Reaction #160894

Reaction equation

N-{4-[4-amino-6-(hydroxymethyl)-pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[4-(trifluoromethyl)pyridin-2-yl]urea

thionyl chloride

L-Selectride

→

desired compound

Yield 59.0%

1-[4-(4-amino-6-methylpyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-fluorophenyl]-3-[4-(trifluoromethyl)pyridin-2-yl]urea

Yield 59.0%

Solvents

CH2Cl2

CH2Cl2

dichloroethane

Conditions

Workup

1. 1
   Otherthe volatiles removed under vacuum
2. 2
   Concentrationconcentrated a second time
3. 3
   workup.WAITThe residue was then placed under high vacuum for 1 h
4. 4
   Temperaturecooled to −78° C
5. 5
   Othermoved to a rt
6. 6
   OtherAfter 1 h the reaction was quenched with MeOH (1 mL)
7. 7
   workup.ADDITIONdiluted with 1 N NaOH (4 mL)
8. 8
   workup.ADDITION2 ml, 30% H2O2 (2 mL) was added dropwise
9. 9
   workup.STIRRINGto stir for 0.5 h
10. 10
    workup.ADDITIONThe mixture was diluted with EtOAc (50 mL)
11. 11
    Washwashed well with sodium thiosulfate solution and brine
12. 12
    DryingThe organic layer was dried with sodium sulfate
13. 13
    Otherthe volatiles removed under vacuum
14. 14
    Otherto provide an amorphous solid

Procedure

A suspension of Intermediate AJ (N-{4-[4-amino-6-(hydroxymethyl)-pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[4-(trifluoromethyl)pyridin-2-yl]urea) (200 mg, 0.433 mmol) in CH2Cl2 (5 mL) was treated with thionyl chloride (129 mg, 1.08 mmol) and allowed to stir for 30 min at rt. The reaction mixture was diluted with dichloroethane (25 mL) and the volatiles removed under vacuum. The residue was suspended in dichloroethane (25 mL) and concentrated a second time. The residue was then placed under high vacuum for 1 h. All material was then suspended in THF (10 mL) and cooled to −78° C. L-Selectride (438 mg, 2.29 mmol) was added and the reaction moved to a rt water bath. After 1 h the reaction was quenched with MeOH (1 mL) and diluted with 1 N NaOH (4 mL). 2 ml, 30% H2O2 (2 mL) was added dropwise, and the reaction allowed to stir for 0.5 h. The mixture was diluted with EtOAc (50 mL) and washed well with sodium thiosulfate solution and brine. The organic layer was dried with sodium sulfate and the volatiles removed under vacuum to provide an amorphous solid. Trituration with CH2Cl2 provided the desired compound as a white solid (111 mg, 59%). 1H-NMR (DMSO-d6) δ 10.10-10.30 (m, 2H), 8.54 (d, 1 H, J=5 Hz), 8.28 (t, 1H, J=8 Hz), 8.02 (s, 1H), 7.81 (s, 1 H), 7.60 (s, 1 H), 7.36-7.40 (m, 1H), 7.28-7.32 (m, 1H), 7.14-7.18 (m, 1H), 2.10 (s, 3H); MS [M+H]+=446.0; LCMS RT=2.97 min.

Source