CS268634B1 - Process for the preparation of 2- (mathylaminoalkoxy) biphenyls and their hydrochloride - Google Patents

Abstract

The solution falls into the field of drug synthesis. Its subject is a method for preparing 2-(2-methylaminoethoxy)- and 2-(3-methylaminopropoxy) biphenyl and their hydrochlorides. The named bases are intermediates in the synthesis of pharmacodynamically active substances and the hydrochlorides themselves have antiraserpine activity and are potential antidepressants. The method for their preparation consists in the reaction of the corresponding 2-(dimethylaminoalkoxy)biphenyls with ethyl chloroformate in boiling benzene and in the subsequent hydrolysis of the resulting ethyl esters of N-((2-biphenylyloxy)alkyl)-N-methylcarbamic acids with boiling ethanolic potassium hydroxide solution. The resulting bases can optionally be converted into crystalline hydrochlorides by neutralization with hydrogen chloride or hydrochloric acid.

Description

The invention relates to a process for the preparation of 2- (methyuninoalkoxy) biphenyls of general formula I in which n is 2 or 3, and their hydrochlorides.

The compounds of the formula I according to the invention are intermediates in the synthesis of pharmacodynamic active ingredients and, in addition, themselves have the properties of potential antidepressants.

In particular, the substances according to the invention can be mentioned as follows:

2- (2-Methylaminoethoxy) biphenyl (i, n = 2) was tested as the hydrochloride.

Its acute toxicity in mice when administered orally, LD50 = _{2 and} 2 mg / kg. At an oral dose of 50 mg / kg, it shows a mild antagonistic effect in the test of the ulcerogenic effect of reserpine in rats, which is typical for antidepressants. It also shows a protective effect in the maximal electroshock test in mice, = 22.7 mg / kg po, which is typical for antiepileptics.

2- (3-Methylaminopropoxy) biphenyl (i, n = 3) was also tested in the form of hydrochloride when administered orally. Acute toxicity in mice, LD 50 ^{= 1 01} s / kg. At an oral dose of 50 mg / kg, it also shows a mild antagonistic effect in a rat reserpine ulcer test.

The process for the preparation of the compounds of the formula I according to the invention consists in a two-step process starting from 2- (dimethylaminoalkoxy) biphenyls of the formula U in which n is the same as in the formula I. benzene. Carbamates of general isor III are formed

in which n denotes the same as in formula I. In the second step, these carbamates are hydrolyzed with a boiling solution of potassium hydroxide in ethanol. The bases of the formula I are obtained, which can optionally be converted into the hydrochlorides by neutralization with hydrogen chloride or hydrochloric acid. The starting materials of the formula II have been described in the literature (Brit. Pat. 521,575). The following examples are merely illustrative of the possibilities of the invention and are not intended to describe all of these possibilities in an exhaustive manner. The substances described in the invention are novel and their identity has been established by analytical and spectral methods.

CS 268 63k Bl

Example 1

2- (2-Hethylaminoethoxy) biphenyl (1, n = 2)

To a stirred solution of 8.5 g of 2- (2-dimethylaminoethoxy) biphenyl in 50 ml of benzene was added dropwise over 10 ml of a solution of 7.8 g of ethyl chloroformate in 20 ml of benzene, the mixture was stirred for 10 minutes at 60-70 ° C and then boiled. 5 h under reflux. After cooling, the mixture was diluted with benzene, washed with 1: 1 dilute hydrochloric acid and water, dried and evaporated. 9.5 g (90%) of oily N- (2- (2-biphenylyloxy) ethyl) -N-methylcarbamic acid oily ester are obtained, which crystallizes from a mixture of benzene and petroleum ether, m.p. 35 DEG-168 DEG.

A mixture of 2.5 g of this product, 22 g of potassium hydroxide and 35 ml of water is stirred and refluxed for 9.5 h. The ethanol was evaporated in vacuo, the residue was diluted with water and extracted with benzene. From the benzene extract, the base is transferred to the aqueous phase by shaking with excess 3MHCl, the separated aqueous solution is basified with aqueous ammonia and the liberated base is isolated by extraction with benzene. Work-up of the extract gave the desired product of formula I (n = 2) as an oil in a yield of 17.3 g (97%). Dissolve in 20 ml of ethanol and add a slight excess of a solution of hydrogen chloride in ether to the solution. Upon standing, crystalline hydrochloride precipitates, which crystallizes from ethanol and melts at 153-155 ° C.

Example 2

2- (3-Methylaminopropoxy) biphenyl (i, n = 3)

Similarly to the previous example, boiling 17.1 g of 2- (3-dimethylaminopropoxy) biphenyl with 15.0 g of ethyl chloroformate in 40 ml of benzene for 6 hours gave 19.0 g (90%) of oily ethyl ester of N- (3 - (2-biphenylyloxy) propyl) -N-methylcarbamic acid, which is further processed without any purification.

Reaction of 12.2 g of this product with a boiling solution of 11.4 g of potassium hydroxide in 20 ml of ethanol (9 h) gives 9.2 g (09%) of the crude oily base of formula I (n = 3). Similarly to the previous example, it is converted into the hydrochloride, which crystallizes from ethanol and melts at 141-143 ° C.

Claims (1)

OBJECT OF THE INVENTION Process for the preparation of 2- (methylaminoalkoxy) biphenyl of general formula I in which n is 2 or J, and their hydrochlorides, characterized in that the 2- (dimethyl-aminoalkoxy) biphenyls of the general formula U <n>, CS 268 Ó3't Bl in which n denotes the same team in boiling benzene, As in formula I, the carbamates obtained are reacted with ethyl chloroformate of formula III (III) in which n is the same as in formula I, hydrolyzed with a boiling solution of potassium hydroxide in ethanol, after which the bases obtained are optionally converted to hydrochlorides by neutralization with hydrogen chloride or hydrochloric acid. .