FORM 2
THE PATENTS ACT 1970
(39 OF 1970)
COMPLETE SPECIFICATION
(SECTION 10)
A NOVEL PROCESS FOR THE PREPARATION OF
2-HALO-4-AMINOQUINAZOLINES
UNICHEM LABORATORIES LIMITED,
A COMPANY REGISTERED UNDER THE COMPANIES ACT, 1956, HAVING ITS REGISTERED OFFICE LOCATED AT
UNICHEM BHAVAN, PRABHAT ESTATE, OFF. S. V. ROAD,
JOGESWARI (WEST), MUMBAI-400 102.
MAHARASHTRA, INDIA
The following specification particulaR1y describes the invention and the manner in which it is to be performed.

A NOVEL PROCESS FOR THE PREPARATION OF
2-HALO-4-AMINOQUINAZOLINES
TECHNICAL FIELD
The present invention relates to a process for the production of 2-halo-4-aminoquinazolines. These chemical compounds are utilized as intermediates in the preparation of antihypertensive agents.
BACKGROUND OF THE INVENTION
US3511836 (Hess, 1970) discloses preparation of 2-chloro-4-aminoquinazolines by
reaction of 2,4-dichloroquinazolines with ammonia in a solvent such as tetrahydrofuran.
US3669968 (Hess, 1972) describes a process for preparing 2-halo-4-amino-6,7,8-
trialkoxy quinazolines by treating 2,4-dihalo-6,7,8-trialkoxy quinazolines with ammonia
in an inert organic solvent.
US4315007 (Manoury, 1982) employ 2-chloro-4-amino-6,7-dimethoxyquinazolines as a
starting material in the preparation of the a-antagonist and antihypertensive compound
viz. alfuzosin hydrochloride.
US4001237 and 4001238 (Partyka et al, 1977; employ 2-chloro-4-amino-6,7-
dimethoxyquinazolines as starting material in the preparation of a series of 6,7-
dimethoxy-4-amino-2-(piprazinyl)quinazolines.
The disadvantages of all these methods are that the 2,4-dihalo-6,7-dialkoxy quinazolines
and 2,4-dihalo-6,7,8-trialkoxy quinazolines are prepared by involving a number of steps
with lower yields in few steps.
US4098788 (Crenshaw et al, 1978,) discloses preparation of 2-halo-4-aminoquinazolines
by a two-step process involving cyclization of substituted-l-phenyl-3-cyanoureas or
substituted-l-phenyl-3-cyanothioureas in the presence of phosphorus halides and
phosphorus oxyhalides to provide a phosphoquinazolines intermediate which are
hydrolyzed to 2-halo-4-aminoquinazolines.
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OBJECT OF THE INVENTION
The object of the present invention is to provide a novel process for the preparation of 2-haJo-4-aminoquinazolines of formula (I):

Another object of the present invention is to provide a process for the preparation of 2-halo-4-aminoquinazolines of formula (I) by involving the use formamide derivatives.
Another object of the present invention is to provide a simple and scalable process for the synthesis of preparation of 2-halo-4-aminoquinazolines derivatives.
Another object of the present invention is to provide 2-halo-4-aminoquinazolines derivatives with a good yield and with good purity.
SUMMARY OF THE INVENTION
According to the present invention there is provided a process for preparation of 2-halo-4-aminoquinazolines of formula (I):

wherein X is a halogen atom selected from the group consisting of chlorine or bromine;
R1, R2 and R3 are independently selected from the group consisting of hydrogen, lower alkyl inclusive or lower alkoxy chains which comprises subjecting a compound of
formula (II)
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wherein
R1, R2 and R3 are as above, and Y is oxygen or sulfur atom, to a intramolecular cyclization in presence of a phosphorous oxyhalides.
According the present invention there is provided a process for the preparation of compound of formula (ED)

Also, according the present invention there is provided a process for the preparation of compound of formula (V)

DETAILED DESCRIPTION OF THE INVENTION
As indicated herein above, the present invention is concerned with the process for the preparation of compounds of the formula (I):
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wherein,
X is a halogen atom selected from the group consisting of chlorine or bromine, and
R1, R2 and R3 are independently selected from the group consisting of hydrogen, lower
alkyl of 1 to 4 carbon atoms inclusive or lower alkoxy chains of 1 to 4 carbon atoms
inclusive,
which comprises subjecting a compound of formula (II)

wherein
R1, R2 and R3 are as above and Y is oxygen or sulfur atom, to a intramolecular
cyclization in presence of a phosphorous oxyhalides to provide compounds of the
formula (I) with better yields and high purity.
Preferred embodiments of the foregoing process for the preparation of compounds
characterized by formula (I) are those wherein:
the compound of formula (II) a formamide derivative wherein R1, R2 and R3 are as
above includes the compound of formula (II) is 3,4-dimethoxy-6-cyanoaniline-l-yl
formamide and 2,3,4-trimethoxy-6-cyanoaniline-l-yl formamide.
In the intramolecular cyclization reaction, compound of formula (II) is treated with
phosphorous oxychloride or phosphorous oxybromide at a temperature in the range of
about 23°C to 105°C preferably 65°C to 70°C for a period of 0.5 hour to 2 hours
preferably 45 min to 1 hour.
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According to the general process of this invention, a formamide derivatives of formula
(II) is intramoleculaR1y cyclized to 2-halo-4-aminoquinazolines compounds of formula
(I) in presence of a phosphorous oxychloride or phosphorous oxybromide.
The transformation can be carried out using equimolar quantity of phosphorous
oxychloride or phosphorous oxybromide using an inert solvent like toluene, xylene,
methylene chloride, ethylene dichloride or chloroform. The transformation also can be
performed by using excess (100 molar eqivalent) phosphorous oxychloride or
phosphorous oxybromide which itself act as a reaction solvent. Commonly used
temperatures for carrying out the cyclization reaction range from 23°C to 105°C
preferably 65°C to 70°C for a period of 0.5 hour to 2 hours preferably 45 min to 1 hour.
As will be appreciated by those skilled in the art, the reaction time and conditions needed
for the cyclization of the compounds of formula (II) vary according to several factors.
For instance, at lower temperatures, longer reaction periods are needed while at higher
temperatures the cyclization reaction is completed in a shorter time. Thus commonly used
temperatures for carrying out the cyclization reaction range from 23°C to 105°C
preferably 65°C to 70°C for a period of 0.5 hour to 2 hours preferably 45 min to 1 hour.
The mixture of 2-halo-4-aminoquinazoline and salt from thereof can be converted to the
pure quinazoline base form by conventional procedures; for instance, by treating the
mixture with a base such as 50% aqueous sodium hydroxide solution. Complete
conversion to the base form is not required when the 2-halo-4-aminoquinazoline of
formula (I) are employed as starting materials in the preparation of quinazoline
antihypertensive agents. For instance, reaction of a mixture of 2-chloro-4-amino-6,7-
dimethoxyquinazoline and hydrochloride salt thereof with tetrahydro-N-[3-
(methylamino)-propyl]-2-furancarboxamide compound, in refluxing iso amyl alcohol
provides(±)-N-[3-[(4-amino-6,7-dimethoxy-2-quinazolinyl) methylamino]propyl]
tetrahydro-2-furancarboxamide.
The starting materials viz. substituted formamide derivatives of formula (II) required, are prepared by treating appropriately substituted benzonitrile derivatives with sodium cyanate in acetic acid.
It is to be understood that by the terms "lower alkyl" and "lower alkoxy", as used herein, it is meant that the carbon chain which comprises these groups include both straight and
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branched carbon chains of 1 to 4 carbon atoms inclusive. Exemplary of these carbon chain radicals are methyl, ethyl, propyl, isopropyl, 1-butyl, 1-methylpropyl, 2-methylpropyl and t-butyl.
By the term 'independently selected ", as used herein, it is meant that R1, R2 and R3
substituents may or may not be identical.
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. The examples that follow are not intended to limit the scope of the invention as defined hereinabove or as claimed below:
Example 1:
3,4-dimethoxy-6-cyanoaniline-1 -yl formamide:
2-Amino-4,5-dimethoxy benzonitrile (100 g, 0.561 mole) is taken in glacial acetic acid (500 ml) and cooled to 10-15°C. To this solution is added a suspension of sodium cyanate (55.02 g, in 250 ml water) in portions over a 60 min period. Acetone ( 2 L) is added and the mixture is maintained at 10-15°C for an additional 30 min. The product is filtered and cake is washed with water (2x IL) followed by acetone (2x 250 ml). The product was dried at 70°C for 24 hours. (90gm, 73 %).
Mass: [M]+ = 221
'HNMR (DMSO): delta 8.4 (1H,bs), 7.6 (1H,s), 7.2 (1H,s), 6.3 (2H,bs), 3.8-3.7 (6H,d).
Example 2:
2-chloro-4-amino-6,7-dimethoxyquinazoline:
3,4-dimethoxy-6-cynoaniline-l-yl formamide (50 g, 0.326 mole) and phosphorous oxy chloride (500ml) is added in one lot at 25-30°C. Then the reaction mixture is heated to 65-70°C for about one hour. After the completion of reaction, the reaction mixture is
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cooled to 25-30°C. The reaction mixture is then poured over the cool water (5-6°C) and stirred further for one hour. The product 2-chloro-4-amino-6,7-dimethoxyquinazotines, is filtered and suck dried. To the wet cake water (5 L) is added and the pH of the suspension was adjusted to 7.5-8.0 using saturated aqueous sodium hydroxide solution. The product
is filtered and the solid obtained is washed with water (5 L) followed by acetone (500 ml). The product is dried at 60-65°C for 24 hours. (41gm, 76 %).
HPLC purity is >99%.
Melting Range: 216-21%°C
Mass: [M+2]+ = 242.2
'HNMRPMSO): delta 8 (2H,bs), 7.6 (1H,s), 7.1 (1H,s), 3.9-3.8 (6H,d).
Example 3:
(±)-N-[3-[(4-amino-6,7-dimethoxy-2-quinazolinyl)methylamino]propyl]tetrahydro-2-
furancarboxamide:
2-Chloro-4-amino-6,7-dimethoxyquinazolines (30gm, 0.125 mole) is stirred with iso amyl alcohol (300 ml) at 25-30°C. Then tetrahydro-N-[3-(methylamino)-propyl]-2-furancarboxamide (26.73gm, 0.15 mole) is added to this mixture and reaction mixture is heated to reflux at 127-128°C for 12 hours. After the completion of reaction, the reaction mixture is cooled to 25-30°C. Then the reaction mixture is further cooled to 8-10°C and reaction mixture is basified to pH 10-11 using 20% aqueous sodium hydroxide solution. Then the aqueous phase is extracted with ethyl acetate (100 ml x 3). The combined ethyl acetate layer is then washed with water (100 ml) and dried over anhydrous sodium sulphate. The solvent is then removed under the reduced pressure at 45-50°C. Then hexane (90 ml) is added to the above residue obtained and stirred at 25-30°C. The solid product obtained is filtered and dried at dried at 50-55°C for 15 hours. (40gm, 80 %). Melting Range: 182-184°C
Mass: [M+l]+ = 390.1
1NMRtCDCla): delta 8.63 (1H,s), 6.98 (1H,s), 6.82 (1H,s) 5.84 (2H,s), 4.51-4.46 (1H,dd), 4.1-3.9 (10H,m), 3.62-3.54 (1H,m), 3.4-3.33 (1H,m), 3.16 (3H,s), 3-2.86 (1H,m), 2.33-2.2 (2H,m), 2-1.17 (3H,m), 1.64-1.55 (1H,m).
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Example 4:
Preparation of anhydrous Alfuzosin hydrochloride.
Alfuzosin base (5g,.013mol) is charged to a flask and ethanol (110ml) added. The
mixture is refluxed for 15 min. and the solid dissolved. Activated charcoal is added to this solution and the suspension is stirred for l0min., filtered and washed with 5ml hot ethanol. The filtrate is cooled down to 20-25°C and the ethanol saturated by hydrogen chloride gas (1.5ml) is added. Then diethyl ether (25ml) and water (0.09ml) were slowly added to the mixture. The mixture is then stirred at room temperature for 20 hours. The mixture is then cooled down to 0-5°C and after stirring for one hour the product is filtered off and washed with 7.5ml of diethyl ether. The crystalline product is dried in a vacuum drier at 120°C for minimum 8 hours. The yield of alfuzosin hydrochloride is 4.85g (88%).
We Claim:
1. A process for the preparation of compounds of formula (I)

wherein
X is a halogen atom selected from the group consisting of chlorine or bromine; and
R1, R2 and R3 are independently selected from the group consisting of hydrogen, lower
alkyl of 1 to 4 carbon atoms inclusive or lower alkoxy chains of 1 to 4 carbon atoms
inclusive,
which comprises subjecting a compound of formula (II)

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wherein
R1, R2 and R3 are as above and Y oxygen or sulfur atom, to a' intramolecular cyclization
in presence of phosphorous oxyhalide.

which comprises subjecting a compound of formula (IV)
2. The process of claim 1, wherein the phosphorous oxyhalide is phosphorous oxychloride or phosphorous oxybromide.
3. The process of claim 1, wherein the compound of formula (H) is treated with phosphorous oxyhalide in molar equivalent or excess.
4. The process of claim 1, wherein the compound of formula (II) is treated with phosphorous oxyhalide in molar equivalent in presence of solvent or excess when itself act as a reaction solvent.
5. The process of claim 4, wherein the excess of phosphorous oxyhalide is upto 100 molar equivalent.
6. The process of claim 4, wherein the solvent used for the reaction is toluene, xylene, methylene chloride, ethylene dichloride, chloroform, phosphorous oxychloride or phosphorous oxybromide itself.
7. The process of claim 1, wherein the reaction carried out at a temperature in the range of 23°C to 105°C, preferably at 65°C to 70°C.
8. The process of the claim 1, wherein the reaction is carried out for a period 0.5hr to 2 hrs preferably 45 min to 1hr .
9. The process of claim 1, wherein the compound of formula (II) is 3,4-dimethoxy-6-cyanoaniline-l-yl formamide.
10. The process of claim 1, wherein the compound of formula (II) is 2,3,4-trimethoxy-6-cyanoaniline-1-yl formamide.
11. A process for the preparation of compound of formula (III)
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to the intramolecular cyclization using equimolar or excess quantity of phosphorous
oxychloride in presence of solvent like toluene, xylene, methylene chloride, ethylene
dichloride, chloroform, phosphorous oxychloride itself at temperatures preferably 65°C to
70°C for a period preferably 45 min to 1 hour.
12. A process for the preparation of compound of formula (V)

which comprises subjecting a compound of formula (VI)

to the intramolecular cyclization using equimolar or excess quantity of phosphorous oxychloride using a solvent toluene, xylene, methylene chloride, ethylene dichloride, chloroform, phosphorous oxychloride itself at temperatures preferably 65°C to 70°C for a period preferably 45 min to 1 hour.
13. A process for the preparation of compounds of formula (I) substantially as herein described and illustrated with reference to the accompanying examples.
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ABSTRACT:
2-Halo-4-aminoquinazolines are produced by a one-step process involving intramolecular cyclization of appropriately substituted formamide derivatives in the presence of
phosphorous oxyhalides. Exemplary of the process is the intramolecular cyclization of
3,4-dimethoxy-6-cyanoaniline-l-yl formamide in the presence of phosphorous oxychloride to 2-chloro-4-amino-6,7-dimethoxyquinazoline. These chemical compounds are utilized as intermediates in the preparation of some of the important antihypertensive agents e.g. 2-chloro-4-amino-6,7-dimethoxyquinazolines is used for the synthesis of alfuzosin hydrochloride.
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