Acetic Acid → 6-(2-Benzyl-1,2,3,4-tetrahydroisoquinolin-7-yloxy)nicotinamide

HRID 130944Notes

Reaction equation

HRID 130944 reaction equation
[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][C:12]3[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][N:13]=3)[CH:9]=2)[CH2:4][CH2:3][NH:2]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>[CH2:21]([N:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][C:8]([O:11][C:12]3[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][N:13]=3)=[CH:7][CH:6]=2)[CH2:1]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1

Participants

7

Reactant 5

HCID 176Acetic AcidHCID 240BenzaldehydeHCID 516892Sodium BicarbonateHCID 5049666Sodium triacetoxyborohydrideHCID 597299686-(1,2,3,4-Tetrahydro-isoquinolin-7-yloxy)-nicotinamide

Product 1

HCID 444340656-(2-Benzyl-1,2,3,4-tetrahydroisoquinolin-7-yloxy)nicotinamideYield 25.7%

Reagents, catalysts & solvents 1

HCID 111,2-DichloroethaneSolvent

Procedure

Combine 6-(1,2,3,4-tetrahydro-isoquinolin-7-yloxy)-nicotinamide (94 mg, 0.35 mmol), benzaldehyde (37 μL, 0.37 mmol), sodium triacetoxyborohydride (96 mg, 0.46 mmol), acetic acid (21 μL, 0.37 mmol), 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 5% methanol in dichloromethane (3×25 mL). Dry the combined 5% methanol in dichloromethane extracts with sodium chloride/magnesium sulfate, filter, and concentrate on a rotary evaporator to yield 100 mg of the crude product. The crude product is purified by flash column chromatography on silica gel eluting with 1% conc. ammonium hydroxide/10% ethanol in chloroform to yield 6-(2-benzyl-1,2,3,4-tetrahydro-isoquinolin-7-yloxy)-nicotinamide 2039910 (30 mg, 0.09 mmol): m/z=360.12 (M+1); 1H NMR (CDCl3, 300.00 MHz): 8.50 (d, 1H); 8.09-8.05 (m, 1H); 7.34-7.20 (m, 5H); 7.09 (d, 1H); 6.87-6.82 (m, 2H); 6.71 (d, 1H); 5.80 (s, 2H); 3.63-3.57 (m, 4H); 2.87-2.69 (m, 4H), HPLC=96% @ 2.98 m (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 5% methanol in dichloromethane (3×25 mL)
  3. dry with materialDry the combined 5% methanol in dichloromethane extracts with sodium chloride/magnesium sulfate
  4. filtrationfilter
  5. concentrationconcentrate on a rotary evaporator
  6. customto yield 100 mg of the crude product
  7. customThe crude product is purified by flash column chromatography on silica gel eluting with 1% conc. ammonium hydroxide/10% ethanol in chloroform

Sources & evidence

ORD record
ord-7b9a061237a04fe4b4917e41c5dcf54e
Source dataset
uspto-grants-2008_06
Patent number
US07381719B2

Reaction notes

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