WO2008084493A2

WO2008084493A2 - A novel process for the preparation of 2-halo-4-aminoquinazolines

Info

Publication number: WO2008084493A2
Application number: PCT/IN2007/000330
Authority: WO
Inventors: Ajit Madhukar Bhobe; Subhash Vishwanath Damle; Rushi Drupadbhai Adhvaryu
Original assignee: Unichem Laboratories Limited
Priority date: 2007-01-09
Filing date: 2007-08-06
Publication date: 2008-07-17
Also published as: WO2008084493A3

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-1-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.

Description

A NOVEL PROCESS FOR THE PREPARATION OF 2-HALO-4-AMINOOUINAZOLINES

TECHNICAL FIELD

The present invention relates to a novel process for the production of 2-halo-4- aminoquinazolines of formula I as shown below. In particular the invention relates to a process for the production of 2-halo-4-aminoquinazolines starting from substituted formamide derivatives, in high yield and purity.

wherein X is a halogen atom selected from the group consisting of chlorine or bromine; Rl, R2 and R3 are independently selected from the group consisting of hydrogen, lower alkyl inclusive or lower alkoxy.

BACKGROUND OF THE INVENTION

2-Halo-4-aminoquinazoline compounds are of importance due to their utility as intermediates in the preparation of antihypertensive agents e.g. Alfuzosin hydrochloride, Prazosin, Bunazosin, Doxazosin or Trimazosin.

US3511836 (Hess, 1970) discloses a multistep process for the preparation of 2-chloro-4- aminoquinazoline starting from anthranilic acid. These compounds are then further derivatized into 2,4-diaminoquinazolines, which has good therapeutic value.

US3669968 (Hess, 1972) describes a process for preparing 2-halo-4-amino-6,7,8-trialkoxy quinazoline, having utility as antihypertensive agents, comprising 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-dimethoxyquinazoline as a starting material in the preparation of the α-antagonist and antihypertensive compound viz. alfuzosin hydrochloride.

US4001237 and 4001238 (Partyka et al, 1977; employ 2-chloro-4-amino-6,7- dimethoxyquinazoline as starting material in the preparation of a series of 6,7-dimethoxy-4- amino-2-(piprazinyl)quinazolines, potent antihypertensive agents.

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 thus resulting in lower yields

US4098788 (Crenshaw et al, 1978J discloses preparation of 2-halo-4-aminoquinazolines by a two-step process involving cyclization of substituted- 1 -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. In this process, hydrolysis is carried out using strong hydrolyzing agents such as formic acid, which is highly corrosive and eye/respiratory tract irritant.

Thus there is a need for a process for the preparation of 2-halo-4-aminoquinazolines, which is simple and high yielding and which also eliminates the need of hazardous phosphorus halides or any strong hydrolyzing agents such as formic acid.

The applicants have surprisingly found that the 2-halo-4-aminoquinazoline compounds can be prepared by a single step process resulting in higher yields. It is particularly found that the single step process can be achieved by cyclizing substituted formamide derivatives in presence of phosphorus oxyhalide, which process involves technical advance compared to the existing prior art and also being cheaper and of economic advantage and also more environmentally friendly because it avoids the use of hazardous phosphorus halide and/or formic acid.

SUMMARY OF THE INVENTION According to the present invention there is provided a process for preparation of 2-halo-4- aminoquinazolines of formula (I):

(D

wherein X is a halogen atom selected from the group consisting of chlorine or bromine;

Rl, 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)

(II) wherein

Rl, R2 and R3 are as above, and Y is oxygen or sulfur atom, to an intramolecular cyclization in presence of a phosphorous oxyhalides.

According the present invention there is provided a process for the preparation of compound of formula (III) being a derivative of the compound of formula I

which comprises subjecting a compound of formula (IV)

(IV)

to the intramolecular cyclization using equimolar or excess quantity of phosphorous oxychloride optionally in presence of solvent..

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

(V)

which comprises subjecting a compound of formula (VI)

OMe Me^OγA^^N~γ^NH ₂ to the intramolecular cyclization using equimolar or excess quantity of phosphorous oxychloride optionally in presence of a solvent.

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):

(I) wherein,

X is a halogen atom selected from the group consisting of chlorine or bromine; and Rl, 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)

(H) wherein

Rl, R2 and R3 are as above and Y is oxygen or sulfur atom, to an 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 Rl, 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 23⁰C to 105⁰C preferably 65⁰C to 7O⁰C for a period of 0.5 hour to 2 hours preferably 45 min to 1 hour.

According to the general process of this invention, a formamide derivatives of formula (II) is intramoleculaily 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 equivalent) phosphorous oxychloride or phosphorous oxybromide which itself act as a reaction solvent. Commonly used temperatures for carrying out the cyclization reaction range from 23⁰C to 105⁰C preferably 65⁰C to 7O⁰C 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 23⁰C to 105⁰C preferably 65⁰C to 7O⁰C 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. This free base is further converted to Alfuzosin Hydrochloride anhydrous form by following the process disclosed in "ACTA Universitatis Palackianae Olomucensis Facultas Rerum Naturalium 2005, CHEMICA 44". 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 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 Rl, 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-l-yl formamide:

2-Amino-4,5-dimethoxy benzonitrile (100 g, 0.561 mole) is taken in glacial acetic acid (500 ml) and cooled to 10-15⁰C. 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 10-15⁰C 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 70⁰C for 24 hours. (90gm, 73 %). Mass: [MH]⁺ = 222

¹H NMR (DMSO): delta 8.4 (lH,bs), 7.6 (lH,s), 7.2 (lH,s), 6.3 (2H,bs), 3.8-3.7 (6H,d).

Example 2:

2-chloro-4-amino-6₅7-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 25-3O⁰C. Then the reaction mixture is heated to 65- 7O⁰C for about one hour. After the completion of reaction, the reaction mixture is cooled to 25-3O⁰C. The reaction mixture is then poured over the cool water (5-6⁰C) and stirred further for one hour. The product 2-chloro-4-amino-6,7-dimethoxyquinazolines, 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 60-65⁰C fox 24 hours. (41 gm, 76 %). HPLC purity is >99%. Melting Range: 276-278⁰C

Mass: [M+2]⁺ = 242.2

¹H NMR (DMSO): delta 8 (2H,bs), 7.6 (lH,s), 7.1 (lH,s), 3.9-3.8 (6H,d). Example 3:

(±)-N-[3-[(4-amino-6,7-dimethoxy-2-quinazolinyl)methylamino]propyl]tetrah.ydro-2- furancarboxamide: 2-Chloro-4-amino-6,7-dimethoxyquinazoline (30gm, 0.125 mole) is stirred with iso amyl alcohol (300 ml) at 25-3O⁰C. 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 127-128⁰C for 12 hours. After the completion of reaction, the reaction mixture is cooled to 25-3O⁰C. Then the reaction mixture is further cooled to 8-1O⁰C 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 45-5O⁰C. Then hexane (90 ml) is added to the above residue obtained and stirred at 25-3O⁰C. The solid product obtained is filtered and dried at dried at 50-55⁰C for 15 hours. (40gm, 80 %). Melting Range: 182-184⁰C Mass: [M+l]⁺ = 390.8

¹HNMR (CDCl₃): delta 8.63 (lH,s), 6.98 (lH,s), 6.82 (lH,s) 5.84 (2H,s), 4.51-4.46 (lH,dd), 4.1-3.9 (10H,m), 3.62-3.54 (lH,mH 3.4-3.33 (lH,m), 3.16 (3H,s), 3-2.86 (lH,m), 2.33-2.2 (2H,m), 2-1.17 (3H,m), 1.64-1.55 (lH,m).

Example 4:

Preparation of anhydrous Alfuzosin hydrochloride: Alfuzosin base (5g, 0.013mol) 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 lOmin., filtered and washed with 5ml hot ethanol. The filtrate is cooled down to 20-25⁰C 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 0-5⁰C 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 12O⁰C for minimum 8 hours. The yield of alfuzosin hydrochloride is 4.85g (88%).

Claims

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 Rl, 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 cpmpound of formula (II)

(H) wherein

Rl, R2 and R3 are as above and Y oxygen or sulfur atom, to an intramolecular cyclization in presence of phosphorous oxyhalide.

2. The process of claim 1, wherein the phosphorous oxyhalide is phosphorous oxychloride or phosphorous oxybrόmide.

3. The process of claim 1, wherein the compound of formula (II) 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.

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.

7. The process of claim 1 , wherein the reaction is carried out at a temperature in the range of 23⁰C to 105⁰C, preferably at 65⁰C to 7O⁰C.

8. The process of the claim 1, wherein the reaction is carried out for a period 0.5 hr to 2 hrs preferably 45 min to 1 hr.

9. The process of claim 1, wherein the compound of formula (II) is 3,4-dimethoxy-6- cyanoaniline-1-yl formamide.

10. The process of claim 1, wherein the compound of formula (II) is 2,3₅4-trimethoxy-6- cyanoaniline-1-yl formamide.

11. A process for the preparation of compound of formula (III)

(III) which comprises subjecting a compound of formula (IV)

σv) to the intramolecular cyclization using equimolar or excess quantity of phosphorous oxychloride optionally in presence of solvent..

12. A process for the preparation of compound of formula (V)

(V) which comprises subjecting a compound of formula (VT)

to the intramolecular cyclization using equimolar or excess quantity of phosphorous oxychloride optionally in presence of a solvent.