US20150038727A1 - Method for preparing silodosin - Google Patents

Method for preparing silodosin Download PDF

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Publication number
US20150038727A1
US20150038727A1 US14/352,557 US201214352557A US2015038727A1 US 20150038727 A1 US20150038727 A1 US 20150038727A1 US 201214352557 A US201214352557 A US 201214352557A US 2015038727 A1 US2015038727 A1 US 2015038727A1
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US
United States
Prior art keywords
compound
formula
silodosin
acetate
process according
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.)
Abandoned
Application number
US14/352,557
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English (en)
Inventor
Parven Kumar Luthra
Sachin Bhuta
Chandrakant Pise Abhinay
N. Chavan Dattatraya
D. Metkar Shashikant
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.)
Sandoz AG
Original Assignee
Sandoz AG
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Sandoz AG filed Critical Sandoz AG
Priority to US14/352,557 priority Critical patent/US20150038727A1/en
Publication of US20150038727A1 publication Critical patent/US20150038727A1/en
Abandoned legal-status Critical Current

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Classifications

    • 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
    • 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
    • C07D209/12—Radicals substituted by oxygen atoms
    • 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 present invention relates to a process for preparing silodosin with high optical purity.
  • Silodosin is commercially available under the tradenames RAPAFLO® or UROREC® as a capsule formulation for oral use containing 4 mg or 8 mg of the drug. The capsules are to be taken orally once daily for the treatment of the signs and symptoms of benign prostatic hyperplasia.
  • U.S. Pat. No. 5,387,603 and EP 0 600 675 disclose silodosin as a therapeutic agent for the treatment for dysurea associated with benign prostatic hyperplasia. The molecular structure of silodosin (XXV) is shown below.
  • silodosin The synthesis of silodosin is relatively complex and requires a sequence of multiple steps.
  • a key intermediate compound in the synthesis of silodosin is the optically active amine compound represented by the general formula R-V:
  • R 1 represents a protecting group and R 2 represents a cyano (CN) or carbamoyl (CONH 2 ) group.
  • the intermediate compound R-V bears the asymmetric carbon atom that imparts the optical activity to silodosin. Therefore, it is important to obtain the compound R-V with high optical purity, because according to the methods reported in the state of the art the optical purity of the compound R-V determines the optical purity of the final product silodosin.
  • JP 2001-199956 discloses a process for the preparation of a compound of formula R-V, wherein 1-(3-benzoyloxypropyl)-7-cyano-5-(2-oxopropyl)-2,3-dihydroindole or the corresponding 7-carbamoyl derivative is reacted with an optically active amine, namely L-2-phenylglycinol or L-1-phenylethanamine, to afford an imine compound of formula III as depicted in the below scheme 1.
  • an optically active amine namely L-2-phenylglycinol or L-1-phenylethanamine
  • the optically active imine III is subjected to catalytic hydrogenation using platinum(IV) oxide as a catalyst affording the diastereomers IV in a ratio of 3.8:1.
  • the chiral auxiliary II is subsequently removed by catalytic hydrogenation using 10% palladium on carbon, i.e. under the typical conditions which lead to the cleavage and removal of benzylic protecting groups from nitrogen or oxygen atoms.
  • the catalytic deprotection reaction affords the desired intermediate compound R-V with an optical purity corresponding to the ratio of the diasteromers obtained in the previous step, i.e. the ratio of compound R-V to S-V is approximately 3.8:1, which corresponds to an optical purity of approximately 58.3% enantiomeric excess (e.e.).
  • the process involves the reaction of an enantiomeric mixture of the compound of formula VI with (1S,2R)-2-benzylaminocyclohexane methanol (VII) to obtain a diastereomeric mixture containing the salt VIII. After a series of crystallizations the diastereomer VIII was obtained with an optical purity of 92.8% diastereomeric excess (d.e.). Subsequently, the salt VIII was treated with an acidic aqueous solution to release the acid R-VI from the salt. After extraction from the aqueous solution with ethyl acetate the acid R-VI is converted into its amide IX. The compound IX is finally subjected to a Hofmann type rearrangement reaction to obtain the desired intermediate compound R-V.
  • WO 2011/030356 discloses a process for the preparation of the intermediate compound R-V, which avoids the resolution of the enantiomers of specific intermediate compounds using chiral auxiliaries or optically active bases.
  • the route of synthesis described in WO 2011/030356 starts from L-alanine (X), which is a naturally occurring optically active amino acid.
  • the process described in WO 2011/030356 is depicted in the below scheme 3.
  • the amino acid is protected by the addition of ethyl chloroformate and subsequently activated by the addition of oxalyl chloride to afford R—(N-ethoxycarbonyl)alanine as an acyl chloride (XI).
  • Said acyl chloride is reacted with hydroxy protected 1-(3-hydroxypropyl)-7-cyano-2,3-dihydroindole of formula XII in a Friedel-Crafts acylation reaction, which gives a compound of formula XIII.
  • the oxo group in compound XIII is reduced to afford a compound of formula XIV that is subsequently subjected to a hydrolysis reaction to yield the key intermediate compound R-V.
  • silodosin with sufficiently high optical purity i.e. a silodosin or a pharmaceutically acceptable salt thereof with an optical purity of at least 95% e.e., preferably at least 98% e.e., more preferred at least 99% e.e., and most preferred at least 99.9% e.e.
  • the key intermediate compound R-V is provided with an optical purity of at least 85% e.e., which affords a crude silodosin with the same optical purity of at least 85% e.e., the crude silodosin can be easily purified by crystallization to obtain the drug with high optical purity. Accordingly, it is not necessary to obtain compound R-V with high optical purity in order to induce a high optical purity in the final product silodosin. It was further found that compound R-V can be obtained with sufficiently high optical purity, i.e. at least 85% e.e., by resolving the enantiomers contained in a racemic mixture of a compound represented by the general formula V:
  • R 1 is the protecting group
  • R 2 is cyano or carbamoyl
  • Suitable hydroxy protecting groups are those well known in the art and which may be removed under conventional conditions without disrupting the remainder of the molecule.
  • Particularly suitable hydroxy protecting groups include, for example, triorganosilyl groups, such as triC 1-6 -alkylsilyl, e.g. trimethylsilyl (TMS) and tert-butyl dimethylsilyl (TBDMS), organocarbonyl and organooxycarbonyl groups, such as acetyl, benzoyl (COPh), C 1-6 -alkoxycarbonyl and 4-methoxybenzoyl-oxycarbonyl, unsaturated C 2-6 -alkyl groups, such as allyl and propargyl, and the benzyl group (Bn).
  • triorganosilyl groups such as triC 1-6 -alkylsilyl, e.g. trimethylsilyl (TMS) and tert-butyl dimethylsilyl (TBDMS)
  • the present invention thus relates to a process for preparing silodosin of formula XXV:
  • step (a) If in step (a) above the mixture of the compound of formula V is only partially resolved, so that the silodosin or pharmaceutically acceptable salt thereof obtained in method step (c) has an optical purity of between 85% and 95% e.e., preferably between 85% and 98% e.e., the purification of the silodosin obtained in step (c) by crystallization from a solvent is required in order to improve the optical purity up to at least 95% e.e., preferably at least 98% e.e., more preferred at least 99% e.e., and most preferred at least 99.9% e.e.
  • the solvent used in method step (d) should contain a carboxylic acid ester, preferably is a carboxylic acid ester.
  • the carboxylic acid ester is a C1-6-alkyl acetate, e.g. ethyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate or a mixture thereof.
  • step (a) The separation of the compound of formula R-V in step (a) may be conducted by
  • the optically active acid is L-tartaric acid.
  • the water-immiscible solvent used in the extraction step (iv) preferably contains or is a carboxylic acid ester.
  • the carboxylic acid ester may be a C 1-6 -alkyl acetate, preferably ethyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate or a mixture thereof.
  • the compound V used in the process of the present invention is obtainable by reducing a compound represented by the general formula XX:
  • R 1 has the same meaning as defined above.
  • the reduction of the compound XX is usually a catalytic hydrogenation using, e.g. platinum on charcoal (e.g. 5% Pt/C) or platinum (IV) oxide as a catalyst.
  • the hydroxy protected compound XV i.e. hydroxy protected 1-(3-hydroxypropyl)-2,3-dihydroindole
  • DMF dimethylformamide
  • POCl 3 phosphoryl chloride
  • the aldol condensation with nitroethane gives compound XVII that is subsequently reduced, e.g. with sodium boranate, to afford the nitro compound XVIII.
  • An additional formyl group is introduced at position 7 of the indoline moiety in a second Vilsmeier reaction to obtain the compound XIX.
  • the intermediate compound XXIV may contain an impurity derived from the reaction of compound R-V with two molecules of compounds XXII or XXIII, i.e. the corresponding tertiary amine.
  • the intermediate compound XXIV may be crystallized in form of its oxalic acid addition salt as described in EP 1 806 340 prior to the following deprotection reaction.
  • the present invention relates to the use of a racemic mixture of a compound of formula V,
  • R 1 is a protecting group
  • R 2 is cyano or carbamoyl, for the preparation of silodosin or a pharmaceutically acceptable salt thereof.
  • the racemic mixture of the compound of formula V may be subjected to an enantiomeric resolution procedure to obtain a0 compound of formula R-V:
  • the silodosin or a pharmaceutically acceptable salt thereof having an optical purity of at least 85% e.e., corresponding to the optical purity obtained in the aforementioned resolution procedure can then be purified by crystallization from a solvent to obtain a silodosin or a pharmaceutically acceptable salt thereof with an optical purity of at least 95% e.e., preferably at least 98% e.e., more preferred at least 99% e.e., most preferred at least 99.9% e.e.
  • the solvent used for crystallizing silodosin or a pharmaceutically acceptable salt thereof contains a carboxylic acid ester, more preferred is a carboxylic acid ester.
  • the carboxylic acid ester include C 1-6 -alkyl acetates as ethyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate and mixtures thereof, most preferred is ethyl acetate, isopropyl acetate or a mixture thereof.
  • the compound XXI-tartrate (10.0 g) was neutralized using an aqueous sodium hydroxide solution.
  • the compound R-V was extracted with ethyl acetate.
  • the ethyl acetate solution containing compound R-V was directly used in the following example 10.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Indole Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
US14/352,557 2011-10-21 2012-10-19 Method for preparing silodosin Abandoned US20150038727A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US14/352,557 US20150038727A1 (en) 2011-10-21 2012-10-19 Method for preparing silodosin

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US201161549800P 2011-10-21 2011-10-21
EP11008484.5 2011-10-21
EP11008484 2011-10-21
PCT/EP2012/004378 WO2013056842A1 (en) 2011-10-21 2012-10-19 Method for preparing silodosin
US14/352,557 US20150038727A1 (en) 2011-10-21 2012-10-19 Method for preparing silodosin

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2012/004378 A-371-Of-International WO2013056842A1 (en) 2011-10-21 2012-10-19 Method for preparing silodosin

Related Child Applications (1)

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US14/976,140 Continuation US9938239B2 (en) 2011-10-21 2015-12-21 Method for preparing silodosin

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Country Status (6)

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US (2) US20150038727A1 (enrdf_load_stackoverflow)
EP (1) EP2768806B1 (enrdf_load_stackoverflow)
CN (1) CN104302621A (enrdf_load_stackoverflow)
ES (1) ES2639196T3 (enrdf_load_stackoverflow)
IN (1) IN2014KN01030A (enrdf_load_stackoverflow)
WO (1) WO2013056842A1 (enrdf_load_stackoverflow)

Families Citing this family (11)

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KR101447574B1 (ko) * 2013-11-29 2014-10-07 동국제약 주식회사 신규 중간체를 이용한 실로도신의 제조방법
KR102114323B1 (ko) * 2013-12-09 2020-05-22 이니스트에스티 주식회사 광학활성 1-(인돌린-5-일)프로판-2-올 유도체의 제조방법
KR101628946B1 (ko) * 2014-07-09 2016-06-09 동방에프티엘(주) 실로도신의 개선된 제조방법
WO2016189552A2 (en) * 2015-05-26 2016-12-01 Ipca Laboratories Limited Novel recovery and recycling process of unwanted enantiomers of 2-aminopropyl indoline derivatives
ES2607639B1 (es) 2015-09-30 2018-02-28 Urquima, S.A Sal de ácido maleico de un intermedio de silodosina
CN106995399A (zh) * 2016-01-25 2017-08-01 北京天泰恒华医药技术有限公司 一种制备赛洛多辛的方法
CN106083689B (zh) * 2016-06-14 2020-07-31 齐鲁制药有限公司 一种赛洛多辛化合物的制备方法
CN106496092B (zh) * 2016-08-30 2019-03-29 江苏宇田医药有限公司 一种用于合成西洛多辛的中间体的制备方法
CN106380438B (zh) * 2016-08-30 2019-07-30 江苏宇田医药有限公司 一种用于合成西洛多辛的吲哚啉衍生物的制备方法
CN106928118B (zh) * 2017-04-11 2022-08-23 常州瑞明药业有限公司 一种制备西洛多辛中间体的方法
EP3892615A1 (en) 2020-04-09 2021-10-13 Minakem Process for the preparation of silodosin

Citations (1)

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Publication number Priority date Publication date Assignee Title
WO2011124704A1 (en) * 2010-04-09 2011-10-13 Ratiopharm Gmbh Process for preparing an intermediate for silodosin

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JP4921646B2 (ja) 2001-03-08 2012-04-25 キッセイ薬品工業株式会社 １−（３−ベンジルオキシプロピル）−５−（２−置換プロピル）インドリン誘導体およびその使用方法
RU2379289C2 (ru) 2004-10-27 2010-01-20 Киссеи Фармасьютикал Ко., Лтд. Соединение индолина и способ его получения
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CN101993406B (zh) * 2009-08-27 2014-01-15 浙江华海药业股份有限公司 光学活性的吲哚啉化合物及其制备方法
WO2011030356A2 (en) * 2009-09-12 2011-03-17 Sandoz Ag Process for the preparation of indoline derivatives and their intermediates thereof
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WO2012131710A2 (en) * 2011-03-30 2012-10-04 Panacea Biotec Ltd Novel process for the synthesis of indoline derivatives

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Publication number Priority date Publication date Assignee Title
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Also Published As

Publication number Publication date
WO2013056842A1 (en) 2013-04-25
US20160176818A1 (en) 2016-06-23
EP2768806B1 (en) 2017-05-31
ES2639196T3 (es) 2017-10-25
CN104302621A (zh) 2015-01-21
US9938239B2 (en) 2018-04-10
IN2014KN01030A (enrdf_load_stackoverflow) 2015-10-09
EP2768806A1 (en) 2014-08-27

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