Acetic Acid → (+/-)-6-[4-(3-Phenyl-pyrrolidin-1-ylmethyl)-phenoxy]-nicotinamide

HRID 492379Notes

Reaction equation

HRID 492379 reaction equation
P(=O)(O)(O)O.[C:6]1([CH:12]2[CH2:16][CH2:15][NH:14][CH2:13]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.N.CO.[CH:20]([C:22]1[CH:37]=[CH:36][C:25]([O:26][C:27]2[CH:35]=[CH:34][C:30]([C:31]([NH2:33])=[O:32])=[CH:29][N:28]=2)=[CH:24][CH:23]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl.CO>[C:6]1([CH:12]2[CH2:16][CH2:15][N:14]([CH2:20][C:22]3[CH:37]=[CH:36][C:25]([O:26][C:27]4[CH:35]=[CH:34][C:30]([C:31]([NH2:33])=[O:32])=[CH:29][N:28]=4)=[CH:24][CH:23]=3)[CH2:13]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1

Participants

8

Reactant 5

HCID 176Acetic AcidHCID 5049666Sodium triacetoxyborohydrideHCID 21705897Ammonia methanolHCID 568514226-(4-Formylphenoxy)pyridine-3-carboxamide2×HCID 687492483-Phenyl-pyrrolidine phosphoric acid salt

Product 1

HCID 59730333(+/-)-6-[4-(3-Phenyl-pyrrolidin-1-ylmethyl)-phenoxy]-nicotinamideYield 88.4%

Reagents, catalysts & solvents 2

HCID 111,2-DichloroethaneSolventHCID 887MethanolSolvent

Procedure

Convert 3-phenyl-pyrrolidine phosphoric acid salt (0.152 g, 1.03 mmol) to the free base by ion exchange chromatography (SCX resin, methanol→2 M ammonia/methanol) and then concentrate. Combine free base with 6-(4-formyl-phenoxy)-nicotinamide (compound of example 332, step 1) (0.150 g, 0.618 mmol), sodium triacetoxyborohydride (0.201 g, 0.948 mmol), and acetic acid (0.053 mL, 0.891 mmol) in 1,2-dichloroethane (9.5 mL) and stir at ambient temperature. After 1 d, purify the reaction mixture by ion exchange chromatography (SCX resin, methanol→2 M ammonia in methanol) and concentrate to provide 0.204 g (88%) of the title compound as a white solid: high resolution mass spectrum (electrospray): m/z calc for C23H24N3O2 374.1869, found 374.1887; 1H NMR (methanol-d4): 8.67 (dd, 1H, J=1.0, 2.4 Hz), 8.29 (dd, 1H, J=2.4, 8.8 Hz), 7.52-7.47 (m, 2H), 7.34-7.28 (m, 4H), 7.25-7.14 (m, 3H), 7.03 (dd, 1H, J=1.0, 8.8 Hz), 3.80 (d, 1H, J=13.2 Hz), 3.77 (d, 1H, J=12.7 Hz), 3.48-3.38 (m, 1H), 3.16 (dd, 1H, J=7.8, 9.3 Hz), 3.00-2.93 (m, 1H), 2.85-2.77 (m, 1H), 2.58 (t, 1H, J=8.8 Hz), 2.44-2.32 (m, 1H), 2.02-1.91 (m, 1H).

Workup

  1. custompurify the reaction mixture by ion exchange chromatography (SCX resin, methanol→2 M ammonia in methanol)
  2. concentrationconcentrate

Sources & evidence

ORD record
ord-27756a7c0e4f48259c76e978812ceebd
Source dataset
uspto-grants-2009_05
Patent number
US07531557B2

Reaction notes

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