乙二醇保護酮：TMSCl的溫和反應，避免高溫的副反應

Original 原料藥工藝 原料藥合成工藝開發 2024-03-20 19:00

• 以前的一個案例，目的是保護酮羰基，但是分子底物中有酯基，沒有嚐試其他保護基源，隻研究了乙二醇保護基源，采用經典條件數據不好。
• 乙二醇、催化量對甲苯磺酸、甲苯、梯度升溫（因為擔心乙二醇和酯交換），隨著溫度的升高，的確有新點出現，但是一出就兩個點，因為不是工藝研究，一個實驗就中止了。

 

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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. 

 

 

實驗操作

 

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).

參考文獻

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