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Synthesis method of deflazacort intermediate with [17a,16a-d] oxazoline structure

A 16a-d, deflazacort technology, applied in the direction of organic chemistry, steroids, etc., can solve the problems of high-purity finished products, difficult separation of protein substances, low fermentation yield, etc., to reduce pollutant emissions, The effect of simple operation and simple purification process

Inactive Publication Date: 2013-04-24
ZHEJIANG PURUI PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although the process route is short, the fermentation yield is low, and some protein substances brought by fermentation are difficult to separate in deflazacort, which brings obstacles to obtain high-purity products

Method used

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  • Synthesis method of deflazacort intermediate with [17a,16a-d] oxazoline structure

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0052] Protective response

[0053] Add 20g of 1,4-diene-11β-hydroxy-16,17-epoxy-3,20-dione progesterone (formula I) into the reaction flask, continue to add 300g of 20% glacial acetic acid aqueous solution, and stir for 5 Control the temperature at 10℃~15℃, add 14g ethyl carbazate, and react at 30℃ for 6 hours; TLC detects that the reaction is complete, cool to 0℃~5℃ and stir for 2 hours, extract to dryness, wash until medium Properties; vacuum drying at 60°C to dryness to obtain 20.5g of protection;

[0054] Upper oxazoline ring reaction

[0055] Put the above protective substance into the reaction flask, add 41ml of DMAC to dissolve it, control the temperature at 25~30℃, pass in ammonia gas, keep the slightly positive pressure in the reaction flask, react for 32 hours, exhaust the ammonia gas at normal pressure and then remove under reduced pressure Ammonia gas for 30 minutes; cool the ice brine to -5°C, control the temperature at -5~0°C, add 5ml glacial acetic acid, then add 21...

Embodiment 2

[0057] Protective response

[0058] Add 20g of 1,4-diene-11a-hydroxy-16,17-epoxy-3,20-dione progesterone (formula I) into the reaction flask, continue to add 300g of 15% formic acid aqueous solution, and stir for 5 minutes , The temperature is controlled at 10-15°C, 12g of methyl carbazate is added, and the temperature is controlled at 30°C to react for 5 hours. The reaction is detected to be completed, and the temperature is reduced to 0-5°C and stirred for 2 hours to crystallize, filtered to dryness with suction, and washed with water until neutral; Vacuum drying at 60°C to dryness to obtain 20g of protective material;

[0059] Upper oxazoline ring reaction

[0060] Put the above-mentioned protective substance into the reaction flask, add 30ml of DMF to dissolve it, control the temperature at 25~30℃, pass in ammonia gas, keep the slightly positive pressure in the reaction flask, react for 30 hours, exhaust the ammonia gas at normal pressure and then remove under reduced pressure ...

Embodiment 3

[0062] Protective response

[0063] Add 20g of 1,4-diene-16,17-epoxy-3,11,20-triketoprogesterone (formula I) into the reaction flask, continue to add 300g of 20% formic acid aqueous solution, stir for 5 minutes, control Add 15g of benzyl carbazate at a temperature of 10-15°C, and react at 30°C for 5 hours. After the reaction is detected, the temperature is reduced to 0-5°C and stirred for 2 hours to crystallize, filtered to dryness with suction, and washed with water until neutral; 60°C Vacuum drying to dryness to obtain 22g of protection;

[0064] Upper oxazoline ring reaction

[0065] Put the above protective substance into the reaction flask, add 30ml of DMAC to dissolve it, control the temperature to 35~40℃, pass in ammonia gas, keep the slightly positive pressure in the reaction flask, react for 40 hours, exhaust the ammonia gas at normal pressure and then remove under reduced pressure Ammonia gas for 30 minutes, cool the ice water to 5℃, add 5ml glacial acetic acid, add 20ml ...

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Abstract

The invention discloses a synthesis method of a deflazacort intermediate with a [17a,16a-d] oxazoline structure. The synthesis method comprises the following steps of: using FORMULA I as an initial raw material, protecting by a protective agent, opening a ring by ammonia, esterifying by acetic anhydride, performing cyclization and then performing deprotection to obtain a [17a,16a-d] oxazoline steroid. The synthesis method comprises specific steps of: step 1, protective reaction; step 2, oxazoline ring addition reaction. The method disclosed by the invention has the characteristics that the raw material is available, the cost is low, the reaction condition is mild, the operation is convenient, the reaction steps are short, the production cost can be effectively reduced, the production period is shortened, and the large-scale production is benefited.

Description

Technical field [0001] The present invention relates to a method for synthesizing a compound, in particular to a method for synthesizing a Defcote intermediate with [17a, 16a-d] oxazoline structure. Background technique [0002] The anti-inflammatory effect of steroids is greatly increased due to the addition of [17a, 16a-d] oxazoline groups, and its representative drug is difcote. Difcote belongs to the third generation of glucocorticoids. Its effect is 40 times that of hydrocortisone and 10-20 times that of prednisolone. It mainly has anti-inflammatory, anti-allergic and increased gluconeogenesis effects. For primary and secondary adrenal hypofunction, collagen diseases, skin diseases, rheumatism, allergic diseases, eye diseases, ulcerative colitis, fulminant and disseminated tuberculosis, idiopathic nephrotic syndrome , Hematopoietic system malignant tumors, etc., have a very wide range of clinical applications, and its structural formula is as follows: [0003] . [0004] The...

Claims

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Application Information

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IPC IPC(8): C07J71/00
Inventor 徐润星张旦估简双喜吴国锋周强李磊沈洪钢
Owner ZHEJIANG PURUI PHARMA
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