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 1040147노트

반응식

HRID 1040147 반응식
[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

참가 물질

7

반응물 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

생성물 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-dimethylcyclohexanecarboxylate수율 49.1%

시약·촉매·용매 2

HCID 178418807HCID 178418807, 화합물촉매HCID 962Water용매

실험 절차

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.

후처리

  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)

출처 및 근거

ORD 기록
ord-fa6fbbdaa50f43d7a393358b76b51eef
출처 데이터셋
uspto-grants-2013_10
특허 번호
US08551984B2

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