Cesium carbonate → 1-[2-({3-Methyl-5-[2-(1,1,1-trifluoro-2-hydroxypropan-2-yl)-1,3-thiazol-5-yl]phenyl}amino)pyrimidin-4-yl]ethanone

HRID 1040136Notes

Reaction equation

HRID 1040136 reaction equation
[NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[S:13][C:12]([C:14]([OH:20])([CH3:19])[C:15]([F:18])([F:17])[F:16])=[N:11][CH:10]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:28]1[N:33]=[C:32]([C:34](=[O:36])[CH3:35])[CH:31]=[CH:30][N:29]=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>CC([O-])=O.CC([O-])=O.[Pd+2].O1CCOCC1>[CH3:8][C:6]1[CH:7]=[C:2]([NH:1][C:28]2[N:33]=[C:32]([C:34](=[O:36])[CH3:35])[CH:31]=[CH:30][N:29]=2)[CH:3]=[C:4]([C:9]2[S:13][C:12]([C:14]([OH:20])([CH3:19])[C:15]([F:18])([F:17])[F:16])=[N:11][CH:10]=2)[CH:5]=1

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 446138781-(2-Chloropyrimidin-4-yl)ethan-1-oneHCID 584561172-[5-(3-Amino-5-methylphenyl)-1,3-thiazol-2-yl]-1,1,1-trifluoropropan-2-ol

Product 1

HCID 584563541-[2-({3-Methyl-5-[2-(1,1,1-trifluoro-2-hydroxypropan-2-yl)-1,3-thiazol-5-yl]phenyl}amino)pyrimidin-4-yl]ethanoneYield 36%

Reagents, catalysts & solvents 2

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

Conditions

Temperature
100 °C

Procedure

To Intermediate 17 (500 mg, 1.654 mmol) in a scintillation vial was added dioxane (8.27 mL), cesium carbonate (1078 mg, 3.31 mmol), and 1-(2-chloropyrimidin-4-yl)ethanone (285 mg, 1.819 mmol). The system was purged and flushed with Ar(g) three times before adding Xantphos (144 mg, 0.248 mmol) and Pd(OAc)2 (40.8 mg, 0.182 mmol). The system was purged and flushed with Ar(g) three times before sealing the system and heating to 100° C. The reaction was stirred overnight and was cooled to room temperature. The reaction mixture was filtered through celite (washed with chloroform) and diluted with water. The organic layer was separated, dried over sodium sulfate, and was concentrated to dryness before purification by column chromatography (10-40% acetone in hexanes, linear gradient) to yield 1-[2-({3-methyl-5-[2-(1,1,1-trifluoro-2-hydroxypropan-2-yl)-1,3-thiazol-5-yl]phenyl}amino)pyrimidin-4-yl]ethanone (250 mg, 0.592 mmol, 36%). MS ESI: [M+H]+ m/z 423.1. 1H NMR (500 MHz, CDCl3) δ 8.66 (d, J=4.9, 1H), 7.95 (s, 2H), 7.34 (dd, J=8.1, 13.0, 3H), 7.10 (s, 1H), 2.73 (s, 3H), 2.42 (s, 3H), 1.85 (s, 3H). rhSYK activity=+++

Workup

  1. customThe system was purged
  2. customflushed with Ar(g) three times
  3. customThe system was purged
  4. customflushed with Ar(g) three times
  5. temperaturewas cooled to room temperature
  6. filtrationThe reaction mixture was filtered through celite (washed with chloroform)
  7. additiondiluted with water
  8. customThe organic layer was separated
  9. dry with materialdried over sodium sulfate
  10. concentrationwas concentrated to dryness before purification by column chromatography (10-40% acetone in hexanes, linear gradient)

Sources & evidence

ORD record
ord-a573cf4a16cf4a9ea7ee75fccbbc8e1c
Source dataset
uspto-grants-2013_10
Patent number
US08551984B2

Reaction notes

Loading…