Researchers who often do experiments know that organic synthesis is a process of preparing more complex target molecules from simple raw materials through one or more chemical reactions. Generally, it requires fewer steps,and cheap raw materials. 761440-16-8, name is 2,5-Dichloro-N-(2-(isopropylsulfonyl)phenyl)pyrimidin-4-amine. A new synthetic method of this compound is introduced below., Safety of 2,5-Dichloro-N-(2-(isopropylsulfonyl)phenyl)pyrimidin-4-amine
Isopropanol (445 kg) was added to 2,5-dichloro-N-(2-(isopropylsulfonyl)phenyl)pyrimidin-4-amine (70.2 kg, 203 mol, 1.15 eq.) and 2-Isopropoxy-5-methyl-4-(piperidin-4-yl)aniline dihydrochloride (56.7 kg, 176 mol). The mixture was heated for approx. 16 hours at reflux. Water (47 kg) was added and the mixture cooled to 0 C. The solid was filtered and washed with isopropanol/water. To the wet product, isopropanol (680 kg) and water (55 kg) was added and the slurry heated to reflux. The obtained clear solution was cooled to 0 C., filtered and dried under vacuum to yield 5-chloro-N2-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine dihydrochloride (=ceritinib dihydrochloride; 84.5 kg [t.q., contains 10% w/w isopropanol], 76.0 kg [100%], 68% yield). Ethanol (155 kg) and water (113 kg) were added to 5-chloro-N2-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-dihydrochloride; 45.0 kg [t.q., contains 10% w/w isopropanol], 40.5 kg [100%], 64.2 mol) and the mixture heated to 55 C. Aqueous NaOH (147 L of a 1 M solution, 2.3 eq.) was added slowly and then cooled to 20 C. After filtration, the product was recrystallized from ethanol and dried under vacuum to yield ceritinib (33.2 kg, 93% yield based on ceritinib dihydrochloride) as an almost white powder. 1H-NMR (400 MHz, CDCl3): delta=1.33 (d, J=6.8 Hz, 6H), 1.38 (d, J=6.1 Hz, 6H), 1.59-1-78 (m, 5H), 2.18 (s, 3H), 2.75-2.83 (m, 3H), 3.20-3.24 (m, 2H), overlaps 3.28 (sept, J=6.8 Hz, 1H), 4.56 (sept, J=6.1 Hz, 1H), 6.82 (s, 1H), 7.25-7.29 (m, 1H), 7.56 (br. s, 1H), 7.64 (m, 1H), 7.94 (m, 1H), 8.01 (br. s, 1H), 8.16 (br. s, 1H), 8.60 (m, 1H), 9.51 (br. s, 1H) ppm. 13C-NMR (100 MHz, CDCl3): delta=15.4, 18.9, 22.3, 33.9, 38.6, 47.5, 55.4, 71.4, 105.7, 111.0, 120.6, 123.1, 123.7, 124.9, 126.7, 127.3, 131.2, 134.7, 138.3, 138.5, 144.7, 155.3, 155.4, 157.5 ppm, Elemental analysis: calculated (%) for C28H36ClN5O3S: C 60.26, H 6.50, N 12.55, O 8.60 Cl 6.35, S 5.74, found: C 60.15, H 6.45, N 12.72, O 8.58, Cl 6.43, S 5.67.)
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Reference:
Patent; Novartis AG; Davis, Mark Clinton; Gong, Baoqing; Har, Denis; Kapferer, Tobias; Zheng, Xuchun; (25 pag.)US2020/39935; (2020); A1;,
Pyrimidine | C4H4N2 – PubChem,
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