Phosphorus trichloride → 2-Hydroxymethyl-5,7-dimethyl-3-(2-methylsulfamoyl-phenyl)-4-oxo-3,4-dihydroquinazoline-6-carboxylic Acid Butyl Ester

HRID 1039369Notes

Reaction equation

HRID 1039369 reaction equation
[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:38])=[C:8]2[C:13](=[CH:14][C:15]=1[CH3:16])[N:12]=[C:11]([CH2:17][O:18]CC1C=CC=CC=1)[N:10]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[S:32](=[O:36])(=[O:35])[NH:33][CH3:34])[C:9]2=[O:37])=[O:5])[CH3:2].[CH2:39](OC(=O)C1C(C)=CC(NC(=O)COCC2C=CC=CC=2)=C(C(O)=O)C=1C)[CH3:40].NC1C=CC=CC=1S(NC)(=O)=O.P(Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>C(OCC)C.C(OCC)(=O)C.C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:38])=[C:8]2[C:13](=[CH:14][C:15]=1[CH3:16])[N:12]=[C:11]([CH2:17][OH:18])[N:10]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[S:32](=[O:35])(=[O:36])[NH:33][CH3:34])[C:9]2=[O:37])=[O:5])[CH2:2][CH2:39][CH3:40]

Participants

9

Reactant 5

HCID 24387Phosphorus trichlorideHCID 516892Sodium BicarbonateHCID 11328402-amino-N-methylbenzene-1-sulfonamideHCID 66815225HCID 66815225, compoundHCID 86597582HCID 86597582, compound

Product 1

HCID 115980582-Hydroxymethyl-5,7-dimethyl-3-(2-methylsulfamoyl-phenyl)-4-oxo-3,4-dihydroquinazoline-6-carboxylic Acid Butyl Ester

Reagents, catalysts & solvents 3

HCID 1140TolueneSolventHCID 3283Diethyl EtherSolventHCID 8857Ethyl AcetateSolvent

Procedure

Preparation of 2-Benzyloxymethyl-5,7-dimethyl-3-(2-methylsulfamoyl-phenyl)-4-oxo-3,4-dihydro-quinazoline-6-carboxylic acid ethyl ester: To a mechanically-stirred suspension of 4-(Benzyloxyacetyl)amino-2,6-dimethyl-isophthalic acid 1-ethyl ester (27 g, 0.07 mol), 2-amino-N-methyl-benzenesulfonamide (13 g, 0.07 mol) and anhydrous toluene (500 mL) in a three-necked round bottom flask is added phosphorus trichloride (51 mL, 0.56 mol) via an addition funnel. The reaction mixture is stirred at room temperature for 5 minutes and then heated to reflux. After 45 minutes LCMS analysis indicates that the reaction is complete. The suspension is cooled to room temperature and the solution phase is decanted from the solid material. The solution and solid material are worked-up separately. The toluene solution is partitioned between ethyl acetate and saturated aqueous NaHCO3 solution with vigorous stirring to give a clear biphasic solution. The organic and aqueous phases are separated and the aqueous phase is extracted (×2) with ethyl acetate. The organic phases are combined, dried over anhydrous Na2SO4, and evaporated in vacuo to give an orange oil. Similarly, the solid material is stirred, vigorously with ethyl acetate and saturated aqueous NaHCO3 solution to give a clear biphasic solution. The organic and aqueous phases are separated and the aqueous phase is extracted (×2) with ethyl acetate. The organic phases are combined, dried over anhydrous Na2SO4, and evaporated in vacuo to give an orange oil. Trituration of the orange oil with diethyl ether provides a yellow solid, which is removed by filtration, washed with diethyl ether and air-dried to provide the title compound.

Workup

  1. temperatureheated to reflux
  2. waitAfter 45 minutes LCMS analysis indicates that the reaction
  3. temperatureThe suspension is cooled to room temperature
  4. customthe solution phase is decanted from the solid material
  5. customThe toluene solution is partitioned between ethyl acetate and saturated aqueous NaHCO3 solution
  6. stirringwith vigorous stirring
  7. customto give a clear biphasic solution
  8. customThe organic and aqueous phases are separated
  9. extractionthe aqueous phase is extracted (×2) with ethyl acetate
  10. dry with materialdried over anhydrous Na2SO4
  11. customevaporated in vacuo
  12. customto give an orange oil
  13. customto give a clear biphasic solution
  14. customThe organic and aqueous phases are separated
  15. extractionthe aqueous phase is extracted (×2) with ethyl acetate
  16. dry with materialdried over anhydrous Na2SO4
  17. customevaporated in vacuo
  18. customto give an orange oil
  19. customis removed by filtration
  20. washwashed with diethyl ether
  21. customair-dried

Sources & evidence

ORD record
ord-9d885935b87c474480f8c865db5b976e
Source dataset
uspto-grants-2013_10
Patent number
US08552015B2

Reaction notes

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