Trifluoroacetic acid → 1-(2-fluoro-4-(trifluoromethyl)phenyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide

HRID 1473457Notes

Reaction equation

HRID 1473457 reaction equation
COC1C=C(OC)C=CC=1C[N:6]([C:31]1[S:32][CH:33]=[CH:34][N:35]=1)[S:7]([C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[C:16]([C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][C:21]=1[F:30])=[N:15][CH:14]=[CH:13]2)(=[O:9])=[O:8].C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:30][C:21]1[CH:22]=[C:23]([C:26]([F:27])([F:29])[F:28])[CH:24]=[CH:25][C:20]=1[C:16]1[C:17]2[C:12](=[CH:11][C:10]([S:7]([NH:6][C:31]3[S:32][CH:33]=[CH:34][N:35]=3)(=[O:9])=[O:8])=[CH:19][CH:18]=2)[CH:13]=[CH:14][N:15]=1

Participants

4

Reactant 2

HCID 6422Trifluoroacetic acidHCID 86687501N-(2,4-dimethoxybenzyl)-1-(2-fluoro-4-(trifluoromethyl)phenyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide

Product 1

HCID 866875021-(2-fluoro-4-(trifluoromethyl)phenyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

A microwave vial was charged with 1-chloro-N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (Intermediate OOO; 0.250 g, 0.525 mmol), (2-fluoro-4-(trifluoromethyl)phenyl)boronic acid (0.164 g, 0.788 mmol), Pd(PPh3)4 (0.061 g, 0.053 mmol), and potassium carbonate (0.363 g, 2.63 mmol). Dioxane (2.63 mL) and Water (0.875 mL) were added, the vial was flushed with argon and sealed, and heated in a microwave reactor at 90° C. for 30 minutes. The reaction was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried with sodium sulfate, filtered, and concentrated. The material was purified via silica gel column chromatography (12 g, gradient elution 0 to 50% EtOAc:Heptane) to afford N-(2,4-dimethoxybenzyl)-1-(2-fluoro-4-(trifluoromethyl)phenyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (0.271 g, 0.449 mmol, 85% yield) as a white solid. N-(2,4-dimethoxybenzyl)-1-(2-fluoro-4-(trifluoromethyl)phenyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (35 mg, 0.058 mmol) was dissolved in 1 mL of DCM and TFA (0.1 ml, 1.298 mmol) was added. The reaction was stirred for 30 minutes at room temperature. The reaction was concentrated, dissolved in methanol, and passed through an SCX ion exchange column (pre-wetted with methanol). The column was flushed several times with methanol, then the product was liberated by flushing the column several times with 2.0 M ammonia in methanol. The product-containing filtrate was concentrated to afford 1-(2-fluoro-4-(trifluoromethyl)phenyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm=12.92 (br. s., 1H), 8.77 (d, J=5.7 Hz, 1H), 8.62 (d, J=1.6 Hz, 1H), 8.24 (d, J=5.6 Hz, 1H), 7.99-7.91 (m, 2H), 7.89-7.77 (m, 3H), 7.27 (d, J=4.6 Hz, 1H), 6.87 (d, J=4.6 Hz, 1H). m/z (ESI) 454.1 (M+H)+.

Workup

  1. concentrationThe reaction was concentrated
  2. dissolutiondissolved in methanol
  3. customThe column was flushed several times with methanol
  4. customby flushing the column several times with 2.0 M ammonia in methanol
  5. concentrationThe product-containing filtrate was concentrated

Sources & evidence

ORD record
ord-96543baae3654e7fa94ef76c16462be1
Source dataset
uspto-grants-2015_04
Patent number
US09012443B2

Reaction notes

Loading…