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

Article abstract of DOI:10.1039/c1gc15537g

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. The Royal Society of Chemistry.

Full text of DOI:10.1039/c1gc15537g

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Synthesis of ranitidine (Zantac) from cellulose-derived
5-(chloromethyl)furfural†
Mark Mascal* and Saikat Dutta
Received 11th May 2011, Accepted 29th August 2011
DOI: 10.1039/c1gc15537g
The biomass-derived platform chemical 5-(chloro-
methyl)furfural is converted into the blockbuster antiulcer
drug ranitidine (Zantac) in four steps with an overall 68%
isolated yield.
of furfural 2. The furan ring in 3 is aminomethylated to 4,
which reacts with cysteamine in concentrated aq. HCl to give
5. The patent literature puts the yields of both of these steps
at <50%,7 although more recent studies report conversions of
82%8 and 75%9 for 4 and 5, respectively. Condensation of 5 with
1-methylthio-1-methylamino-2-nitroethylene 7 then provides 1,
with yields of up to 90% having been reported for this reaction.10
In a reversal of roles in 4, the dimethylamino group can be
quaternized and serve as the leaving group for the introduction
of cysteamine,11 but this necessitates the re-introduction of the
dimethylaminomethyl function from the hydroxymethyl group,
which lengthens the synthesis.
Other approaches to 1 have been developed which avoid
the use of cysteamine altogether, in which the OH group of
either 3 or 4 is converted to SH and then aminoethylated
using aziridine, 2-chloroethylamine, chloroacetonitrile, or N-(2-
chloroethyl) phthalimide.3
A key intermediate in the synthesis of 1 is 1-methylthio-
1-methylamino-2-nitroethylene 7. This can be prepared by
addition of the nitromethane anion to CS2 and methylation to
give 1,1-bis(methylthio)-2-nitroethylene 6, followed by substi-
tution of one of the MeS groups with methylamine (Scheme
2). The terminal aminonitroethylene fragment of 1 can also
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
Ranitidine 1, sold under the trade name Zantac, is a histamine
H2-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. H2, cat.; b. CH2O, Me2NH, H+ cat.; c.
HSCH2CH2NH2, 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: 1H and 13C
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.
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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.
Scheme 4 Reagents: a. HSCH2CH2NHAc, NaH, THF, 91%; b.
Me2NH, NaBH4, MeOH, 90%; c. 2 M KOH, reflux, 94%; d. 7, H2O,
55 ◦C, 88%.
Scheme 3 Reagents: a. HSCH2CH2NH2; b. MeNH2; c. 4 or derivative.
We have recently shown that 5-(chloromethyl)furfural (CMF)
12 can be derived in a single step from either sugars, cellulose,
or raw cellulosic biomass in isolated yields between 80–90%,13
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
12 in three steps with an overall yield of 68%.14
of CMF 12 as a biomass-derived platform chemical for the
green synthesis of pharmaceuticals and other value-added
products.
Acknowledgements
This research was supported by the US National Science Foun-
dation, grant CBET 0932391. The authors also acknowledge
the assistance of Nabin Meher and Mikae¨l Le Meur in the early
development of this project.
Looking at the structures of CMF 12 and ranitidine 1, a
functional correspondence can clearly be seen, wherein the
(dimethylamino)methyl group could be envisaged to be intro-
duced by reductive amination of the C O group, and the sulfide
bond formed by taking advantage of the reactive chloromethyl
functionality.
Our approach to 1 is presented in Scheme 4. Here, the
key thioethylamino fragment is introduced in excellent yield
by reaction of 12 with commercial N-acetylcysteamine. Early
attempts to substitute 12 with cysteamine itself or directly with
fragment 10 were found to proceed in low yields. Treatment of 14
with Me2NH and NaBH4 then gives amine 15,15 and hydrolysis
of the acetyl group provides 5. Our synthesis then merges with
the literature at the reaction of 5 with reagent 7,10 which in our
hands proceeded to give 1 in 90% yield.16
Notes and references
1 R. Wright, J. Health Care Market., 1996, 16, 24.
2 J. Bradshaw, Chron. Drug Discovery, 1993, 3, 45.
3 R. G. Glushkov, E. V. Adamskaya, T. I. Vozyakova and A. F. Oleinik,
Khimiko-Farmatsevticheskii Zhurnal, 1990, 24, 53 and references
therein.
4 Z. Han and B. Zhou, Yiyao Gongye, 1986, 17, 515.
5 M. Hohnjec, J. Kuftinec, M. Malnar, M. Skreblin, F. Kajfez, A. Nagl
and N. Blazevic, Analytical Profiles of Drug Substances, 1986, 15,
533.
6 B. J. Price, J. W. Clitherow and J. Bradshaw, US Patent 4128658,
1978.
7 S. Hirai, H. Hirano, H. Arai, Y. Kiba, H. Shibata, Y. Kusayanagi,
M. Yotsuji, K. Hashiba and K. Tanada, US Patent 4643849, 1987.
8 F. Liu, Y. Liu, B. Li, Y. Duan and G. Xu, Huaxue Tongbao, 2003, 66,
w121.
9 K. S. K. Murthy, G. Weeratunga, B. K. Radatus and K. P. S. Sidhu,
US Patent 5750714, 1998.
10 J. M. Khanna, N. Kumar and B. Khera, P. C. Ray, US Patent 5696275,
1997.
11 T. H Brown, M. A Armitage, R. C Blakemore, P. Blurton, G. J.
Durant, C. R Ganellin, R. J. Ife, M. E Parsons, D. A Rawlings and
B. P Slingsby, Eur. J. Med. Chem., 1990, 25, 217; B. Alhede, F. P.
Clausen, Eur. Patent 0219225, 1989.
The strength of the approach described in Scheme 4, apart
from the use of a renewable starting material, is that all the
reaction yields are high (average 91%), culminating in an overall
68% yield of 1. If this result is superimposed on previously
reported yields of 12 from biomass sources,13 the outcome
would be 61, 57, and 54% isolated chemical yields of ranitidine
1 from sucrose, cellulose, and corn stover, respectively. From
a green chemistry perspective, it is also noteworthy that no
chromatography is required at any step in the synthesis. In
terms of formal green metrics, we calculate an atom economy,17
including all stoichiometric reagents (organic and inorganic),
of 56.3% (see ESI†), which is good for a multistep process. We
suggest that this efficient, renewable approach to the synthesis
of ranitidine 1 will not only provide facile, economic access
to this familiar drug, but also stimulate further development
12 F. Moimas, C. Angeli, G. Comisso, P. Zanon and E. Decorte,
Synthesis, 1985, 509.
13 M. Mascal and E. B. Nikitin, Angew. Chem., Int. Ed., 2008, 47, 7924;
M. Mascal and E. B. Nikitin, ChemSusChem, 2009, 2, 859.
14 M. Mascal and S. Dutta, Green Chem., 2011, 13, 40.
15 The reductive amination of furfural derivatives has been described:
A. Cukalovic and C. V. Stevens, Green Chem., 2010, 12, 1201; A. J.
Aasena and J. Skramstad, Arch. Pharm. Pharm. Med. Chem., 1998,
331, 228.
16 The 1H and 13C NMR chemical shifts of 1 are consistent with reported
values in the literature: T. J. Cholerton, J. H. Hunt, G. Klinkert and
M. Martin-Smith, J. Chem. Soc., Perkin Trans. 2, 1984, 1761.
17 B. M. Trost, Science, 1991, 254, 1471.
3102 | Green Chem., 2011, 13, 3101–3102
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The Royal Society of Chemistry 2011
©