Preparation method of isavuconazonium sulfate and intermediate thereof
A technology of isavuconazole sulfate and chloroethyl chloroformate, applied in the field of drug synthesis, can solve the problems of low purity of final product, cumbersome process, time-consuming and labor-intensive, etc.
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preparation example 1
[0108]
[0109] Synthesis of A2:
[0110] A1 (100g), 40% (NH 4 ) 2 Add S (2000mL) and THF (1800mL) into a 5L three-necked flask in turn, heat up to an internal temperature of 27-30°C under mechanical stirring, and keep warm for reaction (requires condensation reflux and exhaust gas absorption device), react for 4 days, and monitor the reaction by TLC ( Developing solvent: dichloromethane / methanol=10 / 1), the reaction of raw material A1 is basically complete. Separate the upper organic phase from the reaction solution, extract the lower aqueous phase with 1000mL and 500mL of ethyl acetate, combine the upper layer solution, wash with cold 0.2N NaOH 1500mL×2, and then wash with pure water 1000mL×2. Concentrate to dryness under reduced pressure at 45°C to obtain 112 g of white solid crude product, HPLC: 97.7%.
[0111] Refining: Add 112g of the crude product A2 into a 1L three-necked flask, add 330mL of methyl tert-butyl ether, stir and heat to reflux for 1h, drop to room tem...
preparation example 2
[0113] Synthesis of C1:
[0114]
[0115] Add THF 750mL, CO (66g) into a 3L three-necked flask, cool down to the internal temperature 0~-5°C under mechanical stirring, add Boc-sarcosine 89.8g, DMAP (17.4g) and DCM (750mL), the system dissolves After clearing, add 91.8 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, keep it warm at 0~-5°C for about 20 hours, and monitor it by TLC (developer: acetone) until the reaction is complete. The reaction solution was filtered, and the filtrate was concentrated and dried under reduced pressure at 30°C to obtain an oil, which was dissolved by adding 2L of DCM, washed once with 1L of deionized water, washed with 1L×2 of 2% ammonia water, and then washed with 1L×2 of deionized water. The phase was concentrated under reduced pressure at 30°C to 35°C to obtain 193.8 g of a color-like solid.
[0116] Refining: Add 450 mL of isopropanol to 193.8 g of solids, stir and heat to reflux until dissolved, stir and crystallize at ...
Embodiment 1
[0118] Synthesis of A3:
[0119]
[0120] Add A2 (30g) into a 1L three-neck flask, add 195mL of 95% ethanol, and heat up to dissolve under magnetic stirring. The reaction was incubated at 65°C for about 15 hours, monitored by TLC (developing solvent: dichloromethane / methanol=15 / 1) until the reaction was complete. After the reaction is completed, lower the internal temperature to 40°C, add 30 mL of deionized water to the reaction solution, adjust the pH of the system to 5-6 with triethylamine, concentrate the reaction solution at 40°C-45°C, and remove the remaining concentrated water. Add 350mL of toluene and 350mL of water to the oil, stir to dissolve, separate the organic phase, and then wash with 0.2N H 2 SO 4 The aqueous solution was washed with 200mL×2, and then purified water was washed with 200mL×3, and the toluene phase was concentrated under reduced pressure at 45°C-55°C to obtain about 46g of oil (crude product A3).
[0121] Refining: Dissolve A3 oil with 90mL of ...
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