Fernando Huerta, Erik Leonhardt, Lianyan Xu, Trevor Laird, John Dillon, David M. Parry, Thomas Galeandro-Diamant. “AI-driven design of a cost-effective synthetic route to malaria drug Ganaplacide.” ChemRxiv (). https://doi.org/10.26434/chemrxiv.15006146/v2

Supporting information is appended to the main paper

4-benzyl-3,3-dimethylpiperazin-2-one
Identifier 2-Bn
¹H NMR (400 MHz, MeOD) δ 7.40 – 7.34 (m, 2H), 7.30 (td, J = 6.7, 1.6 Hz, 2H), 7.25 – 7.19 (m, 1H), 3.64 (s, 2H), 3.15 – 3.10 (m, 2H), 2.68 – 2.61 (m, 2H), 1.43 (s, 6H)
¹³C NMR (101 MHz, MeOD) δ 176.60, 139.80, 128.13, 127.93, 126.63, 61.34, 52.96, 41.50, 40.88, 20.42
LRMS m/z calcd. For C₁₃H₁₈N₂O [M+H]⁺ 219.15; Found 219
HPLC (254nm,4nm) Ret. Time (min) 4.59; Rel. Ret. Time 1.00; Area% 99.18
HPLC (254nm,4nm) Ret. Time (min) 5.25; Rel. Ret. Time 1.14; Area% 0.36
HPLC (254nm,4nm) Ret. Time (min) 6.39; Rel. Ret. Time 1.39; Area% 0.46
SI, pp. 11, 27
1-benzyl-6,6-dimethyl-5-(methylthio)-1,2,3,6-tetrahydropyrazine
Identifier 4-Bn
¹H NMR (400 MHz, DMSO) δ 7.34 – 7.27 (m, 4H), 7.22 (dq, J = 5.7, 2.7 Hz, 1H), 3.58 (s, 2H), 3.48 (t, J = 5.3 Hz, 2H), 2.42 (t, J = 5.3 Hz, 2H), 2.16 (s, 3H), 1.38 (s, 6H)
¹³C NMR (101 MHz, DMSO) δ 171.28, 140.60, 128.62, 128.58, 127.14, 60.54, 53.12, 50.67, 42.46, 23.08, 12.68
LRMS m/z calcd. For C₁₄H₂₀N₂S [M+H]⁺ 249.14; Found 249
HPLC (254nm,4nm) Ret. Time (min) 4.99; Rel. Ret. Time 0.84; Area% 4.83
HPLC (254nm,4nm) Ret. Time (min) 5.53; Rel. Ret. Time 0.93; Area% 1.95
HPLC (254nm,4nm) Ret. Time (min) 5.75; Rel. Ret. Time 0.97; Area% 0.52
HPLC (254nm,4nm) Ret. Time (min) 5.93; Rel. Ret. Time 1.00; Area% 50.06
HPLC (254nm,4nm) Ret. Time (min) 6.16; Rel. Ret. Time 1.04; Area% 2.92
HPLC (254nm,4nm) Ret. Time (min) 6.51; Rel. Ret. Time 1.10; Area% 31.29
HPLC (254nm,4nm) Ret. Time (min) 6.67; Rel. Ret. Time 1.13; Area% 0.14
HPLC (254nm,4nm) Ret. Time (min) 6.85; Rel. Ret. Time 1.16; Area% 3.49
HPLC (254nm,4nm) Ret. Time (min) 7.59; Rel. Ret. Time 1.28; Area% 0.33
HPLC (254nm,4nm) Ret. Time (min) 7.67; Rel. Ret. Time 1.29; Area% 1.63
HPLC (254nm,4nm) Ret. Time (min) 7.84; Rel. Ret. Time 1.32; Area% 0.25
HPLC (254nm,4nm) Ret. Time (min) 7.97; Rel. Ret. Time 1.34; Area% 1.37
HPLC (254nm,4nm) Ret. Time (min) 8.28; Rel. Ret. Time 1.40; Area% 0.17
HPLC (254nm,4nm) Ret. Time (min) 8.41; Rel. Ret. Time 1.42; Area% 0.17
HPLC (254nm,4nm) Ret. Time (min) 8.52; Rel. Ret. Time 1.44; Area% 0.05
HPLC (254nm,4nm) Ret. Time (min) 8.76; Rel. Ret. Time 1.48; Area% 0.45
HPLC (254nm,4nm) Ret. Time (min) 9.47; Rel. Ret. Time 1.60; Area% 0.37
SI, pp. 11, 27
7-benzyl-2-(4-fluorophenyl)-8,8-dimethyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-3-amine hydrochloride
Identifier 7-Bn-HCl
¹H NMR (400 MHz, MeOD) δ 7.64 (ddt, J = 8.2, 5.1, 2.5 Hz, 2H), 7.43 (d, J = 7.2 Hz, 2H), 7.35 (t, J = 7.4 Hz, 2H), 7.27 (td, J = 7.9, 5.6 Hz, 3H), 3.86 (t, J = 5.4 Hz, 2H), 3.81 (s, 2H), 3.03 (t, J = 5.3 Hz, 2H), 1.73 (s, 6H)
¹³C NMR (101 MHz, MeOD) δ 163.62, 161.16, 143.63, 138.81, 133.20, 128.60, 128.52, 128.21, 128.19, 127.07, 124.02, 123.99, 115.85, 115.63, 111.92, 56.14, 51.33, 42.23, 41.11, 22.33
LRMS m/z calcd. For C₂₁H₂₃FN (freebase) [M+H]⁺ 351.20; Found 351
HPLC (254nm,4nm) Ret. Time (min) 5.91; Rel. Ret. Time 1.00; Area% 100.00
SI, pp. 12, 28
sodium(7-benzyl-2-(4-fluorophenyl)-8,8-dimethyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-3-yl)(4-fluorophenyl)amide
Identifier 9-Bn-Salt
¹H NMR (400 MHz, MeOD) δ 7.77 – 7.69 (m, 2H), 7.45 – 7.39 (m, 2H), 7.35 – 7.29 (m, 2H), 7.28 – 7.19 (m, 2H), 7.18 – 7.13 (m, 1H), 7.06 – 6.99 (m, 2H), 6.92 – 6.85 (m, 2H), 6.57 – 6.50 (m, 2H), 3.58 (dd, J = 6.2, 4.6 Hz, 2H), 2.90 – 2.82 (m, 2H), 1.68 (s, 6H)
¹³C NMR (101 MHz, MeOD) δ 164.33, 161.91, 158.96, 156.63, 150.14, 144.28, 144.26, 141.13, 133.94, 131.51, 131.48, 129.64, 129.41, 129.20, 129.12, 128.13, 125.66, 116.90, 116.67, 115.98, 115.77, 115.02, 114.95, 58.41, 53.51, 43.22, 42.89, 24.01
LRMS m/z calcd. For C₂₇H₂₆F₂N₄ (freebase) [M+H]⁺ 445.22; Found 445
HPLC (254nm,4nm) Ret. Time (min) 5.63; Rel. Ret. Time 0.87; Area% 0.11
HPLC (254nm,4nm) Ret. Time (min) 6.12; Rel. Ret. Time 0.94; Area% 0.10
HPLC (254nm,4nm) Ret. Time (min) 6.50; Rel. Ret. Time 1.00; Area% 99.79
SI, pp. 13, 28
N,2-bis(4-fluorophenyl)-8,8-dimethyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-3-amine
Identifier 9
¹H NMR (400 MHz, MeOD) δ 7.64 – 7.55 (m, 2H), 6.89 (ddt, J = 9.8, 7.6, 3.0 Hz, 2H), 6.82 – 6.73 (m, 2H), 6.49 – 6.38 (m, 2H), 3.60 (t, J = 5.5 Hz, 2H), 3.09 (t, J = 5.5 Hz, 2H), 1.46 (s, 6H)
¹³C NMR (101 MHz, MeOD) δ 162.82, 160.39, 157.49, 155.15, 147.74, 142.68, 132.04, 129.90, 129.87, 127.63, 127.56, 124.57, 115.40, 115.17, 114.49, 114.28, 113.60, 113.52, 51.73, 41.66, 37.42, 26.80
LRMS m/z calcd. For C₂₀H₂₀F₂N₄ [M+H]⁺ 355.17; Found 355
HPLC (254nm,4nm) Ret. Time (min) 5.05; Rel. Ret. Time 0.93; Area% 0.05
HPLC (254nm,4nm) Ret. Time (min) 5.44; Rel. Ret. Time 1.00; Area% 99.78
HPLC (254nm,4nm) Ret. Time (min) 6.24; Rel. Ret. Time 1.15; Area% 0.07
HPLC (254nm,4nm) Ret. Time (min) 6.39; Rel. Ret. Time 1.17; Area% 0.05
HPLC (254nm,4nm) Ret. Time (min) 7.31; Rel. Ret. Time 1.34; Area% 0.06
SI, pp. 14, 29
2-amino-1-(2-(4-fluorophenyl)-3-((4-fluorophenyl)amino)-8,8-dimethyl-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)ethan-1-one (ganaplacide free-base)
Identifier Ganaplacide
¹H NMR (400 MHz, MeOD) δ 7.61 (dd, J = 8.5, 5.6 Hz, 2H), 6.90 (t, J = 8.8 Hz, 2H), 6.79 (t, J = 8.7 Hz, 2H), 6.46 (dd, J = 8.8, 4.3 Hz, 2H), 3.70 (d, J = 4.6 Hz, 2H), 3.57 (d, J = 4.5 Hz, 2H), 3.40 (s, 2H), 1.84 (s, 6H)
¹³C NMR (101 MHz, MeOD) δ 172.27, 162.89, 160.46, 157.58, 155.25, 147.74, 142.62, 132.47, 129.81, 129.77, 127.69, 127.62, 124.65, 115.52, 115.30, 114.58, 114.37, 113.69, 113.61, 59.39, 43.71, 41.06, 40.82, 25.02
LRMS m/z calcd. For C₂₂H₂₃F₂N₅O [M+H]⁺ 412.19; Found 412
HPLC (254nm,4nm) Ret. Time (min) 5.75; Rel. Ret. Time 1.00; Area% 96.05
HPLC (254nm,4nm) Ret. Time (min) 5.91; Rel. Ret. Time 1.03; Area% 0.03
HPLC (254nm,4nm) Ret. Time (min) 6.01; Rel. Ret. Time 1.05; Area% 2.51
HPLC (254nm,4nm) Ret. Time (min) 6.20; Rel. Ret. Time 1.08; Area% 0.52
HPLC (254nm,4nm) Ret. Time (min) 6.37; Rel. Ret. Time 1.11; Area% 0.55
HPLC (254nm,4nm) Ret. Time (min) 6.44; Rel. Ret. Time 1.12; Area% 0.11
HPLC (254nm,4nm) Ret. Time (min) 6.70; Rel. Ret. Time 1.17; Area% 0.24