The method of reducing the content of ethyl ester of 3-dimethylamino-2 - phenylpropionic acid in solutions of ethyl ester of 2 - dimethylamino-1-phenyl-3-cyclohexen-1-carboxylic acid

 

(57) Abstract:

The described method of reducing the amount of ethyl ester of 3-dimethylamino-2-phenylpropionic acid in polluted specified ether solution of ethyl ester of 2-dimethylamino-1-phenyl-3-cyclohexen-1-carboxylic acid is not miscible with water solvent by mixing this solution with 0.5 to 2.0 equivalents of carboxylic acid per mole of the ethyl ester of 2-dimethylamino-1-phenyl-3-cyclohexen-1-carboxylic acid, followed by stirring the resulting mixture at a temperature of 50-100oC.

The present invention relates to a method for reducing the amount of ethyl ester of 3-dimethylamino-2-phenylpropionic acid [2] ethyl ester 2-dimethylamino-1-phenyl-3-cyclohexen-1-carboxylic acid [1], which is the initial product to obtain analgesic of Tilidine. Tilidin is a TRANS-isomer ethyl ester 2-dimethylamino-1-phenyl-3-cyclohexen-1-carboxylic acid and commercially available in the form of a hemihydrate of tilidinhydrochlorid.

Ethyl ester of 2-dimethylamino-1-phenyl-3-cyclohexen-1-carboxylic acid is formed in the form of CIS/TRANS-isomeric mixture in the interaction of ethyl ether athropology acid with 1-dimethylaminoethanol the HEXEN-1-carboxylic acid, which does not require the use of 1-dimethylaminopyridine for the reaction with ethyl ether athropology acid selected form; on the contrary, this method is carried out so that CROTONALDEHYDE is subjected to interaction with dimethylamine in the presence of potassium carbonate as the water-binding means, and catalytic amounts of quinone in an inert solvent at temperatures of from 3 to 5oWith and thus obtained reaction product is subjected to interaction with ethyl ether athropology acid, obtaining the ethyl ester of 2-dimethylamino-1-phenyl-3-cyclohexen-1-carboxylic acid (CIS/TRANS-isomeric mixture).

The synthesis is accompanied by the formation as a side component ethyl ester of 3-dimethylamino-2-phenylpropionic acid.

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Formally, the ethyl ester of 3-dimethylamino-2-phenylpropionic acid formed in the reaction mixture by adding dimethylamine to ethyl ether athropology acid and dimethylamine is released, for example, as a result of polycondensation 1-dimethylaminopyridine or as a consequence of the processes of condensation between 1-dimethylaminoethanol and excess crotonic aldehyde.

The number of generated kolichestvo ethyl ester athropology acid and dimethylamine and in addition, it is influenced by the type of solvent [Ann. Chem. 728, 64 (1969)]. The presence of potassium carbonate in the reaction time, apparently, inhibits the formation of ethyl ester athropology acid.

Ethyl ester of 3-dimethylamino-2-phenylpropionic acid is not removed by a known method (German patent application DE 1923620) isolation and purification of the ethyl ester of 2-dimethylamino-1-phenyl-3-cyclohexen-1-carboxylic acid (CIS/TRANS-isomeric mixture). When the separation of the isomers with the aim of highlighting Tilidine (TRANS-isomer) in a known manner (German patent application DE 1923620, patent application GB 1226318), for example, by selective complexation with zinc ions or selective salt formation with oxalic acid, even the accumulation of impurities relative to the active substance (German patent application DE 1923620), resulting to achieve the specified maximum value content of ethyl ester of 3-dimethylamino-2-phenylpropionic acid 0,10% tilidin-hydrochloride-hemihydrate is necessary to carry out the separation of the ether, for example, by recrystallization of the salt Tilidine.

Although in the German patent application DE 1923620 implies that poluchenii it is possible to achieve the content of the ethyl ester of 3-dimethylamino-2-phenylpropionic acid is about 0.1%. In practice, however, it turns out that this content is from 0.3 to 2%.

There is therefore a need for a simple and cheap way of reducing the amount of ethyl ester of 3-dimethylamino-2-phenylpropionic acid at an early stage of the process of obtaining Tilidine.

The object of the present invention is a method of reducing the amount of ethyl ester of 3-dimethylamino-2-phenylpropionic acid in polluted this ether solution of ethyl ester of 2-dimethylamino-1-phenyl-3-cyclohexen-1-carboxylic acid is not miscible with water solvent, which consists in the fact that this solution is mixed with 0.5 to 2.0 equivalents of carboxylic acid per mole of the ethyl ester of 2-dimethylamino-1-phenyl-3-cyclohexen-1-carboxylic acid and the mixture is stirred at a temperature of 50-100oC.

As is not miscible with water solvent suitable aromatic hydrocarbons such as toluene, cyclic or acyclic aliphatic hydrocarbons, such as cyclohexane, or aliphatic ethers such as diisopropyl ether. As carboxylic acids suitable aromatic and aliphatic carboxylic acids, such as formic acid, and preferably acetic Ki the th ether 2-dimethylamino-1-phenyl-3-cyclohexen-1-carboxylic acid.

Thus obtained mixture is stirred at a temperature of 50-100oWith, preferably 70-90oSince, typically, for about 0.5-2 hours until the content of the ethyl ester of 3-dimethylamino-2-phenylpropionic acid, valid for the further process of obtaining.

Upon completion of the reaction, ethyl ester 2-dimethylamino-1-phenyl-3-cyclohexen-1-carboxylic acid produce in the usual manner from the reaction mixture. So, for isolation and purification of the ether, the reaction mixture can be mixed with water and podselect. Then the aqueous phase can be separated, the organic phase, optionally washed with a solution of sodium sulfite and focus.

Thereby obtaining the ethyl ester of 2-dimethylamino-1-phenyl-3-cyclohexen-1-carboxylic acid, which contains less than 0,10% ethyl ester of 3-dimethylamino-2-phenylpropionic acid.

When cleaning is preferably used CIS/TRANS-isomeric mixture formed during the synthesis of the ethyl ester of 2-dimethylamino-1-phenyl-3-cyclohexen-1-carboxylic acid. When removing the ethyl ester of 3-dimethylamino-2-phenylpropionic acid new way of CIS/TRANS-isomerization of ethyl ether 2-dimethylamino-1-phenyl-3-cyclohexen-1-carboxylic Ylamino-1-phenyl-3-cyclohexen-1-carboxylic acid in acetic acid or aqueous acetic acid solution establishes the equilibrium isomers (DE 1951587). As a new way to clean almost no CIS/TRANS-isomerization, this method can be applied to Tilidine, that is, TRANS-isomer ethyl ester 2-dimethylamino-1-phenyl-3-cyclohexen-1-carboxylic acid. Needless to say, the ethyl ester of 2-dimethylamino-1-phenyl-3-cyclohexen-1-carboxylic acid for cleaning may be in CIS-form.

The proposed method is formally based on the elimination of dimethylamine ethyl ester of 3-dimethylamino-2-phenylpropionic acid. Resulting from the elimination of the diamine Antropova acid does not interfere with further processing, but nevertheless it can be easily removed by extraction of the solution of the ethyl ester of 2-dimethylamino-1-phenyl-3-cyclohexen-1-carboxylic acid acid and acid leaching of the organic extract is not miscible with water solvent.

Thus, the advantage of the proposed method is that when receiving Tilidine this method allows the early work simply, quickly and cheaply to reduce the amount of ethyl ester of 3-dimethylamino-2-phenylpropionic acid so that the ether does not already blagopri the-3-cyclohexen-1-carboxylic acid (CIS/TRANS-isomeric mixture) [the content of the ethyl ester of 3-dimethylamino-2-phenylpropionic acid (IHVR): 1%], dissolved in 40 ml of cyclohexane is heated with 3.0 g (0.05 mol) of acetic acid for 2 hours under reflux. After cooling, add 30 ml of water. A two-phase mixture is alkalinized with sodium hydroxide solution. Then separated from the aqueous phase. The organic phase is washed with 30 ml of water and concentrate. Get a 13.4 g (98%) of an isomeric mixture of ethyl ester of 2-dimethylamino-1-phenyl-3-cyclohexen-1-carboxylic acid constant composition in terms of the ratio of CIS/TRANS-isomers with the content of ethyl ester of 3-dimethylamino-2-phenylpropionic acid of 0.05% (IHVR).

The method of reducing the content of ethyl ester of 3-dimethylamino-2-phenylpropionic acid in polluted specified ether solution of ethyl ester of 2-dimethylamino-1-phenyl-3-cyclohexen-1-carboxylic acid in a water-immiscible solvent, which comprises adding to this solution 0.5 to 2.0 equivalents of carboxylic acid per mole of the ethyl ester of 2-dimethylamino-1-phenyl-3-cyclohexen-1-carboxylic acid and stirring the resulting mixture at a temperature of 50-100oWith, and the content of the ethyl ester of 3-dimethylamino-2-phenylpropionic acid is below 0.10%.

 

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