WO2008038301A1 - A process for the preparation of carvedilol - Google Patents

A process for the preparation of carvedilol 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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Prior art keywords
aliphatic
acid
solvents
carvedilol
mixture
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PCT/IN2007/000389
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French (fr)
Inventor
Sanjay Suri
Tapan Kashyap
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Morepen Laboratories Limited
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Publication of WO2008038301A1 publication Critical patent/WO2008038301A1/en

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D209/00Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56Ring systems containing three or more rings
    • C07D209/80[b, c]- or [b, d]-condensed
    • C07D209/82Carbazoles; Hydrogenated carbazoles
    • C07D209/88Carbazoles; 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)

Abstract

The present invention provides a more simplified, cost effective, commercially feasible process for the preparation of Carvedilol (I) comprising a step of reacting 4-hydroxy oarbazole (II) with epichlorohydrin and directly isolating the intermediate 4-(2,3- epoxypropoxy) carbazole (III) which on purification followed by reaction with 2-(2- methoxyphenoxy) ethylamine (IV) yields crude Carvedilol (I). The crude Carvedilol (I) is converted to pure product either through solvent crystallization (without salt formation) or through salt formation followed by salt cleavage and solvent crystallization resulting in highly pure (i.e. ICH grade) Carvedilol.

Description

A PROCESS FOR THE PREPARATION OF CA RVEDILOL.
FIELD OF INVENTION
The present invention particularly relates to an improved process for the preparation of Carvedilol of formula (I) in high yield and high HPLC purity.
More particularly, 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.
BACKGROUND OF THE INVENTION Carvedilol, (±) l~(9H-carbazol-4-yloxy)-3-[[2-(2-methoxyphenoxy)-ethyl]-amino]-2- propanoi having structure (I), is a non selective β-adrenergic blocker with αι -blocking activity.
Figure imgf000002_0001
(I)
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.
Various routes of synthesis have been used or suggested for the preparation of Carvedilol. Thus, US 4,503,067, US 5,071,868, US 2002/0143045, EP 918055, EP 0127099, EP 0004920, WO 02/00216, WO 2004/041783Al, WO
2004/094378Al, WO2005/080329A1 reported the synthesis of Carvedilol by different methods. 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 500C 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 1000C to minimize the formation of compound (V) as by-product.
Figure imgf000003_0001
(V)
This patent does not disclose the yield and the purity of the Carvedilol obtained. At higher temperature, in the absence of solvent there is possibility of degradation that results in low yield. Also the use of large amount of 2- (2-methoxyphenoxy) ethylamine (IV) makes the process uneconomical.
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.
US 5,071,868 reports the preparation of intermediate 4-(2,3-epoxypropoxy) carbazole by reaction of 4-hydroxy carbazole with epichlorohydrin followed by quenching of reaction mass, extraction of the same in organic solvent and recovery of solvent to obtain crude sample of 4-(2,3-epoxypropoxy) carbazole, which then re-crystallized twice for its purification. It results, in the loss of yield. Further, the process disclosed in this patent claims (R)-(+)- and (S)(-)- enantiomers of carvedilol. Thus in addition to low yield the process becomes cumbersome and cost extensive due to multiple crystallization.
PCT publication WO 02/00216 describes the preparation of Carvedilol (I) by reaction of 4-(2,3-epoxypropoxy) carbazole with compound 2-(2-methoxyphenoxy) ethylamine of formula (IV) using excess of (IV). Further, the advantage of using compound (IV) in excess is not mentioned. In addition, it takes longer time (>24hr) at 4°C for crystallization of product which is. not only time consuming and requiring sophisticated infrastructure for maintaining stringent process parameters but also economically unviable. The patent teaches isolation of Carvedilol (I) is isolated as its hydrochloride salt employing strong mineral acids. The use of strong mineral acids for the salt formation may lead to decomposition of product.
It is evident from above matter that although prior art looks very comfortable, but it is very difficult to reproduce it practically at commercial scale production. According to the US Patent 4503067, the reaction time itself is 25 hours with lesser yields. While in WO 02/00216 the product is crystallized out in 40 hours at 4°C and according to the European Patent EP 918055, the final stage involves catalytic hydrogenation for debenzylation. Thus these processes are not feasible on production scale and prove to lack industrial applicability. Therefore it has long standing need in industry to provide a simple, economical, precise, reproducible, and industrially feasible process for the preparation and purification of Carvedifol that can meet the standards stipulated by ICH.
After painstaking research the inventors have arrived at an improved process the preparation and purification of Carvedilol that can meet the standards stipulated by ICH. 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. Additionally, by reacting 4-(2,3-epoxypropoxy)carbazole with 2-(2- methoxyphenoxy) ethylamine in a suitable organic solvent while maintaining the ratio of 4-(2,3-epoxypropoxy) carbazole to 2-(2-methoxyphenoxy)ethylamine more than is 1: 1.5-1.9, formation of disubstituted impurity (B) is minimized thereby getting increased yield and avoiding repeated purifications steps.
SUMMARY OF THE INVENTION
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.
Other 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 αuenching 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.
Figure imgf000006_0001
(H) (III)
Figure imgf000006_0002
(IV)
Figure imgf000006_0003
(I) DETAILED DESCRIPTION OF THE INVENTION
According to one embodiment of this invention 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. According to above embodiment of this invention, the reaction temperature in step (a) ranges from 0° to 80°C, more preferably 10° to 600C, and most preferably 20° to 400C.
The solvent used in step (a) is selected from
• aliphatic sulphoxides such as dimethyl sulphoxide.
• N-substiruted aliphatic amides like N,N-dimethyl formamide. * cyclic aliphatic ethers such as tetrahydrofuran, dioxane etc.
• aliphatic ketones like acetone, methyl isobutyl ketone, methyl ethyl ketone etc. or a mixture thereof,
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 7Λ_ and most preferably 0.5-
LQiL
The organic solvent used in step c) and d) is selected from
• aliphatic esters like ethyl acetate, propyl acetate, butyl acetate etc.
• CpC5 alkanols like methanol, ethanol, propanol, butanol etc.
• aliphatic nitriles such as acetonitrile or propionitrile etc.
• 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.
9 aliphatic halogenated/non halogenated and aromatic hydrocarbons like dichloromethane, chloroform, carbon tetrachloride, Cj-C8 aliphatic long chain or branched chain hydrocarbons, toluene, xylenes, benzene. or a mixture thereof,
The temperature in step c) ranges from 30° to 1200C, more preferably 40° to 1000C, and most preferably 50° to 800C,
The temperature in step d) for isolation, filtration and washing of material ranges from -10° to 400C, more preferably 0° to 200C, and most preferably 0° to 100C.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/ crystallization as such or by adding some antisolvent h) isolating the separated material by, conventional methods like filtration, decantation etc followed by washing with suitable organic solvent to get product i) optiυnallv crystallizing above product in suitable organic solvent to get ICH grade Carvedilol
According to above embodiment of this invention, 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
• ether solvents like monoglyme, diglyme etc
• 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
» aliphatic ketones like acetone, methyl isobutyl ketone, methyl ethyl ketone 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 0-1500C, preferably 50-900C, and most preferably 60-900C, 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,
In accordance with another embodiment of this invention, there is provided 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
According to above embodiment of this invention, 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-d) above is selected from
• ether solvents like monoglyme, diglyme etc, • 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
• aliphatic ketones like acetone, methyl isobutyl ketone, methyl ethyl ketone 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 1500C, preferably 50° to 900C, and most preferably 60° to 900C.
The present invention will be fully understood from the following examples. However these examples are mere illustrative and should not construe the scope of the invention. Any variation obvious to the person skilled in the art are being covered in the ambit of the protection.
EXAMPLE I
Preparation of 4-(2,3-epoxypropoxy) carbazole
To lOOg of 4-hydroxy carbazole (II) in dimethyl sulfoxide (250ml.) at 10°-30°C, IN aq. NaOH solution (545ml.) is added and the reaction mixture is stirred at 10°-30°C for 15-20 minutes. Epichlorohydrin (80g) is added at 10°-30°C over a period of 30-45 minutes and the resultant reaction mixture is stirred at 20-250C for 25-30 hr.
The progress of reaction is monitored by TLC/HPLC. After completion of reaction, the solid, thus precipitated out, was filtered followed by washing with water (300ml). The wet cake was dissolved in ethyl acetate (300ml) at 60-65°. The resulting solution is cooled to 0-50C and stirred for lhr. The solid, thus obtained, was filtered and washed with chilled ethyl acetate (10ml). The product was dried at 40-450C for 6-8 hr until moisture content is <1.0%.
(10Og; 76.57%); HPLC purity > 99.6»%
EXAMPLE Il
Preparation of Carvedilol salicylate
To a solution of lOOg of 4-(2,3-epoxypropoxy) carbazole (III) in isopropyl alcohol (200 ml) at 10-300C, 2-(2-methoxyphenoxy) ethylamine (125 g) was added and the reaction mixture is stirred at 75-800C for reaction completion. Reaction mass is cooled and added to a solution of salicylic acid (90- g) in isopropyl alcohol. Mass is refluxed to get precipitation. Mass is cooled and product is filtered and washed with isopropyl alcohol. Solid is dried to get 160 g Carvedilol salicylate which can be optionally recrystallized.
EXAMPLE III
Preparation of Carvedilol
To 16O g of 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).
Product was recrystallized in ethyl acetate to get ICH grade Carvedilol (95 g)
EXAMPLE IV Preparation of Carvedilol tosylate
To a solution of lOOg of 4-(2,3-qpoxypropoxy) carbazole (III) in monoglyme (200 ml) at 10-300C, 2-(2-methoxyphenoxy) ethylamine (125 g) was added and the reaction mixture was refluxed for reaction completion. Monoglyme was recovered and mass was diluted with isopropyl alcohol. Reaction mass is cooled and added to a solution of p-toluene sulfonic acid in IPA. Mass is refluxed for 2 hrs. Mass is cooled to 15-20° C for complete crystallization. Product is filtered and washed with isopropyl alcohol. Solid is dried to get 180 g Carvedilol tosylate which can be optionally recrystallized.
EXAMPLE V Preparation of Carvedilol
To 180 g of Carvedilol tosylate is added 500 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 (75 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 (HOg). Product was recrystallized in ethyl acetate to get ICH grade Carvedilol ( 10Og)
ADVANTAGES 1. In the preparation of intermediate 4-(2,3-epoxypropoxy) carbazole (III), tedious work-up such as quenching of reaction mixture, use of solvent, extraction of material by using solvent, recovery of solvent etc are avoided which ultimately results in cost reduction, process simplification and reduction in batch time cycle 2. Since intermediate (III) is directly isolated as solid, therefore any degradation of material due to recovery of solvent used for extraction of material, is avoided
3. The product Carvedilol (I) obtained by present embodiment is of high purity. In other words, the product is almost free of impurity (ICH grade)
4. Due to high purity, the product will be more stable and appropriate for pharmaceutical formulations.

Claims

WE CLAIM:
1 . A process for the preparation of Carved ilol which comprises,
(a) reacting 4-hydroxycarbazole with epichlorohydrin in organic solvent in presence of a base (b) isolating the precipitated 4-(2,3-epoxy propoxy) carbazole as solid cake followed by dissolving the said wet cake in organic solvent and
(c) reacting the 4-(2,3-epoxy propoxy) carbazole so obtained with 2-(2- methoxyphenoxy) ethylamine in organic solvent, and
(d) recovering carvedilol, wherein the ratio of carbazoole to amine being maintained between 1 : 10.
2. A process as claimed in claim 1 wherein, organic solvent used in step (a) comprising aliphatic sulphoxides; N-substituted aliphatic amide; aliphatic ethers; aliphatic ketones or a mixture thereof.
3. A process as claimed in claims 1 & 2 wherein aliphatic sulphoxide is dimethyl sulphoxide.
4. A process as claimed in claims 1 & 2 wherein N-substituted aliphatic amide is N,N-dimethylformamide.
5. A process as claimed in claims 1 & 2 wherein cyclic aliphatic ethers are tetrahydrofuran or dioxane.
6. A process as claimed in claims 1 & 2 wherein aliphatic ketones are isobutyl ketone or methyl ethyl ketone.
7. A process as claimed in claim 1 wherein, base used in step (a) is selected from alkali or alkaline earth metal hydroxides, carbonates, bicarbonates, organic amines.
8. A process as claimed in claim 1 wherein, molar ratio of base with reference to
4-hydroxycarbazole (II) being 3:1, preferably 2: 1 and more preferably 0.5-1.0:1.
9. A process as claimed in claim 1 wherein, the reaction of 4-hydroxycarbazole with epichlorohydrin is performed under stirring at a temperature up to 3O0C.
10. A process as claimed h claim I wherein, the isolation is carried out by filtration.
1 1. A process as claimed in claim 1 wherein, organic solvent used for dissolution in step (b) comprises aliphatic esters; C1-C5 alkanols; aliphatic nitriles; aliphatic ethers; aliphatic ketones; aliphatic halogenated/non halogenated and aromatic hydrocarbons; or a mixture thereof.
12. A process as claimed in claim 1 1 wherein, aliphatic esters are ethyl acetate, propyl acetate or butyl acetate or a mixture thereof.
13. A process as claimed in claim 1 1 wherein, aliphatic nitriles are acetonitrile or propionitrile or a mixture thereof.
14. A process as claimed in claim 1 1 wherein, aliphatic ethers are diisopropyl ether, methyl tertiary butyl ether, diethyl ether, dibutyl ether or a mixture thereof.
15. A process as claimed in claim 11 wherein, aliphatic ketones are acetone, methyl isobutyl ketone, methylethyl ketone, butanone or a mixture thereof.
16. A process as claimed in claim 11 wherein, aliphatic halogenated/non halogenated and aromatic hydrocarbons are dichloromethane, chloroform, carbon tetrachloride, Cs-Cs aliphatic long chain or branched chain hydrocarbons, toluene, xylenes, benzene or a mixture thereof.
17. A process as claimed in claim 1 wherein, the dissolution in step (b) was carried out at a temperature ranging from 40° to 1000C, preferably 50° to 800C
18. A process as claimed in claim 1 wherein, the cooling is carried out to a temperature of -10° to 400C, preferably 0° to 200C, and more preferably 0° to 100C before proceeding step (c).
19. A process of claim 1 wherein, the reaction temperature in step (c) ranges from 0-1500C, preferably 50-90°C, and most preferably 60-900C.
20. A process as claimed in claim 1 wherein the recovery of Carvedilol is carried out through crystallization.
21. A process as claimed in claim 1 wherein the recovery of Carvedilol is carried out through salt formation followed by salt cleaving and solvent crystallization.
22. A process as claimed in claim 1 wherein the recovery of Carvedilol is carried out by precipitation employing anti-solvent.
23. A process as claimed in claim 1 wherein, solvents used for reacting the 4-(2,3- epoxy propoxy) carbazole with 2-(2-methoxyphenoxy) ethylamine are ether solvents; cyclic aliphatic ethers aliphatic ketones; alcoholic solvents; polar solvents; aliphatic ketones, ester solvents; or a mixture thereof.
24. A process as claimed in claim 1 wherein, the ratio of 4-(2,3-epoxypropoxy) carbazole with 2-(2-methoxyphenoxy) ethylamine is 1: 5, preferably 1 : 2 still more preferably 1 : 1-1.95 and most preferably 1 : 1.5-1.9.
25. A process as claimed in claim 21 wherein, solvents used for salt formation are ether solvents; cyclic aliphatic ethers aliphatic ketones; alcoholic solvents; polar solvents; aliphatic ketones, ester solvents; or a mixture thereof.
26. A process as claimed in claims 23 & 25 wherein, ether solvents are monoglynie, diglyme.
27. A process as claimed in claims 23 & 25 wherein, cyclic aliphatic ethers are tetrahydrofuran, dioxane.
28. A process as claimed in claims 23 & 25 wherein, aliphatic ketones are acetone, methyl isobutyl ketone, methyl ethyl ketone, butanone.
29. A process as claimed in claims 23 & 25 wherein, alcoholic solvents are C1-C5 linear or branched alcohols selected from methanol, ethanol, isopropyl alcohol, propanol, butanol, t-butanol, monoethylene glycol, diethylene glycol.
30. A process as claimed in claims 23 & 25 wherein, polar solvents are N,N- dimethyl formamide, dimethyl sulfoxide.
31. A process as claimed in claims 23 & 25 wherein, aliphatic ketones are acetone, ' methyl isobutyl ketone, methyl ethyl ketone.
32. A process as claimed in claims 23 & 25 wherein, ester solvents are ethyl acetate, propyl acetate, butyl acetate.
33. A process as claimed in claims 23 & 25 wherein, nitrite solvents are acetonitrile, propionitrile etc or a mixture thereof.
34. A process as claimed in claim 23 wherein, acid employed for salting comprising aromatic acids selected from salicylic acid, benzoic acid; taitaric acid and substituted tartaric acid; sulfonic acids selected from para toluene sulfonic acid, methane sulfonic acid; aliphatic acids selected from acetic acid, propionic acid, fumeric acid, oxalic acid, citric acid, malic acid, cinnamic acid.
35. A process as claimed in claim 22 wherein, the antisolvents comprises low polar organic solvent selected from hydrocarbons, ethers or water.
36. A process as claimed in claim 22 wherein, the antisolvent is added at temperature in the range of 0-150°C, preferably 50-90°C, and most preferably 60-90°C.
37. A process as claimed in claim 21 wherein, the base used for cleaving salt is alkali or alkaline earth metal hydroxides, carbonates, bicarbonates, organic amines like triethyl amine.
PCT/IN2007/000389 2006-09-26 2007-09-05 A process for the preparation of carvedilol WO2008038301A1 (en)

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CN106045900A (en) * 2016-07-07 2016-10-26 佛山市隆信医药科技有限公司 Preparation method of carvedilol phosphate hemihydrate

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