880468-89-3

Basic information

• Product Name: (R)-tert-Butyl 1-(benzylamino)-3-methoxy-1-oxopropan-2-ylcarbamate
• Synonyms: (R)-tert-Butyl 1-(benzylamino)-3-methoxy-1-oxopropan-2-ylcarbamate;tert-butyl N-[(1R)-1-(benzylcarbaMoyl)-2-Methoxyethyl]carbaMate;LacosaMide interMediate;O-methyl-N-alpha-[phenylmethoxy]carbonyl]-N-(phenylmethyl)-D-Serinamide;-3-methoxy-1-oxopropan-2-ylcarbamate;-tert-Butyl 1-(benzylamino);tert-butyl (R)-(1-(benzylamino)-3-methoxy-1-oxopropan-2-yl)carbamate;Carbamic acid,[(1R)-1-(methoxymethyl)-2-oxo-2-[(phenylmethyl)amino]ethyl]-, 1,1-dimethylethylester (9CI)
• CAS NO: 880468-89-3
• Molecular Formula: C₁₆H₂₄N₂O₄
• Molecular Weight: 308.37
• EINECS: 1592732-453-0
• Product Categories: API
• Mol File: 880468-89-3.mol
• Article Data: 26

Chemical Properties

• Melting Point: 63-64 °C
• Boiling Point: 507.6±50.0 °C(Predicted)
• Appearance: /
• Density: 1.103±0.06 g/cm3(Predicted)
• Storage Temp.: Sealed in dry,Room Temperature
• Solubility: Chloroform (Slightly), DMSO (Slightly)
• PKA: 10.62±0.46(Predicted)
• CAS DataBase Reference: (R)-tert-Butyl 1-(benzylamino)-3-methoxy-1-oxopropan-2-ylcarbamate(CAS DataBase Reference)
• NIST Chemistry Reference: (R)-tert-Butyl 1-(benzylamino)-3-methoxy-1-oxopropan-2-ylcarbamate(880468-89-3)
• EPA Substance Registry System: (R)-tert-Butyl 1-(benzylamino)-3-methoxy-1-oxopropan-2-ylcarbamate(880468-89-3)

Safety Data

• Hazardous Substances Data: 880468-89-3(Hazardous Substances Data)

Usage

Uses

(R)-tert-Butyl 1-(Benzylamino)-3-methoxy-1-oxopropan-2-ylcarbamate is an intermediate in the synthesis of functionalized amino acids, and in the synthesis of antiepileptic drug (R)-lacosamide.

Synthetic route

N-Boc-O-methyl-D-serine pivalic anhydride + benzylamine (100-46-9) → tert-butyl [(2R)-1-(benzylamino)-3-methoxy-1-oxopropan-2-yl]carbamate (880468-89-3)

Conditions	Yield
In dichloromethane at 0 - 5℃; for 0.5h;	100%

tert-butyl-N-[(1R)-2-(benzylamino)-1-(hydroxymethyl)-2-oxo-ethyl]carbamate (1253790-58-7) + dimethyl sulfate (77-78-1) → tert-butyl [(2R)-1-(benzylamino)-3-methoxy-1-oxopropan-2-yl]carbamate (880468-89-3)

Conditions	Yield
With tetrabutylammomium bromide; sodium hydroxide In water; toluene at 0 - 30℃; for 1.5h;	96.28%
With sodium hydroxide; tetra(n-butyl)ammonium hydrogensulfate In dichloromethane; water at 4 - 25℃; Inert atmosphere;	75.8%
Stage #1: tert-butyl-N-[(1R)-2-(benzylamino)-1-(hydroxymethyl)-2-oxo-ethyl]carbamate; dimethyl sulfate With tetra(n-butyl)ammonium hydrogensulfate; sodium hydroxide In dichloromethane; water at 4 - 25℃; Cooling with ice; Inert atmosphere; Stage #2: With ammonium hydroxide In dichloromethane; water	75.8%

2,4-dioxo-3-azaspiro[5.5]undecan-3-yl N-(tert-butoxycarbonyl)-O-methyl-D-serinate + benzylamine (100-46-9) → tert-butyl [(2R)-1-(benzylamino)-3-methoxy-1-oxopropan-2-yl]carbamate (880468-89-3)

Conditions	Yield
at 20℃; for 3h;	90.4%

benzylamine (100-46-9) + (R)-2-((tert-butoxycarbonyl)amino)-3-methoxypropionic acid (86123-95-7) → tert-butyl [(2R)-1-(benzylamino)-3-methoxy-1-oxopropan-2-yl]carbamate (880468-89-3)

Conditions	Yield
Stage #1: (R)-2-((tert-butoxycarbonyl)amino)-3-methoxypropionic acid With 4-methyl-morpholine; isobutyl chloroformate In tetrahydrofuran at -78℃; Inert atmosphere; Stage #2: benzylamine In tetrahydrofuran at -78 - 20℃; for 1h;	90%
With 4-methyl-morpholine; isobutyl chloroformate In tetrahydrofuran at -78 - 30℃; for 1h; Inert atmosphere;	90%
Stage #1: (R)-2-((tert-butoxycarbonyl)amino)-3-methoxypropionic acid With 4-methyl-morpholine In tetrahydrofuran at -78℃; for 0.0833333h; Inert atmosphere; Stage #2: benzylamine With isobutyl chloroformate In tetrahydrofuran at -78 - 20℃; for 1h; Inert atmosphere;	90%

tert-butyl-N-[(1R)-2-(benzylamino)-1-(hydroxymethyl)-2-oxo-ethyl]carbamate (1253790-58-7) + trimethoxonium tetrafluoroborate (420-37-1) → tert-butyl [(2R)-1-(benzylamino)-3-methoxy-1-oxopropan-2-yl]carbamate (880468-89-3)

Conditions	Yield
With N,N,N',N'-tetramethyl-1,8-diaminonaphthalene In dichloromethane at 20℃; for 16h; Inert atmosphere; Green chemistry;	81%

tert-butyl-N-[(1R)-2-(benzylamino)-1-(hydroxymethyl)-2-oxo-ethyl]carbamate (1253790-58-7) + methyl p-toluene sulfonate (80-48-8) → tert-butyl [(2R)-1-(benzylamino)-3-methoxy-1-oxopropan-2-yl]carbamate (880468-89-3)

Conditions	Yield
With tetrabutylammomium bromide; potassium hydroxide In toluene at -1 - 2℃; Solvent; Reagent/catalyst; Temperature;	80%
With tetrabutylammomium bromide; potassium hydroxide In water; toluene at 20℃; for 3h; Reagent/catalyst;	60.97g
With tetrabutylammomium bromide; sodium hydroxide In water at 20℃; for 3h;	38.5 g
With tetrabutylammomium bromide; sodium hydroxide In water; toluene at 20℃; for 3h;	38.5 g

benzylamine (100-46-9) → tert-butyl [(2R)-1-(benzylamino)-3-methoxy-1-oxopropan-2-yl]carbamate (880468-89-3)

Conditions	Yield
Multi-step reaction with 2 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 View Scheme
Multi-step reaction with 2 steps 1.1: methyl chloroformate; 4-methyl-morpholine / dichloromethane / 0.5 h / 35 °C 1.2: 20 °C 2.1: sodium hydroxide; tetrabutylammomium bromide / toluene; water / 2 - 27 °C View Scheme
Multi-step reaction with 2 steps 1.1: isobutyl chloroformate; 4-methyl-morpholine / dichloromethane / 5 °C 1.2: 0 - 5 °C 2.1: potassium hydroxide / 5 °C 2.2: 5 °C View Scheme

di-tert-butyl dicarbonate (24424-99-5) → tert-butyl [(2R)-1-(benzylamino)-3-methoxy-1-oxopropan-2-yl]carbamate (880468-89-3)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: sodium hydroxide / water / 10 h / 20 - 25 °C 2.1: sodium hydroxide / water / 0.5 h / 0 - 5 °C 2.2: 14 h / 5 - 10 °C 2.3: 0 - 5 °C 3.1: chloroformic acid ethyl ester; 4-methyl-morpholine / dichloromethane / 0.25 h / -15 - -10 °C 3.2: 3 h / -15 - 25 °C View Scheme
Multi-step reaction with 3 steps 1.1: sodium hydroxide / water 1.2: 16 h / 20 °C 1.3: pH 3.5 - 4 2.1: 4-methyl-morpholine; isobutyl chloroformate / dichloromethane / 1 h / -20 - 20 °C 3.1: sodium hydroxide / tetrabutylammomium bromide / dichloromethane; water / 2 h / 5 - 20 °C View Scheme
Multi-step reaction with 3 steps 1.1: dmap; sodium hydroxide / water; tert-butyl alcohol / 11 h / 20 °C 2.1: sodium hydroxide; tetrabutylammomium bromide / dichloromethane / 0.5 h / 0 - 5 °C 2.2: 20 °C 3.1: 4-methyl-morpholine; isobutyl chloroformate / dichloromethane / -10 - -5 °C 3.2: 20 °C View Scheme

(R)-N-tert-butoxycarbonyl serine (3262-72-4, 3850-40-6, 6368-20-3, 90582-28-8, 84311-18-2) → tert-butyl [(2R)-1-(benzylamino)-3-methoxy-1-oxopropan-2-yl]carbamate (880468-89-3)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: sodium hydroxide / water / 0.5 h / 0 - 5 °C 1.2: 14 h / 5 - 10 °C 1.3: 0 - 5 °C 2.1: chloroformic acid ethyl ester; 4-methyl-morpholine / dichloromethane / 0.25 h / -15 - -10 °C 2.2: 3 h / -15 - 25 °C View Scheme
Multi-step reaction with 2 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 View Scheme
Multi-step reaction with 2 steps 1: 4-methyl-morpholine; isobutyl chloroformate / dichloromethane / 1 h / -20 - 20 °C 2: sodium hydroxide / tetrabutylammomium bromide / dichloromethane; water / 2 h / 5 - 20 °C View Scheme

tert-butyl [(2R)-1-hydroxy-3-methoxypropan-2-yl]carbamate → tert-butyl [(2R)-1-(benzylamino)-3-methoxy-1-oxopropan-2-yl]carbamate (880468-89-3)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: sodium chlorite; sodium hypochlorite; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical / acetonitrile / 6 h / 35 °C / pH 6.7 / aq. phosphate buffer 2.1: 4-methyl-morpholine; isobutyl chloroformate / tetrahydrofuran / -78 °C / Inert atmosphere 2.2: 1 h / -78 - 20 °C View Scheme
Multi-step reaction with 2 steps 1: sodium chlorite; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; sodium hypochlorite / acetonitrile; aq. phosphate buffer / 7 h / 35 °C / pH 6.7 2: 4-methyl-morpholine; isobutyl chloroformate / tetrahydrofuran / 1 h / -78 - 30 °C / Inert atmosphere View Scheme
Multi-step reaction with 2 steps 1.1: potassium dihydrogenphosphate; sodium chlorite; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; sodium hypochlorite / acetonitrile / 3 h / 20 °C 2.1: 4-methyl-morpholine / tetrahydrofuran / 0.08 h / -78 °C / Inert atmosphere 2.2: 1 h / -78 - 20 °C / Inert atmosphere View Scheme

(R)-N-tert-butoxycarbonyl serine (3262-72-4, 3850-40-6, 6368-20-3, 90582-28-8, 84311-18-2) + benzylamine (100-46-9) → tert-butyl [(2R)-1-(benzylamino)-3-methoxy-1-oxopropan-2-yl]carbamate (880468-89-3)

Conditions	Yield
Multi-step reaction with 2 steps 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: sodium hydroxide / tetra(n-butyl)ammonium hydrogensulfate / dichloromethane; water / 4 - 25 °C / Inert atmosphere View Scheme
Multi-step reaction with 2 steps 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: tetra(n-butyl)ammonium hydrogensulfate; sodium hydroxide / dichloromethane; water / 4 - 25 °C / Cooling with ice; Inert atmosphere View Scheme

(4R)-3-(tert-butyloxycarbonyl)-4-(methoxymethyl)-5-oxazolidinone → tert-butyl [(2R)-1-(benzylamino)-3-methoxy-1-oxopropan-2-yl]carbamate (880468-89-3)

Conditions	Yield
Multi-step reaction with 2 steps 1: triethylamine / tert-butyl methyl ether / 60 - 65 °C 2: tert-butyl methyl ether / 60 - 65 °C View Scheme

(R)-tert-butyl (1-(benzylamino)-3-methoxy-1-oxopropan-2-yl)-N-(hydroxymethyl)carbamate → tert-butyl [(2R)-1-(benzylamino)-3-methoxy-1-oxopropan-2-yl]carbamate (880468-89-3)

Conditions	Yield
In tert-butyl methyl ether at 60 - 65℃; Solvent; Temperature;	9 g

(R)-2-((tert-butoxycarbonyl)amino)-3-methoxypropionic acid (86123-95-7) → tert-butyl [(2R)-1-(benzylamino)-3-methoxy-1-oxopropan-2-yl]carbamate (880468-89-3)

Conditions	Yield
Multi-step reaction with 3 steps 1: toluene-4-sulfonic acid / toluene / 120 - 130 °C / Dean-Stark 2: triethylamine / tert-butyl methyl ether / 60 - 65 °C 3: tert-butyl methyl ether / 60 - 65 °C View Scheme
Multi-step reaction with 2 steps 1: 4-methyl-morpholine / dichloromethane / 1 h / 0 - 5 °C 2: dichloromethane / 0.5 h / 0 - 5 °C View Scheme

tert-butyl (R)-4-(methoxymethyl)-2,2-dimethyloxazolidine-3-carboxylate (721928-19-4) → tert-butyl [(2R)-1-(benzylamino)-3-methoxy-1-oxopropan-2-yl]carbamate (880468-89-3)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: p-toluenesulfonic acid monohydrate / methanol / 5 h / 20 °C 2.1: potassium dihydrogenphosphate; sodium chlorite; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; sodium hypochlorite / acetonitrile / 3 h / 20 °C 3.1: 4-methyl-morpholine / tetrahydrofuran / 0.08 h / -78 °C / Inert atmosphere 3.2: 1 h / -78 - 20 °C / Inert atmosphere View Scheme

4-hydroxymethyl-2,2-dimethyloxazolidine-3-carboxylic acid tert-butyl ester (108149-63-9) → tert-butyl [(2R)-1-(benzylamino)-3-methoxy-1-oxopropan-2-yl]carbamate (880468-89-3)

Conditions

Yield

Multi-step reaction with 4 steps 1.1: sodium hydride / tetrahydrofuran; mineral oil / 0.5 h / 20 °C 2.1: p-toluenesulfonic acid monohydrate / methanol / 5 h / 20 °C 3.1: potassium dihydrogenphosphate; sodium chlorite; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; sodium hypochlorite / acetonitrile / 3 h / 20 °C 4.1: 4-methyl-morpholine / tetrahydrofuran / 0.08 h / -78 °C / Inert atmosphere 4.2: 1 h / -78 - 20 °C / Inert atmosphere View Scheme

benzylamine (100-46-9) + (R)-2-((tert-butoxycarbonyl)amino)-3-methoxypropionic acid (86123-95-7) → tert-butyl [(2R)-1-(benzylamino)-3-methoxy-1-oxopropan-2-yl]carbamate (880468-89-3) + tert-butyl-N-[(1R)-2-(benzylamino)-1-(hydroxymethyl)-2-oxo-ethyl]carbamate (1253790-58-7) + benzylcarbamic acid isobutyl ester (69805-82-9) + C16H24N2O4 + C19H23N3O3 + C17H26N2O4

Conditions	Yield
Stage #1: (R)-2-((tert-butoxycarbonyl)amino)-3-methoxypropionic acid With 4-methyl-morpholine; isobutyl chloroformate In dichloromethane at -10 - 0℃; for 3.5h; Stage #2: benzylamine In dichloromethane at -10 - 15℃; for 2h; Overall yield = 150.3 g;	A n/a B n/a C n/a D n/a E n/a F n/a

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%

tert-butyl [(2R)-1-(benzylamino)-3-methoxy-1-oxopropan-2-yl]carbamate (880468-89-3) + trifluoroacetic acid (76-05-1) → (R)-2-amino-N-benzyl-3-methoxypropanamide trifluoroacetate

Conditions	Yield
In dichloromethane at 20℃; for 2h;	100%

tert-butyl [(2R)-1-(benzylamino)-3-methoxy-1-oxopropan-2-yl]carbamate (880468-89-3) → (R)-2-amino-N-benzyl-3-methoxypropionamide hydrochloride (1322062-76-9)

Conditions	Yield
With hydrogenchloride In methanol at 50℃; for 2h;
With hydrogenchloride In dichloromethane; water for 1h;	n/a

Upstream product

• 1253790-58-7 tert-butyl-N-[(1R)-2-(benzylamino)-1-(hydroxymethyl)-2-oxo-ethyl]carbamate 
• 420-37-1 trimethoxonium tetrafluoroborate 
• 100-46-9 benzylamine 
• 86123-95-7 (R)-2-((tert-butoxycarbonyl)amino)-3-methoxypropionic acid 
• 108149-63-9 4-hydroxymethyl-2,2-dimethyloxazolidine-3-carboxylic acid tert-butyl ester 
• 721928-19-4 tert-butyl (R)-4-(methoxymethyl)-2,2-dimethyloxazolidine-3-carboxylate 
• 3262-72-4 (R)-N-tert-butoxycarbonyl serine 
• 721927-59-9 tert-butyl [(2R)-1-hydroxy-3-methoxypropan-2-yl]carbamate 
• 24424-99-5 di-tert-butyl dicarbonate 
• 77-78-1 dimethyl sulfate 
• 80-48-8 methyl p-toluene sulfonate 

Downstream Products

• 196601-69-1 (R)-2-amino-N-benzyl-3-methoxypropanamide 
• 175481-36-4 lacosamide 
• 1322062-76-9 (R)-2-amino-N-benzyl-3-methoxypropionamide hydrochloride 

Relevant articles and documents

Preparation method of lacosamide

The invention provides a novel methylation method of a lacosamide synthesis intermediate, which comprises the following steps: methylating a compound I in a reaction solvent at a proper temperature byusing trimethyloxyonium tetrafluoroborate as a methylation reagent under alkaline condition to obtain a methylation product II. The reaction formula is shown in the specification. The method has theadvantages of mild reaction condition, simple post-treatment, green methylation reagent, no high toxicity and high reaction yield, and conforms to the safe and environment-friendly green chemical concept. The method is suitable for laboratory small-scale preparation and large-scale industrial production.

AN IMPROVED PROCESS FOR THE PREPARATION OF LACOSAMIDE

The present invention relates to an improved process for the synthesis of (R)- Lacosamide in which free base of O-methyl-N-benzyl-D-Serinamide is not isolated before acylation. The process avoids the use of column chromatography and chiral resolution for the preparation of different stages of Lacosamide.

A raco amide analogs of the separation method

The invention discloses a separation method of a lacosamide analogue. The separation method of the lacosamide analogue represented in formula I includes the steps of (a), subjecting a reaction mother solution of the lacosamide analogue to water scrubbing, acid pickling and water scrubbing; (b), steaming to remove an organic solvent by means of vacuum concentration to obtain oily matter; (c), subjecting the oily matter to normal-phase column chromatography or high-performance preparative liquid chromatography to obtain a compound in the formula I. A preparation method of the reaction mother solution of the lacosamide analogue includes the step of subjecting a compound in formula II and a methylation reagent to substitution reaction in a two-phase solvent of the organic solvent and water in the presence of alkali and a phase transfer catalyst so as to obtain the reaction mother solution. The lacosamide analogue represented in the formula I is a necessity for quality control of the lacosamide analogue. By the aid of the separation method, the lacosamide analogue can be separated out efficiently.