DE3147150C2 - Process for the production of epoxypropane derivatives - Google Patents

Abstract

The invention relates to a method for producing epoxypropane derivatives by reacting phenolates with epichlorohydrin in a solvent mixture of water and dimethyl sulfoxide with a composition of 1: 0.05 to 1: 2.

Description

0)

in which

R ^{1 represents} a straight-chain or branched alkanoylamino radical with up to 10 carbon atoms and

R ² denotes an alkyl radical with up to 6 carbon atoms

by reaction of a phenolate of the general formula (II)

R ³ - CO

(Π)

in which

R ¹ and R ^{2 have} the meaning given above

and
M means an alkali metal,

with epichlorohydrin of formula (III)

+ Cl-CH ₂ -CH

(DT)

CH ₃

in a solvent in the presence of alkali alcoholate, characterized in that the reaction is carried out in a solvent mixture of water and dimethyl sulfoxide of the composition 1: 0.05 to 1: 2 at temperatures between 10 and 50 ^° C. in the presence of alkali hydroxide

2. The method according to claim 1, characterized in that that one in a solvent mixture of water and Dimethyisuifoxid the composition 1: 0.2 to 1: 1.2 works.

3. Process according to Claims 1 and 2, characterized in that the reaction is carried out at Temperatures between 15 and 30 "C performs

4. Process according to claims 1 to 3, characterized in that compounds of the general formula (II) in which

R ^{1 represents} a straight-chain or branched alkanoylamino radical with up to 6 carbon atoms and

R ² denotes an alkyl radical with up to 4 carbon atoms

The present invention relates to a new advantageous process for the preparation of epoxypropane derivatives.

Such epoxypropane derivatives are valuable starting products in numerous chemical reactions. In particular, they are used as immediate precursors for Compounds with ^ -receptors blocking action, which are valuable drugs of Meaning.

ίο It has already become known, epoxypropane compounds using various organic solvents in the presence of alkali ions from phenolates and epichlorohydrin (cf. DE-OS 18 15 808). In the technical implementation

is this method has so far been preferred in anhydrous medium in the presence of alkali alcoholate worked (see. The embodiments in DE-OS 18 15 808).

Surprisingly, it has been found that epoxypropane derivatives of the general formula (1)

R ² -CO

CH ₂

in which

R ^{1 represents} a straight-chain or branched alkanoylamino radical with up to 10 carbon atoms and

R ² denotes an alkyl radical with up to 6 carbon atoms,

obtained when phenolates of the general formula (II) OM

R ² - CO

in which
R ¹ and R ^{2 have} the meaning given above

M means an alkali metal

with epichlorohydrin of formula (III)
O

+ Cl-CH ₂ -CH CH ₂

in a solvent mixture of water and dimethyl sulfoxide of the composition 1: 0.5 to 1: 2, preferably 1: 0.2 to 1: 1.2 at temperatures between 10 and 50 ^° C., preferably at 15 to 30 ^° C., in ' CgC "

Water / dimethyl sulfoxide ratios are very particularly preferred from 1: 0.4 to 1: 0.9.

With knowledge of the prior art, it could not be expected that by using the inventive specific solvent consisting of dimethyl sulfoxide and water in the specified Quantities obtained the epoxypropane compounds in such high yields and in such purity can be. The method according to the invention has the following advantages over those previously known Procedure on:

a) The epoxypropane derivatives are obtained in higher yield;

b) the reaction product contains the epoxypropane derivatives in higher purity, so that expensive There are no cleaning steps in the further implementation;

c) the reaction takes place practically at room temperature, so that there are no major energy costs;

d) through the use of cheap alkaline solution, the Use of alcoholates should be avoided.

The table below shows that the use of the solvent mixture according to the invention DMSO / water gives better yields and higher purities than the use of mixtures Alcohol, dimethylformamide (DMF) and acetone with water.

Tabel

Implementation of phenolates of the formula (II) with epichlorohydrin. Organic solvent: water in a ratio of 0.6: 1 each.

Yield *) Content of Yield in% Impurity in% re. inclination on pure in% substance Methanol / water 82.4 3U 56.8 Ethanol / water 81.8 28.4 58.6 Isopropanol / water 81.8 30.4 56.9 Acetone / water 77.8 28.3 55.8 DMF / water 69.0 30.4 48.0 DMF / NaOEt 92.0 40.4 54.8 xxr - 91.0 38.0 56.4 DMSO / water 91.5 16.8 76.1

*) The yield data relate to all of them Cases on directly accruing, not further purified product.

The further implementation of the epoxypropane derivatives to valuable active pharmaceutical ingredients takes place z. B. by reaction with alkylamines in inert organic solvents by customary methods (see DE-OS 18 15 808).

Of particular interest is the preparation of epoxypropane derivatives of the general formula (I) in which R ^{1 stands} for an alkanoylamino radical with up to 6 carbon atoms and R ^{2 stands} for an alkyl radical with up to 4, in particular with t> 2, carbon atoms

Particularly suitable alkali hydroxides are sodium and potassium hydroxide, especially sodium hydroxide, called

Examples
example 1

/
Q-CH ₂ -CH CH ₂

CH ₃ CO

NHCO-C ₃ H-Kn)

360 parts by weight of 5% sodium hydroxide solution, 100 parts by weight of 2-acetyl-4-n-butyramido-phenol, 833 parts by weight of epichlorohydrin and 200 parts by volume of DMSO are combined and stirred for 24 hours at room temperature. The precipitate is filtered off, washed with water and dried to give 114 parts by weight (913%), mp 130-132 ⁰ C and a Gehait of 83.2%..

The comparative experiments 1 to 6 of the table were carried out analogously to Example! 1 performed instead of DMSO the specified organic solvent was used in each case

Examples 2-5

Examples 2-5 are as in example! 1 carried out; however, instead of 200 parts by volume DMSO used the amounts given below

DMSO
Vüi.-Part

Yield in% content of
pollution

Yield in %

Pure substance

Example 2 100 Example 3 300 Example 4 400 Example 5 500

90.0 24.1 86.2 22.5 8th!," 20.7 61.7 18.2 Example 6

68.3
66.8
64.9
50.5

Procedure as in Example 1, but instead of the 5% sodium hydroxide solution, 5% potassium hydroxide solution is used. Yield: 90.5% with a content of 82.5%.

Claims (1)

Claims; 1. Process for the production of epoxypropane derivatives of the general formula (1) R ² -CO Ο —CH ₁ -CH-
\ CH,