Tris(furan-2-yl)phosphane → 2,2-Difluoro-N-[(1S,2R)-1-fluoromethyl-2-hydroxy-2-(4-{6-[(methanesulfonyl-methoxy-amino)-methyl]-pyridin-3-yl}-phenyl)-ethyl]-acetamide

HRID 1520470Notes

Reaction equation

HRID 1520470 reaction equation
Br[C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]([O:14][CH3:15])[S:10]([CH3:13])(=[O:12])=[O:11])=[N:6][CH:7]=1.[F:16][CH:17]([F:36])[C:18]([NH:20][C@H:21]([CH2:34][F:35])[C@H:22]([OH:33])[C:23]1[CH:28]=[CH:27][C:26]([Sn](C)(C)C)=[CH:25][CH:24]=1)=[O:19].O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1>CN1CCCC1=O.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:16][CH:17]([F:36])[C:18]([NH:20][C@H:21]([CH2:34][F:35])[C@H:22]([OH:33])[C:23]1[CH:24]=[CH:25][C:26]([C:2]2[CH:7]=[N:6][C:5]([CH2:8][N:9]([S:10]([CH3:13])(=[O:12])=[O:11])[O:14][CH3:15])=[CH:4][CH:3]=2)=[CH:27][CH:28]=1)=[O:19]

Participants

7

Reactant 3

HCID 521585Tris(furan-2-yl)phosphaneHCID 866954252,2-Difluoro-N-[(1S,2R)-1-fluoromethyl-2-hydroxy-2-(4-trimethylstannanyl-phenyl)-ethyl]-acetamideHCID 86695426N-(5-Bromo-pyridin-2-ylmethyl)-N-methoxy-methane sulfonamide

Product 1

HCID 866954272,2-Difluoro-N-[(1S,2R)-1-fluoromethyl-2-hydroxy-2-(4-{6-[(methanesulfonyl-methoxy-amino)-methyl]-pyridin-3-yl}-phenyl)-ethyl]-acetamideYield 16%

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 962WaterSolventHCID 13387N-methyl-2-pyrrolidoneSolvent

Conditions

Temperature
80 °C

Procedure

To a stirred solution of N-(5-Bromo-pyridin-2-ylmethyl)-N-methoxy-methane sulfonamide (0.2 g, 0.678 mmol) in N-Methyl-2-pyrrolidone (8 mL) is added and 2,2-Difluoro-N-[(1S,2R)-1-fluoromethyl-2-hydroxy-2-(4-trimethylstannanyl-phenyl)ethyl]-acetamide (0.27 g, 0.678 mmol). Reaction mixture is degassed with nitrogen for 15 minutes then added tris(dibenzylideneacetone)dipalladium(0) (0.06 mg, 0.068 mmol) and Tri-2-furylphosphine (0.03 g, 0.136 mmol) simultaneously. The resulting reaction mixture is stirred at 80° C. for 5 hours. Diluted with water and extracted with ethyl acetate. Organic layer is dried over sodium sulphate, solvent is evaporated in vacuo and purified by combi-flash using 50% ethyl acetate in hexane as an eluent to afford the title compound (0.05 g). 1HNMR (400 MHz, DMSO-d6) δ: 3.16 (s, 3H), 3.49 (s, 3H), 4.30-4.37 (m, 1.5H), 4.41-4.46 (m, 0.5H), 4.46 (s, 2H), 4.54-4.56 (m, 0.5H), 4.65-4.68 (m, 0.5H), 4.89 (m, 1H), 5.94 (d, J=4.2 Hz, 1H), 6.20 (t, J=53.76 Hz, 1H), 7.47 (d, J=8.2 Hz, 2H), 7.59 (d, J=8.16 Hz, 1H), 7.74 (d, J=8.2 Hz, 2H), 8.14-8.16 (dd, J1=2.32 Hz, J2=8.16 Hz, 1H), 8.86 (d, J=8.72 Hz, 1H), 8.91 (d, J=2.08 Hz, 1H). LCMS (m/z): [M+H]=461.9.

Workup

  1. customReaction mixture
  2. customis degassed with nitrogen for 15 minutes
  3. customThe resulting reaction mixture
  4. extractionextracted with ethyl acetate
  5. dry with materialOrganic layer is dried over sodium sulphate, solvent
  6. customis evaporated in vacuo
  7. custompurified by combi-flash

Sources & evidence

ORD record
ord-3037f8af53164cfaa9c7e3805b935552
Source dataset
uspto-grants-2015_07
Patent number
US09073894B2

Reaction notes

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