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Cyclic utilization method of sterides epoxy isomer

An isomer and epoxy technology, applied in the field of pharmaceutical synthesis, can solve the problems of high intermediate purity, unenvironmental protection, low reaction yield, etc., and achieve the effect of simple circulation

Active Publication Date: 2018-05-25
GUANGXI WANDE PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] The purpose of the present invention is to propose a method for recycling steroidal epoxy isomers with mild conditions, which has solved the problems of large potential safety hazards, environmental protection, low reaction yield and high purity of intermediates in the above-mentioned prior art

Method used

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  • Cyclic utilization method of sterides epoxy isomer
  • Cyclic utilization method of sterides epoxy isomer
  • Cyclic utilization method of sterides epoxy isomer

Examples

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preparation example Construction

[0026] The preparation method of Ulipristal:

[0027] Take 10g of Ul-diene in a 250ml four-neck flask, add 100ml of dichloromethane to dissolve, add 5.5g of hexafluoroacetone, 8.9g of Na 2 HPO 4 , 120gH 2 O. 5.6g of 50% hydrogen peroxide, reacted at 0-5°C for 8h, detected by TLC, the reaction was complete. Post-treatment: Wash with 60ml of 5% sodium thiosulfate, 60ml of saturated sodium bicarbonate, 60ml of saturated brine, dry over anhydrous sodium sulfate, spin off dichloromethane to obtain 10.9g, send to HPLC, isomer α / β= 2.6:1.

[0028] Epoxy isomer recycling

[0029]

Embodiment 1

[0031] Take 3.32g (3Eqv.) of biphenyl, Ul-αorβ: 3.0g (1Eqv.) into a 50ml three-necked flask, add 30ml of dichloromethane to dissolve, evacuate nitrogen, add lithium block: 0.14g (3.0Eqv.), React at 30°C for 4h, add 8ml of methanol to quench and stir for 30min, dilute with water, extract twice with 21ml of dichloromethane, combine the organic layers and extract with 39ml of water and 39ml of saturated saline respectively, dry over anhydrous sodium sulfate, and spin dry at 45°C to obtain Add 10ml of petroleum ether to the transparent oil and stir for 1 hour to make a slurry. A white solid precipitates out. Suction filtration, washing with petroleum ether, and drying give: 3.05g, yield: 91.8%, HPLC: 94.0%.

Embodiment 2

[0033] Take 2.57g (3.5Eqv.) of biphenyl, 0.54g (0.6Eqv.) of diphenylmethane, and Ul-αorβ: 2.0g (1Eqv.) into a 50ml three-necked flask, add 20ml of tetrahydrofuran to dissolve, pump out helium, and add Sodium block: 0.38g (3.5Eqv.), react at 20°C for 6h, TLC detects that there are raw materials and large polar impurities (probably intermediate), add 0.05g sodium, and react for another 2h. The vast majority are products, with very few raw materials. Add 4ml of methanol to quench and stir for 30min, dilute with water, extract twice with 14ml of dichloromethane, combine the organic layers, extract with 26ml of water and 26ml of saturated brine respectively, dry over anhydrous sodium sulfate, spin dry at 45°C to obtain a transparent oil, add 10ml of petroleum ether was beaten and stirred for 1 hour, and a white solid was precipitated, filtered with suction, washed with petroleum ether, and dried to obtain: 2.35g, yield: 91.4%. HPLC: 91.4%.

[0034] The preparation method of mifep...

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Abstract

The invention provides a cyclic utilization method of sterides epoxy isomer. Biphenyl organic solvent is reacted with active metal lithium, sodium, and potassium, and others, and reduced to be conjugated double bond; under the alkali environment, the ketal protection radical group is not influenced, and 17- hydroxyl is also not influenced, thus the position of double bond is not changed and doublebonds are directly transformed to be raw material of the last step, and the raw materials are recycled. The method adopts one-step reduction, and solves the existing common technique of opening loopof epoxy bond firstly and then dewatering to be double bonds, and avoids that the ketal protection radical can be damaged by directly reducing epoxy bond to be double bonds by metal in the alkali environment; the epoxy isomer beta and a part of alpha isomer are directly reduced to be the raw material containing conjugated double bond in last step, thus a simple cycle is realized.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a method for recycling steroidal epoxy isomers. Background technique [0002] Steroid hormone drugs (steroidhormonedrugs) refer to hormone drugs containing steroidal structure in their molecular structure, which is an important class of clinically important drugs, mainly including adrenal cortex hormones and sex hormones. As an important adrenocortical hormone drug, betamethasone is an isomer of dexamethasone. It acts on prednisolone and dexamethasone in the same way. It has anti-inflammatory, anti-rheumatic, anti-allergic and immunosuppressive properties Pharmacological effects, betamethasone and its analogues have become one of the most widely used drugs in clinic. [0003] In the synthesis process of ulipristal and mifepristone, the existing epoxy technology inevitably obtains two isomers of α and β, and the content of the worthless β epoxy isomer accounts for 20%. -50%, the re...

Claims

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Application Information

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IPC IPC(8): C07J71/00
CPCC07J71/001Y02P20/55
Inventor 杨坤杨正业黄瑞禄
Owner GUANGXI WANDE PHARMA