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

HRID 1040132Notes

Reaction equation

HRID 1040132 reaction equation
Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([Cl:9])=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:12]=[C:13]([C:18]2[S:22][C:21]([C:23]3([OH:27])[CH2:26][CH2:25][CH2:24]3)=[N:20][CH:19]=2)[CH:14]=[C:15]([CH3:17])[CH:16]=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:9][C:5]1[C:6]([CH3:8])=[N:7][C:2]([NH:10][C:11]2[CH:12]=[C:13]([C:18]3[S:22][C:21]([C:23]4([OH:27])[CH2:26][CH2:25][CH2:24]4)=[N:20][CH:19]=3)[CH:14]=[C:15]([CH3:17])[CH:16]=2)=[N:3][CH:4]=1

Participants

6

Reactant 4

HCID 11430Potassium CarbonateHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 212786212,5-Dichloro-4-methylpyrimidineHCID 584563951-[5-(3-Amino-5-methylphenyl)-2-thiazolyl]cyclobutanol

Product 1

HCID 584562941-(5-{3-[(5-Chloro-4-methylpyrimidin-2-yl)amino]-5-methylphenyl}-1,3-thiazol-2-yl)cyclobutanolYield 44.7%

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-methylpyrimidine (63 mg, 0.38 mmol), Intermediate 15 (100 mg, 0.38 mmol), Pd2(dba)3 (35 mg, 0.038 mmol), XPhos (92 mg, 0.19 mmol), and potassium carbonate (106 mg, 0.768 mmol). The vial was evacuated and backfilled with argon three times. Fully degassed tent-amyl alcohol (1.3 mL) was added to the flask, which was sealed and stirred at 90° C. overnight. The reaction was then cooled to room temperature, diluted with DCM and directly purified by Chromatography on silica gel (0-100% ethyl acetate in hexanes) to provide 1-(5-{3-[(5-chloro-4-methylpyrimidin-2-yl)amino]-5-methylphenyl}-1,3-thiazol-2-yl)cyclobutanol (65 mg, 0.17 mmol, 44%) as a dark brown solid. MS ESI: [M+H]+ m/z 387.1 1H NMR (500 MHz, dmso) δ 9.81 (s, 1H), 8.44 (s, 1H), 7.97 (s, 1H), 7.91 (s, 1H), 7.47 (s, 1H), 7.08 (s, 1H), 6.51 (s, 1H), 2.58-2.50 (m, 2H), 2.45 (s, 3H), 2.37-2.27 (m, 5H), 1.93-1.82 (m, 2H). rhSYK activity=+++

Workup

  1. additionA flask was charged with a stir bar
  2. customThe vial was evacuated
  3. additionFully degassed tent-amyl alcohol (1.3 mL) was added to the flask, which
  4. customwas sealed
  5. temperatureThe reaction was then cooled to room temperature
  6. additiondiluted with DCM
  7. customdirectly purified by Chromatography on silica gel (0-100% ethyl acetate in hexanes)

Sources & evidence

ORD record
ord-3dd29c3089d8459cac1fea76c1d477fb
Source dataset
uspto-grants-2013_10
Patent number
US08551984B2

Reaction notes

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