p-Toluenesulfonic acid → HCID 86687948, compound

HRID 2406328Notes

Reaction equation

HRID 2406328 reaction equation
[NH2:1][C:2]1[CH:11]=[C:10]([O:12][CH3:13])[C:5]([C:6]([O:8]C)=O)=[C:4]([O:14][CH3:15])[C:3]=1[F:16].[OH-].[Na+].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:52]1[CH2:57][CH2:56][O:55][CH2:54][CH2:53]1.C(=O)(O)[O-].[Na+].Cl[C:64]1[N:69]=[C:68]([NH:70][CH3:71])[C:67]([C:72]([F:75])([F:74])[F:73])=[CH:66][N:65]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C.O.C(Cl)Cl>[F:16][C:3]1[C:4]([O:14][CH3:15])=[C:5]([C:6]([N:52]2[CH2:57][CH2:56][O:55][CH2:54][CH2:53]2)=[O:8])[C:10]([O:12][CH3:13])=[CH:11][C:2]=1[NH:1][C:64]1[N:69]=[C:68]([NH:70][CH3:71])[C:67]([C:72]([F:75])([F:73])[F:74])=[CH:66][N:65]=1

Participants

12

Reactant 8

HCID 6101p-Toluenesulfonic acidHCID 8083MorpholineHCID 14798Sodium HydroxideHCID 81531DiisopropylethylamineHCID 516892Sodium BicarbonateHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 210775872-Chloro-N-methyl-5-(trifluoromethyl)pyrimidin-4-amineHCID 86687949HCID 86687949, compound

Product 1

HCID 86687948HCID 86687948, compoundYield 8%

Reagents, catalysts & solvents 3

HCID 702EthanolSolventHCID 962WaterSolventHCID 6344DichloromethaneSolvent

Conditions

Temperature
60 °C

Procedure

A mixture of methyl 4-amino-3-fluoro-2,6-dimethoxybenzoate (114 mg, 0.5 mmol) and 1N NaOH (1.5 mL) in ethanol (5 mL) was heated at 60° C. for 18 hours. The solvent was removed in vacuo. The residue was dissolved in water (2 mL), cooled in ice bath and acidified by dropwise addition of 2N HCl to pH 3. The reaction was evaporated to dryness and the residue was dissolved in DCM (10 mL) and then DIPEA (260 μL, 1.5 mmol) and HATU (208 mg, 0.6 mmol) were added, followed by morpholine (66 μL, 0.75 mmol). The mixture was allowed to stir at RT for one hour and then saturated aqueous sodium bicarbonate solution (10 mL) was added. The mixture was passed through a hydrophobic frit and the solvent was removed in vacuo. The residue was taken up in dioxane (2 mL) then 2-chloro-N-methyl-5-(trifluoromethyl)pyrimidin-4-amine (105 mg, 0.5 mmol) and para-toluene sulfonic acid (95 mg, 0.50 mmol) were added. The resulting mixture was heated to 100° C. for 30 minutes. After return to room temperature, DCM (10 mL) and water (10 m) were added and the organic phase was passed through a hydrophobic frit. The solvent was removed in vacuo and the residue was purified by reversed phase HPLC to give (3-fluoro-2,6-dimethoxy-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-phenyl)(morpholino)methanone (18 mg, 8% over three steps) as an off-white solid. LCMS (10 cm_ESCI_Formic_MeCN): [M+H]+=460 at 3.32 min. 1H NMR (400 MHz, CDCl3): δ 8.20 (s, 1H), 8.04 (d, J=6.0 Hz, 1H), 7.36 (brs, 1H), 5.30 (brs, 1H), 3.97 (s, 3H), 3.85-3.82 (m, 5H), 3.80-3.78 (m, 2H), 3.75-3.73 (m, 2H), 3.29-3.27 (m, 2H), 3.11 (d, J=4.8 Hz, 3H).

Workup

  1. customThe solvent was removed in vacuo
  2. dissolutionThe residue was dissolved in water (2 mL)
  3. temperaturecooled in ice bath
  4. additionacidified by dropwise addition of 2N HCl to pH 3
  5. customThe reaction was evaporated to dryness
  6. dissolutionthe residue was dissolved in DCM (10 mL)
  7. customthe solvent was removed in vacuo
  8. temperatureThe resulting mixture was heated to 100° C. for 30 minutes
  9. customThe solvent was removed in vacuo
  10. customthe residue was purified by reversed phase HPLC

Sources & evidence

ORD record
ord-ca2451663ebb4677bef973fc595128ae
Source dataset
uspto-grants-2014_08
Patent number
US08809331B2

Reaction notes

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