Triethylamine → 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]-1,4-benzenedicarboxamide

HRID 564598Notes

Reaction equation

HRID 564598 reaction equation
[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:32][CH3:33])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][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].[NH2:34][CH2:35][C:36]1[CH:37]=[CH:38][C:39]([F:63])=[C:40]([C:42]2[CH:47]=[CH:46][CH:45]=[C:44]([CH2:48][N:49]3[CH2:54][CH2:53][N:52](C(OC(C)(C)C)=O)[C@@H:51]([CH3:62])[CH2:50]3)[CH:43]=2)[CH:41]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>C(Cl)Cl>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:32][CH3:33])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:31]=[CH:30][C:26]([C:27]([NH:34][CH2:35][C:36]4[CH:41]=[C:40]([C:42]5[CH:47]=[CH:46][CH:45]=[C:44]([CH2:48][N:49]6[CH2:54][CH2:53][NH:52][C@@H:51]([CH3:62])[CH2:50]6)[CH:43]=5)[C:39]([F:63])=[CH:38][CH:37]=4)=[O:28])=[CH:25][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]

Participants

6

Reactant 4

HCID 8471TriethylamineHCID 2733084Methanaminium, N-((1H-benzotriazol-1-yloxy)(dimethylamino)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 251325161,1-dimethylethyl (2S)-4-{[5'-(aminomethyl)-2'-fluoro-3-biphenylyl]methyl}-2-methyl-1-piperazinecarboxylateHCID 578133384-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]benzoic acid

Product 1

HCID 44180990N-{[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]-1,4-benzenedicarboxamideYield 31.3%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a solution of 4-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino) carbonyl]benzoic acid (0.0452 g, 0.10 mmol) in DCM (1.0 mL) was added 1,1-dimethylethyl (2S)-4-{[5′-(aminomethyl)-2′-fluoro-3-biphenylyl]methyl}-2-methyl-1-piperazine carboxylate (0.0414 g, 0.10 mmol), HBTU (0.0569 g, 0.15 mmol), and Et3N (0.0281 mL, 0.20 mmol). This mixture was stirred at room temperature for 1 h, concentrated, and purified using a Gilson HPLC (with TFA). TFA (1 drop in each tube ˜12 mL), was added to Fractions containing product and solvent was concentrated using a GeneVav EZ-2 evaporator. The compound was purified again using a Gilson HPLC (with TFA) and evaporating the solvent using a GeneVav EZ-2 evaporator. Then product was basified with an amine cartridge to afford 0.0234 g (31%) of the title compound. LC-MS m/z 747 (M+H)+; 1H-NMR (400 MHz, CD3OD) δ ppm 1.33 (d, J=6.78 Hz, 3 H) 1.41 (t, J=7.53 Hz, 3 H) 1.50 (t, J=7.15 Hz, 3 H) 1.80-1.97 (m, 2 H) 2.06-2.15 (m, J=13.05 Hz, 2 H) 2.57-2.69 (m, 1 H) 2.75-2.88 (m, J=15.06 Hz, 1 H) 3.11-3.20 (m, 2 H) 3.33-3.39 (m, 3 H) 3.46-3.56 (m, J=13.80 Hz, 2 H) 3.64-3.74 (m, 2 H) 4.00-4.10 (m, J=3.01 Hz, 4 H) 4.31-4.42 (m, 1 H) 4.47 (q, J=7.19 Hz, 2 H) 4.58-4.64 (m, 2 H) 4.70-4.77 (m, 2 H) 7.18 (dd, J=10.54, 8.53 Hz, 1 H) 7.37-7.42 (m, 1 H) 7.43-7.47 (m, 1 H) 7.48-7.54 (m, 2 H) 7.54-7.59 (m, 1 H) 7.62-7.66 (m, 1 H) 7.93-8.01 (m, 4 H) 8.30 (s, 1 H).

Workup

  1. concentrationconcentrated
  2. custompurified
  3. additionTFA (1 drop in each tube ˜12 mL), was added to Fractions
  4. additioncontaining product and solvent
  5. concentrationwas concentrated
  6. customa GeneVav EZ-2 evaporator
  7. customThe compound was purified again
  8. customevaporating the solvent
  9. customa GeneVav EZ-2 evaporator

Sources & evidence

ORD record
ord-e890433ca6d549f8a4e76ce47d110cf4
Source dataset
uspto-grants-2011_11
Patent number
US08067408B2

Reaction notes

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