Preparation of 2-ethoxybenzamidine hydrochloride_Kain Industrial Additive

Background and overview^[1]

2-Ethoxybenzamidine hydrochloride is a pharmaceutical intermediate that can be prepared from 2-ethoxybenzonitrile in one step. There are reports in the literature that 2-ethoxybenzamidine hydrochloride can be used to prepare phosphodiesterase inhibitors.

Preparation^[1]

Suspend 21.4 g (400 mmol) ammonium chloride in 375 ml toluene and cool the suspension to 0°C. 200 ml of 2M trimethylaluminum in hexane were added dropwise and the mixture was stirred at room temperature until gas evolution had ceased. 29.44 g (200 mmol) of 2-ethoxybenzonitrile were added and the reaction mixture was stirred at 80 °C (bath) overnight. The cooled reaction mixture was added to a suspension of 100 g of silica gel and 950 ml of chloroform under ice cooling, and the mixture was stirred at room temperature for 30 minutes. The mixture was suction filtered, and the filter residue was washed with the same amount of methanol. The mother liquor is evaporated, the residue obtained is stirred with a mixture of methylene chloride and methanol (9:1), the solid is suction-filtered, and the mother liquor is evaporated. Obtained 30.4 g (76%) of colorless solid. 200 MHz ¹H-NMR (DMSO-d6): 1.36 (t, 3H); 4.12 (quart., 2H); 7.10 (t, 1H); 7.21 (d, 1H); 7.52 ( m, 2H); 9.30 (s, broad, 4H).

Apply^[1]

US6476029 reports that 2-ethoxybenzamidine hydrochloride can be used to prepare the above compounds and their derivatives. The above compounds are potent inhibitors of one or more phosphodiesterases (cGMP-PDEs). Increased cGMP concentrations can lead to beneficial anticoagulant, antithrombotic, antivasospasm, vasodilation and diuretic effects. It can affect short- or long-term regulation of muscle and heart strength, impulses, and cardiac conduction.

References

[1] US6476029