CS268633B1 - Process for the preparation of 6- (diethylaminoalkoxy) - 10,11-dihydrodibenzo / b, f / thiepin-10-ol and their maleates - Google Patents

Abstract

The solution falls into the field of drug synthesis. Its subject is a method for preparing 6-(2-dimethylaminoethoxy)- and 6-(3-dimethylaminopropoxy)-10,11-dihydrodibenzo/b,f/thiepin-10-ol and their maleates. These substances are both intermediates in the synthesis of pharmacodynamically active compounds and, on the other hand, they themselves exhibit centrally depressant (tranquilizing) activity. The method for their preparation consists in the reduction of 6-(2-dimethylaminoethoxy)- and 6-(3-dimethylaminopropoxy)dibenzo/b,f/-thiepin-10(11H)-one with sodium borohydride in aqueous ethanol and, if necessary, subsequent neutralization of the obtained bases with maleic acid.

Description

The invention relates to a process for the preparation of 6- (dimethylaminoalkoxy) -10,11-dihydrodylbenzo [b, f] thiepin-10-ol of the general formula I

in which n is 2 or 3, and its maleates.

The compounds of the formula I according to the invention are primarily intermediates for the preparation of pharmacodynamically active substances and, in addition, themselves have some useful biological properties. It acts, for example, centrally damping.

Specific biological results obtained with the substances according to the invention:

6- (2-Dimethylaminoethoxy) -10,11-dihydrodibenzo [b, f] thiepin-10-ol was tested as the hydrogen maleate. Its acute toxicity in mice after intravenous administration, LD 50 = 27.5 mg / kg. In the rotating rod test in mice, it induces ataxia, suggesting a damping effect; Εϋ ^ θ ³ 5 «7 ί · ^ν ·

6- (3-Dimethylaminopropoxy) -10,11-dihydrodibenzo [b, f] thiepin-10-ol was also in the form of hydrogen maleate. Its acute toxicity, LD ^ O = 18.9 mg / kg efficacy in the rotating rod test, ED ^ ₀ = 7.2 mg / kg iv

The process for the preparation of the compounds of the formula I according to the invention consists in the tons of the formula II centrally tested in the reduction to (II), in which n is the same as in the formula I, with sodium borohydride in aqueous ethanol. The starting ketones of the formula II have not yet been described in the literature and their preparation is therefore given in the examples. The compounds of the formula I prepared are basic in nature and crystalline hydrogen maleatates are obtained according to the invention by neutralizing them with maleic acid. All substances described in the invention are novel and their identity has been ensured by analytical and spectral methods. The examples are merely illustrative of the possibilities of the invention and it is not intended to describe all of these possibilities.

Example 1

6- (2-Dimethylaninoethoxy) -10,11-dihydrodibenzo [b, f] thiepin-10-ol (i, n s 2)

To a stirred solution of 6.5 g of 6- (2-dimethylaminoothoxy) dibenzo [b, f] thiepin-10 (1H) -one in 70 ml of ethanol is added dropwise a solution of 2.0 g of sodium borohydride in 20 ml of water containing 0 , 5 ml of a solution of sodium hydroxide. The mixture was refluxed for 5 h. The volatiles were evaporated in vacuo, the residue ee partitioned between water and benzene, the benzene solution ee dried and evaporated. 5.9 g (90%) of the desired automotive product are obtained, which is purified by crystallization from ethanol, m.p. 12 DEG-T25 DEG C. .

CS 268 633 B1

The starting 6- (2-dimethylaminoethoxy) dibenzo [b, f] thiepin-10 (1H) -one, which has not yet been described in the literature, is prepared in this way;

To a solution of sodium ethoxide prepared from 3.06 sodium and 350 ml ethanol was added 12.12 g of 6-hydroxydibenzo [b, f] thiepin-10 (11H) -one (Protiva M, et al., Collect. , p-hem, Pcmrmm, 40, 2667 (1975)) and 10.8 g of 2-dimethylaminoethyl chloride hydrochloride, and the mixture was stirred and refluxed for 9 hours. After standing overnight, the precipitated sodium chloride is filtered off with suction, the filtrate is slightly acidified with dilute hydrochloric acid and evaporated in vacuo. The residue is dissolved in water, washed with benzene, basified with aqueous ammonia and (66%) an oily base which crystallizes from cyclohexane and melts in pure form at 69-71 ° C. It can be characterized by conversion to crystalline hydrochloride, m.p. 176-179 ° C.

Example 2

6- (3-Dimethylaminopropoxy) -10,11-dihydrodibenzo [b, f] thiepin-10-ol (I, n = 3)

As in the previous example, 6.6 g of 6- (3 "dimethylaminopropoxy) dibenzo [b, b] thiepin-10 (11H) -one are reduced with 2.0 g of sodium borohydride in a mixture of 50 ml of ethanol, 20 ml of benzene and 20 ml of benzene. ml of water. 4.8 g (73%) of crude desired product are obtained, which is purified by crystallization from methanol, m.p. 166 DEG-169 DEG.

The required starting 6- (3-dimethylaminopropoxy) dibenzo [b, f] thiepin-10 (11H) -one was prepared in a similar manner as described for the lower homologue in Example 1, by reacting 6.7 6 6-hydroxydibenzo [b, f / thiepin-10 (11H) -one (cited) with 6.6 g of 3-dimethylaminopropyl chloride hydrochlorides in sodium ethoxide solution (1.73 B sodium, 200 ml ethanol) (reflux for 10 h). 6.4 g (71%) of an oily, albeit almost homogeneous substance are thus obtained, which is used without further purification in this state. For characterization, it can be converted into crystalline hydrochloride, m.p. 181-183 ° C (ethanol-ether),

Claims (1)

OBJECT OF THE INVENTION Process for the preparation of 6- (dimethylaminoalkoxy) -10,11-dihydrodibenzo [b, f] thiepin-10-ol of general formula I OH in which n is 2 or 3, and their maleates, characterized in that the ketones of the general formula II 0 (01,) ^ (01 ^ (II), CS 268 633 B1 in which n is the same as in the formula I, are reduced with sodium borohydride in aqueous ethanol and the base of the formula I obtained is converted into the maleate, if appropriate by neutralization with malonic acid.