A kind of preparation method of macrolide
A macrolide and ring-closing reaction technology, applied in the field of macrolide preparation, can solve the problems of low conversion rate, difficult purification, affecting the quality of finished products, etc., and achieves convenient post-processing, less side reactions, and safe operation. Effect
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Embodiment 1
[0059] Example 1 Preparation of compound of formula III-1 (R=-AcO)
[0060]
[0061] Dissolve 2.05g of the acetyl-protected compound of formula II-1 (2.90mmol) in 20ml of DMF / THF mixed solution (9:1), add 0.39g potassium tert-butoxide (3.48mmol) in batches at -20°C After completion, the mixture was stirred at -20°C for 0.5 hours, and then 1.01 g of NFSI (N-fluorobisbenzenesulfonamide) (3.19 mmol) was added. After the addition, the reaction was continued at -20°C for two hours. After sampling HPLC to detect the completion of the reaction, add a small amount of water to quench the reaction, dilute the reaction solution with 50ml ethyl acetate, then wash with saturated brine several times (50ml / time), dry with anhydrous sodium sulfate, filter and spin dry to obtain the crude product (can be Used directly in the next step). The crude product was purified by column chromatography (silica gel 200-300 mesh, Qingdao Huanghai), and 4 L ethyl acetate was used as the eluent to obtain 1.57 ...
Embodiment 2
[0063] Example 2 Preparation of compound of formula IV-1
[0064]
[0065] 7.23g of compound III-1 (0.01mol) was dissolved in 100ml of methanol and stirred at room temperature overnight. After sampling to detect the completion of the reaction, the solvent of the reaction solution was evaporated to obtain 7 g of white solid, and the crude product can be used directly in the next step. The crude product was purified by column chromatography (silica gel 200-300 mesh, Qingdao Huanghai), 4L dichloromethane: methanol = 30:1 and 1% triethylamine as the eluent, to obtain 5.78g foamy white solid IV-1 (collected Rate 85%).
[0066] ESI(M+1)=682.
Embodiment 3
[0067] Example 3 Preparation of Solithromycin of Formula IA (Cp=-NH 2 )
[0068]
[0069] 6.82 g of the compound of formula IV-1 (0.01 mol) and 6.93 g of the compound of formula VA-1 (0.03 mol) were mixed in 100 ml of acetonitrile: water = 9:1, and the above mixture was heated to reflux overnight. Sampling to detect the completion of the reaction, stop heating, after the reaction solution is cooled to room temperature, evaporate the organic solvent, dilute with 50ml of water, extract with 20ml of dichloromethane*3, combine the organic phases, dry with anhydrous sodium sulfate, filter with suction, spin dry , Column chromatography purification, (silica gel 200-300 mesh, Qingdao Huanghai), 4L dichloromethane: methanol = 30:1 and 1% triethylamine as the eluent, to obtain 6.34g foamy white solid, namely Soliomyces IA (yield 75%).
[0070] ESI(M+1) / 2=423.
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