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WO2009115902A1 - Procédé permettant de préparer du carvedilol par protection silyle d'amine substituée - Google Patents

Procédé permettant de préparer du carvedilol par protection silyle d'amine substituée Download PDF

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Publication number
WO2009115902A1
WO2009115902A1 PCT/IB2009/000551 IB2009000551W WO2009115902A1 WO 2009115902 A1 WO2009115902 A1 WO 2009115902A1 IB 2009000551 W IB2009000551 W IB 2009000551W WO 2009115902 A1 WO2009115902 A1 WO 2009115902A1
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WO
WIPO (PCT)
Prior art keywords
carvedilol
formula
compound
viii
give
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/IB2009/000551
Other languages
English (en)
Inventor
Indravadan Ambalal Modi
Sanjay Laxamanbhai Patel
Sanjay Muktawat
Ramasubbu Chadrasekaran
Ravi Ponnaiah
Bakulesh Mafatlal Khamar
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.)
Cadila Pharmaceuticals Ltd
Original Assignee
Cadila Pharmaceuticals Ltd
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 Cadila Pharmaceuticals Ltd filed Critical Cadila Pharmaceuticals Ltd
Publication of WO2009115902A1 publication Critical patent/WO2009115902A1/fr
Anticipated expiration legal-status Critical
Ceased 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
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/80—[b, c]- or [b, d]-condensed
    • C07D209/82—Carbazoles; Hydrogenated carbazoles
    • C07D209/88—Carbazoles; Hydrogenated carbazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/10—Compounds having one or more C—Si linkages containing nitrogen having a Si-N linkage

Definitions

  • the invention relates to an improved process for preparation of Carvedilol.
  • the present invention relates to process for making Carvedilol, chemically known as ( ⁇ )- 1 -(carbazol-4-yloxy)-3-[[2-(2-methoxyphenoxy)ethyl]-amino]-2-propanol having structural formula -I
  • Carvedilol contains one chiral center.
  • the racemic mixture containing equal amounts of R(+) and S(-) enantiomers is commercial product.
  • European patent no. 918055 discloses two processes for preparation of Carvedilol.
  • the process (A) comprises reaction of 4-(oxiranylmethoxy)-9H-carbazole with N-[2- ⁇ 2'-(methoxy)- phenoxy ⁇ -ethyl]-benzylamine in a protic organic solvent to give benzyl protected Carvedilol [ Formula-Ill ], which on debenzylation using catalytic hydrogenation gives carvedilol.
  • the process (B) comprisies reaction of protected N-[2- ⁇ 2'-(methoxy)-phenoxy ⁇ -ethyl]- benzyl amine (Formula-IV) with epichlorohydrin to form chloro compound, 1-[N- ⁇ benzyl ⁇ -2'-( ⁇ 2"- (methoxy)-phenoxy)-ethyl ⁇ -amino]-3-chloro-propan-2-ol (Formula-V).
  • the intermediate chloro compound (Formula-V) reacts with 4-(hydroxyl)-9H-carbazole (Formula-VI) in the presence of base to give benzyl protected carvedilol (Formula-Ill) which is converted to carvedilol using catalytic hydrogenation.
  • the US patent 7,126,008 discloses process for preparing Carvedilol comprising reaction of 4- (oxiran-2-yl-methoxy)-9H-carbazole with 2-(2-methoxyphenoxy)-ethylamine, wherein the ethyl amine compound is taken in large excess to minimize the formation of bis impurity (Formula-ll) making the process commercially less attractive.
  • Other processes for making Carvedilol are also known, international application No.
  • WO2004/041783 discloses the process for preparation of Carvedilol comprising reacting 4- (oxiranylmethoxy)-9H-carbazole with a salt of 2-(2-methoxyphenoxy)-ethylamine in presence of alkaline earth metal carbonate in C 2 -C 5 alcohols as solvents. The product on crystallization in ethyl acetate yields 41% Carvedilol.
  • the international application No. WO/2006/061364 discloses reaction of 4-(oxiran-2-ylmethoxy)-9H-carbazole with 2-(2-methoxyphenoxy)- ethylamine using ethyl acetate as solvent. All the processes reported so far, produce Carvedilol in low yields or make use of expensive catalyst.
  • An object of the invention is to provide a novel process for preparing Carvedilol by reaction of 4-(oxiran-2-yl-methoxy)-9H-carbazole [Formula-VII] and substituted silyl protected 2-
  • Yet another object of the invention is to provide novel substituted silylated carvedilol intermediate [Formula-IX]
  • the most preferred being one with Still, yet another object of the invention is to provide a novel substituted silyl protected
  • 2-(2-methoxy phenoxy)-ethylamine as an intermediate for the preparation of Carvedilol and process for the preparation thereof.
  • the novel process of this invention is illustrated in scheme-1.
  • the process comprises of following steps. a) reacting 2-(2-methoxyphenoxy)ethylamine [Formula-Villa ] with silylating agent in an organic solvent to give N-substituted silylated compound of Formula-(VIII), wherein silyl substituent P is - Si(R 1 )(R 2 )(R 3 ) wherein Ri,R 2 ,& R 3 is C 1 -C 4 alkyl , b) reacting compound of Formula-(VIII) with 4-(2,3-Epoxypropoxy)-carbazole [Formula- VII] to give substituted silyl protected compound [Formula-IX] , wherein P is as defined above, c) desilylation of substituted silyl protected Carvedilol to give Carvedilol, followed by isolation and purification to give high purity carvedilol.
  • Yet another aspect of the invention is to provide a novel substituted silyl protected 2-(2- methoxy phenoxy)-ethylamine (Formula-VIII) as an intermediate for the preparation of Carvedilol.
  • the silyl protected amine compound is prepared by silylation of an amine compound using silylating agents such as hexamethyl disilazane, trimethyl chlorosilane, bistrimethyl silyl urea (BSU) 1 bistrimethyl acetamide (BSA), tert-butyl dimethyl silyl chloride.
  • the reaction is carried out at 2O 0 C to 15O 0 C, preferably at 25 0 C to 100 0 C, more preferably at 50 0 C to 100 0 C.
  • the substituted silyl protected amine compound [Formula-VIII] is reacted with an epoxy intermediate [Formula-VII] to give substituted silyl protected Carvedilol [Formula-IX] .
  • the reaction is carried out in solvent selected from aromatic hydrocarbons such as benzene, toluene, xylene or mixtures thereof ; ethers such as Tetrahydrofuran [THF] ,dioxane,2- methyl THF, dipropyl ether.di n-butyl ether, Methyl tertiary butyl ether [MTBE], monoglyme or mixtures thereof; chlorinated solvents such as dichloro methane, chloroform, carbon tetra chloride, chlorobenzene or mixtures thereof; amides such as N,N-dimethyl formamide, N 1 N- dimethyl acetamide, N-methyl pyrrolidone , N.N'dimethyl imidazoline 2-one, N 1 N 1 N', N'- tetramethyl urea or mixtures thereof ; nitriles such as acetonitrile, propionitrile or mixtures thereof; the preferred solvent being toluene
  • the substituted silyl protected Carvedilol compound gives carvedilol upon deprotection.
  • the deprotection is preferably carried out in aqueous acid followed by isolation of Carvedilol from reaction mass and purification to provide high purity carvedilol.
  • 2-(2-methoxyphenoxy)ethyl amine in toluene is reacted with with trimethylsilylchloride in presence of acid scavenger like trialkyl amine, preferably triethyl amine to give trimethyl silyl protected2-(2- methoxyphenoxy)ethyl amine which is then reacted with 4-(2,3-epoxypropoxy)carbazole at about reflux temperature for about 4-5 hrs.
  • the reaction mass is then cooled and acid preferably , phosphoric acid solution is added slowly, followed by addition of water (50ml). The layer is allowed to separate and liq. ammonia is added to give pH -9-9.5.
  • Example -1 Preparation of Carvedilol i
  • Bis-trimethylsilylurea (21.35gm) was added to 2-(2-methoxyphenoxy)ethyl amine (17.47gm) in toluene (75 ml) at RT.
  • the reaction mass was heated at reflux temperature for 3 hrs and allowed to cool at 80 to 85 0 C temperature.
  • 4-(2,3-epoxypropoxy)carbazole (25gm) was added and refluxed for 5-6 hrs.
  • the reaction mass was further allowed to cool at temperature of 55 to 60 0 C.
  • Water 25 ml was added and stirred for 15 minutes. The solvent is removed by distillation under reduced pressure at 55 to 6O 0 C.
  • Ethyl acetate (2x 500ml) was added and stirred.

Landscapes

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

Abstract

L'invention concerne un nouveau procédé permettant de préparer du carvedilol par réaction de 4-(oxiran-2-yl-méthoxy)-9H-carbazole et d'un composé substitué de 2-(2-méthoxy phénoxy)-éthylamine protégé par un groupe silyle pour donner un intermédiaire de carvedilol protégé par un groupe silyle. L'intermédiaire de carvedilol protégé par un groupe silyle donne du carvedilol, après désilylation. L'invention propose en outre un nouveau composé substitué de 2-(2-méthoxy phénoxy)-éthylamine protégé par un groupe silyle en tant qu'intermédiaire clé pour la préparation du carvedilol.
PCT/IB2009/000551 2008-03-19 2009-03-19 Procédé permettant de préparer du carvedilol par protection silyle d'amine substituée Ceased WO2009115902A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN562MU2008 2008-03-19
IN562/MUM/2008 2008-03-19

Publications (1)

Publication Number Publication Date
WO2009115902A1 true WO2009115902A1 (fr) 2009-09-24

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2009/000551 Ceased WO2009115902A1 (fr) 2008-03-19 2009-03-19 Procédé permettant de préparer du carvedilol par protection silyle d'amine substituée

Country Status (1)

Country Link
WO (1) WO2009115902A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102190613A (zh) * 2010-03-14 2011-09-21 浙江华海药业股份有限公司 一种卡维地洛的制备方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4503067A (en) * 1978-04-13 1985-03-05 Boehringer Mannheim Gmbh Carbazolyl-(4)-oxypropanolamine compounds and therapeutic compositions
EP0918055A1 (fr) * 1997-11-24 1999-05-26 Egis Gyogyszergyar Rt. Procédé pour la préparation de 1-(9'H-carbazol-4'yloxy)-3-(2''-(2'''-méthoxy-phénoxy)éthyl)-amino)-propan-2-ol (carvedilol) et composés intermédiaires
US20040225132A1 (en) * 2000-06-28 2004-11-11 Jean Hildesheim Carvedilol

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4503067A (en) * 1978-04-13 1985-03-05 Boehringer Mannheim Gmbh Carbazolyl-(4)-oxypropanolamine compounds and therapeutic compositions
EP0918055A1 (fr) * 1997-11-24 1999-05-26 Egis Gyogyszergyar Rt. Procédé pour la préparation de 1-(9'H-carbazol-4'yloxy)-3-(2''-(2'''-méthoxy-phénoxy)éthyl)-amino)-propan-2-ol (carvedilol) et composés intermédiaires
US20040225132A1 (en) * 2000-06-28 2004-11-11 Jean Hildesheim Carvedilol

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
ATKINS R K ET AL: "ALKYLATION OF N TRIMETHYLSILYLATED PRIMARY AMINES WITH ARYLETHYLENE OXIDES AN EFFICIENT SYNTHESIS OF 1 PHENETHANOLAMINES", TETRAHEDRON LETTERS, vol. 27, no. 22, 1986, pages 2451 - 2454, XP002536852, ISSN: 0040-4039 *
KUWABE S I ET AL: "Palladium-catalyzed intramolecular C-O bond formation.", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY 12 DEC 2001, vol. 123, no. 49, 12 December 2001 (2001-12-12), pages 12202 - 12206, XP002536853, ISSN: 0002-7863 *
SHUKER A J ET AL: "The Application of High-Throughput Synthesis And Purification To The Preparation Of Ethanolamines", TETRAHEDRON LETTERS, ELSEVIER, AMSTERDAM, vol. 38, no. 35, 1 September 1997 (1997-09-01), pages 6149 - 6152, XP004086721, ISSN: 0040-4039 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102190613A (zh) * 2010-03-14 2011-09-21 浙江华海药业股份有限公司 一种卡维地洛的制备方法

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