U.S. patent application number 13/855549 was filed with the patent office on 2014-06-12 for process for preparing vilazodone hydrochloride.
This patent application is currently assigned to Erregierre S.p.A.. The applicant listed for this patent is Matteo Bonaldi, Daniele De Zani, Massimo Ferrari. Invention is credited to Matteo Bonaldi, Daniele De Zani, Massimo Ferrari.
Application Number | 20140163227 13/855549 |
Document ID | / |
Family ID | 46582865 |
Filed Date | 2014-06-12 |
United States Patent
Application |
20140163227 |
Kind Code |
A2 |
Ferrari; Massimo ; et
al. |
June 12, 2014 |
PROCESS FOR PREPARING VILAZODONE HYDROCHLORIDE
Abstract
The present invention relates, in a first aspect, to a process
preparing vilazodone hydrochloride that comprises the reaction of
3-(4-chloro-1-hydroxy-butyl)-1H-indol-5-carbonitrile with
5-piperazin-1-yl-benzofuran-2-carboxylate methyl hydrochloride with
the formation of a 1,4-piperazine, with subsequent dehydration,
hydrogenation and treatment with ammonia, to obtain vilazodone in
free base form that is then converted into the hydrochloride
thereof.
Inventors: |
Ferrari; Massimo; (Cenate
Sotto, IT) ; De Zani; Daniele; (Roncello, IT)
; Bonaldi; Matteo; (24020 Schilpario, IT) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Ferrari; Massimo
De Zani; Daniele
Bonaldi; Matteo |
Cenate Sotto
Roncello
24020 Schilpario |
|
IT
IT
IT |
|
|
Assignee: |
Erregierre S.p.A.
San Paolo D'Argon
IT
|
Prior
Publication: |
|
Document Identifier |
Publication Date |
|
US 20130225818 A1 |
August 29, 2013 |
|
|
Family ID: |
46582865 |
Appl. No.: |
13/855549 |
Filed: |
April 2, 2013 |
Current U.S.
Class: |
544/373;
548/491 |
Current CPC
Class: |
C07D 209/12 20130101;
C07D 405/12 20130101 |
Class at
Publication: |
544/373;
548/491 |
International
Class: |
C07D 405/12 20060101
C07D405/12 |
Foreign Application Data
Date |
Code |
Application Number |
Apr 2, 2012 |
IT |
M12012A000531 |
Claims
1. A process for preparing vilazodone, in particular in the form of
hydrochloride, comprising the steps of A) reacting
3-(4-chloro-1-hydroxy-butyl)-1H-indol-5-carbonitrile of formula (I)
##STR00023## with 5-piperazin-1-yl-benzofuran-2-carboxylate methyl
hydrochloride of formula (II) ##STR00024## to give
5-{4-[4-(5-cyano-1H-indol-3-yl)4-hydroxybutyl]-piperazin-1-yl}benzofuran--
2-carboxylate methyl of formula (III) ##STR00025## B) treating the
compound of formula (III), obtained from step A, with an
acidification agent to obtain
5-{4-[4-(5-cyano-1H-indol-3-yl)4-hydroxy-butyl]-piperazin-1-yl}benzofuran-
-2-carboxylate methyl of formula (IV) ##STR00026## C) hydrogenating
the compound of formula (IV) with H.sub.2 to obtain
5-{4-[4-(5-cyano-1H-indol-3-yl)4-hydroxy-butyl]-piperazin-1-yl}benzo-fura-
n-2-carboxylate methyl of formula (V) ##STR00027## D) treating the
compound of formula (V) obtained from step C) with ammonia to
obtain
5-(4-[4-(5-cyano-1H-indol-3-yl)butyl]piperazin-1-yl)benzo-furan-2-carboxa-
mide of formula (VI), ##STR00028## E) optionally treating the
compound of formula (VI) with hydrochloride acid to obtain
vilazodone hydrochloride of formula (VII) ##STR00029##
2. A process according to claim 1, wherein step A) is carried out
in the presence of a weak base and an organic solvent.
3. A process according to claim 2, wherein the weak base is sodium
bicarbonate and the organic solvent is a dipolar aprotic
solvent.
4. The process according to claim 2 wherein the organic solvent is
N,N-dimethylacetamide.
5. A process according to claim 1 wherein the acidification agent
in step B) is ammonium chloride.
6. A process according to claim 1, wherein step B) comprises
heating the compound of formula (III) in a mixture with
N,N-dimethylacetamide and ammonium chloride.
7. A process according to claim 1 wherein the hydrogenation step C)
with H.sub.2 is carried out in the presence of a Pd/C or Raney
nickel catalyst and an alcoholic solvent.
8. A process according to claim 1 wherein in step D) the compound
of formula (V) is dissolved in an alcoholic solvent, wherein
gaseous ammonia is bubbled.
9. The process according to claim 8 wherein the alcoholic solvent
is methanol.
10. A process according to claim 1, further comprising preparing
the compound of formula (I), through the steps of i) condensing
1H-indol-5-carbonitrile (5-cyanoindole) of formula (X) ##STR00030##
with 4-chlorobutyryl chloride to give
3-(4-chlorobutyryl)-1H-indol-5-carbonitrile of formula (XI),
##STR00031## ii) reducing
3-(4-chlorobutyrryl)-1H-indol-5-carbonitrile of formula (XI) with a
reducing agent to obtain
3-(4-chloro-1-hydroxy-butyl)-1H-indol-5-carbonitrile of formula
(I), wherein the reduction reaction in step ii) is carried out with
sodium borohydride.
11. A process according to claim 10, wherein step i) comprises
preparing a solution of 4-chlorobutyrryl in a chlorinated organic
solvent, preferably methylene chloride, in the presence of an
activating agent, preferably aluminum chloride, and adding the
solution containing 1H-indol-5-carbonitrile in a chlorinated
organic solvent, preferably methylene chloride, to this
solution.
12. A process according to claim 10 wherein step ii) comprises
dissolving the sodium borohydride reducing agent in an alkaline
aqueous solution and adding the sodium borohydride solution to
3-(4-chlorobutyrryl)-1H-indol-5-carbonitrile of formula (XI)
dissolved in a suitable organic solvent, preferably tetrahydrofuran
and water.
13. A compound which is an intermediate of process of claim 1
having the formula (I) ##STR00032##
14. A compound which is an intermediate of process of claim 1
having the formula (III) ##STR00033##
15. A compound which is an intermediate of process of claim 1
having the formula (IV) ##STR00034##
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority of Italian Patent
Application MI2012A000531 filed on Apr. 2, 2012.
FIELD OF THE INVENTION
[0002] The present invention relates to a process for producing
vilazodone, typically in base or hydrochloride form.
[0003] The present invention originates in the sector of processes
for preparing pharmacologically active substances, in particular
piperazine-based substances.
BACKGROUND OF THE INVENTION
[0004] Vilazodone is the
5-5-{4-[(4-(5-Cyano-1H-indol-3-yl)butyl]piperazin-1-yl}-benzofuran-2-carb-
oxylate methyl molecule provided with molecular weight equal to
477.99.
[0005] From a pharmacological point of view, vilazodone is a
selective serotonin reuptake inhibitor (SSRI) and a partial agonist
of 5-HT1A receptors.
[0006] On account of this action thereof, vilazodone falls within
the class of antidepressant drugs and finds application in the
treatment of psychiatric diseases and in the treatment of major
depressive syndrome (MDD) in particular.
[0007] Vilazodone and the preparation thereof were described, for
example, in U.S. Pat. No. 5,532,241.
[0008] In particular two related routes of Vilazodone preparation
are known.
[0009] The first synthesis route provides for the condensing of
indol-5-carbonitrile with 4-chlorobutyrylchloride to give
3-(4-chlorobutyryl)-1H-indol-5-carbonitrile, which is reduced with
diborane, to give 3-(4-chlorobutyl)-1H-indol-5-carbonitrile. The
reaction of the latter compound with
5-(1-piperazinyl)benzofuran-2-carboxylic acid (V) leads to the
expected 1,4-disubstituted piperazine
5-{4-[4-(5-cyano-1H-indol-3-yl)-4-hydroxy-butyl]-piperazin-1-yl}benzofura-
n-2-carboxylate methyl. Finally, the carboxyl group of the
piperazine is converted into the carboxamide of interest by
reaction with 2-chloro-1-methylpyridinium methanesulphonate (CMPM)
and ammonia gas.
[0010] A second related synthesis route provided for hydrogenation
of the 5-nitrobenzofuran-2-carboxylic acid ethyl ester with Raney
nickel and H2 in MeOH to give the corresponding compound of
5-aminobenzofuran with bis(2-chloroethyl) amine in dichloromethane
to give 5-(1-piperazinyl)-benzofuran-2-carboxylic acid ethyl ester.
The reaction of the latter compound with di-tert-butyl dicarbonate
in THF provides the protected amino compound
5-[4-(tert-butoxycarbonyl)-1-piperazinyl]benzofuran-2-carboxylic
acid ethyl ester, which is first reacted with formamide and sodium
alkoxide in N-methylpyrrolidone to provide the corresponding amide,
and then deprotected by treatment with HCl/MeOH to give
5-(1-piperazinyl)benzofuran-2-carboxamide. Finally, this amide is
condensed with 3-(4-chlorobutyl)-1H-indol-5-carbonitrile to give
vilazodone.
[0011] Also known by Timo H. et al. in J. Med. Chem 2004, 47,
4684-4692 pp. 4684-4692 is a process for preparing vilazodone that
provides for an initial phase in which indol-5-carbonitrile is
condensed with 4-chlorobutyrylchloride to give
3-(4-chlorobutyryl)-1H-indol-5-carbonitrile, which is then reduced
with sodium bis(2-methoxyethoxy)-aluminium hydride in toluene
(vitride), to give 3-(4-chlorobutyl)-1H-indol-5-carbonitrile which
is then reacted with 5-piperazin-1-yl-benzofuran-2-carboxylate
hydrochloride to give the expected piperazine.
[0012] However, the use of a reducing agent such as vitride in the
synthesis process makes it difficult to manage the production
system and requires a series of precautions which make the process
of the prior art hardly feasible and cost-effective from an
industrial point of view. Furthermore, vitride is a particularly
expensive reducing agent.
[0013] Currently, the increasing demand for vilazodone has resulted
in a pressing need to avail of alternative processes for the
preparation thereof.
[0014] One of the aims of the invention thus consists of providing
a process for preparing vilazodone that is economically
advantageous.
[0015] Another aim of the invention consists of providing a process
for producing a synthesis intermediate of vilazodone without
resorting to the use of vitride as reducing agent.
SUMMARY OF THE INVENTION
[0016] The Applicant, with the aim of finding alternative processes
for preparing vilazodone hydrochloride in view, has surprisingly
found an alternative synthesis route through novel intermediates,
avoiding the use of vitride as a reducing agent.
[0017] In particular, the Applicant has found a process for
preparing vilazodone hydrochloride through novel synthetic
intermediates with high production yields.
[0018] In accordance with a first aspect of the invention, a
process is provided for preparing vilazodone, in hydrochloride form
in particular, comprising the steps of [0019] A) Reacting
3-(4-chloro-1-hydroxy-butyl)-1H-indol-5-carbonitrile of formula
(I)
##STR00001##
[0019] with 5-piperazin-1-yl-benzofuran-2-carboxylate methyl
hydrochloride of formula (II)
##STR00002##
to give
5-{4-[4-(5-cyano-1H-indol-3-yl)4-hydroxybutyl]-piperazin-1-yl}ben-
zofuran-2-carboxylate methyl of formula (III)
##STR00003## [0020] B) Treating the compound of formula (III),
obtained from step A, with an acidification agent to obtain
5-{4-[4-(5-cyano-1H-indol-3-yl)4-hydroxy-butyl]-piperazin-1-yl}benzofuran-
-2-carboxylate methyl of formula (IV)
[0020] ##STR00004## [0021] C) Hydrogenating the compound obtained
in step B) to obtain
5-{4-[4-(5-cyano-1H-indol-3-yl)4-hydroxy-butyl]-piperazin-1-yl}benzofuran-
-2-carboxylate methyl of formula (V)
[0021] ##STR00005## [0022] D) Treating with ammonia the compound
(V) obtained from step C) to obtain
5-(4-[4-(5-cyano-1H-indol-3-yl)butyl]piperazin-1-yl)benzo-furan-2-carboxa-
mide (vilazodone in free base form)
[0022] ##STR00006## [0023] E) Treating the vilazodone in free base
form obtained from step D) with hydrochloric acid to obtain
vilazodone hydrochloride of formula (VII)
##STR00007##
[0024] The Applicant has also surprisingly found that it is
possible to obtain the starting compound
3-(4-chloro-1-hydroxy-butyl)-1H-indol-5-carbonitrile of formula (I)
by operating a reduction with a selected sodium borohydride-based
reducing agent.
[0025] In accordance with a second aspect, a process is thus
provided for preparing a compound of formula (I) comprising
reacting 5-cyanoindole (1H-indol-5-carbonitrile) of formula (X)
##STR00008##
with 4-chlorobutyryle chloride in the presence of a suitable
solvent system, to obtain
3-(4-chloro-1-hydroxy-butyl)-1H-indol-5-carbonitrile of formula
(XI)
##STR00009##
[0026] Reducing 3-(4-chlorobutyrryl)-1H-indol-5-carbonitrile of
formula (XI) with a reducing agent to obtain
3-(4-chloro-1-hydroxy-butyl)-1H-indol-5-carbonitrile of formula
(I),
##STR00010##
said process being characterized in that the reducing agent used is
sodium borohydride.
[0027] According to some aspects, the present invention relates to
the intermediate compounds of formula (I), (III) and (IV),
previously identified.
BRIEF DESCRIPTION OF THE DRAWINGS
[0028] FIG. 1 illustrates a complete diagram of the synthesis
reactions of vilazodone hydrochloride of formula (VII) and of the
starting compounds of formula (I) and (II).
DETAILED DESCRIPTION OF THE INVENTION
[0029] The Applicant has identified an alternative process for
preparing vilazodone and the hydrochloride salt thereof, which
provides for the passage through specific synthesis intermediates.
The process of the invention allows vilazodone and the
hydrochloride salt thereof to be produced with high purity using
reducing agents that are more manageable than the ones used in
conventional processes.
[0030] In accordance with a first aspect of the invention a process
is provided for preparing vilazodone, in hydrochloride form in
particular, comprising the steps of [0031] A) Reacting
3-(4-chloro-1-hydroxy-butyl)-1H-indol-5-carbonitrile of formula
(I)
##STR00011##
[0031] with 5-piperazin-1-yl-benzofuran-2-carboxylate methyl
hydrochloride of formula (II)
##STR00012##
in the presence of organic bases, for example amine bases, such as
for example triethylamine or inorganic bases such as sodium or
potassium bicarbonate, sodium or potassium carbonate, to give
5-{4-[4-(5-cyano-1H-indol-3-yl)4-hydroxybutyl]-piperazin-1-yl}benzofuran--
2-carboxylate methyl of formula (III)
##STR00013## [0032] B) Treating the compound obtained from step A
with an acidification agent such as for example ammonium chloride
to obtain
5-{4-[4-(5-cyano-1H-indol-3-yl)4-hydroxy-butyl]-piperazin-1-yl}ben-
zofuran-2-carboxylate methyl of formula IV
[0032] ##STR00014## [0033] C) Hydrogenating the compound of formula
(IV) with H.sub.2 to obtain
5-{4-[4-(5-cyano-1H-indol-3-yl)4-hydroxy-butyl]-piperazin-1-yl}benzofuran-
-2-carboxylate methyl of formula (V)
[0033] ##STR00015## [0034] D) Treating the compound of Formula (V)
obtained from step C) with ammonia to obtain
5-(4-[4-(5-cyano-1H-indol-3-yl)butyl]piperazin-1-yl)benzofuran-2-carboxam-
ide (vilazodone in free base form) of formula (VI)
[0034] ##STR00016## [0035] E) Optionally, treating the vilazodone
in free base form obtained from step D) with hydrochloric acid to
obtain vilazodone hydrochloride of formula (VII)
##STR00017##
[0036] In accordance with some embodiments, step A) of the process
is carried out in the presence of a suitable base.
[0037] In some embodiments, a suitable base used in step A) of the
process of the invention comprises a carbonate or bicarbonate of an
alkaline or alkaline-earth metal, such as for example sodium or
potassium bicarbonate, sodium or potassium carbonate.
[0038] In some embodiments in step A) of the process, a dipolar
aprotic solvent, such as for example N,N-dimethylacetamide, is
used.
[0039] In certain embodiments, step A) of the process of the
invention comprises a separation step of the organic mass using a
suitable organic solvent such as, for example, ethyl acetate.
[0040] In certain embodiments the acidification agent of step B) of
the process of the invention comprises a weak acid. A suitable weak
acid is represented by ammonium chloride.
[0041] In certain embodiments, step B) of the method comprises
heating the reaction mixture at the basis of the compound of
formula (III) and the acidification agent at temperature
substantially suitable for completing the reaction. A suitable
temperature is comprised within the range of 80 to 110.degree. C.
By way of example temperatures in the 100.degree. C.+/-5.degree. C.
range are particularly suitable for achieving high reaction yields
in suitable timeframes.
[0042] In some embodiments, the hydrogenation step C) of the
process is carried out with H.sub.2 in the presence of a suitable
catalyst system, such as for example Pd/C or Raney nickel.
[0043] Typically, the hydrogenation step with H.sub.2 is carried
out in the presence of a suitable, preferably alcoholic solvent, in
particular methanol.
[0044] By way of example, step C) comprises hydrogenating the
compound of formula (IV) within a hydrogenator, with aPd/C
catalyst, to 4-6%, in methanol.
[0045] In some embodiments, in step D) of the process, the compound
of the formula (V) is dissolved in a suitable alcoholic solvent,
typically methanol. Typically, the ammonia in gaseous form is
bubbled into the solution of the compound of formula (V) in
methanol until saturation of the solution.
[0046] In some embodiments, the solution treated with ammonia is
distilled to obtain vilazodone base of formula (VI).
[0047] According to some embodiments, step E) of the process
comprises the dissolving of vilazodone base in a suitable polar
organic solvent, such as acetone for example, and treating with an
HCl-based solution, at 35-39% for example, until vilazodone
hydrochloride of formula (VII) is obtained.
[0048] The applicant has further identified, in accordance with
other aspects of the invention, a synthesis route of the compound
of formula (I) that comprises an aromatic acylation reaction
followed by a reduction made with a specific sodium borohydride
reducing system.
[0049] In accordance with a second aspect of the invention a
process is thus provided for preparing
3-(4-chloro-1-hydroxy-butyl)-1H-indol-5-carbonitrile of formula (I)
comprising [0050] i) The condensing of 1H-indol-5-carbonitrile
(5-cyanoindole) of formula (X)
##STR00018##
[0050] with 4-chlorobutyryle chloride typically in the presence of
a suitable solvent system to give
3-(4-chlorobutyryl)-1H-indol-5-carbonitrile formula (XI),
##STR00019## [0051] ii) reducing
3-(4-chlorobutyrryl)-1H-indol-5-carbonitrile of formula (XI) with a
reducing agent to obtain
3-(4-chloro-1-hydroxy-butyl)-1H-indol-5-carbonitrile of formula
(I), said process being characterized in that the reduction in step
ii) is carried out with sodium borohydride.
[0052] According to some embodiments, step i) of the process
comprises preparing a solution of 4-chlorobutyryle chloride in a
chlorinated solvent, typically methylene chloride (DCM), in the
presence of an activator such as aluminium chloride and the
addition to this solution of another cyanoindole-based solution
(1H-indol-5-carbonitrile) in a chlorinated organic solvent such as
methylene chloride.
[0053] Thereafter, the resulting mixture can be poured into an
aqueous solution containing HCl, typically at 30-36%. The mixture
is then distilled, at a temperature falling within the range of 70
to 90.degree. C. for example. It is then possible to extract the
compound 3-(4-chlorobutyryl)-1H-indol-5-carbonitrile of formula
(XI) with a suitable solvent, for example ethyl acetate.
[0054] According to some embodiments, the reducing step ii)
comprises the dissolution of the sodium borohydride-based reducing
agent in an alkaline aqueous solution, typically a solution of NaOH
20 to 40% by weight in water and the addition of the sodium
borohydride solution to the
3-(4-chlorobutyryl)-1H-indol-5-carbonitrile of formula (XI)
dissolved in a suitable organic solvent, for example
tetrahydrofuran and water.
[0055] The mixture obtained is typically subjected to agitation,
preferably at a temperature higher than room temperature, for
example comprised between 30-40.degree. C., for a suitable period
of time, for example comprised between 2 and 4 hours, to then
proceed to extraction with a suitable solvent, such as for example
methylene chloride, and subsequent crystallization.
[0056] Typically, the compound
3-(4-chloro-1-hydroxy-butyl)-1H-indol-5-carbonitrile of formula
(I), obtained In accordance with the second aspect of the
invention, can be used as starting reagent of the process for
preparing vilazodone free base or hydrochloride, in accordance with
the first aspect of the present invention.
[0057] In accordance with another aspect, the present invention
relates to the intermediate compound having the Formula (I)
##STR00020##
[0058] In accordance with another aspect, the present invention
relates to the intermediate compound having the formula (III)
##STR00021##
[0059] In accordance with another aspect, the present invention
relates to the intermediate compound having the Formula (IV)
##STR00022##
[0060] Typically, the compound
5-piperazin-1-yl-benzofuran-2-carboxylate methyl of Formula (II)
can be prepared by esterifying the 5-aminobenzofuran-2-carboxylic
acid with HCl, and then condensing with bis-(2-chloroethyl)amine
and salifying the product obtained with HCl.
[0061] Specifically, the compound of Formula (II)
5-piperazin-1-yl-benzofuran-2-carboxylate methyl hydrochloride can
be prepared
[0062] by reacting 5-aminobenzofuran-2-carboxylic acid with HCl,
for example by bubbling gaseous HCl, in the presence of a typically
alcoholic solvent, to obtain the 5-aminobenzofuran-2-carboxylic
methyl ester acid,
[0063] by reacting 5-aminobenzofuran-2-carboxylic acid with
bis-(2-chloroethyl)amine hydrochloride, typically in an aqueous
environment and separating an organic phase containing
5-piperazin-1-yl-benzofuran-2-carboxylate methyl,
[0064] by bubbling HCl in a solution containing
5-piperazin-1-yl-benzofuran-2-carboxylate methyl dissolved in a
suitable dipolar aprotic solvent, such as for example
N,N-dimethylformamide to obtain
5-piperazin-1-yl-benzofuran-2-carboxylate methyl hydrochloride
(II).
[0065] The 5-piperazin-1-yl-benzofuran-2-carboxylate methyl of
Formula (II) thus obtained by means can be used as starting
material in the process for preparing vilazodone free base or
hydrochloride, in accordance with the first aspect of the present
invention.
[0066] FIG. 1 illustrates in detail the operating steps of one
embodiment of the process of the invention and of for preparing the
compounds or synthesis intermediates of Formula (I) and (II).
[0067] Specifically, in the first reaction line there is
schematically illustrated the synthesis of
5-piperazin-1-yl-benzofuran-2-carboxylate methyl hydrochloride (II)
by cyclization of 5-aminobenzofuran-2-carboxylic acid with
bis(2-chloro-ethyl)amine.
[0068] In the second reaction line is schematically illustrated the
synthesis of the intermediate
3-(4-chloro-1-hydroxy-butyl)-1H-indol-5-carbonitrile of Formula (I)
through the condensing of indol-5-carbonitrile with
4-chlorobutyrylchloride to give
3-(4-chlorobutyryl)-1H-indol-5-carbonitrile, which is reduced with
sodium borohydride, to give 3-(4-chloro-1-hydroxy-butyl)-1
H-indol-5-carbonitrile.
[0069] In the third and fourth reaction line is schematically
illustrated the synthesis process of vilazodone hydrochloride
according to the first aspect of the invention starting from the
reaction of the compounds
3-(4-chloro-1-hydroxy-butyl)-1H-indol-5-carbonitrile of Formula (I)
and 5-piperazin-1-yl-benzofuran-2-carboxylate methyl hydrochloride
of formula (II) through the formation of the expected
1,4-piperazine of formula (III), which by subsequent dehydration,
hydrogenation and treatment with ammonia, leads to the sought after
carboxamide of Formula (VI), then converted into the hydrochloride
salt of Formula (VII).
[0070] The present invention will now be illustrated with reference
to the following examples, which are provided for illustrative
purposes only and are not to be construed as limiting of the scope
of protection resulting from the claims.
Example 1
Process for preparing 5-Piperazin-1-yl-benzofuran-2-carboxylate
methyl hydrochloride
Synthesis of 5-aminobenzofuran-2-carboxylic acid methyl ester
TABLE-US-00001 [0071] Load into a flask:
5-aminobenzofuran-2-carboxylic acid 40 g Methanol 200 g HCl gas 10
g Heat the ground under reflux for 20 hours. Dry distil and add to
the residue Toluene 40 g Distilled water 200 g Ammonia 30% 20 g
Stir under reflux until complete dissolution Cool at 5.degree. C.
until crystallization. Filter and wash with: Distilled water 15 g
Dry There are obtained 32.3 g Yield 74.8%
Synthesis of 5-piperazin-1-yl-benzofuran-2-carboxylate methyl
hydrochloride
TABLE-US-00002 [0072] Load into a flask:
5-Aminobenzofuran-2-carboxylic acid 32 g methyl ester
Bis-(2-chloroethyl)amine hydrochloride 31.4 g Distilled water 128 g
Heat under reflux, then add Sodium acetate 43.2 g Stir then reflux
for 1 hour then add at 30.degree. C. Methylene chloride 96 g
Ammonia 38.4 g Stir at 30.degree. C., separate the organic phase,
which is dry distilled under vacuum, then add to the residue:
N,N-dimethylformamide 80 g Bubble in the solution HCl gas q.s. at
pH <1 Cool the precipitated mass at r.t., filter and wash with:
Acetone 32 g Dry There are obtained 31.7 g Yield: 63.8%
Example 2
Process for preparing the intermediate
3-(4-Chloro-1-hydroxybutyl)-1H-indol-5-carbonitrile
Synthesis of 3-(4-Chlorobutyryl)-1H-indol-5-carbonitrile
TABLE-US-00003 [0073] Load into a flask: Aluminium trichloride 93 g
Methylene chloride 320 g Heat under reflux, then add:
4-chlorobutyryle chloride 100 g While maintaining the reflux add a
separately prepared solution of: 5-Cyano-indole 40 g Methylene
chloride 160 g Stir at reflux for 30 minutes then pour the reaction
in a flask containing Distilled water 400 g Hydrochloric acid 32%
32 g On completion of casting distil up to 80.degree. C. Add: Ethyl
acetate 200 g Cool at 5.degree. C., filter and wash with: Ethyl
acetate 60 g Distilled water 120 g Dry There are obtained 58 g
Yield: 83.6%
Synthesis of the intermediate compound
3-(4-Chloro-1-hydroxybutyl)-1H-indol-5-carbonitrile
TABLE-US-00004 [0074] Load into a flask:
3-(4-Chlorobutyryl)-1H-indol-5-carbonitrile 58 g Tetrahydrofuran
116 g Distilled water 11.6 g Heat at 30-35.degree. C., then add a
separately prepared solution of: Distilled water .29 g 30% NaOH 0.3
g Sodium borohydride 7 g Stir at 35.degree. C. for 3 hours then add
Methylene chloride 116 g Stir at 35.degree. C., separate the lower
organic phase then dry then add Methanol 72.5 g Distilled water 29
g Stir at 35.degree. C. to crystallization, cool at 5.degree. C.,
filter and wash with Distilled water 11.6 g Dry There are obtained
43 g Yield: 73.5%
Example 3
Process for Preparing Vilazodone (Free Base/Hydrochloride
Synthesis of the intermediate
5-{4-[4-(5-Cyano-1H-indol-3-yl)-4-hydroxybutyl]-piperazin-1-yl}benzofuran-
-2-carboxylate methyl
TABLE-US-00005 [0075] Load into a flask:
5-Piperazin-1-yl-benzofuran-2-carboxylate 11.9 g methyl
hydrochloride Sodium bicarbonate 6.7 g N,N-dimethylacetamide 30 g
Potassium iodide 1.3 g
3-(4-Chloro-1-hydroxybutyl)-1H-indol-5-carbonitrile 12 g Heat at
75.degree. C. for 28 h then add: Distilled water 50 g Ethyl acetate
50 g Cool to 5.degree. C., filter and wash with: Distilled water 10
g Dry There are obtained 11 g Yield 58%
Synthesis of the intermediate
5-{4-[4-(5-Cyano-1H-indol-3-yl)-but-3-enyl]-piperazin-1-yl}-benzofuran-2--
carboxylate methyl
TABLE-US-00006 [0076] Load into a flask:
5-{4-[4-(5-Cyano-1H-indol-3-yl)-4-hydroxybutyl]- 3 g
piperazin-1-yl}-benzofuran-2-carboxylate methyl DMA 15 g Ammonium
chloride 0.32 g Heat the mixture at 100.degree. C. for 7 hours Cool
to 20.degree. C. then add Ethyl acetate 25 g Aqueous solution of
sodium bicarbonate 10% 10 g Stir and separate the organic phase,
then distil to an oily residue Dissolve all the residue (4.3 g)
obtained in Methanol 25 g and transfer the solution thus obtained
directly into the hydrogenator for the next step
Synthesis of
5-{4-[(4-(5-Cyano-1H-indol-3-yl)-butyl]-piperazin-1-yl}-benzofuran-2-carb-
oxylate methyl
TABLE-US-00007 [0077] Load into the hydrogenator the solution of
5-{4-[4-(5-Cyano-1H-indol-3-yl)-but-3-enyl]- 4.3 g
piperazin-1-yl}-benzofuran-2-carboxylate methyl crude oil in
Methanol 25 g Pd/C 5% 0.4 g Hydrogenate at 15-30.degree. C. at 1.5
bar for 2 hours Filter the catalyst on cardboard and distil the
filtrate to wet crude oily residue. Dissolve this residue (approx.
4 g) in Methanol 10 g and use this solution directly for the next
step Synthesis of Vilazodone base In the solution of
5-{4-[(4-(5-Cyano-1H-indol-3-yl)butyl]- 4 g (approx.)
piperazin-1-yl}-benzofuran-2-earboxylate methyl crude oil in
Methanol 100 g Bubble ammonia gas until saturation of the solution.
Stir at room temperature for 20 hours Then distil the solution to a
solid residue of Vilazodone base (approx. 3 g) that is used
directly for the next step. Synthesis of Vilazodone hydrochloride
Load into a flask Vilazodone base 2 g Acetone 12 g Stir under
reflux until complete dissolution of the powder, then load: HCl 37%
0.45 g Cool to 45.degree. C. (a precipitate is formed). Cool to
5.degree. C. then filtered and wash with acetone (5 g). Dry
55.degree. C. There are obtained approximately 1.5 g of Vilazodone
hydrochloride.
* * * * *