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Preparation method for 21-halogenated steroid

A technology for halogenated steroids and compounds, which is applied in the field of preparation of 21-halogenated steroids and can solve the problems of short steps and complicated reaction process, etc.

Active Publication Date: 2018-05-25
HUNAN NORCHEM PHARMACEUTICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] It has also been reported that a 21-chloro group is constructed while introducing a side chain, thereby directly synthesizing halobetasol. This method is novel, the steps are short, and the yield is high, but it needs to use highly toxic cyanide. Special Silicon reagent, complex reaction process

Method used

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  • Preparation method for 21-halogenated steroid
  • Preparation method for 21-halogenated steroid
  • Preparation method for 21-halogenated steroid

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Experimental program
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Embodiment approach

[0032] The preparation method of the 21-halogenated steroid compound of one embodiment, comprises the following steps:

[0033] The compound of formula I is used as a raw material, and the 21-halogenated reaction with a halogenating reagent is carried out in a mixed solvent of organic solvent and water, and then hydrolyzed under acidic conditions to obtain a 21-halogenated steroid compound of formula II.

[0034] The structural formulas of the 21-halogenated steroid compound of formula I and formula II are as follows:

[0035]

[0036] Wherein, the dotted line represents a single bond or a double bond;

[0037] R 1 is carbonyl or OH;

[0038] R 2 for H, CH 3 , Cl or F;

[0039] R 3 Is H, F, Cl, OH or no group, R 4 is carbonyl, OH or H; or, R 3 with R 4 For the epoxy group;

[0040] R 5 H, α-CH 3 or β-CH 3 ;

[0041] R 6 is H, Si(CH 3 ) 3 、COCH 3 、COCH 2 CH 3 ;

[0042] R 7 for Si(CH 3 ) 3 、COCH 3 、COCH 2 CH 3 、CH 3 or CH 2 CH 3 ;

[0043] X is...

Embodiment 1

[0066]

[0067] In a three-necked flask with a thermometer and a stirring magnet, add 100g (0.364mol) of compound Ia, 5mL (0.036mol) of triethylamine, 500mL of acetone and 100mL of water, stir evenly, and cool the system to 0-5°C. (0.300mol) NCS was slowly added to the reaction flask in batches, and the temperature was kept at 0-5°C during the process. NCS was added in 5 batches, and added once every 20 minutes. After the addition was completed, continue to keep stirring for 1-2 hours. TLC detects that the reaction raw materials disappear completely (benzene:acetone=6:1), stop the reaction, add dropwise 100mL of 20wt% sodium sulfite solution to quench the reaction, add 30mL of 36wt% concentrated hydrochloric acid, adjust the pH to about 2, and raise the temperature of the system to 25-30 The reaction was continued at ℃ for 1-3 hours, TLC detected that the hydrolysis was complete, and 20% NaOH solution was added dropwise to adjust the system to neutrality. Concentrate the ac...

Embodiment 2

[0069]

[0070] In a three-neck flask with a thermometer and a stirring magnet, add 100g (0.314mol) of compound Ib, 500mL of acetone, 100mL of water and 5g (0.047mol) of sodium carbonate and stir evenly. The system is cooled to 5-10°C, and 40g (0.300 mol) NCS was slowly added to the reaction bottle in batches, and the temperature was kept at 5-10°C during the process. NCS was added in 5 batches, and added once every 20 minutes. After the addition was completed, continue to keep stirring for 1-2 hours. TLC detects that the reaction raw materials disappear completely (benzene:acetone=6:1), stop the reaction, add 20g of sodium sulfite solid to quench the reaction and stir for 30min, add 30mL of 36wt% concentrated hydrochloric acid dropwise, adjust the pH of the system to 1, and heat up to 30-40°C The reaction was continued for 1-3 hours, and the hydrolysis was detected by TLC, and 20% NaOH solution was added dropwise to adjust the system to neutrality. Concentrate the acetone ...

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Abstract

The invention discloses a preparation method for 21-halogenated steroid. The preparation method comprises the following steps: using a compound as shown in the formula I as a raw material, firstly executing a 21-bit halogenating reaction with a halogenating agent in a mixed solvent of an organic solvent and water, and executing a hydrolysis reaction under the acidic condition, to obtain the 21-halogenated steroid as shown in the formula II. The above preparation method is simple, the condition is moderate, the applicability to the target product 21-halogenated steroid as shown in the formula II is extensive, and the yield and the purity of the 21-halogenated steroid are high. Problems of a traditional method that the synthetic route is long and the yield is low can be avoided.

Description

technical field [0001] The invention relates to the technical field of preparation of steroids, in particular to a preparation method of 21-halogenated steroids. Background technique [0002] Adrenocortical hormone is a very important class of steroid hormone drug molecules, including cortisone, betamethasone and dexamethasone and many other products. These compounds all have 21-substituent groups, and the most common ones basically have 21-hydroxyl, such as hydrocortisone, betamethasone and fluocinolone, etc., can also continue to be derivatized such as dexamethasone sodium phosphate, betamethasone dipropionate and betamethasone valerate, etc., which are derived from 21-halogenated intermediates are synthesized, and some drug molecules have 21-halogenated groups, such as clobetasol, mometasone furoate and halcinonide, etc., all have 21-chloro groups. Therefore, the synthesis of 21-halogenated steroids is very important. [0003] In the traditional synthesis route of 21-ha...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J7/00C07J71/00
CPCC07J7/0085C07J71/0015
Inventor 唐杰刘喜荣曾春玲李凯孔祥夫刘涌
Owner HUNAN NORCHEM PHARMACEUTICAL CO LTD
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