New method for preparing dexmedetomidine hydrochloride

A technology for dexmedetomidine hydrochloride and dexmedetomidine, which is applied in the field of pharmaceutical chemical synthesis and can solve the problem of low yield and the like

Inactive Publication Date: 2014-04-02
北京华禧联合科技发展有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The purpose of the present invention is to solve the problem of low yield in the prior art, aiming to find a route with easy-to-obtain raw materials, mild reaction conditions and high yield

Method used

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  • New method for preparing dexmedetomidine hydrochloride
  • New method for preparing dexmedetomidine hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0011] Preparation of 1-(1-chloroethyl)-2,3-dimethylbenzene (2)

[0012] In a 1000mL three-neck flask, add 200mL of tetrahydrofuran (THF) and 12g (0.5mol) of magnesium strips, heat to reflux, add dropwise 150mL of a THF solution of 92.5g (0.5mol) of 2,3-dimethylbromobenzene, and reflux for 1 hour; Cool to room temperature, dropwise add acetaldehyde 36mL (0.64mol) / THF100mL, continue to reflux for 1h, evaporate THF under reduced pressure, slowly add NH 4 Cl aqueous solution (25g NH 4 C1+80mL water) and ethyl acetate 300mL. Static stratification, with anhydrous Na 2 S0 4 Dry the organic phase, filter, evaporate the solvent, and then distill under reduced pressure to collect fractions at 115-118°C / 300Pa. Add anhydrous ZnCl 2 200g and 300mL of concentrated HCl, fully dissolved and added 150g (1mol) of the above fraction, and stirred vigorously for 4h. Layered, anhydrous CaCl 2 The organic phase was dried, filtered, the filtrate was evaporated to remove the solvent, and disti...

Embodiment 2

[0014] Preparation of medetomidine (1)

[0015] In a 1000mL three-necked flask, add 0.2mol of Lewis acid and 200mL of solvent, dropwise add TMSI14.7mL (0.1mol) and 40mL of solvent under ice bath, and continue to stir for 30min; slowly add compound 216.9g (0.1mol) and 40mL of solvent, control The temperature of the external bath was continued to stir for 1 h; then continued to stir at room temperature for 15 h. Under ice bath (below 10°C), add 400 mL of water dropwise, stir well to make it completely hydrolyzed, transfer the reaction solution to a separatory funnel and let it stand for stratification; Use solvent 200mL×3 to extract in the funnel; after combining the organic phases, wash 100mL×3 times with water, and use Na 2 SO 4 After drying, the solvent was evaporated to obtain a light yellow viscous substance, which was dissolved in 2 mol / L HC aqueous solution, and 5 mol / L NaOH was added dropwise to produce a flocculent white precipitate, which was filtered and dried to ob...

Embodiment 3

[0017] Preparation of dexmedetomidine

[0018] In a 500 mL three-neck flask, compound 1 (17.5 g, 87 mmol) was added to 120 mL of isopropanol-water (volume ratio 1:1) solution, heated to 80° C. to completely dissolve the solid. At this temperature, add D-DTTA (18.5g, 48mmol) into the reaction system to dissolve it. After stirring for 30 minutes, stop heating, cool to 15°C, and continue stirring for 3 hours. A large amount of white precipitates gradually precipitate out of the system. Filter it quickly and use Wash with cold isopropanol several times, filter with suction to obtain a white solid, dissolve it in 100mL of water, slowly add saturated Na 2 CO 3 , the solution until the pH value of the system was 7-8, and fully stirred for 1h, extracted with ethyl acetate (50mL×3), combined the organic phases, anhydrous Na 2 SO 4 After drying, the ethyl acetate was distilled off under reduced pressure to obtain a white solid (S)-1 (7.7 g), with a yield of 44%.

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Abstract

The invention provides a new method for preparing dexmedetomidine hydrochloride. According to the method, Lewis acid is used as a catalyst, and racemized medetomidine is prepared by a Friedel-Crafts reaction; and the racemized medetomidine is resolved by (+)-di-p-toluoyl-tartaric acid [(+)-DDTA] to obtain dexmedetomidine. The dexmedetomidine is salified in hydrochloric acid to obtain dexmedetomidine hydrochloride.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical chemical synthesis, and in particular relates to a preparation method of dexmedetomidine hydrochloride. Background technique [0002] Dexmedetomidine hydrochloride, chemical name (R)-4-[1-(2,3-dimethylphenyl)ethyl]-1H imidazole monohydrochloride, its structure is as follows: [0003] [0004] Dexmedetomidine is the active dextrorotary form of medetomidine, a sedative-hypnotic drug developed by Orion pharma Abott. This product is highly effective α 2 - Adrenergic receptor agonist, with 8 times higher affinity for adrenergic receptors than clonidine, short half-life and small effective dose, suitable for sedation of patients who start intubation and use ventilator during intensive care treatment. This product can still improve the stability of hemodynamics during operation and reduce the incidence of myocardial ischemia. its alpha 2 / α 1 Selectivity up to 45000. Dexmedetomidine hydro...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D233/58
CPCC07D233/58
Inventor 魏爱伟党文娟毕华
Owner 北京华禧联合科技发展有限公司
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