Cesium carbonate → Racemic methyl-4-(5-{3-[(5-fluoro-4-methylpyrimidin-2-yl)amino]-5-methylphenyl}-1,3-thiazol-2-yl)-4-hydroxy-2,2-dimethylcyclohexanecarboxylate

HRID 410652Notes

Reaction equation

HRID 410652 reaction equation
Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([F:9])=[CH:4][N:3]=1.[CH3:10][O:11][C:12]([CH:14]1[CH2:19][CH2:18][C:17]([C:21]2[S:22][C:23]([C:26]3[CH:31]=[C:30]([CH3:32])[CH:29]=[C:28]([NH2:33])[CH:27]=3)=[CH:24][N:25]=2)([OH:20])[CH2:16][C:15]1([CH3:35])[CH3:34])=[O:13].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+]>CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:10][O:11][C:12]([CH:14]1[CH2:19][CH2:18][C:17]([C:21]2[S:22][C:23]([C:26]3[CH:31]=[C:30]([CH3:32])[CH:29]=[C:28]([NH:33][C:2]4[N:7]=[C:6]([CH3:8])[C:5]([F:9])=[CH:4][N:3]=4)[CH:27]=3)=[CH:24][N:25]=2)([OH:20])[CH2:16][C:15]1([CH3:35])[CH3:34])=[O:13]

Participants

6

Reactant 4

HCID 10796Cesium carbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 207780732-Chloro-5-fluoro-4-methylpyrimidineHCID 67429727Methyl 4-(5-(3-amino-5-methylphenyl)thiazol-2-yl)-4-hydroxy-2,2-dimethylcyclohexanecarboxylate

Product 1

HCID 67250082Racemic methyl-4-(5-{3-[(5-fluoro-4-methylpyrimidin-2-yl)amino]-5-methylphenyl}-1,3-thiazol-2-yl)-4-hydroxy-2,2-dimethylcyclohexanecarboxylateYield 86.5%

Reagents, catalysts & solvents 1

HCID 167845palladium(II) acetateCatalyst

Conditions

Temperature
110 °C

Procedure

Racemic 2-chloro-5-fluoro-4-methylpyrimidine (50.0 mg, 0.341 mmol), methyl-4-[5-(3-amino-5-methylphenyl)-1,3-thiazol-2-yl]-4-hydroxy-2,2-dimethylcyclohexanecarboxylate (128 mg, 0.341 mmol), Pd(OAc)2 (15.3 mg, 0.0680 mmol), Xantphos (59.2 mg, 0.102 mmol), and Cs2CO3 (222 mg, 0.682 mmol) were combined in a flask and degassed with argon. To this solid mixture was added dioxane (2.0 mL), and the resulting mixture was degassed with argon for 5 min. The reaction mixture was heated to 110° C. for 1.5 h. The reaction was cooled to ambient temperature, then diluted with saturated aqueous NaCl and EtOAc. The layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The resulting crude product was purified by column chromatography on silica (10-30% EtOAc/hexanes gradient) to afford racemic methyl-4-(5-{3-[(5-fluoro-4-methylpyrimidin-2-yl)amino]-5-methylphenyl}-1,3-thiazol-2-yl)-4-hydroxy-2,2-dimethylcyclohexanecarboxylate (143 mg, 0.295 mmol, 86% yield). MS ESI: [M+H]+ m/z 485.

Workup

  1. customdegassed with argon
  2. additionTo this solid mixture was added dioxane (2.0 mL)
  3. customthe resulting mixture was degassed with argon for 5 min
  4. temperatureThe reaction was cooled to ambient temperature
  5. additiondiluted with saturated aqueous NaCl and EtOAc
  6. customThe layers were separated
  7. extractionthe aqueous layer was extracted with EtOAc
  8. dry with materialThe combined organic layers were dried over sodium sulfate
  9. filtrationfiltered
  10. concentrationconcentrated in vacuo
  11. customThe resulting crude product was purified by column chromatography on silica (10-30% EtOAc/hexanes gradient)

Sources & evidence

ORD record
ord-13cbedf949f2436d80bbb8c6e77d72c1
Source dataset
uspto-grants-2014_06
Patent number
US08759366B2

Reaction notes

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