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Compound V (5.00 g, 0.031 mol) was dissolved in dry dichloromethane (150 mL). Afterwards, oxalylchloride (5.25 mL, 0.062 mol) was added, followed by a catalytic amount of Nu,Nu-dimethylformamide (about 0.05 mL). The mixture was then stirred at room temperature under an inert atmosphere for 70 minutes and evaporated to dryness. The oily residue was dissolved in dry tetrahydrofuran (THF) (50 mL) and added to an aqueous ammonia (26percent, 100 mL) cooled in an ice-water bath. The mixture was stirred at 0-5 °C for 20 minutes and then additional 40 minutes at room temperature. After the reaction was completed, the mixture was poured into a separation funnel and extracted by EtOAc (2 x 250 mL). The combined organic extracts were washed with saturated NaHC03 solution (2 x 100 mL), dried over MgS04 and evaporated to dryness. The crude product was crystallized from z'PrOH/hexane to give the title compound as an off- white solid (3.41 g, 69percent).
(2E/Z, 4E)-N-Isobutyl 3-methyl-12-(1-chloro-3-isoquinolinyloxy)dodeca-2,4-dienamide Starting from 1-chloro-3-hydroxyquinoline and using the modified Stage a of Example CII 2-Nitrophenylacetic acid (ex Aldrich) (18.1 g) dissolved in 0.1M.aq.sodium hydroxide (100 ml) was subjected to catalytic hydrogenation (at 30-40 psi) over 10percent palladium on charcoal (2 g) until uptake ceased. The resultant solution was subjected first to diazotisation and then reaction with sodium cyanide and cuprous cyanide according to Simchen and Hafner, Ann. Chem., 1974, 1802 to give crude 2-cyanophenylacetic acid (14.9 g).
Compound V (50.0 g, 0.310 mol) was charged to a 1 L jacketed reactor and suspended in dry ethyl acetate (700 mL). Thionyl chloride (27.2 mL, 0.372 mol) was added in one portion and the mixture was then heated at 45 °C for 2 hours. The mixture was then concentrated at a temperature 40-50 °C and reduced pressure (50- 200 mbar) to a volume of approximately 600 mL. Afterwards, the residue was cooled to 0 °C , followed by addition of aniline (62.2 mL, 0.682 mol) dissolved in ethyl acetate (150 mL). The rate of the addition was controlled to keep the temperature of the reaction mixture below 25 °C. After the addition was finished, the mixture was stirred at room temperature for 30 minutes, followed by addition of 2.5percent aqueous NaCl (200 mL) and heating the obtained mixture to 40-45°C with stirring. When all of the solid material was dissolved, the water phase was separated. The solvent in the remaining phase was replaced by isopropanol (iPrOH) by adding and evaporating of iPrOH in several portions (4 x 100 mL), then the mixture was concentrated at 40- 45 °C under reduced pressure (50-200 mbar) to a volume of approximately 400 mL, followed by addition of water (200 mL). The mixture was cooled to 0 °C, stirred at the same temperature for 30 minutes and filtered. The obtained product was then washed with 50percent aqueous iPrOH (180 mL) and dried in an inert atmosphere at room temp overnight to give compound Ill-a as an off- white solid (67.1 g, yield 92percent>) with a HPLC purity of ~92percent>. The product was analyzed by PXRD, and the PXRD pattern is shown in Figure 4.
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