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Method for preparing dexmedetomidine

A technology of medetomidine and cyanimidazole, applied in the field of medicine, can solve the problems of high requirements on production equipment, high pressure on safety and environmental protection, unfavorable industrialized production, etc., and achieves low requirements on production equipment, reduced production costs, and easy industrialized production. Effect

Inactive Publication Date: 2010-12-22
中国中化股份有限公司 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] In the existing method for preparing medetomidine, the sources of raw materials are difficult and expensive, and need to use protecting groups and deprotecting groups, the route is lengthy, the reaction conditions are harsh, difficult to control, the operability is poor, and the requirements for production equipment are high. The pressure of safety and environmental protection is high, the product purification is difficult, and the yield is low, so it is not conducive to industrial production

Method used

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  • Method for preparing dexmedetomidine
  • Method for preparing dexmedetomidine
  • Method for preparing dexmedetomidine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] Medetomidine is prepared according to the following route:

[0035]

[0036] Preparation of 4-imidazolecarboxylic acid

[0037] Add 1.5 liters of acetic anhydride to 4,5-imidazoledicarboxylic acid (40 g, 0.2564 mol), stir and heat to the reflux temperature of acetic anhydride to react for 5 hours. Cool to room temperature. The resulting suspension was filtered to remove suspended solids, and the filtrate was concentrated to dryness under reduced pressure to obtain a brown-black viscous solid. Add 600 ml of water and stir at room temperature for 1 hour. Raise the temperature to 100°C and stir for 1 hour under heating, then cool down to 60°C, add 4 g of activated carbon and 600 ml of ethanol, and heat to reflux for 1 hour. When the temperature was lowered to 70°C, it was filtered with suction while it was hot to obtain a light yellow liquid, which was left to cool at room temperature for crystallization, and then further crystallized at 0°C for 12 hours, filtered wi...

Embodiment 2

[0052] In the same manner as in Example 1, ethyl 4-imidazolecarboxylate was obtained.

[0053] Preparation of 4-amidoimidazole

[0054] In the autoclave, add ethyl 4-imidazole formate (17.35 g, 0.124 mol) and 25 ml of concentrated ammonia (25%, density = 0.91 g / cm 3 ) (wherein ammonia is 0.335 mol) and ammonium chloride (0.85 g, 0.016 mol), and then reacted at 30° C. for 12 hours. The reaction solution was evaporated to dryness to obtain a brown solid, which was added with 100 ml of water, heated until the solid was dissolved, and left to cool at room temperature for crystallization. Further crystallization at 0° C. for 12 hours, suction filtration, and drying gave 12 g of 4-amidoimidazole with a yield of 88%.

[0055] Preparation of 4-cyanoimidazole

[0056] 4-amidoimidazole (7.4 g, 0.067 mol) and 16 g of thionyl chloride (0.134 mol) were reacted at 40° C. for 12 hours, and the thionyl chloride was distilled off under reduced pressure. 20 ml of ice water was added under a...

Embodiment 3

[0063] In the same manner as in Example 1, ethyl 4-imidazolecarboxylate was obtained.

[0064] Preparation of 4-amidoimidazole

[0065] In the autoclave, add 4-imidazole formic acid ethyl ester (17.35 grams, 0.124 mole), 900 milliliters of concentrated ammonia water (25%, density=0.91g / cm 3 ) (wherein ammonia is 12.044 mol) and ammonium chloride (6.5 g, 0.122 mol), and then reacted at 100° C. for 1 hour. The reaction solution was evaporated to dryness to obtain a brown solid, which was added with 50 ml of water, heated until the solid was dissolved, and left to cool at room temperature for crystallization. Further crystallization at 0° C. for 12 hours, suction filtration, and drying gave 9.4 g of 4-amidoimidazole with a yield of 85%.

[0066] Preparation of 4-cyanoimidazole

[0067] 4-amidoimidazole (7.4 g, 0.067 mol) and 400 g of thionyl chloride (3.35 mol) were reacted at 76° C. for 8 hours, and the thionyl chloride was distilled off under reduced pressure. 20 ml of ice ...

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Abstract

The invention relates to a method for preparing dexmedetomidine, which comprises the following steps of: 1) providing 4-imidazole formic ether, 2) reacting the 4-imidazole formic ether with stronger ammonia water and ammonium chloride so as to form 4-imidazole acid amide, 3) reacting the 4-imidazole acid amide with a cyaniding agent so as to form 4-cyano-group imidazole, and 4) generating the dexmedetomidine from the 4-cyano-group imidazole. The method of the invention needs no blocking group and de-blocking group, uses the cheap raw materials which are easily obtained, has simple route, requires mild reaction condition, has low demand on production device and has a small volume of the three wastes. The prepared dexmedetomidine has high yield coefficient and high purity and is fit for industrial production.

Description

technical field [0001] The invention relates to the field of medicine, in particular, the invention relates to a method for preparing medetomidine. Background technique [0002] α-2 receptor agonists are widely used in clinical anesthesia because of their sedative and analgesic effects and inhibition of sympathetic nerve activity. The structural formula of medetomidine (medetomidine), one of the α-2 receptor agonists, is as follows: [0003] [0004] Its chemical name is 4-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole, and it was launched in the United States and Japan in 1997 and 2004, respectively, due to the selection of its α-2 receptor Sex (α-2 / 1=1620:1) is much higher than the selectivity of clonidine α-2 receptors (α-2 / 1=220:1), and the half-life is short (2 hours) shorter than that of clonidine Short, potency is 3 times higher than the potency of clonidine and has attracted much attention (see Br J Anaesth, 1993, 71 (1): 108-118 pages; Anaesthesia, 1999, 54 (2): 14...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D233/58
Inventor 陈维翁科杰杨建军
Owner 中国中化股份有限公司
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