This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes.
Article Cite This: ACS Omega 2019, 4, 6546−6550
http://pubs.acs.org/journal/acsodf
Concise Synthesis of Lacosamide with High Chiral Purity Meng-Di Chen,† An-Jiang Yang,‡ Zhong Li,‡ Fei-Fei Hu,‡ Jiang-Tao Yang,‡ Sheng-Hua Gao,‡ Fu-Li Zhang,*,‡ and Chun-Jie Zhao*,† †
School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, China Shanghai Institute of Pharmaceutical Industry, China State Institute of Pharmaceutical Industry, 285 Gebaini Road, Shanghai 201203, China
‡
Downloaded via 91.243.90.49 on April 10, 2019 at 15:43:40 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.
S Supporting Information *
ABSTRACT: An efficient synthesis process of an antiepileptic drug, lacosamide, with high chiral purity has been developed. A series of acids were screened to form salts with the key intermediate 4, and phosphoric acid, an inexpensive and achiral reagent, turned out to be the best counterion, which could enhance both chemical purity and chiral purity of the key intermediate 4. 4-Phosphate was used for the successful synthesis of lacosamide with high chemical and chiral purities.
1. INTRODUCTION Epilepsy is one of the most common diseases of the nervous system, and it is a medical emergency and life-threatening condition that imposes quite a burden on the affected patients and society in general.1,2 Various antiepileptic drugs were expected to treat epilepsy to reduce seizure frequency and severity, and provide acceptable tolerability without side effects.3−7 Lacosamide, chemically known as (R)-2-acetamido-N-benzyl-3-methoxypropionamide, is the active ingredient of Vimpat owned by UCB Pharma. It is an effective and welltolerated antiepileptic drug, which has been approved and is currently being used clinically in the United States and Europe.6,8,9 In the past decades, many routes have been developed to synthesize lacosamide.10−14 However, its commercial routes were based on the synthetic route reported by UCB Pharma, involving the O-methylation of an N-Boc-D-serine, benzylamide formation, N-deprotection, and N-acetylation.15 However, the main problem of the present synthetic routes (Scheme 1) is the partial racemization.16 We have repeated this route several times and noticed that it was not robust enough and the chiral purity of some batches was just about 92−96%, caused by partial racemization, which led to low chiral purity of 4 ((R)-2-amino-N-benzyl-3-methoxyproplonamide) and sequentially the final product, lacosamide. We hypothesized that the partial racemization might be due to the strongly alkaline reagents used in the reaction, which led to partially high concentration of the base and sequential racemization in the dropping process. This chiral impurity is hard to remove and is a main drawback in terms of industrial productivity of the process. Although some methods to improve the chiral purity of lacosamide were reported, such as chiral resolution of using expensive chiral auxiliaries, supercritical fluid chromatogram, preparative high-performance liquid chromatography (HPLC), or crystallizing with a chiral acid, these methods still suffer from low yield, © 2019 American Chemical Society
cumbersome operations, unaffordable cost, or dimmed prospect for scale-up.17−19 Herein, we aim to report a new concise method to improve the chiral purity of lacosamide by increasing the chiral purity of intermediate 4 through an inexpensive and achiral reagent, phosphoric acid.
2. RESULTS AND DISCUSSION Considering the structures and properties of the intermediates of this route, we initially wanted to increase the purity of 4 by forming a salt with an acid, as well as obtaining a solid product for the convenience of transportation, storage, and usage. Currently, all of the intermediates of this route are oily, which are difficult to purify. We screened various acids to form salts with 4 in different solvents and tried to found the most suitable acid and solvent. The results are summarized in Table 1. We found that only (−)-dibenzoyl-L-tartaric acid (L-DBTA), (+)-dibenzoyl-D-tartaric acid (D-DBTA), (−)-di-p-toluoyl-L-tartaric acid (LDTTA), and phosphoric acid could easily form crystalline salts in four solvents. Salts with all of the other investigated acids remained soluble or formed oily or gluelike separations. Both chemical purity and chiral purity of the 4-salts were determined by HPLC (Table 2). It has been shown that the chemical purity was improved up to above 99% from initially 97% as prepared by the procedures of WO2006037574, and only D-DBTA and H3PO4 showed improved chiral purity. What surprised us most was that the chiral purity of the 4phosphate could be enhanced up to 97−99% from initially 93%, especially considering that phosphoric acid is an achiral acid (Figures 1 and 2). Received: September 28, 2018 Accepted: December 14, 2018 Published: April 10, 2019 6546
DOI: 10.1021/acsomega.8b02564 ACS Omega 2019, 4, 6546−6550
ACS Omega
Article
Scheme 1. Synthetic Route for the Commercialization of Lacosamide
Table 1. Screened Acids and the Statuses of Corresponding Salts entrya 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
acid L-tartaric
acid D-mandelic acid citric acid fumaric acid b L-DBTA b D-DBTA b L-DTTA malic acid lactic acid succinic acid aspartic acid glutamic acid HCl H2SO4 H3PO4 HOAc malonic acid adipic acid MeSO3H pTsOHb
ACN
DCM
iPrOH
THF
J O J J C C C O O O O C O O
J O J J C C C O O O C O O
J O J C C C O O C O
J O O J C C C O O C O O
Table 2. Chemical Purity and Chiral Purity of the Intermediate 4-saltsa entry
acid
solvent
chemical purity (%)
chiral purity (%)
yield (%)
1
D-DBTA
2
L-DBTA
3
L-DTTA
4
H3PO4
ACN DCM iPrOH THF ACN DCM iPrOH THF ACN DCM iPrOH THF ACN DCM iPrOH THF
99 99 99 99 99 99 99 99 99 99 99 99 98 98 98 98
95 97 94 98 93 91 95 92 90 87 87 87 99 99 97 99
76 76 70 61 88 92 77 63 90 95 93 84 80 76 79 77
a
Reaction conditions: to a 5 mL glass vial filled with intermediate 4 (0.2 g) in different solvents (2 mL), an acid (1.0 equiv) was added and stirred for 2 h at 25 °C. bAbbreviations: L-DBTA = (−)-dibenzoyl-L-tartaric acid, D-DBTA = (+)-dibenzoyl-D-tartaric acid, L-DTTA = (−)-di-p-toluoyl-L-tartaric acid, pTsOH = p-toluene sulfonic acid, J = jellylike precipitate, O = oily layer, C = crystallized, = liquid. a
The initial purity of 4: chemical purity = 97%, chiral purity = 93%.
shown that this method could effectively improve the chiral purity of the partially racemized 4. However, it is not suitable for the totally racemic 4. Considering the novelty of this method and the interesting phenomenon, we tried to understand the proposed reason that phosphoric acid could improve the chiral purity of 4 (Scheme 3). Therefore, we confirmed the chiral purity of 4 in the mother liquor and found that the chiral purity of 4 was about 50% and the yield of the rac-4-phosphate was lower than that of (R)-4-phosphate. It is proposed that the solubility of (R)-4-phosphate is lower compared to that of the rac-4-phosphate. Phosphoric acid is used in equimolar quantities; thus, the amine 4 is completely protonated in solution because of the lower solubility of the
To explore the scope of this method, we tried to prepare a phosphate of 4 using a free base of 4 with different initial chiral purity (the racemic 4 was prepared from racemic serine) and found that the initial chiral purity had a great impact on the chiral purity of the phosphate (Scheme 2 and Table 3). It was 6547
DOI: 10.1021/acsomega.8b02564 ACS Omega 2019, 4, 6546−6550
ACS Omega
Article
Figure 1. HPLC chromatograms of chemical purity: blank control (black), intermediate 4 (blue), and 4-phosphate (red).
Figure 2. HPLC chromatograms of the comparison of chiral purity: racemic 4 (black), partially racemized 4 (red), and 4-phosphate (blue).
3. CONCLUSIONS In conclusion, a new method to synthesize lacosamide has been developed by improving both chemical and chiral purities of the key intermediate 4 by preparing a phosphate of 4. The preparation process was carried out under a mild condition, affording lacosamide with 62.84% overall yield.
Scheme 2. Preparation of the Phosphate
Table 3. Chiral Purity of Filter Cake and 4 in the Mother Liquor
4. EXPERIMENTAL SECTION 4.1. 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 using a Bruker 600 MHz spectrometer. Chemical shift data was reported in δ (ppm) from the internal standard tetramethylsilane. High-resolution mass spectra were recorded on a Bruker maXis 4G Q-TOF instrument. Differential scanning calorimetry (DSC) were measured on a DSC Q2000 V24.10 Build 122 instrument. Purities of the inprogress-control samples, the isolated intermediates, and the final product were analyzed by high-performance liquid chromatography (HPLC, normalized area percentage). The HPLC analyses were carried out by a standard method on a Dionex UItiMate 3000 HPLC instrument. The chemical purity was analyzed using an Agilent Eclipse XDB-C18 (5 μm, 46 mm × 250 mm), 30 °C, 1 mL/min, 210 nm, and 45 min. Mobile phase: A (20 mM 1-octane sulfonic acid sodium salt, pH 2.1), B (acetonitrile). The mobile-phase gradient is shown in Table 4. The chiral purity was analyzed using a Chiral Pak AD-H, (5 μm, 46 mm × 250 mm), 30 °C, 1 mL/min, 210 nm, and 25 min. Mobile phase: A (0.05% diethylaminein N-hexane), B
chiral purity (%) before salt formation batch number 1 2 3 4
50 88 93 94
after salt formation filter cake
4 in the mother liquor
yield of filter cake (%)
51 96 98 99
48 51 51 50
72 83 85 86
(R)-4-phosphate compared to that of the rac-4-phosphate, and the salt of the chiral amine crystallizes out. The chiral purity of 4 was 94% before and then was enhanced up to 99% after salt formation. The phosphate was used to prepare lacosamide by acetylation with Ac2O in the presence of sodium bicarbonate in a biphasic solvent (CH2Cl2/ H2O = 8:2) at room temperature to obtain lacosamide of high chemical purity and chiral purity (chemical purity: 100%, chiral purity: 99.93%) (Scheme 4). (The corresponding chromatograms could be found in the Supporting Information.) 6548
DOI: 10.1021/acsomega.8b02564 ACS Omega 2019, 4, 6546−6550
ACS Omega
Article
Scheme 3. Proposed Reaction of the Chiral Enrichment
4.4. Preparation of (R)-2-Amino-N-benzyl-3-methoxyproplonamide (Intermediate 4). To the solution of 3 in CH2Cl2 prepared as above was added 36% HCl (245.0 g, 2.425 mol, 5.0 equiv) at 0−10 °C, and the mixture was stirred for 2 h. Water (300 mL) was added, and the aqueous phase was collected, whereas the organic phase was extracted with water (100 mL) and all aqueous phases were combined. The combined aqueous layer was basified to pH 10−12 with 40 wt % NaOH aq at 25−35 °C and then extracted with CH2Cl2 (2 × 500 mL). The organic layers were combined and washed with water (200 mL) and evaporated to dryness to obtain 101.5 g of 4, with crude yield 100%, chemical purity 98%, and chiral purity 94%. 4.5. Preparation of (R)-2-Amino-N-benzyl-3-methoxypropionamide Phosphate (Intermediate 4-Phosphate). The solution of 4 (100.9 g, 0.484 mol) in CH2Cl2 (1000 mL) was cooled to 0−5 °C. Phosphoric acid (85% wt, 56.3 g, 1.0 equiv) was added, and the mixture was stirred for 2 h. The solid was filtered off and washed with CH2Cl2 (500 mL) and dried at 45 °C under vacuum to produce the desired product 4-phosphate (132.1 g, 85.5% yield, chemical purity 100.0%, chiral purity 98.80%). Anal. calcd for C11H22N2O6P: C, 43.14; H, 6.25; N, 9.15. Found: C, 43.08; H, 6.23; N, 9.36; mp 193.15−196.34 °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 (t, J = 4.7 Hz, 1H), 3.82 (d, J = 4.8 Hz, 2H), 3.36 (s, 3H). 13C 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. High resolution mass spectrometry electrospray ionization (HRMSESI) m/z calcd for C11H22N2O6P: 209.1285, found 209.1289. 4.6. Preparation of (R)-2-Acetamido-N-benzyl-3-methoxypropionamide (Lacosamide). NaHCO3 (54.4 g, 0.647 mol, 1.5 equiv) was added to a mixture of 4-phosphate (132.1 g, 0.431 mol), water (260 mL, 2 V), and CH2Cl2 (1060 mL, 8 V). The reaction mixture was cooled to 0−5 °C, and Ac2O (44.1 g, 0.431 mol, 1.0 equiv) was added slowly. Then, the mixture was stirred at 20−25 °C for 3 h. The organic layer was washed with 8% NaHCO3 aqueous solution (260 mL, 2 V) and water (260 mL, 2 V). After being evaporated to dryness to obtain the crude product, ethyl acetate (500 mL, 5 V) was added. The mixture was heated to reflux until it was dissolved and then cooled to about 0 °C by gradient cooling. Stirring was continued at 0 °C for 2 h. The precipitate was filtered and finally dried at 40 °C under vacuum (76.6 g, 62.84% yield, chemical purity 100.0%, chiral purity 99.93%). Anal. calcd for C13H18O3N2: C, 62.38; H, 7.25; N, 11.19. Found: C, 62.33; H, 7.22; N, 11.41; mp 144.92−145.67 °C; 1H NMR (600 MHz,
Scheme 4. Preparation of Lacosamide
Table 4. Mobile-Phase Gradient of HPLC time (min)
mobile phase B (%,v/v)
0 4 7 15 25 40 40 45
15 15 20 20 45 45 15 15
(isopropyl alcohol). The gradient started at 15% of B, and the ratio remained unchanged until 25 min. 4.2. Preparation of (R)-2-N-Boc-amino-3-methoxypropanoic Acid (Intermediate 2). A suspension of N-BocD-serine (100.0 g, 0.48 mol) and tetrabutylammonium bromide (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 stirred for 30 min. Dimethyl sulfate ((CH3)2SO4, 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 to 5 °C. The mixture was stirred for 12 h. Water (300 mL) was added, and the aqueous layer was acidified to a pH of
