HU206356B - Process for producing new, hydrate crystalline form of 8-chloro-1-methyl-6-phenyl-4h-1,2,4-triazolo/4,3-a//1,4/benzodiazepine - Google Patents

Abstract

8-Chloro-1-methyl-6-phenyl-4H-1,2,4-triazolo (4,3-a) benzodiazepine hydrate is included as a novel tabular crystal form of the alprazolam from the anhydrous compound by treatment with water or aqueous solvents. The preparation of this hydrate can be combined with a purification operation {8-chloro-1-methyl-6-phenyl-4H-1,2,4-triazolo (4,3-a) benzodiazepine hydrate; alprazolam; 1,2,4-triazolo (4,3-a) (1,4) benzodiazepine; new crystal form; Hydrate; Cleaning}

Description

The present invention relates to a novel hydrate crystal form of 8-chloro-1-methyl-6-phenyl-4H-1,2,4-triazolo [4,3-a] [1,4] benzodiazepine, characterized in that it is free of crystalline water. -chloro-1-methH-6-phenyl4H-1,2,4-triazolo [4,3-a] [1,4] benzodiazepine is treated with solvents containing water or water. The treatment results in the formation of a pharmacologically advantageous bridge of the compound which is unknown to date.

Scope of the description: 4 pages

HU 206 356 B

HU 206 356 Β

This invention relates to a novel hydrate crystal form of 8-chloro-1-methyl-6-phenyl-4H-1,2,4-triazolo [4,3-a] [1,4] benzodiazepine (alprazolam). The present invention can be used in the manufacture of pharmaceuticals to produce a preferred crystalline form of said axiolytic drug having antidepressant activity.

Several processes are known for the preparation of 8-chloro-1-methyl-6-phenyl-4H1,2,4-triazolo [4,3-a] [1,4] benzodiazepine, free of crystalline water (U.S. Patent No. 83360, 115674, 7113800). Dutch Patent Application Publication Nos. 2203782, 2242938, 2402363 and 3,413,709). In each case, the final product is recrystallized from an organic solvent (mainly ethyl acetate) or a mixture of solvents such as acetone and hexane or dichloromethane, ethyl acetate and ether. No. 7,113,800. Example 32 of Dutch Patent Application Publication No. 2402363; According to Example 1 of US Patent Application, 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 by recrystallization from ethyl acetate. 228-229 ° C.

However, long needle-shaped crystals are disadvantageous in drug technology because they are tangled and misplaced. No. 3980789. U.S. Pat. No. 5,123,198 discloses pharmacologically acceptable salts of 8-chloro-1-methyl-6-phenyl-4H-1,2,4-triazolo [4,3-a] [1,4] benzodiazepine with physiologically tolerable inorganic and organic acids. use. Finally, USP XXI and Clarke's book "Isolation and Indentification of Drugs" (2nd Ed. London 1986, p. 331) contain references to 8-chloro-1-methyl-6-phenyl-4H1.2.4- certain anhydrous polymorphs of triazolo [4,3-a] [1,4] benzodiazepine. However, hydrate formation in this case is not known from the literature.

SUMMARY OF THE INVENTION The present invention is directed to the development of a new preferred crystalline form of 8-chloro-1-methyl-6-phenyl-4H-1,2,4-triazolo [4,3-a] [1,4] benzodiazepine, a known anxiolytic drug. can be produced economically without any technical investment. We set the following conditions:

- be technological and equipment specific;

- excipients that are toxic or harmful to the environment must not be used;

- the solvent can be easily recovered;

- the procedure should be economical;

it is technologically advantageous to process and

- higher purity product.

The task, therefore, was to find a new crystal form of 8-chloro-1-methyl-6-phenyl-4H-1,2,4-triazolo [4,3-a] [1,4] benzodiazepine, as well as a process. , which meets the above requirements and also serves the purification of the target product.

This object is solved by the present invention by crystalline-free 8-chloro-1-methyl-6-phenyl-4H-1,2,4-triazolo [4,3-a] [1,4] benzodiazepine with water or aqueous solvent, optionally at elevated temperature. The active ingredient hydrate is formed, which forms disk-like crystals. According to the invention, the treatment conditions can be varied within wide limits, for example the hydrate formation is complete even if the anhydrous 8-chloro-1-methyl-6-phenyl-4H-1,2,4-triazolo [4,3- a] [1,4] benzodiazepine suspension in water. the suspension is stirred at room temperature. To speed up the process at elevated temperatures, for example

We can also work at temperatures between 40 ° C and 70 ° C. The reaction medium may also be an aqueous organic solvent, preferably a solvent which is miscible with water in any proportion, such as alcohols, acetone, acetonitrile. The water content of the solvent may be varied within a wide range and may be, for example, from 10 to 50%, preferably from 10 to 20%. In the case of an aqueous solvent, it is also possible to work at elevated temperatures. However, to improve the yield, the mixture must be cooled before isolation.

Alternatively, a solvent which can absorb only a limited amount of water, e.g. esters. In this case, the water content must be at least 3%, otherwise the hydrate formation will be slowed down. The solid to liquid ratio may vary within wide limits, for example from 1: 5 to 1: 100. In any case, the mixing of the suspension must be ensured.

Recrystallization may also be carried out; in this case, the anhydrous 8-chloro-1-methyl-6-phenyl-4H-1,2,4-triazolo [4,330a] [1,4] benzodiazepine is dissolved in a suitable aqueous solvent by boiling. Upon cooling, the hydrate crystallizes immediately. The organic solvents mentioned above, i.e., alcohols, acetone, acetonitrile or esters, may be used with appropriate water content. A particular variant is the use of an azeotropic mixture, for example, isopropanol containing 10% by volume of water or acetonitrile containing 18% by volume of water. This recrystallization is particularly advantageous when the starting, anhydrous crystalline 8-chloro-1-methyl-6-phenyl-4H-1,2,4-triazolo [4,3-a] [1,4] benzo40 diazepine is not yet completely pure . In this case, purification is carried out together with hydrate formation. Depending on the nature 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 clarify the solution in aqueous solvent with activated carbon. It is also advantageous to repeat the treatment with activated charcoal with the resulting hydrate to obtain a particularly pure product.

Thus, the process according to the invention can be used, on the one hand, for the addition of crystalline water, optionally pure 8-chloro-1-methyl-6-phenyl-4H-1,2,4-triazolo [4,3a] [1,4] benzodiazepine optionally by simultaneous purification to 8-chloro-1-methyl-6-phenyl-4H-1,2,4-triazolo [4,3-a] [1.4] benzodiazepine hydrate and purification of the product in its hydrate form, and may be recovered in the form of a purified hydrate.

The process of the present invention is particularly surprising because the 8-chloro-1-methyl-6-phenyl-4H-1,2,4-triazolo [4,3-a] [1.4] benzodiazepine hydrate has not yet been despite the fact that the anhydrous product has been known for about 20 years, it is a valuable drug

HU 206 356 Β (alprazolam) has been tested many times. Surprisingly, anhydrous 8-chloro-1-methyl-6-phenyl-4H-1,2,4-triazolo [4,3a] [1,4] benzodiazepine, even in a heterogeneous aqueous phase (water solubility of the active ingredient at room temperature is only 0.009%). ) to form a hydrate. On the other hand, the hydrate is not hygroscopic. Therefore, it is surprising that hydrates are formed in aqueous solvents (3% water is sufficient for ethyl acetate). The hydrate differs from the anhydrous product not only in its crystalline form but also in its melting range; the latter starts at 120 ° C, thus more than 100 ° C lower than the melting point of the crystalline-free form. The presence of hydrate is evidenced by the IR spectrum: at 3420 cm-1 there is a broad HO band.

Execution examples

EXAMPLE 1 8 g of anhydrous 8-chloro-1-methyl-6-phenyl-4H-1,2,4-triazolo [4,3-a] [1,4] benzodiazepine - white needle crystals are suspended in 100 ml of water and the suspension is and stirred at room temperature for 6 hours. The white crystalline solid is filtered off with suction and washed with water (3 x 20 mL). The material is air-dried at room temperature. 10.9 g of a slab (diamond) crystal are obtained, which begins to melt at about 120 ° C (onset, sintering, then recrystallization from 140 ° C). At 190-200 ° C, needles sublimate from the crystalline mass; droplets are formed. The main amount melts at 229-232 ° C.

Calculated for C ₁₇ H ₁₃ ClN ₄ + 2 H ₂ O (344.80):%,

H ₂ O 10.4 C, 59.21 H4,97 Cl, 10.28 N, 16.25 found,%: H ₂ O 9.3 C, 59.81 H4,90 Cl, 10.35 N, 16.10 59.73 4.95 10.36 16.24 It is wide at 3420 cnr in the IR spectrum bar bizo-

opens the hydrate formation.

Example 2 g of crystalline anhydrous 8-chloro-1-methyl-6-phenyl-4H, 2,4-triazolo [4,3-a] [1,4] benzodiazepine (crystalline form: needles) in 110 ml of 3.5% water in ethyl acetate containing boiling. The solution was allowed to cool with stirring, the white crystalline material was suctioned off after standing for several hours and washed with solvent. 4.8 g of lamellar, mostly transparent, rhomboidal crystals were obtained, with melting behavior similar to that described in Example 1.

Elemental analysis based on C ₁₇ Hi ₃ C 1 N ₄ + 2 H ₂ O (344.80;):

Calculated: H ₂ 010.4% The found H ₂ O is stirred for 95% hours. After about 45 minutes, the continuous crystal transformation is already recognizable, because the crystals containing the crystalline water settle much faster than the light needles. Optical examination (microscope) showed that after 2 hours the conversion was complete. For safety, the mixture was stirred for an additional 1 hour, then the white crystals were filtered off with suction and washed with solvent. Yield: 8.4 g. The melting behavior is as described in Example 1.

Calculated for C ₇ H ₁₃ ClN ₄ + 2 H ₂ O (344.80):%,

H ₂ O 10.4 C, 59.21 H, 4.97 Cl, 10.28 N, 16.25 found,%: H ₂ O 9,8 C, 59.72 H4.90 Cl, 10.46 N, 16.10 59.66 4.81 10.46 16,20

Example 4 Anhydrous 8-chloro-1-methyl-6-phenyl-4H-1,2,4-triazolo [4,3-a] [1,4] benzodiazepine was dissolved in 50 ml of 82% acetonitrile by boiling. . During cooling, the product containing crystalline water crystallizes. Yield:

8.4 g.

Calculated for C ₁₇ H ₁₃ ClN ₄ + 2 H ₂ O (344.80):%

H ₂ 010.4 found,% C, 59.21 H4,97 Cl, 10.28 N, 16.25 H ₂ O 9.2 C, 59.37 H5,03 Cl, 10.53 N, 16.26 59.39 4.91 10.62 16.14

Example 5 8-Chloro-1-methyl-6-phenyl-4H-1,2,4-triazolo [4,3-a] [1,4] benzodiazepine hydrate in 50 ml of 90% isopropanol under reflux. dissolved. After cooling, the hydrate recrystallizes. Yield: 4.0 g white, white crystals.

Elemental analysis based on C ₁₇ H ₁₃ ClN ₄ + 2 H ₂ O (344.80):

Calculated: H ₂ 010,4 010,0 _2% Found H%

Example 6 g of crude 8-chloro-1-methyl-6-phenyl-4H-1,2,4-triazolo [4,3-a] [1,4] benzodiazepine (m.p. 222-230 ° C, brownish-brown set) Dissolve two smaller side spots in thin layer chromatography (50 mL) in 90 mL of 90% isopropanol at reflux. The solution is refluxed with charcoal for 10 minutes and the charcoal is filtered hot. After cooling, the white hydrate crystallizes. The product is filtered off with suction, washed with 2 x 5 ml of 90% isopropanol and then air-dried at 20-25 ° C for 24 hours. Yield: 4.1 g, m.p. 120-132 ° C (drop formation, sintering, recrystallization, whereby the plate crystals become opaque under a microscope). Mp 227-231 ° C.

Elemental analysis of C | Based on ₇ H ₁₃ C ₁ N ₄ + 2 H ₂ O (344.80):

Calculated: H ₂ 010.4% Found: H ₂ O 9.8%

Example 3 g anhydrous 8-chloro-1-methyl-6-phenyl-4H-1,2,4-triazolo [4,3-a] [1,4] benzodiazepine (as white needles) at room temperature in 100 ml 90% os isopropanol

HU 206 356 Β

TLC:

(chloroform: acetone: ethanol = 60:20:20) shows only one spot, 8-chloro-1-methyl-6-phenyl-4H, 2,4-triazolo [4,3-a] [1,4 ] benzodiazepine: _Rf = 0.45.

PATENT CLAIMS

Claims (8)

PATENT CLAIMS A process for the preparation of a novel hydrate crystalline form of 8-chloro-1-methyl-6-phenyl-4H-1,2,4-triazolo [4,3-a] [1,4] benzodiazepine, characterized by: to treat 8-chloro-1-methyl-6-phenyl-4H-1,2,4-triazolo [4,3-a] [1,4] benzodiazepine, free of crystalline water, with water or a solvent containing water. 2. A process according to claim 1 wherein the solvent is a solvent wholly or partially miscible with water, The process according to claim 1 or 2, wherein the solvent is an alcohol, acetone, acetonitrile or an ester. 20 4. Process according to any one of claims 1 to 3, characterized in that an alcohol, acetone or acetonitrile is used which has a water content of 10-50% by volume, preferably 10-20% by volume, or an ester containing at least 3% by volume of water. 5. A process according to any one of claims 1 to 3, wherein the aqueous or aqueous solvent treatment of 8-chloro-1-methyl-6-phenyl-4H1,2,4-triazolo [4,3-a] [1,4] benzodiazepine is carried out in suspension. , optionally at an elevated temperature of 40-70 ° C. A process according to any one of claims 1-5, wherein the 8-chloro-1-methyl-6-phenyl-4H1,2,4-triazolo [4,3-a] [1,4] benzodiazepine treatment with aqueous solvent while completely dissolving under heating, crystallization as hydrate by cooling the solution. 7. A process according to any one of claims 1 to 3, wherein the crude 8-chloro-1-methyl-6-phenyl-4H1,2,4-triazolo [4,3-a] [1,4] benzodiazepine is dissolved in an aqueous solvent with activated carbon before cooling. treated 8. Process according to any one of claims 1 to 3, characterized in that the 8-chloro-1-methyl-6-phenyl-4H1,2,4-triazolo [4,3-a] [1,4] benzodiazepine hydrate is redissolved under reflux. the solution is optionally treated with activated carbon and the product is recovered from the solution upon cooling. Published by the National Office for Inventions, Budapest Responsible for the publication: dr. Gabriella Swoboda Head of Department »