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Organic Process Research & Development
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1 were transferred to Reactor 2 over 15 min while keeping the internal temperature of Reactor 2 below 30 °C. The
mixture in Reactor 2 was then stirred for an additional 15. The layers were allowed to separate the bottom layer was
discharged. 21 wt% NaOEt in EtOH (1.90 kg, 6.00 mol, 2.0 equiv) was added to the reactor and the solution was
heated to 70 °C and stirred for 1 h. The reaction was concentrated to ~10 L via a vacuum distillation (pressure: ~210
mbar, internal temp: 30-45 °C). EtOH (10.0 L, 7.9 kg) was added to the reactor over the course of a constant-volume
distillation while maintaining an internal temperature below 55 °C (pressure: ~210 mbar, internal temp: 30-45 °C).
Then H2O (7.5 L) was added to the reactor over the course of a constant volume distillation while maintaining an
internal temperature below 60 °C (pressure: ~130 mbar, temp: 30-45 °C). An additional 21 wt% NaOEt in EtOH (300
g, 0.75 mol, 0.25 equiv) was added, and the reaction was heated to 75 °C for 1.5 h (reaction complete upon 24D/11D)
A% ≤1.0% by HPLC analysis).. The contents of Reactor 2 were cooled to 5 °C over 7 h, and stirred at 5 °C for 2 h.
The mixture was then filtered and the wet cake was rinsed with H2O:EtOH (4.0 L, 3:1) at 15 °C and H2O (4.0 L) at
20 °C. The solids were dried under vacuum at 40 °C for 12 h to afford 11D as a light-yellow solid (684 g, 71%, 92.3
w/w%). HPLC 97.9% 11D; mp 186 °C (DSC); FTIR (cm-1, neat) 3236, 2926, 2905, 2842, 1640, 1608, 1444, 1375,
1219, 1196; 1H NMR (400 MHz, DMSO-d6) δ 8.93 (d, J = 7.7 Hz, 1H), 7.93 (d, J = 8.0 Hz, 1H), 7.50 (d, J = 8.0 Hz,
1H), 7.28 (t, J = 7.6 Hz, 1H), 7.13 (t, J = 7.6 Hz, 1H), 6.86 (d, J = 7.8 Hz, 1H), 4.55 (s, 2H), 4.36 (s, 1H), 2.99 (t, J =
12.7 Hz, 2H), 1.82 – 1.69 (m, 3H), 1.38 (d, J = 6.2 Hz, 2H), 1.12 (ddt, J = 15.6, 11.8, 6.0 Hz, 2H); 13C NMR (101
MHz, DMSO-d6) δ 157.8, 152.1, 144.1, 134.2, 127.7, 124.0, 118.9, 117.0, 110.1, 95.8, 44.6, 38.7, 32.1, 31.8. HRMS:
calcd for C17H19D2N4O [M+H]+ : 299.1835; found: 299.1836.
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2-(1-(Benzo[4,5]imidazo[1,2-a]pyrimidin-2-yl)piperidin-4-yl)ethyl-1,1-d2 4-methylbenzenesulfonate (1D). To a
20 L reactor (Reactor 1) under nitrogen at 20 °C was charged 2-(1-(benzo[4,5]imidazo[1,2-a]pyrimidin-2-yl)piperidin-
4-yl)ethan-1,1-d2-1-ol (11D, 0.687 kg, 2.30 mol) followed by TsOH•H2O (0.531 kg, 2.76 mol, 1.2 equiv). MeCN (2.7
kg, 3.4 L) was added and the reaction was stirred for 15 min. Ts2O (1.50 kg, 4.61 mol, 2.0 equiv) was added followed
by MeCN (0.49 kg, 0.63 L) to rinse the reaction vessel. This slurry was then stirred at 20 °C for 16 h. Upon completion
of the reaction (reaction complete upon 11D/1D) A% ≤2.0% by HPLC analysis)., H2O (0.69 kg, 0.69 L) was added
while keeping the internal temperature below 30 °C. NMP (4.3 kg, 4.1 L) was added while keeping the internal
temperature below 30 °C. The reaction mixture was then stirred for 15 min. Meanwhile, to a separate reactor (Reactor
2) at 20 °C was added aqueous 20 wt% K3PO4 (6.9 L). The contents of Reactor 1 were added to Reactor 2 over 2 h.
The contents of Reactor 2 were then agitated for 1 h. The mixture was filtered and the wet cake was washed with H2O
(6.9 L 2). The solids were dried under vacuum at 20 °C for 2 h followed by drying under vacuum at 35 °C for of 12
h to afford 1D as an off-white solid (0.888 kg, 89%, 96.7 w/w%). HPLC: 99.3% 1D; mp 151°C (DSC); FTIR (cm-1,
neat) 1639, 1610, 1438, 1355, 1264, 1204, 1173, 1125; 1H NMR (400 MHz, Chloroform-d) δ 8.23 (d, J = 7.8 Hz, 1H),
7.84 – 7.77 (m, 2H), 7.71 (d, J = 8.1 Hz, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.37 (dd, J = 7.6, 5.1 Hz, 3H), 7.23 – 7.14 (m,
1H), 6.40 (d, J = 7.8 Hz, 1H), 4.58 (s, 2H), 2.94 (t, J = 12.9 Hz, 2H), 2.46 (s, 3H), 1.73 (s, 1H), 1.60 (d, J = 6.5 Hz,
2H), 1.18 (qd, J = 12.4, 4.1 Hz, 2H); 13C NMR (101 MHz, Chloroform-d) δ 157.8, 145.1, 132.7, 130.0, 128.0, 127.8,
124.8, 119.8, 118.7, 108.8, 108.8, 95.5, 95.4, 67.9, 45.2, 35.2, 32.5, 31.7, 21.8. HRMS: calcd for C24H25D2N4O3S
[M+H]+ : 453.1924; found: 453.1913.
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