NO138658B - ANALOGICAL PROCEDURES FOR THE PREPARATION OF NEW THERAPEUTICALLY ACTIVE PIPERIDE DERIVATIVES AND THEIR SALTS - Google Patents

Description

Process for the production of therapeutically effective fluorine-containing benzodiazepine derivatives.

The present invention relates to a method for the production of fluorine-containing benzodiazepine derivatives, which can be visualized by the following general formula:

where R 1 and R 3 mean hydrogen or lower alkyl group and one of them

with R 3 designated substituents means one trifluoromethyl group and the other

hydrogen

and acid addition salts of these compounds.

The method according to the invention is characterized by reacting a halide with the general formula: where Rt and R:i have the preceding meaning and X means halogen,

with ammonia or a primary amine, with the formula R,-NH2, where R2 has the preceding meaning, whereby a structural change occurs in the molecule and the pyrimidine ring is expanded to a 1,4-diazepine structure, and that, if desired, it is transferred obtained product to an acid addition salt.

The method according to the invention is preferably carried out at room temperature in water or an organic solvent, such as lower aliphatic alcohols, dioxane or tetrahydrofuran. The primary amine is a lower alkylamine, such as methylamine, ethylamine, propylamine or isopropylamine.

The salt formation can be carried out e.g. with mineral acids such as halogen hydrogen acids, e.g. hydrochloric acid, or sulfuric, nitric or phosphoric acid.

The compounds corresponding to the preceding formula II are new, but for which no special protection is required. The procedures for their manufacture can be taken from the subsequent design examples, which reveal their synthesis in detail (cf. Norwegian patent no. 99 734).

The final products according to the method according to the invention exhibit sedative properties and can be used as sedatives or muscle relaxants. They are also suitable as anticonvulsants. The administration of the bases and salts takes place in the usual way according to pharmaceutical practice.

The following examples illustrate the method according to the invention. All temperatures are given in C°.

Example 1 :

0.5 g of 2-chloromethyl-4-phenyl-6-trifluoromethyl-quinazolin-3-oxide is treated with 10 ml of a saturated solution of ammonia in methanol. The reaction mixture is allowed to stand at room temperature for 5 hours, then diluted with ether and washed 3 times with water. The ether solution is separated and dried overnight. The solvent is evaporated in vacuo and the residue recrystallized from benzene-hexane. 7-trifluoromethyl-2-amino-5-phenyl-3H-1,4-benzodiazepine-4-oxide is obtained in the form of white needles, which melt at 229-231°.

The starting material can be prepared as follows: 80 g of sodium nitrite is added slowly while stirring to 460 ml of concentrated sulfuric acid. After heating to 70°, a clear solution is obtained. This solution is cooled and added at a temperature of between 10 and 20° slowly with 200 g of 2-chloro-5-trifluoromethyl-aniline. The reaction mixture is stirred for 1 hour at 20° and then poured into a mixture of 200 g of sodium chloride and 1.6 kg of ice. The excess sodium chloride is filtered off and a solution of 280 g of zinc chloride in 300 ml of water is added to the filtrate, whereby a zinc chloride double salt of the corresponding diazone compound separates. After standing overnight at 0°, the double salt is filtered off and washed with a cold saturated salt solution.

To a solution of 120 g of sodium cyanide and 72 g of cuprocyanide in 300 ml of water, 291 g of the wet zinc chloride double salt are added while stirring and cooling with ice. After the addition of 24 g of sodium carbonate, the reaction mixture is first stirred for 1 hour at 20°, then for a further 1/2 hour at 70°. The reaction mixture is cooled and extracted with ether, whereby crude 2-chloro-5-trifluoromethyl-benzonitrile is obtained. This is purified by steam distillation and crystallization of the organic part of the distillate from hexane. The pure compound melts at 39-40°.

A solution of 39 g of 2-chloro-5- trifluoromethyl-benzonitrile in 200 ml of benzene. 400 ml of the solvent is distilled off, and the reaction mixture is heated for 16 hours under reflux. The Grignard complex is cleaved with 40 g of ammonium chloride and 200 g of ice and the mixture is extracted with benzene. From the benzene solution, 2-chloro-5-trifluoromethylbenzophenoneimine hydrochloride precipitates upon addition of 40 ml of concentrated hydrochloric acid. It is filtered off, washed with benzene and dried in vacuo; pp. p. 248-251°. 60 g of 2-chloro-5-trifluoromethyl-benzophenoneimine hydrochloride are heated overnight with a mixture of 300 ml of toluene and 300 ml of 25% sulfuric acid with stirring and reflux. The toluene layer is separated, washed with water, dried and evaporated in vacuo. The residue is crystallized from hexane, whereby pure 2-chloro-5-trifluoromethyl-benzophenone with a melting point of 39-40° is obtained. 50 g of 2-chloro-5-trifluoromethyl-benzo-phenone and 500 ml of concentrated ammonia are reacted in a closed vessel for 10 hours at 140° in the presence of 10 g of cuprochloride as catalyst. The reaction product is extracted with ether, the ether extract is evaporated in vacuo and the residue is dissolved in hexane. The resulting solution is purified by chromatography to a 10-fold amount of neutral aluminum oxide (Brockmann activity II). By elution with a hexane/ether mixture (1:1) and the evaporation of the solvent, 2-amino-5-trifluoromethyl-benzophenone is obtained which, recrystallized from hexane, gives yellowish crystals with a melting point of 81-82°.

13.3 g of 2-amino-5-trifluoromethyl-benzo-phenone in 60 ml of ethanol are heated for 24 hours with 6 g of hydroxylamine hydrochloride under reflux. The reaction mixture is set to approx. pH 6 by the addition of a solution of 12 g of sodium acetate in 100 ml of water. The mixture is extracted with ether, whereby an oil is obtained, which by repeated crystallization from a mixture of ether and

hexane gives 2-amino-5-trifluoromethyl-benzo-phenone-oxime with melting point 175-177°.

2.8 g of 2-amino-5-trifluoromethyl-benzo-phenone-oxime are dissolved in 15 ml of acetic acid and, after adding 1.5 ml of chloroacetyl chloride, the solution is kept for 1 hour at 20° and then for 2 hours at 70°. The mixture is diluted with ether and washed with water. The ether solution is evaporated in vacuo and gives a solid residue, which recrystallized from methylene chloride-ether gives pure yellow 2-chloro-methyl-4-phenyl-6-trifluoromethyl-quinazolin-3-oxide with a melting point of 149-150°.

Example 2:

500 mg of 2-chloro-methyl-4-phenyl-6-trifluoromethyl-quinazolin-3-oxide is treated for 5 hours at 25° with 10 ml of a 40% solution of methylamine in methanol. The reaction mixture is diluted with water and then extracted with ether. The ether solution is concentrated in vacuo and the crude reaction product obtained is purified by crystallization from ether-hexane. 7-trifluoromethyl-2-methylamino-5-phenyl-3H-1,4-benzodiazepine-4-oxide is obtained in the form of colorless crystals, which melt at 257-258°.

100 mg of this compound are dissolved in 5 ml of methanol and then treated with 3 ml of 0.1 N hydrochloric acid at 25°. The reaction mixture is evaporated at 40° and the residue is crystallized from methanol-ether. The pure hydrochloride of 7-trifluoromethyl-2-methylamino-5-phenyl-3H-1,4-benzo-diazepine 4-oxide is obtained in the form of white prisms; melting point 222° (decomposition).

When using 2-chloromethyl-4-phenyl-7-trifluoromethyl-quinazolin-3-oxide as starting material, according to the method described in examples 1 and 2, 8-trifluoro-methyl-2-amino-5-phenyl-3H- 1,4-benzodiazepine-4-oxide and 8 trifluoromethyl-2-methyl-amino-5-phenyl-3H-1,4-benzodiazepine-4-oxide are obtained.

Example 3:

A mixture of 4.4 g of crude 2(α-chloro-ethyl)-4-phenyl-6-trifluoromethyl-quinazolin-3-oxide (m.p. 140-145° C) in 125 ml of a

.The 21% solution of methylamine in methanol is stirred at room temperature overnight. About. 25 minutes after adding the quinazoline to the methylamine solution, a white product begins to crystallize. The excreted 3-methyl-2-methyl-amino-5-phenyl-7-trifluoromethyl-3H-1,4-benzodiazepine-4-

oxide is filtered off, washed with methanol and dried. 3.6 g of a material with a melting point of 252-253° is obtained (83% yield). Recrystallization from acetonitrile gives colorless discs with a melting point of 257-258°.

The starting material can be produced as

following:

A solution of 10 g of 2-amino-5-trifluoromethyl-benzophenone-α-oxime in 200 ml of ether is cooled in an ice bath to approximately 5° and then stirred with 50 ml of water. 5 g (4 ml) of 2-chloro-propionyl chloride are then slowly added, keeping the reaction mixture weakly alkaline while simultaneously adding 10% caustic soda. After complete addition, the reaction mixture is stirred cold for a further 30 minutes. The aqueous layer is then separated and washed once with benzene. The benzene layer is added to the original ether layer and washed with cold water, dried over sodium sulfate and then evaporated to dryness. The residue is crystallized from a mixture of methylene chloride and hexane, which gives 8 g of 2'-benzoyl-2-chloro-4'-trifluoromethyl-propionanilide oxime with a melting point of 169.5-170° (colorless discs). From the mother liquor, a further 1.6 g of the product is obtained from recrystallization from methylene chloride (total yield 72.5%). Further recrystallization does not change the melting point.

A solution of 7.3 g of 2'-benzyl-2-chloro-4'-trifluoromethyl-propionanilide oxime in 175 ml of acetic acid is saturated with hydrogen chloride. The temperature rises from 23 to 37° and the color of the solution becomes yellow. After standing at room temperature overnight, the solvent is distilled off in a vacuum. The residue is dissolved in 150 ml of benzene and again brought to dryness in a vacuum. The yellow, crystallized precipitate is dissolved in methylene chloride and washed with ice water. After drying the organic layer over sodium sulphate, the solvent is distilled off, whereby a yellow, crystalline residue remains, which is recrystallized from hexane. 3.5 g of yellow needles are obtained from crude 2-(α-chloro-ethyl)-4-phenyl-6-trifluoro-methyl-quinazolin-3-oxide with a melting point of 140-145°. 1.2 g of additional reaction material with a melting point of 140-145° is obtained from the mother liquor (total yield 69%).

Claims (1)

Process for the preparation of therapeutically effective fluorine-containing benzodiazepine derivatives with the general formula: in which R{ and R, mean hydrogen or a lower alkyl group, and one of the substituents denoted by R. means a trifluoromethyl group and the other hydrogen, and acid addition salts of these compounds, characterized by reacting a halide with the general formula: in which R, and R3 have the preceding meaning and X means halogen, with ammonia or a primary amine of the formula R2-NH2, where R has the above meaning, and, if desired, converts the reaction product obtained with an acid into an acid addition salt.