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2nd September 2013 @ 01:18

AEW 81-1 (275 mg, 1.72 mmol, 1 equiv.), EDCI (395 mg, 2.06 mmol, 1.2 equiv.) and HOBt (23 mg, 0.17 mmol, 0.1 equiv.) were stirred in CH2Cl2 (15 mL) and stirred at room temperature for 15 minutes. 4-Aminoantipyrine (238, 1.49 mmol, 1.1 equiv.) was added and the reaction mixture stirred for 16 hours.

A saturated aqueous solution of NaHCO3 was added and the the layers were separated and the aqueous layer was extracted with CH2Cl2. Combined organic layers were washed with water, brine and then dried (MgSO4) to give a red/brown tar that didn't dissolve in NMR solvents.

Reaction abandonded.


Hazard and Risk Assessment

See AEW 64-1

Attached Files
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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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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Attached Files
11th August 2013 @ 09:52
Aew: 1-19

Total yield: 3.34 g, 73% yield. Better yield on 2 g scale.
Reaction Scheme

DMF (10.0 mL) was stirred under a nitrogen atmosphere in an ice-bath. Phosphoryl chloride (2.36 mL, 25.4 mmol, 1.2 equiv.) was added and the reaction stirred for 25 minutes. Reaction still colourless. A solution of pyrrole AEW 10-2 (4.00 g, 21.0 mmol, 1 equiv.) in DMF (10 mL) was added dropwise over 10 minutes. The reaction was removed from the ice-bath and allowed to warm to room temperature. 

After 1 h 20 mins, reaction was complete by TLC. Poured over ice (200 ml). pH adjusted to 9 (meant to be 6) (approx. 20% NaOH) and left stirring overnight. In the morning pH was 1. 20% NaOH added until pH 11 and the reaction mixture was left to stir for a further 40 minutes. The solid was filtered and washed with water to form a wet beige paste. Recrystallised from (MeCN/water) to give a free-flowing pale brown solid (2.36 g, 10.9 mmol, 52% yield). Second crop of crystals was still paste-like, they were dissolved in EtOAc and combined with the mother liquor. MeCN and EtOAc was removed under reduced pressure and the aqueous layer was extracted with EtOAC, washed with brine, dried (MgSO4) filtered and evaporated to yield a brown solid (976 mg, 4.49 mmol, 21% yield). Both fractions = good by 1H NMR. 

Data:

AEW 2-3A proton.pdf
AEW 2-3A.zip
AEW 2-3B proton.pdf
AEW 2-3B.zip

Original Experiment:
Scale up (11 mmol): Formylation of 1-(4-fluorophenyl)-2,5-dimethyl-1H-pyrrole (PMY 2-4)

Starting material synthesis:
Repeat Preparation of 1-(4-Fluoro-phenyl)-2,5-dimethyl-1H-pyrrole (AEW 1-1)

References:

  1. Gangjee, A.; Patel, J.; Kisliuk, R. L.; Gaumont, Y; J. Med. Chem., 1992, 35 (20), 3678–3685. doi:10.1021/jm00098a013

 

  • Manetti, F.; Magnani, M.; Castagnolo, D.; Passalacqua, L.; Botta, M.; Corelli, F.; Saddi, M.; Deidda, D; De Logu, A. ChemMedChem, 2006, 1, 973–989. doi: 10.1002/cmdc.200600026


InChI=1S/C12H12FN/c1-9-3-4-10(2)14(9)12-7-5-11(13)6-8-12/h3-8H,1-2H3
gave
InChI=1S/C13H12FNO/c1-9-7-11(8-16)10(2)15(9)13-5-3-12(14)4-6-13/h3-8H,1-2H3

Hazard and Risk Assessment:

AEW 2-1.pdf
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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) .

Attached Files