CZ292869B6 - Process for preparing N-[3-(3-cyanopyrazolo[1,5-a]pyrimidin-7-yl)phenyl]-N-ethyl acetamide - Google Patents

Abstract

In the present invention, there is disclosed a process for preparing N-[3-(3-cyanopyrazolo[1,5-a]pyrimidin-7-yl)phenyl]-N-ethyl acetamide of the general formula I, known under the zaleplon term, by the condensation of N-[3-[3-(dimethylamino)-1-oxo-2-propenyl]-.NY.-phenyl]acetamide of the general formula II, with 3-amino-4-cyanopyrazole of the general formula III, in a mixture of water with an organic solvent and in the presence of a strong acid cation-exchange resin.

Description

Technical field

The invention relates to a novel process for the preparation of N- [3- (3-cyanopyrazolo [1,5-a] pyrimidin-7-yl) phenyl] -N-ethylacetamide of formula I, known as zaleplon, which is used as a sedative and hypnotic.

(AND)

BACKGROUND OF THE INVENTION

Several different processes for the preparation of zaleplon of formula I have been described so far.

The earliest preparation disclosed in U.S. Pat. No. 4,626,538 describes the synthesis of zaleplon by condensation of N- [3- [3- (dimethylamino) -1-oxo-2-propenyl-N-phenyl] acetamide of formula Π with 3-amino-4-cyanopyrazole of formula III, by refluxing in acetic acid.

U.S. Pat. No. 5,714,607 describes a more advantageous (twice as fast) process with the addition of water.

In WO 02/100828, zaleplon of formula I is prepared by condensation of N- [3- [3- (dimethylamino) -1-oxo-2-propenyl-N-phenyl] acetamide of formula II and 3-amino-4-cyanopyrazole of formula ID in a mixture of water with a water miscible organic solvent, in an acidic environment, which is provided by the addition of a mineral acid.

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The disadvantage of these processes is the formation of the isomeric N- [3- (3-cyanopyrazolo [1,5-a] pyrimidin-5-yl) phenyl] -N-ethylacetamide of formula IV, [WO 02/100828], which is supported by an acidic environment , in an amount of several percent.

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SUMMARY OF THE INVENTION

These disadvantages, in particular the disadvantage of the higher content of unwanted by-product of formula IV, are solved by the process according to the invention, which is a process for the preparation of N- [3- (3-cyanopyrazolo [1,5-a] pyrimidin-7-yl) phenyl] -N-ethylacetamide AND

(I) by condensation of N- [3- [3- (dimethylamino) -1-oxo-2-propenyl] -N-phenyl] acetamide of formula II with 3-amino-4-cyanopyrazole of formula III,

(ΠΙ), in a mixture of water and an organic solvent.

It is an object of the invention that the reaction is carried out in the presence of a strongly acidic cation exchanger.

Further, the molar ratio of the cation exchanger used to N- [3- [3- (dimethylamino) -1-oxo-2-propenyl] -N-phenyl] acetamide of formula II and 3-amino-4-cyanopyrazole of formula ΠΙ is one to two times .

Another principle is that very moderate temperatures of from 20 to 50 ° C are sufficient for the reaction.

Another principle is that short reaction times of 4 to 12 hours are sufficient for the reaction.

The use of a cation exchanger to form an acidic environment is a major consideration for carrying out the process of the present invention. This arrangement of the reaction results in the presence in the reaction solution of H ⁺ ions in the minimum possible amount and the reaction proceeds on the surface of the cation exchanger.

The advantage of this procedure is that one of the products - dimethylamine - is removed from the solution, which is trapped on the cation exchanger and thereby moves the reaction in the desired direction.

Both the low temperatures and the short reaction times used in the reaction are of considerable importance since they prevent possible isomerization.

The reaction is readily accomplished without special demands on organic solvents. A wide variety of solvents such as alcohols such as ethanol, isopropyl alcohol or n-butanol, ethers such as tetrahydrofuran, aromatic solvents such as toluene may be used.

According to the process of the invention, N- [3- (3-cyanopyrazolo [1,5-a] pyrimidin-7-yl) phenyl] -Nethylacetamide of the formula I is obtained in high quality with a low content of undesired by-product isomeric N- [3- (3-Cyanopyrazolo [1,5-a] pyrimidin-5-yl) phenyl] -N-ethylacetamide of formula IV.

DETAILED DESCRIPTION OF THE INVENTION

The principles of the invention are explained in more detail in the following examples. These examples are illustrative only and in no way limit the scope of the invention.

Example 1 (general procedure)

A mixture of 2.6 g (10 mmol) of N- [3- [3- (dimethylamino) -1-oxo-2-propenyl] -N-phenylacetamide, 1.1 g of 30 (10.1 mmol) of 3-amino-4 cyanopyrazole, 35 ml of water, 20 ml of organic solvent, and 10 to 10 ml

The 20mL cation exchanger was vigorously stirred at 20-50 ° C for 4-12 hours. The reaction was monitored by TLC. The mixture is then cooled to 0-5 ° C and filtered off with suction. The precipitate was digested at 60 ° C in 2x25 ml of ethanol and after addition of 1 ml of concentrated aqueous ammonia was filtered off with suction.

The product is filtered off from the filtrate after concentration to 3 to 5 ° C and dried under vacuum at 60 ° C.

The effect of the different reaction conditions is illustrated in Table 1.

Table 1

attempt number mval / cation exchanger organic solvent T (° C) Recovery (%) purity (%) Isomer content (%) 1 10 / D Methanol 25 47.3 99.30 0.54 2 10 / D Ethanol 20 May 58.2 98.95 0.25 3 11 / D Toluene 25 61.8 95.90 3.24 4 11 / D Tert-butanol 25 90.1 99.40 0.26 5 11 / D Tetrahydrofuran 25 88.6 99.50 0.20 6 11 / A Ethanol 25 78.8 99.60 0.27 7 11 / A Ethanol 35 81.3 99.30 0.20 8 I5 / A Ethanol 25 61.8 99.27 0.24 9 20 / A Isopropyl alcohol 50 71.6 99.06 0.32 10 11 / D Isopropyl alcohol 25 86.1 99.35 0.01 11 11 / D Isobutanol 25 75.2 97.70 0.86

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D-Dowex 50W

Characteristics: Strongly acid sulphonated styrene-divinylbenzene copolymer, functional group AR-SO3H, capacity 5 mval / g dry cation exchanger

A - Amberlit IR 120

Characteristics: strongly acidic sulfonated styrene-divinylbenzene copolymer, AR-SO3H functional group, capacity 5 mval / g dry cation exchanger

Industrial applicability

The process for the preparation of N- [3- (3-cyanopyrazolo [1,5-a] pyrimidin-7-yl) phenyl] -N-ethylacetamide of the formula I according to the invention can be applied under advantageous technical-economic conditions, while maintaining a sufficiently high quality under mild reaction conditions.

Claims (4)

Process for the preparation of N- [3- (3-cyanopyrazolo [1,5-a] pyrimidin-7-yl) phenyl] -N-ethylacetamide 25 of formula I, By condensation of N- [3- [3- (dimethylamino) -1-oxo-2-propenyl] -N-phenyl] acetamide of formula II with 3-amino-4-cyanopyrazole of formula III, OH), in a mixture of water and an organic solvent, characterized in that the reaction is carried out in the presence of a strongly acidic cation exchanger. Process according to Claim 1, characterized in that the molar ratio of the cation exchanger used to N- [3- [3- (dimethylamino) -1-oxo-2-propenyl] -N-phenyl] acetamide of the formula II and 3-amino4 The cyanopyrazole of formula III is one to two times. Process according to any one of claims 1 to 2, characterized in that the reaction is carried out at temperatures from 20 to 50 ° C. Process according to any one of claims 1 to 3, characterized in that the reaction is carried out for 15 to 4 hours.