Trifluoroacetic acid → Merestinib

HRID 1662031Notes

Reaction equation

HRID 1662031 reaction equation
[F:1][C:2]1[CH:30]=[C:29]([NH:31][C:32]([C:34]2[C:35](=[O:48])[N:36]([C:41]3[CH:46]=[CH:45][C:44]([F:47])=[CH:43][CH:42]=3)[C:37]([CH3:40])=[CH:38][CH:39]=2)=[O:33])[CH:28]=[CH:27][C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[C:14]1[CH:15]=[N:16][N:17](C(OC(C)(C)C)=O)[CH:18]=1)[N:10]([CH3:26])[N:9]=[CH:8]2.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:30]=[C:29]([NH:31][C:32]([C:34]2[C:35](=[O:48])[N:36]([C:41]3[CH:42]=[CH:43][C:44]([F:47])=[CH:45][CH:46]=3)[C:37]([CH3:40])=[CH:38][CH:39]=2)=[O:33])[CH:28]=[CH:27][C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[C:14]1[CH:15]=[N:16][NH:17][CH:18]=1)[N:10]([CH3:26])[N:9]=[CH:8]2

Participants

5

Reactant 3

HCID 6422Trifluoroacetic acidHCID 12052TriethylsilaneHCID 66766832HCID 66766832, compound

Product 1

HCID 44603533Merestinib

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a round bottom flask is added tert-butyl 4-(5-(2-fluoro-4-(1-(4-fluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamido)phenoxy)-1-methyl-1H-indazol-6-yl)-1H-pyrazole-1-carboxylate (1.92 g, 2.94 mmol) and DCM (50 mL) followed by triethylsilane (1.88 mL, 11.77 mmol) and TFA (17.8 mL, 235.35 mmol). The reaction mixture is allowed to stir at RT for 1.5 hours. The solvent is removed and diluted into DCM (150 mL) and washed with saturated aqueous NaHCO3 solution (2×100 mL). The organic solution is dried with Na2SO4, and concentrated under reduced pressure to give a solid material. The solid is purified on a silica gel column eluting with DCM (A) and a 10% MeOH in DCM solution (B), gradient from 100% (A) to 75%(A):25%(B) over 70 min, held at this 75:25 ratio for 15 min to give the title compound as an off-white solid. The solid is dissolved in hot EtOH (50 mL) followed by a portion-wise addition of distilled water (250 mL) causing a white solid to precipitate. The solid is filtered over a Buchner funnel and washed with distilled water (3×15 mL), air dried, and vacuum dried at 60° C. for 15 hours to give the title compound as an off-white solid (1.27 g, 78% yield). MS (m/z): 552.8 (M+H).

Workup

  1. customThe solvent is removed
  2. additiondiluted into DCM (150 mL)
  3. washwashed with saturated aqueous NaHCO3 solution (2×100 mL)
  4. dry with materialThe organic solution is dried with Na2SO4
  5. concentrationconcentrated under reduced pressure
  6. customto give a solid material
  7. customThe solid is purified on a silica gel column
  8. washeluting with DCM (A)
  9. waita 10% MeOH in DCM solution (B), gradient from 100% (A) to 75%(A):25%(B) over 70 min
  10. waitheld at this 75:25 ratio for 15 min

Sources & evidence

ORD record
ord-46903ae470404f9b8f8d62b44c224628
Source dataset
uspto-grants-2011_10
Patent number
US08030302B2

Reaction notes

Loading…