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WO2008038301A1 - Procédé pour la préparation de carvédilol - Google Patents

Procédé pour la préparation de carvédilol Download PDF

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Publication number
WO2008038301A1
WO2008038301A1 PCT/IN2007/000389 IN2007000389W WO2008038301A1 WO 2008038301 A1 WO2008038301 A1 WO 2008038301A1 IN 2007000389 W IN2007000389 W IN 2007000389W WO 2008038301 A1 WO2008038301 A1 WO 2008038301A1
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WO
WIPO (PCT)
Prior art keywords
aliphatic
acid
solvents
carvedilol
mixture
Prior art date
Application number
PCT/IN2007/000389
Other languages
English (en)
Inventor
Sanjay Suri
Tapan Kashyap
Original Assignee
Morepen Laboratories Limited
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 Morepen Laboratories Limited filed Critical Morepen Laboratories Limited
Publication of WO2008038301A1 publication Critical patent/WO2008038301A1/fr

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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

Definitions

  • the present invention particularly relates to an improved process for the preparation of Carvedilol of formula (I) in high yield and high HPLC purity.
  • the invention relates to a process wherein the intermediate 4-(2,3- epoxypropoxy) carbazole is isolated directly as solid in high yield and in excellent purity from reaction mixture and tedious work-up, such as extraction of intermediate using solvent, recovery of solvent etc, is avoided. Furthermore, the highly pure (ICH grade) Carvedilol is obtained either through solvent crystallization (without salt formation) or through salt formation followed by salt cleavage and solvent crystallization.
  • Carvedilol has a chiral centre and can exist either as individual stereo isomer or as in racemic form. Racemic Carvedilol is the active ingredient of COREG ® , which is indicated for the treatment of congestive heart failure and for the management of hypertension. Since Carvedilol is a multiple action drug, its beta-blocking activity affects the response to certain nerve impulses in parts of the body. Carvedilol is also known to be a vasodilator resulting primarily from alfa-adrenoceptor blockade. The multiple actions of Carvedilol are responsible for the anti hypertensive efficacy of the drug and for its effectiveness in managing congestive heart failure.
  • US 4503067 discloses a process for preparation of Carvedilol wherein A- (oxiran-2-ylmethoxy)-9H-carbazole is reacted with 2- (2- methoxyphenoxy) ethylamine (IV) in a molar ratio of 1: 1.1 and the reaction was carried out at 50 0 C temperature for 25 hours. The process gives low yield of 39 %. A considerable amount of by-product (formula V) is formed, resulting in a low yield of desired product and making the purification difficult.
  • A- (oxiran-2-ylmethoxy)-9H-carbazole is reacted with 2- (2- methoxyphenoxy) ethylamine (IV) in a molar ratio of 1: 1.1 and the reaction was carried out at 50 0 C temperature for 25 hours.
  • the process gives low yield of 39 %.
  • a considerable amount of by-product (formula V) is formed, resulting in a low yield of desired product and making the purification difficult
  • US 2002/0143045 discloses the preparation of Carvedilol by reaction of 4- (oxiran-2-ylmethoxy)-9H carbazole with 2- (2-methoxyphenoxy) ethylamine in 1: 1.5 to 1 : 100 molar ratio without solvent in neat condition at 100 0 C to minimize the formation of compound (V) as by-product.
  • Patent applications WO2005/080329A2 and WO2004/094378A1 discloses the formation of oxalic acid, tartaric acid, benzoic acid and salicylic acid salts of Carvedilol • followed by its conversion to Carvedilo! and then purification of resulting product in organic solvents whereas WO2004/041783A1 reported the use of 2-(2- methoxyphenoxy) ethylamine hydrogen chloride monohydrate and EP918055 discloses the use of N-benzylated 2-(2-methoxyphenoxy) ethylamine for its reaction with 4-(2,3- epoxypropoxy) carbazole for preparation of Carvedilol (I). Due to toxic nature of N- benzyl impurity, European pharmacopoeia has fixed the limits of this impurity not more than 0.02% and practically it is very difficult to achieve. Further, the catalytic hydrogenation in final stage is not advisable.
  • the novelty of the present invention resides in preparing intermediate of carvedilol in which the tedious work-up, extraction steps, and repeated purifications are avoided in order to get increased yield and purity along with reduced reaction steps for reduction in batch time cycle and avoiding any degradation of the final product and intermediate.
  • the main object of the present invention is to provide an improved process for the preparation of Carvedilol obviating the drawbacks of the existing processes.
  • Another object of the present invention is to provide a process for the preparation of Carvedilol in high yield, high HPLC purity.
  • Another object of the invention is to provide a process wherein the intermediate 4-(2,3- epoxypropoxy)carbazole is isolated directly as solid in high yield and in excellent purity from reaction mixture and tedious work-up such as extraction of intermediate using solvent , recovery of solvent etc, is avoided. Furthermore, the highly pure (ICH grade) Carvedilol is obtained either through solvent crystallization (without salt formation) or through salt formation followed by salt cleavage and solvent crystallization.
  • Yet another object is to provide a more simplified , time saving, cost effective and commercially feasible process for the manufacture of Carvedilol (I).
  • Yet another object of the invention is to provide a process for the manufacture of intermediate of formula (III) in high yield and in excellent purity avoiding the tedious work-up such as ⁇ uenching of reaction mixture, use of organic solvent for extraction and recovery of solvent etc. This automatically results in cost reduction, prc t-ess simplification and reduction in batch time cycle.
  • Still another object of the invention is to provide a process that can be reproducible and overcome the anomalies of the reported processes to provide Carvedilol (I) of high purity (ICH grade) without increasing reaction steps.
  • a process 'or the manufacturing and purification of Carvedilol intermediates comprises: a) reacting 4-hydroxycarbazole under stirring with epichlorohydrin in organic solvent in presence of base. b) filtering the precipitated solid and washing with water. c) dissolving the wet cake of step (b) in an organic solvent at elevated temperature. d) isolating the material by cooling, washing with solvent and then drying in a conventional manner to get 4-(2,3-epoxy propoxy) carbazole (III) as solid.
  • the reaction temperature in step (a) ranges from 0° to 80°C, more preferably 10° to 60 0 C, and most preferably 20° to 40 0 C.
  • the solvent used in step (a) is selected from
  • N-substiruted aliphatic amides like N,N-dimethyl formamide.
  • cyclic aliphatic ethers such as tetrahydrofuran, dioxane etc.
  • the base used in step a) is selected from alkali or alkaline earth metal hydroxides, carbonates, bicarbonates, organic amines etc.
  • the molar ratio of base w.r.t. 4- hydroxycarbazole (II) is taken as 3j_l . , more preferably 7 ⁇ _ and most preferably 0.5-
  • the organic solvent used in step c) and d) is selected from
  • aliphatic ethers like diisopropyl ether, methyl tertiary butyl ether, diethyl ether, dibutyl ether etc. a aliphatic ketones like acetone, methyl isobutyl ketone, methylethyl ketone, butanone etc.
  • the temperature in step c) ranges from 30° to 120 0 C, more preferably 40° to 100 0 C, and most preferably 50° to 80 0 C,
  • step d) for isolation, filtration and washing of material ranges from -10° to 40 0 C, more preferably 0° to 20 0 C, and most preferably 0° to 10 0 C.ccordance with the other embodiment of this invention, there is provided a process the preparation of Carvedilol which comprises: a) reacting 4-(2,3-epoxypropoxy) carbazole (III) with 2-(2-methoxyphenoxy) ethylamine (IV) in a suitable organic solvent b) optionally recovering the organic solvent under vacuum and dissolving the residue in another suitable organic solvent c) treating above mass with suitable acid to get salt separated in the form of solid, gummy mass or as an oil d) removing the solvent from conventional methods like filtration, decantation or layer separation etc e) optionally washing above salt with suitable organic solvents f) optionally crystallizing above salt with suitable organic solvents g) suspending/ dissolving the salt in suitable organic solvent and basifying the mass at suitable temperature to get separation/ crystal
  • the ratio of 4-(2,3-epoxypropoxy) carbazole (III) with 2-(2-methoxyphenoxy) ethylamine (IV) in step a) is 1 ; 10, preferably 1 : 5, more preferably 1 : 2 and still more preferably 1 : 1-1.95 and most preferably 1 : 1.5-1.9.
  • the suitable organic solvent used in step a), b), e), f), g), h), i) above is selected from
  • cyclic aliphatic ethers such as tetrahydrofuran, dioxane etc.
  • aliphatic ketones like acetone, methyl isobutyl ketone, methyl ethyl ketone, butanone etc.
  • alcoholic solvents like C1-C5 linear or branched alcohols like methanol, ethanol, isopropyl alcohol, propanol, butanol, t-butanol, monoethylene glycol, diethylene glycol etc. » polar solvents like N,N-dimethyl formamide, dimethyl sulfoxide etc
  • ester solvents like ethyl acetate, propyl acetate, butyl acetate etc
  • nitrile solvents like acetonitrile, propionitrile etc or a mixture thereof
  • the antisolvent in step g) may be any low polar organic solvent like hydrocarbons, ethers or water if the solvent taken above is water miscible,
  • the reaction temperature in step a) and g) ranges from 0-150 0 C, preferably 50-90 0 C, and most preferably 60-90 0 C
  • Suitable acid in step c) above may be, aromatic acids like salicylic acid, benzoic acid; tartaric acid and substituted tartaric acid; sulfonic acids like para toluene sulfonic acid, methane sulfonic acid etc; aliphatic acids like acetic acid, propionic acid, tumeric acid, oxalic acid, citric acid, malic acid, cinnamic acid etc
  • the suitable base used in step g) above is selected from alkali or alkaline earth tnetai hydroxides, carbonates, bicarbonates, organic amines like tmthyl amine etc,
  • a process for the preparation of Carvedilol which comprises: a) reacting 4-(2,3-epoxypropoxy) carbazole (III) with 2-(2-methoxyphenoxy) ethylamine (IV) in a suitable organic solvent b) optionally recovering the organic solvent under vacuum and dissolving the residue in another suitable organic solvent followed by cooling c) isolating the separated material by, conventional methods like filtration, decantation etc followed by washing with suitable organic solvent to get product d) optionally crystallizing above product in suitable organic solvent to get ICH grade Carvedilol
  • the ratio of 4-(2,3-epoxypropoxy) carbazole (III) with 2-(2-methoxyphenoxy) ethylamine (IV) in step a) is 1: 10, preferably 1: 5, more preferably 1: 2 and still more preferably 1: 1-1.95 and most preferably 1 : 1.5-1.9,
  • step a-d) is selected from
  • ether solvents like monoglyme, diglyme etc, • cyclic aliphatic ethers such as tetrahydrofuran, dioxane etc.
  • alcoholic solvents like C 1 -C 5 linear or branched alcohols like methanol, ethanol, isopropyl alcohol, propanol, butanol, t-butanol, monoethylene glycol, diethylene glycol etc.
  • ester solvents like ethyl acetate, propyl acetate, butyl acetate etc
  • nitrile solvents like acetonitrile, propionitrile etc or a mixture thereof
  • the reaction temperature in step a) ranges from 0° to 150 0 C, preferably 50° to 90 0 C, and most preferably 60° to 90 0 C.
  • Carvedilol salicylate is added 650 ml of isopropyl alcohol and aqueous solution of sodium hydroxide to get alkaline pH. Mass is heated to get clear solution. Solution is filtered over hyflo. Filtrate is cooled to ambient temperature. Water (90 ml) is added to get complete crystallization. Slurry is filtered, cake is washed with water to remove excess alkali. Cake is dried to get Carvedilol (105g).
  • the product Carvedilol (I) obtained by present embodiment is of high purity. In other words, the product is almost free of impurity (ICH grade)

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

Abstract

La présente invention concerne un procédé faisable à l'échelle industrielle, plus simple et économique pour la préparation de Carvédilol (I), comprenant une étape consistant à faire réagir du 4-hydroxycarbazole (II) avec de l'épichlorhydrine et à isoler directement le 4-(2,3-époxypropoxy)carbazole (III) intermédiaire qui après purification suivie d'une réaction avec de la 2-(2-méthoxyphénoxy)éthylamine (IV) produit du Carvédilol (I) brut. On convertit le Carvédilol (I) brut en produit pur soit grâce à une recristallisation dans un solvant (sans formation de sel), soit grâce à la formation d'un sel suivie du clivage du sel et de la recristallisation dans un solvant, ce qui aboutit à du Carvédilol extrêmement pur (c'est-à-dire de qualité ICH).
PCT/IN2007/000389 2006-09-26 2007-09-05 Procédé pour la préparation de carvédilol WO2008038301A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN1711/DEL/2006 2006-09-26
IN1711DE2006 2006-09-26

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WO2008038301A1 true WO2008038301A1 (fr) 2008-04-03

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Cited By (2)

* 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
CN106045900A (zh) * 2016-07-07 2016-10-26 佛山市隆信医药科技有限公司 一种磷酸卡维地洛的制备方法

Citations (7)

* 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
US5071868A (en) * 1983-05-26 1991-12-10 Boehringer Mannheim Gmbh Process for the preparation of optically-active carbazole derivatives, new r- and s-carbazole derivatives and pharmaceutical compositions containing these compounds
US20020099223A1 (en) * 2001-01-25 2002-07-25 Michelangelo Scalone Process for preparing heterocyclic indene analogs
WO2004094378A1 (fr) * 2003-04-21 2004-11-04 Matrix Laboratories Ltd Procede de fabrication de carvedilol, forme-ii
US20050080329A1 (en) * 2003-07-29 2005-04-14 Kabushiki Kaisha Toshiba Ultrasound doppler diagnostic apparatus and image date generating method
WO2005115981A2 (fr) * 2004-04-22 2005-12-08 Usv Limited Nouveau procede de preparation de 1-(9h-carbazol-4-yloxy)-3-[[2-(-methoxyphenoxy)-ethyl] amino]-propan-2-ol
EP1741700A1 (fr) * 2005-07-06 2007-01-10 IPCA Laboratories Limited Procédé de préparation de carvedilol

Patent Citations (7)

* 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
US5071868A (en) * 1983-05-26 1991-12-10 Boehringer Mannheim Gmbh Process for the preparation of optically-active carbazole derivatives, new r- and s-carbazole derivatives and pharmaceutical compositions containing these compounds
US20020099223A1 (en) * 2001-01-25 2002-07-25 Michelangelo Scalone Process for preparing heterocyclic indene analogs
WO2004094378A1 (fr) * 2003-04-21 2004-11-04 Matrix Laboratories Ltd Procede de fabrication de carvedilol, forme-ii
US20050080329A1 (en) * 2003-07-29 2005-04-14 Kabushiki Kaisha Toshiba Ultrasound doppler diagnostic apparatus and image date generating method
WO2005115981A2 (fr) * 2004-04-22 2005-12-08 Usv Limited Nouveau procede de preparation de 1-(9h-carbazol-4-yloxy)-3-[[2-(-methoxyphenoxy)-ethyl] amino]-propan-2-ol
EP1741700A1 (fr) * 2005-07-06 2007-01-10 IPCA Laboratories Limited Procédé de préparation de carvedilol

Cited By (3)

* 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
CN106045900A (zh) * 2016-07-07 2016-10-26 佛山市隆信医药科技有限公司 一种磷酸卡维地洛的制备方法
CN106045900B (zh) * 2016-07-07 2019-03-08 佛山市隆信医药科技有限公司 一种磷酸卡维地洛的制备方法

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