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16th December 2013 @ 05:00

Procedure:

AEW 103-3 (20 mg, 0.10 mmol, 1 equiv.) was stirred with CuI (19 mg, 1.0 mmol) in anhydrous MeCN (1 mL) and stirred for 5 minutes at room temperature under Ar. Trimethylsilyl 2,2-difluoro-2-(fluorosulfonyl)acetate (24 microL, 30 mg, 0.12 mmol) was added slowly and the reaction mixture stirred at room temperature for 30 mins - starting material seen on TLC. The reaction was sealed under Ar and heated to 100 ˚C for 1 h. Trimethylsilyl 2,2-difluoro-2-(fluorosulfonyl)acetate (24 microL, 30 mg, 0.12 mmol) was added and then the reaction mixture was allowed to cool, opened carefully to release pressure and water was added to quench the reaction. Volatiles were evaporated in vacuo and then the aqueous layer was extracted with EtOAc (10 mL x 3), combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated to give a brown oil.

Neither TLC or NMR look promising. Possibility that Cu remains in solution and could be effecting NMR. Filtration through silica returns no product.

Data:

Crude NMR prior to filtration:

AEW 104-4.zip

Ref Spectra from CRO:

Ref spec CHF2.pdf

Hazard and Risk Assessment:

HIRAC AEW 104-3.pdf

Class 3 reaction: on 20 mg scale.

signed by Peter Rutledge 16th Dec 2013

InChi:

InChI=1S/C9H8F2O3/c1-14-9(13)8(12)5-2-3-6(10)7(11)4-5/h2-4,8,12H,1H3

to

InChI=1S/C10H8F4O3/c1-16-9(15)8(17-10(13)14)5-2-3-6(11)7(12)4-5/h2-4,8,10H,1H3

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16th December 2013 @ 04:50

Procedure:

NaH (3 mg, 0.12 mmol, 1.2 equiv.) was washed with hexanes (1 mL x 3) to remove the mineral oil and then CuI (19 mg, 1.0 mmol) was added. AEW 103-3 (20 mg, 0.10 mmol, 1 equiv.) in anhydrous MeCN (1 mL) was added dropwise at room temperature under Ar (5 mins) and then stirred for 5 minutes at room temperature under Ar, followed by the slow addition of trimethylsilyl 2,2-difluoro-2-(fluorosulfonyl)acetate (24 microL, 30 mg, 0.12 mmol). The reaction mixture was stirred at rt for 30 minutes - starting material seen on TLC. Trimethylsilyl 2,2-difluoro-2-(fluorosulfonyl)acetate (24 microL, 30 mg, 0.12 mmol) was added and then the reaction was sealed under Ar and heated to 100 ˚C for 1 h. Reaction mixture turned black and some solvent seems to have leached through the seal may have to repeat. The reaction mixture was allowed to cool, opened carefully to release pressure and water was added to quench the reaction. Volatiles were evaporated in vacuo and then the aqueous layer was extracted with EtOAc (10 mL x 3), combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated to give a brown oil. 

Data:

Neither TLC or NMR look promising. NMR Shows returned SM.

Data:

Crude NMR prior to filtration:

AEW 104-3.cdxml

Ref Spectra from CRO:

Ref spec CHF2.pdf

Hazard and Risk Assessment:

HIRAC AEW 104-3.pdf

Class 3 reaction: on 20 mg scale.

signed by Peter Rutledge 16th Dec 2013

InChi:

InChI=1S/C9H8F2O3/c1-14-9(13)8(12)5-2-3-6(10)7(11)4-5/h2-4,8,12H,1H3

to

InChI=1S/C10H8F4O3/c1-16-9(15)8(17-10(13)14)5-2-3-6(11)7(12)4-5/h2-4,8,10H,1H3

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10th December 2013 @ 04:45

Prep according to J.Med. Chem. 200952, 7653–7668 DOI: 10.1021/jm900716v

See also: Synthesis of methyl 2-(difluoromethoxy)-2-(3,4-difluorophenyl)acetate (AEW 104-1) - Order of addition changed to match that of the prep above and CsF was purified by crystalisation from aqueous solution with addition of EtOH. MeCN taken from solvent drying columns rather than the mol sieve dried bottle in the lab.

 

 

Procedure:

NaH (11 mg, 0.25 mmol) was washed with hexanes (1 mL x 3) to remove the mineral oil and then stirred in anhydrous MeCN. AEW 103-3 (50 mg, 0.25 mmol) in anhydrous MeCN (2 mL) was added dropwise at room temperature under Ar (5 mins) - initial change of colourless suspension to pale red solution then turned yellow (same colour as AEW 103-3). Stirred for 5 minutes at room temperature under Ar.

CsF (375 mg, 2.5 mmol) was then added, followed by the slow addition of trimethylsilyl 2,2-difluoro-2-(fluorosulfonyl)acetate (49 microL, 63 mg, 0.25 mmol) over 3 minutes. Gas evolved and solution turned from yellow to colourless and then gradually back to yellow. CsF appears to remain as a suspension at the bottom of the flask despite modifying stirring speed.

After 30 mins, spot on baseline but still SM so trimethylsilyl 2,2-difluoro-2-(fluorosulfonyl)acetate (49 microL, 63 mg, 0.25 mmol) was added dropwise over 3 minutes and the reaction mixture stirred for another 30 mins. Had to stop reaction due to fumehood shutdown.

Water (2 mL) was added slowly to quench the reaction which was then poured onto more water (10 mL) and then volatiles removed in vacuo. Aqueous residue was extracted with EtOAc (3 x 5 mL), combined and dried over MgSO4, filtered and evaporated to give a brown film.

Flash column chromatography over silica (EtOAc). Two fractions collected - one UV vis at solvent front = grease and second = SM.

Data:

AEW 104-2 sec frac.zip
AEW 104-2 col top spot.zip

Hazard and Risk Assessment:

Class 3 reaction:

HIRAC AEW 104-1.pdf
on 50 mg scale.

signed by Peter Rutledge 9th Dec 2013

InChi:

InChI=1S/C9H8F2O3/c1-14-9(13)8(12)5-2-3-6(10)7(11)4-5/h2-4,8,12H,1H3

to

InChI=1S/C10H8F4O3/c1-16-9(15)8(17-10(13)14)5-2-3-6(11)7(12)4-5/h2-4,8,10H,1H3

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9th December 2013 @ 08:39

requires HRMS, IR and 19F NMR 

Crude AEW 102-3 (1.42 g) was dissolved in MeOH (10 mL) and a few drops of H2SO4 was added and the reaction mixture stirred at 80 ˚C for 14 hours. Reaction complete by TLC. Poured over water (20 mL) and extracted into EtOAc (20 mL x3). Combined organic layers were dried over MgSO4, filtered and evaporated to give an amber oil - 1.27 g. Crude material was filtered by flash column chromatography over silica (EtOAc) to give a yellow oil (1.12 g, 5.54 mmol, 79% yield over three steps).

Column is really just a filtration - one higher spot comes out in fraction 1, product collected fractions 2-5.

Data:

TLC (30% EtOAc in hexane)

AEW 103-3.jpg
 

NMR data in agreement with CRO prep

AEW 103-3 proton.pdf
AEW 103-3 carbon.pdf

1H NMR (300 MHz): δ 7.30–724 (1H, m), 7.16–7.10 (2H, m), 5.14 (1H, s), 3.79 (3H, s);

13C NMR (75 MHz, CDCl3) δ: 173.4, 150.4 (d, 248.4), 150.3 (d, J 248.8), 135.0 (m), 122.6, 17.4 (d, J 17.8), 115.7 (d, J 18.7), 71.7. 53.3.

Ref NMR from CRO:

Methyl ESTER NMR.pdf

Hazard and Risk Assessment:

HIRAC AEW 103-1.pdf

InChi:

InChI=1S/C8H6F2O3/c9-5-2-1-4(3-6(5)10)7(11)8(12)13/h1-3,7,11H,(H,12,13)

to

InChI=1S/C9H8F2O3/c1-14-9(13)8(12)5-2-3-6(10)7(11)4-5/h2-4,8,12H,1H3

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9th December 2013 @ 04:31

Prep according to J.Med. Chem. 200952, 7653–7668 DOI: 10.1021/jm900716v

 

Procedure:

AEW 103-1 (20 mg, 0.1 mmol) in anhydrous MeCN (1 mL) was stirred at room temperature under Ar. NaH (4 mg, 0.1 mmol) was washed with hexanes (1 mL x 3) to remove the mineral oil and then added in two portions (effervesence) under Ar at room temperature. 

CsF (150 mg, 1.0 mmol) was then added, followed by the slow addition of trimethylsilyl 2,2-difluoro-2-(fluorosulfonyl)acetate (27 mg, 0.1 mmol) was added dropwise over 5 minutes. Reaction mixture stirred for 30 minutes, still spot at SM can't see any others even when stained. Reaction mixture quenched by addition of water, volatiles removed in vacuo and then aqueous layer extracted with EtOAc, dried over MgSO4, filtered and evaporated to give a brown oil.

Data:

AEW 104-1.zip

NMR shows promising peaks around 6 ppm, but not clearly a triplet. Also, looks like Ar protons are present but methyl ester peak doesn't integrate with this - almost gone.

AEW 104-1.zip

Hazard and Risk Assessment:

Class 3 reaction:

HIRAC AEW 104-1.pdf

signed by Peter Rutledge 9th Dec 2013

InChi:

InChI=1S/C9H8F2O3/c1-14-9(13)8(12)5-2-3-6(10)7(11)4-5/h2-4,8,12H,1H3

to

InChI=1S/C10H8F4O3/c1-16-9(15)8(17-10(13)14)5-2-3-6(11)7(12)4-5/h2-4,8,10H,1H3

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Attached Files