Exploratory Process Development of Lorlatinib

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 w...

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Bibliographic Details
Published in:Organic process research & development 2018-09, Vol.22 (9), p.1289-1293
Main Authors: Li, Bryan, Barnhart, Richard W, Hoffman, Jacqui E, Nematalla, Asaad, Raggon, Jeffrey, Richardson, Paul, Sach, Neal, Weaver, John
Format: Article
Language:English
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Summary: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.
ISSN:1083-6160
1520-586X
DOI:10.1021/acs.oprd.8b00210