Sodium Carbonate → 1,1-Dimethylethyl 4-{[5'-{[({1-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]cyclopropyl}carbonyl)amino]methyl}-2'-(methyloxy)-3-biphenylyl]methyl}-1-piperidinecarboxylate

HRID 657416Notes

Reaction equation

HRID 657416 reaction equation
BrC1C=C(C[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])C=CC=1OC.CC1(C)C(C)(C)OB([C:49]2[CH:50]=[C:51]([CH2:55][CH:56]3[CH2:61][CH2:60][N:59]([C:62]([O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:63])[CH2:58][CH2:57]3)[CH:52]=[CH:53][CH:54]=2)O1.[C:70]([O-:73])([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][NH:11][C:12]([C:14]3([C:17]([NH:19][CH2:55][C:51]4[CH:50]=[CH:49][C:54]([O:73][CH3:70])=[C:53]([C:49]5[CH:54]=[CH:53][CH:52]=[C:51]([CH2:55][CH:56]6[CH2:57][CH2:58][N:59]([C:62]([O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:63])[CH2:60][CH2:61]6)[CH:50]=5)[CH:52]=4)=[O:18])[CH2:15][CH2:16]3)=[O:13])[C:22]([NH:34][CH:35]3[CH2:36][CH2:37][O:38][CH2:39][CH2:40]3)=[C:23]2[CH:31]=[N:30]1)[CH3:33]

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 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

Product 1

HCID 578199281,1-Dimethylethyl 4-{[5'-{[({1-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]cyclopropyl}carbonyl)amino]methyl}-2'-(methyloxy)-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

Process (A) 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), 1,1-dimethylethyl 4-{[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}-1-piperidinecarboxylate (25.7 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 minutes 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 dried using a EZ2 GeneVac evaporator and then combined to give 1,1-dimethylethyl 4-{[5′-{[({1-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]cyclopropyl}carbonyl)amino]methyl}-2′-(methyloxy)-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 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 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′-(4-piperidinylmethyl)-3-biphenylyl]methyl}-1,1-cyclopropanedicarboxamide as a solid (22 mg, 38.1%). LC-MS m/z 709 (M+H)+, 0.81 min (ret time); 1H NMR (400 MHz, DMSO-d6) δ 1.03-1.26 (m, 5H) 1.29-1.36 (m, 7H) 1.41-1.66 (m, 5H) 1.84-1.91 (m, 2H) 2.44-2.51 (m, 2H) 2.83 (q, J=7.53 Hz, 2H) 2.94-3.00 (m, 2H) 3.49-3.56 (m, 2H) 3.71 (s, 3H) 3.80-3.87 (m, 2H) 4.03-4.09 (m, 1H) 4.24 (d, J=5.52 Hz, 2H) 4.31 (q, J=7.28 Hz, 2H) 4.38 (d, J=6.27 Hz, 2H) 6.71-6.78 (m, 1H) 7.00 (d, J=8.28 Hz, 1H) 7.06-7.34 (m, 6H) 7.99 (s, 1H) 8.43 (t, J=5.77 Hz, 1H) 9.03 (t, J=5.77 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 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. customThe product fractions were dried
  10. customa EZ2 GeneVac evaporator

Sources & evidence

ORD record
ord-5925f5ebc44c4b0c91caf7def072913c
Source dataset
uspto-grants-2011_12
Patent number
US08071588B2

Reaction notes

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