Industrial Process for Alfuzosin Hydrochloride

Priority Claim
This application claims the priority of our earlier application No: 1248/CHE/2005, filed on 6th September 2005 and 1811/CHE/2005 filed on 12th December 2005.
Field of the Invention:
The present invention relates to an Industrial process for the preparation of Alfuzosin hydrochloride, which is chemically known as hydrochloric acid salt of Ni-(4-amino-6,7-dimethoxyquinazol-2-yl)-Ni-methyl-N2-(tetrahydrofuroyl-2)-propylenediamine compound of formula-1.

Alfuzosin is a selective antagonist of post-synaptic ai-adrenoreceptors which are located in the prostate, bladder base, bladder neck, prostatic capsule and prostatic urethtra. Alfuzosin hydrochloride is indicated for the treatment of the signs and symptoms of benign prostatic hyperplasia and is sold under the brand name Uroxatral.
Background of the Invention:
US Patent 4,315,007 claims Alfuzosin and its pharmaceutically acceptable salt and method of treating for cardiovascular disorder. The US Patent 4,315,007 patent discloses a process for the preparation of Alfuzosin hydrochloride in two synthetic schemes, which comprises the reaction of 4-amino-2-chloro-6 J-dimethoxyquinazoline and 3-methylamino propionitrile gives N-(4-amino-6,7-dimethoxyquinazol-2-yl)-N-mehtylpropionitrile on reduction with Raney Ni gives Nl -(4-amino-6,7-dimethoxyquinazol-2-yl)Nl-methylpropylene diamine. This diamine condenses with carbonyl diimidazole derivative of tetrahydrofuroic acid to give Alfuzosin hydrochloride.

The main drawback of the above said process, alfuzosin hydrochloride was recrystallized in a mixture of ethanol and ether solvents. Those solvents are not recommendable for commercial scale-up.
Another synthetic scheme of US Patent 4,315,007 comprises reaction of tetrahydrofuroic -2-acid with ethyl chloroformate in presence of triethylamine further with 3- (methylamino)-propionitrile to give 2-cyano-N-methyl-N-tetrahydrofuroylamine. Reduction of this nitrile in presence of rhodium on alumina gives Nl-methyl-N2-tetrahydrofiiroyl propylene diamine. The resulted diamine condenses with 4-amino-2-chloro-6,7-dimethoxyquinazoline gives Alfuzosin hydrochloride.
The drawback of the above said process, which involves reduction of nitrile compound in presence of rhodium on alumina forms unwanted isomer (Ref. JMC, 1986, Vol.29, No.l) and also the usage of expensive reagent like rhodium on alumina which is commercially not recommendable.
The EP patent 0179689 Bl also discloses the process for the synthesis of alkylene diamines (i.e., Alfuzosin hydrochloride), which comprises reaction of tetrahydrofuroic acid methyl ester and 3-methylamino propane 1,3 diamine gives Nl-methyl-N2-tetrahydrofuronyl propylene diamine. The resulted diamine condenses with 4-amino-2-chloro-697-dimethoxyquinazoline to give Alfuzosin hydrochloride.
The US 5545738 patent claims dihydrate form of alfuzosin hydrochloride, process for the preparation of anhydrous, monohydrate, dihydrate, trihydrate and tetrahydrate forms of Alfuzosin hydrochloride.
WO 2006/03449 patent publication claimed the crystalline alfuzosin base and process for the preparing the same. The process involves dissolving the impure alfuzosin base in a keto or alcoholic solvent and crystallizing the alfuzosin base from solution.
WO 2006/090268 patent publication claimed polymorphs Form A of alfuzosin and polymorphic Form-I and Form-II of alfuzosin hydrochloride and process for preparing the same.
There is a need in the art for industrially viable process for the preparation of Alfuzosin hydrochloride.
The main objective of the present invention is to provide an industrial process for the preparation of Alfuzosin hydrochloride.

Brief description of the Invention
Accordingly the first aspect of the present invention provides an industrial process for the preparation of Alfuzosin hydrochloride which is chemically known as hydrochloric acid salt of Ni-(4-amino-6,7-dimethoxyquinazol-2-yl)-Ni-methyl-N2-(tetrahydrofuroyl-2)-propylenediamine of formula-1.

Industrial process for the preparation of Alfuzosin hydrochloride compound of formula-1 comprises of the following steps
a) Reacting an acid compound of formula-2 with methanol in presence of a suitable
acid catalyst to give ester compound of formula-3, which in-situ reacting with
diamine compound of formula-4 in a suitable solvent to give amide compound of
formula-5,
b) Reacting the amide compound of formula-5 with quinazoline compound of formula-6
in a suitable organic solvent to give alfuzosin compound of formula-7,
c) Purifying alfuzosin compound of formula-7 by using a suitable solvent selected from
alcoholic solvents, keto solvents, ester solvents and chloro solvents,
d) Converting the alfuzosin compound of formula-7 into alfuzosin hydrochloride
compound of formula-1 by treating with suitable alcoholic hydrochloric acid in a
suitable solvent.
The second aspect of the present invention is to provide an industrial process for the preparation of non-solvated alfuzosin hydrochloride compound of formula-1, which comprises of the following steps,
a) Reacting alfuzosin compound of formula-7 with suitable alcoholic hydrochloric
acid in a suitable solvent,
b) Isolating the alfuzosin hydrochloride by adding suitable anti-solvents,

c) Slurrying the above obtained wet alfuzosin hydrochloride in a suitable solvent,
d) Separating the precipitated solid by filtration and drying the material to get the
non-solvated alfuzosin hydrochloride compound of formula-1.
Brief Description of the Drawings
Figure-1: Illustrates the powder X-ray diffraction pattern of Non-solvated Alfuzosin
hydrochloride
Figure-2: Illustrates the IR spectrum of Non-solvated Alfuzosin hydrochloride. Figure-3: Illustrates the DSC of Non-solvated Alfuzosin hydrochloride.
Detailed description of the invention:
The first aspect of the present invention provides an industrial process for the preparation of Alfuzosin hydrochloride, chemically known as hydrochloric acid salt of Ni-(4-amino-6,7-dimethoxyquinazol-2-yl)-Ni-methyl-N2-(tetrahydrofuroyl-2)-propylenediamine of formula-1,

Which comprises of the following steps a) Reacting an acid compound of formula-2

with suitable alcohol such as methanol in presence of a suitable acid catalyst such as sulphuric acid to give ester compound of formula-3, which in-situ reacting with diamine compound of formula-4 in a suitable alcoholic solvent like methanol to give amide compound of formula-5,


b) Reacting amide compound of formula-5 with quinazoline compound of formula-6

in a suitable solvents selected from the solvents like C1-C5 alcohol, toluene, acetone, Xylene, sulfolane, isoamylalcohol and dimethylformamide preferably sulfolane and isoamylalcohol, most preferably isoamylalcohol at a temperature ranges from 35°C to reflux temperature of the solvent to give the alfuzosin compound of formula-7,

c) Purifying the compound of formula-7 by using alcoholic solvents like methanol,
ethanol, isopropyl alcohol and propanol, keto solvents acetone,
methylisobutylketone, methylethylketone, nitrile solvents like acetonitrile, ester
solvents like ethyl acetate, methyl acetate, isopropyl acetate and methyl isopropyl
acetate, chloro solvents like methylene chloride and chloroform preferably chloro
solvents and ester solvents, most preferably ester solvents such as ethyl acetate,
d) Reacting the compound of formula-7 with suitable alcoholic hydrochloric acid
selected from methanolic hydrochloric acid, isopropanolic hydrochloric acid or
ester hydrochloric acid such as ethyl acetate hydrochloric acid preferably
methanolic hydrochloric acid in a suitable organic solvents selected from C1.C4
alcohols and isolating the alfuzosin hydrochloride compound of formula-1 by

adding the reaction mixture to suitable anti-solvents selected from the solvents like ethylacetate, methylacetate, isopropyl acetate, methyl isopropyl acetate, toluene, cyclohexane and n-heptane at the temperature from 0°C to reflux temperature of the solvent used.
The second aspect of the present invention is to provide an industrial process for the preparation of non-solvated alfuzosin hydrochloride, which comprises of the following steps,
a) Reacting the alfuzosin compound of formula-7 with suitable alcoholic
hydrochloric acid selected from methanolic hydrochloric acid, isopropanolic
hydrochloric acid or ester hydrochloric acid such as ethyl acetate hydrochloric
acid preferably methanolic hydrochloric acid in a suitable organic solvents
selected from C1.C4 alcohols,
b) Isolating the alfuzosin hydrochloride by adding suitable solvents selected from
ethylacetate, methylacetate, isopropyl acetate, methyl isopropyl acetate, toluene,
cyclohexane and n-heptane and hexanes,
c) Slurrying the above obtained wet alfuzosin hydrochloride in anti-solvents like
ethylacetate, methylacetate, isopropyl acetate, methyl isopropyl acetate, toluene,
cyclohexane and n-heptane,
d) Separating the precipitated solid by filtration and drying the material to get the
non-solvated alfuzosin hydrochloride compound of formula-1.
Related substances by HPLC of Alfuzosin hydrochloride is carried out using a liquid chromatograph is equipped with variable wavelength UV-Detector and integrator, Inertsil ODS-2, 150x4.6 mm, 5(im or equivalent column, 1.5 ml/min flow rate at 254 nm, ambient temperature, and the buffer is used 5 ml of perchloricacid in 900 ml water, pH is adjusted to 3.5 with dilute sodium hydroxide and dilute to 1000 ml with water. Mobile phase (Buffer: Acetonitrile: THF; 800:200:10)

The process described in the present invention was 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.
Example-l:
Preparation of Nl-Methyl-N2-(tetrahyrofuroyl-2-)-propylene diamine
Added 1.68 liters of sulphuric acid to a mixture of 35 Kgs. of 2-tetrahydrofuroic acid and 350 liters of methanol at 25-35°C. Stirred the reaction mixture for 5 hours at 25-35°C. Added 29.47 Kgs. of methyl amino propyl amine slowly to the above reaction mixture at 25-35°C. Heated the reaction mixture to 40-45°C. Stirred the reaction mixture for 40 hours at 40-45 °C. Distilled the solvent completely under reduced pressure at below 65°C. Cooled the reaction mixture to 25-35°C. Added 175 liters of isopropyl alcohol to the above reaction mixture at 25-35°C. Stirred the reaction mixture for 40 minutes at 25-35°C. Filtered the inorganic solids and washed with isopropyl alcohol. Distilled the filtrate under reduced pressure at below 75°C. Cooled the residue to 25-35°C to get the title compound. Yield: 54.4 Kgs.
Example-2:
Preparation of Nl-(4-amino-6,7-dimethoxyquinazol-2-yl)-Nl-methyl-N2-(tetrahydro
furoyl-2)-propylenediamine
Heated a suspension of 38.4 Kgs. of 4-amino-2-chloro-657-dimethoxyquinazoline and 20 Kgs. of Nl-methyl-N2-tetrahydrofuroyl propylene diamine in 53 liters of isoamylalcohol to reflux temperature of 125-135°C. Stirred the reaction mixture for 14 hours at reflux temperature. Distilled the solvent completely under reduced pressure at below 120°C. Cooled the reaction mixture to 40-50°C. Added 70 liters of acetone to the above reaction mixture and distilled the solvent completely under reduced pressure at below 55°C. Cooled the reaction mixture to 40-50°C. Added 176 liters of acetone to the above reaction mixture at 40-50°C. Further cooled the reaction mixture to 25-35°C. Stirred the reaction mixture for 60 minutes and filtered the solid. Added 350 liters of

water to the above obtained wet material and treated with activated carbon. Added 140 liters of acetone to the filtrate. Cooled the reaction mixture to 10-15°C. Adjusted the pH of the reaction mixture to 13.6 with 20% sodium hydroxide solution at 10-15°C. Stirred the reaction mixture for 10 hours at 10-15°C. Filtered the obtained solid and washed with a mixture of water and acetone. Added 176 liters of ethyl acetate to the above obtained wet solid. Heated the reaction mixture to reflux temperature of 60-65°C. Stirred the reaction mixture at reflux for 60 minutes. Cooled the reaction mixture to 0-5°C. Stirred the reaction mixture for 90 minutes. Filtered the precipitated solid and washed with ethyl acetate. Dried the material at 70-80°C to get the title compound. Yield: 29.9 Kgs. HPLC purity: 99.99%
ExampIe-3:
Purification of Alfuzosin compound
Heated a mixture of 40 Kgs. of alfuzosin compound of formula-7 and 250 liters of methylenedichloride to reflux temperature of 60-65°C. Stirred the reaction mixture for 60 minutes at reflux. Cooled the reaction mixture to 0-5°C. Stirred the reaction mixture for 90 minutes at 0-5°C. Filtered the precipitated solid and washed with methylenedichloride. Dried the material at 70-80°C to get the title compound. Yield: 28 Kgs. HPLC purity: 99.99%
ExampIe-4:
Purification of Alfuzosin compound
Heated a mixture of 40 Kgs. of alfuzosin compound of formula-7 and 250 liters of acetonitrile to reflux temperature of 60-65°C. Stirred the reaction mixture for 60 minutes at reflux. Cooled the reaction mixture to 0-5°C. Stirred the reaction mixture for 90 minutes at 0-5°C. Filtered the precipitated solid and washed with acetonitrile. Dried the material at 70-80°C to get the title compound. Yield: 28 Kgs. HPLC purity: 99.99%

Example-5:
Purification of Alfuzosin compound
Heated a mixture of 40 Kgs. of alfuzosin compound of formula-7 and 250 liters of ethyl acetate to reflux temperature of 60-65°C. Stirred the reaction mixture for 60 minutes at reflux. Cooled the reaction mixture to 0-5 °C. Stirred the reaction mixture for 90 minutes at 0-5°C. Filtered the precipitated solid and washed with ethyl acetate. Dried the material at 70-80°C to get the title compound. Yield: 31 Kgs. HPLC purity: 99.99%
Example-6:
Preparation of Alfuzosin hydrochloride
Heated a suspension of 13 Kgs. of Nl-(4-amino-6,7-dimethoxyquinazol-2-yl)-Nl-methyl-N2-(tetrahydro furoyl-2)-propylenediamine and 65 liters of methanol to 50-55°C. Adjusted the pH of the reaction mixture below two with methanolic hydrochloric acid. Added the above reaction mixture slowly to the 175 liters of ethyl acetate at 25-35°C. Stirred the reaction mixture for 60 minutes at 25-35°C. Filtered the obtained solid and washed with ethyl acetate. Added 195 liters of ethyl acetate to the above obtained wet material. Heated the reaction mixture to reflux. Stirred the reaction mixture for 30 minutes at reflux. Cooled the reaction mixture to 25-35°C. Stirred the reaction mixture for 60 minutes at 25-35°C. Filtered the precipitated solid and washed with ethyl acetate. Dried the material at 95-105°C for 8 hours to get the title compound. Yield: 12.5 Kgs. HPLC: 99.99% Moisture content: 0.6% (w/w)

Example-7:
Preparation of non-solvated Alfuzosin hydrochloride
Heated a suspension of 13 Kgs. of Nl-(4-amino-6,7-dimethoxyquinazol-2-yl)-Nl-methyl-N2-(tetrahydro furoyl-2)-propylenediamine and 65 liters of methanol to 50-55°C. Adjusted the pH of the reaction mixture to below two with methanolic hydrochloric acid. Added the above reaction mixture slowly to the 175 liters of ethyl acetate at 25-35°C. Stirred the reaction mixture for 60 minutes at 25-35°C. Filtered the obtained solid and washed with ethyl acetate. Added 195 liters of ethyl acetate to the above obtained wet material. Heated the reaction mixture to reflux. Stirred the reaction mixture for 30 minutes at reflux. Cooled the reaction mixture to 25-35°C. Stirred the reaction mixture for 60 minutes at 25-35°C. Filtered the precipitated solid and washed with ethyl acetate. Added 195 liters of ethyl acetate to the above obtained wet material. Heated the reaction mixture to reflux. Stirred the reaction mixture for 30 minutes at reflux. Cooled the reaction mixture to 25-35°C. Filtered the precipitated solid and washed with ethyl acetate. Dried the material at 95-105°C for 8 hours to get the title compound. Yield: 12.2 Kgs. HPLC purity: 99.99% Moisture content: 0.5 %(w/w)

We Claim:
1. An Industrial process for the preparation of the alfuzosin compound of formula-1

Which comprises of the following steps
a) Reacting an acid compound of formula-2

with suitable alcohol such as methanol in presence of a suitable acid catalyst such as sulphuric acid to give ester compound of formula-3, which in-situ reacting with diamine compound of formula-4 in a suitable alcoholic solvent like methanol to give amide compound of formula-5,

b) Reacting amide compound of formula-5 with quinazoline compound of formula-6

in a suitable solvents selected from the solvents like C1-C5 alcohol, toluene, acetone, Xylene, sulfolane, isoamylalcohol and dimethylformamide preferably
13

sulfolane and isoamylalcohol, most preferably isoamylalcohol at a temperature ranges from 35°C to reflux temperature of the solvent to give the alfuzosin compound of formula-7,

c) Purifying the compound of formula-7 by using alcoholic solvents like methanol,
ethanol, isopropyl alcohol and propanol, keto solvents acetone,
methylisobutylketone, methylethylketone, nitrile solvents like acetonitrile, ester
solvents like ethylacetate, methylacetate, isopropyl acetate, methyl isopropyl
acetate, chlorosolvents like methylene chloride and chloroform preferably
chlorosolvents and ester solvents, most preferably ester solvents such as ethyl
acetate,
d) Reacting the compound of formula-7 with suitable alcoholic hydrochloric acid
selected from methanolic hydrochloric acid, isopropanolic hydrochloric acid or
ester hydrochloric acid such as ethyl acetate hydrochloric acid preferably
methanolic hydrochloric acid in a suitable organic solvents selected from Ci_C4
alcohols and isolating the alfuzosin hydrochloride compound of formula-1 by
adding the reaction mixture to the suitable anti-solvents selected from the solvents
like ethylacetate, methylacetate, isopropyl acetate, methyl isopropyl acetate,
toluene, cyclohexane and n-heptane at the temperature from 0°C to reflux
temperature of the solvent used.
2. The process according to claim 1 a), wherein the solvent used is methanol at a
temperature ranges from 0°C to reflux temperature of the solvent preferably at 25-
35°C.
3. The process according to claim 1 a), wherein the esterification of compound of
formula-2 with methanol in the presence of suitable acid catalyst such as sulfuric

acid, thionyl chloride, preferably sulfuric acid used in the range of 0.05 moles to 0.5 moles preferably 0.1 moles.
4. The process according to claim 1 a), wherein the in-situ condensation of compound of
formula-3 with compound of formula-4 in presence of C1-C3 alcohols preferably
methanol at a temperature ranges of 0° to reflux temperature of solvent used
preferably at 40-45°C.
5. The process according to claim 1 b), where in the solvent used is selected from the
C1-C5 alcohols, sulfolane, toluene, acetone, Xylene and dimethyl formamide
preferably isoamylalcohol at a temperature of about 100°C to reflux temperature of
the solvent used, preferably 125-135°C.
6. The process according to claim 1 c), wherein the solvent used for purification is
Acetonitrile.
7. The process according to claim 1 c), wherein the solvent used for purification is
Methylenechloride.
8. The process according to claim 1 c), wherein the solvent used for purification is Ethyl
acetate.
9. An industrial process for the preparation of non-solvated alfuzosin hydrochloride
compound of formula-1 comprises of the following steps,
a) Reacting the alfuzosin compound of formula-7 with suitable alcoholic hydrochloric acid selected from methanolic hydrochloric acid, isopropanolic hydrochloric acid or ester hydrochloric acid such as ethyl acetate hydrochloric acid preferably methanolic hydrochloric acid in a suitable organic solvents selected from C1.C4 alcohols,

b) Isolating the alfuzosin hydrochloride by adding suitable anti-solvents like
ethylacetate, methylacetate, isopropyl acetate, isopropyl acetate and methyl
isopropyl acetate, toluene, cyclohexane and n-heptane,
c) Slurrying the above obtained wet alfuzosin hydrochloride in solvents selected
from ethylacetate, methylacetate, isopropyl acetate, isopropyl acetate, methyl
isopropyl acetate, toluene, cyclohexane and n-heptane and hexanes.
d) Separating the precipitated solid by filtration and drying to get the non-solvated
alfuzosin hydrochloride compound of formula-1.
10. The process according to claim 9 b) and 9 c) wherein the solvent is ethyl acetate for isolation and slurry.