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Chemistry and Pharmacology of Drug Discovery
Oteseconazole (1) can also be synthesized through other routes as well. A later
patent by Hoekstra et al. shows several different routes than the bench top synthesis. The
tetrazole unit can be installed early in the synthetic process. The ester 39 is reacted with
an ethyl ester of the tetrazole group 46. The resulting ester group on 47 can then be
removed with base and acid to provide structure 48. The Suzuki reaction can take place
here to generate 50, which is then reacted with the 2,4-difluorophenylring that has a metal
bound in the 1-position, such as a Grignard. In the presence of a chiral catalyst such as
BINOL that will form the final product (Figure
Figure 8. Bench route synthesis of oteseconazole (1)49
9).
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Chapter 6. Oteseconazole (Vivjoa)
Figure 9. Installation of the tetrazole by use of a Claisen condensation reaction
Another way that oteseconazole (1) can be synthesized is by forming the
tetrazole from a nitro group directly on the molecule by an asymmetric Henry reaction
with the ketone from 41. The resulting nitro group 52 is then reacted with sodium azide
in the presence of triethyl orthoformate and acetic acid to provide the 1-tetrazole group
53. This may be done before or after the Suzuki reaction on the pyridyl ring (Figure
10).
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A similar strategy may be employed by first installing a cyano group onto
molecule 41 by using TMS-CN with a chiral catalyst and base. The resulting cyano group
is then reduced to the corresponding amine 55 and then the tetrazole can be formed to
produce 53. This process can also be accomplished before or after the Suzuki reaction on
the pyridyl ring (Figure
Chemistry and Pharmacology of Drug Discovery
Figure 10. Asymmetric Henry reaction of (42)
11).
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Chapter 6. Oteseconazole (Vivjoa)
Figure 11. Reduction of nitrile before cyclization
7. Summary
Oteseconazole (1) is a new development in the treatment of Candida fungal infections. Its
use of a tetrazole has led to an improvement in the efficacy of treatment when compared
to previous medications as well as a new level of selectivity between human and fungal
CYP activity. The tetrazole moiety has been shown to bind with the heme-atom in C.
albicans CYP51 with an MIC
administered pill, while many of the previous azoles were topical creams. Oteseconazole
(1) shows good promise in the long-term treatment of RVVC.
of ≤ 0.001 μg/mL. It has succeeded in being an orally
50
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Section II. ONCOLOGY DRUGS
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