Cesium carbonate → 1-[5-(3-Chloro-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclobutanol

HRID 1039995Notes

Reaction equation

HRID 1039995 reaction equation
[NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[S:13][C:12]([C:14]3([OH:18])[CH2:17][CH2:16][CH2:15]3)=[N:11][CH:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl[C:20]1[N:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][N:21]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[Cl:8][C:6]1[CH:5]=[C:4]([C:9]2[S:13][C:12]([C:14]3([OH:18])[CH2:17][CH2:16][CH2:15]3)=[N:11][CH:10]=2)[CH:3]=[C:2]([NH:1][C:20]2[N:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][N:21]=2)[CH:7]=1

Participants

8

Reactant 4

HCID 10796Cesium carbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 27739122-Chloro-4-(trifluoromethyl)pyrimidineHCID 674320031-[5-(3-Amino-5-chlorophenyl)-1,3-thiazol-2-yl]cyclobutanol

Product 1

HCID 584563471-[5-(3-Chloro-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclobutanolYield 55.8%

Reagents, catalysts & solvents 3

HCID 167845palladium(II) acetateCatalystHCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent

Procedure

The product of Step 3 (460 mg, 1.720 mmol), 2-chloro-4-(trifluoromethyl)pyrimidine (314 mg, 1.638 mmol), Xantphos (284 mg, 0.492 mmol), palladium (II) acetate (73.6 mg, 0.328 mmol), cesium carbonate (1.068 g, 3.28 mmol) and dioxane (12.3 mL) were heated at 90° C. for 90 minutes. The reaction mixture was diluted with ethyl acetate, washed with water and dried over Na2SO4. Filtration and solvent evaporation gave a residue which was further purified by column chromatography on silica gel, eluting with 40% ethyl acetate in hexane to afford 1-[5-(3-chloro-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclobutanol as a brown solid (390 mg, 55.8%). 1H NMR (500 MHz, CDCl3): δ 8.71 (d, J=4.7 Hz, 1H); 7.92 (s, 1H); 7.85 (s, 1H); 7.78 (s, 1H); 7.69 (s, 1H); 7.25 (s, 1H); 7.13 (d, J=4.8 Hz, 1H); 3.81 (s, 1H); 2.73 (s, 2H); 2.58-2.47 (m, 2H); 2.13-1.97 (m, 2H) MS APCI: [M+H]+ m/z 427.1. rhSYK activity=++

Workup

  1. washwashed with water
  2. dry with materialdried over Na2SO4
  3. filtrationFiltration and solvent evaporation
  4. customgave a residue which
  5. customwas further purified by column chromatography on silica gel
  6. washeluting with 40% ethyl acetate in hexane

Sources & evidence

ORD record
ord-95e6165e45894bd5ae60a4a7b8ec13f5
Source dataset
uspto-grants-2013_10
Patent number
US08551984B2

Reaction notes

Loading…