WO2022055267A1

WO2022055267A1 - Method for preparing alkyl-d-alaninate

Info

Publication number: WO2022055267A1
Application number: PCT/KR2021/012254
Authority: WO
Inventors: 강명구; 이경원; 안병훈; 조재하; 이원재; 정대연; 서용식; 노상원
Original assignee: 주식회사 엘지화학; 주식회사 팜한농
Priority date: 2020-09-09
Filing date: 2021-09-09
Publication date: 2022-03-17
Also published as: KR20220033458A; CN116171269A

Abstract

The present specification relates to a method for preparing alkyl-D-alaninate, the method comprising a step for supplying an inert gas into a reaction solution when using aniline to synthesize alkyl-D-alaninate.

Description

Method for preparing alkyl-D-alaninate

This application claims the benefit of the filing date of Korean Patent Application No. 10-2020-0115468, filed with the Korean Intellectual Property Office on September 9, 2020, the entire contents of which are incorporated herein by reference.

The present specification relates to a method for preparing alkyl-D-alaninate.

Methyl N-(2,6-dimethylphenyl)-D-alaninate is a crop protection agent such as Metalaxyl-M, Benalaxyl-M, and Furalaxyl-M (= N- of Methyl N-(2,6-dimethylphenyl)-D-alaninate) It is commercially important as a synthetic intermediate for the preparation of acyl derivatives).

As a general scheme for synthesizing methyl N-(2,6-dimethylphenyl)-D-alaninate, Methyl (s)-2-(methanesulfonyloxy)propanoate or Methyl (s)-2-(p-toluenesulfonyloxy)propanoate It is known to use organic or inorganic base and 2,6-dimethylamine, and when the reaction is exposed to O2(g), Product(=Methyl N-(2,6-dimethylphenyl)-D-alaninate ), a dimer of 2,6-dimethylamine (= Azo structure compound) is produced as a subcomponent of the oxidation reaction, and its appearance deteriorates to dark red and dark, reducing the commercial value of the product, which is difficult to remove with a general purification method.

Accordingly, it is an important task to develop a high-purity manufacturing method that is effective in suppressing the generation of the oxidation reaction subcomponent during the reaction and can be applied to mass production.

The present specification provides a method for preparing alkyl-D-alaninate.

Herein, when synthesizing a compound of Formula 3 using a reaction solution comprising a compound of Formula 1 and a compound of Formula 2,

It provides a method for producing an alkyl-D-alaninate comprising the step of supplying an inert gas into the reaction solution.

[Formula 1]

[Formula 2]

[Formula 3]

In Formulas 1 to 3,

R1 and R2 are a methyl group, R3 is a methyl group, or p-tolyl group,

R4 and R5 are each hydrogen or a methyl group, and R6 is hydrogen.

In the method for preparing alkyl-D-alaninate of the present specification, the inert gas is selected from the group consisting of nitrogen gas, helium gas, neon gas, and argon gas.

In the method for producing alkyl-D-alaninate of the present specification, the volume of the reactor in which the compound of Formula 3 is synthesized is A, and the volume of the reaction solution inside the reactor is 90% by volume of the volume of the reactor Below, the flow rate of the inert gas is 0.02A/min to 0.2A/min.

The purification method of alkyl-D-alaninate of the present specification can obtain alkyl-D-alaninate with improved yield while being of high purity.

Hereinafter, the present specification will be described in detail.

The present specification is characterized in synthesizing alkyl-D-alaninate in an inert gas atmosphere.

The present specification is characterized in that an alkyl-D-alaninate is synthesized using a compound of Formula 2 below while supplying an inert gas to the inside of the reaction solution.

[Formula 2]

In Formula 2, R4 and R5 are each independently hydrogen or an alkyl group having 1 to 4 carbon atoms, and R6 is hydrogen or an alkyl group having 1 to 4 carbon atoms.

When the compound of Formula 2 is exposed to oxygen, a side reaction as shown in Formula 5 below may occur due to oxidation.

[Formula 5]

In Formula 5, definitions of R4 to R6 are the same as in Formula 2.

When 2,6-dimethylaniline is used as the compound of Formula 2, impurities having the following structure may be generated by oxidation.

On the other hand, when synthesizing alkyl-D-alaninate using the compound of Formula 1, if the reaction proceeds while supplying an inert gas into the reaction solution, residual oxygen dissolved in the reaction solution or oxygen flowing from the outside It lowers the probability of the oxidation reaction of formula (2) that may occur by contact with and discharges the residual oxygen dissolved in the reaction solution.

[Formula 1]

[Formula 2]

[Formula 3]

In Formulas 1 to 3,

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

R3 is an alkyl group having 1 to 4 carbon atoms, or a phenyl group unsubstituted or substituted with an alkyl group having 1 to 4 carbon atoms;

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

R6 is hydrogen or an alkyl group having 1 to 4 carbon atoms.

In the method for producing alkyl-D-alaninate of the present specification, the volume of the reactor in which the compound of Formula 3 is synthesized is A, and the volume of the reaction solution inside the reactor is 90% by volume of the volume of the reactor Below, the flow rate of the inert gas is 0.02A/min to 0.2A/min. If this is satisfied, the effect of blocking the discharge of residual oxygen in the reaction solution or the inflow of external oxygen is effective, so there is little or no formation of subcomponents of Formula 5, and raw materials (reactants, Formula 1 and Formula 2) and the product (Formula 3) are evaporated to a vent line and no yield loss due to discharge occurs. It is possible to suppress the generation of the subcomponent of Chemical Formula 5 while preserving the yield only when the process is performed within the above-described range.

In the present specification, based on the total weight of the solution in which the synthesis of the compound of Formula 3 is completed, the content of the minor component of Formula 5 may 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 wt% or less, 0.2 wt% or less, or 0.1 wt% or less.

In the present specification, based on the total weight of the alkyl-D-alaninate obtained by purifying the synthesis of the compound of Formula 3, the content of the minor component of Formula 5 may be 0 wt% or more and 0.5 wt% or less, and 0.5 wt% % or less, 0.4 wt% or less, 0.3 wt% or less, 0.2 wt% or less, 0.1 wt% or less, 0.09 wt% or less, 0.08 wt% or less, 0.07 wt% or less, 0.06 wt% or less, 0.05 wt% or less, 0.04 wt% or less % or less, 0.03 wt% or less, 0.02 wt% or less, or 0.01 wt% or less. Most preferably, based on the total weight of the alkyl-D-alaninate obtained by purifying the synthesis of the compound of formula (3), the minor component of formula (5) is not detected.

Examples of substituents in the present specification are described below, but are not limited thereto.

The term “substituted” means that a hydrogen atom bonded to a carbon atom of a compound is replaced with another substituent, and the position to be substituted is not limited as long as the position at which the hydrogen atom is substituted, that is, a position where the substituent is substitutable, is not limited, and when two or more are substituted , two or more substituents may be the same as or different from each other.

As used herein, the term “substituted or unsubstituted” refers to a halogen group; nitrile group; nitro group; hydroxyl group; amine group; silyl group; boron group; alkoxy group; an alkyl group; cycloalkyl group; aryl group; And it means that it is substituted with one or two or more substituents selected from the group consisting of a heterocyclic group, is substituted with a substituent to which two or more of the above-exemplified substituents are connected, or does not have any substituents. For example, “a substituent in which two or more substituents are connected” may be a biphenyl group. That is, the biphenyl group may be an aryl group or may be interpreted as a substituent in which two phenyl groups are connected.

In the present specification, the alkyl group may be linear or branched, and the number of carbon atoms is not particularly limited, but is preferably 1 to 4. Specific examples of the alkyl group include, but are not limited to, 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, and a tert-butyl group.

In the method for preparing alkyl-D-alaninate of the present specification, R1 and R2 are methyl groups, and R3 is a methyl group or a phenyl group substituted with a methyl group.

In the production method of the alkyl-D-alaninate of the present specification, R3 is a methyl group, or a p-tolyl group (p-Tolyl group).

In the method for preparing alkyl-D-alaninate of the present specification, R4 and R5 are each hydrogen or a methyl group, and R6 is hydrogen.

In the method for preparing alkyl-D-alaninate of the present specification, the compound of Formula 2 may be 2,6-dimethylaniline (2,6-dimethylaniline).

The method for preparing alkyl-D-alaninate of the present specification further includes the step of purifying the synthetic solution after the synthesis of the compound of Formula 3 is completed.

The purifying step may include adding distilled water to the synthesis solution; adjusting the filtrate to pH 3 or less by adding more acid; and layer separation to obtain an organic layer. Through such acidic water washing, the basic compound of Formula 2 contained in the synthesis-completed solution may be removed.

In the method for producing alkyl-D-alaninate of the present specification, adding distilled water to the organic layer; layer separation to obtain an organic layer again; and depressurizing the obtained organic layer again to obtain alkyl-D-alaninate.

Hereinafter, the present specification will be described in more detail through examples. However, the following examples are only for illustrating the present specification, and not for limiting the present specification.

[Example 1]

Toluene (20 mL), methyl (s)-2-(methanesulfonyloxy)propanoate (20.00 g, 109.78 mmol), triethylamine (12.22 g, 120.75 mmol) and 2, 6-Dimethylaniline (2,6-Dimethylaniline) (106.43 g, 878.24 mmol) was added. Then, while flowing N ₂ (g) at a flow rate of 60 mL/min to bubbling into the reaction solution of the reactor, the mixture was stirred at room temperature for 1 hour, and the internal temperature was raised to 100° C. to 105° C. for 20 hours stirred for a while.

After the reaction mixture was cooled to room temperature, H ₂ O (32 mL) was added to dissolve the resulting solids. Toluene (40 mL) was added thereto, followed by stirring, and the organic layer obtained by layer separation was washed 3 times with H ₂ O (96 mL). The washed organic layer was concentrated under reduced pressure to obtain methyl N-(2,6-dimethylphenyl)-D-ananinate in a yield of 62.2%. Appearance is a transparent light yellow liquid.

[Example 2]

Toluene (20 mL), methyl (s)-2-(methanesulfonyloxy)propanoate (20.00 g, 109.78 mmol), triethylamine (12.22 g, 120.75 mmol) and 2, 6-Dimethylaniline (2,6-Dimethylaniline) (106.43 g, 878.24 mmol) was added. After that, while flowing N ₂ (g) at a flow rate of 200 mL/min to bubbling into the reaction solution of the reactor, the mixture was stirred at room temperature for 1 hour, and the internal temperature was raised to 100 ~ 105 ℃ for 20 hours stirred for a while.

After the reaction mixture was cooled to room temperature, H ₂ O (32 mL) was added to dissolve the resulting solids. Toluene (40 mL) was added thereto, followed by stirring, and the organic layer obtained by layer separation was washed 3 times with H ₂ O (96 mL). From the organic layer washed with water, methyl N-(2,6-dimethylphenyl)-D-ananinate was obtained in 62.4% yield. Appearance is a transparent light yellow liquid.

[Comparative Example 1]

Toluene (20 mL), methyl (s)-2-(methanesulfonyloxy)propanoate (Methyl (s)-2-(methanesulfonyloxy)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 added. Thereafter, the internal temperature was raised to 100° C. to 105° C. and stirred for 20 hours. At this time, the air atmosphere refers to an atmosphere in which no artificial treatment was performed on the gas in the space in which the experiment was conducted.

After the reaction mixture was cooled to room temperature, H ₂ O (32 mL) was added to dissolve the resulting solids. Toluene (40 mL) was added thereto, followed by stirring, and the organic layer obtained by layer separation was washed 3 times with H ₂ O (96 mL). The washed organic layer was concentrated under reduced pressure to obtain methyl N-(2,6-dimethylphenyl)-D-alaninate in a yield of 63.4%. Appearance is an opaque dark brown liquid.

[Comparative Example 2]

Toluene (20 mL), methyl (s)-2-(methanesulfonyloxy)propanoate (20.00 g, 109.78 mmol), triethylamine (12.22 g, 120.75 mmol) and 2, 6-Dimethylaniline (106.43 g, 878.24 mmol) was added. After that, after stirring at room temperature for 1 hour while flowing (purging) N ₂ (g) to the top of the reaction solution of the reactor, the internal temperature was raised to 100 ~ 105 ℃ and stirred for 20 hours. At this time, nitrogen was supplied at a flow rate of 60 mL/min.

After the reaction mixture was cooled to room temperature, H ₂ O (32 mL) was added to dissolve the resulting solids. Toluene (40 mL) was added thereto, followed by stirring, and the organic layer obtained by layer separation was washed 3 times with H ₂ O (96 mL). The washed organic layer was concentrated under reduced pressure to obtain methyl N-(2,6-dimethylphenyl)-D-ananinate in a yield of 62.7%. Appearance is a transparent orange liquid.

[Experimental Example 1]

The properties obtained in Examples 1 and 2 and Comparative Examples 1 and 2 were analyzed by GC / FID under the following conditions to confirm the purity and area percentage of the subcomponent peak for the oxidation reaction relative to the total peak area, and are shown in Table 1.

Column: [HP-5] (0.25 mm ID × 30 m L, 0.25 μm d.f. capillary)

Oven temperature

Initial Value & Hold Time: 50℃, 5min

Program Rate: 10℃/min

Final Value & Hold Time: 320℃, 18 min

Injector temperature: 340℃

Detector temperature: 340℃

Gas Flow rate: Column(N ₂ ): 1 mL/min

Split ratio: 1/20

Injection volume: 1.0 uL

	반응 조건reaction conditions	순도water	부성분subcomponent	수율transference number
실시예 1Example 1	60 mL/min의 유량으로 버블링Bubbling at a flow rate of 60 mL/min	99.2%99.2%	N.DN.D.	62.2%62.2%
실시예 2Example 2	200 mL/min의 유량으로 버블링Bubbling at a flow rate of 200 mL/min	99.2%99.2%	N.DN.D.	52.4%52.4%
비교예 1Comparative Example 1	공기분위기air atmosphere	96.9%96.9%	2.23%2.23%	63.4%63.4%
비교예 2Comparative Example 2	60 mL/min의 유량으로 퍼징Purge at a flow rate of 60 mL/min	98.6%98.6%	0.52%0.52%	62.7%62.7%

Through Table 1, compared to Comparative Example 1 synthesized in an air atmosphere and Comparative Example 2 synthesized under purging conditions in which N ₂ (g) is flowed to the upper portion of the reaction solution, nitrogen is supplied to bubble into the reaction solution. It can be seen that the synthesized Examples 1 and 2 are of high purity because subcomponents generated by the oxidation reaction of 2,6-dimethylaniline are not detected. In addition, based on a 500 mL reactor, Example 1 in which the flow rate of nitrogen satisfies the condition of 10 mL (0.02 × 500 mL)/min to 100 mL (0.2 × 500 mL)/min. It can be seen that this is higher.

Claims

When synthesizing a compound of Formula 3 using a reaction solution comprising a compound of Formula 1 and a compound of Formula 2,

Method for producing alkyl-D-alaninate comprising supplying an inert gas into the reaction solution:

[Formula 1]

[Formula 2]

[Formula 3]

In Formulas 1 to 3,

R1 and R2 are methyl groups, R3 is a methyl group, or p-tolyl group;

R4 and R5 are each hydrogen or a methyl group, and R6 is hydrogen.
The method according to claim 1, wherein the inert gas is selected from the group consisting of nitrogen gas, helium gas, neon gas, and argon gas.
The method according to claim 1, When the volume of the reactor in which the synthesis of the compound of Formula 3 is carried out is A, and the volume of the reaction solution inside the reactor is 90% by volume 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 A method for producing an alkyl-D-alaninate.