Potassium Sodium Tartrate → (S)-2-hydroxy-N-(5-methylpyrazin-2-yl)-3-((R)-1-(triisopropylsilyloxy)propan-2-yloxy)propanamide

Participants

Reaction Conditions

Reaction Steps

Trimethylaluminium (2M solution in toluene) (72.5 mL, 145 mmol) was added to 5-methylpyrazin-2-amine (13.64 g, 125.0 mmol) in toluene (520 mL) cooled to 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 20 minutes. (R)-methyl 2-hydroxy-3-((S)-1-(triisopropylsilyloxy)propan-2-yloxy)propanoate (Intermediate AU5) (33.5 g, 100.0 mmol) in toluene (130 mL) was added and the reaction was allowed to warm to room temperature and then stirred at 72° C. for 2.5 hours. The reaction mixture was allowed to cool then poured into a stirred mixture of ethyl acetate (500 mL) and aqueous solution of Rochelle salt (20% w/v, 500 mL). The mixture was stirred for 15 minutes then the organics separated and washed with water (500 mL) followed by brine (500 mL), then dried (MgSO4), filtered and concentrated. The residues were dissolved in iso-hexane (300 mL) and stood for 15 minutes at 20° C. before cooling to 5° C. over 30 minutes. The solid formed was isolated by filtration, washed with iso-hexane cooled to 5° C. (200 mL) and dried at 40° C. under high vacuum to afford the product (26.7 g, 64%). The filtrates were combined and concentrated to 100 mL total volume and the mixture stood for 16 hours. The solid formed was isolated by filtration, washed with iso-hexane cooled to 5° C. (100 mL), dried at 40° C. under high vacuum and combined with the initial batch to afford the product (30.1 g, 73%). 1H NMR (400 MHz, CDCl3) δ 1.04-1.17 (24H, m), 2.54 (3H, s), 3.62-3.67 (3H, m, 3.81-3.85 (1H, m), 4.05-4.09 (1H, m), 4.22 (1H, d), 4.34 (1H, q), 8.13 (1H, d), 9.12 (1H, s), 9.44 (1H, d); m/z (ES+) (M+H)+=412.34; HPLC tR=3.82 min.

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