2-METHOXY-BENZAMIDINE HCL synthesis

Yield:51818-19-0 80%

Reaction Conditions:

Stage #1: 2-methoxy-benzonitrilewith lithium hexamethyldisilazane in diethyl ether;hexane at 0 - 20; for 72 - 72.0833 h;
Stage #2: with hydrogenchloride in diethyl ether;hexane;water; for 0.5 h;Product distribution / selectivity;

Steps:

26.a; 153.a; 168.a

To anhydrous ether at O⁰C was introduced to flask under argon, LiHMDS (94 ml, 93.9 rηmol) was introduced and stirred for 5 min_^2-methoxy-benzonitrile (5g, 37.6 mmol) was then added and the mixture was stirred at room temperature for 3 days. When all the starting material is consumed the reaction mixture was concentrated and 200 mL of cold 1 N HCI was added and stirred for 0.5 h. The aqueous layer was extracted with diethyl ether then adjusted the pH of the aqueous layer to 13 by addition of 6N NaOH. The 2-(methyloxy)benzenecarboxirnidamide free base was extracted with dichloromethane (x3). The combined organic layers were dried over Na₂SO₄ and concentrated to give pure product in 91% yield.; 2-Methoxybenzonitrile (5 g, 37.5 mmol) was added to a 0 ⁰C solution of LiHMDS (94 ml_, 1M in hexanes) in anhydrous Et₂O (75 mL, 0.5 M) under N₂. After warming to room temperature, the mixture stirred for three days. The resulting reaction mixture was quenched by the addition of 1 N HCI. The layers were separated and the aqueous phase was extracted 2 times with Et₂θ. The aqueous layer was cooled in an ice-bath, adjusted to pH 12, and extracted 3 times with dichlormethane. The organic portions were pooled, dried over Na₂SO₄, and concentrated to a brown oil which solidified to a brown solid under vacuum (4.5 g, 80% yield): ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.57 (dd, J=7.58, 1.77 Hz, 1 H) 7.35 - 7.41 (m, 1 H) 6.94 - 7.03 (m, 2 H) 5.24 (s, 3 H) 3.89 (s, 3 H),; At O ⁰C anhydrous ether was introduced to flask under Argon, LiHMDS (94 ml, 93.9 mmol) was then introduced and stirred for 5 mins. 2-Methoxy-benzonitrile (5g, 37.6 mmol) was added and the mixture was stirred at room temperature for 2-3 days. When all the starting material was consumed, solvent was removed and 200 mL cold 1N HCl was added and stirred to make HCI salt. Extracted with Et₂O (3X 300 mL) and then pH was adjusted to 13 by 6N NaOH. Extraction with CH₂CI2 and dried over Na₂SO₄. Filtered and the filtrate was concentrated to obtain the above benzamidine compound in 91 % yield.

References:

WO2007/62370,2007,A2 Location in patent:Page/Page column 58; 148; 159