Potassium Carbonate → (S)-3-(4-chloro-2-fluorophenyl)-8-methyl-N-(4-methyl-1-(methylamino)-1-oxopentan-2-yl)-6,7,8,9-tetrahydro-5H-imidazo[1,5-a][1,4]diazepine-1-carboxamide

HRID 1971124Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 1971124
Br[C:2]1[N:6]2[CH2:7][CH2:8][CH2:9][N:10]([CH3:12])[CH2:11][C:5]2=[C:4]([C:13]([NH:15][C@@H:16]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:17]([NH:19][CH3:20])=[O:18])=[O:14])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:31][C:32]1[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:33]=1B(O)O>O1CCOCC1.O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd].[Pd]>[Cl:38][C:36]1[CH:35]=[CH:34][C:33]([C:2]2[N:6]3[CH2:7][CH2:8][CH2:9][N:10]([CH3:12])[CH2:11][C:5]3=[C:4]([C:13]([NH:15][C@@H:16]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:17]([NH:19][CH3:20])=[O:18])=[O:14])[N:3]=2)=[C:32]([F:31])[CH:37]=1

Komponenten

8

Edukt 3

HCID 11430Potassium CarbonateHCID 4193595(4-Chloro-2-fluorophenyl)boronic acidHCID 57635259(S)-3-bromo-8-methyl-N-(4-methyl-1-(methylamino)-1-oxopentan-2-yl)-6,7,8,9-tetrahydro-5H-imidazo[1,5-a][1,4]diazepine-1-carboxamide

Produkt 1

HCID 57635533(S)-3-(4-chloro-2-fluorophenyl)-8-methyl-N-(4-methyl-1-(methylamino)-1-oxopentan-2-yl)-6,7,8,9-tetrahydro-5H-imidazo[1,5-a][1,4]diazepine-1-carboxamideAusbeute 40 %

Reagenzien, Katalysatoren, Lösungsmittel 4

HCID 23938PalladiumKatalysatorHCID 11979704Tetrakis(triphenylphosphine)palladiumKatalysatorHCID 962WaterLösungsmittelHCID 312751,4-DioxaneLösungsmittel

Reaktionsbedingungen

Temperatur
110 °C

Versuchsvorschrift

A mixture of intermediate 55B (47 mg, 0.12 mmol), potassium carbonate (40 mg, 0.29 mmol), 2-fluoro-4-chlorophenylboronic acid (0.25 mmol) and palladium tetrakis(triphenylphosphine) (20 mg) in dioxane (1.0 mL) and water (0.5 mL) was heated at 110° C. in a sealed vial for 4 h. After cooling down to room temperature, the mixture was passed through a thiol-based palladium scavenger resin (PolymerLabs). The residue was concentrated to dryness, to which MeOH (0.5 mL) was added. The solution was filtered to remove insoluble material and purified by prep LC-MS with 5% MeCN/water to 95 MeCN/water (0.1% formic acid) in 15 min. Pure fractions were evaporated with a Savant speedvac. The oil residue was taken up in DCM (1.0 mL) and diluted with hexane (1.0 mL). Evaporation under air flow with mild heating give white solid product Compound 529 at 40% yield. 1H-NMR (400 MHz, CDCl3) δ: 0.96 (t, J=4.8 Hz, 6H), 1.59-1.72 (m, 2H), 1.81-1.90 (m, 3H), 2.47 (s, 3H), 2.56 (br, 2H), 2.78 (d, J=4.8 Hz, 3H), 2.98 (br, 2H), 3.96 (br, 2H), 4.52-4.58 (m, 1H), 6.48 (br, 1H), 7.21-7.24 (dd, J=2.0, 9.6 Hz, 1H), 7.29-7.31 (dd, J=1.7, 10.0 Hz, 1H), 7.39 (d, J=8.4 Hz, 1H), 7.50 (t, J=8.0 Hz, 1H). LCMS (+ESI) m/z 450.2, 452.2 [M+H]+.

Aufarbeitung

  1. temperatureAfter cooling down to room temperature
  2. concentrationThe residue was concentrated to dryness, to which MeOH (0.5 mL)
  3. additionwas added
  4. filtrationThe solution was filtered
  5. customto remove insoluble material
  6. custompurified by prep LC-MS with 5% MeCN/water to 95 MeCN/water (0.1% formic acid) in 15 min
  7. customPure fractions were evaporated with a Savant speedvac
  8. additiondiluted with hexane (1.0 mL)
  9. customEvaporation under air flow
  10. temperaturewith mild heating

Quellen und Nachweise

ORD-Eintrag
ord-88b9f23198aa4f66a0ef16b72869f793
Quelldatensatz
uspto-grants-2013_04
Patentnummer
US08431565B2

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