Sodium Carbonate → 1,1-dimethylethyl (2S)-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'-fluoro-3-biphenylyl)methyl]-2-methyl-1-piperazinecarboxylate

HRID 657438Notes

Reaction equation

HRID 657438 reaction equation
C(N1C2=NC(CC)=C(C[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:44]5[CH2:49][CH2:48][NH:47][C@@H:46]([CH3:50])[CH2:45]5)[CH:38]=4)[C:33]([F: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(NC3CCOCC3)=C2C=N1)C.BrC1C=C(CN([CH2:71][C:72]2[C:73]([NH:85][CH:86]3[CH2:91][CH2:90][O:89][CH2:88][CH2:87]3)=[C:74]3[CH:82]=[N:81][N:80]([CH2:83][CH3:84])[C:75]3=[N:76][C:77]=2[CH2:78][CH3:79])C(C2(C(N)=O)CC2)=O)C=CC=1F.C[C@H]1CN(CC2C=CC=C(B3OC(C)(C)C(C)(C)O3)C=2)CCN1[C:115]([O:117][C:118]([CH3:121])([CH3:120])[CH3:119])=[O:116].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]>[CH2:83]([N:80]1[C:75]2=[N:76][C:77]([CH2:78][CH3:79])=[C:72]([CH2:71][NH:28][C:26]([C:23]3([C:21]([NH:20][CH2:29][C:30]4[CH:35]=[CH:34][C:33]([F:36])=[C:32]([C:37]5[CH:42]=[CH:41][CH:40]=[C:39]([CH2:43][N:44]6[CH2:49][CH2:48][N:47]([C:115]([O:117][C:118]([CH3:121])([CH3:120])[CH3:119])=[O:116])[C@@H:46]([CH3:50])[CH2:45]6)[CH:38]=5)[CH:31]=4)=[O:22])[CH2:24][CH2:25]3)=[O:27])[C:73]([NH:85][CH:86]3[CH2:87][CH2:88][O:89][CH2:90][CH2:91]3)=[C:74]2[CH:82]=[N:81]1)[CH3:84]

Participants

8

Reactant 4

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 69012088N1-{[1,6-Diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N1-[(6-fluoro-3'-{[(3S)-3-methyl-1-piperazinyl]methyl}-3-biphenylyl)methyl]-1,1-cyclopropanedicarboxamideHCID 69012226N1-[(3-bromo-4-fluorophenyl)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 866333581,1-dimethylethyl (2S)-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'-fluoro-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

In an alternate preparation of the compound prepared in Example 138, a mixture of N1-[(3-bromo-4-fluorophenyl)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 (2S)-2-methyl-4-{[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}-1-piperazinecarboxylate (33.9 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 a crude residue. It was purified by reverse phase hplc with a Gilson HPLC (acidic conditions: 0.1% TFA in the solvents), eluting with 15 to 80% 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′-{[({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′-fluoro-3-biphenylyl)methyl]-2-methyl-1-piperazinecarboxylate. The compound 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 and washed with 1 N NaOH, 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-fluoro-3′-{[(3S)-3-methyl-1-piperazinyl]methyl}-3-biphenylyl)methyl]-1,1-cyclopropanedicarboxamide (8 mg, 13.8%). LC-MS m/z 711 (M+H)+, 0.70 min (ret time).

Workup

  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 a 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 15 to 80% 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-cd6b87a40f9b4982b3b488aadc694869
Source dataset
uspto-grants-2011_12
Patent number
US08071588B2

Reaction notes

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