SU1051081A1 - Process for preparing derivatives of 1,3,4,5-tetrahydro-2h-1,4-benzdiazepine-2 - Google Patents

Description

This invention relates to a method for the preparation of derivatives 1, 3,; 5-tetra HYDRO-2H-1, 4-benzdiaeepinone 5-2 of the general formula U) Mal-NNH R - hydrogen, chlorine; Nar - chlorine or bromine with valuable pharmacological properties. A known method of producing derivatives of 1, 3,., 5-tetragus Dro-2H-1, it01-benzdiazepinone-2 of the general formula by cyclization of the acid of halo Hal boiling in xylene. The yield of the target product in this one-step process does not exceed Q%. The original acid of the formula I is obtained by multistage synthesis according to the scheme:

Bng

3

UHsHcii

Hal

soo

Nhé

HCiH2UOOCi H5

Hal K

The yield of the target product I in the calculation on the initial benzophenone according to the scheme is about 5% (for the corresponding 7СР derivative, an example of concrete preparation of 7Br-derivative is not described) 11.

The disadvantages of this method are 40 - low yield of the target product, multistage and complexity of obtaining raw materials.

The purpose of the invention is to increase the yield of the target product and simplify the process as a whole.

This goal is achieved by the fact that according to the method of obtaining the derivatives of 1, 3, 5-tetrahydro-2H-1, -benzdiazepinone-2, a derivative of 2-amino-5-50 -halogenbenzhydrol of the formula

.NH

Hai

Bng

Hdhjdooh

Hal

R

where R, Hp are given values,

in chloroform medium, it is subjected to sequential treatment with trifluoroacetic anhydride in the presence of triethylamine at a temperature of -14 to -20 ° C for 30-35 minutes and with methyl glycine ester hydrochloride, in the presence of triethylamine at 20-22 ° C for 1.5-2 h, and by boiling for 2, 5–3 h, followed by removal of chloroform and treating the residue with a methanol solution of hydrochloric acid / yuty when heated in a boiling water bath for 30–35 minutes.

The process is carried out as follows:

 ndlLtUbHg oo l Q

Hal

The starting 2-amino-5 halo benzhydrol is obtained from the corresponding benzophenone in one step by reduction.

Example 1 To a solution of 31, 25 g (0.1 mol) of 2-amino-2-chloro-5 bromo-benzhydrol in 200 ml of chloroform, 18.3 ml (0.13 mol) of trifluoroacetic anhydride in 0 are added in 6-8 minutes ml of chloroform, and then 19.6 m (0.14 mol) of triethylamine. The solution is stirred from -1 to -16 ° C for 30 minutes. Then, a solution of 16.3 g (0.13 mol) is added to it at -16 ° C. ) glycine methyl ester hydrochloride in 90 ml of chloroform with 36, A ml (0.26 mol of triethylamine.

The temperature of the reaction mixture was raised to 20-22 ° C, stirred for 2 hours and then boiled for 3 hours. The solution was evaporated in vacuo, 100 ml of diethyl ether, 150 ml of hydrochloric acid were added to the residue, the mixture was stirred and the ether layer was decanted. 80 ml of methanol was added to the residue, the acid-alcohol solution was heated on a boiling water bath for 30 minutes (the end was determined by the absence of Rf, 0 in the thin-layer chromatogram of the product with Rf, 0, in the system acetone: hexane 1: 2, Sllutol plates), cooled to 2-cs, ammonia is added to pH. The precipitated precipitate is filtered off, washed with water to pH 7, after drying, recrystallized from acetone: diethyl ether (1: 3) to obtain 30.3 g (86) of 7-bromo-5-phenyl- (ortho-chloro) -1, 3 ,, 5 tetrahydro-2H-1, + - benzodiazepinone-2 (substance). M.p. 212-213 C; R 0.32 (acetone: hexane 1: 2, Silutol plate).

7-Lrom-5-phenyl ortho-chloro) -1,3, 5-tetrahydro-2H-1, -benzdiazepinone-2 colorless crystalline substance, m.p. 212-213 C (from a solution of acetone: diethyl ether 1: 3), insoluble in water, soluble in ethanol, methanol, acetone, chloroform, diethyl ether, ethyl acetate. Found: C 51.1; H 3.2; N 8.0.

C, gH, 2N, OBrCe

Calculated,%: C 51.2; H 3.1; N 7.9b

Mgcd spectrum: And 351 (calculation mol. Weight. 351.5).

IR spectrum (tablets with KBG), cm: 1675 (); 3280, (N-H).

Example2. Under similar conditions, 7-chloro-5-phenyl-1, 3, 5-tetrahydro-2H-1, -benzdiazepinone-2 is obtained from 2-amino-5-chlorobenzhydrol and glycine methyl ester hydrochloride in a yield of 93%. C, C, T. 18318 4 s (from methanol).

Thus, the proposed method allows to obtain 1,3., 5-tetrahydro-2H- 1, 4-benzodiazepinone-2 derivatives in one synthesis step with a yield of 86.93% (instead of 5% by a known method)

Claims (1)

METHOD FOR PRODUCING DERIVATIVES 1,3,4,5-TETRAHYDRO-2H ~ 1,4-BENZDIAZEPINO-2 of the general formula where R is hydrogen, chloro; On the? - chlorine or bromine, starting from the diphenylmethane derivative, characterized in that, where is R, Na? have the given values in the medium, chloroform is subjected to sequential treatment with trifluoroacetic anhydride in the presence of triethylamine at a temperature of -14 to -20 ° C for 30 * 35 min and glycine methyl ester hydrochloride in the presence of triethylamine at 20-22 ° C for 1.52 h, and then when boiling for 2.5 ~ 3 h, followed by removal of chloroform and treatment of the residue with a water-methanol solution of hydrochloric acid while heating in a boiling water bath for 30-35 min. TWTWF '‘“ ’ng' *