Lithium Hexamethyldisilazide → HCID 136409065, compound

HRID 1473408Notes

Reaction equation

HRID 1473408 reaction equation
[CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][NH:6][C:7]1[S:8][CH:9]=[CH:10][N:11]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[O:28]=[C:29]1[C:38]2[C:33](=[CH:34][C:35]([S:39](OC3C(F)=C(F)C(F)=C(F)C=3F)(=[O:41])=[O:40])=[CH:36][CH:37]=2)[N:32]=[CH:31][NH:30]1>O1CCCC1>[CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][N:6]([C:7]1[S:8][CH:9]=[CH:10][N:11]=1)[S:39]([C:35]1[CH:34]=[C:33]2[C:38]([C:29](=[O:28])[NH:30][CH:31]=[N:32]2)=[CH:37][CH:36]=1)(=[O:41])=[O:40]

Participants

5

Reactant 3

HCID 2733832Lithium Hexamethyldisilazide2×HCID 49931979N-(2,4-dimethoxybenzyl)thiazol-2-amineHCID 136409066HCID 136409066, compound

Product 1

HCID 136409065HCID 136409065, compound

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

A solution of N-(2,4-dimethoxybenzyl)thiazol-2-amine (0.791 g, 3.16 mmol) in tetrahydrofuran (11.57 ml) was cooled in a dry ice-acetone bath for 5 min. Lithium bis(trimethylsilyl)amide (1M in THF) (3.31 ml, 3.31 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-oxo-3,4-dihydroquinazoline-7-sulfonate (1.18, 3.01 mmol) in THF (12 mL) was added drop wise, and the reaction was stirred for 30 minutes. An additional equivalent of lithium bis(trimethylsilyl)amide (1M in THF) (3.31 ml, 3.31 mmol) was added and the reaction was stirred for 30 minutes. 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 three times with ethyl acetate, and the combined organic layers were dried with sodium sulfate, filtered, and concentrated. The material was dissolved in ethyl acetate and loaded onto a silica cartridge, leaving a tan solid on top. The solid was scraped out of the cartridge and set aside. The remaining material was purified by chromatography on a 40-g silica gel column with 0 to 100% EtOAc/Heptane followed by a 10% MeOH/DCM flush. The product containing fractions were concentrated and combined with the previously isolated material to afford N-(2,4-dimethoxybenzyl)-4-oxo-N-(thiazol-2-yl)-3,4-dihydroquinazoline-7-sulfonamide as a tan solid. (ESI) 481.1 (M+Na)+.

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. stirringthe reaction was stirred for 30 minutes
  5. customquenched with saturated ammonium chloride solution
  6. additiondiluted with ethyl acetate
  7. washwashed with water
  8. extractionThe aqueous layer was extracted three times with ethyl acetate
  9. dry with materialthe combined organic layers were dried with sodium sulfate
  10. filtrationfiltered
  11. concentrationconcentrated
  12. dissolutionThe material was dissolved in ethyl acetate
  13. customleaving a tan solid on top
  14. customThe remaining material was purified by chromatography on a 40-g silica gel column with 0 to 100% EtOAc/Heptane
  15. customflush
  16. additionThe product containing fractions
  17. concentrationwere concentrated

Sources & evidence

ORD record
ord-470b1410b6434f66b2078e06b0e17db3
Source dataset
uspto-grants-2015_04
Patent number
US09012443B2

Reaction notes

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