Dimethylformamide → HCID 18002307, Verbindung

HRID 478926

Reaktionsgleichung

Reaktionsgleichung von HRID 478926
C[C:2]1[C:6](C(O)=O)=[C:5](C)[NH:4][C:3]=1/[CH:11]=[C:12]1\[C:13](=[O:22])[NH:14][C:15]2[C:20]\1=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C.[N:57]1([CH:63]2[CH2:68][CH2:67]N[CH2:65][CH2:64]2)[CH2:62][CH2:61][O:60][CH2:59][CH2:58]1.[Li+].[Cl-].[CH3:71][N:72]([CH:74]=[O:75])[CH3:73]>C(Cl)(Cl)Cl.C(O)(C)C>[CH3:65][CH:64]1[CH:63]([N:57]2[CH2:62][CH2:61][O:60][CH2:59][CH2:58]2)[CH:68]([CH3:67])[CH2:73][N:72]([C:74](/[C:11](/[C:3]2[NH:4][CH:5]=[CH:6][CH:2]=2)=[C:12]2\[C:13](=[O:22])[NH:14][C:15]3[C:20]\2=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[O:75])[CH2:71]1

Komponenten

8

Edukt 6

HCID 6228DimethylformamideHCID 8471TriethylamineHCID 151348Benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphateHCID 433294Lithium ChlorideHCID 7957244-MorpholinopiperidineHCID 10979489Sunitinib acid

Produkt 1

HCID 18002307HCID 18002307, VerbindungAusbeute 85 %

Reagenzien, Katalysatoren, Lösungsmittel 1

HCID 21906603Chloroform isopropyl alcoholLösungsmittel

Versuchsvorschrift

(3Z)-3-(3,5-Dimethyl-4-carboxy-1H-pyrrol-2-ylmethylidene)-5-fluoro-1,3-dihydro-2H-indol-2-one (120 mg, 0.40 mmol), prepared as described in published PCT Application WO01/60814, and BOP (221 mg, 0.50 mmol) were suspended in DMF (5 mL) with good stirring at room temperature and triethylamine (134 μL, 0.96 mmol) was added. After 10-15 min., to the homogeneous reaction mixture was added the 4-(morpholin-4-yl)piperidine (85 mg, 0.50 mmol) all at once. The reaction mixture was stirred for 48 h (might be done much earlier), then transferred to a funnel containing chloroform-isopropanol (5/1) and 5% aq. LiCl. The cloudy-orange organic phase was separated, washed with additional 5% aq LiCl (2×), 1 M aq NaOH (3×), satd aq NaCl (1×), and then dried (Na2SO4) and evaporated to yield the crude product (96.3% pure; trace hexamethylphosphoramide (HMPA) by 1HNMR). This crude product was then further purified by passage through a very short column (3 cm) of silica gel (5 to 15% gradient of MeOH in dichloromethane (DCM)) where a trace of faster moving 3E-isomer was removed. The pure fractions were evaporated and recrystallized overnight from a satd EtOAc soln which was diluted with Et2O (˜3-fold) and chilled at 0° C. The mother liquor was decanted to yield after full vacuum the desired compound as orange crystals (153 mg 85%).

Aufarbeitung

  1. stirringThe reaction mixture was stirred for 48 h (might be done much earlier)
  2. customtransferred to a funnel
  3. customThe cloudy-orange organic phase was separated
  4. washwashed with additional 5% aq LiCl (2×), 1 M aq NaOH (3×)
  5. dry with materialdried (Na2SO4)
  6. customevaporated
  7. customto yield the crude product (96.3% pure; trace hexamethylphosphoramide (HMPA) by 1HNMR)
  8. customThis crude product was then further purified by passage through a very short column (3 cm) of silica gel (5 to 15% gradient of MeOH in dichloromethane (DCM)) where a trace
  9. customwas removed
  10. customThe pure fractions were evaporated
  11. customrecrystallized overnight from a satd EtOAc soln which
  12. additionwas diluted with Et2O (˜3-fold)
  13. temperaturechilled at 0° C
  14. customThe mother liquor was decanted

Quellen und Nachweise

ORD-Eintrag
ord-8af2736c52ed441987cac7e91a4e0e96
Quelldatensatz
uspto-grants-2003_11
Patentnummer
US06642232B2

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