WO2009001369A1 - An improved process for the preparation of alfuzosin hydrochloride - Google Patents
An improved process for the preparation of alfuzosin hydrochloride Download PDFInfo
- Publication number
- WO2009001369A1 WO2009001369A1 PCT/IN2007/000329 IN2007000329W WO2009001369A1 WO 2009001369 A1 WO2009001369 A1 WO 2009001369A1 IN 2007000329 W IN2007000329 W IN 2007000329W WO 2009001369 A1 WO2009001369 A1 WO 2009001369A1
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- WIPO (PCT)
- Prior art keywords
- formula
- compound
- alfuzosin
- hydrochloride
- preparation
- Prior art date
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- WNMJYKCGWZFFKR-UHFFFAOYSA-N CN(CCCNC(C1OCCC1)=O)c1nc(N)c(cc(c(OC)c2)OC)c2n1 Chemical compound CN(CCCNC(C1OCCC1)=O)c1nc(N)c(cc(c(OC)c2)OC)c2n1 WNMJYKCGWZFFKR-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic 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
- C07D405/02—Heterocyclic 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
- C07D405/12—Heterocyclic 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
Definitions
- the present invention relates to an improved process for the preparation of Alfuzosin hydrochloride of formula (I) comprising a step of reacting compound of formula (IV) with compound of formula (V) in presence of aprotic solvent to obtain compound of formula (III) which is a useful intermediate for synthesis of Alfuzosin hydrochloride of formula (I)
- Alfuzosin Hydrochloride is prescribed for treatment of symptoms associated with benign prostatic hyperplasia (BPH) such as urinary frequency, nocturia, weak stream, hesitancy and incomplete emptying. It is chemically known as (R,S)-N-[3-[(4-amino-6,7-dimethoxy-2- quinazolinyl)methylamino] propyl] tetrahydro-2-furancarboxamide hydrochloride. It functions as an antagonist of ⁇ i-arenergic receptor, and is useful as antihypertensive agent and dysuria curing agent.
- BPH benign prostatic hyperplasia
- Alfuzosin hydrochloride is first disclosed in U.S. patent no. 4,315,007.
- the process for the preparation of Alfuzosin hydrochloride as disclosed in the patent is described in synthetic diagram as shown is Scheme-I and Scheme-II.
- the process for preparation of compound of formula (I) as disclosed in Scheme-II involves condensation of compound of formula (IV) with compound of formula (V) in the presence of isoamyl alcohol at reflux temperature.
- the compound of formula (I) obtained by this process contains many impurities and the yield of reaction is also low. This affects the purity and quality of final compound viz. Alfuzosin Hydrochloride of formula (I). Further, this process involves additional step of purification of compound of formula (II) by converting it to hydrochloride salt.
- GB 2231571, CN 1616438, WO 200630449, WO 2006090268, US 20070066824 and US 20070105880 are other patents and/or patent applications which discloses process for the preparation of Alfuzosin and pharmaceutically acceptable salts thereof and the intermediates which are useful therein.
- reaction of compound of formula. (IV) with compound of formula (V) in aprotic solvent results in high purity and yield of compound of formula (III). Further, the process does not involve additional step of purification of compound of formula (II) as reported in prior art process.
- the primary object of the present invention is to provide an improved process for the preparation of Alfuzosin Hydrochloride of formula (I).
- Another object of the present invention is to provide an improved process for the preparation of Alfuzosin Hydrochloride of formula (I) which utilises compound of formula (III) of high purity and yield.
- Another object of the present invention is to provide a process which result in high purity of compound of formula (III)
- Yet further object of the present invention is to provide a process for the preparation of Alfuzosin Hydrochloride of formula (I) which avoids step of purification of compound of formula (II) and thus resulting in less number of synthetic steps.
- the present invention provides a process for the preparation of Alfuzosin Hydrochloride of formula (I) comprising a step of reacting compound of formula (IV) with compound of formula (V) in presence of aprotic solvent.
- Another aspect of present invention provides a process for the preparation of compound of formula (III) comprising of reacting compound of formula (IV) with compound of formula (V) in presence of aprotic solvent.
- Yet another aspect of the present invention provides a process for the preparation of Alfuzosin Hydrochloride of formula (I) which comprising steps of,
- one embodiment provides an improved process for the preparation of Alfuzosin Hydrochloride of formula (I) as shown in the synthetic representation given in Scheme-Ill.
- Another embodiment of the present invention provides a process for the preparation of Alfuzosin Hydrochloride of formula (I) comprising steps of,
- Yet another embodiment of present invention provides a process for preparation of Alfuzosin Hydrochloride of formula (I) comprising a step of reacting compound of formula (IV) with compound of formula (V) in presence of aprotic solvent to obtain compound of formula (III).
- First step involves reacting compound of formula (IV) with compound of formula (V) in aprotic solvent.
- An aprotic solvent is selected from dimethyl acetamide and methyl isobutyl ketone or mixtures thereof
- the reaction can be carried out in temperature range of about 25 °C to reflux temperature of the solvent.
- N-(4-amino-6,7-dimethoxyquinazol-2-yl)-N-methyl-2-cyanoethylamine of formula (III) obtained by process of present invention has purity greater than about 98%.
- the hydrogenation of compound of formula (III) can be earned out at pressure of about 10- 15 kg hydrogen pressure.
- the solvent can be selected from methanol, ethanol and the like.
- the reaction can be carried out at ambient temperature or at reflux temperature of the solvent.
- the compound of formula (II) thus obtained can be reacted further without purification, with tetrahydrofuoic acid in presence of solvent and an activating agent.
- the solvent can be selected from methelenedichloride or dimethylformamide and the like or mixtures thereof.
- the activating agent can be selected from carbonyl diimidazole or thionyl chloride and the like.
- Alfuzosin base thus obtained can be converted to its hydrochloride salt with or without isolating the base.
- the crude base is purified to obtain pure base which is further dissolved in an alcoholic solvent and treated with alcoholic-HCl.
- the reaction mixture obtained after reaction of compound of formula (II) and (VI) is treated with aqueous solution of base preferably sodium hydroxide. Further the layers are separated and the solvent is removed to obtain residue. This residue without further purification is dissolved in an alcoholic solvent and treated with alcoholic- HCl to obtain Alfuzosin Hydrochloride.
- Alcohol can be selected from methanol, ethanol, 2- propanol, isopropanol and the like or mixtures thereof.
- reaction mixture is cooled and the crystals are filtered under nitrogen atmosphere and dried to obtain Alfuzosin Hydrochloride.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to an improved process for the preparation of Alfuzosin hydrochloride of formula (I) comprising a step of reacting compound of formula (IV) with compound of formula (V) in presence of aprotic solvent to obtain compound of formula (III) which is a useful intermediate for synthesis of Alfuzosin hydrochloride of formula (I).
Description
AN IMPROVED PROCESS FOR THE PREPARATION OF ALFUZOSIN HYDROCHLORIDE
Field of the Invention
The present invention relates to an improved process for the preparation of Alfuzosin hydrochloride of formula (I) comprising a step of reacting compound of formula (IV) with compound of formula (V) in presence of aprotic solvent to obtain compound of formula (III) which is a useful intermediate for synthesis of Alfuzosin hydrochloride of formula (I)
Background of the Invention
Alfuzosin Hydrochloride is prescribed for treatment of symptoms associated with benign prostatic hyperplasia (BPH) such as urinary frequency, nocturia, weak stream, hesitancy and incomplete emptying. It is chemically known as (R,S)-N-[3-[(4-amino-6,7-dimethoxy-2- quinazolinyl)methylamino] propyl] tetrahydro-2-furancarboxamide hydrochloride. It functions as an antagonist of αi-arenergic receptor, and is useful as antihypertensive agent and dysuria curing agent.
Alfuzosin hydrochloride is first disclosed in U.S. patent no. 4,315,007. The process for the preparation of Alfuzosin hydrochloride as disclosed in the patent is described in synthetic diagram as shown is Scheme-I and Scheme-II.
Scheme-I
CN isoamyl alcohol
The process for preparation of compound of formula (I) as disclosed in Scheme-II involves condensation of compound of formula (IV) with compound of formula (V) in the presence of isoamyl alcohol at reflux temperature. The compound of formula (I) obtained by this process contains many impurities and the yield of reaction is also low. This affects the purity and quality of final compound viz. Alfuzosin Hydrochloride of formula (I). Further, this process
involves additional step of purification of compound of formula (II) by converting it to hydrochloride salt.
GB 2231571, CN 1616438, WO 200630449, WO 2006090268, US 20070066824 and US 20070105880 are other patents and/or patent applications which discloses process for the preparation of Alfuzosin and pharmaceutically acceptable salts thereof and the intermediates which are useful therein.
Unexpectedly the present inventors have found out that reaction of compound of formula. (IV) with compound of formula (V) in aprotic solvent results in high purity and yield of compound of formula (III). Further, the process does not involve additional step of purification of compound of formula (II) as reported in prior art process.
Object of the invention The primary object of the present invention is to provide an improved process for the preparation of Alfuzosin Hydrochloride of formula (I).
Another object of the present invention is to provide an improved process for the preparation of Alfuzosin Hydrochloride of formula (I) which utilises compound of formula (III) of high purity and yield.
Further another object of the present invention is to provide a process which result in high purity of compound of formula (III)
Yet further object of the present invention is to provide a process for the preparation of Alfuzosin Hydrochloride of formula (I) which avoids step of purification of compound of formula (II) and thus resulting in less number of synthetic steps.
Summary of the invention
The present invention provides a process for the preparation of Alfuzosin Hydrochloride of formula (I) comprising a step of reacting compound of formula (IV) with compound of formula (V) in presence of aprotic solvent.
Another aspect of present invention provides a process for the preparation of compound of formula (III) comprising of reacting compound of formula (IV) with compound of formula (V) in presence of aprotic solvent.
Yet another aspect of the present invention provides a process for the preparation of Alfuzosin Hydrochloride of formula (I) which comprising steps of,
(a) reacting compound of formula (IV) with compound of formula (V) in presence of aprotic solvent to obtain compound of formula (III) (b) carrying out hydrogenation of compound of formula (III) to obtain compound of formula (II)
(c) condensing compound of formula (II) without purification, with tetrahydrofuroic acid of formula (VI) to obtain Alfuzosin base
(d) converting Alfuzosin base to corresponding hydrochloride salt to obtain Alfuzosin Hydrochloride of formula (I)
Further aspect of the present invention provides a process for the preparation of Alfuzosin Hydrochloride of formula (I) which does not involve purification of compound of formula (H).
Detailed description of the invention
In accordance with the object of the present invention one embodiment provides an improved process for the preparation of Alfuzosin Hydrochloride of formula (I) as shown in the synthetic representation given in Scheme-Ill.
Scheme-Ill
Another embodiment of the present invention provides a process for the preparation of Alfuzosin Hydrochloride of formula (I) comprising steps of,
(a) reacting compound of formula (IV) with compound of formula (V) in presence of aprotic solvent to obtain compound of formula (III)
(b) carrying out hydrogenation of compound of formula (III) to obtain compound of formula (II)
(c) condensing compound of formula (II) without purification, with tetrahydrofuroic acid of formula (VI) to obtain Alfuzosin base
(d) converting Alfuzosin base to corresponding hydrochloride salt to obtain Alfuzosin Hydrochloride of formula (I)
Yet another embodiment of present invention provides a process for preparation of Alfuzosin Hydrochloride of formula (I) comprising a step of reacting compound of formula (IV) with compound of formula (V) in presence of aprotic solvent to obtain compound of formula (III).
First step involves reacting compound of formula (IV) with compound of formula (V) in aprotic solvent. An aprotic solvent is selected from dimethyl acetamide and methyl isobutyl ketone or mixtures thereof
The reaction can be carried out in temperature range of about 25 °C to reflux temperature of the solvent.
N-(4-amino-6,7-dimethoxyquinazol-2-yl)-N-methyl-2-cyanoethylamine of formula (III) obtained by process of present invention has purity greater than about 98%.
The hydrogenation of compound of formula (III) can be earned out at pressure of about 10- 15 kg hydrogen pressure. The solvent can be selected from methanol, ethanol and the like. The reaction can be carried out at ambient temperature or at reflux temperature of the solvent.
The compound of formula (II) thus obtained can be reacted further without purification, with tetrahydrofuoic acid in presence of solvent and an activating agent. The solvent can be selected from methelenedichloride or dimethylformamide and the like or mixtures thereof. The activating agent can be selected from carbonyl diimidazole or thionyl chloride and the like.
Alfuzosin base thus obtained can be converted to its hydrochloride salt with or without isolating the base. In the case of isolation of the base, the crude base is purified to obtain pure base which is further dissolved in an alcoholic solvent and treated with alcoholic-HCl. In the case of direct conversion, the reaction mixture obtained after reaction of compound of formula (II) and (VI) is treated with aqueous solution of base preferably sodium hydroxide. Further the layers are separated and the solvent is removed to obtain residue. This residue without further purification is dissolved in an alcoholic solvent and treated with alcoholic-
HCl to obtain Alfuzosin Hydrochloride. Alcohol can be selected from methanol, ethanol, 2- propanol, isopropanol and the like or mixtures thereof.
The process of the present invention is described by the following examples, which are illustrative only and should not be construed so as to limit the scope of the invention in any manner.
EXAMPLES
Example-1
A mixture of 10 gm (0.04174 moles) 2-chloro-4-amino-6,7-dimethoxy quinazoline, 7.0 gm 3-methylaminopropionitirle (0.83 moles) and 30 ml N,N-dimethylacetamide was heated at 80-85 0C for 12-15 hrs. The progress of reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled and water was added to it. The reaction mixture was chilled for 1-2 hr and filtered off. The solid mass was dried to obtain 10.4 gm of N-(4- amino-6,7-dimethoxyquinazol-2-yl)-N-methyl-2-cyanoethylamine. HPLC purity. >98%
Example -2
A mixture of 10 gm (0.04174 moles) 2-chloro-4-amino-6,7-dimethoxy quinazoline, 7.0 gm 3-methylaminopropionitirle (0.83 moles) and 50 ml methylisobutylketone is refluxed for 48 hrs. The progress of reaction was monitored by TLC. After completion of the reaction, the reaction mixture is cooled to O0C and maintained for 1-2 hrs. The reaction mixture is filtered off and washed with methylisobutylketone. Further it is dried to obtained 10.2 gm of N-(4- amino-6,7-dimethoxyquinazol-2-yl)-N-methyl-2-cyanoethylamine. HPLC purity: >98%
Example -3
To 10 gm (0.0348 moles) of N-(4-amino-6,7-dimethoxyquinazol-2-yl)-N-methyl-2- cyanoethylamine was added 200 ml ammonical methanol (10%), 10 gm raney nickel in an autoclave. The reaction mass was hydrogenated under a pressure of 10 kg and a temperature
of 50-55 0C for 7-8 hrs. The progress of reaction was monitored by TLC. After completion of the reaction, the reaction mass was cooled to room temperature and the catalyst was filtered off through hyflo bed. The solvent was distilled off to obtain oily residue. To it was added 120 ml dichloromethane and the reaction mass was stirred for 30 min and filtered off through hyflo bed, The solvent was distilled off to obtain N]-(4-amino-6,7-dimethoxyquinaxol-2-yl)-
Nj-methylpropylene diamine. HPLC purity: >98%
Example -4
To 88 ml dichloromethane was added 24.5 gm (0.1512 moles) carbonyl diimidazole and 17.53 gm (0.1512 moles) tetrahydrofuroic acid. The reaction mass was stirred for 30 min. at
10-150C and then refluxed for one hour. 22 gm (0.07561 moles) Ni-(4-amino-6,7- dimethoxyquinazol-2-yl)-Ni-methylpropylenediamine in 66 ml dichloromethane was added to it at 38-40 0C. The progress reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled and filtered off through hyflo bed. To the filtrate was added 110 ml of water and adjusted pH 10-12 by using 2N NaOH solution. The organic layer was separated and washed with water and then with brine. The solvent is distilled off and ethanol is added to the residual oil. Calculated amount of isopropanolic HCl is added to it and refluxed to get clear solution. Charcoal is added to it and filtered through hyflo bed.
The reaction mixture is cooled and the crystals are filtered under nitrogen atmosphere and dried to obtain Alfuzosin Hydrochloride.
Claims
1. A process for the preparation of Alfuzosin Hydrochloride of formula (I) compring steps of,
(a) reacting compound of formula (IV) with compound of formula (V) in presence of aprotic solvent to obtain compound of formula (III)
(b) carrying out hydrogenation of compound of formula (III) to obtain compound of f foorrmmuullaa ( (ITIi))
(c) condensing compound of formula (II) without purification, with tetrahydrofuroic acid of formula (VI) to obtain Alfuzosin base
2. A process for preparation of Alfuzosin Hydrochloride of formula (I) comprising a step of reacting compound of formula (IV) with compound of formula (V) in presence of aprotic solvent to obtain compound of formula (III)
3. A process as claimed in claim 1 and 2 wherein, said aprotic solvent is selected from dimethyl acetamide and methyl isomethyl ketone or mixtures thereof
4. A process as claimed in claim 1 wherein, said hydrogenation is carried out at 10-15 kg hydrogen pressure
5. A process as claimed in claim 1 wherein, step (c) is carried out in presence of solvent and an activating agent
6. A process as claimed in claim 5 wherein, said solyent is selected from methelenedichloride and dimethylformamide or mixtures thereof
7. A process as claimed in claim 5 wherein, said activating agent is carbonyl diimidazole or thionyl chloride
8. A process as claimed in claim 1 wherein, said Alfuzosin base is converted to Alfuzosin Hydrochloride of formula (I) by dissolving it into alcoholic solvent and treating with alcoholic-HCl
9. A process as claimed in claim 9 wherein, said alcoholic solvent is methanol, ethanol, 2-propanol and isopropanol or mixtures thereof
10. A process as claimed in claim 8 wherein, said Alfuzosin base can be converted to Alfuzosin Hydrochloride of formula (I) directly or after purification
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN1207MU2007 | 2007-06-22 | ||
| IN1207/MUM/2007 | 2007-06-22 |
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| Publication Number | Publication Date |
|---|---|
| WO2009001369A1 true WO2009001369A1 (en) | 2008-12-31 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/IN2007/000329 WO2009001369A1 (en) | 2007-06-22 | 2007-08-06 | An improved process for the preparation of alfuzosin hydrochloride |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113801069A (en) * | 2020-06-15 | 2021-12-17 | 鲁南制药集团股份有限公司 | Alfuzosin hydrochloride intermediate compound |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4315007A (en) * | 1978-02-06 | 1982-02-09 | Synthelabo | 4-Amino-6,7-dimethoxyquinazol-2-yl alkylenediamines |
| WO2006090268A2 (en) * | 2005-02-28 | 2006-08-31 | Glenmark Pharmaceuticals Limited | Processes for the preparation of alfuzosin and salts thereof and novel crystalline forms of alfuzosin |
| US20070105880A1 (en) * | 2005-11-08 | 2007-05-10 | Torrent Pharmaceuticals Limited | Process for the preparation of alfuzosin |
-
2007
- 2007-08-06 WO PCT/IN2007/000329 patent/WO2009001369A1/en active Application Filing
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4315007A (en) * | 1978-02-06 | 1982-02-09 | Synthelabo | 4-Amino-6,7-dimethoxyquinazol-2-yl alkylenediamines |
| WO2006090268A2 (en) * | 2005-02-28 | 2006-08-31 | Glenmark Pharmaceuticals Limited | Processes for the preparation of alfuzosin and salts thereof and novel crystalline forms of alfuzosin |
| US20070105880A1 (en) * | 2005-11-08 | 2007-05-10 | Torrent Pharmaceuticals Limited | Process for the preparation of alfuzosin |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113801069A (en) * | 2020-06-15 | 2021-12-17 | 鲁南制药集团股份有限公司 | Alfuzosin hydrochloride intermediate compound |
| CN113801069B (en) * | 2020-06-15 | 2024-03-15 | 鲁南制药集团股份有限公司 | Alfuzosin hydrochloride intermediate compound |
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