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

HRID 1877641Notes

Reaction equation

HRID 1877641 reaction equation
C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.Cl[C:31]1[CH:40]=[CH:39][C:38]([C:41]2[CH:42]=[CH:43][C:44]3[O:48][C:47]([C:49]4[CH:54]=[CH:53][C:52]([F:55])=[CH:51][CH:50]=4)=[C:46]([C:56](=[O:59])[NH:57][CH3:58])[C:45]=3[CH:60]=2)=[CH:37][C:32]=1[C:33]([O:35][CH3:36])=[O:34].P([O-])([O-])([O-])=O.[K+].[K+].[K+].[Cl:69][C:70]1[CH:75]=[CH:74][CH:73]=[CH:72][C:71]=1B(O)O>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.O1CCOCC1>[Cl:69][C:70]1[CH:75]=[CH:74][CH:73]=[CH:72][C:71]=1[C:31]1[C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:37][C:38]([C:41]2[CH:42]=[CH:43][C:44]3[O:48][C:47]([C:49]4[CH:50]=[CH:51][C:52]([F:55])=[CH:53][CH:54]=4)=[C:46]([C:56](=[O:59])[NH:57][CH3:58])[C:45]=3[CH:60]=2)=[CH:39][CH:40]=1

Participants

9

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 27343222-Chlorophenylboronic acidHCID 112698722-Dicyclohexylphosphino-2',6'-dimethoxybiphenylHCID 59275297Methyl 2-chloro-5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzoate

Product 1

HCID 59275458Methyl 2'-chloro-4-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)biphenyl-2-carboxylateYield 80%

Reagents, catalysts & solvents 4

HCID 167845palladium(II) acetateCatalystHCID 962WaterSolventHCID 6342AcetonitrileSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
130 °C

Procedure

To a microwave vial was added dioxane (6 mL), water (0.600 mL), dicyclohexyl(2′,6′-dimethoxy biphenyl-2-yl)phosphine (S-Phos, 16.42 mg, 0.040 mmol), methyl 2-chloro-5-(2-(4-fluorophenyl)-3-(methyl carbamoyl)benzofuran-5-yl)benzoate (87.6 mg, 0 2 mmol), tribasic potassium phosphate (0.170 g, 0.800 mmol), palladium(II) acetate (8.98 mg, 0.040 mmol), and 2-chlorophenylboronic acid (0.094 g, 0.600 mmol). The vial was capped, degassed, flushed with N2 and heated in the microwave for 10 minutes at 130° C. The solvent was removed and the crude reaction mixture was 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 to give 43.8 mgs (80% yield) of methyl 2′-chloro-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 2.92-2.97 (m, 3H), 3.60-3.62 (m, 3H), 7.19-7.26 (m, 2H), 7.27-7.34 (m, 3H), 7.37 (d, J=8.03 Hz, 1H), 7.41-7.45 (m, 1H), 7.46-7.52 (m, 1H), 7.62-7.67 (m, 1H), 7.68-7.73 (m, 1H), 7.92 (dd, J=7.91, 2.13 Hz, 1H), 8.05 (d, J=1.25 Hz, 1H), 8.12-8.19 (m, 2H), 8.29 (d, J=2.01 Hz, 1H). LCMS m/z 514.2 (M+H), Rt=3.908 min., 93% purity.

Workup

  1. customThe vial was capped
  2. customdegassed
  3. customflushed with N2
  4. customThe solvent was removed
  5. customthe crude reaction mixture
  6. custompurified
  7. customThe solvent was removed

Sources & evidence

ORD record
ord-ba67373d8ef848bfac110bdbff1c49f1
Source dataset
uspto-grants-2012_11
Patent number
US08309558B2

Reaction notes

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