Acetonitrile → N-(3-methoxy-5-(3-methoxypropoxy)benzyl)cyclopropanamine

온도

-10 °C

A mixture of 3-hydroxy-5-methoxy-benzoic acid methyl ester (4.71 g, 25.9 mmol), K2CO3 (5.72 g, 41.4 mmol) and toluene-4-sulfonic acid 3-methoxy-propyl ester (8.18 g, 33.5 mmol) in DMA (60 ml) is stirred for 14 h at 140° C. The mixture is distributed between ethyl acetate and H2O. The aqueous layer is separated and extracted twice with ethyl acetate. The combined organic layers are dried (Na2SO4) and evaporated to afford crude 3-methoxy-5-(3-methoxy-propoxy)-benzoic acid methyl ester. MS: 255.3 [M+H]+; tR (HPLC, Nucleosil C18; 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 8 min, flow 1.5 ml/min): 6.12 min. A mixture of 3-methoxy-5-(3-methoxy-propoxy)-benzoic acid methyl ester (6.94 g, 27.3 mmol), aqueous 5N NaOH solution (25 ml, 125 mmol) and methanol (50 ml) is stirred for 1 h at 50° C. Methanol is evaporated and the residue distributed between 2N HCl and ethyl acetate. The aqueous layer is separated and extracted twice with ethyl acetate. The combined organic extracts are dried (Na2SO4) and evaporated to afford crude 3-methoxy-5-(3-methoxy-propoxy)-benzoic acid. tR (HPLC, Nucleosil C18; 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 8 min, flow 1.5 ml/min): 4.97 min. A mixture of 3-methoxy-5-(3-methoxy-propoxy)-benzoic acid (6.55 g, 27.3 mmol), thionyl chloride (19.8 ml, 273 mmol) in CH2Cl2/tetrahydrofuran (1:1; 30 ml) is stirred for 2 h at 45° C. The reaction mixture is evaporated in vacuo. After addition of CH2Cl2 (30 ml), the mixture is cooled to 5° C. and treated dropwise with cyclopropylamine. The cooling bath is removed and the reaction stirred for 14 h at RT. After dilution with CH2Cl2, the organic phase is washed with a saturated NaHCO3-solution, dried over Na2SO4 and evaporated to afford N-cyclopropyl-3-methoxy-5-(3-methoxy-propoxy)-benzamide. MS: 280.3 [M+H]+; tR (HPLC, Nucleosil C18; 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 8 min, flow 1.5 ml/min): 4.79 min. N-Cyclopropyl-3-methoxy-5-(3-methoxy-propoxy)-benzamide (7.92 g, 28.4 mmol) is diluted with tetrahydrofuran (50 ml), the mixture is stirred, cooled to −10° C. and treated by dropwise addition under N2 during 1 h of a borane tetrahydrofuran complex solution (˜1M in tetrahydrofuran, 85.2 ml, 85.2 mmol). The cooling bath is removed and stirring is continued for 14 h at RT. The reaction is quenched with H2O, acidified with 4N HCl, basified with 4N NaOH and extracted three times with ethyl acetate. The combined organic extracts are dried (Na2SO4) and evaporated. The borane complex thus received is treated with methanol (60 ml) and kept for 5 h at reflux temperature. Methanol is distilled off and the residue is stirred for a few minutes with 4N HCl. The mixture is basified with 4N NaOH and extracted three times with ethyl acetate. The combined organic extracts are dried (Na2SO4) and evaporated to yield cyclopropyl-[3-methoxy-5-(3-methoxy-propoxy)-benzyl]-amine as a brown oil. MS: 266.4 [M+H]+; tR (HPLC, Nucleosil C18; 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 8 min, flow 1.5 ml/min): 3.85 min.