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Figure S4. Schematic presentation of continuous flow process to synthesize Rosiglitazone intermediate 5. Packed bead KOH cartridge long term efficiency: The continuous intermediate 5 synthesis setup as aforementioned in figure S4. Stock solution of compound 3 (0.25 M in DMF) and stock solution of compound 4 (0.28 M in DMF) were charged in two separate syringes. Stock solutions of Compound 3 and compound 4 was introduced into a T-mixer with same flow rate of 100 µL/min. using two separate pumps. The outlet of the T-mixer was connected to a packed bead KOH cartridge (id = 7 mm, length = 150 mm, vol. = 6 mL). The out-flowing product mixture of 5 from pack bead KOH cartridge was analysed by GC-MS and data has been plotted on figure 2.
Source publication
The thiazolidinediones manufacturing in a batch process is often carried out at different locations, where each successive batch collects a certain amount of intermediate followed by its transportation to another location. Thiazolidinediones containing APIs are unstable at ambient temperature. In this regard, manufacturing sites need huge storage c...
Citations
... Zn(II) is the primary constituent of a wide number of enzymes that perform structural, catalytic, and co-catalytic roles due to its distinctive physicochemical characteristics, Lewis acid nature, and potential to stabilize a variety of coordination geometries encouraging ligand exchange (Chowdhury et al. 2020;Erxleben 2019). Numerous Zn(II) complexes have been studied for their potential medicinal benefits, including their ability to cure neurodegenerative illnesses and act as anticonvulsants, anti-diabetic, anticancer, anti-inflammatory, and antibacterial agents (Deswal et al. 2022a, b;Agarwal et al. 2022;Purwa et al. 2022). In contrast to conventional metal based chemotherapeutic medicines, Zn(II) derivatives have been demonstrated to be potent anticancer agents that usually show fewer in vivo side effects and evoke novel mechanisms of anticancer activity (Barman et al. 2017). ...
In the present manuscript, novel macrocyclic Schiff base complexes [Zn(N4MacL1)Cl2–Zn(N4MacL3)Cl2] were synthesized by the reaction of ZnCl2 and macrocyclic ligands (N4MacL1–N4MacL3) derived from diketone and diamines under microwave irradiation method and conventional method. The structures of the obtained complexes were identified by various spectrometric methods such as Fourier transformation infra-red (FT-IR), nuclear magnetic resonance (NMR), high-resolution mass spectrometry (HR-MS), powder X-ray diffraction, molar conductivity, and UV–vis. The structures of the synthesized compounds were optimized by using the def2–TZV/J and def2–SVP/J Coulomb fitting basis sets at B3LYP level in density functional theory (DFT) calculations. The macrocyclic Schiff base complexes exhibited higher activities against Gram-positive bacteria (Staphylococcus aureus and Bacillus cereus), Gram-negative bacteria (Escherichia coli and Xanthomonas campestris), and fungal strains (Fusarium oxysporum and Candida albicans) in comparison to macrocyclic Schiff base ligands. Furthermore, the newly synthesized macrocyclic compounds were assessed for their anticancer activity against three cell lines: A549 (human alveolar adenocarcinoma epithelial cell line), HT-29 (human colorectal adenocarcinoma cell line), and MCF-7 (human breast adenocarcinoma cell line) using the MTT assay. The obtained results showed that the macrocyclic complex [Zn(N4MacL3)Cl2] displayed the highest cytotoxic activity (2.23 ± 0.25 µM, 6.53 ± 0.28 µM, and 7.40 ± 0.45 µM for A549, HT-29, and MCF-7 cancer cell lines, respectively). Additionally, molecular docking investigations were conducted to elucidate potential molecular interactions between the synthesized macrocyclic compounds and target proteins. The results revealed a consistent agreement between the docking calculations and the experimental data.
Graphical abstract
... Chemical shifts for 13 Thiazolidine-2,4-dione was prepared following literature protocols. 1,2 5-Substituted thiazolidine-2,4-diones were synthesized using a method previously developed by our research group. ...
... 4.55 (dd, J = 9.9 Hz, J = 3.8 Hz, 1H), 3.56 (dd, J = 14.1 Hz, J = 3.9 Hz, 1H), 3.14 (dd, J = 14.1 Hz, J = 9.9 Hz, 1H). 13 Hz, 1H). 13 Pioglitazone hydrochloride was prepared following a literature method. ...
... 13 Hz, 1H). 13 Pioglitazone hydrochloride was prepared following a literature method. 11 In a 10 mL flask, 1.0 mmol of Pioglitazone was added, followed by the addition of 1.8 mL of isopropyl alcohol and 0.5 mL of hydrochloric acid. ...
A transition-metal free methodology for the chemoselective reduction of benzylidene thiazolidine-2,4-diones and similar heterocycles is described, allowing the preparation of a broad scope of the corresponding reduced derivatives in up to 90% yield. The protocol has a simple and safe experimental setup, in which water was employed as the hydrogen source. To further demonstrate the synthetic utility of this transformation, the antidiabetic API Pioglitazone was prepared in 81% yield. To the best of our knowledge, this is the first hydride and transition-metal free protocol for the synthesis of Pioglitazone, highlighting its potential utility as a greener alternative in both academic and industrial synthesis.
Optimization is gaining huge attention in industries like pharmaceuticals, fine chemicals, and petrochemicals to maximize reaction yield, minimize waste, and improve process efficiency. Optimization is keeping pace with variations in multiple reaction conditions and sustaining a shift from laboratory to industry. Herein, we report an integrated continuous flow reactor platform with Bayesian optimization (BO) assisted reaction optimization that can autonomously explore the optimal conditions for photochemical bromination reaction of biologically active sartan intermediates. Further, the controlled optimized parameter is extended towards the efficient solar light utility for bromination reaction, and the reaction is achieved in 32 sec of residence time with an excellent space-time yield of 7 kg.L-1h-1. The individual photobromination and nucleophilic substitution steps for sartan intermediate synthesis smoothly transitioned from the mg.h-1 to Kg.h-1 production. In addition, autonomously explored bromination conditions are integrated with continuous flow tools for synthesizing, extracting, and purifying the Angiotensin II receptor blocker intermediate within only 7.2 min.
Over the past few decades, many solar radiation (Heat + Light)-based reactions have been developed that allow utilization of the thermal/light to facilitate chemical reactions. However, fluctuating light intensity, cloud, night, global location etc. render the system less efficient (approximately 33%, being workable for only 8 h out of 24 h). Radiation-induced direct C-H activation with aqueous ammonia is rarely reported. Herein, we report an innovative approach that merge a solar tracker with artificial radiation induced in-situ generation of explosive diazo-compound and further extended to N-H insertion into biological active molecule.
Novel heterobimetallic complexes of type [Zn(L)2M2(R)4Cl2], where M = Sn(IV) and Si(IV); R = –CH3 and –C6H5, were prepared by reacting the methanolic solution of monometallic complex [Zn(L)2Cl2] with group fourteen organometallic dichloride [(CH3)2SnCl2/(C6H5)2SnCl2/(CH3)2SiCl2/(C6H5)2SiCl2]. The structures of the obtained complexes were identified by various spectrometric methods such as Fourier transformation infra-red (FT-IR), nuclear magnetic resonance (NMR), electrospray ionization mass spectrometry, powder X-ray diffraction, molar conductivity, and UV–Vis. Density functional theory (DFT) calculations were performed to explore the quantum chemical properties of the newly designed Zn(II) complexes. In vitro antimicrobial, anti-inflammatory, and anticancer activities of Schiff base ligand [L], mononuclear complex [Zn(L)2Cl2] and its corresponding heterobimetallic complexes, [Zn(L)2M2(R)4Cl2], were evaluated. The heterobimetallic complexes exhibited higher activities against Gram-positive bacteria (Bacillus Subtilis and Bacillus cereus), Gram-negative bacteria (Xanthomonas Campestris and Pseudomonas aeruginosa), and fungal strains (Aspergillus flavus and Fusarium oxysporum) in comparison with both the Schiff base ligand and the monometallic complex. This enhanced performance of the heterobimetallic complexes can be attributed to the synergistic effect. The heterobimetallic complex [Zn(L)2Sn2(C6H5)4Cl2] showed the highest potential of inflammation inhibition with IC50 = 5.2 µg/mL, very close to standard drug sodium diclofenac (IC50 = 4.59 µg/mL). Furthermore, the synthesized compounds were assessed for their anticancer activity against three cell lines: human colon (HCT-116), human breast (MDA-MB-231), and human lung cancer cells (A549) using the MTT assay. The obtained results showed that the heterobimetallic complex [Zn(L)2Sn2(C6H5)4Cl2] displayed the highest cytotoxic activity (IC50 = 3.12 ± 0.25, 3.72 ± 0.26, and 3.94 ± 0.14 for HCT-116, MDA-MB-231 and A549, respectively). These findings suggest that the newly formulated metal complexes could be explored further in the pursuit of drug development.
Graphical abstract
A novel nanotextured Ni@Cu material embedded electro micro-flow reactor with minimal electrode distance has been employed to synthesize biphenyls via the construction of a new C–C bond. The reported protocol is devoid of noble metal and involves co-reductant/oxidant-free conditions in a fast manner for the synthesis of substituted/unsubstituted biphenyl systems. The electro-reactor volume has been optimized for the gram scale biphenyl synthesis and further extended for an integrated total process system reducing the tedious downstream process by selective removal of unwanted chemicals/solvent. The continuous micro-flow synthesis of daclatasvir is now accomplished with a good yield.
Batch process shows great potential in antiretroviral Darunavir (DRV) synthesis, but the longer process time, expensive catalyst, shortage of skilled manpower, laborious post-synthetic work-up, transport of one intermediate from one place to another, and need of maintaining the expensive storage inventory are some major limitations. Herein, we report the first-ever individual continuous flow sequence involving 7 steps and an integrated micro-total process system machine (μ-TPSM) for the last 4 steps of API DRV synthesis. Employing this μ-TPSM, DRV could be synthesized within 41 min. of total residence time with 71% isolated yield, and an output of 0.8 g/h. The use of Raney-Ni instead of palladium on carbon renders the process more affordable.
