Multistep Continuous-Flow Synthesis of (-)-Oseltamivir

Article abstract of DOI:10.1055/s-2016-0036-1588899

A continuous-flow synthesis of (-)-oseltamivir composed of five flow units was accomplished. In each unit, the following reactions proceed efficiently: (1) a diphenylprolinol silyl ether mediated Michael reaction, (2) a domino reaction of Michael and intermolecular Horner-Wadsworth-Emmons reactions, (3) protonation, (4) epimerization, and (5) reduction of a nitro group to an amine. (-)-Oseltamivir was obtained in 13% total yield through a single flow with a residence time of 310 minutes.

Full text of DOI:10.1055/s-2016-0036-1588899

SYNTHESIS
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©
Georg Thieme Verlag Stuttgart · New York
2016, 48, A–E
A
paper
Synthesis
S. Ogasawara, Y. Hayashi
Paper
Multistep Continuous-Flow Synthesis of (–)-Oseltamivir
Shin Ogasawara
Yujiro Hayashi*
Department of Chemistry, Graduate School of Science, Tohoku
University, 6-3 Aramaki-Aza, Aoba-ku, Sendai 980-8578, Japan
yhayashi@m.tohoku.ac.jp
http://www.ykbsc-chem.com/
Dedicated to Professor Dieter Enders on the occasion of his 70th
birthday
Received: 23.08.2016
Accepted after revision: 29.09.2016
Published online: 03.11.2016
while a three minute synthesis of racemic ibuprofen over
three flow reactors and one-membrane separation was re-
ported by Jamison.13 Despite these excellent syntheses, it
was a challenge to synthesize (–)-oseltamivir with three
continuous chiral centers through a multistep continuous-
flow method in a single passage. In comparison with the
batch system, the flow system was easy to increase the pro-
ductivity in the long time operation or directly applicable
to a larger scale after optimization on a small scale. We an-
ticipated that a continuous-flow synthesis of (–)-oseltami-
vir would be more efficient.
DOI: 10.1055/s-2016-0036-1588899; Art ID: ss-2016-z0587-op
Abstract A continuous-flow synthesis of (–)-oseltamivir composed of
five flow units was accomplished. In each unit, the following reactions
proceed efficiently: (1) a diphenylprolinol silyl ether mediated Michael
reaction, (2) a domino reaction of Michael and intermolecular Horner–
Wadsworth–Emmons reactions, (3) protonation, (4) epimerization, and
(
5) reduction of a nitro group to an amine. (–)-Oseltamivir was ob-
tained in 13% total yield through a single flow with a residence time of
10 minutes.
3
9
In our one-pot synthesis of (–)-oseltamivir in 2013, we
Key words Tamiflu, continuous flow, time economy, total synthesis,
organocatalysis
simply added the reagents sequentially without evapora-
tion or solvent swap. Thus, we considered that we could ap-
ply flow techniques to the synthesis of (–)-oseltamivir.
However, one of the most critical issues when our one-pot
®
Tamiflu , or (–)-oseltamivir phosphate, is one of the
most effective drugs for the treatment of influenza.1 Be-
cause of its importance, more than 60 different synthetic
9
procedure is applied to a flow method is the total reaction
2
routes have been developed. Our group has a long-stand-
ing interest in the effective synthesis of this drug. On the
one hand, we developed three-pot and two-pot syntheses
of (–)-oseltamivir (1) in 2009 and 2010, respectively, by us-
ing an asymmetric Michael reaction of an aldehyde and ni-
time. As it takes 57 hours for completion of the total syn-
thesis, although it is a one-pot procedure, a very long reac-
tion tube has to be prepared, which is not practical. It was
necessary to shorten the reaction time. For this purpose, we
have investigated the time-economical synthesis of (–)-os-
eltamivir through a batch system. Recently, we accom-
plished a 60-minute total synthesis of (–)-oseltamivir, opti-
mizing the reactions according to time, decreasing the
number of reaction steps, and using microwave (MW) irra-
diation. Even without microwave irradiation, (–)-oseltami-
3
4
5
troalkene catalyzed by diphenylprolinol silyl ether as a key
6
7
8
step. Ma, Sebesta, and Lu reported the synthesis of (–)-
oseltamivir from (Z)-nitroalkene 2, independently. We fur-
ther accomplished a one-pot procedure in 2013 by using
(
Z)-nitroalkene 2 as a starting material.9
2a
A flow synthesis, on the other hand, has attracted con-
vir could be synthesized within 170 minutes (Scheme 1).
siderable attention recently because of its efficiency, pro-
As the reaction is completed within a short time, we ap-
plied flow techniques to this rapid synthesis of (–)-osel-
tamivir, which will be described in this communication.
Although we shortened the reaction time, there re-
mained problems to be solved for the application of a flow
method. (1) In a flow system, generally all reagents have to
be soluble in the solvent except for polymer-supported re-
agents, but nitroalkene 2 was barely soluble in the reaction
10
ductivity, safety, and reproducibility. Moreover, continu-
ous-flow techniques have been developed to combine a
multistep synthesis with a single, continuous, and uninter-
rupted reactor network without isolation of the intermedi-
11
ate. Kobayashi recently reported the synthesis of (R)- and
(
S)-rolipram with a single chiral center with four flow reac-
12
tors in a single flow, all using heterogeneous catalysts,
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–E

B
Synthesis
S. Ogasawara, Y. Hayashi
Paper
O
P
O
1
0 mol%
10 mol%
EtO
EtO
S
Ph
OEt
AcHN
Ar
N
Ar
Ph
OSiPh2Me
7
N
O
2
NO2
O
N
H
4
H
H
5
t-BuOK (3.0 equiv)
EtOH (0.3 M)
O
O
CO2Et
Ar = 3,5-(CF3)2C6H3
H
40 mol% HCO2H
ClC6H5 (0.3 M)
0
°C, 20 min
AcHN
AcHN
O
20 °C, 30 min
NO2
N+
H
O
OK
3
6
8
TMSCl (15 equiv)
Zn (30 equiv)
O
CO2Et
O
CO2Et
O
CO2Et
TMSCl (3.0 equiv)
40 °C
TBAF (3.0 equiv)
40 °C, 20 min
–
5
NO2
S/5R = 1:5
Five reaction steps in one-pot sequence; total yield 14%; total time 170 minutes
5
EtOH (0.07 M)
AcHN
AcHN
AcHN
70 °C, 100 min
9
9
NO2
5S/5R = 1:1
NH2
–)-oseltamivir (1)
(
5
Scheme 1 Time-economical one-pot synthesis of (–)-oseltamivir without microwave irradiation reported in 20162a
solvent. (2) Zinc was employed in the reduction of the nitro
group to an amine, and it is problematic to conduct this
transformation in a flow system.
To address these problems, we first optimized the syn-
thetic procedure of (–)-oseltamivir by using a batch system.
We then applied the optimized procedure to the flow syn-
thesis. After extensive optimization of the reaction condi-
tions, we succeeded in creating a continuous-flow synthe-
sis of (–)-oseltamivir, which is summarized in Scheme 2.
This flow synthesis consists of five units, which we will de-
scribe in turn.
Flow unit 1 involved the asymmetric Michael reaction
of pentan-3-yloxyacetaldehyde (3) and (Z)-N-2-nitroethe-
nylacetamide (2). We previously noted that Schreiner’s
thiourea 5,14 with a combination of diphenylprolinol silyl
ether 4, dramatically accelerates the reaction, and that the
reaction time was shortened without affecting either the
diastereo- or enantioselectivities. As nitroalkene 2 dissolves
Scheme 2 Continuous-flow synthesis of (–)-oseltamivir
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–E

C
Synthesis
S. Ogasawara, Y. Hayashi
Paper
only partially in an aromatic solvent, a suspended solution
in chlorobenzene (0.3 M) gradually became clear as the re-
action proceeded in the batch synthesis.2a However, in the
flow system, nitroalkene 2 must be soluble in the solvent
from the outset. When a polar solvent was employed, ni-
troalkene 2 dissolved, but an epimerization of the syn form
to the undesired anti-Michael adduct occurs quickly with a
corresponding decrease of the chemical yield. After opti-
mizing the solvent and concentration of nitroalkene 2, we
obtained good results by using toluene as the solvent under
dilute conditions. The reaction proceeds within 1 hour to
afford the Michael product in good yield with high syn-se-
lectivity and excellent enantioselectivity (95%, dr = 14:1,
flow system. After a protonation occurred in the flow sys-
tem at –40 °C, the reaction mixture was combined with an
EtOH solution of TBAF in the next Comet-X-01. The combi-
nation was allowed to flow for 67 minutes at 60 °C, and
equal amounts of R- and S-isomers were formed.
Flow unit 5 effected the reduction of the nitro group to
an amine. In the batch system, it took 2 hours for this re-
duction using Zn and TMSCl. Because Zn is a solid, we used
a column system for this reduction. A column (Biotage,
SNAP Empty cartridge 10 g)18 was packed with zinc (5 g)
and Celite (8 g), and was attached to the flow system. Celite
was used to avoid clogging.
First we added TMSCl then the reaction mixture was
flowed through the column. Partial undesired epimeriza-
tion of the 5S-isomer 9 to 5R-isomer 9 was observed after
the addition of TMSCl. We found that the concentration of
TMSCl was crucial to suppress this epimerization. After op-
timizing the reaction conditions for a flow system, a mix-
ture of TMSCl in EtOH (0.6 M) was introduced from the bot-
tom of the column, which effectively reduced the nitro
group in the flow system without epimerization. The re-
duction was conducted at 70 °C and the residence time was
120 minutes. The column was replaced every 5 hours be-
cause Zn activity gradually decreased over a long period.
On the other hand, the column was found to be stable for 5
hours. When three columns were continuously employed
for 15 hours, the conversions of several exiting solutions
showed almost same value.
(–)-Oseltamivir was isolated by using an acid–base ex-
traction and purified by column chromatography. The total
residence time through the five flow units was 310 min-
utes. Except for unit 5, a reaction tube with a bore size of
0.96 mm was used, and the flow rate and concentration of
the nitroalkene 2 were 0.04 mL/min and 0.04 M, respective-
ly. A column packed with Zn and Celite was employed in
unit 5. Under these conditions, we obtained 58 mg of (–)-
oseltamivir per 15 hours (13% yield).
97% ee), when a dilute clear toluene solution (0.04 M) of ni-
troalkene 2 was used (Scheme 2). A toluene solution of ni-
troalkene 2, alkoxyaldehyde 3, thiourea derivative 5, and
ClCH CO H was mixed with a toluene solution of catalyst 4
2
2
15,16
by using a Comet-X-01 micromixing device
at 20 °C. The
above mixture was allowed to flow in the tube for 71 min-
utes to provide Michael adduct 6. When the reaction was
quenched at this stage, the conversion (91%, dr = 10:1, 97%
ee) was almost same as that of the batch system.
Flow unit 2 involved a domino reaction of Michael and
intermolecular Horner–Wadsworth–Emmons reactions.
We already optimized this step in a batch system, in which
2a
soluble t-BuOK was selected as a base instead of insoluble
9
Cs CO at 0 °C. We conducted the reactions in a flow sys-
2
3
tem as follows: phosphoryl acrylate 7 and t-BuOK were
added separately through the use of a T-shaped mixer and a
Comet-X-01 device to avoid the Michael addition of EtOH to
phosphoryl acrylate 7. After a toluene solution of phos-
phoryl acrylate 7 was added to the reaction mixture, an
EtOH solution of t-BuOK was added by using the next mix-
er. Although the reaction proceeded smoothly, a solid ap-
peared in the second mixer and clogged the flow path over
time. THF was premixed with t-BuOK in EtOH to prevent
the precipitation. As a result, after a 35-minute residence
time at 0 °C, cyclohexene 9 was obtained in approximately
In summary, a continuous-flow synthesis of (–)-osel-
tamivir with five flow units was accomplished. All reagents
except for Zn were dissolved in solvent. The multistep con-
tinuous-flow synthesis for (–)-oseltamivir with three con-
tinuous chiral centers was successfully realized without
isolating any intermediates by using a single flow.
17
6
0% yield when the reaction was quenched at this stage,
in which the undesired 5R-isomer was predominantly gen-
erated (5S/5R=1:5).
Flow unit 3 protonated the nitronate anion. At the end
of the domino reaction, potassium nitronate 8 (Scheme 1)
was formed, which needed to be protonated before an epi-
merization. Protonation was accomplished by the addition
of TMSCl in EtOH, which produced HCl in situ, with a resi-
dence time of 7 minutes at –40 °C.
All reactions were monitored by thin-layer chromatography (TLC) us-
ing Merck silica gel 60 F254 plates (0.25 mm thickness). Compounds
were visualized by UV, KMnO or sulfuric acid molybdenum. A Com-
Flow unit 4 effected an epimerization from the 5R-iso-
mer to the 5S-isomer. In the previous report of the batch
4
et-X-01 micromixing device was obtained from Techno Applications
15
Co., Ltd. Syringe pumps (PHD2000 or Catamaran HII-10B) were ob-
tained from Harvard Apparatus or Techno Applications Co., Ltd. ‘SNAP
2a
synthesis, we optimized the rapid epimerization and
found that tetrabutylammonium fluoride (TBAF) is effec-
tive, although complete epimerization could not be
achieved (5S/5R = 1:1). The appropriate flow rates and resi-
dence times were optimized for epimerization by using a
18 1
Empty cartridge’ was purchased from Biotage Japan Co., Ltd. H and
13C NMR spectra were recorded with an Agilent-400 MR (400 MHz for
1
13
H NMR, 100 MHz for C NMR) instrument. High-resolution ESI-TOF
mass spectra were measured with a Thermo Orbitrap instrument.
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Synthesis
S. Ogasawara, Y. Hayashi
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(–)-Oseltamivir (1); Flow Synthetic Procedure
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(
(
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4
adjust to pH 11. The aqueous layer was extracted three times with
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3
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Supporting Information
(
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0036-1588899.
S
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Synthesis
S. Ogasawara, Y. Hayashi
Paper
4
1
9, 2010. (d) Tanaka, K.; Miyagawa, T.; Fukase, K. Synlett 2009,
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(
17) The yield was determined by H NMR analysis using 1,3,5-tri-
methoxybenzene as internal standard.
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–E