Dihydropyridine contained thioketone compound, pharmaceutically-acceptable salt thereof, preparation and application thereof
A technology of dihydropyridinethione and compound, applied in the field of medicine, can solve problems such as poor drug-like properties, and achieve the effect of novel synthesis method
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Embodiment 1
[0024] Embodiment 1: the synthesis of compound Ia
[0025] The catalyst trans 4,5-methanol-L proline (0.025 mmol, 5 mol %), quinidine thiourea (0.025 mmol, 5 mol %) and 1,2-dichloromethane (2 ml) were added to the reaction in the bottle. After the mixture was stirred at room temperature for 10 minutes, the compound IIa (R 1 = Ph, 0.5 mmol), thiourea ( 0.75 mmol) in 1,2-dichloromethane solution (1 ml) was added and stirred at room temperature for 3 hours, then compound IIIa (R 2 = (CH 3 ) 2 CH, R 3 = CH 3 , 0.55mmol) was added and stirred at 50°C for 15 hours. After the reaction was completed, the reaction solution was cooled to room temperature, and 147 mg of pure product Ia was obtained as a yellow solid through column chromatography (petroleum ether / ethyl acetate = 4 / 1), with a yield of 93%.
[0026]
[0027] [α] D 25 = 69 o (c = 0.5, MeOH); 1 H NMR (500 MHz, CDCl 3 ) δ 8.05 (d, J = 12.3Hz, 1H), 7.69 (s, 1H), 7.37 – 7.23 (m, 5H), 6.50 (d, J = 15.3 Hz...
Embodiment 2
[0028] Embodiment 2: the synthesis of compound Ib
[0029]
[0030] Referring to the synthetic method of Ia in Example 1, 161 mg of yellow solid was obtained, and the yield was 92%.
[0031] [α] D 25 = 97 o (c = 0.5, MeOH); 1 H NMR (500 MHz, CDCl 3 ) δ 7.65 (s, 1H),7.58 (s, 1H), 7.28 (s, 4H), 6.45 (d, J = 15.8 Hz, 1H), 6.12 (dd, J = 15.8,6.3 Hz, 1H), 5.02 (d, J = 3.9 Hz, 1H), 4.10 (dd, J = 13.9, 7.0 Hz, 1H), 3.77(s, 3H), 1.25 (d, J = 7.0 Hz, 3H), 1.17 (s, 3H); 13 C NMR (125 MHz, CDCl 3( s), 58.42 (s), 53.53 (s), 51.74(s), 27.36 (s), 19.97 (s), 19.56 (s), 18.43 (s); ee value: 96 %, detected by HPLC (Daicel Chiralpak OD-H, i -PrOH / Hexane = 20 / 80, UV 254 nm, flow rate 1.0 mL / min) t R = 10.445 min (major); t R = 15.304 min (minor); ESI-MS m / z 351.09279 ([M+H] + , C 17 h 19 ClN 2 o 2 S requires 350.08558).
Embodiment 3
[0032] Example 3: Synthesis of Compound Ic
[0033]
[0034] Referring to the synthetic method of Ia in Example 1, 181 mg of yellow solid was obtained, and the yield was 92%.
[0035] [α] D 25 = 119 o (c = 0.5, MeOH); 1 H NMR (500 MHz, CDCl 3 ) δ 7.51 (s, 1H),7.44 (d, J = 8.2 Hz, 2H), 7.28 (s, 1H), 7.24 (d, J = 8.2 Hz, 2H), 6.45 (d, J = 15.9 Hz, 1H), 6.14 (dd, J = 15.8, 6.3 Hz, 1H), 5.02 (s, 1H), 4.13 – 4.09(m, 1H), 3.78 (s, 3H), 1.18 (t, J = 6.9 Hz, 6H); 13 C NMR (125 MHz, CDCl 3 ( s), 53.53 (s), 51.75 (s), 27.35(s), 22.66 (s), 19.99 (s), 19.60 (s); Enantiomeric excess: 96 %, determined by HPLC (Daicel Chiralpak OD-H, i -PrOH / Hexane = 10 / 90, UV 254 nm, flow rate1.0 mL / min) t R = 9.423 min (major) ; t R = 14.582 min (minor); ESI-MS m / z395.04237 ([M+H] + , C 17 h 19 BrN 2 o 2 S requires 394.03506).
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