Organic Letters
Letter
and water was added to induce crystallization. The product was
then isolated in 90% yield with excellent purity.
Scheme 5. Streamlined Continuous Aldol Reaction
In conclusion, a novel chemical synthesis of doravirine was
developed which utilizes a continuous aldol reaction as the key
step for de novo construction of advanced pyridone
intermediate 10. Microbatch snapshot experiments aided in
optimizing conditions for the continuous aldol reaction.
Ultimately, the high-yielding, robust conversion of ester 7a to
pyridone 10 was enabled through continuous flow by avoiding
preformation of an unstable enolate intermediate. N-Methy-
lated triazolinone 16 was synthesized in high yield from the
bulk commodity reagents phenyl chloroformate, methylamine,
hydrazine, and glycolic acid. Ultimately, doravirine was
prepared in 52% overall yield along the longest linear sequence
with excellent control of chemical purity. The described
synthesis is convergent and productive and lays the foundation
for a robust scalable process toward doravirine.
(28 equiv) at 60 °C. Crystallization of the product was induced
by switching the solvent from a mixture of methanol, toluene,
and ammonia to pure methanol, and from this mixture
pyridone 10 was isolated in 68% yield with high purity.
Previous synthetic approaches to 1 involved alkylation of
pyridone 10 with an N-H triazolinone and subsequent N-
methylation. This sequence provided 1 in only modest yield
due to incomplete chemoselectivity for methylation of N-420
and the resultant challenging purification. A more convergent
approach to 1 would employ N-methylated electrophile 16
directly in the alkylation of 10.
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedure/data and discussion. This material is
To reduce this approach to practice an efficient synthesis of
16 was required.4b Base-mediated cyclodehydration of acylated
semicarbazides is an established method to produce the desired
1,2,4-triazol-3-one architecture and was targeted as the key
bond-forming step for the optimal synthesis of 16.21 Starting
from phenyl chloroformate, carbamate formation with aqueous
methylamine provided 12 in 96% isolated yield (Scheme 6).22
AUTHOR INFORMATION
■
Corresponding Authors
Notes
The authors declare no competing financial interest.
Scheme 6. Streamlined Synthesis of Triazolinone 16
ACKNOWLEDGMENTS
■
We gratefully acknowledge I. Jeon and G. Qian (Merck & Co.,
Inc.) for general assistance, C. Lee, P. Cheung, R. Arvary, and S.
Ceglia (Merck & Co., Inc.) for analytical assistance, E. Martel
and M. Weisel (Merck & Co., Inc.) for assistance with high-
pressure experimentation, D. DiRocco (Merck & Co., Inc.) for
HTE assistance, R. Reamer (Merck & Co., Inc.) for NMR
assistance, and A. Brunskill (Merck & Co., Inc.) for X-ray
structure determination.
Semicarbazide 13 was generated by the addition of hydrazine in
hot 2-propanol and converted without isolation to acylated
adduct 14 in 81% yield over the two steps. Base-mediated
cyclization with sodium hydroxide in n-propanol/water
afforded triazolinone 15 in 85% isolated yield. Chlorination
of the primary alcohol with thionyl chloride in ethyl acetate
provided the key fragment 16 in 87% isolated yield.
Having demonstrated an efficient route to N-Me triazolinone
16, we evaluated the final alkylation reaction to generate 1
directly (Scheme 7). Extensive evaluation of the reaction
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̂
́
Scheme 7. Final Alkylation
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