Dimethylformamide → HCID 21717181, compound

HRID 1386305Notes

Reaction equation

HRID 1386305 reaction equation
[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[CH2:7]2)([O-:3])=[O:2].[H-].[Na+].[Cl:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([O:29][CH2:30][CH2:31][CH2:32][N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[C:24]([O:27][CH3:28])[CH:25]=2)[N:20]=[CH:19][N:18]=1.CN(C=O)C>C1COCC1>[ClH:16].[CH3:28][O:27][C:24]1[CH:25]=[C:26]2[C:21](=[CH:22][C:23]=1[O:29][CH2:30][CH2:31][CH2:32][N:33]1[CH2:34][CH2:35][O:36][CH2:37][CH2:38]1)[N:20]=[CH:19][N:18]=[C:17]2[CH:7]1[C:6]2[C:10](=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[NH:9][C:8]1=[O:13]

Participants

6

Reactant 4

HCID 6228Dimethylformamide2×HCID 24758Sodium hydrideHCID 2303665-Nitro-2-oxindoleHCID 118239414-Chloro-6-methoxy-7-(3-morpholin-4-ylpropoxy)quinazoline

Product 1

HCID 21717181HCID 21717181, compoundYield 29%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent3×

Procedure

A solution of 5-nitrooxindole (1.26 g, 7.1 mmol), (prepared as described for the starting material in Example 21), in THF (10 ml) was added dropwise to sodium hydride (284 mg, 7.1 mmol, prewashed with THF) in THF (15 ml). The mixture was stirred for 30 minutes at ambient temperature and a solution of 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (600 mg, 1.8 mmol, (prepared as described for the starting material in Example 5), in THF (10 ml) and DMF (3 ml) was added dropwise. The mixture was stirred for 30 minutes at ambient temperature, then heated at 75° C. for 1.5 hours. DMF (4 ml) was added and the mixture stirred for 12 hours at ambient temperature. The solvent was removed by evaporation, the residue was partitioned between ethyl acetate and water and the aqueous layer was adjusted to pH8 with 2M hydrochloric acid. The precipitated product was collected by filtration, washed with water and dried under vacuum. The solid was dissolved in a mixture of DMF and dilute hydrochloric acid (pH2) and was purified on a Diaion (trade mark of Mitsubishi) HP20SS resin column, eluting with a gradient of methanol and dilute hydrochloric acid (pH2). The purified solid was dissolved in methanol and 7M ethanolic hydrogen chloride (1.5 ml) was added. The volatiles were removed by evaporation and the solid residue was triturated with a mixture of methanol and ether. The solid was collected by filtration and dried under vacuum to give 6-methoxy-7-(3-morpholinopropoxy)-4-(5-nitrooxindol-3-yl)-quinazoline hydrochloride (275 mg, 29%).

Workup

  1. stirringThe mixture was stirred for 30 minutes at ambient temperature
  2. temperatureheated at 75° C. for 1.5 hours
  3. stirringthe mixture stirred for 12 hours at ambient temperature
  4. customThe solvent was removed by evaporation
  5. customthe residue was partitioned between ethyl acetate and water
  6. filtrationThe precipitated product was collected by filtration
  7. washwashed with water
  8. customdried under vacuum
  9. dissolutionThe solid was dissolved in a mixture of DMF and dilute hydrochloric acid (pH2)
  10. customwas purified on a Diaion (trade mark of Mitsubishi) HP20SS resin column
  11. washeluting with a gradient of methanol and dilute hydrochloric acid (pH2)
  12. dissolutionThe purified solid was dissolved in methanol
  13. addition7M ethanolic hydrogen chloride (1.5 ml) was added
  14. customThe volatiles were removed by evaporation
  15. customthe solid residue was triturated with a mixture of methanol and ether
  16. filtrationThe solid was collected by filtration
  17. customdried under vacuum

Sources & evidence

ORD record
ord-20ae9a910e4e44e3bc0bef7de165c9f1
Source dataset
uspto-grants-2001_07
Patent number
US06265411B1

Reaction notes

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