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Method for preparing high-purity dexmedetomidine hydrochloride crystal from high-purity intermediate crystal

A technology of dexmedetomidine hydrochloride and dexmedetomidine, which is applied in the field of crystal preparation technology, can solve the problem that the crystal form of the product dexmedetomidine hydrochloride has not been reported, and achieve significant technical advantages and research value , easy to save the effect

Inactive Publication Date: 2015-12-23
HAINAN GENERAL & KANGLI PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0008] References at home and abroad have no reports on the crystal form of the intermediate dexmedetomidine malate and the crystal form of the product dexmedetomidine hydrochloride

Method used

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  • Method for preparing high-purity dexmedetomidine hydrochloride crystal from high-purity intermediate crystal
  • Method for preparing high-purity dexmedetomidine hydrochloride crystal from high-purity intermediate crystal
  • Method for preparing high-purity dexmedetomidine hydrochloride crystal from high-purity intermediate crystal

Examples

Experimental program
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Effect test

Embodiment 1

[0053] Embodiment 1 A kind of preparation method of 4-[(1S)-1-(2,3-dimethylphenyl) ethyl]-1H-imidazole hydrochloride (dexmedetomidine hydrochloride) crystal, its steps as follows:

[0054] 1) Add 2200 mL of chloroform and 165 mL of titanium tetrachloride into a dry 10 L reaction flask, stir and cool down. At -10°C to 10°C, add dropwise a solution made of 246mL N-trimethylsilyl imidazole and 670mL chloroform within 0.5h, keep warm at -10°C to 10°C and stir for 0.5h after the dropwise addition, and then keep at -10°C to 10°C, add dropwise a solution of 169.0g 1-(1-chloroethyl)-2,3-dimethylbenzene (purity 95.6%) and 670mL chloroform within 0.5h, and keep warm at -10°C to 10°C after the dropwise addition Stir for 0.5h. Afterwards, the temperature was raised to reflux for 6 h. Cool down to below 25°C, add 3000mL of water to quench, and then adjust the solution to pH=9 with 4mol / L sodium hydroxide solution. The mixed solution was layered, the aqueous phase was extracted with chl...

Embodiment 2

[0064] Embodiment 2 A kind of preparation method of 4-[(1S)-1-(2,3-dimethylphenyl) ethyl]-1H-imidazole hydrochloride (dexmedetomidine hydrochloride) crystal, its steps as follows:

[0065] 1) Add 2200 mL of chloroform and 165 mL of titanium tetrachloride into a dry 10 L reaction flask, stir and cool down. At -10°C to 10°C, add dropwise a solution made of 246mL N-trimethylsilyl imidazole and 670mL chloroform within 0.5h, keep warm at -10°C to 10°C and stir for 0.5h after the dropwise addition, and then keep at -10°C to 10°C, add dropwise a solution of 169.0g 1-(1-chloroethyl)-2,3-dimethylbenzene (purity 95.6%) and 670mL chloroform within 0.5h, and keep warm at -10°C to 10°C after the dropwise addition Stir for 0.5h. Afterwards, the temperature was raised to reflux for 6 h. Cool down to below 25°C, add 3000mL of water to quench, and then adjust the solution to pH=11 with 4mol / L sodium hydroxide solution. The mixture was separated into layers, the aqueous phase was extracted ...

Embodiment 3

[0071] Embodiment 3 A kind of preparation method of 4-[(1S)-1-(2,3-dimethylphenyl) ethyl]-1H-imidazole hydrochloride (dexmedetomidine hydrochloride) crystal, its steps as follows:

[0072] 1) Add 2200 mL of chloroform and 165 mL of titanium tetrachloride into a dry 10 L reaction flask, stir and cool down. At -10°C to 10°C, add dropwise a solution made of 246mL N-trimethylsilyl imidazole and 670mL chloroform within 0.5h, keep warm at -10°C to 10°C and stir for 0.5h after the dropwise addition, and then keep at -10°C to 10°C, add dropwise a solution of 169.0g 1-(1-chloroethyl)-2,3-dimethylbenzene (purity 95.6%) and 670mL chloroform within 0.5h, and keep warm at -10°C to 10°C after the dropwise addition Stir for 0.5h. Afterwards, the temperature was raised to reflux for 6 h. Cool down to below 25°C, add 3000mL of water to quench, and then adjust the solution to pH=9 with 4mol / L sodium hydroxide solution. The mixture was separated into layers, the aqueous phase was extracted w...

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Abstract

The invention discloses a high-purity intermediate crystal of dexmedetomidine, a preparation method of the high-purity intermediate crystal, a high-purity dexmedetomidine hydrochloride crystal prepared from the high-purity intermediate crystal and a method for preparing the high-purity dexmedetomidine hydrochloride crystal from the high-purity intermediate crystal. The prepared intermediate crystal is dextro-4[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-L-(-) malate which has the purity of 99.9%, the total related substance impurity content of less than 0.10%, the single impurity content of less than 0.05%, the optical purity of 100.0% and the elemental analysis and theoretical value difference of less than 0.3% and is stable in property and easy to store; and the high-purity dexmedetomidine hydrochloride crystal, namely, 4-[1-2,3-dimethylphenyl)ethyl]-1H-imidazole hydrochloride, prepared from the intermediate crystal prepared by using the method, has the purity of 99.9%, the total related substance impurity content of less than 0.10%, the single impurity content of less than 0.05%, the optical purity of 100.0% and the elemental analysis and theoretical value difference of less than 0.3% and is stable in property and easy to store.

Description

technical field [0001] The invention relates to the technical field of crystal preparation, in particular to a novel α 2 - The key intermediate of the adrenoceptor agonist dexmedetomidine hydrochloride (chemical name: 4-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole hydrochloride A method for preparing dexmedetomidine malate (4-[(1S)-1-(2,3-dimethylphenyl) ethyl]-1H-imidazole-L-malate) crystal, and A method for preparing high-purity dexmedetomidine hydrochloride crystals by using the intermediate crystals. Background technique [0002] The structural formula of dexmedetomidine hydrochloride (chemical name: 4-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole hydrochloride) is as follows: [0003] [0004] Its important intermediate dexmedetomidine malate (4-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-L-malate) has the following structural formula: [0005] [0006] The US FDA approved dexmedetomidine hydrochloride injection for sedation in intensive care units in ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D233/58C07B57/00
CPCC07D233/58C07B57/00C07B2200/13
Inventor 余丹戴正琳邵振徐朕李宇熙陈龙
Owner HAINAN GENERAL & KANGLI PHARMA
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