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

HRID 662113Notes

Reaction equation

HRID 662113 reaction equation
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])[N: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.[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]>[CH2:34]([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[N: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]

Participants

7

Reactant 3

HCID 10340Sodium CarbonateHCID 578132571,1-dimethylethyl (2S)-2-methyl-4-{[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}-1-piperazinecarboxylateHCID 57819372N-[(3-bromo-4-methylphenyl)methyl]-N'-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-2,6-pyridinedicarboxamide

Product 1

HCID 866333521,1-dimethylethyl (2S)-4-[(5'-{[({6-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]-2-pyridinyl}carbonyl)amino]methyl}-2'-methyl-3-biphenylyl)methyl]-2-methyl-1-piperazinecarboxylate

Reagents, catalysts & solvents 3

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

A mixture of 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}-2,6-pyridinedicarboxamide (100 mg, 0.158 mmol), 1,1-dimethylethyl (2S)-2-methyl-4-{[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}-1-piperazinecarboxylate (65.6 mg, 0.158 mmol), Na2CO3 (50.1 mg, 0.473 mmol) and PdCl2(dppf) (11.53 mg, 0.016 mmol) 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 minutes and it was then heated in a Biotage microwave at normal absorption for 10 minutes 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 a crude residue. It was purified with a Gilson HPLC (with 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 dried using a EZ2 GeneVac evaporator and then combined to give 1,1-dimethylethyl (2S)-4-[(5′-{[({6-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]-2-pyridinyl}carbonyl)amino]methyl}-2′-methyl-3-biphenylyl)methyl]-2-methyl-1-piperazinecarboxylate. 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 the residue was purified with a Gilson HPLC (with 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 and converted to the free base with 1 N NaOH, and the basified solution was 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 N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-[(6-methyl-3′-{[(3S)-3-methyl-1-piperazinyl]methyl}-3-biphenylyl)methyl]-2,6-pyridinedicarboxamide as a solid (10 mg, 8.53%). LC-MS m/z 744 (M+H)+, 1.33 min (ret time); 1H NMR (400 MHz, DMSO-d6) δ 0.91 (d, J=6.27 Hz, 3H) 1.21 (t, J=7.53 Hz, 3H) 1.33 (t, J=7.15 Hz, 3H) 1.47-1.64 (m, 3H) 1.87-1.94 (m, 2H) 2.18 (s, 3H) 2.64-2.68 (m, 6H) 2.94-3.00 (m, 2H) 3.46 (s, 2H) 3.49-3.62 (m, 2H) 3.82-3.87 (m, 2H) 4.08-4.14 (m, 1H) 4.29-4.35 (m, 2H) 4.56-4.59 (m, 4H) 6.90 (d, J=8.53 Hz, 1H) 7.09-7.29 (m, 6H) 7.35 (t, J=7.53 Hz, 1H) 8.01 (s, 1H) 8.13-8.33 (m, 3H) 9.50 (t, J=6.27 Hz, 1H) 9.70 (t, J=6.27 Hz, 1H).

Workup

  1. customThe mixture was degassed
  2. customby bubbling argon through it for 5 minutes
  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 a crude residue
  7. customIt was purified with a Gilson HPLC (with 0.1% TFA in the solvents),
  8. washeluting with 10 to 70% CH3CN in water at a flow rate of 20 mL/min
  9. customThe product fractions were dried
  10. customa EZ2 GeneVac evaporator

Sources & evidence

ORD record
ord-504c05191c5f44cca3cc1b94ed5b8586
Source dataset
uspto-grants-2011_12
Patent number
US08084449B2

Reaction notes

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