CS241903B1 - Preparation method 2- (4-fluoro-4'-halogeno) - Google Patents

Abstract

The solution falls into the field of synthetic drugs. Its subject is a method for preparing 2-(4-fluoro-4-halobenzhydryloxy)ethylamines of the formula I, in which R is a fluorine atom or a bromine atom, « is a hydrogen atom or methyl and the NR2Ø2 residue is a dimethylan or pyrrolidine residue, and their hydrochlorides. The substances of formula I and especially their hydrochlorides are characterized by dopamine mimetic activity, which is the basis for their practical use in the therapy of parkinsonism. The preparation method consists in the reaction of the corresponding benzhydrols and 1,1-diarylethanols first with sodium hydride and then β 2-dimethylaminoethyl chloride or 2-pyrrolidinoethyl chloride in boiling benzene. The obtained crude bases 1 are purified by distillation in vacuum and neutralization with hydrogen chloride in ether are converted into crystalline hydrochlorides

Description

The present invention relates to a process for the preparation of 2- (4-fluoro-4'-halobenzhydryloxy) ethylamines of formula I,

(AND)

) Wherein R is fluorine or bromine, R 2 is hydrogen or methyl ^{in the} 3 and the radical NR R is either a radical-dimethylamine or pyrrolidine, and their hydrochlorides.

Patents (Belg. 796 354; Brit. 1 363 986; Fr. 2 181 791; Switzerland 576 941 to 576 943; US 4 003 932; Germany 2 311 067) as well as some reports in the scientific press (Van Beek MC, Timmerman H., J.Pharm. Pharmacol., 26, 57 (1974) Prous JR (Annual Drug Data Report 2, 101, 1979) discloses for compounds of formula II the following:

RAZ (II) in which R represents a fluorine atom or a chlorine atom and R represents a hydrogen atom or a methyl atom, as well as for their salts, the pharmacological effects of dopaminomimetics and potential antidepressants. Such agents find practical use in the therapy of parkinsonism and mental depression. Surprisingly, it has now been found that the tertiary amines of formula (I), the preparation of which is the object of the present invention, have analogous effects. Their advantage over the compounds of formula II is their easier synthetic accessibility.

241 903

Compounds of formula I and their hydrochlorides show similar effects as psychostimulants (excitations, tremors, convulsions) at high doses, induce behavioral stimulation syndrome in rats with indications of oral stereotyping as after apomorphine, and intensive anticataleptic effects in rats at higher doses (against perfenazine catalepsy) while having only low antihistarain and antireserpine activity.

A typical compound of the invention is N- [2- (4,4'-difluorobenzhydryloxy) ethyl] pyrrolidine hydrochloride which, when administered intravenously, has acute toxicity in mice, LD ₅₀ → 52 mg / kg. At sublethal intravenous doses, it induces excitation and tremor in mice, and convulsions at the highest doses. In a rotating rod test in mice, it has a discoordinating effect (apparently based on excitation); ED50 is 8.9 mg / kg

i.v. , the effect reaching a maximum at 5 min after administration. In the test for affecting spontaneous locomotor activity of mice in the beam method, it has only a very low depressant effect, D ^ q is greater than 50 mg / kg orally. At an intravenous dose of 5.2 mg / kg, the duration of thiopental sleep in mice increases 8.8 times. At an intravenous dose of 10 mg / kg to male rats, it induces behavioral activation syndrome with oral stereotypes (similar to apomorphine) and tremor. They are not aggressive after placing them in the group. At an oral dose of 100 mg / kg, it blocks virtually 100% catalepsy in rats induced by a standard dose of perfenazine. It shows only low antihistamine efficacy in histamine aerosol and histamine detoxification tests in guinea pigs and low antireserpine efficacy in the rescerin ulcerogenic effect antagonist test in rats.

The process for preparing the compounds of the formula I according to the invention consists in reacting the benzhydrols of the formula III

X in which R and R are the same as in Formula I, with sodium hydride in benzene and subsequent treatment with the chloro derivatives of formula IV,

C1CH ₂ OH ₂ MS ² S ³ (IV)

241 903

in which the radical NR @ 1 R @ 4 also denotes the same as in formula I, while boiling the reaction mixture. The oily bases of formula (I) are isolated in the examples as described above and are generally distilled under vacuum without decomposition, and neutralization with hydrogen chloride in ether gives crystalline hydrochlorides. Of the required starting materials, only the benzhydrol of formula III in which R is bromine and R is methyl has not been described so far; its preparation is described in the example. For known starting materials, if not commercially available, references are given in the examples regarding their preparation. The identity of all the novel compounds described in this invention was assured by conventional analyzes. The examples below give further details of the process for preparing the individual compounds of formula I according to the invention. However, they are not intended to fully describe all the possibilities of the invention.

Example 1

N, N-Dimethyl-2- (4,4'-difluorobenzhydryloxy) ethylamine

1.30 g of sodium hydride in 30 ml of benzene are suspended in a nitrogen atmosphere, and a solution of 8.0 g of 4,4 ' -difluorobenzhydrol (Gunther FA, Blinn RC, J.Amer.Chem.Soc. 72, 4282, 1950) is added. ) in 40 ml of benzene and refluxed for 5 h. The mixture was then cooled to room temperature and a solution of 5.5 g of 2-dimethylaminoethyl chloride in 15 ml of benzene was added dropwise with stirring over 5 minutes. The mixture was refluxed for 4 h.

After cooling, 15 ml of water are carefully decomposed under stirring in a nitrogen atmosphere with stirring, stirred until the inorganic fractions are dissolved, diluted with benzene and the organic phase is separated from the aqueous phase.

It is washed with water, dried over potassium carbonate and evaporated under reduced pressure. The residue was distilled under vacuum; 9.40 g (89%) of a base boiling at 140-142 [deg.] C / 0.13 kPa are obtained. Neutralization of this base with hydrogen chloride in an ether solution yields crystalline hydrochloride which is recrystallized from a mixture of ethanol and ether and then melts at 125-126 ° C.

Example 2

N, N-Dimethyl-2- (4-bromo-4'-fluorobenzhydryloxy) ethylamine

Similar to Example 1, a reaction of 8.0 g of 4-bromo-4'-fluorobenzhydrol is carried out (Eckstein Z. et al., Bull.Acad.Polon.Sci., Ser.Sci.Chim.Geol.Geogr. 2, 803, 1959) Chem., 54, 21 005,

1960). 1.05 g of sodium hydride and 4.1 g of 2-dimethylaminoethyl chloride

241 903 in 85 ml of benzene and the reaction mixture was similarly worked up. 8.50 g (85%) of an oily base are obtained, boiling at 173 DEG-175 DEG C./0.2 mbar. It gives hydrochloride melting at 123 to 124 ° C (ethanol-ether) ·

Example 3

N- [2- (4,4'-Difluorobenzhydryloxy) ethyl] pyrrolidine

Similar to Example 1, the reaction is carried out with 7.70 g of 4,4'-difluorobenzhydrol, 1.25 g of sodium hydride and 6.3 g of 2-pyrrolidinoethyl chloride (V / right JB, et al., J.Amer.Chem.Soc 22 (3098, 1948) in 90 ml of benzene and the reaction mixture is similarly worked up. There was obtained 9.80 g (91%) of an oily base boiling at 165-168 ° C / 0 mm Hg. This gave the hydrochloride melting at 178-179 ° C (ethanol-ether).

Example 4

N- / 2- (4-Bromo-4 * -fluorobenzylene dryoxy) ethyl / pyrrolidine

Similar to Example 1, the reaction was carried out 8.0. g of 4-bromo-4'-fluorobenzhydrol, 1.0 g of sodium hydride and 5.10 g of 2-pyrrolidinoethyl chloride in 90 ml of benzene and the reaction mixture are similarly treated. cuje. 9.0 g (84%) of an oily base are obtained, boiling at 190-193 ° C / 0.20 kPa. It gives the hydrochloride melting at 157-158 ° C (ethanol ether).

Example 5

Ν, Ν-Dimethyl-2- (1,1-bis (4-fluorophenyl) ethoxy) ethylamine

Similar to Example 1, a reaction of 8.0 g of 1,1-bis (4-fluorophenyl) ethanol (Grummitt O et al., J.Amer.Chem.Soc.

22, 2,279, 1950). 1.2 g of sodium hydride and 4.85 g of 2-dimethylaminoethyl chloride in 85 ml of benzene are treated similarly. 8.20 g (79%) of an oily base boiling at 142-145 ° C are obtained.

0.13 kPa. It gives the hydrochloride melting at 164-165 ° C (ethanol ether).

Example 6

N, N-Dimethyl-2- [1- (4-bromophenyl) -1- (4-fluorophenyl) ethoxy] ethylamine

Similar to Example 1, a reaction of 9.15 g of 1- (4-bromophenyl) -1- (4-fluorophenyl) ethanol, 1.1 g of sodium hydride and 4.9 g of 2-dimethylaminoethyl chloride in 90 ml of benzene is carried out and the reaction mixture is is similarly processed. 10.0 g (89%) of an oily base are obtained, boiling at 165-168 ° C / 0.13 kPa. It gives the hydrochloride melting at 157-158 ° C (ethanol-ether). 241 903

The starting material 1- (4-bromophenyl) -1- (4-fluorophenyl) ethanol used is a novel compound which can be prepared by the following procedure: A solution of Grignard reagent is prepared by reacting 1.82 g of magnesium with 10.7 g of methyl iodide in 45 ml of ether. To this end, a solution of 19.0 g of 4-bromo-4 ' -fluorobenzophenone (Eckstein Z. et al., Cited in Example 2) in 45 ml of benzene was added dropwise over 30 minutes at room temperature.

The mixture is then refluxed for 90 minutes, quenched with ice and 90 ml of a 20% ammonium chloride solution after cooling. The aqueous layer was separated and extracted with a mixture of benzene and ether. The extract was combined with a separate ether layer, washed with 50 ml of 5% sodium carbonate solution, dried and evaporated. The residue is 19.5 g (97%) of crude oily 1- (4-bromophenyl) -1- (4-fluorophenyl) ethanol which is used in the work without further purification.

Example 7

N- (2- / 1,1-Bis (4-fluorophenyl) ethoxy / ethyl) pyrrolidine

Similar to Example 1, 8.2 g of 1,1-bis (4-fluorophenyl) ethanol, 1.25 g of sodium hydride and 6.3 g of 2-pyrrolidinoethyl chloride in 100 ml of benzene are reacted and the reaction mixture is similarly worked up. 9.30 g (80%) of an oily base are obtained, boiling at 172 DEG-175 DEG C./0.16 mm Hg. It gives the hydrochloride melting at 169-170 ° C (ethanol-ether).

Example 8

N- (2- / 1- (4-Bromophenyl) -1- (4-fluorophenyl) ethoxy / ethyl) pyrrolidine

Analogously to Example 1, 10.3 g of 1- (4-bromophenyl) -1- (4-fluorophenyl) ethanol, 1.25 g of sodium hydride and 6.3 g of 2-pyrrolidinoethyl chloride in 110 ml of benzene are carried out and the reaction mixture is is similarly processed. 11.5 g (84%) of an oily base are obtained, boiling at 192-195 ° C / 0.2 kPa. It gives the hydrochloride melting at 183-184 (ethanol-ether).

Claims (3)

OBJECT OF THE INVENTION 241 903 A process for the preparation of 2- (4-fluoro-4z-halobenzhydryloxy) ethylamines of formula I, wherein R is fluorine or bromine, R is hydrogen or methyl and NR2R3 is either dimethylamine or pyrrolidine, and their hydrochlorides, characterized in that the benzhydrols of formula (III), (III) 1 vz, in which R and R are the same as in formula I, first subjected to sodium hydride in boiling benzene and then to chloro derivatives of formula IV, cich ₂ ch ₂ nr ² r ³ (IV) In which the residue NR R is again the same as in formula I, also while boiling the reaction mixture, the crude base I obtained is purified by distillation in vacuo and converted into the hydrochlorides by neutralization with hydrogen chloride in ether. Printed by Moravian printing works, center. 11 100, People's Militia Class 3, Olomouc Price: 2,40 Kčs