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Organic Process Research & Development
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ether (3 x 200 mL) and washed by brine solution (100 mL). The organic layer was concentrated in vacuo
to afford compound (10a-b) as oil.
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1-(4-(2-bromoethoxy)phenyl)-1H-imidazole (10a). The compound 10a was synthesized following the
general procedure described for compound (10a-b), using 40 equivalents of 1,2-dibromo ethane. The
compound 10a was obtained as a dark brown oil (35 g, 84% yield) which was used for next reaction
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without any further purification. H NMR (DMSO-d6, 400 MHz) δ: 3.81 (t, J = 5.6 Hz, 2H), 4.36 (t, J =
5.6 Hz, 2H), 7.06 – 7.08 (m, 1H), 7.09-7.11 (m, 2H), 7.53 - 7.57 (m, 2H), 7.64 – 7.65 (t, J = 1.2 Hz, 1H),
8.13 (d, J = 0.8 Hz, 1H); 13C NMR (DMSO-d6, 100 MHz) δ: 31.39, 68.11, 115.90, 118.84, 121.99,
129.57, 131.31, 135.51, 156.64; ESI-MS (m/z): 268.9 [M + H]+.
1-(4-(2-chloroethoxy)phenyl)-1H-imidazole (10b). The compound 10b was synthesized following the
above general procedure described for compound (10a-b). The compound 10b was obtained as a dark
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brown oil (21 g, 60% yield). % purity: 87.44% (HPLC); H NMR (CDCl3, 400 MHz) δ: 3.83 (t, J = 5.6
Hz, 2H), 4.26 (t, J = 5.6 Hz, 2H), 6.98 - 7.02 (m, 2H), 7.18 (s, 1H), 7.20 (s, 1H), 7.28 – 7.32 (m, 2H), 7.76
(d, J = 0.8 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ: 41.82, 68.43, 115.78, 118.70, 123.23, 130.14, 131.31,
135.80, 157.53; ESI-MS (m/z): 223.0 [M + H]+.
2-((2-(4-(1H-imidazol-1-yl)phenoxy)ethyl)thio)-5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-1-(4-fluoro
phenyl)-1H-imidazole (ZY12201). A mixture of compound 7 (9 g, 0.024 mol), 1-(4-(2-
bromoethoxy)phenyl)-1H-imidazole (10a) (12.9 g, 0.048 mol), potassium carbonate (10.0 g, 0.072 mol)
in acetone (100 mL) was stirred at room temperature for 2 h. Reaction mixture was diluted with acetone
(90 mL), filtered and concentrated in vacuo to afford crude product (~19.5 g). The crude product was
purified by a short column chromatography over silica gel with 1-3% methanol/chloroform as eluent to
furnish compound ZY12201 (11.95 g, 80%) as white solid.
White powder; mp: 108 ºC; % purity: 99.57%; 1H NMR (400 MHz, DMSO-d6): δ = 1.49 (s, 6H), 3.42 (t,
J = 6.4 Hz, 2H), 3.72 (s, 3H), 3.84 (s, 3H), 4.27 (t, J = 6.4 Hz, 2H), 6.49 – 6.55 (m, 4H), 6.64 (d, J = 8.8
Hz, 1H), 6.80 - 6.85 (m, 2H), 6.98 – 7.00 (m, 2H), 7.15 (s, 1H), 7.18 – 7.20 (m, 2H), 7.27 – 7.29 (m, 2H),
7.77 (br s, 1H); 13C NMR and DEPT (100 MHz, DMSO-d6): δ = 29.61 (CH3), 31.54 (CH2), 38.12 (C),
55.99 (CH3), 56.05 (CH3), 67.17 (CH2), 109.96 (CH), 110.83 (CH), 115.38 (CH), 115.61 (CH), 115.75
(CH), 118.45 (CH), 118.84 (CH), 123.22 (CH), 125.99 (CH), 130.01 (C), 130.97 (CH), 131.06 (C),
132.07 (C), 139.89 (C), 143.37 (C), 144.18 (C), 147.58 (C), 148.70 (C), 157.89 (C), 162.49 (C) (d, JC,F
=
248 Hz); MS (EI): m/z (%) = 559.1 (100%) (M)+, 560.5 (M+H)+; ESI-Q-TOF-MS: m/z [M+H]+ calcd for
[C31H31FN4O3S + H]+: 559.2134; found: 559.2244; IR (KBr): ν = 3495, 3367, 3063, 2931, 2829, 1602,
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