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

HRID 1473545Notes

Reaction equation

HRID 1473545 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.[N:42]1[CH:47]=[CH:46][C:45]([NH2:48])=[N:44][CH:43]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([NH:48][C:45]4[CH:46]=[CH:47][N:42]=[CH:43][N:44]=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

5

Reactant 3

HCID 689584-AminopyrimidineHCID 2733832Lithium HexamethyldisilazideHCID 86687601Perfluorophenyl 1-(2-chloro-3'-fluoro-5-methoxy-[1,1'-biphenyl]-4-yl)isoquinoline-6-sulfonate

Product 1

HCID 866876041-(2-chloro-3'-fluoro-5-methoxy-[1,1'-biphenyl]-4-yl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamideYield 65.5%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

A round-bottom flask was charged with perfluorophenyl 1-(2-chloro-3′-fluoro-5-methoxy-[1,1′-biphenyl]-4-yl)isoquinoline-6-sulfonate (INTERMEDIATE TTTT; 72.97 mg, 0.120 mmol) pyrimidin-4-amine (Alfa Aesar, Ward Hill, Mass., 12.52 mg, 0.132 mmol), and THF (598 μl) to give a clear, lightly-colored solution. The flask was cooled in an ice-bath for 5 min, then lithium bis(trimethylsilyl)amide (1M in THF) (251 μl, 0.251 mmol) was added drop wise over 30 s to give a yellow suspension. After 30 min, the mixture was purified directly by chromatography on silica gel (12-g Redi-Sep Gold column, 3.5 MeOH/DCM, then 3.5-10% MeOH/DCM). A few mixed fractions were discarded, and the remainder of fractions containing product were combined and concentrated to give 1-(2-chloro-3′-fluoro-5-methoxy-[1,1′-biphenyl]-4-yl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide (40.83 mg, 0.078 mmol, 65.5% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ=13.12 (br. s., 1H), 8.71 (s, 1H), 8.67 (s, 1H), 8.57 (s, 1H), 8.24 (d, J=6.6 Hz, 1H), 8.14 (d, J=5.8 Hz, 1H), 7.99 (dd, J=1.8, 8.9 Hz, 1H), 7.81 (d, J=8.9 Hz, 1H), 7.58 (dt, J=6.3, 8.0 Hz, 1H), 7.54 (s, 1H), 7.49-7.40 (m, 2H), 7.35-7.29 (m, 1H), 7.27 (s, 1H), 7.02 (d, J=6.6 Hz, 1H), 3.70 (s, 3H). m/z (ESI) 521.2 (M+H)+.

Workup

  1. customto give a clear, lightly-colored solution
  2. temperatureThe flask was cooled in an ice-bath for 5 min
  3. customto give a yellow suspension
  4. customthe mixture was purified directly by chromatography on silica gel (12-g Redi-Sep Gold column, 3.5 MeOH/DCM
  5. additionA few mixed fractions
  6. additionthe remainder of fractions containing product
  7. concentrationconcentrated

Sources & evidence

ORD record
ord-816e96f94aab42ae96bda44f527528fa
Source dataset
uspto-grants-2015_04
Patent number
US09012443B2

Reaction notes

Loading…