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Preparation process of dexmedetomidine hydrochloride for ICU (intensive care unit) sedation and analgesia

A technology of dexmedetomidine hydrochloride and dexmedetomidine, which is applied in the field of preparation technology of dexmedetomidine hydrochloride, can solve the problems of harsh synthesis conditions and unsatisfactory yield of intermediate medetomidine, and achieve Ease of industrial production, shortened reaction time, and convenient operation

Inactive Publication Date: 2017-04-26
QINGDAO CHENDA BIOLOGICAL SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] The proposal of the present invention is mainly aimed at the problems of harsh synthetic conditions and unsatisfactory yield of intermediate medetomidine in the preparation of existing dexmedetomidine hydrochloride

Method used

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  • Preparation process of dexmedetomidine hydrochloride for ICU (intensive care unit) sedation and analgesia
  • Preparation process of dexmedetomidine hydrochloride for ICU (intensive care unit) sedation and analgesia
  • Preparation process of dexmedetomidine hydrochloride for ICU (intensive care unit) sedation and analgesia

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0028] Preparation of ionic liquids

[0029] ①[Omim]BF 4 (l-octyl-3-methylimidazolium tetrafluoroboric acid)

[0030] 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 chlorinated l-o...

Embodiment 1

[0038] Preparation of 4-[1-(2,3-Dimethylphenyl)ethyl]-1H-imidazole

[0039] FeCl 3 3.2g (20mmol), 1-(1-chloroethyl)-2,3-dimethylbenzene 16.8g (100mmol), imidazole 7.5g (110mmol) and ionic liquid ([omim]BF 6 ) 35ml into the reaction flask, stirred and reacted at 75°C for 0.5 hours, after monitoring the reaction, poured into water, extracted with dichloromethane, washed the organic phase three times with water, dried the organic phase with anhydrous sodium sulfate, concentrated under reduced pressure, and weighed petroleum ether. Crystallization gave 17.0 g of 4-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole, with a yield of 84.8%.

[0040] 1 HNMR (400MHz, CDCl 3 ): δ7.32(s,1H),7.06-6.95(m,3H),6.69(s,1H),4.40(q,J=21.2,7.2,1H),2.29(s,3H),2.31(s ,3H), 1.59 (d, J=7.6,3H).

Embodiment 2

[0042] Preparation of 4-[1-(2,3-Dimethylphenyl)ethyl]-1H-imidazole

[0043] FeCl 3 ·6H 2 O 8.1g (30mmol), 1-(1-chloroethyl)-2,3-dimethylbenzene 16.8g (100mmol), imidazole 8.2g (120mmol) and ionic liquid [Bmim]BF 6 Add 45ml into the reaction flask, stir and react at 80°C for 0.5 hours, monitor the completion of the reaction, pour 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 16.9 g of 4-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole was obtained with a yield of 84.2%.

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Abstract

The invention discloses a preparation process of dexmedetomidine hydrochloride for ICU (intensive care unit) sedation and analgesia. The preparation process includes the steps: first, stirring and reacting 1-(1-halogenated ethyl)-2, 3-dimethyl benzene and imidazole in ionic liquid under catalysis of ferric trichloride to obtain 4-[1-(2, 3-dimethyl phenyl) ethyl]-1H-imidazole; second, refluxing the 4-[1-(2, 3-dimethyl phenyl) ethyl]-1H-imidazole obtained in the first step and L-(+)-tartaric acid in absolute ethyl alcohol, and performing standing, cooling and suction filtration to obtain dexmedetomidine tartrate; third, stirring the dexmedetomidine tartrate in sodium hydroxide aqueous solution, extracting methylene dichloride, concentrating the solution, stirring the solution in saturated hydrochloric acid methanol solution to obtain the dexmedetomidine hydrochloride. The method is short in reaction time, high in yield, milder in condition and suitable for industrial popularization.

Description

technical field [0001] The invention belongs to the technical field of drug synthesis, and relates to a preparation process of dexmedetomidine hydrochloride used for ICU sedation and analgesia. 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, and the spe...

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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