DESC:Field of the Invention:
The present application relates to an alternative process for Etrasimod L-Arginine and
intermediates thereof, is represented by the following structural formula-I.
5
Formula-I
Background of the Invention:
Etrasimod approved as L-Arginine, having chemical name of (3R)-7-[[4-cyclopentyl-3-
10 (trifluoro ethyl)phenyl]methoxy]-1,2,3,4- tetrahydro cyclopent [b] indole-3-acetate (1:1), is a
sphingosine 1-phosphate receptor modulator indicated for the treatment of moderately to
severely active ulcerative colitis in adults. Etrasimod as L-Arginine with the brand name of
VELSIPITY™ approved in US by Pfizer in the form of tablet.
15 The US patent US8580842B2 is first reported as etrasimod generically and
specifically as pharmaceutically acceptable salts. The patent US’842 disclosed various
processes for intermediates of etrasimod. The said patent reported purification of etrasimod
by chiral prep HPLC to get the desired isomer of etrasimod.
The US patent US8853419B2 reported an alternative process for preparation of
20 intermediates of etrasimod and intermediates thereof. The said patent reported enzymatic
process for to get the chiral isomers of etrasimod.
The US patent US1030126B2 reported various salts for etrasimod and process
thereof.
Based on drawbacks in the prior art process and certain limitations, there is a need for
25 providing an improved process for the preparation of etrasimod, which involves simple
3
experimental procedures, well suited to industrial production, which avoids the use of chiral preparative HPLC, column chromatography purification, and which affords highly pure etrasimod. The present invention provides an alternative process for preparation of etrasimod and intermediates thereof and free from other impurities or isomers and nitroso amine 5 impurities. The present invention involves cost effective key starting material, reagents and solvents, and suitable industrial production.
Brief Description: The first aspect of the present invention is to provide an alternative process for (3R)-7-[[4-cyclopentyl-3-(trifluoromethyl)phenyl] methoxy]-1,2,3,4- tetrahydro cyclopent 10 [b]indole -3-acetate, L-Arginine compound of formula-1 The second aspect of the present invention is to alternative process for (3R)-7-[[4-cyclopentyl-3-(trifluoromethyl)phenyl] methoxy]-1,2,3,4- tetrahydro cyclopent [b]indole-3-acetate compound of formula-3.
Brief description of the drawings: 15 Figure 1: Illustrates the PXRD pattern of crystalline form of (3R)-7-[[4-cyclopentyl-3-(trifluoro methyl)phenyl] methoxy]-1,2,3,4- tetrahydro cyclopent [b]indole -3-acetate, L-Arginine compound of formula-1 Figure 2: Illustrates the DSC of crystalline form of (3R)-7-[[4-cyclopentyl-3-(trifluoro methyl)phenyl] methoxy]-1,2,3,4- tetrahydro cyclopent [b]indole -3-acetate, L-20 Arginine compound of formula-1
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, pet ether, toluene, pentane, cycloheptane, methyl cyclohexane, m-, o-, or p-xylene and the like; “ether solvents” 25 such as dimethoxymethane, tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, furan, diethyl ether, ethylene 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 30
4
dimethylacetamide (DMA), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N-methyl pyrrolidone (NMP) and the like; “chloro solvents” such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride 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 5 methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 2-methoxyethanol, l,2-ethoxy ethanol, 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. 10
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 15 alkoxides” 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 20 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 aluminum hydride, sodium borohydride, BF3 etherate solution, Pd/C, Raney-nickel. 25 The first aspect of the present invention is to provide an alternative process for (3R)-7-[[4-cyclopentyl-3-(trifluoromethyl)phenyl] methoxy]-1,2,3,4- tetrahydro cyclopent [b] indole -3-acetate, L-Arginine compound of formula-I
5
Comprising of:
a) reacting compound of formula-1 in presence of lipase and hydrolyzing, in solvent to
provide compound of formula-2.
5
b) reacting the compound of formula-2 with compound of formula-A with suitable reagent,
solvent to provide compound of formula-3,
c) reacting the compound of formula-3 with L-arginine, solvent to provide compound of
10 formula-I
d) optionally purifying the compound of formula-I with suitable reagent, solvent to provide
pure compound of formula-I.
Wherein in step-a), b), c), and d) the suitable solvent is selected from hydrocarbon solvents,
chloro solvents, ether solvents, polar aprotic solvents, polar protic solvents, ester solvent,
15 nitrile solvent, ketone solvent, alcohol solvent, water or any mixture thereof; the suitable
temperature is 0-150°C.
Wherein in step-a) suitable liphase is selected from the group consisting of lipase B Candida
Antarctica, lipase Mucor miehei, and fluorescens, menhaden oil, tuna oil and borage oil,
6
pancreatic lipase, Aspergillus niger, rhizomucor delemar, rhizomucor miehei, and Mucor
javanicus, phosphate buffer and mixture thereof. The hydrolyzing-step solvent comprises
dimethyl formamide, dimethylacetamide, dimethyl sulfoxide, tetrahydrofuran, chloro
solvents, ether solvents, polar aprotic solvents, polar protic solvents, ester solvent, nitrile
5 solvent, ketone solvent, alcohol solvent, water or any mixture thereof.
Wherein in step-b) suitable reagents is selected inorganic base, organic base and mixture
thereof; Wherein in step-d) suitable reagents is selected from HCl, HBr, Acetic acid, trifluoro
acetic acid, citric acid, malic acid, para toluene sulfuric acid, tartaric acid, formic acid,
fumaric acid, organic base, inorganic base and mixture thereof.
10 The preferred embodiment of the present invention is to provide an alternative
process for (3R)-7-[[4-cyclopentyl-3-(trifluoromethyl)phenyl] methoxy]-1,2,3,4- tetrahydro
cyclopent [b] indole -3-acetate, L-Arginine compound of formula-I
Comprising of:
15 a) reacting compound of formula-1 with CALB (Candida antarctica lipase B) enzyme in
MTBE, potassium buffer solution to provide compound of formula-2,
b) esterifying the compound of formula-2 with Candida antarctica lipase B, ADDZYME in
MTBE, triethyl orthoformate, ethanol to provide compound of formula-2a,
7
c) reacting the compound of formula-2a with compound of formula-A in presence of cesium
carbonate in acetonitrile to provide compound of formula-3a,
a) hydrolyzing the c 5 ompound of formula-3a with LiOH in dioxane, water to provided
compound of formula-3,
b) reacting the compound of formula-3 with L-arginine in IPA, water to provide compound
of formula-I
The other preferred embodiment of the present invention is to provide an alternative
10 process for (3R)-7-[[4-cyclopentyl-3-(trifluoromethyl)phenyl] methoxy]-1,2,3,4- tetrahydro
cyclopent [b] indole -3-acetate, L-Arginine compound of formula-I
Comprising of:
a) reacting compound of formula-1a with CALB (Candida antarctica lipase B) enzyme in
15 MTBE, potassium buffer solution, ethanol to provide compound of formula-2a,
8
b) reacting the compound of formula-2a with compound of formula-A in presence of cesium
carbonate in acetonitrile to provide compound of formula-3a,
c) hydrolyzing the c 5 ompound of formula-3a with LiOH in dioxane, water to provided
compound of formula-3,
d) reacting the compound of formula-3 with L-arginine in IPA, water to provide compound
of formula-I.
10 The other preferred embodiment of the present invention is to provide an alternative
process for compound of formula-3
Comprising of:
a) reacting compound of formula-1a with suitable reagents, solvents to provide compound of
formula-2b,
15 (where in R: H, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl; R’ is H)
9
b) reacting the compound of formula-2b with compound of formula-A in presence of suitable
reagent, solvents to provide compound of formula-3b,
c) hydrolyzing the compound of formula-3b with suitable reagents, solvents to provided
5 compound of formula-3,
d) reacting the compound of formula-3 with L-arginine in IPA, water to provide compound
of formula-I.
Wherein in step-a), b), c), and d) the suitable solvent is selected from hydrocarbon solvents,
10 chloro solvents, ether solvents, polar aprotic solvents, polar protic solvents, ester solvent,
nitrile solvent, ketone solvent, alcohol solvent, water or any mixture thereof; the suitable
temperature is 0-150°C.
Wherein in step-a) suitable reagent are selected from the group consisting of lipase
B Candida Antarctica, lipase Mucor miehei, and fluorescens, menhaden oil, tuna oil and
15 borage oil, pancreatic lipase, Aspergillus niger, rhizomucor delemar, rhizomucor miehei, and
Mucor javanicus, phosphate buffer and mixture thereof; further, the suitable reagents are
selected from thionyl chloride, oxalyl chloride, sulfuric acid, diethyl sulfate, The
hydrolyzing-step solvent comprises dimethyl formamide, dimethylacetamide, dimethyl
sulfoxide, tetrahydrofuran, chloro solvents, ether solvents, polar aprotic solvents, polar protic
20 solvents, ester solvent, nitrile solvent, ketone solvent, alcohol solvent, water or any mixture
thereof.
Wherein in step-b) suitable reagents is selected inorganic base, organic base and mixture
thereof; Wherein in step-c, d) suitable reagents is selected from HCl, HBr, acetic acid,
10
trifluoro acetic acid, citric acid, malic acid, para toluene sulfuric acid, tartaric acid, formic
acid, fumaric acid, organic base, inorganic base and mixture thereof.
The other preferred embodiment of the present invention is to provide a process for
5 the preparation of compound formula-2a
comprising of:
a) reacting compound of formula-2 with suitable reagent, solvent to provide compound of
formula-2.
10
Wherein is the suitable reagents are thionyl chloride, oxalyl chloride, sulfuric acid, diethyl
sulfate, organic base, inorganic base, the suitable solvent is selected from hydrocarbon
solvents, chloro solvents, ether solvents, polar aprotic solvents, polar protic solvents, ester
15 solvent, nitrile solvent, ketone solvent, alcohol solvent, water or any mixture thereof; the
suitable temperature is 0-150°C.
The other aspect of the present invention is to provide a purification process for
compound of formula-I
Comprising of
20 a) stirring compound of formula-I in a suitable solvent at suitable temperature,
b) optionally adding anti solvent to the solution obtained in step-a) and stirring at suitable
temperature,
c) isolating the compound obtained in step-a) or step-b) to get the pure compound of
11
formula-I.
Wherein in step-a to c) the suitable solvent is selected from hydrocarbon solvents, chloro
solvents, ether solvents, polar aprotic solvents, polar protic solvents, ester solvent, nitrile
solvent, ketone solvents, alcohol solvent, water or any mixture thereof; the suitable
5 temperature is 0-100°C.
The compound of formula-I produced by the process of the present invention has
purity of at least about 95%; preferably of at least about 97%; more preferably of at least 20
about 98%; most preferably of at least about 99% as measured by HPLC.
The other isomer of compound of formula-I is having preferably < 0.5 %, more
10 preferably < 0.15 %; and other related impurities are preferably < 0.5 %, more preferably <
0.15 % in compound of formula-I of the present invention.
The process of the present invention can be represented schematically as follows:
Scheme-1:
15
The other aspect of the present invention is to provide a process for compound of
formula-2 (R ' : methyl, ethyl, propyl, H)
12
The other aspect of the present invention is to provide a process for compound of
formula-5 (R ' : methyl, ethyl, propyl, H)
5
R: H, Me, Ethyl, propyl, Isopropyl, t-butyl, benzyl, phenyl, benzoyl, acetyl, CBZ,
trialkyl, silyl, alkyl aryl silyl, di-tert-butyl dicarbonate.
The other aspect of the present invention is to provide a process for compound of
formula-5
10
R: H, Me, Ethyl, propyl, Isopropyl, t-butyl, benzyl, phenyl, benzoyl, acetyl, CBZ
The suitable chiral reagents are (S)-(-)-a-(1-Naphthyl)ethylamine, (R)-(-)-a-(1-Naphthyl)
ethylamine, (S)1-Phenylethylamine, (R)1-Phenylethylamine, Cinchonidine, (S)-Nitresolve,
(R)-Nitresolve; the suitable solvent is selected from hydrocarbon solvents, chloro solvents,
15 ether solvents, polar aprotic solvents, polar protic solvents, ester solvent, nitrile solvent,
ketone solvents, alcohol solvent, water or any mixture thereof; the suitable temperature is 0-
150°C.
The second aspect of the present invention is to provide a process for etrasimod
compound of formula-3.
20 Scheme-2:
13
The other aspect of the present invention is to provide a process for etrasimod compound of
formula-3,
Scheme-3:
5
(3R)-7-[[4-cyclopentyl-3-(trifluoromethyl)phenyl] methoxy]-1,2,3,4- tetrahydro
cyclopent [b]indole -3-acetate, L-Arginine compound of formula-I produced by the present
10 invention can be further micronized or milled to get the desired particle size to achieve
desired solubility profile based on different forms of pharmaceutical composition
14
requirements. Techniques that may be used for particle size reduction include, but are not limited to ball, roller and hammer mills, and jet mills, milling or micronization may be performed before drying, or after the completion of drying of the product. PXRD analysis of (3R)-7-[[4-cyclopentyl-3-(trifluoromethyl)phenyl] methoxy]-1,2,3,4- tetrahydro cyclopent [b]indole -3-acetate, L-Arginine compound of formula-I was 5 carried out using BRUKER D8 ADVANCED/AXS X-Ray diffractometer using Cu Ka radiation of wavelength 1.5406 A° and continuous scan speed of 0.03°/min. IR spectra were recorded on a Perkin-Elmer FTIR spectrometer. (3R)-7-[[4-cyclopentyl-3-(trifluoromethyl)phenyl] methoxy]-1,2,3,4- tetrahydro cyclopent [b]indole -3-acetate, L-Arginine compound of formula-I used in the present 10 invention is synthesized by the prior known processes.
The process described in the present invention was demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention.
Examples: 15
Example-1: Preparation of compound of formula-2 [(R)-2-(7-hydroxy-1,2,3,4-tetra hydrocyclopenta[b]indol-3-yl)acetic acid] A round bottom flask was charged with compound of formula-1 (50 g) in acetonitrile (250 ml) in potassium phosphate buffer (15 ml, 1.0 M, pH=7.80), addition of lipase B, Candida antarctica, immobilized recombinant from yeast (3.0 g) The resultant suspension was stirred 20 at 40° C under Nitrogen atmosphere for 10 hr. The reaction mixture was diluted with 1M citric acid and adjusted the pH to 4 and filtered and washed the solid with acetonitrile. The combined filtrates were concentrated under vacuum to give crude residue. The obtained residue was partitioned between ethyl acetate and brine solution. The organic layers were separated, and the aqueous layer was extracted with ethyl acetate. The combined organic 25 layers were washed with water and dried over sodium sulphate and concentrated, dried to get the title compound.
Yield: 21.8 g
Example-2: Preparation of compound of formula-3 [(R)-2-(7-((4-cyclopentyl-3-(trifluoro methyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid] 30
15
A round bottom flask was charged with compound-2 (5 g), cesium carbonate (2.5 eq), 4-(chloromethyl)-1-cyclopentyl-2-(trifluoromethyl) benzene (1 moll) in dimethyl formamide (50 mL). The mixture was stirred for 30 minutes at room temperature and heated at 50° C and stirred for 6 h. The mixture was cooled and filtered the solid and the filtrate was concentrated on a 50 percent solution, further charged with hexanes and stirred for 30 min to 5 precipitate the solid compound. The obtain solid compound was filtered and dried to get the title compound.
Yield: 2.5 g.
Example-3: Preparation of compound of formula-2 [(R)-2-(7-hydroxy-1,2,3,4-tetra hydrocyclopenta[b]indol-3-yl)acetic acid] 10 A round bottom flask was charged with compound of formula-1 (50 g) in MTBE (1000 ml), water (500 ml) was heated to 40-50°C, stirred for 30 min. Cooled the reaction mixture, and separated the layers. The organic layer was charged with CALB enzyme on celite (12.5 g), potassium phosphate buffer (500 ml), the resultant suspension was stirred at 20-30°C for 12 hr. Filtered the reaction mixture and washed with MTBE, the obtained filtrate solution was 15 charged with sodium bicarbonate solution and stirred for 20 min and separated both layers. The aqueous layer pH was adjusted to 1.2 by HCl solution and charged with methyl tert butyl ether stirred for 30 min. Separated both layers and the organic layer was washed with brine solution and evaporated to get the title compound.
Yield: 18.5 g 20
Example-4: Preparation of compound of formula-2a[R)-ethyl 2-(7-hydroxy-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate] A round bottom flask was charged with compound of formula-2 (10 g) in methyl iso butyl ether (300 ml), ethanol (20 ml) was heated to 50-60°C, stirred for 30 min. Filtered the unwanted and washed with methyl iso butyl ether. The filtrate solution was charged with 25 triethyl orthoformate (28 ml), ADDZYME 015 (1 g) and the resultant suspension was stirred at 20-30°C for 12 hr. Filtered the reaction mixture and washed with methyl iso butyl ether, the obtained filtrate solution was charged with 10 % sodium bicarbonate solution and stirred for 20 min and separated both layers. The organic layers was washed with brine solution and dried evaporated to get the title compound. 30
16
Yield: 6.5 g
Example-5: Preparation of compound of formula-3a [(R)-ethyl 2-(7-((4-cyclopentyl-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate].
A round bottom flask was charged with compound-2a (10 g), acetonitrile (100 ml), cesium carbonate (16.5 g), 4-(chloromethyl)-1-cyclopentyl-2-(trifluoromethyl) benzene (10.62 g) 5 and stirred for 8 h at 55-65°C. Cooled the mixture, filtered the unwanted solid and washed with acetonitrile. The filtrate was evaporated to get the residue compound. Further, the obtain compound was co-distilled with isopropanol and dried to get the title compound.
Yield: 14.5 g.
Example-6: Preparation of compound of formula-3 [(R)-2-(7-((4-cyclopentyl-3-(tri 10 fluoro methyl) benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid]
A round bottom flask was charged with compound-3a (12.5 g), 1,4-dioxane (50 ml), lithium hydroxide (3.2 g) and stirred for 3 h at 55-65°C. Cooled the mixture, quenched with water and adjusted the pH of the reaction mixture to 1.5 with dil. HCl and charged with dichloromethane. The organic layer was separated and evaporated to get the title compound. 15
Yield: 10 g.
Example-7: Preparation of compound of formula-2a[R)-ethyl 2-(7-hydroxy-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate] A round bottom flask was charged with compound of formula-2 (2 g), ethanol (10 ml) and sulfuric acid (0.85 g) was stirred at 5 to 15°C for 8 h. The reaction mixture was distilled off 20 completely, further charged with dichloromethane and water and stirred for 20 min. Both the layers were separated, and the organic layer was evaporated and dried to get the title compound.
Yield: 1.2 g
Example-8: Preparation of compound of formula-2a[R)-ethyl 2-(7-hydroxy-1,2,3,4-25 tetrahydrocyclopenta[b]indol-3-yl) acetate]
A round bottom flask was charged with 2-(7-hydroxy-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid (10 g) in methyl tert butyl ether (300 ml), ethanol (20 ml) was heated to 50-60°C, stirred for 30 min. Filtered the unwanted and washed with methyl tert butyl ether. The filtrate solution was charged with triethyl orthoformate (28 ml), ADDZYME 015 (1 g) and 30
17
the resultant suspension was stirred at 20-30°C for 12 hr. Filtered the reaction mixture and washed with MTBE, the filtrate solution was charged with 10 % sodium bicarbonate solution and stirred for 20 min and separated both layers. The organic layers were washed with brine solution and dried evaporated to get the title compound.
Yield: 6.0 g 5
Example-9: Preparation of compound of formula-I [Etrasimod L-arginine] A round bottom flask was charged with compound of formula-3 (15 g) isopropanol (135 ml) were heated to 55-65°C for 30 min. A solution of L-arginine (5.7 g in water 22.5 ml) was added to the above solution and stirred for 1 h at 55-65°C. Cooled the solution to 25-35°C filtered the obtained solid and washed with isopropanol to get the title compound. 10
Yield: 11.6 g. Purity by HPLC:98.84 , chiral HPLC: 99.83 %
Example-10: Purification process for compound of formula-I A round bottom flask was charged with compound of formula-I (53.5 g) isopropanol (140 ml), acetonitrile (140 ml), water (48 ml) were heated to 65-75°C for 1 h. Cooled the reaction mixture to 40-50°C and stirred for 30 min, filtered the solid obtain and washed with a 15 mixture of isopropanol, acetonitrile and water, dried to get the title compound.
Yield: 74.7 g; Purity by HPLC: 99.7 %, chiral HPLC: 99.93 % (other isomer: 0.07% ) ,CLAIMS:We claim:
1. An alternative process for (3R)-7-[[4-cyclopentyl-3-(trifluoromethyl)phenyl] methoxy] -
1,2,3,4- tetrahydro cyclopent [b] indole -3-acetate, L-Arginine compound of formula-I
5 Comprising of:
a) reacting compound of formula-1 in presence of lipase and hydrolyzing, in solvent to
provide compound of formula-2.
b) reacting the compound of formula-2 with compound of formula-A with suitable reagent,
10 solvent to provide compound of formula-3,
c) reacting the compound of formula-3 with L-arginine, solvent to provide compound of
formula-I
d) optionally purifying the compound of formula-I with suitable reagent, solvent to provide
15 pure compound of formula-I.
2. A process for preparation of compound of formula I as per claim 1, wherein in step-a), b),
c), and d) the suitable solvent is selected from hydrocarbon solvents, chloro solvents, ether
19
solvents, polar aprotic solvents, polar protic solvents, ester solvent, nitrile solvent, ketone
solvent, alcohol solvent, water or any mixture thereof; the suitable temperature is 0-150°C.
Wherein in step-a) suitable enzymes is selected from the group consisting of lipase
B Candida Antarctica, lipase Mucor miehei, and fluorescens, menhaden oil, tuna oil and
5 borage oil, pancreatic lipase, Aspergillus niger, rhizomucor delemar, rhizomucor miehei, and
Mucor javanicus, phosphate buffer and mixture thereof. The hydrolyzing-step solvent
comprises dimethyl formamide, dimethylacetamide, dimethyl sulfoxide, tetrahydrofuran,
chloro solvents, ether solvents, polar aprotic solvents, polar protic solvents, ester solvent,
nitrile solvent, ketone solvent, alcohol solvent, water or any mixture thereof.
10 Wherein in step-b) suitable reagents is selected inorganic base, organic base and mixture
thereof; Wherein in step-d) suitable reagents is selected from HCl, HBr, Acetic acid, trifluoro
acetic acid, citric acid, malic acid, para toluene sulfuric acid, tartaric acid, formic acid,
fumaric acid, organic base, inorganic base and mixture thereof.
3. An alternative process for (3R)-7-[[4-cyclopentyl-3-(trifluoromethyl)phenyl] methoxy]-
15 1,2,3,4- tetrahydro cyclopent [b] indole -3-acetate, L-Arginine compound of formula-I
comprising of:
a) reacting compound of formula-1 with CALB (Candida antarctica lipase B) enzyme in
methyl tert butyl ether, potassium buffer solution to provide compound of formula-2,
20
b) esterifying the compound of formula-2 with Candida antarctica lipase B, ADDZYME in
methyl tert butyl ether, triethyl orthoformate to provide compound of formula-2a,
20
c) reacting the compound of formula-2a with compound of formula-A in presence of cesium
carbonate in acetonitrile to provide compound of formula-3a,
d) hydrolyzing the c 5 ompound of formula-3a with LiOH in dioxane, water to provided
compound of formula-3,
e) reacting the compound of formula-3 with L-arginine in IPA, water to provide compound
of formula-I
4. An alternative process for (3R)-7-[[4-cyclopentyl-3-(trifluoromethyl) phenyl] methoxy]-
10 1,2,3,4- tetrahydro cyclopent [b] indole -3-acetate, L-Arginine compound of formula-I
Comprising of:
a) reacting compound of formula-1a with CALB (Candida antarctica lipase B) enzyme in
methyl tertbutyl ether, potassium buffer solution, ethanol to provide compound of formula-
15 2a,
21
b) reacting the compound of formula-2a with compound of formula-A in presence of cesium
carbonate in acetonitrile to provide compound of formula-3a,
c) 5 hydrolyzing the compound of formula-3a with LiOH in dioxane, water to provided
compound of formula-3,
d) reacting the compound of formula-3 with L-arginine in IPA, water to provide compound
of formula-I.
10 5. An improved process for the preparation of compound of formula-2a
comprising of:
a) reacting compound of formula-1a with CALB (Candida antarctica lipase B) enzyme in
methyl tertbutyl ether, potassium buffer solution, ethanol to provide compound of formula-
2a.
22
6. An alternative process for the preparation of compound formula-2a
comprising of:
a) reacting compound of formula-1 with CALB (Candida antarctica lipase B) enzyme in
5 methyl tertbutyl ether, potassium buffer solution to provide compound of formula-2,
b) esterifying the compound of formula-2 with Candida antarctica lipase B, ADDZYME in
methyl tertbutyl ether, triethyl orthoformate, ethanol to provide compound of formula-2a.
10 7. An alternative process for the preparation of compound formula-2a
comprising of:
a) reacting compound of formula-2 with suitable reagent, solvent to provide a compound of
formula-2a.
15
23
8. A process for the preparation of compound of formula-2a as per claim 7, the suitable reagents are thionyl chloride, oxalyl chloride, sulfuric acid, diethyl sulfate, organic base, inorganic base, the suitable solvent is selected from alcohol solvents or mixture of alcohol solvent with other solvents such as hydrocarbon solvents, chloro solvents, ether solvents, polar aprotic solvents, polar protic solvents, ester solvent, nitrile solvent, ketone solvent, water; the suitable temperature is 0-150°C.