Dimethylacetamide → [(1-{2-Fluoro-4-[6-({[3-(trifluoromethyl)phenyl]acetyl}amino)pyridin-3-yl]phenyl}cyclobutyl)oxy]acetic acid

HRID 1397510Notes

Reaction equation

HRID 1397510 reaction equation
[F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([CH2:9][C:10]([NH:12][C:13]2[N:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=2)=[O:11])[CH:6]=[CH:7][CH:8]=1.Br[C:25]1[CH:30]=[CH:29][C:28]([C:31]2([O:35][CH2:36][C:37]([OH:39])=[O:38])[CH2:34][CH2:33][CH2:32]2)=[C:27]([F:40])[CH:26]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CN(C)C(=O)C>[Pd](Cl)Cl.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2].O.C(O)C>[F:40][C:27]1[CH:26]=[C:25]([C:16]2[CH:17]=[N:18][C:13]([NH:12][C:10](=[O:11])[CH2:9][C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:23])([F:22])[F:1])[CH:4]=3)=[CH:14][CH:15]=2)[CH:30]=[CH:29][C:28]=1[C:31]1([O:35][CH2:36][C:37]([OH:39])=[O:38])[CH2:34][CH2:33][CH2:32]1

Participants

8

Reactant 4

HCID 31374DimethylacetamideHCID 62657Potassium Phosphate, TribasicHCID 687205752-(1-(4-Bromo-2-fluorophenyl)cyclobutoxy)acetic acidHCID 687207776-({[3-(Trifluoromethyl)phenyl]acetyl}amino)pyridin-3-ylboronic acid

Product 1

HCID 25106327[(1-{2-Fluoro-4-[6-({[3-(trifluoromethyl)phenyl]acetyl}amino)pyridin-3-yl]phenyl}cyclobutyl)oxy]acetic acid

Reagents, catalysts & solvents 3

HCID 178454861HCID 178454861, compoundCatalystHCID 702EthanolSolventHCID 962WaterSolvent

Conditions

Temperature
90 °C

Procedure

A 4 mL vial was charged with the product from Example 61A (17.7 mg, 0.055 mmol) and the product from Example 60B (16.56 mg, 0.055 mmol), dibasic potassium phosphate (28.5 mg, 0.164 mmol), 1,1′-bis(di-tert-butylphosphino)ferrocene palladium (II) dichloride (0.357 mg, 0.546 μmol), N,N-dimethylacetamide (1 ml), ethanol (1.000 mL), and water (0.500 mL). The suspension was stirred and heated to 90° C., whereupon the reaction became homogenous. After heating at 90° C. for 1 hour, the reaction was cooled to room temperature. The reaction was then partitioned between with ethyl acetate (2 mL) and water (2 mL). The layers were separated, and the organic was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase HPLC (mobile phase: 10%-100% acetonitrile in 0.1% trifluoroacetic acid aqueous solution during 60 min, C18 column) to give the title product, 1H NMR (300 MHz, DMSO-d6) δ ppm 1.59-1.72 (m, 1 H), 1.95-2.07 (m, 1 H), 2.38-2.45 (m, 4 H), 3.65 (s, 2 H), 3.89 (s, 2 H), 7.46-7.52 (m, 1 H), 7.55-7.67 (m, 5 H), 7.73 (s, 1 H), 8.11-8.18 (m, 2 H), 8.73 (br s, 1 H), 10.94 (s, 1 H). MS (ESI) m/z 503 [M+H]+.

Workup

  1. temperatureAfter heating at 90° C. for 1 hour
  2. temperaturethe reaction was cooled to room temperature
  3. customThe reaction was then partitioned between with ethyl acetate (2 mL) and water (2 mL)
  4. customThe layers were separated
  5. dry with materialthe organic was dried over anhydrous sodium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated under reduced pressure
  8. customThe residue was purified by reverse-phase HPLC (mobile phase: 10%-100% acetonitrile in 0.1% trifluoroacetic acid aqueous solution during 60 min, C18 column)

Sources & evidence

ORD record
ord-18b82552c3bd43b2a1e99dcfb44958f2
Source dataset
uspto-grants-2014_12
Patent number
US08901152B2

Reaction notes

Loading…