DD212957A5 - PROCESS FOR THE PREPARATION OF 1-ISOPROPYLAMINO-3-ARYLOXY-2-PROPANOLS AND MEANS FOR THEIR PREPARATION - Google Patents

Abstract

The invention relates to a novel production process of title compounds which can be used as beta-blockers in medicine. The aim of the invention is a cost-effective design of the process with improved yield. It is an object of the invention to provide a new preparation process for 1-isopropylamino-3-aryloxy-2-propanols via a novel intermediate. According to the invention, compounds of the general formula Ar-O-Ch-2-CH (OH) -CH 2 -NHCH (CH deep 3) deep 2, where Ar is a substituted aromatic radical, are obtained by reacting a compound of the formula (see overleaf). reacted with a compound of the formula ArOH and removed from the resulting compound IV, the benzhydryl group.

Description

Berlin, 5, 4, 84 AP C 07 C / 258 478 7 63 351 12/37

A process for the preparation of l-isopropylamino-S-aryloxy-Z- propanols ,,,, ,,,

Field of application of the invention

The invention relates to a novel process for the preparation of isopropylamino-3-aryloxy-2-propanols of the general formula

ArOCH ₂ CHCH ₂ NHCH (CH ₃ ) ₂ OH

wherein Ar is a substituted aromatic radical. These compounds can be used in medicine as blockers.

Known tec hni solutions

A process for the preparation of the abovementioned compounds are known for example from the GS-PS 1,247,384 and 1,285,038 and SE-PS 354 851. However, the starting materials used in these processes, in particular the phenol component, are relatively expensive. Even the yields are not always satisfactory »

aim the invention

It is an object of the invention to make the process more cost effective and with improved yield.

, "Err J-Γι O

63 351 12/37

Essence of the invention

It is an object of the present invention to develop a novel process for the preparation of isopropylamino-S-aryloxy-propanols via a novel intermediate,

According to the invention, the new compound 3- (N-isopropyl-N-benzhydrylamino) -1, 2-epoxypropane of the general formula II

CH (CH ₃ ) ₂

- CH - CH ₂ - N '

with a compound of general formula III

ArOH

III

implemented, wherein Ar is an aromatic radical.

The reaction product is a compound of general formula IV

ArOCH ₂ CHCH ₂ N.OH

^CH

IV

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The benzylhydryl group of this compound can be removed under mild conditions, for example by means of ants or acetic acid or by catalytic hydrogenation. "Removal produces benzhydrol, which can be recovered and converted into benzhydryl chloride or bromide."

The main advantage of the process of the invention is that it is now possible to first produce an intermediate to which the most expensive part of the compound, the phenolic moiety, is attached. This intermediate of formula II is common to all the desired end products. Thus it is easy to prepare all the different β-blockers using only one starting material, intermediate II. The end products can be obtained in high yields, so that this process is also very economical. "

The preferred reaction conditions are: reaction temperature at about 130 C, inert atmosphere (for example nitrogen atmosphere) and presence of an alkaline catalyst such as sodium or potassium tert-butoxide.

The following examples describe in detail the preparation of the intermediate and the preparation of the final products

example 1

Preparation of the intermediate of the formula II

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a) 1-Chloro-3- (N-isopropyl-N-benzhydrylamino) -2-propanol

590 g (6.4 mol) of 1-chloro-2,3-epoxypropane and 225 g (1 mol) of isopropylbenzhydrylarea were refluxed at 120 ° C. for 20 hours. The excess 1-chloro-2,3-epoxypropane was removed at low pressure to give 318 g (about '100 %) of the desired product as a viscous oil having a boiling point of 150 C (0.2 mm (partial decomposition).

b) 3- (N-Isopropyl-N-benzhydrylamino) -1,2-epoxypropane

318 g (1 mol) of the crude product obtained in stage a) and 112 g (1 mol) of potassium tert-butoxide were heated in 1000 ml of thylac et amide for 5 hours at 70.degree. The potassium chloride was filtered off and the solvents evaporated at reduced pressure from the filtrate. This gave 280 g (about 100 %) of the desired product as a viscous oil, boiling point 128 ° C / 0.15 mm.

Example 2

a) 1- (N-isopropyl-N-benzhydrylamino) -3- (2-acetyl-4-butyramidophenoxy) -2-propanol

28.1 g (0.1 raol) of the crude product obtained in step b) of Example 1 and 22.1 g (0.1 mol) of 2-acetyl-4-butyramidophenol and O, 3 g of potassium tert-butoxide in 17 ml of DMA were heated for 20 hours at 130 ⁰ C under nitrogen. The

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The reaction mixture was dissolved in 250 ml of toluene and washed with dilute NaOH solution and water. The solvent was removed under reduced pressure. The product can be recrystallised from ether, m.p. 115-117 ° C.

b.) l ~ isopropylamino-3 - (2-acetyl-4-butyrarnida-phenoxy) -2-propanol (acebutolol)

25.0 g (0.05 mol) of the product obtained in step a) and 1 g of 10% palladium on carbon catalyst in 100 ml of methanol was hydrogenated at normal temperature and pressure in a hydrogen atmosphere for 2-3 hours. The mixture was filtered and the solvent removed under reduced pressure. The residue was dissolved in 1N hydrochloric acid and extracted with methylene chloride. The aqueous layer was treated with charcoal, filtered and the filtrate made alkaline with NaOH solution. The desired product is obtained in crystallized form, yield 16.0 g (95%), mp 119-122 ⁰ C.

Example 3

a) 1 ~ (N-isopropyl-N-benzhydrylamino) -3 - / "" 4- (2-methoxy-ethyl)

28.1 g (OjI mol) of the product obtained in step b) of Example 1 and 15.2 g (0.1 mol) of 4- (2-methoxyethyl) phenol and 0.3 g of potassium tert-butoxide in 20 ml of DMA were heated at 130 ° C for 20 hours. The separation was carried out as in example 2, step a), whereby 42.0 g (97 %) of the

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- 5a - 'wished product as a viscous oil.

b) 1-isopropylamino-3- / 4- (2-methoxyethyl) phenoxy-J7-2-propanol (methoprolol)

The benzhydryl group of the product of step a) was removed as in example 2 step b). The mixture was filtered and the solvent removed under reduced pressure. The residue was dissolved in 1 N hydrochloric acid and extracted with methylene chloride to remove the benzhydrol or diphenylmethane. The aqueous solution was made alkaline and the product extracted with toluene. The solvent was removed at reduced pressure to give the desired product; Melting point about 45 ⁰ C, yield 95%.

Example 4

a) 1- (N-isopropyl-N-benzhydrylamino) -3- (4-carbamoylmethylphenoxy) -2-propanol

The procedure was analogous to that of Example 2, step

a) and 28.1 g of compound II and 15.1 g of carbamoylmethylphenyl were used. This gave 42.3 g (98 %) of the desired product as a viscous oil,

b) 1-Isopropylamino-3- (4-carbamoylmethylphenoxy) -2-propanol (Atenolol)

Procedure ¹ was as in Example 2, step b) to give the desired product; Yield 94% _t Melting point 146-148 ⁰ C.

Claims (4)

Erfindunqsanspruch 1, Process for the preparation of compounds of general formula I. -CH ₃ Ar-O-CH ₀ -CH-CH ₀ -NHCH ' OH ^CH 3 wherein Ar is a substituted aromatic radical, characterized in that a compound of general formula II . _nu CH ^ * CH CH "-CH-CH-N. _h .  c. " that is 3- (N-isopropyl-N-benzhydrylaraino) -1,2-epoxypropane with a compound of general formula III Ar-OH where Ar is the o, g. Is reacted to form a compound of general formula IV CH- subst. Ar-O-CH ₂ -CH-CH ₃ -N-C OH CH ^CH 3 63 351 12/37 d. i. l- (N-isopropyl-N-benzhydrylamino) -3 ~ subst. Aryl-2-propanol from which the benzhydryl group is removed. 2. The method according to item 1, characterized in that the reaction of the compound of formula II with the compound of formula III is carried out in the presence of an alkaline catalyst. 3. The method according to item 2, characterized in that the alkaline catalyst is potassium or sodium tert-butoxide. 4. The method according to item 3, characterized in that the reaction in dimethylacetamide!
Nitrogen atmosphere takes place. Reaction in dimethylacetamide at about 130 C below