Cesium carbonate → Methyl 4-(2-amino-2-oxoethoxy)-5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxybenzoate

HRID 1877638Notes

Reaction equation

HRID 1877638 reaction equation
[NH2:1][C:2](=[O:18])[CH2:3][O:4][C:5]1[C:14](Br)=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([O:16][CH3:17])[CH:6]=1.O1CCOCC1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[O:33][C:34]3[CH:44]=[CH:43][C:42](B4OC(C)(C)C(C)(C)O4)=[CH:41][C:35]=3[C:36]=2[C:37]([NH:39][CH3:40])=[O:38])=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(Cl)Cl.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.O>[NH2:1][C:2](=[O:18])[CH2:3][O:4][C:5]1[C:14]([C:42]2[CH:43]=[CH:44][C:34]3[O:33][C:32]([C:29]4[CH:28]=[CH:27][C:26]([F:25])=[CH:31][CH:30]=4)=[C:36]([C:37](=[O:38])[NH:39][CH3:40])[C:35]=3[CH:41]=2)=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([O:16][CH3:17])[CH:6]=1

Participants

8

Reactant 4

HCID 10796Cesium carbonateHCID 312751,4-DioxaneHCID 592754752-(4-fluorophenyl)-N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamideHCID 67210885Methyl 4-(2-amino-2-oxoethoxy)-5-bromo-2-methoxybenzoate

Product 1

HCID 59275516Methyl 4-(2-amino-2-oxoethoxy)-5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxybenzoateYield 33.9%

Reagents, catalysts & solvents 3

HCID 178418397HCID 178418397, compoundCatalystHCID 962WaterSolventHCID 6344DichloromethaneSolvent

Conditions

Temperature
85 °C

Procedure

To a sealed tube was added methyl 4-(2-amino-2-oxoethoxy)-5-bromo-2-methoxybenzoate (318 mg, 1.0 mmol), dioxane (30 mL), water (6.00 mL), 2-(4-fluorophenyl)-N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide (593 mg, 1.500 mmol), cesium carbonate (489 mg, 1.500 mmol), and tetrakis(triphenylphosphine)palladium(0) (23.11 mg, 0.020 mmol). The vessel was sealed and the mixture heated overnight at 85° C. The reaction mixture was cooled, diluted with 200 mL of DCM, washed sequentially with 50 mL of 1M HCl then brine. The product was extracted and the resulting yellow solution was evaporated to dryness. The aqueous layers were combined, cooled for 5 minutes in an ice bath and the solids that formed were filtered and dried under vacuum. The solids were then combined and triturated sequentially with diethyl ether then ice cold acetonitrile (10 mL each) giving 171.6 mgs (30% yield) of methyl 4-(2-amino-2-oxoethoxy)-5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxybenzoate as a white 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. HPLC purity was determined using a Shimadzu analytical LC at 254 nm and 256 nm with a Waters Sunfire C18 3.5 μm 4.6×150 mm column employing water/acetonitrile/0.1% trifluoroacetic acid with a gradient of 10-100% B (B=95% HPLC grade acetonitrile/0.1% trifluoroacetic acid/5% HPLC grade water), (A=95% HPLC grade water/0.1% trifluoroacetic acid/5% HPLC grade acetonitrile), in10 minutes with a 10 minute hold at a rate of 1 mL/minute. The HPLC purity was then confirmed with an orthogonal solvent system and column using a Shimadzu analytical LC with a Waters Phenyl XBridge C18 3.5 μm 4.6×150 mm column employing water/methanol/10 mM ammonium bicarbonate with a gradient of 10-100% B (B=95% HPLC grade methanol/10 mM ammonium bicarbonate/5% HPLC grade water), (A=95% HPLC grade water/10 mM ammonium bicarbonate/5% HPLC grade methanol), in 10 minutes with a 10 minute hold at a rate of 1 mL/minute. 1H NMR (400 MHz, CD3OD) δ ppm 3.04 (s, 3H), 3.92 (s, 3H), 4.03 (s, 3H), 4.71 (s, 2H), 6.85 (s, 1H), 7.33 (t, J=8.78 Hz, 2H), 7.57-7.64 (m, 1H), 7.66-7.73 (m, 1H), 7.87 (s, 1H), 7.96 (s, 1H), 8.00-8.08 (m, 2H). LCMS m/z 507.3 (M+H), Rt=2.635 min. HPLC Rt=8.193 min. (Sunfire C18), 100% purity and Rt=10.678 min. (Phenyl XBridge C18), 100% purity.

Workup

  1. customThe vessel was sealed
  2. temperatureThe reaction mixture was cooled
  3. washwashed sequentially with 50 mL of 1M HCl
  4. extractionThe product was extracted
  5. customthe resulting yellow solution was evaporated to dryness
  6. temperaturecooled for 5 minutes in an ice bath
  7. customthe solids that formed
  8. filtrationwere filtered
  9. customdried under vacuum
  10. customtriturated sequentially with diethyl ether

Sources & evidence

ORD record
ord-bdc2d4e4b8af4eb59bdf60ebe57c4461
Source dataset
uspto-grants-2012_11
Patent number
US08309558B2

Reaction notes

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