SU330635A1 - - Google Patents

Description

Method for producing benzodiazepine derivatives

The invention relates to a method for producing new benzodiazbpine derivatives having valuable pharmacological properties.

The method is based on the known oxidation reaction of 2-aminomethylindole with the extension of a five-membered cycle to a seven-membered one.

A method for producing new benzodiazepine derivatives of the general formula is described.

CL-CO

I o

9n "2n

C

/ SNg

N

where RI is a hydrogen atom, a halo, nitro or trifluoromethyl group;

m carbon atoms or trifluoromethyl;

R4-alkyl with one to four carbon atoms;

n is an integer from 1 to 3; or their salts, which consists in the fact that the derivative of 2-aminomethylindole of the general formula

where RI, R2, Ra, R4 "p are as defined above,

interact with an oxidizing agent;

The target product is isolated in a free cell or phosphate. Oxidants used in the proposed method include, for example, ozone, hydrogen peroxide, peracids (e.g., n-formic acid, perbenzoic acid), chromic acid, and potassium permanganate. Usually, the reaction proceeds easily at room temperature, it can be conducted at a higher or lower temperature, for example, in the interval from 0 to 100 ° C, or at the boiling point of the solvent, preferably in the range from 10 to 60 ° C, depending on specified reaction control conditions, as well as depending on the oxidant used. The preferred oxidizing agent is ozone or chromic acid. The reaction is advisable to conduct in the environment of the solvent. The choice of solvent depends on the oxidizing agent used; it is selected by a ds group, including water, acetone, carbon tetrachloride, formic acid, acetic acid, sulfuric acid, etc. The oxidizing agent is used in stoichiometric amounts or with excess.

When chromic acid is oxidized in acetic acid, it is advisable to take chromic acid with a two-to three-fold excess versus an equimolar amount, and the reaction can be carried out at a compacted temperature. The 2-aminomethylpdol derivative is dissolved or suspended in a solvent, then an oxidizing agent is added to the solution or suspension with stirring.

When ozone is oxidized, it is advisable to conduct the reaction at room temperature, the 2-aminomethyl indium derivative is dissolved or suspended in a solvent, for example formic acid, acetic acid, carbon tetrachloride, and ozone is bubbled into the solution or suspension with stirring.

The desired product is isolated from the reaction mixture in crude form by extraction, and then purified by recrystallization from a suitable solvent, for example ethanol, isopropanol, by known methods.

The benzodiazepine derivatives obtained in this way form addition salts with inorganic and organic acids, for example, with hydrochloric, hydrobromic, sulfuric, phosphoric, nitric, acetic, maleic, fumaric, tartaric, tartaric, citric, camphorsulfonic, ethanesulfonic, auretic, arsh, oyster, tartaric, citric, phosphoric, nitric, acetic, maleic, fumaric, tartaric, and hydrochloric acids. P.

Example. A solution of 1 g of chromic anhydride in 1 ml of water is poured into a mixture of 1 g of 1- (p-acetoxyethyl) -2-aminomethyl-3 feiyl-5-chloroindol hydrochloride in 20 ml of acetic acid. The mixture is stirred for about a day at room temperature. The reaction mixture is diluted with water, basified with an aqueous solution of ammonia (caustic ammonium) and extracted with ether. The ether extracts are combined and the pad is dried with sodium sulfate, the solvent is distilled off. The residue is chromatographed on silica gel, eluted with chloroform to give 1- (p-acetoxyethyl) -5-phenyl- / chlor-1, 3-dihydro-2H-1,4-benzodiazepin-2-one. Its hydrochloride is obtained by reaction with an ethereal solution of hydrogen chloride and recrystallized from a mixture of methanol and

acetone; colorless prisms with m. pl. 193-195 ° С (during decomposition).

Similarly, the following compounds are obtained;

i- (§ - acetoxyethyl) - 6 - feiyl-l, 3-dihydro2I-l, 4-benzodiazepip-2-it;

1- (p-acetoxyethyl) -5-phenyl-7-chloro-1,3-dihydro-2H-1; 4-benzodiazepin-2-one;

1- (P - acetoxyethyl) - 5-phenyl-7-bromo-1,3-dihydro-2H-1; 4-benzodiazepin-2-one;

1- (P - acetoxyethyl) -5-phenyl-7-nitro-1,3-dihydro-2H-1, 4-benzodiazepin-2-one;

1- (P - acetoxyethyl) - 5-phenyl-7-trifluoromethyl-1, 3-dihydro-2H-1,4-benzodiazip-2-one; 1- (p-acetoxyethyl) -5-phenyl-b- (or 8) - chloro, 3-dihydro-2H-1,4-benzodiazip-2-op, 1 - (P - acetoxyethyl) - 5 - (o - chlorophenyl) - 7-chloro-1, 3-dihydro-2P-1,4-benzodiazepin-2-oi;

1- (P - acetoxyethyl) -5- (o-bromophenyl) -7 chloro-1, 3-dihydro-2H-1,4-benzodiazepin-2-one;

1- (p-acetoxyethyl) -5- (o-chlorophenyl) -7-nitro-1, a-dihydro-2H-1,4-benzodiazipip-2-one;

1- (P - acetoxyethyl) -5- (o-tolyl) -7-chloro-1,3-dihydro-2P-1; 4-benzodiazepin-2-one; 1- (P - propioyloxyethyl) -5-feiyl-7-chloro, 3-dihydro-2H-1,4-benzodiazepin-2-one;

1- (P - propiopyloxyethyl) -5- (o-chlorophenyl) 7-chloro-1, 3-dihydro -2H-1,4-benzodiazepin-2-one; 1- (P-butyryloxyethyl) -5-propyl-7-chloro-1,3-dihydro-2H-1; 4-benzodiazepin-2-one;

1- (p - acetoxypropyl) -5- (o-chlorophenyl) -7 chloro-1, 3-dihydro-2H-1,4-benzodiazepin-2-one;

1-acetoxymethyl-5- (o-chlorophenyl) -7-chloro, 3-dihydro-2H-1,4-benzodiazepin-2-one; 1- (a - acetoxyethyl) -5- (o-chlorophenyl) -7 chloro-1, 3-dihydro-2P-1,4-benzodiazepia-2-one;

1- (7-acetoxypropyl) -5- (o-chlorophenyl) -7 chloro-1, 3-dihydro-2P-1,4-benzodiazin-2-oi;

1- (7-acetoxypropyl) -5-phenyl-7-chloro-1,3-dihydro-2H-1, 4-benzodiazepin-2-one;

I- (Y - acetoxypropyl) -5- (o-tolpl) -7-chloro, 3-dihydro-2H-1,4-benzodiazepin-2-one;

1- (P - acetoxyethyl) -5- (d - chlorophenyl) - 7 chloro-1, 3-dihydro-2H-1,4-benzodiazepin-2-one; 1 - ((3-isobutyryloxyethyl) -5- (o-chlorophenyl) 7-chloro-1,3-dihydro-2H-1,4-bepodiazepin-2-one; 1- (P-isobutyryloxyethyl) -5-fepyl- 7-chloro, 3-dihydro-2H-1,4-benzodiazepin-2-one;

Claims (3)

1- (| 5-valeryloxyethyl) -5- (o-chlorophenyl) -7 chloro-1, 3-dihydro-2P-1,4-benzodiazepin-2-one. where Ri is a hydrogen atom, halogen, nitro or trifluoromethylgroup; Ra and Ra are each individually a hydrogen atom, chlorine, bromine, alkyl with one to four carbon atoms or trifto1pmethylgra: ppa; R-i is alkyl with one to four carbon atoms; n is an integer from 1 to 3; or salts thereof, characterized in that the 2-aminomethylindole derivative of the general formula R, -CO O Spnzp R, where Ri, Rz, Rs, R4 and p are as defined above, is subjected to interaction with an oxidizing agent, followed by isolation of the target product in a free state or in the form of a salt by usual methods. 2. Method according to l. 1, characterized in that ozone, hydrogen peroxide, peracids, chromic acid or potassium permanganate are used as the oxidizing agent. 3. A method according to claim 1, characterized in that the reaction is carried out in an inert solvent.