Citric Acid → (S)-2-(tert-butyldimethylsilyloxy)-3-isopropoxy-N-(5-(methylthio)pyridin-2-yl)propanamide

Participants

Reaction Conditions

Reaction Steps

Trimethylaluminium (2M in toluene) (10.40 mL, 20.80 mmol) was added to 5-(methylthio)pyridin-2-amine (CAS no. 77618-99-6) (2.54 g, 18.09 mmol) in toluene (100 mL) cooled to 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 20 minutes. (S)-methyl 2-(tert-butyldimethylsilyloxy)-3-isopropoxypropanoate (Intermediate C7b) (5 g, 18.09 mmol) was added and the reaction was allowed to warm to room temperature. The reaction was allowed to stir at room temperature for 1 hour. The temperature was increased to 60° C. and stirred for a further 24 hours. The reaction mixture was neutralised with citric acid (1M, aq) and then diluted with water and EtOAc (200 mL). The organic layer was separated and the aqueous layer re-extracted with EtOAc (100 mL). The combined organics were dried (MgSO4), filtered and evaporated in vacuo. The crude product was purified by flash silica chromatography, elution gradient 0 to 50% Et2O in isohexane to afford the product (3.95 g, 56.8%). 1H NMR (400 MHz, DMSO) δ 0.10-0.13 (6H, d), 0.90-0.92 (9H, m), 1.04-1.07 (6H, m), 2.40 (3H +DMSO, s), 3.54-3.63 (3H, m), 4.42-4.44 (1H, m), 7.77-7.80 (1H, dd), 8.03-8.06 (1H, d), 8.26 (1H, d), 9.49 (1H, s); m/z (ES+) (M+H)+=385; HPLC tR=3.66 min.

Provenance & Evidence