Organic Process Research & Development
Article
degassed. Separately, THF (339 L), 31 (24.2 kg, 41.4 mol), 13
(15.1 kg, 51.3 mol, 1.24 equiv), and di-tert-butyl dicarbonate
(2.33 kg, 10.7 mol, 0.26 equiv) were combined, and the mixture
was degassed 5 times and heated to 40 °C. Next, the catalyst
[1,1′-bis(di-tert-butylphosphino)]ferrocene palladium(II) di-
chloride (Pd-118) (0.40 kg, 0.61 mol, 0.015 equiv) was
added, followed by the degassed aqueous potassium phosphate
tribasic solution. The mixture was stirred at 45 °C for a total of
70 min, resulting in complete conversion to product. The
mixture was cooled to 20 °C, and the phases were separated.
The organic layer was vacuum-distilled at 60 °C, and 225 L of
distillate was collected. The mixture was stirred at 55 °C for 2
h, cooled to 20 °C within 3 h, and held at this temperature for
19 h. The slurry was filtered, and the reactor and wet cake were
washed with a mixture of THF (30 L) and water (30 L). The
product was dried on a filter dryer under vacuum and a stream
of N2. This wet cake (14.3% loss on drying) was divided into
two equal portions (16.3 kg each), suspended in a mixture of
THF (420 L) and water (20 L), and heated to 60 °C. To this
mixture was added thiol-functionalized silica gel (3.87 kg). The
mixtures were stirred at 60 °C for 6 h and filtered, and the
reactor was rinsed with 60 °C THF (20 L). The filtrate (846 L)
was vacuum-distilled at 60 °C to one-third of the original
volume. To the concentrate was added IPA (223 L), and then
the mixture was vacuum-distilled. This step was repeated with
additional IPA (223 L) at 60 °C. The resultant concentrate was
cooled to 10 °C within 2 h and held at this temperature for 17
h, after which the slurry was filtered and the wet cake was
washed with cold IPA. The product was dried in a filter dryer
with vacuum and a stream of N2, resulting in 17 (25.12 kg, 99.7
area %, 86.9 wt %, 80.8% yield) with low metal content (14
108.9, 108.7, 108.4, 108.2, 107.8, 35.5, 21.7. HR-MS: calcd for
C30H22F2N6O3 + H, 553.1794; found, 553.1788.
ASSOCIATED CONTENT
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S
* Supporting Information
1H and 13C NMR spectra for the compounds in Scheme 12
along with experimentals for Schemes 1, 5, and 6. This material
AUTHOR INFORMATION
Corresponding Author
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
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We thank David Mitchell, Sau-Chi Betty Yan, Mike Prunier,
Janet Boggs, Todd Simard, Bob Murff, Jim Ray, John Howell,
Pat Pollock, Dave Robbins, Steve Myers, Jeff Wei, Lori Hilden,
Susan Reutzel-Edens, Zac Gunter, and Steve Bandy for their
contributions.
REFERENCES
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1
ppm Pd; <1 ppm Pt, Zn; 5.5 ppm Fe). H NMR (DMSO-d6,
400 MHz): δ 11.95 (s, 1H), 8.62 (s, 1H), 8.46 (d, 1H, J = 8.0
Hz), 8.40 (s, 1H), 8.19 (s, 1H), 7.97 (m, 2H), 7.44 (m, 4H),
7.34 (s, 1H), 7.28 (d, 1H, J = 9.2 Hz), 6.92 (t, 1H, J = 9.2 Hz),
6.69 (d, 1H, J = 8.0 Hz), 4.10 (s, 3H), 2.06 (s, 3H), 1.58 (s,
9H). 13C NMR (DMSO-d6, 100 MHz): δ 163.0, 161.6, 160.7,
153.3, 147.4, 146.9, 144.0, 143.2, 139.6, 139.5, 137.1, 134.8,
132.1, 130.1, 130.0, 128.9, 122.6, 121.4, 119.8, 117.0, 116.7,
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for C35H30F2N6O5 + H, 653.2319; found, 653.2313.
N-(3-Fluoro-4-((1-methyl-6-(1H-pyrazol-4-yl)-1H-inda-
zol-5-yl)oxy)phenyl)-1-(4-fluorophenyl)-6-methyl-2-oxo-
1,2-dihydropyridine-3-carboxamide (1, LY2801653). Ab-
solute ethanol (430 L), 17 (25.0 kg, 33.30 mol), and a seed of
the correct form (87 g, 0.005 equiv) were combined. The
resultant suspension was heated to reflux, and 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU) (6.14 kg, 40.3 mol,
1.21 equiv) was added. The mixture was refluxed for 9 h
(resulting in 99.92% conversion), cooled to 10 °C over 14 h,
and stirred at 10 °C for 2.5 h. The slurry was filtered on a filter
dryer, and the reactor and wet cake were washed with cold
ethanol (54 L). The product was dried in a filter dryer by
applying vacuum and a stream of N2, resulting in 1 (18.54 kg,
1
99.4 area %, 98.75 wt %, 99.5% yield). H NMR (DMSO-d6,
400 MHz): δ 12.98 (s, 1H), 11.93 (s, 1H), 8.46 (d, 1H, J = 7.6
Hz), 8.16 (s, 1H), 8.03 (s, 1H), 8.00 (s, 1H), 7.96 (dd, 1H, J =
2.4 Hz, J = 13.2 Hz), 7.91 (s, 1H), 7.45 (m, 4H), 7.25 (m, 2H),
6.86 (t, 1H, J = 9.6 Hz), 6.68 (d, 1H, J = 8.0 Hz), 4.07 (s, 3H),
2.05 (s, 3H). 13C NMR (DMSO-d6, 100 MHz): δ 163.2, 163.0,
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138.0, 137.3, 134.5, 134.4, 134.1, 131.9, 130.1, 130.0, 127.4,
124.1, 121.8, 119.7, 117.0, 116.8, 116.7, 116.4, 116.1, 116.0,
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dx.doi.org/10.1021/op400317z | Org. Process Res. Dev. 2014, 18, 501−510