Diisopropylethylamine → Tetrahydro-furan-2-ylmethyl-acetamide

Temperature

60 °C

A mixture of hydroxyl-{3-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine-5-yl]-phenyl}-acetic acid (0.2 g, 0.38 mmol), methyl-(tetrahydro-furan-2-ylmethyl)-amine (0.7 g, 0.57 mmol), diisopropylethylamine (DIEA, 200 μl, 1.14 mmol), N,N,N′N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (HATU, 216 mg, 0.57 mmol) in THF (5 ml) was stirred at 60° C. until no solid remained. The reaction mixture was taken up in 10 ml ethyl acetate and subsequently extracted with 1N HCl, saturated NaHCO3, brine, dried with Na2SO4, concentrated to dryness. The crude was purified by silica chromatography. The resulting material was dissolved in 3 ml of methanol and aqueous NaOH (1 ml, 2 N in H2O) was added and the mixture stirred overnight at room temperature. The solvent was removed under reduced pressure and the residue neutralized with 500 μl of 1N HCl. The resulting crude was directly purified by mass-triggered reverse phase HPLC to afford 2-hydroxyl-2{3-[3-(2-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenyl}-N-methyl-N-(tetrahydro-furan-2-ylmethyl-acetamide as an off-white powder (51 mg, 28% yield). 1H NMR (500 MHz, DMSO-d6) δ 1.35-1.45 (m, 1H), 1.61-1.79 (m, 3H), 2.89-2.92 (d, 3H), 3.14-3.68 (m, 4H), 3.84 (s, 3H), 3.92-3.98 (m, 1H), 5.47 (d, 1H), 7.05 (m, 1H, 7.15 (d, 1H), 7.31 (m, 1H), 7.36 (m, 1H), 7.45-7.48 (m, 1H), 7.56-7.59 (m, 1H), 7.63-7.70 (m, 2H), 7.73 (m, 1H), 8.14 (m, 1H), 8.52 (m, 1H). MS: m/z 472.2 (M+H+).

1. extractionsubsequently extracted with 1N HCl, saturated NaHCO3, brine
2. dry with materialdried with Na2SO4
3. concentrationconcentrated to dryness
4. customThe crude was purified by silica chromatography
5. dissolutionThe resulting material was dissolved in 3 ml of methanol
6. additionaqueous NaOH (1 ml, 2 N in H2O) was added
7. stirringthe mixture stirred overnight at room temperature
8. customThe solvent was removed under reduced pressure
9. customThe resulting crude was directly purified by mass-triggered reverse phase HPLC

ORD record

ord-ce0f7365ecc64ec3887ff3ef2f1a7c05

Source dataset

uspto-grants-2012_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08242280B2