Reference of 2475-80-1, In the chemical reaction process, reaction time, type of solvent, can easily affect the result of the reaction, thereby determining the yield and properties of the reaction product. An updated downstream synthesis route of 2475-80-1 as follows.
To 2-nitro-5-methoxy-benzoic acid (4 g, 20.3 mmol) in 35 mL of methanol was added trimethylsilyldiazomethane (35 mL, 70 mmol, 2 M in dichloromethane) at RT dropwise. The mixture was stirred at RT for 10 h. To the mixture was added several drops of acetic acid. The resulting solution was concentrated in vacuo to give a brown solid. To this intermediate was added 150 mg of Pd/C (10%). The mixture was stirred under 40 psi of hydrogen gas for 5 h. The mixture was filtered and washed with dichloromethane. The filtrate was concentrated m vacuo to give a dark red oil. To this aniline intermediate were added 30 mL of ethanol and 5 mL of concentrated HCl. To this mixture at 00C was dropwise added a solution of sodium nitrite (5.6 g, 81.2 mmol) in 15 mL of water to form the diaza salt. After 1 h at 00C, to the resulting dark red solution was slowly added sodium azide (8.6 g, 132 mmol) in 15 mL of water. After 1 h at O0C, the slurry was filtered and washed with saturated sodium carbonate solution and water to give the azide as a red solid. The same DIBALH reduction procedure as described above gave the benzyl alcohol as a dark red oil. To this oil in 100 mL of dichloromethane was added PCC (8 g) at O0C. The mixture was stirred at RT for 4 h and purified by Biotage (2-20% ethyl acetate in hexane) to give the aryl azide aldehyde intermediate as a light yellow solid. To a solution of this intermediate (1.1 g, 6.3 mmol), malononit?le (423 mg, 0 40 mL, 6 4 mmol) and 15 mL of dichloromethane was added a solution of pipe?dine (145 mg, 0.17 mL, 1.7 mmol) in 5 mL of dichloromethane. After 2 h at RT, the mixture was filtered and the solid was washed with dichloromethane to give the tricycle as a brown solid. To this intermediate (0.66 g, 2 9 mmol) m 10 mL of DME and 20 mL of dichloromethane was added DIBALH (7.04 mL, 7.04 mmol, 1 M in hexane) at – 780C The mixture was stirred at -780C for 3 days. The mixture was then quenched with water and saturated Rochelle’s salt (200 mL) at -780C. The aqueous layer was then extracted with 30% isopropyl alcohol in chloroform. The combined fractions were dried with sodium sulfate and concentrated in vacuo. The residue was purified by RP-HPLC to give a light yellow solid A similar homologation sequence described in EXAMPLE 86 gave the intermediate enamide. To a slurry of this enamide (18 mg) in 150 mL of methanol was added p-toluenesulfonylhydrazide (400 mg). The mixture was heated at reflux overnight. After removing the solvent, the residue was purified by RP-HPLC to give a pale yellow solid. Following the similar hydrolysis and demethylation procedures as described for the preparation of EXAMPLE 86, the desired compound was obtained as a white solid 1H NMR (CD3OD, 500 MHz) delta 8.50 (1H, d), 8.47 (1H, d), 8.00 (1H, d), 7.84 (1H, s), 7.52 (1H, t), 7.34 (1H, dd), 7.29 (1H, d), 7.11 (1H, t), 3.50 (2H, t), 3.06 (2H, t); LCMS m/z 378 (M++1).
According to the analysis of related databases, 2475-80-1, the application of this compound in the production field has become more and more popular.
Reference:
Patent; MERCK & CO., INC.; WO2006/52555; (2006); A2;,
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