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

HRID 657421Notes

Reaction equation

HRID 657421 reaction equation
[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:30][CH3:31])=[C:10]([CH2:19][NH:20][C:21]([CH:23]([CH2:27][CH2:28][CH3:29])[C:24](O)=[O:25])=[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].[NH2:32][CH2:33][C:34]1[CH:35]=[CH:36][C:37]([F:61])=[C:38]([C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([CH2:46][N:47]3[CH2:52][CH2:51][N:50]([C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[C@@H:49]([CH3:60])[CH2:48]3)[CH:41]=2)[CH:39]=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]([CH2:30][CH3:31])=[C:10]([CH2:19][NH:20][C:21]([CH:23]([CH2:27][CH2:28][CH3:29])[C:24]([NH:32][CH2:33][C:34]3[CH:35]=[CH:36][C:37]([F:61])=[C:38]([C:40]4[CH:45]=[CH:44][CH:43]=[C:42]([CH2:46][N:47]5[CH2:52][CH2:51][N:50]([C:53]([O:55][C:56]([CH3:58])([CH3:57])[CH3:59])=[O:54])[C@@H:49]([CH3:60])[CH2:48]5)[CH:41]=4)[CH:39]=3)=[O:25])=[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

6

Reactant 4

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 578198952-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]pentanoic acid

Product 1

HCID 866333601,1-dimethylethyl (2S)-4-({5'-[({2-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]pentanoyl}amino)methyl]-2'-fluoro-3-biphenylyl}methyl)-2-methyl-1-piperazinecarboxylate

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

A mixture of 2-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]pentanoic acid (120 mg, 0.278 mmol), 1,1-dimethylethyl (2S)-4-{[5′-(aminomethyl)-2′-fluoro-3-biphenylyl]methyl}-2-methyl-1-piperazinecarboxylate (115 mg, 0.278 mmol), HBTU (105 mg, 0.278 mmol) and Et3N (0.039 mL, 0.278 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 crude residue. The crude product was purified with a Gilson HPLC (with 1% TFA in the solvent) eluting with 10 to 70% CH3CN in water at a flow rate of 20 mL/min. The product fractions were dried using a EZ2 GeneVac evaporator, combined and concentrated to give the intermediate 1,1-dimethylethyl (2S)-4-({5′-[({2-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]pentanoyl}amino)methyl]-2′-fluoro-3-biphenylyl}methyl)-2-methyl-1-piperazinecarboxylate. It was re-dissolved in 25% TFA in DCM (2 ML) and stirred for 2 h. Solvent was evaporated under a stream of nitrogen and 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 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 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]-2-propylpropanediamide as a solid (53 mg, 26.2%). LC-MS m/z 727 (M+H)+, 0.72 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 crude residue
  6. customThe crude product was purified with a Gilson HPLC (with 1% TFA in the solvent)
  7. washeluting with 10 to 70% CH3CN in water at a flow rate of 20 mL/min
  8. customThe product fractions were dried
  9. customa EZ2 GeneVac evaporator
  10. concentrationconcentrated

Sources & evidence

ORD record
ord-97facb725a5d4f8c9b3cc83c335a7b2b
Source dataset
uspto-grants-2011_12
Patent number
US08071588B2

Reaction notes

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