Process for the preparation of d-alanine alkyl esters

Abstract

The present specification relates to a method of preparing D-alanine alkyl ester, the method comprising supplying an inert gas to a reaction solution when synthesizing D-alanine alkyl ester using aniline.

Description

Technical Field

[0001] This application claims priority and benefit to Korean Patent Application No. 10-2020-0115468, filed on September 9, 2020, with the Korean Intellectual Property Office, the entire disclosure of which is incorporated herein by reference.

[0002] This specification relates to a method for preparing D-alanine alkyl esters. Background Technology

[0003] N-(2,6-dimethylphenyl)-D-alanine methyl ester is a synthetic intermediate required for the preparation of fungicides (=N-acyl derivatives of N-(2,6-dimethylphenyl)-D-alanine methyl ester), such as Metalaxyl-M, Benalaxyl-M and Furalaxyl-M in crop protectants, and has significant commercial value.

[0004] As a general procedure for synthesizing N-(2,6-dimethylphenyl)-D-alanine methyl ester, it is known to use methyl (s)-2-(methanesulfonyloxy)propionate or methyl (s)-2-(p-toluenesulfonyloxy)propionate, an organic or inorganic base, and 2,6-dimethylamine. In this case, when the reaction is exposed to O2(g), in addition to the product (=N-(2,6-dimethylphenyl)-D-alanine methyl ester), a dimer of 2,6-dimethylamine (=azo compound) is produced as an oxidative reaction subcomponent, and its properties turn reddish-black, darken and deteriorate, reducing the commercial value of the product, and the dimer is difficult to remove by general purification methods.

[0005] Therefore, an important solution is to develop a high-purity preparation method that can effectively suppress the generation of the corresponding oxidation reaction subcomponents during the reaction process and can be applied to large-scale production. Summary of the Invention

[0006] Technical issues

[0007] This specification provides a method for preparing D-alanine alkyl esters.

[0008] Technical solution

[0009] This specification provides a method for preparing D-alanine alkyl esters, the method comprising supplying an inert gas to the reaction solution when synthesizing a compound of formula 3 using a reaction solution comprising a compound of formula 1 and a compound of formula 2.

[0010] [Chemical Formula 1]

[0011]

[0012] [Chemical Formula 2]

[0013]

[0014] [Chemical Formula 3]

[0015]

[0016] In Chemical Formula 1 to Chemical Formula 3,

[0017] R1and R2are methyl, and R3is methyl or p-tolyl,

[0018] R4and R5are each hydrogen or methyl, and R6is hydrogen.

[0019] In the method for producing a D-alanine alkyl ester of the present specification, the inert gas is selected from nitrogen, helium, neon, and argon.

[0020] In the method for producing a D-alanine alkyl ester of the present specification, when the volume of the reactor in which the compound of Chemical Formula 3 is synthesized is A, and the volume of the reaction solution in the reactor is 90% or less of the volume of the reactor, the flow rate of the inert gas is 0.02 A / min to 0.2 A / min.

[0021] Advantages

[0022] The method for purifying a D-alanine alkyl ester of the present specification can obtain a D-alanine alkyl ester with high purity and improved yield. DETAILED DESCRIPTION

[0023] Hereinafter, the present specification will be described in detail.

[0024] The technical feature of the present specification is to synthesize a D-alanine alkyl ester in an inert gas atmosphere.

[0025] The technical feature of the present specification is to synthesize a D-alanine alkyl ester using a compound of the following Chemical Formula 2 while supplying an inert gas to a reaction solution.

[0026] [Chemical Formula 2]

[0027]

[0028] In Chemical Formula 2, R4and R5are each independently hydrogen or an alkyl group having 1 to 4 carbon atoms, and R6is hydrogen or an alkyl group having 1 to 4 carbon atoms.

[0029] When the compound of Chemical Formula 2 is exposed to oxygen, a side reaction such as the following Chemical Formula 5 can occur due to an oxidation reaction.

[0030] [Chemical Formula 5]

[0031]

[0032] In Chemical Formula 5, the definitions of R4 to R6 are the same as those in Chemical Formula 2.

[0033] When 2,6-dimethylaniline is used as the compound of Chemical Formula 2, an impurity having the following structure can be generated through an oxidation reaction.

[0034]

[0035] In contrast, in a process of synthesizing a D-alanine alkyl ester using a compound of the following Chemical Formula 1, when the reaction is performed while supplying an inert gas to a reaction solution, the probability of an oxidation reaction of Chemical Formula 2 occurring due to contact with residual oxygen dissolved in the reaction solution or oxygen flowing in from the outside is reduced, and the residual oxygen dissolved in the reaction solution is discharged.

[0036] The present specification provides a method of preparing a D-alanine alkyl ester, that is, the method includes supplying an inert gas to a reaction solution when synthesizing a compound of the following Chemical Formula 3 using a reaction solution including a compound of the following Chemical Formula 1 and a compound of the following Chemical Formula 2.

[0037] [Chemical Formula 1]

[0038]

[0039] [Chemical Formula 2]

[0040]

[0041] [Chemical Formula 3]

[0042]

[0043] In Chemical Formulas 1 to 3,

[0044] R1 and R2 are each independently an alkyl group having 1 to 4 carbon atoms,

[0045] R3 is an alkyl group having 1 to 4 carbon atoms, or is a phenyl group which is unsubstituted or substituted with an alkyl group having 1 to 4 carbon atoms,

[0046] R4 and R5 are each independently hydrogen or an alkyl group having 1 to 4 carbon atoms, and

[0047] R6 is hydrogen, or an alkyl group having 1 to 4 carbon atoms.

[0048] In the method of preparing a D-alanine alkyl ester of the present specification, the inert gas is selected from nitrogen, helium, neon, and argon.

[0049] In the method for producing D-alanine alkyl ester of the present specification, when the volume of the reactor in which the compound of Formula 3 is synthesized is A, and the volume of the reaction solution in the reactor is 90% by volume or less of the reactor, the flow rate of the inert gas is 0.02 A / min to 0.2 A / min. When the above conditions are satisfied, the effect of discharging the residual oxygen in the reaction solution or blocking the inflow of external oxygen is effective, so that the formation of the sub-ingredient of Formula 5 is extremely small or does not occur, and when the high-temperature reaction is performed by the gas flow, the yield loss caused by the evaporation and discharge of the raw material (Formula 1 and Formula 2 are reactants) and the product (Formula 3) into the ventilation pipe does not occur. Only when the reaction is performed within the above range, the generation of the sub-ingredient of Formula 5 can be suppressed while maintaining the yield.

[0050] In the present specification, the content of the sub-ingredient of Formula 5 can be 0% by weight or more and 0.5% by weight or less, 0.5% by weight or less, 0.4% by weight or less, 0.3% by weight or less, 0.2% by weight or less, or 0.1% by weight or less, based on the total weight of the solution in which the compound of Formula 3 is synthesized.

[0051] In the present specification, the content of the sub-ingredient of Formula 5 can be 0% by weight or more and 0.5% by weight or less, 0.5% by weight or less, 0.4% by weight or less, 0.3% by weight or less, 0.2% by weight or less, 0.1% by weight or less, 0.09% by weight or less, 0.08% by weight or less, 0.07% by weight or less, 0.06% by weight or less, 0.05% by weight or less, 0.04% by weight or less, 0.03% by weight or less, 0.02% by weight or less, or 0.01% by weight or less, based on the total weight of the D-alanine alkyl ester obtained by purifying the compound of Formula 3 synthesized. Most preferably, the sub-ingredient of Formula 5 is not detected based on the total weight of the D-alanine alkyl ester obtained by purifying the compound of Formula 3 synthesized.

[0052] Examples of the substituents in the present specification will be described below, but are not limited thereto.

[0053] The term "substituted" means that a hydrogen atom bonded to a carbon atom of a compound is changed to another substituent, and the position to be substituted is not limited as long as the position is a position where a hydrogen atom is substituted, i.e., a position where a substituent can be substituted, and when two or more are substituted, the two or more substituents can be the same as or different from each other.

[0054] In the present specification, the term "substituted or unsubstituted" means substituted with one or two or more substituents selected from a halogen group, a nitrile group, a nitro group, a hydroxyl group, an amine group, a silyl group, a boron group, an alkoxy group, an alkyl group, a cycloalkyl group, an aromatic group, and a heterocyclic group, a substituent substituted with two or more substituents of the above-mentioned examples, or no substituent. For example, "a substituent substituted with two or more substituents" can be a biphenyl group. That is, the biphenyl group can also be an aromatic group, and can be interpreted as a substituent substituted with two phenyl groups.

[0055] In the present specification, the alkyl group can be linear or branched, and the number of carbon atoms is not particularly limited, and is preferably 1 to 4. Specific examples of the alkyl group include a methyl group, an ethyl group, a propyl group, an n-propyl group, an isopropyl group, a butyl group, an n-butyl group, an isobutyl group, a t-butyl group, and the like, but are not limited thereto.

[0056] In the method for producing the D-alanine alkyl ester of the present specification, R1and R2are a methyl group, and R3is a methyl group, or a phenyl group substituted with a methyl group.

[0057] In the method for producing the D-alanine alkyl ester of the present specification, R3is a methyl group, or a p-tolyl group.

[0058] In the method for producing the D-alanine alkyl ester of the present specification, R4and R5are each a hydrogen or a methyl group, and R6is a hydrogen.

[0059] In the method for producing the D-alanine alkyl ester of the present specification, the compound of Chemical Formula 2 can be 2,6-dimethylaniline.

[0060] The method for producing the D-alanine alkyl ester of the present specification further includes purifying the solution in which the synthesis of the compound of Chemical Formula 3 is completed, after the synthesis of the compound of Chemical Formula 3 is completed.

[0061] The purification of the solution further includes adding distilled water to the solution in which the synthesis of the compound of Chemical Formula 3 is completed, adjusting the pH of the filtrate to 3 or less by further adding an acid thereto, and obtaining an organic layer by separation of layers. By this washing with an acid, the basic compound of Chemical Formula 2 contained in the solution in which the synthesis is completed can be removed.

[0062] The method for producing the D-alanine alkyl ester of the present specification includes adding distilled water to the organic layer, obtaining the organic layer again by separation of layers, and obtaining the D-alanine alkyl ester from the organic layer obtained again under reduced pressure.

[0063] Hereinafter, the present specification will be described in more detail by examples. However, the following examples are provided only for exemplification of the present specification, and are not intended to limit the present specification.

[0064] Example 1

[0065] Toluene (20 mL), (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, 878.24 mmol) were charged into a 500 mL reactor at room temperature. Thereafter, the reaction solution was stirred at room temperature for 1 hour while bubbling N2(g) into the reaction solution in the reactor at a flow rate of 60 mL / min, and the reaction solution was stirred for 20 hours by raising the internal temperature to 100 to 105°C.

[0066] The reaction mixture was cooled to room temperature, and then the resulting solid was dissolved by adding H2O (32 mL) thereto. After toluene (40 mL) was added thereto, the resulting mixture was stirred, and the organic layer was separated by washing with H2O (96 mL) three times. The washed organic layer was concentrated under reduced pressure to obtain N-(2,6-dimethylphenyl)-D-methyl alaninate at a yield of 62.2%. It was a clear yellowish liquid in nature.

[0067] Example 2

[0068] Toluene (20 mL), (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, 878.24 mmol) were charged into a 500 mL reactor at room temperature. Thereafter, the reaction solution was stirred at room temperature for 1 hour while bubbling N2(g) into the reaction solution in the reactor at a flow rate of 200 mL / min, and the reaction solution was stirred for 20 hours by raising the internal temperature to 100 to 105°C.

[0069] The reaction mixture was cooled to room temperature, and then the resulting solid was dissolved by adding H2O (32 mL) thereto. After toluene (40 mL) was added thereto, the resulting mixture was stirred, and the organic layer was separated by washing with H2O (96 mL) three times. N-(2,6-dimethylphenyl)-D-methyl alaninate was obtained from the washed organic layer at a yield of 62.4%. It was a clear yellowish liquid in nature.

[0070] Comparative Example 1

[0071] Toluene (20 mL), (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, 878.24 mmol) were charged into a 500 mL reactor at room temperature under an air atmosphere. Thereafter, the reaction solution was stirred for 20 hours by raising the internal temperature to 100 to 105°C. In this case, the air atmosphere means an atmosphere in which the gas in the space where the experiment is performed is not artificially treated.

[0072] The reaction mixture was cooled to room temperature, and the resulting solid was dissolved by adding H2O (32 mL) thereto. After adding toluene (40 mL) thereto, the resulting mixture was stirred, and the organic layer obtained by separating the layers was washed with H2O (96 mL) three times. The washed organic layer was concentrated under reduced pressure to obtain N-(2,6-dimethylphenyl)-D-alanine methyl ester at a yield of 63.4%. It was an opaque dark brown liquid in nature.

[0073] Comparative Example 2

[0074] Toluene (20 mL), (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, 878.24 mmol) were charged into a 500 mL reactor at room temperature. Thereafter, the reaction solution was stirred for 1 hour at room temperature while N2(g) was supplied to the upper part of the reactor reaction solution, and the reaction solution was stirred for 20 hours by raising the internal temperature to 100 to 105°C. In this case, the nitrogen gas was supplied at a flow rate of 60 mL / min.

[0075] The reaction mixture was cooled to room temperature, and the resulting solid was dissolved by adding H2O (32 mL) thereto. After adding toluene (40 mL) thereto, the resulting mixture was stirred, and the organic layer obtained by separating the layers was washed with H2O (96 mL) three times. The washed organic layer was concentrated under reduced pressure to obtain N-(2,6-dimethylphenyl)-D-alanine methyl ester at a yield of 62.7%, which was a clear orange liquid in nature.

[0076] Experimental Example 1

[0077] The properties obtained in Examples 1 and 2 and Comparative Examples 1 and 2 were analyzed by GC / FID under the following conditions, the purity of the oxidation reaction and the area percentage of the sub-ingredient peak with respect to the total peak area were confirmed, and are shown in Table 1.

[0078] Column: [HP-5] (0.25 mm ID x 30 mL, 0.25 μm d.f. capillary)

[0079] Oven temperature

[0080] Initial value and holding time: 50 °C, 5 min

[0081] Program rate: 10 °C / min

[0082] Final value and holding time: 320 °C, 18 min

[0083] Injector temperature: 340 °C

[0084] Detector temperature: 340 °C

[0085] Gas flow: Column (N2): 1 mL / min

[0086] Split ratio: 1 / 20

[0087] Injection volume: 1.0 uL

[0088] [Table 1]

[0089] Reaction conditions Purity Sub-fraction Yield Example 1 Bubbling at a flow rate of 60 mL / min 99.2％ N.D 62.2％ Example 2 Bubbling at a flow rate of 200 mL / min 99.2％ N.D 52.4％ Comparative Example 1 Air atmosphere 96.9％ 2.23％ 63.4％ Comparative Example 2 Sparging at a flow rate of 60 mL / min 98.6％ 0.52％ 62.7％

[0090] As can be seen from Table 1, the impurities produced from the oxidation reaction of 2,6-dimethylaniline were not detected in Examples 1 and 2 synthesized under the condition that nitrogen gas was supplied to produce bubbles in the reaction solution, and thus the purity was higher than Comparative Example 1 synthesized in an air atmosphere and Comparative Example 2 synthesized under a purge condition in which N2(g) was introduced into the upper portion of the reaction solution. Furthermore, it can be seen that the yield of Example 1, in which the nitrogen gas flow rate satisfied the condition of 10 mL (0.02 x 500 mL) / min to 100 mL (0.2 x 500 mL) / min based on a 500 mL reactor, was higher than that of Example 2 in which the nitrogen gas flow rate did not satisfy the above condition.

Claims

1. A method for producing D-alanine alkyl ester, the method comprising supplying nitrogen gas to a reaction solution when synthesizing a compound of the following Chemical Formula 3 using a reaction solution containing a compound of the following Chemical Formula 1 and a compound of the following Chemical Formula 2, and purifying the reaction solution in which the synthesis of the compound of Chemical Formula 3 is completed after the synthesis of the compound of Chemical Formula 3 is completed: [Chemical Formula 1] [Chemical Formula 2] [Chemical Formula 3] [Chemical Formula 5] In Chemical Formulas 1 to 3 and 5, R1 and R2 are methyl, and R3 is methyl or p-tolyl, R4 and R5 are each hydrogen or methyl, and R6 is hydrogen, when the volume of a reactor for synthesizing the compound of Chemical Formula 3 is A, and the volume of the reaction solution in the reactor is 90% by volume or less of the reactor, the flow rate of the nitrogen gas is 0.02 A / min to 0.2 A / min, the content of a subcomponent of Chemical Formula 5 is 0% by weight or more and 0.5% by weight or less, based on the total weight of the solution in which the synthesis of the compound of Chemical Formula 3 is completed, and the content of a subcomponent of Chemical Formula 5 is 0% by weight or more and 0.01% by weight or less, based on the total weight of D-alanine alkyl ester obtained by purifying the synthesized compound of Chemical Formula 3.

2. The method for producing D-alanine alkyl ester according to claim 1, wherein the compound of Chemical Formula 1 is a compound of the following Chemical Formula 4. wherein [Chemical Formula 4] ​ ​

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