p-Toluenesulfonic acid → HCID 136038024, compound

HRID 1498753Notes

Reaction equation

HRID 1498753 reaction equation
[NH2:1][C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[C:6]([O:11][CH3:12])[C:5]([CH2:13][N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[C:4]([O:20][CH3:21])[CH:3]=1.[CH3:22][C:23]1[CH:24]=[C:25]([CH:28]=[C:29]([CH3:32])[C:30]=1[OH:31])[CH:26]=O.S([O-])(O)=O.[Na+].C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C.O>[OH:31][C:30]1[C:29]([CH3:32])=[CH:28][C:25]([C:26]2[NH:10][C:8](=[O:9])[C:7]3[C:2](=[CH:3][C:4]([O:20][CH3:21])=[C:5]([CH2:13][N:14]4[CH2:19][CH2:18][O:17][CH2:16][CH2:15]4)[C:6]=3[O:11][CH3:12])[N:1]=2)=[CH:24][C:23]=1[CH3:22]

Participants

7

Reactant 4

HCID 6101p-Toluenesulfonic acidHCID 752223,5-Dimethyl-4-hydroxybenzaldehydeHCID 23665763Sodium BisulfiteHCID 86621926HCID 86621926, compound

Product 1

HCID 136038024HCID 136038024, compoundYield 6.6%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 31374DimethylacetamideSolvent

Conditions

Temperature
115 °C

Procedure

A solution of 6-tert-butoxycarbonylamino-2,4-dimethoxy-3-morpholin-4-ylmethyl-benzoic acid (1.8 g, 4.54 mmol), EDCl.HCl (1.31 g, 6.82 mmol), HOBt (1.23 g, 9.09 mmol), and triethylamine (3.3 mL, 23.7 mmol) in THF (50 mL) was stirred at room temperature for 1 h. Ammonium hydroxide (50% aqueous, 10 mL) was then added to the reaction mixture. The resulting mixture was stirred at room temperature for 6 h. The reaction was quenched by adding water (50 mL), extracted with DCM (3×100 mL), and concentrated using a rotary evaporator. The residue was further purified by column (SiO2, DCM/MeOH/EtOAc=2:1:4) to provide 0.9 g of (2-carbamoyl-3,5-dimethoxy-4-morpholin-4-ylmethyl-phenyl)-carbamic acid tert-butyl ester (50%). A solution of (2-carbamoyl-3,5-dimethoxy-4-morpholin-4-ylmethyl-phenyl)-carbamic acid tert-butyl ester (0.9 g, 2.74 mmol) in HOAc (20 mL) and 12 N HCl aqueous (20 mL) was stirred at 50° C. for 1 h and then concentrated to dryness using a rotary evaporator. The residue was mixed with saturated sodium bicarbonate aqueous (40 mL), extracted with DCM (3×100 mL), and concentrated. The residue was further purified by column (SiO2, DCM/MeOH/EtOAc=3:2:3) to provide 0.6 g of 6-amino-2,4-dimethoxy-3-morpholin-4-ylmethyl-benzamide (89%). A mixture of 6-amino-2,4-dimethoxy-3-morpholin-4-ylmethyl-benzamide (0.6 g, 2.03 mmol), 3,5-dimethyl-4-hydroxy benzaldehyde (0.61 g, 4.06 mmol), sodium hydrogensulfite (1.24 g, 7.0 mmol) and p-toluenesulfonic acid (1.14 g, 6 mmol) in N,N-dimethyl acetamide (20 mL) was stirred at 115° C. for 6 h. The reaction mixture was cooled to room temperature, diluted with water (50 mL), extracted with EtOAc, and concentrated. Purification by column chromatography afforded a solid residue, which was made into slurry in a mixed solvent of DCM-hexanes (3 mL-20 mL). The slurry was filtered and washed with hexanes to provide 2-(4-hydroxy-3,5-dimethylphenyl)-5,7-dimethoxy-6-(morpholinomethyl)quinazolin-4(3H)-one (56 mg, 6.6%) as a light yellow solid. Selected data: MS (ES) m/z: 426.0; MP 237.0-239.1° C.

Workup

  1. temperatureThe reaction mixture was cooled to room temperature
  2. extractionextracted with EtOAc
  3. concentrationconcentrated
  4. customPurification by column chromatography
  5. customafforded a solid residue, which
  6. filtrationThe slurry was filtered
  7. washwashed with hexanes

Sources & evidence

ORD record
ord-172a32a15eeb4c84a54720cb8ea0f419
Source dataset
uspto-grants-2015_12
Patent number
US09199990B2

Reaction notes

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