Trifluoroacetic acid → 4-(4-chloro-2-methoxyphenyl)-N-(1,2,4-thiadiazol-5-yl)quinazoline-7-sulfonamide

HRID 1473687Notes

Reaction equation

HRID 1473687 reaction equation
COC1C=C(OC)C=CC=1C[NH:6][C:7]1[S:11][N:10]=[CH:9][N:8]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[C:44]3[C:39](=[CH:40][C:41]([S:45]([O:48]C4C(F)=C(F)C(F)=C(F)C=4F)(=[O:47])=O)=[CH:42][CH:43]=3)[N:38]=[CH:37][N:36]=2)=[C:31]([O:60][CH3:61])[CH:30]=1.C(O)(C(F)(F)F)=O>O1CCCC1>[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[C:44]3[C:39](=[CH:40][C:41]([S:45]([NH:6][C:7]4[S:11][N:10]=[CH:9][N:8]=4)(=[O:47])=[O:48])=[CH:42][CH:43]=3)[N:38]=[CH:37][N:36]=2)=[C:31]([O:60][CH3:61])[CH:30]=1

Participants

6

Reactant 4

HCID 6422Trifluoroacetic acidHCID 2733832Lithium HexamethyldisilazideHCID 57732216N-(2,4-dimethoxybenzyl)-1,2,4-thiadiazol-5-amineHCID 86687771Perfluorophenyl 4-(4-chloro-2-methoxyphenyl)quinazoline-7-sulfonate

Product 1

HCID 866877704-(4-chloro-2-methoxyphenyl)-N-(1,2,4-thiadiazol-5-yl)quinazoline-7-sulfonamide

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

A solution of N-(2,4-dimethoxybenzyl)-1,2,4-thiadiazol-5-amine (0.112 g, 0.445 mmol) in tetrahydrofuran (1.780 ml) was cooled in a dry ice-acetone bath for 5 min. Lithium bis(trimethylsilyl)amide (1M in THF) (0.490 ml, 0.490 mmol) was added drop wise, then the flask was removed from the cooling bath for 5 min. The flask was again cooled into a dry ice-acetone bath for 20 min, resulting in the formation of a thick slurry. A solution of perfluorophenyl 4-(4-chloro-2-methoxyphenyl)quinazoline-7-sulfonate (Intermediate AAAAAA; 0.230 g, 0.445 mmol) in THF (1.5 mL) was added drop wise, and the reaction was stirred for two hours. The reaction was warmed to room temperature and quenched with saturated ammonium chloride solution, 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 filtrate was purified by chromatography on an 12-g Redi-Sep Gold column with 0-50% EtOAc/Heptane. The material was dissolved in 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 and purified via column chromatography (RediSep Gold 12 g, gradient elution 0-10% MeOH:DCM) to afford 4-(4-chloro-2-methoxyphenyl)-N-(1,2,4-thiadiazol-5-yl)quinazoline-7-sulfonamide as a white solid. 1H NMR (400 MHz, DMSO-d6) δ=9.48 (s, 1H), 8.49 (s, 1H), 8.40 (d, J=1.6 Hz, 1H), 7.97 (dd, J=1.8, 8.7 Hz, 1H), 7.87 (d, J=8.8 Hz, 1H), 7.47 (d, J=8.1 Hz, 1H), 7.39 (d, J=1.7 Hz, 1H), 7.25 (dd, J=1.8, 8.1 Hz, 1H), 3.72 (s, 3H). m/z (ESI) 434.0 (M+H)+.

Workup

  1. customthe flask was removed from the cooling bath for 5 min
  2. temperatureThe flask was again cooled into a dry ice-acetone bath for 20 min
  3. customresulting in the formation of a thick slurry
  4. customquenched with saturated ammonium chloride solution
  5. additiondiluted with ethyl acetate
  6. washwashed with water
  7. extractionThe aqueous layer was extracted with ethyl acetate
  8. dry with materialthe combined organic layers were dried with sodium sulfate
  9. filtrationfiltered
  10. concentrationconcentrated
  11. customThe filtrate was purified by chromatography on an 12-g Redi-Sep Gold column with 0-50% EtOAc/Heptane
  12. dissolutionThe material was dissolved in DCM
  13. stirringThe reaction was stirred for 30 minutes at room temperature
  14. concentrationThe reaction was concentrated
  15. custompurified via column chromatography (RediSep Gold 12 g, gradient elution 0-10% MeOH:DCM)

Sources & evidence

ORD record
ord-b398627066554adb9568a0817505e54a
Source dataset
uspto-grants-2015_04
Patent number
US09012443B2

Reaction notes

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