SU411684A3 - - Google Patents

Description

The invention relates to the field of the preparation of compounds which can be used as physiologically active substances.

A known method for producing an azabicycloaliphatic compound of the general formula Ag-C (X) -Alk-Get, where Ar is a monocyclic aryl group, for example, phenyl, substituted by homogeneous or dissimilar substituents;

X is an oxygen atom or hydroxy group;

Alk - allyl residue, butyl group, propyl, vinyl;

Get-3-azabicyclo-3,2,2 -popil, which consists in the fact that these compounds are obtained using the reaction of the interaction of het-amchex ketones with an organometallic compound.

In order to simplify the process for preparing these compounds, a method for the preparation of azabicycloaliphatic compounds of the formula

Ag-C (X) -Alk-Geth,

where the AG is a monocyclic aryl group, for example, a phenyl group substituted by the same or different substituents, a monocyclic monoheterocyclic group of an aromatic character;

X is an oxygen atom, free or esterified to an ether or ester

hydroxy group together with a hydrogen atom or a lower alkyl residue containing up to 7 carbon atoms;

Alk-group having one or several double bonds, containing from 3 to about carbon atoms and separating the group -C (X) - and Get by at least three carbon atoms;

A geth is a binicloalkyleneamide group containing 6-10 carbon atoms as ring and bridging members that can be interrupted by one nitrogen atom, substituted, for example, by a lower alklnuyu group, or can be connected by a DRESS or several double bonds, or replaced by a lower alkyl group ,

The compound consisting of the structure Ar- (X X) -Alk - O 1, where Ar, X and Alk have the indicated meanings, interacts with compounds of the formula H-Get, where Get has the indicated values, in the medium of an organic solvent with the release of the desired product in the free state or in the form of its salt by conventional methods. The action is carried out mainly at elevated temperatures.

Example 1. To a mixture of 20 g of 3-azabicyclo3, 2.2-: nonane, 50.4 g of carbo + sodium and several potassium iodide crystals in 1400 ml of dry toluene, 44.8 g of xjiop-ii-fluorobutyropheion were added and boiled the reaction mixture for 48 hours under reflux. After cooling to room temperature, 400 ml of distilled water is added and ne: stir the reaction mixture for 15 minutes. Separate the layers; dry the toluene solution over anhydrous sodium sulfate and evaporate under reduced pressure. The residue is dissolved in 20 ml of isopropanol and brought to pH 2 with a solution of dry hydrochloric acid gas in isopropanol. By adding 50 ml of dry ether, a solid crystalline material is obtained, which after recrystallization from a mixture of isopropanol and ether (4 fluorophenyl) hydrochloride gives -oxo-1-n-butyl-3-azabicyclo 3, 2,2-nonan, melting point 189-190 ° C. Get the free base by adding 1 n. An aqueous solution of sodium hydroxide to an aqueous solution of salt or extracted with toluene.

Example 2. A solution of 2.2 g of (4-fluorophenyl) -4-hydroxy-1-n-butyl-3-azabicyclo 3, 2.2 -nonane in a mixture of 2 ml of isopropanol and 20 ml of dry ether is brought to rP 2 the introduction of dry gas of hydrochloric acid in ethyl acetate. Upon cooling, a crystalline precipitate is formed, which is filtered and recrystallized from a mixture of methanol, isopropanol and ether. The thus obtained (4-fluorophenyl) -4-hydroxy-1-n-butyl-3 - azabicyclr 3, 2.2-but the anhydrochloride melts at 216-217 ° C.

Example 3. To a mixture of 6 g of 3-azabicyclo 3, 2,2-nonan, 16 g of sodium carbonate and several potassium iodide crystals in 400 ml of dried toluene, 15 g of y-chloro-methoxybutyrofenone are added and the reaction mixture is boiled 48 hours with reflux.

After cooling to room temperature, 200 ml of water is added and, after 15 minutes, the salts are separated and the toluene solution is dried over anhydrous sodium sulfate and evaporated under reduced pressure. Dissolve the residue in 10 ml of isopropanol and bring the solution by adding dry hydrochloric acid in isopropanol to a pH of 2. After adding 50 ml of dry ether, a crystalline solid is precipitated, which is recrystallized from a mixture of isopropanol and ether. Thus, (4-methoxyphenyl) -4-ox-1CO-1-n-butyl-3-azabicyclo-3,2,2 ethanone hydrochloride is obtained, which melts at 188 ° C. Add 1 n. an aqueous sodium salt, a tree to the aqueous solution of the indicated salt and extract the precipitated base.

Example 4. To a mixture of 3.2 g of cis-4,5,6,7,8,9 hexahydroisoindoline, 8 g of sodium carbonate and a few crystals of potassium iodide in 200 ml of dry toluene, 7.4 g of uchloro-fluorobutyrophenone was added. The reaction mixture is boiled under reflux for 48 hours, then cooled to room temperature.

diluted with 50 ml of distilled water and stirred for 15 minutes. Separate the aqueous layer and dry the toluene solution over anhydrous sodium sulfate. Toluene is distilled under reduced pressure, the residue is dissolved in 20 ml of isopropanol and the solution is adjusted to pH 2 with a solution of dry hydrogen chloride in isopropanol. After addition of 100 ml of absolute ether, a crystalline precipitate is formed, it is recrystallized from a mixture of isopropanol and ether, and cis-2-4- (4fluorophenyl) -4-oxo-1-n-butyl hydrochloride is obtained in 4,5,6,7 , 8,9-hexahydroisoindoline, which melts as

hemihydrate at 158-159 ° C. By adding aqueous sodium hydroxide to an aqueous solution of this salt and subsequent extraction with ether, a free base is obtained.

Example 5. A mixture of 10 g of 3-azabicyclo 3, 2.2 -nonane, 26.5 g of anhydrous sodium carbonate and several potassium iodide crystals in 700 ml of dry toluene is treated with 26 g of d-y-dichlorobutyrophenone, and the reaction mixture is boiled 48 hours under reflux, then cooled to room temperature and diluted with 400 ml of water. After 15 minutes of stirring, separate the layer and dry the organic solution over anhydrous.

sodium sulfate and evaporated it under reduced pressure. The residue was dissolved in 25 ml of isopropanol, the solution was adjusted to pH 2, dry hydrochloric acid was added thereto and zopropanol, and 150 ml was added.

simple ether. The precipitated crystalline material is recrystallized from a mixture of isopropanol and ether to give (4-chlorophenyl) -4-oxo-1n-butyl-3-azabicyclo-3, 2.2 -nonane hydrochloride, which

melts at 242 ° C. The free compound is obtained by adding 1 n. an aqueous solution of sodium hydroxide to an aqueous solution of said salt and extraction of the isolated base.

By the method described in Examples 1-5, the following compounds can be obtained by selecting the desired starting materials:

3-4-oxo-4- (4-tert-butyl-phenyl) -1-n-butyl-3-azabicyclo-3, 2.2 -nonane, the hydrochloride of which melts at 244-245 ° C after recrystallization from methanol;

(3-Fluorophenyl) -4-oxo-1 - butyl-3 zabicyclo-3, 2.2 -nonane, the maleate of which, after recrystallization from a mixture of methanol,

isopropanol and ether melts at 139-

140 ° C;

3- 4-oxo-4- (3-thienyl-1-n-butyl-3-azabicyclo-3, 2.2 -nonane, the hydrochloride of which melts after recrystallization from a mixture of m-methanol, isopropanol and ether at

228 ° C;

(4-Isopropylphenyl) -4-oxo-1-n-butyl-3-azabicyclo-3,2,2 -nonane, the hydrochloride of which melts after recrystallization

from a mixture of methanol, isopropanol and ether at 243 ° C;

3-4- (4-bromophenyl) -4-oxo-1-n-butyl-3-azabicyclo-3, 2.2 -nonane, the hydrochloride of which melts after recrystallization from methanol at 267-268 ° C;

, 4-dimethylphenyl) -4-oxo-1-n-butyl 3-azabicyclo-3,2,2 -nonane, hydrochloride; which is melted after recrystallization from a mixture of methanol, isopropanol and ether at 247-248 ° C;

(2,4-Dimethoxyphenyl) -4-oxo-1-butyl 3-azabicyclo-3, 2,2 -nonane, the hydrochloride of which melts after recrystallization, from a mixture of methanol, isopropanol and ether at 182-183 ° C;

3-4-oxo-4-phenyl-1-n-butyl-3-azabicyclo-3,2,2-pine, the hydrochloride of which melts after recrystallization from methanol at 230-232 ° C;

(4-methylphenyl) -4-oxo-1-n-butyl-3 azabicyclo-5, 2.2 -nonane, the hydrochloride of which melts after recrystallization from a mixture of methanol, isopropanol and ether at 225-226 ° C;

(2,5-dimethylphenyl) -4-oxo-1-n-butyl-3-azabicyclo-5,2,2 -nonane, the hydrochloride of which melts after recrystallization from a mixture of methanol and ether at 203-204 ° C;

(4-hydroxyfbnyl) -4-axo-1-n-butyl 3-azabicyclo-3, 2.2 -nonane, the hydrochloride of which melts after recrystallization from a mixture of methanol and ether at 312-313 ° C (decomposition);

(2,4-dimethylphenyl) -4-oxo-1-n-butyl 3-azabicyclo-3, 2,2 -nonane, the hydrochloride of which melts after recrystallization from a mixture of methanol, isopropanol and ether at 203-204 ° C;

(3-trifluoromethylphenyl) -4-oxo-1-n-butyl-3-azabicyclo-3,2,2 -nonane, whose hydrochloride, after recrystallization from a mixture of methanol and isopropanol, melts at 210 ° C;

(4-Fluorophenyl) -5-oxo-1-n-pentyl-3azo-cyclo-3, 2.2 -nonane, the hydrochloride of which, after recrystallization from a mixture of isopropanol, ether and hexane, melts at 85-86 ° C;

3-4- {2-thienyl) -1-n-butyl-3-azabicyclo 3, 2.2 -nonane, the hydrochloride of which, after recrystallization from a mixture of methanol and isopropanol, melts at 220-222 ° C;

3-4-oxo-4- (4-fvnoxyphenyl) -1-n-butyl-3 azabicyclo-3, 2.2 -nonane, the hydrochloride of which, after recrystallization from a mixture of methanol and isopropanol, melts at 237-238 ° C;

(3-Methylphenyl) -4-oxo-1-n-butyl-3 azabicyclo-3, 2.2 -nonane, the hydrochloride of which melts after recrystallization from a mixture of methanol and ether at 183-185 ° C.

(4-biphenylyl) -4-oxo-1-n-butyl-3 azabicyclo-3, 2.2 -nonane, the hydrochloride of which melts after recrystallization from a mixture of methanol and isopropanol at 263-265 ° C; 3- | 4- (4-phorphenyl) -2-methyl-4-oxo-1 - n-butyl-3-azabicyclo-3, 2,2-noyan, the maleate of which. After recrystallization from methanol jr of ether - melts - at .-- G45-.G46 ° C.

-Prim-e .. 6:; K: mixtures.8: g: .yl-3,9-diazabicyclo-4, 2,1 -nonane, -16-, 5 g of anhydrous sodium carbonate and several crystals of iodide Kali c. 500 ml dry toluene, add

15 g of Y-chloro-p-fluorobutyrophenone; the mixture is boiled, the reaction mixture is heated for 48 hours under reflux, then cooled to room temperature, and 200 ml of water are added. and. stir the toluene solution for 15 minutes. Are divided

the layers and the toluene solution are dried over anhydrous sodium sulfate and evaporated under reduced pressure. Koglosh A. and. the residue in ethyl acetate .m -: Ether .and extracted with 2 n. hydrochloric acid; bring the acidic extract with a saturated solution of sodium carbonate to an alkaline reaction and extract the liberated compound with ethyl acetate. (the organic extract is over anhydrous sodium sulfate and evaporated to dryness.

CicTHTOK is dissolved in benzene and chromatographed in a column of 74 g of alumina; the benzene eluted fraction gives a colorless oil, which is dissolved in 10 ml of isopropanol and treated with ether

solution of maleic acid. Thus, maleate 3-4- (4-fluorophenyl) -4-oxo-1-n-butyl 9-methyl-3, 9-diazabicyclo-4,2,1 -nonane is obtained, which melts after recrystallization from a mixture of methanol, isopropanol and ether at 118-120 ° C. The addition of 1 ". an aqueous solution of sodium hydroxide to the aqueous solution of this salt is isolated base and then extracted it. The starting material used in the example can be made in the following manner.

A solution of 18.9 g of tropinonoxime in 129 ml of dry pyridine is cooled to 0 ° C and a solution of 5 g of 4-acetylaminobenzenesulfonyl chloride in 129 ml of dry is added to it dropwise.

pyridine; during the addition, the temperature is kept at 5 ° C.

The reaction mixture is kept for 2 hours at 10 ° and for a further 2 hours at 20 °, then cooled to 0 ° C and processed

it is cold as ice with water so that the temperature does not rise above 10 ° C. The reaction mixture is concentrated under reduced pressure at 65-70 ° C and absorbed, the oily residue is obtained in water. By adding potassium carbonate, the solution is made alkaline, saturated with sodium chloride, and the solution is made alkaline. The organic extract is dissolved over sodium sulfate and evaporated to dryness. Crystalline

the residue is recrystallized from petroleum ether (b.p. 60-80 ° C); the 9-methyl-4-oxo-3,9-diazabicyclo-4,2,1 ionane obtained in this way melts at 88 ° C and forms, after adding the solution, dry hydrochloric acid

acid in isopropanol monohydrochloride, which melts after recrystallization from a mixture of methanol and isopropanol at 258 ° C (decomposition).

A solution of 12.24 g of 9-meta-4-pK Co 3.9 Diazabicylo-4, 2.1 - “onan in 400 m. Of dry hectare of ether under processing conditions under 6.4 conditions. g of lithium aluminum hydride ;;; The reaction mixture is refluxed for 20 hours and cooled to 0 ° C. The excess BosstanTel is decomposed by adding 13 ml of ethyl acetate 6.5 ml of 10% hydroxy sodium and 6.5 ml of water in the indicated sequence. Filter the suspension, dry the filtrate over. anhydrous sodium sulfate and evaporated to dryness. Dissolve the residue in a mixture of isopropol and ether and treat it with a simple ethereal solution of dry hydrochloric acid; FLOOR thus, 9-methyl-3,9-diazabicyclo (4,2,1) nonandity dichloride, which melts after recrystallization from a mixture of methylene chloride and hexane At 220 ° C (decomposition). An oily free compound is obtained by treating the ethanolic solution of this salt with sodium ethoxide and making it in the usual manner.

Subject invention

Claims (2)

1. A method of producing azabidic aliphatic compounds of the general formula Ag-C (X) -Alk-Geth, where the AG is a monocyclic free aryl group, for example, phenyl, or is substituted by the same or different substituents, or my cyclic monoheterocyclic group of an aromatic character; . X-aT-Om-KisloroDa, free or esterified in idle time or ester hydroxy group together with a hydrogen atom or a lower alkyl residue containing up to 7 carbon atoms; Alk - alkylene group having one or several double bonds, which may contain from 3 to 5 carbon atoms and separates the groups -C (X) and Geth with at least 3 carbon atoms; A geth is a bicycloalkylene-amino group containing 6-10 carbon atoms as ring -and bridging members that can be interrupted by a single nitrogen atom substituted, for example, by a lower alkyl group, or can be connected by one or several doubles, or substituted by a lower alkyl group, characterized in that the reactive ester of the compound of formula Ag-C (X) - Alk-OH, where Ar, X and Alk have the given values, interacts with the compound of the formula H-Get, where the Geth has the given values, in the medium of an organic solvent with the release of the target product in free form or in the form of its salt by conventional methods. 2. A method according to claim 1, characterized in that the reaction is carried out preferably at an elevated temperature.