Sodium Carbonate → 1,1-dimethylethyl 4-[(2'-chloro-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}-3-biphenylyl)methyl]-1-piperidinecarboxylate

HRID 662108Notes

Reaction equation

HRID 662108 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[Cl:8].CC1(C)C(C)(C)OB([C:51]2[CH:52]=[C:53]([CH2:57][CH:58]3[CH2:63][CH2:62][N:61]([C:64]([O:66][C:67]([CH3:70])([CH3:69])[CH3:68])=[O:65])[CH2:60][CH2:59]3)[CH:54]=[CH:55][CH:56]=2)O1.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]>[Cl:8][C:7]1[CH:6]=[CH:5][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:3][C:2]=1[C:55]1[CH:56]=[CH:51][CH:52]=[C:53]([CH2:57][CH:58]2[CH2:59][CH2:60][N:61]([C:64]([O:66][C:67]([CH3:70])([CH3:69])[CH3:68])=[O:65])[CH2:62][CH2:63]2)[CH:54]=1

Participants

7

Reactant 3

HCID 10340Sodium CarbonateHCID 578134461,1-Dimethylethyl 4-{[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}-1-piperidinecarboxylateHCID 57819384N-[(3-bromo-4-chlorophenyl)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 689121201,1-dimethylethyl 4-[(2'-chloro-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}-3-biphenylyl)methyl]-1-piperidinecarboxylate

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-chlorophenyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-2,6-pyridinedicarboxamide (50 mg, 0.076 mmol), 1,1-dimethylethyl 4-{[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}-1-piperidinecarboxylate (24.07 mg, 0.076 mmol), Na2CO3 (24.27 mg, 0.229 mmol) and PdCl2(dppf) (5.59 mg, 7.63 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 minutes and was then heated in the 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 4-[(2′-chloro-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}-3-biphenylyl)methyl]-1-piperidinecarboxylate. 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 saturated 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-{[6-chloro-3′-(4-piperidinylmethyl)-3-biphenylyl]methyl}-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-2,6-pyridinedicarboxamide as a solid (13 mg, 22.7%). LC-MS m/z 749 M+, 0.80 min (ret time).

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-87b8a970b004446c9127a3ed12e54ea3
Source dataset
uspto-grants-2011_12
Patent number
US08084449B2

Reaction notes

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