FI66841B - PROCEDURE FOR FRAMSTATION OF AV 1-ISOPROPYL-AMINO-3- (2-ACETYL-4-BUTYRAMIDOPHENOXY) -2-PROPANOL - Google Patents

Description

66841 Process for the preparation of 1-isopropylamino-3- (2-acetyl-4-butyramidophenoxy) -2-propanol

The invention relates to acebutolol, i.e. 1-isopropyl-5-amino-3- (2-acetyl-4-butyramidophenoxy) -2-propanol (I) f- (COCH3 / H3 CH3CH2CH2CONH - <'OyD [: H2CHCH2NHCH1 N-' OH \ h3 10 manufacturing methods.

Asebutolol is a known drug.

GB 12473-4 discloses a process for the preparation of acebutolol in which 3- (2-acetyl-4-butyramidophenoxy-15s) -1,2-propylene oxide (II) / COCH 3

CH3CH2CH2CONH- ^ Qy-OCH2CH —CH2 II

20 is reacted with isopropylamine.

Application No. JP 57-2246 (published 7/1-82) (ref. Chem. Abstr. 97: 5962) discloses 1-isopropylamino-3- (2-allylphenoxy) -, 1-propylamino-3-phenoxy- or a process for the preparation of 1-isopropylamino-3- (2-allyloxyphenoxy) -2-propanol in which the corresponding 4-phenoxymethyl-1,3,2-dioxation of 1-2-oxide (III)

PhO-CH-CH CH-, IIT

2i I 2 30 I 1

V

0 is reacted with isopropylamine.

General methods for the preparation of 1-isopropylamino-3-aryloxy-2-propanols 35 are described, for example, in Kemisk Tidskrift, 1976, Nos. 10, 48 and Kemia-Kerni. 1978, No. 5, 186.

66841 2

Some variations in the preparation of acebutolol are also disclosed in patent applications FI 803226 and FI B03227.

It has now been found that acebutolol can be prepared by administering 4 - ((2- (1-methyl-2,5-dioxalanyl) -4-butyramido-5-phenoxy) methyl) -1,3,2-dioxathionan-2 -oxide (IV) CH0-CH-I 2 l 2 10 / Cl 2 -CH 3

0Η30Η20Η200ΝΗ- ^ Ο ^ -00Η20Η-CH2 IV

React with isopropylamine and treat the 1-isopropylamino-3- (2- (1-methyl-2,5-dioxalanyl) -4- (butyramidophenoxy) -2-propanol thus obtained with a mineral acid.

The compound of formula IV is novel. It can be prepared by giving the CV of 3- (2- (1-methyl-2,5-dioxanynyl) -20 4-butyramidophenoxy) -1,2-propanediol)

CFL CFL

i 2 i 2 25 / "CH3

CH3CH2CH2CONH-> CH2-CH-CH2 V

OH OH

react with thionyl chloride. The reaction is preferably carried out in an inert solvent at normal or reduced temperature in the presence of a tertiary amine.

The compound of formula V is also new. It is best prepared by ketalizing 2-acetyl-4-butyramido-phenol to 2- (1-methyl-2,5-dioxalanyl) -4-butyramidophenol 35 and reacting it with glycidol in the presence of a basic catalyst.

3,66841

The reaction of compound IV with isopropylamine is carried out by heating in a suitable organic solvent, preferably acetonitrile.

The intermediate 1-isopropylamino-3- (2-5 (1-methyl-2,5-dioxalanyl) -4-butyranophenoxy) -2-propanol is best treated in acetone with hydrochloric acid. This directly gives the hydrochloride salt of acebutolol, which is a form used in pharmaceutical preparations.

Adverse side reactions are the major weakness of the method of GB 1247384 10. In particular, when compound II

prepared from the corresponding phenol and epichlorohydrin, the phenol also reacts with the reaction product II. In addition, the reaction of compound II with isopropylamine readily leads to the corresponding isomeric 1-propanol. The overall yield of the process is already low in itself, and is further reduced by the purification measures required.

The method of application OP 57-2246 cannot be applied to the preparation of acebutolol, since 4 - ((2-acetyl-4-butyramidophenoxy) methyl) -1,3,2-dioxathiolane-2-oxide 20 cannot be prepared by the methods described.

The yield of the process according to the invention is good and only insignificant by-products are formed in negligible amounts. This also makes the method suitable for industrial production.

25

Example a) 3- (2- (1-Methyl-2,5-dioxalanyl) -4-butyramidophenoxy) -1,2-propanediol (V)

A solution of 4.5 g (0.06 mol) of glycidol in 60 ml of 1,1,2-trichloroethylene is slowly added to a boiling solution of 13.3 g (0.05 mol) of 2- (1 -methyl-2,5-dioxanyl) -4-butyramidophenyl and a catalytic amount of sodium methoxy in 60 ml of 1,1,2-trichloroethylene. The mixture is refluxed for 24 h under a nitrogen atmosphere.

The solvent is evaporated in vacuo to give 17.0 g (100%) of the desired product; 1 H-NMR (CHCl 3): δ = 0.097 (3Ht), 1.70 (2Hsxt), 1.72 (3Hs), 2.30 (2Ht), 3.50. . . 4.20 (11 Hm).

66841 δ 6.90 (1Hd), 7.50 ... 7.72 (2Hm), 9.10 (1Hs).

b) 4 - ((2- (1-Methyl-2,5-dioxalanyl) -4-butyramido-phenoxy) methyl) -1,3,2-dioxathiolane-2-oxide (IV)

A solution of 4.4 ml of thionyl chloride in 6 ml of dichloromethane is added to a solution of 17 g (0.06 mol) of compound V and 6.1 g (0.06 mol) of triethylamine in 60 ml of dichloromethane at 0 ° C: in. The mixture is stirred for 15 min at 0-5 ° C, washed with 0.1N hydrochloric acid and water and dried over Na 2 SO 4. The solution is evaporated to dryness in vacuo to give 20.7 g (93%) of the desired product; 1 H-NMR: 0.97 (3Ht), 1.70 (3Hs), 1.75 (2Hsxt), 2.30 (2Ht), 3.55 ... 4.80 (8Hm), 5.20 (1Hkv) ), 6.80 (1Hd), 7.40. . . 7.65 (1 Hs).

c) 1- (Isopropylamino-3- (2-acetyl-4-butyramido-phenoxy) -2-propanol (I) 19.3 g (0.05 mol) of compound IV and 30 ml of isopropylamine in 100 ml The solvents are removed under reduced pressure and acetone is added to the residue, the mixture is filtered and 0.04 mol of concentrated hydrochloric acid is added to the filtrate to give 16.4 g (88%) of acetobutol hydrochloride (m.p. 141-3 ° C). .

Il

Claims (7)

1. A process for the preparation of 1- 4 - ((2- (1-methyl-2,5-dioxalanyl) -4-butyramide-phenoxy) -methyl) -1,3,2-dioxathiolane-2-oxide CH 2 I 2 15 0 ^, 0 / C „CH 3 is reacted with isopropylamine and then the resulting 1-isopropylamino-3- (2- (1-methyl-2,5-dioxalanyl) -4-butyramidophenoxy-2 is treated -Propano 1 with mineral acid and, if desired, the obtained salt is converted to a free base 2. Process according to claim 1, characterized in that the reaction of 4 - ((2- (1-methyl-2,5-dioxalanyl) (4-Butyramidophenoxy) methyl) -1,3,2-dioxathiolane-2-oxide with isopropylamine is carried out in an organic solvent 1. Process according to claim 2, characterized in that the solvent is acetonitrile. 1 II 66841 4. A process according to claim 3, characterized in that the reaction is carried out by refluxing for approx. 20 hours. 35 Process according to any of claims 1 to 4, characterized in that the mineral acid is hydrochloric acid. i / t i