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Potassium Carbonate → 1,1-dimethylethyl (2S)-4-[(5'-{[({3-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]phenyl}carbonyl)amino]methyl}-2'-methyl-3-biphenylyl)methyl]-2-methyl-1-piperazinecarboxylate

HRID 564585
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Druckvorschau

Reaktionsgleichung

Reaktionsgleichung von HRID 564585
Br[C:2]1[CH:3]=[C:4]([CH2:9][NH:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([NH:21][CH2:22][C:23]3[C:24]([NH:36][CH:37]4[CH2:42][CH2:41][O:40][CH2:39][CH2:38]4)=[C:25]4[CH:33]=[N:32][N:31]([CH2:34][CH3:35])[C:26]4=[N:27][C:28]=3[CH2:29][CH3:30])=[O:20])[CH:14]=2)=[O:12])[CH:5]=[CH:6][C:7]=1[CH3:8].[CH3:43][C@H:44]1[CH2:49][N:48]([CH2:50][C:51]2[CH:56]=[CH:55][CH:54]=[C:53](B3OC(C)(C)C(C)(C)O3)[CH:52]=2)[CH2:47][CH2:46][N:45]1[C:66]([O:68][C:69]([CH3:72])([CH3:71])[CH3:70])=[O:67].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:34]([N:31]1[C:26]2=[N:27][C:28]([CH2:29][CH3:30])=[C:23]([CH2:22][NH:21][C:19]([C:15]3[CH:14]=[C:13]([C:11]([NH:10][CH2:9][C:4]4[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([C:55]5[CH:54]=[CH:53][CH:52]=[C:51]([CH2:50][N:48]6[CH2:47][CH2:46][N:45]([C:66]([O:68][C:69]([CH3:72])([CH3:71])[CH3:70])=[O:67])[C@@H:44]([CH3:43])[CH2:49]6)[CH:56]=5)[CH:3]=4)=[O:12])[CH:18]=[CH:17][CH:16]=3)=[O:20])[C:24]([NH:36][CH:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)=[C:25]2[CH:33]=[N:32]1)[CH3:35]
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Komponenten

8

Edukt 3

HCID 11430Potassium CarbonateHCID 578132571,1-dimethylethyl (2S)-2-methyl-4-{[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}-1-piperazinecarboxylateHCID 57813288N-[(3-Bromo-4-methylphenyl)methyl]-N'-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-1,3-benzenedicarboxamide

Produkt 1

HCID 67006781
1,1-dimethylethyl (2S)-4-[(5'-{[({3-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]phenyl}carbonyl)amino]methyl}-2'-methyl-3-biphenylyl)methyl]-2-methyl-1-piperazinecarboxylate

Reagenzien, Katalysatoren, Lösungsmittel 4

HCID 178418397HCID 178418397, VerbindungKatalysatorHCID 962WaterLösungsmittelHCID 8857Ethyl AcetateLösungsmittelHCID 312751,4-DioxaneLösungsmittel

Versuchsvorschrift

N-[(3-Bromo-4-methylphenyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-1,3-benzenedicarboxamide (0.032 g, 0.05 mmol), 1,1-dimethylethyl (2S)-2-methyl-4-{[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}-1-piperazinecarboxylate (0.0316 g, 0.076 mmol), potassium carbonate (0.021 g, 0.15 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.0029 g, 0.0025 mmol) were combined in dioxane (1.5 mL) and water (0.5 mL). The mixture was microwaved at 150° C. for 30 min. Then the reaction mixture was diluted with EtOAc and washed with H2O 3×. The organic phase was dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified via CombiFlash on a 12 g column eluted with 0-10% MeOH/CH2Cl2 to give 1,1-dimethylethyl (2S)-4-[(5′-{[({3-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]phenyl}carbonyl)amino]methyl}-2′-methyl-3-biphenylyl)methyl]-2-methyl-1-piperazinecarboxylate. This was taken up in 10% TFA/CH2Cl2 (2 mL) and stirred at room temperature for 3 h. The solvents were pumped off, and the crude product was purified using a Gilson HPLC with a TFA system. The purified compound was taken up in EtOAc, washed 3× with 2.5 N NaOH, 1× with brine, dried over anhydrous Na2SO4, filtered, and concentrated to give the title compound as a white solid. LC-MS m/z 743.2 (M+H)+, 1.40 min (ret time); mp 115-118° C. Analytical HPLC shows 100% purity, (ret time 10.211 min).

Aufarbeitung

  1. customThe mixture was microwaved at 150° C. for 30 min
  2. washwashed with H2O 3×
  3. dry with materialThe organic phase was dried over anhydrous Na2SO4
  4. filtrationfiltered
  5. concentrationconcentrated
  6. customThe residue was purified via CombiFlash on a 12 g column
  7. washeluted with 0-10% MeOH/CH2Cl2

Quellen und Nachweise

ORD-Eintrag
ord-f4891d8779934491ba180cb404d1dde6
Quelldatensatz
uspto-grants-2011_11
DOI
10.6084/m9.figshare.5104873.v1
Patentnummer
US08067408B2

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