AZD5069：磺酰胺Ullmann反应的放大生产研究
文摘
科学
2024-09-28 08:03
天津
- 关键的磺酰胺偶联反应（化合物11和化合物8反应），采用Buchwald反应，成本上很难控制，经对比研究确认了Ullmann反应条件，实验室转移到车间前，从生产角度进一步研究了部分参数。
- 下图标识：氧气残留1%(蓝线），残留2.5%（红线），残留5%（绿线），A，B，C三点是补加催化剂过程。
- 相比低含量氧气残留的蓝线，氧气含量高的红线和绿线在200min内不能实现完全转化
- A，B，C三点补加催化剂后，两个氧气残留较多的反应，都能完成转化，反应的补救措施有了。
- 实验室可以保证氧气残留很少（低于10ppm），但是生产中很难实现，按照1000ppm残留，研究催化剂的用量。
- 从20%降低到15%，再降低到10%，目的降低杂质12和杂质14的量，实验证实工艺可接受的量是15%
- 氮气脱气过程发现，随着反应加热，上层空间氧气含量增多，为了降低催化剂的失活时间，脱气过程在50度下进行，也就是催化剂在50度加到已经脱气的混合体系中，然后升温到90度反应。
- 1.2eq.磺酰胺8，1.5eq.碳酸钾，15mol%碘化亚铜，14.5mol%配体，乙腈和乙酸正丁酯（降低后处理去除全乙腈为溶剂的压力，混合溶剂后处理直接分液）为混合溶剂，90度，氧气1000ppm。
- 催化剂50度加完，刚升温到90度，相当于零点，转化47%（entry 1），转化很快
- 随着反应进行转化速度减慢，大约8小时完成转化，四个杂质均在可控范围内。
- 二价铜离子水溶性更好，氨水络合二价铜离子，更容易去除。
- 车间生产相比实验室，一价铜离子因为接触不到足够的氧气，体系中主要还是一价铜离子，采用硫酸铁溶液氧化，可以实现一价铜到二价铜。
- 反应转化完成，加水溶解固体，加入硫酸铁溶液，分液，酸性会导致化合物9水解。
- 硫酸铁溶液中加入硫酸钠溶液，可以降低化合物9的水解风险，同时还能让分液很快完成，界限更清晰。
- 有机相中包含一些可能是铁盐的悬浮物，用硫酸钠溶液再洗涤一次，不仅能去除这些悬浮物，还能让有机相更澄清。
- 文献提及关于铜离子的去除研究还需要进一步优化，其中采用硫酸钠溶液洗涤，这个很有意思。
A solution of 11 (197.4 kg, 31% w/w in n-butyl acetate, 133.5 mol), 8 (22.6kg, 166 mol), potassium carbonate (27.5 kg, 199 mol, 325mesh), and n-butyl acetate (462 kg) was charged to the reactor and heated to 50 °C with a nitrogen purge of the headspace.R,R-trans-N,N-dimethlycyclohexane-1,2-diamine solution (7.2kg, 27% 13 mol) and acetonitrile (10 kg) were charged to a 50 L vessel. Copper (I) iodide (4.1 kg, 21.5 mol) was added via a glove bag under stirring. The contents were held for 15min before being transferred to the slurry of 11/8/n-butyl acetate/base as a dump charge, followed by a line wash of n-butyl acetate (28 kg). The contents were heated to 90 °C and held for 8 h. The reaction slurry was cooled to 20 °C, and water (31 kg) was added to dissolve the solids. The lower aqueous phase was separated to waste. The organic phase was washed successively with a solution of ferric sulfate (49 kg, 100 mol) and sodium sulfate (14.2 kg, 100 mol) in water (290 kg) and then with a solution of sodium sulfate (4.74 kg, 33.4 mol) in water (131 kg). A water wash (131 kg) was applied; then, the biphasic mixture was screened via an in-line filter containing harbolite before separation of the lower aqueous phase. A wash with a solution of potassium bicarbonate (3.37 kg, 33.6 mol) in water (130 kg) was followed by a screen via an in-line filter containing harbolite, followed by separation of the aqueous phase. Finally, the organic phase was washed with water (131 kg). https://doi.org/10.1021/acs.oprd.1c00475
