SU786891A3 - Method of preparing derivatives of 3-azabicyclo /3,1,0/ hexene of their salts, racemates or optically active active antipodes - Google Patents

Abstract

889 Substituted 3-azabicyclo3.1.0!hexanes, acid addition salts, method of use and method of preparation are described. The compounds have anxiolytic and analgesic activity.

Description

as a salt, as a racemate or as an optically active antipode.

Preferably, benzene or tetrahydrofuran, or ether, or toluene is used as an inert solvent.

Acids such as hydrochloric, sulfuric, nitric, maleic, are used to convert free compounds to salts.

Example, Preparation of racemic 1- (p-chlorophenyl) -3-azabicycio 3,1, Oj-hexane hydrochloride.

A solution of 2 g of diethyl 1- (p-chlorophenyl-cis-1, 2-cyclopropanecarboxylag in 25 ml of ethanol is treated with 13.5 ml of 1N potassium hydroxide solution. The reaction mixture is heated under reflux for 3.5 hours and then allowed to stand at room temperature overnight. Ethanol is distilled off under reduced pressure and the aqueous solution is extracted with ether to remove a small amount of mineral oil. The aqueous solution is treated with 13.5 ml of 1 and hydrochloric acid and 2 ml of b. acids. The oily aqueous mixture is extracted four times with chloroform The chloroform solution is dried, decolorized and concentrated under reduced pressure to obtain a yellow solid. Two recrystallizations from ethyl acetate-petroleum ether (30-70) give 0.85 g of a white solid 1- (p-chlorophenyl) -cis- 1,2-cyclopropane dicarboxylic acid, mp 162-163 s.

5.7 g of the above acid and 2.02 g of urea in 200 ml of xylene are heated under reflux for 22 hours, cooled, diluted with benzene and washed with water. The organic layer was diluted with chloroform, dried, concentrated under reduced pressure, and recrystallized from ethyl acetate and petroleum ether to give 1- (p-chlorophenyl) -1,2-cyclopropane dicarboxymide.

To a stirred solution of 30 ml of bis (2-methoxyethoxy) -aluminum sodium hydride (70% benzene solution) is added dropwise a solution of 2.2 g of 1-P-chlorophenyl -1, 2-cyclopropanecarboximide in 100 ml of benzene in a flow of E | 30 min at room temperature under nitrogen. For supporting and dissolving the reaction vessel is slightly heated. The clear yellow solution is then heated under reflux in a nitrogen atmosphere for 1 hour. The solution is cooled and the excess reagent is decomposed with 5N. sodium hydrate. Water is added to the mixture and the benzene phase is separated. The aqueous phase is extracted with ether and the ether extracts are mixed with the benzene phase and dried over magnesulfate. This organic phase is evaporated under reduced pressure to give a viscous liquid, which crystallizes into a sticky, off-white solid, consisting of a racemic base of 1- (P-chloro-phenyl) -3-azabicyclo 3, 1.0 hexane. This solid is dissolved in ethanol, acidified with alcoholic hydrogen chloride, and ether is added to form an off-white hydrochloride crystals.

 fero is recrystallized from ethanol to give whitish crystals, mp. 215-2170С.

Example 2. Obtaining (-) (p-chlorophenyl) -3-azabi: hiclo | 3, 1, Oj S -hexane hydrochloride.

To a stirred solution of 30 ml of bis- (2-methoxyethoxy) -aluminum sodium hydride (70% benzene solution) is added dropwise a solution of 6.6 g

0 () 1 (p-chlorophenyl) -1,2-cyclopropanecarboximide in 500 ml of benzene for 3 hours at room temperature under a nitrogen atmosphere. The clear yellow solution is heated with reverse

refrigerator for 90 minutes under a nitrogen atmosphere, and then left, overnight at room temperature. Excess hydride reagent is decomposed by carefully adding 25 ml of 5N. sodium hydroxide. Next, the mixture is diluted with 200 ml of water. The benzene phase is separated and the aqueous phase is extracted with chloroform. The mixed benzene and chlorofor phases are dried over magnesium sulphate

and concentrated under reduced pressure to obtain (-) - 1- (p-chlorophenyl) -3-azabicyclo 3, 1, Oj-hexane as a yellow solid. This solid is dissolved in ethanol.

and acidified with 10 ml of 2.3 n. ethanolic hydrogen chloride. Adding ether causes the hydrochloride of this base to precipitate as a solid, which is collected and dried to give white crystals, m.p.

l97-200 C, toC3r ° -679,

Example 3. Preparation of (+) (p-chlorophenyl) -3-azabicyclo 3,1, O hexanchlorohydrate.

Sample 192.5 g of racemic

The cis-1- (p-chlorophenyl) -1,2-cyclopropane dicarboxylic acid and 142 g of (-) - 2-aminobutanol in 1600 ml of acetone are left to stand for 48 hours, filtered and washed with acetone to obtain a solid. This solid is dissolved in 460 ml of warm water and acidified, then filtered and dried in a dry window. A sheet of 107.5 g of this crude (+.) Diacid and 79.3 g of (-) -. 2-aminobutanol in 892 ml of acetone is left standing for several hours. The solid is filtered off, dissolved in 200 ml of warm water, acidified with concentrated hydrochloric acid, cooled, and filtered. This solid is recrystallized from acetonyl, to obtain (+) -cis-1- {p-chlorophenyl) -1,2-cyclopropane dicarboxylic acid 10.5 g of this (+) - dibasic acid and 3.9 g of urea in 325 ml the xylene is stirred and then heated with a reverse fridge for 7.5 h, then left to stand overnight. Distillation of xylene, cooling and filtration give a white solid, which is recrystallized from ethanol to give

(+) - 1- (p-chlorophenyl) -1,2-cyclopropanecarboxymide +63.

To a stirred solution of 30 ml of sodium bis- (2-methoxyethoxy) -aluminum hydride (70% benzene solution) is added dropwise a solution of 4.5 g

(+) -1- (p-chlorophenyl) -1,2-cyclopropanecarboximide in 400 ml of benzene for a 45 min period with stirring at room temperature under nitrogen atmosphere. The clear yellow solution was heated under reflux under nitrogen for 90 minutes and left overnight at room temperature. Excess hydride reagent is decomposed by carefully adding 25 ml of 5N. sodium hydroxide. The mixture is diluted with 200 ml of water and the benzene phase is distilled off. The aqueous phase is extracted with chloroform. The mixed benzene and chloroform phases of drying over magnesium sulfate and concentrated under reduced pressure to give (+) (p-chlorophenyl) -3-azabicyclo, 1., 0 -hexane as a sticky yellow solid. The latter is dissolved in ethanol, acidified with 20 ml of ether and cryotalls are obtained. They are recrystallized from acetonitrile to give the hydrochloride as white crystals, m.p. 190-192 ° C,

M +.

Example 4. Obtaining racemic 1-phenyl-3-azabicyclo 3,1,0-hexane hydrochloride,

To a stirred solution of 30 ml of bis (2-methoxyethoxy) aluminum n-atrium hydride (70% benzene solution) is added dropwise a solution of 6.6 g of 1-phenyl-1,2-cyclopropanecarboximide in 400 ml of benzene over 1 h at room temperature in an atmosphere of nitrogen. The reaction mixture is then heated with obratnpch. refrigerator under nitrogen for 90 minutes. Excess hydride reagent is decomposed by carefully adding 25 ml of 10N. sodium hydroxide. The mixture is diluted with 200 ml of water and the benzene phase is separated. The aqueous phase is extracted with chloroform and the combined organic extracts are dried over magnesium sulfate. The solution is concentrated under reduced pressure to obtain a brown liquid, which is dissolved in ethanol and acidified with 5 ml of 2.3 N. ethanolic hydrogen chloride. A solid is precipitated by the addition of ether, which is recrystallized from acetonitrile, semi fjaH white crystals, m.p. 166-168 0. Example 5. Preparation of racemic 3-methyl-1-phenyl-3-azabicyclo 3, 1, OJ hexane hydrochloride.

Q To a stirred solution of 30 ml of bis (2-methoxyethoxy alum sodium hydride (70% benzene solution) is added dropwise a solution of 5.5 g of M-methyl-1-phenyl-1,2-cyclopropanecarboximide in 400 ml of benzene in flow for 1 hour at room temperature- under nitrogen atmosphere. The mixture is heated under reflux under nitrogen atmosphere for 90 minutes. Excess hydride reagent is decomposed by

0 carefully added 25 ml of 10 n. sodium hydroxide and then diluted to 200 ml with water. The benzene phase is separated and the aqueous phase is extracted with chloroform. The combined organic phases are dried over magnesium sulphate and concentrated at. lower pressure, getting liquid. The latter is dissolved in ethanol and acidified with 15 ml of 2.3 N. ethanol

Q hydrogen chloride. Adding ether causes a solid to form, which is recrystallized from isopropyl alcohol-hexane to give white crystals, m.p.

, 158-160 S.

Example 6. Obtaining 1- (m. -Chlorophenyl) -3-azabicyclo 3,1, oj hexane hydrate.

A weighed amount of 53.6 g of ethyl m-chlorophenylacetate (obtained by esterification with the corresponding acid),

51.5 g of N-bromosuccinimide and 1 g of benzoyl peroxide in 1.25 l of carbon tetrachloride are stirred with a metal nichrome stirrer under reflux for 20 hours. The mixture is cooled, filtered and concentrated to an orange oil. Distillation in vacuo gives ethyl-inC-bromo-m-chlorophenylacetate.

Q To a stirred suspension of 4.4 g of sodium hydride in 500 ml of ether under a nitrogen atmosphere, 0.5 ml of ethanol is added. Then a mixture of 27.8 g of the above ester, 10 g of ethyl acrylate and 1 ml of ethanol and

 the mixture is stirred at room temperature overnight. Ethanol is then added to decompose unreacted sodium hydride and the mixture is washed with 100 ml of water, 50 ml of 1N. hydrochloric acid, three times diluted with sodium bicarbonate and finally 100 ml of water. The product is dried and concentrated under reduced pressure to a yellow liquid, which is 1- (m-chlorophenyl) -1,2-cyclopropanecarboxylic acid diethyl ester. A portion of 22 g of this dibasic ester in 150 ml of ethanol and 150 ml of 1N. sodium hydroxide is heated under reflux IB for 3.5 hours and then left to stand at room temperature overnight. The mixture is concentrated and extracted with ether. The aqueous phase is acidified with 1N. hydrochloric acid, extracted three times with chloroform, dried and concentrated under reduced pressure to a yellow oil, which is recrystallized from ethyl acetate-petroleum ether to give cis-1- (m-chlorophenyl) -1,2-cyclopropane dicarboxylic acid in the form of a white solid. A portion of 5.7 g of this acid and 2.02 g of urea in 200 ml of xylene is heated under reflux for 22 hours, cooled, diluted with benzene and washed with water. The organic layer was diluted with chloroform and dried, concentrated under reduced pressure, and recrystallized from ethyl acetate and petroleum ether to give 1- (m-chlorophenyl) -1,2-cyclopropanecarboximide. To a stirred solution of 30 ml of bis- (2-methoxyethoxy) -aluminum sodium hydride (70% benzene solution is added dropwise a solution of 4.0 g of 1- (m-chlorophenyl) -1,2-cycPropane dicarboxymide in 400 ml of benzene in for 1 h at room temperature under a nitrogen atmosphere.The reaction mixture is heated under reflux under a nitrogen atmosphere for 90 minutes, the excess hydride reagent is decomposed with 25 ml of 10N sodium hydroxide and the mixture is diluted with 200 ml of water — the benzene phase is distilled and the aqueous the phase is extracted with chloroform. The mixed organic phases are dried on magnesium sulfate and concentrate under reduced pressure to obtain a viscous orange-brown liquid. This liquid is dissolved in this ethanol and acidified with 2.3N ethanolic hydrogen chloride. A solid is precipitated by the addition of ether, which is recrystallized from isopropanol to obtain 1- (m-chlorophenyl) -3-, azabicyclo {| 3,1,0 hexane hydrochloride in the form of white crystals 182IB OC .. P-p and me er 7. Preparation of 1- (m-fluoro phenyl) -3-azabicyclo s, 1, qJhexachnlp hydrate. A portion of 46.2 g of 1- (m-phenophenyl) -acetic acid is dissolved in 120 m of ethanol. 1.2 ml of sulfuric acid was added to the solution, the mixture was heated under reflux for 4.5 hours, and then left to stand at room temperature overnight. 400 ml of water are then added and the mixture is extracted three times with ether, dried over magnesium sulphate and concentrated under reduced pressure to a liquid. Distillation in vacuo gives ethyl-1- (m-fluorophenyl) -. -acetate. A mixture of .49.3 g of ethyl 1- (m-fluorophenyl) acetate, 53 g of j-bromosuccinimide and 0.95 g of benzoyl peroxide in 1.6 l of carbon tetrachloride is heated under reflux and stirred with a metal nichrome stirrer for The mixture is concentrated to an orange oil for 24 hours and distilled in vacuo to give ethyl-L-bromo-1- (m-fluorophenyl) acetate. To a suspension of 11 g of sodium hydride in mineral oil in 1 l of ether under a nitrogen atmosphere, with stirring, a mixture of 65 g of ethyl-U-bromo-1- (m-fluorophenyl) -acetate, 25 g of ethyl acrylate and 2 ml of ethanol is added dropwise. The temperature is maintained at 25-29 ° C with stirring overnight. The mixture is cooled, a few milliliters of ethanol is added to decompose unreacted sodium hydride and the mixture is washed successively with water, 1N. hydrochloric acid, dilute sodium bicarbonate and saturated sodium chloride solution, then concentrated to a liquid which is distilled under vacuum to give 1- (m-fluorophenyl) -1,2-cyclopropane dicarboxylic acid diethyl ester. A mixture of 20.5 g of the above dibasic acid ester and 160 jvui 1 n. Potassium hydrate oxide in 150 ml of ethanol is heated under reflux for 3.5 hours and concentrated. The mixture is acidified with 1N. hydrochloric acid, extracted three times with chloroform, dried and concentrated under reduced pressure to a solid. The latter was recrystallized twice from a mixture of ethyl acetate-petroleum ether to give cis-1- (m-fluorophenyl) -1, 2-cyclopropane dicarboxylic acid. A stirred mixture of 8.0 g of the above dibasic acid and 2.6 g of urea in 500 ml of xylene is heated under reflux for 22 hours. The solution is diluted with benzene, washed with water and dried over magnesium sulfate. The organic layer was concentrated under reduced pressure to give 1- (m-fluorophenyl) -1,2-cyclopropanecarboximide as a whitish solid. A solution of 5.6 g of 1- (m-fluorophenyl -2,2-cyclopropanecarboximide in 400 ml of benzene is added dropwise to a stirred solution of 30 ml of bis (2-methoxyethoxy) -aluminium hydride sodium in 400 ml of benzene over 90 minutes in a nitrogen atmosphere at room temperature The reaction mixture is heated at reflux under nitrogen for 9 D minutes, the excess hydride reagent is decomposed by carefully adding 25 ml of water, the benzene phase is distilled off and the aqueous phase is extracted with chloroform.

The combined organic solutions were dried over magnesium sulphate and concentrated under reduced pressure to give a mixture of an oily solid and a viscous liquid. This mixture is dissolved in ethanol and acidified with ethanolic hydrogen chloride. Upon addition of ether, a precipitate formed, which was recrystallized from acetonitrile to give 1- (m-fluorophenyl-3-azabicyclo 3,1.0 hexane hydrochloride as gray crystals, mp 140-146 s.

Example 8. Obtaining (-) - -phenyl-3-azabidiclo 3, 1, Oj hexane hydrochloride.

To a stirred suspension of 18.7 g of (-) - 1-phenyl-1,2-diclopropanecarboxmide in 500 ml of benzene in a nitrogen atmosphere, 150 ml of bis (2-methoxy-ethoxy) sodium aluminum hydride (70% benzene solution) are added over 10 min. The mixture was stirred at room temperature for 2 hours, heated under reflux for 2 hours, heated under reflux for 4 hours, and then left to stand at room temperature for 20 hours. Then, 150 ml was carefully added with stirring. n sodium hydroxide. The organic layer is washed with water, dried over magnesium sulfate, and evaporated under reduced pressure to a yellow oil. It. the oil is dissolved in 300 ml of ether. Dry hydrogen chloride is bubbled through the mixture until precipitation occurs, and the mixture is filtered to obtain colorless crystals. They are recrystallized from acetonitrile to give pale yellowish brown crystals, m.p. 170172 ° C.

PRI me R 9. Receiving racemic 1-phenyl-3-azabicyclo p, 1.0 hexane.

Analogously to Example 8, but using 1-phenyl-1,2-cyclopropane dicarboxyimide without adding hydrogen chloride gas, a racemic mixture of 1-phenyl-3-azabicyclo 3, 1.0 hexane, mp. 130 .133 C / 15 mmHg

Example 10. Obtaining (-) - 3-methyl-1-phenyl-3-azabicyclo 3,1, Oj hexachlorohydrate ..

To a solution of 18.7 g of (-) - 1-phenyl-1,2-cyclopropanecarboxymide in 10 ml of anhydrous dimethylformamide was added 5.0 g of sodium hydride (54% in mineral oil) over 15 minutes. The mixture is stirred for 30 minutes, and. 10 ml of iodomethane are then added to it over b min. Next mixture

left to stand for 15 minutes, heated on the steam bath for 15 minutes, cooled and poured into 250 ml of water. The crystals are filtered off, washed with petroleum ether and air dried to obtain (-) - N-methyl-1-phenyl-1,2-cyclopropane dicarboxymide.

To a stirred solution of 5.0 g of (-) - M-methyl-1-phenyl-1,2-cyclopropanecarboximide in 125 ml of benzene in an az atmosphere, add 30 ml

o Bis (2-methoxyethoxy) sodium aluminum hydride (70% benzene solution) for 10 minutes. The mixture is heated under reflux for 5 hours, cooled and gently poured to

5 she 60 ml 10 n. sodium hydroxide. The organic layer is washed with water, dried over magnesium sulfate and evaporated under reduced pressure to give an amber oil. This oil is dissolved in 250 ml of ether, saturated

0 Hydrogen chloride and filtered to obtain colorless crystals. The latter is recrystallized from acetonitrile to give colorless crystals, m.p. 194-19 ° C, -73 °.

five

Example. Obtaining (-) - 1- (p-chlorophenyl-3-methyl-3-azabicyclo {3, 1, Oj hexane hydrochloride.

5.0 g of sodium hydride (54% in mineral oil) was added to a solution of 22.1 g of (-) p-chloro-phenyl) -, 2-cyclopropanecarboxymide in 100 ml of anhydrous dimethylformamide over a period of 15. min. The mixture is stirred for

5 to 30 minutes and then 10 ml of iodomethane are added over 5 minutes. This mixture is left to stand for 15 minutes, heated on the steam bath for 15 minutes, cooled and poured into 250 ml of water. The crystals are filtered off, washed.

0 petroleum ether and dried in air to give colorless crystals of (-) - N-methyl-l- (p-chlorophenyl) -1,2-cyclopropanecarboximide.

To mix the MoMi solution of 11.8 g

5 of the above product in 60 ml of benzene under a nitrogen atmosphere, 60 ml of sodium bis (2-methoxyethoxy) aluminum hydride (70% benzene, solution) are added over 10 minutes. The mixture was heated under reflux for 5 hours, cooled, and 60 ml of 10N was carefully poured into it. sodium hydroxide. The organic layer is washed with water, dried over magnesium sulfate and evaporated under reduced pressure to an amber oil. The oil is dissolved in 250 ml of ether, saturated with hydrogen chloride and filtered to give colorless crystals. Recrystallization from acetonitrile gives colorless crystals, m.p. 211-2120s,

Example 12. Preparation of (, +). (P-chlorophenyl) -3-methyl-3-azabicycloS3, 1, hexane hydrochloride.

5 to a stirred solution of 11.08 i (+) (pgchlorophenyl-1,2-cyclopropane carboximide in 50 ml of anhydrous dimethylformamide was added 2.5 g of sodium hydride (54% in mineral oil for 15 min under nitrogen atmosphere. The mixture was stirred 30 5 ml of iodomethane is added for 5 minutes, the mixture is left to stand for 15 minutes, heated on the steam bath for 15 minutes, cooled and poured into 125 ml of water. The crystals are filtered, washed with petroleum ether and dried, The {+) - c-methyl-1- (p-chlorophenyl -1,2-cyclopropanedicarboximide) crystals are colorless. To a solution of 3.92 g of (+) - M-methyl-1- (p-chlorophenyl) -1,2-cyclopropanecarboxymide in 100 ml of benzene, 20 ml of bis- (2-methoxyethoxy) aluminum hydride are added under nitrogen atmosphere. sodium (70% benzene solution) for 10 minutes. The mixture is stirred for 2 hours at room temperature and then heated under reflux for 2 hours. Then carefully add 20 ml of sodium hydroxide 20. The layer is washed with water, dried over magnesium sulphate and evaporated under reduced pressure to give an oil. The oil is dissolved in 200 ml of ether and saturated with dry hydrogen chloride to give a colorless crystalline precipitate, which is recrystallized from acetonitrile to give (+) - 1- (p-chlorophenyl) -3-methyl-3-azabicyclo | 3/1, O j hesanhydrochloride in the form of pale yellow-brown crystals, mp 209210 C, to3 + 67 ° C. Example 13. Preparation of racemic 1- (p-chlorophenyl-3-methyl-3-azabicyclo-3, 1.0 hexane hydrochloride. To a stirred solution of 44.2 of racemic .1- (p-chlorophenyl) -1,2-cyclopropanecarboximide In 200 ml of anhydrous dimethylformamide, 10.0 g of sodium hydride (50% in micronized oil) are added over 5 minutes, 20 ml of iodomethane are slowly added with stirring over a period of 5 minutes, then the mixture is heated on a steam bath for 30 minutes and cooled and poured into 500 ml of water. The solid is collected by filtration and the transition stalls from heptane / ethyl acetate mixture to colorless crystals of racemic H -methyl-1- (p-chl phenyl) -1,2-cyclopropanecarboximide To a stirred solution of 11.8 of the above product in 250 ml of bisol under nitrogen is added 60 ml of sodium bis- (2-methoxyethoxy) aluminum nitride (70% benzene solution) for 10 minutes. After holding for 16 hours, the mixture is heated under reflux for 4 hours, cooled, and 60 ml of 10N are gently poured into it. hydroxide oxide. on three . The organic layer is dried over sodium sulphate, then over magnesium sulphate, filtered and evaporated under reduced pressure to obtain the free base as a pale yellow oil. The oil is dissolved in 200 ml of ether and saturated with dry hydrogen chloride gas. The solid is precipitated and recrystallized from acetonitrile to give pale yellowish-brown plates, m.p. 180-1820С. Example 14. Preparation of 3-phenethyl-1-phenyl-3-azabicyclo 3, 1, Oj hexane hydrochloride. To a stirred solution of 9.35 g of 1-phenyl-1,2-cyclopropanecarboximide in 50 ml of dimethylformamide, 2.5 g of sodium hydride are added (50% in mineral oil for 5 minutes). This mixture is heated and stirred for 30 minutes, 0.1 g of potassium iodide is added to it, and then 9.25 g of phenethyl bromide. The mixture is stirred for 30 minutes, heated on a steam bath for 15 minutes, stirred at room temperature for 15 minutes, and then poured into 1 liter of water, acidified with acetic acid. The mixture is extracted with methylene chloride, this solution is mixed with 5 0 g of magnesium silicate and evaporated under reduced pressure. The remaining powder is placed on a column of magnesium silicate and eluted with 1 l of petroleum ether, 500 ml of methylene chloride, 1 l of chloroform and evaporated to give N-phenyl-1-phenyl-1, 2-cyclopropanecarboxymide in as a colorless oil. To a solution of 5.80 g of the above compound in 50 ml of benzene, 10 ml of sodium bis (2-methoxyethoxy) aluminum hydride (70% benzene solution) is added with stirring. The mixture is left to stand for 18 hours, heated under reflux for 2 hours, cooled and treated with 10 ml of 10N. sodium hydroxide, as described in Example 13, a crystalline product, mp. 207-209 ° C., Example 15. Preparation of 1- (p-trifluoromethylphenyl) -3-azabicyclo 3,1, o-hexane hydrochloride. Using the method of example 6, ethyl-p- (trifluoromethyl} -phenylacetate is converted to etyl-bromo-p- (trifluorome-. Tyl) phenylacetate (b.p.92-95 ° C / / 0.4 mm Hg). Art.) This substance is subjected to reaction with sodium ethyl acrylate hydride to obtain diethyl 1- (p-trifluoromethylphenyl) -1,2-cyclopropanecarboxylate, bp 109-110 s / / 0.2 mm Hg. Hydrolysis 1 n potassium hydroxide gives .cis-1- (p-trifluoromethylphenyl) -1,2-cyclopropane dicarboxylic acid as colorless crystals, mp 1-1-162 ° C. This dibasic acid is then reacted with urea to obtain 1- (n-trifto methylphenyl} -1,2-tsiklopropandikarboksimid as colorless crystals, m.p. 1b4-165 ° C.

To a solution of 3.5 g of this imide in 75 ml of benzene was added 20 ml of sodium bis (2-methoxyethoxy) aluminum hydride. ri (70% benzene solution). The mixture is heated under reflux for 1 hour, cooled to room temperature, and the excess hydride reagent is decomposed with 20 ml 10 and. sodium hydroxide. The benzene layer is washed with water, dried over magnesium sulfate and evaporated under reduced pressure to give an amber oil. This oil is dissolved in ether and dry hydrogen chloride gas is bubbled into the solution. The resulting precipitate is collected by filtration and recrystallized from isopropyl alcohol to obtain a product, so pl. 249-251 ° C.

Example 16. Obtaining 3-ethyl-1-phenyl-3-azabicyclo, 1.0 hexane hydrochloride.

To 15.9 g of 1-phenyl-3-azabicyclo 3, 1, 0j hexane in 20 ml of pyridine, 20 ml of acetic anhydride are added. The mixture was left to stand at room temperature overnight, and then evaporated to obtain an oil. This oil is dissolved in a mixture of ether and methylene chloride, washed with dilute hydrochloric acid and then sodium bicarbonate, dried over magnesium sulfate and evaporated to a pale amber liquid. The latter is crystallized from hexane and get the product - Z-acetyl-1-phenyl-3-azabicyclo, 1.0 hexane, so pl. 63-65 C.

A weighed amount of 10.0 g of 3-acetyl-1-phenyl-3-azabicyclo 3,1.0 hexane obtained above in 100 ml of benzene is treated with 25 ml of sodium bis (3-methoxyethoxy) aluminum hydride (70% benzene solution), as described in the examples above, to obtain yellowish brown crystals, mp 148-15200.

Example 17. Preparation of 1- (p-methoxyphenyl) -3-azabicyclo 3, 1.0 hexane hydrochloride.

A mixture of 2.6 g of diethyl 1- (p-methoxyphenyl) -1,2-cyclopropane carboxylate (prepared as in example b from ethyl p-methoxyphenylacetate}, 20 ml. 1N of potassium hydroxide and 20 ml of ethanol is heated in reverse condensate for 3.5 hours and ethanol is distilled off. 20 ml of 1N hydrochloric acid are added, and then additional portions of the acid until the pH is equal to unity. The mixture is extracted three times with chloroform,

dried and concentrated to a yellow solid. This substance is recrystallized from ethyl acetate-hexane to obtain the cis-1- (g-methoxyphenyl) -, 2-cyclopropane dicarboxylic acid as a pale yellow solid.

6.6 g of this dibasic acid;

2.4 g of urea and 300 ml of xylene are boiled under reflux and with stirring for 24 hours. The mixture is cooled, diluted with 25 ml of benzene, washed with water, dried, concentrated under reduced pressure to obtain a solid, which is recrystallized from ethyl acetate-hexane mixtures to give 1- (p-methoxyphenyl) -1,2-cyclopropanecarboximide.

3.0 g of the above product is mixed with 70 ml of benzene and 20 ml of sodium bis (2-methoxyethoxy) aluminum hydride (70% benzene solution) is added with stirring over 5 minutes. After stirring for 30 minutes and refluxing for 1 hour, the mixture is cooled and 20 ml of 20 N are added. sodium hydroxide and then saturated sodium chloride. The organic layer is dried over magnesium sulfate, filtered, and evaporated to an oil. The oil is dissolved in ether and hydrogen chloride gas is bubbled through the solution. The resulting solid is recrystallized from isopropyl alcohol to give pale pink patches, mp. 174-175c.

Example 18. Obtaining (+) - -fechyl-3-azabicyclo 3,1, oj hexane hydrochloride.

To a stirred suspension of 10 g of (+) - 1-phenyl-1,2-cyclopropanecarboximide in 300 ml of benzene in a nitrogen atmosphere, 80 ml of sodium bis (2-methoxyethoxy) aluminum hydride (70% benzene solution) are added. The mixture was stirred at room temperature for 2 hours / refluxed for 4 hours, stirred at room temperature for 20 hours, and then slowly added 80 ml of 10 N with stirring. sodium hydroxide. The organic layer is washed with saturated sodium chloride, water, dried over magnesium sulfate and filtered. The filtrate is evaporated

5, ether is added and dry hydrogen chloride gas is bubbled. The product is isolated by filtration and then recrystallized from acetonitrile to give colorless needles, so pl. 169-17lc, + 68 °

0

Example 19. Obtaining 1- (3,4p dichlorophenyl) - 3-azabicyclo 3 / 1.0 hexane.

A solution of 59.5 g of 3, 4-dichlorophene: - hydrochloric acid in 500 ml of anhydrous

5 of ethanol is saturated with anhydrous hydrogen chloride and then heated under reflux for 2 hours. The mixture is concentrated under reduced pressure to 200 ml, diluted with 200 m of water and neutralized with concentrated ammonium hydroxide. This aqueous mixture is extracted 3 times with chloroform. Concentration and discoloration of chloroform extracts gives ethyl 3,4-dichlorophenylacetate. in the form of a yellow oil. In a three-necked flask equipped with a nichrome stirrer and reflux condenser, 7.0 g of ethyl 3, 4-dichlorophenylacetate, 5.9 g of 11-bromosuccinimide, 0.1 g of benzoyl peroxide and 150 ml of carbon tetrachloride are placed. The reaction mixture is heated under reflux for 18 hours, cooled and filtered. The carbon tetrachloride filtrate is concentrated under reduced pressure to obtain a dark orange liquid. Vacuum distillation at 115-120 0 / 0.5 mm Hg. gives ethyl-c-bromo-3, 4-dichlorophenylacetate as a pale yellow liquid. This product is converted to diethyl-cis-1- (3,4-dichlorophenyl) -1,2-cyclopropane carboxylate in a known manner. A mixture of 150 g of this dibasic ester and 66 g of 85% KOH in 500 ml of water and 500 ml of ethanol is boiled with a reflux condenser for 6 hours and then quickly frozen by pouring into ice. The oily product is extracted into ether and the aqueous layer is acidified with 100 ml of 12N. hydrochloric acid. The oily lower layer crystallizes slowly, forming a colorless crystalline cake. It is recrystallized from ethanol-ethyl acetate to obtain colorless crystals of 1- (3,4-dichlorophenyl) -1,2-cyclopropane dicarboxylic acid. A mixture of 30.3 g of this dibasic and 12.6 g of urea in 1 l xylene is refluxed for 6 hours. The solvent is distilled off under reduced pressure, and the crystalline residue is suspended with water. The colorless crystals are collected by filtration, washed with water and air dried to obtain 1- (3,4-dichlorophenyl) -1,2-cyclopropanecarboximide. To 40 ml of a 1 M solution of borane tetrahydrofuran is added with stirring S under nitrogen at 0 ° C. a solution of 2.56 g of this imide in 50 ml of tetrahydrofuran for 15 min. The solution is heated in a steam bath for 1 h, and then cooled in ice, 20 ml of 6N are added. soy acid, and tetrahydrofuran is distilled off under reduced pressure. The residue is alkalinized 75 ml of 5 n. sodium hydroxide and extracted with efrom. The extract is dried over sulfate TOM magnesium, filtered and the filtrate is saturated with hydrogen chloride. The precipitated crystals are collected by filtration and recrystallized from isopropyl alcohol to obtain 1.70 g of 1- (3, 4-dichlorophenyl) -3-azabicyclo 3, 1.0.-Hexanchlorohydrate as colorless crystals, mp. 180181 ° C. The following imides, obtained by the above method, are likewise reduced to the corresponding 3-azabicyclo 3,1,0 hexanes: Imide The product of the reduction of 1- (p-ethylfe-1- (p-ethylphenyl) -3nyl) -1,2-cyclo- - azabicyclo 3,1,0 propanedicarb-hexane hydrochloride, oximide, m.p. 207-209С; m.p. 102-1040C; 1- (pn-hexyl-1-p-hexylphenyl) -3phenyl) -2,2-azabicyclo 3,1,0-cyclopropane-hexanchlorohydrate, dicarboximide, mp. 181-183 0; m.p. 115-117 ° C; 1- (m-lol) 1- (m-tolyl) -3-azabicyclo p, 1.03 hexane-1, 2-cyclopropanedicarboxychlohydrate, 129-131 C; mid, t. 164-16 OS; 1- (p-bromofe1- (p-bromophenyl) -3 -. -Azabicyclo 3, 1, oj nyl) -1,2-cyclopropane dicarbhexanhlorohydrate, m.p. 231-2330CJ oximide, m.p. ISO-SLS; 1 - (, p-fluorofe1- (p-fluorophenyl) -Znyl) -1,2-diclo-azabicyclo 3,1,0 propane dicarbhexane hydrochloride, mp. 170-172 ° C oksimid, so pl. 146-148 ° C. Example 20. Preparation of I- (m-methoxyphenyl) -3-methyl-3-azabicyclo 3, 1, oZhexane hydrochloride. A portion of 92.3 g of m-anisidine is dissolved in 225 ml of concentrated hydrochloric acid, 150 ml of water and 150 g of ice, and the mixture is cooled to. This mixture is carefully diazotized with vigorous stirring at 0-5. With 52.5 g of sodium nitrite in 120 ml of water. This mixture is then added to 83.25 g of N-methylmaleimide in 225 ml of acetone at; 0 ° C. The pH was adjusted to 3.0, and 25.5 g of copper chloride dihydrate (1) was added to the mixture in one portion, followed by the addition of 200 ml of acetone with stirring. Evaporation of the acetone and decanting of the aqueous layer gave a black residue, which is boiled with 1 liter of benzene, dried over magnesium sulfate, and filtered through a Büchner funnel containing 50 g of activated magnesium silicate. The residue is boiled with 1 l of benzene and filtered through activated magnesium silicate. The dark filtrate is evaporated under reduced pressure and then heated for 10 minutes with 100 ml of 2,6-lutidine to carry out dehydrochlorination. The resulting solution is mixed with 500 ml of water and 400 ml of pyridine and filtered. The crystalline cake is pressed to release dark oil and then boiled with 500 Ml of 90% ethanol. This mixture is cooled and filtered to give 2- (m-methoxyphenyl) -N-methylmaleimide as orange crystals, m.p. 138-14bs.

This product is converted to 1- (m-hydroxyphenyl) -M-methyl-1,2-cyclopropanecarboximide in a known manner.

To a mixture of 3.0 g of this imide in 70 ml of benzene, 20 ml of sodium bis (2-methoxyethoxy) aluminum hydride (70% benzene solution) are added over a period of 5 minutes under nitrogen and with nei stirring. This mixture is stirred for 30 minutes, heated under reflux for 1 hour, cooled and 20 ml of 10 are poured thereto. sodium hydroxide and then saturated sodium chloride. The organic layer was dried over magnesium sulphate, filtered and evaporated to give crystals, which were recrystallized from ether. The reaction with gaseous hydrogen chloride and recrystallization from isopropyl alcohol gives a crystalline product -1- (m-methoxyphenyl) -3-methyl-3-azabicyclse 3,1,0 hexane hydrochloride, m.p. 148-1500С.

PRI me R 21. Preparation of (+) - (1-phenyl) -3-methyl-3-azabicyclo 3, 1, OJ hexane.

A mixture of 10 g of (+) - 1-phenyl-1,2-cyclopropanecarboximide, 2.67 g of sodium hydride ((.50% in mineral oil}, 50 ml of dimethylformamide and 5 ml of methyl iodide) is reacted and the mixture is poured onto 500 ml of water. This mixture is extracted with methylene chloride, washed with water, dried over magnesium sulfate and evaporated. The residue is adsorbed on activated magnesium silicate in a Buchner funnel and washed with 250 ml of benzene. The eluate is washed with 500 ml of methylene chloride and evaporated to obtain green crystals (+) - 1-phenyl-N-methyl-1, 2-cyclopropanecarboximide.

A weighed amount of 3.0 g of this imide in 700 ml of absolute benzene is reacted with 200 ml of sodium bis (2-methoxyethoxy) aluminum hydride (70% benzene solution). The mixture was stirred for 15 minutes at room temperature, and then on the steam bath for 15 minutes. After cooling, the reaction mixture was worked up as described in Example 12 to give (+) - 1-phenyl-3-methyl-3-azabicyclo, 1.0 hexane hydrochloride as crystals, m.p. 188-190c, + 72 °.

- Example 22. Obtaining l- (ri-nitrophenyl) -3-azabicycly 3,1,0 hexachlorohydrate.

To a stirred suspension, 20.6 g of 1-phenylcyclopropane-1,2-dicarboxylic acid in 25 ml of concentrated sulfuric acid at O-C are added

15 ml of concentrated nitric acid for 30 minutes. The resulting solution is then stirred at ambient temperature — for

About 30 minutes, then poured into ice. The crystalline product is recrystallized from hexane-ethyl acetate to give 1- (p-nitrophenyl) -cyclopropan-1, 2-dicarboxylic acid as

5 colorless crystals, so pl. 138-144 ° C. The above dibasic acid is converted to 1- {p-nitrophenyl) -1, 2-cyclopropanecarboximide, m.p. 171-173-С in a manner written in

(1 measure 6.

A solution of the above imide in tetrahydrofuran is added to a 1 M solution of borane tetrahydrofuran at 0 ° C under a nitrogen atmosphere. The solution is heated under reflux for 1 hour, cooled to about 5 hours and then 6 n. hydrochloric acid. The tetrahydrofuran is distilled off under reduced pressure, and the residue is partitioned between ether and sodium hydroxide. Ether solution containing 1-cp-nitrophenyl) -3-azabicyclo | 3, 1, o. Hexane, dried over magnesium sulfate and filtered, and hydrogen chloride is added to the filtrate,

5 to obtain a brown solid, so pl. 215-217 ° C. . Example 23. Obtaining 1- (o-chlorophenyl) -3-azabicyclo 3,1, Oj hexane hydrochloride.

0 A stirred mixture of 36.9 g of methyl o-chlorophenylacetate, 36.0 g of N-bromosuccinimide and 2 drops of 48% hydrobromic acid in 500 ml of carbon tetrachloride is boiled.

g under reflux for 20 h, and then filtered through magnesium silicate. Evaporation under reduced pressure gives methyl-o (, - bromo-o-chlorophenylacetate as a pale yellow liquid).

To a stirred suspension of 4.8 g of sodium hydride (50% in mineral oil) in 100 ml of a mixture of benzene-N, N-dimethylformamide (1: 1) is added a mixture of 26.3 g of the above bromo ester and 8.69 g methyl acrylate for 30 min. The mixture is stirred at ambient temperature for 4 hours, the excess sodium hydride is decomposed by 2 ml of methanol and this

0 Pour the mixture into 500 ml of water. The organic layer is washed with water, dried over magnesium sulphate and evaporated, yielding dimethyl-1 - (, o-chlorophenyl) -1,2-cyclopropane dicarboxylate

5 as a brown oil.

The above-dibasic acid ester (17.35 g) and 200 ml of 1N. Potassium hydroxide in 50 ml of ethanol is refluxed for 6 hours. The solution is evaporated to half the volume under reduced pressure and acidified to give 1- (o-chlorophenyl) -1,2-cyclopropanecarboxylic acid as a brown oil.

A mixture of 10.0 g of the above dibasic acid and 3.4 g of urea in 500 ml of xylene is refluxed for 6 hours. The solution is washed with water and sodium bicarbonate and then dried over magnesium sulfate, to give a yellowish-brown solid. Recrystallization from ethanol gives 1-o-chlorophenyl) -1,2-cyclopropanecarboximide as colorless crystals, m.p. 154-15bs.

To 1.25 g of the above imide in 30 ml of benzene were added 9 ml of bis (2-methoxyethoxy), sodium aluminum hydride (70% benzene solution) over 2 minutes with stirring. The solution is stirred at ambient temperature for 15 minutes and then heated under reflux for 30 minutes. To the cooled solution was added 10 ml of 10N. sodium hydroxide and benzene layer are washed with water, dried over magnesium sulphate and filtered. The filtrate is evaporated under reduced pressure, the residual oil is dissolved in ether, and anhydrous hydrogen chloride gas is added to this solution. The precipitated product is recrystallized from isopropyl alcohol to give 1- (o-chlorophenyl) -3-azabicyclo 3.1 / 0} hexane hydrochloride as colorless crystals, m.p. 188-190s

Example 24. Preparation of l- (fn-tolyl) -3-azabicyclo, l, 0 hexane hydrochloride.

230 ml of thionyl chloride is added to 120 g of p-tolylacetic acid and the solution is left to stand at room temperature for 2 hours, after which it is heated to 1 hour. To this solution are added 285 g of M-bromosuccinimide and 10 drops 4 of 8% hydrobromic acid and then the mixture is refluxed for 1 hour in an oil bath at. Then the additional 90 ml of tifnil chloride and the heating with reversed hot water continue for another 45 minutes. The mixture was distilled under reduced pressure to distill off 250 ml of thionyl chloride, and the residual liquid was poured into 500 ml of cold methanol with stirring and cooling was continued on ice for 15 minutes. This solution was evaporated under reduced pressure to give a dark oil, which was dissolved in 100 ml of chloroform. The solution is washed with 500 ml of water, dried over magnesium sulphate, and filtered. The filtrate is evaporated under reduced pressure to give a dark oil, which is distilled to form 94 g of the bromo ester as a pale yellow liquid, i.e. p. 115-120s / / 0.05 mm Hg The pale yellow liquid is then reacted with a mixture of sodium methyl acrylate hydride in ether (as in Example b) to obtain dimethyl-cis-1- (p-tolyl) -1,2-cyclopropane dicarboxylate, mp. 58-59 C. Hydrolysis 1 n. potassium oxide hydrate followed by acidification of the solution with hydrochloric acid (as in Example 6 gives cis-1- (p-tolyl) -1,2-cyclopropane dicarboxylic acid as colorless crystals, mp 188190 C. This dibasic acid is then reacted with urea (as in example 6}, to obtain 1- (p-tolyl) -, 2-cyclopropane dicarbox MFA in the form of pale yellow crystals, mp. 82-85 ° C.

To a mixture of 20.1 g of this imide in 600 ml of benzene, 160 ml of bis (2-methoxyethoxy) are added. sodium aluminum hydride and carried out the reaction as in Example 8, and then excess reagent is decomposed with 160 ml of 10N. sodium hydroxide. The benzene layer is washed with water, dried over magnesium sulfate and filtered. The filtrate is evaporated under reduced pressure to give a dark oil, which is dissolved in ether, and then dry hydrogen chloride is bubbled into the solution. The resulting precipitate is collected by filtration and recrystallized from acetonitrile-methanol to give 12.1 g of l-l (p-ttoliJ 3-azabidic 3, 1, o hexanhydrochloride as pale yellowish-brown plates, mp 207-208 C.

As described in the above example, 1-p-cumyl) -1,2-cyclopropanecarboximide, mp. 147-148 C gives 1- (p-cumyl) -3-azabicyclo 3,1, OD of hexanhydrochloride, so pl. 231-232ОС.

The following imides were reduced in the above manner to form the corresponding amnichlorohydrates:

Imid3-Azabicyclo Sz, 1, O5

hexane

1- (3-bromo-4-met-. L- (3-6pOM-4-MeTOKCt exiphenyl) -2/2-phenyl) -3-azabicycl azacyclopropane-, 1.0 hexanchlor dicarboximide, hydrate, mp. 208t. Pl. 184-18;; 211 ° C; 1- (o-tolyl-1,2-cyc-1- (o tolyl) -3lopropanecarboxy-azabitsyklo mid). EZ, 1.03 hexane hydrochloride.

Example 25. Preparation of (+) -1-Sp-tolyl) -3-azabicyclo 3, 1, OD hexanhydrochloride.

94.8 g of racemic 1- (p-tolyl) -1, 2-cyclopropanecarboxylic acid (Example 24} and 73.8 g of {-) -eL- (1-naphthyl) -ethylamine are dissolved in 300 ml of tetrahydrofuran, the solution is diluted 300 ml of ethyl ether and allowed to stand at room temperature until crystallization is complete. The mixture is filtered and the crystals that are collected are washed with cold tetrahydrofuran to obtain 4.95 g of salt consisting of a mole equivalent of (+) (P tolyl) -, 2-cyclopropane dicarboxylic acid and 1 mole equivalent of (-) (1-naphthyl). ) - ethylamine. The salt is shaken with a solution of sodium hydroxide and ether. The aqueous phase is acidified with 12N. hydrochloric acid, and the product is collected by filtration, obtaining 26.0 (+) -1 - (p-tolyl) -1, 2-cyclopropane dicarboxylic acid as colorless crystals, about 1 + 192 ° C.

A weighed amount of 15.0 g of (+) - 1- (p-tolyl) -1, -cyclopropanecarboxylic acid, 6.6 g of urea and 500 ml of xylene. Refluxing with stirring for 5 hours. The reaction mixture is then hot filtered and the filtrate evaporated under reduced pressure to give +) - 1- {p-tolyl) -1,2-cyclopropanecarboxymide as colorless crystals, mp. 1481550s.

A portion of 14 g of the above product is mixed with 420 ml of benzene and 112 ml of sodium bis (2-methoxyethoxy) aluminum hydride (70% benzene solution) is added with stirring over 15 minutes. After heating under reflux for 1.5 h, the mixture is cooled and 160 ml of 10 N are added. sodium hydroxide. The organic layer is dried over sodium sulfate, filtered and evaporated to an oil. The oil is dissolved in ether and hydrogen chloride gas is bubbled into the mixture. The solid forming material was recrystallized from acetonitrile to give (+) (p-tolyl) -3-azabicyclo 3,1.0 hexanhydrochloride as colorless crystals, mp. 208-210 s, - TCHioa +64.5

one

The above dibasic racemic acid is mixed with an equimolar amount of brucine in ethanol to give a salt consisting of 1 mol equivalent (-) - 1- (p-tolyl -, 2-cyclopropane dicarboxylic acid 1 mol mol equivalent of brucine,. Treatment of this salt , as stated above, gives (-) - 1- (p-tolyl) -1,2-cyclopropanecarboxylic acid in the form of colorless crystals, -189 °.

The above (way) (-) - 1- (T1tolyl) -1,2-cyclopropane dicarboxylic acid is converted into (-) - l- (tl-tolyl) -1,2-cyclopropanecarboximide, mp. 145-148 ° C., and then it is reduced, as indicated above, to obtain (-) - l- (ji-tolyl) -3-azabicyclo, 1, Ci hexane hydrochloride as colorless crystals, m.p. 204-2070c, oi. -64 °. Example 26. Preparation of 1- (m-chlorophenyl) -3-methyl-3-azabicyclo 3, hexane hydrochloride.

By the method of Example 10, 1- (m-chlorophenyl) -methyl-1,2-cyclopropanecarboximide, mp. 72-7, obtained from 1 - (, m-chlorophenyl) -1, 2-cyclo-propane dicarboximide (Example 6), and methyl iodide give 1- (m-chlorophenyl) -3-methyl-3-azabicyclo | 3.1, 0 hexane hydrochloride in the form of colorless crystals, so pl. 180-182 ° C.

5 Example 27. Preparation of 1- (m-. Methoxyphenyl) -3-azabicyclo 3,1, O} hexane hydrochloride.

Methyl-m-methoxymandelate is reacted with phosphorus tribromide,

0 to obtain methyl bromo- (α-methoxyphenyl) -acetate as a pale yellow liquid and then it is used without further purification.

Similarly, the following esters of mandelic acid can be converted to the following bromo esters:

Almond ester-Bromo-ester ester ester

ethyl - (p-hexyl) -man-ethyl bromo - (p-hex0 delat; silphenyl) -acetate;

ethyl- (p-isopropyl) -ethyl bromo- (p-k-mandelate mil) -acetate;

methyl- (m-methyl) -man-methylbromo- (m5, delat; -tolyl) -acetate,

. methyl- (o-methyl) -man-methylbromo- (o- /

delat,.-tolyl) -acetate.

A mixture of 37, O g dimethyl-1- (m-methoxyphenyl) -1,2-cyclopropane dicarboxylate,

prepared as in Example 6 from methyl bromo- (m-methoxyphenyl) -acetate and methyl acrylate, 20 g of potassium hydroxide and 200 ml of water-methanol (1: 1 is refluxed under reflux);

5 hours 16 hours and then the methanol is distilled off. Then, concentrated hydrochloric acid is added in increasing portions until the pH value is 1. The mixture is extracted three times with ether, dried and concentrated to give cis-1- (m-methoxyphenyl) -1,2-cyclopropane dicarboxylic as pale yellow resin.

 A portion of 34.7 g of this dibasic 5 acid, 12 g of urea and 750 ml of xylene is refluxed for 5 hours. The mixture is cooled and the surface solution is drained and filtered through magnesium silicate, and the filter Rat is concentrated under reduced pressure to obtain a solid substance. which is recrystallized from ethanol to obtain 1- (m-methoxyphenyl) -1, 2-cyclopropanecarboximide, l :. square

125-127 C.

Claims (2)

65 3 g of the above product are mixed with ml of benzene and over the course of 5 minutes, 20 ml of bis (2-methoxyethoxy-aluminum sodium hydride (70% solution in base) is added with stirring. After stirring for 30 minutes and refluxing for 1 h. The mixture is cooled and 20 ml of 10 ml of sodium hydroxide solution is added to it, followed by saturation. Sodium chloride is washed with water and then dried over magnesium sulfate, filtered and evaporated to an oil. the solution is purged with gas of hydrogen chloride. The resulting solid is recrystallized from acetonitrile to give 1- (m-methoxy-phenyl) -3-azabicyclo 3,1.0-hexane hydrochloride as colorless crystals, mp 150-152 ° C. The novel compounds of formula 1 have pharmacological activity, in particular, they can be used as pain relievers Formula 1: A method for producing Zzazabicyclo 3, 1, O} hexane derivatives of the general formula where the phenyl ring is unsubstituted or substituted by one or two halogens with 1-6 branched or unbranched alkyls carbon atoms, alkoxyls with 1-6 carbon atoms, triftbrmetilami or nitro groups T X - hydrogen, unbranched alkyl with 1-8 carbon atoms or alkyl phenyl with 1-3 carbon atoms, or their salts, racemates or optically active antipodes, about t and Part of the fact that the compound is a general formula. X wherein the phenylene ring is unsubstituted or substituted by the substituents indicated above; X is as defined above) R is hydrogen or oxygen with the proviso that at least one substituent R is oxygen is subjected to reduction with lithium aluminum hydride, 2-methoxyether oxyaluminium hydride or diborane in an inert aprotic solvent at 0125 s followed by isolation of the desired product in free form or as a salt, as a racemate or as an optically active antipode. 2. The method according to claim 1, which is also distinguished by the fact that benzene or tetrahydrofuran, or ether, or toluene is used as an inert aprotic solvent. Priority by featured. 15.09.76- Phenylene ring is unsubstituted or substituted by One or two identical halogens, linear or branched alkyls with 1-6 carbon atoms, alkoxyls with 1-6 carbon atoms, trifluoromethyl or nitro groups -X-hydrogen, non-branched alkyl with 1-8 atoms carbon or alkylphenyl with 1-3 carbon atoms. 06.23.77- the phenylene ring is unsubstituted or substituted by one or two different halogens, straight-chained or branched alkylamin with 1-6 carbon atoms, alkoxyls with 1-6 carbon atoms, trfluoromethyl or nitro groups X - hydrogen, non-branched alkyl with 1-8 carbon atoms or alkylphenyl with 1-3 carbon atoms. Sources of information taken into account during the examination 1. Gaylord N. Reduction by complex metal hydrides, M., ed. IL, M., 1965, p. 552-555.