Application of 3718-04-5, 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 3718-04-5 as follows.
Example 35 (E)-2-(4-fluorophenyl)- 1 -methyl- 1 -(4-(2-( 1 -propyl- lH-imidazol-4-yl)vinyl)phenyl)- 1.2.3.4- tetrahvdroisoquinolin-6-ol To a 30 mL vial, 4-vinyl-lH-imidazole (400 mg, 4.25 mmol) was dissolved in THF (2 mL) and the solution was cooled to 0 C. The reaction vial was charged with 60% sodium hydride in mineral oil (170 mg, 4.25 mmol) and the reaction mixture stirred for 10 min at 0 C. To the mixture was added 1-iodopropane (0.415 mL, 4.25 mmol) and the reaction was stirred overnight at room temperature. The reaction was quenched with saturated ammonium chloride (15 mL) and diluted with dichloromethane (25 mL). The organic phases were combined, passed through a phase separator and concentrated to afford the crude product. The crude material was purified by column chromatography (1-10% dichloromethane/methanol) to afford a mixture of l-propyl-4-vinyl-lH-imidazole and l-propyl-5-vinyl-lH-imidazole (511 mg, 3.72: 1). l-propyl-4-vinyl-lH-imidazole: NMR (400 MHz, CHLOROFORM-^ delta 0.83 – 0.91 (m, 3 H), 1.66 – 1.82 (m, 2 H), 3.74 – 3.90 (m, 2 H), 5.11 (dd, J=11.12, 1.52 Hz, 1 H), 5.73 – 5.87 (m, 1 H), 6.52 (dd, J=17.18, 11.12 Hz, 1 H), 6.80 (s, 1 H), 7.58 (s, 1 H). l-propyl-5-vinyl-lH-imidazole: NMR (400 MHz, CHLOROFORM-^ delta 0.78 – 0.93 (m, 3 H), 1.63 – 1.82 (m, 2 H), 3.76 – 3.90 (m, 2 H), 5.22 (d, J=11.12 Hz, 1 H), 5.57 (d, J=17.18 Hz, 1 H), 6.41 (dd, J=17.43, 11.37 Hz, 1 H), 7.17 (s, 1 H), 7.63 (s, 1 H). To a microwave vial, l-(4-bromophenyl)-2-(4-fluorophenyl)-6-methoxy-l- methyl- 1, 2,3 ,4-tetrahydroisoquinoline (0.13 g, 0.305 mmol) was dissolved in DMF (2 mL) and triethylamine (213 mu^, 1.525 mmol). To the solution was added a mixture of 1 -propyl -4-vinyl- lH-imidazole and l-propyl-5 -vinyl- lH-imidazole (125 mg, 0.915 mmol) and Pd(PPh3)2Cl2 (0.032 g, 0.046 mmol). The system was flushed with nitrogen and heated at 150 C for 1 h under microwave radiation. The mixture was cooled to room temperature and quenched with saturated ammonium chloride. The reaction mixture was extracted with dichloromethane (3 x), the organic layers were combined, passed through a phase separator, and concentrated to give crude material. The crude material was purified by silica gel chromatography (0-75% ethyl acetate/heptanes) to afford mixture of two isomers (141 mg, 0.293 mmol, 96% yield). LC MS (m/z, MH+): 482.1. A mixture of (E)-2-(4-fluorophenyl)-6-methoxy-l-methyl-l-(4-(2-(l-propyl- lH-imidazol-4-yl)vinyl)phenyl)- 1,2,3 ,4-tetrahydroisoquinoline and (E)-2-(4-fluorophenyl)-6- methoxy- 1 -methyl- 1 -(4-(2-( 1 -propyl- 1 H-imidazol-5-yl)vinyl)phenyl)- 1 ,2,3 ,4- tetrahydroisoquinoline (0.141 g, 0.293 mmol) was dissolved in dichloromethane (2.93 mL) and cooled to 0 C. Ethanethiol (404 mu , 5.46 mmol) was added followed by aluminum chloride (293 mg, 2.196 mmol). The reaction was warmed to room temperature and stirred for 3 h. The reaction was quenched with water and brought to pH 6 with saturated sodium bicarbonate. The aqueous layer was extracted thrice with dichloromethane. The organic layers were combined, passed through a phase separator, and concentrated. The crude material was purified by silica gel chromatography (0-75% ethyl acetate/heptanes) to afford a mixture of the two isomer products (69 mg). This mixture was urified via SFC (25% methanol with 10 mM ammonium hydroxide in carbon dioxide) to provide one single isomer (E)-2-(4-fluorophenyl)- 1 -methyl- l-(4-(2-(l -propyl- lH-imidazol-4-yl)vinyl)phenyl)-l,2,3,4-tetrahydroisoquinolin-6-ol as a white solid (17 mg, 12% yield). LC MS (m/z, MH+): 468.2. NMR (400 MHz, METHANOL-^) delta 0.86 (t, J=7.33 Hz, 3 H), 1.56 (s, 3 H), 1.78 (sxt, J=7.28 Hz, 2 H), 2.73 – 2.84 (m, 1 H), 2.93 – 3.05 (m, 1 H), 3.09 – 3.17 (m, 1 H), 3.31 – 3.40 (m, 1 H), 3.96 (t, J=7.07 Hz, 2 H), 5.39 (s, 1 H), 6.37 – 6.44 (m, 1 H), 6.45 – 6.61 (m, 5 H), 6.62 – 6.70 (m, 2 H), 6.85 – 6.95 (m, 1 H), 7.00 – 7.11 (m, 3 H), 7.27 (d, J=8.08 Hz, 2 H).
According to the analysis of related databases, 3718-04-5, the application of this compound in the production field has become more and more popular.
Reference:
Patent; NOVARTIS AG; BURKS, Heather Elizabeth; KARKI, Rajeshri Ganesh; KIRBY, Christina Ann; NUNEZ, Jill; PEUKERT, Stefan; SPRINGER, Clayton; SUN, Yingchuan; THOMSEN, Noel Marie-france; WO2015/92634; (2015); A1;,
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