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Exploratory Process Development of Lorlatinib
Organic Process Research & Development ( IF 3.1 ) Pub Date : 2018-08-01 00:00:00 , DOI: 10.1021/acs.oprd.8b00210 Bryan Li 1 , Richard W. Barnhart 1 , Jacqui E. Hoffman 2 , Asaad Nematalla 1 , Jeffrey Raggon 1 , Paul Richardson 2 , Neal Sach 2 , John Weaver 1
Organic Process Research & Development ( IF 3.1 ) Pub Date : 2018-08-01 00:00:00 , DOI: 10.1021/acs.oprd.8b00210 Bryan Li 1 , Richard W. Barnhart 1 , Jacqui E. Hoffman 2 , Asaad Nematalla 1 , Jeffrey Raggon 1 , Paul Richardson 2 , Neal Sach 2 , John Weaver 1
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The original synthesis of lorlatinib (1) was applied and improved in the first GMP campaign. In this approach, a slow addition of the boronate ester was critical in suppressing the formation of a homocoupled impurity in the Suzuki–Miyaura coupling, and the chemoselective hydrolysis of methyl ester was accomplished by potassium trimethylsilanoate. The synthesis was completed with macrocyclic amidation followed by deprotection of the Boc groups. A thorough process safety evaluation of HATU enabled its use as the coupling reagent for the macrocylic amidation, which improved the yield and eliminated the only chromatographic operation in the synthetic sequence.
中文翻译：
罗拉替尼的探索性方法开发
最初的GMP运动应用了lorlatinib（1）的原始合成方法并对其进行了改进。在这种方法中，缓慢添加硼酸酯对抑制Suzuki-Miyaura偶联中均偶联杂质的形成至关重要，而甲酯的化学选择性水解是通过三甲基硅酸钾完成的。合成通过大环酰胺化完成，然后将Boc基团脱保护。经过全面的工艺安全性评估，HATU使其可用作大环酰胺化的偶联剂，从而提高了收率并消除了合成序列中唯一的色谱操作。
更新日期：2018-08-01
中文翻译：
罗拉替尼的探索性方法开发
最初的GMP运动应用了lorlatinib（1）的原始合成方法并对其进行了改进。在这种方法中，缓慢添加硼酸酯对抑制Suzuki-Miyaura偶联中均偶联杂质的形成至关重要，而甲酯的化学选择性水解是通过三甲基硅酸钾完成的。合成通过大环酰胺化完成，然后将Boc基团脱保护。经过全面的工艺安全性评估，HATU使其可用作大环酰胺化的偶联剂，从而提高了收率并消除了合成序列中唯一的色谱操作。
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