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Synthetic process of dexmedetomidine hydrochloride

A technology of dexmedetomidine hydrochloride and dexmedetomidine, which is applied in the field of drug synthesis, can solve the problems of complex reaction operation and low total yield of the process, and achieve the effect of simple operation and controllable quality

Pending Publication Date: 2020-08-18
TIANJIN PHARMA GROUP XINZHENG
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0014] The purpose of the present invention is to solve the problem of complex reaction operation and low process total yield in the prior art, and provides a synthesis process of dexmedetomidine hydrochloride, which uses 1-(1-chloroethyl)-2,3- Xylene and trimethylsilimidazole are used as starting materials to synthesize dexmedetomidine hydrochloride through alkylation, resolution, dissociation and salt formation. It has the advantages of simple operation, high yield, controllable production and stable quality of raw materials. The advantages

Method used

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  • Synthetic process of dexmedetomidine hydrochloride

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Embodiment 1

[0032] Embodiment 1: medetomidine is synthesized

[0033] Under nitrogen protection, titanium tetrachloride (5.62g, 29.65mmol) was added to dichloromethane (55ml), cooled to 25°C, starting material-2 (7.49g, 53.37mmol) was diluted with dichloromethane (10ml) , added dropwise to the reaction solution, temperature controlled not to exceed 35°C, and stirred for 30 minutes after addition; starting material-1 (5.00g, 29.65mmol) was diluted with dichloromethane (10)ml, added to the reaction solution, added After heating up to 35°C for 2 hours, take the reaction liquid for monitoring, add water (50ml), stir for 15 minutes, discard the upper organic layer, extract the remaining solution with water (50ml*2), combine the aqueous phases, and use methyl tert-butyl Ether (50ml) was extracted by reaction, and the aqueous phase was extracted with 30% NaOH solution and dichloromethane (50ml*2) to adjust alkali (pH ≥ 10), washed with water (50ml), dried over anhydrous sodium sulfate, and final...

Embodiment 2

[0034] Embodiment 2: medetomidine is synthesized

[0035] Under nitrogen protection, titanium tetrachloride (6.18g, 32.62mmol) was added in dichloromethane (55ml), cooled to 0-10°C, starting material-2 (7.49g, 53.37mmol) was mixed with dichloromethane (10ml ) was diluted, quickly added to the reaction solution, and stirred for 30 minutes after the addition; the starting material-1 (5.00g, 29.65mmol) was diluted with dichloromethane (10)ml, added to the reaction solution, and the temperature was raised to 35°C after the addition React for 2 hours, take the reaction solution for monitoring, add water (50ml), stir for 30 minutes, discard the upper organic layer, extract the remaining solution with water (50ml*2), combine the aqueous phases, and react with methyl tert-butyl ether (50ml) extraction, the aqueous phase was extracted with 30% NaOH solution and dichloromethane (50ml*2) to adjust alkali (pH ≥ 10), washed with water (50ml), dried over anhydrous sodium sulfate, and finall...

Embodiment 3

[0036] Embodiment 3: the synthesis of dexmedetomidine tartrate

[0037] Add medetomidine (5.00g, 24.96mmol) into ethanol (80ml), add 0.4eq L-tartrate, heat to 75°C and stir to dissolve, cool to 15°C for crystallization for 1 hour, filter to obtain tartrate Crude. The crude tartrate was added to 90% ethanol / water (30ml), heated to 70°C to dissolve, cooled to 5°C to crystallize for 1 hour, filtered, and dried to obtain a white solid. The white solid was obtained by repeating the above steps and then refined once to obtain the finished product of tartrate. Finally, it was filtered, washed with an appropriate amount of ethanol, and drained. The rate is 36.2%.

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Abstract

The present invention provides a dexmedetomidine hydrochloride synthesis process, and relates to the technical field of drug synthesis, the dexmedetomidine hydrochloride synthesis process uses 1-(1-chloroethyl)-2,3-xylene and trimethylsilylimidazole as starting materials, and alkylation, resolution, dissociation and salification reactions are performed to synthesize the dexmedetomidine hydrochloride. According to the method, L-tartaric acid is used as a resolving agent, and the resolving efficiency is improved by controlling the proportion of the resolving agent and the number of resolving times; a one-step method is adopted for free salification, intermediate quality control and purification steps are not needed, the purity of the prepared finished product is larger than 99.8%, the isomeris not larger than 0.2%, through process optimization, the efficiency of the synthesis process is remarkably improved, and the obtained finished product directly meets the commercial production requirements of raw material medicines.

Description

technical field [0001] The invention relates to the technical field of drug synthesis, in particular to a process for synthesizing dexmedetomidine hydrochloride. Background technique [0002] Dexmedetomidine Hydrochloride Injection is an α2-adrenoceptor agonist jointly developed by Abott (USA) and Orion Pharma of Finland. It was approved for marketing in the US on December 17, 1999, with the trade name PRECEDEX® . Presetex intravenous injection 200μg "Pfizer" was launched in Japan in March 2006. The licensee is Pfizer (HOSPIRA was acquired by Pfizer) and the trade name is Precedex®. It was listed in EMA on September 16, 2011. The licensee is Orion Pharma of Finland, and the trade name is Dexdor®. So far, the original preparation of dexmedetomidine hydrochloride injection has not been imported into China. This product has the characteristics of short half-life and small dosage, and is clinically suitable for sedation of patients who start intubation and use ventilator duri...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D233/58
CPCC07D233/58C07B2200/07
Inventor 周红建李俊霞白艳鹤李阳平何盛江余顺雄
Owner TIANJIN PHARMA GROUP XINZHENG
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