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

HRID 564657Notes

Reaction equation

HRID 564657 reaction equation
[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10](C=O)[CH:9]=2)=[CH:6][C:5]([CH2:16][NH:17][C:18]([C:20]2[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([C:27]([NH:29][CH2:30][C:31]3[C:32]([NH:44][CH:45]4[CH2:50][CH2:49][O:48][CH2:47][CH2:46]4)=[C:33]4[CH:41]=[N:40][N:39]([CH2:42][CH3:43])[C:34]4=[N:35][C:36]=3[CH2:37][CH3:38])=[O:28])[CH:21]=2)=[O:19])=[CH:4][CH:3]=1.[N:51]1([C:57](OC(C)(C)C)=O)[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C>CS(C)=O>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:57][N:51]3[CH2:52][CH2:53][NH:54][CH2:55][CH2:56]3)[CH:9]=2)=[CH:6][C:5]([CH2:16][NH:17][C:18]([C:20]2[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([C:27]([NH:29][CH2:30][C:31]3[C:32]([NH:44][CH:45]4[CH2:50][CH2:49][O:48][CH2:47][CH2:46]4)=[C:33]4[CH:41]=[N:40][N:39]([CH2:42][CH3:43])[C:34]4=[N:35][C:36]=3[CH2:37][CH3:38])=[O:28])[CH:21]=2)=[O:19])=[CH:4][CH:3]=1

Participants

6

Reactant 4

HCID 176Acetic AcidHCID 143452tert-Butyl piperazine-1-carboxylateHCID 2724942TriacetoxyborohydrideHCID 57813308N-[(6-chloro-3'-formyl-3-biphenylyl)methyl]-N'-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-5-methyl-1,3-benzenedicarboxamide

Product 1

HCID 57813518N-{[6-Chloro-3'-(1-piperazinylmethyl)-3-biphenylyl]methyl}-N'-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-5-methyl-1,3-benzenedicarboxamideYield 70.9%

Reagents, catalysts & solvents 1

HCID 679Dimethyl SulfoxideSolvent

Conditions

Temperature
60 °C

Procedure

N-[(6-Chloro-3′-formyl-3-biphenylyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-5-methyl-1,3-benzenedicarboxamide (30.36 mg, 0.044 mmol), 1,1-dimethylethyl 1-piperazinecarboxylate (82 mg, 0.44 mmol, 10 eq) and acetic acid (2.51 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 4-[(2′-chloro-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}-3-biphenylyl)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 23.82 mg (64.1%) of the title compound. LC-MS m/z 763 (M+H)+, 1.32 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 4-[(2′-chloro-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}-3-biphenylyl)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-24a9e48325594fefa74f4c99cc6cf607
Source dataset
uspto-grants-2011_11
Patent number
US08067408B2

Reaction notes

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