196601-69-1

Basic information

• Product Name: (R)-2-amino-N-benzyl-3-methoxypropanamide
• Synonyms: (R)-2-amino-N-benzyl-3-methoxypropanamide;2(R)-Amino-N-benzyl-3-methoxypropionamide;(R)-2-Amino-n-benzyl-3-methoxypropionamide;LacosaMide I;(R)-AMino-N-benzyl-3-MethoxypropionaMide;(2R)-2-amino-3-methoxy-N-(phenylmethyl)Propanamide;N-Desacetyl Lacosamide
• CAS NO: 196601-69-1
• Molecular Formula: C₁₁H₁₆N₂O₂
• Molecular Weight: 208.25694
• EINECS: 606-353-2
• Mol File: 196601-69-1.mol
• Article Data: 38

Chemical Properties

• Boiling Point: 421.947 °C at 760 mmHg
• Flash Point: 208.986 °C
• Appearance: /
• Density: 1.107
• Vapor Pressure: 0mmHg at 25°C
• Refractive Index: 1.535
• Storage Temp.: 2-8°C(protect from light)
• Solubility: Chloroform (Slightly), Methanol (Slightly, Sonicated)
• PKA: 15.04±0.46(Predicted)
• Stability: Hygroscopic
• CAS DataBase Reference: (R)-2-amino-N-benzyl-3-methoxypropanamide(CAS DataBase Reference)
• NIST Chemistry Reference: (R)-2-amino-N-benzyl-3-methoxypropanamide(196601-69-1)
• EPA Substance Registry System: (R)-2-amino-N-benzyl-3-methoxypropanamide(196601-69-1)

Safety Data

• HazardClass: IRRITANT
• Hazardous Substances Data: 196601-69-1(Hazardous Substances Data)

Usage

Uses

(R)-2-Amino-N-benzyl-3-methoxypropionamide is an impurity of Lacosamide which is a potent anticonvulsant.

InChI:InChI=1/C11H16N2O2/c1-15-8-10(12)11(14)13-7-9-5-3-2-4-6-9/h2-6,10H,7-8,12H2,1H3,(H,13,14)/t10-/m1/s1

Synthetic route

(R)-N-benzyl 2-N-(benzylcarboxycarbonyl)amino-3-methoxypropionamide (196601-68-0) → (R)-2-amino-N-benzyl-3-methoxypropanamide (196601-69-1)

Conditions	Yield
With hydrogen; palladium on activated charcoal In methanol for 3h; Ambient temperature;	100%
With hydrogen; palladium on activated charcoal In methanol at 20℃; under 760 Torr; for 4h;	96%
With palladium 10% on activated carbon; hydrogen at 20℃;	95%

tert-butyl [(2R)-1-(benzylamino)-3-methoxy-1-oxopropan-2-yl]carbamate (880468-89-3) → (R)-2-amino-N-benzyl-3-methoxypropanamide (196601-69-1)

Conditions	Yield
With hydrogenchloride; water In dichloromethane at 0 - 30℃; for 2h;	100%
With hydrogenchloride; water In dichloromethane at 0 - 30℃; for 2h;	100%
With hydrogenchloride In dichloromethane; water at 0 - 10℃; for 1h;	100%

C17H19N3O4 → (R)-2-amino-N-benzyl-3-methoxypropanamide (196601-69-1)

Conditions	Yield
Stage #1: C17H19N3O4 With 5%-palladium/activated carbon; hydrogen In ethyl acetate at 20℃; under 760.051 Torr; for 4h; Stage #2: With [bis(acetoxy)iodo]benzene In acetonitrile at 0℃; for 0.5h; Stage #3: With sulfuric acid at 20℃; for 1h; enantioselective reaction;	95%

tert-butyl-N-[(1R)-2-(benzylamino)-1-(hydroxymethyl)-2-oxo-ethyl]carbamate (1253790-58-7) + dimethyl sulfate (77-78-1) → (R)-2-amino-N-benzyl-3-methoxypropanamide (196601-69-1)

Conditions	Yield
Stage #1: tert-butyl-N-[(1R)-2-(benzylamino)-1-(hydroxymethyl)-2-oxo-ethyl]carbamate; dimethyl sulfate With water; sodium hydroxide; tetrabutylammomium bromide In dichloromethane at -10 - -5℃; Stage #2: With hydrogenchloride In dichloromethane; water at 25 - 30℃; for 2h;	90.71%

N-Benzyl-2-Amino-3-Methoxypropionamide (262845-82-9) → (R)-2-amino-N-benzyl-3-methoxypropanamide (196601-69-1)

Conditions	Yield
With L-Tartaric acid; phosphoric acid; benzaldehyde In methanol at 50℃; pH=6;	72%

benzylamine (100-46-9) + N-acetyl-N'-(3,4-dichlorophenylhaloacetyl)-hydrazide → (R)-2-amino-N-benzyl-3-methoxypropanamide (196601-69-1)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: 4-methylmorpholine / tetrahydrofuran / 0.03 h / -78 °C 1.2: isobutyl chloroformate / tetrahydrofuran / 0.03 h 1.3: 65 percent / tetrahydrofuran / -78 - 20 °C 2.1: 90 percent / Ag2O / acetonitrile / 20 °C 3.1: 96 percent / H2 / Pd/C / methanol / 4 h / 20 °C / 760 Torr View Scheme

(R)-N-benzyl 2-N-(benzyloxycarbonyl)amino-3-hydroxypropionamide (219835-31-1) → (R)-2-amino-N-benzyl-3-methoxypropanamide (196601-69-1)

Conditions	Yield
Multi-step reaction with 2 steps 1: 90 percent / Ag2O / acetonitrile / 20 °C 2: 96 percent / H2 / Pd/C / methanol / 4 h / 20 °C / 760 Torr View Scheme
Multi-step reaction with 2 steps 1: 84 percent / Ag2O / acetonitrile / 72 h / Ambient temperature 2: 100 percent / H2 / 10percent Pd/C / methanol / 3 h / Ambient temperature View Scheme
Multi-step reaction with 2 steps 1: silver(l) oxide / acetonitrile / 120 h / 20 °C 2: palladium 10% on activated carbon; hydrogen / methanol / 5 h / 20 °C / 760.05 Torr View Scheme
Multi-step reaction with 2 steps 1.1: sodium hydroxide; tetrabutylammomium bromide / water; tert-butyl methyl ether / 12 h / -10 - 5 °C 2.1: hydrogenchloride; water / 0.75 h / 40 - 45 °C 2.2: 0 - 5 °C View Scheme

benzylamine (100-46-9) + chloride of/the/ 2-nitro-toluene-sulfonic acid-(4) → (R)-2-amino-N-benzyl-3-methoxypropanamide (196601-69-1)

Conditions	Yield
Multi-step reaction with 3 steps 1: tetrahydrofuran / 1 h / Ambient temperature 2: 84 percent / Ag2O / acetonitrile / 72 h / Ambient temperature 3: 100 percent / H2 / 10percent Pd/C / methanol / 3 h / Ambient temperature View Scheme

N-benzyl-O-methyl-N2-trityl-D-serinamide (1159573-88-2) → (R)-2-amino-N-benzyl-3-methoxypropanamide (196601-69-1)

Conditions	Yield
Stage #1: N-benzyl-O-methyl-N2-trityl-D-serinamide With hydrogenchloride In dichloromethane; water at 20℃; for 0.5h; Stage #2: With ammonia In water
Stage #1: N-benzyl-O-methyl-N2-trityl-D-serinamide With acetic acid In ethanol at 20℃; for 0.5h; Stage #2: With ammonia In water Product distribution / selectivity;
With hydrogenchloride In dichloromethane; water at 20℃; for 0.5h; Product distribution / selectivity;

C20H24N2O4 + (R)-N-benzyl 2-N-(benzylcarboxycarbonyl)amino-3-methoxypropionamide (196601-68-0) → C12H18N2O2 + (R)-2-amino-N-benzyl-3-methoxypropanamide (196601-69-1)

Conditions	Yield
With palladium 10% on activated carbon; hydrogen In ethyl acetate at 30 - 35℃; under 3750.38 - 4500.45 Torr; for 1h;

(R)-N-benzyl-2-amino-3-methoxypropionamide oxalate → (R)-2-amino-N-benzyl-3-methoxypropanamide (196601-69-1)

Conditions	Yield
With sodium hydroxide In water

benzylamine (100-46-9) → (R)-2-amino-N-benzyl-3-methoxypropanamide (196601-69-1)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: 4-methyl-morpholine; isobutyl chloroformate / dichloromethane / -5 °C 1.2: -5 - 0 °C 2.1: potassium hydroxide / dichloromethane / 5 °C 2.2: 5 °C 3.1: hydrogenchloride / dichloromethane; water / 25 - 30 °C 3.2: 25 - 30 °C / pH 10 - 11 View Scheme
Multi-step reaction with 3 steps 1.1: 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; 4-methyl-morpholine / ethyl acetate / 3.5 h / 4 - 25 °C / Inert atmosphere 2.1: sodium hydroxide / tetra(n-butyl)ammonium hydrogensulfate / dichloromethane; water / 4 - 25 °C / Inert atmosphere 3.1: hydrogenchloride; water / dichloromethane / 3 h / 25 °C 3.2: 4 - 8 °C View Scheme
Multi-step reaction with 3 steps 1.1: 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; 4-methyl-morpholine / ethyl acetate / 3.5 h / 4 - 25 °C / Cooling with ice; Inert atmosphere 2.1: tetra(n-butyl)ammonium hydrogensulfate; sodium hydroxide / dichloromethane; water / 4 - 25 °C / Cooling with ice; Inert atmosphere 3.1: hydrogenchloride; water / dichloromethane / 3 h / 25 °C 3.2: 4 - 8 °C View Scheme

tert-butyl-N-[(1R)-2-(benzylamino)-1-(hydroxymethyl)-2-oxo-ethyl]carbamate (1253790-58-7) → (R)-2-amino-N-benzyl-3-methoxypropanamide (196601-69-1)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: potassium hydroxide / dichloromethane / 5 °C 1.2: 5 °C 2.1: hydrogenchloride / dichloromethane; water / 25 - 30 °C 2.2: 25 - 30 °C / pH 10 - 11 View Scheme
Multi-step reaction with 2 steps 1.1: sodium hydroxide / tetra(n-butyl)ammonium hydrogensulfate / dichloromethane; water / 4 - 25 °C / Inert atmosphere 2.1: hydrogenchloride; water / dichloromethane / 3 h / 25 °C 2.2: 4 - 8 °C View Scheme
Multi-step reaction with 2 steps 1.1: tetra(n-butyl)ammonium hydrogensulfate; sodium hydroxide / dichloromethane; water / 4 - 25 °C / Cooling with ice; Inert atmosphere 2.1: hydrogenchloride; water / dichloromethane / 3 h / 25 °C 2.2: 4 - 8 °C View Scheme

(R)-N-benzyl-2-(dibenzylamino)-3-methoxypropanamide (1346691-15-3) → (R)-2-amino-N-benzyl-3-methoxypropanamide (196601-69-1)

Conditions	Yield
With hydrogen; palladium(II) hydroxide In methanol at 25 - 30℃; under 3677.86 Torr; for 8h; Inert atmosphere;
With hydrogen; palladium(II) hydroxide In methanol at 25 - 30℃; under 3750.38 Torr; for 8h; Inert atmosphere;

(2R)-2-amino-3-hydroxy-N-(phenylmethyl)propanamide (175481-39-7) → (R)-2-amino-N-benzyl-3-methoxypropanamide (196601-69-1)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: ethyl acetate / 1 h / 25 - 30 °C 1.2: 1 h / 25 - 30 °C 2.1: sodium hydroxide; water / tetrabutylammomium bromide / dichloromethane / -10 - -5 °C 2.2: 2 h / 25 - 30 °C View Scheme
Multi-step reaction with 3 steps 1.1: triethylamine / tetrahydrofuran 2.1: potassium hydroxide; tetrabutylammomium bromide / ethyl acetate 3.1: hydrogenchloride / water / Reflux 3.2: pH 8 - 9 View Scheme
Multi-step reaction with 3 steps 1: triethylamine / tetrahydrofuran 2: tetrabutylammomium bromide; potassium hydroxide / ethyl acetate 3: hydrogenchloride; water / Reflux View Scheme

(2R)-2-azido-N-benzyl-3-hydroxypropanamide (1357171-71-1) → (R)-2-amino-N-benzyl-3-methoxypropanamide (196601-69-1)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: hydrogen / 5%-palladium/activated carbon / ethyl acetate / 1 h / 25 - 30 °C / 2795.17 Torr / Autoclave 2.1: ethyl acetate / 1 h / 25 - 30 °C 2.2: 1 h / 25 - 30 °C 3.1: sodium hydroxide; water / tetrabutylammomium bromide / dichloromethane / -10 - -5 °C 3.2: 2 h / 25 - 30 °C View Scheme

(2S)-N-benzyl-2-bromo-3-hydroxypropanamide (1357171-70-0) → (R)-2-amino-N-benzyl-3-methoxypropanamide (196601-69-1)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: sodium azide / N,N-dimethyl-formamide / 50 - 55 °C 2.1: hydrogen / 5%-palladium/activated carbon / ethyl acetate / 1 h / 25 - 30 °C / 2795.17 Torr / Autoclave 3.1: ethyl acetate / 1 h / 25 - 30 °C 3.2: 1 h / 25 - 30 °C 4.1: sodium hydroxide; water / tetrabutylammomium bromide / dichloromethane / -10 - -5 °C 4.2: 2 h / 25 - 30 °C View Scheme

(R)-N-benzyl-2-(ethoxycarbonylamino)-3-hydroxypropionamide (1320360-91-5) → (R)-2-amino-N-benzyl-3-methoxypropanamide (196601-69-1)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: potassium hydroxide; tetrabutylammomium bromide / ethyl acetate 2.1: hydrogenchloride / water / Reflux 2.2: pH 8 - 9 View Scheme
Multi-step reaction with 2 steps 1: tetrabutylammomium bromide; potassium hydroxide / ethyl acetate 2: hydrogenchloride; water / Reflux View Scheme

(R)-N-benzyl-2-(ethoxycarbonylamino)-3-methoxypropionamide (1320360-92-6) → (R)-2-amino-N-benzyl-3-methoxypropanamide (196601-69-1)

Conditions	Yield
Stage #1: (R)-N-benzyl-2-(ethoxycarbonylamino)-3-methoxypropionamide With hydrogenchloride In water Reflux; Stage #2: With sodium hydroxide In water pH=8 - 9;
With hydrogenchloride; water Reflux;

(2R)-2-amino-N-benzyl-3-hydroxypropanamide hydrochloride (1322062-75-8) → (R)-2-amino-N-benzyl-3-methoxypropanamide (196601-69-1)

Conditions	Yield
Multi-step reaction with 4 steps 1: sodium hydroxide / water / 20 - 25 °C / pH 8 - 9 2: triethylamine / tetrahydrofuran 3: tetrabutylammomium bromide; potassium hydroxide / ethyl acetate 4: hydrogenchloride; water / Reflux View Scheme

N-benzyl-2-amino-3-methoxypropanamide N-formyl-L-leucine salt → (R)-2-amino-N-benzyl-3-methoxypropanamide (196601-69-1)

Conditions	Yield
With alkaline salt solution In dichloromethane; water	1.59 g

(R)-tert-butyl (1-(benzylamino)-3-methoxy-1-oxopropan-2-yl)-N-(hydroxymethyl)carbamate → (R)-2-amino-N-benzyl-3-methoxypropanamide (196601-69-1)

Conditions	Yield
Multi-step reaction with 2 steps 1: tert-butyl methyl ether / 60 - 65 °C 2: hydrogenchloride; water / dichloromethane / 2 h / 0 - 30 °C View Scheme

(R)-N-benzyl-2-(isoindolin-2-yl)-3-methoxypropanamide → (R)-2-amino-N-benzyl-3-methoxypropanamide (196601-69-1)

Conditions	Yield
With hydrazine hydrate In isopropyl alcohol at 0 - 25℃; for 2h; Inert atmosphere;
With hydrazine hydrate In isopropyl alcohol at 0 - 25℃; for 2h; Inert atmosphere;

C10H12ClNO2 → (R)-2-amino-N-benzyl-3-methoxypropanamide (196601-69-1)

Conditions	Yield
Multi-step reaction with 4 steps 1: methanol / 3 h / 0 - 20 °C / Inert atmosphere 2: triethylamine; dmap / dichloromethane / 12 h / 20 °C / Inert atmosphere; Cooling with ice 3: sodium azide / water; N,N-dimethyl-formamide / 6 h / 70 °C / Inert atmosphere 4: 5%-palladium/activated carbon; hydrogen / methanol / 3 h / 20 °C / Autoclave View Scheme

(S)-N-benzyl-2-hydroxy-3-methoxypropanamide (1567820-75-0) → (R)-2-amino-N-benzyl-3-methoxypropanamide (196601-69-1)

Conditions	Yield
Multi-step reaction with 3 steps 1: triethylamine; dmap / dichloromethane / 12 h / 20 °C / Inert atmosphere; Cooling with ice 2: sodium azide / water; N,N-dimethyl-formamide / 6 h / 70 °C / Inert atmosphere 3: 5%-palladium/activated carbon; hydrogen / methanol / 3 h / 20 °C / Autoclave View Scheme

(S)-1-(benzylamino)-3-methoxy-1-oxopropan-2-yl 4-toluenesulfonate (1567820-77-2) → (R)-2-amino-N-benzyl-3-methoxypropanamide (196601-69-1)

Conditions	Yield
Multi-step reaction with 2 steps 1: sodium azide / water; N,N-dimethyl-formamide / 6 h / 70 °C / Inert atmosphere 2: 5%-palladium/activated carbon; hydrogen / methanol / 3 h / 20 °C / Autoclave View Scheme

(R)-2-azido-N-benzyl-3-methoxypropanamide → (R)-2-amino-N-benzyl-3-methoxypropanamide (196601-69-1)

Conditions	Yield
With 5%-palladium/activated carbon; hydrogen In methanol at 20℃; for 3h; Autoclave;

D-o-methylserine (86118-11-8) + benzylamine (100-46-9) → (R)-2-amino-N-benzyl-3-methoxypropanamide (196601-69-1) + (S)-N-benzyl 2-amino-3-methoxypropionamide (474534-78-6)

Conditions	Yield
With tris(2,2,2-trifluoroethyl) borate at 125℃; under 760.051 Torr; for 4h;	A n/a B n/a

acetic anhydride (108-24-7) + (R)-2-amino-N-benzyl-3-methoxypropanamide (196601-69-1) → lacosamide

Conditions	Yield
With pyridine; dmap In tetrahydrofuran for 1h; Ambient temperature;	90%
With pyridine In tetrahydrofuran at 20℃; for 1h; enantioselective reaction;	88%
at 10 - 25℃;	81.8%

2-Bromoacetyl bromide (598-21-0) + (R)-2-amino-N-benzyl-3-methoxypropanamide (196601-69-1) → N-benzyl-2-(2-bromo-acetylamino)-3-methoxy-propionamide

Conditions	Yield
With sodium hydrogencarbonate; sodium carbonate In dichloromethane at 5 - 10℃;	78%

Isopropenyl acetate (108-22-5) + (R)-2-amino-N-benzyl-3-methoxypropanamide (196601-69-1) → lacosamide

Conditions	Yield
In Isopropyl acetate at 23 - 75℃;	68.9%

acetyl chloride (75-36-5) + (R)-2-amino-N-benzyl-3-methoxypropanamide (196601-69-1) → lacosamide

Conditions	Yield
With triethylamine at 10 - 25℃;	62.4%
With triethylamine In dichloromethane at 10 - 25℃;	3.12 g
With sodium carbonate In toluene at 0 - 5℃; for 1h; Inert atmosphere;	935 mg
With sodium carbonate In toluene at 0 - 5℃; for 1h;	935 mg
With triethylamine at 0 - 20℃; for 1.58333h; Inert atmosphere;	108 mg

acetaldehyde (75-07-0) + (R)-2-amino-N-benzyl-3-methoxypropanamide (196601-69-1) → N-benzyl-2-ethylamino-3-methoxy-propionamide

Conditions	Yield
With sodium cyanoborohydride In methanol at 20℃; for 0.166667h;	51%

acetic anhydride (108-24-7) + (R)-2-amino-N-benzyl-3-methoxypropanamide (196601-69-1) → (2S)-2-(acetylamino)-N-benzyl-3-methoxypropanamide + lacosamide

Conditions	Yield
In dichloromethane at 20℃; for 2h;

C12H18N2O2 + acetic anhydride (108-24-7) + (R)-2-amino-N-benzyl-3-methoxypropanamide (196601-69-1) → C14H20N2O3 + lacosamide

Conditions	Yield
With triethylamine In ethyl acetate at 20℃; for 1h;

oxalic acid (144-62-7) + (R)-2-amino-N-benzyl-3-methoxypropanamide (196601-69-1) → (R)-N-benzyl-2-amino-3-methoxypropionamide oxalate

Conditions	Yield
In isopropyl alcohol at 0 - 32℃; for 1.25h;

Upstream product

• 1159573-88-2 N-benzyl-O-methyl-N₂-trityl-D-serinamide 
• 196601-68-0 (R)-N-benzyl 2-N-(benzylcarboxycarbonyl)amino-3-methoxypropionamide 
• 1322062-75-8 (2R)-2-amino-N-benzyl-3-hydroxypropanamide hydrochloride 
• 86118-11-8 D-o-methylserine 
• 100-46-9 benzylamine 
• 1567820-77-2 (S)-1-(benzylamino)-3-methoxy-1-oxopropan-2-yl 4-toluenesulfonate 
• 1567820-75-0 (S)-N-benzyl-2-hydroxy-3-methoxypropanamide 
• 1320360-92-6 (R)-N-benzyl-2-(ethoxycarbonylamino)-3-methoxypropionamide 
• 1320360-91-5 (R)-N-benzyl-2-(ethoxycarbonylamino)-3-hydroxypropionamide 
• 1357171-70-0 (2S)-N-benzyl-2-bromo-3-hydroxypropanamide 
• 1357171-71-1 (2R)-2-azido-N-benzyl-3-hydroxypropanamide 
• 175481-39-7 (2R)-2-amino-3-hydroxy-N-(phenylmethyl)propanamide 
• 1253790-58-7 tert-butyl-N-[(1R)-2-(benzylamino)-1-(hydroxymethyl)-2-oxo-ethyl]carbamate 
• 77-78-1 dimethyl sulfate 

Downstream Products

• 175481-36-4 lacosamide 
• 175481-36-4 (2S)-2-(acetylamino)-N-benzyl-3-methoxypropanamide 

Relevant articles and documents

Synthetic route of lacosamide

The invention discloses a new synthesis route of lacosamide. The new synthesis route comprises the following steps: taking glycine ethyl ester hydrochloride as an initial raw material to react with methylbenzene, benzophenone and p-toluenesulfonic acid to obtain a compound of formula M1; reacting the compound of formula M1 with Xmethyl methyl ether to generate a compound of formula M2; reacting the compound of formula M2 with benzylamine under the catalytic action of sodium ethoxide to generate a compound of formula M3; reacting the compound of formula M3 under the action of acid to generate acompound of formula M4; reacting the compound of formula M4 with Ltartaric acid to generate a compound of formula M5; and enabling the compound of formula M5 to react with acetic anhydride to generate the lacosamide compound. The synthesis route has the advantages that the atom economy is high, the use of isopropyl chloroformate highly toxic products for preparing amide is avoided, the use of methylation reagents methyl iodide or dimethyl sulfate is avoided, the yield is high, and the like.

Direct, Enantioselective, and Nickel(II) Catalyzed Reactions of N-Azidoacetyl Thioimides with Trimethyl Orthoformate: A New Combined Methodology for the Rapid Synthesis of Lacosamide and Derivatives

A direct and highly enantioselective reaction of N-azidoacetyl-1,3-thiazolidine-2-thione with trimethyl orthoformate catalyzed by Tol-BINAPNiCl2 in the presence of TESOTf and 2,6-lutidine is reported. The heterocyclic scaffold can be easily removed by addition of a wide array of amines to give the corresponding enantiomerically pure 2-azido-3,3-dimethoxypropanamides in high yields. Appropriate manipulation of the N-benzyl amide derivative provides an efficient access to the antiepileptic agent lacosamide through a new enantioselective C?C bond-forming process. DFT computational studies uncover clues for the understanding of the remarkable stereocontrol of the addition of a nickel(II) enolate to a putative oxocarbenium intermediate from trimethyl orthoformate.

Improved preparation method of modified lacosamide

The invention discloses an improved preparation method of modified lacosamide, which is simple to operate, high in chiral purity and low in cost. According to the improved preparation method, in step 1, amidation is carried out on amino by utilizing di-tert butyl dicarbonate (Boc for short), wherein conditions are moderate and the chiral purity is high and at least reaches 90 percent or more; in step 4, high-selectivity dimethyl sulfate is used as a methylation reagent; the cost is low and the conditions are moderate; the methylation yield is high and the improved preparation method is more suitable for large-scale application. The improved preparation method has the most important innovation points that the Boc is used as an N-protection agent and a Boc protecting group can be simply and conveniently removed by adding acid and a hydrogenation removal means does not need to be used. Secondly, the low-price dimethyl sulfate is used for carrying out methylation and the conditions are moderate; the methylation yield is high and the improved preparation method is more suitable for large-scale application.