New, azide-free transformation of epoxides into 1,2-diamino compounds: Synthesis of the anti-influenza neuraminidase inhibitor oseltamivir phosphate (Tamiflu)

Article abstract of DOI:10.1021/jo005702l

A new, azide-free transformation of the key precursor epoxide 6 to the influenza neuraminidase inhibitor prodrug oseltamivir phosphate (1, Tamiflu) is described. This sequence represents a new and efficient transformation of an epoxide into a 1,2-diamino compound devoid of potentially toxic and hazardous azide reagents and intermediates and avoids reduction and hydrogenation conditions. Using catalytic MgBr2·OEt₂ as a new, inexpensive Lewis acid, the introduction of the first amino function was accomplished by opening of the oxirane ring with allylamine followed by Pd/C-catalyzed deallylation to the amino alcohol 16. The introduction of the second amino group was then accomplished via an efficient reaction cascade involving a domino sequence preferably utilizing a transient imino protection. Selective acetylation of the resulting diamine 17 was achieved under acidic conditions providing the crystalline 4-acetamido-5-N-allylamino-derivative 18, which upon deallylation over Pd/C and phosphate salt formation afforded drug substance 1. The overall yield of this route from 6 of 35-38% exceeds the yield of the azide-based process (27-29%) and does not require any chromatographic purification.

Full text of DOI:10.1021/jo005702l

2044
J . Org. Chem. 2001, 66, 2044-2051
New , Azid e-F r ee Tr a n sfor m a tion of Ep oxid es in to 1,2-Dia m in o
Com p ou n d s: Syn th esis of th e An ti-In flu en za Neu r a m in id a se
In h ibitor Oselta m ivir P h osp h a te (Ta m iflu )
Martin Karpf* and Rene´ Trussardi
F. Hoffmann-La Roche Ltd., Pharmaceuticals Division, Non-Clinical Development,
Chemical Process Research, Grenzacherstrasse 124, CH-4070, Basel, Switzerland
martin.karpf@roche.com
Received October 27, 2000
A new, azide-free transformation of the key precursor epoxide 6 to the influenza neuraminidase
inhibitor prodrug oseltamivir phosphate (1, Tamiflu) is described. This sequence represents a new
and efficient transformation of an epoxide into a 1,2-diamino compound devoid of potentially toxic
and hazardous azide reagents and intermediates and avoids reduction and hydrogenation conditions.
Using catalytic MgBr2‚OEt2 as a new, inexpensive Lewis acid, the introduction of the first amino
function was accomplished by opening of the oxirane ring with allylamine followed by Pd/C-catalyzed
deallylation to the amino alcohol 16. The introduction of the second amino group was then
accomplished via an efficient reaction cascade involving a domino sequence preferably utilizing a
transient imino protection. Selective acetylation of the resulting diamine 17 was achieved under
acidic conditions providing the crystalline 4-acetamido-5-N-allylamino-derivative 18, which upon
deallylation over Pd/C and phosphate salt formation afforded drug substance 1. The overall yield
of this route from 6 of 35-38% exceeds the yield of the azide-based process (27-29%) and does not
require any chromatographic purification.
In tr od u ction
synthesis of 6 was further developed5 in order to allow
the manufacture of 1 on a commercial scale.
Oseltamivir phosphate,1 (1, Tamiflu, Ro 64-0796, GS
4104) is the prodrug of the potent and selective competi-
tive inhibitor2 2 of influenza A and B neuraminidase,
comparing well with the inhibitory activities of Zan-
amivir3 (3, Relenza, GG 167). In contrast to the hetero-
cyclic analogue 3, the carbocyclic ester 1 can be orally
administered for the treatment and prevention of influ-
enza infections. The drug discovery synthesis2 of 1
starting from (-)-quinic acid 4 and proceeding through
the N-tritylaziridine 5 was projected to attain various
derivatives with different ether side chains introduced
by aziridine ring opening. For larger scale preparation
of 1, a practical 12-step synthesis4 was specifically
designed on the basis of the access to the key precursor
epoxide 6 obtained from 4 or (-)-shikimic acid 7. The
(1) Kim, C. U.; Lew, W.; Williams, M. A.; Wu, H.; Zhang, L.; N.;
Chen, X.; Escarpe, P. A.; Mendel, D. B.; Laver, W. G.; Stevens, R. C.
J . Med. Chem. 1998, 41, 2451.
(2) Kim, C. U.; Lew, W.; Williams C. U.; Liu, H.; Zhang, l.;
Swaminathan, S.; Bischofberger, N.; Chen, M. S.; Mendel, D. B.; Tai,
C. Y.; Laver, W. G.; Stevens, R. C. J . Am. Chem. Soc. 1997, 119, 681.
(3) (a) von Itzstein, M.; Wu, W.-Y.; J in, B. Carbohydr. Res. 1994,
259, 301. (b) von Itzstein, M.; Wu, W.-Y.; Kok, G. B.; Pegg, M. S.;
Dyason, J . C.; J in, B.; Phan T. V.; Smythe, M. L.; White, H. F.; Oliver,
S. W.; Colman, P. M.; Varghese, J . N.; Ryan, D. M.; Wood, J . M.;
Bethell, R. C.; Hothman, V. J .; Cameron, J . M.; Penn, C. R. Nature
(London) 1993, 363, 418. (c) von Itzstein, M.; Taylor, N. R. J . Med.
Chem. 1994, 37, 616.
(4) Rohloff, J . C.; Kent K. M.; Postich, M. J .; Becker, M. W.;
Chapman, H. H. Kelly, D. E.; Lew, W.; Louie, M. S.; McGee, L. R.;
Prisbe, E. J .; Schultze, L. M.; Yu, R. H.; Zhang. L. J . Org. Chem. 1998,
63, 4545.
The synthesis4 of 1 from 6 proceeds through the
intermediates shown in Scheme 1 in an overall yield of
27-29% and involves potentially toxic and hazardous
azide reagents, intermediates and reaction conditions.
Although the use of azide chemistry on an industrial scale
is well documented,6 the potential hazards related to its
application prompted us to evaluate an azide-free syn-
(5) Federspiel, M.; Fischer, R.; Hennig, M.; Mair, H. J .; Oberhauser,
T.; Rimmler, G.; Albiez, T.; Bruhin, J .; Estermann, H.; Gandert, C.;
Go¨ckel, V.; Go¨tzo¨, S.; Hoffmann, U.; Huber, G.; J anatsch, G.; Lauper,
S.; Ro¨ckel-Sta¨bler, O.; Trussardi, R.; Zwahlen, A. G. Org. Process Res.
Dev. 1999, 3, 266.
10.1021/jo005702l CCC: $20.00 © 2001 American Chemical Society
Published on Web 02/24/2001

Synthesis of Oseltamivir Phosphate
J . Org. Chem., Vol. 66, No. 6, 2001 2045
Sch em e 1
Sch em e 2
implementation of magnesium bromide etherate (MgBr2‚
OEt2) for this purpose,9 affording the same product
mixture in only 16 h.
thesis in order to establish an independent, safe, and
efficient alternative route amenable to a risk-free large-
scale industrial production of 1.
Since selective hydrogenolysis of 12 to the amino
alcohol 16 without affecting the conjugated cyclohexene
double bond was not achievable, a search for an amine
suitable for the overall transformation 6 f 16 was
started. This investigation finally led to the selection of
allylamine as the reagent of choice not only for the
MgBr2‚OEt2-catalyzed epoxide ring opening reaction to
15 and the subsequent Pd/C-catalyzed deallylation to 16
but also for the short, selective and effective introduction
of the second amino function present in 17. The details
of this new and efficient reaction sequence, summarized
in Scheme 3 and finally leading to the drug substance 1
in good overall yield, will be discussed below.
The epoxide ring-opening reaction of 6 using allylamine
(2 equiv) and MgBr2‚OEt2 (0.2 equiv) in various solvents
led to the 5-N-allylamino derivative 15 accompanied by
the regioisomer 19 (15/19 ∼ 10:1 to 13:1) but only to trace
amounts of the aromatic derivative 14 (about 1% or less).
Whereas the reaction in THF at 65 °C for 12 h yielded
90% of 15 and 19 after hydrolytic workup, a nearly
quantitative yield (97%) was obtained in a 9:1 mixture
of t-BuOMe/MeCN at 55 °C for 16 h. The reaction also
proceeded well in various other solvents10 but the use of
Resu lts a n d Discu ssion
For an efficient azide-free transformation of 6, a
suitable nonazide nitrogen nucleophile and appropriate
conditions had to be found, which are compatible with
the functional groups present and the pronounced ten-
dency of such highly functionalized cyclohexene deriva-
tives toward aromatization. For the epoxide ring opening
of 6, a substantial number of parallel experiments were
performed using several amines and related nitrogen
nucleophiles under various noncatalytic and catalytic
conditions.7 All experiments resulted in either no or
incomplete conversion accompanied by substantial aro-
matization leading to variable amounts of 144 along with
nonidentified byproducts. The first positive results were
achieved using 2 equiv of benzylamine and 0.2 equiv of
ytterbium trifluoromethanesulfonate (Yb(OTf)3),8 provid-
ing the amino alcohol 12 after reflux in THF for 24 h
together with its regioisomer 13 (∼15%) in 93% yield as
shown in Scheme 2. Since Yb(OTf)3 is a high molecular
weight, expensive, and therefore barely technical cata-
lyst, an extensive search for a more practicable promoter
for the oxirane ring opening led to the discovery and
(10) High yields of 15 and 19 were also obtained in MeCN (95% at
65 °C/15 h, 94% at 82 °C/5 h) or in t-BuOMe (91% at 111 °C/∼5 bar/1
h), in toluene (93% at 110 °C/3 h), in i-PrOAc (92% at 88 °C/5 h) and
in (i-Pr)2O (91% at 110 °C/∼5 bar/3 h) but in EtOAc (78 °C/3 h) the
yield dropped to 81%.
(11) Essentially no reaction ensued using CaCl2 or ZnCl2 and partial
aromatization was observed with FeCl2 or NiCl2. Various amounts of
product 15 and aromatization product 14 were formed using MgBr2‚
6H2O, anhydr MgBr2, anhydr. MgI2, LiOTf, LiBr or Zn(OTf)2 but
starting material 6 was still present even after 15-20 h at reflux. The
formation of polar byproducts was observed using LiCl whereas BF3‚
OEt2 and Sc(OTf)3 led to extensive decomposition. TiCl4 led to the
formation of the corresponding chlorohydrin.
(6) (a) Peer, M. Inf. Chim. 1997, 393, 98. (b) Van Brussel, W. Belg.
Spec. Chem. 1996, 16(4), 142. (c) Stohlmeier, M., Thewalt, K. Chem.
Ind. Dig. 1993, 6(2), 124.
(7) A reaction substructure search on commercially available reac-
tion databases revealed a large number of reactions involving the
transformation of epoxides to 2-amino alcohols under a variety of
reaction conditions. For typical conditions and additional references,
see: (a) Rampalli S.; Chaudhari, S. S.; Akamanchi, K. G. Synthesis
2000, 78. (b) Sekar, G.; Singh, V. K. J . Org. Chem. 1999, 64, 287. (c)
Auge´, J .; Leroy, F. Tetrahedron Lett. 1996, 37, 7715. (d) Hodgson, D.
M.; Gibbs, A. R.; Lee, G. P. Tetrahedron 1996, 52, 14361. (e) Carre´, M.
C.; Houmounou, J . P.; Caubere, P. Tetrahedron Lett. 1985, 26, 3107
and references therein.
(12) Afarinkia, K.; Cadogan, J . I. G.; Rees, C. W. Synlett 1990, 7,
415.
(13) Murahashi, S. I.; Yoshimura, N.; Tsumiyama, M.; Kojima, T.
J . Am. Chem. Soc. 1983, 105, 5002.
(8) Chini, M.; Crotti, P.; Favero, L.; Macchia, F.; Pineschi, M.
Tetrahedron Lett. 1994, 35, 433.
(14) Guibe´, F. Tetrahedron 1998, 54, 2967 and references therein.
(15) Several aromatic (i.e., furfural, 2-pyridinecarboxaldehyde, 4-meth-
oxy-, 3-nitrobenzaldehyde) and aliphatic aldehydes (propionaldehyde,
pivalaldehyde, 2-methylpentenal, 2-ethylbutyraldehyde, chloral (hy-
drate), ethyl glyoxylate (50% in toluene)) as well as some ketones
(cyclopentanone, cyclohexanone and 1,1-dimethoxyacetone) were tested
as carbonyl components for imine formation with 16. However none
of these substrates revealed a clear advantage compared to the use of
benzaldehyde with regard to relevant parameters (yield, reaction time,
commercial availability, price, toxicity, ease of removal after activation
of the 4-hydroxy group etc.). In contrast to the imines generated from
aromatic aldehydes the imines from aliphatic aldehydes revealed a
tendency towards condensation and/or oxazolidine formation, thus
impeding their efficient use as N-protecting groups. Attempts towards
the direct conversion of the crude product of the deallylation step 15
f 16 containing the imine 23 via mesylation and allylation led only
to low yields of 17.
(9) To our knowledge, the only use of magnesium bromide in an
epoxide opening process leading to â-amino alcohols involves the
transformation of 2,3-epoxyamines to 3-hydroxyazetidines interpreted
by initial bromination of the epoxide and subsequent intramolecular
bromide substitution: Karikomi, M.; Arai, K.; Toda T. Tetrahedron
Lett. 1997, 38, 6059. In our case an analogous successive substitution
process can be ruled out based on the configuration of the products
obtained. Note added in proof: A reviewer has drawn our attention to
a very recent report describing the MgBr2 promoted opening of an
epoxide: Kauffman, G. S.; Harris, D.; Dorow, R. L.; Stone, B. R. P.;
Parsons, R. L.; Pesti, J . A.; Magnus, N. A.; Fortunak, J . M.; Confalone,
P. N.; Nugent, W. A. Org. Lett. 2000, 2, 3119. The 2-fold molar excess
of the Lewis acid applied to induce epoxide opening parallels our
observations of lower activity of MgBr2 compared to the catalytic
activity of MgBr2‚OEt2 as summarized in footnote 11.

2046 J . Org. Chem., Vol. 66, No. 6, 2001
Karpf and Trussardi
Sch em e 3
water immiscible solvents is preferred allowing a very
simple workup procedure, namely stirring of the reaction
mixture with 1 M aqueous ammonium sulfate or chloride
in order to remove the magnesium salts. An exploratory
screening11 of potential alternative catalysts for the
epoxide opening reaction using allylamine in THF re-
vealed a clear preference for MgBr2‚OEt2 regarding
reaction time, workup procedure, and yield.
system. The amount of 25 was effectively reduced to a
level of about 1-2% by using ethanolamine instead.
The deallylation of 15 to 16 was achieved in 77% yield
with Pd/C in EtOH12 in the presence of ethanolamine at
reflux for 3 h followed by acidic workup. The product
contained about 4% of the isomer 20 derived from 19
present in the epoxide ring opening product. The addition
of ethylenediamine or ethanolamine to the reaction
mixture was shown to initiate and to promote the
deallylation process considerably. Although the role of
these auxiliaries is not fully understood, evidence for
their role as propionaldehyde scavengers was obtained
by GC/MS analysis of reactions mixtures with ethylene-
diamine, revealing peaks interpretable as the propional-
dehyde derived condensation products 21 and 22. The
same analysis indicated the presence of the (unstable)
imine 23 or the corresponding enamine, the products of
the Pd-catalyzed double bond isomerization process and
the potential precursors of the condensation product 24,
which was isolated as a minor byproduct. The structure
of 24 was confirmed by independent synthesis from 16
and 2-methyl-2-pentenal. The use of ethylenediamine as
an additive led to the formation of about 7-10% of the
N-propylamino derivative 25, indicating the activity of
ethylenediamine as a potential hydrogen source in the
While numerous catalytic methods are described for
the removal of N-allylic protecting groups including
homogeneous palladium π-allyl methodology,14 the
straightforward method applied here was clearly advan-
tageous regarding practicality and efficiency.
The direct conversion of 16 to 17 with concomitant
introduction of the second amino function was achieved
without isolation of the intermediates. The sequence
shown in Scheme 4 started with the protection of the
5-amino group by formation of the benzaldehyde imine
26 through azeotropic removal of water in t-BuOMe
directly followed by mesylation. After filtration of NEt3‚
HCl, the t-BuOMe solution of 27 was treated for 15 h
with 4 equiv of allylamine in an autoclave at 112 °C at
3.5-4.5 bar resulting in an 80% yield of 17 after acidic
hydrolysis. This sequence requiring just one filtration and
workup constitutes a new, straightforward and practical
conversion of an amino alcohol into a vicinal diamine
employing readily available and safe reagents. The
efficiency of this transformation is mainly due to the
reversible protection of the amino group as the benz-
aldehyde imine.15
The unexpected presence of 30 as the final product of
the reaction sequence before hydrolysis rose the question
concerning the actual intermediates in the process.
Analytical tracking showed the temporary formation and
disappearance of both the imine 2816 and of the aziridine
9. Therefore, we assume that the domino sequence starts
with the trans imination reaction of 27 with allylamine
(16) De Kimpe, N.; De Smaele, D.; Sakonyi, Z. J . Org. Chem. 1997,
62, 2448.
(17) The appearance of 28 and 9 in the reaction mixture together
with the observation that secondary amines (dimethylamine, diallyl-
amine) are unreactive towards 27 provide sufficient evidence against
the postulation of a mechanistic alternative, namely a direct conversion
of 27 to 30 via extrusion of mesylate forming a benzylidene-aziridinium
type intermediate opened in 5-position by allylamine.

Synthesis of Oseltamivir Phosphate
J . Org. Chem., Vol. 66, No. 6, 2001 2047
Sch em e 4
For the final transformation of the 4-acetamido inter-
mediate 18 to the drug substance 1 the deallylation
conditions had to be elaborated which prevented the 4,5-
acetyl migration to form the isomer 35.18 An exploratory
investigation of the main factors controlling the acetyl
migration tendency in EtOH at reflux revealed acceler-
ated interconversion under acidic conditions (e.g., AcOH.
NEt3‚HCl, H3PO4) or in the presence of salts (e.g., NaOAc,
NaHCO3). To efficiently suppress acetyl migration it is
therefore important to exclude any proton sources and
salts.
Deallylation of 18 over 10% Pd/C in refluxing EtOH
and ethanolamine followed by acidic hydrolysis provided
the free base of the drug substance 1. The use of
ethanolamine instead of ethylenediamine as an auxiliary
to promote the deallylation allowed to reduce the amount
of 36 in the free base from initially 7-10% to about
1-1.5% and to simultaneously shorten the reaction time
from about 12 to 3 h. After complete deallylation,
filtration of the catalyst, acidic hydrolysis and extraction,
the phosphate salt of 1 was formed19 to yield drug
substance 1 of high purity (99.7%) in a yield of 68-73%
from 18 or about 35-38% overall from the epoxide 6.
The reaction sequence described (Scheme 3) represents
a new, unprecedented azide-free transformation of an
epoxide into a 1,2-diamino compound avoiding reduction
and hydrogenation conditions. Due to the efficient 5-step
reaction cascade including a domino sequence involving
transient imino-protection, the number of reaction steps
performed as well as the overall yield of ∼35-38%
compare favorably with the 27-29% yield of the corre-
sponding five-step azide reaction sequence4 (Scheme 1).
Since no potentially hazardous azide reagents and in-
termediates are involved, the new synthesis is safer and
amenable to industrial scale production.
to form 28 and the aminomesylate 29. The fast ring
closure to the aziridine 9 however prevents 29 to be
detected in the reaction mixture. The subsequent aziri-
dine ring opening catalyzed by methanesulfonic acid
liberated in the aziridine ring closure step, led initially
to the diamine 17 which by trans imination with 28 s
present in the reaction mixture s forms the imino
derivative 30.17 The reaction sequence was found to
proceed also in other aprotic solvents (e.g., EtOAc,
toluene) but the best results concerning overall yield,
simplicity of implementation, and purity of the product
17 were obtained in t-BuOMe.
The acetylation of 17 using 1 equiv of acetic anhydride
and NEt3 in EtOAc yielded a mixture of the desired
product 18, about 20% of the 4,5-diacetyl derivative 31
and about 20% of starting material 17. However, selective
acetylation at the 4-amino group was achieved under
acidic conditions with 1 equiv of acetic anhydride in 10
equiv of acetic acid and 1 equiv of MeSO3H in EtOAc at
room temperature. This selectivity is interpreted by
effective protonation of the secondary 5-amino group
under acidic conditions preventing its acetylation and
reflects the substantial pKa difference in 17 of more than
1
2
3 units (pKa 4.2, pKa 7.9, measured in 0.1 M aq KNO3
containing 3% MeOH). The product 18 was obtained by
extractive workup in pure, crystalline form (mp 109 °C,
HPLC area >98%) and in an overall yield of about 50 to
54% based on 6. Interestingly the use of an excess of Ac2O
under acidic conditions did not lead to 31 but to the
imidazoline 32.
Exp er im en ta l Section
Alternatively, a stepwise procedure for the transforma-
tion of 16 to 17 via the N-formyl derivatives 33 and 34
was elaborated. Formylation of the amino alcohol 16 with
ethyl formate in an autoclave at 100 °C led to 33 followed
by mesylation to form 34. After deformylation (MeSO3H,
EtOH, reflux, 2.5 h), the aminomesylate 29 obtained was
treated with allylamine in EtOAc in an autoclave at 112
°C to yield the 4-amino-5-N-allylamino-intermediate 17
via the nonisolated aziridine 9. Selective acetylation then
led to 18 in an overall yield of 57% based on 16.
Gen er a l Meth od s. Unless otherwise noted, reagents and
solvents were used as received from commercial suppliers. All
reactions were carried out under argon atmosphere. Thin-layer
chromatography (TLC) was performed on silica gel 60 F254
plates, 0.25 mm (Merck). Column chromatography on silica
gel 60 (mesh 70-230, Merck) was used to provide reference
samples for analytical purposes of products and byproducts.
Qualitative HPLC was performed on a Merck-Hitachi L6200
system with UV detection at a wavelength of 210 nm using
Symmetry C18 columns (250 × 4.6 mm, Waters) with gradient
elution H2O/MeCN containing 10% of a phosphate buffer at
(18) Oliya, R.; Yuan, L.-C.; Dahl, T. C.; Swaminathan, S.; Wang,
K.-Y.; Lee, W. A. Pharmaceut. Res. 1998, 15, 1300.
(19) Mair, H. J . F. Hoffmann-La Roche Ltd., European Patent
Application No. 99,124,223.1, Dec 3, 1999.

2048 J . Org. Chem., Vol. 66, No. 6, 2001
Karpf and Trussardi
pH 3.0. For acid sensitive samples Phenomenex Luna C18
columns (30 × 4.6 mm, Phenomenex) were used with gradient
elution H2O/MeCN containing 10% of a borate buffer at pH
8.0. Quantitative HPLC analysis using 1,3-dinitrobenzene as
internal standard was performed on a Hewlett-Packard 1050
system using Symmetry C18 columns (250 × 4.6 mm, Waters)
with UV detection (diode array) and elution with H2O/MeCN
containing a phosphate buffer at pH 3.0 and dodecyl sulfate
or Symmetry C8 columns (250 × 4.6 mm, Waters) with
gradient elution H2O/MeCN containing a phosphate buffer at
heated to 55 °C, whereby complete dissolution occurred after
about 1.5 h. The clear yellow solution was refluxed for 15 h,
after which time qualitative HPLC analysis (pH 3) showed less
than 1.0% (area) of the starting material 6. The yellowish,
turbid solution was cooled to about 30 °C and stirred vigorously
with 1 M aqueous (NH4)2SO4 for 15 min, whereby a clear two-
phase mixture evolved after initial cloudiness. The organic
phase was separated, filtered and evaporated in a rotary
evaporator at 48 °C in vacuo to a volume of about 580 mL.
The solid particles were filtered and the brown solution was
evaporated at 48 °C in vacuo for 2 h to yield 312.8 g of crude
15 and 19 (containing 86.6% of 15 and 7.0% of 19 based on
quantitative HPLC analysis (pH 3) corresponding to a 97%
yield of 15 and 19 from 6) as a brown-yellow oil that was used
in the next step without further purification. Reference
samples of 15 and 19 were obtained by column chromatogra-
phy using t-BuOMe/EtOH ) 9:1 containing 1% aq. NH3 as the
eluent. 15: IR (film) ν 3540, 2967, 2936, 2877, 1716, 1657,
1
pH 6.0. H NMR spectra were recorded using tetramethylsi-
lane as an internal standard. Spectra are given in ppm (δ) and
coupling constants, J , are reported in Hertz. Peaks in IR
spectra are reported in cm-1. Low-resolution electron impact
mass spectra (EI-MS) were obtained at an ionization voltage
of 70 eV or by positive ion spray ionization (ISP-MS). Data
are reported in the form of m/z (intensity relative to base )
100).
1
Eth yl (3R,4S,5R)-5-N-Ben zyla m in o-3-(1-eth ylp r op oxy)-
4-h yd r oxy-1-cycloh exen e-1-ca r boxyla te (12). To a stirred
solution of 6 (5.08 g, 20 mmol) in THF (20 mL) was added
MgBr2‚OEt2 (1.03 g, 4.0 mmol) and benzylamine (4.4 mL, 40
mmol). The yellow suspension was heated to reflux for 12 h
and evaporated in a rotary evaporator at 48 °C in vacuo. The
remaining turbid oil was treated with EtOAc (20 mL) and
extracted six times with 5 M aqueous NH4Cl solution. The
organic phase was separated, dried over Na2SO4, filtered, and
evaporated in a rotary evaporator at 48 °C in vacuo to yield
6.88 g (95%) of 12 and 13 as a brown oil containing 15% of the
isomer 13. A reference sample of 13 was obtained from 20 as
described below. 12: IR (film) ν 2966, 2935, 2877, 1715, 1654,
1463, 1244, 1094 cm-1; H NMR (250 MHz, CDCl3) δ 6.90-
6.83 (m, 1H), 6.01-5.83 (m, 1H), 5.27-5.06 (m, 2H), 4.21 (q,
J ) 7.0 Hz, 2H), 4.16-4.09 (m, 1H), 3.67-3.54 (m, 1H), 3.52-
3.35 (m, 2H), 3.28-3.16, (m, 1H), 3.03-2.80 (m, 2H), 2.80-
2.65 (s br, 1H), 2.06-1.92 (m, 1H), 1.69-1.44 (m, 5H), 1.30 (t,
J ) 7.0 Hz, 3H), 0.94 (t, J ) 7.3 Hz, 3H), 0.89 (t, J ) 7.3 Hz,
3H); ISP-MS (m/z) 312.5 (M+ + H). Anal. Calcd for C17H29
-
NO4: C, 65.57; H, 9.39; N, 4.50. Found: C, 65.49; H, 9.36; N,
4.63. 19: IR (film) ν 3422, 2966, 2936, 2877, 1717, 1653, 1464,
1246, 1056, 921 cm-1; 1H NMR (250 MHz, CDCl3) δ 6.86-6.81
(m, 1H), 6.00-5.82 (m, 1H), 5.26-5.06 (m, 2H), 4.21 (q, J )
7.0 Hz, 2H), 4.03-3.94 (m, 1H), 3.73-3.61 (m, 1H), 3.56-3.30
(m, 3H), 2.88-2.75, (m, 1H), 2.74-2.64 (m, 1H), 2.39-2.24 (m,
1H), 1.69-1.44 (m, 6H), 1.29 (t, J ) 7.0 Hz, 3H), 0.93 (t, J )
7.3 Hz, 3H), 0.92 (t, J ) 7.3 Hz, 3H); EI-MS (m/z) 312 (M+, 2),
240 (2), 224 (4), 213 (8), 143 (13), 99 (100); HRMS (m/z) calcd
for C17H29NO4 + H+ 312.2175, obsd 312.2176.
1
1495, 1455, 1382, 1367, 1335, 1250, 1090, 976, 699 cm-1; H
NMR (250 MHz, CDCl3) δ 7.40-7.19 (m, 5H), 6.89-6.82 (m,
1H), 4.21 (q, J ) 7.3 Hz, 2H), 4.15-4.09 (m, 1H), 3.98 (d, J )
13.0 Hz, 1H), 3.75 (d, J ) 13.0 Hz, 1H), 3.68-3.61 (m, 1H),
3.49-3.37 (m, 1H), 3.10-2.83 (m, 2H), 2.9-2.2 (s br, 2H),
2.16-2.00 (m, 1H), 1.63-1.43 (m, 4H), 1.30 (t, J ) 7.0 Hz, 3H),
0.93 (t, J ) 7.3 Hz, 3H), 0.87 (t, J ) 7.3 Hz, 3H); EI-MS (m/z)
361 (M+, 1), 343 (6), 330 (12), 290 (35), 274 (20), 260 (10), 149
(52), 120 (19), 106 (26), 91 (100). Anal. Calcd for C21H31NO4:
C, 69.78; H, 8.64; N, 3.87. Found: C, 69.61; H, 8.35; N, 3.96.
Eth yl (3R,4R,5S)-4-N-Ben zyla m in o-3-(1-eth ylp r op oxy)-
5-h yd r oxy-1-cycloh exen e-1-ca r boxyla te (13). A stirred
solution of 20 (0.95 g, 3.5 mmol) and benzaldehyde (0.37 mL,
3.5 mmol) in t-BuOMe (10 mL) was heated to reflux for 2 h on
a Dean-Stark condenser. After distillation of solvent (∼5 mL),
t-BuOMe (5 mL) was added, and the solution was evaporated
in a rotary evaporator at 48 °C in vacuo to dryness. The
remaining white solid (1.11 g) was dissolved in EtOH (12.6
mL) and treated with NaBH4 (133 mg, 3.5 mmol), and the
slightly yellow solution was stirred at reflux for 24 h. The
yellow solution was evaporated at 45 °C in vacuo, and the
remaining yellow crystalline mass was dissolved in EtOAc
(12.6 mL) and extracted with aqueous NaHCO3 (12.6 mL). The
organic phase was separated and dried over Na2SO4, filtered,
and evaporated in a rotary evaporator at 48 °C in vacuo to
yield 0.87 g of crude 13 (69%) which was purified by column
chromatography using (i-Pr)2O/t-BuOMe ) 1:1 containing 0.5%
aqueous NH3 as the eluent: IR (film) ν 2964, 2936, 2876, 1714,
Eth yl (3R,4S,5R)-5-Am in o-3-(1-eth ylpr opoxy)-4-h ydr oxy-
1-cycloh exen e-1-ca r boxyla te (16) a n d Eth yl (3R,4R,5S)-
4-Am in o-3-(1-eth ylp r op oxy)-5-h yd r oxy-1-cycloh exen e-1-
ca r boxyla te (20). To a stirred solution of 15 (312.8 g,
containing 7% of the isomer 19, purity 94.6% (15 and 19), 0.95
mol) and ethanolamine (66.2 mL, 1.10 mol) in EtOH (1560 mL)
was added 10% Pd/C catalyst (31.3 g). The black suspension
was heated to reflux for 3 h, cooled to 40 °C, and filtered, and
the filter cake was washed with EtOH (100 mL). The combined
filtrates were cooled to 0-5 °C and treated with intensive
stirring with concentrated H2SO4 (59.0 mL, 1.10 mol), keeping
the temperature below 30 °C. The resulting yellowish suspen-
sion was evaporated in a rotary evaporator at 48 °C in vacuo,
and the remaining oily, yellow crystals (956 g) were dissolved
in water and the orange solution was extracted with a mixture
of t-BuOMe (500 mL) and hexane (500 mL). The organic phase
was extracted with 0.5 M aqueous H2SO4 (260 mL), and the
combined aqueous phases (pH ) 2.3) were cooled to 10 °C and
treated with stirring with 50% aqueous KOH (128 mL),
keeping the temperature in the range of 5-20 °C until a pH
of 9.5 was reached. The organic phase was separated, and the
aqueous phase was extracted three times with t-BuOMe (1000
mL, twice 500 mL). The combined organic phases were dried
over Na2SO4 (1000 g) and filtered, and the filter cake was
washed with t-BuOMe (300 mL). The combined filtrates were
evaporated in a rotary evaporator at 48 °C in vacuo and dried
in vacuo for 2 h to yield 271.4 g of crude 16 and 20 (containing
69.1% of 16 and 4.0% of 20 based on quantitative HPLC
analysis (pH 3) corresponding to a 77% yield of 16 and 20) as
a red oil which was used in the next step without further
purification. A reference sample of 16 was obtained by column
chromatography using CH2Cl2/EtOH ) 95:5 containing 0.5%
aqueous NH3 as the eluent. A reference sample of 20 was
prepared by reduction (PPh3, THF, room temperature, 22 h)
of the known4 ethyl (3R,4S,5R)-4-azido-3-(1-ethylpropoxy)-5-
hydroxy-1-cyclohexene-1-carboxylate followed by column chro-
matography using t-BuOMe/EtOH ) 95:5 containing 1%
aqueous NH3 as the eluent. 16: IR (film) ν 3585, 2966, 2935,
2877, 1715, 1651, 1483, 1247, 1100, 1063, 977 cm-1; 1H NMR
(250 MHz, CDCl3) δ 6.92-6.85 (m, 1H), 4.21 (q, J ) 7.0 Hz,
1
1653, 1496, 1454, 1365, 1238, 1118, 1049, 733, 698 cm-1; H
NMR (250 MHz, CDCl3) δ 7.38-7.22 (m, 5H), 6.87-6.83 (m,
1H), 4.21 (q, J ) 7.3 Hz, 2H), 4.08-4.02 (m, 1H), 4.06 (d, J )
12.7 Hz, 1H), 3.88 (d, J ) 12.7 Hz, 1H), 3.77-3.67 (m, 2H),
3.46-3.38 (m, 1H), 2.87-2.73 (m, 2H), 2.37-2.26 (s, 1H), 1.68-
1.45 (m, 5H), 1.30 (t, J ) 7.0 Hz, 3H), 0.95 (t, J ) 7.3 Hz, 3H),
0.92 (t, J ) 7.3 Hz, 3H); ISP-MS (m/z) 362.3 (M+ + H). Anal.
Calcd for C21H31NO4: C, 69.78; H, 8.64; N, 3.87. Found: C,
70.14; H, 8.95; N, 3.62.
Eth yl (3R,4S,5R)-5-N-Allyla m in o-3-(1-eth ylp r op oxy)-4-
h yd r oxy-1-cycloh exen e-1-ca r b oxyla t e (15) a n d E t h yl
(3R,4R,5S)-4-N-Allyla m in o-3-(1-eth ylpr op oxy)-5-h ydr oxy-
1-cycloh exen e-1-ca r boxyla te (19). To a stirred solution of
6 (254.3 g, purity 96.9%, 0.97 mol) in t-BuOMe (900 mL) and
MeCN (100 mL) were added MgBr2‚OEt2 (51.7 g, 0.20 mol)
and allylamine (150 mL, 2.0 mol). The yellow suspension was

Synthesis of Oseltamivir Phosphate
J . Org. Chem., Vol. 66, No. 6, 2001 2049
2H), 4.12 (t, J ) 4.3 Hz, 1H), 3.57-3.38 (m, 2H), 3.19-3.07,
(m, 1H), 2.88-2.75 (m, 1H), 2.1-1.6 (m, 5H), 1.66-1.45 (m,
4H), 1.30 (t, J ) 7.0 Hz, 3H), 0.94 (t, J ) 7.3 Hz, 3H), 0.91 (t,
J ) 7.3 Hz, 3H); ISP-MS (m/z) 272.3 (M+ + H). Anal. Calcd
for C14H25NO4: C, 61.97; H, 9.29; N, 5.16. Found: C, 61.91;
H, 9.22; N, 5.10. 20: IR (Nujol) ν 3201, 2957, 2922, 2853, 1712,
were treated with stirring with 50% aqueous KOH (694 mL)
keeping the temperature in the range of 10-25 °C until pH
∼10 was reached. The brown, turbid mixture was extracted
twice with t-BuOMe (1000 and 400 mL), and the combined
organic extracts were stirred over charcoal (32 g) and filtered.
The filter cake was washed with t-BuOMe (200 mL), and the
combined filtrates were evaporated in a rotary evaporator in
vacuo at 47 °C to yield brown-red, amorphous crystals (285.4
g) which were dissolved with stirring in a mixture of t-BuOMe
(570 mL) and n-hexane (285 mL) at 50 °C. The brown solution
was cooled to -20 to -25 °C with stirring in the course of 45
min and stirred for 5 h at this temperature whereby brown
crystals precipitated. The suspension was filtered over a
precooled (-20 °C) glass filter funnel, and the filter cake was
washed with a precooled (-20 °C) mixture of t-BuOMe (285
mL) and n-hexane (143 mL) and dried in a rotary evaporator
in vacuo at 48 °C to yield 200.33 g of crude 18 (containing
86.9% of 18 based on quantitative HPLC analysis (pH 3)
corresponding to 83% of 18 from 17) as beige crystals, which
was used in the next step without further purification: mp
100-104 °C; IR (film) ν 3271, 3084, 2970, 2923, 1715, 1650,
1
1654, 1577, 1458, 1375, 1244, 1056, 936 cm-1; H NMR (250
MHz, CDCl3) δ 6.82-6.76 (m, 1H), 4.21 (q, J ) 7.0 Hz, 2H),
3.84-3.74 (m, 1H), 3.67-3.53 (m, 1H), 3.44-3.32 (m, 1H),
2.91-2.72, (m, 2H), 2.7-1.7 (s br, ∼3H), 2.33-2.16 (m, 1H),
1.68-1.43 (m, 4H), 1.29 (t, J ) 7.0 Hz, 3H), 0.94 (t, J ) 7.3
Hz, 6H); EI-MS (m/z) 272 (M+ + H+, 4), 213 (21), 184 (11),
143 (100), 97 (59). Anal. Calcd for C14H25NO4: C, 61.97; H,
9.29; N, 5.16. Found: C, 62.08; H, 9.24; N, 5.07.
E t h yl (3R,4R,5S)-5-N-Allyla m in o-4-a m in o-3-(1-et h yl-
p r op oxy)-1-cycloh exen e-1-ca r boxyla te (17). A stirred solu-
tion of 16 (271.4 g, containing 4% of the isomer 20, purity
73.1% (16 and 20), 0.74 mol) and benzaldehyde (102.1 mL, 1.01
mol) in t-BuOMe (2710 mL) was heated to reflux for 2 h on a
Dean-Stark condenser during which time about 9 mL of water
separated. In the course of 30 min, 1350 mL of solvent were
distilled and the red solution containing 26 (reaction monitor-
ing by HPLC analysis (pH 8) was cooled to 0 to 5 °C, treated
with triethylamine (167.3 mL, 1.18 mol), then dropwise with
methanesulfonyl chloride (77.7 mL, 0.99 mol) keeping the
temperature in the range of 0-5 °C in the course of 85 min
during which time an orange precipitate formed. After the
mixture was stirred for 45 min, methanesulfonyl chloride (15.6
mL, 0.18 mol) was added dropwise, the orange suspension was
stirred for 25 min and filtered, and the filter cake was washed
with t-BuOMe (300 mL). The combined filtrates containing 27
were treated with allylamine (300.5 mL, 4.0 mol), and the clear
red solution was heated with stirring in a 3 L autoclave and
1 bar of Ar to 110-112 °C in the course of 45 min, stirred at
this temperature for 15 h at a pressure of 3.5-4.5 bar, and
cooled to 45 °C during 1 h. The red solution was evaporated
in a rotary evaporator in vacuo at 48 °C and the remaining
red gel (566 g) containing 17 and 30 was dissolved with
intensive stirring in a two-phase mixture of 2 N aqueous HCl
(1000 mL) and EtOAc (1000 mL). The organic phase was
separated and extracted with 2 N aqueous HCl (1000 mL), and
the combined aqueous phases were washed with EtOAc (500
mL), cooled to 10 °C, and treated with stirring with 50%
aqueous KOH (256 mL) until pH 10 was reached keeping the
temperature in the range of 10-20 °C. The organic phase was
separated, the aqueous phase was extracted twice with t-
BuOMe (1000 and 500 mL), and the combined extracts were
evaporated in a rotary evaporator at 48 °C in vacuo to yield
277.9 g of crude 17 (containing 66.1% of 17 based on quantita-
tive HPLC analysis (pH 3) corresponding to 80% of 17 from
16) as a red-brown oil, which was used in the next step without
further purification. A reference sample of 17 was obtained
by column chromatography using t-BuOMe/EtOH ) 95:5
containing 1% aqueous NH3 as the eluent: IR (film) ν 3375,
3298, 2970, 2924, 2875, 1709, 1645, 1466, 1261, 1096, 1064
cm-1; 1H NMR (250 MHz, CDCl3) δ 6.82-6.74 (m, 1H), 6.02-
5.82 (m, 1H), 5.28-5.04 (m, 2H), 4.22 (q, J ) 7.0 Hz, 2H), 3.87-
3.77 (m, 1H), 3.51-3.33 (m, 2H), 3.31-3.15 (m, 1H), 2.92-
2.68 (m, 2H), 2.67-2.53 (m, 1H), 2.06-1.89 (m, 1H), 1.85-
1.40 (m, 7H), 1.30 (t, J ) 7.0 Hz, 3H), 0.94 (t, J ) 7.3 Hz, 6H);
ISP-MS (m/z) 311.2 (M+ + H). Anal. Calcd for C17H30N2O3: C,
65.77; H, 9.74; N, 9.02. Found: C, 65.60; H, 9.51; N, 8.98.
Eth yl (3R,4R,5S)-4-N-Acetyla m in o-5-N-a llyla m in o-3-(1-
eth ylp r op oxy)-1-cycloh exen e-1-ca r boxyla te (18). A red
solution of 17 (278.0 g, purity 66.1%, 0.59 mol) in t-BuOMe
(1400 mL) was cooled to 0-5 °C and treated with stirring with
AcOH (512 mL, 9.0 mol), whereby the temperature rose to 23
°C. After the mixture was cooled to 0-5 °C, MeSO3H (58.1
mL, 0.90 mol) was added in the course of 27 min followed by
dropwise addition of Ac2O (84.7 mL, 0.90 mol) in the course of
40 min keeping the temperature in the range of 0-5 °C. The
brown reaction mixture was stirred for 14 h at room temper-
ature and then vigorously stirred with water (1400 mL), and
the brown organic phase was extracted with 1 M aqueous
MeSO3H (450 mL). The combined aqueous phases (pH ∼1.6)
1457, 1377, 1080, 1055 cm-1
;
1H NMR (250 MHz, CDCl3) δ
6.83-6.76 (m, 1H), 5.95-5.77 (m, 1H), 5.60-5.50 (m, 2H),
5.24-5.03 (m, 2H), 4.30-4.15 (m, 3H), 3.73-3.61 (m, 1H),
3.43-3.29 (m, 2H), 3.27-3.12 (m, 2H), 2.80-2.62 (m, 1H),
2.28-2.12 (m, 1H), 2.02 (s, 3H), 1.78-1.62 (s br, 1H), 1.60-
1.42 (m, 4H), 1.30 (t, J ) 7.0 Hz, 3H), 0.90 (t, J ) 7.3 Hz, 6H);
EI-MS (m/z) 352 (M+, 4), 307 (4), 280 (4), 206 (100), 140 (50).
Anal. Calcd for C19H32N2O4: C, 64.75; H, 9.15; N, 7.95.
Found: C, 64.56; H, 9.13; N, 8.04.
Eth yl (3R,4R,5S)-4-N-Acetyla m in o-5-a m in o-3-(1-eth yl-
p r op oxy)-1-cycloh exen e-1-ca r boxyla te (1). A solution of 18
(176.2.0 g, purity 86.9%, 440 mmol) in EtOH (880 mL) was
treated with ethanolamine (30.0 mL, 500 mmol) and 10% Pd/C
catalyst (17.6 g). The black suspension was heated to reflux
for 3 h, cooled to room temperature, and filtered. The filter
cake was washed with EtOH (100 mL), and the combined
filtrates were evaporated in a rotary evaporator at 75 bar in
vacuo (<20 mbar) at 50 °C. The brown, oily residue (207.3 g)
was treated with 2 N aqueous HCl (600 mL), and the brown
solution was distilled in a rotary evaporator at 50 °C and 75
mbar for 5 min whereby vigorous gas evolution occurred
(propionaldehyde). The solution was cooled to room tempera-
ture, washed with t-BuOMe (600 mL), and treated with
stirring and cooling with 25% aqueous NH3 (110 mL) keeping
the temperature below room temperature until pH ∼9-10 was
reached and a brown emulsion formed. The emulsion was
extracted with EtOAc (3 × 600 mL), and the combined extracts
were dried over Na2SO4 (200 g) and filtered. The filter cake
was washed with EtOAc (200 mL), and the combined filtrates
were evaporated in a rotary evaporator at 50 °C in vacuo (<20
mbar) to yield a brown oil (158.6 g) which was dissolved in
EtOH (650 mL). The brown solution was added in the course
of 1 min with stirring to a hot solution (50 °C) solution of 85%
o-phosphoric acid (57.60 g, 0.50 mol) in EtOH (2500 mL). The
resulting solution was cooled in the course of 1 h to 22 °C. At
40 °C seed crystals of 1 (about 10 mg) were added whereby
crystallization started. The beige suspension was cooled in the
course of 2 h to -20 to -25 °C and stirred at this temperature
for 5 h. The suspension was filtered over a precooled (-20 °C)
glass filter funnel for 2 h. The filter cake was first washed
with EtOH (200 mL, precooled to -25 °C), then with acetone
(twice 850 mL), then with n-hexane (twice 1000 mL), then
dried for 3 h to yield 124.9 g (70%) of 1 as white crystals: mp
205-207 °C (lit.4 mp 203-204 °C).
E t h yl
4-N-Acet yla m in o-3-(1-et h ylp r op oxy)-5-N-(2-
m eth ylp en t-2-en ylid en ea m in o)-1-cycloh exen e-1-ca r box-
yla te (24). A solution of 16 (543 mg, 2.0 mmol) and 2-methyl-
2-pentenal (196 mg, 2.0 mmol) in toluene (5.4 mL) was heated
to reflux on a Dean-Stark condenser for 2 h and evaporated
to dryness at 45 °C in vacuo (<15 mbar) to yield 680 mg (97%)
of 24 as a yellow oil: IR (film) ν 3549, 2964, 2935, 2876, 1714,
1643, 1628, 1462, 1376, 1240, 1099, 1054 cm-1; 1H NMR (250
MHz, CDCl3) δ 7.89 (s, 1H), 6.91-6.84 (m, 1H), 5.94-5.83 (m,
1H), 4.27-4.14 (m, 3H), 3.87-3.78 (m, 1H), 3.62-3.51 (m, 1H),

2050 J . Org. Chem., Vol. 66, No. 6, 2001
Karpf and Trussardi
3.50-3.40 (m, 1H), 2.76-2.62 (m, 1H), 2.38-2.17 (m, 4H), 1.82
(s, 3H), 1.64-1.48 (m, 4H), 1.29 (t, J ) 7.0 Hz, 3H), 1.04 (t, J
) 7.4 Hz, 3H),0.93 (t, J ) 7.3 Hz, 3H), 0.92 (t, J ) 7.3 Hz,
3H); ISP-MS (m/z) 352.4 (M+ + H, 7), 280.2 (100). Anal. Calcd
for C20H33NO4: C, 68.34; H, 9.46; N, 3.99. Found: C, 68.36;
H, 9.41; N, 3.99.
of 29 from 34) as a red oil, which was used in the next step
without further purification. A reference sample of 29 was
prepared analogously from a pure reference sample of 34: IR
(film) ν 3382, 2967, 2937, 2878, 1715, 1654, 1464, 1356, 1252,
1177, 1070, 966 cm-1; 1H NMR (250 MHz, CDCl3) δ 6.89-6.77
(m, 1H), 4.52 (dd, J ) 9.0, 3.7 Hz, 1H), 4.42-4.32 (m, 1H),
4.22 (q, J ) 7.1 Hz, 2H), 3.63-3.36 (m, 2H), 3.14 (s, 3H), 2.97-
2.84 (m, 1H), 2.20-2.04 (m, 1H), 2.00-1.75 (s br, 2H), 1.73-
1.46 (m, 5H), 1.30 (t, J ) 7.3 Hz, 3H), 0.95 (t, J ) 7.3 Hz, 3H),
0.90 (t, J ) 7.4 Hz, 3H); ISP-MS (m/z) 350.3 (M++ H); HRMS
(m/z) calcd for C15H28NO6S 350.1637, obsd 350.1626.
E t h yl (3R,4R,5S)-5-N-Allyla m in o-4-a m in o-3-(1-et h yl-
p r op oxy)-1-cycloh exen e-1-ca r boxyla te (17) fr om 29. A red
solution of crude 29 (45.66 g, purity 75.1%, 98 mmol) in EtOAc
(250 mL) was treated with allylamine (29.5 mL, 390 mmol)
and heated with stirring in an autoclave and 1 bar of Ar to
112 °C in the course of 45 min, stirred at this temperature for
6 h at a pressure of 3.5 to 6.0 bar and cooled to room
temperature during 50 min whereby a precipitate formed. The
red suspension was vigorously stirred with 1 M aqueous
NaHCO3 (230 mL) for 20 min, the organic phase was sepa-
rated, dried over Na2SO4 (100 g), filtered, and evaporated in
a rotary evaporator at 45 °C in vacuo to yield 41.80 g of crude
17 (containing 55.0% of 17 based on quantitative HPLC
analysis (pH 3) corresponding to 76% of 17 from 29) as a red
oil, which was used in the acetylation step as described above
without further purification.
E t h yl (3R,4S,5R)-3-(1-E t h ylp r op oxy)-4-h yd r oxy-5-N-
p r op yla m in o-1-cycloh exen e-1-ca r boxyla te (25). From the
crude product 16 (6.0 g) of an experiment performed in analogy
to the deallylation of 15 described above but using ethylene-
diamine instead of ethanolamine as the promoter the 5-N-
propylamino derivative 25 (0.4 g) was separated by column
chromatography on silica gel (170 g) using t-BuOMe containing
1% aqueous NH3 as the eluent: IR (film) ν 3440, 2963, 2934,
2876, 1716, 1654, 1463, 1244, 1098 cm-1; 1H NMR (250 MHz,
CDCl3) δ 6.93-6.80 (m, 1H), 4.21 (q, J ) 7.0 Hz, 2H), 4.16-
4.09 (m, 1H), 3.63-3.52 (m, 1H), 3.46 (qui, J ) 6.0 Hz, 1H),
2.98-2.66, (m, 4H), 2.59-2.45 (s, 1H), 2.07-1.88 (m, 1H),
1.73-1.40 (m, 6H), 1.30 (t, J ) 7.0 Hz, 3H), 0.94 (t, J ) 7.2
Hz, 3H), 0.89 (t, J ) 7.3 Hz, 3H); EI-MS (m/z) 313 (M+, 4),
282 (26), 242 (56), 212 (54), 101 (100). Anal. Calcd for C17H31
-
NO4: C, 65.14; H, 9.97; N, 4.47. Found: C, 65.24; H, 9.84; N,
4.55.
Eth yl (3R,4S,5R)-5-N-Ben zylid en ea m in o-3-(1-eth ylp r o-
p oxy)-4-h yd r oxy-1-cycloh exen e-1-ca r boxyla te (26). A so-
lution of 16 (272 mg, 1.0 mmol) and benzaldehyde (117 mg,
1.1 mmol) in toluene (2.7 mL) was heated to 110 °C for 30
min and evaporated in a rotary evaporator to dryness at 45
°C in vacuo (<15 mbar) to yield 360 mg (100%) of 26 as a
yellow oil: IR (film) ν 3540, 2966, 2934, 2876, 1714, 1644, 1451,
Eth yl (3R,4R,5S)-5-N-Allylam in o-4-N-ben zyliden eam in o-
3-(1-eth ylp r op oxy)-1-cycloh exen e-1-ca r boxyla te (30). A
solution of 17 (0.93 g, 3.0 mmol) and benzaldehyde (0.30 mL,
3.0 mmol) in (i-Pr)2O (10 mL) was heated to reflux for 2 h and
evaporated to dryness in a rotary evaporator at 45 °C in vacuo
(<15 mbar) to yield 1.17 g (98%) of 30 as a yellow oil as a
mixture of E/ Z isomers: IR (film) ν 2965, 2937, 2876, 1715,
1644, 1462, 1241, 1098, 1060 cm-1; 1H NMR (250 MHz, CDCl3,)
δ 8.38 (s, ∼0.7H), 7.81-7.72 (m, ∼1.3H), 7.53-7.25 (m, ∼4H),
6.87-6.77 (m, 1H), 5.93-5.66 (m, 1H), 5.25-4.94 (m, 2H), 4.58
(s, ∼0.3H), 4.32-4.13 (m, ∼2.4H), 4.08-3.98 (m, ∼0.3H), 3.50-
3.10 (m, ∼5H), 2.93-2.57 (m, ∼1.3H), 2.35-2.00 (m, ∼0.7H),
1.80-1.20 (m, ∼8H), 1.02-0.79 (m, ∼4H), 0.61 (t, J ) 7.3 Hz,
∼2H); ISP-MS (m/z) 399.4 (M+ + H). Anal. Calcd for
1
1244, 1101, 1055 cm-1; H NMR (250 MHz, CDCl3) δ 8.39 (s,
1H), 7.81-7.68 (m, 2H), 7.47-7.33 (m, 3H), 6.95-6.88 (m, 1H),
4.33-4.23 (m, 1H), 4.22 (q, J ) 7.0 Hz, 2H), 3.94-3.86 (m,
1H), 3.82-3.71 (m, 1H), 3.47 (qui, J ) 5.8 Hz, 1H), 2.85-2.72
(m, 1H), 2.65-2.48 (s br, 1H), 2.47-2.33 (m, 1H), 1.68-1.48
(m, 4H), 1.29 (t, J ) 7.0 Hz, 3H), 0.94 (t, J ) 7.3 Hz, 3H), 0.93
(t, J ) 7.3 Hz, 3H); ISP-MS (m/z) 360.3 (M+ + H). Anal. Calcd
for C21H29NO4: C, 70.17; H, 8.13; N, 3.90. Found: C, 70.24;
H, 8.06; N, 3.97.
Eth yl (3R,4S,5R)-5-N-Ben zylid en ea m in o-3-(1-eth ylp r o-
p oxy)-4-m et h a n esu lfon yloxy-1-cycloh exen e-1-ca r b oxy-
la te (27). To a solution of 26 (360 mg, 1.0 mmol) and
triethylamine (153 µL, 1.1 mmol) in EtOAc (3.6 mL) cooled to
0-5 °C was added with stirring MeSO2Cl (87 µL, 1.1 mmol)
and the mixture stirred for 1 h at room temperature. The white
suspension was extracted with 1 M aqueous NaHCO3 (3 mL),
and the organic phase was separated and dried over Na2SO4,
filtered, and evaporated to dryness in a rotary evaporator at
45 °C in vacuo (<15 mbar) to yield 410 mg (94%) of 27 as a
yellow oil: IR (film) ν 2968, 2937, 2877, 1715, 1646, 1581, 1452,
1359, 1244, 1178, 987 cm-1; 1H NMR (250 MHz, CDCl3) δ 8.37
(s, 1H), 7.77-7.66 (m, 2H), 7.47-7.36 (m, 3H), 6.95-6.88 (m,
1H), 4.83 (dd, J ) 9.7, 4.0 Hz, 1H), 4.47-4.38 (m, 1H), 4.22
(q, J ) 7.0 Hz, 2H), 4.08-3.95 (m, 1H), 3.56 (qui, J ) 5.8 Hz,
1H), 2.93 (s, 3H), 2.88-2.74 (m, 1H), 2.60-2.45 (m, 1H), 1.68-
1.47 (m, 4H), 1.29 (t, J ) 7.0 Hz, 3H), 0.97 (t, J ) 7.3 Hz, 3H),
0.92 (t, J ) 7.3 Hz, 3H); ISP-MS (m/z) 438.3 (M+ + H); HRMS
(m/z) calcd for C22H31NO6S 438.1950, obsd 438.1951.
Eth yl (3R,4S,5R)-5-Am in o-3-(1-eth ylp r op oxy)-4-m eth -
an esu lfon yloxy-1-cycloh exen e-1-car boxylate (29). A stirred
orange solution of crude 34 (58.39 g, purity 67.8%, 105 mmol)
in EtOH (290 mL) was treated with MeSO3H (10.7 mL, 165
mmol) and heated to reflux for 160 min. The red-brown
reaction mixture was evaporated in a rotary evaporator at 45
°C in vacuo to dryness, and the remaining red-brown oil was
dissolved in H2O (260 mL) and extracted with t-BuOMe (260
mL). The organic phase was extracted with H2O (52 mL), and
the combined aqueous phases were cooled to 0-5 °C and
treated dropwise with 50% aqueous KOH (13.7 mL) keeping
the temperature below 10 °C until a pH of 9.4 was reached.
The beige emulsion was extracted twice with EtOAc (260 and
70 mL), the combined extracts were dried over Na2SO4 (160
g), filtered, and evaporated in a rotary evaporator at 45 °C in
vacuo to yield 45.66 g of crude 29 (containing 75.1% of 34 based
on quantitative HPLC analysis (pH 3) corresponding to 93%
C
24H34N2O3: C, 72.33; H, 8.60; N, 7.03. Found: C, 72.33; H,
8.59; N, 7.12.
Eth yl (3R,4R,5S)-5-N-Acetyl-N-a llyla m in o-4-N-ben zyl-
ideneamino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate
(31). To a solution of 18 (3.70 g, 11.9 mmol) in t-BuOMe (37
mL) was added with stirring at 0-5 °C NEt3 (1.66 mL, 11.9
mmol) followed by dropwise addition of Ac2O (1.13 mL, 11.9
mmol) in the course of 10 min. The yellowish solution was
stirred at room temperature for 19 h and extracted with 1 M
aqueous NaHCO3 (37 mL), the organic phase separated and
dried over Na2SO4 and filtered, and the filtrate was evaporated
to dryness in a rotary evaporator at 50 °C in vacuo (<15 mbar)
to yield a yellow oil (2.90 g) which was purified by column
chromatography on silica gel (90 g) using EtOAc containing
1% aqueous NH3 as the eluent to yield 1.83 g (44%) of 31 as a
slightly yellowish oil: IR (film) ν 3311, 3084, 2966, 2937, 2877,
1716, 1650, 1629, 1555, 1417, 1249, 1130, 1079 cm-1; 1H NMR
(250 MHz, CDCl3) δ 6.83-6.72 (m, 1H), 6.18-6.02 (m, 1H),
5.76-5.57 (m, 1H), 5.21-5.08 (m, 2H), 4.98-4.65 (s br, 1H),
4.32-3.97 (m, 4H), 3.93-3.78 (m, 2H), 3.32 (qui, J ) 5.7 Hz,
1H), 2.65-2.25 (m, 2H), 2.07 (s, 3H), 1.94 (s, 3H), 1.58-1.40
(m, 4H), 1.28 (t, J ) 7.2 Hz, 3H), 0.90 (t, J ) 7.3 Hz, 3H), 0.86
(t, J ) 7.4 Hz, 3H); ISP-MS (m/z) 395.4 (M+ + H). Anal. Calcd
for C21H34N2O5: C, 63.94; H, 8.69; N, 7.10. Found: C, 63.87;
H, 8.96; N, 6.71.
Eth yl (3aR,4R,7aS)-1-Allyl-2-m eth yl-4-(1-eth ylpr opoxy)-
3a ,4,7,7a -tetr a h yd r oben zim id a zole-6-ca r boxyla te (32). A
yellow solution of 18 (1.76 g, 5.0 mmol) in EtOAc (16 mL) and
a 50% solution of propane phosphonic acid anhydride in EtOAc
(3.25 mL, 5.5 mmol) was heated with stirring to reflux for 7
h, cooled to room temperature, and extracted with 1 M aqueous
Na2CO3 (16 mL). The organic phase was separated and dried
over Na2SO4 and filtered, and the filtrate was evaporated to
dryness in a rotary evaporator at 45 °C in vacuo (<5 mbar) to

Synthesis of Oseltamivir Phosphate
J . Org. Chem., Vol. 66, No. 6, 2001 2051
yield a brown oil (1.55 g) which was purified by column
chromatography on silica gel (90 g) and using t-BuOMe
containing 1% aqueous NH3 as the eluent to yield 1.23 g (74%)
of 32 as a yellow oil: IR (film) ν 2966, 2936, 2876, 1715, 1679,
1658, 1601, 1370, 1236, 1103, 1062 cm-1; 1H NMR (250 MHz,
CDCl3) δ 6.83-6.76 (m, 1H), 5.76-5.57 (m, 1H), 5.22-5.08 (m,
2H), 4.21-4.05 (m, 3H), 3.74-3.58 (m, 3H), 3.16-3.01 (m, 1H),
2.92-2.76 (m, 1H), 2.75-2.62 (m, 1H), 2.24-2.05 (m, 1H), 1.97
(d, J ) 1.8 Hz, 3H), 1.67-1.38 (m, 4H), 1.23 (t, J ) 7.2 Hz,
3H), 0.89 (t, J ) 7.4 Hz, 3H), 0.87 (t, J ) 7.4 Hz, 3H); EI-MS
(m/z) 335 (M+ + H, 21), 334 (M+, 10), 263 (100), 248 (52), 142
(64), 123 (53), 96 (88). Anal. Calcd for C19H30N2O3: C, 68.23;
H, 9.04; N, 8.38. Found: C, 68.25; H, 9.09; N, 8.26.
separated and dried over Na2SO4 (130 g), filtered, and evapo-
rated in a rotary evaporator at 45 °C in vacuo to yield 58.39 g
of crude 34 (containing 67.8% of 34 based on quantitative
HPLC analysis (pH 3) corresponding to 100% of 34 from 33)
as an orange-red oil, which was used in the next step without
further purification. A reference sample of 34 (mixture of
rotamers containing ∼6% of EtOAc) was prepared from a pure
reference sample of 33: IR (film) ν 3270, 2967, 2938, 2878,
1715, 1682, 1358, 1338, 1249, 1177 cm-1; 1H NMR (250 MHz,
CDCl3) δ 8.34-8.27 (m, 1H), 6.92-6.70 (m, 1H), 6.65-6.48 (m,
1H), 6.10-5.65 (s br, 1H), 4.86 (dd, J ) 10.7, 3.7 Hz, 1H), 4.73-
4.55 (m, 1H), 4.38-4.10 (m, 4H), 3.59-3.35 (m, 1H), 3.25-
2.98 (m, 5H), 2.46-2.26 (m, 1H), 1.70-1.20 (m, 12H), 0.95 (t,
J ) 7.3 Hz, 3H), 0.89 (t, J ) 7.3 Hz, 3H); EI-MS (m/z) 377
(M+, 2), 290 (50), 244 (28), 194 (27), 166 (34), 148 (100), 142
(39), 96 (37). Anal. Calcd for C16H27NO7S + 5.77% EtOAc: C,
51.12; H, 7.32; N, 3.50; S, 8.00. Found: C, 51.10; H, 7.30; N,
3.55; S, 7.96.
Eth yl (3R,4R,5S)-4-N-Acetyla m in o-3-(1-eth ylp r op oxy)-
5-N-p r op yla m in o-1-cycloh exen e-1-ca r boxyla te (36). This
compound was separated by column chromatography as a
byproduct of a deallylation experiment of 18 to 1 as described
above using ethylenediamine as the promoter: IR (film) ν 3425,
3279, 2963, 2937, 1718, 1648, 1558, 1368, 1251, 1097, 1056
cm-1; 1H NMR (250 MHz, CDCl3) δ 6.83-6.75 (m, 1H), 5.55-
5.43 (m, 1H), 4.34-4.14 (m, 3H), 3.68-3.52 (m, 1H), 3.36 (qui,
J ) 5.6 Hz, 1H), 3.25-3.11 (m, 1H), 2.82-2.58 (m, 2H), 2.57-
2.43 (m, 1H), 2.27-2.08 (m, 1H), 2.01 (s, 3H), 1.65-1.38 (m,
7H), 1.30 (t, J ) 7.2 Hz, 3H), 0.90 (t, J ) 7.2 Hz, 9H); EI-MS
(m/z) 355 (M+ + H, 15), 282 (49), 208 (100), 142 (50), 100 (29).
Anal. Calcd for C19H34N2O4: C, 64.38; H, 9.67; N, 7.90.
Found: C, 64.18; H, 9.44; N, 8.00.
Eth yl (3R,4S,5R)-5-N-Acetyla m in o-3-(1-eth ylp r op oxy)-
4-h yd r oxy-1-cycloh exen e-1-ca r boxyla te (33). A stirred
solution of crude 16 (40.70 g, containing ∼4% of the isomer
20, purity 82.2% (16 and 20), 123 mmol) in ethyl formate (200
mL) was heated with stirring in an autoclave under 1 bar of
Ar in the course of 35 min to 100 °C, stirred at this temper-
ature for 6 h at a pressure of 4-5 bar and cooled to 45 °C
during 1 h. The red solution was treated twice with toluene
(2 × 150 mL) and evaporated in a rotary evaporator at 45 °C
in vacuo to yield 46.24 g of crude 33 (containing 67.7% of 33
based on quantitative HPLC analysis (pH 3) corresponding to
85% of 33 from 16) as a red oil, which was used in the next
step without further purification. A reference sample of 33
(mixture of rotamers containing ∼2% toluene) was prepared
from a pure reference sample of 16: IR (film) ν 3295, 2967,
2937, 2878, 1715, 1673, 1536, 1463, 1385, 1247, 1100 cm-1
;
1H NMR (250 MHz, CDCl3) δ 8.26 (s, 1H), 6.95-6.85 (m, 1H),
5.77-5.65 (m, 1H), 4.35-4.04 (m, 4H), 3.81-3.55 (m, 1H),
3.52-3.38 (m, 1H), 3.18-3.04 (m, 1H), 2.75-2.35 (s br, 1H),
2.18-2.08 (m, 1H), 1.67-1.43 (m, 4H), 1.30 (t, J ) 7.0 Hz, 3H),
0.94 (t, J ) 7.2 Hz, 3H), 0.89 (t, J ) 7.3 Hz, 3H); EI-MS (m/z)
300 (M+ + H, 4), 253 (52), 212 (55), 183 (100), 166 (90), 148
(82), 138 (74), 96 (59). Anal. Calcd for C15H25NO5 + 1.79%
toluene: C, 60.74; H, 8.42; N, 4.60. Found: C, 60.87; H, 8.47;
N, 4.64.
Ack n ow led gm en t. The authors thank Mr. Marc
Duchene, Mr. Mischa Huber, Mr. Dieter Muri, and Mrs.
Nathalie Sala for skillful experimental work and Mr.
Marcel Althaus, Mr. J ean-Claude J ordan, and Mr.
Vladimir Meduna for providing analytical support. We
also thank the members of the Analytical Services of
Hoffmann-La Roche Ltd., Basel, for efficiently and
persistently providing and interpreting the physical
data of all compounds described. The careful reading of
the manuscript by Mark Rogers-Evans, Hans Hilpert,
Thomas Oberhauser, and Ulrich Widmer is gratefully
acknowledged.
Eth yl (3R,4S,5R)-3-(1-Eth ylp r op oxy)-5-N-for m yla m in o-
4-m eth a n esu lfon yloxy-1-cycloh exen e-1-ca r boxyla te (34).
To a stirred orange solution of crude 33 (46.24 g, purity 67.7%,
105 mmol) in EtOAc (460 mL) and NEt3 (23.7 mL, 170 mmol)
was added dropwise at 0-5 °C MeSO3Cl (13.2 mL, 170 mmol)
in the course of 30 min, during which time a white precipitate
formed. After the mixture was stirred without cooling for 2 h,
the white suspension was filtered, the filter cake was washed
with EtOAc (45 mL), and the combined filtrates were extracted
with 1 M aqueous NaHCO3 (116 mL). The organic phase was
J O005702L