Elvitegravir intermediate and its preparation method and application
An intermediate and reaction technology, which is applied in the field of drug synthesis, can solve the problems of unsuitability for industrial production, expensive reaction reagents, complex reactions, etc., and achieve the effects of cheap and easy to obtain, high total molar yield, and simple preparation process
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Embodiment 1
[0035] Embodiment 1: preparation formula II intermediate
[0036]
[0037] Dissolve the compound of formula IV (17.21g, 38.5mmol) and triethylamine (5.83g, 57.7mmol) in 70mL of dichloromethane, cool to 5-10°C, add acetyl chloride (4.53g, 57.8mmol); the addition is complete , reacted at room temperature for 30min; the reaction was completed, the reaction solution was washed once with 2N hydrochloric acid aqueous solution, and washed twice with saturated brine; the liquid was separated, the organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain bright yellow 18.55 g of oil (namely: intermediate of formula II), the molar yield is 98.5%, and the HPLC purity is 95.0%.
[0038] 1 HNMR (DMSO-d 6 300MHz) δ0.72(3H,d,J=6.6Hz),1.10(3H,d,J=6.6Hz),1.28(3H,t,J=7.0Hz),2.21(3H,s),2.27(1H ,br),3.77(1H,br),4.23(2H,q,J=7.0Hz),4.56(1H,br),5.12(1H,t,J=4.9Hz),8.09(1H,d,J= 11.1Hz), 8.62(1H, d, J=7.5Hz), 8.68(1H, s); ...
Embodiment 2
[0040] Embodiment 2: preparation formula II intermediate
[0041]
[0042] The compound of formula IV (40.0g, 0.1mol) was dissolved in 150mL of chloroform, pyridine (16g, 0.2mol) and N,N-dimethylaminopyridine (2.4g, 0.02mol) were added at room temperature, and then acetic anhydride (12.24 g, 0.12mol); the addition was completed, and reacted in an ice bath for 30 minutes; the reaction was completed, and 80 mL of water was added to the reaction solution for liquid separation, and the organic phase was washed successively with 80 mL of 2N hydrochloric acid aqueous solution and 80 mL of saturated aqueous sodium bicarbonate solution; liquid separation, organic The phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 39.34 g of a bright yellow oil (namely: the intermediate of formula II), with a molar yield of 89% and an HPLC purity of 96.5%.
[0043] 1 HNMR (DMSO-d 6 300MHz) δ0.75(3H,d,J=6.6Hz),1.13(3H,d,J=...
Embodiment 3
[0045] Embodiment 3: preparation formula III intermediate
[0046]
[0047] Under the protection of nitrogen, suspend zinc powder (160.0g, 2.46mol) in 380mL tetrahydrofuran, add dropwise a solution of 3-chloro-2-fluorobenzyl iodide (604.8g, 2.24mol) in 110mL tetrahydrofuran at room temperature, the dropwise addition is completed , stirred at room temperature for 30 min to obtain a tetrahydrofuran solution of 3-chloro-2-fluorobenzyl zinc iodide;
[0048] The formula II intermediate (547.0g, 1.12mol) was dissolved in 130mL tetrahydrofuran, and palladium acetate (3.82g, 0.017mol) and the 3-chloro-2-fluorobenzyl iodide obtained in the previous step were added under the protection of argon. The tetrahydrofuran solution of zinc, after the dropwise addition, was heated to reflux, and the reflux reaction was completed (after about 1.5 hours), the reaction solution was cooled, filtered, and 100mL of 20% ammonium chloride aqueous solution was added to the filtrate, and the organic ph...
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