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31st January 2012 @ 00:42
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Benzoyl protection of PMY 9-1 (PMY 33-1) for biological testing.

Reaction Scheme

Reaction start time: 12.15 31/01/12
PMY 9-1 (1.00 g, 3.82 mmol, 1 equiv.) in DCM (15 mL) was stirred in an ice bath. DIPEA (0.73 mL, 4.21 mmol, 1.1 equiv.) followed by benzoyl chloride (0.49 mL, 4.21 mmol, 1.1 equiv.) were added. After 1 hour, reaction allowed to warm to room temperature. After 1.5 hours, TLC shows reaction not complete. 5 hrs, not complete. Further benzoyl chloride (0.05 mL, 0.42 mmol, 0.11 equiv.) added. After 21 hours, reaction still not complete. 2M HCl (5 mL) was added and the reaction stirred for 1 hour. 10% NaHCO3 was added until basic, then separated. The organic was washed with water (10 mL), brine then dried (MgSO4) and concentrated to an orange foam/gum. Chromatography (50-100% EtOAc/hexane) gave:

PMY 33-1-A colourless oil
PMY 33-1-B white solid
PMY 33-1-C (0.64 g) almost colourless thick oil, solidified on standing to white solid not consistent with expected product by 1H NMR.
PMY 33-1-D (0.14 g, 100% EtOAc flush), possible product by 1H NMR, impure.

TLC (10% MeOH/DCM) visualised with UV and vanillin:
TLC 90 minutes
TLC 5 hours
TLC 21 hours

Left to right: PMY 9-1-A (impure, 2 spots), mix, reaction mixture.
Consumption of impurity observed.


See also: Synthesis of side-chain of TCMDC-123794 (PMY 9-1)

Risk and Hazard Assessment:
Risk Assessment
Attached Files
30th January 2012 @ 23:01
Product not isolated, "lost" on silica. Repeated successfully PMY 31-5

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Synthesis of the amide analogue of TCMDC-123812 by coupling of glycinamide and acid PMY 8-4 via the acid chloride.

Reaction Scheme

Reaction start time: 10.55 31/01/12
PMY 8-4 (100 mg, 0.43 mmol, 1 equiv.) was stirred in dry PhMe (2 mL) and cooled in ice. Thionyl chloride (50 μL, 0.67 mmol, 1.6 equiv.) was added followed by DMF (20 μL). After 50 minutes, the reaction was allowed to warm to room temperature. After 2 hour 40 mins at room temperature, reaction was concentrated under reduced pressure. Further PhMe (4 mL) was added and concentrated again. Hexane (3 mL) was added and the residue stirred for 15 mins at room temperature, then filtered (syringe filter). The pale yellow solution was dropped spilling approx half before being concentrated under reduced pressure to a yellow gum which was dissolved in dry THF (2 mL). Glycinamide.HCl (57 mg, 0.51 mmol, 1.2 equiv.) and DIPEA (0.13 mL, 0.99 mmol, 2.3 equiv.) were stirred for 15 minutes (did not dissolve). THF solution of acid chloride was added and the mixture heated to 80 °C. After overnight heating, TLC shows 2 new products and a small amount of SM. Reaction was a white precipitate in a slightly yellow oil. Reaction concentrated. Mass spec of crude (MeOH then filtered) does not show expected product. Anhydride observed ([M+Na] 471, [2M+Na] 919.00) and an unknown ([M+Na] 553, [2M+Na] 1083). Residue was purified by chromatography (10-45% EtOAc/hexane), two fractions, early running 31-4-A and later running 31-4-B. The red spot on the TLC should have come off the column but didn't. Column obviously not flushed thoroughly enough.

Note: Glycinamide.HCl (57 mg) DIPEA (0.13 ml) mix (attempted freebase) is not fully soluble in THF, nor DMF (4 mL).

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


Reference:
Patent:WO2006076202

See also:
Coupling of pyrrole carboxylic acid PMY 8-3 and glycinamide (PMY 31-3)

Risk and Hazard Assessment:
See: Synthesis of TCMDC-123812 via acid chloride (PMY 10-1)
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Attached Files
23rd January 2012 @ 06:59
Target synthesised in 89% yield.

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Repeat of PMY 8-3 hydrolysis of Ethyl 1-(4-fluorophenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate to give the desired acid(1-(4-Fluorophenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylic acid).

Reaction Scheme

Reaction start time: 17.45 23/01/11
The remaining PMY 6-2 (2.16 g, 8.27 mmol, 1 equiv.) was dissolved in EtOH (approx 30 mL) and 20% NaOH (40 mL, approx 17 equiv.). Heated to reflux. After overnight reflux, the reaction was cooled in ice. approx 15% HCl was added slowly until a pale precipitate formed. The mixture was stirred for a further 15 minutes and then filtered. The pale brown cake was washed with water (2 × 25 mL). After drying under vacuum the product was obtained as a pale brown powder (1.73 g, 89%).

NMR:
1H NMR


Risk and Hazard Assessment:
As for Hydrolysis of Ethyl 1-(4-fluorophenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate (PMY 8-1)

See also:
Hydrolysis of Ethyl 1-(4-fluorophenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate (PMY 8-3)
Hydrolysis of Ethyl 1-(4-fluorophenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate (PMY 8-2)
Linked Posts
Attached Files
23rd January 2012 @ 00:48
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Synthesis of the amide analogue of TCMDC-123812 by coupling of glycinamide and acid PMY 8-3 using DCC/HOBt conditions following tip from Bill Jackson (Creative Chemistry)

Reaction Scheme

Reaction start time: 13.47 23/01/12
PMY 8-3 (100 mg, 0.43 mmol, 1 equiv.), Glycinamide.HCl (52 mg, 0.47 mmol, 1.1 equiv.) and pyridine (0.04 mL, 0.48 mmol, 1.1 equiv.) were stirred in DCM (15 mL) and dry DMF (3 mL) at 0 °C. Anhydrous HOBt (87 mg, 0.64 mmol, 1.5 equiv.) was added followed by DCC (0.10 mL, 0.64, 1.5 equiv.). After 3 hours, TLC shows formation of a new product, SM remains. Reaction left overnight. After 19 hours, TLC shows only a small trace of SM and a new product. Mixture was poured into brine (20 mL) and the layers separated. The organic layer was dried (MgSO4) and concentrated under reduced pressure. The residue (brown oil with precipitate) was adsorbed onto a short silica column and purified by chromatography (30%-50% EtOAc/hexane). 2 spots collected. Top spot (red stain), PMY 31-3-A and almost baseline spot (UV, no vanillin stain) PMY 31-3-B. PMY 31-3-A contains 1H NMR signals associated with pyrrole component, no expected methylene signal for coupled product. Also contains dicyclohexylurea (DCU) type signals. 31-3-B contains DCU and HOBt type signals, no pyrrole.

TLC visualised with UV and vanillin:
TLC 3 hrs
TLC 19 hrs

3 hrs: left plate, 10% MeOH/DCM; Rightplate, 50% EtOAc/hexane. 19hrs (50% EtOAc/hexane).

NMR:
1H NMR 31-3-B
1H NMR 31-3-A


Mass Spec:
PMY 31-3-A MassSpec

ESI+, not consistent with expected product. 462 [M+Na] (consistent with PMY 12-1-A, urea-by product.

Risk and Hazard Assessment:
RA
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Attached Files
19th January 2012 @ 00:24
===

Synthesis and isolation of the acid chloride of PMY 8-3 for coupling reactions.

Reaction Scheme

Reaction start time: 11.55 19/01/12
PMY 8-3 (400 mg, 1.71 mmol, 1 equiv.) was stirred in dry PhMe (10 mL). 1 drop DMF added followed by thionyl chloride (0.4 mL, 5.55 mmol, 3.2 equiv.). The reaction was heated to reflux. After 4 hours, reaction cooled and left under nitrogen overnight.Lab electrical shutdown. Reaction concentrated under reduced pressure. Mixture bumped on Büchi, some mass lost. Concentrated twice more from toluene (2 × 25 mL). Brown solid. 1H NMR shows only trace pyrrole peaks. Messy.

NMR:
1H NMR crude


Risk and Hazard Assessment:
As for Synthesis of TCMDC-123812 via acid chloride (PMY 10-1), except formation of acid chloride at reflux.
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Attached Files