Field of the Invention:
The present invention relates to an improved process for synthesis of N-[3-[(4-Amino-6,7-dimethoxy-2-quinazolinyl) methyl amino]propyl]tetrahydro-2-furancarboxamide represented by general formula (I), comprising reaction of N-methyl-N-(4-amino-6,7-dimethoxy-2-quinazolinyl)-l,3-propanediamine (II) and tetrahydro - 2-furoic acid (III) in the presence of an inert organic solvent.
Background Information:
Alfuzosin, chemically known as N-[3-[(4-Amino-6,7-dimethoxy-2-quinazolinyl)methyl amino] propyl]tetrahydrO-2-furancarboxamide is represented by the following formula (I).

Alfuzosin is known to be an antagonist of α1-adrenergic receptor, and is useful as antihypertensive agent and dysuria curing agent (Japanese Examined Patent Application Publication HEI No.5-64930). The alfuzosin hydrochloride is also disclosed in Japanese Examined Patent Application Publication SHO No. 60-23114.
Recently, Alfuzosin has been approved for the treatment of benign prostratic hyperplasia (BPH). Alfuzosin is a non-selective αl - adrenoreceptor antagonist that is quite uroselective in its distribution and as a result is used for the treatment of BPH.
Synthesis of N-[3-[(4-Amino-657-dimethoxy-2-quinazolinyl) methyl amino] propyl]tetrahydro-2-furancarboxamide formula (I) is described in the US patent no US 4315007 and in J. MED. CHEM .29, 19-25 (1986).

us No. 6,313,293 Bldescribes preparing an amide (side chain) by reacting a secondary amine with carboxylic acid in a molten form in the presence of silicon amines.
US No. 6,313,294 Bldescribes preparing an amide (side chain) by reacting a secondary amine with an ester in a molten form in the absence of a solvent.
GB 2, 231,571 A describes process for preparation of quinazoline derivatives wherein the quinazoline ring is formed in the penultimate step for the synthesis of the alfuzosin.
One of the key steps in the synthesis of N-[3-[(4-Amino-6,7-dimethoxy-2-quinazolinyl) methyl amino] propyl]tetrahydro-2"furancarboxamide (I) as described in US patent No. 4315007 is formation of amide bond i.e. bond "a" in structure-I

Number of methods have been reported in literature for the synthesis of amides. These involve:
a). Reaction of amines with esters under heating where amide bond is directly formed. These reactions are generally carried out in presence of suitable solvents.
b). The conventional methods for direct conversion of carboxylic acids to amines either at a very high reaction temperature (over 190° C) or by using coupling agents such as carbodiimides, phosphorus agents or uronium salts.
c). By derivatizing acid to corresponding chloride followed by reaction with amine with or without external base.

U. S. Patent No: 4315007 describes formation of amide bond of alfuzosin by
condensation of N-methyl-N-(4-amino-657-dimethoxy-2-quinazolinyl)-1,3-
propanediamine with tetrahydro - 2-furoic acid using N,N'-Carbonyldiimidazole (CDI) as condensing agent in Tetra hydrofuran (THF) (Scheme 1).

Use of N.N-Carbonyldiimidazole (CDI) as condensing agent in the process increases the cost of the process and cause problems in isolation of the desired product. Also the use of this condensing agent is disadvantageous because of stability, handling and tedious work up procedure.
Thus, an alternative improved process has been desired for the synthesis of alfuzosin.
In a surprising discovery we found that the amide bond "a" in alfuzosin of structure I can be easily formed by condensation of N-methyl-N-(4-amino-657-dimethoxy-2-quinazolinyl)-l,3-propanediamine (II) with tetrahydro - 2-furoic acid (III) in the presence of an inert organic solvent at temperature of about 60 - 140° C ( Scheme 2).


This novel process does not require any condensing agent for the preparation of alfuzosin (I) and does not suffer from any of the draw back of prior art which makes use of condensing agents like CDI.
Summary of the invention:
It is an object of the invention to provide a process for the synthesis of N-[3-[(4-AminO-6,7-dimethoxy-2-quinazolinyl) methyl amino] propyl]tetrahydro-2-furancarboxamide (I).
A yet another object of the present invention is to provide for a process for the synthesis of N-[3-[(4-Amino-6,7-dimethoxy-2-quinazolinyl) methyl amino] propyl]tetrahydro-2-furancarboxamide (I) by heating N-methyl-N-(4-amino-6,7-dimethoxy-2-quinazolinyl)-l,3-propanediamine (II) and tetrahydro - 2-furoic acid (III) in the presence of an inert solvent.
A yet further object of the present invention is to provide for a process for the synthesis of N-[3-[(4-Amino-6,7-dimethoxy-2-quinazolinyl) methyl amino] propyl]tetrahydro-2-furancarboxamide (I) by heating N-methyl-N-(4-amino-6,7-dimethoxy-2-quinazolinyl)-13-propanediamine (II) and tetrahydro - 2-furoic acid (III) in the presence of a solvent selected from toluene, xylenes, or mixtures thereof
A still yet another object of the present invention to provide for a process for the synthesis of N-[3-[(4-Amino-6,7-dimethoxy-2-quinazolinyl) methyl amino] propyl]tetrahydro-2-furancarboxamide (I) by heating N-methyl-N-(4-amino-6,7-dimethoxy-2-quinazolinyl)-13-propanediamine (II) and tetrahydro - 2-furoic acid (III) to about 60 - 140°C in the presence of a solvent selected from toluene, xylenes, or mixtures thereof
Detailed description of the invention:
The following definitions are set forth to illustrate and define the meaning and scope of the various terms used to describe the invention herein.

As used herein, the term " q.s" means adding a quantity sufficient to achieve a stated function, e.g., to bring a solution to the desired volume, (i.e., 100%).
As used, the term " inert organic solvent" means a solvent inert under the conditions of the reaction being described in conjunction therewith. The inert organic solvents of the present invention are selected from toluene, xylenes, benzene and mixtures thereof Particularly preferred inert organic solvents are toluene, xylenes or mixture thereof
As used herein, the term "reaction time" means the time period in which the indicated chemical reaction takes place.
As used herein, the term " pot temperature" means the temperature of the reaction mixture in which the chemical reaction takes place. Unless specified to the contrary, the ranges of molar equivalents, reaction time, temperature and solute concentration described here in are approximate.
For example, the phrases: 1) using an excess (between 1.01 to 3.0 molar equivalents); 2) a reaction time of 20 to 100 hours; 3) an initial pot temperature range of 30° to 120°'C; 4) with a ratio of N-methyl-N- (4-amino-6, 7-dimethoxy-2-quinazolinyl)-l,3-propanediamine (II) to solvent of 1 gm: 1.0 ml to 1 gm: 40 ml and 5), the reaction completion is 70 to 100% are respectively intended to mean 1) using an excess (between about 1.0 to about 3.0 molar equivalents); 2) a reaction time of about 20 to about 100 hours; 3) an initial pot temperature range of about 30° to about 120°C; 4) with a ratio of N-methyl-N- (4-amino-6, 7-dimethoxy-2-quinazolinyl)-1,3-propanediamine (II) to solvent of about 1 gm : 1.0 ml to about 1 gm : 40 ml and 5) the reaction completion is about 70 to about 100%.
Isolation and purification of the compound described herein can be effected, if described, by any; suitable separation or purification procedure such as, for example, filtration extraction, crystallization, column chromatography thin-layer or thick layer chromatography, or a combination of these procedures. Specific illustrations of

suitable separation and isolation procedures can be had by reference to the examples herein below. However, other equivalent separation or isolation procedures can, of course also be used.
The alfuzosin of formula (I) can preferably be prepared by a method comprising the following steps.
a). The N-methyl-N-(4-amino-6,7-dimethoxy-2-quinazolinyl)-13-propanediamine (II) required for the synthesis can be conveniently prepared as per the process outlined in the US patent No. 4315007 Scheme 3.


d). heating reaction mixture to about 60 - 140° C for 20 - 100 hours (most preferably 60 hours).
e). stripping off the solvent from the reaction mixture under atmospheric pressure and finally applying reduced pressure to remove the traces of solvent, thus providing alfuzosin as a thick viscous residue.
f). adding water to the viscous residue, basifying it with base and extracting using halogenated hydrocarbons like chloroform, methylene dichloride etc.
g). after washing organic layer with water, charcoalizing the organic layer with carbon,
h). stripping off halogenated hydrocarbons to obtain crude alfuzosin.
i). finally purifying and isolating pure alfuzosin (I) from crude alfuzosin using alcoholic solvents viz. methanol, ethanol, propanol etc.
The alfuzosin (I) obtained by method of the present invention can be converted in to its pharmaceutically acceptable salts. In particularly the alfuzosin (I) can be transformed into its hydrochloride salt by suspending alfuzosin free base in alcohol and adding quantitative amount of alcoholic hydrochloride following the method described in U.S. Patent No. 4,315,007 (Example II).
The following examples are given to enable those skilled in the art to more clearly understand and to practice the present invention. They should not be considered as limiting the scope of the invention, but merely as being illustrative and representative thereof
Example I: Preparation of Alfuzosin using toluene as an inert organic solvent: -
To 10 gm of N-methyl-N- (4-amino-6, 7-dimethoxy-2-quinazolinyl)-1,3-propanediamine (II) prepared as per the process described in US patent No. 4,315,007 in 100 ml toluene was taken in a reaction flask provided with reflux condenser and dean-stark apparatus. A solution of tetrahydro-2-furoic acid (12 gm) in 10 ml toluene

was slowly added to the reaction mixture under vigorous stirring over a period of 2 hours. The resulting mixture was maintained under stirring at a temperature of about 100° C for 70 hours. Toluene was distilled out under atmospheric pressure and finally stripping off the traces by applying a high vacuum. Water (100 ml) was added to the residue and resulting reaction mass was basified with aqueous sodium hydroxide. The product was extracted with methylene dichloride (120 ml). The organic layer was washed with water (150 ml), dried over anhydrous sodium sulfate, charcoalized and concentrated under vacuum to obtain crude alfuzosin as a viscous residue (10 gm).
Alfuzosin (crude) prepared as above (10 gm) was suspended in methanol (30 ml) and heated to reflux. The reaction mixture was cooled and the white precipitated product was filtered off at ambient temperature and dried at 70° C for 6 hours at atmospheric pressure to yield about 7.0 gm of alfuzosin.
Example II: Preparation of Alfuzosin using xylene as an inert organic solvent: -
To 10 gm of N-methyl-N- (4-amino-6, 7-dimethoxy-2-quinazolinyl)-1,3-propanediamine (II) prepared as per the process described in US patent No. 4,315,007 in 100 ml xylene was taken in a reaction flask provided with reflux condenser and dean-stark apparatus. A solution of tetrahydro-2-furoic acid (12 gm) in 10 ml xylene was slowly added to the reaction mixture under vigorous stirring over a period of 2 hours. The resulting mixture was maintained under stirring at a temperature of about 125° C for 50 hours. Xylene was distilled out under reduced pressure and finally stripping off the traces by applying a high vacuum. Water (100 ml) was added to the residue and resulting reaction mass was basified with aqueous sodium hydroxide. The product was extracted with methylene dichloride (120 ml). The organic layer was washed with water (150 ml), dried over anhydrous sodium sulfate, charcoalized and concentrated under vacuum to obtain crude alfuzosin as a viscous residue (10 gm).
Alfuzosin (crude) prepared as above (10 gm) was suspended in methanol (30 ml) and heated to reflux. The reaction mixture was cooled and the white precipitated product was filtered off at ambient temperature and dried at 70° C for 6 hours at atmospheric pressure to yield about 5.0 gm of alfuzosin.

Example III: Preparation of Alfuzosin hydrochloride: To alfuzosin free base (20 gm) prepared as per the example-I in propan-2-ol (200 ml) was added theoretical amount of ethanolic HCl under inert nitrogen atmosphere. The resulting mixture was stirred for 5 hours at 25 - 30°C; the resulting solid was filtered under inert atmosphere of nitrogen gas, washed with isopropylalcohol. The wet product was dried under 2 mm pressure at 70±5^ C for 24 hours to yield 20 gm of alfuzosin hydrochloride, melting point 232-235° C. Identification of the product was confirmed by NMR studies.
1HNMR(DMSO). 6 1.79 -1.85 (m, 6H), 3.14 - 3.17 (t, 2H), 3.21 (s, 3H), 3.67 - 3.78 (m, 4H), 3.84 - 3.88 (2s, 6H), 4.19 - 4.22 (m, IH), 7.60-7.76 (2s, 2Ar-H), 7.91 (s, broad, 1H, NH), 8.51 - 8.88 (2s, 2H, NH2), 11.9 (s, broad, 1H, HCl).
It is to be understood while at the invention has been described in conjunctions with the detailed description thereof, the foregoing description is intended to illustrate and not to limit the scope of the invention which is defined by the scope of the appended claims. Other aspects like advantages and modifications are within the scope of the following claims.

WE CLAIM :
1. A process for preparing N-[3-[(4-Amino-6,7-dimethoxy-2-quinazolinyl) methyl
amino]propyl]tetrahydro-2-furancarboxamide of the formula (1) comprising
the step of heating N-methyl-N- (4-amino-6, 7-dimethoxy-2-quinazolinyl)-l,3-
propanediamine of the formula (II) and tetrahydro - 2-furoic acid of the
formula (III) to a temperature ranging from 30° to 170°C in the presence of an
inert solvent.

2. The process as claimed in claim 1, wherein said inert organic solvent is
selected from the group consisting of toluene, xylene, benzene, and mixtures
thereof.
3. The process as claimed in claim 1, wherein the heating is carried out at 60° -
140°C.
4. The process as claimed in claim 1, wherein the inert solvent is toluene and
heating is carried out at 60° -120° C most preferably at 100°C.
5. The process as claimed in claim 1, wherein the inert solvent is xylene and
heating is carried out at 60° - 140°C most preferably at 100°C.
6. The process as claimed in claiml, wherein the ratio of amine represented by formula (II) to inert organic solvent is ranging from 1 gm: 1 ml to 1 gm: 40 ml.
7. The process as claimed in claim 1, wherein the ratio of amine represented by formula II is ranging from about 1.0 to 5.0 molar equivalents of carboxylic acid of formula (III) is used.

8. Use of the alfuzosin of formula (I) prepared according to claim 1 for preparing
alfuzosin hydrochloride in a manner known per se.
9. N-[3-[(4-Amino-6,7-dimethoxy-2-quinazolinyl) methyl amino] propyl]
tetrahydro-2-furancarboxamide (Afixzosin) of the formula I

prepared by the process claimed in any one of the claims 1 to 7.
10. Alfuzosin hydrochloride obtained from the alfuzosin in a known manner.