Cesium carbonate → methyl (S)-6-(1-(1-(tert-butoxycarbonyl)azetidin-3-yl)-1H-pyrazol-4-yl)-5-cyclobutoxy-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate

HRID 1051657Notes

Reaction equation

HRID 1051657 reaction equation
Br[C:2]1[C:3]([O:17][CH:18]2[CH2:21][CH2:20][CH2:19]2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]([O:14][CH3:15])=[O:13])[C@@H:7]([CH3:16])[CH2:6][CH2:5]2.CC1(C)C(C)(C)OB([C:30]2[CH:31]=[N:32][N:33]([CH:35]3[CH2:38][N:37]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:36]3)[CH:34]=2)O1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O>[C:42]([O:41][C:39]([N:37]1[CH2:38][CH:35]([N:33]2[CH:34]=[C:30]([C:2]3[C:3]([O:17][CH:18]4[CH2:21][CH2:20][CH2:19]4)=[C:4]4[C:9](=[CH:10][CH:11]=3)[N:8]([C:12]([O:14][CH3:15])=[O:13])[C@@H:7]([CH3:16])[CH2:6][CH2:5]4)[CH:31]=[N:32]2)[CH2:36]1)=[O:40])([CH3:45])([CH3:43])[CH3:44]

Participants

6

Reactant 3

HCID 10796Cesium carbonateHCID 54576812tert-Butyl 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]azetidine-1-carboxylateHCID 118075694(S)-methyl 6-bromo-5-cyclobutoxy-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate

Product 1

HCID 118086210methyl (S)-6-(1-(1-(tert-butoxycarbonyl)azetidin-3-yl)-1H-pyrazol-4-yl)-5-cyclobutoxy-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylateYield 104.6%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

A mixture of methyl (S)-6-bromo-5-cyclobutoxy-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate (0.096 g, 0.254 mmol), tert-butyl 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate (0.113 g, 0.325 mmol), and cesium carbonate (0.264 g, 0.811 mmol) in dioxane (2.0 mL) and water (0.40 mL) was purged with nitrogen to remove any oxygen. XPhos Precatalyst 2nd Generation (0.020 g, 0.027 mmol) was added and the reaction was purged with nitrogen and then heated at 100° C. for 16 h. The reaction mixture was concentrated and the residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The aqueous phase was separated and extracted with ethyl acetate, and the combined organic phases were concentrated to afford an oil. This material was purified via column chromatography on silica gel (Biotage 10 g column, gradient elution with 25-50% ethyl acetate-hexane) to afford methyl (S)-6-(1-(1-(tert-butoxycarbonyl)azetidin-3-yl)-1H-pyrazol-4-yl)-5-cyclobutoxy-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate (0.132 g, 98%) as a colorless oil. MS (ESI, pos. ion) m/z 497 [M+H]+.

Workup

  1. customwas purged with nitrogen
  2. customto remove any oxygen
  3. additionXPhos Precatalyst 2nd Generation (0.020 g, 0.027 mmol) was added
  4. customthe reaction was purged with nitrogen
  5. concentrationThe reaction mixture was concentrated
  6. customthe residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution
  7. customThe aqueous phase was separated
  8. extractionextracted with ethyl acetate
  9. concentrationthe combined organic phases were concentrated
  10. customto afford an oil
  11. customThis material was purified via column chromatography on silica gel (Biotage 10 g column, gradient elution with 25-50% ethyl acetate-hexane)

Sources & evidence

ORD record
ord-dd046cdffda046a58d405a8b6bc1365e
Source dataset
uspto-grants-2016_07
Patent number
US09388161B2

Reaction notes

Loading…