Nitrogen → Methyl 5-(6-chloro-2-(4-fluorophenyl)-3-(methylcarbamoyl)furo[2,3-b]pyridin-5-yl)-2-methoxynicotinate

HRID 1854733Notes

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].[CH3:23][O:24][C:25]1[N:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][C:26]=1[C:27]([O:29][CH3:30])=[O:28].C(=O)([O-])[O-].[Cs+].[Cs+].N#N>O.CN(C=O)C.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:32]1[CH:33]=[N:34][C:25]([O:24][CH3:23])=[C:26]([CH:31]=1)[C:27]([O:29][CH3:30])=[O:28]

Participants

Conditions

Temperature: 65 °C

Procedure

A mixture of 5-bromo-6-chloro-2-(4-fluorophenyl)-N-methylfuro[2,3-b]pyridine-3-carboxamide (1.15 g, 2.99 mmol), commercially available methyl 2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinate (1.05 g, 3.58 mmol), Pd(Ph3P)4 (0.517 g, 0.448 mmol) and cesium carbonate (1.95 g, 5.97 mmol) was degassed/charged with N2 and diluted with Water (0.5 ml)/DMF (5 mL). The resultant mixture was then degassed, charged with N2, and heated in a 65° C. oil bath and allowed to stir under N2 atmosphere for 4 h. LCMS shows desired product as well as some SM. The reaction was halted by cooling to rt and, the reaction mixture was diluted with EtOAc and sat. 1M HCl. The layers were separated and the aq layer was extracted with EtOAc (3×10 mL). The combined organic extracts were washed with water, brine, dried over Na2SO4 filtered and concentrated. The resultant solid was then flashed on silica gel eluting with a 0-100% EtOAc in hexanes mixture over 12 CV and then held at 100% EtOAc for 8 CV to give methyl 5-(6-chloro-2-(4-fluorophenyl)-3-(methylcarbamoyl)furo[2,3-b]pyridin-5-yl)-2-methoxynicotinate (630 mg, 1.31 mmol, 45% yield) as a tan solid. LC-MS retention time: 1.69 min; m/z (observed boronic acid M+H): 470. 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 1 min, and an analysis time of 3 min where solvent A was 10% acetonitrile/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90% acetonitrile/0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode. 1H NMR (500 MHz, DMSO-d6) δ 8.43 (d, J=2.5 Hz, 1H), 8.29 (d, J=2.5 Hz, 1H), 8.22 (s, 1H), 7.93 (dd, J=8.9, 5.1 Hz, 2H), 7.26-7.20 (m, 2H), 5.91 (br. s., 1H), 4.13 (s, 3H), 3.94 (s, 3H), 2.99 (d, J=5.0 Hz, 3H).

Workup

customThe resultant mixture was then degassed
additioncharged with N2
temperatureby cooling to rt
additionthe reaction mixture was diluted with EtOAc and sat. 1M HCl
customThe layers were separated
extractionthe aq layer was extracted with EtOAc (3×10 mL)
washThe combined organic extracts were washed with water, brine
dry with materialdried over Na2SO4
filtrationfiltered
concentrationconcentrated

Sources & evidence

ORD record: ord-ab09955b75db4f7eb617d42be6928519
Source dataset: uspto-grants-2015_02
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08962651B2

Reaction notes

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