FI58125C - PROCEDURE FOR FRAMSTATING AV 6,7-DIMETOXY-4-AMINO-2- (4- (2-FUROYL) -1-PIPERAZINYL) QUINAZOLINE WITH BLODTRYCKSSAENKANDE VEKAN - Google Patents

Description

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Patent- och regiftarttyraiMn 'AnaMctn utlagd och utUkrlften publtc «r * d 29.08.80 (32) (33) (31) Pyy * 1 · * 1 /« tuelkeu * —Begird prtorltet (71) Orion Group, Nilsiänkatu 10- 00, 00510 Helsinki 51 »

Suomi-Finlancl (Fl) (72) Erkki Juhani Honkanen, Helsinki, Aino Kyllikki Pepper, Espoo, Finland-Finland (Fl) (7 * +) Berggren Oy Ab (5U) Method for lowering antihypertensive β-dimethoxy-V-amino For the preparation of -2- [N- (2-furoyl) -1-piperazinyl] quinazoline -Forfarande för framställning av 6,7-dimethoxy-1 + -amino-2- [U- (2-furoyl) -1-piperazinyl] quinazoline with a solution This invention relates to a process for the preparation of the antihypertensive 6,7-dimethoxy-4-amino-2- [4- (2-furoyl) -1-piperazinyl] -quinazoline of the formula CH3 °] QfN * r \ _ / ~ oc ' The process according to the invention is characterized in that 3,4-dimethoxy-6- [4- (2-furoyl) -1-piperazinylthiourea / benzonitrile of the formula ch3 ° ν-γ1 ™ i 'G oc Ό

C O ^ '^' CN

is reacted with methyl iodide to form methyl N- (3,4-dimethoxy-6-cyanophenyl) - [4- (2-furoyl) -1-piperazinyl] thioformamidate of formula 2,581

PH Ω · ν N = C - N N - OC —y 'S

3 KjT '^ -7 111

CN

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

The starting 3,4-dimethoxy-6- [4- (2-furoyl) -1-piperazinylthiourea] benzonitrile (II) is a novel compound. It can be prepared by first reacting 3,4-dimethoxy-6-aminobenzonitrile (IV) with thiophosgene to 3,4-dimethoxy-6-isothiocyanato-benzonitrile (V) CH 2 O

jQC

CH30 CN CN

IV V

and further with 1- (2-furoyl) -piperazine (VI) to 3,4-dimethoxy-6- [4- (2-furoyl) -1-piperazinylthiourea] -benzonitrile (II).

CH-, 0 CN

* V II

Alternatively, a compound of formula II may be prepared by first reacting 1- (2-furoyl) piperazine (VI) with thiophosgene to give the acid chloride VII.

„/„ „/ ° s CSC1, Cl-C-f / N - ooS ° \

\ _f 'oc \ J -b il \ _ / \ J

S

VI VII

and then with 3,4-dimethoxy-6-aminobenzonitrile (IV).

3,581 25 CH3 ° v ^ / NH2 CH oA ^ cN / - \ τΟ-'ύ - ^ 0C «· s 3

VII II

The process for the preparation of 6,7-dimethoxy-4-amino-2- [4- (2-furoyl) -1-piperazinyl] -quinazoline according to the invention can, if desired, be carried out in such a way that starting from 3,4-dimethoxy-6-isothiocyanate benzo - from the nitrile (V), all the necessary reactions are carried out without isolating the intermediates in the same reaction vessel and solvent.

The compound of the invention is also known as prazosin and has a potent antihypertensive effect (Cohen, Journal of Clinical Pharmacology 1 () (1970) p. 408).

U.S. Patent 3,511,836 discloses several methods for preparing 6,7-dimethoxy-4-amino-2- (74-substituted) -1-piperazinyl-7-quinazolines. In one of these methods for preparing prazosin, 6,7-dimethoxy-4-amino-2-chloroquinazoline is reacted with (2-furoyl) -1-piperazine.

CH..Q. / C1__,

3 ^ / o N

1 (111 + HN N-OC and N-prazosin CH, O | NH2

Dutch patent publication 7 206 067 discloses a process for the preparation of prazosin in which 3,4-dimethoxy-6-aminobenzonitrile is reacted with 1-cyano-4- (2-furoyl) piperazine.

ch3o ^^ / mh2 / - \ o + NC-N N-OC— ^ \ -> prazosin CH30 ^ "^ CN ^^ '- 4,588

Finnish patent application 3514/74 discloses a process for the preparation of prazosin in which 4,5-dimethoxy-2-aminobenzonitrile is reacted with methyl 4- (2-furoyl) -piperazin-1-yl-formimidate or thioformimidate.

Cli3 ° yf \ r NH2 / \ o

+ HN - C - N N - CO N

CH, O CN N- '' - '3 OCH3 The starting thioformimidate compound can be prepared by reacting 4- (2-furoyl) piperazine with ammonium thiocyanate to the corresponding thioformamide and methylating this methyl with iodide. The preparation has proved to be very difficult in practice because two isomers are formed in the first step; 4- (2-furoyl) piperazine thioformamide and piperazinium thiocyanate, which are laborious to separate.

. 0 v / V NH. SCN o / \ _ ^ / 0. / ^ ® θ / ° ^ co. / ^ co - H_J- cnh2 ^ Q- ^ XJh 501 s

CH 3 I

a "CO -N N - C - NH0 sch3

The corresponding formimidate compound has been proposed to be prepared from 1-cyano-4- (2-furoyl) piperazine and methanol using an acid catalyst such as HCl.

/ CH, 0H / HCl O / V

/ ° '"' j— CO - N N - CN -----> C V-Co - N N - C = NH

\ _f \ _ / li w I

However, the preparation of this compound is very difficult because nitrilium chloride is formed in the reaction.

.O / \ S V- CO - N N - C = NH-HCl \ _J \ - / i

Cl

However, nitrilium chloride forms some prazosin when reacted with an aminobenzene compound in the presence of an alkali metal hydride. This is because the nitrilium salt decomposes under the action of the base catalyst back to 1-cyano-4- (2-furoyl) -piperazine, which further reacts as described in Dutch patent publication 7206067.

Common to all the above methods is that the final product is formed in a reaction between two different molecules.

A special feature of the process according to the application, on the other hand, is that prazosin is prepared by an intramolecular cyclization reaction.

Of the known methods, the most useful is the method disclosed in Example 6 of Dutch Patent Publication No. 7206067, according to which prazosin can be prepared in a yield of about 30%. However, impurities are formed in the reaction, the removal of which from the final product has proved to be very laborious. The crude product has to be crystallized several times before it meets the requirements for the purity of the drug raw material. In this case, the yield of pure product decreases. With the process according to the invention, difficult-to-remove impurities are not formed during the preparation of prazosin and the pure end product is obtained in about 50-60% better yield.

According to the invention, prazosin is prepared by a new method based on an intramolecular cyclization reaction. The preparation steps of the starting material required in the process as well as the preparation of the final product can be carried out in the same reaction vessel without isolating the intermediates, which makes the process easily applicable to industrial production. With the process according to the invention, pure prazosin can be prepared in considerably better yield than by the best known process.

The following examples illustrate the invention.

Example 1. 6,7-Dimethoxy-4-amino-2- [4- (2-furoyl) -1-piperazinyl] -quinazoline (I) 7.0 g (0.017 mol) of methyl N- (3, 4-Dimethoxy-6-cyanophenyl) - (4- (2-furoyl) -1-piperazinyl) thioformamidate is dissolved in 100 ml of formamide and 2.0 g (0.051 mol) of sodium amide are added. The solution was saturated with NH 4 at 0 ° C. The temperature of the solution 7 58125 is slowly raised to 120 ° C and heated for 24 hours at this temperature while conducting NH 4 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 to dryness in vacuo. The product is crystallized from ethanol-water (50:15). 6,7-Dimethoxy-4-amino-2- [4- (2-furoyl) -1-piperazinyl] quinazoline is obtained. Sp. 262-264 ° C. The IR and NMR spectra of the product were identical to those of a compound prepared according to methods previously described in the literature.

C19H21N5 ° 4 Calcd. C = 59.52 Hav. C = 59.28 H = 5.52 H = 5.88 N = 18.27 N = 17.99

Example 2. 6,7-Dimethoxy-4-amino-2- [4- (2-furoyl) -1-piperazinyl] -quinazoline (I) 9.7 g (0.044 mol) 3,4-dimethoxy-6- isothiocyanate benzonitrile (V) is suspended in 100 ml of formamide and 7.9 g (0.044 mol) of 1- (2-furoyl) piperazine (VI) dissolved in 65 ml of formamide are gradually added thereto at room temperature. After the addition, stirring is continued at room temperature until the 3,4-dimethoxy-6-isothiocyanate benzonitrile is completely dissolved (3-4 hours). 12.5 g (0.088 mol) of methyl iodide are then added to the mixture and the mixture is heated at 60 [deg.] C. for 9 hours. The excess methyl iodide is evaporated off and the solution is saturated with N 2 at 0 ° C and 6.9 g (0.176 mol) of sodium amide are added to the solution. The temperature is raised to 120-140 ° C and heated for 24 hours at this temperature while conducting NH 4 gas. The cooled reaction mixture is poured into ice water (ca. 150 ml) and extracted with chloroform (8 x 50 ml). The chloroform extract is washed with water, treated with activated carbon, dried and evaporated to dryness in vacuo. The residue is crystallized from ethanol-water (50:15). 6,7-Dimethoxy-4-amino-2- [4- (2-furoyl) -1-piperazinyl] quinazoline is obtained.

Sp. 263-265 ° C.

Claims (1)

A new process for the preparation of the antihypertensive 6,7-dimethoxy-4-amino-2- [4- (2-furoyl) -1-piperazinyl] quinazoline of the formula »CH3 ° ttC" ^ O '^ Ό ch3o NH2 known that 3,4-dimethoxy-6- [4- (2-furoyl) -1-piperazinylthiocarbamido] -benzonitrile of the formula [0 CH 0 - CN N - OC —SN 3] fjr \ \ J CH30 CN is subjected to to react with methyl iodide in an organic solvent, suitably at a temperature of 50 to 100 ° C, to give methyl N- (3,4-dimethoxy-6-cyanophenyl) - N- (2-furoyl) -1-piperazinyl] thioformamididate of formula CH 3 O CN and this compound are cyclized by heating with ammonia in a polar solvent, suitably at a temperature of 100-150 ° C, in the presence of an alkali metal amide.