Water → HCID 46199030, Verbindung

HRID 588039Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 588039
CS(O)(=O)=O.[NH2:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[N:12]([CH:18]1[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]1=[O:25])[CH2:11]2.C1N=CN([C:31](N2C=NC=C2)=[O:32])C=1.[F:38][C:39]1[CH:44]=[C:43]([F:45])[CH:42]=[CH:41][C:40]=1[C:46]1[N:47]=[C:48]([NH2:51])[S:49][CH:50]=1.O>CN(C=O)C.C(OCC)(=O)C>[F:38][C:39]1[CH:44]=[C:43]([F:45])[CH:42]=[CH:41][C:40]=1[C:46]1[N:47]=[C:48]([NH:51][C:31]([NH:6][CH2:7][C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C:13](=[O:17])[N:12]([CH:18]2[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]2=[O:25])[CH2:11]3)=[O:32])[S:49][CH:50]=1

Komponenten

7

Edukt 4

HCID 962WaterHCID 682631,1'-CarbonyldiimidazoleHCID 6113704-(2,4-Difluorophenyl)-1,3-thiazol-2-amineHCID 866307653-(5-(Aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione methanesulfonate

Produkt 1

HCID 46199030HCID 46199030, VerbindungAusbeute 13 %

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 6228DimethylformamideLösungsmittelHCID 8857Ethyl AcetateLösungsmittel

Versuchsvorschrift

A mixture of 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione methanesulfonic acid salt (0.40 g, 1.1 mmol) and CDI (0.18 g, 1.1 mmol) in DMF (5 mL) was stirred at room temperature for 18 h. To the mixture was added 4-(2,4-difluoro-phenyl)-thiazol-2-ylamine (0.23 g, 1.1 mmol) at room temperature, and the mixture was stirred at 100° C. for 2 days. To the mixture was added water (25 mL) and ethyl acetate (20 mL). The mixture was stirred at room temperature for 2 h. The suspension was filtered and the solid was washed with water (20 mL), ethyl acetate (20 mL) and water (20 mL) to give a solid. The solid was purified with Prep HPLC to give 1-[4-(2,4-difluoro-phenyl)-thiazol-2-yl]-3-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-urea as a white solid (70 mg, 13% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 6.43 min (97.7%); mp: 264-266 0C; 1H NMR (DMSO-d6) □ 1.93-2.05 (m, 1H, CHH), 2.30-2.45 (m, 1H, CHH), 2.55-2.68 (m, 1H, CHH), 2.82-3.00 (m, 1H, CHH), 4.32 (d, J=17.4 Hz, 1H, CHH), 4.41-4.54 (m, 3H, CH2, CHH), 5.11 (dd, J=5.1, 13.2 Hz, 1H, NCH), 7.09-7.24 (m, 2H, Ar, NH), 7.28-7.41 (m, 2H, Ar), 7.46 (d, J=7.7 Hz, 1H, Ar), 7.53 (s, 1H, Ar), 7.71 (d, J=7.9 Hz, 1H, Ar), 7.93-8.10 (m, 1H, Ar), 10.85 (s, 1H, NH), 10.98 (s, 1H, NH); 13C NMR (DMSO-d6) □ 22.48, 31.18, 42.94, 47.12, 51.57, 104.54 (t, JC-F=26.4 Hz), 110.67 (d, JC-F=14.3 Hz), 111.81 (dd, JC-F=3.3, 20.9 Hz), 118.91 (dd, JC-F=2.8, 11.6 Hz), 121.95, 123.03, 126.95, 130.29 (dd, JC-F=4.4, 9.9 Hz), 130.49, 141.44, 142.45, 143.95, 154.02, 159.48 (dd, JC-F=252.2, 12.1 Hz), 159.36, 161.24 (dd, JC-F=246.9, 13.2 Hz), 167.88, 170.98, 172.85: LCMS MH=512: Anal. Calcd for C24H19N5O4F2S: C, 56.36; H, 3.74; N, 13.69. Found: C, 56.16; H, 3.80; N, 14.07.

Aufarbeitung

  1. stirringthe mixture was stirred at 100° C. for 2 days
  2. stirringThe mixture was stirred at room temperature for 2 h
  3. filtrationThe suspension was filtered
  4. washthe solid was washed with water (20 mL), ethyl acetate (20 mL) and water (20 mL)
  5. customto give a solid
  6. customThe solid was purified with Prep HPLC

Quellen und Nachweise

ORD-Eintrag
ord-c3d694a46a6b49b891c0a710b72f0e4f
Quelldatensatz
uspto-grants-2016_01
Patentnummer
US09227954B2

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