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27th August 2013 @ 06:53

Problems with product decomposing before HRMS result. Query biological results.

See also Synthesis of amine-linked analogue of TCMDC-123812 via reductive amination using sodium cyanoborohydride in acidic conditions (AEW 12-1) and Synthesis of amine-linked analogue of TCMDC-123812 via reductive amination using sodium cyanoborohydride in acidic conditions (AEW 12-2)

Procedure:

AEW (100 mg, 0.46 mmol, 1 equiv) was dissolved in anhydrous MeOH (4 mL) and AcOH (0.15 mL) was added. Pyrrolidine (44 mg, 0.05 mL, 0.3 mmol, 1.3 equiv) in anhydrous MeOH (1 mL) was added and the reaction mixture stirred at room temperature for 1h. Sodium cyanoborohydride (32 mg, 0.52 mmol, 1.1 equiv.) was added in two portions over two minutes and the reaction mixture stirred at room temperature for 12 h. Then volatiles removed in vacuo, residue treated with aqueous 1 M NaOH and extracted with DCM (x2). Organics washed with brine, drieed and then filtered and evaporated to yield a crude orange oil (160 mg).

Hazard and Risk Assessment:

See Synthesis of amine-linked analogue of TCMDC-123812 via reductive amination using sodium cyanoborohydride in acidic conditions (AEW 12-1)

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27th August 2013 @ 05:01

Repeat of Reductive amination of pyrrole aldehyde with crude PMY 53-2 (PMY 56-1)

AEW (100 mg, 0.46 mmol, 1 equiv.) and crude AEW 83-1 (75 mg) were dissolved in MeOH (5 mL) and acetic acid (0.13 mL) and stirred at room temperature for 1 h. Sodium cyanoborohydride (32 mg, 0.5 mmol, 1.1 equiv.) was added in 3 portions over 5 mins and stirred at room temperature overnight. Reaction complete by TLC.

MeOH removed in vacuo and then the crude orange oil treated with 1M NaOH (5 mL). The mixture was then extracted with DCM (2 x 10 mL). The organic extracts were washed with brine then dried (MgSO4) and concentrated to give an orange oil.

Crude indicated desired product - Purified by flash column (1-20% MeOH with 0.5% NH3) no product recovered.


Data: (TLC, 5% MeOH in CH2Cl2)

AEW 83-1.jpg

Hazard and Risk Assessment:

See Reductive amination of pyrrole aldehyde with crude PMY 53-2 (PMY 56-1)

 

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21st August 2013 @ 06:22

Resynthesis of PMY 53-2 for characterisation. Pure SM obtained which should aid synthesis.

 

AEW 74-1 (330 mg, 1.85 mmol, 1 equiv.) and 10% Pd/C (50 mg, 15 wt%) were suspended in ethanol (12 mL) in EtOH was added to the catalyst suspension and the mixture hydrogenated in the high pressure tube overnight at 100 psi initial. Reaction mixture was stirred for 16.5 hours and the pressure had fallen to 70 psi by morning. 

Septum was pierced and the reaction mixture was filtered over Celite, washed with MeOH and evaporated to provide a very pale straw liquid which crystallised at the high vac. 270 mg recovered- indicative of reaction not being complete. Shown by 1H NMR to be a 1:0.8 mixture of product and SM. To be resubmitted to the same reaction conditions at 5pm as hydrogen cylinder in use by UG lab.

Stirred for 4 further days at 100psi H2 under the conditions outlined above and then the same work-up was performed.

Clear oil with white crystal flakes formed: NMR indicates complete reduction to the desired product with some impurities underneath the aliphatic signals. Decided to use crude in AEW 83-1.

 

Data:

AEW 82-1 crude 16.5 h.pdf
AEW 82-1.zip

AEW 82-1 4 day proton.pdf
AEW 82-1 4 days.zip

Hazard and Risk Assessment:

AEW 82-1 HIRAC.pdf
Attached Files
20th August 2013 @ 06:07
Aew: 81-90

Attempted synthesis of side chain in greater purity. See also

 

13 μL of conc. HCl was added to a suspension of glycolic acid (1.0 g, 13.2 mmol, 1 equiv.) in 3,4-dihydro-2H-pyran (3.6 mL, 39 mmol, 3 equiv.) and the reaction mixture was heated to 80 ˚C  for 30 minutes.

Volatiles were evaporated, and the resulting residue was purified by flash column chromatography over silica (Ethyl acetate/Petrol 3:7). Two major fractions collected - very streaky TLC plates with elution of all spots. I think that the material deteriorated on storage in the fridge - should have purified immediately. Second fraction cleaner than first - to be used in next reaction AEW 84-1.

http://www.jbc.org/content/276/45/41638.full.pdf+html

Data:

1H NMR:

Fraction A:

AEW 81-1-A proton.pdf

Fraction B:

AEW 81-1-B proton.pdf
AE 81-1-B impure Carbon.pdf

Hazard and Risk Assessment:

AEW 81-1 HIRAC.pdf
Attached Files
15th August 2013 @ 07:08

Repeat synthesis see PMY 9-1 to make side-chain of TCMDC-123794 4-aminoantipyrine.

 

Crude (AEW 75-1) ("27.0 mmol") was stirred in toluene (40 mL). The material crystallised and was dissolved by heating. 4-aminoantipyrine (5.73 g, 28.2 mmol, 1.05 equiv.) was added and the reaction heated to reflux. 

 

NMR:

Risk and Hazard Assessment:

Risk Assessment

See also:
Synthesis of Glycolic Acid Acetonide (PMY 7-1)


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