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25th June 2012 @ 06:55
Mostly clean desired product progressed to next step. Reaction to be scaled up (smaller amount of benzaldehyde) and purified for final characterisation.

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Double reductive alkylation of glycinamide. First using benzaldehyde to provide benzyl-protected glycinamide, then using formaldehyde to provide the N-methyl.

PMY51-1.png

Reaction Start Time:15.50 25/06/12
Glycinamide.HCl (500 mg, 4.52 mmol, 1 equiv.) was dissolved in minimum water. Sodium hydroxide (0.18 mg, 4.5 mmol, 1 equiv.) was added. A precipitate forms. The mixture was concentrated under reduced pressure. Methanol (15 mL) and AcOH (1.5 mL) and benzaldehyde (0.60 mL, 5.9 mmol, 1.3 equiv.) were added. Sodium cyanoborohydride (370 mg, 5.90 mmol, 1.3 equiv.) was added portionwise to the hazy solution, allowing bubbling to cease between portions. Stirred at room temperature overnight. Concentrated under reduced pressure then basified using 2M NaOH(aq) and extracted using DCM (3 × 20 mL). Washed with brine, dried (MgSO4) and concentrated under reduced pressure to a thick oil. Dried under vacuum to a white solid (0.59 g). The aqueous layer was saturated with brine and re-extracted with DCM (3 × 20 mL), dried (MgSO4) and concentrated. White solid (0.65 g total). 1H NMR consistent with literature NMR values but also unknown signals at 3.64 (s), 3.10 (s) 2:1 integrals). Integration is also out with respect to aromatic region. Mass Spec consistent with product 187.3 [M+Na] and bis-benzylated product 277.5 [M+Na]

The white solid was dissolved in methanol (10 mL) and AcOH (0.25 mL). Aqueous formaldehyde solution (37 wt. %, 0.7 mL, 9 mmol, 2 equiv.) was added. After stirring for approx 5 minutes, sodium cyanoborohydride (300 mg, 4.75 mmol, 1.05 equiv.) was added portionwise over 10 minutes. Reaction stirred overnight at room temperature. Concentrated under reduced pressure. 2M NaOH (10 mL) was added and stirred for 10 minutes. The mixture was extracted using DCM (3 × 15 mL). The extracts were washed with brine then dried (MgSO4) and concentrated under reduced pressure to a colourless translucent thick oil (0.64 g). 1H NMR shows consumption of previous product but some remains, the impurity peaks are retained and peaks consistent with expected product appear. Consistent with 1H NMR reported in patent EP0714885 (A2). Impurity peaks probably bis-benzylated compound, integral ratio and excess aromatic protons support this. Mass spec consistent with product 201.4 [M+Na] and bis-benzyl product 277.5 [M+Na]. Purified by chromatography on silica (4% MeOH/DCM), partial separation; white crystalline solid PMY 51-1-A (0.19 g), colourless viscous oil that solidified on standing PMY 51-1-B (0.41 g, 39%, more polar than A).

PMY 51-1-A bis-benzylated product by 1H NMR. Mpt 95-97 °C
PMY 51-1-B 2-(benzyl(methyl)amino)acetamide, bis-benzyl and other impurities by 1H NMR. Mostly desired product.

TLC visualised with UV and vanillin:
TLC EtOAc/hexane

70% EtOAc/hexane: Left to right: Step 1 crude product, mixture, step 2 crude product, benzaldehyde, benzyl alcohol.

Column TLC

Unstained.

NMR:
1H PMY 51-1-A, bisbenzyl
1H product, impure after column
1H NMR crude
1H NMR crude, step 1


Mass Spec:
Mass Spec step 2
Mass Spec step 1


TLC DCM/MeOH

5% MeOH/DCM: Left to right: Step 1 crude product, mixture, step 2 crude product.

TLC supports that top spot probably the impurity observed in both NMR spectra.

Reference:
doi: 10.1016/j.tetasy.2008.01.016
NMR details: Synthesis 1983, 04, 529
EP0714885 (A2)

Risk and Hazard Assessment:
See: Synthesis of amine-linked analogue of TCMDC-123812 via reductive amination using sodium cyanoborohydride (PMY 38-4)
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Attached Files
Scheme
TLC EtOAc/hexane
TLC DCM/MeOH
Mass Spec step 1
Mass Spec step 2
Column TLC
1H PMY 51-1-A, bisbenzyl
1H product, impure after column
1H NMR crude
1H NMR crude, step 1