DE2305092A1 - Alpha-aminomethylbenzyl alcohol derivs. - prepd. by redn. of corresponding protected derivs. - Google Patents

Abstract

Title cpds. of formula (I): (where one of A and B = H or OH, the other -NR1R2; R1 is diff. from R2 and H or alkyl; R2 = H or -CO-R4; R4 = H or alkyl opt. substd. with OH, alkoxy or acylamino; R3 = alkyl or phenylalkyl opt. substd. with hydroxyl, alkyl, alkoxyl or acylamino), are prepd. by catalytic redn. of cpds. in which one or more H atoms of the mono-substd. amino gp. and its hydroxyl gps. are protected by e.g., benzyl, or (p-NO2)-benzyloxycarbonyl. (II) are beta-adrenergic stimulants and are very active on smooth respiratory muscles.

Description

α-Aminomethylbenzyl alcohol derivatives The present invention relates generally to novel α-aminomethylbenzyl alcohol derivatives, and more specifically, it relates to novel α-aminomethylbenzyl alcohol derivatives having the general formula (I) wherein one of A and B represents a hydrogen atom or a hydroxyl group, while the other of these represents one Group (in which R1, which is different from R2, represents a hydrogen atom or an alkyl group and R2 represents a hydrogen atom or a -CO-R4 group, on which R4 represents a hydrogen atom or an alkyl group which is substituted by a hydroxyl group, an alkoxyl group or an acylamino group may) and R3 denotes an alkyl group or a phenylalkyl group which may be substituted by a hydroxyl group, an alkyl group, an alkoxyl group or an acylamino group.

The compounds of this invention are useful as β-adrenergic stimulants usable and therefore they have a great effect on the smooth respiratory muscles Activity @ and are useful as bronchodilator agents.

As a-alkylmethylbenzyl alcohol derivatives, for example, are known: 3-Amino-4-hydroxy- @isopropylaminobenzyl alcohol (see Dutch patent 85,197; "Chemical Abstract, 52, 11121d (1958)), 5-ethoxyearbonylamino-4-hydroxy-α-isopropylaminobenzyl alcohol (cf.

Belgian patent 765,986), a- (isopropylaminomethyl) -4-hydroxy-3-ureidobenzyl alcohol (See Japanese Patent Application Laid-Open Publication 2674 / 17t) and the like.

However, the compounds of this invention have more excellent ones bronchodilator activity than these known compounds.

In Formula I, which represents the compounds of this invention, are given as examples of the alkyl group represented by the substituents R1, R3 and R4 are represented, a methyl group, an ethyl group, a propyl group, a Isopropyl group, a n-butyl group, a tert-butyl group, a 1,3-dimethylbutyl group, a 1,3-dimethylpentyl group, a 2,3-dimethylbutyl group, a 2,3, 3-trimethylbutyl group and the like called.

Examples of the alkoxyl group in the substituents R3 and R4 are a methoxy group, an ethoxy group, an isopropoxy group, a tert-butoxy group, a neopentyloxy group and the like; Examples of the acylamino group in the Substituents R3 and R4 are an acetamido group, a proplomido group, a benzamido group, one Pyridine carbonyl anido group and the like.

The particularly useful compounds of this invention are 3-formamido-4-hydroxy-α [N- (1-methyl-2-p-hydroxyphenylethyl) aminomethyl] benzyl alcohol, 3-formamido-4-hydroxy-α- [N- (1-methyl-2-p-methoxyphenylethyl) aminomethyl] benzyl alcohol, 4-hydroxy-3-methylamino-α- (N-tert-butylaminomethyl) benzyl alcohol and the like.

When A of Formula I is the prepared compounds of this invention, A is hydroxyl and B is Group.

The compounds of this invention are represented by the formula I ' (I '), in which R1, R2 and R3 have the same meaning as in the formula I and, more specifically, the formula I' comprises the following three formulas: where R3 and R in the above formulas have the same meaning as in formula I.

As starting materials for making those described above Compounds are those compounds used in which one or more hydrogen atoms the mono-substituted amino group and its hydroxyl group with a protecting group which is easily split off by reduction, such as a benzyl group, a benzyloxycarbonyl group, a p-nitrobenzyloxycarbonyl group and the like.

Furthermore, the starting material for the compounds to be prepared which has a hydroxyl group to the benzene ring via = CH-, i.e. a secondary hydroxyl group, can be the compound which has a carbonyl group in the position owns.

The compounds of this invention can by catalytic reduction, e.g. of the starting material or its salts, in a solvent, e.g. ethanol, Isopropanol, ethyl acetate and the like, at normal temperature or at elevated temperatures Temperature, under normal pressure or high pressure in the presence of a catalyst e.g. palladium, platinum and the like produced according to the usual working conditions will.

Practical examples of the raw materials for manufacture of the compounds of this invention are the following: 3-formamido-4-benzyloxy-a-fN-benzyl-N-isopropylaminoethyl) benzyl alcohol, 3-acetamido-4-benzyloxy-a- (tert-butylaminomethyl) benzyl alcohol, 3-propionamido-4-hydroxy - α- (N-benzyl-N-n-butylaminomethyl) benzyl alcohol, 3-nicotinoylamino-4-benzyloxy-a-0N-benzyl-N- (2,3-dimethylbutyl) ~ amino] acetophenone, 3-formamido-4-benzyloxy-α- (3-p-hydroxyphenyl-1-methylpropylamino) acetophenone, 3-acetamido-4-hydroxy-a-; N-benzyl-N- (4-phenyl-2,3,3-trimethylbutyl) -amino] acetophenone, 3-formamido-4-benzyloxy-α- [N-benzyl-N- (1-methyl-2-p-hydroxyphenylethyl) aminomethyl] benzyl alcohol, 3-acetamido-4-benzyloxy-α- [N- (1-methyl-3-mtolylpropyl) aminomethyl] benzyl alcohol, 3-Benzyloxyacetamido-4-hydroxy-oi- N-benzyl-N (1-ethyl-2-p-methoxyphenylpropyl) amino] acetophenone, 3- (3-Benzyloxypropionamido) -4-benzyloxycarbonyloxy-α- [N- (1-methyl-2-m-ace @ amidophenyl) amino] acetophenone, 3- (2-Acetamidopropionamido) -4-hydroxy-α- [N-benzyl-N- (1-methyl-3-o-tolylpropyl) amino] acetophenone, 3-butyrylamino-4-hydroxy-α- [N- (o-methyl-methoxyphenylpropyl) amino] acetophenone, 3-formylamino-4-benzyloxy-a-lN-benzyl-N-l, l-dimethyl-2-p-hydroxyphenylethyl) aminomethyli benzyl alcohol, 3-acetamido-4-benzyloxya-EN-benzyl-N- (o-methyl-m-acetamidophenylethyl ) atriinomethyl] benzyl alcohol, 3-formamido-4-hydroxy-α- [N-benzyl-N- (1-ethyl-2-p-hydroxyphenylethyl) aminomethyl benzyl alcohol, -Formamido-4-benzyloxy-a- IN-benzyP-N - (- methyl-2-p-acetamidophenylethyl) aminomethylbenzyl alcohol, 3-Benzyloxyacetamido-4 hydroxy-a-gN-benzyl-N- (1-methyl-2-p-propoxyphenylethyl) amino] acetophenone, 3-Acetamidopropionamido-4-benzyloxy-ci- {N -benzyl-N- (1-methyl-2-p-ethoxyphenylethyl ) aminomethyl; benzyl alcohol, 3-formamido-a- (N-benzyl-N-isopropylaminomethyl) benzyl alcohol, 3-formamido-α- (N-benzyl-N-tert-butylaminomethyl) acetophenone.

When the hydroxyl groups of groups R3 and R4 of these starting materials for the preparation of the compounds of this invention through benzyl groups, benzyloxycarbonyl groups and the like have been substituted, the substituents of the hydroxyl groups become split off to the hydroxyl groups in the practical execution of the already mentioned To obtain reduction.

The products produced with the formula I can be isolated and purified using the usual chemical working methods. Since the compounds of this invention with the formula 1 at least one asymmetric Having carbon atom, the compounds of this invention include all possible optically active forms and racemic mixtures. The racemic mixtures can be separated by methods known per se, e.g., by formation optically active acids addition salts and their separation by fractional crystallization.

The pharmacological effects of the compounds of this invention will be illustrated by the following investigations and their results, whereby for Compare these can be compared with known compounds.

Study I activity of an isolated bronchial smooth muscle (in vitro test): The trachea was taken from Guinea pigs, in a spiral shape cut and the isolated bronchial preparation was suspended in a mangus bath. Then Tyrode liquid was used as a nutrient solution and this was brought to 37 ° C held. Then 10 5 g / ml of histamine or methacholine chloride was added to the experimental formulation as agonists (added. After the contraction of the trachea a temporary State When the stability was reached, the test sample became the ones shown in the following Table is given, added cumulatively to the experimental set-up. One dose for 50-oil relaxation of the bronchial muscles was designated as ED50.

Study II Experimental anti-asthmatic effect (in vivo test): A guinea pig was placed in an 11 liter glass kettle and then became a broncho-constricting agent to the pig by spraying by means of a Nebulizer administered. Then when 0.01% histamine or methacholine chloride solution was sprayed in 10 seconds) the guinea pig showed symptoms of dyspnoea (breathing disturbance). 10 mg / kg of the sample was given orally to Guinea pigs 30 minutes or 2 hours before Administration of bronchocontractive agent administered. If the guinea pig did not show any symptoms of dyspnoea, the sample was considered effective.

The results obtained in the above investigations will be shown in the following table. Sample investigation I investigation II (ED50, g / ml) (a / b) @@ + histamine methacholine- histamine methacholine chloride chloride 30 '120' 30 '120' Pr @@ ukt according to example 5 1 x 10-9 5 x 10-8 5/5 3/5 4/5 1/5 "" 14 2 x 10-7 6 x 10-6 5/5 5/5 5/5 4/5 "" 11 9.4 x 10-10 1.1 x 10-8 5/5 5/5 5/5 5 / 5 "" 12 3.6 x 10-9 8.4 x 10-8 5/5 5/5 5/5 5/5 "" 25 4.6 x 10-10 4.6 x 10-9 5/5 5 / 5 5/5 5/5 Known connections A 3 x 10-7 3 x 10-6 3/5 2/5 5/5 3/4 B 5 x 10-6> 10-4 1/5 0/5 1/5 0/5 C 9 x 10-8> 10-4 1/5 1/5 0/5 0/5 D 10 x 10-8 9.6 x 10-8 5/5 5/5 5/5 5/5 E 2.7 x 10-9 2.1 x 10-8 5/5 5/5 5/5 5/5 (+): (a) effective Number (b) number tested.

The known compounds used above are: A: 3-Amino-4-hydroxy-α-isopropylaminomethylbenzyl alcohol (Dutch patent specification 85,197).

B: 3-Ethoxyearbonylamino-4-hydroxy-α-isopropylaminomothylbenzyl alcohol (Belgian patent 765,986).

C: 4-Hydroxy-3- (N '-methylureido) -a-isopropylaminomethylbenzyl alcohol (Japanese Patent Application Laid-Open No. 2674 / '71).

D: solbutamol; 4-Hydroxy-3-hydroxymethyl-α-tert-butylaminomethylb enzyl alcohol E: trimetoquinol; L-1- (3,4,5-trimethoxybenzyl) -6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride.

From the above results it can be clearly seen that the Compounds of this invention are similar to known bronchodilator agents and unlike structures superior to the compounds of this invention was.

The compounds of this invention can be used in various forms Treatment and contraception use.

In general, they are considered to be salts of pharmahologically non-toxic Acids used. For example, they can be used as salts of such inorganic acids, such as hydrochloric acid, sulfuric acid, phosphoric acid and the like or the like organic acids such as fumaric acid, maleic acid, acetic acid, lactic acid, citric acid and the like, find use.

The compounds of this invention can be administered orally or parenterally will. In the case of oral administration, they can be in the form of sugar-coated Tablets, bucoal tablets or capsules are used. You can also in the form of ærosolen as Inhalation can be administered. Farther they can be administered subcutaneously, intramuscularly or intravenously as an injection.

The dosage of the compounds of this invention depends on the condition of the patient and their age, and so are appropriate oral dosage ranges from 0.3 to 1.5 mg / day for the adult.

Reference Example 1 a) 5.4 g of 4-benzyloxy-3-nitroacetophenone was added to e0 ml of chloroform dissolved. To the solution was added dropwise a mixture of 3.2 g of bromine and 5 ml Added chloroform with stirring. The mixture was stirred for a further 30 minutes. The reaction product was concentrated under reduced pressure. The crystalline obtained The residue was washed with 20 ml of benzene and dried. There was 5.5 g of 4-benzyloxy-3-nitro-a-bromoacetophenone obtain. The product had a melting point of 135-136 ° C. according to its recrystallization lization from chloroform.

b) In 60 ml of tetrahydrofuran was 5.3 g of 4-benzyloxy-3-nitro-oi-bromoacetophenone dissolved. Then 4.5 g of N-benzyl-N-isopropylamine was added to the solution and the mixture was stirred overnight at room temperature. Then became after filtering off the precipitates formed thereby, the filtrate under reduced The pressure was concentrated and the crystalline residue obtained was washed with ethanol. 5.5 g of yellow crystalline 4-benzyloxy-3-nitro-a- (N-benzyl-N-isopropylamino) acetophenone were obtained obtain. The product showed a melting point after recrystallization from ethanol at 92-930C.

c) In 35 ml of ethanol, 3.5 g of 4-benzyloxy-3-nitro-a- (N-benzyl-N-isopropylaniino) acetophenone suspended.

After adding 0.4 g of sodium borohydride to the suspension was the mixture is stirred for 3 hours at room temperature. After distilling off the Ethanol from the reaction product under reduced pressure became the residue with Water added. The batch was extracted with benzene. The extract was made with water washed and dried over anhydrous magnesium sulfate. Then this one was under concentrated under reduced pressure. 3.4 g of pale yellow crystalline 4-benzyloxy- 3-nitro-a- (N-benzyl-N-isopropylaminomethyl) benzyl alcohol was obtained. The product had a melting point of 97 ° C. after recrystallization from ethanol.

d) 3 g of 4-benzyloxy-3-nitro-a- (N-benzyl-N-isopropylaminomethylbenzyl alcohol) were added to 30 ml of 50% strength aqueous acetic acid solution dissolved. To the solution, 1.5 g of iron powder was added and then 30 minutes refluxed by heating. After filtering off the insoluble components from the reaction product, the filtrate was concentrated under reduced pressure. to 20 ml of 5% strength aqueous sodium carbonate solution were added to the residue obtained in this way and then the product was extracted with benzene. The extract was washed with water and then dried over anhydrous magnesium sulfate. The extract was then concentrated under reduced pressure. It became brownish crystalline 3-amino-4-benzyloxy-a- (N-benzyl-N-isopropylaminomethyl) benzyl alcohol obtain.

The product was recrystallized from 2: 5 benzene-n-hexane and possessed then a melting point of 63-650C. The yield of this product obtained was 2.2 g.

e) In 5 ml of a mixture of acetic anhydride and formic acid was Dissolved 1.9 g of 3-amino-4-benzyloxy-a- (N-benzyl N-isopropylaminomethyl) benzyl alcohol and left to stand overnight. The solution was concentrated under reduced pressure. To the residue obtained, 20 ml of 5% aqueous sodium carbonate solution was added. The product was then extracted with 30 ml of benzene. The extract was made with water washed and dried over anhydrous magnesium sulfate and then under reduced pressure Pressure restricted. It became 4-benzyl-oxy-3-formylamino-a- (N-bx8yl-N-isopropylaminomethyl) -o-formylbenzyl alcohol obtain.

The product was dissolved in 10 ml of 90% methanol (remainder 10% water). To the solution was added 0.5 g of sodium carbonate and the mixture for 30 minutes stirred at room temperature. Then the solvent was reduced under reduced pressure Distilled off pressure and the residue obtained was extracted with benzene. Of the The extract was washed with water, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. It became 1.9 g more brownish oily 4-benzyloxy-3-formylamino-a- (N-benzyl-N-isopropylaminomethyl) benzyl alcohol obtain.

Reference Example 2 a) 5 g of 3-amino-4-benzyloxyacetophenone was added to 30 ml of pyridine dissolved. 3.9 g of benzyloxyacetyl chloride was added with cooling and that The mixture was stirred overnight at room temperature. The solvent was distilled off from the reaction product under reduced pressure. The residue formed was dissolved in 50 ml of chloroform. Then the solution was twice with 20 ml Water washed. Then the solution was dried over anhydrous sodium sulfate and Chloroform was distilled off under reduced pressure. By Recrystallization of the yellow crystals from ethanol gave 7.5 g of 4-benzyloxy-3-benzyloxyacetylaminoacetophenone obtained with a melting point of 104-1050C.

b) In 50 ml of chloroform, 1.9 l of benzyloxy-3-benzyloxyacetylaminoacetophenone was added dissolved. To the solution, 0.78 g of bromine was added and the mixture became 30% Stirred minutes at room temperature. Then chloroform and hydrogen bromide distilled off from the reaction mixture under reduced pressure. The received Crystals were recrystallized from chloroform-n-hexane. There was 1.85 g of 4-benzyloxy-3-benzyloxyacetylamino-a-bromoacetophenone obtained with a melting point of 155-1570C.

c) 4 g of 4-benzyloxy-3-benzyloxyacetylamino-a-bromoacetophenone was added to 100 ml of tetrahydrofuran dissolved at 40-500C. Then 2.68 g of N-benzyl-N-isopropylamine was added to the solution added. The mixture was left overnight at the same temperature (40-50 ° C) stirred. The reaction mixture was cooled and the N-benzyl-N-is formed Propylamine hydrochloride was filtered off and then the solvent was taken distilled off under reduced pressure. After dissolving the yellow oily so obtained Material (5g) in 100 ml of ethanol was added to the solution 0.5 g of sodium borohydride and the mixture was stirred for 4 hours at room temperature. Then it became Solvent is distilled off from the reaction product under reduced pressure. the obtained white crystals were recrystallized from ethanol. It became 2.3 g 4-Benzyloxy-3-benzyloxyacetylamino-a- (N-benzyl-N-isopropylaminomethyl) benzyl alcohol obtained with a melting point of 93-950C.

Reference Example 3 a) In 50 ml of chloroform, 5.4 g of 4-hydroxy-3-nitroacetophenone was added dissolved. Then 5 ml of a chloroform solution of 4.8 g of bromine was graded dropwise added to the solution. The mixture was then stirred for 15 minutes and then concentrated under reduced pressure to give yellow crystals. Recrystallization of the product from benzene-n-hexane gave 6.3 g of crystalline material a-Bromo-4-hydroxy-3-nitroacetophenone with a melting point of 69-71 ° C. was obtained.

b) 5.2 g of a-bromo-4-hydroxy-3-nitropgenone was added to 50 ml of methyl ethyl ketone dissolved. Then 9 g of N-benzylisopropylamine was added to the solution and that The mixture was stirred overnight at room temperature. After filtering off of the precipitated N-benzylisopropylamine hydrobromide, the filtrate was concentrated. It became crude yellowish brown oily 4-hydroxy-3-nitro-α- (N-benzyl-N-isopropylamino) acetophenone obtain.

c) In 50 ml of ethanol, the crude 4-hydroxy-3-nitro-α- (N-benzyl-N-isopropylamino) acetophenone obtained above was obtained dissolved and then 1.5 g of sodium borohydride was added to the solution. That The mixture was stirred overnight at room temperature. The reaction product was concentrated under reduced pressure. Then, the obtained residue became water and the product was extracted with benzene. The extract was made with water washed and dried over anhydrous magnesium sulfate. Then the solvent became distilled off and obtained a yellow-brown oily material. The oily product was subjected to silica gel column chromatography. The product was then using isolated from benzene as eluant.

4 g of 4-hydroxy-3-nitro were obtained from the collected eluates -a- (N-benzyl-N-isopropylaminomethyl) benzyl alcohol won.

d) 2.7 g of 4-hydroxy-3-nitro-α- (N-benzyl-N-isopropylaminomethyl) benzyl alcohol were added to 30 ml of methanol (manufactured according to the above specification) dissolved. Then became the solution Given 1 g of Raney nickel catalyst.

The catalytic reduction of the compound was carried out at normal temperature and normal pressure carried out. After 600 ml of hydrogen was absorbed, the implementation canceled. After filtering off the catalyst and adding 8> 2 nil 1 normal hydrogen chloride-ethanol solution to the filtrate became the reaction product concentrated under reduced pressure. 2.7 g of yellow-brown powdery 5-amino-4-hydroxy-a- (N-benzyl-N-isopropylaminomethyl) benzyl alcohol hydrochloride were obtained obtain.

e) 1.2 g of the 3-amino-4-hydroxy-α- (N-benzyl-N-isopropylaminomethyl) benzyl alcohol hydrochloride prepared above was added to 20 ml of pyridine dissolved. Then, 0.20 g of formic acid and 0.85 g of dicylohexylcarbodiimide were added to the solution added while cooling to below 0 ° C. The mixture was left overnight at room temperature stirred. The dicyclohexylurea which separated out was filtered off. The filtrate was concentrated. Water was added to the obtained residue and the mixture was washed with ethyl acetate. The formed aqueous solution was neutralized by adding sodium carbonate and then was washed with ethyl acetate extracted. The extracts were dried and concentrated. It became a brown residue obtain. The residue was subjected to silica gel column chromatography. The product was made using a 5: 1 chloroform-acetone mixture as Eluant obtained. The eluates then became 0.5 g of yellow powdery 3-formylamino-4-hydroxy-a- (N-benzyl-N-isopropylaminomethyl) benzyl alcohol won.

Reference Example 4 a) 5 g of 3-amino-4-benzyloxyacetophenone was added to 15 ml of pyridine dissolved. To the solution, 3 ml of acetic anhydride was added and the mixture became Left to stand at room temperature for 2 hours. Then the reaction product was under concentrated under reduced pressure and the resulting crystalline residue was washed with ethanol washed. 5.3 g of white crystalline 3-acetylamino-4-benzyloxyacetophenone were obtained obtain. The product had a melting point after recrystallization from ethanol at 130-133 ° C.

b) In 45 ml of chloroform, 5 g of 3-acetylamino-4-benzylpxyacetophenone was added dissolved. Then, a solution of 2.8 g of bromine in 5 was added dropwise to the solution ml of chloroform were gradually added, the mixture initially being warmed. The mixture was stirred for a further 20 minutes. Then 50 ml of benzene was added to the mixture and the crystals thereby precipitated were separated by filtration and dried. 5.5 g of white crystalline 3-acetylamino-4-henzyloxya-bromoacetophenone were obtained obtained with the melting point at 1810C.

c) In 40 ml of acetonitrile and 10 ml of dimethylformamide, 1.85 g of p-acetylamino-4-benzyloxy-a-bromoacetophenone was added dissolved. 1.5 g of N-benzyl-N-isopropylamine was added to the solution and that Mixture stirred for 2 hours at 40-500C. Then the mixture was at overnight Left to stand at room temperature. The precipitates thus formed were filtered off and the filtrate was concentrated under reduced pressure. The residue was then dissolved in ethyl acetate and the insolubles were filtered off. An ethanol solution of hydrogen chloride was added to the filtrate, whereby crystalline deposits occurred.

The precipitates were separated by filtration and put into water dissolved under heating. The insoluble fractions were separated off by filtration and the solution was neutralized by the addition of aqueous sodium carbonate solution. The reaction product was extracted with ethyl acetate and the extract was then washed with water, dried and concentrated under reduced pressure. It was 1.2 g of 3-acetylamino-4-benzyloxy-a- (N-benzyl-N-isopropylamino) acetophenone were obtained.

d) 1 g of 3-acetylamino-4-benzylx; fya- (N-benzyl-N-isopropylamino) acetophenone was added to 20 ml of ethanol dissolved.

0.2 g of sodium borohydride was added to the solution and the mixture was stirred overnight. The reaction product became under reduced pressure constricted. Water was added to the obtained residue and the product became extracted with ethyl acetate. The extract was washed with water and made over anhydrous Dried magnesium sulfate. Then the extract was concentrated under reduced pressure.

0.9 g of 3-acetylamino-4-benzyloxy-a- (N-benzyl-N-isopropylaminomethyl) benzyl alcohol was obtained obtain.

Reference Example 5 a) In 60 ml of chloroform, 5.4 g of 4-benzyloxy-3-nitroacetophenone was added dissolved. To the solution was added dropwise a mixture of 3.2 g of bromine and 5 ml Chloroform added with stirring. The mixture was then stirred for a further 30 minutes. The reaction product was concentrated under reduced pressure and the crystalline residue obtained was washed with 20 ml of benzene and dried. 5.5 g of 4-benzyloxy-3-nitroa-bromoacetophenone with a melting point of 135-1360C were obtained obtain.

b) A mixture consisting of 4.6 g of 4-benzyloxy-3-nitroa-bromoacetophenone and 6.4 g of N-benzyl-N- (l-methyl-2-p-hydroxyphenylethyl) amine was used together with 50 ml of methyl ethyl ketone heated to 70-80C for 30 minutes.

After cooling the reaction product, the precipitates formed became filtered off and the filtrate was concentrated under reduced pressure. After the addition from ethanol to the residue obtained, the product was deposited in crystalline form. The crystals were separated by filtration and recrystallized from ethanol. 5.5 g of 4-benzyloxy-3-nitroa-0N-benzyl-N- (1-methyl-2-p-hydroxyphenylethyl) amine-3-acetophenone were obtained obtained with the melting point at 84-85 ° C.

c) In 100 ml of ethanol, 4.5 g of 4-benzyloxy-3-nitro-a- [N-benzyl-N- (1-methyl-2-p-hydroxyphenylethyl) amino] acetophenone suspended. 0.5 g of sodium borohydride was added to the suspension. The mixture was stirred for one hour at room temperature. Then came ethanol distilled off from the reaction product under reduced pressure. Then became water added to the residue and the product was extracted with benzene. The extract was washed with water and dried over anhydrous magnesium sulfate. then the extract was concentrated under reduced pressure. It became 4.4 g more yellowish crystalline powdery 4-benzyloxy-3-nitro-a- [N-benzyl-N-tl-methyl-2-p-hydroxyphenylethyl ) aminomethyß obtained benzyl alcohol.

d) In 40 ml of 60% aqueous acetic acid solution, 4.3 g of 4-benzyloxy-3-nitro-α- [N-benzyl-N- (1-methyl-2-p-hydroxyphenylethyl) aminomethyl] benzyl alcohol was added dissolved. 1.5 g of iron powder was added to the solution.

The mixture was refluxed for 30 minutes by heating. After the insoluble components were filtered off from the reaction product, the product became concentrated under reduced pressure. 10% aqueous solution was added to the residue obtained Sodium carbonate solution was added and the product was extracted with benzene. The extract was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. It became 3.7 g of brownish crystalline powdery 3-hmino- 4-benzyloxy-a-N-benzyl-N- (1-methyl-2-p-hydroxyphenylethyl) aminomethylJbenzyl alcohol.

e) In 10 ml of 5: 3 acetic anhydride-formic acid mixture was 3.3 g -amino-4-benzyloxy-a- dissolved tN-benzyl-N- (l-methyl-2-p-hydroxyphenylethyl) aminomethyl] benzyl alcohol After allowing the mixture to stand overnight at room temperature, the mixture became concentrated under reduced pressure. The residue obtained was dissolved in 50 ml of methanol dissolved. To the solution, 3 ml of water and 3 g of sodium carbonate were added. The mixture was stirred for one hour at room temperature. Methanol was taking distilled off from the mixture under reduced pressure and the residue was washed with ethyl acetate extracted. The extract was washed with water and over anhydrous magnesium sulfate dried. The solvent was distilled off from the extract. It became 3.4 g pale brown powdery 4-benzyloxy-3-formylamino-a-0N-benzyl-N-tl-methyl-2-p -hydroxyphenylethyl) aminomethyl] benzyl alcohol obtain. In 30 ml of benzene, 2.5 g of the pale brown obtained above was added Powder dissolved and the solution was left to stand overnight at room temperature, whereby crystals were deposited. The crystals were separated and extracted from ethyl acetate-benzene recrystallized. There was 1.2 g of white crystalline product with a melting point obtained at 13.5-137 ° C.

Nuclear Magnetic Resonance Spectrum: (CDCl3) @: 4.50 ppm (m, 1H, CH belonging to the hydroxyl group), 3.46, 3.87 ppm (AB band, q, 2H, CH2 belonging to the N).

This product is called 4-benzyloxy-3-formylamino-a- [N-benzyl-N- (1-methyl-2-p-hydroxyphenylethyl) aminomethyl called benzyl alcohol.

Furthermore, the solvent was removed from the remaining mother liquor distilled off from the above step and the residue obtained became a Subjected to silica gel column chromatography. Then by using 10: 2 Benzene-ethyl acetate mixture obtained 0.8 g of white crystalline powder.

Nuclear Magnetic Resonance Spectrum: (CDCl3) #: 4.34 ppm (m, 1H, CH belonging to the hydroxyl group), 3.76 ppm (S, 2H, CH2 belonging to the N).

This product is called 4-benzyloxy-3-formylamino-a-CN-benzyl-N- (1-methyl-2-p-hydroxyphenyl) aminomethylbenzyl alcohol B 1 denotes.

Reference Example 6 a) In 270 ml of chloroform, 27 g of 4-benzyloxy-3-nitroacetophenone was added dissolved. To the solution was added dropwise graded a mixture, consisting of 16 g of bromine and 10 ml of chloroform added with stirring. The mixture was stirred for a further 30 minutes. The reaction mixture was reduced under reduced pressure Pressure restricted. The obtained crystalline residue became with a mixture.

consisting of 50 ml of benzene and 50 ml of n-hexane washed and dried. There were 31 g of 4-benzyloxy-3-nitro-abromacetophenone with a melting point of 135 - Received 1360C.

b) A mixture consisting of 30.5 g of 4-benzyloxy-3-nitroa-bromoacetophenone and 28.5 g of N-benzyl-N-tert -butylamine. together with 300 ml of methyl ethyl ketone Refluxed for 3 hours by heating. After cooling, they were formed Precipitates filtered off. The filtrate was concentrated under reduced pressure and the crystals formed were separated. Then these were made from ethanol recrystallized. 30 g of 4-benzyloxy-3-nitro-a- (N-benzyl-N-tert-butylamino) acetophenone were obtained obtained with a melting point of 99-100 ° C.

c) In a mixture consisting of 200 ml of ethanol and 150 ml of tetrahydrofuran 30 g of 4-benzyloxy-3-nitroa- (N-benzyl-N-tert-butylamino) acetophenone was dissolved.

After adding 3 g of sodium borohydride to the solution, the Mixture stirred for 3 hours at room temperature. The reaction product was taking concentrated under reduced pressure, and water was added to the residue. Then became from this approach the product is extracted with benzene. The extract was made with water washed and dried over anhydrous magnesium sulfate. Then this one was under concentrated under reduced pressure. 30 g of oily 4-benzyloxy-3-nitro-a- (N-benzyl-N-tert -butylaminomethyl) benzyl alcohol.

d) 30 g of 4-benzyloxy-3-nitro-a- (N-benzyl-N-tert -butylaminomethyl) benzyl alcohol. Then, 12 g of iron powder was added to the solution added. The mixture was refluxed with heating for 25 minutes. The reaction mixture was filtered while hot and the filtrate was reduced under reduced pressure Pressure restricted. Then 50 ml of 10% aqueous sodium carbonate solution was added to the residue added and the product extracted with benzene. The extract was made with water washed and dried over anhydrous magnesium sulfate. Then this one was under reduced pressure and a crystalline residue was obtained. By Recrystallization of the product from a mixture of 40 ml of benzene and 60 ml of n-hexane 23 g of 3-amino-4-benzyloxy-a- (N-benzyl-N-tert -butylaminomethyl) benzyl alcohol was obtained with a melting point of 68-69 ° C.

e) In 50 ml of 5: 3 acetic anhydride-formic acid mixture, 20 g of 3-amino-4-benzyloxy-a- (N-benzyl-N-tert -butylaminomethyl) benzyl alcohol and left to stand overnight. Then became the solution concentrated under reduced pressure. The residue obtained was in Dissolved 120 ml of methanol. Then 5 ml of water and 7.5 g of sodium carbonate were added to the solution added.

The mixture was stirred for one hour at room temperature. then the solvent was distilled off from the reaction mixture under reduced pressure and the residue obtained was extracted with benzene. The extract was made with water washed and dried over anhydrous magnesium sulfate. Then this one was under concentrated under reduced pressure. It was 20.5 g of oily 4-benzyloxy-3-formylamino-a- (N-benzyl-N-tert -butylaminomethyl) benzyl alcohol.

f) In 30 ml of anhydrous tetrahydrofuran, 5 g of 4-benzyloxy-3-formylamino-a- (N-benzyl-N-tert -butylaminomethyl) benzyl alcohol. The resulting solution was stirred with stirring dropwise to a solution of 20 ml of tetrahydrofuran and 20 ml of ether, which as Additive containing 3 g of lithium aluminum hydride was added. Thereafter, the obtained The mixture was kept under reflux for one hour by heating. Then became drop by drop Gradually added 20 ml of water to the reaction mixture and then added Stirred for 1 hour. The reaction mixture was filtered and the filtrate became concentrated under reduced pressure.

The residue was extracted with benzene. The extract was made with Washed with water, dried and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (with 70 ml of silica gel as a filling). The third through eighth fractions (each fraction was 40 ml) were collected using chloroform as the eluant. Then these were under diminished Pressure restricted. 2.8 g of pale yellow oily 4-benzyloxy-3-methylamino-a- (N-benzyl-N-tert -butylaminomethyl) benzyl alcohol was obtained.

g) In 5 ml of 5: 3 acetic anhydride-formic acid mixture, 1.5 g of 4-benzyloxy-3-methylamino-α- (N-benzyl-N-tert -butylaminomethyl) benzyl alcohol and the solution was left to stand overnight calmly. The mixture was then concentrated under reduced pressure and the formed The residue was dissolved in 50 ml of methanol.

After adding 3 ml of ice water and 2 g of sodium carbonate was the resulting mixture was stirred for one hour. The reaction product was taking concentrated under reduced pressure and the residue obtained was extracted with benzene. After washing the extract with Water and drying the extract over anhydrous magnesium sulfate, the solvent was reduced under reduced pressure distilled off. 1.5 g of brownish oily 4-benzyloxy-3- (N-methyl-N-formylamino) -a- (N-benzyl - N-tert -butylaminomethyl) benzyl alcohol.

Reference Example 7 a) In 100 ml of chloroform, 16.5 g of p-nitroacetophenone was added dissolved. Then 16 g of bromine was added dropwise to the solution at room temperature, and the mixture was stirred for 30 minutes. The solvent was reduced under Distilled pressure from the mixture.

A yellow crystalline residue was obtained.

This was recrystallized from benzene-n-hexane. It became 18.8 g 4-nitro-a-bromoacetophenone with a melting point of 100-1010C was obtained. the The yield was 77%.

Elemental analysis for C8H6NO3Br: C (%) H (%) N (%) Br (%) Calculated: 39v37 2.48 5.74 32.74 Found: 39.22 2.30 5.41 32.33 b) In 50 ml of anhydrous acetonitrile 10 g of a-bromo-4-nitroacetophenone was dissolved. 13.7 g of N-benzyl-N-tert were added to the solution -butylamine added at normal temperature. The mixture was stirred for 2 hours. After the solvent has been distilled off from the mixture under reduced pressure 100 ml of benzene was added to the residue. Then it became N-Benzyl-N-tert -butylamine hydrobromide filtered off, and benzene was removed from the filtrate under reduced pressure, thereby obtaining a red-black liquid became. To the liquid 10 ml of ethanol was added and the crystals thereby formed were filtered off and then these were recrystallized from ethanol. It became 3.5 g of a yellow needle-like shape crystalline 4-nitro-a- (N-benzyl-N-tert-butylamino) acetophenone with a melting point obtained at 88-90 ° C.

Elemental analysis for C1gH22N203: C {%) H (%) N (%) Calculated: 69.92 6.79 8.58 Found: 69.73 6.81 8.71 c) In 200 ml of ethanol, 5 g of 4-nitro-a- (N-benzyl-N-tert -butylamino) acetopherone dispersed. 1 g of sodium borohydride was added to the dispersion given and the mixture stirred at room temperature, whereby the acetophenone compound gradually went into solution. After the compound has completely gone into solution the solution was stirred for a further 30 minutes. Then the solvent became distilled off from the batch under reduced pressure, whereby yellow crystals are obtained became. By recrystallizing them from ethanol, 4 g of yellow needle-shaped crystalline 4-nitro-a- (N-benzyl-N-tert -butylaminomethyl) -benzyl alcohol with the Melting point obtained at 111-112 ° C.

Elemental analysis for C1gH24N203: C (%) H (%) N (%) Calculated: 69.49 7.37 8.53 Found: 69.19 7.49 8.72 d) In 100 ml of anhydrous methanol was added 4 g 4-Nitro-a- (N-benzyl-N-tert -butylaminomethyl) benzyl alcohol dissolved. to the solution was added 1 g of Raney nickel and the catalytic reduction was at Normal temperature and normal pressure carried out until 1080 ml of hydrogen was absorbed became. After filtering off the catalyst, the solvent was reduced under reduced pressure Pressure was distilled off and an oily material was obtained. By cleaning the oily material in a 100 ml silica gel column using benzene as Developing solvent, a yellow liquid was obtained. When left standing Crystals were formed from the liquid at room temperature.

These were separated by filtration and they were made from ethanol-n-hexane recrystallized. 2.13 g of yellow, needle-shaped, crystalline 4-amino-a- (N-benzyl-N-tert -Butylaminomethyl) benzyl alcohol with the melting point at 88-900C.

Elemental analysis for C19H26N20: C (%) H (%) N (%) Calculated: 76.47 8.78 9.39 Found: 76.59 9.11 9.53 e) In 10.6 ml 5: 3 acetic anhydride-formic acid mixture 2.13 g of 4-amino-a- (N-benzyl-N-tert -butylaminomethyl) benzyl alcohol was dissolved. The solution was stirred overnight at room temperature. Then became excess Acetic anhydride and excess formic acid are distilled off under reduced pressure. An oily material was obtained. The product was dissolved in 30 ml of methanol and to the solution were added 5 ml of water and an excess amount of sodium carbonate was added and the resulting mixture was stirred for one hour at room temperature. The solvent was then removed from the reaction mixture under reduced pressure distilled off. The obtained oily matter was dissolved in 50 ml of benzene and the solution became washed with water until the washing solution reacted neutrally. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. There was 2 g of caramel-like 4-formylamino-a- (N-benzyl-N-tert-butylaminomethyl) benzyl alcohol obtain.

The proposed structure of this compound was due to the nuclear magnetic Resonance spectrum and infrared absorption spectrum fully confirmed.

Reference Example 8 a) In 200 ml of methanol, 16.0 g of 4-benzyloxy-3-formylalino-a-IN-benzyl-N- (1-methyl-2-p-hydroxyphenylethyl) aminomethyl] benzyl alcohol was added [A] (prepared according to Reference Example 5) dissolved. Then the solution became 30 ml of 4.8 normal hydrochloric acid added.

The mixture was heated under for an hour and 30 minutes Held at reflux. After the reaction had ended, the reaction product was cooled, and 10 g of potassium hydroxide and 50 ml of water were added. The resulting mixture was stirred for one hour. The solvent was taking from the reaction product distilled off under reduced pressure. The residue obtained was extracted with benzene. The extract was washed with water and dried over anhydrous magnesium sulfate. Then it was concentrated under reduced pressure. It became 14.5 g more crystalline powdery -amino-4-benzyloxy-a-rN-benzyl-N - (- methyl-2-p-hydroxyphenylSthyl) aminomethyl | benzylal alcohol [A] obtained.

b) In 20 ml of acetic anhydride, 4.0 g of 3-amino-4-benzyloxya - WN-benzyl-N- (1-methyl-2-p-hydroxyphenylSthyl) aminomethyl benzyl alcohol FAM (manufactured according to the above regulation). The mixture was heated to 65-80 ° C Heated for hour and 30 minutes. The reaction mixture was under reduced pressure constricted. The residue was in a mixture of 15 ml of methanol and 20 g of potassium hydroxide dissolved. The solution was stirred for one hour at room temperature.

Then methanol was distilled off under reduced pressure. The received Water was added to the residue and the mixture was then extracted with benzene. The extract was washed with water and dried over anhydrous magnesium sulfate. Thereafter the solvent was distilled off. 3.8 g of crystalline, powdery 4-benzyloxy-3-acetylamino-a-0N-benzyl-N- (1-methyl-2-p-hydroxyphenylethyl) aminomethyl] benzyl alcohol were obtained [A] obtained. By recrystallization of 2.0 g of the product thus obtained 20 ml of ethanol became 1.6 g of crystalline pure product with a melting point of 141 - 143 0C received.

Elemental analysis for C32H36N204: C (%) H (%) N (%) Calculated: 75.55 6.92 5.34 Found: 75.62 7.03 5.21 Reference Example 9 In 20 ml of anhydrous pyridine was 2 g of 3-amino-4-benzyloxy-a- EN-benzyl-N- (1-methyl-2-p-hydroxyphenylethyl) aminomethyl] benzyl alcohol (prepared according to Reference Example 8 above a) dissolved. The solution was cooled to temperatures from -200C to -30 ° C. A solution of 2.28 g of benzyloxyacetyl chloride in 5 ml of toluene was added dropwise added dropwise to the solution, which was kept cooled in this way, with stirring, and the temperature of the mixture was slowly brought to room temperature. To Stirring the mixture overnight, the solvent was reduced under reduced pressure Distilled pressure. The residue obtained was mixed with 50 ml of benzene and 50 ml of water mixed. The benzene solution was washed three times with water and benzene became distilled from the reaction mixture under reduced pressure, leaving a red oily material was obtained. The product was dissolved in 50 ml of ethanol. then 5 ml of water and 10 ml of 4 normal sodium hydroxide solution were added to the solution and the resulting mixture was stirred for two hours. Then the pH of the The reaction mixture was adjusted to 3 by adding 1 normal hydrochloric acid and an excess amount of sodium carbonate was added. Then came ethanol distilled off under reduced pressure and the residue was extracted with benzene. The extract was washed three times with water and over anhydrous sodium sulfate dried and concentrated in vacuo to give a yellow, oily material was obtained. The product was then subjected to silica gel column chromatography (65 ml) subject. The product was made using a 9: 1 benzene-acetone mixture eluted, and the eluate was concentrated under reduced pressure. It was 3-Benzyloxyacetylamino-4-benzyloxy-a- CN-benzyl-N- (1-methyl-2-p-hydroxyphenylethyl) aminomethylbenzyl alcohol was obtained.

Nuclear Magnetic Resonance Spectrum (CDCl3): 9 1.00 ppm. (d, 3H, CH-CH3), 4.08 ppm. (4th The invention will now be practically illustrated by the following examples.

Example 1 In 20 ml of ethanol there was 1.4 g of 4-benzyloxy-3-formylaminoa - (N-benzyl-N-isopropylaminomethyl) benzyl alcohol dissolved. 0.2 g of oily palladium carbon was added to the solution and the catalytic Reduction was carried out at normal temperature and normal pressure. After consumption the reaction was terminated by 165 ml of hydrogen. The catalyst was filtered off and the solvent was distilled off under reduced pressure.

The residue formed was in a small amount of small amount of ethanol dissolved. Then a lot of ether was added to the solution and the solution was left to stand, whereby crystals were separated out. By severing the Crystals by filtration became 0.7 g of 3-formylamino-4-hydroxy-α- (isopropylaminomethyl) benzyl alcohol obtain.

When 120 mg of the product obtained above to 2 ml of ethanol solution with 30 mg of funaric acid was added and the mixture was allowed to stand deposited white crystals. The crystals were separated by filtration. It became 3-formylamino-4-hydroxy-a- (isopropylaminomethyl) benzyl alcohol 1/2 fumarate with a melting point of 179-1900C (with decomposition).

Elemental analysis for C14H20N205: C (%) H ($) N (%) Calculated: 56.75 6.80 9.45 Found: 56.71 6.76-9.70 Example 2 In 100 ml of methanol was 2.3 g 4-Benzyloxy-3-benzyloxyacetylamino-a (N-benzyl-N-isopropylaminomethyl) benzyl alcohol dissolved. To the solution was added 4.3 ml of normal hydrochloric acid in ethanol given dissolved, then 0.3 g of 10% palladium carbon was added. The catalytic reduction was carried out at normal pressure and at normal temperature. When 300ml of hydrogen were absorbed, the reaction was terminated. The catalyst was then filtered off and then the solvent was distilled off under reduced pressure. As a residue white crystals were obtained. By recrystallizing it from methanol-n-hexane was 600 mg of 4-hydroxy-3-hydroxyacetylamino-a- (isopropylaminomethyl) benzyl alcohol hydrochloride obtained with a melting point of 188-190 0C.

Elemental analysis for C13H 20N204.HCl: C (%) H (%) N (%) Calculated: 51.23 6.95 9.19 Found: 50.79 7.03 9.03 Example 3 In 20 ml of ethanol was added 1 g of 3-acetylamino-4-benzyloxya- (N-benzyl-N-isopropylaminomethyl) benzyl alcohol dissolved. 0.2 g of 10% palladium carbon was added to the solution. The catalytic Reduction was carried out at normal pressure and temperature. After consumption the reaction was terminated by 115 ml of separated hydrogen. Then the The catalyst was filtered off and the reaction product was taken under reduced pressure concentrated to give an oily material. The oily material was dissolved in ethyl acetate and then a 3 normal hydrochloric acid-ethanol solution was added to the solution, whereby crystals were deposited. The solvent was removed by decantation and the crystals were washed with ethyl acetate and dried. There was 0.5 g of crystalline powdery 3-acetylamino-4-hydroxy-α- (isopropylaminomethyl) benzyl alcohol hydrochloride obtain.

Elemental analysis for C13H20N203.HCl C (%) H (%) Calculated: 54.07 7.33 9.70 Found: 53.81 7.28 9.63 Example 4 1.4 g of 4-benzyloxy-3-ethoxycarbonylamino-a- (N-benzyl-N-isopropylaminomethyl) benzyl alcohol were added to 20 ml of ethyl acetate dissolved. 0.2 g of 10% palladium carbon was added to the solution. Then the catalytic reduction carried out at normal temperature and normal pressure. After this Consumption of 145 ml of absorbed hydrogen, the reaction was terminated. then the catalyst was filtered off and the reaction product was reduced under reduced pressure Pressure was concentrated to give an oily material. The oily material was dissolved in 2 ml of ethanol and 30 ml of ether. Then 3 normal hydrogen chloride-ethanol solution added to the solution, whereby crystals precipitated. The crystals were through Filtration separated and recrystallized from 1: 1 ethanol-ether. It became 0.6 g of 3-ethoxycarbonylamino-14-hydroxy-a- (isopropylaminomethyl) benzyl alcohol hydrochloride with a melting point of 1780.

Elemental analysis for C14H22N20 zCl: C (%) H (%) N (%) Calculated: 52.75 7.27 8.79 Found: 52.75 7.32 8.81 Example 5 2.5 g of 4-benzyloxy-3-formylaminoa- (N-benzyl-N-tert -butylaminomethyl) benzyl alcohol. 0.2 g of 10% palladium carbon was added to the solution given and the catalytic reduction was carried out at normal temperature and Normal pressure carried out. After 280 ml of hydrogen had been absorbed, the reaction was continued completed. After filtering off the catalyst, the reaction product was reduced under reduced pressure Pressure restricted. 1.3 g of crystalline, powdery 3-formylamino-4-hydroxy-a- (tert -butylaminomethyl) benzyl alcohol. 1.2 g of the product obtained became too 15 ml of methanol, which contained 0.3 g of fumaric acid dissolved therein, was added, and the mixture was left to stand at -40C overnight, giving rise to white crystals say goodbye. By separating the crystals by filtration, 1.14 g of 3-formylamino-4-hydroxy-a- (tert -butylaminomethyl) benzyl alcohol 1/2-fumarate with a melting point of 195-196 0C obtain.

Elemental analysis for C15H22N205: C (%) H (%) N (%) Calculated: 58.05 7.15 9.03 Found: 58.03 7.21 8.94 Example 6 1 g of 3-acetylamino-4-benzyloxya- (N-benzyl-N-isopropylamino) acetophenone was added to 15 ml of ethanol dissolved. 0.2 g of 10% palladium carbon was added to the solution.

Then the catalytic reduction was carried out at normal temperature and at Normal pressure carried out. After absorbing 168 ml of hydrogen, the reaction was started completed. The catalyst was filtered off and the reaction product was taken concentrated under reduced pressure. There was 0.45 g of crude 3-acetylamino-4-hydroxy-a- (isopropylaminomethyl) benzyl alcohol obtain. If 250 mg of the product obtained is added to 5 ml of ethanol, which is 60 mg of fumaric acid in dissolved form, crystals were formed.

After separation of the crystals by filtration, 150 mg of 3-acetylamino-4-hydroxy-a- (isopropylaminomethyl) -after standing benzyl alcohol 1/2 fumarate obtained with the melting point at 189-192 ° C.

Elemental analysis for C15H 22N205: C (%) H (%) N (%) Calculated: 58.05 7.15 9.03 Found; 57.72 7.26 8.93 Example 7 0.7 g of 4-benzyloxy-3-formylaminoa- (N-isopropyl-N-benzylamino) acetophenone was added to 10 ml of methanol dissolved. Then 0.2 g of 10% palladium carbon was added to the solution and the catalytic reduction was carried out at normal temperature and normal pressure. As soon 120 ml of hydrogen was absorbed, the reaction was terminated. The catalyst was filtered off. The reaction product was concentrated. 0.3 g of crude 3-formylamino-4-hydroxya- (N-isopropylaminomethyl) benzyl alcohol was obtained obtain. 240 mg of the product was dissolved in 3 ml of ethanol and then 60 mg of fumaric acid was added to the solution. The mixture was allowed to stand at room temperature left, causing crystals to deposit. These were filtered off. 75 mg of 3-formylamino-4-hydroxy-a- (isopropylaminomethyl) benzyl alcohol-1 / 2 fumarate with the melting point at 179-1810C.

The product had the same infrared absorption spectrum as that product obtained according to example 1.

Example 8 1 g of 4-benzyloxy-3-formylamino-a- (N-benzyl-N-tert -butylamino) acetophenone dissolved. 0.2 g of 10% palladium carbon was added to the solution added and the catalytic reduction was carried out at normal temperature and normal pressure carried out. As soon as 165 ml of hydrogen absorbed the implementation ended.

After filtering off the catalyst, the reaction product was concentrated. There was 0.5 g of crude 3-formylamino-4-hydroxy-a- (tert -butylaminomethyl) benzyl alcohol obtain. 250 mg of the product was dissolved in 5 ml of ethanol containing 60 mg of fumaric acid and then the mixture was left to stand at room temperature, whereby crystals were deposited. These were separated off by filtration. There was 100 mg of 3-formylamino-4-hydroxy-a- (tert -butylaminomethyl) benzyl alcohol 1/2 fumarate obtained with the melting point at 195-1960C.

The product had the same infrared absorption spectrum as that according to example 5 produced compound.

Example 9 In 10 ml of ethanol was added 0.45 g of 3-formylamino-4-hydroxya- (N-benzyl-N-isopropylaminomethyl) benzyl alcohol dissolved. Then 0.1 g of 10% palladium carbon was added to the solution. The catalytic Reduction was carried out at normal temperature and normal pressure. As soon as 36 ml of hydrogen absorbed, the reaction was terminated.

After filtering off the catalyst, the reaction product was taken under concentrated under reduced pressure. It became 0.32 g of white crystalline powdery 3-formylamino-4-hydroxy-α- (isopropylaminomethyl) benzyl alcohol obtain.

240 mg of the product were dissolved in 3 ml of ethanol and 60 mg of fumaric acid was added. The mixture was allowed to stand at room temperature for crystals to separate calmly. 250 mg of white crystalline 3-formylamino-4-hydroxy-a- (isopropylaminomethyl ) obtained benzyl alcohol 1/2 fumarate.

The product had the same infrared absorption spectrum as that which was obtained for the compound according to Example 1.

Example 10 0.9 g of 3-formylaniino-4-hydroxya- (N-benzyl-N-tert-butylaminomethyl) benzyl alcohol was added to 10 ml of ethanol dissolved. 0.1 g of 10% palladium carbon was added to the solution. Then the catalytic reduction carried out at normal temperature and normal pressure. After this 65 ml of hydrogen was absorbed, the reaction was terminated. The catalyst was filtered off and the reaction product was concentrated under reduced pressure.

0.65 g of white crystalline powdery 3-formylamino-4-hydroxy-a- (tert -butylaminomethyl) benzyl alcohol. 500 mg of the product was dissolved in 5 ml of ethanol dissolved, and then 120 mg of fumaric acid was added to the solution. The mixture was left to stand at room temperature until crystals had separated. These were filtered off. 520 mg of 3-formylamino-4-hydroxy-a- (tert-butylaminomethyl) benzyl alcohol 1/2 fumarate were obtained obtain.

The product showed the same infrared absorption spectrum as that Product manufactured according to Example 5.

Example 11 In 20 ml of ethanol, 1.1 g of 4-benzyloxy-3-formylaminou- CN-b eniyl-N- (l-methyl-2-p-hydroxyphenylethyl) aminomethylbenzyl alcohol [A] (prepared according to Reference Example 5) suspended. Then became the suspension 0.1 g of 10% palladium carbon was added and the catalytic reduction was carried out at normal temperature and normal pressure were carried out until 105 ml of hydrogen had been absorbed.

The catalyst was filtered off and the filtrate was reduced under reduced pressure Pressure restricted. 0.7 g of white, crystalline, powdery 3-formylamino-4-hydroxy-α- [N- (1-methyl-2-p-hydroxyphenylethyl) aminomethyl benzyl alcohol 1 A obtained.

0.34 g of the product prepared above was dissolved in 95% ethanol dissolved along with 0.06 g of fumaric acid and the solution turned to form crystals ditched.

The crystals were separated. 0.33 g of 3-formylamino-4-hydroxy-α- [N- (1-methyl-2-p-hydroxyphenylethyl) aminomethyl was obtained benzyl alcohol [A] -1 / 2 fumarate with the melting point at 151.8-1530C.

Elemental analysis for C20H24N206: C (%) H (%) N (%) Calculated: 61.85 6.23 7.21 Found: 61.52 6.31 7.31 Example 12 1.0 g of 4-benzyloxy-3-formylamino-α- [N-benzyl-N- (1-methyl- 2-p-hydroxyphenylethyl) aminomethylbenzyl alcohol Vol (prepared according to Reference Example 5) dissolved. Then the solution became 0.1 g 10% palladium carbon added. The catalytic reduction was carried out at normal temperature and normal pressure were carried out until 95 ml of hydrogen had been absorbed.

Then the catalyst was filtered off and the reaction product became concentrated under reduced pressure. It became 0.65 g slightly brownish powdery 3-formylamino-4-hydroxy-a N- (l-methyl-2-p-hydroxyphenylethyl) aminomethyl] benzyl alcohol [B] obtained.

0.34 g of the product obtained above was dissolved in 95% ethanol dissolved together with 0.06 g of fumaric acid.

Then the solution was left to stand for crystallization. the crystals formed were separated.

0.3 g of 3-formylamino-4-hydroxy-a- [N- (1-methyl-2-p-hydroxyphenylethyl) aminomethyl] benzyl alcohol was obtained [B] 1/2 fumarate with the melting point at 15.1-1550C.

Elemental analysis for C20H24N2Q6: C (%) H (X) N (%) Calculated: 61.85 6.23 7.21 Found: 61.73 6.27 7.19 Example 13 In 20 ml of ethanol, 1.5 g of 4-benzyloxy-3-formylamino-α- [N-benzyl-N- (1-methyl- 3-cyclohexylpropyl) aminomethyl] dissolved benzyl alcohol. 0.12 g of 10% strength palladium carbon was added to the solution and the catalytic reduction was carried out at normal temperature and normal pressure until 140 ml of hydrogen was absorbed. After filtering off the catalyst the reaction product was concentrated under reduced pressure. It became 0.9 g whiter crystalline powdery 3-formylamino-4-hydroxy-a-iN- (1-methyl-3-cyclohexylpropyl) aminomethylibenzyl alcohol obtain.

470 mg of the product obtained above were in 7 ml of 0.2 normal Acetic acid, dissolved in ethanol, dissolved.

The solution was concentrated to 2-3 ml. Aether was added and the mixture was allowed to stand to form crystals. The formed white crystals were filtered off. There was 0.5 g of 3-formylamino-4-hydroxy-α- [N- (1 methyl-3-cyclohexylpropyl) aminomethylbenzyl alcohol acetate obtained with the melting point at 138-140 ° C.

Elemental analysis for C21H34N205: C (%) H (%) N (%) Calculated: 63.94 8.69 7.10 Found: 64.31 9.92 7.46 Example 14 In 30 ml of ethanol, 2.7 g of 4-benzyloxy-3-methylaminoa- (N-benzyl-N-tert -butylaminomethyl) benzyl alcohol (manufactured according to reference example 6 f) dissolved. 0.3 g of 10% palladium carbon was added to the solution and the catalytic reduction was carried out at normal pressure and normal temperature until 310 ml of hydrogen had been absorbed. After filtering off the catalyst the reaction product was concentrated under reduced pressure. It became 1.3 g more powdery 4-Hydroxy-3-methylamino-a- (tert -butylaminomethyl) benzyl alcohol was obtained. If ethanol was added to the product, white crystals were formed. After recrystallization from ethanol the product had a melting point of 173 ° C.

Elemental analysis for C13H22Nz02: C (%) H (%) N (%) Calculated: 65.52 9.30 11.75 Found: 65.43 9.57 11.52 Example 15 In 20 ml of ethanol was added 1.4 g of 4-benzyloxy-3- (N-methyl-N-formylamino) -a- (N-benzyl -N-tert -butylaminomethyl) benzyl alcohol (prepared according to reference example 6 g) dissolved. 0.1 g of 10% palladium carbon was added to the solution and the catalytic reduction was carried out was carried out until 150 ml of hydrogen had been absorbed. The catalyst was filtered off and the reaction product was concentrated under reduced pressure. 0.8 g of white crystalline powdery 4-hydroxy-3- <N-methyl-N-formylamino) -a-tert -butylaminomethylbenzyl alcohol obtained. 360 mg of the product were in 6 ml of ethanol dissolved along with 85 mg of fumaric acid and the solution became crystal deposit ditched.

The deposited white crystals were separated by filtration. 390 mg of 4-hydroxy-3- (N-methyl-N-formylamino) -a-tert-butylaminomethylbenzyl alcohol 1/2 fumarate were obtained obtained with the melting point at 1880C.

Elemental analysis for C16H24N2O5: C (%) H (%) N (%) Calculated: 59.24 7.46 8.64 Found: 59.16 7.47 8.34 Example 16 In 100 ml of anhydrous methanol was 1.8 g of 4-formylamino-α- (N-benzyl-N-tert -butylaminomethyl) benzyl alcohol dissolved. Then, 100 mg of 10% palladium carbon was added to the solution at normal temperature and carried out at normal pressure until the absorption of hydrogen has ceased completely was. After filtering off the catalyst, the solvent was reduced under Pressure distilled off from the reaction product. It became 1.46 g of a caramel-like material obtain. The product was dissolved in 20 ml of ethanol and then there was 358 mg of fumaric acid added. The mixture was left to stand at 400 degrees, producing needle-like crystals were deposited and then separated by filtration. It became 950 mg 4-Formylamino-α- (N-tert -butylaminomethyl) benzyl alcohol 1/2 fumarate with a Melting point obtained at 125 - 1270C. (White crystals) Elemental analysis for C15Hp2N204: C (%) H (%) N (%) Calculated: 61> 21 7> 53 9.52 Found: 6O.93 7.70 9.23 Example 17 1.1 g of 3-formylamino-a- (N-benzyl-N-tert-butylaminomethyl) benzyl alcohol was added to 15 ml of ethanol dissolved. 0.1 g of 10% palladium carbon was added to the solution and the catalytic Reduction was carried out at normal temperature and normal pressure up to 76 ml of hydrogen had been absorbed. After filtering off the catalyst became the reaction product was concentrated under reduced pressure. It became 750 mg white crystalline powder obtained.

Thereafter, 470 mg of the product prepared above and 116 mg of fumaric acid dissolved in 3 ml of ethanol. Then the solution was made with ether up to slight turbidity was added and the mixture was left to stand for crystals to separate out. The white crystals formed were separated by filtration. It became 530 mg of 3-formylamino-a- (N-tert -butylaminomethyl) benzyl alcohol 1/2 fumarate with the melting point obtained at 1820C.

Elemental analysis for C15H22N204: C (%) H (%) N (%) Calculated: 61.21 7.53 9.52 found; 61.16 7.76 9.44 Reference Example 10 In 30 ml of anhydrous pyridine 4 g of 3-amino-4-benzyloxy - «- 9-benzyl-N- (1-methyl-2-p-hydroxyphenyl-thyl) aminomethyl benzyl alcohol hydrochloride and 3.5 g of N-acetyl-R-alanine dissolved. Then became to 5.5 g of dicyclohexylcarbodiimide were added to the solution while cooling with ice. The mixture was stirred overnight. After filtering off the deposited precipitates the reaction mixture was concentrated under reduced pressure and the residue was dissolved in 30 ml of methanol. Then 10 ml of normal sodium hydroxide solution was added to the solution was added and the mixture was stirred for 3 hours. Then 1 became normal Hydrochloric acid was added to adjust to pH 3 and then excess was added Sodium carbonate added. The mixture obtained was stirred for 30 minutes. The reaction product was concentrated under reduced pressure and the residue was then extracted with 50 ml of chloroform. The extract was used three times washed with water and dried over anhydrous magnesium sulfate and then was he concentrated under reduced pressure. 4 g of yellow oily material was obtained. The obtained material was subjected to silica gel column chromatography (75 ml) and a subjected to further silica gel column chromatography (35 ml). It became 800 mg of pure caramel-like 3- (N-acetyl-ß-alanyl) amino-4-benzyloxy-a- LN-benzyl-N- (1-methyl- 2-p-hydroxyphenylethyl) aminomethylbenzyl alcohol is obtained. In the above Chromatography purification treatments were 4: 2: 1 ethyl acetate-benzene-methanol as Developing solvent uses elemental analysis for C36H41N305: C (%) H (%) N (%) Calculated; 72.58 6.94 7.05 Found: 72.44 6.98 6.86 Reference Example 11 a) a Mixture consisting of 4.1 g of 4-benzyloxy-3-nitro - «- bromo-acetophenone, 6.6 g of N-benzyl-N- ( 1-methyl-2-pacetylaminophenylethyl) amine and 41 ml of methyl ethyl ketone were heated to 65-800C heated for an hour. After cooling the reaction mixture, the formed Crystals were filtered off and the filtrate was concentrated under reduced pressure. The residue thus formed was dissolved in 40 ml of ethanol at temperatures below 50.degree and the solution was allowed to stand at room temperature to crystallize out.

The crystals were separated by filtration. It was 3.7 g 4-Benzyloxy-3-nitro-a-0N-benzyl-N- (1-methyl-2-p-acetylaminophenylethyl) amino3acetophenone obtain.

b) 2.7 g of 4-benzyloxy-3-nitro-α- [N-benzyl-N- (1-methyl-2-p-acetylaminophenylethyl) amino] acetophenone were added to 30 ml of methanol suspended. Then, 0.6 g of sodium borohydride was added to the suspension while cooling with ice added and the mixture was stirred for 1 hour, then water was added to the Added to the reaction mixture, and methanol was distilled off therefrom under reduced pressure and the product was extracted with benzene.

The extract was washed with water and over anhydrous magnesium sulfate dried and then concentrated under reduced pressure. It became 2.6 g more yellowish powdery 4-benzyloxy-3-nitro-α- [N-benzyl-N- (1-methyl-2-p-acetylaminophenylethyl) aminomethylj benzyl alcohol.

c) 1.3 g of 4-benzyloxy-3-nitro-α- | Ñ-benzyl-N- (l-methyl-2-p-acetylaminophenylethyl) aminamethylbenzol alcohol was added to 20 ml of methanol dissolved. Then 0.7 g of iron powder, 0.6 ml of 4.8 normal hydrochloric acid were added to the solution and 3 ml of water were added and the mixture was heated by heating for 2 hours and 30 minutes Refluxed for minutes. After filtering off the insoluble parts of the reaction mixture was added to the mixture, 0.8 g of sodium carbonate and The batch was carried out for 2 hours to the reaction mixture obtained water was added, methanol was distilled off under reduced pressure and then extracted with benzene. The extract was washed with water, over dried anhydrous magnesium sulfate and concentrated under reduced pressure. 1.1 g of crystalline, powdery 3-amino-4-benzyloxy-α- [N-benzyl-N- (1-methyl-2-p-acetylaminophenylethyl) aminomethylj benzyl alcohol.

d) In 6 ml of 5: 3 acetic anhydride-formic acid mixture became 1.0 g of 3-amino-4-benzyloxy-rN-benzyl-N- (imethyl-2-p-acetylaminophenylethyl) aminomethyl Benzyl alcohol dissolved and left to stand overnight. The reaction mixture was then concentrated under reduced pressure after standing. The residue was dissolved in a mixture of 10 ml of methanol and 2 ml of water and added to the solution 0.5 g of potassium hydroxide was added. The mixture was left for one hour at room temperature stirred. Then methanol was removed from the reaction mixture under reduced pressure distilled off, the residue was mixed with water and then it was mixed with benzene extracted. Thereafter, the extract was washed with water and dried over anhydrous Dried magnesium sulfate. The solvent was distilled off therefrom and it 0.9 g of crystalline powdery 4-benzyloxy-3-formylamino-α- [N-benzyl-N- Obtained (1-methyl-2-p-acetylaminophenylethyl) aminomethyl benzyl alcohol.

Nuclear Magnetic Resonance Spectrum (CDCl3) 6: 2.04 ppm (S, 3H, H der Methyl group from the p-acetylamino group), 8.38 ppm (S, 1H, H of the formyl group), 4.4 ppm (m, 1H, H of the methine group belonging to the hydroxyl group).

In the following Reference Examples, the same was given above Procedure repeated, but using different starting materials.

A.) Using 2.7 g of 4-benzyloxy-3-nitro-abromacetophenone and 4.8 g of N-benzyl-N- (1-methyl-2- {3,4,5-trimethoxyphenyl} ethyl) amine as starting materials 1.2 g of crystalline powdery 4-benzyloxy-3-formylamino-a-FN-benzyl-N- (1-methyl-2 - ,, 4 , 5-trimethoxyphenyiJ ethyi) aminomethylj benzyl alcohol obtain.

Nuclear Magnetic Resonance Spectrum (CDCl3): d: 3.6 ppm., 3.7 ppm. (9H, H from the methyl group of the 3,4,5-trimethoxy group), 8.36 ppm. (S, 1H5 H of the formyl group), 4.46 ppm. (m, 1H, H of the methine group belonging to the hydroxyl group).

B.) By using 10.4 g of 4-benzyloxy-3-nitro-CL-bromoacetophenone and 15.2 g of N-benzyl-N- (1-methyl-3-hydroxyphenylpropyl) amine as starting materials was 5.9 g of 4-benzyloxy-3-formylamino-α- [N-benzyl-N- (1-methyl-3-p-hydroxyphenylpropyl) aminomethyllbenzyl alcohol - obtain.

Nuclear Magnetic Resonance Spectrum (CDCl3): 6: 1.76 ppm. (m, 2H, H the methylene group in the 2-position of the 3-p-hydroxyphenylpropyl group), 8.38 (S, 1H, H of the formyl group), 4.56 ppm (m, 1H, H of the methine group belonging to the hydroxyl group).

C.) Using 6.75 g of 4-benzyloxy-3-nitro-abromacetophenone and 9.2 g of N-benzyl-N-p-tolylisopropylamine as starting materials was 3.7 g of 3-formylamino-4-benzyloxy-α- [N-benzyl-N- (1-methyl-2-p-tolylethyl) aminomethylbenzyl alcohol obtain.

Nuclear Magnetic Resonance Spectrum (CDCl3): 6: 2.30 ppm. (S, 3H, -CH3), 5.02 ppm. (S, 2H, -OCH2-).

D.) Using 7.55 g of 4-benzyloxy-3-nitro-abromacetophenone and 11.6 g of N-benzyl-N- (1-ethyl-2-pmethoxyphenylethyl) amine as starting materials 1.5 g of 3-formylamino-4-benzyloxy-α- [N-benzyl-N- (1-ethyl-2-p-methoxyphenylethyl) aminomethylJbenzyl alcohol.

Elemental analysis for C26H30N2O4: C (%) H (%) N (%) Calculated: 75.81 7.11 5.20 Found: 75.67 7.25 5.37 Reference Example 12 a) A mixture of 9.4 g 4-benzyloxy-3-nitro-a-bromoacetophenone and 13.7 g of N-benzyl-N- (1-methyl-2-pmethoxyphenylethyl) amine was heated to 70-800C for one hour together with 50 ml of methyl ethyl ketone. To cooling the solution and filtering off the precipitates formed was the The filtrate was concentrated under reduced pressure. Ethanol was added to the residue, whereby Crystals were caused to deposit. The crystals were collected by filtration separated and recrystallized from ethanol. 12.8 g of 4-benzyloxy-3-nitro-α- [N-benzyl-N- (1-methyl-2-p-methoxyphenylethyl) amino] acetophenone were obtained obtained with the melting point at 100-1020C.

b) In 200 ml of ethanol, 12.8 g of 4-benzyloxy-3-nitro-CL- N-benzyl-N- (1-methyl-2-p-methoxyphenylethyl) aminoI -acetophenone suspended. To the suspension 1.8 g of sodium borohydride was added and the mixture was stirred overnight. Then, ethanol was distilled off from the reaction product and became the residue Water added. The product was then extracted with benzene. The extract was washed with water and dried over anhydrous magnesium sulfate. The extract was concentrated under reduced pressure. 10.7 g of yellow oily 4-benzyloxy-3-nitro-α- [N-benzyl-N- (1-methyl-2-p-methoxyphenyl-ethyl) amine were obtained yl] benzyl alcohol.

c) In 70 ml of methanol, 10.7 g of 4-benzyloxy-3-nitroa- LN-benzyl-N- (1-methyl- 2-p-methoxypheny läthyl) aminomethylbenzyl alcohol dissolved. Then became to the solution 15 ml -2.2 normal hydrochloric acid solution, 10 ml water and 5.4 g iron powder added. The mixture was refluxed for one hour held. After filtering off the insoluble matter from the reaction mixture the filtrate was concentrated under reduced pressure and then 50 ml of benzene, 10 ml of water and 10 g of sodium carbonate were added and the mixture was then extracted with benzene. The extract was washed with water and dried over anhydrous magnesium sulfate. The extract was concentrated under reduced pressure. It became 8.8 g of yellow caramel-like 3-Amino-4-benzyloxy-a-N -benzyl-N- (1-methyl-2-p-methoxyphenylethyl) aminomethyl¼ obtained benzyl alcohol.

d) In 20 ml of 5: 3 acetic anhydride-formic acid mixture was 5.5 g of 3-amino-4-benzyloxy-α- [N-benzyl-N- (1-methyl-2-p-methoxyphenylethyl) aminomethyl] benzyl alcohol dissolved and then the solution was allowed to stand at room temperature overnight. The solution was concentrated under reduced pressure. The residue was with 50m1 Methanol, 3 ml of water and 3.5 g of sodium carbonate were mixed and the mixture became Stirred for 2 hours at room temperature. Then methanol became from the reaction product distilled off under reduced pressure and the residue formed was washed with benzene extracted. The extract was washed with water and over anhydrous magnesium sulfate dried and then the solvent was distilled off. It became 5.1 g more crystalline powdery 4-benzyloxy-3-formylamino-α- [N-benzyl-N- (1-methyl-2-p-methoxyphenylethyl) aminomethylbenzyl alcohol obtain. Then 4.9 g of the product was in 2Q ml of methanol dissolved and it. 1 g of fumaric acid was added to the solution. The mixture was under concentrated under reduced pressure. The residue was dissolved in 80 ml of ethyl acetate and the solution was left to stand overnight for the purpose of crystallization. The educated Crystals were filtered off and recrystallized from isopropanol. It was 3.2 g white crystalline 4-benzyloxy-3-formylamino-α- [N-benzyl-N- (1-methyl-2-p-methoxyphenylethyl) aminomethyß benzyl alcohol-1-sumarate obtained with the melting point at 173 0C.

In 30 ml of 90% methanol there was 3 g of the product prepared above suspended and then 1.5 g of sodium carbonate was added to the suspension and it was stirred for 30 minutes. The mixture was concentrated under reduced pressure. The residue was mixed with 10 ml of water and extracted with 30 ml of benzene. The extract was washed with water and was dried over anhydrous magnesium sulfate dried. Then the extract was concentrated under reduced pressure. It was 2.3 g of a white powder were obtained.

Nuclear Magnetic Resonance Spectrum (CDCl3): a: 4.52 ppm. (m, IH, CH 3.48 ppm., 3.87 ppm (AB Type Quartett, 2H, CH2 belonging to N).

This product is referred to as 4-benzyloxy-3-formylamino-α- [N-benzyl-N- (1-methyl-2-p-methoxyphenyl) aminomethyl] benzyl alcohol [A] designated.

Furthermore, the solvent was distilled off from the mother liquor, after the separation of the crystals from 4-benzyloxy-3-formylamino-α- [N-benzyl-N- (1-methyl-2-p-methoxyphenylethyl) aminomethylbenzyl alcohol-ifumarate A. was obtained in the above step. The residue was dissolved in 30 ml of methanol dissolved.

Then 3 ml of water and 1.5 g of sodium carbonate were added to the solution and the mixture was stirred for 30 minutes. Then the approach was reduced Pressure restricted. The residue was mixed with 10 ml of water and was mixed with benzene extracted. The extract was washed with water and over anhydrous magnesium sulfate dried. Then the solvent was distilled off. 2.3 g became slightly brownish powdery 4-benzyloxy-3-formylamino-α- [N-benzyl-N- (1-methyl-2-p-methoxyphenylethyl) aminomethyl] benzyl alcohol obtain.

The product was made using silica gel column chromatography of 10: 1 benzene: ethyl acetate as the eluent subjected, which under reduced Pressure was reduced. A white powder was obtained.

Nuclear Magnetic Resonance Spectrum (CDCl3): a: 4.40 ppm. (m, 1H, CH belonging to the hydroxyl group), 3.73 ppm. (S, 2H, CH2 belonging to the N).

This is referred to as 4-benzyloxy-3-formylamino-α- [N-benzyl-N- (1-methyl-2-p-methxyphenyl) aminomethybenzyl alcohol [B].

Reference example 13 a) A mixture of 2.7 g of t-benzyloxy-3-acetylamino-abromo-acetophenone und4s0g benzyl-N- (1-methyl-2-p-hydroxyphenylethyl) amine was added together with 80 ml Stirring methyl ethyl ketone at room temperature for 4 hours. After filtering off the precipitates formed, the filtrate was concentrated under reduced pressure. Of the The residue was subjected to silica gel column chromatography. The product was then separated using a 10: 2 benzene-ethyl acetate mixture as the eluant. It became 2.2 g of yellowish crystalline powdery 4-Benzyloxy-3-acetylamino-α- [N-benzyl-N- (1-methyl-2-p-hydroxyphenylethyl) amino] acetophenone obtain.

b) 0.9 g of 4-benzyloxy-3-acetylamino-α- [N-benzyl-N- (1-methyl-2-p-hydroxyphenylethyl) amino] was added to 18 ml of ethanol acetophenone dissolved. Then 0.1 g of 10% palladium carbon was added to the solution. Thereafter, the catalytic reduction was carried out at normal temperature and normal pressure carried out until 78 ml of hydrogen had been absorbed. After filtering off of the catalyst, the filtrate was concentrated under reduced pressure.

The residue obtained was subjected to silica gel column chromatography subject. The eluate was converted into ethyl acetate-benzene-methanol mixture using a 4: 2: 1 mixture 0.5 g of yellowish, crystalline, powdery 3-acetylamino-4-hydroxy-α- [N- (1-methyl-2-p-hydroxyphenylethyl) -amino-acetophenone obtain.

Nuclear Magnetic Resonance Spectrum (D6-DMSO): 6: 2.12 ppm. (S, 3H, H on the methyl group of the 3-acetylamino group), 0.98 ppm. (d, 3H, H on the 1-methyl group), 4.10 ppm. (2H, H on the methylene group between carbonyl group and amino group).

Example 17 In 12 ml of ethanol was added 1.2 g of 4-benzyloxy-3-acetylaminoa- [N-benzyl-N- (1-methyl-2-p-hydroxyphenylethyl) aminomethylbenzyl alcohol (prepared according to Reference Example 8) dissolved. Then the solution became 0.2 g 10% palladium carbon was added. After that, the catalytic reduction was at Normal temperature and normal pressure were carried out until 110 ml of hydrogen had been absorbed was. After filtering off the catalyst, the filtrate was under pre-ruined Pressure restricted. It became 0.75 g of crystalline powdery 3-acetylamino-4-hydroxy-α- [N- (1-methyl-2-p-hydroxyphenylethyl) aminomethyl] benzyl alcohol obtain.

Elemental analysis for C19H24N2O4: C (%) H (%) N (%) Calculated: 66.26 7.02 8.13 Found: 66.43 6.81 7.88 Example 18 In 50 ml of ethanol, 1.2 g of 3-benzyloxyacetylamino-4-benzyloxy-α- [N-benzyl-N- (1-methyl- 2-p-hydroxyphenylethyl) aminomethyl] benzyl alcohol dissolved. 0.5 g of oily palladium-on-carbon was added to the solution.

The catalytic reduction was carried out at normal temperature and normal pressure stirred until 137 ml of hydrogen had been absorbed. After filtering off of the catalyst, the filtrate was concentrated under reduced pressure. It was 0.8 g of white, caramel-like 3-hydroxyacetylamino-4-hydroxy-a-CNZ methyl-2-p-hydroxyphenylethyl) aminomethyl] benzyl alcohol obtain.

Nuclear Magnetic Resonance Spectrum (D6-DMSO): o: 0.90 ppm. (i.e. 3H, # CH-CH3), 3.98 ppm. (S, 2H, 4.50 ppm. (m, IH fCH-OH).

Example 19 In 30 ml of methanol became 800 mg of 3- (N-acetyl-β-alanyl) amino 4-benzyloxy-a-rN-benzyl-N- (1-methyl-2-p-hydroxyphenylethyl) aminomethyl benzyl alcohol (prepared according to Reference Example 10) dissolved. Then the solution became 50 mg 10% palladium carbon added. The catalytic reduction was carried out at normal temperature and normal pressure were carried out until 65 ml of hydrogen had been absorbed. then the catalyst was filtered off. The filtrate was under diminished Pressure restricted. 470 mg of white, caramel-like 3- (N-acetyl-β-alanyl) amino-4-hydroxy-α- | N- (1-methyl-2-p-hydroxyphenylSthyl) aminomethyl benzyl alcohol.

Nuclear Magnetic Resonance Spectrum (D6-DMSO): d: 0.90 ppmi (d, 3H, # CHCH3), 1.80 ppm. (S, 3H -COCH3), 4.45 ppm. (m, 1H #CHOH).

Example 20 0.7 g of 4-benzyloxy-3-formylamino-α- [N-benzyl-N- (1-methyl-2-p-acetylaminophenylethyl) aminomethyl alcohol was added to 7 ml of ethanol dissolved. 0.15 g of 10% palladium carbon was added to the solution. The catalytic Reduction was carried out at normal temperature and at normal pressure until 61 ml of hydrogen had been absorbed.

After filtering off the catalyst, the filtrate was reduced under reduced pressure Pressure restricted. 0.34 g of crystalline, powdery 3-formylamino-4-hydroxy-α- [N- (1-methyl-2-p-acetylaminophenylethyl) aminomethyl] benzyl alcohol was obtained obtain.

Nuclear Magnetic Resonance Spectrum (D6-DMSO): 6: 2.04 ppm. (S, 3H, H on the methyl group from the p-acetylamino group), 8.30 ppm. (S, 1H, H of the formyl group), 4.48 ppm. (m, 1H, H on the methine group belonging to the hydroxyl group).

Example 21 In 12 ml of ethanol, 1.2 g of 4-benzyloxy-3-formylaminoa-rN-benzyl-N- (1-methyl-2 -; '3,4,5-trimethoxyphenyl} ethyl) aminomethyl3benzyl alcohol (prepared according to Reference Example 11) dissolved. To the addition of 0.2 g of 10% palladium carbon to the solution became the catalytic reduction carried out until 110 ml of hydrogen were absorbed.

The catalyst was then filtered off and the filtrate was taken concentrated under reduced pressure. 0.7 g of crystalline, powdery 3-formylamino-4-hydroxy-α- [N- (1-methyl-2-t3,4,5-trimethoxyphenyl> ethyl) aminomethylbenzyl alcohol was obtained obtain.

Elemental analysis for C21H28N206: C (%) H (%) N (%) Calculated: 62.36 6.98 6.93 Found: 61.99 6.98 6.66 Example 22 2.2 g of 4-benzyloxy-3-formylamino-α- [N-benzyl-N- (1-methyl- 3-p-hydroxyphenylpropyl) aminomethyl benzyl alcohol (prepared according to Reference Example 11) dissolved. Became the solution 0.3 g of 10% palladium carbon was added and then the catalytic reduction was carried out Carried out at normal temperature and normal pressure until 195 ml of hydrogen are absorbed had been. The catalyst was filtered off and the filtrate was reduced under reduced pressure Pressure restricted. 1.3 g of crystalline powdery 3-formylamino-4-hydroxy-α- [N- (1-methyl-3-hydroxyphenylpropyl) aminomethyl] benzyl alcohol was obtained obtain.

0.60 g of the product obtained and 0.102 g of fumaric acid were in 95% Dissolved ethanol and the solution was left to stand for crystallization, whereby white crystals came to deposit. The crystals were filtered off. It 0.55 g of 3-formylamino-4-hydroxy-a- [N- (1-methyl-3-p-hydroxyphenylpropyl) aminomethyl] benzyl alcohol 1/2 fumarate was obtained Obtained monohydrate.

Elemental Analysis for C21H28N207: C (%) H (%) N (%) Calculated: 59.99 6.71 6.66 Found: 60.07 6.81 6.74 Example 23 In 50 ml of ethanol 1.62 g of 3-formylamino-4-benzyloxy-CL-S-benzyl-N- (1-methyl ^ 2-p-tolylethyl) aminomethylobenzyl alcohol (prepared according to Reference Example 11) dissolved.

0.3 g of 10% palladium carbon was added to the solution and the catalytic Reduction was carried out at normal pressure and at normal temperature until 154 ml of hydrogen had been absorbed. The catalyst was filtered off and 8 ml of water and 186 mg of fumaric acid were added to the remaining ethanol solution. The solvent was removed from the resulting solution under reduced pressure. The residue was dissolved in ethanol and benzene was added to the solution until the solution became slightly cloudy. When the approach is left in the refrigerator was formed, 550 mg of white crystals were formed. The crystals were filtered off and recrystallized from ethanol-benzene. It was 3-formylamino-4-hydroxy-α- [N- (1-methyl-2-p-tolylethyl) aminomethyl] -benzyl alcohol-1/2 fumarate. 1/2 hydrate with a melting point of 132-1330C (with decomposition).

Elemental analysis for C21H26N205. 1 / 2H20: C (%) H (%) N (%) Calculated: 63.78 6.88 7.08 Found: 63.99 6.70 6.82 Example 24 In 10 ml of ethanol, 200 mg of 3-formylamino-4-benzyloxya-N-benzyl-N- (1-ethyl-2-p-methoxyphenylethyl) aminomethyij + dissolved benzyl alcohol. To the solution, 50 mg of 10 goat palladium carbon was added and the catalytic reduction was carried out at normal temperature and normal pressure until 31 ml of hydrogen had been absorbed. After filtering off the catalyst was that Solvent distilled off under reduced pressure.

There were 100 mg of white, caramel-like 3-formylamino-4-hydroxy-α- [N- (1-ethyl-2-p-methoxyphenylethyl) aminomethyl] benzyl alcohol obtain.

Nuclear Magnetic Resonance Spectrum (D6-DMSO): 6: 0.85 ppm. (3H, -CH2CH3), 1.25 ppm (2H, -CH2CH3), 4.47 ppm. (1H, -CHOH), 8.31 ppm. (111, Example 25 0.52 g of 3-formylamino-4-benzyloxya-S-bensyl-N- (1-methyl-2-p-methoxyphenylEthyl) aminomethylbenzyl alcohol (prepared according to reference example 12d) was dissolved in 10 ml of ethanol. To the solution was added 0.2 g of 10% palladium carbon, and then catalytic reduction was carried out at normal temperature and pressure until 48 ml of hydrogen was absorbed.

After filtering off the catalyst, the filtrate was reduced under reduced pressure Pressure restricted. 0.55 g of white crystalline powdery 3-formylamino-4-hydroxya- LN- (1-methyl-2-p-methoxyphenylethyl) aminomethyi benzyl alcoholrA7 obtained. 0.35 g of the product was dissolved in 7 ml of 95% ethanol along with 0.06 g of fumaric acid and the solution was left to stand for crystallization. The crystals became separated by filtration. 0.34 g of white, crystalline 3-formylamino-4-hydroxy-α- [N- (1-methyl-2-p-methoxyphenylethyl) aminomethyl] benzyl alcohol [A] 1/2 fumarate with a melting point of 138 - 1400C (with decomposition).

Elemental analysis for C21H26N206 * H20: C (%) H (%) N (%) Calculated: 59.99 6.71 6.66 Found: 59.63 6.65 6.71 Example 26 In 30 nil ethanol 0.79 g of 3-formylamino-4-benzyloxy-α- [N-benzyl-N- (1-methyl-2-p-methoxyphenylethyl) aminomethyl] benzyl alcohol was obtained BB (prepared according to reference example 12 d) dissolved. Then became the solution 0.2 g of oily palladium carbon was added and the catalytic reduction was carried out at normal pressure and carried out at normal temperature until 73 ml of hydrogen was absorbed.

The catalyst was filtered off and the filtrate was reduced under reduced pressure Pressure restricted. 0.57 g of white powdery 3-formylamino-4-hydroxy-α [N- (1-methyl-2-pmethoxyphenylethyl) aminomethyl] benzyl alcohol was obtained [B] obtained.

0.57 g of the product was dissolved in 8 ml of 95% ethanol along with 0.087 g fumaric acid dissolved. Then 0.5 ml of water was added to the solution and allowed to crystallize ditched. The white crystals formed were separated by filtration. There were 0.3 g of 3-formylamino-4-hydroxy-a- | N- (1-methyl-2-p-methoxyphenylethyl) s aminomethylbenzyl alcoholC B] -1 / 2 fumarate with a melting point of 154-155 ° C (below Decomposition).

Elemental analysis for C21H26N2O62 / 3H2O: C (%) H (%) N (%) Calculated: 60.89 6.6.5 6.76 Found: 60.94 6.69 6.77 Example 27 In 3.5 ml of ethanol was added 0.28 g of 3-acetylamino-4-hydroxy-α- [N- (1-methyl-2-p-hydroxyphenylethyl) amino] acetophenone dissolved. Then 0.16 g of 10% palladium carbon was added to the solution and the catalytic reduction was carried out at normal temperature and normal pressure until 20 ml of hydrogen had been absorbed. After filtering off the catalyst the filtrate was reduced under reduced Pressure restricted. It was 0.21 g of crystalline powdery 3-acetylamino-4-hydroxy-α- [N- (1-methyl-2-hydroxyphenylethyl) aminomethyl] benzyl alcohol obtain.

The infrared absorption spectrum of this product agreed with the infrared absorption spectrum of the product prepared according to Example 17.

Example 28 (tablets) Formulation: 3-acetamido-4-hydroxy-α-C isopropylaminomethyl) benzyl alcohol 1/2 fumarate 100 mg lactose 100.0 g starch 35.0 g talc 5.0 g From the above formulation 1000 tablets were produced, each tablet was 7 mm in diameter. If necessary, these can be provided with a coating.

Example 29 (injection) formulation: 3-acetamido-4-hydroxy-a- (isopropylaminomethyl) benzyl alcohol-1 / 2fumarate 50 mg -sodium chloride 8.5 g citric acid 1.0 g made up with water 1000 ml pH 4.0 - 6> 0 The above formulation became 1000 injection ampoules made with 1 ml content each. The injection preparation was made by dissolving the the aforementioned components in water, sterilization by filtration, filling manufactured in ampoules and their melting.

Claims (1)

Claims 1. α-Aminomethylbenzyl alcohol with the general formula wherein one of A and B represents a hydrogen atom or a hydroxyl group while the other of them wherein R1, which is different from R2, represents a hydrogen atom or an alkyl group and R2 represents a hydrogen atom or a -CO-R4 group in which R4 represents a hydrogen atom or an alkyl group which is represented by a hydroxyl group, an alkoxyl group or an acylamino group and R3 a Means an alkyl group or a phenylalkyl group which is substituted by a hydroxyl group, an alkyl group, an alkoxyl group or an acylamino group. 2. α-aminomethylbenzyl alcohol according to claim 1, wherein the alcohol is a 3-amino-4-hydroxy-α-aminomethylbenzyl alcohol having the general formula is where R1, which is different from R2, is a hydrogen atom or an alkyl group, R2 is a hydrogen atom or a -CO-R4 group where R4 is a hydrogen atom or an alkyl group which is substituted by a hydroxyl group, an alkoxyl group or an acylamino group and R3 represents an alkyl group or a phenylalkyl group which may be substituted by a hydroxyl group, an alkyl group, an alkoxyl group or an acylamino group. 3. a-aminomethylbenzyl alcohol according to claim 1, one of A and B is hydrogen and the other is. where R1 where R1 oR2 4. a-aminomethylbenzyl alcohol according to claim wherein A is a hydroxyl group and B is a formamide group and R 'represents a 1-methyl-2-p-hydroxyphenylethyl group, that is to say that the alcohol of the 3-formamido-4-hydroxy-α- [N - (1-methyl-2-p-hydroxyphenylethyl) aminomethyl] benzyl alcohol. 5. α-aminomethylbenzyl alcohol according to claim wherein A is a hydroxyl group and B is a formamide group and R3 is a 1-methyl-2-p-methoxyphenylethyl group means, i.e. the alcohol 3-formamido-4-hydroxy-a-0N- (1-methyl-2-p-methoxyphenalethyl) aminomethyl | benzyl alcohol is. 6. α-aminomethylbenzyl alcohol according to claim 1, wherein A is a hydroxyl group and B represents a formamide group and R3 is a tert-butyl group, i.e., the Alcohol is 3-formamido-4-hydroxy-a-tert-butylaminomethylbenzyl alcohol. 7. α-aminomethylbenzyl alcohol according to claim 1, wherein A is a hydroxyl group and B a methylamino group and R3 a tert-butyl group, i.e. the alcohol 4-hydroxy-3-methyl-amino-a-tert-butylaminoethylbenzyl alcohol is. 8. Acid addition salts of the compounds mentioned in Claims 1 to 7 of pharmaceutically acceptable non-toxic inorganic or organic acids. 9. Process for the preparation of α-aminomethylbenzyl alcohols having the general formula in which A, B and R3 have the meaning already mentioned, characterized in that compounds or their acid addition salts with the above formula in which one or more hydrogen atoms of the mono-substituted amino group and its hydroxyl group are replaced by a benzyl group, a benzyloxycarbonyl group or a p-nitrobenzyloxycarbonyl group is protected, freed from these protective groups by reduction with hydrogen and optionally converted into the acid addition salts by adding non-toxic inorganic or organic acids. 10. Pharmaceutical preparations, characterized by a content of the connection with the in the Response 1 to 8 mentioned composition. 11. Use of the compounds mentioned in claims 1 to 8 as an active ingredient with bronchodilator effect for the manufacture of pharmaceuticals Preparations for humans and animals.