Research and Development of a Second-Generation Process for Oseltamivir Phosphate, Prodrug for a Neuraminidase Inhibitor

Article abstract of DOI:10.1021/op0302107

A second-generation manufacturing process from a shikimic acid-derived epoxide to oseltamivir phosphate features a magnesium chloride - amine complex-catalyzed ring opening of the epoxide by tert-butylamine, a selective O-sulfonylation of the resulting tert-butylamino alcohol, a surprisingly efficient cleavage of a tert-butyl group from an aliphatic tert-butylamide, and the isolation of oseltamivir phosphate from a palladium-catalyzed allyl transfer reaction mixture. The overall yield from the epoxide to oseltamivir phosphate has been increased from 27 to 29% or 35-38% for two previous processes, respectively, to 61%.

Full text of DOI:10.1021/op0302107

Organic Process Research & Development 2004, 8, 86−91
Research and Development of a Second-Generation Process for Oseltamivir
Phosphate, Prodrug for a Neuraminidase Inhibitor
Peter J. Harrington, * Jack D. Brown, Tommaso Foderaro, and Robert C. Hughes
Roche Colorado Corporation - Boulder Technology Center, 2075 North 55th Street, Boulder, Colorado 80301, U.S.A.
Abstract:
A second-generation manufacturing process from a shikimic
acid-derived epoxide to oseltamivir phosphate features a
magnesium chloride-amine complex-catalyzed ring opening of
the epoxide by tert-butylamine, a selective O-sulfonylation of
the resulting tert-butylamino alcohol, a surprisingly efficient
cleavage of a tert-butyl group from an aliphatic tert-butylamide,
and the isolation of oseltamivir phosphate from a palladium-
catalyzed allyl transfer reaction mixture. The overall yield from
Figure 1. Oseltamivir phosphate and the neuraminidase
inhibitor.
the epoxide to oseltamivir phosphate has been increased from
27 to 29% or 35-38% for two previous processes, respectively,
to 61%.
Scheme 1. Gilead route to oseltamivir phosphate 1
Introduction
Oseltamivir phosphate (1, Tamiflu, Ro 64-0796, GS 4104)
is a prodrug for 2, a competitive inhibitor of influenza A
and B neuraminidase (Figure 1). Oseltamivir phosphate 1 is
orally administered for the treatment and prevention of
influenza infections.
Our second-generation process parallels previous pro-
cesses recently described by Gilead1 and Roche-Basel.2 The
three processes utilize (1) the same starting epoxide, (2) a
regioselective ring opening of the epoxide with ammonia
equivalent A, (3) a conversion of an amino alcohol to an
aziridine, and (4) a regioselective ring opening of an aziridine
with ammonia equivalent B. The three processes diverge in
the choice of ammonia equivalents A and B, promoters for
the epoxide and aziridine openings, and methods for un-
masking the ammonia equivalents.
Scheme 2. Roche-Basel route to oseltamivir phosphate 1
The Gilead route uses azide and Brønsted acid for both
ring openings and azide reduction with phosphine to reveal
both amino groups (Scheme 1). The result is an efficient
process but one requiring expertise in handling two low-
molecular weight azides on a production scale. In addition,
a competitive conjugate addition of azide results in low levels
of â-azido ester associated with a positive Ames test when
present in the final drug substance. The Roche-Basel route
uses allylamine-magnesium bromide etherate to open ep-
oxide 3 and allylamine-Brønsted acid to open an aziridine.
Both amino groups are revealed by heterogeneous palladium-
(0)-catalyzed allyl isomerization and in situ enamine hy-
* Corresponding author. Telephone: (303)-938-6529. Fax: (303)-938-6590.
E-mail: peter.harrington@roche.com.
drolysis (Scheme 2). This route addresses the azide handling
and Ames test isues. Our second-generation route uses tert-
butylamine-magnesium chloride to open epoxide 3 and
diallylamine-Brønsted acid to open an aziridine. The first
amino group is revealed by acid-mediated tert-butyl group
(1) 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.
(2) (a) Karpf, M.; Trussardi, R. EP 1059283, 2000. (b) Karpf, M.; Trussardi,
R. J. Org. Chem. 2001, 66, 2044.
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10.1021/op0302107 CCC: $27.50 © 2004 American Chemical Society
Published on Web 12/05/2003

Scheme 3. Second-generation route to oseltamivir
phosphate 1
epoxide 3 to amino alcohol 4 using this preformed tert-
butylamine-magnesium chloride complex.4
Aziridine Formation. The Roche-Basel process relies on
an efficient protection-deprotection strategy to achieve
selective O-sulfonylation of the amino alcohol. Selective
O-sulfonylation can be accomplished without protection-
deprotection when an amino alcohol has an electron-
withdrawing (sulfonyl, acyl, phosphoryl) or bulky (trityl,5
diphenylmethyl,6 even R-methylbenzyl7) nitrogen subsititu-
ent. Mesylation and cyclization of tert-butylamino alcohol
4 is simple and efficient (93%).
Aziridine Opening. The acid-catalyzed addition of nu-
cleophiles to aziridines has been extensively exploited in
synthesis. Clean inversion of stereochemistry is typically
observed, indicative of an SN2 mechanism. The mechanism
may vary, depending on the specific acid catalyst, nucleo-
phile, nitrogen substituent, and carbon substituents.8
There is good precedent for the acid-catalyzed ring
opening of N-alkylaziridines by aliphatic amines. Ring
opening of 7-azabicyclo[4.1.0]heptane with ammonia or an
amine yields the trans-1,2-diaminocyclohexane.9 Ring open-
ing of a 7-azabicyclo[4.1.0]heptane by an amine in water
containing ammonium chloride is the preferred method for
construction of the trans-diaminocyclohexane portion of
many κ-opioid analgesics.10 Ring opening of N-benzyl-7-
azabicyclo[4.1.0]heptane by benzylamine is catalyzed by
ytterbium triflate (20 mol %) or lithium bis-trifluoromethane-
sulfonimidate (20-50 mol %).11,12 Lithium perchlorate (1
equiv) facilitates the ring opening of N-[(S)-R-phenylethyl]-
cyclohexene aziridine by (S)-R-phenylethylamine.7
Karpf and Trussardi used methanesulfonic acid for ring
opening of an aziridine by allylamine as part of their four-
step domino sequence.2 We have demonstrated the sulfonic
acid-promoted opening of aziridine 5 by diallylamine (93%
yield using 1.24 equiv of PhSO3H and 1.35 equiv of
diallylamine at 120 °C for 5.5 h). Comparable results can
be achieved using a Lewis acid catalyst (10-20 mol %) such
as copper (II) chloride, bromide, or triflate, zinc chloride,
zinc triflate, or boron trifluoride etherate.
cleavage after acetylation. The second amino group is
revealed by allyl group transfer to 1,3-dimethylbarbituric acid
catalyzed by a homogeneous palladium(0)-phosphine catalyst
(Scheme 3). This route addresses the azide handling and
Ames test issues and has the highest overall yield from
expensive epoxide 3 to final drug substance.
Epoxide Opening using Magnesium Chloride. The
addition of nitrogen nucleophiles to epoxides has been
extensively exploited in synthesis. Since epoxide 3 is prone
to aromatization on reaction with strong bases, ring opening
with a metal amide was not an option.2 Karpf and Trussardi
demonstrated catalysis (0.15-0.25 equiv) of the reaction of
epoxide 3 with allylamine using “magnesium halide deriva-
tives”. These are defined as anhydrous or hydrated magne-
sium chloride, magnesium bromide or magnesium iodide,
or an etherate, in particular a dimethyl etherate, a diethyl
etherate, a dipropyl etherate, or a diisopropyl etherate thereof.
We confirmed magnesium bromide diethyl etherate
catalysis of epoxide 3 opening with tert-butylamine. We also
pursued magnesium chloride catalysis in an effort to reduce
catalyst cost and eliminate the ethyl ether byproduct. The
rate of formation of the amino alcohol 4 is slow when the
order of reagent addition is magnesium chloride, epoxide,
then amine. We suggest that magnesium chloride quickly
converts epoxide 3 to a chlorohydrin and that the chlorohy-
drin only slowly reverts to epoxide 3 under the reaction
conditions.3 The rate of formation of the amino alcohol 4 is
faster when the order of reagent addition is magnesium
chloride, amine, and then epoxide. The addition of tert-
butylamine to anhydrous magnesium chloride produced a
sparingly soluble tert-butylamine-magnesium chloride com-
plex. Much less chlorohydrin is formed in the conversion of
(4) Surprisingly little is known about complexes of magnesium halides with
amines. Addition of excess N,N,N′,N′-tetramethylethylenediamine (TMEDA)
or N,N,N′,N′-tetraethylethylenediamine (TEED) to magnesium bromide in
ethyl ether affords a (1:1) complex.4a,b Amine complexation was utilized to
monoprotect R,ω-alkanediamines.4c (a) Coates, G. E.; Heslop, J. A. J. Chem.
Soc. A 1968, 514. (b) Evans, D. F.; Khan, M. S. J. Chem. Soc. A 1967,
1648. (c) Ham, J.-Y.; Kang, H.-S. Bull. Korean Chem. Soc. 1994, 15, 1025.
(5) Nakajima, K.; Takai, F.; Tanaka, T.; Okawa, K. Bull. Chem. Soc. Jpn. 1978,
51, 1577.
(6) Poch, M.; Verdaguer, X.; Moyano, A.; Perica`s, M. A.; Riera, A. Tetrahedron
Lett. 1991, 32, 6935.
(7) Anaya de Parrodi, C.; Moreno, G. E.; Quintero, L.; Juaristi, E. Tetrahe-
dron: Asymmetry 1998, 9, 2093.
(8) Padwa, A., Ed. ComprehensiVe Heterocyclic Chemistry II; Katritzky, A.
R., Rees, C. W., Scriven, E. F. V., Eds. in Chief; Pergamon: Oxford, UK,
1996; Vol. 1A, pp 26-27.
(9) Winternitz, F.; Mousseron, M.; Dennilauler, R. Bull. Soc. Chim. Fr. 1956,
382.
(10) (a) Szmuszkovicz, J.; Von Voigtlander, P. F. J. Med. Chem. 1982, 25, 1125.
(b) Rees, D. J. Heterocycl. Chem. 1987, 24, 1297. (c) Clark, C. R.;
Halfpenny, P. R.; Hill, R. G.; Horwell, D. C.; Hughes, J.; Jarvis, T. C.;
Rees, D. C.; Schofield, D. J. Med. Chem. 1988, 31, 831. (d) Halfpenny, P.
R.; Hill, R. G.; Horwell, D. C.; Hughes, J.; Hunter, J. C.; Johnson, S.; Rees,
D. C. J. Med. Chem. 1989, 32, 1620. (e) Rees, D. C. J. Heterocycl. Chem.
1990, 27, 147.
(11) Meguro, M.; Asao, N.; Yamamoto, Y. Tetrahedron Lett. 1994, 35, 7395.
(12) Cossy, J.; Bellosta, V.; Alauze, V.; Desmurs, J.-R. Synthesis 2002, 2211.
(3) Ueda, Y.; Maynard, S. C. Tetrahedron Lett. 1988, 29, 5197.
Vol. 8, No. 1, 2004 / Organic Process Research & Development
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Acetylation. The efficient acetylation of secondary amines
with acetic anhydride is well documented. However, the
acetylation we intended to accomplish is uniquely difficult.
In fact, heating a mixture of diamine 6 and two equivalents
of acetic anhydride at 90 °C for 1 h resulted in low
conversion. While pyridine does catalyze the acetylation, the
high water solubility and teratogenicity of pyridine compli-
cate recovery/recycle or disposal on a production scale. We
demonstrated that pyridine can be replaced by calcium oxide,
magnesium oxide, lithium carbonate, sodium carbonate,
potassium acetate, sodium acetate, dipotassium hydrogen
phosphate, or tripotassium phosphate.13
Cleavage of the tert-Butyl Acetamide. The efficient
cleavage of the tert-butyl group from the nitrogen of aliphatic
acetamide 7 was a key observation. While tert-butyl cleavage
from the oxygen of ethers, carbamates, and esters has been
extensively exploited in synthetic protection-deprotection
strategies for many years, tert-butyl cleavage from the
nitrogen of amines, carbamates, and amides has received less
attention. The tert-butyl group of a cyclopropylamine can
be cleaved upon prolonged heating in acid (aqueous 2 N
HCl at reflux for 3-5 days).14 Reaction of an N-substituted-
N-tert-butyl carbamate with triflic acid at 25 °C afforded a
carbamate-protected primary amine.15 Acid hydrolysis of
N-tert-amyl and N-tert-octyl acetamides produced the cor-
responding alkene, ammonia, and acetic acid.16 Researchers
at Lederle Labs concluded that the removal of a tert-butyl
group from an amide nitrogen “was too difficult for practical
application to peptide synthesis.” 17 Encouraging results have
been reported for aromatic amides: reaction of N-tert-butyl
benzamide with 98% sulfuric acid for 5 min at 25 °C afforded
benzamide (99%). tert-Butyl cleavage with trifluoroacetic
acid at reflux was a key step in a short synthesis of lunularic
acid, a growth inhibitor found in Lunularia cruciata.18
We found reaction of tert-butyl acetamide 7 with one
equivalent of hydrogen chloride in ethanol at < 25 °C
produces a precipitate of the hydrochloride salt 8. Isolation
of salt 8 is the only cleanup required in the sequence between
epoxide 3 and oseltamivir phosphate 1. The tert-butyl group
of salt 8 is then cleaved with trifluoroacetic acid at 25-50
°C or with hydrogen chloride in ethanol at reflux.
Deallylation. Two general methods are available for
amine deallylation: metal catalyzed double bond isomer-
ization and enamine hydrolysis or palladium(0) catalyzed
allyl transfer to a nucleophilic allyl scavenger. Deallylation
by isomerization/hydrolysis with (PPh3)3RhCl in aqueous
acetonitrile was the key step in the synthesis of anticapsin
from L-tyrosine.19 Alternative conditions for isomerization
and enamine hydrolysis are Pd/C and methanesulfonic acid
in water.20 Since oseltamivir is prone to acetyl migration
under acidic conditions or in the presence of salts, Karpf
and Trussardi developed new conditions for the isomerization
and enamine cleavage: Pd/C and ethanolamine in refluxing
ethanol (70% yield for deallylation and phosphate salt
formation).2
The removal of allyl protecting groups by η3-allyl
palladium-mediated transfer to a nucleophilic scavenger has
recently been reviewed.21 Amine deallylation by allyl transfer
to 1,3-dimethylbarbituric acid (NDMBA) was reported by
Guibe´ in 1993.22 More recently, R-allyl-R-amino acid esters
were produced by allylation of an amino acid ester, [2,3]-
Stevens rearrangement, and amine deallylation with ND-
MBA.23 2-Mercaptobenzoic acid24 and p-toluenesulfinic
acid25 are also effective scavengers. Deallylation of N-allyl
histidine derivatives was demonstrated with both NDMBA
and, under milder conditions, with phenylsilane/acetic acid.26
We developed a palladium-catalyzed allyl group transfer to
NDMBA in ethanol which allowed us to carry the allyl
transfer reaction mixture directly into the phosphate salt
formation (88% yield for deallylation and phosphate salt
formation).
The key features of the second-generation process are a
magnesium chloride-amine complex catalyzed ring opening
of epoxide 3, a selective O-sulfonylation of the resulting tert-
butylamino alcohol 4, a surprisingly efficient cleavage of
the tert-butyl group from aliphatic amide 8, oseltamivir
phosphate 1 isolation from a palladium-catalyzed allyl
(13) While there is little precedent for the use of tripotassium phosphate as an
acetylation catalyst, we found that tert-butyl acetamide yields using this
base nearly matched yields obtained using sodium acetate. Leppa¨nen, S.;
Strandman, L.; Takala, S.; Pajunen, P.; Koskikallio, J. Acta Chem. Scand.
1973, 27, 3572. (b) Jpn. Kokai Tokkyo Koho 58074639, 1983; Chem Abstr.
1983, 99, 159009a.
Cleavage of the pentyl group is competitive using
hydrogen chloride in ethanol at reflux. Cleavage to an
alcohol, intramolecular transfer of the acetyl group from
nitrogen to oxygen, then transesterification to ethanol
produces diamino alcohol 10 (eq 1).
(14) De Kimpe, N.; Sulmon, P.; Brunet, P. J. Org. Chem. 1990, 55, 5777.
(15) Earle, M. J.; Fairhurst, R. A.; Heaney, H.; Papageorgiou, G. Synlett 1990,
621.
(16) Ritter, J. J.; Minieri, P. P. J. Am. Chem. Soc. 1948, 70, 4045.
(17) Callahan, F. M.; Anderson, G. W.; Paul, R.; Zimmerman, J. E. J. Am. Chem.
Soc. 1963, 85, 201.
(18) (a) Lacey, R. N. J. Chem. Soc. 1960, 1633. (b) Reitz, D. B.; Massey, S. M.
J. Org. Chem. 1990, 55, 1375.
(19) Laguzza, B. C.; Ganem, B. Tetrahedron Lett. 1981, 22, 1483.
(20) (a) Liu, Q.; Marchington, A. P.; Boden, N.; Rayner, C. M. J. Chem. Soc.,
Perkin Trans. 1 1997, 511. (b) Jaime-Figueroa, S.; Liu, Y.; Muchowski, J.
M.; Putman, D. G. Tetrahedron Lett. 1998, 39, 1313.
(21) Guibe´, F. Tetrahedron 1998, 54, 2967.
(22) Garro-Helion, F.; Merzouk, A.; Guibe´, F. J. Org. Chem. 1993, 58, 6109.
(23) Arbore´, A. P. A.; Cane-Honeysett, D. J.; Coldham, I.; Middleton, M. L.
Synlett 2000, 236.
(24) (a) Lemaire-Audoire, S.; Savignac, M.; Geneˆt, J. P.; Bernard, J.-M.
Tetrahedron Lett. 1995, 36, 1267. (b) Lemaire-Audoire, S.; Savignac, M.;
Dupuis, C.; Geneˆt, J. P. Bull. Soc. Chim. Fr. 1995, 132, 1157. (c) Bailey,
W. F.; Jiang, X.-L. J. Org. Chem. 1996, 61, 2596. (d) Zhang, D.; Liebeskind,
L. S. J. Org. Chem. 1996, 61, 2594.
(25) Honda, M.; Morita, H.; Nagakura, I. J. Org. Chem. 1997, 62, 8932.
(26) Malanda Kimbonguila, A.; Boucida, S.; Guibe´, F.; Loffet, A. Tetrahedron
1997, 53, 12525.
Cleavage of the acetyl group back to diamine 6 followed
pentyl ether cleavage is unlikely: no diamino alcohol 10 is
produced from diamine 6 and hydrogen chloride in ethanol
after 4 h at reflux.
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transfer reaction mixture. The overall yields from epoxide 3
for the three processes are: Gilead 27-29%, Roche-Basel
35-38%, and second-generation 61%.
mL of water was added. The suspension was stirred for 15
min, and the layers were separated. The organic layer was
concentrated in vacuo (rotary evaporator at 40 °C and 25
mmHg) to afford 132.2 g of orange oil with trace solids (LC
assay 86 wt % 5, 93% yield).
Experimental Section
An analytical sample was prepared by radial chromatog-
raphy on silica gel; 1H NMR (CDCl3) δ 6.80-6.78 (m, 1H),
4.17 (dq, 2H, J ) 7.5 Hz, J ) 1.5 Hz), 4.15-4.14 (m 1H),
3.39 (p, 1H, J ) 6.0 Hz), 2.62-2.52 (m, 2H), 2.13-2.11
(m, 1H), 2.00 (d, 1H, J ) 6.0 Hz), 1.61-1.51 (m, 4H), 1.26
(t, 3H, J ) 7.5 Hz), 1.00 (s, 9H), 0.98 (t, 3H, J ) 7.5 Hz),
0.92 (t, 3H, J ) 7.5 Hz); 13C NMR (CDCl3) δ 167.3, 134.4,
128.6, 82.4, 70.9, 60.7, 53.3, 33.2, 29.9, 27.0, 26.9, 26.8,
25.0, 14.5, 10.2, 9.9; IR (neat) 3575, 2970, 2930, 2875, 1720,
1650, 1460, 1370, 1250, 1230, 1215, 1080, 1070, 1050, 670
cm-1. HRFABMS found m/z 310.2378 (M + H+), calcd for
C18H32NO3 310.2382.
Ethyl (3R,4R,5S)-5-N,N-Diallylamino-4-(1,1-dimethyl-
ethyl)amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxy-
late (6). Benezensulfonic acid (72.0 g, 0.454 mol, 1.24 equiv)
was added to a mixture of 132.2 g (0.367 mol at 86 wt %)
of the aziridine 5 and 61.2 mL (48.16 g, 0.496 mol, 1.35
equiv) of diallylamine. The suspension was heated at 120
°C (bath) for 5.5 h.
The solution was cooled to <90 °C, and 150 mL of
toluene was added. The solution was cooled to 10 °C, and
a solution of 18.5 g (0.463 mol) sodium hydroxide in 250
mL of water was added. After stirring the suspension for 30
min, the layers were separated. The aqueous layer was
extracted with 50 mL of toluene twice. The combined organic
layers were concentrated in vacuo (40 °C and 25 mmHg) to
afford 157.2 g of brown oil (LC assay 88.1 wt % 6, 92.8%
yield).
An analytical sample was prepared by radial chromatog-
raphy on silica gel; 1H NMR (CDCl3) δ 6.87 (t, 1H, J ) 2.5
Hz), 5.79 (m, 2H), 5.17 (d, 2H, J ) 17.5 Hz), 5.11 (d, 2H,
J ) 10.5 Hz), 4.22 (q, 2H, J ) 7.0 Hz), 3.94-3.92 (m, 1H),
3.41-3.36 (m, 1H), 3.31-3.27 (dm, 2H, J ) 14 Hz), 2.92
(dd, 2H, J ) 14 Hz, J ) 8.0 Hz), 2.81 (dd, 1H, J ) 10.5
Hz, J ) 6.5 Hz), 2.69 (dt, 1H, J ) 10.5 Hz, J ) 4.5 Hz),
2.56 (dd, 1H, J ) 17.0 Hz, J ) 4.5 Hz), 2.19 (dt, 1H, J )
17.0 Hz, J ) 3 Hz), 1.82-1.74 (m, 1H), 1.64-1.56 (m, 1H),
1.51-1.38 (m, 2H), 1.31 (t, 3H, J ) 7.0 Hz), 1.15 (s, 9H),
0.91 (t, 3H, J ) 7.5 Hz), 0.87 (t, 3H, J ) 7.5 Hz); 13C NMR
(CDCl3) δ 167.1, 137.9, 136.9, 130.3, 117.7, 80.1, 78.8, 60.9,
58.5, 55.3, 52.6, 50.7, 31.1, 26.7, 25.3, 22.5, 14.5, 10.5, 9.87;
IR (neat) 3590, 3640-3000, 2980, 2930, 2875, 2820, 1720,
1665, 1640, 1230, 675 cm-1. HRFABMS found m/z 407.3280
(M + H+), calcd for C24H43N2O3 407.3274.
Ethyl (3R,4S,5R)-5-N-(1,1-Dimethylethyl)amino-3-(1-
ethylpropoxy)-4-hydroxy-1-cyclohexene-1-carboxylate (4).
A magnesium chloride-amine complex was first prepared
by adding 65 mL (45.2 g, 0.619 mol, 1.50 equiv) of tert-
butylamine to a suspension of 35.7 g (0.375 mol, 0.90 equiv)
of magnesium chloride in 200 mL of dry toluene at 25 °C.
The colorless slurry was stirred at 25 °C for 6 h. A solution
of 105.0 g (0.413 mol) of epoxide 327 in 250 mL of dry
toluene was added via an 18-gauge stainless steel cannula
to the magnesium chloride-amine complex suspension at
20-25 °C. The resulting suspension was heated at 50 °C
for 8 h. More tert-butylamine (52 mL, 36.2 g, 0.495 mol,
1.20 equiv) was added, and the solution was heated for an
additional 12 h.
After cooling the yellow solution to 25 °C, 200 mL of
10% w/w aqueous citric acid solution was added and the
solution stirred at 25 °C for 30 min. The layers were
separated. The organic layer was concentrated in vacuo
(rotary evaporator at 40 °C and 25 mmHg and then vacuum
pump at 25 °C and 1 mmHg for 17 h) to afford 135.3 g of
orange oil (LC assay 96.0 wt % 4, 96.1% yield).
An analytical sample was prepared by radial chromatog-
raphy on silica gel; 1H NMR (CDCl3) δ 6.84-6.82 (m, 1H),
4.23 (t, 1H, J ) 4.0 Hz), 4.20 (q, 2H, J ) 7.0 Hz), 3.6-3.0
(br, 1H, NH or OH), 3.55 (p, 1H, J ) 6.0 Hz), 3.37 (dd,
1H, J ) 4.0 Hz, J ) 9.5 Hz), 3.12-3.08 (m, 1H, J ) 5.0
Hz), 2.91 (dd, 1H, J ) 5.5 Hz, J ) 17 Hz), 1.97-1.91 (m,
1H, J ) 8.0 Hz, J ) 17 Hz), 1.59-1.54 (m, 4H), 1.29 (t,
3H, J ) 7.0 Hz), 1.13 (s, 9H), 0.95 (t, 3H, J ) 7.5 Hz),
0.91 (t, 3H, J ) 7.5 Hz); 13C NMR (CDCl3) δ 166.9, 135.7,
131.7, 82.8, 72.6, 71.3, 61.0, 51.3, 48.9, 34.3, 30.5, 26.8,
26.7, 14.5, 10.4, 9.5; IR (neat) 3600-3300, 2970, 2940,
2880, 1720, 1660, 1470, 1400, 1370, 1240, 1110, 1080, 1060,
670 cm-1. HRFABMS found m/z 328.2481 (M + H+), calcd
for C18H34NO4 328.2488.
Ethyl (3R,4S,5R)-4,5-(1,1-Dimethylethyl)imino-3-(1-
ethylpropoxy)-1-cyclohexene-1-carboxylate (5). Methane-
sulfonyl chloride (32.9 mL, 48.7 g, 0. 425 mol, 1.07 equiv)
was added to a solution of 135.3 g (0.397 mol at 96.0 wt %)
of the crude alcohol 4 in 500 mL of dry toluene at 5 °C
(cool H2O bath) over 30 min. The solution was warmed to
10 °C and stirred for 60 min. Triethylamine (112 mL, 81.3
g, 0.804 mol, 2.03 equiv) was added dropwise at <5 °C over
45 min. The resulting suspension was stirred at 5 °C for 20
min, heated to 70 °C (bath) over 2 h, and then held at 70 °C
for an additional 3 h.
Ethyl (3R,4R,5S)-4-N-Acetyl(1,1-dimethylethyl)amino-
5-N,N-diallylamino-3-(1-ethylpropoxy)-1-cyclohexene-1-
carboxylate (7). Acetic anhydride (158.5 mL, 171.5 g, 1.68
mol, 4.94 equiv) was added to a mixture of 157.1 g (340
mmol at 88.1 wt % assay) of diamine 6 and 41.35 g (504
mmol, 1.48 equiv) of anhydrous sodium acetate. The
resulting suspension was heated at 110-116 °C and 200 rpm
for 4 h.
After cooling the suspension to <15 °C, a solution of
anhydrous potassium carbonate (55.6 g, 0.402 mol) in 200
(27) An industrial synthesis of epoxide 3 has been described: 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.; Janatsch, G.; Lauper, S.; Rockel-Sta¨bler, O.; Trussardi, R.;
Zwahlen, A. G. Org. Process Res. DeV. 1999, 3, 266.
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The suspension was cooled to 50 °C, diluted with 600
mL of heptane, cooled to 25 °C, and then left standing
overnight. The suspension was cooled to 0 °C and then
quenched by dropwise addition of a solution of 121.0 g (3.03
mol) of sodium hydroxide in 485 mL of H2O over 190 min
at 0-5 °C. The suspension was stirred and warmed to 25
°C over 40 min. The layers were separated, and the aqueous
layer was extracted with 100 mL of heptane. The combined
organic layers were washed with 100 mL of H2O and then
concentrated in vacuo (rotary evaporator at 30 °C and 40-
10 mmHg) to afford 175.35 g of brown syrup with trace
solids (LC assay 82.1 wt % 7, 94.4% yield).
An analytical sample was prepared by radial chromatog-
raphy on silica gel; 1H NMR (CDCl3) δ 6.87 (m, 1H), 5.81-
5.73 (m, 2H), 5.12 (d, 2H, J ) 17 Hz), 5.07 (d, 2H, J )
10.5 Hz), 5.02-4.85 (br), 4.22 (dt, 2H, J ) 7 Hz), 3.85-
3.75 (br), 3.58-3.46 (br), 3.28 (br), 3.24 (br d, 2H, J ) 14
Hz), 2.88 (dd, 2H, J ) 14 Hz, J ) 8 Hz), 2.46-2.38 (m,
2H), 2.28-2.18 (br, 3H), 1.88 (br), 1.63-1.54 and 1.44-
1.34 (m, m, 4H), 1.51 (s, 9H), 1.31 (t, 3H, J ) 7 Hz), 0.93
(t, 3H, J ) 7.5 Hz), 0.81 (t, 3H, J ) 7.5 Hz); 13C NMR
(CDCl3) δ 172.5, 166.8, 140.5, 137.2, 130.7, 117.1, 79.5,
73.2, 62.2, 60.9, 56.0, 53.2, 32.2, 31.8, 27.2, 26.6, 25.4, 23.6,
14.5, 10.0, 9.9; IR (neat) 3570, 3090, 2975, 2940, 2880, 2820,
1720, 1625, 1475, 1450, 1370, 1240, 1120, 1060, 675 cm-1.
HRFABMS found m/z 449.3368 (M + H+), calcd for
C26H45N2O4 449.3379.
Ethyl (3R,4R,5S)-4-N-Acetyl(1,1-dimethylethyl)amino-
5-N,N-diallylamino-3-(1-ethylpropoxy)-1-cyclohexene-1-
carboxylate‚HCl (8). A solution of crude tert-butyl aceta-
mide 7 (175.3 g, 321 mmol at 82.1 wt %) in 295 mL of
anhydrous ethanol was prepared at 300 rpm. A solution of
dry hydrogen chloride (14.94 g HCl, 410 mmol, 1.28 equiv)
in 50 mL of anhydrous ethanol was prepared at < 25 °C
and then added to the crude tert-butyl acetamide solution at
13-20 °C over several minutes. Ethanol (5 mL) was used
to complete the transfer. The suspension was then cooled to
0-5 °C at 150 rpm. Heptane (350 mL) was added dropwise
over 27 min, and then the suspension was cooled to -15 °C
and stirred for 60 min. The precipitate was suction filtered,
washed with 50 mL of 1:1 ethanol-heptane at -15 °C,
washed with 100 mL of heptane at -5 °C, and then dried in
vacuo (vacuum oven at 50 °C and 15 mmHg for 40 h) to
afford 142.96 g of a fluffy beige-tan solid (LC assay 100.7
wt % 8, 91.9% yield).
Ethyl (3R,4R,5S)-4-N-Acetylamino-5-N,N-diallylamino-
3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate (9). A
mixture of 142.94 g (295 mmol at 100.0 wt %) of the
hydrochloride salt 8 and 200 mL of trifluoroacetic acid was
heated at 50 °C for 1.5 h.
The solution was cooled to 25 °C and 200 mL of toluene
was added. The solution was concentrated on a rotary
evaporator at 48 °C (bath) and 80-50 mmHg. This dilution-
concentration procedure was repeated twice more. The
solution was then diluted with 400 mL of toluene, cooled to
0-2 °C, and diluted further with 60 mL of H2O. A solution
of 44.46 g (1.11 mol) sodium hydroxide in 87.7 g H2O was
prepared then added portionwise at 0 to 2 °C until the
aqueous layer was pH 12-13. The layers were separated.
The aqueous layer was extracted with 75 mL toluene. The
combined organic layers were washed with 50 mL of H2O
and then concentrated in vacuo (rotary evaporator at 35 °C
and 40-30 mmHg) to afford 165.52 g of brown syrup with
trace solids (LC assay 67.5 wt % 9, 96.6% yield).
After precipitation with heptane, an analytical sample was
prepared by recrystallization from heptane-ethyl acetate, mp
1
101.8-102.3 °C; H NMR (CDCl3) δ 6.73 (m, 1H), 5.76-
5.68 (m, 2H), 5.35 (d, 1H), 5.16 (d, 2H, J ) 16.5 Hz), 5.07
(d, 2H, J ) 10 Hz), 4.21 (q, 2H, J ) 7 Hz), 4.08 (dm, 1H,
J ) 9 Hz), 3.91 (dt, 1H, J ) 11.5 Hz, J ) 9 Hz), 3.32 (p,
1H, J ) 5.5 Hz), 3.28 (dm, 2H, J ) 14.5 Hz), 3.05 (dt, 1H,
J ) 11.5 Hz, J ) 5 Hz), 2.92 (dd, 2H, J ) 14.5 Hz, J ) 7.5
Hz), 2.58 (dd, 1H, J ) 17 Hz, J ) 5 Hz), 2.17 (ddt, 1H, J
) 17 Hz, J ) 10.5 Hz, J ) 3.5 Hz), 2.00 (s, 3H), 1.54-
1.47 (m, 4H), 1.30 (t, 3H, J ) 7 Hz), 0.91 (t, 3H, J ) 7
Hz), 0.87 (t, 3H, J ) 7 Hz); 13C NMR (CDCl3) δ 170.4,
166.9, 138.5, 137.3, 129.9, 116.9, 82.4, 77.7, 61.1, 56.5, 53.5,
52.5, 26.3, 25.8, 23.9, 23.7, 14.5, 9.8, 9.5; IR (KBr) 3270,
3110, 2980-2960, 2930, 2880, 2810, 1720, 1650, 1580,
1470, 1450, 1380, 1270, 1235, 1120, 1075, 1055, 925 cm-1.
HRFABMS found m/z 393.2756 (M + H+), calcd for
C22H37N2O4, 393.2753. Anal. Calcd for C22H36N2O4: C,
67.32; H, 9.24; N, 7.14. Found: C, 67.00; H, 9.42; N, 7.03.
Ethyl (3R,4R,5S)-4-N-Acetylamino-5-amino-3-(1-eth-
ylpropoxy)-1-cyclohexene-1-carboxylate phosphate [1:1]
(1). 1,3-Dimethylbarbituric acid (NDMBA) (15.17 g, 97.2
mmol), 0.8493 g (3.24 mmol, 4.0 mol %) of triphenylphos-
phine, 0.1817 g (0.809 mmol, 1.0 mol %) of palladium
acetate, and 58 mL of absolute ethanol were charged to a
solution of 43.06 g of diallylamino acetamide 9 (81.0 mmol
at 73.8 wt %) in 133 mL of absolute ethanol. The flask was
sealed and the mixture stirred under a nitrogen sweep for
10 min. The solution was heated at 35 °C for 2 h.
A satisfactory elemental analysis could not be obtained
1
for this salt; H NMR (CDCl3) δ 6.97 (br, 1H), 6.61-6.51
(m, 1H), 6.35-6.25 (m, 1H), 5.53-5.39 (m, 4H), 5.01-
4.98 (br d, 1H), 4.77-4.70 (m, 1H), 4.26 (q, 2H, J ) 7 Hz),
4.24-4.18 (br, 1H), 4.06-3.99 (br, 1H), 3.88 (br t, 1H),
3.51-3.44 (m, 1H), 3.41-3.33 (m, 1H), 3.33-3.27 (m, 1H),
2.80-2.73 (br d, 1H), 2.66-2.58 (m, 1H), 2.62 (m, 1H),
2.54 (s, 3H), 1.68 (s, 9H), 1.68-1.54 (m, 2H), 1.46-1.34
(m, 2H), 1.34 (t, 3H, J ) 7 Hz), 0.96 (t, 3H, J ) 7.5 Hz),
0.82 (t, 3H, J ) 7.5 Hz); 13C NMR (CDCl3) δ 175.9, 165.5,
140.0, 128.3, 127.4, 127.0, 125.1, 124.0, 79.7, 71.0, 61.4,
59.3, 58.9, 58.2, 55.4, 53.0, 32.5, 28.1, 26.6, 25.1, 24.2, 14.3,
10.1, 10.0.
The resulting solution of oseltamivir 2 was cooled and
then transferred to a 250-mL addition funnel. Absolute
ethanol (25 mL) was used to complete the transfer. A 500-
mL flask was charged with 9.40 g of 85% phosphoric acid
and 120 mL of absolute ethanol. The phosphoric acid-
ethanol mixture was heated to 50 °C, and then 160 mL
(∼two-thirds of the total volume) of the solution of oselta-
mivir 2 was added. Seed crystals of oseltamivir phosphate 1
(102 mg) were added to initiate crystallization. The resulting
suspension was stirred at 50 °C for 45 min, and then the
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remaining solution of oseltamivir 2 was added dropwise over
30 min. The addition funnel was rinsed with 8 mL of absolute
ethanol. The suspension was cooled to -17 to -18 °C over
15 h and then maintained at that temperature for an additional
2 h. The precipitate was suction filtered using a jacketed
fritted funnel, washed with 50 mL of acetone five times,
washed with 50 mL of heptane three times, and then dried
in vacuo (<50 °C and 15-20 mmHg with nitrogen sweep)
to afford 29.38 g of colorless solid (LC assay 99.9 wt %1,
88.4% yield).
Supporting Information Available
Analytical methods (PDF). This material is available free
of charge via the Internet at http://pubs.acs.org.
Received for review September 3, 2003.
OP0302107
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