Resorcinol compound, preparation method thereof and application of resorcinol compound in nervous system diseases
A compound and crystal hydrate technology, applied in the field of medicinal chemistry and chemical synthesis, can solve the problems of low oral bioavailability, poor physical and chemical properties, low melting point, etc.
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Embodiment 1
[0149] Embodiment 1 prepares following formula compound 1
[0150]
[0151] Refer to the literature (WO 2019033168; WO 2019033164) to prepare methyl cannabidiolate 1-1, take methyl cannabidiolate 1-1 (1.5g) and dissolve it in 10mL methylamine / ethanol solution, and react in a sealed tube at 100 degrees Overnight, TLC monitored the end of the reaction. After concentrating the reaction solution, the product was separated by column chromatography (petroleum ether / ethyl acetate=100 / 1→20 / 1). The product was slurried with petroleum ether and filtered to obtain the title compound 1, 212 mg as a solid. 1 H NMR (400MHz, CDCl 3 )δ11.21(br,1H),6.30(br,1H),6.21(s,1H),5.88(br,1H),5.54(s,1H),4.53(s,1H),4.39(s,1H ),4.07(br,1H),2.98(d,3H),2.64(t,2H),2.41–2.39(m,1H),2.37–2.17(m,1H),2.11–2.05(m,1H), 1.82–1.76(m,2H),1.78(s,3H),1.70(s,3H),1.67–1.56(m,2H),1.37–1.30(m,4H),0.90(t,3H).ESI- MS m / z370.2(M-H) - .
Embodiment 2
[0152] Embodiment 2 prepares following formula compound 2
[0153]
[0154] Add oxalyl chloride (4.1g, 2eq) dropwise to dichloromethane (40mL) and DMF (2.35g, 1.2eq), control the temperature at -10-0°C, keep warm for 2 minutes, dissolve CBD (8.45g) in 40mL di Chloromethane, CBD was added dropwise to the above system at -10°C, and reacted for 0.5 hours. TLC (petroleum ether / ethyl acetate=20 / 1) monitored that the reaction was complete. The reaction was quenched with saturated sodium bicarbonate solution, the dichloromethane layer was separated, dried over anhydrous sodium sulfate, concentrated and passed through the column, PE→PE / acetone=100 / 1, and 9.42g of product 2-a was isolated with a yield of 99% %. The NMR confirmation was consistent with the literature report (WO 2020031179).
[0155] Dissolve compound 2-a in methanol, add 1eq of NaBH 4 , react overnight at room temperature, concentrate to dryness and directly pass through the column to obtain the title compound wit...
Embodiment 3
[0156] Embodiment 3 prepares following formula compound 3
[0157]
[0158] Compound 2-a (3 g) was dissolved in a dichloromethane / methanol (50 / 50 mL) mixed system, methylamine ethanol solution (10 eq) was added, stirred overnight under nitrogen, and the disappearance of the starting material was monitored by TLC. The reaction solution was concentrated to dryness, 50 mL of methanol was added, NaBH was added dropwise under ice-cooling 4 (1eq) in methanol solution, stirred for 15 minutes, the reaction was complete. Add water and ethyl acetate (20mL / 50mL), adjust the pH to 8 with HCl, separate the ethyl acetate layer, concentrate and dry it through the column, PE / EA=2 / 1→EA, and obtain 1.8g of the title compound 3 in a yield of 40 %. 1 HNMR (400MHz, CDCl 3 )δ6.16(s,1H),5.94(m,1H),5.59(s,1H),4.53(m,1H),4.42(m,1H),4.11–4.04(m,1H),3.88(s ,2H),2.51–2.41(m,2H),2.41(s,3H),2.20–2.10(m,1H),2.10–2.05(m,1H),1.81–1.77(m,2H),1.77(s ,3H),1.70(s,3H),1.50–1.43(m,2H),1.32–1.25(m,4H),0.88(t...
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