Dimethylformamide → Nalpha-(2,6-dichlorobenzoyl)-4-{1-methyl-6-(N-formyl-N-methyl-aminomethyl)-quinazoline-2,4[1H,3H]-dion-3-yl}-L-phenylalanine isopropyl ester

HRID 557446Notes

Reaction equation

HRID 557446 reaction equation
[CH3:1]N(C)C=O.[CH:6]([O:9][C:10](=[O:47])[C@H:11]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[C:39](=[O:40])[C:38]3[C:33](=[CH:34][CH:35]=[C:36]([CH2:41][N:42]([CH:44]=[O:45])[CH3:43])[CH:37]=3)[NH:32][C:31]2=[O:46])=[CH:26][CH:25]=1)[NH:12][C:13](=[O:22])[C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:21])([CH3:8])[CH3:7].C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC(S(OC)(=O)=O)=CC=1>O.C(O)(=O)C>[CH:6]([O:9][C:10](=[O:47])[C@H:11]([CH2:23][C:24]1[CH:25]=[CH:26][C:27]([N:30]2[C:39](=[O:40])[C:38]3[C:33](=[CH:34][CH:35]=[C:36]([CH2:41][N:42]([CH:44]=[O:45])[CH3:43])[CH:37]=3)[N:32]([CH3:1])[C:31]2=[O:46])=[CH:28][CH:29]=1)[NH:12][C:13](=[O:22])[C:14]1[C:15]([Cl:21])=[CH:16][CH:17]=[CH:18][C:19]=1[Cl:20])([CH3:8])[CH3:7]

Participants

7

Reactant 4

HCID 6228DimethylformamideHCID 6645Methyl p-toluenesulfonateHCID 11430Potassium CarbonateHCID 58018316Nalpha-(2,6-dichlorobenzoyl)-4-{6-(N-formyl-N-methyl-aminomethyl)quinazoline-2,4[1H,3H]-dion-3-yl}-L-phenylalanine isopropyl ester

Product 1

HCID 58018317Nalpha-(2,6-dichlorobenzoyl)-4-{1-methyl-6-(N-formyl-N-methyl-aminomethyl)-quinazoline-2,4[1H,3H]-dion-3-yl}-L-phenylalanine isopropyl esterYield 94%

Reagents, catalysts & solvents 2

HCID 176Acetic AcidSolventHCID 962WaterSolvent2×

Conditions

Temperature
23 °C

Procedure

There was added, to 21.26 L of N,N-dimethylformamide (DMF), 5.445 kg of Nα-(2,6-dichlorobenzoyl)-4-{6-(N-formyl-N-methylamino-methyl)-quinazoline-2,4[1H,3H]-dion-3-yl}-L-phenylalanine isopropyl ester, the resulting mixture was stirred at 23° C. and in a nitrogen gas stream to dissolve the isopropyl ester compound. Then 2.46 kg of potassium carbonate and 2.491 kg of methyl p-toluene-sulfonate were added to the resulting solution and the mixture was stirred with heating at 55 to 65° C. After the confirmation of the progress of the N-methylation reaction by HPLC, 2.14 kg of acetic acid was added to the mixture and subsequently the mixture was stirred with heating at 50° C. for one hour. To the reaction solution, there was dropwise added 10.9 L of water, followed by the addition of 6 g of seed crystals and stirring of the mixture at 50° C. for 2 hours. To the resulting slurry, there was further added 10.9 L of water, the mixture was cooled to 25° C. and stirred overnight. The precipitates thus obtained were recovered by the filtration using a centrifuge and the resulting cake was washed with 21.8 kg of water. The resulting wet crystals were dried under reduced pressure at 60° C. to thus give 5.235 kg of the title compound as a white crystalline solid (yield: 94%).

Workup

  1. stirringthe mixture was stirred
  2. temperaturewith heating at 55 to 65° C
  3. additionwas added to the mixture
  4. stirringsubsequently the mixture was stirred
  5. temperaturewith heating at 50° C. for one hour
  6. additionfollowed by the addition of 6 g of seed crystals
  7. stirringstirring of the mixture at 50° C. for 2 hours
  8. temperaturethe mixture was cooled to 25° C.
  9. stirringstirred overnight
  10. customThe precipitates thus
  11. customobtained
  12. filtrationwere recovered by the filtration
  13. washthe resulting cake was washed with 21.8 kg of water

Sources & evidence

ORD record
ord-8f321448d8ea4d46bdb8dcb824679927
Source dataset
uspto-grants-2011_11
Patent number
US08058432B2

Reaction notes

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