Potassium Phosphate, Tribasic → 3-chloro-1-(2-methoxy-4-(trifluoromethyl)phenyl)-N-(4-methoxybenzyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide

HRID 1473389Notes

Reaction equation

HRID 1473389 reaction equation
Br[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([N:15]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[C:16]3[S:17][CH:18]=[CH:19][N:20]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([Cl:30])[N:3]=1.[CH3:31][O:32][C:33]1[CH:38]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:36]=[CH:35][C:34]=1B(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O.O1CCOCC1>[Cl:30][C:4]1[N:3]=[C:2]([C:34]2[CH:35]=[CH:36][C:37]([C:39]([F:42])([F:41])[F:40])=[CH:38][C:33]=2[O:32][CH3:31])[C:11]2[C:6]([CH:5]=1)=[CH:7][C:8]([S:12]([N:15]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=1)[C:16]1[S:17][CH:18]=[CH:19][N:20]=1)(=[O:14])=[O:13])=[CH:9][CH:10]=2

Participants

6

Reactant 3

HCID 62657Potassium Phosphate, Tribasic2×HCID 24901776(2-Methoxy-4-(trifluoromethyl)phenyl)boronic acid2×HCID 866874301-bromo-3-chloro-N-(4-methoxybenzyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide2×

Product 1

HCID 866874313-chloro-1-(2-methoxy-4-(trifluoromethyl)phenyl)-N-(4-methoxybenzyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamideYield 741.3%

Reagents, catalysts & solvents 2

HCID 962WaterSolvent2×HCID 312751,4-DioxaneSolvent2×

Conditions

Temperature
90 °C

Procedure

This reaction was conducted in two separate vials. For the first reaction, a vial was charged with 1-bromo-3-chloro-N-(4-methoxybenzyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (57.11 mg, 0.109 mmol), (2-methoxy-4-(trifluoromethyl)phenyl)boronic acid (25.1 mg, 0.114 mmol), Pd(AmPhos)2Cl2 (3.85 mg, 5.44 μmol), potassium phosphate (69.3 mg, 0.326 mmol), 1,4-dioxane (408 μl), and water (136 μl). The vial was flushed with Ar (g), then sealed and heated in a microwave reactor for 15 min at 90° C. A second vial was charged with 1-bromo-3-chloro-N-(4-methoxybenzyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (422 mg, 0.804 mmol), (2-methoxy-4-(trifluoromethyl)phenyl)boronic acid (186 mg, 0.844 mmol), Pd(AmPhos)2Cl2 (28.5 mg, 0.040 mmol), potassium phosphate (512 mg, 2.412 mmol), 1,4-dioxane (3015 μl), and water (1005 μl). The vial was flushed with Ar (g), then sealed and heated in a Biotage Initiator microwave reactor for 15 min at 90° C. The reaction mixtures from each vial were combined, and the combined mixture was extracted with EtOAc (3×). The combined organic extracts were concentrated, and the residue was purified by chromatography on silica gel (40-g column, 20 to 60% EtOAc/Heptane) to give 3-chloro-1-(2-methoxy-4-(trifluoromethyl)phenyl)-N-(4-methoxybenzyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (Intermediate RRR; 500.9 mg, 0.808 mmol, 89% yield) as an off-white foam: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm=8.15 (t, J=1.1 Hz, 1H), 7.77 (s, 1H), 7.68-7.65 (m, 2H), 7.50 (s, 1H), 7.44-7.38 (m, 2H), 7.30 (d, J=8.8 Hz, 2H), 7.27 (s, 1H), 7.04 (d, J=3.6 Hz, 1H), 6.73 (d, J=8.8 Hz, 2H), 5.11 (s, 2H), 3.76 (s, 3H), 3.73 (s, 3H); m/z (ESI) 620.2 (M+H)+.

Workup

  1. customseparate vials
  2. customFor the first reaction
  3. customThe vial was flushed with Ar (g)
  4. customsealed
  5. customThe vial was flushed with Ar (g)
  6. customsealed
  7. temperatureheated in a Biotage Initiator microwave reactor for 15 min at 90° C
  8. customThe reaction mixtures from
  9. extractionthe combined mixture was extracted with EtOAc (3×)
  10. concentrationThe combined organic extracts were concentrated
  11. customthe residue was purified by chromatography on silica gel (40-g column, 20 to 60% EtOAc/Heptane)

Sources & evidence

ORD record
ord-554bfd130a334957861aa7ee6099c00d
Source dataset
uspto-grants-2015_04
Patent number
US09012443B2

Reaction notes

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