Safinamide 1 salt and its manufacturing method, safinamide mesylate manufacturing method, and safinamide purification method

Abstract

This invention provides a method for producing safinamide and its salts that have high optical purity with reduced enantiomerity. [Solution] A method for producing a salt of safinamide having high optical purity is provided, by contacting a mixture containing safinamide and its enantiomers with an acid selected from the group consisting of L-tartaric acid, L-glutamic acid, and D-mandelic acid in a reaction solvent.

Description

Technical Field

[0001] The present invention relates to a first acid salt of safinamide and a method for producing the same, a method for producing safinamide mesylate, and a method for purifying safinamide.

Background Art

[0002] (S)-2-[[4-[(3-Fluorobenzyl)oxy]benzyl]amino]propanamide is represented by the following formula (I) and is an organic compound having the composition formula C H 19 FN2O2. Hereinafter, (S)-2-[[4-[(3-fluorobenzyl)oxy]benzyl]amino]propanamide is also referred to as safinamide. This safinamide is a monoamine oxidase B (MAO-B) inhibitor and is useful for the treatment of Parkinson's disease and the like (see Patent Document 1).

[0003]

Chemical Formula

[0004] As a method for producing safinamide, for example, in Patent Document 1, (S)-2-[[4-[(3-fluorobenzyl)oxy]benzylidene]amino]propanamide (IV), which is a Schiff base, is synthesized from 4-(3-fluorobenzyloxy)benzaldehyde (II) and L-alanine amide hydrochloride (III), and this is reduced using catalytic hydrogenation, a hydride reducing agent, or the like to synthesize safinamide (I).

[0005]

Chemical Formula

Prior Art Documents

Patent Documents

[0006]

Patent Document 1

[0007] The object of the present invention is to provide a method for producing safinamide and its salts that have high optical purity with reduced enantiomerity. [Means for solving the problem]

[0008] In response to the above-mentioned problems, the present inventors diligently investigated methods for producing safinamide. As a result, they found that by contacting a mixture containing safinamide and its enantiomers with a specific optically active acid in a reaction solvent to obtain a safinamide salt, the enantiomers contained in the resulting safinamide salt can be significantly reduced.

[0009] In other words, the present invention is a method for producing a first salt of safinamide, characterized by contacting a first mixture containing safinamide and its enantiomers with a first acid selected from the group consisting of L-tartaric acid, L-glutamic acid, and D-mandelic acid in a reaction solvent to obtain a first salt of safinamide. The production method of the present invention can preferably be adopted in the following embodiments.

[0010] 1) Further comprising contacting the first mixture and the first acid in the reaction solvent to obtain a first solution, and precipitating the first salt of safinamide in the first solution. 2) The reaction solvent contains water. 3) The reaction solvent is a mixed solvent of water and a first organic solvent selected from the group consisting of methanol, 2-propanol, acetonitrile, and acetone. 4) In the mixed solvent, the ratio V1 / V2 of the volume of water V1 to the volume of the first organic solvent V2 is 0.5 or more and 10 or less. 5) The amount of the first acid with respect to 1 mol of the safinamide is 0.5 mol or more and 3 mol or less. 6) The amount of the reaction solvent with respect to 1 g of the safinamide is 3 mL or more and 50 mL or less.

Advantages of the Invention

[0011] According to the production method of the present invention, safinamide having a high optical purity with reduced enantiomers and its salts can be produced.

Brief Description of the Drawings

[0012] [Figure 1] Graph of the X-ray diffraction chart of the safinamide tartrate according to Example 2. [Figure 2] Digital microscope image of the safinamide tartrate according to Example 2. [Figure 3] TG-DTA spectrum of the safinamide tartrate according to Example 2. [Figure 4] DSC spectrum of the safinamide tartrate according to Example 2. [Figure 5] Graph of the X-ray diffraction chart of the safinamide mesylate. [Figure 6] Graph of the X-ray diffraction chart of the safinamide tartrate according to Example 10. [Figure 7] Digital microscope image of the safinamide tartrate according to Example 10.

Modes for Carrying Out the Invention

[0013] The safinamide obtained by the method of Patent Document 2 contains, as an impurity, the enantiomer of safinamide, (R)-2-[[4-[(3-fluorobenzyl)oxy]benzyl]amino]propanamide (IA):

[0014]

Chemical Formula

[0015] This impurity (IA) may be present. This impurity is difficult to reduce even during the mesylate conversion process, and is present in safinamide mesylate (V), which is used as a pharmaceutical raw material:

[0016] [ka]

[0017] It may still remain in that case.

[0018] In the method described in Patent Document 2, the content of impurities (IA) in safinamide is the enantiomer (IIIA) present as an impurity in the raw material L-alaninamide hydrochloride (III):

[0019] [ka]

[0020] This can depend on the content of certain components. Therefore, to reduce impurities (IA), it may be necessary to use high-purity L-alanineamide(III), which can increase manufacturing costs.

[0021] In the method described in Patent Document 2, the content of impurities (IA) in safinamide may depend on the reaction conditions of the Schiff base (IV) formation reaction. Therefore, precise control of the reaction may be necessary to reduce the amount of impurities (IA).

[0022] [ka]

[0023] The present invention is characterized by contacting a first mixture containing safinamide and its enantiomers with a first acid selected from the group consisting of L-tartaric acid, L-glutamic acid, and D-mandelic acid in a reaction solvent to obtain a first salt of safinamide. This method makes it possible to produce safinamide and its salts with higher optical purity compared to conventional methods.

[0024] The manufacturing method of the present invention will be described below.

[0025] <First mixture> The first mixture comprises safinamide and its enantiomers. The first mixture is not particularly limited and can be commercially available or produced by known methods. Examples of known production methods include those described in Patent Documents 1, 2, and 3.

[0026] Specifically, safinamide can be obtained by the following method. First, 4-(3-fluorobenzyloxy)benzaldehyde (II), L-alaninamide hydrochloride (III), and triethylamine are dissolved in methanol to synthesize the Schiff base (S)-2-[[4-[(3-fluorobenzyl)oxy]benzylidene]amino]propanamide (IV). After reducing the resulting methanol solution with sodium borohydride and then removing the solvent, safinamide (I) can be produced.

[0027] [ka]

[0028] Alternatively, safinamide (I) can be produced by dissolving 1-[[4-(chloromethyl)phenoxy]methyl]-3-fluorobenzene (VI), L-alaninamide hydrochloride (III), calcium hydroxide, and potassium iodide in dimethyl sulfoxide.

[0029] [ka]

[0030] The purity of safinamide produced as described above, when analyzed by liquid chromatography (HPLC) under the conditions described in the examples, is, for example, 90.0-99.9%, although this varies depending on the production conditions. Safinamide may also contain its enantiomer (IA). The content of enantiomer (IA) as determined by HPLC is, for example, 0.10-1.00%.

[0031] The first mixture may be in any form, such as powder, lump, liquid, or a mixture thereof, and may also be in a wet or solution state containing water, an organic solvent, etc.

[0032] <First acid> The first acid comprises at least one acid selected from the group consisting of L-tartaric acid, L-glutamic acid, and D-mandelic acid.

[0033] L-tartaric acid, L-glutamic acid, and D-mandelic acid are not particularly limited and can be commercially available or produced by known methods.

[0034] The amount of the first acid is not particularly limited, but it is preferably, for example, 0.5 moles or more, and more preferably 0.5 moles or more and 3 moles or less, per mole of safinamide.

[0035] L-tartaric acid, L-glutamic acid, and D-mandelic acid may be in any form, such as powder, lump, liquid, or a mixture thereof, and may also be in a wet or solution form containing water or an organic solvent.

[0036] <Contact in the reaction solvent> The first salt of safinamide can be obtained by contacting a first mixture containing safinamide and its enantiomers with a first acid in a reaction solvent. Specifically, the first mixture and the first acid are dissolved by heating and stirring in a reaction solvent to obtain a first solution. By cooling the first solution to a suitable temperature, crystals of the first salt of safinamide are precipitated. The first salt of safinamide can be obtained by cooling and filtering the resulting suspension.

[0037] In the precipitation of the first salt of safinamide, it is preferable to add a seed crystal, i.e., a small amount of crystal of the first salt of safinamide. The temperature at which the seed crystal is added varies depending on the manufacturing conditions and is not limited, but it is preferably between 25°C and 45°C. Considering the reproducibility of the process, the manufacturing speed, and the quality of the resulting crystals, it is preferable to add the seed crystal.

[0038] Furthermore, the first salt of safinamide obtained by the above method can be used as a seed crystal in the production of the first salt of safinamide.

[0039] In the present invention, the improvement in optical purity is due to the difference in solubility in the solvent between the first salt of safinamide and the first salt of its enantiomer. Therefore, it is preferable to use a solvent with a large difference in solubility as the reaction solvent. This varies depending on the type of acid, but for example, water can be used. As alcohols, methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, isobutyl alcohol, and tert-butyl alcohol can be used, as well as acetonitrile, acetone, and 1,4-dioxane, and these can be used in combination. Furthermore, a mixed solvent of water and an organic solvent selected from the group consisting of methanol, 2-propanol, acetonitrile, and acetone can be used as the reaction solvent. When using a mixed solvent, the ratio V1 / V2 of the volume of water to the volume of the organic solvent is preferably 0.1 or more, and more preferably 0.5 or more and 10 or less.

[0040] The reaction solvent may consist solely of water. By using a reaction solvent consisting only of water, crystals of the first salt of safinamide, which have the characteristic peaks described later, can be obtained.

[0041] The amount of reaction solvent is not particularly limited, but it is preferably, for example, 1 mL or more, more preferably 3 mL or more, and even more preferably 3 mL to 50 mL per 1 g of safinamide.

[0042] The contact temperature in the reaction solvent is not particularly limited, but is preferably 20°C or higher, more preferably 40°C or higher, and even more preferably 60°C to 80°C.

[0043] The contact time in the reaction solvent is not particularly limited, however, for longer contact times, impurities such as (S)-2-[[4-[(3-fluorobenzyl)oxy]benzyl]amino]propionic acid (IB):

[0044] [ka]

[0045] This may result in the formation of by-products. For this reason, the contact time is preferably 24 hours or less, more preferably 12 hours or less, and even more preferably 2 hours or more and 6 hours or less.

[0046] <Safinamide I salt> The safinamide salt 1 obtained by the above method has a high purity of 99.9% or more, although this varies depending on the manufacturing conditions, and also has high optical purity with enantiomer content of 0.10% or less.

[0047] The first salt of safinamide is represented by the following formula (VII). In the following formula, X is at least one first acid selected from the group consisting of L-tartaric acid, L-glutamic acid, and D-mandelic acid.

[0048] [ka]

[0049] The first salt of safinamide may take the form of a solvate or solvate, depending on the manufacturing conditions, and both are included within the scope of the present invention. As a solvate, it may take the form of a hydrate containing water molecules, for example, or an organic solvent hydrate containing organic solvent molecules. That is, the first salt of safinamide may be the solvate, solvate, or a mixture thereof.

[0050] The structure of the first salt of the obtained safinamide can be confirmed, for example, by nuclear magnetic resonance (NMR) spectroscopy.

[0051] The obtained safinamide 1 salt can be purified in terms of its purity and optical purity by any method. Specifically, the safinamide 1 salt can be purified by dissolving it in water by heating, then cooling and precipitating it. The obtained safinamide 1 salt may be further washed.

[0052] The first salt of safinamide preferably has peaks in the powder X-ray diffraction chart using Cu-Kα rays, with diffraction angles 2θ within the ranges of 5.4±0.2°, 16.2±0.2°, 21.7±0.2°, 23.4±0.2°, and 27.3±0.2°. Such a first salt of safinamide has relatively large crystal particles, which has the advantage of improved handling during production. Such a first salt of safinamide can be obtained, for example, by using water alone as the reaction solvent. The first salt of safinamide having these peaks is preferably safinamide L-tartrate monohydrate.

[0053] The measurement conditions for the powder X-ray diffraction chart of the first salt of safinamide are, for example, as follows:

[0054] Measurement device: D2 PHASER (manufactured by BRUKER) Target: Cu Voltage: 30kV Current: 10mA Step width: 0.02° Step time: 0.10 seconds 2θ scanning range: 5.0~60.0° When safinamide L-tartrate monohydrate is heated at a rate of 10°C / min, it may exhibit the thermogravimetric (TG-DTA) spectrum shown in Figure 3. In this TG spectrum, the crystal shows a weight loss of approximately 4% due to dehydration at approximately 105°C.

[0055] When safinamide L-tartrate monohydrate is heated at a rate of 10°C / min, it may exhibit the differential scanning calorimetry (DSC) spectrum shown in Figure 4. In this DSC spectrum, the crystal shows endothermic peaks at approximately 119°C and 129°C.

[0056] <Method for producing safinamide mesylate> Safinamide mesylate can be produced using the first salt of safinamide obtained by the above method as an intermediate. There are no particular restrictions on the method of production, but for example, it can be produced by desalting the salt of safinamide, that is, by extracting safinamide using an organic solvent under basic conditions, and then adding methanesulfonic acid to the resulting solution containing safinamide. The resulting safinamide mesylate has a high purity of 99.9% or more, depending on the production conditions, and a high optical purity with enantiomer content of 0.10% or less.

[0057] <Improvement of optical purity> Improvement of optical purity means that, in an optically active compound that may contain both enantiomers, the proportion of the target compound relative to the proportion of its enantiomers increases. In other words, according to the present invention, using a mixture containing safinamide and its enantiomers, the proportion of safinamide or its salt can be increased relative to the proportion of safinamide's enantiomers or its salts. [Examples]

[0058] The present invention will be described in detail below with reference to manufacturing examples, embodiments, and comparative examples, but the present invention is not limited by these manufacturing examples, embodiments, and comparative examples.

[0059] The structure of the first salt of safinamide obtained in the examples is: 1 This was confirmed by NMR spectroscopy based on H-NMR data.

[0060] The purity and optical purity of safinamide obtained in the manufacturing examples, case studies, and comparative examples were measured by the following methods.

[0061] <Purity of Safinamide> The purity of safinamide was measured by HPLC (high-performance liquid chromatography). The equipment and measurement conditions used are as follows:

[0062] Equipment: High-performance liquid chromatography (HPLC) Model: Alliance e2695 (Waters Corporation) Detector: Ultraviolet absorption altimeter (λ=220nm) Column: Inertsil ODS-3 (particle size: 5 μm, inner diameter: 4.6 mm, column length: 250 mm) (manufactured by GL Sciences Co., Ltd.) Column temperature: 40℃ Sample temperature: 15℃ Injection volume: 10μL Solvent: Water / acetonitrile mixture (6:4) Mobile phase A: 1.74 g of dipotassium hydrogen phosphate is dissolved in 1000 mL of distilled water, and the pH is adjusted to 7.0 by adding phosphoric acid. Mobile phase B: Acetonitrile Flow rate: 1.0mL / min Measurement time: 50 minutes Mobile phase delivery: The concentration gradient was controlled by changing the mixing ratio of mobile phase A and mobile phase B as shown in Table 1 below.

[0063] [Table 1]

[0064] Under the above HPLC conditions, the safinamide(I) peak is observed at approximately 15.0 minutes. In the following manufacturing examples and examples, the purity of safinamide is the peak area % value measured under the above conditions.

[0065] <Optical purity of safinamide> The optical purity of safinamide and its salts was measured by HPLC (High-Performance Liquid Chromatography). The equipment and measurement conditions used are as follows.

[0066] Equipment: High-performance liquid chromatography (HPLC) Model: Alliance e2695 (Waters Corporation) Detector: Ultraviolet absorption altimeter (λ=226nm) Two Chiralpak IB columns (particle size: 5 μm, inner diameter: 4.6 mm, column length: 250 mm) (manufactured by Daicel Corporation) are connected in series. Column temperature: 25℃ Sample temperature: 15℃ Injection volume: 20μL Solvent: Water / acetonitrile mixture (6:4) Mobile phase A: Dissolve 12.0 g of sodium dihydrogen phosphate in 800 mL of distilled water, add phosphoric acid to adjust the pH to 3.0, then add distilled water to make a total volume of 1000 mL. Prepare the solution by adding 300 mL of methanol and 50 mL of acetonitrile to 650 mL of this solution. Mobile phase B: Prepared by adding 100 mL of acetonitrile to 600 mL of methanol. Flow rate: 0.7mL / min Measurement time: 100 minutes Mobile phase delivery: The concentration gradient was controlled by changing the mixing ratio of mobile phase A and mobile phase B as shown in Table 2 below.

[0067] [Table 2]

[0068] Under the above HPLC conditions, the peak for safinamide (I) was observed at approximately 34.4 minutes, and the peak for its enantiomer (IA) was observed at approximately 36.4 minutes. In the following production examples, case studies, and comparative examples, the content of enantiomers in safinamide and safinamide salts is expressed as the peak area % value measured under the above conditions.

[0069] <Powder X-ray diffraction spectrum> The powder X-ray diffraction spectrum of the first salt of safinamide was measured using an X-ray diffractometer. The equipment and measurement conditions used are as follows.

[0070] Equipment: X-ray diffractometer Model: D2 PHASER (manufactured by BRUKER) Target: Cu Voltage: 30kV Current: 10mA Step width: 0.02° Step time: 0.10 seconds 2θ scanning range: 5.0~60.0° <Thermogravimetric measurement (TG-DTA)> The thermal analysis of the first salt of safinamide was performed using a differential thermogravimetric analyzer. The equipment and measurement conditions used are as follows.

[0071] Equipment: Simultaneous differential thermogravimetry measurement equipment Model: TG8120 (manufactured by Rigaku Corporation) Sample cell: Aluminum pan Heating rate: 10℃ / min Temperature range: 20~260℃ <Differential Scanning Calorimetry (DSC)> The thermal analysis of the first salt of safinamide was performed using a differential scanning calorimeter. The equipment and measurement conditions used are as follows.

[0072] Equipment: Differential scanning calorimeter Model: DSC8230 (manufactured by Rigaku Corporation) Sample cell: Aluminum pan Heating rate: 10℃ / min Temperature range: 20~260℃ <Manufacturing Example 1> (Example of safinamide(I) crystal production) 2.98 g of L-alaninamide hydrochloride (III) and 3.33 mL of triethylamine were dissolved in 42.5 mL of methanol and stirred at 25°C for 15 minutes. 5.00 g of 4-(3-fluorobenzyloxy)benzaldehyde (II) was added and the mixture was stirred at 25°C for 3 hours. The methanol solution of the resulting (S)-2-[[4-[(3-fluorobenzyl)oxy]benzylidene]amino]propanamide (IV) was cooled to 0°C. 0.822 g of sodium borohydride was slowly added to this solution so that the liquid temperature did not exceed 5°C. After the addition, the mixture was stirred at 0°C for 1 hour. The methanol solution of the resulting safinamide (I) was distilled under reduced pressure. 40.0 mL of toluene, 20.0 mL of water, and 2.00 g of sodium carbonate were added to this solution and the mixture was heated to 80°C and stirred. The aqueous layer was removed, and 20.0 mL of water was added again to the organic layer containing safinamide. The separation of the aqueous and organic layers was repeated at 80°C using the same procedure. 20.0 mL of toluene was added to the organic layer, and the mixture was heated and stirred at 80°C. The organic layer containing safinamide was slowly cooled to 25°C and stirred at 25°C for 3 hours. This suspension was filtered, and the resulting crystals were washed three times with 5.00 mL of toluene to obtain safinamide(I) crystals. The HPLC purity of the obtained safinamide(I) crystals was 99.83%, and the enantiomer (IA) content was 0.152%.

[0073] <Example 1> (Preparation of safinamide L-tartrate seed crystals) To 1.00 g of safinamide (I) crystals obtained by Preparation Example 1, 5.00 mL of water and 1.00 mL of methanol were added and heated to 65°C, then stirred. 0.496 g of L-tartaric acid was added and stirred for 15 minutes. This was cooled to 20°C. This was filtered, and the resulting crystals were washed with 1.00 mL of water to obtain safinamide L-tartrate (VIII):

[0074] [ka]

[0075] We obtained the seed crystal.

[0076] (Example of safinamide L-tartrate manufacturing) To 1.00 g of safinamide(I) crystals obtained by Preparation Example 1, 5.00 mL of water and 1.00 mL of methanol were added and heated to 65°C, and the mixture was stirred. 0.496 g of L-tartaric acid was added and the mixture was stirred for 15 minutes. The mixture was cooled to 60°C, and seed crystals of safinamide L-tartrate(VIII) were added and the mixture was stirred for 30 minutes. This suspension was cooled to 20°C. The mixture was filtered, and the resulting crystals were washed with 1.00 mL of water to obtain safinamide L-tartrate(VIII) crystals. The HPLC purity of the obtained safinamide L-tartrate(VIII) was 99.90%, and the yield and enantiomer content are shown in Table 3.

[0077] The NMR spectroscopic analysis results of the obtained safinamide L-tartrate were as follows.

[0078] 1 H-NMR(400MHz,D2O)δ1.55(d,J=7.85Hz,3H),4.00(q,J=7.22Hz,1H),4.16(s,2H),4.51(s,2H),5.18(s,2H),7. 07-7.14(m,3H),7.23(d,J=9.73Hz,1H),7.28(d,J=7.85Hz,1H),7.39(d,J=8.16Hz,2H),7.43(q,J=5.89Hz,1H) <Examples 2-7 and Comparative Examples 1-4> Each of the first salts of safinamide was obtained in the same manner as in Example 1, except that the solvents used were changed from water and methanol to the solvent types and amounts shown in Table 3, and L-tartaric acid was changed to the optically active acid shown in Table 3.

[0079] [Table 3]

[0080] Figure 1 shows the powder X-ray diffraction spectrum of safinamide L-tartrate obtained in Example 2, Table 4 shows the diffraction angle 2θ, Figure 2 shows the digital microscope image, Figure 3 shows the TG-DTA spectrum, and Figure 4 shows the DSC spectrum. The safinamide L-tartrate obtained in Example 2 is considered to be a monohydrate.

[0081] [Table 4]

[0082] The NMR spectroscopic analysis results of safinamide L-glutamate obtained in Example 6 are as follows.

[0083] 1 H-NMR(400MHz,D2O)δ1.55(d,J=6.91Hz,3H),2.03-2.16(m,2H),2.35-2.43(m,2H),3.75(dd,J=5.02Hz,3H),3.99(q,J=7.22Hz,1H),4.1 4(s,2H),5.16(s,2H),7.06-7.13(m,3H),7.22(d,J=9.73Hz,1H),7.27(d,J=7.53Hz,1H),7.39(d,J=8.79Hz,2H),7.42(q,J=5.96Hz,1H) The NMR spectroscopic analysis results of safinamide D-mandelate obtained in Example 7 are as follows.

[0084] 1 H-NMR(400MHz,D2O)δ1.54(d,J=7.22Hz,3H),3.99(q,J=6.91Hz,1H),4.16(s,2H),4.97(s,1H),5 .21(s,2H),7.06-7.15(m,3H),7.25(d,J=9.73Hz,1H),7.30(d,J=7.53Hz,1H),7.39-7.46(m,8H) <Example 8> To 1.50 g of safinamide L-tartrate (VIII) obtained in Example 1, 5.00 mL of water and 1.00 mL of methanol were added and heated to 65°C, and the mixture was stirred. This was cooled to 65°C, and a seed crystal of safinamide L-tartrate (VIII) was added and the mixture was stirred for 30 minutes. This suspension was cooled to 20°C. This was filtered, and the obtained crystals were washed with 1.00 mL of water to obtain safinamide L-tartrate (VIII) crystals. The HPLC purity of the obtained safinamide L-tartrate crystals was 99.92%, and the enantiomer (IA) content was 0.038%.

[0085] <Example 9> 12.0 mL of toluene and 3.90 mL of water were mixed with 1.20 g of sodium carbonate and heated to 50°C, then stirred. 1.50 g of safinamide L-tartrate (VIII) obtained in Example 1 was added, and the mixture was heated to 80°C and stirred. The aqueous layer was removed, and another 3.90 mL of water was added to the organic layer containing safinamide. The separation of the aqueous and organic layers was repeated at 80°C using the same procedure. The resulting safinamide (I) solution in toluene was distilled under reduced pressure. 19.3 mL of ethyl acetate was added, and the mixture was heated to 60°C and stirred. 0.215 mL of methanesulfonic acid was added dropwise, and the mixture was cooled to 25°C and stirred at 25°C for 3 hours. The suspension was filtered, and the resulting crystals were washed three times with 2.51 mL of ethyl acetate to obtain safinamide mesylate (V) crystals. The HPLC purity of the obtained safinamide mesylate (V) crystals was 99.95%, and the enantiomer (IA) content was 0.070%.

[0086] Figure 5 shows the powder X-ray diffraction spectrum of the obtained safinamide mesylate, and Table 5 shows the diffraction angle 2θ.

[0087] [Table 5]

[0088] <Example 10> 1.00 g of safinamide(I) crystals obtained by Preparation Example 1 was mixed with 10.0 mL of methanol and heated to 65°C, then stirred. 0.496 g of L-tartaric acid was added and stirred for 15 minutes, then cooled to 20°C. This suspension was filtered, and the resulting crystals were washed with 1.00 mL of methanol to obtain safinamide L-tartrate(VIII) crystals.

[0089] Figure 6 shows the powder X-ray diffraction spectrum of the obtained safinamide L-tartrate, Table 6 shows the diffraction angle 2θ, and Figure 7 shows the digital microscope image.

[0090] [Table 6]

[0091] Preferred embodiments are described below.

[0092] [1] A method for producing a primary salt of safinamide, comprising contacting a first mixture containing safinamide and its enantiomers with a first acid selected from the group consisting of L-tartaric acid, L-glutamic acid, and D-mandelic acid in a reaction solvent to obtain a primary salt of safinamide.

[0093] [2] The method for producing a product according to [1], further comprising contacting the first mixture with the first acid in the reaction solvent to obtain a first solution, and precipitating the first salt of safinamide in the first solution.

[0094] [3] The method of production according to [1] or [2], wherein the reaction solvent comprises water.

[0095] [4] The method for producing the reaction solvent according to [1] or [2], wherein the reaction solvent consists solely of water.

[0096] [5] The method for producing the product according to any one of [1] to [3], wherein the reaction solvent is a mixed solvent of water and a first organic solvent selected from the group consisting of methanol, 2-propanol, acetonitrile, and acetone.

[0097] [6] The manufacturing method according to [4], wherein in the mixed solvent, the ratio V1 / V2 of the volume of water V1 to the volume of the first organic solvent V2 is 0.5 or more and 10 or less.

[0098] [7] The method for producing the product according to any one of [1] to [5], wherein the amount of the first acid per mole of safinamide is 0.5 moles or more and 3 moles or less.

[0099] [8] The method for producing the product according to any one of [1] to [6], wherein the amount of the reaction solvent per 1 g of safinamide is 3 mL or more and 50 mL or less.

[0100] [9] A method for producing safinamide mesylate, comprising desalting the safinamide 1 salt obtained by any one of the methods in [1] to [7] and contacting it with methanesulfonic acid to obtain safinamide mesylate.

[0101]

[10] A purification method comprising contacting a first mixture containing safinamide and its enantiomers with a first acid selected from the group consisting of L-tartaric acid, L-glutamic acid, and D-mandelic acid in a reaction solvent to obtain a first salt of safinamide.

[0102]

[11] A salt of safinamide with a first acid selected from the group consisting of L-tartaric acid, L-glutamic acid, and D-mandelic acid.

[0103]

[12] The salt according to claim 11, wherein the X-ray diffraction chart using Cu-Kα rays has peaks within the range of diffraction angles 2θ of 5.4±0.2°, 16.2±0.2°, 21.7±0.2°, 23.4±0.2°, and 27.3±0.2°.

Claims

1. A method for producing a primary salt of safinamide, comprising contacting a first mixture containing safinamide and its enantiomers with a first acid selected from the group consisting of L-tartaric acid, L-glutamic acid, and D-mandelic acid in a reaction solvent to obtain a primary salt of safinamide.

2. The method for producing the product according to claim 1, further comprising contacting the first mixture with the first acid in the reaction solvent to obtain a first solution, and precipitating the first salt of safinamide in the first solution.

3. The manufacturing method according to claim 1, wherein the reaction solvent includes water.

4. The manufacturing method according to claim 1, wherein the reaction solvent consists solely of water.

5. The production method according to claim 1, wherein the reaction solvent is a mixed solvent of water and a first organic solvent selected from the group consisting of methanol, 2-propanol, acetonitrile, and acetone.

6. The manufacturing method according to claim 5, wherein in the mixed solvent, the ratio V1 / V2 of the volume of water V1 to the volume of the first organic solvent V1 is 0.5 or more and 10 or less.

7. The manufacturing method according to claim 1, wherein the amount of the first acid per mole of safinamide is 0.5 moles or more and 3 moles or less.

8. The manufacturing method according to claim 1, wherein the amount of the reaction solvent per 1 g of safinamide is 3 mL or more and 50 mL or less.

9. A method for producing safinamide mesylate, comprising desalting the first salt of safinamide obtained by the method of claim 1, and then contacting it with methanesulfonic acid to obtain safinamide mesylate.

10. A purification method comprising contacting a first mixture containing safinamide and its enantiomers with a first acid selected from the group consisting of L-tartaric acid, L-glutamic acid, and D-mandelic acid in a reaction solvent to obtain a first salt of safinamide.

11. A salt of safinamide with a first acid selected from the group consisting of L-tartaric acid, L-glutamic acid, and D-mandelic acid.

12. The salt according to claim 11, wherein the X-ray diffraction chart using Cu-Kα rays has peaks within the range of diffraction angles 2θ of 5.4±0.2°, 16.2±0.2°, 21.7±0.2°, 23.4±0.2°, and 27.3±0.2°.

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