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 595934ノート

反応式

HRID 595934 の反応式
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

参加物

8

反応物 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

生成物 1

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

試薬・触媒・溶媒 3

HCID 178418807HCID 178418807、化合物触媒HCID 80711,2-Dimethoxyethane溶媒HCID 8857Ethyl Acetate溶媒

反応条件

温度
120 °C

実験手順

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)

後処理

  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

出典と根拠

ORDレコード
ord-c2de10ee74314ecd8c6bc39e078a82b6
出典データセット
uspto-grants-2016_01
特許番号
US09242996B2

反応ノート

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