乙二醇保护酮：TMSCl的温和反应，避免高温的副反应

Original 原料药工艺 原料药合成工艺开发 2024-03-20 19:00

• 以前的一个案例，目的是保护酮羰基，但是分子底物中有酯基，没有尝试其他保护基源，只研究了乙二醇保护基源，采用经典条件数据不好。
• 乙二醇、催化量对甲苯磺酸、甲苯、梯度升温（因为担心乙二醇和酯交换），随着温度的升高，的确有新点出现，但是一出就两个点，因为不是工艺研究，一个实验就中止了。

 

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• When azeotropic distillation was applied to remove water in toluene in the presence of catalytic p-toluenesulfonic acid for the formation of the ketal 6, we found that the reaction was difficult to go to full conversion.
• Moreover, the gradual formation of some  unknown impurities was observed upon heating with time.
• To overcome this issue, we developed a mild and convenient method for the synthesis of ketals employing commercially available MSTFA [2,2,2-trifluoro-N-methyl-N-(trimethylsilyl)- acetamide] as an effective TMS source.
• The advantage of this new methodology includes the use of stoichiometric diol under mild conditions. However, the application of MSTFA is not economical enough to meet our aim of process sustainability in this case. 

 

 

实验操作

 

To the reactor containing 7 (150 kg, 713.4 mol) from step 1 was charged ethylene glycol (600 L) to give a yellow biphasic mixture. 

After the mixture was cooled to 10−15 °C. TMSCl (193.5 kg, 1783.5 mol, 2.5 equiv) was charged over NLT 15 min, at a rate to maintain the internal temperature between 20 and 30 °C (orange biphasic mixture obtained). Sufficient agitation was needed to achieve mixing. After the mixture was kept for 20−25 °C for 2 h, agitation was stopped and kept for at least for 15 min at 20−25 °C. 

After 150 L of the bottom ethylene glycol layer was removed, the mixture was cooled to 0−5 °C. NaOH (96 kg, 1854.8 mol, 2.6 equiv) in water (600L) was charged at a rate to maintain the internal temperature below 20 °C (light yellow cloudy biphasic mixture obtained).

参考文献

https://doi.org/10.1021/acs.oprd.4c00008