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23rd February 2012 @ 00:13
Reaction did not results in desired product. Reduced aldehyde observed and decomposition during attempted chromatography.

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Reductive amination of PMY 2-5 with glycinamide.

38-1.png

Reaction Start Time: 11.30 23/02/12
Glycinamide hydrochloride (132 mg, 1.20 mmol, 1.3 equiv.) and sodium hydroxide (55 mg, 1.38 mmol, 1.5 equiv.) were briefly refluxed in methanol (10 mL). PMY 2-5 (200 mg, 0.92 mmol, 1 equiv.) in MeOH (10 mL) was added to the still warm solution of glycinamide. After 2 hours, TLC shows some streaking of starting material on the plate (potential hydrolysis of imine on the plate). Mol. sieves added to the reaction. After a further 2 hours, no change by TLC. Sodium borohydride (38 mg, 1.01 mmol, 4.4 hydride equiv.) added to the reaction. After 4 days, the reaction was a brown slurry (significant grinding of the mol. sieves). 1M HCl (5 mL) was added and the reaction stirred for 30 minutes. The mixture was filtered and the filtrate concentrated under reduced pressure. The residue was dissolved in water (20 mL) and extracted with DCM (3 × 15 mL). The organic extracts were combined and washed with brine and dried (MgSO4) then concentrated under reduced pressure to a slightly brown oil (60 mg). Purified by chromatography (0-10% MeOH/DCM). Multiple spots obtained and split into 2 fractions; 38-1-A (trace), 38-1-B, brown oil (20 mg). 1H NMR is not consistent with desired product nor recovered alcohol.

TLC (25% EtOAc/hexane) visualised with UV and vanillin:
TLC 2 hours
TLC 4 days


NMR:
1H NMR crude
1H NMR PMY 38-1-B
1H NMR PMY 38-1-A


Risk and Hazard Assessment:
Risk Assessment


Reference:
doi 10.1016/j.ica.2006.01.006
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22nd February 2012 @ 22:39
Recovered starting material (ca. 90%), suspect sodium hydride quenched by wet THF. To be repeated.

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Synthesis of the ether-linked analogue of TCMDC-123812 from alcohol PMY 18-2 and 2-bromoacetamide.

37-1.png

Reaction Start Time: 14.45 23/02/12
Sodium hydride (60% in mineral oil, 40 mg, 1 mmol, 1.1 equiv.) was suspended in THF (5 mL) in an ice bath. PMY 18-2 (crude) was dissolved in THF (5 + 2 mL) and added portionwise to the sodium hydride suspension and the reaction allowed to warm to room temperature. After 15 minutes, 2-bromoacetamide (152 mg, 1.10 mmol, 1.1 equiv.) in THF (5 mL) was added dropwise to the pale yellow solution. The reaction turns hazy. After 1 hour, no reaction observed by TLC. Reaction left to stir over 4 days. TLC shows no change, SM only. Saturated NH4Cl(aq)) (5 mL) was added, after stirring for 5 minutes, EtOAc (10 mL) was added and the layers separated. The aqueous layer was extracted with further EtOAc (2 × 10 mL). The combined organic layers were washed with brine, dried (MgSO4) and concentrated to an orange oil (195 mg). NMR consistent with PMY 15-1/18-1 (alcohol), quite clean by 1H NMR. Suspect THF not dry enough/NaH quenched before reaction commenced.

TLC (25% EtOAc/hexane) visualised with UV and vanillin:
TLC 4 days


NMR:
1H NMR


Risk and Hazard Assessment:
Risk Assessment
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22nd February 2012 @ 22:37
Used crude in PMY 37-1

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Reduction of pyrrole-3-carbaldehyde, PMY 2-5, to the corresponding alcohol.

Reaction Scheme

Reaction start time: 10.30 23/02/12
PMY 2-5 (200 mg, 0.92 mmol, 1 equiv.) was dissolved in MeOH (approx 15 mL). Sodium borohydride (32 mg, 0.92 mmol, 4 hydride equiv.) was added. After 3 hours, reaction not complete. The batch of borohydride seemed wet, potentially partially hydrolysed. Further sodium borohydride (32 mg, 0.92, 4 hydride equiv.) added. After a further hour, the reaction is essentially complete by TLC. Acetone (5 mL) added to the reaction. After stirring for 10 minutes, the reaction was concentrated under reduced pressure. The residue was dissolved in water (10 mL) and DCM (10 mL). The layers were separated and the aqueous layer extracted with DCM (2 × 10 mL). The combined organic extracts were washed with brine, then dried (MgSO4) and concentrated under reduced pressure to a thick orange oil. Used directly in: Synthesis of ether-linked analogue of TCMDC-123812 (PMY 37-1)

TLC (25% EtOAc/hexane) visualised with UV and vanillin:
TLC 3 hours


Risk and Hazard Assessment:
As for Reduction of pyrrole-3-carbaldehyde using sodium borohydride (PMY 18-1) and Reduction of pyrrole-3-ester PMY 6-1 using lithium aluminium hydride (PMY 15-2), except using the less hazardous sodium borohydride as the reductant.
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20th February 2012 @ 05:47
Target synthesised in 80% yield.

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Synthesis of 1-(4-fluorophenyl)-2,5-dimethyl-1H-pyrrole-3-carbaldehyde by Vilsmeier-Haack formylation of 1-(4-Fluoro-phenyl)-2,5-dimethyl-1H-pyrrole.

Reaction Scheme PY14.png

Reaction Start Time: 15.45 EST 20/02/12
DMF (15 mL) was stirred under a nitrogen atmosphere in an ice-bath. Phosphoryl chloride (
3.5 mL, 38.1 mmol, 1.2 equiv.) was added and the reaction stirred for 25 minutes. Reaction still colourless. A solution of pyrrole PMY 1-6 (6.00 g, 31.5 mmol, 1 equiv.) in DMF (10 mL) was added dropwise over 5 minutes. The reaction was removed from the ice-bath and allowed to warm to room temperature. After 30 minutes, TLC shows reaction almost complete. After 45 minutes, reaction was poured into ice/water (200 mL) and 5M NaOH added until pH 6. The green suspension was allowed to stand. After 16 hours, the mixture was a brown suspension. pH was now 1, adjusted to 10 by addition of 5M NaOH. Allowed to stand for 20 minutes, then filtered. The pale brown solid was recrystallised from warm acetonitrile (approx 100-150 mL) and water. The brown crystals were filtered out, washed with water and dried under vacuum (5.51 g, 80%).

TLC (20% EtOAc/hexane) visualised with UV and vanillin:
TLC


Risk and Hazard Assessment:
See: Formylation of 1-(4-fluorophenyl)-2,5-dimethyl-1H-pyrrole (PMY 2-1)

See also:
Preparation of 1-(4-fluorophenyl)-2,5-dimethyl-1H-pyrrole-3-carbaldehyde
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14th February 2012 @ 06:07
Target synthesised in 34% yield. 05/03/12 Purified further by trituration (Et2O) to obtain the pure product as a white powder (28 mg).

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Synthesis of TCMDC-123794 using the method used for MY 31-5 and PMY 34-1 for the preparation of the acid chloride. Acid chloride batch JRC 3-1.

PMY11-5.png

Reaction start time: 17.30 14/02/12
PMY 9-1 (100 mg, approx 0.38 mmol, approx 1.2 equiv. Contains slight impurity) and DIPEA (0.16 mL, 1.22 mmol, 2.3 equiv.) were stirred in dry THF (2 mL). A solution of acid chloride JRC 3-1 (80 mg, 0.32 mmol, 1 equiv.) in THF (3 mL) was added to the mixture and the reaction heated to 80 °C. After 17 hours, TLC shows new products and SM. 4-DMAP (approx. 20 mg, 0.16 mmol, 0.5 equiv.) added. After a further one hour, reaction still shows SM by TLC. Cooled to room temperature and concentrated under reduced pressure. Residues (orange oily solid) purified by chromatography (45% EtOAc/hexane, then 2% MeOH/DCM) gave impure product (80 mg) as a yellow solid. Further chromatography (55-100% EtOAc/hexane) gave the product (52 mg, 34%) as a off-white crystals. Mostly pure by 1H NMR.

TLC (10% MeOH/DCM) visualised with UV and vanillin:
TLC 17 hours

left plate, 17 hours. Right plate, 18 hours.

NMR:
1H NMR after 1st column
1H NMR triturated impurities
1H NMR triturated
1H NMR after 2st column


Mass Spec:
ESI mass spec


See also:
Coupling of pyrrole carboxylic acid PMY 8-4 and glycinamide derivative PMY30-3 (PMY 34-1)
Coupling of pyrrole acid chloride PMY 32-2 and glycinamide (PMY 31-5)
Synthesis of TCMDC-123794 via acid chloride (PMY 11-2)
Synthesis of TCMDC-123794 via acid chloride (PMY 11-4)
Synthesis of TCMDC-123794 via acid chloride (PMY 11-4)

Risk and Hazard Assessment:
See: Synthesis of TCMDC-123812 via acid chloride (PMY 10-1)
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