Sodium Carbonate → n1-{[1,6-Diethyl-4-(tetrahydro-2h-pyran-4-ylamino)-1h-pyrazolo[3,4-b]pyridin-5-yl]methyl}-n1-({6-(methyloxy)-3'-[(1-methyl-4-piperidinyl)methyl]-3-biphenylyl}methyl)-1,1-cyclopropanedicarboxamide

HRID 657408Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 657408
Br[C:2]1[CH:3]=[C:4]([CH2:10][N:11]([CH2:20][C:21]2[C:22]([NH:34][CH:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=[C:23]3[CH:31]=[N:30][N:29]([CH2:32][CH3:33])[C:24]3=[N:25][C:26]=2[CH2:27][CH3:28])[C:12]([C:14]2([C:17]([NH2:19])=[O:18])[CH2:16][CH2:15]2)=[O:13])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH3:41][N:42]1[CH2:47][CH2:46][CH:45]([CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[C:51](B3OC(C)(C)C(C)(C)O3)[CH:50]=2)[CH2:44][CH2:43]1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:32]([N:29]1[C:24]2=[N:25][C:26]([CH2:27][CH3:28])=[C:21]([CH2:20][N:11]([CH2:10][C:4]3[CH:3]=[C:2]([C:53]4[CH:52]=[CH:51][CH:50]=[C:49]([CH2:48][CH:45]5[CH2:46][CH2:47][N:42]([CH3:41])[CH2:43][CH2:44]5)[CH:54]=4)[C:7]([O:8][CH3:9])=[CH:6][CH:5]=3)[C:12]([C:14]3([C:17]([NH2:19])=[O:18])[CH2:16][CH2:15]3)=[O:13])[C:22]([NH:34][CH:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=[C:23]2[CH:31]=[N:30]1)[CH3:33]

Komponenten

7

Edukt 3

HCID 10340Sodium CarbonateHCID 578134541-Methyl-4-{[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}piperidineHCID 68636994N1-{[3-bromo-4-(methyloxy)phenyl]methyl}-N1-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-1,1-cyclopropanedicarboxamide

Produkt 1

HCID 69014751n1-{[1,6-Diethyl-4-(tetrahydro-2h-pyran-4-ylamino)-1h-pyrazolo[3,4-b]pyridin-5-yl]methyl}-n1-({6-(methyloxy)-3'-[(1-methyl-4-piperidinyl)methyl]-3-biphenylyl}methyl)-1,1-cyclopropanedicarboxamideAusbeute 29,1 %

Reagenzien, Katalysatoren, Lösungsmittel 3

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)KatalysatorHCID 962WaterLösungsmittelHCID 312751,4-DioxaneLösungsmittel

Reaktionsbedingungen

Temperatur
100 °C

Versuchsvorschrift

A mixture of N1-{[3-bromo-4-(methyloxy)phenyl]methyl}-N1-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-1,1-cyclopropanedicarboxamide (50 mg, 0.081 mmol), 1-methyl-4-{[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}piperidine (32.7 mg, 0.081 mmol), Na2CO3 (25.9 mg, 0.244 mmol) and PdCl2(dppf) (5.96 mg, 8.15 μmol) was diluted in a mixture of 1,4-dioxane (3 mL) and water (1 mL) in a 2-5 mL Biotage microwave reaction tube. The mixture was degassed by bubbling argon through it for 5 min and was then heated in a Biotage microwave at normal absorption for 10 min at 100° C. The crude mixture was filtered through a PL-Thiol MP SPE+ and was then washed with ethyl acetate and water. The organic layer was concentrated under vacuum to obtain the crude residue. It was purified by reverse phase hplc with a Gilson HPLC (acidic conditions: 0.1% TFA in the solvents), eluting with 10 to 70% CH3CN in water at a flow rate of 20 mL/min. The product fractions were combined and 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-(methyloxy)-3′-[(1-methyl-4-piperidinyl)methyl]-3-biphenylyl}methyl)-1,1-cyclopropanedicarboxamide as a solid (17 mg, 28.9%). LC-MS m/z 723 (M+H)+, 0.82 min (ret time); 1H NMR (400 MHz, DMSO-d6) δ 1.18-1.24 (m, 5H) 1.29-1.36 (m, 7H) 1.41-1.67 (m, 5H) 1.84-1.92 (m, 3H) 2.18 (br. s., 2H) 2.50-2.57 (m, 4H) 2.73-2.94 (m, 4H) 3.49-3.56 (m, 2H) 3.71 (s, 3H) 3.78-3.88 (m, 2H) 3.97-4.10 (m, 1H) 4.24 (d, J=5.77 Hz, 2H) 4.31 (q, J=7.28 Hz, 2H) 4.36-4.40 (m, 2H) 6.73-6.77 (m, 1H) 7.00 (d, J=8.53 Hz, 1H) 7.05-7.34 (m, 6H) 7.99 (s, 1H) 8.42 (t, J=5.77 Hz, 1H) 9.03 (t, J=5.77 Hz, 1H).

Aufarbeitung

  1. customThe mixture was degassed
  2. customby bubbling argon through it for 5 min
  3. filtrationThe crude mixture was filtered through a PL-Thiol MP SPE+
  4. washwas then washed with ethyl acetate and water
  5. concentrationThe organic layer was concentrated under vacuum
  6. customto obtain the crude residue
  7. customIt was purified by reverse phase hplc with a Gilson HPLC (acidic conditions
  8. wash0.1% TFA in the solvents), eluting with 10 to 70% 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-16d497beabfd40059f9ffce799794aa8
Quelldatensatz
uspto-grants-2011_12
Patentnummer
US08071588B2

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