Synthesis of Amines, Carbamates and Amides by Multi‐Step Continuous Flow Synthesis

Abstract

Abstract:We report the continuous flow synthesis of acyl azides in various continuous flow systems and demonstrate that liquid-liquid separation may be incorporated to prepare anhydrous solutions of the acyl azide, which may be subsequently reacted with appropriate nucleophiles to prepare amines, carbamates and amides within a fully integrated multi-step

Multi‐Step Continuous‐Flow Organic Synthesis: Opportunities and Challenges

“…In 2017, the Watts group used acid chloride 1 to react with sodium azide, where azido benzoyl 2 was generated withouts eparation andt hen added to the liquid-liquid separation module for Curtius rearrangementt o obtain phenyl isocyanate 3. [4] The compound 3 was then combined with an ucleophilic reagent such as methanol or carboxylic acid, and thus carbamate 4 or amide 5 was produced ( Figure 2). If the liquid-liquids eparation module was not added, water as an ucleophilic reagent would react with phenyli socyanatet og enerate aniline.…”

The evolution of Tamiflu synthesis, 20 years on: Advent of enabling technologies the last piece of the puzzle?

“…Most recently, Watts group reported a 8-step total flow synthesis of Tamiflu starting from ethyl shikimate 35 derived from shikimic acid ( Scheme 7 ) [ 52 , 53 ] Taking lessons from the previously reported shikimic acid-based routes, [ 28 , 30 , 48 , 49 , 51 , 54 ] the authors aimed to ensure azide chemistry safety, processing time reduction and process overall yield improvement by taking advantage of continuous flow chemistry technology. Flow chemistry technology is an enabling technology, which has attracted considerable attention in synthetic chemistry and pharmaceutical industry owing its efficiency, easy scale-up, safety and reproducibility; industry is now using the technology up to 2000 tonnes per annum [ [55] , [56] , [57] , [58] , [59] ] This has seen numerous approaches for pharmaceutical drugs being redesigned into continuous flow synthesis [ 56 , 58 , [60] , [61] , [62] , [63] , [64] , [65] ] The technology allows for in situ generation and consumption of dangerous intermediates, preventing their accumulation thus enhancing process safety [ 55 , [66] , [67] , [68] ] Additionally, microreactors can handle exotherms extremely well, due to the inherent high surface area to volume ratio and rapid heat dissipation unlike the conventional batch process [ 55 , 69 ].

Scheme 7 Continuous flow synthesis towards Tamiflu 1a by Sagandira and Watts.

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“…To address the aforementioned safety concerns associated with the use of potentially explosive acyl azide 111 , [ 91 ] Hayashi and coworkers [ 32 ] demonstrated the handling of the Curtius rearrangement reaction of acyl azide 111 to isocyanate 112 by taking advantage of continuous flow technology ( Scheme 16 ). Acyl azide 111 is a potentially explosive compound owing to its nitro and azide moieties [ 32 ] As aforementioned, continuous flow technology allows for in situ generation and consumption of dangerous intermediates, preventing their accumulation thus enhancing process safety [ 55 , [66] , [67] , [68] ] Additionally, microreactors can handle exotherms extremely well, due to the inherent high surface area to volume ratio and rapid heat dissipation unlike the conventional batch process [ 55 , 69 ] With this in mind, the authors treated acyl chloride 110 with TMSN 3 and pyridine in the first reactor at room temperature for 26 min to afford acyl azide 111 . Acyl azide 111 formed in situ underwent Curtius rearrangement to isocyanate 112 which is trapped with AcOH in the second reactor at 110 °C for 80 min residence time to afford acetamide 113 in 84% yield and the same yield was obtained at 10 g scale ( Scheme 16 ) [ 32 ] The reaction was easily scaled-up in this system using parallel experiments.…”

Continuous-Flow Synthesis of (–)-Oseltamivir Phosphate (Tamiflu)

“…1,[7][8][9] The legitimate (-)-shikimic acid (2) availability concerns in the early years of the development of this drug have long been solved. [9][10][11] However, the concerns associated with the use of potentially hazardous azide chemistry are yet to be addressed. There have been enormous efforts in this regard mainly through devel-opment of azide-chemistry-free routes.…”

“…Continuous-flow synthesis has emerged as a useful technique in synthetic chemistry, largely motivated by its numerous advantages relative to batch; these include improved synthetic efficiency, safety, and selectivity. [11][12][13][14][15][16][17][18][19] The only literature on continuous-flow total synthesis of (-)-oseltamivir phosphate (1) is a five-step procedure by Hayashi and Ogasawara, 10 which started from Michael addition and avoided azide chemistry. Although their approach showed ingenuity in synthesizing a compound with three chiral centers through a multistep continuous-flow procedure starting from the Michael reaction in a single passage, the throughput of 58 mg per 15 h (total yield of 13%) was insufficient to meet demand.…”