Water → HCID 58902348, compound

HRID 1640204Notes

Reaction equation

HRID 1640204 reaction equation
[C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]([CH:14]2[CH2:23][CH2:22][C:21]3[C:16](=[CH:17][C:18]([O:24][C:25]4[CH:30]=[CH:29][N:28]=[C:27]([NH:31][CH3:32])[CH:26]=4)=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:33](Cl)(=[O:35])[CH3:34].O>C1COCC1>[C:33]([N:31]([CH3:32])[C:27]1[CH:26]=[C:25]([O:24][C:18]2[CH:17]=[C:16]3[C:21]([CH2:22][CH2:23][CH:14]([C:12]([NH:11][C:7]4[CH:8]=[CH:9][CH:10]=[C:5]([C:1]([CH3:3])([CH3:2])[CH3:4])[CH:6]=4)=[O:13])[CH2:15]3)=[CH:20][CH:19]=2)[CH:30]=[CH:29][N:28]=1)(=[O:35])[CH3:34]

Participants

5

Reactant 3

HCID 962WaterHCID 6367Acetyl chloride2×HCID 58902470HCID 58902470, compound

Product 1

HCID 58902348HCID 58902348, compound

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
0 °C

Procedure

To a solution of N-(3-tert-butylphenyl)-7-{[2-(methylamino)pyridin-4-yl]oxy}-1,2,3,4-tetrahydronaphthalene-2-carboxamide (337 mg, 0.78 mmol) in THF (8 mL) was added TEA (0.219 mL, 1.57 mmol). The reaction mixture was cooled to 0° C. and acetyl chloride (0.062 mL, 0.86 mmol) was added dropwise. The reaction mixture was allowed to stir at 0° C. for 5 hr. during which time further portions of TEA (0.219 mL, 1.57 mmol) and acetyl chloride (0.62 mL, 0.86 mmol) were added. Water was added and the mixture was extracted with EtOAc. The organic solutions were combined, washed with water and brine, dried over Na2SO4 and concentrated. The residue was purified by column chromatography. The product was further purified by HPLC (250 mm C18 column) eluting with 40% A/60% B to 100%/0% B (25 min gradient) (A=99/1 H2O in AcCN, 0.1% FA, B=95/5 AcCN/H2O, 0.1% FA). The product was dissolved in DCM and MeOH and 2M HCl-Et2O solution was added. The solvents were evaporated to provide 7-({2-[acetyl(methyl)amino]pyridin-4-yl}oxy)-N-(3-tert-butylphenyl)-1,2,3,4-tetrahydronaphthalene-2-carboxamide I-395 as the HCl salt (22 mg, 5.4%). 1H NMR (300 MHz, d6-DMSO, HCOOH Salt) δ: 9.94 (s, 1H), 8.31 (d, 1H), 7.63 (t, 1H), 7.50 (d, 1H), 7.24-7.18 (m, 2H), 7.10-7.05 (m, 2H), 6.76 (dd, 3H), 3.24 (s, 3H), 2.95-2.71 (m, 5H), 2.13-1.99 (m, 4H), 1.85-1.72 (m, 1H), and 1.26 (s, 9H). LCMS: (FA) ES+470.2, ES−472.9

Workup

  1. extractionthe mixture was extracted with EtOAc
  2. washwashed with water and brine
  3. dry with materialdried over Na2SO4
  4. concentrationconcentrated
  5. customThe residue was purified by column chromatography
  6. customThe product was further purified by HPLC (250 mm C18 column)
  7. washeluting with 40% A/60% B to 100%/0% B (25 min gradient) (A=99/1 H2O in AcCN, 0.1%
  8. dissolutionThe product was dissolved in DCM
  9. additionMeOH and 2M HCl-Et2O solution was added
  10. customThe solvents were evaporated

Sources & evidence

ORD record
ord-5cca180e9b3d4027977e7bc2a8bc2d96
Source dataset
uspto-grants-2012_02
Patent number
US08110687B2

Reaction notes

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