Acetone cardice → (3-(4-(1H-Pyrazol-1-yl)benzyl)-4-chloro-2-methoxyquinolin-6-yl)bis(1-methyl-1H-1,2,3-triazol-5-yl)methanol

HRID 928844Notes

Reaction equation

HRID 928844 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]CCCC.[CH3:32][N:33]1[C:37]([C:38]([C:40]2[N:44]([CH3:45])[N:43]=[N:42][CH:41]=2)=[O:39])=[CH:36][N:35]=[N:34]1.C(=O)=O.CC(C)=O>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]([C:37]3[N:33]([CH3:32])[N:34]=[N:35][CH:36]=3)([C:40]3[N:44]([CH3:45])[N:43]=[N:42][CH:41]=3)[OH:39])=[CH:16][CH:15]=4)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1

Participants

6

Reactant 4

HCID 18522661Acetone cardiceHCID 867155963-(4-(1H-Pyrazol-1-yl)benzyl)-6-bromo-4-chloro-2-methoxyquinoline2×HCID 86715669bis(1-methyl-1H-1,2,3-triazol-5-yl)methanone2×HCID 178418339Butyllithium

Product 1

HCID 74220947(3-(4-(1H-Pyrazol-1-yl)benzyl)-4-chloro-2-methoxyquinolin-6-yl)bis(1-methyl-1H-1,2,3-triazol-5-yl)methanol

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

A solution of 3-(4-(1H-pyrazol-1-yl)benzyl)-6-bromo-4-chloro-2-methoxyquinoline (0.271 g, 0.632 mmol; Intermediate 16) in THF (6 mL) was stirred under argon at ˜−70° C. while n-BuLi (1.63 M in hexanes, 0.368 mL, 0.6 mmol) was added dropwise by syringe over 1 minute. After another 2 minutes, a solution of bis(1-methyl-1H-1,2,3-triazol-5-yl)methanone (0.128 g, 0.664 mmol; Intermediate 43) in THF (6 mL) was added dropwise over 2 minutes, and the reaction was allowed to warm to room temperature overnight as the dry ice/acetone bath slowly warmed (11 hours). The resulting yellow mixture was quenched in one portion at 0° C. with 5 M aqueous NH4Cl (1 mL), and the organic layer was dried (Na2SO4), filtered, and concentrated. The residue was dry load flash chromatographed with a DCM to 100% EtOAc gradient to yield the impure title compound. This was then triturated from ˜0.5 mL DMSO+˜2 mL MeOH at 70° C., and the opaque milky mixture was allowed to cool to room temperature, filtered, and the white filter cake washed with MeOH (2×2 mL). The filter cake was air dried at 110° C. to provide the title compound as a white powder. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.41 (d, J=2.53 Hz, 1H), 8.16 (d, J=2.02 Hz, 1H), 7.96 (s, 1H), 7.90 (d, J=8.59 Hz, 1H), 7.74 (s, 1H), 7.71 (d, J=4.55 Hz, 2H), 7.46 (dd, J=2.27, 8.84 Hz, 1H), 7.36 (d, J=8.59 Hz, 2H), 7.19 (s, 2H), 6.51 (s, 1H), 4.30 (s, 2H), 4.06 (s, 3H), 3.84 (s, 6H); MS m/e 542.3 [M+H]+.

Workup

  1. additionwas added dropwise by syringe over 1 minute
  2. temperatureslowly warmed (11 hours)
  3. customThe resulting yellow mixture was quenched in one portion at 0° C. with 5 M aqueous NH4Cl (1 mL)
  4. dry with materialthe organic layer was dried (Na2SO4)
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customThe residue was dry load flash
  8. customchromatographed with a DCM to 100% EtOAc gradient

Sources & evidence

ORD record
ord-f81661cb3b7d451c92b6643cde3d7e83
Source dataset
uspto-grants-2016_03
Patent number
US09290476B2

Reaction notes

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