The method of obtaining derivatives of hexahydroazepin or their salts with mineral or organic acids

 

(57) Abstract:

Usage: as substances having the property to connect with Sigma receptors. The inventive product: derived hexahydroazepin General formula I

< / BR>
where A is-CC-, -CH=CH-(CIS), -CH2-CH2-, X is hydrogen or halogen, Y is cyclohexyl, or if X is hydrogen, Y is phenyl, or their salts with mineral or organic acids.

The invention relates to the field of obtaining derivatives of hexahydroazepin General formula:

< / BR>
where A denotes-CC-,, -CH=CH-(CIS), -CH2-CH2-,

X is hydrogen or halogen,

Y cyclohexyloxy group, or when X is hydrogen, Y is phenyl

or their salts with mineral or organic acids, with the property that specifically bind to Sigma receptors, in particular, with receptors of the Central nervous system that allows them to be used as protivoponosnye agents.

The aim of the invention is to develop on the basis of known methods method of obtaining compounds hexahydroazepin series, possessing valuable pharmacological properties.

When biochemical and pharmacological testing of compounds I and their salts showed his sposobnostyam as a ligand or3H-(+)-3 PPP or3H-DTG and in vivo in mice with legenday 3H-3 RRR.

The table shows the pharmacological testing of the compounds of the present invention in comparison with compounds from patent US.

Figures in the table confirm that the compounds I according to the invention exhibit higher and/or more specific binding to Sigma receptors.

The compounds I are low-toxic, in particular, their acute toxicity is compatible with their use as medicines.

Example 1. Hydrochloride of 1-(1-hexahydroazepin-yl)-3-(3-chloro-4-cyclohexylphenol)-3-propene.

A) 3-chloro-4-cyclohexyl-1-ethynylbenzene.

Small factions within 30 minutes add 129 g pentachloride phosphorus to 118,3 g of 3-chloro-4-cyclohexylacetophenone. For one hour, heated to 105oC, maintained at this temperature for one and a half hours, then incubated for six hours at a temperature of 115oC. the Resulting resin is extracted with ethyl ether, the ether phase is washed by 5% Paon, dried and concentrated. Obtain 107 g of 3-chloro-cyclohexylstyrene. This product was transferred to a solution of 450 ml of ethanol, then heated at reflux the silt ether, dry and concentrate to obtain 72, 5 g of the product of gross. After distillation under reduced pressure gain of 41.7 g of liquid. Boiling point: 102 104oC at 4 mm RT. Art. (533 PA).

B) Hydrochloride of 1-(1-hexahydroazepin-yl)-3-(3-chloro-4-cyclohexylphenol)-3-propene.

When the ambient temperature is stirred mixture of 9.5 g of the product obtained above under A) and 0.18 g of copper chloride in 40 ml of dimethoxyethane. In this case, this solution is added dropwise a mixture 5,16 g hexahydroazepin and 6,28 g of 35% formaldehyde in water in solution in 40 ml of dimethoxyethane and then the reaction mixture is heated at reflux for 1 hour. The solvent was concentrated in vacuo, the residue absorb 5% solution Paon, extracted with ether, washed with water and saturated sodium chloride solution, dried on Na2SO4, filtered and concentrated in vacuo. Sediment consume 250 ml of ethyl acetate, and the addition of hydrochloric ether allows to obtain the hydrochloride, which kristallisera and was isolated by filtration. Weight of 14.8 G. of melting Point 198oC.

Example 2.

Hydrochloride CIS-3-(1% hexahydroazepin-yl)-1-(3-chloro-4-cyclohexylphenol)-1-propene.

Hydronaut at atmospheric pressure is re 100 ml of ethyl acetate and 5 ml of methanol in the presence of 0.4 g of 5% Pd on barium sulphate. The catalyst is separated by filtration, the filtrate was concentrated in vacuo and the residual oil chromatographic on silica gel, eluant: dichloromethane/methanol 98/2 95/5. The fraction of pure product was concentrated in vacuo, the residue absorb 150 ml of ethyl acetate, and the addition of hydrochloric ether allows to obtain the hydrochloride, which is separated by filtration. Weight of 8.8 G. of melting Point 168oC.

Example 3.

Hydrochloride of 1-(1-hexahydroazepin-yl)-2(3-chloro-4-cyclohexylphenol)ethane.

A mixture of 50 g of 4-cyclohexyl-3-chloracetophenone, of 37.7 g of the hydrochloride hexahydroazepin, 8.5 g of trioxymethylene and 50 ml of ethanol is heated at reflux for 2 hours in the presence of 0.85 ml of concentrated hydrochloric acid. The mixture passes into the hot mass. The residue is cooled, filtered and washed with ethanol. Sediment recrystallized in a minimum of ethanol. The obtained colorless crystals washed with ethanol, then dried. The mass of 42.7, melting Point 208oC.

Example 4.

Hydrochloride of 1-(1-hexahydroazepin-yl)-3-(3-chloro-4-cyclohexylphenol)-3-propanol.

In a suspension of 30 g of the compound obtained according to example 3, in 250 ml of methanol are added 20 ml of sodium hydroxide, then cooled SIAs. Mix make uniform by adding 100 ml of T. N. F. Leave to increasing temperature and stirred for 12 hours. Then add 700 ml of cold water and extracted with a mixture of ether. The organic phase is separated, washed with water to neutrality, dried and finally concentrated in vacuo. Get to 26.9 g of oil, of 6.9 g of which was dissolved in 200 ml of isopropyl ether. In ethanol add a solution of hydrochloric acid to obtain an acidic pH. The resulting residue out, then kristallisera in ethanol. Obtain 4.8 g of colorless compounds. The melting point of 198 200oC.

Example 5.

Hydrochloride TRANS-3-(1-hexahydroazepin-yl)-1-(3-chloro-4-cyclohexylphenol)-1-propene.

Heated at reflux 20 g of the base, corresponding to the compound obtained in example 4, and 16.3 g of the monohydrate of paratoluenesulfonyl in 500 ml of toluene for 24 hours in an apparatus equipped with a water separator. The mixture is cooled and add a mixture of 10 ml of sodium hydroxide in 300 ml of water. The organic phase is separated at that time, as the aqueous phase is extracted with ether. The combined organic phases are washed with water, dried, and then concentrated. Gain of 18.2 g of oil, which absorb isopropyl ether is finally, recrystallized in acetonitrile. Obtain 10.7 g of colorless compounds. The melting point 216oC.

Example 6.

Hydrochloride of 1-(1-hexahydroazepin-yl)-3-(3-chloro-4-cyclohexylphenol)propane.

A solution of 5 g of the compound obtained in example 5, hydronaut under ordinary pressure in the presence of 250 mg of palladium on coal (5%). Theoretical volume (304 ml) of hydrogen absorb about 1/2 hour. Then the catalyst is filtered and the solution concentrated to dryness. Recrystallizing in acetonitrile, the residue gives 3.2 g of colorless compounds.

The melting point 196 197oC.

Example 7.

Hydrochloride(hexahydroazepin-1-yl)-3-(biphenyl-4-yl)-1-propyne-1.

A) Biphenylenediisocyanate (SR 49435A).

In 1 l of ethanol was dissolved 40 g of biphenylmethane. Prepare a solution 22,72 g of the hydrochloride procarbazine and 16.7 g of sodium acetate in 1 liter of water. Mix both solution and then heated for two hours to 70oC and kept under stirring at ambient temperature for one night. Wring out the precipitate, washed with water, with acetone, then a simple ether and dried, obtaining, or 47.6 g of the desired product.

In) (biphenyl-4-yl)acetylene.

Gay acetic acid. Heated to 60oC for 1 hour, then up to 80oC for 24 hours. The resulting derived selenodesy heated for one and a half hours, i.e. before complete decomposition, which corresponds to the termination of nitrogen excretion. The medium is evaporated to dryness, extracted with simple ether, filtered, the organic phase is washed with water, an alkaline solution of sodium (5%), then with water again. Exercise silicon chromatography, elwira chloroform, and get to 8.14 g of the desired product.

C) Hydrochloride (hexahydroazepin-1-yl)-3-(biphenyl-4-yl)-1-propyne-1.

To a mixture of 9.4 g of the compound obtained in the previous step, with 0.2 g of copper chloride (II) in 50 ml of dimethoxyethane add one drop of 7.9 ml of 30% aqueous formaldehyde solution, then a solution of 6.3 g hexahydroazepin in 30 ml of dimethoxyethane. Heated to 70oC for 1 h 30 min, and then left overnight with stirring at ambient temperature. The reaction medium was concentrated in vacuo, extracted oily residue using a simple ether, washed three times with water, dried on magnesium sulfate and evaporated in vacuum. Dissolve the resulting oil in 500 ml of simple ether and bubbled with gaseous hydrogen chloride. From C (melting point).

Example 8.

The hydrochloride of the CIS(hexahydroazepin-1-yl)-3-(biphenyl-4-yl)-1-propen-1(SR 49430A).

Dissolve 5 g of the compound obtained in example 7, in 70 ml of ethyl acetate and 40 ml of methanol, add 1 g of palladium on barium sulphate and placed overnight in a hydrogen environment at atmospheric pressure. Filter the catalyst, washed with methanol, then evaporated to dryness. Gain of 3.3 g of the desired product with a melting point F 180 181oC.

Example 9.

Hydrochloride (hexahydroazepin-1-yl)-1-(biphenyl-4-yl)-3-propane) (SR 49431A). Dissolve 5 g of the compound obtained in example 7 in 100 ml of methanol, add 1 g of palladium on coal and placed in a hydrogen environment at atmospheric pressure for one night. Filter the catalyst, washed with methanol and evaporated to dryness. Get a 4.53 g of the desired product with a melting point F 194 195oC.

The method of obtaining derivatives of hexahydroazepin General formula I

< / BR>
where A-CC-, -CH=CH-(CIS), -CH2-CH2-;

X is hydrogen or halogen;

Y cyclohexyloxy group, or when X is hydrogen, Y is phenyl,

or their salts with mineral or organic acids, characterized in that the formaldehyde and hexahydroazepin subjected to interaction the second connection I, where A-CC-a, if necessary or subjected to hydrogenation in the presence of a metal catalyst on the carrier, to obtain a compound I, where A is CH=CH-(CIS), which optionally hydronaut to compounds I, where A is CH2-CH2- or acetylene derivative I, where A-CC-, hydronaut to compounds I, where A is CH2-CH2- and target products isolated in free form or as salts with mineral or organic acids.

2. The method according to p. 1, characterized in that use phenylacetylene derived, where Y is cyclohexyl.

3. The method according to p. 1, characterized in that use phenylacetylene derived, where Y is cyclohexyl, X is chlorine, carry out hydrogenation to obtain CIS-3-(hexahydroazepin-1-yl)-1-(3-chloro-4-cyclohexylphenol)-propen-1 and then translate it into additive salt.

 

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The invention relates to certain derivatives of piperidine, the way its receipt, to compositions containing these compounds and to their use as fungicides

FIELD: process engineering.

SUBSTANCE: proposed method additionally exploits caprolactam water solution feed pump with heat exchanger communicated via pipeline with steam expander, caprolactam flow rate transducer and valve, heater communicated via pipeline with first stage heating chamber first inlet with temperature, pressure and steam flow rate gages with valve. Its outlet is connected with first stage separator with pressure gage with its first outlet connected with second stage heating chamber first inlet connected with heater. Its second outlet is connected via pipelines with first and second stage heating chamber second inlet and second stage separator with vacuum pickup connected via pipeline with condensers with condensate collector and first steam ejection plant with flow rate gage and valve to inlet of which steam is fed. Note here that second stage separator is connected via pipeline with barometric collector with flow rate and valve, pump to feed caprolactam water solution to third stage heater. Second outlet of the latter is connected via pipeline with first and second steam ejection plant wit steam flow rate gage and valve. Third stage heater outlet is connected via pipeline with third stage heating chamber with temperature gage and flow rate gage with valve. First outlet of the latter is communicated third stage separator communicated with condensers of second steam ejection plant. Note here that first inlet is connected via pipeline with third stage heating chamber and its second outlet is connected with caprolactam evaporates solution. Note also that preset are flow rate of caprolactam solution, steam to heater, first stage heating chamber, barometric collector level, steam for steam ejection plant and third stage heating chamber to act on appropriate valves.

EFFECT: higher efficiency and quality, simplified process.

1 cl, 2 dwg

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