Potassium Carbonate → 1-(5-{3-[(5-Chloro-4-methoxypyrimidin-2-yl)amino]-5-methylphenyl}-1,3-thiazol-2-yl)cyclobutanol

HRID 1040130Notes

Reaction equation

HRID 1040130 reaction equation
Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([Cl:10])=[CH:4][N:3]=1.[NH2:11][C:12]1[CH:13]=[C:14]([C:19]2[S:23][C:22]([C:24]3([OH:28])[CH2:27][CH2:26][CH2:25]3)=[N:21][CH:20]=2)[CH:15]=[C:16]([CH3:18])[CH:17]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C(=O)([O-])[O-].[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:10][C:5]1[C:6]([O:8][CH3:9])=[N:7][C:2]([NH:11][C:12]2[CH:13]=[C:14]([C:19]3[S:23][C:22]([C:24]4([OH:28])[CH2:27][CH2:26][CH2:25]4)=[N:21][CH:20]=3)[CH:15]=[C:16]([CH3:18])[CH:17]=2)=[N:3][CH:4]=1

Participants

6

Reactant 4

HCID 11430Potassium CarbonateHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 497617462,5-Dichloro-4-methoxypyrimidineHCID 584563951-[5-(3-Amino-5-methylphenyl)-2-thiazolyl]cyclobutanol

Product 1

HCID 584562461-(5-{3-[(5-Chloro-4-methoxypyrimidin-2-yl)amino]-5-methylphenyl}-1,3-thiazol-2-yl)cyclobutanolYield 60.5%

Reagents, catalysts & solvents 1

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalyst

Conditions

Temperature
90 °C

Procedure

A flask was charged with a stir bar, 2,5-dichloro-4-methoxypyrimidine (69 mg, 0.38 mmol), Intermediate 15 (100 mg, 0.38 mmol), Pd2(dba)3 (35.2 mg, 0.038 mmol), XPhos (92 mg, 0.19 mmol), and potassium carbonate (106 mg, 0.77 mmol). The vial was fully evacuated and backfilled with argon three times. Fully degassed tert-amyl alcohol (1.30 mL) was added to the reaction mixture, which was sealed and stirred at 90° C. overnight. The reaction was then cooled to room temperature. The crude mixture was taken-up in DCM and directly purified by Chromatography on silica gel (0-100% ethyl acetate/hexanes) to provide 1-(5-{3-[(5-chloro-4-methoxypyrimidin-2-yl)amino]-5-methylphenyl}-1,3-thiazol-2-yl)cyclobutanol (93 mg, 0.23 mmol, 60%) as a dark blue solid. MS ESI: [M+H]+ m/z 403.1. 1H NMR (500 MHz, dmso) δ 9.78 (s, 1H), 8.32 (s, 1H), 7.98 (s, 1H), 7.89 (s, 1H), 7.46 (s, 1H), 7.10 (s, 1H), 6.50 (s, 1H), 4.05 (s, 3H), 2.56-2.50 (m, 2H), 2.36-2.27 (m, 5H), 1.94-1.82 (m, 2H). rhSYK activity=+++

Workup

  1. additionA flask was charged with a stir bar
  2. customThe vial was fully evacuated
  3. additionFully degassed tert-amyl alcohol (1.30 mL) was added to the reaction mixture, which
  4. customwas sealed
  5. temperatureThe reaction was then cooled to room temperature
  6. customdirectly purified by Chromatography on silica gel (0-100% ethyl acetate/hexanes)

Sources & evidence

ORD record
ord-9720554fbe2f426183814f32d53f4655
Source dataset
uspto-grants-2013_10
Patent number
US08551984B2

Reaction notes

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