p-Toluenesulfonic acid → HCID 71451847, compound

HRID 2406324Notes

Reaction equation

HRID 2406324 reaction equation
Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[C:18]([O:19][CH3:20])=[CH:17][C:16]([C:21]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)=[O:22])=[C:15]([F:29])[CH:14]=2)[N:3]=1.CC1C=CC(S(O)(=O)=O)=CC=1.CC[N:43]([CH:47]([CH3:49])[CH3:48])C(C)C.C(=O)(O)[O-].[Na+]>O1CCOCC1.C(Cl)Cl>[CH:47]1([NH:43][C:2]2[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]3[C:18]([O:19][CH3:20])=[CH:17][C:16]([C:21]([N:23]4[CH2:24][CH2:25][O:26][CH2:27][CH2:28]4)=[O:22])=[C:15]([F:29])[CH:14]=3)[N:3]=2)[CH2:49][CH2:48]1

Participants

7

Reactant 4

HCID 6101p-Toluenesulfonic acidHCID 81531DiisopropylethylamineHCID 516892Sodium BicarbonateHCID 86687947HCID 86687947, compound

Product 1

HCID 71451847HCID 71451847, compoundYield 33%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

To a solution of (4-(4-chloro-5-(trifluoromethyl)pyrimidin-2-ylamino)-2-fluoro-5-methoxyphenyl)-(morpholino)methanone (120 mg, 0.28 mmol) in dioxane (2 mL) was added pTSA (52 mg, 0.28 mmol) and D4-cyclopropylamine (17 mg, 0.28 mmol). The mixture was heated to 100° C. for 2 hours. LSMS of crude sample indicated only 10% of desired material. DIPEA (100 μL, 0.56 mmol) and D4-cyclopropylamine (17 mg, 0.28 mmol) were added and the mixture was heated to 100° C. for one hour. After return to room temperature, DCM (20 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. The residue was purified by reversed phase HPLC to give (4-(4-(cyclopropylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-2-fluoro-5-methoxyphenyl)(morpholino)-methanone (42 mg, 33%) as an off-white solid. LCMS (10 cm_ESCI_Bicarb_MeCN): [M+H]+=460 at 3.41 min. 1H NMR (400 MHz, CDCl3): δ 8.77 (d, J=12.8 Hz, 1H), 8.20 (s, 1H), 7.94 (s, 1H), 6.91 (d, J=5.6 Hz, 1H), 5.48 (s, 1H), 3.92 (s, 3H), 3.80-3.74 (m, 4H), 3.69-3.67 (m, 2H), 3.44-3.43 (m, 2H).

Workup

  1. temperaturethe mixture was heated to 100° C. for one hour
  2. customthe solvent was removed in vacuo
  3. customThe residue was purified by reversed phase HPLC

Sources & evidence

ORD record
ord-0eaae9be625a489facdd46d8fe676a13
Source dataset
uspto-grants-2014_08
Patent number
US08809331B2

Reaction notes

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