Synthetic method of chiral spiro [chroman-4, 1'-indane] molecule

[0023] Example 1: Synthesis of ethyl 5-(2-bromo-5-hydroxyphenyl)-3-carbonylvalerate (b):

[0024]

[0025] To a 3000 mL dry reaction flask, add 3-(2-bromo-5-hydroxyphenyl)-propionic acid a (40 g, 163 mmol) and carbonyl diimidazole CDI (28.6 g, 176 mmol), and add tetrahydrofuran (700 mL) to dissolve. It was replaced with an argon atmosphere, and the reaction was stirred at room temperature for 8 hours. A solution of magnesium monoethyl malonate (39 g, 253 mmol) in tetrahydrofuran (300 mL) was added to the reaction system, and the reaction was continued to stir at room temperature for 12 hours. TLC monitored the reaction to be complete. 1N HCl was added to the system for acidification, extracted with ether (2×150 mL), and the organic phases were combined, washed with saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. Add diatomaceous earth to suction and filter, remove solvent under reduced pressure, and column chromatography (petroleum ether / ethyl

[0026] Example 2: Synthesis of 4'-bromo-5-hydroxy-7'-hydroxy-spiro[chroman-4,1'-indan]-2-one (c):

[0027]

[0028] To a 1000 mL dry reaction flask, ethyl 5-(2-bromo-5-hydroxyphenyl)-3-carbonylvalerate b (17.8 g, 56.5 mmol) was added, and dichloromethane (300 mL) was added to dissolve. Replace the system with an argon atmosphere, and use an ice water bath to control the temperature in the system to below 5°C. Then trifluoromethanesulfonic acid (15.0 mL, 169 mmol) was slowly added dropwise. After the addition was completed, the ice bath was removed, and the system was stirred and reacted at room temperature for 0.5 hours. TLC monitored that all the raw materials were completely converted, and a large amount of yellow solid was precipitated in the system. Resorcinol (6.2g, 56.5mmol) was added to the reaction system, and the reaction was continued to be stirred at room temperature for 1 hour. TLC monitored that all intermediates were completely converted. The reaction was quenched by

[0029] Example 3: Synthesis of 4′-bromo-7-hydroxy-7′-methoxy-2′,3′-dihydrospiro[色MAN-4,1′-indene]-2-one:

[0030]

[0031] The preparation method is the same as that of Example 2. It is a pale yellow solid with a yield of 97%. 1 H NMR(400MHz,DMSO)δ9.70(s,1H),7.45(d,J=8.6Hz,1H), 6.82(d,J=8.7Hz,1H), 6.66–6.59(m,1H), 6.46 (m, 2H), 3.60 (s, 3H), 3.26 (d, J = 15.9 Hz, 1H), 3.03-2.95 (m, 2H), 2.95-2.89 (m, 1H), 2.29-2.15 (m, 2H ).