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Synthetic method of betamethasone or prednisolone intermediate

A synthesis method and progesterone technology, which are applied in the production of steroids, bulk chemicals, organic chemistry, etc., can solve the problems of troublesome strain selection, low yield, environmental pollution, etc., and achieve low environmental pollution and operation. Simple, avoid duplication effects

Inactive Publication Date: 2014-02-19
SHANGHAI NEW HUALIAN PHARMA
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, this method is relatively advanced and has high yield. The disadvantage is that strain selection is troublesome, and it is not easy to obtain
(2) Reduction of 11-carbonyl to 11β-hydroxyl. This method appeared relatively early, but it needs to protect 3,20-dicarbonyl first, and then remove the protecting group after reduction to 11β-hydroxyl. The yield is not high.
(3) Use 9(11)-alkene bromohydryl addition, and then reduce and remove 9α-bromine to obtain 11β-hydroxyl. The yield of this method is also high, but chromium compounds or other metals need to be used in the reaction. serious environmental pollution

Method used

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  • Synthetic method of betamethasone or prednisolone intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] (a) Add 10g (0.029mol) 11α-hydroxy-1,4-diene-16,17-epoxyprogesterone (ii), about 140ml tetrahydrofuran, 10.1g (0.059mol) Diethyl nitrogen dicarboxylate and 29.9g (0.116mol) triphenylphosphine, stirred for 30 minutes, cooled to -10~-5°C, and started to drop 11.3g (0.061mol) methyl p-toluenesulfonate at -10°C After about 1 hour, the drop was completed, and then the temperature was raised to 20° C., and the reaction was incubated for 2 hours, and the reaction was followed by TLC. Recover tetrahydrofuran from the reaction solution to obtain a solid, add 20ml of methanol, stir for 30 minutes, cool to 0-5°C, filter to obtain 11β-p-toluenesulfonyl-16,17-epoxy-1,4-dienyl progesterone (iii).

[0030] (b) The 11β-p-toluenesulfonyl-16,17-epoxy-1,4-dienyl progesterone (iii) is directly put into another clean 500ml three-necked bottle without drying, and 20ml of glacial acetic acid and 48% HBr 10ml, stirred at 20°C for 3 hours, followed by TLC until the reaction was complete, adde...

Embodiment 2

[0035] (a) Add 10g (0.029mol) 11α-hydroxy-1,4-diene-16,17-epoxyprogesterone (ii), about 140ml tetrahydrofuran, 10.1g (0.059mol) Dipropyl nitrogen dicarboxylate and 29.9g (0.116mol) triphenylphosphine, stirred for 30 minutes, cooled to -10~-5°C, and started to drop 11.3g (0.061mol) methyl p-toluenesulfonate at -10°C After about 1 hour, the drop was completed, and then the temperature was raised to 22° C., and the reaction was incubated for 2.5 hours, and the reaction was followed by TLC. Recover tetrahydrofuran from the reaction solution to obtain a solid, add 20ml of methanol, stir for 30 minutes, cool to 0-5°C, filter to obtain 11β-p-toluenesulfonyl-16,17-epoxy-1,4-dienyl progesterone (iii).

[0036] (b) The 11β-p-toluenesulfonyl-16,17-epoxy-1,4-dienyl progesterone (iii) is directly put into another clean 500ml three-necked bottle without drying, and 20ml of glacial acetic acid and 48% HBr 10ml, stirred at 22°C for 3 hours, followed by TLC until the reaction was complete, a...

Embodiment 3

[0041] (a) Add 10g (0.029mol) 11α-hydroxy-1,4-diene-16,17-epoxyprogesterone (ii), about 140ml toluene, 10.1g (0.059mol) Diethyl nitrogen dicarboxylate and 29.9g (0.116mol) triphenylphosphine, stirred for 30 minutes, cooled to -10~-5°C, and started to drop 11.3g (0.061mol) methyl p-toluenesulfonate at -10°C After about 1 hour, the drop was completed, and then the temperature was raised to 25° C., and the reaction was incubated for 3 hours, and the reaction was followed by TLC. Recover toluene from the reaction solution to obtain a solid, add 20ml of methanol, stir for 30 minutes, cool to 0-5°C, filter to obtain 11β-p-toluenesulfonyl-16,17-epoxy-1,4-dienyl progesterone (iii).

[0042] (b) The 11β-p-toluenesulfonyl-16,17-epoxy-1,4-dienyl progesterone (iii) is directly put into another clean 500ml three-necked bottle without drying, and 20ml of glacial acetic acid and 48% HBr 10ml, stirred at 25°C for 3 hours, followed by TLC until the reaction was complete, added 400ml of ice w...

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Abstract

The invention discloses a synthetic method of 11 beta,17 alpha-dihydroxy-1,4-diene pregne-3,20-diketone-21-acetate. The invention employs 11 alpha-hydroxy-1,4-diene-16,17-epoxy progesterone (ii) as a starting material, which together with methyl p-toluenesulfonate is subjected to a Mitunobu reaction for inversion under the catalysis of diethyl azodiformate and triphenyl phosphine to obtain 11 beta-p-toluenesulfonyl-16,17 epoxy-1,4-diene progesterone (iii), namely a 11 beta-hydroxy protector; the (iii) is subjected to protective group removal in the presence of HBr, and 16,17-epoxy addition to obtain 11 beta, 17 alpha-dihydroxy-16 beta-bromo-1,4-allyl progesterone (iv); the (iv) is subjected to 3 steps to synthesize 11 beta,17 alpha-dihydroxy-1,4-diene pregne-3,20-diketone (v), which is added with iodine to obtain 11 beta,17 alpha-dihydroxy-1,4-diene pregne-3,20- diketone-21-iodine (vi); and the (vi) is subjected to replacement with potassium acetate to obtain the 11 beta,17 alpha-dihydroxy-1,4-diene pregne-3,20-diketone-21-acetate (i). The method provided by the invention can avoid complex strain breeding, has the advantages of simple operation, high yield, little environmental pollution, and has good industrial application prospect.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, in particular to a method for synthesizing an intermediate of betamethasone or prednisolone. Background technique [0002] 11β,17α-Hydroxy-1,4-enpregna-3,20-dione-21-acetate (i) belongs to pharmaceutical intermediates and can be used to prepare prednisolone, betamethasone and their derivatives , the starting material for its synthesis is 11α-hydroxy-1,4-diene-16,17-epoxyprogesterone (ii), also known as mold dehydrogenation product, which is more industrially produced and has a wide source of raw materials. At present, there are three methods for producing 11β-hydroxyl: (1) Biological fermentation method, which uses bacteria that can directly oxidize 11β-hydroxyl to produce in one step. At present, this method is relatively advanced, with high yield, but the disadvantage is that strain selection is troublesome and difficult to obtain. (2) Reduction of 11-carbonyl to 11β-hydroxyl. This method a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J5/00
CPCY02P20/55
Inventor 李晓龙柏挺田旭彪吴庆安周福群周秋火
Owner SHANGHAI NEW HUALIAN PHARMA
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