FORM2
THE PATENTS ACT, 1970
(39 of 1970) &
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10; rule 13)
1. Title of the invention. - NOVEL PROCESS FOR THE PREPARATION OF
ALFUZOSIN HYDROCHLORIDE
2. Applicant(s)
(a) NAME : ALEMBIC LIMITED
(b) NATIONALITY An Indian Company.
(c) ADDRESS : Alembic Campus, Alembic Road, Vadodara - 390 003, Gujarat, India.
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed:

Field of the Invention
The present invention related to a novel process for the preparation of Alfuzosin hydrochloride of formula (I). It also provides novel intermediate of formula (IX) and its use for preparation of Alfuzosin hydrochloride of formula (I).

The present invention also relates to a process for the preparation of novel intermediate of formula (XI) which leads to preparation of compound of formula (II) which is a useful intermediate for the preparation 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-quinazo!inyl)methylamino] propyl] tetrahydro-2-furancarboxamide hydrochloride. It functions as an antagonist of α1-arenergic receptor, and is useful as antihypertensive agent and dysuria curing agent.
2

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
3

isoamyl alcohol at reflux temperature. The compound of formula (II) obtained by the process has following drawbacks:
(i) the reaction involves high pressure hydrogenation which is difficult to exploit at
commercial scales
(ii) there is formation of impurity of formula (A)
CH3 CH3

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.
The impurity of formula (A) has not been reported in any of the prior art processes. The inventors of present invention have isolated and characterized this impurity.
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 compound of formula (II) can be prepared without use of high pressure hydrogenation.
Object of the invention
It is therefore the primary object of the present invention is to provide an improved process for the preparation of Alfuzosin hydrochloride of formula (I).
4

Another object of the present invention is to provide novel compound of formula (XI) which is useful for preparation of compound of formula (II).
Yet another object of the present invention is to provide a process for the preparation of compound of formula (II) utilizing novel compound of formula (XI)
Further object of the present invention is to provide a process for preparation of compound of formula (II) which avoids hydrogenation step thus avoiding formation of impurity (A) during the synthesis.
Yet further object of the present invention is to provide novel compounds of formula (A), (B), (C) and (D).
Summary of the invention
The present invention provides a process for the preparation of Alfuzosin hydrochloride of formula (I) comprising steps of
(a) reacting l-bromo-3-chloro-propane of formula (VII) with phthalimide of formula (VIII) to obtain compound of formula (IX)
(b) reacting compound of formula (IX) with methyl amine to obtain compound of formula (X)
(c) reacting compound of formula (X) with compound of formula (IV) to obtain compound of formula (XI)
(d) deprotecting compound of formula (XI) to obtain compound of formula (II)
(e) condensing compound of formula (II) with activated tetrahydrofuranoic acid of formula (V) to obtain Alfuzosin base
(f) treating Alfuzosin base with hydrochloric acid to obtain Alfuzosin hydrochloride of formula (I).
Another aspect of the present invention provides novel compound of formula (IX).
5

Yet another aspect of the present invention provides a process for the preparation of compound of formula (XI) comprising steps of;
(a) reacting l-bromo-3-chloro-propane of formula (VII) with phthalimide of formula (VIII) to obtain compound of formula (IX)
(b) reacting compound of formula (IX) with methyl amine to obtain compound of formula (X)
(c) reacting compound of formula (X) with compound of formula (IV) to obtain compound of formula (XI)
Further aspect of the present invention provides a process for the preparation of compound of formula (II) further comprising step of deprotecting compound of formula (XI) to obtain compound of formula (II)
Yet further aspect of the present invention provides use of compound of formula (XI) obtained by the process of present invention in the process for the preparation of Alfuzosin hydrochloride of formula (I).
Still further aspect of the present invention provides novel compounds of formula (A), (B),
(C) and (D).
One more aspect of the present invention provides compound of formula (A), (B), (C) and
(D) which are useful as reference marker in testing the purity of a sample of compound of
formula (I) or pharmaceutical dosage form comprising compound of formula (I).
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.
6

Another embodiment of the present invention provides novel intermediate of formula (XI)
Yet another embodiment of present invention provides a process for the preparation of

Another embodiment of the present invention provides novel intermediate of formula (XI)
Yet another embodiment of present invention provides a process for the preparation of Alfuzosin hydrochloride of formula (I) comprising steps of
(a) reacting l-bromo-3-chloro-propane of formula (VII) with phthalimide of formula (VIII) to obtain compound of formula (IX)
7

(b) reacting compound of formula (IX) with methyl amine to obtain compound of formula (X)
(c) reacting compound of formula (X) with compound of formula (IV) to obtain compound of formula (XI)
(d) deprotecting compound of formula (XI) to obtain compound of formula (II)
(e) condensing compound of formula (II) with activated tetrahydrofuranoic acid of formula (V) to obtain Alfuzosin base
(f) reacting Alfuzosin base with hydrochloric acid to obtain Alfuzosin hydrochloride of formula (I).
Further embodiment of the present invention provides a process for the preparation of compound of formula (XI) comprising steps of;
(a) reacting l-bromo-3-chloro-propane of formula (VII) with phthalimide of formula (VIII) to obtain compound of formula (IX)
(b) reacting compound of formula (IX) with methyl amine to obtain compound of formula (X)
(c) reacting compound of formula (X) with compound of formula (IV) to obtain compound of formula (XI).
Still further embodiment of the present invention provides a process for the preparation of compound of formula (II) further comprising step of deprotecting compound of formula (XI) to obtain compound of formula (II).
One of the embodiments of the present invention provides impurity of formula (A)

which is formed while carrying out the hydrogenation of compound of formula (III) to obtain compound of formula (II).
8

Step (a) comprises of reacting l-bromo-3-chloro-propane of formula (VII) with phthalimide of formula (VIII) in presence of polar aprotic solvent and a base. The polar aprotic solvent can be selected from group comprising of dimethylformamide, dimethylsulphoxide, dimethyhlacetamide, and the like or mixtures thereof.
The reaction is carried out in presence of base selected from alkali or alkaline metal carbonate selected from group comprising of sodium carbonate, potassium carbonate, magnesium carbonate, calcium carbonate and the like or mixtures thereof, preferably potassium carbonate.
The reaction is carried out in temperature range of about 25°C to about reflux temperature of the solvent used, preferably in range of 40CC to 80°C.
The compound of formula (IX) obtained in step (a) is further reacted with methyl amine gas in presence of chlorinated solvent selected from group comprising of dichloromethane, chloroform, dichloroethane, carbon tetrachloride and the like or mixtures thereof
The reaction is carried out in temperature range of about 0°C to about ambient temperature.
In step (c) compound of formula (X) obtained in step (b) is reacted with compound of formula (IV) in presence of solvent preferably isoamyl alcohol to obtain compound of formula (XI). The reaction can be carried out at temperature range of about 25°C to about reflux temperature of the solvent.
While carrying out step (c), if methyl amine used in step (b) is not removed completely then it gives rise to impurity (B) and (C).

9

The inventors of present invention have identified and characterized impurity (B) and (C) which are formed during process of present invention.
Compound of formula (XI) obtained can be deprotected using hydrazine hydrate in presence of alcoholic solvent to obtain compound of formula (II). Alcoholic solvent can be selected from group comprising of methanol, ethanol and the like or mixtures thereof. The reaction can be carried out at temperature range of about 25°C to about reflux temperature of the solvent used.
In step (e), the compound of formula (II) thus obtained can be reacted further without purification, with tetrahydrofuroic 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.
The inventors of present invention have identified and characterized yet another impurity (D) formed during step (e).

This impurity is formed due to reaction of amino group at 4-position of 6,7-dimethoxyquinaoline ring with activated tetrahydrofuroic acid.
Compounds of formula (A), (B), (C) and (D) are useful as reference markers for the analysis like testing the purity or stability to degradation of a sample of compound of formula (I) and pharmaceutical formulations thereof
10

Alfuzosin base thus obtained in step (e) 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-HC1. 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: Preparation of2-(3-chIoropropyI)-l H -isoindole-l,3(2H)-dione
To 26 gm of l-bromo-3-chloro-propane and 16 gm of phthalimide is added 60 ml of dimethyl
formamide and 27 gm of potassium carbonate. The reaction mixture is heated under stirring at 50-55°C for about 4 hrs. After the completion of the reaction the reaction the reaction mixture mixture is cooled and poured over mixture of ice and water. The crystals obtained are filtered and dried to obtain the title compound
Example-2: Preparation of 2-[3-(methyIamino)propyl]-l H -isoindoIe-l,3(2 H)-dione
To 22 gm of 2-(3-chloropropyl)-l H f-isoindole-l,3(2 H)-dione is added 110 ml of
dichloromethane and methyl amine gas is passed through the reaction mixture. After completion of the reaction the solvent is distilled off and water is added to the residue. The crystals obtained are filtered and dried to obtained the title compound
11

Example-3: Preparation of 2-(3-((4-amino-6,7-dimethoxyquinazolin-2-yl)(methyl) amino)propyl)isoindoline-l,3-dione
To 10 gm of 2-[3-(methylamino)propyl]-lH -isoindole-l,3(2H)-dione is added 5.5 gm of 2-chloro-4-amino-6,7-dimethoxyquinazoline and 70 ml of isoamyl alcohol. The reaction mixture is refluxed for 7 hrs under stirring. After completion of the reaction, the reaction mixture is cooled to obtain crystals of title compound which are filtered and dried.
Example-4: Preparation of Ni-(4-amino-6,7-dimethoxyquinazoI-2-yl)-Ni-
methylpropylenediamine
To 6 gm of 2-(3-((4-amino-6,7-dimethoxyquinazolin-2-yl)(methyl)amino)propyl) isoindoline-l,3-dione is added 16 ml of hydrazine hydrate and 30 ml of methanol. The reaction mixture is refluxed for 4 to 5 hrs. under stirring. After completion of the reaction the reaction mixture is cooled to room temperature and the solid is filtered. To wet cake thus obtained is added caustic lye and toluene and stirred for 1 to 2 hours. The organic layer is separated and washed with water and brine solution. The solvent is distilled off to obtain the title compound.
ExampIe-5: (R,S)-N-[3-[(4-amino-6,7-dimethoxy-2-quinazolinyl)methylamino] propyl] tetrahydro-2-furancarboxamide hydrochloride (Alfuzosin hydrochloride)
To 9 ml dichloromethane was added 3 gm of carbonyl diimidazole and 1.8 gm of tetrahydrofuroic acid. The reaction mass was stirred for 30 min. at 10-15°C and then refluxed for one hour. 2.2 gm of Ni-(4-amino-6,7-dimethoxyquinazol-2-yl)-Nr methylpropylenediamine in 7 ml of dichloromethane was added to it at 38-40°C. After completion of the reaction, the reaction mixture was cooled and filtered off through hyflo bed. To the filtrate was added 11 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 was distilled off and ethanol was added to the residue. Calculated amount of isopropanolic HC1 was added to it and refluxed to get clear solution. Charcoal was added to it and filtered through hyflo bed. The reaction mixture was cooled; the crystals were filtered under nitrogen atmosphere and dried to obtain Alfuzosin hydrochloride.
12

We claim,

1. A process for the preparation of Alfuzosin hydrochloride of formula (I) comprising steps of,

(a) reacting l-bromo-3-chloro-propane of formula (VII) with phthalimide of formula (VIII) to obtain compound of formula (IX)

(b) reacting compound of formula (IX) with methyl amine to obtain compound of formula (X)

(c) reacting compound of formula (X) with compound of formula (IV) to obtain compound of formula (XI)

(d) deprotecting compound of formula (XI) to obtain compound of formula (II)
13

(e) condensing compound of formula (II) with activated tetrahydrofuranoic acid of formula (V) to obtain Alfuzosin base

(f) reacting Alfuzosin base with hydrochloric acid to obtain Alfuzosin hydrochloride of formula (I).
2. A compound of formula (XI)


H3C0
H3C0

3. A process for the preparation of compound of formula (XI) comprising steps of;
(a) reacting l-bromo-3-chloro-propane of formula (VII) with phthalimide of formula (VIII) to obtain compound of formula (IX)
(b) reacting compound of formula (IX) with methyl amine to obtain compound of formula (X)
14

(c) reacting compound of formula (X) with compound of formula (IV) to obtain compound of formula (XI)
4. A process for the preparation of compound of formula (II) further comprising step of deprotecting compound of formula (XI).
5. A process as claimed in claim 1 and 3, wherein step (a) is carried out in presence of solvent and a base.
6. A process as claimed in claim 5, wherein said solvent is selected from group comprising of polar aprotic solvent selected from dimethylformamide, dimethylsulfoxide and dimethylacetamide.
7. A process as claimed in claim 5, wherein said base is selected from group comprising of alkali or alkaline metal carbonate.
8. A process as claimed in claim 7, wherein said alkali or alkaline metal carbonate is selected from sodium carbonate, potassium carbonate, magnesium carbonate and calcium carbonate.
9. A process as claimed in claim 1, wherein step (b) is carried out in presence of solvent.
10. A process as claimed in claim 9, wherein said solvent is selected from group comprising of chlorinated solvent.
11. A process as claimed in claim 10, wherein said chlorinated solvent is selected from dichloromethane, chloroform, dichloroethane and carbon tetrachloride.
12. A process as claimed in claim 1 and 3, wherein step (c) is carried out in the presence of solvent.
15

13. A process as claimed in claim 13, wherein said solvent is isoamyl alcohol
14. A process as claimed in claim 1 step (d) and claim 4, wherein deprotection is carried out using hydrazine hydrate in presence of alcoholic solvent.
15. A process as claimed in claim 14, wherein said alcoholic solvent is selected from group comprising of methanol and ethanol.
16. A process as claimed in claim 1, wherein step (e) is carried out in presence of solvent and an activating agent.
17. A process as claimed in claim 16 wherein, said solvent is selected from methelenedichloride and dimethylformamide or mixtures thereof
18. A process as claimed in claim 16 wherein, said activating agent is carbonyl diimidazole or thionyl chloride.
19. A process as claimed in claim 1, wherein in step (f) the Alfuzosin base is converted to Alfuzosin hydrochloride of formula (I) by dissolving it into alcoholic solvent and treating with alcoholic-HCl.
20. A process as claimed in claim 19 wherein, said alcoholic solvent is methanol, ethanol, 2-propanol and isopropanol or mixtures thereof.
21. Use of compound of formula (XI) in the process for the preparation of compound of formula (II)
22. Use of compound of formula (XI) in the process for the preparation of Alfuzosin hydrochloride of formula (I).
23. A compound of formula (A)
16

24. A compound of formula (B)


25. A compound of formula (C)

26. Compound of formula (D)

27. Use of compound selected from group comprising of formula (A), (B), (C) and (D) as reference marker for testing the purity of a sample of compound of formula (I) or pharmaceutical dosage form comprising compound of formula (I).
Dated this 7th day of September 2007

Ashwini Sandu
Of S. Majumdar & Co. Applicant's Agent
18

ABSTRACT
The present invention related to a novel process for the preparation of Alfuzosin hydrochloride of formula (I). It also provides novel intermediate of formula (IX) and its use for preparation of Alufzosin hydrochloride of formula (I).

The present invention also relates to a process for the preparation of novel intermediate of formula (XI) which leads to preparation of compound of formula (II) which is a useful intermediate for the preparation of Alfuzosin hydrochloride of formula (I)