A preparation method of androsta-17β-n-(2,5-bis(trifluoromethyl))benzamide

A technology of trifluoromethyl and benzamide, applied in the field of preparation of pharmaceutical intermediates, can solve the problems of weak nucleophilic attack ability, large amount of pyridine used, slow reaction and the like, achieves enhanced nucleophilic attack ability, facilitates industrialized implementation, Yield-enhancing effect

Active Publication Date: 2017-02-08
HUNAN KEREY BIOTECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] 1. A large amount of pyridine is used, which is unhealthy, environmentally friendly and uneconomical;
[0007] 2. After the acid chloride is formed, there will be a large amount of pyridinium hydrochloride, sulfur dioxide and excess thionyl chloride in the system, which will bring uncontrollable side reactions and consume more 2,5-bis(trifluoromethyl)aniline, Affect quality, yield and cost;
[0008] 3. The formation of acid chloride into amide is a nucleophilic reaction. Generally, organic amines are alkaline and have strong nucleophilic attack ability. They react with acid chloride quickly and completely. However, due to the Bistrifluoromethylphenyl has a strong electron-pulling effect, making 2,5-bis(trifluoromethyl)aniline, an organic amine, actually weakly acidic, so its nucleophilic attack ability is very weak, and it reacts very well with acid chlorides. Slow, not thorough, high temperature still can't react completely, poor quality, yield is extremely low (theoretical weight yield should be 166.25%, and theoretical molar yield is 100%, but the weight yield of traditional method has only about 86%, i.e. molar The yield is about 51.73%)
If pyridine is used as a solvent, the water will precipitate and the material will be polluted and uneconomical

Method used

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  • A preparation method of androsta-17β-n-(2,5-bis(trifluoromethyl))benzamide
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Examples

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Effect test

Embodiment 117

[0039] Example 1 Preparation of 17β-N-(2,5-bis(trifluoromethyl))benzamido-4-androsten-3-one

[0040] A. At room temperature, in a 2000L enamel amide reaction kettle equipped with a thermometer and a stirrer, pump 300kg of toluene and 85kg of 2,5-bis(trifluoromethyl)aniline, stir, circulate water through the jacket, and slowly add them dropwise 1M methylmagnesium chloride tetrahydrofuran solution 360kg, stirred and kept warm for later use;

[0041] B. At room temperature, in a 2000L enamel amide reaction kettle equipped with a thermometer and agitator, pump 700kg of toluene, stir, add 4DMAP 5kg, fine powder anhydrous potassium carbonate 260kg, 3-keto-4-androstene-17β carboxylate Acid (05) 100kg, cooling water was passed through the jacket, 45kg of thionyl chloride was added dropwise at 20°C to 30°C, and the plate was spotted for 3 hours after the dropwise addition until the basic reaction was complete, and water was added for quick washing three times (1000kg of water was added...

Embodiment 217

[0042] Example 2 Preparation of 17β-N-(2,5-bis(trifluoromethyl))benzamido-4aza-5-androsten-3-one

[0043]The preparation method is the same as in Example 1, the only difference is that in this example, the substrate 3-keto-4-androstene-17β carboxylic acid (05) is replaced by 3-keto-4aza-5-androstene-17β Carboxylic acid (06). Finally, 148.95kg of 17β-N-(2,5-bis(trifluoromethyl))benzamido-4aza-5-androsten-3-one (02) was obtained, the weight yield was 148.95%, and the molar yield The rate is 89.43%.

Embodiment 317

[0044] Example 3 Preparation of 17β-N-(2,5-bis(trifluoromethyl))benzamido-4azandrost-3-one

[0045] The preparation method is the same as in Example 1, the only difference being that in this example, the substrate 3-keto-4-androstene-17β carboxylic acid (05) is replaced with 3-keto-4 azaandrostene-17β carboxylic acid ( 07). Finally, 153.86kg of 17β-N-(2,5-bis(trifluoromethyl))benzamido-4azandrost-3-one (03) was obtained, with a weight yield of 153.86% and a molar yield of 92.61%. .

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Abstract

The invention provides a preparation method of androstane-17beta-N-(2,5-bis (trifluoromethyl)) benzamide. The preparation method comprises the following steps: (1) in the presence of an acid-binding agent, carrying out acyl chloride forming reaction between androstane-17beta carboxylic acid and thionyl chloride to obtain androstane-17beta acyl chloride; (2) enabling the androstane-17beta acyl chloride and 2,5-bis(trifluoromethyl) aniline to generate amide forming reaction in the presence of a hydrogen stripping agent to obtain androstane-17beta-N-(2,5-bis (trifluoromethyl)) benzamide, wherein the acid-binding agent is anhydrous potassium carbonate fine powder. The preparation method disclosed by the invention can be used for simply preparing the androstane-17beta-N-(2,5-bis (trifluoromethyl)) benzamide with low toxicity, high quality, high yield and low cost.

Description

technical field [0001] The invention relates to a preparation method of a pharmaceutical intermediate, in particular to a preparation method of androsta-17β-N-(2,5-bis(trifluoromethyl))benzamide. Background technique [0002] Dutasteride is a drug for the treatment of benign prostatic hyperplasia and alopecia developed by Glaxo, with definite curative effect and few side effects. Its important intermediate androst-17β-N-(2,5-bis(trifluoromethyl))benzamide is amide formed from 2,5-bis(trifluoromethyl)aniline and androsta-17β-carboxylic acid Then, the general reaction formula is as follows: [0003] [0004] The current traditional production method is: use aromatic hydrocarbons or chlorinated hydrocarbons or DMF or pyridine as a solvent, a large amount of pyridine catalyzes and binds acids, and after forming acid chlorides, add a large excess of 2,5-bis(trifluoromethyl)aniline, high temperature Form amides, post-treatment is anhydrous concentration under reduced pressure...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07J75/00C07J41/00C07J73/00
CPCC07J41/0066C07J75/00
Inventor 左前进甘红星谢来宾
Owner HUNAN KEREY BIOTECH
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