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4th July 2012 @ 04:41
Product obtained, contaminated with impurity. === Scaled up double reductive alkylation of glycinamide (PMY 51-1) with reduced equivalents of benzaldehyde. First using benzaldehyde to provide benzyl-protected glycinamide, then using formaldehyde to provide the N-methyl. [b]Reaction Start Time: 14.15 04/07/12[/b] Glycinamide hydrochloride (2.00 g, 18.1 mmol, 1 equiv.) was dissolved in water (2 mL, heated then cooled). Sodium hydroxide (0.77 g, 19.3 mmol, 1.07 equiv) was added. A precipitate formed. Water removed under vacuum. Residue stirred in methanol (45 mL) and acetic acid (4.5 mL). Hazy partial solution. Benzaldehyde (1.85 mL, 18.1 mmol, 1 equiv.) added and the mixture stirred at room temperature for 20 minutes. Sodium cyanoborohydride (1.25 g, 19.9 mmol, 1.1 equiv.) was added portionwise over 25 minutes. After stirring at room temperature for 18 hours, the reaction was concentrated under reduced pressure and 1M NaOH added until basic. Extracted with DCM (4 × 20 mL). The organic extracts were washed with brine then dried (MgSO4) and concentrated under reduced pressure to a off-white solid (2.36 g, 79% of theory). 1H NMR consistent with PMY 51-1. Ratio 2.8:1 mono:bis-benzylated product. 17.00 05/07/12 Solid dissolved in methanol (40 mL) and AcOH (1 mL). Aqueous formaldehyde (37% wt. 3 mL) added and stirred for 5 minutes. Sodium cyanoborohydride (1.19 g, 19 mmol, 1.05 equiv.) was added portionwise. After 17 hours at "room temp" (approx 10-13 °C lab temperature), TLC shows product, bis-benzyl and SM. Further sodium cyanoborohydride (approx. 0.25 g, approx. 4.7 mmol, approx. 0.26 equiv.) added and reaction heated to 20 °C. After a further 2.5 hours, no change by TLC. Reaction concentrated under reduced pressure. 1M NaOH added until basic. Extracted with DCM (4 × 30 mL). Extracts washed with brine then dried (MgSO4) and concentrated to a thick slightly yellow oil (2.46 g). Purified by chromatography on silica (2-4% MeOH/DCM). Partial separation. Product fraction consistent with PMY 51-1-B, colourless viscous oil (1.88 g) purified again by chromatography (3% MeOH/DCM). Colourless oil that crystallised on standing (1.30 g, 40% over 2 steps). 1H NMR shows 2 products; product and unknown! Marker kept, material to be progressed without further purification. [b]TLC (5% MeOH/DCM) visualised with UV and vanillin:[/b] [data]2631[/data] [b]NMR:[/b] [data]2637[/data][data]2815[/data] [b]See also:[/b] [blog]3354[/blog] [b]Risk and Hazard Assessment:[/b] See: [blog]2606[/blog] Reaction scaled up from previous by factor of 4 (from 4.5 to 18.1 mmol).
Attached Files
TLC stage 2, 17 hours
1H NMR, 1st step
1H and 13C NMR 300 MHz