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AssigneeTianjin Weijie Pharmaceutical Co., Ltd
InventorsHonghai Song, Zhicun Sun, Haiping Huang, Chao Zhang
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The present invention discloses a preparation method of 2,3-dimethyl phenyl-1-trityl-imidazole-4-ketone. In accordance with this method, imidazole-4-ethyl formate is used as a raw material; ethyl formate is used for amino protection, 1-trityl-1H-imidazole-4-formic acid is obtained after basic hydrolysis; 1-trityl-1H-imidazole-4-formic acid and N,O-dimethylhydroxylamine hydrochloride are subjected to condensation so as to obtain N-methoxyl-N-methyl-1-trityl-1H-imidazole-4-formamide; and N-methoxyl-N-methyl-1-trityl-1H-imidazole-4-formamide and a Grignard reagent prepared by the reaction of 2,3-dimethylbromobenzene with magnesium are subjected to a Grignard reaction, and then the target product 2,3-dimethyl phenyl-1-trityl-1H-imidazole-4-ketone is obtained. Compared with the reported preparation methods, the preparation method is more convenient to operate and is beneficial for industrial production.
A preparation method of dexmedetomidine intermediate 2,3-dimethylphenyl-1-trityl-1H-imidazole-4-ketone, characterized in that, said preparation method comprises the following steps in turn:
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With hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals,…:…
Having two double bonds between ring members or between ring members and non-ring members: with substituted hydrocarbon radicals attached to ring…
Heterocyclic compounds
About 7 years 11 months of term left · ends 9 Oct 2034 (estimated)
The present invention belongs to the technical field of medicines, in particular to a preparation method of dexmedetomidine intermediate, 2,3-dimethyl phenyl-1-trityl-imidazole-4-ketone.
Medetomidine is a racemic mixture of two optical enantiomers, which namely levmedetomidine (LEV) and dexmedetomidine (DEX), at an equal ratio (MacDonald et al., 1991; Savola and Virtanen, 1991). Such compound has high selectivity on 2-epinephrine acceptor, and is a novel alpha2-receptor stimulant with 4-replaced imidazole ring (Savola et al, 1986).
At present, there are several known methods for preparing the medetomidine.
The preparation method of the dexmedetomidine intermediate, 2,3-dimethyl phenyl-1-trityl-imidazole-4-ketone provided by the present invention is described in detail below.
Add 100 g (0.714 mol, 1.0 eq) of imidazole-4-ethyl formate and 1.4 L of dichloromethane to a 2 L four-mouth bottle equipped with a mechanical stirring and a thermometer to form a suspension; add 219 g (0.787 mol, 1.1 eq) of triphenylchloromethane and 79.4 g (0.787 mol, 1.1 eq) of triethylamine to the suspension, slowly heat to 25˜30° C., the liquid turns clear. Continue to stir for 20 h to the reaction finish. Add 200 mL water and stir 30 mins, then standing for layered. Separate the organic phase and extract the water phase by 100 mL dichloromethane. Combine the organic phase and wash it once by 200 mL water. Concentrate the organic phase to get alight yellow oil; then 500 mL diethyl ether is added, a great amount of white solids are generated when the mixed solution is stirred; filter and dry to obtain 269 g 1-trityl-1H-imidazole-4-ethyl formate, with a yield of 98% and a purity of 90% (HPLC).
Add 600 mL Methanol and 650 ml tetrahydrofuran to a 5 L dried four-mouth bottle equipped with a mechanical stirring and a thermometer, then add 125 g (0.327 mol, 1.0 eq) 1-trityl-1H-imidazole-4-ethyl formate; stir to form a suspension; 1 L sodium hydroxide solution (2M, 6 eq) is dropped into the suspension, wherein the temperature is controlled to be 10˜20° C. Stir for 5 hrs and then the reaction ends. 1 L Hydrochloric acid solution (2M) is slowly dropped and a great amount of white solids are generated when the mixed solution is stirred. Adjust pH value to 5˜6. Filter and dry to obtain 112 g 1-trityl-1H-imidazole-4-formic acid, with a yield of 96% and a purity of 97% (HPLC).