Triazolopyrazine Series

AEW 288-1 (xx mg, xx mmol, 1.00 equiv.) was dissolved in anhydrous THF (x mL) under N₂ and then stirred at 0 ˚C. MeMgBr (xx mL, xx mmol, 2.02 equiv, 3.0 M in THF) was added and the reaction mixture stirred at 0˚C for 5 min and then allowed to warm to rt.

Strings:

InChI=1S/C16H13F3N4O4/c1-2-25-14(24)9-26-13-8-20-7-12-21-22-15(23(12)13)10-3-5-11(6-4-10)27-16(17,18)19/h3-8H,2,9H2,1H3

to

InChI=1S/C16H15F3N4O3/c1-15(2,24)9-25-13-8-20-7-12-21-22-14(23(12)13)10-3-5-11(6-4-10)26-16(17,18)19/h3-8,24H,9H2,1-2H3

O=C(OCC)COC1=CN=CC2=NN=C(C3=CC=C(OC(F)(F)F)C=C3)N21

to

OC(C)(C)COC1=CN=CC2=NN=C(C3=CC=C(OC(F)(F)F)C=C3)N21

AEW 289-1 (150 mg, 0.30 mmol) was dissolved in a 1:1 mixture of dioxane/DCM (8 mL) to give an orange red solution. 4M HCl in dioxane (2.5 mL) was added (reaction formed gel that then dissolved) and the reaction mixture stirred at RT for 9 h. TLC showed some SM but had to stop reaction as long weekend. Reaction mixture was evaporated and then partitioned between EtOAc and water. Aqueous layer was neutralised with a saturated solution of sodium hydrogen carbonate and then extracted with EtOAc (x 4). Combined organics were washed with water (20 mL), brine (30 mL) and then dried over MgSO₄, filtered and evaporated to give a birght orange oil that was purified by column chromatography using the Biotage Isolera.

Gradient - EtOAc.

Two fractions collected.

Second fraction -bright orange oil. NMR looks like product, contains EtOAc so dried further at vacuum prior to submission.

NMR:

Ref: http://www.commonorganicchemistry.com/Rxn_Pages/THP_Protection/THP_Protection_HCl_Dep.htm 

Strings:

InChI=1S/C26H26F2N4O4/c27-26(28)36-21-11-9-19(10-12-21)25-31-30-22-14-29-15-23(32(22)25)34-16-20(18-6-2-1-3-7-18)17-35-24-8-4-5-13-33-24/h1-3,6-7,9-12,14-15,20,24,26H,4-5,8,13,16-17H2

to

InChI=1S/C21H18F2N4O3/c22-21(23)30-17-8-6-15(7-9-17)20-26-25-18-10-24-11-19(27(18)20)29-13-16(12-28)14-4-2-1-3-5-14/h1-11,16,21,28H,12-13H2

FC(OC(C=C1)=CC=C1C2=NN=C3N2C(OCC(C4=CC=CC=C4)COC5OCCCC5)=CN=C3)F

to

OCC(C1=CC=CC=C1)COC2=CN=CC3=NN=C(C4=CC=C(OC(F)F)C=C4)N32

SSP-4 2016 Edwin Tse's Group

MMV693154, OSM-S-352

47 mg

Data:

FC(C=C1)=CC=C1C2=NN=C3C=NC=C(OCCC4=CC=CC=C4)N32

SSP-3 2016: Liam's Group

118 mg

Data:

SSP-2 2016 Edwin C's Group

Fractions were TLC'd and confirmed to have similar Rf values. Three flasks were combined and purified using the Biotage Isolera^TM on a hand packed 50 g column using a petroleum benzine and EtOAc gradient.

Product collected as a pale brown solid 206 mg.