Application of Biocatalytic Reductive Amination for the Synthesis of a Key Intermediate to a CDK 2/4/6 Inhibitor

Abstract

Biocatalytic reductive amination catalyzed by engineered imine reductase (RedAms) is a new and powerful tool for the synthesis of substituted chiral amines. Herein, we describe a streamlined synthesis of compound 3, a key intermediate to a CDK 2/4/6 inhibitor 1, relying on the enzymatic reductive amination of a hydroxyketone to introduce the chiral secondary amine with high diastereoselectivity. The improved synthesis of the hydroxyketone precursor by a titanium-catalyzed reductive cyclization and the process development for two SNAr reactions en route to 3 are also presented.

Reductive aminations by imine reductases: from milligrams to tons

“…This was followed up by a study of a reductive amination reactions focusing on the synthesis of a key intermediate for an inhibitor of the oncology target CDK/2/4/6. 83 88 IRED enzymes were screened for the ability to catalyze the kinetic resolution and reductive amination of 200 mM racemic hydroxyketone 57 with 120 mM benzylamine hydrochloride p to give secondary amine product 57p ( Scheme 22 ). The enzyme IR007, identified as the best candidate, was subjected to directed evolution, to give a final variant IR007-143 of superior activity, giving 43% conversion from a substrate concentration of 50 g L −1 .…”

Highlights of the Recent Patent Literature─Focus on Biocatalysis Innovation

“…After filtration to remove the catalyst, (R,R)-10 was isolated by crystallization of its p-TsOH salt from EtOAc/MeOH in 94% yield with 99.9% ee. 13 GlaxoSmithKline reported an IRED-catalyzed reductive amination as a key step in their synthesis of the LSD1 inhibitor GSK2879552 for the treatment of small-cell lung cancer (Scheme 5). 14 In the original chemical reductive amination, the cyclopropylamine fragment 14A/14B was resolved via a classical resolution with mandelic acid to furnish 14B in 35% yield, followed by reductive amination of aldehyde 13 with 14B mediated by sodium borohydride to provide amine 15.…”

“…Pfizer recently published another scalable process using a biocatalytic reductive amination for the preparation of the CDK 2/4/6 inhibitor drug candidate ebvaciclib for the treatment of cancer (Scheme ). The initial approach, shown on the left side of Scheme , employed a transamination step to convert ketone 9 to amine ( R , R )- 10 while also resolving the quaternary asymmetric center. A commercially available transaminase, ATA-71, was selected for further study because it provided high selectivity for the desired enantiomer ( R , R )- 10 .…”

New Trends and Future Opportunities in the Enzymatic Formation of C−C, C−N, and C−O bonds

“…Firstly, they investigated the use of a RedAm for the synthesis of an amino alcohol intermediate in the synthesis of a cyclindependent kinase (CDK) 2/3/4 inhibitor (Scheme 23B). [207] The initial process involved a transaminase-mediated reductive amination although issues concerning product isolation prompted the authors to reconsider the route by using an IRED with benzylamine as coupling partner. After initial screening, a wild-type enzymes IR007 was used as a template for evolution in efforts to improve activity and stability.…”