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

HRID 2406327ノート

反応式

HRID 2406327 の反応式
[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

参加物

11

反応物 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

生成物 1

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

試薬・触媒・溶媒 3

HCID 962Water溶媒HCID 6344Dichloromethane溶媒2 回HCID 6422Trifluoroacetic acid溶媒

反応条件

温度
100 °C

実験手順

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).

後処理

  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

出典と根拠

ORDレコード
ord-82227033653b46d8a67b01ebe2adff87
出典データセット
uspto-grants-2014_08
特許番号
US08809331B2

反応ノート

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