Trifluoroacetic acid → (S)-4-(2-amino-5-(4-methyltetrahydro-2H-pyran-4-yl)pyridin-3-yl)-2-fluoro-N-(2-hydroxy-1-phenylethyl)benzamide

HRID 595934노트

반응식

HRID 595934 반응식
Br[C:2]1[C:3]([NH2:15])=[N:4][CH:5]=[C:6]([C:8]2([CH3:14])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:7]=1.[F:16][C:17]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[CH:31][C:18]=1[C:19]([NH:21][C@@H:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:23][OH:24])=[O:20].C(=O)([O-])[O-].[Na+].[Na+].C(O)(C(F)(F)F)=O>COCCOC.C(OCC)(=O)C.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>[NH2:15][C:3]1[C:2]([C:33]2[CH:32]=[CH:31][C:18]([C:19]([NH:21][C@@H:22]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:23][OH:24])=[O:20])=[C:17]([F:16])[CH:34]=2)=[CH:7][C:6]([C:8]2([CH3:14])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:5][N:4]=1

참가 물질

8

반응물 4

HCID 6422Trifluoroacetic acidHCID 10340Sodium CarbonateHCID 1180457983-bromo-5-(4-methyltetrahydro-2H-pyran-4-yl)pyridin-2-amineHCID 123975973(S)-2-fluoro-N-(2-hydroxy-1-phenylethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide

생성물 1

HCID 118045845(S)-4-(2-amino-5-(4-methyltetrahydro-2H-pyran-4-yl)pyridin-3-yl)-2-fluoro-N-(2-hydroxy-1-phenylethyl)benzamide수율 34.5%

시약·촉매·용매 3

HCID 178418807HCID 178418807, 화합물촉매HCID 80711,2-Dimethoxyethane용매HCID 8857Ethyl Acetate용매

반응 조건

온도
120 °C

실험 절차

To a solution of 3-bromo-5-(4-methyltetrahydro-2H-pyran-4-yl)pyridin-2-amine (70 mg, 0.26 mmol) in DME (4 mL) was added (S)-2-fluoro-N-(2-hydroxy-1-phenylethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (298 mg, 0.77 mmol) and sodium carbonate (0.64 mL, 1.29 mmol). The mixture was purged with nitrogen for 10 min, then PdCl2(dppf)-CH2Cl2 (31.6 mg, 0.039 mmol) was added. The reaction mixture was heated to 120° C. in an oil bath for 2 h. The reaction mixture was diluted with ethyl acetate, washed with water, brine, dried over sodium sulfate and concentrated. The resulting residue was purified by flash column chromatography on silicagel (ISCO) eluting with 0-100% ethyl acetate in heptane to give 70 mg crude product, which was purified by HPLC to give (S)-4-(2-amino-5-(4-methyltetrahydro-2H-pyran-4-yl)pyridin-3-yl)-2-fluoro-N-(2-hydroxy-1-phenylethyl)benzamide (40.8 mg, 0.089 mmol, 34.5% yield) as TFA salt. LCMS (m/z): 450 (MH+), 0.61 min; 1H NMR (400 MHz, CDCl3) δ ppm 8.22 (t, J=7.83 Hz, 1H) 7.77-7.65 (m, 2H) 7.50 (dd, J=11.74, 7.43 Hz, 1H) 7.42-7.36 (m, 4H) 7.33 (d, J=7.43 Hz, 2H) 7.21 (d, J=11.74 Hz, 1H) 5.33 (d, J=4.70 Hz, 1H) 4.08-3.94 (m, 2H) 3.83-3.65 (m, 4H) 1.97 (ddd, J=13.40, 8.12, 5.09 Hz, 2H) 1.72 (d, J=13.69 Hz, 2H) 1.35 (s, 3H)

후처리

  1. customThe mixture was purged with nitrogen for 10 min
  2. washwashed with water, brine
  3. dry with materialdried over sodium sulfate
  4. concentrationconcentrated
  5. customThe resulting residue was purified by flash column chromatography on silicagel (ISCO)
  6. washeluting with 0-100% ethyl acetate in heptane
  7. customto give 70 mg crude product, which
  8. customwas purified by HPLC

출처 및 근거

ORD 기록
ord-c2de10ee74314ecd8c6bc39e078a82b6
출처 데이터셋
uspto-grants-2016_01
특허 번호
US09242996B2

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