880468-89-3

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

• 100-46-9 benzylamine 
• 86123-95-7 (R)-2-((tert-butoxycarbonyl)amino)-3-methoxypropionic acid 
• 1253790-58-7 tert-butyl-N-[(1R)-2-(benzylamino)-1-(hydroxymethyl)-2-oxo-ethyl]carbamate 
• 420-37-1 trimethoxonium tetrafluoroborate 
• 80-48-8 methyl p-toluene sulfonate 
• 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 

Downstream Products

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

Relevant academic research and scientific papers

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.

Improved Synthesis and Impurity Identification of (R)-Lacosamide

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.

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 intermediate of methylation method (by machine translation)

The invention is mainly discloses a synthesis scheme in the process of synthesis of the methylation reaction method, the toxic and carcinogenic, cheap a methylating agent such as methyl benzene sulfonic acid methyl ester and the like as the alkylating agent, using inexpensive alkali such as potassium hydroxide to methylation reaction. The present invention can effectively avoid the generation of the N - methyl impurity, and the productive rate is high, will not produce the racemization, hydroxy has good selectivity, is more suitable for industrial production. (by machine translation)

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.

A raco amide analogs and its preparation method

The invention discloses a Lacosamide analogue and a preparation method thereof, and provides the Lacosamide analogue shown in a formula (I). The invention further provides the preparation method of the Lacosamide analogue shown in the formula (I), including: subjecting a compound shown in a formula (II) and methylated solution in two-phase solvent of organic solvent and water, and in the presence of alkali and phase transfer catalyst to substitution reaction for 20 to 100 hours, so as to obtain the compound shown in the formula (I). The Lacosamide analogue shown in the formula (I) is a necessity for quality control of Lacosamide; the preparation method can be used for efficiently synthesizing the analogue.

A raco amide analogs of the application

The invention discloses application of a lacosamide analogue to the end point control of a reaction for preparation of a compound as shown in the formula III from a compound as shown in the formula II while the lacosamide analogue serves as a standard substance. The lacosamide analogue is obtained through preparation and separation, and is a related impurity of a lacosamide finished product, wherein the impurity impacts the quality and the yield of a final lacosamide product greatly. Therefore, the lacosamide analogue has a far-reaching significance in application to intermediate quality control and lacosamide end point control.

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.

A rakow amide preparation method

A preparing process of lacosamide is disclosed. D-serine is adopted as an initial raw material. The method includes: performing amino protection, performing methylation, condensing with benzylamine under a condition of existence of a carboxyl activator, removing an amino protection group, and performing amidation to obtain the lacosamide. The total yield is higher than 66%. The method is high in yield, simple and convenient to operate, high in product purity and especially suitable for industrial production.

3-Azaspiro[5,5]undecan-2,4-dioxo-3-yl diphenyl phosphate (ASUD-diphenyl phosphate), a new reagent for the synthesis of the N-protected amino acid-ASUD ester

A new reagent, 3-azaspiro[5,5]undecan-2,4-dioxo-3-yl diphenyl phosphate (ASUD-diphenyl phosphate) is described for the synthesis of N-protected amino acid-ASUD esters which are active esters useful in the synthesis of peptides. This compound was synthesized by reacting N-hydroxy-3-azaspiro[5,5]undecane-2,4-dione (HO-ASUD) with diphenyl chlorophosphate in the presence of a base at room temperature and was obtained in high yields. The ASUD-diphenyl phosphate reagent reacts with N-protected amino acids under mild conditions to give the corresponding ASUD active esters, while preserving the enantiomeric purity of the amino acid. The new reagent is a stable crystalline compound and eliminates the need for DCC, a potent skin allergen, used previously for the synthesis of N-protected amino acid-ASUD ester.