Current Green Chemistry - Volume 4, Issue 3, 2017

Background: Biocatalysis has many attractive features in the context of green chemistry, due to the high efficiency of chemical transformations and the renewable character of the enzymes used. Since the beginning of this century, ILs have emerged as exceptionally interesting non-aqueous reaction media for biotransformations because of their unique solvent properties, headed by their negligible vapour pressure and their exceptional ability to maintain enzymes in active and stable conformations. However, the goal of green chemistry is much more than simply replacing hazardous solvents with environmentally benign ones, and it is necessary to devise new clean methodologies that will fulfil the sustainable requirements for efficient transformations of substrates, product recovery and the reuse of all the elements of the reaction system. Results: The use biocatalyst in IL/scCO2 biphasic systems was the first approach forward to develop integral green chemical processes in non-aqueous environments. The combination of these sustainable tools provides synergies in both biocatalyst performance (i.e. improved activity and enantioselectivity, enhanced stability, etc.), and the genuine separation technologies of nearly pure products. Sponge-Like Ionic Liquids (SLILs) were recently reported as a new platform for green biocatalytic chemical processes using straightforward technologies. These SLILs are a new class of hydrophobic ILs based on cations with long alkyl side-chains (e.g. 1-octadecyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide, ([C18mim][NTf2], etc.), which behaves as a sponge-like system by switching from liquid to solid phase as the temperature changes. Thus, such ILs are able to dissolve (“soak up”) hydrophobic compounds as a liquid phase, and products can then be “wrung out” by centrifugation of the resulting solid phase after cooling. Based on this property, clean biocatalytic processes for the production of nearly pure compounds of high added value (e.g. geranyl acetate, anisyl acetate, biodiesel, monolaurin, etc.) can be easily designed by the coupling of both biotransformation and separation steps, in a sustainable approach of high potential for practical applications at industrial level. Conclusions: The use of biocatalytic approaches in green non-conventional reaction media holds much promise for the development of a sustainable chemical manufacturing industry. The combination of enzymes with multiphase neoteric systems (SLILs, ILs and/or scCO2) should be explored in the near future, as a clear strategy for developing integral new green multi-catalytic synthetic processes of industrial interest (e.g. pharmaceutical drugs).

Background: In this investigation, nano-Fe3O4@ZrO2-H3PO4 (n-FZPA), as a magnetic catalyst for the preparation of some important fluoroquinolones has been reported. Methods: These compounds were synthesized by the two-component reaction of piperazine derivatives or (4aR,7aR)-octahydro-1H-pyrrolo[3,4-b] pyridine with a series of 7-halo-6-fluoroquinolone-3- carboxylic acids upon reflux condition in water as a green solvent. Results: In the final outcomes, it was found that n-FZPA has high catalytic activity for the preparation of fluoroquinolone derivatives in high yield. Besides, the recyclability of this material has been investigated showing that the n-FZPA could be reused at least three times without any change in its catalytic properties. Conclusion: This novel and green catalytic procedure provides quick pathway to the target products upon refluxing water with the simple work128;up procedure, and without the use of dangerous organic solvents.

Background: Difluoro- and trifluoromethyl thioethers, i.e., –SCHF2 and –SCF3, which have strong electron-withdrawing effects and extremely high lipophilicities, have recently received interest because of their pharmacological and agrochemical applications. Methods: Here, we developed a novel synthetic methodology for SCHF2 and SCF3 compounds using an electrochemical microreactor (ECMR), which enables flash electrochemical reactions because of the intrinsic short diffusion distances. A mixed solution containing the disulfide or thiol substrate, triethylamine, and difluoro- or trifluoroacetic acid, which release CF3 and CHF2 radicals by Kolbe electrolysis, was electrolyzed using a constant current under microfluidic conditions. The disulfide or thiol substrate (e.g., cystine or cysteine derivative) was converted into the corresponding SCHF2 and SCF3 compound or their sulfoxide forms within 30 s; however, aromatic thiols/disulfides and tert- and secthiols/ disulfides were not suitable in this synthesis. All the flow reactions progressed under mild conditions without any catalysts or redox reagents and using traditional CF3 and CHF2 sources, which are generally expensive and hazardous. In addition, the ECMR technology could successfully be applied to direct conversion of cysteinyl thiol in the glutathione derivative (a tripeptide with a γGlu–Cys–Gly sequence) into SCF3 and SCHF2 groups. Results: The results suggest that the ECMR is a powerful and an environmentally friendly tool in the development of small organic molecule and peptide-based drugs containing –SCHF2 and –SCF3 moieties.

Background: A convenient method for the efficient synthesis of xanthenedione derivatives 4a-r using a dimedone/1,3 cyclohexanedione and various aldehydes in the presence of POMV1 and water as a green solvent is described. Results: This approach is environmentally benign with clean synthetic procedure, short reaction time, easy work-up procedure, excellent yield (80-93%) and regeneration of catalyst which made this protocol efficient and safe. Conclusion: Some novel derivatives were also synthesized using this protocol.

Background: Synthetic processes reported for ivabradine hydrochloride (1), a heart rate lowering drug (an antianginal agent), are inefficient and uneconomical at an industrial scale due to their inability to control the formation of process related impurities. Generation of huge amount of solvent and solid waste due to repeated purifications and/or chromatographic purifications to eliminate impurities makes them industrially unsuitable hence requires the development of practical and greener process for 1. Method: Based on the spectral analysis and synthetic route followed for 1, the structures for the impurities were identified and confirmed by their synthesis. Evaluated the genesis of these impurities based on the mechanistic understanding of the reaction pathways and established suitable strategies to eliminate/ minimize by optimizing the process parameters. The greenness and productivity of newly developed process were determined using process evaluation benchmarks such as process mass intensity (PMI), e-factor, atom economy, and volume time output (VTO). Results: Established process delivered greener, productive and efficient method for 1 with an overall yield of around 62.0% and HPLC purity of >99.9%. Conclusion: An efficient, economic and industrially feasible process for the synthesis of 1 is established which not only controls the formation of impurities but also minimizes the aqueous, organic and solid waste substantially to achieve the greener and productive process.

Background: Literature reports various methods for the synthesis of diphenhydramine hydrochloride each of these has one or the other drawback such as low as ~39% atom efficiency or high reaction temperature, usage of corrosive bromine and formation of hazardous by product or else it requires strong scrubbing system which generates huge amounts of inorganic waste, in some cases molar equivalents of P-toluenesulfonic acid was used which was further eliminated as waste with low product output and thus not economically viable, literature also reports continuous flow process which requires PFA tube reactor with very high temperature ~175°C addition to this it also uses IPA-HCl for salt preparation which is prone for the formation of genotoxic impurity 2-chloropropane. Methods: Objective of present work is to overcome the limitations studied in literature to improve the process in terms of atom efficiency, cost effectiveness, robust, commercially viable, industrially scalable, minimum environmental hazards considering principles of green chemistry. We have developed the process in such as way that atom efficiency at halogenation stage is enhanced by ~93% compared to ~39% when diphenylmethane reacts with bromine. HCl gas generated in-situ or if needed supplied to prepare diphenhydramine hydrochloride salt instead of using IPA-HCl to eliminate chances of formation of genotoxic impurity if any. Conclusion: In order to achieve the continuous improvement process, we have developed modified process for the synthesis of diphenhydramine hydrochloride which elimination of use of corrosive bromine, overall time cycle reduced by ~40%, overall process atom efficiency enhanced by ~45%, eliminated chance of formation of genotoxic impurity by avoiding use of IPA-HCl solvent for final stage, by carrying out reaction in either water as a universal green solvent or solvent free conditions with high yield to obtain pharmacopeial quality of the final active pharmaceutical ingredient. We assert to have a better process in terms of atom efficiency, minimal wastage, operability and quality.