With the rapid development and complex challenges of chemical substances, new drug synthesis pathways are usually the most effective.19365-08-3,3-Hydroxypiperidin-2-one,as a common compound, the synthetic route is as follows.
General procedure: Potassium carbonate or caesium carbonate (1.5-2.5 eq.) was baked in a reaction vessel under reduced pressure. It was cooled to RT and flooded with argon. Palladium acetate (0.1-0.36 eq.), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (Xantphos, 0.18-0.36 eq.) and dioxane (0.04-0.12M) were added, and the suspension was degassed in an argon stream at room temperature for 10 min. Subsequently, the appropriate amide (1.0-1.2 eq.) and the appropriate 7-chloro-4-oxo-1,4-dihydro-1,8-naphthyridine (1.0 eq.) were added. The mixture was stirred at 80-110 C. for 1 h (or until conversion was complete by analytical HPLC or thin-layer chromatography with appropriate eluent mixtures). The mixture was cooled to RT and all volatile components were removed under reduced pressure, or alternatively the reaction mixture was poured into water, the pH was adjusted to pH 1 with 1M aqueous hydrochloric acid, the mixture was extracted with ethyl acetate, the combined organic phases were washed with saturated aqueous sodium chloride solution, dried over magnesium sulphate and filtered, and the solvent was removed under reduced pressure. The crude product was then purified either by normal phase chromatography (eluent: cyclohexane/ethyl acetate mixtures or dichloromethane/methanol mixtures) or preparative RP-HPLC (water/acetonitrile gradient). According to GP2, 150 mg (283 mumol) of the compound from Example 80A were reacted with 39.1 mg (340 mumol) of rac-3-hydroxypiperidin-2-one in the presence of 58.7 mg (425 mumol) of potassium carbonate, 13 mg (57 mumol) of palladium(II) acetate and 33 mg (57 mumol) of Xantphos in 2.5 ml of dioxane. The crude product was purified by means of preparative HPLC (column: Chromatorex C18, 10 mum, 125*40 mm, solvent: acetonitrile/0.1% formic acid gradient; (0 to 3 min. 10% acetonitrile to 40 min. 90% acetonitrile and a further 3 min. 90% acetonitrile), and 102 mg (59% of theory, 100% purity) of the title compound were obtained. 1H NMR (400 MHz, DMSO-d6) delta [ppm]=11.34 (br. d, 1H), 8.89 (s, 1H), 8.70 (d, 1H), 8.17-8.09 (m, 1H), 7.94-7.75 (m, 1H), 7.68-7.56 (m, 2H), 7.41-7.27 (m, 3H), 6.51-6.39 (m, 1H), 5.52-5.46 (m, 1H), 4.27-4.17 (m, 1H), 3.71-3.58 (m, 1H), 3.54-3.40 (m, 1H), 2.12-2.01 (m, 1H), 1.86-1.71 (m, 1H), 1.71-1.57 (m, 1H). LC-MS (Method 3): Rt=2.11 min; 609 [M+H]+. 91.2 mg of the title compound (racemic diastereomer mixture) were separated into the enantiomeric diastereomers by chiral HPLC (preparative HPLC: column: Daicel Chiralpak AZ-H 5 mum 250×30 mm; eluent: 50% isohexane, 20% ethanol; temperature: 25 C.; flow rate: 50 ml/min; UV detection: 220 nm). This gave (in the sequence of elution from the column) 17.8 mg of diastereomer 1 (96.5% de) Rt=3.19 min, 14.5 mg (95% de) of diastereomer 2 Rt=4.21 min, 17.4 mg (97% de) of diastereomer 3 Rt=6.11 min, and 14.5 mg (97% de) of diastereomer 4 Rt=10.80 min. [Analytical HPLC: column: Daicel AZ-3 3 mum 50×4.6 mm; eluent: 50% isohexane, 50% ethanol; temperature: 30 C.; flow rate: 1 ml/min; UV detection: 220 nm] Example 248 1-(2,4-Difluorophenyl)-N-[1-(2,6-difluorophenyl)-2,2,2-trifluoroethyl]-7-[3-hydroxy-2-oxopiperidin-1-yl]-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide (diastereomer 1) 1H NMR (400 MHz, DMSO-d6) delta [ppm]=11.34 (br. d, 1H), 8.89 (s, 1H), 8.70 (d, 1H), 8.17-8.10 (m, 1H), 7.93-7.76 (m, 1H), 7.68-7.57 (m, 2H), 7.40-7.27 (m, 3H), 6.51-6.39 (m, 1H), 5.52-5.46 (m, 1H), 4.27-4.18 (m, 1H), 3.71-3.59 (m, 1H), 3.54-3.41 (m, 1H), 2.12-2.01 (m, 1H), 1.83-1.73 (m, 2H), 1.71-1.58 (m, 1H). LC-MS (Method 3): Rt=2.12 min; 609 [M+H]+. Example 249 1-(2,4-Difluorophenyl)-N-[1-(2,6-difluorophenyl)-2,2,2-trifluoroethyl]-7-[3-hydroxy-2-oxopiperidin-1-yl]-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide (diastereomer 2) 1H NMR (400 MHz, DMSO-d6) delta [ppm]=11.37-11.31 (m, 1H), 8.89 (s, 1H), 8.70 (d, 1H), 8.13 (dd, 1H), 7.94-7.75 (m, 1H), 7.68-7.56 (m, 2H), 7.41-7.26 (m, 3H), 6.51-6.38 (m, 1H), 5.52-5.46 (m, 1H), 4.27-4.16 (m, 1H), 3.72-3.58 (m, 1H), 3.53-3.39 (m, 1H), 2.12-2.01 (m, 1H), 1.83-1.73 (m, 2H), 1.72-1.57 (m, 1H). LC-MS (Method 3): Rt=2.13 min; 609 [M+H]+. Example 250 1-(2,4-Difluorophenyl)-N-[1-(2,6-difluorophenyl)-2,2,2-trifluoroethyl]-7-[3-hydroxy-2-oxopiperidin-1-yl]-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide (3rd diastereomer) 1H NMR (400 MHz, DMSO-d6) delta [ppm]=11.37-11.31 (m, 1H), 8.89 (s, 1H), 8.70 (d, 1H), 8.13 (dd, 1H), 7.94-7.75 (m, 1H), 7.68-7.56 (m, 2H), 7.40-7.26 (m, 3H), 6.51-6.39 (m, 1H), 5.52-5.46 (m, 1H), 4.26-4.17 (m, 1H), 3.72-3.59 (m, 1H), 3.52-3.40 (m, 1H), 2.12-2.01 (m, 1H), 1.84-1.73 (m, 2H), 1.72-1.58 (m, 1H). LC-MS (Method 3): Rt=2.12 min; 609 [M+H]+. Example 251 1-(2,4-Difluorophenyl)-N-[1-(2,6-difluorophenyl)-2,2,2-trifluoroethyl]-7-[3-hydroxy-2-oxopiperidin-1-yl]-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide (4th diastereomer) 1H NMR (400 MHz, DMSO-d6) delta [ppm]=11.34 (br. d, 1H), 8.89 (s, 1H), 8.70 (d, 1H), 8.17-8.09 (m, 1H), 7.93-7.76 (m, 1H), 7.68-7.57 (m, 2H), 7.40-7.2…
19365-08-3, As the paragraph descriping shows that 19365-08-3 is playing an increasingly important role.
Reference：
Patent; Bayer Pharma Aktiengesellschaft; TELLER, Henrik; STRAUB, Alexander; BRECHMANN, Markus; MUeLLER, Thomas; MEININGHAUS, Mark; NOWAK-REPPEL, Katrin; TINEL, Hanna; MUeNTER, Klaus; FLIEGNER, Daniela; MONDRITZKI, Thomas; BOULTADAKIS ARAPINIS, Melissa; MARQUARDT, Tobias; VAKALOPOULOS, Alexandros; REBSTOCK, Anne-Sophie; WITTWER, Matthias Beat; (342 pag.)US2018/297994; (2018); A1;,
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