Ammonium Chloride → 7-Chloro-3-(4,6-dimethoxy-2-pyrimidinyl)phthalide

HRID 863742Notes

Reaction equation

HRID 863742 reaction equation
[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:9](=[O:10])[O:8][CH2:7]2.[Li+].CC([N-]C(C)C)C.CS([C:24]1[N:29]=[C:28]([O:30][CH3:31])[CH:27]=[C:26]([O:32][CH3:33])[N:25]=1)(=O)=O.[NH4+].[Cl-]>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:9](=[O:10])[O:8][CH:7]2[C:24]1[N:29]=[C:28]([O:30][CH3:31])[CH:27]=[C:26]([O:32][CH3:33])[N:25]=1

Participants

7

Reactant 4

HCID 25517Ammonium ChlorideHCID 2991747-ChlorophthalideHCID 8383634,6-Dimethoxy-2-(methylsulfonyl)pyrimidineHCID 2724682Lithium diisopropylamide

Product 1

HCID 190506527-Chloro-3-(4,6-dimethoxy-2-pyrimidinyl)phthalide

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-70 °C

Procedure

1.68 g (0.0 mol) of 7-chlorophthalide is added to 100 ml of dry THF and the mixture cooled to -70° C. 6.8 ml (0.01 mol) of 1.5M LDA is then added over 3 minutes and the reaction mixture stirred at -70° C. for 15 minutes. 2.18 g (0.01 mol) of 2-methylsulfonyl-4,6-dimethoxypyrimidine in 50 ml of THF is then added and the mixture stirred for 4 hrs with temperature being maintained at -75° to -70° C. The reaction mixture is neutralized with 1.5 g of NH4Cl in 5 ml of water, warmed and concentrated on a rotovaporator. The concentrate is partitioned between CH2Cl2 /H2O (50 ml each) and the aqueous phase separated and treated with further 30 ml of CH2Cl2. The combined CH2Cl2 phases are washed with 30 ml of water, separated and concentrated. The concentrate was flash chromatographed on silica gel using 80/20 hexane/ethyl acetate (500 ml), 50/50 hexane/ethyl acetate (500 ml) and 80/20 acetone/methanol (500 ml) (30 fractions×50 ml). The title compound (fractions 9-23) was obtained after recrystallization from hexane/CH2Cl2 as a white solid, m.p. 148°-149° C.

Workup

  1. stirringthe mixture stirred for 4 hrs with temperature
  2. temperaturebeing maintained at -75° to -70° C
  3. temperaturewarmed
  4. concentrationconcentrated on a rotovaporator
  5. customThe concentrate is partitioned between CH2Cl2 /H2O (50 ml each)
  6. customthe aqueous phase separated
  7. additiontreated with further 30 ml of CH2Cl2
  8. washThe combined CH2Cl2 phases are washed with 30 ml of water
  9. customseparated
  10. concentrationconcentrated
  11. customchromatographed on silica gel using 80/20 hexane/ethyl acetate (500 ml), 50/50 hexane/ethyl acetate (500 ml) and 80/20 acetone/methanol (500 ml) (30 fractions×50 ml)

Sources & evidence

ORD record
ord-b19f715fb99e485296c8b14cac225529
Source dataset
uspto-grants-1996_10
Patent number
US05561101

Reaction notes

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