DE2151716B2 - Process for the preparation of esters of 2-aryl-2-dimethylamino-lalkanols - Google Patents

Description

in the

A is hydrogen or RO, where R 'is a lower alkyl radical and π is either zero or I ₁ 2 or 3,

R ² denotes a lower alkyl radical,

Y is hydrogen or halogen or an alkoxy radical and a is either zero or 1, 2 or 3,

X either a single bond or oxygen,

ρ is either zero or 1, 2 or 3,

characterized in that an ester of the formula

15th

25th

-X- (CH ₂ L-COOR

(D

in which X, Y, a and ρ have the same meaning as above have and R is a lower alkyl radical, with an amino alcohol of the formula

(H)

in which A, R ² and η have the same meaning as above,

in benzene, toluene or xylene or a mixture this solvent with a molar ratio between ester and amino alcohol of C5 «to 2, one Temperature between 70 and 145 ° C and a reaction time between 30 minutes and 4 hours in the presence of a metal alcoholate as a catalyst in a concentration between 0.02 and 0.1 mol each Moles of amino alcohol transesterified.

2. The method according to claim I _1, characterized in that the reaction is carried out at a molar ratio between ester and amino alcohol of 1.5 to 1, a temperature of 100 to 110 ° C and a reaction time between 1 and 2 hours

In a known process (FR-PS 13 44 455) one leaves a C-quaternary amino alcohol according to the following equation act on an acid chloride:

(RO) _n

R ² (R ¹ O) ₁

C-CH ₂ OH + R ⁵ COX -N (R ³ ) ₂

In the above formula, R ¹ and R ^{2 have} the same meaning as in the process according to the invention; R ³ denotes hydrogen or a ^{lower alkyl radical, R 5} denotes an alkyl, aryl or aralkyl radical and X a halogen atom, in particular chlorine. This known synthesis of the amino ester of the formula A is accompanied by the formation of a non-negligible amount of a by-product with properties which differ from the desired product and which must be separated off by crystallization. This in turn leads to a loss of the amino ester. In order to overcome this disadvantage, other synthetic routes were used. It was found that a reaction carried out according to the usual regulations for transesterification can, under certain process conditions, lead to a compound whose molecular weight and empirical formula match that of the amino ester A, but which differs from the latter in terms of its running behavior in the thin-layer chromatogram and its pharmacological properties . It has been found that these are esters of amino alcohols which are tertiary with regard to the position of the OH group. A mixture of esters of such amino alcohols and an amino alcohol according to formula A was therefore to be expected when using the usual methods.

C-CH ₂ -O-CO-R ⁵

N (R ³ J ₂

The process according to the invention for the preparation of the esters mentioned in claim 1 aims at this from, with the help of a specific combination of process conditions, the formation of by-products, in particular the esters of tertiary amino alcohols mentioned, reliably to be avoided.

This is achieved according to the invention by a transesterification between an ester of an aliphatic Low molecular weight alcohol of the formula

in which X, Y, a and ρ have the same meaning as indicated in claim 1 and R is a lower alkyl radical, and an amino alcohol of a higher molecular weight M) of the formula

Kc '

(in

R ² N (CHj) ₂

in which A, R ² and η have the same meaning as in claim 1,

in benzene, toluene or xylene or a mixture of the solvents mentioned at a molar ratio between the ester and the amino alcohol between 0.5 and 2, a temperature of the reaction medium between 70 and 145 "C and a reaction time between 30 minutes and 4 hours in the presence of a Metal alcoholates as a catalyst, the concentration of which is between 0.02 and 0.1 mol per mol of amino alcohol Such a process represents a specific combination of process conditions under which the Formation of the cyclic cations of the ethylene-ammonium compound type, which otherwise occur as intermediates restricted and the conversion of this

Cations to undesired esters of tertiary amino alcohols do not require reaction energy provided.

The process, which is based on a transesterification, immediately gives a reaction product that does not have any Loss-generating cleaning is more required.

The esters obtained can be converted into salts in a known manner in order to facilitate their usability will.

In the course of its investigations, the applicant established a number of parameters to be observed, which are essentially compiled in the following table:

Mole VIoI Mole Ester i \ mino- Na-Alko alcohol holat 0.5 0.075 1 I. 0.075 1 0.020 14th 0.075 14th 0.075 14th 0.075 14th 0.075 2 0.075 2 0.1Ow

Reaction solvent Benzene toluene xylene

reaction time

Gross mole Ester III

3 hours. 0.2 3 hours. 04 4 hours 0.3 04 hours 0.4 1 H. 0.6 2 hours. 0.7 2 hours. 0.6 2 hours. 0.7 4 hours 0.45

As far as the molar ratios between the ester I used and the amino alcohol II used are concerned, so these can vary between & 4 and 2. However, the best ratio is around 14

In order to achieve the specific effect of the reaction, the temperature of the reaction medium must be kept in a range between 70 and 145 ° C. According to a preferred embodiment of the invention, the temperature is between 100 and 110 ^° C.

Depending on these temperatures, the reaction time must advantageously be between 30 minutes and 4 hours but between 1 and 2 hours.

The reaction medium, which is of paramount importance, consists of non-polar solvents such as Benzene, toluene and xylene. Two of these solvents can be used in different ratios be mixed in order to obtain a binary reaction medium, or together in a three-component mixture different ratios can be used.

To the yield and the specific effect of the To improve the reaction, the use of a transesterification catalyst is required. To this The purpose of the reaction medium can be metal alcoholates, in particular sodium methylate or -äthy / at in ratios between 0.02 to 0.1 mol per mole of amino alcohol II add, as from the aforementioned Table can be seen.

Failure to observe these parameters and their limits thus determined leads to the formation of secondary products, which contaminate the product produced and thus make expensive cleaning necessary.

In particular, reaction times of more than 4 hours lead to the occurrence of side reactions in turn lead to the formation of secondary substances.

Carrying out the process according to the invention within the limits defined above, on the other hand, allows the direct preparation of pure amino alcohol esters of type III with, at the same time, excellent yields (up to 794% of theory).
] ■> Examples for carrying out the method according to the invention are given below.

example 1

3,44-Trimethoxybenzoic acid-2-phenyl-2-dimethylamino-n-butyl ester

A solution of 194 kg of 2-phenyl-2-dimethylaminon-butanol and 34 kg of 3,4,5-trimethoxybenzoic acid methyl ester in 400 l of toluene is refluxed.

4-> After dehydration, the solution is at 80 ° cooled. 5 kg of sodium methylate are added, the mixture is gradually heated to about 110 ° and this temperature is maintained Upright for 2 hours. After the solution has cooled to about 25 °, 25 l of concentrated hydrochloric acid are added.

ίο The acidic aqueous fraction is washed out with toluene. The aqueous phase is made alkaline with sodium carbonate and extracted with methylene chloride. Dip organic phase is washed out to neutrality, then dried and evaporated. From the-

The vapor residue is crystallized from ethanol at 70 °. Yield: 22 kg of product, melting point: 78-80 °.

Example 2

3,44-Trimethoxybenzoic acid-2-phenyl-2-dimethylamino-n-butyl ester maleate

87.4 kg of 3,4,5-trimethoxybenzoic acid-2-phenyl-2-dimethylamino-n-butyl ester are heated and 283 kg of maleic acid in 3501 of water until homogenized. Man filter the solution and then let it rest. After crystallization, 106 kg of product are obtained. Melting point: 105-106 ° C.

Example 3

4-chloro-phenoxyacetic acid-2-phenyl-2-dimethylamino-n-butyl ester hydrochloride

19.5 kg of 2-phenyl-2-dimethylamino-n-butanol and 32.5 kg of ethyl p-chlorophenoxyacetate, dissolved in 4001 toluene, are obtained by fractional distillation of the Solvent dehydrated

The solution is cooled to 80 ⁰ C. After addition of 5 kg of sodium methylate, the reaction medium is gradually heated to 110 ° and held for 2 hours at this temperature. After cooling, the product is extracted with hydrochloric acid. The aqueous acidic

Fraction is washed out with toluene, then made alkaline with sodium hydroxide solution

The emulsion is extracted with methylene chloride, then washed until neutral and dried

Evaporation of the organic phase leads to an oily crude residue which hardens after cooling Yield; 29 kg.

The product is dissolved in 2001 diisopropyl ether This is done after gaseous hydrogen chloride has been passed through The crude hydrochloride obtained is centrifuged off

The product is purified by recrystallization from ethyl acetate

Yield: 22 kg, melting point: 101 -103 ⁰ C.

Claims (1)

Claims; 1. Process for the preparation of esters of 2-AryI-2-dimethylamino-1-alkanoIen of the general formula 10 N (CH ₃ J ₂