Synthesis of ranitidine (Zantac) from cellulose-derived 5-(chloromethyl)furfural

Abstract

The biomass-derived platform chemical 5-(chloromethyl)furfural is converted into the blockbuster antiulcer drug ranitidine (Zantac) in four steps with an overall 68% isolated yield.Ranitidine 1, sold under the trade name Zantac, is a histamine H 2 -receptor antagonist which is used in the management of gastroesophageal reflux disease (GERD) and the treatment of gastric and duodenal ulcers. It was introduced by Glaxo (now GlaxoSmithKline) in 1981 and by 1986 had total sales in excess of $1 billion, the first-ever drug to achieve this milestone. 1 Although Zantac has been largely surplanted as a prescription drug by modern proton pump inhibitors such as omeprazole (Prilosec) and esomeprazole (Nexium), it has recently been reformulated for over-the-counter sales as a general antacid preparation.The synthesis of ranitidine 1 has been described for the most part in the patent literature, and has been the subject of multiple reviews. 2-5 Given the commercial interest in this molecule, all of the synthetically reasonable disconnections have been probed in one way or another, but perhaps the most straightforward approach up to now remains that which was described in the original patent (Scheme 1). 6 This route starts from furfuryl alcohol 3, which can be sourced from the reduction Scheme 1 Reagents a. H 2 , cat.; b. CH 2 O, Me 2 NH, H + cat.; c. HSCH 2 CH 2 NH 2 , aq. HCl; d. 7.

5‐(Chloromethyl)furfural is the New HMF: Functionally Equivalent But More Practical in Terms of its Production From Biomass

“…Finally, CMF has also been used as the synthetic core of value‐added products in the agrochemical and pharmaceuticals markets, including δ‐aminolevulinic acid ( 5 ; natural herbicide and photodynamic therapy drug), ranitidine ( 6 ; drug to control gastric reflux, sold over the counter as Zantac), prothrin ( 7 ; synthetic pyrethroid insecticide), and furan fatty acids ( 8 ; dietary antioxidants and anti‐inflammatory compounds) . The efficient and green synthesis of value‐added co‐products is a strategy to leverage business models organized around low‐margin, high‐volume products such as biofuels or even paper …”

Cellulose fast pyrolysis for platform chemicals: assessment of potential targets and suitable reactor technology

“…Like HMF, CMF can be oxidized to 2,5 furan dicarboxylic acid (FDCA), which is another important platform chemical . Ranitidine – a popular antihistamine drug – can also be produced from 5‐CMF . Thus, 5‐CMF is an acceptable alternative to 5‐HMF, which is rapidly gaining attention in the scientific community.…”

Green Synthesis of Fluorescent Peptidomimetic Triazoles from Biomass‐Derived 5‐(Chloromethyl)furfural

“…CMF is amenable to functional group transformation to obtain a range of products such as alcohols,, azides, acid chlorides, diacidchlorides, furan derivatives, value‐added chemicals, etc. All these derivatives are useful intermediates of pharmaceuticals and agrochemicals . In addition to this, CMF is an integral part of many bioactive natural products.…”

“…In addition to this, CMF is an integral part of many bioactive natural products. Selected examples of such CMF bearing natural molecules are presented in Scheme ,. Although much progress has been made in expanding the potential of CMF as a green platform chemical, still a long way to go to expand the applications of CMF in other areas of materials development; for example bioactive peptidomimetics and fluorescent probes.…”