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

HRID 1473547Notes

Reaction equation

HRID 1473547 reaction equation
[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

Participants

5

Reactant 3

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

Product 1

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

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

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)+.

Workup

  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

Sources & evidence

ORD record
ord-617723d3131847dd97760482e353dd38
Source dataset
uspto-grants-2015_04
Patent number
US09012443B2

Reaction notes

Loading…