Triethylamine → 1,1-dimethylethyl 4-[(3'-{[({1-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]cyclopropyl}carbonyl)amino]methyl}-3-biphenylyl)methyl]-1-piperidinecarboxylate

HRID 657415Notes

Reaction equation

HRID 657415 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].[NH2:31][CH2:32][C:33]1[CH:34]=[C:35]([C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][CH:46]3[CH2:51][CH2:50][N:49]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[CH2:48][CH2:47]3)[CH:40]=2)[CH:36]=[CH:37][CH:38]=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]([CH2:29][CH3:30])=[C:10]([CH2:19][NH:20][C:21]([C:23]3([C:26]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:39]5[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][CH:46]6[CH2:51][CH2:50][N:49]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[CH2:48][CH2:47]6)[CH:40]=5)[CH:36]=[CH:37][CH:38]=4)=[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]

Participants

6

Reactant 4

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 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 690106661,1-dimethylethyl 4-[(3'-{[({1-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]cyclopropyl}carbonyl)amino]methyl}-3-biphenylyl)methyl]-1-piperidinecarboxylate

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), 1,1-dimethylethyl 4-{[3′-(aminomethyl)-3-biphenylyl]methyl}-1-piperidinecarboxylate (70.9 mg, 0.241 mmol), HBTU (110 mg, 0.289 mmol) and Et3N (0.101 mL, 0.722 mmol) in DCM (3 mL) was stirred at room temperature overnight. The reaction 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 (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 dried under GeneVac and then combined to give the intermediate 1,1-dimethylethyl 4-[(3′-{[({1-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]cyclopropyl}carbonyl)amino]methyl}-3-biphenylyl)methyl]-1-piperidinecarboxylate. It was then dissolved in 2 mL of 25% TFA in DCM and stirred at room temperature for 3 h. The crude products were 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 and washed with 1 N NaOH and extracted with ethyl acetate twice. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under vacuum to N1-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N1-{[3′-(4-piperidinylmethyl)-3-biphenylyl]methyl}-1,1-cyclopropanedicarboxamide as a solid (32 mg, 19.6%). LC-MS m/z 678 (M+H)+, 0.79 min (ret time).

Workup

  1. customThe reaction 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 (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. customThe product fractions were dried under GeneVac

Sources & evidence

ORD record
ord-041d77fee9c441409f5b897f4a4c0fe9
Source dataset
uspto-grants-2011_12
Patent number
US08071588B2

Reaction notes

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