Preparation method of hydrocortisone

A technology of hydrocortisone and calcium chloride, applied in the direction of organic chemistry, steroids, etc., can solve the problems of high acid corrosion, high energy consumption, large investment, etc., and achieve the effect of good quality and yield

Active Publication Date: 2012-03-07
ZHEJIANG XIANJU PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The preparation method of 9(11)-alkenes is also described in Chinese patent 200510014479.5: the acidic dehydrating agent phosphorus pentachloride (PCl 5 ), phosphorus trichloride (PCl 3 ), phosphorus oxychloride (POCl 3 ), etc., are relatively poisonous or highly toxic, and are also very corrosive to acid
In addition, cryogenic equipment is required for production, which requires large investment and energy consumption

Method used

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  • Preparation method of hydrocortisone
  • Preparation method of hydrocortisone
  • Preparation method of hydrocortisone

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0058] A preparation method of hydrocortisone, comprising the steps of:

[0059] (1) Ketal reaction: Preparation of 17α-hydroxy-4-pregnene-11-one-3,20-diethylene glycol ketal (Ⅲ)

[0060] Put 50g of 17α-hydroxy-4-pregnene-3,11,20-trione (Ⅱ), 150ml of ethylene glycol and 150ml of triethyl orthoformate into the reaction flask, stir, and add 2.5g of p-toluenesulfonic acid , stirred and reacted at 30-35°C for 8 hours; after the reaction was completed, add 1500ml of water for water analysis, filter, wash with water until neutral, drain, and dry to obtain 17α-hydroxy-4-pregnene-11-one-3,20 - Diethylene glycol ketal (III) 60.8 g. MP: 228~233℃, [α] D 20 =-12.2° (10 mg / ml chloroform).

[0061] (2) Reduction reaction: Preparation of 11β,17α-dihydroxy-4-pregnene-3,20-diethylene glycol ketal (Ⅳ)

[0062] Put 50g of 17α-hydroxy-4-pregnene-11-one-3,20-diethylene glycol ketal (Ⅲ), 500ml of tetrahydrofuran, and 50ml of methanol into the reaction flask, stir, and slowly add 15g of sodium ...

Embodiment 2

[0073] Other operations are the same as embodiment 1, the difference is:

[0074] (2) Reduction reaction: Preparation of 11β,17α-dihydroxy-4-pregnene-3,20-diethylene glycol ketal (Ⅳ)

[0075] Put 50g of 17α-hydroxy-4-pregnene-11-one-3,20-diethylene glycol ketal (Ⅲ), 500ml of tetrahydrofuran, and 50ml of methanol into the reaction flask, stir, and slowly add 25g of potassium borohydride, Reflux for 48 hours; concentrate under reduced pressure to recover the solvent, add 1500ml of water for water analysis, filter, wash with water until neutral, drain and dry to obtain 11β,17α-dihydroxy-4-pregnene-3,20-diethylenedi Alcohol ketal (IV) 49.5g. MP: 219~225℃, [α] D 20 =-39.0° (10 mg / ml chloroform).

[0076] After testing, the MP of hydrocortisone prepared in this example: 215.5-219°C, [α] D 20 (Specific optical rotation) = +165.8° (10 mg / ml absolute ethanol), HPLC content: 98.7%, yield 77.1%.

Embodiment 3

[0078] Other operations are the same as embodiment 1, the difference is:

[0079] (3) Hydrolysis reaction: Preparation of 11β,17α-dihydroxy-4-pregnene-3,20-dione (Ⅴ)

[0080] In the reaction flask, put 50g of 11β,17α-dihydroxy-4-pregnene-3,20-diethylene glycol ketal (Ⅳ), 200ml of chloroform and 200ml of methanol, add 10ml of 50% sulfuric acid, and dissolve in 10 The reaction was stirred at ~20°C for 3 hours. After the reaction is completed, add ammonia water to neutralize, concentrate under reduced pressure to recover the solvent, concentrate until the dichloromethane is exhausted, add 1500ml of water for water analysis, filter, wash, drain, and dry to obtain 11β,17α-dihydroxy-4-pregnene- 3,20-diketone (Ⅴ) 38.2g. MP: 214~217.5℃, [α] D 20 =+152.6° (10mg / ml absolute ethanol).

[0081] After testing, the MP of hydrocortisone prepared in this example: 215-219°C, [α] D20 (Specific optical rotation) = +164.1° (10 mg / ml absolute ethanol), HPLC content: 98.5%, yield 77.8%.

[0...

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Abstract

The invention, relating to the field of pharmaceutical synthesis, particularly relates to a preparation method of hydrocortisone, comprising the following steps: using an intermediate 17 alfa-hydroxy-4-pregnene-3,11,20- triketone (II) in a Rhizopus nigricans method as raw material, successively carrying out ketal reaction, reduction reaction, hydrolysis reaction, iodine adding reaction, and displacement reaction to obtain hydrocortisone acetate (VII), and finally carrying out sodium hydroxide hydrolysis reaction to obtain the hydrocortisone (I). The invention has the advantages of easy obtainment of raw material, common auxiliary materials, and no need of using toxic, highly toxic, and carcinogenic reagents. The method is more efficient than the process in the prior art, and the products has good quality and yield.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a method for preparing green and environment-friendly hydrocortisone. Background technique [0002] Hydrocortisone (HC), also known as Cortisol, has a chemical name of 11β, 17α, 21-trihydroxypregn-4-ene-3,20-dione, which is produced in steroid hormone drugs One of the largest varieties is also the raw material for the preparation of several other important steroid drugs. At present, it is recorded in Chinese, American, British, French, Japanese and European Pharmacopoeias. Hydrocortisone is a medium-acting adrenal cortex hormone drug, which can affect glucose metabolism and has anti-inflammatory, anti-viral, anti-shock and anti-allergic effects. It is mainly used for the replacement therapy of adrenal hypofunction and congenital adrenal The treatment of cortical hyperplasia is also used for rheumatoid arthritis, rheumatic fever, gout, bronchial asthma, allergic diseases, and can b...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J5/00
Inventor 方伟明唐苏杭
Owner ZHEJIANG XIANJU PHARMA
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