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Synthesis of PF-07059013
PF-07059013: A Noncovalent Modulator of Hemoglobin for Treatment of Sickle Cell Disease.
J. Med. Chem. 2021;
Key wordsPF-07059013 - sickle cell anemia - biocatalysis - ketoreductase - Pfitzinger quinoline synthesis - Mitsunobu reaction
Sickle cell disease is a common genetic disorder that affects 15 million people worldwide. It is caused by a single point mutation on the β-chain of adult hemoglobin. PF-07059013 is a noncovalent modulator of hemoglobin that has entered phase I clinical trials for the treatment of sickle cell disease.
Key steps in the synthesis depicted are (1) the asymmetric reduction of ketone E using the ketoreductase KRED101 from Codexis to afford enantiopure F in 94% yield (>99% ee), (2) the construction of quinoline I using a Pfitzinger reaction, and (3) a Mitsunobu reaction that links fragments F and K.
18 March 2021 (online)
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