Process for the preparation of d-alanine alkyl esters, d-alanine alkyl esters, derivatives thereof and pharmaceutical or agricultural products comprising the same

Abstract

The present specification relates to a method of preparing D-alanine alkyl ester, D-alanine alkyl ester, D-alanine alkyl ester derivative, and a pharmaceutical or agricultural product comprising the same, the method of preparing D-alanine alkyl ester comprising distilling a composition comprising a compound of Chemical Formula 3 synthesized by reacting Chemical Formula 1 with Chemical Formula 2 at a pressure of 1 torr to 60 torr and a temperature of 60°C to 200°C.

Description

TECHNICAL FIELD

[0001] This application claims priority to and the benefit of Korean Patent Application Nos. 10-2021-0084514 and 10-2021-0084517, filed on June 29, 2021, in the Korean Intellectual Property Office, the disclosures of which are incorporated by reference herein in their entireties.

[0002] The present specification relates to a method of preparing D-alanine alkyl ester, D-alanine alkyl ester, D-alanine alkyl ester derivatives, and a pharmaceutical or agricultural product comprising the same. BACKGROUND

[0003] N-(2,6-dimethylphenyl)-D-alanine methyl ester has an important commercial value as a synthetic intermediate required for preparing crop protection agents such as metalaxyl-M, benalaxyl-M, and ofurace-M.

[0004] As a conventional method of synthesizing N-(2,6-dimethylphenyl)-D-alanine methyl ester, it is known to use (s)-methyl 2-(methylsulfonyloxy)propanoate or (s)-methyl 2-(p-toluenesulfonyloxy)propanoate and an organic or inorganic base, and 2,6-dimethylamine. In this case, a disubstituted impurity is produced due to over-reaction, the commercial value of the product is deteriorated, making it difficult to remove the impurity by a conventional purification method of crystallization or recrystallization.

[0005] Accordingly, designing a specific method capable of reducing the content of a disubstituted impurity produced due to over-reaction is an important issue to be urgently addressed. SUMMARY

[0006] TECHNICAL PROBLEM

[0007] The present specification provides a method of preparing D-alanine alkyl ester, D-alanine alkyl ester, D-alanine alkyl ester derivatives, and a pharmaceutical or agricultural product comprising the same.

[0008] TECHNICAL SOLUTION

[0009] One exemplary embodiment of the present specification provides a method of preparing D-alanine alkyl ester, the method including: synthesizing a compound of the following Chemical Formula 3 by reacting a compound of the following Chemical Formula 1 with a compound of the following Chemical Formula 2; and

[0010] The composition including the compound of Chemical Formula 3 is distilled at a pressure of 1 torr to 60 torr and a temperature of 60°C to 200°C.

[0011] [Chemical Formula 1]

[0012]

[0013] [Chemical Formula 2]

[0014]

[0015] [Chemical Formula 3]

[0016]

[0017] In Chemical Formula 1 to Chemical Formula 3,

[0018] R1 is methyl or an aryl group substituted with a methyl group,

[0019] R2 and R3 are the same as or different from each other, and each is independently hydrogen; deuterium; or a methyl group,

[0020] R4 is a methyl group.

[0021] Another exemplary embodiment of the present specification provides a method of preparing a D-alanine alkyl ester derivative, the method including: synthesizing a compound of the following Chemical Formula 3 by reacting a compound of the following Chemical Formula 1 with a compound of the following Chemical Formula 2;

[0022] distilling a composition including the compound of Chemical Formula 3 at a pressure of 1 torr to 60 torr and a temperature of 60℃ to 200℃; and

[0023] synthesizing a compound of the following Chemical Formula 6 by adding a compound of the following Chemical Formula 5 to the distilled composition.

[0024] [Chemical Formula 1]

[0025]

[0026] [Chemical Formula 2]

[0027]

[0028] [Chemical Formula 3]

[0029]

[0030] [Chemical Formula 5]

[0031]

[0032] [Chemical Formula 6]

[0033]

[0034] In Chemical Formula 1 to Chemical Formula 3, Chemical Formula 5, and Chemical Formula 6,

[0035] R1 is methyl or an aryl group substituted with a methyl group,

[0036] R2and R3are the same as or different from each other, and each is independently hydrogen; deuterium; or methyl,

[0037] R4is methyl,

[0038] R5is methylene substituted with methoxy; methylene substituted with phenyl; or furanyl.

[0039] Another exemplary embodiment of the present specification provides a composition comprising a compound of the following Chemical Formula 3 and a compound of the following Chemical Formula 4, wherein the content of the compound of the following Chemical Formula 4 is 0.1 area% or less based on the total GC area of the composition.

[0040] [Chemical Formula 3]

[0041]

[0042] [Chemical Formula 4]

[0043]

[0044] In Chemical Formula 3 and Chemical Formula 4,

[0045] R2and R3are the same as or different from each other, and each is independently hydrogen; deuterium; or methyl,

[0046] R4is methyl.

[0047] Still another exemplary embodiment of the present specification provides a D-alanine alkyl ester derivative prepared by reacting a compound of Chemical Formula 3 with a compound of the following Chemical Formula 5 in the above composition.

[0048] [Chemical Formula 5]

[0049]

[0050] In Chemical Formula 5,

[0051] R5is methylene substituted with methoxy; methylene substituted with phenyl; or furanyl.

[0052] Still another exemplary embodiment of the present specification provides a pharmaceutical or agricultural product comprising the above D-alanine alkyl ester derivative.

[0053] Advantageous Effects

[0054] The preparation method according to one exemplary embodiment of the present specification can prepare a D-alanine alkyl ester having a low content of a disubstituted impurity due to over-reaction.

[0055] High-purity D-alanine alkyl esters can be prepared according to a preparation method of one exemplary embodiment of this specification.

[0056] The preparation method according to an exemplary embodiment of this specification enables the high purity of D-alanine alkyl esters to be confirmed by visual inspection. Attached Figure Description

[0057] Figure 1 This is the UV-Vis absorption spectrum of methanol (blank solvent).

[0058] Figure 2 This is the UV / vis transmission spectrum of methanol (blank solvent).

[0059] Figure 3 The UV / vis absorption spectrum is that of the methanol solution containing 10 mg / mL of chemical formula 3-1 in Example 2.

[0060] Figure 4 The UV / vis transmission spectrum is that of the methanol solution containing 10 mg / mL of chemical formula 3-1 in Example 2.

[0061] Figure 5 The UV / vis absorption spectrum is that of the methanol solution containing 10 mg / mL of chemical formula 6-1 in Example 2.

[0062] Figure 6 The UV / vis transmission spectrum is that of the methanol solution containing 10 mg / mL of chemical formula 6-1 in Example 2. Detailed Implementation

[0063] This specification will be described in detail below.

[0064] In this specification, when a part “contains” a constituent element, unless otherwise specifically described, this does not mean that another constituent element is excluded, but rather that another constituent element may be further contained.

[0065] An exemplary embodiment of this specification provides a method for preparing D-alanine alkyl esters, the method comprising: synthesizing a compound of formula 3 by reacting a compound of formula 1 below with a compound of formula 2 below; and distilling a composition comprising the compound of formula 3.

[0066] [Chemical Formula 1]

[0067]

[0068] [Chemical Formula 2]

[0069]

[0070] [Chemical Formula 3]

[0071]

[0072] In Chemical Formula 1 to Chemical Formula 3,

[0073] R1 is a methyl group or an aryl group substituted with a methyl group,

[0074] R2 and R3 are the same as or different from each other, and each is independently hydrogen; deuterium; or a methyl group,

[0075] R4 is a methyl group.

[0076] In one exemplary embodiment of the present specification, the distillation of the composition is distillation of the composition at a pressure of 1 Torr to 60 Torr and a temperature of 60°C to 200°C.

[0077] Both the compound of Chemical Formula 3 and the compound of Chemical Formula 4 are viscous liquids. This is because, unlike materials having conventional solid properties, it is not possible to use a method such as crystallization or recrystallization after dissolution, and even when the material is dissolved in an organic solvent while being washed with water, it is difficult to remove Chemical Formula 4, and the yield is reduced due to the loss of Chemical Formula 3 in the water layer. Specifically, when an organic layer washing method of separating an organic layer by washing the organic layer with water by phase separation without distillation is used, the content of Chemical Formula 4 as an impurity generated from the reaction mixture is hardly reduced. When such an organic layer washing method is used, Chemical Formula 3 in the composition is rather lost due to washing with water, resulting in a low yield.

[0078] The present applicant devised a method of removing Chemical Formula 4 by distilling the compound of Chemical Formula 3.

[0079] When distillation is performed outside the respective pressure and temperature ranges, or without using the combination thereof, it is not possible to obtain a composition containing Chemical Formula 3 from the reaction mixture by distillation.

[0080] In contrast, when distillation is performed using the combination of the pressure and temperature ranges in one exemplary embodiment of the present specification, the above-described disadvantages are compensated for, and thus, it is possible to obtain a composition containing Chemical Formula 3 with a low content of Chemical Formula 4 at a relatively high yield without the loss of water washing.

[0081] Since the combination of the pressure and temperature ranges in one exemplary embodiment of the present specification is not a high-temperature or vacuum pressure condition that is difficult to achieve in a mass production process, it has an advantage in that the pressure and temperature can be sufficiently applied to mass production in a factory.

[0082] In one exemplary embodiment of the present specification, the distillation of the composition is distilling the composition at a pressure of 1 Torr or more, 2 Torr or more, 3 Torr or more, 4 Torr or more, or 5 Torr or more, and 60 Torr or less, 55 Torr or less, 50 Torr or less, 45 Torr or less, 40 Torr or less, 35 Torr or less, 30 Torr or less, 25 Torr or less, 20 Torr or less, 15 Torr or less, 10 Torr or less, 9 Torr or less, 8 Torr or less, or 7 Torr or less.

[0083] In one exemplary embodiment of the present specification, the distillation of the composition is distilling the composition at a pressure of 1 Torr or more, 2 Torr or more, 3 Torr or more, 4 Torr or more, or 5 Torr or more, and 60 Torr or less, 55 Torr or less, 50 Torr or less, 45 Torr or less, 40 Torr or less, 35 Torr or less, 30 Torr or less, 25 Torr or less, 20 Torr or less, 15 Torr or less, 10 Torr or less, 9 Torr or less, 8 Torr or less, or 7 Torr or less.

[0084] In one exemplary embodiment of the present specification, the distillation of the composition is distilling the composition at a temperature of 70°C or more, 70°C or more, 80°C or more, 90°C or more, 100°C or more, 110°C or more, 115°C or more, or 118°C or more, and 200°C or less, 190°C or less, 180°C or less, 170°C or less, 160°C or less, 150°C or less, 140°C or less, or 130°C or less.

[0085] In one exemplary embodiment of the present specification, the distillation of the composition is distilling the composition at a temperature of 70°C or more, 70°C or more, 80°C or more, 90°C or more, 100°C or more, 110°C or more, 115°C or more, or 118°C or more, and 200°C or less, 190°C or less, 180°C or less, 170°C or less, 160°C or less, 150°C or less, 140°C or less, or 130°C or less.

[0086] In one exemplary embodiment of the present specification, the distillation is distilling the composition comprising the compound of Chemical Formula 3 at a pressure of 5 Torr to 10 Torr and a temperature of 110°C to 150°C.

[0087] In one exemplary embodiment of the present specification, the distillation is distilling the composition comprising the compound of Chemical Formula 3 at a pressure of 5 Torr to 7 Torr and a temperature of 118°C to 130°C.

[0088] In one exemplary embodiment of the present specification, the distillation of the composition is removing a disubstituted impurity generated by over-reaction, specifically, removing the compound of the following Chemical Formula 4 as a disubstituted impurity. Thereby, a high-purity compound of Chemical Formula 3, i.e., D-alanine alkyl ester, can be prepared, and the purity of final products such as metalaxyl-M, benalaxyl-M, and ofurace-M synthesized using D-alanine alkyl ester as an intermediate can also be improved.

[0089] In one exemplary embodiment of the present specification, the distillation of the composition is to prepare a composition in which the content of the compound of the following Chemical Formula 4 is 0.1 area% or less, based on the total GC area of the composition.

[0090] [Chemical Formula 4]

[0091]

[0092] In Chemical Formula 4,

[0093] R2and R3are the same as or different from each other, and each is independently hydrogen; deuterium; or methyl,

[0094] R4is methyl.

[0095] In one exemplary embodiment of the present specification, in the distillation of the composition, the distillation can be performed once or more, specifically a number of times, such as once or more, twice or more, or three or more times.

[0096] In one exemplary embodiment of the present specification, by the distillation of the composition, the content of the compound of Chemical Formula 4 can be 0.1 area% or less, 0.09 area% or less, or 0.08 area% or less, based on the total GC area of the composition, and the lower the content of the compound of Chemical Formula 4 is, the better, and thus, there is no particular limitation on the lower limit thereof.

[0097] In one exemplary embodiment of the present specification, the content of the compound of Chemical Formula 2 is 2 equivalents to 10 equivalents, based on the compound of Chemical Formula 1. In this case, the equivalents of Chemical Formula 2 used are appropriate, and thus, have the advantage of being able to control the side reaction while increasing the reaction rate.

[0098] Another exemplary embodiment of the present specification provides a method of preparing a D-alanine alkyl ester derivative, the method including: synthesizing a compound of the following Chemical Formula 3 by reacting a compound of the following Chemical Formula 1 with a compound of the following Chemical Formula 2; distilling a composition containing the compound of Chemical Formula 3 at a pressure of 1 torr to 60 torr and a temperature of 60°C to 200°C; and synthesizing a compound of the following Chemical Formula 6 by adding a compound of the following Chemical Formula 5 to the distilled composition.

[0099] [Chemical Formula 1]

[0100]

[0101] [Chemical Formula 2]

[0102]

[0103] [Chemical Formula 3]

[0104]

[0105] [Chemical Formula 5]

[0106]

[0107] [Chemical Formula 6]

[0108]

[0109] In Chemical Formula 1 to Chemical Formula 3, Chemical Formula 5, and Chemical Formula 6,

[0110] R1is a methyl group or an aryl group substituted with a methyl group,

[0111] R2and R3are the same as or different from each other, and each is independently hydrogen; deuterium; or a methyl group,

[0112] R4is a methyl group,

[0113] R5is a methylene group substituted with a methoxy group; a methylene group substituted with a phenyl group; or a furanyl group.

[0114] In the present specification, when the aryl group is a monocyclic aryl group, the number of carbon atoms thereof is not particularly limited, but is preferably from 6 to 25. Specific examples of the monocyclic aryl group include a phenyl group, a biphenyl group, a terphenyl group, and the like, but are not limited thereto.

[0115] When the aryl group is a polycyclic aryl group, the number of carbon atoms thereof is not particularly limited, but is preferably from 10 to 24. Specific examples of the polycyclic aryl group include a naphthyl group, an anthryl group, a phenanthryl group, a pyrenyl group, a perylenyl group, a fluorenyl group, and the like, but are not limited thereto.

[0116] In the present specification, the fluorenyl group can be substituted, and adjacent substituents can be bonded to each other to form a ring.

[0117] In one exemplary embodiment of the present specification, R1is a methyl group; or a phenyl group substituted with a methyl group.

[0118] In one exemplary embodiment of the present specification, R1is a methyl group; or and is a bonding position.

[0119] In one exemplary embodiment of the present specification, R2and R3are the same as or different from each other, and each is independently hydrogen; or a methyl group.

[0120] In one exemplary embodiment of the present specification, R2and R3are methyl groups.

[0121] In one exemplary embodiment of the present specification, R5 is methylene substituted with methoxy. In other words, R5 is in a state in which any one hydrogen of the methyl group is substituted with methoxy. In this case, the compound of Chemical Formula 6 is metalaxyl-M.

[0122] In one exemplary embodiment of the present specification, R5 is methylene substituted with phenyl. In other words, R5 is in a state in which any one hydrogen of the methyl group is substituted with phenyl. In this case, the compound of Chemical Formula 6 is benalaxyl-M.

[0123] In one exemplary embodiment of the present specification, R5 is furanyl. In this case, the compound of Chemical Formula 6 is furalaxyl-M.

[0124] Yet another exemplary embodiment of the present specification provides a composition comprising the compound of the following Chemical Formula 3 and the compound of the following Chemical Formula 4, wherein the content of the compound of the following Chemical Formula 4 is 0.1 area% or less based on the total GC area of the composition.

[0125] [Chemical Formula 3]

[0126]

[0127] [Chemical Formula 4]

[0128]

[0129] In Chemical Formula 3 and Chemical Formula 4,

[0130] R2 and R3 are the same as or different from each other, and each is independently hydrogen; deuterium; or methyl,

[0131] R4 is methyl.

[0132] In the present specification, the description of the composition refers to the description of the method of preparing D-alanine alkyl ester and derivatives thereof as described above.

[0133] Another exemplary embodiment of the present specification provides a D-alanine alkyl ester derivative prepared by reacting the compound of Chemical Formula 3 with the compound of the following Chemical Formula 5 in the above composition.

[0134] [Chemical Formula 5]

[0135]

[0136] In Chemical Formula 5,

[0137] R5 is methylene substituted with methoxy; methylene substituted with phenyl; or furanyl.

[0138] In the present specification, the description of the D-alanine alkyl ester derivative refers to the description of the method for producing the D-alanine alkyl ester and its derivative as described above.

[0139] The first exemplary embodiment of the present specification provides a D-alanine alkyl ester derivative containing a D-alanine alkyl ester derivative and methanol, wherein the absorbance at 266 nm is 3.00 or less and the absorbance at 274 nm is 2.60 or less in a UV / vis absorption spectrum of a solution having a concentration of 10 mg / mL.

[0140] The second exemplary embodiment of the present specification provides a D-alanine alkyl ester derivative containing a D-alanine alkyl ester derivative and methanol, wherein the absorbance at 266 nm is 3.00 or less and the absorbance at 274 nm is 2.6 or less in a UV / vis absorption spectrum of a solution having a concentration of 10 mg / mL; and a D-alanine alkyl ester derivative containing a D-alanine alkyl ester derivative and methanol, wherein the transmittance at 266 nm is 0.10 or more and the transmittance at 274 nm is 0.29 or more in a UV / vis transmittance spectrum of a solution having a concentration of 10 mg / mL.

[0141] The third exemplary embodiment of the present specification provides a D-alanine alkyl ester derivative containing a D-alanine alkyl ester derivative and methanol, wherein the absorbance at 266 nm is 3.00 or less in a UV / vis absorption spectrum of a solution having a concentration of 10 mg / mL; and a D-alanine alkyl ester derivative containing a D-alanine alkyl ester derivative and methanol, wherein the transmittance at 266 nm is 0.10 or more in a UV / vis transmittance spectrum of a solution having a concentration of 10 mg / mL.

[0142] The fourth exemplary embodiment of the present specification provides a D-alanine alkyl ester derivative containing a D-alanine alkyl ester derivative and methanol, wherein the absorbance at 274 nm is 2.60 or less in a UV / vis absorption spectrum of a solution having a concentration of 10 mg / mL; and a D-alanine alkyl ester derivative containing a D-alanine alkyl ester derivative and methanol, wherein the transmittance at 274 nm is 0.29 or more in a UV / vis transmittance spectrum of a solution having a concentration of 10 mg / mL.

[0143] The lower the absorbance and the higher the transmittance in the ultraviolet / visible spectrum, the closer the material is to a clear and transparent water-like state when the material is in a dissolved (solution) state, as seen by the naked eye. In general, the more in the above state, the brighter and closer to white the appearance becomes when the liquid is formulated, and thus, it is advantageous in that it is commercially advantageous. For example, in the case of an injection solution, the state of the contents can be seen because the injection solution is contained in a transparent vial, and thus, manufacturing companies prefer the solution state to appear as a colorless transparent active ingredient. Therefore, when the liquid is formulated, a yellow color that is not brown, a yellow color that is more transparent than a turbid yellow, and a state closer to water become advantageous in appearance.

[0144] In one exemplary embodiment of the present specification, the D-alanine alkyl ester derivative is Chemical Formula 6-1 below, which is prepared by reacting a compound of Chemical Formula 3-1 below distilled at a pressure of 1 torr to 60 torr and a temperature of 60°C to 200°C with a compound of Chemical Formula 5-1 below. In other words, the D-alanine alkyl ester derivative can be N-(methoxyacetyl)-N-(2,6-dimethylphenyl)-D-alanine methyl ester prepared by reacting distilled N-(2,6-dimethylphenyl)-D-alanine methyl ester with a compound of Chemical Formula 5-1 below.

[0145] [Chemical Formula 3-1]

[0146]

[0147] [Chemical Formula 5-1]

[0148]

[0149] [Chemical Formula 6-1]

[0150]

[0151] In one exemplary embodiment of the present specification, impurities of Chemical Formula 4-1 below are removed by distillation of Chemical Formula 3-1.

[0152] [Chemical Formula 4-1]

[0153]

[0154] The compound of Chemical Formula 3-1 and the compound of Chemical Formula 4-1 are both viscous liquids. This is because, unlike materials having conventional solid properties, a method such as dissolution followed by crystallization or recrystallization cannot be employed, and even if the material is washed with water while dissolved in an organic solvent, it is difficult to remove Chemical Formula 4-1, and the yield is reduced due to loss of Chemical Formula 3-1 in the water layer. Specifically, when an organic layer washing method in which the organic layer is separated by washing the organic layer with water by phase separation without distillation is used, the content of Chemical Formula 4-1 as an impurity produced from the reaction mixture is hardly reduced. When such an organic layer washing method is used, Chemical Formula 3-1 in the composition is rather lost due to washing with water, resulting in a low yield.

[0155] When distillation is performed using the combination of the pressure and temperature ranges in one exemplary embodiment of the present specification, a composition containing Chemical Formula 3-1 and having a low content of Chemical Formula 4-1 can be obtained at a relatively high yield without the loss of water washing. In this case, considering that the above-described state is a state in which Chemical Formula 4-1 is contained as an impurity, the state of Chemical Formula 3-1 before or after distillation can be represented as a composition containing Chemical Formula 3-1 or a composition containing Chemical Formula 3-1 and Chemical Formula 4-1.

[0156] In one exemplary embodiment of the present specification, the distillation of the compound of Chemical Formula 3-1 is distillation of Chemical Formula 3-1 at a pressure of 1 torr to 50 torr, 1 torr to 40 torr, 1 torr to 30 torr, 1 torr to 20 torr, or 5 torr to 20 torr.

[0157] In one exemplary embodiment of the present specification, the distillation of the compound of Chemical Formula 3-1 is distillation of Chemical Formula 3-1 at a temperature of 70°C to 200°C, 80°C to 200°C, 90°C to 200°C, 100°C to 200°C, 110°C to 200°C, 120°C to 200°C, or 130°C to 200°C.

[0158] In one exemplary embodiment of the present specification, when the compound of Chemical Formula 3-1 is distilled, the distillation can be performed once or more, specifically a number of times, such as once or more, twice or more, or three or more times.

[0159] In one exemplary embodiment of the present specification, by the distillation of the compound of Chemical Formula 3-1, the content of the compound of Chemical Formula 4-1 can be 0.1 area% or less, 0.09 area% or less, or 0.08 area% or less, based on the total GC area of the compound of Chemical Formula 3-1 distilled, and the content of the compound of Chemical Formula 4-1 is lower the better, and thus, there is no particular limitation on the lower limit thereof.

[0160] In one exemplary embodiment of the present specification, the D-alanine alkyl ester derivative is prepared by reacting a compound of the following Chemical Formula 3-1 with a compound of the following Chemical Formula 5-1, and the content of a compound of the following Chemical Formula 4-1 is 0.1 area% or less based on the total GC area of the compound of Chemical Formula 3-1.

[0161] [Chemical Formula 3-1]

[0162]

[0163] [Chemical Formula 5-1]

[0164]

[0165] [Chemical Formula 6-1]

[0166]

[0167] [Chemical Formula 4-1]

[0168]

[0169] In one exemplary embodiment of the present specification, the absorbance at 266 nm can be 3.60 or less and the absorbance at 274 nm can be 3.40 or less in the UV / vis absorption spectrum of a methanol solution containing 10 mg / mL of the distilled compound of Chemical Formula 3-1.

[0170] In one exemplary embodiment of the present specification, the transmittance at 266 nm can be 0.03 or more and the transmittance at 274 nm can be 0.04 or more in the UV / vis transmittance spectrum of a methanol solution containing 10 mg / mL of the distilled compound of Chemical Formula 3-1.

[0171] Since the compound of Chemical Formula 3-1 has a low absorbance and a high transmittance, the compound prepared by using the compound of Chemical Formula 3-1, that is, the compound of Chemical Formula 6-1, can also have a low absorbance and a high transmittance. The compound of Chemical Formula 6-1 synthesized from the compound of Chemical Formula 3-1 has a high transparency, and thus, it is possible to prepare a D-alanine alkyl ester derivative satisfying the absorbance or transmittance conditions of the present specification.

[0172] Still another exemplary embodiment of the present specification provides a pharmaceutical or agricultural product including the above-described D-alanine alkyl ester derivative.

[0173] In this case, the pharmaceutical or agricultural product includes not only a state including the D-alanine alkyl ester derivative itself, but also a state modified for various uses, that is, a state modified by a necessary chemical reaction.

[0174] In the present specification, the agricultural product can be various agrochemicals such as herbicides, crop protectants, and fungicides.

[0175] Hereinafter, the present specification will be described in more detail by examples. However, the following examples are provided only for illustrating the present specification, and are not intended to limit the present specification.

[0176] [Example]

[0177] [Example 1]

[0178] At room temperature, (s)-methyl 2-(methylsulfonyloxy)propanoate (20.00 g, 109.78 mmol), triethylamine (12.22 g, 120.75 mmol), and 2,6-dimethylaniline (106.43 g, 274.45 mmol) were added to a reactor containing toluene (20 mL), the internal temperature was raised to 120 to 130°C, and then the mixture was stirred.

[0179] After confirming that unreacted (s)-methyl 2-(methylsulfonyloxy)propanoate remaining in the reaction mixture was 1.0 area% or less (GC analysis result), the reaction mixture was cooled to room temperature. Thereafter, the internal pressure was reduced to 60 torr at room temperature. In a state where the internal pressure was in the range of 1 to 60 torr, after diluting the crude N-(2,6-dimethylphenyl)-D-alanine methyl ester obtained by distillation in toluene (100 mL) by slowly adjusting the internal temperature from 60°C to 200°C, the organic layer obtained by washing the crude N-(2,6-dimethylphenyl)-D-alanine methyl ester once with 1N aqueous HCl (20 mL) was washed once with distilled water (30 mL), and then concentrated under reduced pressure, thereby obtaining N-(2,6-dimethylphenyl)-D-alanine methyl ester having a purity of 98.52 GC area% at a yield of 80%.

[0180] [Example 2]

[0181] At room temperature, (s)-methyl 2-(methylsulfonyloxy)propanoate (20.00 g, 109.78 mmol), triethylamine (12.22 g, 120.75 mmol), and 2,6-dimethylaniline (106.43 g, 274.45 mmol) were added to a reactor containing toluene (20 mL), the internal temperature was raised to 120 to 130°C, and then the mixture was stirred.

[0182] After confirming that unreacted (s)-methyl 2-(methylsulfonyloxy)propanoate remaining in the reaction mixture was 1.0 area% or less (GC analysis result), the reaction mixture was cooled to room temperature. Thereafter, the internal pressure was reduced to 50 torr at room temperature. In a state in which the internal pressure was in the range of 1 torr to 50 torr, crude Chemical Formula 3-1 (= N-(2,6-dimethylphenyl)-D-methylalaninate) was obtained by distillation by slowly increasing the internal temperature from 50°C and adjusting to 150°C. After diluting the crude Chemical Formula 3-1 with toluene (100 mL), the organic layer obtained by washing the crude Chemical Formula 3-1 once with 1N aqueous HCl solution (20 mL) was washed once with distilled water (30 mL), and then concentrated under reduced pressure. Thereby, colorless transparent Chemical Formula 3-1 (= N-(2,6-dimethylphenyl)-D-methylalaninate) was obtained in a yield of 80%, the purity thereof was 98.5%, the absorbance at a wavelength of 266 nm was 3.569 (the transmittance was 0.027), and the absorbance at a wavelength of 274 nm was 3.353 (the transmittance was 0.044).

[0183] Chemical Formula 3-1 (18.08 g, 87.24 mmol) was diluted in toluene (60 mL). To this, NaHCO3 (8.03 g, 95.96 mol) was added and the internal temperature was cooled to -5°C to 0°C, and then Chemical Formula 2 (= methoxyacetyl chloride) (10.37 g, 95.96 mmol) was slowly added so that the internal temperature was maintained, and then the temperature was maintained at 0°C to 10°C while the resulting mixture was stirred. After confirming that unreacted Chemical Formula 1 remaining in the reaction mixture was 0.1 area% or less (GC analysis result), the pH was confirmed to be 7 to 8 by washing the reaction mixture twice with distilled water (60 mL), and then the organic layer obtained by layer separation was concentrated under reduced pressure. Thereby, bright yellow Chemical Formula 6-1 (= N-(2,6-dimethylphenyl)-N-(methoxyacetyl)-D-methylalaninate) was obtained in a yield of 90%, the purity thereof was 98.8%, the absorbance at a wavelength of 266 nm was 2.974 (the transmittance was 0.106), and the absorbance at a wavelength of 274 nm was 2.527 (the transmittance was 0.297).

[0184] [Comparative Example 1]

[0185] (s)-methyl 2-(methylsulfonyloxy)propanoate (20.00 g, 109.78 mmol), triethylamine (12.22 g, 120.75 mmol), and 2,6-dimethylaniline (106.43 g, 274.45 mmol) were added to a reactor containing toluene (20 mL), the internal temperature was increased to 120°C to 130°C, and then the mixture was stirred.

[0186] After confirming that unreacted (s)-methyl 2-(methylsulfonyloxy)propanoate remained in the reaction mixture was 1.0 area% or less (result of GC analysis), the reaction mixture was cooled to room temperature, and then the solid produced by adding H2O (40 mL) thereto was dissolved, and then diluted in toluene (100 mL), after which the organic layer obtained by washing the solid with 1 N aqueous HC1 (40 mL) three times was washed twice with a 1 N NaOH solution (40 mL), and then the organic layer was washed once with distilled water (30 mL), after which it was concentrated under reduced pressure to obtain (s)-methyl 2-(methylsulfonyloxy)propanoate in a yield of 68% and a purity of 97.24 GC area%.

[0187] [Comparative Example 2]

[0188] (s)-methyl 2-(methylsulfonyloxy)propanoate (20.00 g, 109.78 mmol), triethylamine (12.22 g, 120.75 mmol), and 2,6-dimethylaniline (106.43 g, 274.45 mmol) were added to a reactor containing toluene (20 mL) at room temperature, the internal temperature was raised to 120 to 130°C, and then the mixture was stirred.

[0189] After confirming that unreacted (s)-methyl 2-(methylsulfonyloxy)propanoate remained in the reaction mixture was 1.0 area% or less (result of GC analysis), the reaction mixture was cooled to room temperature. After that, the internal pressure was reduced to 100 Torr at room temperature, and while the internal pressure was in the range of 61 to 100 Torr, the internal temperature was slowly raised and adjusted to 200°C from 60°C, but N-(2,6-dimethylphenyl)-D-alanine methyl ester could not be obtained.

[0190] [Comparative Example 3]

[0191] (s)-methyl 2-(methylsulfonyloxy)propanoate (20.00 g, 109.78 mmol), triethylamine (12.22 g, 120.75 mmol), and 2,6-dimethylaniline (106.43 g, 274.45 mmol) were added to a reactor containing toluene (20 mL) at room temperature, the internal temperature was raised to 120 to 130°C, and then the mixture was stirred.

[0192] After confirming that the remaining unreacted (s)-methyl 2- (methanesulfonyloxy)propanoate in the reaction mixture was 1.0 area% or less (GC analysis result), the reaction mixture was cooled to room temperature, and then the solid produced by adding H2O (40 mL) thereto was dissolved and then diluted in toluene (100 mL). The organic layer obtained by washing the diluted solid with 1 N aqueous HC1 (40 mL) three times was washed twice with a 1 N NaOH solution (40 mL), and then the organic layer was washed once with distilled water (30 mL), after which it was concentrated under reduced pressure. As a result, yellow chemical formula 3-1 (= N- (2, 6-dimethylphenyl)-D-methyIalaninate) was obtained in a yield of 68%, which had a purity of 97.2%, an absorbance at a wavelength of 266 nm of 3.842 (a transmittance of 0.014), and an absorbance at a wavelength of 274 nm of 3.685 (a transmittance of 0.021).

[0193] Chemical formula 3-1 (18.08 g, 87.24 mmol) was diluted in toluene (60 mL). After adding NaHC03(8.03 g, 95.96 mmol) thereto and cooling the internal temperature to -5 to 0°C, chemical formula 5-1 (= methoxyacetyl chloride) (10.37 g, 95.96 mmol) was slowly added thereto such that the internal temperature was maintained, and then the resulting mixture was stirred while maintaining the temperature at 0 to 10°C. After confirming that the remaining unreacted chemical formula 3-1 in the reaction mixture was 0.1 area% or less (GC analysis result), the reaction mixture was washed twice with distilled water (60 mL). After confirming that the pH was 7 to 8, the organic layer obtained by layer separation was concentrated under reduced pressure. As a result, brown chemical formula 6-1 (= N- (2, 6-dimethylphenyl)-N- (methoxyacetyl)-D-methyIalaninate) was obtained in a yield of 90%, which had a purity of 97.4%, an absorbance at a wavelength of 266 nm of 3.211 (a transmittance of 0.062), and an absorbance at a wavelength of 274 nm of 2.841 (a transmittance of 0.144).

[0194] [Experimental Example 1]

[0195] Samples were taken from the syntheses of Example 1 and Comparative Examples 1 and 2, and were measured by gas chromatography analysis with a flame ionization detector (GC / FID) using a Shimadzu GC-2030 under the following conditions. The results are summarized in Table 1 below. In this case, each purity and content refers to GC area% based on the total GC area measured by GC / FID.

[0196] In this case, GC / FID analysis of the reaction mixture was measured using a Shimadzu GC-2030 under the following conditions.

[0197] Column: [HP-5] (0.25 mm ID x 30 mL, 0.25 μm d.f. capillary)

[0198] Oven temperature

[0199] Initial value and hold time: 50 °C, 5 min

[0200] Program rate: 10 °C / min

[0201] Final value and hold time: 320 °C, 18 min

[0202] Injector temperature: 340 °C

[0203] Detector temperature: 340 °C

[0204] Gas flow rate: Column (N2): 1 mL / min

[0205] Split ratio: 1 / 20

[0206] Injection volume: 1.0 uL

[0207] [Table 1]

[0208]

[0209] From Table 1, it can be confirmed that when distillation is not performed, the yield is significantly reduced due to washing with water, and at the same time, the impurity of Chemical Formula 4 is not well removed, and in the case of Comparative Example 2 in which the distillation conditions are not appropriate, even if distillation is performed, the target compound is not captured, and thus, the final product cannot be obtained. In contrast, when distillation is performed under the conditions of the present specification, it can be confirmed that the yield is high, and at the same time, the impurity of Chemical Formula 4 is also significantly removed.

[0210] [Experimental Example 2]

[0211] In order to confirm the absorbance and transmittance, samples were taken at each step of Example 2 and Comparative Example 3, and the absorbance and transmittance were measured using a UV / Vis spectrophotometer, and the measurement was performed using Agilent Technologies, Cary 8454 UV-Vis under the following conditions. The results are summarized in Table 2 below.

[0212] In addition, the absorbance and transmittance spectra of Example 2, Comparative Example 3, and methanol as a blank solvent are shown in Figures 1 to 6

[0213] Analytical concentration: 10 mg / mL

[0214] Dilution solvent (or blank solvent): MeOH

[0215] Analytical wavelength: 266 nm and 274 nm​

[0216] Analytical cell: quartz cell, path length 10 mm

[0217] [Table 2]

[0218]

[0219] In the ultraviolet / visible spectrum, the lower the absorbance and the higher the transmittance, the closer the material appears to a clear, transparent water-like state to the naked eye when the material is in a dissolved (solution) state. In Table 2, it can be confirmed that, when comparing the absorbance at 266 nm of Formula 6-1 as a D-alanine alkyl ester derivative, Example 2 shows 2.974, satisfying the range of 3.00 or less, but Comparative Example 3 shows 3.211, exceeding 3.00. In addition, it can be confirmed that the absorbance at 274 nm of Formula 6-1 is 2.527 in Example 2, satisfying the range of 2.60 or less, but is 2.841 in Comparative Example 3, exceeding 2.60.

[0220] In Table 2, it can be confirmed that, when comparing the transmittance at 266 nm of Formula 6-1 as a D-alanine alkyl ester derivative, Example 2 is 0.106, satisfying the range of 0.10 or more, and Comparative Example 3 is 0.062, less than 0.10. In addition, it can be confirmed that the transmittance at 274 nm of Formula 6-1 is 0.297 in Example 2, satisfying the range of 0.29 or more, but is 0.144 in Comparative Example 3, less than 0.29.

[0221] Thus, Example 2 is more clear and more transparent than Comparative Example 3 by naked eye observation, and Example 2 having improved transparency has a high aesthetic appearance, and thus is highly preferred in commerce.

Claims

1. A method for producing a D-alanine alkyl ester, the method comprising: synthesizing a compound of the following Chemical Formula 3 by reacting a compound of the following Chemical Formula 1 with a compound of the following Chemical Formula 2; and distilling a composition comprising the compound of Chemical Formula 3 at a pressure of 1 torr to 60 torr and a temperature of 60°C to 200°C: [Chemical Formula 1] [Chemical Formula 2] [Chemical Formula 3] wherein, in Chemical Formulas 1 to 3, R1 is a methyl group or an aryl group substituted with a methyl group, R2 and R3 are the same as or different from each other, and each is independently hydrogen; deuterium; or a methyl group, R4 is a methyl group.

2. The method of claim 1, wherein, The distillation of the composition is a distillation to produce a composition in which the content of a compound of the following Chemical Formula 4 is 0.1 area% or less based on the total GC area of the composition: [Chemical Formula 4] In Chemical Formula 4, R2 and R3 are the same as or different from each other, and each is independently hydrogen; deuterium; or a methyl group, R4 is a methyl group.

3. The method of claim 1, wherein, The content of the compound of Chemical Formula 2 is 2 equivalents to 10 equivalents based on the compound of Chemical Formula 1.

4. A method for producing a D-alanine alkyl ester derivative, the method comprising: synthesizing a compound of the following Chemical Formula 3 by reacting a compound of the following Chemical Formula 1 with a compound of the following Chemical Formula 2; distilling a composition comprising the compound of Chemical Formula 3 at a pressure of 1 torr to 60 torr and a temperature of 60°C to 200°C; and synthesizing a compound of the following Chemical Formula 6 by adding a compound of the following Chemical Formula 5 to the distilled composition: [Chemical Formula 1] [Chemical Formula 2] [Chemical Formula 5] [Chemical Formula 6] In Chemical Formulas 1 to 3, Chemical Formula 5, and Chemical Formula 6, R1 is a methyl group or an aryl group substituted with a methyl group, R2 and R3 are the same as or different from each other, and each is independently hydrogen; deuterium; or a methyl group, R4 is a methyl group, R5 is a methylenyl group substituted with a methoxy group; a methylenyl group substituted with a phenyl group; or a furanyl group.

5. The method of claim 1 or 4, wherein, The distillation is a distillation of a composition comprising the compound of Chemical Formula 3 at a pressure of 5 torr to 10 torr and a temperature of 110°C to 150°C.

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