Synthetic Route of 18711-13-2,Some common heterocyclic compound, 18711-13-2, name is 4,7-Dichloroindoline-2,3-dione, molecular formula is C8H3Cl2NO2, traditional synthetic route has been very mature, but the traditional synthetic route has various shortcomings, such as complicated route, low yield, poor purity, etc, below Introduce a new synthetic route.
4,7-Dichloroisotin (4.26 g, 19.7 mmol, 1 equiv, Alfa Aesar lot 10173559) and MeOH (70 mL, 16.4 vol) were charged to a 250-mL, three-neck, round-bottom flask equipped with nitrogen line, overhead mechanical stirrer, and a temperature probe. Diethylamine (0.43 g, 0.30 equiv, Sigma- Aldrich lot SHBD5313V) was added over 1 min via syringe (the slurry becomes dark red). l-[4-(Methylamino)phenyl]ethanone 3 (11.4 g, 3.9 equiv, Sigma- Aldrich lot 01129HHV) was added in portions via a plastic funnel, over 15 min. The funnel was rinsed with MeOH (2 x 15 mL, 7.0 vol). The reaction was stirred at ambient temperature (approximately 18-20 C) and periodically sampled for in-process control (IPC) by HPLC. After 40 h of reaction, additional diethylamine was charged to the reaction via syringe (0.16 g, 0.11 equiv) and the stirring continued at ambient temperature. After 64 h, a light slurry formed. Additional diethylamine was charged to the reaction via syringe (0.13 g, 0.09 equiv) and the stirring continued at ambient temperature. After 92 h of reaction IPC by HPLC analysis showed 2.1% AUC of isatin 1 present in the reaction mixture. Additional diethylamine was charged to the reaction via syringe (0.07 g, 0.05 equiv) for a total of 0.55 equiv of base and the stirring continued at ambient temperature over the weekend. After a total of seven days, the reaction was concentrated under reduced pressure (water bath <40 C), the solid residue was dissolved in a mixture of dichloromethane (450 mL) and MeOH (50 mL) at 30 C, and adsorbed over 20 g of silica gel. Purification was carried out in a Combiflash CompanionTM XL system with a RediSep disposable flash 220 g silica gel column (catalog 69-2203-422). Elution of the residual starting material 3 was accomplished with dichloromethane (approximately 20 column vol, while the product TK- 202 was eluted with 10% methanol in dichloromethane. The product containing fractions, where product had already started to precipitate, were combined in two different lots and partially concentrated under reduced pressure. The resulting slurries were filtered and the solid cakes were washed with MeOH to afford two fractions that were dried under high vacuum at ambient temperature for 24 h, then 50 C for 24 h, to afford lot BIO-W-30-17 and lot BIO-W-30-18. The filtrate from both crystallizations were combined and subjected to a second chromatographic purification (on a 40-g RediSep Gold column, catalog 69- 2203-347) using a gradient from dichloromethane to 5% methanol in dichloromethane for elution. The product containing fractions (purity higher than 99% AUC by HPLC) were combined and the product was allowed to precipitate over 2 h. The solid was filtered off, washed with methanol, and dried under high vacuum for 24 h at 50 C to afford lot BIOW- 30-19. A second set of fractions containing product of approximately 95% AUC purity by HPLC were combined, the solid was filtered off, re-dissolved in dichloromethane, and added 20% methanol to precipitate overnight. The precipitated TK-202 was filtered and washed with methanol, then dried under high vacuum for 24 h at 50 C to afford lot BIO-W-30-16. The total combined weight of 5.99 g corresponds to 83% yield of compound. Solid is off- white (with a very pale peach to tan shade). These compound has a wide range of applications. It is believed that with the continuous development of the source of the synthetic route 4,7-Dichloroindoline-2,3-dione, its application will become more common.