Acetic Acid → N-{[1,6-Diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N'-[(6-fluoro-3'-{[(3S)-3-methyl-1-piperazinyl]methyl}-3-biphenylyl)methyl]-5-methyl-1,3-benzenedicarboxamide

HRID 564655Notes

Reaction equation

HRID 564655 reaction equation
[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:49][CH3:50])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[C:27]([CH3:29])[CH:26]=[C:25]([C:30]([NH:32][CH2:33][C:34]4[CH:35]=[C:36]([C:41]5[CH:46]=[CH:45][CH:44]=[C:43]([CH:47]=O)[CH:42]=5)[C:37]([F:40])=[CH:38][CH:39]=4)=[O:31])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[CH3:51][C@H:52]1[CH2:57][NH:56][CH2:55][CH2:54][N:53]1C(OC(C)(C)C)=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C>CS(C)=O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:49][CH3:50])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[C:27]([CH3:29])[CH:26]=[C:25]([C:30]([NH:32][CH2:33][C:34]4[CH:35]=[C:36]([C:41]5[CH:46]=[CH:45][CH:44]=[C:43]([CH2:47][N:56]6[CH2:55][CH2:54][NH:53][C@@H:52]([CH3:51])[CH2:57]6)[CH:42]=5)[C:37]([F:40])=[CH:38][CH:39]=4)=[O:31])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]

Participants

6

Reactant 4

HCID 176Acetic AcidHCID 2724942TriacetoxyborohydrideHCID 10081508tert-Butyl (2S)-2-methylpiperazine-1-carboxylateHCID 57813273N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N'-[(6-fluoro-3'-formyl-3-biphenylyl)methyl]-5-methyl-1,3-benzenedicarboxamide

Product 1

HCID 57813378N-{[1,6-Diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N'-[(6-fluoro-3'-{[(3S)-3-methyl-1-piperazinyl]methyl}-3-biphenylyl)methyl]-5-methyl-1,3-benzenedicarboxamideYield 60.2%

Reagents, catalysts & solvents 1

HCID 679Dimethyl SulfoxideSolvent

Conditions

Temperature
60 °C

Procedure

N-{[1,6-Diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-[(6-fluoro-3′-formyl-3-biphenylyl)methyl]-5-methyl-1,3-benzenedicarboxamide (30 mg, 0.044 mmol), 1,1-dimethylethyl (2S)-2-methyl-1-piperazinecarboxylate (89 mg, 0.44 mmol, 10 eq) and acetic acid (2.54 μL, 0.044 mmol, 1 eq) were dissolved in DMSO (1.5 mL). The mixture was stirred in VX-2500 Multi-Tube Vortexer for overnight at room temperature. MP-triacetoxyborohydride (133 mg, 0.310 mmol, 7 eq) was then added and the mixture was stirred again in VX-2500 Multi-Tube Vortexer for overnight at room temperature. The reaction mixture was filtered through a polypropylene cartridge (10 mL tube) on Bohdan Miniblock in a reaction tube and concentrated in a Glas-Col evaporator. Methanol (2 mL) then hydrochloric acid (5 μL) were added for the deprotection of 1,1-dimethylethyl (2S)-4-[(5′-{[({3-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]-5-methylphenyl}carbonyl)amino]methyl}-2′-fluoro-3-biphenylyl)methyl]-2-methyl-1-piperazinecarboxylate. The vial containing the reaction mixture was closed and stirred in a Glas-Col evaporator for overnight at 60° C. The reaction mixture was then concentrated and purified using a Gilson HPLC with a water-acetonitrile with 0.1% TFA buffer. The desired product fractions were combined, filtered through amine cartouche (500 mg) on Bohdan Miniblock and concentrated in a Glas-Col evaporator, giving 20.16 mg (53.8%) of the title compound. LC-MS m/z 761 (M+H)+, 1.31 min (ret time).

Workup

  1. filtrationThe reaction mixture was filtered through a polypropylene cartridge (10 mL tube) on Bohdan Miniblock in a reaction tube
  2. concentrationconcentrated in a Glas-Col evaporator
  3. additionMethanol (2 mL) then hydrochloric acid (5 μL) were added for the deprotection of 1,1-dimethylethyl (2S)-4-[(5′-{[({3-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]-5-methylphenyl}carbonyl)amino]methyl}-2′-fluoro-3-biphenylyl)methyl]-2-methyl-1-piperazinecarboxylate
  4. additionThe vial containing the reaction mixture
  5. customwas closed
  6. concentrationThe reaction mixture was then concentrated
  7. custompurified
  8. filtrationfiltered through amine cartouche (500 mg) on Bohdan Miniblock
  9. concentrationconcentrated in a Glas-Col evaporator

Sources & evidence

ORD record
ord-71b7066f9cb04f6fbb83b2bf2d2f3b3f
Source dataset
uspto-grants-2011_11
Patent number
US08067408B2

Reaction notes

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