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

HRID 662126
Notes
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Reaction equation

HRID 662126 reaction equation
CC(C1CN(CC2C=C(C3C=C(CNC(C4C=CC=C(C(NC[C:38]5[C:39]([NH:51][CH:52]6[CH2:57][CH2:56][O:55][CH2:54][CH2:53]6)=[C:40]6[CH:48]=[N:47][N:46]([CH2:49][CH3:50])[C:41]6=[N:42][C:43]=5[CH2:44][CH3:45])=O)N=4)=O)C=CC=3C)C=CC=2)CCN1C([O-])=O)(C)C.C(N1[C:68]2=N[C:70]([CH2:93][CH3:94])=[C:71]([CH2:80][NH:81][C:82]([C:84]3[N:89]=[C:88]([C:90]([OH:92])=O)[CH:87]=[CH:86][CH:85]=3)=[O:83])[C:72](NC3CCOCC3)=[C:67]2C=N1)C.NCC1C=[C:99]([C:103]2C=C[CH:106]=[C:105]([CH2:109][CH:110]3[CH2:115][CH2:114][N:113]([C:116](OC(C)(C)C)=O)[CH2:112][CH2:111]3)[CH:104]=2)C=CC=1.[CH3:123][N:124](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>C(Cl)Cl>[CH2:49]([N:46]1[C:41]2=[N:42][C:43]([CH2:44][CH3:45])=[C:38]([CH2:123][NH:124][C:90]([C:88]3[CH:87]=[CH:86][CH:85]=[C:84]([C:82]([NH:81][CH2:80][C:71]4[CH:70]=[C:93]([C:94]5[CH:99]=[CH:103][CH:104]=[C:105]([CH2:109][CH:110]6[CH2:115][CH2:114][N:113]([CH3:116])[CH2:112][CH2:111]6)[CH:106]=5)[CH:68]=[CH:67][CH:72]=4)=[O:83])[N:89]=3)=[O:92])[C:39]([NH:51][CH:52]3[CH2:57][CH2:56][O:55][CH2:54][CH2:53]3)=[C:40]2[CH:48]=[N:47]1)[CH3:50]
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

7

Reactant 5

HCID 8471TriethylamineHCID 2733084Methanaminium, N-((1H-benzotriazol-1-yloxy)(dimethylamino)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 57813360tert-Butyl 4-{[3'-(aminomethyl)biphenyl-3-yl]methyl}piperidine-1-carboxylateHCID 578193746-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]-2-pyridinecarboxylic acid
HCID 86633354
1,1-Dimethylethyl-4-[(5'-{[({6-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]-2-pyridinyl}carbonyl)amino]methyl}-2'-methyl-3-biphenylyl)methyl]-1-piperazinecarboxylate

Product 1

HCID 44193617N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N'-({3'-[(1-methyl-4-piperidinyl)methyl]-3-biphenylyl}methyl)-2,6-pyridinedicarboxamideYield 22.2%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

Process (A) A mixture of 6-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]-2-pyridinecarboxylic acid (84 mg, 0.186 mmol), 1,1-dimethylethyl 4-{[3′-(aminomethyl)-3-biphenylyl]methyl}-1-piperidinecarboxylate (54.7 mg, 0.186 mmol), HBTU (o-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate) (84 mg, 0.223 mmol) and Et3N (0.129 mL, 0.928 mmol) in DCM (3 mL) 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 with a Gilson HPLC (with 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, converted to the free base with saturated NaHCO3 and the basified solution was 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 N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-({3′-[(1-methyl-4-piperidinyl)methyl]-3-biphenylyl}methyl)-2,6-pyridinedicarboxamide as a white solid (30 mg, 22.2%). LC-MS m/z 729 (M+H)+, 0.80 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 with a Gilson HPLC (with 0.1% TFA in the solvents),
  7. washeluting with 10 to 70% CH3CN in water at a flow rate of 20 mL/min
  8. extractionthe basified solution was extracted with ethyl acetate twice
  9. washThe combined organic layers were washed with brine
  10. dry with materialdried over sodium sulfate
  11. filtrationfiltered
  12. concentrationconcentrated under vacuum

Sources & evidence

ORD record
ord-a4dc6b71f51849aca2669394241d3e6f
Source dataset
uspto-grants-2011_12
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US08084449B2

Reaction notes

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On this pageParticipantsProcedureWorkupSources & evidenceReaction notes