FORM 2
THE PATENTS ACT 1970
(Act 39 of 1970)
&
THE PATENTS RULE, 2003
COMPLETE SPECIFICATION
(SECTION 10 and Rule 13)
TITLE OF THE INVENTION
"A PROCESS FOR ISOLATION OF ALFUZOSTN HYDROCHLORIDE"
Emcure Pharmaceuticals Limited.
an Indian Company, registered under the Indian Company's Act
1957 and having its Registered Office at
Emcure House, T-184, M.I.D.C., Bhosari, Pune-411026, India.
THE FOLLOWING SPECIFICATION PARTICULARLY DESCRIBES THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED.

FIELD OF THE INVENTION
The present invention relates to a process for preparation of alfuzosin hydrochloride conforming to regulatory specifications. Specifically, the invention relates to a process for isolation of alfuzosin hydrochloride, which is free from the associated impurities which are normally encountered during coupling of N-l-(4-amino-6,7-dimethoxyquinazoI-2-yl)-N-l -methylpropylenediamine with tetrahydrofuroic acid.
BACKGROUND OF THE INVENTION
Alfuzosin of formula (I), chemically known as (R,S)-N-[3-[(4-Amino-6,7-dimethoxy-2-quinazolinyl)methylamino]propyl]tetrahydro-2-furancarboxamide is administered as its hydrochloride salt (la), which exhibits therapeutic action as an antagonist of a-adrenergic receptors for treatment of hypertension and dysuria.

Alfuzosin hydrochloride was approved by USFDA on June 12, 2003 and is marketed under the brand name 'Uroxatral' as extended release oral tablet with 10 mg strength.

Various researchers have attempted to synthesize the active pharmaceutical ingredient (API) alfuzosin hydrochloride of formula (la).
US 4,315,007 discloses a method for preparing alfuzosin hydrochloride comprising reaction of N1 -(4-amino-6,7-dimethoxyquinazol-2-yl)-N1 -methylpropylenediamine with tetrahydrofuroic acid in presence of carbonyldiimidazole (CDI) and tetrahydrofuran as solvent The obtained crude alfuzosin free base was found to have associated impurities along with unreacted starting material and was very difficult to purify even after employing several purification methods like crystallization, solvent precipitation etc. Further, these impurities were difficult to remove even in the final step of alfuzosin hydrochloride, which thus rendered the process incapable for commercial scale.
Further, an Indian application IN 1717/MUM/2007 while disclosing a process for preparation of alfuzosin hydrochloride salt also mentions that an additional impurity D is also formed during the preparation of alfuzosin.

Impurity D is apparently formed due to the acylation of the amino group at the 4-position of 6,7-dimethoxyquinoline ring. Further, Indian application also mentions that the method disclosed in US 4,315,007 patent also gives rise to impurity D, which is difficult to remove from the final product; therefore it was necessary to eliminate such impurity in the preparation of alfuzosin hydrochloride.

US 20070066824 describe a process for preparation of alfuzosin base free from associated impurities like alfuzosin dimer and other impurities. The process involves the esterification of tetrahydrofuroic acid with an alcohol to provide the corresponding ester, which on reaction with N-methyl-l,3-propanediamine gives N1-methyl-N2-tetrahydrofuroyl-l,3-propanediamine, subsequent treatment with 4-amino-2-chloro-6,7-dimethoxyquinazoline followed by treatment with an aqueous base gives alfuzosin base. Further, the yield although moderate, does not mention the level of associated impurities which are likely to be formed in the acylation step with furoic acid and which is likely to be carried forward during subsequent reactions. Hence, there is need to develop an efficient process for preparation of alfuzosin.
WO 2006090268 describes a process for preparation of Alfuzosin base by condensation of N-(4-amino-6,7-dimethoxyquinazol-2-yl)-N-methylpropylene diamine with tetrahydrofuroic. acid in the presence of thionyl chloride/dichloromethane. Alfuzosin was obtained in the form of a gum, which was extracted with ethyl acetate and concentrated to give alfuzosin free base. Example (3) discloses a yield of 84% for the final coupling reaction with purity of 99.5%. However, replication of above experiments in our laboratory, showed unreacted N-{4-amino-6,7-dimethoxyquinazo!-2-yl)-N-methylpropylenediamine, even after several hours of the coupling reaction. It was necessarily to eliminate these impurities before conversion of free base to hydrochloride salt.
WO 2006030449 discloses another method for preparation of alfuzosin base comprising reaction of diamino intermediate with tetrahydrofuroic acid which however does not proceed to completion and requires several crystallizations or chromatographic purification for purifying the impure alfuzosin base.
WO 2009016387 describes another process for preparation of alfuzosin hydrochloride by treating tetrahydrofuran-2-carboxylic acid with N-(4-amino-6,7-

dimethoxyquinazol-2-yl)-N-methylpropylenediamine in presence of
hexamethyldisilazane (HMDS) and dichloromethane as solvent. However, in view of environmental safety, HMDS is not a viable reagent for industrial scale.
US 2007105880 disclose a process for preparation of alfuzosin base and purification
of crude alfiizosin in solvents like ketones, alcohols and aromatic hydrocarbons.
Further, alfiizosin base prepared by reaction of N-(4-amino-6,7-
dimethyloxyquinazoline-2-yl)-N-methylpropane-1,3-diamine with carbonyl
diimidazole (CDI) in presence of activated tetrahydrofuroic acid is impure in nature and consequently it requires repetitive crystallization before converting free base into alfuzosin hydrochloride salt. Thus, the method has shortcoming such as the use of multiple crystallizations steps in isolating pure alfuzosin base, which results in low over all yield and further escalates the cost.
WO 2008015525 relates to a method for the purification of N-(3-aminopropyl)-6,7-
dimethoxy-N-raethylquinazoline-2,4-diamine by preparing its acid addition salt with
an organic dicarboxylic acid in an alcohol. Further, the invention relates to an
improved process for preparation of alfuzosin hydrochloride by reacting N-(3-
aminopropyl)-6,7-dimethoxy-N-methylquinazoline-2,4-diamine with 1-
(tetrahydrofiiran-2-ylcarbonyl)-lH-imidazole in presence of acetonitrile as solvent The crude alfuzosin base is purified repeatedly with dichloromethane-methanol solvent mixture till purity reaches to 99.6%. The repetitive crystallization of crude alfuzosin to get pure product leads to low yield, which increases the cost of industrial production of alfuzosin.
WO 2007074364 relates to an improved process for the preparation of N-[3-[(4-amino-6,7-dimemoxy-2-quinazolinyl)methylamino]propyl]tetrahydrofuran-2-carboxamide (alfuzosin). The method involves reaction with tetrahydrofuran-2-carboxylic acid in presence of coupling agents like ethyl chloroformate, DCC or pivaloyl chloride in presence of triethylamine and dichloromethane. The mixed

anhydride thus formed was treated with N-(4-amino-6,7-dimethoxyquinazolin-2-yl)-N-methylpropane-1,3-diamine. Thereafter, pH was adjusted to 4.0-4.5. The organic layer was discarded and the pH of the aqueous layer was raised to 10-10.5 with aqueous sodium hydroxide. The aqueous layer was extracted with methylene dichloride and solvent distilled out. The concentrated mass was stirred with acetone to afford Alfuzosin 75% yield with purity 99.97%.
However, the use of coupling agents likes ethyl chloroformate, DCC, or pivaloyl chlorides are not suitable due to the possible allergic reaction with the skin and eyes and also due to its corrosive property.
US 20070105880 describe a process for the preparation of aliuzosin and its hydrochloride salts. Further, process involves purification of crude alfuzosin by using organic solvent. It also discloses free base has purity of 99.4%. However, replication of these experiments at our laboratory indicated that the unreacted starting diamine was present in the crude alfuzosin free base and could not be removed by conventional purification techniques.
WO2008152514 discloses a process to prepare alfuzosin free from impurities through N-acetyl derivatives of alfuzosin as an intermediate. The process employed for preparation of alfuzosin base is similar to the prior art method. In the purification process alfuzosin base was converted to N-acetyl derivatives. Finally, N-acetyl alfuzosin on treatment with methanolic hydrochloric acid to give alfuzosin hydrochloride. However, the replication of this experiment at our laboratory shows unreacted starting material to the extent of 5 to 15 %.
IN 250942 discloses an improved process for preparation of alfuzosin hydrochloride free from solvate form. The process involves dissolving alfuzosin free base in ethyl acetate and optionally with an organic acid, pH adjusted to below 3 with hydrochloric acid in ethyl acetate; finally pure alfuzosin hydrochloride was isolated from ketone or acetate solvent However, the specification did not disclose any purity of starting

material or the final product. Further, it was observed that degradation of alfuzosin hydrochloride due to the presence of trace of acetic acid in alfuzosin hydrochloride salt to starting materials.
IN 260/CHE/2005 discloses a process for preparation of alfuzosin comprising coupling of N-(4-amino-6,7-dimethoxyquinazolin-2-yl)-N-methylpropane-l,3 -diamine with tetrahydrofuroic acid in an inert solvent like xylene, toluene or benzene at reflux temperature without any coupling agent. Finally alfuzosin crude was purified by utilizing methanol as solvent. It should be noted that in absence of any activating agent, the coupling was very slow and at high temperatures there is a strong possibility of generating impurities which would require an additional purification steps.
Like any synthetic compound, alfuzosin salts may contain extraneous compounds or impurities that can come as unreacted starting materials, by-products of the reaction or degradation products.'It is also known in the art that impurities in an API may arise due to degradation of the API. Impurities which are formed during commercial manufacturing processes must be within the regulatory limits.
Thus, there is a need to develop a process for the preparation of alfuzosin hydrochloride (la), which reduces the formation of impurities below regulatory limits and does not require column chromatography or repeated crystallization for getting the desired purity.
OBJECTS OF THE INVENTION
An object of the present invention is to provide an efficient process for preparation of alfuzosin hydrochloride, which is free from associated impurities and does not utilize column chromatography or other purification methods.

Another object of the present invention is to provide a isolation process for reducing the undesired impurities formed during the coupling of N-I-(4-amino-6,7-dimethoxyquinazol-2-yl)-N-l-methylpropylenediamine with tetrahydrofuroic acid by quenching and extracting the reaction mixture with an organic solvent and treating the organic layer with an aqueous solution of organic acid and finally isolating desired product conforming to regulatory specifications.
SUMMARY OF THE INVENTION
An aspect of the present invention relates to a process for preparation of alfuzosin hydrochloride comprising reaction of N-l-(4-amino-6,7-dimethoxyquinazol-2-yl)-N-1-methylpropylenediamine with tetrahydrofuroic acid in an organic solvent, concentrating the mixture and quenching with an aqueous solution of a base, adding a water-immiscible organic solvent, treating the organic layer with an aqueous solution of an organic acid, concentrating the mixture and isolating alfuzosin hydrochloride of desired purity by adding an alcoholic mixture of hydrochloric acid.
Yet another aspect of the invention relates to preparation of alfuzosin free base having N-(4-amino-6,7-dimethoxyquinazolin-2-yl)-N-methylpropane-l,3-diamine impurity and other associated impurities below regulatory limits.
DETAILED DESCRIPTION OF THE INVENTION
The present inventors have found that the coupling reaction of Nl-(4-amino-6,7-dimethoxyquinazol-2-yl)-Nl-methylpropylenediamine and tetrahydrofuroic acid in presence of organic solvent results in the formation of associated impurities, which could be either a by-product or unreacted starting material. The present inventors have separated and identified the impurity.

It was unexpectedly found after several experiments that associated impurities like un-reacted starting material could be eliminated during the work up, which involved washing the reaction mixture with an aqueous solution of an organic acid like mandelic acid. The resulting Alfuzosin base or its hydrochloride salt isolated from the mandelic acid salt was found to have associated impurities below the permissible regulatory limits. Thus additional steps of purification, which could considerably lower the yield were avoided.
One embodiment of the present invention relates to a process for N1-(4-amino-6,7-dimethoxyquinazoI-2-yl)-Nl-methylpropylenediamine and tetrahydrofuroic acid in an organic solvent. The synthetic sequence for alfuzosin is represented in Scheme I.

The starting Nl-(4-amino-6,7-dimethoxyquinazol-2-yl)-Nl -methylpropylenediamine (II) may be obtained by the process disclosed in the prior art.
The detailed reaction process for alfuzosin is described in the following steps;
1. reaction of Nl-(4-amino-6,7-dimethoxyquinazol-2-yl)-Nl-methylpropytene diamine (II) with tetrahydrofuroic acid and coupling agent in an organic solvent,
2. concentration of the reaction mixture,

3. add organic solvent neutralize with aqueous alkaline solution and separate organic layer,
4. treat organic layer with an aqueous solution of organic acid,
5. concentrate the organic solvent and add alcoholic solution of hydrochloric acid, add ether solvent, and filter to give alfuzosin hydrochloride (la) of desired purity with impurity level according to regulatory limits.
The coupling of Nl-(4-amino-6,7-dimethoxyquinazol-2-yl)-Nl-methylpropylene diamine (II) with tetrahydrofuroic acid in an organic solvent was carried out at reflux temperature.
The solvents for coupling reaction is selected from the group comprising of ethers like tetrahydrofiiran, esters like methyl acetate, hydrocarbons like cyclohexane etc.
After completion of coupling reaction, solvent was distilled under reduce pressure at temperature below 45°C.
In another embodiment of the invention, after concentration of solvent residue is treated with an organic solvent and neutralized with aqueous alkali or alkaline metal base solution and followed by layer separation. The solvent used for dissolving residue is selected from halogenated solvents like methylene dichloride, ethylene dichloride, and chloroform or other water insoluble solvents.
The present inventors after carrying out several experiments unexpectedly found out that the reaction mixture after concentration and quenching with an aqueous solution of a base and a water-immiscible solvent followed by washing of the organic layer with an aqueous solution of an organic acid provided alfuzosin free base which had all the associated impurities below regulatory limits.

The obtained organic layer treated with aqueous solution of organic acid. The organic acid was selected from the group comprising of acetic acid, formic acid oxalic acid, malonic acid, succinic acid, fumaric acid, malic acid, mandelic acid, tartaric acid, preferably mandelic acid. The strength of aqueous solution of organic acid is in the range of 1% to 15%, preferably between 3 to 5%.
The elimination of impurity by washing with aqueous solution of organic acid is an essential part of the invention during isolation of alfuzosin hydrochloride. Further, the inventors also found that such a in-built removal of undesirable impurities was not possible by employing a mineral acid like HC1, H2SO4 etc.
Therefore, the present inventors have established a process wherein alfuzosin is isolated after treatment with aqueous solution of organic acid.
The recovered Nl -(4-amino-6,7-dimethoxyquinazol-2-yl)-Nl-methylpropylene diamine (H) obtained from the aqueous organic acid washings may be re-used in the preparation of alfuzosin after neutralizing the mandelate salt with a base.
Further the organic layer after treatment wilh aqueous solution of organic acid is optionally washed with sodium chloride solution and concentrated under reduced pressure. Finally, alfuzosin free base is treated with a mixture of hydrochloric acid and alcohol to give alfuzosin hydrochloride of desired purity and yield.
A further advantage of the invention is that the present invention did not require multiple crystallization or column chromatography for purification of alfuzosin free base as reported in prior art methods, which considerably increases the yield and substantially reduces the production cost.

Furthermore, the invention provides a process for preparation of alfuzosin hydrochloride, which eliminates the presence of Nl-(4-amino-6,7-dimethoxyquinazol-2-yl)-Nl-methylpropylenediamine (H) and other associated impurities in the final product as compared to prior art methods.
The principles, preferred embodiments and modes of operation of the present invention have been described in the foregoing specification. The present invention is described herein below with reference to examples, which are illustrative only and should not be construed to limit the scope of the present invention in any manner.
EXAMPLE:
Example 1: Preparation of alfuzosin hydrochloride (I):
Nl -(4-amino-6,7-dimethoxyquinazol-2-yl)-Nl -methylpropylenediamine (II) (1 OOgms; 0.34 moles), tetrahydrofuroic acid (56 gms; 0.467 moles) and CDI (61.24 gms; 0.38 moles) were added to tetrahydrofuran at 20°C to 30°C with stirring. The reaction mixture was heated to 63-68°C for 2-3 hours under stirring. After reaction completion as monitored by TLC, the mixture was cooled to 45°C to 50DC and the mixture was concentrated under reduced pressure. Dichloromethane (2000ml) and sodium hydroxide solution (IN, 1000ml) was added to the residue and the organic layer separated. Dichloromethane layer was washed with 1% solution of mandelic acid (1500ml) followed by optional washing with sodium chloride solution and concentrated to obtain a residue. Ethanol (2000ml) and solution of hydrochloric acid (100 ml) were added to the residue and the pH was adjusted to 2.0-3.0, followed by addition of MTBE (500 ml) with stirring and filtered after product separated out. The wet cake was washed with ethanol-MTBE (100 ml) and dried. Yield: 60gms. Purity > 99.5%

We Claim.
1. An improved process for preparation of alfuzosin hydrochloride comprising;
a) reaction of N-l-(4-amino-6,7-dimethoxyquinazol-2-yl)-N-l-methylpropylenediamine with tetrahydrofuroic acid in an organic solvent
b) quenching with an aqueous solution of a base, adding an organic solvent,
c) treating the organic layer with an organic acid,
d) isolating alfuzosin hydrochloride of desired purity by adding an alcoholic mixture of hydrochloric acid.

2. The process as claimed in claim 1(a) wherein, organic solvent for coupling reaction is selected from the group comprising of ethers, esters, and hydrocarbons.
3. The process as claimed in claim 2 wherein, organic solvent is selected from the group tetrahydrofuran, methyl acetate, ethyl acetate and cyclohexane.
4. The process as claimed in claim 1(b) wherein the organic solvent is selected from the group comprising of halogenated solvents like methylene dichloride, ethylene dichloride and chloroform.
5. The process as claimed In claim 1(c) wherein the organic acid is selected from the group comprising of acetic acid, formic acid oxalic acid, malonic acid, succinic acid, fumaric acid, malic acid, mandelic acid, tartaric acid but preferably mandelic acid.
6. The process as claimed in claim 5 wherein the organic acid is employed as an aqueous solution.
7. The process as claimed in claim 6 wherein, the strength of aqueous solution of organic acid is from 1% to 15%, preferably between 3 to 5%.

8. The process as claimed in claim 1 is free from N-(4-amino-6,7-dimethoxyquinazol-2-yl)-N-methylpropylenediamine impurity and other associated impurities.