Acetic Acid → 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]butanediamide

HRID 657436Notes

Reaction equation

HRID 657436 reaction equation
[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:44][CH3:45])=[C:10]([CH2:19][NH:20][C:21](=[O:43])[CH2:22][CH2:23][C:24]([NH:26][CH2:27][C:28]3[CH:29]=[C:30]([C:35]4[CH:40]=[CH:39][CH:38]=[C:37](C=O)[CH:36]=4)[C:31]([F:34])=[CH:32][CH:33]=3)=[O:25])[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[C@H:47]1[CH2:52][NH:51][CH2:50][CH2:49][N:48]1[C:53](OC(C)(C)C)=O.[C:60](O)(=O)C>CS(C)=O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:44][CH3:45])=[C:10]([CH2:19][NH:20][C:21](=[O:43])[CH2:22][CH2:23][C:24]([NH:26][CH2:27][C:28]3[CH:29]=[C:30]([C:35]4[CH:36]=[CH:37][CH:38]=[C:39]([CH2:53][N:48]5[CH2:47][CH2:52][NH:51][C@@H:50]([CH3:60])[CH2:49]5)[CH:40]=4)[C:31]([F:34])=[CH:32][CH:33]=3)=[O:25])[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

5

Reactant 3

HCID 176Acetic AcidHCID 10081508tert-Butyl (2S)-2-methylpiperazine-1-carboxylateHCID 57819870N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N'-[(6-fluoro-3'-formyl-3-biphenylyl)methyl]butanediamide

Product 1

HCID 44242214N-{[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]butanediamideYield 38.9%

Reagents, catalysts & solvents 1

HCID 679Dimethyl SulfoxideSolvent

Procedure

In an alternate preparation of the above titled compound previously described in Examples 135 and 143, N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-[(6-fluoro-3′-formyl-3-biphenylyl)methyl]butanediamide (36.9 mg. 0.06 mmol) was diluted in DMSO (1.5 mL) and dispensed into a 1 dram vial containing 1,1-dimethylethyl (2S)-2-methyl-1-piperazinecarboxylate (0.18 mmol) and acetic acid (3.6 mg, 0.6 mmol) and fitted with a magnetic stir bar. The resulting solution was stirred at room temperature for 4 h. MP-B(OAc)3H (0.6 mmol, 140 mg) was added and the solution was stirred for another 12 h. The polymer reagent was filtered off and to the filtrate were added MeOH (2.0 mL) and 1 drop of concentrated HCl. This solution was heated at 60 C. ° for 12 h. Purification was completed via reverse phase HPLC using a Gilson (acidic conditions with 0.1% TFA in the solvents). The product after HPLC purification was dissolved in 3 mL of MeOH and passed through a 0.5 g amine column (washed with 8 mL of MeOH) to afford 16.3 mg of the title compound (38.9%). LC-MS m/z 700 (M+H)+, 0.66 min (ret time).

Workup

  1. customfitted with a magnetic stir bar
  2. stirringthe solution was stirred for another 12 h
  3. filtrationThe polymer reagent was filtered off and to the filtrate
  4. additionwere added MeOH (2.0 mL) and 1 drop of concentrated HCl
  5. temperatureThis solution was heated at 60 C
  6. wait° for 12 h
  7. customPurification
  8. customThe product after HPLC purification
  9. dissolutionwas dissolved in 3 mL of MeOH
  10. washpassed through a 0.5 g amine column (washed with 8 mL of MeOH)

Sources & evidence

ORD record
ord-a4cade1a263c415ab496f702e3a2c594
Source dataset
uspto-grants-2011_12
Patent number
US08071588B2

Reaction notes

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