Triphenylphosphine → 4-(4-Chloro-2-fluoroanilino)-4-methoxyquinazoline hydrochloride

HRID 1838588Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 1838588
N(C(OCC)=O)=N[C:3](OCC)=[O:4].[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)=[C:26](OC)[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.OCCCN1CCC[C@H]1C(N)=O>C(Cl)Cl>[ClH:13].[Cl:13][C:14]1[CH:33]=[CH:32][C:17]([NH:18][C:19]2([O:4][CH3:3])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]=[CH:21][NH:20]2)=[C:16]([F:34])[CH:15]=1

Komponenten

6

Edukt 4

HCID 11776Triphenylphosphine2×HCID 220568ethyl N-ethoxycarbonyliminocarbamate2×HCID 45116058(S)-1-(3-hydroxypropyl)pyrrolidine-2-carboxamide2×HCID 1355137204-(4-Chloro-2-fluorophenylamino)-7-hydroxy-6-methoxyquinazoline

Produkt 1

HCID 1784939664-(4-Chloro-2-fluoroanilino)-4-methoxyquinazoline hydrochlorideAusbeute 102,3 %

Reagenzien, Katalysatoren, Lösungsmittel 1

HCID 6344DichloromethaneLösungsmittel

Versuchsvorschrift

Diethyl azodicarboxylate (209 mg, 1.2 mmol) was added dropwise to a mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (128 mg, 0.4 mmol), (prepared as described for the starting material in Example 2), triphenylphosphine (314 mg, 1.2 mmol) and (S)-1-(3-hydroxypropyl)-pyrrolidine-2-carboxamide (97 mg, 0.56 mmol), (prepared as described for the starting material in Example 50), in methylene chloride (4 ml). The mixture was stirred for 2 hours at ambient temperature, and further triphenylphosphine (105 mg, 0.4 mmol) and (S)-1-(3-hydroxypropyl)-pyrrolidine-2-carboxamide (49 mg, 0.28 mmol) were added followed by the dropwise addition of diethyl azodicarboxylate (70 mg, 0.4 mmol). The mixture was stirred for 1 hour at ambient temperature, and was purified by pouring directly onto a silica column eluting with methylene chloride/acetonitrile/methanol (6/3/1 followed by 60/25/15). The purified oil was triturated with ether, collected by filtration, washed with ether and dried under vacuum. The solid was dissolved in methylene chloride and 2M ethereal hydrogen chloride (0.5 ml) was added. The mixture was diluted with ether and the resulting precipitate was collected by filtration, washed with ether and dried under vacuum to give (S)-743-(2-carbamoylpyrrolidin-1-yl)propoxy)-4-(4-chloro-2-fluoroanilino)-4-methoxyquinazoline hydrochloride (70 mg, 32%).

Aufarbeitung

  1. custom(prepared
  2. custom(prepared
  3. stirringThe mixture was stirred for 1 hour at ambient temperature
  4. customwas purified
  5. additionby pouring directly onto a silica column
  6. washeluting with methylene chloride/acetonitrile/methanol (6/3/1 followed by 60/25/15)
  7. customThe purified oil was triturated with ether
  8. filtrationcollected by filtration
  9. washwashed with ether
  10. customdried under vacuum
  11. dissolutionThe solid was dissolved in methylene chloride
  12. addition2M ethereal hydrogen chloride (0.5 ml) was added
  13. additionThe mixture was diluted with ether
  14. filtrationthe resulting precipitate was collected by filtration
  15. washwashed with ether
  16. customdried under vacuum

Quellen und Nachweise

ORD-Eintrag
ord-dcf457f51986487f9e9062cfa56e71b0
Quelldatensatz
uspto-grants-2004_01
Patentnummer
US06673803B2

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