Diethyl Ether → HCID 57758309, compound

HRID 1094894Notes

Reaction equation

HRID 1094894 reaction equation
[NH2:1][C:2]1[C:7]2=[C:8]([C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20]([NH:22][C:23]4[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:24]=4[F:33])=[O:21])=[CH:15][CH:14]=3)[C:9]([CH2:11]O)=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1.S(Cl)(Cl)=O.CCC(C)[BH-](C(C)CC)C(C)CC.[Li+].CCOCC>C1COCC1.ClCCCl>[NH2:1][C:2]1[C:7]2=[C:8]([C:13]3[CH:14]=[CH:15][C:16]([NH:19][C:20]([NH:22][C:23]4[CH:28]=[C:27]([C:29]([F:30])([F:31])[F:32])[CH:26]=[CH:25][C:24]=4[F:33])=[O:21])=[CH:17][CH:18]=3)[C:9]([CH3:11])=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1

Participants

7

Reactant 4

HCID 3283Diethyl EtherHCID 24386Thionyl ChlorideHCID 3611392Lithium tri-s-butylborohydrideHCID 57758061HCID 57758061, compound

Product 1

HCID 57758309HCID 57758309, compoundYield 84%

Reagents, catalysts & solvents 2

HCID 111,2-DichloroethaneSolventHCID 8028TetrahydrofuranSolvent3×

Conditions

Temperature
-45 °C

Procedure

A suspension of N-{4-[4-amino-6-(hydroxymethyl)pyrrolo[2,1-f][1,2,4]-triazin-5-yl]phenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea (423 mg, 0.930 mmol) in THF 5 (mL) and 1,2-dichloroethane (5 mL) was treated with thionyl chloride (148 μL, 2.05 mmol) at rt. After 10 min the reaction appeared complete by RP-HPLC. After 30 min the reaction was concentrated under vacuum. The residue was suspended in 1,2-dichloroethane and sonicated briefly, then concentrated again under vacuum (2×). The resulting solid (412 mg, 0.86 mmol) was suspended in THF (20 mL) and cooled to −45° C. This suspension was treated with 1.0 M L-Selectride in THF (8.6 mL, 8.6 mmol). After 15 min the reaction was complete by HPLC. The reaction mixture was removed from the ice bath and quenched with MeOH (1 mL), then treated with 1 M sodium hydroxide (2 mL) and 30% hydrogen peroxide (2 mL). After 15 min stirring, the mixture was diluted with EtOAc (200 mL) and water (200 mL). The organic layer was washed with brine and dried with sodium sulfate. Concentration of the organic layer and trituration with ether:hexanes gave the title compound as an white powder (323 mg, 0.73 mmol, 84% yield). 1H-NMR (CD3OD-d6) δ 8.61 (d, J=8 Hz, 1H), 7.73 (s, 1H), 7.62 (d, J=9 Hz, 2H), 7.48 to 7.50 (m, 1H), 7.35 (d, J=9 Hz, 2H), 7.31 to 7.36 (m, 2H), 2.14 (s, 3H); MS [M+H]+=445.1; LCMS RT=2.80.

Workup

  1. concentrationAfter 30 min the reaction was concentrated under vacuum
  2. customsonicated briefly
  3. concentrationconcentrated again under vacuum (2×)
  4. waitAfter 15 min the reaction was complete by HPLC
  5. customThe reaction mixture was removed from the ice bath
  6. customquenched with MeOH (1 mL)
  7. additiontreated with 1 M sodium hydroxide (2 mL) and 30% hydrogen peroxide (2 mL)
  8. additionthe mixture was diluted with EtOAc (200 mL) and water (200 mL)
  9. washThe organic layer was washed with brine
  10. dry with materialdried with sodium sulfate

Sources & evidence

ORD record
ord-3940f22da92344dfbce7cf1279900f14
Source dataset
uspto-grants-2012_03
Patent number
US08133995B2

Reaction notes

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