Development of Scalable Conditions for the Ugi Reaction-Application to the Synthesis of (R)-Lacosamide

Article abstract of DOI:10.1021/acs.oprd.5b00228

The Ugi reaction is applied for the preparation of (R)-lacosamide, an important drug for the treatment of epilepsy. To this end, key issues associated with the Ugi reaction, such as a practical preparation of the foul-smelling isocyanide as well as the efficient introduction of chirality via a cheap and easily removable chiral directing group, were solved. Enantiomerically pure (>99.9% ee) drug substance meeting all required purity specifications is prepared in operationally simple four steps in 40% overall yield from the commodity chemical benzylamine.

Full text of DOI:10.1021/acs.oprd.5b00228

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Full Paper
Development of Scalable Conditions for the Ugi Reaction
– Application to the Synthesis of (R)-Lacosamide
Hermut Wehlan, Jan Oehme, Alexander Schäfer, and Kai Rossen
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.5b00228 • Publication Date (Web): 12 Oct 2015
Downloaded from http://pubs.acs.org on October 12, 2015
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Development of Scalable Conditions for the Ugi
Reaction – Application to the Synthesis of (R)-
Lacosamide
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Hermut Wehlan*, Jan Oehme, Alexander Schäfer and Kai Rossen
Chemical and Biological Development, Sanofi, Industriepark Hoechst, Dꢀ65926 Frankfurt,
Germany
ABSTRACT: The Ugi reaction is applied for the preparation of (R)ꢀlacosamide, an important
drug for the treatment of epilepsy. To this end, key issues associated with the Ugi reaction, such
as a practical preparation of the foulꢀsmelling isocyanide as well as the efficient introduction of
chirality via a cheap and easily removable chiral directing group were solved. Enantiomerically
pure (>99.9% ee) drug substance meeting all required purity specifications is prepared in
operationally simple four steps in 40% overall yield from the commodity chemical benzylamine.
INTRODUCTION
A number of reactions are very widely applied by the chemical community and are
consequently assumed to have a high level of maturity in their development. However, a more
critical assessment often reveals that key parameters required to perform the respective reaction
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reliably on any scale are missing from the literature. One such reaction for which this holds is the
Ugi reaction. Despite its industrial birth in 1959 in the Central Research laboratories of Bayer
AG and its very wide adoption by the chemical community (over 3000 Scifinder hits), the
authors are not aware of any large scale implementation of the Ugi reaction. Several reasons for
this apparent discrepancy between its popularity and lack of utilization on large scale can be
explained by three major challenges of the Ugi reaction:
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ꢀ
ꢀ
ꢀ
the preparation and handling of foul smelling isocyanides
the need to find appropriate chiral auxiliaries for the introduction of chirality
the need to remove these auxiliaries with high yield
This publication reports the solution to these problems using as an example a short, efficient
and highꢀyielding preparation of lacosamide 1.
Lacosamide 1 is a cornerstone of modern epilepsy treatment and has found widespread
acceptance among patients and physicians.2
O
H
N
N
H
OMe
O
1
Figure 1. (R)ꢀLacosamide 1.
RESULTS AND DISCUSSION
Despite its deceptively simple structure as a derivative of Dꢀserine the reported syntheses are
cumbersome.3 Until recently the starting material, protected Dꢀserine 2, was expensive and
difficult to obtain. The synthesis from Dꢀserine requires a finicky Oꢀmethylation of compound 3
(reportedly requiring Ag2O as base), the need to use a urethane protecting group such as Cbz to
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allow a racemization free formation of the Nꢀbenzyl amide 3, and consequently an unproductive
protection/deprotection prior to the installation of the Nꢀacetamide of amine 5 in the final step
(d), as shown in Scheme 1.3a
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O
O
O
(a)
(b)
CbzHN
CbzHN
CbzHN
OH
N
N
H
H
OH
OH
OMe
2
3
4
(c)
O
O
H
N
H2N
(d)
N
N
H
H
O
OMe
OMe
1
5
Scheme 1. a) isobutyl chloroformate, Nꢀmethyl morpholine, PhCH2NH2, 84%; b) MeI, Ag2O,
84%; c) H2/PdꢀC, 100%; d) Ac2O, pyridine, DMAP, 90%.3a
The concept, outlined in Scheme 2, makes use of the power of the Ugi reaction of compounds
6ꢀ9 to set up the complete skeleton of the molecule in a single step to yield compound 10,
followed by the removal of the chiral auxiliary R*.4
-C
R*
N
O
N+
O
O
N
R*
1
H
+
+
+
O
NH2
OH
OMe
OMe
6
7
8
9
10
Scheme 2. Synthesis of lacosamide via four component Ugi reaction.4
The chemistry was developed so that lacosamide 1 could be prepared using a very concise
process from commodity chemicals in an overall yield of 40% with excellent chemical (>99.9
area %) and optical purity (>99.9% ee). The following describes the best solution and details the
rationale for the choices.
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The odor of isocyanides is repugnant. Benzyl isocyanide 9 is no exception and its foul smell is
also very persistent. Detailed handling suggestions are described in the experimental section; it is
expected that these will prove useful for other isocyanides as well. At this point it is appropriate
to discuss some misconceptions about benzyl isocyanide. Commercially available benzyl
isocyanide frequently appears to be partly decomposed, leading to the assumption that the
compound is unstable. While contaminated benzyl isocyanide is indeed unstable when heated
and can decompose rapidly to a black tar when a distillation is attempted, clean benzyl
isocyanide is quite stable. Indeed, an accelerated reaction calorimetry (ARC) test indicated no
decomposition after storage at 125 °C for 24 h.
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However, preparation and isolation of the pure isocyanide is often unnecessarily burdensome.
Among possible approaches, the dehydration of formamides is most attractive and POCl3 is the
most frequently used dehydrating agent.5 Indeed, a recent publication demonstrates how POCl3
can be used in combination with DIPEA in toluene to convert the formamide to the isocyanide in
flow.6 While this strategy might have been a viable solution, it was not pursued because of the
problems associated with POCl3 and the need to avoid the formation of precipitates in flow.
Especially the second reason would have induced a very low volumetric productivity, which is a
key driver for the economic viability of any process and is frequently ignored.
When the use of flow chemistry requires high dilutions and therefore high volumes of solvent,
the purported advantages of a reaction in flow are essentially obviated. In addition, the benzyl
formamide 12 is not readily commercially available and the frequentlyꢀused formylation
procedure via formation of the mixed anhydride between acetic anhydride and formic acid is not
attractive.7 The alternative is a simple condensation between benzylamine 11 and ethyl formate,
resulting in the quantitative formation of the highly crystalline Nꢀbenzyl formamide 12.8 Rather
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than isolating the compound, a simple solvent switch into toluene set the stage for the
dehydration, with the resulting formation of isocyanide after azeotropic distillation of toluene.
Rather than resorting to the alreadyꢀmentioned unattractive POCl3, it was decided to explore
alternative dehydrations of the formamide with the goal of finding a less cumbersome procedure.
Using Corey’s dehydration method9 of formamides with tosylchloride/pyridine resulted in a nonꢀ
stirrable mixture of precipitates at reasonable concentrations. Gratifyingly, the use of pyridine
and mesyl chloride10 in 4 volumes of toluene kept the mixture manageable at high concentrations
and resulted in the rapid and quantitative dehydration of the formamide with the formation of
crystalline pyridine salts (hydrochloride/methanesulfonate).
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1.4 equiv. HCO2Et
2 equiv. MsCl
6 h, 60 °C
then toluene
4.3 eq. pyridine
1 h, 40 °C, toluene
NH2
N
N+
O
C-
H
11
12
9
Scheme 3. Oneꢀpot procedure for benzyl isocyanide 9.
Addition of water to the reaction vessel dissolved the salts and the isocyanide is obtained in
essentially quantitative yield as solution in toluene. Thus the isocyanide could be prepared in an
operationally simple oneꢀpot procedure from benzylamine. The resulting isocyanide solution is
approx. 2.5 molar and can be either used directly or be concentrated by a simple stripping of
some toluene. This approach is very practical and it should be possible to extend it to isocyanides
other than benzyl isocyanide. The oneꢀpot preparation in a closed vessel minimizes
manipulations and possible exposure to the odiferous compound.
To the authors’ best knowledge, and in line with the mechanism of the Ugi reaction, there is no
totally satisfactory solution to using the Ugi reaction for the preparation of enantiomerically pure
compounds.11 Enantioselective catalysts are not known, thus necessitating the utilization of a
chiral primary amine as inducer. High diastereoselectivity, crystalline products and efficient and
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highꢀyielding removal of the chiral auxiliary are necessary prerequisites for a successful
implementation of an Ugi reaction.
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Having secured a viable access to the benzyl isocyanide, chiral amines12 could then be
assessed. As the Ugi reaction is a fourꢀcomponent reaction, the order of addition of the
components must be defined. The Ugi reaction between acetic acid (6), benzyl isocyanide 9,
propionaldehyde 13 and phenethylamine 7a (Scheme 4) was studied as a model reaction.
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-C
O
N+
O
N
O
N
H
+
+
+
O
NH2
OH
6
7a
13
9
14
Scheme 4. Components of a model Ugi reaction.
Despite the fact that four different components are combined in an Ugi reaction, the order of
addition has not received much attention in the literature. A common description is “mixed
together”, or in more detailed protocols the imine is preformed from aldehyde, amine and
carboxylic acid followed by the addition of the isocyanide last.13 This order appears logical from
the mechanism of the Ugi reaction and the sensitivity of isocyanides in acidic medium (hydration
of 9 to formamide 12); it should also avoid the competing direct addition of the isocyanide into
the aldehyde, known as the Passerini three component reaction.14 However, application of the
standard protocol to our model system resulted in a complex mixture with less than 10
area % of the desired product 14.
Apparently the enolizable aldehyde suffered degradation when the isocyanide is absent –
caused by aldol addition/condensation reactions – leading to diverse Ugi by-products.
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A search for alternative procedures revealed a description of the amine added as the last
component15 and application of this concept formed product 14 almost quantitatively.
Gratifyingly, the competing Passerini reaction is much slower, so that at most, traces of the
corresponding product can be detected.
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We found that the aldehyde can be added last, leading also to a clean conversion to
product 14. This order should be even preferred when scaling-up the reaction (vide infra)
due to a highly exothermic salt formation in addition to the reaction heat produced in the
Ugi reaction.
It is remarkable that by changing the order of addition a clean and rapid transformation
can be essentially completed in less than 30 min. It appears that this critical information is
not fully recognized by the community applying the Ugi reaction. As even traces of residual
isocyanide impart a strong smell to the reaction mixture, it is advisable to keep the
essentially completed reaction closed for an additional 10 h, when the amount of residual
isocyanide is below 0.1% and is no longer detectable by its odor.
A strong rationale for the choice of the Ugi route for the preparation of lacosamide is the
desire to use methoxyacetaldehyde 8, which avoids an alcohol methylation in the synthesis.
However methoxyacetaldehyde is an unstable, volatile (bp. 90 °C),16a highly water soluble,
colorless liquid which cannot be obtained on scale and a commercial sample turned out to be
entirely decomposed. Methoxyacetaldehyde 8 is described in the older literature, but without a
full experimental procedure, and its preparation was a struggle. Several conceivable approaches
were examined, but failed to lead to viable solutions (Scheme 5). As an example, the oxidative
cleavage of 1ꢀOꢀmethyl glycerol 8c with sodium periodate furnished 8 in 46% yield.16b
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O
OH
8d
6
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8
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OH
OH
Cl
O
O
O
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8c
8e
O
O
8
O
O
OH
OH
O
O
O
HO
HO
8a
8b
8f
Scheme 5. Synthetic approaches towards methoxyacetaldehyde 8.
Methoxyacetaldehyde dimethylacetal 8a would appear to be an attractive starting material as it
is commercially available on scale and would require only a simple acetal deprotection.
However, the use of various acidic catalysts in aqueous medium for the deprotection, as
described in the literature17 resulted in complex reaction mixtures and a low yield of the desired
product, presumably a result of acid catalyzed methyl ether cleavage17. Fortunately, the simple
heating of the acetal in water18 for 6ꢀ10 h leads to almost complete conversion obtaining the
aldehyde as an approx. 2 M solution in water. This aqueous solution is stable, presumably in the
form of its hydrate, for at least two years in the refrigerator. This route provided the first
convenient and easy access to this interesting aldehyde building block.
With a viable access to the aldehyde and the isocyanide at hand, a systematic screen of
commercially available chiral amines for reactivity and selectivity was performed. The resulting
diastereomers were not separable by simple flashꢀchromatography; the use of chiral stationary
phases was required in order to obtain preparative quantities of the respective diastereomers for
assessment of their crystalline properties. The need to prepare a high purity drug requires
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purification by crystallization and so a crystallization of the resulting diastereomers was
attempted. The results are summarized in Table 1.
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S
S
R1
R
R1
R
2O
S
2O
-C
N+
S
R
O
N
N
R1
R2
O
N
H
N
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+
H
+
+
+
O
O
NH2
OH
OMe
OMe
OMe
10a-k (SR)
10a-k (SS)
6
7a-k
8
9
R
R
R1
O
R
2O
R1
O
R
S
2O
-C
N+
R
O
R
N
N
R1
R2
O
N
H
N
+
H
+
+
+
NH2
OH
OMe
OMe
OMe
10a-k (RR)
10a-k (RS)
6
7a-k
8
9
Scheme 6. Possible diastereomers obtained from a chiral amine in the presented Ugi reaction.
In line with observations from the literature,11,12 the diastereoselectivity of the Ugi reaction is
poor: approx. 3:2 for most chiral amines (Table 1), with some amines being slightly better (entry
11) or slightly worse (entry 10). There is a clear temperature dependence of the
diastereoselectivity, improving to about 69:31 at ꢀ10 °C and eroding almost totally at 60 °C
(entry 7 and 13). Having separated the diastereomers on a preparative scale, it was consistent that
in the case of the amines 7 and 13 the minor (R,R) and (S,S) diastereomers were highly
crystalline.
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Table 1. Selectivity of Ugi reaction with various chiral amines. a: ꢀ10 °C, b: 60 °C.
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6
7
8
9
Entry
Amine 7
R1
Ph
R2
Me
Et
10SR:10SS 10RS:10RR
(S)ꢀ1ꢀPhenethylamine 7a
(S)ꢀ1ꢀPhenpropylamine 7b
(S)ꢀ1ꢀNaphtylethylamine 7c
(S)ꢀ2ꢀNaphtylethylamine 7d
(R)ꢀ2ꢀMethoxyphenethylꢀ
amine 7e
65:35
65:35
55:45
60:40
ꢀꢀ
ꢀꢀ
ꢀꢀ
1
2
3
4
5
10
11
12
13
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Ph
1ꢀNaphthyl
2ꢀNaphthyl
2ꢀMeOC6H4
Me
Me
Me
ꢀꢀ
ꢀꢀ
60:40
(S)ꢀ4ꢀMethoxyphenethylꢀ
amine 7f
4ꢀMeOC6H4
4ꢀMeOC6H4
4ꢀNO2C6H4
Me
Me
Me
65:35
69:31a
65:35
ꢀꢀ
ꢀꢀ
ꢀꢀ
6
7
8
(S)ꢀ4ꢀMethoxyphenethylꢀ
amine 7f
(S)ꢀ4ꢀNitrophenethylꢀ
amine 7g
(S)ꢀ1ꢀAminoindane 7h
(S)ꢀ1ꢀAminotetraline 7i
(S)ꢀ1ꢀPhenylꢀ2ꢀcyanoethylꢀ
amine 7j
1ꢀIndanyl
1ꢀTetralinyl
55:45
50:50
70:30
ꢀꢀ
ꢀꢀ
ꢀꢀ
9
10
11
Ph
CH2CN
(R)ꢀ4ꢀMethoxyphenethylꢀ
amine 7k
4ꢀMeOC6H4
4ꢀMeOC6H4
Me
ꢀꢀ
ꢀꢀ
65:35
12
13
(R)ꢀ4ꢀMethoxyphenethylꢀ
amine 7k
Me
55:45b
Given these data, it is clear that the choice of chiral amine directing group will be dictated by
commercial availability of the amine and by the ease of the final deprotection. Attempted
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hydrogenolytic deprotection of either 1ꢀ or 2ꢀnaphthylethylamine (10c,d-SR) could not be
accomplished despite screening several reaction conditions and Pd/C catalysts. In line with
expectations, the use of the commercially available phenethylamine (10a-SR) failed to be
amenable to hydrogenolytic deprotection.
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The application of the amine 7j in Ugi reactions (entry 11) should be explained. To the best of
our knowledge, amines with an electronꢀwithdrawing group in betaꢀposition have unique
properties, which was recognized by Ugi in a seminal publication in 1964, as a deprotection of
10j is possible under basic conditions by elimination.19 Only one reference to this highly
attractive chiral ammonia equivalent was found: Ugi examined the reaction, albeit with racemic
material only, and subsequently, this chiral ammonia equivalent does not appear to have found
any application in diastereoselective Ugi reactions. While the obtained diastereoselectivities are
in the expected 2:1 range, the facile and efficient subsequent deprotection under basic (THF,
KOtBu) conditions is a very useful addition to the repertoire of chiral directing groups. This is
even more valuable as the amine 7j is commercially available – at least on small scale – thus
significantly extending the scope of synthetic opportunities afforded by the Ugi condensation. It
should be noted that attempts to achieve similar results with derivatives of the cheaply available
aspartic acid failed to give satisfactory results in the Ugi condensation, so that the work then
focused on other available amines.
These results led to the choice of (S)ꢀ4ꢀmethoxyphenethylamine 7f, a chiral ammonia
equivalent that is commercially available in both enantiomeric forms on scale and that is
removed under mild acidic conditions (vide infra).20 According to entry 6 and 7 (Table 1), the
diastereoselectivity is approx. 65:35 and almost 70:30 under optimized conditions in favor of the
desired (S,R)ꢀdiastereomer. Consequently, the chemistry was developed using (S)ꢀ4ꢀ
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methoxyphenethylamine and the strategy on how to utilize the properties of the product to
circumvent the poor diastereoselectivity of the Ugi reaction will be described next (scheme 7).
7
8
O
O
9
S
S
O
-C
O
O
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N+
S
R
S
O
N
N
O
N
N
+
H
H
+
+
+
O
O
NH2
OH
OMe
OMe
OMe
10f (SR)
10f (SS)
6
7f
8
9
Scheme 7. Ugi reaction employing (S)ꢀ4ꢀmethoxyphenethylamine.
For the optimized Ugi condensation, an approx. 33% by weight solution of 4ꢀmethoxy
phenethylamine 7f (1.03 equiv) was neutralized in an exothermic reaction in EtOH with AcOH
(1.07 equiv). After cooling to about 5 °C, the suspension was added to a concentrated benzyl
isocyanide 9 solution in 1 volume of toluene (1.0 equiv) at 10 °C, followed by the final addition
of the methoxyacetaldehyde 8 solution (1.1 equiv) at ꢀ10 °C. By using this order of addition it is
possible to remove the heat of reaction resulting from the reaction of the carboxylic acid and the
amine, before adding the isocyanide and the aldehyde, thus making it possible to conveniently
perform the reaction at low temperature on scale. In order to assure the better stereocontrol and a
complete reaction of the isocyanide (minimization of the associated pungent odor), the reaction
was left first for 2 h at ꢀ10 °C, then for 2 h at 0 °C and was then reacted for about 18 h at ambient
temperature, even though the reaction is essentially complete after 1 h stirring at room
temperature.
The resulting reaction mixture contained 10f-(SR) and 10f-(SS) in a combined assay yield of
about 95% in a diastereomeric ratio of 69 to 31. Gratifyingly, the amount of isocyanide in the
reaction mixture – and thus the pungent smell – was reduced to a level that allows normal
manipulation of the reaction mixture. As mentioned above, the (S,S)ꢀdiastereomer is a highly
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crystalline compound that crystallizes directly from the reaction mixture after removal of solvent
and replacement by a defined EtOH/water mixture. After filtering off the (S,S)ꢀdiastereomer in
high purity, the diasteromeric ratio of the mother liquor was increased to 92:8. The mother liquor
was concentrated and the crude product was obtained after a standard aqueous workꢀup and a
solvent switch to isopropyl acetate (IPAC). It was possible to crystallize the desired (S,R)ꢀ
diastereomer from IPAC/MCH (methylcyclohexane) and 10f-(SR) was obtained in 34% yield
(based on isocyanide) with a satisfactory diastereomeric purity of >99.7%. After concentrating
the resulting mother liquor, a second crop of desired (S,R)ꢀdiastereomer contaminated with about
20% of the (S,S)ꢀdiastereomer was obtained. Combining several batches of the second crop and
repeating the sequence of removal of the undesired (S,S)ꢀdiastereomer followed by the
crystallization of the desired diastereomer from IPAC resulted in a 52 to 55% yield from
isocyanide 9 of 10f-(SR) diastereomer with excellent chemical and diastereromeric purity as a
white crystalline product.
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The high crystallinity of one of the diastereomers could enable a crystallizationꢀdriven
asymmetric transformation and thus a, in theory, quantitative yield of the desired diastereomer, if
the chiral center of the amino acid could be epimerized. While this would appear to be quite
easy, in reality all attempts to achieve an epimerization of this chiral center in 10 using a plethora
of reaction conditions failed. Forcing conditions led to decomposition, presumably by
elimination of methanol and the subsequent degradation of the resulting acrylate system. As this
decomposition mode is specific to this compound, substrates lacking the leaving group are likely
to function successfully in a crystallizationꢀdriven asymmetric transformation, thus expanding
the utility of the Ugi reaction.
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9
Having established an efficient access to the required diastereomer in crystalline form in a
gratifying 52ꢀ55% overall yield from isocyanide 9, the subsequent removal of the chiral directing
group remained the outstanding challenge. A screen of various acidic and hydrogenolytic
conditions quickly revealed that the use of formic acid resulted in a rapid and clean deprotection
at 80 °C, with the formation of a fairly nonpolar and undefined oligomer resulting from the
polymerization of the intermediate 4ꢀmethoxybenzyl cation. While the removal of this byꢀ
product was readily achieved by extractions with toluene or MCH, a betterꢀdefined product from
the deprotection was clearly preferable considering that the drug substance stage had been
reached. To this end, the deprotection was performed in the presence of anisole, which generated
cleanly and in quantitative yield the corresponding mixture of para and ortho bisꢀ4ꢀ
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methoxyphenyl ethane isomers 15 and 16 (Figure 2).21
OMe
MeO
OMe
OMe
15
16
Figure 2. Para and ortho bisꢀ4ꢀmethoxyphenyl ethane isomers.
These nonpolar side products could be readily removed by extraction using MCH. After
removal of the bulk of the formic acid by distillation, the remaining formic acid was neutralized
by the addition of an aqueous solution of trisodium citrate. Lacosamide 1 is extracted into
isopropyl acetate and crystallized from the same solvent resulting in 82% yield, >99.9% purity
and 99.9% ee.
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CONCLUSIONS
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8
In summary, an Ugi four component condensation approach was utilized to synthesize
lacosamide 1 in an overall yield of 40% starting from benzylamine 11. The resulting API met the
required quality specification. The synthesis is scalable; a less developed version of the Ugi
reaction described here has been used to prepare 50 kg of inꢀspecification lacosamide. The
preparation method of isocyanide 9 and the optimization of the Ugi condensation using an easilyꢀ
removable and inexpensive chiral auxiliary holds promise for applications beyond lacosamide.
9
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EXPERIMENTAL SECTION
Methoxyacetaldehyde 8. A mixture of 100 mL (93 g, 0.77 mol) methoxyacetaldehyde
dimethylacetal 8a and 280 ml (15.5 mol) of water was refluxed for 8 h under argon atmosphere.
The reaction was followed by GC and the response factor was 3:2 for an equimolar
acetal/aldehyde mixture (Agilent HPꢀ5MS, 30 m x 0.25 mm x 0.25 µm, 50 °C/3 min – 30 °C/min
to 290 °C – 290 °C/5 min, FID, Rt acetal 8a: 4.85 min, aldehyde 8: 2.86 min). At the end of the
reflux, about 5ꢀ10 area % of the acetal remained, but are inconsequential for the subsequent
reaction. The mixture was cooled to 20 °C and methoxyacetaldehyde 8 was used directly or
stored in a refrigerator or freezer. GC: Rt = 2.86 min.
For a further characterization, 10 mL of this solution were extracted with 3 x 10 mL
dichloromethane. The combined organic layers were dried with MgSO4 and carefully
concentrated (40 °C, 250 mbar) yielding about 1 g of crude methoxyacetaldehyde 8 with some
DCM and MeOH. 1HꢀNMR (CDCl3, 400 MHz): 3.47 (s, 3H, OCH3), 4.05 (s, 2H, CH2), 9.73 (s,
CHO).
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Benzyl isocyanide 9. Ethyl formate (192 g, 2.60 mol, 1.3 equiv) was heated to 50 °C and
benzylamine 11 (214 g, 2.00 mol, 1.0 equiv) was added over 30 min. After completion of the
addition, the mixture was refluxed for 10 h resulting in an almost complete consumption of the
benzylamine (<1 area %) The resulting solution of 12 (>98 area %) was solventꢀswitched into
toluene by twice distilling off 150 mL toluene (50 °C, 65 mbar). Additional toluene (270 mL)
and pyridine (160 g) were added at 50 °C to result in an about 40 wt % solution of 12 that could
be cooled to 17 °C without precipitating product. HPLC (Merck Chromolith Performance
RP18e, A. H2O/0.05% TFA, B: MeCN/0.05% TFA, 10ꢀ>70% B 10 min, 4 mL/min, 40 °C): Rt =
1.28 min.
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An additional 120 mL toluene and 77 g pyridine (4.3 equiv pyridine) were added to the
solution of 12 (97 g, 290 mmol, 1.0 equiv) before the subsequent addition of mesyl chloride
(70.7 g, 617 mmol, 2.1 equiv) over 10 min (temperature below 40 °C). After stirring for 1 h at
35ꢀ40 °C the mixture was cooled to 0ꢀ5 °C and water (200 mL) was added while maintaining the
temperature below 20 °C. After stirring for 1 h at 0 °C the phases were separated and the organic
layer was washed with 70 mL water (residues of isocyanide in the aqueous layer were
decomposed by 10% v/v conc. sulfuric acid, 30 min at rt). The content of isocyanide 9 in the
light brown organic layer was analyzed by GC (81% toluene, 17% isocyanide about 32 g, 0.27
mol 93ꢀ94% yield of isocyanide). The organic layer was distilled at 35 °C/60 mbar to a total
volume of about 60 mL yielding an approx. 50 vol % solution of 9 in toluene (the distilled
toluene fraction was treated with 0.3 volume iPrOH containing 30% of a 40% H2SO4 to destroy
the isocyanide odor). GC: (Agilent HPꢀ5MS, 30 m x 0.25 mm x 0.25 µm, 50 °C/3 min – 30
°C/min to 290 °C – 290 °C/5 min, FID) Rt = 8.80 min.
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(R)-2-{Acetyl-[(S)-1-(4-methoxy-phenyl)-ethyl]-amino}-N-benzyl-3-methoxy-
5
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8
propionamide 10f-(SR). To a solution of (S)ꢀ1ꢀ(4ꢀMethoxyꢀphenyl) ethylamine 7f (43.0 g, 284
mmol, 1.0 equiv) in EtOH (110 mL) and H2O (20 mL) was added AcOH 6 (17.4 g, 290 mmol,
1.02 equiv) over 30 min maintaining the temperature at 15 °C. The resulting suspension was
transferred to the 0 °C isocyanide/toluene (about 270 mmol, 0.95 equiv) solution with a 20 mL
EtOH rinse. While maintaining the temperature at ꢀ10 °C, the aqueous methoxyacetaldehyde 8
(162 mL, ~1.85 M, ~300 mmol, 1.06 equiv) solution was slowly added to the 3ꢀcomponent
mixture. After 2 h at ꢀ10 °C the mixture was stirred for 2 h at 0 °C and then for 18 h at 20 °C, at
which point the residual 9 was below 0.1 area %. The minor (S,S)ꢀdiastereomer was removed by
a solvent switch from toluene/EtOH/water to 250 mL of EtOH/water 3:2. After filtration and
wash of the filter cake with cold 100 mL of EtOH/water 1:1, 23 g of 10f-(SS) were obtained in
99.7% purity. The resulting mother liquors were enriched in the desired diastereomer 10f-(SR)
(90:10). After distillative removal of the EtOH and addition of 400 mL IPAC, the organic phase
was washed successively with 90 mL 1 M NaHSO4 and 50 mL water. The solution was
concentrated to about 300 mL and addition of about 85 mL of MCH precipitated the desired
diastereomer 10f-(SR) which was obtained after filtration and wash of the filter cake with cold
9
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40 mL of MCH/IPAC 1:1 (32 g, 84 mmol, 31% yield based on isocyanide, 99.8% purity)
.
The mother liquor (approx. 450 mL containing about 45 g of 10f-(SS) and 10f-(SR) with about
20:80 was concentrated to approx. 350 mL and addition of 100 mL of MCH precipitated a
second crop (27.4 g) with high purity as a mixture of diastereomers with a ratio of 17:83
(S,S):(S,R).
Several batches of second crops were combined to obtain further additional product: the
resulting 98.5 g were dissolved in 300 mL of IPAC at reflux. On cooling to 50 °C, the undesired
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(S,S)ꢀdiastereomer precipitated after seeding and was removed by filtration (14 g). Further
concentration of the mother liquor to 240 mL and seeding resulted in the precipitation of 34.6 g
of 10f-(SR) in comparable purity (>99.5 %). The cycle was repeated several times so that the
yield of the (S,R)ꢀdiastereomer was approx. 52ꢀ55% (based on isocyanide).
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Major diastereomer 10f-(S,R): Mp.: 82 °C (IPAC/MCH); chiral HPLC (Chiralpak ADꢀH/120
(250x4.6 mm), Heptane:EtOH:MeOH 2:1:1 +0.1% TFA, 30 °C, 1 mL/min): Rt = 5.96 min;
HPLC (Merck Chromolith Performance RP18e, A. H2O/0.05% TFA, B: MeCN/0.05% TFA, 10ꢀ
>70% B 10 min, 4 mL/min, 40 °C): Rt = 3.65 min; NMR (250 MHz, 390 K): 1.55 (d, 3H, CH3),
2.07 (s, 3H, Ac), 3.03 (s, 3H, OMe), 3.28 (dd, 1H, CH or CH2OMe), 3.79 (s, 3H, OMe), 3.92ꢀ
410 (m, 2H, CH or CH2ꢀOMe), 4.28 ꢀ4.46 (m, 2H, CH2Ph), 5.18 (q, 1H, ArCH), 6.88ꢀ6.96 (m,
2H, ArꢀH), 7.20ꢀ7.38 (m, 7H, ArꢀH), 7.71 (bs, 1H, NH); LCꢀMS: MH+ 385 (250, 135).
Minor diastereomer 10f-(S,S): Mp.: 128 °C (EtOH/water); chiral HPLC (vide supra): Rt = 5.73
min; HPLC (vide supra): Rt = 3.53 min; NMR (250 MHz, 390 K): 1.62 (d, 3H, CH3), 2.06 (s,
3H, Ac), 3.32 (s, 3H, OMe), 3.73 (dd, 1H, CH or CH2ꢀOMe), 3.94 (dd, 1H, CH or CH2OMe),
4.12ꢀ4.25 (m, 3H, CH, CH2Ph), 5.27 (q, 1H, CH), 7.07ꢀ7.44 (m, 10H, ArꢀH); LCꢀMS: MH+ 385.
(R)-Lacosamide 1. (S,R)ꢀdiasteromer 10f (50 g, 0.13 mol, 1.0 equiv) was dissolved in 50 mL
anisole and formic acid (95 mL, 16 equiv, 85% solution) was added. The mixture was heated one
hour at 82 °C. After cooling to 25 °C, water (100 mL) was added and the mixture was extracted
twice with 100 mL MCH. To remove the formic acid, the aqueous layer was first concentrated
under reduced pressure (60 mbar, 45 °C), before adding an additional 100 mL water and
repeating the concentration. After addition of IPAC (160 mL), the biꢀphasic mixture was heated
to 40 °C and the pH was adjusted to 4 using an aqueous trisodium citrate solution (400g/L). The
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phases were separated, the aqueous layer was extracted twice with 100 mL IPAC and the
combined organic layers were washed with 10 mL water. The organic phase was concentrated to
approx. 300 mL, at which point seeding resulted in crystallization of 1 (27 g, 0.11 mol, 83%,
>99.9% purity, >99.9% ee) as colorless crystals. Mp.: 146 °C (IPAC); chiral HPLC (Chiralpak
ADꢀH/91 (250x4.6 mm), EtOH, 30 °C, 1 mL/min): Rt = 13.7 min; HPLC (Merck Chromolith
Performance RP18e, A. H2O/0.05% TFA, B: MeCN/0.05% TFA, 10ꢀ>70% B 10 min, 4 mL/min,
40 °C): Rt = 1.15 min; NMR (500 MHz, 300 K): 1.87 (s, 3H, Ac), 3.25 (s, 3H, OMe), 3.49 (dd,
1H, CH2OMe), 3.53 (dd, 1H, CH2OMe), 4.29 (d, 2H, CH2Ph), 4.46ꢀ4.53 (m, 1H, CH), 72.20ꢀ
7.35 (m, 5H, ArꢀH), 8.09 (d, 1H, NH), 8.49 (t, 1H, NH); LCꢀMS: MH+ 251.
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ACKNOWLEDGMENT
We thank K. RahnꢀHotze und M. Schaffrath for the preparative separation of the diastereomers.
REFERENCES
(1) Ugi, I.; Meyr, U.; Fetzer, C.; Steinbrückner C. Angew. Chem. 1959, 71, 386.
(2) (a) Choi, D.; Stables, J. P. and Kohn, H. J. Med. Chem.1996, 39, 1907. (b) US 5773475,
1998 by Kohn, H.
(3) (a) Andurkar, S. V.; Stables, J. P. and Kohn, H. Tetrahedron Asymmetry 1998, 9, 3841. (b)
Choi, D.; Stables, J. P. and Kohn, H. J. Med. Chem. 1996, 39, 1907. (c) Riedner, J. EP
1,642,889, 2006. (d) Pandey, B.; Shah, K. WO2011,039,781, 2011. (e) Vrbanec, C.; Harca, M.;
Sucec, A.; Sahnic, D.; Avdagic, A. WO 2010,107,993, 2010. (f) Bouvy, D.; Merschaert, A.;
Pinilla, V.; Hamann, J.; Kanzler, R.; Thomas, A. WO 2010,052,011, 2010. (g) Madhra, M. K.;
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Page 20 of 22
1
2
3
4
5
6
7
8
9
Singh, P. K.; Khanduri, C. H. US 2009,143,472, 2009. Further synthesis of Lacosamide (h)
Morieux, P.; Stables, J.P. and Kohn, H. Bioorg. Med. Chem. 2008, 16, 8968. (i)
Muthukrishnan, M.; Mujahid, M.; Sasikumar, M. and Mujumdar, P. Tetrahedron: Asymmetry
2011, 22, 1353. (j) Wang, Z.ꢀY. ; Xu, L. ; Liu, J., Zhang, H., Gao, J.; Liu, Q.; and Jiao, Q.
Chem. Res. Chin. Univ. 2012, 28, 833. (k) Wadavro, S. B.; Narikimalli, A., Narseiah, A. V.
Synthesis 2013, 45, 3383. (l) Stecko, S. J. Org. Chem. 2014, 79, 6342. (m) Garg, Y. and
Pandey, S. K. J. Org. Chem. 2015, 80, 4201.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(4) Wehlan, H.; Rossen, K.; Oehme, J.; Kral, W. WO2013,072330, 2013.
(5) Obrecht, R; Herrmann, R.; Ugi, I. Synthesis 1985, 400.
(6) Sharma, S.; Maurya, R. A.; Min, K.; Jeong, G.ꢀY.; Kim, D.ꢀP. Angew. Chem. Int. Ed. 2013,
52, 7564.
(7) (a) Krishnamurthy, S. Tetrahedron Lett. 1982, 23, 3315; (b) Huffman, C. W. J. Org. Chem.
1958, 23, 727.
(8) Guilford, W. J.; Dallas, J.; Arnaiz, D. J. Label Compds. Radiopharm. 2001, 44, 247.
(9) Hertler, W. R.; Corey, E. J. J. Org. Chem. 1958, 23, 1221.
(10) Swindell, C. S.; deSolms, S. J. Tetrahedron Lett. 1984, 25, 3801.
(11) (a) Doemling, A.; Ugi, I. Angew. Chem. Int. Ed. 2000, 39, 3168. (b) De Graaff, C.;
Ruijter, E. and Orru, R. V. Chem. Soc. Rev. 2012, 41, 3969. (c) Zaretsky, S.; Adachi, S.;
Rotstein, B.H.; Hickey, J.L.; Scully, C.C.G.; St Denis, J. D.; Courtemanche, R.; Yu, J.C.Y.;
Chung, B.K.W. and Yudin, A.K. J. Org. Chem. 2014, 79, 9948. (d) Yue, T.; Wang, M.ꢀX.;
Wang, D.ꢀX.; Masson, G. and Zhu, J. Angew. Chem. Int. Ed. 2009, 48, 6717. (e) Nenajdenko,
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Organic Process Research & Development
1
2
3
4
5
6
7
8
9
V. G.; Gulevich, A. V.; Chernichenko, K.Y.; Sokolova, N.V. and Balenkova, E. S. Mendeleev
Commun. 2011, 21, 245. (f) Linderman, R.J.; Binet, S. and Petrich, S. R. J. Org. Chem. 1999,
64, 336.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(12) Ramón, D. J.; Yus, M. Angew. Chem. Int. Ed. 2005, 44, 1602 (and references cited
therein).
(13) Marcaccini, S; Torroba, T. Nature Protocols 2007, 2, 632.
(14) Passerini, M. Gazz. Chim. Ital. 1921, 51, 126.
(15) Rikimaru, K.; Yanagisiwa, A.; Kan, T. Fukuyama Synlett 2004, 41.
(16) (a) Nathan L. Drake, N. L.; Duvall, H. M.; Jacobs , T. L.; Thompson, H. T.; Sonnichsen,
H. M. J. Am. Chem. Soc. 1938, 60, 73. (b) Hatch, F. L.; Nesbitt, S. S. J. Am. Chem. Soc. 1945,
67, 39.
(17) Fedoronko, M.; Temkovic, P.; Koenigstein, J.; Kovacik, V.; Tvaroska, I. Carbohydr. Res.
1980, 87, 35.
(18) Non scalable microwave assisted cleavage of acetals described by Procopio, A.; Gaspari,
M.; Nardi, M.; Oliverio, M.; Tagarelli, A.; Sindona, G. Tetrahedron Lett. 2007, 48, 8623.
(19) Ugi, I; Offermann, K. Chem. Ber. 1964, 97, 2996.
(20) (a) Chen, C.ꢀH.; Genapathy, S.; Fischer, P. M. and Chan, W. C. Org. Biomol. Chem. 2014,
12, 9764. (b) Wang, W.; Joyner, S.; Khoury, K.A.S. and Doemling, A. Org. Biomol. Chem.
2010, 8, 529. (c) Kazmeier, U.; Hebach, C.; Watzke, A.; Maier, S.; Mues, H. and Huch, V.
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Org. Biomol. Chem. 2005, 3, 136. (d) Klossowski, S.; Brodzka, A.; Zysk, M. and Ostaszewski,
R. Tetrahedron: Asymmetry 2014, 25, 435.
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(21) Reeves, J.T.; Fandrick, D. R.; Tan, Z.; Song, J. J.; Rodriguez, S.; Qu, B.; Kim, S.;
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Niemeier, O.; Li, Z.; Byrne, D. J. Org. Chem. 2013, 78, 3616.
Table of Contents Graphic
-C
O
N+
H
Ugi
O
N
O
N
H
OMe
R*
+
+
+
O
NH2
OH
OMe
LACOSAMIDE
ACS Paragon Plus Environment
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