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Method for synthesizing dexmedetomidine hydrochloride intermediate

A technology for dexmedetomidine hydrochloride and intermediates, applied in the field of pharmaceutical chemical synthesis, can solve the problems of chiral product dependence on resolution, unsatisfactory synthesis yield, and short reaction time, achieving short reaction time and high selectivity , the effect of improving the utilization rate

Inactive Publication Date: 2017-04-26
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 present invention aims at the unsatisfactory synthesis yield of the existing dexmedetomidine hydrochloride intermediate 4-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole, and it is necessary to obtain the chiral product Rely on the defects of resolution, provide a method for synthesizing 4-[1-(2,3-dimethylphenyl) ethyl]-1H-imidazole, the method has short reaction time and high yield, especially, Good selectivity for the target (S)-isomer

Method used

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  • Method for synthesizing dexmedetomidine hydrochloride intermediate
  • Method for synthesizing dexmedetomidine hydrochloride intermediate

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Experimental program
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Embodiment 1

[0029] Synthesis of Dexmedetomidine Hydrochloride Intermediate (4-[1-(2,3-Dimethylphenyl)ethyl]-1H-imidazole)

[0030] In the three-necked flask, in the presence of nitrogen, 31.8 g (300 mmol) of sodium carbonate, 28.2 g (100 mmol) of 1-(1-trifluoromethanesulfonate) ethyl-2,3-dimethylbenzene, [1, 1'-bis(diphenylphosphino)ferrocene]palladium dichloride 3.5g (5mmol), imidazole 8.2g (120mmol) and 52ml[BuPy]BF 4 , stirred and reacted at 70°C for 30 minutes, 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 recrystallized petroleum ether to obtain 4-[1-( 2,3-Dimethylphenyl)ethyl]-1H-imidazole 17.6g, yield 84.7%, (S)-4-[1-(2,3-Dimethylphenyl)ethyl]-1H -Imidazole ee value 79.89%.

[0031] 1 HNMR (400MHz, CDCl 3 ): δ7.35(s,1H),7.08-6.95(m,3H),6.71(s,1H),4.40(q,J=21.2,7.2,1H),2.29(s,3H),2.31(s ,3H), 1.57 (d...

Embodiment 2

[0033] Synthesis of Dexmedetomidine Hydrochloride Intermediate (4-[1-(2,3-Dimethylphenyl)ethyl]-1H-imidazole)

[0034] In the three-necked flask, in the presence of nitrogen, 21.2 g (200 mmol) of sodium carbonate, 28.2 g (100 mmol) of 1-(1-trifluoromethanesulfonate) ethyl-2,3-dimethylbenzene, [1, 1'-bis(diphenylphosphino)ferrocene]palladium dichloride 10g (15mmol), imidazole 8.9g (130mmol) and 52ml[BuPy]BF 4 , stirred and reacted at 80° C. for 30 minutes, 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 recrystallized petroleum ether to obtain 4-[1-( 2,3-Dimethylphenyl)ethyl]-1H-imidazole 17.1g, yield 82.2%, (S)-4-[1-(2,3-Dimethylphenyl)ethyl]-1H -Imidazole ee value 81.02%.

Embodiment 3

[0036] Synthesis of Dexmedetomidine Hydrochloride Intermediate (4-[1-(2,3-Dimethylphenyl)ethyl]-1H-imidazole)

[0037] In a three-necked flask, in the presence of nitrogen, add 40 g of sodium carbonate, 28.2 g (100 mmol) of 1-(1-trifluoromethanesulfonate) ethyl-2,3-dimethylbenzene, [1,1'-bis (Diphenylphosphino) ferrocene] palladium dichloride 7g (10mmol), imidazole 10.2g (150mmol) and 52ml [BuPy] BF4 , stirred and reacted at 90°C for 30 minutes, and 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 recrystallized petroleum ether to obtain 4-[1-( 2,3-Dimethylphenyl)ethyl]-1H-imidazole 17.2g, yield 82.5%, (S)-4-[1-(2,3-Dimethylphenyl)ethyl]-1H -Imidazole ee value 82.41%.

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Abstract

The invention discloses a method for synthesizing a dexmedetomidine hydrochloride intermediate. The synthesis method comprises the step that 1-(1-trifluoromethanesulfonate)ethyl-2,3-dimethylbenzene and imidazole are subjected to stirring reacting in ionic liquid in the presence of alkali and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride to obtain the dexmedetomidine hydrochloride intermediate 4-[1-(2,3-dimethylbenzene)ethyl]-1H-imidazole. The method is short in reacting time and high in product production efficiency and yield and has the good selectivity on a target (S)-isomer.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical chemical synthesis, and relates to a method for synthesizing an intermediate of dexmedetomidine hydrochloride. Background technique [0002] Dexmedetomidine hydrochloride was listed for the first time in the United States in March 2000. The drug is an α2-adrenoceptor agonist developed jointly by Orion Pharma of Finland and Abott of the United States. The chemical name of dexmedetomidine hydrochloride is (S)-4-[1-(2,3-Dimethylphenyl)ethyl]-1H-imidazole hydrochloride, the specific structure is as follows: [0003] [0004] 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 du...

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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