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

HRID 547178Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 547178
[Cl:1][N:2]([C:10]1[C:19]2[C:14](=[CH:15][C:16]([OH:22])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][N:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[F:9].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:42]1[CH2:47][CH2:46][N:45]([CH2:48][C:49]#[C:50][CH2:51]O)[CH2:44][CH2:43]1.N(C(OCC)=O)=NC(OCC)=O.C(Cl)[Cl:66]>>[OH2:20].[ClH:1].[Cl:66][C:6]1[CH:7]=[CH:8][C:3]([NH:2][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH2:51][C:50]#[C:49][CH2:48][N:45]4[CH2:46][CH2:47][O:42][CH2:43][CH2:44]4)=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)=[C:4]([F:9])[CH:5]=1

Komponenten

6

Edukt 5

HCID 6344DichloromethaneHCID 11776Triphenylphosphine2×HCID 220568ethyl N-ethoxycarbonyliminocarbamate2×HCID 31128494-Morpholinobut-2-YN-1-OL2×HCID 1359906824-(Chloro-2-fluoroanilino)7-hydroxy-6-methoxyquinazoline

Produkt 1

HCID 187534514-(4-Chloro-2-fluoroanilino)-6-methoxy-7-(4-morpholinobut-2-yn-1-yloxy)quinazoline hydrochloride hydrateAusbeute 18 %

Versuchsvorschrift

4-(Chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (250 mg, 0.78 mmol), (prepared as described for the starting material in Example 2), and triphenylphosphine (512 mg, 1.9 mmol) were added to a stirred solution of 4-morpholino-2-butyn-1-ol (182 mg, 1.1 mmol), (J. Am. Chem. Soc. 1957, 79, 6184), in methylene chloride (4 ml) under argon. Diethyl azodicarboxylate (0.307 ml, 1.9 mmol) was added dropwise and the reaction mixture was stirred for 30 minutes at ambient temperature. Additional 4-morpholino-2-butyn-1-ol (60 mg, 0.39 mmol), triphenylphosphine (102 mg, 0.39 mmol) and followed by diethyl azodicarboxylate (61 μl, 0.39 mmol) were added and the mixture was stirred for a further 15 minutes at ambient temperature. The solvent was removed by evaporation and the residue was purified by column chromatography eluting with methylene chloride/acetonitrile/methanol (60/37/3 followed by 60/35/5 and 55/37/8). The resulting purified oil was dissolved in a mixture of methylene chloride and methanol and ethereal hydrogen chloride (1 ml of a 2.9M solution) was added. The volatiles were removed by evaporation, the solid residue suspended in ether and collected by filtration. The product was recrystallised from 2-propanol/methanol/ether, collected by filtration, washed with 2-propanol and ether and dried to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(4-morpholinobut-2-yn-1-yloxy)quinazoline hydrochloride hydrate (75 mg, 18%).

Aufarbeitung

  1. additionwere added
  2. stirringthe mixture was stirred for a further 15 minutes at ambient temperature
  3. customThe solvent was removed by evaporation
  4. customthe residue was purified by column chromatography
  5. washeluting with methylene chloride/acetonitrile/methanol (60/37/3 followed by 60/35/5 and 55/37/8)
  6. customThe resulting purified oil
  7. dissolutionwas dissolved in a mixture of methylene chloride and methanol and ethereal hydrogen chloride (1 ml of a 2.9M solution)
  8. additionwas added
  9. customThe volatiles were removed by evaporation
  10. filtrationcollected by filtration
  11. customThe product was recrystallised from 2-propanol/methanol/ether
  12. filtrationcollected by filtration
  13. washwashed with 2-propanol and ether
  14. customdried

Quellen und Nachweise

ORD-Eintrag
ord-e8f66be59d7d499480969cfb3c1c00a0
Quelldatensatz
uspto-grants-2011_05
Patentnummer
USRE042353E1

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