Tetrahydrofuran → HCID 57955165, compound

HRID 73691Notes

Reaction equation

HRID 73691 reaction equation
[NH2:1][C:2]1[C:7]2=[C:8]([C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][C:26]4[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:27]=4[F:36])=[O:24])=[CH:18][CH:17]=3)[C:9]([CH2:13][O:14][CH3:15])=[C:10]([CH2:11][OH:12])[N:6]2[N:5]=[CH:4][N:3]=1.O=S(Cl)Cl.[CH2:41]1COCC1>C(Cl)Cl>[NH2:1][C:2]1[C:7]2=[C:8]([C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][C:26]4[CH:31]=[C:30]([C:32]([F:33])([F:34])[F:35])[CH:29]=[CH:28][C:27]=4[F:36])=[O:24])=[CH:18][CH:17]=3)[C:9]([CH2:13][O:14][CH3:15])=[C:10]([CH2:11][O:12][CH3:41])[N:6]2[N:5]=[CH:4][N:3]=1

Participants

5

Reactant 3

HCID 8028TetrahydrofuranHCID 24386Thionyl Chloride2×HCID 57955156HCID 57955156, compound

Product 1

HCID 57955165HCID 57955165, compoundYield 53%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a solution of Example 23 (N-{4-[4-amino-7-(hydroxymethyl)-6-(methoxy-methyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[2-fluoro-5-(trifluoro-methyl)-phenyl]urea (22 mg, 0.04 mmol)) in anhydrous THF (1 mL) and CH2Cl2 (1 mL) was added SOCl2 (0.006 ml, 0.08 mmol). After 20 min, analytical HPLC shoved half of the starting material remained. Additional SOCl2 (0.01 ml) was added and the reaction was stirred at rt for 2.5 h until completion. The mixture was evaporated to dryness and CH2Cl2 (3 ml) was added. The solvent was evaporated to dryness and the crude concentrate was re-suspended in CH2Cl2 and evaporated to remove the excess SOCl2 completely. To the resulting solid was added anhydrous MeOH (1 ml) and Hunig's base (0.008 ml), the reaction was stirred at 70° C. overnight. After 16 h, the reaction was cooled to rt and solvent was evaporated. The crude material was taken up in ethyl acetate, washed with aq. saturated sodium bicarbonate three times and dried over Na2SO4. After concentration, the resulting crude was purified via column chromatography (5:95 v/v MeOH—CH2Cl2) to afford 12 mg of the title compound (yield 53%). 1H-NMR (DMSO-d6) δ 9.32 (s, 1H), 8.96 (d, J=3 Hz, 1H), 8.63 (dd, J=7, 3 Hz, 1H), 7.92 (s, 1H), 7.59 (t, J=3 Hz, 2H), 7.57 to 7.32 (m, 4H), 4.73 (s, 2H), 4.28 (s, 2H), 3.26 (s, 3H), 3.24 (s, 3H) ppm; MS [M+H]+=519.1; LCMS RT=2.84 min

Workup

  1. customThe mixture was evaporated to dryness and CH2Cl2 (3 ml)
  2. additionwas added
  3. customThe solvent was evaporated to dryness
  4. concentrationthe crude concentrate
  5. customevaporated
  6. customto remove the excess SOCl2 completely
  7. additionTo the resulting solid was added anhydrous MeOH (1 ml) and Hunig's base (0.008 ml)
  8. stirringthe reaction was stirred at 70° C. overnight
  9. waitAfter 16 h
  10. temperaturethe reaction was cooled to rt
  11. customsolvent was evaporated
  12. washwashed with aq. saturated sodium bicarbonate three times
  13. dry with materialdried over Na2SO4
  14. concentrationAfter concentration
  15. customthe resulting crude was purified via column chromatography (5:95 v/v MeOH—CH2Cl2)

Sources & evidence

ORD record
ord-1e6a18e9b73940d199f42e2dcfac4ec5
Source dataset
uspto-grants-2014_09
Patent number
US08829185B2

Reaction notes

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