Improved Synthesis and Impurity Identification of (R)-Lacosamide

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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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Organic Process Research & Development

Improved Synthesis and Impurity Identification 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

1 ACS Paragon Plus Environment

Organic Process Research & Development 1 2 3 4 5 6 7 8 9 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

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Table of Contents graphic


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Abstract

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-aminoN-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.

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 3 ACS Paragon Plus Environment


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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%). Scheme 1. First-Generation Synthetic Route of (R)-Lacosamide 1 OH H2N

OH

O 2 D-Serine

Ac2O CH2Cl2, rt, 1 h 27% Recrystallized twice

OH

HCl H2N

MeOH, reflux 18 h

O N H

OH H N O 5

O O 3

BnNH2 reflux, 18 h 27% over 2 steps

MeI (10 equiv.), Ag2O(5 equiv.) MeCN, rt, 4 d

H2N

OH H N O 4

O

O N H

H N

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 4 ACS Paragon Plus Environment

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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.

Scheme 2. Second-Generation Synthetic Route of (R)-Lacosamide 1



OH OH

H2N

O 2 D-Serine O

OH 2 H N N H H O 5

Ac2O AcOH, rt, 24 h

H O

O H

N H

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1) IBCF, NMM, THF, -78oC OH

O 6

MeI (2 equiv.), Ag2O (5 equiv.) MeCN, rt, 4 d 80%

2) BnNH2, -78oC~rt, 37% over 2 steps

O

O N H

H N

O 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 6 ACS Paragon Plus Environment

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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. Scheme 3. Third-Generation Synthetic Route of (R)-Lacosamide 1 OH BocHN

OH

O 7 Boc-D-Serine

CH2Cl2, 1 h

O 10

H N

Ac2O CH2Cl2, 5~15 oC, 0.5 h 69.8% over 3 steps

O

O N H

O BocHN

2) BnNH2, -5 oC~rt, 1 h

O 8

O H2N

OH

BocHN

Toluene, 99.9%



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. Table 1. The impurity profiles for (R)-Lacosamide 1

Step

0

1 OH

SM& IM

O

OH

O 11 D-Serine

OH

BocHN 8

OH H2N

2

OCH3

OH

BocHN

7 Boc-D-Serine

3

OCH3

O

O

OCH3

OCH3

NHBn

BocHN

4

NHBn

H2N

O

9

NHBn

AcHN O 1

10

OH H2N

OH

O 11 D-Serine

O

Byproducts in steps

1 2 3 4 5 6 7 8 9 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

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OH BocHN

O 7 Boc-D-Serine

OH

OH

OH

NHBn O 14

BocHN

H3C

NHBn

H2N

O

20 AcHN

N H

OH H N O 23

OAc H N O

OCH3

O H3C

O CH3

NHBn

N H

OCH3

O H3C

O 15

O CH3

24

NHBn

N H

O 15


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OCH3

O N H

BnHN

NHBn 16

OCH3

O BnHN

O

N H

NHBn 16

O

O BnHN

CH3

O 17

OCH3 Boc

N CH3 O

OH 12

BocHN 13 O

OCH3

OCH3 Boc

N CH3 O

NHBn 18

HN CH3 O

OCH3

OCH3 OH

CH3

NHBn

BocHN O 19

H2N

NHBn

OCH3 H N O

22

O

21

O H3C

OCH3 N CH3 O

H3C

N H

NHBn 25

OCH3 H N O 26

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 General Methods. All of the reagents and solvents were obtained from commercial suppliers and used without further purification. 1H NMR and

13C

NMR spectra were

recorded by a Bruker 400 or 600 MHz spectrometer. Chemical shift data are reported in δ (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 μ m,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 ADH,(5 μ m,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

15

4

15 16 ACS Paragon Plus Environment

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7

20

15

20

25

45

40

45

40

15

45

15

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

Improved Synthesis and Impurity Identification of (R)-Lacosamide

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