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New method for preparing 16alpha-hydroxyprednisolone

A technology of hydroxyprednisolone and prednisolone dehydroxyacetate, which is applied in the production process field of synthesizing 16a-hydroxyprednisolone, can solve the problems of high production cost, low synthesis yield, and many side reactions , to achieve the effects of simple and convenient production operation, high yield and reduced preparation cost

Active Publication Date: 2019-04-19
HUNAN KEREY BIOTECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] The purpose of the present invention is to propose a new 17a-prednisolone dehydroxyacetate and 16a- Hydroxyprednisolone synthetic method, to overcome the many defects of existing production technology

Method used

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  • New method for preparing 16alpha-hydroxyprednisolone
  • New method for preparing 16alpha-hydroxyprednisolone

Examples

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preparation example Construction

[0019] Further, the specific operation steps of the preparation method of 17a-prednisolone dehydroxyacetate are as follows:

[0020] Step A, preparation of protective material: dissolve prednisolone acetate in an organic solvent, add alkali catalyst and trimethylchlorosilane, stir and react at 10-50°C for 3-4 hours, after the reaction, evaporate under reduced pressure Organic solvent, then adding tap water for water analysis, filtering, washing, and drying to obtain the protected product: 11-trimethylsilyl etherified prednisolone acetate, with a weight yield of about 120-125%;

[0021] Step B. Preparation of 17a-prednisolone dehydroxyacetate: Dissolve the protective compound prepared in the above A into an organic solvent, add an organic base catalyst, and keep warm at 10-100°C and feed SO 3 Gas dehydration reaction for 6-12 hours, TLC to confirm the reaction end point, after the reaction, directly add acid aqueous solution to hydrolyze and deprotect at 10-100 ° C, TLC to conf...

Embodiment 1

[0030] Step A, preparation of protection:

[0031] In a 1000ml three-necked bottle, add 100g prednisolone acetate, 600ml dichloromethane, 100g pyridine, stir to dissolve the solid completely, slowly add 80g trimethylchlorosilane dropwise at 20-25℃, about 1.5-2 After adding in 1 hour, continue to insulate and stir the reaction at 20-25°C for 3 to 4 hours after dropping, and confirm the end point of the reaction by TLC. After the reaction, 90-95% of the organic solvent dichloromethane is recovered by vacuum distillation below 30°C, and then Add 600ml of tap water, stir and crystallize at 10-15°C for 3-4 hours, filter, send the filtrate to a wastewater treatment tank for treatment, wash the filter cake with water, and dry it below 60°C to obtain the protected product: 11-trimethylsilyl etherified acetic acid Prednisolone 123.6g, HPLC content 97.6%, weight yield 123.6%;

[0032] B, preparation 17a-prednisolone dehydroxyacetate:

[0033] In a 2000ml three-necked flask, add 100g o...

Embodiment 2

[0037] A. Preparation of protective materials:

[0038] In a 1000ml three-necked bottle, add 100g of prednisolone acetate, 600ml of chloroform, and 80g of triethylamine, stir to dissolve the solid completely, and slowly add 80g of trimethylchlorosilane dropwise at 20-25°C, about 1.5 - After adding in 2 hours, continue to insulate and stir the reaction at 20-25°C for 3-4 hours, and confirm the end point of the reaction by TLC. After the reaction, recover 90-95% of the organic solvent chloroform by distillation under reduced pressure below 30°C , then add 600ml of tap water, stir and crystallize at 10-15°C for 3-4 hours, filter, send the filtrate to the wastewater treatment tank for treatment, wash the filter cake with water, and dry below 60°C to obtain the protected product: 11-trimethylsilyl ether Prednisolone acetate 123.2g, HPLC content 97.2%, weight yield 123.2%;

[0039] B, preparation 17a-prednisolone dehydroxyacetate:

[0040] In a 2000ml three-neck flask, add 100g of...

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Abstract

The invention provides a new method for preparing 16alpha-hydroxyprednisolone. The method comprises the following steps that A, a protector is prepared, wherein prednisolone acetate and trimethylchlorosilane are catalyzed by organic base to generate a 11th-site silicon etherification reaction, and then the protector is obtained; B, dehydration, hydrolysis deprotection and refining are conducted, wherein the protector and SO3 are catalyzed by organic base to generate a 17th-site dehydration reaction, after the reaction, acid is directly added to make the 11th site deprotected, and a crude 17alpha-dehydroxylated prednisolone acetate product is obtained; the crude product is refined to obtain a 17alpha-dehydroxylated prednisolone acetate product; C, the 17alpha-dehydroxylated prednisolone acetate product is used as a raw material to prepare the 16alpha-hydroxyprednisolone. The problems are solved that in a traditional production technology of the 17alpha-dehydroxylated prednisolone acetate, more side reactions and impurities are generated in the dehydration process, and the impurities are difficult to refine; the total yield of the synthesized 16alpha-hydroxyprednisolone is greatly improved, and the production cost is reduced.

Description

technical field [0001] The invention belongs to the preparation technology of steroid hormone drug intermediates, and specifically refers to a production technology for synthesizing 16a-hydroxyprednisolone by using prednisolone acetate as a raw material. Background technique [0002] 17a-prednisolone dehydroxyacetate (molecular formula C 23 h 26 o 6 ), chemically named 11b,21-dihydroxypregna-1,4,16-triene-3,20-dione-21-acetate, is a steroid that produces deflazacort and nedd The key intermediate of corticosteroid drugs, using it as a raw material, can synthesize deflazacort through 3-step reactions, and can also prepare desonide and budesonide through 3-step reactions. Deflazacort, a third-generation steroidal glucocorticoid drug, is mainly used clinically for primary and secondary adrenal cortical insufficiency, rheumatism, collagen disease, skin disease, fulminant and The treatment of disseminated pulmonary tuberculosis, hematopoietic system diseases, ulcerative coliti...

Claims

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Application Information

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IPC IPC(8): C07J5/00
CPCC07J5/0092
Inventor 甘红星胡爱国吴来喜
Owner HUNAN KEREY BIOTECH
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