Potassium Phosphate, Tribasic → Ethyl (2R)-4-{5-fluoro-2-oxo-4-[4-(2H-1,2,3-triazol-2-yl)phenyl]pyridin-1(2H)-yl}-2-methyl-2-(methylsulfonyl)butanoate

HRID 468645Notes

Reaction equation

HRID 468645 reaction equation
[F:1][C:2]1[C:3](I)=[CH:4][C:5](=[O:21])[N:6]([CH2:8][CH2:9][C@@:10]([CH3:20])([S:16]([CH3:19])(=[O:18])=[O:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:7]=1.CC1(C)C(C)(C)OB([C:31]2[CH:36]=[CH:35][C:34]([N:37]3[N:41]=[CH:40][CH:39]=[N:38]3)=[CH:33][CH:32]=2)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CC1CCCO1.O.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:1][C:2]1[C:3]([C:31]2[CH:36]=[CH:35][C:34]([N:37]3[N:41]=[CH:40][CH:39]=[N:38]3)=[CH:33][CH:32]=2)=[CH:4][C:5](=[O:21])[N:6]([CH2:8][CH2:9][C@@:10]([CH3:20])([S:16]([CH3:19])(=[O:18])=[O:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:7]=1

Participants

8

Reactant 3

HCID 62657Potassium Phosphate, TribasicHCID 67249679Ethyl (2R)-4-(5-fluoro-4-iodo-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanoateHCID 672515672-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2H-1,2,3-triazole

Product 1

HCID 86670651Ethyl (2R)-4-{5-fluoro-2-oxo-4-[4-(2H-1,2,3-triazol-2-yl)phenyl]pyridin-1(2H)-yl}-2-methyl-2-(methylsulfonyl)butanoateYield 67.4%

Reagents, catalysts & solvents 4

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 962WaterSolvent2×HCID 73012-MethyltetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
60 °C

Procedure

Pd(dppf)Cl2 (484 mg, 0.59 mmol) was added to a mixture of ethyl (2R)-4-(5-fluoro-4-iodo-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanoate, T2, (2.20 g, 4.94 mmol), 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2H-1,2,3-triazole (2.01 g, 7.41 mmol), and potassium phosphate (3.95 g, 14.8 mmol) in 2-methyltetrahydrofuran (200 mL) and deionized water (40 mL). The reaction was heated to 60° C. and was vigorously stirred at this temperature overnight. The reaction was diluted with EtOAc (100 mL) and water (100 mL) and was filtered through a celite pad (˜1 inch). The filter pad was washed with EtOAc (100 mL) and the filtrates were combined. The aqueous layer was separated and was extracted with EtOAc (2×100 mL). The combined organics were washed with brine (100 mL), dried (MgSO4), filtered and concentrated. The crude material was purified via flash chromatography using a Varian SF25-40 g column and an eluent of EtOAc in hexanes (30-100%) to afford the title compound as a yellow solid (1.54 g, 67.4%). MS (LCMS) m/z 463.0 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.23 (t, 3H) 1.62 (s, 3H) 2.18-2.32 (m, 1H) 2.52-2.66 (m, 1H) 3.16 (s, 3H) 3.92-4.07 (m, 2H) 4.08-4.24 (m, 2H) 6.59 (d, J=7.81 Hz, 1H) 7.72-7.84 (m, 2H) 8.10 (d, J=6.63 Hz, 1H) 8.12-8.17 (m, 2H) 8.18 (s, 2H).

Workup

  1. filtrationwas filtered through a celite pad (˜1 inch)
  2. washThe filter pad was washed with EtOAc (100 mL)
  3. customThe aqueous layer was separated
  4. extractionwas extracted with EtOAc (2×100 mL)
  5. washThe combined organics were washed with brine (100 mL)
  6. dry with materialdried (MgSO4)
  7. filtrationfiltered
  8. concentrationconcentrated
  9. customThe crude material was purified via flash chromatography

Sources & evidence

ORD record
ord-dca7c565ae7848afb167b2c0c84db1e2
Source dataset
uspto-grants-2014_01
Patent number
US08624034B2

Reaction notes

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