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

HRID 1051745Notes

Reaction equation

HRID 1051745 reaction equation
[F:1][C@@H:2]1[C@@H:7](OS(C)(=O)=O)[CH2:6][CH2:5][N:4]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:3]1.[CH:20]1([O:24][C:25]2[C:34]([C:35]3[CH:36]=[N:37][NH:38][CH:39]=3)=[CH:33][CH:32]=[C:31]3[C:26]=2[CH2:27][CH2:28][C@H:29]([CH3:44])[N:30]3[C:40]([O:42][CH3:43])=[O:41])[CH2:23][CH2:22][CH2:21]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[C:16]([O:15][C:13]([N:4]1[CH2:5][CH2:6][C@@H:7]([N:37]2[CH:36]=[C:35]([C:34]3[C:25]([O:24][CH:20]4[CH2:21][CH2:22][CH2:23]4)=[C:26]4[C:31](=[CH:32][CH:33]=3)[N:30]([C:40]([O:42][CH3:43])=[O:41])[C@@H:29]([CH3:44])[CH2:28][CH2:27]4)[CH:39]=[N:38]2)[C@@H:2]([F:1])[CH2:3]1)=[O:14])([CH3:19])([CH3:18])[CH3:17]

Participants

6

Reactant 3

HCID 10796Cesium carbonateHCID 52324472(3S,4S)-tert-Butyl 3-fluoro-4-((methylsulfonyl)oxy)piperidine-1-carboxylateHCID 118075439(S)-methyl 5-cyclobutoxy-2-methyl-6-(1H-pyrazol-4-yl)-3,4-dihydroquinoline-1 (2H)-carboxylate

Product 1

HCID 118076351(S)-methyl 6-(1-((3 S,4R)-1-(tert-butoxycarbonyl)-3-fluoropiperidin-4-yl)-1H-pyrazol-4-yl)-5-cyclobutoxy-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylateYield 56%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
100 °C

Procedure

(3S,4S)-tert-Butyl 3-fluoro-4-((methylsulfonyl)oxy)piperidine-1-carboxylate (96 mg, 0.322 mmol) was added to a solution of (S)-methyl 5-cyclobutoxy-2-methyl-6-(1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate (100 mg, 0.293 mmol) and cesium carbonate (153 mg, 0.469 mmol) in DMF (1.0 mL), and the reaction mixture was heated at 100° C. for 1 hour. The reaction solution was cooled to room temperature, diluted with water and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with water (2×25 mL) and brine (25 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified via column chromatography on silica gel (Biotage 25 g column, gradient elution with 20-30% ethyl acetate in hexanes) to afford methyl (S)-6-(1-((3S,4R)-1-(tert-butoxycarbonyl)-3-fluoropiperidin-4-yl)-1H-pyrazol-4-yl)-5-cyclobutoxy-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate (89 mg, 56%) as a colorless oil. MS (ESI, pos. ion) m/z 543 [M+H]+.

Workup

  1. temperatureThe reaction solution was cooled to room temperature
  2. extractionextracted with ethyl acetate (3×50 mL)
  3. washThe combined organic layers were washed with water (2×25 mL) and brine (25 mL)
  4. dry with materialdried over anhydrous sodium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated in vacuo
  7. customThe crude product was purified via column chromatography on silica gel (Biotage 25 g column, gradient elution with 20-30% ethyl acetate in hexanes)

Sources & evidence

ORD record
ord-8cfd67ab36874152a949c9af7c06bf3a
Source dataset
uspto-grants-2016_07
Patent number
US09388161B2

Reaction notes

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