FIELD OF THE INVENTION
The present invention relates to an improved, cost-effective and commercially
viable process for preparing an indoline derivative of formula I, a key
intermediate used in the synthesis of silodosin, through novel intermediates.
Formula I
5 BACKGROUND OF THE INVENTION
Silodosin is a well known pharmaceutically active ingredient useful for the
treatment of dysuria and similar diseases having IUPAC name 1-(3-
hydroxypropyl)-5-[(2R)-({2-[2-[2-(2,2,2-trifluoroethoxy)phenoxy] ethylamino)
propyl] indoline-7-carboxamide and is represented by following chemical
10 structure.
It is first disclosed in US patent 5,387,603 and is marketed under trade name
Rapaflo. In US patent 5,387,603 process for the preparation of silodosin and its
various derivatives alongwith indoline intermediates is disclosed. Mainly in patent
'603 silodosin is prepared using two key intermediates, 1-acetyl-5-(2-
15 aminopropyl)indoline-7-carbonitrile and 2-[2-(2,2,2-trifluoroethoxy) phenoxy]
ethyl methanesulfonate as shown below in scheme 1.
3
N
CN
H
N
CH3
O
OCH2CF3
O
O
OMs
CF3
N
CN
NH2
CH3
O
O
N
CN
N
CH3
O
OCH2CF3
O
Boc
N
H
CN
N
CH3
O
OCH2CF3
Boc
N
H
CONH2
N
CH3
O
OCH2CF3
Boc
N
CONH2
N
CH3
O
OCH2CF3
Boc
OTBDMS
EtOH, NaHCO3
i)Mandelic Acid/EtOH
ii)Dry MDC,
Boc anhydride
EtOH, NaOH
Acetic Acid
DMSO,
30% H2O2,
NaOH,
Acetic Acid i) 2-(TBDMS) ethyl
4-nitrobenzene sulfonate
THF, TBAF
TFA, MDC,
Na2CO3
N
CONH2
N
O
OCH2CF3
OH
N
CONH2
H
N
CH3
O
OCH2CF3
OH
Boc
CH3
Scheme 1
Indoline intermediate, 1-acetyl-5-(2-aminopropyl)indoline-7-carbonitrile as
shown in above scheme, is prepared by starting from N-acetyl indoline as shown
below in scheme 2. Major 5 drawback of above invention is that process is
multistep including the steps of acylation, bromination, reduction, nitration,
nitroreduction, cyanation and azidation and involves use of pyrophoric reagents.
Further in order to prepare the desired hydroxy propyl side chain for silodosin, the
resulting indoline intermediate, namely, 1-acetyl-5-(2-aminopropyl)indoline-7-
10 carbonitrile needs to be further alkylated. These drawbacks collectively make said
process unattractive for commercial purpose.
4
Scheme 2
There are several processes known, for the preparation of silodosin and its
indoline intermediate in publications like JP4634560; JP4921646; JP-2006-
188470; WO2011/1247 5 04 and WO2011/101864. In most of the disclosures,
silodosin is prepared by following reaction as shown below in scheme 3.
N
OH
CN
HN
O
OCH2CF3
N
OR
CN
HN
O
OCH2CF3
N
OR
CN
NH2
O
O CF3
N
OH
CONH2
HN
O
OCH2CF3
Base, Solvent
OMs
wherein R is benzoyl, benzyl, tetrahydropyranyl, 2-trimethylsilylethyl, dinitrophenyl, diphenyl
methyl and the like
Scheme 3
5
Since silodosin is an optical active compound, and optical activity is imparted by
optical active indoline intermediate which bears the asymmetric carbon atom.
Because of this, process for preparation of indoline compound attracts the major
attention of research community and resulted the various approaches for the
5 synthesis of indoline intermediate and are incorporated herein as reference.
In Japanese patent JP4634560 (Publication no.2001-199956) optically active
prealkylated indoline intermediate is prepared by a process as shown below in
scheme 4.
10 wherein Bz represents benzoyl [-COC6H5]
Scheme 4
In this patent, specifically indoline intermediate of formula I, is prepared using 1-
(3-benzoyloxypropyl)-7-cyano-5(2-nitropropyl)indoline. In the disclosed process
1-(3-benzoyloxypropyl)-7-cyano-5(2-nitropropyl)indoline is converted to 1-(3-
15 benzoyloxypropyl)-7-cyano-5(2-oxopropyl)indoline using hydrogen peroxide,
and purified by column chromatography followed by crystallization. The resulting
oxopropyl indoline compound is further reacted with L-2-phenylglycinol to afford
6
imine, which is converted to amino derivative by reduction. The amino derivative
is obtained as a mixture of diastereomers in the ratio 3.8:1.This premix is then
reacted with palladium on carbon to remove the benzylic protective group and
affords the optical purity of approximately 58.3% enantiomeric excess (e.e).
5 Further to increase the optical purity, a fractional crystallization of the desired
enantiomer as L-tartaric acid salt is performed. Alternatively the diastereomers
were separated by column chromatography. The process as described above is
very cumbersome and uses repeated crystallization, column chromatography and
expensive reagent like L-2-phenylglycinol, therefore commercially not viable.
10 In Chinese publication CN102746210 a process for preparation of indoline
intermediate of formula I is described by using (R)-2-nitro propanoic acid. The
method includes introducing benzoyloxopropyl into 1st position of indoline
moiety, combining with (R)-2-nitropropionic acid for acylation reaction by means
of Friedel-Crafts reagents, reducing the resulting product by the aid of triethyl
15 silane in trifluoroacetic acid, introducing formyl group at 7th position by means of
formylation to obtain (R)-1-[1-(3-benzoyl oxo propyl)-5-(2-nitropropyl) 7-
formoxyl], reacting the resulted formyl derivative with hydroxylamine
hydrochloride, pyridine and acetic anhydride, followed by catalytic reduction to
obtain the target indoline intermediate of formula I as shown below in scheme 5:
20
wherein Bz represents benzoyl [-COC6H5]
Scheme 5
7
This process requires (R)-2-nitropropionic acid to introduce optical activity, but
said acid is highly reactive and susceptible to racemize and it is likely that after
Friedal-Crafts acylation, desired chiral purity may not be achieved, since
disclosure is silent about chiral purity of intermediates.
5 A PCT publication WO2011/030356 discloses a process for the preparation of Nprotected
7-carbamoyl indoline compound which avoids the resolution of the
enantiomers of specific intermediate compounds using chiral auxiliaries or
optically active bases. The process involves protection of R-Alanine, using
ethylchloroformate, the resulting R-(N-ethoxy carbonyl) alanine is subsequently
10 activated using oxalyl chloride to afford ethoxycarbonyl alanine compound which
is used to acylate 7-cyano indoline compound under Friedal-Crafts acylation
reaction. Further reaction steps involves the reduction of oxo group of resulting
compound, followed by carbamoyl formation and hydrolysis reactions produces
the (R)-5-(2-aminopropyl)-1-(3-propyl protected)-7-carbamoyl indoline
15 compounds, said disclosure is silent about the formation of indoline intermediate
of formula I. Schematic presentation of reactions is shown below in scheme 6:
Scheme 6
In one another Japanese patent JP4921646 (Publication no.2002-265444) a
20 process for preparation of an indoline derivative, having different substitution, is
described using (R)-3-[1-(3-benzyloxypropyl)-7-cyanoindoline-5-yl]-2-methyl
propionic acid. In disclosed process, resolution of cyano indoline methylpropionic
8
acid is performed by making diastereomeric salt of it with (1S,2R)-2-
benzylaminocyclohexane methanol. A 92.8% diastereomeric excess (d.e.) salt is
obtained after a series of crystallization steps, this salt is further hydrolyzed and
converted to corresponding carbonitrile intermediate then to amide and then to
5 indoline derivative of formula I, as shown below in scheme 7.
wherein Bn represents benzyl
Scheme 7
The said process involve use of very expensive reagent (1S,2R)-2-
10 benzylaminocyclohexane methanol which makes the process unattractive from
cost point of view.
In another Japanese patent publication 2006-188470, indoline derivative, having
different hydroxy protection group like benzyl, is prepared by starting from Nprotected-
5-bromo indoline compound. In a reaction sequence, N-protected-5-
15 bromo indoline compound is converted to (R)-5-(N-ketooxybenzyl or ketooxy-tbutyl
group protected-aminopropyl)-1-(3-benzyl or tetrahydropyranyl propyl)-7-
cyano indoline compound, which undergo reduction in presence of triethylsilyl
hydride, then obtained product is brominated, further nitrile formation and
hydrolysis gives desired indoline intermediate. In this process, benzyl protecting
20 group is used which is difficult to remove in final stages. A reaction scheme
disclosed in patent publication is represented below in scheme 8
9
wherein Bn represents benzyl
Scheme 8
As most of the literature described above uses the reduction of aliphatic nitro
group to an amino group in a multifunctional 5 substrate via keto group which
makes the process lengthy. Hence efforts has been made to modify the process in
a PCT publication WO2011/124704 which discloses a direct hydrogenation of
achiral nitro compound namely 1-(3-benzoyloxypropyl)-7-cyano-5-(2-
nitropropyl)indoline using Pd/C and/or Pt/C as a catalyst to obtain corresponding
10 racemic amino indoline intermediate which is resolved using optically active acid.
Similarly in PCT publication WO2012/131710 and in Chinese patent publication
CN102702067, processes for the preparation of tartarate salt of indoline
intermediate of formula I is disclosed by reducing corresponding nitro
intermediate using suitable reagent and followed by treatment with optically
15 active acid such as tartaric acid for resolution.
In view of the above, it is observed that most of the processes involves
formylation and further conversion to cyano group at 7-position in indoline ring
on corresponding nitro intermediates, but proton α to nitro group in methylene is
highly reactive and may interfere with formyl group during its preparation and
20 conversion to cyano. So there is an urgent need in the art to provide an
10
advantageous process for preparing indoline derivative which is relatively easy,
cost effective, involving less steps and provides indoline derivative in an excellent
yield in a high optical and chemical purity. The present invention aims to provide
an improved and commercially viable process for the preparation of indoline
5 derivative.
OBJECT OF THE INVENTION
The main object of the present invention is to provide a cost effective process for
the preparation of indoline derivative of formula I, including its derivatives or
solvates, a key intermediate useful in the synthesis of silodosin.
10 Yet another object of the present invention is to provide a cost effective process
for the preparation of indoline derivative of formula I, including its derivatives or
solvates, using novel compounds.
Yet one another object of the present invention is to provide a novel compounds,
useful in the preparation of indoline derivative of formula I.
15 Still another object of the present invention is to provide a process for synthesis of
silodosin using indoline derivative of formula I, prepared by using novel
compounds.
SUMMARY OF THE INVENTION
Accordingly, the present invention provides an improved, cost effective and
20 commercially viable process for preparation of indoline derivative of formula I, a
key intermediate for the preparation of silodosin or pharmaceutically acceptable
salts thereof.
Formula I
According to one embodiment, the present invention provides a process for the
preparation of indoline derivative of formula I, including its derivatives or
25 solvates, which comprises the steps of:
11
a) reducing 5-nitro-propenyl indoline compound of formula II with a suitable
reducing agent, in a suitable solvent
Formula II
to form 5-aminopropyl indoline compound of formula III
Formula III
b) protecting the amino group of 5-aminopropyl indoline compound of
formula III using 5 a suitable amino protecting group to form 5-
aminoprotected propyl indoline compound of formula IV
Formula IV
wherein R1 and R2 represent amino protecting group; wherein R1 or R2
can be independently hydrogen, substituted or unsubstituted alkyl, aryl,
aralkyl, allyl, benzyl, substituted or unsubstituted alkoxycarbonyl,
10 vinyloxycarbonyl, allyloxycarbonyl, benzyloxycarbonyl, phenyloxy
carbonyl, formyl, acetyl, benzoyl and the like; both R1 and R2 collectively
form cyclic imide and the like; provided both R1 and R2 cannot be
hydrogen together;
c) formylating the 5-aminoprotected propyl indoline compound of formula
15 IV using formylating reagent to form 5-aminoprotected propyl-7-formyl
indoline compound of formula V
12
Formula V
wherein R1 and R2 represent amino protecting group as defined above
d) converting the 5-aminoprotected propyl-7-formyl indoline compound of
formula V using a suitable reagent to form 5-aminoprotected propyl-7-
cyano indoline compound of formula VI
Formula VI
5 wherein R1 and R2 represent amino protecting group as defined above
e) deprotecting the amino protecting group from the 5-aminoprotected
propyl-7-cyano indoline compound of formula VI using a suitable
deprotecting reagent to form indoline derivative of formula VII,
Formula VII
f) resolving the indoline intermediate of formula VII by treating with a
10 suitable optical active acid to prepare indoline derivative of formula I.
According to one other embodiment, the present invention provides a novel
intermediate compounds of formulae III, IV, V and VI and processes of preparing
these intermediates.
According to one other embodiment, the present invention provides a process for
15 preparation of silodosin of following formula and pharmaceutically acceptable
salts thereof,
13
which comprises the steps of:
a) reducing 5-nitro-propenyl indoline compound of formula II with a suitable
reducing agent, in a suitable solvent
Formula II
to form 5-aminopropyl indoline compound of formula III
Formula III
b) protecting the amino group 5 of 5-aminopropyl indoline compound of
formula III using a suitable amino protecting group to form 5-
aminoprotected propyl indoline compound of formula IV
Formula IV
wherein R1 and R2 represent amino protecting group ; wherein R1 or R2
can be independently hydrogen, substituted or unsubstituted alkyl, aryl,
10 aralkyl, allyl, benzyl, substituted or unsubstituted alkoxycarbonyl,
vinyloxycarbonyl, allyloxycarbonyl, benzyloxycarbonyl, phenyloxy
carbonyl, formyl, acetyl, benzoyl and the like; both R1 and R2 collectively
14
form cyclic imide and the like; provided both R1 and R2 cannot be
hydrogen together;
c) formylating the 5-aminoprotected propyl indoline compound of formula
IV using formylating reagent to form 5-aminoprotected propyl-7-formyl
5 indoline compound of formula V
Formula V
wherein R1 and R2 represent amino protecting group as defined above
d) converting the 5-aminoprotected propyl-7-formyl indoline compound of
formula V using a suitable reagent to form 5-aminoprotected propyl-7-
cyano indoline compound of formula VI
Formula VI
10 wherein R1 and R2 represent amino protecting group as defined above
e) deprotecting the amino protecting group from 5-aminoprotected propyl-7-
cyano indoline compound of formula VI using a suitable deprotecting
reagent to form indoline intermediate of formula VII,
Formula VII
f) resolving the indoline intermediate of formula VII by treating with a
15 suitable optical active acid to prepare indoline derivative of formula I,
g) converting indoline derivative of formula I to silodosin.
15
DETAILED DESCRIPTION OF THE INVENTION
As used herein term “indoline inetrmediate” refers to 3-[5-(R)(2-aminopropyl)-7-cyano-1-indolinyl]propyl benzoate
Accordingly, the present invention provides an improved, cost effective and commercially viable process for the preparation of indoline derivative of formula 5 I and its derivatives or solvates through novel intermediates.
According to one embodiment, present invention provides a process for the preparation of indoline derivative of formula I by starting from 5-nitro-propenyl indoline compound of formula II. The process involves reduction of double bond and nitro group of 5-nitro-propenyl indoline compound of formula II, protecting 10 the amino group of 5-aminopropyl indoline compound of formula III, formylating the 5-aminoprotected propyl indoline compound of formula IV, converting 5-aminoprotected propyl 7-formyl indoline compound of formula V to 5-aminoprotected propyl 7-cyano indoline compound of formula VI, deprotecting the amino protecting group from the 5-aminoprotected propyl 7-cyano indoline 15 compound, to prepare racemic indoline compound of formula VII, and resolution of indoline compound of formula VII by preparing the optically active salt and then treated with base to obtain indoline derivative of formula I.
Generally, process involves reduction of 5-nitro-propenyl indoline compound of formula II using a suitable reducing agent to form 5-aminopropyl indoline 20 compound of formula III. This step involves reduction of double bond as well as of nitro group in single step, which forms novel part of the invention. In an alternative embodiment, reduction can be performed in two steps also i.e reduction of double bond followed by reduction of nitro group and preparation of 5-nitro-propyl indoline compound in-between. Suitable reducing agents that can 25 be used to reduce 5-nitro-propenyl indoline compound of formula II can be selected depending upon nature of group to be reduced i.e. double bond and nitro group in singe step or reduction of double bond group first followed by nitro group reduction. Suitable reducing agents can be selected from a group
16
comprising of sodium borohydride, sodium cyanoborohydride, sodium triacetoxy borohydride, sodium trimethoxy borohydride, zinc borohydride, Vitride, hydrogenation catalysts such as palladium on carbon, Raney nickel and the like in combination with hydrogen, platinum, platinum oxide, lithium aluminium hydride, diborane, diisobutyl aluminium hydride, trimethylsilane, phenylsilane, 5 diphenylsilane, diphenylchlorosilane, trichlorosilane, and the like. The suitable solvent for the reduction reaction can be selected depending upon the reaction conditions and nature of reducing agent, which includes, but not limited to C1-5 alcohol, C5-8 aliphatic or aromatic hydrocarbon, C3-8 ester, cyclic or acyclic ether, ketone, glycol, polyethylene glycol, dimethylformamide, dimethylacetamide, 10 acetonitrile, dimethyl sulfoxide, water and the like or mixture thereof.
Starting compound of formula II i.e., 5-nitro-propenyl indoline compound can be prepared by the methods known in art or can be procured from market.
Thereafter, 5-aminopropyl indoline compound of formula III is protected using a suitable amino protecting group. The protecting group can be introduced using 15 any appropriate reagent suitable for the protection and which can be removed at the later stage using appropriate deprotecting agent. Appropriate reagent and appropriate deprotecting agent for amine can be perceived by those well versed in the art from ‘Protecting Groups by Philip J. Kocienski (Thieme, 2000)’ or ‘Protective Groups in Organic Synthesis by Theodora W. Greene, Peter G.M. 20 Wuts’ or available and well documented in the literature. The suitable protecting group includes, but not limited to substituted or unsubstituted alkyl, aryl, aralkyl, allyl, benzyl, substituted or unsubstituted alkoxycarbonyl, vinyloxycarbonyl, allyloxycarbonyl, benzyloxycarbonyl, phenyloxycarbonyl, formyl, acetyl, benzoyl, cyclic imide and the like. The amino protecting reagents that can be used for the 25 protection of amino group can be selected from methyl chloroformate, ethyl chloroformate, 2,2,2-trichloroethyl chloroformate, 2-trimethylsilyl ethyl chloroformate, 2-phenylethyl chloroformate, 2-chloroethyl chloroformate, 2-
17
adamantly chloroformate, vinyl chloroformate, benzoyl chloroformate, benzyl chloroformate, FMOC-Chloride, 9-(2-sulfo) fluorenyl methyl, 9-(2,7-dibromo) fluorenyl methyl, 17-tetrabenzo[a,c,g,i] fluorenyl methyl, 2-chloro-3-indenylmethyl, Benz-inden-3-ylmethyl, DBD-T mol, Bsmoc, Pyoc-chloride, Boc anhydride, trifluroacetic anhydride, tetra chloro phthalic anhydride, N-2,3-5 diphenylmaleic anhydride, formic acetic anhydride, acetic anhydride, substituted halo acetic anhydride, acid chloride in amine, phthalic anhydride, substituted phthalic anhydride, N-2,3-diphenylmaleic anhydride, alkylhalide, benzylhalide, allylhalide, triphenylmethylhalide, alkyl or aryl sulfonyl halide, tert-butyldimethysilyl ether and the like. Suitable solvent includes, but not limited to 10 halogenated hydrocarbon, C3-8 ketone, C5-8 aliphatic or aromatic hydrocarbon, C3-8 ester, C2-8 ether, C2-5 nitriles, water, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone and the like or mixture thereof.
After preparation of 5-aminoprotected propyl indoline compound of formula IV, it undergoes introduction of cyano group at position 7 of indoline ring. This is 15 achieved through formylation reaction followed by conversion to cyano group. It is advantageous to introduce cyano group at position 7 of indoline ring on protected amino intermediate of formula IV, since introduction of cyano group at position 7 of indoline ring through formylation on corresponding nitro intermediates may cause interference of formyl group with proton α to nitro group 20 and can generate undesired compounds. The formylation of 5-aminoprotected propyl indoline compound of formula IV can be performed using any suitable formylating reagent. Particularly said step is performed under Vilsmeier-Haack reaction conditions in presence of N,N-dimethylformamide and phosphorous oxy chloride to form 5-aminoprotected propyl-7-formyl indoline compound of 25 formula V.
Conversion of formyl group to cyano group to obtain 5-aminoprotected propyl-7-cyano indoline compound of formula VI can be carried out using methods known
18
in the art. Particularly said reaction is accomplished using hydroxylamine hydrochloride, pyridine and acetic anhydride at a suitable temperature till completion of reaction.
The indoline compounds of formulae III, IV, V, and VI are novel intermediates of present invention and forms an inventive part of present invention. 5
The resulting 5-aminoprotected propyl-7-cyano indoline compound of formula VI can be converted to 5-amino propyl-7-cyano indoline compound of formula VII by cleavage of the amino protecting group using a suitable deprotecting agent. Generally, the deprotecting agent and the reaction conditions for deprotection of amino protecting group is chosen appropriately depending upon the nature of 10 protecting group. The amino-protecting group can be removed using conventional procedures and reagents. For example, a benzyl protecting group can be removed by hydrogenolysis in the presence of a catalyst, such as palladium; a tert-butoxycarbonyl group can be removed by treatment with acid, such as hydrochloric acid, p-toluenesulfonic acid and the like; a tert-butyldimethylsilyl 15 group can be removed by treatment with a source of fluoride ions, such as triethylamine trihydrofluoride; phthalimido group can be deprotected by treatment with hydrazine hydrate.
The racemic intermediate, 5-amino propyl-7-cyano indoline compound of formula VII, can be converted to indoline derivative of formula I by resolution. Resolution 20 is achieved by treating racemic 5-amino propyl-7-cyano indoline compound of formula VII with a resolving agent such as optically active acids, in a suitable solvent.The acids for this purpose can be selected from any suitable optically active acid such as L-(+)tartaric acid, D-(-)-tartaric acid, L-(-)-malic acid, D-(+)-malic acid, N-acetyl-L-glutamic acid, N-acetyl-D-glutamic acid, (+)-camphor 25 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-
19
tartaric acid, (+)-di-p-toluyl d-tartaric acid, L-aspartic acid, R(-)-acetoxy mandelic acid, R(+)-2-(4-hydroxyphenoxy)propionic acid.
The solvent used in reaction can be selected from the group comprising of C1-5 alcohol; C3-8 ketone; C2-5 nitriles; C3-8 ester; cyclic or acyclic ether or mixtures thereof. Thereafter desired resulting optically active salt is isolated and treated 5 with suitable base in suitable solvent to prepare indoline derivative of formula I. The indoline derivative of formula I prepared as per the present invention having chemical and chiral HPLC purity of greater than 99%.
Generally, the reaction at different stages to prepare compounds of formulae II, III, IV, V and VI can be performed at a suitable temperature ranging from -10°C 10 to reflux temperature of solvent used for specific reaction for few minutes to few hours or till completion of reaction.
The order and manner of combining the reactants at any stage of the process are not critical and may be varied. The reactants may be added to the reaction mixture as solids, or may be dissolved individually and combined as solutions. Further, 15 any of the reactants may be dissolved together as sub-groups, and those solutions may be combined in any order. Wherever required, the completion of reaction at the stage of compounds of formula II, III, IV, V, and VI can be monitored by any one of the chromatographic techniques such as thin layer chromatography (TLC), high pressure liquid chromatography (HPLC), ultra-high pressure liquid 20 chromatography (UPLC), and the like.
After completion of reaction, products of formula II, III, IV, V, and VI of present invention can be isolated or used as such in the next step without isolation or optionally recovered from the reaction mixture by suitable techniques known in prior art such as evaporation, filtration or washing etc. Isolation and purification 25 of final compound and intermediates described here in the present invention can be effected, if desired, by any suitable separation or purification procedure such as, for example, filtration, extraction, crystallization, derivatization, slurry wash,
20
salt preparation or combination of these procedures. However, other equivalent procedures such as acid-base treatment could, of course, also be used. Preferably crude intermediates are used directly in the next stage without any purification.
The intermediate described here in the present invention include their salts, hydrates, solvates, racemates, enantiomers, polymorphs etc. 5
The solvents used for the purification of compounds of the present invention may be selected depending upon the nature of compound to be purified. However the solvent can be chosen amongst water; C1-5 alcohol; C3-8 ketone; C5-8 aliphatic or aromatic hydrocarbon; C3-8 ester; cyclic or acyclic ether; C2-5 nitriles; halogenated solvents such as methylene chloride, chloroform, carbon tetrachloride and the 10 like; aprotic solvents such as N,N-dimethyl formamide, dimethylsulfoxide, dimethylacetamide, N-methyl pyrrolidinone, sulpholane or mixtures thereof; of which alcoholic solvents, alkyl nitrile and aromatic hydrocarbon are preferred.
In one another embodiment compound of formula I synthesized above as per the disclosure of present invention is condensed with compound of formula 2-[2-15 (2,2,2-trifluoroethoxy)phenoxy]ethyl methanesulfonate to obtain the desired drug substance silodosin. The condensation reaction takes place as per the literature process or can be prepared as per the disclosure given herein but not in any way limits the present invention and compound of formula I can be converted to silodosin using techniques available in the art. Generally, the compound of 20 formula I, can be condensed with 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl methanesulfonate to form 3-{7-cyano-5-[(2R)-2-({2-(2,2,2-trifluoroethoxy)-phenoxy]ethyl}amino)propyl)-1-indolinyl-propyl benzoate intermediate. The resulting intermediate can optionally be converted to a suitable acid addition salt. Hydrolysis of the resulting intermediate can be carried out using a suitable base in 25 the presence of a suitable solvent to prepare 1-(3-hydroxypropyl)-5-[(2R)-2-({2-[2,2,2-trifluoro-ethoxy)phenoxy]ethylamino)propyl]-1-indolinyl-7-carbonitrile intermediate. The resulting intermediate can optionally be converted to suitable
21
acid addition salts. The corresponding acid addition salt can be hydrolyzed further in the presence of a suitable base and a suitable oxidizing agent, in an organic solvent to prepare silodosin. .
EXAMPLES:
Example 1: Preparation of 3-[5-(2-aminopropyl)-1-indolinyl]propyl benzoate 5
To a solution of 3-{5-[2-nitro-1-propenyl]-1-indolinyl}propyl benzoate (10g) in tetrahydrofuran (150ml) was added Raney-Nickel (25g, wet) at ambient temperature. The reaction mass was then transferred to an autoclave under nitrogen gas atmosphere and agitated for 4 hours under 3-5 kg/cm2 hydrogen pressure. After completion of reaction, reaction mass was filtered through hyflo 10 bed. The solvent was distilled off under reduced pressure at 45- 50°C to produce 8.9g of title compound.
Example 2: Preparation of 3-[5-(2-aminopropyl)-7-cyano-1-indolinyl]propyl benzoate
STEP 1: Preparation of 3-{5-[2-(3-oxo-2H-isoindol-2-oyl)propyl]-1-15 indolinyl}propyl benzoate
To a solution of 3-[5-(2-aminopropyl)-1-indolinyl]propyl benzoate (0.5g) in dimethylformamide (1ml), phthalic anhydride (0.25g) was added. The reaction mixture was then heated to 60-70oC for about two hours. After completion of reaction, reaction mixture was cooled to 20-25°C, diluted with ethyl acetate 20 (10ml) and washed with water (5mlx3). The ethyl acetate solution after drying over anhydrous sodium sulphate was distilled off under reduced pressure at 45- 50°C to obtain 0.65g of title compound .
STEP 2: Preparation of 3-{7-formyl-5-[2-(3-oxo-2H-isoindol-2-oyl)propyl]-1-indolinyl}propyl benzoate 25
To ice cooled dimethylformamide (1.3ml), phosphorus oxychloride (0.29g) was added drop wise over a period of about 20 minutes and the mixture was stirred for about 30 minutes. Thereafter, a solution of 3-{5-[2-(3-oxo-2H-isoindol-2-oyl)propyl]-1-indolinyl}propyl benzoate (0.55g) in dry dimethylformamide
22
(1.0ml) was added drop wise over a period of about 35 minutes and the mixture was stirred for 2 hours at 50°C. Reaction mixture was cooled and water (7ml) was added drop wise and stirred overnight. The solid, thus obtained, was filtered to get 0.52g of the title compound.
STEP 3: Preparation of 3-{7-cyano-5-[2-(3-oxo-2H-isoindol-2-oyl)propyl]-1-5 indolinyl}propyl benzoate
To a solution of 3-{7-formyl-5-[2-(3-oxo-2H-isoindol-2-oyl)propyl]-1-indolinyl}propyl benzoate (0.51g) in dry tetrahydrofuran (1.0ml), hydroxylamine hydrochloride (0.12g) and pyridine (0.4ml) were added and the mixture was stirred for one hour at 50°C. Acetic anhydride (0.3 ml) was added slowly and 10 reaction mixture was further stirred for 30 minutes at same temperature. The mixture was then heated under reflux for 3 hours, water was added and the mixture was extracted with ethyl acetate. Organic layer was washed successively with 1N hydrochloric acid, saturated sodium bicarbonate solution, brine solution, and concentrated under reduced pressure. The resulting product was purified to 15 obtain 0.35g of title compound.
STEP 4: Preparation of 3-[5-(2-aminopropyl)-7-cyano-1-indolinyl] propyl benzoate
To a cooled solution of 3-{7-cyano-5-[2-(3-oxo-2H-isoindol-2-oyl)propyl]-1-indolinyl}propyl benzoate (0.32g) in ethanol (1.2ml), aqueous hydrazine hydrate 20 (0.5ml) was added slowly. Thereafter temperature was raised and reaction mixture was refluxed for 2.0 hours. After completion of reaction, the mass was cooled to 25-30°C, water was added and extracted with ethyl acetate. Organic layer was washed with water and brine solution, and solvent was distilled off under reduced pressure to obtain 0.25g of title compound. 25
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Example 3: Preparation of 3-[5-(2-aminopropyl)-7-cyano-1-indolinyl] propyl benzoate
STEP 1: Preparation of 3-[5-(2-benzylaminopropyl)-1-indolinyl]propyl benzoate
To a solution of 1-(3-benzoyloxypropyl)-5-(2-aminopropyl) indoline (0.6g) in 5 isopropanol (3ml), benzyl bromide (0.4g) and triethylamine (0.2ml) were added and the reaction mass was heated to reflux for 3.0 hours. After completion of reaction, solvent was distilled off and the resulting material was dissolved in ethyl acetate (4ml). The resulting solution was successively washed with sodium bicarbonate, water and brine solution. The solvent was distilled off under reduced 10 pressure to obtain 0.68g of title compound.
STEP 2: Preparation of 3-[5-(2-benzylaminopropyl)-7-formyl-1-indolinyl] propyl benzoate
To ice cooled dry dimethyl formamide (1.3 ml), phosphorus oxychloride (0.29g) was added drop wise over a period of about 20 minutes, and the mixture was 15 stirred for about 30 minutes. Thereafter a solution of 3-[5-(2-benzylaminopropyl)-1-indolinyl]propyl benzoate (0.6g) in dimethyl formamide (1.0 ml) was added drop wise and the reaction mixture was stirred for 2 hours at 50°C. Reaction mass was cooled and water (7ml) was added drop wise. The resulting crystals were filtered and dried to obtain 0.55g of title product. 20
STEP 3: Preparation of 3-[5-(2-benzylaminopropyl)-7-cyano-1-indolinyl] propyl benzoate
To a solution of 3-[5-(2-benzylaminopropyl)-7-formyl-1-indolinyl]propyl benzoate (0.52g) in dry tetrahydrofuran (1ml),; hydroxylamine hydrochloride (0.12g) and pyridine (0.4ml) were added and the mixture was stirred for 1 hour at 25 50°C. Acetic anhydride (0.3ml) was added slowly and stirred for further 30 minutes at same temperature, and thereafter at reflux for 3 hours. Water was added and the product was extracted in ethyl acetate. Organic layer was washed
24
successively with 1N hydrochloric acid,sodium bicarbonate solution and brine solution, and concentrated under reduced pressure. The residue was purified to obtain 0.38g of title compound.
STEP 4: Preparation of 3-[5-(2-aminopropyl)-7-cyano-1-indolinyl] propyl benzoate 5
3-[5-(2-Benzylaminopropyl)-7-cyano-1-indolinyl]propyl benzoate (0.35g) was dissolved in methanol (1ml) and THF (0.5ml) and 10%Pd/C (0.1g ) was added. Reaction mass was agitated for 2.0 hours under 4.0 kg/cm2 pressure. After the reaction was over, the reaction mass was cooled to 25-30°C, catalyst was filtered off through hyflow bed and filtrate was distilled under reduced pressure to obtain 10 0.28g of title compound.
Example 4: Preparation of 3-[5-(2-aminopropyl)-7-cyano-1-indolinyl]propyl benzoate tartarate salt
To a solution of 3-[5-(2-aminopropyl)-7-cyano-1-indolinyl]propyl benzoate (0.46g) in acetone (2 ml), an aqueous solution of L-(+)-tartaric acid (0.06g in 15 0.4ml water) was added drop wise at room temperature. The reaction mixture was stirred at room temperature for 12-15 hours. The precipitated salt was filtered and washed with a mixture of 1:1 acetone and water (0.4 ml). This salt was crystallized using acetone:water (1:1) to obtain pure title compound.
Example 5: Preparation of 3-[5-(R)(2-aminopropyl)-7-cyano-1-indolinyl] 20 propyl benzoate
3-[5-(2-Aminopropyl)-7-cyano-1-indolinyl]propyl benzoate tartarate salt (50mg) was added to a mixture of ethyl acetate (0.5 ml) and an aqueous solution (0.5ml) of potassium carbonate (135mg). The reaction mixture was stirred at 20-30oC for 2 hours. After completion of reaction, layers were separated. The aqueous layer 25 was extracted again with ethyl acetate solution (0.5ml). The combined ethyl acetate layer was washed with an aqueous potassium carbonate solution (0.3ml) and, filtered and the filtrate was concentrated to get the title compound.

We Claim
1. A process for the preparation of indoline derivative of formula I, including
its derivatives or solvates,
Formula I
comprises the steps of;
a) reducing 5 5 -nitro-propenyl indoline compound of formula II
Formula II
with a suitable reducing agent, in a suitable solvent, to form 5-
aminopropyl indoline compound of formula III;
Formula III
b) protecting the amino group of 5-aminopropyl indoline compound of
formula III using a suitable amino protecting reagent to form 5-
10 aminoprotected propyl indoline compound of formula IV,
Formula IV
wherein R1 and R2 represent amino protecting group; wherein R1 or R2
can be independently hydrogen, substituted or unsubstituted alkyl, aryl,
26
aralkyl, allyl, benzyl, substituted or unsubstituted alkoxycarbonyl,
vinyloxycarbonyl, allyloxycarbonyl, benzyloxycarbonyl, phenyloxy
carbonyl, formyl, acetyl, benzoyl and the like; both R1 and R2 collectively
form cyclic imide and the like; provided both R1 and R2 cannot be
5 hydrogen together;
c) formylating 5-aminoprotected propyl indoline compound of formula IV
using a suitable formylating reagent to form 5-aminoprotected propyl-7-
formyl indoline compound of formula V,
Formula V
wherein R1 and R2 represent amino protecting group as defined above;
10 d) converting 5-aminoprotected propyl-7-formyl indoline compound of
formula V using a suitable reagent to form 5-aminoprotected propyl-7-
cyano indoline compound of formula VI
Formula VI
wherein R1 and R2 represent amino protecting group as defined above;
e) deprotecting the amino protecting group from 5-aminoprotected propyl-7-
15 cyano indoline compound of formula VI using a suitable deprotecting
reagent to form indoline derivative of formula VII;
Formula VII
f) resolving the indoline intermediate of formula VII by treating with a
suitable optical active acid to prepare indoline derivative of formula I.
27
2. The process as claimed in claim 1, wherein in step a) a suitable reducing agent is selected from a group comprising of sodium borohydride, sodium cyanoborohydride, sodium triacetoxy borohydride, sodium trimethoxy borohydride, zinc borohydride, Vitride, a hydrogenation catalyst such as palladium on carbon, Raney nickel and the like in combination with 5 hydrogen, platinum, platinum oxide, lithium aluminium hydride, diborane, diisobutyl aluminium hydride, trimethylsilane, phenylsilane, diphenylsilane, diphenylchlorosilane, trichlorosilane, and the like;a suitable solvent is selected from C1-5 alcohol, C5-8 aliphatic or aromatic hydrocarbon, C3-8 ester, cyclic or acyclic ether, ketone, glycol, 10 polyethylene glycol, dimethylformamide, dimethylacetamide, acetonitrile, dimethyl sulfoxide, water or mixture thereof.
3. The process as claimed in claim 1, wherein in step a) a suitable reducing agent is preferably selected from sodium borohydride, palladium on carbon, Raney nickel, lithium aluminium hydride. 15
4. The process as claimed in claim 1, wherein in step b) a suitable amino protecting reagent is selected from methyl chloroformate, ethyl chloroformate, 2,2,2-trichloroethyl chloroformate, 2-trimethylsilyl ethyl chloroformate, 2-phenylethyl chloroformate, 2-chloroethyl chloroformate, 2-adamantly chloroformate, vinyl chloroformate, benzoyl chloroformate, 20 benzyl chloroformate, FMOC-Chloride, 9-(2-sulfo) fluorenyl methyl, 9-(2,7-dibromo) fluorenyl methyl, 17-tetrabenzo[a,c,g,i] fluorenyl methyl, 2-chloro-3-indenylmethyl, Benz-inden-3-ylmethyl, DBD-T mol, Bsmoc, Pyoc-chloride, Boc anhydride, trifluroacetic anhydride, tetra chloro phthalic anhydride, N-2,3-diphenylmaleic anhydride, formic acetic 25 anhydride, acetic anhydride, substituted halo acetic anhydride, acid chloride in amine, phthalic anhydride, substituted phthalic anhydride, N-2,3-diphenylmaleic anhydride, alkylhalide, benzylhalide, allylhalide,
28
triphenylmethylhalide, alkyl or aryl sulfonyl halide, tert-butyldimethysilyl ether and the like; a suitable solvent is selected from halogenated hydrocarbon, C3-8 ketone, C5-8 aliphatic or aromatic hydrocarbon, C3-8 ester, C2-8 ether, C2-5 nitriles, water, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone and the like 5 or mixture thereof.
5. The process as claimed in claim 1, wherein in step b) a suitable amino protecting reagent is preferably selected from ethyl chloroformate, phthalic anhydride, substituted phthalic anhydride, alkylhalide, benzylhalide, triphenylmethylhalide, alkyl or aryl sulfonyl halide. 10
6. The process as claimed in claim 1,wherein in step c) formylating reaction is performed under Vilsmeier-Haack reaction conditions in presence of N,N-dimethylformamide and phosphorous oxy chloride.
7. The process as claimed in claim 1, wherein in step d) a suitable reagent is hydroxylamine hydrochloride, pyridine and acetic anhydride. 15
8. The process as claimed in claim 1,wherein in step f) a suitable optically active acid is selected from 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, (-)-20 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 or the like; a suitable solvent is selected from C1-5 alcohol; C3-8 ketone; C2-5 nitrile; C3-8 ester; cyclic or acyclic ether or mixtures thereof. 25
9. The process as claimed in claim 1,wherein in step f) a suitable optically active acid is preferably L-(+)tartaric acid.
29
10. A process for preparation of silodosin of following formula and
pharmaceutically acceptable salts thereof,
5 which comprises the steps of:
a) preparing indoline derivative of formula I, using process as claimed in
claim 1,
b) converting the indoline derivative of formula I to silodosin.