Acetic Acid → 6-{4-[2-(Benzyl-methyl-amino)-ethyl]-phenoxy}-nicotinamide

HRID 130910Notes

Reaction equation

HRID 130910 reaction equation
[CH3:1][NH:2][CH2:3][CH2:4][C:5]1[CH:20]=[CH:19][C:8]([O:9][C:10]2[CH:18]=[CH:17][C:13]([C:14]([NH2:16])=[O:15])=[CH:12][N:11]=2)=[CH:7][CH:6]=1.[CH:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C(=O)(O)[O-].[Na+]>ClCCCl.O1CCCC1>[CH2:21]([N:2]([CH3:1])[CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:9][C:10]2[CH:18]=[CH:17][C:13]([C:14]([NH2:16])=[O:15])=[CH:12][N:11]=2)=[CH:19][CH:20]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1

Participants

8

Reactant 5

HCID 176Acetic AcidHCID 240BenzaldehydeHCID 516892Sodium BicarbonateHCID 5049666Sodium triacetoxyborohydrideHCID 597303256-[4-(2-Methylamino-ethyl)-phenoxy]-nicotinamide

Product 1

HCID 597302926-{4-[2-(Benzyl-methyl-amino)-ethyl]-phenoxy}-nicotinamideYield 58%

Reagents, catalysts & solvents 2

HCID 111,2-DichloroethaneSolventHCID 8028TetrahydrofuranSolvent

Procedure

Combine 6-[4-(2-Methylamino-ethyl)-phenoxy]-nicotinamide (135 mg, 0.5 mmol), benzaldehyde (53 μL, 0.52 mmol), sodium triacetoxyborohydride (0.21 g, 1.0 mmol), acetic acid (30 μL, 0.52 mmol), tetrahydrofuran (1 mL), and 1,2-dichloroethane (5 mL) then stir at room temperature for 18 hours. Dilute the reaction with saturated aqueous sodium bicarbonate solution and extract with ethyl acetate (3×50 mL). Dry the combined ethyl acetate extracts with sodium chloride/magnesium sulfate, filter, and concentrate on a rotary evaporator to yield 200 mg of the crude product. The crude product is purified by flash column chromatography on silica gel eluting with (0.5% conc. ammonium hydroxide/5% ethanol) to (1% conc. ammonium hydroxide/10% ethanol) in chloroform to yield 6-{4-[2-(benzyl-methyl-amino)-ethyl]-phenoxy}-nicotinamide (106 mg, 0.29 mmol): m/z=362.07 (M+1); 1H NMR (CDCl3, 300.00 MHz): 8.58 (s, 1H); 8.16 (dd, 3.0 Hz, 1H); 7.33-7.22 (m, 7H); 7.05 (d, 2H); 6.95 (d, 1H); 5.86 (br s, 2H); 3.63 (s, 2H); 2.89-2.72 (m, 4H); 2.34 (s, 3H), HPLC=100% (5/95 to 95/5 ACN/(0.1%TFA in water) over 10 minutes, Zorbax® SB-Phenyl 4.6 mm×15 cm×5 micron, λ=254 nM.

Workup

  1. additionDilute
  2. extractionextract with ethyl acetate (3×50 mL)
  3. dry with materialDry the combined ethyl acetate
  4. filtrationfilter
  5. concentrationconcentrate on a rotary evaporator
  6. customto yield 200 mg of the crude product
  7. customThe crude product is purified by flash column chromatography on silica gel eluting with (0.5% conc. ammonium hydroxide/5% ethanol) to (1% conc. ammonium hydroxide/10% ethanol) in chloroform

Sources & evidence

ORD record
ord-fb5eac6ec7dd4a6eba876419dade4683
Source dataset
uspto-grants-2008_06
Patent number
US07381719B2

Reaction notes

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