Acetic Acid → HCID 178489406, compound

HRID 2389011Notes

Reaction equation

HRID 2389011 reaction equation
[F:1][C:2]1[C:3]([NH:30][CH:31]2[CH2:36][CH2:35][C:34](=O)[CH2:33][CH2:32]2)=[C:4]([CH:10]=[C:11]([C:13]2[CH:14]=[C:15]3[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[O:28][CH3:29])=[N:20][NH:19][C:16]3=[N:17][CH:18]=2)[CH:12]=1)[C:5]([N:7]([CH3:9])[CH3:8])=[O:6].C([BH3-])#N.[Na+].[NH:42]1[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1.C(O)(=O)C>CO.O>[F:1][C:2]1[C:3]([NH:30][CH:31]2[CH2:32][CH2:33][CH:34]([N:42]3[CH2:47][CH2:46][O:45][CH2:44][CH2:43]3)[CH2:35][CH2:36]2)=[C:4]([CH:10]=[C:11]([C:13]2[CH:14]=[C:15]3[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[O:28][CH3:29])=[N:20][NH:19][C:16]3=[N:17][CH:18]=2)[CH:12]=1)[C:5]([N:7]([CH3:9])[CH3:8])=[O:6]

Participants

7

Reactant 4

HCID 176Acetic AcidHCID 8083MorpholineHCID 5003444Sodium cyanoborohydrideHCID 178489407HCID 178489407, compound

Product 1

HCID 178489406HCID 178489406, compound

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 962WaterSolvent

Procedure

3-Fluoro-5-[3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-N,N-dimethyl-2-(4-oxo-cyclohexylamino)-benzamide (91 mg, 0.14 mmol), sodium cyanoborohydride (17.5 mg, 0.28 mmol), and morpholine (37 μL, 0.41 mmol) were dissolved in 1.7 mL methanol, containing 5% v/v of glacial acetic acid and 2% v/v of water. The reaction was stirred for 2 hrs at ambient temperature and quenched with a saturated sodium bicarbonate solution. The mixture was concentrated, suspended in a minimal amount of water and loaded onto a 5 g C18 functionalized silica gel cartridge. The cartridge was washed with 1 N aqueous potassium hydrogensulfate and water. Elution with acetonitrile and evaporation of the solvent afforded a brown oil which was purified by reverse-phase HPLC to afford 10.4 mg (0.014 mmol, 10%) of both diastereoisomers of 3-fluoro-5-[3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-N,N-dimethyl-2-(4-morpholin-4-yl-cyclohexylamino)-benzamide as a white powder. More polar diastereoisomer (4.5 mg) 1H NMR (500 MHz, DMSO-d6) δ13.75 (bs, 1H), 8.81 (d, J=2 Hz, 1H), 8.27 (d, J=2 Hz, 1H), 8.16 (s, 1H), 7.62 (dd, J1=7.5 Hz, J2=1.5 Hz, 1H), 7.58 (dd, J1=13.5 Hz, J2=2 Hz, 1H), 7.45 (ddd, J1=8 Hz, J2=7 Hz, J3=1.5 Hz, 1H), 7.30 (d, J=2 Hz, 1H), 7.20 (d, J=8 Hz, 1H), 7.08 (td, J1=7.5 Hz, J2=1 Hz, 1H), 4.56 (d, J=9 Hz, 1H), 3.82 (s, 3H), 3.53 (t, J=4.5 Hz, 4H), 3.11 (m, 1H), 2.99 (bs, 3H), 2.90 (s, 3H), 2.43 (t, J=4.5 Hz, 4H), 2.14 (m, 1H), 1.88 (m, 2H), 1.82 (m, 2H), 1.17 (m, 4H). MS: m/z 573.4 (M+H+). Less polar diastereoisomer (5.9 mg) 1H NMR (500 MHz, DMSO-d6) δ13.77 (bs, 1H), 8.82 (s, 1H), 8.30 (s, 1H), 7.61 (m, 2H), 7.45 (t, J=8 Hz, 1H), 7.34 (m, 1H), 7.20 (d, J=8 Hz, 1H), 7.08 (t, J=8 Hz, 1H), 4.87 (d, J=9 Hz, 1H), 3.82 (s, 3H), 3.56 (m, 5H), 2.96 (m, 6H), 2.41 (m, 4H), 2.14 (m, 1H), 1.65 (m, 2H), 1.51 (m, 2H), 1.48 (m, 4H). MS: m/z 573.3 (M+H+).

Workup

  1. customquenched with a saturated sodium bicarbonate solution
  2. concentrationThe mixture was concentrated
  3. washThe cartridge was washed with 1 N aqueous potassium hydrogensulfate and water
  4. washElution
  5. customwith acetonitrile and evaporation of the solvent
  6. customafforded a brown oil which
  7. customwas purified by reverse-phase HPLC

Sources & evidence

ORD record
ord-d122fdb3b62a47e08a04a7e2db555efc
Source dataset
uspto-grants-2012_09
Patent number
US08268994B2

Reaction notes

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