3-[2-(dimethylamino)ethoxy]-4-methoxybenzenamine synthesis

Yield:170229-68-2 98%

Reaction Conditions:

with hydrogen;palladium 10% on activated carbon in ethanol; under 2585.81 Torr;

Steps:

22

To a solution of 2-methoxy-5-nitro-phenol (10 g) , (2-chloro- ethyl) -dimethyl-amine hydrochloride (9.37 g) in dimethylformamide (15OmL) was added NaH (2.98 g) slowly under N₂ and at room temperature. The mixture was then stirred at 140 ⁰C heating with an oil bath for 5 hours. The reaction was concentrated to dryness, dissolved in 2 M HCl (200 iuL) and washed with ethyl acetate (2x100 mL) . The aqueous layer was basified with K₂CO3, extracted with dichloromethane (3x200 mL) EPO and ethyl acetate (2x100 ?iL) , dried over Na₂SO₄, filtered, concentrated to give [2- (2-Methoxy-5-nitro-phenoxy) -ethyl] - dimethylamine (9.17 g, 65% yield). LCMS (m/z) M+H: 241.1.The preceding product (10.53 g) and 10% Pd/C (1 g) were mixed with EtOH (200 mL) and hydrogenated at 50 psi overnight. The reaction mixture was filtered through a Celite plug, and the filter cake was washed with MeOH. The filtrate was concentrated to dryness to give 3- (2-dimethylamino-ethoxy) -4- methoxy-phenylamine (9.05 g, 98% yield). LCMS (m/z) M+H: 211.2.2-bromo-4- (6, 6-dimethyl-4-oxo-3-trifluoromethyl-4, 5, 6, 7- tetrahydro-indazol-1-yl) -benzonitrile (500 mg, 1 eq) , 3- (2- dimethylamino-ethoxy) -4-methoxy-phenylamine (306 mg, 1.2 eq) , Pd(OAc)₂ (14 mg) , DPPF (66 mg) , and NaOtBu (214 mg, 2 eq) were mixed in toluene (5 mL) and microwaved at 140°C for 25 minutes. Then 10 mL of EtOH (4) /H₂O (1) were added, followed by NaOH (700 mg, 2 eq) and H₂O₂ (1 mL) . The mixture was microwaved at 100°C for 15 min, then concentrated to dryness, and purified by flash chromatography, eluting with 20% EtOH in dichloromethane to give the title compound (480 mg, 71% two-step yield) . LCMS (m/z) : M+H = 560.3.

References:

WO2006/91963,2006,A1 Location in patent:Page/Page column 106-107