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9th February 2014 @ 06:45

Conclusion: Frustratingly, this union doesn't seem to be working.

Going to attempt model reaction with AEW 97 and an alternative primary alcohol to see if THP group is the problem.

GitHub Tag: Issue #115

Starting materials:

4-(5-Chloro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)benzonitrile (AEW 97-7) and Synthesis of 2-(3,4-difluorophenyl)-2-((tetrahydro-2H-pyran-2-yl)oxy)ethanol (AEW 113-2) 

Freshly hexane washed NaH (27 mg, 1.1 mmol, 2 equiv.) was stirred in THF (6.3 mL) and a solution of AEW 113-2 fraction two (144 mg, 0.56 mmol, 1 equiv.) in THF ( mL) was added dropwise and the resulting mixture was stirred for 15 minutes. AEW 97-7 (143 mg, 0.56 mmol, 1.01 equiv.) was added to the mixture (pale yellow solution turned deep red) and the resulting mixture was allowed to stir for a further 1.5 hours. No change seen by TLC. Stirred for a further 1.5 hours, TLC looked streaky unsure about product or decomposition so stopped reaction. The reaction mixture was poured onto ice water, extracted with EtOAc (x 3) and then combined organic layers were washed with brine, dried (MgSO4) filtered and evaporated.

The first wash was NMR'ed and found to contain a messy mixture of products that looked to consist of mainly alcohol SM - chloride peaks very weak in NMR and a ppt formed in the NMR tube.

The aqueous layers contained a solid too, so this was extracted with 2-MeTHF,washed with brine, dried (MgSO4) filtered and evaporated to yield a yellow solid which is thought to be the diol resulting from deprotection of AEW 113-2.

Data:

AEW 114-2 first wash.zip
AEW 114-2 second wash (2MeTHF).zip

Hazard and Risk Assessment:

HIRAC AEW 114-1.pdf

But on larger scale

InChi:

InChI=1S/C13H16F2O3/c14-10-5-4-9(7-11(10)15)12(8-16)18-13-3-1-2-6-17-13/h4-5,7,12-13,16H,1-3,6,8H2

and

InChI=1S/C12H6ClN5/c13-10-6-15-7-11-16-17-12(18(10)11)9-3-1-8(5-14)2-4-9/h1-4,6-7H

to 

InChI=1S/C25H21F2N5O3/c26-19-9-8-18(11-20(19)27)21(35-24-3-1-2-10-33-24)15-34-23-14-29-13-22-30-31-25(32(22)23)17-6-4-16(12-28)5-7-17/h4-9,11,13-14,21,24H,1-3,10,15H2

Attached Files
AEW 114-2 first wash.zip
AEW 114-2 second wash (2MeTHF).zip