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The preparation method of 16α-hydroxyprednisolone

A technology of hydroxyprednisolone and dimethyl hydantoin, applied in the field of medicinal chemistry, can solve the problems of multiple impurities, difficult purification, low yield and the like, and achieve high reactivity, increase reaction yield, and reduce reaction temperature. Effect

Active Publication Date: 2020-10-16
AURISCO PHARMACEUTICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the yield of this method is low, especially when the temperature is high during the debromination reaction, more impurities will be produced, and the purification is difficult.

Method used

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  • The preparation method of 16α-hydroxyprednisolone
  • The preparation method of 16α-hydroxyprednisolone
  • The preparation method of 16α-hydroxyprednisolone

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0021] Preparation of 11,16,17,21-tetrahydroxypregna-1,4-diene-9-bromo-3,20-dione-11-formate-21-acetate compound Ⅱ

[0022] Put DMF200mL, 16,17,21-trihydroxypregna-1,4,9-triene-3,20-dione-21-acetate compound I40.0g (0.10mol, 1.0 equiv), under the protection of nitrogen, cool down to 0°C, add 14.3g (0.05mol, 0.5equiv) of 1,3-dibromo-5,5-dimethylhydantoin, stir to dissolve, slowly add perchloric acid 4.0 mL (0.05mol, 0.5equiv), pay attention to control the reaction temperature at -5℃~5℃. After the addition was completed, TLC detected that the reaction was complete. Add 50 mL of 4% sodium sulfite solution dropwise to terminate the reaction. The reaction solution was poured into 1000 mL of ice water, and the white solid II was obtained by water analysis and suction filtration, and dried to obtain 51.5 g of the product, with a molar yield of 98.2%. , HPLC purity 99.1%.

[0023] Preparation of 11,16,17,21-tetrahydroxypregna-1,4-diene-3,20-dione-11-formate-21-acetate compound III ...

Embodiment 2

[0028] Preparation of compound Ⅱ

[0029] Put 200mL of DMF and 40.0g (0.10mol, 1.0equiv) of compound I solid into a dry and clean reaction bottle. ) after stirring to dissolve, slowly add perchloric acid 7.9mL (0.10mol, 1.0equiv) dropwise, pay attention to control the reaction temperature at -5°C ~ 5°C. After the addition was complete, TLC detected that the reaction was complete. Add 50mL of 4% sodium sulfite solution dropwise to terminate the reaction, pour the reaction solution into 1000mL of ice water, water analysis and suction filtration to obtain a white solid compound II, and dry at 50°C to obtain 51.4g of the product, mol Yield 98.0%, HPLC purity 99.2%.

[0030] Preparation of compound III

[0031] Add compound II51.4g (0.098mol, 1.0equiv), CrCl 2 24.6g (0.20mol, 2.0equiv), N,N-dimethylformamide 500mL, finally add thioglycolic acid 18.4g (0.20mol, 2.0equiv), control the reaction temperature 5 ~ 15 ℃, TLC detection of complete reaction, the reaction The solution wa...

Embodiment 3

[0035] Preparation of compound Ⅱ

[0036] Put 200mL of DMF and 40.0g (0.10mol, 1.0equiv) of compound I solid into a dry and clean reaction bottle. ) after stirring to dissolve, slowly add perchloric acid 9.5mL (0.12mol, 1.2equiv) dropwise, pay attention to control the reaction temperature 0 ~ 5 ℃. After the addition was complete, TLC detected that the reaction was complete. Add 50mL of 4% sodium sulfite solution dropwise to terminate the reaction. The reaction solution was poured into 1000mL of ice water, water analysis and suction filtration to obtain a white solid compound II, which was dried at 50°C to obtain 46.2g of the product, molar yield The yield was 96.3%, and the HPLC purity was 99.1%.

[0037] Preparation of compound III

[0038] Add 46.2g (0.0963mol, 1.0equiv) of compound II, 31.5g (0.48mol, 5.0equiv) of zinc powder, 2.56g (0.01mol, 0.1equiv) of chromium chloride hexahydrate, 300 mL of N-methylpyrrolidone, and finally 2.04 g (0.19 mol, 2.0 equiv) of mercaptopro...

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Abstract

The invention discloses a preparation method of 16alpha-hydroxyprednisolone. The method comprises the following steps: dissolving a 16,17,21-trihydroxypregn-1,4,9(11)-triene-3,20-dione-21-acetate compound I and a halogenating reagent into N,N-dimethylformamide, adding HClO4 to form a 11,16,17,21-tetrahydroxypregn-1,4-diene-9-bromo(chloro / iodo)-3,20-dione-11-formate-21-acetate compound 11; adding adehalogenation reagent and a hydrogen donor to remove a 9-position halogen; and finally adding an alkaline liquid, performing a hydrolysis reaction, and adding an acid for neutralization to obtain the 16alpha-hydroxyprednisolone. The method provided by the invention achieves remarkable effects, has the advantages of fewer reaction steps, a high conversion rate, less impurities, low costs and simple operation, is suitable for industrialized production, and has greater application value.

Description

technical field [0001] The invention relates to medicinal chemistry, in particular to a preparation method of medicine, in particular to a preparation method of 16α-hydroxyprednisolone. Background technique [0002] Neide glucocorticoids are widely used in the treatment of refractory asthma and inflammation, especially budesonide and ciclesonide have the advantages of small dosage, strong local anti-inflammatory effect, and small systemic side effects. It is suitable for children, so it has become the first choice for clinical treatment of severe asthma and allergic rhinitis. 16α-Hydroxyprednisolone is an important intermediate used in the synthesis of Ned-like glucocorticoid drugs budesonide, ciclesonide and desonide, etc. Patent CN201310698900.3 reports a prednisolone The synthetic route as the starting material, undergoes cyclization, ring opening, esterification, elimination, oxidation, cyclization, and hydrolysis to obtain 16α-hydroxyprednisolone, and then reacts with ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07J5/00
Inventor 谢晓强徐雅峰张德法褚礼涛陈文娇
Owner AURISCO PHARMACEUTICAL CO LTD
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