3-Methyl-2-nitrobenzenecarboxamide To a solution of 3-methyl-2-nitrobenzoic acid (13.2 g) in tetrahydrofuran (150 ml) was added slowly at ambient temperature triethylamine (11.0 ml). After stirring for 30 minutes, the solution was cooled in an ice bath and ethyl chloroformate (7.6 ml) was added dropwise. Following the addition the thick mixture was stirred for 1 hour while maintaining the temperature at about 0°. Next, gaseous ammonia was bubbled through the well stirred mixture until it was well saturated (about 15 minutes). The cooling bath was removed and the mixture was allowed to warm slowly to ambient temperature with stirring for 2 hours. The mixture was partitioned between ethyl acetate and water; some gentle warming was required to solubilize all of the solid material. The layers were separated; the organic phase was washed with brine, dried over Na2 SO4 and concentrated to leave a white solid. Trituration with ether/hexane followed by filtration afforded the carboxamide (12.5 g, 95%); m.p. 189°-191°; tlc, Rf =0.08, silica gel, ethyl acetate:hexane (1:1).
A solution of 3-methyl-2-nitrobenzoic acid (50.00 g, 276 mmol) in dichloromethane (500 mL) and triethylamine (41 .83 g, 414 mmol) was cooled to 0 °C. Isopropyl chloroformate (50.74 g, 414 mmol) was added drop-wise and the reaction was stirred for 1 hour at 0 °C. Concentrated aqueous ammonium hydroxide (300 mL) was then added to the reaction, which was stirred for an additional 30 minutes at 0 °C. Filtration afforded C19 as a white solid. Yield: 41 .6 g, 231 mmol, 84%. 1H NMR (400 MHz, DMSO-c/6) δ 2.28 (s, 3H), 7.53-7.61 (m, 3H), 7.71 (br s, 1 H), 8.21 (br s, 1 H).
Preparation of (R)-alpha-ethyl-2-oxo-l -pyrrolidineacetamide from (R)-alpha-ethyl-2- oxo-1-pyrrolidineacetic acid; A suspension of (S)-alpha-ethyl-2-oxo-l-pyrrolidineacetic acid (35 g, 0.20 mol) in methylene chloride (225 ml) was cooled to 00C and triethylamine (41 g, 0.40 mol) and methanesulfonyl chloride (29 g, 0.26 mol) were added dropwise. The mixture was stirred at O0C for 30 min., then a stream of ammonia was purged in the solution at O0C for 2 hours. The insoluble solids were filtered and the filtrate was concentrated. The product was recrystallized from m ethyl isobutyl k etone to g ive 27.5g (78 %) of (R)- alpha-ethyl-2-oxo- 1 -pyrrolidineacetamide.
Methylene chloride (6000 mL), trans-4-isopropylcyclohexane (200 g) followed by para toluene sulfonyl chloride (208.38 g) and triethyl amine (409 mL) were added in a round bottom flask at 25-300C. The contents were maintained for 8 hours. D-Phenylalanine (150 g) was added to the above reaction mass over 30 minutes at 25-300C. The contents were maintained for 18 hours. 778 mL of 10% HCL solution was added to the reaction mass and stirred for 30 minutes. Methylene dichloride layer was taken and 1500 mL DM water was added and the mixture was stirred for 30 minutes repeatedly twice. The organic layer was dried with sodium sulphate (5 g), filtered and distilled off completely at 35- 400C. Methylene chloride (400 mL) and 1600 mL of cyclohexane was added into above crude at 25-300C. The contents were heated to 60-650C (minimum 3 to 4 hours), and then maintained the contents for 1 hour at 0-50C. Filtered, washed with chilled cyclohexane (200 mL) and dried under vacuum for 8-10 hours at 50-550C to get the title compound (216 g, 75%).
4- (N,N-dimethylamino)pyridine (36.6 g, 0.3 mol) was added to a stirred suspension of 5- chlorothiophene-2-carboxylic acid (16.25 g, 0.1 mol) in dichloromethane ( 162 ml) at 0- 5°C and the resulting solution was stirred for 10 minutes. A mixture of p-toluenesulfonyl chloride ( 19.05 g, 0.1 mol) and dichloromethane (50 ml) was added to the above solution at -5°C. The resulting solution was stirred for 1 hour at -5°C to produce a reaction mass containing the sulfonyl ester intermediate, followed by portion wise addition of 4-[4-[(5S)- 5- (aminomethyl)-2-oxo- l ,3-oxazolidin-3-yl]phenyl] morpholine-3-one (29.1 g, 0.1 mol, chiral purity: 99.9%). The reaction mixture was stirred for 2 hours at 25-30°C, followed by the addition of water ( 1 62 ml) and then stirring for 15 minutes. The separated solid was filtered, washed with dichloromethane (50 ml) and water ( 100 ml), and the resulting wet material was dried at 80-85°C for 3 to 5 hours to produce 37.3 g of pure rivaroxaban as a white crystalline solid (Theoretical Yield: 85.6%; Purity by HPLC: 99.9%; and Chiral Purity by HPLC: 99.9%). )
To acid 5 (4.0 g, 14.1 mmol) in CH2Cl2 (70 mL) at 23℃ was added 1, 1’-carbonyldiimidazole (3.65 g, 22.5 mmol) in equal portions over 15 min. After the final addition, stirring was continued for 10 min, then N,O-dimethylhydroxylamine • HCl (3.43 g, 35.16 mmol) was added in one portion. The reaction was allowed to stir at 23℃ for 3 h. Et2O was added (50 mL) and the reaction mixture was filtered. The filtrate was evaporated, diluted with Et2O (125 mL), washed with 5% aq. citric acid (2 x 50 mL) and brine (50 mL), and dried over MgSO4. The crude product was purified by flash chromatography (3:1 hexanes: EtOAc) to afford Weinreb amide 6 (4.29 g, 93% yield) as a colorless oil. Rf 0.42 (2:1 hexanes:EtOAc); 1H NMR (300 MHz, CDCl3): δ 5.43 (m, 1H), 4.72 (s, 1H), 4.17-4.11 (m, 1H), 3.71 (s, 3H), 3.22 (s, 3H), 2.59-2.24 (comp. m, 3H), 2.03 (dd, J = 14.6 Hz, 4.1 Hz, 1H), 1.75-1.71 (m, 3H), 0.86 (s, 9H), 0.11 (s, 3H), 0.09 (s, 3H).
To a strirred solution of 2chloro3nitro5(trifluoromethyl)benzoic acid (2.7 g, 10 mmol, 1.0 equiv.), pyridine (0.50 ml,6.2 mmol, 0.62 equiv.), and Boc2O(2.8 g, 13.0 mmol, 1.3 equiv.)in 1,4-dioxane (10 ml) at room temperature was added ammonium bicarbonate (1.00 g, 12.6 mmol, 1.26 equiv.). The reaction was stirred overnight at room temperature and then partitioned between EtOAc (50 ml) and H2O (50 ml). The organic layer was separated, washed consecutively with water 50 ml) and 0.6 N aqueous HCl (50 ml), dried (Mg2SO4), and filtered. The filtrate was concentrated under reduced pressure to provide 2 as a white solid [yield 2.42 g, 90%; m.p. 190-193 C; literature (Welch et al., 1969) 195-197 C]. 1H NMR and MS data are consistent with previously reported spectra(Cooper et al., 2013).