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

HRID 564601Notes

Reaction equation

HRID 564601 reaction equation
[O:1]=[C:2]1[NH:7][CH2:6][CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.[H-].[Na+].[CH2:17]([N:19]1[C:23]2=[N:24][C:25]([CH2:64][CH3:65])=[C:26]([CH2:35][NH:36][C:37]([C:39]3[CH:44]=[CH:43][CH:42]=[C:41]([C:45]([NH:47][CH2:48][C:49]4[CH:50]=[C:51]([C:56]5[CH:61]=[CH:60][CH:59]=[C:58]([CH2:62]I)[CH:57]=5)[C:52]([F:55])=[CH:53][CH:54]=4)=[O:46])[CH:40]=3)=[O:38])[C:27]([NH:28][CH:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[C:22]2[CH:21]=[N:20]1)[CH3:18]>CN(C=O)C>[CH2:17]([N:19]1[C:23]2=[N:24][C:25]([CH2:64][CH3:65])=[C:26]([CH2:35][NH:36][C:37]([C:39]3[CH:44]=[CH:43][CH:42]=[C:41]([C:45]([NH:47][CH2:48][C:49]4[CH:50]=[C:51]([C:56]5[CH:61]=[CH:60][CH:59]=[C:58]([CH2:62][N:7]6[CH2:6][CH2:5][NH:4][CH2:3][C:2]6=[O:1])[CH:57]=5)[C:52]([F:55])=[CH:53][CH:54]=4)=[O:46])[CH:40]=3)=[O:38])[C:27]([NH:28][CH:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[C:22]2[CH:21]=[N:20]1)[CH3:18]

Participants

5

Reactant 3

HCID 24758Sodium hydrideHCID 3157178Tert-butyl 3-oxopiperazine-1-carboxylateHCID 67005650N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N'-{[6-fluoro-3'-(iodomethyl)-3-biphenylyl]methyl}-1,3-benzenedicarboxamide

Product 1

HCID 57813292N-{[1,6-Diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N'-({6-fluoro-3'-[(2-oxo-1-piperazinyl)methyl]-3-biphenylyl}methyl)-1,3-benzenedicarboxamideYield 13%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent2×

Procedure

To a solution of 1,1-dimethylethyl 3-oxo-1-piperazinecarboxylate (0.027 g, 0.135 mmol) in DMF (0.25 mL) was added NaH (0.0033 g, 0.135 mmol). This mixture was stirred at room temperature for 5 min whereupon a solution of the above N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-{[6-fluoro-3′-(iodomethyl)-3-biphenylyl]methyl}-1,3-benzenedicarboxamide in DMF (0.25 mL) was added. The resulting mixture was stirred for 15 h and purified with a Gilson HPLC (with TFA). The relevant HPLC fractions collected and treated with TFA (0.10 mL), the solvent concentrated on GeneVav EZ-2 evaporator, purified again with Gilson HPLC (with TFA), solvent concentrated on GeneVav EZ-2 evaporator, and the residue basified with an amine cartridge to afford 0.0143 g (13%) of the title compound. LC-MS m/z 747 (M+H)+; 1H-NMR (400 MHz, CD3OD) δ ppm 1.40 (t, J=7.65 Hz, 3 H) 1.49 (t, J=7.15 Hz, 3 H) 1.81-1.93 (m, 2 H) 2.09 (d, J=12.55 Hz, 2 H) 3.16 (q, J=7.53 Hz, 2 H) 3.48-3.55 (m, 2 H) 3.55-3.61 (m, 2 H) 3.62-3.72 (m, 2 H) 3.93 (s, 2 H) 3.99-4.08 (m, 2 H) 4.30-4.40 (m, 1 H) 4.47 (q, J=7.11 Hz, 2 H) 4.60 (s, 2 H) 4.72 (d, J=4.77 Hz, 4 H) 7.15 (dd, J=10.67, 8.41 Hz, 1 H) 7.32-7.41 (m, 2 H) 7.44 (t, J=7.53 Hz, 1 H) 7.47-7.54 (m, 3 H) 7.60 (t, J=7.91 Hz, 1 H) 8.00-8.08 (m, 2 H) 8.29 (s, 1 H) 8.38 (t, J=1.63 Hz, 1 H).

Workup

  1. additionwas added
  2. custompurified with a Gilson HPLC (with TFA)
  3. customThe relevant HPLC fractions collected
  4. additiontreated with TFA (0.10 mL)
  5. concentrationthe solvent concentrated on GeneVav EZ-2 evaporator
  6. custompurified again with Gilson HPLC (with TFA), solvent
  7. concentrationconcentrated on GeneVav EZ-2 evaporator

Sources & evidence

ORD record
ord-ae6a3f90cd984b4db4693b5c73a23440
Source dataset
uspto-grants-2011_11
Patent number
US08067408B2

Reaction notes

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