Water → 3-(2-methyl-5-nitro-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione

HRID 1777263Notes

Reaction equation

HRID 1777263 reaction equation
[CH3:1][C:2]1O[C:4](=[O:15])[C:5]2[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.Cl.[NH2:17][CH:18]1[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]1=[O:25].CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.O>C(#N)C.C(OCC)(=O)C>[CH3:1][C:2]1[N:17]([CH:18]2[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]2=[O:25])[C:4](=[O:15])[C:5]2[C:6](=[CH:8][CH:9]=[CH:10][C:11]=2[N+:12]([O-:14])=[O:13])[N:7]=1

Participants

7

Reactant 4

HCID 962Water2×HCID 111923Propylphosphonic anhydrideHCID 1345483-Aminopiperidine-2,6-dione hydrochlorideHCID 666429832-methyl-5-nitro-4H-benzo[d][1,3]oxazin-4-one

Product 1

HCID 666429823-(2-methyl-5-nitro-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dioneYield 89%

Reagents, catalysts & solvents 2

HCID 6342AcetonitrileSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
60 °C

Procedure

A slurry of compound 2 was treated with 3-aminopiperidine-2,6-dione hydrochloride 3 (1.1 equiv.) in acetonitrile and a solution of 1-propanephosphonic acid cyclic anhydride (“T3P”) (2 equiv.) in ethyl acetate at 75-80° C. After 3 to 5 days, the total of compounds 1a and 2 was less than 1% area normalized (typically 0.05% area normalized). The reaction mixture was cooled to 55 to 65° C. Water was charged over 30 min, maintaining the temperature at 60° C. throughout the addition. During the first portion of water addition, an exotherm was observed. The mixture was further cooled to 20 to 30° C. over 1 hr. The resulting solid was filtered and washed with a mixture of acetonitrile and water (1:1). The solid was transferred back to the reactor and was agitated with a mixture of acetonitrile and water (1:1) between 20 to 30° C. for 1 hr. The mixture was filtered and the filter cake was washed with a mixture of acetonitrile and water (1:1). The filter cake was dried in a vacuum oven to afford compound 4 as a white solid: HPLC purity: 98.9 to 99.2%; yield: 89 to 93%; MS (m/e): 317 (M+1).

Workup

  1. customat 75-80° C
  2. temperaturemaintaining the temperature at 60° C.
  3. additionthroughout the addition
  4. temperatureThe mixture was further cooled to 20 to 30° C. over 1 hr
  5. filtrationThe resulting solid was filtered
  6. washwashed with a mixture of acetonitrile and water (1:1)
  7. filtrationThe mixture was filtered
  8. washthe filter cake was washed with a mixture of acetonitrile and water (1:1)
  9. customThe filter cake was dried in a vacuum oven

Sources & evidence

ORD record
ord-35a843b09fe349aa994424ee8b33a914
Source dataset
uspto-grants-2016_02
Patent number
US09266858B2

Reaction notes

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