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Synthesis method of 16alpha-hydroxy prednisolone

A technology of hydroxyprednisolone and a synthesis method, which is applied in the directions of steroids, chemical recovery, organic chemistry, etc., can solve the problems of long synthesis steps, complicated product post-processing, etc., and achieves high efficiency, convenient post-processing, and high productivity. Effect

Active Publication Date: 2013-01-02
浙江东晖药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In the existing synthetic route, the synthetic steps are long and the post-processing of the product is complicated

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Embodiment 1: the preparation of diphenylmethane gemini surfactant

[0031] 1) Add 33.6g of diphenylmethane to a four-necked reaction flask equipped with an electric stirrer, a thermometer, a reflux condenser, a dropping funnel, and an HCl gas introduction device, and add 3g of catalyst anhydrous AlCl 3 Fully stir and disperse evenly, pass HCl gas, keep warm at 45-50°C, dropwise add olefins whose amount is twice that of diphenylmethane, control the dropwise addition within 20-30min, and then gradually raise the reaction temperature to 70°C, Heat preservation reaction for 8 hours, wash with water until neutral, remove the catalyst in the system to obtain the alkylation product;

[0032] 2） In a four-necked reaction flask equipped with an electric stirrer, a thermometer, a reflux condenser, a dropping funnel, and an HCl gas absorption device, add the alkylation product obtained in step 1), and add the alkylation product obtained in step 1) dropwise under vigorous stirrin...

Embodiment 2

[0034] The preparation of embodiment 2 16α-hydroxyprednisolone

[0035] Prednisolone 0.1g (2.77×10 -4 mol) and diphenylmethane gemini surfactant 1g were added in the reaction flask, and the temperature was kept at 120°C for dehydration reaction. The reaction process was followed and monitored by TLC, and the mixed solvent of cyclohexane: acetone (volume ratio)=5:5 was used as Developing agent, until the raw material point disappears, cool to room temperature, add hydrogen peroxide 0.028g (8.31×10 -4 mol), reacted at 50°C for 20 hours, then added 5 milliliters of water, TLC (with cyclohexane: acetone (volume ratio) = 5:5 mixed solvent as developing solvent) after tracking the end of the reaction, added 3 ×5mL toluene extraction, the raffinate was combined and recycled, the combined extracts were washed with 3×5 mL distilled water, the organic layer was separated, dried over anhydrous magnesium sulfate, and distilled to constant weight under reduced pressure to obtain formula...

Embodiment 3

[0036] Example 3 Prednisolone 0.1g (2.77 × 10 -4 mol) and the raffinate containing diphenylmethane gemini surfactant that embodiment 2 obtains and new diphenylmethane gemini surfactant add altogether 2g in the reaction flask, keep temperature at 150 ℃, and the reaction process is tracked and monitored with TLC, with Hexanaphthene: the mixed solvent of acetone (volume ratio)=5: 5 is used as developing agent, until raw material point disappears, then, is cooled to room temperature, adds hydrogen peroxide 0.009g (2.77×10 -4 mol), reacted at 50°C for 10 hours, then added 6 milliliters of water, TLC (using cyclohexane: acetone (volume ratio) = 5:5 mixed solvent as developing solvent) after tracking the end of the reaction, added 3 ×5mL toluene extraction, the raffinate was evaporated to dryness and recovered for later use, the extracts were combined, washed with 3×5 mL distilled water, the organic layer was separated, dried over anhydrous magnesium sulfate, and distilled under re...

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Abstract

The invention provides a synthesis method of 16alpha-hydroxy prednisolone, belonging to the technical field of fine chemical synthesis method. The synthesis method comprises the following steps: using prednisolone with a structure as shown in formula (I) as a raw material, performing dehydration reaction to generate a double-bond compound under the action of gemini surfactant as shown in formula (II), then adding aqueous hydrogen peroxide solution for further reaction, and adding water to hydrolyze after finishing reaction so as to obtain the target product 16alpha-hydroxy prednisolone, wherein the gemini surfactant is diphenylmethane gemini surfactant. According to the synthesis method, gemini surfactant is simultaneously used as a reaction medium and a catalyst, and can be recovered and reused after reaction finishes, the process is simple, the after-treatment is convenient, the obtained products have the characteristics of high productivity, good efficiency, and less waste, the yield is greater than 85%, and the gemini surfactant can be recycled, and therefore the synthesis method is an economical, practical and environment-friendly technology and is suitable for popularization and application.

Description

technical field [0001] The invention belongs to the technical field of fine chemical synthesis methods, and in particular relates to a synthesis method of 16α-hydroxyprednisolone. Background technique [0002] 16α-Hydroxyprednisolone is an important intermediate of ciclesonide, a drug for treating asthma. The synthesis methods of 16α-hydroxyprednisolone reported so far are all based on prednisolone, which forms a ring with triethyl orthoacetate under the catalysis of pyridinium p-toluenesulfonate, and selectively opens the ring under weakly acidic conditions. To obtain acetylated products, and then react with acetic anhydride under alkaline conditions to form diacetylated products, then heat in the presence of potassium acetate to remove a molecule of acetic acid to obtain (11β)-hydroxy-21-acetoxy-1,4,16- Pregnatriene-3,20-dione compound. The compound is selectively dihydroxylated under the action of potassium permanganate, and deacetylated in the presence of sodium hydrox...

Claims

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Application Information

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IPC IPC(8): C07J5/00
CPCY02P20/584
Inventor 陈熙强王勇裴文
Owner 浙江东晖药业有限公司
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