Tetrahydrofuran → 1-(2-chloro-3'-fluoro-5-methoxy-[1,1'-biphenyl]-4-yl)-N-(1,2,5-thiadiazol-3-yl)isoquinoline-6-sulfonamide

HRID 1473546Notes

Reaction equation

HRID 1473546 reaction equation
[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18](OC4C(F)=C(F)C(F)=C(F)C=4F)(=[O:20])=[O:19])=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)[C:5]([O:33][CH3:34])=[CH:4][C:3]=1[C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[CH:36]=1.[S:42]1[N:46]=[CH:45][C:44]([NH2:47])=[N:43]1.C1COCC1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>CO>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([NH:47][C:44]4[CH:45]=[N:46][S:42][N:43]=4)(=[O:20])=[O:19])=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)[C:5]([O:33][CH3:34])=[CH:4][C:3]=1[C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[CH:36]=1

Participants

6

Reactant 4

HCID 8028TetrahydrofuranHCID 2733832Lithium HexamethyldisilazideHCID 108986591,2,5-Thiadiazol-3-amineHCID 86687601Perfluorophenyl 1-(2-chloro-3'-fluoro-5-methoxy-[1,1'-biphenyl]-4-yl)isoquinoline-6-sulfonate

Product 1

HCID 866876051-(2-chloro-3'-fluoro-5-methoxy-[1,1'-biphenyl]-4-yl)-N-(1,2,5-thiadiazol-3-yl)isoquinoline-6-sulfonamideYield 57.1%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Procedure

A vial was charged with perfluorophenyl 1-(2-chloro-3′-fluoro-5-methoxy-[1,1′-biphenyl]-4-yl)isoquinoline-6-sulfonate (INTERMEDIATE TTTT; 45 mg, 0.074 mmol), 1,2,5-thiadiazol-3-amine (8.21 mg, 0.081 mmol), and THF (0.5 mL) to give a clear solution. The vial was cooled in an ice-water bath for 5 min, then lithium bis(trimethylsilyl)amide (1M in THF) (162 μl, 0.162 mmol) was added drop wise. After 10 min, the mixture was diluted with a small amount of methanol to give a solution which was purified directly by chromatography 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-(1,2,5-thiadiazol-3-yl)isoquinoline-6-sulfonamide (22.2 mg, 0.042 mmol, 57.1% yield) as a light-yellow solid. 1H NMR (400 MHz, DMSO-d6) δ=12.50 (br. s., 1H), 8.81-8.69 (m, 2H), 8.50 (s, 1H), 8.18 (d, J=5.4 Hz, 1H), 8.00 (dd, J=1.9, 8.9 Hz, 1H), 7.88 (d, J=8.9 Hz, 1H), 7.65-7.52 (m, 2H), 7.48-7.39 (m, 2H), 7.35-7.29 (m, 1H), 7.27 (s, 1H), 3.70 (s, 3H). m/z (ESI) 527.2 (M+H)+.

Workup

  1. customto give a clear solution
  2. temperatureThe vial was cooled in an ice-water bath for 5 min
  3. customto give a solution which
  4. customwas purified directly by chromatography on silica gel (12-g Redi-Sep Gold column, 0-5% MeOH/DCM)

Sources & evidence

ORD record
ord-6cfc0ea83cc2452481474b2ee426c4ba
Source dataset
uspto-grants-2015_04
Patent number
US09012443B2

Reaction notes

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