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A kind of steroid 21 hydroxy chlorination or bromination method

A technology of bromination and chlorination, applied in the direction of organic chemical methods, chemical instruments and methods, steroids, etc., can solve the problems of expensive reagents, low reaction yield, and difficult removal of triphenylphosphine

Active Publication Date: 2022-08-09
TIANJIN PHARMA GROUP CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] US4273770 etc. adopt the sulfonation of 21-position hydroxyl group to carry out chlorination or bromination reaction again, the shortcoming of this method is to adopt two-step reaction, and reaction yield is low, only has 30~40%, and introduces genotoxic impurity easily; US4113680 uses DMSO As the reaction solvent, propionyl chloride is used as the chlorination reagent. The disadvantage of this method is that the substrate is relatively single and the reaction selectivity is not high;
[0005] WO2005 / 044759 uses triphenylphosphine as a catalyst to carry out chlorination or bromination reactions. The disadvantage of this method is that triphenylphosphine is not easy to remove and is not conducive to production; SYNTHETIC COMMUNICATIONS, 23 (15), 2199-2211 (1993) passed Vilsmeier reagent is used for chlorination, the disadvantage of this method is that Vilsmeier is relatively expensive, which is not conducive to production
[0006] It can be seen that the above methods have complex processes, low yields, expensive reagents, and low substrate selectivity. Therefore, it is of great significance to develop a new method for the 21-position hydroxyl chloride or bromination of steroids.

Method used

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  • A kind of steroid 21 hydroxy chlorination or bromination method
  • A kind of steroid 21 hydroxy chlorination or bromination method
  • A kind of steroid 21 hydroxy chlorination or bromination method

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Experimental program
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Effect test

Embodiment 1

[0049]

[0050] Compound 1 (5.0g) was dissolved in pyridine (30ml), nitrogen gas was introduced, the temperature was lowered to 0°C, chlorosuccinimide (2.5g) was added, and SO was added dropwise. 2 / pyridine (20% w / v to pyridine, 10 ml), after 1 h of reaction, the reaction solution was diluted into 500 ml of 0°C water, stirred for 1 h, filtered, and dried to obtain compound 2 (5.1 g, molar yield 97.2%) ， purity 98.2％ ).

Embodiment 2

[0052]

[0053] Compound 3 (1.0g) was dissolved in dimethylformamide (25ml), nitrogen was introduced, the temperature was lowered to 5°C, dichlorohydantoin (1.5g) was added, and SO was added dropwise. 2 / pyridine (20% by weight to pyridine, 4 ml), after 2 hours of reaction, the reaction solution was diluted into 100 ml of 0°C water, stirred for 1 hour, filtered, and dried to obtain compound 4 (1.0 g, yield 95.6%, purity 98.5％ ).

Embodiment 3

[0055]

[0056]Compound 5 (15.0g) was dissolved in dichloromethane (500ml), the temperature was lowered to 10°C, chlorosuccinimide (10.0g) was added, lutidine (45ml) was added, and SO was passed through 2 (20% by weight to lutidine), after 0.5h of reaction, 100ml of water was added, and after stirring for 10min, the liquid was separated, and the organic phase was distilled under reduced pressure to remove the solvent to obtain compound 6 (15.3g, molar yield 98.2%, purity 9 8 . 9 ％ ).

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Abstract

The invention discloses a method for chlorinating or brominating a 21-position hydroxy group of a steroid. The compound of formula B is prepared by reacting with a chlorinating or brominating reagent in the presence of SO2 by taking a compound of formula A as a starting material. The process conditions are mild, environment-friendly, the reagents used are easy to obtain, easy to operate, low cost, high yield, and suitable for industrialized large-scale production.

Description

technical field [0001] The invention relates to a method for chlorination or bromination of a 21-position hydroxy group of a steroid, and belongs to the technical field of pharmacy. Background technique [0002] The 21-hydroxy chloro or bromo steroid is an important steroid drug or drug intermediate structure with a wide range of uses. [0003] At present, there have been many literature reports on the method of chlorination or bromination of the 21-position hydroxy group of steroids, which are introduced as follows: [0004] US4273770 etc. use 21-hydroxyl sulfonation and then carry out chlorination or bromination reaction. The disadvantage of this method is that it adopts two-step reaction, the reaction yield is low, only 30-40%, and it is easy to introduce genotoxic impurities; US4113680 uses DMSO For the reaction solvent, with propionyl chloride as the chlorination reagent, the shortcoming of the method is that the substrate is relatively single, and the reaction selecti...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07J7/00C07J17/00C07J71/00C07B39/00
CPCC07B39/00C07J7/0085C07J17/00C07J71/0015C07J71/0031
Inventor 李亚玲孙建磊
Owner TIANJIN PHARMA GROUP CORP
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