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Method for preparing steroide compound 17-alpha ester

A technology of steroidal compound and hydrocortisone, which is applied in the field of preparation of steroidal compound 17α-ester, can solve the problems such as unresolved reaction selectivity, and achieve the effects of improving hydrolysis conversion rate, mild reaction conditions and low cost

Active Publication Date: 2012-08-01
ZHEJIANG XIANJU PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

And many hydrolysis reagents have about 10% 21-ester generation, such as Japanese patent JP60048998 uses solid silica gel as hydrolysis reagent, and Japanese patent JP56040700 uses cation exchange resin as hydrolysis reagent, which cannot solve the impurity problem caused by poor reaction selectivity

Method used

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  • Method for preparing steroide compound 17-alpha ester
  • Method for preparing steroide compound 17-alpha ester
  • Method for preparing steroide compound 17-alpha ester

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preparation example Construction

[0027] The preparation method of steroidal compound 17α-ester of the present invention, to have 17α, 21-dihydroxy steroid compound (as analogs such as hydrocortisone, prednisolone, prednisone, dexamethasone, betamethasone) As a raw material, dissolve the raw material in a cyclic ester solvent (such as dioxane), add triethyl orthobutyrate (or trimethyl orthobutyrate, or one of the original esters with seven carbons or less), and then add Catalyst (such as p-toluenesulfonic acid, naphthalenesulfonic acid, benzenesulfonic acid, or sulfo-salicylic acid, etc.) to react to form a cyclic ester; dissolve the produced cyclic ester in a hydrolysis solvent (such as methanol) , adding an orientation reagent (such as ammonium chloride aqueous solution), and then adding a hydrolysis reagent (such as aluminum trichloride aqueous solution), hydrolyzed into 17α-ester.

[0028] Adopt the present invention to prepare hydrocortisone butyrate, use hydrocortisone (compound 1) as raw material, obtai...

Embodiment 1

[0035] Put 40L dioxane and 4Kg hydrocortisone into a 200L cyclic ester reaction tank, stir and dissolve for 10 minutes, adjust the temperature to 20°C, add 4.4L triethyl orthobutyrate, then add 40.0gPTS, and stir for 2.5 hours. TLC showed the reaction was complete.

[0036] Heat up and concentrate under reduced pressure until nearly dry, add 20L of saturated sodium bicarbonate solution, stir for 10 minutes, then add 160L of ice water to fully stir and harden; when fine off-white solids are seen after dispersion, let stand for about 10 hours.

[0037] Centrifuged tap water was fully washed, and the weight of the wet product was 6.1Kg after drying. Put the obtained wet product into a 300L hydrolysis tank, add 180L of industrial methanol, adjust the temperature to about 20°C, stir to dissolve, add 20L of ammonium chloride saturated aqueous solution, and then add 50L of 0.28% aluminum trichloride aqueous solution, at 20 Stir for 1.5 hours at °C. TLC showed the reaction was compl...

Embodiment 2

[0040] Put 40L dioxane and 4Kg hydrocortisone into a 200L cyclic ester reaction tank, stir and dissolve for 10 minutes, adjust the temperature to 20°C, add 4.4L triethyl orthobutyrate, then add 40.0gPTS, and stir for 2.5 hours. TLC showed the reaction was complete.

[0041] Heat up and concentrate under reduced pressure until nearly dry, add 20L of saturated sodium bicarbonate solution, stir for 10 minutes, then add 160L of ice water to fully stir and harden; when fine off-white solids are seen after dispersion, let stand for about 10 hours.

[0042] Centrifuged tap water was fully washed, and the weight of the wet product was 6.2Kg after drying. Put the obtained wet product into a 300L hydrolysis tank, add 180L of industrial methanol, adjust the temperature to about 20°C, stir to dissolve, add 20L of ammonium chloride saturated aqueous solution, and then add 50L of 0.28% aluminum trichloride aqueous solution, at 20 Stir for 1.5 hours at °C. TLC showed the reaction was compl...

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Abstract

The invention discloses a method for preparing a sterides compound 17-alpha ester. The method comprises the following steps of: dissolving 17 alpha, 21-dihydroxyl sterides compound serving as a raw material in a cyclic ester solvent; adding an ester and a catalyst into the mixture and reacting the mixture to prepare a cyclic ester; and dissolving the prepared cyclic ester in a hydrolysis solvent,adding an orientation reagent and a hydrolysis reagent into the mixed solution and hydrolyzing the cyclic ester into the 17-alpha ester. The sterides compound is hydrocortisone, prednisolone, prednisone, hexadecadrol or betamethasone. The method has selective hydrolysis effect,, and can effectively enhance the conversion rate of a product, greatly increase product yield and greatly promote the preparation capability of a sterides medicament.

Description

technical field [0001] The invention relates to a preparation method of a chemical substance, in particular to a preparation method of a steroidal compound 17α-ester. Background technique [0002] Hydrocortisone butyrate, the English name is Hydrocortisone Butyrate, and the chemical name is 11β, 17α, 21-trihydroxy-pregna-4-ene-3,20-dione-17α-butyrate. Structural formula: [0003] [0004] Hydrocortisone butyrate belongs to the adrenal cortex hormone drug, which has various pharmacological effects such as anti-inflammation, anti-allergy and immune suppression. Its medicinal effect is moderate, suitable for various eczema, dermatitis, allergic skin diseases, and it is a kind of external medicine with wide adaptability. [0005] The existing methods for preparing hydrocortisone butyrate mostly obtain products through hydrolysis of 17α and 21-cyclic esters, which can reach a very high yield level. However, if the hydrolysis reagents used for hydrolysis are different, the r...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07J75/00C07J5/00
Inventor 许东新
Owner ZHEJIANG XIANJU PHARMA
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