SI8010058A8 - Process for obtaining 6,7-dimethoxy-4-amino-2-/4-(2-furoyl) -piperazinyl/-quinazoline chlorohydrate of an antihypertensive effect - Google Patents

Description

1. Field of technology

The invention is from the field of organic chemistry, closer to heterocyclic chemistry. According to the International Classification it belongs to group C07D 405/14.

in SF 76 3614. Comparing this process with the method of the present invention, it is obvious that both methods are used as the starting material of the formula II, but clisification is achieved by different methods. According to the process of the present invention, prazosin hydrochloride is obtained in good yield (93-95%) and in a very pure form (purity 99.7-99.8%).

2. Technical problem

The invention relates to a novel, improved process for the production of 6,7-dlmethocal-4-amino-2- / 4- (2-furoyl) -1 · piperazinyl / quinazoline hydrochloride, i. prazosin hydrochloride, of the formula:

3. State of the art

Previous procedures for obtaining presosin have been described in the following patents, for example: US 5 511 836, NL 72 06067 and DT 2457911.

In the practical implementation of the said procedures, however, there are many technical difficulties. In addition, using these methods yields are quite low and product purification is difficult. In the process for obtaining the blanks according to Finnish Patent SF 76 3614, the disadvantages that have occurred in the previous processes have been significantly eliminated and at the same time the yield has been increased.

4. Description of the solution

It is now surprisingly observed that the leakage yield, and at the same time the product purity, can be greatly improved and the preparation and purification processes can be simplified if the above quinazoline ring closure reaction is carried out with a large excess of the ammonium chloride used according to the present invention, rather than gaseous of ammonia. In this case, an alkaline catalyst (sodium amide, etc.) is not required to perform the reaction. In addition, the desired prazosin chloride is obtained directly in the reaction, in a very good yield (93-95%). The purity of the crude product is also very high, about 99.5%. The desired degree of purity (99.7 - 99.8%) is obtained by simple crystallization of this crude product. The total yield in this case is 85-86%.

The process for the preparation of prazosin hydrochloride according to the invention represents a very significant step forward in the art.

Starting compound, methyl-N- (3,4-dimethoxy-6-cyanophenyl) - N - (4- (2-furoyl) -1-piperazinyl) -thioformidate of formula (II)

In the process for the preparation of gaps according to SF 76 3614, quinazoline ring closure is carried out intramolecularly using methyl N- (3,4-dimethoxy-6-cyanophenyl) - 4- (2-furoyl) -1-piperazinyl / thioformamidate as starting material , of formula (II). This compound reacts with ammonia in formamide, in the presence of an alkane catalyst such as sodium amide, according to the following reaction formula:

N “C I

SCH

N - Ct / 3

In this process, the void yield is 40-50% of the crude product with a purity of 95-97%. Thereafter, the product must be converted to the hydrochloride, which is in fact a drug, and must crystallize several times before obtaining the required purity for medical use (99.7-99.8%). The overall yield drops to around 35%.

The closest previously known process for the preparation of gaps is described to be heated at an elevated temperature of 100 to 140 ° C, preferably about 120 ° C, for 15-20 hours, with a large excess of ammonium chloride, in a polar solvent such as formamide, by feeding of gaseous nitrogen.

Practical reaction and separation and purification of the product are very simplified. In addition, the use of sodium amide, which is difficult to handle in large quantities, is avoided here.

When ammonia and sodium amide are used, the reaction takes place in an alkaline medium, when a certain displacement of the furoyl groups present in the form of the solvent-formyl formyl group is present in the void ring. On the other hand, the ammonium chloride solution is poorly acidic and the aforementioned alteration is difficult to occur. The complete elimination of these impurities, education at low concentrations, has proven to be very difficult in practice.

Methyl-N- (3,4-dimethoxy-6-cyanophenyl) - N- (4- (2-furoyl) -1piperazinyl / thioformamidate (11) can be obtained in 7075% yield by reaction of 3,4-dimethoxy-6-aminobenzonitrile with methyl iodide as described in Finnish Patent SF 76 3613.

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The invention is illustrated by the following example:

6,7-dimethoxy-4-amino-2- / 4- (2-furoyl) -1-piperazinyl / quinazoline chloride

275 g (0.66 mol) of methyl-N- (3,4-dimethoxy-6-cyanophenyl) - [4- (2furoyl) -1-piperazinyl] thioformamidate was dissolved in 3000 ml of formamide, and 1375 g (25.7) was added with stirring. mole) ammonium chloride. Subsequently, the reaction mixture was heated at 120 ° C for 15-20 h, stirring and introducing gaseous nitrogen to remove the methane thiol produced (it could be absorbed by sodium hypochlorite solution). The resulting blank hydrochloride gradually crystallized from the reaction mixture. After the reaction has ceased, 3-4 kg of ice are added to the mixture. The product was washed, washed with cold water and acetone and dried. Yield 254259 g (93-95%). Purity 99.5% (High Pressure Chromatography). The product crystallizes from about 10 lit. water / ethanol mixture (15:50). Yield 232-235 g (85-86%). Purity 99.7-99.8% (High Pressure Chromatography). The IR, NMR, and mass spectra of the product are identical to the corresponding spectra of prazosin hydrochloride produced by the methods described in the previous literature.

pressing). The product crystallizes from about 10 lit. water / ethanol mixture (15:50). Yield 232-235 g (85-86%). Purity 99.7-99.8% (High Pressure Chromatography). The IR, NMR, and mass spectra of the product are identical to the corresponding spectra of prazosin hydrochloride produced by the methods described in the previous literature.

Claims (2)

PATENT REQUIREMENTS 1. A process for the preparation of 6,7-dimethoxy-4-amino-2- [4- (2-furoyl) 1-piperazinyl / quinazoline hydrochloride (with antihypertensive effect) of the formula: characterized in that the starting compound is methyl-N- (3,4-dimethoxy-6-oiophenyl) - [4- (2-furoyl) -1-piperazinyl] -thloformidate of formula (II) 6,7-dimethoxy-4-amino-2- [4- (2-furoyl) -1-piperazinyl] quinazoline chloride 275 g (0.66 mol) of methyl-N- (3,4-dimethoxy-6-cyanophenyl) - [4- (2furoyl) -1-piperazinyl] thioformamidate was dissolved in 3000 ml of formamide, and 1375 g (25.7) was added with stirring. mole) ammonium chloride. Thereafter, the reaction mixture was heated at 120 ° C for 15-20 h, stirring and introducing gaseous nitrogen to remove the methane thiol produced (it could be absorbed by sodium hypochlorite solution). The resulting prazosin hydrochloride gradually crystallized from the reaction mixture. After the reaction has ceased, 3-4 kg of ice is added to the mixture. The product was washed, washed with cold water and acetone and dried. Yield 254259 g (93-95%). Purity 99.5% (High-temperature chromatography at an elevated temperature of 100-140 ° C, preferably 120 ° C for 15-20 hours with a large excess of ammonium chloride in polar solvent such as formamld, with the addition of gaseous nitrogen. 2. A process according to claim 1, wherein ss ammonium chloride uses in an amount of 30-40 moles of NH ₄ Cl per 1 mole of the compound of formula (II).