A kind of amide compound, its pharmaceutical composition, preparation method and use
An amide compound, a pharmaceutical technology, applied in the field of medicine, can solve the problems such as the inability to guarantee the analgesic demand during the peak period of postoperative pain, the inability to meet the chronic pain, the limited action time, etc., and achieve long-term sensory and/or motor block activity. , Long onset time, less side effects
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[0060] In the second aspect, this embodiment provides a method for preparing the above-mentioned amide compound or a pharmaceutically acceptable salt thereof, which includes:
[0061] Under basic conditions, in an organic solvent, compound II and compound III are subjected to condensation reaction;
[0062]
[0063] More preferably, the base used above includes but not limited to: diethylamine, triethylamine, 4-dimethylaminopyridine, DBU, lithium carbonate, sodium bicarbonate, sodium carbonate, potassium carbonate, potassium bicarbonate, carbonic acid Cesium, potassium phosphate, potassium hydrogen phosphate, sodium phosphate, sodium hydrogen phosphate, lithium acetate, sodium acetate, potassium acetate; preferably, the base used in the above reaction is diethylamine, triethylamine, 4-dimethylaminopyridine.
[0064] More preferably, the temperature of the above reaction is 10-30°C, or 13-28°C, or 15-25°C.
[0065] More preferably, the reaction time of the above reaction is...
Embodiment 1
[0086] Preparation of compound 1:
[0087]
[0088] Compound A (3mmol, 0.94g) and dichloromethane (10mL) were added to a 100mL round bottom flask, and compound 1 (3mmol, 600mg) was added dropwise with stirring at room temperature, and reacted for 12 hours. The reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol=20:1) to obtain 1.3 g of the target product (Compound 1), with a yield of 84%.
[0089] Rf = 0.4, developing agent dichloromethane: methanol: 10:1 color development: ultraviolet
[0090] HRMS:[C 24 h 34 N 3 o 5 S] + , calcd 476.2214, found 476.2226.
[0091] 1 H NMR (400MHz, CDCl 3 ): δ10.04(s,1H),7.89-7.87(d,J=8Hz,2H),7.25-7.23(d,J=8Hz,2H),7.09-7.06(m,1H),7.02-7.00( d,2H),3.86(br,2H),4.57(br,2H),3.86(br,2H),3.78-3.73(m,4H),2.38(s,3H),2.18(s,6H),1.38 -1.34(t,J=6.8Hz,6H). 13 C NMR (100MHz, CDCl 3 ): δ162.07, 151.39, 144.49, 136.27, 135.35, 132.85, 129.58, ...
Embodiment 2
[0093] Preparation of Compound 2:
[0094]
[0095] Compound A (3mmol, 0.94g) and dichloromethane (15mL) were added to a 100mL round bottom flask, and compound 2 (3.5mmol, 540mg) was added dropwise with stirring at room temperature, and reacted for 12 hours. The reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol=20:1) to obtain 1.2 g of the target product (compound 2), with a yield of 86%.
[0096] Rf = 0.4, developing agent dichloromethane: methanol: 10:1 color development: ultraviolet
[0097] HRMS:[C 23 h 31 ClN 3 o 3 ] + , calcd 432.2048, found 432.2059.
[0098] 1 H NMR (400MHz, CDCl 3 ): δ10.31(s,1H),9.75(s,1H),7.64-7.62(d,J=8.4Hz,2H),7.22-7.19(m,2H),7.10-7.04(m,4H), 5.02-5.00(m,2H),4.66(br,2H),3.92-3.86(m,4H),3.78-3.74(m,2H),2.25(s,6H),1.43-1.40(t,J=6.8 Hz,6H). 13 C NMR (100MHz, CDCl 3 ): δ162.16, 152.39, 136.80, 135.25, 132.72, 128.79, 128.35, 128.25,...
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