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

HRID 1854733
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Druckvorschau

Reaktionsgleichung

Reaktionsgleichung von HRID 1854733
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]
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Komponenten

8

Edukt 4

HCID 947NitrogenHCID 10796Cesium carbonateHCID 46739267Methyl 2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinateHCID 904024175-bromo-6-chloro-2-(4-fluorophenyl)-N-methylfuro[2,3-b]pyridine-3-carboxamide

Produkt 1

HCID 90402449Methyl 5-(6-chloro-2-(4-fluorophenyl)-3-(methylcarbamoyl)furo[2,3-b]pyridin-5-yl)-2-methoxynicotinate
Ausbeute 45 %

Reagenzien, Katalysatoren, Lösungsmittel 3

HCID 178418397HCID 178418397, VerbindungKatalysatorHCID 962WaterLösungsmittelHCID 6228DimethylformamideLösungsmittel

Reaktionsbedingungen

Temperatur
65 °C

Versuchsvorschrift

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).

Aufarbeitung

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

Quellen und Nachweise

ORD-Eintrag
ord-ab09955b75db4f7eb617d42be6928519
Quelldatensatz
uspto-grants-2015_02
DOI
10.6084/m9.figshare.5104873.v1
Patentnummer
US08962651B2

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