Method for preparing dexmedetomidine hydrochloride for anesthesia and sedation during operation

A technology for dexmedetomidine hydrochloride and sedation, which is applied in the field of preparation of dexmedetomidine hydrochloride, can solve the problems of harsh synthesis conditions, long reaction time, and low yield, and achieve convenient operation, low cost, and shortened reaction the effect of time

Inactive Publication Date: 2017-05-10
QINGDAO CHENDA BIOLOGICAL SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0010] The purpose of the present invention is to overcome the synthesis of existing dexmedetomidine hydrochloride, especially its intermediate 4-[1-(2,3-dimethylphenyl) ethyl]-1H-imidazole synthesis conditions are harsh, the reaction The defects of too long time, high cost and low yield provide a new preparation method of dexmedetomidine hydrochloride

Method used

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  • Method for preparing dexmedetomidine hydrochloride for anesthesia and sedation during operation
  • Method for preparing dexmedetomidine hydrochloride for anesthesia and sedation during operation

Examples

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preparation example Construction

[0026] Preparation of ionic liquids

[0027] [Omim] BF 4 (i.e. l-octyl-3-methylimidazolium tetrafluoroborate ionic liquid)

[0028] Add 82.1g N-methylimidazole and 163.5g 1-chlorooctane in the 500mL three-neck flask that stirrer, reflux condenser and thermometer are housed, and add 80mL cyclohexane and toluene respectively as reaction intermediary, control the The temperature was 75°C, and after stirring for 48 hours, the solvent in the upper layer and unreacted raw materials were removed by pouring. The oily liquid in the lower layer was washed with ethyl acetate 4 times while hot (20 mL each time), and the liquid in the lower layer was transferred to a one-necked bottle, and depressurized. Part of the solvent and unreacted raw materials in the raw materials were removed by rotary evaporation. After the rotary evaporation was completed, it was transferred to a vacuum drying oven at a temperature of 70° C. and dried in vacuum for 36 hours to obtain the intermediate product c...

Embodiment 1

[0036] Preparation of 4-[1-(2,3-Dimethylphenyl)ethyl]-1H-imidazole

[0037] In the reaction vessel, add FeCl 3 ·6H 2 O1.35g (5mmol), 2,3-dimethylstyrene 13.2g (100mmol), imidazole 7.5g (110mmol) and ionic liquid ([omim] BF 6 ) in 30ml at 30°C for 0.5 hours. After monitoring the reaction, pour it into water, extract with dichloromethane, wash the organic phase three times with water, dry the organic phase with anhydrous sodium sulfate, concentrate under reduced pressure, and recrystallize petroleum ether to obtain 4-[1 -(2,3-Dimethylphenyl)ethyl]-1H-imidazole 17.5g, yield 87.3%, R / S configuration=42:58.

[0038] 1 HNMR (400MHz, CDCl 3 ): δ7.32(s,1H),7.07-6.95(m,3H),6.69(s,1H),4.41(q,J=21.2,7.2,1H),2.29(s,3H),2.31(s ,3H), 1.59 (d, J=7.6,3H).

Embodiment 2

[0040] Preparation of 4-[1-(2,3-Dimethylphenyl)ethyl]-1H-imidazole

[0041] In the reaction vessel, add FeCl 3 ·6H 2 O 0.81g (3mmol), 2,3-dimethylstyrene 13.2g (100mmol), imidazole 8.2g (120mmol) and ionic liquid [Bmim] BF 6 Stir the reaction in 35ml at 25°C for 0.5 hours, monitor the completion of the reaction, pour it into water, extract with dichloromethane, wash the organic phase three times with water, dry the organic phase with anhydrous sodium sulfate, concentrate under reduced pressure, and recrystallize petroleum ether to obtain 4-[1- (2,3-Dimethylphenyl)ethyl]-1H-imidazole 17.4g, yield 86.8%, R / S=40:60.

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Abstract

The invention discloses a method for preparing dexmedetomidine hydrochloride for anesthesia and sedation during an operation. The method comprises the following steps: (a) stirring and reacting 2,3-dimethyl styrene and imidazole in ionic liquid to obtain 4-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole in the presence of an iron salt; (b) reacting the 4-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole with L-(+)-tartaric acid, and performing suction filtering to obtain dexmedetomidine tartrate; (c) stirring the dexmedetomidine tartrate in an aqueous solution of sodium hydroxide, performing dichloromethane extraction and concentration, and stirring in a saturated hydrochloric acid methanol solution to obtain the dexmedetomidine hydrochloride. According to the method, the ionic liquid is used for alkylation reaction of the imidazole under catalysis of the iron salt, so that the reaction time is effectively shortened, and high yield is achieved; fewer steps are required, and the cost is lower; conditions in each step are mild, use of a large amount of lewis acid is avoided, and easiness for industrial production is achieved.

Description

technical field [0001] The invention belongs to the technical field of drug synthesis, and relates to a preparation method of dexmedetomidine hydrochloride used for intraoperative anesthesia and sedation. Background technique [0002] Dexmedetomidine hydrochloride is an α2-adrenoceptor agonist jointly developed by Orion Pharma of Finland and Abott of the United States. It was first launched in the United States in March 2000. Dexmedetomidine hydrochloride has anti-sympathetic, sedative and analgesic effects. Compared with medetomidine, it has stronger selectivity and a shorter half-life. It can be used clinically for intubation and ventilator patients during intensive care treatment At the same time, the drug can also reduce the dosage of anesthetics, improve the stability of hemodynamics during the operation and reduce the incidence of myocardial ischemia. The chemical name of dexmedetomidine hydrochloride is (S)-4-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole hydrochloride, ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D233/58
CPCC07D233/58
Inventor 吕燕华
Owner QINGDAO CHENDA BIOLOGICAL SCI & TECH
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