Cesium carbonate → 5-(6-Chloro-2-(4-fluorophenyl)-3-(methylcarbamoyl)furo[2,3-b]pyridin-5-yl)-2-fluorobenzoic acid

HRID 1854729Notes

Reaction equation

HRID 1854729 reaction equation
Br[C:2]1[CH:3]=[C:4]2[C:11]([C:12]([NH:14][CH3:15])=[O:13])=[C:10]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[O:9][C:5]2=[N:6][C:7]=1[Cl:8].B([C:26]1[CH:27]=[CH:28][C:29]([F:35])=[C:30]([CH:34]=1)[C:31]([OH:33])=[O:32])(O)O.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:8][C:7]1[N:6]=[C:5]2[O:9][C:10]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)=[C:11]([C:12](=[O:13])[NH:14][CH3:15])[C:4]2=[CH:3][C:2]=1[C:26]1[CH:27]=[CH:28][C:29]([F:35])=[C:30]([CH:34]=1)[C:31]([OH:33])=[O:32]

Participants

5

Reactant 3

HCID 10796Cesium carbonateHCID 27632423-Carboxy-4-fluorophenylboronic AcidHCID 904024175-bromo-6-chloro-2-(4-fluorophenyl)-N-methylfuro[2,3-b]pyridine-3-carboxamide

Product 1

HCID 904024345-(6-Chloro-2-(4-fluorophenyl)-3-(methylcarbamoyl)furo[2,3-b]pyridin-5-yl)-2-fluorobenzoic acidYield 69.2%

Reagents, catalysts & solvents 1

HCID 178418397HCID 178418397, compoundCatalyst

Conditions

Temperature
65 °C

Procedure

A mixture of 5-bromo-6-chloro-2-(4-fluorophenyl)-N-methylfuro[2,3-b]pyridine-3-carboxamide (3.0 g, 7.8 mmol), 5-borono-2-fluorobenzoic acid (1.58 g, 8.60 mmol), Pd(Ph3P)4 (0.90 g, 0.78 mmol) and cesium carbonate (3.82 g, 11.7 mmol) was evacuated and charged with N2 (3×) and then diluted with water (0.95 ml)/DMF (9.5 ml). The mixture was again evacuated and charged with N2 (3×) and heated to 65° C. under N2 atmosphere. The reaction was allowed to stir at 65° C. for 16 h. LCMS showed peak with the expected M+H. The mixture was diluted with EtOAc (30 mL) and washed with 1M HCl, and sat aq NaCl. The organic phase was dried over Na2SO4, filtered and concentrated to give solid which was triturated with DCM to give the expected product 5-(6-chloro-2-(4-fluorophenyl)-3-(methylcarbamoyl)furo[2,3-b]pyridin-5-yl)-2-fluorobenzoic acid (2.4 g, 5.4 mmol, 69% yield) consistent by LCMS and NMR. LC-MS retention time: 2.64 min; m/z (MH+): 443. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 3u C18 2.0×30 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 1 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 2 min, and an analysis time of 4 min where solvent A was 5% MeOH/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% MeOH/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode. 1H NMR (400 MHz, DMSO-d6) δ 13.46 (br. s, 1H), 8.55 (d, J=4.8 Hz, 1H), 8.21 (s, 1H), 8.10-8.04 (m, 2H), 8.00 (dd, J=7.0, 2.5 Hz, 1H), 7.82 (ddd, J=8.5, 4.5, 2.5 Hz, 1H), 7.52-7.39 (m, 3H), 2.82 (d, J=4.8 Hz, 3H).

Workup

  1. customwas evacuated
  2. additioncharged with N2 (3×)
  3. additiondiluted with water (0.95 ml)/DMF (9.5 ml)
  4. customThe mixture was again evacuated
  5. additioncharged with N2 (3×)
  6. additionThe mixture was diluted with EtOAc (30 mL)
  7. washwashed with 1M HCl
  8. dry with materialThe organic phase was dried over Na2SO4
  9. filtrationfiltered
  10. concentrationconcentrated
  11. customto give solid which
  12. customwas triturated with DCM

Sources & evidence

ORD record
ord-16452cb89e014fcaa80669ffe45902a6
Source dataset
uspto-grants-2015_02
Patent number
US08962651B2

Reaction notes

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