Triethylamine → N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N'-[(6-fluoro-3'-{[(3S)-3-methyl-1-piperazinyl]methyl}-3-biphenylyl)methyl]butanediamide

HRID 657401Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 657401
[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:28][CH3:29])=[C:10]([CH2:19][NH:20][C:21](=[O:27])[CH2:22][CH2:23][C:24]([OH:26])=O)[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[NH2:30][CH2:31][C:32]1[CH:33]=[CH:34][C:35]([F:59])=[C:36]([C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([CH2:44][N:45]3[CH2:50][CH2:49][N:48](C(OC(C)(C)C)=O)[C@@H:47]([CH3:58])[CH2:46]3)[CH:39]=2)[CH:37]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:28][CH3:29])=[C:10]([CH2:19][NH:20][C:21](=[O:27])[CH2:22][CH2:23][C:24]([NH:30][CH2:31][C:32]3[CH:37]=[C:36]([C:38]4[CH:43]=[CH:42][CH:41]=[C:40]([CH2:44][N:45]5[CH2:50][CH2:49][NH:48][C@@H:47]([CH3:58])[CH2:46]5)[CH:39]=4)[C:35]([F:59])=[CH:34][CH:33]=3)=[O:26])[C:11]([NH:12][CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]

Komponenten

7

Edukt 4

HCID 8471TriethylamineHCID 2733084Methanaminium, N-((1H-benzotriazol-1-yloxy)(dimethylamino)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 251325161,1-dimethylethyl (2S)-4-{[5'-(aminomethyl)-2'-fluoro-3-biphenylyl]methyl}-2-methyl-1-piperazinecarboxylateHCID 578198724-({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)-4-oxobutanoic acid

Produkt 1

HCID 44242214N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N'-[(6-fluoro-3'-{[(3S)-3-methyl-1-piperazinyl]methyl}-3-biphenylyl)methyl]butanediamideAusbeute 44,4 %

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 6344DichloromethaneLösungsmittel2×HCID 6422Trifluoroacetic acidLösungsmittel

Versuchsvorschrift

A mixture of 4-({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)-4-oxobutanoic acid (80 mg, 0.19 mmol), 1,1-dimethylethyl (2S)-4-{[5′-(aminomethyl)-2′-fluoro-3-biphenylyl]methyl}-2-methyl-1-piperazinecarboxylate (82 mg, 0.19 mmol), HBTU (87 mg, 0.23 mmol) and Et3N (0.13 mL, 0.96 mmol) in DCM (3 mL) was stirred at room temperature overnight. The reaction was quenched with saturated NaHCO3 and extracted with DCM twice. The combined organic layers were then washed with water followed by a brine wash. The organic layer was then concentrated under vacuum to give a crude residue: LC-MS m/z 799 (M+H)+. The crude residue was dissolved in 25% TFA in DCM (2 mL) and stirred at RT for 2 h. It was purified with a Gilson HPLC (with 0.1% TFA condition) eluting with 10 to 70% CH3CN in water at a flowrate of 20 mL/min. The fractions were combined and then converted to the free base with saturated NaHCO3. The organic layer was dried over sodium sulfate, filtered and then concentrated to give N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-[(6-fluoro-3′-{[(3S)-3-methyl-1-piperazinyl]methyl}-3-biphenylyl)methyl]butanediamide as a solid (59 mg, 44%). LC-MS m/z 699 (M+H)+.

Aufarbeitung

  1. customThe reaction was quenched with saturated NaHCO3
  2. extractionextracted with DCM twice
  3. washThe combined organic layers were then washed with water
  4. washwash
  5. concentrationThe organic layer was then concentrated under vacuum
  6. customto give a crude residue
  7. stirringstirred at RT for 2 h
  8. customIt was purified with a Gilson HPLC (with 0.1% TFA condition)
  9. washeluting with 10 to 70% CH3CN in water at a flowrate of 20 mL/min
  10. dry with materialThe organic layer was dried over sodium sulfate
  11. filtrationfiltered
  12. concentrationconcentrated

Quellen und Nachweise

ORD-Eintrag
ord-8a270431001d45a693c0b582f42eb46c
Quelldatensatz
uspto-grants-2011_12
Patentnummer
US08071588B2

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