1,4-Dioxane → methyl(1S,4R)-4-(5-{3-cyclopropyl-5-[(4-methylpyrimidin-2-yl)amino]phenyl}-1,3-thiazol-2-yl)-4-hydroxy-2,2-dimethylcyclohexanecarboxylate

HRID 1040147Notes

Reaction equation

HRID 1040147 reaction equation
[CH:1]1([C:4]2[CH:5]=[C:6]([NH:19][C:20]3[N:25]=[C:24]([CH3:26])[CH:23]=[CH:22][N:21]=3)[CH:7]=[C:8](B3OC(C)(C)C(C)(C)O3)[CH:9]=2)[CH2:3][CH2:2]1.Br[C:28]1[S:32][C:31]([C@@:33]2([OH:45])[CH2:38][CH2:37][C@H:36]([C:39]([O:41][CH3:42])=[O:40])[C:35]([CH3:44])([CH3:43])[CH2:34]2)=[N:30][CH:29]=1.O1CCOCC1.C(=O)(O)[O-].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.O>[CH:1]1([C:4]2[CH:9]=[C:8]([C:28]3[S:32][C:31]([C@@:33]4([OH:45])[CH2:38][CH2:37][C@H:36]([C:39]([O:41][CH3:42])=[O:40])[C:35]([CH3:43])([CH3:44])[CH2:34]4)=[N:30][CH:29]=3)[CH:7]=[C:6]([NH:19][C:20]3[N:25]=[C:24]([CH3:26])[CH:23]=[CH:22][N:21]=3)[CH:5]=2)[CH2:2][CH2:3]1

Participants

7

Reactant 4

HCID 312751,4-DioxaneHCID 516892Sodium BicarbonateHCID 58456230N-[3-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-4-methylpyrimidin-2-amineHCID 58456350(1S,4R)-4-(5-Bromo-thiazol-2-yl)-4-hydroxy-2,2-dimethyl-cyclohexanecarboxylic acid methyl ester

Product 1

HCID 67430830methyl(1S,4R)-4-(5-{3-cyclopropyl-5-[(4-methylpyrimidin-2-yl)amino]phenyl}-1,3-thiazol-2-yl)-4-hydroxy-2,2-dimethylcyclohexanecarboxylateYield 49.1%

Reagents, catalysts & solvents 2

HCID 178418807HCID 178418807, compoundCatalystHCID 962WaterSolvent

Procedure

A reaction mixture containing N-[3-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-4-methylpyrimidin-2-amine (60 mg, 0.171 mmol), methyl(1S,4R)-4-(5-bromo-1,3-thiazol-2-yl)-4-hydroxy-2,2-dimethylcyclohexanecarboxylate (62.5 mg, 0.179 mmol), PdCl2(dppf)-CH2Cl2 adduct (27.9 mg, 0.034 mmol), 1,4-dioxane (1.2 mL), water (0.1 mL), and aqueous sodium bicarbonate solution (2 M, 0.171 mL, 0.342 mmol) was irradiated in the microwave for 15 minutes at 160° C. The reaction mixture was partitioned between ethyl acetate (30 mL) and saturated aqueous sodium bicarbonate solution (15 mL). The layers were separated and the organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel flash column chromatography (25-50% ethyl acetate/hexanes) to afford methyl(1S,4R)-4-(5-{3-cyclopropyl-5-[(4-methylpyrimidin-2-yl)amino]phenyl}-1,3-thiazol-2-yl)-4-hydroxy-2,2-dimethylcyclohexanecarboxylate (41.3 mg, 0.084 mmol, 49% yield) as an off-white, solid.

Workup

  1. customwas irradiated in the microwave for 15 minutes at 160° C
  2. customThe reaction mixture was partitioned between ethyl acetate (30 mL) and saturated aqueous sodium bicarbonate solution (15 mL)
  3. customThe layers were separated
  4. washthe organic layer was washed with brine
  5. dry with materialdried over sodium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customThe crude product was purified by silica gel flash column chromatography (25-50% ethyl acetate/hexanes)

Sources & evidence

ORD record
ord-fa6fbbdaa50f43d7a393358b76b51eef
Source dataset
uspto-grants-2013_10
Patent number
US08551984B2

Reaction notes

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