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WO2012147019A1 - Procédé amélioré de préparation de la silodosine - Google Patents

Procédé amélioré de préparation de la silodosine Download PDF

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Publication number
WO2012147019A1
WO2012147019A1 PCT/IB2012/052015 IB2012052015W WO2012147019A1 WO 2012147019 A1 WO2012147019 A1 WO 2012147019A1 IB 2012052015 W IB2012052015 W IB 2012052015W WO 2012147019 A1 WO2012147019 A1 WO 2012147019A1
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WO
WIPO (PCT)
Prior art keywords
propyl
formula
group
compound
trifluoroethoxy
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/IB2012/052015
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English (en)
Inventor
Buchi Reddy Reguri
Venkateshwar Goud THIRUMANI
Nagamani Nagabushanam
Kamala RAMASAMY
Suresh DEVINENI
Mahaboob Basha Shaik
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Orchid Pharma Ltd
Original Assignee
Orchid Chemicals and Pharmaceuticals Ltd
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Filing date
Publication date
Application filed by Orchid Chemicals and Pharmaceuticals Ltd filed Critical Orchid Chemicals and Pharmaceuticals Ltd
Publication of WO2012147019A1 publication Critical patent/WO2012147019A1/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
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D209/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with an alkyl or cycloalkyl radical attached to the ring nitrogen atom

Definitions

  • the present invention provides a process for the preparation of Silodosin of formula (I). More particularly, the present invention provides the process for preparation of tartrate salt of 3-[7-cyano-5[(2R)-2-( ⁇ 2-[2-(2,2,2- trifluoroethoxy)phenoxy ] ethyl ⁇ amino)propyl] -2, 3 -dihydro- 1 H-indol- 1 -y 1 ⁇ propyl benzoate of formula (IV), which is a precursor in the preparation of Silodosin.
  • a compound 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 (IV) is a key intermediate for preparation of Silodosin.
  • the chemical name of Silodosin is l-(3- hydroxypropyl)-5-[(2R)-2-( ⁇ 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl ⁇ amino) propyl]-2,3-dihydro-lH-indole-7-carboxamide and structurally represented as
  • U.S.Pat. No. 5,387,603 discloses Silodosin as therapeutic agents for the treatment of dysuria, urinary disturbance associated with benign prostatic hyperplasia.
  • U.S.Pat. No. 6,310,086 discloses a process for preparing a Silodosin analogue compound from reaction of (R)-3- ⁇ 5-(2-aminopropyl)-7-cyano-2,3- dihydro- 1 H-indol- 1 -yl jpropylbenzoate with 2-(2-Ethoxyphenoxy)ethyl methane sulfonate and finally isolated as residue and purified by column chromatography on silicagel.
  • the said literature process has certain drawbacks like use of column chromatography.
  • U.S.Pat. No. 7,834,193 discloses the process for preparation of monooxalate salt of 3- ⁇ 7-cyano-5-[(2R)-2-( ⁇ 2-[2-(2,2,2- trifluoroethoxy)phenoxy ] ethyl ⁇ amino)propyl] -2, 3 -dihydro- 1 H-indol- 1 -y 1 ⁇ propyl benzoate (IV).
  • This patent specifically discloses the preparation of monooxalate salt of formula (IV) helps to remove N,N-dialkyl impurity to certain extend.
  • CN 101993405 A discloses the reaction of (R)-5-(2-aminopropyl)-l-(3-(4- fluorobenzoyloxy)propyl)-7-cyanoindoline with 2-(2-(2,2,2-trifluoroethoxy) phenoxy)ethyl methane sulfonate followed by oxalic acid salt preparation.
  • the main objective of the present invention is to provide tartrate 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, which is a precursor in the synthesis of Silodosin.
  • Another objective of the present invention is to provide a process for the preparation of tartrate salt of 3- ⁇ 7-cyano-5-[(2R)-2-( ⁇ 2-[2-(2,2,2- trifluoroethoxy)phenoxy ] ethyl ⁇ amino)propyl] -2, 3 -dihydro- 1 H-indol- 1 -y 1 ⁇ propyl benzoate, which is easy to implement in industry with good yield and high purity.
  • Still another objective of the present invention is to provide a process for preparation of highly pure Silodosin from tartrate salt of 3- ⁇ 7-cyano-5-[(2R)-2-( ⁇ 2- [2-(2,2,2-trifluoroethoxy)phenoxy]etl yl ⁇ amino)propyl]-2,3-dihydro- lH-indol- 1 - yljpropyl benzoate.
  • first aspect of the present invention provides a process for the preparation of Silodosin which comprising steps of;
  • R represents hydroxyl protecting group selected from group comprising benzoyl, benzyl, benzyloxycarbonyl, tetrahydropyran, tert-butoxycarbonyl and L is a leaving group selected from group comprising chloro, bromo, iodo, alkylsulphonyloxy, arylsulphonyloxy;
  • second aspect of the present invention provides a process for the preparation of tartrate salt of compound of formula (IV) which comprising steps of: a) obtaining a solution of 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 (IV) in a solvent;
  • step (a) adding tartaric acid to step (a);
  • Fig. 1 illustrates the X-ray powder diffraction pattern of tartrate 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 (IV) of the present invention.
  • Fig. 2 illustrates the X-ray powder diffraction pattern of l-(3-hydroxypropyl)-5- [(2R)-2-( ⁇ 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl- ⁇ amino)propyl]-2,3-dihydro- 1H- indole-7-carbonitrile (V) of the present invention.
  • the solvent used in step (i) is selected from group comprising of ethylacetate, methylacetate, butylacetate, isopropylacetate, methoxy ethylacetate, acetone, methylisobutylketone, 2- pentanone, ethylmethylketone, diethylketone, methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutylalcohol, tert-butylalcohol, isoamylalcohol, 2- methoxyethanol, acetonitrile, dichloromethane, toluene, xylene or mixture thereof; preferably acetonitrile and the base used in step (i) is selected from an inorganic or organic base.
  • the inorganic base is selected from group comprising of sodium bicarbonate, potassium bicarbonate, lithium carbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide or mixture thereof and the organic base is selected from group comprising of diisopropylamine, diisopropylethylamine triethylamine, dimethylamine, trimethyl amine, pyridine or mixtures thereof.
  • the solvent used in step (ii) & a) is selected from group comprising of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutylalcohol, tert-butylalcohol, isoamylalcohol, 2- methoxyethanol ethylacetate, methyl acetate, butyl acetate, isopropyl acetate, methoxyethylacetate, acetone, methylisobutylketone, 2-pentanone, ethylmethylketone, diethylketone, acetonitrile, water and the like or mixtures there of.
  • the tartaric acid used in step (b) is either racemic or its stereoisomer preferably L (+)-tartaric acid.
  • process for preparation of tartrate salt of formula (IV) comprising treating compound of formula (IV) with an tartaric acid in a solvent at a temperature in the range of 20 °C to reflux of the used solvent.
  • the isolation of acid addition salt is done either by cooling the solution or by addition anti-solvent which is selected from group comprising of hexane, heptane, cyclohexane, cycloheptane, diisopropylether, MTBE, diethyl ether or mixture thereof.
  • R is a hydroxyl protecting group or H; and R 1 is either -CN or -CONH 2
  • the solvent used in step (iii) is selected from group comprising of methanol, ethanol, n-propanol, isopropanol, n- butanol, isobutylalcohol, tert-butylalcohol, isoamylalcohol water or mixture thereof; and base is selected from group comprising of lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, or mixture thereof.
  • the solvent used in step (iv) is selected from group comprising of dimethylformamide, dimethylacetamide, dimethylsulphoxide, sulfolane, water or mixture thereof and base is selected from group comprising of sodium bicarbonate, potassium bicarbonate, lithium carbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide or mixture thereof and the isolation of Silodosin done by either cooling the solution or addition of anti- solvent.
  • the preparation of Silodosin by its tartrate 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 (IV) found to have advantages, as this process yields final compound in good purity, yield and cost effective as well as the obtained Silodosin is highly pure and suitable for pharmaceutical compositions.
  • the silodosin obtained according to the invention can be optionally purified by crystallization methods like re-crystallization, dissolution followed by precipitation using anti-solvent.
  • the solvents used for crystallization includes but not limited to acetone, methylisobutylketone, ethylmethylketone, 2-pentanone, diethylketone, ethylacetate, n-butylacetate, tert-butylacetate, isopropylacetate, 2-methoxyethyl acetate, toluene, chlorobenzene, acetonitrile, dichloromethane, methanol, ethanol, isopropanol, n- butanol, tert-butyl alcohol, isoamyl alcohol, water, hexane, heptane, pentane, cyclohexane, petroleum ether or mixture thereof.
  • This purification removes all impurities, especially the de
  • the Silodosin obtained as per present invention can be further micronized, milled or sieved to get the desired particle size (D90 less than 200 preferably less than 100 more preferably less than 20 microns).
  • Silodosin prepared by the present invention is a free flow solid and suitable for pharmaceutical composition.
  • the starting material of 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl methansulfonate (II) is prepared by conventional method of prior art processes or by following Scheme-I OR II; SCHEME-I
  • Example 1 Preparation of tartrate 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
  • IV Method A: To the solution of 3- ⁇ 7-cyano-5-[(2R)-2-aminopropyl]-2,3-dihydro-lH- indol-l-yl ⁇ propyl benzoate (II) (1 mole) in acetonitrile were added sodium carbonate (41.3 grams) and 2-(2-(2,2,2-trifluoroethoxy)phenoxy)e
  • reaction mass cooled to room temperature, water and ethylacetate added over it, stirred and layer separated.
  • the obtained organic layer was washed with brine solution.
  • L (+) tartaric acid 29.2 grams was added at room temperature and stirred.
  • the solid obtained was filtered the solid and dried under vacuum at 50 ° - 55 °C; Yield: 110 grams.
  • Method B A mixture of acetonitrile, 3- ⁇ 7-cyano-5-[(2R)-2-aminopropyl]-2,3- dihydro-lH-indol-l-yl ⁇ propyl benzoate tartrate salt (II) (10 grams), potassium carbonate (13.4 grams) and 2-(2-(2,2,2-trifluoroethoxy)phenoxy)ethyl methane sulfonate (7.9 grams) of formula (III) was heated to reflux temperature till reaction completion. After reaction completion, the reaction mass quenched with water and extracted using ethylacetate twice.
  • Mobile Phase -A Dissolve about 2.72 g of potassium dihydrogen orthophosphate in 1000 ml of water. Adjust the pH 3.0 ⁇ 0.05 using Orthophosphoric acid, Filter the solution through 0.2 ⁇ porosity membrane filter and degas); Mobile Phase-B (Use filtered acetonitrile as mobile phase B); Diluent-Mix thoroughly water and Acetonitrile in the ratio 1 : 1;
  • Method A The compound of l-(3-hydroxypropyl)-5-[(2R)-2-( ⁇ 2-[2-(2,2,2- trifluoroethoxy)phenoxy] ethyl- ⁇ amino)propyl] -2,3 -dihydro- 1 H-indole-7- carbonitrile of formula (V) in dimethylsulfoxide was treated with 48% hydrogen peroxide and 20% sodium hydroxide solution and stirred at room temperature till completion of reaction. After completion of reaction, reaction mass quenched with 5% sodium bisulphite solution and ethylacetate was added over it. The ethylacetate layer was separated and treated with 20 % aqueous hydrochloric acid.
  • the aqueous layer separated, neutralized with sodium bicarbonate solution and extracted with ethylacetate.
  • the separated organic layer was washed with 10% sodium bicarbonate solution, brine solution and dried under vacuum.
  • the organic layer distilled upto residue under vacuum at 50-55°C. The obtained residue was crystallized in ethylacetate.
  • Method A To the mixture of toluene and acetonitrile solvent, Silodosin was added over it and heated to 50° - 55 °C for complete dissolution. The reaction mass gradually cooled to room temperature and maintained for completion of solid formation. The obtained solid is filtered, washed with toluene and dried under vacuum.
  • Method B To the mixture of ethyl acetate and toluene solvent, Silodosin was added over it and heated to 60° - 65 °C for complete dissolution. The reaction mass gradually cooled to room temperature and maintained for completion of solid formation. The obtained solid is filtered, washed with toluene and dried under vacuum.

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

Abstract

L'invention concerne un procédé de préparation de la silodosine représentée par la formule (I). L'invention concerne plus particulièrement un procédé de préparation d'un sel de tartrate de 3-[7-cyano-5[(2R)-2-({2-[2-(2,2,2- trifluoroethoxy)phenoxy]ethyl}amino)propyl]-2, 3-dihydro-1H-indol-1 -yl }propyl benzoate représenté par la formule (IV) qui est un précurseur dans la préparation de la silodosine.
PCT/IB2012/052015 2011-04-26 2012-04-21 Procédé amélioré de préparation de la silodosine Ceased WO2012147019A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN1449/CHE/2011 2011-04-26
IN1449CH2011 2011-04-26

Publications (1)

Publication Number Publication Date
WO2012147019A1 true WO2012147019A1 (fr) 2012-11-01

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Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103265470A (zh) * 2013-05-29 2013-08-28 华润赛科药业有限责任公司 一种赛洛多辛二烷基化物的合成方法
CN104557662A (zh) * 2014-12-26 2015-04-29 华润赛科药业有限责任公司 赛洛多辛二烷基化合物的合成方法
WO2015015512A3 (fr) * 2013-07-29 2015-04-30 Ind-Swift Laboratories Limited Procédé de préparation de silodosine et de sa forme gamma
WO2015119057A1 (fr) * 2014-02-06 2015-08-13 宇部興産株式会社 Procédé de production d'un composé indoline
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
JP2016003183A (ja) * 2014-06-13 2016-01-12 株式会社トクヤマ １−（３−ベンゾイルオキシプロピル）−７−シアノ−５−［（２ｒ）−２−（｛２−［２−（２，２，２−トリフルオロエトキシ）フェノキシ］エチル｝アミノ）プロピル］インドリンまたはその塩を製造する方法
WO2016042441A1 (fr) 2014-09-18 2016-03-24 Mankind Research Centre Nouveau procédé de préparation de silodosine largement pure
JP2016064988A (ja) * 2014-09-22 2016-04-28 株式会社トクヤマ １‐（３‐ベンゾイルオキシプロピル）‐７‐シアノ‐５‐［（２ｒ）‐２‐（｛２‐［２‐（２，２，２‐トリフルオロエトキシ）フェノキシ］エチル｝アミノ）プロピル］インドリンの酒石酸塩を製造する方法
KR20160048561A (ko) * 2014-10-24 2016-05-04 보령제약 주식회사 실로도신 γ 결정형의 제조방법
JP2016088847A (ja) * 2014-10-30 2016-05-23 株式会社トクヤマ （‐）‐１‐（３‐ヒドロキシプロピル）‐５‐［［（２ｒ）‐２‐（｛２‐［２‐（２，２，２‐トリフルオロエトキシ）フェノキシ］エチル｝アミノ）プロピル］‐２，３‐ジヒドロ‐１ｈ‐インドール‐７‐カルボキサミド］）の製造方法
WO2018100565A1 (fr) * 2016-11-30 2018-06-07 Granules India Limited Procédé de préparation de composés d'indoline
EP3357907A4 (fr) * 2015-09-30 2018-08-15 Urquima, S.A Sel d'acide maléïque d'un intermédiaire de silodosine
CN109574903A (zh) * 2017-09-28 2019-04-05 安徽省庆云医药股份有限公司 一种制备西洛多辛中间体的方法
US10377710B2 (en) 2015-03-05 2019-08-13 Mankind Pharma Ltd. Process for the preparation of considerably pure Silodosin
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
CN116063220A (zh) * 2023-03-07 2023-05-05 山西库邦生物医药科技有限公司 一种西洛多辛的制备方法

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JP2006188470A (ja) * 2005-01-07 2006-07-20 Kissei Pharmaceut Co Ltd インドリン誘導体およびその製造方法
US7834193B2 (en) * 2004-10-27 2010-11-16 Kissei Pharmaceutical Co., Ltd. Indoline compound and process for producing the same
CN101993405A (zh) * 2009-08-27 2011-03-30 浙江华海药业股份有限公司 吲哚啉衍生物、及其制备方法和用途

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US7834193B2 (en) * 2004-10-27 2010-11-16 Kissei Pharmaceutical Co., Ltd. Indoline compound and process for producing the same
JP2006188470A (ja) * 2005-01-07 2006-07-20 Kissei Pharmaceut Co Ltd インドリン誘導体およびその製造方法
CN101993405A (zh) * 2009-08-27 2011-03-30 浙江华海药业股份有限公司 吲哚啉衍生物、及其制备方法和用途

Cited By (26)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103265470B (zh) * 2013-05-29 2015-10-28 华润赛科药业有限责任公司 一种赛洛多辛二烷基化物的合成方法
CN103265470A (zh) * 2013-05-29 2013-08-28 华润赛科药业有限责任公司 一种赛洛多辛二烷基化物的合成方法
WO2015015512A3 (fr) * 2013-07-29 2015-04-30 Ind-Swift Laboratories Limited Procédé de préparation de silodosine et de sa forme gamma
CN105960394A (zh) * 2014-02-06 2016-09-21 宇部兴产株式会社 二氢吲哚化合物的制造方法
US9932308B2 (en) 2014-02-06 2018-04-03 Ube Industries, Ltd. Method for producing indoline compound
WO2015119057A1 (fr) * 2014-02-06 2015-08-13 宇部興産株式会社 Procédé de production d'un composé indoline
US9643921B2 (en) 2014-02-06 2017-05-09 Ube Industries, Ltd. Method for producing indoline compound
JPWO2015119057A1 (ja) * 2014-02-06 2017-03-23 宇部興産株式会社 インドリン化合物の製造方法
KR20160110517A (ko) 2014-02-06 2016-09-21 우베 고산 가부시키가이샤 인돌린 화합물의 제조 방법
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
JP2016003183A (ja) * 2014-06-13 2016-01-12 株式会社トクヤマ １−（３−ベンゾイルオキシプロピル）−７−シアノ−５−［（２ｒ）−２−（｛２−［２−（２，２，２−トリフルオロエトキシ）フェノキシ］エチル｝アミノ）プロピル］インドリンまたはその塩を製造する方法
WO2016042441A1 (fr) 2014-09-18 2016-03-24 Mankind Research Centre Nouveau procédé de préparation de silodosine largement pure
JP2016064988A (ja) * 2014-09-22 2016-04-28 株式会社トクヤマ １‐（３‐ベンゾイルオキシプロピル）‐７‐シアノ‐５‐［（２ｒ）‐２‐（｛２‐［２‐（２，２，２‐トリフルオロエトキシ）フェノキシ］エチル｝アミノ）プロピル］インドリンの酒石酸塩を製造する方法
KR20160048561A (ko) * 2014-10-24 2016-05-04 보령제약 주식회사 실로도신 γ 결정형의 제조방법
KR101673160B1 (ko) 2014-10-24 2016-11-07 보령제약 주식회사 실로도신 γ 결정형의 제조방법
JP2016088847A (ja) * 2014-10-30 2016-05-23 株式会社トクヤマ （‐）‐１‐（３‐ヒドロキシプロピル）‐５‐［［（２ｒ）‐２‐（｛２‐［２‐（２，２，２‐トリフルオロエトキシ）フェノキシ］エチル｝アミノ）プロピル］‐２，３‐ジヒドロ‐１ｈ‐インドール‐７‐カルボキサミド］）の製造方法
CN104557662A (zh) * 2014-12-26 2015-04-29 华润赛科药业有限责任公司 赛洛多辛二烷基化合物的合成方法
US10377710B2 (en) 2015-03-05 2019-08-13 Mankind Pharma Ltd. Process for the preparation of considerably pure Silodosin
EP3357907A4 (fr) * 2015-09-30 2018-08-15 Urquima, S.A Sel d'acide maléïque d'un intermédiaire de silodosine
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
US10421719B2 (en) 2015-09-30 2019-09-24 Urquima S.A. Maleic acid salt of a silodosin intermediate
WO2018100565A1 (fr) * 2016-11-30 2018-06-07 Granules India Limited Procédé de préparation de composés d'indoline
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
EP3450426A4 (fr) * 2017-05-10 2019-11-06 Zhejiang Tianyu Pharmaceutical Co., Ltd. Procédé pour la synthèse de silodosine et d'un intermédiaire de celle-ci
CN109574903A (zh) * 2017-09-28 2019-04-05 安徽省庆云医药股份有限公司 一种制备西洛多辛中间体的方法
CN116063220A (zh) * 2023-03-07 2023-05-05 山西库邦生物医药科技有限公司 一种西洛多辛的制备方法

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