Triazolopyrazine Series

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

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

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

Isolated P1

Isolated P2

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

55% ACN and the other 45 % ACN

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.