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

HRID 1473547노트

반응식

HRID 1473547 반응식
[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

참가 물질

5

반응물 3

HCID 18102163-IsoxazolamineHCID 2733832Lithium Hexamethyldisilazide2회HCID 86687601Perfluorophenyl 1-(2-chloro-3'-fluoro-5-methoxy-[1,1'-biphenyl]-4-yl)isoquinoline-6-sulfonate

생성물 1

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

시약·촉매·용매 1

HCID 8028Tetrahydrofuran용매

실험 절차

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)+.

후처리

  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

출처 및 근거

ORD 기록
ord-617723d3131847dd97760482e353dd38
출처 데이터셋
uspto-grants-2015_04
특허 번호
US09012443B2

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