Title of Invention

AN IMPROVED PROCESS FOR THE PREPARATION OF ALFUZOSIN HYDROCHLORIDE

Abstract Title of the invention: An improved process for the preparation of Alfuzosin hydrochloride (Formula I)
Full Text




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, which is chemically known as Ni-(4-Amino-6,7-dimethoxyquinazol-2 yl)-Nl-methyl-N2-(tetrahydrofuroyl-2)-propylene diamine, represented by formula (I).

Alfuzosin hydrochloride is known to be an antagonist of a, - adrenergic receptor, and is useful as antihypertensive agent and dysuria curing agent.

Field of the Invention
The present invention relates to an improved process for the preparation of Alfuzosin hydrochloride, which is chemically known as Ni-(4-Amino-6,7-dimethoxyquinazol-2 yl)-Nl-methyl-N2-(tetrahydrofiiroyl-2)-propylene diamine, represented by formula (I).

Alfuzosin hydrochloride is known to be an antagonist of a, - adrenergic receptor, and is useful as antihypertensive agent and dysuria curing agent.

Background of the Invention
The US Patent 4,315,007 claims Alfuzosin and its pharmaceutical^ acceptable salts and method of treating a cardiovascular disorder. The patent also discloses the processes for the preparation of Alfuzosin hydrochloride in the two synthetic schemes.
The EP patent 0179689 Bl also discloses the process for the synthesis of alkylene diamines (i.e., Alfuzosin hydrochloride), which comprises reaction of tetrahydrofiiroic acid methyl ester and 3-methylamino propane 1,3 diamine gives Nl-methyl-N2-tetrahydrofiironyl propylene diamine. The resulted diamine condenses with 4-amino-2-chloro-6,7-dimethoxyquinazoline to give Alfuzosin hydrochloride.
The US 5545738 patent discloses the process for the preparation of anhydrous monohydrate, dihydrate, trihydrate and tetrahydrate forms of Alfuzosin hydrochloride.
Disadvantages of the prior art processes
The process disclosed in prior art references US 4,315,007 patent have one disadvantage is that Alfuzosin HCl was recrystallized in a mixture of ethanol and ether, these solvents are not recommendable for commercial scale-up. Major problem with the prior art processes is producing the solvated forms.
Advantages over prior art processes
• The object of the present invention is to provide an improved process for the preparation of non solvated Alfuzosin hydrochloride
• Cost effective process
• Environment friendly and easy scale-up.

Brief description of the Invention
The present invention provides an improved process for the preparation of Nl-(4-amino-6,7-dimethoxyquinazole-2-yl)-N-methyl-N2-(tetrahydrofuroyl-2)-propylene diamine hydrochloride of formula (I).
The process of the present invention comprises the reaction of Alfuzosin free base with Acetic acid and Ethylacetate HC1 gives Non solvated Alfuzosin hydrochloride of formula (I) by the way of following steps.
1. Dissolving the Alfuzosin free base compound of Formula (II) in a mixture of an organic acid (C1-C5) like formic acid, acetic acid preferably acetic acid and a solvent like ethylacetate, methanol, acetone preferably Ethylacetate at 25-35°C.
2. Adjusting the pH of the mass to below 3 using hydrochloric acid in a solvent like methanol, isopropyl alcohol and ethylacetate i.e., hydrochloric acid in methanol, hydrochloric acid in isopropyl alcohol, hydrochloric acid in Ethylacetate preferably hydrochloric acid in ethylacetate at 25-35°C.
3. Purifying the wet material in a solvent selected from keto solvents or acetate solvents like acetone, butanone, ethylacetate, methyl acetate preferably ethylacetate at 25-35°C to get the Non solvated Alfuzosin hydrochloride.
The process of the present invention is simple, cost effective environment friendly and commercially suitable over the prior art references.
Alfuzosin hydrochloride IR analysis is carried out on Thermo Nicolet-380 model, Thermal analysis is carried out on Waters DSC Q-10 model and RS/OVI analysis carried out on Shimadzu GC-2010 with AOC 5000 (Auto sampler) with Flame Ionization detector.

Brief description of the drawings :
> IR Spectrum of Alfuzosin hydrochloride is shown in Figure -1.
> DSC Thermogram of Alfuzosin hydrochloride is shown in Figure - 2.
> RS/OVI Chromotogram of Alfuzosin hydrochloride is shown in Figure - 3.
Detailed description of the Invention
Accordingly, the present invention provides an improved process for the preparation of Nl-(4-amino-6,7-dimethoxy quinazol-2-yl)-Nl-methyl-N2-(tetrahydrofuroyl-2)-propylene diamine hydrochloride of formula (I),.
The process of the present invention is schematically represented as follows

The present invention provides an improved process for the preparation of Formula (I) shown in the above scheme, which comprises of the following steps.

Dissolving the Alfuzosin free base compound of Formula (II) in a mixture of an organic acid (C1-C5) like formic acid, acetic acid preferably acetic acid and a solvent like ethylacetate, methanol, acetone preferably Ethylacetate at 25-35°C. Adjusting the pH of the mass to below 3 using hydrochloric acid in a solvent like methanol, isopropyl alcohol and ethylacetate i.e., hydrochloric acid in methanol, hydrochloric acid in isopropyl alcohol, hydrochloric acid in Ethylacetate preferably hydrochloric acid in ethylacetate at 25-35°C. 3. Purifying the wet material in a solvent selected from keto solvents or acetate solvents like acetone, butanone, ethylacetate, methyl acetate preferably ethylacetate at 25-35°C to get the Non solvated Alfuzosin hydrochloride.
Step 1 is carried out by dissolving the Alfuzosin free base compound of Formula (II) in a mixture of acetic acid and ethylacetate, then carbon treatement was given to the above solution, Filtrate was added to the excess ethylacetate solvent.
Step 2 is pH adjustment of the reaction mass to below 3 using hydrochloric acid in ethylacetate at 25-35°C.
Step 3 is carried out for the purification of the material by using ethylacetate.
The process described in the present invention were demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention.

Examples
Example-1
Preparation of Nl-(4-amino-6,7-dimethoxyquinazoI-2-yI)-Nl-mehtyI-N2-(tetrahydrofuroyl-2)-propylene diamine hydrochloride
Slowly added 200 ml of Ethylacetate to the 100 gr of Nl-(4-amino-6,7-dimethoxyquinazol-2-yl)-Nl-methyl-N2-(tetrahydrofuronyl-2)-propylene diamine and 100 ml of acetic acid at 25-35°C. The resulted mixture was treated with acidic carbon. Filtered the mass through hyflow. Filtrate was added to 1600 ml of ethyl acetate at 25-35°C. pH of the reaction mass adjusted to below 3 with 150 ml of ethyl acetate HCl in 45 minutes duration. Stirred the reaction mass at 25-35°C for 90 minutes. Filtered the solid and washed with ethyl acetate (100 ml). Wet compound taken in 1000 ml of ethyl acetate and stirred for 60 minutes at 25-35°C. Filtered the solid and washed the solid with ethyl acetate (100 ml). Dried the solid at 75-85°C till to get moisture content less than 1.0%. The yield of the title compound is 100 gr (91.50%).

We Claim :
1. A Process for the preparation of compound of Formula (I)

which comprises of the following steps
a) Dissolving the Alfuzosin free base compound of Formula (II) in a mixture of an organic acid (C1-C5) like formic acid, acetic acid preferably acetic acid and a solvent like ethylacetate, methanol, acetone preferably Ethylacetate at 25-35°C.
b) Adjusting the pH of the mass to below 3 using hydrochloric acid in a solvent like methanol, isopropyl alcohol and ethylacetate i.e., hydrochloric acid in methanol, hydrochloric acid in isopropyl alcohol, hydrochloric acid in Ethylacetate preferably hydrochloric acid in ethylacetate at 25-3 5°C.
c) Purifying the wet material in a solvent selected from keto solvents or acetate solvents like acetone, butanone, ethylacetate, methyl acetate preferably ethylacetate at 25-35°C to get the Non solvated Alfuzosin hydrochloride.

2. Process according to Claim la, Dissolving the Alfuzosin free base compound of formula (II) in a mixture of Acetic acid and Ethylacetate.
3. Process according to claim lb. in which the pH adjustment to below 3 using ethylacetate hydrochloride.
4. Process according to claim 1c, in which the solvent is ethylacetate for purification.



Documents:

1811-CHE-2005 AMENDED PAGES OF SPECIFICATION 12-04-2011.pdf

1811-CHE-2005 AMENDED CLAIMS 12-04-2011.pdf

1811-CHE-2005 AMENDED PAGES OF SPECIFICATION 10-01-2012.pdf

1811-CHE-2005 AMENDED CLAIMS 10-01-2012.pdf

1811-CHE-2005 CORRESPONDENCE OTHERS 10-01-2012.pdf

1811-CHE-2005 CORRESPONDENCE OTHERS 12-12-2011.pdf

1811-CHE-2005 EXAMINATION REPORT REPLY RECEIVED 12-04-2011.pdf

1811-CHE-2005 AMENDED PAGES OF SPECIFICATION 25-10-2011.pdf

1811-CHE-2005 AMENDED CLAIMS 25-10-2011.pdf

1811-CHE-2005 CORRESPONDENCE OTHERS 25-10-2011.pdf

1811-CHE-2005 CORRESPONDENCE PO.pdf

1811-CHE-2005 FORM-18.pdf

1811-che-2005-abstract.pdf

1811-che-2005-claims.pdf

1811-che-2005-correspondnece-others.pdf

1811-che-2005-description(complete).pdf

1811-che-2005-drawings.pdf

1811-che-2005-form 1.pdf

1811-che-2005-form13.pdf

abs-1811.jpg


Patent Number 250942
Indian Patent Application Number 1811/CHE/2005
PG Journal Number 07/2012
Publication Date 17-Feb-2012
Grant Date 09-Feb-2012
Date of Filing 12-Dec-2005
Name of Patentee MSN LABORATORIES LIMITED
Applicant Address DR.MANNE SATYANARAYANA REDDY CHAIRMAN AND MANAGERING DIRECTOR, MSN LABORATORIES LIMITED, FACTORY :SY.NO:317&323 RUDRARAM(VIL),PATANCHERU(MDL), MEDAK (DIST),ANDHRA PRADESH-502329AA
Inventors:
# Inventor's Name Inventor's Address
1 MANNE SATYANARAYANA REDDY DR.MANNE SATYANARAYANA REDDY CHAIRMAN AND MANAGERING DIRECTOR, MSN LABORATORIES LIMITED, FACTORY :SY.NO:317&323 RUDRARAM(VIL),PATANCHERU(MDL), MEDAK (DIST),ANDHRA PRADESH-502329
2 BAIRY KONDAL REDDY BAIRY KONDAL REDDY, POST &VIL:CHINTHAMADAKA, M/O:SIDDIPET, DIST :MEDAK PIN:502107 ANDHRA PRADESH INDIA
3 VENKATESH MUMMADI VENKATESH MUMMADI FLAT NO:102, SAI REVANTH RESIDENCE,BESIDE COMMUNITY HALL BALAGINAGAR,KUKATPALLY ANDHRA PRADESH ,INDIA 500072
4 MUPPA KISHORE KUMAR MUPPA KISHORE KUMAR LIG-34 DHARMAREDDY COLONY, PHASE-1, NEAR JNTUC, HYDERBAD,ANDHRA PRADESH INDIA-500072
PCT International Classification Number C07D 307/24
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA