FIELD OF THE INVENTION
The invention belongs to the field of organic chemistry and relates to a novel,
improved, commercially viable and industrially advantageous process for the synthesis
of compounds useful as intermediate in the synthesis of α-1 adrenoceptor blockers,
including (R)-l-(3-hydroxypropyl)-5-[2-[2-[2-(2,2,2-trifluoroethoxy) phenoxy]
ethylamino] propyl] indoline 7-carboxamide (hereinafter referred to by its generic
name "Silodosin"), its pharmaceutically acceptable derivatives, salts or solvates.
BACKGROUND
The following discussion of the prior art is intended to present the invention in an
appropriate technical context and allow its significance to be properly appreciated.
Unless clearly indicated to the contrary, however reference to any prior art in this
specification should be construed as an admission that such art is widely known or
forms part of common general knowledge in the field.
Silodosin is the adopted name of the drug compound chemically known as l-(3-
hydroxypropyl)-5-[(2R)-({2-[2-[2-(2,2,2-
trifluoroethoxy)phenoxy]ethyl}amino)propyl]indoline-7-carboxamide and is
represented by the following structural Formula XVI:
Silodosin is a selective alpha-1 adrenergic receptor antagonist, indicated for the
treatment of the signs and symptoms of benign prostatic hyperplasia (BPH). Presently,
silodosin is marketed in the US under the trade name of Rapaflo. Heretofore, only a
few processes for the manufacture of Silodosin have become known. Literature
2
suggests that silodosin has been obtained from two intermediates viz. indoline and
phenoxyethyl intermediates. There have been many literature references on the
synthesis of these intermediates.
US patent no. 5387603 discloses the synthesis of silodosin and 1,5,7 trisubstituted
indoline intermediate using N-acylated indoline as starting material. The preparation
involves the steps of bromination, reduction, nitration, nitro reduction, cyanation and
azidation. Further, the racemic mixture of indoline intermediate is used for preparation
of silodosin. The total procedure is very complex having more number of process steps
including optical resolution at final stages of the synthesis and the pyrophoric reagents
used in the process are very difficult to handle on a large scale.
Japanese application no. 2001199956 discloses the synthesis of indoline derivative
using indoline and propylbenzoate as starting material and the preparation is carried out
in a series of reactions including Vilsmeir-Haack formylation, nitration and reduction.
One of the intermediate of the preparation reaction is l-(3-benzoyloxypropyl)-7-cyano-
5-(2-oxopropyl) indoline. However, some of the stages of the preparation of indoline
intermediate as per JP 2001-199956 are difficult. The conversion of l-(3-
benzoyloxypropyl)-7-cyano-5(2-nitropropyl)indoline to 1 -(3-benzoyloxypropyl)-7-
cyano-5(2-oxopropyl)indoline by hydrogen peroxide provides a very low yield and
requires product purification by column chromatography followed by crystallization.
The keto compound was further converted to amine derivative using L-2-
phenylglycinol with hydrogen gas in the presence of platinum oxide to obtain the
diastereomer ratio of 3.8:1. This premix is then hydrogenated with Pd/C and treated
with L-tartaric acid to get enantiomerically pure indoline intermediate. This process is
very complicated and costly.
Japanese application no. 2002265444 discloses preparation of l-(3-benzyloxypropyl)-
5-(2-substituted propyl) indoline. The patent specifically discloses preparation of 5-(2-
aminopropyl)-l-(3-benzyloxypropyl) indoline-7-carbonitrile from (R)-3-[l-(3-
benzyloxypropyl)-7-cyanoindoline-5yl]-2-methylpropionic acid. The route of synthesis
followed in this patent involves pyrophoric reagents like n-BuLi, which is difficult to
3
handle in large scale synthesis. Some of the reagents like Witting salt and resulting
agent are not commercially available.
Japanese application no. 2006188470 discloses the synthesis of a similar indoline
intermediate using N-protected indoline as starting material and the process is carried
out in a series of reactions involving reduction, bromination, nitrile formation and
hydrolysis. The indoline intermediate obtained is used for preparation of silodosin. The
reagents used in the process are sodium/cupper cyanide for nitrile substitution and
Triethylsilyl hydride for reduction which are very difficult to handle in large scale
manufacturing.
PCT application no. WO2006046499 discloses the synthesis of silodosin which
comprises the steps of reacting indole intermediate with phenoxyethyl intermediate and
further carrying out the removal of hydroxyl protecting group and hydrolysis of the
nitrile group.
Although there are synthetic processes available for the synthesis of the indoline
compound useful as silodosin intermediate, there is need to explore novel synthetic
schemes that could be more economic and scalable. The present invention provides a
novel, improved, commercially viable and industrially advantageous process for the
synthesis of indoline intermediate and its pharmaceutically acceptable derivatives,
salts or solvates thereof useful as intermediate in the synthesis of silodosin, its
derivatives and pharmaceutically acceptable salts
SUMMARY OF THE INVENTION
The present invention relates to an improved process for the synthesis of indoline
intermediates, its pharmaceutically acceptable derivatives, salts or solvates thereof,
useful in the synthesis of a-1 adrenoceptor blockers such as silodosin.
In one aspect, the present invention provides a novel process for the preparation of
indoline derivatives of Formula LA, Formula IB, their pharmaceutically acceptable
derivatives, salts or solvates thereof.
4
wherein R is a hydroxyl protecting group.
The present invention further provides a novel process for the preparation of indoline
derivatives of Formula IA, Formula IB, their pharmaceutically acceptable derivatives,
salts or solvates thereof, useful as a key intermediate in the synthesis of silodosin, its
pharmaceutically acceptable derivatives, salts or solvates thereof.
In another aspect, the present invention specifically provides a process for the
preparation of tartarate salt of 3-(5-((R)-2-aminopropyl)-7-cyanoindolin-l-yl) propyl
benzoate of Formula I
comprising:
5
(a) reducing the nitro group of compound of Formula XI with a suitable reducing
agent in a suitable solvent to obtain amine compound of Formula XII,
(b) resolving the racemic mixture of amine compound of Formula XII obtained in
step (a), either by isolating it or without isolating, using suitable enantiopure
acid in presence of suitable solvent to obtain tartarate salt of 3-(5-((R)-2-
aminopropyl)-7-cyanoindolin-l-yl) propyl benzoate of Formula I.
In yet another aspect, the present invention specifically provides a novel process for the
preparation of Tartarate salt of 3-(5-((R)-2-aminopropyl)-7-cyanoindolin-l-yl) propyl
benzoate of Formula I
which comprises the steps of:
(a) reacting benzoic acid of Formula II
with l-bromo-3-chloropropane of Formula III
to obtain 3- chloropropylbenzoate of Formula IV;
(b) reacting the compound 3-chloro-propylbenzoate of Formula IV with an indoline
of Formula V
to obtain 3-(Indolin-l-yl) propyl benzoate of Formula VI;
(c) subjecting the compound of Formula VI to a formylation step, specifically a
Vilsmeier-Haack reaction in the presence of N,N-dimethylformamide and
phosphorus oxychloride to produce a formyl compound of Formula VII;
(d) reacting compound of Formula VII with 2- nitroethane to obtain a compound 3-
(5-(2-nitrovinyl)indolin-l-yl)propyl benzoate of Formula VIII;
7
(e) reducing 3-(5-(2-nitrovinyl)indolin-l-yl)propyl benzoate of Formula VIII to 3-
(5-(2-nitropropyl) indolin-1-yl) propyl benzoate of Formula IX;
(f) subjecting 3-(5-(2-nitropropyl) indolin-1-yl) propyl benzoate of Formula IX to a
formylation step, specifically a Vilsmeier-Haack reaction in the presence of
N,N-dimethylformamide and phosphorus oxychloride to obtain 3-(7-formyl-5-
(2-nitropropyl)indolin-l-yl)propyl benzoate of Formula X;
(g) converting 3-(7-formyl-5-(2-nitropropyl)indolin-l-yl)propyl benzoate of
Formula X to 3-(7-cyano-5-(2-nitropropyl)-indolin-l-yl)-propyl benzoate of
Formula XI;
8
(h) reducing the nitro group of compound of Formula XI of to obtain compound of
Formula XII; and
(i) converting the compound of Formula XII, either by isolating it or without
isolating, to tartarate salt of 3-(5-((R)-2-aminopropyl)-7-cyanoindolin-l-yl)
propyl benzoate of Formula I.
In an aspect, the present invention provides a process for the preparation of indoline
derivatives of Formula IC, Formula ID, their pharmaceutically acceptable derivatives,
salts or solvates thereof
by hydrolyzing compound of Formula IA or Formula IB obtained by following novel
process as disclosed in any of the embodiments of the present invention with
methanolic KOH.
9
In yet another aspect, the present invention provides an improved, commercially viable
and industrially advantageous process for the preparation of silodosin of Formula XVI
its pharmaceutical^ acceptable derivatives, salts or solvates thereof, comprising the
following steps;
(1) reacting compound of Formula IB obtained by following novel process as
disclosed in any of the embodiments of the present invention with 2-[2-(2,2,2-
trifluoroethoxy)phenoxy]ethyl methane sulfonate of Formula XIII
to obtain compound of Formula XIVA
wherein R is a hydroxyl protecting group;
(2) removing the hydroxyl protecting group of compound of Formula XIVA to
yield compound of Formula XV;
10
(3) hydrolyzing compound of Formula XV to obtain silodosin of Formula XVI; and
(4) optionally converting silodosin of Formula XVI of step (3) to its pharmaceutical
acceptable derivatives, salts or solvates.
The present invention even further discloses an improved, commercially viable and
industrially advantageous process for the preparation of silodosin of Formula XVI
its pharmaceutically acceptable derivatives, salts or solvates thereof, comprising the
following steps:
(1) reacting compound of Formula ID obtained by following novel process as
disclosed in any of the embodiments of the present invention with 2-[2-(2,2,2-
trifluoroethoxy)phenoxy]ethyl methane sulfonate of Formula XIII
to obtain compound of Formula XV;
11
(2) hydrolyzing compound of Formula XV to obtain silodosin of Formula XVI; and
(3) optionally converting silodosin of Formula XVI of step (3) to its pharmaceutical
acceptable derivatives, salts or solvates.
In a specific aspect, the present invention provides an improved, commercially viable
and industrially advantageous process for the preparation of silodosin of Formula XVI
its pharmaceutically acceptable derivatives, salts or solvates thereof, comprising the
following steps:
(1) reacting compound of Formula I obtained by following novel process as
disclosed in any of the embodiments of the present invention with 2-[2-(2,2,2-
trifluoroethoxy)phenoxy]ethyl methane sulfonate of Formula XIII
to obtain compound of Formula XIV;
12
(2) removing the hydroxyl protecting group of compound of Formula XTV to yield
compound of Formula XV;
(3) hydrolyzing compound of Formula XV to obtain silodosin of Formula XVI; and
(4) optionally converting silodosin of Formula XVI of step (3) to its
pharmaceutically acceptable derivatives, salts or solvates thereof.
These and other features, aspects and advantages of the present subject matter will
become better understood with reference to the following description. This summary is
provided to introduce a selection of concepts in a simplified form. This summary is not
intended to limit the scope of the claimed subject matter.
DETAILED DESCRD?TION OF THE INVENTION
The present invention relates to a novel and improved commercially viable and
industrially advantageous process for the synthesis of Indoline derivatives of Formula
IA and its pharmaceutically acceptable derivatives, salts or solvates thereof, useful as
intermediates in the synthesis of compounds that act as a-1 adrenoceptor blockers.
13
Definitions:
The invention described herein in detail using the terms defined below unless otherwise
specified.
The term "suitable solvent" refers to a solvent or a mixture of two or more solvents,
which induces conditions which are favorable for the reaction to proceed as intended.
The term "suitable base" refers to a reagent or a mixture of two or more reagents, which
facilitates the displacement of a suitable leaving group from the reactant.
The term "suitable reducing agent" refers to a reagent, or a mixture of two or more
reagents, which facilitates the reduction reaction. The term "suitable hydroxyl
containing reagent" refers to organic compounds characterized by the presence of at
least one hydroxyl group.
The term "hydroxyl protecting group" refers to a moiety that prevents chemical
reactions from occurring on the hydroxyl group to which that protecting group is
attached. A hydroxyl protecting group must be removable by a chemical reaction.
Suitable hydroxyl protecting group include, but not limited to, acetyl, t-butyl, tbutoxymethyl,
methoxymethyl, tetrahydropyranyl, 1-ethoxyethyl, l-(2-
chloroethoxy)ethyl, 2-trimethylsilylethyl, p-chlorophenyl, 2,4-dinitrophenyl, benzyl,
benzoyl, 2,6-dichlorobenzyl, diphenylmethyl, p-nitrobenzyl, triphenylmethyl (trityl), 4-
methoxytrityl, 4,4'-dimethoxytrityl, trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, tbutyldiphenylsilyl,
triisopropylsilyl, benzoylformate, chloroacetyl, trichloroacetyl,
trifluoroacetyl, pivaloyl, 9-fluorenyl-methyl carbonate, monomethoxytrityl,
dimethoxytrityl, trimethoxytrityl and the like.
Enantiopure acid refers to acid with specific chirality which will form salt and separate
the isomers.
The Vilsmeier-Haack reaction is a widely used formylation reaction. It can be applied
to introduce an aldehyde group on activated aromatic compounds. In general N, Ndimethylformamide
(DMF) and a chlorinating agent such as POCI3 are used to generate
the Vilsmeier-Haack reagent.
The term "pharmaceutically acceptable salt" refers to salts prepared from
pharmaceutically acceptable non-toxic inorganic or organic acids. The salts may be
prepared during the final isolation and purification of the compounds by making acidic
addition salts. Representative salts of basic compounds of the present invention can be
14
prepared by reacting free base form of the compound with a suitable acid, including,
but not limited to acetate, trifluoroacetate, adipate, citrate, aspartate, benzoate,
benzenesulphonate, bisulfate, besylate, butyrate, camphorsulphonate, difluconate,
hemisulfate, heptanoate, formate, fumarate, lactate, maleate, methanesulfonate,
naphthylsulfonate, nicotinate, oxalate, picrate, pivalate, succinate, tartrate,
trichloracetate, glutamate, p-toluenesulphonate, hydrochloric, hydrobromic, sulphuric,
phosphoric and the like.
The term "derivatives" or pharmaceutically acceptable derivatives refers to any
compound prepared from Formula (IA), Formula (IB), Formula (IC), Formula (ID) or
silodosin respectively by some chemical or physical process and may include, but is not
limited to, esters, ethers, amino derivative and the like.
It must be noted that as used herein and in the appended claims, the singular forms "a",
"an", and "the" include plural reference unless the context clearly dictates otherwise. As
well, the terms "a" (or "an"), "one or more" and "at least one" can be used
interchangeably herein. It is also to be noted that the terms "comprising", "including",
"characterized by" and "having" can be used interchangeably.
In an aspect, present invention provides a novel process for the preparation of indoline
derivatives of Formula IA, Formula IB, their pharmaceutically acceptable derivatives,
salts or solvates thereof.
wherein R is a hydroxyl protecting group; which process comprises the steps of:
(a) reacting a hydroxyl containing reagent of Formula HA
wherein R is hydroxyl protecting group, with compound of Formula IIIA
15
wherein X is Br, CI, OH and Y is Br, CI; to obtain 3-substituted propyl ether or
ester derivative of Formula IVA
wherein R is as define above;
(b) reacting the compound of Formula IVA with an indoline compound of Formula
V
to obtain 3-(Indolin-l-yl) propyl derivative of Formula VI A;
(c) subjecting the compound of Formula VIA to a formylation step, specifically a
Vilsmeier-Haack reaction in the presence of N, N-dimethylformamide and
phosphorus oxychloride to produce a formyl compound of Formula VILA;
(d) reacting compound of Formula VILA with 2- nitroethane to obtain 3-(5-(2-
nitrovinyl)indolin-l-yl)propyl derivative of Formula VIIIA;
16
(e) reducing 3-(5-(2-nitrovinyl)indolin-l-yl)propyl derivative of Formula VIIIA to
3-(5-(2-nitropropyl) indolin-1-yl) propyl derivative of Formula IXA;
(f) subjecting 3-(5-(2-nitropropyl) indolin-1-yl) propyl derivative of Formula IXA
to a further formylation step, specifically a Vilsmeier-Haack reaction in the
presence of N,N-dimethylformamide and phosphorus oxychloride to obtain 3-
(7-formyl-5 -(2-nitropropyl)indolin-1 -yl)propyl derivative of Formula XA;
(g) converting 3-(7-formyl-5-(2-nitropropyl)indolin-l-yl)propyl derivative of
Formula XA to 3-(7-cyano-5-(2-nitropropyl)-indolin-l-yl)-propyl derivative of
Formula XIA;
(h) reducing the nitro group of compound of Formula XIA to obtain compound of
Formula IA; and
(i) converting the compound of Formula IA, either by isolating it or without
isolating, to tartarate salt of Formula IB.
The suitable hydroxyl containing reagent used in step (a) of the present invention is not
limited to any particular reagent, as long as it does not have an adverse effect in the
condensation reaction resulting in formation of an ether derivative. In a preferred
embodiment benzoic acid can be used as the hydroxyl containing reagent.
Suitable solvents that can be used in steps (a) to (i) of the present invention may be
selected from a group comprising of polar protic solvents such as n-butanol,
isopropanol, n-propanol, ethanol, methanol, water and the like; polar aprotic solvents
such as dichloromethane, tetrahydrofuran, ethyl acetate, acetone, methyl isobutyl
ketone, dimethylformamide, dimethylacetamide, acetonitrile, dimethyl sulfoxide and
the like; non polar solvents such as hexane, benzene, toluene, 1,4-dioxane, chloroform,
diethyl ether, methyl t-butyl ether and the like; and inorganic solvents such as ammonia
(NH3), concentrated sulfuric acid (H2SO4) and the like; combination of two or more
solvents from the list and the like.
18
Suitable base that can be used in step (a) and step (b) of the present invention may be
selected from a group comprising of alkali metal hydroxides such as lithium hydroxide,
sodium hydroxide, potassium hydroxide and the like; alkali metal carbonates such as
sodium carbonate, potassium carbonate and the like; alkali metal phosphates such as
sodium phosphate, sodium hydrogen phosphate, potassium phosphate, potassium
hydrogen phosphate and the like; alkali metal bicarbonates such as sodium bicarbonate,
potassium bicarbonate and the like; alkali metal alkoxide such as potassium t-butoxide,
sodium ethoxide; alkali metal hydride such as potassium hydride, sodium hydride; and
lower alkyl amine such as triethylamine, diisopropylethylamine, tributylamine, and the
like; pyridine, dimethylaminopyridine, N-methylpyrrolidinone, N-methylmorpholine
and the like; other tertiary amine such as N-methylmorpholine, triisooctylamine,
pyridine, 2,6-lutidine, quinoline, N-methyl pyrroldinone and the like.
Suitable reducing agents that can be used in step (e) and step (h) of the present
invention may be selected from a group comprising of Sodium Borohydride, Vitride,
Sodium cyanoborohydride, sodium triacetoxy borohydride, sodium trimethoxy
borohydride, zinc borohydride, hydrogenation catalysts such as palladium, nickel and
the like in combination with hydrogen and the like.
The isolation of the solid in step (i) of the present invention can be carried out by
conventional techniques, such as, for example, filtering, decanting, centrifuging and the
like, or by filtering under an inert atmosphere using gases, such as, for example,
nitrogen and the like.
The temperature range to carry out the step (a) to step (i) of the present invention may
be selected from about 0°C to about 120°C.
Steps (a) to (i) of the present invention can be carried out either by isolating the product
in each step or without the need of isolating the product in each step.
The products of steps (a) to (i) of the present invention may be used with or without
purification in their respective next step.
19
Steps (a) to (i) of the present invention may be carried out for any desired time periods
to achieve the desired product yield and purity. Typical reaction times can vary from
about 1 hour to 20 hours, or longer.
In certain preferred embodiments, steps (a) to (i) of the present invention can be carried
out in a single reactor (one pot reaction).
In an embodiment, the present invention provides a process for the preparation of
compound of Formula I
wherein the said compound is isolated as a crystalline compound/amorphous compound
or a mixture of crystalline and amorphous forms.
In another embodiment, the present invention provides the compound of Formula I
obtained by the process of the present application, which is the key intermediate for the
preparation of Silodosin, with both chemical and chiral HPLC purity greater than about
95%, preferably greater than about 99%, more preferably greater than about 99.5% and
most preferably greater than about 99.8%.
In a specific embodiment, the present invention relates to a novel process for the
preparation of indoline derivatives of Formula IC, Formula ID, their pharmaceutically
acceptable derivatives, salts or solvates thereof
20
by hydrolyzing compound of Formula IA or Formula IB obtained by following novel
process as disclosed in any of the embodiments of the present invention with
methanolic KOH.
In another aspect, the present invention specifically provides a process for preparation
of tartarate salt of 3-(5-((R)-2-aminopropyl)-7-cyanoindolin-l-yl) propyl benzoate of
Formula I
comprising:
(a) reducing the nitro group of compound of Formula XI with a suitable reducing
agent in a suitable solvent to obtain amine compound of Formula XII; and
(b) resolving the racemic mixture of amine compound of Formula XII obtained in
step (a), either by isolating it or without isolating, using suitable enantiopure
21
acid in presence of suitable solvent to obtain tartarate salt of 3-(5-((R)-2-
aminopropyl)-7-cyanoindolin-l-yl) propyl benzoate of Formula I.
Suitable reducing agents that can be used in step (a) of the present invention may be
selected from a group comprising of Fe, Fe in acidic media like NH4CI or HC1 or acetic
acid, Sn in acidic media like HC1, Zn, Zn in acidic media like HC1 or NH4CI or acetic
acid, NaBFLt with catalytic NiCl2.6H20 or C0CI2.6H2O, Lithium borohydride, diborane,
Sodium aluminium hydride, hydrazine hydrate, sodiumdithionate, sodium sulfide,
ammonium sulfide, hydrogenation catalysts such as nickel, Raney nickel, rhodium, Pd-
C combined with borohydrides, cyclohexene, acidic media like formic acid, H3PO2 etc.,
Raney cobalt, Raney iron, lithium aluminum hydride, sodium amalgam, platinum
oxide, borane-tetrahydrofuran complex and the like in combination with hydrogen and
the like.
The enantiopure acid used in step (b) of the present invention is selected from group
comprising of L-(+)-Tartaric acid, D-(-)-Tartaric acid, L-(-)-Malic acid, D-(+)-Malic
acid, N-Acetyl-L-glutamic acid, N-Acetyl-D-glutamic acid, (+)-Camphor sulfonic acid,
(-)-Camphor sulfonic acid, S-(+)-Mandelic acid, R-(-)-Mandelic acid, (+)-Di benzoyl-
D-tartaric acid, (-)-Di benzoyl-L-tartaric acid, (-)-Di-/7-toluyl L-tartaric acid, (+)-Di-ptoluyl
D-tartaric acid. L-aspartic acid, R(-)-Acetoxy mandelic acid, R(+)-2-(4-
Hydroxyphenoxy)propionic acid and the like. Tartaric acid is the preferred enantiopure
acid.
In yet another aspect, the present invention specifically provides a novel process for the
preparation of Tartarate salt of 3-(5-((R)-2-aminopropyl)-7-cyanoindolin-l-yl) propyl
benzoate of Formula I
22
which comprises the steps of:
(a) reacting benzoic acid of Formula II
with l-bromo-3-chloropropane of Formula III
to obtain 3- chloropropylbenzoate of Formula IV;
(b) reacting the compound 3- chloro- propylbenzoate of Formula IV with an
indoline of Formula V
to obtain 3-(Indolin-l-yl) propyl benzoate of Formula VI;
23
(c) subjecting the compound of Formula VI to a formylation step, specifically a
Vilsmeier-Haack reaction in the presence of N,N-dimethylformamide and
phosphorus oxychloride to produce a formyl compound of Formula VII;
(d) reacting compound of Formula VII with 2- nitroethane to obtain a compound
3-(5-(2-nitrovinyl)indolin-l-yl)propyl benzoate of Formula VIII;
(e) reducing 3-(5-(2-nitrovinyl)indolin-l-yl)propyl benzoate of Formula VIII to 3-
(5-(2-nitropropyl) indolin-1-yl) propyl benzoate of Formula IX;
(f) subjecting 3-(5-(2-nitropropyl) indolin-1-yl) propyl benzoate of Formula IX to a
formylation step, specifically a Vilsmeier-Haack reaction in the presence of
N,N-dimethylformamide and phosphorus oxychloride to obtain 3-(7-formyl-5-
(2-nitropropyl)indolin-l-yl)propyl benzoate of Formula X;
(g) converting 3-(7-formyl-5-(2-nitropropyl)indolin-l-yl)propyl benzoate of
Formula X to 3-(7-cyano-5-(2-nitropropyl)-indolin-l-yl)-propyl benzoate of
Formula XI;
(h) reducing the nitro group of compound of Formula XI of to obtain compound of
Formula XII; and
(i) converting the compound of Formula XII, either by isolating it or without
isolating, to tartarate salt of 3-(5-((R)-2-aminopropyl)-7-cyanoindolin-l-yl)
propyl benzoate of Formula I.
25
In yet another aspect, the present invention provides an improved, commercially viable
and industrially advantageous process for the preparation of silodosin of Formula XVI
its pharmaceutically acceptable derivatives, salts or solvates thereof, comprising the
following steps:
(1) reacting compound of Formula IB obtained by following novel process as
disclosed in any of the embodiments of the present invention with 2-[2-(2,2,2-
trifluoroethoxy)phenoxy]ethyl methane sulfonate of Formula XIII
to obtain compound of Formula XIVA
wherein R is a hydroxyl protecting group;
(2) removing the hydroxyl protecting group of compound of Formula XIVA to
yield compound of Formula XV
26
(3) hydrolyzing compound of Formula XV to obtain silodosin of Formula XVI; and
(4) optionally converting silodosin of Formula XVI of step (3) to its pharmaceutical
acceptable derivatives, salts or solvates.
The present invention even further discloses an improved, commercially viable and
industrially advantageous process for the preparation of silodosin of Formula XVI
its pharmaceutically acceptable derivatives, salts or solvates thereof, comprising the
following steps:
(1) reacting compound of Formula ID obtained by following novel process as
disclosed in any of the embodiments of the present invention with 2-[2-(2,2,2-
trifluoroethoxy)phenoxy]ethyl methane sulfonate of Formula XIII
to obtain compound of Formula XV;
27
(2) hydrolyzing compound of Formula XV to obtain silodosin of Formula XVI; and
(3) optionally converting silodosin of Formula XVI of step (3) to its pharmaceutical
acceptable derivatives, salts or solvates.
In further specific embodiment, the present invention discloses an improved,
commercially viable and industrially advantageous process for the preparation of
silodosin of Formula XVI
its pharmaceutically acceptable derivatives, salts or solvates thereof, comprising the
following steps:
(1) reacting compound of Formula I obtained by following the processes as
disclosed in any of the embodiments of the present invention with 2-[2-(2,2,2-
trifluoroethoxy)phenoxy]ethyl methane sulfonate of Formula XIII
to obtain compound of Formula XIV;
28
(2) removing the hydroxyl protecting group of compound of Formula XIV to yield
compound of Formula XV;
(3) hydrolyzing compound of Formula XV to obtain silodosin of Formula XVI; and
(4) optionally converting silodosin of Formula XVI of step (3) to its pharmaceutical
acceptable derivatives, salts or solvates.
Suitable solvents that can be used in steps (1) to (4) of the present invention may be
selected from a group comprising of polar protic solvents such as n-butanol,
isopropanol, n-propanol, ethanol, methanol, water and the like; polar aprotic solvents
such as dichloromethane, tetrahydrofuran, ethyl acetate, acetone, methyl isobutyl
ketone, dimethylformamide, dimethylacetamide, acetonitrile (MeCN), dimethyl
sulfoxide and the like; non polar solvents such as hexane, benzene, toluene, 1,4-
dioxane, chloroform, diethyl ether, methyl t-butyl ether and the like; and inorganic
solvents such as ammonia (NH3), concentrated sulfuric acid (H2SO4) and the like.
29
The temperature range to carry out the steps (1) to (4) of the present invention may be
selected from about 0°C to about 80°C.
Steps (1) to (4) of the present invention may be carried out either by isolating the
product in each step or without the need of isolating the product in each step.
The isolation of the solid in step (4) of the present invention can be carried out by
conventional techniques, such as, for example, filtering, decanting, centrifuging and the
like, or by filtering under an inert atmosphere using gases, such as, for example,
nitrogen and the like.
Steps (1) to (4) may be carried out for any desired time periods to achieve the desired
product yield and purity. Typical reaction times can vary from about 1 hour to 20
hours, or longer.
Reaction steps (1) to (4) of the present invention may be carried out in a single reactor
(one pot reaction).
The steps (1) to (4) of the present invention may be carried out in a single reactor (One
pot reaction).The products of steps (1) to (4) of the present invention may be used with
or without purification in their respective next step.
The product obtained in steps (1) to (4) of the present invention may be purified by
pharmaceutically acceptable salt formation in suitable solvents
The product obtained in any step of the present invention may be purified by using
column chromatography and recrystallization can be carried out in suitable solvents.
The process of the present invention is short, utilizes readily available starting materials
and does not involve the use of hazardous or difficult to handle reagents. Each step of
the process of the present invention is high yielding and affords products of very high
purity. Thus the process is easy to scale up for industrial scale manufacturing.
30
EXAMPLES
The invention is explained in detail in the following examples which are given solely
for the purpose of illustration only and therefore should not be construed to limit the
scope of the invention.
The following terms/symbol/abbreviations/chemical Formulae are employed in the
examples:
ml : Millilitre
g : Gram
mg : Milligram
h : Hours
mol : mole
psi : Pounds per square inch
Example 1: Preparation of 3-Chloropropylbenzoate of Formula IV:
To a slurry solution of Benzoic acid (186 g, 1.52 mol) in ethyl acetate (200 ml) was
added l-Bromo-3-chloropropane (200 g, 1.27 mol) followed by the addition of Triethyl
amine (256.9 g, 2.54 mol) at 10°C and stirred for 12 h at 40°C. The mixture was diluted
with water (800 ml), extracted with ethyl acetate (200 ml) and the organic layer was
washed with aqueous bicarbonate solution (150 ml) and followed by water (400 ml).
The ethyl acetate was concentrated to give 225.4 g of 3-Chloropropyl benzoate of
Formula IV crude and it is used in next step without purification.
Example 2: Preparation of 3-(Indolin-l-yl) propyl benzoate of Formula VI
To mixture of Indoline (135.4 g, 1.14 mol), dimethylamino pyridine (13.9 g, 0.114 mol)
and triethyl amine (460 g) was added 3-Chloropropyl benzoate crude (225.4 g) at room
temperature and the reaction mass was stirred at 120°C for 36 h. The reaction mass was
cooled to room temperature and diluted with ethyl acetate (678 ml) and washed twice
with water (452 ml, 220 ml). 10% aqueous hydrochloric acid solution (800 ml) was
added to the ethyl acetate layer to make pH 2-3 at 10-15 °C. The layers were separated
and acidic aqueous layer was extracted one more time with ethyl acetate (452 ml). The
combined organic layers were concentrated and the product was crystallized using 20%
31
hydrochloric acid in isopropyl alcohol (362 ml) and ethyl acetate (200 ml) to give 212 g
of 3-(Indolin-l-yl) propyl benzoate of Formula VI as a hydrochloride salt.
Example 3: Preparation of 3-(5-Formylindolin-l-yl) propyl benzoate of Formula
VII and 3-(5-(2-Nitrovinyl)indolin-l-yl)propyl benzoate of Formula VIII
The process followed for preparation of 3-(5-Formylindolin-l-yl) propyl benzoate of
Formula VII and 3-(5-(2-Nitrovinyl)indolin-l-yl)propyl benzoate of Formula VIII is
same as the process disclosed in any of the prior art including Japanese patent
2001199956.
Example 4: Preparation of 3-(5-(2-Nitropropyl) indolin-1-yl) propyl benzoate of
Formula IX
To solution of 3-(5-(2-Nitrovinyl)indolin-l-yl)propyl benzoate (200g, 0.546 mol) in
mixture of chloroform (1920 ml) and isopropyl alcohol (480 ml) was added sodium
borohydride (31.1 g, 0.81 mol) lot wise at 15-20°C and stirred at room temperature for
4h. The mixture was cooled and neutralized by adding aqueous hydrochloric acid
solution (58.5 ml in 146.6 ml water) followed by water (400 ml). The layers were
separated and the organic layer was washed with water (800 ml) and concentrated
under reduced pressure to give 207.3 g of 3-(5-(2-Nitropropyl) indolin-1-yl) propyl
benzoate of Formula IX and it is used directly in next step without further purification.
Example 5: Preparation of 3-(7-Formyl-5-(2-nitropropyl)indolin-l-yl)propyl
benzoate of Formula X and 3-(7-cyano-5-(2-nitropropyl)-indolin-l-yl)-propyl
benzoate of Formula XI
The process followed for preparation of 3-(7-Formyl-5-(2-nitropropyl)indolin-lyl)
propyl benzoate of Formula X and 3-(7-Cyano-5-(2-nitropropyl)-indolin-l-yl)-
propyl benzoate of Formula XI is same as the process disclosed in any of the prior art
including Japanese patent 2001199956.
Example 6: Preparation of 3-(5-(2-Aminopropyl)-7-cyanoindolin-l-yl)propyl
benzoate of Formula XII and Tartarate salt of (3-(5-((R)-2-Aminopropyl)-7-
cyanoindolin-1-yl) propyl benzoate) of Formula I
32
To solution of 3-(7-Cyano-5-(2-nitropropyl)-indolin-l-yl)-propyl benzoate of Formula
X (100 g, 0.25 mol) in mixture of ethyl acetate (600 ml) and methanol (400 ml) was
added 10% Pd-C (20 g) (50% wet) at room temperature. The mixture was transferred to
autoclave and treated with hydrogen (200 psi pressure) at 40-45 °C for 45 h. The
mixture was filtered through celite bed and the filtrate was concentrated to give 3-(5-(2-
Aminopropyl)-7-cyanoindolin-l-yl)propyl benzoate of Formula XII as a thick gel. The
obtained 3-(5-(2-Aminopropyl)-7-cyanoindolin-l-yl)propyl benzoate of Formula XII
crude was dissolved in tetrahydrofuran (2700 ml) and was added a solution of L (+)-
tartaric acid (35.12 g) in water (300 ml). The mixture was heated to 60-65°C for lh and
allowed to cool to room temperature and stirred for 15-20 h. The precipitated material
was filtered and the solid was recrystallized from a mixture of tetrahydrofuran: water
(9:1) (780 ml) to give 35 g of Tartarate salt of (3-(5-((R)-2-aminopropyl)-7-
cyanoindolin-1-yl) propyl benzoate) of Formula I. (FTPLC purity >99% and chiral
purity 93-97%).
Example 7: Preparation of 3-(5-(2-aminopropyl)-7-cyanoindolin-l-yI)propyl
benzoate of Formula XII
Procedure-1: To a stirring solution of 3-(7-Cyano-5-(2-nitropropyl)-indolin-l-yl)-
propyl benzoate of Formula XI (3 g, 7.63mmol) in a mixture of water (15 ml) and
methanol (30 ml) was added con. HC1 (6 ml) followed by Fe (1.70 g, 30.53mmol). The
mixture was heated to 60-65 °C for 17 h. After completion of the reaction, the mixture
was filtered and the residue was washed with Methanol (5 ml). The filtrate was
concentrated under vacuum and the residue was dissolved in water and washed with
isopropyl ether (2x15 ml). The product was extracted from aqueous layer with MDC
(40 ml). The organic layer was treated with aqueous sodium hydroxide solution and
washed twice with water (2 x 25 ml). The organic layer was concentrated under
vacuum to get 2.5 g of3-(5-(2-aminopropyl)-7-cyanoindolin-l-yl)propyl benzoate of
Formula XII as a thick mass(HPLC purity is: 90.64%).
Procedure-2: To a stirring solution of 3-(7-Cyano-5-(2-nitropropyl)-indolin-l-yl)-
propyl benzoate of Formula XII (10 g, 25.4mmol) in methanol (50 ml) was added con.
HC1 (10 ml) followed by Zn (3.35 g, 50.08mmol). The mixture was heated to 60-65 °C
for 20 h. After completion of the reaction, the mixture was filtered and the residue was
washed with Methanol (5 ml). The filtrate was concentrated under vacuum and the
33
residue was dissolved in water and washed with isopropyl ether (2x20 ml). The MDC
(80 ml) was added to the aqueous layer and basified the mixture by adding aqueous
20% NaOH solution. The obtained solid slurry mass was filtered and both the layers
were separated from the filtrate. The organic layer was washed twice with water (2 x
100 ml) and concentrated under vacuum to get 8.5 g of 3-(5-(2-aminopropyl)-7-
cyanoindolin-l-yl)propyl benzoate of Formula XII as a thick mass (HPLC purity is
above 95 %).
Procedure-3: To a stirring solution of 3-(7-Cyano-5-(2-nitropropyl)-indolin-l-yl)-
propyl benzoate of Formula XI (1 g, 2.54 mmol) in a mixture of methanol (20 ml) and
water (10 ml) was added NH4CI (0.57 g, 10.17 mmol) followed by Fe (0.28 g, 5.08
mmol). The mixture was heated to 60-65 °C for 15 h. After completion of the reaction,
the mixture was filtered and the residue was washed with methanol (5 ml). The filtrate
was concentrated under vacuum and the residue was dissolved in Ethyl acetate (30 ml).
The organic layer was successively washed with aqueous sodium bicarbonate solution
and twice with water (2X20 ml) and concentrated under vacuum to get 0.78 g of 3-(5-
(2-aminopropyl)-7-cyanoindolin-l-yl) propyl benzoate of Formula XII as a thick mass.
Procedure-4: To a stirring solution of 3-(7-Cyano-5-(2-nitropropyl)-indolin-l-yl)-
propyl benzoate of Formula XI (1 g, 2.54 mmol) in methanol (20 ml) was added NH4CI
(0.57 g, 10.17 mmol) followed by Zn (0.34 g, 5.08 mmol). The mixture was heated to
60-65 °C for 20 h. After completion of the reaction, the mixture was filtered and the
residue was washed with methanol (5 ml). The filtrate was concentrated under vacuum
and the residue was dissolved in Ethyl acetate (30 ml). The organic layer was
successively washed with aqueous sodium bicarbonate solution and twice with water
(2x20 ml) and concentrated under vacuum to get 0.82 g of 3-(5-(2-aminopropyl)-7-
cyanoindolin-1-yl) propyl benzoate of Formula XII as a thick mass.
Procedure-5: To a stirring solution of 3-(7-Cyano-5-(2-nitropropyl)-indolin-l-yl)-
propyl benzoate of Formula XI (10 g) in methanol (240 ml) was added acetic acid (5
ml) followed by Raney Ni (1 g). The mixture was transferred to an autoclave and
treated with hydrogen (150 psi pressure) at 40-45°C for 45 h. The mixture was filtered
through celite bed and the filtrate was concentrated. The crude was dissolved in Ethyl
acetate (100 ml) and the organic layer was washed with 5% aqueous sodium
bicarbonate solution (100 ml). The organic layer was separated and washed with water
34
(100 ml). The organic layer was concentrated to give 9.2 g of 3-(5-(2-Aminopropyl)-7-
cyanoindolin-1-yl) propyl benzoate of Formula XII as a thick mass.
Example 8: Preparation of Tartarate salt of (3-(5-((R)-2-aminopropyl)-7-
cyanoindolin-1-yl) propyl benzoate) of Formula I
The 3-(5-(2-Aminopropyl)-7-cyanoindolin-l-yl)propyl benzoate of Formula XII (9 g)
crude (prepared from any of the procedure as per example 7) was dissolved in
tetrahydrofuran (270 ml) and was added a solution of L (+)-tartaric acid (3.51 g) in
water (30 ml). The mixture was heated to 60-65°C for lh and allowed to cool to room
temperature and stirred for 15-20 h. The precipitated material was filtered and the solid
was recrystallized from mixture of tetrahydrofuran: water (9:1) (78 ml) to give 3.5 g of
Tartarate salt of (3-(5-((R)-2-aminopropyl)-7-cyanoindolin-l-yl) propyl benzoate) of
Formula I. (HPLC purity >99% and chiral purity 93-97%).
Example 9: Preparation of Silodosin
Procedure 1: To a solution of Tartrate salt of 3-(5-((R)-2-aminopropyl)-7-
cyanoindolin-1-yl) propyl benzoate (I) (50, 0.097 mol) in ethyl acetate (500 ml) was
added water (500 ml) followed by addition of aqueous solution of Potassium carbonate
(Potassium carbonate (130 g) dissolved in water (200 ml)). The mixture was stirred for
lh at room temperature and the layers were separated. The organic layer was washed
with water (500 ml) and concentrated under reduced pressure. The obtained crude was
dissolved in Isopropyl alcohol (750 ml), Sodium carbonate (11.3 g, 0.107 mol) and 2-
[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl methane sulfonate of Formula XIII (36.7 g,
1.16 mol) were added. The mixture was stirred at 80°C for 40-50 h. After completion
of the reaction, the mixture was cooled and water (500 ml) was added. The organic
layer was extracted with ethyl acetate twice (2 x 500 ml). The combined organic layers
were evaporated to obtain the product and the product obtained was purified by column
chromatography using dichloromethane and methanol in different ratios as a mobile
phase. The appropriate fractions were combined together and distilled under reduced
pressure to give 38 gm of 3-{7-cyano-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)-
phenoxy]ethyl}amino)propyl)-2,3-dihy dro-lH-indol-1-yl) -propyl benzoate of
Formula XIV (HPLC purity: 99.5%).
35
The conversion of Formula XIV to Silodisn was followed by procedures disclosed in
any of the prior art including United States patent application 20070197627 and United
States patent 5,387,603.
Procedure 2: To a solution of Tartrate salt of 3-(5-((R)-2-aminopropyl)-7-
cyanoindolin-1-yl) propyl benzoate (I) (50 g, 0.097 mol) in ethyl acetate (500 ml) was
added water (500 ml) followed by addition of aqueous solution of Potassium carbonate
(Potassium carbonate (130 g) was dissolved in water 9200 ml)). The mixture was
stirred for lh at room temperature and the layers were separated. The organic layer was
washed with water (500 ml) and concentrated under reduced pressure. The obtained
crude was dissolved in Isopropyl alcohol (750 ml), Sodium carbonate (11.3 g, 0.107
mol) and 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl methane sulfonate of Formula XIII
(36.7 g, 1.16 mol) were added. The mixture was stirred at 80°C for 40-50 h. After
completion of the reaction, the mixture was cooled to room temperature and added
aqueous KOH solution (7.9 g of KOH dissolved in 37.5 ml of water) and stirred for 10-
12 h. The solvent was evaporated under reduced pressure and water (500 ml) was
added to the crude mass. The product was extracted with ethyl acetate twice (2x 500
ml) and the combined organic layer was washed with 5% aqueous sodium bicarbonate
solution (250 ml). The organic layer was further washed with water (250 ml) and the
ethyl acetate was evaporated to get the crude mass, which was dissolved in isopropyl
alcohol (300 ml) and was added 8.7 gm of oxalic acid at room temperature. The
mixture was stirred for 5-6 h and the solid obtained was filtered and washed with
isopropyl alcohol (50 ml) and dried at 50°C to give 30 gm of l-(3-Hydroxypropyl)-5-
[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}amino)propyl]-2,3-dihydro-lHindole-
7-carbonitrile as an oxalic acid salt (HPLC purity: >99 %). The salt was
dissolved in water (150 ml) added ethyl acetate (300 ml), basified with K2C03 aqueous
solution (150 ml) and washed the organic layer with water (150 ml). The organic layer
was concentrated to get l-(3-Hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-
trifluoroethoxy)phenoxy]ethyl}amino)propyl]-2,3-dihydro-lH-indole-7-carbonitrile of
Formula XVI as a thick gel (HPLC purity: >99 %)
The conversion of Formula XVI to Silodisn was followed by procedures disclosed in
any of the prior art including United States patent application 20070197627 and United
States patent 5,387,603.
36
Example 10: Preparation of 5-((R)-2-aminopropyl)-l-(3-hydroxypropyl) indoline-
7-carbonitrile of Formula IC
To a mixture of Tartrate salt of 3-(5-((R)-2-aminopropyl)-7-cyanoindolin-l-yl) propyl
benzoate of Formula (I) (5 gm) in methanol (50 ml) and water (50 ml) was added
potassium hydroxide and stirred the reaction mass for overnight at room temperature.
The mixture was concentrated under reduced pressure and water (100 ml) was added.
The mixture was extracted three times with 5% of Methanol: Methylene Dichloride (3
x 100 ml) and the combined organic layers were distilled to give 1.7 gm of 5-((R)-2-
aminopropyl)-1 -(3 -hydroxypropyl)indoline-7-carbonitrile of Formula IC.

We Claim:
1. A process for the preparation of indoline derivatives of Formula IA, Formula IB,
their pharmaceutically acceptable derivatives, salts or solvates thereof.
wherein R is a hydroxyl protecting group;
which process comprises the steps of:
(a) reacting a hydroxyl containing reagent of Formula IIA
wherein R is a hydroxyl protecting group, with compound of Formula IIIA
wherein X is Br, C1, OH and Y is Br, C1; to obtain 3-substituted propyl ether or
ester derivative of Formula IVA
wherein R is as define above;
(b) reacting the compound of Formula IVA with an indoline compound of Formula
V
to obtain 3-(indolin-l-yl) propyl derivative of Formula VI A;
38
(c) subjecting the compound of Formula VIA to a formylation step, specifically a
Vilsmeier-Haack reaction in the presence of N, N-dimethylformamide and
phosphorus oxychloride to produce a formyl compound of Formula VILA;
(d) reacting compound of Formula VILA with 2-nitroethane to obtain 3-(5-(2-
nitrovinyl)indolin-l-yl)propyl derivative of Formula VILLA
(e) reducing 3-(5-(2-nitrovinyl)indolin-l-yl)propyl derivative of Formula VILLA to
3-(5-(2-nitropropyl) indolin-1-yl) propyl derivative of Formula IXA
(f) subjecting 3-(5-(2-nitropropyl) indolin-1-yl) propyl derivative of Formula IXA
to a further formylation step, specifically a Vilsmeier-Haack reaction in the
presence of N,N-dimethylformamide and phosphorus oxychloride to obtain 3-
(7-formyl-5-(2-nitropropyl)indolin-l-yl)propyl derivative of Formula XA
(g) converting 3-(7-formyl-5-(2-nitropropyl)indolin-l-yl)propyl derivative of
Formula XA to 3-(7-cyano-5-(2-nitropropyl)-indolin-l-yl)-propyl derivative of
Formula XIA
(h) reducing the nitro group of compound of Formula XIA to obtain compound of
Formula IA,
(i) converting the compound of Formula IA, either by isolating it or without
isolating, to tartarate salt of Formula IB
40
2. The process according to claim 1, wherein the hydroxyl protecting group is
selected from a group comprising of acetyl, t-butyl, t-butoxymethyl,
methoxymethyl, tetrahydropyranyl, 1-ethoxyethyl, l-(2-chloroethoxy)ethyl, 2-
trimethylsilylethyl, p-chlorophenyl, 2,4-dinitrophenyl, benzyl, benzoyl, 4-
fluorobenzoyl, 2,6-dichlorobenzyl, diphenylmethyl, p-nitrobenzyl,
triphenylmethyl (trityl), 4-methoxytrityl, 4,4'-dimethoxytrityl, trimethylsilyl,
triethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, triisopropylsilyl,
benzoylformate, chloroacetyl, trichloroacetyl, trifluoroacetyl, pivaloyl, 9-
fluorenyl-methyl carbonate, monomethoxytrityl, dimethoxytrityl, trimethoxytrityl
and the like.
3. The process according to claim 1, wherein the steps (a) to (i) are carried out in the
presence of a suitable solvent selected from a group comprising of polar protic
solvents such as n-butanol, isopropanol, n-propanol, ethanol, methanol, water and
the like; polar .aprotic solvents such as dichloromethane, tetrahydrofuran, ethyl
acetate, acetone, methyl isobutyl ketone, dimethylformamide, dimethylacetamide,
acetonitrile, dimethyl sulfoxide and the like; non polar solvents such as hexane,
benzene, toluene, 1,4-dioxane, chloroform, diethyl ether, methyl t-butyl ether and
the like; and inorganic solvents such as ammonia (NH3), concentrated sulfuric
acid (H2SO4) and the like; combination of two or more solvents from the list and
the like.
4. The process according to claim 1, wherein the reducing agents used in step (e)
and step (h) is selected from a group comprising of Sodium Borohydride, Vitride,
Sodium cyanoborohydride, sodium triacetoxy borohydride, sodium trimethoxy
41
borohydride, zinc borohydride, hydrogenation catalysts such as palladium, nickel
and the like in combination with hydrogen and the like.
5. The process according to claim 1, wherein the reducing agents used in step (h) is
nickel or Raney nickel.
6. The process for the preparation of indoline derivatives of Formula IC, Formula
ID, their pharmaceutically acceptable derivatives, salts or solvates thereof
by hydrolyzing compound of Formula IA or Formula IB
with methanolic KOH.
7. A process for preparation of tartarate salt of 3-(5-((R)-2-aminopropyl)-7-
cyanoindolin-1-yl) propyl benzoate of Formula I
42
comprising:
(a) reducing the nitro group of compound of Formula XI with a suitable reducing
agent in a suitable solvent to obtain amine compound of Formula XII,
(b) resolving the racemic mixture of amine compound of Formula XII obtained in
step (a), either by isolating it or without isolating, using suitable enantiopure
acid in presence of suitable solvent to obtain tartarate salt of 3-(5-((R)-2-
aminopropyl)-7-cyanoindolin-l-yl) propyl benzoate of Formula I.
8. A process according to claim 7, wherein the suitable reducing agents used in step
(a) is selected from the group comprising of Fe, Fe in acidic media like NH4C1 or
HC1 or acetic acid, Sn in acidic media like HC1, Zn, Zn in acidic media like HC1
or NH4C1 or acetic acid, NaBH4 with catalytic NiC12.6H20 or CoC12.6H20,
Lithium borohydride, diborane, Sodium aluminium hydride, hydrazine hydrate,
sodiumdithionate, sodium sulfide, ammonium sulfide, hydrogenation catalysts
such as nickel, Raney nickel, rhodium, Pd-C combined with borohydrides ,
cyclohexene , acidic media like formic acid, H3P02 etc., Raney cobalt, Raney
iron, lithium aluminum hydride, sodium amalgam, platinum oxide, boranetetrahydrofuran
complex and the like in combination with hydrogen and the like.
43
9. A process according to claim 8, wherein the reducing agent is nickel or Raney
nickel.
10. A process according to claim 7, wherein the enantiopure acid used in step (b) is
selected from group comprising of L-(+)-Tartaric acid, D-(-)-Tartaric acid, L-(-)-
Malic acid, D-(+)-Malic acid, N-Acetyl-L-glutamic acid, N-Acetyl-D-glutamic
acid, (+)-Camphor sulfonic acid, (-)-Camphor sulfonic acid, S-(+)-Mandelic acid,
R-(-)-Mandelic acid, (+)-Di benzoyl-D-tartaric acid, (-)-Di benzoyl-L-tartaric
acid, (-)-Di-p-toluyl L-tartaric acid, (+)-Di-p-toluyl D-tartaric acid. L-aspartic
acid, R(-)-Acetoxy mandelic acid, R(+)-2-(4-Hydroxyphenoxy)propionic acid and
the like.
11. A process for the preparation of Tartarate salt of 3-(5-((R)-2-aminopropyl)-7-
cyanoindolin-1-yl) propyl benzoate of Formula I
which comprises the steps of:
(a) reacting benzoic acid of Formula II
with l-bromo-3-chloropropane of Formula III
to obtain 3- chloropropylbenzoate of Formula IV
44
reacting the compound 3-chloro-propylbenzoate of Formula IV with an indoline
of Formula V
to obtain 3-(indolin-l-yl) propyl benzoate of Formula VI
(c) subjecting the compound of Formula VI to a formylation step, specifically a
Vilsmeier-Haack reaction in the presence of N, N-dimethylformamide and
phosphorus oxychloride to produce a formyl compound of Formula VII;
(d) reacting compound of Formula VII with 2- nitroethane to obtain a compound
3-(5-(2-nitrovinyl)indolin-l-yl)propyl benzoate of Formula VIII
45
(e) reducing 3-(5-(2-nitrovinyl)indolin-l-yl)propyl benzoate of Formula VIII to 3-
(5-(2-nitropropyl) indolin-1-yl) propyl benzoate of Formula IX
(f) subjecting 3-(5-(2-nitropropyl) indolin-1-yl) propyl benzoate of Formula IX to a
formylation step, specifically a Vilsmeier-Haack reaction in the presence of
N,N-dimethylformamide and phosphorus oxychloride to obtain 3-(7-formyl-5-
(2-nitropropyl)indolin-l-yl)propyl benzoate of Formula X:
(g) converting 3-(7-formyl-5-(2-nitropropyl)indolin-l-yl)propyl benzoate of
Formula X to 3-(7-cyano-5-(2-nitropropyl)-indolin-l-yl)-propyl benzoate of
Formula XI
46
(h) reducing the nitro group of compound of Formula XI of to obtain compound of
Formula XII,
and
(i) converting the compound of Formula XII, either by isolating it or without
isolating, to tartarate salt of 3-(5-((R)-2-aminopropyl)-7-cyanoindolin-l-yl)
propyl benzoate of Formula I.
12. A compound of Formula I obtained by following the process according to claim
11.
13. A process for the preparation of silodosin of Formula XVI
47
its pharmaceutically acceptable derivatives, salts or solvates thereof, comprising the
following steps;
(1) reacting compound of Formula IB
with 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl methane sulfonate of Formula
XIII
to obtain compound of Formula XIVA
wherein R is a hydroxyl protecting group;
48
(2) removing the hydroxyl protecting group of compound of Formula XIVA to
yield compound of Formula XV
(3) hydrolyzing compound of Formula XV to obtain silodosin of Formula XVI
(4) optionally converting silodosin of Formula XVI of step (3) to its pharmaceutical
acceptable derivatives, salts or solvates.
14. A process for the preparation of silodosin of Formula XVI
its pharmaceutical^ acceptable derivatives, salts or solvates thereof,
comprising the following steps:
(1) reacting compound of Formula ID obtained by following novel process as
disclosed in any of the embodiments of the present invention with 2-[2-(2,2,2-
trifluoroethoxy)phenoxy]ethyl methane sulfonate of Formula XIII
to obtain compound of Formula XV
49
(2) hydrolyzing compound of Formula XV to obtain silodosin of Formula XVI
(3) optionally converting silodosin of Formula XVI of step (2) to its pharmaceutical
acceptable derivatives, salts or solvates.
15. A process for the preparation of silodosin of Formula XVI
its pharmaceutically acceptable derivatives, salts or solvates thereof,
comprising the following steps;
(1) reacting compound of Formula I
50
with 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl methane sulfonate of Formula
XIII
to obtain compound of Formula XIV
(2) removing the hydroxyl protecting group of compound of Formula XIV to yield
compound of Formula XV
(3) hydrolyzing compound of Formula XV to obtain silodosin of Formula XVI
(4) optionally converting silodosin of Formula XVI of step (3) to its pharmaceutical
acceptable derivatives, salts or solvates.
16. Use of a compound of Formula IB
51
wherein R is a hydroxyl protecting group;
or compound of Formula I
for the preparation of silodosin and its pharmaceutically acceptable salts.