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Preparation of dexmedetomidine hydrochloride key intermediate

A technology for dexmedetomidine hydrochloride and an intermediate, which is applied in the field of preparing 1--1-ethanol, can solve the problems of high cost, many reaction steps, complicated operations and the like, and achieves fast reaction speed, easy control of conditions, Simple to use effects

Active Publication Date: 2010-08-18
北京华禧联合科技发展有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Both methods start with the Grignard reaction. Although the reaction principle is relatively simple and the yield is high, there are many reaction steps. The reaction environment needs to be strictly controlled in an anhydrous, anaerobic, and carbon dioxide-free environment. The operation is cumbersome and the cost is relatively high.

Method used

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  • Preparation of dexmedetomidine hydrochloride key intermediate
  • Preparation of dexmedetomidine hydrochloride key intermediate
  • Preparation of dexmedetomidine hydrochloride key intermediate

Examples

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example 1

[0023] Example 1 Preparation of 1-(2,3-dimethylphenyl)-1-(1H-imidazol-4-yl)ethanol

[0024] Add 97.5g of zinc powder (1.5mol), 3.9g of lead powder (0.018mol) and 150ml of dry THF into a 1L three-neck flask, heat to reflux, and stir for 3h. Allow to cool naturally. Under the ice-salt bath, 150ml of THF solution in which 76.2g of iodine (0.3mol) was dissolved was slowly added dropwise to the three-necked flask, and the temperature was controlled below 30°C during the dropwise addition. After dropping, stir and react at about 0°C for 30 minutes. Continue to cool down to -10°C, slowly add dropwise a solution of 76.8g (0.39mol) of 4-iodoimidazole dissolved in 210ml of dry THF, control the temperature at -10°C to -5°C, and keep stirring for 30min after dropping. After that, continue to slowly add 44.4g (0.3mol) of 2,3-dimethylacetophenone dropwise at -10°C ~ -5°C. After the drop is complete, the temperature is naturally raised to room temperature, and the reaction is stirred for 2...

example 2

[0025] Example 2 Purification of 1-(2,3-dimethylphenyl)-1-(1H-imidazol-4-yl)ethanol

[0026] Add 18g of the obtained crude product into 50ml of ethanol to dissolve, add 100ml of water and mix evenly, crystallize at -5°C to 0°C for 12 hours, a large amount of white crystals precipitate, filter with suction, wash the filter cake twice with 10ml of water, the obtained white crystals are in After drying under reduced pressure at 50°C for 12 hours, 16.8 g (93.3%) of the product was obtained. The purity by PHLC was 98.37%, and the mp was 134°C-137°C.

example 3

[0027] Example 3 Purification of 1-(2,3-dimethylphenyl)-1-(1H-imidazol-4-yl)ethanol

[0028] Take 17.6g of the crude product, add 50ml of ethanol to dissolve it, add 50ml of water, stir and mix evenly, the resulting solution is crystallized at -5°C to 0°C for 12 hours, a large amount of white crystals are precipitated, suction filtered, the filter cake is washed twice with 10ml of water, and The resulting white crystals were vacuum-dried at 50°C for 12 hours to obtain 16.1 g (91.5%) of the product, with a purity of 99.23% by HPLC and an mp of 137°C-140°C.

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Abstract

The invention relates to a preparation method of dexmedetomidine hydrochloride key intermediate, an [alpha]2 receptor agonist, namely 1-(2,3-dimethyl)-1-(1H-imidazole-4-yl)ethanol (I). The preparation method is characterized in that reformastsky reaction is adopted, 4-iodoimidazol (II) can be reacted with 2,3-dimethyl acetophenone (III) fast at No.1 position without the need of protection to result in target product; the preparation method has the advantages of easy control of reaction conditions, simple operation, high quality and yield of the product and great availability of raw materials, and ensures the quality of the final synthetic product, namely dexmedetomidine hydrochloride.

Description

technical field [0001] The present invention relates to a kind of preparation method of the key intermediate of new preparation dexmedetomidine hydrochloride, exactly the present invention relates to a kind of new preparation 1-(2,3-dimethylphenyl)-1-( The method for the preparation of 1H-imidazol-4-yl)ethanol Background technique [0002] 1-(2,3-Dimethylphenyl)-1-(1H-imidazol-4-yl)ethanol is the key intermediate of α2 receptor agonist dexmedetomidine hydrochloride, which is dexmedetomidine hydrochloride Synthetic essential part, its structural formula is as follows: [0003] [0004] There are mainly two routes in the existing methods for synthesizing 1-(2,3-dimethylphenyl)-1-(1H-imidazol-4-yl)ethanol. In CN101530272A, 2,3-dimethylbenzaldehyde is used as a starting material, and after Grignard reaction with 4-iodo-1-triphenylmethyl-1H-imidazole, oxidation, Grignard reaction, removal The imidazole protecting group affords the product. US4826864 uses 2,3-dimethylbromob...

Claims

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Application Information

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IPC IPC(8): C07D233/64
Inventor 刘元斌王建航张志芳
Owner 北京华禧联合科技发展有限公司
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