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22nd October 2012 @ 01:45
Mnr: MNR49-50
Hydrolisis of MNR49-1 to give MNR50-1

See - Synthesis on MNR49-1

MNR50_scheme.png
MNR50-1_table.PNG

Hazard Assessment
HIRAC MNR50.pdf


Procedure

reaction on at 11am 22/10/12

NaOH (10.6 g, 265 mmol) was added to a solution of MNR49-1 (6.6 g, XX mmol) in EtOH (90 mL) and water (45 mL) and then heated to reflux for 90 minutes. The reaction was allowed to cool to room temperature and was then cooled in an ice bath and then acidified to pH 1 using conc. HCl. The white precipitate was then filtered and rinsed with water to give a crude (wet) off white solid (9.9 g). The crude was then recrystallised in Et2O (250 ml) and left to stand overnight. The fine white crystals were filtered and washed with Et2O and dried under vacuum. The filtrate was also concentrated and dried under vacuum.

1st crop - 3.285 g 14.91 mmol, 56%
filtrate - 2.012 g, 9.14 mmol, 34% - almost as clean as the crystals

upon standing overnight, more precipitate had formed in the acidified aqueous layer. This was filtered, washed with water and dried under vacuum.

2nd filter - 0.711 g, 3.23 mmol, 12% - nmr was as clean as the recrystallised product.

Total mass recovered - 6.008 g, >26.6 mmol, 102%

No more purification was carried out at this time but the 3 samples were kept separate.

NMR

1st crop
mnr50-1_recryst1_1H.pdf
mnr50-1_recryst1_13C.pdf
mnr50-1_recryst1.zip


Filtrate
mnr50-1_crude_1H.pdf
mnr50-1_crude.zip


2nd filter
mnr50-1_filt2_1H.pdf
mnr50-1_filt2.zip
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17th October 2012 @ 04:57
Mnr: MNR49-50
Synthesis of ethyl 1-(4-fluorophenyl)-5-methyl-1H-pyrazole-4-carboxylate (MNR49-1)

See also
MJT2-1 - (0.955 g, 3.85 mmol, 73%)
MJT2-2 - (2.27 g, 9.2 mmol, 58%}
Refs
US20060211603 - Example 109 - page 80

MNR49_scheme.png
MNR49-1_table.PNG

Hazard Assessment
HIRAC MNR49.pdf


Procedure

reaction on t 10am 18/10/12

Dimethylformamide dimethyl acetal (4.17 mL, 31.4 mmol) was added to ethyl acetoacetate (3.97 mL, 31.4 mmol) and the mixture was heated to reflux (110 °C). After 30 mins TLC showed complete consumption of ethyl acetoacetate. Due to NMR timming and breaking the salt the reaction was allowed to cool to room temperature and sat for a further 2 hours.

TLC after 30 mins, 25% EtOAc/Hex
mnr49-1-int_25%EtOAc_1hour.JPG


Breaking the HCl salt
While the above was refluxing, NaOH (20 mL, 2M) was added to 4-fluorophenylhydrazine hydrochloride (5.1 g, 31.4 mmol) and the mixture was heated to give a transparent orange solution. This was extracted with ethyl acetate (3 x 25 mL), the organics were combined and washed with brine (30 mL). The organic fraction was then dried over MgSO4, filtered and concentrated to give 4-fluorophenylhydrazine (3.84 g, 30.46 mmol) as an orange oil.

on at 1230 18/10/12

4-fluorophenylhydrazine (3.84 g, 30.46 mmol) was dissolved in ethanol (60 mL) and added dropwise to the enamine ketone, the reaction was then heated to reflux at 80 °C. After 4 hours TLC showed complete consumption of 4-fluorophenylhydrazine (reaction was completed sooner but I was out of the lab). The reaction was allowed to cool to room temperature then was concentrated under reduced pressure and stored in the fridge overnight.

TLC after 1 hour 25% EtOAc/Hex
mnr49-1_10%EtOAc_4hours.JPG

TLC after 4 hours 10% EtOAc/Hex
mnr49-1_10%EtOAc_4hours_nin.JPG


Crude NMR did not show product nor did TLC co-spotting with MJT2-1. The crude was then taken up in EtOAC (30 mL) and washed with saturated NaHCO3 (25 mL), the organic layer was separated and the aqueous layer was extracted with EtOAc (5 x 30 mL). TLC of this now showed product. The layers were combined, dried, filtered and concentrated to give the crude as a red oil (7.62 g)

Column - 10-30% EtOAc/Hex

Fracs 10-29 - 4.02 g
Fracs 20 only - 2.895 g

Total product recovered 6.915 g, 27.9 mmol, 89%

NMR

Starting materials
mnr49-1 ethyl acetoacetate 1H.pdf
ethyl_acetoacetate.zip
mnr49-1 Dimethylformamide dimethyl acetal.pdf
Dimethylformamide_dimethyl_acetal.zip

4-fluorophenylhydrazine
mnr49-1 4-flurophenl hydrazine 1H.pdf
4_fluorophenylhydrazine.zip


MNR49-1-Int
mnr49-1-Int 1H.pdf
mrr49-1_int_overlay_1H.pdf
mnr49-1_int.zip


MNR49-1
mnr49-1-frac20_conc_1H.pdf
mnr49-1-frac20_conc_13C.pdf
mnr49-1_frac20_conc.zip

mnr49-1_frac10-39_1H.pdf
mnr49-1_frac10-39.zip
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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.

===

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.

===

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.

===

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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