DE2366625C2 - - Google Patents

Description

The present invention relates to α- aminomethylbenzyl alcohol derivatives according to claims 1 to 11.

The compounds of this invention are intermediates for the manufacture of end products which can be used as β- adrenergic stimulants, which have great activity on smooth respiratory muscles and which are useful as bronchodilator drugs.

Examples of known α- alkylmethylbenzyl alcohol derivatives are: 3-amino-4-hydroxy- α- isopropylaminobenzyl alcohol (cf. Dutch Patent 85 197; Chemical Abstracts 52, 11121d (1958)), 3-ethoxycarbonylamino-4-hydroxy- α- isopropylaminobenzyl alcohol (cf. Belgian patent 76 59 86), α - (isopropylaminomethyl) -4-hydroxy-3-ureidobenzyl alcohol (see Japanese Patent Application Laid-Open 26 74 / '71).

Have the end products that can be produced from the intermediate products however, better bronchodilator activity than this known connections.

In BE-PS 73 96 78 are amino alcohols of the general formula

described in which the substituents have the meanings given there. However, the compounds described therein have the property of blocking the adrenaline- β receptors, so that they have a contracting effect on the bronchial tubes and thereby trigger asthmatic attacks (see above, page 4, paragraph 3, lines 1-2).

The principle of solution of the intermediates of the invention producible end products differs from this stand the technology (BE-PS 7 39 678) in that the end products in 4-position a hydroxy and 3-position acylamino groups exhibit.

The end products described in DE 23 05 092 are can by catalytic reduction, e.g. B. the starting material or its salts, in a solvent, e.g. B. ethanol, Isopropanol, ethyl acetate, at normal temperature or at elevated Temperature, under normal pressure or high pressure, in the presence a catalyst, e.g. B. palladium or platinum, according to the usual Working conditions are established.

Practical examples of the compounds of the present invention the intermediates are and those as starting compounds serve for the production of the final products are the following:

• 1) 3-formamido-4-benzyloxy- α - (N-benzyl-N-isopropylaminomethyl) benzyl alcohol;
• 2) 3-acetamido-4-benzyloxy- α - (tert-butylaminomethyl) benzyl alcohol;
• 3) 3-formamido-4-benzyloxy- α - (3-p-hydroxyphenyl-1-methylpropylamino) acetophenone;
• 4) 3-formamido-4-benzyloxy- α - [N-benzyl-N- (1-methyl-2-p-hydroxyphenylethyl) aminomethyl] benzyl alcohol;
• 5) 3-acetamido-4-benzyloxy- α - [N- (1-methyl-3-m-tolylpropyl) aminomethyl] benzyl alcohol;
• 6) 3-Formamido-4-benzyloxy- α - [N-benzyl-N-1,1-dimethyl-2-p-hydroxyphenylethyl) aminomethyl] benzyl alcohol;
• 7) 3-Formamido-4-benzyloxy- α - [N-benzyl-N- (1-methyl-2-p-acetamidophenylethylaminomethyl] benzyl alcohol;
• 8) 3-Benzyloxyacetamido-4-hydroxy- α - [N-benzyl-N- (1-methyl-2-p-propoxyphenylethyl) amino] acetophenone;
• 9. 3-Acetamidopropionamido-4-benzyloxy- α - [N-benzyl-N- (1-methyl-2-p-ethoxyphenylethyl) aminomethyl] benzyl alcohol.

Table II below is for the above starting materials the structural formulas given.  

Table II

The manufactured products of the invention can be isolated and are cleaned using the usual chemical working methods Find use. Because the compounds of this invention have at least one asymmetric carbon atom the compounds of this invention all possible optically active Forms and racemic mixtures. The racemic mixtures can be separated by methods known per se, e.g. B. by Formation of optically active acid addition salts and their separation by fractional crystallization.

In Table III at the end are the structural formulas of those produced Products specified.  

Example 1 Preparation of 4-benzyloxy-3-formylamino- α - (N-benzyl-N-isopropylaminomethyl) benzyl alcohol

a) 5.4 g of 4-benzyloxy-3-nitroacetophenone was dissolved in 60 ml of chloroform. A mixture of 3.2 g of bromine and 5 ml of chloroform was added dropwise to the solution with stirring. The mixture was further stirred for 30 minutes. The reaction product was concentrated under reduced pressure. The crystalline residue obtained was washed with 20 ml of benzene and dried. 5.5 g of 4-benzyloxy-3-nitro- α- bromoacetophenone were obtained. The product had a melting point of 135-136 ° C after recrystallization from chloroform.

b) 5.3 g of 4-benzyloxy-3-nitro- α- bromoacetophenone was dissolved in 60 ml of tetrahydrofuran. Then 4.5 g of N-benzyl-N-isopropylamine were added to the solution and the mixture was stirred overnight at room temperature. Then, after filtering off the precipitates formed, the filtrate was concentrated under reduced pressure, and the crystalline residue obtained was washed with ethanol. 5.5 g of yellow crystalline 4-benzyloxy-3-nitro- α - (N-benzyl-N-isopropylamino) acetophenone were obtained. The product showed a melting point at 92-93 ° C after recrystallization from ethanol.

c) 3.5 g of 4-benzyloxy-3-nitro- a - (N-benzyl-N-isopropylamino) acetophenone was suspended in 35 ml of ethanol. After adding 0.4 g of sodium borohydride, the mixture was stirred at room temperature for 3 hours. After the ethanol was distilled off under reduced pressure, the residue was crosslinked with water. The mixture was extracted with benzene. The extract was washed with water and dried over anhydrous magnesium sulfate. Then it was concentrated under reduced pressure. 3.4 g of pale yellow crystalline 4-benzyloxy-3-nitro- α - (N-benzyl-N-isopropylaminomethyl) benzyl alcohol were obtained. The product had a melting point at 97 ° C. after recrystallization from ethanol.

d) 3 g of 4-benzyloxy-3-nitro- α - (N-benzyl-N-isopropylaminomethyl) benzyl alcohol was dissolved in 30 ml of 50% aqueous acetic acid solution. 1.5 g of iron powder was added to the solution and then refluxed for 30 minutes. After filtering off the insolubles from the reaction product, the filtrate was concentrated under reduced pressure. To the residue thus obtained, 20 ml of 5% aqueous sodium carbonate solution was added, 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. Brownish crystalline 3-amino-4-benzyloxy- α - (N-benzyl-N-isopropylaminomethyl) benzyl alcohol was obtained.

The product was recrystallized from benzene-n-hexane (2: 5) and then had a melting point at 63-65 ° C. The yield was 2.2 g.

e) 1.9 g of 3-amino-4-benzyloxy- α - (N-benzyl-N-isopropylaminomethyl) benzyl alcohol was dissolved in 5 ml of a mixture of acetic anhydride and formic acid 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 washed with water and dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. 4-Benzyloxy-3-formylamino- α - (N-benzyl-N-isopropylaminomethyl) - o-formylbenzyl alcohol was obtained.

The product was dissolved in 10 ml of 90% methanol (balance 10% water). 0.5 g of sodium carbonate was added to the solution and the mixture was stirred at room temperature for 30 minutes. Then the solvent was distilled off under reduced pressure and the residue obtained was extracted with benzene. The extract was washed with water, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. 1.9 g of brownish oily 4-benzyloxy-3-formylamino- α - (N-benzyl-N-isopropylaminomethyl) benzyl alcohol was obtained. (The product is used in Example 1 according to DE-PS 23 05 092.)

Example 2 Preparation of 4-benzyloxy-3-benzyloxyacetylamino- α - (N-benzyl-N-isopropylaminomethyl) benzyl alcohol

a) 5 g of 3-amino-4-benzyloxyacetophenone was added to 30 ml of pyridine dissolved. There was 3.9 g of benzyloxyacetyl chloride added with cooling and the mixture over Stirred at room temperature overnight. The solvent was reduced from the reaction product under Pressure distilled off. The residue formed was dissolved in 50 ml of chloroform. Then the solution washed twice with 20 ml water, dried over anhydrous sodium sulfate and the chloroform was distilled off under reduced pressure. By recrystallization of the yellow crystals ethanol became 7.5 g of 4-benzyloxy-3-benzyloxyacetylaminoacetophenone with a melting point at Obtained 104-105 ° C.

b) 1.9 g of 4-benzyloxy-3-benzyloxyacetylaminoacetophenone was dissolved in 50 ml of chloroform. 0.78 g of bromine was added to the solution and the mixture was stirred at room temperature for 30 minutes. Then chloroform and hydrogen bromide were distilled off from the reaction mixture under reduced pressure. The crystals obtained were recrystallized from chloroform-n-hexane. 1.85 g of 4-benzyloxy-3-benzyloxyacetylamino- α- bromoacetophenone with a melting point at 155-157 ° C. were obtained.

c) 4 g of 4-benzyloxy-3-benzyloxyacetylamino- α- bromoacetophenone was dissolved in 40 ml of tetrahydrofuran at 40-50 ° C. Then 2.68 g of N-benzyl-N-isopropylamine was added to the solution. The mixture was stirred overnight at the same temperature (40-50 ° C). The reaction mixture was cooled, the N-benzyl-N-isopropylamine hydrochloride formed was filtered off and then the solvent was distilled off under reduced pressure. After the yellow oily material (5 g) thus obtained was dissolved in 100 ml of ethanol, 0.5 g of sodium borohydride was added to the solution, and the mixture was stirred for 4 hours at room temperature. Then the solvent was distilled off from the reaction product under reduced pressure. The white crystals obtained were recrystallized from ethanol. 2.3 g of 4-benzyloxy-3-benzyloxyacetylamino- α - (N-benzyl-N-isopropylaminomethyl) benzyl alcohol with a melting point at 93-95 ° C. were obtained. (The product is processed further in Example 2 in accordance with DE-PS 23 05 092.)

Example 3 Preparation of 3-formylamino-4-hydroxy- α - (N-benzyl-N-isopropylaminomethyl) benzyl alcohol

a) 5.4 g of 4-hydroxy-3-nitroacetophenone was dissolved in 50 ml of chloroform. Then 5 ml of a chloroform solution of 4.8 g of bromine was added dropwise to the solution. Thereafter, the mixture was stirred for 15 minutes and then concentrated under reduced pressure, whereby yellow crystals were obtained. Recrystallization of the product from benzene-n-hexane gave 6.3 g of crystalline α- bromo-4-hydroxy-3-nitroacetophenone with a melting point at 69-71 ° C.

b) 5.2 g of a- bromo-4-hydroxy-3-nitroacetophenone was dissolved in 50 ml of methyl ethyl ketone. Then 9 g of N-benzylisopropylamine was added to the solution and the mixture was stirred overnight at room temperature. After the precipitated N-benzylisopropylamine hydrobromide was filtered off, the filtrate was concentrated. Crude yellowish brown oily 4-hydroxy-3-nitro- α - (N-benzyl-N-isopropylamino) acetophenone was obtained.

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

d) 2.7 g of 4-hydroxy-3-nitro- α - (N-benzyl-N-isopropylaminomethyl) benzyl alcohol (prepared as described above) was dissolved in 30 ml of methanol. Then 1 g of Raney nickel catalyst was added to the solution. The catalytic reduction of the compound was carried out at normal temperature and normal pressure. After 600 ml of hydrogen was absorbed, the reaction was stopped. After filtering off the catalyst and adding 8.2 ml of a 1N hydrogen chloride-ethanol solution to the filtrate, the reaction product was concentrated under reduced pressure. 2.7 g of yellow-brown powdery 3-amino-4-hydroxy- α - (N-benzyl-N-isopropylaminomethyl) benzyl alcohol hydrochloride were obtained.

e) 1.2 g of the 3-amino-4-hydroxy- α - (N-benzyl-N-isopropylaminomethyl) benzyl alcohol hydrochloride prepared above was dissolved in 20 ml of pyridine. Then, 0.20 g of formic acid and 0.85 g of dicyclohexylcarbodiimide were added to the solution while cooling to below 0 ° C. The mixture was stirred overnight at room temperature. The separated dicyclohexylurea was filtered off. The filtrate was concentrated. Water was added to the residue obtained, and the mixture was washed with ethyl acetate. The aqueous solution formed was neutralized by adding sodium carbonate and then extracted with ethyl acetate. The extracts were dried and concentrated. A brown residue was obtained. The residue was subjected to silica gel column chromatography. The product was obtained using a chloroform-acetone mixture (5: 1) as eluent. Then 0.5 g of yellow powdery 3-formylamino-4-hydroxy- α - (N-benzyl-N-isopropylaminomethyl) benzyl alcohol was obtained from the eluates. (The connection is used in Example 8 according to DE-PS 23 05 092).

Example 4 Preparation of 3-acetylamino-4-benzyloxy- α - (N-benzyl-N-isopropylaminomethyl) benzyl alcohol

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

b) 5 g of 3-acetylamino-4-benzyloxyacetophenone was dissolved in 45 ml of chloroform. Then, a solution of 2.8 g of bromine in 5 ml of chloroform was gradually added dropwise to the solution, warming the batch initially. The mixture was stirred for a further 20 minutes. Then 50 ml of benzene was added to the mixture, and the precipitated crystals were separated by filtration and dried. 5.5 g of white crystalline 3-acetylamino-4-benzyloxy- α- bromoacetophenone with the melting point at 181 ° C. were obtained.

c) 1.85 g of 3-acetylamino-4-benzyloxy- α- bromoacetophenone was dissolved in 40 ml of acetonitrile and 10 ml of dimethylformamide. 1.5 g of N-benzyl-N-isopropylamine were added to the solution and the mixture was stirred at 40-50 ° C. for 2 hours. Then the mixture was left overnight 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 dissolved in water with heating. The insoluble matters were separated by filtration and the solution was neutralized by adding 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. 1.2 g of 3-acetylamino-4-benzyloxy- α - (N-benzyl-N-isopropylamino) acetophenone were obtained.

d) 1 g of 3-acetylamino-4-benzyloxy- α - (N-benzyl-N-isopropylamino) acetophenone was dissolved in 20 ml of ethanol. 0.2 g of sodium borohydride was added to the solution and the mixture was stirred overnight. The reaction product was concentrated under reduced pressure. Water was added to the residue obtained and the product extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. 0.9 g of 3-acetylamino-4-benzyloxy- α - (N-benzyl-N-isopropylaminomethyl) benzyl alcohol was obtained (used in Example 3 according to DE-PS 23 05 092).

Example 5 Preparation of 4-benzyloxy-3-formylamino- α - [N-benzyl-N- (1-methyl-2-p-hydroxyphenylethyl) aminomethyl] benzyl alcohol [A]

a) 5.4 g of 4-benzyloxy-3-nitro-acetophenone was dissolved in 60 ml of chloroform. A mixture of 3.2 g of bromine and 5 ml of chloroform was added dropwise to the solution 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-nitro- α- bromoacetophenone with a melting point of 135-136 ° C. were obtained.

b) A mixture consisting of 4.6 g of 4-benzyloxy-3-nitro- α- bromoacetophenone and 6.4 g of N-benzyl-N- (1-methyl-2-p-hydroxyphenylethyl) amine together with 50 ml Methyl ethyl ketone heated to 70-80 ° C for 30 minutes. After the reaction product had cooled, the precipitates formed were filtered off and the filtrate was concentrated under reduced pressure. After the addition of ethanol to the residue obtained, the product was crystallized. The crystals were separated by filtration and recrystallized from ethanol. 5.5 g of 4-benzyloxy-3-nitro- a - [N-benzyl-N- (1-methyl-2-p-hydroxyphenylethyl) amino] - acetophenone with a melting point of 84-85 ° C. were obtained.

c) 4.5 g of 4-benzyloxy-3-nitro- α - [N-benzyl-N- (1-methyl-2-p-hydroxyphenylethyl) amino] - acetophenone was suspended in 100 ml of ethanol. 0.5 g of sodium borohydride was added to the suspension. The mixture was stirred at room temperature for one hour. Then, ethanol was distilled off from the reaction product under reduced pressure, water was 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. 4.4 g of yellowish crystalline powdery 4-benzyloxy-3-nitro- α - [N-benzyl-N- (1-methyl-2-p-hydroxyphenylethyl) aminomethyl] benzyl alcohol were obtained.

d) 4.3 g of 4-benzyloxy-3-nitro- α - [N-benzyl-N- (1-methyl-2-p-hydroxyphenylethyl) aminomethyl] benzyl alcohol was dissolved in 40 ml of 60% aqueous acetic acid solution. 1.5 g of iron powder was added to the solution. The mixture was refluxed for 30 minutes. After the insoluble constituents had been filtered off from the reaction product, the product was concentrated under reduced pressure. 10% aqueous sodium carbonate solution was added to the residue obtained and the product was extracted with benzene. The extract was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. 3.7 g of brownish crystalline powdery 3-amino-4-benzyloxy- α - [N-benzyl-N- (1-methyl-2-p-hydroxyphenylethyl) aminomethyl] benzyl alcohol were obtained.

e) 3.3 g of 3-amino-4-benzyloxy- α - [N-benzyl-N- (1-methyl-2-p-hydroxyphenylethyl) aminomethyl] was added to 10 ml of acetic anhydride-formic acid mixture (5: 3). dissolved benzyl alcohol. After the mixture was left overnight at room temperature, the mixture was concentrated under reduced pressure. The residue obtained was dissolved in 50 ml of methanol. In 3 ml of water and 3 g of sodium carbonate were added to the solution. The mixture was stirred at room temperature for one hour. Methanol was distilled off from the mixture under reduced pressure, and the residue was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off from the extract. 3.4 g of pale brown powdery 4-benzyloxy-3-formylamino- α - [N-benzyl-N- (1-methyl-2-p-hydroxyphenylethyl) aminomethyl] benzyl alcohol were obtained. In 30 ml of benzene, 2.5 g of the pale brown powder obtained above was dissolved and the solution was left overnight at room temperature, whereby crystals were deposited. The crystals were separated and recrystallized from ethyl acetate-benzene. 1.2 g of white crystalline product with a melting point at 135-137 ° C. was obtained.

Nuclear magnetic resonance spectrum NMR (CDCl₃),
δ : 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] benzyl alcohol [A] (in Example 10 according to DE-PS 23 05 092 used).

Example 6 Preparation of 4-benzyloxy-3-formylamino- a - [N-benzyl-N- (1-methyl-2-p-hydroxyphenylethyl) aminomethyl] benzyl alcohol [B]

From the mother liquor remaining in the above step in Example 5 the solvent was distilled off. The residue obtained was subjected to silica gel column chromatography. Then by using Benzene-ethyl acetate mixture (10: 2) 0.8 g of white crystalline powder.

NMR (CDCl₃),
δ : 4.34 ppm (m, 1H, CH belonging to the hydroxyl group), 3.76 ppm (S, 2H, CH₂ belonging to the N).

This product is referred to as 4-benzyloxy-3-formylamino- α - [N-benzyl-N- (1-methyl-2-p-hydroxyphenylethyl) aminomethyl] - benzyl alcohol [B] (used in Example 11 according to DE-PS 23 05 092).

Example 7 Preparation of 4-benzyloxy-3- (N-methyl-N-formylamino) - α - (N-benzyl-N-tert-butylaminomethyl) benzyl alcohol

a) 27 g of 4-benzyloxy-3-nitro-acetophenone was dissolved in 270 ml of chloroform. A mixture of 16 g of bromine and 10 ml of chloroform was added dropwise to the solution with stirring. The mixture was stirred for an additional 30 minutes. The reaction mixture was concentrated under reduced pressure. The crystalline residue obtained was washed with a mixture of 50 ml of benzene and 50 ml of n-hexane and dried. 31 g of 4-benzyloxy-3-nitro- a -bromoacetophenone with a melting point of 135-136 ° C. were obtained.

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

c) 30 g of 4-benzyloxy-3-nitro- α - (N-benzyl-N-tert-butylamino) acetophenone was dissolved in a mixture of 200 ml of ethanol and 150 ml of tetrahydrofuran. After adding 3 g of sodium borohydride to the solution, the mixture was stirred for 3 hours at room temperature. The reaction product was concentrated under reduced pressure and water was added to the residue. The product was then extracted with benzene from this approach. The extract was washed with water and dried over anhydrous magnesium sulfate. Dan was then concentrated under reduced pressure. 30 g of oily 4-benzyloxy-3-nitro- α - (N-benzyl-N-tert-butylaminomethyl) benzyl alcohol were obtained.

d) 30 g of 4-benzyloxy-3-nitro- α - (N-benzyl-N-tert-butylaminomethyl) benzyl alcohol was dissolved in 150 ml of 50% aqueous acetic acid solution. Then 12 g of ice pen powder was added to the solution. The mixture was refluxed for 25 minutes. The reaction mixture was filtered while hot and the filtrate was concentrated under reduced pressure. Then 50 ml of 10% aqueous sodium carbonate solution was added to the residue and the product was extracted with benzene. The extract was washed with water and dried over anhydrous magnesium sulfate. Then this was concentrated 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- α - (N-benzyl-N-tert-butylaminomethyl) benzyl alcohol with a melting point at 68-69 ° C received.

e) 20 g of 3-amino-4-benzyloxy- α - (N-benzyl-N-tert-butylaminomethyl) benzyl alcohol was dissolved in 50 ml of acetic anhydride-formic acid mixture (5: 3) and left to stand overnight. Then the solution was concentrated under reduced pressure. The residue obtained was dissolved in 120 ml of methanol. Then 5 ml of water and 7.5 g of sodium carbonate were added to the solution. The mixture was stirred at room temperature for one hour. Then the solvent was distilled off from the reaction mixture under reduced pressure and 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. 20.5 g of oily 4-benzyloxy-3-formylamino- α - (N-benzyl-N-tert-butylaminomethyl) benzyl alcohol were obtained.

f) 5 g of 4-benzyloxy-3-formylamino- α - (N-benzyl-N-tert-butylaminomethyl) benzyl alcohol was dissolved in 30 ml of anhydrous tetrahydrofuran. The resulting solution was added dropwise while stirring to a solution of 20 ml of tetrahydrofuran and 20 ml of ether containing 3 g of lithium aluminum hydride. Thereafter, the resulting mixture was refluxed for one hour by heating. Then 20 ml of water was added dropwise to the reaction mixture and then stirred for 1 hour. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was extracted with benzene. The extract was washed with water, dried and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (filled with 70 ml of silica gel using chloroform as the eluent. The third to eighth fractions (each fraction was 40 ml) were collected, then concentrated under reduced pressure, becoming 2.8 g weak yellow oily 4-benzyloxy-3-methylamino- α - (N-benzyl-N-tert-butylaminomethyl) benzyl alcohol obtained.

g) 1.5 g of 4-benzyloxy-3-methylamino- a - (N-benzyl-N-tert-butylaminomethyl) benzyl alcohol was dissolved in 5 ml of acetic anhydride-formic acid mixture (5: 3) and the solution was left to stand overnight . The mixture was then concentrated under reduced pressure and the residue formed was dissolved in 50 ml of methanol. After adding 3 ml of ice water and 2 g of sodium carbonate, the resulting mixture was stirred for one hour. The reaction product was concentrated under reduced pressure and the residue obtained was extracted with benzene. After washing the extract with water and drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. 1.5 g of brownish oily 4-benzyloxy-3- (N-methyl-N-formylamino) - α - (N-benzyl-N-tert-butylaminomethyl) benzyl alcohol were obtained. (The connection is used in Example 13 according to DE-PS 23 05 092).

Example 8 Preparation of 4-benzyloxy-3-acetylamino- α - [N-benzyl-N- (1-methyl-2-p-hydroxyphenylethyl) aminomethyl] benzyl alcohol [A]

a) In 200 ml of methanol, 16.0 g of 4-benzyloxy-3-formylamino- α - [N-benzyl-N- (1-methyl-2-p-hydroxyphenylethyl) aminomethyl] benzyl alcohol [A] (was prepared dissolved according to Example 5). Then 30 ml of 4.8 1N hydrochloric acid was added to the solution. The mixture was refluxed for one hour and 30 minutes. After the reaction was completed, the reaction product was cooled, and 10 g of potassium hydride and 50 ml of water were added. The resulting mixture was stirred for one hour. The solvent was distilled off from the reaction product 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. 14.5 g of crystalline powdery 3-amino-4-benzyloxy- a - [N-benzyl-N- (1-methyl-2-p-hydroxyphenylethyl) aminomethyl] benzyl alcohol [A] was obtained.

b) 4.0 g of 3-amino-4-benzyloxy- α - [N-benzyl-N- (1-methyl-2-p-hydroxyphenylethyl) aminomethyl] benzyl alcohol [A] (prepared according to the preceding regulation). The mixture was heated to 65-80 ° C for one hour and 30 minutes and then concentrated under reduced pressure. The residue was dissolved in a mixture of 15 ml of methanol and 2.0 g of potassium hydroxide. The solution was stirred at room temperature for one hour. Then methanol was distilled off under reduced pressure. The residue obtained was mixed with water and then extracted with benzene. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was then distilled off. 3.8 g of crystalline powdery 4-benzyloxy-3-acetylamino- a - [N-benzyl-N- (1-methyl-2-p-hydroxyphenylethyl) aminomethyl] benzyl alcohol [A] was obtained. By recrystallization of 2.0 g of the product thus obtained from 20 ml of ethanol, 1.6 g of crystalline pure product with a melting point of 141-143 ° C. was obtained (further implemented in Example 14 according to DE-PS 23 05 092).

Elemental analysis for C₃₂H₃₆N₂O₄:
Calculated: C 75.55%; H 6.92%; N 5.34% Found: C 75.62%; H 7.03%; N 5.21%

Example 9 Preparation of 3-benzyloxyacetylamino-4-benzyloxy- α - [N-benzyl-N- (1-methyl-2-p-hydroxyphenylethyl) aminomethyl] benzyl alcohol

In 20 ml of anhydrous pyridine, 2 g of 3-amino-4-benzyl oxy- α - [N-benzyl-N- (1-methyl-2-p-hydroxyphenylethyl) aminomethyl] benzyl alcohol [A] (prepared in Example 8 above , Paragraph a) dissolved. The solution was cooled to temperatures from -20 ° C to -30 ° C. A solution of 2.28 g of benzyloxyacetyl chloride in 5 ml of toluene was added dropwise to the solution thus kept cooled while stirring, and the temperature of the mixture was slowly brought to room temperature. After stirring the mixture overnight, the solvent was distilled off under reduced pressure. The residue obtained was mixed with 50 ml of benzene and 50 ml of water. The benzene solution was washed three times with water, and benzene was distilled off under reduced pressure, whereby a red oily material was obtained. The product was dissolved in 50 ml of ethanol. Then 5 ml of water and 10 ml of 4N sodium hydroxide solution were added to the solution, and the resulting mixture was stirred for two hours. Then the pH of the reaction mixture was adjusted to 3 by adding 1N hydrochloric acid and excess sodium carbonate was added. Then ethanol was distilled off under reduced pressure and the residue was extracted with benzene. The extract was washed three times with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure, whereby a yellow, oily material was obtained. The product was then subjected to silica gel column chromatography (65 ml). The product was eluted using a 9: 1 benzene-acetone mixture and the eluate was concentrated under reduced pressure. 3-Benzyloxyacetylamino-4-benzyloxy- α - [N-benzyl-N- (1-methyl-2-p-hydroxyphenylethyl) aminomethyl] benzyl alcohol was obtained (used in Example 15 according to DE-PS 23 05 092).

NMR (CDCl₃):
w : 1.00 ppm. (d, 3H, CH-CH₃), 4.08 ppm.

Example 10 Preparation of 3- (N-acetyl- β- alanyl) amino-4-benzyloxy- α - [N-benzyl-N- (1-methyl-2-p-hydroxyphenylethyl) aminomethyl] benzyl alcohol

4 g of 3-amino-4-benzyloxy- α - [N-benzyl-N- (1-methyl-2-p-hydroxyphenylethyl) aminomethyl] benzyl alcohol hydrochloride and 3.5 g of N-acetyl- β -alanine dissolved. Then 5.5 g of dicyclohexylcarbodiimide was added to the solution with ice cooling. The mixture was stirred overnight. After the deposited precipitates were filtered off, the reaction mixture was concentrated under reduced pressure and the residue was dissolved in 30 ml of methanol. Then 10 ml of 4N sodium hydroxide solution was added to the solution and the mixture was stirred for 3 hours. Then 1N hydrochloric acid was added to adjust to pH 3 and then excess sodium carbonate was added. The resulting mixture 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 washed three times with water, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. 4 g of a yellow oily material were obtained. The material obtained was subjected to silica gel column chromatography (75 ml) and a further silica gel column chromatography (35 ml). 800 mg of pure caramel-like 3- (N-acetyl- b- alanyl) amino-4-benzyloxy- α - [N-benzyl-N- (1-methyl-2-p-hydroxyphenylethyl) aminomethyl] benzyl alcohol were obtained. In the above chromatography purification treatments, 4: 2: 1 ethyl acetate-benzene-methanol was used as the developing solvent. (The product obtained is used in Example 16 according to DE-PS 23 05 092.)

Elemental analysis for C₃₆H₄₁N₃O₅:
Calculated: C 72.58%; H 6.94%; N 7.05% Found: C 72.44%; H 6.98%; N 6.86%

Example 11 Preparation of 4-benzyloxy-3-formylamino- α - [N-benzyl-N- (1-methyl-2-p-acetylaminophenylethyl) aminomethyl] benzyl alcohol

a) A mixture of 4.1 g of 4-benzyloxy-3-nitro- α -bromo-acetophenone, 6.6 g of N-benzyl-N- (1-methyl-2-p-acetylaminophenylethyl) amine and 41 ml of methyl ethyl ketone was heated to 65-80 ° C for one hour. After the reaction mixture was cooled, the crystals formed were filtered off and the filtrate was concentrated under reduced pressure. The residue formed in this way was dissolved in 40 ml of ethanol at temperatures below 50 ° C. and the solution was left to crystallize at room temperature. The crystals were separated by filtration. 3.7 g of 4-benzyloxy-3-nitro- α - [N-benzyl-N- (1-methyl-2-p-acetylaminophenylethyl) amino] acetophenone were obtained

b) 2.7 g of 4-benzyloxy-3-nitro- α - [N-benzyl-N- (1-methyl-2-p-acetylaminophenylethyl) amino] acetophenone was suspended in 30 ml of methanol. Then 0.6 g of sodium borohydride was added to the suspension with ice cooling and the mixture was stirred for 1 hour. Then water was added, methanol was distilled off under reduced pressure, and the product was extracted with benzene. The extract was washed with water and dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. 2.6 g of yellowish powdery 4-benzyloxy-3-nitro- α - [N-benzyl-N- (1-methyl-2-p-acetylaminophenylethyl) aminomethyl] benzyl alcohol were obtained.

c) 1.3 g of 4-benzyloxy-3-nitro- α - [N-benzyl-N- (1-methyl-2-p-acetylaminophenylethyl) aminomethyl] benzyl alcohol was dissolved in 20 ml of methanol. Then 0.7 g of iron powder, 0.6 ml of 4.8 N hydrochloric acid and 3 ml of water were added to the solution and the mixture was refluxed for 2 hours and 30 minutes. After the insolubles had been filtered off, 0.8 g of sodium carbonate was added to the mixture and the mixture was stirred for 2 hours. Water was added to the obtained reaction mixture, methanol was distilled off under reduced pressure, and then extracted with benzene. The extract was washed with water, dried over 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) aminomethyl] benzyl alcohol were obtained.

d) In 6 ml of acetic anhydride-formic acid mixture (5: 3), 1.0 g of 3-amino-4-benzyloxy- α - [N-benzyl-N- (1-methyl-2-p-acetylaminophenylethyl) aminomethyl] Dissolved benzyl alcohol and left 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 0.5 g of potassium hydroxide was added to the solution. The mixture was stirred at room temperature for one hour. Then methanol was distilled off from the reaction mixture under reduced pressure, the residue was mixed with water and then extracted with benzene. The extract was then washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off therefrom and 0.09 g of crystalline powdery 4-benzyloxy-3-formylamino- α - [N-benzyl-N- (1-methyl-2-p-acetylaminophenylethyl) aminomethyl] - benzyl alcohol was obtained. (The product obtained is further implemented in Example 17 in accordance with DE-PS 23 05 092.)

NMR (CDCl₃):
δ : 2.04 ppm (S, 3H, H of the methyl group from the p-acetylamino group), 8.38 ppm (S, 1H, H of the formyl group), 4.4 ppm (m, 1H, H from the methine group to the hydroxyl group proper).

In the following Examples 11 to 14, the same Repeat the above procedure, however using different starting materials.

Example 12 Preparation of 4-benzyloxy-3-formylamino- α - [N-benzyl-N- (1-methyl-2- {3,4,5-trimethoxyphenyl} ethyl) aminomethyl] benzyl alcohol

Using 2.7 g of 4-benzyloxy-3-nitro- α -bromoacetophenone and 4.8 g of N-benzyl-N- (1-methyl-2- {3,4,5-trimethoxyphenyl} ethyl) amine as Starting materials were obtained 1.2 g of crystalline powdery 4-benzyloxy-3-formylamino- α - [N-benzyl-N- (1-methyl-2- {3,4,5-trimethoxyphenyl} ethyl) aminomethyl] benzyl alcohol (in the example 18 according to DE-PS 23 05 092 used).

NMR (CDCl₃):
δ : 3.6 ppm., 3.7 ppm. (9H, H from the methyl group from the 3,4,5-trimethoxy group), 8.36 ppm. (S, 1H), H of the formyl group), 4.46 ppm. (m, 1H, H of the methine group belonging to the hydroxyl group).

Example 13 Preparation of 4-benzyloxy-3-formylamino- α - [N-benzyl-N- (1-methyl-3-p-hydroxyphenylpropyl) aminomethyl] benzyl alcohol

When 10.4 g of 4-benzyloxy-3-nitro- α -bromoacetophenone and 15.2 g of N-benzyl-N- (1-methyl-3-p-hydroxyphenylpropyl) amine were used as starting materials, 5.9 g of 4- Benzyloxy-3-formylamino- α - [N-benzyl-N- (1-methyl-3-p-hydroxyphenylpropyl) aminomethyl] benzyl alcohol obtained (in Example 19 according to DE-PS 23 05 092 (used).

NMR (CDCl₃):
δ : 1.76 ppm. (m, 2H, H of 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, 1 H, H of the methine group belonging to the Hydroxyl group).

Example 14 Preparation of 3-formylamino-4-benzyloxy- α - [N-benzyl-N- (1-methyl-2-p-tolylethyl) aminomethyl] benzyl alcohol

When using 6.75 g of 4-benzyloxy-3-nitro- α -bromoacetophenone and 9.2 g of N-benzyl-Np-tolylisopropylamine as starting materials, 3.7 g of 3-formylamino-4-benzyloxy- α - [N- benzyl-N- (1-methyl-2-p-tolylethyl) aminomethyl] benzyl alcohol obtained (the further processing in Example 20 according to DE-PS 23 05 092).

NMR (CDCl₃):
δ : 2.30 ppm. (S, 3 H, Φ -CH₃), 5.02 ppm. (S, 2H, -OCH₂-).

Example 15 Preparation of 4-benzyloxy-3-formylamino- α - [N-benzyl-N- (1-methyl-2-p-methoxyphenylethyl) aminomethyl] benzyl alcohol [A]

a) A mixture of 9.4 g of 4-benzyloxy-3-nitro- α -bromo-acetophenone and 13.7 g of N-benzyl-N- (1-methyl-2-p-methoxyphenylethyl) amine together with 50 ml Methyl ethyl ketone heated to 70-80 ° C for one hour. After the solution was cooled and the precipitates formed were filtered off, the filtrate was concentrated under reduced pressure. Ethanol was added to the residue, causing crystals to be deposited. The crystals were separated by filtration and recrystallized from ethanol. 12.8 g of 4-benzyloxy-3-nitro- α - [N-benzyl-N- (1-methyl-2-p-methoxyphenylethyl) amino] acetophenone with the melting point at 100-102 ° C. were obtained.

b) 12.8 g of 4-benzyloxy-3-nitro- α - [N-benzyl-N- (1-methyl-2-p-methoxyphenylethyl) amino] - acetophenone was suspended in 200 ml of ethanol. 1.8 g of sodium borohydride was added to the suspension and the mixture was stirred overnight. Then, ethanol was distilled off from the reaction product, and water was added to the residue. 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) aminomethyl] benzyl alcohol were obtained.

c) 10.7 g of 4-benzyloxy-3-nitro- α - [N-benzyl-N- (1-methyl-2-p-methoxyphenylethyl) aminomethyl] benzyl alcohol was dissolved in 70 ml of methanol. Then, 15 ml of 2.2 N hydrochloric acid solution, 10 ml of water and 5.4 g of iron powder were added to the solution. The mixture was refluxed for one hour. After the insoluble matters had been filtered off from the reaction mixture, the filtrate was concentrated under reduced pressure, 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. 8.8 g of yellow caramel-like 3-amino-4-benzyloxy- α - [N-benzyl-N- (1-methyl-2-p-methoxyphenylethyl) aminomethyl] benzyl alcohol were obtained.

d) In 20 ml of acetic anhydride-formic acid mixture (5: 3) 5.5 g of 3-amino-4-benzyloxy- α - [N-benzyl-N- (1-methyl-2-p-methoxyphenylethyl) aminomethyl] Dissolved benzyl alcohol and then the solution was left overnight at room temperature. The solution was concentrated under reduced pressure. The residue was mixed with 50 ml of methanol, 3 ml of water and 3.5 g of sodium carbonate and the mixture was stirred for 2 hours at room temperature. Then methanol was distilled off under reduced pressure and the residue formed was extracted with benzene. The extract was washed with water, dried over anhydrous magnesium sulfate, and then the solvent was distilled off. 5.1 g of crystalline powdery 4-benzyloxy-3-formylamino- α - [N-benzyl-N- (1-methyl-2-p-methoxyphenylethyl) aminomethyl] benzyl alcohol was obtained. Then 4.9 g of the product was dissolved in 20 ml of methanol and 1 g of fumaric acid was added to the solution. The mixture was concentrated under reduced pressure. The residue was dissolved in 80 ml of ethyl acetate and the solution was left overnight to crystallize out. The crystals formed were filtered off and recrystallized from isopropanol. 3.2 g of white crystalline 4-benzyloxy-3-formylamino- α - [N-benzyl-N- (1-methyl-2-p-methoxyphenylethyl) aminomethyl] benzyl alcohol-1-fumarate with the melting point at 173 ° C. receive.

In 30 ml of 90% methanol, 3 g of the above was prepared Product suspended to the Suspension added 1.5 g of sodium carbonate and Stirred for 30 minutes. The mixture was reduced Pressure reduced. The residue was treated with 10 ml Mixed water and extracted with 30 ml of benzene. The Extract was washed with water and over anhydrous Magnesium sulfate dried. Then the extract concentrated under reduced pressure. 2.3 g of one received white powder.

NMR (CDCl₃):
δ : 4.52 ppm. (m, 1H, CH belonging to the hydroxyl group), 3.48 ppm, 3.87 ppm (AB Type Quartet, 2H, CH₂ belonging to the N).

This product is referred to as 4-benzyloxy-3-formylamino- α - [N-benzyl-N- (1-methyl-2-p-methoxyphenylethyl) aminomethyl] benzyl alcohol [A] (in Example 21 according to DE-PS 23 05 092 processed).

Example 16 Preparation of 4-benzyloxy-3-formylamino- α - [N-benzyl-N- (1-methyl-2-p-methoxyphenylethyl) aminomethyl] benzyl alcohol [B]

Furthermore, the solvent was distilled off from the mother liquor obtained in Example 15, which, after the crystals had been separated off from 4-benzyloxy-3-formylamino- α - [N-benzyl-N- (1-methyl-2-p-methoxyphenylethyl) aminomethyl] benzylalko-hol-1-fumarate [A] had been obtained in the above step. The residue was dissolved in 30 ml of methanol. 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. The mixture was then concentrated under reduced pressure. The residue was mixed with 10 ml of water and extracted with benzene. The extract was washed with water and dried over anhydrous magnesium sulfate. Then the solvent was distilled off. 2.3 g of slightly brownish powdery 4-benzyloxy-3-formylamino- α - [N-benzyl-N- (1-methyl-2-p-methoxyphenylethyl) aminomethyl] benzyl alcohol were obtained. The product was subjected to silica gel column chromatography using benzene: ethyl acetate (10: 1) as an eluent, which was concentrated under reduced pressure. A white powder was obtained.

NMR (CDCl₃):
δ : 4.40 ppm. (m, 1H, CH belonging to the hydroxyl group), 3.73 ppm. (S, 2H, CH₂ belonging to N).

This is referred to as 4-benzyloxy-3-formylamino- α - [N-benzyl-N- (1-methyl-2-p-methoxyphenylethyl) aminomethyl] benzyl alcohol [B] (used in Example 22 according to DE-PS 23 05 092 ).

Example 17 Preparation of 3-acetylamino-4-hydroxy- α - [N- (1-methyl-2-p-hydroxyphenylethyl) amino] acetophenone

a) A mixture of 2.7 g of 4-benzyloxy-3-acetylamino- α -bromo-acetophenone and 4.0 g of benzyl-N- (1-methyl-2-p-hydroxy-phenylethyl) amine together with 80 ml Methyl ethyl ketone was stirred at room temperature for 4 hours. After the precipitates formed were filtered off, the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography. The product was then separated using a 10: 2 benzene-ethyl acetate mixture as the eluent. 2.2 g of yellowish crystalline powdery 4-benzyloxy-3-acetylamino- α - [N-benzyl-N- (1-methyl-2-p-hydroxyphenylethyl) amino] acetophenone was obtained.

b) 0.9 g of 4-benzyloxy-3-acetylamino- α - [N-benzyl-N- (1-methyl-2-p-hydroxyphenylethyl) amino] - acetophenone was dissolved in 18 ml of ethanol. Then 0.1 g of 10% palladium carbon was added to the solution. The catalytic reduction was then carried out at normal temperature and pressure until 78 ml of hydrogen had been absorbed. After filtering off the catalyst, the filtrate was concentrated under reduced pressure. The residue obtained was subjected to silica gel column chromatography. From the eluate, using a 4: 2: 1 ethyl acetate-benzene-methanol mixture, 0.5 g of yellowish crystalline powdery 3-acetylamino-4-hydroxy- α - [N- (1-methyl-2-p-hydroxyphenylethyl) - Receive amino] acetophenone (used in Example 23 according to DE-PS 23 05 092).

NMR (D₆-DMSO):
δ : 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).

In Table II are the structural formulas of manufactured products specified.  

Table III

Claims (11)

1. Compounds of the general formula or their salts, in which R¹ denotes one of the following radicals: 2. Compounds of the general formula or their salts, in which R² denotes one of the following radicals: 3. Compounds of the general formula or their salts, in which R³ denotes one of the following radicals: 4. Compounds of the general formula or their salts, in which R⁴ denotes one of the following radicals: 5. Compounds of the general formula or their salts, in which R⁵ denotes one of the following radicals: 6. Compound of the formula or their salts. 7. Compound of the formula or their salts. 8. Compound of the formula or their salts. 9. Compound of the formula or their salts. 10. Compound of the formula or their salts. 11. Compound of the formula or their salts.