SU517258A3 - Method for preparing benzodiazepine derivatives - Google Patents

Description

(54) METHOD FOR OBTAINING BENZODIAZEPIN DERIVATIVES

one

This invention relates to a process for the preparation of novel benzodiazepine derivatives with valuable pharmacological properties.

Based on the known dehydration reaction, the proposed method for the preparation of benzodiazepine derivatives of the general formula

where RI is a halogen or nitro group;

R2 is phenyl, galsidiphenyl or pyridyl;

Ra is hydrogen, alkyl, acyloxyalkyl, dialkylaminoalkyl or carbalkoxy;

R4 is an alkoxy, dialkylaminoalkoxy or alkoxy alkoxy group, and R4 is only an alkoxy or alkoxy alkoxy group, ecjm RS

carbalkoxy, or their salts is that the compound of the general formula

H

where R -R4 is as defined above, is dehydrated, followed by separation of the target product by known techniques. Alkyl and alkoxy usually contain 1-6,

preferably 1-4 carbon atoms.

Ashchl is alkanoyl, e.g. acetyl, propioxy, tert-butyryl, cycloalkanecarbonyl, e.g. cyclopropanecarboyl, aroyl, or aralkanoyl, e.g. benzoyl, feiacegyl, fe1-ylpioxy, which can be replaced by methoxyglues.

Degradation is usually carried out in the presence of

carbodides, for example, Sch1clohexy 1carbodiimide, in an inert organic solvent, such

as benzene, toluene, daoxane, in the temperature range from (-20) to 100 C.

When 3-carbalkoxy derivatives are used, isomeric 3,4-dehydro derivatives of the target compound are formed, which are easily isomerized to 4,5-dehydro-derivatives, for example, when treating with a base, such as alkali metal alkoxide (sodium methoxide), and triethylamine.

The starting compounds can be obtained by exchange reaction between the compound of the general formula

where RI and RZ - as indicated above, and a compound of the general formula

five

R

X-CH-Eb

where RS is hydrogen, alkyl, haloalkyl, carbalkoxy or acyloxyalkyl;

Wb alkoxy-, haloalkoxy- or alkrxial coxy;

X is a halogen, with the subsequent exchange of an aliphatic bound halogen for a dialkylamino group and the reduction of the obtained compound in the presence of platinum oxide.

The exchange reaction is carried out in an inert organic solvent or its mixtures, for example, benzene, toluene, dimethylformamide, dioxane, tetrahydrofuran, tert-butanol, at (-50) -120 ° C.

X may also be a mesyl or a tosyloxy group.

It is more expedient for an exchange reaction to use not an independent compound, but its alkaline derivative, obtained using an alkali metal hydride or amide, such as sodium, or carrying out an exchange reaction in the presence of a base, such as caustic soda triethylamine.

For the exchange of an aliphatic bound halogen with a dialkylamino group, dialkylamine can be used and reacted in a solvent, for example dioxane, dimethylformamide, benzene, toluene, acetone, methyl ethyl ketone.

The reduction in the presence of platinum oxide is advisable to be carried out in an organic solvent such as ice on acetic acid, alcohols, at about -50 ° C, preferably at room temperature.

Inorganic and organic compounds can be used to obtain salts of the target compounds.

acids, for example, hydrochloric, phosphoric, hydrobromic, citric, sulfonic, acetic, formic, succinic, maleic, p -toluenesulfonic.

Example. 0.67 i 7 - chloro - 4 - hydroxy - 1 - (methoxymethyl) - 5 - phenyl - 1,3,4,5 - tetrahydro-2H - 1,4 - benzodiazepin - 2 - it and 0.63 g of dicyclohexylcarbodiimide bale t 16 hours with reflux in the presence of 20 ml

toluene, remove the diclohexyl urea, extract the filtrate three times 2 n. hydrochloric acid, alkalinized extracts with ammonia, extracted with methylene chloride, dried, evaporated, the residue is chromatographed on 15 g

silica gel with 10% acetic acid solution in methylene chloride and get 0.25 g of pure 7 - chlorine 1, 3 - dihydro - 1 - (methoxymethyl) - 5 - phenyl - 2H -1,4 - benzodiazepine - 2 - it. .

Mass spectrum: 314 (M +), 286 (M-1-CO), 269

(M-kSNgOSNz).

NMR - spectrum (SOS1), PPT: 7.8-7.1 (multiplet), 8 aromatic protons), 5.40 (doublet)

and 4.88 (doublet, AV system with CPS, N-CHa -O),

4.84 (doublet) and 3.83 (doublet, AV system with

J 10.5 cpc, Cs - protons), 3.37 (singlet, OCHE).

For the synthesis of the starting products to the solution

28.7 g 7 - chlorine - 1,3 - dihydro 5 - phenyl - 2H 1,4 benzodiazepine - 2 - it - 4 - oxide in 200 ml

dimethylformamide at -20 ° C added 8.1 g

sodium methoxide, stirred for 5 minutes, at -20 ° C, add 12 ml of chlorodimethyl ether, dropwise with stirring, stirred for 30 minutes without cooling, poured into 1 liter of water, treated, as usual, the crude product crystallized

from a mixture of methanol-ether, seed, and get 11.5 g of 7 - chlorine 1,3 dihydro - 1 - (methoxymethyl) - 5 - phenyl - 2H - 1,4 - benzodiazepine - 2 - he-4 - oxide, t .pl. 164-166 ° C. The primer is obtained by chromatography on silica gel in the system

methylene chloride / ethyl acetate (1: 1).

3.3 g of 7 - chloro - 1,3 - dihydro - 1 - (methoxymethyl) - 5 - phenyl - 2H - 1,4 - benzodiazepine - 2 - one-4 - oxide is hydrogenated in 30 ml of glacial acetic acid in the presence of 0 , 3 g of platinum oxide at

At atmospheric pressure and at room temperature until the absorption of 400 ml of hydrogen, the catalyst is separated, ttariyut, dissolve the residue in benzene, extract the solution 2n. with hydrochloric acid, the benzene phase is washed with water, dried, evaporated, the residue is crystallized from methanol and 1.1 g of 7 - chloro - 4 - hydroxy - 1 - (methoxymethyl) - 5 - phenyl - 1,3,4,5 - tetrahydro - are obtained 2H - 1,4-benzodiazepine - 2 - it, so pl. 168-172 ° C. After peg crystallization from methanol so pl. J73-175 ° C

Alkaline extracts alkalinize

soda, extracted with methylene chloride., dried, the extract is evaporated, the residue is recrystallized from methanol and obtain 1.4 g of 7-chloro-1 - (methoxymethyl) -5-fetzl-1,3,4,5-tetrahydro-2I-1,4 - Benzodiazepine - 2 - she.