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Acetic Acid → N1-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N1-[(6-methyl-3'-{[(3S)-3-methyl-1-piperazinyl]methyl}-3-biphenylyl)methyl]-1,1-cyclopropanedicarboxamide

HRID 657418
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Druckvorschau

Reaktionsgleichung

Reaktionsgleichung von HRID 657418
[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:45][CH3:46])=[C:10]([CH2:19][N:20]([CH2:29][C:30]3[CH:31]=[C:32]([C:37]4[CH:42]=[CH:41][CH:40]=[C:39]([CH:43]=O)[CH:38]=4)[C:33]([CH3:36])=[CH:34][CH:35]=3)[C:21]([C:23]3([C:26]([NH2:28])=[O:27])[CH2:25][CH2:24]3)=[O:22])[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].C([N:54]1[CH2:59][CH2:58][NH:57][C@H:56]([CH3:60])[CH2:55]1)(OC(C)(C)C)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:45][CH3:46])=[C:10]([CH2:19][N:20]([CH2:29][C:30]3[CH:31]=[C:32]([C:37]4[CH:42]=[CH:41][CH:40]=[C:39]([CH2:43][N:54]5[CH2:59][CH2:58][NH:57][C@@H:56]([CH3:60])[CH2:55]5)[CH:38]=4)[C:33]([CH3:36])=[CH:34][CH:35]=3)[C:21]([C:23]3([C:26]([NH2:28])=[O:27])[CH2:24][CH2:25]3)=[O:22])[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]
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Komponenten

7

Edukt 4

HCID 176Acetic AcidHCID 2756811(R)-1-Boc-3-methylpiperazineHCID 5049666Sodium triacetoxyborohydrideHCID 86633356N1-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N1-[(3'-formyl-6-methyl-3-biphenylyl)methyl]-1,1-cyclopropanedicarboxamide

Produkt 1

HCID 68638645
N1-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N1-[(6-methyl-3'-{[(3S)-3-methyl-1-piperazinyl]methyl}-3-biphenylyl)methyl]-1,1-cyclopropanedicarboxamide
Ausbeute 48,2 %

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 6344DichloromethaneLösungsmittel2×HCID 6422Trifluoroacetic acidLösungsmittel

Versuchsvorschrift

A mixture of N1-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N1-[(3′-formyl-6-methyl-3-biphenylyl)methyl]-1,1-cyclopropanedicarboxamide (55 mg, 0.088 mmol), (R)—N′-Boc-2-methyl-piperazine (17.69 mg, 0.088 mmol), sodium triacetoxyborohydride (37.4 mg, 0.177 mmol) and acetic acid (6.07 μL, 0.106 mmol) in DCM (2 mL) was stirred at room temperature overnight. The reaction mixture was quenched with saturated NaHCO3 and extracted with DCM twice. The combined organic layers were concentrated under vacuum to give the crude residue. It was re-dissolved in 25% TFA in DCM (2 mL) and stirred at room temperature for 2 h. Solvent was evaporated under a stream of nitrogen and then purified by reverse phase hplc with a Gilson HPLC (acidic conditions: 0.1% TFA in the solvents), eluting with 10 to 60% CH3CN in water at a flow rate of 20 mL/min. The product fractions were combined, washed with saturated NaHCO3 and extracted with ethyl acetate twice. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and then concentrated under vacuum to give N1-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N1-[(6-methyl-3′-{[(3S)-3-methyl-1-piperazinyl]methyl}-3-biphenylyl)methyl]-1,1-cyclopropanedicarboxamide as a solid (30 mg, 48.1%). LC-MS m/z 707 (M+H)+, 0.74 min (ret time); 1H NMR (400 MHz, DMSO-d6) δ 0.88 (d, J=6.27 Hz, 3H) 1.20 (t, J=7.53 Hz, 3H) 1.29-1.36 (m, 7H) 1.40-1.64 (m, 3H) 1.84-1.92 (m, 3H) 2.17 (s, 3H) 2.60-2.67 (m, 4H) 2.73-2.78 (m, 1H) 2.83 (q, J=7.36 Hz, 2H) 3.46 (s, 2H) 3.52 (td, J=11.36, 2.13 Hz, 2H) 3.80-3.87 (m, 2H) 4.04-4.11 (m, 1H) 4.21-4.44 (m, 6H) 6.74 (d, J=7.78 Hz, 1H) 7.04 (d, J=1.76 Hz, 1H) 7.07-7.11 (m, 1H) 7.14-7.21 (m, 3H) 7.26 (d, J=7.78 Hz, 1H) 7.34-7.38 (m, 1H) 7.99 (s, 1H) 8.43 (t, J=5.77 Hz, 1H) 9.02 (t, J=5.77 Hz, 1H).

Aufarbeitung

  1. customThe reaction mixture was quenched with saturated NaHCO3
  2. extractionextracted with DCM twice
  3. concentrationThe combined organic layers were concentrated under vacuum
  4. customto give the crude residue
  5. stirringstirred at room temperature for 2 h
  6. customSolvent was evaporated under a stream of nitrogen
  7. custompurified by reverse phase hplc with a Gilson HPLC (acidic conditions
  8. wash0.1% TFA in the solvents), eluting with 10 to 60% CH3CN in water at a flow rate of 20 mL/min
  9. washwashed with saturated NaHCO3
  10. extractionextracted with ethyl acetate twice
  11. washThe combined organic layers were washed with brine
  12. dry with materialdried over sodium sulfate
  13. filtrationfiltered
  14. concentrationconcentrated under vacuum

Quellen und Nachweise

ORD-Eintrag
ord-d0a8c70c4f4c4d3fab75c04f7d1d16ca
Quelldatensatz
uspto-grants-2011_12
DOI
10.6084/m9.figshare.5104873.v1
Patentnummer
US08071588B2

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