An improved process for the preparation of Alfuzosin hydrochloride and its novel polymorphs

Alfuzosin Hydrochloride Patent draft
The present invention relates to an improved process for the preparation of Alfuzosin hydrochloride, which is chemically known as N1-(4-Amino-6,7-dimethoxyquinazol-2 yl)-N 1 -methyl-N2-(tetrahydrofuroyl-2)-propylene diamine, represented by formula (I) and its novel polymorphs.

Alfuzosin hydrochloride is known to be an antagonist of a, - adrenergic receptor, and is useful as antihypertensive agent and dysuria curing agent.
Prior art processes
US Patent 4,315,007 claims Alfuzosin hydrochloride, its pharmaceutically acceptable salt and method of treating a cardiovascular disorder. The US Patent 4,315,007 patent discloses a process for the preparation of Alfuzosin hydrochloride in the two synthetic schemes, which comprises the reaction of 4-amino-2-chloro-6,7-dimethoxyquinazoline and 3- methylamino propionitrile gives N-(4-amino-6,7-dimethoxyquinazol-2-yl)-N-mehtyl propionitrile 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.
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-tetrahydrofuroyl propylene diamine. The resulted diamine condenses with 4-amino-2-chloro-6,7-dimethoxyquinazoline to give Alfuzosin hydrochloride.
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-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 some disadvantages, such as in the first synthetic scheme resulting the compound with poor yields and carbonyl diimidazole is not commercially available and Alfuzosin HC1 was recrystallised in a mixture of ethanol and ether, these solvents are not recommendable for commercial scaleup.
In second synthetic scheme reduction of nitrile compound in presence of rhodium on alumina forms unwanted isomer also (Ref. JMC, 1986, Vol.29, No.l) and rhodium on alumina is a costly raw material and which is commercially not available.
EP 0179689 Bl also have some disadvantages such as in this scheme isolated tetrahydrofuroic acid methyl ester was used this isolation of tetrahydrofuroic acid methyl ester leads to less yield due to its low boiling nature of the compound and increases the stages.
Advantages over prior art processes
• The object of the present invention is to provide an improved process for the preparation of 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 of formula (I).
The process of the present invention comprises the reaction tetrahydrofuroic acid with methanol in presence of sulfuric acid followed by reaction with 3-methylamino propane-1,3-diamine in methanol gives Nl-methyl-N2-tetrahydrofuroyl propylene diamine. The resulted diamine up on condensation with 4-amino-2-chloro-6,7-dimethoxy quinazoline gives Alfuzosin hydrochloride in isoamyl alcohol medium.

The process of the present invention is simple, cost effective environment friendly and commercially suitable over the prior art references.
After repeated investigations, we the present inventors have found that Alfuzosin hydrochloride can exist in amorphous and solvated forms. These forms can be produced by crystallizing the solid as Alfuzosin hydrochloride from Alfuzosin base using hydrochloric acid in different solvent mediums.
Alfuzosin hydrochloride amorphous and solvated forms there of may be distinguished from each other by means of IR spectra, or thermal analysis. 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.
IR, DSC and RS/OVI analysis of the samples has been shown in figures

Detailed description of the present Invention
Accordingly, the present invention provides an improved process for the preparation of N1 -(4-amino-6,7-dimethoxy quinazol-2-yl)-N 1 -methyl-N2-(tetrahydrofuroyl-2)-propylene diamine of formula (I), and its novel polymorphs,
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.
1. Preparation of compound of formula (III) from compound of formula (II) by esterification with methanol in presence of sulfuric acid
2. Preparation of compound of formula (V) by condensation of formula (III) and formula (IV).
3. Preparation of compound of formula (VII) by condensation of formula (V) and formula (VI).
4. Conversion of formula (VII) into compound of formula (I) by hydrochloride salt formation.
Step 1 and 2 were carried out one pot reaction following by isolation of compound of formula (V)
Step 1 is the process to prepare compound of formula (III), it involves esterfication of compound of formula (II) with methanol in the presence of suitable acid catalyst such as sulfuric acid at the temperature from 0°C to reflux temperature of the solvent used preferably 25-35°C. The catalyst used in the above process ranges from 0.05 moles to 0.5 mole ratio.
Step 2 is preparation of compound of formula (V), involves condensation of compound of formula (III) and formula (IV) in methanol medium at the temperature ranges from 0°C to reflux temperature of the solvent used preferably 25-3 5°C.
Step 1 and 2 are one pot synthesis, compound of Formula (III) of step 1 is not isolating.
Step 3 is carried out for the preparation of compound of Formula (VII) by condensation of compound of Formula (V) and Formula (VI), In suitable solvents such as C4-C5 alcohol, Toluene, Xylene, Dimethylformamide and like, at the temperature ranges from 100°C to reflux temperature of the solvent used, preferably reflux temperature followed by basification in suitable solvents such as water, mixture of acetone and water,methanol and water, dichloromethane and water, isoamylalcohol and water, at the temperature ranges from 0°C to reflux temperature of the solvent used, preferably acetone and water, 10-15°C temperature, followed by purification in suitable solvent such as ethylacetate, Acetone, methanol, isopropyl alcohol and like at the temperature ranges from 40°C to reflux temperature of solvent used.

Step 3 is carried out for the preparation of compound formula (I), involves hydrochloride salt formation by the addition of a suitable hydrochloric acid such as aqueous hydrochloric acid, methanolic hydrochloride, isopropanolic hydrochloride, ethylacetate hydrochloride to the mixture of a suitable solvent C1-C5 alcohol, ethylacetate, cyclohexane, acetone, isopropylacetate and like. Compound of Formula (I) can be prepared by dissolution of compound of Formula (VII), in mixture of suitable organic solvent such as C1-C4 alcohol, and suitable hydrochloric acid such as aqueous hydrochloric acid, methanolic hydrochloride, isopropanolic hydrochloride, ethylacetate hydrochloride and addition to the anti solvents such as C3-C5 alcohol,Toluene, cyclohexane, n-heptane and like at temperature ranges from 0°C to reflux temperature of the solvent used, preferably at 60-65°C temperature.
Another aspect of the present invention provides novel polymorphs of Alfuzosin hydrochloride i.e., Isopropyl alcohol Solvated form of Alfuzosin hydrochloride and Amorphous form of Alfuzosin hydrochloride which comprises of preparation of Isopropyl alcohol form by the addition of isopropanolic hydrochloride to suspension of N1 -(4-amino-6,7-dimethoxyquinazol-2-yl)-N 1 -methyl-N2-(tetrahydrofuronyl-2)-propylene diamine and any other anti solvents like acetone, methanol and isopropyl alcohol. The preparation of Amorphous form of Alfuzosin hydrochloride is carried out by addition of methanolic hydrochloride to the compound of formula (VII) and distill off the solvent completely under reduced pressure.

The processes 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.
Example-1
Preparation of Nl-methyl-N2-tetrahydrofuroyI propylene diamine
Solution of 100 g of tetrahydrofuroic acid (1.0 mole) and 1.0 lit. of methanol was treated with 2.4 ml of sulfuric acid (0.05 mole) and stirred for 4 hours at 25-35°C then 84.2 gr of 3-methyl amino propylene diamine was added and stirred for 36 hours at 40-45°C. Distilled the methanol completely under atmospheric pressure, then charged the 500 ml of isopropyl alcohol and stirred for 45 min. Filtered the unwanted solid and distilled off the filtrate completely at below 80°C under reduced pressure, cool the residue to 25-35°C and unload. The yield of the title compound is 159 gr, (99.10 %).
Example -2
Preparation of Nl-(4-amino-6,7-dimethoxyquinazol-2-yl)-Nl-methyl-N2-(tetrahydrofuroyl-2)-propylenediamine
Suspension to 50 gr of 4-amino-2-chloro-6,7-dimethoxyquinazoline (1.0 mole), 77 gr of Nl-methyl-N2-tetrahydrofuroyl propylene diamine (1.8 mole) and 150 ml of isoamylalcohol was heated reflux for 5 hours then distilled off the solvent at 100-110°C under reduced pressure then cooled to 50-55°C, charged acetone (100 ml) and distilled off the solvent completely under reduced pressure at 50-55°C, then cooled to 25-35°C and stirred for 30-45 minutes, filtered the compound. Charged the wet compound in 750 ml of water and adjust the pH to 6.0-6.5 with 100 ml 10% HC1 solution, observe for clear solution then carbon treatment was given with 7.0 gr of acidic carbon. Charged the 200 ml of acetone into water and adjusted the pH to 12-14 with 100 ml of 10% sodium hydroxide solution at 10-15°C and stirred for 7-8 hours. Filtered the compound and recrystallised the wet compound in 250 ml of methanol. The yield of the title compound is 60 gr (74.07%).

Example-3
Preparation of Nl-(4-amino-6,7-dimethoxyquinazol-2-yl)-Nl-mehtyl-N2-(tetrahydrofuroyl-2)-propylene diamine hydrochloride
Slowly charge 100 ml of methanolic hydrochloride (assay 14%) to the 100 gr of N1 -(4-amino-6,7-dimethoxyquinazol-2-yl)-N 1 -methyl-N2-(tetrahydrofuronyl-2)-propylene diamine and 200 ml of methanol. The resulted mixture was treated with acidic carbon. Filtered the mass through hyflow. Distill off the solvent at 50-60°C under reduced pressure up to 60-70% of the volume present in the mass then charged 200 ml of Ethyl acetate and distilled off the solvent again at 60-70°C under reduced pressure and charged 500 ml of Ethyl acetate to the compound then cooled to 25-35°C and stirred for 45 minutes. Filtered the compound and wash with 50 ml of Ethyl acetate. The yield of the title compound is 90 gr (82.56%).
Preparation of Alfuzosin hydrochloride solvated forms
Example-4
Preparation of isopropylalcohol solvate form of Alfuzosin hydrochloride
Add 7.0 ml of isopropanolic hydrochloride to the suspension of 10.0 gr of Nl-(4-amino-6,7-dimethoxyquinazol-2-yl)-Nl-methyl-N2-(tetrahydrofuronyl-2)-propylene diamine and 100 ml of acetone to adjust the pH to around 2, and stirred the reaction mass for 30 minutes, then filtered the compound. Dry the compound at 100°C under reduced pressure then cool to 25-3 5 °C and unload the compound. Yield of the isopropylalcohol solvate of Alfuzosin HC1 is 10.0 gr (91.74%).
Example-5
Preparation of isopropyl alcohol solvate form of Alfuzosin hydrochloride
10 ml of methanolic hydrochloride is charged to the suspension of 10 gr of Nl-(4-amino-6,7-dimethoxyquinazol-2-y1)-Nl-methyl-N2-(tetrahydrofuronyl-2)-propylene
diamine and 30 ml of methanol and cooled to 10-15°C, slowly added 100 ml of isopropyl alcohol and stirred the reaction mass for 2 hours at 10-15°C. Filtered the compound and washed with 10 ml of isopropyl alcohol. Dry the compound at 100°C for 10-15 hours under reduced pressure. Cool to 25-35°C and unload the compound. The yield of the isopropylalcohol solvate form of Alfuzosin HC1 is 10.0 gr (91.74%).

Example-6
Preparation of Alfuzosin hydrochloride amorphous form
Solution of 10 gr of Nl-(4-amino-6,7-dimethoxyquinazol-2-yl)-Nl-methyl-N2-(tetrahydrofuronyl-2)-propylene diamine, 10 ml of methanolic hydrochloride (14.0% assay) and 30 ml of methanol was filtered and filtrate distilled completely under reduced pressure at 60-65°C. Transferred the compound and dried at 125°C for 2 hours under reduced pressure. The yield of the title compound is 10.5 gr (96.30%)

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

and pharmaceutically acceptable acid addition salts thereof, which comprises
a) The esterification of Tetrahydro -2 -furoic acid (II) with methanol in presence of sulfuric acid
b) Condensation of Methyl amino propyl 1,3-diamine (IV) with Tetrahydro -2-furoic acid methyl ester (III) in presence of methanol
c) Further condensation of Nl-methyl-N2-tetrahydrofuroyl propylene diamine (V) with 4-amino-2-chloro-6,7-dimethoxyquinazoline (VI) in presence of Isoamyl alcohol gives desired compound of Formula (VII) and its purification in a suitable solvent.
d) Formula (VII) thus obtained converted into its pharmaceutically acceptable acid addition salts thereof

2. Process according to claim la. which comprises carrying out the reaction in a solvent methanol at a temperature ranges from 0° to reflux temperature of the solvent preferably at 25-35°C.
3. Process according to claim la. which comprises esterification of compound of formula (II) 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. Process according to claim lb. which comprises preparation of compound of formula (V) involves condensation of compound of formula (III) with compound of formula (IV) in presence of C1-C3 alcohol preferably methanol at a temperature range of 0° to reflux temperature of solvent used preferably at 40-45°C.
5. Process according to claim lc. which comprises for the preparation of compound of formula (VII) by condensation of compound of formula (V) and formula (VI) in a suitable solvent such as C4-C5 alcohol, Toluene, Xylene, Dimethylformamide, sulfolane and like,preferably Iso amyl alcohol, at a temperature ranges from 100°C to reflux temperature of the solvent used,

preferably 125-135°C, in which the purification solvent is Acetone, methanol, isopropyl alcohol, ethyl acetate at the temperature ranges from 40°C to reflux temperature of solvent used preferably methanol.
6. Process according to claim 1d. in which the compound of formula (VII) converted
into its hydrochloride salt of formula (I) by addition of solvent containing
hydrogen chloride, such as Hydrogen chloride in methanol or isopropanol or ethyl
acetate or cyclohexane or acetone or isopropyl acetate and like, preferably
hydrogen chloride in methanol to the formula (VII) (free base) in the solvent
isopropyl alcohol and the temperature is preferably at 25-35°C.

7. Isopropyl alcohol solvated form of Alfuzosin hydrochloride which is
characterized by IR spectrum, DSC Thermogram and Residual solvents.
8. Amorphous form of Alfuzosin hydrochloride , which is characterized by XRD.
9. Process for the preparation of Isopropyl alcohol solvated form of Alfuzosin hydrochloride.
10. Process for the preparation of Amorphous form of Alfuzosin hydrochloride.