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11th December 2011 @ 22:21
SM recovered.

===

Hydrolysis of PMY 27-1 to give the antipyrine glycanamide for coupling to pyrrole acid core. According to literature reference selective hydrolysis with catalytic base is successful, but not yield given.

Reaction Scheme

Reaction Start Time: 09.40 12/12/11
PMY 27-1 (140 mg, 0.38 mmol, 1 equiv.) was stirred in PhMe (20 mL) and heated to reflux. Partial solution. Sodium hydroxide (22 mg, 0.55 mmol, 1.4 equiv.) was added. After 2 hours, TLC shows no reaction. Water (appox. 1 mL) was added. Reaction mixture turns clear then hazy again. After 4 hours (13.40), reaction is a clear solution again. TLC shows conversion to a new product by vanillin dip (overlapping Rf). At 7 hours (16.30), TLC shows SM still remaining. Reaction cooled to room temperature and stored at -20 °C.fumehood shutdown required for 13/12/11. 0900 15/12/11 Reaction reheated to reflux, still colourless. Still not complete by TLC at 1600 15/12/11. Reaction cooled 0930 16/12/11. TLC shows no change. White crystals form on cooling. Filtered and dried under vacuum (62 mg). 1H NMR consistent with PMY 27-1. Filtrate washed with water (2 × 10 mL), brine, dried (MgSO4) and concentrated to a yellow oil (20 mg). Consistent with SM by 1H NMR.

TLC (10% MeOH/DCM) visualised with UV and vanillin:
TLC 7 hours
TLC 4 hours, vanillin dip strongly heated
TLC 4 hours, vanillin dip gently heated
TLC 2 hours


NMR:
1H NMR oil, recov SM.
1H NMR solid, recov SM


Reference:
J. Chem. Pharm. Res., 2010, 2(4):410-41

See also:
Coupling of hippuric acid and 4-aminoantipyrine using T3P (PMY 27-1)
Synthesis of hippuric acid (PMY 26-1)

Risk and Hazard Assessment:
Risk Assessment
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8th December 2011 @ 03:29
Product obtained in 52% yield.

===

Coupling of hippuric acid and 4-aminoantipyrine using T3P to obtain the glycine benzamide.

Reaction Scheme

Reaction start time: 16.30 08/12/11
Hippuric acid PMY 26-1 (200 mg, 1.12 mmol, 1 equiv.) and 4-aminoantipyrine (250 mg, 1.23 mmol, 1.1 equiv.) were dissolved in pyridine (1 mL) and DMF (1 mL) and cooled in ice/water. 50% T3P in EtOAc (1 mL, 1.7 mmol, 1.5 equiv.) was added after 30 minutes, the reaction was allowed to warm to room temperature and the reaction stirred for 16 hours. 0.5M HCl (10 mL) and EtOAc (10 mL) were added. After approx 10 minutes of stirring, copious white precipitate formed. Cooled in ice then filtered, white solid washed with water. Filtrate (pH 4) was separated and the organic layer washed with 5% NaOH (10 mL), water (3 × 10 mL), brine then dried (MgSO4) and concentrated to a orange solid, PMY 27-1-B (24 mg). TLC shows white solid and orange gum to be new products. White solid dried under vacuum, PMY 27-1-A (211 mg, 52%). 27-1-A is consistent with expected product by 1H NMR.

PMY 27-1-A solubility:
DCM (reasonably), acetone (sparingly), EtOAc (sparingly), water (insoluble), [from reaction DMF (readily)].

TLC (10% MeOH/DCM) visualised with UV and vanillin:
TLC 16 hours

TLC before quench. Left to right: PMY 26-1 in DMF, mix, reaction mixture, 4-aminoantipyrine.

After work-up

Left to right: white solid, mix, PMY 26-1 (loaded in acetone), 4-aminoantipyrine, mix, orange solid.

comparison of components

(12% MeOH/DCM) Left to right: white solid, mix, 4-aminoantipyrine, mix, orange solid, mix, PMY 26-1.

NMR:
1H PMY 27-1-A acetone
1H PMY 27-1-A CDCl3
13C NMR


Risk and Hazard Assessment:
As for, Synthesis of TCMDC-123812 using T3P (PMY 10-4)

See also:
Synthesis of hippuric acid (PMY 26-1)

References:
In addition to reference also

10.1021/op900178d
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Attached Files
6th December 2011 @ 23:02
Product obtained in 75% yield.

===

Benzoyl protection of glycine using benzoyl chloride in 10% aqueous sodium hydroxide. Prepared according to Org Syn.

Reaction Scheme

Reaction Start Time: 10.30 07/12/11
Glycine (12.5 g, 0.17 mol, 1 equiv.) was dissolved in NaOH(aq) (13.3 g in approx 130 mL water, 0.33 mol, 2 equiv.). The flask was placed in a room temperature water bath and benzoyl chloride (21 mL, 0.18 mol, 1.06 equiv.) was added portionwise keeping the temperature below 30 °C. Total addition time approx 60 mins. Stirred for a further hour then cooled in ice. Conc. HCl (approx 20 mL) was added and the mixture stirred for 30 mins. pH 3-4. Copious white precipitate. Filtered and washed with water. The cake was transferred to a beaker and triturated with 100 mL hot DCM for 10 minutes. Filtered and washed with DCM (2 × 20 mL). After air drying (10 mins), dissolved in boiling water (approx 500 mL), hot filtered to remove some residual solid and allowed to crystallise slowly overnight. The crystals were filtered out (room temp.) and washed with water to obtain the product hippuric acid as white needles (22.4 g, 75%) after drying under a stream of nitrogen. Mpt. 189-190 °C (water), consistent with literature.

Recrystallised crystals


Solubility:
approx 2 mg/mL in EtOAc: 300 mg sonicated then refluxed in EtOAc (10 mL) for 5 minutes. Allowed to cool to room temperature, filtered and then filtrated concentrated under reduced pressure to obtain white powder (20 mg).

Soluble in DMF (very very approx 50 mg/mL).

NMR:
1H NMR
13C NMR


Risk and Hazard Assessment:
Risk Assessment


References:
J. Chem. Pharm. Res., 2010, 2(4):410-41
Above reference contains procedure with incorrect yield calculation.

Organic Syntheses, Coll. Vol. 2, p.328 (1943); Vol. 12, p.40 (1932)

InChI=1S/C9H9NO3/c11-8(12)6-10-9(13)7-4-2-1-3-5-7/h1-5H,6H2,(H,10,13)(H,11,12)
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Attached Files
6th December 2011 @ 05:19
===

Coupling of acid PMY 8-3 and 4-aminoantipyrine for a analogue of TCMDC-123794 that does not contain the ester linker. Using T3P as coupling reagent.

Reaction Scheme

Reaction start time: approx 1600 07/12/11
PMY 8-3 (50 mg, 0.21 mmol, 1 equiv.), 4-aminoantipyrine (48 mg, 0.24 mmol, 1.1 equiv.) were dissolved in EtOAc (approx. 1 mL) and pyridine (0.1 mL, 1.3 mmol, 6 equiv.) and cooled in salt/ice. T3P 50% in EtOAc (0.26 mL, 0.43 mmol, 2 equiv.) was added and the reaction allowed to warm to room temperature overnight. 0.5M HCl (4 mL) and EtOAc (4 mL) were added and the mixture stirred for 30 minutes. The layers separated and the organic layer washed with further 0.5M HCl (5 mL) then 5% NaOH (2 × 10 mL), water (3 × 5 mL), brine then dried (MgSO4) and concentrated. Mass spec consistent with expected product. Product to be purified by chromatography. Chromatography (0-10% MeOH/DCM) gave slightly cleaner material by NMR, gradient too steep, use circa 3% MeOH/DCM isocratic next time. Reaction to be repeated on larger scale, possibly elevated reaction temperature.

TLC (10% MeOH/DCM) visualised UV and vanillin:
TLC after quench


NMR:
1H NMR post washes


Mass Spec:
m/z (ESI+) 419 [M+H]+, 38%, 441 [M+Na]+, 100%.

Risk and Hazard Assessment:
See Synthesis of TCMDC-123794 Side-chain (PMY 5-1) and Synthesis of TCMDC-123812 using T3P (PMY 10-4)

See also:
Coupling of acid PMY 8-2 and 4-aminoantipyrine using EDC for a linker-less analogue of TCMDC-123794 (PMY 12-3)
Coupling of acid PMY 8-2 and 4-aminoantipyrine for a linker-less analogue of TCMDC-123794 (PMY 12-2)
Coupling of acid PMY 8-2 and 4-aminoantipyrine for a linker-less analogue of TCMDC-123794 (PMY 12-1)
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Attached Files
5th December 2011 @ 05:14
===

Coupling of carboxylic acid PMY 8-2 with glycolamide using propylphosphonic anhydride ( (T3P) and pyridine in ethyl acetate. Attempt to optimise coupling conditions. Method based on reference shown below.

Reaction Scheme

Reaction start time: 15.30 05/12/11
PMY 8-3 (50 mg, 0.21 mmol, 1 equiv.), glycolamide (18 mg, 0.24 mmol, 1.1 equiv.) were dissolved in EtOAc (approx. 1 mL) and DMF (0.2 mL), pyridine (0.1 mL, 1.3 mmol, 6 equiv.) and cooled in salt/ice. T3P 50% in EtOAc (0.26 mL, 0.43 mmol, 2 equiv.) was added dropwise over 3 minutes. 4-DMAP (a few crystals) were added as a solution in EtOAc (0.5 mL) and the reaction allowed to warm to room temperature overnight. After 17 hours, 0.5M HCl (4 mL) was added. The mixture was stirred for approx 1.5 hours. The mixture was diluted with EtOAc (approx 10 mL) and the layers were then separated and the organic washed again with 0.5M HCl (10 mL) followed by brine, then dried (MgSO4) and concentrated to a dark brown solid. 1H NMR shows mostly SM acid and a new product not consistent with desired product. The side reaction signals were observed in the crude mixture in PMY 10-2.

TLC (10% MeOH/DCM) visualised with UV and vanillin:
TLC before quench


NMR:
1H NMR crude


Risk and Hazard Assessment:
See: Synthesis of TCMDC-123794 Side-chain (PMY 5-1)
Propylphosphonic anhydride is corrosive

Reference:
DOI:10.1021/ol201875q

See also:
Synthesis of TCMDC-123812 using DIC/DMAP (PMY 10-3)
Synthesis of TCMDC-123812 via acid chloride (PMY 10-2)
Synthesis of TCMDC-123812 via acid chloride (PMY 10-1)
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Attached Files