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13th August 2012 @ 04:30
Starting material recovered according to TLC. To be resubjected to conditions using DMF as catalyst.

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Conversion of PMY 59-2-B oxazole carboxylic acid (impure) to primary amide via reaction of the acid chloride with ammonia.

PMY60-2.png

Reaction Start Time: 11.55 13/08/12
PMY 59-2-B (28 mg, 0.09 mmol, 1 equiv.) was stirred in PhMe (0.6 mL). Thionyl chloride (0.05 mL, 0.7 mmol, 7.8 equiv.) was added and the reaction stirred at room temperature. After 4 hours, the reaction was concentrated under reduced pressure twice from PhMe (2 mL). THF (4 mL) was added and ammonia gas introduced via a balloon. A colourless precipitate forms. The reaction was allowed to stir overnight under a ammonia atmosphere. TLC shows starting material.

No decomposition observed as for PMY 60-1. Reaction probably requires harsher activation conditions. DMF catalyst to be added next time. LC/MS confirms presence of starting material, no significant decomposition.

TLC (15% MeOH/DCM) visualised with UV and vanillin:
TLC overnight


LC/MS
LCMS


See also:
Hydrolysis of PMY 58-2 methyl ester (PMY 59-2)

Risk and Hazard Assessment:
See: Conversion of PMY 59-1 oxazole carboxylic acid to primary amide (PMY 60-1) and Synthesis of TCMDC-123812 via acid chloride (PMY 10-2)
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6th August 2012 @ 00:23
Reaction successful but in poor yield. Starting material was not entirely clean nor is the product. Used without further purification in PMY 60-2.

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Hydrolysis of PMY 58-2 methyl ester to the acid using aqueous sodium hydroxide.

PMY59-1.png

Reaction Start Time: 12.00 07/08/12
PMY 58-2 (196 mg, 0.62 mmol, 1 equiv.) was dissolved in ethanol (6 mL). A small amount of white powder did not dissolve and was triturated out and kept. Sodium hydroxide (250 mg, 6.2 mmol, 10 equiv.) was dissolved in water (4 mL) and added to the solution of PMY 58-2. After 1.5 hours, reaction complete by TLC. 2M HCl (6 mL) added. The reaction turns hazy but no copious precipitate. The reaction was concentrated under reduced pressure to remove ethanol, crystals form. 2M NaOH (1 mL) added and the mixture gently heated. Crystals do not dissolve. [Still acidic of course, brain malfunction.] Basified to pH14 with dilute NaOH. Washing with DCM results in white suspension/emulsion. Partial separation, DCM layer concentrated to orange solid, PMY 59-2-A. pH adjust of aqueous (approx 60 mL total volume) to ca. pH 10 gave a clear solution. Washed with further DCM (10 mL). HCl added until pH 1, mixture turns cloudy. Extracted with DCM (3 × 20 mL). The combined extracts were washed with brine, dried (MgSO4) and concentrated to a pale yellow solid, PMY 59-2-B (28 mg, 15%). The aqueous layer was concentrated under reduced pressure and triturated with DCM. The combined DCM extracts were washed with brine, dried (MgSO4) and concentrated under reduced pressure to a white solid, PMY 59-2-C.

1H NMR shows:
PMY 59-2-A: unknown impurity.
PMY 59-2-B: Consistent with expected product and impurity. LC/MS consistent shows 301 [M+H]+.

LC/MS:
LCMS


NMR:
1H NMR PMY 59-2-B
1H NMR PMY 59-2-A


See also:
Hydrolysis of PMY 58-2 methyl ester (PMY 59-1)
Scaled-up cyclodehydration of carboxamide PMY 57-2 (PMY 58-2)
Hydrolysis of ethyl 5-methyl-1-phenyl-1H-pyrazole-4-carboxylate (PMY 44-1)
Hydrolysis of Ethyl 1-(4-fluorophenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate (JRC 2-1)
Hydrolysis of Ethyl 1-(4-fluorophenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate (PMY 8-2)

Risk and Hazard Assessment:
As for Hydrolysis of Ethyl 1-(4-fluorophenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate (PMY 8-2)
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1st August 2012 @ 01:54
Decomposition of starting material into multiple unknown products.

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Conversion of PMY 59-1 oxazole carboxylic acid to primary amide via reaction of the acid chloride with ammonia.

PMY60-1.png

Reaction Start Time: 10.55 01/08/12
PMY 59-1 (62 mg, 0.21 mmol, 1 equiv.) was stirred in DCM (5 mL). Oxalyl chloride (53 μL, 0.62 mmol, 3 equiv.) was added. Reaction is a partial solution. DMF (1 drop) was added, bubbling is observed and the reaction becomes a solution. After 1 hour, the reaction was concentrated under reduced pressure. The residue was dissolved in THF (5 mL). Ammonia gas was bubbled through the solution for 30 minutes. A precipitate formed and the reaction was a hazy suspension. After a further hour, TLC shows absence of starting material and numerous product spots. The reaction was concentrated under reduced pressure to a yellow solid.

10.10 02/08/12 The residue was purified by chromatography on silica (5-50% acetone/hexane) 4 fractions obtained.

PMY 60-1-A (approx 10 mg), not consistent with product by 1H NMR.
PMY 60-1-B (approx 10 mg), not consistent with product by 1H NMR.
PMY 60-1-C (approx 10 mg), not consistent with product by 1H NMR.
PMY 60-1-D (approx 10 mg), not consistent with product by 1H NMR.

TLC (50% acetone/hexane) visualised with UV and vanillin:
TLC


LC/MS:
LCMS, 60-1-B


NMR:
1H NMR PMY 60-1-D actual
1H NMR PMY 60-1-C actual
1H NMR PMY 60-1-B
1H NMR PMY 60-1-A


See also:
Hydrolysis of PMY 58-2 methyl ester (PMY 59-1)
Synthesis of TCMDC-123812 via acid chloride (PMY 10-2)
Synthesis of pyrrole amide (PMY 42-1)

Risk and Hazard Assessment:
New form:
RA


Previous risk assessments:
Synthesis of TCMDC-123812 via acid chloride (PMY 10-2)
Synthesis of pyrrole amide (PMY 42-1)
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