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Preparation method for medetomidine intermediate

A technology of medetomidine and intermediates, applied in the field of medicine, to achieve the effect of low price, simple operation and less waste water

Active Publication Date: 2014-02-19
TIANJIN WEIJIE PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The disadvantage of this method is the need to use strong Lewis acids and excess reagents

Method used

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  • Preparation method for medetomidine intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] In a 2L four-necked flask with a mechanical stirrer and a thermometer, add 100g (0.714mol, 1.0eq) ethyl imidazole-4-carboxylate and 1.4L dichloromethane as a solvent, stir to form a suspension, then add 219g Triphenylchloromethane (0.787mol, 1.1eq) and 79.4g (0.787mol, 1.1eq) of triethylamine were slowly heated to between 25°C and 30°C, the reaction liquid became clear, and the reaction was continued for 20h to complete the reaction. Add 200mL of water, stir for 30min, let stand to separate layers, separate the lower organic phase, then extract the aqueous phase with 100mL of dichloromethane, combine the organic phase, wash the organic phase with 200mL of water once, and concentrate the organic phase under reduced pressure to light yellow oily liquid , and then add 500mL ether, a large amount of white solids are produced under stirring, suction filtration, drying to obtain 269g of ethyl 1-trityl-1H-imidazole-4-carboxylate, yield 98%, purity 90% (HPLC).

[0026] Add 600m...

Embodiment 2

[0030] Add 100g (0.714mol, 1.0eq) ethyl imidazole-4-carboxylate and 1.4L dichloromethane as a solvent to a 2L four-neck flask with a mechanical stirrer and a thermometer, stir to form a suspension, add 259g tris Phenylchloromethane (0.93mol, 1.3eq) and 93.8g (0.93mol, 1.3eq) of triethylamine were slowly heated to between 25°C and 30°C, the reaction solution became clear, and the reaction was continued for 20 hours to complete the reaction. Add 200mL of water, stir for 30min, let stand to separate layers, separate the lower organic phase, then extract the aqueous phase with 100mL of dichloromethane, combine the organic phase, wash the organic phase with 200mL of water once, and concentrate the organic phase under reduced pressure to light yellow oily liquid , and then add 500mL ether, a large amount of white solids are produced under stirring, suction filtration, drying to obtain 265g of ethyl 1-trityl-1H-imidazole-4-carboxylate, yield 97%, purity 92% (HPLC).

[0031]Add 600mL ...

Embodiment 3

[0035] Add 100g (0.714mol, 1.0eq) ethyl imidazole-4-carboxylate and 1.4L dichloromethane as a solvent to a 2L four-neck flask with a mechanical stirrer and a thermometer, stir to form a suspension, add 259g tris Phenylchloromethane (0.93mol, 1.3eq) and 93.8g (0.93mol, 1.3eq) of triethylamine were slowly heated to between 25°C and 30°C, the reaction solution became clear, and the reaction was continued for 20 hours to complete the reaction. Add 200mL of water, stir for 30min, let stand to separate layers, separate the lower organic phase, then extract the aqueous phase with 100mL of dichloromethane, combine the organic phase, wash the organic phase with 200mL of water once, and concentrate the organic phase under reduced pressure to light yellow oily liquid , and then add 500mL ether, a large amount of white solids are produced under stirring, suction filtration, drying to obtain 265g of ethyl 1-trityl-1H-imidazole-4-carboxylate, yield 97%, purity 92% (HPLC).

[0036] Add 600mL...

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Abstract

The invention discloses a preparation method for 2,3-dimethylphenyl-1-triphenylmethyl-imidazole-4-one. The method comprises the following steps: with imidazole-4-ethyl formate as a raw material, carrying out amino protection by using triphenylchloromethane and then carrying out basic hydrolysis so as to obtain 1-triphenylmethyl-1H-imidazole-4-formic acid; subjecting 1-triphenylmethyl-1H-imidazole-4-formic acid and N,O-dimethyl hydroxylamine hydrochloride so as to obtain N-methoxy-N-methyl-1-triphenylmethyl-1H-imidazole-4-methanamide; and subjecting N-methoxy-N-methyl-1-triphenylmethyl-1H-imidazole-4-methanamide and a Grignard reagent prepared through a reaction of 2,3-dimethylbromobenzene with magnesium metal to a Grignard reaction so as to produce the target product 2,3-dimethylphenyl-1-triphenylmethyl-imidazole-4-one. Compared with reported preparation methods in the prior art, the preparation method provided by the invention is easier and more convenient to operate and is beneficial for industrial production.

Description

technical field [0001] The invention belongs to the technical field of medicine, in particular to a method for preparing a medetomidine intermediate 2,3-dimethylphenyl-1-trityl-imidazol-4-one. Background technique [0002] Medetomidine is a racemic mixture of two optical enantiomers mixed in equal proportions, the left-handed and right-handed ones commonly known as levmedetomidine (LEV) and dexmedetomidine (DEX). Optical isomers (MacDonald et al., 1991; Savola and Virtanen, 1991). This compound belongs to a new class of alpha2-receptor agonists containing a 4-substituted imidazole ring with high selectivity for 2-adrenergic receptors (Savola et al, 1986). [0003] There are currently several known methods of preparing medetomidine: [0004] Kudzma et al. disclose a multi-step process for the preparation of medetomidine. The disadvantage of this method is the use of highly flammable and corrosive compounds, such as butyllithium, and the low temperature of about -78 °C. ...

Claims

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Application Information

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IPC IPC(8): C07D233/64
CPCC07D233/64C07D233/90
Inventor 宋洪海孙志存黄海平张超
Owner TIANJIN WEIJIE PHARMA
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