Dichloromethane → 4-(4-Chloro-2-fluoroanilino)-6-methoxy-7-(1-methylpyrrolidin-3-yloxy)quinazoline hydrochloride hydrate

HRID 547177Notes

Reaction equation

HRID 547177 reaction equation
C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:20][N:21]1[CH2:25][CH2:24][CH:23]([OH:26])[CH2:22]1.[Cl:27][N:28]([C:36]1[C:45]2[C:40](=[CH:41][C:42]([OH:48])=[C:43]([O:46][CH3:47])[CH:44]=2)[N:39]=[CH:38][N:37]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[F:35].N(C(OCC)=O)=NC(OCC)=O.C(Cl)[Cl:62]>>[OH2:26].[ClH:27].[Cl:62][C:32]1[CH:33]=[CH:34][C:29]([NH:28][C:36]2[C:45]3[C:40](=[CH:41][C:42]([O:48][CH:23]4[CH2:24][CH2:25][N:21]([CH3:20])[CH2:22]4)=[C:43]([O:46][CH3:47])[CH:44]=3)[N:39]=[CH:38][N:37]=2)=[C:30]([F:35])[CH:31]=1

Participants

6

Reactant 5

HCID 6344DichloromethaneHCID 11776Triphenylphosphine2×HCID 930741-Methyl-3-pyrrolidinolHCID 220568ethyl N-ethoxycarbonyliminocarbamate2×HCID 1359906824-(Chloro-2-fluoroanilino)7-hydroxy-6-methoxyquinazoline

Product 1

HCID 187534114-(4-Chloro-2-fluoroanilino)-6-methoxy-7-(1-methylpyrrolidin-3-yloxy)quinazoline hydrochloride hydrateYield 40%

Procedure

Triphenylphosphine (410 mg, 1.5 mmol) and 1-methyl-3-pyrrolidinol (0.128 ml, 1.5 mmol) were added to a solution of 4-(chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (250 mg, 0.78 mmol), (prepared as described for the starting material in Example 2), in methylene chloride (4 ml). Diethyl azodicarboxylate (0.246 ml, 1.5 mmol) was added dropwise and the reaction mixture was stirred for 1 hour at ambient temperature. Additional triphenylphosphine (61 mg, 0.23 mmol) followed by diethyl azodicarboxylate (37 μl, 0.23 mmol) was added and the mixture was stirred for 15 minutes at ambient temperature. The solvent was removed by evaporation and the residue was purified by column chromatography eluting with methylene chloride/methanol (80/20) followed by methylene chloride/methanol/triethylamine (80/20/0.5). The purified product was dissolved in methylene chloride/methanol and the insolubles were removed by filtration. A solution of hydrogen chloride in 2-propanol (0.5 ml of a 5M solution) was added to the filtrate and the volatiles were removed by evaporation. The residue was triturated with 2-propanol and ether, collected by filtration and dried to give 4-(4-chloro-2-fluoranilino)-6-methoxy-7-(1-methylpyrrolidin-3-yloxy)quinazoline hydrochloride hydrate (149 mg, 40%).

Workup

  1. custom(prepared
  2. additionwas added
  3. stirringthe mixture was stirred for 15 minutes at ambient temperature
  4. customThe solvent was removed by evaporation
  5. customthe residue was purified by column chromatography
  6. washeluting with methylene chloride/methanol (80/20)
  7. dissolutionThe purified product was dissolved in methylene chloride/methanol
  8. customthe insolubles were removed by filtration
  9. additionA solution of hydrogen chloride in 2-propanol (0.5 ml of a 5M solution) was added to the filtrate
  10. customthe volatiles were removed by evaporation
  11. customThe residue was triturated with 2-propanol and ether
  12. filtrationcollected by filtration
  13. customdried

Sources & evidence

ORD record
ord-4b99a52eb79c44008efdc4af622906fa
Source dataset
uspto-grants-2011_05
Patent number
USRE042353E1

Reaction notes

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