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

HRID 657390Notes

Reaction equation

HRID 657390 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].C[N:32](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.[Br:62][C:63]1[CH:64]=[C:65]([CH2:71]N)[CH:66]=[CH:67][C:68]=1[O:69][CH3:70]>C(Cl)Cl>[Br:62][C:63]1[CH:64]=[C:65]([CH2:71][N:20]([CH2:19][C:10]2[C:11]([NH:12][CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[C:6]3[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[C:7]3=[N:8][C:9]=2[CH2:29][CH3:30])[C:21]([C:23]2([C:26]([NH2:32])=[O:27])[CH2:24][CH2:25]2)=[O:22])[CH:66]=[CH:67][C:68]=1[O:69][CH3:70]

Participants

6

Reactant 4

HCID 8471TriethylamineHCID 2733084Methanaminium, N-((1H-benzotriazol-1-yloxy)(dimethylamino)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 22026276(3-Bromo-4-methoxyphenyl)methanamineHCID 578198681-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]cyclopropanecarboxylic acid

Product 1

HCID 68636994N1-{[3-bromo-4-(methyloxy)phenyl]methyl}-N1-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-1,1-cyclopropanedicarboxamideYield 11.3%

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 (600 mg, 1.444 mmol), HBTU (657 mg, 1.733 mmol), Et3N (1006 μL, 7.22 mmol) and {[3-bromo-4-(methyloxy)phenyl]-methyl}amine (343 mg, 1.589 mmol) in DCM was stirred at room temperature overnight. The reaction 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 the crude residue. It was then purified 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 and washed with saturated NaHCO3 and extracted with ethyl acetate twice. The combined organic layers were dried over sodium sulfate, filtered and then concentrated under vacuum to give N1-{[3-bromo-4-(methyloxy)phenyl]methyl}-N1-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-1,1-cyclopropanedicarboxamide (100 mg, 11.29%). LC-MS m/z 613 M+, 0.83 min (ret time).

Workup

  1. customThe reaction 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 the crude residue
  6. customIt was then purified 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. dry with materialThe combined organic layers were dried over sodium sulfate
  11. filtrationfiltered
  12. concentrationconcentrated under vacuum

Sources & evidence

ORD record
ord-962cc8dcb33043e89c7515711ff8aac2
Source dataset
uspto-grants-2011_12
Patent number
US08071588B2

Reaction notes

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