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Preparation of 2-Methyl-3-Trifluoromethyl-Aniline A solution of 2,2,2'-trimethyl-3'-trifluoromethyl-propionanilide (10 g.) in 75 ml. ethanol and 75 ml. concentrated HCl was refluxed for 24 hours. The reaction mixture was then concentrated in vacuo and diluted with water. It was then basified with 10percent NaOH solution and extracted with ether. The ether extract was washed with water and brine and dried with MgSO4. Removal of ether gave a pale brown liquid (6.65 g., 98.5percent) which was purified by distillation under reduced pressure (b.p. 108°-110° C., 30 mm.) to give 5.73 g. of 2-methyl-3-trifluoromethyl-aniline which solidified on standing. The physical and spectroscopic properties of the product were found to be identical to those of an authentic sample of 2-methyl-3-trifluoromethyl-aniline prepared by the known method below. STR2
The CH2 Cl2 extracts are dried over K2 CO3 and evaporated to give 2-methyl-3-trifluoromethyl-aniline (MTA) (6.5 g, 96percent yield), an oil which solidifies on standing. STR13 iv.) A mixture of 2-methyl-3-trifluoromethylaniline (368 g, 2.1 moles) and 2-chloronicotinic acid (158.0 9, 1.0 mole) in 400 ml of water is heated at 100° C. for 24 hours together with p-toluenesulfonic acid (15.0 g) monohydrate as the acid catalyst. Potassium hydroxide (ca. 145 g) in water (255 ml) is added and the pH is maintained above 11. After diluting the reaction mixture to 1.2 liters with water, the mixture is cooled to 50° C., adjusted to pH 11, treated with 7 g of a decolorizing charcoal and 15 g of a filter aid, and clarified by filtration. The filtrate is diluted with 750 ml of water and the pH is adjusted to 5.0 with concentrated sulfuric acid.
96%
iii.) 2-methyl-3-trifluoromethylpivalanilide (10.0 g)is hydrolyzed by refluxing in concentrated HBr (40 ml, 48percent) for 3 hours. The mixture is cooled to 20° C. and poured onto ice-water (40.0 g). The pH is adjusted to 9 with concentrated NaOH and the mixture is extracted with two. 30 ml portions of CH2 Cl2. The CH2 Cl2 extracts are dried over K2 CO3 and evaporated to give 2-methyl-3-trifluoromethyl-aniline (MTA) (6.5 g, 96percent yield), an oil which solidifies on standing. STR13
Following the procedure of Example 1, the following substituted aniline compounds:...3-fluoro-2-methylaniline3-iodo-2-methylaniline3-trifluoromethyl-2-methylaniline
With hydrogenchloride; sodium sulfate; In water; at 35 - 75℃; for 3.5h;
Example 135 Synthesis of (+/-)-Isopropyl 5- [acetyl- (3, 5-bistrifluoromethylbenzyl) amino]-9-methyl-8- trifluoromethyl-tetrahydrobenzo [b] azepine-1-carboxylate Step 1. Preparation of 7-methyl-6-trifluoromethyl-lH-indole, 2,3-dione To a solution of chloral hydrate (6.08 g, 36.74 mmol) and anhydrous sodium sulfate (28.5 g, 200.4 mmol) in water (102 mL) add a mixture of hydroxylamine sulfate (28.5 g, 173.68 mmol), 2-methyl-3-trifluoromethyl-phenylamine (5.85 g, 33.4 mmol), concentrated hydrochloric acid (3.5 mL) in water (34 mL). Heat the mixture at 35 °C for 1 h, then heat up to 52 °C for 90 min and at 75°C for 1 hr. Cool the mixture to room temperature and filter the solid. Wash the solid with water and hexane. Dry the solid under vacuum to afford 2-hydroxyimino-N- (2-methyl-3-trifluoromethyl-phenyl)- acetamide. MS (ES+): 245 (M-H). Add the former crude in small portions at 60°C to concentrated sulfuric acid (44 mL) and heat the mixture at 80°C for 1 h. Cool to room temperature, pour into ice water (100 mL) and filter the precipitate. Wash the solid with cool water twice. Dry the solid to afford the title compound (3.54 g, 46percent two steps). MS (ES-): 228 (M-H).
With hydrogenchloride; hydroxylamine sulfate; sodium sulfate; In water; at 35 - 75℃; for 3.5h;
Example 53; Synthesis of (+/-)-isopropyl 5-[(3,5-bistrifluoromethyl-benzyl)-(2-methyl-2fl-tetrazol-5-yl)-amino]-9-methyl-8-trifluormethyl-2,3,4,5-tetrahydrobenzo[]azepine-l-carboxylate; Step 1; Preparation of 7-methyl-6-trifluoromethyl-lH-indole,2,3-dione; To a solution of chloral hydrate (6.08 g, 36.74 mmol) and anhydrous sodium sulfate (28.5g, 200.4 mmol) in water (102 mL) add a mixture of hydroxylamine sulfate (28.5 g,173.68 mmol), 2-methyl-3-trifluoromethyl-phenylamine (5.85 g, 33.4 mmol),concentrated hydrochloric acid ( 3.5 mL) in water (34 mL). Heat the mixture at 35 °C for1 h, then heat up to 52 °C for 90 min and at 75 °C for 1 h. Cool the mixture to roomtemperature and filter the solid. Wash the solid with water and hexane. Dry the solidunder vacuum to afford 2-hydroxyimino-N-(2-methyl-3-trifluoromethyl-phenyl)-acetamide: MS (ES+): 245 (M-H). Add the former crude in small portions at 60 °C toconcentrated sulfuric acid (44 mL) and heat the mixture at 80 °C for 1 h. Cool to roomtemperature, pour into ice water (100 mL) and filter the precipitate. Wash the solid withcool water twice. Dry the solid to afford the title compound (3.54 g, 46percent two steps).
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