirred for 1 hr at 25--35°C. The reaction mixture solvent was distilled, the obtained crude compound was diluted with water (714 mL) ethyl acetate (14.5 mL) and stirred for 30 min. The solution pH was adjusted to 6.0 with sodium hydroxide solution (10 mL) and stirred for 15 min. The both layers were separated, and organic layer was washed with water (2 x 330 mL), and dried the organic layer over sodium sulphate evaporated to get the residue 15 crude compound. The obtained compound was dissolved in ethanol (25.5 mL), and fumaric acid (13.44 g) and ethanol (450 mL) stirred for 1 hr at 45--55 °C. Cooled the reaction solution to 25--35°C and stirred for 13 hr, filtered the obtained solid and dried to get the title compound .
Yield: 101.5 g 20
Purity by HPLC: >99.5 %
Example-7: Preparation of compound of formula-I
A round bottom flask was charged with compound of formula--6 (100.0 g), DMSO (500 mL) stirred for 20 min. Ethyl acetate (500 mL) was charged to the reaction mixture, heated to 45--55°C and stirred for 45 min. Filtered the solution in hot condition, the filtrate solution was 25 gradually cooled to 25--35°C and stirred for 12 hr. Filtered the obtain solid, washed with ethyl acetate (200 mL) and dried at 60--65°C for 12 hr to get the title compound.
Yield: 93 g
Example-8: Preparation of compound of formula-I
A round bottom flask was charged with compound of formula--6 (65.0 g), tetrahydrofuran 30 (520 mL) stirred for 20 min. Ethyl acetate (195 mL) was charged to the reaction mixture,
16
heated to 45--55°C and stirred for 45 min. The solution was gradually cooled to 25--35°C and stirred for 6 hr. Filtered the obtained solid, washed with ethyl acetate (200 mL) and dried at 60--65°C for 12 hr to get the title compound.
Yield: 54.8 g
Example-9: Preparation of compound of formula-9. 5
A round bottom flask was charged with bromocyclohexane (1 eq), FeCl3 ( 5 mol % in THF solution) and TMEDA (1.1 eq) and stirred for 30 mint at 25--35°C. A freshly prepared Grignard reagent solution (2--(trifluoromethyl)phenyl)magnesium bromide (1.1 eq in THF ) was added portion wise to the above reaction mixture and stirred for 1 hr at 35--45°C. The reaction mixture was cooled and diluted with dil HCl (100 mL) and filtered the unwanted 10 solid. The filtrate solution was extracted with ethyl acetate (150 mL), again the aqueous layer was extracted with ethyl acetate (50 mL) and the combined organic layer was dried and evaporated to get the title compound.
Yield 45 g .
Example-10: Preparation of compound of formula-10a (4-(chloromethyl)-1-cyclohexyl-15 2-(trifluoromethyl)benzene)
A round bottom flask was charged with concentrated sulfuric acid (8 eq), was cooled to 0 --5°C, and thionyl chloride ( 2 eq) was added and stirred at same temperature for 30 min. To the resulting mixture was added 1,3,5--trioxane ( 1.5 eq) in portion wise (126.5 g) while the internal temperature was maintained below -5 °C . The compound of formula--9 (1 eq) was 20 added dropwise to the reaction mixture at 0 °C and warmed to 15--25 °C stirred for 24 hr. The reaction mixture was cooled to -5 to 5 °C and quenched by the slow (Caution! exothermic) addition of water (10 V) with stirring while the internal temperature was maintained below 15 °C. The aqueous slurry was extracted with MTBE (350 mL) . The combined MTBE layers were washed with a mixture of saturated sodium bicarbonate and brine followed by water. 25 The organic layer was dried over anhydrous sodium sulphate and filtered, and the solvent was removed under reduced pressure to give the crude title product
Yield: 25.8 g
Example-11: Preparation of compound of formula-2b. (propan-2-one O-4-cyclohexyl-3-(trifluoro methyl) benzyl oxime)) 30
17
A round bottom flask was charged with (4-(chloromethyl)-1-cyclohexyl-2-(trifluoro methyl)benzene) compound of formula-10a ( 1 eq) and propan--2--one oxime (1.2 eq) in acetonitrile (100 mL ) followed by cesium carbonate (1.2 eq) and the mixture was stirred at 20--30°C for 2 hr. The reaction mixture was heated to 50--60 °C and stirred for 3 hr. The reaction mixture was quenched with water (250 mL) and extracted with ethyl acetate (200 5 mL) and separated the layers. The aqueous layer was further extracted with ethyl acetate, the combined organic layer was washed with brine and dried over anhydrous sodium sulpahte and concentrated to get the title compound.
Yield: 35.6 g
Example-12: Preparation of compound of formula-2a (tert-butyl 4-cyclohexyl-3-(tri 10 fluoro methyl)benzyloxycarbamate)
A round bottom flask was charged with (4-(chloromethyl)-1-cyclohexyl-2-(trifluoro methyl)benzene) compound of formula-10 a ( 1 eq) and tert--butyl hydroxycarbamate (1.2 eq) in DMF (25 mL) followed by potassium carbonate (1.2 eq) and the mixture was stirred at 20--30°C for 1 hr. The reaction mixture was heated to 50--60 °C and stirred for 5 hr. The 15 reaction mixture was quenched with water (250 mL) and extracted with dichloromethane (200 mL) and separated the layers. The aqueous layer was further extracted with dichloro methane (50 mL), the combined organic layer was washed with brine and dried over anhydrous sodium sulphate and concentrated to get the title compound.
Yield: 25.8 g 20
Example-13: Preparation of compound of formula-I (crystalline form-B )
A round bottom flask was charged with compound of formula--I (10.0 g), tetrahydrofuran (100 mL) and stirred at 55--65°C for 1 hr. The reaction mixture was distilled off completely and dried at 60--65°C for 2 hr to get the title compound. The obtained PXRD is similar to the crystalline form--B of siponimod hemifumarate. 25
Yield: 8.5 g
Example-14: Preparation of Siponimod from siponimod hemifumatrate
A round bottom flask was charged with compound of formula--I (10.0 g), water (50 mL), ethylacetate (50 mL) the suspension was stirred for 10 min. The solution was basified upto the pH 6.5 with sodium hydroxide solution, and separated the ethyl acetate layer. The organic 30
18
layer was washed with water and dried over sodium sulphate, evaporated the solvent to get the title compound.
The obtained PXRD is similar to the crystalline form--A of siponimod.
Yield: 8.5 g
Example-15: Preparation of compound of formula-4. 5
A round bottom flask was charged with propan-2-one-o-(4-cyclohexyl-3-(trifluoromethyl) benzyl) oxime compound of formula-2b (100 g), methanol (500 mL) and Conc. HCl (300 mL) stirred for 30 min. The reaction mixture was distilled off completely, the reaction mixture was charged with methanol (500 mL) and Con HCl (300 mL) and stirred for 15 min and distilled off completely. The reaction mixture was cooled, adjusted the pH upto 4.0 using 10 triethylamine (50 mL) and stirred for 15 min. To the reaction mixture, a solution of compound--3 (54.03 g in 200 mL of methanol) was added and stirred for 12 hr at 35--45°C. Triethyl amine (18 mL) was added to the reaction mixture to maintain pH between 3.0 to 4.0 and stirred for 6 hr and distilled off completely. Ethyl acetate (100 mL), water (100 mL) were charged to the reaction mixture and stirred for 20 min and separated the both layers.The 15 aqueous layer was charged with ethyl acetate (700 mL) and separated the layer, the combined layers were washed with sodium bicarbonate solution, brine solution and evaporated the solvent and co--distilled with n--heptane (100 mL) to obtain the compound--3.
The obtained compound was charged with heptane (500 mL) and manganese dioxide (228.85 g) was charged portion wise in about 18 hr. Filtered the reaction mixture through hyflow bed 20 washed with heptane ( 200 mL).The unwanted wet cake was washed with n-heptane for several times (4 x 350 mL) and the combined filtrates were distilled off completely. The obtained compound was charged with isopropyl alcohol (300 mL), water (4.5 mL) and stirred for 15 min at 25-35°C and 30 min at 45-55°C. The reaction mixture was cooled, and filtered the solution and washed with isopropanol (50 mL) and dried for 8 hr at 50--60°C to get the 25 title compound.
Yield: 95.5 g.
Example-16: Preparation of compound of formula-6.
A round bottom flask was charged with compound of formula--4 (100 g), compound of formula--5 (33.9 g) in methanol (1700 mL) and stirred for 30 min. Cooled the reaction to 10--30 20°C, added sodium triacetoxy borohydride (98.24 g) portion wise in about 2 hr and stirred
19
for 1 hr at 25--35°C. The reaction mixture solvent was distilled off completely and co--distilled with ethyl acetate (100 ml). The obtained crude compound was diluted with water (700 mL) ethyl acetate (1400 mL) and the solution pH was adjusted to 6.0 with aq.sodium hydroxide solution (60 g in 600 mL of water) and stirred for 15 min. The both layers were separated, the aqueous layer was extracted with ethyl acetate (200 mL) and separated. The combined 5 organic layer was washed with water (350 mL) and dried the organic layer over sodium sulphate and evaporated to get the residue crude compound. The obtained compound was dissolved in ethanol (100 mL), and added to a solution of fumaric acid (13.4 g in 450 mL of ethanol ), stirred for 1 hr at 45--55 °C. Cooled the reaction solution and stirred for 13 hr, filtered the obtained solid washed with ethanol (50 mL) and dried . The obtained wet 10 compound was charged with methanol (1 L) and stirred for 30 min at 58--68°C and 12 h at 25--35°C and filtered the obtained solid and washed with (100 mL). The obtained wet compound was charged with dimethyl sulfoxide (400 mL) and ethyl acetate (400 mL) and stirred for 15 min at 35--45°C. Charged activated carbon (10 g) and stirred for 30 min at 35--45°C. Filtered the reaction mixture and washed with ethyl acetate (100 mL), dimethyl 15 sulfoxide (100 mL) separately. Purified water (500 mL) was added slowly to the above filtrate solution and stirred for 6 hr at 25--35°C. Filtered the obtained solid, washed with water (100 mL) and dried to get the title compound.
Yield: 76.1 g
HPLC >99.70 %; HIUI: 0.05% 20
Example-17: Purification of compound of formula-I (Form-A)
A round bottom flask was charged with compound of formula--6 (100.0 g), dimethylsulfoxide (400 mL) stirred for 20 min. Ethyl acetate (400 mL) was charged to the reaction mixture, heated to 45--55°C and stirred for 45 min. Charged activated carbon (10 g) and stirred for 30 min at 35--45°C and filtered the reaction mass through celite bed and washed with DMSO 25 (100 mL) and ethyl acetate (100 mL). Purified water (500 mL) was added slowly to the filtrated solution and stirred for 12 hr. Filtered the obtained solid, washed with water (100 mL) and dried to get the title compound.
Yield: 97.5 g
30
20
Example-18: process for preparation of (4-bromo-2-ethylphenyl)methanol A round bottom flask was charged with 4-bromo-2-ethyl-benzaldehyde (50 g) in methanol (350 mL) and stirred for 30 min. Cooled the reaction mixture, sodiumborohydride (15 g) was added portion wise in over 30 min and the resulting mixture was gradually warmed up to 25-35°C and stirred. The reaction mixture was quenched with slow addition of ammonium 5 chloride (25 g in 150 mL of water) and charged ethyl acetate (3x100 mL) stirred for 15 min. Separated the both layers, the aqueous layer was extracted with ethyl acetate (50 mL), the combined organic layer was washed with water (50 mL), brine solution and dried over sodium sulphate. The solvent was distilled off completely to afford the title product.
Yield: 43.5 g 10 Example-19: process for preparation of 2-[(4-Bromo-2-ethylbenzyl)oxy]tetrahydro-2H-pyran A round bottom flask was charged with (4-bromo-2-ethylphenyl)methanol (25 g), dichloromethane (420 mL) stirred at 25-35°C for 15 min. To the solution pyridinium p-toluenesulfonate (3.5 g) and 3,4-dihydro-2H-pyran (25 mL) were added slowly and stirred at 15 25-35°C for 16 h. The reaction mixture was diluted with water (100 mL), separated both the layers. The aqueous layer was extracted with dichloromethane (100 mL) and the combined organic layer was dried with sodium sulfate and distilled off to get the title compound.
Yield: 23.5 g
Example-20: process for preparation of compound of formula-1. 20 A round bottom flask was charged with 2-[(4-Bromo-2-ethylbenzyl)oxy]tetrahydro-2H-pyran (20 g), tetrahydrofuran (100 mL) and stirred for 15 min. To the solution magnesium turnings (2.5 g) and isopropyl magnesium chloride tetrahydrofuran solution ( 10 mL ) were added and stirred at 25--35°C for 4 hr . Acetic anhydride ( 1.5 V) was added drop wise to the reaction mixture and stirred for 6 hr . The reaction mixture was quenched with Con. HCl (10 25 mL) and stirred for 2 hr. The reaction mixture was cooled to 25--35°C, charged with water (100 mL) and ethyl acetate (100 mL) stirred for 1 hr. The both layers were separated, the aqueous layer was extracted with ethyl acetate (2 x 50 mL). The combined organic layer was dried over sodium sulfate and distilled off and purified using n--heptane (50 mL) to get the title compound. 30
21
Yield: 18.7 g
Example-21: Preparation of crystalline form-C of Siponimod hemifumarate
A round bottom flask was charged with compound of formula--I (1 g), ethanol: water (5 mL: 9:1) heated to 60--65°C and the suspension was stirred for 30 min. The solution was charged with heptane (5 mL) at same temperature and isolated the obtained solid and dried to get the 5 title compound .
Yield: 0.85 g ,CLAIMS:We claim:
1. A process for preparation of compound of formula-I,
5 Comprising of:
a)Reacting the compound of formula-2 or [2A]
Where R is defined in the schematic representation
with compound-1,
10
Compound-1
using suitable reagent, solvent to provide compound of formula-3,
15 Formula-3
23
b)oxidizing the compound of formula-3 with a suitable reagent, solvent to provide compound
of formula-4,
Formula-4
c)reacting the compound obtained in step-b) 5 with compound of formula-5, in presence of
suitable reagent , solvent, base to provide compound of formula-6,
Formula-6
10
d)optionally purifying the compound obtained in step-c) with suitable solvent to provide
compound formula-I.
2. A process for preparation of compound of formula-I as claimed in claim 1
Wherein in step-a), b), c) and d) the suitable solvent is selected from hydrocarbon solvents,
15 chlorinated hydrocarbons solvents, ether solvents, nitrile solvents, ketone solvents, ester
solvents, polar aprotic solvents, alcoholic solvents, water or any mixture thereof;
Where is in step-a) the suitable suitable reagents are selected from aq.HCl, HCl (g), HBr,
trifluoro acetic acid, an organic base such as triethylamine, diisopropyl ethylamine,
diisopropyl amine or an inorganic base and mixture thereof.
20 wherein in step-b) suitable reagents manganese dioxide, 2,2,6,6-Tetramethyl piperidinyloxy
(TEMPO), 2-iodoxybenzoic acid (IBX), sodium hypochlorite, inorganic base and mixture
thereof;
24
wherein in step-c) the suitable reagent is selected from sodium borohydride, sodium cyano
borohydride, sodium triacetoxy borohydride, potassium triethylborohydride, lithium boro
hydride, potassium borohydride and mixture thereof. fumaric acid, an organic base and
fumaric acid;
5 wherein in step-d) suitable solvent is selected from chlorinated hydrocarbons solvents, ether
solvents, nitrile solvent, ketone solvents, ester solvents, alcohol solvents, polar aprotic
solvents, or water any mixture thereof; suitable temperature 0-100°C.
3.A process for the preparation of compound of formula-I,
Comprising of:
10 a)Reacting the compound of formula-2b with compound-1,
using HCl and triethylamine in methanol to provide compound of formula-3,
15 Formula-3
b)oxidizing the compound of formula-3 with manganese dioxide in n-heptane to provide
compound of formula-4,
Formula-4
25
c)reacting the compound obtained in step-b) with azitidine carboxylic acid the compound of
formula-5, in presence of sodium triacetoxy borohydride in methanol to provide siponimod,
in-situ treating with fumaric acid in methanol to provide compound of formula-6,
5 Formula-6
d) purifying the compound obtained in step-c) in dimethyl sulfoxide, ethyl acetate and water
to provide compound formula-I.
4. A process for purification of the compound of formula-I
Comprising of;
10 a)Suspending siponimod hemifumarate in a suitable solvent,
b)adding anti-solvent to the solution obtained in step-a) to provide solid compound,
c)isolating the compound obtained in step-b) to get the pure compound of formula-I.
5. A process for preparation of compound of formula-I as claimed in claim 4
suitable solvent is selected from chlorinated hydrocarbons solvents, ether solvents, nitrile
15 solvents, ketone solvents, ester solvents, alcohol solvents, polar aprotic solvents, or water any
mixture thereof; suitable temperature 0-100°C.
6. A Process for preparation of crystalline form-A of the compound of formula-I
Comprising of;
a)Suspending siponimod hemifumarate in a dimethyl sulfoxide and ethyl acetate,
20 b)adding purified water to the solution obtained in step-a) to provide solid compound,
c)isolating the compound obtained in step-b) to get the pure compound of formula-I as form-
A.
7. The compound of formula-I obtained according to any of preceding claims having purity
> 95%, preferably > 99% by HPLC.