Cesium carbonate → HCID 131732445, compound

HRID 1848759Notes

Reaction equation

HRID 1848759 reaction equation
Br[C:2]1[CH:38]=[C:37]([F:39])[C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[C:13]([O:16][CH2:17][C:18]4[C:23]([F:24])=[CH:22][C:21]([CH3:25])=[CH:20][N:19]=4)[CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C@H:26]2[CH2:31][CH2:30][CH2:29][CH2:28][C@H:27]2[C:32]([O:34][CH2:35][CH3:36])=[O:33])=[C:4]([F:40])[CH:3]=1.[F:41][CH:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1.C([O-])([O-])=O.[Cs+].[Cs+]>CC(P(C(C)(C)C)C(C)(C)C)(C)C.CC(P(C(C)(C)C)C(C)(C)C)(C)C.[Pd].C1(C)C=CC=CC=1>[F:40][C:4]1[CH:3]=[C:2]([N:45]2[CH2:46][CH2:47][CH:42]([F:41])[CH2:43][CH2:44]2)[CH:38]=[C:37]([F:39])[C:5]=1[CH2:6][N:7]1[C:11]2[CH:12]=[C:13]([O:16][CH2:17][C:18]3[C:23]([F:24])=[CH:22][C:21]([CH3:25])=[CH:20][N:19]=3)[CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[C@H:26]1[CH2:31][CH2:30][CH2:29][CH2:28][C@H:27]1[C:32]([O:34][CH2:35][CH3:36])=[O:33]

Participants

6

Reactant 3

HCID 10796Cesium carbonateHCID 27591594-FluoropiperidineHCID 131732444HCID 131732444, compound

Product 1

HCID 131732445HCID 131732445, compound

Reagents, catalysts & solvents 2

HCID 2734558Bis(tri-tert-butylphosphine)palladium(0)CatalystHCID 1140TolueneSolvent

Conditions

Temperature
110 °C

Procedure

To a 5 mL vial were added racemic cis-ethyl 2-(1-(4-bromo-2,6-difluorobenzyl)-6-((3-fluoro-5-methylpyridin-2-yl)methoxy)-1H-benzo[d]imidazol-2-yl)cyclohexanecarboxylate (150 mg, 0.24 mmol), Pd(t-Bu3P)2 (12 mg, 0.024 mmol), 4-fluoropiperidine (28 mg, 0.27 mmol), Cs2CO3 (238 mg, 0.73 mmol) and toluene (1 mL). The mixture was heated at 110° Celsius for 1 h. The mixture was cooled to RT, concentrated to dryness and purified by FCC to afford racemic cis-ethyl 2-(1-(2,6-difluoro-4-(4-fluoropiperidin-1-yl)benzyl)-6-((3-fluoro-5-methylpyridin-2-yl)methoxy)-1H-benzo[d]imidazol-2-yl)cyclohexanecarboxylate. To the resulting ethyl ester, in a 5 mL vial, was added HCl (5 mL, 6 N). The mixture was heated at 100° Celsius for 16 h. The mixture was cooled to RT then concentrated to dryness. The residue was purified using FCC to provide the title compound. MS (ESI): mass calcd. for C33H34F4N4O3, 610.26; m/z found, 611.3 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 6.71 (s, 1H), 6.00-5.97 (m, 1H), 5.95 (d, J=8.8 Hz, 1H), 5.59 (d, J=2.3 Hz, 1H), 5.38 (dd, J=8.8, 2.3 Hz, 1H), 5.07-4.97 (m, 2H), 3.96 (d, J=15.9 Hz, 1H), 3.80 (d, J=15.9 Hz, 1H), 3.68-3.59 (m, 2H), 3.22-3.16 (m, 1H), 2.21-2.15 (m, 1H), 1.93-1.83 (m, 2H), 1.74-1.66 (m, 2H), 1.35-1.28 (m, 1H), 0.87 (s, 3H), 0.83-0.72 (m, 1H), 0.50-0.35 (m, 5H), 0.32-0.14 (m, 4H), 0.01-0.14 (m, 2H).

Workup

  1. temperatureThe mixture was cooled to RT
  2. concentrationconcentrated to dryness
  3. custompurified by FCC

Sources & evidence

ORD record
ord-5044564729ca418aa529ce3224d602c4
Source dataset
uspto-grants-2015_02
Patent number
US08952177B2

Reaction notes

Loading…