CS197312B2 - Method of producing 3,4-dimethoxy-6-/4-/2-furoyl/-1-piperazinyl-thiocarbamido/benzonitrile - Google Patents

Abstract

3,4-Dimethoxy-6-[4-(2-furoyl)-1-piperazinylthiocarbamido]-benzonitr ile of the formula II is prepared by reacting 3,4-dimethoxy-6-isothiocyanatobenzonitrile with thiophosgene to give 3,4-dimethoxy-6-isothiocyanatobenzonitrile and reacting the compound which has been obtained with 1-(2-furoyl)piperazine. Alternatively, 1-(2-furoyl)piperazine can be reacted with thiophosgene to give 4-(2-furoyl)piperazinylthiocarbonyl chloride and the compound which has been obtained can be reacted with 3,4-dimethoxy-6-aminobenzonitrile. 3,4-Dimethoxy-6-[4-(2-furoyl)-1-piperazinylthiocarbamido]benzo-nitr ile can be used as an intermediate for the preparation of 6,7-dimethoxy-4-amino-2-[4-(2-furoyl)-1-piperazinyl]quinazoline (Prazosin), which possesses antihypertensive activity. <IMAGE>

Description

The present invention relates to a process for the preparation of 3,4-dimethoxy-6- [4- (2-fluoroyl) -1-piperazinylthiocarbamido] benzonitrile of formula II below, which is an intermediate for the preparation of 6,7-dimethoxa-4-nmino-2. - [4- (2-furoyl) -1-piperazinyl] quinazoline (prazosine) of formula I,

which is known to be a potent antihypertensive agent [Cohen, Journal of Clinical Pharmacology, 10 (1970)].

Prazosin and compounds of this group can be prepared by several well-known methods as described in U.S. Patent 3,511,836, Dutch Patent 7,206,067, and Germany Patent 2,457,911. the quinazoline ring is formed by reaction between two different molecules.

The present invention provides a process for the preparation of 3,4-dimethoxh-6- [4- (2-furoyl) -4-methoxy-thiocarbamido] benzonitrile of formula II, which is a novel intermediate for. prazosin production, characterized in that:. The method according to claim 1, wherein the quinazoline ring of said end product is formed intramalecularly. Said method is different from the previously described methods.

New. intermediate of formula II, 3,4-dimethoxh-6- (4- (2-furoyl) -1-piperazinylthiocarbba-;

mi6o] -bdzoniiril, can be converted to prazosin of formula (I) by reacting with methylliodide, and the resulting methyl-N- (6-dimethoxh-6-cyanophenyl) - [4- (2-uroyl) -1-piperidinyl-iodoformamidate of formula III

is cyclized by heating with ammonia in a polar solvent and in the presence of an alkali metal amide.

Using the compound of formula II as a starting material, prazosin can also be prepared in a continuous manner, in the same solvent and without isolation of other intermediates, which greatly simplifies production.

According to the invention, 3,4-dimethoxy-6- [4- (2-uroyl) -1-piperazinylthiocarbamido] benzonitrile of formula II is produced by reacting 3,4-dimethoxy-6-aminobenzonitrile of formula IV,

CW ₃ O

CW ₃ O

thiophosgene and 1- (2-furoyl) piperazine of formula VI,

The process of the invention may be carried out. day in two alternative ways. In a first alternative, 3,4-dimethoxy-6-aminobenzonitrile is reacted with phosgene in an inert solvent such as 1,2-dichloroethane at 0 to 20 ° C in the presence of calcium carbonate to form the 3,4-dimethoxy-6. isothiocyanatobenzonitrile of formula V

The IV is reacted with 1- (2-furoyl) piperazine in an inert solvent such as ethyl acetate at a temperature of 0 to 20 ° C.

In a second alternative, thiophosgene and 1- (2-furoyl) piperazine in an inert solvent such as dichloroethane are reacted at 0 to 20 ° C in the presence of a tertiary amine such as triethylamine and the resulting 4- (2-furoyl 1-piperazinylthiocarbonyl chloride) of formula VII

benzonitrile in the same solvent at 0 to 20 ° C in the presence of a tertiary amine.

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

Example 1

and)

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 moles) 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 was stirred for 1 hour at 0 to 5 ^Q C, then 16 hours at 20 ° C and then 1 hour at 35 ° C. The reaction mixture was filtered, 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 (mp 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 calculated:

% C, 54.53;% H, 3.66;% N, 12.72;

S 53.43, H 3.78, N 12.18, S 13.79.

(b)

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

A solution of 11.2 g (0.051 mol) of 3,4-dimethoxy-6-isothiocyanobenzonitrile (V) in 65 ml of ethyl acetate is gradually added, with stirring and cooling to 0 ° C, to a solution of 9.2 g (0.051 mol) of 1- (2-furoyl) piperazine in 65 mL ethyl acetate; The solution was allowed to stand overnight at -25 ° C, the crystallized product was filtered off, washed with cold ethyl acetate and dried. 16.3 g (80% of theory) of 3,4-dimethoxy-6- [4- (2-fluoroyl) -1-piperazinylthiocarbamido] benzonitrile, m.p. 178 DEG-180 DEG C., are obtained.

Calcd for C19H20N4O4S:

% C, 56.99;% H, 5.03;% N, 13.99.

8.01% s, was reacted with 3,4-dimethoxy-6-amino197312

В naiezepo: '

% C, 57.41;% H, 5.39;% N, 14.14;

Example 2

3,4-Dimethoxy-6- [4- (2-fluoroyl-1-piperazinyl-liocarbamido) -benzonitrile (II)

Dissolve 5.0 g (0.028 mol) of 1- (1-uroyl) piperazine (VI) and 2.83 g (0.028 mol) of triethylamine in 60 ml. of dichloromethane and the solution was added, with stirring and cooling to about 0 ° C, to a mixture of 3.86 g (0.0336 mol) of iophiophosgene 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 iriehylamine hydrochloride is filtered off and the solvent is distilled off from the filtrate. The residue, 4- (2-furoyl) piperazinylthiocarbonyl chloride (VII), was dissolved in 50 ml of dichloromethane and the solution was added, with stirring and cooling to 0 ° C, to the solution. 4.98 g (0.02 &lt; mol &gt;) of 3,4-dimethoxy-6-aminobenzonitrile.

(IV) and 2.83 g (0.028 mol) of triethylamine in 60 ml of dichloromethane. The reaction mixture was stirred. 2 hours at 0 ° C and then 2 to 3 hours at room temperature, the precipitated triethylamine hydrochloride was added. filtered, the solution was washed with water, dried over anhydrous magnesium sulfate. and the solvent is distilled off under reduced pressure. Ethyl acetate was added to the residue, the solution was cooled to -25 ° C and the precipitated product was collected. is filtered off. 6.2 g (yield 55% of theory) of 3,4-dimethoxy-6- [4- (2-fluoroyl) -1-piperazinylthiocarbamido) benzonitrile of m.p. 175 DEG -179 DEG C. are obtained. .

Prazosin. can be from. compounds of formula II to produce. as follows. ,

Example. 3

and)

I-Iydrojodide. Methyl N- (3,4-dimethoxy-6-] thiophenyl) - (4- (2-fluoroyl) -1-piperazinyl] iioformamidate (III. HJ)

To a solution of 20.0 g (0.05 mol). 3,4-dimethoxy-6- [4- (2-fluoroyl) -1-piperazinylthiocar-bainidobenzonitrile in 200 ml of bismethoxyethyl ether (dlglyme) is added 14.2 g (0.1 mol) of methyl iodide and the mixture is heated for 9 hours at room temperature. 60 ° C. The solution is cooled to. 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, mp 163 ° C, are obtained. .

Calcd for C20H23IN4O4S:

44.29% C, 4.27% H, 23.39% I,

N, 10.33. S, 5.91. Found:.

44.25%. C, 4.26; H, 22.93;

9.61% N, 5.58% S.

(b)

Methyl N- (3,4-cilmethoxy-6-cyanophenyl- (4- (2-fluoroyl) 1-piperazinyl) ihioformamidate (III)

To a solution of methyl N- (3,4-dimethoxy-6-cyanophenyl) - [4- (2-fluoroyl) -1-piperazinyl] -isoformoformamide hydroiodide (62.0 g, 0.114 mol) in 350 mL. of methanol is added with stirring at 0 to 5 ° C. 186 ml of 25% aqueous ammonia. The mixture was stirred at 0 ° C for 2 hours, then the precipitate was filtered off and washed with ether. It is obtained. 42.7 g (yield 90% of theory) of methyl N- (3,4-dimethoxy-6-quinophenyl) - (4- (2-furcyl) -1-plperazinyl) thioformainidate o 1.1 105-107 ° C.

For C 20 H 22 N 4 O 4 S.

calculated:

C 57.96, H 5.36, 13.52%. N, 7.73% S, found:

58.01% C, 5.54%. H, 13.73; N, 7.53.

c).

6, - Dimothoxa-4-amino-2- [4- (2-fluoroyl) -1-piperazinyl] quinazoline (I)>

To a solution of 7.0 g (0.017 mol). methyl N- (3,4-dimethoxy-6-cyanophenyl) - (4- (2-fluoroyl) -1-piperazinyl) ioformoformamidate in 100 ml of formamide was added 2.0 g (0.051 mol) of sodium amide. saturated at 0 ^Q C with ammonia gas, then the temperature of the mixture. progressively increased to 120 ° C. and ieio temperature. maintained for 24 hrs. for placing the gas. ammonia. after cooling, the reaction mixture was poured into 100 ml of ice water and The mixture was extracted with chloroform (50 ml) and the combined chloroform extracts were washed with water (4.times.50 ml), dried and the solvent was distilled off under reduced pressure, and the residue was recrystallized from ethanol / water (50:15). There was obtained 6, 6-dimethoxymiamino-2- [4- (2-fluoroyl) -1-piperazinyl] -chlorosoline, mp 262-264 [deg.] C. The infrared and nuclear magnetic resonance spectra of the product obtained were identical with analogous spectra. compounds prepared as described in the literature.

For C19H21N5O4 calculated:

59.52%. C, 5.52%. H, 18.27% N, found:

59.28% С, 5.88% Η, 17.99% Ν.

К к 1 and d 4

6,7-Dimethoxy-4-amino-2- [4- (2-fluoroyl) -1-piperazinyl] quinazoline (I)

17.6 (0.044 mol) 3,4-dimethoxy-6- [4- (2-furoyl) -1-piperazinylthiocarbamido] benzonitrile is dissolved in 100 ml of formamide, 12.5 g (0.088 mol) of methyl iodide are added to the solution, and The mixture was heated at 60 DEG C. for 9 hours, excess methyl iodide was distilled off, the solution was saturated at 0 DEG C. with ammonia gas, and 6.9 g (0.176 mol) of sodium amide was added to the mixture. The solution was poured into ice water (150 ml) and the product was extracted into chloroform (8X50 ml) .The combined chloroform extracts were washed with water, decolourised with charcoal. The residue was recrystallized from ethanol / water (50:15) to give 6,7-dimethoxy-4-amino-2- [4- (2-furoyl) -1-piperazinyl] chlorazoline. mp 263-265 ° C.

Claims (2)

A process for the preparation of 3,4-dimethoxy-6- (4- (2-furoyl) -1-piperazinylthiocarbamido] benzonitrile of formula II, 0 to 20 ° C in the presence of calcium carbonate and the resulting 3,4-dimethoxy-6-isothiocyanate tobenzonitrile of formula V ³ (II) which is an intermediate for the production of prazosin, characterized in that 3,4-dimethoxy-6- The aminobenzonitrile of formula IV, thiophosgene and 1- (2-furoyl) piperazine of formula VI The ^{CH 3} ° ^{NCS 3} (V) is reacted with 1- (2-furoyl) piperazine of formula VI in an inert solvent such as ethyl acetate at 0 to 20 ° C. 3. The process of claim 1, wherein thiophosgene and 1- (2-furoyl) piperazine of formula VI are reacted in an inert solvent such as dichloroethane at 0 to 20 ° C in the presence of a tertiary amine such as triethylamine, and the resulting 4- (2-furoyl) piperazinylthiocarbonyl chloride of formula VII 2. A process according to claim 1, wherein 3,4-dimethoxy-6-aminobenzonitrile is reacted with phosgene in an inert solvent such as 1,2-dichloroethane and reacted with 3,4-dimethoxy at a temperature. -6-aminobenzonitrile of formula IV in the same solvent at 0 to 20 ° C in the presence of a tertiary amine.