8-(benzothiazole amide) substituted coumarin compounds, and preparation method and application thereof
A technology of benzothiazolamide and coumarins, applied in the field of medicine, can solve problems such as side effects of patients, neuroprotective effect of Parkinson's disease, etc., and achieve good inhibitory activity, significant protective effect, and effect of preventing Parkinson's disease.
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preparation example 1
[0104] This preparation example prepares intermediate 3 shown in the following formula, and the synthetic route is:
[0105]
[0106] (1) Add n-butyllithium (1.60M n-hexane solution) (14.00mL, 22.33mmol) slowly to 8-bromocoumarin (5.00g, 22.33mmol) in anhydrous tetrahydrofuran at -78°C under nitrogen protection (30mL) solution. After stirring at -78 °C for 3 h, the solution was frozen in a liquid nitrogen bath and then vacuumed, followed by the introduction of 3 (5.29g, 26.80mmol) reacted with concentrated sulfuric acid (1.43mL, 26.80mmol) to generate CO 2 gas. The mixture was stirred at -78 °C for 2 h, then at 20 °C with saturated NH 4 Aqueous Cl solution quenched the reaction. The pH was adjusted to 5 with hydrochloric acid, extracted three times with ethyl acetate (15 mL×3), washed once with saturated brine, and the combined organic phases were dried over anhydrous sodium sulfate and concentrated. The product was purified by silica gel column to obtain coumarin-8-ca...
Embodiment 1
[0109] Compound 1 prepared in this example: N-(2-(4-chlorobenzyl)benzothiazol-4-yl)-2-oxo-2H-chromene-8-amide, its structure is as follows:
[0110]
[0111] A solution of 4-chlorobenzylmagnesium bromide in ether (3.00M, 2.81mL, 8.43mmol) was added dropwise to the stirred N-(2-chlorobenzo[d]thiazol-4-yl)-2- Oxo-2H-chromene-8-carboxamide (2.00 g, 5.62 mmol) in anhydrous dichloromethane (10 mL). After the dropwise addition was completed, the reaction solution was stirred at 0°C for 1 hour, and then water was slowly added dropwise while keeping the temperature of the reaction solution below 10°C. After returning to 20 °C, the reaction solution was diluted with 50 mL of water and dichloromethane (1:1) and passed through a celite pad. Concentrate the organic phase and purify on a silica gel column to obtain 0.62 g of a white solid product with a yield of 25%. The product is characterized as follows:
[0112] 1 H NMR (400MHz, CDCl 3 ):δ8.15-8.35(m,2H),7.63-7.79(m,5H),7.10-7....
Embodiment 2
[0115] Compound 2 prepared in this example: N-(2-(3-chlorobenzyl)benzothiazol-4-yl)-2-oxo-2H-chromene-8-amide, its structure is as follows:
[0116]
[0117] Prepare with reference to the preparation method in embodiment 1, replace 4-chlorobenzylmagnesium bromide with 0.65 g of white solid was obtained, the yield was 26%. The product is characterized as follows:
[0118] 1 H NMR (400MHz, CDCl 3 ):δ8.15-8.35(m,2H),7.63-7.79(m,5H),7.12-7.44(m,4H),6.02(m,1H),3.85(s,2H).
[0119] HR-MS(ESI):[M+H]+C 24 h 16 ClN 2 o 3 The calculated value of S is 447.0570, and the measured value is 447.0578.
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