Continuous Flow Process for Reductive Deoxygenation of ω-Chloroketone in the Synthesis of Vilazodone

Abstract

A continuous flow process for the reductive deoxygenation of 3-(4-chlorobutanoyl)-1H-indole-5carbonitrile to 3-(4-chlorobutyl)-1H-indole-5-carbonitrile was developed using a continuous stirred tank reactor (CSTR) setup. The opportunity for process optimization as well as scale-up feasibility was investigated at a laboratory scale. Advantages of a continuous process such as increased product yield, minimized impurity formation, enhanced safety, and increased overall purity of the isolated material thereby avoiding a purification step were demonstrated. Both sodium borohydride and a borane•THF complex were explored as reducing agents in conjunction with iron trichloride which produced high purity 3-(4-chlorobutyl)-1H-indole-5-carbonitrile not requiring further purification in higher yield than the standard batch process.

Practical and Scalable Manufacturing Process for a Novel Dual-Acting Serotonergic Antidepressant Vilazodone

“…Finally, 15 and 16 were made to react together to obtain the target product vilazodone with a yield of 90.0%. 7,16 Based on the above preliminary results, three scale-up experiments were carried out (Table 3). Two 2 kg scale experiments and a 3 kg scale experiment were conducted, which proceeded smoothly to provide vilazodone with a 56.2% yield and 99.93% purity after recrystallization.…”

“…The experimental results showed that the optimal reaction temperature was 100 °C, and the reaction time was 1.5 h to obtain the product 15 in 82.0% yield. Finally, 15 and 16 were made to react together to obtain the target product vilazodone with a yield of 90.0%. , …”

“…Due to the similar properties of 3a and 3b, the difficulty of product purification increases, and the total yield of the route reduces. After this, many scientific researchers have made improvements and optimizations on the basis of this route, − but the corresponding impurities will inevitably be produced. The total yield of the route and product purity remain the existing challenges.…”

Continuous stirred tank reactors in fine chemical synthesis for efficient mixing, solids-handling, and rapid scale-up

“…In contrast to the previous systems, the agitation is performed by moving the whole reactor rather than only the agitator parts. Figure 12 shows one such system [31][32][33].…”

“…12 shows one such system. [31][32][33] Yao et al 33 presented a continuous approach to the phosphorylation of 2,2′-methylene-bis(4,6-di-tert-butyl)phenol, comparing both tubular reactors and ACR. One particularly challenging aspect of this synthesis is an insoluble side product, triethylamine hydrochloride, produced during phosphorylation.…”