FORM 2 THE PATENTS ACT 1970
(39 OF 1970)
PROVISIONAL SPECIFICATION
(SECTION 10)
AN IMPROVED PROCESS FOR PREPARATION OF ALFUZOSIN AND ITS INTERMEDIATES
UNICHEM LABORATORIES LIMITED,
A COMPANY REGISTERED UNDER THE INDIAN COMPANY
ACT, 1956, HAVING ITS REGISTEREb OFFICE LOCATED AT
UNICHEM BHAVAN, PRABHAT ESTATE, OFF S.V. ROAD,
JOGESHWARI (WEST), MUMBAI400102.
MAHARASTRA, INDIA
The following specification particularly describes the invention and the manner in which it is to be performed.
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AN IMPROVED PROCESS FOR PREPARATION OF ALFUZOSIN AND ITS INTERMEDIATES
FIELD OF INVENTION
The present invention relates to an improved process for the preparation of antihypertensive drug alfuzosin and its intermediate.
BACKGROUND OF THE INVENTION
(±!)-N-[3-[(4-amino-6,7-dimethoxy-2-quinazolinyl)methylamino]propyl]tetrahydro-2-fufancarboxamide having formula (I),

is called Alfuzosin, which is useful as antihypertensive as well as a-antagonist.
Id prior art Alfuzosin is prepared by a reaction of 4-amino-2-chloro-6,7-dimethoxy
quinazoline compound having formula (II)

with a N'-methyl-N"-tetrahydrofuroyl trimethylenediamine compound represented by the following formula (IIIa),

in the refluxing isoamyl alcohol (J. Med. Chem., 1986, 29, 19), US 4,315007 (1982).

The disadvantage of the above method is that the starting material 4-amino-2-chloro-6,7-difriethoxy quinazoline, of the formula (II) is prepared from veratraldehyde by several number steps by involving lower yields in a few steps.
The GB 2231571 (1991) discloses another method for the synthesis of (±)-N-[3-[(4-ariiino-6,7-dimethoxy-2-quinazolinyl)methylamino]propyl]tetrahydro-2-fujrancarboxamide having formula (I). The reaction process involves the reaction of N-cyano-N'(3,4-dimethoxyphenyl)-s-methyl thiourea with N'-methyl-N"-tetrahydrofuroyl trimethylenediamine in IP A as a reaction solvent results into the formation of N-(3,4-dihiethoxy phenyl)-N-methyl-N/3-(tetrahydro-2-furoyl amino)-propyl-N'- cyano giianidine. This guanidine derivative upon cyclization affords (±)-N-[3-[(4-amino-6,7-dimethoxy-2-quinazolinyl)methylamino]propyl]tetrahydro-2-furancarboxamide (I).
OBJECT OF THE INVENTION
The object of the present invention is to provide a simpler process for the synthesis of
Alfuzosin.
Another object of the present invention is to provide a Alfuzosin with a good yield and
with good purity.
Another object of the present invention is to prepare a Alfuzosin through novel
intermediates
Another object of the present invention is to provide a novel processes of making
substituted urea and hence guanidine derivatives thereof.
SUMMARY OF THE INVENTION
(i)-N-[3-[(4-amino-6,7-dimethoxy-2-quinazolinyl)methyl amino]propyl]tetrahydro-2-furancarboxamide (I), is prepared from the condensation of 4-amino-2-chloro-6,7-dijmethoxy quinazoline compound having formula (II) with N'-methyl-N"-te^rahydrofuroyl trimethylenediamine (IIIa). Up to nine steps are used to synthesize the 4-amino-2-chloro-6,7-dimethoxy quinazoline form vertraldehyde {J. Med. Chem., 1977, 20, 146). The major drawback of this method (Scheme 1) is of lower yields (between about 5
3

and 25%) with a tedious process which involves the large number of steps till to get Alfuzosin product.

(Scheme 1)
The GB2231571 discloses another method (Scheme 2) for the synthesis of (±)-N-[3-[(4-amino-6,7-dimethoxy-2-quinazolinyl)methylamino]propyl]tetrahydro-2-fulrancarboxamide (I). The reaction of N-cyano-N'(3,4-dimethoxyphenyl)-s-methyl thiourea with N'-methyl-N"-tetrahydrofuroyl trimethylenediamine in IPA as a reaction so'lvent affords N-(3,4-dimethoxy phenyl)-N-methyl-N/3-(tetrahydro-2-furoyl amino)-p^opyl-N'- cyano guanidine. This guanidine derivative upon cyclization affords (±)-N-[3-[(4-amino-6,7-dimethoxy-2-quinazolinyl)methylamino]propyl]tetrahydro-2-furancarboxamide (I).


(Scheme 2)
As in (Scheme 1), this process also fails to provide good yields, because of the number of
steps involved in the preparation of the starting material, 2-chloroquinazoline. It is
therefore an object of this invention to provide an improved and more efficient methods
for the synthesis of the compounds such as ureas and guanidines as well as the cyclized
guanidine viz. (±)-N-[3-[(4-amino-6,7-dimethoxy-2-
quinazolinyl)methylamino]propyl]tetrahydro-2-furancarboxamide (I) with good yields.
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It I is still a further object of the invention to provide such compounds for example
cyclized guanidine viz. (±)-N-[3-[(4-amino-6,7-dimethoxy-2-
quinazolinyl)methylamino]propyl]tetrahydro-2-furancarboxamide (I) with good purity. It is still further object of this invention is to provide a novel intermediates including substituted urea and guanidines derivatives to synthesize (±)-N-[3-[(4-amino-6,7-di'rnethoxy-2-quinazolinyl)methylamino]propyl]tetrahydro-2-furancarboxamide. According to the present aspect of the invention a method of manufacture of compound such as ureas and guanidines as well as the cyclized guanidine viz. (±)-N-[3-[(4-amino-6,l7-dimethoxy-2-quinazolinyl)methylamino]propyl]tetrahydro-2-furancarboxamide having formula (I), are provided by comprising:
(a) converting an amine to its corresponding urea derivative;
(b)Reacting this urea derivative with an substituted amines (III) compounds wherein -R is benzyl, triphenyl methyl, p-methylbenzyl or p-methoxybenzyl in presence of solvent like pyridine, N-methyl morpholine, 2,6-dimethyl pyridine or Hunig's base and at reflux temp60-l 16°C

(b) reacting the resulting substituted urea with an electrophile preferably like POCI3, may also comprise: PCI5, P2O5, tosyl chloride, and in some instances mesyl chloride, ethyl chloroformate to yield a reaction product which further reacts with ammonia or an amine to provide an asymmetrically substituted guanidines.
(c) cyclizing the resulting substituted guanidine to provide (±)-N-[3-[(4-amino-6,7-dimethoxy-2-quinazolinyl)methylamino]propyl]tetrahydro-2-furancarboxamide
(I)-T IUS, the product obtained (+)-N-[3-[(4-amino-6,7-dimethoxy-2-quinazolinyl)methyl
amino]propyl]tetrahydro-2-furancarboxamide (I) is of higher yields and high purity. Furthermore, compounds of the invention may be prepared by a "one pot" synthesis,
1
starting from the substituted urea.

In] accordance with the present invention, the reaction scheme of preparation of of (±)-N-
[3-[(4-amino-6,7-dimethoxy-2-quinazolinyl)methyl lamino]propyl]tetrahydro-2-
furancarhoxarnide (\\ is shown in Scheme 3 & Scheme 4



The initial reactants are all available and are easily manufactured as would be understood by persons skilled in the art.
Although the invention has been described with reference to specific embodiments, this description is not meant to be construed in a limiting sense. Various modifications of the disclosed embodiments, as well as alternate embodiments of the invention, will become apparent to persons skilled in the art upon reference to the description of the invention. It is therefore contemplated that such modifications can be made without departing from the spirit or scope of the present invention as defined.
EXAMPLES
The following examples are presented for illustration only, and are not intended to limit • the scope of the invention or appended claims.

Example la
3,|4-dimethoxy-6-cyanoaniline-l-yl formamide (V):
3,]4-Dimethoxyanthranilonitrile (100 g, 0.561 mol) is taken in glacial acetic acid (500 ml) arid cooled to +10°C. To this solution is added a suspension of sodium cyanate (55.02 g, mole in 250 ml water) in ml portions over a period of 60 min. Acetone ( 2 L) is added arid the mixture is maintained at +5°C for an additional 30 min., product (V) is filtered and cake is washed with water (2x 1L) followed by acetone (2x 250 ml). (70 gm, 56 %).
Example lb
N-[3-[(4-amino-6,7-dimethoxy-2-quinazolinyl)methylamino]propyl]tetrahydro-2-furancarboxamide (I):
3,]4-dimethoxy-6-cynoaniline-l-yl formamide (5 g, 0.0226 mol) (V) and N'-methyl-N"-tetrahydrofuranyl trimethylenediamine ( 5.04 g, 0.027mol) (IIIa) are suspended in 100 ml dry pyridine and the mixture is refluxed for 3.5 hours. The reaction mixture is then cooled to 20 °C. Phosphorous oxychloride (3.836 g, 0.0249 mol) is added and the resulting solution is heated to 70 °C and maintained for 30 min. The reaction mixture is removed from the heat and allowed to cool to room temperature to get the compound (ill). Anhydrous NH3 gas is moderately purged through the reaction mixture and the internal temperature is allowed to rise independently to a maximum temperature (70 °C to 80 °C). When the internal temperature drops below the previously attained maximum temperature, the reaction mixture is slowly heated to 80 °C. Alternatively ammonium carbonate can be used as a source of ammonia. The reaction mixture is cooled to 60 °C arid then vacuum distilled to a minimum volume. The residual pyridine is azeotroped off with a small amount of water. Water (20 ml) and n-butanol (60 ml) are added to the aqueous solution and the mixture is heated to 60 °C. The warm mixture is basified to pH 10 with dropwise addition of 10% sodium hydroxide solution. The layers are separated arid the aqueous phase is further extracted with three portions (20ml x 3) of n-butanol. The organic extractions are combined and filtered through a bed of celite. The filtrate is dried over sodium sulphate, concentrated under reduced pressure and applied to a silica column. It ions then eluted with chlorofom:methanol mixture. The fractions are combined arid concentrated under reduced pressure to obtain the pure product (I) (5 g, 57 %).
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Alfuzosin base (5g, 0.013mol) was charged to a flask and ethanol (11 Oral) added. The mixture was refluxed for 15 min. and the solid was dissolved. Activated charcoal was added, the suspension was stirred for l0min., filtered and washed with 5ml hot ethanol. The filtrate was cooled down to 20-25°C and the ethanol saturated by hydrogen chloride gas (1.5ml) was added. Then diethyl ether (25ml) and water (0.09ml) were slowly added to the mixture. The mixture was then stirred at room temperature for 15-20 hours. The mixture was then cooled down to 0-5 C and one hour stirring the product was filtered off arid washed by 7.5ml of diethyl ether. The crystalline product was dried at vacuum drier at|120°Cfor minimum 8 hours. The yield of Alfuzosin hydrochloride was 4.85g (88.7%).
Example 2a
N-[1-[(4-amino-6,7-dimethoxy-2-quinazolinyl)methyl]-N'-(3-benzyl)propanediamine (XIII):
3,J4-dimethoxy-6-cynoaniline-l-yl formamide (5 g, 0.0226 mol) (V) and N-methyl-N'-benzyl-l,3-propane diamine (5.04 g, 0.027 mol) (Illb) are suspended in 100ml dry pyridine and the mixture is refluxed for 3.5 hours. The reaction mixture is then cooled to 20 °C. Phosphorous oxychloride (3.836 g, 0.0249mol) is added and the resulting solution is | heated to 70 °C and maintained for 30 min. The reaction mixture is removed from the heat and allowed to cool to room temperature to get the compound (XI). Anhydrous NH3 gas is moderately purged through the reaction mixture and the internal temperature is allowed to rise independently to a maximum temperature (70 °C to 80 °C). When the internal temperature drops below the previously attained maximum temperature, the reaction mixture is slowly heated to 80 °C. Alternatively ammonium carbonate can be used as a source of ammonia). The reaction mixture is cooled to 60 °C and then vacuum distilled to a minimum volume. The residual pyridine is azeotroped off with a small amount of water. Water ( 20 ml) and n-butanol ( 60 ml) are added to the aqueous solution and the mixture is heated to 60 °C. The warm mixture is basified to pH 10 with dropwise addition of 10% sodium hydroxide solution. The layers are separated and the aqueous phase is further extracted with three portions (20ml x 3) of n-butanol. The organic extractions are combined and filtered through a bed of celite. The filtrate is dried over sodium sulphate, concentrated under reduced pressure and applied to a silica column. It is

then eluted with chlorofom:methanol mixture. The fractions are combined and concentrated under reduced pressure to obtain the pure product.
Example 2b
N-[3-[(4-amino-6,7-dimethoxy-2-quinazolinyl)methylamino]propyl]tetrahydro-2-furancarboxamide (I):
N-[1- [(4-amino-6,7-dimethoxy-2-quinazolinyl)methyl] -N' -(3 -benzy l)propanediamine is subjected to debenzylation using 10% Pd-C as a catalyst at hydrogen pressure of 2-3 Kg/sq. in using methanol as a solvent. Reaction was monitored (TLC), after the completion of the reaction mixture was carefully filtered through a hyflow bed and the hyflow bed was washed with methanol. Methanol was then removed under the reduced pressure. The residue was taken in toluene and to this slowly added a solution of 2-jtetrahydrofuroic acid chloride (in toluene) (1.1 equivalents), and reaction mixture was stirred at 40-50 °C till the reaction was complete. After the completion of the reaction reaction mixture was cooled and toluene layer then washed with saturated sodium bicarbonate solution followed by brine. The organic layer was separated and dried over arihydrous sodium sulphate. The solvent was then removed by distillation under reduced pressure to obtain the pure product.
Alfuzosin base (5g, 0.013mol) was charged to a flask and ethanol (110ml) added. The
mixture was refluxed for 15 min. and the solid was dissolved. Activated charcoal was
i
added, the suspension was stirred for l0min., filtered and washed with 5ml hot ethanol. The filtrate was cooled down to 20-25°C and the ethanol saturated by hydrogen chloride gas (1.5ml) was added. Then diethyl ether (25ml) and water (0.09ml) were slowly added to the mixture. The mixture was then stirred at room temperature for 15-20 hours. The mixture was then cooled down to 0-5°C and one hour stirring the product was filtered off and washed by 7.5ml of diethyl ether. The crystalline product was dried at vacuum drier at 120°Cfor minimum 8 hours. The yield of alfuzosin hydrochloride was 4.85g (88.7%).
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ABSTRACT:
Improved method for the synthesis of an Antihypertensive reagent like Alfuzosin is described. Thus, this process includes the synthesis of novel intermediates like substituted urea derivatives and guanidines as well as the cyclized guanidine viz. (±)-N' [3|[(4-amino-6,7-dimethoxy-2-quinazolinyl)methylamino]propyl]tetrahydro-2-
furancarboxamide (I) with good yields.