The method of obtaining (22r,s)- 1617th-butylidenedioxy - 11, 21-dihydroxypregna-1,4-diene-3,20-dione


(57) Abstract:

Usage: in medicine, in particular in the synthesis of known anti-inflammatory and anti-allergic drug. The inventive product (22R, S)- 16, 17-butylidenedioxy - 11, 21-dihydroxypregna-1,4-diene-3.2 0-dione, the angle of rotation at 25°C (+)100 (0.2, dichloromethane). mol.m. 430. Reagent 1: 11, 16, 17 21-tetrahydroxypregna-1,4-diene-3,20-dione. Reagent 2: butanal. Process conditions: in the midst of acetonitrile in the presence of p-toluenesulfonic acid. The reaction is stopped by adding water and aqueous sodium bicarbonate. The recrystallization lead from methylene chloride and methanol by the addition of ligroin, hexane, cyclohexane or heptane, and the recrystallization in methanol and water. 2 C. p. F.-ly.

The invention relates to a new manufacturing process (22R, S)-16, 17 butylidenedioxy-11, 21-dihydroxypregna-1,4 - diene-3,20 - dione(budezonida)

(I) by reaction 11, 16, 17, 21-tetrahydroxypregna-1,4-diene - 3,20-dione (16-hydroxyprednisolone)

(II) butanal CH3CH2CH2SNO in the environment of a solvent in the presence of an acid catalyst.

In accordance with a known process, the essence of which is disclosed in [3] budesonide is produced by the reaction of 16-hydrox allocate by dilution of the reacted mixture in methylene chloride, neutralization by washing in aqueous potassium carbonate and water and evaporation of the solvent followed by crystallization from ether-ligroin. Then the product was purified by chromatography, for example, the installation of "Sephadex". The main disadvantages of dioxane lie in its ability to penetrate the protective coating on the skin to form peroxide. Another disadvantage of the known process is the use of perchloric acid is a strong oxidizer, resulting in its use as a catalyst affects the deterioration of the quality of the selection of the reaction product, and this complicates and increases the cost of subsequent cleaning process and processing of the product.

The purpose of the invention is to create a new process, which is a more qualitative evolution reaction product and provide a simpler and more economical processing and purification of the product.

The objective is achieved by the process according to the invention is carried out in acetonitrile, and the catalyst used p-toluensulfonate.

The combination of less basic (compared to dioxane solvent of acetonitrile and amenites, for example n-toluenesulfonic acid gives better the second process, uses dioxane and perchloric acid.

According to a preferred embodiment of this invention the reaction is stopped by adding water and adjusting properly the pH of the reaction mixture. This can be done by adding to water water carbonate hydrogenating sodium. After that, the product crystallizes. The crystals are filtered off, dissolved in methylene chloride and methanol, and then crystallized by adding a suitable hydrocarbon type naphtha, hexane, cyclohexane or heptane, receiving the crude product, which is then recrystallized in methanol with water in order to obtain pure budezonida.

The manufacturing process budezonida according to the invention consists, therefore, of the two stages.

Stage 1. Production of crude budezonida.

16-hydroxyprednisolone reacts with butanal in acetonitrile. As the catalyst added n-toluensulfonate acid. The reaction mixture was diluted with water and aqueous carbonate hydrogenating sodium. After cooling down to 5-15aboutWith the crystallized product is filtered and washed with water. Then a wet or dry environment filtrate is dissolved in chloride. Add methanol and precipitated the resulting crude budesonide by adding naphtha or other suitable hydrocarbon (e.g. hexane, heptane or cyclohexane), after which the crude budesonide filtered.

Stage 2. Producing pure budezonida.

The crude budesonide dissolved in methanol at a temperature of about 60aboutC. the Solution is filtered through a dense filter and crystallized product by adding water. After cooling to a temperature of 5-20aboutWith, filtration and washing in methanol-water, budesonide dried in a vacuum at a temperature of 40-45aboutC. This process easier, much cheaper and less dangerous to health than the known process.

Working example. The reaction is performed in nitrogen atmosphere. of 15.4 g of n-toluensulfonate acid are dissolved in 200 ml of acetonitrile. To the solution was added 50.0 g 16-hydroxyprednisolone and 17.6 ml of butanol. The temperature is increased to 25aboutC. After 30 min dissolves most of the material. Shortly thereafter, the product begins to crystallize. After 3 h the reaction is stopped by adding 75 ml of a saturated aqueous solution of carbonate hydrogenating sodium, resulting crystallized product. Visionscope pressure 40-65), receiving crude budesonide.

The crude budesonide will recrystallized from methanol-water, getting clean budesonide ratio of isomers A B1 1 (determined by liquid chromatography high pressure), []25100,0about(0,2; CH2Cl2); M+430 (theoretical value 430,5).

The method of obtaining (22R,S) - 16, 17 butylidenedioxy - 11, 21-dihydroxypregna-1,4-diene-3,20-dione of the formula

< / BR>
interaction 11, 16, 17, 21-tetrahydroxypregna-1,4-diene-3,20-dione of the formula

< / BR>
with butanal CH3CH2CH2CHO in the environment of a solvent in the presence of a catalyst, wherein the reaction is carried out in the acetonitrile using as catalyst p-toluenesulfonic acid.

2. The method according to p. 1, characterized in that the reaction is stopped by adding water and adjusting the pH of the reaction mixture by adding, for example, sodium hydrogen carbonate in water.

3. The method according to p. 1 or 2, characterized in that the obtained upon termination of the reaction, the crystals of the target product is filtered off, dissolved in methylene chloride and methanol, and then crystallized by adding a hydrocarbon type of naphtha, hexane, cyclohexane or heptane, receiving the crude product with


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