Facile method for the synthesis of oseltamivir phosphate

Article abstract of DOI:10.1007/s11172-013-0024-2

A ten-step scheme for the preparation of an antiviral agent, ethyl (3R,4R,5S)-4-acetylamino-5-amino-3-(pent-3-yloxy)cyclohex-1-enecarboxylate phosphate, from (-)-shikimic acid was studied. The main parameters of the synthesis were determined and the optimal conditions for the preparation of the intermediate compounds were selected. The total yield of oseltamivir phosphate calculated based on (-)-shikimic acid was 27%.

Full text of DOI:10.1007/s11172-013-0024-2

Russian Chemical Bulletin, International Edition, Vol. 62, No. 1, pp. 163—170, January, 2013
163
Facile method for the synthesis of oseltamivir phosphate
A. I. Kalashnikov, S. V. Sysolyatin, G. V. Sakovich, E. G. Sonina, and I. A. Shchurova
Institute for Problems of Chemical and Energetic Technologies, Siberian Branch of the Russian Academy of Sciences,
1 ul. Sotsialisticheskaya, 659322 Biisk, Russian Federation.
Fax: +7 (385) 430 1725. Eꢀmail: admin@ipcet.ru
A tenꢀstep scheme for the preparation of an antiviral agent, ethyl (3R,4R,5S)ꢀ4ꢀacetylꢀ
aminoꢀ5ꢀaminoꢀ3ꢀ(pentꢀ3ꢀyloxy)cyclohexꢀ1ꢀenecarboxylate phosphate, from (–)ꢀshikimic acid
was studied. The main parameters of the synthesis were determined and the optimal conditions
for the preparation of the intermediate compounds were selected. The total yield of oseltamivir
phosphate calculated based on (–)ꢀshikimic acid was 27%.
Key words: oseltamivir phosphate, ethyl (3R,4R,5S)ꢀ4ꢀacetylaminoꢀ5ꢀaminoꢀ3ꢀ(pentꢀ3ꢀ
yloxy)cyclohexꢀ1ꢀenecarboxylate, (–)ꢀshikimic acid, aziridines, azides.
Avian influenza virus H5N1 is a threat to the populaꢀ
tion as a potential source of the pandemia. The mortality
rate of the virus is more than 50%. To date, no cases of
transmission of the H5N1 from person to person are
known. However, in September 2011 at the Congress in
Malta it was reported that the more dangerous versions
of the virus A(H5N1) was developed in the medical cenꢀ
ter of Rotterdam, which can be transmitted through airꢀ
borne droplets.1 While there is news from England on
the development of universal vaccination against the
flu H5N1 of all the modifications, these studies appear
as the successful development of biological weapꢀ
ons. Therefore, the problem of development of defense
against the pandemia of this dangerous virus becomes very
important.
According to the data of
World Health Organization, osꢀ
eltamivir phosphate 1 (marketꢀ
ed under the name Tamiflu)2 is
one of the medicinal agents caꢀ
pable to defend from the panꢀ
demia.
from the seed shells of star anise grown in the southꢀwest
China. Some material is produced by the enzymatic method
using E. coli bacteria.10 However, the use of conifers as the
raw material can not be excluded.11 Thus, for example,
the dry pine needles of the winter period contain up to
1.5% of shikimic acid.12 One of the shortest ways of the
synthesis of oseltamivir from shikimic acid is given in the
present work (Scheme 1). The synthesis consists of 10 step
and includes synthesis and isolation of the intermediate
products 3—11.
Ethyl shikimate 3 (see Refs 13 and 14) was formed by
esterification of (–)ꢀshikimic acid 2 with ethanol in the
presence of an acid catalyst. Our studies showed that the
conversion of 2 reached 96% after 7 h of reflux when TsOH
was used.14 However, the removal of TsOH from the final
product was accompanied by the large losses of compound 3.
It was found that when thionyl chloride was used as
the catalyst and the waterꢀbinding agent,13 the 93.5% conꢀ
version was reached only after 15—17 h, whereas the conꢀ
tent of the main compound in product 3 was 93% (HPLC
data). The best results were obtained when a heteroꢀ
geneous catalyst, the KUꢀ2ꢀ8 cationite in the H+ꢀform,
was used with the gradual removal of water from the reꢀ
action mixture by the azeotropic distillation with ethanol
with subsequent reꢀaddition of the condensate through
the column filled with zeolite NaA. When the ratio
shikimic acid : KUꢀ2ꢀ8 = 1 : 1, the reaction reached comꢀ
pletion within 13—15 h (with 99.5% conversion), the puꢀ
rity of compound 3 was on the 99% level. A decrease in the
amount of KUꢀ2ꢀ8 used by a half increased the reaction
time to 22—24 h. Some of the compound 3 was absorbed
on the cationite, therefore, the maximal yield was achieved
when KUꢀ2ꢀ8 was reused (2—10 cycles). If triethyl orthoꢀ
formate was used for the removal of water, the purity of
compound 3 was within 92—93%.
The agent inhibits the virus
enzyme neuraminidase, thus preventing the virus from comꢀ
ing out of the human cells and its further reproduction.
About 30 approaches and different modifications to the
preparation of oseltamivir are described in the literature.3—9
The yield of the product depends on the number of steps in
the synthesis and the starting materials used and ranges
from 5 to 57%. For the practical purposes, the methods
which use available reagents, give acceptable yields, and
guarantee the preparation of the desired stereoisomer are
of the largest interest. The approaches based on the use of
natural (–)ꢀshikimic acid belong to such methods.5—9 To
date, the major amount of shikimic acid 2 is extracted
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 1, pp. 0165—0171, January, 2013.
1066ꢀ5285/13/6201ꢀ163 © 2013 Springer Science+Business Media, Inc.

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Kalashnikov et al.
Scheme 1
6, 7: R = Et (a), Me (b), CHMe2 (c)
Reagents: i. H+, EtOH; ii. MsCl, Et3N, AcOEt, iii. NH4N3; iv. (RO)3P; v. BF3•Et2O, pentanꢀ3ꢀol; vi. H2SO4, EtOH; vii. Ac2O;
viii. NaN3; ix. Ph3P; x. H3PO4.
Trimesylate 4 was formed smoothly enough by treatꢀ
ment of triol 3 with MsCl in the presence of triethylamine.7
The content of impurities in the product obtained did not
exceed 5%. However, the use of the crude compound 4 in
the subsequent steps of the synthesis led to the accumulaꢀ
tion of the impurities and, as a consequence, to a decrease
in the yield. Therefore, trimesylate 4 was isolated by the
stepꢀwise crystallization. The yield of the crystalline prodꢀ
uct was 88—89%, whereas the content of the main comꢀ
pound was 98—99%.
Ethyl (3S,4R,5R)ꢀ3ꢀazidoꢀ4,5ꢀbis(methanesulfonylꢀ
oxy)cyclohexꢀ1ꢀenecarboxylate (5) (see Ref. 6) was formed
by treatment of product 4 with sodium azide, which reꢀ
sulted in the regioselective substitution for the one of the
methanesulfonyl groups (at position 3) and the inversion
of configuration of the carbon atom at position 3 from R
to S. Azide 5 is a poorly purifiable liquid, decomposing on
standing. For the subsequent steps of the synthesis to be
successful, it was important to minimize the amount of
impurities in compound 5. At the same time, the considꢀ
erable basicity of sodium azide caused the side reactions
with elimination of the MsO groups remained and aromaꢀ
tization of the sixꢀmembered ring to proceed. In this case,
the content of ethyl esters of 3ꢀmethanesulfonyloxyꢀ and
3ꢀazidobenzoic acids in the reaction products reached
10%. When the basic DMF was used as the solvent, the
aromatization reaction became predominant. The conꢀ
tent of impurities was decreased to 3—5% by the use of the
less basic ammonium azide (generated in situ from NaN3
and NH4Cl) and by the carrying out the reaction in MeOH.
The next step included treatment of azide 5 with alkyl
phosphite (the Schtaudinger reaction). The liberation of
nitrogen and the formation of the intermediate iminoꢀ
phosphites 12a—c started already during mixing the comꢀ
ponents (Scheme 2), the intermediate were converted to
aziridines 6a—c upon heating. The highest rate of formaꢀ
tion of compound 12 was observed when trimethyl phosꢀ
phite was used, the reaction with triisopropyl phosphite
was the slowest one. For compounds 6a—c to be formed,
it was enough to reflux the solution of iminophosphites
12a—c in toluene for 7 h. The aziridines 6a—c are liquids
and can be isolated in the pure form only by preparative
chromatography, therefore, products 6a—c were used in
the following steps without purification.
For the preparation of ethyl (3R,4S,5R)ꢀ4ꢀ(dialkoxyꢀ
phosphorylamino)ꢀ5ꢀmethanesulfonyloxyꢀ3ꢀ(pentꢀ3ꢀylꢀ
oxy)cyclohexꢀ1ꢀenecarboxylates 7a—c, the solutions of azirꢀ
idines 6a—c in pentanꢀ3ꢀol were treated with BF3•Et2O

Synthesis of oseltamivir phosphate
Russ.Chem.Bull., Int.Ed., Vol. 62, No. 1, January, 2013
165
Scheme 2
6, 12: R = Et (a), Me (b), CHMe2 (c)
Reagents: i. (RO)3P; ii. PhMe, reflux; iii. Ph3P, THF; iv. Et3N, H2O; v. H2O; vi. Ph3P, AcOH; vii. NaBH4 or H2, Pd/C; viii. Ac2O.
(see Scheme 1). The analysis of the reaction mixtures by
HPLC showed that the reactions were almost complete
and the content of 7a—c in the reaction products was
within 75—80%. However, the isolation of the products in
the pure form with good yields had proved a rather diffiꢀ
cult problem. The samples of 7a and 7b isolated by preparꢀ
ative chromatography are crystalline compounds with
melting points of 102—104 and 97—98 C, respectively,
whereas the product 7c is a liquid. In the course of our
studies, we selected the conditions under which the greatꢀ
er part of compound 7a (66.2% from the theoretical yield
calculated based on azide 5) was isolated from the reacꢀ
tion mixture in the crystalline form, that is convenient for
industrial application. The product obtained had rather
high purity (98%, HPLC data). An additional amount
of compound 7a can be isolated by concentration of
the reaction mixture and treatment of the residue with
water. The pentanꢀ3ꢀol obtained by evaporation from the
reaction mixture contained water, up to 3% of toluene
(impurities to compound 5), up to 2% of pentanꢀ2ꢀol,
esters of pentanol and fluoroboric and difluoroboric acids
(GLC data). Such a composition of the evaporated liquid
allows one to comparatively easy regenerate the solvent,
which includes an alkaline treatment and rectification.
Since the pure dimethylphosphorylamide 7b and diꢀ
isopropylphosphorylamide 7c were successfully isolated
only by preparative chromatography, a possibility of
their use without purification in the synthesis of ethyl
(3R,4S,5R)ꢀ4ꢀacetamidoꢀ5ꢀmethanesulfonyloxyꢀ3ꢀ(pentꢀ
3ꢀyloxy)cyclohexꢀ1ꢀenecarboxylate (9) was tested.
The attempt to synthesize aziridine by the reaction of
compound 5 with triphenylphosphine6 was unsuccessful
(see Scheme 2). Initially, a fast formation of iminophosꢀ
phorane 13 was observed, however, with time the reaction

166
Russ.Chem.Bull., Int.Ed., Vol. 62, No. 1, January, 2013
Kalashnikov et al.
led (HPLC data) to the formation of triphenylphosphine
oxide, ethyl mꢀaminobenzoate 14, and several more uniꢀ
dentified products.15 Apparently, the use of rather basic
agents, such as triphenylphosphine (the phosphorus analog
of triphenylamine) and triethylamine, caused (as in the
preceding step) the formation of aromatic compounds.
Carrying out the reaction in acetic acid through the hyꢀ
drolysis and acylation mainly led to ethyl 3ꢀacetamidoꢀ4,5ꢀ
bis(methanesulfonyloxy)cyclohexꢀ1ꢀenecarboxylate (15).
The use of reducing agent (NaBH4 or H2—Pd/C) led
to the reduction of the azide group, however, no cyclizaꢀ
tion of the oꢀaminomesylate 16 obtained to aziridine was
observed. After treatment of the reaction products with
acetic anhydride, only acetamide 15 was isolated.
The replacement of the dialkoxyphosphoryl group in
compounds 7a—c with the acetyl group was carried out in
two steps (see Scheme 1). First, compounds 7a—c were
treated with a mixture of ethanol and sulfuric acid. Such
conditions provided the hydrolysis of the amide group to
the amine one, with the ester bond remaining intact. The
analysis of the reaction mixture by HPLC showed the
virtually complete absence of impurities and the stability
of amine 8 formed. For the reaction to reach completion,
it was enough 14—16 h of reflux. The acidic solution of
amine 8 obtained was neutralized with aqueous NaHCO3
and acetylated with acetic anhydride under heterogeneous
conditions. The reaction was easy enough to proceed. For
its completion, it was enough to use 1.5 mol of acetic
anhydride and 30 min. As in the preceding steps, a strongꢀ
ly alkaline reaction medium caused the side reactions to
take place and a decrease in the yield of ethyl (3R,4S,5R)ꢀ
4ꢀacetamidoꢀ5ꢀmethanesulfonyloxyꢀ3ꢀ(pentꢀ3ꢀyloxy)ꢀ
cyclohexꢀ1ꢀenecarboxylate 9. The yield of acetamide 9
calculated based on compound 7a was 82.8%, its yield
calculated based on the starting azide 5 (four steps) was
52.6%. The use of crude products 7b,c with the content of
impurities about 25% instead of compound 7a significantly
hindered isolation of the pure acetamide 9. Thus, when 7c
was used the yield of acetamide 9 calculated on the startꢀ
ing azide 5 was 37.4%.
the azide at position 5 was accompanied by the inversion
at atom C(5) from Rꢀ to Sꢀconfiguration and proceeded in
EtOH at a considerable rate only at high temperature. For
the reaction to reach completion, a large excess of sodium
azide was required. Thus, the use of 3 mol of NaN3 (per 1 mol
of acetamide 9) and carrying out the reaction by reflux in 78%
aqueous ethanol led to the 95% conversion of acetamide 9
within 15 h. When the amount of sodium azide was reducꢀ
ed to 2 mol, the same conversion required more than 24 h.
The yield of ethyl (3R,4R,5S)ꢀ4ꢀacetamidoꢀ5ꢀazidoꢀ3ꢀ
(pentꢀ3ꢀyloxy)cyclohexꢀ1ꢀenecarboxylate (10) was 72%.
The molecule of compound 10 besides the azide group
contains an easily reducible activated double bond, thereꢀ
fore, the choice of reducing agents was limited. When
sodium borohydride was used, the reduction at room temꢀ
perature occurred slowly. The conversion of 70% at the
ratio NaBH4 : 10 = 1 : 1 was reached within 2 days. The
reaction resulted in the formation of a mixture of products
(Scheme 3), which contained, besides the expected ethyl
(3R,4R,5S)ꢀ4ꢀacetamidoꢀ5ꢀaminoꢀ3ꢀ(pentꢀ3ꢀyloxy)cycloꢀ
hexꢀ1ꢀenecarboxylate (oseltamivir, 11), the product of the
complete reduction, viz., ethyl 4ꢀacetamidoꢀ5ꢀaminoꢀ3ꢀ
(pentꢀ3ꢀyloxy)cyclohexaneꢀ1ꢀcarboxylate (17).
The use of catalytic hydrogenation required a thorꢀ
ough control of the reaction. Thus, when the palladium
catalyst (5% Pd/C) was used the rate of reduction of the
azide group was 6 times as fast as the rate of the reduction
of the double bond, and the yield of the product 1 (after
purification) was 63%. The Raney nickel16 and the Lindꢀ
lar catalyst5 (Pd/BaSO4) are described to be successfulꢀ
ly used in the known methods for the reduction of the
azide group.
The highest selectivity of reduction was obtained when
triphenylphosphine was used. The mechanism of the proꢀ
cess described in the literature includes three steps. The
formation of azidophosphorane takes place initially, which
rapidly eliminates nitrogen to be converted to iminophosꢀ
phorane. The following step of the process is the hydrolyꢀ
sis of the iminophosphorane obtained upon the action of
water. The process is comparatively long (14 h at the temꢀ
perature of 45 C). The unavoidable presence of water and
the basicity of the medium (all the products are bases) lead
to the side reactions: the hydrolysis of the ester bond and
The final steps of the synthesis included the replaceꢀ
ment of the MsO group with the azide one and its reducꢀ
tion to the amine. The exchange of the mesyl group with
Scheme 3

Synthesis of oseltamivir phosphate
Russ.Chem.Bull., Int.Ed., Vol. 62, No. 1, January, 2013
167
1053, 932, 873, 837, 749. 1H NMR ((CD3)2CO), : 6.77 (s, 1 H,
CH); 4.37 (s, 1 H, CH); 4.18 (q, 1 H, CH, J = 7.1 Hz); 3.95
(m, 2 H, CH2); 3.68 (m, 1 H, CH); 2.99 (dd, 1 H, CH2, J = 4.4 Hz,
J = 12.4 Hz); 2.71 (dd, 1 H, CH2, J = 4.6 Hz, J = 12.9 Hz); 1.28
(t, 3 H, CH3, J = 7.0 Hz). 13C NMR ((CD3)2CO), : 166.9
(C=O), 139.5 (CH), 128.8 (C), 66.3 (CH), 60.6 (CH2), 30.5
(CH2), 14.4 (CH3).
the aromatization of the sixꢀmembered ring (with the elimꢀ
ination of some groups), therefore, the yield of the reducꢀ
tion products was lower than theoretical. The reaction can
take place in aqueous alcohols (methanol, ethanol). The
use of tertꢀbutyl methyl ether increases the content of imꢀ
purities. The best results were provided by THF with the
sequential dosage of 10 and water to the solution of triphꢀ
enylphosphine. The addition of a small amount of acetic
acid increases the yield of the product by 3—5%. The
replacement of AcOH with phosphoric acid does not reꢀ
sult in the increase of the yield, whereas the use of H3PO4
in the amount of 1 mol per 1 mol of 10 according to the
TLC data completely blocks hydrolysis of iminophosꢀ
phorane. Treatment of compound 11 (see Refs 5 and 16)
with phosphoric acid in a mixture of EtOH—AcOEt leads
to the preparation of oseltamivir phosphate 1.
The synthesis of compound 1 under consideration (see
Scheme 1) does not require the use of nonstandard appliꢀ
ances, uses the minimum amount of expensive reagents,
and can be easily and rapidly accomplished by any chemꢀ
ical production. The total yield of oseltamivir phosphate
calculated on shikimic acid for the given tenꢀstep syntheꢀ
sis was 27%.
Ethyl (3R,4S,5R)ꢀ3,4,5ꢀtriꢀOꢀmethanesulfonylshikimate (4).
A suspension of ethyl shikimate 3 (55.0 g) in ethyl acetate
(550 mL) and MsCl (94 mL) was cooled to 0 C, followed by
a gradual addition of triethylamine (186 mL) over 2 h with vigorꢀ
ous stirring, keeping the temperature below 3 C. The mixture
was kept for 2 h at 0 C, diluted with 1 M HCl (200 mL), and
stirred for 15 min. The organic layer was separated, washed with
2% aqueous Na2CO3 (3×100 mL) and 20% aq. NaCl (100 mL).
The organic layer was filtered through a paper filter, concentratꢀ
ed to a half volume in vacuo at 40 C, and allowed to stand for
16 h. A precipitated product was filtered off and washed with
ethyl acetate. The filtrate was reꢀconcentrated to isolate two
more portions of compound 4. The total yield of compound 4
22
was 100.0 g (84.2%), m.p. 99—100 C, []D25 –110.3 (c 1.0,
EtOAc) (cf. Ref. 6: m.p. 97.8—99.0 C, []D –119.4 (c 1.0,
EtOAc)). Found (%): C, 32.69; H, 4.57; S, 22.26. C12H20O11S3.
Calculated (%): C, 33.02; H, 4.62; S, 22.04. IR, /cm–1: 3033,
1
2942, 1714, 1658, 1348, 1260, 1180, 1105. H NMR (CDCl3),
: 6.76 (s, 1 H, CH); 5.46 (t, 1 H, CH, J = 4.1 Hz); 5.04 (m, 1 H,
CH); 4.95 (dd, 1 H, CH, J = 4.3 Hz, J = 3.9 Hz); 4.20 (m, 2 H,
CH2); 3.12 (d, 9 H, 3 CH3, J = 4.3 Hz); 3.07 (s, 1 H, CH2); 2.67
(dd, 1 H, CH2, J = 6.2 Hz, J = 12.8 Hz); 1.26 (t, 3 H, CH3,
J = 7.1 Hz). 13C NMR (CDCl3), : 164.3 (C=O), 132.8 (C),
129.8 (CH), 74.4 (CH2), 72.8 (2 CH), 61.6 (CH2), 38.5 (CH3),
30.2 (CH2), 13.9 (CH3).
Experimental
1
H and 13C NMR spectra were recorded on a Bruker AMꢀ400
spectrometer (400.13 (1H) and 100.61 MHz (13C)) in DMSOꢀd6,
(CD3)2CO, D2O, and CDCl3. Chemical shift are given relative
to SiMe4. IR spectra of compounds were recorded on a Infralyꢀ
um FTꢀ801 spectrometer in KBr pellets. HPLC analysis was
performed on an Agilent 1200 instrument; a 2.1×15ꢀmm preꢀ
column, Zorbax SBꢀ18 (3 m) sorbent; a 2.1×150ꢀmm column,
Zorbax SBꢀ18 (5 m) sorbent. Composition and quality of prodꢀ
ucts were determined by an UV detector ( = 213 nm) using
a gradient elution. Eluent A: 0.2% aqueous orthophosphoric acid,
eluent B: acetonitrile. Specific optical rotation was determined
Ethyl (3S,4R,5R)ꢀ3ꢀazidoꢀ4,5ꢀbis(methanesulfonyloxy)cycloꢀ
hexꢀ1ꢀenecarboxylate (5). Sodium azide (14.4 g, 0.22 mol) was
added in small portions to suspension of compound 4 (60.0 g,
0.14 mol) and NH4Cl (22.2 g) in MeOH (210 mL) over 1.5 h
with vigorous stirring, maintaining the temperature below 10 C. The
reaction mixture was kept at room temperature for 5 h, diluted
with toluene (210 mL), a precipitate was separated by filtration,
the filtrate was concentrated in vacuo on a rotary evaporator.
The residue was dissolved in a mixture of water (60 mL) and
toluene (200 mL). The layers were separated, the organic phase
was dried with MgSO4, the solvent was evaporated in vacuo on
a rotary evaporator at 45 C to obtain compound 5 (52.5 g, 98%),
a dense liquid with the content of the main compound 95%
(HPLC data). An analytical sample of product 5 was purified by
preparative chromatography (eluent ethyl acetate—hexane
on a P 3002 KRUSS polarimeter. Shikimic acid containing 99%
of the main compound (HPLC data) was prepared by crystalliꢀ
zation of the commercial product (SHANGHAI AZ IMPORT
& EXPORT CO., LTD) from water. Zeolite NaA was dried for
12 h at 270 C. Anhydrous ethanol (the content of water 0.8%)
was prepared by drying over zeolite NaA. Silica gel 60 Å,
0.06—0.20 mm (Acros Organics) was used for preparative chroꢀ
matography.
Ethyl shikimate (3). A mixture of shikimic acid 2 (50 g,
0.287 mol), anhydrous ethanol (200 mL), and KUꢀ2ꢀ8 cationite
(50 g) (reuse) were placed in a flask, the flask was connected to
a Sohxlet apparatus, which was preliminary loaded with zeolite
NaA (160 g). The mixture was refluxed for 15 h with magnetic
stirring. The solution obtained was cooled and filtered, the catꢀ
ionite was washed with anhydrous ethanol (3×100 mL), the solꢀ
vent was evaporated in vacuo. The residue was treated with diꢀ
ethyl ether (350 mL) and filtered to obtain compound 2 (54.0 g,
93.0%), m.p. 97.8—99.0 C, the content of the main compound
was 99.0% (HPLC data); []D22 –45.4 (c 1.0, H2O). Found (%):
C, 54.00; H, 7.16. C9H14O5. Calculated (%): C, 53.46; H, 6.98.
IR, /cm–1: 3354, 2911, 1717, 1654, 1456, 1372, 1238, 1092,
22
25
(1 : 1)), []D +48.1 (c 1.0, EtOAc) (cf. Ref. 6: []D +45.1
(c 1.9, EtOAc)). Found (%): C, 34.83; H, 4.47; N, 10.96; S, 16.73.
C11H17N3O8S2. Calculated (%): C, 34.46; H, 4.47; N, 10.96; S,
16.73. IR, /cm–1: 2940, 2108, 1717, 1661, 1446, 1358, 1253,
1176, 1075, 1016. 1H NMR (CDCl3), : 6.65 (s, 1 H, CH); 4.80
(m, 1 H, CH); 4.68 (m, 1 H, CH); 4.30 (t, 1 H, CH, J = 3.9 Hz);
4.19 (q, 2 H, CH2, J = 7.2 Hz); 3.14 (s, 3 H, CH3); 3.06 (s, 3 H,
CH3); 2.63 (m, 2 H, CH2); 1.25 (m, 3 H, CH3). 13C NMR
(CDCl3), : 164.08 (C=O), 131.9 (CH), 130.1 (C), 78.9 (CH),
73.8 (CH), 61.6 (CH2), 60.9 (CH), 39.2 (CH3), 38.8 (CH3), 30.9
(CH2), 14.0 (CH3).
Ethyl (3R,4S,5R)ꢀ4ꢀ(diethoxyphosphorylamino)ꢀ5ꢀmethaneꢀ
sulfonyloxyꢀ3ꢀ(pentꢀ3ꢀyloxy)cyclohexꢀ1ꢀenecarboxylate (7a).
Triethyl phosphite (23.5 mL, 22.6 g) was added carefully to

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Kalashnikov et al.
a solution of compound 5 (47.5 g) in toluene (124 mL). The
reaction mixture was kept at room temperature for 1 h, then
refluxed for 7 h, and cooled. The solvent was evaporated in vacuo
on a rotary evaporator to obtain the residue (54.9 g) mainly
containing compound 6a. The residue was dissolved in pentanꢀ
3ꢀol (120 mL), followed by the addition of BF3•Et2O (17.3 mL)
in small portions over 1 h at 0—3 C. The reaction mixture was
kept for 16 h at room temperature, then diluted with water
(50 mL). The organic layer was separated, washed with 5%
aq. NaHCO3 (2×30 mL), water (2×30 mL), and placed into
a refrigerator (4 C). After 1—2 days, a precipitate formed was
filtered off and washed with Et2O (50 mL) to obtain compound 7a
(35.5 g), a white crystalline product with m.p. 102—104 C
(cf. Ref. 7: m.p. 99.5—102.8 C). The filtrate was concentrated
in vacuo on a rotary evaporator at 55 C (bath temperature), the
residue was dissolved in Et2O (50 mL) and let to stand for several
days. Then, the second portion of the product was filtered off.
The total yield of compound 7a was 40.0 g (66.2%); []D22 –54
(c 1.0, EtOAc). Found (%): C, 46.53; H, 7.35; N, 3.01; S, 7.03.
C19H38NO9PS. Calculated (%): C, 47.00; H, 7.47; N, 2.88;
S, 6.60. IR, /cm–1: 3238, 1714, 1356, 1175, 1101, 1032. 1H NMR
(CDCl3), : 6.75 (s, 1 H, CH); 4.98 (s, 1 H, CH); 4.13 (q, 2 H,
CH2, J = 7.2 Hz); 4.00 (m, 5 H, 2 CH2, CH); 3.61 (m, 1 H, CH);
3.33 (m, 2 H, CH, NH); 3.03 (s, 3 H, CH3); 2.68 (s, 2 H, CH2);
1.47 (m, 4 H, 2 CH2); 1.26 (m, 9 H, 3 CH3); 0.86 (q, 6 H, 2 CH3,
J = 7.2 Hz). 13C NMR (CDCl3), : 165.4 (C=O), 135.1 (CH),
128.2 (C), 81.2 (CH), 77.7 (CH3), 77.2 (CH2), 73.3 (2 CH),
62.4 (CH2), 60.8 (CH2), 53.3 (CH), 38.0 (CH3), 28.5 (CH2),
25.9 (CH2), 25.5 (CH2), 15.9 (CH3), 15.8 (CH3), 9.4 (CH3),
9.1 (CH3).
ed (%): C, 49.11; H, 7.85; N, 2.73; S, 6.24. IR, /cm–1
:
2978, 2937, 1715, 1658, 1464, 1356, 1233, 1174, 1142, 1102,
1
982, 907, 836, 798, 749. H NMR (CDCl3), : 6.71 (s, 1 H,
CH); 5.08 (t, 1 H, CH, J = 10.2 Hz); 4.87 (m, 1 H, CH); 4.51
(m, 2 H, 2 CH); 4.18 (q, 2 H, CH2, J = 7.0 Hz); 3.99 (m, 1 H,
CH); 3.40 (s, 1 H, NH); 3.32 (m, 1 H, CH); 3.24 (m, 3 H, CH3);
2.71 (dd, 1 H, CH2, J = 5.9 Hz, J = 13.5 Hz); 2.65 (dd, 1 H,
CH2, J = 5.9, J = 11.8); 1.48 (m, 4 H, 2 CH2); 1.24 (m, 15 H,
5 CH3); 0.86 (q, 6 H, 2 CH3, J = 7.1 Hz). 13C NMR (CDCl3),
: 166.2 (C=O), 135.0 (CH), 129.1 (C), 81.1 (CH), 74.4 (CH),
71.1 (CH), 70.1 (2 CH), 60.9 (CH2), 53.6 (CH), 38.1 (CH3),
28.5 (CH2), 25.6 (2 CH2), 24.1 (CH3), 14.5 (4 CH3), 9.7 (CH3),
9.4 (CH3).
Ethyl 3ꢀacetamidoꢀ4,5ꢀbis(methanesulfonyloxy)cyclohexꢀ1ꢀ
enecarboxylate (15). Triphenylphosphine (2.4 g) was added to
a solution of compound 5 (2.7 g) in glacial acetic acid (20 mL) at
room temperature. The reaction mixture was kept for 1.5 h, then
triethylamine (3 mL) was added, and after 30 min water (5 mL)
was added. The mixture was kept at room temperature for 12 h.
The solvent was evaporated in vacuo on a rotary evaporator. The
residue obtained was dissolved in a mixture of ethyl aceꢀ
tate—hexane (1 : 2, 20 mL) and separated by preparative chroꢀ
matography (eluent ethyl acetate—hexane, 1 : 2). The fraction 1
(0.45 g) contained triphenylphosphine, ethyl mꢀaminobenzoate,
and an unidentified product (HPLC data), the fraction 2 (1.9 g)
contained ester (15), m.p. 145—146 C. Found (%): C, 38.95;
H, 5.35; N, 3.62; S, 16.15. C13H21NO9S2. Calculated (%):
C, 39.09; H, 5.30; N, 3.51; S, 16.06. IR, /cm–1: 3204, 2984,
1
2944, 1710, 1658, 1353, 1267, 1222, 1174, 1035, 963. H NMR
(DMSOꢀd6), : 8.34 (s, 1 H, CH); 6.45 (d, 1 H, CH, J = 12.3 Hz);
5.07 (s, 1 H, CH); 4.76 (s, 2 H, CH2); 4.11 (s, 2 H, CH2); 3.18
(m, 8 H, 2 CH3, CH2); 1.83 (d, 3 H, CH3, J = 14.3 Hz); 1.17
(s, 3 H, CH3). 13C NMR (DMSOꢀd6), : 168.9 (C=O), 167.5
(C=O), 139.0 (CH), 132.4 (C), 128.0 (CH), 83.3 (CH), 83.2
(CH), 61.7 (CH2), 53.8 (CH), 38.9 (CH3), 38.6 (CH3), 26.6
(CH2), 23.4 (CH3), 14.3 (CH3).
Ethyl (3R,4S,5R)ꢀ4ꢀ(dimethoxyphosphorylamino)ꢀ5ꢀmethaꢀ
nesulfonyloxyꢀ3ꢀ(pentꢀ3ꢀyloxy)cyclohexꢀ1ꢀenecarboxylate (7b)
was obtained similarly to compound 7a from trimethyl phosꢀ
phite (20.4 g) and compound 5 (47.5 g). The evaporation of the
washed reaction mixture gave a dense product (65.3 g), with
the content of compound 7b being 83% (HPLC data). An anaꢀ
lytical sample was purified by preparative chromatography
(eluent ethyl acetate) to obtain compound 7b as colorless crysꢀ
tals, m.p. 97—98 C. Found (%): C, 44.72; H, 6.98; N, 2.94;
S, 7.11. C17H32NO9PS. Calculated (%): C, 44.63; H, 7.05;
N, 3.06; S, 7.01. IR, /cm–1: 3196, 2963, 1712, 1660, 1466,
Ethyl (3R,4S,5R)ꢀ4ꢀacetamidoꢀ5ꢀmethanesulfonyloxyꢀ3ꢀ
(pentꢀ3ꢀyloxy)cyclohexꢀ1ꢀenecarboxylate (9). A solution of comꢀ
pound 7a (40.0 g) in a mixture of H2SO4 (conc.) (36.5 mL) and
EtOH (190 mL) was heated at 78 C for 16 h. The reaction mixture
was diluted with AcOEt (380 mL) and water (80 mL), neutralꢀ
ized with 20% aq. Na2CO3 to pH 6.5—7.0, followed by the addiꢀ
tion of Ac2O (7.7 mL). The mixture was kept for 30 min at room
temperature, maintaining pH 6.5—7.0 by the addition of aq.
Na2CO3. After addition of Ac2O (3.8 mL) and keeping for 30 min,
the organic layer was separated, the aqueous layer was extracted
with AcOEt (240 mL). The combined organic layers were washed
with 5% aq. NaHCO3 (90 mL), dried with Na2SO4 and the
solvent was evaporated in vacuo on a rotary evaporator until
a dense suspension was formed. The suspension was diluted with
tertꢀbutyl methyl ether (35 mL), the product was filtered off,
washed with ButOMe to obtain compound 9 (19.1 g). The filꢀ
trate was reꢀconcentrated, treated with ButOMe to isolate a secꢀ
ond portion of the product (2.6 g). The filtrate was concentrated,
the residue was recrystallized from a mixture of ButOMe—EtOAc
(5.5 : 1). The total yield of product 9 was 26.5 g (82.1%), m.p.
1
1359, 1340, 1306,1264, 1234, 1178, 1105, 971, 909. H NMR
(CDCl3), : 6.85 (s, 1 H, CH); 5.01 (s, 1 H, CH); 4.22 (q, 2 H,
CH2, J = 6.9 Hz); 4.04 (s, 1 H, CH); 3.75, 3.79 (both, 6 H,
2 CH3); 3.50 (q, 1 H, CH, J = 6.7 Hz); 3.41 (t, 1 H, CH,
J = 5.6 Hz); 3.25 (t, 1 H, CH, J = 10.1 Hz); 3.10 (s, 3 H, CH3);
2.73 (dd, 1 H, CH2, J = 7.4 Hz, J = 10.6 Hz); 1.55 (m, 4 H,
2 CH2); 1.33 (t, 3 H, CH3, J = 8.3 Hz); 0.96 (q, 6 H, 2 CH3,
J = 7.1 Hz). 13C NMR (CDCl3), : 165.5 (C=O), 135.3 (CH),
128.6 (C), 81.6 (CH), 77.8 (CH), 73.7 (CH), 61.1 (CH2), 53.6
(CH), 38.4 (CH3), 28.8 (CH2), 26.2 (CH2), 25.9 (CH2), 25.5
(CH2), 14.2 (CH3), 9.7 (CH3), 9.4 (CH3).
Ethyl (3R,4S,5R)ꢀ4ꢀ(diisopropoxyphosphorylamino)ꢀ5ꢀmethaꢀ
nesulfonyloxyꢀ3ꢀ(pentꢀ3ꢀyloxy)cyclohexꢀ1ꢀenecarboxylate (7c)
was obtained similarly to compound 7a from triisopropyl phosꢀ
phite (26.0 g) and compound 5 (47.5 g). The evaporation of the
washed reaction mixture gave a dense product (67.5 g), with the
content of compound 7c being 81% (HPLC data). An analytical
sample was purified by preparative chromatography (eluent ethyl
acetate) to obtain compound 7c as a light yellow liquid. Found (%):
C, 49.21; H, 7.75; N, 2.75; S, 6.13. C21H40NO9PS. Calculatꢀ
22
138—139 C, []D –85 (c 1.0, CHCl3) (cf. Ref. 7: m.p.
129.8—31.9 C, []D25 –85 (c 0.7, EtOAc)). Found (%): C, 52.53;
H, 7.96; N, 3.22; S, 7.83. C17H29NO7S. Calculated (%): C, 52.16;
H, 7.47; N, 3.58; S, 8.19. IR, /cm–1: 3307, 1716, 1656, 1536,
1346, 1255, 1177, 1098, 1051. 1H NMR (CDCl3), : 6.77 (s, 1 H,

Synthesis of oseltamivir phosphate
Russ.Chem.Bull., Int.Ed., Vol. 62, No. 1, January, 2013
169
CH); 6.75 (m, 1 H, NH); 5.00 (s, 1 H, CH); 4.12 (m, 3 H, CH,
CH2); 3.99 (d, 1 H, CH, J = 5.4 Hz); 3.28 (q, 1 H, CH,
J = 6.2 Hz); 2.97 (s, 3 H, CH3); 2.69 (s, 2 H, CH2); 1.90 (s, 3 H,
CH3); 1.42 (m, 4 H, 2 CH2); 1.20 (t, 3 H, CH3, J = 6.9 Hz); 0.78
(t, 6 H, 2 CH3, J = 6.2 Hz). 13C NMR (CDCl3), : 171.8 (C=O),
165.0 (C=O), 136.1 (CH), 127.6 (C), 78.2 (2 CH), 75.1 (2 CH),
61.2 (CH2), 50.1 (CH3), 48.7 (CH2), 47.8 (CH2), 38.3 (CH3),
38.0 (CH3), 30.0 (CH2), 22.0 (CH3), 13.6 (CH3).
additional portion of compound 1 (1.4 g, 7.3%) was obtained,
the content of the main compound was 90.0% (HPLC data),
[]22 –34.2 (c 1.0, H2O) (cf. Refs 5 and 7: m.p. 203—204 C,
D
[]D20 –39 (c 1.0, H2O). Found (%): C, 47.21; H, 7.42; N, 6.76.
C16H31N2O8P. Calculated (%): C, 46.94; H, 7.39; N, 6.84. IR,
/cm–1: 3351, 3160, 2967, 2939, 2878, 1721, 1660, 1552, 1374,
1
1337, 1294, 1246, 1129, 1069, 1032, 951, 875, 731. H NMR
(D2O), : 8.34 (d, 1 H, CH, J = 9.0 Hz); 6.65 (s, 1 H, CH); 4.18
(q, 2 H, CH2, J = 6.5 Hz); 3.73 (m, 1 H, CH); 3.38 (m, 1 H,
CH2); 3.02 (m, 1 H, CH2); 2.50 (s, 4 H, CH, CH3); 2.26 (m, 1 H,
CH); 1.88 (s, 3 H, CH3); 1.46 (m, 4 H, 2 CH2); 1.24 (t, 3 H,
CH3, J = 7.0 Hz); 0.94 (m, 6 H, 2 CH3). 13C NMR (D2O),
: 174.8 (C=O), 166.5 (C=O), 139.0 (CH), 128.0 (C), 83.3 (CH),
75.3 (CH), 61.7 (CH2), 53.8 (CH), 49.4 (CH), 29.3 (CH2),
26.6 (CH2), 26.0 (CH2), 23.4 (CH3), 14.3 (CH3), 9.6 (CH3),
9.3 (CH3).
B. A mixture of compound 10 (5.0 g), the catalyst (6% Pd/C,
0.5 g), and EtOH (100 mL) was placed into a 500ꢀmL flask. The
air was thrice vacuumꢀevacuated, filling the flask with hydroꢀ
gen. The reduction was carried out with stirring (3 h, 24 C).
Then, the mixture was filtered from the catalyst, a 85% aq. H3PO4
(1.1 mL) was added to the filtrate, and the solvent was evaporatꢀ
ed in vacuo on a rotary evaporator until a solid product was
obtained. The residue was dissolved in anhydrous ethanol (35 mL)
with heating, diluted with AcOEt (35 mL). After cooling, oseltaꢀ
mivir phosphate (3.9 g, 63%) was filtered off, m.p. 200—201 C,
the content of the main compound was 97.5% (HPLC data).
The filtrate, according to the HPLC data, contained mixture of
products 1 and 17.
C. The carrying out the synthesis by similar method with the
increase in the hydrogenation time to 12 h and refilling the flask
with hydrogen (to remove the liberated nitrogen) led to the conꢀ
sumption of 340 mL of hydrogen and the formation of prodꢀ
uct 17. A prolonged concentration of the solution obtained (after
the addition of H3PO4) on a rotary evaporator in vacuo gave
a crystalline product (6.3 g), m.p. 216—217 C. 13C NMR
(CDCl3), : 173.6 (C=O), 171.0 (C=O), 80.7 (CH), 75.5 (CH),
60.7 (CH2), 55.7 (CH), 51.2 (CH), 37.8 (CH), 35.0 (CH2), 31.8
(CH2), 26.0 (CH2), 25.7 (CH2), 23.8 (CH3), 14.5 (CH3), 9.9
(CH3), 9.3 (CH3).
Ethyl (3R,4R,5S)ꢀ4ꢀacetamidoꢀ5ꢀazidoꢀ3ꢀ(pentꢀ3ꢀyloxy)ꢀ
cyclohexꢀ1ꢀenecarboxylate (10). A solution of NaN3 (17.7 g) in
water (36 mL) was added to a solution of compound 9 (23.5 g) in
EtOH (260 mL) and the mixture was refluxed for 24 h. The
solvent was evaporated in vacuo, followed by the addition of
AcOEt (200 mL) and water (20 mL). The organic layer was
separated, washed with 20% aq. NaCl (15 mL), and dried with
MgSO4. The solvent was evaporated in vacuo until a dense susꢀ
pension was formed. The suspension was filtered and washed
with ButOMe (3×25 mL) to isolate the first portion of the product
(12.1 g). The filtrate was reꢀconcentrated to obtain the second
portion of the product (2.1 g). Then, the filtrate was concentratꢀ
ed to dryness, the residue was recrystallized from ButOMe to
additionally obtain 1.1 g of compound 10. The portions of the
product (15.3 g) were combined and recrystallized from a mixꢀ
ture of ButOMe—AcOEt (6.5 : 1, v/v, 75 mL) to obtain product
10 (14.6 g, 72.0%), m.p. 137—138 C, []D22 –51.5 (c 1.0,
20
CHCl3) (cf. Refs 5 and 7: m.p. 137—138 C, []D –44 (c 1.0,
CHCl3)). Found (%): C, 56.54; H, 7.52; N, 16.62. C16H26N4O4.
Calculated (%): C, 56.79; H, 7.74; N, 16.56. IR, /cm–1: 3270,
2972, 2105, 1716, 1660, 1563, 1375, 1332, 1254, 1079. 1H NMR
(CDCl3), : 7.15 (d, 1 H, CH, J = 8.4 Hz); 6.69 (s, 1 H, CH);
4.03 (d, 1 H, CH, J = 8.0 Hz); 3.91 (m, 1 H, CH, J = 5.2 Hz);
3.80 (q, 2 H, CH2, J = 7.0 Hz); 3.65 (dd, 1 H, CH, J = 10.5 Hz,
J = 9.0 Hz); 3.29 (t, 1 H, NH, J = 5.5 Hz); 2.78 (dd, 1 H, CH2,
J = 5.5 Hz, J = 12.5 Hz); 2.18 (m, 1 H, CH2); 1.97 (s, 3 H, CH3);
1.44 (m, 4 H, 2 CH2); 1.24 (t, 3 H, CH3, J = 7.2 Hz); 0.83 (m, 6 H,
2 CH3). 13C NMR (CDCl3), : 171.2 (C=O), 165.7 (C=O),
138.1 (CH), 127.8 (C), 82.1 (CH), 74.3 (CH), 60.9 (CH2), 58.0
(CH), 56.3 (CH), 30.2 (CH2), 26.0 (CH2), 25.4 (CH2), 23.3
(CH3), 14.0 (CH3), 9.3 (CH3), 9.0 (CH3).
Ethyl (3R,4R,5S)ꢀ4ꢀacetamidoꢀ5ꢀaminoꢀ3ꢀ(pentꢀ3ꢀyloxy)ꢀ
cyclohexꢀ1ꢀenecarboxylate phosphate (oseltamivir phosphate, 1).
A. Compound 10 (14.2 g) and water (12 mL, acidified with two
drops of AcOH) were sequentially added to a suspension of triꢀ
phenylphosphine (13.0 g) in tetrahydrofuran (100 mL) at room
temperature. The mixture was stirred until the temperature
ceased to rise and heated at 45 C for 16 h. The reaction mixture
was concentrated to dryness in vacuo on a rotary evaporator. The
residue was dissolved in EtOH (20 mL) and reꢀconcentrated.
Then the residue, containing oseltamivir 11 and triphenylphosꢀ
phine oxide, was dissolved in a mixture of EtOH—AcOEt (48 mL,
1 : 1). A solution obtained was slowly added dropwise to the
solution of 85% aq. H3PO4 (2.84 mL, 6.12 g) in a mixture of
EtOH—AcOEt (140 mL, 1 : 1) heated to 50—55 C. A suspenꢀ
sion of the product was slowly cooled (4—5 h), the product was
filtered off and washed with acetone (4×10 mL). After drying in
air, compound 1 (14.4 g, 83.6%) was obtained, m.p. 201—202 C,
the content of the main compound was 98.8% (HPLC data).
The filtrate was concentrated on a rotary evaporator in vacuo,
the residue was dissolved with vigorous stirring in acetone left
after washing. The suspension obtained was filtered off, the resiꢀ
due was washed with acetone (4×10 mL). After drying in air, an
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Received November 9, 2012;
in revised form January 15, 2013