Method for producing safinamide or salt thereof

Abstract

To provide a method for producing safinamide or a salt thereof, enabling high yield and low impurity.SOLUTION: A method for producing safinamide or a salt thereof is provided. This production method includes contacting a crude of (S)-2-[[4-[(3-fluorobenzyl)oxy]benzyl]amino]propanamide or a salt thereof with a basic adsorbent in the presence of a first solvent.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to a method for producing safinamide or a salt thereof.

Background Art

[0002] (S)-2-[[4-[(3-Fluorobenzyl)oxy]benzyl]amino]propanamide is a therapeutic agent for Parkinson's disease, also known as safinamide (SND). Safinamide is contained in tablets, for example, in the form of safinamide mesylate. Safinamide mesylate is represented by the following formula (I).

[0003]

Chemical Formula

Prior Art Documents

Patent Documents

[0004]

Patent Document 1

Patent Document 2

Patent Document 3

Patent Document 4

Patent Document 5

Summary of the Invention

Problems to be Solved by the Invention

[0005] An object of the present invention is to provide a method for producing safinamide or a salt thereof with high yield and few impurities.

Means for Solving the Problems

[0006] According to one aspect, there is provided a method for producing safinamide or a salt thereof. This production method includes contacting a crude form of (S)-2-[[4-[(3-fluorobenzyl)oxy]benzyl]amino]propanamide or a salt thereof with a basic adsorbent in the presence of a first solvent.

Advantages of the Invention

[0007] According to the present invention, there is provided a method for producing safinamide or a salt thereof with high yield and few impurities.

Embodiments for Carrying Out the Invention

[0008] According to an embodiment, there is provided a method for producing (S)-2-[[4-[(3-fluorobenzyl)oxy]benzyl]amino]propanamide or a salt thereof. Hereinafter, (S)-2-[[4-[(3-fluorobenzyl)oxy]benzyl]amino]propanamide is also referred to as safinamide or SND.

[0009] The production method according to the embodiment includes contacting a crude form of safinamide or a salt thereof with a basic adsorbent in the presence of a first solvent. According to this production method, safinamide or a salt thereof with few impurities can be obtained in high yield. The reason is considered as follows.

[0010] First, the crude form of safinamide (SND) is obtained, for example, by reducing (S)-2-[4-(3-fluorobenzyloxy)benzylideneamino]propanamide (SN-05) obtained by reacting 4-[(3-fluorophenyl)methoxy]benzaldehyde (SN-03) with L-alanine amide hydrochloride (SN-04) as shown in the following formula. These syntheses can be carried out in one pot.

[0011]

Chemical formula

[0012] The crude form of the salt of safinamide can be obtained, for example, by contacting the crude form of safinamide with an acid.

[0013] The safinamide obtained by such a method is, for example, extracted by liquid separation and then crystallized and taken out. The obtained crystals can be washed with water or an organic solvent. However, depending on such a washing treatment, impurities may not be sufficiently removed. Further, when column purification is performed on the crude form of safinamide, for example, to remove such impurities, although the purity increases, the yield significantly decreases.

[0014] As a result of intensive research by the present inventors, it has been found that these impurities include (S)-2-[[4-[(3-fluorobenzyl)oxy]benzyl]amino]propionic acid represented by the following formula (2). Hereinafter, (S)-2-[[4-[(3-fluorobenzyl)oxy]benzyl]amino]propionic acid represented by the formula (2) is also referred to as SN-IP.

[0015]

Chemical formula

[0016] Furthermore, as a result of further research by the present inventors, it has been found that SN-IP is significantly removed by a basic adsorbent as compared with the case of using other types of adsorbents. This is presumably because SN-IP is acidic. Therefore, according to the method according to the embodiment, the amount of impurities is small, and safinamide or its salt can be obtained in a high yield.

[0017] Hereinafter, the manufacturing method according to the embodiment will be described in detail.

[0018] The manufacturing method according to the embodiment includes contacting a crude form of safinamide or its salt with a basic adsorbent in the presence of a first solvent.

[0019] A basic adsorbent is, for example, an adsorbent that exhibits a value of the pH of water greater than 7 when 100 g of the adsorbent is immersed in 1 L of water at 25°C. The pH of the basic adsorbent may be 8 or higher, and may be 9 or higher and 13 or lower. The pH of the basic adsorbent is preferably 10.0 or higher and 12.5 or lower.

[0020] Examples of the basic adsorbent include at least one selected from the group consisting of basic alumina and basic silica gel. From the viewpoint of reducing impurities, it is preferable to use basic alumina as the basic adsorbent. From the viewpoint of increasing the yield, it is preferable to use basic silica gel as the basic adsorbent.

[0021] The basic alumina may be composed only of aluminum atoms and oxygen atoms, or may contain other atoms. Examples of the other atoms include hydrogen, carbon, sodium, silicon, and iron. The basic alumina may be a composite oxide of A12O3 and at least one oxide selected from the group consisting of Na2O3, Fe2O3, and SiO2. In the composite oxide, the proportion occupied by A12O3 is, for example, 90% by mass or more.

[0022] The pH of the basic alumina is preferably 8 or higher and 12 or lower.

[0023] The basic alumina particles may be in any form of powder, lump, or sphere. The average particle size of the basic alumina particles by the laser diffraction / scattering method is, for example, 0.05 mm or more and 0.3 mm or less. The average particle size is preferably 0.1 mm or more and 0.2 mm or less.

[0024] The basic alumina is a porous body. The specific surface area of the acid-basic alumina by the BET method is, for example, 100 m 2 / g or more and 300 m 2 / g or less. The specific surface area is preferably 150 m 2 / g or more and 250 m 2 / g or less.

[0025] The basic alumina may be α-alumina or γ-alumina.

[0026] The silica gel is, for example, particles of silica gel modified with an aminopropyl group. The pH of the silica gel is preferably 8.5 or more and 11.5 or less.

[0027] The silica gel particles may be in any form of powder, lump, crushed form, or spherical form. The average particle size of the silica gel particles by the laser diffraction / scattering method is, for example, 0.03 mm or more and 0.3 mm or less. The average particle size is preferably 0.04 mm or more and 0.1 mm or less.

[0028] The silica gel particles are a porous body. The specific surface area of the silica gel particles by the BET method is, for example, 200 m 2 / g or more and 1000 m 2 / g or less. The specific surface area is preferably 300 m 2 / g or more and 900 m 2 / g or less.

[0029] The amount of the basic adsorbent with respect to 1 g of the crude safinamide or its salt is, for example, 0.01 g or more and 0.5 g or less based on the weight of the safinamide contained in the crude form. The amount of the basic adsorbent is preferably 0.03 g or more and 0.4 g or less, and more preferably 0.05 g or more and 0.3 g or less.

[0030] As the first solvent, water, an organic solvent, or a mixed solvent thereof is used. The first solvent preferably contains an organic solvent. The organic solvent preferably contains at least one selected from the group consisting of esters, ketones, alcohols, ethers, nitriles, and aromatic hydrocarbons. Specific examples of the organic solvent include esters such as methyl formate, ethyl formate, propyl formate, butyl formate, methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, methyl propionate, ethyl propionate, methyl acetoacetate, ethyl acetoacetate, ethyl benzoate, propyl benzoate, ethyl isovalerate, and methyl salicylate; ketones such as acetone, methyl ethyl ketone, acetylacetone, and diacetone alcohol; alcohols such as methanol, ethanol, 1-propanol, 2-propanol, and allyl alcohol; ethers such as tetrahydrofuran and dioxane; nitriles such as acetonitrile; and aromatic hydrocarbons such as benzene, toluene, and xylene. Among these, considering the solubility of safinamide or its salt, esters, ketones, alcohols, and aromatic hydrocarbons are more preferable. As the organic solvent, at least one selected from the group consisting of ethyl acetate, chloroform, toluene, ethanol, acetonitrile, and tetrahydrofuran (THF) may be used.

[0031] The amount of the first solvent relative to 1 g of the crude safinamide or its salt may be appropriately determined in consideration of the type of the solvent used, the temperature at which contact is made, etc., and is, for example, 1 mL or more and 100 mL or less. From the viewpoint of contact efficiency, the amount of the first solvent relative to 1 g of the crude safinamide or its salt is preferably 3 mL or more and 75 mL or less, and more preferably 5 mL or more and 50 mL or less.

[0032] The contact between the crude safinamide or its salt and the basic adsorbent is carried out, for example, within a temperature range of 0 °C or more and the reflux temperature or less. This contact is preferably carried out within a temperature range of 40 °C or more and 80 °C or less. This contact may also be carried out under a room temperature environment of 20 °C or more and 40 °C or less.

[0033] The contact between the crude safinamide or its salt and the basic adsorbent may be appropriately determined by analyzing the amount of impurities in the solution, etc., and is carried out, for example, within the range of 1 minute or more and 50 hours or less. This contact time is preferably within the range of 10 minutes or more and 2 hours or less. During this contact time, the mixture of the crude safinamide or its salt and the basic adsorbent is preferably continuously stirred.

[0034] The crude safinamide can be obtained, for example, by reducing SN-05 obtained by contacting SN-03 and SN-04 as described above. SN-03 can be synthesized by a known method.

[0035] The amount of SN-04 relative to 1 mol of SN-03 is, for example, 0.5 mol or more and 5 mol or less. The contact between SN-03 and SN-04 is carried out, for example, within the range of 0°C or more and 50°C or less. The contact between SN-03 and SN-04 may be carried out in the presence of a second solvent. As the second solvent, the same compounds as those listed for the first solvent can be used.

[0036] By contacting the reaction product obtained by contacting SN-03 and SN-04 with a reducing agent, a crude safinamide is obtained. The reaction product contains SN-05. After taking out SN-05 as a solid from the reaction product, it may be contacted with a reducing agent. In that case, the quality of the obtained crude safinamide is higher and the content of SN-IP is lower than when it is not taken out. However, the yield of the crude safinamide is significantly reduced compared to when it is not taken out. That is, it is more preferable to use the crude safinamide obtained when it is not taken out in the present invention because the effects of the present invention can be obtained more.

[0037] As the reducing agent, for example, at least one selected from the group consisting of alkali metal borohydrides, sodium triacetoxyborohydride, and sodium tricyanoborohydride is used. The alkali metal borohydride includes at least one selected from the group consisting of sodium borohydride, lithium borohydride, and potassium borohydride. If the desired reduction reaction proceeds, it is not limited to these, and in addition to hydrogen, reducing agents such as aluminum hydride compounds, borane complexes, and silane compounds may also be used.

[0038] The amount of the reducing agent relative to 1 mol of the reaction product is, for example, 0.5 mol or more and 5 mol or less. The contact between the reaction product and the reducing agent is carried out, for example, within the range of -20°C or higher and 50°C or lower. The contact between the reaction product and the reducing agent can be carried out in the presence of the second solvent.

[0039] The crude safinamide may be extracted by liquid separation treatment. In the liquid separation treatment, for example, a mixed solvent of water and an organic solvent is used. As the organic solvent, for example, an organic solvent that can be layered with water, such as toluene, ethyl acetate, dichloromethane, and chloroform, is used. The crude safinamide is taken out as a solid from the cooled organic layer, for example. The obtained crude product may be subjected to drying and washing treatments. Alternatively, the crude safinamide can also be obtained as a solid by removing the organic solvent from the organic layer by concentration under reduced pressure or the like. Without going through these operations, the organic layer, that is, the solution containing the crude safinamide, may be directly used for the contact operation with the basic adsorbent.

[0040] The crude safinamide may contain the above-mentioned impurity SN-IP in addition to safinamide. That is, the crude safinamide may be a mixture.

[0041] In the crude safinamide, the area ratio of safinamide by high performance liquid chromatography is, according to one example, 95.0% or more, and according to another example, 98.0% or more. There is no particular upper limit to this ratio, but according to one example, it is 99.99% or less. The calculation method of this area ratio will be described in detail in the examples.

[0042] In the crude safinamide, the area ratio of SN-IP by high performance liquid chromatography is, according to one example, 5.0% or less, and according to other examples, 2.0% or less. There is no particular lower limit for this ratio, but according to one example, it is 0.01% or more.

[0043] In the presence of a first solvent, after contacting the crude safinamide with a basic adsorbent, the basic adsorbent may be removed, for example, by filtration or the like. By crystallizing the safinamide in the first solvent, crystals of safinamide can be obtained. At this time, by coexisting an acid, crystals of a salt of safinamide can also be obtained. Examples of the acid include inorganic acids containing mineral acids such as hydrochloric acid, hydrogen chloride, hydrobromic acid, hydrogen bromide, sulfuric acid, sulfurous acid, fuming sulfuric acid, nitric acid, fuming nitric acid, nitrous acid, phosphoric acid, boric acid, borofluoric acid, carbonic acid, silicic acid, etc., carboxylic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, butyric acid, valeric acid, caproic acid, lauric acid, lactic acid, cyclohexanecarboxylic acid, oxalic acid, malonic acid, succinic acid, glutamic acid, adipic acid, fumaric acid, maleic acid, malic acid, citric acid, aconitic acid, benzoic acid, phthalic acid, mellitic acid, cinnamic acid, etc., and sulfonic acids such as methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, etc. Methanesulfonic acid is preferably used as the acid.

[0044] The area ratio of safinamide in the crystals of this safinamide by high performance liquid chromatography is, according to one example, 99.5% or more, and according to other examples, 99.9% or more. There is no particular upper limit for this ratio, but according to one example, it is 99.99% or less.

[0045] The area ratio of SN-IP in the crystals of this safinamide by high performance liquid chromatography is, according to one example, 0.5% or less, and according to other examples, 0.1% or less. There is no particular lower limit for this ratio, but according to one example, it is above the detection limit value (0.001%) by high performance liquid chromatography.

[0046] By contacting the crystal of safinamide with an acid, a salt of safinamide can be obtained. Examples of the acid include inorganic acids containing mineral acids such as hydrochloric acid, hydrogen chloride, hydrobromic acid, hydrogen bromide, sulfuric acid, sulfurous acid, fuming sulfuric acid, nitric acid, fuming nitric acid, nitrous acid, phosphoric acid, boric acid, borofluoric acid, carbonic acid, silicic acid, etc.; carboxylic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, butyric acid, valeric acid, caproic acid, lauric acid, lactic acid, cyclohexanecarboxylic acid, oxalic acid, malonic acid, succinic acid, glutamic acid, adipic acid, fumaric acid, maleic acid, malic acid, citric acid, aconitic acid, benzoic acid, phthalic acid, mellitic acid, cinnamic acid, etc.; and sulfonic acids such as methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, etc. It is preferable to use methanesulfonic acid as the acid.

[0047] In addition, the contact between the crude safinamide and the basic adsorbent may be carried out in the presence of an acid. According to this method, the purification of safinamide and the formation of a salt can be carried out simultaneously.

[0048] Alternatively, instead of contacting the crude safinamide with the basic adsorbent, the salt of the crude safinamide and the basic adsorbent may be contacted.

Examples

[0049] Hereinafter, the present invention will be described in detail with reference to examples, but the present invention is not limited by these examples. It is not limited.

[0050] <Example 1> (Production of the crude safinamide) A 10 L four-necked flask equipped with a stirring blade and a thermometer was charged with 238 g (1.91 mol) of L-alanine amide hydrochloride and 3.4 L of methanol, and stirred at about 20 °C under a nitrogen atmosphere. Further, 193 g (1.91 mol) of triethylamine was added, and the mixture was stirred at about 20 °C. Subsequently, 400 g (1.74 mol) of 4-[(3-fluorophenyl)methoxy]benzaldehyde was added, and the mixture was stirred at about 20 °C for 3 hours. After cooling to near 0 °C, 66 g (1.74 mol) of sodium borohydride was added little by little over 1 hour at 5 °C or lower. Then, the mixture was stirred at near 0 °C for 1 hour. After concentration under reduced pressure at 40 °C, 5.1 L of toluene and 3.0 L of water were added to the obtained residue, and the mixture was stirred at 60 °C for 1 hour. After standing at 60 °C for 15 minutes, the aqueous layer was removed, and the obtained organic layer was washed twice with 0.8 L of water. The washed organic layer was cooled to 20 °C and stirred at around the same temperature for 1 hour. The precipitate was filtered off, and the obtained solid was washed three times with 0.4 L of toluene. The obtained wet solid was dried under reduced pressure at 40 °C for 14 hours to obtain 383 g (1.27 mol) of a crude product of safinamide ((S)-2-[[4-[(3-fluorobenzyloxy]benzyl]amino]propanamide). As a result of analyzing the crude product by HPLC, the purity of safinamide was 98.56%, the content of SN-IP was 0.51%, and the content of other impurities was at most 0.32%.

[0051] (Treatment of the adsorbent for the crude safinamide) A 500 mL four-necked flask equipped with a stirring blade and a thermometer was charged with 10 g (33.1 mmol) of the crude safinamide obtained in Example 1 and 300 mL of ethyl acetate, and stirred at 65 °C for 30 minutes. Subsequently, 1 g of basic silica gel was added as an adsorbent, and the mixture was stirred at 65 °C for 2 hours. The basic silica gel was filtered off to obtain a solution containing safinamide. As a result of analyzing the solution by HPLC, the purity of safinamide was 99.23%, the content of SN-IP was 0.03%, and the content of other impurities was at most 0.28%. Further, as a result of quantitatively analyzing the content of safinamide in the solution by HPLC, it was 9.3 g, and the recovery rate of safinamide in the contacting operation was 93%.

[0052] (Production of the mesylate of safinamide) To a 500 mL four-necked flask equipped with a stirring blade and a thermometer, a solution containing the above safinamide was added, and after stirring at 55 °C, 3.5 g (36.4 mmol) of methanesulfonic acid was added dropwise at 65 °C or lower over 40 minutes. It was cooled to 20 °C and stirred at around the same temperature for 2 hours. The precipitate was filtered off, and the obtained solid was washed 3 times with 33 mL of ethyl acetate. The obtained wet solid was dried under reduced pressure at 40 °C for 14 hours to obtain 11.8 g (29.6 mmol) of the mesylate of safinamide ((S)-2-[[4-[(3-fluorobenzyloxy]benzyl]amino]propanamide). The yield of the mesylate of safinamide based on the crude safinamide was 89.4%. Further, as a result of analyzing the mesylate by HPLC, the purity of safinamide was 99.89%, the content of SN-IP was 0.03%, and the content of other impurities was at most 0.07%.

[0053] <Examples 2 to 10, Comparative Examples 1 to 4> It was carried out in the same manner as in Example 1 except that no adsorbent was used or the type and amount of the adsorbent, the type of organic solvent, and the contact temperature with the adsorbent were changed. The conditions and results are shown in Table 2.

[0054] <Example 11> To a 500 mL four-necked flask equipped with a stirring blade and a thermometer, 10 g (25.1 mmol) of the mesylate of safinamide obtained in Comparative Example 1 and 300 mL of ethyl acetate were added, and the mixture was stirred at 65 °C for 30 minutes. Next, 1 g of basic silica gel was added, and the mixture was stirred at 65 °C for 2 hours. The basic silica gel was filtered off to obtain a solution containing the mesylate of safinamide. As a result of analyzing the solution by HPLC, the purity of safinamide was 99.89%, the content of SN-IP was 0.03%, and the content of other impurities was at most 0.07%. Further, as a result of quantitatively analyzing the content of the mesylate of safinamide in the solution by HPLC, it was 9.2 g, and the recovery rate of the mesylate of safinamide in the contact operation was 92%.

[0055] A solution containing the mesylate of safinamide was added to a 500 mL four-necked flask equipped with a stirring blade and a thermometer, and the mixture was stirred at 55 °C and then cooled to 20 °C and stirred at around this temperature for 2 hours. The precipitate was filtered off, and the resulting solid was washed three times with 33 mL of ethyl acetate. The obtained wet solid was dried under reduced pressure at 40 °C for 14 hours to obtain 8.7 g (21.8 mmol) of the mesylate of safinamide. As a result of analyzing the mesylate by HPLC, the purity of safinamide was 99.91%, the content of SN-IP was 0.03%, and the content of other impurities was at most 0.04%.

[0056] <Evaluation Test> The purity of safinamide and the contents of SN-IP and other impurities in the safinamide obtained in Example 1 and the mesylates of safinamide obtained in Examples 1 to 11 and Comparative Examples 1 to 4 were measured by HPLC (high performance liquid chromatography). The apparatus and measurement conditions used for the measurement were as follows.

[0057] Apparatus: Liquid chromatograph (manufactured by Waters Corporation) Detector: Ultraviolet absorptiometer (manufactured by Waters Corporation) Measurement wavelength: 220 nm Column: A stainless steel tube with an inner diameter of 4.6 mm and a length of 250 mm filled with octadecylsilylated silica gel for liquid chromatography

[0058] Column temperature: Constant temperature around 40 °C Mobile phase A: 10 mM phosphoric acid (pH 7.0) Mobile phase B: Acetonitrile Measurement time: 50 minutes Liquid feeding of the mobile phase: The concentration gradient control is carried out by changing the mixing ratio of mobile phase A and mobile phase B as shown in Table 1.

[0059]

Table 1

[0060] ​In the HPLC analysis under the said conditions, the retention time of safinamide derived from safinamide or its salt is around 14.2 minutes, and its purity is the ratio of the peak area value of safinamide to the total of the area values of all peaks measured under the said conditions. On the other hand, the retention time of SN-IP is around 4.1 minutes, and its content is the ratio of the peak area value of SN-IP to the total of the area values of all peaks measured under the said conditions. Similarly, the content of other impurities is also indicated by the ratio of the peak area value of each impurity to the total of the area values of all peaks. The detection limit value of impurities under the said conditions is 0.003% as the content. Further, when measuring the salt of safinamide, if a peak of the acid forming the salt is detected, the said peak is excluded and the purity of the said safinamide, the content of SN-IP and other impurities are evaluated. Incidentally, when measuring the mesylate salt of safinamide, methanesulfonic acid is not detected.

[0061]

Table 2

[0062] The preferred embodiments of the invention are appended below. [1] A process for producing (S)-2-[[4-(3-fluorobenzyloxy)benzyl]amino]propanamide or a salt thereof, comprising contacting a crude form of (S)-2-[[4-[(3-fluorobenzyl)oxy]benzyl]amino]propanamide or a salt thereof with a basic adsorbent in the presence of a first solvent. [2] The crude form of (S)-2-[[4-[(3-fluorobenzyl)oxy]benzyl]amino]propanamide or a salt thereof contains (S)-2-[[4-[(3-fluorobenzyl)oxy]benzyl]amino]propionic acid represented by the following formula (2), and the production method according to [1].

[0063]

Chemical formula

[0064] [3] The crude form of the (S)-2-[[4-[(3-fluorobenzyloxy]benzyl]amino]propanamide or a salt thereof is obtained by reducing the (S)-2-[4-(3-fluorobenzyloxy)benzylideneamino]propanamide obtained by contacting 4-[(3-fluorophenyl)methoxy]benzaldehyde with L-alanine amide hydrochloride, according to the production method described in [1] or [2]. [4] The contact between the crude form of the (S)-2-[[4-[(3-fluorobenzyl)oxy]benzyl]amino]propanamide or a salt thereof and the basic adsorbent is carried out in the presence of an acid, according to the production method described in any one of [1] to [3]. [5] The basic adsorbent is at least one selected from the group consisting of basic alumina and basic silica gel, according to the production method described in any one of [1] to [4]. [6] The first solvent contains at least one selected from the group consisting of esters, ketones, alcohols, ethers, nitriles, and aromatic hydrocarbons, according to the production method described in any one of [1] to [5]. [7] The contact between the crude form of the (S)-2-[[4-[(3-fluorobenzyl)oxy]benzyl]amino]propanamide or a salt thereof and the adsorbent is carried out within the range of 0 °C or higher and the reflux temperature or lower, according to the production method described in any one of [1] to [6].

Claims

1. A method for producing (S)-2-[[4-(3-fluorobenzyloxy)benzyl]amino]propanamide or a salt thereof, comprising contacting a crude form of (S)-2-[[4-[(3-fluorobenzyl)oxy]benzyl]amino]propanamide or a salt thereof with a basic adsorbent in the presence of a first solvent.

2. The method according to claim 1, wherein the crude form of (S)-2-[[4-[(3-fluorobenzyl)oxy]benzyl]amino]propanamide or a salt thereof contains (S)-2-[[4-[(3-fluorobenzyl)oxy]benzyl]amino]propionic acid represented by the following formula (2). 【Chemical 1】

3. The method according to claim 1, wherein the crude form of (S)-2-[[4-[(3-fluorobenzyloxy]benzyl]amino]propanamide or a salt thereof is obtained by reducing (S)-2-[4-(3-fluorobenzyloxy)benzylideneamino]propanamide obtained by contacting 4-[(3-fluorophenyl)methoxy]benzaldehyde with L-alanine amide hydrochloride.

4. The method according to claim 1, wherein the contact between the crude form of (S)-2-[[4-[(3-fluorobenzyl)oxy]benzyl]amino]propanamide or a salt thereof and the basic adsorbent is carried out in the presence of an acid.

5. The method according to claim 1, wherein the basic adsorbent is at least one selected from the group consisting of basic alumina and basic silica gel.

6. The method according to claim 1, wherein the first solvent contains at least one selected from the group consisting of esters, ketones, alcohols, ethers, nitriles, and aromatic hydrocarbons.

7. The method according to claim 1, wherein the contact between the crude form of (S)-2-[[4-[(3-fluorobenzyl)oxy]benzyl]amino]propanamide or a salt thereof and the adsorbent is carried out within a range of 0°C or higher and the reflux temperature or lower.

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