Two-step Continuous Flow Research Articles

Two-step continuous flow process of sodium tanshinone IIA sulfonate using a 3D circular cyclone-type microreactor

A sustainable and practical process is presented for the direct synthesis of sodium tanshinone IIA sulfonate (STS). Our approach was inspired by the well-established and industrially applied batch synthetic route for STS production. We constructed a telescoped two-step continuous flow platform. This involved a continuous tanshinone IIA sulfonation and in-line salt formation. For the setup, we constructed a 3D circular cyclone-type microreactor using femtosecond laser micromachining. Compared to the 68% yield for 2 h in batch, the two-step continuous flow had an STS yield of 90%, achieved for a total residence time of <3.0 min under optimal conditions. The proposed continuous flow method vastly simplified the operation and improved procedural safety, while significantly reducing the required acid content and wastewater production.

Flow Synthesis of Nature-Inspired Mitochondria-Targeted Phenolic Derivatives as Potential Neuroprotective Agents.

A series of phenolic derivatives designed to selectively target mitochondria were synthesized under flow conditions starting from natural phenolic acids. The two-step continuous flow protocol, performed in Cyrene, a bioavailable dipolar aprotic solvent, allowed the isolation of the MITO compounds in moderate to good yields. The MITO compounds obtained, as a first step, were tested for their safety by cell viability analysis. The cytocompatible dose, in human neuronal cell line SH-SH5Y, depends on the type of compound and the non-toxic dose is between 3.5 and 125 µM. Among the seven MITO compounds synthesized, two of them have shown interesting performances, being able to protect mitochondria from oxidative insult.

Development of an Efficient, High Purity Continuous Flow Synthesis of Diazepam

In an effort to strengthen the resiliency of supply chains for active pharmaceutical ingredients (API), continuous manufacturing processes may be optimized with respect to improved chemoselectivity, production rate, yield, and/or process intensity. We report an efficient two-step continuous flow synthesis of diazepam, an agent on the World Health Organization’s (WHO) list of essential medicines. Different conditions were rapidly screened in microfluidic chip reactors by varying residence times, temperatures, solvents, and ammonia sources to identify the best telescoped reaction conditions. We report a telescoped flow synthesis that uses two microreactors in series set to 0°C and 60°C, respectively, to produce a 96% yield of 91% pure diazepam within 15 min using an NH4Br/NH4OH solution in the second step. Diazepam of &amp;gt;98% purity was obtained after a single recrystallization.

Two-step continuous flow synthesis of α-terpineol

α-Terpineol is a naturally occurring monoterpene present in essential oils, of high value on the market as it is widely used as flavoring in the cosmetics and food industry. This study aims to produce α-terpineol by two different synthetic strategies, using both batch and continuous flow systems, focusing on the optimization of the process, improving the reaction conversion and selectivity. The first strategy adopted was a one-stage hydration reaction of (+)-α-pinene by an aqueous solution of chloroacetic acid (molar ratio 1:1 between pinene and the acid) in continuous flow conditions. This reaction was carried out at 80 °C with a residence time of 15 min, obtaining good conversion (72%) and selectivity (76%), and productivity of 0.53 kg.day−1. The second strategy accomplished was a two-step cascade reaction with (+)-limonene as starting material, where the first step is a chemospecific double bond addition using trifluoroacetic acid, and the second step is the basic hydrolysis of the ester promoted by a solution of sodium hydroxide (2.25 M) in methanol (1:1). This reaction was adapted to a continuous flow condition, where all steps involved a residence time of 40 min, at 25 °C, with no quenching between steps required, with 97% conversion, 81% selectivity and up to 0.14 kg.day−1.

Engineering of continuous bienzymatic cascade process using monolithic microreactors – In flow synthesis of trehalose

Here, we present a two-step continuous flow enzymatic synthesis process in monolithic microreactors using basic sugars as substrates. In the first step UDP-glucose pyrophosphorylase (TaGalU) catalyses the synthesis of uridine-diphosphate-glucose (UDP-Glc) using uridine triphosphate (UTP) and glucose-1-phosphate (Glc-1-P). This is followed by the trehalose transferase (mCherry-TuTreT) catalysed reaction of UDP-Glc and Glc, to obtain trehalose. First, procedures for immobilisation of both enzymes on functionalised silica supports were studied and it was found that covalent bonding by amino groups using a glutaraldehyde linker gives highly active biocatalysts. Due to a drastic difference in temperature range of activity and stability of the immobilised enzymes a bi-reactor cascade was rationally the best solution. Depending on the applied flow rate and hence reaction (residence) time (1.5–10 min) the space-time-yield values varied, respectively, from 1.9 to 14.4 and 8.3 to 49.6 gproduct·L-1·h−1·mgprotein-1, for UDP-glucose pyrophosphorylase and trehalose transferase catalysed reactions. Prolonged (100 h) continuous flow operation showed that the system is operationally stable, but owing to neutral pH, it is prone to microbiological infections. They can be eliminated applying an antibacterial/antifungal therapy or preventive actions by storing and washing the reactors with a NaN3 solution. The presented process paves the way for the continuous in flow synthesis of natural and non-natural trehalose analogues and disaccharides.

Two-step continuous flow synthesis of amide via oxidative amidation of methylarene

A green and efficient method for the synthesis of amides has been developed through oxidative amidation between methylarenes with amines in a two-step continuous flow system. This method integrates methylarene oxidation and amide formation into a single operation which is usually accomplished separately. Oxidation with tert-butyl hydroperoxide (TBHP) as “green” oxidant, the synthesis of amides under mild reaction conditions in continuous flow system and the utilization of methylarenes as starting material make this methodology novel and environment friendly. The practical value of this method is highlighted through the synthesis of high-profile pharmaceutical agents, acetylprocainamide.

Synthesis and scale-up of water-soluble quaternary cationic monomers in a continuous flow system

A novel, simple, power-saving and effective method for the synthesis and scale-up of cationic water-soluble polyelectrolytes represented by dimethyldiallylammonium chloride (DMDAAC) with commercially available reagents in a two-step continuous flow system has been developed.

Two-Step Continuous Synthesis of Dicarbonyl Indoles via I2/DMSO-Promoted Oxidative Coupling: A Green and Practical Approach to Valuable Diketones from Aryl Acetaldehydes

A green and practical method for the synthesis of C-3 dicarbonyl indoles from aryl acetaldehydes and indoles was developed under I2/DMSO conditions, employing an assembled two-step continuous flow system. Moderate to good yields of dicarbonyl indole derivatives have been achieved by consuming a lower dosage of iodine and shorter reaction time without amine catalysts added, which presents major advantages over reactions in a traditional batch. Moreover, this method was also compatible with the synthesis of α-ketoamides and α-ketoesters by adjusting the reaction parameters of a continuous flow system, which indicates its good universality. And a possible mechanism was proposed based on DMSO18 isotopic labeled experiments.

Organocatalyzed Decarboxylative Trichloromethylation of Morita-Baylis-Hillman Adducts in Batch and Continuous Flow.

Two protocols for the organocatalyzed decarboxylative trichloromethylation of Morita-Baylis-Hillman (MBH) substrates have been developed. Applying sodium trichloroacetate, as the trichloromethyl anion precursor, in combination with an organocatalyst and acetylated MBH-alcohols, the desired trichloromethylated products were obtained in good yields at room temperature in batch. The method was next extrapolated into a two-step continuous flow protocol, starting directly from the MBH alcohols, in combination with tributylamine acting both as base and catalyst. The flow process proved superior to the batch approach, reducing the reaction time from 16 hours to only 20 minutes, with increased yields for all investigated entries. Two examples were also taken to scale-up in flow producing more than 10 grams of both trichloromethylated targets. Finally, substitution of the organocatalyst to (DHQ)2 PHAL or (DHQD)2 PHAL induced chiral transfer to the generated stereocenter in the reaction attaining selectivities with nearly 90 % ee.

Preparation of benzimidazole N-oxides by a two-step continuous flow process

A continuous flow process for the synthesis of nitrobenzimidazole N-oxides from 2,6-dinitrochlorobenzene and amines or amino acids is reported. The process, performed in a two-step sequence, is faster than previously reported batch processes and avoids some of the isolation and purification steps.

A two-step continuous flow synthesis of 1,4-disubstituted 1,2,3-triazoles under metal- and azide-free conditions

A new method for the formation of 1,4-disubstituted 1,2,3-triazoles in a continuous flow system under metal- and azide-free conditions has been developed. The corresponding products were obtained in moderate to good yields.

Acoustothermal heating of polydimethylsiloxane microfluidic system

We report an observation of rapid (exceeding 2,000 K/s) heating of polydimethylsiloxane (PDMS), one of the most popular microchannel materials, under cyclic loadings at high (~MHz) frequencies. A microheater was developed based on the finding. The heating mechanism utilized vibration damping in PDMS induced by sound waves that were generated and precisely controlled using a conventional surface acoustic wave (SAW) microfluidic system. The refraction of SAW into the PDMS microchip, called the leaky SAW, takes a form of bulk wave and rapidly heats the microchannels in a volumetric manner. The penetration depths were measured to range from 210 μm to 1290 μm, enough to cover most sizes of microchannels. The energy conversion efficiency was SAW frequency-dependent and measured to be the highest at around 30 MHz. Independent actuation of each interdigital transducer (IDT) enabled independent manipulation of SAWs, permitting spatiotemporal control of temperature on the microchip. All the advantages of this microheater facilitated a two-step continuous flow polymerase chain reaction (CFPCR) to achieve the billion-fold amplification of a 134 bp DNA amplicon in less than 3 min.

A Two-Step Continuous Flow Synthesis of 4-Nitropyridine

4-Nitropyridine, a key intermediate in medicinal products, was successfully prepared from pyridine N-oxide in a two-step -approach. Pyridine N-oxide was nitrated with HNO3 and H2SO4 to give 4-nitropyridine N-oxide, followed by reaction with PCl3 to give the final product. The continuous flow methodology was used to minimise accumulation of the highly energetic and potentially explosive nitration product to enable the safe scale-up of 4-nitropyridine with no 2-nitropyridine by-product. By employing continuous extraction in the nitration step and applying the optimised conditions, a throughput of 0.716 kg 4-nitropyridine product per day from pyridine N-oxide with 83% yield and high selectivity in a continuous flow system was achieved.

A two-step continuous flow synthesis of amides from alcohol using a metal-free catalyst

A two-step continuous flow synthesis of amides from alcohol using metal-free catalyst with good yield.

An Acoustothermal Microheater with Omni-temperature Controllability

Here we report the first observation of rapid volumetric heating of polydimethylsiloxane (PDMS) under cyclic loadings at a range of high (∼MHz) frequencies. Based on the finding, we developed a microheater which utilizes the vibration damping of PDMS, the most commonly used material in microfluidics, induced by sound waves generated and precisely controlled by a surface acoustic wave (SAW) microfluidic system. An omni-temperature controllability of the microheater enabled us to perform two-step continuous flow polymerase chain reaction for a billion-fold amplification of 134bp DNA amplicon in less than 45sec.

Safe Generation and Direct Use of Diazoesters in Flow Chemistry

A safe and fast method for the production of β-hydroxy-α-diazoesters in continuous flow technology is described. The synthesis involves the formation of ethyl diazoacetate in situ and the addition to several aldehydes in a two-step continuous flow microreactor setup. Rhodium acetate catalyzes a subsequent 1,2-hydride shift to give access to β-keto esters in a three-step sequence.

A Scalable Two-Step Continuous Flow Synthesis of Nabumetone and Related 4-Aryl-2-butanones

Three different continuous flow strategies for the generation of important 4-aryl-2-butanone derivatives including the anti-inflammatory drug nabumetone [4-(6-methoxy-2-naphthalenyl)-2-butanone] and the aroma compounds raspberry ketone [4-(4-hydroxyphenyl)-2-butanone] and its methyl ether [4-(4-methoxyphenyl)-2-butanone] were evaluated. All three protocols involve the initial preparation of the corresponding 4-aryl-3-buten-2-ones via Mizoroki–Heck, Wittig, or aldol strategies, which is then followed by selective hydrogenation of the C═C double bond to the desired 4-aryl-2-butanones. The synthetic routes to 4-aryl-3-buten-2-ones were first optimized/intensified on small scale to reaction times of 1–10 min using batch microwave heating technology and then translated to a scalable continuous flow process employing commercially available stainless steel capillary tube reactors. For the synthesis of 4-(4-methoxyphenyl)-3-buten-2-one a further scale-up using a custom-built mesofluidic mini-plant flow system capable of processing several liters per hour was designed to further expand the scale of the process. The final hydrogenation step was performed using a fixed-bed continuous flow hydrogenator employing Ra/Ni as a catalyst.

Bioleaching of spent Ni-Cd batteries and phylogenetic analysis of an acidophilic strain in acidified sludge

Biohydrometallurgy is a novel method to recycle discarded batteries, in which sewage sludge is used as microorganisms and culture due to the presence of indigenous Thiobacilli. A two-step continuous flow leaching system consisting of an acidifying reactor and a leaching reactor was introduced to achieve the bioleaching of spent nickel-cadmium (Ni-Cd) batteries. The acid supernatant produced in the acidifying reactor by the microorganisms with ferrous ions as the substrate was conducted into the leaching reactor to dissolve electrode materials. The efficiency of a batch treatment of batteries was examined. The results showed that the complete dissolution of two AA-sized Ni-Cd batteries with 0.6 L/d acid supernatant took about 30, 20, and 35 days for Ni, Cd, and Co, respectively. But the dissolution ability of the three metals was different. Cd and Co can be leached mostly for pH below 4.0 while the complete dissolution of Ni can be achieved for pH below 2.5. Meanwhile, a strain (named Thiooxidans. WL) accounting for the reduction of pH in the acidified sludge was isolated and sequenced. It was identified to be 100% similar to Acidithiobacillus ferrooxidans strain Tf-49 based on 16S rDNA sequence analysis. The relevant phylogenetic tree constructed indicates that the strain should be classified into genus Acidithiobacillus ferrooxidans.