Trimethylsilylacetylene → 4-(4-Ethynyl-2-fluoro-phenylamino)-1-methyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid ethyl ester

4-(2-Fluoro-4-iodo-phenylamino)-1-methyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid ethyl ester (1.0 g, 2.40 mmol) was reacted with ethynyl-trimethyl-silane (0.70 mL, 4.80 mmol) in the presence of CuI (0.23 g, 1.20 mmol), (Ph3P)2PdCl2 (0.085 g, 0.12 mmol) and TEA (10 mL) in THF/DMF (4:1, 25 mL) which was stirred at room temperature for 24 hours. The reaction mixture was filtered pass through a pad of alumina (neutral). The filtrate was partitioned between water (20 mL) and EtOAc (100 mL). The organic layer was dried and concentrated under reduced pressure. The resulting residue was dissolved in THF (10 mL) and treated with the tetrabutylammonium fluoride (1M in THF, 2.40 mL, 2.4 mmol) which was stirred at room temperature for 15 hours. The reaction was partitioned between water (20 mL), and EtOAc (100 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The resulting residue was purified by column chromatography on silica gel (5% MeOH/CH2Cl2 as eluant) to give 4-(4-Ethynyl-2-fluoro-phenylamino)-1-methyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid ethyl ester as a light brown solid (0.67 g, 88%). 1H NMR [(CDCl3, 400 MHz] δ9.56 (s, 1H), 8.22 (s, 1H), 7.38 (dd, J=10.1, 1.9 Hz, 1H), 7.25 (s, 2H), 6.01 (s, 1H), 4.38 (q, J=7.1 Hz, 2H), 3.53 (s, 3H), 3.09 (s, 1H), 1.38 (t, J=7.1 Hz, 3H). Anal. Calcd for C17H15FIN2O3: C, 64.96; H, 4.81; N, 8.91. Found: C, 64.89; H, 4.40; N, 8.64.

1. filtrationThe reaction mixture was filtered pass through a pad of alumina (neutral)
2. customThe filtrate was partitioned between water (20 mL) and EtOAc (100 mL)
3. customThe organic layer was dried
4. concentrationconcentrated under reduced pressure
5. dissolutionThe resulting residue was dissolved in THF (10 mL)
6. stirringwas stirred at room temperature for 15 hours
7. customThe reaction was partitioned between water (20 mL), and EtOAc (100 mL)
8. dry with materialThe organic layer was dried over MgSO4
9. filtrationfiltered
10. concentrationconcentrated in vacuo
11. customThe resulting residue was purified by column chromatography on silica gel (5% MeOH/CH2Cl2 as eluant)

ORD-Eintrag

ord-14624939fb764c3d8b212edea37dfe94

Quelldatensatz

uspto-grants-2007_09

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US07273877B2