A Viedma ripening route to an enantiopure building block for Levetiracetam and Brivaracetam

Article abstract of DOI:10.1039/c8ob02660b

A simple route to enantiomerically pure (S)-2-aminobutyramide-the chiral component of the anti-epileptic drugs Levetiracetam and Brivaracetam has been developed. This approach is based on the rational design and application of a Viedma ripening process. The practical potential of the process is demonstrated on a large scale.

Full text of DOI:10.1039/c8ob02660b

Organic &
Biomolecular Chemistry
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A Viedma ripening route to an enantiopure
building block for Levetiracetam and
Brivaracetam†
Iaroslav Baglai,a Michel Leeman,b Richard M. Kelloggb and Willem L. Noorduin
Cite this: Org. Biomol. Chem., 2019,
17, 35
Received 26th October 2018,
Accepted 5th November 2018
a
*
DOI: 10.1039/c8ob02660b
rsc.li/obc
A simple route to enantiomerically pure (S)-2-aminobutyramide – yield and enantiomeric excess (ee) from the racemate is thus
the chiral component of the anti-epileptic drugs Levetiracetam and very desirable.
Brivaracetam has been developed. This approach is based on the
We here present a simple and efficient route to the
rational design and application of a Viedma ripening process. The building block (S)-2-aminobutyramide 2 with ee > 99% in vir-
practical potential of the process is demonstrated on a large scale.
tually quantitative yield. Our approach relies on a recently dis-
covered deracemization technique that combines simple grind-
ing of crystals with racemization in solution. This attrition-
enhanced deracemization (Viedma ripening) allows total con-
version of a racemate to a single enantiomer of the desired
chirality.8–14 Under near-equilibrium conditions a solid phase
of the racemate is entirely converted into a solid phase of the
enantiomer of choice by grinding of a slurry. The fundamental
basis for this remarkable process is understood although the
details remain the subject of continuing discussion. However,
there is consensus that the process has two prerequisites: (1) the
enantiomers of the racemate must crystallize as a conglomerate,
i.e. a mechanical mixture of enantiopure crystals, and (2) racemi-
zation in the solution in contact with the crystals must occur, i.e.
the enantiomers must interconvert in the liquid phase. These
requirements limit the choice of suitable molecules. Satisfactory
racemization conditions are often not obvious, and despite the
recent progress made in calculating crystal structures,15 conglom-
erate formation remains still unpredictable and statistically
occurs only for 5–10% of chiral organic compounds.16 As a
result, it remains challenging to design new suitable compounds
for attrition-enhanced deracemization.
Simple synthetic routes to enantiomerically pure building
blocks are essential for the cost-effective production of
pharmaceutical
compounds.
Levetiracetam
1a
and
Brivaracetam 1b are commonly used for the treatment of epi-
lepsy.1,2 The essential building block for both of these drugs is
enantiomerically pure (S)-2-aminobutyramide 2. A key step in
the preparation is the introduction of the desired absolute (S)
configuration at the chiral center.3–7 In the initial route devel-
oped by the originator UCB, chromatographic separation of
the enantiomers of racemic 1a by simulated moving bed
technology was used to produce enantiomerically pure 1a.4
Currently, however, most generic producers of 1a,b start with
the single enantiomer of the unnatural amino acid (S)-2-ami-
nobutyric acid amide 2 (Scheme 1), prepared by classical
resolution of the racemate using diastereomeric salt formation
with enantiomerically pure D-(−)-mandelic acid or L-(+)-tartaric
acid.5–7 For all of these resolution techniques, the theoretical
yield of the desired (S) enantiomer is limited to 50%. To over-
come this yield restriction, the undesired (R) enantiomer may
be “externally” racemized and resolved again, although a draw-
back is that this often requires a multi-step process. To our
knowledge, attempts to develop a classical resolution com-
bined with in situ racemization for the obtainment of enantio-
merically pure 2 have not yet been successful, let alone been
developed into an industrially viable process. A simple and
robust process to produce only the (S)-enantiomer in high
To the best of our knowledge, in the currently employed
synthetic routes to compounds 1a,b none of the reported
aAMOLF, Science Park 104, 1098 XG Amsterdam, The Netherlands.
E-mail: noorduin@amolf.nl
bSyncom BV, Kadijk 3, 9747 AT Groningen, The Netherlands
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
c8ob02660b
Scheme 1 (S)-2-Aminobutyramide (S)-2, a chiral building block for
Levetiracetam 1a and Brivacetam 1b.
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intermediates or final products crystallizes as a conglomerate.
Since conglomerate behavior is essential, but unpredictable,
we need a library approach to design a new conglomerate
intermediate that racemizes in solution.
Recently we developed an α-aminonitrile-based method-
ology that allows the absolute asymmetric synthesis of highly
sterically hindered α-amino acids via formation of intermedi-
ate racemizable conglomerates.17 Moreover, we demonstrated
the crucial role of balanced physicochemical properties
(crystallinity/acidity) of conglomerates suitable for Viedma
ripening. However, based on these results we envisaged that
low crystallinity and/or high solubility of analogous
α-aminobutyronitrile imines would likely hinder their appli-
cation in a Viedma ripening process.
Fig. 1 Conglomerate identification: as expected for conglomerate for-
mation, XRPD diffractograms of the racemates and enantiomerically
pure forms of 3a (left) and 3b (right) are identical.
Considering this analysis, and relying on previous experi-
ence,18,19 we designed a library of amino acid amide 2 deriva-
tives to identify a racemizable conglomerate. In short, we
allowed racemate 2 to react with a selection of aromatic
aldehydes to yield a library of imines (Schiff bases) 3a–f
(Scheme 2). All products were nicely crystalline probably owing
to the hydrogen bonding network.
To identify the library entries that crystallize as conglomer-
ates, the imines were screened by second harmonic generation
(SHG) measurements,20,21 followed by comparison of the race-
mate and enantiomerically pure form using X-Ray powder
diffraction (XRPD) and differential scanning calorimetry
(DSC). From this screen, the imines 3a,b formed with benz-
aldehyde and with 2-methylbenzaldehyde, respectively, were
identified as conglomerates as can be judged from the identi-
cal XRPD diffractograms (Fig. 1) of the enantiomerically pure
and racemic crystals. For economic reasons, compound 3a was
chosen for detailed investigation although from preliminary
experiments it was established that 3b also undergoes com-
plete deracemization on attrition (ESI†).
As anticipated, despite the lower acidity of imines 3 as com-
pared to the previously reported phenylglycinamides
derivatives,22–24 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) was
found to racemize (S)-3a at ambient temperature at rates suit-
able for deracemization. To optimize the racemization con-
ditions, we examined the racemization of (S)-3a with DBU in
multiple solvents. As illustrated in Fig. 2, the racemization rate
is dependent on solvent and is clearly fastest in acetonitrile
and toluene.
We investigated the deracemization of 3a by attrition
(Viedma ripening) in all four solvents. In the initial small-scale
experiments, a reaction vessel was placed in a temperature
controlled ultrasonic bath and sonicated at 20 °C. To direct
the outcome of the deracemization the solid phase was seeded
with the desired (S) enantiomer to obtain approximately
10–15% starting ee in (S) in the solid phase. The enrichment
in the solid phase during the process was monitored by first
isolating the solid phase using filtration, which promptly
stopped the racemization. Subsequently, the enantiomeric
excess of the solid phase was analyzed using HPLC on a chiral
column. Within
6 hours, complete deracemization was
Scheme 2 Schematic illustration of the imines library preparation and
deracemization of the identified conglomerates 3a,b.
Fig. 2 Racemization of (S)-3a (0.5 mg mL−1) with DBU (3.3 μL mL−1) in
various solvents at ambient temperature.
36 | Org. Biomol. Chem., 2019, 17, 35–38
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observed in acetonitrile. Despite lower rates, experiments in liquid phase can be easily recovered. Furthermore, we con-
toluene and methyl tert-butyl ether also led to complete dera- firmed that such filtered liquid phase can be recycled to
cemization. In n-heptane only a slight enrichment of the solid perform another deracemization experiment (ESI†). The
phase was detected before the slurry turned into a “glue-like” process is thus virtually quantitative in an economic operation
sticky substance after 3 days of attrition (Fig. 3). This solvent procedure.
effect might be due to the fact that heptane is a poorer emulga-
Finally, to obtain the desired enantiomerically pure build-
tor than acetonitrile and, to a lesser extent, toluene. The latter ing block (S)-2 for Levetiracetam 1a and Brivaracetam 1b dera-
solvents have both a polar and less polar side, which assists in cemized (S)-3a was hydrolyzed under acidic conditions to
stabilizing the crystal surface, thus hindering destabilization provide the HCl salt of (S)-2 with complete preservation of
of the dispersion, especially under high attrition rates. These stereochemistry at the chiral center with >99% ee in nearly
observations suggest that an ideal solvent for Viedma ripening quantitative yield (ESI†).
not only supports swift racemization and crystallization/
dissolution, but also acts as a dispersion agent.
In summary, we introduce a practical absolute asymmetric
synthesis route to the chiral key precursor for Levetiracetam
The deracemization reaction rate k can be estimated from and Brivacetam. Owing to its simplicity, robustness and vir-
the relation ee(t) = ee(0)exp(kt), in which ee(0) and ee(t) are tually quantitative yield, this Viedma ripening approach pro-
the enantiomeric excess in the solid phase at the beginning of vides an attractive cost-effective alternative to the current
the experiment t = 0 and time t respectively.25 As expected, the routes. Only mechanical attrition at ambient temperature of
time evolution of the ee in the solid phase follows the the corresponding benzaldehyde Schiff base at near equili-
exponential behavior that is typical for this process (Fig. 3).
brium is required combined with simple, high yielding con-
Although racemization and deracemization are somewhat densation chemistry and equally high yielding hydrolyses with
more rapid in acetonitrile compared to toluene, the formation low cost mineral acids. Finally, these results show that the
of small amounts of an unidentified and undesired side- invention of a practical Viedma ripening process does not
product as well as the relatively high solubility of 3a made the merely rely on the design and identification of a racemizable
former solvent less attractive for a continuous large-scale conglomerate, but rather requires a holistic approach in which
process. Further optimization of the reaction conditions was a multitude of factors is taken into account (e.g. reagents, reac-
performed using toluene as a solvent, in which both racemiza- tion conditions, attrition, solvent, etc.).
tion and deracemization occurred with suitable rates for practi-
cal application.
To demonstrate the potential of practical application of this Conflicts of interest
method we performed our process on a relatively large scale –
The authors declare no conflict of interest.
starting with 15 g of 3a. To obtain the desired (S)-enantiomer,
we created an initial ee of 14% in the solid phase by seeding
with the (S)-enantiomer. Despite the relatively high solid
content compared to the initial experiments, complete derace-
Acknowledgements
mization of the solid phase was achieved within 60 hours at
20 °C (Fig. S1, ESI†), providing the desired (S)-3a in 77% iso-
lated yield and 99% ee. The racemic material remaining in the
This work was supported by AMOLF funds for Topsector-
related research.
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