CS217258B1 - Method of preparation of l-phenyl-2,3-dimethyl-4-isopropylamino-5-pyrazolon - Google Patents

Abstract

The invention relates to a method for preparing l-phenyl-2·, 3-dimethyl-4-isopropylamino-5-pyrazelene from l-phenyl-2,3-dimethyl-4-nitroso-5-pyrazolone, l-phenyl-2,3-dimethyl-4-amino-5-pyrazolone or its amino-substituted derivatives, such as l-phenyl-2,3-diethyl-4-formylamine- -5-pyrazolone or l-phenyl-2,3-dinethyl-4-sulfenamino-5-pyrazolone, by reaction with acetone and reduction. The reduction is carried out with metallic zinc with the gradual addition of hydrochloric acid, the concentration of hydrochloric acid in the reaction mixture being maintained in the range of 15 to 25% by weight.

Description

The invention relates způsebu l-phenyl-2, 3-dioietyl ^{isepro-4-R-5-.min} pyrazolene reductive alkylation of L-phenyl-2,3-dimethyl-4-amino-5-pyrazelenu, substituted jehe AI- derivatives of 1-phenyl-2,3-dimethyl-4-nitro-5-pyrazeleu with acetone and zinc in an acidic medium.

In principle, two methods for the preparation of 1-phenyl-2,3-dimethyl-4-iseprepylamino-5-piperazene are known in the art. The first method is based on 1-phenyl-2,3-dimethyl-4-nitrese-5-pyrazelene, which is reduced in an acidic environment by amalgameval zinc, or is based directly on a functional derivative of 1-phenyl-2,3-dimethyl 4-amino-5-pyrazelone such as 1-phenyl-2,3-dimethyl-4-fermylamine-5-pyrazelene or 1-phenyl-2,3-dimethyl-5-pyrazelene-4-sulfamic acid. These compounds are condensed with acetone in an acidic medium and the synthesis is completed by a final reduction, again with amalgamovate zinc in an acidic medium, preferably in a hydrochloric acid medium.

According to the second method, it is best to start from the corresponding 4-nitro or 4-nitreseaerivative which is catalytically reduced with hydrogen and immediately condensed with acetone in situ to give the desired product. The product is isolated in ebeu by extraction, preferably into ethyl ectane and crystallization. Finally, it is usually converted by hydrogen halide precipitation to a more stable hydrohalide, preferably hydrochloride.

Both known methods have some serious drawbacks. In the first case, it is primarily the difficult work of g highly toxic mercury, which in the process becomes a constant environmental threat. In the latter case, otherwise very elegant, the lack of the need for the use of large amounts of expensive catalysts, palladium or platinum. According to the literature, 3 parts of a pyrazolo-1 derivative are used to catalyze the hydrogenation, one part of a pallauvian catalyst, which is unbearable. Such a large amount of catalyst is likely to be necessary because, during the reaction, unrecognized causes cause deactivation.

It has now been found that the reduction in the preparation of 1-phenyl-2,3-dimethyl-4-iseprepylamine-5-pyrazelene can be carried out by direct zinc in a hydrochloric acid environment without the need to prepare its amalgam.

A process for preparing 1-phenyl-2,3-dimethyl-4-isepropylamine-5-pyrazelene of formula

Pedal tehe invention starts from ^{L-phenyl-2,3-J} d.imetyl nitrese 4-5-pyrazelenu sky l-phenyl-2, 3-dimethyl-4-amino-5-pyrazelenu sky jehe to amineskupině substituted derivatives, such as is 1-phenyl-2,3-dimethyl-4-fermylainine-5-p-pyrazelene or 1-phenyl-2,3-dimethyl-5-pyrazelene-4-sulfamic acid and acetone. The reduction is carried out with zinc metal with a rich addition of hydrochloric acid. Gradual addition of Acid avoids the violent evolution of hydrogen.

AND

The desired optimum concentration of hydrochloric acid in the reaction mixture depends on the quality and surface area of the zinc used and should be determined experimentally. It ranges from 15 to 25% by weight.

The present process eliminates the need to use toxic mercury 6, resulting in technological simplification and cheaper production, improved hygiene conditions at work, and elimination of the major negative environmental impact.

(1-phenyl-2,3-dimethyl-4-iseprepylamine-5-pyrazelene is used as an essential component of medication analgesics and has strong anti-rheumatic effects.

The process of the invention is illustrated in more detail in the following examples.

•. 1

Example 1 70 ml of 17% hydrochloric acid was introduced into a stirred flask equipped with a thermometer, a reflux condenser with a fume exhaust vent and a metering orifice and a first small portion (about 9 g) of a total of 90 g of 1-phenyl- 2,3-dimethyl-4-nitreso-5-pyrazelone and 50 g of zinc. The mixture was stirred vigorously while maintaining the cooling temperature at 50 ° C. Once the reaction mixture had decolorized, another portion of 1-phenyl-2,3-dimethyl-4-nitrese-5-pyrazelene was added. The reduction rate was maintained within the acceptable limits of the addition of concentrated hydrochloric acid. After the addition of half the amount of 1-phenyl-2,3-demtyl-4-nitrese-5-pyrazolone, an additional 50 g of zinc and induction were introduced in a similar manner, i.e. by alternating introduction of 1-phenyl-2,3-dimethyl-4. -nitrose-5-pyrazolene and concentrated hydrochloric acid, brought to the end. In total, the reduction consumes 370 ml of concentrated hydrochloric acid. The colorless reaction mixture in which the zinc was practically quantitatively dissolved, containing 1-phenyl-2,3-dimethyl-4-amino-5-pyraselon in a zinc chloride solution, was mixed with 200 ml of acetone and heated to boiling for 2 h. 80 g of zinc were added once and a second reduction was carried out by slowly adding 140 ml of concentrated hydrochloric acid. The addition of hydrochloric acid was carried out at the boiling point of the reaction mixture, lasting for 2 hours and after the addition of all the mixture was reduced as demonstrated by thin layer chromatography. The colorless solution was filtered while hot and then slowly charged with 1000 ml of concentrated aqueous ammonia solution under vigorous cooling. The resulting solution was extracted four times with 100 ml of ethyl acetate and the combined organic layers dried over a small amount of sodium sulfate were concentrated to 200 ml. After cooling to -10 DEG C., 65 g of 1-phenyl-2,3-dimethyl-4-iseprepylamiin beta-5-pyrazolo, i.e. 62% of theoretical, were isolated from the resulting crystal suspension. The product is a colorless crystalline solid, chromatographically uniform, mp 81 ° C. An additional 10 g of product was obtained from the mother liquors after concentration, resulting in a total synthesis yield of 81%.

Example 2

600 ml of benzene solution containing 101 g of 1-phenyl-2,3-dimethyl-4-amine-5-pyrazelone was mixed with 200 ml of 17% hydrochloric acid and the aqueous layer into which quantitatively 1-phenyl-2,3-dimethyl.- The 4-amino-5-pyrazolene was passed in the farm of its hydrochloride, separated.

150 ml of acetone was then added to the solution and the solution was heated to boiling for 2 hours. Then 90 g of zinc was added and by slow addition of concentrated hydrochloric acid (170 ml) the resulting candensation product was reduced at boiling point. Insulation according to the procedure given!

in Example 1, a total of 105 g of a substance was obtained which was identified by chromatography and melting point as 1-phenyl-2,3-dimethyl-4-isopropylamino-5 * pyrazolene. Thus, a yield of 86% of the product relative to the starting solution of 1-phenyl-2,3-dimethyl-4-amino-5-pyrazolone was obtained.

Example 3

To an aqueous solution containing 96 g of 1-phenyl-2,3-dimethyl-4-formylamino-5-pyrazolene in 400 ml of a solution was added 200 ml of acetene and the solution was acidified by addition of 10 ml of concentrated hydrochloric acid and heated to boiling for 1 hour. Then, 80 g of zinc was added in one portion and the resulting iseprepylidene-aminepyrazolone derivative was reduced by slowly adding a total of 170 ml of concentrated hydrochloric acid. The temperature during the reduction was allowed to rise to the boiling point of the mixture. Upon completion of the reduction, the mixture was freed of residual zinc by filtration and the product was isolated in the same manner as described in Example 1. 74 g of 1-phenyl-2,3-dimethyl-4-iaopropylamino-5-pyrazelone, i.e. 73% of theoretical, were obtained. .

Example 4

150 ml of acetone and a solution were added to 400 ml of an aqueous section of a stream containing 120 g of selenium 1-phenyl-2,3-dimethyl-5-pyrrolidin-4-sulfamic acid, whose acidity was adjusted to pH = 4. was heated to boil. Upon reaching the boiling point of the mixture, 100 h of zinc was added and the mixture was reduced by controlled addition of concentrated hydrochloric acid. A total of 210 ml of concentrated hydrochloric acid was consumed for the reduction. The product was isolated as in Example 1. 61 g of the product identified as in Example 1 was obtained, which is 63% of the theoretical.

Claims (1)

A process for preparing 1-phenyl-2,3-dimethyl-4-isopropylamine-5-pyrazolene of the formula CH, CH ·} - ' CH-WH-C-CH C 3 C f Λ ^{z X} 0 ^from N CH ₃ from 1-phenyl-2,3-dimethyl-4-nitreso-5-pyrazelone, 1-phenyl-2,3-diaiethyl-4-amino-5-pyraaelene or its amino-substituted derivatives, such as 1-phenyl-2,3-dimethyl-4-formylamino-5-pyrazelene or 1-phenyl-2,3-dimethyl-4-sulfamine-5-pyrazelene, by reaction with acetone and reduction, characterized in that the reduction is carried out with zinc metal with the gradual addition of hydrochloric acid, the concentration of hydrochloric acid in the reaction mixture being maintained in the range of 15 to 25% hmet.