CH630625A5 - Process for the preparation of antihypertensive 6,7-dimethoxy-4-amino-2-[4-(2-furoyl)-1-piperazinyl]quinazoline - Google Patents

Description

The present invention relates to a process for the preparation of 6,7-dimeth-oxy-4-amino-2- [4-furoyl) -l-piperazinyl] quinazoline, which has a hypotensive effect. This compound, which is known under the name prazosin, is known to have an extremely strong hypotensive effect [Cohen, Journal of Clinical Pharmacology, 10 (1970)]. This compound has the formula I.

—Oc

(I)

US Pat. No. 3,511,836 describes several processes for the preparation of 6,7-dimethoxy-4-amino-2 - [(4-substituted) -l-piperazinyl] quinazolines. One of these prazosin-35 production processes consists in reacting 6,7-dimeth-oxy-4-amino-2-chloro-quinazoline and (2-furoyl) -l-piperazine according to the following reaction scheme:

/ "X

HN N - OC

-O

-) Prazosin I

In NL-PS 7 206 067 a further process is described, inter alia for the production of prazosin, in which 3,4-dimethoxy-6-aminobenzonitrile with l-cyano-4- (2-furoyl) -50-piperazine according to the following reaction scheme is implemented:

CH,

CH3O

CH.

CH3O

NH,

CN

r \

+ NC-N N

v_y

-) Prazosin I

DE-OS 2 457 911 sets out a third process at 6 ° for the production of prazosin, the following. The reaction scheme is based:

NH,

Q

/

+ A — N

\

N

v_ /

-) Prazosin I

3rd

630625

NH NH

where Q = CN or and A = CN,

NH,

NH,

NH NH

or

OR SR

where: R = alkyl of 1 to 6 carbon atoms, however

NH NH

such that when Q is CN, A is C ^ or ^.

OR SR

With the present invention, a new prazosin production process is to be created which differs from the already known processes in that the formation of the quinazoline ring within the molecule forms the final compound, and not, as in the previously known processes, by mutual reaction of two separate ones Molecules. The process according to the invention for the production of prazosin, i.e. of 6,7-dimethoxy-4 - amino-2- [4- (2-furoyl) -l-piperazinyl] quinazoline, is characterized in that 3,4-dimethoxy-6- [4- (2-furoyl) -l-piper-anzinylthiocarbamido] benzonitrile of the formula II

(ii)

with methyl iodide to form methyl N- (3,4-dimeth-oxy-6-cyanophenyl) - [4- (2-furoyl) - 1-piperazinyl] thioform-lo amidate of the formula III

oc

(iii)

is reacted, and this compound is cyclized by heating with ammonia in a polar solvent in the presence of alkali metal amide.

The 3,4-dimethoxy-6- [4 - (2-furoyl) -l-piperazinylthiocarbamido] benzonitrile (II) used as the starting material is a new compound which, starting from 3,4-dimethoxy-6- aminobenzonitrile and l- (2-furoyl) piperazine can easily be obtained according to the 25 processes characterized by the following reaction schemes:

ch30.

• ncs ch30

CSC £

II

l, t \ _7 ~ o> - \\

VI

VII

According to the first alternative, 3,4-dimethoxy-6-aminobenzonitrile (IV) and thiophosgene first become 3,4-dimethoxy-6-isothiocyanatobenzonitrile (V) and then this further with l- (2-furoyl) piperazine (VI) converted to 3,4-dimethoxy-6-- [4- (2-furoyl) -1 -piperazinylthiocarbamido] benzonitrile (II). Alternatively, compound II can also be prepared by first reacting l- (2-furoyl) piperazine (VI) with thiophosgene to give acid chloride VII 65 and then using 3,4-dimethoxy-6-aminobenzonitrile (IV) Reacting brings.

The method according to the invention can also be carried out in such a way that prazosin production is

630625

4th

Starting from 3,4-dimethoxy-6- [4- (2-furoyl) -l-piperazinylthìo-carbamido] benzonitrile II or even from 3,4-dimethoxy-6 - isothiocyanatobenzonitrile V continuously in the same reaction vessel and in the same solvent , such as in formamide, without isolation of intermediates.

The following examples serve to illustrate the invention.

example 1

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

27.0 g (0.15 mol) of 3,4-dimethoxy-6-aminobenzonitrile (IV) are dissolved in 150 ml of 1,2-dichloroethane and a mixture of 23.0 g (0.2 Mol) thiophosgene, 100 ml 1,2-dichloroethane, 20.0 g (0.2 mol) calcium carbonate and 200 ml water are gradually added. After the addition has taken place, the mixture is stirred at 0-5 ° C. for a further hour, then at 20 ° C. for 16 hours and finally at 35 ° C. for one hour. The reaction mixture is filtered and the dichloroethane layer is separated off, washed with dilute hydrochloric acid and with water and dried using MgSO 4. The solvent is removed in vacuo and the crystalline residue (mp. 126-7 ° C) is used as such in the following step. 31.0 g (94% of the theoretical amount) of 3,4-dimethoxy-6-isothiocyanatobenzonitrile are obtained.

Cj0H8N2O2S:

Calc .: C 54.53 H 3.66 N 12.72 S 14.56 Observ .: C 53.43 H 3.78 N 12.18 S 13.79

b) 3,4-dimethoxy-6- [4- (2-furoyl) -l-piperazinylthiocarbamido] benzonitrile (II)

11.2 g (0.051 mol) of 3,4-dimethoxy-6-isothiocyanato-benzonitrile (V) are dissolved in 65 ml of ethyl acetate and at 0 ° C with constant stirring a solution of 9.2 g (0.051 mol) of l- ( 2-Furoyl) piperazine and 65 ml of ethyl acetate are gradually added. The solution is left overnight at -25 ° C, during which the product crystallizes out. The crystals are filtered off, washed with cold ethyl acetate and dried. 16.3 g (80% of the theoretical amount) of 3,4-dimethoxy-6- [4- (2-furoyl) -1-piperazinyl-thiocarbamido] benzonitrile are obtained. Mp 178-180 ° C.

Ci9H20N4O4S:

Calc .: C 56.99 H 5.03 N 13.99 S 8.01 Observ .: C 57.41 H 5.39 N 14.14 S 7.68

Example 2

3,4-dimethoxy-6- [4- (2-furoyl) -l-piperazinylthiocarbamido] benzonitrile (II)

5.0 g (0.028 mol) of l- (2-furoyl) piperazine (VI) and 2.83 g (0.028 mol) of triethylamine are dissolved in 60 ml of dichloromethane. This solution is added to a mixture of 3.86 g (0.0336 mol) of thiophosgene and 50 ml of dichloromethane with constant stirring at about 0 ° C. After the addition, stirring is continued for two hours at 0 ° C. and then for three hours at room temperature. The triethylamine hydrochloride is filtered off and the solution is evaporated in vacuo. The rest, 4- (2-furoyl) piperazinylthiocarbonyl chloride (VII), is redissolved in 50 ml dichloromethane and, with constant stirring at 0 ° C., a solution of 4.98 g (0.028 mol) 3,4-dimethoxy-6 -aminoben2onitril (IV), 2.83 g (0.028 mol) triethylamine and 60 ml dichloromethane added. The whole is stirred for two hours at 0 ° C and then 2-3 hours at room temperature. The triethylamine hydrochloride is filtered off and the solution is washed with water, dried with the aid of MgSO4 and evaporated in vacuo. Then ethyl acetate is added, cooled to -25 ° C and filtered. 6.2 g (55% of the theoretical amount) of 3,4-dimethoxy-6- [4- (2 - furoyl) -l-piperazinylthiocarbamido] benzonitrile are obtained. Mp 175-8 ° C.

Example 3

a) Methyl-N- (3,4-dimethoxy-6-cyanophenyl) - [4- (2-furoyl) -l - piperazinylthioformamidate hydroiodide (III-HI)

20.0 g (0.05 mol) of 3,4-dimethoxy-6- [4- (2-furoyl) -l-pi-perazinylthiocarbamidojbenzonitril are dissolved in 200 ml of bis-methoxyethyl ether (diglyme); 14.2 g (0.1 mol) of methyl iodide are added to the solution. The mixture is heated at 60 ° C. with a reflux condenser. The solution is cooled to room temperature and filtered. The crystalline reaction product is washed with ether and dried. 24.6 g (90% of theoretical amount) of methyl N- (3,4-dimethoxy-6-cyanophenyl) - [4- (2-furoyl) -1-piperazinyl] thioformamidate hydroiodide are obtained. Mp 163 ° C. C2oH23IN404S:

Calc .: C 44.29 H 4.27 I 23.39 N 10.33 S 5.91 Observ .: C 44.25 H 4.26 I 22.93 N 9.61 S 5.58

b) Methyl N- (3,4-dimethoxy-6-cyanophenyl) - [4- (2-furoyl) - l-piperazinyl] thioformamidate (III)

62.0 g (0.114 mol) of methyl N- (3,4-dimethoxy-6-cyano-phenyl) - [4- (2-furoyl) -l-piperazinyl] thioformamidate hydro-iodide are at 0-5 ° C dissolved in 350 ml of methanol; 186 ml of 25 percent ammonia solution are added to this solution with constant stirring. The whole is stirred for two hours at 0 ° C, filtered and washed with ether. 42.7 g (90% of the theoretical amount) of methyl N- (3,4-dimethoxy-6-cyanophenyI) - [4- (2-furoyl) -l-piperazinyl] thio-formamidate are obtained. 105-7 ° C.

C20CH22N4O4S:

Calc .: C 57.95 H 5.36 N 13.52 S 7.73 Observ .: C 58.01 H 5.54 N 13.73 S 7.53

c) 6,7-dimethoxy-4-amino-2- [4- (2-furoyl) -l-piperazinylJ-quinazoline (I)

7.0 g (0.017 mol) of methyl-N- (3,4-dimethoxy-6-cyanophenyl) - [4- (2-furoyl) -l-piperazinyl] thioformamidate are dissolved in 100 ml of formamide; 2.0 g (0.051 mol) of sodium amide are added to the solution. The solution saturated with NH3 gas at 0 ° C. The temperature of the solution is slowly increased to 120 ° C. and kept at this value for 24 hours with the simultaneous supply of NH3 gas. The cooled reaction mixture is poured into 100 ml of ice water and extracted 6-7 times with 50 ml of chloroform. The chloroform extract is washed 4 times with 50 ml of water, dried and evaporated in vacuo. The product is crystallized from an ethanol-water mixture (50:15). 6,7-Dimethoxy-4-amino-2- [4- (2-furoyl) -1-piperazinyl] -quinazoline is obtained. Mp 262-264 ° C. The IR and NMR spectra of this product were identical to the spectra of the compound prepared by methods previously described in the literature.

C19H21N504:

Calc .: C 59.52 H 5.52 N 18.27 Observ .: C 59.29 H 5.88 N 17.99

Example 4

6,7-dimethoxy-4-amino-2- [4- (2-furoyl) -l-piperazinyl] -quinazoline (I)

9.7 (0.044 mol) of 3,4-dimethoxy-6-isothiocyanatobenzo-nitrile (V) are suspended in 100 ml of formamide; the sus-

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

5

630625

7.9 g (0.044 mol) of l- (2-furoyl) piperazine (VI), dissolved in 65 ml of formamide, are gradually added at room temperature with constant stirring. After the addition, stirring is continued at room temperature until all 3,4-dimethoxy-6-isothiocyanato-benzonitrile has dissolved (3-4 hours). Thereafter, 12.5 g (0.088 mol) of methyl iodide are added to the mixture and the whole is heated at 60 ° C for nine hours. The excess methyl iodide is evaporated, the solution is saturated with NH3 gas at 0 ° C., and 6.9 g (0.176 mol) of sodium amide are added to the solution. The temperature is increased to 120-140 ° C. and kept at this value for 24 hours with the simultaneous supply of NH3 gas. The cooled reaction mixture is poured into about 150 ml of ice water and extracted with chloroform (8 X 50 ml). The 5 chloroform extract is washed with water, treated with activated carbon, dried and evaporated in vacuo. The residue is crystallized from an ethanol-water mixture (50:15). 6,7-Dimethoxy-4-ami-no-2- [4- (2-furoyl) -l-piperazinyl] quinazoline is obtained. Mp 263 to io 265 ° C.

v

Claims (2)

630625 2nd PATENT CLAIMS 1. Process for the preparation of hypotensive 6,7-dimethoxy-4-amino-2- [4- (2-furoyl) -l-piperazinyl] quinazoline of the formula I ch. ch3o pi yo -tt (i) nh, characterized in that 3,4-dimethoxy-6- [4- (2 - furoyl) -l-piperazinylthiocarbamido] benzonitrile of the formula II amide or bis-methoxyethyl ether or in a mixture of these substances. 3. The method according to claim 1 or 2, characterized in that the cyclization at a temperature 5 from 100 to 150 ° C in formamide or N, N-dimethylform amide using 1 to 3 equivalents of alkali metal amide. 4. The method according to claims 1 to 3, characterized in that one carries out the reaction of the compound of the formula II with the methyl iodide and the cyclization of the resultant compound of the formula III continuously in the same solvent and without isolation of intermediates. CH3 ° \ / - \ / nh -oc 15 \ // di) CIÎ30- with methyl iodide to methyl N- (3,4-dimethoxy-6-cyano-phenyl) - [4- (2-furoyl) -l-piperazinyl] thioformamidate of the formula III (III) reacted and this cyclized by heating together with ammonia in a polar solvent in the presence of alkali metal amide. 2. The method according to claim 1, characterized in that the compound of formula II with the methyl iodide at 50 to 100 ° C in formamide, N, N-dimethylform