Continuous‐Flow Synthesis of (R)‐Propylene Carbonate: An Important Intermediate in the Synthesis of Tenofovir

Abstract

(R)‐Propylene carbonate is an important intermediate in the synthesis of tenofovir pro‐drugs such as tenofovir alafenamide fumarate (TAF) and tenofovir diisoproyl fumarate (TDF). Independent of the pro‐drug type, tenofovir presents a chiral secondary hydroxy derivative, which can be obtained directly from (R)‐propylene carbonate. Herein, we report our chemo‐enzymatic continuous‐flow strategy towards (R)‐propylene carbonate starting from a very cheap and renewable raw material, glycerol. We were able to synthesize (R)‐propylene carbonate in seven continuous‐flow steps, starting from glycerol, in good‐to‐excellent yields (66–93 %) and excellent selectivity (E > 200).

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

“…Having solved the shikimic acid availability concerns over the years by developing more efficient extraction and purification processes or alternatively by fermentation using genetically engineered E.coli bacteria, [ 25 , [28] , [29] , [30] ] the use of hazardous azide chemistry needs more attention. The application of continuous flow technology in Tamiflu synthesis proved to be a potential enabling tool for safe handling of the hazardous azide chemistry as well as improving efficiency [ 32 , 53 , 92 ] Continuous flow synthesis has attracted considerable attention in synthetic chemistry and pharmaceutical industry in the last decade owing to its well-documented advantages, [ [55] , [56] , [57] , [58] , [59] , 65 , 67 , 79 , [96] , [97] , [98] , [99] , [100] ] resulting in numerous pharmaceutical drugs approaches being redesigned into continuous flow synthesis [ 56 , 58 , [60] , [61] , [62] , [63] , [64] , [65] , 106 ] In this light, we envisage that Tamiflu synthesis can hugely benefit from continuous flow technology application to afford truly efficient synthetic procedures. Furthermore, the promising Tamiflu synthetic approaches which were previously ruled out for large scale synthesis in batch based on either safety concerns or poor efficiency can be reconsidered in flow.…”

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

“…Chemo-enzymatic continuous-flow strategy to synthesize the (R)-propylene carbonate 88,a ni mportant intermediate for tenofovir pro-drugs, was reportedb yS ouza and co-workers. [29] In seven steps, their approacht ransformed widely available, sustainable, and inexpensive glycerol 85 into the desired product 88 with an overall yield of 20 %a nd excellent enantioselectivity (E > 200;F igure 27). Pd/C-catalyzed hydrogenolysis of the epoxidew as employed to generate the racemic diol.…”

Flow Chemistry Supporting Access to Drugs in Developing Countries

“…Tenofovir disoproxil fumarate 7 and tenofovir alafenamide fumarate 8 (Fig. 5) are nucleotide prodrugs for the treatment of HIV/AIDS and hepatitis B [26,27]. They are usually used in combination with emtricitabine and efavirenz.…”

“…They are usually used in combination with emtricitabine and efavirenz. The de Souza group [27] in Brazil reported a chemo-enzymatic continuous flow process for (R)propylene carbonate, an important intermediate in the synthesis of tenofovir prodrugs (Fig. 6).…”