Triphenylphosphine → 4-(4-Chloro-2-fluoroanilino)6-methoxy-7-(2-(3-oxomorpholino)ethoxy)quinazoline hydrochloride

HRID 2227960Notes

Reaction equation

HRID 2227960 reaction equation
N(C(OCC)=O)=NC(OCC)=O.[Cl:13][C:14]1[CH:33]=[CH:32][C:17]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([OH:31])=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][N:20]=2)=[C:16]([F:34])[CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:55][CH2:56][N:57]1[CH2:62][CH2:61][O:60][CH2:59][C:58]1=[O:63]>C(Cl)Cl.C1COCC1>[ClH:13].[Cl:13][C:14]1[CH:33]=[CH:32][C:17]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([O:31][CH2:55][CH2:56][N:57]4[CH2:62][CH2:61][O:60][CH2:59][C:58]4=[O:63])=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][N:20]=2)=[C:16]([F:34])[CH:15]=1

Participants

7

Reactant 4

HCID 11776Triphenylphosphine2×HCID 220568ethyl N-ethoxycarbonyliminocarbamate2×HCID 152874004-(2-Hydroxyethyl)morpholin-3-one2×HCID 1355137204-(4-Chloro-2-fluorophenylamino)-7-hydroxy-6-methoxyquinazoline

Product 1

HCID 187534774-(4-Chloro-2-fluoroanilino)6-methoxy-7-(2-(3-oxomorpholino)ethoxy)quinazoline hydrochlorideYield 79.6%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolvent2×HCID 8028TetrahydrofuranSolvent

Procedure

Diethyl azodicarboxylate (400 mg, 2.3 mmol) was added dropwise to a mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (250 mg, 0.78 mmol), (prepared as described for the starting material in Example 2), triphenylphosphine (615 mg, 2.3 mmol) and 4-(2-hydroxyethyl)-3-morpholinone (170 mg, 1.17 mmol), (EP 580402A2), in methylene chloride (5 ml) under nitrogen. The mixture was stirred for 4 hours at ambient temperature, methylene chloride (5 ml) was added and stirring was continued for a further 18 hours at ambient temperature. THF (5 ml). 4-(2-hydroxyethyl)-3-morpholinone (113 mg, 0.78 mmol). triphenylphosphine (204 mg, 0.78 mmol) were added and diethyl azodicarboxylate (136 mg, 0.78 mmol) was then added dropwise. The mixture was stirred for 5 minutes at ambient temperature, and was purified by pouring directly onto a silica column, eluting with methylene chloride/ethyl acetate/methanol (5/4/1). The purified solid was dissolved in methylene chloride and 2M methanolic hydrogen chloride (0.5 ml) was added. The mixture was concentrated by evaporation and then diluted with ether. The resulting precipitate was collected by filtration, washed with ether and dried under vacuum to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(3-oxomorpholino)ethoxy)quinazoline hydrochloride (150 mg, 39%).

Workup

  1. custom(prepared
  2. stirringstirring
  3. waitwas continued for a further 18 hours at ambient temperature
  4. stirringThe mixture was stirred for 5 minutes at ambient temperature
  5. customwas purified
  6. additionby pouring directly onto a silica column
  7. washeluting with methylene chloride/ethyl acetate/methanol (5/4/1)
  8. dissolutionThe purified solid was dissolved in methylene chloride
  9. addition2M methanolic hydrogen chloride (0.5 ml) was added
  10. concentrationThe mixture was concentrated by evaporation
  11. additiondiluted with ether
  12. filtrationThe resulting precipitate was collected by filtration
  13. washwashed with ether
  14. customdried under vacuum

Sources & evidence

ORD record
ord-5c34867f46cb4b1aafc7b0db1dff3792
Source dataset
uspto-grants-2002_07
Patent number
US06414148B1

Reaction notes

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