Organic Process Research & Development
ARTICLE
1C, J(13C,19F) = 5.1 Hz), 124.5, 123.5(d, 1C, J(13C,19F) = 15.6 Hz),
122.1, 116.0, 115.8, (d, 1C, J(13C,19F) = 25.6 Hz), 114.8, 66.1 (2C),
55.2 (2C), 53.3, 21.1, 13.5; ESI-HRMS calc’d for C19H20ON4Cl2F
(M + H)+ 409.09927, found 409.09972.
form a solution. Concentration of the solution at 80 °C to 500 L
gave a slurry. In order to maximize recovery, the slurry was aged
at 2ꢀ5 °C for 7.5 h, isolated by filtration, and washed with
heptane (210 kg, 309 L). The solids were dried at 75ꢀ85 °C to
afford 1 as a crystalline solid (89.9 kg, 96% yield); mp =
235.6ꢀ237.2 °C; IR(cmꢀ1) 3359, 3262, 2920, 2804, 1588,
1-tert-Butyl-3-methyl-1H-pyrazol-5-amine (4). To a reac-
tion vessel was charged NaOH (2 M, 4012 mL, 8.02 mol) and
solid tert-butylhydrazine hydrochloride (1,002 g, 8.04 mol) was
added to form a solution. Next, 3-aminobut-2-enenitrile (690 g,
8.0 mol) was added and the resulting reaction mixture heated to
90 °C for 18 h. The reaction mixture was cooled to 5 °C and the
resulting precipitate filtered to provide 4 (1.13 kg, 86% yield);
mp = 68ꢀ70 °C; HPLC tR = 3.66 min; IR(cmꢀ1) 3440, 3340,
3236, 2983, 2938, 1625, 1555; 1H NMR (400 MHz, DMSO-d6)
5.17 (s, 1H), 4.69 (br, 2H), 1.94 (s, 3H), 1.47 (s, 9H); 13C NMR
(100 MHz, DMSO-d6) 146.6, 142.8, 91.3, 56.8, 29.0 (3C), 13.8;
ESIHRMS calc’d for C8H16N3 (M + H)+ 154.13387, found
154.13382.
1
1539; H NMR (400 MHz, DMSO-d6) 11.82 (s, 1H), 9.39 (s,
1H), 7.40 (dd, 1H, J = 2.0, 10.0 Hz), 7.09 (dd, 1H, J = 2.0,
8.4 Hz), 6.99 (t, 1H, J = 8.4 Hz), 6.99 (s, 1H), 6.07 (s, 1H), 4.20
(s, 2H), 3.73 (s, 2H), 3.62 (t, 4H, J = 4.8 Hz), 2.47 (m, 4H), 2.29
(s, 3H), 2.17 (s, 3H); 13C NMR (100 MHz, DMSO-d6) 160.1
(d, 1C, J(13C,19F) = 246.6 Hz), 149.8, 148.5, 137.8, 137.5, 131.4
(d, 1C, J(13C,19F) = 10.1 Hz), 131.1 (d, 1C, J(13C,19F) = 4 Hz),
124.6, 124.5, 120.5, 115.6 (d, 1C, J(13C,19F) = 25.6 Hz), 108.3,
94.8, 66.2 (2C), 55.3, 53.4 (2C), 21.0, 13.3, 10.6; ESI-HRMS
calc’d for C23H26ON7ClF (M + H)+ 470.18659, found 470.18684.
N-(1-tert-Butyl-3-methyl-1H-pyrazol-5-yl)-3-(4-chloro-2-
fluorobenzyl)-2-methyl-8-(morpholinomethyl)imidazo[1,2-
b]pyridazin-6-amine (42). Chloride 5 (82.6 kg, 98.1% potency,
198.0 mol), pyrazole 4, (33.1 kg, 96.3% potency, 208.0 mol),
xylenes (654 L), NaOH (118.1 kg of 7.4% aqueous, 218.5 mol)
were charged to a reactor and the mixturewas inerted with a
nitrogen atmosphere. XantPhos (1.00 kg, 1.73 mol) and Pd2-
(dba)3 (0.80 kg, 0.87 mol) were then added, and the mixture was
heated under reflux for 40 h. The mixture was cooled to <60 °C,
and THF (508 L) was added. Cooling to 25ꢀ30 °C, filtration of a
residue and removal of the water layer was followed by addition
of fresh water (269 kg) and stirring at 25ꢀ30 °C for ∼1 h. The
water layer was removed, and the organic layer was stirred with
mercaptopropyl-functionalized silica gel (6.8 kg) at 50ꢀ60 °C
for 10 h. Removal of the silica was then accomplished by
filtration, concentration of the filtrates to 300 L, and the addition
of heptane (329 L) at 80 °C in a slurry. The slurry was cooled to
10ꢀ15 °C and stirred for 3 h. Filtration of the solids and washing
with heptane (60 kg) afforded 42 after drying. (82.4 kg, 79%
yield); mp = 188ꢀ189 °C; IR(cmꢀ1) 3299, 2950, 2912, 2853,
2819, 1610, 1573, 1484; 1H NMR (400 MHz, DMSO-d6) 8.36
(s, 1H), 7.27 (dd, 1H, J = 2.0, 0.8 Hz), 7.00ꢀ6.95 (m, 2H), 6.80
(s, 1H), 5.91 (s, 1H), 3.99 (s, 2H), 3.75 (d, 2H, J = 0.8 Hz), 3.61
(t, 4H, J = 4.4 Hz), 2.47 (brt, 4H, J = 4.0 Hz), 2.30 (s, 3H), 2.18
(s, 3H), 1.45 (s, 9H); 13C NMR (100 MHz, DMSO-d6) 160.1 (d,
1C, J(13C,19F) = 246.9 Hz), 152.5, 143.6, 137.2, 136.9, 135.9,
134.7, 132.4 (d, 1C, J(13C,19F) = 20.0 Hz), 131.4 (d, 1C,
J(13C,19F) = 10.4 Hz), 123.9 (m, 2C), 120.8, 115.5 (d, 1C,
J(13C,19F) = 25.6 Hz), 106.6, 103.8, 66.1 (2C), 58.6, 55.3, 53.4
(2C), 29.5 (3C), 21.6, 14.0, 13.2; ESI-HRMS calc’d for
C27H34ON7ClF (M + H)+ 526.24919, found 526.24932.
3-(4-Chloro-2-fluorobenzyl)-2-methyl-N-(5-methyl-1H-
pyrazol-3-yl)-8-(morpholinomethyl)-imidazo[1,2-b]pyrida-
zin-6-amine (1). A reactor was charged with water (170 L),
TFA (22.4 kg, 196.5 mol) and 42 (34 kg, 99.0% potency,
64.0 mol). This mixture was heated to 95ꢀ100 °C for 7 h, and
then cooled to 50ꢀ55 °C, at which time EtOH (139 kg) was
added. The pH of the solution was then adjusted to 10ꢀ11 using
NaOH (11.2 kg in 56 kg water). A slurry formed, and was stirred
at 60 °C for 8 h, and then cooled to 15ꢀ20 °C. The solids were
isolated by filtration and washed with water (51 kg). The solids
were dried to afford technical grade 1 as a solid (27.8 kg,
86% yield). Final Recrystallization: A vessel was charged with
n-BuOH (843 kg, 1041 L) and technical grade 1 (105 kg, 89.1%
potency, 199.0 mol); the mixture was heated to 95ꢀ100 °C to
’ ASSOCIATED CONTENT
Supporting Information. 1H and 13C NMR spectra for
S
b
compounds 1, 4, 5, 6, 7, 8, 31, and 42. This material is available
’ AUTHOR INFORMATION
Corresponding Author
’ ACKNOWLEDGMENT
We thank the following individuals for their valuable con-
tributions to this work: Mr. Tim Woolsey, Dr. Charsetta Grant,
Mr. Chauncey Jones, Mr. James Aikins, Mr. Steven Pedersen, Mr.
John Howell, and Mr. William Diseroad. For X-ray crystallo-
graphic assistance, we thank Mr. Benjamin Diseroad and Dr.
Greg Stephenson. We also acknowledge Professors Marvin
Miller, William Roush, Peter Wipf and Erik Carreira for invalu-
able discussions during the course of this work.
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dx.doi.org/10.1021/op200229j |Org. Process Res. Dev. 2012, 16, 70–81