Triazolopyrazine Series

N.B. Try without work-up next time

AEW 312-1 (376 mg, 0.78 mmol) was dissolved in EtOH (8 mL). CuCl₂.2H₂O (6.5 mg, 0.04 mmol, 5 mol%) was added and the reaction heated at reflux.

The solvent was removed and ethyl acetate was added. The mixture was washed with water and brine. The organic layers were dried (MgSO₄), filtered and concentrated under reduced pressure to give the crude product as crispy mustard coloured sollid.

The recrystallised from ethanol - gave powder rather than crystals.

A mustard powder was collected and dried at the high vac o/n. Combined mother liquors were evaporated to give a mustard semi solid - (150 mg, 0.38, 48% yield).

Data:

Strings

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

to

InChI=1S/C20H13F2N5O2/c21-15-6-5-14(7-16(15)22)17(28)11-29-19-10-24-9-18-25-26-20(27(18)19)13-3-1-12(8-23)2-4-13/h1-7,9-10,17,28H,11H2

FC1=C(F)C=CC(C(OC2OCCCC2)COC3=CN=CC4=NN=C(C5=CC=C(C#N)C=C5)N43)=C1

to

FC1=C(F)C=CC(C(O)COC2=CN=CC3=NN=C(C4=CC=C(C#N)C=C4)N32)=C1

AEW (200 mg, 0.78 mmol, 1.0 equiv.), potassium hydroxide (154 mg, 2.74 mmol, 3.5 equiv.) and 18-crown-6 (15 mg, 0.05 mmol, 0.07 equiv.) were stirred in toluene (6 mL) and AEW alcohol (147 mg, 0.78 mmol, 1.0 equiv.) was added and the reaction mixture stirred at 40 ˚ C for 30 mins. 

TLC showed reaction complete (5:2 EtOAc/hex)

Directly applied crude mixture to Biotage Isolera and obtained one fraction as a cream solid (208 mg, 0.51 mmol, 65% yield).

Data:

300 MHz NMR Recryst:

Strings

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

and

InChI=1S/C9H10F2O2/c1-13-9(5-12)6-2-3-7(10)8(11)4-6/h2-4,9,12H,5H2,1H3

to

InChI=1S/C21H15F2N5O2/c1-29-18(15-6-7-16(22)17(23)8-15)12-30-20-11-25-10-19-26-27-21(28(19)20)14-4-2-13(9-24)3-5-14/h2-8,10-11,18H,12H2,1H3

ClC1=CN=CC2=NN=C(C3=CC=C(C#N)C=C3)N21

and

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

to

FC1=C(F)C=CC(C(OC)COC2=CN=CC3=NN=C(C4=CC=C(C#N)C=C4)N32)=C1

Submitted to HRMS

Need 1H, 13C and 19F from service

IR and mp

AEW (450 mg, 1.76 mmol, 1.0 equiv.), potassium hydroxide (345 mg, 6.16 mmol, 3.5 equiv.) and 18-crown-6 (33 mg, 0.12 mmol, 0.07 equiv.) were stirred in toluene (11 mL) and AEW alcohol (455 mg, 1.76 mmol, 1.0 equiv.) was added and the reaction mixture stirred at rt for 30 mins. 

TLC showed reaction complete (9:1 EtOAc/hex)

F1: 400 mg

F2:

F3:

Strings

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

and

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

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

ClC1=CN=CC2=NN=C(C3=CC=C(C#N)C=C3)N21

and

OCC(OC1OCCCC1)C2=CC(F)=C(F)C=C2

to

FC1=C(F)C=CC(C(OC2OCCCC2)COC3=CN=CC4=NN=C(C5=CC=C(C#N)C=C5)N43)=C1

Procedure

HM7-1(80 mg, 339.39µmol, 1.0 equiv.), potassium hydroxide (66.65mg, 1.19mmol, 3.5 equiv.) and 18-crown-6 (6.28mg, 23.76µmol, 0.07 equiv.) were stirred in toluene (5 mL) and AEW alcohol (59.04mg, 373.33µmol, 1.1 equiv.) was added and the reaction mixture stirred at rt for 30 mins.

Water (20 mL) was added and the mixture was extracted with EtOAc (3 x 40 mL). Combined organic layers were washed with water (20 mL), brine (20 mL), dried (MgSO₄) filtered and evaporated then purified by flash column chromatography using the Biotage Isolera^TM

Log

25th Aug

The reaction started at 4:00pm and left under room temperature overnight.

26th Aug

TLC was performed (75% EtOAc in petroleum) showing that the reaction has yet gone completion. Warm up. 

HIRAC

String

from

InChI=1S/C12H14ClN3/c13-9-5-4-6-10-11(9)12(15-14-10)16-7-2-1-3-8-16/h4-6,11H,1-3,7-8H2

and

InChI=1S/C8H8F2O/c9-7-2-1-6(3-4-11)5-8(7)10/h1-2,5,11H,3-4H2

to

InChI=1S/C20H21F2N3O/c21-15-8-7-14(13-16(15)22)9-12-26-18-6-4-5-17-19(18)20(24-23-17)25-10-2-1-3-11-25/h4-8,13,19H,1-3,9-12H2

Procedure

AEW 309-1 (~4.95 mmol, 1.00 equiv.) was dissolved in anhydrous diethyl ether (50 mL) and cooled to 0 ˚C. LiAlH₄ (1 M in THF, 3.17 mL, 4.17 mmol, 0.64 equiv.) was added dropwise and the reaction mixture stirred for ten mins at 0 ˚C and then allowed to reach RT whilst stirring o/n.

 ice bath. Acetone added dropwise to quench excess LAH and then a saturated soln of Rochelle's salt was added (dropwise at start then with pouring, 80 mL). Stirred at 0 ˚C and then rt overnight. Work up: Ether extraction of aqueous, then acidified aqueous to pH 5. Extracted with ether (x2), dried combined organic layers (MgSO₄), filtered and evaporated to give a crude yellow liquid (1.34 g, 5.67 mmol, 109% yield) dried further at highvac prior to NMR.

Column

F1: product + impurity -  xx mg

F2: Clean product - 375 mg

Data:

Crude NMR

Strings

InChI=1S/C10H10F2O3/c1-14-9(10(13)15-2)6-3-4-7(11)8(12)5-6/h3-5,9H,1-2H3

to

InChI=1S/C9H10F2O2/c1-13-9(5-12)6-2-3-7(10)8(11)4-6/h2-4,9,12H,5H2,1H3

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

to

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