WO2012014186A1 - Process for the preparation of silodosin and its novel intermediates - Google Patents

Process for the preparation of silodosin and its novel intermediates Download PDF

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Publication number
WO2012014186A1
WO2012014186A1 PCT/IB2011/053421 IB2011053421W WO2012014186A1 WO 2012014186 A1 WO2012014186 A1 WO 2012014186A1 IB 2011053421 W IB2011053421 W IB 2011053421W WO 2012014186 A1 WO2012014186 A1 WO 2012014186A1
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Prior art keywords
formula
compound
salt
process according
hydrogen
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PCT/IB2011/053421
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French (fr)
Inventor
Ram Chander Aryan
Ramnik Sharma
Pudi Giri Naidu
Anamika Mishra
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Ranbaxy Laboratories Limited
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Publication of WO2012014186A1 publication Critical patent/WO2012014186A1/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

Definitions

  • the present invention relates to novel intermediates of silodosin and a process for their preparation.
  • the present invention also relates to a process for the preparation of silodosin using the novel intermediates.
  • Silodosin of Formula I a selective alpha- 1 adrenergic receptor antagonist, chemically designated as l-(3-Hydroxypropyl)-5-[(2i?)-2-( ⁇ 2-[2-(2,2,2- trifluoroethoxy)phenoxy]ethyl ⁇ amino)propyl]-2,3-dihydro-lH-indole-7-carboxamide, marketed under the brand name Rapaflo®, is indicated for the treatment of the signs and symptoms of benign prostatic hyperplasia (BPH).
  • BPH benign prostatic hyperplasia
  • U.S. Patent No. 5,387,603 provides processes for the preparation of silodosin and its intermediates which involve deprotecting l-(3-hydroxypropyl)-5-[2-[N-tert- butoxycarbonyl-2-(2,2,2-trifluoroethoxyphenoxy)ethylamino]propyl]indoline-7- carboxamide with trifluoroaceticacid in methylenechloride.
  • U.S. Publication No. 2007/0197627 provides a process for the preparation of silodosin which involves dissolving 3- ⁇ 7-cyano-5-[(2R)-2-( ⁇ 2-[2-(2,2,2- trifluoroethoxy)phenoxy] ethyl ⁇ amino)propyl ] -2,3 -dihydro- 1 H-indol- 1 -yl ⁇ propyl benzoate with oxalic acid and isopropanol under heating.
  • Japanese Patent Registration No. JP 3331048; Japanese Publication Nos. JP 2001199956; JP 2002265444; JP 2006188470; Chinese Publication No. 101412690; U.S. Publication No. 2006/0142374; and PCT Publication No. WO 2011/030356 provide various processes for the preparation of silodosin, its salt, polymorphs or its intermediates.
  • the present invention is directed to a method for the preparation of silodosin or a pharmaceutically acceptable salt or solvate thereof using novel intermediates with the objective of developing an efficient, economical and commercially viable process.
  • the present invention provides for a compound of Formula 1 or a salt thereof;
  • R is a benzyl group.
  • the present invention provides for a compound of Formula 2 or a salt thereof;
  • R can be selected from hydrogen or a carboxyl protecting group.
  • the present invention provides for a compound of Formula 3 or a salt thereof;
  • R can be selected from hydrogen or a carboxyl protecting group.
  • the present invention provides for a compound of Formula 4 or a salt thereof;
  • R can be selected from hydrogen or a carboxyl protecting group.
  • the present invention provides for a compound of Formula 5 or a salt thereof;
  • R can be selected from hydrogen or a carboxyl protecting group.
  • the present invention provides for a compound of Formula 6 or a salt thereof;
  • R can be selected from hydrogen or a carboxyl protecting group.
  • the present invention provides for a a compound of Formula 7 or a salt thereof;
  • R can be selected from hydrogen or a carboxyl protecting group.
  • the present invention provides for a compound of Formula 8 or a salt thereof;
  • R can be independently selected from hydrogen or a carboxyl protecting group.
  • the present invention provides for a compound of Formula 9 or a salt thereof;
  • R can be independently selected from hydrogen or a carboxyl protecting group.
  • the present invention provides for a compound of Formula 10 or a salt thereof;
  • R can be independently selected from hydrogen or a carboxyl protecting group.
  • the present invention provides for a compound of Formula 11 or a salt thereof;
  • R can be independently selected from hydrogen or a carboxyl protecting group.
  • the present invention provides for a compound of Formula 12 or a salt thereof;
  • R can be independently selected from hydrogen or a carboxyl protecting group.
  • the present invention provides for a process for the preparation of compound of Formula 1 or a salt thereof;
  • R can be selected from hydrogen or a carboxyl protecting group, the process includes: treating a compound of Formula la or a salt thereof;
  • R can be selected from hydrogen or a carboxyl protecting group, with 2,3- dihydro-lH-indole to obtain compound of Formula 1, or a salt thereof.
  • the present invention provides for a process for the preparation of compound of Formula 2 or a salt thereof;
  • R can be selected from hydrogen or a carboxyl protecting group
  • the process includes: treating a compound of Formula 1
  • R can be selected from hydrogen or a carboxyl protecting group, with a formylating agent to obtain compound of Formula 2 or a salt thereof.
  • the present invention provides for a process for preparation of compound of Formula 3 or a salt thereof;
  • R can be selected from hydrogen or a carboxyl protecting group, the process includes: treating a compound of Formula 2 or a salt thereof;
  • R can be selected from hydrogen or a carboxyl protecting group, with nitroethane to obtain compound of Formula 3 or a salt thereof.
  • the present invention provides for a process for the preparation of compound of Formula 4 or a salt thereof;
  • R can be selected from hydrogen or a carboxyl protecting group, the process includes: treating a compound of Formula 3 or a salt thereof;
  • R can be selected from hydrogen or a carboxyl protecting group, with a reducing agent to obtain compound of Formula 4 or a salt thereof.
  • the present invention provides for a process for the preparation of compound of Formula 5 or a salt thereof;
  • R can be selected from hydrogen or a carboxyl protecting group, the process includes: treating a compound of Formula 4 or a salt thereof;
  • R can be selected from hydrogen or a carboxyl protecting group, with a formylating agent to obtain compound of Formula 5 or a salt thereof.
  • the present invention provides for a process for preparation of compound of Formula 6 or a salt thereof;
  • R can be selected from hydrogen or a carboxyl protecting group, the process includes: treating a compound of Formula 5 or a salt thereof;
  • R can be selected from hydrogen or a carboxyl protecting group, with hydroxylamine or its salt to obtain compound of Formula 6 or a salt thereof.
  • the present invention provides for a process for preparation of compound of Formula 7 or a salt thereof;
  • R can be selected from hydrogen or a carboxyl protecting group, the process includes: treating a compound of Formula 6 or a salt thereof;
  • R can be selected from hydrogen or a carboxyl protecting group, with hydrogen peroxide to obtain compound of Formula 7 or a salt thereof.
  • the present invention provides for a process for the preparation of compound of Formula 8 or a salt thereof;
  • R can be independently selected from hydrogen or a carboxyl protecting group, the process includes: hydrolyzing a compound of Formula 6 or a salt thereof;
  • R can be the same as defined above.
  • the present invention provides for a process for the preparation of compound of Formula 9 or a salt thereof;
  • R can be independently selected from hydrogen or a carboxyl protecting group, the process includes: oxidation of a compound of Formula 8 or a salt thereof;
  • R can be the same as defined above.
  • the present invention provides for a process for the preparation of compound of Formula 10 or a salt thereof;
  • R can be independently selected from hydrogen or a carboxyl protecting group, the process includes: treating a compound of Formula 9 or a salt thereof;
  • R can be the same as defined above with R-(+)-a-methylbenzylamine.
  • the present invention provides for a process for the preparation of compound of Formula 11 or a salt thereof;
  • R can be independently selected from hydrogen or a carboxyl protecting group
  • the process includes: hydrogenolysis of compound of Formula 10 or a salt thereof
  • R can be the same as defined above.
  • the present invention provides for a process for the preparation of compound of Formula 12 or a salt thereof;
  • R can be independently selected from hydrogen or a carboxyl protecting group, the process includes: treating a compound of Formula 11 or its salt thereof;
  • R can be the same as defined above, with a compound of Formula 13.
  • the present invention provides for a process for the preparation of silodosin or a salt thereof of Formula I;
  • the process includes: treating a compound of Formula 12 or a salt thereof;
  • R can be independently selected from hydrogen or a carboxyl protecting group with a reducing agent.
  • the present invention provides for a process for the preparation of silodosin or a salt thereof;
  • the process includes:
  • R can be independently selected from hydrogen or a carboxyl protecting group
  • R can be the same as defined above; c) converting the compound of Formula 9 or a salt thereof to a compound of Formula 10 or a salt thereof;
  • R can be the same as defined above; converting the compound of Formula 10 or a salt thereof to a compound of Formula 11 or a salt thereof;
  • R can be the same as defined above, e) treating the compound of Formula 11 or its salt thereof with a compound of Formula 13
  • R can be the same as defined above; and f) converting the compound of Formula 12 or its salt thereof to silodosin or a salt thereof.
  • carboxyl protecting group refers to a moiety that can be selectively attached to and removed from a carboxyl group to prevent it from participating in undesired chemical reactions, without unacceptably adverse affects on desired reactions.
  • carboxyl protecting groups include esters, such as methyl, ethyl, t- butyl, (un)substituted benzyl, and silyl esters, /7-methoxybenzyl, benzoylmethyl, p- nitrobenzyl, 4-pyridylmethyl, 2,2,2-trichloroethyl, 2,2,2-tribromoethyl, t-butyl, t-amyl, allyl, diphenylmethyl, triphenylmethyl, adamantyl, 2-benzyloxyphenyl, 4- methylthiophenyl, tetrahydrofur-2-yl, tetrahydropyran-2-yl, pentachloropheny
  • the present invention provides for a compound of Formula 1 or a salt thereof;
  • R is a benzyl group.
  • the present invention also provides for a compound of Formula 2 or a salt thereof;
  • R can be selected from hydrogen or a carboxyl protecting group.
  • the present invention provides for a compound of Formula 3 or a salt thereof;
  • R can be selected from hydrogen or a carboxyl protecting group.
  • the present invention provides for a compound of Formula 4 or a salt thereof;
  • R can be selected from hydrogen or a carboxyl protecting group.
  • the present invention provides for a compound of Formula 5 or a salt thereof;
  • R can be selected from hydrogen or a carboxyl protecting group.
  • the present invention also provides for a compound of Formula 6 or a salt thereof;
  • R can be selected from hydrogen or a carboxyl protecting group.
  • the present invention provides for a compound of Formula 7 or a salt thereof;
  • R can be selected from hydrogen or a carboxyl protecting group.
  • the present invention provides for a compound of Formula 8 or a salt thereof;
  • R can be independently selected from hydrogen or a carboxyl protecting group.
  • the present invention provides for a compound of Formula 9 or a salt thereof;
  • R can be independently selected from hydrogen or a carboxyl protecting group.
  • the present invention provides for a compound of Formula 10 or a salt thereof;
  • R can be independently selected from hydrogen or a carboxyl protecting group.
  • the present invention also provides for a compound of Formula 1 1 or a salt thereof;
  • R can be independently selected from hydrogen or a carboxyl protecting group.
  • the present invention provides for a compound of Formula 12 or a salt thereof;
  • R can be independently selected from hydrogen or a carboxyl protecting group.
  • the present invention also provides for a process for the preparation of compound of Formula 1 or a salt thereof;
  • R can be selected from hydrogen or a carboxyl protecting group, the process includes: treating a compound of Formula la or a salt thereof;
  • R can be selected from hydrogen or a carboxyl protecting group, with 2,3- dihydro-lH-indole to obtain compound of Formula 1 or a salt thereof.
  • Treating a compound of Formula la with 2,3-dihydro-lH-indole can be performed preferably in the presence of one or more of organic or inorganic bases selected from the group of alkali metal and alkaline earth metal carbonates or bicarbonates or hydroxides, for example, potassium bicarbonate, sodium bicarbonate, potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, calcium hydroxide, and the like; primary, secondary, and tertiary amines, such as pyridine, piperidine, triethylamine, diisopropylethylamine, N-methylmorpholine, and the like;
  • organic or inorganic bases selected from the group of alkali metal and alkaline earth metal carbonates or bicarbonates or hydroxides, for example, potassium bicarbonate, sodium bicarbonate, potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, calcium hydroxide, and the
  • Treating a compound of Formula la with 2,3-dihydro-lH-indole can be performed preferably in the presence of one or more solvents.
  • solvent includes any solvent or solvent mixture, including, for example, water, esters, alkanols, halogenated hydrocarbons, ketones, ethers, polar aprotic solvents, or mixtures thereof.
  • the esters may include one or more of ethyl acetate, ⁇ -propyl acetate, isopropyl acetate, and n-butyl acetate.
  • alkanols include those primary, secondary and tertiary alcohols having from one to six carbon atoms.
  • Suitable alkanol solvents include methanol, ethanol, «-propanol, isopropanol and butanol.
  • Examples of halogenated hydrocarbons include dichloromethane, chloroform, and 1 ,2-dichloroethane.
  • ketones include acetone, methyl ethyl ketone, and the like.
  • ethers include diethyl ether, tetrahydrofuran, and the like.
  • a suitable polar aprotic solvent includes one or more of N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulphoxide, acetonitrile and N-methylpyrrolidone.
  • Treating a compound of Formula la with 2,3-dihydro-lH-indole can be performed preferably at a temperature of from 20°C to the reflux temperature for a time period sufficient to complete the reaction, preferably for about 30 minutes to 20 hours.
  • the compound of Formula 1 can be isolated by a common isolation technique, such as cooling, extraction, one or more of washing, crystallization, precipitation, filtration, filtration under vacuum, decantation and centrifugation, or a combination thereof.
  • the isolated compound of Formula 1 may be further purified by salt formation, crystallization or chromatographic methods, or a combination thereof.
  • the compound of Formula 1 is a suitable intermediate for the preparation of silodosin.
  • the present invention also provides for a process for the preparation of compound of Formula 2 or a salt thereof;
  • Formula 2 wherein R can be selected from hydrogen or a carboxyl protecting group, the process includes: treating a compound of Formula 1 or a salt thereof;
  • R can be selected from hydrogen or a carboxyl protecting group, with a formylating agent to obtain compound of Formula 2 or a salt thereof.
  • the formylating agent can be selected from the group of N,N-dimethylformamide, triformamide, tri(diformylamino)methane, tris(dichloromethyl)amine or ⁇ , ⁇ , ⁇ , ⁇ - tetraformylhydrazine or a mixture thereof in the presence of a Lewis acid, for example, phosphorous oxychloride, aluminum trichloride or boron trichloride.
  • a Lewis acid for example, phosphorous oxychloride, aluminum trichloride or boron trichloride.
  • the preferred formylating agent may be a mixture of N,N-dimethylformamide and phosphorous oxychloride.
  • the formylating agent can be preferably taken in an amount of 0.5 to 3 times the quantity of compound of Formula 1.
  • Treating a compound of Formula 1 with the formylating agent can be preferably performed in one or more solvents.
  • solvent includes any solvent or solvent mixture, including, for example, water, esters, alkanols, halogenated hydrocarbons, ketones, ethers, polar aprotic solvents, or mixtures thereof.
  • the esters may include one or more of ethyl acetate, ⁇ -propyl acetate, isopropyl acetate, and rc-butyl acetate.
  • alkanols include those primary, secondary and tertiary alcohols having from one to six carbon atoms.
  • Suitable alkanol solvents include methanol, ethanol, rc-propanol, isopropanol and butanol.
  • Examples of halogenated hydrocarbons include dichloromethane, chloroform, and 1,2-dichloroethane.
  • ketones include acetone, methyl ethyl ketone, and the like.
  • ethers include diethyl ether, tetrahydrofuran, and the like.
  • a suitable polar aprotic solvent includes one or more of N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulphoxide, acetonitrile and N-methylpyrrolidone.
  • Treating a compound of Formula 1 with formylating agent can be performed preferably at a temperature of from 0°C to 50°C for a time period sufficient to complete the reaction, preferably for about 10 minutes to 12 hours.
  • the compound of Formula 2 can be isolated by a common isolation technique such as cooling, extraction, one or more of washing, crystallization, precipitation, filtration, filtration under vacuum, decantation and centrifugation, or a combination thereof.
  • the isolated compound of Formula 2 may be further purified by salt formation, crystallization or chromatographic methods, or a combination thereof.
  • the compound of Formula 2 is a suitable intermediate for the preparation of silodosin.
  • the present invention also provides for a process for the preparation of compound of Formula 3 or a salt thereof;
  • R can be selected from hydrogen or a carboxyl protecting group, the process includes: treating a compound of Formula 2 or a salt thereof;
  • R can be selected from hydrogen or a carboxyl protecting group, with nitroethane to obtain compound of Formula 3 or a salt thereof.
  • Treating a compound of Formula 2 with nitroethane can be performed preferably in the presence of base under nitrogen atmosphere and optionally in the presence of solvent.
  • Preferable base may include one or more of organic or inorganic bases selected from the group of alkali metal and alkaline earth metal carbonates or bicarbonates or hydroxides, for example, potassium bicarbonate, sodium bicarbonate, potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, calcium hydroxide, and the like; primary, secondary, and tertiary amines such as pyridine, piperidine, triethylamine, diisopropylethylamine, N- methylmorpholine, and the like; ammonia and ammonium salts.
  • organic or inorganic bases selected from the group of alkali metal and alkaline earth metal carbonates or bicarbonates or hydroxides, for example, potassium bicarbonate, sodium bicarbonate, potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, calcium hydroxide, and the like; primary, secondary, and tertiary amines such as
  • solvent includes any solvent or solvent mixture, including, for example, water, esters, alkanols, halogenated hydrocarbons, ketones, ethers, polar aprotic solvents, or mixtures thereof.
  • the esters may include one or more of ethyl acetate, ⁇ -propyl acetate, isopropyl acetate, and n-butyl acetate.
  • alkanols include those primary, secondary and tertiary alcohols having from one to six carbon atoms.
  • Suitable alkanol solvents include methanol, ethanol, H-propanol, isopropanol and butanol.
  • Examples of halogenated hydrocarbons include dichloromethane, chloroform, and 1 ,2-dichloroethane.
  • ketones include acetone, methyl ethyl ketone, and the like.
  • ethers include diethyl ether, tetrahydrofuran, and the like.
  • a suitable polar aprotic solvent includes one or more of N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulphoxide, acetonitrile and N-methylpyrrolidone.
  • Treating a compound of Formula 2 with nitroethane can be performed preferably at a temperature of from 10°C to 90°C for a time period sufficient to complete the reaction, preferably for about 10 minutes to 12 hours.
  • the compound of Formula 3 can be isolated by a common isolation technique such as cooling, extraction, one or more of washing, crystallization, precipitation, filtration, filtration under vacuum, decantation and centrifugation or a combination thereof.
  • the compound of Formula 3 can be isolated preferably by distilling out the unreacted nitroethane under vacuum at 50°C.
  • the mixture may be further treated with one or more of the aforementioned solvents followed by washing with aqueous sodium bicarbonate solution, brine and evaporation of solvent optionally under vacuum.
  • the isolated compound of Formula 3 may be further purified by salt formation, crystallization or chromatographic methods, or a combination thereof.
  • the compound of Formula 3 is a suitable intermediate for the preparation of silodosin.
  • the present invention also provides for a process for the preparation of compound of Formula 4 or a salt thereof;
  • R can be selected from hydrogen or a carboxyl protecting group, the process includes: treating a compound of Formula 3 or a salt thereof;
  • R can be selected from hydrogen or a carboxyl protecting group, with a reducing agent to obtain compound of Formula 4 or a salt thereof.
  • the reducing agent can be selected from the group of sodium hydride, potassium hydride, sodium borohydride, potassium borohydride, lithium aluminium hydride or lithium borohydride, sodium cyanoborohydride or sodium triacetoxy borohydride, palladium over carbon or Raney nickel, or a mixture thereof.
  • the preferred reducing agent is sodium borohydride.
  • Treating a compound of Formula 3 with a reducing agent can be performed preferably in one or more solvent.
  • the reducing agent can be employed preferably in an amount of 0.1 to 1 time of the quantity of compound of Formula 3.
  • solvent includes any solvent or solvent mixture, including, for example, water, esters, alkanols, halogenated hydrocarbons, ketones, ethers, polar aprotic solvents, or mixtures thereof.
  • the esters may include one or more of ethyl acetate, ⁇ -propyl acetate, isopropyl acetate, and n-butyl acetate.
  • alkanols include those primary, secondary and tertiary alcohols having from one to six carbon atoms.
  • Suitable alkanol solvents include methanol, ethanol, «-propanol, isopropanol and butanol.
  • Examples of halogenated hydrocarbons include dichloromethane, chloroform, and 1,2-dichloroethane.
  • ketones include acetone, methyl ethyl ketone, and the like.
  • ethers include diethyl ether, tetrahydrofuran, and the like.
  • a suitable polar aprotic solvent includes one or more of N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulphoxide, acetonitrile and N-methylpyrrolidone.
  • Treating a compound of Formula 3 with a reducing agent can be performed preferably at a temperature of from about 0°C to about 50°C for a time period sufficient to complete the reaction, preferably for about 10 minutes to 12 hours.
  • the compound of Formula 4 can be isolated by a common isolation technique such as cooling, extraction, adjusting the pH, one or more of washing, crystallization, precipitation, filtration, filtration under vacuum, decantation and centrifugation, or a combination thereof.
  • the isolated compound of Formula 4 may be further purified by salt formation, crystallization or chromatographic methods, or a combination thereof.
  • the compound of Formula 4 is a suitable intermediate for the preparation of silodosin.
  • the present invention also provides for a process for the preparation of compound of Formula 5 or a salt thereof;
  • R can be selected from hydrogen or a carboxyl protecting group, the process includes: treating a compound of Formula 4 or a salt thereof;
  • R can be selected from hydrogen or a carboxyl protecting group, with a formylating agent to obtain compound of Formula, or a salt thereof.
  • the formylating agent can be selected from the group of N,N-dimethylformamide, triformamide, tri(diformylamino)methane, tris(dichloromethyl)amine or ⁇ , ⁇ , ⁇ , ⁇ - tetraformylhydrazine or a mixture thereof in the presence of a Lewis acid, for example, phosphorous oxychloride, aluminum trichloride or boron trichloride.
  • a Lewis acid for example, phosphorous oxychloride, aluminum trichloride or boron trichloride.
  • the preferred formylating agent may be a mixture of N,N-dimethylformamide and phosphorous oxychloride.
  • the formylating agent can be preferably taken in an amount of 0.5 to 3 times the quantity of the compound of Formula 4.
  • Treating a compound of Formula 4 with a formylating agent can be preferably performed in one or more solvent.
  • solvent includes any solvent or solvent mixture, including for example, water, esters, alkanols, halogenated hydrocarbons, ketones, ethers, polar aprotic solvents, or mixtures thereof.
  • the esters may include one or more of ethyl acetate, w-propyl acetate, isopropyl acetate, and n-butyl acetate.
  • alkanols include those primary, secondary and tertiary alcohols having from one to six carbon atoms.
  • Suitable alkanol solvents include methanol, ethanol, n-propanol, isopropanol and butanol.
  • Examples of halogenated hydrocarbons include dichloromethane, chloroform, and 1,2-dichloroethane.
  • ketones include acetone, methyl ethyl ketone, and the like.
  • ethers include diethyl ether, tetrahydrofuran, and the like.
  • a suitable polar aprotic solvent includes one or more ofN,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulphoxide, acetonitrile and N-methylpyrrolidone.
  • Treating a compound of Formula 4 with formylating agent can be performed preferably at a temperature of from 0°C to the 50°C for a time period sufficient to complete the reaction, preferably for about 10 minutes to 12 hours.
  • the compound of Formula 5 can be isolated by a common isolation technique such as cooling, extraction, one or more of washing, crystallization, precipitation, filtration, filtration under vacuum, decantation and centrifugation, or a combination thereof.
  • the isolated compound of Formula 5 may be further purified by salt formation, crystallization or chromatographic methods, or a combination thereof.
  • the compound of Formula 5 is a suitable intermediate for the preparation of silodosin.
  • the present invention also provides for a process for the preparation of compound of Formula 6 or a salt thereof;
  • R can be selected from hydrogen or a carboxyl protecting group, the process includes: treating a compound of Formula 5 or a salt thereof;
  • R can be selected from hydrogen or a carboxyl protecting group
  • Treating a compound of Formula 5 or a salt thereof with hydroxylamine or its salt, preferably the hydrochloride salt, can be performed in the presence of a catalyst or a dehydrating agent in one or more solvent optionally in the presence of a base.
  • the dehydrating agent/catalyst can be selected from the group of acetic anhydride, phthalic anhydride, P 2 0 5 , TiCl 4 , oxalyl chloride, KF/A1 2 0 3, NH 3 /H 2 0 2 , 1 2 in NH 3 , Na 2 S0 4 , or a mixture thereof.
  • the dehydrating agent/catalyst can also be selected from the group consisting of ruthenium or rhodium metal complexes, such as, [RuCl 2 (/?-cymene)] 2 , [RuCl 2 (benzene)] 2 , RuH 2 (PPh 3 ) 4 , RuCl 2 (PPh 3 ) 3 , Ru 3 (CO) 12 , [Rh(OAc) 2 ] 2 .
  • ruthenium or rhodium metal complexes such as, [RuCl 2 (/?-cymene)] 2 , [RuCl 2 (benzene)] 2 , RuH 2 (PPh 3 ) 4 , RuCl 2 (PPh 3 ) 3 , Ru 3 (CO) 12 , [Rh(OAc) 2 ] 2 .
  • solvent includes any solvent or solvent mixture, including, for example, water, esters, alkanols, halogenated hydrocarbons, ketones, ethers, polar aprotic solvents, or mixtures thereof.
  • the esters may include one or more of ethyl acetate, ⁇ -propyl acetate, isopropyl acetate, and n-butyl acetate.
  • alkanols include those primary, secondary and tertiary alcohols having from one to six carbon atoms.
  • Suitable alkanol solvents include methanol, ethanol, rc-propanol, isopropanol and butanol.
  • halogenated hydrocarbons include dichloromethane, chloroform, and 1 ,2-dichloroethane.
  • ketones include acetone, methyl ethyl ketone, and the like.
  • ethers include diethyl ether, tetrahydrofuran, and the like.
  • a suitable polar aprotic solvent includes one or more of N,JV-dimethylformamide, N, jV-dimethylacetamide, dimethylsulphoxide, acetonitrile and N-methylpyrrolidone.
  • the base may include one or more of organic or inorganic bases selected from the group consisting of alkali metal and alkaline earth metal carbonates or bicarbonates or hydroxides, for example potassium bicarbonate, sodium bicarbonate, potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, calcium hydroxide, and the like; primary, secondary, and tertiary amines, such as pyridine, piperidine, triethylamine, diisopropylethylamine, N-methylmorpholine, and the like; ammonia and ammonium salts. Treating a compound of Formula 5 with hydroxylamine or its salt can be performed under nitrogen atmosphere preferably at a temperature of from 0°C to the reflux temperature for a time period sufficient to complete the reaction.
  • organic or inorganic bases selected from the group consisting of alkali metal and alkaline earth metal carbonates or bicarbonates or hydroxides, for example potassium bicarbonate, sodium bicarbonate, potassium carbonate
  • the compound of Formula 6 can be isolated by a common isolation technique, such as, quenching, cooling, extraction, one or more of washing, crystallization, precipitation, filtration, filtration under vacuum, decantation and centrifugation, or a combination thereof.
  • a common isolation technique such as, quenching, cooling, extraction, one or more of washing, crystallization, precipitation, filtration, filtration under vacuum, decantation and centrifugation, or a combination thereof.
  • the isolated compound of Formula 6 may be further purified by salt formation, crystallization or chromatographic methods, or a combination thereof.
  • the compound of Formula 6 is a suitable intermediate for the preparation of silodosin.
  • the present invention also provides for a process for the preparation of compound of Formula 7 or a salt thereof;
  • R can be selected from hydrogen or a carboxyl protecting group, the process includes: treating a compound of Formula 6 or a salt thereof;
  • R can be selected from hydrogen or a carboxyl protecting group, with hydrogen peroxide to obtain compound of Formula 7, or a salt thereof.
  • Treating a compound of Formula 6 with hydrogen peroxide can be performed preferably in one or more solvents, optionally in the presence of a base.
  • solvent includes any solvent or solvent mixture, including, for example, water, esters, alkanols, halogenated hydrocarbons, ketones, ethers, polar aprotic solvents, or mixtures thereof.
  • the esters may include one or more of ethyl acetate, n-propyl acetate, isopropyl acetate, and n-butyl acetate.
  • alkanols include those primary, secondary and tertiary alcohols having from one to six carbon atoms.
  • Suitable alkanol solvents include methanol, ethanol, n-propanol, isopropanol and butanol.
  • Examples of halogenated hydrocarbons include dichloromethane, chloroform, and 1,2-dichloroethane.
  • ketones include acetone, methyl ethyl ketone, and the like.
  • ethers include diethyl ether, tetrahydrofuran, and the like.
  • a suitable polar aprotic solvent includes one or more ofN,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulphoxide, acetonitrile andN-methylpyrrolidone.
  • the base may include one or more of organic or inorganic bases selected from the group consisting of alkali metal and alkaline earth metal carbonates or bicarbonates or hydroxides, for example, potassium bicarbonate, sodium bicarbonate, potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, calcium hydroxide, and the like; primary, secondary, and tertiary amines such as pyridine, piperidine, triethylamine, diisopropylethylamine, N- methylmorpholine, and the like; ammonia and ammonium salts.
  • organic or inorganic bases selected from the group consisting of alkali metal and alkaline earth metal carbonates or bicarbonates or hydroxides, for example, potassium bicarbonate, sodium bicarbonate, potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, calcium hydroxide, and the like; primary, secondary, and tertiary amines
  • Treating a compound of Formula 6 with hydrogen peroxide can be performed under nitrogen atmosphere preferably at a temperature of from 20°C to 80°C for a time period sufficient to complete the reaction, preferably for about 30 minutes to 24 hours.
  • the compound of Formula 7 can be isolated by a common isolation technique, such as cooling, extraction, one or more of washing, crystallization, precipitation, filtration, filtration under vacuum, decantation and centrifugation, or a combination thereof.
  • a common isolation technique such as cooling, extraction, one or more of washing, crystallization, precipitation, filtration, filtration under vacuum, decantation and centrifugation, or a combination thereof.
  • the isolated compound of Formula 7 may be further purified by salt formation, crystallization or chromatographic methods, or a combination thereof.
  • the compound of Formula 7 is a suitable intermediate for the preparation of silodosin.
  • the present invention also provides for a process for the preparation of compound of Formula 8 or a salt thereof;
  • R can be independently selected from hydrogen or a carboxyl protecting group, the process includes: hydrolyzing a compound of Formula 6, or a salt thereof;
  • R can be the same as defined above.
  • Hydrolysis of a compound of Formula 6 or a salt thereof can be performed in the presence of an acid, optionally in a solvent at a temperature of about 35°C to about reflux temperature under stirring for a time period sufficient to complete the reaction.
  • the acid can be selected from the group of organic acid, inorganic acid, or a mixture thereof.
  • the organic acid can be acetic acid, trifluoroacetic acid, difluoroacetic acid, oxalic acid, formic acid, or a mixture thereof.
  • the inorganic acid can be
  • hydrochloric acid sulfuric acid, nitric acid, phosphoric acid, or a mixture thereof.
  • solvent includes any solvent or solvent mixture, including, for example, water, esters, alkanols, halogenated hydrocarbons, ketones, ethers, polar aprotic solvents, or mixtures thereof.
  • the esters may include one or more of ethyl acetate, n-propyl acetate, isopropyl acetate, and n-butyl acetate.
  • alkanols include those primary, secondary and tertiary alcohols having from one to six carbon atoms.
  • Suitable alkanol solvents include methanol, ethanol, «-propanol, isopropanol and butanol.
  • Examples of halogenated hydrocarbons include dichloromethane, chloroform, and 1,2-dichloroethane.
  • ketones include acetone, methyl ethyl ketone, and the like.
  • ethers include diethyl ether, tetrahydrofuran, and the like.
  • a suitable polar aprotic solvent includes one or more of N.N-dimethylformamide, N,N-dimethylacetamide, dimethylsulphoxide, acetonitrile and N-methylpyrrolidone.
  • the compound of Formula 8 can be isolated by a common isolation technique such as quenching, cooling, extraction, one or more of washing, crystallization, precipitation, filtration, filtration under vacuum, decantation and centrifugation, or a combination thereof.
  • the isolated compound of Formula 8 may be further purified by salt formation, crystallization from solvent or chromatographic methods, or a combination thereof.
  • the compound of Formula 8 is a suitable intermediate for the preparation of silodosin.
  • the present invention also provides for a process for the preparation of compound of Formula 9 or a salt thereof;
  • R can be independently selected from hydrogen or a carboxyl protecting group, the process includes: oxidation of a compound of Formula 8 or a salt thereof;
  • R can be the same as defined above.
  • Oxidation of compound of Formula 8 or a salt thereof involves treating a compound of Formula 8 or a salt thereof with an oxidizing agent and a base in one or more of solvent at a temperature of from about 20°C to about 80°C for a time period sufficient to complete the reaction.
  • the oxidizing agent can be selected from hydrogen peroxide or a mixture of urea and hydrogen peroxide.
  • the base may include one or more of organic or inorganic bases selected from the group consisting of alkali metal and alkaline earth metal carbonates or bicarbonates or hydroxides, for example, potassium bicarbonate, sodium bicarbonate, potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, calcium hydroxide, and the like; primary, secondary, and tertiary amines such as pyridine, piperidine, triethylamine, diisopropylethylamine, N- methylmorpholine, and the like; ammonia and ammonium salts.
  • organic or inorganic bases selected from the group consisting of alkali metal and alkaline earth metal carbonates or bicarbonates or hydroxides, for example, potassium bicarbonate, sodium bicarbonate, potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium hydr
  • solvent includes any solvent or solvent mixture, including, for example, water, esters, alkanols, halogenated hydrocarbons, ketones, ethers, polar aprotic solvents, or mixtures thereof.
  • the esters may include one or more of ethyl acetate, ⁇ -propyl acetate, isopropyl acetate, and n-butyl acetate.
  • alkanols include those primary, secondary and tertiary alcohols having from one to six carbon atoms.
  • Suitable alkanol solvents include methanol, ethanol, «-propanol, isopropanol and butanol.
  • halogenated hydrocarbons include dichloromethane, chloroform, and 1 ,2-dichloroethane.
  • ketones include acetone, methyl ethyl ketone, and the like.
  • ethers include diethyl ether, tetrahydrofuran, and the like.
  • a suitable polar aprotic solvent includes one or more of N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulphoxide, acetonitrile and N-methylpyrrolidone.
  • the compound of Formula 9 can be isolated by a common isolation technique, such as, cooling, extraction, one or more of washing, crystallization, precipitation, filtration, filtration under vacuum, decantation and centrifugation, or a combination thereof.
  • the isolated compound of Formula 9 may be further purified by salt formation, crystallization or chromatographic methods, or a combination thereof.
  • the compound of Formula 9 is a suitable intermediate for the preparation of silodosin.
  • the present invention also provides for a process for the preparation of compound of Formula 10 or a salt thereof;
  • R can be independently selected from hydrogen or a carboxyl protecting group, the process includes: treating a compound of Formula 9 or a salt thereof;
  • R can be the same as defined above, with R-(+)-a-methylbenzylamine.
  • Treating a compound of Formula 9 or a salt thereof with R-(+)-a- methylbenzylamine may be performed in the presence of hydrogen source and a catalyst or a reducing agent in one or more solvent at a temperature of from about 35°C to about 70°C for a time period sufficient to complete the reaction.
  • the catalyst may be selected from transition metal compounds.
  • transition metal compounds include nickel compounds, such as, Raney nickel, palladium compounds such as palladium/carbon and palladium hydroxide, platinum compounds, such as, platinum oxide and platinum/carbon, ruthenium compounds, such as, ruthenium oxide and rhodium compounds, such as rhodium/carbon.
  • the reducing agents may be selected from boranes or metal hydrides such as, sodium hydride, potassium hydride, sodium borohydride, potassium borohydride, lithium aluminium hydride or lithium borohydride, sodium cyanoborohydride.
  • Treating a compound of Formula 9 with R-(+)-a-methylbenzylamine may be performed at normal pressure, or at somewhat elevated pressure, depending on the choice of catalyst. In general, it may be carried out at a hydrogen pressure in the range of from about 1 kg to 5 kg.
  • solvent includes any solvent or solvent mixture, including, for example, water, esters, alkanols, halogenated hydrocarbons, ketones, ethers, polar aprotic solvents, or mixtures thereof.
  • the esters may include one or more of ethyl acetate, ⁇ -propyl acetate, isopropyl acetate, and n-butyl acetate.
  • alkanols include those primary, secondary and tertiary alcohols having from one to six carbon atoms.
  • Suitable alkanol solvents include methanol, ethanol, H-propanol, isopropanol and butanol.
  • Examples of halogenated hydrocarbons include dichloromethane, chloroform, and 1 ,2-dichloroethane.
  • ketones include acetone, methyl ethyl ketone, and the like.
  • ethers include diethyl ether, tetrahydrofuran, and the like.
  • a suitable polar aprotic solvent includes one or more of N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulphoxide, acetonitrile and N-methylpyrrolidone.
  • the compound of Formula 10 can be isolated by a common isolation technique such as cooling, extraction, one or more of washing, crystallization, precipitation, filtration, filtration under vacuum, decantation and centrifugation, or a combination thereof.
  • the isolated compound of Formula 10 may be further purified by salt formation, crystallization or chromatographic methods, or a combination thereof.
  • the compound of Formula 10 is a suitable intermediate for the preparation of silodosin.
  • the present invention also provides for a process for the preparation of compound of Formula 1 1 or a salt thereof;
  • R can be independently selected from hydrogen or a carboxyl protecting group
  • the process includes: hydrogenolysis of compound of Formula 10 or a salt thereof
  • R can be the same as defined above.
  • Hydrogenolysis of compound of Formula 10 or a salt thereof may be performed in the presence of hydrogen source and a catalyst or a reducing agent in one or more solvents for a time period sufficient to complete the reaction.
  • the catalyst may be selected from transition metal compounds.
  • transition metal compounds may include nickel compounds such as Raney nickel, palladium compounds, such as, palladium/carbon and palladium hydroxide, platinum compounds, such as, platinum oxide and platinum/carbon, ruthenium compounds, such as, ruthenium oxide and rhodium compounds, such as rhodium/carbon.
  • the reducing agent may be selected from boranes or metal hydrides, such as, sodium hydride, potassium hydride, sodium borohydride, potassium borohydride, lithium aluminium hydride or lithium borohydride, sodium cyanoborohydride.
  • Hydrogenolysis of compound of Formula 10 or a salt thereof may be performed at normal pressure, or at somewhat elevated pressure depending on the choice of catalyst. In general, it may be carried out at a hydrogen pressure in the range of from about 1 kg to 5 kg.
  • solvent includes any solvent or solvent mixture, including, for example, water, esters, alkanols, halogenated hydrocarbons, ketones, ethers, polar aprotic solvents, or mixtures thereof.
  • the esters may include one or more of ethyl acetate, ⁇ -propyl acetate, isopropyl acetate, and n-butyl acetate.
  • alkanols include those primary, secondary and tertiary alcohols having from one to six carbon atoms.
  • Suitable alkanol solvents include methanol, ethanol, «-propanol, isopropanol, butanol and t-butanol.
  • Examples of halogenated hydrocarbons include dichloromethane, chloroform, and 1,2-dichloroethane.
  • ketones include acetone, methyl ethyl ketone, and the like.
  • ethers include diethyl ether, tetrahydrofuran, and the like.
  • a suitable polar aprotic solvent includes one or more of N,N-dimethylformamide, N.N-dimethylacetamide,
  • the compound of Formula 11 can be isolated by a common isolation technique, such as cooling, extraction, one or more of washing, crystallization, precipitation, filtration, filtration under vacuum, decantation and centrifugation, or a combination thereof.
  • the isolated compound of Formula 11 may be further purified by salt formation, crystallization or chromatographic methods, or a combination thereof.
  • the compound of Formula 11 is a suitable intermediate for the preparation of silodosin.
  • the present invention also provides for a process for the preparation of compound of Formula 12 or a salt thereof;
  • R can be independently selected from hydrogen or a carboxyl protecting group, the process includes: treating a compound of Formula 11 or its salt thereof;
  • R can be the same as defined above, with a compound of Formula 13.
  • Treating a compound of Formula 1 1 or its salt thereof with a compound of Formula 14 may be performed in one or more solvents in the presence of a base at a temperature of from about 40°C to reflux temperature for a time period sufficient to complete the reaction.
  • solvent includes any solvent or solvent mixture, including, for example, water, esters, alkanols, halogenated hydrocarbons, ketones, ethers, polar aprotic solvents, or mixtures thereof.
  • the esters may include one or more of ethyl acetate, ⁇ -propyl acetate, isopropyl acetate, and n-butyl acetate.
  • alkanols include those primary, secondary and tertiary alcohols having from one to six carbon atoms.
  • Suitable alkanol solvents include methanol, ethanol, «-propanol, isopropanol, butanol and ⁇ -butanol.
  • Examples of halogenated hydrocarbons include dichloromethane, chloroform, and 1,2-dichloroethane.
  • ketones include acetone, methyl ethyl ketone and the like.
  • ethers include diethyl ether, tetrahydrofuran, and the like.
  • a suitable polar aprotic solvent includes one or more of N,N-dimethylformamide, N,N-dimethylacetamide,
  • the base may include one or more of organic or inorganic bases selected from the group consisting of alkali metal and alkaline earth metal carbonates or bicarbonates or hydroxides, for example, potassium bicarbonate, sodium bicarbonate, potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, calcium hydroxide, and the like; primary, secondary, and tertiary amines such as pyridine, piperidine, triethylamine, diisopropylethylamine, N- methylmorpholine, and the like; ammonia and ammonium salts.
  • organic or inorganic bases selected from the group consisting of alkali metal and alkaline earth metal carbonates or bicarbonates or hydroxides, for example, potassium bicarbonate, sodium bicarbonate, potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, calcium hydroxide, and the like; primary, secondary, and tertiary amines
  • the compound of Formula 12 can be isolated by a common isolation technique, such as, cooling, extraction, one or more of washing, crystallization, precipitation, filtration, filtration under vacuum, decantation and centrifugation, or a combination thereof.
  • a common isolation technique such as, cooling, extraction, one or more of washing, crystallization, precipitation, filtration, filtration under vacuum, decantation and centrifugation, or a combination thereof.
  • the isolated compound of Formula 12 may be further purified by salt formation, crystallization or chromatographic methods, or a combination thereof.
  • the compound of Formula 12 is a suitable intermediate for the preparation of silodosin.
  • the present invention also provides for a process for the preparation of silodosin or a salt thereof of Formula I;
  • R can be independently selected from hydrogen or a carboxyl protecting group with a reducing agent.
  • Treating a compound of Formula 12 with reducing agent can be preferably performed in one or more solvent.
  • the reducing agent may be selected from boranes or metal hydride, such as sodium hydride, potassium hydride, sodium borohydride, potassium borohydride, lithium aluminium hydride or lithium borohydride, sodium cyanoborohydride.
  • solvent includes any solvent or solvent mixture, including, for example, water, esters, alkanols, halogenated hydrocarbons, ketones, ethers, polar aprotic solvents, or mixtures thereof.
  • the esters may include one or more of ethyl acetate, «-propyl acetate, isopropyl acetate, and n-butyl acetate.
  • alkanols include those primary, secondary and tertiary alcohols having from one to six carbon atoms.
  • Suitable alkanol solvents include methanol, ethanol, «-propanol, isopropanol and butanol.
  • Examples of halogenated hydrocarbons include dichloromethane, chloroform, and 1,2-dichloroethane.
  • ketones include acetone, methyl ethyl ketone, and the like.
  • ethers include diethyl ether, tetrahydrofuran, and the like.
  • a suitable polar aprotic solvent includes one or more ofN,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulphoxide, acetonitrile andN-methylpyrrolidone.
  • Treating a compound of Formula 12 with a reducing agent can be performed preferably at a temperature of from about 0°C to about 60°C for a time period sufficient to complete the reaction, preferably for from about 10 minutes to 12 hours.
  • silodosin can be isolated by a common isolation technique such as cooling, extraction, adjusting the pH, one or more of washing, crystallization, precipitation, filtration, filtration under vacuum, decantation and centrifugation, or a combination thereof.
  • the isolated silodosin may be further purified by salt formation, crystallization or chromatographic methods, or a combination thereof.
  • the present invention also provides for a process for the preparation of silodosin or a salt thereof;
  • the process includes: a) providing a compound of Formula 8 or a salt thereof;
  • R can be independently selected from hydrogen or a carboxyl protecting group
  • R can be the same as defined above; c) converting the compound of Formula 9 or a salt thereof to a compound of Formula 10 or a salt thereof;
  • R can be the same as defined above; and f) converting the compound of Formula 12 or its salt thereof to silodosin or a salt thereof.
  • Formula I Step a) of providing a compound of Formula 8 or a salt thereof includes hydrolysis a compound of Formula 6 or a salt thereof;
  • R can be independently selected from hydrogen or a carboxyl protecting group.
  • Hydrolysis of a compound of Formula 6 or a salt thereof can be performed in the presence of an acid optionally in a solvent at a temperature of from about 35°C to about reflux temperature under stirring for a time period sufficient to complete the reaction.
  • the acid can be selected from the group consisting of organic acid, inorganic acid, or a mixture thereof.
  • Preferred organic acid can be acetic acid, trifluoroacetic acid, difluoroacetic acid, oxalic acid, formic acid, or a mixture thereof.
  • Preferred inorganic acid can be hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, or a mixture thereof.
  • solvent includes any solvent or solvent mixture, including, for example, water, esters, alkanols, halogenated hydrocarbons, ketones, ethers, polar aprotic solvents, or mixtures thereof.
  • the esters may include one or more of ethyl acetate, n-propyl acetate, isopropyl acetate, and n-butyl acetate.
  • alkanols include those primary, secondary and tertiary alcohols having from one to six carbon atoms.
  • Suitable alkanol solvents include methanol, ethanol, n-propanol, isopropanol and butanol.
  • Examples of halogenated hydrocarbons include dichloromethane, chloroform, and 1 ,2-dichloroethane.
  • ketones include acetone, methyl ethyl ketone, and the like.
  • ethers include diethyl ether, tetrahydrofuran, and the like.
  • a suitable polar aprotic solvent includes one or more of N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulphoxide, acetonitrile and N-methylpyrrolidone.
  • Step b) of converting compound of Formula 8 or a salt thereof to compound of Formula 9 or a salt thereof includes oxidation of compound of Formula 8 or a salt thereof with oxidizing agent in one or more of solvent in presence of one or more of base at a temperature of from about 20°C to about 80°C for a time period sufficient to complete the reaction.
  • the oxidizing agent can be selected from hydrogen peroxide or a mixture of urea and hydrogen peroxide.
  • the base may include one or more of organic or inorganic bases selected from the group consisting of alkali metal and alkaline earth metal carbonates or bicarbonates or hydroxides, for example, potassium bicarbonate, sodium bicarbonate, potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, calcium hydroxide, and the like; primary, secondary, and tertiary amines, such as pyridine, piperidine, triethylamine, diisopropylethylamine, N- methylmorpholine, and the like; ammonia and ammonium salts.
  • organic or inorganic bases selected from the group consisting of alkali metal and alkaline earth metal carbonates or bicarbonates or hydroxides, for example, potassium bicarbonate, sodium bicarbonate, potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, calcium hydroxide, and the like; primary, secondary, and tertiary amine
  • solvent includes any solvent or solvent mixture, including, for example, water, esters, alkanols, halogenated hydrocarbons, ketones, ethers, polar aprotic solvents, or mixtures thereof.
  • the esters may include one or more of ethyl acetate, ⁇ -propyl acetate, isopropyl acetate, and n-butyl acetate.
  • alkanols include those primary, secondary and tertiary alcohols having from one to six carbon atoms.
  • Suitable alkanol solvents include methanol, ethanol, -propanol, isopropanol and butanol.
  • Examples of halogenated hydrocarbons include dichloromethane, chloroform, and 1,2-dichloroethane.
  • ketones include acetone, methyl ethyl ketone, and the like.
  • ethers include diethyl ether, tetrahydrofuran, and the like.
  • a suitable polar aprotic solvent includes one or more of N,N-dimethylformamide, N, N-dimethylacetamide, dimethylsulphoxide, acetonitrile and vV-methylpyrrolidone.
  • Step c) of converting a compound of Formula 9 or a salt thereof to compound of Formula 10 or a salt thereof includes treating a compound of Formula 9 or a salt thereof with R-(+)-a-methylbenzylamine.
  • Treating a compound of Formula 9 or a salt thereof with R-(+)-a- methylbenzylamine may be performed in the presence of a hydrogen source and a catalyst or a reducing agent in one or more solvents at a temperature of from about 35°C to about 70°C for a time period sufficient to complete the reaction.
  • the catalyst may be selected from transition metal compounds.
  • transition metal compounds include nickel compounds such as Raney nickel, palladium compounds, such as palladium/carbon and palladium hydroxide, platinum compounds, such as, platinum oxide and platinum/carbon, ruthenium compounds, such as, ruthenium oxide and rhodium compounds, such as rhodium/carbon.
  • the reducing agents may be selected from boranes or metal hydrides, such as, sodium hydride, potassium hydride, sodium borohydride, potassium borohydride, lithium aluminium hydride or lithium borohydride, sodium cyanoborohydride.
  • Treating a compound of Formula 9 with R-(+)-a-methylbenzylamine may be performed at normal pressure, or at somewhat elevated pressure depending on the choice of catalyst. In general, it may be carried out at a hydrogen pressure in the range from about 1 kg to 5 kg.
  • solvent includes any solvent or solvent mixture, including, for example, water, esters, alkanols, halogenated hydrocarbons, ketones, ethers, polar aprotic solvents, or mixtures thereof.
  • the esters may include one or more of ethyl acetate, ⁇ -propyl acetate, isopropyl acetate, and n-butyl acetate.
  • alkanols include those primary, secondary and tertiary alcohols having from one to six carbon atoms.
  • Suitable alkanol solvents include methanol, ethanol, «-propanol, isopropanol and butanol.
  • Examples of halogenated hydrocarbons include dichloromethane, chloroform, and 1,2-dichloroethane.
  • ketones include acetone, methyl ethyl ketone, and the like.
  • ethers include diethyl ether, tetrahydrofuran, and the like.
  • a suitable polar aprotic solvent includes one or more of N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulphoxide, acetonitrile and N-methylpyrrolidone.
  • the compound of Formula 10 can be isolated by a common isolation techniques known in the art or can be carried to next step of the process without isolation.
  • Step d) of converting compound of Formula 10 or a salt thereof to compound of Formula 1 1 or a salt thereof includes hydrogenolysis of a compound of Formula 10 or a salt thereof.
  • Hydrogenolysis of compound of Formula 10 or a salt thereof may be performed in the presence of a hydrogen source and a catalyst or a reducing agent in one or more solvents for a time period sufficient to complete the reaction.
  • the catalyst may be selected from transition metal compounds.
  • transition metal compounds may include nickel compounds, such as Raney nickel, palladium compounds, such as, palladium/carbon and palladium hydroxide, platinum compounds, such as, platinum oxide and platinum/carbon, ruthenium compounds, such as ruthenium oxide and rhodium compounds, such as rhodium/carbon.
  • the reducing agents may be selected from boranes or metal hydrides, such as, sodium hydride, potassium hydride, sodium borohydride, potassium borohydride, lithium aluminium hydride or lithium borohydride, sodium cyanoborohydride.
  • Hydrogenolysis of compound of Formula 10 or a salt thereof may be performed at normal pressure, or at somewhat elevated pressure depending on the choice of catalyst. In general, it may be carried out at a hydrogen pressure in the range of from about 1 kg to 5 kg.
  • solvent includes any solvent or solvent mixture, including, for example, water, esters, alkanols, halogenated hydrocarbons, ketones, ethers, polar aprotic solvents, or mixtures thereof.
  • the esters may include one or more of ethyl acetate, H-propyl acetate, isopropyl acetate, and n-butyl acetate.
  • alkanols include those primary, secondary and tertiary alcohols having from one to six carbon atoms.
  • Suitable alkanol solvents include methanol, ethanol, H-propanol, isopropanol and butanol.
  • Examples of halogenated hydrocarbons include dichloromethane, chloroform, and 1,2-dichloroethane.
  • ketones include acetone, methyl ethyl ketone, and the like.
  • ethers include diethyl ether, tetrahydrofuran, and the like.
  • a suitable polar aprotic solvent includes one or more of N.N-dimethylformamide, N,JV-dimethylacetamide, dimethylsulphoxide, acetonitrile and N-methylpyrrolidone.
  • the compound of Formula 11 can be isolated by the common isolation techniques known in the art or can be carried to next step of the process without isolation.
  • Step e) of treating a compound of Formula 11 or its salt thereof with a compound of Formula 13 may be performed in one or more solvents in presence of a base at a temperature of from about 40°C to reflux temperature for a time period sufficient to complete the reaction.
  • the base may include one or more of organic or inorganic bases selected from the group consisting of alkali metal and alkaline earth metal carbonates or bicarbonates or hydroxides, for example, potassium bicarbonate, sodium bicarbonate, potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, calcium hydroxide, and the like; primary, secondary, and tertiary amines, such as, pyridine, piperidine, triethylamine, diisopropylethylamine, N- methylmorpholine and the like; ammonia and ammonium salts.
  • organic or inorganic bases selected from the group consisting of alkali metal and alkaline earth metal carbonates or bicarbonates or hydroxides, for example, potassium bicarbonate, sodium bicarbonate, potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, calcium hydroxide, and the like; primary, secondary, and tertiary amine
  • solvent includes any solvent or solvent mixture, including, for example, water, esters, alkanols, halogenated hydrocarbons, ketones, ethers, polar aprotic solvents, or mixtures thereof.
  • the esters may include one or more of ethyl acetate, «-propyl acetate, isopropyl acetate, and n-butyl acetate.
  • alkanol include those primary, secondary and tertiary alcohols having from one to six carbon atoms.
  • Suitable alkanol solvents include methanol, ethanol, «-propanol, isopropanol butanol and t-butanol.
  • halogenated hydrocarbons include dichloromethane, chloroform, and 1,2-dichloroethane.
  • ketones include acetone, methyl ethyl ketone, and the like.
  • ethers include diethyl ether, tetrahydrofuran, and the like.
  • a suitable polar aprotic solvent includes one or more of N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulphoxide, acetonitrile and N-methylpyrrolidone.
  • the compound of Formula 12 can be isolated by a common isolation techniques known in the art or can be carried to next step of the process without isolation.
  • Step f) of converting a compound of Formula 12 or a salt thereof to silodosin or a salt thereof includes treating a compound of Formulal2 or a salt thereof with a reducing agent in one or more solvent.
  • the reducing agents may be selected from boranes or metal hydrides, such as sodium hydride, potassium hydride, sodium borohydride, potassium borohydride, lithium aluminium hydride or lithium borohydride, sodium cyanoborohydride.
  • solvent includes any solvent or solvent mixture, including, for example, water, esters, alkanols, halogenated hydrocarbons, ketones, ethers, polar aprotic solvents, or mixtures thereof.
  • the esters may include one or more of ethyl acetate, w-propyl acetate, isopropyl acetate, and n-butyl acetate.
  • alkanols include those primary, secondary and tertiary alcohols having from one to six carbon atoms.
  • Suitable alkanol solvents include methanol, ethanol, w-propanol, isopropanol and butanol.
  • halogenated hydrocarbons include dichloromethane, chloroform, and 1 ,2-dichloroethane.
  • ketones include acetone, methyl ethyl ketone, and the like.
  • ethers include diethyl ether, tetrahydrofuran, and the like.
  • a suitable polar aprotic solvent includes one or more of N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulphoxide, acetonitrile and N-methylpyrrolidone.
  • Treating a compound of Formula 12 with a reducing agent can be performed preferably at a temperature of from about 0°C to about 50°C for a time period sufficient to complete the reaction, preferably for from about 10 minutes to 12 hours.
  • silodosin can be isolated by a common isolation technique, such as, cooling, extraction, adjusting the pH, one or more of washing, crystallization, precipitation, filtration, filtration under vacuum, decantation and centrifugation, or a combination thereof.
  • the isolated silodosin may be further purified by salt formation, crystallization or chromatographic methods, or a combination thereof.
  • Triethylamine (25 ml) and 2,3-dihydro-lH-indole (18 g) were added to N,N- dimethylformamide (116.6 ml) under nitrogen.
  • the solution was stirred for 5 minutes and benzyl 3-chloropropanoate (59.8 g) was added to it drop wise over a period of 15 minutes at 25°C to 32°C.
  • the reaction mixture was then stirred at 80°C to 85°C for 15 hours.
  • the reaction mass was cooled to 25°C to 32°C and water (400 ml) was added to it.
  • the reaction mixture was extracted with toluene (400 ml x 3) and the toluene layer was washed with sodium bicarbonate followed by brine solution.
  • Example 3 Preparation of Benzyl 3-(5-Formyl-23-Dihvdro-l z-Indol-l-Yl Propanoate Phosphorous oxychloride (0.33 ml) was added drop wise to cold (0°C to 5°C) N,N- dimethylformamide (1.16 ml) under a nitrogen atmosphere and stirred for 15 minutes at 0°C. The reaction mixture was heated to 50°C and stirred for 1 hour.
  • the reaction mixture was cooled to 0°C and a solution of benzyl 3-(2,3-dihydro-lH-indol-l- yl)propanoate (500 mg) dissolved in N,N-dimethylformamide (0.23 ml) was added drop wise at 0°C to 5°C and stirred for 15 minutes at 0°C.
  • the reaction mixture was then further stirred for 2 hours at 25°C to 32°C and cooled to 10°C.
  • the reaction mixture was poured into chilled water (20 ml) and stirred at 25°C to 32°C for 1 hour.
  • the reaction mixture was then extracted with ethyl acetate (20 ml x 2).
  • the ethyl acetate layer was washed with an aqueous sodium bicarbonate solution followed by brine. Ethyl acetate was distilled off under vacuum at 60°C to obtain titled compound.
  • Phosphorous oxychloride 22 ml was added drop wise to cold (0°C to 5°C) N,N- dimethylformamide (70.28 ml) under a nitrogen atmosphere and stirred for 15 minutes at 0°C.
  • the reaction mixture was heated to 50°C and stirred for 1 hour.
  • the reaction mixture was cooled to 0°C and added drop wise a solution of benzyl 3-(2,3-dihydro-lH- indol-l-yl)propanoate (30 g) dissolved in N,N-dimethylformamide (13.79 ml) for 45 minutes at 0°C to 5°C and stirred for 15 minutes at 0°C.
  • reaction mixture was then further stirred for 2 hours at 25°C to 32°C and cooled to 10°C.
  • the reaction mixture was poured into chilled water (500 ml) and stirred at 25°C to 32°C for 1 hour.
  • Sodium bicarbonate (10 g) was added to the reaction mixture to obtain pH 7.
  • the reaction mixture was then extracted with ethyl acetate (500 ml x 2) and the ethyl acetate layer was washed with aqueous sodium bicarbonate solution followed by brine. Ethyl acetate was distilled off under vacuum at 60°C to obtain the titled compound.
  • Phosphorous oxychloride (5.46 ml) was added dropwise to cooled N,N- dimethylformamide (19.1 ml) at 0°C under a nitrogen atmosphere and stirred for 5 minutes. The reaction mixture was heated to 50°C to 55°C and stirred for 1 hour. A solution of benzyl-3-[5-(2-nitropropyl)-2,3-dihydro-lH-indol-l-yl]propanoate (8 g) dissolved in N,N-dimethylformamide (3.8 ml) was added dropwise to the reaction mixture at 0°C and stirred for 15 minutes. The reaction mixture was stirred further at 25°C to 32°C for 3.5 hours and cooled to 0°C.
  • Benzyl-3-[7-formyl-5-(2-nitropropyl)-2,3-dihydro-lH-indol-l-yl]propanoate (100 mg) and hydroxylamine hydrochloride (51.9 mg) and pyridine (0.05 ml) were added to tetrahydrofuran (0.15 ml) under a nitrogen atmosphere at 25°C to 32°C and stirred for 10 minutes. The reaction mixture was stirred at 50°C to 60°C for 1 hour. Acetic anhydride (0.1 ml) was added into the reaction mixture and stirred for 3 hours at 50°C to 60°C. Again, acetic anhydride (0.1 ml) was added and stirred further for 3 hours.
  • Reaction mixture was cooled to 25°C to 32°C and water (2 ml) was added to it.
  • the reaction mixture was extracted with toluene (2 ml x 3).
  • the toluene layer was washed with aqueous sodium bicarbonate solution followed by brine.
  • the organic layer was dried with sodium sulfate and distilled off under vacuum at 60°C to obtain a colored liquid (90 mg).
  • the liquid was purified by column chromatography on silica gel (60-120 mesh) by elution with dichloromethane:hexane mixture to obtain titled compound.
  • Dichloromethane (10 ml) was added to the reaction mixture and filtered through a cotton plug to remove the excess phthalic anhydride.
  • the dichloromethane layer was washed with aqueous ammonia (5%).
  • the organic layer was separated and dried with sodium sulfate and distilled off under vacuum at 45 °C to obtain a light colored liquid (90 mg).
  • the liquid was purified by column chromatography on silica gel (60-120 mesh) by elution with dichloromethane:hexane mixture to obtain the titled compound.
  • methyl ester compound of Example 10 can be prepared by following the Examples 1 to 9.
  • a transesterification of the benzyl group by the methyl group can be carried out at any stage with hydrochloric acid in methanol.
  • the aqueous phase was extracted with dichloromethane (10 ml x 3) and dichloromethane was then washed with aqueous sodium bicarbonate solution followed by brine.
  • Dichloromethane layer was dried with sodium sulfate and distilled off under vacuum at 30°C to obtain a pale yellow liquid (90 mg).
  • the liquid was purified by column chromatography on silica gel (60-120 mesh) by elution with ethylacetate:hexane mixture to obtain the titled compound.
  • Example 12 Preparation of Methyl 3-
  • a drop of sulfuric acid was added to methyl 3-[7-cyano-5-(2-nitropropyl)-2,3- dihydro-lH-indol-l-yl]propanoate (15 mg) dissolved in trifluoroacetic acid (0.5 ml) and the reaction was heated to 85°C for 8 hours.
  • the reaction mixture was quenched with dilute ammonium hydroxide solution (10 ml) and was extracted with dichloromethane (3 ml x 2).
  • the dichloromethane layer thus obtained was distilled off to obtain the titled compound.
  • dimethylsulfoxide 150 ml were stirred for 16 hours at 25°C to 32°C.
  • the ethyl acetate layer was distilled off under vacuum at 60°C to obtain the titled compound.
  • Triethyl amine was added (0.7ml) to the reaction mixture and was refluxed for 5 hours further followed by addition of 2-[2-(2,2,2- trifluoroethoxy)phenoxy] ethyl methanesulfonate in lots (0.3 g). After 16 hours of overnight refluxing, 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl methanesulfonate (0.25 g) was added and further refluxed for 5 hours.
  • t-Butanol was distilled off on rotavapour and ethyl acetate (20 ml) and water (20 ml) were added to the residue. The reaction mixture was acidified to pH 3 with concentrated hydrochloric acid.
  • the aqueous layer was washed twice with ethyl acetate (20 ml x 2).
  • the aqueous layer was basified with ammonium hydroxide and the free base was extracted with ethyl acetate.
  • the ethyl acetate layer was washed with water, dried over sodium sulfate and distilled off under vacuum at 55°C to obtain the titled compound.
  • Ethyl acetate was distilled off on rotavapour and the residue obtained was dissolved in methanol (25 ml). Oxalic acid (3.5 g) was added to methanol solution and stirred until dissolved. Methanol was distilled off and the residue obtained was dissolved in water (50 ml) and stirred at 50°C for 10 minutes and the aqueous phase was extracted with ethyl acetate twice (20 ml x 2). The aqueous phase was basified with ammonium hydroxide and extracted with ethyl acetate twice (20 ml x 2). The ethyl acetate layer was washed with water thrice (20 ml x 3). Ethyl acetate was distilled off on rotavapour to obtain the colourless, oily and viscous titled compound.

Abstract

The present invention relates to novel intermediates of silodosin and a process for their preparation. The present invention further relates to a process for the preparation of silodosin using the novel intermediates.

Description

PROCESS FOR THE PREPARATION OF SILODOSIN AND ITS NOVEL
INTERMEDIATES
Field of the Invention
The present invention relates to novel intermediates of silodosin and a process for their preparation. The present invention also relates to a process for the preparation of silodosin using the novel intermediates.
Background of the Invention
Silodosin of Formula I, a selective alpha- 1 adrenergic receptor antagonist, chemically designated as l-(3-Hydroxypropyl)-5-[(2i?)-2-({2-[2-(2,2,2- trifluoroethoxy)phenoxy]ethyl}amino)propyl]-2,3-dihydro-lH-indole-7-carboxamide, marketed under the brand name Rapaflo®, is indicated for the treatment of the signs and symptoms of benign prostatic hyperplasia (BPH).
Figure imgf000002_0001
Formula I
U.S. Patent No. 5,387,603 provides processes for the preparation of silodosin and its intermediates which involve deprotecting l-(3-hydroxypropyl)-5-[2-[N-tert- butoxycarbonyl-2-(2,2,2-trifluoroethoxyphenoxy)ethylamino]propyl]indoline-7- carboxamide with trifluoroaceticacid in methylenechloride.
U.S. Publication No. 2007/0197627 provides a process for the preparation of silodosin which involves dissolving 3-{7-cyano-5-[(2R)-2-({2-[2-(2,2,2- trifluoroethoxy)phenoxy] ethyl } amino)propyl ] -2,3 -dihydro- 1 H-indol- 1 -yl } propyl benzoate with oxalic acid and isopropanol under heating. The mixture thus obtained is seeded with 3-{7-cyano-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}amino)propyl]-2,3- dihydro-lH-indol-l-yl}propyl benzoate monooxalate to precipitate the crystal of 3-{7- cyano-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}amino)propyl]-2,3-dihydro- lH-indol-l-yl}propyl benzoate monooxalate. The oxalate salt of 3-{7-cyano-5-[(2R)-2- ({2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}amino)propyl]-2,3-dihydro-lH-indol-l- yl}propyl benzoate thus obtained is subsequently hydrolyzed with aqueous potassium hydroxide solution in methanol at room temperature overnight to yield l-(3- hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]-ethyl}amino)propyl]- 2,3-dihydro-lH-indole-7-carbonitrile and further hydrolyzing l-(3-hydroxypropyl)-5- [(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]-ethyl}amino)propyl]-2,3-dihydro-lH- indole-7-carbonitrile in dimethylsulfoxide with aqueous sodium hydroxide solution and 30% hydrogen peroxide solution at a temperature of 20°C to 25°C to obtain silodosin.
Japanese Patent Registration No. JP 3331048; Japanese Publication Nos. JP 2001199956; JP 2002265444; JP 2006188470; Chinese Publication No. 101412690; U.S. Publication No. 2006/0142374; and PCT Publication No. WO 2011/030356 provide various processes for the preparation of silodosin, its salt, polymorphs or its intermediates.
There is a need for a novel and efficient synthetic route for the preparation of silodosin that provides good yield and high enantiomeric purity. The present invention is directed to a method for the preparation of silodosin or a pharmaceutically acceptable salt or solvate thereof using novel intermediates with the objective of developing an efficient, economical and commercially viable process.
Summary of the Invention
In one general aspect, the present invention provides for a compound of Formula 1 or a salt thereof;
Figure imgf000003_0001
Formula 1
wherein R is a benzyl group.
In another general aspect, the present invention provides for a compound of Formula 2 or a salt thereof;
Figure imgf000004_0001
Formula 2
wherein R can be selected from hydrogen or a carboxyl protecting group.
In another general aspect, the present invention provides for a compound of Formula 3 or a salt thereof;
Figure imgf000004_0002
Formula 3
wherein R can be selected from hydrogen or a carboxyl protecting group.
In yet another general aspect, the present invention provides for a compound of Formula 4 or a salt thereof;
Figure imgf000004_0003
Formula 4
wherein R can be selected from hydrogen or a carboxyl protecting group.
In another general aspect, the present invention provides for a compound of Formula 5 or a salt thereof;
Figure imgf000004_0004
Formula 5
wherein R can be selected from hydrogen or a carboxyl protecting group. In another general aspect, the present invention provides for a compound of Formula 6 or a salt thereof;
Figure imgf000005_0001
Formula 6
wherein R can be selected from hydrogen or a carboxyl protecting group.
In another general aspect, the present invention provides for a a compound of Formula 7 or a salt thereof;
Figure imgf000005_0002
Formula 7
wherein R can be selected from hydrogen or a carboxyl protecting group.
In yet another general aspect, the present invention provides for a compound of Formula 8 or a salt thereof;
Figure imgf000005_0003
Formula 8
wherein R can be independently selected from hydrogen or a carboxyl protecting group.
In another general aspect, the present invention provides for a compound of Formula 9 or a salt thereof;
Figure imgf000005_0004
Formula 9 wherein R can be independently selected from hydrogen or a carboxyl protecting group.
In yet another general aspect, the present invention provides for a compound of Formula 10 or a salt thereof;
Figure imgf000006_0001
Formula 10
wherein R can be independently selected from hydrogen or a carboxyl protecting group.
In another general aspect, the present invention provides for a compound of Formula 11 or a salt thereof;
Figure imgf000006_0002
Formula 11
wherein R can be independently selected from hydrogen or a carboxyl protecting group.
In another general aspect, the present invention provides for a compound of Formula 12 or a salt thereof;
Figure imgf000006_0003
Formula 12
wherein R can be independently selected from hydrogen or a carboxyl protecting group.
In yet another general aspect, the present invention provides for a process for the preparation of compound of Formula 1 or a salt thereof;
Figure imgf000007_0001
Formula 1
wherein R can be selected from hydrogen or a carboxyl protecting group, the process includes: treating a compound of Formula la or a salt thereof;
Figure imgf000007_0002
Formula la
wherein R can be selected from hydrogen or a carboxyl protecting group, with 2,3- dihydro-lH-indole to obtain compound of Formula 1, or a salt thereof.
In another general aspect, the present invention provides for a process for the preparation of compound of Formula 2 or a salt thereof;
Figure imgf000007_0003
Formula 2
wherein R can be selected from hydrogen or a carboxyl protecting group, the process includes: treating a compound of Formula 1
Figure imgf000007_0004
Formula 1
wherein R can be selected from hydrogen or a carboxyl protecting group, with a formylating agent to obtain compound of Formula 2 or a salt thereof.
In another general aspect, the present invention provides for a process for preparation of compound of Formula 3 or a salt thereof;
Figure imgf000008_0001
Formula 3
wherein R can be selected from hydrogen or a carboxyl protecting group, the process includes: treating a compound of Formula 2 or a salt thereof;
Figure imgf000008_0002
Formula 2
wherein R can be selected from hydrogen or a carboxyl protecting group, with nitroethane to obtain compound of Formula 3 or a salt thereof.
In yet another general aspect, the present invention provides for a process for the preparation of compound of Formula 4 or a salt thereof;
Figure imgf000008_0003
Formula 4
wherein R can be selected from hydrogen or a carboxyl protecting group, the process includes: treating a compound of Formula 3 or a salt thereof;
Figure imgf000008_0004
Formula 3
wherein R can be selected from hydrogen or a carboxyl protecting group, with a reducing agent to obtain compound of Formula 4 or a salt thereof. In another general aspect, the present invention provides for a process for the preparation of compound of Formula 5 or a salt thereof;
Figure imgf000009_0001
Formula 5
wherein R can be selected from hydrogen or a carboxyl protecting group, the process includes: treating a compound of Formula 4 or a salt thereof;
Figure imgf000009_0002
Formula 4
wherein R can be selected from hydrogen or a carboxyl protecting group, with a formylating agent to obtain compound of Formula 5 or a salt thereof.
In another general aspect, the present invention provides for a process for preparation of compound of Formula 6 or a salt thereof;
Figure imgf000009_0003
Formula 6
wherein R can be selected from hydrogen or a carboxyl protecting group, the process includes: treating a compound of Formula 5 or a salt thereof;
Figure imgf000009_0004
Formula 5 wherein R can be selected from hydrogen or a carboxyl protecting group, with hydroxylamine or its salt to obtain compound of Formula 6 or a salt thereof.
In another general aspect, the present invention provides for a process for preparation of compound of Formula 7 or a salt thereof;
Figure imgf000010_0001
Formula 7
wherein R can be selected from hydrogen or a carboxyl protecting group, the process includes: treating a compound of Formula 6 or a salt thereof;
Figure imgf000010_0002
Formula 6
wherein R can be selected from hydrogen or a carboxyl protecting group, with hydrogen peroxide to obtain compound of Formula 7 or a salt thereof.
In yet another general aspect, the present invention provides for a process for the preparation of compound of Formula 8 or a salt thereof;
Figure imgf000010_0003
Formula 8
wherein R can be independently selected from hydrogen or a carboxyl protecting group, the process includes: hydrolyzing a compound of Formula 6 or a salt thereof;
Figure imgf000011_0001
Formula 6
wherein R can be the same as defined above.
In another general aspect, the present invention provides for a process for the preparation of compound of Formula 9 or a salt thereof;
Figure imgf000011_0002
Formula 9
wherein R can be independently selected from hydrogen or a carboxyl protecting group, the process includes: oxidation of a compound of Formula 8 or a salt thereof;
Figure imgf000011_0003
Formula 8
wherein R can be the same as defined above.
In another general aspect, the present invention provides for a process for the preparation of compound of Formula 10 or a salt thereof;
Figure imgf000011_0004
Formula 10
wherein R can be independently selected from hydrogen or a carboxyl protecting group, the process includes: treating a compound of Formula 9 or a salt thereof;
Figure imgf000012_0001
Formula 9
wherein R can be the same as defined above with R-(+)-a-methylbenzylamine.
In another general aspect, the present invention provides for a process for the preparation of compound of Formula 11 or a salt thereof;
Figure imgf000012_0002
Formula 11
wherein R can be independently selected from hydrogen or a carboxyl protecting group, the process includes: hydrogenolysis of compound of Formula 10 or a salt thereof
Figure imgf000012_0003
Formula 10
wherein R can be the same as defined above.
In yet another general aspect, the present invention provides for a process for the preparation of compound of Formula 12 or a salt thereof;
Figure imgf000012_0004
Formula 12
wherein R can be independently selected from hydrogen or a carboxyl protecting group, the process includes: treating a compound of Formula 11 or its salt thereof;
Figure imgf000013_0001
Formula 11
wherein R can be the same as defined above, with a compound of Formula 13.
Figure imgf000013_0002
Formula 13
In another general aspect, the present invention provides for a process for the preparation of silodosin or a salt thereof of Formula I;
Figure imgf000013_0003
Formula I
the process includes: treating a compound of Formula 12 or a salt thereof;
Figure imgf000013_0004
Formula 12
wherein R can be independently selected from hydrogen or a carboxyl protecting group with a reducing agent.
In another general aspect, the present invention provides for a process for the preparation of silodosin or a salt thereof;
Figure imgf000014_0001
Formula I
the process includes:
a) providing a compound of Formula 8 or a salt thereof
Figure imgf000014_0002
Formula 8
wherein R can be independently selected from hydrogen or a carboxyl protecting group;
converting the compound of Formula 8 or a salt thereof to a compound of Formula 9 or a salt thereof;
Figure imgf000014_0003
Formula 9
wherein R can be the same as defined above; c) converting the compound of Formula 9 or a salt thereof to a compound of Formula 10 or a salt thereof;
Figure imgf000014_0004
Formula 10
wherein R can be the same as defined above; converting the compound of Formula 10 or a salt thereof to a compound of Formula 11 or a salt thereof;
Figure imgf000015_0001
Formula 11
wherein R can be the same as defined above, e) treating the compound of Formula 11 or its salt thereof with a compound of Formula 13
Figure imgf000015_0002
Formula 13
to provide a compound of Formula 12 or its salt thereof;
Figure imgf000015_0003
Formula 12
wherein R can be the same as defined above; and f) converting the compound of Formula 12 or its salt thereof to silodosin or a salt thereof.
Figure imgf000015_0004
Formula I Detailed Description of the Invention
As used herein, the term "carboxyl protecting group" refers to a moiety that can be selectively attached to and removed from a carboxyl group to prevent it from participating in undesired chemical reactions, without unacceptably adverse affects on desired reactions. Examples of carboxyl protecting groups include esters, such as methyl, ethyl, t- butyl, (un)substituted benzyl, and silyl esters, /7-methoxybenzyl, benzoylmethyl, p- nitrobenzyl, 4-pyridylmethyl, 2,2,2-trichloroethyl, 2,2,2-tribromoethyl, t-butyl, t-amyl, allyl, diphenylmethyl, triphenylmethyl, adamantyl, 2-benzyloxyphenyl, 4- methylthiophenyl, tetrahydrofur-2-yl, tetrahydropyran-2-yl, pentachlorophenyl, acetonyl, p-toluenesulphonylethyl, and methoxymethyl among others. Other carboxyl protecting groups are well known in the art.
The present invention provides for a compound of Formula 1 or a salt thereof;
Figure imgf000016_0001
Formula 1
wherein R is a benzyl group.
The present invention also provides for a compound of Formula 2 or a salt thereof;
Figure imgf000016_0002
Formula 2
wherein R can be selected from hydrogen or a carboxyl protecting group.
The present invention provides for a compound of Formula 3 or a salt thereof;
Figure imgf000016_0003
Formula 3 wherein R can be selected from hydrogen or a carboxyl protecting group.
The present invention provides for a compound of Formula 4 or a salt thereof;
Figure imgf000017_0001
Formula 4
wherein R can be selected from hydrogen or a carboxyl protecting group.
The present invention provides for a compound of Formula 5 or a salt thereof;
Figure imgf000017_0002
Formula 5
wherein R can be selected from hydrogen or a carboxyl protecting group.
The present invention also provides for a compound of Formula 6 or a salt thereof;
Figure imgf000017_0003
Formula 6
wherein R can be selected from hydrogen or a carboxyl protecting group.
The present invention provides for a compound of Formula 7 or a salt thereof;
Figure imgf000017_0004
Formula 7
wherein R can be selected from hydrogen or a carboxyl protecting group.
The present invention provides for a compound of Formula 8 or a salt thereof;
Figure imgf000018_0001
Formula 8
wherein R can be independently selected from hydrogen or a carboxyl protecting group. The present invention provides for a compound of Formula 9 or a salt thereof;
Figure imgf000018_0002
Formula 9
wherein R can be independently selected from hydrogen or a carboxyl protecting group.
The present invention provides for a compound of Formula 10 or a salt thereof;
Figure imgf000018_0003
Formula 10
wherein R can be independently selected from hydrogen or a carboxyl protecting group.
The present invention also provides for a compound of Formula 1 1 or a salt thereof;
Figure imgf000018_0004
Formula 11
wherein R can be independently selected from hydrogen or a carboxyl protecting group.
The present invention provides for a compound of Formula 12 or a salt thereof;
Figure imgf000019_0001
Formula 12
wherein R can be independently selected from hydrogen or a carboxyl protecting group.
The present invention also provides for a process for the preparation of compound of Formula 1 or a salt thereof;
Figure imgf000019_0002
Formula 1
wherein R can be selected from hydrogen or a carboxyl protecting group, the process includes: treating a compound of Formula la or a salt thereof;
Figure imgf000019_0003
Formula la
wherein R can be selected from hydrogen or a carboxyl protecting group, with 2,3- dihydro-lH-indole to obtain compound of Formula 1 or a salt thereof.
Treating a compound of Formula la with 2,3-dihydro-lH-indole can be performed preferably in the presence of one or more of organic or inorganic bases selected from the group of alkali metal and alkaline earth metal carbonates or bicarbonates or hydroxides, for example, potassium bicarbonate, sodium bicarbonate, potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, calcium hydroxide, and the like; primary, secondary, and tertiary amines, such as pyridine, piperidine, triethylamine, diisopropylethylamine, N-methylmorpholine, and the like;
ammonia and ammonium salts.
Treating a compound of Formula la with 2,3-dihydro-lH-indole can be performed preferably in the presence of one or more solvents. The term "solvent" includes any solvent or solvent mixture, including, for example, water, esters, alkanols, halogenated hydrocarbons, ketones, ethers, polar aprotic solvents, or mixtures thereof.
The esters may include one or more of ethyl acetate, ^-propyl acetate, isopropyl acetate, and n-butyl acetate. Examples of alkanols include those primary, secondary and tertiary alcohols having from one to six carbon atoms. Suitable alkanol solvents include methanol, ethanol, «-propanol, isopropanol and butanol. Examples of halogenated hydrocarbons include dichloromethane, chloroform, and 1 ,2-dichloroethane. Examples of ketones include acetone, methyl ethyl ketone, and the like. Examples of ethers include diethyl ether, tetrahydrofuran, and the like. A suitable polar aprotic solvent includes one or more of N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulphoxide, acetonitrile and N-methylpyrrolidone.
Treating a compound of Formula la with 2,3-dihydro-lH-indole can be performed preferably at a temperature of from 20°C to the reflux temperature for a time period sufficient to complete the reaction, preferably for about 30 minutes to 20 hours.
After the completion of the reaction, the compound of Formula 1 can be isolated by a common isolation technique, such as cooling, extraction, one or more of washing, crystallization, precipitation, filtration, filtration under vacuum, decantation and centrifugation, or a combination thereof. The isolated compound of Formula 1 may be further purified by salt formation, crystallization or chromatographic methods, or a combination thereof.
The compound of Formula 1 is a suitable intermediate for the preparation of silodosin.
The present invention also provides for a process for the preparation of compound of Formula 2 or a salt thereof;
Figure imgf000020_0001
Formula 2 wherein R can be selected from hydrogen or a carboxyl protecting group, the process includes: treating a compound of Formula 1 or a salt thereof;
Figure imgf000021_0001
Formula 1
wherein R can be selected from hydrogen or a carboxyl protecting group, with a formylating agent to obtain compound of Formula 2 or a salt thereof.
The formylating agent can be selected from the group of N,N-dimethylformamide, triformamide, tri(diformylamino)methane, tris(dichloromethyl)amine or Ν,Ν,Ν,Ν- tetraformylhydrazine or a mixture thereof in the presence of a Lewis acid, for example, phosphorous oxychloride, aluminum trichloride or boron trichloride.
The preferred formylating agent may be a mixture of N,N-dimethylformamide and phosphorous oxychloride.
The formylating agent can be preferably taken in an amount of 0.5 to 3 times the quantity of compound of Formula 1.
Treating a compound of Formula 1 with the formylating agent can be preferably performed in one or more solvents.
The term "solvent" includes any solvent or solvent mixture, including, for example, water, esters, alkanols, halogenated hydrocarbons, ketones, ethers, polar aprotic solvents, or mixtures thereof.
The esters may include one or more of ethyl acetate, ^-propyl acetate, isopropyl acetate, and rc-butyl acetate. Examples of alkanols include those primary, secondary and tertiary alcohols having from one to six carbon atoms. Suitable alkanol solvents include methanol, ethanol, rc-propanol, isopropanol and butanol. Examples of halogenated hydrocarbons include dichloromethane, chloroform, and 1,2-dichloroethane. Examples of ketones include acetone, methyl ethyl ketone, and the like. Examples of ethers include diethyl ether, tetrahydrofuran, and the like. A suitable polar aprotic solvent includes one or more of N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulphoxide, acetonitrile and N-methylpyrrolidone.
Treating a compound of Formula 1 with formylating agent can be performed preferably at a temperature of from 0°C to 50°C for a time period sufficient to complete the reaction, preferably for about 10 minutes to 12 hours.
After the completion of the reaction, the compound of Formula 2 can be isolated by a common isolation technique such as cooling, extraction, one or more of washing, crystallization, precipitation, filtration, filtration under vacuum, decantation and centrifugation, or a combination thereof.
The isolated compound of Formula 2 may be further purified by salt formation, crystallization or chromatographic methods, or a combination thereof.
The compound of Formula 2 is a suitable intermediate for the preparation of silodosin.
The present invention also provides for a process for the preparation of compound of Formula 3 or a salt thereof;
Figure imgf000022_0001
Formula 3
wherein R can be selected from hydrogen or a carboxyl protecting group, the process includes: treating a compound of Formula 2 or a salt thereof;
Formula 2
wherein R can be selected from hydrogen or a carboxyl protecting group, with nitroethane to obtain compound of Formula 3 or a salt thereof. Treating a compound of Formula 2 with nitroethane can be performed preferably in the presence of base under nitrogen atmosphere and optionally in the presence of solvent.
Preferable base may include one or more of organic or inorganic bases selected from the group of alkali metal and alkaline earth metal carbonates or bicarbonates or hydroxides, for example, potassium bicarbonate, sodium bicarbonate, potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, calcium hydroxide, and the like; primary, secondary, and tertiary amines such as pyridine, piperidine, triethylamine, diisopropylethylamine, N- methylmorpholine, and the like; ammonia and ammonium salts.
The term "solvent" includes any solvent or solvent mixture, including, for example, water, esters, alkanols, halogenated hydrocarbons, ketones, ethers, polar aprotic solvents, or mixtures thereof.
The esters may include one or more of ethyl acetate, ^-propyl acetate, isopropyl acetate, and n-butyl acetate. Examples of alkanols include those primary, secondary and tertiary alcohols having from one to six carbon atoms. Suitable alkanol solvents include methanol, ethanol, H-propanol, isopropanol and butanol. Examples of halogenated hydrocarbons include dichloromethane, chloroform, and 1 ,2-dichloroethane. Examples of ketones include acetone, methyl ethyl ketone, and the like. Examples of ethers include diethyl ether, tetrahydrofuran, and the like. A suitable polar aprotic solvent includes one or more of N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulphoxide, acetonitrile and N-methylpyrrolidone.
Treating a compound of Formula 2 with nitroethane can be performed preferably at a temperature of from 10°C to 90°C for a time period sufficient to complete the reaction, preferably for about 10 minutes to 12 hours.
After the completion of the reaction, the compound of Formula 3 can be isolated by a common isolation technique such as cooling, extraction, one or more of washing, crystallization, precipitation, filtration, filtration under vacuum, decantation and centrifugation or a combination thereof. The compound of Formula 3 can be isolated preferably by distilling out the unreacted nitroethane under vacuum at 50°C. The mixture may be further treated with one or more of the aforementioned solvents followed by washing with aqueous sodium bicarbonate solution, brine and evaporation of solvent optionally under vacuum.
The isolated compound of Formula 3 may be further purified by salt formation, crystallization or chromatographic methods, or a combination thereof.
The compound of Formula 3 is a suitable intermediate for the preparation of silodosin.
The present invention also provides for a process for the preparation of compound of Formula 4 or a salt thereof;
Figure imgf000024_0001
Formula 4
wherein R can be selected from hydrogen or a carboxyl protecting group, the process includes: treating a compound of Formula 3 or a salt thereof;
Figure imgf000024_0002
Formula 3
wherein R can be selected from hydrogen or a carboxyl protecting group, with a reducing agent to obtain compound of Formula 4 or a salt thereof.
The reducing agent can be selected from the group of sodium hydride, potassium hydride, sodium borohydride, potassium borohydride, lithium aluminium hydride or lithium borohydride, sodium cyanoborohydride or sodium triacetoxy borohydride, palladium over carbon or Raney nickel, or a mixture thereof. The preferred reducing agent is sodium borohydride. Treating a compound of Formula 3 with a reducing agent can be performed preferably in one or more solvent.
The reducing agent can be employed preferably in an amount of 0.1 to 1 time of the quantity of compound of Formula 3.
The term "solvent" includes any solvent or solvent mixture, including, for example, water, esters, alkanols, halogenated hydrocarbons, ketones, ethers, polar aprotic solvents, or mixtures thereof.
The esters may include one or more of ethyl acetate, ^-propyl acetate, isopropyl acetate, and n-butyl acetate. Examples of alkanols include those primary, secondary and tertiary alcohols having from one to six carbon atoms. Suitable alkanol solvents include methanol, ethanol, «-propanol, isopropanol and butanol. Examples of halogenated hydrocarbons include dichloromethane, chloroform, and 1,2-dichloroethane. Examples of ketones include acetone, methyl ethyl ketone, and the like. Examples of ethers include diethyl ether, tetrahydrofuran, and the like. A suitable polar aprotic solvent includes one or more of N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulphoxide, acetonitrile and N-methylpyrrolidone.
Treating a compound of Formula 3 with a reducing agent can be performed preferably at a temperature of from about 0°C to about 50°C for a time period sufficient to complete the reaction, preferably for about 10 minutes to 12 hours.
After the completion of the reaction, the compound of Formula 4 can be isolated by a common isolation technique such as cooling, extraction, adjusting the pH, one or more of washing, crystallization, precipitation, filtration, filtration under vacuum, decantation and centrifugation, or a combination thereof.
The isolated compound of Formula 4 may be further purified by salt formation, crystallization or chromatographic methods, or a combination thereof.
The compound of Formula 4 is a suitable intermediate for the preparation of silodosin.
The present invention also provides for a process for the preparation of compound of Formula 5 or a salt thereof;
Figure imgf000026_0001
Formula 5
wherein R can be selected from hydrogen or a carboxyl protecting group, the process includes: treating a compound of Formula 4 or a salt thereof;
Figure imgf000026_0002
Formula 4
wherein R can be selected from hydrogen or a carboxyl protecting group, with a formylating agent to obtain compound of Formula, or a salt thereof.
The formylating agent can be selected from the group of N,N-dimethylformamide, triformamide, tri(diformylamino)methane, tris(dichloromethyl)amine or Ν,Ν,Ν,Ν- tetraformylhydrazine or a mixture thereof in the presence of a Lewis acid, for example, phosphorous oxychloride, aluminum trichloride or boron trichloride.
The preferred formylating agent may be a mixture of N,N-dimethylformamide and phosphorous oxychloride.
The formylating agent can be preferably taken in an amount of 0.5 to 3 times the quantity of the compound of Formula 4.
Treating a compound of Formula 4 with a formylating agent can be preferably performed in one or more solvent.
The term "solvent" includes any solvent or solvent mixture, including for example, water, esters, alkanols, halogenated hydrocarbons, ketones, ethers, polar aprotic solvents, or mixtures thereof.
The esters may include one or more of ethyl acetate, w-propyl acetate, isopropyl acetate, and n-butyl acetate. Examples of alkanols include those primary, secondary and tertiary alcohols having from one to six carbon atoms. Suitable alkanol solvents include methanol, ethanol, n-propanol, isopropanol and butanol. Examples of halogenated hydrocarbons include dichloromethane, chloroform, and 1,2-dichloroethane. Examples of ketones include acetone, methyl ethyl ketone, and the like. Examples of ethers include diethyl ether, tetrahydrofuran, and the like. A suitable polar aprotic solvent includes one or more ofN,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulphoxide, acetonitrile and N-methylpyrrolidone.
Treating a compound of Formula 4 with formylating agent can be performed preferably at a temperature of from 0°C to the 50°C for a time period sufficient to complete the reaction, preferably for about 10 minutes to 12 hours.
After the completion of the reaction, the compound of Formula 5 can be isolated by a common isolation technique such as cooling, extraction, one or more of washing, crystallization, precipitation, filtration, filtration under vacuum, decantation and centrifugation, or a combination thereof.
The isolated compound of Formula 5 may be further purified by salt formation, crystallization or chromatographic methods, or a combination thereof.
The compound of Formula 5 is a suitable intermediate for the preparation of silodosin.
The present invention also provides for a process for the preparation of compound of Formula 6 or a salt thereof;
Figure imgf000027_0001
Formula 6
wherein R can be selected from hydrogen or a carboxyl protecting group, the process includes: treating a compound of Formula 5 or a salt thereof;
Figure imgf000027_0002
Formula 5 wherein R can be selected from hydrogen or a carboxyl protecting group, with
hydroxylamine or its salt to obtain compound of Formula 6 or a salt thereof.
Treating a compound of Formula 5 or a salt thereof with hydroxylamine or its salt, preferably the hydrochloride salt, can be performed in the presence of a catalyst or a dehydrating agent in one or more solvent optionally in the presence of a base.
The dehydrating agent/catalyst can be selected from the group of acetic anhydride, phthalic anhydride, P205, TiCl4, oxalyl chloride, KF/A1203, NH3/H202, 12 in NH3, Na2S04, or a mixture thereof.
The dehydrating agent/catalyst can also be selected from the group consisting of ruthenium or rhodium metal complexes, such as, [RuCl2(/?-cymene)]2, [RuCl2(benzene)]2, RuH2(PPh3)4, RuCl2(PPh3)3, Ru3(CO)12, [Rh(OAc)2]2.
The term "solvent" includes any solvent or solvent mixture, including, for example, water, esters, alkanols, halogenated hydrocarbons, ketones, ethers, polar aprotic solvents, or mixtures thereof. The esters may include one or more of ethyl acetate, ^-propyl acetate, isopropyl acetate, and n-butyl acetate. Examples of alkanols include those primary, secondary and tertiary alcohols having from one to six carbon atoms. Suitable alkanol solvents include methanol, ethanol, rc-propanol, isopropanol and butanol. Examples of halogenated hydrocarbons include dichloromethane, chloroform, and 1 ,2-dichloroethane. Examples of ketones include acetone, methyl ethyl ketone, and the like. Examples of ethers include diethyl ether, tetrahydrofuran, and the like. A suitable polar aprotic solvent includes one or more of N,JV-dimethylformamide, N, jV-dimethylacetamide, dimethylsulphoxide, acetonitrile and N-methylpyrrolidone.
The base may include one or more of organic or inorganic bases selected from the group consisting of alkali metal and alkaline earth metal carbonates or bicarbonates or hydroxides, for example potassium bicarbonate, sodium bicarbonate, potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, calcium hydroxide, and the like; primary, secondary, and tertiary amines, such as pyridine, piperidine, triethylamine, diisopropylethylamine, N-methylmorpholine, and the like; ammonia and ammonium salts. Treating a compound of Formula 5 with hydroxylamine or its salt can be performed under nitrogen atmosphere preferably at a temperature of from 0°C to the reflux temperature for a time period sufficient to complete the reaction.
After the completion of the reaction, the compound of Formula 6 can be isolated by a common isolation technique, such as, quenching, cooling, extraction, one or more of washing, crystallization, precipitation, filtration, filtration under vacuum, decantation and centrifugation, or a combination thereof.
The isolated compound of Formula 6 may be further purified by salt formation, crystallization or chromatographic methods, or a combination thereof.
The compound of Formula 6 is a suitable intermediate for the preparation of silodosin.
The present invention also provides for a process for the preparation of compound of Formula 7 or a salt thereof;
Figure imgf000029_0001
Formula 7
wherein R can be selected from hydrogen or a carboxyl protecting group, the process includes: treating a compound of Formula 6 or a salt thereof;
Figure imgf000029_0002
Formula 6
wherein R can be selected from hydrogen or a carboxyl protecting group, with hydrogen peroxide to obtain compound of Formula 7, or a salt thereof.
Treating a compound of Formula 6 with hydrogen peroxide can be performed preferably in one or more solvents, optionally in the presence of a base. The term "solvent" includes any solvent or solvent mixture, including, for example, water, esters, alkanols, halogenated hydrocarbons, ketones, ethers, polar aprotic solvents, or mixtures thereof.
The esters may include one or more of ethyl acetate, n-propyl acetate, isopropyl acetate, and n-butyl acetate. Examples of alkanols include those primary, secondary and tertiary alcohols having from one to six carbon atoms. Suitable alkanol solvents include methanol, ethanol, n-propanol, isopropanol and butanol. Examples of halogenated hydrocarbons include dichloromethane, chloroform, and 1,2-dichloroethane. Examples of ketones include acetone, methyl ethyl ketone, and the like. Examples of ethers include diethyl ether, tetrahydrofuran, and the like. A suitable polar aprotic solvent includes one or more ofN,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulphoxide, acetonitrile andN-methylpyrrolidone.
The base may include one or more of organic or inorganic bases selected from the group consisting of alkali metal and alkaline earth metal carbonates or bicarbonates or hydroxides, for example, potassium bicarbonate, sodium bicarbonate, potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, calcium hydroxide, and the like; primary, secondary, and tertiary amines such as pyridine, piperidine, triethylamine, diisopropylethylamine, N- methylmorpholine, and the like; ammonia and ammonium salts.
Treating a compound of Formula 6 with hydrogen peroxide can be performed under nitrogen atmosphere preferably at a temperature of from 20°C to 80°C for a time period sufficient to complete the reaction, preferably for about 30 minutes to 24 hours.
After the completion of the reaction, the compound of Formula 7 can be isolated by a common isolation technique, such as cooling, extraction, one or more of washing, crystallization, precipitation, filtration, filtration under vacuum, decantation and centrifugation, or a combination thereof.
The isolated compound of Formula 7 may be further purified by salt formation, crystallization or chromatographic methods, or a combination thereof.
The compound of Formula 7 is a suitable intermediate for the preparation of silodosin. The present invention also provides for a process for the preparation of compound of Formula 8 or a salt thereof;
Figure imgf000031_0001
Formula 8
wherein R can be independently selected from hydrogen or a carboxyl protecting group, the process includes: hydrolyzing a compound of Formula 6, or a salt thereof;
Figure imgf000031_0002
Formula 6
wherein R can be the same as defined above.
Hydrolysis of a compound of Formula 6 or a salt thereof can be performed in the presence of an acid, optionally in a solvent at a temperature of about 35°C to about reflux temperature under stirring for a time period sufficient to complete the reaction.
The acid can be selected from the group of organic acid, inorganic acid, or a mixture thereof. The organic acid can be acetic acid, trifluoroacetic acid, difluoroacetic acid, oxalic acid, formic acid, or a mixture thereof. The inorganic acid can be
hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, or a mixture thereof.
The term "solvent" includes any solvent or solvent mixture, including, for example, water, esters, alkanols, halogenated hydrocarbons, ketones, ethers, polar aprotic solvents, or mixtures thereof.
The esters may include one or more of ethyl acetate, n-propyl acetate, isopropyl acetate, and n-butyl acetate. Examples of alkanols include those primary, secondary and tertiary alcohols having from one to six carbon atoms. Suitable alkanol solvents include methanol, ethanol, «-propanol, isopropanol and butanol. Examples of halogenated hydrocarbons include dichloromethane, chloroform, and 1,2-dichloroethane. Examples of ketones include acetone, methyl ethyl ketone, and the like. Examples of ethers include diethyl ether, tetrahydrofuran, and the like. A suitable polar aprotic solvent includes one or more of N.N-dimethylformamide, N,N-dimethylacetamide, dimethylsulphoxide, acetonitrile and N-methylpyrrolidone.
After the completion of the reaction, the compound of Formula 8 can be isolated by a common isolation technique such as quenching, cooling, extraction, one or more of washing, crystallization, precipitation, filtration, filtration under vacuum, decantation and centrifugation, or a combination thereof.
The isolated compound of Formula 8 may be further purified by salt formation, crystallization from solvent or chromatographic methods, or a combination thereof.
The compound of Formula 8 is a suitable intermediate for the preparation of silodosin.
The present invention also provides for a process for the preparation of compound of Formula 9 or a salt thereof;
Figure imgf000032_0001
Formula 9
wherein R can be independently selected from hydrogen or a carboxyl protecting group, the process includes: oxidation of a compound of Formula 8 or a salt thereof;
Figure imgf000032_0002
Formula 8
wherein R can be the same as defined above.
Oxidation of compound of Formula 8 or a salt thereof involves treating a compound of Formula 8 or a salt thereof with an oxidizing agent and a base in one or more of solvent at a temperature of from about 20°C to about 80°C for a time period sufficient to complete the reaction.
The oxidizing agent can be selected from hydrogen peroxide or a mixture of urea and hydrogen peroxide. The base may include one or more of organic or inorganic bases selected from the group consisting of alkali metal and alkaline earth metal carbonates or bicarbonates or hydroxides, for example, potassium bicarbonate, sodium bicarbonate, potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, calcium hydroxide, and the like; primary, secondary, and tertiary amines such as pyridine, piperidine, triethylamine, diisopropylethylamine, N- methylmorpholine, and the like; ammonia and ammonium salts.
The term "solvent" includes any solvent or solvent mixture, including, for example, water, esters, alkanols, halogenated hydrocarbons, ketones, ethers, polar aprotic solvents, or mixtures thereof. The esters may include one or more of ethyl acetate, ^-propyl acetate, isopropyl acetate, and n-butyl acetate. Examples of alkanols include those primary, secondary and tertiary alcohols having from one to six carbon atoms. Suitable alkanol solvents include methanol, ethanol, «-propanol, isopropanol and butanol. Examples of halogenated hydrocarbons include dichloromethane, chloroform, and 1 ,2-dichloroethane. Examples of ketones include acetone, methyl ethyl ketone, and the like. Examples of ethers include diethyl ether, tetrahydrofuran, and the like. A suitable polar aprotic solvent includes one or more of N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulphoxide, acetonitrile and N-methylpyrrolidone.
After the completion of the reaction, the compound of Formula 9 can be isolated by a common isolation technique, such as, cooling, extraction, one or more of washing, crystallization, precipitation, filtration, filtration under vacuum, decantation and centrifugation, or a combination thereof.
The isolated compound of Formula 9 may be further purified by salt formation, crystallization or chromatographic methods, or a combination thereof. The compound of Formula 9 is a suitable intermediate for the preparation of silodosin.
The present invention also provides for a process for the preparation of compound of Formula 10 or a salt thereof;
Figure imgf000034_0001
Formula 10
wherein R can be independently selected from hydrogen or a carboxyl protecting group, the process includes: treating a compound of Formula 9 or a salt thereof;
Figure imgf000034_0002
Formula 9
wherein R can be the same as defined above, with R-(+)-a-methylbenzylamine.
Treating a compound of Formula 9 or a salt thereof with R-(+)-a- methylbenzylamine may be performed in the presence of hydrogen source and a catalyst or a reducing agent in one or more solvent at a temperature of from about 35°C to about 70°C for a time period sufficient to complete the reaction.
The catalyst may be selected from transition metal compounds. Examples of transition metal compounds include nickel compounds, such as, Raney nickel, palladium compounds such as palladium/carbon and palladium hydroxide, platinum compounds, such as, platinum oxide and platinum/carbon, ruthenium compounds, such as, ruthenium oxide and rhodium compounds, such as rhodium/carbon. The reducing agents may be selected from boranes or metal hydrides such as, sodium hydride, potassium hydride, sodium borohydride, potassium borohydride, lithium aluminium hydride or lithium borohydride, sodium cyanoborohydride. Treating a compound of Formula 9 with R-(+)-a-methylbenzylamine may be performed at normal pressure, or at somewhat elevated pressure, depending on the choice of catalyst. In general, it may be carried out at a hydrogen pressure in the range of from about 1 kg to 5 kg. The term "solvent" includes any solvent or solvent mixture, including, for example, water, esters, alkanols, halogenated hydrocarbons, ketones, ethers, polar aprotic solvents, or mixtures thereof.
The esters may include one or more of ethyl acetate, ^-propyl acetate, isopropyl acetate, and n-butyl acetate. Examples of alkanols include those primary, secondary and tertiary alcohols having from one to six carbon atoms. Suitable alkanol solvents include methanol, ethanol, H-propanol, isopropanol and butanol. Examples of halogenated hydrocarbons include dichloromethane, chloroform, and 1 ,2-dichloroethane. Examples of ketones include acetone, methyl ethyl ketone, and the like. Examples of ethers include diethyl ether, tetrahydrofuran, and the like. A suitable polar aprotic solvent includes one or more of N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulphoxide, acetonitrile and N-methylpyrrolidone.
After the completion of the reaction, the compound of Formula 10 can be isolated by a common isolation technique such as cooling, extraction, one or more of washing, crystallization, precipitation, filtration, filtration under vacuum, decantation and centrifugation, or a combination thereof.
The isolated compound of Formula 10 may be further purified by salt formation, crystallization or chromatographic methods, or a combination thereof.
The compound of Formula 10 is a suitable intermediate for the preparation of silodosin. The present invention also provides for a process for the preparation of compound of Formula 1 1 or a salt thereof;
Figure imgf000036_0001
Formula 11
wherein R can be independently selected from hydrogen or a carboxyl protecting group, the process includes: hydrogenolysis of compound of Formula 10 or a salt thereof
Figure imgf000036_0002
Formula 10
wherein R can be the same as defined above.
Hydrogenolysis of compound of Formula 10 or a salt thereof may be performed in the presence of hydrogen source and a catalyst or a reducing agent in one or more solvents for a time period sufficient to complete the reaction.
The catalyst may be selected from transition metal compounds. Examples of transition metal compounds may include nickel compounds such as Raney nickel, palladium compounds, such as, palladium/carbon and palladium hydroxide, platinum compounds, such as, platinum oxide and platinum/carbon, ruthenium compounds, such as, ruthenium oxide and rhodium compounds, such as rhodium/carbon. The reducing agent may be selected from boranes or metal hydrides, such as, sodium hydride, potassium hydride, sodium borohydride, potassium borohydride, lithium aluminium hydride or lithium borohydride, sodium cyanoborohydride.
Hydrogenolysis of compound of Formula 10 or a salt thereof may be performed at normal pressure, or at somewhat elevated pressure depending on the choice of catalyst. In general, it may be carried out at a hydrogen pressure in the range of from about 1 kg to 5 kg. The term "solvent" includes any solvent or solvent mixture, including, for example, water, esters, alkanols, halogenated hydrocarbons, ketones, ethers, polar aprotic solvents, or mixtures thereof.
The esters may include one or more of ethyl acetate, ^-propyl acetate, isopropyl acetate, and n-butyl acetate. Examples of alkanols include those primary, secondary and tertiary alcohols having from one to six carbon atoms. Suitable alkanol solvents include methanol, ethanol, «-propanol, isopropanol, butanol and t-butanol. Examples of halogenated hydrocarbons include dichloromethane, chloroform, and 1,2-dichloroethane. Examples of ketones include acetone, methyl ethyl ketone, and the like. Examples of ethers include diethyl ether, tetrahydrofuran, and the like. A suitable polar aprotic solvent includes one or more of N,N-dimethylformamide, N.N-dimethylacetamide,
dimethylsulphoxide, acetonitrile and N-methylpyrrolidone.
After the completion of the reaction, the compound of Formula 11 can be isolated by a common isolation technique, such as cooling, extraction, one or more of washing, crystallization, precipitation, filtration, filtration under vacuum, decantation and centrifugation, or a combination thereof.
The isolated compound of Formula 11 may be further purified by salt formation, crystallization or chromatographic methods, or a combination thereof.
The compound of Formula 11 is a suitable intermediate for the preparation of silodosin.
The present invention also provides for a process for the preparation of compound of Formula 12 or a salt thereof;
Figure imgf000037_0001
Formula 12
wherein R can be independently selected from hydrogen or a carboxyl protecting group, the process includes: treating a compound of Formula 11 or its salt thereof;
Figure imgf000038_0001
Formula 11
wherein R can be the same as defined above, with a compound of Formula 13.
Figure imgf000038_0002
Formula 13
Treating a compound of Formula 1 1 or its salt thereof with a compound of Formula 14 may be performed in one or more solvents in the presence of a base at a temperature of from about 40°C to reflux temperature for a time period sufficient to complete the reaction.
The term "solvent" includes any solvent or solvent mixture, including, for example, water, esters, alkanols, halogenated hydrocarbons, ketones, ethers, polar aprotic solvents, or mixtures thereof.
The esters may include one or more of ethyl acetate, ^-propyl acetate, isopropyl acetate, and n-butyl acetate. Examples of alkanols include those primary, secondary and tertiary alcohols having from one to six carbon atoms. Suitable alkanol solvents include methanol, ethanol, «-propanol, isopropanol, butanol and ί-butanol. Examples of halogenated hydrocarbons include dichloromethane, chloroform, and 1,2-dichloroethane. Examples of ketones include acetone, methyl ethyl ketone and the like. Examples of ethers include diethyl ether, tetrahydrofuran, and the like. A suitable polar aprotic solvent includes one or more of N,N-dimethylformamide, N,N-dimethylacetamide,
dimethylsulphoxide, acetonitrile and N-methylpyrrolidone.
The base may include one or more of organic or inorganic bases selected from the group consisting of alkali metal and alkaline earth metal carbonates or bicarbonates or hydroxides, for example, potassium bicarbonate, sodium bicarbonate, potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, calcium hydroxide, and the like; primary, secondary, and tertiary amines such as pyridine, piperidine, triethylamine, diisopropylethylamine, N- methylmorpholine, and the like; ammonia and ammonium salts.
After the completion of the reaction, the compound of Formula 12 can be isolated by a common isolation technique, such as, cooling, extraction, one or more of washing, crystallization, precipitation, filtration, filtration under vacuum, decantation and centrifugation, or a combination thereof.
The isolated compound of Formula 12 may be further purified by salt formation, crystallization or chromatographic methods, or a combination thereof.
The compound of Formula 12 is a suitable intermediate for the preparation of silodosin.
The present invention also provides for a process for the preparation of silodosin or a salt thereof of Formula I;
Figure imgf000039_0001
Formula 12
wherein R can be independently selected from hydrogen or a carboxyl protecting group with a reducing agent.
Treating a compound of Formula 12 with reducing agent can be preferably performed in one or more solvent. The reducing agent may be selected from boranes or metal hydride, such as sodium hydride, potassium hydride, sodium borohydride, potassium borohydride, lithium aluminium hydride or lithium borohydride, sodium cyanoborohydride.
The term "solvent" includes any solvent or solvent mixture, including, for example, water, esters, alkanols, halogenated hydrocarbons, ketones, ethers, polar aprotic solvents, or mixtures thereof.
The esters may include one or more of ethyl acetate, «-propyl acetate, isopropyl acetate, and n-butyl acetate. Examples of alkanols include those primary, secondary and tertiary alcohols having from one to six carbon atoms. Suitable alkanol solvents include methanol, ethanol, «-propanol, isopropanol and butanol. Examples of halogenated hydrocarbons include dichloromethane, chloroform, and 1,2-dichloroethane. Examples of ketones include acetone, methyl ethyl ketone, and the like. Examples of ethers include diethyl ether, tetrahydrofuran, and the like. A suitable polar aprotic solvent includes one or more ofN,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulphoxide, acetonitrile andN-methylpyrrolidone.
Treating a compound of Formula 12 with a reducing agent can be performed preferably at a temperature of from about 0°C to about 60°C for a time period sufficient to complete the reaction, preferably for from about 10 minutes to 12 hours.
After the completion of the reaction, silodosin can be isolated by a common isolation technique such as cooling, extraction, adjusting the pH, one or more of washing, crystallization, precipitation, filtration, filtration under vacuum, decantation and centrifugation, or a combination thereof.
The isolated silodosin may be further purified by salt formation, crystallization or chromatographic methods, or a combination thereof.
The present invention also provides for a process for the preparation of silodosin or a salt thereof;
Figure imgf000041_0001
Formula I
the process includes: a) providing a compound of Formula 8 or a salt thereof;
Figure imgf000041_0002
Formula 8
wherein R can be independently selected from hydrogen or a carboxyl protecting group;
converting the compound of Formula 8 or a salt thereof to a compound of Formula 9 or a salt thereof;
Figure imgf000041_0003
Formula 9
wherein R can be the same as defined above; c) converting the compound of Formula 9 or a salt thereof to a compound of Formula 10 or a salt thereof;
Figure imgf000041_0004
Formula 10 wherein R can be the same as defined above,
converting the compound of Formula 10 or a salt thereof to a compound of Formula 11 or a salt thereof;
Figure imgf000042_0001
Formula 11
wherein R can be the same as defined above; e) treating the compound of Formula 11 or its salt thereof with a compound of Formula 13
Figure imgf000042_0002
Formula 13
to provide a compound of Formula 12 or its salt thereof;
Figure imgf000042_0003
Formula 12
wherein R can be the same as defined above; and f) converting the compound of Formula 12 or its salt thereof to silodosin or a salt thereof.
Figure imgf000042_0004
Formula I Step a) of providing a compound of Formula 8 or a salt thereof includes hydrolysis a compound of Formula 6 or a salt thereof;
Figure imgf000043_0001
Formula 6
wherein R can be independently selected from hydrogen or a carboxyl protecting group.
Hydrolysis of a compound of Formula 6 or a salt thereof can be performed in the presence of an acid optionally in a solvent at a temperature of from about 35°C to about reflux temperature under stirring for a time period sufficient to complete the reaction.
The acid can be selected from the group consisting of organic acid, inorganic acid, or a mixture thereof. Preferred organic acid can be acetic acid, trifluoroacetic acid, difluoroacetic acid, oxalic acid, formic acid, or a mixture thereof. Preferred inorganic acid can be hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, or a mixture thereof.
The term "solvent" includes any solvent or solvent mixture, including, for example, water, esters, alkanols, halogenated hydrocarbons, ketones, ethers, polar aprotic solvents, or mixtures thereof.
The esters may include one or more of ethyl acetate, n-propyl acetate, isopropyl acetate, and n-butyl acetate. Examples of alkanols include those primary, secondary and tertiary alcohols having from one to six carbon atoms. Suitable alkanol solvents include methanol, ethanol, n-propanol, isopropanol and butanol. Examples of halogenated hydrocarbons include dichloromethane, chloroform, and 1 ,2-dichloroethane. Examples of ketones include acetone, methyl ethyl ketone, and the like. Examples of ethers include diethyl ether, tetrahydrofuran, and the like. A suitable polar aprotic solvent includes one or more of N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulphoxide, acetonitrile and N-methylpyrrolidone.
After the completion of the reaction, the compound of Formula 8 can be isolated by the common isolation techniques known in the art or can be carried to next step of the process without isolation. Step b) of converting compound of Formula 8 or a salt thereof to compound of Formula 9 or a salt thereof includes oxidation of compound of Formula 8 or a salt thereof with oxidizing agent in one or more of solvent in presence of one or more of base at a temperature of from about 20°C to about 80°C for a time period sufficient to complete the reaction.
The oxidizing agent can be selected from hydrogen peroxide or a mixture of urea and hydrogen peroxide.
The base may include one or more of organic or inorganic bases selected from the group consisting of alkali metal and alkaline earth metal carbonates or bicarbonates or hydroxides, for example, potassium bicarbonate, sodium bicarbonate, potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, calcium hydroxide, and the like; primary, secondary, and tertiary amines, such as pyridine, piperidine, triethylamine, diisopropylethylamine, N- methylmorpholine, and the like; ammonia and ammonium salts.
The term "solvent" includes any solvent or solvent mixture, including, for example, water, esters, alkanols, halogenated hydrocarbons, ketones, ethers, polar aprotic solvents, or mixtures thereof.
The esters may include one or more of ethyl acetate, ^-propyl acetate, isopropyl acetate, and n-butyl acetate. Examples of alkanols include those primary, secondary and tertiary alcohols having from one to six carbon atoms. Suitable alkanol solvents include methanol, ethanol, -propanol, isopropanol and butanol. Examples of halogenated hydrocarbons include dichloromethane, chloroform, and 1,2-dichloroethane. Examples of ketones include acetone, methyl ethyl ketone, and the like. Examples of ethers include diethyl ether, tetrahydrofuran, and the like. A suitable polar aprotic solvent includes one or more of N,N-dimethylformamide, N, N-dimethylacetamide, dimethylsulphoxide, acetonitrile and vV-methylpyrrolidone.
After the completion of the reaction, the compound of Formula 9 can be isolated by a common isolation technique known in the art or can be carried to next step of the process without isoaltion. Step c) of converting a compound of Formula 9 or a salt thereof to compound of Formula 10 or a salt thereof includes treating a compound of Formula 9 or a salt thereof with R-(+)-a-methylbenzylamine.
Treating a compound of Formula 9 or a salt thereof with R-(+)-a- methylbenzylamine may be performed in the presence of a hydrogen source and a catalyst or a reducing agent in one or more solvents at a temperature of from about 35°C to about 70°C for a time period sufficient to complete the reaction.
The catalyst may be selected from transition metal compounds. Examples of transition metal compounds include nickel compounds such as Raney nickel, palladium compounds, such as palladium/carbon and palladium hydroxide, platinum compounds, such as, platinum oxide and platinum/carbon, ruthenium compounds, such as, ruthenium oxide and rhodium compounds, such as rhodium/carbon. The reducing agents may be selected from boranes or metal hydrides, such as, sodium hydride, potassium hydride, sodium borohydride, potassium borohydride, lithium aluminium hydride or lithium borohydride, sodium cyanoborohydride.
Treating a compound of Formula 9 with R-(+)-a-methylbenzylamine may be performed at normal pressure, or at somewhat elevated pressure depending on the choice of catalyst. In general, it may be carried out at a hydrogen pressure in the range from about 1 kg to 5 kg.
The term "solvent" includes any solvent or solvent mixture, including, for example, water, esters, alkanols, halogenated hydrocarbons, ketones, ethers, polar aprotic solvents, or mixtures thereof.
The esters may include one or more of ethyl acetate, ^-propyl acetate, isopropyl acetate, and n-butyl acetate. Examples of alkanols include those primary, secondary and tertiary alcohols having from one to six carbon atoms. Suitable alkanol solvents include methanol, ethanol, «-propanol, isopropanol and butanol. Examples of halogenated hydrocarbons include dichloromethane, chloroform, and 1,2-dichloroethane. Examples of ketones include acetone, methyl ethyl ketone, and the like. Examples of ethers include diethyl ether, tetrahydrofuran, and the like. A suitable polar aprotic solvent includes one or more of N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulphoxide, acetonitrile and N-methylpyrrolidone.
After the completion of the reaction, the compound of Formula 10 can be isolated by a common isolation techniques known in the art or can be carried to next step of the process without isolation.
Step d) of converting compound of Formula 10 or a salt thereof to compound of Formula 1 1 or a salt thereof includes hydrogenolysis of a compound of Formula 10 or a salt thereof.
Hydrogenolysis of compound of Formula 10 or a salt thereof may be performed in the presence of a hydrogen source and a catalyst or a reducing agent in one or more solvents for a time period sufficient to complete the reaction.
The catalyst may be selected from transition metal compounds. Examples of transition metal compounds may include nickel compounds, such as Raney nickel, palladium compounds, such as, palladium/carbon and palladium hydroxide, platinum compounds, such as, platinum oxide and platinum/carbon, ruthenium compounds, such as ruthenium oxide and rhodium compounds, such as rhodium/carbon. The reducing agents may be selected from boranes or metal hydrides, such as, sodium hydride, potassium hydride, sodium borohydride, potassium borohydride, lithium aluminium hydride or lithium borohydride, sodium cyanoborohydride. Hydrogenolysis of compound of Formula 10 or a salt thereof may be performed at normal pressure, or at somewhat elevated pressure depending on the choice of catalyst. In general, it may be carried out at a hydrogen pressure in the range of from about 1 kg to 5 kg.
The term "solvent" includes any solvent or solvent mixture, including, for example, water, esters, alkanols, halogenated hydrocarbons, ketones, ethers, polar aprotic solvents, or mixtures thereof.
The esters may include one or more of ethyl acetate, H-propyl acetate, isopropyl acetate, and n-butyl acetate. Examples of alkanols include those primary, secondary and tertiary alcohols having from one to six carbon atoms. Suitable alkanol solvents include methanol, ethanol, H-propanol, isopropanol and butanol. Examples of halogenated hydrocarbons include dichloromethane, chloroform, and 1,2-dichloroethane. Examples of ketones include acetone, methyl ethyl ketone, and the like. Examples of ethers include diethyl ether, tetrahydrofuran, and the like. A suitable polar aprotic solvent includes one or more of N.N-dimethylformamide, N,JV-dimethylacetamide, dimethylsulphoxide, acetonitrile and N-methylpyrrolidone.
After the completion of the reaction, the compound of Formula 11 can be isolated by the common isolation techniques known in the art or can be carried to next step of the process without isolation.
Step e) of treating a compound of Formula 11 or its salt thereof with a compound of Formula 13 may be performed in one or more solvents in presence of a base at a temperature of from about 40°C to reflux temperature for a time period sufficient to complete the reaction.
The base may include one or more of organic or inorganic bases selected from the group consisting of alkali metal and alkaline earth metal carbonates or bicarbonates or hydroxides, for example, potassium bicarbonate, sodium bicarbonate, potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, calcium hydroxide, and the like; primary, secondary, and tertiary amines, such as, pyridine, piperidine, triethylamine, diisopropylethylamine, N- methylmorpholine and the like; ammonia and ammonium salts.
The term "solvent" includes any solvent or solvent mixture, including, for example, water, esters, alkanols, halogenated hydrocarbons, ketones, ethers, polar aprotic solvents, or mixtures thereof.
The esters may include one or more of ethyl acetate, «-propyl acetate, isopropyl acetate, and n-butyl acetate. Examples of alkanol include those primary, secondary and tertiary alcohols having from one to six carbon atoms. Suitable alkanol solvents include methanol, ethanol, «-propanol, isopropanol butanol and t-butanol. Examples of halogenated hydrocarbons include dichloromethane, chloroform, and 1,2-dichloroethane. Examples of ketones include acetone, methyl ethyl ketone, and the like. Examples of ethers include diethyl ether, tetrahydrofuran, and the like. A suitable polar aprotic solvent includes one or more of N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulphoxide, acetonitrile and N-methylpyrrolidone.
After the completion of the reaction, the compound of Formula 12 can be isolated by a common isolation techniques known in the art or can be carried to next step of the process without isolation.
Step f) of converting a compound of Formula 12 or a salt thereof to silodosin or a salt thereof includes treating a compound of Formulal2 or a salt thereof with a reducing agent in one or more solvent.
The reducing agents may be selected from boranes or metal hydrides, such as sodium hydride, potassium hydride, sodium borohydride, potassium borohydride, lithium aluminium hydride or lithium borohydride, sodium cyanoborohydride.
The term "solvent" includes any solvent or solvent mixture, including, for example, water, esters, alkanols, halogenated hydrocarbons, ketones, ethers, polar aprotic solvents, or mixtures thereof. The esters may include one or more of ethyl acetate, w-propyl acetate, isopropyl acetate, and n-butyl acetate. Examples of alkanols include those primary, secondary and tertiary alcohols having from one to six carbon atoms. Suitable alkanol solvents include methanol, ethanol, w-propanol, isopropanol and butanol. Examples of halogenated hydrocarbons include dichloromethane, chloroform, and 1 ,2-dichloroethane. Examples of ketones include acetone, methyl ethyl ketone, and the like. Examples of ethers include diethyl ether, tetrahydrofuran, and the like. A suitable polar aprotic solvent includes one or more of N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulphoxide, acetonitrile and N-methylpyrrolidone.
Treating a compound of Formula 12 with a reducing agent can be performed preferably at a temperature of from about 0°C to about 50°C for a time period sufficient to complete the reaction, preferably for from about 10 minutes to 12 hours.
After the completion of the reaction, silodosin can be isolated by a common isolation technique, such as, cooling, extraction, adjusting the pH, one or more of washing, crystallization, precipitation, filtration, filtration under vacuum, decantation and centrifugation, or a combination thereof. The isolated silodosin may be further purified by salt formation, crystallization or chromatographic methods, or a combination thereof.
While the present invention has been described in terms of its specific
embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
EXAMPLES
Example 1 : Preparation of Benzyl 3-Chloropropanoate
Benzyl alcohol (50.00 g) and pyridine were added to (1.5 ml) toluene (200 ml) under a nitrogen atmosphere at 25°C to 32°C and the reaction mixture was stirred for 5 minutes. 3-Chloropropionyl chloride (58.8 g) was added to the reaction mixture and stirred at 25°C to 32°C for 4 hours. 3-Chloropropionyl chloride (6.0 g) was added again and stirred further at 25°C to 32°C for 1 hour. The reaction mixture was washed with an aqueous solution of sodium bicarbonate (2.00 g in 200 ml). The organic layer was separated, dried with sodium sulfate and distilled off under vacuum at 70°C to obtain the titled compound.
Yield: 81.20 g
H'NM (in DMSO-d6:400 MHz):2.88-2.91(t, 2H); 3.80-3.84(t, 2H); 5.15(s, 2H); 7.32- 7.40(m,5H).
Example 2: Preparation of Benzyl 3-(2 -Dihvdro-l ¾-Indol-l-Yl Propanoate
Triethylamine (25 ml) and 2,3-dihydro-lH-indole (18 g) were added to N,N- dimethylformamide (116.6 ml) under nitrogen. The solution was stirred for 5 minutes and benzyl 3-chloropropanoate (59.8 g) was added to it drop wise over a period of 15 minutes at 25°C to 32°C. The reaction mixture was then stirred at 80°C to 85°C for 15 hours. The reaction mass was cooled to 25°C to 32°C and water (400 ml) was added to it. The reaction mixture was extracted with toluene (400 ml x 3) and the toluene layer was washed with sodium bicarbonate followed by brine solution. The toluene layer was dried with sodium sulfate and distilled off under vacuum at 60°C to obtain the titled compound (50 g). This product was purified by column chromatography on silica gel (60-120 mesh) using ethyl acetate :hexane mixture as eluent to obtain benzyl 3-(2,3-dihydro-lH-indol-l- yl)propanoate. Yield: 31 g
H1NMR(400MHz,CDCl3):2.63-2.67(t,2H);2.91-2.95 (t,2H);3.30-3.35(t,2H);3.41-3.45 (t,2H);5.08-5.16(s,2H);6.43-6.44 (d,lH); 6.63-6.67 (m,lH);7.04 (m,2H), 7.31-7.38(m,5H)
Example 3: Preparation of Benzyl 3-(5-Formyl-23-Dihvdro-l z-Indol-l-Yl Propanoate Phosphorous oxychloride (0.33 ml) was added drop wise to cold (0°C to 5°C) N,N- dimethylformamide (1.16 ml) under a nitrogen atmosphere and stirred for 15 minutes at 0°C. The reaction mixture was heated to 50°C and stirred for 1 hour. The reaction mixture was cooled to 0°C and a solution of benzyl 3-(2,3-dihydro-lH-indol-l- yl)propanoate (500 mg) dissolved in N,N-dimethylformamide (0.23 ml) was added drop wise at 0°C to 5°C and stirred for 15 minutes at 0°C. The reaction mixture was then further stirred for 2 hours at 25°C to 32°C and cooled to 10°C. The reaction mixture was poured into chilled water (20 ml) and stirred at 25°C to 32°C for 1 hour. The reaction mixture was then extracted with ethyl acetate (20 ml x 2). The ethyl acetate layer was washed with an aqueous sodium bicarbonate solution followed by brine. Ethyl acetate was distilled off under vacuum at 60°C to obtain titled compound.
Yield: 250 mg
H1NMR(400MHz,CDCl3): 2.65-2.68(t,2H), 2.97-3.02(t,2H), 3.54-3.59(m,4H), 5.1(s,2H), 6.42-6.44(d,lH), 7.20-7.36(m,5H), 7.53-7.55(m,2H), 9.67(s,lH)
Example 4: Benzyl 3-(5-Formyl-2,3-Dihvdro-l z-Indol-l-Yl)Propanoate
Phosphorous oxychloride (22 ml) was added drop wise to cold (0°C to 5°C) N,N- dimethylformamide (70.28 ml) under a nitrogen atmosphere and stirred for 15 minutes at 0°C. The reaction mixture was heated to 50°C and stirred for 1 hour. The reaction mixture was cooled to 0°C and added drop wise a solution of benzyl 3-(2,3-dihydro-lH- indol-l-yl)propanoate (30 g) dissolved in N,N-dimethylformamide (13.79 ml) for 45 minutes at 0°C to 5°C and stirred for 15 minutes at 0°C. The reaction mixture was then further stirred for 2 hours at 25°C to 32°C and cooled to 10°C. The reaction mixture was poured into chilled water (500 ml) and stirred at 25°C to 32°C for 1 hour. Sodium bicarbonate (10 g) was added to the reaction mixture to obtain pH 7. The reaction mixture was then extracted with ethyl acetate (500 ml x 2) and the ethyl acetate layer was washed with aqueous sodium bicarbonate solution followed by brine. Ethyl acetate was distilled off under vacuum at 60°C to obtain the titled compound.
Yield: 30 g
Example 5: Preparation of Benzyl 3-{5-[(lg)-2-Nitroprop-l-En-l-Y11-2,3-Dihydro-l ¾- Indol-1 -YllPropanoate
Ammonium acetate (17 g) and benzyl-3-(5-formyl-2,3-dihydro-lH-indol-l- yl)propanoate (30 g) was added to nitroethane (45 ml) under a nitrogen atmosphere. The reaction mixture was heated to 50°C and stirred for 5 hours. Unreacted nitroethane was distilled off under a vacuum at 50°C. The residue was dissolved in ethyl acetate (400 ml) and washed with aqueous sodium bicarbonate solution followed by brine. Ethyl acetate was distilled off under vacuum at 60°C to obtain liquid compound (30 g) which was purified by column chromatography on silica gel (60-120 mesh) by elution with ethyl acetate :hexane mixture to obtain the titled compound.
Yield: 12 g H1NMR(400MHz,CDCl3):2.49(s,3H), 2.65-2.87(t,2H), 2.98-3.02(t,2H), 3.49-3.55(m,4H), 5.12(s,2H), 6.46-6.48(d,lH), 7.20-7.38(m-7H), 8.07(s,lH)
(Mass: 282).
Example 6: Preparation of Benzyl 3-[5-(2-Nitropropyl)-2,3-Dihvdro-l ¾-Indol-l- YllPropanoate
A mixture of tetrahydrofuran (36 ml) and ethanol (12 ml) was cooled to 0°C under a nitrogen atmosphere. Sodium borohydride (4.1 g) was added lot wise to this cold solvent mixture over a period of 30 minutes and stirred further for 5 minutes. A solution of benzyl 3-{5-[(lE)-2-nitroprop-l-en-l-yl]-2,3-dihydro-lH-indol-l-yl}propanoate (12 g) dissolved in tetrahydrofuran (36 ml) was added drop wise to this reaction mixture at 0°C and stirred for 10 minutes. After stirring the reaction mixture at 25°C to 32°C for 2 hours, chilled water (100 ml) was added and acidified with acetic acid till a pH 4.1 was reached. The reaction mixture was stirred further for 1 hour at 25°C to 32°C. The reaction mixture was extracted with ethyl acetate (200 ml x 2) and washed with brine. The ethyl acetate layer was dried with sodium sulfate and distilled off under a vacuum at 60°C to obtain a light brown liquid (12 g). The liquid was purified by column chromatography on silica gel (60-120 mesh) by elution with ethyl acetate:hexane mixture to obtain the title compound.
Yield: 8.4 g
H1NMR(400MHz,CDCl3): 1.50-1.52(d,3H);2.62-2.65 (t,2H);2.85-2.90 (m,3H), 3.16-3.21 (m,lH);3.30-3.34 (t,2H);3.40-3.42 (t,2H);4.65-4.73(m,lH), 5.12(s,2H), 6.40-6.42(d,lH), 6.82-6.84 (m,2H);7.28-7.35(m,5H).
Example 7 : Preparation of Benzyl 3 - r7-Formyl-5-(2-Nitropropyl1 -2,3 -Dihydro- 1 /z-Indol- l-Yl Propanoate
Phosphorous oxychloride (5.46 ml) was added dropwise to cooled N,N- dimethylformamide (19.1 ml) at 0°C under a nitrogen atmosphere and stirred for 5 minutes. The reaction mixture was heated to 50°C to 55°C and stirred for 1 hour. A solution of benzyl-3-[5-(2-nitropropyl)-2,3-dihydro-lH-indol-l-yl]propanoate (8 g) dissolved in N,N-dimethylformamide (3.8 ml) was added dropwise to the reaction mixture at 0°C and stirred for 15 minutes. The reaction mixture was stirred further at 25°C to 32°C for 3.5 hours and cooled to 0°C. Again, a mixture of phosphorous oxychloride in N,N-dimethylformamide (3.25 ml in 10 ml) was added to the reaction mixture at 0°C and stirred for 10 minutes. Further, the reaction mixture was stirred for 14 hours at 25°C to 32°C. Chilled water (200 ml) was added slowly to it and stirred for 1 hour at 25°C to 32°C. The reaction mixture was extracted with ethyl acetate (200 ml x 2). The organic layer was washed with sodium bicarbonate followed by brine. The ethyl acetate layer was then dried with sodium sulfate and distilled off under vacuum at 60°C to obtain a yellow colored liquid (8.7 g). The liquid was purified by column chromatography on silica gel (60-120 mesh) by elution with ethyl acetate:hexane mixture to obtain the titled compound.
Yield: 7.3 g H1NMR(400MHz,CDCl3): 1.53-1.55(d,3H), 2.69-2.73(t,2H), 2.88-2.99(m,3H), 3.15- 3.20(m,lH), 3.57-3.62(t,2H), 3.78-3.81(t,2H), 4.67-4.75(m,lH), 5.12(s,2H), 6.92(s,lH), 7.21(s,lH), 7.30-7.40(m,5H), 9.88(s,lH) Example 8: Preparation Of Benzyl 3-r7-Cvano-5-(2-NitropropylV2 -Dihydro-l/¾-Indol- 1-YHPropanoate
Benzyl-3-[7-formyl-5-(2-nitropropyl)-2,3-dihydro-lH-indol-l-yl]propanoate (100 mg) and hydroxylamine hydrochloride (51.9 mg) and pyridine (0.05 ml) were added to tetrahydrofuran (0.15 ml) under a nitrogen atmosphere at 25°C to 32°C and stirred for 10 minutes. The reaction mixture was stirred at 50°C to 60°C for 1 hour. Acetic anhydride (0.1 ml) was added into the reaction mixture and stirred for 3 hours at 50°C to 60°C. Again, acetic anhydride (0.1 ml) was added and stirred further for 3 hours. Reaction mixture was cooled to 25°C to 32°C and water (2 ml) was added to it. The reaction mixture was extracted with toluene (2 ml x 3). The toluene layer was washed with aqueous sodium bicarbonate solution followed by brine. The organic layer was dried with sodium sulfate and distilled off under vacuum at 60°C to obtain a colored liquid (90 mg). The liquid was purified by column chromatography on silica gel (60-120 mesh) by elution with dichloromethane:hexane mixture to obtain titled compound.
Yield: 50 mg
H1NMR(400MHz,CDCl3): 1.53-1.54(d,3H), 2.74-2.77(t,2H), 2.82-2.9 l(m,3H), 3.08- 3.14(ml,H), 3.54-3.59(t,2H), 3.88-3.92(t,2H), 4.62-4.71(m,lH), 5.15(s,2H), 6.88(s,lH), 6.92(s,lH), 7.31-7.35(m,5H)
Example 9: Preparation of Benzyl 3-|"7-Cvano-(5-(2-Nitropropyl)-2,3-Dihvdro-l/;-Indol- l-YDPropanoate
Hydroxylamine hydrochloride (19.3 mg), triethylamine (27.2 mg) and benzyl 3-[7- formyl-5-(2-nitropropyl)-2,3-dihydro-lH-indol-l-yl]propanoate (100 mg) were added to acetonitrile (5 ml) at 0°C, under a nitrogen atmosphere and stirred for 30 minutes at 0°C to 5°C. Phthalic anhydride (40 mg) was added to the reaction mixture at 0°C in nitrogen atmosphere and refluxed for 26 hours. The reaction mixture was cooled to 25°C to 32°C and distilled off unreacted solvent under vacuum. Dichloromethane (10 ml) was added to the reaction mixture and filtered through a cotton plug to remove the excess phthalic anhydride. The dichloromethane layer was washed with aqueous ammonia (5%). The organic layer was separated and dried with sodium sulfate and distilled off under vacuum at 45 °C to obtain a light colored liquid (90 mg). The liquid was purified by column chromatography on silica gel (60-120 mesh) by elution with dichloromethane:hexane mixture to obtain the titled compound.
Yield: 40 mg
H1NMR(400MHz,CDCl3): 1.52-1.54(d,3H), 2.74-2.77(t,2H), 2.82-2.91(m,3H), 3.08- 3.13(m,lH), 3.54-3.58(t,2H), 3.88-3.91(t,2H), 4.62-4.71(m,lH), 5.15(s,2H), 6.88(s,lH), 6.92(s,lH), 7.28-7.35(m,5H)
Analogously the methyl ester compound of Example 10 can be prepared by following the Examples 1 to 9. Alternatively, a transesterification of the benzyl group by the methyl group can be carried out at any stage with hydrochloric acid in methanol.
Example 10: Preparation Of Methyl 3-r7-Cvano-5-r2-NitropropylV2.3-Dihydro-l/z-Indol- 1-YllPropanoate
A solution of methyl 3-[7-formyl-5-(2-nitropropyl)-2,3-dihydro-lH-indol-l- yljpropanoate (10 g), and hydroxylamine hydrochloride (3.3 g) in acetonitrile were stirred at 70°C to 75°C for 2 hours. Acetonitrile was distilled off on rotavapour at 53 °C to obtain oxime (13.1 g) as sticky brown compound. A solution of this oxime (5 g) and [RuCl2(p- cymene)2]2 (0.05g) in acetonitrile (50 ml) was refluxed at 85°C for 20 hours and the TLC in dichloromethane (95%) + methanol (5%) showed completion of reaction. Acetonitrile was distilled off on rotavapour and the residue obtained was dissolved in dichloromethane (50 ml) and percolated the solution through silica gel (60-120 mesh). Dichloromethane was distilled off on rotavapour to obtain the titled compound as a dark brown oil.
Yield: 3.5 g
H1NMR(400MHz,CDCl3): 1.53-1.54(d,3H), 2.69-2.73(t,2H), 2.83-2.88(dd,lH), 2.93- 2.97(t,2H), 3.08-3.14(dd,lH), 3.60-3.65(t,2H), 3.70(s,3H), 3.87-3.90(t,2H), 4.63- 4.72(m,lH), 6.90(s,lH), 6.93 (s,lH) Example 11 : Preparation of Benzyl 3-[7-Cvano-(5--2-OxopropyO-23-Dihydro-l z-Indol- 1-YllPropanoate
Benzyl-3-[7-cyano-5-(2-nitropropyl)-2,3-dihydro-lH-indol-l-yl]propanoate (100 mg) was added to N.N-dimethylformamide (0.7 ml) at 25°C to 32°C under a nitrogen atmosphere followed by potassium carbonate (100 mg). Hydrogen peroxide (30% in H20, 0.07 ml) was added to the reaction mixture drop wise under nitrogen atmosphere and stirred at 50°C to 60°C for 4 hours. The reaction mixture was then cooled to 25°C to 32°C. Water (5 ml) was added into the reaction mixture at 25°C to 32°C. The aqueous phase was extracted with dichloromethane (10 ml x 3) and dichloromethane was then washed with aqueous sodium bicarbonate solution followed by brine. Dichloromethane layer was dried with sodium sulfate and distilled off under vacuum at 30°C to obtain a pale yellow liquid (90 mg). The liquid was purified by column chromatography on silica gel (60-120 mesh) by elution with ethylacetate:hexane mixture to obtain the titled compound.
Yield: 20 mg
H1NMR(400MHz,CDCl3): 2.17(d,3H), 2.74-2.78(t,2H), 2.89-2.93(t,3H), 3.53-3.59(m,3H), 3.89-3.92(t, 2H), 5.15(s,2H), 6.93(s,lH), 6.94(s,lH), 7.31-7.36(m,5H).
Example 12: Preparation of Methyl 3-|"7-Carbamoyl-5-(2-Nitropropyf)-2,3-Dihydro-l/¾- Indol- 1 -YllPropanoate A drop of sulfuric acid was added to methyl 3-[7-cyano-5-(2-nitropropyl)-2,3- dihydro-lH-indol-l-yl]propanoate (15 mg) dissolved in trifluoroacetic acid (0.5 ml) and the reaction was heated to 85°C for 8 hours. The reaction mixture was quenched with dilute ammonium hydroxide solution (10 ml) and was extracted with dichloromethane (3 ml x 2). The dichloromethane layer thus obtained was distilled off to obtain the titled compound.
Yield: 10 mg
H1NMR(400MHz,CDCl3): 1.53(d,3H), 2.58-2.61 (t,2H), 2.90-3.01 (t,3H), 3.14- 3.24(dd,lH), 3.43-3.51(m, 4H), 3.66(s,3H), 4.69-4.77(m,lH), 5.76(brs,lH), 6.88(brs,lH), 6.99 (s,lH), 7.29(s,lH) Example 13: Preparation of Methyl 3-[7-Carbamoyl-5-(2-Nitropropyl)-2,3-Dihydro-l z- Indol- 1 - YllPropanoate
Methyl 3-[7-cyano-5-(2-nitropropyl)-2,3-dihydro-lH-indol-l-yl]propanoate (85 g) was stirred in a mixture of trifluoroacetic acid (340 ml) and sulfuric acid (30.6 ml) for 4 hours at 70°C to 72°C. Sulfuric acid (8 ml) was added and the reaction was stirred further for 1 hour at 72°C. The reaction mixture was cooled to 25°C to 32°C. The reaction mixture was poured slowly into precooled (10°C) dilute ammonia solution (25% aq.
ammonia 500 ml + water 700 ml) by maintaining temperature below 10°C. The solid thus precipitated was filtered and washed with water. The solid was dissolved in ethyl acetate (500 ml) and the remaining insoluble solid was filtered off. The filtered off solid was dissolved in dichloromethane. The ethyl acetate and dichloromethane layers were washed with water separately and distilled off to obtain the titled compound with 48 g and 18 g yields, respectively.
H1NMR(400MHz,CDCl3): 1.528-1.54(d,3H), 2.58-2.61 (t,2H), 2.91-3.01(t,3H), 3.18- 3.24(dd,lH), 3.41-3.49(m, 4H), 3.66(s,3H), 4.69-4.77(m,lH), 5.92(brs,lH), 6.88(brs,lH), 6.98 (s,lH), 7.29(s,lH)
Example 14: Preparation of Methyl 3-[7-Carbamoyl-5-(2-OxopropyO-2,3-Dihydro-l/z- Indol- 1 - YHPropanoate
Methyl 3-[7-carbamoyl-5-(2-nitropropyl)-2,3-dihydro-lH-indol-l-yl]propanoate (15 g), urea-hydrogen peroxide (8.41g) and potassium carbonate (14.5 g) in
dimethylsulfoxide (150 ml) were stirred for 16 hours at 25°C to 32°C. Water (200 ml) and ethyl acetate (300 ml) were added to the reaction mixture and stirred for 15 minutes. The two layers separated and the aqueous phase was extracted again twice (300 ml x 2) with ethyl acetate. The combined ethyl acetate layers were washed with brine and the ethyl acetate layer was dried over sodium sulfate. The ethyl acetate layer was distilled off under vacuum at 60°C to obtain the titled compound.
Yield: 10.9 g
The compound obtained above was stirred in isopropanol for 15 minutes and filtered to obtain purified methyl 3-[7-carbamoyl-5-(2-oxopropyl)-2,3-dihydro-lH-indol- l-yl]propanoate.
Yield: 5 g
H1NMR(400MHz,CDCl3): 2.16(s,3H), 2.58-2.62(t,2H), 2.98-3.02(t,2H), 3.42-3.54(m,4H), 3.61(s,2H), 3.66(s,3H), 5.74(brs,lH), 6.9(brs,lH), 7.04 (s,lH), 7.31(s,lH) Example 15: Preparation of Methyl 3-(7-Carbamoyl-5-r(2rV2-ir(lr)-l- Phenylethyl1Amino}Propyll-2,3-Dihvdro-l z-Indol-l-Yl}Propanoate
A solution of methyl 3-[7-carbamoyl-5-(2-oxopropyl)-2,3-dihydro-lH-indol-l- yljpropanoate (0.5 g), R-(+)-a-methylbenzylamine (0.22 g), Molecular sieves 4A and Raney Nickel were hydrogenated on Parr shaker at 3.5 kg hydrogen pressure and 50°C for 21 hours. Molecular sieves 4A (1 g) were added to the reaction mixture and the reaction was continued further for 20 hours. 3 more drops of R-(+)a-methylbenzylamine were added and the reaction was continued further for 20 hours. The reaction mixture was filtered and the solvent was distilled off to obtain the titled compound.
Yield: 0.6 g
A portion of compound was purified by preparative TLC for analysis.
H1NMR(400MHz,CDCl3): 0.88-0.90(d,3H), 1.30-1.32(d,3H), 2.39-2.44(dd,lH), 2.56- 2.60(t,2H), 2.7(m, 1H), 2.77(m,lH), 2.94-2.99(t,2H), 3.37-3.41 (m,4H), 3.66(s, 3H), 3.95(m,lH), 5.61(brs,lH), 6.93 (s,lH),7.04(brs, lH),7.2-7.35(m, 7H)
Example 16: Preparation of Methyl 3-{7-Carbamoyl-5-IY2r)-2-(rar)-l- Phenylefhyl] Amino } Propyl] -2,3 -Dihydro- 1 ?-Indol- 1 - Yl } Propanoate
R-(+)-a-methylbenzylamine (10 g), acetic acid (2 g) and Raney-Nickel (40 g) were added to methyl 3-[7-carbamoyl-5-(2-oxopropyl)-2,3-dihydro-lH-indol-l-yl]propanoate (20 g) dissolved in methanol (200 ml). The reaction mixture was hydrogenated at 3.5 kg hydrogen pressure and 50°C for 22 hours. The reaction mixture was filtered through a hyflo. Methanol was distilled off under vacuum at 60°C. Unreacted R-(+)a- methylbenzylamine was removed at 85°C under vacuum to obtain the titled compound.
Yield: 20.9 g
lg of titled compound was purified by column chromatography for analysis.
H1NMR(400MHz,CDCl3): 0.88-0.94(d,3H), 1.30-1.32(d,3H), 2.40-2.44(dd,lH), 2.56-
2.61(t,2H), 2.7-2.75(m, 1H), 2.77-2.81(dd,lH), 2.94-3.00(t,2H), 3.37-3.49(m,4H), 3.66(s, 3H), 3.95(m,lH), 5.65(brs,lH), 6.93 (s,lH),7.03(brs, lH),7.2-7.35(m, 7H) Example 17: Preparation of Methyl 3-(5- (2r)-2-Aminopropyll-7-Carbamoyl-2,3- Dihydro- 1 /z-Indol- 1 - Yl} Propanoate
Methyl 3-{7-carbamoyl-5-[(2R)-2-{[(lR)-l-phenylethyl]amino}propyl]-2,3- dihydro-lH-indol-l-yl}propanoate (2.5 g) was treated with 10% Pd-C (0.75 g) in methanol (25 ml) at H2 (3.5 kg) pressure for 16 hours at 50°C and was then filtered and methanol was distilled off to obtain titled compound.
Yield: 1.1 g
H!NMR(400MHz,CDCl3): 1.21-1.22(d,3H), 2.57-2.63(m,3H), 2.68-2.74(m,lH), 2.96- 3.00(t,2H), 3.25(m,lH), 3.37-3.48(m, 4H), 3.66(s,3H), 6.06(brs,lH), 7.01
(S,1H),7.28(S,1H), 7.35(brs, 1H),7.36(S,1H)
Example 18: Preparation of Methyl 3-{7-Carbamoyl- 5-ϊ(2ή-2-(ί2-\2-(222- Trifluoroethoxy Phenoxy1 Ethyl } Amino) Propyl] -2,3 -Dihydro- 1 /z-Indol- 1 - Yl I Propanoate
A mixture of methyl 3-{5-[(2i?)-2-aminopropyl]-7-carbamoyl-2,3-dihydro-lH- indol-l-yl} propanoate hydrochloride salt (1.2 g), 2-[2-(2,2,2- trifiuoroethoxy)phenoxy] ethyl methanesulfonate (0.6 g) and sodium carbonate (lg) was refluxed for 4 hours in t-Butanol. Triethyl amine was added (0.7ml) to the reaction mixture and was refluxed for 5 hours further followed by addition of 2-[2-(2,2,2- trifluoroethoxy)phenoxy] ethyl methanesulfonate in lots (0.3 g). After 16 hours of overnight refluxing, 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl methanesulfonate (0.25 g) was added and further refluxed for 5 hours. t-Butanol was distilled off on rotavapour and ethyl acetate (20 ml) and water (20 ml) were added to the residue. The reaction mixture was acidified to pH 3 with concentrated hydrochloric acid. The aqueous layer was washed twice with ethyl acetate (20 ml x 2). The aqueous layer was basified with ammonium hydroxide and the free base was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over sodium sulfate and distilled off under vacuum at 55°C to obtain the titled compound.
Yield: 450 mg
This was purified by column chromatography on silica gel column for analysis. H'NMR (400MHZ,CDC13): 1.059-1.07(d,3H), 2.49-2.55(dd, 1H), 2.57-2.6 l(t,2H), 2.71(dd,lH), 3.37-3.47(m,4H), 3.66(s,3H), 4.1(m,2H), 4.11-4.33(q, 2H), 5.6-5.7(brs,lH), 6.89-7.05(m, 7H) 7.34(s, 1H)
Example 19: Preparation of Silodosin
Sodium borohydride (2.5 g) was added to methyl 3-{7-carbamoyl-5-[(2R)-2-({2-
[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}amino)propyl]-2,3-dihydro-lH-indol-l- yl}propanoate (6.7 g) dissolved in tetrahydrofuran (40 ml) and the reaction mixture were heated to 50°C to 55°C and ethanol (5 ml) was added dropwise at 50°C to 55°C over a period of 5 hours. The reaction mixture was stirred for 1 hour further at 50°C to 55°C and was cooled to 25°C to 32°C. Water (70 ml) was added to the reaction mixture and was extracted with ethyl acetate twice (20 ml x 2). Ethyl acetate was distilled off on rotavapour and the residue obtained was dissolved in methanol (25 ml). Oxalic acid (3.5 g) was added to methanol solution and stirred until dissolved. Methanol was distilled off and the residue obtained was dissolved in water (50 ml) and stirred at 50°C for 10 minutes and the aqueous phase was extracted with ethyl acetate twice (20 ml x 2). The aqueous phase was basified with ammonium hydroxide and extracted with ethyl acetate twice (20 ml x 2). The ethyl acetate layer was washed with water thrice (20 ml x 3). Ethyl acetate was distilled off on rotavapour to obtain the colourless, oily and viscous titled compound.
Yield: 1.6 g
The compound obtained above was dissolved in ethyl acetate (5 ml) by heating and hexane was added slowly to obtain a turbid solution and left to stir for 17 hours. The slurry thus obtained was filtered, washed with ethyl acetate (6 ml) - hexane (4 ml) mixture and the compound were dried in vacuum at 50°C for 4 hours to obtain the titled compound as white solid. Yield: 0.65 g
H1NMR(400MHz,CDCl3): 1.06-1.07(d,3H), 1.79(m,2H), 2.04-2.54(dd, 1H), 2.66(dd,2H), 2.92-3.06(m,5H), 3.16-3.19(t, 3H), 3.37-3.42(t, 2H), 3.72-3.25(t,2H), 4.06-4.12(m, 2H), 4.40(q, 2H), 6.17(brs, 1H), 6.73(brs,lH), 6.88-7.05(m 5H), 7.15(s,lH)

Claims

We claim:
1. A compound of Formula 1 or a salt thereof;
Figure imgf000060_0001
Formula 1
wherein R is a benzyl group.
2. A compound of Formula 2 or a salt thereof;
Figure imgf000060_0002
Formula 2
wherein R is selected from hydrogen or a carboxyl protecting group. 3. A compound of Formula 3 or a salt thereof;
Figure imgf000060_0003
Formula 3
wherein R is selected from hydrogen or a carboxyl protecting group. 4. A compound of Formula 4 or a salt thereof;
Figure imgf000060_0004
Formula 4
wherein R is selected from hydrogen or a carboxyl protecting group.
Figure imgf000061_0001
Formula 5
wherein R is selected from hydrogen or a carboxyl protecting group.
6. A compound of Formula 6 or a salt thereof;
Figure imgf000061_0002
Formula 6
wherein R is selected from hydrogen or a carboxyl protecting group.
7. A compound of Formula 7 or a salt thereof;
Figure imgf000061_0003
Formula 7
wherein R is selected from hydrogen or a carboxyl protecting group.
8. A compound of Formula 8 or a salt thereof;
Figure imgf000061_0004
Formula 8
wherein R is independently selected from hydrogen or a carboxyl protecting group. compound of Formula 9 or a salt thereof;
Figure imgf000062_0001
Formula 9
wherein R is independently selected from hydrogen or a carboxyl protecting group. 10. A compound of Formula 10 or a salt thereof;
Figure imgf000062_0002
Formula 10
wherein R is independently selected from hydrogen or a carboxyl protecting group. 11. A compound of Formula 11 or a salt thereof;
Figure imgf000062_0003
Formula 11
wherein R is independently selected from hydrogen or a carboxyl protecting group. 12. A compound of Formula 12 or a salt thereof;
Figure imgf000062_0004
Formula 12
wherein R is independently selected from hydrogen or a carboxyl protecting group.
13. A process for the preparation of a compound of Formula 1 or a salt thereof;
Figure imgf000063_0001
Formula 1
wherein R is selected from hydrogen or a carboxyl protecting group, the process comprising: treating a compound of the Formula la or a salt thereof;
Figure imgf000063_0002
Formula la
wherein R can be selected from hydrogen or a carboxyl protecting group, with 2,3- dihydro-lH-indole to obtain compound of Formula 1 or a salt thereof.
14. The process according to claim 13, wherein treating a compound of Formula la with 2,3-dihydro-lH-indole is performed in the presence of one or more of organic or inorganic bases.
15. The process according to claim 13 , wherein treating a compound of Formula 1 a with 2,3-dihydro-lH-indole is performed in the presence of one or more solvents.
16. The process according to claim 15, wherein the one or more solvents comprise water, esters, alkanols, halogenated hydrocarbons, ketones, ethers, polar aprotic solvents, or mixtures thereof.
17. The process according to claim 13, wherein treating a compound of Formula la with 2,3-dihydro-lH-indole is performed at a temperature of from 20°C to reflux temperature.
18. Use of the compound of Formula 1 for the preparation of silodosin.
19. A process for the preparation of a compound of Formula 2, or a salt thereof;
Figure imgf000064_0001
Formula 2
wherein R can be selected from hydrogen or a carboxyl protecting group, the process comprising: treating a compound of Formula 1 or a salt thereof;
Figure imgf000064_0002
wherein R is selected from hydrogen or a carboxyl protecting group, with a formylating agent to obtain compound of Formula 2, or a salt thereof.
20. The process according to claim 19, wherein the formylating agent is selected from the group consisting of N.N-dimethylformamide, triformamide,
tri(diformylamino)methane, tris(dichloromethyl)amine or N,N,N,N-tetraformylhydrazine or a mixture thereof in the presence of a Lewis acid.
21. The process according to claim 20, wherein the Lewis acid is selected from the group consisting of phosphorous oxychloride, aluminum trichloride or boron trichloride.
22. The process according to claim 19, wherein treating a compound of Formula 1 with a formylating agent is performed in one or more solvents.
23. The process according to claim 22, wherein the one or more solvents comprise water, esters, alkanols, halogenated hydrocarbons, ketones, ethers, polar aprotic solvents, or mixtures thereof.
24. The process according to claim 19, wherein treating a compound of the Formula 1 with formylating agent is performed at a temperature of from 0°C to 50°C.
25. Use of the compound of Formula 2 for the preparation of silodosin.
26. A process for the preparation of a compound of Formula 3 , or a salt thereof;
Figure imgf000065_0001
Formula 3
wherein R is selected from hydrogen or a carboxyl protecting group, the process comprising: treating a compound of Formula 2 or a salt thereof;
Figure imgf000065_0002
wherein R is selected from hydrogen or a carboxyl protecting group, with nitroethane to obtain compound of Formula 3, or a salt thereof.
27. The process according to claim 26, wherein treating a compound of Formula 2 with nitroethane is performed optionally in the presence of one or more solvents.
28. The process according to claim 27, wherein the one or more solvents comprise water, esters, alkanols, halogenated hydrocarbons, ketones, ethers, polar aprotic solvents, or mixtures thereof.
29. The process according to claim 26, wherein treating a compound of Formula 2 with nitroethane is performed in the presence of base.
30. The process according to claim 29, wherein the base comprises one or more of organic or inorganic bases.
31. The process according to claim 26, wherein treating a compound of Formula 2 with nitroethane is performed at a temperature of from 10°C to 90°C.
32. Use of the compound of Formula 3 for the preparation of silodosin.
33. A process for the preparation of a compound of Formula 4, or a salt thereof;
Figure imgf000066_0001
Formula 4
wherein R is selected from hydrogen or a carboxyl protecting group, the process comprising: treating a compound of Formula 3, or a salt thereof;
Figure imgf000066_0002
Formula 3
wherein R is selected from hydrogen or a carboxyl protecting group, with a reducing agent to obtain compound of Formula 4, or a salt thereof.
34. The process according to claim 33, wherein the reducing agent is selected from the group consisting of sodium hydride, potassium hydride, sodium borohydride, potassium borohydride, lithium aluminium hydride or lithium borohydride, sodium
cyanoborohydride or sodium triacetoxy borohydride, or a mixture thereof.
35. The process according to claim 33, wherein treating a compound of Formula 3 with a reducing agent is performed in one or more solvents.
36. The process according to claim 35, wherein the one or more solvents comprise water, esters, alkanols, halogenated hydrocarbons, ketones, ethers, polar aprotic solvents, or mixtures thereof.
37. The process according to claim 33, wherein treating a compound of Formula 3 with a reducing agent is performed at a temperature of from about 0°C to about 50°C.
38. Use of the compound of Formula 4 for the preparation of silodosin.
39. A process for the preparation of a compound of Formula 5, or a salt thereof;
Figure imgf000067_0001
Formula 5
wherein R is selected from hydrogen or a carboxyl protecting group, the process comprising: treating a compound of Formula 4 or a salt thereof;
Figure imgf000067_0002
Formula 4
wherein R is selected from hydrogen or a carboxyl protecting group, with a formylating agent to obtain compound of Formula 5, or a salt thereof.
40. The process according to claim 39, wherein the formylating agent is selected from the group consisting of N,N-dimethylformamide, triformamide,
tri(diformylamino)methane, tris(dichloromethyl)amine or N, NJV, N-tetraformylhydrazine or mixtures thereof in the presence of a Lewis acid.
41. The process according to claim 40, wherein the Lewis acid is selected from the group consisting of phosphorous oxychloride, aluminum trichloride or boron trichloride. 42. The process according to claim 39, wherein treating a compound of Formula 4 with formylating agent is performed in one or more solvents.
43. The process according to claim 42, wherein the one or more solvents comprise water, esters, alkanols, halogenated hydrocarbons, ketones, ethers, polar aprotic solvents, or mixtures thereof.
44. The process according to claim 39, wherein treating a compound of Formula 4 with a formylating agent is performed at a temperature of from 0°C to 50°C.
45. Use of the compound of Formula 5 for the preparation of silodosin.
46. A process for the preparation of a compound of Formula 6 or a salt thereof;
Figure imgf000068_0001
Formula 6
wherein R is selected from hydrogen or a carboxyl protecting group, the process comprising: treating a compound of Formula 5, or a salt thereof;
Figure imgf000068_0002
Formula 5
wherein R is selected from hydrogen or a carboxyl protecting group, with hydroxylamine or its salt to obtain compound of Formula 6, or a salt thereof.
47. The process according to claim 46, wherein treating a compound of Formula 5, or a salt thereof with hydroxylamine or its salt is performed in the presence of a catalyst or a dehydrating agent in one or more solvents, optionally in the presence of a base.
48. The process according to claim 47, wherein the catalyst or the dehydrating agent is selected from the group consisting of acetic anhydride, phthalic anhydride, P205, TiCl4, oxalyl chloride, KF/A1203; NH3/H202, 12 in NH3, Na2S04; or a mixture thereof.
49. The process according to claim 47, wherein the catalyst or the dehydrating agent is selected from the group consisting of ruthenium or rhodium metal complexes, such as, [RuCl2(^-cymene)]2, [RuCl2(benzene)]2, RuH2(PPh3)4, RuCl2(PPh3)3, Ru3(CO)12, or [Rh(OAc)2]2. 50. The process according to claim 47, wherein the one or more solvents comprise water, esters, alkanols, halogenated hydrocarbons, ketones, ethers, polar aprotic solvents, or mixtures thereof.
51. The process according to claim 47, wherein the base comprises one or more of organic or inorganic bases.
52. A process according to claim 46, wherein treating a compound of Formula 5 with hydroxylamine or its salt is performed at a temperature of from 0°C to reflux temperature. 53. Use of the compound of Formula 6 for the preparation of silodosin. 54. A process for the preparation of a compound of Formula 7, or a salt thereof;
Figure imgf000069_0001
Formula 7
wherein R is selected from hydrogen or a carboxyl protecting group, the process comprising: treating a compound of Formula 6, or a salt thereof;
Figure imgf000069_0002
Formula 6
wherein R is selected from hydrogen or a carboxyl protecting group, with hydrogen peroxide to obtain compound of Formula 7, or a salt thereof.
55. The process according to claim 54, wherein treating a compound of Formula 6 with hydrogen peroxide is performed in one or more solvents, optionally in the presence of a base.
56. The process according to claim 55, wherein the one or more solvents comprise water, esters, alkanols, halogenated hydrocarbons, ketones, ethers, polar aprotic solvents, or mixtures thereof. 57. The process according to claim 55, wherein the base comprises one or more of organic or inorganic bases.
58. The process according to claim 54, wherein treating a compound of Formula 6 with hydrogen peroxide is performed at a temperature of from 20°C to 80°C.
59. Use of the compound of Formula 7 for the preparation of silodosin.
60. A process for the preparation of a compound of Formula 8 or a salt thereof;
Figure imgf000070_0001
Formula 8
wherein R can be independently selected from hydrogen or a carboxyl protecting group, the process comprising: hydrolyzing a compound of Formula 6, or a salt thereof;
Figure imgf000070_0002
Formula 6
wherein R can be the same as defined above.
61. The process according to claim 60, wherein the hydrolysis of a compound of Formula 6 or a salt thereof is performed in the presence of an acid, optionally in a solvent.
62. The process according to claim 61 , wherein the acid can be selected from the group consisting of organic acid, inorganic acid, or a mixture thereof.
63. The process according to claim 61, wherein the solvent comprises water, esters, alkanols, halogenated hydrocarbons, ketones, ethers, polar aprotic solvent, or mixtures thereof.
64. The process according to claim 60, wherein the hydrolysis of a compound of Formula 6 or a salt thereof is performed at a temperature of from about 35°C to about reflux temperature.
65. Use of the compound of Formula 8 for the preparation of silodosin.
66. A process for the preparation of a compound of Formula 9 or a salt thereof;
Figure imgf000071_0001
Formula 9
wherein R can be independently selected from hydrogen or a carboxyl protecting group, the process comprising: oxidation of a compound of Formula 8, or a salt thereof;
Figure imgf000071_0002
wherein R can be the same as defined above.
67. The process according to claim 66, wherein the oxidation of a compound of Formula 8 or a salt thereof involves treating a compound of Formula 8 or a salt thereof with an oxidizing agent.
68. The process according to claim 67, wherein the oxidizing agent is selected from hydrogen peroxide or a mixture of urea and hydrogen peroxide.
69. The process according to claim 66, wherein the treating of a compound of Formula 8 with an oxidizing agent is carried out in the presence of one or more bases in one or more solvents.
70. The process according to claim 69, wherein the base comprises one or more of organic or inorganic bases.
71. The process according to claim 69, wherein the one or more solvents comprise water, esters, alkanols, halogenated hydrocarbons, ketones, ethers, polar aprotic solvents, or mixtures thereof.
72. Use of the compound of Formula 9 for the preparation of silodosin.
73. A process for the preparation of a compound of Formula 10 or a salt thereof;
Figure imgf000072_0001
Formula 10
wherein R is independently selected from hydrogen or a carboxyl protecting group, the process comprising: treating a compound of Formula 9, or a salt thereof;
Figure imgf000072_0002
Formula 9
wherein R is the same as defined above with R-(+)-a-methylbenzylamine.
74. The process according to claim 73, wherein the treating of a compound of Formula 9 or a salt thereof with R-(+)-a-methylbenzylamine is performed in the presence of a hydrogen source and a catalyst or a reducing agent in one or more solvents.
75. The process according to claim 74, wherein the catalyst is a transition metal compound.
76. The process according to claim 75, wherein the transition metal compound comprises one or more of palladium compounds, platinum compounds, ruthenium compounds, rhodium compounds and nickel compounds.
77. The process according to claim 74, wherein the reducing agent is selected from boranes or metal hydrides, such as sodium hydride, potassium hydride, sodium
borohydride, potassium borohydride, lithium aluminium hydride or lithium borohydride, or sodium cyanoborohydride.
78. The process according to claim 73, wherein the of treating a compound of Formula 9 or a salt thereof with R-(+)-a-methylbenzylamine is performed at a hydrogen pressure in the range from about 1 to 5 kg.
79. The process according to claim 74, wherein the one or more solvents comprise water, esters, alkanols, halogenated hydrocarbons, ketones, ethers, polar aprotic solvents, or mixtures thereof.
80. Use of the compound of Formula 10 for the preparation of silodosin.
81. A process for the preparation of a compound of Formula 1 1 , or a salt thereof;
Figure imgf000073_0001
Formula 11
wherein R is independently selected from hydrogen or a carboxyl protecting group, the process comprising: hydrogenolysis of compound of Formula 10, or a salt thereof;
Figure imgf000073_0002
Formula 10
wherein R is the same as defined above.
82. The process according to claim 81 , wherein the hydrogenolysis of a compound of Formula 10 or a salt thereof is performed in the presence of a hydrogen source and a catalyst or a reducing agent in one or more solvents.
83. The process according to claim 82, wherein the catalyst is a transition metal compound.
84. The process according to claim 83, wherein the transition metal compound comprises one or more of palladium compounds, platinum compounds, ruthenium compounds, rhodium compounds and nickel compounds.
85. The process according to claim 82, wherein the reducing agent is selected from boranes or metal hydrides, such as sodium hydride, potassium hydride, sodium borohydride, potassium borohydride, lithium aluminium hydride or lithium borohydride, or sodium cyanoborohydride. 86. The process according to claim 81, wherein the hydrogeno lysis of a compound of Formula 10 or a salt thereof is performed at a hydrogen pressure in the range from about 1 kg to 5 kg. 87. The process according to claim 82, wherein the one or more solvents comprise water, esters, alkanols, halogenated hydrocarbons, ketones, ethers, polar aprotic solvents, or mixtures thereof. 88. Use of the compound of Formula 11 for the preparation of silodosin.
89. A process for the preparation of compound of Formula 12, or a salt thereof;
Figure imgf000074_0001
Formula 12
wherein R can be independently selected from hydrogen or a carboxyl protecting group, the process comprising: treating a compound of Formula 11, or its salt thereof;
Figure imgf000074_0002
Formula 11
wherein R can be the same as defined above, with a compound of Formula 13.
Figure imgf000074_0003
Formula 13
90. The process according to claim 89, wherein the treating of a compound of Formula 11 or its salt thereof with a compound of Formula 13 is performed in one or more solvents in the presence of a base.
91. The process according to claim 90, wherein the base comprises one or more of organic or inorganic bases.
92. The process according to claim 90, wherein the one or more solvents comprise water, esters, alkanols, halogenated hydrocarbons, ketones, ethers, polar aprotic solvents, or mixtures thereof.
93. A process according to claim 89, wherein the treating of a compound of Formula 11 or its salt thereof with a compound of Formula 14 is performed at a temperature of from about 40°C to reflux temperature.
94. Use of the compound of Formula 12 for the preparation of silodosin.
95. A process for the preparation of silodosin or a salt thereof of Formula I;
Figure imgf000075_0001
Formula I
the process comprising: treating a compound of Formula 12 or a salt thereof;
Figure imgf000075_0002
Formula 12
wherein R can be independently selected from hydrogen or a carboxyl protecting group, with a reducing agent.
96. The process according to claim 95, wherein the treating of a compound of Formula 12 or a salt thereof with a reducing agent is performed in one or more solvents.
97. The process according to claim 95, wherein the reducing agent is selected from boranes or metal hydrides, such as sodium hydride, potassium hydride, sodium
borohydride, potassium borohydride, lithium aluminium hydride or lithium borohydride, or sodium cyanoborohydride.
98. The process according to claim 96, wherein the one or more solvents comprise water, esters, alkanols, halogenated hydrocarbons, ketones, ethers, polar aprotic solvents, or mixtures thereof.
99. The process according to claim 95, wherein the treating of a compound of Formula 12 or a salt thereof with the reducing agent is performed at a temperature of from about 0°C to about 60°C.
100. A process for the preparation of silodosin or a salt thereof;
Figure imgf000076_0001
Formula I
the process comprising: a) providing a compound of Formula 8 or a salt thereof;
Figure imgf000076_0002
Formula 8
wherein R can be independently selected from hydrogen or a carboxyl protecting group; b) converting the compound of Formula 8 or a salt thereof to the compound of Formula 9 or a salt thereof;
Figure imgf000076_0003
Formula 9
wherein R can be the same as defined above; C) converting the compound of Formula 9 or a salt thereof to the compound of Formula 10, or a salt thereof:
Figure imgf000077_0001
Formula 10
wherein R can be the same as defined above;
converting the compound of Formula 10 or a salt thereof to the compound of Formula 11 or a salt thereof;
Figure imgf000077_0002
Formula 11
wherein R can be the same as defined above; e) treating a compound of Formula 11 or its salt thereof with a compound of Formula 13;
Figure imgf000077_0003
Formula 13
to provide a compound of Formula 12, or its salt thereof;
Figure imgf000077_0004
Formula 12
wherein R can be the same as defined above; and f) converting a compound of Formula 12 or its salt thereof to silodosin or a salt thereof;
Figure imgf000078_0001
Formula I
101. The process according to claim 100, wherein step a) comprises hydrolysis of a compound of Formula 6, or a salt thereof in the presence of an acid, optionally in a solvent. 102. The process according to claim 101, wherein the acid is selected from the group consisting of organic acids, inorganic acids, or a mixtures thereof.
103. The process according to claim 101, wherein the solvent comprises water, esters, alkanols, halogenated hydrocarbons, ketones, ethers, polar aprotic solvents, or mixtures thereof.
104. The process according to claim 100, wherein step a) is performed at a temperature of from about 35°C to about reflux temperature. 105. The process according to claim 100, wherein step b) comprises oxidation of a compound of Formula 8, or a salt thereof with an oxidizing agent in one or more solvents in the presence of one or more bases.
106. The process according to claim 105, wherein the oxidizing agent is selected from hydrogen peroxide or a mixture of urea and hydrogen peroxide.
107. The process according to claim 105, wherein the base comprises one or more of organic or inorganic bases.
108. The process according to claim 105, wherein the solvent comprises water, esters, alkanols, halogenated hydrocarbons, ketones, ethers, polar aprotic solvents, or mixtures thereof.
109. The process according to claim 100, wherein step c) comprises treating a compound of Formula 9 or a salt thereof with R-(+)-a-methylbenzylamine in the presence of hydrogen source and a catalyst or a reducing agent in one or more solvents.
110. The process according to claim 109, wherein the catalyst is a transition metal compound. 1 11. The process according to claim 109, wherein the transition metal compound comprises one or more of palladium compounds, platinum compounds, ruthenium compounds, rhodium compounds and nickel compounds.
112. The process according to claim 109, wherein the reducing agent is selected from the group consisting of boranes or metal hydrides, such as sodium hydride, potassium hydride, sodium borohydride, potassium borohydride, lithium aluminium hydride or lithium borohydride, or sodium cyanoborohydride.
113. A process according to claim 109, wherein the solvent comprises water, esters, alkanols, halogenated hydrocarbons, ketones, ethers, polar aprotic solvents, or mixtures thereof.
114. The process according to claim 109, wherein the treating of a compound of Formula 9 or a salt thereof with R-(+)-a-methylbenzylamine is performed at a hydrogen pressure in the range from about 1 kg to 5 kg.
115. The process according to claim 100, wherein step d) comprises hydrogenolysis of a compound of Formula 10, or a salt thereof.
1 16. The process according to claim 115, wherein the hydrogenolysis of a compound of Formula 10, or a salt thereof is performed in the presence of hydrogen source and a catalyst or a reducing agent in one or more solvents.
117. The process according to claim 116, wherein the catalyst is a transition metal compound.
118. The process according to claim 116, wherein the transition metal compound comprises one or more of palladium compounds, platinum compounds, ruthenium compounds, rhodium compounds and nickel compounds.
1 19. The process according to claim 1 16, wherein the reducing agent is selected from the group consisting of boranes or metal hydrides, such as sodium hydride, potassium hydride, sodium borohydride, potassium borohydride, or lithium aluminium hydride. 120. The process according to claim 1 16, wherein the solvent comprises water, esters, alkanols, halogenated hydrocarbons, ketones, ethers, polar aprotic solvents, or mixtures thereof. 121. The process according to claim 100, wherein step e) comprises the treating a compound of Formula 11 , or its salt thereof with a compound of Formula 13 in one or more solvent in the presence of a base.
122. The process according to claim 121, wherein the solvent comprises water, esters, alkanols, halogenated hydrocarbons, ketones, ethers, polar aprotic solvents, or mixtures thereof. 123. The process according to claim 121, wherein the base comprises one or more of organic or inorganic bases. 124. The process according to claim 121, wherein step e) is performed at a temperature of from about 40°C to reflux temperature. 125. The process according to claim 100, wherein step f) comprises the treating of a compound of Formula 12 with a reducing agent in one or more solvents.
126. The process according to claim 125, wherein the reducing agent is selected from the group consisting of boranes or metal hydrides, such as sodium hydride, potassium hydride, sodium borohydride, potassium borohydride, lithium aluminium hydride or lithium borohydride, or sodium cyanoborohydride.
127. The process according to claim 125, wherein the solvent comprises water, esters, alkanols, halogenated hydrocarbons, ketones, ethers, polar aprotic solvents, or mixtures thereof. 128. The process according to claim 125, wherein step f) is performed at a temperature of from about 0°C to about 60°C.
PCT/IB2011/053421 2010-07-30 2011-08-01 Process for the preparation of silodosin and its novel intermediates WO2012014186A1 (en)

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IN1813DE2010 2010-07-30
IN2059DE2011 2011-07-21
IN2059/DEL/2011 2011-07-21

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CN110511126A (en) * 2019-09-25 2019-11-29 山东省化工研究院 The method of by-product nitroparaffins is handled in a kind of ammoxidation oximation reaction of TS-1 catalysis

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WO2012147107A2 (en) * 2011-04-29 2012-11-01 Msn Laboratories Limited Novel & improved processes for the preparation of indoline derivatives and its pharmaceutical composition
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CN110511126B (en) * 2019-09-25 2022-09-23 山东省化工研究院 Method for treating byproduct nitroalkane in ammoxidation oximation reaction catalyzed by TS-1

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