2,4-Dichlorobenzaldehyde → 6-[3-(2,4-Dichlorobenzylamino)-pyrrolidin-1-yl]-nicotinonitrile

HRID 252143Notes

Reaction equation

HRID 252143 reaction equation
[NH2:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][N:8]=2)[CH2:3]1.[Cl:15][C:16]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:17]=1[CH:18]=O.[BH4-].[Na+]>CO.ClCCl>[NH3:1].[Cl:15][C:16]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:17]=1[CH2:18][NH:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][N:8]=2)[CH2:3]1

Participants

7

Reactant 3

HCID 134042,4-DichlorobenzaldehydeHCID 4311764Sodium borohydrideHCID 210904066-(3-Aminopyrrolidin-1-yl)nicotinonitrile

Product 2

HCID 222AmmoniaHCID 598603496-[3-(2,4-Dichlorobenzylamino)-pyrrolidin-1-yl]-nicotinonitrileYield 29.9%

Reagents, catalysts & solvents 2

HCID 887MethanolSolvent2×HCID 6344DichloromethaneSolvent

Procedure

Stir a solution of 6-(3-aminopyrrolidin-1-yl)-nicotinonitrile (200 mg, 1.06 mmol) and 2,4-dichlorobenzaldehyde (371 mg, 2.12 mmol) in methanol (10 mL) for 1 hour. Add 10% sodium borohydride on alumina (400 mg) in one portion and stir for 2 hours. Dilute with dichloromethane (50 mL) and filter through a pad of Celite®. Concentrate to give a residue. Dissolve the residue in 5:95 methanol:dichloromethane and filter through a plug of silica gel. Concentrate to a residue and chromatograph by reverse phase chromatography, eluting with acetonitrile (0.1% trifluoroacetic acid):water (0.1% trifluoroacetic acid). Chromatograph on a SCX column eluting with methanol and then a 1:1 solution of 2.0 M ammonia in methanol:dichloromethane to give the title compound (55 mg, 15%). 1H NMR (400 MHz, CDCl3) δ 8.39 (d, 1H, J=1.8 Hz), 7.57-7.54 (m, 1H), 7.38-7.33 (m, 2H), 7.23-7.20 (m, 1H), 6.32 (d, 1H, J=8.8 Hz), 3.90 (s, 2H), 3.80-3.25 (m, 4H), 2.30-2.19 (m, 1H), 2.05-1.90 (m, 1H), 1.76 (br s, 1H); MS (ES): m/z=347.1, 349.0 [M+H]+.

Workup

  1. filtrationfilter through a pad of Celite®
  2. concentrationConcentrate
  3. customto give a residue
  4. filtrationdichloromethane and filter through a plug of silica gel
  5. concentrationConcentrate to a residue and chromatograph by reverse phase chromatography
  6. washeluting with acetonitrile (0.1% trifluoroacetic acid)
  7. washChromatograph on a SCX column eluting with methanol

Sources & evidence

ORD record
ord-ef99375736514cffb0d702489fa3e4cb
Source dataset
uspto-grants-2011_01
Patent number
US07868014B2

Reaction notes

Loading…