Tris(furan-2-yl)phosphane → 2,2-difluoro-N-((1R,2S)-3-fluoro-1-hydroxy-1-(4-(2-(methylsulfonamidomethyl)thiazolo[5,4-b]pyridin-6-yl)phenyl)propan-2-yl)-acetamide

HRID 525602Notes

Reaction equation

HRID 525602 reaction equation
Br[C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([CH2:11][NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[S:8][C:5]2=[N:6][CH:7]=1.[F:17][CH:18]([F:37])[C:19]([NH:21][C@H:22]([CH2:35][F:36])[C@H:23]([OH:34])[C:24]1[CH:29]=[CH:28][C:27]([Sn](C)(C)C)=[CH:26][CH:25]=1)=[O:20].O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1>CN(C)C=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:17][CH:18]([F:37])[C:19]([NH:21][C@H:22]([CH2:35][F:36])[C@H:23]([OH:34])[C:24]1[CH:25]=[CH:26][C:27]([C:2]2[CH:3]=[C:4]3[N:10]=[C:9]([CH2:11][NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[S:8][C:5]3=[N:6][CH:7]=2)=[CH:28][CH:29]=1)=[O:20]

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 86695490N-((6-bromothiazolo[5,4-b]pyridin-2-yl)methyl)methanesulfonamide

Product 1

HCID 866954922,2-difluoro-N-((1R,2S)-3-fluoro-1-hydroxy-1-(4-(2-(methylsulfonamidomethyl)thiazolo[5,4-b]pyridin-6-yl)phenyl)propan-2-yl)-acetamideYield 25.2%

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 962WaterSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
70 °C

Procedure

A mixture of N-((6-bromothiazolo[5,4-b]pyridin-2-yl)methyl)methanesulfonamide (236 mg, 0.732 mmol), 2,2-difluoro-N-((1R,2S)-3-fluoro-1-hydroxy-1-(4-(trimethylstannyl)phenyl)propan-2-yl)acetamide (300 mg, 0.0.732 mmol) and tris(2-furyl)phosphine (34 mg, 0.146 mmol) and Tris(dibenzylideneacetone)dipalladium(0) (68 mg, 0.0732 mmol) in dimethylformamide (3 mL) is heated at 70° C. for 5 hours under nitrogen. The mixture is then cooled, diluted with water (10 mL) and extracted with ethyl acetate (3×15 mL). Extracts are dried over Na2SO4 and concentrated to get crude product. Obtained product purified by HPLC to give the title compound (90 mg): 1HNMR (DMSO-d6): 3.07 (s, 3H), 4.27-4.39 (m, 1.5H), 4.40-4.48 (m, 0.5H), 4.52-4.60 (m, 0.5H), 4.64-4.71 (m, 2.5H) 4.88-4.94 (m, 1H), 6.22 (t, 1H), 7.50 (d, 2H), 7.83 (d, 2H), 8.22-8.33 (m, 1H), 8.62 (bs, 1H), 8.85 (d, 1H), 8.94 (s, 1H). m/z (Cl) M+H 489.

Workup

  1. temperatureThe mixture is then cooled
  2. extractionextracted with ethyl acetate (3×15 mL)
  3. dry with materialExtracts are dried over Na2SO4
  4. concentrationconcentrated
  5. customto get crude product
  6. customObtained product purified by HPLC

Sources & evidence

ORD record
ord-f98ed3e66f754d70b6355458d2cfa1da
Source dataset
uspto-grants-2016_05
Patent number
US09340564B2

Reaction notes

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