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Potassium Carbonate → tert-Butyl 4-(7-fluoro-2-(4-hydroxy-1-(5-propylpyrimidin-2-yl)piperidin-4-yl)-2,3-dihydrobenzofuran-5-yl)-5,6-dihydropyridine-1(2H)-carboxylate

HRID 1025495
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HRID 1025495 반응식
Br[C:2]1[CH:3]=[C:4]([F:27])[C:5]2[O:9][CH:8]([C:10]3([OH:25])[CH2:15][CH2:14][N:13]([C:16]4[N:21]=[CH:20][C:19]([CH2:22][CH2:23][CH3:24])=[CH:18][N:17]=4)[CH2:12][CH2:11]3)[CH2:7][C:6]=2[CH:26]=1.CC1(C)C(C)(C)OB([C:36]2[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH:37]=2)O1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.CCOC(C)=O.CCOCC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:27][C:4]1[C:5]2[O:9][CH:8]([C:10]3([OH:25])[CH2:11][CH2:12][N:13]([C:16]4[N:21]=[CH:20][C:19]([CH2:22][CH2:23][CH3:24])=[CH:18][N:17]=4)[CH2:14][CH2:15]3)[CH2:7][C:6]=2[CH:26]=[C:2]([C:36]2[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH:37]=2)[CH:3]=1
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참가 물질

8

반응물 3

HCID 11430Potassium CarbonateHCID 4642098Tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine-1-carboxylateHCID 674657744-(5-Bromo-7-fluoro-2,3-dihydrobenzofuran-2-yl)-1-(5-propylpyrimidin-2-yl)piperidin-4-ol

생성물 1

HCID 67468836tert-Butyl 4-(7-fluoro-2-(4-hydroxy-1-(5-propylpyrimidin-2-yl)piperidin-4-yl)-2,3-dihydrobenzofuran-5-yl)-5,6-dihydropyridine-1(2H)-carboxylate수율 103.4%

시약·촉매·용매 4

HCID 178418397HCID 178418397, 화합물촉매HCID 962Water용매HCID 312751,4-Dioxane용매HCID 21584169Diethylether ethylacetate용매

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온도
100 °C

실험 절차

To a degassed solution of 4-(5-bromo-7-fluoro-2,3-dihydrobenzofuran-2-yl)-1-(5-propylpyrimidin-2-yl)piperidin-4-ol (0.122 g, 0.280 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (0.112 g, 0.363 mmol), and K2CO3 (97 mg, 0.699 mmol) in dioxane (2.9 mL) and H2O (1 mL) was added Pd(Ph3P)4 (16 mg, 0.014 mmol). Upon completion of addition, the reaction mixture was stirred at 100° C. for 15 hour under argon. At the conclusion of this period, the reaction mixture was cooled to room temperature and then diluted with EtOAc/Et2O (5 mL, 1:1 v/v). The organic layer was washed with aqueous NaHCO3 (saturated, 6 mL) and aqueous NaCl (saturated, 6 mL), dried (Na2SO4), filtered, and then concentrated to yield a residue. The residue was purified by column chromatography (silica gel, hexanes/EtOAc gradient 0 to 60% EtOAc) to afford Compound 1I as a light yellow solid (0.156 g, 97% yield). 1H NMR (500 MHz, CDCl3) δ ppm 8.15 (s, 2 H), 6.96 (s, 1 H), 6.91 (d, J=12.1 Hz, 1 H), 5.90 (br. s., 1 H), 4.67 (t, J=9.1 Hz, 1 H), 4.50-4.63 (m, 2 H), 4.03 (d, J=2.8 Hz, 2 H), 3.60 (t, J=5.6 Hz, 2 H), 3.26-3.40 (m, 3 H), 3.11 (dd, J=15.7, 9.1 Hz, 1 H), 2.33-2.48 (m, 4H), 1.92-2.00 (m, 2 H), 1.68-1.81 (m, 1 H), 1.52-1.67 (m, 4 H), 1.44-1.52 (m, 9H), 0.90-0.97 (t, J=7.3 Hz, 3 H). LC/MS (m/z)=539 (M+H)+.

후처리

  1. additionUpon completion of addition
  2. temperatureAt the conclusion of this period, the reaction mixture was cooled to room temperature
  3. washThe organic layer was washed with aqueous NaHCO3 (saturated, 6 mL) and aqueous NaCl (saturated, 6 mL)
  4. dry with materialdried (Na2SO4)
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customto yield a residue
  8. customThe residue was purified by column chromatography (silica gel, hexanes/EtOAc gradient 0 to 60% EtOAc)

출처 및 근거

ORD 기록
ord-b2dc29e797064332939a60e902b49b54
출처 데이터셋
uspto-grants-2014_05
DOI
10.6084/m9.figshare.5104873.v1
특허 번호
US08729084B2

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