Acetic Acid → N-({6-Cyano-3'-[(1S,4S)-2,5-diazabicyclo [2.2.1]hept-2-ylmethyl]-3-biphenylyl}methyl)-N'-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-1,3-benzenedicarboxamide

HRID 564611Notes

Reaction equation

HRID 564611 reaction equation
[C:1]([C:3]1[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]=O)[CH:10]=2)=[CH:7][C:6]([CH2:17][NH:18][C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([NH:29][CH2:30][C:31]3[C:32]([NH:44][CH:45]4[CH2:50][CH2:49][O:48][CH2:47][CH2:46]4)=[C:33]4[CH:41]=[N:40][N:39]([CH2:42][CH3:43])[C:34]4=[N:35][C:36]=3[CH2:37][CH3:38])=[O:28])[CH:22]=2)=[O:20])=[CH:5][CH:4]=1)#[N:2].[C@H:51]12[CH2:57][C@H:54]([NH:55][CH2:56]1)[CH2:53][N:52]2C(OC(C)(C)C)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CC(O)=O>C(Cl)Cl>[C:1]([C:3]1[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:52]3[CH2:53][C@@H:54]4[CH2:57][C@H:51]3[CH2:56][NH:55]4)[CH:10]=2)=[CH:7][C:6]([CH2:17][NH:18][C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([NH:29][CH2:30][C:31]3[C:32]([NH:44][CH:45]4[CH2:50][CH2:49][O:48][CH2:47][CH2:46]4)=[C:33]4[CH:41]=[N:40][N:39]([CH2:42][CH3:43])[C:34]4=[N:35][C:36]=3[CH2:37][CH3:38])=[O:28])[CH:22]=2)=[O:20])=[CH:5][CH:4]=1)#[N:2]

Participants

6

Reactant 4

HCID 176Acetic AcidHCID 5049666Sodium triacetoxyborohydrideHCID 11521263(1S,4S)-2-Boc-2,5-diazabicyclo[2.2.1]heptaneHCID 57813346HCID 57813346, compound

Product 1

HCID 57813515N-({6-Cyano-3'-[(1S,4S)-2,5-diazabicyclo [2.2.1]hept-2-ylmethyl]-3-biphenylyl}methyl)-N'-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-1,3-benzenedicarboxamide

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

N-[(6-Cyano-3′-formyl-3-biphenylyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-1,3-benzenedicarboxamide (108 mg, 0.000161 mol) in DCM (4 mL) and 1,1-dimethylethyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (46 mg, 0.00023 mol) were mixed with sodium triacetoxyborohydride (68.3 mg, 0.00032 mol) and AcOH (11.6 mg, 11 μL). The solution was stirred overnight at room temperature. LC-MS showed that the reaction was complete. The reaction was quenched with sat. aq. NaHCO3, then extracted with DCM (2×). The combined organic extracts were washed with sat. aq. NaCl and dried (Na2SO4) and concentrated to a glassy foam (227.5 mg). The glassy foam was taken up in DCM (10 mL) containing 25% TFA and allowed to stand at room temperature for 3 h. LC-MS showed the reaction to be complete. Solvent was stripped off. Purification was carried out on Gilson instrument with acetonitrile-water (0.1% TFA) gradient on a C18-RP column. Fractions containing the clean desired product were combined; diluted with EtOAc; washed with sat. aq. NaHCO3; and the aq. phase back-extracted with EtOAc. Combined organic layers were washed with sat. aq. NaCl and dried (Na2SO4) and concentrated to a residue. It was taken up in a small amount of DCM and transferred to a vial and pumped down to afford the title compound as a chalky, white solid [71.5 mg (59%)]. LC-MS m/z 752.3 (M+H)+.

Workup

  1. customThe reaction was quenched with sat. aq. NaHCO3
  2. extractionextracted with DCM (2×)
  3. washThe combined organic extracts were washed with sat. aq. NaCl
  4. dry with materialdried (Na2SO4)
  5. concentrationconcentrated to a glassy foam (227.5 mg)
  6. additioncontaining 25% TFA
  7. waitto stand at room temperature for 3 h
  8. customthe reaction
  9. customPurification
  10. additionFractions containing the clean desired product
  11. additiondiluted with EtOAc
  12. washwashed with sat. aq. NaHCO3
  13. extractionand the aq. phase back-extracted with EtOAc
  14. washCombined organic layers were washed with sat. aq. NaCl
  15. dry with materialdried (Na2SO4)
  16. concentrationconcentrated to a residue

Sources & evidence

ORD record
ord-120709638eb74ed587211b542f8cb299
Source dataset
uspto-grants-2011_11
Patent number
US08067408B2

Reaction notes

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