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J. R. Buck et al. / Tetrahedron Letters 53 (2012) 4161–4165
1.3 MAOS of N-(3-((5-chloro-1H-pyrrolo[2,3-b]pyridine-3-
yl)(hydroxyl)methyl)2,4-difluorophenyl)propane-1-
sulfonamide (7a)
preceding reactions (Table 1, entry 15). Nonetheless, the MAOS
conditions developed for the final-step oxidation of PLX4720 (8a)
were also employed toward PLX4032 (8b). Irradiation of 7b at
100 °C for 10 min gave a 92% yield of the final PLX4032 (8b) (Table
1, entry 16).
In summary, we report optimized, gram-scale syntheses of
PLX4720 and PLX4032 that leverage MAOS. Where, applicable,
the MAOS protocol reported herein significantly improves overall
reaction times while maintaining or even improving synthetic
yields. We envision this methodology could potentially be
extended not only to the synthesis of PLX4032 and PLX4720, but
to other novel azaindoles as well.
The PLX4720 intermediate 7a was originally synthesized in 88%
yield from the reaction of 5 with the azaindole core 5-chloro-1H-
pyrrolo[2,3-b]pyridine (6a) in methanol:water (1:1) for 48 h at
room temperature (Table 1, entry 7).12 Optimization with micro-
wave irradiation resulted in final reaction conditions of 130 °C in
the same solvent system for only a fraction of the original time
(30 min). Purification by flash chromatography on silica gel gave
7a in a matching yield of 88% (Table 1, entry 8).
1.4 MAOS of N-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-
carbonyl)-2,4-difluorophenyl)propane-1-sulfonoamide (8a,
PLX4720)
Acknowledgments
The authors wish to gratefully acknowledge funding from the
National Cancer Institute (NCI): 1R01 CA140628, 1RC1
CA145138-01, K25 CA127349, 1P50 CA128323 (Vanderbilt ICMIC
Program), 2P50 CA095103 (Vanderbilt SPORE in GI Cancer), 5P30
DK058404, and the Kleberg Foundation. The authors wish to thank
Dr. Yiu-Yin Cheung for helpful discussions.
From compound 7a, reported oxidation to PLX4720 (8a) utilized
2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) in a mixture of
water and 1,4-dioxane at room temperature for 2 h, with a yield
of 90% (Table 1, entry 13).12 Under MAOS, an optimized reaction
temperature of 100 °C was achieved with a reduction in reaction
time to 10 min, a factor of 12, while still achieving a comparable
yield of 87% (Table 1, entry 14).
Supplementary data
Supplementary data associated with this article can be found in
2. Synthesis of PLX4320 (8b)
2.1 MAOS of 5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine (6b)
References and notes
Suzuki coupling of 5-bromo-1H-pyrrolo[2,3-b]pyridine (6e)
with 4-(chlorophenyl)boronic acid (6f) in the presence of K2CO3
and Pd(PPh3)2Cl2 in 1,2-dimethoxyethane (DME) for 30 min at
130 °C secured the necessary PLX4032 azaindole core (6b)
(Table 1, entry 6). Previous synthesis of this intermediate required
overnight reflux, with a yield of 81% (Table 1, entry 5),13 thus
underscoring the effectiveness of MAOS in reducing overall
reaction time.
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further, in favor of the published methodology of Bollag et al.13
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2.3 MAOS of N-(3-(5-(4-chlorophenyl)-1H-pyrrolo[2,3-
b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-
sulfonamide (8b, PLX4032)
Bollag et al.13 reported a final oxidation of precursor 7b to
PLX4032 (8b) analogous to Tsai et al.12 The exact yield of this step
is unknown as it was reported in combination with the two