WO2012131710A2 - Novel process for the synthesis of indoline derivatives - Google Patents

Novel process for the synthesis of indoline derivatives Download PDF

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Publication number
WO2012131710A2
WO2012131710A2 PCT/IN2012/000201 IN2012000201W WO2012131710A2 WO 2012131710 A2 WO2012131710 A2 WO 2012131710A2 IN 2012000201 W IN2012000201 W IN 2012000201W WO 2012131710 A2 WO2012131710 A2 WO 2012131710A2
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Prior art keywords
formula
compound
indolin
acid
propyl
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PCT/IN2012/000201
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French (fr)
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WO2012131710A3 (en
Inventor
Rajesh Jain
Jagadeeshwar R RAO
Siripragada Mahender Rao
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Panacea Biotec Ltd
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Priority claimed from IN888DE2011 external-priority patent/IN2011DE00888A/en
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Publication of WO2012131710A3 publication Critical patent/WO2012131710A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • 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 a-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.
  • 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 the treatment tly, silodosin y a few processes for the manufacture of Silodosin have become known.
  • Literature 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.
  • some of the stages of the preparation of indoline intermediate as per JP 2001-199956 are difficult.
  • 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 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.
  • 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.
  • the 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.
  • 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.
  • 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
  • step (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.
  • 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
  • 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
  • the present invention provides an improved, commercially viable and industrially advantageous process for the preparation of silodosin of Formula XVI
  • Formula XVI its pharmaceutically acceptable derivatives, salts or solvates thereof, comprising the following steps;
  • R is a hydroxyl protecting group
  • step (3) 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
  • silodosin of Formula XVI 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.
  • the present invention provides an improved, commercially viable and industrially advantageous process for the preparation of silodosin of Formula XVI
  • step (3) optionally converting silodosin of Formula XVI of step (3) to its pharmaceutically acceptable derivatives, salts or solvates thereof.
  • 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.
  • 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.
  • 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.
  • suitable reducing agent refers to a reagent, or a mixture of two or more reagentS7-whrch ⁇ facilitates — the- reductiun ⁇ reaction
  • containing reagent refers to organic compounds characterized by the presence of at least one hydroxyl group.
  • 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, t- butoxymethyl, 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, t- butyldiphenylsilyl, triisopropylsilyl, benzoylformate, chloroacetyl, trichloroacetyl, trifluoro
  • 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.
  • N, N- dimethylformamide (DMF) and a chlorinating agent such as POCU are used to generate the Vilsmeier-Haack reagent.
  • salts of basic compounds of the present invention can be prepared by reacting free base form of the compound with a suitable acid, including, but not limited to acetate, trifiuoroacetate, 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, hydrobro
  • 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.
  • the singular forms “a”, “an”, and “the” include plural reference unless the context clearly dictates otherwise.
  • the terms “a” (or “an”), “one or more” and “at least one” can be used interchangeably herein.
  • the terms “comprising”, “including”, “characterized by” and “having” can be used interchangeably.
  • 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.
  • R is a hydroxyl protecting group
  • Formula IA (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.
  • 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 (NH 3 ), concentrated sulfuric acid (H 2 S0 4 ) and the like; combination of two or more solvents from the list and
  • 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 biearbonates such as sodium bicarbonate, potassium bicarbonate and the like: alkali metal ⁇ lkoxide ⁇ uch ⁇ S-polassium ⁇ 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
  • 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.
  • steps (a) to (i) of the present invention may be used with or without purification in their respective next step.
  • 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.
  • steps (a) to (i) of the present invention can be carried out in a single reactor (one pot reaction).
  • the present inV-ention ⁇ pmv ides reminda_process ⁇ or remindthe-preparation--of- compound of Formula I
  • 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%.
  • 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
  • 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
  • step (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.
  • 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 NH 4 CI or HCl or acetic acid, Sn in acidic media like HCl, Zn, Zn in acidic media like HCl or NH 4 CI or acetic acid, NaBHj with catalytic NiCl 2 .6H 2 0 or CoCl 2 .6H 2 0, 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, H 3 P0 2 etc.,
  • 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- >-toluyl L-tartaric acid, (+)-Di-p- toluyl D-tartaric acid.
  • Tartaric acid is the preferred enantiopure acid.
  • 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
  • Formula ⁇ (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.
  • the present invention provides an improved, commercially viable and industrially advantageous process for the preparation of silodosin of Formula XVI
  • R is a hydroxyl protecting group
  • step (3) 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
  • step (3) optionally converting silodosin of Formula XVI of step (3) to its pharmaceutical acceptable derivatives, salts or solvates.
  • the present invention discloses an improved, commercially viable and industrially advantageous process for the preparation of silodosin of Formula
  • step (3) 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 (NH 3 ), concentrated sulfuric acid (H 2 S0 4 ) and the like.
  • polar protic solvents such as
  • 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).
  • 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.
  • 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.
  • Example 6 Preparation of 3-(5-(2-Aminopropyl)-7-cyanoindolin-l-yl)propyl benzoate of Formula ⁇ and Tartarate salt of (3-(5-((R)-2-Aminopropyl)-7- cyanoindolin-l-yl) propyl benzoate) of Formula I
  • 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%).
  • 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 -abo-ve-95-%).
  • 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 salt was dissolved in water (150 ml) added ethyl acetate (300 ml), basified with K 2 C03 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 %)

Abstract

The present invention provides an improved process for the synthesis of indoline intermidiate and its pharmaceutically acceptable derivatives, salts or solvates thereof, useful in the synthesis of α-1 adrenoceptor blockers such as silodosin.

Description

NOVEL PROCESS FOR THE SYNTHESIS OF INDOLINE DERIVATIVES
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 a-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 the treatment tly, silodosin
Figure imgf000002_0001
y a few processes for the manufacture of Silodosin have become known. Literature 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.
r
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 l-(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 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 IA, Formula IB, their pharmaceutically acceptable derivatives, salts or solvates thereof.
Figure imgf000005_0001
Formula IA Formula IB
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.
Figure imgf000005_0002
Formula IA Formula IB 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
Figure imgf000005_0003
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 com ound of Formula XII,
Figure imgf000006_0001
Formula XI 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
Figure imgf000006_0002
Formula 1
which comprises the steps of:
(a) reacting benzoic acid of Formula II
B¾Oti
Formula II
with l-bromo-3-chloropropane of Formula III
Figure imgf000006_0003
Formula 01
to obtain 3- chloropropylbenzoate of Formula IV; 'CI
Formula IV
(b) reacting the compound 3-chloro-propylbenzoate of Formula IV with an indoline of Formula V
Figure imgf000007_0001
Formula V
to obtain 3-(Indolin-l-yl) propyl benzoate of Formula VI;
Figure imgf000007_0002
Formula VI
(c) subjecting the compound of Formula VI to a formylation step, specifically a Vilsmeier-Haack reaction in the presence of Ν,Ν-dimethylformamide and phosphorus oxychloride to produce a formyl compound of Formula VII;
Figure imgf000007_0003
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;
Figure imgf000007_0004
Formula VIII (e) reducing 3-(5-(2-nitrovinyl)indolin-l-yl)propyl benzoate of Formula VIII to 3- (5-(2-nitropropyl) indolin-l-yl) propyl benzoate of Formula IX;
Figure imgf000008_0001
Formula IX
(f) subjecting 3-(5-(2-nitropropyl) indolin-l-yl) propyl benzoate of Formula IX to a formylation step, specifically a Vilsmeier-Haack reaction in the presence of Ν,Ν-dimethylformamide and phosphorus oxychloride to obtain 3-(7-formyl-5- (2-nitropropyl)indolin-l-yl)propyl benzoate of Formula X;
Figure imgf000008_0002
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;
Figure imgf000008_0003
Formula XI
(h) reducing the nitro group of compound of Formula XI of to obtain compound of Formula XII; and
Figure imgf000009_0001
Formula XII
(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
Figure imgf000009_0002
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 yet another aspect, the present invention provides an improved, commercially viable and industrially advantageous process for the preparation of silodosin of Formula XVI
Figure imgf000009_0003
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
Figure imgf000010_0001
Formula XIII
to obtain com ound of Formula XIVA
Figure imgf000010_0002
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;
Figure imgf000010_0003
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.
The present invention even further discloses an improved, commercially viable and industrially advantageous process for the preparation of silodosin of Formula XVI
Figure imgf000011_0001
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]eth l methane sulfonate of Formula XIII
Figure imgf000011_0002
Formula XH1
to obtain compound of Formula XV;
Figure imgf000011_0003
Formula XV
(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
Figure imgf000012_0001
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
Figure imgf000012_0002
Formula X (II
to obtain com ound of Formula XIV;
Figure imgf000012_0003
(2) removing the hydroxyl protecting group of compound of Formula XIV to yield compound of Formula XV;
Figure imgf000013_0001
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 DESCRIPTION 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.
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 reagentS7-whrch~facilitates— the- reductiun~reaction
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, t- butoxymethyl, 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, t- butyldiphenylsilyl, 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, N- dimethylformamide (DMF) and a chlorinating agent such as POCU 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 prepared by reacting free base form of the compound with a suitable acid, including, but not limited to acetate, trifiuoroacetate, 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.
Figure imgf000015_0001
Formula IA Formula IB
wherein R is a hydroxyl protecting group; which process comprises the steps of:
(a) reacting a hydroxyl containing reagent of Formula IIA
-OII
Formula IIA
wherein R is hydroxyl protectin group, with compound of Formula IIIA
Figure imgf000015_0002
Formula IIIA
wherein X is Br, CI, OH and Y is Br, CI; to obtain 3-substituted propyl ether or ester derivative of Formula IVA
Figure imgf000015_0003
Formula IVA
wherein R is as define above;
(b) reacting the compound of Formula IVA with an indoline compound of Formula
V
Figure imgf000016_0001
Formula V
to obtain 3-(Indolin-l-yl) propyl derivative of Formula VI A;
Figure imgf000016_0002
Formula VIA
(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;
Figure imgf000016_0003
Formula VIIA
(d) reacting compound of Formula VIIA with 2- nitroethane to obtain 3-(5-(2- nitrovinyl)indolin-l-yl)pro l derivative of Formula VIIIA;
Figure imgf000016_0004
Formula VIIIA
(e) reducing 3-(5-(2-nitrovinyl)indolin-l-yl)propyl derivative of Formula VIIIA to 3-(5-(2-nitropropyl) indolin-l-yl) propyl derivative of Formula IXA;
Figure imgf000017_0001
Formula IX A
(f) subjecting 3-(5-(2-nitropropyl) indolin-l-yl) propyl derivative of Formula IXA to a further formylation step, specifically a Vilsmeier-Haack reaction in the presence of Ν,Ν-dimethylformamide and phosphorus oxychloride to obtain 3-
(7-formyl-5-(2-nitropropyl)indolin-l-yl)propyl derivative of Formula XA;
Figure imgf000017_0002
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;
Figure imgf000017_0003
Formula XIA
(h) reducing the nitro group of compound of Formula XIA to obtain compound of Formula IA; and
Figure imgf000017_0004
Formula IA (i) converting the compound of Formula IA, either by isolating it or without isolating, to tartarate salt of Formula IB.
Figure imgf000018_0001
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 (H2S04) and the like; combination of two or more solvents from the list and the like. 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 biearbonates such as sodium bicarbonate, potassium bicarbonate and the like: alkali metal^lkoxide^uch^S-polassium^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, triisooctyl 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.
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 inV-ention^pmvides„a_process^or„the-preparation--of- compound of Formula I
Figure imgf000020_0001
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
Figure imgf000020_0002
Formula IC Formula ID
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
Figure imgf000021_0001
Formula !.
comprising:
(a) reducing the nitro group of compound of Formula XI with a suitable reducing agent in a suitable solvent to obtain amine com ound of Formula XII; and
Figure imgf000021_0002
Formula XI 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.
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 HCl or acetic acid, Sn in acidic media like HCl, Zn, Zn in acidic media like HCl or NH4CI or acetic acid, NaBHj with catalytic NiCl2.6H20 or CoCl2.6H20, 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.,
Figure imgf000021_0003
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- >-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. 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
Figure imgf000022_0001
Formula I
which comprises the steps of:
(a) reacting benzoic acid of Formula II
BzOH
Formula II
with l-bromo-3-chloropropane of Formula III
Figure imgf000022_0002
Formula III
to obtain 3- chloropropylbenzoate of Formula IV;
Figure imgf000022_0003
Formula IV (b) reacting the compound 3- chloro- propylbenzoate of Formula IV with an indoline of Formula V
Figure imgf000023_0001
Formula V
to obtain 3-(Indolin-l-yl) propyl benzoate of Formula VI;
Figure imgf000023_0002
Formula VI
(c) subjecting the compound of Formula VI to a formylation step, specifically a Vilsmeier-Haack reaction in the presence of Ν,Ν-dimethylformamide and phosphorus oxychloride to produce a formyl compound of Formula VII;
Figure imgf000023_0003
Formula V(I
(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;
Figure imgf000023_0004
Formula VIII
(e)-red cing^(5^^ifr^
(5-(2-nitropropyl) indolin- 1 -yl) propyl benzoate of Formula IX;
Figure imgf000024_0001
Formula IX
(f) subjecting 3-(5-(2-nitropropyl) indolin-l-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 ropyl benzoate of Formula X;
Figure imgf000024_0002
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;
Figure imgf000024_0003
Formula XI
(h) reducing the nitro group of compound of Formula XI of to obtain compound of Formula XII; and
Figure imgf000024_0004
Formula ΧΪΙ (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 yet another aspect, the present invention provides an improved, commercially viable and industrially advantageous process for the preparation of silodosin of Formula XVI
Figure imgf000025_0001
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
Figure imgf000025_0002
Formula XI»
to obtain com ound of Formula XIVA
Figure imgf000025_0003
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
Figure imgf000026_0001
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.
The present invention even further discloses an improved, commercially viable and industrially advantageous process for the preparation of silodosin of Formula XVI
Figure imgf000026_0002
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- trifiuoroethoxy)phenoxy]ethyl methane sulfonate of Formula XIII
Figure imgf000026_0003
Formula ΧΙΙΪ
to obtain compound of Formula XV; OCH2CF3
Formula XV
(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
Figure imgf000027_0001
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
Figure imgf000027_0002
Formula XIII
to obtain compound of Formula XIV; OCH2CF3
Formula XIV
(2) removing the hydroxyl protecting group of compound of Formula XIV to yield compound of Formula XV;
Figure imgf000028_0001
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 (H2S04) and the like.
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. 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-ChIoropropylbenzoate 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% 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:^ eparation-oL3^(5^Eo™^
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-l-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-l-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-yI)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-l- yl)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 ΧΠ and Tartarate salt of (3-(5-((R)-2-Aminopropyl)-7- cyanoindolin-l-yl) propyl benzoate) of Formula I
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- -Aminoprop l)^^
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-l-yl) propyl benzoate) of Formula I. (HPLC purity >99% and chiral purity 93-97%).
Example 7: Preparation of 3-(5-(2-aminopropyl)-7-cyanoindolin-l-yl)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 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 -abo-ve-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 NH4C1 (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 (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-l-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-l-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-l-yl) -propyl benzoate of Formula XIV (HPLC purity: 99.5%).
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-l-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-lH- indole-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.
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.

Claims

1. A process for the preparation of indoline derivatives of Formula I A, Formula IB, their pharmaceutically acceptable derivatives, salts or solvates thereof.
Figure imgf000036_0001
Formula IA Formula IB
wherein R is a hydroxyl protecting group;
which process comprises the steps of:
(a) reacting a hydroxyl containing reagent of Formula IIA
R-Oil
Formula H A
wherein R is a hydroxyl protecting group, with compound of Formula IIIA
Ύ
Formula IHA
wherein X is Br, CI, OH and Y is Br, CI; to obtain 3-substituted propyl ether or ester derivative of Formula IVA
Formula IVA
wherein R is as define above;
(b) reacting the compound of Formula IVA with an indoline compound of Formula V
Figure imgf000036_0002
Formula V
to obtain 3-(indolin-l-yl) propyl derivative of Formula VI A;
Figure imgf000037_0001
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;
Figure imgf000037_0002
Formula VIIA
(d) reacting compound of Formula VIIA with 2-nitroethane to obtain 3-(5-(2- nitrovinyl)indolin- 1 -yl)pro l derivative of Formula VIIIA
Figure imgf000037_0003
Formula VIII A
(e) reducing 3-(5-(2-nitrovinyl)indolin-l-yl)propyl derivative of Formula VIIIA to 3-(5-(2-nitropropyl) indolin-l- l) propyl derivative of Formula IXA
Figure imgf000037_0004
Formula IXA
(f) subjecting 3-(5-(2-nitropropyl) indolin-l-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
Figure imgf000038_0001
Formula X A
(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
Figure imgf000038_0002
Formula XIA
(h) reducing the nitro group of compound of Formula XIA to obtain compound of Formula IA,
Figure imgf000038_0003
i) converting the compound of Formula IA, either by isolating it or without isolating, to tartarate salt of Formula IB
Figure imgf000038_0004
Formula IB
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, ch'loroacetyl, 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 (N¾), concentrated sulfuric acid (H2S04) 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 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
Figure imgf000040_0001
Formula IC Formula ID
by hydrolyzing compound of Formula IA or Formula IB
Figure imgf000040_0002
Formula 1 A 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
Figure imgf000040_0003
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,
Figure imgf000041_0001
Formula XI 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, borane- tetrahydrofuran complex and the like in combination with hydrogen and the like.
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-/>-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
Figure imgf000042_0001
Formula I
which comprises the steps of:
(a) reacting benzoic acid of Formula II
Formula Π
with l-bromo-3-chloropropane of Formula III
Formula til
to obtain 3- chloropropylbenzoate of Formula IV
Formula IV reacting the compound 3-chloro-propylbenzoate of Formula IV with an indoline of Formula V
Figure imgf000042_0002
Formula V
to obtain 3-(indolin-l-yl) propyl benzoate of Formula VI
Figure imgf000043_0001
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;
Figure imgf000043_0002
Formula V(l
(d) reacting compound of Formula VII with 2- nitroethane to obtain a compound 3-(5-(2-nitrovinyl)indolin- 1 ^yl)propyl benzoate of Formula VIII
Figure imgf000043_0003
Formula VIII
(e) reducing 3-(5-(2-nitrovinyl)indolin-l-yl)propyl benzoate of Formula VIII to 3-
(5-(2-nitropropyl) indolin-l-yl) propyl benzoate of Formula IX
Figure imgf000043_0004
Formula IX
(f) subjecting 3-(5-(2-nitropropyl) indolin-l-yl) propyl benzoate of Formula IX to a formylation step, specifically a Vilsmeier-Haack reaction in the presence of Ν,Ν-dimethylformamide and phosphorus oxychloride to obtain 3-(7-formyl-5- (2-nitropropyl)indolin-l-yl)propyl benzoate of Formula X:
Figure imgf000044_0001
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
Figure imgf000044_0002
Formula XI
(h) reducing the nitro group of compound of Formula XI of to obtain compound of Formula XII,
Figure imgf000044_0003
Formula ΧΠ
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.
Figure imgf000045_0001
Formula 1
13. A process for the preparation of silodosin of Formula XVI
Figure imgf000045_0002
Formula XVI
its pharmaceutically acceptable derivatives, salts or solvates thereof, comprising the following steps;
(1) reacting compound of Formula IB
Figure imgf000045_0003
Formula IB
with 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl methane sulfonate of Formula XIII
Figure imgf000045_0004
Formula XUl
to obtain compound of Formula XIVA OCH2CF3
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
Figure imgf000046_0001
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
Figure imgf000046_0002
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]eth l methane sulfonate of Formula XIII
Figure imgf000047_0001
Formula XIII
to obtain compound of Formula XV
Figure imgf000047_0002
Formula XV
(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
Figure imgf000047_0003
Formula XVI
its pharmaceutically acceptable derivatives, salts or solvates thereof, comprising the following steps; *
(1) reacting compound of Formula I
Figure imgf000048_0001
Formula Ϊ
with 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl methane sulfonate of Formula
XIII
Figure imgf000048_0002
Formula XIII
to obtain compound of Formula XIV
Figure imgf000048_0003
(2) removing the hydroxyl protecting group of compound of Formula XIV to yield compound of Formula XV
Figure imgf000048_0004
(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
Figure imgf000049_0001
Formula I
for the preparation of silodosin and its pharmaceutically acceptable salts.
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