SU218756A1 - METHOD OF OBTAINING DIALKYLAMINOETHYL ETHER - Google Patents

Description

This invention relates to the field of producing new alicyclic compounds that can be used as stimulating substances.

A known method for producing dialkylaminoethyl esters of unsaturated acid derivatives of the general formula

ABOUT

sh-

R. ocHjCHjN;

-:, -.,

R.

(R and RO together form CH

Rr-CH

I R.-CH

 /

SN Th

RI, Re and Rv

identical or different alkyl groups from CH3 to

topically dimethylmethylene group (bridge); Rs and R4 - together form

C (OCHs) -CH CH-CH; R4 is a hydrogen or alkoxyphenyl group) by reacting the unsaturated ester with dialkylaminoethanol in the presence of a β-hydroxyl-containing catalyst.

In order to increase the selectivity of the process, it has been proposed to use a compound of the general formula as the ester of unsaturated acid

R; . oh

where R and RO have the indicated value, and as a thidroxyl-containing catalyst, a hydroxylated ion exchange resin previously treated with methanol and diethylaminoethanol.

The implementation of the method shown in the following examples. In 100 ml of 2-dimethylaminoethanol, 25 ml of a pre-treated Dowex 2X4 ion-exchange resin and 2 ml of water are added, and the mixture is then stirred at 20 ° C. After 3 days, the ion exchange resin is filtered off, the filtrate is evaporated in vacuo and the oily residue is dissolved in ether, the solution is washed with water and extracted three times with 30 ml of 2N. hydrochloric acid cooled on ice. The extract is treated with ammonia and exhaustively extracted with ether. After washing with water and drying over sodium sulfate, the ether is distilled off and the residue is distilled in vacuo to give a colorless oil of 1 boil 155 ° C / 12. 1.4835. The ether solution of the obtained ether is mixed with the calculated amount of the ethereal solution of hydrogen chloride, the precipitate is filtered off, washed with ether, 1pe | rivers) is recovered from a mixture of acetone and ether and hydrochloride is obtained, colorless leaves with m. Pl. 115-117 ° C. The compound is highly hygroscopic, sublimated in high vacuum at 100 ° C. Example 2. Dimethylaminoethyl ester of 2-methyl-4- {4-methoxyphenyl) - cyclohexylideneacetic acid. To 17.0 g of 2-methyl-4- (4-methoxyphenyl) -cyclohexylideneacetic acid ethyl ester, dissolved in 100 ml of 2-dimethylaminoethanol, was added 35 g of Douex 2X4 pretreated ion-exchange resin and 3 ml of water. After stirring for three days at 20 ° C, the ion exchange resin is filtered off, the filtrate is dissolved in ether, washed with water and then extracted three times with 40 ml of 2N. hydrochloric acid cooled on ice. The extract is treated with ammonia under ice cooling, exhausted, it is extracted with ether, the extract is dried with sodium sulfate and evaporated in vacuum. The residue is crystallized from lefthol ether, colorless leaves with ina are obtained. 37-39 ° C. The ether solution of the resulting ether is mixed with the calculated amount of the ethereal solution of hydrogen chloride, the precipitate is filtered off, washed again and recrystallized from a mixture of methylene chloride with acetone and get hydrochloride; colorless, strongly hygroscopic leaflets s1pl. 208-210 ° C. The 2-methyl-4- (4-methoxy-phenyl) -cyclohexylidene-acetic acid ethyl ester used as the starting material can be prepared as follows. a) Ycian-Y- (n-methoxyphenyl) - pimelonitrile. To a solution of 441 g (3 mol) of 4-methoxybenzyl cyanide in 1.5 liters of tertiary butanol, -preheated to 40 ° C, add 5 ml of freshly distilled acrylonitrile and 27 g of potassium hydroxide dissolved in 90 ml of methanule. 200 ml of acrylonitrile are added dropwise, so that the temperature does not rise above 40 ° C. At the end of the feed, another 6 ml of a ZOO / about-th solution of potassium hydroxide solution and an additional 195.4 ml (6 mol total) are added over 15 minutes. After stirring for 2 hrs of the ave: and 40 ° C, the reaction mixture is evaporated until the first signs of crystallization appear. The crystals that separated were filtered out and washed with 90 D / o-HbiM methanol. From the mother liquor it is possible to obtain an additional fraction of crystals: colorless crystals with ian. 81-83 ° C. For analysis, the crystals are recrystallized from methanol and colorless tna crystals are dried at 60 ° C for 1 hour. 82-83 ° C. IR absorption spectrum: -band at 2260 (nitrile). b) Methyl ester of 7-Cyan-y - ("- methoxyphenyl) -pimelic acid. To a solution of 390 g (1.54 mol) of y-cyan - y- (p-methoxyphenyl) -pimelonitrile in 6 l of methanol, hydrogen chloride gas is passed. Upon saturation, the reaction mixture was boiled for 2 hours, after which the solvent was distilled off in vacuo and the residue was partitioned between ether and water. The ethereal phase is washed successively with water, with 5 / about-sodium bicarbonate solution and again with water, after which it is dried and evaporated. The remaining oil is distilled under high vacuum, after which a colorless, viscous oil from 1 boil is obtained. 188-190 ° C / 0.005 mm. For analysis, distilled again: 1 boil. 202 ° С / 0.05 mm, п2з 1.5130. IR absorption spectrum: bands at 2230 cm (nitrile) and 1730 cm (ester). c) 4-Pian-4 - (4-methoxyphenyl) - cyclohexanone. To a suspension heated to boiling, 11.7 g (0.51 mol) of sodium and 2.04 g (0.051 mol) of potassium in 350 ml of abs. toluene was added a solution of 163 g (0.51 mol) of y-Dian-y- (p-methoxyphenyl) -pimelic acid methyl ester in 150 ml of toluene with stirring so as to maintain the temperature at which boiling occurs. After the addition is complete, an additional 3 hours is boiled, then excess sodium and potassium are carefully destroyed with 50 ml of methanol and the toluene is distilled off as completely as possible, after which the residue is mixed with 500 ml of 200 / o-acetic acid and distillation is continued. The residue is boiled after adding 150 ml of conc. hydrochloric acid and 300. ml of acetic acid, for 10 hours. After cooling, first carefully neutralize the mixture with a dilute solution of sodium hydroxide, then extract with a mixture of ether and acetic acid, and the ratio of ether to acetic acid is 1: 1. The organic phase is washed sequentially with water, 5 ° / o-ny solution of acetic acid.

carbonate .and again with water, then dried and evaporated. A dark brown, viscous oil remains as a precipitate.

For the purpose of purification, chromatography was carried out with a 3 kg silica gel. After elution with 5 liters of chloroform, which then contains 2.7 g of a dark oil, an oily fraction is obtained with the same solvent, which crystallizes on standing. This fraction is evaporated and obtained after recrystallization from a mixture of carbon tetrachloride with cyclohexamiam, the colorless L: I1STC; and with 1 MW. 93-95 ° C.

UV absorption spectra: maxima at 225, 274, and 280.5 mc (logs 4.06; AP7 and 3.10).

IR absorption spectra: bands at 2250 slg-1 (nitrile) and 1720 cm (6-membered keto).

d) 4-Cyan-4- {4-methoxyphenyl) -1,1 - ethylenedioxycyclohexane.

76 g (0.33 mol) of 4-cyano-4- (4-methoxyphenyl) -cyclohexanone are dissolved in 250 ml of abs. toluene, boiled together with 250 mg of p-toluenesulfonic acid and 25 ml of ethylene glycol in the absence of moisture, and the water resulting from the reaction is simultaneously distilled in the azeotropic mixture. Thereafter, at the end of the water splitting off, which takes about 30 minutes, toluene is distilled off. The residue is dissolved in methylene chloride, washed with sodium bicarbonate solution and water, dried and evaporated. The residue is recrystallized from methanol and get colorless needles with a pl. 115-116 ° C. Infrared Absorption Spectrum: among other bands at 2240 cm (nitrile).

e) 4- (4-Methoxyphenyl) -1,1 - ethylenedioxycyclohexane.

72.3 g (0.265 mol) of 4- (4-methoxyphenyl) -1,1 ethylene dioxycyclohexane is heated by passing a stream of nitrogen for 25 minutes at 100 ° C. When toluene was added, the solvent was distilled off, the residue was dissolved in methylene chloride, washed with sodium bicarbonate solution and water, dried and fumigated. The oily residue is dissolved in non-toll ether, allowed to stand, and the separated crystals are filtered off. The mother liquor is re-treated with 75 ° / o-acetic acid.

For analysis, it is recrystallized from a mixture of ethyl acetate and petroleum ether; receive colorless leaves with 1pl. 74-76 ° C.

UV absorption spectrum: maximum at 222.5, 276 and 282.5 m / s (logs 3.99; 3.22 or 3.15); “Shoulder at 268 MMK (log g 3.08).

Infrared Absorption Spectrum: among others, the band at 1710 (6-membered ketone).

e) 2-Methyl-4- (4-methoxyphenyl) -cyclohexanone.

l m at 30 ° C for 20 minutes a solution of 51 g (0.25 mol) of 4- (4-methoxyphenyl) -cyclohexanone in 500 ml of abs. tertiary butanol. After 30 min. moving at 30 ° C, the reaction mixture is mixed with 7 ml (0.27 mol) of methyl iodide in 50 ml of abs. tertiary butanola and stirred for another 6 hours at 30 ° C. Then the tertiary butanol is distilled off in vacuo, the residue is dissolved in ether, washed with sodium bicarbonate solution and water, dried and evaporated. The resulting crude product chromatographic on 6 kg of the product "Alox. After washing the adsorbent, 2 liters of solution are obtained, which is divided into

following fractions.

Fractions 1-9 benzene - Drop

petroleum ether 1: 1

Fractions 10-20 ben-Dimethyl prozol - petroleum duct

1: 1 broadcast

Fractions 21-67 Ben-Monomethyl

evils - petroleum ether 1: 1

Fraction 68-75 Bin-Original Mathesol Real

Fraction 76 Benzene Condensation Product

After treatment of fractions 21-67, 2-methyl-4- (4-methoxyphenyl) -cyclohexanone is obtained,

crystallized from a mixture of ether and ethereal ether in the form of colorless leaves

with tn. 52-54 ° C.

UV absorption spectrum: maximum at 222.5; 276 and 282.6 mmk (, 03; 3.24 or

3.18); "Shoulders at 268 and 300 MMK (log-e 3.10

or 1.22). IF absorption spectrum: among others

1710 (6-member ketone). g) 2-methyl-4- (4-methoxyphenyl) -cyclohexylideneacetic acid ethyl ester. A solution of 10.9 g of 2-methyl-4- (4-methoxyphenyl) cyclohexanone and 7.8 g of freshly distilled boron trifluoride etherate in 40 ml of abs. ether

displace in the absence of moisture and ice-cooling for 30 minutes with solutions of 3.86 g of ethoxyethylene in 25 ml of abs. ether so that the temperature does not exceed 10 ° C. At the end of the addition, the orange-red reaction mixture is stirred for 30 minutes at room temperature and for 90 minutes under the action of a reflux condenser, then cooled to 0 ° C and decomposed with water. The resulting mixture is drained completely, then washed into a separatory funnel, the water is separated and re-washed with ether. The ethereal phase is successively washed with a 20 / o sodium acetate solution, then with water, dried with sodium sulfate and evaporated.

The residue is further purified by chromatography using 550 g of alumina. Petroleum ether and a mixture of petroleum ether with benzene in

Bent is a colorless oil, spontaneously crystallizing. Recrystallization from cetrole ether gives off colorless leaves. 62-64 ° C.

UV absorption spectrum: maximum at 223.5, 276 and 282.5 shk (log 8 4.43; 3.24 or 3.16); “Shoulder at 268 MMK (logs 3,14).

Example 3. 1,1-Dimethyl-8-methoxy-tetraleneacetic acid 2-p-dimethylaminoethyl ester.

To 19.2 g of 1,1-dimethyl-8-methoxy-xitrateralidene-2-acid ethyl ester, dissolved in 125 ml of -2-dimethylaminoethanol, was added 35 g of a Doux 2X4 pretreated ion exchange resin and 3 ml of water. After three days of stirring at 20 ° C, the ion exchange resin is filtered off, the filtrate is dissolved in ether, washed first with water, then extracted three times with 4 ml of 2 -N. hydrochloric acid cooled on ice.

The extract is neutralized by cooling on ice and brought to alkaline reactive reaction with ammonia solution, exhaustively extracted with ether, the ether phase is dried over sodium sulfate and evaporated in vacuo. The residue is distilled under high vacuum. A light yellow oil is obtained, 1 bp. 147 ° C / 0.01 mm; p 1,5358.

The ether solution of the resulting ester is shifted with the calculated amount of hydrochloric acid dissolved in ether, the precipitate is filtered off, washed and recrystallized from acetone and the hydrochloride is obtained; colorless prisms with 1pl. 183-185 ° C.

The 1,1-dimethyl-8-methoxytetrylidene-2-acid ethyl ester used as the starting material is obtained by the following method.

a) 1,7-Dimethoxynaphthalene.

100 g (0.625 mol) of 1,7-dioxynaphthalene are dissolved in 500 ml of NaO / about-sodium hydroxide solution and added with stirring at 20 ° C to a drop of 120 ml (1.25 mol of dimethyl sulfate solution. After further 100 ml of NaOH / sodium hydroxide solution and 24 ml of dimethyl sulfate are added to the reaction mixture for 30 minutes at 100 ° C, then cooled and extracted with ether in the usual manner. The ether phase is washed with 2N sodium hydroxide solution and water, dried and evaporated. The residue was purified by distillation; a colorless oil with ina. 10 3-105С / 0.05 mm p 1.6167.

b) 8-Methoxy-tetralon-2.

To a solution of 55 g (0.28 mol) of 1,7-dimethoxynaphthalene in 800 ml of abs. ethanol is added by passing a stream of nitrogen for 1 hour to 64.5 g (2.8 mol) of sodium in the form of small pieces. The reaction mixture is then very hot. After the addition is complete, the kilt t 2.5 hours, then cool and mix.

as quickly as possible, first with 757 ml of water, then with 575 ml of concentrated hydrochloric acid. The reaction mixture is heated for 30 minutes at 100 ° C; it is then cooled again and extracted with ether in the usual way. The colorless oil which remains after removal of the ether is dissolved in 100 ml of ethanol and shaken with 500 ml of 40 ° / onoro paiCTBOipia bisulfate. Filtered off

precipitate, the filtrate is extracted with ether, washed until neutral and evaporated. The oily residue is distilled under high vacuum; viscous oil with 1kip. 108-111 ° C, /0.03 mm and n: 1.560 crystallizes after

a short hundred. Recrystallization from petroleum ether gives colorless small needles with a tmelt. 60-61 ° C. UV Absorption Spectrum: among others, the band at 1710 cm (6-membered ketone).

c) 1,1-Dimethyl-8-methoxytetralone-2.

To a solution of 65.8 g (1.68 mol) of potassium in 2000 ml of tertiary butanol, 141.0 g are added by passing a stream of nitrogen at 30 ° C.

(0.80 mol) of 8-methoxyteralone-2, dissolved in 1600 ml of tertiary butanol, and stirred also at 30 ° C. After 30 minutes, the clear dark red solution is mixed with 125 ml (2.0 mol) of methyl iodide dissolved in 400 ml of tertiary butanol, and the reaction mixture is stirred for an additional 6 hours at 30 ° C. For further processing, the tertiary butanol is removed using a rotary evaporator, the remainder

dissolved in methylene chloride, the solution shaken first with 2N. hydrochloric acid, then with a saturated solution of sodium bicarbonate, and then washed until neutral with sodium chloride solution. The organic phase is dried over sodium sulfate and evaporated. The residue is dissolved for purification in a mixture of petroleum ether and benzene in a ratio of 3: 1, filtered through 750 g of alumina to obtain

colorless oil which is distilled under high vacuum: a colorless oil with boiling 97–98 ° C / 0.04 “.” and p 22 1.5414.

The oil crystallizes upon standing. For

analysis crystallized from petroleum ether, get colorless prisms with 1pl. 41-42 ° C. UV absorption spectrum: maximum at 271.5 and 279.5 m / s (loge 3.27 and 3.30), "shoulders at 230 and 305 mk (log 8 3.62 and 1.42). Infrared Absorption in Carbon Tetrachloride: among others, the band at 1712 (6-membered ketone).

d) 1,1-dimethyl-8-methoxytetralidenacetic-2 acid ethyl ester.

A solution of 61.25 g of 1,1-dimethyl-8-methoxy-tetralone-2 and 46.9 g of boron trifluoride etherate B 240 ml of absolute ether are mixed under the conditions of lack of moisture access and passing a stream of nitrogen at O-5 ° C for 45 minutes .

abs the ether. The reaction product, colored in dark color, is thrown in, after 1 hour, cooled to room temperature, vp mixed with a solution of 12 g of ethoxyacetylene in 50 ml of abs. effpra and additionally boil for 6 hours. It is then cooled again to 0 ° C, mixed with 200 ml of water, the aqueous phase is separated and extracted with ether. The combined ether phases are successively washed with 20 / sodium acetate solution and water, dried over sodium sulfate and evaporated: a dark, viscous residue is distilled under high vacuum at a residual pressure of 0.001 mm Hg. Art. and the following fractions are obtained: at a temperature of up to 45 ° C as a headpiece, a colorless, slightly mobile, partially crystallizing liquid with a strong odor. The intermediate fraction at 93-96 ° C is the starting material after crystallization. The main fraction is distilled at 125-135 ° C and distilled again under high vacuum: a yellow, viscous oil with tRHn. 122-124 ° C / 0.01 mm; P 1,5483.

UV absorption spectrum: maximum at 219; 272.5 and 280.5 mmk (logs 4.45; 3.45 or 3.46); “Shoulders at 245, 265 and 295 mmk (log 8 3.86; 3.38 or 2.89, respectively).

Example 4. bornylidene-2-acetic acid p-dimethylaminoethyl ester.

To a solution of 11.1 g of boronidene-2-acetic acid ethyl ester in 100l2-dimethylaminoethanol, 25 g of a pre-treated Dowex 2X4 ion-exchange resin and 2 ml of water are added and the mixture is stirred at room temperature. After 3 days, the ion exchange synthetic resin was filtered, the filtrate was evaporated under a vacuum created by a water jet pump, and the oily residue was dissolved in ether. The ether solution is first washed with water, then extracted three times with 50 ml of 2N. hydrochloric acid cooled with ice.

The extract is brought to a broth medium with an aqueous solution of ammonia and exhaustively extracted with ether. After washing with water and drying over sodium sulfate, the extract is evaporated under a vacuum created by a water-jet pump and the residue is distilled under high vacuum to give a colorless oil with 1 boil. 107-109 ° C / 0.02 mm; 1.4960.

The ether solution of the resulting ester is mixed with the calculated amount of hydrochloric acid dissolved in the ether, the precipitate is filtered off, re-washed and recrystallized from a mixture of acetone with ether and get hydrochloride; colorless prisms with init. 168-170 ° С (determined in the capillary).

Bornylidene-2-acetic acid ethyl ester used as a starting material is obtained by the following method: a solution of 22.8 g (- {-} -camphyl and 15.6 g of freshly distilled boron trifluoride etherate in 100 ml of absolute ether is added dropwise to conditions of the absence of access of moisture by passing a stream of nitrogen at a temperature of minus 10 ° C for 1 hour with stirring to a solution of 7.0 g of ethoxyacetylene in 50 ml of absolute ether. After the addition is complete, boil for 6 hours, then again

cooled to 0 ° C and mixed with water. The aqueous phase is separated and washed with ether. The combined ether phases are washed successively with 200 / o-sodium acetate solution, then with water, dried over

sodium sulfate and evaporated in vacuo. Excess camphor is removed from the residue by sublimation under high vacuum. The residual dark brown oil is distilled under high vacuum: colorless

oil with 1kip. 81-83 ° C / 0.03. ". And. UV Absorption Spectrum: maximum at 227 mmk (logg 4.16); “Shoulder at 280 MMK (logs 2.53).

Example 5. p-Dimethylaminostilla ester of p-menthlidene-3-acetic acid.

To 11.2 g of l-menthylidene-3-acetic acid ethyl ester, dissolved in 100 ml of 2-dimethylaminoethanol, 25 g of a pre-treated Dowex 2X4 ion-exchange resin and 2 ml of water are added, after

which the mixture is stirred at room temperature. After 6 days, the ion exchange resin is filtered off, the filtrate is evaporated under a vacuum created by a water-jet pump, and the oily residue is dissolved in ether.

The ether solution is first washed with water, then extracted three times with 30 ml of 2N. hydrochloric acid cooled on ice.

The extract is alkalized with ice-cooling with ice-cooling and exhaustively extracted with ether.

After washing with water and drying over sodium sulfate, the extract is evaporated in vacuo and the residue is distilled in high vacuum: a colorless oil with a boil. 114

116 ° C / 0.04 mm, 1.4812.

The ether solution of the resulting ester is mixed with the calculated amount of hydrochloric acid dissolved in ether, the precipitate is filtered off, re-washed and recrystallized from a mixture of acetone and ether: 1 and get hydrochloride; colorless leaves with 1pl. 107-109 ° C. He-menthylidene-3-acetic acid ethyl ester used as a starting material is obtained by the following method.

A solution of 15.4 g of menton and 8.5 g of freshly distilled boron trifluoride etherate in 50 ml of absolute ether under conditions of lack of access of moisture and passing a stream of nitrogen at a temperature of minus 15 ° C is mixed dropwise for 1 hour with a solution of 3.5 g ethoxyacetylene in 25 ml of absolute ether. At the end of the addition, the yellow solution solution II

the solution gradually becomes red. After 5 hours, the solution is cooled again to 0 ° C, decomposed with water and the aqueous phase is separated, which in turn is washed again with ether. The combined ether solutions are successively washed with 20 ° / sodium acetate solution and water, then dried over sodium sulfate and evaporated in vacuo. The oily residue is distilled under vacuum created by a water jet pump; colorless oil with 1kip.

135-137 ° С / 12ЖЖ; п 1.4771.

UV Absorption Spectrum: Maximum at 224.5 microns (loge 4.14); "Shoulder at 300 mmk

(,12).

Subject invention

1. A method for producing dialkylaminoethyl esters of unsaturated acid derivatives of general formula

RO

C CH-C // s

P / OCHsCHaN /

RT

(R and Ro together form

CH.

Claims (2)

I., R / B, GOS / S CH Kg All 12 Ri, Re and Ry are the same or different alkyl groups from CH 3 to C 4 H 9; R2HR3 is hydrogen or an alkyl group from CH3 to C4Hd, or together a dimethylmethylene group (bridge); Rg and R4 - together form the group C (OCH3) -CH CH-CH; R4 is hydrogen or an alkoxyphenyl group) by reacting an unsaturated acid ester with dialkylaminoethanol in the presence of a hydroxyl-containing catalyst, characterized in that, in order to increase the selectivity of the process, an unsaturated ester is used as the ester VI 2. The method of claim 1, wherein a hydroxylated ion exchange resin previously treated with methanol and diethylaminoethanol is used as a hydroxyl-containing catalyst.