tert-Butyl 4-(1-methyl-1H-imidazole-5-carbonyl)piperidine-1-carboxylate → HCID 86715668, compound

HRID 928843Notes

Reaction equation

HRID 928843 reaction equation
[N:1]1([C:6]2[CH:26]=[CH:25][C:9]([CH2:10][C:11]3[C:12]([O:23][CH3:24])=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17](Br)=[CH:16][CH:15]=4)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[Li][CH2:28]CCC.[CH3:32][N:33]1[C:37]([C:38]([CH:40]2[CH2:45][CH2:44][N:43]([C:46]([O:48]C(C)(C)C)=O)[CH2:42][CH2:41]2)=[O:39])=[CH:36][N:35]=[CH:34]1>C1COCC1>[N:1]1([C:6]2[CH:26]=[CH:25][C:9]([CH2:10][C:11]3[C:12]([O:23][CH3:24])=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17]([C:38]([OH:39])([C:37]3[N:33]([CH3:32])[CH:34]=[N:35][CH:36]=3)[CH:40]3[CH2:45][CH2:44][N:43]([C:46](=[O:48])[CH3:28])[CH2:42][CH2:41]3)=[CH:16][CH:15]=4)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1

Participants

5

Reactant 3

HCID 66677755tert-Butyl 4-(1-methyl-1H-imidazole-5-carbonyl)piperidine-1-carboxylate2×HCID 867155963-(4-(1H-Pyrazol-1-yl)benzyl)-6-bromo-4-chloro-2-methoxyquinoline2×HCID 178418339Butyllithium

Product 1

HCID 86715668HCID 86715668, compound

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

A solution of 3-(4-(1H-pyrazol-1-yl)benzyl)-6-bromo-4-chloro-2-methoxyquinoline (0.558 g, 1.30 mmol; Intermediate 16) in THF (13 mL) was stirred under argon at ˜−70° C. while n-BuLi (2.56 M in hexanes, 0.484 mL, 1.24 mmol) was added dropwise over 1.5 minutes. After another 2.5 minutes, a solution of 1-(4-(1-methyl-1H-imidazole-5-carbonyl)piperidin-1-yl)ethanone (0.322 g, 1.37 mmol, Intermediate 42: step c) in THF (4.5 mL) was added dropwise over 2.5 minutes, and the dark mixture was stirred in the cold bath for another 5 minutes. The dry ice/acetone bath was then removed and the reaction stirred for 5 minutes under ambient conditions before transferring to an ice bath. After stirring for 2.5 hours at ˜0° C., the reaction was quenched with 5 M aqueous NH4Cl (2 mL) and the organic layer was dried (Na2SO4), filtered, and concentrated. The residue was flash chromatographed with a DCM to 10% MeOH/DCM gradient to provide the title compound as a light yellow foam. 1H NMR (400 MHz, CDCl3) (two conformers) δ ppm 8.17 (br. s, ˜0.5H), 8.12 (br. s, ˜0.5H), 7.85 (d, J=2.53 Hz, 1H), 7.76 (dd, J=2.78, 8.84 Hz, 1H), 7.67 (s, 1H), 7.57 (d, J=8.59 Hz, 2H), 7.44-7.36 (m, 3H), 7.21 (d, J=5.05 Hz, 1H), 7.10 (s, 1H), 6.43 (d, J=2.02 Hz, 1H), 4.71 (d, J=13.14 Hz, ˜0.5H), 4.47-4.61 (m, ˜0.5H), 4.32 (s, 2H), 4.08 (s, 3H), 3.89 (d, J=13.41 Hz, ˜0.5H), 3.69 (d, J=13.14 Hz, ˜0.5H), 3.25 (s, ˜1.5H), 3.21 (s, ˜1.5H), 3.10-3.18 (m, ˜0.5H), 2.87-3.00 (m, ˜0.5H), 2.60 (t, J=12.13 Hz, ˜0.5H), 2.35-2.51 (m, ˜1.5H), 2.29 (d, J=13.40 Hz, ˜0.5H), 2.21 (d, J=13.14 Hz, ˜0.5H), 2.00 (s, ˜1.5H), 1.95 (s, ˜1.5H), 1.10-1.46 (m, 3H). MS m/e 585.3 [M+H]+.

Workup

  1. additionwas added dropwise over 1.5 minutes
  2. customThe dry ice/acetone bath was then removed
  3. stirringthe reaction stirred for 5 minutes under ambient conditions
  4. custombefore transferring to an ice bath
  5. stirringAfter stirring for 2.5 hours at ˜0° C.
  6. customthe reaction was quenched with 5 M aqueous NH4Cl (2 mL)
  7. dry with materialthe organic layer was dried (Na2SO4)
  8. filtrationfiltered
  9. concentrationconcentrated
  10. customchromatographed with a DCM to 10% MeOH/DCM gradient

Sources & evidence

ORD record
ord-cb27173b945642a4bcd680ae819e8c1c
Source dataset
uspto-grants-2016_03
Patent number
US09290476B2

Reaction notes

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