HU225772B1 - Process for producing terazosine - Google Patents

Abstract

The present invention relates to an improved process for the preparation of a compound of formula (I), a pharmaceutically acceptable acid addition salt thereof or a hydrate thereof, a 4-amino-6,7-dimethoxy-2-chloroquinazoline of formula (II) and a compound of formula (III). Reacting 2-tetrahydrofuroylpiperazine in a water-miscible organic solvent in the presence of triethylamine, isolating the base of Formula I, and optionally treating it with a pharmaceutically acceptable acid. According to the invention, a water-miscible organic solvent with a boiling point of from 150 to 190 ° C is diethylene glycol dialkyl ether, where alkyl is methyl or ethyl, preferably diethylene glycol dimethyl ether, diethylene glycol diethyl ether, and the reaction is carried out at the boiling point of the reaction mixture. and the base of formula (I) is precipitated from the reaction mixture with water and, if desired, converted into an acid addition salt or hydrate of the latter in a manner known per se. EN 225 772 Β1 (I) (II) (III) Scope of description 4 pages (including 1 sheet)

Description

The present invention relates to an improved process for the preparation of 1- (4-amino-6,7-dimethoxy-2-quinazoline) -4- (tetrahydro-2-furoyl) piperazine of the formula I and its pharmaceutically acceptable acid addition salts or hydrates thereof. Reacting 4-amino-6,7-dimethoxy-2-chloroquinazoline of formula II with 2-tetrahydrofuroylpiperazine of formula III in a water-miscible organic solvent in the presence of triethylamine, isolating the resulting base of formula I, and optionally treating with a pharmaceutically acceptable acid.

The compound of formula (I) is a drug known as terazosin with antihypertensive activity.

There are essentially two pathways known for the preparation of terazosin.

According to U.S. Patent 4,026,894, 4-amino-6,7-dimethoxy-2-chloroquinazoline II is reacted with 2 molar excess tetrahydrofuroylpiperazine III in 2-methoxyethanol at the boiling point of the reaction mixture. . The reaction time is about 3 hours.

After evaporation of the solvent, an aqueous solution of potassium bicarbonate is added to the residue, the precipitated solid is filtered off, washed with water, suspended in methanol and acidified with hydrochloric acid isopropyl alcohol. The resulting solution is evaporated and the residue is crystallized from isopropyl alcohol. The hydrochloride of the terazosin base of formula (I) is obtained in 65% yield.

In an improved version of the above, rather uneconomical, known process, U.S. Patents 4,251,532 state that reagents II and III are reacted in the presence of excess triethylamine base in 2-methoxyethanol at boiling point 115-120. At 8 ° C for 8 hours. After cooling to room temperature, the reaction mixture is evaporated, the residue is taken up in water at 45 ° C, adjusted to pH 2.5 with concentrated aqueous hydrochloric acid, stirred for 1 hour and filtered. An aqueous solution of ammonium hydroxide was added to the filtrate until a pH of about 8.3 was reached, held at 65 ° C for 1 hour, finally cooled to 15 ° C and stirred for 16 hours at 15-20 ° C. The crystalline product is isolated in 86-87% yield of the base of formula (I).

The latter known process variant is more economical in terms of production than the former, but can be very laborious: it consists of several operations steps and their total duration is too long. The resulting product contains several contaminants which can only be eliminated in significant operations at significant expense.

Another known route for the preparation of terazosin (Hungarian Patent Application No. 203,342) is to provide 4- (tetrahydrofuroyl) piperazin-1-yl / N-cyano-N '- (3,4-dimethoxyphenyl) / carboxamidine (IV). by thermal cyclisation of the compound of formula (I). The process has the disadvantage that equimolar use of toxic heavy metal compounds such as mercury (II) oxide, lead (II) oxide or mercury (II) chloride is required for the preparation of the starting compound (VI), which may cause environmental problems on an industrial scale.

Thus, the known processes do not permit the trouble-free and economical preparation of terazosin of formula (I).

It is an object of the present invention to provide an improved process in which terazosin is readily and economically prepared from readily available starting materials.

It has now been found that the above object is achieved by the reaction of 4-amino-6,7-dimethoxy-2-chloroquinazoline II and 2-tetrahydrofuroylpiperazine III in a water-miscible organic solvent in the presence of triethylamine. water-miscible organic solvent, boiling point 150-190 ° C, diethylene glycol-alkyl ether, where alkyl is methyl or ethyl, preferably diethylene glycol dimethyl ether, diethylene glycol diethyl ether, and the reaction is carried out at reflux temperature. the base of formula (I) is precipitated from the reaction mixture with water.

It has been found that under the conditions of the process of the invention, the reaction of the reagents (II) and (III) is practically quantitative over a period of 1 to 1.5 hours and the formation of by-products is suppressed.

The present invention is based on the discovery that when an organic solvent having a boiling point of 150-190 ° C is used, a reaction temperature of 130-180 ° C can be achieved at the boiling point of the reaction mixture used, and at this higher temperature the compounds II and III The reaction proceeds very rapidly without significant degradation of either the starting compounds or the product formed. In the process known from U.S. Patent No. 4,251,532, however, the boiling point of 2-methoxyethanol as a solvent is only 124-125 ° C, so only 115-120 ° C can be achieved by refluxing the reaction mixture.

At this relatively low reaction temperature, a very long boiling time of at least 8 hours is required for the reaction to occur, but at the same time significant decomposition occurs.

The organic solvents preferably used in the process according to the invention have the following boiling points:

diethylene glycol dimethyl ether 162 ° C, diethylene glycol diethyl ether 180-190 ° C.

In the process according to the invention, the reagents (II) and (III) may be used in equimolar amounts, or the compound (III) may be used in an excess, usually in the range of 20-50%. The triethylamine is generally used in equimolar amounts or in most cases in an amount of 50 to 100% relative to the reagent of formula (II).

Upon completion of the reaction of the compounds of Formulas II and III, diluting the water-miscible organic solvent with water may precipitate the product of Formula I, eliminating the need for complicated and lengthy separation steps in the known process.

The resulting terazosin base of formula (I) is converted, if desired, into an acid addition salt in a manner known per se. To do this, the compound of formula (I) may be prepared with an inorganic acid such as hydrochloric acid, sulfuric acid, phosphoric acid, etc., or

And organic acids such as acetic acid, citric acid, fumaric acid and the like. reacted. Preferably, the hydrochloride of the compound of formula (I) is prepared and the resulting salt formation and crystallization in aqueous medium yields terazosin hydrochloride dihydrate.

Starting compounds of the process of the invention are commercially available.

The process of the invention has several advantages, which are summarized below:

- It is very simple, quick to implement and does not require any special equipment.

- The process volume is small, so large volumes can be produced in relatively small volume devices.

The processing of the reaction mixture consists only of dilution with water.

- Upon precipitation with water, the product precipitates in a well-filterable form.

- There is no need to use pollutants.

- The organic solvent used can be recovered from the aqueous mother liquor by distillation.

- 96% production available.

During the synthesis, by-products are practically non-formed, and the product thus obtained is of very high purity.

The invention is illustrated in detail by the following examples.

Example 1

1- (4-Amino-6,7-dimethoxy-2-quinazolinyl) -4- (tetrahydro-2-furoyl) piperazine

To a suspension of 119.9 g (0.5 mole) of 4-amino-6,7-dimethoxy-2-chloro-quinazoline in 600 ml of diethylene glycol dimethyl ether at room temperature is added 75.9 g (104.5 ml, Triethylamine (75 moles) and 2-tetrahydrofuroylpiperazine (118.4 g, 0.65 moles). After the addition, the reaction mixture was refluxed at 135-140 ° C for 1.5 hours, cooled to room temperature, and water (100 mL) was added. The precipitated crystalline product is filtered off, washed with water and dried. 186.0 g (96%) of 1- (4-amino-6,7-dimethoxy-2-quinazolinyl) -4- (tetrahydro-2-furoyl) piperazine, m.p. 278-280 ° C.

The purity of the product by high performance liquid chromatography was 98.5%.

Test conditions:

chromatographic column: Hypersil-MOS, 5 pm,

200 * 4.6mm (Hewlett-Packard); temperature: 20 ± 1 'C;

mobile phase: 1: 1 mixture of acetonitrile and 0.05% aqueous ammonium carbonate; flow rate 1 ml / min;

detection: UV detector at 254 nm.

Example 2

1- (4-Amino-6,7-dimethoxy-2-quinazolinyl) -4- (tetrahydro-2-furoyl) piperazine

All proceed as in Example 1 except that 500 ml of diethylene glycol diethyl ether are used instead of diethylene glycol dimethyl ether. The reaction mixture is refluxed at 160-170 ° C. 176.3 g (91%) of the product are obtained, which is the same as in Example 1.

Comparative example

The procedure described in Example 1 was followed except that 600 ml of 2-methoxyethanol used in U.S. Patent No. 4,251,532 were used as a solvent instead of diethylene glycol dimethyl ether. The reaction was carried out at the boiling point of the reaction mixture at 115-120 ° C. 157 g (81%) of 1- (4-amino-6,7-dimethoxy-2-quinazolinyl) 4- (tetrahydro-2-furoyl) -piperazine were obtained, m.p. 274-276 ° C.

The purity of the product by high performance liquid chromatography was 85%.

From the comparative example, it can be clearly seen that when a solvent having a boiling point lower than 150 ° C is used, the production of the process according to the invention is significantly degraded and a contaminated product is formed.

Claims (1)

Patent Claim Point A process for the preparation of the compound of formula (I) and its pharmaceutically acceptable acid addition salts or hydrates of the latter, the water-miscible 4-amino-6,7-dimethoxy-2-chloroquinazoline of formula (II) and the 2-tetrahydrofuroylpiperazine of formula (III) reaction in an organic solvent in the presence of triethylamine, isolating the base of formula (I) formed and optionally treating with a pharmaceutically acceptable acid, wherein the water-miscible organic solvent is boiling point 150-190 ° C, diethylene glycol dialkyl ether, wherein alkyl is methyl or ethyl, preferably diethylene glycol dimethyl ether, diethylene glycol diethyl ether, and the reaction is carried out at the boiling point of the reaction mixture, and the base of formula (I) is precipitated from the reaction mixture with water and optionally converting the latter to a hydrate.