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CN-119306782-B - Glucocorticoid Process for the preparation of compounds

CN119306782BCN 119306782 BCN119306782 BCN 119306782BCN-119306782-B

Abstract

The invention relates to a preparation method of a glucocorticoid compound, which comprises the following steps of 1) taking hydrocortisone and trimethyl orthopropionate as starting materials, catalyzing by a catalyst 1to obtain an intermediate 1, wherein the molar ratio of hydrocortisone to the catalyst 1 is 1 (0.1-0.5), adding a hydrolysis reagent ammonium chloride into the intermediate 1, and obtaining an intermediate 2, namely hydrocortisone-17-propyl ester through a hydrolysis method, and 3) obtaining hydrocortisone propyl acetate through esterification reaction of the intermediate 2. The generated three wastes are less, the treatment is easy, and the method has the advantages of green and environmental protection. The yield is high, the purity of the product is high, the production cost is relatively low, a large amount of time and cost can be saved in actual production, and the method is more suitable for industrial production.

Inventors

  • HAO ZHIHUI
  • CUI LIANGLIANG
  • ZHAO LEKAI
  • YANG FENFANG
  • WANG PINGPING
  • Sui Kaili

Assignees

  • 中国农业大学

Dates

Publication Date
20260512
Application Date
20241012

Claims (13)

  1. 1. A method for preparing a glucocorticoid compound, comprising the steps of: ; 1) The preparation method comprises the steps of taking hydrocortisone and trimethyl orthopropionate as starting materials, and catalyzing by a catalyst 1 to obtain an intermediate 1, wherein the molar ratio of hydrocortisone to the catalyst 1 is 1 (0.1-0.5), the reaction temperature is 20-25 ℃, and the reaction time is 5-10 hours; 2) Adding a hydrolysis reagent ammonium chloride and a hydrolysis reaction catalyst 2 aluminum trichloride into the intermediate 1, and obtaining the intermediate 2 by a hydrolysis method, wherein the molar ratio of the intermediate 1 to the hydrolysis reagent is 1 (1-10), the molar ratio of the intermediate 1 to the hydrolysis reaction catalyst 2 is 1 (0.1-3), the mass fraction of the catalyst 2 is 0.2-0.6%, the reaction temperature is 40-50 ℃, and the reaction time is 10-20 hours; 3) And (3) carrying out esterification reaction on the intermediate 2 to obtain hydrocortisone propyl acetate.
  2. 2. The preparation method according to claim 1, further comprising a reaction solvent 1 in step 1), wherein the reaction solvent 1 is selected from the group consisting of 1, 4-dioxane, dimethyl sulfoxide, and N, N-dimethylformamide; washing with a washing solvent 1 after the reaction is finished, wherein the washing solvent 1 is selected from saturated sodium bicarbonate aqueous solution and saturated sodium carbonate aqueous solution; The washing is followed by extraction with an extractant selected from the group consisting of halogenated hydrocarbons, dichloromethane, dichloroethane, ethyl acetate and diethyl ether.
  3. 3. The method according to claim 2, wherein in step 1), the reaction solvent 1 is 1, 4-dioxane; the washing solvent 1 is saturated sodium bicarbonate water solution; The extractant is dichloromethane.
  4. 4. The process according to claim 2, wherein in step 1), the molar ratio of hydrocortisone as starting material to trimethyl orthopropionate is 1 (1-3); 1 mol ratio of hydrocortisone to reaction solvent is 1 (30-50); the mass ratio of hydrocortisone to the washing solvent 1 is 1 (3-10); The molar ratio of hydrocortisone to extractant is 1 (30-40).
  5. 5. The preparation method according to claim 1, wherein in step 2), a reaction solvent 2 is further included, wherein the reaction solvent 2 is selected from the group consisting of water, ethanol, and isopropanol.
  6. 6. The method according to claim 5, wherein in step 2), the reaction solvent 2 is water.
  7. 7. The process according to claim 5, wherein in step 2), The molar ratio of the intermediate 1 to the reaction solvent 2 is 1 (8-12).
  8. 8. The process according to claim 1, wherein in step 2), the optical purity of hydrocortisone-17-propyl ester as the intermediate 2 obtained after the hydrolysis reaction reaches 99% or more, and the reaction yield is 85-90%.
  9. 9. The preparation method according to claim 1, further comprising a reaction solvent 3 in step 3), wherein the reaction solvent 3 is selected from pyridine, N-dimethylformamide, 1, 4-dioxane; the catalyst also comprises an esterification catalyst 3, wherein the esterification catalyst 3 is selected from acetic anhydride, sulfuric acid, hydrochloric acid and acetyl chloride; extracting after the reaction is finished, wherein an extracting agent used in the extraction is selected from halogenated hydrocarbon, dichloromethane, dichloroethane, ethyl acetate and diethyl ether; Washing with a washing reagent 3 after extraction, wherein the washing reagent 3 is selected from sodium chloride solution with a mass fraction of 8-12%; Concentrating under reduced pressure to 15-25% of the volume of the extractant after washing; concentrating, and adding a precipitation reagent to precipitate, wherein the precipitation reagent is selected from cyclohexane.
  10. 10. The preparation method according to claim 9, wherein in step 3), the reaction solvent 3 is pyridine; The esterification catalyst 3 is acetic anhydride; The extractant is dichloromethane.
  11. 11. The process according to claim 9, wherein in step 3), the molar ratio of the intermediate 2 to the reaction solvent 3 is 1 (50-100); The mol ratio of the intermediate 2 to the esterification catalyst 3 is 1 (1-3); the mass ratio of the intermediate 2 to the extraction extractant is 1 (4-10); the mass ratio of the intermediate 2 to the washing reagent 3 is 1 (4-10); the mass ratio of the intermediate 2 to the precipitation reagent is 1 (10-30).
  12. 12. The method according to claim 1, wherein the reaction temperature is 30-35 ℃ and the reaction time is 4-12 hours in step 3).
  13. 13. The method according to claim 2 or 9, wherein the extraction is 2 to 5 times and the washing is 2 to 4 times.

Description

Glucocorticoid Process for the preparation of compounds Technical Field The invention relates to the technical field of veterinary medicines, in particular to a preparation method of a glucocorticoid compound. Background Hydrocortisone and its derivatives are potent adrenocorticoids and are widely used clinically, and the products include hydrocortisone, hydrocortisone acetate, etc. The therapeutic effect of the medicine is equivalent to that of prednisone, the anti-inflammatory effect is stronger and is 3-5 times that of cortisone, but the water salt metabolism effect is weak, and side effects such as water electrolyte disorder and the like are not easy to cause generally. Processes for synthesizing hydrocortisone and derivatives thereof have long been known, and in the prior art, the synthetic route of hydrocortisone propyl acetate has been shown to be ：(Poly)cationicλ3-Iodane-Mediated Oxidative Ring Expansion of Secondary Alcohols(Article)[J].European Journal of Organic Chemistry.2018,Vol.2018(No.12):1460-1464.: In the synthetic route 1, hydrocortisone-21-acetate is used as a raw material to synthesize hydrocortisone propyl acetate through four steps of reaction of hydrolysis, triethyl orthopropionate, hydrolysis and esterification. The synthetic route has low yield and high raw material price, and is not suitable for industrial production. Disclosure of Invention Based on the problems, the invention provides a novel innovative production process route of hydrocortisone propyl acetate, which takes hydrocortisone as a starting material, obtains hydrocortisone propyl acetate through cyclization reaction, hydrolysis reaction and esterification reaction, in each link in the production process, the method is easy to realize under the current fine chemical production condition, simple to operate, convenient to control, high in yield, relatively low in production cost, capable of saving a large amount of time and cost in actual production, and good in economic benefit. The invention provides a preparation method of a glucocorticoid compound, which comprises the following steps: 1) The hydrocortisone and trimethyl orthopropionate are used as starting materials, and after catalysis of the catalyst 1, the intermediate 1 is obtained, wherein the mole ratio of hydrocortisone to the catalyst 1 is 1 (0.1-0.5); 2) Adding a hydrolysis reagent ammonium chloride into the intermediate 1, and obtaining an intermediate 2, namely hydrocortisone-17-propyl ester through a hydrolysis method; 3) And (3) carrying out esterification reaction on the intermediate 2 to obtain hydrocortisone propyl acetate. Further, in step 1), the reaction solvent 1 is selected from 1, 4-dioxane, dimethyl sulfoxide, N-dimethylformamide, preferably 1, 4-dioxane; the washing solvent 1 after the reaction is selected from saturated sodium bicarbonate aqueous solution, saturated sodium carbonate aqueous solution, preferably saturated sodium bicarbonate aqueous solution; the extraction after washing is performed with an extraction extractant selected from the group consisting of halogenated hydrocarbons, dichloromethane, dichloroethane, ethyl acetate and diethyl ether, preferably dichloromethane. Preferably, in step 1), the molar ratio of hydrocortisone to trimethyl orthopropionate as starting material is 1 (1-3); 1 mol ratio of hydrocortisone to reaction solvent is 1 (30-50); The mass ratio of hydrocortisone to the washing solvent 1 is 1 (3-10); The molar ratio of hydrocortisone to extractant is 1 (30-40). Further, in step 2), the reaction solvent 2 is selected from water, ethanol, isopropanol, preferably water; the hydrolysis catalyst 2 is selected from aluminum trichloride and phosphorus trichloride, preferably aluminum trichloride. Preferably, in step 2), the molar ratio of intermediate 1 to hydrolysis reagent is 1 (1-10); The mol ratio of the intermediate 1 to the hydrolysis catalyst 2 is 1 (0.1-3), and the volume fraction of the catalyst 2 is 0.2-0.6%; the molar ratio of the intermediate 1 to the reaction solvent 2 is 1 (8-12). Preferably, the optical purity of the hydrocortisone-17-propyl ester of the product intermediate 2 prepared after the hydrolysis reaction in the step 2) reaches more than 99%, and the reaction yield is 85-90%. Further, in step 3), the reaction solvent 3 is selected from pyridine, dimethylformamide, 1, 4-dioxane, preferably pyridine; the esterification catalyst 3 is selected from acetic anhydride, sulfuric acid, hydrochloric acid and acetyl chloride, preferably acetic anhydride; The extraction solvent after the reaction is selected from halohydrocarbon, dichloromethane, ethyl dichloroethane acetate and diethyl ether, preferably dichloromethane; The washing reagent 3 after extraction is selected from sodium chloride solution with the volume fraction of 8-12%; Concentrating under reduced pressure to 15-25% of the volume of the extractant after washing; the precipitation reagent added after concentration is selected from cyclohexan