A Robust, Recyclable Resin for Decagram Scale Resolution of (±)-Mefloquine and Other Chiral N-Heterocycles

Article abstract of DOI:10.1002/anie.201509256

Decagram quantities of enantiopure (+)-mefloquine have been produced via kinetic resolution of racemic mefloquine using a ROMP-gel supported chiral acyl hydroxamic acid resolving agent. The requisite monomer was prepared in a few synthetic steps without chromatography and polymerization was safely performed on a >30 gram scale under ambient conditions. The reagent was readily regenerated and reused multiple times for the resolution of 150 grams of (±)-mefloquine and other chiral N-heterocylces.

Full text of DOI:10.1002/anie.201509256

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Communications
Chemie
International Edition: DOI: 10.1002/anie.201509256
German Edition: DOI: 10.1002/ange.201509256
Kinetic Resolution
A Robust, Recyclable Resin for Decagram Scale Resolution of ( Æ )-
Mefloquine and Other Chiral N-Heterocycles
Imants Kreituss, Kuang-Yen Chen, Simon H. Eitel, Jean-Michel Adam, Georg Wuitschik,
Alec Fettes, and Jeffrey W. Bode*
Abstract: Decagram quantities of enantiopure (+)-mefloquine
have been produced via kinetic resolution of racemic meflo-
quine using a ROMP-gel supported chiral acyl hydroxamic
acid resolving agent. The requisite monomer was prepared in
a few synthetic steps without chromatography and polymeri-
zation was safely performed on a > 30 gram scale under
ambient conditions. The reagent was readily regenerated and
reused multiple times for the resolution of 150 grams of (Æ)-
mefloquine and other chiral N-heterocylces.
identify a suitable procedure to obtain its (+)-erythro
enantiomer in decagram quantities and high enantiomeric
excess.
Mefloquine (Lariam), is a synthetic quinine derivative
that is one of the most effective medicines for the treatment
and prophylaxis of malaria.[7] It is currently sold as a racemate
and epitomizes the potential pitfalls of marketing and
administering racemic drugs, as some neurological side effects
are suspected to be caused by one of the enantiomers.[8] Our
selection was further encouraged by its molecular structure.
Mefloquine is a good representation of the functional groups
commonly found in pharmaceutical candidates; along with
the piperidine ring, (Æ)-mefloquine includes a free alcohol
and a basic nitrogen in the quinoline core.
In the preliminary studies, our catalytic kinetic resolution
failed to selectively acylate the secondary amine in (Æ)-
mefloquine and gave a complex product mixture. Further-
more, owing to the sterically demanding side chain, sufficient
conversion could not be achieved at room temperature. We
were pleased, however, to find that the use of 0.65 equivalents
of our chiral hydroxymate reagent in THF at 458C afforded
(+)-mefloquine (99:1 e.r.) with good selectivity (s = 23) and
conversion (61%).[9] This promising result was insufficient as
a practical solution to the production of decagram quantities,
as it required time-consuming chromatography to separate
the amine from the amide and reagent byproducts. We
previously developed an immobilized variant of the chiral
hydroxamic acid using commercial aminomethyl polystyrene
resin and demonstrated that this is a suitable option for small-
scale (ca. 1 mmol) resolutions. For practical, large-scale use, it
proved completely inadequate in terms of loading, reaction
time, cost of goods, swelling properties, and solvent usage.
Although we first considered other commercial polymers as
a support, it became quickly clear that a de novo synthesis of
a polymer-bound reagent with the necessary properties would
be required (Scheme 1).
E
nantiopure N-heterocycles are of great and increasing
importance in the pharmaceutical industry. In the last six
years alone, around 30 of the approximately 115 new small-
molecule entities introduced contained at least one chiral N-
heterocycle.[1] In the early stages of drug discovery, where the
focus is on structural diversity, the preparation of chiral N-
heterocyclic building blocks (often in their racemic form) is
key to the rapid progression of medicinal chemistry pro-
grams.[2] As a compound progresses, access to the enantio-
merically pure form is essential, usually on a 10–1000 gram
scale. When the racemate or racemic precursor is easily
accessible, enantiomer resolution is very often the method of
choice and is typically accomplished by diastereomeric salt
formation or preparative HPLC/SFC on chiral supports.[3]
Within this context, our group has developed catalytic and
stoichiometric methods for the kinetic resolution of chiral N-
heterocycles.[4,5] These studies, however, have been limited to
milligram scales and their suitability for resolving decagram
quantities of an advanced intermediate or active pharma-
ceutical ingredient have not been established. To render this
technology into a viable solution for the rapid resolution of
chiral secondary amines on a preparative scale, we selected
(Æ)-mefloquine as a challenging substrate and aimed to
[*] I. Kreituss, Dr. K.-Y. Chen, Prof. Dr. J. W. Bode
Laboratorium für Organische Chemie, Departement Chemie und
Angewandte Biowissenschaften, ETH Zürich
Vladimir-Prelog-Weg 3, CH-8093 Zürich (Switzerland)
E-mail: bode@org.chem.ethz.ch
For the polymer synthesis we evaluated multiple possi-
bilities before selecting ring-opening metathesis polymeri-
Homepage: http://www.bode.ethz.ch/
Dr. S. H. Eitel, Dr. J.-M. Adam
Roche Pharma Research and Early Development, preclinical CMC,
Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd
Grenzacherstrasse 124, CH-4070 Basel (Switzerland)
Dr. G. Wuitschik, Dr. A. Fettes
F. Hoffmann-La Roche Ltd,
PTDCA, Process Research & Development
Bldg 65/618 A, CH-4070 Basel (Switzerland)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201509256.
Scheme 1. Resolution of commercialized mefloquine.[6]
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zation (ROMP).[10] We designed a suitable monomer that
would be linked to the chiral hydroxamic acid moiety as
a tertiary amide. The exo-norbornene-derived amine mono-
mer 5 was obtained in three steps from commercially
available carbic anhydride 2. The endo- isomer was converted
to the exo- isomer via thermal isomerization followed by
recrystallizations to afford the product 3,[11] which was
transformed to the corresponding imide 4 by treatment with
ammonium acetate in refluxing acetic acid; reduction with
LiAlH4 afforded the amine 5.[12] This sequence was conducted
on a 100 gram scale in the academic laboratories and > 1 kg
scale by an industrial partner. The chiral carboxylic acid 8 was
prepared in a three-step route from our previously reported
bromohydroxamic acid 6, which was protected with a benzyl
group and subsequently coupled to benzylacrylate using
a Heck reaction. The one-step reduction of both benzyl
groups and the double bond using Pd/C and atmospheric
pressure of hydrogen gas yielded hydroxamic acid 8.
amorphous solid, which after processing (extensive drying
and grinding for 3–5 min with a ball mill) was rendered into
a free flowing powder. The acetyl group, which we identified
as optimal for polymerization, did not afford sufficient
selectivity for the kinetic resolution and was replaced by the
more selective dihydrocinnamoyl- group by treating the
polymer with propyl amine followed by acylation with
excess of 3-phenylpropionic anhydride (Scheme 3).
Amine 5 and carboxylic acid 8 were coupled using EDC
followed by acylation of the free hydroxamic acid with acetic
anhydride to afford amide 9 in quantitative yield over two
steps. Protection of the hydroxamate with acetic anhydride
proved necessary for high conversion in the polymerization
(Scheme 2).
Scheme 3. Polymerization. Reagents and conditions: a) [(H2Mes)(3-Br-
Py)2(Cl)2Ru=CHPh] 10 (0.2 mol%), CH2Cl2 (0.2m), 83% b) nPrNH2
(excess) in THF, c) 3-phenylpropionic anhydride (excess), THF, 458C.
The quantification of the end material revealed that our
reagent has an active loading of about 1.7 mmolgÀ1 (ca. 80%
of theoretical). It exhibited equal selectivity as the reagent
used in solution phase resolutions. We fine-tuned the
conditions to achieve sufficient conversion to obtain enantio-
pure (+)-erythro-mefloquine.
Importantly, the resolution is operationally straightfor-
ward; simply shaking the amine solution together with the
polymer followed by decantation and polymer wash allowed
us to resolve more than 20 g of racemic mefloquine per cycle.
The considerable difference in polarity between the amine
and the amide product and absence of byproducts allowed us
to recover the unreacted amine in high purity and good yield
via filtration through a short plug of silica.
We found the use of excess of the polymer optimal for
high conversion. This was not at an inconvenience, as the
polymer was fully recovered and regenerated after each cycle
by simple treatment with 3-phenylpropionic anhydride. Seven
cycles of kinetic resolution have been performed using the
same batch of resin, without significant erosion in reactivity or
selectivity (see Table 1). With this single batch of the a-
PEARL resin, over 50 grams of enantiopure (+)-mefloquine
was prepared from about 150 grams of racemic starting
material.[14]
Scheme 2. Synthesis of ROMP monomer. Reagents and conditions:
a) 1,2-dichlorobenzene reflux, then recrystallization from benzene,
30%; b) NH4OAc (3.0 equiv), AcOH reflux, quant; c) LiAlH4
(4.0 equiv), THF, 08C to reflux, quant; d) BnCl (1.0 equiv), K2CO3
(2.0 equiv), DMF, 77%; e) Benzylacrylate (1.1 equiv), Pd(OAc)2
(5 mol%), P(o-tolyl)3 (0.11 equiv), Et3N (5.0 equiv), MeCN, 238C to
reflux, 85%; f) Pd/C (10 wt%), H2, quant; g) EDC (1.0 equiv), DMAP
(0.2 equiv), CH2Cl2, quant; h) Ac2O (1.3 equiv), THF, 238C to 508C,
>99%.
Several catalysts were evaluated for the large scale
ROMP. Grubbs third-generation catalyst 10 proved optimal,
with full conversion in a matter of minutes.[13] The polymer-
izations were successfully performed multiple times on a 30 g
scale under ambient, open-to-air conditions in CH2Cl2. A
monomer to initiator ratio of 500:1 yielded a mechanically
stable polymeric material with a sufficient chain length to
render it insoluble in organic solvents while allowing good
swelling in THF, the optimal solvent for kinetic resolution.
Once the polymerization was complete, the active chain ends
were quenched with an excess of ethyl vinyl ether. The gel-
like material was washed with Et2O to afford a white
Although this reagent was optimized for the resolution of
( Æ )-mefloquine, we have also found that it is effective for the
resolution of
a variety of other chiral N-heterocycles
(Table 2). For this general method we chose to use sub-
stoichiometric amounts of the resolving agent. Most of the
amines exhibit high selectivity (s > 15) towards the reagent
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Table 1: Kinetic resolution of (Æ)-mefloquine.
Table 2: Kinetic resolution of various N-heterocycles.
Entry[a]
Recovered amine
Entry
Recovered amine
1
8
>99:1 e.r.[b]
;
96:4 e.r.;
23% yield
s=7; c=70%
23% yield[c]
s=23, c>70%[d]
Cycle
(Æ)-Mefloquine[a] [g]
s[b]
c[c] [%]
e.r.[d]
Yield [%][e]
1
2
3
4
5
6
7
18.0
22.5
25.0
23.0
22.3
20.0
22.3
26
24
22
22
22
21
20
59
60
61
61
61
61
64
>99:1
>99:1
>99:1
99:1
>99:1
>99:1
>99:1
29
32
30
37
31
32
30
2
3
4
9
93:7 e.r.;
34% yield
s=13; c=57%
96:4 e.r.;
39% yield
s=21; c=55%
[a] Amount of (Æ)-mefloquine. [b] s=selectivity. [c] c=calculated con-
version. [d] Enantiomeric ratio was determined with HPLC or SFC on
a chiral support. [e] Yield of isolated products.
10
11
93:7 e.r.;
40% yield
s=18; c=54%
>99:1 e.r.;
33% yield
s=34; c=60%
and in many cases sufficiently high conversion could be
achieved even without the use of excess polymer. On multiple
occasions (Table 2, entries 1, 6, 7, 10, 11, 13), the unreacted
amine was recovered in 99:1 or higher enantiomeric ratio.
In summary, we have developed a user-friendly method
for the production of enantiopure (+)-erythro-mefloquine
from its racemate using a solid supported hydroxamic acid.
The polymer can be rapidly prepared on a decagram scale in
high yield without chromatography. The reagent has a high
loading, is stable at ambient conditions, can be fully recovered
and reused without loss of reactivity and selectivity and has
been employed on a broad range of N-heterocyles. Unlike
SFC, no infrastructure other than a shaker and a flask are
needed for the preparation of enantiopure N-heterocycles on
an analytical and preparative scale.
86:14 e.r.,
25% yield
s=16; c=49%
>99:1 e.r.;
30% yield
s=20; c=63%
5
6
12
13
87:13 e.r.;
39% yield
s=13; c=50%
79:21 e.r.;
45% yield
s=9; c=46%
99:1 e.r.;
99:1 e.r.;
Experimental Section
38% yield
s=19; c=61%
21% yield
amide not isolated
The polymer-supported resolving agent (50.0 g, ca. 85.0 mmol, ca.
1.3–1.4 equiv) was swollen in THF for 1 h at 458C and washed with
THF (3 ” three volume beds). The free base of (Æ)-mefloquine
(25.0 g, 66.1 mmol, 1.0 equiv) as a solution in THF (180 mL) was
added to the polymer and the mixture was left shaking for 12 h at
458C. The polymer support was washed with THF (4 ” three volume-
beds) and Et2O (2 ” three volume-beds) to afford a solution of the
amide product and the unreacted amine.
7
14
>99:1 e.r.;
36% yield
s=19, c=64%
93:7 e.r.;
45% yield
s=17; c=54%
[a] Reactions were run for 15–24 h in THF at 458C using 0.7 equiv of a-
PEARL. For more details, see the Supporting Information. [b] Enantio-
meric ratio was determined with HPLC or SFC on a chiral support.
[c] Yield of isolated products. [d] s=selectivity, c=calculated conversion.
Acknowledgements
This work was supported by the Swiss Federal Commission
for Technology and Innovation (CTI), F. Hoffmann-La Roche
and the European Research Council (ERC Starting Grant
306793—CASAA). We are grateful to Dr. Alexey Fedorov
and Mr. Dmitry Mazunin (both ETH) for helpful discussions,
and Pierre Schmitt and Raffaele Santillo (both F. Hoffmann-
La Roche) for technical assistance with hydrogenation reac-
tion. Special thanks to Paula L. Nichols (ETH) for facilitating
this project.
Keywords: amines · enantioselective acylation ·
kinetic resolution · N-heterocycles · polymerization
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Received: October 4, 2015
Published online: December 11, 2015
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