Improved Synthesis and Impurity Identification of (R)-Lacosamide

Article abstract of DOI:10.1021/acs.oprd.8b00370

An improved synthesis of Lacosamide 1 with high purity has been developed. Critical parameters of each step were identified as well as the impurities generated. Moreover, a creative method to improve chiral purity and stability of the key intermediate (R)-2-amino-N-benzyl-3-methoxypropionamide 10 by forming salt with an achiral acid (phosphoric acid) was discovered to ensure the chiral purity of (R)-Lacosamide. Phosphoric acid was further developed for the deprotection of the Boc group.

Full text of DOI:10.1021/acs.oprd.8b00370

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Full Paper
Improved Synthesis and Impurity Identification of (R)-Lacosamide
Anjiang Yang, Feifei Hu, Zhong Li, Mengdi Chen, Jianguang Cai,
Linghui Wang, Tao Zhang, Chuanmeng Zhao, and Fu-Li Zhang
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.8b00370 • Publication Date (Web): 08 Mar 2019
Downloaded from http://pubs.acs.org on March 8, 2019
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Improved Synthesis and Impurity Identification
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of (R)-Lacosamide
Anjiang Yang1, Feifei Hu1, Zhong Li1, Mengdi Chen1,2, Jianguang Cai3, Linghui Wang3,
Tao Zhang1, Chuanmeng Zhao1* and Fuli Zhang1*
1 Shanghai Institute of Pharmaceutical Industry, China State Institute of Pharmaceutical
Industry, 285 Gebaini Road, Pudong District, Shanghai 201203, People’s Republic of
China
2
School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103
Wenhua Road, Shenhe District, Shenyang, Liaoning, 110016, People’s Republic of China
3
Department of Organic Process Research and Development, Zhejiang Hisun
Pharmaceutical Company Limited, 46 Waisha Road, Jiaojiang District, Taizhou, Zhejiang
318000, People’s Republic of China
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An improved synthesis of Lacosamide 1 with high purity has been developed. Critical
parameters of each step were identified as well as the impurities generated. Moreover, a
creative method to improve chiral purity and stability of the key intermediate (R)-2-amino-
N-benzyl-3-methoxypropionamide 10 by forming salt with an achiral acid (phosphoric acid)
was discovered to ensure the chiral purity of (R)-Lacosamide. Phosphoric acid was further
developed for the deprotection of the Boc group.
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KEYWORDS
Lacosamide; improved synthesis; chiral purity; phosphoric acid; impurity
1. INTRODUCTION
(R)-Lacosamide
1
is chemically known as (R)-2-acetamido-N-benzyl-3-
methoxypropionamide and the drug substance of Vimpat, which was first launched by
UCB Pharma in the United States, Europe and Japan for adjunctive therapy in the treatment
of partial-onset seizures in patients with epilepsy1.
Several methods were reported to synthesize (R)-Lacosamide 1 in the past decades, and
the first-generation route was reported by Choi and colleagues2 using D-serine as a starting
material (Scheme 1). The advantage of this route was that the chiral center of (R)-
Lacosamide 1 was directly introduced by D-serine. Moreover, it would be more efficient
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and advantageous if there was no need to protect the amino group on D-serine. However,
the fact was that the amino group of 3 could react with the ester group of itself, which
would lead to a low yield (27%) for the first 2 steps. The second disadvantage of this route
was the need of excessive silver oxide (Ag2O, 5 equiv.), which was expensive and
unaffordable for large-scale or industrial manufacture. The third disadvantage was
racemization (approximately 33%), which was the biggest challenge to meet with for the
synthesis of Lacosamide 1 with high chiral purity. In order to obtain optically pure 5,
repeated recrystallization was needed, which led to a low yield of the third step (29%) as
well as the overall yield (6.9%).
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Scheme 1. First-Generation Synthetic Route of (R)-Lacosamide 1
OH
OH
OH
OH
HCl
BnNH2
H
O
N
H2N
H2N
H2N
MeOH, reflux
18 h
reflux, 18 h
27% over 2 steps
O
2
D-Serine
O
3
O
4
OH
O
O
MeI (10 equiv.), Ag2O(5 equiv.)
MeCN, rt, 4 d
Ac2O
H
O
H
N
N
N
H
N
CH2Cl2, rt, 1 h
27%
Recrystallized twice
O
5
H
O
1
Lacosamide
The second-generation synthetic route was also reported by Choi and colleagues2
(Scheme 2), where acetyl group was installed first, followed by amidation and
methylation. The advantage of this route was no racemization, while the yield over the
first two steps was only 37% and it required column chromatography. The reason was
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that the alcoholic hydroxyl group of 6 could be acetylated in the first step or react with
isobutyl chloroformate (IBCF) in the second step respectively. Another disadvantage of
this route was still the need of excessive silver oxide (5 equiv.). We have tried to use
other conditions for the methylation. However, if extreme strong bases were used for the
methylation, only almost totally racemized Lacosamide was obtained. The reason was
that the hydrogen at C(2) position of 5 (marked in blue in Scheme 2) was easily
deprotonated by strong bases, which promoted the racemization. In addition, if the base
was too strong, N-acetyl group (N-Ac) of 5 could easily be methylated, which would lead
to large amount of N-Ac methylated byproducts. As the properties of the byproducts were
quite similar to Lacosamide 1, column chromatography was needed for the purification of
Lacosamide 1, which limited the prospect for commercial manufacture. In contrast, if the
base was too weak , the alcoholic hydroxyl group of 5 could not be deprotonated, which
would lead to the failure of methylation. In summary, deprotonation of C(2)-H and
alcoholic hydroxyl group of 5 should be balanced.
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Scheme 2. Second-Generation Synthetic Route of (R)-Lacosamide 1
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H
O
OH
OH
1) IBCF, NMM, THF, -78oC
Ac2O
O
H2N
H
OH
AcOH, rt, 24 h
2) BnNH2, -78oC~rt,
37% over 2 steps
N
H
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O
2
O
6
D-Serine
OH
O
O
MeI (2 equiv.), Ag2O (5 equiv.)
H
O
H
2
H
N
N
N
N
MeCN, rt, 4 d
80%
H
H
O
O
5
1
Lacosamide
Another route3 similar to the second-generation route, which installed N-Ac first but
changed the order of amidation and methylation, was also reported. However, after N-Ac
being installed, the next step methylation was problematic. The reason was that there were
three positions of N-Ac product 6 (marked in red in Scheme 2) could be methylated by
dimethyl sulfate in combination with lithium hydroxide as reported. It turned out to be a
complex mixture of desired O-methylated product, two mono-methylated byproducts and
some di-methylated byproducts, which made it difficult to isolate the desired O-methylated
product by simple crystallization and limited the prospect for commercial manufacture.
To avoid the intrinsic defect of the first-generation and second-generation synthetic
routes, the third-generation synthetic route4 (Scheme 3) was developed and reported by
UCB Pharma through protecting the amino group of D-serine with the t-butyloxycarbonyl
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group (Boc group) before methylation, amidation and acetylation. The biggest advantage
of this route was that racemization could be greatly reduced using tetrabutylammonium
bromide (TBAB) as a phase transfer catalyst in combination with medium-intensity base
sodium hydroxide and dimethyl sulfate, which avoided the use of silver oxide. In addition,
no obvious racemization occurred in the next three steps. The second advantage was that
methylation on N-H of Boc-D-serine was greatly inhibited due to the steric hindrance of
the Boc group compared with the Ac group of the second-generation route. The third
advantage was high yield (69.8%) under mild reaction conditions with relatively simple
work-up procedures. The first disadvantage of this route was its lack of robustness; the
chiral purity of the product 8 showed a large batch to batch variation as we observed 4-8%
of the wrong enantiomer.. The second disadvantage was that there was no purification for
the intermediates and only the final product Lacosamide 1 was purified, which would make
the quality control difficult.
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Scheme 3. Third-Generation Synthetic Route of (R)-Lacosamide 1
OH
1) IBCF, NMM, CH2Cl2, -10~5 oC, 0.5 h
2) BnNH2, -5 oC~rt, 1 h
O
O
Me2SO4, NaOH aq., TBAB
H
OH
OH
N
BocHN
BocHN
BocHN
Toluene, <10oC, 1 h
100%
O
7
O
8
O
9
Boc-D-Serine
O
O
36% HCl aq.
Ac2O
O
H
H
N
N
H2N
N
CH2Cl2, 1 h
CH2Cl2, 5~15 oC, 0.5 h
69.8% over 3 steps
H
O
O
1
10
Lacosamide
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Other protecting groups were also reported, such as such as the carbobenzoxy group5
(Cbz group) and the trityl group6 (Tr group). While the yield of the route using the Cbz
group (33.9%) or the Tr group (14.0%) was obviously lower. Moreover, the atom economy
was the best in the route using the Boc group.
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Some routes7-8 similar to the third-generation route were reported as well, which just
changed the order of methylation, amidation and acetylation. However, as we mentioned
above, if the order was changed, the impurities would greatly increase, which would
sacrifice the yield or purity significantly.
Other routes were also reported9-16 such as introduction of chiral center by resolution
or asymmetric synthesis, and some of them are novel and quite creative. However,
considering the productivity and cost for scale-up, the third-generation route was
advantageous. Therefore, it was determined that the third-generation route was more
suitable for further investigation of scale-up, especially for commercial manufacture.
Herein, we report an improved synthetic process for (R)-Lacosamide 1, which solved
the slight partial racemization of the third-generation route. Moreover, the impurities
generated in a process play an important role in researching the quality of a drug substance
and evaluating a synthetic route, as well as helping researchers choose the best synthetic
route and conditions. Therefore, we wish to report the impurities generated within this
process, which have not yet been reported to our knowledge.
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2. RESULTS AND DISCUSSION
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The UCB Pharma’s synthetic route involves the following four steps: methylation of
Boc-D-serine 7, condensation of 8 with benzylamine (BnNH2), deprotection of 9, and
acetylation of 10 (Scheme 3).
2.1 The synthesis of 8
During the route selection period it was found that the chemical purity of 8 was 91.7%
when a magnetic stirrer was employed. The major impurities (Table 1) were D-serine 11
(2.3%) and unreacted starting material, Boc-D-serine 7 (2.8%). D-serine 11 was introduced
by the starting material, because the commercial Boc-D-serine 11 contained appoximately
5% D-serine 11. Impurity 12 (0.23%) (Table 1) was also detected as a minor impurity,
which was formed because N-H of Boc-D-serine 7 was also methylated. The major
problem with this reaction was an unstable chiral purity of 8, where the highest was 99.0%
and the lowest was 88.2% for the first 3 batches. It was found that the reason for poor chiral
purity might have been the discontinuous stirring, which led to a somewhat high
concentration of base (high pH) and sequentially racemization. The discontinuous stirring
resulted from the reaction mixture being viscous and hard to stir well using a magnetic
stirrer. To ensure good stirring, we switched to a mechanical stirrer, and it was found that
stirring speed was critical for this reaction. The reaction could not go completely at the
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initial speed of 200 revolutions per min (RPM) until it was adjusted to 450 RPM.
Meanwhile, both chemical and chiral purity were more stable at a speed of 450 RPM. The
influence of temperature was further investigated. If the temperature was lower than -5°C,
the reaction mixture started to freeze and could not be stirred well even by a mechanical
stirrer. In contrast, if the temperature was higher than 10°C, both chemical and chiral purity
decreased. In summary, stirring speed and temperature played important roles in the quality
of 8. Both chemical and chiral purity were improved through controlling both the
temperature and stirring speed.
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2.2 The synthesis of 9
A major impurity (Table 1) could attain up to 8.3% in one of the first three batches,
which could not be removed during workup. After isolation and characterization, it was
confirmed as 15 .
It might be formed because the mixture of 8 and chloroformate (ClCO2iBu or IBCF)
only reacted when N-methylmorpholine (NMM) was added to form the carboxylate salt.
When the base was added too fast, the exothermic neutralization heated up the mixture and
caused the side reaction. Moreover, some 15 reacted with benzylamine and further
produced a small amount of 16 (0.3%). To reduce 15 and 16, the addition time of N-
methylmorpholine was prolonged and the addition rate was also slowed down, especially
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during the addition of the first 1/3 part of N-methylmorpholine. As a result, the amount of
6
7
15 dropped to less than 2.1%.
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The other impurities (Table 1) were 14 (1.1%), 17 (0.83%) and 18 (0.27%). 14 was
introduced because the unreacted Boc-D-serine of the previous step reacted with isobutyl
chloroformate and benzylamine. 17 was formed due to the reaction of isobutyl
chloroformate and benzylamine. 18 was formed because of the reaction of 12, isobutyl
chloroformate and benzylamine as the formation of 9.
2.3 The synthesis of 10 and 10-phosphate (Scheme 4)
The major impurities (Table 1) were 15 (0.47%), 16 (0.27%), 20(1.1%) and 21
(0.24%). 15 and 16 were formed in the previous step. 14, which was formed in the second
step, was deprotected in this step and formed 20 (1.1%). 21 (0.24%) was formed due to the
reaction of 18 and hydrochloric acid.
As the intermediates of the entire process (8, 9 and 10) were oils, and the chiral
purities of them were approximately 95% after optimization, which would produce
Lacosamide 1 with low chiral purity according to the existing procedures. Moreover, it was
found that the chiral purity of 10 could decrease from 95.66% (blue trace in Figure 1) to
nearly 50% (black trace in Figure 1) in 12 months, which meant the chiral purity of 10 free
base was not stable enough. As 10-hydrochloride did not precipitate during the whole step
of deprotection, we failed to obtain 10-hydrochloride according to the existing procedure.
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In order to eliminate the influence of water, we also tried to get 10-hydrochloride by
forming a salt with the obtained free base of 10 using hydrochloric acid – ethyl acetate
solution instead of aqueous hydrochloric acid solution. However, 10-hydrochloride could
not be precipitated in different solvents such as ethyl acetate, isopropanol, tetrahydrofuran,
acetone and dichloromethane. Therefore, to improve chiral purity and stability of 10,
several other acids (L-tartaric acid, fumaric acid, malic acid, succinic acid, sulfuric acid,
phosphoric acid, acetic acid etc.) were screened to form a salt with 10, which had a
relatively lower chiral purity (93.51%). To our surprise, phosphoric acid turned out to be
the best, with both improved chemical and chiral purity17. Additionally, the chiral stability
was also improved significantly, and there was almost no change of chiral purity in 12
months for 10-phosphate. Phosphoric acid was also further employed to deprotect 9 for
the synthesis of 10 and 10-phosphate in one pot. After screening several solvents like ethyl
acetate, isopropanol, tetrahydrofuran, acetone, acetonitrile, isopropyl ether and
dichloromethane, 10-phosphate could be precipitated successfully in acetone.
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Figure 1. Chiral stability of intermediate 10: HPLC chromatograms for the
comparison of chiral purity. Original 10 (blue), 6 months later (red), 12 months later (black).
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2.4 The synthesis of Lacosamide 1 (Scheme 4).
Scheme 4. Synthesis of Lacosamide: comparison between the existing procedures and
our improved method.
OH
O
H
Method 1
Existing Procedures
OCH3
OCH3
N
OCH3
O
N
H
H3C
O
Ac2O
H
H
H
N
N
O
O
N
10
H2N
H3C
N
H3C
N
CH3
CH2Cl2
l
C
H
H
O
O
O
%
6
CH3
3
12
l2
2C
Lacosamide
Chiral purity: 95.13%
10
H
C
O
O
Chiral purity: 93.51%
OCH3
O
H
N
H
Chemical purity: 99.30%
Chemical purity: 98.06%
N
H3C
N
BocHN
H
Impurities generated using Method 1
11
O
9
Chiral purity: 93.39%
Chemical purity: 98.06%
8
5
%
H
3P
e
O4
A
c
OCH3
e
t
o
n
OCH3
H
O
H
Ac2O, Na2CO3
CH2Cl2, H2O
N
H2N
Method2
Our Improved Method
N
H3C
N
1. No Chemical Impurity Detected!!!
2. Chiral purity>99.9%
H3PO4
O
H
O
Lacosamide
10-phosphate
Chiral purity: 98.76%
Chemical purity: 100%
Chiral purity: 99.91%
Chemical purity: 100%
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As for the synthesis of Lacosamide (Scheme 4), two different sources of 10 were
adopted and compared. The first one was free base of 10. Three major impurities (Table
2) detected were 23 (0.31%), 24 (0.23%) and 25 (0.19%). Additionally, if the chiral
purity of 10 free base was lower than 95%, then the chiral purity of Lacosamide 1
synthesized from the free base would be lower than 96%. Lacosamide 1 derived from the
second source of 10 as 10-phosphate, was found to be both chemically (100 % HPLC)
and chirally pure (>99.9 %), making the later as much superior choice of substrate 10.
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Table 1. The impurity profiles for (R)-Lacosamide 1
Step
0
1
2
3
4
OH
OH
OCH3
NHBn
OCH3
OH
O
OCH3
NHBn
OCH3
BocHN
NHBn
AcHN
BocHN
BocHN
SM& IM
H2N
O
O
1
O
7
O
8
9
10
Boc-D-Serine
OH
OH
OH
OH
H2N
H2N
O
11
O
11
D-Serine
D-Serine
OH
O
H
N
OH
H3C
N
H
O
23
OH
NHBn
OH
OH
BocHN
NHBn
14
H2N
BocHN
O
OAc
O
7
20
H
O
N
Boc-D-Serine
AcHN
O
24
OCH3
NHBn
O
OCH3
O
O
H3C
O
CH3
H3C
NHBn
N
O
N
H
H
CH3
O
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OCH3
OCH3
NHBn
O
O
NHBn
BnHN
N
BnHN
N
H
H
O
O
16
16
6
7
8
O
CH3
CH3
BnHN
O
17
9
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OCH3
OH
OCH3
NHBn
OCH3
NHBn
OCH3
NHBn
O
Boc
Boc
N
CH3
N
CH3
HN
CH3
H3C
N
CH3
O
O
O
O
25
18
12
21
OCH3
NHBn
OCH3
OCH3
OCH3
OH
O
O
H
H
N
N
BocHN
H3C
N
H
BocHN
13
H2N
O
19
O
O
22
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3. CONCLUSIONS
Anew strategy to ensure chiral purity of Lacosamide was discovered through
controlling chiral purity of the intermediates 8 and 10. For intermediate 8, parameters were
optimized to ensure a more stable and better chemical purity(>90%) as well as chiral purity
(>95%). For intermediate 10, a new method to improve its chiral purity and stability
through forming a salt with achiral phosphoric acid was developed. Phosphoric acid was
further developed for the deprotecting of 9 as well, which made the deprotecion and salt
forming in one pot. Moreover, the impurity profiles of both existing method and our
improved route were elucidated and compared, which showed our improved route to be
advantageous.
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4. EXPERIMENTAL SECTION
6
7
8
General Methods. All of the reagents and solvents were obtained from commercial
9
suppliers and used without further purification. H NMR and 13C NMR spectra were
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1
recorded by a Bruker 400 or 600 MHz spectrometer. Chemical shift data are reported inδ
(ppm) from the internal standard TMS. High resolution mass spectrum were recorded on a
Bruker maXis 4G Q-TOF instrument. Melting points were measured on a WRS-1B
apparatus. Purities of In-Progress-Control samples, the isolated intermediates and the final
product were analyzed by high-performance liquid chromatography (HPLC, normalized
area percentage). The HPLC analyses were recorded by a standard method on a Dionex
UItiMate 3000 HPLC instrument. The chemical purity was analyzed by using an Angilent
Eclipse XDB-C18 (5 μm,46 mm×250 mm), 30°C, 1 mL/min, 210 nm, 45 min. Mobile
phase: A (20mM 1-octane sulfonic acid sodium salt, pH 2.1), B (acetonitrile). The mobile
phase gradient is shown in Table 2. The chiral purity was analyzed by a Chiral Pak AD-
H,(5 μm,46 mm×250 mm), 30°C, 1 mL/min, 210 nm, 25 min. Mobile phase: A (0.05%
diethylamine in n-hexane), B (isopropyl alcohol). The gradient started with 15% of B; the
ratio was maintained for 25 min.
Table 2: The HPLC mobile phase gradient for chemical purity
Time(min)
Mobile phase B(%,V/V)
0
4
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Preparation of (R)-2-N-Boc-amino-3-methoxypropanoic acid (intermediate 8). A
suspension of N-Boc-D-serine (100.0 g, 0.48 mol, 1.0 equiv.) and tetrabutylammonium
bromide (TBAB, 5.2 g, 0.0195 mol, 0.04 equiv.) in toluene (500 ml) was cooled to 0~10°C.
Then, 20% wt NaOH aq. (97.5 g, 0.48 mol, 1.0 equiv.) was added at 0~10°C, and the
resultant mixture was aged for 30 minutes at 0~10°C. Dimethyl sulfate (246 g, 1.95 mol,
4.0 equiv.) and 50% wt NaOH aq. (179.5 g, 2.245 mol, 4.6 equiv.) were added at -5~5°C
and the mixture was aged for 20 hours at -5~5°C. Water (300 ml) was added to the mixture.
Then, the aqueous layer was separated and acidified to pH <3.5 with 50% citric acid and
extracted with dichloromethane (2×500 ml，1×300 ml). The combined extracts of 8 were
evaporated to dryness to give crude 8. (107.1g, crude yield 100%).
Preparation
of
(R)-N-benzyl-2-N-Boc-amino-3-methoxypropionamide
(intermediate 9). Intermediate 8 was dissolved in dichloromethane(800mL) and cooled to
-10~0oC. Then, isobutyl chloroformateu (66.6 g, 0.49 mol, 1.0 equiv.) was added at -10~-
5°C. The first 1/3 part of N-methylmorpholine (26.3 g, 0.26 mol, 0.53 equiv.) was added
very slowly at -10~-5°C (1~2 h), and the rest 2/3 of N-methylmorpholine (52.6 g, 0.52 mol,
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1.07 equiv.) was further added in 1 h. After addition of N-methylmorpholine, the mixture
was aged for 30 minutes at -10~-5°C. A solution of benzylamine (53.8 g, 0.50 mol, 1.03
equiv.) in dichloromethane (200 mL) was added at -10~-5°C and the mixture was warmed
to 10~15°C. After being aged for 2 hours, the mixture was washed with water (200 ml),
1N HCl (200 ml), 8% sodium bicarbonate aqueous (8% NaHCO3 aq., 200 ml) and water
(200 ml). The organic phase was evaporated to dryness to give crude 9., (150.3g, crude
yield 100%, chemical purity 94.72%, chiral purity 95.33%).
10
11
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Preparation of (R)-2-amino-N-benzyl-3-methoxypropionamide phosphate
(intermediate 10-phosphate). Phosphoric acid (85% wt, 280.9 g, 5.0 equiv.) was added
dropwise to a solution of 9 (150.3 , 0.48 mol, 1.0 equiv.) in acetone (1000 mL) at 0~10°C..
The mixture was warmed to 40°C before being stirred for 6 hours and then cooled to 0~5°C
by gradient cooling. The mixture was stirred at 0~5°C for additional 2 hours forming a
suspension.The solid was collected by filtration, then washed with acetone (100 mL), and
dried at 45°C under vacuum to give 10-phosphate as a white solid (133.7g, 89.0% yield,
chemical purity 100.0%, chiral purity 99.37%). Anal. Calc’d for C11H22N2O6P: C, 43.14;
H, 6.25; N, 9.15. Found: C, 43.08; H, 6.23; N, 9.36; Mp: 178.1~179.0 °C; 1H NMR (600
MHz, D2O) δ 7.34 (ddd, J = 17.1, 11.6, 7.3 Hz, 5H), 4.42 (dd, J = 69.3, 15.2 Hz, 2H), 4.24
13
(t, J = 4.7 Hz, 1H), 3.82 (d, J = 4.8 Hz, 2H), 3.36 (s, 3H); C NMR (600 MHz, D2O) δ
167.29, 137.42, 128.79 (2×C), 127.59, 127.20 (2×C), 69.95, 58.78, 52.83, 43.16.
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Preparation of (R)-2-acetamido-N-benzyl-3-methoxypropionamide (Lacosamide).
Na2CO3 (41.5 g, 0.392 mol, 1.0 equiv.) was added to a mixture of 10-phosphate (120.0 g,
0.392 mol, 1.0 equiv.), water (600 mL) and dichloromethane(1200 mL). Then, the reaction
mixture was stirred for 30 min. The organic phase was collected and cooled to 0~5°C.
Ac2O (40.0 g, 0.392 mol, 1.0 equiv.) was added slowly to the organic phase at 0~5°C.
Then, the mixture was stirred at 10~20°C for 2 hours. Water (600 mL) was added to the
mixture and the organic phase was separated, which was then washed with 8% NaHCO3
aaq. (240 mL) and water (240 mL) respectively. After organic phase being evaporated to
dryness to obtain a crude product, ethyl acetate (600 mL) was added. The mixture was
heated to reflux until it was dissolved, and then cooled to approximately 0°C by gradient
cooling. Stirring was continued at 0°C for additional two hours forming a suspension. The
precipitate was filtered and the obtained cake was dried at 40°C under vaccum (75.3 g, 76.8%
yield, chemical purity 100.0%, chiral purity 99.94%). Anal. Calc’d for C13H18O3N2: C,
62.38; H, 7.25; N, 11.19. Found: C, 62.33; H, 7.22; N, 11.41; Mp 143.7−144.2°C (lit.2 143
10
11
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- 144°C); [ α]25D = +16.4° (c 1, MeOH) {lit.2 16.4° (c 1, MeOH)}; H NMR (600 MHz,
DMSO) δ 8.48 (t, J = 6.0 Hz, 1H), 8.09 (d, J = 8.0 Hz, 1H), 7.35 – 7.17 (m, 5H), 4.48 (dt,
J = 8.0, 5.9 Hz, 1H), 4.28 (d, J = 6.0 Hz, 2H), 3.50 (ddd, J = 15.0, 9.7, 5.8 Hz, 2H), 3.25 (s,
3H), 1.87 (s, 3H); 13C NMR (151 MHz, DMSO) δ 170.22, 169.88, 139.76, 128.66(2×C),
127.42(2×C), 127.13, 72.58, 58.65, 53.11, 42.45, 23.03. HRMS(ESI) m/z calc’d for
C13H18O3N2: 250.1317, found 251.1388([M+H]+); 273.1212([M+Na]+).
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ASSOCIATED CONTENT
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Supporting Information
1H NMR, 13C NMR, ESI-MS, HR-MS, DSC, XRPD and elemental analysis information
for intermediate 10-phosphate and (R)-Lacosamide; 1H NMR, 13C NMR and HR-MS
information for impurities.
AUTHOR INFORMATION
Corresponding Author
*E-mail: zhangfuli1@sinopharm.com (Fuli Zhang) and hotcmeng@163.com
(Chuanmeng Zhao)
ORCID
Anjiang Yang: 0000-0002-6421-4943
Fuli Zhang: 0000-0002-4175-4795
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
We thank the Engineering Research Center for Improvement & Industrialization of
Pharmaceutical Processes for financial support.
References
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