DESC:Field of the Invention:
The present application relates to a process for the preparation of Esketamine
Hydrochloride salt and intermediates thereof, which is represented by the following structural
5 formula-I.
Formula-I.
Background of the Invention:
10 Esketamine Hydrochloride, with the chemical name of (S)-2-(2-chlorophenyl)-2-(methyl
amino) cyclohexanone hydrochloride, is a non-competitive N-methyl D-aspartate (NMDA)
receptor antagonist indicated, in conjunction with an oral antidepressant, for the treatment of
treatment-resistant depression (TRD) as well as major depressive disorder (MDD) associated
with suicidal ideation or behavior in adults approved in US, Europe in 2019 with brand name
15 of Spravato in the form of a nasal spray, is a controlled drug substance.
The GB1330878A first reported esketamine hydrochloride and its preparation. The
process involves resolution of ketamine using different chiral resoluting reagents and
reported its physical properties such as specific optical rotation and melting points etc.
The US6040479B2 reported process for the preparation of esketamine hydrochloride
20 and its preparation using Tartaric acid as chiral resoluting agent.
The US11007200B2 reported various processes for the preparation of esketamine
hydrochloride and its preparation involves usage various chiral resoluting reagents such as
Camphor sulfonic acid, Mandalic acid, D-Tartaric acid, L-Tartaric acid and Naproxen, etc.
25 There are various processes reported for the preparation of esketamine hydrochloride
and intermediates thereof, using different processes and different chiral reagents and
solvents.
Based on drawbacks in the prior art processes, there is a need for providing an
improved process for the preparation of esketamine hydrochloride, its intermediates thereof,
3
which involves simple experimental procedures, well suited to industrial production, which avoids the use of column chromatography purification, and which affords chirally pure esketamine hydrochloride salts. The present invention provides an improved process for preparation of esketamine hydrochloride salt and intermediates thereof, which is efficient, industrially viable and cost 5 effective.
Brief Description:
The first aspect of the present invention is to provide a process for the preparation of (S)-2-(2-chlorophenyl)-2-(methylamino)cyclohexanone hydrochloride the compound of 10 formula-I.
The second aspect of the present invention is to provide a process for the preparation of 2-(2-chlorophenyl)-2-(methylamino)cyclohexanone the compound of formula-II.
Brief description of the drawings:
Figure-1: Illustrates the PXRD pattern of crystalline Form of Ketamine hydrochloride the 15 compound of formula-II according to example-4.
Figure-2: Illustrates the IR of crystalline Form of Ketamine hydrochloride the compound of formula-II according to example-4.
Figure-3: Illustrates the PXRD pattern of crystalline Form of Esketamine hydrochloride the compound of formula-I according to example-6. 20
Figure-4: Illustrates the IR of crystalline Form of Esketamine hydrochloride the compound of formula-I according to example-6.
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, petroleum ether, toluene, 25 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 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, 30
4
ethyl acetate, isopropyl acetate, n-butyl acetate and the like; “polar-aprotic solvents such as
dimethylacetamide (DMA), dimethylformamide (DMF), dimethylsulfoxide (DMSO), Nmethylpyrrolidone
(NMP) and the like; “chlorinated hydrocarbon solvents” such as
dichloromethane, dichloroethane, chloroform, carbontetra chloride and the like; “ketone
5 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-
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,
10 diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, or glycerol and the
like; “polar solvents” such as water or mixtures thereof.
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
15 sodium bicarbonate, potassium bicarbonate and the like; “alkali metal hydroxides” such as
sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; “alkali metal
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
20 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
ethylamine, diisobutylamine, triethylamine, pyridine, piperidine, 4-dimethyl amino pyridine
(DMAP), N-methyl morpholine (NMM), or mixtures thereof.
The first aspect of the present invention provides a process for the preparation of (S)-
25 2-(2-chlorophenyl)-2-(methylamino)cyclohexanone hydrochloride the compound of formula-
I.
Formula-I
5
Comprising of:
a) Resolution of ketamine the compound of formula-5 using suitable chiral agents, in alcohol
to provide the compound of formula-6,
5
b) basifying the compound obtained in step-a) with suitable base, solvent followed by
converting to compound of formula-I in suitable solvent and HCl reagents.
Wherein in step-a) and b) the suitable solvent is selected from hydrocarbon solvents,
chlorinated hydrocarbons solvents, ether solvents, nitrile solvents, ketone solvents, ester
10 solvents, polar aprotic solvents, polar protic solvents, alcoholic solvents, water or any
mixture thereof; suitable chiral agents is L-O,O’-Di-p-toluoyl-D-tartaric acid; L-O,O’-Di-ptoluoyl-
L-tartaric acid; D-tartaric acid, L-tartaric acid, Mandelic acid; The suitable HCl
reagents are selected from aq. HCl, HCl (g), alcoholic HCl, ether HCl, ethyl acetate HCl,
suitable base is inorganic base such as NaOH, KOH and LiOH, aqueous ammonia and
15 mixture thereof; Suitable temperature: 0- 100°C;
The preferred embodiment of the present invention is to provide a process for the
preparation of crystalline Form of compound of formula-I; comprising of:
a) Resolution of the compound of formula-5 using L-O,O’-Di-p-toluoyl-D-tartaric acid in
20 isopropanol to provide the compound of formula-6,
b)filtering the compound obtained in step-a) and stirring in isopropanol at 45-55°C,
c)isolating the compound obtained is step-b) as pure compound of formula-6,
d) treating the compound obtained is step-c) with sodium hydroxide solution in water and
extracting into toluene and evaporated.
25 e) treating the compound obtained in step-d) with isopropanol hydrochloride at 80°C,
f) filtering the compound obtained in step-e) to get the crystalline form of the compound of
6
formula-I.
The other aspect of the present invention provides crystalline Form of Esketamine the
compound of formula-I. The crystalline Form of the present invention is characterized by its
powder X-Ray diffraction pattern having peaks at about 11.90, 14.39, 14.74, 15.93, 16.29,
5 17.23, 19.03, 20.79, 21.10, 21.34, 24.03, 24.57, 27.09, 27.09, 27.330, 28.12, 28.82, 32.16,
33.84, 34.50, 35.04, 39.80 & 42.97 ± 0.2° 2?. The said crystalline Form is further
characterized by its powder X-Ray diffraction pattern substantially in accordance with
figure-3, by its IR absorption spectrum shown in figure-4.
10 The other aspect of the present invention provides a process for the preparation of the
compound of formula-I, Comprising of
Formula-I
a) Reacting the compound of formula-1
15
with Grignard reagent, solvent to provide the compound of formula-2,
b) brominating the compound of formula-2 with brominating reagent to provide the
compound of formula-3,
7
c) reacting the compound of formula-3 with aqueous methylamine using suitable reagent,
solvent to provide the compound of formula-4,
5
[4]
further cyclizing in presence of suitable reagents, solvents to provide compound of formula-5
or it salts,
10
[5]
d) resolution of the compound of formula-5 or its salts using L-O,O’-Di-p-toluoyl-D-tartaric
acid in alcohol solvent to provide the compound of formula-6,
e) basifying the compound obtained in step-d) with suitable base, solvent followed by
15 converting to the compound of formula-I in a suitable solvent and reagents.
f) optionally treating the compound of formula-6 with alcoholic HCl at a suitable temperature
to provide the compound of formula-I.
Wherein in step a) to f) suitable solvent is selected from chlorinated hydrocarbons
solvents, ether solvents, nitrile solvent, ketone solvents, ester solvents, alcohol solvents, polar
20 aprotic solvents, polar protic solvents, or water any mixture thereof; suitable temperature 0-
100°C.
8
The suitable reagents in step-a) chloro cyclopentane, bromo cyclopentane, iodo cyclo
pentane, magnesium, cuprous chloride, copper(I) bromide, copper(I) iodide the preferable
solvents are tetrahydrofuran, 2-methyl tetrahydrofuran, dioxane, diethyl ether, dimethoxy
ethane; The suitable reagents in step-b) bromine, copper(II) bromide, N-bromosuccinimide,
5 sodium bromide, sodium bromate and mixture thereof; preferable solvents are alcoholic
solvents, chlorinated hydrocarbons. The suitable reagents in step-c) aqueous solution
methylamine, magnesium bromide, magnesium chloride, aluminum chloride, aluminum
bromide and mixture thereof; preferable solvents are alcoholic solvents, water, DMF,
dioxane, toluene, xylene, decaline, ethylbenzoate, chlorobenzene, dichloro benzene, alcoholic
10 HCl, ethyl acetate HCl, ether HCl, con HCl, and water mixture thereof; Suitable
temperature: 0- 200°C; The suitable reagents in step-d), e) and f) suitable chiral resolution
agents is L-O,O’-Di-p-toluoyl-D-tartaric acid; L-O,O’-Di-p-toluoyl-L-tartaric acid; D-tartaric
acid, L-tartaric acid; The preferable solvents are selected from alcoholic HCl, ether HCl,
ethyl acetate HCl, aq.HCl and mixture thereof inorganic bases such as NaOH, KOH and
15 LiOH, aqueous ammonia and mixture thereof; Suitable temperature: 0- 100°C;
The Preferred embodiment of the present invention provides a process for the
preparation of the compound of formula-I, comprising of
20 Formula-I
a)Reacting the compound of formula-1
with cyclopentyl magnesium bromide, Cu(I)Cl in 2-methyl tetrahydrofuran to provide the
compound of formula-2,
9
b) brominating the compound of formula-2 with bromine in dichloromethane to provide
the compound of formula-3,
c) reacting the compound of formula-3 with aqueous 5 methylamine in water, isopropanol, to
provide the compound of formula-4,
[4]
further cyclizing in presence of magnesium chloride in xylene at 130-140°C to provide the
10 compound of formula-5 ,
[5]
d) resolution of a compound of formula-5 using L-O,O’-Di-p-toluoyl-D-tartaric acid in
isopropanol to provide the compound of formula-6,
15 e) basifying the compound obtained in step-d) with sodium hydroxide in water, followed by
treating with isopropanol, HCl in isopropanol to provide the compound of formula-I.
The second aspect of the present invention provides a process for the preparation of
the compound of formula-II, comprising of;
10
Formula-II
a) Reacting the compound of formula-1
with cyclopentyl magnesium bromide, Cu(I)Cl in 5 2-methyl tetrahydrofuran to provide the
compound of formula-2,
b) brominating the compound of formula-2 with bromine in dichloromethane to provide
the compound of formula-3,
10
c) reacting the compound of formula-3 with aqueous methylamine in water, isopropanol, to
provide the compound of formula-4,
[4]
15 d) further cyclizing in presence of magnesium chloride in xylene at 130-140°C to provide
the compound of formula-5,
11
[5]
e) treating the compound of formula-5 with isopropanol HCl to provide crystalline form of
the compound of formula-II.
The other aspect of the present invention 5 provides crystalline Form of Ketamine
Hydrochloride the compound of formula-II. The crystalline Form of the present invention is
characterized by its powder X-Ray diffraction pattern having peaks at about 9.11, 11.93,
13.79, 14.54, 15.02, 15.26, 16.80, 18.25, 19.21, 19.52, 20.61, 21.58, 23.95, 24.35, 24.94,
25.32, 25.86, 26.69, 27.51, 27.74, 28.18, 28.38, 29.28, 30.66, 30.86, 31.03, 31.82, 32.91,
10 33.20, 34.11, 35.45, 36.95, 37.25, 37.56 & 38.19 ± 0.2° 2?. The said crystalline form is
further characterized by its powder X-Ray diffraction pattern substantially in accordance
with figure-1, by its IR absorption spectrum shown in figure-2.
The process for the preparation of esketamine hydrochloride and its intermediates
thereof developed by the present inventors produces highly pure esketamine hydrochloride
15 and ketamine 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.
The compound of formula-I and II produced by the process of the present invention
are having chemical purity / chiral purity greater than 99.5%, preferably greater than 99.7%,
20 more preferably greater than 99.9% by HPLC.
Esketamine hydrochloride, Ketamine hydrochloride and its polymorphs produced by
the present 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
requirements. Techniques that may be used for particle size reduction include, but not limited
25 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.
The PXRD analysis of Esketamine hydrochloride, Ketamine hydrochloride was
carried out using BRUKER D8 ADVANCED/AXS X-Ray diffractometer using Cu Ka
12
radiation of wavelength 1.5406 A° and continuous scan speed of 0.03°/min. IR spectra were
recorded on a Perkin-Elmer FTIR spectrometer.
The present invention described as follows in a schematic representation:
5
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.
10
Examples:
Example-1: Preparation of compound of formula-2.
A round bottom flask was charged with magnesium turnings (65.5 g), 2-methyl tetra
hydrofuran (750 mL) and methyliodide (12.9 g) and stirred for 30 min at 25-35°C. Chloro
15 cyclopentane (330.9 g) was added slowly to the above reaction mixture below to 85°C and
13
stirred for 3 hr at 70 to 75°C same temperature. Cooled the reaction mixture to 0--10°C, slowly added a solution of 2--chloro benzonitrile (250 g) in toluene (500 mL) followed by copper (I) chloride in portion wise (2x1.8 g) and stirred for 8 hr at 25--35°C.
The reaction mixture was quenched with diluted HCl (500 mL in 1L of water) and stirred for 8 hr at 25--35°C and separated both the layers. The aqueous layer was extracted 5 with toluene (250 mL), the combined organic layers was washed with ammonia solution (25 ml in 225 mL of water) and brine solution (25 g in 250 mL of water). The organic layer was dried and distilled off completely below to 65--75°C to get the residue compound. The pure title compound was collected under high vacuum distillation at below to 125°C and dried.
Yield: 350 g. Purity by GC: > 99.5% 10
Example-2: Preparation of compound of formula-4
A round bottom flask was charged with dichloromethane (800 mL), bromine (183.4 g) and stirred for 1 hr. A solution of compound of formula-2 (200 g) in dichloromethane (200 mL) was added to the above solution at 5-15°C and stirred for 3 hr at 15-25°C. The reaction mixture was quenched with a solution of sodium metabisulfite (120 g in 600 mL of water) 15 and stirred for 30 min at 25-35°C. Separated the organic layer, the aqueous layer was extracted with dichloromethane (200 mL) and the combined organic layers were washed with sodium bicarbonate and evaporated the organic layer to get a residue. Further, the residue was charged with isopropanol (500 mL) and aqueous mono methylamine (1115 g aqueous 40 %, 1860 ml of water) and stirred for 60 hr at 10-20°C. The reaction mixture was cooled to 0-20 10°C and stirred for 2 hr, the precipitated solid was filtered and washed with water (250 mL). The wet compound was charged with water (800 mL) and stirred for 1 hr at 25-35°C. Filtered the obtained solid, washed with water (200 mL) and dried to get the title compound.
Yield: 197 g. Water content NMT 0.5 w/w;
Example-3: Preparation of compound of formula-5 25
A round bottom flask was charged with compound of formula-4 (100 g) ethyl acetate (200 mL) and stirred at 25--30°C for 10 min. The reaction mixture was cooled to 0--5°C added ethyl acetate HCl (211 g) and stirred for 2 hr. Filtered the obtained solid washed with ethyl acetate (50 mL) and dried. The obtained salt compound was charged with xylene (500 mL), magnesium chloride (10.4 g) and stirred for 8 hr at 125--135°C. Cooled the reaction mixture 30
14
to 25--35°C, Filtered the reaction mixture and washed with xylene (50 mL). Further, the obtained compound was stirred in ethyl acetate (300 mL) and filtered the compound. The compound was charged with water (1L), activated carbon (2 g) and stirred for 30 min. Filtered the reaction mixture and washed with water (100 mL), adjusted pH of the filtrate solution to 11.5 with aqueous ammonia and stirred for 30 min. Filtered the precipitated 5 compound and washed with water (100 mL) and dried to get the title compound.
Yield: 65 g. Water content: NMT: 1 % w/w
Example-4: Preparation of compound of formula-II
A round bottom flask was charged with compound of formula--5 (50 g), isopropanol (500 mL) heated to 40--50°C, charged activated carbon (2 g) and stirred for 30 min. Filtered the 10 reaction mixture and washed with isopropanol (200 mL). The filtrate solution was charged with isopropanol HCl (170 g) and heated to 70--80°C, stirred for 45 min. The reaction mixture was cooled to 25--35°C, filtered the precipitated solid washed with isopropanol and dried to get the title compound.
PXRD of the obtained compound is depicted in figure--1. 15
Yield: 55 g. Purity by HPLC >99.5 %
Example-5: Preparation of compound of formula-6.
A round bottom flask was charged with compound of formula-5 (100 g), isopropanol (500 mL) and heated to 45--55°C, charged L--O, O’ --Di--p--toluoyl--D--tartaric acid (81.3 g) and stirred for 2 hr. Filtered the reaction mixture and washed with isopropanol (50 mL). Further, 20 the obtained solid was stirred in isopropanol (150 mL) at 45--55°C for 2 hr. Filtered the reaction mass and washed with isopropanol (50 mL) and dried to get the title compound.
Yield: 55 g .
Example-6: Preparation of compound of formula-I.
A round bottom flask was charged with compound of formula--6 (50 g), water (500 mL) and 25 adjusted the pH to 11.5 with sodium hydroxide (5 g in 50 mL of water) and stirred for 30 min at 25--35°C. Charged toluene (250 mL) and stirred for 30 min, separated the organic layer. The aqueous layer was extracted with toluene (100 mL) and separated the layers. The combined organic layer was washed with water and distilled off the organic layer. The obtained residue was charged with isopropanol (500 mL) and heated to 40--50°C charged 30
15
activated carbon stirred for 30 min. Filtered the reaction mixture and washed with isopropanol (100 mL).The filtrate solution was charged with isopropanol HCl (32 g) and stirred for 45 min at 70--80°C. Filtered the obtain solid and washed with isopropanol (50 ml) and dried to get the title compound.
Purity by HPLC: >99.5 %; R--isomer < 0.15 %; 5
PXRD of the obtained compound is depicted in figure--3.
Yield: 18 g.
Example-7: Preparation of compound of formula-I.
A round bottom flask was charged with compound of formula-6 (100.0 g), isopropanol (1L
mL) and added slowly 2N isopropanol.HCl (500.0 mL), stirred for 3 hr at 45-55°C. The 10 obtained solid was filtered and washed with isopropanol (100 mL). Further, the compound was stirred in isopropanol (150 ml) at 70--80°C for 2 hr and gradually cooled to 25--35°C and stirred for 1 hr. Filtered the precipitated solid, washed with isopropanol (25 mL) and dried to get the title compound.
Yield: 42.5 g 15
Purity by HPLC: >99.5 %; R--isomer < 0.15%
Example-8: Preparation of compound of formula-5
A round bottom flask was charged with compound of formula-4 (100 g), ethyl acetate (200 mL) and stirred at 25--35°C for 10 min. Cooled the reaction mixture to 5--15°C, added ethyl acetate HCl (281 g) and stirred for 2 hr at 10--15°C. Filtered the obtain solid and washed with 20 ethyl acetate (50 mL) and dried. The obtained salt compound was charged with o--xylene (500 mL), magnesium chloride anhydrous (7.0 g) and stirred for 8 hr at 120--130°C. Cooled the reaction mixture to 25--35°C, and stirred for 30--45 min. Filtered the reaction mixture and washed with o--xylene. The compound was charged with water, activated carbon (2 g) and stirred for 30 min at 25--35°C. Filtered the reaction mixture over hyflo bed, washed with 25 purified water . The obtained compound was charged with concentrated hydrochloric acid, o--xylene at 25--35°C and stirred for 15--20 min. Separated two layers, charge aqueous layer into another clean round bottom flask with o--xylene and stirred for 15--20 min. The aqueous layer was extracted with xylene and adjusted pH of the filtrate solution to 10 with ammonia gas
16
and stirred for 45--60 min at 25--35°C. Filtered the precipitated compound and washed with water and dried to get the title compound.
Yield: 55.7 g. Water content: NMT: 1 % w/w;
Example-9: Preparation of compound of formula-II
A round bottom flask was charged with compound of formula--5 (80 g), isopropanol (400 mL) 5 heated to 40--50°C, charged activated carbon (2 g) and stirred for 30 min. Filtered the reaction mixture over hyflo bed and washed with isopropanol (160 mL). Charged the mixture to another round bottom flask, cooled to 25--35°C, and slowly added concentrated hydrochloric acid (45 g). Heated the reaction mixture to 60--80°C, stirred for 4 hr. Cooled the reaction mass and stirred for 30--45 min at 25--35°C. Filtered the compound and washed with 10 isopropanol. The reaction mixture was cooled to 25--35°C, filtered the precipitated solid and washed with isopropanol and dried to get the title compound.
PXRD of the obtained compound is depicted in figure--1.
Yield: 87.26 g. Purity by HPLC >99.5 %.
Example-10: Preparation of compound of formula-I. 15
A round bottom flask was charged with compound of formula--6 (250 g), water (2.5 L) and adjusted the pH to 11.5 with sodium hydroxide (5 g in 50 mL of water) and stirred for 30 min at 25--35°C. Charged toluene (750 mL) and stirred for 30 min, separated the organic layer. The aqueous layer was extracted with toluene and separated the layers. The combined organic layer was washed with water and distilled off the organic layer. The obtained residue 20 was co--distilled with isopropanol,further charged with isopropanol and heated to 40--50°C and charged activated carbon (3.0 g) stirred for 30 min. Filtered the reaction mixture over hyflo bed and washed with isopropanol at 40--50°C. Charged the filtrate solution into another round bottom flask and cooled to 25--35°C, added concentrated hydrochloric acid and heated to 60--80°C and stirred for 45--60 min. Cooled the reaction mass filter the obtained solid and 25 washed with isopropanol and dried to get the title compound.
Yield: 101.g
Purity by HPLC: >99.5 %; R--isomer < 0.15 %; ,CLAIMS:We claim:
1. A process for the preparation of (S)-2-(2-chlorophenyl)-2-(methylamino) cyclo
hexanone hydrochloride the compound of formula-I.
5 Formula-I
Comprising of:
a) Resolution of the compound of formula-5 using suitable chiral reagent, solvent to provide
compound of formula-6,
10
b) basifying the compound obtained in step-a) with suitable base, solvent followed by
converting to the compound of formula-I in suitable solvent and suitable HCl reagent.
2. A process for preparation of compound of formula-I according to claim 1wherein in stepa)
and b) the suitable solvent is selected from hydrocarbon solvents, chlorinated
15 hydrocarbons solvents, ether solvents, nitrile solvents, ketone solvents, ester solvents, polar
aprotic solvents, polar protic solvents, alcoholic solvents, water or any mixture thereof;
3. A process for preparation of compound of formula-I according to claim 1 the suitable
chiral reagents are L-O,O’-Di-p-toluoyl-D-tartaric acid; L-O,O’-Di-p-toluoyl-L-tartaric acid;
D-tartaric acid, L-tartaric acid, Mandelic acid; The suitable HCl reagent are selected from
20 aq.HCl, HCl (g), alcohlic HCl, ether HCl, ethyl acetate HCl, suitable base , inorganic base
such as NaOH, KOH and LiOH, aqueous ammonia and mixture thereof; Suitable
temperature: 0- 100°C;
4. A process for the preparation of compound of formula-I;
comprising of:
18
a) Resolution of the compound of formula-5 using L-O, O’-Di-p-toluoyl-D-tartaric acid in
isopropanol to provide the compound of formula-6,
b) filtering the compound obtained in step-a) and stirring in isopropanol at 45-55°C,
c) isolating the compound obtained is step-b) as pure compound of formula-6,
5 d) treating the compound obtained is step-c) with sodium hydroxide solution in water and
extracting into toluene and distilling off.
e) treating the compound obtained in step-d) with isopropanol hydrochloride at 80°C,
f) filtering the compound obtained in step-e) and dried to get the crystalline form of the
compound of formula-I.
10 5. A process for the preparation of compound of formula-I, comprising of
Formula-I
a) Reacting the compound of formula-1
15 with cyclopentyl magnesium bromide, Cu(I)Cl in 2-methyl tetrahydrofuran to provide the
compound of formula-2,
b)brominating the compound of formula-2 with bromine in dichloromethane to provide
the compound of formula-3,
19
c) reacting the compound of formula-3 with aqueous methylamine in water, isopropanol, to
provide the compound of formula-4,
5 [4]
further cyclizing in presence of magnesium chloride in xylene at 130-140°C to provide the
compound of formula-5,
[5]
10 d) resoluting the compound of formula-5 using L-O,O’-Di-p-toluoyl-D-tartaric acid in
isopropanol to provide the compound of formula-6,
e) basifying the compound obtained in step-d) with sodium hydroxide in water, followed by
treating with isopropanol, HCl in isopropanol to provide the compound of formula-I.
6. A process for preparation of the compound of formula-II, comprising of;
15
Formula-II
a) Reacting the compound of formula-1
20
with cyclopentyl magnesium bromide, Cu(I)Cl in 2-methyl tetrahydrofuran to provide the
compound of formula-2,
b) brominating 5 the compound of formula-2 with bromine in dichloromethane to provide
the compound of formula-3,
c) reacting the compound of formula-3 with aqueous methylamine in water, isopropanol, to
provide the compound of formula-4,
10
[4]
further cyclizing in presence of magnesium chloride in xylene at 130-140°C to provide the
compound of formula-5,
15 [5]
d) treating the compound of formula-5 in isopropanol HCl to provide crystalline form of the
compound of formula-II.