SU493971A3 - The method of obtaining 5-aryl- / or heteroaryl / -3-hydroxy-1n-1,5-benzodiazepin-2,4- / 3n, 5n / -diones - Google Patents

Description

(54) METHOD FOR OBTAINING 5-ARYL- (OR HETEROARIL) 3-OXY-1H-1, 5-BENZODIAZEPIN2, 4- (3N, 5H) -DIONES

one

The invention relates to a process for the preparation of novel 1,5-benzodiazepine derivatives, which are valuable drugs.

Based on the enamine oxidation reaction, encompassed by the present invention, the method allows to obtain compounds that have better properties than the known analogues of similar action.

A process for the preparation of 5-aryl (or heteroaryl) -3-hydroxy-H-1.5-bisodiazepine-2.4- (3H, 5H) -diones of general formula I is described.

(

where RI denotes a hydrogen atom, or a branched alkyl group with 1-4 carbon atoms, which in a-positivity can be substituted with an oxy group, allyl or cyclopropylmethyl group.

Ra is a phenyl radical which, if necessary, may be substituted by a halogen atom, a trifluoromethyl or a nitro group, or a pyridyl radical and

Nz is a fluorine, chlorine or bromine atom, or trifluoromethyl or a nitro group.

According to the invention, compounds of formula I are obtained by mild oxidation of compounds of formula I

ten

15

where RI, R2 and Ra have the above meaning, and the radicals R, which may be the same or different, mean hydrogen atoms, straight or branched alkyl radicals, preferably with 1-4 carbon atoms.

The oxidation is carried out in a weakly acidic environment at low temperatures using

as an oxidizing agent Kali permanganate. Compounds of formula I in which Ri represents a hydrogen atom can, if necessary, be alkylated by reacting an alkali metal salt of compound I and an alkylating agent, for example, an alkyl halide or dialkyl sulfate.

If RI in formula I is an oxyalkyl radical, the latter can be introduced by reacting a compound of formula I, where RI is a hydrogen atom, with an alkylene oxide in the presence of a strong base, such as Triton B, in an environment with a suitable solvent.

The following compounds of formula I can be prepared according to the invention:

3-hydroxy-5-phenyl-7-trifluoromethyl - 1H - 1.5benzodiazepin-2, 4- (3N, 5H) -dione;

7-bromo-3-hydroxy-5-phenyl - 1H - 1.5 - benzodiazepin-2, 4- (3N, 5H) -dione;

7-chloro-3-hydroxy-5-phenyl-1A-1.5 - benzodiazepin-2, 4- (3N, 5H) -dione;

3-hydroxy-1-methyl-5-phenyl-7-trifluoromethyl-1H1, 5-benzodiazepin-2,4- (3N, 5H) -dione,

7-bromo-3-oxy-1-methyl-5-phenyl-1Hl, 5-benzodiazepin-2,4- (3H, 5H) -dione;

7-chloro-3-hydroxy-1-methyl-5-phenyl-1H-1.5benzodiazepin-2, 4- (3N, 5H) -dione;

7-fluoro-3 hydroxy-I-methyl-5-phenyl-1H-15benzodiazepin-2, 4- (3N, 5H) -dione;

3 - hydroxy - 1 methyl - 7 - nitro - 5 - phenyl 1H-1, 5-benzodiazepine - 2.4 - (3N, 5H) -dione;

1 - methyl - 7 - bromo - 3 - hydroxy - 5 - phenyl-1H1, 5 - benzodiazepin-2,4- (3N, 5H) -dione;

1 - ethyl - 3 - hydroxy - 5 - phenyl - 7 - trifluoromethyl - 1H - 1.5 - benzodiazepine - 2.4 - (3H, 5H) - dione;

3 - hydroxy - 1 - methyl - 5- (o-trifluoromethylphenyl) - 7 - trifluoromethyl - 1H - 1.5 - benzodiazepine - 2.4 - (3N, 5H) - dione;

3 - hydroxy - 5 - (o - trifluoromethylphenyl) -7 chloro - 1H - 1.5 - benzodiazepine - 2.4 - (3N, 5H) -dione;

3-hydroxy-1 methyl-5- (l-nitrophenyl) -7-trifluoromethyl-1H-1, 5-benzodiazepin-2.4 - (3N, 5H) -dione;

5- (tt-chlorophenyl) -3-hydroxy-G-methyl-7-trifluoromethyl - III - 1.5 - benzodiazine-2,4- (3N, 5H) dione;

3-hydroxy-1-isopropyl-5-phenyl-7-trifluoromethyl-1H-1, 5-benzodiazepin-2,4- (3N, 5H) -dione;

3 - hydroxy - 1 hydroxyethyl - 5 - phenyl - 7 - trifluoromethyl - 1H - 1.5 - benzodiazepia - 2.4 (3H, 5H) - dione ;;

1 - allyl - 3 - oxy-5-phenyl-7-trifluoromethyl - 1H - 1.5 - benzodiazepine - 2.4- (3N, 5H) dione;

5 - (o-fluorophenyl) - 3 - hydroxy - 1 - methyl - 7 trifluoromethyl - 1I - 1.5 - benzodiazepine 2, 4- (3N, 5H) -dione;

3-hydroxy-1-methyl-5- (o-nitrophenyl) -7-trifluoromethyl - 1 H-1.5 - benzodiazepin-2.4 - (3H, 5H) -. dione;

5- (o-bromophenyl) -7-chloro-3-hydroxy-1-methyl-1H1, 5-benzodiazepin-2,4- (3N, 5H) -dione; 5- (o-chloro (phenyl) -3-hydroxy-1-methyl-7-trifluoromethyl-1H-1.5-benzodiazepin-2.4- (3H, 5H) dione;

7-chloro-3-hydroxy-1-methyl-5- (o-trifluoromethylphenyl) - 1H - 1.5 - benzodiazepine - 2.4 - (3N,

5H) -dione;

5- (f-fluorophenyl) -3-hydroxy-1-methyl-7-trifluoromethyl-1H-1, 5-benzodiazepine-2.4- (3N, 5H) -dione; 3-hydroxy-1-methyl-5- (f - nitrophenyl) - 7 - trifluoromethyl-1H-1, 5 - benzodiazeline - 2.4 - (3N, 5H) -dione;

5- (p-chlorophenyl) -3-hydroxy-1-methyl-7-trifluoromethyl-1H-1.5-benzodiazepin-2,4- (3N, 5H) -dione;

7-chloro-3-0Xi-1-methyl-5- (a-pyridyl) -1H1, 5-benzodiazepin-2,4- (3N, 5H) -dione;

7 - bromo - 3-hydroxy-1-methyl-5- (a-pyridyl) -1 H1, 5 - benzodiazepin-2,4- (3N, 5H) -dione. The starting compounds of formula II are obtained by reacting a respectively substituted 1H-1,5-benzodiazepine 2,4- (3N, 5H) dione with dialkylformamide and phosphorus pentahalide.

Example 1. 3-hydroxy-5-phenyl-7-trifluoromethyl-1H-1, 5-benzodiazepin-2,4- (3N, 5H) -dione.

To a solution of 15 g (0.04. Mol) 2-dibutylaminomethylidene-7-trifluoromethyl-5-phenyl-1H1, 5-benzodiazepin-2,4- (3N, 5H) -dione in 2.5 l

200 ml of 6% sulfuric acid are added to the acetone.

acid, and then for 20 min. 18 g of potassium permanganate in 400 ml of water. The reaction mixture is unmixed for 1 hour at -25 ° C, filtered, a large part of acetone is evaporated, the residue is taken up in methylene chloride. The organic layer is dried, evaporated; the target product is crystallized from tetrahydrofuran.

Get 9.6 g (72%) of crystals, so pl. 260-264 ° C.

Example 2. 3-Oxy-1-methyl-5-phenyl-7-trifluoromethyl-1H-1, 5 - benzodiazepine - 2,4- (3N, 5H) - dione.

K 3.4 g of 3-hydroxy-5-phenyl-7-trifluoromethyl 1 H-1, 5-benzodiazine Pin-2,4- (3N, 5H) -dione in

200 ml of tetrahydrofuran were added 500 ml of 50% sodium hydride, stirred for 30 minutes, 20 ml of methyl iodide were added and stirred for another 5 hours at room temperature. The reaction mixture is evaporated, and the residue is taken up in methylene chloride, the organic phase is washed, dried and evaporated. The residue is crystallized from methanol. Obtain 2.9 g (78%) of the desired product, so -il. 245-248 ° C.

The compounds of general formula I shown in the table are prepared analogously.