DE1144291B - Process for the preparation of an optically active broncholytically active compound - Google Patents

Description

GERMAN

PATENT OFFICE

N15811IVb / 12q

REGISTRATION DATE: NOVEMBER 3, 1958

NOTICE THE REGISTRATION AND ISSUE OF THE EDITORIAL: 28. F E B R U A R 1963

From British patent specification 789 033 it is known that a compound of the formula

HO

-CH-CH ₂ -

OH

NH-

- CH -

CH ₃

- CH,

-OH

(D

has a particularly interesting broncholytic activity and especially other chemically largely is superior to similar compounds in this regard.

It has now been found that when an optically active compound of this formula is prepared by that by a process known per se, a levorotatory compound of the formula Method of manufacture

an optically active broncholytic

effective connection

Applicant:

N. V. Philips' Gloeilampenfabrieken, Eindhoven (Netherlands)

Representative: Dipl.-Ing. H.'Zoepke, patent attorney, Munich 5, Erhardtstr. 11

Claimed priority: The Netherlands, November 5, 1957 (No. 222 169)

HO

HO

CH-CH ₂ -NH ₂ (II) OH

Hendrik Durk Moed and Jan van Dijk, Weesp

(Netherlands) have been named as inventors

or a salt thereof with a compound of the formula

CH ₂ -C = O (III)

CH ₃

reductively aralkylated, a compound is obtained which has twice as much broncholytic activity like the known compound of the above formula I.

It has been shown to do this Process is important, preferably not the pH of the reaction mixture during the process lower than 3 and not higher than 8 and in particular to choose a pH value between 4 and 7.

This is e.g. B. achievable in that of a salt of the levorotatory l- (3 '-, 4'-dihydroxyphenyl) -2-aminoethanols- (l), in particular from the salt of a weak acid, e.g. B. formic acid, acetic acid, Propionic acid, butyric acid or benzoic acid, especially acetic acid, is assumed. In these In some cases, an excess of the weak acid can safely be used to form the salt. Should that Strong acid salts are used, the best result will be obtained by forming the Salt below the calculated amount of acid, e.g. B. 5 to 10%> remains. Preferably in such a case Use phosphoric acid or hydrochloric acid.

A suitable buffer solution can also be used, ζ. Β. an acetic acid sodium acetate solution, can be used to to maintain the mentioned pH value. Solutions of the salts of weak acids of the levorotatory l-l- (3 ', However, 4'-dihydroxyphenyl) -2-aminoethanols buffer the pH of the reagent even without further additives in a sufficient way; likewise the salts of the secondary amine formed in the reaction such acids.

The reduction is expedient with hydrogen and a metal catalyst, in particular from the Group of precious metals or the nickel group. Catalysts of the precious metals platinum and Palladium, namely platinum in the form of platinum oxide (Adams catalyst), are particularly suitable.

The reductive aralkylation can be carried out in two stages by first adding the Schiff base is formed and then reduced to the desired product; however, it is more advantageous to use the left-handed one 1 -1 - (3 ', 4' - dihydroxyphenyl) - 2 - aminoethanol- (l) with the compound of formula III under implement a simultaneous reduction.

309 537/409

3 4

The reduction can be added to a 2η ammonia solution at room temperature below 10 cm ^3. Thereby atmospheric pressure or with a slight difference the optically active 1- (3 ", 4" -dihydroxy pressure can be carried out. Phenyl) -2- [r-methyl-2 '- (4'"- hydroxyphenyl) -ethyl-

If desired, the reaction and reduc-amino] -ethanol- (l) can be used as a viscous mass. The water ion take place in the presence of a solvent. Story was poured from this mass and the latter suitable solvents are lower alcohols, e.g. B. stirred several times with distilled water, Methanol, ethanol, propanol, butanol. the water being poured off in each case. By

In order to ensure proper separation of the desired heating in a little water, the product of the unreacted starting material then became too crystalline. The crystals were filtered off with suction, with reaching, it is essential to wash the reaction product after io water and dry in vacuo. AusAblauf to solve the reaction in water and yield 4.00 g (0.0132 gram moles) = 53 ° / ₀ of theory. Addition of ammonia from the solution to melting point 152 to 155 ⁰ C with decomposition. Specificides. This results in a pure or essentially fishless rotation of the hydrochloric acid salt into an aqueous pure product. Solution: -25 °.

The method according to the invention produces the 15 The ultraviolet absorption spectrum of the substance, broncholytically very effective, optically active left-hand side measured on a solution in anhydrous ethanol, rotating 1- (3 ", 4" -dihydroxyphenyl) -2- [l'- methyl- had the following characteristic values: 2 '- (4'"- hydroxyphenyl) -ethylamino] -ethanol- (l)
no or no significant racemization occurs. « Maximum (λ - 2800A) = 4750

The broncholytic effect, ie the ability to obtain 20 _ε maximum (λ = 2250 Å) = 14400 by injection with acetylcholine, z. B. in guinea pigs (Cavia), caused constriction of the bron- From this ultraviolet absorption spectrum can be remedied, it can be seen for the levorotatory l- (3 ", that the substance is completely free of starting 4" -dihydroxyphenylr2- [r -methyl-2 '- (4'"- hydroxy substances and by-products is. phenyl) -äthylamino] -ethanol- (l) many times greater than 25 The bronchospasmolytic activity of this substance is that of the corresponding d-form and also considerable and its effect on the blood circulation is greater than that of l- (3 ', 4'-dihydroxyphenyl) -2-isopro- double that of the racemic experiments on guinea pigs (Cavia) described in the Dutch patent pylaminoethanol- (l). registration 195267 binding.

give that the 1-form of l- (3 ", 4" -dihydroxyphenyl) - 30 _A ...., · · 1 _TT

2- [l ^ methyl-2 '- (4' '- hydroxyphenyl) -äthylamino] -ätha- exemplary embodiment II

nols- (l) at a 40-50 times lower A solution of 1.69 g (0.010 gramol) left-

Dosage has a broncholytic effective rotating l- (3 ', 4'-hydroxyphenyl) -2-aminoethakeit as the d-form; it is 2 to 2.5 times nol- (l) and 1.50 g (0.010 gramol) l- (4'-hydroxy) more effective than the racemate and about 16- to 35-phenyl) -propanone- (2) in 3.85 cm ³ 2.48 N-hydrochloric acid 2O times more effective than l- (3 ', 4'-dihydroxy- (0.0095 gramol) and 50 cm ³ anhydrous ethanol phenyl) -2-isopropylaminoethanol- (l) . was in the presence of 0.10 g of finely divided platinum

The by the inventive method he as a catalyst at room temperature under one holding compound can be in the form of their salts, e.g. B. Pressure of about 1.1 atmospheres with hydrogen their hydrochloric acid, phosphoric acid, acetic acid or 40 hydrogenated. The pH of the reaction mixture was benzoic acid salt, in injection liquids about 4.5.

be turned. In tablets, the free base can also be slightly more than the calculated amount

Find application. (0.010 gramol) hydrogen has been absorbed

The method according to the invention is on hand, the hydrogenation was stopped and the catalyst

explained in more detail in the following examples. 45 sator removed by filtration. The filtrate was im

Evaporated in vacuo to a residue of about 3 g. This was mixed with 20 cm ^{3 of} water,

Embodiment I again concentrated to about 3 g, again with 10 cm ³

Water added and this solution with three servings

A suspension of 3.76 g (0.025 gram mol) of concentrated ammonia solution made alkaline, l- (4'-hydroxyphenyl) propanone- (2) and 4.23 g (0.025 which results in the optically active base 1- (3 ", 4 "-Di-Grammol) levorotatory 1- (3 ', 4'-dihydroxyphenyl) - hydroxyphenyl) -2- [r-methyl-2' - (4"'- hydroxyphenyl) -2-aminoethanol- (l) at 50 cm ³ 96 ° / _o sodium ethanol wur- 55 ethylamino] -ethanol as a viscous mass separated out, walls 1.48 cm ³ (0.026 gram moles) of acetic acid and 0.20 g rend the unreacted l- (3 ', 4'-dihydroxyphenyl) -Platinum oxide (Adams catalyst) was added and the 2-aminoethanol remained in solution for a while.Suspension then with hydrogen at Zimmer- This solution was hydrogenated from the settled base at about 0.1 atm. Overpressure. As poured and the viscous Mass again with a little practically no more hydrogen was taken up 60 water was washed.

(after uptake of 0.025 mol), the catalyst was then the base by gentle er-

Sator and undissolved starting material removed by heating in the presence of 3 cm ^{3 of} water after scratching and filtration. The filtrate (pH about 5.5) was crystalline, then filtered off with suction, distilled off with a little alcohol in vacuo and the residue was ^{washed with water and dried in vacuo, after 40 cm 3 of} water had been added three times with diethyl, yield 0.74 g ( = 0.0024 gramol) = 24% of the ether extracted. From the aqueous theory thus obtained. Melting point 151-152 ⁰ C. The ultra-solution of the ether was purified by brief switching violet absorption spectrum of the base and the spezidampfen removed in vacuo. Subsequently, fish rotation of the hydrochloric acid salt corresponded to the

Values that are used for the one produced according to the first example Connection were determined.

This shows that the substance was completely free of raw materials and by-products.

Claims (1)

PATENT CLAIM: Process for the preparation of an optically active broncholytically active compound of the formula HO - HO CH-CH ₂ -NH-CH-CH ₂ -CH -OH or a salt thereof, characterized in that a levorotatory compound of the formula CH. formula HO HO HO CH - CH ₂ - NH ₈ OH CH ₂ -CO CH, reductively aralkylated in a manner known per se. or a salt thereof with a compound of the pamphlets considered: German Patent No. 538 455; German interpretation document T 2021 IVb / 12q. © 309 5S7 / 409 2.