RU2077536C1 - Crystalline 8-chlor-1-methyl-6-phenyl-4h-1,2,4-triazolo(4,3-a)(1,4)-benzodiazepine having plate form - Google Patents

Abstract

FIELD: pharmaceutical industry. SUBSTANCE: anhydrous crystalline 8-chlor-1-methyl-6-phenyl-4H-1,2,4-triazolo/4,3-a//1,4/-benzodiazepine is used as reagent 1, water or aqueous solution (content of water in it is 10-20%) being used as reagent 2. EFFECT: improved quality of desired product.

Description

 The invention relates to a new crystalline form of 8-chloro-1-methyl-6-phenyl-4H-1,2,4-triazolo (4,3-a) (1,4) -benzoazepine (alprazolam). The invention can find application in the pharmaceutical industry to obtain this known anxiolytic with simultaneous antidepressant action.

Various methods are known for the preparation of anhydrous crystalline 8-chloro-1-methyl-6-phenyl-4H-1,2,4-triazolo (4,3-a) (1,4) benzodiazepine, for example, preparation according to the patent DD- PS 83 360 and the patent DD-PS 115674, laid out by the application for the patent of the Netherlands 7113800, as well as the correspondingly laid out applications DN-OS 2203782, 2242938, 2402363 and 3413709. In all cases, the final product is recrystallized from an organic solvent (mainly from ethyl acetate) or a mixture solvents, for example acetone and hexane, or from methylene chloride, ethyl acetate and ether. According to Dutch Patent Application Laid-open 7113800, Example 32 and DE-OS 2402363, Example 1 8-chloro-1-methyl-6-phenyl-4H-1,2,4-triazolo (4,3-a) (1 , 4) benzodiazepine is obtained in the form of colorless needles from ethyl acetate with a melting point of 228-229 ^o C.

 But for use as medicines, long needle crystals are unfavorable, since they are entangled and poorly dosed. From US patent 3980789, in addition, the salt of 8-chloro-1-methyl-6-phenyl-4H-1,2,4-triazolo (4,3-a) (1,4) benzodiazepine with physiologically compatible inorganic and organic salts is known acids suitable for use as a medicine.

 Also in USP XXI and Clarkes, "Isolation and Identification of Drugs." 2nd ed. London, 1986, p. 331 refers to certain anhydrous polymer modifications of 8-chloro-1-methyl-6-phenyl-4H-1,2,4-triazolo (4,3-a) (1,4) benzodiazepine. Hydrate formation is still unknown.

The aim of the invention was the creation of a well-known anxiolytic 8-chloro-1-methyl-6-phenyl-4H-1,2,4-triazolo (4,3-a) (1,4) benzodiazepine, a new preferred economical and low-cost crystalline form, when the following effect is achieved:
lack of technological and hardware features, without the use of toxic and polluting excipients,
simple solvent recovery
profitability of the method
processing preferred in the preparation of the drug,
high purity of the final product.

 Therefore, the task arose to create a new crystalline form of 8-chloro-1-methyl-6-phenyl-4H-1,2,4-triazolo (4,3-a) (1,4) benzodiazepine and to propose a technically feasible way to obtain it, which fulfills the above requirements and at the same time serves as the purification of the target product.

 This task in accordance with the proposed invention is solved in such a way that anhydrous crystalline 8-chloro-1-methyl-6-phenyl-4H-1,2,4-triazolo (4,3-a) (1,4) benzodiazepine is reacted with water or a solvent containing water, if appropriate at an elevated temperature until an appropriate hydrate with a plate-like structure of crystals is obtained. In accordance with the proposed invention, the reaction conditions can be varied within wide limits.

So hydration can be achieved by simply mixing anhydrous 8-chloro-1-methyl-6-phenyl-4H-1,2,4-triazolo (4,3-a) (1,4) benzodiazepine with water in suspension. To accelerate this process, it is possible to work at elevated temperatures, approximately 40-70 ^o C. Mixing with a water-containing solvent is also favorable. As a solvent, it is best to use those that are miscible with water in any proportion, such as alcohols, acetone and acetonitrile. The water content in the solvent can be selected over a wide range, from about 10 to 50%, but preferably from 10 to 20%. You can also work at elevated temperatures. To improve the yield, it is then always necessary to cool everything again at the end of the mixing process. Solvents that dissolve water to a limited extent, such as ether, can also be used. In these cases, the water content is at least 3 vol. since otherwise hydrate formation is slow. The ratio of the solid part to the liquid can be changed within wide limits, approximately in the range from 1: 5 to 1: 100. In any case, it is necessary to carry out good mixing of the suspension.

 You can also anhydrous 8-chloro-1-methyl-6-phenyl-4H-1,2,4-triazolo (4,3-a) (1,4) benzodiazepine as in the process of recrystallization to dissolve in a suitable solvent containing water, with boiling solvent. Upon cooling, the hydrate immediately crystallizes. Suitable organic solvents are those mentioned above, i.e. alcohols, acetone, acetonitrile, and ether, respectively, with a specific water content. A particular form of the method is the use of an azeotropic boiling solvent of a mixture of isopropanol with 10 vol. water or acetonitrile with 18 vol. water. This recrystallization method is especially suitable when the injected anhydrous crystalline 8-chloro-1-methyl-6-phenyl-4H-1,2,4-triazolo (4,3-a) (1,4) benzodiazepine is already in unclean form . Thus, purification is associated with conversion to hydrate, so that purification and hydrate formation can be achieved in one process. Depending on the properties of the crude 8-chloro-1-methyl-6-phenyl-4H-1,2,4-triazolo (4,3-a) (1,4) benzodiazepine, it may be advantageous to transfer its solution to the corresponding aqueous solvent by treatment activated carbon. It may be appropriate to repeat the purification operation with the hydrate obtained in order to obtain a particularly pure final product.

 The method according to the invention can also be used so that crystalline water-free, if appropriate, is already pure 8-chloro-1-methyl-6-phenyl-4H-1,2,4-triazolo (4,3-a) ( 1.4) benzodiazepine, if appropriate, with simultaneous purification, transfer to 8-chloro-1-methyl-6-phenyl-4H-1,2,4-triazolo (4,3-a) (1,4) benzodiazepine hydrate, t .e. also when it is necessary to purify 8-chloro-1-methyl-6-phenyl-4H-1,2,4-triazolo (4,3-a) (1,4) benzodiazepine available as a hydrate and again obtain it as a hydrate .

The invention is particularly unexpected because the hydrate of 8-chloro-1-methyl-6-phenyl-4H-1,2,4-triazolo (4,3-a) (1,4) benzodiazepine has not yet been known, although water-free crystals of this product were synthesized almost 20 years ago and the drug was repeatedly studied and processed as a valuable medicinal substance (alprazolam). It is amazing that anhydrous 8-chloro-1-methyl-6-phenyl-4H-1,2,4-triazolo (4,3-a) (1,4) benzodiazepine even in the heterogeneous aqueous phase (solubility 8-chloro-1 -methyl-6-phenyl-4H-1,2,4-triazolo (4,3-a) (1,4) benzodiazepine in water at room temperature is only 0.009%), even in the absence of a solvent, it turns into a hydrate. On the other hand, anhydrous 8-chloro-1-methyl-6-phenyl-4H-1,2,4-triazolo (4,3-a) (1,4) benzodiazepine is not hygroscopic. It is striking therefore that from a solvent containing water (in the case of ethyl acetate, a water content of about 3 vol. Is sufficient), a hydrate is obtained. The new hydrated form of 8-chloro-1-methyl-6-phenyl-4H-1,2,4-triazolo (4,3-a) (1,4) benzodiazepine differs from the anhydrous product not only in its crystalline form, but also and its range of melting temperature, which, starting from approximately 120 ^o C, more than 100 ^o C lies below the melting temperature of the anhydrous crystalline form. The occurrence of this hydrate is proved in the IR spectrum by the presence of a wide OH band at 3420 cm ^-1 .

Example 1. 10 g of anhydrous crystalline 8-chloro-1-methyl-6-phenyl-4H-1,2,4-triazolo (4,3-a) (1,4) benzodiazepine, white needle crystals, are stirred as a suspension in 100 ml of water for 6 hours at room temperature. Then the white crystalline is suctioned off, as before, the crystallizate is washed three times with 20 ml of water each. Dry in air at room temperature. The yield of plate crystals (rhombs) is 10.9 g. They melt at approximately 120 ^° C with partial melting or sintering followed by recrystallization above 140 ^° C. Initially, light crystals under a microscope are opaque dark, but macroscopically remain white. At a temperature of about 190-200 ^o C, the crystals sublimate from the crystalline mass, droplets appear. The main quantity melts at 229-232 ^o C.

C ₁₇ H ₁₃ ClN ₄ • 2H ₂ O (M.w. 344.80) (see Table 1):
In the IR spectrum, the presence of hydrate is proved by a wide OH band at 3420 cm ^-1 .

 Example 2. 5 g of anhydrous crystalline 8-chloro-1-methyl-6-phenyl-4H-1,2,4-triazolo (4,3-a) (1,4) benzodiazepine (crystals in the form of needles) are dissolved in 100 ml ethyl acetate (water content 3.5 vol.) at the boil. With stirring, it is cooled, the white crystallizate is suctioned off after standing for many hours and washed with a solvent. Obtain 4.8 g of plate, in most transparent diamonds. The melting behavior is the same as described above.

C ₁₇ H ₁₃ ClN ₄ • 2H ₂ O (M.W. 344.80):
Calculated: H ₂ O 10.4% Found: H ₂ O 9.5%
Example 3. 10 g of anhydrous 8-chloro-1-methyl-6-phenyl-4H-1,2,4-triazolo (4,3-a) (1,4) benzodiazepine (in the form of white needles) was stirred for 3 hours at room temperature with 100 ml of 90% (vol.) isopropanol. After approximately 45 minutes, crystal transformation can be clearly seen, since water-containing crystalline plates precipitate much faster on the bottom of the vessel than light needles. After 2 hours, the conversion is complete, which is visually controlled by a microscope. For reliability, the mixture is kept for another 1 h, then white crystals are sucked off and washed with a solvent. Yield 8.4 g. The melting behavior is the same as in Example 1.

C ₁₇ H ₁₃ ClN ₄ • 2H ₂ O (M.w. 344.80) (see Table 2):
Example 4

 10 g of anhydrous 8-chloro-1-methyl-6-phenyl-4H-1,2,4-triazolo (4,3-a) (1,4) benzodiazepine in 50 ml of 82% (vol.) Acetonitrile are dissolved at boiling point. Upon cooling, a crystalline product containing water crystallizes. Yield 8.4 g.

C ₁₇ H ₁₃ ClN ₄ • 2H ₂ O (M.w. 344.80) (see table 3):
Example 5. 5 g of hydrate 8-chloro-1-methyl-6-phenyl-4H-1,2,4-triazolo (4,3-a) (1,4) benzodiazepine is dissolved in 50 ml of 90% (vol. .) isopropanol at boiling point. Upon cooling, the hydrate crystallizes again. Yield 4.0 g of white, plate crystals.

C ₁₇ H ₁₃ ClN ₄ • 2H ₂ O (M.W. 344.80):
Calculated: H ₂ O 10.4% Found: H ₂ O 10.0%
Example 6. 5 g of crude 8-chloro-1-methyl-6-phenyl-4H-1,2,4-triazolo (4,3-a) (1,4) benzodiazepine (T _pl . 222-230 ^o C, brownish crystal aggregates) with 2 small side spots during thin-layer chromatography is dissolved in 50 ml of 90% (vol.) isopropanol at boiling point. An additional 10 minutes are boiled with 0.5 g of activated carbon and filtered while hot. Upon cooling, a white hydrate crystallizes, which is suctioned off and washed with 2 x 5 ml of 90% (vol.) Isopropanol. The output after 24-hour drying in air at 20-25 ^o C, is 4.1 g. T _pl. 120-132 ^o C droplets are formed, sinter and recrystallize, while the lamellar crystals examined under a microscope become opaque. T _pl. 227-231 ^o C.

C ₁₇ H ₁₃ ClN ₄ 2H ₂ (344.80):
Calculated: H ₂ O 10.4% Found: H ₂ 9.8%
In a thin-layer chromatogram (elution mixture of chloroform, acetone, ethanol 60:20:20), only 1 spot is obtained that is identical to 8-chloro-1-methyl-6-phenyl-4H-1,2,4-triazolo (4,3-a ) (1,4) benzodiazepine, Rf 0.45.

Claims (1)

 1 Crystalline 8-chloro-1-methyl-6-phenyl-4H-1,2,4-triazolo (4,3-a) (1,4) benzodiazepine lamellar dihydrate.

Images