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4-Aminopyrimidine → 1-(3'-chloro-5'-fluoro-4-methoxy-[1,1'-biphenyl]-3-yl)-2-oxo-N-(pyrimidin-4-yl)-1,2-dihydroquinoline-6-sulfonamide

HRID 1504510
ノート
印刷プレビュー

反応式

HRID 1504510 の反応式
[NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][N:3]=1.[Cl:8][C:9]1[CH:10]=[C:11]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([N:24]3[C:33]4[C:28](=[CH:29][C:30]([S:34](OC5C(F)=C(F)C(F)=C(F)C=5F)(=[O:36])=[O:35])=[CH:31][CH:32]=4)[CH:27]=[CH:26][C:25]3=[O:49])[CH:17]=2)[CH:12]=[C:13]([F:15])[CH:14]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>CS(C)=O.O1CCCC1.CCOC(C)=O.Cl>[Cl:8][C:9]1[CH:10]=[C:11]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([N:24]3[C:33]4[C:28](=[CH:29][C:30]([S:34]([NH:1][C:2]5[CH:7]=[CH:6][N:5]=[CH:4][N:3]=5)(=[O:35])=[O:36])=[CH:31][CH:32]=4)[CH:27]=[CH:26][C:25]3=[O:49])[CH:17]=2)[CH:12]=[C:13]([F:15])[CH:14]=1
参加物反応条件実験手順後処理出典と根拠反応ノート

参加物

8

反応物 3

HCID 689584-AminopyrimidineHCID 2733832Lithium hexamethyldisilazaneHCID 117737031Perfluorophenyl 1-(3'-chloro-5'-fluoro-4-methoxy-[1,1'-biphenyl]-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonate

生成物 1

HCID 1177371531-(3'-chloro-5'-fluoro-4-methoxy-[1,1'-biphenyl]-3-yl)-2-oxo-N-(pyrimidin-4-yl)-1,2-dihydroquinoline-6-sulfonamide収率 49%

試薬・触媒・溶媒 4

HCID 313
Hydrochloric Acid
溶媒
HCID 679Dimethyl Sulfoxide溶媒
HCID 8028Tetrahydrofuran溶媒2 回
HCID 8857Ethyl Acetate溶媒

反応条件

温度
0 °C

実験手順

4-Aminopyrimidine (0.099 g, 1.038 mmol) was dissolved in dimethyl sulfoxide (1.997 ml), and perfluorophenyl 1-(3′-chloro-5′-fluoro-4-methoxy-[1,1′-biphenyl]-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonate (0.500 g, 0.799 mmol) in tetrahydrofuran (5.99 ml) was added as a solution. The reaction was cooled to 0° C. and LHMDS, 1.0M in THF (1.837 ml, 1.837 mmol) was added drop wise. The reaction mixture was diluted with EtOAc and 1N HCl (aq). The layers were separated, and the aqueous was washed (xl) with EtOAc. The combined organics were dried over magnesium sulfate, filtered and concentrated in vacuo. The crude material was purified via MPLC, eluting with 0-100% ethyl acetate in heptane (with a 10% DCM additive), to yield 1-(3′-chloro-5′-fluoro-4-methoxy-[1,1′-biphenyl]-3-yl)-2-oxo-N-(pyrimidin-4-yl)-1,2-dihydroquinoline-6-sulfonamide (0.210 g, 0.391 mmol, 49.0% yield) as a white solid. m/z (ESI) 537.0 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.73 (s, 3 H) 6.75 (d, J=8.91 Hz, 1 H) 6.80 (d, J=9.64 Hz, 1 H) 7.00 (br. s., 1 H) 7.34-7.42 (m, 2 H) 7.59-7.64 (m, 1 H) 7.68 (t, J=1.61 Hz, 1 H) 7.86 (d, J=2.49 Hz, 1 H) 7.89 (dd, J=8.97, 2.02 Hz, 1 H) 8.02 (dd, J=8.76, 2.44 Hz, 1 H) 8.24 (d, J=9.54 Hz, 1 H) 8.27-8.34 (m, 1 H) 8.43 (s, 1 H) 8.60 (s, 1 H). 1-(3′-chloro-5′-fluoro-4-methoxy-[1,1′-biphenyl]-3-yl)-2-oxo-N-(pyrimidin-4-yl)-1,2-dihydroquinoline-6-sulfonamide was separated by chiral SFC on a Chiralpak AD with 30% isopropanol to give (P)-1-(3′-chloro-5′-fluoro-4-methoxy-3-biphenylyl)-2-oxo-N-4-pyrimidinyl-1,2-dihydro-6-quinolinesulfonamide as peak 1 and (M)-1-(3′-chloro-5′-fluoro-4-methoxy-3-biphenylyl)-2-oxo-N-4-pyrimidinyl-1,2-dihydro-6-quinolinesulfonamide as peak 2. Data for peak 1: m/z (ESI) 537.0 (M+H)+. 1 H NMR (400 MHz, DMSO-d6) δ ppm 3.73 (s, 3 H) 6.75 (d, J=8.81 Hz, 6.79 (d, J=9.64 Hz, 1 H) 6.98 (br. s., 1 H) 7.34-7.41 (m, 2 H) 7.62 (dt, J=7.63 Hz, 1 H) 7.68 (t, J=1.61 Hz, 1 H) 7.86 (d, J=2.38 Hz, 1 H) 7.87-7.91 (m, 1 H) 8.02 (dd, J=8.76, 2.44 Hz, 1 H) 8.23 (d, J=9.54 Hz, 1 H) 8.26-8.31 (m, 1 H) 8.40-8.44 (m, 1 H) 8.59 (s, 1 H). Data for peak 2: m/z (ESI) 537.0 (M+H)+. 1 H NMR (400 MHz, DMSO-d6) δ ppm 3.73 (s, 3H) 6.75 (d, J=9.02 Hz, 1 H) 6.79 (d, J=9.64 Hz, 1 H) 7.00 (br. s., 1 H) 7.35-7.41 (m, 2 H) 7.61 (dt, J=6.43 Hz, 1 H) 7.68 (t, J=1.55 Hz, 1 H) 7.86 (d, J=2.49 Hz, 1 H) 7.87-7.91 (m, 1H) 8.02 (dd, J=8.71, 2.49 Hz, 1 H) 8.24 (d, J=9.64 Hz, 1 H) 8.29 (br. s., 1 H) 8.41-8.44 (m, 1H) 8.59 (s, 1 H). The sulfonamide —NH was not observed in the NMR spectra of the three compounds.

後処理

  1. customThe layers were separated
  2. washthe aqueous was washed (xl) with EtOAc
  3. dry with materialThe combined organics were dried over magnesium sulfate
  4. filtrationfiltered
  5. concentrationconcentrated in vacuo
  6. customThe crude material was purified via MPLC
  7. washeluting with 0-100% ethyl acetate in heptane (with a 10% DCM additive),

出典と根拠

ORDレコード
ord-35aee9a7026e4ffd9828567df08eda2c
出典データセット
uspto-grants-2015_12
DOI
10.6084/m9.figshare.5104873.v1
特許番号
US09212182B2

反応ノート

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