Field of the Invention
The present invention' relates to ( an improved process for the preparation of
Vilazodone and its acid addition salt. The present invention also relates to the process
for the preparation of polymorphs of Vilazodone hydrochloride.
Background of the Invention
Vilazodone is selective serotonin reuptake inhibitor, which also acts as partial agonist
at serotonergic 5-HT1A receptors. It is mainly used for the treatment of major
depressive disorder (MDD). Vilazodone is chemically known as 2-benzofurancarboxamide,
5-[4-[4-(5-cyano-l//-indol-3-yl)butyl]-l-piperazinyl] and has
structural Formula 1:
NH2
Formula 1
The product is marketed in the form of hydrochloride salt. The current pharmaceutical
product containing this drug is being sold in United States byjs4erck using Jhe_trade_
name Viibryd. It is orally administered as tablets containing 10 mg, 20 mg and 40 mg
of Vilazodone as the hydrochloride salt.
Vilazodone and its acid addition salts were first described in US5532241. Example 4
of said patent described process for preparing of Vilazodone" hydrochloride by
reacting l-[4-(5-cyanoindol-3-yl) butyl]-4-(2-carboxybenzofuran-5-yl)-piprazine at
first with 2-chloro-l-methyl pyridinium methanesulfonate in N-methylpyrrolidine
then with dried ammonia gas, customary working up gives the free base Vilazodone
which is further converted to Vilazodone hydrochloride.
US7834020 disclosed Vilazodone hydrochloride anhydrate form IV, amorphous form,
other crystalline forms and process of preparation thereof. The marketed form of
Vilazodone hydrochloride in USA is crystalline form IV.
Journal of Medicinal Chemistry (2004), 47(19), 4684-4692 discloses process for
preparation of Vilazodone as per below mentioned Scheme 1.
Org. Process Res. Dev., 2012. 16 (9), page 1552-1557 discloses process as per below
mentioned Scheme 2:
CN103304547A discloses a process for preparation of Vilazodone as per the below
mentioned Scheme 3:
Wherein R is alkoxy or amino; Ar is substituted or unsubstituted aryl; X is CI or Br.
The processes for the preparation of Vilazodone and its intermediates described in the
aforementioned prior art suffer from disadvantages such as the use of additional and
expensive reagents like 2-chloro-l-methylpyridinium methanesulfonate, 2-chloro-lmethylpyridinium
iodide; use of expensive and hazardous solvents like Nmethylpyrrolidone
and 1- butanol; use of tedious and cumbersome procedures like
multiple process steps, prolonged reaction time periods, column chromatographic
purifications, multiple isolations/ re-crystallizations, and thus resulting in a poor
product yield and quality. Methods involving column chromatographic purifications
are generally undesirable for large-scale operations, thereby making the process
commercially unfeasible.
Many other patent publications have also been disclosed so far, which describes the
process for the preparation of Vilazodone HC1. Still there is a need to develop a
simple, cost effective, high yielding and easy to implement on industrial scale process
for the preparation of Vilazodone and its acid addition salt of Formula 1.
Object of the invention
The principal object of the present invention is to provide a process for the
preparation of Vilazodone or pharmaceutically acceptable salts, hydrates or solvates
thereof, which alleviates the drawbacks of prior art process.
One object of the present invention is to provide an improved, efficient, safe and
convenient process for preparation of Vilazodone and its acid addition salt.
Another object of the present invention is to provide a process for preparation of
Vilazodone hydrochloride by using TV-protected intermediates.
Further another object of the present invention is to provide a process for preparation
of Vilazodone hydrochloride by using p-toluene sulphonyl protected intermediates.
Yet another object of the present invention is to provide a process for the preparation
of crystalline form IV of Vilazodone hydrochloride.
Further yet another object of the present invention is to provide a process for the
preparation of amorphous form of Vilazodone hydrochloride.
Still further yet another object of the present invention is to provide a process for the
preparation of amorphous form of Vilazodone hydrochloride by solvent/anti-solvent
method.
Summary of the invention
In accordance with principal embodiment, the present invention provides a process for
the preparation of Vilazodone and its acid addition salt of Formula 1, comprising the
steps of:
(a) TV-protection of 3-(4-chlorobutyl)-l#-indole-5-cabroimtile of Formula 5;
H
Formula 5
by treating with TV-protecting reagent in presence of base, and suitable solvent,
optionally in the presence of catalyst to provide TV-protected compound of
Formula 16;
i
z
Formula 16
(b) coupling the compound of Formula 16 with compound of Formula 4A or its
salts;
r„ox
Formula 4A
Wherein R is selected from -NH2) -OMe, -OEt, -OPr, O-iPr
in the presence of suitable solvent and base, with or without use of an
activating agent to provide compound of Formula 17 or its acid addition salt;
Formula 17
(c) amidation of compound of Formula 17 or its acid addition salt by treating with
a suitable amidation agent in presence of suitable solvent to provide a
compound of Formula 18;
(d) deprotection of the compound of Formula 18 using suitable deprotecting agent
in the presence of suitable solvent to provide Vilazodone base of Formula 1; ,
(e)_CjQnvertingJVilazodonerbase_into-its.acid-addition^salt.
In accordance with another embodiment, the present invention provides a process for
the preparation of Vilazodone and its hydrochloride salt of Formula 1, comprising the
steps of:
(a) _Af-pfbte.c.tibn„oY 3-(4-chlorobutyl)- lS-indole-5-cabronitrile of Formula 5;
ci
by treating with para-toluenesulfonyl chloride in presence of base, suitable
solvent, optionally in the presence of catalyst to provide of 3-(4-chlorobutyl)-
l-tosyl-l//-indole-5-cabronitrile of Formula 8;
(b) coupling the compound of Formula 8 with compound of Formula 4A or its
salt:
-o p
HN^J
Formula 4A
Wherein R is selected from -NH2, -OMe, ~OEt, -OPr, O-iPr
in the presence of suitable solvent and base, with or without use of an
activating agent to provide compound of Formula 9A or its acid addition salt;
CH3
Formula 9A
(c) ami'datioh of compound of Formula 9A or its acid addition salt by treating
with a suitable amidation agent in presence of suitable solvent to provide a
compound of Formula 19;
O' CONH2
CH3
Formula 19
(d) deprotection of the compound of Formula 19 using suitable deprotecting agent
in the presence of suitable solvent to provide vilazodone base of Formula 1;
(e) converting Vilazodone base into its hydrochloride salt.
In accordance with yet another embodiment, the present invention provides a process
for the preparation of Vilazodone and its hydrochloride salt of Formula 1, comprising
the steps of:
(a) Af-protection of 3-(4-chlorobutyl)-l//-indole-5-cabronitrile of Formula 5;
by treating with p-toluene sulfonyl chloride in presence of a dichloromethane
and tetrabutyl ammonium hydrogen sulfate to provide of 3-(4-chlorobutyl)-ltosyl-
l//-indole-5-cabronitrile of Formula 8;
CH3
Formula 8
(b) coupling the compound of Formula 8 with compound of Formula 4A or its
salt;
Formula 4A
Wherein R is selected from -NH2, -OMe, -OEt, -OPr, O-iPr
in the presence of sodium bicarbonate, N,N-dimethylacetarnide and potassium
iodide to provide compound of Formula 9 A or its acid addition salt;
(c) amidation of compound of Formula 9A or its acid addition salt by treating it
with formamide and sodium methoxide in presence of methanol to provide a
compound of Formula 19;
CH3
Formula 19
(d) deprotection of the compound of Formula 19 using methanolic sodium
methoxide solution in the presence of tetrahydrofuran solvent to provide
vilazodone base of Formula 1;
(e) converting Vilazodone base into its hydrochloride salt.
In accordance with further yet another embodiment the present invention provides a
process for the preparation of compound of formula 19 by amidation of compound of
Formula 9A or its acid addition salt:
CH3
Formula 9A
Wherein R is selected from ~NH2, -OMe, -OEt, -OPr, O-iPr
using formamide and sodium methoxide in presence of methanol as solvent to provide
a compound of Formula 19;
In accordance with further yet another embodiment, the present invention provides a
process for preparation of crystalline form IV of Vilazodone hydrochloride, which
comprises the steps of:
(a) dissolving Vilazodone base in alcoholic solvent;
(b) optionally treating with activated carbon;
(c) adding alcoholic-HCl solution or passing HC1 gas and;
(d) isolating crystalline form IV.
In accordance with further yet another embodiment, the present invention provides a
process for preparation of crystalline form TV of Vilazodone hydrochloride, which
comprises the steps of:
(a) dissolving Vilazodone base in isopropanol;
(b) optionally treating with activated carbon;
(c) adding IPA-HC1 solution or passing HC1 gas and;
(d) isolating crystalline form IV.
In accordance with, still further yet another embodiment, the present invention
provides a process for preparation of amorphous Vilazodone hydrochloride, which
comprises the steps of:
(a) dissolving Vilazodone hydrochloride in mixture of water and water miscible
organic solvents;
(b) optionally treating with activated carbon;
(c) removing the solvent and;
(d) isolating amorphous Vilazodone hydrochloride.
In accordance with, still further yet another embodiment, the present invention
provides a process for preparation of amorphous Vilazodone hydrochloride, which
comprises the steps of:
(a) dissolving Vilazodone hydrochloride in a mixture of water, acetonitrile and
methanol;
(b) optionally treating with activated carbon;
(c) removing the solvent by spray drying and;
(d) isolating amorphous Vilazodone hydrochloride.
In accordance with, still further yet another embodiment, the present invention
provides a process for preparation of amorphous Vilazodone hydrochloride by
solvent/anti-solvent method, which comprises the steps of:
(a) dissolving Vilazodone hy_dro.chlQride_in.a-Suitable-solvent;-
(b) optionally treating with activated carbon;
(c) adding the suitable anti-solvent and;
(d) isolating-amorphous Vilazodone hydrochloride.
Detail description of the drawings:
Fig. 1.X-ray powder diffraction (XRPD) pattern of Vilazodone base obtained
according to example 4. -
Fig.2.X-ray powder diffraction (XRPD) pattern of Vilazodone base isolated from
methanol according to example 5.
Fig.3.X-ray powder diffraction (XRPD) pattern of Vilazodone base isolated from a
mixture of N, N-dimethyl"acetamide, isopropyl alcohol and water according to
example 5.
Fig.4.X-ray powder diffraction (XRPD) pattern of Vilazodone hydrochloride form IV
obtained according to example 6.
Fig.5.X-ray powder diffraction (XRPD) pattern of Vilazodone hydrochloride obtained
according to example 7.
Fig.6.X-ray powder diffraction (XRPD) pattern of amorphous Vilazodone
hydrochloride obtained according to example 8.
Fig.7.X-ray powder diffraction (XRPD) pattern of amorphous Vilazodone
hydrochloride obtained according to example 9.
Fig.8 .X-ray powder diffraction (XRPD) pattern of amorphous Vilazodone
hydrochloride obtained according to example 10.
Detail description of the invention
The present invention provides an efficient and industrially advantageous process for
the preparation of Vilazodone and its acid addition salt of Formula 1.
In accordance with principal embodiment, the present invention provides a process for
the preparation of Vilazodone and its acid addition salt of Formula 1, comprising the
steps of:
(a) iV-proteetion of 3-(4-chlorobutyl)-l//-indble-5-cabronitrire of Formula 5;
ci
H
Formula 5
•by'treating with W-protecting reagent in presence of base, and suitable solvent,
optionally in the presence of catalyst to provide Af-protected compound of
Formula 16:
(b) coupling the compound of Formula 16 with compound of Formula 4A or its
salt;
xrx H N ^
Formula 4 A
Wherein R is selected from -NH2, -OMe, -OEt, -OPr, O-iPr
in the presence of suitable solvent and base, with or without use of an
activating agent to provide compound of Formula 17 or its acid addition salt;
COR
Formula 17
(c) amidation of compound of Formula 17 or its acid addition salt by treating with
a suitable amidation agent in presence of suitable solvent to provide a
compound of Formula 18;
CONHFormula
18
(d) deprotection of the compound of Formula 18 using suitable deprotecting agent
in the presence of suitable solvent to provide vilazodone base of Formula 1;
(e) converting Vilazodone base into its acid addition salt
wherein,
Z represents TV-protecting group selected from the group carboalkoxy or carboaryloxy,
wherein aryl may be substituted or unsubstituted; -S(=02)Ri, wherein Ri is selected
from p-toluene, phenyl, methyl, n-propyl, n-butyl, trifluoromethyl, benzyl, 3-
nitrophenyl, 4-nitrophenyl, 4-methoxyphenyl, 3-aminophenyl, 4-aminophenyl, 4-
methylphenyl, 1 -napthalene, 2-napthalene or like thereof.
First step involves TV-protection of 3-(4-chlorobutyl)-l//-indole-5-cabronitrile of
Formula 5 by treating with TV-protecting reagent in the presence of suitable solvent,
base and with or without use of phase transfer catalyst to provide TV-protected
intermediate of Formula 16.
After completion of reaction, the TV-protected intermediate of Formula 16 is isolated
or may be with isolation coupled with compound of Formula 4A or its salt in the
presence of suitable solvent, base and with or without use of activating agent to
provide compound of Formula 17 or its acid addition salt.
Amidation of compound of Formula 17 or its acid addition salt is carried out by
treating with a suitable amidation agent in presence of suitable solvent to provide a
compound of Formula 18.
Next step involves deprotection of the compound,of Formula 18 using suitable
deprotecting agent in the presence of suitable solvent to provide Vilazodone base of
Formula 1.
Further converting Vilazodone base of Formula 1 into acid addition salt by treating
with suitable source of acid known in the art using suitable solvent.
In accordance with another embodiment, the present invention provides a process for
the preparation of Vilazodone and its hydrochloride salt of Formula 1, comprising the
steps of:
(a) TV-protection of 3-(4-chlorobutyl)-l//-indole-5-cabronitrile of Formula 5;
CI
by treating with para-toluenesulfonyl chloride in presence of base, suitable
solvent, optionally in the presence of catalyst to provide of 3-(4-chlorobutyl)-
l-tosyl-l//-indole-5-cabronitrile of Formula 8;
CH3
Formula 8
(b) coupling the compound of Formula 8 with compound of Formula 4A or its
salt;
o. ,o
H^^^ R
H N . v
Formula 4A
Wherein R is selected from -NH2, -OMe, -OEt, -OPr, O-iPr
in the presence of suitable solvent and base, with or without use of an
activating agent to provide compound of Formula 9A or its acid addition salt;
(c) amidation of compound of Formula 9A or its acid addition salt by treating
with a suitable amidation agent in presence of suitable solvent to provide a
compound- of Formula 19;
0-—CONH2
CH3
Formula 19
(d) deprotection of the compound of Formula 19 using suitable deprotecting agent
in the presence of suitable solvent to provide vilazodone base of Formula 1;
(e) converting Vilazodone base into its hydrochloride salt.
First step involves Af-protection of 3-(4-chlorobutyl)-l//-indole-5-cabronitrile of
Formula 5 by treating with para-toluenesulfoyl chloride in the presence of suitable
solvent, base and with or without use of phase transfer catalyst to provide Af-protected
intermediate of Formula 16. Generally reaction may be carried out at a temperature-of-
—-10-to-30°e-forfewTninutes to few hours or tillcompletipn of reaction -Preferably"
- "reactiorTls "conducted at a temperature of -10 to 10°C, more preferably reaction is
conducted at a temperature of -10 to 0°C and it takes 1 to 3 hours for completion of
the reaction. The reaction completion is monitored by suitable techniques such as thin
layer chromatography (TLC), high performance liquid chromatography (HPLC), ultra
performance liquidichromatography (UPLC) and like thereof.
After completion of reaction, the 3-(4-chlorobutyl)-i-tosyl-l//-indole-5-cabronitrile
of Formula 8 is isolated or without isolating may be taken for next step.
£
o Next step involves coupling of 3-(4-chIorobutyI)-l-tosyl-l//-indole-5-cabronitrile of
3> Formula 8 with compound of Formula 4A or its salt in the presence of suitable
CO o
^-
o
solvent, base and with or without use of activating agent to provide compound of
Formula 9A or its acid addition salt. Generally reaction may be carried out at a
5 temperature of 15°C to reflux temperature for few minutes to few hours or till
completion of reaction. Preferably reaction is conducted at a temperature of 15°C to
CD
O
CO
CO
o
CN
_a
m
E
o
OS
to
o
o
(0
o
CO
to
o
reflux temperature, more preferably reaction, is conducted at a temperature of 70 to
90°C for 22 to 26 hours.
Amidation of compound of Formula 9A or its acid addition salt is carried out by
treating with a suitable amidation agent in presence of suitable solvent to provide a
compound of Formula 19. Generally amidation may be carried out at a temperature
of 0 to 50°C in few minutes to few hour, preferably at a temperature of 20 to 40°C.
Next step involves deprotection of the compound of Formula 19 using suitable
deprotecting agent in the presence of suitable solvent to provide Vilazodone base of
Formula 1.
Suitable solvent used for //-protection in step a) includes but not limited to organic
solvents selected from the group comprising of sulfoxide, amide, esters, ketone,
nitrile, aliphatic or aromatic hydrocarbons, chloro solvents or mixture thereof.
Preferably, selected from dimethyl sulfoxide (DMSO), N,N-dimethylformamide
(DMF), ethyl acetate, propyl acetate, butyl acetate, acetone, propanone, butanone,
methyl isobutyl ketone, acetonitrile, toluene, xylenes, methylene dichloride (MDC),.
ethylene dichloride, chloroform and the like or„mixture-thereofririofe^preferably
-solventusecTis methylene dichloride (MDC).- — ~~
The base used for iV-protection in step a) may be selected from organic or inorganic
base,- wherein inorganic base is selected from alkali or alkaline earth metal
hydroxides, carbonates, bicarbonates selected from such as sodium hydroxide,
potassium hydroxide, calcium hydroxide, magnesium hydroxide, cesium hydroxide,
"sodium carbonate, potassium carbonate, calcium carbonate, magnesium carbonate,
cesium carbonate, sodium bicarbonate, potassium bicarbonate, calcium bicarbonate,
magnesium bicarbonate, cesium bicarbonate, sodium with liquid ammonia, sodamide
or the like and mixture thereof. Organic base is selected from diisopropyl ethyl amine,
triethyl amine, tributyl amine, A^-methyl morpholine, and pyridine or like thereof;
preferably base used is sodium hydroxide.
The phase transfer catalyst used for TV-protection in step a) may be selected from tetra
butyl ammonium bromide (TBAB), tetrapropyl ammonium bromide, tributyl benzyl
ammonium bromide, tetraoctyl ammonium bromide, tetra butyl ammonium iodide,
tetra butyl ammonium hydrogen sulfate (TBAHS), benzyl trimethyl ammonium
chloride, benzyl triethyl ammonium chloride, tetra butyl ammonium acetate, terra
butyl ammonium iodide and ethyl triphenyl phosphonium bromide; preferably phase
transfer catalyst used is tetra butyl ammonium hydrogen sulfate (TBAHS).
Solvent used during coupling in step b) may be selected from but not limited to
organic solvents selected from ketone such as acetone, propanone, butanone, methyl
isobutyl ketone and the like thereof; hydrocarbons are selected from aliphatic
hydrocarbons or aromatic hydrocarbons, aliphatic hydrocarbons are selected from the
group comprising of alkanes or cycloalkanes such as pentane, hexane, heptane,
octane, cyclohexane, cyclopentane and the like, aromatic hydrocarbons are selected
from the group comprising of toluene, xylene. Polar aprotic solvent are selected from
the group comprising of amide such as N,N-dimethylformamide (DMF), N,Ndimethyl
acetamide (DMAC) and the like thereof, preferably solvent used is N,Ndimethyl
acetamide (DMAC).
The base used during coupling in step b) may be selected from organic or inorganic
base, wherein inorganic base is selected from alkali or alkaline earth metal
hydroxides, carbonates, bicarbonates selected from the group comprising of sodium
hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, cesium
hydroxide, sodium carbonate, potassium carbonate, calcium carbonate, magnesium
carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, calcium
bicarbonate, magnesium bicarbonate, cesium bicarbonate; organic bases may be
selected from diisopropyl ethyl amine, triethyl amine, tributyl amine, Af-methyl
morpholine and pyridine or like thereof, preferably base used is sodium bicarbonate.
Activating agent used during coupling in step b) such as sodium iodide (Nal),
potassium iodide and like thereof may also be added, preferably activating agent used
is potassium iodide.
The suitable amidation agent used for amidation in step c) may be selected from
ammonia, formamide, ammonia gas, ammonium carbamate, ammonium formate,
ammonium phosphate, ammonium acetate, ammonium fluoride, ammonium bromide,
ammonium chloride, ammonium iodide, ammonium iodate, ammonium carbonate,
ammonium citrate, ammonium chromate, ammonium dichromate, ammonium
hydroxide, ammonium lactate, ammonium molybdate, ammonium nitrate, ammonium
w>- i_UX. 2.9. 2.SL©. i? "- 31
19-
oxalate, ammonium sulfate, ammonium sulfide, ammonium tartrate, ammonium
triflate, ammonium thiocyanate, ammonium dihydrogen phosphate, urea, methyl
carbamate, ethyl carbamate, propyl carbamate or t-butyl carbamate, magnesium
nitride; mixtures such as sodium methoxide/ammonia, sodium methoxide/formamide,
magnesium methoxide/ammonium chloride, magnesium methoxide/ammonia,
calcium chloride/ammonium chloride and calcium chloride/ ammonia; preferably the
amidation step is conducted by using sodium methoxide and formamide.
The suitable solvent for amidation in step c) is selected from group comprising of
alcohols, halogenated hydrocarbons, ethers, amides, hydrocarbons, and the like or mixture
thereof Alcohols are selected from the group comprising of methanol, ethanol, npropanol,
isopropanol, «-butanol and the like. Halogenated hydrocarbons are selected from
the group comprising of dichloromethane (DCM), chloroform, dichloroethane,
chlorobenzene and the like. Ethers are selected from the group comprising of diethyl ether,
methyl ter/-butyl ether (MTBE), diisopropyl ether, tetrahydrofuran (THF), dioxane and the
like. Amides are selected from the group comprising of A^A^-dimethylformamide (DMF),
AfN-dimethylacetamide (DMAC), N-methylformamide, JV-methylpyrrolidone and the like.
Aliphatic hydrocarbons are selected from the group comprising of alkanes or cycloalkanes
such as pentane, hexane, heptane, octane, cyclohexane, cyclopentane and the like.
Aromatic hydrocarbons are selected from the group comprising of toluene, xylene and the
like or mixture thereof Preferably, solvents used are methanol and THF.
The suitable deprotecting agent for deprotection used in step d) may be selected from
alkali metal alkoxide such as sodium methoxide or acids like HBr, AcOH in presence
of 4-hydroxy benzoic acid, Red Al, super hydrides, H2SO4 or mixtures of
H2SO4/TFA; thiophenol/KOH; thiophenol/K2C03 and like thereof. Preferably
deprotecting agent used is sodium methoxide.
The suitable solvent for deprotection in step d) is selected from group comprising of
nitriles, alcohols, ketones, esters, halogenated hydrocarbons, ethers, amides, hydrocarbons,
and the like or mixture thereof. Preferably, solvents used are methanol and THF.
Further converting Vilazodone base of Formula 1 into its hydrochloride salts by
treating with suitable source of hydrochloric acid known in the art using suitable
solvent.
In accordance with, further yet another embodiment the present invention provides a
process for the preparation of compound of formula 19 by amidation of compound of
Formula 9A or its acid addition salt;
CH3
Formula 9A
Wherein R is selected from -NH2, -OMe, -OEt, -OPr, O-iPr
using formamide and sodium methoxide in presence of methanol as solvent to provide
a compound of Formula 19:
0
/^CONH2
CH3
Formula 19
In accordance with, further yet another embodiment the present invention provides a
process for preparation of crystalline form IV of Vilazodone hydrochloride, which
comprises the steps of:
(a) dissolving Vilazodone base in alcoholic solvent;
(b) optionally treating with activated carbon;
(c) adding alcoholic-HCl solution or passing HC1 gas and;
(d) isolating crystalline form IV.
2-1-
w
E
so_
LL
-O^)^
h-
(D
O
^-
o
^
^—
to
^~
o
CM
"*•*•»•»
^ ™
o
^~
CO
9/91
o
CN i
>
a
•
f £
—O^s^
Alcoholic solvent used in step a) and c) may be selected from the group comprising of
methanol, ethanol, n-propanol, isopropanol, w-butanol and the like or mixture thereof.
The activated carbon treatment can be performed at a temperature of 25°C to reflux
temperature of solvent for 30 to 60 minutes, Preferably activated carbon may be done
at 40 to 80°C, more preferably carbon treatment is done at 50 to 70°C. The carbon or
silica gel can be removed by the suitable technique such as centrifugation, direct
filtration or filtration through hyflo.
Addition of alcoholic-HCl solution or passing HC1 gas can be done at 30 to 80°C,
preferably at 35 to 65°C. The resulting compound crystalline form IV of Vilazodone
hydrochloride can be isolated by suitable techniques such as filtration, centrifugation
and the like thereof known in the art.
In accordance with, further yet another embodiment, the present invention provides a
process for preparation of crystalline form IV of Vilazodone hydrochloride, which
comprises the steps of:
(a) dissolving Vilazodone base in isopropanol;
(b) optionally treatingjwith activate_d carbon; •_...-- - - -- -
(c) adding IPA-HC1 solution or passing HC1 gas;
(d) isolating crystalline form IV.
Accordingly, crystalline Vilazodone hydrochloride Form IV obtained according to the
instant invention possess the relative particle size distribution wherein the 10th
volume percentile particle size D(0.1) is less than about 50 um, the 50th volume
percentile particle size D(0.5) is less than about 100 um, or the 90th volume percentile
particle size D(0.9) is less than about 300 um, or any combination thereof.
The term "particle size distribution" as used herein refers to the relative percentage by
weight or volume of each of the different size fraction of a particulate matter. The
term D(0.1) as used herein is defined as a size of particles where 10 volume percent of
the particle having sizes between the specified value. The term D(0.5) as used herein
is defined as a size of particles where 50 volume percent of the particle having sizes
-K^-IL— a*-, tt-ft-Ji. _ '^^zrzirZ- . —- ~—"—™
between the specified value. The term D(0.9) as used herein is defined as a size of
particles where 90 volume percent of the particle having sizes between the specified
value.
In general, the particle size measurement is determined by Malvern light scattering,
laser light scattering technique etc. In particular the particle size measurement is
measured using a Malvern particle size analyzer.
In accordance with, still further yet another embodiment, the present invention
provides a process for preparation of amorphous Vilazodone hydrochloride, which
comprises the steps of:
(a) dissolving Vilazodone hydrochloride in a mixture of water and water miscible
organic solvents;
(b) optionally treating with activated carbon;
(c) removing the solvent and;
^d}j^oiaiing.amorphous^-ilazodone~hydTOcriloride.
As per this aspect, Vilazodone hydrochloride is dissolved in mixture of water and
water miscible organic solvent used in step a) selected from polar organic solvent
such as acetonitrile, acetone, tetrahydrofuran, methanol, ethanol, isopropanol, acetic
acid, formic acid, preferably solvents used are acetonitrile and methanol af 20 to
70°C, more preferably at 30 to 60°C. The resulting solution is filtered through either
hyflo or micron filter paper, filtrate is cooled and evaporated. The isolated product is
dried under vacuum to get amorphous Vilazodone hydrochloride.
£ The removing of the solvent can be done by any. suitable solvent removing technique
n ' . . - • • • • • • '"
known in the art such as spray drying, lyophilization, distillation, distillation under
vacuum, evaporation, filtration, decantation, and o centrifugation.
o
£ In accordance with, still further yet another embodiment, the present invention
provides a process for preparation of amorphous Vilazodone hydrochloride, which
o
CM
co comprises the steps of:
to
o
- z - r r ± ^ ^ = : —23—
o > •• "
(a) dissolving Vilazodone hydrochloride in a mixture of water, acetonitrile and
methanol;
(b) optionally treating with activated carbon;
(c) removing the solvent by spray drying and;
(d) isolating amorphous Vilazodone hydrochloride.
In accordance with, still further yet another embodiment, the present invention
provides a process for preparation of amorphous Vilazodone hydrochloride by
solvent/anti-solvent method, which comprises the steps of:
(a) dissolving Vilazodone hydrochloride in a suitable solvent;
(b) optionally treating with activated carbon;
(c) adding the suitable anti-solvent and;
(d) isolating amorphous Vilazodone hydrochloride.
Suitable solvents used in step a) for dissolving Vilazodone hydrochloride may include
but are not limited to water; alcohols such as methanol, ethanol, isopropanol, 2-
propanol, 1-butanol, t-butyl alcohol, 1-pentanol, 2-pentanol, amyl alcohol, ethylene
glycol, glycerol and the like; ketones such as acetone, butanone, 2-pentanone, 3-
pentanone, methyl butyl ketone, methyl isobutyl ketone, and the like; esters such as
ethyl formate, methyl acetate, ethyl acetate, propyl acetate, t-butyl acetate, isobutyl
acetate, hydrocarbons such as pentane, hexane, heptane, cyclohexane, toluene, xylene,
methylene dichloride, ethylene dichloride, chlorobenzene, and the like, nitriles such as
acetonitrile, ethers such as diethyl ether, diisopropyl ether, t-butyl methyl ether,
dibutyl ether, tetrahydrofuran, 1,4-dioxane, 2-methoxyethanol, polar aprotic solvents
J such as A^^-dimethylformamide, Af Af-dimethylacetamide, 7V-methylpyrrolidone,
pyridine, dimethylsulfoxide, sulfolane, formamide, acetamide, propanamide,
pyridine, or the like; and mixtures thereof
£
(£>
O
o
CD
o
CN
Suitable anti-solvents added in step c) may include one or more of hydrocarbons like
<3 hexanes, n-heptane, n-pentane, cyclohexane, methylcyclohexane and the like;
CO
m
o
CN
z —24
OS . • ' '
"csr
aromatic hydrocarbons like toluene, xylene, chlorobenzene, ethylbenzene and the like;
ethers like diethyl ether, diisopropyl ether, t-butyl methyl ether, dibutyl ether,
tetrahydrofuran, 1,4-dioxane, 2-methoxyethanol, or the like and mixtures thereof.
Accordingly, amorphous vilazodone hydrochloride obtained according to the instant
invention possess the relative particle size distribution wherein the 10th volume
percentile particle size D(0.1) is less than about 50 urn, the 50th volume percentile
particle size D(0.5) is less than about 50 um, or the 90th volume percentile particle
size D(0.9) is less than about 100 am, or any combination thereof.
The compound l-(2-ethoxycarbonylbenzofuran-5-yl)-piperazine or its salt of Formula
4 is prepared by coupling of Ethyl 5-amino-l-benzofuran-2-carboxylate or its salt of
Formula 3 with Bis(2-chloroethyl)amine hydrochloride in the presence of suitable
solvent and base to provide compound of Formula 4 or its salt. Generally reaction
may be carried out at a 30°C to reflux temperature of the solvent for few minutes to
few hours or till completion of reaction. Preferably reaction is conducted at a
temperature of 100 to 140°C, More preferably reaction is conducted at a temperature
of 120 to 135°C and it takes 55 to 70 hours for completion of the reaction. The
reaction completion is monitored by suitable techniques such as thin layer
chromatography (TLC), high performance liquid chromatography (HPLC), ultraperformance
liquid chromatography (UPLC) and like thereof;
Suitable solvent for coupling of Ethyl 5-amino-l-benzofuran-2-carboxylate
compound or its salt of Formula 3 with Bis(2-chloroethyl)amine hydrochloride may
be selected from but not limited to organic solvents selected from the group
comprising of Af,Af-dimethylformamide, n-butanol, ethyl acetate, DIPEA, toluene,
sulpholane, preferably solvent used is sulpholane.
The base used for coupling of Ethyl 5-amino-l-benzofuran-2-carboxylate or its salt of
Formula 3 with Bis(2-chloroethyl)amine hydrochloride may be selected from organic
or inorganic base, wherein inorganic base is selected from alkali or alkaline earth
metal carbonates, bicarbonates selected from such as sodium carbonate, potassium
carbonate, calcium carbonate, magnesium carbonate, cesium carbonate, sodium
bicarbonate, potassium bicarbonate, calcium bicarbonate, magnesium bicarbonate,
cesium bicarbonate, or the like and mixture thereof. Organic base is selected from
t ^ - l — i — f c - B - -*-• *-'• "**"'
diisopropyl ethyl amine, tnethyl amine, tnbutyl amine, Af-methyl morphohne, and
pyridine or the like thereof; preferably base used is potassium carbonate.
In addition, suitable solvent used for preparation of crystalline Vilazodone form IV or
amorphous form may be selected from group comprising of but not limited to water,
organic solvents selected from ketone such as acetone, propanone, butanone, methyl
isobutyl ketone and the like; hydrocarbons are selected from aliphatic hydrocarbons
or aromatic hydrocarbons. Aliphatic hydrocarbons are selected from the group
comprising of alkanes or cycloalkanes such as pentane, hexane, heptane, octane,
cyclohexane, cyclopentane, methylene dichloride, ethylene dichloride, chlorobenzene
and the like. Aromatic hydrocarbons are selected from the group comprising of
toluene, xylene; esters such as ethyl formate, methyl acetate, ethyl acetate, propyl
acetate, t-butyl acetate, isobutyl acetate; nitriles like acetonitrile; ethers such as
diethyl ether, diisopropyl ether, t-butyl methyl ether, dibutyl ether, tetrahydrofuran,
1,4-dioxane, 2-methoxy ethanol; polar aprotic solvents like N,N-dimethylformamide,
N,N-dimethyl acetamide, N-methylpyrrolidone, pyridine, dimethylsulfoxide,
sulfolane, formamide, acetamide, propanamide, pyridine and the like; alcohols such as
methanol, ethanol, isopropanol, 2-propanol, 1-butanol, t-butyl alcohol, 1-pentanol, 2-
pentanol, amyl alcohol, ethylene glycol, glycerol and the like or mixtures thereof.
In another aspect there is provided a pharmaceutical composition that includes a
therapeutically effective amount of vilazodone hydrochloride according to the process
of the present invention and one or more pharmaceutically acceptable carriers,
excipients or diluents.
In yet another aspect there is provided a use of, a pharmaceutical composition that
includes a therapeutically effective amount of salt of vilazodone hydrochloride
prepared according to the process of the present invention and one or more
pharmaceutically acceptable carriers, excipients or diluents, in the treatment of
depressive disorders, including the sub-type disorders major depressive disorder and
dysthymic disorder, adolescent depression, anxiety disorders, including the sub-type
anxiety disorders chosen from the sub-types panic disorder with and/or without
agoraphobia, agoraphobia, obsessive-compulsive spectrum disorders, social phobia,
? • J t
n P i HT 2A - 1.1-" 2.B..1.G 17 - -* - -1-t,
-26-
specific phobia including neophobia, posttraumatic stress disorder, acute stress
indication or generalized-anxiety disorder and the like.
Major advantages realized in the present invention are that process can be easily and
conveniently scaled-up for industrial large scale production. The process is simple
economic with high throughput, operationally efficient and environment friendly.
Although the following examples illustrate the present invention in more detail but the
examples are not intended in any way to limit the scope of the present invention. It
will thus be readily apparent to the one skilled in the art that varying substitutions and
modifications may be made to the invention disclosed herein without departing from
the scope and spirit of the invention. Thus, it should be understood that although the
present invention has been specifically disclosed by preferred embodiments and
optional features, modifications and variation of the concepts herein disclosed may be
resorted to by those skilled in the art and that such modifications and variations are
considered to be falling within the scope of the invention.
Example 1
-Preparation-of 3-(4-cKIorobutylH^
"carlnmitrile:
To a mixture of 3-(4-chlorobutyl)-l//-indole-5-carbonitrile (150g) in dichloromethane
(2250 ml) was added tetra butyl ammonium hydrogen sulfate (21.8g) and p-TsC(147.5g). The mixture was "cooled to -5 to -10°C and an aqueous solution of NaOH
(129g in 1290 ml water) was added slowly at -10 to 0°C. The reaction mixture was
maintained at -10 to 0°C for 1 to 1.5 hours. After completion of the reaction, the
layers were separated and the organic layer was washed with water. The organicTayer
was concentrated to about 600 ml, added methanol (1650. ml) and again recovered
about 300 ml of solvent at 40 to 45°C. The reaction mixture was stirred for 30
minutes under reflux, cooled, filtered, washed with methanol and dried under vacuum
to obtain the title compound as a white solid.
Example 2
Preparation of ethyK5-(piperazin-l-yl) benzofuran-2-carboxylate:
«•** f^^^L-JtSLz^JL^^J^—±±r^r±±
—2-7-
To a mixture of ethyl-5-aminobenzofuran-2-carboxylate (lOOg) in sulfolane (300 ml),
was added anhydrous potassium carbonate (80.8g), bis(2-chloroethyl)amine
hydrochloride (104.5g). The resulting reaction mixture was maintained at 125 to
130°C for 65 to 80 hours. After completion of reaction, the mixture was cooled to 40
to 50°C and acetone (1500 ml) was added slowly. The slurry was allowed to cool to
room temperature, stirred, and further cooled to 0 to 5°C. The solid was filtered,
washed with acetone and sucked to dryness. The wet solid was slurred in mixture of
ethyl acetate (1500 ml), water (1000 ml) and pH was adjusted to 9 to 10 using
aqueous ammonia solution at 30 to 35 °C. The organic layer was separated and wash
with water. Then the solvent was removed partially under vacuum till 400 ml,
gradually cooled to 0 to 5°C and stirred. The precipitated solid was filtered, washed
with chilled ethyl acetate and sucked to dryness. The wet product was further dried
under vacuum at 40 to 45 °C to obtain title compound as a white solid.
Example 3
Preparation of Ethyl 5-(4-(3-(5-cyano-l-tosyl-lH-indol-3-yl) butyl)-piperazin-lyl)
benzofuran-2-carboxyIate hydrochloride:
To a mixture of ethyl 5-(piperazin-l-yl)benzofuran-2-carboxylate (lOOg) in N,Ndimethyl
acetamide (1000 ml) was added 3-(4-chlorobutyl)-l-[(4-methyl phenyl) -
sulfonyl]-l//-indole-5-carbonitrile (141g), NaHC03 (91.8g) and potassium iodide
(6g). The reaction mixture was maintained at 70 to 80°C for 20 to 25 hours. After
completion _ of the reaction, the reaction mass was cooled to room temperature and
poured into a stirred mixture of water (3000 ml) and dichloromethane (1000 ml). The
organic layer was separated and the aqueous layer was extracted with
dichloromethane (500 ml). To the combined organic layer was added water (500 ml)
and pH was adjusted to 4.5 -5.0 using 10% aqueous hydrochloric acid. Then separated
the organic layer and again added water (500 ml) and pH was adjusted to 4.5 -5.0
using 10% aqueous hydrochloric acid. Further separated the organic layer and washed
with water (500 ml). The organic layer was stirred with activated charcoal (5g) for 30
min. Filtered, through hyflo bed, washed with dichloromethane and the solvent was
distilled until 400 ml remains. The residue was heated with isopropanol (1500 ml) to
65 to 70°C, stirred for 30 min, cooled gradually to room temperature and stirred for 2
hours. Filtered the solid, washed with isopropanol and sucked to dryness. The wet
solid was heated in ethyl acetate (3000 ml) at 65 to 70°C to get a clear solution and a
solution of IPA-HC1 (53.43 g of 24.9% w/w solution) was added slowly. After stirring
for 30 min at 65 to 70°C, the slurry was slowly cooled to room temperature and
stirred for 2 hours. The solid was filtered, washed with ethyl acetate and sucked to
dryness. The wet solid was again stirred with ethyl acetate (1000 ml), stirred, filtered,
washed with ethyl acetate and dried under vacuum to obtain the title compound as a
white solid.
Example 4
Preparation of 5-(4-(3-(5-Cyano-lH-indol-3-yl)-butyl) piperazin-l-yI)benzofuran
- 2-carboxamide (Vilazodone base):
To a mixture of ethyl 5-(4-(3-(5-Cyano-l-tosyl-lH-indol-3-yl)-butyl)-piperazin-lyl)
benzofuran-2-carboxylate hydrochloride (lOOg) in methanol (1000 ml) was added
formamide (500 ml) at room temperature. The reaction mass was cooled to 10 to 20°C
and 30%> methanolic sodium methoxide solution (245g) was added slowly at 15 to
30°C followed by addition of tetrahydrofuran (200 ml) . The reaction mixture was
heated to 45 to 50°C and maintained for 3 hours. After completion of the reaction, the
reaction mass was cooled to 10 to 15°C and stirred for 3 hours. The precipitated solid
was filtered, washed with methanol (100 ml) and suck dried. The wet solid was again
stirred with methanol (500 ml) at room temperature, filtered, washed with methanol
(2x100 ml) and suck dried. The solid obtained was dissolved in tetrahydrofuran (350
ml) at 35 to 50°C to get a clear solution and 30%> methanolic sodium methoxide
solution (13.6g sodium methoxide in 335 ml of methanol) was added slowly. The
reaction mass was maintained at 40 to 50°C for 3 to 4 hours. After completion of the
reaction, the reaction mass was cooled to 10 to 15°C and stirred for 3 hours. The
precipitated solid was filtered, washed with methanol (100 ml) and sucked to dryness.
The solid was again stirred with methanol (500 ml) at 55 to 60°C for 1 hour, cooled,
filtered, washed with methanol and suck dried. The wet solid was stirred with water at
70 to 80°C for 4 hours, cooled, filtered, washed with water and suck dried to obtain
the title compound.
1.7 •- l i
2-9- "
jci i u T
• t — a — "
it. J - - » .
_ 1" .zeiJB,
Example 5
Preparation of 5-(4-(3-(5-Cyano-lH-indol-3-yl)-butyl) piperazin-l-yl)benzofuran
- 2-carboxamide (Vilazodone base):
To a mixture of ethyl 5-(4-(3-(5-Cyano-l-tosyl-lH-indol-3-yl)-butyl)-piperazin-lyl)
benzofuran-2-carboxylate hydrochloride (lOOg) in methanol (1000 ml) was added
formamide (500 ml) at room temperature. The reaction mass was cooled to 10 to 20°C
and 30% methanolic sodium methoxide solution (245 g) was added slowly at 15 to
30°C followed by addition of tetrahydrofuran (200 ml) . The reaction mixture was
heated to 50 to 70°C and maintained for 5 hours. After completion of the reaction, the
reaction mass was cooled to 10 to 15°C and stirred for 3 hours. The precipitated solid
was filtered, washed with methanol (100 ml) and suck dried. The wet solid was again
stirred with methanol (500 ml) at room temperature, filtered, washed with methanol
(2x100 ml) and suck dried. The solid obtained was dissolved in tetrahydrofuran (350
ml) at 40 to 60°C to get a clear solution and 30% methanolic sodium methoxide
solution (13.6g sodium methoxide in 335 ml of methanol) was added slowly. The
reaction mass was maintained at 40 to 50°C for 1 to 2 hours. Then methanol (500 ml)
was added, cooled to room temperature, and stirred for 1 hour. The reaction mixture
was further cooled to 10 to 15°C, stirred for 3 hour, filtered the solid, washed with
methanol (100 ml) and suck dried. The solid was dissolved in N, N-dimethyl
acetamide (350 ml) at room temperature and aqu. sodium hydroxide solution (9 gm in
90 ml water) was added slowly. The reaction mass was maintained at room
temperature for 2 to 3 hours followed by addition of isopropyl alcohol (1400 ml),
water (1400 ml) and stirred for 1 hour. Filtered the solid and washed with aqu.
isopropyl solution, water and suck dried. The wet solid was stirred with water at 70 to
80°C for 4 hours, cooled, filtered, washed with water and suck dried to obtain the title
compound.
Example 6
Preparation of 5-(4-(3-(5-Cyano-lH-indol-3-yl)-butyl) piperazin-l-yl)benzofuran
- 2-carboxamide hydrochloride form-IV (Vilazodone hydrochloride Form-IV):
The wet solid obtained from example 4 was dissolved in isopropyl alcohol (4080 ml)
at reflux temperature, cooled to 55 to 65 °C and stirred with activated charcoal (6g) for
20-30 minutes. The charcoal was filtered through hyflo, washed with IP A (300 ml).
i - uT > o I I - ' > ^ I P , 1 7 : 51
To the filtrate IPA-HC1 solution (prepared by mixing 41.2 g of 12.2% IPA-HC1 in 900
ml IPA) was added at 55 to 65°C. The reaction mixture was maintained at 55 to 65°C
for 60 minutes, cooled to room temperature and stirred for 3 hours. The precipitated
solid was filtered, washed with IPA and dried at about 55 to 60°C under vacuum to
obtain the title compound as an off white solid.
PSD: D(0.1) = 22 urn; D(0.5) = 56 urn; D(0.9) = 113 urn.
Example 7
Preparation of 5-(4-(3-(5-Cyano-lH-indol-3-yl)-butyl) piperazin-l-yl)benzofuran
- 2-carboxamide hydrochloride (Vilazodone hydrochloride):
To a mixture of ethyl 5-(4-(3-(5-Cyano-l-tosyl-lH-indol-3-yl)-butyl)-piperazin-lyl)
benzofuran-2-carboxylate hydrochloride (lOOg) in methanol (1000 ml) was added
formamide (500 ml) at room temperature. The reaction mass was cooled to 10- to
20°C and 30% methanolic sodium methoxide solution (245g) was added slowly at 15-
30°C followed by addition of tetrahydrofuran (200 ml). The reaction mixture was
heated to 45 to 50°C and maintained for 3 hours. After completion of the reaction, the
reaction mass was cooled to 10 to 15°C and stirred for 3 hours. The precipitated solid
was filtered, washed with methanol (100 ml) and suck dried. The wet solid was again
stirred with methanol (500 ml) at room temperature, filtered, washed with methanol
(2x100 ml) and suck dried. The solid obtained was dissolved in tetrahydrofuran (350
ml) at 35 to 50°C to get a clear solution and 30% methanolic sodium methoxide
solution (13.6g sodium methoxide in 335 ml of methanol) was added slowly. The
reaction mass was maintained at 40 to 50°C for 3 to 4 hours. After completion of the
reaction, the reaction mass was cooled to 10 to 15°C and stirred for 3 hours. The
precipitated solid was filtered, washed with methanol (100 ml) and sucked to dryness.
The solid was again stirred with methanol (500 ml) at 55 to 60°C for 1 hour, cooled,
filtered, washed with methanol and suck dried. The wet solid was stirred with water at
70 to 80°C for 4 hours, cooled, filtered, washed with water and suck dried. The wet
material was dissolved in IPA (4500 ml) at 70 to 85°C, further cooled to 55 to 65°C
and stirred with activated charcoal (6g) for 30 min. The charcoal was filtered through
hyflo bed, washed with IPA (300 ml), followed by filtration through 0.45(i filter
paper. The filtrate was heated to 70 to 85°C to get a clear solution and 450 ml IPA
was distilled off from the solution and then cooled to 50 to 60°C. A solution of 12.2%
L K X Z.% - 1-1-- 2.G l.S. 1.7 : 5 I.
IPA-HC1 solution (41.2 g) was added. The reaction mixture was maintained at 50 to
60°C for 1 hour, slowly cooled to room temperature and stirred for 3 hour. The
precipitated hydrochloride salt was filtered, washed with IP A, sucked dried, further
dried at 55 to 60°C under vacuum to obtain the title compound as a pale yellow solid.
Example 8
Preparation of amorphous vilazodone hydrochloride:
Vilazodone hydrochloride (20g) obtained from example 6 in a solvent mixture of
methanol: water: acetonitrile (1:1:1) (1400 ml) was heated to 50 to 60°C for 20 to 30
minutes to get a clear solution. The hot solution was filtered and washed with a
mixture of methanol: water: acetonitrile (1:1:1) (100 ml). The filtrate was spray dried.
The solid obtained was dried under vacuum at 45 to 50°C to obtain the title
compound.
PSD: D(0.1) = 4 urn; D(0.5) = 9 urn; D(0.9) = 19 urn.
Example 9
Preparation of amorphous_yilazodone-hydrochloride-by-lyophilization:
A mixture of Vilazodone hydrochloride (lg) in tetrahydrofuran (12.5 ml), acetonitrile
(12.5 ml) and DM water (12.5 ml) was heated to 45 to 50°C to get a clear solution.
The solution was then cooled to 25 to 30°C and filtered. The filtrate was further
cooled to -60 to -65°C and lyophilized to obtain-the title compound.
Example 10
Preparation of amorphous Vilazodone hydrochloride by lyophilization:
A mixture of Vilazodone hydrochloride (2g) in tetrahydrofuran (30 ml) and DM water
(60 ml) was stirred at room temperature to obtain a clear solution. Tetrahydrofuran
(10 ml) was added into the clear solution, filtered and washed with THF (30 ml). The
filtrate was further cooled to -60 to -65 °C and lyophilized to obtain title compound.

We claim:
1- A process for the preparation of Vilazodone and its acid addition salt
comprising the steps of:
(a) iV-protection of 3-(4-chlorobutyl)-l/f-indole-5-cabronitrile of Formula 5
by treating with JV-protecting reagent in presence of base, and suitable solvent,
optionally in the presence of catalyst to provide ^-protected compound of
Formula 16
Formula 16
(b) coupling the compound of Formula 16 with compound of Formula 4 A or its
salts
£
o
Wherein R is selected from -NH2, -OMe, -OEt, -OPr, O-iPr
in the presence of suitable solvent and base, with or without use of an activating
g agent to provide compound of Formula 17 or its acid addition salt
o
Q - - I X - 2.G16... 1,7 - 3 1 - .ifcjt' -iLA-fc—-fc—-8- * = •£—- £— ^
by treating with p-toluene sulfonyl chloride in presence of a dichloromethane
and tetrabutyl ammonium hydrogen sulfate to provide of 3-(4-chlorobutyl)-ltosyl-
l//-indole-5-cabronitrile of Formula 8
Formula 8
(b) coupling the compound of Formula 8 with compound of Formula 4 A or its salt
°> °
Formula 4A
Wherein R is selected from -NH2, -OMe, -OEt, -OPr, O-iPr
in the presence of sodium bicarbonate, N, JV-dimethylacetamide and potassium
iodide to provide compound of Formula 9 A or its acid addition salt
COR
CH3
Formula 9A
(c) amidation of compound of Formula 9A or its acid addition salt by treating it
with formamide and sodium methoxide in presence of methanol to provide a
compound of Formula 19
T o r* n EJL-ii .X- *-•• » •*—
CH3
Formula 19
(d) deprotection of the compound of Formula 19 using methanolic sodium
methoxide solution in the presence of tetrahydrofuran solvent to provide
vilazodone base;
(e) converting Vilazodone base into its hydrochloride salt.
4. A process for the preparation of compound of Formula 19
O' CONHj
CH3
Formula 19
_by_amidatifin .ofxompound-of-Formula-9A~orits acid addition salt
, CH3
Formula 9 A
Wherein R is selected from -NH2, -OMe, -OEt, -OPr, O-iPr
using formamide and sodium methoxide in presence of methanol as solvent.
5. A process for preparation of crystalline form IV of Vilazodone hydrochloride
comprising the steps of:
(a) dissolving Vilazodone base in alcoholic solvent;
(b) optionally treating with activated carbon;
~}—&~
.37-
(c) adding alcoholic-HCl solution or passing HC1 gas and;
(d) isolating crystalline form IV.
6. A process for preparation of crystalline form IV of Vilazodone hydrochloride
comprising the steps of:
(a) dissolving Vilazodone base in isopropanol;
(b) optionally treating with activated carbon;
(c) adding IPA-HC1 solution or passing HC1 gas and;
(d) isolating crystalline form IV.
7. A process for preparation of amorphous Vilazodone hydrochloride,
comprising the steps of:
(a) dissolving Vilazodone hydrochloride in mixture of water and water miscible
organic solvents;
(b) optionahyjrea^gj^vi^.activatedxarboni
(c) removing the solvent and;
•(d) isolating amorphous Vilazodone hydrochloride.
8. A process for preparation of amorphous Vilazodone hydrochloride-eomprising
the-steps of: • - • - - • -
(a) dissolving Vilazodone hydrochloride in a mixture of water, acetonitrile and
methanol;
I'lO
i £
jo (b) optionally treating with activated carbon;
Iff : co
! -©
! < "*
o
CD
O
CM
(c) removing the solvent by spray drying and;
(d) isolating amorphous Vilazodone hydrochloride.
9. A process for preparation of amorphous Vilazodone hydrochloride by
9
« solvent/anti-solvent method comprising the steps of:
CO
m
o
CM
o lJg^__0£i^IL~2^^
3.8-
a> .
(a) dissolving Vilazodone hydrochloride in a suitable solvent;
(b) optionally treating with activated carbon;
(c) adding the suitable anti-solvent and;
(d) isolating amorphous Vilazodone hydrochloride.
10. The process according to any of the proceeding claim, wherein Solvent/ Antisolvent
is selected from the group comprising of sulfoxides, amides, esters,
ketones, nitriles, alcohols, aliphatic or aromatic hydrocarbons, halogenated
hydrocarbons ,ethers, hydrocarbons, water, acid and the like or mixture thereof
;Base used is selected from organic or inorganic base; Phase transfer catalyst
used is selected from tetra butyl ammonium bromide (TBAB), tetrapropyl
ammonium bromide, tributyl benzyl ammonium bromide, tetraoctyl
ammonium bromide, tetra butyl ammonium iodide, tetra butyl ammonium
hydrogen sulfate (TBAHS), benzyl trimethyl ammonium chloride, benzyl
triethyl ammonium chloride, tetra butyl ammonium acetate, tetra butyl
ammonium iodide and ethyl triphenyl phosphonium bromide; Activating agent
is selected from alkali or alkaline metal halide; Amidation agent used is
selected from ammonia, formamide, ammonia gas, ammonium carbamate,
ammonium formate, ammonium phosphate, ammonium acetate, ammonium
fluoride, ammonium bromide, ammonium chloride, ammonium iodide,
ammonium iodate, ammonium carbonate, ammonium citrate, ammonium
chromate, ammonium dichromate, ammonium hydroxide, ammonium lactate,
ammonium molybdate, ammonium nitrate, ammonium oxalate, ammonium
sulfate, ammonium sulfide, ammonium tartarate, ammonium triflate,
ammonium thiocyanate, ammonium dihydrogen phosphate, urea, methyl
carbamate, ethyl carbamate, propyl carbamate or t-butyl carbamate,
magnesium nitride; mixtures such as sodium methoxide/ammonia, sodium
methoxide/formamide, magnesium methoxide/ammonium chloride,
magnesium methoxide/ammonia, calcium chloride/ammonium chloride and
calcium chloride/ ammonia; Deprotecting agent used is selected from alkali or
alkaline metal alkoxides, acids like HBr, AcOH in presence of 4-hydroxy
> r n n r*rr* JUT- ? O - U - 2.0XG. 3L?' : 3.1
benzoic acid, Red Al, super hydrides, H2SO4 or mixtures of H2SO4/TFA;
thiophenol/KOH; thiophenol/K2C03 and like thereof.