Efavirenz Powder Pharmaceutical Grade Antiviral Raw Material 154598-52-4

The preparation methods

127.57g p-chloroaniline was dissolved in 1200ml chloroform and 1200ml saturated sodium carbonate solution, and 129ml 2, 2-dimethylpropionyl chloride was dripped in 1h. Garnish, stir at room temperature for 23 hours. Solids are collected through filtration, filtrate is layered, and the separated chloroform layer is washed with salt water, dried and concentrated. The residue was recrystallized with boiling ethyl acetate - hexane with the resulting solid, resulting in 185.6g white crystalline compound (I).

100g compound (I) was dissolved in 1L tetrahydrofuran, and 387ml 2.5Inol/L n-butyl lithium hexane solution was added at 0℃ and 1h, and the temperature was maintained at 5℃. After finishing, stir at 0℃ for 1h. Add 115ml ethyl trifluoroacetate at 1h, add and stir for 30min. Add 5% hydrochloric acid and 1L ethyl acetate, separate organic layer, wash with brine, dry, decompress concentration, get 160g yellow oily material. It's suspended at 1 liter, 3 molar. Hydrochloric acid, reflux for 24 hours. Cool, add 1L ethyl acetate, with concentrated ammonia water to alkaline. Separate organic layer, wash with brine, dry, reduced pressure concentration. The residue was expanded by 1.5kg silica gel chromatography with hexane solution of 15% ethyl acetate. Get solid reoccupy boiling hexane recrystallization, 57 g compounds (Ⅱ), yield of 54%, the melting point of 91 ~ 92 ℃.

23g cyclopropyl acetylene was dissolved in 250ml tetrahydrofuran, and 116ml of 3.0mol/L ethyl ether solution of magnesium ethyl bromide was dripped in 1h. After that, we reacted at 0℃ for 1h, and then at 40℃ for 3h. Cool to 0 ℃, in 5 min, partial compounds (Ⅱ) add 15.56 g. After the addition, the mixture was stirred at 0℃ for 1.5h, and then added 700ml saturated ammonium chloride solution. 2×400ml ethyl acetate was used for extraction. After the extraction solution was combined, it was washed with brine, dried, and concentrated to produce a yellow solid. Compounds with boiling hexane recrystallization, 14.67 g (Ⅲ), the other is from the mother liquor can be 2.1 g. Melting point: 153 ~ 154℃.

Compounds (Ⅲ) 15.00 g and 41.98 g carbonyl 2 imidazole (1, 1 '- carbonyldiimidazole) dissolved in 250 ml anhydrous tetrahydrofuran, stir in 55 ℃ for 24 h. Steam the solvent and add 500ml ethyl acetate and 400ml water. The water layer was extracted with ethyl acetate. The extract was combined with the organic layer, washed with 2×200ml 2% hydrochloric acid, saturated sodium bicarbonate and brine, dried, reduced pressure and concentrated to obtain 16.42g solid. Ethyl acetate. Hexane recrystallization, 12.97g pure white crystal racemic Efavirenz, melting point 178 ~ 180℃.

12.97g racemized Efavirenz, 1.02g 4-dimethylamine pyridine and 14.22g(-) -camphoryl chloride were dissolved in 350ml dried dichloromethane under argon protection and ice bath cooling and agitation, and 22.84ml triethylamine was added. Remove the ice bath and let it rise to room temperature. 75 min. Add 500ml chloroform, rinse with 10% lemon acid twice, wash with water and salt water once each. Dry, reduced pressure concentration. Leftovers to boil 200 ml hexane, cool to room temperature, filtering to collect solid, use a small amount of cold hexane wash, vacuum drying 7.79 g compounds (Ⅳ), melting point of 164 ~ 165 ℃, and the purity 99.2% (HPLC).

Under argon gas protection and 60 ℃, the 7.50 g compounds (Ⅳ) dissolved in 150 ml n-butyl alcohol, add 10 ml lmol/L hydrochloride, 72 h in 60 ℃ response. Neutralize with sodium bicarbonate solution and decompress to remove n-butanol. The residue was dissolved in 150ml tetrahydrofuran, and 50ml 2mol/L lithium hydroxide was added, which was reacted for 3h at room temperature. After dilute analysis with ethyl acetate, wash twice with water and once with brine. Dry, reduced pressure concentration. The residue was recrystallized with hexane, yielding 3.43g Efavirenz white crystal, melting point 131 ~ 132℃.