Sintesis de Ranitidina Sintesis de Ranitidina
Sintesis de Ranitidina Sintesis de Ranitidina
Sintesis de Ranitidina Sintesis de Ranitidina
Sintesis de ranitidina
www.rsc.org/greenchem COMMUNICATION
Synthesis of ranitidine (Zantac) from cellulose-derived
5-(chloromethyl)furfural†
Mark Mascal* and Saikat Dutta
Published on 19 September 2011 on http://pubs.rsc.org | doi:10.1039/C1GC15537G
The biomass-derived platform chemical 5-(chloro- of furfural 2. The furan ring in 3 is aminomethylated to 4,
Downloaded by University of Guelph on 04 October 2012
methyl)furfural is converted into the blockbuster antiulcer which reacts with cysteamine in concentrated aq. HCl to give
drug ranitidine (Zantac) in four steps with an overall 68% 5. The patent literature puts the yields of both of these steps
isolated yield. at <50%,7 although more recent studies report conversions of
82%8 and 75%9 for 4 and 5, respectively. Condensation of 5 with
Ranitidine 1, sold under the trade name Zantac, is a histamine 1-methylthio-1-methylamino-2-nitroethylene 7 then provides 1,
H2 -receptor antagonist which is used in the management of with yields of up to 90% having been reported for this reaction.10
gastroesophageal reflux disease (GERD) and the treatment of In a reversal of roles in 4, the dimethylamino group can be
gastric and duodenal ulcers. It was introduced by Glaxo (now quaternized and serve as the leaving group for the introduction
GlaxoSmithKline) in 1981 and by 1986 had total sales in excess of cysteamine,11 but this necessitates the re-introduction of the
of $1 billion, the first-ever drug to achieve this milestone.1 dimethylaminomethyl function from the hydroxymethyl group,
Although Zantac has been largely surplanted as a prescription which lengthens the synthesis.
drug by modern proton pump inhibitors such as omeprazole Other approaches to 1 have been developed which avoid
(Prilosec) and esomeprazole (Nexium), it has recently been the use of cysteamine altogether, in which the OH group of
reformulated for over-the-counter sales as a general antacid either 3 or 4 is converted to SH and then aminoethylated
preparation. using aziridine, 2-chloroethylamine, chloroacetonitrile, or N-(2-
The synthesis of ranitidine 1 has been described for the chloroethyl) phthalimide.3
most part in the patent literature, and has been the subject A key intermediate in the synthesis of 1 is 1-methylthio-
of multiple reviews.2–5 Given the commercial interest in this 1-methylamino-2-nitroethylene 7. This can be prepared by
molecule, all of the synthetically reasonable disconnections have addition of the nitromethane anion to CS2 and methylation to
been probed in one way or another, but perhaps the most give 1,1-bis(methylthio)-2-nitroethylene 6, followed by substi-
straightforward approach up to now remains that which was tution of one of the MeS groups with methylamine (Scheme
described in the original patent (Scheme 1).6 This route starts 2). The terminal aminonitroethylene fragment of 1 can also
from furfuryl alcohol 3, which can be sourced from the reduction be introduced in two steps by direct condensation of 5 with
6, or various analogues thereof, followed by treatment with
methylamine. Yet another alternative is the reaction of 5
with either methyl isocyanate or methyl isothiocyanate and
subsequent replacement of the chalcogen by nitromethane.3,12
This journal is © The Royal Society of Chemistry 2011 Green Chem., 2011, 13, 3101–3102 | 3101
Descargado por Daniel Castillo hernández (danicastandez@gmail.com)
lOMoARcPSD|7509802
View Online
We have recently shown that 5-(chloromethyl)furfural (CMF) of CMF 12 as a biomass-derived platform chemical for the
12 can be derived in a single step from either sugars, cellulose, green synthesis of pharmaceuticals and other value-added
or raw cellulosic biomass in isolated yields between 80–90%,13 products.
and are now in the course of developing new applications and
markets for this renewable platform chemical. For example, the
natural pesticide d-aminolevulinic acid 13 has been derived from Acknowledgements
12 in three steps with an overall yield of 68%.14 This research was supported by the US National Science Foun-
dation, grant CBET 0932391. The authors also acknowledge
the assistance of Nabin Meher and Mikaël Le Meur in the early
development of this project.
3102 | Green Chem., 2011, 13, 3101–3102 This journal is © The Royal Society of Chemistry 2011
Descargado por Daniel Castillo hernández (danicastandez@gmail.com)