THP、叔丁基等保护基都是怕酸的保护基,工艺研究无非一个字“筛”,强弱筛、有水无水筛、有机无机筛......
案例分享
筛选不同的酸,包括无水制备氯化氢,体系会有化合物10产生,一旦产生杂质10,对应条件下很难获得目标物。
加入1-octanethiol (2.2 equiv) 捕获去保护的副产物(entry7),峰面积占比很高,基于副产物的可逆性,改变溶剂的极性,采用混合溶剂甲苯和醇类,化合物10占比明显减少(entry 8)
基于混合溶剂,再次研究了原位产生氯化氢的条件,同时改变温度,反应有效转化99.9%,化合物10未检出。
混合溶剂使用,溶解度的需要、体系环境极性的需要,副产物在哪里的需要(例如两相反应),此案例加入甲苯,杂质10得到明显控制。
实验操作
To a 100 L reactor (R1) under nitrogen with the jacket set to 20°C was charged the homogeneous solution of (3R)-1′-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-3H-spiro[benzofuran-2,4′-piperidin]-3-amine (5) in n-PrOH (26.5 kg solution =5.73 kg 5 by 21.5 wt % assay calculation, 10.6 calculated mol). Then, the contents of R1 were concentrated under a vacuum to 3−4 mL/g total volume. Next, toluene (23 kg, 4.6 mL/g) was added to the reactor, and the contents of R1 were cooled to 0 ± 15 °C.
In a separate 100 L reactor (R2) under nitrogen was charged n-PrOH (12 kg, 1.4 mL/g), followed by toluene (25 kg, 5.0 mL/g). This mixture in R2 was cooled to 0 ± 10°C for the addition of acetyl chloride (8.49 kg, 108 mol, 10.2 equiv) over a minimum of 30 min. Then, the contents of R2 were warmed to 25 ± 5 °C and stirred for a minimum of 30 min before being added slowly to R1 while keeping the internal temperature of R1 below 15 °C.
参考文献
https://doi.org/10.1021/acs.oprd.4c00162