Method for producing safinamide and its salts

Abstract

A method for producing highly pure safinamide with reduced impurities is provided. [Solution] A method for producing high-purity safinamide is provided by contacting a solid containing safinamide, toluene, and water at a temperature of 70°C or higher in the presence of a basic compound, and separating the mixture into an aqueous layer having a pH of 9 or higher and an organic layer containing the safinamide. The basic compound includes, for example, at least one selected from the group consisting of sodium carbonate, potassium carbonate, sodium hydroxide, and triethylamine.

Description

[Technical Field]

[0001] The present invention relates to a method for producing safinamide and its salts. [Background technology]

[0002] (S)-2-[[4-[(3-fluorobenzyl)oxy]benzyl]amino]propanamide is represented by the following formula (I), 17 H 19 It is an organic compound with the formula FN2O2. Hereinafter, (S)-2-[[4-[(3-fluorobenzyl)oxy]benzyl]amino]propanamide will also be referred to as safinamide. This safinamide is a monoaminooxidase B (MAO-B) inhibitor and is useful for treating Parkinson's disease, etc. (see Patent Document 1).

[0003] [ka]

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

[0005] [ka] [Prior art documents] [Patent documents]

[0006] [Patent Document 1] Patent No. 5460613 specification [Patent Document 2] U.S. Patent No. 1,122,5457 [Patent Document 3] Indian Patent No. 387233 Summary of the Invention [Problem to be solved by the invention]

[0007] An object of the present invention is to provide a simple method for producing highly pure safinamide and salts thereof with reduced impurities. [Means for solving the problem]

[0008] In order to solve the above problems, the present inventors have conducted extensive research into methods for producing safinamide, and as a result, have discovered that impurities in the resulting safinamide crystals can be significantly reduced by contacting an organic layer containing safinamide with an aqueous layer under basic conditions, separating the organic layer containing safinamide, and then performing a crystallization procedure.

[0009] That is, the present invention provides a method for producing safinamide, which comprises contacting a solid containing (S)-2-[[4-[(3-fluorobenzyl)oxy]benzyl]amino]propanamide (safinamide), toluene, and water at a temperature of 70°C or higher in the presence of a basic compound, and separating the mixture into an aqueous layer having a pH of 9 or higher and an organic layer containing the safinamide. The production method of the present invention can suitably adopt the following aspects.

[0010] 1) The basic compound includes at least one selected from the group consisting of sodium carbonate, potassium carbonate, sodium hydroxide, and triethylamine.

[0011] 2) The amount of toluene per 1 g of the solid containing safinamide is 3 mL or more and 30 mL or less.

[0012] 3) The amount of water per 1 g of the solid containing safinamide is 1 mL or more and 20 mL or less.

[0013] 4) The ratio V1 / V2 of the volume V1 of the toluene to the volume V2 of the water is 0.5 or more and 5 or less.

[0014] 5) The concentration of (S)-2-[[4-[(3-fluorobenzyl)oxy]benzyl]amino]propionic acid in the organic layer as determined by high performance liquid chromatography is 0.1% or less. [Effects of the Invention]

[0015] According to the production method of the present invention, safinamide and salts thereof having high chemical purity with reduced impurities can be produced by a simple procedure. DETAILED DESCRIPTION OF THE INVENTION

[0016] Safinamide obtained by the method of Patent Document 1 contains (S)-2-[[4-[(3-fluorobenzyl)oxy]benzyl]amino]propionic acid (IA): as an impurity by-produced by hydrolysis of safinamide.

[0017] [ka]

[0018] This impurity (IA) is difficult to reduce even in the mesylate conversion process, and safinamide mesylate (V):

[0019] [ka]

[0020] It may also remain in

[0021] Furthermore, in the method of Patent Document 3, it is necessary to extract safinamide as a hydrochloride salt and then desalt it again to obtain safinamide, which is a complicated procedure.

[0022] The present invention is characterized by contacting a solid containing safinamide, toluene, and water at a temperature of 70°C or higher in the presence of a basic compound, thereby separating into an aqueous layer having a pH of 9 or higher and an organic layer containing safinamide, i.e., subjecting crude safinamide to liquid separation treatment. This method makes it possible to easily produce highly pure safinamide compared to conventional methods. The reason for this is explained below.

[0023] The present inventors investigated a method for easily purifying crude safinamide by separating safinamide from the resulting organic layer. They found that high heating temperatures during the separation process accelerate hydrolysis of the amide moiety of safinamide, making it more likely to produce impurity (IA). They also found that lowering the heating temperature during the separation process prevents sufficient separation of the aqueous and organic layers. Investigating these problems, the present inventors conducted extensive research and found that separation under basic conditions can suppress the formation of impurity (IA) even at high heating temperatures. Furthermore, they found that the salt formed by the reaction of the carboxylic acid impurity (IA) with a base dissolves in the aqueous layer, allowing the impurity (IA) to be separated from the organic layer. Therefore, the method of the present invention can obtain an organic layer containing highly pure safinamide with a low content of impurity (IA), thereby enabling the simple production of highly pure safinamide.

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

[0025] <(S)-2-[[4-[(3-fluorobenzyl)oxy]benzyl]amino]propanamide (safinamide) solid> The solid safinamide is not particularly limited, and commercially available products or products produced by known methods can be used. Examples of known production methods include the methods described in Patent Documents 1, 2, and 3. Hereinafter, solid safinamide will also be referred to as crude safinamide.

[0026] Specifically, crude 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). Sodium borohydride is added to the resulting methanol solution for reduction, and the solvent is then removed to produce crude safinamide (I).

[0027] [ka]

[0028] In another production method, crude 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 crude safinamide produced as described above has a purity of, for example, 90.0 to 99.9% when analyzed by high performance liquid chromatography (HPLC) under the conditions described in the Examples, although this varies depending on the production conditions. Furthermore, the crude safinamide may contain an impurity (IA). The content of the impurity (IA) by HPLC is, for example, 0.01% to 1.00%.

[0031] The crude safinamide may be in any form, such as powder, lump, or a mixture thereof.

[0032] <Separation of aqueous and organic layers> The liquid separation treatment of the solid safinamide uses toluene as the solvent for the organic layer and water as the solvent for the aqueous layer.

[0033] The amount of toluene used as the solvent is sufficient to dissolve safinamide, and can be, for example, 1 mL or more, preferably 3 mL to 30 mL, and more preferably 5 mL to 15 mL, per g of a solid containing safinamide.

[0034] The water used is not particularly limited as long as it does not affect the operation of separating the aqueous layer and the organic layer, and for example, distilled water or ion-exchanged water can be used, as well as an aqueous solution in which an inorganic component or an organic component is dissolved, or a mixture thereof. The amount of water can be, for example, 0.5 mL or more, preferably 1 mL to 20 mL, and more preferably 2 mL to 10 mL, per gram of solid containing safinamide.

[0035] The ratio V1 / V2 of the volume V1 of toluene to the volume V2 of water can be, for example, 0.1 or more and 10 or less, preferably 0.5 or more and 5 or less, and more preferably 1 or more and 3 or less.

[0036] The contact of the safinamide-containing solid with toluene and water is carried out in the presence of a basic compound at a temperature of 70°C or higher. If the contact is carried out at a temperature lower than 70°C, the aqueous layer and the organic layer may not be sufficiently separated, and the amount of impurities in the organic layer may increase. The contact temperature is preferably 75°C or higher, and more preferably 80°C or higher but 90°C or lower.

[0037] After contacting a solid containing safinamide with toluene and water in the presence of a basic compound, the mixture can be separated into an organic layer and an aqueous layer, for example, by stirring while heating. The basic compound is added so that the pH of the resulting aqueous layer is 9.0 or higher. A high pH in the aqueous layer tends to reduce the amount of impurities in the organic layer. The pH of the aqueous layer is, for example, 9 or higher and 14 or lower, preferably 9.5 or higher, more preferably 10 or higher, and even more preferably 11 or higher.

[0038] The separation time is not particularly limited, and separation into an organic layer and an aqueous layer is completed in a relatively short time, for example, 5 minutes to 24 hours, preferably 10 minutes to 12 hours, and more preferably 10 minutes to 1 hour. The method for mixing the components is not particularly limited, and they can be mixed, for example, in a reaction vessel equipped with a stirrer. The order in which the components are added to the reaction vessel is not particularly limited.

[0039] This separation operation is preferably repeated. That is, water is further added to the organic layer obtained by the first separation, and the mixture is heated to 70°C or higher to separate into an organic layer and an aqueous layer, thereby obtaining the organic layer. The amount of water used in this step may be the same as or different from the amount used in the first separation. Furthermore, a basic compound or toluene may be further added. The organic layer obtained by the second separation may be further subjected to separation treatment.

[0040] <Basic compounds> The basic compound refers to a compound capable of increasing the pH of the aqueous layer. The basic compound is not limited, and may be an inorganic base, an organic base, or a combination of these. For example, at least one base selected from the group consisting of metal carbonates, metal hydroxides, metal hydrides, and metal bicarbonates is used. Specific examples of metal carbonates include at least one base selected from the group consisting of lithium carbonate, sodium carbonate, potassium carbonate, magnesium carbonate, and calcium carbonate. Specific examples of metal hydroxides include at least one base selected from the group consisting of lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium hydroxide, and calcium hydroxide. Specific examples of metal hydrides include at least one base selected from the group consisting of lithium hydride, sodium hydride, and potassium hydride. Specific examples of metal bicarbonates include at least one base selected from the group consisting of sodium bicarbonate and potassium bicarbonate. For example, at least one base selected from the group consisting of metal alkoxides, alkylamines, and heterocyclic amines is used. Specific examples of metal alkoxides include at least one selected from the group consisting of sodium methoxide and sodium ethoxide. Specific examples of alkylamines include at least one selected from the group consisting of dimethylamine, trimethylamine, diethylamine, triethylamine, diisopropylethylamine, tetramethylethylenediamine, piperidine, 4-methylmorpholine, and 1,4-diazabicyclo[2.2.2]octane. Specific examples of heterocyclic amines include at least one selected from the group consisting of pyridine, imidazole, and diazabicycloundecene. Of these, it is preferable to use at least one selected from the group consisting of sodium carbonate, potassium carbonate, sodium hydroxide, and triethylamine from the viewpoints of operability and cost.

[0041] These basic compounds may be used alone or in combination.

[0042] Furthermore, these basic compounds may be in any form, such as powder, lump, liquid, or a mixture thereof, or may be in the form of a wet substance or solution containing water or an organic solvent.

[0043] <Safinamide crystals> The purity of the safinamide contained in the organic layer obtained by the above method can be improved or isolated by any method. Specifically, it is preferable to isolate safinamide crystals by crystallization by cooling the organic layer. The safinamide isolated by this method has a high chemical purity of 99.5% or more and can be obtained in a high yield. The obtained crystals may be further washed.

[0044] Furthermore, the concentration of the impurity (IA) in the organic layer obtained by the above method, as determined by high performance liquid chromatography, is preferably 0.15% or less, and more preferably 0.1% or less when considering use for pharmaceutical purposes after a mesylation step.

[0045] <Method for producing safinamide mesylate> The safinamide crystals obtained by the above method can be used as an intermediate to produce safinamide mesylate. The production method is not particularly limited and any known method can be used, for example, by adding methanesulfonic acid to a solution in which safinamide crystals have been dissolved. [Example]

[0046] The present invention will be described in detail below with reference to Production Examples, Examples, and Comparative Examples, but the present invention is not limited to these Production Examples, Examples, and Comparative Examples.

[0047] The purity and impurity contents of safinamide obtained in the Production Examples, Examples, and Comparative Examples were measured by the following methods.

[0048] <Measurement of safinamide purity and impurity content> The purity of safinamide and the contents of other impurities in the safinamide obtained in Production Example 1, Examples 1 to 6, and Comparative Examples 1 to 3 were measured by HPLC (high performance liquid chromatography). The apparatus and measurement conditions used for the measurements are as follows. Equipment: High performance liquid chromatography (HPLC) Model: Alliance e2695 (Waters) Detector: Ultraviolet absorption altimeter (λ=220nm) Column: Inertsil ODS-3 (particle size: 5 μm, inner diameter: 4.6 mm, column length: 250 mm) (GL Sciences) Column temperature: 40℃ Sample temperature: 15℃ Injection volume: 10μL Dissolution solvent: Water / acetonitrile mixture (6:4) Mobile phase A: Dissolve 1.74 g of dipotassium hydrogen phosphate in 1000 mL of distilled water, and add phosphoric acid to adjust the pH to 7.0. Mobile phase B: acetonitrile Flow rate: 1.0mL / min Measurement time: 50 minutes Mobile phase delivery: The mixing ratio of mobile phase A and mobile phase B was changed as shown in Table 1 below to control the concentration gradient.

[0049] [Table 1]

[0050] Under the above HPLC conditions, the peak of safinamide (I) is observed at approximately 15.0 minutes, and the peak of (S)-2-[[4-[(3-fluorobenzyl)oxy]benzyl]amino]propionic acid (IA) is observed at approximately 5.0 minutes. In the following examples and comparative examples, the purity of safinamide and the content of impurities are both values ​​of peak area % measured under the above conditions.

[0051] <Production Example 1> (Preparation Example of Methanol Solution of (S)-2-[[4-[(3-fluorobenzyl)oxy]benzylidene]amino]propanamide (IV)) 2.98 g of L-alaninamide hydrochloride (III) and 3.33 mL of triethylamine were dissolved in 42.5 mL of methanol and stirred for 15 minutes at 25° C. 5.00 g of 4-(3-fluorobenzyloxy)benzaldehyde (II) was added thereto and stirred for 3 hours at 25° C. This yielded a methanol solution of (S)-2-[[4-[(3-fluorobenzyl)oxy]benzylidene]amino]propanamide (IV).

[0052] (Example of production of crude safinamide (I)) The resulting methanol solution of (S)-2-[[4-[(3-fluorobenzyl)oxy]benzylidene]amino]propanamide (IV) was cooled to 0°C. 0.822 g of sodium borohydride was added slowly to this so that the liquid temperature did not exceed 5°C. After the addition, the mixture was stirred at 0°C for 1 hour. The resulting methanol solution of safinamide was distilled under reduced pressure to obtain crude safinamide (I).

[0053] Example 1 To 1.60 g of crude safinamide (I) obtained in Preparation Example 1, 8.00 mL of toluene, 4.00 mL of water, and 400 mg of sodium carbonate were added, and the mixture was heated to 80°C and stirred. The aqueous layer was removed, and 4.00 mL of water was added to the organic layer containing safinamide. The same procedure for separating the aqueous and organic layers was repeated at 80°C. 4.00 mL of toluene was added to the organic layer, and the mixture was heated to 80°C and stirred. The organic layer containing safinamide was slowly 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 1.00 mL of toluene to obtain crystals of safinamide (I). Table 2 shows the pH of the aqueous layer at the first separation, the HPLC purity of the resulting safinamide (I) crystals, and the content of the impurity (S)-2-[[4-[(3-fluorobenzyl)oxy]benzyl]amino]propionic acid (IA).

[0054] <Examples 2 and 3, and Comparative Example 1> Safinamide was obtained in the same manner as in Example 1, except that the amount of sodium carbonate added was changed as shown in Table 2.

[0055] [Table 2]

[0056] <Examples 4 to 6, Comparative Examples 2 to 3> Safinamide was obtained in the same manner as in Example 1, except that a predetermined amount of a basic compound shown in Table 3 was used instead of sodium carbonate.

[0057] [Table 3]

[0058] Preferred embodiments are listed below. [1] A method for producing safinamide, comprising contacting a solid containing (S)-2-[[4-[(3-fluorobenzyl)oxy]benzyl]amino]propanamide (safinamide), toluene, and water at a temperature of 70°C or higher in the presence of a basic compound, and separating the mixture into an aqueous layer having a pH of 9 or higher and an organic layer containing the safinamide. [2] 2. The method according to claim 1, wherein the basic compound comprises at least one selected from the group consisting of sodium carbonate, potassium carbonate, sodium hydroxide, and triethylamine. [3] 2. The method according to claim 1, wherein the amount of toluene per 1 g of a solid containing safinamide is 3 mL or more and 30 mL or less. [4] 2. The method according to claim 1, wherein the amount of water per 1 g of a solid containing safinamide is 1 mL or more and 20 mL or less. [5] 2. The method according to claim 1, wherein a ratio V1 / V2 of a volume V1 of the toluene to a volume V2 of the water is 0.5 or more and 5 or less. [6] 2. The production method according to claim 1, wherein the concentration of (S)-2-[[4-[(3-fluorobenzyl)oxy]benzyl]amino]propionic acid in the organic layer as determined by high performance liquid chromatography is 0.1% or less. [7] A method for producing safinamide mesylate, comprising using safinamide obtained by the method according to claim 1 as an intermediate.

Claims

1. A method for producing safinamide, comprising contacting a solid containing (S)-2-[[4-[(3-fluorobenzyl)oxy]benzyl]amino]propanamide (safinamide), toluene, and water at a temperature of 70°C or higher in the presence of a basic compound, and separating the resulting aqueous layer with a pH of 9 or higher and an organic layer containing the safinamide.

2. The method according to claim 1 , wherein the basic compound comprises at least one selected from the group consisting of sodium carbonate, potassium carbonate, sodium hydroxide, and triethylamine.

3. The method according to claim 1 , wherein the amount of toluene per 1 g of the solid containing safinamide is 3 mL or more and 30 mL or less.

4. The method according to claim 1 , wherein the amount of water per 1 g of a solid containing safinamide is 1 mL or more and 20 mL or less.

5. 2. The method according to claim 1, wherein a ratio V1 / V2 of a volume V1 of the toluene to a volume V2 of the water is 0.5 or more and 5 or less.

6. 2. The method according to claim 1, wherein the concentration of (S)-2-[[4-[(3-fluorobenzyl)oxy]benzyl]amino]propionic acid in the organic layer as determined by high performance liquid chromatography is 0.1% or less.

7. A method for producing safinamide mesylate, comprising using safinamide obtained by the method according to claim 1 as an intermediate.

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