Diisopropylethylamine → (R)-N-(4-chloro-8-oxo-9-(2,2,2-trifluoroethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)-N'-cyano-4-(8-fluoro-2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carboxamidine

HRID 132503

Reaktionsgleichung

Reaktionsgleichung von HRID 132503
[NH2:1][C@H:2]1[C:16](=[O:17])[N:15]([CH2:18][C:19]([F:22])([F:21])[F:20])[CH2:14][C:5]2[C:6]3[CH:7]=[N:8][NH:9][C:10]=3[C:11]([Cl:13])=[CH:12][C:4]=2[CH2:3]1.C(N(CC)C(C)C)(C)C.C1C=CC(O[C:39](OC2C=CC=CC=2)=[N:40][C:41]#[N:42])=CC=1.Cl.[F:51][C:52]1[CH:53]=[CH:54][CH:55]=[C:56]2[C:61]=1[NH:60][C:59](=[O:62])[C:58]([CH:63]1[CH2:68][CH2:67][NH:66][CH2:65][CH2:64]1)=[CH:57]2>CN(C)C=O.CO>[Cl:13][C:11]1[C:10]2[NH:9][N:8]=[CH:7][C:6]=2[C:5]2[CH2:14][N:15]([CH2:18][C:19]([F:21])([F:20])[F:22])[C:16](=[O:17])[C@H:2]([NH:1][C:39]([N:66]3[CH2:67][CH2:68][CH:63]([C:58]4[C:59](=[O:62])[NH:60][C:61]5[C:56]([CH:57]=4)=[CH:55][CH:54]=[CH:53][C:52]=5[F:51])[CH2:64][CH2:65]3)=[N:40][C:41]#[N:42])[CH2:3][C:4]=2[CH:12]=1

Komponenten

7

Edukt 4

HCID 81531DiisopropylethylamineHCID 688090Diphenyl N-CyanocarbonimidateHCID 59732089(7R)-7-amino-4-chloro-9-(2,2,2-trifluoroethyl)-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-oneHCID 673189488-Fluoro-3-(piperidin-4-yl)quinolin-2(1H)-one hydrochloride

Produkt 1

HCID 178512336(R)-N-(4-chloro-8-oxo-9-(2,2,2-trifluoroethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)-N'-cyano-4-(8-fluoro-2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carboxamidineAusbeute 34 %

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 887MethanolLösungsmittelHCID 6228DimethylformamideLösungsmittel

Versuchsvorschrift

(R)-7-Amino-4-chloro-9-(2,2,2-trifluoroethyl)-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one (115 mg, 345.6 mmol) was dissolved in N,N-dimethylformamide (5.0 mL). N,N-Diisopropylethylamine (200 μL, 1.1 mmol) was added to the mixture followed by diphenyl N-cyanocarbonimidate (94 mg, 382.7 μmol). Mixture stirred at room temperature for 40 minutes. 8-Fluoro-3-(piperidin-4-yl)quinolin-2(1H)-one hydrochloride (121 mg, 427.9 μmol) was added to the vessel with stirring. The mixture was heated to 60° C. and held with stirring for 54 hours. The mixture was warmed to 100° C. and with stirring held for 28 hours. Reaction was diluted with methanol. Mixture was purified by prep HPLC (acetonitrile-water-ammonium acetate). Acetonitrile was removed from the fractions by roto-vap. Remaining aqueous was diluted with water. Solids were filtered off and washed with water. Air was pulled through the filter cake for 1 hour. Solids were collected and dried in vacuo. Title compound was obtained as tan solid in 34% yield. 1H NMR (500 MHz, DMSO-D6) δ ppm 13.61 (s, 1 H) 11.82 (s, 1 H) 8.35 (s, 1 H) 7.80 (s, 1 H) 7.52 (dd, J=16.48, 7.63 Hz, 2 H) 7.32-7.39 (m, 1 H) 7.29 (s, 1 H) 7.08-7.19 (m, 1 H) 5.57-5.76 (m, 1 H) 5.40 (d, J=18.01 Hz, 1 H) 4.90 (d, J=17.40 Hz, 1 H) 4.59-4.79 (m, 1 H) 4.27 (d, J=12.82 Hz, 2 H) 4.01-4.17 (m, 1 H) 3.32-3.41 (m, 1 H) 2.98-3.25 (m, 4 H) 1.78-2.00 (m, 2 H) 1.42-1.71 (m, 2 H). High resolution MS m/e (M+H)+=629.1788.

Aufarbeitung

  1. stirringwith stirring
  2. temperatureThe mixture was heated to 60° C.
  3. stirringwith stirring for 54 hours
  4. temperatureThe mixture was warmed to 100° C.
  5. stirringwith stirring
  6. waitheld for 28 hours
  7. customReaction
  8. customMixture was purified by prep HPLC (acetonitrile-water-ammonium acetate)
  9. customAcetonitrile was removed from the fractions by roto-vap
  10. additionRemaining aqueous was diluted with water
  11. filtrationSolids were filtered off
  12. washwashed with water
  13. waitAir was pulled through the filter cake for 1 hour
  14. customSolids were collected
  15. customdried in vacuo

Quellen und Nachweise

ORD-Eintrag
ord-63097be1f9f24af59ab5599eba7b58c9
Quelldatensatz
uspto-grants-2008_06
Patentnummer
US07384931B2

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