WO2005115981A2 - A process for the preparation of 1-(9h-carbazol-4-yloxy)-3-2-(-methoxyphenoxy)-ethyl amino-propan-2-ol - Google Patents

A process for the preparation of 1-(9h-carbazol-4-yloxy)-3-2-(-methoxyphenoxy)-ethyl amino-propan-2-ol Download PDF

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WO2005115981A2
WO2005115981A2 PCT/IN2005/000139 IN2005000139W WO2005115981A2 WO 2005115981 A2 WO2005115981 A2 WO 2005115981A2 IN 2005000139 W IN2005000139 W IN 2005000139W WO 2005115981 A2 WO2005115981 A2 WO 2005115981A2
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formula
carvedilol
carbazole
base
methoxyphenoxy
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PCT/IN2005/000139
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French (fr)
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WO2005115981A3 (en
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Venkatasubramanian Radhakrishnan Tarur
Dhananjay Govind Sathe
Swapnil Jayant Kulkarni
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Usv Limited
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Priority to US10/568,732 priority Critical patent/US20070191456A1/en
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Publication of WO2005115981A3 publication Critical patent/WO2005115981A3/en

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D405/00Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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

  • This invention relates to a novel process for preparation of carvedilol (I) by using eco friendly solvents to obtain the said carvedilol in high purity.
  • Carvedilol is a compound useful in the treatment of hypertension and angina.
  • Carvedilol is a nonselective ⁇ -adrenergic blocking agent, with ⁇ i blocking activity.
  • Carvedilol the first beta blocker labeled in the United States for the treatment of heart failure, has been shown to improve left ventricular ejection fraction and may reduce mortality.
  • Carvedilol is chemically known as l-(9H-carbazol-4yloxy)-3-[[2-(- methoxyphenoxy)-ethyl] amino]-propan-2-ol, of formula (I), is given below.
  • WO0187837 describes another process for preparation of carvedilol or an acid addition salt thereof, prepared by alkylating 5- chloromethyl-3-[2-(2-methoxy-phenoxy)-ethyl]-oxazolidine-2one with 4-hydroxy- carbazole for the formation of 5-(9H-carbazol-4-yloxy methyl)-3-[2-(2-methoxy- phenoxy)-ethyl ⁇ -oxazolidine-2-one or an acid addition salt thereof, which is subsequently decarboxylated.
  • Second stage comprises mainly of reacting the free amine with compound of 4-(2,3-epoxypropoxy)-carbazole, formula (II) to obtain Carvedilol.
  • the process reported above is not the preferred one in a production plant since it involves use of more than one reactor.
  • condensation of compound of formula II with 2-(2-methoxyphenoxy)-ethylamine of formula III is carried out in solvents like ethylene glycol, dimethyl ether, which is very expensive.
  • An object of the present invention is to provide a process for the commercial manufacture of l-(9 H-carbazol-4-yloxy)-3-[[2-(2-methoxyphenoxy)-ethyl] amino]-propan-2-ol, known as Carvedilol, which is simple to carryout in the plant, uses eco friendly solvents and is economical.
  • Another object of the invention is to provide a process for Carvedilol, which is less time consuming involving fewer steps and increases the production efficiency
  • a further object of the invention is to provide a process for Carvedilol, which avoids use of hazardous reagents and use milder reaction conditions.
  • Another object of the invention is to provide a process for Carvedilol, which employs use of less expensive, eco friendly solvents.
  • the present invention discloses a novel process for preparation of carvedilol (I) by using eco friendly solvents to obtain the said carvedilol in high purity
  • the said process comprises, reacting 4-hydroxy carbazole of formula (IV) with epichlorhydrin in presence of an organic solvent and a base at temperatures between 10°C - 30°C; further reacting the resultant 4-(2,3-epoxypropoxy)- carbazole of formula (II) with a salt of 2-(2- methoxyphenoxy) ethylamine of formula (III), preferably hydrochloride salt in presence of a base and a hydroxylic solvent at temperatures between 30 °C - 90 °C.
  • the preferred base is inorganic base preferably alkali metal hydroxide, more -preferably sodium hydroxide in aqueous form.
  • the molar equivalent of base may be from 1 mole to 6 moles, preferably 1.1 molar equivalents based on 4-hydroxy carbazole moles.
  • the organic solvent is selected from alcohols, cyclic ethers, dipolar aprotic solvents and glycol ethers, preferably water miscible (C1-C4) alcohols but, more preferably isopropyl alcohol.
  • the hydroxylic solvent is water or d-C 4 alcohols like methyl alcohol, ethyl alcohol, isopropyl alcohol, butyl alcohol or mixtures thereof but preferably water.
  • the preferred temperature range is 20-30 °C in the reaction between 4-hydroxy carbazole of formula (IV) and epichlorhydrin.
  • the preferred temperature range is 80 °C - 90 °C in the reaction between the compounds of formula II and formula III.
  • the process disclosed in the present invention involves fewer and simpler steps, avoids use of hazardous reagents; uses milder and eco-friendly reagents and solvents. Detailed description of the invention
  • Step I Preparation of compounds of formula II by reacting compounds of formula IV with epichlorohydrin in water miscible organic solvents containing solution of a base at temperatures ranging from 10 to 60 ° C as shown in scheme 3.
  • the organic solvents are selected from alcohols, cyclic ethers, dipolar aprotic solvents and glycol ethers but preferably water miscible (C ⁇ .-C ) alcohols and more preferably Isopropyl alcohol.
  • Bases may be selected from organic like alkyl amines, inorganic like alkaline earth metal and alkali metal salts like sodium carbonate, sodium bicarbonate, sodium hydroxide, calcium hydroxide, barium hydroxide and the likes thereof.
  • Solution of the base includes any one of the above bases in water or any previously mentioned water miscible solvents.
  • the preferred base is sodium hydroxide in water.
  • the molar equivalent of base employed may be from 1 mole to 6 moles based on IV, preferably 1.1 molar equivalents.
  • the co- alkylation can be carried out at temperatures from 10 °C to 60 °C but preferably at 20-30 °C.
  • the process thus involves use of eco friendly solvents like isopropyl alcohol in aqueous inorganic base like sodium hydroxide giving 4-(2,3- epoxypropoxy)-carbazole (II) in 84% yield.
  • This process eliminates use of expensive solvents like 1,4 dioxan and obnoxious solvents like dimethyl sulphoxide. This process further has the benefit of ease of adaptability in the plant.
  • the salts of 2-(2-methoxyphenoxy)-ethylamine of Formula (III) include mineral acid salts like hydrochloride, sulphate, phosphate, or organic acids salts like tartarate, methane sulphonate, para toluene sulphonate, citric acid, malic acid, oxalic acid salts and others there of but preferably the hydrochloride salt which is cheaper and commercially available.
  • the solvents include hydroxylic solvents like water, alcohols, water miscible solvents like dimethyl sulphoxide, glycol ethers, acetone but preferably water, as it is the cheapest and most eco friendly solvent.
  • the bases that may be used for neutralizing the acid addition salts of the amine in situ may be any of the organic bases like trialkylamines, inorganic bases like alkali metal and alkaline earth salts but preferably sodium hydroxide which is very cheap and making the process commercially viable.
  • the condensation is carried out at temperature from RT to 90°C preferably at 80-85°C and the reaction is over in about 30 minutes to an hour.
  • the process of manufacturing Carvedilol by the present invention comprises, use of solvents like water and isopropyl alcohol which are cheap, freely available and eco friendly.
  • the process of the invention involves less number of steps since commercially available 2-(2-methoxy ⁇ henoxy)-ethylamine hydrochloride can be directly condensed with 4-(2,3 epoxypropoxy) carbazole to give Carvedilol without going through an additional step of converting the amine hydrochloride to its free base before condensation with epoxypropoxy carbazole. This eliminates use of solvents which are expensive and eco unfriendly.
  • Overall the process of making carvedilol by the present invention is a novel process, which is eco friendly and industrially viable. The process of this invention completes in lesser reaction times.
  • reaction mixture is monitored by thin layer chromatography (TLC), till the reaction showed complete utilization of 4-hydroxy carbazole.
  • TLC thin layer chromatography

Abstract

The present invention discloses a novel process for preparation of carvedilol by using eco friendly solvents to obtain the said carvedilol in high purity. The said process comprises, reacting 4-hydroxy carbazole of formula (IV) with epichlorhydrin in presence of an organic solvent and a base at temperatures between 10°C - 30°C; further reacting the resultant 4-(2,3-epoxypropoxy)- carbazole of formula (II) with a salt of 2-(2­methoxyphenoxy) ethylamine of formula (III), preferably hydrochloride salt in presence of a base and a hydroxylic solvent at temperatures between 30°C - 90°C.

Description

"A novel process for the preparation of l-(9h-carbazol-4-yloxy)-3-[[2-(- methoxyphenoxy)-ethyl] amino] -propan-2-ol"
Related Applications: This application claims priority from India National patent application serial No. 479/MUM/2004, filed on 07 May 2004.
Technical Field of Invention
This invention relates to a novel process for preparation of carvedilol (I) by using eco friendly solvents to obtain the said carvedilol in high purity. Carvedilol is a compound useful in the treatment of hypertension and angina.
Background and Prior Art
Carvedilol is a nonselective β-adrenergic blocking agent, with α i blocking activity. Carvedilol, the first beta blocker labeled in the United States for the treatment of heart failure, has been shown to improve left ventricular ejection fraction and may reduce mortality. Carvedilol is chemically known as l-(9H-carbazol-4yloxy)-3-[[2-(- methoxyphenoxy)-ethyl] amino]-propan-2-ol, of formula (I), is given below.
Figure imgf000002_0001
(I)
As depicted in scheme 1, the US patent 4,503,067 describes preparation of (I) by reacting 4-(2,3-epoxypropoxy)-carbazole (II) with 2-(2-methoxyphenoxy)-ethylamine (III) using ethylene glycol, dimethyl ether as solvent. The reaction is reported to be carried out for 25 hours at 50 °C. The crude Carvedilol (I) produced, is further crystallized. Scheme 1 :
Figure imgf000003_0001
(II) (III)
CARVEDILOL (I)
As depicted in scheme 2 the British patent application GB 1369580 reports the preparation of 4-(2,3-epoxypropoxy)-carbazole, compound of formula (II) from 4- hydroxy carbazole, compound of formula (IV) and epichlorohydrin using aqueous sodium hydroxide in solvents like 1,4 dioxan; as shown in scheme 2 Scheme 2
Figure imgf000003_0002
(IV) (II)
A major drawback of the process reported in US patent 4,503,067 is the formation of bis- compound formed by reaction of Carvedilol (I) with one more molecule of II. The problem is partly overcome by using the N-benzyl derivative of 2-(2-methoxyphenoxy)- ethylarnine (III) instead of the free amine as reported in patent EP 0918055 A i and Indian Patent 186587, but the N-Benzyl Carvedilol formed needs to be debenzylated using palladium catalyst. Use of palladium increases the cost of the process and also poses the hazards of handling palladium, which is pyrophoric in presence of solvent vapours. This procedure involves additional process steps, which is benzylation and subsequent debenzylation steps resulting in lower yields.
US6699997 reports the preparation of carvedilol, which involves the reaction between 2- (2-methoxy phenoxy) ethyl amine and 4-(oxiran-2-ylmethoxy)-9H-carbazole at 100°C.
To avoid the hazardous axiranyl derivatives in the process for preparation of carvedilol, which is desirable for environmental reasons,WO0187837 describes another process for preparation of carvedilol or an acid addition salt thereof, prepared by alkylating 5- chloromethyl-3-[2-(2-methoxy-phenoxy)-ethyl]-oxazolidine-2one with 4-hydroxy- carbazole for the formation of 5-(9H-carbazol-4-yloxy methyl)-3-[2-(2-methoxy- phenoxy)-ethyl}-oxazolidine-2-one or an acid addition salt thereof, which is subsequently decarboxylated.
The process reported in GB- 1369580 for the preparation of the key intermediates of 4- (2,3-epoxypropoxy)-carbazole, formula (II) uses 1,4-dioxan as a solvent.1, 4-dioxan is an expensive, high boiling solvent and its removal from the product is quite tedious. The complete removal is very difficult requiring the product formed, to be extracted in solvents like dichloromethane and the dichloromethane layer washed with water to remove traces of 1, 4-dioxan. The separation of two immiscible layers is quite cumbersome as aqueous and organic layers are both highly colored and hence difficult to distinguish. Moreover, effluent containing 1, 4 dioxan is also posing disposal problems.
The process mentioned in US patent 4,503,067, although reports preparation of Carvedilol as a single step reaction between 4-(2,3-epoxypropoxy)-carbazole, the compound of formula II with 2-(2-methoxyphenoxy)-ethylamine of formula III, it is essentially a two stage process. 2-(2-methoxyphenoxy)-ethylamine III is commercially available as its hydrochloride salt. First stage involves liberating the amine as a free base from the hydrochloride salt using alkali and extracting the amine thus liberated into organic solvents and solvents removed under reduced pressure. Second stage comprises mainly of reacting the free amine with compound of 4-(2,3-epoxypropoxy)-carbazole, formula (II) to obtain Carvedilol. Hence the process reported above is not the preferred one in a production plant since it involves use of more than one reactor. Moreover, condensation of compound of formula II with 2-(2-methoxyphenoxy)-ethylamine of formula III is carried out in solvents like ethylene glycol, dimethyl ether, which is very expensive.
Objective
An object of the present invention is to provide a process for the commercial manufacture of l-(9 H-carbazol-4-yloxy)-3-[[2-(2-methoxyphenoxy)-ethyl] amino]-propan-2-ol, known as Carvedilol, which is simple to carryout in the plant, uses eco friendly solvents and is economical.
Another object of the invention is to provide a process for Carvedilol, which is less time consuming involving fewer steps and increases the production efficiency,
A further object of the invention is to provide a process for Carvedilol, which avoids use of hazardous reagents and use milder reaction conditions.
Another object of the invention is to provide a process for Carvedilol, which employs use of less expensive, eco friendly solvents.
Summary of the invention:
The present invention discloses a novel process for preparation of carvedilol (I) by using eco friendly solvents to obtain the said carvedilol in high purity wherein, the said process comprises, reacting 4-hydroxy carbazole of formula (IV) with epichlorhydrin in presence of an organic solvent and a base at temperatures between 10°C - 30°C; further reacting the resultant 4-(2,3-epoxypropoxy)- carbazole of formula (II) with a salt of 2-(2- methoxyphenoxy) ethylamine of formula (III), preferably hydrochloride salt in presence of a base and a hydroxylic solvent at temperatures between 30 °C - 90 °C.
The preferred base is inorganic base preferably alkali metal hydroxide, more -preferably sodium hydroxide in aqueous form.
The molar equivalent of base is employed may be from 1 mole to 6 moles, preferably 1.1 molar equivalents based on 4-hydroxy carbazole moles.
The organic solvent is selected from alcohols, cyclic ethers, dipolar aprotic solvents and glycol ethers, preferably water miscible (C1-C4) alcohols but, more preferably isopropyl alcohol.
The hydroxylic solvent is water or d-C4 alcohols like methyl alcohol, ethyl alcohol, isopropyl alcohol, butyl alcohol or mixtures thereof but preferably water.
The preferred temperature range is 20-30 °C in the reaction between 4-hydroxy carbazole of formula (IV) and epichlorhydrin. The preferred temperature range is 80 °C - 90 °C in the reaction between the compounds of formula II and formula III. The process disclosed in the present invention involves fewer and simpler steps, avoids use of hazardous reagents; uses milder and eco-friendly reagents and solvents. Detailed description of the invention
According to the invention there is provided a process for the preparation of 1-(9H- carbazol-4-yloxy)-3-[[2-(2-methoxyphenoxy)-ethyl]amino]-propan-2-ol, (Carvedilol) of formula I, comprising of two steps:
Figure imgf000007_0001
(I)
Step I: Preparation of compounds of formula II by reacting compounds of formula IV with epichlorohydrin in water miscible organic solvents containing solution of a base at temperatures ranging from 10 to 60 ° C as shown in scheme 3.
Scheme 3
Figure imgf000007_0002
(IV) (II) The organic solvents are selected from alcohols, cyclic ethers, dipolar aprotic solvents and glycol ethers but preferably water miscible (Cτ.-C ) alcohols and more preferably Isopropyl alcohol.
Bases may be selected from organic like alkyl amines, inorganic like alkaline earth metal and alkali metal salts like sodium carbonate, sodium bicarbonate, sodium hydroxide, calcium hydroxide, barium hydroxide and the likes thereof. Solution of the base includes any one of the above bases in water or any previously mentioned water miscible solvents. The preferred base is sodium hydroxide in water.
The molar equivalent of base employed may be from 1 mole to 6 moles based on IV, preferably 1.1 molar equivalents.
The co- alkylation can be carried out at temperatures from 10 °C to 60 °C but preferably at 20-30 °C.
The process thus involves use of eco friendly solvents like isopropyl alcohol in aqueous inorganic base like sodium hydroxide giving 4-(2,3- epoxypropoxy)-carbazole (II) in 84% yield. This process eliminates use of expensive solvents like 1,4 dioxan and obnoxious solvents like dimethyl sulphoxide. This process further has the benefit of ease of adaptability in the plant.
Step II: preparation of compounds of formula (I) by reacting compounds of 4-(2,3- epoxypropoxy)-carbazole of formula (II) with amine salts of 2-(2-methoxyphenoxy)- ethylamine of Formula (III) in solvents and in presence of base at temperatures from 30- 90 °C as shown in scheme 4, where R = H, CH2Ph
Scheme 4
DILOL
Figure imgf000009_0001
(II) (III) (I)
The salts of 2-(2-methoxyphenoxy)-ethylamine of Formula (III) that may be used include mineral acid salts like hydrochloride, sulphate, phosphate, or organic acids salts like tartarate, methane sulphonate, para toluene sulphonate, citric acid, malic acid, oxalic acid salts and others there of but preferably the hydrochloride salt which is cheaper and commercially available.
The solvents include hydroxylic solvents like water, alcohols, water miscible solvents like dimethyl sulphoxide, glycol ethers, acetone but preferably water, as it is the cheapest and most eco friendly solvent.
The bases that may be used for neutralizing the acid addition salts of the amine in situ may be any of the organic bases like trialkylamines, inorganic bases like alkali metal and alkaline earth salts but preferably sodium hydroxide which is very cheap and making the process commercially viable. The condensation is carried out at temperature from RT to 90°C preferably at 80-85°C and the reaction is over in about 30 minutes to an hour.
Thus the process of manufacturing Carvedilol by the present invention comprises, use of solvents like water and isopropyl alcohol which are cheap, freely available and eco friendly. The process of the invention involves less number of steps since commercially available 2-(2-methoxyρhenoxy)-ethylamine hydrochloride can be directly condensed with 4-(2,3 epoxypropoxy) carbazole to give Carvedilol without going through an additional step of converting the amine hydrochloride to its free base before condensation with epoxypropoxy carbazole. This eliminates use of solvents which are expensive and eco unfriendly. Overall the process of making carvedilol by the present invention is a novel process, which is eco friendly and industrially viable. The process of this invention completes in lesser reaction times.
Example 1
4-(2,3 -Epoxypropoxy)-carbazole (II)
200. Og (1.09 mole) of 4- hydroxy carbazole is dissolved in 500.0 ml of isopropyl alcohol. To this solution is added dropwise an aqueous solution of sodium hydroxide made from 48 g (1.2 moles) of sodium hydroxide dissolved in 700.0 ml of water. The addition of alkali solution is done by maintaining the temperature at 23 to 28 °C. After the addition of entire quantity of sodium hydroxide solution, the reaction mixture is stirred for 1 hour at the same temperature of 23 to 28 °C. To this solution 236 g (2.55 moles) of epichlorhydrin is added all at once. The reaction mixture is then stirred at room temperature (30-40°C) for 15-20 hours. During this period the reaction mixture is monitored by thin layer chromatography (TLC), till the reaction showed complete utilization of 4-hydroxy carbazole. 4-(2,3-epoxypropoxy) carbazole, thus formed, precipitated from the reaction mixture, which is filtered and the cake is washed with 150ml of water and 150 ml of isopropyl alcohol. The product is dried at 50-55 °C for 4-5 hours.
Yield: 210.0 g. (80.4%) M.P. 133 °c
1H NMR (200 MHZ, in CDC13) δ (ppm) 8.1 (bs, 1H, exchanges with d2O), 6.8-8.3 (m
7H), 4.4-4.2 (m, 2H), 3.5 (m, 1H), 2.8-3 ( , 2H) Example 2:
l-(9H-carbazol-4-yloxy)-3-[[2-(2-methoxyphenoxy)-ethyl]amino]-propan-2-ol
(Carvedilol)
Method A:
To a solution of 94.0g (0.461 moles) of 2-(2-methoxyphenoxy)-ethylamine hydrochloride in 800.0ml water is added sodium hydroxide (pellets or flakes) at room temperature till the pH of the solution is 9 to 9.5, when the solution became clear.
To this clear solution is added lOO.Og (0.418 moles) of 4-(2,3-epoxypropoxy) carbazole all at once. The reaction mixture is then heated at 80-85°C for 45 to 60 minutes when it is monitored by thin layer chromatography, and the TLC showed completion of reaction. The reaction mixture is worked up by the addition of 500.0ml of ethyl acetate and stirring the mixture for 15 min, the ethyl acetate layer is separated, dried over sodium sulphate and evaporated to dryness to obtain Carvedilol, which is recrystallized from ethyl acetate.
Yield: 78. Og (45.99%)
M.P: 114 °C (lit M.P. 113 to 116 °C, Merck index 13th edition)
1H NMR (200 MHZ, in CDC13) δ (ppm) 8.2 (bs,lH, exchanges with d2O), 6.8-8.3 (m
7H) 4.2-4.0 (m 1H), 3.8 (s 3H), 3-3.2 (t 4H), 2.8 (m 4H), 1.9 (bs,lH, exchanges with d2O)
Method B:
To a solution of 94.0g (0.461 moles) of 2-(2-methoxyphenoxy)-ethylamine hydrochloride in 400.0ml water and 400ml isopropyl alcohol is added sodium hydroxide (pellets or flakes) at room temperature till the pH of the solution was 9 to 9.5, when the solution became clear.
To this clear solution is added lOO.Og (0.418 moles) of 4-(2,3-epoxypropoxy) carbazole all at once. The reaction mixture is then refluxed for 4 to 5 hours when it is monitored by thin layer chromatography, and the TLC showed completion of reaction. The reaction mixture is worked up by the addition of 500.0ml of ethyl acetate and stirring the mixture for 15 min, the ethyl acetate layer is separated, dried over sodium sulphate and evaporated to dryness to obtain Carvedilol, which is recrystallized from ethyl acetate.
Yield: 73. Og (43.05%)
M.P: 114 (lit M.P. 113 to 116 °C, Merck index 13th edition)
!H NMR (200 MHZ, in CDC13) δ (ppm) 8.2 (bs,lH, exchanges with d2O), 6.8-8.3 (m
7H) 4.2-4.0 (m IH), 3.8 (s 3H), 3-3.2 (t 4H), 2.8 (m 4H), 1.9 (bs,lH, exchanges with d2O)

Claims

WE CLAIM:
1. A process for the preparation of l-(9 H-carbazol-4-yloxy)-3-[[2-(2- methoxyphenoxy)-ethylJ amino]-propan-2-ol, (Carvedilol) comprising: (a) reacting 4-hydroxy carbazole of formula (IV) with epichlorhydrin in presence of an organic solvent and a base at temperatures between 10°C - 30°C (b) further reacting the resultant 4-(2,3-epoxypropoxy)- carbazole of formula (II) with a salt of 2-(2-methoxyphenoxy) ethylamine of formula (III), preferably hydrochloride salt in presence of a base and a hydroxylic solvent at temperatures between 30 °C - 90 °C.
2. A process as claimed in claim 1, wherein the preferred base is inorganic base preferably alkali metal hydroxide, more preferably sodium hydroxide in aqueous form.
3. A process as claimed in claim 1(b), wherein the molar equivalent of base is employed may be from 1 mole to 6 moles, preferably 1.1 molar equivalents based on 4-hydroxy carbazole moles.
4. A process as claimed in claim 1(a), wherein the said organic solvent is selected from alcohols, cyclic ethers, dipolar aprotic solvents and glycol ethers, preferably water miscible (C1-C4) alcohols but, more preferably isopropyl alcohol.
5. A process as claimed in claim 1(b), wherein the said hydroxylic solvent is water or Cι-C4 alcohols like methyl alcohol, ethyl alcohol, isopropyl alcohol, butyl alcohol or mixtures thereof but preferably water.
6. A process as claimed in claim 1(a), wherein the preferred temperature range is 20-30 °C in the reaction between 4-hydroxy carbazole of formula (IV) and epichlorhydrin.
7. A process as claimed in claim 1(b), where in the preferred temperature range is 80 °C - 90 °C in the reaction between the compounds of formula II and formula III.
8. A process for preparation of Carvedilol as substantially described herein with reference to the foregoing examples 1 to 2.
PCT/IN2005/000139 2004-04-22 2005-05-03 A process for the preparation of 1-(9h-carbazol-4-yloxy)-3-2-(-methoxyphenoxy)-ethyl amino-propan-2-ol WO2005115981A2 (en)

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WO2006135757A1 (en) * 2005-06-09 2006-12-21 Teva Pharmaceutical Industries Ltd. Crystalline forms of carvedilol and processes for their preparation
WO2007097504A1 (en) * 2006-02-23 2007-08-30 Ahn-Gook Pharmaceutical Co., Ltd. Process for the preparation of highly optical pure carvedilol
WO2008038301A1 (en) * 2006-09-26 2008-04-03 Morepen Laboratories Limited A process for the preparation of carvedilol
US7485663B2 (en) 2000-06-28 2009-02-03 Teva Pharmaceutical Industries Ltd. Carvedilol
US7514467B2 (en) 2002-01-15 2009-04-07 Teva Pharmaceutical Industries Ltd. Crystalline solids of carvedilol and processes for their preparation
US8022094B2 (en) 2006-06-28 2011-09-20 Teva Pharmaceutical Industries Ltd. Carvedilol phosphate
CN102190613A (en) * 2010-03-14 2011-09-21 浙江华海药业股份有限公司 Method for preparing carvedilol

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WO2008105794A1 (en) * 2007-02-26 2008-09-04 Teva Pharmaceutical Industries Ltd. Process for the purification of carvedilol or its salts thereof
CN106045900B (en) * 2016-07-07 2019-03-08 佛山市隆信医药科技有限公司 A kind of preparation method of phosphoric acid Carvedilol

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