WO2008015525A2 - An improved process for the preparation of alfuzosin hydrochloride - Google Patents

An improved process for the preparation of alfuzosin hydrochloride Download PDF

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Publication number
WO2008015525A2
WO2008015525A2 PCT/IB2007/002151 IB2007002151W WO2008015525A2 WO 2008015525 A2 WO2008015525 A2 WO 2008015525A2 IB 2007002151 W IB2007002151 W IB 2007002151W WO 2008015525 A2 WO2008015525 A2 WO 2008015525A2
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Prior art keywords
formula
process according
alfuzosin
acid
organic solvent
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PCT/IB2007/002151
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French (fr)
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WO2008015525A3 (en
Inventor
Sampathkumar Upparapalli
Sundaram Bharani Kumar Shanmuga
Hitesh Chandraprakash Sharma
Siripragada Mahender Rao
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Orchid Chemicals & Pharmaceuticals Limited
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Publication of WO2008015525A3 publication Critical patent/WO2008015525A3/en

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    • 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) by reacting iV-(3-aminopropyl)-6,7-dimethoxy-iV- methylquinazolme-2,4-diamme of Formula (II) with l-(tetrahydrofuran-2-ylcarbony I)-IH- imidazole of formula (IV) using acetonitrile as an organic solvent.
  • This invention also relates to a method for the purification of N-(3-aminopropyl)-6,7-dimethoxy-N- methylquinazoline-2,4-diarnine of formula (II), which is a key starting material of Alfuzosin hydrochloride by making its corresponding salt of formula (III) using an organic di-carboxylic acid in an alcoholic solvent wherein, A is denoted as a corresponding moiety of organic di-carboxylic acid.
  • Alfuzosin hydrochloride which is chemically known as ( ⁇ )-N-[3-[(4-Amino-6,7- dimethoxy-2-quinazolinyl)methylamino]propyl]tetrahydro-2-furancarboxamide hydrochloride is an antagonist of Ci 1 -adrenoceptor and has the following structural formula:
  • Alfuzosin hydrochloride is useful as an anti-hypertensive agent and dysuria curing agent and it is marketed as Uroxatral ® by Sanofi-Aventis.
  • U.S. Patent No. 4,315,007 disclosed 4-amino-6,7- dimethoxyquinazol-2-ylalkylenediamine derivatives. These compounds are used as anti- hypertensive agents. Among them Alfuzosin, is the most important anti-hypertensive agent. Processes for the preparations of Alfuzosin hydrochloride and related compounds were described in '007 and GB Patent No. 2231571. According to the disclosure of '007
  • Alfuzosin hydrochloride is prepared by reacting N-(3-aminopropyl)-6,7-dimethoxy-iV ' - methylquinazoline-2,4-diamine with l-(tetrahydrofuran-2-ylcarbonyl)-lH-imidazole using tetrahydrofuran as a solvent.
  • the WO2006/030449 Al (Hetero Drugs Ltd.) patent application discloses the isolation of Albuzosin base and the preparation of Alfuzosin hydrochloride by treating N- (4-amino-6,7-dimethoxy quinazol-2-yl)-N-methyl propylenediamine with activated tetrahydrofuroic acid by adding activated tetrahydrofuroic acid to diamine compound i.e. N-(4-amino-6,7-dimethoxy quinazol-2-yl)-N-methyl propylenediamine, followed by isolating Alfuzosin base and converting Alfuzosin base into pharmaceutically acceptable salt thereof.
  • the crude Alfuzosin has impurities in the level of about 0.6 to 0.8 %.
  • the purification by various solvents does not effectively lead to the purified Alfuzosin to have single impurity content below 0.1 %.
  • the disclosed process has advantages of simple operations, high yield, mild reaction conditions, and is suitable for industrial production over the processes described in the related prior arts.
  • the main objective of the present invention is to provide an improved process for the preparation of a compound of formula (I) in good yield and high chemical purity.
  • Another objective of the present invention is to provide a process for the preparation of a compound of formula (I), which would be easy to implement on commercial scale.
  • Yet another objective of the present invention is to recover acetonitrile and reuse it in the subsequent batches to make process more economical and commercially viable.
  • Still another objective of the present invention is to provide a method for the purification of compound of formula (II), which would result higher chemical purity of a compound of formula (I).
  • the present invention provides an improved process for the preparation of Alfuzosin hydrochloride (I), comprising the steps of;
  • step (b) treating a compound of formula (III) as obtained in step (a) with aqueous alkali solution to get purified N-(3-aminopropyl)-6,7-dimethoxy-N-methylquinazoline-2,4- diamine of formula (II);
  • the step (a) is preferably performed by using an organic di-carboxylic acid which is selected from the group comprising of oxalic acid, malonic acid, succinic acid, malic acid, fumaric acid, maleic acid and the like and most preferably oxalic acid.
  • alcoholic solvent is preferably selected from the group comprising of methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butanol, isobutanol, tertiary butanol, and mixtures thereof; most preferably methanol.
  • the step (a) is preferably performed at a temperature in the range of 20° C to 95° C; most preferably 60° C to 65° C.
  • the step (b) is preferably performed using aqueous alkali solution, which is selected from the group comprising sodium hydroxide solution, potassium hydroxide solution, sodium carbonate solution, potassium carbonate solution, sodium hydrogen carbonate solution and the like, most preferably sodium hydroxide solution.
  • aqueous alkali solution which is selected from the group comprising sodium hydroxide solution, potassium hydroxide solution, sodium carbonate solution, potassium carbonate solution, sodium hydrogen carbonate solution and the like, most preferably sodium hydroxide solution.
  • the step (b) is preferably performed at a temperature in the range of 20° C to reflux temperature and most preferably 20° C to 45° C.
  • organic solvent is preferably selected from the group comprising of acetonitrile, dimethylacetamide, ethyl acetate; most preferably acetonitrile.
  • the preparation of a compound of formula (V) is preferably performed at a temperature in the range of (-) 20°C to reflux temperature and most preferably 55° C to 65° C.
  • organic solvent is preferably selected from chlorinated solvent; most preferably methylenedichloride.
  • water-miscible organic solvent is selected from the group comprising of alcohol, acetone and tetrahydrofuran.
  • water-miscible organic solvent alcohol is preferably selected from the group comprising of methanol, ethanol, n- propyl alcohol, isopropyl alcohol, n-butanol, isobutanol, tertiary butanol, and mixtures thereof; most preferably methanol.
  • alcoholic hydrochloric acid is preferably selected from the group comprising of ethanolic hydrochloric acid, methanolic hydrochloric acid, isopropanolic hydrochloric acid and the like and most preferably isopropanolic hydrochloric acid.
  • alcoholic solvent is preferably selected from the group comprising of methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butanol, isobutanol, tertiary butanol, and mixtures thereof; most preferably isopropyl alcohol.
  • Alfuzosin freebase of formula (V) in step (k) is converted into Alfuzosin hydrochloride of formula (I) without isolating Alfuzosin freebase of formula (V).
  • Example (1) Preparation of oxalate salt of iV-(3-aminopropylV6,7-dimethoxy-iV methylquinazoline-2,4-diamine
  • N-(3-aminopropyl)-6,7-dimethoxy-iV-methylquinazoline-2,4-diamine (4Og) and methanol (320 niL) were taken in a reaction vessel, stirred and heated the contents at 60° C to 65 C to get the clear solution.
  • methanol 40 mL
  • This oxalic acid solution was added drop wise to the reaction vessel containing the diamine at 60° C to 65° C and the reaction mass was maintained for 30 to 35 mins.
  • reaction mass was cooled, filtered, washed with methanol (40 mL) and the material was dried to get oxalate salt of iV-(3- aminopropyl)-6,7-dimethoxy-iV-methylquinazoline-2,4-diamine (45 g).
  • Oxalate salt of iV-(3-aminopropyl)-6,7-dimethoxy-iV-methylquinazoline-2,4- diamine (45 g) was dissolved in water (360 mL) in a reaction vessel.
  • a solution of sodium hydroxide (6.08 g) in water (40 mL) was prepared.
  • Sodium hydroxide solution was added dropwise into oxalate salt of iV-(3-aminopropyl)- 6,7-dimethoxy-N-methylquinazoline-2,4-diamine solution, stirred, filtered, washed the reaction mass with water (160 mL) and the material was dried till the moisture content reached less than 10%. (Yield 39.5 g and HPLC purity 98%).
  • the reaction mass was cooled, 325 mL of methylenedichloride was added, the organic layer was separated and 37.5 mL of methanol and 212.5 mL DM water were added followed by stirring. The organic layers were separated and the process was repeated till the purity reaches more than 99.6 %.
  • the reaction mass was filtered and methylenedichloride was distilled to get residue which was dissolved in isopropyl alcohol, the pH was adjusted 0 to 0.5 with isopropylalcohol / hydrochloric acid and the reaction mass was stirred, filtered under nitrogen and the solid was washed with isopropylalcohol. The material was dried to get Alfuzosin hydrochloride 14.5g. (HPLC purity more than 99.75%).
  • condensation step is carried out at low temperature as compare to innovator process. 2.
  • N-(3-aminopropyl)-6,7-dimethoxy- ⁇ V-methylquinazoline-2 5 4-diamine is added by dissolving in solvent instead of adding in a solid form to make process more simple and feasible at industrial scale
  • distillation of tetrahydrofuran is carried out in the presence of aqueous phase to avoid the reactivity of peroxide in the tetrahydrofuran from the safety point of view.
  • washing with aqueous methanol not only gives high purity but also avoids additional filtration stage.

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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

The present invention relates to an improved process for the preparation of Alfuzosin hydrochloride of formula (I) by reacting N-(3-aminopropyl)-6,7-dimethoxy-N- methylquinazoline-2,4-diamine of formula (II) with 1-(tetrahydrofuran-2-ylcarbonyl)-1 H- imidazole of formula (IV) using acetonitrile as an organic solvent. This invention also relates to a method for the purification of N-(3-aminopropyl)-6,7-dimethoxy-N-methylquinazoline-2,4- diamine of formula (II), which is a key starting material of Alfuzosin hydrochloride by making its corresponding salt of formula (III) using an organic dicarboxylic acid in an alcoholic solvent wherein, A is denoted as a corresponding moiety of organic dicarboxylic acid.

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) by reacting iV-(3-aminopropyl)-6,7-dimethoxy-iV- methylquinazolme-2,4-diamme of Formula (II) with l-(tetrahydrofuran-2-ylcarbony I)-IH- imidazole of formula (IV) using acetonitrile as an organic solvent. This invention also relates to a method for the purification of N-(3-aminopropyl)-6,7-dimethoxy-N- methylquinazoline-2,4-diarnine of formula (II), which is a key starting material of Alfuzosin hydrochloride by making its corresponding salt of formula (III) using an organic di-carboxylic acid in an alcoholic solvent wherein, A is denoted as a corresponding moiety of organic di-carboxylic acid.
Figure imgf000002_0001
Formula (III) Formula (IV)
Background of the Invention
Alfuzosin hydrochloride which is chemically known as (±)-N-[3-[(4-Amino-6,7- dimethoxy-2-quinazolinyl)methylamino]propyl]tetrahydro-2-furancarboxamide hydrochloride is an antagonist of Ci1 -adrenoceptor and has the following structural formula:
Figure imgf000002_0002
Alfuzosin hydrochloride is useful as an anti-hypertensive agent and dysuria curing agent and it is marketed as Uroxatral® by Sanofi-Aventis.
U.S. Patent No. 4,315,007 (henceforth '007) disclosed 4-amino-6,7- dimethoxyquinazol-2-ylalkylenediamine derivatives. These compounds are used as anti- hypertensive agents. Among them Alfuzosin, is the most important anti-hypertensive agent. Processes for the preparations of Alfuzosin hydrochloride and related compounds were described in '007 and GB Patent No. 2231571. According to the disclosure of '007
Alfuzosin hydrochloride is prepared by reacting N-(3-aminopropyl)-6,7-dimethoxy-iV'- methylquinazoline-2,4-diamine with l-(tetrahydrofuran-2-ylcarbonyl)-lH-imidazole using tetrahydrofuran as a solvent.
The WO2006/030449 Al (Hetero Drugs Ltd.) patent application discloses the isolation of Albuzosin base and the preparation of Alfuzosin hydrochloride by treating N- (4-amino-6,7-dimethoxy quinazol-2-yl)-N-methyl propylenediamine with activated tetrahydrofuroic acid by adding activated tetrahydrofuroic acid to diamine compound i.e. N-(4-amino-6,7-dimethoxy quinazol-2-yl)-N-methyl propylenediamine, followed by isolating Alfuzosin base and converting Alfuzosin base into pharmaceutically acceptable salt thereof.
The WO 2006/090268 Al (Glenmark Pharmaceuticals Ltd.) patent application also discloses the isolation of Alfuzosin base and the preparation of Alfuzosin hydrochloride.
Journal of Medicinal Chemistry 1986, 29:19-25 disclosed a series of 4-amino-6,7- dimethoxyquinazoline derivatives including Alfuzosin , which can be prepared by the following steps: (a) 6,7-Dimethoxyquinazolin-2,4-dione is converted to 2,4-dichloro 6,7- dimethoxyquinazoline, followed by selective displacement of the 4-chloro group with ammonia to give 4-amino-2-chloro-6,7-dimethoxyquinazoline (b) 3-(Methylamino)propanenitrile is reacted with the mixed anhydride obtained from tetrahydrofuran-2-carboxylic acid and ethyl chloroformate to form the corresponding amide, which on hydrogenation over rhodium at 800C in the presence of ammonia affords the required corresponding secondary amine via rearrangement of the initially formed primary amine. Condensation of the corresponding amine with 4-amino-2-chloro-6,7- dimethoxyquinazoline in refluxing amyl alcohol gives Alfuzosin hydrochloride.
While certain processes of Alfuzosin hydrochloride preparation are known, but still there is a continuing need for simple and improved processes of preparation of Alfuzosin and its salts.
During the synthesis of Alfuzosin hydrochloride, a number of unknown impurities are formed, of which some are originating from the key starting materials. The impurities, which are formed during the synthesis of Alfuzosin hydrochloride including the contaminants of the reagents, get carried over till the final step of preparation of Alfuzosin hydrochloride. In order to get the highly pure Active Pharmaceutical Ingredient (API) of Alfuzosin, the purification step of key starting material is very essential.
The crude Alfuzosin has impurities in the level of about 0.6 to 0.8 %. The purification by various solvents does not effectively lead to the purified Alfuzosin to have single impurity content below 0.1 %. Due to the high initial levels of unknown process impurities in the API prepared by prior art processes; the impurity content exceeds the acceptable limits, set forth by the regulatory authorities. Thus, there is an urgent need to develop a process which removes the above mentioned deficits of prior art processes and provides an API containing insignificant initial amount of the unknown process impurities, so that the content of the impurity can be kept within the acceptable levels throughout the shelf life of the product, while at the same time satisfying the regulatory requirements.
With reference to the above-discussed procedures, none of the prior art references disclosed or claimed the use of acetonitrile (ACN) as an organic solvent in the condensation step for the preparation of a compound of formula (V) and a purification method of N-(3-aminopropyl)-6,7-dimethoxy-N-methylquinazoline-2,4-diamine of formula (II) which is a key starting material of Alfuzosin hydrochloride, by making corresponding salt of formula (III) using an organic di-carboxylic acid in an alcoholic solvent and further treated with alkaline aqueous solution to give purified N-(3- aminopropyl)-6,7-dimethoxy-N-methylquinazoline-2,4-diamine of formula (II).
With reference to the above-discussed procedures, none of the prior art references disclosed or claimed the use of a mixture of water and water miscible organic solvent (s) for the removal of unknown process impurities during the preparation of Alfuzosin freebase of formula (V).
We focused our research to develop an improved and efficient process for the preparation of compound of formula (I) using acetonitrile as a solvent in the condensation step and a purification method of a compound of formula (II) which is a key starting material of Alfuzosin hydrochloride by making its corresponding salt of formula (III), in substantially good yield and high chemical purity.
We also focused to develop a method for the purification of Alfuzosin freebase of formula (V) by washing with a mixture of water and water miscible organic solvent (s) for the removal of unknown process impurities during the preparation of Alfuzosin freebase of formula (V).
The disclosed process has advantages of simple operations, high yield, mild reaction conditions, and is suitable for industrial production over the processes described in the related prior arts.
Objectives of the Invention
The main objective of the present invention is to provide an improved process for the preparation of a compound of formula (I) in good yield and high chemical purity.
Another objective of the present invention is to develop a method for the purification of a compound of formula (V) using a mixture of water and water miscible organic solvent (s). Another objective of the present invention is to provide an improved process for the preparation of a compound of formula (V) using acetonitrile as an organic solvent.
Another objective of the present invention is to provide a process for the preparation of a compound of formula (I), which would be easy to implement on commercial scale.
Yet another objective of the present invention is to recover acetonitrile and reuse it in the subsequent batches to make process more economical and commercially viable.
Still another objective of the present invention is to provide a method for the purification of compound of formula (II), which would result higher chemical purity of a compound of formula (I).
Summary of the Invention
Accordingly, the present invention provides an improved process for the preparation of Alfuzosin hydrochloride (I), comprising the steps of;
Figure imgf000006_0001
(a) reacting N-(3-aminopropyl)-6,7-dimethoxy-iV-methylquinazoline-2,4-diamine of formula (II) with an organic di-carboxylic acid in an alcoholic solvent to get the corresponding salt of formula (III) wherein, A is denoted as a corresponding moiety of organic di-carboxylic acid;
Figure imgf000007_0001
Formula (II)
Formula (III)
(b) treating a compound of formula (III) as obtained in step (a) with aqueous alkali solution to get purified N-(3-aminopropyl)-6,7-dimethoxy-N-methylquinazoline-2,4- diamine of formula (II);
(c) condensing the purified iV-(3-aminopropyl)-6,7-dimethoxy-iV-methylquinazoline-2,4- diamine of Formula (II) as obtained from the step (b) with l-(tetrahydrofuran-2-yl- carbonyl)-lH-imidazole of formula (IV) using an organic solvent;
Figure imgf000007_0002
Formula (II) Formula <IV>
(d) quenching the reaction mass as obtained in step (c) using brine solution;
(e) separating the organic layer;
(f) distilling the organic solvent; (g) adding an organic solvent to the reaction mass as obtained in step (f); (h) separating the organic layer; (i) washing the organic layer as obtained in step (h) using a mixture of water and water miscible organic solvent (s); Q) separating the organic layer; (k) concentrating the organic layer to get Alfuzosin freebase of formula (V)5 which is in-situ converted into Alfuzosin hydrochloride of formula (I) using suitable alcoholic hydrochloric acid in an alcoholic solvent. The process is shown in the scheme given below:
Figure imgf000008_0001
Formula (II)
Formula (III) Before Purification / Water
Figure imgf000008_0002
Figure imgf000008_0003
Formula (II) Formula (IV) After Purification
(-) 10 to (-) 15 deg. C ACN
Figure imgf000008_0004
Formula (V)
IPA / HCI IPA
Figure imgf000008_0005
Description of the Invention
In an embodiment of the present invention, the step (a) is preferably performed by using an organic di-carboxylic acid which is selected from the group comprising of oxalic acid, malonic acid, succinic acid, malic acid, fumaric acid, maleic acid and the like and most preferably oxalic acid.
In another embodiment of the present invention, in step (a) alcoholic solvent is preferably selected from the group comprising of methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butanol, isobutanol, tertiary butanol, and mixtures thereof; most preferably methanol.
In another embodiment of the present invention, the step (a) is preferably performed at a temperature in the range of 20° C to 95° C; most preferably 60° C to 65° C.
In another embodiment of the present invention, the step (b) is preferably performed using aqueous alkali solution, which is selected from the group comprising sodium hydroxide solution, potassium hydroxide solution, sodium carbonate solution, potassium carbonate solution, sodium hydrogen carbonate solution and the like, most preferably sodium hydroxide solution.
In another embodiment of the present invention, the step (b) is preferably performed at a temperature in the range of 20° C to reflux temperature and most preferably 20° C to 45° C.
In another embodiment of the present invention, in step (c) organic solvent is preferably selected from the group comprising of acetonitrile, dimethylacetamide, ethyl acetate; most preferably acetonitrile. In another embodiment of the present invention, in step (c) the preparation of a compound of formula (V) is preferably performed at a temperature in the range of (-) 20°C to reflux temperature and most preferably 55° C to 65° C.
In another embodiment of the present invention, in step (g) organic solvent is preferably selected from chlorinated solvent; most preferably methylenedichloride.
In another embodiment of the present invention, in step (i) water-miscible organic solvent is selected from the group comprising of alcohol, acetone and tetrahydrofuran.
In another embodiment of the present invention, in step (i) water-miscible organic solvent alcohol is preferably selected from the group comprising of methanol, ethanol, n- propyl alcohol, isopropyl alcohol, n-butanol, isobutanol, tertiary butanol, and mixtures thereof; most preferably methanol.
In another embodiment of the present invention, in step (k) alcoholic hydrochloric acid is preferably selected from the group comprising of ethanolic hydrochloric acid, methanolic hydrochloric acid, isopropanolic hydrochloric acid and the like and most preferably isopropanolic hydrochloric acid.
In yet another embodiment of the present invention, in step (k) alcoholic solvent is preferably selected from the group comprising of methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butanol, isobutanol, tertiary butanol, and mixtures thereof; most preferably isopropyl alcohol.
In still another embodiment of the present invention, Alfuzosin freebase of formula (V) in step (k) is converted into Alfuzosin hydrochloride of formula (I) without isolating Alfuzosin freebase of formula (V).
In the present invention the starting materials are prepared according to the literature available in the prior art. The present invention is illustrated with the following examples, which should not be construed for limiting the scope of the invention.
Example (1) : Preparation of oxalate salt of iV-(3-aminopropylV6,7-dimethoxy-iV methylquinazoline-2,4-diamine
N-(3-aminopropyl)-6,7-dimethoxy-iV-methylquinazoline-2,4-diamine (4Og) and methanol (320 niL) were taken in a reaction vessel, stirred and heated the contents at 60° C to 65 C to get the clear solution. In another container a solution of oxalic acid di- hydrate (8.6 g) in methanol (40 mL) was prepared. This oxalic acid solution was added drop wise to the reaction vessel containing the diamine at 60° C to 65° C and the reaction mass was maintained for 30 to 35 mins. The reaction mass was cooled, filtered, washed with methanol (40 mL) and the material was dried to get oxalate salt of iV-(3- aminopropyl)-6,7-dimethoxy-iV-methylquinazoline-2,4-diamine (45 g).
Oxalate salt of iV-(3-aminopropyl)-6,7-dimethoxy-iV-methylquinazoline-2,4- diamine (45 g) was dissolved in water (360 mL) in a reaction vessel. In another reaction container, a solution of sodium hydroxide (6.08 g) in water (40 mL) was prepared. Sodium hydroxide solution was added dropwise into oxalate salt of iV-(3-aminopropyl)- 6,7-dimethoxy-N-methylquinazoline-2,4-diamine solution, stirred, filtered, washed the reaction mass with water (160 mL) and the material was dried till the moisture content reached less than 10%. (Yield 39.5 g and HPLC purity 98%).
Example (2) : Preparation of Alfuzosin hydrochloride
125 mL of tetrahydrofuran and 13.92 g of carbonyldiimidazole (CDI) were taken in 250ml RBF at 25° C to 35° C and the reaction mass was stirred to get the clear solution.
9.96g of tetrahydrofuran-2-carboxylic acid was added at 25° C to 35° C, the reaction mass was stirred and diluted with 125 mL of tetrahydrofuran and was cooled up to
(-) 10 to (-) 200C. In another reaction vessel 25g of N-(3-aminopropyl)-6,7-dimethoxy-iV- methylquinazoline-2,4-diamine and 250 mL of tetrahydrofuran were taken, stirred and' the reaction mass was heated to 60° C to 65° C till a clear solution was obtained which was cooled and added further to the reaction mass. The reaction was stirred, quenched with 250 mL of 10% brine solution followed by separating the organic layer, which is distilled up to 2 volumes. The reaction mass was cooled, 325 mL of methylenedichloride was added, the organic layer was separated and 37.5 mL of methanol and 212.5 mL DM water were added followed by stirring. The organic layers were separated and the process was repeated till the purity reaches more than 99.6 %. The reaction mass was filtered and methylenedichloride was distilled to get residue which was dissolved in isopropyl alcohol, the pH was adjusted 0 to 0.5 with isopropylalcohol / hydrochloric acid and the reaction mass was stirred, filtered under nitrogen and the solid was washed with isopropylalcohol. The material was dried to get Alfuzosin hydrochloride 14.5g. (HPLC purity more than 99.75%).
Example (3) Preparation of Alfuzosin hydrochloride
125 mL of acetonitrile and 13.92 g of carbonyldiimidazole (CDI) were taken in 250ml RBF at 25° C to 35° C and the reaction mass was stirred to get the clear solution. 9.96g of tetrahydrofuran-2-carboxylic acid was added at 250 C to 35° C, the reaction mass was stirred and diluted with 125 mL of acetonitrile and was cooled up to (-) 10 to (-) 200C. In another reaction vessel 25g of N-(3-aminopropyl)-6,7-dimethoxy-iV'- methylquinazoline-2,4-diamine and 250 mL of acetonitrile were taken, stirred and the reaction mass was heated to 60° C to 65° C till a clear solution was obtained which was cooled and added further to the reaction mass. The reaction was stirred, quenched with 250 mL of 10% brine solution followed by separating the organic layer, which is distilled up to 2 volumes. The reaction mass was cooled, 325 mL of methylenedichloride was added, the organic layer was separated and 37.5 mL of methanol and 212.5 mL DM water were added followed by stirring. The organic layers were separated and the process was repeated till the purity reaches more than 99.6 %. The reaction mass was filtered and methylenedichloride was distilled to get residue which was dissolved in isopropyl alcohol, the pH was adjusted 0 to 0.5 with isopropylalcohol / hydrochloric acid and the reaction mass was stirred, filtered under nitrogen and the solid was washed with isopropylalcohol. The material was dried to get Alfuzosin hydrochloride 14.5g. (HPLC purity more than 99.75%). Advantages
1. In the present invention condensation step is carried out at low temperature as compare to innovator process. 2. In the present invention during condensation step N-(3-aminopropyl)-6,7-dimethoxy- ΪV-methylquinazoline-254-diamine is added by dissolving in solvent instead of adding in a solid form to make process more simple and feasible at industrial scale
3. In the present invention distillation of tetrahydrofuran is carried out in the presence of aqueous phase to avoid the reactivity of peroxide in the tetrahydrofuran from the safety point of view.
4. In the present invention during workup the use of methylenedichloride in extraction of aqueous phase removes the un-reacted iV-(3-aminopropyl)-6,7-dimethoxy-iV- methylquinazoline-2,4-diamine along with the unknown process impurities.
5. In the present invention washing with aqueous methanol not only gives high purity but also avoids additional filtration stage.

Claims

We Claim:
(1) A process for the preparation of Alfuzosin hydrochloride of formula (I), comprising the steps of;
Figure imgf000014_0001
Formula (I)
(a) reacting N-(3-aminopropyl)-6,7-dimethoxy-iV-methylquinazoline-254-diamine of formula (II) with an organic di-carboxylic acid in an alcoholic solvent to get the corresponding salt of formula (III), wherein A is denoted as a corresponding moiety of organic di-carboxylic acid;
Figure imgf000014_0002
Formula (II) Formula (III)
(b) treating a compound of formula (III) as obtained in step (a) with aqueous alkali solution to get purified N-(3-aminopropyl)-6,7-dimethoxy-N-methylquinazoline-254- diamine of formula (II) ;
(c) condensing the purified JV-(3-aminopropyl)-6,7-dimethoxy-iV-methylquinazoline-2,4- diamine of Formula (II) as obtained from the step (b) with l-(tetrahydrofuran~2-yl- carbonyO-lH-imidazole of formula (IV) using an organic solvent;
Figure imgf000015_0001
Formula (II) Formula {IV>
(d) quenching the reaction mass as obtained in step (c) using brine solution;
(e) separating the organic layer;
(f) distilling the organic solvent;
(g) adding an organic solvent to the reaction mass as obtained in step (f); (h) separating the organic layer;
(i) washing the organic layer as obtained in step (h) using a mixture of water and water miscible organic solvent (s); (J) separating the organic layer; (k) concentrating the organic layer to get Alfuzosin freebase of formula (V), which is in-situ converted into Alfuzosin hydrochloride of formula (I) using suitable alcoholic hydrochloric acid in an alcoholic solvent.
Figure imgf000015_0002
Formula (V)
(2) A method for the purification of Alfuzosin free base contained in an organic solvent by washing with a mixture of water and water miscible organic solvent (s).
(3) A process according to claim 1, wherein organic di-carboxylic acid in step (a) is preferably selected from the group comprising of oxalic acid, malonic acid, succinic acid, malic acid, fumaric acid, maleic acid and the like and most preferably oxalic acid.
(4) A process according to claim 1, wherein alcoholic solvent in step (a) is selected preferably from the group comprising of methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butanol, isobutanol, tertiary butanol and mixtures thereof and most preferably methanol.
(5) A process according to claim 1, wherein step (a) is preferably performed at a temperature in the range of 20° C to 95° C and most preferably 60° C to 65° C.
(6) A process according to claim 1, wherein aqueous alkali solution in step (b) is selected from the group comprising sodium hydroxide solution, potassium hydroxide solution, sodium carbonate solution, potassium carbonate solution, sodium hydrogen carbonate solution and the like, most preferably sodium hydroxide solution.
(7) A process according to claim 1, wherein step (b) is performed at a temperature in the range of 20° C to reflux temperature and most preferably 20° C to 45° C.
(8) A process according to claim 1, wherein most preferred organic solvent in step (c) is acetonitrile.
(9) A process according to claim I3 wherein step (c) is preferably performed at a temperature in the range of (-) 200C to reflux temperature and most preferably 55° C to 650 C.
(10) A process according to claim 1, wherein organic solvent in step (g) is preferably selected from the chlorinated solvent and the like and most preferably methylenedichloride .
(H) A process according to claim 1 of step (i) and claim 2, wherein water-miscible organic solvent is selected from the group comprising of alcohol, acetone and tetrahydrofuran.
(12) A process according to claim 11, wherein alcohol is selected preferably from the group comprising of methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butanol, isobutanol, tertiary butanol, and mixtures thereof and most preferably methanol.
(13) A process according to claim 1, wherein alcoholic hydrochloric acid in step (k) is preferably selected from the group comprising ethanolic hydrochloric acid methanolic hydrochloric acid, isopropanolic hydrochloric acid and most preferably isopropanolic hydrochloric acid.
(14) A process according to claim 1, wherein alcoholic solvent in step (k) is selected preferably from the group comprising of methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butanol, isobutanol, tertiary butanol and mixtures thereof and most preferably isopropyl alcohol.
(15) A process according to claim 1, wherein Alfuzosin freebase of formula (V) in step (k) is converted into Alfuzosin hydrochloride of formula (I) without isolating Alfuzosin freebase of formula (V).
PCT/IB2007/002151 2006-07-31 2007-07-27 An improved process for the preparation of alfuzosin hydrochloride WO2008015525A2 (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114591273A (en) * 2022-03-31 2022-06-07 邦恩泰(山东)生物医药科技集团股份有限公司 Synthesis method and application of N-methyl-N' -tetrahydrofuran formyl propane diamine oxalate

Citations (3)

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GB2231571A (en) * 1989-04-21 1990-11-21 Egyt Gyogyszervegyeszeti Gyar Process for the preparation of quinazoline derivatives
CN1616438A (en) * 2004-09-24 2005-05-18 鲁南制药股份有限公司 Process for preparing alfuzosin hydrochloride
WO2006030449A1 (en) * 2004-09-16 2006-03-23 Hetero Drugs Limited Crystalline alfuzosin base

Patent Citations (3)

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GB2231571A (en) * 1989-04-21 1990-11-21 Egyt Gyogyszervegyeszeti Gyar Process for the preparation of quinazoline derivatives
WO2006030449A1 (en) * 2004-09-16 2006-03-23 Hetero Drugs Limited Crystalline alfuzosin base
CN1616438A (en) * 2004-09-24 2005-05-18 鲁南制药股份有限公司 Process for preparing alfuzosin hydrochloride

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114591273A (en) * 2022-03-31 2022-06-07 邦恩泰(山东)生物医药科技集团股份有限公司 Synthesis method and application of N-methyl-N' -tetrahydrofuran formyl propane diamine oxalate
CN114591273B (en) * 2022-03-31 2023-07-21 邦恩泰(山东)生物医药科技集团股份有限公司 Synthesis method and application of N-methyl-N' -tetrahydrofuranyl propylenediamine oxalate

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