伯酰胺制备：胺酯交换法，甲醇钠/甲酰胺的工艺案例汇总
文摘
科学
2024-07-31 07:03
天津
- 维拉佐酮中间体6的合成，化合物5在甲醇钠和甲酰胺条件发生胺酯交换反应，得到伯酰胺，主要杂质是羧酸7。
- 甲酰胺的用量越大，杂质7越小，醇钠用量一般小于甲酰胺。
- 甲酰胺用量少，反应搅拌可能不好，影响反应，溶剂一般采用酰胺类。
- Vixotrigine的工艺研究，最初路线制备伯酰胺，采用氨水30℃反应，收率94%，规模47kg。
- 后期因为最初工艺的PMI问题（PMI=51），以及一锅法投料的需要，改用甲醇钠/甲酰胺条件进行胺酯交换（PMI=15），制备伯酰胺。规模百公斤级别。
- 化合物6和化合物7在甲醇钠条件下进行酚羟基的烷基化，反应完成后，反应体系中，直接加入甲醇钠甲醇溶液和甲酰胺，一锅法制备伯酰胺。
- 主要杂质是酯基水解杂质28，甲醇酯交换杂质8和α-位置消旋杂质27。
- 研究发现，改变加料方式，可以控制消旋杂质27：先加甲酰胺，再滴加甲醇钠的甲醇溶液，避免甲醇钠和α-位作用。
- 化合物20先用硼氢化钠还原双键，构建手性中心，然后用Boc进行氨基保护，
- Boc底物（290mol）的1500L溶剂THF，加入131kg的甲酰胺（10eq.），然后控温32-38℃，滴加156kg甲醇钠甲醇溶液（30%，3eq.），大约1hr加完，保温32-38℃反应12hrs。
The following reaction was performed with 25
kg compound 4. Compound 4 (basis charge, 1.0 equiv) and
DMF (4 L/kg) were charged to a suitable reactor. The
temperature was adjusted to 0−10 °C, and formamide (2.4 L/
kg, 15 equiv) was slowly added while keeping the internal
temperature between 0−10 °C. To this slurry was added
sodium methoxide (0.86 kg/kg, 4.0 equiv) as a solid, in
portions, at such a rate to keep the internal temperature to not
more than 15 °C. The resulting solution was mixed for at least
30 min at 0−10 °C, and the temperature was then adjusted to
20−30 °C. The reaction was mixed for at least 15 min until
complete conversion of compound 4 as evidenced by HPLC
analysis. 案例五
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Org. Process Res. Dev. 2014, 18, 665−667Org. Process Res. Dev. 2020, 24, 2814−2829Org. Process Res. Dev. 2020, 24, 2802−2813Org. Process Res. Dev. 2011, 15, 503–514https://doi.org/10.1021/acs.oprd.4c00117 Organic Process Research & Development 2010, 14, 859–867
