DESC:Field of the Invention:
The present application relates to an improved process for the preparation of
Varenicline Tartaric acid salt, which is represented by the following structural formula-1.
5
Formula-1
Background of the Invention:
Varenicline, as a salt of L-tartaric acid is approved in USA for the treatment of smoking
10 addiction, is available in the market with the brand name CHANTIX® developed by Pfizer
in the form of tablet. Varenicline L-tartrate (Formula-1) is the international commonly
accepted name for 7,8,9,10-tetrahydro-6H-6,10-methano pyrazino[2,3-h][3] benzazepine,
(2R, 3R)-2,3-di hydroxybutanedioate (1:1).
The patent US6410550B2. first disclosed Varenicline free base and pharmaceutically
15 acceptable salts. The US’550 disclosed a process for preparation of varenicline free base and
its hydrochloride salt. The process involves reaction of 10-aza-tricyclo[6.3.1.02,7]do deca-
2(7),3,5-triene hydrochloride salt with trifluoroacetic anhydride in pyridine to obtain 1-(10-
aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone.The obtained
compound reacted with nitric acid in trifluoromethane sulfonic acid to give 1-(4,5-dinitro-
10-aza-tricyclo[6.3.1.02,720 ]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone, which is
hydrogenated with Pd(OH)2 under hydrogen gas in methanol to obtain 1-(4,5-di amino -10-
aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone. The obtained
compound is reacted with glyoxal sodium bisulphate, followed by deprotection by using
sodium carbonate to provide varenicline as free base. The obtained varenicline free base was
25 converted to its hydrochloride salt.
The US68090927B2 reported varenicline L-tartrate salt and its polymorphs and
processes thereof.
The US20080275051A1 reported a process for preparation of varenicline free base
3
by reacting 1--(4,5--diamino--10--aza--tricyclo[6.3.1.02,7]dodeca--2(7),3,5--trien--10--yl)--2,2,2--tri fluoro--ethanone with aqueous glyoxal in a protic alcoholic solvent, the obtained compound was deprotected to obtain varenicline free base. The US2012004239A1 reported a one pot process for preparation of varenicline free base. 5 There are various processes reported for varenicline free base and salts thereof using different solvents, reagents. Based on the prior art processes drawbacks, there is a need for providing an improved process for the preparation of varenicline L-tartrate, which involves simple experimental procedures, well suited to industrial production, which avoids the use of column 10 chromatography purification, and which affords high pure varenicline L-tartrate. The present invention provides an improved process for preparation of Verenicline free base and salts thereof, free from nitroso impurities, which is efficient, industrially viable and cost effective.
Brief Description: 15
The first aspect of the present invention is to provide a process for the preparation of Varenicline tartrate salt free from nitroso impurities.
The second aspect of the present invention is to provide a process for the preparation of Varenicline free from nitroso impurities.
20
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 25 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-30 methylpyrrolidone (NMP) and the like; “chloro solvents” such as dichloromethane,
4
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-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 2-methoxyethanol, l,2-5 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.
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, 10 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” such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert.butoxide, potassium tert-butoxide, lithium tert-butoxide and the like; 15 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 ethylamine, diisobutylamine, triethylamine, pyridine, piperidine, 4-dimethyl amino pyridine (DMAP), N-methyl morpholine (NMM), or mixtures thereof. 20
The term “reducing” agent used in the present invention refers suitable reducing reagents are selected from Lithium aluminium hydride, sodium borohydride, BF3 etherate solution, Pd/C, Ray-nickel;
The term “protecting” agent used in the present invention refers to a suitable protecting reagents that are selected selected from di-tert-butyl dicarbonate, chlorobenzyl formate, 25 benzylbromide, benzylchloride, acetylchloride, fluorenylmethyloxycarbonyl chloride; The term “phase transfer catalyst (PTC)” used in the present invention refers are selected from triethylbenzyl ammonium chloride, tetrabutyl ammoniumbromide, tetrabutyl ammonium chloride, tetrabutyl ammonium acetate, methyl tributyl ammonium chloride, tetrabutyl ammonium hydroxide, tributylbenzylammonium chloride; 30
5
The possible N-Nitrosamine impurities belongs to the nitrosamine class of
compounds. Which are classified as probable or possible human carcinogens (substances
that could cause cancer), based on laboratory tests such as rodent carcinogenicity studies.
5 The possible impurities of N-Nitrosamines in varenicline are drawn as below.
Varenicline Nitroso impurity: 8-nitroso-7,8,9,10-tetrahydro-6H-6,10-methano azepino
[4,5-g] quinoxaline
10
Dinitro nitroso impurity: 7,8-dinitro-3-nitroso-2,3,4,5-tetrahydro-1H-1,5-methanobenzo[d]
azepine
15 Diamino nitroso impurity: 7,8-diamino-3-nitroso-2,3,4,5-tetrahydro-1H-1,5-methanobenzo
[d] azepine
20 The present invention is related to a process for the preparation of varenicline tartrate
salts is free from the all possible nitroso impurities. Preferably Varenicline Nitroso impurity:
less than 1.8 ppm, more preferably less than 0.5 ppm level; Dinitro nitroso impurity and
diamino nitroso impurities are below detection level.
The present invention involves treating the crude varenicline with suitable acid and
25 washing with suitable organic solvents to removes all the possible nitroso impurities. The
6
resulting varenicline acid salt was basified with suitable base to get varenicline free from
nitroso impurities.
Wherein the suitable solvent is selected from chloro solvents, ether solvents, polar
aprotic solvents, ester solvents, alcohol or any mixture thereof; Suitable base is selected from
5 organic bases, inorganic base; suitable acids are selected from HCl, HBr, sulfuric acid, acetic
acid, trifluoroacetic acid, tartaric acid, oxalic acid.
The first aspect of the present invention provides an improved process for the preparation of
varenicline, its tartrate salt free from the possible notroso impurities such as Diamino nitroso
10 impurity, Dinitro nitroso impurity and Varenicline Nitroso impurity. Comprising of:
Formula-1
a) Reacting compound of formula-2
15
Formula-2
with compound of formula-3
Formula-3
20 in presence of magnesium, in suitable solvent to provide compound of formula-4,
Formula-4
b) oxidising the compound obtained in step-a) with suitable reagent, solvent to provide
compound of formula -5,
7
Formula-5
c) reacting the compound obtained in step-b) with suitable reagent, solvent in presence of
phase transfer catalyst to provide compound of formula-6,
5
Formula-6
further reacting the compound of formula-6 in-situ with benzylamine in presence of sodium
borohydride to provide compound of formula-7,
10 Formula-7
d) debenzylating the compound obtained in step-c) in presence of suitable reagent, solvent
to provide compound of formula-8 or free base,
HCl
15 Formula-8
e) protecting the compound obtained in step-d) with trifluoroacetic anhydride in presence
of suitable base, solvent to provide compound of formula-9, further reacting the
compound of formula-9 in-situ with nitration mixture to provide compound of formula-
20 10,
Formula-10
f) reducing the compound obtained in step-e) with palladium catalyst under hydrogen gas
25 atmosphere in suitable solvent to provide compound of formula-11, further reacting the
8
compound of formula-11 in situ with glyoxal solution in water to provide compound of
formula-12,
Formula-12
g) deprotecting the compound obtained is step-5 f) with inorganic base in a suitable solvent to
provide compound of formula-13,
Formula-13
h) purifying the compound-13 by treating with suitable acid and base to remove the nitroso
10 amine impurities,
i) treating the compound obtained in step-g or h) with tartaric acid in a suitable solvent to
obtain compound of formula-1 or 1a ,
Formula-1a
15 j)optionally purifying the compound obtained in step-i) with suitable base in suitable solvent
to provide varenicline, further converting to tartrate salt of compound of formula-1.
Wherein in step-a) the suitable solvent is selected from chloro solvents, ether solvents, or any
mixture thereof; preferably, tetrahydrofuran, ether;
wherein in step-b) the suitable solvent is selected from chloro solvents, ether solvents,
20 ketone solvents, ester solvents or any mixture thereof; preferably acetone; the suitable
oxidising agent is osmium tetroxide; other reagent is N-methylmorpholine N-oxide in
butanol solution;
wherein in step-c) the suitable reagent is sodium periodate; the suitable phase transfer
catalyst is selected from triethylbenzyl ammonium chloride, tetrabutylammoniumbromide,
25 tetrabutyl ammonium chloride, tetrabutyl ammonium acetate, methyltributyl ammonium
9
chloride, tetrabutyl ammonium hydroxide, tributyl benzyl ammonium chloride; the suitable solvent is selected from chloro solvents, ether solvents, polar aprotic solvents, ester solvents or any mixture thereof; preferably dichloromethane; the suitable regents for cyclisation is benzylamine; reducing agent is sodium borohydride, triacetoxy sodiumborohydride;
Wherein in step-d) the suitable solvent is selected from chloro solvents, ether solvents, polar 5 aprotic solvents, polar solvents, alcoholic solvents, ester solvents, Con.HCl or any mixture thereof; preferably methanolic HCl; the suitable palladium catalyst is selected from Pd(OH)2, Pd[P(PPh3)]4 , PdCl2, Pd/C; Preferably Pd(OH)2, Pd/C;
Optionally the other suitable reagent for debenzylation is ethylchloroformate, methyl chloro formate, chloroethyl chloro formate; suitable solvents are selected from toluene, benzene, 10 xylene, methanol, and ethanol;
Wherein in step-e) the suitable solvent is selected from chloro solvents, ether solvents, polar aprotic solvents, ester solvents, or any mixture thereof; preferably dichloromethane; the suitable base is selected from organic bases, inorganic base; preferably triethylamine; protecting agent is trifluoroacetic anhydride; the suitable nitration mixture is trifluoro 15 methane sulphonic acid, nitric acid or Sulfuric acid, nitric acid;
wherein in step-f) the suitable solvent is selected from chloro solvents, ether solvents, polar aprotic solvents, ester solvents, alcohol or any mixture thereof; preferably ethyl acetate;
the suitable palladium catalyst is selected from Pd(OH)2, Pd[P(PPh3)]4 , PdCl2, Pd/C; Preferably Pd(OH)2, Pd/C; 20
Wherein in step-g) the suitable solvent is selected from chloro solvents, ether solvents, polar aprotic solvents, ester solvents, alcohol or any mixture thereof; preferably methanol;
The suitable base is inorganic base; preferably sodium carbonate;
Wherein in step-h, i, j) the suitable solvent is selected from chloro solvents, ether solvents, polar aprotic solvents, ester solvents, alcohol or any mixture thereof; preferably dichloro 25 methane, methanol; the suitable base is selected from inorganic base; preferably sodium hydroxide; suitable acids are selected from HCl, HBr, sulfuric acid, acetic acid, trifluoro acetic acid, tartaric acid and oxalic acid.
10
Preferred embodiment of the present invention provides a process for the preparation
of the compound of formula-1, free from the Diamino nitroso impurity, Dinitro nitroso
impurity and Varenicline Nitroso impurity.
5
Formula-1
Comprising of:
a) reacting compound of formula-2
10 Formula-2
with compound of formula-3
Formula-3
in presence of magnesium in tetrahydrofuran to provide compound of formula-4,
15
Formula-4
b) oxidising the compound obtained in step-a) with osmium tetroxide, in presence of
butanolic solution of N-methylmorpholine N-oxide, in acetone to provide compound of
formula-5,
20
Formula-5
c) reacting the compound obtained in step-b) with sodium periodate in presence of triethyl
benzyl ammonium chloride in dichloromethane to provide compound of formula-6,
11
Formula-6
further reacting the compound of formula-6 in-situ with benzylamine in presence of sodium
borohydride, acetic acid to provide compound of formula-7,
5
Formula-7
d) debenzylating the compound obtained in step-c) in presence of palladium hydroxide in
methanolic HCl to provide compound of formula-8,
10 Formula-8
e) protecting the compound obtained in step-d) with trifluoroacetic anhydride in presence of
triethylamine in dichloromethane to provide compound of formula-9, further reacting the
compound of formula-9 in-situ with nitric acid in trifluoromethane sulfonic acid, to provide
15 compound of formula-10. (or)
Optionally isolating compound of formula-9 reacting with nitricacid in trifluoromethane
sulfonic acid to provide compound of formula-10,
20 Formula-10
f) reducing the compound obtained in step-e) with palladium hydroxide catalyst under
hydrogen gas atmosphere in ethyl acetate to provide compound of formula-11, further
reacting the compound of formula-11 insitu with glyoxal solution in water to provide
25 compound of formula-12,
12
Formula-12
g) deprotecting the compound obtained is step-f) with sodium carbonate in methanol to
provide compound of formula-13,
5
Formula-13
h) treating the compound obtained in step-g) with HCl followed by washing with dichloro
methane and basification with sodium hydroxide solution, extracting with dichloromethane
10 and evaporating to get compound-13,
i) treating the compound obtained in step-h) with tartaric acid in methanol to provide
compound of formula-1 or 1a,
Formula-1a
15 j) purifying the compound obtained in step-h or i) by basification with sodium hydroxide in
dichloromethane followed by converting to tartaric acid salt of varenicline.
The second aspect of the present invention is to provide a process for the preparation
of varenicline tartrate salt free from the Diamino nitroso impurity, Dinitro nitroso impurity
and Varenicline Nitroso impurity.
20
Formula-1
Comprising of:
13
a) reducing the compound of formula-10 with palladium hydroxide catalyst under hydrogen
gas atmosphere in ethyl acetate to provide compound of formula-11, further reacting the
compound of formula-11 in-situ with glyoxal solution in water to provide compound of
formula-12,
5
Formula-12
b) deprotecting the compound obtained is step-a) with sodium carbonate in methanol to
provide compound of formula-13,
10 Formula-13
c) treating the compound obtained in step-b) with HCl followed by washing with dichloro
methane
d) basifying the aqueous layer obtained in step-c) with sodium hydroxide solution and
extracting the compound with dichloromethane and evaporating to get compound-13,
15 e) treating the compound obtained in step-d) with tartaric acid in methanol to provide
compound of formula-1 or 1a.
The other aspect of the of the present invention provides purification process for
20 compound of formula-1
Formula-1
comprising of:
a) Treating the solution of compound of formula-1a in water with suitable organic solvent,
b) separating the aqueous layer and basifying the PH to 7-13 with suitable base,
c) extracting the aqueous layer with suitable solvent and evaporating,
5 d) converting varenicline to compound of formula-1 in methanol.
Wherein in step-a, b, c and d) the suitable solvent is selected from chloro solvents,
ether solvents, polar aprotic solvents, ester solvents, alcohol or any mixture thereof;
preferably dichloro methane, methanol; the suitable base is selected from inorganic base;
10 preferably sodium hydroxide; suitable acids are selected from HCl, HBr, sulfuric acid, acetic
acid, trifluoro acetic acid, tartaric acid oxalic acid; the suitable temperature is 0 to 50°C.
The preferred embodiment of the present invention is purification process for
compound of formula-1
15
Formula-1
comprising of:
a) Treating compound of formula-1a in water with dichloromethane,
b) separating the aqueous layer and basifying the PH to 11-12 with sodium hydroxide
20 solution,
c) extracting the aqueous layer with dichloromethane and evaporating,
d) converting varenicline obtained in step-c) to compound of formula-1 by treating with
tartaric acid in methanol.
The preferred embodiment of the present invention is purification process for varenicline
25 comprising of:
a) Treating the varenicline with dil HCl solution in water,
b) washing the solution obtained in step-a) with suitable organic solvent,
15
c) basifying the PH to 7-13 of solution obtained in step-b) with suitable base,
d) extracting the aqueous layer obtained in step-c) with suitable solvent,
e) evaporating the solvent obtain in step-d) and further converted into varenicline tartrate a compound of formula-1.
Wherein in step-a, b, c and d) the suitable solvent is selected from chloro solvents, 5 ether solvents, polar aprotic solvents, ester solvents, alcohol or any mixture thereof; preferably dichloromethane, methanol; the suitable base is selected from inorganic base; sodium hydroxide, potassium hydroxide suitable acids are selected from HCl, HBr, sulfuric acid, acetic acid, trifluoro acetic acid, tartaric acid oxalic acid. The suitable temperature is 0 to 50°C. 10
The preferred embodiment of the present invention is purification process for varenicline comprising of:
a) Treating the crude varenicline with dil hydrochloric acid in water,
b) washing the solution obtained in step-a) with dichloromethane,
c) basifying PH to 11-12 of the aqueous solution obtained in step-b) with sodium hydroxide, 15
d) extracting the aqueous layer obtained in step-c) with dichloromethane,
e) evaporating the solvent to obtaine varenicline as pure compound.
The preferred embodiment of the present invention is process for preparation of compound of formula-1, comprising varenicline obtained as per the earlier embodiments treated with tartaric acid in methanol. 20
The process for the preparation of varenicline, its tartrate salt developed by the present
inventors produces highly pure varenicline and varenicline tartrate salt without nitroso amine compounds 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. 25
The compound of formula-1a 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
Varenicline tartrate salt and its polymorphs produced by the present invention can be further micronized or milled to get the desired particle size to achieve desired solubility 30
16
profile based on different forms of pharmaceutical composition requirements. Techniques
that may be used for particle size reduction include, but 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.
5 PXRD analysis of Varenicline tartrate was 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.
The process of the present invention can be represented schematically as follows:
10
17
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:
Example-1: Preparation of the compound of formula-1a. 5
A round bottom flask was charged with compound of formula--10 (200 g), ethyl acetate (800 mL) and 20 % palladium hydroxide (2.5 g). The reaction mass was stirred under hydrogen gas pressure 5--6 kg /cm2 for 2 hr at 25--35°C. The reaction mixture was filtered through hyflow, washed with ethyl acetate (50 mL). The filtrate solution was charged with carbon (10 g), stirred for 15 min and filtered the mass through hyflow bed and washed with ethyl acetate 10 (50 mL). The filtrate solution was taken in other round bottom flask and added glyoxal solution (90 g, 40%), water (400 mL) stirred for 2 hr at 25--35°C. The reaction mixture pH was adjusted to 0.5--1.5 with dil HCl (220 mL) stirred for 2 hr, and separated the layers. The aqueous layer was extracted with ethyl acetate (2x200 mL). The combined organic layer was washed with water (200 mL), brine solution (200 mL), distilled off the solvent completely 15 and co distilled with methanol (50 mL).
The crude compound was charged with methanol (800 mL), sodium carbonate solution (90 g in 500 mL of water) and heated to 60--70°C for 3 hr. The reaction mixture was distilled off completely, co distilled with dichloromethane (50 mL). The reaction mass pH was adjusted to 1.5 with HCl (200 mL) and charged with dichloromethane (200 mL) stirred for 10 min. The 20 both layers were separated; the aqueous layer was washed with dichloromethane (2 x 200 mL). The aqueous layer pH was adjusted to 10--12 with sodium hydroxide (20 g in 200 mL water), extracted with dichloromethane (6x200 mL). The combined organic layer was washed with brine solution (200 mL) and dried over sodium sulphate, charged with carbon (10 g) stirred for 15 min. Filtered the reaction mixture through hyflow bed, washed with 25 dichloromethane (55 mL) and distilled off the solvent completely and co--distilled with methanol (50 mL). The crude compound was cooled to 25--35°C, charged with methanol (450 mL), water (18 mL), and carbon (10 g) and stirred for 10 min at same temperature. Filtered the reaction mixture through hyflow bed and wash with methanol (50 mL). The filtrate solution was added, to a solution of tartaric acid (46.9 g) in methanol (450 mL) at 15--25°C 30
18
for 2 hr and stirred for 4 hr. Filtered the obtained solid and washed with methanol (100 mL) and dried to get the title compound.
Yield: 85.5 g. Purity by HPLC: 99.5 %;
Example--2: Preparation of the compound of formula--1.
A round bottom flask was charged with compound of formula--1a (75 g), water (375 mL) and 5 stirred for 10 min. The reaction mixture was washed with dichloromethane (3 x 112 mL) and the resulting aqueous layer pH was adjusted to 12 with sodium hydroxide solution (37.5 g in 75 mL of water) and charged with dichloromethane (375 mL), stirred for 10 min, layers were separated, the aqueous layer was extracted with dichloromethane (2x75 mL). The combined organic layer was washed with brine solution (75 mL) and charged with carbon (7.5 g) to 10 organic layer stirred for 10 min, filtered the organic layer through hyflow bed washed with dichloromethane (75 mL) and distilled off completely, co--distilled with methanol (18.75 mL). The crude compound was charged with methanol (300 mL), water (6 mL) and carbon (7.5 g) stirred for 10 min at 25--35°C. Filtered the solution through hyflow bed and washed with methanol (18.75 mL). The organic layer was added, to a solution of tartaric acid (32.25 15 g) in methanol (300 mL) at 15--25°C for 0.5 hr and stirred for 10 hr. Filtered the obtained solid and washed with methanol (75 mL) and dried to get the title compound.
Yield: 68.0 g.
Purity by HPLC: 99.9 %.
Varenicline nitroso impurity less than 0.1 ppm; dinitro nitroso impurity: not detected 20 diamino nitroso impurity: not detected
25 ,CLAIMS:1. A process for purification of compound of formula-1
5
Formula-1
comprising of:
a) Treating compound of formula-1a with suitable organic solvent in water,
b) separating the aqueous layer obtained in step-a) and basifying the PH to 7-13 with suitable
10 base,
c) extracting the aqueous layer obtained in step-b) with suitable solvent followed by
evaporation,
d) converting the compound obtained in step-c) to compound of formula-1 by treating tartaric
acid in methanol.
15
2. A process for purification of varenicline comprising of:
a) Treating the varenicline with suitable acid in water,
b) washing the solution obtained in step-a) with suitable organic solvent,
c) basifying the PH of solution obtained in step-b) to 7-13 with suitable base,
20 d) extracting the aqueous layer obtained in step-c) with suitable solvent,
e) evaporating the solvent to obtain varenicline.
3. The process according to claim 1, 2 wherein in the suitable solvent is selected from chloro
solvents, ether solvents, polar aprotic solvents, ester solvents, alcohol or any mixture thereof;
25 the suitable base is inorganic base or organic base; the suitable acid is Con.HCl, Dil.HCl,
acetic acid, HBr, sulfuric acid, acetic acid, trifluoro acetic acid, tartaric acid and oxalic acid.
The suitable temperature is 0 to 50°C;
20
4. A process for purification of compound of formula-1
5 Formula-1
comprising of:
a) Treating compound of formula-1a in water with dichloromethane,
b) separating the aqueous layer and basifying the PH to 11-12 with sodium hydroxide,
c) extracting the aqueous layer with dichloromethane and evaporating,
10 d) converting varenicline obtained in step-c) to compound of formula-1 by treating with
tartaric acid in methanol.
5. A process for purification of varenicline comprising of:
a) Treating the crude varenicline with dil hydrochloric acid in water,
15 b) washing the solution obtained in step-a) with dichloromethane,
c) basifying the PH to 11-12 of the aqueous solution obtained in step-b) with sodium
hydroxide,
d) extracting the aqueous layer obtained in step-c) with dichloromethane,
e) evaporating the solvent to obtained varenicline as pure compound.
20
6. A process for preparation of compound of formula-1, varenicline obtained according to
preceding claims treating with tartaric acid in methanol.
7. Varenicline or Varenicline tartrate obtained according to preceding claims having
chemical purity by HPLC >99.9 %;
25 8. Varenicline or Varenicline tartrate obtained according to preceding claims having
Varenicline Nitroso impurity: less than 1.8 ppm, more preferably less than 0.5 ppm level;
Dinitro nitroso impurity and diamino nitroso impurities are below detection level.