Background and overview[1][2]
1-(1-Chloroethyl)-2,3-dimethylbenzene is an organic raw material and a key intermediate for the preparation of dexmedetomidine hydrochloride. Dexmedetomidine is the active dextrorotatory form of medetomidine, a sedative-hypnotic drug developed by Orion Pharma Abott. This product is a highly effective α2-adrenergic receptor agonist, with an affinity for adrenergic receptors that is 8 times higher than that of clonidine. It has a short half-life and a small effective dose. It is suitable for patients who are intubated and on ventilators during intensive care treatment. Calm.
Preparation[1]
Preparation of 1-(1-chloroethyl)-2,3-dimethylbenzene
In a 1000mL three-necked flask, add 200mL of tetrahydrofuran (THF) and 12g of magnesium strips (0.5mo1), heat to reflux, add dropwise 150mL of a THF solution of 92.5g (0.5mo1) of 2,3-dimethylbromobenzene, and reflux After 1 hour, cool to room temperature, add acetaldehyde 36 mL (0.64 mol)/THF 100 mL dropwise, continue to reflux for 1 hour, evaporate THF under reduced pressure, slowly add NH4Cl aqueous solution (25g NH4C1+80mL after cooling) water) and ethyl acetate 300mL. Let stand and separate the layers, dry the organic phase with anhydrous Na2S04, filter, evaporate the solvent, and then distill under reduced pressure to collect the fraction at 115~118℃/300Pa. Add 200g of anhydrous ZnCl2 and 300mL of concentrated HCl. After fully dissolving, add 150g (1mo1) of the above fraction and stir vigorously for 4 hours. Separate layers, dry the organic phase with anhydrous CaC12, filter, evaporate the solvent from the filtrate, distill under reduced pressure, collect the 80~83℃/300Pa fraction, and obtain the product 1-(1-chloroethyl) -2,3-dimethylbenzene (142g, yield 84.2%). 1H-NMR (CDC13)δ: 1.85 (d, J=2.4Hz, 3H, -CHClCH3), 2.28 (s, 3H, ArCH3), 2.29 (s, 3H, ArCH3), 5.41 (q, J=6.8Hz, 1H, -CHClCH3), 7.08～7.14 (m, 2H, ArH), 7.38 (d, J=7.2Hz, 1H , ArH).
Apply[1]
Preparation of medetomidine
In a 1000 mL three-necked flask, add 0.2 mol of Lewis acid and 200 mL of solvent, add 14.7 mL (0.1 mol) of TMSI and 40 mL of solvent dropwise in an ice bath, and continue stirring for 30 min; slowly add 1-(1-chloroethyl) dropwise -2,3-dimethylbenzene 16.9g (0.1mol) and solvent 40mL, control the temperature of the external bath, and continue stirring for 1 hour; then continue stirring at room temperature for 15 hours. Add mL of water dropwise in an ice bath (below 10°C), stir thoroughly to completely hydrolyze, transfer the reaction solution to a separatory funnel and let stand for layering; adjust the pH of the water phase to 8-9 with a mass fraction of 30% NaOH, and then separate the liquid. Use solvent 200mL L NaOH produced a flocculent white precipitate, which was filtered and dried to obtain compound 1.
Elemental analysis (C13H16N2) measured values (calculated value, %): C77.72 (77.96), H8.15 (8.05), N14.01 (13.99). 1H-NMR(CDC13)6: 1.60 (d, J=7.0Hz, 3H), 2.18 (s, 3H), 2.26(S, 3H), 4.42(q, J=7.0Hz, 1H), 6.75(s, 1H), 6.94(t, J=4.4Hz, 1H), 7.08(d, J=4.8Hz, 2H), 7.62 (d, 1H), 11.92 (br, 1H). IR(v/cm-1): 3431(W, -NH), 3082(s, =CH), 2992(s, CH), 1609-1474[s, aromatic (hetero) ring ,skeleton].
Main reference materials
[1] CN201310700021.X A new method for preparing dexmedetomidine hydrochloride
