Piperidin-4-ol → N-{[1,6-Diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N'-({6-fluoro-3'-[(4-hydroxy-1-piperidinyl)methyl]-3-biphenylyl}methyl)-1,3-benzenedicarboxamide

HRID 564638Notes

Reaction equation

HRID 564638 reaction equation
[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:48][CH3:49])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:40]5[CH:45]=[CH:44][CH:43]=[C:42]([CH:46]=O)[CH:41]=5)[C:36]([F:39])=[CH:37][CH:38]=4)=[O:30])[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].[NH:50]1[CH2:55][CH2:54][CH:53]([OH:56])[CH2:52][CH2:51]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:48][CH3:49])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([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:50]6[CH2:55][CH2:54][CH:53]([OH:56])[CH2:52][CH2:51]6)[CH:41]=5)[C:36]([F:39])=[CH:37][CH:38]=4)=[O:30])[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]

Participants

5

Reactant 3

HCID 79341Piperidin-4-ol2×HCID 5049666Sodium triacetoxyborohydride2×HCID 57813252N-{[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]-1,3-benzenedicarboxamide

Product 1

HCID 44181305N-{[1,6-Diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N'-({6-fluoro-3'-[(4-hydroxy-1-piperidinyl)methyl]-3-biphenylyl}methyl)-1,3-benzenedicarboxamideYield 71.3%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a solution of 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]-1,3-benzenedicarboxamide (0.133 g, 0.2 mmol) in DCM (3 mL) was added 4-piperidinol (0.021 g, 0.210 mmol), NaBH(OAc)3 (0.051 g, 0.240 mmol). This mixture was stirred at room temperature for 15 h at which time more 4-piperidinol (0.004 g, 0.04 mmol) was added and stirring continued for 2 h. Then more NaBH(OAc)3 (0.025 g, 0.1 mmol) was added and the mixture was stirred for an additional 2 h. The reaction mixture was filtered, concentrated, and purified using a Gilson HPLC (with 0.1% TFA). The fraction was concentrated and basified with an amine cartridge to afford 0.1067 g of the title compound. LC-MS m/z 748 (M+H)+; 1H NMR (400 MHz, CD3OD) δ ppm 1.40 (t, J=7.65 Hz, 3 H) 1.49 (t, J=7.15 Hz, 3 H) 1.62-1.83 (m, 1 H) 1.83-2.01 (m, 4 H) 2.05-2.27 (m, 3 H) 3.08 (t, J=12.05 Hz, 1 H) 3.16 (q, J=7.36 Hz, 2 H) 3.32-3.41 (m, 2 H) 3.53 (d, J=12.30 Hz, 1 H) 3.62-3.72 (m, 2 H) 3.76-4.10 (m, 3 H) 4.31-4.51 (m, 5 H) 4.61 (s, 2 H) 4.72 (s, 2 H) 7.18 (dd, J=10.67, 8.41 Hz, 1 H) 7.38-7.46 (m, 1 H) 7.50-7.63 (m, 4 H) 7.65-7.76 (m, 2 H) 8.01-8.09 (m, 2 H) 8.29 (s, 1 H) 8.40 (t, J=1.63 Hz, 1 H).

Workup

  1. additionwas added
  2. stirringthe mixture was stirred for an additional 2 h
  3. filtrationThe reaction mixture was filtered
  4. concentrationconcentrated
  5. custompurified
  6. concentrationThe fraction was concentrated

Sources & evidence

ORD record
ord-c9b05afb05af41c4bf29efeac420bbd8
Source dataset
uspto-grants-2011_11
Patent number
US08067408B2

Reaction notes

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