Organic Process Research & Development 2006, 10, 934−936
Technical Notes
A Practical and Scaleable Preparation of 1,4-Anhydroerythritol
Karla G. Childers,* Spencer D. Dreher, Jaemoon Lee, and J. Michael Williams
Department of Process Research, Merck & Co., Inc. P.O. Box 2000, Rahway, New Jersey 07065, U.S.A.
Scheme 1. Acid-catalyzed cyclodehydration
Abstract:
A practical and efficient kilogram-scale preparation of 1,4-
anhydroerythritol from meso-erythritol is described. A novel
silica gel and sodium bicarbonate slurry/filtration protocol is
utilized to purify the product, giving commercial-grade material
in 60-65% yield.
(2) is commercially available in small quantities (25 g),
availability in bulk is limited, presumably due to currently
available methods for its preparation. In this note, we disclose
a practical, highly efficient, kilogram-scale preparation of
1,4-anhydroerythritol (2).
Introduction
Functionalized tetrahydrofurans can be found in numerous
natural products and pharmaceutically useful compounds
possessing a wide range of biological activity.1 The ability
to construct useful synthetic tetrahydrofuran intermediates
for further elaboration is essential for practical implementa-
tion on large scale. In connection with an ongoing program,
we required an efficient and scaleable method for the
preparation of kilogram quantities of 1,4-anhydroerythritol,
2. This simple tetrahydrofuran diol has been utilized in the
synthesis of natural products,2 potential antiviral targets,3
polymers,4 sugar silicates,5 metal complexes,6 and oligo-
nucleotides.7 Additionally, this versatile compound has found
a place in commercial experimentation, including solvent
preparation,8 fuel additive synthesis,9 and as a component
in health and beauty products.10 While 1,4-anhydroerythritol
Literature methods of preparation of 2 involve the
dehydration of meso-erythritol (1) with catalytic amounts of
strong acids including ion-exchange resins,11 mineral acids12
or organic acids (sulfonic acids13 and pyridinium chloride14)
at >120 °C (Scheme 1). Molecular sieves have also been
used to effect the cyclization.15 Since oligomerization
byproducts are a major problem in all of these protocols,
concomitant high-vacuum distillation of 2 is typically
employed to remove the crude product from the reaction
medium. In addition, the crude distilled product, which
typically contains oligomeric byproducts as well as unreacted
1, often requires additional purification (redistillation11,13 or
chromatography14,15) to obtain 2 in sufficiently high purity.
A low-yielding Soxhlet-style extraction utilizing chloroform
has also been reported.16
* To whom correspondence should be addressed. E-mail: karla_childers@
merck.com.
(1) For reviews, see: (a) Boivin, T. L. B. Tetrahedron 1987, 43, 3309. (b)
Harmange, J. C.; Figade´re, B. Tetrahedron Asymmetry 1993, 4, 1711. (c)
Greve, S.; Reck, S.; Friedrichsen, W. Prog. Heterocycl. Chem. 1998, 10,
129. (d) Elliott, M. C.; Williams, E. J. Chem. Soc., Perkin Trans. 1 2001,
2303.
(2) Bu¨chi, G.; Francisco, M. A.; Liesch, J. M.; Schuda, P. F. J. Am. Chem.
Soc. 1981, 103, 3497.
(3) Bera, S.; Nair, V. Tetrahedron 2002, 58, 4865.
(4) Crivello, J. V.; Bratslavsky, S. A. J. Polym. Sci.:, Part A: Polym. Chem.
1994, 32, 2919. Thiem, J.; Haring, T. Makromol. Chem. 1987, 188, 711.
Imai, T.; Satoh, T.; Kaga, H.; Kaneko, N.; Kakuchi, T. Macromolecules
2004, 37, 3113. Braun, D.; Hempler, P. Angew. Makromol. Chem. 1993,
210, 173.
Initial Reaction Optimization
Our initial efforts began by examining known proce-
dures.11,13,14 Attempted dehydration of 1 under the prescribed
literature conditions with concomitant high-vacuum distil-
lation on scales >20 g proved inefficient and difficult to
engineer for large-scale preparation. Additionally, in our
hands, multigram experiments employing various solvents
and acid catalysts gave only moderate conversions (<50%)
(5) Lambert, J. B.; Lu, G.; Singer, S. R.; Kolb, V. M. J. Am. Chem. Soc. 2004,
126, 9611. Tacke, R.; Bertermann, R.; Burschka, C.; Dragota, S. Angew.
Chem., Int. Ed. 2005, 44, 5292.
(6) Klu¨fers, P.; Krotz, O.; Ossberger, M. Eur. J. Inorg. Chem. 2002, 1919.
(7) McLean, M. J.; Holland, D.; Garman, A. J.; Sheppard, R. C. (Zeneca
Limited). WO Patent 93/20092, 1993.
(11) Otey, F. H.; Mehltretter, C. L. J. Org. Chem. 1961, 26, 1673.
(12) Klosterman, H.; Smith, F. J. Am. Chem. Soc. 1952, 74, 5336. Haines, A.
H.; Wells, A. G. Carbohydr. Res. 1973, 27, 261. Bock, K.; Pedersen, C.;
Thøgersen, H. Acta Chem. Scand. B 1981, 35, 441. Winiewski,. A.;
Sokolowski, J.; Szafranek, J. J. Carbohydr. Chem. 1983, 2, 293. Koerner,
T. A. W., Jr.; Voll, R. J.; Younathan, E. S. Carbohydr. Res. 1977, 59, 403.
(13) Himel, C. M.; Edmonds, L. O. (Phillips Petroleum Company). U.S. Patent
2,572,566, 1951.
(8) Manzer, L. E. (E.I. du Pont De Nemours and Co.). WO Patent 03/042201
A1, 2002.
(9) Seemuth, P. D. (Ethyl Corporation). U.S. Patent 4,405,335, 1983.
(10) Goto, N.; Ehara, T.; Mori, T. (Nisshin Oil Mills Ltd.). Japanese Patents
2004339295, 2004; 2004339121, 2004; 2004339100, 2004; 2004339099,
2004; 2004339095, 2004; 2004339094, 2004; 2004339093, 2004;
2004339093, 2004.
(14) Duclos, A.; Fayet, C.; Gelas, J. Synthesis 1994, 10, 1087.
(15) Kurszewska, M.; Skorupa, E.; Kasprzykowska, R.; Sowiski, P.; Winiewski,
A. Carbohydr. Res. 2000, 326, 241-249.
(16) Haines, A. H.; Wells, A. G. Carbohydr. Res. 1973, 27, 261.
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Vol. 10, No. 5, 2006 / Organic Process Research & Development
10.1021/op0601058 CCC: $33.50 © 2006 American Chemical Society
Published on Web 08/10/2006