Methyl iodide → 6-Chloro-4-(1-((4-(4-fluorophenyl)-1-methylpiperidin-4-yl)methoxy)ethyl)-1,3-bis((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2(3H)-one

HRID 913941노트

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HRID 913941 반응식
[Cl:1][C:2]1[CH:3]=[C:4]([CH:21]([O:23][CH2:24][C:25]2([C:38]3[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=3)[CH2:30][CH2:29][N:28]([C:31](OC(C)(C)C)=O)[CH2:27][CH2:26]2)[CH3:22])[C:5]2[N:9]([CH2:10][O:11][CH2:12][CH2:13][Si:14]([CH3:17])([CH3:16])[CH3:15])[C:8](=[O:18])[N:7]([CH3:19])[C:6]=2[CH:20]=1.ClC1C=C(C(OCC2(C3C=CC(F)=CC=3)CCN(C(OC(C)(C)C)=O)CC2)C)C2N(C)C(=O)N(C[O:57][CH2:58][CH2:59][Si:60]([CH3:63])([CH3:62])[CH3:61])C=2C=1.ClC1C=C(C(OCC2(C3C=CC(F)=CC=3)CCN(C(OC(C)(C)C)=O)CC2)C)C2NC(=O)N(COCC[Si](C)(C)C)C=2C=1.ClC1C=C(C(OCC2(C3C=CC(F)=CC=3)CCN(C(OC(C)(C)C)=O)CC2)C)C2N(COCC[Si](C)(C)C)C(=O)NC=2C=1.[H-].[Na+].IC>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:21]([O:23][CH2:24][C:25]2([C:38]3[CH:39]=[CH:40][C:41]([F:44])=[CH:42][CH:43]=3)[CH2:26][CH2:27][N:28]([CH3:31])[CH2:29][CH2:30]2)[CH3:22])[C:5]2[N:9]([CH2:10][O:11][CH2:12][CH2:13][Si:14]([CH3:16])([CH3:17])[CH3:15])[C:8](=[O:18])[N:7]([CH2:19][O:57][CH2:58][CH2:59][Si:60]([CH3:63])([CH3:62])[CH3:61])[C:6]=2[CH:20]=1

참가 물질

8

반응물 6

HCID 6328Methyl iodideHCID 24758Sodium hydrideHCID 57546103Tert-butyl 4-((1-(6-chloro-2-oxo-3-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1h-benzo[d]imidazol-4-yl)ethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylateHCID 57546155Tert-butyl 4-((1-(6-chloro-2-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1h-benzo[d]imidazol-4-yl)ethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylateHCID 57546159tert-Butyl 4-((1-(6-chloro-1-methyl-2-oxo-3-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-benzo[d]imidazol-4-yl)ethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate3회HCID 57546215tert-Butyl 4-((1-(6-chloro-3-methyl-2-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-benzo[d]imidazol-4-yl)ethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate3회

생성물 1

HCID 575459266-Chloro-4-(1-((4-(4-fluorophenyl)-1-methylpiperidin-4-yl)methoxy)ethyl)-1,3-bis((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2(3H)-one

시약·촉매·용매 1

HCID 6228Dimethylformamide용매

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온도
0 °C

실험 절차

tert-Butyl 4-((1-(6-chloro-1-methyl-2-oxo-3-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-benzo[d]imidazol-4-yl)ethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate and tert-Butyl 4-((1-(6-chloro-3-methyl-2-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-benzo[d]imidazol-4-yl)ethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (2:1). To a solution of tert-Butyl 4-((1-(6-chloro-2-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-benzo[d]imidazol-4-yl)ethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate and tert-Butyl 4-((1-(6-chloro-2-oxo-3-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-benzo[d]imidazol-4-yl)ethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (2:1) (84 mg, 0.066 mmol) in dimethylformamide (1 mL) at 0° C. was added sodium hydride (9.5 mg, 0.40 mmol). To this was quickly added iodomethane (0.033 mL, 0.53 mmol). After stirring at 0° C. for 15 min, the reaction was quenched by addition of saturated ammonium chloride. The mixture was diluted with diethyl ether and water and the layers separated. The ethereal was washed with water (2×), then brine, dried over magnesium sulfate, and concentrated. Column chromatography (25%→37% ethyl acetate/n-hexane) gave separation of the two isomers. The first to elute was tert-butyl 4-((1-(6-chloro-1-methyl-2-oxo-3-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-benzo[d]imidazol-4-yl)ethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (major) (53 mg, 0.082 mmol, 62%). The second to elute was tert-Butyl 4-((1-(6-chloro-3-methyl-2-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-benzo[d]imidazol-4-yl)ethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (minor) (26 mg, 0.040 mmol, 30%). tert-Butyl 4-((1-(6-chloro-1-methyl-2-oxo-3-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-benzo[d]imidazol-4-yl)ethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate: 1H-NMR (CDCl3, 500 MHz) δ 7.21 (dd, J=8.9, 5.2 Hz, 2H), 6.97 (dd, J=8.9, 8.5 Hz, 2H), 6.81 (d, J=2.1 Hz, 1H), 6.75 (d, J=1.2 Hz, 1H), 5.36 (d, J=1 1.6 Hz, 1H), 5.04 (d, J=11.3 Hz, 1H), 4.95 (q, J=6.4 Hz, 1H), 3.68 (m, 2H), 3.51 (t, J=8.2 Hz, 2H), 3.35 (s, 2H), 3.20 (d, J=9.2 Hz, 1H), 3.18 (d, J=9.2 Hz, 1H), 3.01 (m, 2H), 2.07 (m, 2H), 1.83 (m, 2H), 1.42 (s, 9H), 1.34 (d, J=6.4 Hz, 3H), 0.72-0.92 (m, 2H), −0.05 (s, 9H); 13C NMR (126 MHz, CDCl3) δ ppm 161.4 (d, J=245 Hz), 155.0, 154.9, 138.7, 138.6, 131.7, 128.7 (d, J=7.7 Hz), 128.3, 128.0, 124.4, 119.4, 115.1 (d, J=21 Hz), 106.9, 104.2, 79.4, 76.7, 71.5, 71.4, 65.9, 41.1, 40.1, 32.2, 32.1, 28.5, 27.4, 23.2, 18.1, −1.4. tert-Butyl 4-((1-(6-chloro-3-methyl-2-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-benzo[d]imidazol-4-yl)ethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate: 1H-NMR (CDCl3, 500 MHz) δ 7.24 (dd, J=8.9, 5.2 Hz, 2H), 7.01 (m, 3H), 6.76 (d, J=2.1 Hz, 1H), 5.23 (s, 2H), 4.75 (q, J=6.4 Hz, 1H), 3.72 (bs, 2H), 3.58 (t, J=8.2 Hz, 2H), 3.43 (s, 3H), 3.27 (d, J=8.9 Hz, 1H), 3.17 (d, J=9.2 Hz, 1H), 3.00 (m, 2H), 2.11 (m, 2H), 1.83 (m, 2H), 1.43 (s, 9H), 1.38 (d, J=6.4 Hz, 3H), 1.25 (m, 2H), 0.91 (m, 2H), −0.04 (s, 9H); 13C NMR (126 MHz, CDCl3) δ ppm 161.5 (d, J=246 Hz), 155.0, 154.7, 138.43, 138.41, 130.3, 128.7 (d, J=7.7 Hz), 127.4, 127.2, 125.7, 120.0, 115.2 (d, J=21 Hz), 108.4, 104.3, 79.5, 77.6, 73.1, 71.0, 66.5, 41.2, 40.1 (br), 32.3, 32.1, 30.6, 28.6, 23.8, 17.9, −1.4.

후처리

  1. customthe reaction was quenched by addition of saturated ammonium chloride
  2. additionThe mixture was diluted with diethyl ether and water
  3. customthe layers separated
  4. washThe ethereal was washed with water (2×)
  5. dry with materialbrine, dried over magnesium sulfate
  6. concentrationconcentrated
  7. customColumn chromatography (25%→37% ethyl acetate/n-hexane) gave
  8. customseparation of the two isomers
  9. washThe first to elute
  10. washThe second to elute

출처 및 근거

ORD 기록
ord-01373c2b92b74664a37ed1a8027a9059
출처 데이터셋
uspto-grants-2011_09
특허 번호
US08026257B2

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