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WO2012062229A1 - Procédé de fabrication du composé (-)-l-(3-hydroxypropyl)-5-[(2r)-2-({2,2,2-trifluoroéthoxy)-phénoxyéthyl}amino)propyl]-2,3-dihydro-lh-indole-7-carboxamide - Google Patents

Procédé de fabrication du composé (-)-l-(3-hydroxypropyl)-5-[(2r)-2-({2,2,2-trifluoroéthoxy)-phénoxyéthyl}amino)propyl]-2,3-dihydro-lh-indole-7-carboxamide Download PDF

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Publication number
WO2012062229A1
WO2012062229A1 PCT/CZ2011/000106 CZ2011000106W WO2012062229A1 WO 2012062229 A1 WO2012062229 A1 WO 2012062229A1 CZ 2011000106 W CZ2011000106 W CZ 2011000106W WO 2012062229 A1 WO2012062229 A1 WO 2012062229A1
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propyl
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Ruzena Vlasakova
Josef Hajicek
Marketa Slavikova
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Zentiva KS
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Zentiva KS
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Priority claimed from CZ20100836A external-priority patent/CZ2010836A3/cs
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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 invention relates to a method of manufacturing (-)-l-(3-hydroxypropyl)-5-[(2 ?)-2- ( ⁇ 2,2,2-trifluoroethoxy)phenoxyethyl ⁇ amino)propyl]-2,3-dihydro-lH-indole-7-carboxamide of formula I
  • silodosin also known under the name silodosin, and of its salts.
  • racemic silodosin is produced using a multi-step method from N- acetylindoline, which is transformed to the 5-(2-brompropionyl)-derivative either by direct acylation with a bromopropionyl halide or in two steps by acylation with propionyl chloride and subsequent bromination.
  • Deoxygenation by means of triethyl silane is followed by nitration into the aromatic ring (HN0 3 ); the nitro compound is then converted to a cyano derivative by reduction (hydrogenation on PtC ⁇ ), diazotization and subsequent reaction of the diazonium salt with copper cyanide.
  • N-acetyl-7-cyano-5-(2- bromopropyl)benzene (A) is then converted in two steps into a primary amine first by substitution with sodium azide and then by hydrogenation of the azide on Pd/BaS0 4 .
  • Introduction of the 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl group to the nitrogen is performed by alkylation of the primary amine by means of alkylating agents B derived from 2- [2-(2,2,2-trifluoroethoxy)phenoxy]ethanol (bromide, mesylate, etc.).
  • the same secondary amine C is alternatively produced by alkylation of 2-[2-(2,2,2- trifluoroethoxy)phenoxy]-ethylamine with the bromide A. Resolution of the racemic amine C is carried out using the low-efficiency formation of salts with (+)-mandelic acid.
  • Amine C is further transformed to an N-Boc-derivative (Boc is a short for tert- butoxycarbonyl derivatives (Boc 2 0)), which is then subjected to alkaline N-deacetylation producing an N-nor-amine. Then, the nitrile is hydrolyzed to the corresponding carboxamide by means of a peroxide in an alkaline environment and the obtained indoline is N-alkylated with 3-ier/-butyldimethylsilyloxypropylalcohol nosylate.
  • silodosin (I) is produced from 3-[5-((2/?)-2-aminopropyl-7-cyanoindolin-l - yl]propanol benzoate, which is alkylated with 2-[2-(2,2,2-trifluoroethoxy)phenyloxy]ethanol mesylate, producing a secondary base, which is depleted of the over-alkylated product in the form of a salt with oxalic acid, then the ester is subjected to alkaline hydrolysis and the synthesis is completed by treatment with an alkali peroxide, resulting in transformation of the nitrile to an amide.
  • This method also manifests the disadvantage that over-alkylated impurities are produced, which have to be
  • the invention provides a new efficient method of manufacturing silodosin of formula I
  • Bn denotes a phenylmethyl group, substituted or unsubstituted in the benzene ring, e.g. benzyl or 4-methoxybenzyl, or the benzhydryl or trityl group, is N-alkylated with an alkylating agent of eneral formula III
  • X denotes a good leaving group, such as a halogen or an alkane sulfonyloxyl group RS0 2 0 or an arene sulfonyloxyl group ArS0 2 0, R means an alkyl group with 1 to 4 carbon atoms and Ar is a substituted or unsubstituted phenyl group; the obtained tertiary amine of general formula IV
  • silodosin is transformed to the respective salts by treatment with pharmaceutically acceptable acids.
  • the invention also provides key intermediates of formulae II
  • Bn denotes a phenylmethyl group, substituted or unsubstituted in the benzene ring, e.g. benzyl or 4-methoxybenzyl, or the benzhydryl or trityl group.
  • the invention provides a method of manufacturing optically pure or optically enriched silodosin of formula I and of its pharmaceutically acceptable salts,
  • Bn denotes a phenylmethyl group, substituted or unsubstituted in the benzene ring, e.g. benzyl or 4-methoxybenzyl, or the benzhydryl or trityl group,
  • X denotes a good leaving group, such as a halogen or an alkane sulfonyloxyl group RS0 2 0 or an arene sulfonyloxyl group ArS0 2 0, R means an alkyl group with 1 to 4 carbon atoms and Ar is a substituted or unsubstituted phenyl group;
  • Step B is selectively N-hydrogenolyzed with hydrogen on a metal catalyst at a pressure of 0.1-5 MPa or by means of ammonium formate, in an inert organic solvent (Step B);
  • Step C is hydrolyzed by treatment with alkaline agents (Step C); and, finally, the amide-ether of g
  • Step D is subjected to O-debenzylation with hydrogenolytic or trialkylhalide dealkylating agents (Step D); and, if desired, the obtained silodosin is transformed to the respective salts by treatment with pharmaceutically acceptable acids.
  • silodosin of formula I can, efficiently and in high purity, be manufactured by an asymmetrical method, which ensures production efficiency and high optical purity of the intermediates, and also prevents formation of twice N-alkylated amines as side products of the alkylation.
  • the process of manufacturing silodosin from the secondary amine of general formula II comprises the following four synthetic steps:
  • Step A Alkylation of the amine of general formula II, wherein Bn denotes a phenylmethyl group, substituted or unsubstituted in the benzene ring, e.g. benzyl or 4- methoxybenzyl, or the benzhydryl or trityl group, is carried out by reaction with an alkylating agent of general formula III, wherein X stands for a good leaving group, such as a halogen or an alkane sulfonyloxyl group or an arene sulfonyloxyl group.
  • Useful halides include a iodide, bromide or chloride.
  • an alkane sulfonyl group such as e.g. methane sulfonyl group, or an arene sulfonyl group, such as benzene sulfonyl group or para-toluene sulfonyl group, can be used.
  • the alkylating agent is used in an amount of 1 to 7 equivalents, preferably 1.5 to 4 equivalents, in the presence of a base.
  • Useful bases include inorganic bases, e.g. potassium or sodium carbonate, or hindered organic bases, such as diisopropylethylamine, in an amount of 0.5 to 8 equivalents, preferably 1 to 5 equivalents.
  • the alkylation is carried out in an inert organic solvent, such as carboxamides, e.g. dimethyl formamide, dimethyl acetamide, or N-methyl pyrrolidone, or alcohols, e.g. ethanol, or dimethyl sulfoxide, in the temperature range from 50°C to the boiling point of the mixture, preferably at 75 to 125°C.
  • an inert organic solvent such as carboxamides, e.g. dimethyl formamide, dimethyl acetamide, or N-methyl pyrrolidone
  • alcohols e.g. ethanol, or dimethyl sulfoxide
  • a chloride, bromide, alkane sulfonate or arene sulfonate is used in the presence of an alkali metal iodide, e.g. sodium or potassium iodide, in an amount of 0.1 to 2 equivalents, commonly 0.5 to 1.1 equivalents, and the reaction is performed in dimethyl formamide at a temperature of 95 to 125°C.
  • an alkali metal iodide e.g. sodium or potassium iodide
  • the alkylating agent and/or also the base is added in portions in the course of the reaction.
  • Step B The removal of the chiral 1 -phenylethyl group in the compound of general formula IV, wherein Bn is as defined above, is carried out by hydrogenolysis with hydrogen on metal catalysts, such as palladium. Gaseous hydrogen is used, or, alternatively, the hydrogenolysis is carried out by means of ammonium formate.
  • the hydrogenolysis is carried out in an inert organic solvent, such as in lower alcohols, e.g.
  • hydrogen on Pd/C is used in the environment of an alcohol, e.g. methanol or ethanol, or their mixtures with water, at a pressure of 0.1 to 3 MPa.
  • an alcohol e.g. methanol or ethanol, or their mixtures with water
  • Step C Transformation of the nitrile group in the compound of formula V, wherein Bn is as defined above, to the carboxamide group is carried out by means of alkaline agents such as alkali metal hydroxides, e.g. sodium or potassium hydroxide, in polar solvents such as methanol, ethanol or dimethyl sulfoxide, at a temperature from -10°C to the boiling point of the mixture.
  • alkaline agents such as alkali metal hydroxides, e.g. sodium or potassium hydroxide
  • polar solvents such as methanol, ethanol or dimethyl sulfoxide
  • Step D Deprotection of the O-benzyl protective group in the compound of general formula VI, wherein Bn is as defined above, is carried out by dealkylation processes by means of deprotecting agents such as hydrogenolytic agents or trialkyl silyl halide agents.
  • deprotecting agents such as hydrogenolytic agents or trialkyl silyl halide agents.
  • Useful hydrogenolytic agents include hydrogen on a metal catalyst, e.g. on palladium or platinum, in inert solvents, e.g. ethanol, methanol, 2-methyltetrahydrofuran or tetrahydrofuran, ethyl acetate, or in their mixtures, in the temperature range of 10 to 50°C.
  • Useful trialkyl silyl halide agents include e.g.
  • trimethyl silyl iodide in an inert solvent e.g. in dichloromethane, chloroform, or toluene, in the temperature range of -5 to + 40°C, preferably in the temperature range from 5 to 25 °C.
  • hydrogen on Pd/C is used in the environment of an alcohol, e.g. methanol or ethanol, or ethyl acetate, or their mixtures.
  • the deprotection is carried out with trimethyl silyl iodide in dichloromethane in the temperature range of 5 to 25 °C.
  • silodosin is finally purified by crystallization from a suitable organic solvent or mixture of solvents, e.g. ethyl acetate, 2-propanol or methanol. If desired, the obtained silodosin is converted to the corresponding salt by treatment with pharmaceutically acceptable acids.
  • the invention provides a method of manufacturing silodosin using the same above-mentioned key intermediates II and IV by a method comprising the following steps:
  • Bn denotes a phenylmethyl group, substituted or unsubstituted in the benzene ring, e.g. benzyl or 4-methoxybenzyl, or the benzhydryl or trityl group
  • X denotes a good leaving group, such as a halogen or an alkane sulfonyloxyl group RSO 2 O or an arene sulfonyloxyl group ArS0 2 0, R means an alkyl group with 1 to 4 carbon atoms and Ar is a substituted or unsubstituted phenyl group,
  • an inert organic solvent selected form the group including carboxamides, N-methyl pyrrolidone, lower alcohols and dimethyl sulfoxide, at the temperatures of from 50°C to the boiling point of the mixture, in the presence or absence of an alkali metal iodide;
  • Step B subjecting the obtained tertiary amine of general formula IV wherein Bn is as defined above,
  • alkali metal hydroxides optionally in the presence of hydrogen peroxide in polar solvents such as methanol, ethanol., glyme or diglyme, or dimethyl sulfoxide, at a temperature of from -10°C to the boiling point of the mixture; and, optionally converting to the respective salts by treating with pharmaceutically acceptable acids.
  • polar solvents such as methanol, ethanol., glyme or diglyme, or dimethyl sulfoxide
  • Step A Alkylation of the amine of general formula II, wherein Bn denotes a phenylmethyl group, substituted or unsubstituted in the benzene ring, e.g. benzyl or 4- methoxybenzyl, or the benzhydryl or trityl group, is carried out by reaction with an alkylating agent of general formula III, wherein X stands for a good leaving group, such as a halogen or an alkane sulfonyloxy group or an arene sulfonyloxy group.
  • Useful halides include a iodide, bromide or chloride.
  • an alkane sulfonyloxyl group such as e.g. methane sulfonyloxyl group, or an arene sulfonyloxyl group, such as benzene sulfonyloxyl group or para-toluene sulfonyloxyl group, can be used.
  • the alkylating agent is used in an amount of 1 to 7 equivalents, preferably 1.5 to 4 equivalents, in the presence of a base.
  • Useful bases include inorganic bases, e.g. potassium or sodium carbonate, or hindered organic bases, such as diisopropylethylamine, in an amount of 0.5 to 8 equivalents, preferably 1 to 5 equivalents.
  • the alkylation is carried out in an inert organic solvent, such as carboxamides, e.g. dimethyl formamide, dimethyl acetamide, or N-methyl pyrrolidone, or alcohols, e.g. ethanol, or dimethyl sulfoxide, in the temperature range from 50°C to the boiling point of the mixture, preferably at 75 to 125°C.
  • an inert organic solvent such as carboxamides, e.g. dimethyl formamide, dimethyl acetamide, or N-methyl pyrrolidone
  • alcohols e.g. ethanol, or dimethyl sulfoxide
  • a chloride, bromide, alkane sulfonate or arene sulfonate is used in the presence of an alkali metal iodide, e.g. sodium or potassium iodide, in an amount of 0.1 to 2 equivalents, commonly 0.5 to 1.1 equivalents, and the reaction is performed in dimethyl formamide at a temperature of 95 to 125°C.
  • an alkali metal iodide e.g. sodium or potassium iodide
  • the alkylating agent and/or also the base is added in portions in the course of the reaction.
  • Step B The simultaneous removal of the chiral 1 -phenyl ethyl group and of the benzyl in the compound of general formula IV is carried out by hydrogenolysis with hydrogen on metal catalysts, such as palladium.
  • the hydrogenolysis is carried out in the presence of strong acids, such as hydrochloric acid, sulfuric acid, or methane sulfonic acid, in an inert organic solvent, such as in lower alcohols, e.g.
  • hydrogen on Pd/C is used in the presence of hydrochloric or sulfuric acid in the environment of an alcohol, e.g. methanol or ethanol, or their mixtures with water, at a pressure of 0.1 to 2 MPa.
  • an alcohol e.g. methanol or ethanol, or their mixtures with water
  • Step C Transformation of the nitrile group in the compound of formula V to the carboxamide group is carried out by means of alkaline agents such as alkali metal hydroxides, e.g. sodium or potassium hydroxide, in polar solvents such as methanol, ethanol or dimethyl sulfoxide, at a temperature from -10°C to the boiling point of the mixture.
  • alkaline agents such as alkali metal hydroxides, e.g. sodium or potassium hydroxide
  • polar solvents such as methanol, ethanol or dimethyl sulfoxide
  • silodosin is finally purified by crystallization from a suitable organic solvent or mixture of solvents, e.g. ethyl acetate, 2-propanol or methanol. If necessary, the obtained silodosin is converted to the corresponding salt by treatment with pharmaceutically acceptable acids.
  • the method in accordance with the invention comprises, as the key step, preparation of an optically pure or optically enriched tertiary amine of general formula IV
  • Bn denotes a phenylmethyl group, substituted or unsubstituted in the benzene ring, e.g. benzyl or 4-methoxybenzyl, or the benzhydryl or trityl group,
  • X stands for a good leaving group, such as a halogen or alkane sulfonyloxyl group RS0 2 0 or arene sulfonyloxyl group ArS0 2 0, R stands for an alkyl group with 1 to 4 carbon atoms and Ar is a substituted or unsubstituted phenyl group.
  • Bn denotes a phenylmethyl group, substituted or unsubstituted in the benzene ring, e.g. benzyl or 4-methoxybenzyl, or the benzhydryl or trityl group.
  • the method of preparing the amine of formula II consists in subjecting the ketone of general formula VII, wherein Bn denotes a phenylmethyl group, substituted or unsubstituted in the benzene ring, e.g. benzyl or 4-methoxybenzyl, or the benzhydryl or trityl group, to diastereoselective reductive amination with the (7?)-amine of formula VIII, which is used in an amount of 0.9 to 1.5 equivalents, preferably 1 to 1.1 equivalents.
  • a necessary precondition for the success of the process is the presence of a Lewis acid, e.g.
  • the reductive amination is carried out in the environment of hydrogen and a metal catalyst in an inert organic solvent in the temperature range from 0°C to the boiling point of the mixture, preferably at 20 to 40°C.
  • the reaction is carried out in an inert organic solvent such as cyclic ethers, e.g. tetrahydrofuran, 2-methyltetrahydrofuran or 1 ,4-dioxane, or their mixtures.
  • the reductive amination is carried out by hydrogen in the presence of benzoic acid under the presence of an Adams' catalyst in tetrahydrofuran, 2- methyltetrahydrofuran or dioxane at a temperature of 20 to 35°C.
  • This invention further provides a method of preparing an optically pure or optically enriched secondary amine of general formula II
  • Bn denotes a phenylmethyl group, substituted or unsubstituted in the benzene ring, e.g. benzyl or 4-methoxybenzyl, or the benzhydryl or trityl group,
  • step 1 is brominated with bromine (step 1); the obtained bromide of general formula X wherein Bn is as defined above,
  • cyanized with cyanides in polar organic solvents selected from dimethyl formamide, dimethyl acetamide, N-methyl pyrrolidone or dimethyl sulfoxide, in the temperature range from 60°C to the boiling point of the mixture (step 2); the prepared cyano-aldehyde of general formula XI
  • step 3 the produced nitrostyrene of general formula XII
  • step 4 is subjected to reductive hydrolysis with metals in a strongly acidic environment of a mineral acid, such as hydrochloric or sulfuric acid, preferably in the presence of metallic ions in the temperature range of 30 to 100°C (step 4); and, finally, the ketone of general formula VII
  • the method of obtaining the secondary amine of general formula II, optically pure, or optically enriched, starts with the aldehyde of general formula IX and comprises the following steps:
  • Step 1 Preparation of a 7-bromo-derivative of general formula X, wherein Bn denotes a phenylmethyl group, substituted or unsubstituted in the benzene ring, e.g. benzyl or 4- methoxybenzyl, or the benzhydryl or trityl group, in which the starting compound of general formula IV, wherein Bn is as defined above, is brominated with molecular bromine in a slightly acidic environment, e.g. in the presence of acetic acid, in the presence or absence of an inert organic solvent, e.g. dichloromethane, chloroform, in the temperature range from 0°C to the boiling point of the mixture, preferably in the range of 10 to 35°C.
  • Bn denotes a phenylmethyl group, substituted or unsubstituted in the benzene ring, e.g. benzyl or 4- methoxybenzyl, or the benz
  • step 1 is carried out with bromine in an acetic acid environment in the temperature range of 5 to 35°C.
  • Step 2 The conversion of the bromide of general formula X to the nitrile of formula XI, wherein Bn denotes a phenylmethyl group, substituted or unsubstituted in the benzene ring, e.g. benzyl or 4-methoxybenzyl, or the benzhydryl or trityl group, is carried out with cyanides, specifically by treatment with copper cyanide in polar organic solvents, e.g. dimethyl formamide, dimethyl acetamide, N-methyl pyrrolidone or dimethyl sulfoxide, in the temperature range from 60°C to the boiling point of the mixture, preferably at from 90°C to 160°C.
  • polar organic solvents e.g. dimethyl formamide, dimethyl acetamide, N-methyl pyrrolidone or dimethyl sulfoxide
  • This method is preferably performed by heating of the bromide of general formula X with copper cyanide in dimethyl formamide to the temperature of from 1 10°C to the boiling point of the mixture.
  • Step 3 The method of preparing the nitrostyrene of general formula XII, wherein Bn denotes a phenylmethyl group, substituted or unsubstituted in the benzene ring, e.g. benzyl or 4- methoxybenzyl, or the benzhydryl or trityl group, is carried out by condensation of the aldehyde of general formula XI, wherein Bn has the above mentioned meaning, with nitroethane, in the presence of a slightly alkaline catalyst, e.g. ammonium acetate, in the presence or absence of an organic solvent, e.g. methanol or ethanol, in the temperature range of 0°C to 40°C.
  • a slightly alkaline catalyst e.g. ammonium acetate
  • an organic solvent e.g. methanol or ethanol
  • This method is preferably performed by condensation of the aldehyde of general formula XI with an excess of nitroethane and in the presence of ammonium acetate, without an organic solvent.
  • Step 4 Reductive hydrolysis of the nitrostyrene of general formula XII to the ketone of general formula VII, wherein Bn denotes a phenylmethyl group, substituted or unsubstituted in the benzene ring, e.g. benzyl or 4-methoxybenzyl, or the benzhydryl or trityl group, is carried out with metals, e.g. iron, in a strongly acidic environment of a mineral acid, e.g. hydrochloric acid or sulfuric acid, preferably in the presence of metallic ions, in the temperature range of 30°C to 100°C.
  • metals e.g. iron
  • Step 5 The method of preparing the secondary amine of formula II, wherein Bn denotes a phenylmethyl group, substituted or unsubstituted in the benzene ring, e.g.
  • benzyl or 4- methoxybenzyl, or the benzhydryl or trityl group consists in subjecting the ketone of general formula VII, wherein Bn is as defined above, to diastereoselective reductive amination with the ( ⁇ )-amine of formula VIII, which is used in an amount of 0.9 to 1.5 equivalents, preferably 1 to 1.1 equivalents.
  • a necessary precondition for the result of the process is the presence of a Lewis acid, e.g. titanium tetraisopropoxide, or a Bronsted acid such as an arene carboxylic acid, e.g.
  • benzoic acid 4-methylbenzoic or 3-methoxybenzoic acids, or aliphatic carboxylic acids, e.g. acetic acid. These acids are used in amounts of 0.1 to 3 equivalents, preferably 0.5 to 1.3 equivalents.
  • the reductive amination is carried out in the environment of hydrogen and a metal catalyst in an inert organic solvent in the temperature range from 0°C to the boiling point of the mixture, preferably 20 to 40°C.
  • the reaction is performed in an inert organic solvent such as a cyclic ether, e.g. tetrahydrofuran, 2-methyltetrahydrofuran or 1,4-dioxane, or their mixtures.
  • the reductive amination is carried out in the presence of benzoic acid with hydrogen in the presence of an Adams' catalyst in tetrahydrofuran, 2-methyltetrahydrofuran or dioxane at a temperature of from 20 to 35°C.
  • Bn PhCH 2 (l-[3-(benzyloxy)propyl]- 5-[(2R)-2-( ⁇ 2-[2-(2,2,2-trifluoroethoxy)-phenoxy]ethyl ⁇ amino)propyl]indoline-7- carboxamide)
  • Bn PhCH 2 (l -[3-(benzyloxy)propyl]-5- [(2 )-2-([(17?)-l -phenylethyl] ⁇ 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl ⁇ amino)propyl]- indoline-7-carbonitrile)
  • the mixture is cooled with an ice bath, 0.08 ml (0.80 mmol) of a 30% solution of hydrogen peroxide are added dropwise and the reaction mixture is stirred first under cooling with an ice bath for 10 min, and then at the laboratory temperature for 15 hours. Then, the mixture is cooled with an ice bath again, 0.03 ml (0.3 mmol) of a 30% solution of hydrogen peroxide are added and the mixture is stirred for another 3 hours while it is left to heat up to the laboratory temperature. Then, a solution of sodium pyrosulfite (60 mg) in 1.5 ml of water is added.
  • the mixture is filtered over a kieselguhr layer.
  • the organic phase is separated and the aqueous phase is shaken with chloroform (1x 10 ml).
  • the combined organic fractions are then dried with anhydrous sodium sulfate.
  • After evaporation of the solvent the obtained dark oil is purified in a chromatographic column. 1.85 g (5,3 mmol) of the pure product are obtained.
  • the combined organic fractions are washed with water (lx 150 ml) and a saturated solution of sodium hydrogen carbonate (1x 100 ml), and dried with anhydrous magnesium sulfate. Evaporating the solvent offers 39.7 g (0.11 mol) of a green-black oil.
  • the product need not be further purified; it is used in the raw condition for the subsequent reaction.
  • the mixture is filtered over a kieselguhr layer.
  • the organic phase is separated and the aqueous phase is shaken with chloroform (1x 10 ml).
  • the combined organic fractions are then dried with anhydrous sodium sulfate.
  • After evaporation of the solvent the obtained dark oil is purified in a chromatographic column. 1.85 g (5,3 mmol) of the pure product are obtained.
  • the reaction is terminated by addition of 250 ml of water (spontaneous heating up to ca. 35°C will occur); after stirring for 4 hrs 250 ml of ethyl acetate are added, the layers are separated and the aqueous phase is extracted with ethyl acetate (lx 250 ml). The combined organic fractions are washed with water (1x 250 ml), a saturated solution of sodium hydrogen carbonate (2x 250 ml) and brine (lx 150 ml). After drying with anhydrous sodium sulfate and evaporation of the solvent the raw product is chromatographically purified. 33.9 g (0.1 1 mol) of a red oil are obtained.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Indole Compounds (AREA)
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Abstract

L'invention concerne un procédé de fabrication d'un composé de silodosine optiquement pur ou optiquement enrichi, représenté par la formule I, et des sels pharmaceutiquement acceptables de celui-ci. Dans le procédé, une amine secondaire représentée par la formule générale II, dans laquelle Bn représente un groupe phénylméthyle, substitué ou non substitué dans le noyau benzène, p. ex. benzyle ou 4-méthoxybenzyle, ou le groupe benzhydryle ou trityle, est (a) N-alkylée à l'aide d'un agent alkylant représenté par la formule générale III, dans laquelle X représente un bon groupe partant, tel qu'un groupe halogène ou un groupe alcane sulfonyloxyle RS020, ou un groupe arène sulfonyloxyle ArS020, R représente un groupe alkyle doté de 1 à 4 atomes de carbone, et Ar représente un groupe phényle substitué ou non substitué; (b) l'amine tertiaire obtenue, représentée par la formule générale IV, dans laquelle Bn est tel que défini précédemment, est hydrogénolysée à l'aide d'hydrogène sur un catalyseur métallique; (c) et le nitrile obtenu, représenté par la formule V, dans laquelle Bn est tel que défini précédemment, est hydrolysé par un traitement utilisant des agents alcalins; et éventuellement (d) une O-débenzylation supplémentaire de l'amide-éther représenté par la formule générale VI, est mise en œuvre au moyen d'agents désalkylants, Bn étant tel que défini précédemment; et le composé de silodosine obtenu est, au besoin, transformé en ses sels respectifs par un traitement utilisant des acides pharmaceutiquement acceptables.
PCT/CZ2011/000106 2010-11-12 2011-11-07 Procédé de fabrication du composé (-)-l-(3-hydroxypropyl)-5-[(2r)-2-({2,2,2-trifluoroéthoxy)-phénoxyéthyl}amino)propyl]-2,3-dihydro-lh-indole-7-carboxamide Ceased WO2012062229A1 (fr)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
CZ2010835 2010-11-12
CZPV2010-835 2010-11-12
CZ20100837A CZ303061B6 (cs) 2010-11-12 2010-11-12 Zpusob výroby (-)-1-(3-hydroxypropyl)-5-[(2R)-2-({2,2,2-trifluorethoxy)fenoxyethyl}amino)propyl]-2,3-dihydro-1H-indol-7-karboxamidu
CZPV2010-837 2010-11-12
CZPV2010-836 2010-11-12
CZ20100836A CZ2010836A3 (cs) 2010-11-12 2010-11-12 Zpusob výroby (-)-1-(3-hydroxypropyl)-5-[(2R)-2-({2,2,2-trifluorethoxy)fenoxyethyl}amino)propyl]-2,3-dihydro-1H-indol-7-karboxamidu

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WO2013072935A3 (fr) * 2011-10-10 2013-10-10 Cadila Healthcare Limited Procédé de préparation du silodosin
WO2014118606A3 (fr) * 2013-01-29 2014-12-18 Alembic Pharmaceuticals Limited Nouveau procédé de préparation de silodosine
WO2015085827A1 (fr) 2013-12-09 2015-06-18 上海科胜药物研发有限公司 Procédé pour la préparation de silodosine et intermédiaire correspondant
US10421719B2 (en) 2015-09-30 2019-09-24 Urquima S.A. Maleic acid salt of a silodosin intermediate
EP3892615A1 (fr) 2020-04-09 2021-10-13 Minakem Procédé de préparation de silodosine

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WO2013072935A3 (fr) * 2011-10-10 2013-10-10 Cadila Healthcare Limited Procédé de préparation du silodosin
US9394251B2 (en) 2011-12-26 2016-07-19 Zhejiang Jiuzhou Pharmaceutical Co., Ltd. Silodosin intermediate and preparation method therefor
WO2013097456A1 (fr) * 2011-12-26 2013-07-04 浙江九洲药业股份有限公司 Intermédiaire de silodosine et procédé de préparation de celui-ci
WO2014118606A3 (fr) * 2013-01-29 2014-12-18 Alembic Pharmaceuticals Limited Nouveau procédé de préparation de silodosine
JP2017502009A (ja) * 2013-12-09 2017-01-19 上海科勝薬物研発有限公司 シロドシン及びその中間体の製造方法
CN105745191A (zh) * 2013-12-09 2016-07-06 上海科胜药物研发有限公司 一种西洛多辛及其中间体的制备方法
WO2015085827A1 (fr) 2013-12-09 2015-06-18 上海科胜药物研发有限公司 Procédé pour la préparation de silodosine et intermédiaire correspondant
EP3081554A4 (fr) * 2013-12-09 2017-08-16 Shanghai Syncores Technologies, Inc. Procédé pour la préparation de silodosine et intermédiaire correspondant
US9745264B2 (en) 2013-12-09 2017-08-29 Shanghai Syncores Technologies, Inc. Method for preparing silodosin and intermediate thereof
CN105745191B (zh) * 2013-12-09 2019-04-09 上海科胜药物研发有限公司 一种西洛多辛及其中间体的制备方法
US10421719B2 (en) 2015-09-30 2019-09-24 Urquima S.A. Maleic acid salt of a silodosin intermediate
EP3892615A1 (fr) 2020-04-09 2021-10-13 Minakem Procédé de préparation de silodosine
WO2021205023A1 (fr) 2020-04-09 2021-10-14 Minakem Procédé de préparation de silodosine

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