Cesium carbonate → (S)-4-(Benzyloxy)-1-(1-(2-(3-fluoropyrrolidin-1-yl)ethyl)-1H-indazol-5-yl)pyridin-2(1H)-one

HRID 2387493Notes

Reaction equation

HRID 2387493 reaction equation
[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[NH:20][N:19]=[CH:18]3)[C:11](=[O:24])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:26][CH2:27][N:28]1[CH2:32][CH2:31][C@H:30]([F:33])[CH2:29]1.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O.O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[N:20]([CH2:26][CH2:27][N:28]2[CH2:32][CH2:31][C@H:30]([F:33])[CH2:29]2)[N:19]=[CH:18]3)[C:11](=[O:24])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1

Participants

6

Reactant 3

HCID 10796Cesium carbonateHCID 55298321HCID 55298321, compoundHCID 576255174-(benzyloxy)-1-(1H-indazol-5-yl)pyridin-2(1H)-one

Product 1

HCID 25054547(S)-4-(Benzyloxy)-1-(1-(2-(3-fluoropyrrolidin-1-yl)ethyl)-1H-indazol-5-yl)pyridin-2(1H)-oneYield 8.4%

Reagents, catalysts & solvents 2

HCID 679Dimethyl SulfoxideSolventHCID 962WaterSolvent

Procedure

To a solution of 4-(benzyloxy)-1-(1H-indazol-5-yl)pyridin-2(1H)-one (0.51 g, 1.6 mmol) in DMSO (5.0 mL) was added (S)-1-(2-chloroethyl)-3-fluoropyrrolidine (0.24 g, 1.6 mmol) and Cs2CO3 (3.1 g, 9.5 mmol). The reaction mixture was stirred at ambient temperature for 18 h, and then the reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (4×20 mL). The organic extracts were washed with brine (3×20 mL) and dried (Na2SO4). Purification by flash chromatography (silica gel, CH2Cl2/80:18:2 CH2Cl2/MeOH/NH4OH, 100.0 to 0:100), followed by additional flash column chromatography (silica gel, CH2Cl2/10% MeOH in CH2Cl2, 100:0 to 10:90), followed by treatment with activated charcoal, followed by final purification by preparative HPLC (Phenomenex Luna C18 (2), 250.0×21.2 mm, 10 micron, H2O with 0.05% TFA and CH3CN with 0.05% TFA) gave the title compound (58.3 mg, 8%) as a white powder: 1H NMR (500 MHz, CDCl3) δ 8.04 (s, 1H), 7.67 (d, J=1.5 Hz, 1H), 7.55 (d, J=9 Hz, 1H), 7.45-7.37 (m, 6H), 7.31-7.30 (m, 1H), 6.12-6.10 (m, 2H), 5.16 (dt, J=55.5, 4.5 Hz, 1H), 5.07 (s, 2H), 4.58 (t, J=7.0 Hz, 2H), 3.01 (br m, 2H), 2.97-2.93 (m, 2H) 2.92-2.90 (m, 1H), 2.56 (br s, 1H), 2.17-2.03 (m, 2H); ESI MS m/z 433 [M+H]+; HPLC (Method A)>99% (AUC), tR=13.9 min.

Workup

  1. extractionextracted with EtOAc (4×20 mL)
  2. washThe organic extracts were washed with brine (3×20 mL)
  3. dry with materialdried (Na2SO4)
  4. customPurification by flash chromatography (silica gel, CH2Cl2/80:18:2 CH2Cl2/MeOH/NH4OH, 100.0 to 0:100)
  5. custompurification by preparative HPLC (Phenomenex Luna C18 (2), 250.0×21.2 mm, 10 micron, H2O with 0.05% TFA and CH3CN with 0.05% TFA)

Sources & evidence

ORD record
ord-3493992c614d4f9ab83858d6e1ba5a1f
Source dataset
uspto-grants-2012_09
Patent number
US08268868B2

Reaction notes

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