p-Toluenesulfonic acid → HCID 71451847, compound

HRID 2406323Notes

Reaction equation

HRID 2406323 reaction equation
Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:11][CH2:10]2)[C:5]([C:12]([F:15])([F:14])[F:13])=[CH:4][N:3]=1.CC1C=CC(S(O)(=O)=O)=CC=1.[NH2:27][C:28]1[C:36]([O:37][CH3:38])=[CH:35][C:31]([C:32]([OH:34])=O)=[C:30]([F:39])[CH:29]=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:73]1[CH2:78][CH2:77][O:76][CH2:75][CH2:74]1.C(=O)(O)[O-].[Na+]>O1CCOCC1.C(Cl)Cl>[CH:9]1([NH:8][C:6]2[C:5]([C:12]([F:15])([F:14])[F:13])=[CH:4][N:3]=[C:2]([NH:27][C:28]3[C:36]([O:37][CH3:38])=[CH:35][C:31]([C:32]([N:73]4[CH2:78][CH2:77][O:76][CH2:75][CH2:74]4)=[O:34])=[C:30]([F:39])[CH:29]=3)[N:7]=2)[CH2:11][CH2:10]1

Participants

10

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 529829634-Amino-2-fluoro-5-methoxybenzoic acidHCID 58459927HCID 58459927, compound

Product 1

HCID 71451847HCID 71451847, compoundYield 16%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

To 2-chloro-N-cyclopropyl-5-(trifluoromethyl)pyrimidin-4-amine (237 mg, 1 mmol) in dioxane (3 mL) was added pTSA (190 mg, 1 mmol) and 4-amino-2-fluoro-5-methoxybenzoic acid (185 mg, 1 mmol). The mixture was heated to 100° C. for 5 h and then the mixture was allowed to cool to RT. The precipitated solid was collected by filtration, washed with dioxane and diethyl ether and then dried. The residue was suspended in DCM (5 mL) and then DIPEA (0.1 mL, 1.5 mmol) and HATU (228 mg, 0.6 mmol) were added, followed by morpholine (0.03 mL, 0.6 mmol). The mixture was allowed to stir at RT for 4 h and then DCM (10 mL) and saturated aqueous sodium bicarbonate solution (15 mL) were added. The separated organic phase was passed through a hydrophobic frit and the solvent was removed in vacuo. Purification of the residue via silica gel column chromatography (0-10% methanol in DCM) gave (4-(4-(cyclopropylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-2-fluoro-5-methoxyphenyl)(morpholino)methanone (36 mg, 16%) as an off-white solid. LCMS (10 cm_ESCI_Bicarb_MeCN): [M+H]+=456 at 2.93 min. 1H NMR (400 MHz, CDCl3): δ 8.77 (d, J=12.6 Hz, 1H), 8.20 (s, 1H), 7.94 (s, 1H), 6.91 (d, J=6.0 Hz, 1H), 5.48 (s, 1H), 3.92 (s, 3H), 3.84-3.76 (m, 4H), 3.68 (t, J=4.5 Hz, 2H), 3.44 (br s, 2H), 2.94-2.87 (m, 1H), 1.03-0.96 (m, 2H), 0.70-0.65 (m, 2H).

Workup

  1. temperatureto cool to RT
  2. filtrationThe precipitated solid was collected by filtration
  3. washwashed with dioxane and diethyl ether
  4. customdried
  5. customthe solvent was removed in vacuo
  6. customPurification of the residue via silica gel column chromatography (0-10% methanol in DCM)

Sources & evidence

ORD record
ord-c3cd51faf11b4c0994ea317fde750135
Source dataset
uspto-grants-2014_08
Patent number
US08809331B2

Reaction notes

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