Methyl 2-(cyanoMethyl)-3-Methoxybenzoate synthesis

Yield: 95%

Reaction Conditions:

with sodium iodide in N,N-dimethyl-formamide;acetonitrile for 10 h;Heating / reflux;

Steps:

1.9 1.9
Into a 500 mL 3-neck round bottom flask was added 10 g (61.75 mmol) of 2-bromomethyl, 3-methoxy methyl benzoate, 4.0 g (81.6 mmol) of NaCN, 0.30 g (2 mmol) of NaI, 100 mL of CH₃CN, and 50 mL of DMF. The reaction mixture was heated and refluxed for 10 hours. The precipitate (NaBr) was filtered off, and the solution was concentrated on an evaporator. 300 mL of water and 200 mL of ether were added and then shaken in a separatory funnel. The water was extracted twice with 100 mL of ether. The ether fractions were dried over MgSO₄, and concentrated to yield methyl 3-methoxy-2-cyanomethylbenzoate (95-100% yield). This ester (0.053 mmol, 10.51 g) was stirred vigorously in 100 mL of CH₃OH. Ba(OH)₂ H2O (0.079 mmol, 14.97 g) was added and the mixture stirred at room temperature overnight. The CH₃OH was removed on a rotary evaporator. 150 mL of water, 200 mL of CH₂Cl₂, and 50 mL of 6N HCl were added, and then stirred in a flask to dissolve all residues. The mixture was transferred to a separatory funnel, acidified with 6N HCl to pH 1-2. The CH₂Cl₂ phase was separated and the aqueous phase extracted twice with 50 mL of CH₂Cl₂. The CH₂Cl₂ extracts were combined, dried over MgSO₄ and charcoal, filtered, and evaporated to yield 8.8 g of a white solid, 2-cyanomethyl-3-methoxybenzoic acid, (87%). Methyl 3-methoxy-2-cyanomethylbenzoate: ¹H NMR (CDCl₃, 300 MHz) δ (ppm): 7.6 (d, 1H), 7.4 (t, 1H), 7.1 (d, 1H), 4.18 (s, 2H), 3.94 (s, 3H), 3.926 (s, 3H). TLC (1:1 ethyl acetate: hexane) 0.55. 2-Cyanomethyl-3-methoxybenzoic acid: ¹H NMR (300 Mhz, CDCl₃) δ (ppm): 7.55 (d, 1H), 7.45 (t, 1H), 7.3 (d, 1H), 4.121 (d, 2H), 3.91, (s, 3H). TLC (1:1 ethyl acetate: hexane

References:

Hormann, Robert Eugene;Potter, David W.;Chortyk, Orestes;Tice, Colin M.;Carlson, Glenn Richard;Meyer, Andrew;Opie, Thomas R. US2006/20146, 2006, A1 Location in patent:Page/Page column 32