Dichloromethane → 5-chloro-8-fluoro,2-methyl-3-[(4-methylphenyl)sulfonyl]pyrrolo[2',3':4,5]pyrimido[6,1-b]quinazolin-7(3H)-one HCl salt

HRID 1014560Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 1014560
[Cl:1]C1N=C(Cl)C2C(C)=CN(S(C3C=CC(C)=CC=3)(=O)=O)C=2N=1.NC1C=CC=C(F)C=1C(O)=O.C(N(C(C)C)CC)(C)C.[Cl:43][C:44]1[N:45]=[C:46]([NH:64][C:65]2[CH:73]=[CH:72][CH:71]=[C:70]([F:74])[C:66]=2[C:67]([OH:69])=O)[C:47]2[CH:52]=[C:51]([CH3:53])[N:50]([S:54]([C:57]3[CH:62]=[CH:61][C:60]([CH3:63])=[CH:59][CH:58]=3)(=[O:56])=[O:55])[C:48]=2[N:49]=1.C(Cl)(=O)C(Cl)=O.ClCCl>C(O)(C)C.C(OCC)(=O)C.C1COCC1.CN(C=O)C>[ClH:1].[Cl:43][C:44]1[N:45]2[C:46](=[N:64][C:65]3[C:66]([C:67]2=[O:69])=[C:70]([F:74])[CH:71]=[CH:72][CH:73]=3)[C:47]2[CH:52]=[C:51]([CH3:53])[N:50]([S:54]([C:57]3[CH:62]=[CH:61][C:60]([CH3:63])=[CH:59][CH:58]=3)(=[O:56])=[O:55])[C:48]=2[N:49]=1

Komponenten

11

Edukt 6

HCID 6344DichloromethaneHCID 65578Oxalyl chloride2×HCID 81531DiisopropylethylamineHCID 5211422-Amino-6-fluorobenzoic acidHCID 582908522,4-Dichloro-5-methyl-7-tosyl-7h-pyrrolo[2,3-d]pyrimidineHCID 594418482-({2-chloro-6-methyl-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-6-fluorobenzoic acid

Produkt 1

HCID 673158975-chloro-8-fluoro,2-methyl-3-[(4-methylphenyl)sulfonyl]pyrrolo[2',3':4,5]pyrimido[6,1-b]quinazolin-7(3H)-one HCl saltAusbeute 37,8 %

Reagenzien, Katalysatoren, Lösungsmittel 4

HCID 3776IsopropanolLösungsmittelHCID 6228DimethylformamideLösungsmittelHCID 8028TetrahydrofuranLösungsmittelHCID 8857Ethyl AcetateLösungsmittel

Reaktionsbedingungen

Temperatur
85 °C

Versuchsvorschrift

To a suspension of 2,4-dichloro-5-methyl-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidine (535 mg, 1.50 mmol) and 2-amino-6-fluorobenzoic acid (233 mg, 1.50 mmol) in isopropanol (5 mL) was added diisopropylethylamine (971 mg, 7.51 mmol) and the mixture was heated at 85° C. for ˜48 h. At this time the reaction was diluted with ethyl acetate (100 ml) and washed with a solution of 1N HCl, a saturated solution of sodium bicarbonate and a saturated solution of NaCl, then dried over sodium sulfate. Solvents were removed under reduced pressure to afford a solid containing about 60% 2-({2-chloro-6-methyl-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-6-fluorobenzoic acid (726 mg, 1.52 mmol). This material was dissolved in THF (10 mL) and DMF (few drops) and a solution of 2M oxalyl chloride in dichloromethane (0.90 mL, 1.80 mmol) was added dropwise. LCMS analysis indicated a small amount of starting material remained so an additional 0.1 eq of oxalyl chloride was added. The reaction mixture was cooled in an ice bath and filtered via a buchner funnel and the solid washed with THF. The solid was dried under reduced pressure to afford 5-chloro-8-fluoro-2-methyl-3-[(4-methylphenyl)sulfonyl]pyrrolo[2′,3′:4,5]pyrimido[6,1-b]quinazolin-7(3H)-one HCl salt (280 mg, 0.0.57 mmol). ESIMS (M+H)+=457

Aufarbeitung

  1. washwashed with a solution of 1N HCl
  2. dry with materiala saturated solution of sodium bicarbonate and a saturated solution of NaCl, then dried over sodium sulfate
  3. customSolvents were removed under reduced pressure
  4. customto afford a solid
  5. additionwas added
  6. temperatureThe reaction mixture was cooled in an ice bath
  7. filtrationfiltered via a buchner funnel
  8. washthe solid washed with THF
  9. customThe solid was dried under reduced pressure

Quellen und Nachweise

ORD-Eintrag
ord-09d0afe8b19b4396b500be68f00db9e5
Quelldatensatz
uspto-grants-2011_07
Patentnummer
US07981903B2

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