|
With hydroxylamine; In water; dimethyl sulfoxide; at 75℃; for 36h;Inert atmosphere;Product distribution / selectivity; |
Example 16Ethyl 2-ethoxy-l -((2'-((hydroxyamino)iminomethyl)biphenyl-4-yl)methyl)-lH-benzo[flf]- imidazole-7-carboxylate (lb) - using aqueous hydroxylamineA 50 % (w/w) aqueous solution of hydroxylamine (3 ml) was added to a stirred mixture of the nitrile (IVb, 8.6 g, 20 mmol) and DMSO (60 ml) and the mixture was stirred under nitrogen at the temperature of 75 C for 17 h. Then, another 50 % aqueous hydroxylamine (2 ml) was added and heating was continued for another 7 h. According to HPLC, the mixture contains 72.8 % of the product (lb), 20.2 % of the starting nitrile (IVb) and 2.3 % of the desethyl nitrile (VIb). After addition of another 50 % aqueous hydroxylamine (2 ml) the heating was continued for another 12 h. According to HPLC, the mixture contains 91.3 % of the product (lb), 0.5 % of the starting nitrile (IVb) and 2.9 % of the desethyl nitrile (VIb). After cooling, water (50 ml) was added dropwise, the mixture was stirred for 30 minutes and then the insoluble fraction was aspirated and washed with water (100 ml). After drying, 8.9 g of the product (97.1 %) were obtained containing, according to HPLC, 98.6 % of the product (lb), 0.3 % of the starting nitrile (IVb) and 0.2 % of the desethyl nitrile (VIb). By crystallizing a sample from ethyl acetate, an absolutely pure product (according to HPLC) was obtained, having a melting point of 209-21 1 C. NMR spectrum (DMSO-cft5): NMR (500 MHz, DMSO) delta (ppm): 9.19 (bs, 1H, OH), 7.69 (dd, J = 7.9, 1.2 Hz, 1H, Ar), 7.46 (dd, J = 7.9, 1.2 Hz, 1H, Ar), 7.45-7.32 (m, 3H, Ar), 7.35 (d, J = 8.4 Hz, 2H, Ar), 7.27 (dd, J = 7.6, 1.5 Hz, 1 H, Ar), 7.19 (t, J = 7.9 Hz, 1H, Ar), 6.93 (d, J = 8.4 Hz, 2H, Ar), 5.55 (bs, 2H, NH2), 5.53 (s, 2H, N-CH2-Ar), 4.62 (q, J = 7.1 Hz, 2H, OCH2CH3), 4.22 (q, J = 7.1 Hz, 2H, COOCH2CH . 1.42 (t, J= 7.1 Hz, 3H, OCH2CH3), 1.18 (t, J = 7.1 Hz, 3H, COOCH2CH3). |
|
With hydroxylamine; In ethanol; at 75℃; |
(1) Preparing a hydroxylamine ethanol solution, mixing the hydroxylamine ethanol solution and the starting material in the reaction vessel, the molar ratio of hydroxylamine to the starting material in the hydroxylamine ethanol solution is 1.1:1, heating to 75 C, refluxing, and the reaction is finished. Thereafter, the mixture was cooled, filtered, and the filter cake was added to a mixed solution of 0.5 N hydrochloric acid and ethanol. The volume ratio of hydrochloric acid to ethanol was 1:4, stirred, and then filtered, and a 1 N sodium hydroxide solution was added dropwise to the filtrate to adjust the pH. Until the solid is precipitated, then filtered and washed with cold ethanol to give intermediate 1 and dried; |
|
With hydroxylamine hydrochloride; sodium hydrogencarbonate; In dimethyl sulfoxide; at 25 - 85℃; |
Put 39.2g of hydroxylamine hydrochloride and 240mL of dimethyl sulfoxide into a four-necked flask, stir until dissolved, add 65.52g of sodium bicarbonate at 25 C, warm to 50 C, stir for 50min, add raw materials (AQST- SM) 20g, heated to 80-85 C, holding reaction for 20-22 hours, TLC spot plate reaction was almost complete (no obvious spots of AQST-SM);After the reaction, drop to room temperature, add 480 mL of water dropwise, stir for 0.5 hours, filter, rinse the filter cake with 80 ml of purified water, and filter to dryness; transfer the filter cake to the flask, add 160 ml of isopropanol, and raise the temperature to 60-65 , stir and beat for 45 50min, cool down to room temperature, filter, rinse the filter cake with a small amount of isopropanol, suction filter to dryness; place the wet product of AQST-1 on a plate, and dry under reduced pressure in a vacuum oven at 50 C until the weight , Collect powder to get AQST-1; |