Technical field
[0001]The present invention, N- benzyl-2-bromo-3-methoxy propionic acid amide, and a method of manufacturing the intermediates.
BACKGROUND
[0002]N- benzyl-2-bromo-3-methoxy propionic acid amide (hereinafter, sometimes referred to as "BMBA".) Is utilized as a synthetic intermediate useful lacosamide pharmaceutically antiepileptic agents, various production methods are known.
[0003]
　Patent Document 1, 2,3-dibromo the propionic acid alkyl or a derivative thereof as a starting material, is to synthesize 2-bromo-3-methoxy propionic acid as an intermediate. Furthermore, by using an alkyl chloroformate, after synthesizing the mixed acid anhydride from 2-bromo-3-methoxy-propionic acid The process of obtaining a BMBA reacted with benzylamine is disclosed.
[0004]
　However, in the method described in Patent Document 1, due to the use expensive 2,3-dibromo-propionic acid alkyl or a derivative thereof, and an alkyl chloroformate, it has been desired inexpensive manufacturing method by an industrial. Further, since the intermediate 2-bromo-3-methoxy propionic acid has a high solubility in water, in order to increase the recovery rate, after the reaction solution was concentrated, strongly acidic conditions, isobutyl acetate using Te, multiple from the aqueous phase, it is necessary to carry out an extraction operation, not satisfactory as an industrial production process from the viewpoint of production efficiency.
[0005]
　Patent Document 2, the acrylonitrile was induced to acrylamide in the presence of sulfuric acid, is reacted with benzyl alcohol, is to synthesize an intermediate N- benzyl acrylamide. The manufacturing method of inducing N- benzyl acrylamide to BMBA is disclosed.
[0006]
　However, in the method described in Patent Document 2, since it is necessary to use acrylonitrile as a raw material and a solvent, in the case of an industrial batch reaction process, the residence time of the acrylamide to acrylonitrile and generation becomes longer, intended the polymerization reaction is prone not, it is difficult to control the reaction heat due to polymerization reaction. Moreover, when distilling off the excess acrylonitrile by vacuum concentration, the oxygen-free state or under heating proceeds readily polymerization reaction, there is a possibility that clogging of the condenser due to the high viscosity polymerization reaction takes place. Therefore, it is desired safe production process by industrial. Furthermore, as calculated from the results of Example 1 of Patent Document 2, the yield 64% of N- benzyl-2,3-dibromo-propionic acid amide for benzyl alcohol, BMBA yield for benzyl alcohol stays in 62%. In addition, in the method described in Patent Document 2, for use in a large amount of concentrated sulfuric acid, the reactor of the higher material is required, since it is necessary to process a large amount of strongly acidic waste liquid, easy production process more environmentally it has been desired.
CITATION
Patent Document
[0007]
Patent Document 1: WO 2010/052011 Patent
Patent Document 2: International Publication No. WO 2012/069855
Summary of the Invention
Problems that the Invention is to Solve
[0008]
　The present invention has been made in view of these problems, an object of the N- benzyl-2-bromo-3-methoxy propionic acid amide, high yield, low cost and safe to manufacture, industrial It is to provide an excellent synthetic route to.
Means for Solving the Problems
[0009]
　The present inventors have made intensive studies, as a result, is reacted with diacrylate anhydride with benzylamine, N- Through the the step of obtaining benzyl acrylamide, in high yield, low cost and safe N- benzyl-2- It found that it is possible to produce a-bromo-3-methoxy-propionic acid amide, and completed the present invention.
[0010]
　That is, the present invention provides the following specific embodiments.
[1] a diacrylate anhydride and benzylamine are reacted in a solvent, amidation step to obtain the N- benzyl acrylamide; and N- benzyl acrylamide and bromine are reacted in a solvent, N- benzyl-2, bromination obtaining a 3-dibromo-propionic acid amide; a and the N- benzyl-2,3-dibromo-propionic acid amide and methanol in the presence of a base, is reacted, N- benzyl-2-bromo-3-methoxy-propionic method for producing N- benzyl-2-bromo-3-methoxy propionic acid amide characterized by having in this order; methoxylated to obtain the acid amide.
[0011]
[2] diacrylate anhydride subjected to the amidation step, characterized in that is obtained by reacting acrylic acid and a condensing agent in a solvent according to [1] N-benzyl-2 - method of manufacturing bromo-3-methoxy propionic acid amide.
[3] The solvent used in the amidation step, characterized in that a mixed solvent of an organic solvent and water, according to [1] or [2] N-benzyl-2-bromo-3-methoxy method for producing a propionic acid amide.
[4], characterized in that the presence of a base in the solvent to be used in the amidation step, [1] ~ N-benzyl-2-bromo-3-methoxy propionic according to any one of [3] method for producing an acid amide.
[0012]
[5] a diacrylate anhydride and benzylamine are reacted in a solvent, amidation step to obtain the N- benzyl acrylamide; and N- and benzyl acrylamide and bromine are reacted in a solvent, N- benzyl-2 , 3-dibromo-brominated to obtain a propionic acid amide; method for producing a characterized as having in this order N- benzyl-2,3-dibromo-propionic acid amide.
[0013]
[6] diacrylate anhydride subjected to the amidation step, characterized in that is obtained by reacting acrylic acid and a condensing agent in a solvent according to [5] N-benzyl-2 the method of 3-dibromo-propionic acid amide.
[7] The condensing agent, characterized in that a carbodiimide condensing agent, method for producing N- benzyl-2,3-dibromo-propionic acid amide according to [6].
[8] The solvent used in the amidation step, characterized in that a mixed solvent of an organic solvent and water, [5] according to any one of ~ [7] N-benzyl-2, method for producing a 3-dibromo-propionic acid amide.
[9], characterized in that the presence of a base in the solvent to be used in the amidation step, [5] - [8] in any one into according N- benzyl-2,3-dibromo-propionic acid amide the method of production.
[0014]
[10] a diacrylate anhydride and benzylamine are reacted in a solvent, amidation step to obtain N- benzyl acrylamide; characterized by having a method for producing a N- benzyl acrylamide.
[0015]
[11] diacrylate anhydride subjected to the amidation step, characterized in that is obtained by reacting acrylic acid and a condensing agent in a solvent, according to [10] N-benzyl acrylamide the method of production.
[12], wherein the condensing agent is a carbodiimide-based condensation agent, [11] The method for producing N- benzyl acrylamide described.
[13] The solvent used in the amidation step, characterized in that a mixed solvent of an organic solvent and water, [10] Production of N- benzyl acrylamide according to any one of - [12] Method.
[14] characterized in that said the presence of a base in the solvent to be used in the amidation step, [10] - [13] The method for producing a N- benzyl acrylamide according to any one of.
The solvent used in [15] the amidation step is a mixed solvent of hydrophobic organic solvent and water, characterized in that the presence of a base to the aqueous phase, any one of [10] to [14] method for producing N- benzyl-2-bromo-3-methoxy propionic acid amide according to claim.
The invention's effect
[0016]
　According to the present invention, N- benzyl-2-bromo-3-methoxy propionic acid amide in high yields, can be inexpensively and safely manufactured, it is industrially advantageous. As for the intermediates useful in the preparation of N- benzyl-2-bromo-3-methoxy propionic acid amide, high yield, it is possible to provide a process for producing inexpensively and safely.
DESCRIPTION OF THE INVENTION
[0017]
　It will be described in detail embodiments of the present invention. The following embodiments are illustrative of embodiments of the present invention, the present invention is not limited only to the embodiments. Further, the present invention can be carried out arbitrarily changed within a range not departing from the gist thereof. In the present specification, for example, reference numerical range of "1 to 100" is intended to encompass both the lower limit value "1" and the upper limit value "100". Further, notation other numerical ranges are also the same.
[0018]
[1. Manufacturing Method of N- benzyl-2-bromo-3-methoxy propionic acid amide
　preparation method of the BMBA of the present invention is shown in the synthesis scheme below. That, and a diacrylate anhydride with benzyl amine represented by the formula (2), the formula (3) represented by N- benzyl acrylamide (hereinafter, sometimes referred to as "NBA".) The obtained amidation step from the NBA and bromine, N- benzyl-2,3-dibromo-propionic acid amide represented by the formula (4) (hereinafter, sometimes referred to as "BBA".) brominated to obtain a, BBA and methanol and a base, N- benzyl-2-bromo-3-methoxy propionic acid amide represented by the formula (5) at least three steps (hereinafter sometimes. referred to as "BMBA") as a methoxy step it is intended to include in this order. Furthermore, the manufacturing method of BMBA of the present invention, prior to the amidation step, the acrylic acid and a condensing agent of formula (1), may have a condensation step of obtaining a diacrylate anhydride .
[0019]
[Formula 1]

[0020]

　First, a description will be given of the condensation step. Condensation step, the acrylic acid and a condensing agent are reacted in a solvent, to give compound diacrylate anhydride.
[0021]
(Raw material)
　acrylic acid used in the condensation step, it is possible to use acrylic acid commercially available. The purity of the acrylic acid is not particularly limited as long as it is industrially available, usually 90% or more, preferably 99% or more.
[0022]
　Condensing agent used in the condensation step is for causing dimerized by condensing acrylic acid, preferably dehydration condensation agent. As the condensing agent, a carbodiimide condensing agent, imidazole-based condensing agent, triazine condensing agent, phosphonium condensing agent, halonium condensing agent, uronium-based condensing agent, Harouroniumu condensation agents. Specific examples of the carbodiimide condensing agent, 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide, N, N'-dicyclohexylcarbodiimide, N, N'-diisopropylcarbodiimide and the like, preferably N , it is a N'- dicyclohexylcarbodiimide. Specific examples of imidazole-based condensing agent, N, N'-carbonyl diimidazole, 1,1'-carbonyl-di (1,2,4-triazole), N, N'-carbonyl diimidazole and the like. Specific examples of the triazine condensing agent, 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methyl morpholinium = chloride and the like. Specific examples of the phosphonium condensing agent, trifluoromethane sulfonic acid (4,6-dimethoxy-1,3,5-triazin-2-yl) - (2-octoxy-2-oxoethyl) dimethyl ammonium and the like. Specific examples of the halonium condensing agent, 1H-benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate, 1H-benzotriazol-1-yl oxytripyrrolidinophosphonium two ium hexafluorophosphate salt, (7-azabenzotriazole-1-yloxy) tripyrrolidinophosphonium hexafluorophosphate, chloro tripyrrolidinophosphonium two ium hexafluorophosphate, bromotris (dimethylamino) phosphonium hexafluorophosphate, 3- (diethoxyphosphoryloxy) -1,2,3-benzotriazine -4 (3H) - one, and the like. Specific examples of the uronium-based condensing agent, O- (benzotriazol-1-yl) -N, N, N ', N'- tetramethyl Hexafluorophosphate, O-(7- azabenzotriazole-1-yl) -N, N, N ', N'- tetramethyluronium hexafluorophosphate, O-(N-succinimidyl) - N, N, N ', N'- tetramethyluronium tetrafluoroborate, O- (N-succinimidyl) -N, N, N', N'- tetramethyluronium hexafluorophosphate, O- ( 3,4-dihydro-4-oxo-1,2,3-benzotriazine-3-yl) -N, N, N ', N'- tetramethyluronium tetrafluoroborate, S- (1-oxide - 2-pyridyl) -N, N, N ', N'- tetramethyl Chi uronium tetrafluoroborate, O-[2- oxo -1 (2H) - pyridyl] -N, N, N', N'- tetramethyluronium fluoride Borate salts, {{[(1-cyano-2-ethoxy-2-oxoethylidene) amino] oxy} -4-morpholino methylene} dimethylammonium hexafluorophosphate salts. Examples of Harouroniumu condensing agent, 2-chloro-1,3-dimethyl imidazolinium hexafluorophosphate, 1- (chloro-1-pyrrolidinylcarbonyl methylene) pyrrolidinium hexafluorophosphate, 2 - fluoro-1,3-dimethyl-imidazolinium hexafluorophosphate, fluoro -N, N, N ', N'- tetramethyl formamidinium hexafluorophosphate salts. Among these, carbodiimide condensing agent, imidazole-based condensing agent, the triazine condensing agent preferably carbodiimide condensing agent is more preferable. Condensing agent used in the condensation step, it is used singly, or two or more may be used in any combination and ratio.
[0023]
　The proportion of the amount of acrylic acid and a condensation agent, condensing agent relative to 1 mol of acrylic acid, usually 0.3 mole or more, preferably 0.4 mol or more, more preferably 0.45 mol or more, and usually 1 mol or less, preferably 0.8 mol or less, more preferably 0.6 mol or less. When the amount of the condensing agent is too small, the reaction does not satisfactorily performed, while when too much, the more the residual amount of the condensing agent unreacted, the reaction solution obtained after completion of the reaction in the condensation step in the case of using a directly amidation step, the reaction liquid and the benzylamine may not mix well, may influence the reaction.
[0024]
　In the condensation step, typically using a solvent. As the solvent used in the condensation step can be dissolved or dispersed acrylic acid and a condensing agent, the reaction of these raw materials are not particularly limited as long as the progress, it is possible to use a hydrophobic or hydrophilic organic solvents. These organic solvents, such as toluene, xylene and like aromatic hydrocarbons; n- hexane, aliphatic hydrocarbons such as n- heptane: ethyl acetate, esters such as isopropyl acetate; methyl -t- butyl ether, methyl cyclopentyl ether, tetrahydrofuran, ethers such as 2-methyltetrahydrofuran; and the like; dimethylformamide; dimethyl sulfoxide, acetone, methyl ethyl ketone and methyl isobutyl ketone. Among these, aromatic hydrocarbons are hydrophobic organic solvents, preferably aliphatic hydrocarbons, from the viewpoint of cost and productivity, toluene, n- hexane, more preferably n- heptane, more preferably toluene.
[0025]
　The amount of the solvent used, with respect to 1g of acrylic acid, usually 1mL above lower limit, preferably 2mL, more preferably at least 3 mL, and usually 20mL or less but preferably not 15mL or less, more preferably it is less than or equal to 10mL.
[0026]
(Reaction Conditions)
　The reaction temperature of the condensation step is usually -30 ° C. or higher as the lower limit is preferably -10 ° C. or higher, more preferably -5 ° C. or higher, and usually 30 ° C. is the upper limit, preferably 10 ° C. or less, more preferably 5 ° C. or less.
　If the reaction temperature is too low, there are cases where the reaction does not proceed sufficiently, while when the reaction temperature is too high, the product may decompose.
[0027]
　The pressure during the reaction is atmospheric pressure or can be carried out under pressure, usually, may be a normal pressure.
　The reaction time is not particularly can be set appropriately limited, it is usually 0.5 hour to 24 hours.
[0028]
　In the condensation step, the supply order of the acrylic acid and the condensing agent is not particularly limited as long as the generated diacrylate anhydrides, for example, charged with either one component of the acrylic acid and the condensing agent together with the solvent in the reactor in this as sock liquid at the reaction conditions, it can be carried out by supplying the other component. Above all, it was charged a mixture of the condensing agent and solvent the sock liquid into the reactor, it is preferred to supply the acrylic acid while controlling the internal temperature contrast.
[0029]
　When supplying the acrylic acid in the reaction system, it may supply a mixture of acrylic acid and a solvent may be supplied alone acrylate, may be supplied by a combination of these methods. Similarly, when supplying the condensing agent to the reaction system, may supply a mixture of condensing agent and solvent, may be supplied with a condensing agent alone, it is supplied by a combination of these methods good. Solvent when mixing the acrylic acid or a condensing agent and solvent may be the same as the solvent used in the condensation process.
[0030]
　In the condensation step, since exothermic during the reaction, it is preferable to carry out the reaction while controlling the internal temperature. Therefore, the condensation step may, for example, it is preferable to use a reactor having a temperature controlling jacket, etc. that can be stirred tank and heating and cooling.
[0031]
　Condensation step is preferably carried out in an inert gas atmosphere. The inert gas is not particularly limited, nitrogen, argon, helium and the like. Among these, nitrogen is preferred.
[0032]
　As described above, by condensation reacting the acrylic acid with a condensing agent, it is possible to obtain a reaction liquid containing a diacrylate anhydride. Diacrylate anhydride obtained by the condensation step can be used in the amidation step. Further, after the reaction by condensation step, the reaction solution containing the diacrylate anhydride can be used in the amidation step. At this time, the reaction solution, because it may contain by-products derived from the condensation agent to be generated during the reaction, may be suitably removed by-product separated and solid-liquid separation. For example, in the case of using N, a N'- dicyclohexylcarbodiimide as a condensing agent, because the dicyclohexylurea precipitated as a by-product, it is preferable to this by-product to solid-liquid separation. At this time, for a 5 ° C. or less temperature in the solid-liquid separation, the separation of the by-product precipitated preferred. Incidentally, washing the by-product was separated, may be recovered diacrylate anhydride adhering. Although the solvent used for washing is not particularly limited, and may be a solvent used in the above-mentioned condensation step. Diacrylate anhydride contained in the reaction liquid after the solid-liquid separation of by-products, extraction, concentration, distillation, by a known means such as chromatography, can be isolated and purified.
[0033]

　Next, a description will be given amidation step. Amidation step diacrylate anhydride and benzylamine are reacted in a solvent, to give compound NBA.
[0034]
(Raw material)
　diacrylate anhydride used in the amidation step may be directly used the reaction solution obtained in the condensation step, the reaction liquid after the solid-liquid separation with respect to the reaction solution obtained in the condensation step may be used, may be used diacrylate anhydride isolated from the reaction solution obtained in the condensation step may be a commercially available diacrylate anhydride. Among them, it is preferable to use a reaction solution obtained in the condensation step, it is more preferable to use a reaction liquid after the solid-liquid separation on the reaction liquid obtained in the condensation step.
[0035]
　The amount of benzylamine, to the diacrylate anhydride 1 mol, the lower limit is usually 0.2 mole or more, preferably 0.5 mol or more, more preferably 0.7 mol or more, particularly preferably 0. 9 is a mole or more, and the upper limit is usually 3 moles or less, preferably 1.5 mol or less, more preferably 1.3 mol or less, particularly preferably 1.1 mol or less.
　When the amount of benzylamine is too small, a yield may be decreased, while when too large, there is a by-product is produced.
[0036]
　The amidation step, typically using a solvent. As the solvent used in the amidation step, can dissolve or disperse the diacrylate anhydride and benzylamine, the reaction of these raw materials are not particularly limited as long as the progression, usually an organic solvent may be used. The organic solvent may be either hydrophobic organic solvent and hydrophilic organic solvent, particularly preferably contains a hydrophobic organic solvent.
[0037]
　Examples of the hydrophobic organic solvent, such as toluene, xylene and like aromatic hydrocarbons; n- hexane, aliphatic hydrocarbons such as n- heptane: ethyl acetate, etc. esters such as isopropyl acetate and the like. Among these, from the viewpoint of cost and productivity, toluene, n- hexane, n- heptane are preferred, more preferably toluene.
[0038]
　The hydrophilic organic solvent, such as methanol, ethanol, alcohols such as isopropyl alcohol, butanol; dimethyl ether, diethyl ether, diisopropyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, tetrahydropyran, ether and 1,4-dioxane; acetone , ketones such as methyl ethyl ketone; and dimethyl sulfoxide and the like; dimethylformamide. Among them, ethers are preferable, and tetrahydrofuran, 2-methyltetrahydrofuran, tetrahydropyran, 1,4-dioxane is more preferable.
[0039]
　In the present invention, as a solvent for the amidation step it can be used in combination with water and an organic solvent. That is, in the amidation step, as the solvent, the organic solvent and water, it is particularly preferable to use a mixed solvent of a hydrophobic organic solvent and water. In this case, the carrying out the amidation step in a two-phase system of an organic solvent phase and an aqueous phase. By performing the amidation step in a two-phase system, it is possible to suppress the amount of benzylamine, can reduce the production cost. Further, by removing the aqueous phase of acrylic acid by-product in the amidation step from the organic solvent phase, to improve the reactivity of benzylamine, it is possible to increase the NBA yield.
[0040]
　When performing amidation step in a two-phase system, the proportion of water to organic solvent is an organic solvent, the lower limit is usually 0.1 times by mass or more, preferably 0.2 times by mass or more, more preferably and 0.3 mass times, the upper limit, usually 1 mass times or less, preferably 0.9 times by mass or less, more preferably 0.8 times by mass or less.
[0041]
　The amount of the solvent to be used, relative diacrylate anhydride 1g, the lower limit is usually 1mL or more, preferably 2mL, more preferably at least 3 mL, The upper limit, normally less than 25 mL, preferably not more than 20mL , more preferably not more than 15 mL.
[0042]
　Amidation step is carried out in the presence of a base is preferable from the viewpoint of enhancing the reactivity. That is, it is preferable to present the base in the solvent. Among them, the solvent is a mixed solvent of an organic solvent and water, it is preferable to present the base in the solvent. In particular, the solvent is a mixed solvent of hydrophobic organic solvent and water, it is preferable to present the base in the aqueous phase. This example, solvent can be a mixed solvent of an aqueous solution containing an organic solvent and a base comprising a hydrophobic organic solvent is carried out by reacting in a two-phase system of an organic solvent phase and an aqueous phase. In this case, the by-produced acrylic acid with removal in the aqueous phase from the organic solvent phase in the amidation step, the acrylic acid contained in the aqueous phase by neutralization with a base, to improve the reactivity of benzylamine, it is possible to further increase the NBA yield.
[0043]
　As the base, although it is possible to use at least one compound selected from the group consisting of inorganic bases and organic bases, usually, an inorganic base is generally used. The inorganic base is not particularly limited, for example, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; sodium carbonate, alkali metal carbonates such as potassium carbonate; sodium hydrogen carbonate, an alkali metal such as potassium hydrogen carbonate hydrogen carbonates; sodium acetate, alkali metal acetates such as potassium acetate, inorganic bases based compounds and the like. The organic base is not particularly limited, for example, pyrrolidine, pyrrole, piperidine, heterocyclic amines such as pyridine; dimethylamine, trimethylamine, diethylamine, an organic amine such as triethylamine, an organic salt-based compounds and the like. Among these, preferably sodium hydroxide, sodium carbonate, potassium hydroxide, potassium carbonate, an inorganic base as sodium hydrogen carbonate, more preferably sodium hydroxide, potassium carbonate, sodium hydrogen carbonate. Base used in the amidation step can be used singly, or two or more may be used in any combination and ratio.
[0044]
　The base is present in the solvent, but to neutralize the acrylic acid to be produced, since the base strength is too strong material diacrylate anhydride may decompose, typically, it is preferable to use a weak base. However, when the reaction is carried out in a two-phase system using a mixed solvent of a hydrophobic organic solvent and water as a solvent, good results can be obtained by using a strong base.
　The pH of the aqueous phase in the reaction mixture, the lower limit is usually 7.2 or more, in particular, in the case of using a weak base is usually 7.2 or more, preferably 7.5 or more, more preferably 8 or more, and the upper limit, usually 11 or less, preferably 10.5 or less, more preferably 10 or less. In the case of using a strong base, typically 11 or more, preferably 11.5 or more, more preferably 12 or more. In the case of using only the hydrophobic organic solvent as the solvent is a hydrophobic organic solvent is mixed with 10 times by mass of water, pH of the separated aqueous phase is preferably in the range above.
[0045]
　The amount of the base, slightly different depending on the kind of the base to be used, relative diacrylate anhydride 1 mol, the lower limit is usually 0.5 mol or more, preferably 0.7 mol or more, more preferably 0. and at 9 mol or more, and the upper limit is usually 3 moles or less, preferably 2 mol or less, more preferably 1.2 mol or less. By the amount used is within these ranges, it is possible to suppress the generation of decomposition products.
[0046]
(Reaction Conditions)
　The reaction temperature of the amidation step is not particularly limited as long as the reaction proceeds, the lower limit is usually 0 ℃ or higher, preferably 10 ° C. or higher, more preferably 20 ° C. or higher, the upper limit is generally 50 ° C. or less, preferably 40 ° C. or less, more preferably 30 ° C. or less.
　If the reaction temperature is too low, there are cases where the reaction does not proceed sufficiently, while when the reaction temperature is too high, the decomposition of the product occurs. The temperature of the reaction mixture in the reaction is preferably kept constant.
[0047]
　The pressure during the reaction is atmospheric pressure or can be carried out under pressure, usually, may be a normal pressure.
　The reaction time is not particularly can be set appropriately limited, it is usually 0.5 hour to 24 hours.
[0048]
　In the amidation step, the supply order of the diacrylate anhydride and benzylamine are not particularly limited, for example, it is charged either one component of the diacrylate anhydride and benzylamine with the solvent in the reactor insole as a liquid at the reaction conditions, it can be carried out by supplying the other component. Among them, a mixture of benzylamine and the solvent in the reactor, it was stirred with an aqueous solution containing a base and laying fluid, it is preferred to supply the diacrylate anhydride thereto. Accordingly, to suppress the decomposition of the diacrylate anhydride, it is possible to increase the NBA yield. It is more preferable to supply the diacrylate anhydride while controlling the internal temperature of the sock liquid.
[0049]
　When supplying the diacrylate anhydride to the reaction system, may supply a mixture of diacrylate anhydride as a solvent, it may be supplied with diacrylate anhydride alone, supplied by a combination of these methods it may be. Similarly, when supplying benzylamine reaction system may supply a mixture of benzylamine and solvent may be supplied with benzylamine alone, be supplied by a combination of these methods good. Solvent when diacrylate anhydride acid or benzylamine are mixed with a solvent may be used those similar to the solvents used in the amidation step, it is preferable to use a hydrophobic organic solvent.
[0050]
　In the amidation step, the base may be supplied a mixture with a solvent, a base alone may be supplied, may be supplied by a combination of these methods. Among them, it is preferred to supply the aqueous solution of a mixture of base and water. Base case of supplying a mixture with water, for example, can be used an aqueous solution prepared by adjusting the concentration of base to 5 mass% to 20 mass%. Solvent in the case of a mixed solvent of an organic solvent and water can be present base in water. At this time, the reaction is preferably performed under stirring conditions.
[0051]
　Amidation step is preferably carried out in an inert gas atmosphere. The inert gas is not particularly limited, nitrogen, argon, helium and the like. Among these, nitrogen is preferred.
[0052]
　NBA obtained by amidation step can be used in the bromination step. After reaction with the amidation step, typically, it can be used as a reaction solution containing the NBA bromination step. Alternatively, the NBA from the reaction solution is isolated, the NBA isolated may be used in the bromination step. From the industrial production standpoint, it is preferable to use as a reaction solution obtained by the amidation step to brominated process.
[0053]
　The amidation step with a single-phase system of an organic solvent phase only, and when the reaction was carried out in the absence of a base may be used as the reaction solution bromination step. In the organic solvent phase only a single phase system, and when the reaction was performed in the presence of a base, after completion of the reaction, for example, the residual base by washing with an acidic aqueous solution such as hydrochloric acid to neutralize, separatory operation the aqueous phase except the organic solvent phase can be used for the bromination step. When the reaction was carried out in a two-phase system of an organic solvent phase and the aqueous phase, after completion of the reaction, the aqueous phase removed by liquid separation operation, the organic solvent phase can be used for the bromination step. NBA contained in the organic solvent phase, extraction, concentration, distillation, crystallization, by a known means such as column chromatography, can be isolated and purified. For example, the reaction liquid after completion of the reaction the organic solvent was distilled off and concentrated under reduced pressure and vacuum drying, can be obtained NBA.
[0054]

　Subsequently, a description will be given of brominated process. Bromination step, the NBA and bromine are reacted in a solvent, to give compound BBA.
[0055]
(Raw material)
　NBA used in the bromination step may be directly used and the reaction liquid obtained in the amidation step, may be used NBA isolated from the reaction solution obtained in the amidation step, commercially available it may be used in the NBA. Among them, from the industrial production viewpoint, it is preferable to use the reaction solution obtained in the amidation step. Also, if the amidation step reaction was performed in the two-phase system of an organic solvent phase and an aqueous phase, it is preferable to use an organic solvent phase, excluding the aqueous phase.
[0056]
　The amount of bromine, relative to NBA1 mol, the lower limit is usually 0.3 mole or more, preferably 0.5 mol or more, more preferably 0.7 mol or more, and the upper limit is usually 3 mol or less, preferably 2 mol or less, more preferably 1.5 mol or less.
[0057]
　The bromination process typically using a solvent. As the solvent used in the bromination step, can dissolve or disperse the NBA and bromine, the reaction of these raw materials it is not particularly limited as long as the progress, it is possible to use the same organic solvent and the condensation step. It may also be used in the reaction a mixture of organic solvent and water.
[0058]
　The amount of the solvent used for NBA1g, the lower limit is usually 1mL or more, preferably 3mL, more preferably at least 5 mL, The upper limit, normally less than 25 mL, preferably 20mL or less, more preferably 15mL is less than or equal to.
[0059]
　Bromination reaction is preferably carried out under acidic conditions. As a result, it is possible to suppress the decomposition of the NBA. The pH of the reaction system during the bromination reaction, the lower limit is usually pH2 or more, preferably pH3 or more, and the upper limit, usually less than pH 7, preferably pH6 less. Adjustment of pH is not particularly limited, for example acetic acid, hydrochloric acid, can be carried out by mixing an acid such as sulfuric acid.
[0060]
(Reaction Conditions)
　The reaction temperature of the bromination step, the lower limit is usually 0 ℃ or higher, preferably 10 ° C. or higher, more preferably 20 ° C. or higher, and the upper limit, usually 50 ° C. or less, preferably 40 ° C. or less, more preferably 30 ° C. or less.
[0061]
　The pressure during the reaction is atmospheric pressure or can be carried out under pressure, usually, may be a normal pressure.
　The reaction time is not particularly can be set appropriately limited, it is usually 0.5 hour to 24 hours.
[0062]
　The reaction of bromination step, the mixture containing the NBA and the solvent and laying fluid, is preferably performed by supplying bromine contrast. When supplying bromine to the reaction system, it may supply a mixture of bromine and a solvent, may be supplied with bromine alone, may be supplied by a combination of these methods.
[0063]
　In the bromination step, acid provides the acid may be fed an aqueous solution mixed with water, may be supplied in acid alone, but may be supplied by a combination of these methods, typically as an aqueous solution . Thus, bromination step, the reaction of bromination may be performed in a two-phase system of an organic solvent phase and an aqueous phase. At this time, the reaction is preferably performed under stirring conditions.
[0064]
　After completion of the reaction, usually with a dehalogenating agent, it is preferable to carry out the dehalogenation process to inactivate unreacted bromine.
　The dehalogenating agent is not particularly limited, sodium sulfite, sodium bisulfite, potassium sulfite, ammonium sulfite, sulfite salts such as iron sulfite; sodium thiosulfate, potassium thiosulfate, calcium thiosulfate, thiosulfate salts such as ammonium thiosulfate , and the like. Among these, preferably sulfite, among others sodium sulfite.
[0065]
　The amount of the dehalogenating agent to be brominated to 1 mole used, the lower limit is usually 0.1 mol or more, preferably 0.3 mol or more, and the upper limit is usually 1 mol or less, preferably is 0.7 mol or less.
　When the amount of dehalogenation agent is too large, the liquid resistance becomes strongly basic, which may by-products increase.
[0066]
　As the method of supplying to the reaction system of dehalogenation agent may be supplied alone or is also supplied to those premixed with water, typically using an aqueous solution. Dehalogenating agent is typically supplied after bromine and NBA were reacted.
[0067]
　Incidentally, dehalogenation treatment is preferably performed under acidic conditions. As a result, it is possible to suppress the decomposition of the BBA. The pH of the reaction system when performing dehalogenation process, the lower limit is usually pH2 or more, preferably pH3 or higher, and the upper limit, usually less than pH 7, preferably pH6 less. Adjustment of pH is not particularly limited, for example acetic acid, hydrochloric acid, can be carried out by mixing an acid such as sulfuric acid. Acid, and supply order of dehalogenating agent is not particularly limited, may supply dehalogenating agent after the supply of the acid, the acid after the supply of the dehalogenating agent may be supplied, but dehalogenation after the supply of the acid it is preferable to supply the agent.
[0068]
　When reacted in a two-phase system of an organic solvent phase and the aqueous phase, after completion of the reaction, except the aqueous phase by a liquid separation operation. The BBA contained in the organic solvent phase, extraction, concentration, distillation, crystallization, by a known means such as column chromatography, can be isolated and purified. For example, crystals precipitating by cooling the reaction system after the completion of the reaction, precipitated crystals to solid-liquid separation, and further washing with toluene and vacuum dried to obtain a BBA.
[0069]

　further subsequently described methoxy step. Methoxylation step, the BBA and methanol are reacted in the presence of a base, to give compound BMBA.
[0070]
(Raw material)
　BBA used in methoxylation step can be used BBA obtained in bromination step.
[0071]
　Examples of the base used in methoxylation step is not particularly limited, lithium hydroxide, sodium hydroxide, alkali metal hydroxides, sodium carbonate or potassium hydroxide, alkali metal carbonates, sodium hydrogen carbonate and potassium carbonate, and lithium methoxide, sodium methoxide, alkali metal methoxide or potassium methoxide, and the like; alkali metal hydrogen carbonates such as potassium hydrogen carbonate, sodium acetate, an inorganic base compounds such as alkali metal acetates such as potassium acetate . Among these, preferably sodium hydroxide, sodium carbonate, potassium hydroxide, potassium carbonate, more preferably sodium hydroxide.
[0072]
　The amount of the base used for BBA1 mol, the lower limit is usually 1 mole or more, preferably 2 moles or more, and the upper limit is usually 10 moles or less, preferably 5 mol or less.
[0073]
　Methoxy step, when using an inorganic salt-based compound as the base, the reaction is carried out in methanol. When using an alkali metal methoxide as the base, usually the reaction is carried out in methanol, as long as the reaction of methoxylated progresses, may be further used other solvents. As the solvent, for example, ethanol, propanol, isopropyl alcohol, alcohols such as tert- butyl alcohol; ethers such as tetrahydrofuran: toluene, xylene, ethylbenzene and the like; chlorobenzene, aromatic halogen-containing hydrocarbons of dichlorobenzene hydrogen; n- hexane, aliphatic hydrocarbons such as n- heptane, and the like.
[0074]
　The amount of methanol, relative to BBA1g, the lower limit is usually 1mL or more, preferably 1.5mL, more preferably at least 2 mL, The upper limit, normally less than 20 mL, preferably 15mL or less, more it is preferably at most 10 mL.
[0075]
(Reaction Conditions)
　The reaction temperature of methoxylation step, the lower limit is usually -20 ° C. or higher, preferably -10 ° C. or higher, more preferably 0 ℃ or higher, and the upper limit, usually 80 ° C. or less, preferably is 70 ° C. or less, more preferably 50 ° C. or less.
　The pressure during the reaction is atmospheric pressure or can be carried out under pressure, usually, may be a normal pressure.
　The reaction time is not particularly can be suitably set limit, 0.1 hours to 100 hr, preferably 0.2 hr to 80 hours, more preferably from 0.3 to 24 hours.
[0076]
　BBA, bases, and supply order of methanol is not particularly limited as long as BMBA generated, for example, any of one of the components of the BBA and base as laying solution which was charged with methanol into the reactor, the reaction conditions can be carried out by at below, it supplies the other components. Above all, it was charged a mixture of the BBA and methanol into a reactor and laying fluid, it is preferable to supply a base while controlling the internal temperature contrast.
[0077]
　When supplying the BBA is the reaction system, it may supply a mixture of BBA and methanol, may be supplied by BBA alone, may be supplied by a combination of these methods. Similarly, when supplying base to the reaction system, a base may be supplied a mixture with methanol, a base alone may be supplied, may be supplied by a combination of these methods.
[0078]
　BBA may be supplied in bulk, it may be supplied by a plurality of times. Further, the base may be supplied collectively, may be supplied a plurality of times.
[0079]
　Methoxy step is preferably carried out in an inert gas atmosphere. The inert gas is not particularly limited, nitrogen, argon, helium and the like. Among these, nitrogen is preferred.
[0080]
　After completion of the reaction, the BMBA contained in the reaction solution, extraction, concentration, distillation, crystallization, by a known means such as column chromatography, can be isolated and purified. For example, the methanol is supplied distilled off under reduced pressure or water after the reaction, to precipitate crystals by cooling the reaction system, and the precipitated crystals to solid-liquid separation, further washed with water and dried in vacuo Accordingly, it is possible to obtain the BMBA.
[0081]
　As described above, BMBA manufacturing method of the present invention includes amidation step, bromination process, and methoxy step, it is possible to obtain a BMBA utilized as synthetic intermediates of lacosamide. In this manufacturing method, by passing through the amidation step to obtain the NBA by reacting a diacrylate anhydride and benzylamine, when synthesizing the NBA with acrylonitrile and benzyl alcohol (e.g., Patent Document 2) as compared with , it can be obtained BBA and BMBA in high yield. Further, in this manufacturing method, it is possible to use acrylic acid widely distributed in the market as a starting material, and since it is no use of large quantities of concentrated sulfuric acid, there is no need of the processing of strongly acidic waste liquid, excellent production efficiency there is provided a manufacturing method of environmental load and excellent low industrial with.
[0082]
[2. N- benzyl-2,3-dibromo-propionic acid amide of the production method]
　Production method of BBA of the present invention contains the above-mentioned amidation process, and brominated steps at least. Furthermore, the manufacturing method of the BBA of the present invention, prior to the amidation step may be one having the above-described condensation process.
[0083]
　According to the production method of the present invention, similarly to the manufacturing method of BMBA described above, the BBA, high yield can be produced inexpensively and safely. Also, BBA may be utilized as synthetic intermediates of BMBA, and lacosamide. Using the BBA obtained by the present manufacturing method, for example, by going through the subsequent methoxy step, it is possible to obtain a BMBA.
[0084]
[3. Manufacturing Method of N- benzyl acrylamide
　NBA production method of the present invention contains at least the above-described amidation step. Furthermore, NBA production method of the present invention, prior to the amidation step may be one having the above-described condensation process.
[0085]
　According to this manufacturing method, for obtaining a NBA by reacting a diacrylate anhydride and benzylamine, to acrylonitrile as a starting material (e.g., Patent Document 2) polymerization reaction due to occur, the polymerization reaction and the polymerization reaction by suppressing the generation of heat, in high yield NBA, it can be produced safely. Also, NBA may utilize BBA, BMBA, and as a synthetic intermediate for lacosamide. Using NBA obtained by the present manufacturing method, for example, by going through the subsequent bromination step, and methoxy step, it is possible to obtain a BMBA.
Example
[0086]
[(Manufacturing method of the BBA) Example 1]

[Formula 2]

　a nitrogen gas supply pipe, a thermometer, a 100mL reactor equipped with a stirrer, under nitrogen atmosphere, as a condensing agent N, N'-dicyclohexylcarbodiimide (hereinafter, sometimes referred to as "DCC".) (20.5 g, 0.10 mol), toluene as solvent (64.8 g, 75 mL) was supplied and the reaction solution at 500rpm for while stirring, the internal temperature was cooled so that the temperature range of -5 ℃ ~ 5 ℃. After cooling, stirring a toluene solution of DCC, as a raw material of acrylic acid (15.1 g, 0.21 mol) was added dropwise while controlling the internal temperature within said temperature range. After completion of the dropwise addition, further reaction was stirred for 30 minutes at an internal temperature of 0 ℃, the reaction was run.
　After stirring, the white solid precipitated dicyclohexylurea was filtered off by suction filtration, the dicyclohexylurea and washed with toluene (25.9 g, 30 mL), to obtain a cleaning solution. Then, the combined filtrate and washings to one, to obtain a toluene solution of diacrylate anhydride.
[0087]

[Formula 3]

　a nitrogen gas supply pipe, a thermometer, a 500mL reactor fitted with a stirrer, under nitrogen atmosphere, as a raw material benzyl amine (11.7 g, 0.11 mol), toluene as the solvent (25.9 g, 30 mL), 9% aqueous sodium hydroxide as base (87.9 g, 0.20 mol) was supplied, while stirring the reaction solution at 300 rpm, and cooled the inner temperature to be 0 ℃ . Dropping After cooling, the reaction solution as a sock liquid, under stirring, so that the internal temperature of the toluene solution of diacrylate anhydride obtained in step 1 does not exceed 5 ° C., while controlling the temperature range of 0 ~ 5 ° C. did. After completion of the dropwise addition, the temperature was raised to the jacket temperature at 25 ° C., and stirred for 30 minutes.
　After the stirring, the reaction solution was allowed to stand for 5 minutes, the aqueous phase was removed by liquid separation operation to obtain a NBA toluene solution.
[0088]

[Formula 4]

　Water (7.5 g) was fed to the resulting NBA toluene solution in Step 2, so that the pH of the aqueous phase is 3 by addition of 2 mol / L hydrochloric acid It was adjusted to. After pH adjustment, with agitation at 300 rpm, bromine (17.9 g, 0.11 mol) was added dropwise over 30 minutes. After completion of the dropwise addition, stirring for 2 hours further at an inner temperature of 25 ° C., the reaction was carried out.
　After the stirring, 15% aqueous sodium sulfite solution to the reaction mixture as a dehalogenating agent (95.5 g, 0.11 mol) was supplied, adjusted 2 mol / L hydrochloric acid was added as the acid as the pH of the aqueous phase is 4 did. After pH adjustment, the internal temperature of the reaction mixture was heated to 65 ° C., the reaction was allowed to stand for 2 minutes to remove the aqueous phase by a liquid separation operation.
　After removing the aqueous phase, with stirring toluene solution of BBA at 300 rpm, the jacket temperature of the reactor was cooled to 52 ° C., was confirmed deposition of crystals. After crystal precipitation was cooled to an internal temperature of 0 ° C., and stirred for further 2 hours a slurry of BBA at 0 ° C.. After completion of the stirring, the precipitated solid was filtered off with suction filtration, filtered off solid was washed with toluene 13.0 g, to obtain wet crystals of BBA. By the obtained wet crystals are dried under reduced pressure at an external temperature of 45 ° C., to obtain a BBA as a white solid (23.4 g, 67% yield based on benzyl amine). Results of NMR measurement of BBA shown below, and from the results of melting point measurement, product it was confirmed that the BBA. In the examples herein, NMR measurements were made with a Bruker Co. AV400N.
　 1 H-NMR (400 MHz, CDCl 3 )
δ；３．８６（１Ｈ，ｄｄ，Ｊ＝４．４Ｈｚ，５．８Ｈｚ），４．０１（１Ｈ，ｄｄ，Ｊ＝２．０Ｈｚ，８．３Ｈｚ），４．４８－４．５３（３Ｈ，ｍ），６．４０（１Ｈ，ｂｒ），７．３０－７．３６（５Ｈ，ｍ）
　融点：１２０℃
[0089]
Example 2 (method for producing BMBA)]
[Chemical Formula 5]

　a nitrogen gas supply pipe, a thermometer, a 100mL reactor equipped with a stirrer, under nitrogen atmosphere, BBA obtained in Example 1 (22.0 g, 0 and .069 mol), was supplied methanol (66.1 g, 83 mL), with stirring at 400 rpm, and cooled the inner temperature to be 20 ° C.. After cooling, powdery sodium hydroxide as base (5.50 g, 0.138 mol), the internal temperature was fed divided into six to not exceed 30 ° C.. After feeding, stirring for 30 minutes at an internal temperature of 20 ° C., the reaction was carried out. After the stirring, water was added dropwise (66.0 g), was confirmed the precipitation of crystals. After crystal precipitation was cooled external temperature to -2 ° C.. After cooling and stirred for 1.5 hours at an internal temperature of 0 ℃ further.
　After completion of the stirring, the precipitated solid is suction filtered, the resulting crystals were washed with water (22.0 g). After washing, the resulting solid was dried under reduced pressure at 45 ° C. to give BMBA as a white solid (18.0 g, 96% yield based on BBA, chemical purity 97.6 area%) was. Measurements of chemical purity (area%), using the Agilent Technologies Co. Agilent 1290, was carried out by HPLC under the following conditions.
　Column: Cadenza CD-C18 (150mm × 4.6mm, 3μm)
　Mobile phase A: 0.1% TFA aqueous solution
　mobile phase B: Acetonitrile
　Gradient B solution concentration: (15% / 0 min) → (50% / 15 min ) → (50% / 20 min)
　flow rate: 1 mL / min
　injection volume: 5 [mu] L
　detection wavelength: 215 nm
　Column temperature: 40 ° C.
　Analysis time: 20 min
[0090]
　Results of NMR measurement of BMBA shown below, and from the results of melting point measurement, product was confirmed to be BMBA.
　 1 H-NMR (400 MHz, CDCl 3 )
[delta]; 3.43 (3H, s), 3.90 (2H, ddd, J = 14.4 Hz, 5.9 Hz, 4.8 Hz), 4.44 (IH, t, J = 4.8Hz), 4.48 (2H, d, J = 5.6Hz), 6.87 (1H, br), 7.26-7.32 (5H, m)
　mp: 79 ° C.
[0091]
[Example 3 (production method of NBA)]
　in Step 1 of Example 1, the amount of each component, the DCC 7.16 g (0.035 mol), 41.5 g of toluene, acrylic acid 5.04g change in (0.070 mol), and change the benzylamine 3.75 g (0.035 mol) in step 2, change the 9% aqueous solution of sodium hydroxide to sodium bicarbonate 3.00 g (0.036 mol) except that the using the same method to give the NBA a toluene solution.
　Toluene solution of the resulting NBA was concentrated under reduced pressure to distill off the toluene. After concentration and vacuum dried at 45 ° C., as a white solid NBA5.65g (chemical purity: 97 area%). Measurements of chemical purity (area%), using the Agilent Technologies Co. Agilent 1290, was carried out by HPLC under the following conditions.
　Column: Cadenza CD-C18 (150mm × 4.6mm, 3μm)
　Mobile phase A: 0.1% TFA aqueous solution
　mobile phase B: Acetonitrile
　Gradient B solution concentration: (15% / 0 min) → (50% / 15 min ) → (50% / 20 min)
　flow rate: 1 mL / min
　injection volume: 5 [mu] L
　detection wavelength: 215 nm
　column temperature: 40 ° C.
　analysis time: 20 min
[0092]
　Results of NMR measurement of the NBA shown below, and from the results of melting point measurement, product it was confirmed that the NBA.
　 1 H-NMR (400 MHz, CDCl 3 ) Deruta7.25-7.33 (m, 5H), 6.29 (dd, IH, J = 1.5,15.4Hz), 6.25 (IH, br) , 6.13 (dd, 1H, J = 6.8,10.2Hz), 5.64 (dd, 1H, J = 1.6,8.7Hz), 4.48 (d, 2H, J = 5 .8Hz)
　Melting point: 65 ℃

The scope of the claims

[Requested item 1]A diacrylate anhydride and benzylamine are reacted in a solvent, amidation step to obtain the N- benzyl acrylamide;
　and N- benzyl acrylamide and bromine are reacted in a solvent, N- benzyl-2,3-dibromo bromination step propionic acid amide; and
　the N- benzyl-2,3-dibromo-propionic acid amide and methanol in the presence of a base, are reacted, the N- benzyl-2-bromo-3-methoxy propionic acid amide ; methoxylated obtaining
a method for producing N- benzyl-2-bromo-3-methoxy propionic acid amide, characterized in that it comprises in this order.
[Requested item 2]
　Diacrylate anhydride to be subjected to the amidation step, according to claim 1, characterized in that is obtained by reacting acrylic acid and a condensing agent in a solvent N- benzyl-2-bromo - method for producing 3-methoxy propionic acid amide.
[Requested item 3]
　The solvent used in the amidation step, characterized in that a mixed solvent of an organic solvent and water, the production of N- benzyl-2-bromo-3-methoxy propionic acid amide according to claim 1 or 2 Method.
[Requested item 4]
　Characterized in that the presence of a base in the solvent to be used in the amidation step, the manufacturing method of the N- benzyl-2-bromo-3-methoxy propionic acid amide according to any one of claims 1 to 3, .
[Requested item 5]
　A diacrylate anhydride and benzylamine are reacted in a solvent, amidation step to obtain the N- benzyl acrylamide; and
　the N- benzyl acrylamide and bromine are reacted in a solvent, N- benzyl-2,3 ; dibromopropionate brominated to obtain the acid amide
method for producing a characterized as having in this order N- benzyl-2,3-dibromo-propionic acid amide.
[Requested item 6]
　Diacrylate anhydride subjected to the amidation step, characterized in that is obtained by reacting acrylic acid and a condensing agent in a solvent, according to claim 5 N-benzyl-2,3 - method of manufacturing dibromo acid amide.
[Requested item 7]
　The condensing agent, characterized in that a carbodiimide condensing agent, method for producing N- benzyl-2,3-dibromo-propionic acid amide according to claim 6.
[Requested item 8]
　The solvent used in the amidation step, characterized in that a mixed solvent of an organic solvent and water, N- benzyl-2,3-dibromo-propionic acid according to any one of claims 5-7 method for producing amides.
[Requested item 9]
　Characterized in that the presence of a base in the solvent to be used in the amidation step, the manufacturing method of the N- benzyl-2,3-dibromo-propionic acid amide according to any one of claims 5-8.
[Requested item 10]
　A diacrylate anhydride and benzylamine are reacted in a solvent, amidation step to obtain N- benzyl acrylamide;
characterized by having a method for producing a N- benzyl acrylamide.
[Requested item 11]
　Diacrylate anhydride subjected to the amidation step, characterized in that is obtained by reacting acrylic acid and a condensing agent in a solvent, method for producing N- benzyl acrylamide according to claim 10 .
[Requested item 12]
　Characterized in that said condensing agent is a carbodiimide-based condensation agent, method for producing N- benzyl acrylamide according to claim 11.
[Requested item 13]
　The solvent used in the amidation step, characterized in that a mixed solvent of an organic solvent and water, the production method of the N- benzyl acrylamide according to any one of claims 10-12.
[Requested item 14]
　Characterized in that the presence of a base in the solvent to be used in the amidation step, the method of producing N- benzyl acrylamide according to any one of claims 10-13.
[Requested item 15]
　The solvent used in the amidation step is a mixed solvent of hydrophobic organic solvent and water, characterized in that the presence of a base in the aqueous phase, according to any one of claims 10 ~ 14 N - method for producing benzyl-2-bromo-3-methoxy propionic acid amide.