Method for producing trione compounds

Abstract

The present invention provides a method for producing a trione compound, said method being characterized by producing a trione compound represented by formula (IV) (wherein R1 and R2 are as defined in formula (I); and R3 and Ar are as defined in formula (III)) by removing water from a mixed liquid that is obtained by mixing at least one starting material compound which is selected from among dicarboxylic acid compounds represented by formula (I) (wherein R1 and R2 may be the same or different, and each represents a hydrogen atom or a uleine group-protecting group) and anhydrous compounds represented by formula (II) (wherein R1 and R2 are as defined in formula (I)) with an optically active amine compound represented by formula (III) (wherein R3 represents an alkyl group, an aralkyl group or an aryl group; and Ar represents an optionally substituted aromatic ring group) in an aprotic polar organic solvent that has a boiling point of 100°C or higher.

Description

[Technical field]

[0001] The present invention relates to a novel method for producing a trione compound. [Background technology]

[0002] Trione compounds are compounds that contain three carbonyl groups and are useful as materials, synthetic intermediates, and raw materials in a variety of fields.

[0003] As one of the synthesis methods utilizing a trione compound as a synthetic intermediate, a method for producing biotin (a type of water-soluble vitamin) shown below is known (see Patent Document 1).

[0004] [ka]

[0005] Conventionally, the trione compounds have been produced, for example, by the following method (see Patent Documents 1, 2, and 3).

[0006] The examples of Patent Documents 1 and 2 describe adding an optically active amine compound to toluene containing an anhydride compound of a dicarboxylic acid compound and mixing at reflux temperature. The examples of Patent Document 2 describe adding an optically active amine compound to mesitylene containing an anhydride compound of a dicarboxylic acid compound and mixing at reflux temperature.

[0007] In addition to the above-mentioned method, an example of Patent Document 3 describes mixing a mixture of a dicarboxylic acid compound, an optically active amine compound, and o-xylene at reflux temperature. [Prior art documents] [Patent documents]

[0008] [Patent Document 1] U.S. Pat. No. 3,876,656 [Patent Document 2] JP 2018-108978 A [Patent Document 3] International Publication No. 2018 / 025722 Brochure Summary of the Invention [Problem to be solved by the invention]

[0009] However, the present inventors have found through their investigations that there is room for improvement in the following respects when attempting to produce a trione compound by the method described in the above-mentioned patent document.

[0010] That is, as described above, in the conventional manufacturing method of trione compounds, the reaction is usually carried out in an aromatic hydrocarbon organic solvent. However, these solvents have low flash points. Therefore, from the viewpoint of industrial use, it has been desired to carry out the reaction in a solvent that is safe and easy to handle. The flash point of mesitylene is 49°C, the flash point of o-xylene is 32°C, and the flash point of toluene is 4°C. The above flash point values ​​are all values ​​measured in a closed cup.

[0011] In addition, the compounds that are the raw materials for the trione compound (dicarboxylic acid compounds and their dehydrated anhydrides, etc.) have low solubility in the organic solvents, and therefore, unless a relatively large amount of organic solvent is used, the raw materials may precipitate in the reaction system, making it impossible to carry out a uniform reaction.

[0012] Moreover, when a large amount of organic solvent is used, the raw material concentration decreases, and the raw materials need to be reacted for a relatively long time in order to contact each other sufficiently. Moreover, when the trione compound is removed from the reaction system after the reaction, it may take a lot of effort to remove the large amount of organic solvent.

[0013] Therefore, an object of the present invention is to provide a novel method for producing a trione compound which solves the above problems. [Means for solving the problem]

[0014] The present inventors have conducted extensive research to solve the above problems. As a result, they have found that a trione compound can be produced safely and stably by carrying out the reaction in a specific organic solvent. Furthermore, they have found that the use of the organic solvent allows the reaction time to be relatively short and post-treatment to be easy, which has led to the completion of the present invention.

[0015] That is, the present invention provides: In an aprotic polar organic solvent (hereinafter also referred to as a reaction solvent) having a boiling point of 100°C or higher, The following formula (I)

[0016] [ka]

[0017] (In the formula, R 1 and R 2 are each a hydrogen atom or a urea group protecting group, and may be the same or different groups. A dicarboxylic acid compound represented by the formula (hereinafter, also simply referred to as a dicarboxylic acid compound), The following formula (II)

[0018] [ka]

[0019] (In the formula, R 1 and R 2 has the same meaning as in the above formula (I). At least one raw material compound selected from anhydrous compounds represented by the following formula (hereinafter, also simply referred to as anhydrous compound): The following formula (III)

[0020] [ka]

[0021] (In the formula, R 3is an alkyl group, an aralkyl group, or an aryl group, and Ar is an aromatic ring group which may have a substituent. An optically active amine compound represented by the formula (hereinafter, also simply referred to as an optically active amine compound), By removing water from the mixture obtained by mixing the above, The following formula (IV)

[0022] [ka]

[0023] (In the formula, R 1 and R 2 has the same meaning as in the above formula (I), and Ar has the same meaning as in the above formula (III). A method for producing a trione compound (hereinafter, also simply referred to as a trione compound) represented by the following formula: It is. Effect of the Invention

[0024] According to the production method of the present invention, a trione compound can be efficiently produced. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0025] The present invention provides a method for producing a trione compound by removing water from a mixed liquid obtained by mixing a raw material compound and an optically active amine compound in a specific organic solvent.

[0026] The present invention will be described in detail below.

[0027] <Aprotic polar organic solvent (reaction solvent) with a boiling point of 100°C or higher> The present invention is characterized in that a solvent having a boiling point of 100° C. or higher, containing no proton-donating group, and having a polar group is used as the reaction solvent. Although not particularly limited, a solvent having a flash point exceeding 50° C., more preferably a solvent having a flash point of 55° C. or higher, is preferred.

[0028] In the present invention, by using a reaction solvent having the above boiling point, in the <removal of water from the mixed liquid> described in detail below, mainly water can be easily removed from the reaction system. Therefore, the higher the boiling point of the reaction solvent, the better, more preferably 110°C or higher, even more preferably 120°C or higher, and even more preferably 140°C or higher. There is no particular limit to the upper limit of the boiling point, but from the practical standpoint of ease of removing the solvent itself, etc., it is preferably 300°C or lower. When an organic solvent having a boiling point of less than 100°C is used, water is difficult to vaporize, and removal of water tends to be difficult.

[0029] The type of reaction solvent is not particularly limited as long as it satisfies the above requirements, does not affect the reaction, and dissolves the raw material compound and the optically active amine compound. Therefore, a typical commercially available organic solvent can be used. Examples of such organic solvents include amides, sulfoxides, and sulfones.

[0030] Examples of amides include dimethylacetamide (DMA, boiling point: 165°C, flash point (closed cup): 66°C), dimethylformamide (DMF, boiling point: 153°C, flash point (closed cup): 58°C), N-methyl-2-pyrrolidone (NMP, boiling point: 204°C, flash point (closed cup): 86°C), and N,N-dimethylimidazolidone (DMI, boiling point: 222°C, flash point (closed cup): 95°C).

[0031] Examples of sulfoxides include dimethyl sulfoxide (DMSO, boiling point: 189° C., flash point (closed cup): 89° C.).

[0032] Examples of sulfones include tetrahydrothiophene 1,1-dioxide (sulfolane, boiling point: 285° C., flash point (open cup): 177° C.).

[0033] Among these, in consideration of stability, yield, cost, etc., amides are preferred, and dimethylacetamide and N-methyl-2-pyrrolidone are particularly preferred.

[0034] The reaction solvent may be a mixture of a plurality of solvents or may be used alone. Considering ease of operation, it is preferable to use a single solvent.

[0035] The amount of the reaction solvent used is not particularly limited, but is preferably as small as possible in terms of reaction rate, economy, and handling. However, if the amount is too small, operations such as filtration tend to become difficult in the <post-treatment> described in detail below. Therefore, specifically, the amount of the reaction solvent used is preferably 0.5 to 5 mL, more preferably 0.7 to 3 mL, and even more preferably 1 to 2 mL per 1 g of the raw material compound. The reaction solvent may be a mixture of two or more of the above solvents, and in this case, the total amount of the mixed solvents may be within the above range.

[0036] <Raw material compound (substrate)> In the present invention, at least one selected from a dicarboxylic acid compound and an anhydride compound is used as a raw material (substrate).

[0037] (Dicarboxylic acid compounds) The dicarboxylic acid compound is represented by the following formula (I):

[0038] [ka]

[0039] It is a compound represented by the formula:

[0040] [R 1 , and R 2 Explanation of In the formula, R 1 , and R 2are each a hydrogen atom or a urein group protecting group, and may be the same or different groups. The urein group is a -NHCONH- group, and the urein group protecting group is a protecting group that replaces a hydrogen atom bonded to the nitrogen atom of the urein group to convert the urein group into a functional group that is inactive in the target reaction. The urein group protecting group is not particularly limited as long as it can be removed from the nitrogen atom of the urein group after the target reaction is completed. Examples of the urein group protecting group include an alkyl group, an aryl group, an aralkyl group, and an acyl group. Among them, an alkyl group having 1 to 10 carbon atoms, an aryl group having 6 to 10 carbon atoms, an aralkyl group having 7 to 11 carbon atoms, and an acyl group having 1 to 11 carbon atoms are included. In particular, each is preferably a benzyl group (Bn group).

[0041] This dicarboxylic acid compound is a known compound, and is exemplified in Patent Documents 1-3.

[0042] [Suitable dicarboxylic acid compound] In the present invention, a particularly suitable dicarboxylic acid compound for producing a more useful trione compound is, for example, a compound represented by the following formula (IA) (wherein R 1 , and R 2 benzyl group (Bn group).

[0043] [ka]

[0044] (anhydrous compound) The anhydrous compound is represented by the following formula (II):

[0045] [ka]

[0046] It is a compound represented by the formula:

[0047] In the formula, R 1 , and R2 has the same meaning as in formula (I).

[0048] The method for producing the anhydride compound is not particularly limited. For example, the anhydride compound can be produced by dehydrating and cyclizing the dicarboxylic acid compound.

[0049] [Suitable anhydrous compounds] In the present invention, particularly preferred anhydrous compounds for producing a more useful trione compound include those represented by the following formula (II-A) (wherein R 1 , and R 2 benzyl group (Bn group).

[0050] [ka]

[0051] (Raw material compound) In the present invention, at least one selected from a dicarboxylic acid compound and an anhydride compound is used as the raw material compound. Therefore, the raw material compound may be a dicarboxylic acid compound alone, an anhydride compound alone, or a mixture of these. In the case of a mixture, the total amount is the amount (mass, moles) of the raw material compound used.

[0052] When the anhydrous compound is used as a part or the whole of the raw material compound, as described above, it can be produced by dehydrating and cyclizing the dicarboxylic acid compound. Therefore, after the dicarboxylic acid compound and an organic solvent are introduced into a reaction vessel, the dicarboxylic acid compound is heated and dehydrated, and the obtained anhydrous compound can be used as the raw material compound as it is. The organic solvent used at this time is not particularly limited, but in consideration of operability, it is preferable to use the reaction solvent described in the above-mentioned <Aprotic polar organic solvent (reaction solvent) having a boiling point of 100° C. or more>. In addition, the anhydrous compound obtained by dehydrating the dicarboxylic acid compound can be taken out from the reaction solvent once and used.

[0053] [Suitable raw material compounds] When the anhydrous compound is left in the ambient air, it gradually reacts with the moisture contained in the ambient air and returns to a dicarboxylic acid compound. For this reason, it is preferable to use a dicarboxylic acid compound alone as a raw material compound. By doing so, it is not necessary to take out the anhydrous compound from the reaction solvent, or to strictly manage the storage state of the anhydrous compound, and the like, and the operability is excellent. In addition, in this case, since an unstable compound is not used, the reaction can proceed stably. Therefore, it is preferable to first mix the reaction solvent and the dicarboxylic acid compound.

[0054] <Optically active amine compounds (substrates)> In the present invention, the other raw material (substrate) is an optically active amine compound represented by the following formula (III):

[0055] [ka]

[0056] It is a compound represented by the formula:

[0057] [Explanation of Ar] In the above formula (III), Ar is an aromatic ring group which may have a substituent.

[0058] The aromatic ring group of Ar is a monocyclic, preferably monocyclic, or bicyclic aromatic ring group. The number of ring-constituting carbon atoms in the aromatic ring group is 6 to 18, preferably 6 to 14, and more preferably 6 to 10. The aromatic ring group may be a monocyclic (monocyclic) aromatic ring group or a condensed polycyclic aromatic ring group. When the aromatic ring group is a condensed polycyclic group, it may be a partially saturated condensed polycyclic aromatic ring group.

[0059] The number of substituents that the aromatic ring group of Ar may have can be appropriately determined depending on the number of carbon atoms, number of members, etc. of the aromatic ring group. The number of substituents that the aromatic ring group may have is preferably 0 to 3, more preferably 0 to 2, and even more preferably 0 or 1.

[0060] Ar is preferably a group represented by the following formula (III-a) or (III-b).

[0061] [ka]

[0062] R 4 , R 5 , and R 6 are each a hydrogen atom, an alkyl group, an alkoxy group, or a halogen atom. Among these, a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, an alkoxy group having 1 to 3 carbon atoms, or a halogen atom is preferred. 4 , R 5 , and R 6 are preferably all hydrogen atoms.

[0063] [R 3 Explanation of R 3 is an alkyl group, an aralkyl group, or an aryl group. Of these, an alkyl group having 1 to 10 carbon atoms, an aralkyl group having 7 to 11 carbon atoms, or an aryl group having 6 to 10 carbon atoms is preferred. Of these, an alkyl group having 1 to 10 carbon atoms is preferred, and a methyl group is particularly preferred.

[0064] [Suitable optically active amine compound] In the present invention, examples of particularly suitable optically active amine compounds for producing more useful trione compounds include those represented by the following formula (III-aa) (in the above formula (III), R 3 is a methyl group, Ar is a phenyl group (in the above formula (III-a), R 4 , R 5 , and R 6 are all hydrogen atoms).

[0065] [ka]

[0066] The amount of the optically active amine compound used is not particularly limited, but is preferably 1 to 2 moles, more preferably 1 to 1.5 moles, per mole of the raw material compound.

[0067] <Mixing the raw material compound with the optically active amine compound in the reaction solvent> In the present invention, the method for mixing the raw material compound and the optically active amine compound in the reaction solvent is not particularly limited. For example, the raw material compound and the reaction solvent are introduced into a reactor having a stirring function, the optically active amine compound is added to the reactor, and the mixture is stirred and mixed.

[0068] The temperature at which these are mixed (mixing temperature) is not particularly limited, but is preferably 10 to 60° C., and more preferably 15 to 40° C. from the viewpoint of ease of operation.

[0069] The pressure during mixing is not particularly limited. Specifically, the mixing may be performed under any atmosphere, such as atmospheric pressure, reduced pressure, or pressurized pressure. The atmosphere during mixing is not particularly limited. Specifically, the mixing may be performed under an air atmosphere or an inert gas atmosphere.

[0070] The time for mixing these (mixing time) may be appropriately determined by checking the mixed state of the raw material compound and the optically active amine compound. Under the above mixing conditions, it is sufficient to stir and mix for 0.5 to 1 hour after the total amount of these is introduced into the reactor. This time is only the time for mixing before dehydration. Therefore, this mixing time is different from the reaction time described later.

[0071] After the mixed liquid is obtained by the above method, the <Removal of water from the mixed liquid> can be carried out as described in detail below.

[0072] <Removal of water from a mixture (reaction)> In the present invention, the reaction proceeds by removing water from the mixture, and the trione compound represented by the formula (IV) can be produced. This water is considered to be water generated during the reaction of the raw material mixture with the optically active amine compound, for example, water generated when the dicarboxylic acid compound becomes an anhydride compound, or water generated when the anhydride compound reacts with the optically active amine compound to obtain an amide compound that is ring-closed to become a trione compound.

[0073] The operation of removing the water is preferably carried out in a state in which the reaction system is sufficiently mixed, and it is preferable to remove the water while stirring and mixing.

[0074] In addition, the removal (reaction) of water is preferably carried out in a state where the mixed liquid is heated. Furthermore, it is preferable to remove water from a solution in which the raw material compounds and the like contained in the mixed liquid are uniformly dissolved. For these reasons, it is preferable to perform the water removal while maintaining the temperature (reaction temperature) in the range of 100 to 200°C, and more preferably in the range of 100 to 180°C. If the reaction temperature is within this range, dehydration is sufficiently carried out under atmospheric pressure, and the reaction proceeds.

[0075] The water removed while maintaining the temperature within this range is liberated from the mixture as steam containing mainly water, and therefore, for example, water removal can be performed using an apparatus equipped with a cooler (e.g., a Dean-Stark dehydrator).

[0076] The time for removing the water (reaction time) is not particularly limited, and may be appropriately determined while checking the state of the trione compound produced by an analytical instrument such as HPLC. According to the present invention, the reaction proceeds in a shorter time than in the past, so that a reaction time of 0.5 to 5 hours, preferably 1 to 3 hours, is sufficient.

[0077] In the above <Mixing of raw material compounds and optically active amine compound in reaction solvent>, when the mixing temperature is in the range of 100 to 200°C, the raw material compounds and the optically active amine compound may be stirred and mixed while being maintained as is. In this case, the mixing time is included in the reaction time. In addition, when the mixing temperature is less than 100°C, after stirring and mixing the entire amount of these, the temperature may be raised (temperature adjustment) while stirring and mixing so that the resulting mixed liquid has a temperature range of 100 to 200°C. In this case, the mixing time is not included in the reaction time. The reaction time is the time during which the temperature of the mixed liquid is maintained within the temperature range of 100 to 200°C after it has reached the range.

[0078] <Post-processing> In the present invention, after removing water from the mixed solution, it is preferable to carry out the following post-treatment. Specifically, it is preferable to adjust the temperature of the obtained reaction solution to a temperature range of 75 to 130°C, preferably 75 to 100°C, and then mix this reaction solution with water to precipitate a solid (trione compound). By doing so, the trione compound, which is poorly soluble in water, is precipitated in the reaction solution, and the target product can be easily obtained by a known operation such as filtration.

[0079] It is preferable that the reaction liquid is in the above-mentioned temperature range during the above-mentioned mixing of the reaction liquid with water, which allows effective precipitation of the solid (trione compound).

[0080] The amount of water used at this time is not particularly limited, and may be any amount that allows sufficient precipitation of the resulting trione compound. Specifically, it is preferable to use 3 to 6 mL, preferably 3.5 to 5 mL, of water per 1 g of the raw material compound. The amount of water is preferably 2 to 4 mL, more preferably 2.5 to 3.5 mL, of water per 1 mL of reaction solvent.

[0081] In addition, the reaction liquid and water can be mixed in an amount necessary for precipitating a solid (trione compound) all at once, or the amount can be arbitrarily divided and mixed intermittently.

[0082] When the aforementioned amount of water is mixed at once, for example, 3 to 6 mL of water per 1 g of the raw material compound is added to the reaction solution at once.

[0083] When the amount of water is mixed intermittently in any divided amounts, it can be carried out, for example, by dropping the amount of water to the reaction solution over a period of about 0.5 to 2 hours. Also, for example, it can be carried out by dropping 0.1 to 0.6 mL of water per 1 g of the raw material compound to the reaction solution, stirring for 5 to 15 minutes, then dropping 0.3 to 1.3 mL of water per 1 g of the raw material compound, and then adding 2.6 to 4.1 mL of water per 1 g of the raw material compound at once, and stirring for 5 to 15 minutes.

[0084] Among them, it is preferable to intermittently mix the above amount of water. By doing so, the temperature of the reaction liquid is likely to satisfy the above temperature range. In addition, precipitation of the solid (trione compound) can be carried out slowly over time. For these reasons, the precipitation can be carried out effectively.

[0085] In addition, by intermittently mixing the above amount of water, the precipitated solid (trione compound) is easily loosened, and separation procedures such as filtration can be easily performed. Thus, intermittent mixing of water is preferable from the viewpoint of ease of production.

[0086] After the resulting reaction liquid is mixed with water, the temperature of the reaction liquid is further adjusted to a temperature range of 15 to 35° C., and the mixture is preferably stirred and mixed for 0.5 to 1.5 hours.

[0087] The precipitated solid (trione compound) is filtered and dried.

[0088] When the obtained trione compound has a sufficiently high purity, it may be used in the next reaction as it is, or may be further purified. In such a case, the purification method may be, for example, a method in which the obtained trione compound and a solvent are stirred and mixed, and washed. Examples of the solvent used in this case include water and alcohols such as ethanol. Among them, water is preferred in terms of the cost required to obtain the solvent and the yield of the obtained trione compound.

[0089] A preferred example of the production method of the present invention is shown in the following reaction scheme.

[0090] [ka]

[0091] By carrying out the above-mentioned method, it is possible to produce in high yield a trione compound that can be used for various applications such as a raw material or intermediate for medicines. In particular, the trione compound obtained by such a method can be suitably used as a raw material for the production method of the following amido alcohol compound, which is a synthetic intermediate for biotin.

[0092] [ka] EXAMPLES

[0093] The present invention will be described in detail below with reference to examples. However, these are merely specific examples and the present invention is not limited to these.

[0094] The evaluations in the examples and comparative examples were carried out by the following methods.

[0095] <High performance liquid chromatography (HPLC) measurement conditions> Apparatus: High performance liquid chromatography (HPLC). Detector: ultraviolet spectrophotometer (measurement wavelength: 254 nm). Column, packing material: X Bridge C18 5μm (4.6×150) Column temperature: 30℃ Mobile phase: [Liquid A] acetonitrile, [Liquid B] acetic acid:water = 1:400 The mixing ratio of mobile phases A and B is changed as shown in Table 1 below to control the concentration gradient.

[0096] [Table 1]

[0097] Flow rate: 0.6mL / min.

[0098] Under the above HPLC measurement conditions, the trione compound has a peak at about 18.0 minutes.

[0099] In the following Examples and Comparative Examples, the purity value of the trione compound is a value calculated from the ratio of the peak area value of each compound to the sum of the area values ​​of all peaks (excluding peaks derived from the solvent) measured in accordance with the above-mentioned HPLC measurement conditions.

[0100] [Example 1] This is an example of the production of a trione compound from a dicarboxylic acid compound represented by the following formula.

[0101] [ka]

[0102] <Mixing the raw material compound with the optically active amine compound in the reaction solvent> In a 500 mL four-neck flask, cis-1,3-dibenzyl-2-oxo-4,5-imidazolidinedicarboxylic acid (50.00 g, 0.141 mol; dicarboxylic acid compound) and N-methyl-2-pyrrolidone (65 mL; reaction solvent) were added and stirred at room temperature (about 25 ° C.). To the obtained suspension, (R)-α-methylbenzylamine (17.10 g, 0.141 mol; optically active amine compound) and N-methyl-2-pyrrolidone (10 mL; reaction solvent) were added at the same temperature and stirred for 10 minutes to obtain a mixed solution. The amount of reaction solvent (N-methyl-2-pyrrolidone) contained in the mixed solution was 75 mL (1.5 mL per 1 g of dicarboxylic acid compound).

[0103] <Removal of water from the mixture> A Dean-Stark tube and a cooling tube were attached to the four-necked eggplant flask, and nitrogen was flowed for 1 minute to replace the nitrogen. The mixture was heated to 160° C. and stirred for 1 hour. Water accumulated in the Dean-Stark tube was removed as needed.

[0104] <Post-processing> After stirring, the temperature of the resulting reaction solution was lowered to 100°C, and 225 mL of water was added dropwise thereto over 30 minutes (the amount of water used was 4.5 mL per 1 g of dicarboxylic acid compound and 3 mL per 1 mL of reaction solvent). The temperature of the reaction solution was further lowered to about room temperature (about 25°C), and the solution was stirred at the same temperature for 1 hour, and the solid (trione compound) was filtered. The filtered crystals were washed twice with ethanol (50 mL). The washed solid (trione compound) was dried with air at 60°C for 48 hours to obtain a trione compound (57.28 g, yield 92.4%, HPLC purity 98.85%).

[0105] [Example 2] <Mixing the raw material compound with the optically active amine compound in the reaction solvent> The reaction solvent was changed to dimethylacetamide in <Mixing of raw material compounds and optically active amine compound in reaction solvent> of Example 1. Other than this, the same operation as in <Mixing of raw material compounds and optically active amine compound in reaction solvent> of Example 1 was performed.

[0106] <Removal of water from the mixture> In the <Removal of water from the mixed solution> of Example 1, the mixed solution was heated to 140° C. and stirred for 2 hours. Other than this, the same operation as in the <Removal of water from the mixed solution> of Example 1 was carried out.

[0107] <Post-processing> In the <Post-treatment> of Example 1, after stirring, the temperature of the obtained reaction liquid was lowered to 120°C, and 225 mL of water was added dropwise thereto over 60 minutes. In addition, the wet body after washing with ethanol was dried by blowing air at 60°C for 8 hours. Other than this, the same operations as in the <Post-treatment> of Example 1 were performed.

[0108] As a result, a trione compound was obtained (58.21 g, yield 93.9%, HPLC purity 99.23%).

[0109] [Example 3] <Mixing the raw material compound with the optically active amine compound in the reaction solvent> In Example 1 <Mixing of raw material compounds and optically active amine compound in reaction solvent>, the capacity of the four-neck flask was 100 mL, the amount of dicarboxylic acid compound was 10.00 g (0.028 mol), the reaction solvent and its amount used (reaction solvent contained in the mixed solution) was 15 mL of dimethylacetamide, and the amount of optically active amine compound used was 3.42 g (0.028 mol).Other than this, the same operation as in Example 1 <Mixing of raw material compounds and optically active amine compound in reaction solvent> was performed.

[0110] <Removal of water from the mixture> In the <Removal of water from the mixed solution> of Example 1, the mixed solution was heated to 140° C. and stirred for 2 hours. Other than this, the same operation as in the <Removal of water from the mixed solution> of Example 1 was carried out.

[0111] <Post-processing> After stirring, the temperature of the resulting reaction solution was lowered to 85°C, and 4 mL of water (0.4 mL per 1 g of dicarboxylic acid compound) was slowly dropped therein while maintaining the same temperature. Stirring was continued for 10 minutes at the same temperature. After that, 11 mL of water (1.1 mL per 1 g of dicarboxylic acid compound) was slowly dropped therein while maintaining the same temperature. Then, 30 mL of water (3.0 mL per 1 g of dicarboxylic acid compound) was added at once, and the mixture was stirred for 10 minutes at the same temperature. The amount of water used was 45 mL (4.5 mL per 1 g of dicarboxylic acid compound).

[0112] Thereafter, the temperature of the reaction solution was cooled to about room temperature (about 25° C.) over 30 minutes, and the mixture was stirred at the same temperature for 1 hour, and the solid (trione compound) was filtered.

[0113] The filtered crystals were washed twice with ethanol (10 mL). The washed solid (trione compound) was dried with air at 60° C. for 17 hours to obtain a trione compound (11.10 g, yield 89.5%, HPLC purity 99.23%).

[0114] [Example 4] <Mixing the raw material compound with the optically active amine compound in the reaction solvent> In Example 1 <Mixing of raw material compounds and optically active amine compound in reaction solvent>, the capacity of the four-neck flask was 100 mL, the dicarboxylic acid compound was 10.00 g, the reaction solvent and its amount used (reaction solvent contained in the mixed solution) was 15 mL of dimethylacetamide, and the amount of the optically active amine compound used was 3.42 g (0.028 mol).Other than this, the same operation as in Example 1 <Mixing of raw material compounds and optically active amine compound in reaction solvent> was performed.

[0115] <Removal of water from the mixture> In the <Removal of water from the mixed solution> of Example 1, the mixed solution was heated to 150° C. and stirred for 2 hours. Except for this, the same operation as in the <Removal of water from the mixed solution> of Example 1 was carried out.

[0116] <Post-processing> After stirring, the temperature of the resulting reaction solution was lowered to 85°C, and 3.5mL of water (0.35mL per 1g of dicarboxylic acid compound) was slowly dropped therein while maintaining the same temperature. Stirring was continued for 10 minutes at the same temperature. Then, 0.45mL of water (0.045mL per 1g of dicarboxylic acid compound) was slowly dropped therein while maintaining the same temperature. Then, 37mL of water (3.7mL per 1g of dicarboxylic acid compound) was added at once, and the mixture was stirred for 10 minutes at the same temperature. The amount of water used was 40.95mL (4.10mL per 1g of dicarboxylic acid compound).

[0117] Thereafter, the temperature of the reaction solution was cooled to about room temperature (about 25° C.) over 30 minutes, and the mixture was stirred at the same temperature for 1 hour, and the solid (trione compound) was filtered.

[0118] The filtered crystals were washed with water (20 mL), and the washed solid (trione compound) was dried with air at 60° C. for 4 hours to obtain a trione compound (11.37 g, yield 91.7%, HPLC purity 98.83%).

[0119] [Example 5] The reaction and post-treatment were carried out under the same conditions as in Example 2, except that the amount of dimethylacetamide was 50 mL (1.0 mL per 1 g of dicarboxylic acid compound), to obtain a trione compound (59.44 g, yield 95.88%, HPLC purity 96.23%).

[0120] [Example 6] The reaction and post-treatment were carried out under the same conditions as in Example 2, except that the amount of dimethylacetamide was 100 mL (2.0 mL per 1 g of dicarboxylic acid compound), to obtain a trione compound (43.66 g, yield 70.43%, HPLC purity 99.53%).

[0121] [Reference example 1] <Mixing the raw material compound with the optically active amine compound in the reaction solvent> In a four-necked eggplant flask, cis-1,3-dibenzyl-2-oxo-4,5-imidazolidinedicarboxylic acid (100 g, 282 mmol; dicarboxylic acid compound), (R)-α-methylbenzylamine (90.2 g, 737 mmol; optically active amine compound) and o-xylene (400 mL, 4 mL per 1 g of the dicarboxylic acid compound) were mixed to obtain a mixed liquid.

[0122] <Removal of water from the mixture> A Dean-Stark tube and a cooling tube were attached to a four-necked eggplant flask, and nitrogen was passed through for 1 minute to replace the atmosphere. The mixture was heated to the reflux temperature (154°C) and stirred for 10 hours. The water that had accumulated in the Dean-Stark tube was removed at appropriate times, and the end of the reaction was determined when no more water was remaining.

[0123] <Post-processing> The reaction solution obtained was distilled under reduced pressure, and the concentrated residue was heated at 220° C. for 1 hour, and then 2-propanol was added thereto for crystallization, followed by filtration to obtain a trione compound (112 g, yield 90%).

[0124] [Reference example 2] The reaction mixture obtained in the same reaction as in Reference Example 1 was cooled to room temperature, and then 400 mL of water (4.0 mL per 1 g of dicarboxylic acid compound, 1 mL per 1 mL of reaction solvent) was added to attempt crystallization, but stirring became difficult and post-treatment was not possible.

Claims

1. In one or more organic solvents selected from dimethylacetamide, dimethylformamide, N-methyl-2-pyrrolidone, and N,N-dimethylimidazolidone, The following formula (I) 【Chemistry 1】 (In the formula, R １ and R ２ are each a hydrogen atom or a urea group protecting group, and may be the same or different groups. and a dicarboxylic acid compound represented by the formula: The following formula (II) 【Chemistry 2】 (In the formula, R １ and R ２ has the same meaning as in formula (I). At least one raw material compound selected from anhydrous compounds represented by the formula: The following formula (III): 【Chemistry 3】 (In the formula, R ３ is an alkyl group, an aralkyl group, or an aryl group, and Ar is an aromatic ring group which may have a substituent. and an optically active amine compound represented by the formula: By removing water from the mixture obtained by mixing the above, The following formula (IV): 【Chemistry 4】 (In the formula, R １ and R ２ has the same meaning as in formula (I), R ３ and Ar have the same meaning as in formula (III). A method for producing a trione compound, comprising producing a trione compound represented by the following formula:

2. 2. The method for producing a trione compound according to claim 1, wherein the amount of the organic solvent used is 0.5 to 5 mL per 1 g of the raw material compound.

3. The method for producing a trione compound according to claim 1 or 2, wherein the raw material compound is a dicarboxylic acid compound represented by formula (I).

4. After producing the trione compound represented by formula (IV) in the organic solvent by the method according to any one of claims 1 to 3, A method for producing a trione compound, comprising mixing a solution containing the trione compound and the organic solvent with water to precipitate the trione compound.

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