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WO2012131710A2 - Nouveau procédé pour la synthèse de dérivés d'indoline - Google Patents

Nouveau procédé pour la synthèse de dérivés d'indoline Download PDF

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

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

Definitions

  • the invention belongs to the field of organic chemistry and relates to a novel, improved, commercially viable and industrially advantageous process for the synthesis of compounds useful as intermediate in the synthesis of a-1 adrenoceptor blockers, including (R)-l-(3-hydroxypropyl)-5-[2-[2-[2-(2,2,2-trifluoroethoxy) phenoxy] ethylamino] propyl] indoline 7-carboxamide (hereinafter referred to by its generic name "Silodosin”), its pharmaceutically acceptable derivatives, salts or solvates.
  • Silodosin is the adopted name of the drug compound chemically known as l-(3- hydroxypropyl)-5-[(2R)-( ⁇ 2-[2-[2-(2,2,2- trifluoroethoxy)phenoxy]ethyl ⁇ amino)propyl]indoline-7-carboxamide and is represented by the following structural Formula XVI:
  • silodosin the treatment tly, silodosin y a few processes for the manufacture of Silodosin have become known.
  • Literature suggests that silodosin has been obtained from two intermediates viz. indoline and phenoxyethyl intermediates. There have been many literature references on the synthesis of these intermediates.
  • US patent no. 5387603 discloses the synthesis of silodosin and 1,5,7 trisubstituted indoline intermediate using N-acylated indoline as starting material.
  • the preparation involves the steps of bromination, reduction, nitration, nitro reduction, cyanation and azidation. Further, the racemic mixture of indoline intermediate is used for preparation of silodosin.
  • the total procedure is very complex having more number of process steps including optical resolution at final stages of the synthesis and the pyrophoric reagents used in the process are very difficult to handle on a large scale.
  • Japanese application no. 2001199956 discloses the synthesis of indoline derivative using indoline and propylbenzoate as starting material and the preparation is carried out in a series of reactions including Vilsmeir-Haack formylation, nitration and reduction.
  • One of the intermediate of the preparation reaction is l-(3-benzoyloxypropyl)-7-cyano- 5-(2-oxopropyl) indoline.
  • some of the stages of the preparation of indoline intermediate as per JP 2001-199956 are difficult.
  • Japanese application no. 2002265444 discloses preparation of l-(3-benzyloxypropyl)- 5-(2-substituted propyl) indoline.
  • the patent specifically discloses preparation of 5-(2- aminopropyl)-l-(3-benzyloxypropyl) indoline-7-carbonitrile from (R)-3-[l-(3- benzyloxypropyl)-7-cyanoindoline-5yl]-2-methylpropionic acid.
  • the route of synthesis followed in this patent involves pyrophoric reagents like n-BuLi, which is difficult to handle in large scale synthesis. Some of the reagents like Witting salt and resulting agent are not commercially available.
  • Japanese application no. 2006188470 discloses the synthesis of a similar indoline intermediate using N-protected indoline as starting material and the process is carried out in a series of reactions involving reduction, bromination, nitrile formation and hydrolysis.
  • the indoline intermediate obtained is used for preparation of silodosin.
  • the reagents used in the process are sodium/cupper cyanide for nitrile substitution and Triethylsilyl hydride for reduction which are very difficult to handle in large scale manufacturing.
  • PCT application no. WO2006046499 discloses the synthesis of silodosin which comprises the steps of reacting indole intermediate with phenoxyethyl intermediate and further carrying out the removal of hydroxyl protecting group and hydrolysis of the nitrile group.
  • the present invention provides a novel, improved, commercially viable and industrially advantageous process for the synthesis of indoline intermediate and its pharmaceutically acceptable derivatives, salts or solvates thereof useful as intermediate in the synthesis of silodosin, its derivatives and pharmaceutically acceptable salts SUMMARY OF THE INVENTION
  • the present invention relates to an improved process for the synthesis of indoline intermediates, its pharmaceutically acceptable derivatives, salts or solvates thereof, useful in the synthesis of a-1 adrenoceptor blockers such as silodosin.
  • the present invention provides a novel process for the preparation of indoline derivatives of Formula IA, Formula IB, their pharmaceutically acceptable derivatives, salts or solvates thereof.
  • R is a hydroxyl protecting group
  • the present invention further provides a novel process for the preparation of indoline derivatives of Formula IA, Formula IB, their pharmaceutically acceptable derivatives, salts or solvates thereof, useful as a key intermediate in the synthesis of silodosin, its pharmaceutically acceptable derivatives, salts or solvates thereof.
  • the present invention specifically provides a process for the preparation of tartarate salt of 3-(5-((R)-2-aminopropyl)-7-cyanoindolin-l-yl) propyl benzoate of Formula I
  • step (b) resolving the racemic mixture of amine compound of Formula XII obtained in step (a), either by isolating it or without isolating, using suitable enantiopure acid in presence of suitable solvent to obtain tartarate salt of 3-(5-((R)-2- aminopropyl)-7-cyanoindolin-l -yl) propyl benzoate of Formula I.
  • the present invention specifically provides a novel process for the preparation of Tartarate salt of 3-(5-((R)-2-aminopropyl)-7-cyanoindolin-l-yl) propyl benzoate of Formula I
  • the present invention provides a process for the preparation of indoline derivatives of Formula IC, Formula ID, their pharmaceutically acceptable derivatives, salts or solvates thereof
  • the present invention provides an improved, commercially viable and industrially advantageous process for the preparation of silodosin of Formula XVI
  • Formula XVI its pharmaceutically acceptable derivatives, salts or solvates thereof, comprising the following steps;
  • R is a hydroxyl protecting group
  • step (3) optionally converting silodosin of Formula XVI of step (3) to its pharmaceutical acceptable derivatives, salts or solvates.
  • the present invention even further discloses an improved, commercially viable and industrially advantageous process for the preparation of silodosin of Formula XVI
  • silodosin of Formula XVI hydrolyzing compound of Formula XV to obtain silodosin of Formula XVI; and (3) optionally converting silodosin of Formula XVI of step (3) to its pharmaceutical acceptable derivatives, salts or solvates.
  • the present invention provides an improved, commercially viable and industrially advantageous process for the preparation of silodosin of Formula XVI
  • step (3) optionally converting silodosin of Formula XVI of step (3) to its pharmaceutically acceptable derivatives, salts or solvates thereof.
  • the present invention relates to a novel and improved commercially viable and industrially advantageous process for the synthesis of Indoline derivatives of Formula IA and its pharmaceutically acceptable derivatives, salts or solvates thereof, useful as intermediates in the synthesis of compounds that act as a-1 adrenoceptor blockers.
  • suitable solvent refers to a solvent or a mixture of two or more solvents, which induces conditions which are favorable for the reaction to proceed as intended.
  • suitable base refers to a reagent or a mixture of two or more reagents, which facilitates the displacement of a suitable leaving group from the reactant.
  • suitable reducing agent refers to a reagent, or a mixture of two or more reagentS7-whrch ⁇ facilitates — the- reductiun ⁇ reaction
  • containing reagent refers to organic compounds characterized by the presence of at least one hydroxyl group.
  • hydroxyl protecting group refers to a moiety that prevents chemical reactions from occurring on the hydroxyl group to which that protecting group is attached. A hydroxyl protecting group must be removable by a chemical reaction.
  • Suitable hydroxyl protecting group include, but not limited to, acetyl, t-butyl, t- butoxymethyl, methoxymethyl, , tetrahydropyranyl, 1-ethoxyethyl, l-(2- chloroethoxy)ethyl, 2-trimethylsilylethyl, p-chlorophenyl, 2,4-dinitrophenyl, benzyl, benzoyl, 2,6-dichlorobenzyl, diphenylmethyl, p-nitrobenzyl, triphenylmethyl (trityl), 4- methoxytrityl, 4,4'-dimethoxytrityl, trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, t- butyldiphenylsilyl, triisopropylsilyl, benzoylformate, chloroacetyl, trichloroacetyl, trifluoro
  • Enantiopure acid refers to acid with specific chirality which will form salt and separate the isomers.
  • the Vilsmeier-Haack reaction is a widely used formylation reaction. It can be applied to introduce an aldehyde group on activated aromatic compounds.
  • N, N- dimethylformamide (DMF) and a chlorinating agent such as POCU are used to generate the Vilsmeier-Haack reagent.
  • salts of basic compounds of the present invention can be prepared by reacting free base form of the compound with a suitable acid, including, but not limited to acetate, trifiuoroacetate, adipate, citrate, aspartate, benzoate, benzenesulphonate, bisulfate, besylate, butyrate, camphorsulphonate, difluconate, hemisulfate, heptanoate, formate, fumarate, lactate, maleate, methanesulfonate, naphthylsulfonate, nicotinate, oxalate, picrate, pivalate, succinate, tartrate, trichloracetate, glutamate, p-toluenesulphonate, hydrochloric, hydrobro
  • derivatives refers to any compound prepared from Formula (IA), Formula (IB), Formula (IC), Formula (ID) or silodosin respectively by some chemical or physical process and may include, but is not limited to, esters, ethers, amino derivative and the like.
  • the singular forms “a”, “an”, and “the” include plural reference unless the context clearly dictates otherwise.
  • the terms “a” (or “an”), “one or more” and “at least one” can be used interchangeably herein.
  • the terms “comprising”, “including”, “characterized by” and “having” can be used interchangeably.
  • present invention provides a novel process for the preparation of indoline derivatives of Formula IA, Formula IB, their pharmaceutically acceptable derivatives, salts or solvates thereof.
  • R is a hydroxyl protecting group
  • Formula IA (i) converting the compound of Formula IA, either by isolating it or without isolating, to tartarate salt of Formula IB.
  • the suitable hydroxyl containing reagent used in step (a) of the present invention is not limited to any particular reagent, as long as it does not have an adverse effect in the condensation reaction resulting in formation of an ether derivative.
  • benzoic acid can be used as the hydroxyl containing reagent.
  • Suitable solvents that can be used in steps (a) to (i) of the present invention may be selected from a group comprising of polar protic solvents such as n-butanol, isopropanol, n-propanol, ethanol, methanol, water and the like; polar aprotic solvents such as dichloromethane, tetrahydrofuran, ethyl acetate, acetone, methyl isobutyl ketone, dimethylformamide, dimethylacetamide, acetonitrile, dimethyl sulfoxide and the like; non polar solvents such as hexane, benzene, toluene, 1,4-dioxane, chloroform, diethyl ether, methyl t-butyl ether and the like; and inorganic solvents such as ammonia (NH 3 ), concentrated sulfuric acid (H 2 S0 4 ) and the like; combination of two or more solvents from the list and
  • Suitable base that can be used in step (a) and step (b) of the present invention may be selected from a group comprising of alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; alkali metal carbonates such as sodium carbonate, potassium carbonate and the like; alkali metal phosphates such as sodium phosphate, sodium hydrogen phosphate, potassium phosphate, potassium hydrogen phosphate and the like; alkali metal biearbonates such as sodium bicarbonate, potassium bicarbonate and the like: alkali metal ⁇ lkoxide ⁇ uch ⁇ S-polassium ⁇ t-butoxide,- sodium ethoxide; alkali metal hydride such as potassium hydride, sodium hydride; and lower alkyl amine such as triethylamine, diisopropylethylamine, tributylamine, and the like; pyridine, dimethylaminopyridine, N-methylpyrrolidinone, N-methylmorpholine and the like
  • Suitable reducing agents that can be used in step (e) and step (h) of the present invention may be selected from a group comprising of Sodium Borohydride, Vitride, Sodium cyanoborohydride, sodium triacetoxy borohydride, sodium trimethoxy borohydride, zinc borohydride, hydrogenation catalysts such as palladium, nickel and the like in combination with hydrogen and the like.
  • the isolation of the solid in step (i) of the present invention can be carried out by conventional techniques, such as, for example, filtering, decanting, centrifuging and the like, or by filtering under an inert atmosphere using gases, such as, for example, nitrogen and the like.
  • the temperature range to carry out the step (a) to step (i) of the present invention may be selected from about 0°C to about 120°C.
  • Steps (a) to (i) of the present invention can be carried out either by isolating the product in each step or without the need of isolating the product in each step.
  • steps (a) to (i) of the present invention may be used with or without purification in their respective next step.
  • Steps (a) to (i) of the present invention may be carried out for any desired time periods to achieve the desired product yield and purity. Typical reaction times can vary from about 1 hour to 20 hours, or longer.
  • steps (a) to (i) of the present invention can be carried out in a single reactor (one pot reaction).
  • the present inV-ention ⁇ pmv ides reminda_process ⁇ or remindthe-preparation--of- compound of Formula I
  • the present invention provides the compound of Formula I obtained by the process of the present application, which is the key intermediate for the preparation of Silodosin, with both chemical and chiral HPLC purity greater than about 95%, preferably greater than about 99%, more preferably greater than about 99.5% and most preferably greater than about 99.8%.
  • the present invention relates to a novel process for the preparation of indoline derivatives of Formula IC, Formula ID, their pharmaceutically acceptable derivatives salts or solvates thereof
  • the present invention specifically provides a process for preparation of tartarate salt of 3-(5-((R)-2-aminopropyl)-7-cyanoindolin-l-yl) propyl benzoate of
  • step (b) resolving the racemic mixture of amine compound of Formula XII obtained in step (a), either by isolating it or without isolating, using suitable enantiopure acid in presence of suitable solvent to obtain tartarate salt of 3-(5-((R)-2- aminopropyl)-7-cyanoindolin-l-yl) propyl benzoate of Formula I.
  • Suitable reducing agents that can be used in step (a) of the present invention may be selected from a group comprising of Fe, Fe in acidic media like NH 4 CI or HCl or acetic acid, Sn in acidic media like HCl, Zn, Zn in acidic media like HCl or NH 4 CI or acetic acid, NaBHj with catalytic NiCl 2 .6H 2 0 or CoCl 2 .6H 2 0, Lithium borohydride, diborane, Sodium aluminium hydride, hydrazine hydrate, sodiumdithionate, sodium sulfide, ammonium sulfide, hydrogenation catalysts such as nickel, Raney nickel, rhodium, Pd- C combined with borohydrides, cyclohexene, acidic media like formic acid, H 3 P0 2 etc.,
  • the enantiopure acid used in step (b) of the present invention is selected from group comprising of L-(+)-Tartaric acid, D-(-)-Tartaric acid, L-(-)-Malic acid, D-(+)-Malic acid, N-Acetyl-L-glutamic acid, N-Acetyl-D-glutamic acid, (+)-Camphor sulfonic acid, (-)-Camphor sulfonic acid, S-(+)-Mandelic acid, R-(-)-Mandelic acid, (+)-Di benzoyl- D-tartaric acid, (-)-Di benzoyl-L-tartaric acid, (-)-Di- >-toluyl L-tartaric acid, (+)-Di-p- toluyl D-tartaric acid.
  • Tartaric acid is the preferred enantiopure acid.
  • the present invention specifically provides a novel process for the preparation of Tartarate salt of 3-(5-((R)-2-aminopropyl)-7-cyanoindolin-l-yl) propyl benzoate of Formula I
  • Formula ⁇ (i) converting the compound of Formula XII, either by isolating it or without isolating, to tartarate salt of 3-(5-((R)-2-aminopropyl)-7-cyanoindolin-l-yl) propyl benzoate of Formula I.
  • the present invention provides an improved, commercially viable and industrially advantageous process for the preparation of silodosin of Formula XVI
  • R is a hydroxyl protecting group
  • step (3) optionally converting silodosin of Formula XVI of step (3) to its pharmaceutical acceptable derivatives, salts or solvates.
  • the present invention even further discloses an improved, commercially viable and industrially advantageous process for the preparation of silodosin of Formula XVI
  • step (3) optionally converting silodosin of Formula XVI of step (3) to its pharmaceutical acceptable derivatives, salts or solvates.
  • the present invention discloses an improved, commercially viable and industrially advantageous process for the preparation of silodosin of Formula
  • step (3) optionally converting silodosin of Formula XVI of step (3) to its pharmaceutical acceptable derivatives, salts or solvates.
  • Suitable solvents that can be used in steps (1) to (4) of the present invention may be selected from a group comprising of polar protic solvents such as n-butanol, isopropanol, n-propanol, ethanol, methanol, water and the like; polar aprotic solvents such as dichloromethane, tetrahydrofuran, ethyl acetate, acetone, methyl isobutyl ketone, dimethylformamide, dimethylacetamide, acetonitrile (MeCN), dimethyl sulfoxide and the like; non polar solvents such as hexane, benzene, toluene, 1,4- dioxane, chloroform, diethyl ether, methyl t-butyl ether and the like; and inorganic solvents such as ammonia (NH 3 ), concentrated sulfuric acid (H 2 S0 4 ) and the like.
  • polar protic solvents such as
  • the temperature range to carry out the steps (1) to (4) of the present invention may be selected from about 0°C to about 80°C.
  • Steps (1) to (4) of the present invention may be carried out either by isolating the product in each step or without the need of isolating the product in each step.
  • the isolation of the solid in step (4) of the present invention can be carried out by conventional techniques, such as, for example, filtering, decanting, centrifuging and the like, or by filtering under an inert atmosphere using gases, such as, for example, nitrogen and the like.
  • Steps (1) to (4) may be carried out for any desired time periods to achieve the desired product yield and purity. Typical reaction times can vary from about 1 hour to 20 hours, or longer.
  • Reaction steps (1) to (4) of the present invention may be carried out in a single reactor (one pot reaction).
  • steps (1) to (4) of the present invention may be carried out in a single reactor (One pot reaction).
  • the products of steps (1) to (4) of the present invention may be used with or without purification in their respective next step.
  • steps (1) to (4) of the present invention may be purified by pharmaceutically acceptable salt formation in suitable solvents
  • the product obtained in any step of the present invention may be purified by using column chromatography and recrystallization can be carried out in suitable solvents.
  • the process of the present invention is short, utilizes readily available starting materials and does not involve the use of hazardous or difficult to handle reagents.
  • Each step of the process of the present invention is high yielding and affords products of very high purity. Thus the process is easy to scale up for industrial scale manufacturing.
  • Example 6 Preparation of 3-(5-(2-Aminopropyl)-7-cyanoindolin-l-yl)propyl benzoate of Formula ⁇ and Tartarate salt of (3-(5-((R)-2-Aminopropyl)-7- cyanoindolin-l-yl) propyl benzoate) of Formula I
  • the product was extracted from aqueous layer with MDC (40 ml).
  • the organic layer was treated with aqueous sodium hydroxide solution and washed twice with water (2 x 25 ml).
  • the organic layer was concentrated under vacuum to get 2.5 g of3-(5-(2-aminopropyl)-7-cyanoindolin-l-yl)propyl benzoate of Formula XII as a thick mass(HPLC purity is: 90.64%).
  • the MDC (80 ml) was added to the aqueous layer and basified the mixture by adding aqueous 20% NaOH solution. The obtained solid slurry mass was filtered and both the layers were separated from the filtrate. The organic layer was washed twice with water (2 x 100 ml) and concentrated under vacuum to get 8.5 g of 3-(5-(2-aminopropyl)-7- cyanoindolin-l-yl)propyl benzoate of Formula XII as a thick mass (HPLC purity is -abo-ve-95-%).
  • the product was extracted with ethyl acetate twice (2x 500 ml) and the combined organic layer was washed with 5% aqueous sodium bicarbonate solution (250 ml). The organic layer was further washed with water (250 ml) and the ethyl acetate was evaporated to get the crude mass, which was dissolved in isopropyl alcohol (300 ml) and was added 8.7 gm of oxalic acid at room temperature.
  • the salt was dissolved in water (150 ml) added ethyl acetate (300 ml), basified with K 2 C03 aqueous solution (150 ml) and washed the organic layer with water (150 ml).
  • the organic layer was concentrated to get l-(3-Hydroxypropyl)-5-[(2R)-2-( ⁇ 2-[2-(2,2,2- trifluoroethoxy)phenoxy]ethyl ⁇ amino)propyl]-2,3-dihydro-lH-indole-7-carbonitrile of Formula XVI as a thick gel (HPLC purity: >99 %)

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Indole Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un procédé amélioré pour la synthèse d'intermédiaire d'indoline et de ses dérivés, sels ou solvates pharmaceutiquement acceptables, utiles dans la synthèse de bloqueurs du récepteur α-1-adrénergique comme la silodosine.
PCT/IN2012/000201 2011-03-30 2012-03-27 Nouveau procédé pour la synthèse de dérivés d'indoline Ceased WO2012131710A2 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
IN888/DEL/2011 2011-03-30
IN3289/DEL/2011 2011-11-18
IN3289DE2011 2011-11-18
IN888DE2011 IN2011DE00888A (fr) 2011-03-30 2012-03-27

Publications (2)

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WO2012131710A2 true WO2012131710A2 (fr) 2012-10-04
WO2012131710A3 WO2012131710A3 (fr) 2013-03-14

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Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013056842A1 (fr) * 2011-10-21 2013-04-25 Sandoz Ag Procédé de préparation de silodosine
WO2014167507A1 (fr) 2013-04-09 2014-10-16 Mankind Research Centre Intermédiaires de n-haloalkylindoline, leur procédé et leur utilisation dans la préparation de silodosine et de ses dérivés
CN104230782A (zh) * 2013-06-09 2014-12-24 昆明积大制药股份有限公司 一种赛洛多辛的合成方法
WO2015015512A3 (fr) * 2013-07-29 2015-04-30 Ind-Swift Laboratories Limited Procédé de préparation de silodosine et de sa forme gamma
CN104744336A (zh) * 2013-12-26 2015-07-01 安徽省庆云医药化工有限公司 一种西洛多辛中间体及其制备方法,以及用该中间体制备西洛多辛的方法
WO2015126076A1 (fr) * 2014-02-20 2015-08-27 한미정밀화학주식회사 Nouvel intermédiaire utilisé dans la préparation de la silodosine, son procédé de préparation, et procédé de préparation de silodosine l'utilisant
JP2016023186A (ja) * 2014-07-24 2016-02-08 キョンボ ファーム カンパニー リミテッド シロドシンの製造方法および中間体
WO2016042441A1 (fr) 2014-09-18 2016-03-24 Mankind Research Centre Nouveau procédé de préparation de silodosine largement pure
KR20160109041A (ko) * 2015-03-09 2016-09-21 제이투에이치바이오텍 (주) 광학 활성을 갖는 인돌린 유도체 또는 이의 염의 신규 제조 방법
KR20160109736A (ko) 2015-03-13 2016-09-21 주식회사 한서켐 실로도신 제조 중간체의 제조방법
ES2607639A1 (es) * 2015-09-30 2017-04-03 Urquima, S.A Sal de ácido maleico de un intermedio de silodosina
CN106928118A (zh) * 2017-04-11 2017-07-07 常州瑞明药业有限公司 一种制备西洛多辛中间体的方法
US20170362174A1 (en) * 2015-03-05 2017-12-21 Sony Corporation A novel process for the preparation of considerably pure silodosin
CN108047116A (zh) * 2017-12-28 2018-05-18 常州瑞明药业有限公司 R-5-(2-氨基丙基)-1-(3-羟基丙基)-7-腈基吲哚啉的制备方法
WO2018205919A1 (fr) * 2017-05-10 2018-11-15 浙江天宇药业股份有限公司 Procédé pour la synthèse de silodosine et d'un intermédiaire de celle-ci
KR20200004492A (ko) * 2018-07-04 2020-01-14 주식회사 가피바이오 실로도신 합성용 중간체의 제조 방법 및 이를 이용한 실로도신의 제조 방법

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CN104744336A (zh) * 2013-12-26 2015-07-01 安徽省庆云医药化工有限公司 一种西洛多辛中间体及其制备方法,以及用该中间体制备西洛多辛的方法
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JP2016023186A (ja) * 2014-07-24 2016-02-08 キョンボ ファーム カンパニー リミテッド シロドシンの製造方法および中間体
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KR20160109041A (ko) * 2015-03-09 2016-09-21 제이투에이치바이오텍 (주) 광학 활성을 갖는 인돌린 유도체 또는 이의 염의 신규 제조 방법
KR101686087B1 (ko) 2015-03-09 2016-12-15 제이투에이치바이오텍 (주) 광학 활성을 갖는 인돌린 유도체 또는 이의 염의 신규 제조 방법
KR20160109736A (ko) 2015-03-13 2016-09-21 주식회사 한서켐 실로도신 제조 중간체의 제조방법
ES2607639A1 (es) * 2015-09-30 2017-04-03 Urquima, S.A Sal de ácido maleico de un intermedio de silodosina
JP2018530556A (ja) * 2015-09-30 2018-10-18 ウルキマ，ソシエダッド アノニマ シロドシン中間体のマレイン酸塩
WO2017055664A1 (fr) * 2015-09-30 2017-04-06 Urquima, S.A Sel d'acide maléïque d'un intermédiaire de silodosine
US10421719B2 (en) 2015-09-30 2019-09-24 Urquima S.A. Maleic acid salt of a silodosin intermediate
CN106928118A (zh) * 2017-04-11 2017-07-07 常州瑞明药业有限公司 一种制备西洛多辛中间体的方法
WO2018205919A1 (fr) * 2017-05-10 2018-11-15 浙江天宇药业股份有限公司 Procédé pour la synthèse de silodosine et d'un intermédiaire de celle-ci
JP2019523777A (ja) * 2017-05-10 2019-08-29 浙江天宇薬業股▲ふん▼有限公司 シロドシンおよびその中間体の合成方法
CN108047116A (zh) * 2017-12-28 2018-05-18 常州瑞明药业有限公司 R-5-(2-氨基丙基)-1-(3-羟基丙基)-7-腈基吲哚啉的制备方法
CN108047116B (zh) * 2017-12-28 2021-08-13 常州瑞明药业有限公司 R-5-(2-氨基丙基)-1-(3-羟基丙基)-7-腈基吲哚啉的制备方法
KR20200004492A (ko) * 2018-07-04 2020-01-14 주식회사 가피바이오 실로도신 합성용 중간체의 제조 방법 및 이를 이용한 실로도신의 제조 방법
KR102163068B1 (ko) 2018-07-04 2020-10-07 주식회사 가피바이오 실로도신 합성용 중간체의 제조 방법 및 이를 이용한 실로도신의 제조 방법

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