Abstract
A series of mono- or bis-quaternary ammonium salts derived from cinchonidine or quinine was synthesized and screened as potent phase-transfer catalysts for the reaction of aza-Michael cyclization, the key step in the synthesis of letermovir. During the reaction of aza-Michael cyclization, the screened monoquaternary ammonium salt quinine derivative Q1 transferred 7 to 8 with 91.9% yield and 58% ee. The application of Q1 was preferred, due to its enantioselectivity, the possibility of reuse, and the lower cost in large-scale preparation. Furthermore, the racemization condition of letermovir enantiomer was also explored for the possibility to develop the resolution/racemization process. With the optimal catalyst Q1 in hand, the synthesis of letermovir may be more convenient and economical in the future.
Highlights
Human cytomegalovirus (HCMV) infections remain a prevalent cause for morbidity and mortality in immunosuppressed solid-organ and bone-marrow transplant patients, and the most frequent cause of opportunistic viral infection following transplantation.[1,2]
Our data suggested that monoquaternary ammonium salts, both from cinchonidine (C1–C4) and quinine (Q1– Q4), had a good effect on enantioselectivity; for example, both entry 1 and entry 8 gave the enantiomeric ratio of 8a:8b at 79:21
The results further demonstrated that the benzyl substituted with two trifluoromethyl was better than that substituted with one trifluoromethyl (C1 versus C2 or C3; Q1 versus Q2 or Q3), so compound Q1 could be considered as the potential phase-transfer catalyst (PTC)
Summary
Human cytomegalovirus (HCMV) infections remain a prevalent cause for morbidity and mortality in immunosuppressed solid-organ and bone-marrow transplant patients, and the most frequent cause of opportunistic viral infection following transplantation.[1,2] The incidence of HCMV infection in the general population ranges from 36 to 90%, and the seropositivity increases with age and tends to be highest among lower socioeconomic groups.[3,4] Letermovir is a novel antiviral compound currently used for the prevention of HCMV infections. Before the approval of letermovir, the first line of systemic anti-HCMV drugs includes ganciclovir, foscarnet, and cidofovir, which are derivatives of nucleosides and all target the DNA polymerase, yet, associated with significant side effects such as clinically significant myelosuppression,[5,6] leading to the limited use of them in HCMV therapy.[7] developing a safe and effective agent for HCMV therapy has been an area of unmet need that is urgently needed in cytomegalovirus (CMV) management. Unlike other anti-CMV therapies, letermovir disturbs the late stages of viral replication rather than inhibiting the viral DNA polymerase,[9,10] with no significant myelotoxicity or nephrotoxicity appearing.[11]
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.