With the rapid development and complex challenges of chemical substances, new drug synthesis pathways are usually the most effective.858515-65-8,4-Methyl-1H-indole-3-carboxylic acid,as a common compound, the synthetic route is as follows.
858515-65-8, A procedure for converting quinuclidin-4-ylmethyl 4-methyl-l//-indole-3-carboxylate phosphate salt (93% assay purity; mix of polymorphs) to quinuclidin-4-ylmethyl 4-methyl-lH- indole-3-carboxylate phosphate salt (polymorphic Form A) is shown in Scheme 1. step 1: A solution of 4-methyl-lH-indole-3-carboxylic acid (1.88 kg) in DMF (0.54 kg) I was added to DCM (63 kg) in a reactor. The system was vacuumed and refilled with N2 for three cycles. The solution was heated to 25-35 C (internal temperature). Oxalyl chloride (2.7 kg) Lambda was added drop-wise over 2 hr while maintaining the temperature at 25-35 C under nitrogen. The mixture was stirred for 4 hrs at 25-35 C under nitrogen. The reaction mixture was concentrated under vacuum (0.08 Mpa) at 30-35 C to about 15-20 L and evaporated at 35 ¡À 5 C using a rotary evaporator to remove DCM and oxalyl chloride until an obvious distillate was observed. The reaction mixture was charged with DCM (15.0 kg) and evaporated to dryness, and this charge-evaporate procedure was repeated for two cycles. Fifteen kilograms of DCM was charged to the mixture and stirred to obtain a clear solution, and an additional 15 kg of DCM was charged to the mixture in the rotary evaporator. The solution in the rotary evaporator was transferred to a dropping tank under nitrogen. Quinuclidin-4-ylmethanol N-borane complex (1.5 kg) and Et3N (1.65 kg) were added to a reactor containing DCM (15.0 kg). The mixture was cooled to 0-5 C (internal temperature), and the solution from the dropping tank in the previous step was added over 2 hrs under nitrogen at 0-5 C. The mixture was heated to 15-25 C with stirring and was stirred at 15- 25 C for 16 hrs under nitrogen. Saturated NH4CI solution (20.3 kg) was added dropwise to quench this reaction at 15-25 C. The mixture was stirred for 30 min and settled aside for 15 min. The organic layer was separated and washed with brine (40.8 kg) and dried with anhydrous Na2SC4 (3.0 kg). The solid was filtered, and the cake was washed with DCM (3.0 kg).
The synthetic route of 858515-65-8 has been constantly updated, and we look forward to future research findings.
Reference£º
Patent; ALPHARMAGEN, LLC; NG, John, Sau-Hoi; NG, Raymond; (86 pag.)WO2017/120532; (2017); A1;,
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