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Preparation method of methylprednisolone key intermediate

A technology for methylprednisolone and intermediates, which is applied in the field of preparation of steroid drug intermediates, can solve the problems of complex reaction route, high production cost and high raw material cost, and achieves simple reaction, easy operation and high industrial value. Effect

Inactive Publication Date: 2014-02-26
HUNAN NORCHEM PHARMACEUTICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

It adds an iodine atom to the carbon atom at the 21st position through an iodine-up reaction, and obtains a replacement product through a replacement reaction. The iodine-up reaction uses iodine, which is highly toxic and expensive, and the production cost is relatively high. It is known through experiments that the up-iodine, The displacement step cannot be replaced by other halogens such as chlorine or bromine
This patent application selects mold oxide as the starting material, which needs to be prepared by diosgenin through ring-opening, acetylation, oxidation, hydrolysis, elimination, epoxidation, oxidation, etc., and the raw material cost is high
The reaction route of this patent application is complicated, and methylprednisolone is prepared through 12 steps of reaction, and the operation is loaded down with trivial details, and the reported yield is 40.7%, and the yield is relatively low

Method used

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Examples

Experimental program
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Effect test

Embodiment 1

[0012] (1) Cyanohydrination reaction

[0013] Put 60 kg of compound Ⅰ, add 60 kg of acetone, 60 kg of tap water, 3 kg of triethylamine, 60 kg of potassium cyanide, heat up to 60°C for 15 hours, add 600 kg of water, stir for water analysis, centrifuge after water analysis, filter The cake was washed with water until neutral, and dried at 60°C to obtain 60 kg of compound II with a mass yield of 100%.

[0014] (2) Protection response

[0015] Take 60 kg of compound II, add 180 kg of dichloromethane and stir to dissolve completely, add 18 kg of imidazole, add 36 kg of trimethylchlorosilane dropwise at a temperature of 10°C, react at 25°C for 3 hours after the dropwise addition, add 18 kg of carbonic acid Potassium aqueous solution (potassium carbonate aqueous solution contains 0.6 kg of potassium carbonate and 17.4 kg of water), adjust the pH to neutral, add 600 kg of water to concentrate dichloromethane, water analysis, centrifugation, and dry the filter cake to obtain 75 kg of ...

Embodiment 2

[0021] (1) Cyanohydrination reaction

[0022] Put 60 kg of compound Ⅰ, add 240 kg of acetone, 0.6 kg of diisopropylamine, 6 kg of potassium cyanide, heat up to 50 ° C for 20 hours, add 600 kg of water, stir for water analysis, centrifuge after water analysis, wash the filter cake to medium After drying at 70°C, 59 kg of compound II was obtained with a mass yield of 98.3%.

[0023] (2) Protection response

[0024] Take 60 kg of compound II, add 120 kg of dichloromethane and stir to dissolve completely, add 6 kg of imidazole, add 36 kg of trimethylchlorosilane dropwise at 0°C, react at 0°C for 3 hours after the dropwise addition, add 18 kg of carbonic acid Sodium bicarbonate aqueous solution (sodium bicarbonate aqueous solution contains 0.6 kg of sodium bicarbonate and 17.4 kg of water), adjust the pH to 8. Dichloromethane was concentrated by adding 500 kg of water, analyzed in water, centrifuged, and the filter cake was dried to obtain 73 kg of compound III with a mass yield ...

Embodiment 3

[0030] (1) Cyanohydrination reaction

[0031] Put in 60 kg of compound I, add 6 kg of methanol, 60 kg of triethylamine, and 120 kg of potassium cyanide, heat up to 100 ° C for 1 hour, add 800 kg of water, stir for water analysis, centrifuge after water analysis, and wash the filter cake to medium properties, and dried at 70°C to obtain 59.4 kg of compound II with a mass yield of 99%.

[0032] (2) Protection response

[0033] Take 60 kg of compound II, add 600 kg of chloroform and stir to dissolve completely, add 60 kg of imidazole, add 36 kg of trimethylchlorosilane dropwise at a temperature of 50°C, react at 50°C for 1 hour after the dropwise addition, add 18 kg of pyridine , adjust the pH to 9. Add 500 kg of water to concentrate dichloromethane, water analysis, centrifugation, and dry the filter cake to obtain 75.3 kg of compound III, with a mass yield of 125.5%.

[0034] (3) Low temperature reaction

[0035] Take 75 kg of compound III, add 750 kg of tetrahydrofuran, coo...

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Abstract

The invention relates to a preparation method of a methylprednisolone key intermediate. According to the method, compound I serving as reactant is subjected to cyanohydrination reaction, protective reaction, low-temperature reaction and hydrolysis reaction to prepare the methylprednisolone key intermediate, namely, the compound V. The preparation method is low in production cost and high in yield, and the reaction line is as shown in the specification.

Description

technical field [0001] The invention relates to a preparation method of a steroid drug intermediate, in particular to a preparation method of a key intermediate of methylprednisolone. Background technique [0002] Prednisolone is an important steroid hormone. Chinese invention patent application, patent number: ZL200810059713.X discloses a synthesis method of methylprednisolone, using fungal oxide as the starting material, followed by Platts oxidation, bromination, debromination, and 6-position methylprednisolone Basement, 6-position methylation, ketal protection, 11-position reduction, ketal hydrolysis, 1,2-position dehydrogenation, 21-position iodine, 21-position substitution, 21-position hydrolysis reaction to obtain methylprednisolone. It adds an iodine atom to the carbon atom at the 21st position through an iodine up reaction, and obtains a replacement product through a replacement reaction. The iodine up reaction uses iodine, which is highly toxic and expensive, and t...

Claims

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Application Information

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IPC IPC(8): C07J51/00C07J7/00
Inventor 刘喜荣
Owner HUNAN NORCHEM PHARMACEUTICAL CO LTD
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