Method for producing safinamide and method for producing safinamide mesylate

Abstract

This invention provides a method for producing safinamide that is suitable for manufacturing safinamide mesylate without the need to isolate and purify safinamide. [Solution] The method for producing safinamide comprises a safinamide synthesis step comprising a second mixing step and a second reaction step. In the second mixing step, a second hydrophobic solution 30 in which 4-[(3-fluorobenzyl)oxy]benzaldehyde is dissolved in a second hydrophobic solvent is mixed with a second amphiphilic solution in which alaninamide is dissolved in a second amphiphilic solvent. In the second reaction step, 4-[(3-fluorobenzyl)oxy]benzaldehyde and alaninamide are reacted in the presence of hydrogen gas and a catalyst to obtain a second reaction solution 70 in which safinamide is dissolved in a mixed solvent containing the second hydrophobic solvent and the second amphiphilic solvent. The catalyst has one or more of the following as active ingredients: platinum, ruthenium, rhodium, iridium, and nickel.

Description

Technical Field

[0001] This application relates to a method for producing safinamide suitable for continuously producing safinamide mesylate, and a method for producing safinamide mesylate including this method for producing safinamide.

Background Art

[0002] Safinamide mesylate, known as a therapeutic agent for improving the wearing-off phenomenon in Parkinson's disease, is synthesized through the following three-step reaction process (Patent Document 1). In the first reaction step, as shown in the following chemical reaction formula, 4-[(3-fluorobenzyl)oxy]benzaldehyde is synthesized by reacting 3-fluorobenzyl chloride with 4-hydroxybenzaldehyde in the presence of a base and a phase transfer catalyst.

[0003]

Chemical Formula

[0004] In the second reaction step, as shown in the following chemical reaction formula, in the presence of hydrogen gas and a catalyst, 4-[(3-fluorobenzyl)oxy]benzaldehyde obtained in the first reaction step is reacted with alaninamide generated from alaninamide hydrochloride and a base to synthesize safinamide (Patent Document 2).

[0005]

Chemical Formula

[0006] In the third reaction step, as shown in the following chemical reaction formula, safinamide obtained in the second reaction step is reacted with methanesulfonic acid to synthesize safinamide mesylate.

[0007]

Chemical Formula

[0008] Conventional methods for producing safinamide mesylate involved batch processes for all reaction steps, which presented the following problems: The products obtained in the first and second reaction steps had to be isolated and purified by crystallization. This resulted in a large amount of waste being generated during the isolation and purification process. Furthermore, concentrating the product-containing solution to improve the recovery efficiency of the isolation and purification required a significant amount of energy. [Prior art documents] [Patent Documents]

[0009] [Patent Document 1] U.S. Patent Application Publication No. 2021 / 0040033 [Patent Document 2] Japanese Patent Publication No. 2013-139446 [Overview of the project] [Problems that the invention aims to solve]

[0010] The object of this application is to provide a method for producing safinamide that allows for the continuous production of safinamide mesylate from safinamide without the need to isolate and purify safinamide, and a method for producing safinamide mesylate that includes this method for producing safinamide. [Means for solving the problem]

[0011] The present invention provides a method for producing safinamide, comprising a safinamide synthesis step which includes a second mixing step in which a second hydrophobic solution in which 4-[(3-fluorobenzyl)oxy]benzaldehyde is dissolved in a second hydrophobic solvent is mixed with a second amphiphilic solution in which alaninamide is dissolved in a second amphiphilic solvent, and a second reaction step in which 4-[(3-fluorobenzyl)oxy]benzaldehyde and alaninamide are reacted in the presence of hydrogen gas and a catalyst containing one or more of platinum, ruthenium, rhodium, iridium, and nickel as active ingredients to obtain a second reaction solution in which safinamide is dissolved in a mixed solvent containing a second hydrophobic solvent and a second amphiphilic solvent.

[0012] The present invention provides a method for producing safinamide mesylate, comprising a second mixing step in which a second hydrophobic solution in which 4-[(3-fluorobenzyl)oxy]benzaldehyde is dissolved in a second hydrophobic solvent is mixed with a second amphiphilic solution in which alaninamide is dissolved in a second amphiphilic solvent, and a second mixing step in which 4-[(3-fluorobenzyl)oxy]benzaldehyde and alaninamide are reacted in the presence of hydrogen gas and a catalyst containing one or more of platinum, ruthenium, rhodium, iridium, and nickel as active ingredients, and a second hydrophobic step The safinamide synthesis step comprises a second reaction step to obtain a second reaction solution in which safinamide is dissolved in a mixed solvent containing an aqueous solvent and a second amphiphilic solvent; a concentration step to obtain a third reaction solution by reducing the content of the second amphiphilic solvent in the second reaction solution; and a precipitation step to precipitate safinamide mesilate by mixing the third reaction solution with a third hydrophobic solution in which methanesulfonic acid is dissolved in a third hydrophobic solvent, and reacting safinamide with methanesulfonic acid. [Effects of the Invention]

[0013] The present invention relates to a method for producing safinamide, in which raw materials are reacted in the presence of a catalyst containing a predetermined active ingredient. As a result, a reaction solution containing safinamide in high purity is obtained. This reaction solution can be used directly as a raw material for the synthesis reaction of safinamide mesylate. [Brief explanation of the drawing]

[0014] [Figure 1] A schematic diagram of the first reaction apparatus that can be used in the first reaction step of the embodiment. [Figure 2] A schematic diagram of a second reactor that can be used in the second reaction step of the embodiment. [Figure 3] A schematic diagram of a third reaction apparatus that can be used in the third reaction step of the embodiment. [Figure 4] A schematic diagram of a safinamide mesylate production apparatus that carries out the first, second, and third reaction steps in succession. [Modes for carrying out the invention]

[0015] Hereinafter, the method for producing safinamide of the present application and the method for producing safinamide mesylate will be described based on embodiments and examples. The method for producing safinamide will be described as one step of the method for producing safinamide mesylate. When indicating two numerical ranges using "~", these two numerical values are also included in this range. Also, duplicate descriptions will be omitted as appropriate. The method for producing safinamide mesylate according to the embodiment of the present application includes a 4-[(3-fluorobenzyl)oxy]benzaldehyde synthesis step (hereinafter sometimes referred to as "the first reaction step"), a safinamide synthesis step (hereinafter sometimes referred to as "the second reaction step"), and a safinamide mesylate synthesis step (hereinafter sometimes referred to as "the third reaction step").

[0016] (First reaction step: Synthesis of 4-[(3-fluorobenzyl)oxy]benzaldehyde) In the first reaction step, as shown in the following chemical reaction formula, 4-[(3-fluorobenzyl)oxy]benzaldehyde is synthesized from 3-fluorobenzyl chloride and 4-hydroxybenzaldehyde.

[0017] [Chemical formula]

[0018] The first reaction step comprises a first mixing step, a first reaction step, and a collection step. In the first mixing step, the first hydrophobic solution and the first hydrophilic solution are mixed. The first hydrophobic solution is a solution in which 3-fluorobenzyl chloride and 4-hydroxybenzaldehyde are dissolved in the first hydrophobic solvent. The hydrophobic solvent is a solvent that, when mixed with the same mass in water at 25°C and stirred, separates into two phases, and when mixed with the same mass in diethyl ether at 25°C and stirred, remains as a single phase. The hydrophobic solution is a solution using the hydrophobic solvent as the solvent. The first hydrophobic solvent is not particularly limited as long as it is a solvent that separates into a hydrophilic phase and two phases. Examples of first hydrophobic solvents include benzene, toluene, xylene, mesitylene, ethyl acetate, propyl acetate, butyl acetate, diethyl ether, dibutyl ether, cyclopentyl methyl ether, and 4-methyltetrahydropyran.

[0019] The first hydrophilic solution is a solution in which the first base and the phase transfer catalyst are dissolved in the first hydrophilic solvent. The hydrophilic solvent is a solvent that, when mixed with the same mass of diethyl ether at 25°C and stirred, separates into two phases, and when mixed with the same mass of water at 25°C and stirred, remains as a single phase. Furthermore, the hydrophilic solution is a solution that uses a hydrophilic solvent as the solvent. The first hydrophilic solvent is not particularly limited as long as it is a solvent that separates into two phases with a hydrophobic phase. The first hydrophilic solvent is preferably water.

[0020] The first base is not particularly limited as long as it is soluble in the first hydrophilic solvent. Examples of the first base include sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium phosphate, and potassium phosphate. Furthermore, it is preferable that the first base is contained in the first hydrophilic solution in amounts of at least one equivalent each of 3-fluorobenzyl chloride and 4-methyltetrahydropyran.

[0021] The phase transfer catalyst dissolves in the first hydrophobic solvent and the first hydrophilic solvent. The phase transfer catalyst allows the reaction between 3-fluorobenzyl chloride and 4-methyltetrahydropyran, which are insoluble in the first hydrophilic solvent, and the first base, which is insoluble in the first hydrophobic solvent, to proceed when the first hydrophobic solution and the first hydrophilic solution are simply mixed without proper mismatch. Preferably, the phase transfer catalyst is present in the first hydrophilic solution in amounts of 0.01 to 1 equivalent each of 3-fluorobenzyl chloride and 4-methyltetrahydropyran contained in the first hydrophobic solution. Examples of phase transfer catalysts include tetrabutylammonium bromide, dodecyltriethylammonium bromide, and potassium iodide. In this embodiment, the phase transfer catalyst is dissolved in the first hydrophilic solvent; however, it may also be dissolved in the first hydrophobic solvent, or in both the first hydrophobic solvent and the first hydrophilic solvent.

[0022] In the first reaction step, 3-fluorobenzyl chloride and 4-hydroxybenzaldehyde are reacted in the presence of a first base and a phase transfer catalyst to produce 4-[(3-fluorobenzyl)oxy]benzaldehyde. In other words, a first reaction solution containing 4-[(3-fluorobenzyl)oxy]benzaldehyde is obtained. Subsequently, the first reaction solution separates into two phases: a hydrophilic phase and a hydrophobic phase containing 4-[(3-fluorobenzyl)oxy]benzaldehyde. In the collection step, the hydrophilic phase is separated and removed from the first reaction solution to collect a second hydrophobic solution, which is the hydrophobic phase and contains 4-[(3-fluorobenzyl)oxy]benzaldehyde.

[0023] A method for continuously obtaining this second hydrophobic solution using a first reactor that can be used in the first reaction step will be described. Figure 1 schematically shows a flow-type first reactor 10. The first reactor 10 includes a pump 14 for transferring the first hydrophobic solution 12, a pump 18 for transferring the first hydrophilic solution 16, a T-tube 20, a reaction field 22, a pressure regulating valve 24, a liquid-liquid separator 26, and a flow path 28 through which these components are connected and through which the liquid flows. In Figure 1, only some of the flow paths are labeled 28, but the straight lines connecting each component and the arrow downstream of the liquid-liquid separator 26 are also flow paths.

[0024] The concentrations of 3-fluorobenzyl chloride and 4-hydroxybenzaldehyde in the first hydrophobic solution 12 are not particularly limited as long as they do not hinder the flow within the first reaction apparatus 10. The respective concentrations are preferably 0.01 to 3 mol / L, more preferably 0.1 to 2 mol / L, and particularly preferably 0.5 to 1.5 mol / L. Furthermore, it is preferable that the 3-fluorobenzyl chloride is present in the first hydrophobic solution 12 in an amount equal to or greater than 1 equivalent of 4-hydroxybenzaldehyde.

[0025] The flow rate ratio of pumps 14 and 18 is set so that the first base contained in the first hydrophilic solution 16 is mixed with at least one equivalent each of 3-fluorobenzyl chloride and 4-methyltetrahydropyran contained in the first hydrophobic solution 12. The flow rate ratio of pump 14 to pump 18 is preferably 1:0.5 to 1:2. The first hydrophobic solution 12 and the first hydrophilic solution 16, transported by pumps 14 and 18 respectively, are mixed by joining them in the T-tube 20. These mixtures are then transported to the reaction field 22.

[0026] Examples of reaction fields 22 include tubular reactors and column reactors. When a tubular reactor is used as reaction field 22, as in this embodiment, the phase transfer catalyst is dissolved together with the first base in the first hydrophilic solvent. When a column reactor is used as reaction field 22, there are no particular restrictions on the column packing material, but it is preferable that the packing material be a basic ion exchange resin. In reaction field 20, 3-fluorobenzyl chloride and 4-hydroxybenzaldehyde react to continuously produce 4-[(3-fluorobenzyl)oxy]benzaldehyde.

[0027] In other words, when the mixture of the first hydrophobic solution 12 and the first hydrophilic solution 16 passes through the reaction field 20, it becomes a first reaction solution containing 4-[(3-fluorobenzyl)oxy]benzaldehyde. The first reaction apparatus 10 may be equipped with heating means for heating the reaction field 20 as needed. The same applies to the second reaction apparatus described later. Examples of heating means include jacketed constant temperature baths, oven heaters, water baths, and oil baths. The temperature of the reaction field 20 is preferably 25 to 150°C, more preferably 50 to 130°C, and particularly preferably 80 to 120°C.

[0028] A pressure regulating valve 22 is provided downstream of the reaction field 20. The pressure regulating valve 22 adjusts the pressure in the reaction field 20 so that the first hydrophobic solvent and the first hydrophilic solvent do not boil. This pressure depends on the boiling points of the first hydrophobic solvent and the first hydrophilic solvent and the temperature of the reaction field 20, but is preferably 0.01 to 0.5 MPa, and more preferably 0.1 to 0.3 MPa. A liquid-liquid separator 26 is provided downstream of the pressure regulating valve 22. The liquid-liquid separator 26 can separate and remove the hydrophilic phase from the first reaction solution.

[0029] The liquid-liquid separator 26 is not particularly limited as long as it can separate the hydrophobic phase and the hydrophilic phase. Examples of liquid-liquid separators 26 include membrane separators and mixer-settler apparatuses. The second hydrophobic solution 30, which is the hydrophobic phase in which 4-[(3-fluorobenzyl)oxy]benzaldehyde is dissolved in the second hydrophobic solvent, is then collected. The compositions of the first hydrophobic solvent and the second hydrophobic solvent are approximately the same.

[0030] (Second reaction step: Synthesis of safinamide) In the second reaction step, as shown in the chemical equation below, safinamide is synthesized by reacting 4-[(3-fluorobenzyl)oxy]benzaldehyde with alaninamide, which is produced from an acidic salt of alaninamide such as alaninamide hydrochloride and a base.

[0031] [ka]

[0032] The second reaction step comprises a second mixing step and a second reaction step. In the second mixing step, the second hydrophobic solution and the second amphiphilic solution are mixed. The second hydrophobic solution is a solution in which 4-[(3-fluorobenzyl)oxy]benzaldehyde is dissolved in the second hydrophobic solvent. This second hydrophobic solution may be the second hydrophobic solution obtained in the first reaction step. In other words, in the second reaction step, safinamide can be synthesized without purifying the 4-[(3-fluorobenzyl)oxy]benzaldehyde synthesized in the first reaction step. This is because the second hydrophobic solution obtained in the first reaction step contains almost no impurities such as components that hinder the synthesis of safinamide and components that are by-products along with the formation of safinamide.

[0033] Therefore, the first and second reaction steps can be carried out continuously. This "continuously" includes not only cases where the apparatus for the first and second reaction steps are connected via a flow path, but also cases where the solution containing 4-[(3-fluorobenzyl)oxy]benzaldehyde obtained in the first reaction step is temporarily stored in a container and then supplied from this container to the apparatus for the second reaction step. The same applies when the second and third reaction steps, described later, are carried out continuously.

[0034] The second amphiphilic solution is a solution in which alaninamide is dissolved in a second amphiphilic solvent. Alaninamide can be obtained by reacting an acidic salt of alaninamide with a base, for example. Examples of acidic salts of alaninamide include alaninamide hydrochloride and alaninamide hydrobromide. The "second" in "second amphiphilic solution" and "second amphiphilic solvent" refers to their use in the second reaction step, and the first amphiphilic solution and first amphiphilic solvent are not specified in this application.

[0035] An amphiphilic solvent is a solvent that remains in a single phase when mixed with water at 25°C by the same mass, stirred, and then left to stand, or when mixed with diethyl ether at 25°C by the same mass, stirred, and then left to stand. An amphiphilic solution is a solution that uses an amphiphilic solvent as the solvent. The second amphiphilic solvent is not particularly limited as long as alaninamide and alaninamide acid salts are soluble in it, but it is preferably methanol, ethanol, and one or more isopropyl alcohols.

[0036] In the second reaction step, 4-[(3-fluorobenzyl)oxy]benzaldehyde and alaninamide are reacted in the presence of hydrogen gas and a catalyst to produce safinamide. That is, a second reaction solution is obtained in which safinamide is dissolved in a mixed solvent containing a second hydrophobic solvent and a second amphiphilic solvent. Preferably, the second amphiphilic solution contains at least one equivalent of alaninamide of 4-[(3-fluorobenzyl)oxy]benzaldehyde contained in the second hydrophobic solution.

[0037] Hydrogen gas is present in an amount of 1 equivalent or more of 4-[(3-fluorobenzyl)oxy]benzaldehyde contained in the second hydrophobic solution. Preferably, hydrogen gas is present in an amount of 1 to 20 equivalents of 4-[(3-fluorobenzyl)oxy]benzaldehyde contained in the second hydrophobic solution, more preferably 2 to 10 equivalents, and particularly preferably 4 to 10 equivalents. Note that if the second reaction step is carried out in a batch manner, it becomes difficult to control the amount of hydrogen gas supplied, and side reactions are a concern.

[0038] The catalyst contains one or more of platinum, ruthenium, rhodium, iridium, and nickel as active ingredients. The active ingredients of a catalyst are components contained in the catalyst that have the function of promoting a predetermined reaction. By using a catalyst containing one or more of platinum, ruthenium, rhodium, iridium, and nickel as active ingredients, safinamide can be synthesized in high yield from 4-[(3-fluorobenzyl)oxy]benzaldehyde and alaninamide using a flow formula. Components other than the active ingredients in the catalyst include the support. The support is preferably activated carbon, sulfur-modified activated carbon, silica gel, alumina, titania, ceria, or polystyrene resin.

[0039] A method for continuously obtaining a second reaction solution containing dissolved safinamide using a second reactor that can be used in the second reaction step is described. Figure 2 schematically shows a flow-type second reactor 40. The second reactor 40 includes a pump 44 for transferring a second amphiphilic solution 42, a pump 48 for transferring a second base solution 46 in which a second base is dissolved in an amphiphilic solvent, T-tubes 50, 52, 54, a pump 58 for transferring a second hydrophobic solution 30, a gas supply pipe 60, a reaction field 62, a pressure regulating valve 64, and a flow path 68 connecting these components through which liquid and gas flow. In Figure 2, only some of the flow paths are labeled 68, but the straight lines connecting each component and the arrows downstream of the pressure regulating valve 64 are also flow paths.

[0040] The concentration of the alaninamide acid salt in the second amphiphilic solution 42 is not particularly limited as long as it does not hinder the flow within the second reaction apparatus 40, but is preferably 0.01 to 3 mol / L, more preferably 0.1 to 2 mol / L, and particularly preferably 0.5 to 1.5 mol / L. The amphiphilic solvent that is the solvent for the second base solution 46 is not particularly limited as long as the second base dissolves in it and it is compatible with the second amphiphilic solution 42, but is preferably methanol, ethanol, and one or more isopropyl alcohols.

[0041] The second base is not particularly limited as long as it can convert the alaninamide acid salt to alaninamide, but it is preferably triethylamine, tripropylamine, tributylamine, or diisopropylethylamine. The concentration of the second base in the second base solution 46 is not particularly limited as long as it does not hinder flow within the second reaction apparatus 40, but it is preferably 0.01 to 3 mol / L, more preferably 0.1 to 2 mol / L, and particularly preferably 0.5 to 1.5 mol / L. Furthermore, it is preferable that the second base is present in the second base solution 46 in an amount of 1 equivalent or more of the alaninamide acid salt contained in the second amphiphilic solution 42.

[0042] The flow rate ratio of pumps 44 and 48 is set so that the second base contained in the second base solution 46 is mixed with at least one equivalent of alaninamide hydrochloride contained in the second amphiphilic solution 42. The flow rate ratio of pump 44 to pump 48 is preferably 1:0.5 to 1:2. The second amphiphilic solution 42 and the second base solution 46, transported by pumps 44 and 48 respectively, are mixed by joining them in the T-tube 50. The second hydrophobic solution 30, transported by pump 58, is further joined to these mixtures in the T-tube 52.

[0043] The flow rate of pump 58 is set so that the alaninamide contained in the mixture of the second amphiphilic solution 42 and the second base solution 46 merges with at least one equivalent of 4-[(3-fluorobenzyl)oxy]benzaldehyde contained in the second hydrophobic solution 30. The flow rate of pump 58:flow rate of pump 44:flow rate of pump 48 is preferably 1:0.5:0.5 to 1:2:2. Downstream of the T-pipe 52, the second amphiphilic solution 42, the second base solution 46, and the second hydrophobic solution 30 are miscible. This prevents clogging of the flow path 68. Subsequently, hydrogen gas supplied from the gas supply pipe 60 merges further in the T-pipe 54 and is transferred to the reaction field 62.

[0044] In the reaction field 62, it is preferable to use a column reactor in which a heterogeneous catalyst is packed into the column. This heterogeneous catalyst is a catalyst in which one or more of the above-mentioned platinum, ruthenium, rhodium, iridium, and nickel are active ingredients. A diluent may be packed into the column together with the heterogeneous catalyst. The diluent is preferably Celite, silica gel, or alumina. The mass of heterogeneous catalyst packed into the column to the mass of diluent is preferably 1:0 to 1:20, more preferably 1:0 to 1:10, and particularly preferably 1:0 to 1:5. In the reaction field 62 in which hydrogen gas and catalyst are present, 4-[(3-fluorobenzyl)oxy]benzaldehyde and alanineamide react to produce safinamide.

[0045] In other words, downstream of the reaction field 62, a second reaction solution 70 flows in which safinamide is dissolved in a mixed solvent containing a second hydrophobic solvent and a second amphiphilic solvent. Safinamide is obtained by collecting the second reaction solution 70, distilling off the mixed solvent, and crystallizing it. The second reaction solution 70 can also be used as a raw material for the third reaction step. A pressure regulating valve 64 is provided downstream of the reaction field 62. By pressurizing the reaction field 62 with the pressure regulating valve 64, boiling of the liquid in the reaction field 62 is prevented. The amount of pressurization is preferably 0 to 1.0 MPa, and more preferably 0 to 0.5 MPa.

[0046] (Third reaction step: Synthesis of safinamide mesylate) In the third reaction step, safinamide and methanesulfonic acid are reacted to synthesize safinamide mesylate, as shown in the chemical equation below. In other words, safinamide is converted to safinamide mesylate. In this embodiment, an example of synthesizing safinamide mesylate using the second reaction solution obtained in the second reaction step will be described.

[0047] [ka]

[0048] The third reaction step comprises a concentration step and a precipitation step. In the concentration step, the content of the second amphiphilic solvent in the second reaction solution is reduced to obtain the third reaction solution. The concentration step reduces the amount of the second amphiphilic solvent in which safinamide is easily soluble, making it easier for safinamide mesylate to precipitate in the subsequent precipitation step. Furthermore, the concentration step allows the second and third reaction steps to be carried out continuously without purifying the safinamide obtained in the second reaction step.

[0049] In the concentration process, a hydrophilic medium may be added to the second reaction solution, and after extracting the second amphiphilic solvent into the hydrophilic medium, the hydrophilic phase may be separated and removed to reduce the content of the second amphiphilic solvent in the second reaction solution. Examples of hydrophilic mediums include water and aqueous solutions of inorganic salts. In the precipitation process, the third reaction solution obtained in the concentration process is mixed with a third hydrophobic solution in which methanesulfonic acid is dissolved in a third hydrophobic solvent, and safinamide and methanesulfonic acid are reacted to precipitate safinamide mesylate.

[0050] The third hydrophobic solvent is not particularly limited as long as it dissolves methanesulfonic acid, but it is preferably benzene, toluene, xylene, mesitylene, ethyl acetate, propyl acetate, butyl acetate, diethyl ether, dibutyl ether, cyclopentyl methyl ether, and 4-methyltetrahydropyran. The third hydrophobic solution contains methanesulfonic acid in an amount of 1 equivalent or more of safinamide contained in the second reaction solution. The amount of methanesulfonic acid contained in the third hydrophobic solution is preferably 1.0 to 2.0 equivalents, more preferably 1.0 to 1.5 equivalents, and particularly preferably 1.0 to 1.1 equivalents of safinamide contained in the second reaction solution.

[0051] A method for precipitating safinamide mesylate using a third reactor that can be used in the third reaction step will be described. Figure 3 schematically shows a flow-type third reactor 80. The third reactor 80 includes a pump 82 for transferring the second reaction solution 70, a concentrator 84, a precipitation container 86, a stirrer 88, and a flow path 90 through which these components are connected and the liquid flows. In Figure 3, only some of the flow paths are labeled 90, but the straight lines connecting each component and the arrow downstream of the concentrator 84 are also flow paths.

[0052] The second reaction solution 70 is transferred to the concentrator 84 by the pump 82. In the concentrator 84, the content of the second amphiphilic solvent in the second reaction solution 70 is reduced. More specifically, a hydrophilic medium is added to the second reaction solution 70, the second amphiphilic solvent is extracted into this hydrophilic medium, and the two phases are separated into a hydrophobic phase and a hydrophilic phase. The hydrophilic phase is removed, and the third reaction solution, which is the hydrophobic phase, is supplied to the deposition container 86. A membrane separation device or a mixer-settler device can be used to separate the hydrophobic and hydrophilic phases.

[0053] The precipitation container 86 is pre-filled with a third hydrophobic solution 92 in which methanesulfonic acid is dissolved in a third hydrophobic solvent. A flask can be used as the precipitation container 86. The third reaction solution is supplied to the third hydrophobic solution 92 while stirring it with a stirrer 88. A mechanical stirrer can be used as the stirrer 88. The methanesulfonic acid contained in the third hydrophobic solution 92 reacts with safinamide contained in the third reaction solution, and safinamide mesilate precipitates in the precipitation container 86. After that, the substance in the precipitation container 86 is filtered, and the filtrate is dried to obtain safinamide mesilate. [Examples]

[0054] Figure 4 schematically shows a safinamide mesylate production apparatus 100 that can carry out the first, second, and third reaction steps in succession. The safinamide mesylate production apparatus 100 was used in the examples, reference examples, and comparative examples.

[0055] (First reaction step: Synthesis of 4-[(3-fluorobenzyl)oxy]benzaldehyde) <Example 1> A first hydrophobic solution 12, in which 3-fluorobenzyl chloride is dissolved at 1.1 M and 4-hydroxybenzaldehyde is dissolved at 1.0 M in 4-methyltetrahydropyran (4-Me THP), a first hydrophobic solvent, was transferred at a flow rate of 0.04 mL / min using pump 14 (Takumina Co., Ltd., Q-5; pumps 18, 25, 96, and 98 described later are the same). A first hydrophilic solution 16, an aqueous solution in which potassium hydroxide (KOH), a first base, is dissolved at 2.0 M and tetrabutylammonium bromide (TBAB), a phase transfer catalyst, is dissolved at 0.1 M in water, a first hydrophilic solvent, was transferred at a flow rate of 0.04 mL / min using pump 18.

[0056] The first hydrophobic solution 12 and the first hydrophilic solution 16 were mixed in a T-tube 20 and kept in a reaction field 22, which was a tube reactor (SUS316 tube, inner diameter 1.0 mm, length 714 cm) maintained at 110°C with a heater (EYELA, LCR-1300), for 70 minutes. At this time, the pressure in the reaction field 22 was set to 0.2 MPa with a pressure regulating valve (EYELA, BPR-1000) 24. 4-Me THP was transferred using a pump 25 at a flow rate of 0.06 mL / min, and the first reaction solution containing 4-[(3-fluorobenzyl)oxy]benzaldehyde that had passed through the reaction field 22 was diluted.

[0057] The diluted first reaction solution was transferred to liquid-liquid separator 26 (Zaiput, SEP-10, hydrophilic membrane, 0.5 μm pore size) and the aqueous phase was separated and removed. The organic phase, which was an approximately 0.4 M 4-Me THP solution containing the target substance 4-[(3-fluorobenzyl)oxy]benzaldehyde, was sampled and the yield was calculated by HPLC (similarly, all yields were calculated by HPLC hereafter). After 7 hours and 30 minutes from the start of liquid delivery by pumps 14 and 18, the yield of 4-[(3-fluorobenzyl)oxy]benzaldehyde stabilized at 99%, and the organic phase was collected in a container as the second hydrophobic solution 30 (approximately 0.40 M 4-[(3-fluorobenzyl)oxy]benzaldehyde solution). Eighteen hours after the start of collection, the transfer of the second hydrophobic solution 30 was started using pump 58 (EYELA, EUI-22-110P; pumps 44, 48, 82, 83, and 94 described later are the same), and the process proceeded to the second reaction step.

[0058] <Reference example 1> 1.0 mmol of 3-fluorobenzyl chloride, 1.0 mmol of 4-hydroxybenzaldehyde, 2.0 mmol of potassium hydroxide, 0.10 mmol of tetrabutylammonium bromide, 2 mL of 4-methyltetrahydropyran, 1 mL of water, and a stirrer bar were placed in a test tube. The test tube was heated to 80°C and the mixture was reacted for 3 hours while rotating the stirrer bar at 600 rpm. After the reaction was complete, the test tube was cooled to room temperature, 1 mL of 1N hydrochloric acid was added, and the organic phase was analyzed by HPLC to obtain 4-[(3-fluorobenzyl)oxy]benzaldehyde in 88% yield.

[0059] (Second reaction step: Synthesis of safinamide) <Example 2> Using pumps 44 and 48, a 0.44 M (1.1 equivalent) methanol solution 42 of alaninamide hydrochloride and a 0.40 M (1.0 equivalent) methanol solution 46 of triethylamine, a secondary base, were transferred at a rate of 0.1 mL / min each and joined in a T-tube 50. The mixture was then retained for 4 minutes in a PTFE tube (not shown) located downstream of the T-tube 50. Downstream of the PTFE tube, the alaninamide hydrochloride was converted to alaninamide, resulting in a methanol solution, which is a secondary amphiphilic solution in which alaninamide is dissolved in methanol, a secondary amphiphilic solvent.

[0060] Using pump 58, the second hydrophobic solution 30 in the container was transferred at a flow rate of 0.1 mL / min and mixed with the methanol solution of alaninamide in a T-tube 50. This mixture was transferred to a column reactor 59 (EYELA, MCR-1000, inner diameter 10 mm, length 10 cm) packed with glass beads and heated to 80°C, where it was preheated for a residence time of 10 minutes. This preheating promoted the formation of an imine from alaninamide and 4-[(3-fluorobenzyl)oxy]benzaldehyde. Subsequently, hydrogen gas, adjusted to a flow rate of 5 mL / min using a mass flow controller 61, was added via a T-tube 54.

[0061] After this merging, a sulfur-modified platinum-carbon catalyst (3% mass Pt, manufactured by Kawaken Fine Chemicals Co., Ltd.): Celite 545 (manufactured by Fujifilm Wako Pure Chemical Corporation) was packed in a mass ratio of 1:4 and transferred to reaction field 62, a column reactor (manufactured by EYELA, MCR-1000, inner diameter 10 mm, length 10 cm) heated to 110°C. Since a sulfur-modified platinum-carbon catalyst is used as the catalyst for the flow-type synthesis of safinamide, the reductive amination reaction by hydrogenation of the imine proceeds efficiently, and safinamide can be synthesized continuously. At this time, the pressure in reaction field 62 was set to 0.4 MPa using a pressure regulating valve (manufactured by EYELA, BPR-1000) 64.

[0062] In reaction field 62, 4-[(3-fluorobenzyl)oxy]benzaldehyde reacted with alaninamide in the presence of hydrogen gas and a catalyst to produce safinamide. Six hours after the start of pumping with pumps 44, 48, and 58, the yield of safinamide stabilized at 99%, and the organic phase was collected in a container as the second reaction solution 70 (approximately 0.13 M safinamide solution). In other words, the second reaction solution 70 was obtained in which safinamide was dissolved in a mixed solvent of 4-Me THP (a secondary hydrophobic solvent) and methanol (a secondary amphiphilic solvent) with a yield of 99%. Eighteen hours after the start of collection, the transfer of the second reaction solution 70 was started with pump 82, and the reaction proceeded to the third step.

[0063] <Example 3> Safinamide was synthesized sequentially in the same manner as in Example 2, except that the sulfur-modified platinum-carbon catalyst was replaced with platinum-carbon (5% by mass, manufactured by N.E. Chemcat, STD, the same applies hereafter). A second reaction solution 70 containing dissolved safinamide was obtained in 80% yield.

[0064] <Comparative Example 1> The sequential synthesis of safinamide was attempted in the same manner as in Example 2, except that the sulfur-modified platinum-carbon catalyst was replaced with palladium-carbon (5% by mass Pd, N.E. Chemcat, STD). Although 4-[(3-fluorobenzyl)oxy]benzaldehyde was converted 100%, the yield was 0% due to decomposition reactions or excess reactions. It was found that palladium is not suitable as a catalyst for synthesizing safinamide by the flow method.

[0065] <Reference example 2> 0.88 mmol of alaninamide hydrochloride, 0.88 mmol of triethylamine, 5 mL of 4-methyltetrahydropyran, and a stirrer bar were placed in an autoclave container and stirred at room temperature for 30 minutes. 0.87 mmol of 4-[(3-fluorobenzyl)oxy]benzaldehyde and 50 mg of platinum carbon were added and the container was sealed. After replacing the gas in the autoclave container with hydrogen gas, it was pressurized to 0.5 MPa. The autoclave container was heated to 80°C and stirred for 3 hours. The autoclave container was cooled to room temperature, opened, and filtered using ethyl acetate, confirming that the filtrate contained safinamide in a yield of 58%.

[0066] (Third reaction step: Synthesis of safinamide mesylate) <Example 4> Using pumps 82 and 83, the second reaction solution 70, which is approximately 0.13 M safinamide solution, was transferred at 0.3 mL / min, and ethyl acetate (AcOEt) was transferred at 0.1 mL / min. These were then combined in a T-tube 85 and transferred to mixer-settler 84a (manufactured by Mac Engineering Co., Ltd., MSL-IT-04-00-00; mixer-settler 84b is the same). Meanwhile, using pump 94, a 5% sodium chloride aqueous solution ("saline solution" in Figure 4), which is the washing solution, was transferred to mixer-settler 84b at 0.4 mL / min.

[0067] The organic phase was transferred to mixer settler 84b after passing through mixer settler 84a. The aqueous phase that passed through mixer settler 84b was withdrawn at a rate of 0.3 mL / min using pump 96 and transferred to mixer settler 84a, after which it was separated and removed at a rate of 0.3 mL / min using pump 98. In this way, a third reaction solution was obtained in which the methanol content in the second reaction solution 70 was reduced by adding an aqueous sodium chloride solution, which is a hydrophilic medium, to the second reaction solution 70, extracting methanol from the second reaction solution 70, and then separating and removing the aqueous phase.

[0068] This third reaction solution was a solution in which safinamide was dissolved in a solvent of 4-methyltetrahydropyran:ethyl acetate in a mass ratio of 1:1, containing approximately 1% by mass of methanol. The flask, which served as the precipitation vessel, held the third hydrophobic solution 92, which was a 4-methyltetrahydropyran solution of methanesulfonic acid, was kept warm at 25°C, and the third reaction solution transferred from the mixer settler 84b was added dropwise to precipitate safinamide mesilate. After this dropwise addition was carried out for 150 minutes, the mixture was stirred at room temperature for 30 minutes, filtered, and dried to obtain safinamide mesilate in a yield of 85% (83% of the total yield from the three reaction steps in Examples 1, 2, and 4). [Explanation of Symbols]

[0069] 10 First Reactor 12. First hydrophobic solution 14,18,25,44,48,58,82,83,94,96,98 pumps 16 First hydrophilic solution 20,50,52,54,85 ​​T-tube 22,62 reaction field 24,64 Pressure regulating valve 26 Liquid-liquid separator 28,68 channels 30 Second hydrophobic solution 40 Second Reactor 42 Second amphiphilic solvent 46 Second base solution 59 Column Reactor 60 Gas supply pipe 61 Mass Flow Controller 70 Second reaction solution 80 Third Reactor 84 Concentrator 84a, 84b Mixer Settler 86 Precipitation container 88 Agitator 92 Third Hydrophobic Solution 100 Safinamide mesylate manufacturing equipment

Claims

1. A second mixing step involves mixing a second hydrophobic solution in which 4-[(3-fluorobenzyl)oxy]benzaldehyde is dissolved in a second hydrophobic solvent with a second amphiphilic solution in which alaninamide is dissolved in a second amphiphilic solvent. A second reaction step involves reacting 4-[(3-fluorobenzyl)oxy]benzaldehyde with alaninamide in the presence of hydrogen gas and a catalyst containing one or more of platinum, ruthenium, rhodium, iridium, and nickel as active ingredients to obtain a second reaction solution in which safinamide is dissolved in a mixed solvent containing the second hydrophobic solvent and the second amphiphilic solvent. A method for producing safinamide, comprising a safinamide synthesis step.

2. In claim 1, A first mixing step involves mixing a first hydrophobic solution in which 3-fluorobenzyl chloride and 4-hydroxybenzaldehyde are dissolved in a first hydrophobic solvent with a first hydrophilic solution in which a first base and a phase transfer catalyst are dissolved in a first hydrophilic solvent. The first reaction step involves reacting the 3-fluorobenzyl chloride with the 4-hydroxybenzaldehyde to obtain a first reaction solution containing 4-[(3-fluorobenzyl)oxy]benzaldehyde, A collection process involves separating and removing the hydrophilic phase from the first reaction solution and collecting the second hydrophobic solution. A method for producing safinamide, further comprising a 4-[(3-fluorobenzyl)oxy]benzaldehyde synthesis step, which includes the above, prior to the safinamide synthesis step.

3. In claim 2, A method for producing safinamide, wherein the first hydrophilic solvent is water.

4. In any of claims 1 to 3, A method for producing safinamide, wherein the second amphiphilic solvent is methanol, ethanol, and one or more isopropyl alcohols.

5. A second mixing step involves mixing a second hydrophobic solution in which 4-[(3-fluorobenzyl)oxy]benzaldehyde is dissolved in a second hydrophobic solvent with a second amphiphilic solution in which alaninamide is dissolved in a second amphiphilic solvent. A second reaction step involves reacting 4-[(3-fluorobenzyl)oxy]benzaldehyde with alaninamide in the presence of hydrogen gas and a catalyst containing one or more of platinum, ruthenium, rhodium, iridium, and nickel as active ingredients to obtain a second reaction solution in which safinamide is dissolved in a mixed solvent containing the second hydrophobic solvent and the second amphiphilic solvent. A safinamide synthesis step comprising, A concentration process to obtain a third reaction solution by reducing the content of the second amphiphilic solvent in the second reaction solution, A precipitation process is performed in which the third reaction solution is mixed with a third hydrophobic solution in which methanesulfonic acid is dissolved in a third hydrophobic solvent, and the safinamide and methanesulfonic acid are reacted to precipitate safinamide mesylate. A safinamide mesylate synthesis step comprising, A method for producing safinamide mesylate having the following properties.

6. In claim 5, A method for producing safinamide mesylate, wherein in the concentration process, a hydrophilic medium is added to the second reaction solution, the second amphiphilic solvent is extracted into the hydrophilic medium, and then the hydrophilic phase is separated and removed to reduce the content of the second amphiphilic solvent in the second reaction solution.

7. In claim 5, A first mixing step involves mixing a first hydrophobic solution in which 3-fluorobenzyl chloride and 4-hydroxybenzaldehyde are dissolved in a first hydrophobic solvent with a first hydrophilic solution in which a first base and a phase transfer catalyst are dissolved in a first hydrophilic solvent. The first reaction step involves reacting the 3-fluorobenzyl chloride with the 4-hydroxybenzaldehyde to obtain a first reaction solution containing 4-[(3-fluorobenzyl)oxy]benzaldehyde, A collection process involves separating and removing the hydrophilic phase from the first reaction solution and collecting the second hydrophobic solution. A method for producing safinamide mesylate, further comprising a 4-[(3-fluorobenzyl)oxy]benzaldehyde synthesis step, which includes the above, prior to the safinamide synthesis step.

8. In any of claims 5 to 7, A method for producing safinamide mesylate, wherein the second amphiphilic solvent is methanol, ethanol, and one or more isopropyl alcohols.

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