DE2524394A1 - ALPHA-AMINOMETHYL-3-AETHYL-4-HYDROXYBENZYL ALCOHOL DERIVATIVES, THE PROCESS FOR THEIR MANUFACTURING AND MEDICINAL PRODUCTS - Google Patents

Description

" Ck -aminomethyl-3-ethyl ~ 4-hydroxybenzyl alcohol derivatives, process for their preparation and pharmaceuticals"

Priority: June 3, 1974, V.St.A., No. 475 675

The invention relates to the subject matter characterized in the claims.

The compounds of the invention provide β-adrenergic Sfc stimulants with relatively greater effect on the respiratory smooth muscles than on the heart muscles. Therefore, iron these compounds have a direct bronchodilator effect with minimal cardiac irritation at the same time, as is customary pharmacological test methods is shown.

Two such test methods carried out in vitro for the determination of selective β-stimulating effects are as follows:

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1. Effect of the compound under investigation on the involuntary Tone of the tracheal chain in guinea pigs as a measure of the ß-stimulating effect on the smooth muscles of the airways.

2. Effect of the connection under investigation on the speed the involuntary strike of the right atrium of the heart in guinea pigs as a measure of the ß-stimulating effect the heart muscles.

The compounds of the invention have a selective bronchodilator Effect on, since they are effective in the aforementioned test method 1 at a lower dose than in the aforementioned test method 2, which means a positive separation ratio.

In the general formula I, R preferably denotes a hydrogen atom and R> preferably an isopropyl, tert-butyl, Cyclopropyl, cyclopentyl, 4-hydroxyphenyrisopropyl, 3,4-methylenedioxyphenylisopropyl or 3,4-diinethoxyphenylisopropyl group.

The compounds of the invention can also be used in the form of salts with acids. Such salts are more common Way made with inorganic or organic acids. Examples of corresponding acids are the maleic, Fumaric, benzoin, ascorbic, pamoic, amber, bismethylene salicylic, Methanesulfone, ethane disulfone, vinegar, oxaline, propionic, . Wine, salicylic, lemon, gluconic, asparagine, stearic,

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Palmitin, itaeon, glycol, p-aminobenzoe, glutamine, benzene sulf onic, hydrochloric, hydrobromic, sulfuric, cyclohexyl sulfamic, phosphoric and nitric acid.

The compounds of the invention contain two asymmetric carbon atoms and can exist as diastereomers, the can be separated into the corresponding d- and 1-isomers. The invention encompasses mixtures of optical antipodes of the compounds of the invention as well as the corresponding isolated antipodes.

A particularly preferred compound of the invention TF _(c tert ~ butylamino-methyl) -3- (i, 2-dihydroxyethyl) -4-hydroxybenzyl alcohol, of the arbitrary tone of the trachea in guinea pig away in a _5Q ED -value of 0.018 mcg / ml relaxed , while this compound increases the rate of contraction of the right ventricle in guinea pigs at an ED of 1.9 mcg / ml. These activities result in an absolute separation ratio of 105, which represents a 21O-fold improvement over the corresponding effect of d, 1-actual> proterenol (absolute separation ratio 0.5), with corresponding preparations being carried out in vitro in each case.

In the process according to the invention, starting materials of the general Formula IV used, in which A is an acetyl group, this group is used in stage c in the reduction with Sodium borohydride converted into a hydroxyl group. Compounds of the general formula I are then obtained in which E is a V / as-

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means hydrogen atom.

In the preparation of the compounds according to the invention in which R represents a methyl group, the corresponding 1-methoxy-2-acetoxy- or 1-acetoxy-2-methoxyacetophenone derivatives of the general formula IV are used.

In stage d v / ild the benzyl alcohol derivative of the general formula VIII is preferably made using palladium-on-carbon hydrogenated as a catalyst.

The benzyl alcohol derivatives of the general formula VIII are new compounds and are valuable intermediate products for production of the compounds of general formula I.

The acetophenone derivatives of the general formula IV are prepared by known processes. For this purpose, for example, methyl salicylate is used acetylated in a Friedel-Crafts reaction with acetyl chloride to give 5-acetylsalicylic acid methyl ester, which then in the presence of potassium hydroxide or potassium carbonate with benzyl chloride is converted into the corresponding benzyl ether. This ether is reacted with ethylene glycol and p-toluenesulfonic acid. The 1,3-dioxolane obtained is with lithium aluminum hydride for corresponding salicylic alcohol is reduced. This compound becomes the corresponding benzaldehyde using manganese dioxide oxidized, its aldehyde group subsequently by reaction with trimethylsulfonium iodide and sodium hydride in dimethyl sulfoxide is converted to the corresponding epoxy group. When treating

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of the epoxide with perchloric acid in dioxane becomes 4-benzyloxy-3- (1,2-dihydroxyethyl) acetophenone obtain. If the epoxide mentioned is used in the presence of an acid as a catalyst, methanol is used implemented, 3- (2-hydroxy-i-methoxyethyl) acetophenone is formed. Will said epoxy with a mixture of sodium methoxide and methanol reacted, a mixture of the corresponding primary and secondary alcohol is obtained, from which 3- (1-hydroxy-2-methoxyethyl) acetophenone can be separated. In the subsequent acetylation in pyridine, the corresponding acetylated acetophenone derivative of the general Porinel IV manufactured.

In U.S. Patent 3,644,353 are # -aininoalkyl-4-hydroxy-3- (hydroxyalkyl) benzyl alcohol derivatives described. The compounds of the invention do not differ from these compounds only in their structure but also in their very different behavior in their bronchodilatory effect and their Irritation of the heart.

The compounds of the invention may be administered orally or parenterally in the usual doses and in the form of conventional preparations including ₇ in the form of aerosols, will be administered.

Preparation of 4-benzyloxy-3- (1,2-diacetoxyethyl) acetophenone A solution of 75 g (0.5 mol) of methyl salicylate in 200 ml of tetrachlorethylene is cooled in an ice bath and then with a solution of 40 g (0.5 mol Mol) acetyl chloride added in 200 ml of tetrachlorethylene. To the cooled mixture are in the course of

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Given 15 minutes while maintaining a temperature below 25 ⁰ C 133 g (1 »0 mol) of aluminum chloride. When the addition is complete, the mixture is stirred for 4 hours at a temperature of 25 ° C. and then poured into ice water. The organic layer which forms is separated off, washed first with water and then with aqueous saturated sodium bicarbonate solution, dried and evaporated. The oily residue is unicrystallized from hexane. 5-Acetylsalicylic acid methyl ester with a temperature of 60 to 62 ^° C. is obtained.

A mixture of 54 g (0.278 mol) of the compound obtained, 33.4 ml (0.292 mol) benzyl chloride, 40.3 g (0.292 mol) potassium carbonate and 3 g of sodium iodide in 750 ml of acetone from 16 to 18 Stirred under reflux for hours. The reaction mixture is cooled and filtered. The solvent is distilled off from the filtrate. The residue is dissolved in ethyl acetate, the solution is washed with water, dried and concentrated. After adding

from hexane and cooling the mixture, the benzyl ether of 5-acetylsalicylic acid methyl ester is obtained. F. 68 to 70 ⁰ C.

A mixture of 54 g (0.19 mol) of the benzyl ether obtained, 25 ml of ethylene glycol and 2.0 g of p-toluenesulfonic acid in 500 ml Benzene is refluxed for 16 to 18 hours, the water formed being separated off with a Dean-Stark trap will. After cooling, the reaction mixture is washed with aqueous 5% sodium carbonate solution, then washed with water and dried. After the benzene has been distilled off, the corresponding 1,3-dioxolane derivative is obtained in the form of an oil.

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252A394 _,

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A solution of this oil in 300 ml of diethyl ether is slowly added with stirring to a suspension of 7.0 g of lithium aluminum hydride in 500 ml of diethyl ether. The resulting mixture is refluxed for 2 hours and then stirred at a temperature of 24 ° C. for 16 to 18 hours. After destroying the excess of lithium aluminum hydride by adding 14 ml you v / ater and 11.5 ml of aqueous sodium hydroxide solution lOprozentiger v / ith the mixture filtered. The diethyl ether is distilled off from the filtrate. 2 ~ (4-Benzyloxy-3-hydroxymethylphenyl) -2-siethyl-1,3-dioxolane is obtained in the form of an oil.

A solution of 13.5 g (0.045 mol) of the compound obtained in 350 ml of methylene chloride is stirred with 100 g of activated manganese dioxide for 1 hour. The reaction mixture is filtered off, the filter cake being washed thoroughly with methylene chloride. After evaporation of the filtrate gives 2- (4-benzyloxy-3-formylphenyl) -2-methyl-1,3-dioxolane, melting at 78 to 80 ⁰ C.

A suspension of 2.42 g (50.4 mmol) of sodium hydride (50 percent dispersion freed from mineral oil by washing) in 35 ml of anhydrous dimethyl sulfoxide is ^{heated to a temperature of 65 0} O for 1 hour under an argon atmosphere. The clear solution obtained is treated with 50 ml of anhydrous tetrahydrofuran and, after cooling to a temperature of -15 ° C., a solution of 9.46 g (46.4 mmol) of trimethylsulfonium iodide in 50 ml of anhydrous dimethylsulfoxide is added. After 3 minutes, a solution of 13.8 g (46.4 mmol) of 2- (4-benzyloxy-3-formylphenyl) -2-methyl-1,3-dioxolane in 75 ml of tetra-

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given hydrofuran. The mixture is allowed to return to ambient temperature with stirring cool and continue stirring for 16-18 hours. The reaction mixture is then poured into water / water

and the mixture obtained was extracted with diethyl ether. The Εχε

the tract is washed with water, dried and evaporated. Man receives 2- / 4-benzyloxy-3- (i, 2-epoxyethyl) -phenyl7-2-methyl-1,3-dioxolane in the form of an oil.

A solution of 8.8 g (0.028 mol) of the compound obtained in a mixture of 100 ml of dioxane and 20 ml of water is added at a temperature of 24 ° C. with 1.5 ml of perchloric acid. Hach 15 minutes, the acid is neutralized by addition of aqueous of 5 per cent sodium carbonate solution and distilled off from the mixture, the solvent. The residue is taken up in ethyl acetate, the solution is washed with water, dried and evaporated. 4-Benzyloxy-3- (1,2-dihydroxyethyl) acetophenone with a melting point of 121 to 123 ° 0 is obtained.

A solution of 7.2 g (0.025 mol) of the compound obtained in

a mixture of 40 ml of pyridine and 15 ml of acetic anhydride is stirred at a temperature of 24 ° C. for 16 to 18 hours. Excess acetic anhydride is then decomposed by cooling the reaction mixture, adding 10 ml of methanol and stirring for 30 minutes. The mixture is then poured into water and extracted with diethyl ether. The extract is washed well with dilute hydrochloric acid and then with water and dried. After the diethyl ether has been distilled off, 4-benzyloxy-3- (1,2-diacetoxyethyl) acetophenone is obtained in the form of an L 509850/1034 j

- 9 -
Obtain oil.

The examples illustrate the preparation of the compounds according to the invention.
5

example 1

A solution of 8.9 g (0.024 mol) of 4-benzyloxy-3- (1,2-diacetoxyethyl) acetophenone in 250 ml of tetrahydrofuran is stirred with 1.82 ml of 2-pyrrolidone and 11.93 g (0.024 mol) Pyrrolidone hydrotribromide added. The mixture is refluxed for 2 1/2 hours and then filtered. The filtrate is concentrated and then water is added. The separated oil is dissolved in diethyl ether, the solution is washed with water, dried and evaporated. Are obtained (X-Bron> -4-benzyloxy-3- (1,2-diacetoxyäthyl) acetophenone, mp 79.5 to 82 ⁰ C.

A solution of a mixture of 4.4 g (9.8 mmol) of the obtained Compound and 3.04 g (18.6 mmol) of N-Bonzyl-fert.-butylamine in 50 ml of acetonitrile is refluxed for 3 1/2 hours. The reaction mixture is cooled and after adding 100 ml of diethyl ether filtered. The piltrate is evaporated. The oily residue is applied to a column charged with alumina and eluted with a mixture of hexane and chloroform (4: 6) as the eluent. The second fraction removed from the column contains 4-benzyloxy-3- (1,2-diacetoxyethyl) - £ X- (N-benzyl-N-tert-butylamino) -acetophenone, this is subsequently converted into the corresponding hydrochloride by reaction with hydrogen chloride in diethyl ether is convicted.

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- ίο -

■ The residue j A solution of 2.0 g (3.53 mol) of the obtained hydrochloride in 100 ml ethanol is "reacted for 16 to 18 hours at a temperature of 24 ⁰ C with 1.0 g of sodium borohydride. The solvent is then evaporated. is taken up in ethyl acetate, and the solution is washed with water and dried. After the ethyl acetate has been distilled off, 4-benzyloxy-3- (1,2-dihydroxyethyl) - (X- (N-benzyl-tert-butylaminomethyl) is obtained. Benzyl alcohol in the form of an oil The compound obtained is converted into the corresponding hemifumarate in ethanol as a solvent with 0.5 equivalents of fumaric acid, mp 147.5 to 149 ° C

A mixture of 800 mg (1.78 mmol) of the aforementioned benzyl alcohol derivative obtained in the form of an oil in 100 ml of ethanol and 500 mg of 10 percent palladium-on-carbon is in a Parr bomb for 23 minutes at a temperature of 25 ° C and a Hydrogenated pressure of about 3.9 at. The R _e is filtered off action mixture. A solution of 104 mg (0.89 mmol) of fumaric acid in ethanol is added to the filtrate. After the solvent has been distilled off, # - (tert-butylaminomethyl) -3- (1,2-dihydroxyethyl) -4-hydroxybenzyl alcohol hemifumarate with a melting point of 190 to 191.5 G (decomp.) Is obtained.

With appropriate use of N-benzylisopropylamine in the reaction with iX-bromo-4-benzyloxy-3- (i, 2-diacetoxyethyl) acetophenone and further work-up according to the above example, 3- (1,2-dihydroxyethyl) -4-hydroxy-0f- (isopropylaminomethyl) benzyl alcohol is obtained obtain. .

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Example 2

According to Example 1, Of-Bromo-4-benzyloxy-3- (i, 2-diacetoxyethyl) acetophenone is used with N-benzylcyclopentylamine to 4-benzyloxy-3- (1,2-diacetoxyethyl) - (X- (lI-'benzylcyclopentylamino) -acetophenone- hydrochloride implemented. With appropriate reductions with sodium borohydride and subsequently with the use of palladium on carbon becomes CX- (cyclopentylaminomethyl) -5- (1,2-dihydroxyethyl) 4-hydroxybenzyl alcohol obtained.

By reacting CV-bromo-4-benzyloxy-3- (1 , 2-diacetoxyethyl) acetophenone with N-benzyl - ^^ - dimethoxyphenylisopropylamine and subsequent reduction and reaction with hydrogen, 3- (1,2-dihydroxyethyl) -K - / 2- (3,4-dimethoxyphenyl) -1-methylethylaminomethyl7-4-hydroxy'benzyl alcohol obtained.

In a corresponding manner when using N-benzylcyclopropylmethylamine according to the aforementioned reaction route (X- (cyclopropylmethylaminomethyl) -3- (1,2-dihydroxyethyl) -4 ~ hydroxybenzyl alcohol obtain.

*

Example 3

According to Example 1, 4-benzyloxy-tfbromo-3- (1,2-diacetoxyethyl) acetophenone is obtained by condensing with N-benzylphenylisopropylamine and subsequent reduction and reaction with hydrogen 3- (1,2-Dihydroxyethyl) -4-hydroxy-oil- (2-phenyl-1-methylethylaminomethyl) -benzyl alcohol obtain.

When using 4-benzyloxy ~ 0 (-bromo-3- (i, 2-

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diacetoxyethyl) acetophenone and N-benzyl-3,4-dibenzyloxyphenylisopropylamine as the end product 3- (1,2-dihydroxyethyl) - # - / 2- (3,4-dihydroxyphenyl) -1 -methylethylaminomethyl / ^ - hydroxybenzyl alcohol.
5

In a corresponding manner, 4 ~ benzyloxy-C * -bromo-3- (1,2-diacetoxyethyl) acetophenone and N-benzyl-4-benzyloxyphenylisopropylamine as the end product 3- (1,2-dihydroxyethyl) -ö (- / 2- (4-hydroxyphenyl) -1 -methyläthylajninomethyllj ^ -hydroxybenzylalkohol produced.

Example 4

According to Example 1, 4-benzyloxy-0 ⁱ -TDroin-3- (i, 2-diacetoxyethyl) acetophenone is reacted with N-benzyl-2- (4-methoxyphenyl) -1,1-dimethylethylamine. After the appropriate reductions, 3- (1,2- dihydroxyethyl) -W- / 2- (4-methoxyphenyl) -1,1-dimethylethylaminomethyl7-4-hydroxybenzyl alcohol is obtained.

Example 5

According to Example 1, cy-bromo-4-benzyloxy-3- (1,2-diacetoxyethyl) acetophenone is used with N-benzyl-2- (3,4-methylenedioxyphenyl) -1-methylethylamine heated to reflux. 4-Benzyloxy-3- (1,2-diac et oxyethyl) - (X- / N- "benzyl-2- (3,4-methylenedioxyphenyl) ~ is obtained i-methylethylamine pZ-acetophenone. After the appropriate reductions 3- (1,2-DihydroxyäthylJ ^ -hydroxy-O'-Z ^ -C3,4-methylenedioxyphenyl) -1-methylethylaminomethyl / benzyl alcohol is obtained.

•. In a corresponding manner, by implementing the above

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■ j Bromacetophenohderivats rait N ~ Benzyl-2- (4-benzyloxyphenyl) -1, 1-dimethylethylamine as the reaction product 4-benzyloxy-3- (1,2-diaetoxyethyl) - # - / N-benzyl-2- (4-benzyloxyphenyl) -1,1-dimethylethylamino_7-acetophenone obtained by appropriate reductions in 3- (i, 2-dihydroxyethyl) -4-hydroxy- (V-Z2- (4-hydroxyphenyl) -1 , i-dimethylethylaminomethyl ^ -benzyl alcohol is transferred.

Example 6 A solution of 10.0 g (0.032 mol) of 2- / 4-benzyloxy-3- (1,2-epoxyethyl) -phenyl7-2-methyl-1,3-dioxolane in 700 ml of v / anhydrous methanol becomes vigorous stirred with 70 g of an ion exchange resin (Dowex 50). The ion exchange resin was washed beforehand with 3 η hydrochloric acid, then with water and finally with methanol and then ^{dried for 6 hours at a temperature of 95 °} C. under reduced pressure. After 5 minutes, the ion exchange resin is filtered off from the solution and the filtrate is evaporated to dryness. The residue is dissolved in ethyl acetate and the solution is washed with 1 η hydrochloric acid and then with water, dried and evaporated to dryness. The residue is digested with diethyl ether. There is obtained 4-benzyloxy-3- (2-hydroxy ~ 1-methoxyethyl) acetophenone, mp 78 to 80 ⁰ C.

A solution of 10.6 g (0.035 mol) of the compound obtained in 50 ml of pyridine is mixed with 13 ml of acetic anhydride and ^{stirred at a temperature of 25 °} C. for 18 hours. The mixture is then cooled, 15 ml of methanol are added, the mixture is stirred for 20 ml. Mats and poured into ethyl acetate. The resulting mixture

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is well gev / ash with 5% hydrochloric acid, dried and evaporated to dryness. After chromatograpMscher Purification of the residue obtained 4-benzyloxy-5- (2-acetoxyt-1-methoxyethyl) acetophenone, mp 67 to 70 ⁰ C.

A solution of 6.6 g (18.4 mmol) of the compound obtained in 100 ml of chloroform is mixed with a solution of 0.975 ml (19 mmol) of bromine in 20 ml of chloroform. After 5 minutes, an additional drop of bromine is added and stirring is continued for a further 10 minutes. The mixture is washed with an aqueous sodium bisulfite solution and then with water, dried and evaporated to dryness. Crystalline fr-bromo-4-bensyl ~ oxy-3- obtained (2-acetoxy-1-methoxyethyl) -acetophenone from P. 79-80 ⁰ C,

A mixture of 4.7 g (11.16 mmol) of the compound obtained and 2.86 g (17.5 mmol) of N-benzyl-tert-butylamine in 35 ml of acetonitrile is refluxed for 5 hours and then stirred at a temperature of 25 ° C for 18 hours. After adding 150 ml of diethyl ether are then cooled and the reaction mixture is filtered. The piltrate is evaporated to dryness. The residue is passed through a column loaded with silica gel using a mixture of diethyl ether and chloroform (1: 9) as the eluent, purified by chromatography. The first fraction becomes Evaporated dry. (V- (N-benzyl-N-tert-butylamino) 4-benzyloxy-3- (2-acetoxy-1-metho3cyethyl) acetophenone.

A solution of 1.6 g (3.18 mmol) of the compound obtained in .100 ml of methanol is mixed with 1.6 g of sodium borohydride and

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Stirred at a temperature of 25 ^° C. for 18 hours. After the reaction mixture has been evaporated to dryness, the residue is dissolved in ethyl acetate and the solution is washed with water, dried and evaporated to dryness. After purifying the residue by chromatography, (V- (IT-benzyl-N ~ tert-butylaminomethyl) -4-benzyloxy-3- (2-hydroxy-1-methoxyethyl) benzyl alcohol is obtained.

A solution of 0.7 g (1> 5 ml-Iol) of the compound obtained in 150 ml of ethanol is made using 0.7 g of 10 percent tiger Palladium-on-carbon for 25 minutes at a pressure of about 3 »5 at hydrogenated. After the catalyst has been filtered off, the filtrate is released evaporated. D6- (tert-butylaminomethyl) -4-hydroxy-3- (2-hydroxy-1-methoxyethyl) benzyl alcohol is obtained. The corresponding fumarate melts at 230 C (decomp.).

Example 7

A solution of 10.0 g (32.1 mmol) 2- / 4-benzyloxy ~ 3- (1-, 2-epoxyethyl) -phenyl7-2-methyl-1,3-dioxolane and sodium methoxide (prepared using 2 , 5 g of sodium) in 500 ml of methanol is heated for 5 hours under reflux and then stirred for 18 hours at a temperature of 25 ⁰ C. The reaction mixture is evaporated to dryness and the residue is dissolved in diethyl ether. The solution is washed with water, dried and evaporated to dryness, a mixture of 3- (1-hydroxy-2-methoxyethyl) phenyl and 3- (2-hydroxy-1-methoxyethyl) phenyldioxolane being obtained. A solution of 10.0 g of the resulting • mixture and 6.1 g of freshly recrystallized triphenyl! Methyl-

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■ j chloride in 25 ml of pyridine is 2 1/2 hours at a temperature of 60 to 70 ⁰ C then -and- 18 hours 55 Ms heated 6O ⁰ C. The reaction mixture is evaporated and the residue is dissolved in a mixture of diethyl ether and water. The solution is washed well with water, dried and evaporated. The residue is chromatographed on a column charged with aluminum oxide in order to separate the triphenylmethyl ether of 5- (2-hydroxy-1-methoxyethyl) -phenyldioxolane from unreacted 3- (1-hydroxy-2-methoxyethyl) -phenyldioxolane. This is dissolved in tetrahydrofuran and the solution treated with 1 η hydrochloric acid and then extracted. 4-Benzyloxy-5- (1-hydroxy-2-methoxyethyl) acetophenone is obtained.

4 »3 g (14» 3 mmol) of the acetophenone derivative obtained is in T5 dissolved 60 ml of pyridine and acetylated with 5 ml of acetic anhydride, the mixture being stirred at a temperature of 25 ° C for 18 hours. The reaction mixture is cooled in sequence, 10 ml of methanol are added, the mixture is stirred for a further 30 minutes and poured into V / water. The mixture obtained is extracted with diethyl ether. The extract is washed well with 1 η hydrochloric acid and then with water, dried and evaporated to dryness. Of the The residue is purified by chromatography on a column loaded with silica gel using diethyl ether as the mobile phase. The first fraction is collected and evaporated to dryness. The residue is made from a mixture of chloroform and hexane recrystallized '. 4-Benzyloxy-3- (1-acetoxy-2-methoxyethyl) acetophenone is obtained from 83 to 84 ° C.

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A solution of 2.9 g (8.49 mmol) of the compound obtained in 200 ml of chloroform are mixed with 0.478 ml (9.34 mmol) of bromine. After 30 minutes the reaction mixture is quenched with water and then washed with 5 percent sodium bicarbonate solution, dried and evaporated to dryness. The residue is recrystallized. ^ -Bromo-4- "benzyloxy-3- (i-acetoxy-2-methoxyethyl) acetophenone is obtained from F. 91 Ms 93 C.

A mixture of 3.0 (7.13 mmol) of the obtained compound and 2.21 g (13.56 mmol) of N-benzyl-tert-butylamine in 50 ml of acetonitrile is refluxed for 4 hours. Then the solvent is distilled off and the residue that remains in Diethyl ether added. The resulting solution is washed well with water, dried and treated with a solution of hydrogen chloride treated in diethyl ether. Then the solvent is decanted off and the remaining gummy hydrochloride dissolved in water. The solution is washed with diethyl ether, made alkaline and then extracted with diethyl ether. The extract is washed with water, dried and evaporated. CT - (- N-Benzyl-N-tert-butylamino) -4-benzyloxy-3- (1-acetoxy-2-methoxyethyl) acetophenone is obtained.

A solution of 2.2 g (4.37 mmol) of the compound obtained in 70 ml of ethanol is mixed with 2.5 g of sodium borohydride. After a reaction time of 18 hours at a temperature of 25 ^° C., the solvent is distilled off. The residue is dissolved in a mixture of 50 ml of methanol and 10 ml of a 20 percent potassium carbonate solution. The mixture is 30 minutes

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heated to reflux. After distilling off the methanol
the remaining mixture is extracted with ethyl acetate.
The extract is washed with water, dried and evaporated to dryness. The residue is chromatographically purified on a column filled with silica gel using diethyl ether as the mobile phase. The first fraction is collected and evaporated. This gives £ y- (N-benzyl-N-tert-butylaminomethyl) ~ 4-benzyloxy-3- (1-hydroxy-2-methoxyethyl) benzyl alcohol,

A mixture of 1.0 g (2.16 mmol) of the obtained compound
and 1.0 g of 10 percent palladium on carbon in 120 ml of ethanol
is hydrogenated for 10 minutes at a pressure of about 3.5 atm. To
after filtering off the catalyst from the reaction mixture, the piltrate is concentrated and treated with a solution of hydrogen chloride in

Treated diethyl ether. IX- (tert-butylaminoniethyl) -4-hydroxy-3- (1-hydroxy-2-methoxyethyl) benzyl alcohol hydrochloride from F is obtained. 194 to 195 ⁰ C

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Claims (11)

• Claims . y # -aminomethyl-3-ethyl-4-hydroxy-benzyl alcohol derivatives of general formula I ' OR OH (D in which R is a hydrogen atom or a methyl group ", where tiiv. l / civlen radicals R not at the same time each have a methyl group represent, and R .. is a branched lower alkyl radical with 3 to 5 carbon atoms, a cycloalkyl or cycloalkylmethyl radical, wherein the cycloalkyl radical has 3 to 6 carbon atoms has, or a radical of the general formula II 15 (II) denotes in which Rp and R ^ are identical or different and each denotes a hydrogen atom or a hydroxyl or methoxy group or R ₂ and R- are in the ortho position to one another and thereby form a methylenedioxy group and R. represents a hydrogen atom or a methyl group, and their salts with acids. 2. (K- (tert-Butylaminomethyl) -3- (1,2-dihydroxyethyl) -4-hydroxybenzyl alcohol. • 3. (X - (Cyclopentylaminomethyl) -3- (1,2-dihydroxyethyl) -4- _L hydroxybenzyl alcohol. 5Q9850 / 1034-1 4. 0c- (Isopropylaminoraethyl) -3- (1,2 ~ dihydroxyethyl) -4-hydroxybenzyl alcohol. 5. Cx - [2- { 3,4-methylenedioxyphenyl) -1-methylethylaminomethyl7 3- (1,2-dihydroxyethyl) -4-hydroxybenzyl alcohol. 6. iV-./2-(4-hydroxyphenyl)-1,1 -dime thy läthylaminome thy l7-3- (1,2-dihydroxyethyl) -4-hydroxybenzyl alcohol γ, <y- (tert-butylaminomethyl) -4-hydroxy-3- (2-hydroxy-1-methoxyethyl) - "benzyl alcohol. 8. £ y- (tert-butylaminomethyl) -4-hydroxy-3- (1-hydroxy-2- methoxyethyl) benzyl alcohol.
15th 9. Compound of the general formula III ROCH ^ifr rV ^iH - ^CH 2? ^R i ^CH 2 ^C 6 ^H 5 in which R and R ^ have the meaning given in claim 1. 10. Process for the preparation of the compounds according to claim 1 to 8, characterized in that one is in each case in a manner known per se
a) an acetophenone derivative of the general formula IV ^L. 509850/1034 A-O xv V (IV) C ₆ H ₅ CH ₂ O in which A is an acetyl or methyl group, the A radicals do not represent a methyl group at the same time, brominated with bromine or pyrrolidone hydrotribromide, b) the resulting CY-bromoacetophenone derivative of the general formula V
10 in which A has the above meaning with an N-benzylamine derivative of the general formula VI C ₆ H ₅ CH ₂ NHR _{1 (VI)} converts, in which R .. has the meaning given in claim 1, c) the obtained Oc-benzylaminoacetophenone derivative of the general Formula VII A-O C ₆ H ₅₂ ^ J ^CH 2 ^C 6 ^H 5 in which A and R _{1 have} the above meaning, reduced with sodium borohydride,
d) the benzyl alcohol derivative of the general formula VIII obtained L. 509850/1034 -J E OCH ^(VIII) in which R has the meaning given in claim 1 and IL · the above meaning have, catalytically hydrogenated and optionally e) the compound of general formula I obtained with converted into a salt by an acid. 11. Medicaments containing a compound according to claim 8 and customary carriers and / or diluents and / or auxiliary materials. 509850 / 103A