Potassium Phosphate, Tribasic → Methyl 2'-carbamoyl-4-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)biphenyl-2-carboxylate

HRID 1025176Notes

Reaction equation

HRID 1025176 reaction equation
[C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1B(O)O)(=[O:3])[NH2:2].Cl[C:14]1[CH:23]=[CH:22][C:21]([C:24]2[CH:25]=[CH:26][C:27]3[O:31][C:30]([C:32]4[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=4)=[C:29]([C:39](=[O:42])[NH:40][CH3:41])[C:28]=3[CH:43]=2)=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17].P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.O1CCOCC1>[C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:14]1[C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:20][C:21]([C:24]2[CH:25]=[CH:26][C:27]3[O:31][C:30]([C:32]4[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=4)=[C:29]([C:39](=[O:42])[NH:40][CH3:41])[C:28]=3[CH:43]=2)=[CH:22][CH:23]=1)(=[O:3])[NH2:2]

Participants

8

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 2737809(2-Aminocarbonylphenyl)boronic acidHCID 112698722-Dicyclohexylphosphino-2',6'-dimethoxybiphenylHCID 59275297Methyl 2-chloro-5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzoate

Product 1

HCID 59275687Methyl 2'-carbamoyl-4-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)biphenyl-2-carboxylateYield 37.2%

Reagents, catalysts & solvents 3

HCID 167845palladium(II) acetateCatalystHCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
130 °C

Procedure

To a microwave vial was added dioxane (9 mL), water (0.900 mL), 2-carbamoylphenylboronic acid (148 mg, 0.900 mmol), methyl 2-chloro-5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzoate (131 mg, 0.3 mmol), tribasic potassium phosphate (255 mg, 1.200 mmol), dicyclohexyl (2′,6′-dimethoxybiphenyl-2-yl)phosphine (S-Phos, 24.63 mg, 0.060 mmol), and palladium(II) acetate (13.47 mg, 0.060 mmol). The vial was capped, degassed, flushed with N2 and heated in the microwave for 13 minutes at 130° C. The reaction mixture was filtered and solvent removed under a stream of nitrogen. The crude product was then taken up in 4 mL of acetonitrile and purified using a Shimadzu preparative HPLC employing acetonitrile/water/trifluoroacetic acid where solvent A was 10% acetonitrile/90% water/0.1% trifluoroacetic acid and solvent B was 10% water/90% acetonitrile/0.1% trifluoroacetic acid with a Waters Sunfire 5 μm C18 19×150 mm column at a gradient of 20-100% B and a flow rate of 25 mL/min. over 20 minutes with a 10 minute hold. The solvent was removed giving 58.3 mgs (36% yield) of methyl 2′-carbamoyl-4-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)biphenyl-2-carboxylate as a yellow solid. The LC/MS data was obtained on a Shimadzu analytical LC/Micromass Platform LC (ESI+) at 220 nm using the following set of conditions: Phenomenex Luna 3 μm C18, 2×50 mm column, with a gradient of 0-100% B (B=90% HPLC grade acetonitrile/0.1% trifluoroacetic acid/10% HPLC grade water), (A=90% HPLC grade water/0.1% trifluoroacetic acid/10% HPLC grade acetonitrile), in 4 minutes with a 1 minute hold at a rate of 0.8 mL/minute. 1H NMR (400 MHz, THF-d8) δ ppm 2.93 (d, J=4.52 Hz, 3 H), 3.62 (s, 3 H), 6.35 (br. s., 2 H), 7.09-7.15 (m, 1 H), 7.22 (t, J=8.91 Hz, 2 H), 7.31-7.43 (m, 3 H), 7.52 (d, J=4.27 Hz, 1 H), 7.58-7.71 (m, 3 H), 7.81 (dd, J=8.03, 2.01 Hz, 1 H), 8.01 (d, J=1.25 Hz, 1 H), 8.09-8.20 (m, 3 H). LCMS m/z 523.3 (M+H), Rt=3.051 min., 96% purity.

Workup

  1. customThe vial was capped
  2. customdegassed
  3. customflushed with N2
  4. filtrationThe reaction mixture was filtered
  5. customsolvent removed under a stream of nitrogen
  6. custompurified
  7. customThe solvent was removed

Sources & evidence

ORD record
ord-e85dcc10a33e4df680291d7eb79cdc2b
Source dataset
uspto-grants-2014_05
Patent number
US08722688B2

Reaction notes

Loading…