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21st February 2017 @ 02:23

See EGT 163-1

 


Outcome


Rationale

Attempt to esterify the acid to the ethyl ester.

Procedure

3,4-difluorophenylacetic acid (10.0 g, 58.1 mmol, 1 equiv.) and p-TsOH (100 mg, 0.581 mmol, 0.01 equiv.) were dissolved in EtOH (132 mL) and the reaction heated to reflux (80 oC). The reaction was cooled to rt and the solvent removed to give AEW 324-1 as a clear pale yellow oil 

Notes

Theoretical yield = 11.63 g

w/prod = 

Ref: WO 1999008697 A1

 

HIRAC

 

AEW 324-1.doc
AEW 324-1.pdf

Strings

OC(CC1=CC(F)=C(F)C=C1)=O

to

O=C(OCC)CC1=CC(F)=C(F)C=C1

InChI=1S/C8H6F2O2/c9-6-2-1-5(3-7(6)10)4-8(11)12/h1-3H,4H2,(H,11,12)

to

InChI=1S/C10H10F2O2/c1-2-14-10(13)6-7-3-4-8(11)9(12)5-7/h3-5H,2,6H2,1H3

Attached Files
9th February 2017 @ 01:51

At the start of the series four campaign, OSM inherited data for MMV669844, an enantioenriched compound. No ee data was obtained however.

The racemic compound, MMV897709 has been synthesised in the labs at Sydney and submitted for biological data. Initial results suggest that the R-enantiomer is slightly more active than the racemic mixture but this will be confirmed by measurement of both compounds in the same assay.

Mark Butler from The University of Queensland kindly offered to perform a preparative chiral HPLC-separation of MMV897709. 

Dave Edwards conducted the analysis required to find a suitable method for separation. The best result was obtained with "a  Phenomenex Cellulose 3 (250 x 4.6mm, 5µm) column run using the isocratic conditions 70 % mobile phase A, 0.05% formic acid in water and 30 %mobile phase B, 0.05% formic acid in acetonitrile.  I have run the sample on four other chiral columns (Cellulose 1,2 and 4) without separating the peaks. I have also tried different ratios MPA to B".

HPLC Trace

DE_AEW_313_1_Cellulose_3_30ACN_001.pdf

Isolated P1

DE8000_99_AEW313_1_P2_10_002.pdf

Isolated P2

DE8000_99_AEW313_1_P1_10_001.pdf

Dave also tried other conditions that failed to separate the enantiomers.

55% ACN and the other 45 % ACN

DE_AEW313_T60_45ACN_002.pdf
DE_AEW313_T60_55ACN_001.pdf
 

Dave is using an analytical colum to separate the isomers to gain ~1mg of each enantiomer for testing. Ideally we would like to locate a preparative column and ask for its owner to separate larger quantities of material for further analysis.

 

Attached Files
15th December 2016 @ 00:00

Outcome

The product was successfully synthesised in XX

Rationale

Attempt to couple the alcohol to the OCHF2 core.

Procedure

AEW 322-1 (203 mg, 1.01 mmol, 1 equiv.) was added to toluene (4 mL) along with AEW 205 (300 mg, 1.01 mmol, 1 equiv.), potassium hydroxide (187 mg, 3.34 mmol, 3.3 equiv.) and 18-crown-6 (21 mg, 0.04 mmol, 0.08 equiv.). The reaction was stirred at rt.

The reaction was diluted with water (20 mL), then extracted with ethyl acetate (3 x 15 mL). The organic layers were washed with water (2 x 20 mL) until the aqueous layer became neutral, followed by brine (15 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to give the crude product as a dark brown solid (130.2 mg, 63%). The crude product was purified by flash chromatography on silica (25-100% ethyl acetate in hexanes) to give AEW 323-1 as brown powder ()


Strings


ClC1=CN=CC2=NN=C(C3=CC=C(OC(F)F)C=C3)N21

and

OCC(N(C)C)C1=CC=C(F)C(F)=C1

to

FC(F)OC(C=C1)=CC=C1C2=NN=C3N2C(OCC(N(C)C)C4=CC=C(F)C(F)=C4)=CN=C3

 

InChI=1S/C12H7ClF2N4O/c13-9-5-16-6-10-17-18-11(19(9)10)7-1-3-8(4-2-7)20-12(14)15/h1-6,12H

and

InChI=1S/C10H13F2NO/c1-13(2)10(6-14)7-3-4-8(11)9(12)5-7/h3-5,10,14H,6H2,1-2H3

to

InChI=1S/C22H19F4N5O2/c1-30(2)18(14-5-8-16(23)17(24)9-14)12-32-20-11-27-10-19-28-29-21(31(19)20)13-3-6-15(7-4-13)33-22(25)26/h3-11,18,22H,12H2,1-2H3


Notes

Theoretical yield = 467 mg

Start at 

Stopped at

Attached Files
13th December 2016 @ 03:08

Outcome

The product was successfully synthesised and taken directly to the next step.

Rationale

Repeat attempt with ethyl ester starting material.

Procedure

AEW 321-1 (506 mg, 1.33 mmol, 1 equiv.) was dissolved in anhydrous THF (6 mL) and cooled to 0 oC. LiAlH4 (1 M in THF, 1.33 mL, 1.33 mmol, 0.64 equiv.) was added dropwise and the reaction mixture stirred for 10 min at 0 oC, then at rt overnight.

The reaction was cooled to rt, then in an ice bath. LAH was quenched with ethyl acetate dropwise, then a saturated solution of Rochelle's slat was added. The mixture was stirred at 0 oC, then at rt for 1.5 h.

The organic layer was separated and the aqueous layer extracted with ethyl acetate (2 x). The combined organic layers were dried (MgSO4), filtered and concentrated under reduced pressure to give the crude product as a yellow oil (406 mg, 97%).

 

Strings

O=C(OCC)C(N(C)C)C1=CC(F)=C(F)C=C1

to

OCC(N(C)C)C1=CC(F)=C(F)C=C1

InChI=1S/C12H15F2NO2/c1-4-17-12(16)11(15(2)3)8-5-6-9(13)10(14)7-8/h5-7,11H,4H2,1-3H3

to

InChI=1S/C10H13F2NO/c1-13(2)10(6-14)7-3-4-8(11)9(12)5-7/h3-5,10,14H,6H2,1-2H3

Attached Files
7th December 2016 @ 08:55

Outcome

Ref: EGT 165-1


 

Rationale

Attempt to displace the bromine with dimethylamine.

Procedure

EGT 164-1 (580 mg, 2.08 mmol, 1 equiv.) was dissolved in DMF (6 mL). Dimethylamine solution (33% in alcohol, 0.38 mL, 2.08 mmol, 1 equiv.) and K2CO3 (862 mg, 6.23 mmol, 3 equiv.) were added and the reaction stirred at rt. The reaction was filtered and the solvent removed. The residue was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc and the combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure to give the crude product as a yellow oil (800 mg - further drying required, 590 mg).

NMR

AEW 321-1 crude proton.mnova
AEW 321-1 crude proton.jcamp
AEW 321-1 crude proton.png
AEW 321-1.zip

Checked NMR = good but DMF

AEW 321-1.zip

Dissolved in EtOAc and washed with water (x3) then brine, the dried dried (Na2SO4), filtered and concentrated under reduced pressure to give ..

 

Strings

O=C(OCC)C(Br)C1=CC(F)=C(F)C=C1

to

O=C(OCC)C(N(C)C)C1=CC(F)=C(F)C=C1

 

InChI=1S/C10H9BrF2O2/c1-2-15-10(14)9(11)6-3-4-7(12)8(13)5-6/h3-5,9H,2H2,1H3

to

InChI=1S/C12H15F2NO2/c1-4-17-12(16)11(15(2)3)8-5-6-9(13)10(14)7-8/h5-7,11H,4H2,1-3H3


Notes

Theoretical yield = 506 mg

Start reaction at 4pm Mon

Stopped at 11 am Tue

 

Ref: WO 1999008697 A1

Attached Files