Triethylamine → N1-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N1-({3'-[(1-methyl-4-piperidinyl)methyl]-3-biphenylyl}methyl)-1,1-cyclopropanedicarboxamide

HRID 657412Notes

Reaction equation

HRID 657412 reaction equation
[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:29][CH3:30])=[C:10]([CH2:19][NH:20][C:21]([C:23]3([C:26](O)=[O:27])[CH2:25][CH2:24]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].[CH3:31][N:32]1[CH2:37][CH2:36][CH:35]([CH2:38][C:39]2[CH:40]=[C:41]([C:45]3[CH:50]=[CH:49][CH:48]=[C:47]([CH2:51]N)[CH:46]=3)[CH:42]=[CH:43][CH:44]=2)[CH2:34][CH2:33]1.C[N:54]1CCC(CC2C=C(C3C=CC=C(CN)C=3)C=CC=2)CC1.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]([CH2:29][CH3:30])=[C:10]([CH2:19][N:20]([CH2:51][C:47]3[CH:46]=[C:45]([C:41]4[CH:42]=[CH:43][CH:44]=[C:39]([CH2:38][CH:35]5[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]5)[CH:40]=4)[CH:50]=[CH:49][CH:48]=3)[C:21]([C:23]3([C:26]([NH2:54])=[O:27])[CH2:24][CH2:25]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 578198681-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]cyclopropanecarboxylic acidHCID 68641574({3'-[(1-Methyl-4-piperidinyl)methyl]-3-biphenylyl}methyl)amine 1-{3'-[(1-methyl-4-piperidinyl)methyl]-3-biphenylyl}methanamine

Product 1

HCID 69012064N1-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N1-({3'-[(1-methyl-4-piperidinyl)methyl]-3-biphenylyl}methyl)-1,1-cyclopropanedicarboxamideYield 10.8%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

A mixture of 1-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]cyclopropanecarboxylic acid (100 mg, 0.241 mmol), ({3′-[(1-methyl-4-piperidinyl)methyl]-3-biphenylyl}methyl)amine 1-{3′-[(1-methyl-4-piperidinyl)methyl]-3-biphenylyl}methanamine (92 mg, 0.241 mmol), HBTU (110 mg, 0.289 mmol) and Et3N (0.101 mL, 0.722 mmol) in DCM was stirred at room temperature overnight. The crude mixture was quenched with saturated NaHCO3 and extracted with DCM twice. The combined organic layers were washed with brine and then concentrated under vacuum to give crude residue. The crude product was purified by reverse phase hplc with a Gilson HPLC (acidic conditions: 0.1% TFA in the solvents), eluting with 10 to 70% CH3CN in water at a flow rate of 20 mL/min. The product fractions were combined, washed with saturated NaHCO3 and extracted with ethyl acetate twice. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and then concentrated under vacuum to give N1-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N1-({3′-[(1-methyl-4-piperidinyl)methyl]-3-biphenylyl}methyl)-1,1-cyclopropanedicarboxamide as a solid (18 mg, 10.8%). LC-MS m/z 692 (M+H)+, 0.75 min (ret time).

Workup

  1. customThe crude mixture was quenched with saturated NaHCO3
  2. extractionextracted with DCM twice
  3. washThe combined organic layers were washed with brine
  4. concentrationconcentrated under vacuum
  5. customto give crude residue
  6. customThe crude product was purified by reverse phase hplc with a Gilson HPLC (acidic conditions
  7. wash0.1% TFA in the solvents), eluting with 10 to 70% CH3CN in water at a flow rate of 20 mL/min
  8. washwashed with saturated NaHCO3
  9. extractionextracted with ethyl acetate twice
  10. washThe combined organic layers were washed with brine
  11. dry with materialdried over sodium sulfate
  12. filtrationfiltered
  13. concentrationconcentrated under vacuum

Sources & evidence

ORD record
ord-7f3bf5273ce142c7abf247df537be2ef
Source dataset
uspto-grants-2011_12
Patent number
US08071588B2

Reaction notes

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