A Partial Classical Resolution/Preparative Chiral Supercritical Fluid Chromatography Method for the Rapid Preparation of the Pivotal Intermediate in the Synthesis of Two Nonsteroidal Glucocorticoid Receptor Modulators

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• 作者：Nuria de Mas ; Kenneth J. Natalie Jr. ; Fernando Quiroz ; Victor W. Rosso ; Doris C. Chen ; David A. Conlon
• 刊名：Organic Process Research & Development
• 出版年：2016
• 出版时间：May 20, 2016
• 年：2016
• 卷：20
• 期：5
• 页码：934-939
• 全文大小：261K
• 年卷期：0
• ISSN：1520-586X

文摘

Preparative chiral supercritical fluid chromatography (SFC) employing an enantioenriched feedstock obtained via partial classical resolution enabled rapid access to kilogram quantities of a key intermediate common to two glucocorticoid (GC) receptor modulator candidates for which neither chemical nor enzymatic resolutions provided the desired chiral purity (>99.0 HPLC area percent). We developed a partial classical resolution of the racemate that afforded 85:15 enantioenriched mixtures with 90% recovery of the desired enantiomer and reduced the SFC processing time by 54%. The SFC method used a 5 cm × 28 cm column packed in-house with 20 μm Chiralpak AD, a total column flow rate of 150 g/min, a cosolvent composition of 12% methanol, and a column back pressure of 75 bar. The feed processing rate was up to 80 mL/h, which translated to 67 g/day of the enantioenriched mixture or 57 g/day of the desired enantiomer. This combined classical resolution/SFC process was employed to obtain a total of 1.0 kg of the desired enantiomer with an enantiomeric excess greater than 99.5% in 79% isolated yield by running the SFC separation over 23 days, 24 h/day, and 5 days/week. Stable column pressure drops of 7–11 bar were measured throughout the manufacturing campaign. This separation approach enabled the first large-scale preparation of the two GC compounds and permitted their evaluation in toxicological and first-in-human studies within a few months of entering development.