Methods, compositions, and medicaments or agricultural products comprising N-acyl derivatives

Abstract

This specification relates to a method for preparing an N-acyl derivative, the N-acyl derivative thus prepared, and a pharmaceutical or agricultural product containing the derivative, wherein the method for preparing the N-acyl derivative distills a first composition comprising a compound of formula 1 and uses the distilled first composition.

Description

Technical Field

[0001] This patent application claims priority and benefit to Korean Patent Application No. 10-2021-0084509, filed with the Korean Intellectual Property Office on June 29, 2021, the entire contents of which are incorporated herein by reference.

[0002] This application relates to a method for preparing N-acyl derivatives, compositions, and pharmaceuticals or agricultural products comprising said compositions. Background Technology

[0003] N-acyl derivatives of N-(2,6-dimethylphenyl)-D-alanine methyl ester are commercially important as fungicides in crop protectants.

[0004] Methods for preparing N-acyl derivatives are generally known to be derived from D-alanine alkyl esters such as N-(2,6-dimethylphenyl)-D-alanine methyl ester.

[0005] However, this synthetic method inevitably produces genotoxic impurities in the final N-acyl derivative. These impurities are difficult to remove by conventional purification methods such as crystallization or recrystallization due to the liquid nature of the final product.

[0006] Therefore, designing a specific method to reduce the content of corresponding genotoxic impurities is an important problem that urgently needs to be solved. Summary of the Invention

[0007] Technical issues

[0008] This specification is intended to provide a method for preparing N-acyl derivatives, the N-acyl derivatives prepared thereby, and pharmaceuticals or agricultural products containing the derivatives.

[0009] Technical solution

[0010] An exemplary embodiment of this specification provides a method for preparing an N-acyl derivative, the method comprising: distilling a first composition comprising a compound of formula 1 below; synthesizing a compound of formula 3 below by adding a compound of formula 2 below to the distilled first composition; synthesizing a compound of formula 5 below by reacting the compound of formula 3 with a compound of formula 4 below; and synthesizing a compound of formula 7 below by reacting the compound of formula 5 with a compound of formula 6 below.

[0011] [Chemical Formula 1]

[0012]

[0013] [Chemical Formula 2]

[0014]

[0015] [Chemical Formula 3]

[0016]

[0017] [Chemical Formula 4]

[0018]

[0019] [Chemical Formula 5]

[0020]

[0021] [Chemical Formula 6]

[0022]

[0023] [Chemical Formula 7]

[0024]

[0025] In chemical formulas 1 to 7

[0026] R1 is a methyl group or an aryl group substituted with a methyl group.

[0027] R2 and R3 may be the same as or different from each other, and each is independently hydrogen; deuterium; or methyl.

[0028] R4 and R5 are methyl groups.

[0029] Another exemplary embodiment of this specification provides a method for preparing an N-acyl derivative, the method comprising: synthesizing a compound of formula 3 by adding a compound of formula 2 to a first composition comprising a compound of formula 1 below, wherein the content of a compound of formula 8 below is less than 0.05 area % based on the total GC area of ​​the first composition; synthesizing a compound of formula 5 below by reacting the compound of formula 3 with a compound of formula 4 below; and synthesizing a compound of formula 7 below by reacting the compound of formula 5 with a compound of formula 6 below.

[0030] [Chemical Formula 1]

[0031]

[0032] [Chemical Formula 2]

[0033]

[0034] [Chemical Formula 3]

[0035]

[0036] [Chemical Formula 4]

[0037]

[0038] [Chemical Formula 5]

[0039]

[0040] [Chemical Formula 6]

[0041]

[0042] [Chemical Formula 7]

[0043]

[0044] [Chemical Formula 8]

[0045]

[0046] In chemical formulas 1 to 7

[0047] R1 is a methyl group or an aryl group substituted with a methyl group.

[0048] R2 and R3 may be the same as or different from each other, and each is independently hydrogen; deuterium; or methyl.

[0049] R4 and R5 are methyl groups.

[0050] Another exemplary embodiment of this specification provides a composition comprising a compound of formula 7 below and a compound of formula 10 below, wherein the content of the compound of formula 10 below is less than 0.05 area % based on the total GC area of ​​the composition.

[0051] [Chemical Formula 7]

[0052]

[0053] [Chemical Formula 10]

[0054]

[0055] In chemical formulas 7 and 10,

[0056] R2 and R3 may be the same as or different from each other, and each is independently hydrogen; deuterium; or methyl.

[0057] R4 and R5 are methyl groups.

[0058] Another exemplary embodiment provides a medicine or agricultural product comprising the above-described composition.

[0059] Beneficial effects

[0060] The preparation method according to an exemplary embodiment of this specification can prepare an N-acyl derivative having a low content of genotoxic impurities.

[0061] High-purity N-acyl derivatives can be prepared according to a preparation method of one exemplary embodiment of this specification. Detailed Implementation

[0062] This instruction manual will be described in detail below.

[0063] 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 contained.

[0064] An exemplary embodiment of this specification provides a method for preparing an N-acyl derivative, the method comprising: distilling a first composition comprising a compound of formula 1 below; synthesizing a compound of formula 3 below by adding a compound of formula 2 below to the distilled first composition; synthesizing a compound of formula 5 below by reacting the compound of formula 3 with a compound of formula 4 below; and synthesizing a compound of formula 7 below by reacting the compound of formula 5 with a compound of formula 6 below.

[0065] Another exemplary embodiment of this specification provides a method for preparing an N-acyl derivative, the method comprising: distilling a first composition comprising a compound of formula 1 below; synthesizing a compound of formula 3 below by adding a compound of formula 2 below to the distilled first composition; synthesizing a compound of formula 5 below by reacting the compound of formula 3 with a compound of formula 4 below; distilling a second composition comprising a compound of formula 5; and synthesizing a compound of formula 7 below by adding a compound of formula 6 below to the distilled second composition.

[0066]

[0067] In chemical formulas 1 to 7, R1 is methyl or aryl substituted with methyl, R2 and R3 are the same or different from each other and are each independently hydrogen; deuterium; or methyl, and R4 and R5 are methyl.

[0068] This synthetic method inevitably produces impurities, such as the following chemical formula 10, which induces genotoxicity in the final N-acyl derivative.

[0069] [Chemical Formula 10]

[0070]

[0071] Because the material of Formula 10 is genotoxic and clastogenic, causing mutations in the DNA that makes up genes, and these mutations can manifest as a disaster in the next generation as genetic diseases are expressed, it is necessary to remove the material through purification processes or control it to very low levels.

[0072] However, since compounds of formula 7 and formula 9 have high boiling points above 295°C, it is difficult to distill the compounds in large-scale production processes. Therefore, it is difficult to separate and purify the compounds by distillation in the final composition state.

[0073] Therefore, in this specification, by removing the precursor that produces the compound of formula 10 by distillation in the pre-synthesis step of formula 7, the probability of producing the compound of formula 10 is reduced, and the compound of formula 7 can be synthesized more easily with high purity. This is possible because the compound of formula 1 in the first composition and the compound of formula 6 in the second composition have boiling points at levels that allow distillation even in large-scale production processes.

[0074] Specifically, as in the reaction scheme below, Formula 10 is prepared from Formula 8, which is an impurity of Formula 1.

[0075] [Reaction Protocol]

[0076]

[0077] In the reaction scheme, the definitions of R1 to R5 are the same as those in chemical formulas 1 to 7.

[0078] In this specification, before allowing Formula 1 to participate in the reaction, a portion of Formula 8 can be removed by distillation to reduce the possibility of impurities being generated, thereby reducing the content of the compound of Formula 10, which is difficult to separate during the synthesis of the final N-acyl derivative.

[0079] In one exemplary embodiment of this specification, the distillation of the first composition is to prepare a first composition in which the content of the compound of Formula 8 below is less than 0.05 area % based on the total GC area of ​​the first composition. Specifically, the content of the compound of Formula 8 in the first composition is reduced by distilling the first composition containing both the compound of Formula 1 and the compound of Formula 8 below to remove the compound of Formula 8 below from the first composition.

[0080] [Chemical Formula 8]

[0081]

[0082] In one exemplary embodiment of this specification, the distillation of the first composition may be performed once or multiple times, specifically several times, such as once or more, twice or more, or three or more times.

[0083] In one exemplary embodiment of this specification, by distilling the first composition, the content of the compound of formula 8 can be less than 0.05 area%, less than 0.04 area%, or less than 0.03 area% based on the total GC area of ​​the first composition, and the lower the content of the compound of formula 8, the better; therefore, there is no particular limitation on its lower limit.

[0084] In one exemplary embodiment of this specification, the first composition is distilled at a pressure of 40 to 60 Torr and a temperature of 70 to 100°C. In this case, since the amount of Formula 9 to be removed in the next distillation step is reduced, it is advantageous to obtain a second composition with a higher content of Formula 5. Furthermore, since the distillation conditions of the first composition are not high-temperature or excessively low vacuum pressure conditions unsuitable for large-scale production, it is advantageous that the distillation conditions can be easily applied to large-scale production processes.

[0085] In this specification, before allowing chemical formula 5 to participate in the reaction, a portion of chemical formula 9 can be removed by distillation to reduce the possibility of impurities, thereby reducing the content of the compound of chemical formula 10, which is difficult to separate during the synthesis of the final product.

[0086] In one exemplary embodiment of this specification, the distillation of the second composition is to prepare a second composition in which the content of the compound of Formula 9 below is less than 0.05 area % based on the total GC area of ​​the second composition. Specifically, the content of the compound of Formula 9 in the second composition is reduced by distilling the second composition containing both the compound of Formula 5 and the compound of Formula 9 below to remove the compound of Formula 9 below from the second composition.

[0087] [Chemical Formula 9]

[0088]

[0089] In chemical formula 9, R2 and R3 are the same or different from each other, and each is independently hydrogen; deuterium; or methyl, and R4 is methyl.

[0090] In one exemplary embodiment of this specification, in the distillation of the second composition, distillation may be performed once or multiple times, specifically several times, such as once or multiple times, twice or more, or three or more times.

[0091] In one exemplary embodiment of this specification, by distillation of the second composition, the content of the compound of Formula 9 can be less than 0.05 area%, less than 0.04 area%, or less than 0.03 area%, based on the total GC area of ​​the second composition, and the lower the content of the compound of Formula 9, the better; therefore, there is no particular limitation on its lower limit.

[0092] In one exemplary embodiment of this specification, the second composition is distilled at a pressure of 2 to 20 Torr and a temperature of 130°C to 200°C. In this case, since the amount of Formula 10 to be removed in the next distillation step is reduced, it is advantageous to obtain a third composition with a higher content of Formula 7.

[0093] In one exemplary embodiment of this specification, the amount of the compound of formula 2 is 1.0 equivalent to 2.0 equivalent, based on the compound of formula 1.

[0094] In one exemplary embodiment of this specification, the amount of the compound of formula 4 is from 2.0 equivalents to 10.0 equivalents, based on the compound of formula 3. In this case, the equivalent of formula 4 used is appropriate, and therefore, it has the advantage of being able to control side reactions while increasing the reaction rate.

[0095] In one exemplary embodiment of this specification, the amount of the compound of formula 6 is from 1.0 equivalent to 2.0 equivalent, based on the compound of formula 5.

[0096] In one exemplary embodiment of this specification, based on the total GC area of ​​the third composition comprising the compound of formula 7, the content of the compound of formula 10 is less than 0.05 area %. Throughout the reaction scheme, before each compound participates in the reaction, the compounds of formula 1 and formula 5 are distilled to remove compounds of formula 8 and formula 9 as impurities, thus reducing the content of the compound of formula 10 in the final product of the final synthesis. Specifically, based on the total GC area of ​​the third composition, the content of the compound of formula 10 is less than 0.05 area %, less than 0.04 area %, less than 0.03 area %, and less than 0.02 area %.

[0097] [Chemical Formula 10]

[0098]

[0099] In chemical formula 10,

[0100] R2 and R3 may be the same as or different from each other, and each is independently hydrogen; deuterium; or methyl.

[0101] R4 and R5 are methyl groups.

[0102] Another exemplary embodiment of this specification provides a method for preparing an N-acyl derivative, the method comprising: synthesizing a compound of formula 3 by adding a compound of formula 2 to a first composition comprising a compound of formula 1 below, wherein the content of a compound of formula 8 below is less than 0.05 area % based on the total GC area of ​​the first composition; synthesizing a compound of formula 5 below by reacting the compound of formula 3 with a compound of formula 4 below; and synthesizing a compound of formula 7 below by reacting the compound of formula 5 with a compound of formula 6 below.

[0103] Another exemplary embodiment of this specification provides a method for preparing an N-acyl derivative, the method comprising: synthesizing a compound of formula 3 by adding a compound of formula 2 to a first composition comprising a compound of formula 1, wherein the content of a compound of formula 8 is less than 0.05 area % based on the total GC area of ​​the first composition; synthesizing a compound of formula 5 by reacting the compound of formula 3 with a compound of formula 4; and synthesizing a compound of formula 7 by adding a compound of formula 6 to a second composition comprising a compound of formula 5, wherein the content of a compound of formula 9 is less than 0.05 area % based on the total GC area of ​​the second composition.

[0104] [Chemical Formula 1]

[0105]

[0106] [Chemical Formula 2]

[0107]

[0108] [Chemical Formula 3]

[0109]

[0110] [Chemical Formula 4]

[0111]

[0112] [Chemical Formula 5]

[0113]

[0114] [Chemical Formula 6]

[0115]

[0116] [Chemical Formula 7]

[0117]

[0118] [Chemical Formula 8]

[0119]

[0120] [Chemical Formula 9]

[0121]

[0122] In chemical formulas 1 to 7 and 9, R1 is methyl or aryl substituted with methyl, R2 and R3 are the same or different from each other and are each independently hydrogen; deuterium; or methyl, and R4 and R5 are methyl.

[0123] Another exemplary embodiment of this specification provides a composition comprising a compound of formula 7 below and a compound of formula 10 below, wherein the content of the compound of formula 10 below is less than 0.05 area % based on the total GC area of ​​the composition.

[0124] [Chemical Formula 7]

[0125]

[0126] [Chemical Formula 10]

[0127]

[0128] In chemical formulas 7 and 10,

[0129] R2 and R3 may be the same as or different from each other, and each is independently hydrogen; deuterium; or methyl.

[0130] R4 and R5 are methyl groups.

[0131] Here, the description of N-acyl derivatives can be found in the foregoing description of the method for preparing N-acyl derivatives.

[0132] In this specification, when the aryl group is a monocyclic aryl group, there is no particular limitation on the number of carbon atoms, but it is preferably 6 to 25. Specific examples of monocyclic aryl groups include phenyl, biphenyl, terphenyl, etc., but are not limited thereto.

[0133] When the aryl group is a polycyclic aryl group, there is no particular restriction on the number of carbon atoms, but it is preferably 10 to 24. Specific examples of polycyclic aryl groups include naphthyl, anthraceneyl, phenanthryl, pyrene, peryl, etc. It includes, but is not limited to, methyl, fluorene, etc.

[0134] In this specification, the fluorene group may be substituted, and adjacent substituents may bond together to form a ring.

[0135] In one exemplary embodiment of this specification, R1 is methyl; or phenyl substituted with methyl.

[0136] In one exemplary embodiment of this specification, R1 is methyl; or and It is the bonding position.

[0137] In one exemplary embodiment of this specification, R2 and R3 may be the same as or different from each other, and each is independently hydrogen; or methyl.

[0138] In one exemplary embodiment of this specification, R2 and R3 are methyl groups.

[0139] This specification provides a pharmaceutical or agricultural product comprising the above-described composition. In this case, the pharmaceutical or agricultural product includes not only the state containing N-acyl derivatives as in the composition, but also derivatives modified for various uses, i.e., derivatives modified by necessary chemical reactions.

[0140] In this specification, the agricultural products mentioned can be various agricultural chemicals, such as herbicides, crop protectants, and fungicides. Detailed Implementation

[0142] The present specification will be described in more detail below by way of examples. However, the examples provided below are for illustrative purposes only and are not intended to limit the scope of the specification.

[0143] [Example]

[0144] [Example 1]

[0145] A solution containing 100 g (0.96 mol) of L-methyl lactate (manufactured by TCI, purity ≥ 98% (GC)) was injected into the flask, the internal pressure was adjusted to 60 Torr, and the temperature was raised to 70 °C.

[0146] L-methyl lactate was distilled by raising the temperature from 70°C to 100°C while simultaneously reducing the internal pressure from 60 Torr to 40 Torr. As a result, the distillation yielded L-methyl lactate with a yield of 95%, based on the total GC area of ​​the distilled solution, resulting in an L-lactic acid content of 0.05 area%.

[0147] Distilled L-lactate (104.11 g, 1.0 mol) and triethylamine (154.60 mL, 111.31 g, 1.1 mol) were added to a reactor containing 400 mL of dichloromethane at room temperature, and the internal temperature was cooled to 0 °C. p-Toluenesulfonyl chloride (209.70 g, 1.1 mol) was slowly added while maintaining the internal temperature between 0 °C and 5 °C. After the addition was complete, the resulting mixture was stirred for 4 hours while maintaining the internal temperature between 0 °C and 5 °C. After confirming that the remaining unreacted L-lactate in the reaction mixture was less than 1.0 area % (GC analysis result), 400 mL of 1N hydrochloric acid (HCl) aqueous solution was added, and the mixture was stirred while maintaining the internal temperature between 15 °C and 20 °C. Then, 400 mL of 1% sodium bicarbonate (NaHCO3) aqueous solution was added to the organic layer obtained by separation, and the mixture was stirred. The organic layer was then separated and concentrated under reduced pressure to obtain methyl (s)-2-(p-toluenesulfonyloxy)propionate with a purity of 98.40 GC area% and a yield of 79% (204.05 g, 0.79 mol).

[0148] 2,6-Dimethylaniline (56.30 g, 464.58 mmol) was added to the prepared methyl (s)-2-(p-toluenesulfonyloxy)propionate (20.00 g, 77.43 mmol), and the mixture was stirred by raising the internal temperature to 120-130 °C. After confirming that the remaining unreacted methyl (s)-2-(p-toluenesulfonyloxy)propionate in the reaction mixture was less than 1.0 area % (GC analysis result), the remaining 2,6-dimethylaniline was separated by distillation while slowly reducing the internal pressure to 20 Torr and was discarded. Subsequently, impurities were separated by distillation by raising the temperature from 130 °C to 200 °C while reducing the internal pressure from 20 Torr to 2 Torr, thereby obtaining crude N-(2,6-dimethylphenyl)-D-alanine methyl ester (13.64 g, 65.82 mmol) with a purity of 95.22 GC area % and a yield of 85%.

[0149] The N-(2,6-dimethylphenyl)-D-alanine methyl ester obtained by distillation was directly diluted in toluene (100 mL) and washed once with 1N HCl aqueous solution (20 mL). The resulting organic layer was washed once with distilled water (30 mL) and then concentrated under reduced pressure to obtain N-(2,6-dimethylphenyl)-D-alanine methyl ester with a purity of 98.52 GC area% and a yield of 81% (13.00 g, 62.72 mmol).

[0150] After adding NaHCO3 (6.85 g, 81.54 mmol) and toluene (52 mL), the resulting mixture was cooled to -5°C to 0°C, and then methoxyacetyl chloride (8.85 g, 81.54 mmol) was added dropwise. After the addition was complete, the resulting mixture was stirred for 3 hours to maintain the internal temperature at 10°C to 15°C. After confirming that the remaining unreacted N-(2,6-dimethylphenyl)-D-alanine methyl ester in the reaction mixture was less than 1.0 area % (GC analysis result), H2O (52 mL) was added, and the pH was confirmed to be 7 to 8 by adding 1 N NaOH dropwise. The aqueous layer was then discarded by chromatography. H2O (26 mL) was added to the separated organic layer, and after stirring, the aqueous layer was discarded again by chromatography. After removing foreign matter by filtering the separated organic layer, the residue was concentrated under reduced pressure to obtain N-(2,6-dimethylphenyl)-N-(methoxyacetyl)-D-alanine methyl ester with a purity of 98.82 GC area% and a yield of 84% (14.72 g, 52.68 mmol). In this case, based on the total GC area of ​​the obtained N-(2,6-dimethylphenyl)-N-(methoxyacetyl)-D-alanine methyl ester, the genotoxicity was 0.02 area%.

[0151] [Example 2]

[0152] A solution containing 100 g (manufactured by TCI, purity greater than 98% (GC), 0.96 mol) of L-methyl lactate was injected into the flask, the internal pressure was adjusted to 60 Torr, and the temperature was raised to 70 °C.

[0153] L-methyl lactate was distilled by raising the temperature from 70°C to 100°C while simultaneously reducing the internal pressure from 60 Torr to 40 Torr. As a result, at room temperature, the distilled L-methyl lactate (104.11 g, 1.0 mol) was introduced into a reactor containing 400 mL of dichloromethane, resulting in an L-lactic acid content of 0.05 area% based on the total GC area of ​​the distilled solution. Triethylamine (154.60 mL, 111.31 g, 1.1 mol) was further added, and the internal temperature was cooled to 0°C. p-Toluenesulfonyl chloride (209.70 g, 1.1 mol) was slowly added while maintaining the internal temperature between 0°C and 5°C. After the addition was complete, the resulting mixture was stirred for 4 hours while maintaining the internal temperature between 0°C and 5°C. After confirming that the remaining unreacted L-lactate methyl ester in the reaction mixture was less than 1.0 area % (GC analysis result), 400 mL of 1N hydrochloric acid (HCl) aqueous solution was added, and the mixture was stirred while maintaining the internal temperature at 15°C to 20°C. Then, 400 mL of 1% sodium bicarbonate (NaHCO3) aqueous solution was added to the organic layer obtained by layer separation, and the mixture was stirred. Subsequently, the organic layer was separated and concentrated under reduced pressure to give (S)-2-(p-toluenesulfonyloxy)propionate methyl ester with a purity of 98.36 GC area % and a yield of 79% (204.44 g, 0.79 mol).

[0154] 2,6-Dimethylaniline (56.30 g, 464.58 mmol) was added to the prepared methyl (s)-2-(p-toluenesulfonyloxy)propionate (20.00 g, 77.43 mmol), and the mixture was stirred by raising the internal temperature to 120°C to 130°C.

[0155] After confirming that the remaining unreacted methyl (s)-2-(p-toluenesulfonyloxy)propionate in the reaction mixture was less than 1.0 area % (GC analysis result), the internal temperature was cooled to room temperature (RT), toluene (100 mL) was added, and the resulting mixture was cooled again to 0 °C, stirred for 1 hour, and then filtered. The organic layer obtained by washing the filtrate twice with 1 N HCl aqueous solution (20 mL) was washed once with distilled water (30 mL) and then concentrated under reduced pressure to give N-(2,6-dimethylphenyl)-D-alanine methyl ester (10.11 g, 48.78 mmol) with a purity of 97.42 GC area % and a yield of 63%.

[0156] After adding NaHCO3 (5.33 g, 63.41 mmol) and toluene (40 mL), the resulting mixture was cooled to -5°C to 0°C, and then methoxyacetyl chloride (6.88 g, 63.41 mmol) was added dropwise. After the addition was complete, the resulting mixture was stirred for 3 hours to maintain the internal temperature at 10°C to 15°C. After confirming that the remaining unreacted N-(2,6-dimethylphenyl)-D-alanine methyl ester in the reaction mixture was less than 1.0 area % (GC analysis results), H2O (40 mL) was added, and the pH was confirmed to be 7 to 8 by adding 1 N NaOH dropwise. The aqueous layer was then discarded by stratification. H2O (20 mL) was added to the separated organic layer, and after stirring, the aqueous layer was discarded by stratification. After removing foreign matter by filtration of the separated organic layer, the residue was concentrated under reduced pressure to obtain N-(2,6-dimethylphenyl)-N-(methoxyacetyl)-D-alanine methyl ester with a purity of 97.62 GC area% and a yield of 84% (11.45 g, 40.98 mmol). In this case, based on the total GC area of ​​the obtained N-(2,6-dimethylphenyl)-N-(methoxyacetyl)-D-alanine methyl ester, the genotoxicity was 0.11% area.

[0157] [Comparative Example 1]

[0158] At room temperature, 104.11 g (1.0 mol) of undistilled L-lactic acid methyl ester, thus containing 0.20 area % of L-lactic acid in the total GC area, was placed in a reactor containing 400 mL of dichloromethane. Triethylamine (154 mL, 111.31 g, 1.1 mol) was added, and the internal temperature was cooled to 0 °C. p-Toluenesulfonyl chloride (209.70 g, 1.1 mol) was slowly added while maintaining the internal temperature between 0 °C and 5 °C. After the addition was complete, the resulting mixture was stirred for 4 hours while maintaining the internal temperature between 0 °C and 5 °C. After confirming that the remaining unreacted L-lactic acid methyl ester in the reaction mixture was less than 1.0 area % (GC analysis result), 400 mL of 1N hydrochloric acid (HCl) aqueous solution was added, and the resulting mixture was stirred while maintaining the internal temperature between 15 °C and 20 °C. Then, 400 mL of 1% sodium bicarbonate (NaHCO3) aqueous solution was added to the organic layer obtained by layer separation, and the resulting mixture was stirred. The organic layer was then separated and concentrated under reduced pressure to obtain methyl (s)-2-(p-toluenesulfonyloxy)propionate with a purity of 98.23 GC area% and a yield of 79% (204.38 g, 0.79 mol).

[0159] 2,6-Dimethylaniline (56.30 g, 464.58 mmol) was added to the prepared methyl (s)-2-(p-toluenesulfonyloxy)propionate (20.00 g, 77.43 mmol), and the mixture was stirred by raising the internal temperature to 120°C to 130°C.

[0160] After confirming that the remaining unreacted methyl (s)-2-(p-toluenesulfonyloxy)propionate in the reaction mixture was less than 1.0 area % (GC analysis result), the internal temperature was cooled to room temperature (RT), toluene (100 mL) was added, and the resulting mixture was cooled again to 0 °C, stirred for 1 hour, and then filtered. The organic layer obtained by washing the filtrate twice with 1 N HCl aqueous solution (20 mL) was washed once with distilled water (30 mL), and then concentrated under reduced pressure to give N-(2,6-dimethylphenyl)-D-alanine methyl ester with a purity of 97.40 GC area % and a yield of 64% (10.27 g, 49.56 mmol).

[0161] After adding NaHCO3 (5.41 g, 64.43 mmol) and toluene (40 mL), the resulting mixture was cooled to -5°C to 0°C, and then methoxyacetyl chloride (6.99 g, 64.43 mmol) was added dropwise. After the addition was complete, the resulting mixture was stirred for 3 hours to maintain the internal temperature at 10°C to 15°C. After confirming that the remaining unreacted N-(2,6-dimethylphenyl)-D-alanine methyl ester in the reaction mixture was less than 1.0 area % (GC analysis result), H2O (40 mL) was added, and the pH was confirmed to be 7 to 8 by adding 1 N NaOH dropwise. The aqueous layer was then discarded by stratification. H2O (20 mL) was added to the separated organic layer, and after stirring, the aqueous layer was discarded by stratification. After removing foreign matter by filtering the separated organic layer, the residue was concentrated under reduced pressure to obtain N-(2,6-dimethylphenyl)-N-(methoxyacetyl)-D-alanine methyl ester with a purity of 97.57 GC area% and a yield of 83% (11.49 g, 41.13 mmol). In this case, based on the total GC area of ​​the obtained N-(2,6-dimethylphenyl)-N-(methoxyacetyl)-D-alanine methyl ester, the genotoxicity was 0.19% area%.

[0162] [Experimental Example 1]

[0163] Samples were taken from each step of the synthesis in Examples 1 and 2, and Comparative Example 1, and measured using gas chromatography with a flame ionization detector (GC / FID) on 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 % of the total GC area based on GC / FID.

[0164] Column: [HP-5] (0.25mm ID×30mL, 0.25μm df capillary)

[0165] Oven temperature

[0166] Initial value and holding time: 50℃, 5 minutes

[0167] Program speed: 10℃ / min

[0168] Final value and holding time: 320℃, 18 minutes

[0169] Syringe temperature: 340℃

[0170] Detector temperature: 340℃

[0171] Gas flow rate: Column (N2): 1 mL / min

[0172] Flow split ratio: 1 / 20

[0173] Injection volume: 1.0uL

[0174] [Table 1]

[0175]

[0176] As can be seen from Table 1, in Comparative Example 1, where no distillation was performed, the final compound had low purity and a high content of impurities of Formula 10. It can be confirmed that Example 1, where all compounds of Formula 1 and Formula 5 were distilled, has higher purity and a lower content of impurities of Formula 10, even compared to Example 2, where only the compound of Formula 1 was distilled.

Claims

1. A method for preparing N-acyl derivatives, the method comprising: Distillation of a first composition comprising a compound of chemical formula 1 below; The compound of chemical formula 3 is synthesized by adding a compound of chemical formula 2 to the first distilled composition; The compound of formula 5 is synthesized by reacting the compound of formula 3 with the compound of formula 4 below; Distillation of a second composition comprising a compound of formula 5; and The compound of formula 7 is synthesized by adding a compound of formula 6 below to the distilled second composition. The first composition is distilled at a pressure of 40 to 60 Torr and a temperature of 70 to 100°C. The second composition is distilled at a pressure of 2 to 20 Torr and a temperature of 130°C to 200°C. The second composition is prepared by distillation, wherein the content of the compound of chemical formula 9 is less than 0.05 area % based on the total GC area of ​​the composition. [Chemical Formula 1] [Chemical Formula 2] [Chemical Formula 3] [Chemical Formula 4] [Chemical Formula 5] [Chemical Formula 6] [Chemical Formula 7] [Chemical Formula 9] In chemical formulas 1 to 7 and 9 R1 is a methyl group or an aryl group substituted with a methyl group. R2 and R3 may be the same as or different from each other, and each is independently hydrogen; deuterium; or methyl. R4 and R5 are methyl groups.

2. The method according to claim 1 further comprises purifying the synthesized compound of formula 7. in, Based on the total GC area of ​​the third composition containing the purified compound of formula 7, the content of the compound of formula 10 is less than 0.05 area %. [Chemical Formula 10] In chemical formula 10, R2 and R3 may be the same as or different from each other, and each is independently hydrogen; deuterium; or methyl. R4 and R5 are methyl groups.

Images