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}-1,3-benzenedicarboxamide

HRID 564591Notes

Reaction equation

HRID 564591 reaction equation
[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]=O)[CH:9]=2)=[CH:6][C:5]([CH2:16][NH:17][C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([NH:28][CH2:29][C:30]3[C:31]([NH:43][CH:44]4[CH2:49][CH2:48][O:47][CH2:46][CH2:45]4)=[C:32]4[CH:40]=[N:39][N:38]([CH2:41][CH3:42])[C:33]4=[N:34][C:35]=3[CH2:36][CH3:37])=[O:27])[CH:21]=2)=[O:19])=[CH:4][CH:3]=1.[N:50]1(C(OC(C)(C)C)=O)[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(C(F)(F)F)=O>ClCCCl.C(Cl)Cl>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][N:50]3[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]3)[CH:9]=2)=[CH:6][C:5]([CH2:16][NH:17][C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([NH:28][CH2:29][C:30]3[C:31]([NH:43][CH:44]4[CH2:49][CH2:48][O:47][CH2:46][CH2:45]4)=[C:32]4[CH:40]=[N:39][N:38]([CH2:41][CH3:42])[C:33]4=[N:34][C:35]=3[CH2:36][CH3:37])=[O:27])[CH:21]=2)=[O:19])=[CH:4][CH:3]=1

Participants

8

Reactant 5

HCID 176Acetic AcidHCID 6422Trifluoroacetic acidHCID 143452tert-Butyl piperazine-1-carboxylate2×HCID 5049666Sodium triacetoxyborohydride2×HCID 57813357HCID 57813357, compound

Product 1

HCID 57813268N-{[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}-1,3-benzenedicarboxamide

Reagents, catalysts & solvents 2

HCID 111,2-DichloroethaneSolventHCID 6344DichloromethaneSolvent

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}-1,3-benzenedicarboxamide (0.034 g, 0.05 mmol), 1,1-dimethylethyl 1-piperazinecarboxylate (0.0112 g, 0.06 mmol), and acetic acid (0.0036 g, 0.06 mmol) were combined in 1,2-dichloroethane (2 mL), and the mixture stirred for thirty min. Sodium triacetoxyborohydride (0.0148 g, 0.07 mmol) was added and the mixture stirred overnight at room temperature. Some starting material still remained, so additional 1,1-dimethylethyl 1-piperazinecarboxylate (0.004 g, 0.02 mmol) and sodium triacetoxyborohydride (0.005 g, 0.024 mmol) were added and the mixture again stirred overnight at room temperature. Solvents were concentrated, and the residue taken up in EtOAc, washed with 1N NaOH, brine, dried over anhydrous Na2SO4, filtered, and concentrated to give the protected product. This was treated with 10% TFA in CH2Cl2 for 3 h. The product was purified using a Gilson HPLC with a TFA system. The purified compound was taken up in EtOAc, washed 3× with 2.5 N NaOH, 1× with brine, dried over anhydrous Na2SO4, filtered, and concentrated to afford the title compound as a white solid. LC-MS m/z 749.1 (M+H)+, 1.47 min (ret time); mp 127-130° C. Analytical HPLC shows 98.8% purity, (ret time 10.129 min).

Workup

  1. stirringthe mixture stirred overnight at room temperature
  2. customthe mixture again stirred overnight
  3. customat room temperature
  4. concentrationSolvents were concentrated
  5. washwashed with 1N NaOH, brine
  6. dry with materialdried over anhydrous Na2SO4
  7. filtrationfiltered
  8. concentrationconcentrated
  9. customto give the protected product
  10. customThe product was purified
  11. washwashed 3× with 2.5 N NaOH, 1× with brine
  12. dry with materialdried over anhydrous Na2SO4
  13. filtrationfiltered
  14. concentrationconcentrated

Sources & evidence

ORD record
ord-74f67aa47f0d4c9b9c1573c3a3e5596e
Source dataset
uspto-grants-2011_11
Patent number
US08067408B2

Reaction notes

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