The malonic acid, the Wittig-Horner, and Claisen syntheses for the preparation of Ro 24-5904 (1) are analyzed using the Andraos' reaction analysis metrics system. Although this analysis showed the direct coupling of 4-cyclobutyl-2-methylthiazole (19) with 3-nitrobenzaldehyde (5) is the most atom efficient route, the excess of 3-nitrobenzaldehyde (5) required for a reasonable reaction rate at the reported conditions significantly detracts from this chemistry. The malonic acid based synthesis to 3-nitrocinnamide (9) is atom efficient; however the thionation strategy and the use of Lawesson's reagent preclude its consideration. As demonstrated in the elegant Wittig-Horner route, the thionation with hydrogen sulfide is 100%, but the formation of a stoichiometric amount of potassium diethyl phosphate causes the waste mass efficiency to be similar to that for the process with Lawesson's reagent (10). A review of the literature has shown that there is a paucity of general environmentally benign thionating methods and focused R&D activities in a unified approach with different sectors of the chemical industry may serve to alleviate this situation.

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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.

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magnified imageIsocarboxazid rearranges on heating to 5‐acetonyl‐2‐benzyl‐4‐hydroxy‐1,2,3‐triazole in DMF at 150°C, in the ionic liquid, [bmin]HSO at 100°C or as a melt at 105°C. This is the first reported example of the Boulton–Katritzky rearrangement of an acyl hydrazide. J. Heterocyclic Chem., (2009)