Method for producing (2R)-1-(morpholin-4-yl)-2-[(oxan-2-yl)oxy]propan-1-one

Abstract

To provide an efficient method for producing (2R)-1-(morpholin-4-yl)-2-[(oxan-2-yl)oxy]propan-1-one.SOLUTION: In one aspect, there is provided a method for producing (2R)-1-(morpholin-4-yl)-2-[(oxan-2-yl)oxy]propan-1-one. This production method comprises contacting (2R)-2-hydroxy-1-(morpholin-4-yl)propan-1-one and 3,4-dihydro-2H-pyran in the presence of pyridinium paratoluenesulfonate at a temperature of 40°C or higher.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a process for preparing (2R)-1-(morpholin-4-yl)-2-[(oxan-2-yl)oxy]propan-1-one. [Background technology]

[0002] Fosravuconazole lysine ethanolate is useful as a therapeutic agent for treating onychomycosis. Fosravuconazole lysine ethanolate is represented by the following formula:

[0003] [ka] [Prior art documents] [Patent documents]

[0004] [Patent Document 1] U.S. Patent No. 6,300,353 [Patent Document 2] Patent No. 5046959 specification [Non-patent literature]

[0005] [Non-Patent Document 1] The Process Development of Ravuconazole: An Efficient Multikilogram Scale Preparation of an Antifungal Agent, Org. Process Res. Dev. 2009,13,4,716-728 Summary of the Invention [Problem to be solved by the invention]

[0006] An object of the present invention is to provide an efficient method for producing (2R)-1-(morpholin-4-yl)-2-[(oxan-2-yl)oxy]propan-1-one. [Means for solving the problem]

[0007] According to one aspect, there is provided a method for producing (2R)-1-(morpholin-4-yl)-2-[(oxan-2-yl)oxy]propan-1-one, comprising contacting (2R)-2-hydroxy-1-(morpholin-4-yl)propan-1-one with 3,4-dihydro-2H-pyran in the presence of pyridinium paratoluenesulfonate at a temperature of 40° C. or higher. [Effects of the Invention]

[0008] According to the present invention, there is provided an efficient method for producing (2R)-1-(morpholin-4-yl)-2-[(oxan-2-yl)oxy]propan-1-one. DETAILED DESCRIPTION OF THE INVENTION

[0009] The production method according to the embodiment includes contacting (2R)-2-hydroxy-1-(morpholin-4-yl)propan-1-one with 3,4-dihydro-2H-pyran in the presence of pyridinium paratoluenesulfonate at a temperature of 40°C or higher to obtain (2R)-1-(morpholin-4-yl)-2-[(oxan-2-yl)oxy]propan-1-one.

[0010] (2R)-1-(morpholin-4-yl)-2-[(oxan-2-yl)oxy]propan-1-one can be an intermediate for synthesizing fosravuconazole lysine ethanol adduct. (2R)-1-(morpholin-4-yl)-2-[(oxan-2-yl)oxy]propan-1-one can be obtained, for example, by contacting (R)-(+)-methyl lactate with morpholine to obtain (2R)-2-hydroxy-1-(morpholin-4-yl)propan-1-one, and then contacting this with 3,4-dihydro-2H-pyran, as shown in the following formula:

[0011] Hereinafter, (R)-(+)-methyl lactate will also be referred to as FS-A01, (2R)-2-hydroxy-1-(morpholin-4-yl)propan-1-one will also be referred to as FS-A02, (2R)-1-(morpholin-4-yl)-2-[(oxan-2-yl)oxy]propan-1-one will also be referred to as FS-A03, and 3,4-dihydro-2H-pyran will also be referred to as DHP.

[0012] [ka]

[0013] According to the method of the embodiment, FS-A03 can be efficiently produced, and the reason for this is believed to be as follows.

[0014] First, when FS-A02 is brought into contact with DHP, methanesulfonic acid (MsOH) or paratoluenesulfonic acid monohydrate (PTS·HO) is sometimes used as an acid catalyst. However, the inventors' investigations revealed that, although FS-A03 can be synthesized by the reaction under these acid catalysts, a large amount of several impurities is produced as by-products. The inventors discovered that the production of these impurities is due to the decomposition of FS-A03 caused by the use of a strong acid as an acid catalyst.

[0015] In the method according to the embodiment, pyridinium paratoluenesulfonate (PPTS) is used as the acid catalyst. PPTS is a weaker acid than strong acids such as MsOH. Therefore, decomposition of FS-A03 does not occur, and the by-production of impurities can be suppressed. However, because PPTS is a weak acid, the reaction between FS-A02 and DHP does not proceed easily at room temperature. The reaction can be accelerated by heating the contact temperature to 40°C or higher. According to the method according to the embodiment, FS-A03 with few impurities can be produced in high yield.

[0016] The manufacturing method according to the embodiment will be described in detail below.

[0017] (FS-A03 manufacturing method) The production method according to the embodiment includes contacting (2R)-2-hydroxy-1-(morpholin-4-yl)propan-1-one with 3,4-dihydro-2H-pyran in the presence of pyridinium paratoluenesulfonate at a temperature of 40°C or higher to obtain (2R)-1-(morpholin-4-yl)-2-[(oxan-2-yl)oxy]propan-1-one.

[0018] The starting material, (2R)-2-hydroxy-1-(morpholin-4-yl)propan-1-one, can be produced by known methods. For example, it can be obtained by contacting (R)-(+)-methyl lactate with morpholine. This contact may be carried out at a temperature ranging from 40°C to 100°C. This contact may also be carried out in an alcohol solution of sodium methoxide. If this solution is used, it is preferable to remove the solution and use the (2R)-2-hydroxy-1-(morpholin-4-yl)propan-1-one after washing. (2R)-2-hydroxy-1-(morpholin-4-yl)propan-1-one can be a viscous liquid.

[0019] The contact temperature between (2R)-2-hydroxy-1-(morpholin-4-yl)propan-1-one and 3,4-dihydro-2H-pyran is preferably 50°C or higher and 120°C or lower. Reaction at a relatively high temperature tends to increase the yield of (2R)-1-(morpholin-4-yl)-2-[(oxan-2-yl)oxy]propan-1-one. The contact temperature may be 60°C or higher, 70°C or higher, or even 80°C or higher. When a reaction solvent is used, the contact temperature is preferably the reflux temperature of the reaction solvent.

[0020] The contact time between (2R)-2-hydroxy-1-(morpholin-4-yl)propan-1-one and 3,4-dihydro-2H-pyran is, for example, 1 hour or more and 48 hours or less, and preferably 3 hours or more and 18 hours or less.

[0021] The contact of (2R)-2-hydroxy-1-(morpholin-4-yl)propan-1-one with 3,4-dihydro-2H-pyran may be carried out in the presence of a reaction solvent. The reaction solvent may be, for example, at least one organic solvent selected from the group consisting of tetrahydrofuran, toluene, ethyl acetate, and acetone. The reaction solvent preferably contains at least one solvent selected from the group consisting of tetrahydrofuran and toluene.

[0022] The amount of pyridinium paratoluenesulfonate relative to 1 mole of (2R)-2-hydroxy-1-(morpholin-4-yl)propan-1-one is, for example, 0.001 moles or more and 0.1 moles or less, preferably 0.01 moles or more and 0.08 moles or less, and more preferably 0.03 moles or more.

[0023] The amount of 3,4-dihydro-2H-pyran relative to 1 mole of (2R)-2-hydroxy-1-(morpholin-4-yl)propan-1-one is, for example, 1 mole or more and 10 moles or less, preferably 1.5 moles or more and 7.5 moles or less, and more preferably 2.0 moles or more and 5.0 moles or less.

[0024] The (2R)-1-(morpholin-4-yl)-2-[(oxan-2-yl)oxy]propan-1-one obtained by the above method may be cooled to room temperature and then subjected to separation treatment or the like. According to the method of the present embodiment, (2R)-1-(morpholin-4-yl)-2-[(oxan-2-yl)oxy]propan-1-one having a purity of 90% or more can be obtained in a high yield of 90% or more. This purity can be measured by high performance liquid chromatography as described in the Examples.

[0025] The (2R)-1-(morpholin-4-yl)-2-[(oxan-2-yl)oxy]propan-1-one obtained by the above method can be used as an intermediate for synthesizing fosravuconazole lysine ethanolate. Fosravuconazole lysine ethanolate can be produced by known methods. Fosravuconazole lysine ethanolate can be produced, for example, by the steps shown below.

[0026] [ka]

[0027] [ka] [Example]

[0028] The present invention will be described in detail below with reference to examples, but the present invention is not limited by these examples. It is not limited to: <Evaluation test> (Purity measurement of FS-A03) The purity of (2R)-1-(morpholin-4-yl)-2-[(oxan-2-yl)oxy]propan-1-one (FS-A03) obtained in the example was measured under the following conditions. Equipment: Gas chromatography (GC) Model: 7890B (Agilent) Detector: FID Detector temperature: 280℃ Inlet temperature: 250℃ Linear speed: 30cm / sec Column: DB-5, inner diameter 0.32 mm, length 30 m, film thickness 1.5 μm (Agilent) Column temperature: After sample injection, the column temperature is increased from 60°C to 250°C at a rate of 10°C / min and maintained at this temperature for 5 minutes.

[0029] Under the above conditions, the peak positions determined by gas chromatography were as follows: FS-A02:15.2 minutes FS-A03:21.4 minutes Example 1 To a mixture of 7.6 g (48 mmol) of (2R)-2-hydroxy-1-(morpholin-4-yl)propan-1-one (FS-A02) and 10 mL of tetrahydrofuran, 12.1 g (144 mmol, 3.0 eq.) of 3,4-dihydro-2H-pyran (DHP) was added dropwise. 0.60 g (2.4 mmol, 0.05 eq.) of pyridinium paratoluenesulfonate (PPTS) was added and the mixture was stirred under reflux for 7 hours. The mixture was cooled to room temperature and added dropwise to 15 mL of 5% aqueous sodium bicarbonate. The organic layer was separated, and the aqueous layer was extracted with 15 mL of ethyl acetate. The combined organic layer was washed with 15 mL of 10% brine and dried over magnesium sulfate. This liquid was concentrated under reduced pressure to obtain 10.8 g (yield 92.4%) of (2R)-1-(morpholin-4-yl)-2-[(oxan-2-yl)oxy]propan-1-one (FS-A03).

[0030] <Example 2> (2R)-1-(morpholin-4-yl)-2-[(oxan-2-yl)oxy]propan-1-one (FS-A03) was obtained in the same manner as in Example 1, except that the solvent was toluene and the reaction temperature was 50°C.

[0031] Example 3 (2R)-1-(morpholin-4-yl)-2-[(oxan-2-yl)oxy]propan-1-one (FS-A03) was obtained in the same manner as in Example 1, except that the solvent was toluene and the amount of 3,4-dihydro-2H-pyran (DHP) was 6.1 g (72 mmol, 1.5 eq.).

[0032] Example 4 (2R)-1-(morpholin-4-yl)-2-[(oxan-2-yl)oxy]propan-1-one (FS-A03) was obtained in the same manner as in Example 1, except that the solvent was changed to toluene.

[0033] <Comparative Example 1> (2R)-1-(morpholin-4-yl)-2-[(oxan-2-yl)oxy]propan-1-one (FS-A03) was obtained in the same manner as in Example 1, except that the acid added was 0.23 g (2.4 mmol, 0.05 eq.) of methanesulfonic acid (MsOH), 6.1 g (72 mmol, 1.5 eq.) of 3,4-dihydro-2H-pyran (DHP), and the reaction temperature was 20°C.

[0034] <Comparative Example 2> (2R)-1-(morpholin-4-yl)-2-[(oxan-2-yl)oxy]propan-1-one (FS-A03) was obtained in the same manner as in Example 1, except that the acid added was 0.27 g (2.4 mmol, 0.05 eq.) of trifluoroacetic acid (TFA) and the reaction temperature was 20°C.

[0035] <Comparative Example 3> (2R)-1-(morpholin-4-yl)-2-[(oxan-2-yl)oxy]propan-1-one (FS-A03) was obtained in the same manner as in Example 1, except that the reaction temperature was 20°C.

[0036] <Comparative Example 4> (2R)-1-(morpholin-4-yl)-2-[(oxan-2-yl)oxy]propan-1-one (FS-A03) was obtained in the same manner as in Example 1, except that the solvent was dichloromethane, the added acids were 0.027 g (0.14 mmol, 0.003 eq.) of p-toluenesulfonic acid monohydrate (PTS·HO) and 4.9 g (58 mmol, 1.2 eq.) of 3,4-dihydro-2H-pyran (DHP), and the reaction temperature was 0°C.

[0037] <Comparative Example 5> (2R)-1-(morpholin-4-yl)-2-[(oxan-2-yl)oxy]propan-1-one (FS-A03) was obtained in the same manner as in Example 1, except that the solvent was dichloromethane, the acid added was 0.27 g (2.4 mmol, 0.05 eq.) trifluoroacetic acid (TFA), and the reaction temperature was 20°C.

[0038] <Comparative Example 6> (2R)-1-(morpholin-4-yl)-2-[(oxan-2-yl)oxy]propan-1-one (FS-A03) was obtained in the same manner as in Example 1, except that the solvent was dichloromethane and the reaction temperature was 20°C.

[0039] <Comparative Example 7> (2R)-1-(morpholin-4-yl)-2-[(oxan-2-yl)oxy]propan-1-one (FS-A03) was obtained in the same manner as in Example 1, except that the solvent was toluene and the reaction temperature was 20°C.

[0040] [Table 1]

[0041] Preferred aspects of the invention are listed below. [1] A method for producing (2R)-1-(morpholin-4-yl)-2-[(oxan-2-yl)oxy]propan-1-one, comprising contacting (2R)-2-hydroxy-1-(morpholin-4-yl)propan-1-one with 3,4-dihydro-2H-pyran at a temperature of 40°C or higher in the presence of pyridinium paratoluenesulfonate to obtain (2R)-1-(morpholin-4-yl)-2-[(oxan-2-yl)oxy]propan-1-one. [2] The method according to [1], wherein the temperature at which the (2R)-2-hydroxy-1-(morpholin-4-yl)propan-1-one and the 3,4-dihydro-2H-pyran are contacted is 50°C or higher and 120°C or lower. [3] The production method according to [1] or [2], wherein the contact of the (2R)-2-hydroxy-1-(morpholin-4-yl)propan-1-one with the 3,4-dihydro-2H-pyran is carried out in the presence of an organic solvent selected from the group consisting of tetrahydrofuran, toluene, ethyl acetate, and acetone. [4] The method according to any one of [1] to [3], wherein the amount of the pyridinium paratoluenesulfonate relative to 1 mole of the (2R)-2-hydroxy-1-(morpholin-4-yl)propan-1-one is 0.001 moles or more and 0.1 moles or less. [5] The method according to any one of [1] to [4], wherein the amount of the 3,4-dihydro-2H-pyran relative to 1 mole of the (2R)-2-hydroxy-1-(morpholin-4-yl)propan-1-one is 1 mole or more and 10 moles or less. [6] A method for producing fosravuconazole lysine ethanol adduct, comprising using the (2R)-1-(morpholin-4-yl)-2-[(oxan-2-yl)oxy]propan-1-one obtained by the method according to any one of [1] to [5].

Claims

1. A method for producing (2R)-1-(morpholin-4-yl)-2-[(oxan-2-yl)oxy]propan-1-one, comprising contacting (2R)-2-hydroxy-1-(morpholin-4-yl)propan-1-one with 3,4-dihydro-2H-pyran at a temperature of 40°C or higher in the presence of pyridinium paratoluenesulfonate to obtain (2R)-1-(morpholin-4-yl)-2-[(oxan-2-yl)oxy]propan-1-one.

2. 2. The method according to claim 1, wherein the temperature at which the (2R)-2-hydroxy-1-(morpholin-4-yl)propan-1-one and the 3,4-dihydro-2H-pyran are contacted is 50° C. or higher and 120° C. or lower.

3. The production method according to claim 1, wherein the contact of the (2R)-2-hydroxy-1-(morpholin-4-yl)propan-1-one with the 3,4-dihydro-2H-pyran is carried out in the presence of a reaction solvent selected from the group consisting of tetrahydrofuran, toluene, ethyl acetate, and acetone.

4. 2. The method according to claim 1, wherein the amount of pyridinium paratoluenesulfonate relative to 1 mole of (2R)-2-hydroxy-1-(morpholin-4-yl)propan-1-one is 0.001 moles or more and 0.1 moles or less.

5. The method according to claim 1, wherein the amount of the 3,4-dihydro-2H-pyran relative to 1 mole of the (2R)-2-hydroxy-1-(morpholin-4-yl)propan-1-one is 1 mole or more and 10 moles or less.

6. A method for producing fosravuconazole lysine ethanolate, comprising using the (2R)-1-(morpholin-4-yl)-2-[(oxan-2-yl)oxy]propan-1-one obtained by the method of claim 1.

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