Safinamide manufacturing method

Abstract

According to the manufacturing method of the present invention, high-purity 4-(3-fluorobenzyloxy)benzaldehyde crystals and safinamide can be produced with high production efficiency. [Solution] According to the present invention, a method for producing crystals of 4-(3-fluorobenzyloxy)benzaldehyde is provided. This production method includes dissolving a solid containing 4-(3-fluorobenzyloxy)benzaldehyde in a (C3-C4) alkanol to obtain a first solution, precipitating the 4-(3-fluorobenzyloxy)benzaldehyde in the first solution to obtain a first dispersion, and mixing a (C6-C7) alkane with the first dispersion.

Description

Technical Field

[0001] The present invention relates to a method for producing 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 17 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, 4-(3-fluorobenzyloxy)benzaldehyde (IV) is synthesized from 3-fluorobenzyl chloride (II) and 4-hydroxybenzaldehyde (III), and L-alanine amide hydrochloride (V) is allowed to act on this to synthesize (S)-2-[[4-[(3-fluorobenzyl)oxy]benzylidene]amino]propanamide (VI), which is a Schiff base, 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 high-purity 4-(3-fluorobenzyloxy)benzaldehyde crystals and safinamide with high production efficiency. [Means for solving the problem]

[0008] In response to the above-mentioned problems, the inventors diligently investigated methods for producing 4-(3-fluorobenzyloxy)benzaldehyde. As a result, they discovered that high-purity crystals of 4-(3-fluorobenzyloxy)benzaldehyde can be produced by dissolving 4-(3-fluorobenzyloxy)benzaldehyde in a (C3-C4) alkanol, precipitating the 4-(3-fluorobenzyloxy)benzaldehyde in this solution to obtain a dispersion, and then mixing it with a (C6-C7) alkane.

[0009] In other words, the present invention involves dissolving a solid containing 4-(3-fluorobenzyloxy)benzaldehyde in a (C3-C4) alkanol to obtain a first solution, The first dispersion is obtained by precipitating the 4-(3-fluorobenzyloxy)benzaldehyde in the first solution, The first dispersion is mixed with an (C6-C7) alkane. The present invention provides a method for producing 4-(3-fluorobenzyloxy)benzaldehyde crystals, characterized by the following. The production method of the present invention can preferably be adopted in the following embodiments. 1) The amount of the (C3-C4) alkanol relative to 1 g of a solid containing 4-(3-fluorobenzyloxy)benzaldehyde shall be between 0.5 mL and 10 mL. 2) The amount of the (C6-C7) alkane relative to 1 g of a solid containing 4-(3-fluorobenzyloxy)benzaldehyde shall be between 1 mL and 50 mL. 3) The ratio V2 / V1 of the volume V1 of the (C3-C4) alkanol to the volume V2 of the (C6-C7) alkane shall be 0.5 or more and 15 or less. 4) The method includes precipitating 4-(3-fluorobenzyloxy)benzaldehyde by adding a seed crystal to the first solution. [Effects of the Invention]

[0010] According to the manufacturing method of the present invention, high-purity 4-(3-fluorobenzyloxy)benzaldehyde crystals and safinamide can be produced with high production efficiency. [Modes for carrying out the invention]

[0011] Patent Document 1 describes a method for producing 4-(3-fluorobenzyloxy)benzaldehyde crystals, which involves dissolving 4-(3-fluorobenzyloxy)benzaldehyde in toluene, adding seed crystals, and then adding n-hexane. However, since the solvents used in this method all have low conductivity and are prone to generating static electricity, there is a risk of fire and other problems in large-scale production.

[0012] Furthermore, Patent Document 2 describes a method in which 4-(3-fluorobenzyloxy)benzaldehyde is dissolved in 40 mL of 2-propanol and 600 mL of n-heptane in a solid containing 4-(3-fluorobenzyloxy)benzaldehyde synthesized from 100 g of 4-hydroxybenzaldehyde, and then cooled. However, our own investigations have shown that this method has poor reproducibility in crystal formation, and that the phenomenon of the solution turning into oil instead of crystals forming occurs frequently. Also, according to Patent Document 2, the purity of the resulting 4-(3-fluorobenzyloxy)benzaldehyde crystals is 99.01%.

[0013] The present invention is characterized by dissolving a solid containing 4-(3-fluorobenzyloxy)benzaldehyde in a (C3-C4) alkanol to obtain a first solution, precipitating 4-(3-fluorobenzyloxy)benzaldehyde in the first solution to obtain a first dispersion, and mixing a (C6-C7) alkane into the first dispersion. According to this method, compared with the conventional method, crystals of high-purity 4-(3-fluorobenzyloxy)benzaldehyde can be produced under conditions of high yield without oiling.

[0014] Hereinafter, the production method of the present invention will be described.

[0015] <Solid of 4-(3-fluorobenzyloxy)benzaldehyde> The solid of 4-(3-fluorobenzyloxy)benzaldehyde is not particularly limited, and commercially available products or those produced by known methods can be used. As an example of a known production method, the methods described in Patent Document 1 and Patent Document 2 can be mentioned. Hereinafter, the solid of 4-(3-fluorobenzyloxy)benzaldehyde is also referred to as the crude form of 4-(3-fluorobenzyloxy)benzaldehyde.

[0016] Specifically, the crude form of 4-(3-fluorobenzyloxy)benzaldehyde is obtained by the following method. First, 3-fluorobenzyl chloride (II), 4-hydroxybenzaldehyde (III), potassium carbonate and potassium iodide are dissolved in ethanol and heated to synthesize 4-(3-fluorobenzyloxy)benzaldehyde (IV). The obtained ethanol solution is filtered, and the solvent of the filtrate is distilled off to produce a crude form of 4-(3-fluorobenzyloxy)benzaldehyde (IV).

[0017]

Chemical formula

[0018] The crude 4-(3-fluorobenzyloxy)benzaldehyde produced as described above has a purity of, for example, 90.0-99.9% when analyzed by liquid chromatography (HPLC) under the conditions described in the examples, although this varies depending on the production conditions.

[0019] Crude 4-(3-fluorobenzyloxy)benzaldehyde may be in any form, such as powder, lump, or a mixture thereof.

[0020] <(C3-C4) Alkanol> A (C3-C4) alkanol is a compound in which one or more hydrogen atoms in an alkane skeleton with 3 or 4 carbon atoms are substituted with a hydroxyl group. (C3-C4) alkanols are not limited and may include propanol and propanediol, butanol and butanediol, or a combination thereof. Specific examples of (C3-C4) alkanols include at least one selected from the group consisting of 1-propanol, 2-propanol, 1-butanol, 2-butanol, isobutyl alcohol, and tert-butyl alcohol. These (C3-C4) alkanols may be single or multiple.

[0021] <(C6-C7) Alkanes> (C6-C7)alkanes are alkane compounds having 6 or 7 carbon atoms. (C6-C7)alkanes are not limited and may include hexane and its structural isomers, heptane and its structural isomers, or a combination thereof. Specific examples of (C6-C7)alkanes include at least one selected from the group consisting of n-hexane, 2-methylpentane, 3-methylpentane, 2,2-dimethylbutane, 2,3-dimethylbutane, n-heptane, 2-methylhexane, 3-methylhexane, 2,2-dimethylpentane, 2,3-dimethylpentane, 2,4-dimethylpentane, 3,3-dimethylpentane, 3-ethylpentane, and 2,2,3-trimethylbutane. These (C6-C7)alkanes may be single or multiple.

[0022] <First solution of 4-(3-fluorobenzyloxy)benzaldehyde> The first solution of 4-(3-fluorobenzyloxy)benzaldehyde uses a (C3-C4) alkanol as the solvent.

[0023] The amount of (C3-C4) alkanol solvent should be sufficient to dissolve 4-(3-fluorobenzyloxy)benzaldehyde. For example, for a solid containing 1 g of 4-(3-fluorobenzyloxy)benzaldehyde, the solvent can be 0.1 mL or more, preferably 0.5 mL to 10 mL, and more preferably 0.5 mL to 5 mL.

[0024] The temperature of the first solution should be sufficient to dissolve 4-(3-fluorobenzyloxy)benzaldehyde, and can be, for example, 30°C or higher, preferably 35°C or higher, and more preferably 35°C to 50°C.

[0025] <First dispersion of 4-(3-fluorobenzyloxy)benzaldehyde> The first dispersion of 4-(3-fluorobenzyloxy)benzaldehyde is obtained by precipitating 4-(3-fluorobenzyloxy)benzaldehyde crystals in the first solution. The first solution of 4-(3-fluorobenzyloxy)benzaldehyde can be cooled to, for example, 30°C, and then, while stirring, a seed crystal, i.e., a small amount of 4-(3-fluorobenzyloxy)benzaldehyde crystals can be added to precipitate the 4-(3-fluorobenzyloxy)benzaldehyde crystals.

[0026] The temperature at which the seed crystal is added varies depending on the manufacturing conditions and is not restricted, but it is preferably between 27°C and 33°C. Although it is possible to obtain the first dispersion without adding the seed crystal, it is preferable to add the seed crystal when considering the reproducibility of the process and the manufacturing speed.

[0027] Crystals of 4-(3-fluorobenzyloxy)benzaldehyde can be produced by mixing a (C6-C7) alkane with a first dispersion of 4-(3-fluorobenzyloxy)benzaldehyde. When a (C6-C7) alkane is mixed with a first solution in which no 4-(3-fluorobenzyloxy)benzaldehyde crystals have precipitated, a phenomenon of oil formation may occur without crystal precipitation. In other words, by adding a (C6-C7) alkane to a first dispersion in which a small amount of 4-(3-fluorobenzyloxy)benzaldehyde crystals have precipitated in a (C3-C4) alkanol, a large amount of 4-(3-fluorobenzyloxy)benzaldehyde crystals can be precipitated without oil formation.

[0028] The amount of solvent for the (C6-C7) alkane should be sufficient to precipitate 4-(3-fluorobenzyloxy)benzaldehyde. For example, this can be done with 0.5 mL or more of solvent per 1 g of solid containing 4-(3-fluorobenzyloxy)benzaldehyde, preferably between 1 mL and 50 mL, and more preferably between 1 mL and 20 mL.

[0029] The ratio V2 / V1 of the volume V1 of the (C3-C4) alkanol to the volume V2 of the (C6-C7) alkane can be, for example, 0.1 or more, preferably 0.5 to 15, and more preferably 0.5 to 10.

[0030] The temperature at which the (C6-C7) alkanes are mixed varies depending on the manufacturing conditions and is not limited, but can be, for example, 35°C or lower, and preferably 25°C to 35°C.

[0031] <Crystals of 4-(3-fluorobenzyloxy)benzaldehyde> The 4-(3-fluorobenzyloxy)benzaldehyde contained in the dispersion obtained by the above method can be purified and isolated by any method. Specifically, it is preferable to isolate the 4-(3-fluorobenzyloxy)benzaldehyde crystals by cooling and filtering the dispersion. The temperature at which the dispersion is cooled can be, for example, 35°C or lower, preferably 25°C or lower, and more preferably 0°C to 10°C.

[0032] The 4-(3-fluorobenzyloxy)benzaldehyde crystals isolated by this method have a high chemical purity of 99.5% or more and can be obtained in high yield. The obtained crystals may be subjected to further washing treatment.

[0033] <(S)-2-[4-(3-fluorobenzyloxy)benzylamino]propanamide (Safinamide) manufacturing method> (S)-2-[4-(3-fluorobenzyloxy)benzaldehyde]propanamide (safinamide) can be produced using 4-(3-fluorobenzyloxy)benzaldehyde obtained by the above method as an intermediate. There are no particular restrictions on the method of production, and known methods can be used. For example, safinamide can be produced by adding crystalline 4-(3-fluorobenzyloxy)benzaldehyde to a solution of L-alaninamide hydrochloride and reacting it, followed by the addition of a reducing agent. [Examples]

[0034] The present invention will be described in detail below with reference to examples and comparative examples, but the present invention is not limited by these examples and comparative examples.

[0035] The purity of safinamide obtained in the examples and comparative examples was measured by the following method.

[0036] <Purity of 4-(3-fluorobenzyloxy)benzaldehyde> The purity of 4-(3-fluorobenzyloxy)benzaldehyde obtained in Examples 1-7 and Comparative Example 1 was measured by HPLC (High-Performance Liquid Chromatography). The apparatus and measurement conditions used for this measurement are as follows. 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.

[0037] [Table 1]

[0038] Under the above HPLC conditions, the peak for 4-(3-fluorobenzyloxy)benzaldehyde was observed at approximately 35.9 minutes, and the peak for safinamide was observed at approximately 15.0 minutes. In the following examples, the purity of 4-(3-fluorobenzyloxy)benzaldehyde and safinamide is the value of the peak area % measured under the above conditions.

[0039] <Example 1> (Preparation of crude 4-(3-fluorobenzyloxy)benzaldehyde(IV)) 10.0 mL of 3-fluorobenzyl chloride(II), 10.0 g of 4-hydroxybenzaldehyde(III), 12.4 g of potassium carbonate, and 1.36 g of potassium iodide were dissolved in 100 mL of ethanol and stirred at 25°C for 15 minutes. This was heated to 90°C and stirred under reflux for 5 hours. The solution was cooled to 25°C and filtered, and the filtrate was distilled under reduced pressure. 50.0 mL of toluene and 15.0 mL of water were added to the obtained solid and heated to 60°C and stirred for 30 minutes. The aqueous layer was removed and the organic layer was distilled under reduced pressure to obtain 18.4 g of crude 4-(3-fluorobenzyloxy)benzaldehyde(IV).

[0040] (Preparation of 4-(3-fluorobenzyloxy)benzaldehyde(IV) crystals) 18.4 g of crude 4-(3-fluorobenzyloxy)benzaldehyde(IV) was dissolved in 20.0 mL of 2-propanol by heating to 40°C. This 2-propanol solution was cooled to 30°C, and seed crystals of 4-(3-fluorobenzyloxy)benzaldehyde were added and stirred for 30 minutes. 60.0 mL of n-heptane was added dropwise to this dispersion and cooled to 0°C. This was filtered, and the resulting crystals were washed with 15.0 mL of n-heptane to obtain 16.2 g of 4-(3-fluorobenzyloxy)benzaldehyde(IV) crystals. The purity and yield of the obtained 4-(3-fluorobenzyloxy)benzaldehyde are shown in Table 2.

[0041] <Examples 2-5> Crystals of 4-(3-fluorobenzyloxy)benzaldehyde were obtained in the same manner, except that 2-propanol was replaced with (C3-C4) alkanols from Table 2, or n-heptane was replaced with (C6-C7) alkanes from Table 2.

[0042] <Example 6> 18.4 g of crude 4-(3-fluorobenzyloxy)benzaldehyde(IV), obtained by the same method as in Example 1, was dissolved in 40.0 mL of 2-propanol and 20.0 mL of n-heptane by heating to 40°C. This solution was cooled to 25°C, and seed crystals of 4-(3-fluorobenzyloxy)benzaldehyde were added and stirred for 30 minutes. 20.0 mL of n-heptane was added dropwise to this dispersion and cooled to 0°C. This was filtered, and the resulting crystals were washed with 15.0 mL of n-heptane to obtain crystals of 4-(3-fluorobenzyloxy)benzaldehyde(IV).

[0043] <Comparative Example 1> Crystals of 4-(3-fluorobenzyloxy)benzaldehyde were obtained using the same method, except that the amount of 2-propanol added was changed to that shown in Table 2, or that n-heptane was not added.

[0044] [Table 2]

[0045] In Table 2 above, the solvent amounts for (C3-C4) alkanols and (C6-C7) alkanes are relative to 18.4 g of crude 4-(3-fluorobenzyloxy)benzaldehyde.

[0046] <Comparative Example 2> 18.4 g of crude 4-(3-fluorobenzyloxy)benzaldehyde(IV), obtained by the same method as in Example 1, was mixed with 20.0 mL of 2-propanol and heated to 40°C to dissolve. This 2-propanol solution was cooled to 35°C and stirred for 30 minutes. 60.0 mL of n-heptane was added dropwise to the solution, which had not precipitated any 4-(3-fluorobenzyloxy)benzaldehyde crystals, and the solution was cooled to 25°C. The solution became cloudy, and no 4-(3-fluorobenzyloxy)benzaldehyde crystals precipitated, instead turning into an oil.

[0047] <Comparative Example 3> 18.4 g of crude 4-(3-fluorobenzyloxy)benzaldehyde(IV), obtained by the same method as in Example 1, was mixed with 20.0 mL of 2-propanol and 60.0 mL of n-heptane, and heated to 40°C to dissolve. When this solution was cooled to 25°C, the solution became cloudy, and no crystals of 4-(3-fluorobenzyloxy)benzaldehyde precipitated, instead turning into an oil.

[0048] <Comparative Example 4> 18.4 g of crude 4-(3-fluorobenzyloxy)benzaldehyde(IV), obtained by the same method as in Example 1, was mixed with 4.00 mL of 2-propanol and 60.0 mL of n-heptane, and heated to 40°C to dissolve. When this solution was cooled to 25°C, the solution became cloudy, and no crystals of 4-(3-fluorobenzyloxy)benzaldehyde precipitated, instead turning into an oil.

[0049] <Example 7> (Preparation of (S)-2-[4-(3-fluorobenzyloxy)benzylamino]propanamide (safinamide)(I)) 2.98 g of L-alaninamide hydrochloride (V) 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 (IV) obtained in Example 1 was added and the mixture was stirred at 25°C for 3 hours. This yielded a methanol solution of (S)-2-[[4-[(3-fluorobenzyl)oxy]benzylidene]amino]propanamide (VI). The methanol solution of (S)-2-[[4-[(3-fluorobenzyl)oxy]benzylidene]amino]propanamide (VI) 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 safinamide obtained was subjected to vacuum distillation to obtain solid safinamide (I). To 1.60 g of the obtained safinamide(I) solid, 8.00 mL of toluene, 4.00 mL of water, and 400 mg of sodium carbonate were added and heated to 80°C, with stirring. The aqueous layer was removed, and 4.00 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. 4.00 mL of toluene was added to the organic layer and heated to 80°C, with stirring. 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 obtained crystals were washed three times with 1.00 mL of toluene to obtain safinamide(I) crystals. The purity of the obtained safinamide(I) was 99.8%.

[0050] Preferred embodiments are described below. [1] The first solution is obtained by dissolving a solid containing 4-(3-fluorobenzyloxy)benzaldehyde in (C3-C4) alkanol, The first dispersion is obtained by precipitating the 4-(3-fluorobenzyloxy)benzaldehyde in the first solution, The first dispersion is mixed with an (C6-C7) alkane. A method for producing crystals of 4-(3-fluorobenzyloxy)benzaldehyde, which contains the active ingredient. [2] The manufacturing method according to claim 1, wherein the amount of the (C3-C4) alkanol relative to 1 g of a solid containing 4-(3-fluorobenzyloxy)benzaldehyde is 0.5 mL or more and 10 mL or less. [3] The manufacturing method according to claim 1, wherein the amount of the (C6-C7) alkane relative to 1 g of a solid containing 4-(3-fluorobenzyloxy)benzaldehyde is 1 mL or more and 50 mL or less. [4] The manufacturing method according to claim 1, wherein the ratio V2 / V1 of the volume V1 of the (C3-C4) alkanol to the volume V2 of the (C6-C7) alkane is 0.5 or more and 15 or less. [5] The method for producing 4-(3-fluorobenzyloxy)benzaldehyde according to claim 1, comprising adding a seed crystal to the first solution to precipitate the 4-(3-fluorobenzyloxy)benzaldehyde. [6] A method for producing (S)-2-[4-(3-fluorobenzyloxy)benzylamino]propanamide (safinamide), comprising using crystals of 4-(3-fluorobenzyloxy)benzaldehyde obtained by the method of claim 1 as an intermediate.

Claims

1. The first solution is obtained by dissolving a solid containing 4-(3-fluorobenzyloxy)benzaldehyde in (C3-C4) alkanol, The first dispersion is obtained by precipitating the 4-(3-fluorobenzyloxy)benzaldehyde in the first solution, The first dispersion is mixed with an (C6-C7) alkane. A method for producing crystals of 4-(3-fluorobenzyloxy)benzaldehyde, which contains the active ingredient.

2. The manufacturing method according to claim 1, wherein the amount of the (C3-C4) alkanol relative to 1 g of the solid containing the 4-(3-fluorobenzyloxy)benzaldehyde is 0.5 mL or more and 10 mL or less.

3. The manufacturing method according to claim 1, wherein the amount of the (C6-C7) alkane relative to 1 g of the solid containing the 4-(3-fluorobenzyloxy)benzaldehyde is 1 mL or more and 50 mL or less.

4. The manufacturing method according to claim 1, wherein the ratio V2 / V1 of the volume V1 of the (C3-C4) alkanol to the volume V2 of the (C6-C7) alkane is 0.5 or more and 15 or less.

5. The method for producing 4-(3-fluorobenzyloxy)benzaldehyde according to claim 1, comprising adding a seed crystal to the first solution to precipitate the 4-(3-fluorobenzyloxy)benzaldehyde.

6. A method for producing (S)-2-[4-(3-fluorobenzyloxy)benzylamino]propanamide, comprising using crystals of 4-(3-fluorobenzyloxy)benzaldehyde obtained by the method of claim 1 as an intermediate.

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