NO147165B - DEVICE FOR AUTOMATIC MONITORING OF A NET INDEPENDENT POWER SUPPLY CHARGING CONDITION OF THE HUMIDITY OF THE RESPONSIBILITY IN A DEVICE FOR POSITIONING OF TRAFFIC DEVICES - Google Patents

Description

Process for the production of therapeutically effective ethanolamines.

The present invention relates to an I

method for the production of tera-

therapeutically active ethanolamines of the general formula:

where the substituent R, is a cyclohexyl or cyclohexen-(3)-yl residue as optional

may be methyl-substituted in 3- and/or

4-position, and the substituents R2, R3 and R4

means hydrogen, hydroxy, methoxy or

ethoxy, as well as their acid addition salts.

The method according to the invention is

characterized by condensing a

ketone with formula:

where R, has the above-mentioned meaning and

X is a chlorine or bromine atom, either directly

or after reduction of the oxy group to

hydroxy group while forming the corresponding halohydrin and dehydrohalogenation of the halohydrin to the corresponding

1-epoxyethyl compound with the general

formula:

with an arylethylamine of the general formula:

4

where R2, RH and R4 have the above-mentioned meaning, whereby however occurring hydroxy groups are optionally protected, after which the condensation product, if it is a 3-aza-pentanone-(l), is catalytically hydrogenated to the corresponding 3-aza-pentanol-(l), and the 1,5-disubstituted 3-aza-pentanol-(1) thus obtained, after transfer of any protected groups to hydroxy groups, if desired, is converted into an acid addition salt or, if it contains

holds a cyclohexenyl group, this - if desired - corresponding cyclohexyl group is hydrogenated.

The cyclohexenyl ketones of formula II can be prepared by means of a Diels-Alder condensation of butadiene-(1,3) or similarly substituted butadiene-(1,3) and 1,4-dichlorobutanone-(2) or 1,4-dibromobuta- non-(2).

The cyclohexyl ketones of formula II can be prepared by treating a hexa-hydrobenzoic acid halide or a corresponding methyl-substituted derivative thereof with diazomethane and then subjecting the resulting diazomethyl ketone to a treatment with hydrogen chloride or hydrogen bromide.

The reduction of a ketone with formula II, which is carried out according to the invention, can e.g. carried out with the help of potassium borohydride in ethanol (appropriately in the presence of saturated sodium bicarbonate solution at 0-5° C) or with the help of aluminum isopropylate in isopropanol. The use of the latter reducing agent is preferred. The emerging halohydrins are new compounds.

The dehydrohalogenation can e.g. take place in such a way that the reduction product is treated with a diluted alcoholic alkali metal hydroxide solution at a low temperature. A suitable method consists, for example, of in allowing a solution of the reduction product in methanol to react with a dilute solution of potassium hydroxide in methanol at a temperature below 0° C. The dehydrohalogenation products are, with the exception of 1-epoxyethyl-cyclohexene-(3)- and 1-epoxyethyl-cyclohexane, new connections.

The condensation of the 1-epoxyethyl compound with an amine of formula III is conveniently carried out in the presence of a condensing agent at approx. 20° C. Suitable condensing agents are e.g. sodium hydroxide, sodium acetate or sodium carbonate. It is appropriate to use sodium hydroxide as a condensing agent and to work at a temperature of approx. 20° C. The condensation can also, if desired, be carried out in a nitrogen atmosphere. The condensation can also take place by heating the epoxyethyl compound with the amine of formula III.

In order to arrive at the process products, one can also condense a ketone of formula II with an amine of formula II and then reduce the condensation product catalytically. Condensation can be induced by mixing the starting materials, e.g. at low temperature, e.g. at -20° C. It is preferred to use 2 mol of amine to 1 mol of ketone and to let the reaction take place in a solvent. For subsequent catalytic reduction, the use of Raney nickel is suitable. One then works appropriately at 20° C and under atmospheric pressure.

In an addition reaction, the cyclothiexenyl process products or their salts can be reduced catalytically to the corresponding cyclohexyl compounds, respectively their salts. A suitable catalyst for such a reduction is e.g. palladium charcoal.

When the production of 5-(hydroxyphenyl)-3-aza-pentan-l-ols is intended, a variation of the method according to the present invention can be based on an amine of formula III, in which the hydroxyl groups present are protected on the phenyl residue by benzylation. After the invention has completed condensation and reduction, the products are then catalytically debenzylated.

The process products can be transferred to salts, e.g. by treating the bases with the usual inorganic acids, hydrochloric acid, hydrobromic acid, sulfuric acid, or with the usual organic acids; tartaric acid, citric acid, etc.

The process products possess hypotensive properties and can therefore find use as pharmaceuticals, e.g. in the form of pharmaceutical preparations.

The following examples will illustrate the method according to the present invention. In these, the temperatures are given in °C.

Example 1.

1-(2-chloro-1-hydroxyethyl)-3,4-dimethyl-cyclohexene-(3).

5 liters of ethyl alcohol, 3 liters of saturated sodium bicarbonate solution and 746.72 g of 1-chloroacetyl-3,4-dimethyl-cyclohexene-(3) are introduced into a 10 liter round flask with stirring device, powder funnel and thermometer. The mixture is cooled with vigorous stirring in an ice bath to 5° C. 118.69 g (2.2 mol) of potassium borohydride are then added in portions over the course of 3 hours. Initially, the temperature rises after each addition to 10° C. The mixture is then stirred for a further two hours at 5° C and allowed to stand at this temperature for 16 hours. It is then filtered, the residue is washed out twice with ethyl alcohol and the alcohol is removed at water bath temperature in a vacuum. 2 liters of water are added to the residue, after which the product is extracted by shaking three times with 650 ml of ether. The combined ether extracts are washed twice, each time with 200 ml of water, then the ethereal phase is separated, dried over sodium sulphate, filtered and concentrated in vacuo. The residue is subjected to a fractional high-vacuum distillation at 0.7-1.0 mm Hg, whereby the fraction that distills over at a bath temperature of 140-160° C (temperature in the flask 103-118°) is captured. The yield is 612 g (81.1 percent) of a product with a boiling point of 92-94° C/0.075 mm; n V = 1.5037.

The same product can also be obtained in the following way: In a two liter four-necked round flask, which is coated with 107.25 g (0.525 mol) of aluminum isopropylate in one liter of dry isopropyl alcohol, is added while stirring, over the course of approx. 5 minutes at a temperature of 110° C. 93.37 g (0.5 mol) of 1-chloroacetyl-3,4-dimethyl-cyclohexene-(3). The remaining ketone is washed with 200 ml of isopropanol. The mixture is then brought to the boiling point (oil bath temperature 120° C) and held for 20 minutes under reflux cooling. Then cool quickly with ice water to approx. 25° C. Then remove approx. 600-700 ml of isopropanol in vacuum at a water bath temperature of 40-45° C. The remainder is poured onto a mixture of ice, water and 150 ml of concentrated hydrochloric acid, stirring vigorously. The product is then extracted three times, each time with 500 ml of ether. The combined ether extracts are washed twice, each time with 200 ml of water and then dried over sodium sulphate. After removal of ether in vacuum, the residue is distilled at a pressure of 0.8-1 mm Hg at a bath temperature of approx. 145—155° (internal temperature 102—116°); yield 86.71 g (91.9 per cent). l- epoxyethyl- 3, 4- dimethyl- cyclohexene-(3). 900 ml of methanol and 613.3 g (3.25 mol) of 1-(2-chloro-1-hydroxyethyl)-3,4-dimethyl-cyclohexene-( 3). To this solution, which has been cooled in an ice/common salt bath to a temperature of -15° C, a solution of 214.5 g (3.25 mol) of 85 percent potassium hydroxide in 2 liters of methanol is added with slow stirring within 2 1/2 hours. The mixture is stirred for a further two hours at 0° C and allowed to stand for 16 hours at 5° C. Separated potassium chloride is removed by filtration and washing out with methanol. The majority of the methanol is then removed in the water bath (35-40° C) in a vacuum. 1.5 liters of water are then added to the residue, after which the mixture is extracted three times, each time with 650 ml of ether. The combined ether extracts are ashed twice, each time with 400 ml of water, separated and dried over sodium sulphate, after which the ether is distilled off under reduced pressure. The remainder is fractionally distilled, whereby the fraction is captured, which fraction under a pressure of 12 mm distills over at a bath temperature of 130-140° C (internal temperature 102-108° C). You thus get 426.06 g (86.1 percent) of a product with a boiling point of 95-98° C/10 mm; n ^ = 1.4807. 1 - [3, 4- dimethyl-cyclohexen-(3)-yl]-5-(3,4-dimethoxyphenyl)-3-aza-pentanol-(1)-hydrochloride.

A 1 liter three-neck round-bottomed flask is coated with 260.4 g (1.32 mol) (3,4-dimethoxy-phenyl)-ethylamine, 182.64 g (1.20 mol) 1-epoxy-ethyl-3 ,4-dimethyl-cyclohexene-(3) and 144 ml of 2n-sodium hydroxide. The mixture is stirred well under nitrogen at 20° C. for 90 hours. 600 ml of water is then added to the thick, colorless paste, after which the product is extracted three times, each time with 500 ml of ether. The ether extracts are washed once with water and then dried over sodium sulphate. These operations are also carried out under a nitrogen atmosphere. The ether is then removed in a vacuum in a water bath at 20-25° C. The colourless, partially solid residue is dissolved in 250 ml of methanol and added with stirring and a nitrogen atmosphere at 0° C approx. 250 ml of an ethereal hydrogen chloride solution (ether saturated with hydrogen chloride at 0° C). At the same time, 300 ml of ether is added separately to the same reaction vessel, to facilitate stirring. The mixture is kept overnight at 0° C. The hydrochloride is then filtered off and washed out with 250 ml of ether. The solid filter residue is sucked dry, suspended in 1200 ml of 2 N hydrochloric acid, and the entire mixture is stirred under a nitrogen atmosphere at 20° C. for 30 minutes. The solid portion that separates out is filtered off and dried in vacuum over the course of several days at 20° C. over phosphorus pentoxide. The dried product is then added as a whole while stirring to 3600 ml of boiling isopropyl alcohol. The salt dissolves quickly, and the solution is immediately filtered further in a warm state using a folding filter. The clear, yellow filtrate is allowed to stand at 0° C under a nitrogen atmosphere for 16 hours, after which it is filtered off from the resulting product. This gives 232 g (52.3 percent) of hydrochloride, which is washed with isopropyl alcohol and dried in vacuum over phosphorus pentoxide at 20° C. To make the salt odorless, it is then allowed to dry in the dark for a further 12 hours in the air. The salt is obtained as colorless crystals with a melting point of 159.5 - 162.5° C (decomposition); it is analytically pure.

The starting material l-chloroacetyl-3,4-dimethyl-cyclohexene-(3) can be prepared as follows: In a 10 liter three-necked round flask with a stirrer, dropping funnel and energy cooler, introduce 3420 ml of dioxane, 180 ml of water, 643.3 ( 6.65 mol) of potassium acetate and 1.0 g of hydroquinone. The suspension is further added with stirring 451.77 g (5.5 mol) of 2,3-dimethylbutadiene-(1,3) and then 853.11 g (6.05 mol) of 1,4-dichlorobutanone-(2) at a temperature of 20° C. The addition is distributed over a period of approx. 15 minutes. Thereby the internal temperature rises. Stir for an hour at approx. 20° C and then for 16 hours at 45° C. When the temperature has reached 45° C, a weak exothermic reaction sets in, and the internal temperature rises to approx. 55° C. Finally, the thick, pasty mixture is filtered and the remaining potassium chloride is washed out three times with dioxane. The filtrate is concentrated to syrup consistency in a water bath at 40° C. in a vacuum. Then add 2 liters of water and extract the mixture three times, each time with 1 liter of ether. The combined ether solutions are washed twice, each time with 500 ml of water and dried over sodium sulfate. The residue is filtered, concentrated and distilled in a vacuum. The fractions, which distill at a bath temperature of 130-150° C (internal temperature 102-116° C) under a pressure of 0.7-0.8 mm Hg, are collected and distilled once more, whereby one obtains 793, 72 g (77 percent) of a product with a boiling point of 82-84° C/0.15 mm Hg; n = 1.4972.

Example 2.

1 - [ 3, 4- dimethyl- cyclohexene-( 3)]-5-( 3, 4- dimethoxy- phenyl)- 3- aza-pentanone-( 1) - hydrochloride. 18.65 g (0.1 mol) of 1-chloroacetyl-3,4-dimethyl-cyclohexene-(3) in 50 ml of dry ether and 36.2 g (0.2 mol) of (3,4-dimethoxy-phenyl) -ethylamine in 75 ml of dry ether is cooled to -20° C and mixed together. During 24 hours, the combined solutions are kept between 0 and 5° C. 50 ml of ether are then added and 16.84 g of (3,4-dimethoxy-phenyl)-ethylamine hydrochloride is removed by filtration. The filtrate is concentrated in vacuo and added estene methanol and ethereal hydrogen chloride solution. Thereby the hydrochloride is precipitated. Æan obtains 5.88 g (16 per cent) of the hydrochloride with a melting point of 191-196° C. After recrystallization from ethanol, the hydrochloride melts at 196-200° C. l-[ 3, 4-dimethyl-cyclohexene- (3)-yl]-5-(3,4-dimethoxy-phenyl)-3-aza-pentanol-(1)-hydrochloride.

1.84 g (0.002 mol) 1-[3,4-dimethyl-lyclohexen-(3)-yl]-5-(S^-dimethoxy-eny^-S-aza-pentanone-U) in 50 ml of metha- iol is catalytically reduced at atmospheric thrust and 20° C with Raney nickel. After

>absorption of 128 ml of hydrogen (theory 121 ni) decreases the reaction rate, and the hydrogenation is then interrupted. The catalyst is filtered off, the filtrate is concentrated and the residue is treated with ether, which contains hydrogen chloride. This yields 1.5 g (81 per cent) of hydrochloride with a melting point of 162-164° C.

In a similar way as in the two examples above, the following preparations are obtained: L-[3,4-dimethyl-cyclohexen-(3)-yl]-5-:enyl-3-aza-pentanol-(1)-hydrochloride , melting point 203.5—207° C; L-[3,4-dimethyl-cyclohexen-(3)-yl]-5-(2-methoxy-phenyl)-3-aza-pentanol-(1)-lydrochloride, melting point 120-125°C; 1-[3,4-dimethyl-cyclohexen-(3)-yl]-5-(3-methoxy-phenyl)-3-aza-pentanol-(1)-lydrochloride, melting point 219-221°C; 1-[3,4-dimethyl-cyclohexen-(3)-yl]-5-(4-methoxy-phenyl)-3-aza-pentanol-(1)-hydrochloride, melting point 219-221°C;

1-[3,4-dimethyl-cyclohexen-(3)-yl]-5-(3,4-diethoxy-phenyl)-3-aza-pentanol-(1)-hydrochloride, melting point 160.5—163, 5 C;

1-[3,4-dimethyl-cyclohexen-(3)-yl]-5-(3-ethoxy-4-methoxy-phenyl)-3-aza-pentanol-(1)-hydrochloride, melting point 145—150° C;

1-[3,4-dimethyl-cyclohexen-(3)-yl]-5-(3-methoxy-4-ethoxy-phenyl)-3-aza-pentanol-(1)-hydrochloride, melting point 142—145° C .

Example 3.

1- 13, 4-dimethyl-cyclohexen-(3)-yl]-5-(3,4,5-trimethoxy-phenyl)-3-aza-pentanol-(1)- hydrochloride.

14.85 g of (3,4,5-trimethoxy-phenyl)-ethylamine hydrochloride and a solution of 2.51 g of sodium hydroxide in 10 ml of water are mixed together under cooling, to release the

free base. To this mixture is added 7.65 g of 1-epoxyethyl-3,4-dimethyl-cyclohexene-(3) (prepared according to the instructions in example 1). The mixture is shaken for 68 hours at 20° C., then water is added and the basic components are extracted twice with ether. After evaporation of the ether, the base is dissolved in methanol and ethereal hydrogen chloride solution is added. 11.01 g of hydrochloride with a melting point of 135.5-140° C is obtained. For purification, the hydrochloride is suspended for half an hour at 20° C in 2 N hydrochloric acid, after which the product is filtered and recrystallized from methanol/ether. The pure hydrochloride crystallizes as colorless prisms with a melting point of 149-151° C.

Example 4. 1-[3,4-dimethyl-cyclohexen-(3)-yl]-5-(4-benzyloxy-3-methoxy-phenyl)-3-azapentanol-(1)-hydrochloride. 9.79 g of (4-benzyloxy-3-methoxy-phenyl)-ethylamine hydrochloride is suspended in water, after which the suspension is made alkaline by the addition of 2 N caustic soda. After extraction with ether, the base is shaken with 5.1 g of 1-epoxy-ethyl-3,4-dimethyl-cyclohexene-(3) (prepared according to the instructions in example 1), 2 ml of 2 N sodium hydroxide solution and 2 ml of ethanol under a nitrogen atmosphere in -pet of 96 hours at 20° C. The basic components are obtained as in example 3. The amount of crude hydrochloride thus obtained is 9.83 g with a melting point of 140-147° C. Pure hydrochloride with a melting point of 165-168° C gives by suspending the crude hydrochloride in water, filtering and recrystallizing twice from ethanol. 1-[3,4-dimethyl-cyclohexen-(3)-yl]-5-(4-hydroxy-3-methoxy-phenyl)-3-azapentanol-(1)-hydrochloride.

1.12 g of benzyloxy compound (prepared according to the information in the above section) is hydrated in 20 ml of methanol at 20° C and atmospheric pressure over palladium charcoal. After absorbing 65 ml of hydrogen, filter off the catalyst and dilute the filtrate with ether. This precipitates 0.78 g (87 per cent) of hydrochloride with a melting point of 171-178° C. After recrystallization from ethanol, the melting point is 180-184° C.

In a similar manner as described in this example, 1-[3,4-dimethyl-cyclohexen-(3)-yl]-5-(3-hydroxy-4-methoxy-phenyl)-3-aza-pentanol-( 1) - hydrochloride with melting point 195-198° C. Example 5. 1-(2-chloro-1-hydroxy-ethyl)-3(or 4)-methyl-cyclohexene-( 3 ).

To 69.04 g of 1-chloroacetyl-3-(or 4)-methyl-cyclohexene-(3) (prepared from 2-methyl-butadiene-(1,3) and 1,4-dichloro-buta-non-(2 ) analogously to the information in example 1) in 1 liter of ethanol and 350 ml of saturated sodium bicarbonate solution, 15.7 g of potassium borohydride is added portionwise at a temperature of 0° C and over a period of 30 minutes. After stirring for 16 hours between 0-15° C, the solvent is removed in vacuo. The chlorohydrin formed is extracted with ether, and distilled after evaporation of the latter. The boiling point of chlorohydrin is 72-80° C/0.3 mm Hg (41.05 g). l- epoxyethyl- 3-( or 4)- methyl- cyclohexene-(3). To 17.47 g of the chlorohydrin obtained in the above section in 30 ml of methanol, 100 ml of 1 N potassium hydroxide solution is added at 0° C. with careful stirring over the course of two hours. After stirring for 3 hours at 20° C., the solvent is removed in vacuo, water is added and the epoxyethyl compound is extracted with ether. The ethereal solution is dried over sodium sulfate and then evaporated. 8.67 g of epoxy with a boiling point of 78° C/7 mm is obtained; n 2," = 1.4722. 1-[3 (or 4)-methyl- cyclohexen-(3)-yl]- 5-( 3, 4- dimethoxy phenyl)- 3- aza- pentanol- ( 1)- hydrochloride. 9.06 g of (3,4-dimethoxyphenyl)-ethylamine and 6.91 g of 1-epoxyethyl-3 (or 4)-methyl-cyclohexene-(3) are heated on a boiling water bath during four hours. The excess amine (5.27 g) is distilled off (boiling point 120-122° C/0.3 mm). The residue is dissolved in methanol and converted to hydrochloride by the addition of ethereal hydrogen chloride solution. 2.35 g of pure hydrochloride with a melting point of 168-174° C is obtained after recrystallization from methanol/ether in the form of colorless prisms. . 1 - [3 (or 4)- methyl- cyclohexyl]- 5-( 3, 4- dimethoxy phenyl) - 3- aza-pentanol- ( 1)- hydrochloride.

3.56 g of 1-[3(or 4)-methyl-cyclohexen-(3)-yl]-5-(3,4-dimethoxy-phenyl)-3-aza-pentanol-(1)-hydrochloride are hydrated in 50 ml of methanol in the presence of 2 g of 5% palla-

dium coal at approx. 20° C and normal pressure.

After absorption of 308 ml of hydrogen by

22° C (theory 242 ml), the reaction is stopped, the solution is filtered and the filtrate concentrated

wooded. Hydrochloride (1.77 g) was obtained

has a melting point of 188.5—191.5° C after recrystallization twice from isopropyl

alcohol. The yield after recrystallization is 1.16 g.

Example 6.

(2-chloro-1-hydroxy-ethyl)-cyclohexane.

30.5 g of chloroacetyl-cyclohexane (prepared from hexahydrobenzoic acid chloride by be-

treat this with diazomethane and to be-

treat the obtained diazomethylketone with hydrochloric acid) in 270 ml of ethanol and 167 ml of met-

tet sodium bicarbonate solution is reduced at -10° C by portionwise addition of 7.5 g of potassium borohydride over the course of 3/4 hour. The ethyl alcohol is removed by distillation at

35° C. After adding water and ether to the residue, the ethereal phase is worked up as usual, which gives 26.5 g (86 per cent) of chlorohy-

drin with a boiling point of 64-65.5° C/0.6 mm in the form of a colorless oil.

1- epoxyethylcyclohexane.

To a solution of 26.56 g of (2-chloro-1-hydroxyethyl)-cyclohexane in 50 ml of metha-

nol is added while stirring at 0° C

in the course of two hours 81.6 ml of a methanolic solution of potassium hydroxide (prepared /ed solution of 13.2 g of potassium hydroxide

.100 ml of methanol). The mixture is further stirred for three hours, after which methyl-

the alcohol is removed and water is added. Then

the product is taken up in ether, the ether phase is dried, the ether is evaporated and the

stir the remainder, whereby 16.7 g (81 per cent) is obtained

iv the desired epoxy with a melting point of 33° C/30 mm as colorless oil. 1 - cyclohexyl-5-(3,4-dimethoxy-phenyl)-3-aza-pentanol-(1) and its hydrochloride.

6.31 g of 1-epoxyethyl cyclohexane, 10.87

g (3,4-dimethoxy-phenyl)-ethylamine and 10

ml of water is shaken at 20° C for 68 hours. Thereby, 15.43 g of base is precipitated in the form of a colourless,

white, solid mass, which after recrystallization

serine from ethyl acetate has a melting point of 104—108° C. By treating the base with ethanol, ether and hydrogen chloride, the hydrochloride is obtained, which after recrystallization from isopropanol precipitates in the form of needles with a melting point of 159—161.5° C.

Claims (2)

1. Process for the production of therapeutically effective ethanolamines with the general formula: where the substituent R is a cyclohexyl or cyclohexen-(3)-yl residue which may optionally be methyl-substituted in the 3- and/or 4-position, and the substituents R2, R:i and R4 mean hydrogen, hydroxy, methoxy or ethoxy, as well as their acid addition salts, characterized by condensing a ketone with formula: where R has the above-mentioned meaning and X is a chlorine or bromine atom, either directly or after reduction of the oxo group to a hydroxy group while forming it to corresponding halohydrin and dehydrohalogenation of the halohydrin to the corresponding 1-epoxyethyl compound with the general formula: with an arylethylamine of the general formula: where R2, R.j and R4 have the meaning mentioned above, whereby however occurring hydroxy groups are optionally protected, whereupon the condensation product if it is a 3-aza-pentanone-(1), is catalytically hydrogenated to the corresponding 3-aza-pentanol-(1), and the thus obtained 1,5-disubstituted 3-aza-pentanol.-(l), after transferring any protected groups to hydroxy groups, if desired, is converted into an acid addition salt or, if it contains a cyclohexenyl group, this is hydrogenated — if desired — to the corresponding cyclohexyl group. 2. Process according to claim 1, characterized in that 1-chloroacetyl-3,4-dimethyl-, 1-chloroacetyl-3-methyl- or 1-chloroacetyl-4-methyl-cyclohexene-(3) is used as starting compound with formula II and 3,4-dimethyloxy-phenyl-ethylamine is used as starting compound with formula III.