Technical field of invention:
The present invention relates to novel process for preparation of varenicline, which is a
nicotine partial agonist used for the treatment of nicotine dependency and several CNS
disorders. The present invention also relates to the novel amorphous form of varenicline
L-tartarate, amorphous form of varenicline L-tartarate with povidone and process for
their preparation.
Background of the invention:
Varenicline is nicotinic partial agonist and is known by chemical name 5.8.14-
triazatetracyclo[10.3.1.02.11.04.9]hexadeca-2(ll)-3.5.7.9-pentaene. The L-tartarate salt of
varenicline marketed by Pfizer under the trade name Chantix in USA is used for the
treatment of nicotine dependency. Varenicline represented by structural formula (1) is
disclosed in US patent 6,410,550 and its L-tartarate salt represented by structural formula
(2) is disclosed in US patent 6,890,927.

Few references in the prior art are directed towards synthesis of varenicline. The
disclosures in the prior art, which arc most relevant to the present invention are discussed
in details below.
The product patent for varenicline, US 6,410,550 B1 and its continuation patent US
6,951,938 B2 teaches a process for preparation of varenicline, which is depicted in the
synthetic scheme given below:


The diamino compound (where P= nitrogen protecting group such as trifluoroacetyl or t-
BOC) is subjected to cyclization with a cyclizing agent selected from a derivative of
glyoxal (3) or sodium bisulfite ethanedione addition adduct (4)

whereby, R1 and R2 are selected independently from hydrogen, C1-C6 alkyl, aryl and
heteroaryl. to afford N-protccted varenicline. which is further subjected to deprotection in
presence of a base to afford varenicline free base.
The patent application US 2008/275051 A1 teaches a process for preparation of
varenicline, wherein the cyclization of diamino compound is effected by employing
aqueous glyoxal in a protic alcoholic solvent.
The patent application US 2007/185327 Al teaches a process for preparation of
varenicline, wherein the cyclization of diamino compound is carried out by employing
2,3-dihydroxy-1,4-dioxanc as a cyclizing agent.
The survey of prior art reveals that ample efforts have not been taken for studying
polymorphs of varenicline L-tartaratc. The US patent 7.265,119 is the lone reference in

the prior art which describe various polymorphs of varenicline L-tariarate which are
discussed in details below:
US patent 7,265,119 discloses three different polymorphic forms, viz., anhydrous form
A, anhydrous form B and hydrated form C of varenicline L-tartarate. Form A is a
kinetically favored polymorph, which will convert under appropriate conditions to
thermodynamically more favored form B. Form C is a monohydrate, which maintains its
one equivalent of water under vacuum at moderate temperature for 24 hours but
eventually over time will lose water and convert to anhydrous form B. Anhydrous form B
is thermodynamically stable polymorph of varenicline L-tartarate.
The existence of sole prior art document points towards the fact that efforts to find out
different polymorphs of varenicline tartarate are meager. In the hands of inventors of
present invention, two new amorphous forms of varenicline tartarate are obtained.
Summary of the invention:
The present invention provides a novel process for preparation of varenicline comprising
the steps of:
(i) reacting diamino compound (5) with 2.3-dichloro-1,4-dioxane (6) in presence
of a base to obtain N-protected varenicline (7);
(ii) deprotecting compound (7) to obtain varenicline free base (1): and
(iii) optionally converting varenicline (1) to varenicline tartarate (2).
The present invention also provides novel amorphous form of varenicline L-tartarate,
amorphous form of varenicline L-tartaralc with povidone and process for their
preparation. The process for preparation of amorphous form of varenicline L-tartarate
involves spray drying of the aqueous solution of varenicline L-tartarate.
Description of the drawings:
Figure 1 illustrates powder x-ray diffraction pattern of amorphous form of varenicline
L-tartarate.

Figure 2 illustrates thermogravimetric analysis (TGA) thermogram of amorphous form
of varenicline L-tartarate.
Figure 3 illustrates infrared spectrum of amorphous form of varenicline L-tartarate.
Figure 4 illustrates powder x-ray diffraction pattern of amorphous form of varenicline
L-tartarate with povidone.
Figure 5 illustrates thermogravimetric analysis (TGA) thermogram of amorphous form
of varenicline L-tartarate with povidone.
Figure 6 illustrates infrared spectrum of amorphous form of varenicline L-tartarate with
povidone.
Description of the invention:
The present invention provides a novel process for preparation of varenicline comprising
the steps of:
(i) reacting diamino compound (S) with 2,3-dichloro-1,4-dioxane (6) in presence
of a base to obtain N -protected varenicline (7);
(ii) deprotecting compound (7) to obtain varenicline free base (1); and
(iii) optionally converting varenicline (1) to varenicline tartarate (2).
The process of present invention is depicted in the synthetic scheme given below:


In one embodiment, the invention provides a novel process for preparation of N-protected
varenicline by condensation of the diamino compound (5) with 2.3-dichloro-1,4-dioxane
(6). P is amino protecting group such as benzyl, acetyl, formyl, trifluoroacetyl, t-BOC, p-
nitrobenzyl, trichloroacetyl, -COOCH2CCl3, -COO(C1-C6)alkyl and the like.
The starting diamino compound (5) is prepared according to the methods known in prior
art.
The molar equivalents of 2,3-dichloro-1,4-dioxanc (6) with respect to diamino compound
(5) is in the range of 1 to 1.8, more preferably 1.4.
The reaction is carried out in a polar organic solvent selected from the group consisting
of lower alcohols such as methanol, ethanol. n-propanol. isopropanol; ketones such as
acetone, ethylmethyl ketone, diethyl ketone, mcthylisobutyl ketone; lower aliphatic esters
such as ethyl acetate, methyl acetate; dinethylformamide. dimethyl sulfoxide, acetonitrile
and water or mixtures thereof. More preferably a mixture of lower alcohol and water is
employed, most preferably a mixture of isopropanol and water is employed.
The ratio of isopropanol: water in the solvent mixture is in the range of 10: 90 to 90: 10.
More preferably the ratio of solvent mixture is in range of 60: 40 to 40: 60, most
preferably the solvent mixture of isopropanol and water in ratio of 80:20 is employed.
In another aspect of present invention. reaction is carried out in presence of an organic or
inorganic base. The organic base is selected from tricthylamine. diisopropylethyl amine,
pyridine and the like while inorganic base is selected from hydroxides of alkali metals or
alkaline earth metals such as sodium hydroxide, potassium hydroxide, lithium hydroxide;
bicarbonates of alkali metals or alkaline earth metals such as sodium bicarbonate,
potassium bicarbonate and the like; carbonates of alkali metals or alkaline earth metals
such as sodium carbonate, potassium carbonate; and ammonia and mixtures thereof. Most
preferably tricthylamine is used as a base.

The condensation reaction is carried out at a temperature ranging from 0 to S0°C, more
preferably in range of 0 to 30°C. most preferably at 15-20°C. The reaction mixture is
stirred for 10-40 hours, most preferably for 25-30 hours.
In another embodiment of the present invention N-protccted varenicline (7) is subjected
to removal of protecting group by methods known in the literature such as acidic or
alkaline hydrolysis and catalytic hydrogenation to obtain varenicline free base. The
varenicline free base is optionally converted to varenicline tartarate by reaction with
tartaric acid as described in the process covered by our co-pending application
850/KOL/2009 dated 11 June 2009.
In yet another aspect, the present invention provides novel amorphous form of
varenicline L-tartarate, amorphous form of varenicline L-tartarate with povidone and
process for their preparation.
In one embodiment of the invention, the amorphous form of varenicline L-tartarate is
identified by the following characterization data:
PXRD: Powder x-ray diffraction pattern of amorphous form is as depicted in figure 1.
TGA: The thermogravemetric analysis thermogram (TGA) of novel amorphous form is
as depicted in figure 2.
IR spectrum: The IR spectrum of novel amorphous form is as depicted in figure 3 and
exhibit following major peaks (in cm-1): 3272.4. 3319.1. 2800.4. 2615.9, 1871.6, 1723.9.
1594.3,1409.0,1263.9 and 679.7
Melting range: 205.7-205.8°C
In an another embodiment of the invention, amorphous form of varenicline L-tartarate
with povidone is characterized by following characterization data:
PXRD: Powder x-ray diffraction pattern of amorphous form with povidone is as depicted
in figure 4.

TGA: The thcrmogravemelric analysis thermogram (TGA) of novel amorphous form
with povidone is as depicted in figure 5.
IR Spectrum: The IR spectrum of novel amorphous form with povidone is as depicted in
figure 6 and exhibits following major peaks (in cm-1): 3271.7, 3318.9, 2799.9, 1867.2,
1727.6,1651.35,1595.5, 1479.7, 1269.8 and 679.7
Melting range: 207.2-208.9°C
In another embodiment, the present invention provides a process for preparation of
amorphous form of varenicline L-tartarate and/or amorphous form of varenicline L-
tartarate with povidone comprising the steps of:
(i) preparing a solution of varenicline L-tartarate in water;
(ii) optionally adding povidone:
(iii) stirring the mixture; and
(iv) isolating amorphous form with povidone.
Povidone also known as polyvinylpyrrolidone is a water soluble polymer made from the
monomer N-vinylpyrrolidone. In solution, it has excellent wetting properties and readily
forms films. This makes it good as a coating or an additive to coatings. Other polymers
such as cross povidone can also be used, which is a highly crosslinked form of povidone.
Preferably 5 to 20 volumes of water is employed for the preparation of aqueous solution
of varenicline L-tartarate, most preferably 10 volumes of water is employed.
Amorphous form of varenicline L-tartarate is accomplished by spray drying technique,
wherein the inlet temperature is kept at around 120-160°C and outlet temperature is set at
around 60-80°C. The aqueous solution of varenicline L-tartarate is purged through the
inlet of spray dryer at a flow rate of 2-4 ml/min and solid obtained in the receiver is
collected.

Other methods such as lyophilization of aqueous solution of varenicline L-tartarate or
that of varenicline L-tartarate with povidone can also be employed to obtain amorphous
form.
The invention is further illustrated by following examples, which should not be construed
as limiting to the scope of invention.
Experimental:
Example 1
Preparation of 2,3-dichloro-1,4-dioxanc (6)
161.6 ml of sulfuryl chloride was added dropwise to 84.6 ml of 1.4 dioxane at 0°C over a
period of 1 hour. The reaction mixture was heated to 60°C and stirred for 18 hours. The
mixture was cooled to room temperature and nitrogen was bubbled through the reaction
mixture for 1 hour. The product obtained was purified by distillation under reduced .
pressure to afford of 2,3-dichloro-1,4-dioxane as a colorless liquid.
Yield = 114.5 g (72%)
Example 2
Preparation of N-protected varenicline (7)
5 g of diamino compound (S) was dissolved in 125 ml (80: 20) mixture of isopropanol
and water and cooled to 0°C. 4.42 g of tricthylamine and 3.85 g of 2, 3-dichloro-l. 4-
dioxane (6) were added to the solution. The mixture was warmed to 15-20°C and stirred
for 30 hours. The mixture was concentrated under reduced pressure, ethyl acetate was
added and washed twice with water. Layers were separated and the organic layer was
distilled off. Cyclohexane was added to the residue and stirred for 2 hours. The solid was
filtered and dried under vacuum at 40°C.
Yield = 4.2g (85%)
Example 3
Preparation of varenicline free base (1)
4 g of N-protected varenicline (7) was slurried in 25 ml methanol. 25ml of 11% aqueous
sodium carbonate was added and the mixture was heated at 70°C for 2-3 hours. The

mixture was concentrated, treated with water and extracted with dichloromethane. Layers
were separated, organic layer was dried over sodium sulfate and distilled of!'.
Cyclohexane was added slowly to the residue and stirred for 1 hour. The solid was
filtered off and dried.
Yield = 1.9 g (80%)
HPLC Purity = 99.6%
Example 4
Preparation of amorphous form of varenicline L-tartaratc
10 g of varenicline L-tartarate was dissolved in 100 ml of water. 1 g of activated carbon
was added, stirred for 1 hour and filtered. Filtrate was purged through the spray dryer
inlet (Inlet temperature: 120-160°C; outlet temperature: 60-80°C; flow rate: 2-4 ml/min).
7 g of solid was collected from the receiver
Example 5
Preparation of amorphous form of varenicline tartarate with povidone
10 g of varenicline L-tartarate was dissolved in 100 ml of water. 1 g of povidone (PVPK
30) and 1 g of activated carbon was added. The mixture was stirred for 1 hour and
filtered. Filtrate was purged through the spray dryer inlet (Inlet temperature: 120-160°C:
outlet temperature: 60-80°C; flow rate: 2-4 ml/min). 7 g of solid was collected from the
receiver.

We Claim:
1. A novel process for preparation of varenicline of formula (1)

comprising the steps of:
(iv) reacting diamino compound of formula (5) with 2,3-dichloro-1,4-dioxane of
formula (6) in presence of base to obtain N-protected varenicline of formula
(7);

(v) deprotecting compound (7) to obtain varenicline free base (1); and
(vi) optionally converting varenicline (1) to varenicline I.-tartarate of formula (2).
2. A process according to claim 1, wherein 1 to 1.8 molar equivalents of 2,3-
dichloro-1,4-dioxane (6), most preferably 1.4 molar equivalents is employed.
3. A process according to claim 1. wherein step (i) is carried out in a solvent selected
from group consisting of lower alcohols such as methanol, ethanol, n-propanol,
isopropanol; ketones such as acetone, cthylmcthyl ketone, diethyl ketone,
methylisobulyl ketone; lower aliphatic esters such as ethyl acetate, methyl acetate;
dincthylformamide. dimethyl sulfoxide, acetonitrile and water or mixtures
thereof.
4. A process according to claim 1, wherein step (i) is carried in a solvent mixture
comprising of isopropanol and water.
5. A process according to claim 1, wherein the ratio of isopropanol: water is in the
range of 10:90 to 90:10, more preferably in range of 60:40 to 40:60, most
preferably 80:20.

6. process according to claim 1, wherein the base employed in step (i) is selected
from organic bases such as triclhylamine, diisopropylethyl amine or pyridine.
7. A process according to claim 1, wherein the base employed in step (i) is selected
from inorganic bases such as hydroxides of alkali metals or alkaline earth metals
such as sodium hydroxide, potassium hydroxide, lithium hydroxide; bicarbonates
of alkali metals or alkaline earth metals such as sodium bicarbonate, potassium
bicarbonate; carbonates of alkali metals or alkaline earth metals such as sodium
carbonate, potassium carbonate; and ammonia.
8. A process according to claim 1. wherein the base employed in step (i) is
tricthylamine.
9. A process according to claim 1, wherein the reaction of step (i) is carried out at a
temperature of 0 to 30°C, most preferably at 15-20°C.
10. A novel amorphous form of varenicline I.-tartarate, which exhibits powder x-ray
diffraction pattern as depicted in figure 1.
11. A process for preparation of amorphous form of varenicline L-tartarate
comprising the steps of:
(i) preparing a solution of varenicline L-tartarate in water;
(ii) stirring the mixture; and
(iii) isolating amorphous form of varenicline L-tartarate.
12. A process according to claim 11, wherein amorphous form is isolated by spray
drying.
13. A process according to claim 11, wherein S to 20 volumes of water is used to
prepare aqueous solution of varenicline L-tartarate. most preferably 10 volumes
of water is used. A
14. A novel amorphous form of varenicline L-tartarate with povidone, which exhibits
powder x-ray diffraction pattern as depicted in figure 3.
15. A process for preparation of amorphous form of varenicline L-tartarate with
povidone comprising the steps of:
(i) preparing a solution of varenicline L-tartarate in water;
(ii) adding povidone;
(iii) stirring the mixture; and

(iv) isolating amorphous form of varenicline L-tartarate with povidone.
16. A process according to claim IS, wherein amorphous form with povidone is
isolated by spray drying.
17. A process according to claim 15. wherein 5 to 20 volumes of water is used to
prepare aqueous solution of varenicline L-tartarate, most preferably 10 volumes
of water is used.
The present invention relates to novel process for preparation of varenicline. The
invention also relates to novel amorphous form of varenicline L-tartarate, amorphous
form of varenicline L-tartarate with povidone (PVPK 30) and process for their
preparation.