SK286118B6 - Method of purifying lorazepam - Google Patents

Abstract

Described is a method of purifying lorazepam consisting of removing synthesis products, disintegrants, water or other solvent creating solvate with lorazepam by its crysatalisation or mixture in organic solvent such as ethers, esters or ketone. In this manner prepared lorazepam being use in pharmaceutical industry for the manufacture of medicaments.

Description

The invention relates to a process for the purification of lorazepam used in the pharmaceutical industry for the manufacture of medicaments for the treatment of psychiatric disorders.

BACKGROUND OF THE INVENTION

The first benzodiazepine drug was introduced in the 1950s, since then a large number of benzodiazepine derivatives having sedative, relaxing and muscle-relaxing properties have been discovered. These agents are used to treat e.g. depression, phobia, insomnia, muscle cramps.

Lorazepam, 7-chloro-5- (2-chlorophenyl) -1,3-dihydro-3-hydroxy-2H-1,4-benzodiazepin-2-one is a member of the aforementioned group of pharmaceutical substances.

Lorazepam can be prepared by several methods, e.g. in DE 2043614, CH 538490, CH590852 or ES 386 050. The latter file is based on the Polon reaction of 7-chloro-5-phenyl-4-oxo-1,3-dihydrobenzo [e] [1,4] diazepine-2- and acetic anhydride in the presence of acetic acid (described in detail for the preparation of 2-dechlorlorazepam (Oxazepam) in Spanish Patent Specification 386 050 (1970)). Analogous to 7-chloro-5- (2-chlorophenyl) -4-oxo-1,3-dihydrobenzo [e] [1,4] diazepin-2-one (1, Scheme 1), 3-acetoxy- 7-chloro-5- (2-chlorophenyl) -1,3-dihydrobenzo [e] [1,4] diazepin-2-one (2) followed by hydrolysis in an alkaline medium affords lorazepam (3).

Scheme 1. Process for preparing lorazepam

Lorazepam prepared by the aforesaid or other processes contains, in addition to synthesis impurities and / or decomposition products, in particular N-oxide L It also contains a bound solvent in the crystal lattice, e.g. water, acetone, alcohols (Rimbaud J. et al. II Farmaco 44, 519 (1989); acetonitrile, carbon tetrachloride, Chauvet A. et al. J. Thermal Anal. 38, 1593 (1992) and the like).

US 3,296,249 discloses a process for preparing lorazepam by removing an acetyl group from 7-chloro-5- (2-chlorophenyl) -1,3-dihydro-3-acetoxy-277-1,4-benzodiazepin-2-one (2) hydrolysis with ethanolic sodium hydroxide solution; upon completion of the hydrolysis, the precipitate obtained is filtered off, washed with water and crystallized from ethanol. However, the obtained lorazepam is an ethanol solvate of lorazepam (II Farmaco, 44, 512-529; 1989).

Since lorazepam is a thermolabile substance, at elevated temperature it switches to 6-chloro-4- (2-chlorophenyl) quinazoline-2-carbaldehyde (Chauvet, Ann.pharm.fr. 53, 256 (1995)) remove bound solvents.

Unsolvated lorazepam was prepared e.g. by treating the corresponding solvate with benzene (J. Therm. Anal. 38, 1593 (1992)). The preparation of solvent-free lorazepam is the subject of US 6,350,870 according to which desolvation is carried out by heating (42-80 ° C) lorazepam solvate (hydrate, alcoholate) in a strictly defined organic solvent: ethyl acetate, cyclohexane, dichloromethane, toluene and mixtures thereof, cooling the suspension to temperature. 10 -15 ° C, washing the crystals with an organic solvent and drying.

A disadvantage of this procedure is that it does not remove the pollutants introduced into the process or in the process, possibly during storage and handling, in particular 7-chloro-5- (2-chlorophenyl) -4-oxo-1,3-dihydrobenzo [e] [ 1,4] diazepin-2-one and uses ecologically problematic solvents, in particular dichloromethane, to remove bound crystals in the crystal lattice.

SUMMARY OF THE INVENTION

SUMMARY OF THE INVENTION The present invention provides a process for purifying lorazepam from concomitant substances formed during its synthesis or decomposition thereof, in particular 7-chloro-5- (2-chlorophenyl) -4-oxo-1,3-dihydrobenzo [e] [1,4] diazepine- 2

-one and the solvents forming lorazepam solvate by crystallization or mixing in an organic solvent from the group of ethers, esters and ketones.

The process of purification of lorazepam according to the invention has the advantage over known processes in that it removes the reaction and decomposition impurities as well as the solvents forming with solvates of lorazepam, in particular the hydrate and alcoholates, providing lorazepam with the desired physical properties in high yield. The lorazepam thus prepared is used to prepare dosage forms.

A process for purifying lorazepam from synthesis products, decomposition products, water or other solvents forming a solvate with lorazepam, e.g. hydrate, alcoholate, in that the solvate of lorazepam is crystallized in ethers or ketone-type solvents, the crystal is separated and desolvated by stirring in ethers, esters or ketone-type solvents at elevated temperature and after cooling the product is isolated.

Suitable organic solvents for crystallization of lorazepam are, in particular, cyclic ethers, in particular tetrahydrofuran or ketones, methyl isobutyl ketone and methyl ethyl ketone. Crystallization from tetrahydrofuran selectively removes e.g. 7-chloro-5- (2-chlorophenyl) -4-oxo-1,3-dihydrobenzo [e] [1,4] diazepin-2-one, or 3-acetoxy-7-chloro-5- (2-chlorophenyl) ) -l, 3-dihydro-benzo [e] [l, 4] diazepin-2-one. Tetrahydrofuran, however, forms a solvate with lorazepam and it is decomposed by desolvation by mixing in organic solvents of the ether type, such as aliphatic ethers having a carbon number of 6 to 8, acetic acid esters with alcohols having carbon numbers of 1,3 and 4, aromatic hydrocarbons, or of the type of ketones, particularly in methyl isobutyl ketone.

The lorazepam solvate is mixed with an organic solvent or a mixture of organic solvents in a ratio of 1: 0.5 to 20 w / v, preferably 1: 3 to 9 w / v in the temperature range from 30 ° C to the boiling point of the solvent used, preferably 35 to 70 ° C, for 0.1 to 48 hours. Subsequently, the solution or suspension is cooled to a temperature below 25 ° C, preferably 10 to 15 ° C. The Lorazepam is then separated by filtration, decanting or centrifugation, washed with the pure solvent used for purification and dried at a temperature of 20 to 100 ° C, preferably 40 to 60 ° C.

The following examples describe the embodiment of the invention in more detail, but do not limit its scope in any way.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

Lorazepam methanolate (5 g) is dissolved in tetrahydrofuran (25 ml), the suspension is stirred at 65 ° C for 1 h, cooled to 15 ° C, the lorazepam crystals are filtered off, washed with tetrahydrofuran, dried at 30 ° C under reduced pressure for 2 h. This procedure gave lorazepam 4.37 g, (HPLC purity 99.9%), tetrahydrofuran content greater than 3000 ppm. This solvate (4.5 g) was stirred in diisopropyl ether (z-Pr) ₂ O (40 mL) at 65 ° C for 60 min, the suspension was cooled to 15 ° C, the crystals were filtered off, washed with diisopropyl ether, dried at 35 ° C for 2 h under reduced pressure. 4.4 g of pure lorazepam (purity 99.9%) were obtained, residual solvents: 650 ppm of diisopropyl ether.

Example 2

Lorazepam methanolate (5 g) is dissolved in methyl isobutyl ketone (40 mL), the solution is stirred at 50 ° C for 30 min, then cooled to 15 ° C, the pure lorazepam crystals are filtered off, washed with methyl isobutyl ketone and dried at 20 ° C first at atmospheric pressure, then under vacuum (26 mmHg) for 1 hour. This gave a product (purity 99.7%) of 3.82 g, residual solvents 420 ppm methyl isobutyl ketone.

Example 3

Lorazepam ethanolate (5 g) is dissolved in methyl ethyl ketone (30 mL), the solution is stirred at 50 ° C for 30 min, then cooled to 15 ° C, the pure lorazepam crystals are filtered off, washed with methyl ethyl ketone and dried at 50 ° C at atmospheric pressure 3 h. This procedure yielded the product (purity 99.7%) in an amount of 3.94 g, residual solvents 350 ppm methyl ethyl ketone.

Example 4

Lorazepam ethanolate (5 g) is stirred in diisopropyl ether (z-Pr) ₂ O (40 mL), at 60 ° C for 80 min, the suspension is cooled to 15 ° C, the crystals are filtered off, washed with diisopropyl ether, dried at 35 ° C. ° C for 2 h under reduced pressure. 4.21 g of pure lorazepam (purity 99.6%) were obtained, residual solvents: 700 ppm of diisopropyl ether.

Example 5

Lorazepam methanolate (5 g) was stirred in n-dibutyl ether (35 mL), the suspension was heated at 80 ° C for 1 h, then cooled to 12 ° C. The pure lorazepam crystals are aspirated, washed with dibutyl ether and dried at 80 ° C for 3 hours under reduced pressure. 4.41 g of pure lorazepam (purity 99.6%) were obtained, residual solvents: 500 ppm n-dibutyl ether.

Example 6

Lorazepam ethanolate (5 g) was stirred in 30 ml of butyl acetate. A further procedure is given in Example 4. Pure lorazepam (purity 99.8%) was obtained in an amount of 4.02 g, residual solvents 600 ppm, butyl acetate.

Example 7

The Lorazepam solvate with acetone (5 g) was stirred in 35 ml of a 1: 1 (v / v) tetrahydrofuran-diisopropyl ether mixture. The suspension was heated at 65 ° C for 1 h, then cooled to 15 ° C. The lorazepam crystals are aspirated, washed with diisopropyl ether and dried at 40 ° C under reduced pressure. Pure lorazepam (purity 99.8%) was obtained in an amount of 4.40 g.

Example 8

The Lorazepam solvate with tetrahydrofuran (5 g) was stirred for 1 h in 45 ml of a 1: 1 (v / v) diisopropyl ether-dibutyl ether mixture. Following the procedure of Example 4. Pure lorazepam (purity 99.9%) was obtained in an amount of 4.47 g.

Example 9

Lorazepam hydrate (5 g) was stirred for 1 h in 45 ml diethyl ether at 35 ° C for 1 hour, following the procedure as described in Example 1. Pure lorazepam (purity 99.6%) was obtained in an amount of 4.51 g.

Example 10

Lorazepam hydrate (5 g) is stirred for 1 h in 40 ml of tetrahydrofuran-diisopropyl ether 1: 1 (v / v) at 65 ° C. Further procedure as in Example 6. Pure lorazepam (purity 99.7%) was obtained in an amount of 4.49 g.

Example 11

Lorazepam ethanolate (5 g) is dissolved in tetrahydrofuran (25 mL), the suspension is stirred at 65 ° C for 1 h, cooled to 12 ° C, the lorazepam crystals are filtered off, washed with tetrahydrofuran, dried at 45 ° C under reduced pressure for 2 h. This procedure yielded lorazepam 4.60 g, (HPLC purity 99.9%), tetrahydrofuran content greater than 3000 ppm. This solvate (4.5 g) was stirred in toluene (35 mL) at 75 ° C for 60 min., The suspension was cooled to 15 ° C, the crystals were filtered off, washed with toluene, dried at 45 ° C for 2 h. under reduced pressure. 4.4 g of pure lorazepam (purity 99.9%) were obtained, residual solvents: 400 ppm toluene.

Industrial usability

The process of purification of lorazepam according to the invention represents a substantial advantage in terms of technical demands, yield and environmental burden over known processes. The thus prepared lorazepam is used in the pharmaceutical industry for the manufacture of medicaments.

Claims (9)

PATENT CLAIMS Process for the purification of lorazepam from synthesis products, decomposition substances, in particular 7-chloro-5- (2-chlorophenyl) -4-oxo-1,3-dihydrobenzo [e] [1,4] diazepin-2-one, water or other solvents forming a solvate with lorazepam, characterized in that the crude solvate of lorazepam is crystallized in a solvent selected from tetrahydrofuran, methyl isobutyl ketone and methyl ethyl ketone, the lorazepam crystal is separated and desolvated by stirring in a solvent selected from ethers, esters or aromatic carbonates in a mixture, at a temperature of from 30 ° C to the boiling point of the solvent and after cooling, the product is isolated. Process according to claim 1, characterized in that the desolvation is carried out in aliphatic ethers having a carbon number of 6 to 8. Process according to claim 1, characterized in that the desolvation is carried out in acetic esters of aliphatic alcohols having 1 to 4 carbon atoms. The process according to claim 1, characterized in that the desolvation is carried out in toluene. The process according to claim 1, characterized in that the desolvation is carried out in ethyl acetate. Process according to claim 1, characterized in that the crystallization is carried out in tetrahydrofuran and the desolvation is carried out in one or a mixture of several aliphatic ethers having 6 to 8 carbon atoms. The process according to claim 1, characterized in that the crystallization is carried out in tetrahydrofuran tetrahydrate and the desolvation is carried out in toluene. Process according to claim 1, characterized in that the amount of organic solvent or solvent mixture used is 0.5 to 20 ml per 1 g of lorazepam solvate. The method of claim 1 wherein the assembly is agitated for from 0.1 to 48 hours.