A practical synthesis of (-)-oseltamivir

Article abstract of DOI:10.1002/anie.200701754

(Chemical Equation Presented) Keep it simple: Still in hot demand, the influenza drug (-)-oseltamivir phosphate (tamiflu; see scheme) has now been synthesized from pyridine by using inexpensive reagents. A strict minimum of purification steps are required in a synthetic route which features an asymmetric Diels-Alder reaction, a bromolactonization, a Hofmann rearrangement, and a domino transformation of a bicyclo[2.2.2] system into an aziridine intermediate.

Full text of DOI:10.1002/anie.200701754

Communications
DOI: 10.1002/anie.200701754
Drug Synthesis
A Practical Synthesis of (À)-Oseltamivir**
Nobuhiro Satoh, Takahiro Akiba, Satoshi Yokoshima, and Tohru Fukuyama*
(
À)-Oseltamivir phosphate (1·H PO , tamiflu) is a potent
could best be constructed by an asymmetric Diels–Alder
reaction between dihydropyridine 6 and the acrylic acid
derivative 7.
3
4
inhibitor of neuraminidase and is used worldwide as a drug
[
1]
for influenza of both type Aand type B. The recent spread
of the avian virus H5N1 has prompted governments to
stockpile tamiflu as a precautionary measure against an
influenza pandemic. However, the high cost of the drug
makes it difficult for developing countries to stockpile
tamiflu. The starting material in the current industrial syn-
thesis of oseltamivir is shikimic acid, which is obtained either
by the extraction of Chinese star anise or by the fermentation
of genetically engineered E. coli through tedious purification
processes. Furthermore, special production facilities are
needed to handle the explosive intermediates and reagents
involved. Therefore, intensive efforts have been made to
improve the synthesis of oseltamivir. Herein, we report a
practical synthesis of oseltamivir.
Our synthesis commenced with the reduction of pyridine
(8) in the presence of benzyl chloroformate to give dihydro-
[
4]
pyridine 9 (Scheme 2). Asymmetric Diels–Alder reactions
between dihydropyridine derivatives and acrylic acid deriv-
atives have not yet been developed to a high enough level to
[
5]
be used practically in synthesis. We therefore turned to a
two-step sequence involving the use of acrolein. The treat-
ment of 9 with acrolein in the presence of the MacMillan
[
2]
[6]
catalyst (10) at room temperature led to a mixture of
aldehydes which included the desired Diels–Alder adduct
[
7]
11. This mixture was subjected without purification to Kraus
oxidation to give the corresponding carboxylic acid 12 among
[
3]
[
8]
the products. After the removal of basic impurities by
washing a solution of the product mixture in ethyl acetate
with dilute HCl, the carboxylic acids were extracted into an
aqueous solution of sodium bicarbonate. Upon addition of
bromine, a facile bromolactonization proceeded to give the
desired lactone 13. As acidic by-products remain in the
aqueous phase, simple extraction followed by crystallization
from methanol afforded practically pure 13 (> 99% ee) in
Our retrosynthesis of oseltamivir (1) is outlined in
Scheme 1: We proposed the bicyclo[2.2.2] lactam 2 with a
2
6% yield from benzyl chloroformate. Thus, neither tedious
chromatographic separations nor expensive reagents are
needed to prepare bromolactone 13.
Having developed a highly efficient route to this key
intermediate, we then focused on the further transformation
of 13 into oseltamivir. The Cbz group in 13 was exchanged for
a Boc group by hydrogenolysis in the presence of Boc O to
2
[
9]
give 14 (92% yield), which was oxidized with a catalytic
amount of RuO ·nH O (10 mol%) and NaIO to furnish
2
2
4
[
10]
Scheme 1. Retrosynthesis of oseltamivir (1).
imide 15 in 86% yield.
Ammonolysis of the lactone
followed by mesylation of the resulting alcohol afforded
mesylate 17 in 86% yield from 15. When treated with
iodobenzene diacetate and allyl alcohol, amide 17 underwent
the Hofmann rearrangement to give allyl carbamate 18 in
leaving group X at C2 as a key precursor to 1 and envisaged
that 2 could be derived from carboxylic acid 3 by either a
Curtius or a Hofmann rearrangement of the corresponding
amide. Lactone 4, a precursor of 3, could in turn be derived
from 5 by halolactonization. Finally, the bicyclic system 5
[
11]
88% yield.
As initially anticipated, 18 underwent a series of trans-
formations upon treatment with a slight excess of sodium
ethoxide (2.02 equiv) at 08C: Thus, ethanolysis of the N-Boc
lactam, dehydrobromination, and aziridine formation pro-
vided 19 in 87% yield. The regioselective cleavage of
aziridine 19 was effected by treatment with BF ·Et O in 3-
[
*]N. Satoh, T. Akiba, Dr. S. Yokoshima, Prof. T. Fukuyama
Graduate School of Pharmaceutical Sciences
University of Tokyo
7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan)
3
2
Fax: (+81)3-5802-8694
E-mail: fukuyama@mol.f.u-tokyo.ac.jp
[1,12]
pentanol to give ether 20 in 62% yield.
Removal of the
Boc group and acetylation of the resulting amine afforded 21
in 88% yield. Finally, deprotection of the Alloc-substituted
[**]This research was supported financially in part by a grant for the
2
1
1st Century COE Program and a Grant-in-Aid (15109001 and
6073205) from the Ministry of Education, Culture, Sports, Science,
amine with a combination of Pd/C, Ph P, and 1,3-dimethyl-
3
barbituric acid in ethanol at reflux, removal of the Pd/C
catalyst by filtration, concentration in vacuo, and the addition
and Technology of Japan. We are indebted to Dr. Kunisuke Izawa of
Ajinomoto Co. for an ample supply of d-phenylalanine.
[
3d]
of phosphoric acid furnished crystalline oseltamivir phos-
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
phate (1·H PO ) in 76% yield. The spectroscopic data of
3
4
5
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ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2007, 46, 5734 –5736

Angewandte
Chemie
Scheme 2. Synthesis of oseltamivir phosphate (1·H PO ). Alloc=allyloxycarbonyl, Bn=benzyl, Boc=tert-butoxycarbonyl, Cbz=benzyloxycarbonyl,
3
4
Ms=methanesulfonyl, M.S.=molecular sieves, TFA=trifluoroacetic acid.
oseltamivir phosphate obtained by this synthetic route are
consistent with those reported in the literature.
[1] C. U. Kim, W. Lew, M. A. Williams, H. Liu, L. Zhang, S.
[
3a]
Swaminathan, N. Bischofberger, M. S. Chen, D. B. Mendel, C. Y.
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2] S. Abrecht, P. Harrington, H. Iding, M. Karpf, R. Trussardi, B.
Wirz, U. Zutter, Chimia 2004, 58, 621.
We believe that our synthetic route to 1 is highly practical
for a number of reasons: First, inexpensive and commonly
used reagents are employed. The relatively expensive catalyst
RuO ·nH O can be recovered and reused (see reference [8]
[
[
3] a) J. C. Rohloff, K. M. Kent, M. J. Postich, M. W. Becker, H. H.
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2
2
and the Supporting Information). Furthermore, although the
overall yield of lactone 13 from benzyl chloroformate is
rather low (26%), this intermediate can be obtained as
crystals on a large scale without tedious purification proce-
dures. The other reactions proceed in high yields, and a
majority of the intermediates are obtained as crystals. In
practice, no chromatographic purifications are required for
the conversion of 13 into 17 or for the conversion of 20 into 1.
In conclusion, we have synthesized oseltamivir phosphate
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(
(
1·H PO ) in 22% yield from the readily available lactone 13
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Shibasaki, J. Am. Chem. Soc. 2006, 128, 6312; g) X. Cong, Z.-J.
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3
4
metric Diels–Alder reaction, a bromolactonization, and a
Hofmann rearrangement as key transformations. We believe
that the overall yield of 1 prepared by the route described
would be much improved in a production-scale operation and
that our synthesis is thus a viable alternative to the Roche–
Gilead synthesis in which shikimic acid is employed as the
starting material. Furthermore, our synthetic route has great
potential for the generation of a wide range of tamiflu
analogues.
[
[5] For enantioselective Diels–Alder reactions of dihydropyridines,
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dropyridines, see: c) M. Mehmandoust, C. Marazano, R. Singh,
B. Gillet, M. CØsario, J.-L. Fourrey, B. C. Das, Tetrahedron Lett.
Received: April 20, 2007
Published online: June 26, 2007
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tions of chiral acrylic acid derivatives with dihydropyridines, see:
Keywords: antiviral agents · Diels–Alder reaction ·
domino reactions · lactones · rearrangement
.
Angew. Chem. Int. Ed. 2007, 46, 5734 –5736ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5735

Communications
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propyl acetate, a safer solvent than dichloroethane, could be
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1
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[
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[12] The relatively low yield of 20 was attributed to the concomitant
formation of oxazolidinone 22. The mixture was readily sepa-
rable by chromatography on silica gel.
[
[
2983.
[
10] In an experiment with 4.5 g of 14, 93% of the RuO ·nH O used
2
2
could be recovered by the addition of isopropanol to the
reaction mixture followed by filtration. The recovered material
could be reused and showed no sign of deterioration (see the
5
736
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ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2007, 46, 5734 –5736