A green synthetic process for the preparation of water-soluble drugs: pegylation of menadiol and podophyllotoxin

Abstract

Pegylation of drugs is a frequently employed strategy used to improve the pharmacokinetics and pharmacodynamics of drugs. Despite this, the virtues of pegylation as a green synthetic approach to enhance the water solubility of drugs has not been discussed. Using two well-known active pharmaceutical ingredients, menadiol sodium diphosphate (1) and the semisynthetic natural product, etoposide phosphate (3), green metrics for the processes of pegylation versus phosphorylation are presented and discussed. Menadiol (2) was prepared by an ultrasound mediated reduction of menadione (9). In a study done by the National Cancer Institute, PEG podophyllotoxin 12 was screened for activity against 60 different human cancer cell lines and the desired anticancer properties of podophyllotoxin (5) were retained. As podophyllotoxin (5) is a natural product, the concept of ''green drugs'' is espoused.

Simplified Application of Material Efficiency Green Metrics to Synthesis Plans: Pedagogical Case Studies Selected from Organic Syntheses

“…Within this area, the most frequently encountered metrics that students use to evaluate reaction performance are reaction yield (RY), atom economy (AE), E-factor, global or general reaction mass efficiency (gRME), − and process mass intensity (PMI). , This choice of material efficiency metrics mirrors what the research literature by academic and industrial groups has also gravitated to and now has been widely accepted. − Editors of leading journals such as Organic Process Research & Development have initiated recent changes to submission guidelines for articles so that they include this suite of metrics to substantiate claims of greenness for chemical reactions or processes. , …”

Inclusion of Environmental Impact Parameters in Radial Pentagon Material Efficiency Metrics Analysis: Using Benign Indices as a Step Towards a Complete Assessment of “Greenness” for Chemical Reactions and Synthesis Plans

“…The application of a universal set of green metrics to assess material efficiencies of chemical reactions and synthesis plans is well described. − Various groups have successfully used such metrics to assess relative performances of multiple routes to specific target molecules − and to make choices about selecting “greenest” routes based on such assessments. Recently, the pharmaceutical industry has adopted the process mass intensity (PMI) metric as a useful and general tool to evaluate the greenness of synthesis plans. , The definition of this metric is identical to that of the inverse of global reaction mass efficiency (RME) defined earlier by Andraos for individual reactions or entire synthesis plans; namely, the ratio of the sum of masses of all input materials (reagents, catalysts, reaction solvents, workup materials, and purification materials) needed to make a target product to the mass of the target product collected.…”

Menadione: a platform and a target to valuable compounds synthesis

“…Still about reduction reactions, Niemczyk and Van Arnum described a green methodology for reduction of menadione ( 10 ), during the pegylation of 14 to improving the solubility of the studied compounds [ 118 ]. The authors reduced 10 with sodium dithionite under ultrasound irradiation, generating the reduced adduct in 79% yield ( Scheme 20 ).…”