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16th October 2012 @ 01:27
Synthesis des-methyl pyrazole analogue of TCMDC-123812. Repeat of PMY 66-1 but with 2-bromoacetamide as the limiting reagent.

PMY66-1.png

Reaction Start Time: 13.10 16/10/12
PMY 65-1 (99 mg, 0.48 mmol, 1.2 equiv.) was dissolved in DMF (1 mL) at room temperature. Potassium carbonate (133 mg, 0.96 mmol, 2.4 equiv.) was added followed by 2-Bromoacetamide (55 mg, 0.40 mmol, 1 equiv.).

See also:
Synthesis des-methyl pyrazole analogue of TCMDC-123812 (PMY 66-1)
Ester synthesis (AEW 5-3)
Hydrolysis of PMY 64-1 ethyl ester (PMY 65-1)

Risk and Hazard Assessment:
As for: Synthesis des-methyl pyrazole analogue of TCMDC-123812 (PMY 66-1)
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11th October 2012 @ 03:49
Product obtained according to 1H NMR evidence. Low yield due to inefficient extraction and losses on DMSO NMR samples. Further characterisation data to be collected.

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Synthesis des-methyl pyrazole analogue of TCMDC-123812 using method developed by Alice Williamson.

PMY66-1.png

Reaction Start Time: 15.55 11/10/12
PMY 65-1 (83 mg, 0.35 mmol, 1 equiv.)[calculation error: should be 0.40 mmol] was dissolved in DMF (2 mL) at room temperature. 2-Bromoacetamide (59 mg, 0.43 mmol, 1.2[1.1] equiv.) was added followed by potassium carbonate (98 mg, 0.71 mmol, 2[1.8] equiv.). TLC at 40 mins shows SM and potential product under DMF peak. Not conclusive from initial TLC. Reaction stirred overnight. Partionioned with water and EtOAc (10 mL 1:1). Extracted with EtOAc (3 × 10 mL). Combined organic layers were washed with water (2 × 10 mL), brine and dried (MgSO4) concentrated under reduced pressure and high vacuum to a white solid (36 mg). Crude 1H NMR consistent with expected product and unreacted 2-bromoacetamide (approx 1.1:1 product:acetamide). Aqueous/DMF layer re-extracted using DCM (4 × 10 mL).

Solid recrystallised from hot methanol (approx 4 mL) to obtain colourless needles (10 mg, 9% yield after losses from DMSO NMR samples and recryst). 1H NMR consistent with expected product, clean except very minor impurity doublet at 3.17 ppm. LC/MS shows clean product (264 [M+H]+)

Mpt. 220-221 °C (MeOH)

NMR:
1H NMR crude
1H NMR recrystallised


Sample submitted for service NMR.

TLC (10% MeOH/DCM) visualised with UV and vanillin:
TLC 40 min


LC/MS:
LC/MS after recryst

0to100ov30 MNR method

See also:
Ester synthesis (AEW 5-3)
Hydrolysis of PMY 64-1 ethyl ester (PMY 65-1)

Risk and Hazard Assessment:
As for: Synthesis of ether-linked analogue of TCMDC-123812 (PMY 37-1) except the safer base, potassium carbonate and dimethylformamide as solvent (flammable, harmful in contact with skin or inhaled, eye irritant, may damage unborn child).
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10th October 2012 @ 05:21
Product obtained in 89% yield.

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Hydrolysis of pyrazole ester PMY 64-1 using sodium hydroxide.

PMY65-1.png

Reaction Start Time: 15.40 10/10/12
PMY 64-1 (324 mg, 1.38 mmol, 1 equiv.) was stirred in Ethanol (approx 6 mL). Partial solution. 20% Sodium hydroxide solution (4 mL, approx. 20 mmol) was added and the reaction heated to reflux. Reaction is a solution. After 40 mins, reaction almost complete by TLC. After 1.5 hours, SM still remains by TLC. Reaction left overnight. No change by TLC. Reaction cooled and 32% HCl(aq) added until a white precipitate forms (pH 1). Filtered to obtain a fine white solid (253 mg, 89% of theory).

TLC (25% EtOAc/hexane) visualised with UV and vanillin:
TLC


NMR:
Data available. Upload not working.

See Also:
Deamination of 5-aminopyrazole PMY 63-1 (PMY 64-1)
Hydrolysis of Ethyl 1-(4-fluorophenyl)-5-methyl-1H-pyrazole-4-carboxylate (MJT 3-1)
Hydrolysis of Ethyl 1-(4-fluorophenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate (PMY 8-3)

Risk and Hazard Assessment:
See: Hydrolysis of Ethyl 1-(4-fluorophenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate (PMY 8-1)
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8th October 2012 @ 01:39
Product obtained in 66% yield.

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Deamination of the pyrazole PMY 63-1 using isoamyl nitrite using a literature procedure from Sutherland et al.

PMY64-1.png

Reaction Start Time: 13.30 08/10/12
Aminopyrazole PMY 63-1 (700 mg, 2.81 mmol, 1 equiv.) was dissolved in THF (15 mL) and isoamyl nitrite (1.5 mL, 11.2 mmol, 4 equiv.) was added. The reaction was heated to reflux. After 19 hours, the reaction was complete by TLC. The mixture was concentrated under reduced pressure and the yellow residue was recrystallised from hot ethanol. White needles. 1H NMR consistent with expected product, unknownm impurity peak at 4.78 ppm. Literature NMR in DMSO. Recrystallised again (EtOH/water) to give white needles (435 mg, 66%).

Mpt. 121-122 °C (EtOH). Consistent with literature.

TLC (25% EtOAc/hexane) visualised with UV and vanillin:
TLC 19 hours


NMR:
1H NMR
before recryst. Recrystallised NMR available, upload problem currently.

See also:
Synthesis of 5-aminopyrazole-4-ester (PMY 63-1)

Reference:
DOI:10.1021/jm901378u.

Risk and Hazard Assessment:
Risk Assessment
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4th October 2012 @ 07:56
Synthesis of ethyl 5-amino-1-(4-fluorophenyl)-1H-pyrazole-4-carboxylate using a literature procedure from Sutherland et al. Material to be deaminated using isoamyl nitrite.

PMY63-1.png

Reaction Start Time: 18.08 04/10/12
4-fluorophenylhydrazine hydrochloride (813 mg, 5.0 mmol, 1 equiv),ethyl 2-cyano-3-ethoxyacrylate (935 mg, 5.5 mmol, 1.1 equiv.), sodium acetate trihydrate (1.50 g, 11.0 mmol, 2.2 equiv.) were stirred in acetic acid (7.5 ml) and water (2.5 mL). Heated to 100 °C. After overnight heating, the reaction was poured over ice. The precipitate was filtered and recrystallised (MeOH/water) to obtain pale tan needles (976 mg, 78%). 1H, 13C, 19F NMR consistent with expected product.

Mpt. 152-153 °C (MeOH/water).

TLC (20% EtOAc/hexane) visualised with UV and vanillin:
TLC


Reference:
DOI:10.1021/jm901378u.

Risk and Hazard Assessment:
Risk Assessment
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