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2nd September 2013 @ 01:26

See also: Coupling of Boc-Gly-OH and 4-aminoantipyrine (PMY 29-2) but with EDCI and HOBt.

Procedure:
Boc-Gly-OH (400 mg, 2.28 mmol, 1 equiv.), EDCI (524 mg, 2.74 mmol, 1.2 equiv.) and HOBt (30 mg, 0.22 mmol, 0.1 equiv.) were stirred in CH2Cl2 (20 mL) and stirred at room temperature for 15 minutes. 4-Aminoantipyrine (510 mg, 2.54 mmol, 1.1 equiv.) was added and the reaction mixture stirred overnight.

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 an orange/brown oil. 

No NMR data recorded - inconclusive result.

Data:

TLC in 10% MeOH in CH2Cl2

Hazard and Risk Assessment:

See Coupling of Boc-Gly-OH and 4-aminoantipyrine (PMY 29-2)

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3rd February 2012 @ 02:41
Target synthesised in 67% yield over 2 steps. Needs 13C, 19F

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Coupling of acid chloride of PMY 8-4 and glycinamide derivative PMY 30-3 (crude) to access the amide analogue of TCMDC-123794.

Reaction Scheme

Reaction start time: 10.40 03/02/12
PMY 8-4 (178 mg, 0.76 mmol, 1 equiv.) was stirred in dry PhMe (4 mL) and cooled in ice. Thionyl chloride (100 μL, 1.38 mmol, 1.8 equiv.) was added followed by DMF (20 μL). The reaction was allowed to warm to room temperature. After 3.5 hours, reaction was concentrated under reduced pressure twice from PhMe (3 mL). Triturated with hexane (4 mL), filtered (syringe filter) and concentrated to a yellow solid. The acid chloride was dissolved in dry THF (4 mL).

Crude PMY 30-3 was stirred in dry THF (4 mL) and DIPEA (0.99 mL, 7.63 mmol, 10 equiv.) was added. After stirring for 5 minutes, the acid chloride solution was added and the reaction heated to 80 °C. After 20 hours, the reaction was cooled to room temperature and left under a nitrogen atmosphere. TLC shows reaction complete. After 2 days, the reaction was concentrated under reduced pressure to an orange oil. Oil crystallised when attempting to load onto silica column. Adsorbed onto silica and purified by chromatography (50-100% EtOAc/hexane, then 5% MeOH/DCM) to obtain an orange oil that solidified on standing (1.25 g). The oil was dissolved in DCM (10 mL) and washed with 10% NaHCO3 (10 mL), water (3 × 10 mL) and brine then dried (MgSO4) and concentrated under reduced pressure to a yellow solid (170 mg, 70% of theory), consistent with a mixture of expected product and DIPEA by 1H NMR. After further drying under high vacuum, 1H NMR is free of DIPEA (162 mg, 67% over 2 steps based on PMY 30-3).

TLC (10% MeOH/DCM) visualised with UV and vanillin:
TLC 20 hours


NMR:
1H NMR with residual DIPEA
1H NMR, dried under high vac


Mass Spec:
m/z (ESI+) 498 [M+Na]+, 100%.
Mass Spec


See also:
Coupling of pyrrole acid chloride PMY 32-2 and glycinamide (PMY 31-5)
Deprotection of Boc-Gly-4-aminoantipyrine (PMY 30-3)
Synthesis of pyrrole acid chloride of PMY 8-4 (PMY 32-2)

Risk and Hazard Assessment:
See: Synthesis of TCMDC-123812 via acid chloride (PMY 10-1)
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2nd February 2012 @ 06:30
Target synthesised in 39% yield. Requires 13C, 19F

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Synthesis of the amide analogue of TCMDC-123812 by coupling of glycinamide and preformed acid chloride PMY 32-2.

Reaction Scheme

Reaction start time: 18.00 02/02/12
Glycinamide.HCl (51 mg, 0.51 mmol, 1.2 equiv.) and DIPEA (0.11 mL, 0.89 mmol, 2.3 equiv.) in dry DMF (6 mL). Incomplete solution (even on heating). PMY 32-2 (90 mg, 0.39 mmol, 1 equiv.) was dissolved in dry THF (4 mL) and added to the Glycinamide suspension. Reaction heated to 80 °C. After overnight heating, reaction was cooled to room temperature. After standing over the weekend, the mixture was concentrated under reduced pressure. The residue was purified by chromatography (50-100% EtOAc/hexane then 0-20% MeOH/DCM) to obtain a clear yellow oil (162 mg, 145% of theory!). 1H NMR shows residual DIPEA (salt?) and expected product. After drying under high vacuum overnight, mass still greater than theory (134 mg). White powder dissolved in 10% NaHCO3 (10 mL) and DCM (10 mL, yellow solution) some insoluble powder. Separated and the organic washed with water (3 × 10 mL), brine and dried (MgSO4) and concentrated under reduced pressure to a white powder (44 mg, 39%). Mpt 193-195 °C.

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

DMF interfering with TLC.

NMR:
1H NMR with residual DIPEA
1H NMR, dried under high vac


Mass Spec:
m/z (ESI+) 312 [M+Na]+, 100%
Mass Spec


See also:
Coupling of pyrrole carboxylic acid PMY 8-3 and glycinamide (PMY 31-4)
Synthesis of pyrrole acid chloride of PMY 8-4 (PMY 32-2)

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