FORM 2
iTHE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rulel3)
1. TITLE OF THE INVENTION:
PROCESS FOR PREPARATION OF ALFUZOSIN OR SALT THEREOF IN HIGH PURITY AND IMPROVED YIELD
2. APPLICANT (S)
(a) NAME: WOCKHARDT LTD.
(b) NATIONALITY: INDIAN
(c) ADDRESS: Wockhardt Towers, Bandra-Kurla Complex, Bandra (East),
Mumbai-400 051.
3. PREAMBLE TO THE DESCRIPTION
The present invention relates to an efficient process for the preparation of alfuzosin or pharmaceutically acceptable salt thereof in high purity and improved yields.
The following specification particularly describes the invention and the manner in
which it is to be performed.
4. DESCRIPTION
The present invention relates to an efficient process for the preparation of alfuzosin or pharmaceutically acceptable salt thereof in high purity and improved yields.

Alfuzosin is an alphai-adrenergic blocker indicated for the treatment of benign prostatic hyperplasia (BPH). It is chemically N-[3-[( 4-Amino-6,7-dimethoxy-2-quinazolinyl)methylamino]propyl]tetrahydro-2-furan carboxamide of Formula I. It is marketed in the form of its hydrochloride salt for the treatment of BPH.

1 6 DEC 2005


US Patent number 4,315,007 (the '007 Patent) and Journal of Medicinal Chemistry 29, 19-25 (1986) provides two processes for preparation of alfuzosin or salt thereof. Both the processes either involve high vacuum distillation of intermediates or high-pressure hydrogenation of nitrile intermediate. The anhydrous product obtained by following these processes is usually contaminated with amorphous form and is highly hygroscopic. In addition, the product obtained is not adequately pure for incorporation in to the pharmaceutical dosage forms. Isolation of alfuzosin base and its characterization is also not provided in these references.
British Patent No GB 2231571 (the '571 Patent) provides another process for preparation of alfuzosin, which also involves intermediate of US patent 4,315007, that requires high vacuum distillations. The disclosed method also use corrosive chemicals such as phosphorous trichloride and phosphorous oxychloride. The yields obtained as per this process are lower and the product purity is not disclosed. The '571 Patent does not provide process for isolation of alfuzosin base or its physical characterization.
US Patent No 5,545,738 (the 738 Patent) provides processes for preparation of alfuzosin hydrochloride dihydrate from the anhydrous alfuzosin hydrochloride obtained as per the '007 Patent. The 738 Patent do not disclose a process for preparation or isolation of alfuzosin base.
The present inventors have surprisingly found that alfuzosin or salt thereof can be prepared in high purity by a process, which do not involve high vacuum distillation to
isolate and purify intermediates. Further the present inventors have found that by
i
changing the reaction conditions hydrogenation of the nitrile intermediate can be
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carried out at much lower hydrogen pressure than that reported in the known art. The present inventors have further isolated alfuzosin base in solid form. The solid alfuzosin base can be purified and then can be converted it to its salt having purity more than 99% when measured by HPLC.

wherein the said process comprises of,
a) reacting an amine of Formula II or salt thereof,

with a mixed anhydride of tetrahydro-2-furoic acid of Formula III,

In one of the aspect of the present invention there is provided a process for preparation of alfuzosin of Formula I or salt thereof,
wherein R is alkyl, aryl, aralkyl or an ester residue, in presence of a proton
acceptor,
b) isolating alfuzosin or salt thereof from the reaction mass thereof.
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In another aspect of the present invention there is provided a process for preparation of alfuzosin of Formula I or salt thereof,

wherein the said process comprises of, a) hydrogenating a nitrile of Formula V,

in presence of Raney nickel and alcohol using base selected from group comprising of alkali metal or alkaline earth metal hydroxide, hydride or alkoxide, to
get amine of Formula II,

b) reacting an amine of Formula II or salt thereof with a mixed anhydride of tetrahydro-2-furoic acid of Formula III in presence of a proton acceptor,

c) isolating alfuzosin or salt thereof from the reaction mass thereof.
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In yet another aspect of the present invention there is provided a process for preparation of nitrile of Formula V,
wherein the said process comprises of,
a) reacting aminoquinazoline of Formula VI with 3-(methylamino)propionitrile in presence of a non-alcoholic, polar aprotic solvent,

b) isolating nitrile of Formula V from the reaction mass thereof.
A yet another aspect of the present invention provides an isolated, solid alfuzosin base of Formula I. The solid alfuzosin base can also be isolated in crystalline form having X-Ray Diffraction (XRD) pattern as depicted in Figure 1 of the accompanied drawing. The infra-red (IR) spectrum of crystalline alfuzosin base is depicted in Figure 2 of the accompanied drawing. The Differential Scanning Calorimetry (DSC) thermogram of crystalline alfuzosin base is depicted in Figure 3 of the accompanied drawing.
In another aspect of the present invention there is provided a process for purification of alfuzosin base which comprises of,
a) mixing alfuzosin base in a suitable organic solvent,
b) isolating pure alfuzosin base from the mixture thereof.
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A yet another aspect of the present invention provides pharmaceutical compositions comprising isolated, solid alfuzosin base along with pharmaceutical^ acceptable carrier / diluent.
A yet another aspect of the present invention provides a process for preparation of .acid addition salt of alfuzosin, which comprises of reacting isolated solid alfuzosin base with an acid.
A yet another aspect of the present invention provides anhydrous alfuzosin hydrochloride having purity greater than 99% by HPLC. One of the embodiments of the present invention provides anhydrous alfuzosin hydrochloride having purity greater than 99.5%. A yet another embodiment of the present invention provides anhydrous alfuzosin hydrochloride having purity greater than 99.9%.
Aminoquinazoline of Formula VI (as provided hereinbefore) can be prepared by processes known in the art and can be used as starting material for the present invention. It is reacted with 3-(methylamino)propionitrile in presence of non-alcoholic, polar aprotic solvent at an elevated temperature of about 110-150°C. The solvent choice is decided by the fact that it assists the reaction completion and at the same time has no solubility for the product. Example of such solvent is N,N-dimethylacetamide. After completion of the reaction the mass is cooled and the product, nitrile of Formula V (as provided hereinbefore), is filtered from the reaction mass without further work-up or any high vacuum distillation.
The nitrile of Formula V is subjected to hydrogenation in presence of an alcohol as solvent and Raney Nickel as catalyst using base selected from group comprising of alkali metal or alkaline earth metal hydroxide, hydride or alkoxide at a hydrogen pressure of about 175-300 pound per square inch (PSI). The temperature of the reaction is maintained at about the reflux temperature of the alcohol to be used. The alcohol can be selected from group comprising of methanol, ethanol, n-propanol, isopropanol or mixtures thereof. The base can be selected from group comprising of sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium or potassium hydride, sodium or potassium methoxide, ethoxide, isopropoxide or tert-butoxide. After completion of the hydrogenation, the pressure is released and the catalyst is filtered.
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The filtrate is concentrated and the residue is treated with aqueous alkali solution and stirred to get slurry. The solid separated is filtered and washed with water and dried to get the desired amine of Formula II (as provided hereinbefore). No further processing is required for the purification purpose and the so obtained product can be used as such for next reactions.
Tetrahydro-2-Furoic acid of Formula IIIA (as provided hereinbefore) is converted to its mixed anhydride by reacting it with a compound of Formula IV, wherein R is substituted or un-substituted Chalky I, aryl, arakyl or a suitable ester residue and X is a halogen, in presence of a suitable organic solvent in presence of a base.

Some examples of compound of Formula IV are methyl chloroformate, ethyl chloroformate, phenyl chloroformate or benzyl chloroformate. The organic solvent can be selected from group comprising of aromatic hydrocarbon, halogenated hydrocarbon, non-polar aprotic solvent or mixtures thereof. The base can be selected from amine, alkoxide or the like. To the so obtained mixed anhydride of 2-furoic acid of Formula III (as provided hereinbefore) is added Nr(4-amino-6,7-dimethoxyquinazol-2yl)-N-i-methylpropyldiamine of Formula II under controlled rate of addition and the resultant mass is further stirred for about 1-4 hours. After completion of reaction, the reaction mass is basified, mixed with water and the organic layer is separated, washed with water and finally concentrated under reduced pressure. The residue is mixed with methanol and stirred to form slurry, which is filtered to get alfuzosin base in solid form.
The so obtained base can be purified by several ways. It can be slurry washed with a suitable solvent or can be recrystallized from a suitable organic solvent to remove the impurities. It can also be treated with activated charcoal to remove coloring impurities. The suitable organic solvent comprises of C1-4alkanol, polar aprotic solvent, aromatic hydrocarbon or mixtures thereof. The isolated, solid alfuzosin base has been first time characterized by the present inventors and has XRD, IR and DSC as depicted in Figure 1, 2 and 3 respectively.
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The isolated, solid alfuzosin base so obtained can be converted to its acid addition salt by dissolving it in a suitable organic solvent and treating it with an acid. For example, in order to obtain hydrochloride salt of alfuzosin, the solution of isolated solid alfuzosin base in C1-4 alkanol is reacted with hydrogen chloride. The mixture can be heated to reflux followed by addition of an anti-solvent at elevated temperature. The resultant mass can be gradually cooled to about 0-35°C and filtered to get the anhydrous alfuzosin hydrochloride having purity greater than 99% by HPLC.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
EXAMPLE 1
N-(4-amino-6,7-dimethoxyquinazol-2-yl)-N-methyl-2-cyanoethylamine (II)
A mixture of 4-Amino-2-chloro-6,7-dimethoxyquinazoline (500 gm) and 3-(methylamino)propionitrile (265 gm) in N,N-dimethylacetamide (1.0 L ) was heated at 125 to 135°C for two hours. The reaction mixture was cooled to ambient temperature and the separated solids were filtered. The wet solid so obtained was washed with N,N-dimethylacetamide and dried to get the title compound.
Yield: 465 gm
EXAMPLE 2
Ni-( 4-Amino-6,7-dimethoxyquinazol-2-yl )-Ni-methylpropylenediamine (III)
A mixture of N-(4-Amino-6,7-dimethoxyquinazol-2-yl)-N-methyl-2-cyanoethylamine (450 gm) in methanolic sodium hydroxide solution (152 gm sodium hydroxide dissolved in 4.0 L methanol) was hydrogenated under 200 PSI of hydrogen pressure
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at 70 to 80°C in presence of Raney Nickel for 2 to 3 hours. After the reaction, the catalyst was filtered and the filtrate was concentrated to get a residue, which was stirred with dilute sodium hydroxide solution for three hours. The resulting slurry was filtered and the solid obtained was washed with water and dried under vacuum to get the title compound.
Yield: 373 gm
EXAMPLE 3
N-[3-[(4-Amino-6,7-dimethoxy-2-quina2olinyl)methylamino]propyl]tetrahydro-2-furan carboxamide (Alfuzosin)
To a mixture of terahydrofuroic-2-acid (99.7 gm) and dichloromethane (600ml) at 0 to 5°C, was added triethylamine (86.8 gm). To the resulting reaction mixture was added ethyl chloroformate (93.2 gm) at low temperature. The reaction mixture was further stirred for one hour and a slurry of Ni-(4-Amino-6,7-dimethoxyquinazol-2-yl)-Ni-methylpropylenediamine (100 gm) in dichloromethane (400 ml) was added. The resultant mixture was stirred for about one hour for the completion of the reaction and sodium hydroxide solution (500 ml, 1N) was added. The layers were separated and the organic layer was washed with sodium hydroxide solution and concentrated under vacuum. The residue thus obtained was stirred with methanol (200 ml) for three hours to get slurry, which was filtered to get alfuzosin base in isolated, solid form. The crude product thus obtained was re-crystallized with methanol to get pure, isolated, solid alfuzosin base. Yield: 75 gm Purity: 99.8%
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EXAMPLE 4
N-[3-[ (4-Amino-6,7-dimethoxy-2-quinazolinyl )methylamino]propyl]tetrahydro-2-furan carboxamide hydrochloride (Alfuzosin hydrochloride)
To a suspension of N-[3-[(4-Amino-6,7-dimethoxy-2-quinazolinyl)methyl amino]propyl] tetahydro-2-furan carboxamide (70 gm) in methanol (350 ml) was methanolic hydrogen chloride solution. The resulting reaction mixture was heated to about 60°C and to it was added isopropyl ether (700 ml). The resultant mass was gradually cooled to room temperature and the separated solids were collected by filtration to get the hydrochloride salt of alfuzosin in anhydrous form. Yield: 70 gm Purity: 99.9%
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WE CLAIM:

wherein the said process comprises of,
a) reacting an amine of Formula II or salt thereof,

with a mixed anhydride of tetrahydro-2-furoic acid of Formula III,

1. A Drocess for DreDaration of alfuzosin of Formula I or salt thereof
wherein R is alkyl, aryl, aralkyl or an ester residue, in presence of a proton
acceptor,
isolating alfuzosin or salt thereof from the reaction mass thereof.
A process as claimed in claim 1 wherein the mixed anhydride of 2-furoic acid is with ethyl chloroformate.
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3. A process for preparation of alfuzosin of Formula I or salt thereof.

wherein the said process comprises of,
a) hydrogenating a nitrile of Formula V,

in presence of Raney nickel and alcohol using base selected from group comprising of alkali metal or alkaline earth metal hydroxide, hydride or alkoxide,
to get amine of Formula II.

b) reacting an amine of Formula II or salt thereof with a mixed anhydride of tetrahydro-2-furoic acid of Formula III in presence of a proton acceptor,

c) isolating alfuzosin or salt thereof from the reaction mass thereof.
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4. A process of claim 4 wherein the base is sodium hydroxide.
5. A process of claim 4 wherein the alcohol is methanol.
6. A process for preparation of nitrile of Formula V,

wherein the said process comprises of,
a) reacting aminoquinazoline of Formula VI with 3-(methylamino)propionitrile in presence of a non-alcoholic, polar aprotic solvent,

b) isolating nitrile of Formula V from the reaction mass thereof.
7. An isolated, solid alfuzosin base.
8. An isolated, solid alfuzosin base having XRD pattern as depicted in Figure 1.
9. A pharmaceutical compositions comprising isolated, solid alfuzosin base along with
pharmaceutically acceptable carrier / diluent for treatment of benign prostatic hyperplasia (BPH).
10. A process for preparation of acid addition salt of alfuzosin, which comprises of reacting isolated solid alfuzosin base with an acid.
11. Anhydrous alfuzosin hydrochloride having purity greater than 99% by HPLC.

12. Anhydrous alfuzosin hydrochloride of claim 12 having purity greater than 99.5%.
13. A pharmaceutical composition comprising anhydrous alfuzosin hydrochloride of claims 10-12 along with a pharmaceutically acceptable carrier / diluent for treatment of benign prostratic hyperplasia (BPH)
Dated this l6_TH day of December 2005.

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