SU453841A3 - Method for producing benzodiazepine derivatives - Google Patents

Description

one

The invention relates to a process for the preparation of new benzodiazine derivatives, which possess their pharmacological properties and exhibit greater activity than known compounds.

A method for the preparation of benzodiazenine derivatives of the general formula 1 based on the known reaction is proposed.

R, -CH-E4 ./O

-N-C

SN-to.

X

C-n

I

U,

where RI is halo or nitro;

R2 is phenyl, halo-phenyl or pyridyl radical;

RS is a hydrogen atom, an alkyl, hydroxyalkyl, acyloxyalkyl, carbalkoxy or dialkylaminoalkyl radical;

H4-alkoxy, dialkylaminoalkoxy, oxyalkyloxy, alkoxyalkoxy, alkylthio, alkylsulfinyl or alkylsulfonyl radical, and R5 is a hydrogen atom or a carbalkoxy radical,

moreover, R4 does not mean dalkylaminoalkox, if Ra is a carbalkoxydradical,

or their salts, consisting in the fact that the compound of General formula II

Rrch-e4

xf

N-c; cHCH-N I 1

B, RA

where RI-Rs have the indicated meanings; R (, is a mesyl or tosyl radical,

the aid of a strong base is converted into its 4,5-dehydro compound; The target product is isolated in the free state of NLP in the form of a salt with known zriemes.

The cleavage of mesyl or tosylgrune from the compound of formula II is carried out with a strong base, alkali metal hydrides with sodium hydride, alkali metal alkoxides with sodium methoxide, triethylamine and alkali metal amides with sodium amide, and so on, in an anhydrous medium. The process is expediently carried out in an inert organic solvent, for example, 3 ethers, alcohols - ethanol, hydrocarbons - benzene, toluene, dimethylformamide and at a temperature O-120 ° C. In this reaction, an isomeric compound of formula I can also be obtained, which has a double bond in position 3, 4 and not in position 4, 5. Isomerization of the latter is carried out by treatment with a base, for example, alkali metal alcohols — sodium methoxide, alkali metal hydrides. - sodium hydride, triethylamine. The reaction is carried out mainly in an inert organic solvent — hydrocarbons, ethers, alcohols, etc., and at temperatures between -40 and + 120 ° C. The term “alkyl alone or in combination, such as“ alkoxy ”, includes straight chain and branched hydrocarbon residues with 1-6, preferably with 1-4 carbon atoms, such as methyl, ethyl, isopropyl, etc. The term“ acyl encompasses acylgrunps, such as alkanoyl residues, such as acetyl, propionyl, 7pb-butyryl, cycloalkane carbonyl residues — cyclopropanecarbonyl, aroyl, or aralkanoyl-residues — benzoyl, phenacetyl, phenylpropionyl, which, if appropriate, can also have methoxy substituents. The term halide encompasses fluorine, chlorine, bromine and iodine. Compounds of general formula I, which are of a “parabolic nature”, form acid addition salts with inorganic or organic acids — hydrochloric, phos)) hydrochloric, hydrobromic, citric, sulfuric, acetic, formic, amber, maleic / g-toluenesulfonic acid and etc. ... Example. 0.4 g of sodium methoxide is added to a solution of 1 g of 7-chloro-1- (methoxymethyl) -5-phenyl-4 - (p-toluenesulfonyl) -1,3,4,5-tetrahydro-2H-1, 4 -benzodiazepin-2-one in 20 ml of dimethylformamide. The reaction mixture is stirred under nitrogen for 30 minutes, then neutralized with glacial acetic acid and evaporated in vacuo. The residue is taken up in ether and extracted three times with 2N. hydrochloric acid. The ether washings were alkalized with concentrated ammonia, extracted three times with methylene chloride and drained. After evaporation of the methylene chloride extract, 0.6 g of a yellow oil is obtained, which is chromatographed on 20 g of silica gel with 10% ethyl acetate in methylene chloride to give 0.4 g of 7-chloro-1,3-dihydro-1- (methoxymethyl) - 5: fepil-2P-1, 4-beisodiasenin-2-one. L.® -314, main fragMass spectrum: cops at 269 (MF-CHNOSH3). --286 (M "- CO). NMR spectrum :. 7.8 - 7.1 ppm (.multiplet), 8 aromatic protons, (CDCLs), 5.40 ppc (doublet) and 4.88 ppm (doublet), LV system with J 10 cpc, N-CH2-O ; 4.84 ppt (doublet) and 3.83 ppt (doublet), the AB system with J 10.5 cpc, Cz - protons; 3.37 ppm (singlet), OS Iz. The original connection receive the following method. To a solution of 28.7 g of 7-chloro-1,3-dihydro-5-phenyl-2H-1, 4-benzodiazepin-2-one-4-oxide in 200 ml of dimethylformamide was added at -20 ° with 8.1 g of methoxide. sodium and move for 5 min. At -20 ° C, 12 ml of chloromethyl ether are added dropwise with stirring. After the addition, stirring is continued for 30 minutes without cooling. The reaction mixture is poured into 1 liter of water and treated as usual. By crystallization of the crude product by seeding from methanol-ether, 11.5 g of 7-chloro-1, 3-dihydro-1- (methoxymethyl) -5-phenyl-2P-1, 4-benzodiazepin-2-one-4-oxide are obtained. , melted at 164-166 ° C. Seed crystals are obtained by chromatography on silica gel in the solvent system methylene chloride - ethyl acetate (1: 1). 4.5 g of zinc powder was added in portions to a solution of 3.3 g of 7-chloropl, 3-dihydro-l- (methoxymethyl) -5-phenyl-2P-1, 4-benzoide zeiin-2-on-4 -oxide in 40 ml of methylene chloride and 10 ml of glacial acetic acid. At the end of the addition, it is stirred for 30 minutes, filtered and the filtrate is washed with aqueous ammonia and water; the methylene chloride solution is dried and evaporated. By crystallization of the residue from alcohol, 2.4 g of 7-chloro-1,3,4,5-tetrahydro-1- (methoxymethyl) -5-phenyl-2I-1, 4-benzodiazepin-2-one, t. Il. 136-1-38 ° С (from alcohol). To a solution of 3.2 g of 7-chloro-1- (methoxymethyl).-5-phenyl-1,3,4,5-tetrahydro-2P-1,4-benzodiazepin-2-one in 20 ml of pyridine and 2, 3 g of tosyl chloride and left to stand for 3 hours at compressed temperature. After removal of pyridine in vacuo, the residue is dispersed in methylene chloride and in 2N. hydrochloric acid. The methylene chloride phase is then washed with a 10% soda solution and water, concentrated and evaporated; the crystalline residue is recrystallized from metaiol-methylene chloride and 7-chloro-1- (methoxymethyl) -5-phenyl-4- (-toluenesulfonyl) -1,3,4,5-tetragndro-2P-1, 4-benzodiazepin-2- is obtained he, t. pl. 218-220 ° C. The following compounds are prepared in a dialogue manner: 1,3-dngydro-1 - (methoxymethyl) -7-1Itro-5-phenyl-2I-1, 4-bepodiazipip-2-011, m.p. 139-14GS (from benzene - alcohol); 7-chloro-5- (o-chlorophenyl) -1,3-dihydrO: 1- (methoxymethyl) -2H-1,4-benzodiazepia-2-one, so pl. 139-140 ° C (from methanol); 5- (o-chlorophenyl) -1,3-dihydro-1- (methoxymethyl) -7-pitro-2P -1,4-beisodiazepine -2-op, so nl. 136-137 ° C (from methanol); 7-chloro-1,3-digpdro-5- (o-fluorophenyl) -1- (methoxymethyl) -2H-1,4-benzodiazepin-2-one, so pl. 113-114 ° C (from methanol);

1 - (ethoxymethyl) -1,3-dihydro-7-nitro-5-fe11yl-2H-1, 4-benzodiazepia-2-one, t. Pl. 105-107 ° C (from alcohol);

7-chloro-1,3-dihydro-1 - (1-methoxyethyl) -5-phenyl-2H-1, 4-benzodiazepin-2-one ,. m.p. 131-132 ° C (from methylene chloride - hexane);

1,3-dihydro-1- (1-methoxyethyl) -7-nitro-5-phenyl-2H-1, 4-benzodiazepin-2-one, t.nl. 189-190 ° C (from methanol);

I- (1-ethoxyethyl) -1,3-dihydro-7-nitro-5-phenyl-2H-1; 4-benzodiazepin-2-one; m. Pl. 172-174 ° C (from alcohol);

1,3 - dihydro - 7-nitro-5-phenyl-1 - (propoxymethyl) -2H-1,4-benzodiazepin-2-one, so pl. 73-76 ° C (from alcohol);

1,3-dihydro-1- (hexyloxymethyl) -7-yitro-5-phenyl-2H-1, 4-benzodiazepin-2-one, so pl. 108-109 ° С (from ether);

1,3-dihydro-1 - (2-methoxyethoxy) -meptl-7-nitro-5-phenyl-2H-1, 4-benzodiazepin-2 - it, so pl. 120-12GS (from methanol);

1- (carbomethoxymethoxymethyl) -1,3-dihydro-7-nitro-5-phenyl-2H-1, 4-benzodiazepine-2-one, t. Pl. 157--159 ° C (from methanol);

1 - (carbomethoxymethoxymethyl) - 7 - chloro-1, 3-dihydro-5-phenyl-2H-1,4-benzodiazepip-2-one, so pl. 195-196 ° C (from methanol - methylene chloride);

7-chloro-1,3-dihydro-1- (2-hydroxyethoxy) -methyl-5-phenyl-2H-1,4-benzodnazepin-2-one, so pl. 129-131 ° C (from ether);

1- (2-acetoxn-1-methoxy) -ethyl-7-chloro-1, 3-digndro-5-fennl-2H-1,4-benzodiazipip-2on, mp. 110-11 GS (from alcohol);

7-chloro-1,3-dihydro-1 - (2-hydroxy-1-methoxn) -til - 5-phenyl-2H-1,4-benzodiazepine - 2-it, so pl. 157-159 ° C (from alcohol);

1,3-dihydro-1- (methyltno) -meptl-7-pitro-5-phenyl-2H-1, 4-benzodiazipip-2-one, so pl. 142-143 ° C (from alcohol);

7-chloro-1,3-dihydro-1- (methylthio) -methyl-5-phenyl-2H-1, 4-benzodiazepin-2-one, so pl. 115-117 ° C (from ether - hexane);

7-chloro-5- (o-chlorfepyl) - 1,3-dihydro - 1 (methylthio) -methyl -2H-1,4-benzodnazepin-2-one, so pl. 127-129 ° C (from ethyl acetate - hexane);

1,3-dihydro-1- (methylsulfinyl) -methyl-7-pitro-5-phenyl-2H-1, 4-bepodiazepine-2-one, so pl. 190-192 ° C (from ethyl acetate);

7-chloro-1,3-dihydro-1- (methylsulfinyl) -methyl-5-phenyl-2H-1,4-benzodiazepin-2-one, so pl. 158-159 ° C (from ethyl acetate - hexane);

7-chloro-5- (o-chlorophenyl) -1,3-dihydro-1- (methylsulfinyl) -methyl-2H-1,4-benzodiazepin-2-one, so pl. 150-152 ° C (from ethyl acetate - simple ether);

1,3-dihydro-1- (methylsulphopyl) -methyl-7-nitro-5-phenyl-2H-1, 4-benzodiazepip-2-it, so pl. 190-192 ° C (from alcohol - methyl methylene);

7-chloro-1,3-dihydro-1 - (methylsulfonyl) -methyl-5-phenyl-2H-1,4-benzodiazepin-2-one.

m.p. 162-164 ° C (from ethyl acetate - simple ether); . .

7-chloro-5- (o-chlorophenyl) -1,3-dihydro-1 - (methylsulfonyl) -methyl -2H-1,4-bispodiazepin-2-one, so pl. 110-115 ° C (from alcohol);

7-chloro-1,3-dngidro-1 - (methoxymethyl) ethyl 5-phenyl-2H-1,4-benzodnazepin-2-one-3-carboxylic acid ethyl ester, t. pl.

161 - 164 ° С (from methylene chloride - ether);

7-chloro-1,3-dihydro-5-phenyl-1 (2- (1-pyrrolidinyl) -ethoxy-methyl} -2H-1 hydrochloride, 4-benzodiazepin-2-one hydrochloride, mp 163-166 ° C (from acetone - simple ether);

7-chloro-1,3-dihydro-1- 2- (diatylamino) -ethoxy-methyl {-5-phenyl-2H-1 .4-benzodiazepin-2-one hydrochloride, m.p. 175-177 ° C (from ocetone - simple ether);

1- (1-ethoxy) -ethyl-1,3-dihydro-7-nptro-5-phenyl-21-1-1, 4-basepodnipip-2-op, t. Pl. 170-173 ° C (from ether);

7-chloro-1,3-dihydro-1 - (1-methoxy-2-ppvaloyloxy-ethyl) -5-phenyl-2H-1,4-benzodiazepine -2-one, so pl. 101 - 103 ° C (from ether - hexane);

7-chloro-1,3-dngidro-1-1-methoxn-2- (3,4,5-trimethoxybenzoyloxy) ethyl-5-phenyl-1H-1, 4-bispodiazep-2-op, t. Pl. 146-148 ° C.

7-chloro-1- (2-cyclopropanecarbonyloxy-1-methoxyethyl) -1,3-dihydro-5-phenyl-2H -1,4-benzodiazep mo-2-op, m.p. (from ethanol);

7-chloro-1,3-dihydro-1- -methoxy-2- (-methoxyphenylacetoxy) -ethyl-5-phen 1-2H-1,4-benzodiazepin-2-op, t. Pl. 95-97 ° C (from ether - hexane);

1,3-digpdro-1- (metokspmetil) -7-bromo-5- (2-pyridyl) -2H-1,4-benzodiappn-2-one, mass spectrum of which: 359/361, 314/316, 280 , 208, 45.

Subject invention

The method of obtaining bopdiazepine derivatives of the general formula

K3-CH-R4 i-C (

CH-Rg

Rch,

where RI is a haloyl group;

55 Ks - fepyl, halo-phenyl or pyridyl radical;

Ks is a hydrogen atom, alkyl, oxyalkyl, acyloxyalkyl, dialkylaminoalkyl or carbalkoxyradic 1;

60 R4 - alkoxy, dialkylMynoalkoxy, oxyalkoxy, alkoxyalkoxy, alkylthio, alkylsulphinyl or alkylsulphonyl radical and Rs-hydrogen atom ylp carbalkoxy radical, and RJ is not .disalm alkoxy alkoxy,

65 if Ra is a carbalkoxy radical, or their salts, characterized in that

compound of formula

; CH-B:

eight

where the RI-RS has the indicated meanings and Ra is a mesyl or tosyl radical,

converted into the corresponding 4,5-dehydro compound by means of a strong base, followed by isolation of the desired product in the free State or as a salt by known methods.