Abstract:We present a comprehensive review of the advent and impact of continuous flow chemistry with regard to the synthesis of natural products and drugs, important pharmaceutical products and definitely responsible for a revolution in modern healthcare. We detail the beginnings of modern drugs and the large scale batch mode of production, both chemical and microbiological. The introduction of modern continuous flow chemistry is then presented, both as a technological tool for enabling organic chemistry, and as a fun… Show more
“…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.…”
Section: Discussionmentioning
confidence: 99%
“…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 ]. …”
Section: Alternative Synthetic Approachesmentioning
Influenza is a serious respiratory disease responsible for significant morbidity and mortality due to both annual epidemics and pandemics; its treatment involves the use of neuraminidase inhibitors. (−)-Oseltamivir phosphate (Tamiflu) approved in 1999, is one of the most potent oral anti-influenza neuraminidase inhibitors. Consequently, more than 70 Tamiflu synthetic procedures have been developed to date. Herein, we highlight the evolution of Tamiflu synthesis since its discovery over 20 years ago in the quest for a truly efficient, safe, cost-effective and environmentally benign synthetic procedure. We have selected a few representative routes to give a clear account of the past, present and the future with the advent of enabling technologies.
“…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.…”
Section: Discussionmentioning
confidence: 99%
“…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 ]. …”
Section: Alternative Synthetic Approachesmentioning
Influenza is a serious respiratory disease responsible for significant morbidity and mortality due to both annual epidemics and pandemics; its treatment involves the use of neuraminidase inhibitors. (−)-Oseltamivir phosphate (Tamiflu) approved in 1999, is one of the most potent oral anti-influenza neuraminidase inhibitors. Consequently, more than 70 Tamiflu synthetic procedures have been developed to date. Herein, we highlight the evolution of Tamiflu synthesis since its discovery over 20 years ago in the quest for a truly efficient, safe, cost-effective and environmentally benign synthetic procedure. We have selected a few representative routes to give a clear account of the past, present and the future with the advent of enabling technologies.
“… 9 One of the most attractive benefits in a continuous flow approach is the opportunity to integrate several reaction steps (the so-called telescoped synthesis) to rapidly generate focused libraries of bioactive compounds as well as enough material for clinical trials in medicinal chemistry programs. 10 Recently, our group has demonstrated the telescoped synthesis of highly substituted 3-thio-1,2,4-triazoles, including their gram-scale preparation and application to the continuous flow synthesis of an API. 11 Integration of processing steps through telescoped reactions allows for the expedient preparation of target compounds since there is no need for intermediate isolation, which also leads to reduced waste generation through the reduction in solvent use.…”
An integrated batch and continuous
flow process has been developed
for the gram-scale synthesis of goniothalamin. The synthetic route
hinges upon a telescoped continuous flow Grignard addition followed
by an acylation reaction capable of delivering a racemic goniothalamin
precursor (
16
) (20.9 g prepared over 3 h), with a productivity
of 7 g·h
–1
. An asymmetric Brown allylation
protocol was also evaluated under continuous flow conditions. This
approach employing (−)-Ipc
2
B(allyl) provided an
(
S
)-goniothalamin intermediate in 98% yield and 91.5%
enantiomeric excess (ee) with a productivity of 1.8 g·h
–1
. For the final step, a ring-closing metathesis reaction was explored
under several conditions in both batch and flow regimes. In a batch
operation, the Grubbs second-generation was shown to be effective
and highly selective for the desired ring closure product over those
arising from other modes of reactivity, and the reaction was complete
in 1.5 h. In a flow operation, reactivity and selectivity were attenuated
relative to the batch mode; however, after further optimization, the
residence time could be reduced to 16 min with good selectivity and
good yield of the target product. A tube-in-tube reactor was investigated
for in-situ ethylene removal to favor ring-closing over cross-metathesis,
in this context. These results provide further evidence of the utility
of flow chemistry for organometallic processing and reaction telescoping.
Using the developed integrated batch and flow methods, a total of
7.75 g of goniothalamin (
1
) was synthesized.
This work investigates batch and
continuous-flow heterogeneous
catalytic hydrogenation of a mixture of cafestol and kahweol (C&K)
to obtain pure cafestol. These diterpenes were extracted from green
coffee beans, and hydrogenation was performed using well-established
palladium catalysts (Pd/C, Pd/CaCO
3
, Pd/BaSO
4
, and Pd/Al
2
O
3
) and a carbon black-supported
Pd catalyst coated by a covalently tethered SiO
2
shell
with mesoporous texture (Pd/CB@SiO
2
), all partially deactivated
with quinoline. Pd/C 10% poisoned with 1 wt % quinoline gave the best
result for batch reaction, producing cafestol from kahweol with high
selectivity (>99%) after 10 min. Excellent selectivity was also
obtained
with the catalyst Pd/CB@SiO
2
with only 1% Pd. In addition,
Pd/C-quinoline adapted for continuous-flow experiments exhibited the
best catalytic activity, also providing cafestol with excellent selectivity
(>99%) after 9.8 s.
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