1,4-Dioxane → 4-(4-chloro-2-methylphenyl)-N-(1,2,4-thiadiazol-5-yl)quinoline-7-sulfonamide

HRID 1473518Notes

Reaction equation

HRID 1473518 reaction equation
Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([N:15](CC3C=CC(OC)=CC=3OC)[C:16]3[S:20][N:19]=[CH:18][N:17]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[Cl:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[C:35]([CH3:42])[CH:34]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>O>[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([S:12]([NH:15][C:16]4[S:20][N:19]=[CH:18][N:17]=4)(=[O:13])=[O:14])=[CH:9][CH:10]=3)[N:5]=[CH:4][CH:3]=2)=[C:35]([CH3:42])[CH:34]=1

Participants

6

Reactant 4

HCID 312751,4-DioxaneHCID 62657Potassium Phosphate, TribasicHCID 5017600(4-Chloro-2-methylphenyl)boronic acidHCID 866875714-chloro-N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)quinoline-7-sulfonamide

Product 1

HCID 866875734-(4-chloro-2-methylphenyl)-N-(1,2,4-thiadiazol-5-yl)quinoline-7-sulfonamideYield 49.6%

Reagents, catalysts & solvents 1

HCID 962WaterSolvent

Conditions

Temperature
90 °C

Procedure

A vial was charged with 4-chloro-N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)quinoline-7-sulfonamide (INTERMEDIATE QQQQ, 55.8 mg, 0.117 mmol), (4-chloro-2-methylphenyl)boronic acid (Indofine Chemical, Hillsborough, N.J., 21.93 mg, 0.129 mmol), Pd(AmPhos)2Cl2 (4.14 mg, 5.85 mmol), potassium phosphate (74.5 mg, 0.351 mmol), 1,4-dioxane (439 μl), and water (146 μl). The vial was flushed with Ar (g), then sealed and heated in a Biotage Initiator microwave reactor for 30 min h at 90° C. LCMS showed two peaks with mass of protected desired product. The mixture was extracted with EtOAc (3×), and the combined organic extracts were concentrated. The residue was dissolved in DCM (1 mL) and TFA (0.5 mL). After 1 h, triflic acid (0.05 mL) was added drop wise. Following an additional 1 h of stirring, the mixture was diluted with 2-PrOH, then concentrated. The residue was purified by chromatography on silica gel (25-g Interchim column, 0-60% EtOAc/Heptane, then with 100% EtOAc). The resulting material was further purified by chromatography on silica gel (12-g Redi-Sep Gold column, 0-6% MeOH/DCM) to give 4-(4-chloro-2-methylphenyl)-N-(1,2,4-thiadiazol-5-yl)quinoline-7-sulfonamide (24.08 mg, 0.058 mmol, 49.4% yield) as a light-yellow solid. 1H NMR (400 MHz, DMSO-d6) δ=9.10 (d, J=4.4 Hz, 1H), 8.48 (d, J=1.8 Hz, 1H), 8.42 (s, 1H), 7.88 (dd, J=2.0, 8.8 Hz, 1H), 7.61-7.53 (m, 3H), 7.43 (dd, J=1.9, 8.1 Hz, 1H), 7.29 (d, J=8.1 Hz, 1H), 1.97 (s, 3H). m/z (ESI) 417.2 (M+H)+.

Workup

  1. customThe vial was flushed with Ar (g)
  2. customsealed
  3. extractionThe mixture was extracted with EtOAc (3×)
  4. concentrationthe combined organic extracts were concentrated
  5. dissolutionThe residue was dissolved in DCM (1 mL)
  6. additiontriflic acid (0.05 mL) was added drop wise
  7. waitFollowing an additional 1 h
  8. additionthe mixture was diluted with 2-PrOH
  9. concentrationconcentrated
  10. customThe residue was purified by chromatography on silica gel (25-g Interchim column, 0-60% EtOAc/Heptane
  11. customThe resulting material was further purified by chromatography on silica gel (12-g Redi-Sep Gold column, 0-6% MeOH/DCM)

Sources & evidence

ORD record
ord-4244fd649faf4a799388986066ff7f77
Source dataset
uspto-grants-2015_04
Patent number
US09012443B2

Reaction notes

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