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21st March 2012 @ 00:18
Product obtained.

===

Synthesis of TCMDC-123794 using the method used for PMY 10-6. Acid chloride batch PMY 32-3.

PMY11-5.png

Reaction start time: 15.30 21/03/12
PMY 9-1 was dried under reduced pressure for 4 hours prior to reaction (420 mg, 1.61 mmol, 2.0 equiv.) and was stirred with 4-DMAP (120 mg, 0.98 mmol, 0.5 equiv.) and DIPEA (0.30 mL, 1.72 mmol, 2.2 equiv.) in anhydrous THF (3 mL). PMY 32-3 (50 mg/mL in THF, 4 mL, 0.79 mmol, 1 equiv.) was added dropwise over 5 minutes to the orange solution at room temperature. A precipitate forms within 10 minutes. After 1 hour, product is forming, SM still remains. No change after 18 hours at room temperature. Reaction was adsorbed onto silica and purified by chromatography (50% EtOAc/hexane). After a long running column, 2 fractions containing product were collected, PMY 11-6-A and -B. Both triturated (Et2O and EtOAc) to obtain white powder PMY 11-6-A (69 mg) and PMY 11-6-B.

TLC (66% EtOAc/hexane) visualised with UV and vanillin:
TLC 1 hour
TLC 18 horus
TLC 2 hours

Left to right: 1 hr; JRC 2-1, M, RM, M, PMY 9-1. 2 hr; JRC 2-1, M, RM, M, PMY 11-5. 18 hr; JRC 2-1, M, RM.

Mass Spec:
ESI mass spec


See also:
Synthesis of TCMDC-123812 via acid chloride (PMY 10-6)
Synthesis of TCMDC-123794 via acid chloride, improved method (PMY 11-5)
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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20th March 2012 @ 23:51
Yield: 55
Reagent: JRC_2-1
Product obtained in 55% crude yield used in PMY 11-6 and PMY 42-1.

===

Synthesis and isolation of the acid chloride of PMY 8-4 for coupling reactions.

Reaction Scheme

Reaction start time: 10.40 21/03/12
Acid JRC 2-1 (500 mg, 2.14 mmol, 1 equiv.) was stirred in dry PhMe (3 mL) and cooled in ice. Thionyl chloride (0.31 mμL, 4.29 mmol, 2 equiv.). The reaction was allowed to warm to room temperature. After 3 hours, the reaction was concentrated under reduced pressure twice from PhMe (3 mL). The residue was triturated twice with hexane (8 + 2 mL) and the filtrate concentrated under reduced pressure to obtain the acid chloride as a yellow solid (298 mg, 55%). The product was used without further purification.

See also:
Synthesis of TCMDC-123812 via acid chloride (PMY 10-6)
Synthesis of pyrrole acid chloride of PMY 8-4 (PMY 32-2)
Hydrolysis of Ethyl 1-(4-fluorophenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate (JRC 2-1)
Synthesis of pyrrole acid chloride of PMY 8-3 (PMY 32-1)

Risk and Hazard Assessment:
As for Synthesis of TCMDC-123812 via acid chloride (PMY 10-1).
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15th March 2012 @ 03:34
===

To overcome solubility issues with glycinamide, the salt-break and imine formation will be attempted in aqueous methanolic conditions employing sodium cyanoborohydride as reducing agent.

38-4.png

Reaction Start Time: 15.00 15/03/12
Glycinamide hydrochloride (66 mg, 0.60 mmol, 1.3 equiv.) was dissolved in water (approx 0.2 mL). 1M NaOH solution (1 mL, 1 mmol, 2.2 equiv.) was added followed by aldehyde PMY 2-5 (100 mg, 0.46 mmol, 1 equiv.). Methanol was added to the slurry until dissolved (approx. 15-20 mL) and the mixture stirred for 1.5 hours. Sodium cyanoborohydride (43 mg, 0.69 mmol, 1.5 equiv) was added as a solution in methanol (2 mL). Drying with MgSO4 was omitted due to potential for the glycinamide to precipitate if water is removed. If no reaction is observed, the reaction will be dried. After 2 hours, no reaction. Stirred at room temperature overnight. No reaction by TLC. MgSO4 added and the reaction heated to reflux. 19/03/12 Reaction is complete by TLC with a single less-polar product spot. Desired product should be considerably more polar than SM. Reaction is a colourless solution with white powder. Reaction cooled and filtered, washed through with further MeOH. The filtrate was concentrated under reduced pressure. The residue was stirred in DCM (50 mL) and washed with 10% NaHCO3 (10 mL), brine then dried (MgSO4) and concentrated under reduced pressure to a brown oil (77 mg). 1H NMR shows only one product. Unknown, only additional Methyl singlet. Not consistent with desired product.

TLC (10% MeOH/DCM) visualised with UV and vanillin:
TLC before workup
TLC 3 hours, reflux
Initial TLC


NMR:
1H NMR crude


Reference:
doi:10.1002/0471264180.or059.01
http://www.orgsyn.org/orgsyn/orgsyn/prepContent.asp?prep=cv6p0499

Risk and Hazard Assessment:
Risk Assessment diagram
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14th March 2012 @ 23:25
SM recovered.

===

Synthesis of amine-linked analogue of TCMDC-123812 via reductive amination using sodium triacetoxyborohydride in 1,2-DCE.

38-3.png

Reaction Start Time: Approx 10.45 15/03/12
Glycinamide hydrochloride (66 mg, 0.60 mmol, 1.3 equiv.) was stirred in 1,2-DCE (5 mL) with freshly activated mol. sieves. Triethylamine (82 μL, 0.60 mmol, 1.3 equiv.) was added and the reaction stirred for approx 5 minutes. Aldehyde PMY 2-5 (100 mg, 0.46 mmol, 1 equiv.) was added. After 30 minutes, sodium triacetoxyborohydride (195 mg, 0.92 mmol, 2.0 equiv.) was added. Reaction is a hazy suspension. Further 1,2-DCE (10 mL) was added. Still a hazy suspension. No reaction after approx. 23 hours by TLC. MgSO4 added and the reaction heated to reflux. 19/03/12 Reaction is a dark brown mixture, no change by TLC. Reaction was cooled and filtered through celite (DCM). 10% NaHCO3 (25 mL) was added to the filtrate and stirred for 10 minutes. The layers separated and the aqueous extracted with DCM (2 × 20 mL). The combined extracts were washed with brine, dried (MgSO4) and concentrated under reduced pressure to a brown solid/gum (148 mg). 1H NMR shows mostly SM aldehyde.

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


NMR:
1H NMR crude


See also:
Synthesis of amine-linked analogue of TCMDC-123812 via reductive amination using sodium triacetoxyborohydride (PMY 38-2)

Risk and Hazard Assessment:
See: Synthesis of amine-linked analogue of TCMDC-123812 via reductive amination (PMY 38-1)
Also 1,2-dichloroethane is irritant to eyes, skin and respitory system, highly flammable and may cause cancer.
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13th March 2012 @ 06:15
===

Synthesis of amine-linked analogue of TCMDC-123812 via reductive amination using sodium triacetoxyborohydride as reductant. 38-1 gave mainly the alcohol. A milder reducing agent should help here.

38-2.png

Reaction Start Time: 11.10 14/03/12
Glycinamide hydrochloride (132 mg, 1.20 mmol, 1.3 equiv.) was stirred in DCM (40 mL). Triethylamine (0.17 mL, 1.20 mmol, 1.3 equiv.) was added and the mixture stirred for 10 minutes. Reaction turns briefly hazy. aldehyde PMY 2-5 (200 mg, 0.92 mmol, 1 equiv.) was added followed by freshly activated molecular sieves. The reaction stirred for 5 minutes. Sodium triacetoxyborohydride (214 mg, 1.01 mmol, 1.1 equiv.) was added and the reaction left to stir at room temperature. After 2 hours, the reaction is still a hazy solution/suspension. TLC shows mainly starting material, no reduced aldehyde, minor polar spot (red stain). A few drops (4-5) of glacial acetic acid were added and stirring continued. After 3 hours, TLC shows no major change, potentially some more conversion. After overnight reaction, still no change by TLC. A further portion of AcOH (0.3 mL) was added. After a further 7 hours, a small amount of reduced aldehyde is observed on TLC. No further change overnight (16/03/12). Reaction filtered through celite and 10% NaHCO3 (30 mL) added to the filtrate.

TLC (10% MeOH/DCM) visualised with UV and vanillin:
TLC 2 hours
TLC 3 hours


NMR:
1H NMR precipitate
1H NMR


Risk and Hazard Assessment:
See: Synthesis of amine-linked analogue of TCMDC-123812 via reductive amination (PMY 38-1)

Reference:
doi:10.1021/jo960057x
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