3-Isoxazolamine → 1-(2-Chloro-3'-fluoro-5-methoxy-[1,1'-biphenyl]-4-YL)-N-(isoxazol-3-YL)isoquinoline-6-sulfonamide

HRID 1473547ノート

反応式

HRID 1473547 の反応式
[O:1]1[CH:5]=[CH:4][C:3]([NH2:6])=[N:2]1.[Cl:7][C:8]1[CH:13]=[C:12]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([S:24](OC4C(F)=C(F)C(F)=C(F)C=4F)(=[O:26])=[O:25])=[CH:21][CH:22]=3)[CH:17]=[CH:16][N:15]=2)[C:11]([O:39][CH3:40])=[CH:10][C:9]=1[C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([F:47])[CH:42]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[Cl:7][C:8]1[CH:13]=[C:12]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([S:24]([NH:6][C:3]4[CH:4]=[CH:5][O:1][N:2]=4)(=[O:26])=[O:25])=[CH:21][CH:22]=3)[CH:17]=[CH:16][N:15]=2)[C:11]([O:39][CH3:40])=[CH:10][C:9]=1[C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([F:47])[CH:42]=1

参加物

5

反応物 3

HCID 18102163-IsoxazolamineHCID 2733832Lithium Hexamethyldisilazide2 回HCID 86687601Perfluorophenyl 1-(2-chloro-3'-fluoro-5-methoxy-[1,1'-biphenyl]-4-yl)isoquinoline-6-sulfonate

生成物 1

HCID 866876061-(2-Chloro-3'-fluoro-5-methoxy-[1,1'-biphenyl]-4-YL)-N-(isoxazol-3-YL)isoquinoline-6-sulfonamide

試薬・触媒・溶媒 1

HCID 8028Tetrahydrofuran溶媒

実験手順

A vial was charged with isoxazol-3-amine (6.09 microliters, 6.93 mg, 0.082 mmol) (from Aldrich Co.), perfluorophenyl 1-(2-chloro-3′-fluoro-5-methoxy-[1,1′-biphenyl]-4-yl)isoquinoline-6-sulfonate (INTERMEDIATE TTTT, 45.67 mg, 0.075 mmol) and THF (0.5 mL) to give a clear solution. The vial was cooled in an ice-water bath for 10 min, then lithium bis(trimethylsilyl)amide (1M in THF) (65.9 μl, 0.065 mmol) was added. After 40 min, additional portions of amine (10 microliters) and LHMDS solution (0.05 mL) were added. LCMS after 10 min showed mainly the desired product. The mixture was purified directly on silica gel (12-g Redi-Sep Gold column, 0-5% MeOH/DCM) to give 1-(2-chloro-3′-fluoro-5-methoxy-[1,1′-biphenyl]-4-yl)-N-(isoxazol-3-yl)isoquinoline-6-sulfonamide (23.72 mg, 0.047 mmol, 62.1% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ=11.92 (br. s., 1H), 8.78-8.72 (m, 2H), 8.69 (d, J=1.7 Hz, 1H), 8.16 (d, J=5.5 Hz, 1H), 8.01-7.84 (m, 2H), 7.64-7.53 (m, 2H), 7.49-7.40 (m, 2H), 7.37-7.29 (m, 1H), 7.27 (s, 1H), 6.50 (d, J=1.9 Hz, 1H), 3.70 (s, 3H). m/z (ESI) 510.2 (M+H)+.

後処理

  1. customto give a clear solution
  2. temperatureThe vial was cooled in an ice-water bath for 10 min
  3. waitLCMS after 10 min showed mainly

出典と根拠

ORDレコード
ord-617723d3131847dd97760482e353dd38
出典データセット
uspto-grants-2015_04
特許番号
US09012443B2

反応ノート

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