RU2612970C1 - Method for 1-benzyl-4-propioanilido-4-piperidinecarbonitrile preparation - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to a method for 1-benzyl-4-propioanilido-4-piperidinecarbonitrile preparation from 1-benzyl-4-anilino-4-piperidinecarbonitrile, propionic acid chloride and triethylamine. Interaction between gaseous ketene formed in a separate flask with 1-benzyl-4-anilino-4-piperidinecarbonitrile forms the target amide in high yield (84% of the theoretic value).

EFFECT: increased output of suitable product.

3 dwg

Description

The invention relates to research in the field of medicine, biology and chemistry, in particular to the optimization of methods for producing opiate receptor agonists, one of which is 1-benzyl-4-propioanilido-4-piperidinecarbonitrile, which is used as an intermediate in the preparation of highly effective analgesics.

The main directions of ongoing research in the synthesis of new compounds is the improvement of methods for producing various subtypes of compounds that act on opiate receptors.

Under these conditions, studies on the optimization of the synthesis of compounds of a number of piperidines as main intermediates in the preparation of k-receptor agonists are becoming relevant.

One such compound is 1-benzyl-4-propioanilido-4-piperidinecarbonitrile.

The preparation of this compound is known to involve the interaction of 1-benzyl-4-anilino-4-piperidinecarbonitrile with propionic acid chloride in the presence of triethylamine as an acceptor of the resulting hydrogen chloride reaction (URL: http://www.patents.com/us-4791120 .html). The yield of the target substance is not more than 66% (figure 1).

The difficulty of this method lies in the fact that it becomes necessary to rinse the chloroform layer with water to remove the organic salt triethylamine hydrochloride, in connection with this there is a loss of the main substance (2). In addition, after the addition of propionic acid chloride to the reaction, an induction period occurs, ending with a sharp spontaneous heating of the mixture due to the breaking of covalent bonds.

Empirically, 1-benzyl-4-propioanilido-4-piperidinecarbonitrile (2) was obtained in a manner different from the existing one in that the propionic acid chloride (3) and triethylamine (4) did not participate in the synthesis of the desired carbonitrile. These compounds interact in a separate bottle to form triethylamine hydrochloride (5) and ketene (6) (Figure 2).

It is the active gaseous ketene (6) with t _bales. = 26 ° C was further bubbled into a chloroform solution of 1-benzyl-4-anilino-4-piperidinecarbonitrile (1) and the target amide was formed (figure 3). The yield of 1-benzyl-4-propioanilido-4-piperidinecarbonitrile (2) was 84%.

Thus, it was possible to obtain the target compound in a manner whose advantages are, firstly, in the absence of the need to wash the chloroform layer after the reaction with water to remove triethylamine hydrochloride, which significantly reduces the loss of the main substance. Secondly, the ketene formed completely enters the reaction mixture, and in a pure form, which also increases the yield of the compound. Thirdly, we get rid of the induction period, since there is no breaking of the С-Сl bond. Fourth, the impurities existing in triethylamine and propionic acid chloride do not react with 1-benzyl-4-anilino-4-piperidinecarbonitrile due to the presence of a separate container for them, which also increases the yield of the target substance, and in addition allows use triethylamine and propionic acid chloride without prior purification.

The preparation of the starting compound (1) was carried out according to the method developed by the authors of the patent URL: http://www.patents.com/us-4791120.html. The remaining stages are described in the following methods.

Ketene Synthesis (6)

A three-necked flask with a capacity of 500 ml is equipped with a magnetic stirrer (an anchor with a Teflon coating), a bypass tube, a thermometer, a dropping funnel with a capacity of 250 ml. 278 ml (2 mol) of compound (4) are placed in a flask; 86.8 ml (2 mol) of compound (3) are added to a dropping funnel. With vigorous stirring at a temperature of 30 ° C, compound (3) is added dropwise to compound (4). The resulting ketene enters the next reaction through a branch pipe. The yield of compound (6) is 97%. Mass spectrum, m / z ( _Irel ): 377 (14), 279 (35), 187 (91), 91 (100).

Synthesis of 1-benzyl-4-propioanilido-4-piperidinecarbonitrile (2)

A 1000 ml three-necked flask is equipped with a magnetic stirrer, a reflux condenser with a dehumidifier, a thermometer, and a bubbler. 200 g of compound (1), 350 ml of chloroform are added to the flask. With gentle stirring at room temperature, ketene is bubbled through the solution for 30 minutes, periodically changing the desiccant in the reflux condenser. The filtrate was evaporated. 215 g (84%) of compound (2) are obtained. Mass spectrum, m / z ( _Irel ): 405 (12), 384 (11), 261 (41), 91 (100).

Claims (1)

A method of producing 1-benzyl-4-propioanilido-4-piperidinecarbonitrile from 1-benzyl-4-anilino-4-piperidinecarbonitrile, propionic acid chloride and triethylamine, characterized in that the propionic acid chloride and triethylamine do not participate in the synthesis of the target carbonite interact with each other in a separate bottle with the formation of triethylamine hydrochloride and ketene.

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