HUP0200663A2 - Novel method for producing doxazosin mesylate in a crystalline modification designated as form a - Google Patents

Description

.··. .-.7.3-. 192/BE

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new

P02 0 0 663 process for the preparation of doxazosin mesylate in a crystalline modification called Form A

The invention relates to a new process for the preparation of doxazosin mesylate in a crystalline modification called Form A.

Doxazosin (= 4-amino-2-[4-(1,4-benzodioxane-2-carbonyl)-1-piperazinyl]-6,7-dimethoxyquinazoline) is a known antihypertensive agent (see Merck Index, 12th Edition, 1966, No. 3489). The substance is used in the monomesylate form. The first report on the polymorphic forms of doxazosin mesylate was published in the Chinese Journal of Medicinal Chemistry, _5(4), 266-270 (1995). There, three crystal modifications of doxazosin mesylate are described. The different modifications are designated as A-, B- and C-modifications in the cited literature. The A-modification is obtained by recrystallization of doxazosin mesylate from ethanol, while the B- and C-modifications are formed by recrystallization of doxazosin mesylate from chloroform and water, respectively. Although the aforementioned literature only mentions doxazosin, according to the published data, it is doxazosin mesylate.

Of the three forms, only Form A is suitable for pharmaceutical use. The Chinese Journal of Medicinal Chemistry describes a preparation method for Form A of doxazosin mesylate, which is obtained by recrystallization of doxazosin mesylate from ethanol, but there is no industrially applicable method for specifically obtaining this modification.

In EP-A 849 266, they include doxazosin

-mesylate has a crystal modification called (III)-form, which is identical to Form A of doxazosin mesylate.

EP-A 849 266 also discloses a process for the preparation of doxazosin mesylate form A, starting from doxazosin. In this process, doxazosin is preferably converted into doxazosin acetate with acetic acid in an organic solvent, such as ethyl acetate, under heat. The hot solution is filtered, mixed with methanesulfonic acid and optionally stirred under heat until crystallization occurs. The precipitated solvent adduct is separated off after cooling and heated in a moist lower alcohol, such as methanol or ethanol, and the resulting solution is then cooled and the precipitated crystals (= doxazosin mesylate form A) are separated off.

A further process for the preparation of doxazosin mesylate form A is disclosed in patent application PCT/EP98/08360 dated December 18, 1998. In this process, the starting material is also doxazosin. In order to prepare doxazosin mesylate form A, doxazosin is dissolved with methanesulfonic acid in a mixture of an aprotic polar solvent, such as N,N-dimethylformamide and N-methyl-2-pyrrolidone, and methanol; the solution thus obtained is optionally deturbed and the resulting clear solution is stirred until no more precipitate forms. The precipitate (= the D-modification of doxazosin mesylate) is separated, washed with methanol and heated in a moist state in ethanol. After cooling, the A-modification of doxazosin mesylate formed is isolated. The process is also successful if we only work in methanol when dissolving doxazosin with methanesulfonic acid.

The cited Chinese literature describes the process for obtaining doxazosin mesylate form A from ethanol.

73.192/BE, as already mentioned, does not represent a process applicable on an industrial scale specifically for the extraction of doxazosin mesylate form A. Furthermore, this literature article does not provide the preparation of doxazosin mesylate, which serves as a starting material for the production of the individual forms.

As for the two other processes for the preparation of doxazosin mesylate form A, which are given above, they may be suitable for use on a larger scale. However, both are very expensive. In neither case is the preparation of doxazosin mesylate form A possible by simply reacting doxazosin with methanesulfonic acid. Rather, according to the process of EP 849 266, the acetate is first prepared from doxazosin with acetic acid, which is mixed in solution with methanesulfonic acid. A solvent adduct then crystallizes out, which must be isolated. Only heating this adduct in a low molecular weight alcohol provides the desired form A of doxazosin mesylate. According to PCT/EP98/08360, the form called the D-modification of doxazosin mesylate is first prepared from doxazosin and methanesulfonic acid, which must be isolated. Only subsequent heating of this D-form in ethanol provides the desired A-form of doxazosin mesylate.

We have now found a simple, industrially applicable process for the preparation of the A-modification of doxazosin mesylate.

The invention relates to a process for the preparation of doxazosin mesylate form A, which consists in dissolving doxazosin in a mixture of methanesulfonic acid, an aprotic, polar organic solvent and methanol, and optionally filtering the resulting solution, optionally seeding it with crystals of doxazosin mesylate form A, heating it, and after cooling, isolating the product formed, washing it with an organic solvent and drying it.

For the reaction of doxazosin with methanesulfonic acid, the two substances are used in a molar ratio of 1:1. Preferably, a slight molar excess of the sulfonic acid (up to about 10%) is used.

Aprotic polar organic solvents include, for example, N,N-dimethylformamide and, in particular, N-methyl-2-pyrrolidone. The ratio of doxazosin to methanol and aprotic polar organic solvent (weight/volume/volume) is approximately 1:(5-15) : (1.5-4), preferably 1:(8-12) : (2-3). If the solution obtained by adding methanesulfonic acid to the mixture of doxazosin, methanol and aprotic polar organic solvent is turbid, it is advisable to remove the turbidity, for example by filtration. In the case where the turbidity is to be removed, for example by filtration, it is advisable to add part of the methanol only after filtration.

The clear solution obtained after addition of methanesulfonic acid to the mixture of doxazosin, methanol and an aprotic polar solvent and optionally filtration is then preferably seeded with crystals of doxazosin mesylate form A and then heated. Here, it is preferred to work by heating to the boiling point using a reflux condenser. The reaction mixture is generally kept at this temperature for 3-9 hours, preferably 4-6 hours.

The resulting crystal suspension is then cooled to room temperature and stirred briefly at room temperature.

73.192/BE

The solid product (modification A of doxazosin mesylate) is then isolated and washed with an organic solvent, preferably a low molecular weight alcohol, particularly preferably methanol, and dried in a conventional manner, for example under vacuum.

The new process provides the A-modification of doxazosin mesylate in a very simple manner with an overall yield of over 85%. The purity of the A-modification obtained by the new process is excellent. Another significant advantage of the new process is that a solution is formed after the addition of methanesulfonic acid. This makes it possible to remove any foreign particles that may be present by filtration.

Example 1:

In a 500 ml three-necked round-bottomed flask, a mixture of 22.6 g of doxazosin, 45 ml of N-methyl-2-pyrrolidone and 210 ml of methanol is mixed with 5.05 g of anhydrous methanesulfonic acid while stirring. At this time, the internal temperature rises to 30°C and a solution is formed. The reaction mixture is seeded with 0.5 g of doxazosin mesylate form A, at which time these seed crystals do not dissolve. After seeding, the mixture is heated to boiling temperature (boiling point 68°C; seed crystals do not dissolve) using a reflux condenser and stirred at this temperature for 4 hours, at which time additional crystals form. It is then cooled to room temperature and stirred at this temperature for 15 minutes. The precipitated product is filtered off with suction, washed with 2x50 ml of methanol and dried under vacuum at 75°C. This gives 24.6 g of doxazosin mesylate form A. This corresponds to a yield of 87.8% based on the doxazosin used, minus the material used for seeding.

13.192/BE.

The Debye-Scherrer X-ray diffractogram, Differential Scanning Thermogram and IR spectrum data shown in Figures 1-3 are obtained with the doxazosin mesylate thus obtained.

Example 2:

In a 500 ml three-necked round-bottomed flask, a mixture of 22.6 g of doxazosin, 45 ml of N-methyl-2-pyrrolidone and 210 ml of methanol is mixed with 5.05 g of anhydrous methanesulfonic acid while stirring. At this time, the internal temperature rises to 30°C and a solution is formed. After the addition of methanesulfonic acid is complete, the solution is heated to boiling temperature using a reflux condenser (boiling point 68°C) and stirred at this temperature for 4 hours (crystallization occurs during stirring at boiling temperature). It is then cooled to room temperature and stirred at this temperature for 15 minutes. The precipitated product is filtered off with suction, washed with 2 x 50 ml of methanol and dried under vacuum at 75°C. Thus, 23.5 g of doxazosin mesylate form A are obtained. This corresponds to a yield of 85.7% based on the doxazosin used.

Example 3:

In a 500 ml three-necked round-bottomed flask, a mixture of 22.6 g of doxazosin, 45 ml of N-methyl-2-pyrrolidone and 190 ml of methanol is mixed with 5.05 g of anhydrous methanesulfonic acid while stirring. At this time, the internal temperature rises to 30°C and a solution forms. 152/3E starts. After the addition of methanesulfonic acid is complete, the reaction mixture is filtered into another 500 ml three-necked round-bottomed flask. The filter is washed with 20 ml of methanol. The combined filtrate is heated to boiling temperature using a reflux condenser (boiling point 68°C) and stirred at this temperature for 4 hours (crystallization occurs during stirring at boiling temperature). After the stirring time at the boiling temperature has elapsed, it is cooled to room temperature and stirred at this temperature for 15 minutes. The precipitated product is filtered off with suction, washed with 2 x 50 ml of methanol and dried under vacuum at 75°C. This gives 23.4 g of doxazosin mesylate form A. This corresponds to a yield of 85.4% based on the doxazosin used.

73.192/BE

Claims (1)

PATENT CLAIMS 1. A process for the preparation of doxazosin mesylate form A, characterized in that doxazosin is dissolved with methanesulfonic acid in a mixture of an aprotic, polar organic solvent and methanol, the resulting solution is optionally filtered, optionally seeded with crystals of doxazosin mesylate form A, heated, and after cooling, the resulting product is isolated, washed with an organic solvent and dried. The authorized person: 7 3.192/BE