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14th August 2013 @ 01:23
Aew: 60-80

AEW 73-1 (80 mg, 0.26 mmol, 1 equiv.) was dissolved in CH2Cl2 (2.6 mL), EDCI (60 mg, 0.31 mmol, 1.2 equiv.) and HOBt (3.5 mg, 0.03 mmol, 0.1 equiv.) were added and the mixture stirred for 20 minutes. Ammnonia (28% aq. soln., 0.24 mL, 0.39 mmol, 1.5 equiv.) was added and the reaction mixture stirred at room temperature. Reaction mixture stirred for 4 hours, still SM. Stirred o/n still SM by TLC. Reaction quenched by addition of an aqueous solution of sodium hydrogen carbonate and then extracted with CH2Cl2, washed with brine, dried (MgSO4), filtered and evaporated to yield a yellow oil with white/yellow crystals. Purified by column using 1-10% MeOH in DCM. Gave desired poduct as white semi-solid (52 mg, 0.17 mmol, 66% yield).

Data:

TLC 5% MeOH in CH2Cl(20 h)

AEW 77-1.pdf


500 MHz

AEW 77-1.zip
AEW 77-1.pdf
AEW 77-1.pdf

Hazard and Risk Assessment:

AEW 77-1.pdf

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8th August 2013 @ 09:02
Aew: 60-80

Resynthesis of glycolic acid acetonide. See also Synthesis of Glycolic Acid Acetonide (PMY 7-1).

Started 11.30 am Thursday 15th August

Condensation of acetone and glycolic acid to give the protected/activated glycolic acid acetonide for further side chain elaboration.


Glycolic acid (2.05 g, 27.0 mmol, 1 equiv.) was stirred in acetone (40 mL) with a few crystals of p-TSA for 1 hour. NaHCO3 (approx 1 g) was added and dried (MgSO4) before filtration and partially concentration to a colourless oil. 

NMR:

 

References:

 

Risk and Hazard Assessment
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Risk Assessment
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8th August 2013 @ 06:03
Aew: 60-80

Repeat of Reductive alkylation of glycinamide (PMY 51-2)


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. The reaction was stirred for 20 mins but no precipitate formed (as previously described by PMY). Water removed under vacuum to give a white crystalline residue. The residue was stirred in methanol (45 mL) and acetic acid (4.5 mL) to give a 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 and left to stir at room temperature overnight (5.40 pm).

After stirring at room temperature for 40 hours the reaction was concentrated under reduced pressure (Reaction mixture dropped in the Buchi Bath - bath basified and disposed) 1M NaOH added to recovered mixture until basic. Extracted with CH2Cl2 (x4). The organic extracts were washed with brine, dried (MgSO4) and concentrated to give an off-white solid (~2 g).

Sunday 20:52 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 and the reaction mixture left to stir at room temperature. After 36 hours the reaction mixture was concentrated under reduced pressure. 1M NaOH added until basic. Extracted with CH2Cl2 (4 × 30 mL). Extracts washed with brine then dried (MgSO4) and concentrated to a thick very pale yellow oil that solidified at the high vac (1.9 g).

Purified by chromatography on silica (2-4% MeOH/DCM).

First fraction: AEW 74-1-A = colourless oil

AEW 74-1-A proton.pdf

Second fraction: AEW 74-1-B = white solid

AEW 74-1-B proton.pdf

Third fraction: AEW 74-1-C = white solid

AEW 74-1-C proton.pdf

 

First fraction is impurtity, AEW 74-1-B and C look like pure product, ready for hydrogenation and possible submission for testing?

NMR Data

Intermediate 1

AEW 74-1 proton crude INT.pdf
AEW 74-1 int.zip

Crude Product

AEW 74-1 crude product 1H NMR.pdf
AEW 74-1 crude product.zip

AEW 74-1 A.zip
AEW 74-1 B.zip
AEW 74-1 C.zip

Hazard and Risk Assessment:

See: Synthesis of amine-linked analogue of TCMDC-123812 via reductive amination using sodium cyanoborohydride (PMY 38-4) Reaction scaled up from previous by factor of 4 (from 4.5 to 18.1 mmol), but has already been performed on this scale see: Reductive alkylation of glycinamide (PMY 51-2) .

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