Sintesis de Ranitidina Sintesis de Ranitidina

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Sintesis de ranitidina

Química Heterocíclica (Instituto Politécnico Nacional)

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Green Chemistry Dynamic Article Links

Cite this: Green Chem., 2011, 13, 3101

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

Received 11th May 2011, Accepted 29th August 2011


DOI: 10.1039/c1gc15537g

The biomass-derived platform chemical 5-(chloro- of furfural 2. The furan ring in 3 is aminomethylated to 4,
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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

Scheme 1 Reagents a. H2 , cat.; b. CH2 O, Me2 NH, H+ cat.; c.


HSCH2 CH2 NH2 , aq. HCl; d. 7.

Department of Chemistry, University of California Davis, 1 Shields


Avenue, Davis, CA, 95616, US. E-mail: mascal@chem.ucdavis.edu;
Fax: 530-752-8995; Tel: 530-754-5373
† Electronic supplementary information (ESI) available: 1 H and 13 C
NMR spectra and experimental details for the preparation of com-
pounds 14, 15, 5, and 1. See DOI: 10.1039/c1gc15537g Scheme 2 Reagents: a. KOH; b. MeI; c. MeNH2 .

This journal is © The Royal Society of Chemistry 2011 Green Chem., 2011, 13, 3101–3102 | 3101
Descargado por Daniel Castillo hernández (danicastandez@gmail.com)
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Finally, the right hand side of the molecule can be built up


first and linked to 4 or a derivative thereof in which the OH has
been converted into a leaving group (halide, sulfonate ester) as
shown in Scheme 3.
Published on 19 September 2011 on http://pubs.rsc.org | doi:10.1039/C1GC15537G

Scheme 4 Reagents: a. HSCH2 CH2 NHAc, NaH, THF, 91%; b.


Me2 NH, NaBH4 , MeOH, 90%; c. 2 M KOH, reflux, 94%; d. 7, H2 O,
Scheme 3 Reagents: a. HSCH2 CH2 NH2 ; b. MeNH2 ; c. 4 or derivative. 55 ◦ C, 88%.
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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.

Looking at the structures of CMF 12 and ranitidine 1, a Notes and references


functional correspondence can clearly be seen, wherein the
1 R. Wright, J. Health Care Market., 1996, 16, 24.
(dimethylamino)methyl group could be envisaged to be intro- 2 J. Bradshaw, Chron. Drug Discovery, 1993, 3, 45.
duced by reductive amination of the C O group, and the sulfide 3 R. G. Glushkov, E. V. Adamskaya, T. I. Vozyakova and A. F. Oleinik,
bond formed by taking advantage of the reactive chloromethyl Khimiko-Farmatsevticheskii Zhurnal, 1990, 24, 53 and references
functionality. therein.
4 Z. Han and B. Zhou, Yiyao Gongye, 1986, 17, 515.
Our approach to 1 is presented in Scheme 4. Here, the 5 M. Hohnjec, J. Kuftinec, M. Malnar, M. Skreblin, F. Kajfez, A. Nagl
key thioethylamino fragment is introduced in excellent yield and N. Blazevic, Analytical Profiles of Drug Substances, 1986, 15,
by reaction of 12 with commercial N-acetylcysteamine. Early 533.
6 B. J. Price, J. W. Clitherow and J. Bradshaw, US Patent 4128658,
attempts to substitute 12 with cysteamine itself or directly with
1978.
fragment 10 were found to proceed in low yields. Treatment of 14 7 S. Hirai, H. Hirano, H. Arai, Y. Kiba, H. Shibata, Y. Kusayanagi,
with Me2 NH and NaBH4 then gives amine 15,15 and hydrolysis M. Yotsuji, K. Hashiba and K. Tanada, US Patent 4643849, 1987.
of the acetyl group provides 5. Our synthesis then merges with 8 F. Liu, Y. Liu, B. Li, Y. Duan and G. Xu, Huaxue Tongbao, 2003, 66,
w121.
the literature at the reaction of 5 with reagent 7,10 which in our 9 K. S. K. Murthy, G. Weeratunga, B. K. Radatus and K. P. S. Sidhu,
hands proceeded to give 1 in 90% yield.16 US Patent 5750714, 1998.
The strength of the approach described in Scheme 4, apart 10 J. M. Khanna, N. Kumar and B. Khera, P. C. Ray, US Patent 5696275,
from the use of a renewable starting material, is that all the 1997.
11 T. H Brown, M. A Armitage, R. C Blakemore, P. Blurton, G. J.
reaction yields are high (average 91%), culminating in an overall Durant, C. R Ganellin, R. J. Ife, M. E Parsons, D. A Rawlings and
68% yield of 1. If this result is superimposed on previously B. P Slingsby, Eur. J. Med. Chem., 1990, 25, 217; B. Alhede, F. P.
reported yields of 12 from biomass sources,13 the outcome Clausen, Eur. Patent 0219225, 1989.
12 F. Moimas, C. Angeli, G. Comisso, P. Zanon and E. Decorte,
would be 61, 57, and 54% isolated chemical yields of ranitidine Synthesis, 1985, 509.
1 from sucrose, cellulose, and corn stover, respectively. From 13 M. Mascal and E. B. Nikitin, Angew. Chem., Int. Ed., 2008, 47, 7924;
a green chemistry perspective, it is also noteworthy that no M. Mascal and E. B. Nikitin, ChemSusChem, 2009, 2, 859.
chromatography is required at any step in the synthesis. In 14 M. Mascal and S. Dutta, Green Chem., 2011, 13, 40.
15 The reductive amination of furfural derivatives has been described:
terms of formal green metrics, we calculate an atom economy,17 A. Cukalovic and C. V. Stevens, Green Chem., 2010, 12, 1201; A. J.
including all stoichiometric reagents (organic and inorganic), Aasena and J. Skramstad, Arch. Pharm. Pharm. Med. Chem., 1998,
of 56.3% (see ESI†), which is good for a multistep process. We 331, 228.
16 The 1 H and 13 C NMR chemical shifts of 1 are consistent with reported
suggest that this efficient, renewable approach to the synthesis
values in the literature: T. J. Cholerton, J. H. Hunt, G. Klinkert and
of ranitidine 1 will not only provide facile, economic access M. Martin-Smith, J. Chem. Soc., Perkin Trans. 2, 1984, 1761.
to this familiar drug, but also stimulate further development 17 B. M. Trost, Science, 1991, 254, 1471.

3102 | Green Chem., 2011, 13, 3101–3102 This journal is © The Royal Society of Chemistry 2011
Descargado por Daniel Castillo hernández (danicastandez@gmail.com)

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