p-Toluenesulfonic acid → (5-Chloro-2-fluoro-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)phenyl)-(morpholino)methanone

HRID 2406327Notes

Reaction equation

HRID 2406327 reaction equation
[NH2:1][C:2]1[C:14]([Cl:15])=[CH:13][C:5]([C:6]([O:8]C(C)(C)C)=O)=[C:4]([F:16])[CH:3]=1.Cl[C:18]1[N:23]=[C:22]([NH:24][CH3:25])[C:21]([C:26]([F:29])([F:28])[F:27])=[CH:20][N:19]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.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:74]1[CH2:79][CH2:78][O:77][CH2:76][CH2:75]1.C(=O)(O)[O-].[Na+]>ClCCl.FC(F)(F)C(O)=O.O>[Cl:15][C:14]1[C:2]([NH:1][C:18]2[N:23]=[C:22]([NH:24][CH3:25])[C:21]([C:26]([F:29])([F:28])[F:27])=[CH:20][N:19]=2)=[CH:3][C:4]([F:16])=[C:5]([C:6]([N:74]2[CH2:79][CH2:78][O:77][CH2:76][CH2:75]2)=[O:8])[CH:13]=1

Participants

11

Reactant 7

HCID 6101p-Toluenesulfonic acidHCID 8083MorpholineHCID 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 68684306Tert-butyl 4-amino-5-chloro-2-fluorobenzoate

Product 1

HCID 71585128(5-Chloro-2-fluoro-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)phenyl)-(morpholino)methanoneYield 28.8%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6344DichloromethaneSolvent2×HCID 6422Trifluoroacetic acidSolvent

Conditions

Temperature
100 °C

Procedure

A solution of tert-butyl 4-amino-5-chloro-2-fluorobenzoate (50 mg, 0.20 mmol) in dichloromethane (2 mL) and trifluoroacetic acid (2 mL) was stirred at room temperature for 3 hours then the reaction was evaporated to dryness. The residue was taken up in dioxane (3 mL) then 2-chloro-N-methyl-5-(tri-fluoromethyl)pyrimidin-4-amine (42 mg, 0.20 mmol) and para-toluene sulfonic acid (38 mg, 0.20 mmol) were added. The resulting mixture was heated to 100° C. for 2 h. 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 dissolved in DCM (3 mL) and then DIPEA (140 μL, 0.8 mmol) and HATU (85 mg, 0.22 mmol) were added, followed by morpholine (18 μL, 0.2 mmol). The mixture was allowed to stir at RT for 4 h and then saturated aqueous sodium bicarbonate solution (25 mL) was added. The mixture was passed through a hydrophobic frit and the solvent was removed in vacuo. The residue was purified by reversed phase HPLC to give (5-chloro-2-fluoro-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)phenyl)-(morpholino)methanone (25 mg, 28%) as an off-white solid. LCMS (10 cm_ESCI_Bicarb_MeCN): [M+H]+=434 at 3.02 min. 1H NMR (400 MHz, CDCl3): δ 8.64 (d, J=12.8 Hz, 1H), 8.22 (s, 1H), 7.72 (brs, 1H), 7.48 (d, J=6.8 Hz, 1H), 5.30 (brs, 1H), 3.80-3.77 (m, 4H), 3.66-3.68 (m, 2H), 3.41-3.39 (m, 2H), 3.12 (d, J=4.8 Hz, 3H).

Workup

  1. customthe reaction was evaporated to dryness
  2. customThe solvent was removed in vacuo
  3. dissolutionthe residue was dissolved in DCM (3 mL)
  4. customthe solvent was removed in vacuo
  5. customThe residue was purified by reversed phase HPLC

Sources & evidence

ORD record
ord-82227033653b46d8a67b01ebe2adff87
Source dataset
uspto-grants-2014_08
Patent number
US08809331B2

Reaction notes

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