Triazolopyrazine Series

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

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

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

Checked NMR = good but DMF

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