Dichloromethane → HCID 44156291, compound

HRID 662103Notes

Reaction equation

HRID 662103 reaction equation
[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:32][CH3:33])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[N:28]=[C:27]([C:29](O)=[O:30])[CH:26]=[CH:25][CH: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].[NH2:34][CH2:35][C:36]1[CH:37]=[CH:38][C:39]([F:63])=[C:40]([C:42]2[CH:47]=[CH:46][CH:45]=[C:44](CN3CCN(C(OC(C)(C)C)=O)[C@@H](C)C3)[CH:43]=2)[CH:41]=1.CN(C(O[N:72]1N=[N:79][C:74]2C=CC=[CH:78][C:73]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:88][CH2:89]N(CC)CC.[CH2:95](Cl)Cl>C(O)(C(F)(F)F)=O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:32][CH3:33])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:24]=[CH:25][CH:26]=[C:27]([C:29]([NH:34][CH2:35][C:36]4[CH:41]=[C:40]([C:42]5[CH:47]=[CH:46][CH:45]=[C:44]([CH2:95][N:79]6[CH2:89][CH2:88][NH:72][C@@H:73]([CH3:78])[CH2:74]6)[CH:43]=5)[C:39]([F:63])=[CH:38][CH:37]=4)=[O:30])[N:28]=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 6344Dichloromethane2×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 578193746-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]-2-pyridinecarboxylic acid

Product 1

HCID 44156291HCID 44156291, compoundYield 39%

Reagents, catalysts & solvents 1

HCID 6422Trifluoroacetic acidSolvent

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 (80 mg, 0.18 mmol), 1,1-dimethylethyl (2S)-4-{[5′-(aminomethyl)-2′-fluoro-3-biphenylyl]methyl}-2-methyl-1-piperazinecarboxylate (76 mg, 0.18 mmol), HBTU (80 mg, 0.21 mmol) and Et3N (0.12 mL, 0.88 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 then washed with water followed by a brine wash. The organic layer was then concentrated under vacuum to give a crude residue: LC-MS m/z 848 (M+H)+. The crude residue was dissolved in 25% TFA in DCM (2 mL) and stirred at RT for 2 h. It was purified with a Gilson HPLC (with 0.1% TFA condition), eluting with 10 to 70% CH3CN in water in a flowrate of 20 mL/min. The fractions were combined and then converted to the free base with saturated NaHCO3. The organic layer was recovered and dried over sodium sulfate, filtered and then concentrated 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]-2,6-pyridinedicarboxamide as a solid (51 mg, 39%). LC-MS m/z 748 (M+H)+.

Workup

  1. customThe reaction was quenched with saturated NaHCO3
  2. extractionextracted with DCM twice
  3. washThe combined organic layers were then washed with water
  4. washwash
  5. concentrationThe organic layer was then concentrated under vacuum
  6. customto give a crude residue
  7. stirringstirred at RT for 2 h
  8. customIt was purified with a Gilson HPLC (with 0.1% TFA condition)
  9. washeluting with 10 to 70% CH3CN in water in a flowrate of 20 mL/min
  10. customThe organic layer was recovered
  11. dry with materialdried over sodium sulfate
  12. filtrationfiltered
  13. concentrationconcentrated

Sources & evidence

ORD record
ord-0103fffa40104adba9c5aac763e24d49
Source dataset
uspto-grants-2011_12
Patent number
US08084449B2

Reaction notes

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