Hydrochloric Acid → 1-Cyclopropyl-2,2,2-trifluoro-1-[5-(3-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]ethanol

HRID 410509Notes

Reaction equation

HRID 410509 reaction equation
[CH:1]1([C:4]([C:6]2[S:7][C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][C:18]4[N:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][N:19]=4)[CH:12]=3)=[CH:9][N:10]=2)=[O:5])[CH2:3][CH2:2]1.[F:28][C:29]([Si](C)(C)C)([F:31])[F:30].[F-].C[N+](C)(C)C.CC([O-])(C)C.[K+].CCCC[N+](CCCC)(CCCC)CCCC.[F-].Cl>O1CCCC1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].CCOCC>[CH:1]1([C:4]([C:6]2[S:7][C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][C:18]4[N:23]=[C:22]([C:24]([F:25])([F:26])[F:27])[CH:21]=[CH:20][N:19]=4)[CH:12]=3)=[CH:9][N:10]=2)([OH:5])[C:29]([F:31])([F:30])[F:28])[CH2:3][CH2:2]1

Participants

10

Reactant 6

HCID 313Hydrochloric AcidHCID 67803Tetramethylammonium fluorideHCID 552549(Trifluoromethyl)trimethylsilane3×HCID 2724141Tetrabutylammonium FluorideHCID 23665647Potassium tert-butoxideHCID 58456406HCID 58456406, compound

Product 1

HCID 584563141-Cyclopropyl-2,2,2-trifluoro-1-[5-(3-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]ethanolYield 67.6%

Reagents, catalysts & solvents 3

HCID 2724141Tetrabutylammonium FluorideCatalystHCID 3283Diethyl EtherSolventHCID 8028TetrahydrofuranSolvent

Procedure

TBAF (1 M, 3.71 μL, 3.71 μmol) was added to a stirred, cooled (0° C.) mixture of cyclopropyl[5-(3-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]methanone (29 mg, 0.074 mmol) and (trifluoromethyl)trimethylsilane (14.24 μL, 0.089 mmol) in tetrahydrofuran (0.2 mL) and the mixture was stirred at room temperature for 4 h. Additional TMSCF3 (20 μL) and tetramethyammonium fluoride (0.811 mg, 7.43 μmol) were added and the mixture was left to stir overnight. Additional TMSCF3 (22 μL) and KOtBu (1M in TIM, 74 μL) were added to the mixture and left to stir for 2 days. The mixture was treated with TBAF (74 μL), ether and HCl, and extracted with ethyl acetate. The combined organics were concentrated, and purified by flash chromatography to give 1-cyclopropyl-2,2,2-trifluoro-1-[5-(3-{[4-(trifluoromethyl)-pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]ethanol (23 mg, 0.050 mmol, 67.2% yield). APCI: [M+H]+ m/z 461.1. 1H NMR (400 MHz, CDCl3): δ 8.72 (d, J=4.9 Hz, 1H); 8.19 (s, 1H); 7.97 (s, 1H); 7.52 (d, J=8.3 Hz, 1H); 7.48-7.40 (m, 2H); 7.32 (d, J=7.8 Hz, 1H); 7.12 (d, J=4.9 Hz, 1H); 4.53 (s, 1H); 1.58-1.51 (m, 1H); 1.01-0.94 (m, 1H); 0.77-0.67 (m, 1H); 0.59-0.51 (m, 2H). rhSYK activity=+++

Workup

  1. temperaturecooled
  2. waitthe mixture was left
  3. stirringto stir overnight
  4. waitleft
  5. stirringto stir for 2 days
  6. extractionextracted with ethyl acetate
  7. concentrationThe combined organics were concentrated
  8. custompurified by flash chromatography

Sources & evidence

ORD record
ord-f0cd0ba6ea1c4c41ad1d56b54decad78
Source dataset
uspto-grants-2014_06
Patent number
US08759366B2

Reaction notes

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