1) Preparation of medetomidine
Into the 20L dry glass reaction kettle, add 1.86kg of trimethylsilimidazole and 9.85L of dichloromethane in turn, stir for 10min, start to add 2.52kg of titanium tetrachloride dropwise, control the internal temperature to 20～30℃, and continue stirring 30min, continue to add 1.33kg of 1-(2,3-dimethylbenzene) ethanol dropwise under the temperature adjustment, after the drop is completed, continue to stir the reaction for 18h, take samples for TLC detection or HPLC detection. After the completion of the reaction, the reaction solution was added to 10L of ice water, stirred for 20min, left to stand for stratification, the aqueous phase and the organic phase were separated, the organic phase was discarded, the pH of the aqueous phase was adjusted to 10 with sodium hydroxide, and 12L of dichloromethane was added for extraction. , separate the organic phase, add 4L of dichloromethane to the aqueous phase again for extraction, and combine the organic phases. The organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain 2.23 kg of a yellow oily liquid, which was a crude product of medetomidine, with a yield of 89.9%.
2) Refinement of medetomidine
In the 30L dry glass reaction kettle, add 2.23kg of medetomidine crude product successively, 22.3L of dehydrated alcohol and 0.65kg of L-(+) tartaric acid, stir and heat up to make the solids dissolve completely, turn off the heating, naturally cool down and stir, and crystallize 10h, filter, collect the solid, add the obtained white solid to 22.3L of dichloromethane and 5.6L of water, stir, add sodium hydroxide, adjust the pH to pH 10, stir for 15min, stand for stratification, separate the organic phase, add no The water was dried over sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain 1.56 kg of yellow oily liquid, which was a refined product of medetomidine, and the yield was 70.0%.
3) Preparation of Dexmedetomidine
In the 50L dry glass reactor, add 1.56kg of refined medetomidine, 31.8L of dehydrated alcohol and 0.42kg of L-(+) tartaric acid successively, stir and heat up to make the solids dissolve completely, turn off the heating, and naturally cool down to room temperature , crystallized for 10h, filtered, and the solid was collected. The obtained white solid was added to 31.8L of dichloromethane and 10.6L of water, stirred, added with sodium hydroxide, adjusted to pH 10, stirred for 15min, left to stand for stratification, and the organic phase was separated. , was dried by adding anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain 0.47kg of white solid, which was dexmedetomidine.
4) Preparation of Dexmedetomidine Hydrochloride
0.47kg of dexmedetomidine was added to 9.4L of dichloromethane, stirred to dissolve all the solids, and after the solution was clear, 390ml of 9N hydrochloric acid ethanol was added dropwise. 37.6L of petroleum ether was added dropwise, and a large amount of white solid was precipitated. After the drop was completed, stirring and crystallization was carried out for 2 h, suction filtration, and the filter cake was blast-dried to constant weight to obtain 0.54 kg of dexmedetomidine hydrochloride, with a total yield of 18.4 %.
