(6-Methoxypyridin-3-yl)(thiazol-5-yl)methanone → (3-(4-(1H-Pyrazol-1-yl)benzyl)-4-chloro-2-methoxyquinolin-6-yl)(6-methoxypyridin-3-yl)(thiazol-5-yl)methanol

HRID 928831Notes

Reaction equation

HRID 928831 reaction equation
C([Li])CCC.[N:6]1([C:11]2[CH:31]=[CH:30][C:14]([CH2:15][C:16]3[C:17]([O:28][CH3:29])=[N:18][C:19]4[C:24]([C:25]=3[Cl:26])=[CH:23][C:22](Br)=[CH:21][CH:20]=4)=[CH:13][CH:12]=2)[CH:10]=[CH:9][CH:8]=[N:7]1.[CH3:32][O:33][C:34]1[N:39]=[CH:38][C:37]([C:40]([C:42]2[S:46][CH:45]=[N:44][CH:43]=2)=[O:41])=[CH:36][CH:35]=1>C1COCC1>[N:6]1([C:11]2[CH:31]=[CH:30][C:14]([CH2:15][C:16]3[C:17]([O:28][CH3:29])=[N:18][C:19]4[C:24]([C:25]=3[Cl:26])=[CH:23][C:22]([C:40]([C:37]3[CH:38]=[N:39][C:34]([O:33][CH3:32])=[CH:35][CH:36]=3)([C:42]3[S:46][CH:45]=[N:44][CH:43]=3)[OH:41])=[CH:21][CH:20]=4)=[CH:13][CH:12]=2)[CH:10]=[CH:9][CH:8]=[N:7]1

Participants

5

Reactant 3

HCID 86715595(6-Methoxypyridin-3-yl)(thiazol-5-yl)methanone2×HCID 867155963-(4-(1H-Pyrazol-1-yl)benzyl)-6-bromo-4-chloro-2-methoxyquinoline2×HCID 178418339Butyllithium

Product 1

HCID 86715663(3-(4-(1H-Pyrazol-1-yl)benzyl)-4-chloro-2-methoxyquinolin-6-yl)(6-methoxypyridin-3-yl)(thiazol-5-yl)methanol

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
0 °C

Procedure

n-Butyllithium (0.154 mL, 0.246 mmol; 1.6 M in hexane) was added dropwise to a solution of 3-(4-(1H-pyrazol-1-yl)benzyl)-6-bromo-4-chloro-2-methoxyquinoline (0.081 g, 0.189 mmol, Intermediate 16) in dry THF (4 mL) at −78° C. over a 5 minute period. After complete addition stirring was continued at −78° C. for 30 minutes then (6-methoxypyridin-3-yl)(thiazol-5-yl)methanone (0.046 g, 0.189 mmol, Intermediate 15) dissolved in THF (1.9 mL) was slowly added and the reaction warmed in an ice bath to 0° C. The mixture was stirred for 30 minutes, quenched with saturated aqueous NH4Cl then warmed to room temperature. After stirring for 10 minutes layers were separated and the aqueous layer extracted with EtOAc. The combined organic extracts were dried over Na2SO4, filtered, evaporated in vacuo and chromatographed (0-100% EtOAc in DCM) to provide the title compound. 1H NMR (400 MHz, MeOH-d4) δ ppm 3.94 (s, 3H) 4.08 (s, 3H) 4.35 (s, 2H) 6.43-6.52 (m, 1H) 6.88 (d, J=9.09 Hz, 1H) 7.37 (d, J=8.08 Hz, 2H) 7.54-7.63 (m, 3H) 7.66-7.72 (m, 2H) 7.77 (dd, J=8.59, 2.53 Hz, 1H) 7.85 (d, J=8.59 Hz, 1H) 8.12 (dd, J=13.14, 2.53 Hz, 2H) 8.20 (s, 1H) 9.08 (s, 1H); MS (ESI) 570.

Workup

  1. additionAfter complete addition
  2. additionwas slowly added
  3. stirringThe mixture was stirred for 30 minutes
  4. customquenched with saturated aqueous NH4Cl
  5. temperaturethen warmed to room temperature
  6. stirringAfter stirring for 10 minutes layers
  7. customwere separated
  8. extractionthe aqueous layer extracted with EtOAc
  9. dry with materialThe combined organic extracts were dried over Na2SO4
  10. filtrationfiltered
  11. customevaporated in vacuo
  12. customchromatographed (0-100% EtOAc in DCM)

Sources & evidence

ORD record
ord-fb267525925642e2b5b74c9725a11b7a
Source dataset
uspto-grants-2016_03
Patent number
US09290476B2

Reaction notes

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