CS195347B2 - Process for preparing antihypertensive 6,7-dimethoxy4-4-amino-2-/4-/2-furoyl/-1-piperazinyl/quinazoline - Google Patents

Abstract

6,7-dimethoxy-4-amino-2-[4-(2-furoyl)-1-piperazinyl]quinazoline of the formula I is prepared by reacting 3,4-dimethoxy-6-[4-(2-furoyl)-1-piperazinylthiocarbamido]benzonitrile with methyl iodide to give methyl N-(3,4-dimethoxy-6-cyanophenyl)-[4-(2-furoyl)-1-piperazinyl]thioformam idate and cyclising the resulting compound. The cyclisation is carried out by heating with ammonia in a polar solvent in the presence of alkali metal amide. By virtue of the new process, the yield and the purity of the end product can be increased by comparison with the previously known processes. The process can also be carried out as a one pot process. <IMAGE>

Description

The invention relates to a process for the preparation of an antihypertensively active 6,7-dimethoxy-4-amino-2. - [4- (2-fluoroyl) -1-piperazinyl] quinazoline of formula I.

(and)

This compound, known as prazosin, has potent antihypertensive activity (Cohen, Journal of Clinical Pharmacology, 10 (1970)).

U.S. Pat. No. 3,511,836 discloses several methods for producing 6,7-dimethoxy-4-amino-2 - [(4-substituted) -1-piperazinyl] quinazoline. The reaction of 6,7-dimethoxy-4-amino-2-chloroquinazoline with (2-furoyl) -1-piperazine according to the following scheme is considered to be the prototype of these methods for the preparation of prazosin:

NH ₂

Dutch Patent No. 7,206,067 describes, among other methods, a process for the preparation of prazosin; according to this method, 3,4-dimethoxy-6-aminobenzonitrile is reacted with 1-cyano-4- (2-uroyl) piperazine according to the following reaction scheme:

In German Patent Specification No. 2,457,911, this method is shown in the following repopulated another method of producing prazosin; tactics scheme

⁺ A - ^^ - OCqj ⁰ ^ ^ ^O5 P ^{r, n} in which Q is -CH _or-NH2, and A represents -CN,

nabo

in which R represents an alkyl group having 1 to 6 carbon atoms; however, -11 Q represents a -CN group, A represents a group

.NH or

SUMMARY OF THE INVENTION The present invention provides a new and more economical process for the preparation of prazosin of formula (i), which differs from the previously described processes in that the quinazoline ring of the end product is formed intramolecularly and not similarly to known methods.

According to the invention, 6,7-dimethoxy-4-amino-2- [4- (2-fluoroyl) -1-piperazinyl] quinazoline (prazosine) of formula (I) may be prepared by the production of 3,4-dimethoxy-6- (4- (2-furoyl) -1-piperazinylthiocarbamido) benzonitrile of formula II

(//)

reacts with methyl iodide at a temperature of up to 100 ^and C in a polar solvent, and the resulting methyl N- (3,4-dimethoxy-6-cyanophenyl) - (4- (2-fluoroyl) -1-piperazinyl) - thlof ormi give the formula III

SCH ₃

III is cyclized by heating with ammonia to a temperature of 100 to 150 ° C, in a polar solvent and in the presence of an alkali metal amide.

The reaction of the compound of formula II with methyl iodide is preferably carried out in the form of formamide, Ν, Ν-dimethylformamide or bis-methoxyethyl ether (diglyme), or in mixtures of the solvents mentioned.

The cyclization is preferably carried out in formamide or N, N-dimethylformamide in the presence of 1 to 3 equivalents of an alkali metal amide.

According to a preferred embodiment of the invention, the reaction of compound II with methyl iodide and cyclization of the resulting compound of formula III is carried out continuously in one and the same solvent without isolation of the intermediate.

The starting 3,4-dimethoxy-6- [4- (2-furoyl) -1-piperazinylthiocarbamido] benzonitrile of formula II is a novel compound which can be easily produced using 3,4-dimethoxy-6-aminobenzonitrile and 1- (2- furoyl) plperazine starting materials, by the methods depicted in the following reaction schemes.

* νιι | *in/

CH ₃ O ^, NH - 1 - -θ-ίΤηΤ)

ΙΟΙ S ^O (II)

In the process of the first alternative,

The 3,4-dimethoxy-6-aminobenzonitrile of formula IV is reacted with thiophosgene and the resulting

3,4-Dimethoxy-6-isothiocyanatobenzonitrile of formula V is reacted with 1- (2-furoyl) piperazine of formula VI to give 3,4-dimethoxy-6- (4- (2-furoyl) -1-piperazinylthiocarbamide) benzonitrile of formula II. can be prepared by reacting 1- (2-furoyl) piperazine VI with thiophosgene and reacting the resulting thiocarbonyl chloride VII with 3,4-dimethoxy-6-aminobenzonitrile IV.

The process according to the invention can also be carried out by preparing prazosin of formula I using 3,4-dimethoxy-6- [4- (2-furoyl) -1-piperazinylthiocarbamido] benzonitrile II as the starting material, or using 3, 3 4-dimethoxy-6-isothiocyanatobenzonitrile of formula V as a starting material, in a continuous manner, in one reaction vessel and in one solvent, such as in formamide, without isolation of the intermediates.

The process of the invention has certain advantages over U.S. Pat. No. 3,511,836. First, prazosin yields are considerably higher, since the intramolecular cyclization of the compound of formula III occurs very readily with ammonia, eliminating the methylmercapto group such as methylmercaptan. Second, the formation of several hardly removable impurities is lower, which facilitates the purification of the final product. The process according to the invention is very simple and the reaction can be carried out in one batch. The preparation of prazosin according to the invention is more economical.

The process according to the invention is explained in more detail in the following examples.

Examples

Example 1

(a) 3,4-Dimethoxy-6-isothiocyanatobenzonitrile (V)

A solution of 27.0 g (0.15 mol) of 3,4-dimethoxy-6-aminobenzonitrile (IV) in 150 ml of 1,2-dichloroethane is gradually added, at 0-5 ° C, to a mixture of 23.0 g (0.2 mol) of thiophosgene, 100 ml of 1,2-dichloroethane, 20.0 g (0.2 mol) of calcium carbonate and 200 ml of water, and the suspension is stirred for 1 hour at 0-5 ° C, then for 16 hours at 20 ° C and then at -35 ° C for 1 hour. The reaction mixture was filtered, the dichloroethane layer was separated, washed with dilute hydrochloric acid and water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the crystalline residue (m.p. 126-127 ° C) was used as such in the next step. 31.0 g (94% of theory) of 3,4-dimethoxy-6-isothiocyanatobenzonitrile are obtained.

For C10H8N2O2S Calcd: 54.53 _0/0 C, 3.66% H, 12.72% N,

14.56% S;

found: 53.43% C, 3.78% H> 12.18 1% N, 13.79% S.

(b) 3,4-Dimethoxy-6- [4- (2-furoyl) -1-piperazinylthlokarbamido] benzonitrile (II)

A solution of 11.2 g (0.051 mol) of 3,4-6-dimetho'xy išothiokyanatobenzonitrilu (V) in 65 ml of ethyl acetate was gradually added under stirring and cooling to 0 ^Q C к solution of 9.2 g (0.051 mol) of 1- (2-furoyl) piperazine in 65 mL of ethyl acetate. The solution was allowed to stand overnight at -25 ° C, the crystallized product was filtered off, washed with cold ethyl acetate and extracted with

dries. Give 16.3 g (yield 80- 1 ^1¼ theory)

3,4-dimethoxy-6- [4- (2-fluoroyl) -1-piperazinylthiocarbamide] benzonitrile, m.p. 178 DEG-180 DEG.

H, 5.03; N, 13.99. S, 8.01-%. .

Found:% C, 57.41;% H, 5.39;% N, 14.14;% S% 7.68.

Example 2.

3,4-Dimethoxy-6- (4- (2-fluoro) -1-piperazinylthiocarbamido] benzonitrile (II)

5.0 g (0.028 mol) of 1- (2-furoyl) piperazine (VI) and 2.83 g (0.028 mol) of triethylamine are dissolved in 60 ml of dichloromethane and the solution is added, with stirring and cooling, to about 0 ° C, to a mixture of 3.86 g (0.0336 mol) of thiophosgene with 50 ml of dichloromethane. The reaction mixture is stirred at 0 ° C for 2 hours and at room temperature for 3 hours, the precipitated triethylamine hydrochloride is filtered off and the solvent is distilled off under reduced pressure. The residue, 4- (2-furoyl) piperazinylthiocarbonyl chloride (VII) is dissolved in 50 ml of dichloromethane and the solution is added, with stirring and cooling to 0 ° C, to a solution of 4.98 g (0.028 mol) of 3,4-dimethoxy-6- of amlnobenzoniiril (IV) and 2.83 g (0.028 mol) of triethylamine in 60 ml of dichloromethane The reaction mixture is stirred at - 0 ° C for 2 hours and then at room temperature for 2-3 hours, the precipitated triethylamine hydrochloride is filtered off, washed water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure, ethyl acetate was added to the residue, the solution was cooled to -25 ° C and the precipitated product was filtered off to give 6.2 g (yield 55% of theory). dimethoxy-6- [4- (2-furoyl) -1-piperazinylthiocarbamido] benzonitrile, mp 175-178 ° C.

Example 3

(a) 'Methyl N- (3,4-dimethoxy-6-cyanophenyl) - [4- (2-furanyl) -1-piperazinyl] thioformidate (III. HJ)'

To a solution of 20.0 g (0.05 mol) 3,4-dimsthoxy-6- [4- (2-fluoroyl) -1-piperazinylthiocarbamido] benzonitrile in 200 mL of bismethoxyethyl ether (diglyme) is added 14.2 g (0, 1 mol) of methyl iodide and the mixture is heated. 9 hours at 60 ° C. The solution is cooled to room temperature, the precipitated crystalline reaction product is filtered off, washed with ether and dried. 24.6 g (yield 90 -% of theory) of methyl N- (3,4-dimethoxy-6-cyanophenyl) - (4- (2-fluoroyl) -1-piperazinyl) thioformamidate hydroiodide, m.p. 163 ° C, are obtained. .

For C20H23N4O4S calculated: C, 44.29; H, 4.27; J, 23.39; N, 10.33; S, 5.91;

Found: C, 44.25; H, 4.26; H, 22.93. N, 9.61; S, 5.58%.

b] Methyl N- (3,4-dimethoxy-6-cyanophenyl- [4- (2-fluoroyl) -1-piperazinyl] thioformamide (III)

To a solution of 62.0 g (0.114 mol) of methyl N- (3,4-dimethoxy-6-cyanophenyl) - [4- (2-uroyl) -1-piperazinyl) thiophamidamide hydroiodide in ~ 350 ml of methanol was stirred, at 0-5 ° C, 186 ml of 25% aqueous ammonia are added. The mixture was stirred at 0 ° C for 2 hours, then the precipitate was filtered and washed with ether. 42.7 g (yield 90% of theory) of methyl N- (3,4-dimethoxx-6-cynophenyl) -

- [4- (2-fluoroyl) -1-piperazinyl) thioformamidate, mp 105-107 ° C.

For C20H22N4O4S: C, 57.95; H, 5.36; N, 13.52; S, 7.73%.

found: 58.01 o / o c, 5.54% H, 13.73% N,

7,53% S.

c) 6,7-Dimethoxy-4-amino-2- (4- (2-furoyl) -1-piperazinyl-quinolizole) (I)

To a solution of 7.0 g (0.017 mol) of methyl N-

- (3,4-Dimethoxy-6-cyano-phenyl) - [4- (2-fluoroyl) -1-piperazinyl] -thioformamide - 2.0 g (0.051 mol) of sodium amide are added in 100 ml of formamide. The solution is saturated - at 0 ° C with ammonia gas, then the temperature of the mixture is slowly raised to 120 ° C and maintained at this temperature for 2424 hours while introducing the full ammonia. After cooling, the reaction mixture is poured into 100 ml of ice-water and the solution is shaken 6-7 times with 50 ml of chloroform each. The chloroform extracts were combined, washed with water (4.times.50 ml), dried and the solvent was distilled off under reduced pressure. The residue was recrystallized from ethanol-water (50: 15); 6,7-dimethoxy-4-amino-2- [4- (2-fluoro) -1-piperazinyl] chioazoline, m.p. = 262-264 ° C. The infrared spectrum and the nuclear-magnetic resonance spectrum of the product obtained are identical to those of the compounds prepared as described in the literature.

For C19H21N5O4: C, 59.52; H, 5.52; N, 18.27; Found: C 59.28, H 5.88, N 17.99. Example 4

6,7-Dimethoxy-4-amino-2- [4- (2-furoyl) -1-piperazinyl] chlorazoline (I)

To a suspension of 9.7 g (0.044 mol) of 3,4-dimethoxy-6-isothiocyanatobenzonitrile (V) in 100 ml of formamide, a solution of 7.9 g (0.044 mol) of 1- [2] is added successively with stirring at room temperature. (furoyl) piperazine (VI) in 65 ml of formamide. The mixture was stirred at room temperature until all 3,4-dimethoxy-6-isothiocyanatobenzonitrile was dissolved (3-4 hours). 12.5 g (0.088 mol) of methyl iodide are added to the reaction mixture and the mixture is heated at 60 ° C for 9 hours. Excess methyl iodide was distilled off, the solution was saturated at 0 ° C with ammonia gas, and then 6.9 g (0.176 mol) of sodium amide was added. The temperature of the solution was raised to 120-140 ° C and maintained at that temperature for 24 hours while introducing ammonia gas. After cooling, the reaction mixture was poured into ice water (about 150 mL) and the product was shaken into chloroform (8X 50 mL).

The combined chiloprotectants are washed with water, decolourised with charcoal, dried and the solvent distilled off under reduced pressure. The residue is recrystallized from ethanol / water (50: 15) to give 6,7-dimethoxy-4-amino-2- [4- (2-fluoroyl) -1-piperazinyl] quinazoline, m.p. 263-265 ° C.

Claims (4)

A process for the preparation of an antihypertensively active 6,7-dimethoxy-4-amino-2- [4- (2-furoyl) -1-piperazinyl] quinoline of the formula I, characterized in that 3,4-dimethoxy-6- ( The 4- (2-fluoroyl) -1-piperazinylthiocarbamido] benzone III of formula II is reacted with methyl iodide at 50-100 ° C in a polar solvent to form the methyl N- (3,4-dimethoxy-6-cyanophenyl) 1- (4- (2-fluoroyl) -1-piperazinyl) thioformamide III (III) is cyclized by heating with ammonia at 100-150 ° C in a polar solvent and in the presence of an alkali metal amide. 2. A process according to claim 1 wherein the reaction of the compound of formula II with methyl iodide is carried out in the formamide, Ν, Ν-dimethylformamide or bismethoxyethyl ether, or mixtures of said solvents. 3. The process of claim 1 or 2, wherein the cyclization is carried out in formamide or Ν, Ν-dimethylformamide in the presence of 1 to 3 equivalents of an alkali metal amide. 4. A process according to any one of claims 1 to 3, wherein the reaction of the compound of formula II with methyl iodide and the cyclization of the resulting compound of formula III are carried out continuously in one and the same solvent without isolation of the intermediate.