SU455536A3 - The method of obtaining derivatives of azepine or their salts - Google Patents

Description

one

The invention relates to the preparation of new azepine derivatives, which can be used in the pharmaceutical industry.

The proposed method is based on the known reaction of replacing hydrogen with bromine.

The use of the known bromination reaction to obtain compounds of the azepine range leads to the production of new azepip derivatives with high biological activity.

And the proposed method of obtaining azepine derivatives of the general formula

Bgbg

where RI is oxygen, lower alkyl, or a residue replaced by hydrogen by hydrolysis, the compound of the general formula

tt And

with

ten

where Rl is lower alkyl or a residue that is replaced by hydrogen by hydrolysis, is brominated in an inert solvent, followed by isolating the desired product as a base or by salting it in a known manner.

N-bromosuccinimide, N-bromomaleimide, N-bromophthalimide is preferably used as the brominating agent. For

accelerating the reaction, the reaction mixture is irradiated with a UV lamp or an ordinary 200 watt incandescent lamp.

The residues Rl which can be converted to a hydrogen atom by hydrolysis are, for example, an acetyl group, a benzoyl group, a methoxycarbonyl, ethoxycarbonyl, phenoxycarbonyl group. The hydrolysis is preferably carried out in acidic

for example, using hydrogen bromide in water or in glacial acetic acid.

Example 1 a) To a solution of 98 g of 10,11-dimethyl-5H-dibenz (b, /) azepine, so pl. 131-132 ° C, in 295 ml of toluene, but drop by drop, stirring for 30 minutes, 39.5 g of acetyl chloride. The reaction mixture is then boiled under reflux for five hours, evaporated in vacuo and the residue is taken up in ether. The ether solution is washed with water, dried over sodium sulfate and evaporated. The residue, which is recrystallized from petroleum ether, gives 5-acetyl-10,11-dimethyl-5H-dibenz (b, /) asection, mp. 109-PGS;

b) 101 g of 5-acetyl-10,11-dimethyl-5H-dibenz (b, /) azepipa is dissolved in 1 l of carbon tetrachloride and 138 g of iN-bromosuccinimide is added. The mixture is heated to boiling by stirring at iomosh, and two lamps of 200 volts or an ultraviolet lamp. Boiling is continued until all of the N-bro. Succinimide undergoes an exchange reaction. The reaction mixture is then cooled to 0 ° C and 200 ml of water are added. The precipitated crystalline 5-acetyl-10,11 bis-bromomethyl-5H-dibenz (& /) chain (so pl. 175-176 ° C) is sucked off.

Example 2 a) To a solution of 223 g of 5-methyl 5, 11-dihydro-10H-dibenz (b, f) azenin-10-one in 1.5 liters of absolute benzene is added in 1 hour over cannon and constantly stirring the suspension 43 g of sodium amide in 120 ml of toluene at 65-75 ° C. Then the reaction mixture is refluxed for two hours. The suspension is cooled to 45-50 ° C, 221 g of methyl iodide is added dropwise over 1 hour at this temperature and stirring is continued for 16 hours at 45--50 ° C. Next, the reaction mixture is cooled to 5-10 ° C and 250 ml of water are carefully added. The organic phase is separated, washed with water, dried over sodium sulfate to a volume of about 400 ml. 200 ml of petroleum ether was added to this concentrated solution, as a result of which 5,11-dimethyl-5,11-dihydro-OH - dibenz (b, f) a3enHH-10-OH, t.p. at 128-130 ° C;

b) To a solution of the Compound Gr pry, extruded from 47 g of magnesium, 273 g of methyl iodide and 540 ml of absolute ether, is added dropwise over 1.5 hours, and with vigorous stirring a solution of 228 g of 5,11-dimethyl-5, 11-dihydro-10H - dibenz (L, I) azepin-10-o in 950 ml abs. benzene, and maintain the reaction temperature from -5 to 0 ° C. Then the suspension is heated to 50 ° C and at this temperature continue stirring for 20 hours. The reaction mixture is cooled to 0 ° C and poured into the mixture with 1 l 2 n. hydrochloric acid and 500 g of ice. The organic phase is separated and the aqueous phase is extracted again with benzene. The combined organic solutions are washed with water, dried over sodium sulfate and evaporated in vacuo. The residue that is recrystallized from gasoline,

gives 5,10,11-trimethyl-10-11 - dihydro - 5H-dibepz (s, /) azepin-10-ol, so pl. 102-104 ° C;

c) A mixture of 89 g of 5,10,11-trimethyl-10,11-dihydro-5H-dibenz (6, /) azepin-10-ol and 890 g of polyphosphoric acid is stirred vigorously for one hour at 95-100 ° C. Then the reaction mixture is cooled and slowly poured into 3 l of water at 40 ° C, while the reaction temperature does not exceed 60-70 ° C. The precipitated product is filtered under suction at 20 ° C, 1 l of 2n solution is added. ammonia and unbound base are extracted with benzene. The benzoic solution is washed with water, dried pad with potassium carbonate and evaporated. The residue, which is recrystallized from gasoline, gives 5,10,11-trimethyl-5H - dibenz (b, /) azepine, t. Nl. 109-111 ° C;

d) 23.5 g of 5,10,11-trimethyl-5P-dibenz (6,) azepine is dissolved in 300 ml of carbon tetrachloride

and add 36 g of N-bromo succinidum. The mixture is heated to kineni by stirring and refreshing, by burning two lamps of 200 volts or an ultraviolet lamp. The boiling is continued until the entire iiN-bromo-succinimide is not exposed.

exchange reactions. Then it is cooled to 20 ° C and 50 ml of water are added. The organic phase is separated, washed with water, dried over sodium sulfate and evaporated in vacuo at 40 ° C. The residue is dissolved in 50 ml of ether, the solution is cooled to 0 ° C, and 5-methyl-10,11-bis-brom.methyl51-1-dibepz (b, /) azell (a), tl. 127-130 ° C.

Subject invention

The method of obtaining the azepipe derivatives of the formula

" with

where RI is hydrogen, lower alkyl, the residue replaced by hydrogen by hydrolysis,

or salts thereof, characterized in that the compound of the general formula

N and

where Rl is lower alkyl, or residue, substitution e

hydrogenated by hydrolysis, brominated

65 for example, N-bromosuccinimide in an inert solvent, followed by isolation of the desired product as a base or salt conversion in a known manner. 6 Priority by signs: 12/19/68 with Ri - hydrogen or methyl group; 10.29.69 with Ri - ethyl or propyl group.