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

HRID 662105Notes

Reaction equation

HRID 662105 reaction equation
[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:54][CH3:55])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:24]=[N:25][CH:26]=[C:27]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:40]5[CH:45]=[CH:44][CH:43]=[C:42]([CH2:46][N:47]6[CH2:52][CH2:51][NH:50][C@@H:49]([CH3:53])[CH2:48]6)[CH:41]=5)[C:36]([F:39])=[CH:37][CH:38]=4)=[O:30])[CH:28]=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(N1C2=NC(CC)=C(CNC(C3C=C(C(O)=O)C=NC=3)=O)C(NC3CCOCC3)=C2C=N1)C.NCC1C=CC(F)=C(C2C=CC=C(CN3CCN([C:110]([O:112][C:113]([CH3:116])([CH3:115])[CH3:114])=[O:111])[C@@H](C)C3)C=2)C=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]([CH2:54][CH3:55])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[C:27]([C:29]([NH:31][CH2:32][C:33]4[CH:38]=[CH:37][C:36]([F:39])=[C:35]([C:40]5[CH:45]=[CH:44][CH:43]=[C:42]([CH2:46][N:47]6[CH2:52][CH2:51][N:50]([C:110]([O:112][C:113]([CH3:116])([CH3:115])[CH3:114])=[O:111])[C@@H:49]([CH3:53])[CH2:48]6)[CH:41]=5)[CH:34]=4)=[O:30])[CH:26]=[N:25][CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]

Participants

7

Reactant 5

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 44192863n-{[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]-3,5-pyridinedicarboxamideHCID 578193875-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]-3-pyridinecarboxylic acid

Product 1

HCID 866333501,1-dimethylethyl (2S)-4-[(5'-{[({5-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]-3-pyridinyl}carbonyl)amino]methyl}-2'-fluoro-3-biphenylyl)methyl]-2-methyl-1-piperazinecarboxylate

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

As an alternate process for preparing the compound of Example 131, a mixture of 5-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]-3-pyridinecarboxylic acid (50 mg, 0.110 mmol), 1,1-dimethylethyl (2S)-4-{[5′-(aminomethyl)-2′-fluoro-3-biphenylyl]methyl}-2-methyl-1-piperazinecarboxylate (45.7 mg, 0.110 mmol), HBTU (o-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate) (50.3 mg, 0.133 mmol) and Et3N (0.046 ml, 0.331 mmol) in DCM was stirred at room temperature over the weekend. 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 (2S)-4-[(5′-{[({5-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]-3-pyridinyl}carbonyl)amino]methyl}-2′-fluoro-3-biphenylyl)methyl]-2-methyl-1-piperazinecarboxylate. This intermediate 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 the free base was obtained by adding 1 N NaOH, and the aqueous layer was extracted with ethyl acetate twice. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under vacuum to 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]-3,5-pyridinedicarboxamide as a solid (10 mg, 12.1%). LC-MS m/z 748 (M+H)+, 0.70 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-b5c783f4048e4da0949d3493ba67ddee
Source dataset
uspto-grants-2011_12
Patent number
US08084449B2

Reaction notes

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