WO2009115906A2 - An improved process for preparation of carvedilol involving halohydrin derivative - Google Patents
An improved process for preparation of carvedilol involving halohydrin derivative Download PDFInfo
- Publication number
- WO2009115906A2 WO2009115906A2 PCT/IB2009/000556 IB2009000556W WO2009115906A2 WO 2009115906 A2 WO2009115906 A2 WO 2009115906A2 IB 2009000556 W IB2009000556 W IB 2009000556W WO 2009115906 A2 WO2009115906 A2 WO 2009115906A2
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- WIPO (PCT)
- Prior art keywords
- carvedilol
- formula
- carbazol
- yloxy
- compound
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- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
Definitions
- the present invention relates to process for making Carvedilol, ( ⁇ )-1-(carbazol-4- yloxy)-3-[[2-(2-methoxyphenoxy)ethyl]-amino]-2-propanol. It is nonselective ⁇ -adrenergic blocker with ⁇ 1 -blocking activity having following structural formula:
- Carvedilol is in racemic mixture form wherein S-(-) enantiomer is responsible for nonselective ⁇ -adrenoreceptor blocking activity and R-(+) and S-(-) enantiomers in both at equal potency shows ⁇ -adrenergic blocking activity.
- the US patent 4,503,067 discloses process for preparation of Carvedilol comprising reaction of 4-(2,3-epoxypropoxy)carbazole with 2-(2-methoxyphenoxy)-ethylamine using ethylene glycol, dimethyl ether as solvent to yield 39% Carvedilol.
- the instant process results into the formation of bis-compound which can never be avoided by instant process. Moreover, it is difficult to remove impurity even after purification of Carvedilol.
- European patent no. 918055 discloses two processes for preparation of Carvedilol.
- the process (A) comprises the reaction of 4-(oxiranylmethoxy)-9H-carbazole with protected N-[2- ⁇ 2 1 -(methoxy)-phenoxy ⁇ -ethyl]-benzylamine in a protic organic solvent to give benzyl protected Carvedilol.
- the process (B) comprises the reaction of protected N-[2- ⁇ 2'- (methoxy)-phenoxy ⁇ -ethyl]-benzyl amine with epichlorohydrin to form chloro compound, 1- [N- ⁇ benzyl ⁇ -2'-( ⁇ 2''-(methoxy)-phenoxy)-ethyl ⁇ -amino]-3-[chloro]-propan-2-ol.
- the intermediate chloro compound of reacts with 4-(hydroxyl)-9H-carbazole and thus forms benzyl protected Carvedilol.
- the end product is obtained via debenzylation of benzyl protected Carvedilol by catalytic hydrogenation.
- the US patent 7,126,008 discloses process for preparation of Carvedilol comprising reaction of 4-(oxiran-2-yl-methoxy)-9H-carbazole with 2-(2-methoxyphenoxy)-ethylamine, wherein the free amine compound is taken in molar excess ratio to reduce the formation of the bis-substituted impurities.
- PCT application No. WO2004/041783 discloses the process for preparation of Carvedilol wherein the 4-(oxiranylmethoxy)-9H-carbazole (Compound of formula I) reacts with an amine 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.
- PCT application No. WO/2006/061364 discloses reaction of 4-(oxirane-2-ylmethoxy)- 9H-carbazole (Compound of formula I) with 2-(2-methoxyphenoxy)-ethylamine using ethyl acetate as solvent.
- An object of present invention is to provide a process for the preparation of Carvedilol by reacting 1-(9H-carbazol-4-yloxy)-3-chloropropan-2-ol or 1-(9H-carbazol-4-yloxy)-3-bromo- propan-2-ol with 2-(2-methoxyphenoxy)-ethylamine or derivatives thereof.
- Yet another object of the invention is to provide 1-(9H-carbazol-4-yloxy)-3- chloropropan-2-ol or 1-(9H-carbazol-4-yloxy)-3-bromopropan-2-ol useful for the preparation of Carvedilol or its derivatives and/or pharmaceutically acceptable salts thereof.
- Yet another object of the invention is to provide a single step process for the preparation of Carvedilol substantially free from bis compound.
- the process for the preparation of Carvedilol as illustrated in the reaction scheme 1 comprises: a. reacting 4-(2,3-epoxy propoxy)carbazole with hydrochloric acid or hydrobromic acid to give corresponding 1-(9H-carbazol-4-yloxy)-3-chloropropan-2-ol or 1-(9H-carbazol- 4-yloxy)-3-bromopropan-2-ol, b. reacting the compound obtained in (a) with a compound of formula- Ha 1 to give a compound of formula-Ill c. separating crude residue results in to Carvedilol which up on purification gives pure Carvedilol.
- the present invention also provides process for the preparation of Carvedilol as illustrated in the reaction scheme 2 comprises: a. reacting 4-(2,3-epoxy propoxy)carbazole with hydrochloric acid or hydrobromic acid to give corresponding 1-(9H-carbazol-4-yloxy)-3-chloropropan-2-ol or 1-(9H-carbazol- 4-yloxy)-3-bromopropan-2-ol, b. reacting the compound obtained in (a) with a compound of formula- Ma 1 to give a compound of formula-Ill c. separating crude residue results in to the formation of protected Carvedilol which upon suitable deprotection reaction results into the formation of crude Carvedilol. d. The crude Carvedilol on purification gives highly pure Carvedilol.
- the reaction involves the use of hydrochloric acid or hydrobromic acid.
- the reaction is carried out at O 0 C to 100 0 C; preferably temperature is 15 0 C to 50 0 C 1 more preferably at 25°C-30°C.
- Toluene is added to the reaction mass to remove water under reduced pressure. The residue is cooled to 25 o C-30°C.
- Toluene and 2-(2- methoxyphenoxy)-ethylamine is added followed by addition of potassium carbonate.
- the reaction mass is heated to 80°C to 85°C and maintained for 13 hours. Water is added and stirred. Toluene layer is separated and distilled under reduced pressure at 65 - 70 0 C. Ethyl acetate is added to the residue and stirred at ambient temperature for half an hour. The reaction mass is gradually cooled and stirred. The residue is filtered and washed with chilled ethyl acetate to give Carvedilol (5.5 gm). The end product is dried under reduced pressure to give Carvedilol (> 97% HPLC purity).
- the protecting groups are selected from benzyl, substituted silyl derivatives etc. wherein the substituted silyl derivatives are preferable selected from hexamethyl disilazane, trimethyl chlorosilane, bistrimethyl silyl urea (BSU) 1 bistrimethyl acetamide (BSA), tert-butyl dimethyl silyl (TBDMS) or tert-butyl-diphenyl silyl
- Carvedilol which is obtained by reaction of (S)-1-(9H-carbazol-4-yloxy)-3-halopropan-2-ol with 2-(2-methoxyphenoxy)-ethylamine.
- Example-2 Preparation of Carvedilol 48 % HBr solution [35 ml] was added to 4-(2,3-Epoxy propoxy)carbazole (25 gm) in lsopropyl alcohol (50 ml ) at 25-30 0 C and heated to 60 0 C and maintained for about one hour with stirring. The solvent was distilled under reduced pressure and allow the reaction mass to cool at room temperature. Triethyl amine (16 gm) and 2-(2-methoxyphenoxy)-ethylamine (35 gm) were added to reaction mass and heated to 60 0 C and maintained for about 2 hours with stirring. Traces of lsopropyl alcohol was distilled under reduced pressure at 45-50 0 C.
- Carvedilol obtained by the present invention is indicated for the treatment of mild-to- severe heart failure of ischemic or cardiomyopathic origin. It is also indicated to reduce cardiovascular mortality during the acute phase of myocardial infarction and for the management of essential hypertension. Since Carvedilol is multiple action drug, its ⁇ - adrenoreceptor blocking activity affects the response to certain nerve impulses in parts of the body. Carvedilol is known to be vasodilator resulting primarily from ⁇ -adrenoceptor blockade. The multiple drug actions of Carvedilol are responsible for the antihypertensive efficacy of the drug and for its effectiveness in managing congestive heart failure.
Abstract
The present invention relates to a cost effective and industrially viable process for th preparation of Carvedilol involving halohydrin derivative
Description
FIELD OF INVENTION
The present invention relates to a cost effective and industrially viable process for the preparation of Carvedilol involving halohydrin derivative
BACKGROUND OF INVENTION
The present invention relates to process for making Carvedilol, (±)-1-(carbazol-4- yloxy)-3-[[2-(2-methoxyphenoxy)ethyl]-amino]-2-propanol. It is nonselective β-adrenergic blocker with α1-blocking activity having following structural formula:
Carvedilol is in racemic mixture form wherein S-(-) enantiomer is responsible for nonselective β-adrenoreceptor blocking activity and R-(+) and S-(-) enantiomers in both at equal potency shows α-adrenergic blocking activity.
The US patent 4,503,067 discloses process for preparation of Carvedilol comprising reaction of 4-(2,3-epoxypropoxy)carbazole with 2-(2-methoxyphenoxy)-ethylamine using ethylene glycol, dimethyl ether as solvent to yield 39% Carvedilol. The instant process results into the formation of bis-compound which can never be avoided by instant process. Moreover, it is difficult to remove impurity even after purification of Carvedilol.
The use of a secondary amine which is a derivative of primary amine of the formula Il containing protective group doesn't allow the formation of bis compound.
European patent no. 918055 discloses two processes for preparation of Carvedilol. The process (A) comprises the reaction of 4-(oxiranylmethoxy)-9H-carbazole with protected N-[2-{21-(methoxy)-phenoxy}-ethyl]-benzylamine in a protic organic solvent to give benzyl protected Carvedilol. The process (B) comprises the reaction of protected N-[2-{2'- (methoxy)-phenoxy}-ethyl]-benzyl amine with epichlorohydrin to form chloro compound, 1- [N-{benzyl}-2'-({2''-(methoxy)-phenoxy)-ethyl}-amino]-3-[chloro]-propan-2-ol. The intermediate chloro compound of reacts with 4-(hydroxyl)-9H-carbazole and thus forms benzyl protected Carvedilol.
The end product is obtained via debenzylation of benzyl protected Carvedilol by catalytic hydrogenation.
The US patent 7,126,008 discloses process for preparation of Carvedilol comprising reaction of 4-(oxiran-2-yl-methoxy)-9H-carbazole with 2-(2-methoxyphenoxy)-ethylamine, wherein the free amine compound is taken in molar excess ratio to reduce the formation of the bis-substituted impurities.
PCT application No. WO2004/041783 discloses the process for preparation of Carvedilol wherein the 4-(oxiranylmethoxy)-9H-carbazole (Compound of formula I) reacts with an amine salt of 2-(2-methoxyphenoxy)-ethylamine in presence of alkaline earth metal carbonate in C2-C5 alcohols as solvents. The product on crystallization in ethyl acetate yields 41% Carvedilol.
PCT application No. WO/2006/061364 discloses reaction of 4-(oxirane-2-ylmethoxy)- 9H-carbazole (Compound of formula I) with 2-(2-methoxyphenoxy)-ethylamine using ethyl acetate as solvent.
As the scale-up of the known processes of Carvedilol results in low yields and poor quality end products, they become commercially unattractive. It is therefore desirable to provide processes that are commercially applicable.
SUMMARY OF THE INVENTION An object of present invention is to provide a process for the preparation of Carvedilol by reacting 1-(9H-carbazol-4-yloxy)-3-chloropropan-2-ol or 1-(9H-carbazol-4-yloxy)-3-bromo- propan-2-ol with 2-(2-methoxyphenoxy)-ethylamine or derivatives thereof. Yet another object of the invention is to provide 1-(9H-carbazol-4-yloxy)-3- chloropropan-2-ol or 1-(9H-carbazol-4-yloxy)-3-bromopropan-2-ol useful for the preparation of Carvedilol or its derivatives and/or pharmaceutically acceptable salts thereof. Yet another object of the invention is to provide a single step process for the preparation of Carvedilol substantially free from bis compound.
DETAIL DESCRIPTION OF THE INVENTION
In accordance with the present invention, the process for the preparation of Carvedilol as illustrated in the reaction scheme 1 comprises: a. reacting 4-(2,3-epoxy propoxy)carbazole with hydrochloric acid or hydrobromic acid to give corresponding 1-(9H-carbazol-4-yloxy)-3-chloropropan-2-ol or 1-(9H-carbazol- 4-yloxy)-3-bromopropan-2-ol, b. reacting the compound obtained in (a) with a compound of formula- Ha1 to give a compound of formula-Ill c. separating crude residue results in to Carvedilol which up on purification gives pure Carvedilol.
The present invention also provides process for the preparation of Carvedilol as illustrated in the reaction scheme 2 comprises: a. reacting 4-(2,3-epoxy propoxy)carbazole with hydrochloric acid or hydrobromic acid to give corresponding 1-(9H-carbazol-4-yloxy)-3-chloropropan-2-ol or 1-(9H-carbazol- 4-yloxy)-3-bromopropan-2-ol, b. reacting the compound obtained in (a) with a compound of formula- Ma1 to give a compound of formula-Ill c. separating crude residue results in to the formation of protected Carvedilol which upon suitable deprotection reaction results into the formation of crude Carvedilol. d. The crude Carvedilol on purification gives highly pure Carvedilol.
Deprotection
Carvedilol
defined above
In a preferred embodiment the reaction involves the use of hydrochloric acid or hydrobromic acid. The reaction is carried out at O0C to 1000C; preferably temperature is 150C
to 500C1 more preferably at 25°C-30°C. Toluene is added to the reaction mass to remove water under reduced pressure. The residue is cooled to 25oC-30°C. Toluene and 2-(2- methoxyphenoxy)-ethylamine is added followed by addition of potassium carbonate.
The reaction mass is heated to 80°C to 85°C and maintained for 13 hours. Water is added and stirred. Toluene layer is separated and distilled under reduced pressure at 65 - 700C. Ethyl acetate is added to the residue and stirred at ambient temperature for half an hour. The reaction mass is gradually cooled and stirred. The residue is filtered and washed with chilled ethyl acetate to give Carvedilol (5.5 gm). The end product is dried under reduced pressure to give Carvedilol (> 97% HPLC purity).
When an amino protected 2-(2-methoxyphenoxy)-ethylamine is used in the above reaction instead of 2-(2-methoxyphenoxy)-ethylamine, above reaction results in the formation of pure protected Carvedilol. The protecting groups are selected from benzyl, substituted silyl derivatives etc. wherein the substituted silyl derivatives are preferable selected from hexamethyl disilazane, trimethyl chlorosilane, bistrimethyl silyl urea (BSU)1 bistrimethyl acetamide (BSA), tert-butyl dimethyl silyl (TBDMS) or tert-butyl-diphenyl silyl
(TBDPS) groups. The protected Carvedilol is optionally deprotected to give crude Carvedilol followed purification using any solvent, though ethyl acetate is preferred. In another embodiment of this reaction, it is possible to provide (S)-isomer of
Carvedilol which is obtained by reaction of (S)-1-(9H-carbazol-4-yloxy)-3-halopropan-2-ol with 2-(2-methoxyphenoxy)-ethylamine.
The present invention is illustrated with the given non-limiting examples.
Example 1 : Preparation of Carvedilol
4-(2,3-Epoxypropoxy)carbazole (10 gms) was added to a solution of hydrochloric acid [25 ml] at 25-300C. The reaction mass was stirred for 5 hours at 25 - 30°C, then the reaction mass was heated to 75-80°C. Water was distilled out at 75 - 85°C and then Toluene was added to remove water under reduced pressure at 75-800C. The residue was cooled to 25-30°C. Toluene (100 ml) and 2-(2-methoxyphenoxy)-ethylamine (10.45 gm) was added followed by addition of K2CO3 (9.45 gm). The reaction mass was heated to 80 - 85°C and maintained for about 13 hours. Water (100 ml) was added and stirred for 5 - 10 minutes. Toluene layer was separated and distilled out under reduced pressure at 65 - 700C. Ethyl acetate was added to the residue and stirred at ambient temperature for half an hour. The reaction mass was gradually cooled to 0-5°C and stirred for 2 hrs. The reaction mass was filtered, washed with chilled ethyl acetate to obtain Carvedilol (5.5 gm). The product was dried under reduced pressure to give Carvedilol (>97% HPLC purity).
Example-2 Preparation of Carvedilol 48 % HBr solution [35 ml] was added to 4-(2,3-Epoxy propoxy)carbazole (25 gm) in lsopropyl alcohol (50 ml ) at 25-300C and heated to 600C and maintained for about one hour with stirring. The solvent was distilled under reduced pressure and allow the reaction mass to cool at room temperature. Triethyl amine (16 gm) and 2-(2-methoxyphenoxy)-ethylamine (35 gm) were added to reaction mass and heated to 600C and maintained for about 2 hours with stirring. Traces of lsopropyl alcohol was distilled under reduced pressure at 45-500C. Water (50 ml), Toluene (100 ml) and 50 ml ethyl acetate were added at 500C1 and stirred for 15 minutes. The organic layer was allowed to separate and washed with water at 500C then dried with sodium sulfate (10 gm). Solvent was distilled under reduced pressure up to 550C. Ethyl acetate (55 ml) was added to residue and stirred for 30 minutes. The reaction mass was cooled to 0-50C and filtered to get Carvedilol (12 gm). The product was dried to give Carvedilol (>97% HPLC purity). Carvedilol obtained by the present invention is indicated for the treatment of mild-to- severe heart failure of ischemic or cardiomyopathic origin. It is also indicated to reduce cardiovascular mortality during the acute phase of myocardial infarction and for the management of essential hypertension. Since Carvedilol is multiple action drug, its β- adrenoreceptor blocking activity affects the response to certain nerve impulses in parts of the body. Carvedilol is known to be vasodilator resulting primarily from α-adrenoceptor blockade. The multiple drug actions of Carvedilol are responsible for the antihypertensive efficacy of the drug and for its effectiveness in managing congestive heart failure.
Claims
1. A process of preparing Carvedilol comprising steps: a. reacting 4-(2,3-epoxy propoxy) carbazole with hydrohalic acid to give 1-(9H- carbazol-4-yloxy)-3-halopropan-2-ol of formula I, b. reacting compound of formula I with 2-(2-Methoxy-phenoxy)-ethylamine compound of formula-ll to give a compound of formula-Ill
Formula I Formula Ha wherein,
X = CI for I1 or Br for I"
protecting groups 
c. separating crude from the reaction mass and purifying with solvent to give Carvedilol. d. the compound of formula III optionally deprotected if R is an amino protecting group and separating crude from the reaction mass followed by purifying with solvent to give Carvedilol.
2. The process claimed in claim-1 wherein the preferred hydrohalic acid is HCI or HBr.
3. The process as claimed in claim-1 wherein the reaction is carried out at 00C to 100 0C1 preferably at 25-300C.
4. The process as claimed in claim-1 wherein the solvent is selected from ethers such as tetrahydro furan [THF], dioxane, methyl tert. butyl ether, di-n-propyl ether; nitriles such as acetonitrile, propionitrile; aliphatic and alicyclic solvents such as hexane, heptane, cyclohexane, methyl cyclohexane; ketonic solvents such as acetone, methyl ethyl ketone, methyl isobutyl ketone; alcohols such as C1 to C5; benzotrifluoride, sulfolane, dimethyl sulfoxide [DMSO]1 N,N-dimethyl formamide [DMF], N1N- dimethyl acetamide
[DMA], N-methyl 2-pyrrolidone, 1,3-dimethyl imidazolidin-2-one, 1,3 dimethyl propylene urea, tetramethyl urea; sulfolane , aromatic hydrocarbons such as benzene, toluene, xylene.
5. The process of claim-5 wherein the preferred solvent is toluene or 2-propanol.
6. The process as claimed in claim-1 wherein the base is selected from carbonates such as sodium carbonate, potassium carbonate, cesium carbonate; alkoxides of C1 to C4 alcohols; or organic tertiary amine bases such as C1 to C4 trialkyl amines, N- methylmorpholine, N-methylpyrrolidine, N-methylpiperidine, Diaza(1,3)bicycle- [5.4.0]undecane [DBU], 1 ,5-Diazabicyclo[4.3.0]non-5-ene[DBN] and 1,4- diazabicyclo[2.2.2]octane [DABCO].
7. The process of claim-7 wherein the preferred base is potassium carbonate or triethyl amine.
8. The process as claimed in claim-1 (d) wherein, the amino protecting group is selected from benzyl or silyl derivative.
9. The process as claimed in claim-1 (d) wherein, deprotection of (i) deprotection of benzyl group is carried out using metal catalyst or (ii) trimethyl silyl group is earned out using aqueous acid.
10. The process as claimed in claim-1 wherein purification is carried out using Ethylacetate, acetonitrile and methylisobutylketone or mixtures thereof.
11. The process of claim-10 wherein carvedilol is preferably purified using ethyl acetate.
12. 1-(9H-carbazol-4-y!oxy)-3-chloropropan-2-ol or 1-(9H-carbazol-4-yloxy)-3-bromopropan- 2-ol useful for the preparation of Carvedilol or its derivatives and/or pharmaceutically acceptable salts thereof.
13. A process for the preparation of Carvedilol by reacting 1-(9H-carbazoM-yloxy)-3- chloropropan-2-ol or 1-(9H-carbazol-4-yloxy)-3-bromo-propan-2-ol or their derivatives with 2-(2-methoxyphenoxy)-ethylamiπe or derivatives thereof.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN560MU2008 | 2008-03-19 | ||
| IN560/MUM/2008 | 2008-03-19 |
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| Publication Number | Publication Date |
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| WO2009115906A2 true WO2009115906A2 (en) | 2009-09-24 |
| WO2009115906A3 WO2009115906A3 (en) | 2009-11-12 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102190613A (en) * | 2010-03-14 | 2011-09-21 | 浙江华海药业股份有限公司 | Method for preparing carvedilol |
Citations (2)
| 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 (en) * | 1997-11-24 | 1999-05-26 | Egis Gyogyszergyar Rt. | Process and intermediates for preparing 1-[9'H-carbazol-4'-yloxy]-3-[ 2''-(2'''- methoxy -phenoxy)-ethyl)-amino]-propan-2-ol[carvedilol] |
-
2009
- 2009-03-19 WO PCT/IB2009/000556 patent/WO2009115906A2/en active Application Filing
Patent Citations (2)
| 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 (en) * | 1997-11-24 | 1999-05-26 | Egis Gyogyszergyar Rt. | Process and intermediates for preparing 1-[9'H-carbazol-4'-yloxy]-3-[ 2''-(2'''- methoxy -phenoxy)-ethyl)-amino]-propan-2-ol[carvedilol] |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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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| WO2009115906A3 (en) | 2009-11-12 |
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