WO2023277587A1 - Method for preparing n-acyl derivative, composition, and pharmaceutical or agricultural product containing same - Google Patents

Method for preparing n-acyl derivative, composition, and pharmaceutical or agricultural product containing same Download PDF

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WO2023277587A1
WO2023277587A1 PCT/KR2022/009352 KR2022009352W WO2023277587A1 WO 2023277587 A1 WO2023277587 A1 WO 2023277587A1 KR 2022009352 W KR2022009352 W KR 2022009352W WO 2023277587 A1 WO2023277587 A1 WO 2023277587A1
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formula
compound
composition
area
methyl
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PCT/KR2022/009352
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French (fr)
Korean (ko)
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강명구
김지원
안병훈
이경원
이원재
정대연
조재하
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주식회사 엘지화학
주식회사 팜한농
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Priority to CN202280014397.2A priority Critical patent/CN116829531A/en
Publication of WO2023277587A1 publication Critical patent/WO2023277587A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N37/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids
    • A01N37/44—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids containing at least one carboxylic group or a thio analogue, or a derivative thereof, and a nitrogen atom attached to the same carbon skeleton by a single or double bond, this nitrogen atom not being a member of a derivative or of a thio analogue of a carboxylic group, e.g. amino-carboxylic acids
    • A01N37/46—N-acyl derivatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/14—Preparation of carboxylic acid amides by formation of carboxamide groups together with reactions not involving the carboxamide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/22—Separation; Purification; Stabilisation; Use of additives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/70—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/72—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms
    • C07C235/74—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of a saturated carbon skeleton

Definitions

  • the present specification relates to a method for preparing an N-acyl derivative, a composition, and pharmaceuticals or agricultural products containing the same.
  • N-acyl derivatives of methyl N-(2,6-dimethylphenyl)-D-alaninate are commercially available as fungicides among crop protection agents. important as
  • N-acyl derivatives are synthesized via an alkyl D-alaninate such as methyl N-(2,6-dimethylphenyl)-D-alaninate.
  • this synthesis method inevitably generates impurities that cause genotoxicity in the final N-acyl derivative.
  • impurities are difficult to remove by general purification methods such as crystallization or recrystallization because of the physical properties of the final product having a liquid state.
  • the present specification is intended to provide a method for preparing an N-acyl derivative, an N-acyl derivative prepared thereby, and a pharmaceutical or agricultural product containing the same.
  • An exemplary embodiment of the present specification is distilling a first composition including a compound represented by Formula 1; synthesizing a compound of Formula 3 below by adding a compound of Formula 2 to the distilled first composition; synthesizing a compound of Formula 5 by reacting the compound of Formula 3 with a compound of Formula 4; and reacting the compound of Formula 5 with a compound of Formula 6 to synthesize a compound of Formula 7 below.
  • 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 independently hydrogen; heavy hydrogen; or a methyl group;
  • R4 and R5 are methyl groups.
  • the compound of Formula 2 is added to the first composition in which the content of the compound of Formula 8 is 0.05 area% or less based on the total GC area of the first composition including the compound of Formula 1 below to synthesize a compound represented by Formula 3; synthesizing a compound of Formula 5 by reacting the compound of Formula 3 with a compound of Formula 4; and reacting the compound of Formula 5 with a compound of Formula 6 to synthesize a compound of Formula 7 below.
  • 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 independently hydrogen; heavy hydrogen; or a methyl group;
  • R4 and R5 are methyl groups.
  • the content of the compound of Formula 10 is 0.05 area% or less based on the total GC area of the composition Provided a composition do.
  • R2 and R3 are the same as or different from each other, and each independently hydrogen; heavy hydrogen; or a methyl group;
  • R4 and R5 are methyl groups.
  • Another embodiment of the present specification provides a pharmaceutical or agricultural product containing the above-described composition.
  • the production method of one embodiment of the present specification can prepare an N-acyl derivative having a low content of impurities that cause genotoxicity.
  • the manufacturing method of one embodiment of the present specification can produce a high-purity N-acyl derivative.
  • An exemplary embodiment of the present specification is distilling a first composition including a compound represented by Formula 1; synthesizing a compound of Formula 3 below by adding a compound of Formula 2 to the distilled first composition; synthesizing a compound of Formula 5 by reacting the compound of Formula 3 with a compound of Formula 4; and reacting the compound of Formula 5 with a compound of Formula 6 to synthesize a compound of Formula 7 below.
  • Another embodiment of the present specification is distilling a first composition comprising a compound of Formula 1; synthesizing a compound of Formula 3 below by adding a compound of Formula 2 to the distilled first composition; synthesizing a compound of Formula 5 by reacting the compound of Formula 3 with a compound of Formula 4; distilling a second composition containing the compound of Chemical Formula 5; and adding a compound of Formula 6 to the distilled second composition to synthesize a compound of Formula 7 below.
  • 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 independently represents hydrogen; heavy hydrogen; or a methyl group
  • R4 and R5 are methyl groups.
  • This synthesis method itself inevitably produces impurities such as the following Chemical Formula 10 that cause genotoxicity in the final N-acyl derivative.
  • the substance of Chemical Formula 10 has genotoxicity and clastogenicity and causes mutations in DNA constituting genes, which is the expression of genetic disorders and can appear as a disaster in future generations. should be eliminated or maintained at very low levels.
  • the precursor for producing the compound 10 is removed by distillation in a step before the synthesis of the formula 7 to lower the probability of producing the compound 10, so that the compound of formula 7 with high purity can be more easily synthesized.
  • the compound of formula 1 of the first composition and the compound of formula 6 of the second composition have boiling points at a level at which distillation is possible even in a large-scale process.
  • Formula 10 is generated from Formula 8, which is an impurity of Formula 1.
  • the step of distilling the first composition is a step of preparing a first composition in which the content of the compound represented by Formula 8 is 0.05 area% or less based on the total GC area of the first composition to be. Specifically, the first composition containing the compound of Formula 1 and the compound of Formula 8 was distilled to remove the compound of Formula 8 from the first composition to reduce the content of the compound of Formula 8 in the first composition. .
  • the distillation in the step of distilling the first composition, may be performed one or more times, specifically, one or more times, two or more times, or three or more times.
  • the content of the compound of Formula 8 is 0.05 area% or less, 0.04 area% or less, or 0.03 area% based on the total GC area of the first composition % or less, and the lower the content of the compound of Formula 8, the better, so the lower limit is not particularly limited.
  • the first composition in the step of distilling the first composition, is distilled at a pressure of 40 torr to 60 torr and a temperature of 70 ° C to 100 ° C.
  • the production amount of Chemical Formula 9 to be removed in the next distillation step is reduced, there is an advantage in that a second composition having a higher content of Chemical Formula 5 can be obtained.
  • the distillation conditions of the first composition are not high temperature or too low vacuum pressure conditions that are not suitable for mass production, there is an advantage that it can be easily applied even in mass production processes.
  • the content of the compound of Formula 10, which is difficult to separate when synthesizing the final product, can be reduced by removing some of Formula 9 through distillation before participating in the reaction of Formula 5 to lower the probability of impurities being generated.
  • the step of distilling the second composition is a step of preparing a second composition in which the content of the compound represented by Formula 9 is 0.05 area% or less based on the total GC area of the second composition to be. Specifically, the second composition containing the compound of Formula 5 and the compound of Formula 9 was distilled to remove the compound of Formula 9 from the second composition to reduce the content of the compound of Formula 9 in the second composition. .
  • R2 and R3 are the same as or different from each other, and each independently hydrogen; heavy hydrogen; or a methyl group, and R4 is a methyl group.
  • distillation in the step of distilling the second composition, distillation may be performed one or more times, specifically, one or more times, two or more times, or three or more times.
  • the content of the compound of Formula 9 is 0.05 area% or less, 0.04 area% or less, or 0.03 area% based on the total GC area of the second composition % or less, and the lower the content of the compound of Formula 8, the better, so the lower limit is not particularly limited.
  • the second composition in the step of distilling the second composition, is distilled at a pressure of 2 torr to 20 torr and a temperature of 130 ° C to 200 ° C.
  • a third composition having a higher content of Chemical Formula 7 can be obtained.
  • the content of the compound of Formula 2 is 1.0 equivalent to 2.0 equivalent.
  • the content of the compound of Formula 4 is 2.0 equivalent to 10.0 equivalent. In this case, there is an advantage in that side reactions can be controlled while the reaction rate is increased because the equivalent amount of Chemical Formula 4 is appropriate.
  • the content of the compound of Formula 6 is 1.0 equivalent to 2.0 equivalent.
  • the content of the compound of Formula 10 is 0.05 area% or less based on the total GC area of the third composition including the compound of Formula 7.
  • the compound of formula 1 and the compound of formula 5 were distilled before participating in the reaction, respectively, to remove impurities of the compounds of formulas 8 and 9, and the content of the compound of formula 10 in the final product was reduced.
  • the content of the compound represented by Formula 10 is 0.05 area % or less, 0.04 area % or less, 0.03 area % or less, or 0.02 area % or less.
  • R2 and R3 are the same as or different from each other, and each independently hydrogen; heavy hydrogen; or a methyl group;
  • R4 and R5 are methyl groups.
  • Another embodiment of the present specification is based on the total GC area of the first composition containing the compound of Formula 1 below, by adding the compound of Formula 2 to the first composition in which the content of the compound of Formula 8 is 0.05 area% or less Synthesizing a compound represented by Chemical Formula 3; synthesizing a compound of Formula 5 by reacting the compound of Formula 3 with a compound of Formula 4; and reacting the compound of Formula 5 with a compound of Formula 6 to synthesize a compound of Formula 7 below.
  • the compound of Formula 2 is added to the first composition in which the content of the compound of Formula 8 is 0.05 area% or less based on the total GC area of the first composition including the compound of Formula 1 below to synthesize a compound represented by Formula 3; synthesizing a compound of Formula 5 by reacting the compound of Formula 3 with a compound of Formula 4; And the compound of Formula 6 is added to a second composition in which the content of the compound of Formula 9 is 0.05 area% or less based on the total GC area of the second composition including the compound of Formula 5, to obtain a compound of Formula 7 It provides a method for producing an N-acyl derivative comprising the step of synthesizing.
  • 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 independently hydrogen; heavy hydrogen; or a methyl group
  • R4 and R5 are methyl groups.
  • the content of the compound of Formula 10 is 0.05 area% or less based on the total GC area of the composition.
  • R2 and R3 are the same as or different from each other, and each independently hydrogen; heavy hydrogen; or a methyl group;
  • R4 and R5 are methyl groups.
  • the description of the N-acyl derivative may refer to the description of the method for preparing the N-acyl derivative described above.
  • the aryl group is a monocyclic aryl group
  • the number of carbon atoms is not particularly limited, but preferably has 6 to 25 carbon atoms.
  • the monocyclic aryl group may be a phenyl group, a biphenyl group, a terphenyl group, and the like, but is not limited thereto.
  • the aryl group is a polycyclic aryl group
  • the number of carbon atoms is not particularly limited. It is preferable that it is carbon number 10-24.
  • the polycyclic aryl group may be a naphthyl group, anthracenyl group, phenanthryl group, pyrenyl group, perylenyl group, chrysenyl group, fluorenyl group, and the like, but is not limited thereto.
  • the fluorenyl group may be substituted, and adjacent substituents may bond to each other to form a ring.
  • R1 is a methyl group; or a phenyl group substituted with a methyl group.
  • R1 is a methyl group; or is, is the binding position.
  • R2 and R3 are the same as or different from each other, and each independently hydrogen; or a methyl group.
  • R2 and R3 are methyl groups.
  • the present specification provides a pharmaceutical or agricultural product containing the above-described composition. At this time, not only the state containing the N-acyl derivative in the composition as it is, but also pharmaceuticals or agricultural products containing derivatives modified for each use, that is, modified through an essential chemical reaction, are included.
  • the agricultural products may be various agricultural chemicals such as herbicides, crop protection agents, and fungicides.
  • Distilled methyl-L-lactate (104.11g, 1.0 mol) and triethylamine (154.60mL, 111.31g, 1.1 mol) were added to a reactor containing 400 mL of dichloromethane at room temperature, The internal temperature was cooled to 0 °C. While maintaining the internal temperature at 0 ° C to 5 ° C, p-Toluenesulfonyl chloride (209.70 g, 1.1 mol) was slowly added, and after the addition was completed, while maintaining the internal temperature at 0 ° C to 5 ° C Stir for 4 hours.
  • Methyl N- (2,6-dimethylphenyl) -D-alaninate obtained by distillation was diluted in toluene (100 mL) as it is, washed once with 1N HCl aqueous solution (20 mL), and the obtained organic layer was distilled water (30 mL). ) and then concentrated under reduced pressure to obtain methyl N-(2,6-dimethylphenyl)-D-alaninate with a purity of 98.52 GC area% and a yield of 81% (13.00 g, 62.72 mmol).
  • methyl L-lactate (104.11 g, 1.0 mol) obtained by distillation to contain 0.05 area% of L-lactic acid was mixed with 400 mL of dichloromethane at room temperature. was put into the reactor. Triethylamine (154.60 mL, 111.31 g, 1.1 mol) was further added thereto, and the internal temperature was cooled to 0°C.
  • Methyl L-lactate (104.11 g, 1.0 mol) containing 0.20 area% of L-lactic acid out of the total GC area without distillation was introduced into a reactor containing 400 mL of dichloromethane at room temperature, and then triethylamine (154 mL) was added. , 111.31 g, 1.1 mol) was added and the internal temperature was cooled to 0 °C. While maintaining the internal temperature at 0 ° C to 5 ° C, p-toluenesulfonyl chloride (209.70 g, 1.1 mol) was slowly added, and after the addition was completed, the mixture was stirred for 4 hours while maintaining the internal temperature at 0 ° C to 5 ° C.
  • Comparative Example 1 in which no distillation was performed, had a low purity of the final compound and a high content of impurities represented by Chemical Formula 10. Even when compared with Example 2 in which only the compound of Formula 1 was distilled, Example 1 in which distillation was performed on both the compounds of Formulas 1 and 5 showed higher purity and a lower content of impurities of Formula 10.

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Abstract

The present specification relates to a method for preparing an N-acyl derivative by distilling a first composition comprising a compound of chemical formula 1, and using the distilled first composition, an N-acyl derivative prepared thereby, and a pharmaceutical or agricultural product comprising same.

Description

N-아실 유도체의 제조방법, 조성물 및 이를 포함하는 의약품 또는 농업용품Method for preparing N-acyl derivative, composition and medicine or agricultural product containing the same
본 명세서는 2021년 06월 29일 한국특허청에 제출된 한국 특허 출원 제10-2021-0084509호의 출원일의 이익을 주장하며, 그 내용 전부는 본 명세서에 포함된다.This specification claims the benefit of the filing date of Korean Patent Application No. 10-2021-0084509 filed with the Korean Intellectual Property Office on June 29, 2021, all of which are incorporated herein.
본 명세서는 N-아실 유도체의 제조방법, 조성물 및 이를 포함하는 의약품 또는 농업용품에 관한 것이다.The present specification relates to a method for preparing an N-acyl derivative, a composition, and pharmaceuticals or agricultural products containing the same.
메틸 N-(2,6-디메틸페닐)-D-알라니네이트 (Methyl N-(2,6-dimethylphenyl)-D-alaninate)의 N-아실(N-acyl) 유도체는 작물보호제중 살균제로써 상업적으로 중요하다.N-acyl derivatives of methyl N-(2,6-dimethylphenyl)-D-alaninate (Methyl N-(2,6-dimethylphenyl)-D-alaninate) are commercially available as fungicides among crop protection agents. important as
N-아실 유도체의 제조 방법은 메틸 N-(2,6-디메틸페닐)-D-알라니네이트와 같은 알킬 D-알라니네이트를 거쳐서 합성하는 것이 일반적으로 알려져있다.It is generally known that N-acyl derivatives are synthesized via an alkyl D-alaninate such as methyl N-(2,6-dimethylphenyl)-D-alaninate.
다만, 이러한 합성법으로는 최종 N-아실 유도체에서 유전독성을 유발하는 불순물이 생성될 수 밖에 없다. 그러나, 이 불순물은 액체 성상을 지닌 최종물의 물성때문에 결정화 또는 재결정과 같은 일반적인 정제방법으로는 제거가 어렵다.However, this synthesis method inevitably generates impurities that cause genotoxicity in the final N-acyl derivative. However, these impurities are difficult to remove by general purification methods such as crystallization or recrystallization because of the physical properties of the final product having a liquid state.
그러므로, 해당 유전독성 불순물의 함량을 줄일 수 있는 구체적인 방법을 고안하는 것은 중요한 해결과제이다.Therefore, it is an important challenge to devise specific methods to reduce the content of genotoxic impurities.
본 명세서는 N-아실 유도체의 제조방법, 이로 제조된 N-아실 유도체 및 이를 포함하는 의약품 또는 농업용품을 제공하고자 한다.The present specification is intended to provide a method for preparing an N-acyl derivative, an N-acyl derivative prepared thereby, and a pharmaceutical or agricultural product containing the same.
본 명세서의 일 실시상태는 하기 화학식 1의 화합물을 포함하는 제1 조성물을 증류하는 단계; 상기 증류된 제1 조성물에 하기 화학식 2의 화합물을 첨가하여 하기 화학식 3의 화합물을 합성하는 단계; 상기 화학식 3의 화합물을 하기 화학식 4의 화합물과 반응시켜 하기 화학식 5의 화합물을 합성하는 단계; 및 상기 화학식 5의 화합물을 하기 화학식 6의 화합물과 반응시켜 하기 화학식 7의 화합물을 합성하는 단계를 포함하는 N-아실 유도체의 제조방법을 제공한다.An exemplary embodiment of the present specification is distilling a first composition including a compound represented by Formula 1; synthesizing a compound of Formula 3 below by adding a compound of Formula 2 to the distilled first composition; synthesizing a compound of Formula 5 by reacting the compound of Formula 3 with a compound of Formula 4; and reacting the compound of Formula 5 with a compound of Formula 6 to synthesize a compound of Formula 7 below.
[화학식 1][Formula 1]
Figure PCTKR2022009352-appb-img-000001
Figure PCTKR2022009352-appb-img-000001
[화학식 2][Formula 2]
Figure PCTKR2022009352-appb-img-000002
Figure PCTKR2022009352-appb-img-000002
[화학식 3][Formula 3]
Figure PCTKR2022009352-appb-img-000003
Figure PCTKR2022009352-appb-img-000003
[화학식 4][Formula 4]
Figure PCTKR2022009352-appb-img-000004
Figure PCTKR2022009352-appb-img-000004
[화학식 5][Formula 5]
Figure PCTKR2022009352-appb-img-000005
Figure PCTKR2022009352-appb-img-000005
[화학식 6][Formula 6]
Figure PCTKR2022009352-appb-img-000006
Figure PCTKR2022009352-appb-img-000006
[화학식 7][Formula 7]
Figure PCTKR2022009352-appb-img-000007
Figure PCTKR2022009352-appb-img-000007
상기 화학식 1 내지 7에서, In Formulas 1 to 7,
R1은 메틸기 또는 메틸기로 치환된 아릴기이며, R1 is a methyl group or an aryl group substituted with a methyl group;
R2 및 R3은 서로 같거나 상이하고, 각각 독립적으로 수소; 중수소; 또는 메틸기이고, R2 and R3 are the same as or different from each other, and each independently hydrogen; heavy hydrogen; or a methyl group;
R4 및 R5는 메틸기이다.R4 and R5 are methyl groups.
본 명세서의 또 다른 실시상태는 하기 화학식 1의 화합물을 포함하는 제1 조성물의 전체 GC 면적을 기준으로, 하기 화학식 8의 화합물의 함량이 0.05 면적% 이하인 제1 조성물에 하기 화학식 2의 화합물을 첨가하여 하기 화학식 3의 화합물을 합성하는 단계; 상기 화학식 3의 화합물을 하기 화학식 4의 화합물과 반응시켜 하기 화학식 5의 화합물을 합성하는 단계; 및 상기 화학식 5의 화합물을 하기 화학식 6의 화합물과 반응시켜 하기 화학식 7의 화합물을 합성하는 단계를 포함하는 N-아실 유도체의 제조방법을 제공한다.In another embodiment of the present specification, the compound of Formula 2 is added to the first composition in which the content of the compound of Formula 8 is 0.05 area% or less based on the total GC area of the first composition including the compound of Formula 1 below to synthesize a compound represented by Formula 3; synthesizing a compound of Formula 5 by reacting the compound of Formula 3 with a compound of Formula 4; and reacting the compound of Formula 5 with a compound of Formula 6 to synthesize a compound of Formula 7 below.
[화학식 1][Formula 1]
Figure PCTKR2022009352-appb-img-000008
Figure PCTKR2022009352-appb-img-000008
[화학식 2][Formula 2]
Figure PCTKR2022009352-appb-img-000009
Figure PCTKR2022009352-appb-img-000009
[화학식 3][Formula 3]
Figure PCTKR2022009352-appb-img-000010
Figure PCTKR2022009352-appb-img-000010
[화학식 4][Formula 4]
Figure PCTKR2022009352-appb-img-000011
Figure PCTKR2022009352-appb-img-000011
[화학식 5][Formula 5]
Figure PCTKR2022009352-appb-img-000012
Figure PCTKR2022009352-appb-img-000012
[화학식 6][Formula 6]
Figure PCTKR2022009352-appb-img-000013
Figure PCTKR2022009352-appb-img-000013
[화학식 7][Formula 7]
Figure PCTKR2022009352-appb-img-000014
Figure PCTKR2022009352-appb-img-000014
[화학식 8][Formula 8]
Figure PCTKR2022009352-appb-img-000015
Figure PCTKR2022009352-appb-img-000015
상기 화학식 1 내지 7에서, In Formulas 1 to 7,
R1은 메틸기 또는 메틸기로 치환된 아릴기이며, R1 is a methyl group or an aryl group substituted with a methyl group;
R2 및 R3은 서로 같거나 상이하고, 각각 독립적으로 수소; 중수소; 또는 메틸기이고, R2 and R3 are the same as or different from each other, and each independently hydrogen; heavy hydrogen; or a methyl group;
R4 및 R5는 메틸기이다.R4 and R5 are methyl groups.
본 명세서의 다른 실시상태는 하기 화학식 7의 화합물과, 하기 화학식 10의 화합물을 포함하는 조성물에서, 상기 조성물의 전체 GC 면적을 기준으로, 하기 화학식 10의 화합물의 함량이 0.05 면적% 이하인 조성물을 제공한다. In another embodiment of the present specification, in a composition including a compound of Formula 7 and a compound of Formula 10, the content of the compound of Formula 10 is 0.05 area% or less based on the total GC area of the composition Provided a composition do.
[화학식 7][Formula 7]
Figure PCTKR2022009352-appb-img-000016
Figure PCTKR2022009352-appb-img-000016
[화학식 10][Formula 10]
Figure PCTKR2022009352-appb-img-000017
Figure PCTKR2022009352-appb-img-000017
상기 화학식 7 및 10에서,In Formulas 7 and 10,
R2 및 R3은 서로 같거나 상이하고, 각각 독립적으로 수소; 중수소; 또는 메틸기이고, R2 and R3 are the same as or different from each other, and each independently hydrogen; heavy hydrogen; or a methyl group;
R4 및 R5는 메틸기이다.R4 and R5 are methyl groups.
본 명세서의 다른 실시상태는 상술한 조성물을 포함하는 의약품 또는 농업용품을 제공한다.Another embodiment of the present specification provides a pharmaceutical or agricultural product containing the above-described composition.
본 명세서의 일 실시상태의 제조방법은 유전독성을 유발하는 불순물의 함유량이 낮은 N-아실 유도체를 제조할 수 있다. The production method of one embodiment of the present specification can prepare an N-acyl derivative having a low content of impurities that cause genotoxicity.
본 명세서의 일 실시상태의 제조방법은 고순도의 N-아실 유도체를 제조할 수 있다.The manufacturing method of one embodiment of the present specification can produce a high-purity N-acyl derivative.
이하에서 본 명세서에 대하여 상세히 설명한다.Hereinafter, this specification will be described in detail.
본 명세서에서 어떤 부분이 어떤 구성요소를 "포함" 한다고 할 때, 이는 특별히 반대되는 기재가 없는 한 다른 구성요소를 제외하는 것이 아니라 다른 구성 요소를 더 포함할 수 있는 것을 의미한다.In this specification, when a part is said to "include" a certain component, it means that it may further include other components without excluding other components unless otherwise stated.
본 명세서의 일 실시상태는 하기 화학식 1의 화합물을 포함하는 제1 조성물을 증류하는 단계; 상기 증류된 제1 조성물에 하기 화학식 2의 화합물을 첨가하여 하기 화학식 3의 화합물을 합성하는 단계; 상기 화학식 3의 화합물을 하기 화학식 4의 화합물과 반응시켜 하기 화학식 5의 화합물을 합성하는 단계; 및 상기 화학식 5의 화합물을 하기 화학식 6의 화합물과 반응시켜 하기 화학식 7의 화합물을 합성하는 단계를 포함하는 N-아실 유도체의 제조방법을 제공한다.An exemplary embodiment of the present specification is distilling a first composition including a compound represented by Formula 1; synthesizing a compound of Formula 3 below by adding a compound of Formula 2 to the distilled first composition; synthesizing a compound of Formula 5 by reacting the compound of Formula 3 with a compound of Formula 4; and reacting the compound of Formula 5 with a compound of Formula 6 to synthesize a compound of Formula 7 below.
본 명세서의 다른 실시상태는 하기 화학식 1의 화합물을 포함하는 제1 조성물을 증류하는 단계; 상기 증류된 제1 조성물에 하기 화학식 2의 화합물을 첨가하여 하기 화학식 3의 화합물을 합성하는 단계; 상기 화학식 3의 화합물을 하기 화학식 4의 화합물과 반응시켜 하기 화학식 5의 화합물을 합성하는 단계; 상기 화학식 5의 화합물을 포함하는 제2 조성물을 증류하는 단계; 및 상기 증류된 제2 조성물에 하기 화학식 6의 화합물을 첨가하여 하기 화학식 7의 화합물을 합성하는 단계를 포함하는 N-아실 유도체의 제조방법을 제공한다.Another embodiment of the present specification is distilling a first composition comprising a compound of Formula 1; synthesizing a compound of Formula 3 below by adding a compound of Formula 2 to the distilled first composition; synthesizing a compound of Formula 5 by reacting the compound of Formula 3 with a compound of Formula 4; distilling a second composition containing the compound of Chemical Formula 5; and adding a compound of Formula 6 to the distilled second composition to synthesize a compound of Formula 7 below.
Figure PCTKR2022009352-appb-img-000018
Figure PCTKR2022009352-appb-img-000018
상기 화학식 1 내지 7에서, R1은 메틸기 또는 메틸기로 치환된 아릴기이며, R2 및 R3은 서로 같거나 상이하고, 각각 독립적으로 수소; 중수소; 또는 메틸기이고, R4 및 R5는 메틸기이다.In Formulas 1 to 7, 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 independently represents hydrogen; heavy hydrogen; or a methyl group, and R4 and R5 are methyl groups.
이러한 합성법 자체로는 최종 N-아실 유도체에서 유전독성을 유발하는 하기 화학식 10과 같은 불순물이 생성될 수 밖에 없다.This synthesis method itself inevitably produces impurities such as the following Chemical Formula 10 that cause genotoxicity in the final N-acyl derivative.
[화학식 10][Formula 10]
Figure PCTKR2022009352-appb-img-000019
Figure PCTKR2022009352-appb-img-000019
상기 화학식 10의 물질은 유전독성(genotoxicity) 및 염색체이상유발성(clastogenicity)를 지녀 유전자를 이루는 DNA의 변이에 원인이 되며, 이는 유전적 장애의 발현으로써 후세대에 재해로 나타날 수 있으므로 정제과정을 거쳐 제거하거나 매우 낮은 수치로 관리되어야 한다.The substance of Chemical Formula 10 has genotoxicity and clastogenicity and causes mutations in DNA constituting genes, which is the expression of genetic disorders and can appear as a disaster in future generations. should be eliminated or maintained at very low levels.
그러나, 상기 화학식 7의 화합물과 화학식 9의 화합물은 대량공정에서 증류하기 어려운 295℃ 이상인 고온의 끓는점을 가지기 떄문에 최종 조성물 상태에서 증류로 분리정제가 어렵다. However, since the compound of Formula 7 and the compound of Formula 9 have a high boiling point of 295 ° C. or higher, which is difficult to distill in a large-scale process, it is difficult to separate and purify the final composition by distillation.
이에, 본 명세서에서는 상기 화학식 7의 합성 전(前) 단계에서 상기 화합물 10을 생성하게 하는 전구체를 증류로 제거하여 상기 화합물 10의 생성확률을 낮추어 보다 쉽게 순도가 높은 화학식 7의 화합물을 합성할 수 있다. 이는 제1 조성물의 화학식 1의 화합물과 제2 조성물의 화학식 6의 화합물은 대량공정에서도 증류가 가능한 수준의 끓는점을 가지고 있기 때문에 가능하다.Accordingly, in the present specification, the precursor for producing the compound 10 is removed by distillation in a step before the synthesis of the formula 7 to lower the probability of producing the compound 10, so that the compound of formula 7 with high purity can be more easily synthesized. there is. This is possible because the compound of formula 1 of the first composition and the compound of formula 6 of the second composition have boiling points at a level at which distillation is possible even in a large-scale process.
구체적으로, 하기 반응식과 같이, 화학식 1의 불순물인 화학식 8로부터 화학식 10이 생성된다.Specifically, as shown in the following reaction scheme, Formula 10 is generated from Formula 8, which is an impurity of Formula 1.
[반응식][reaction formula]
Figure PCTKR2022009352-appb-img-000020
Figure PCTKR2022009352-appb-img-000020
상기 반응식에서, R1 내지 R5의 정의는 화학식 1 내지 7에서의 정의와 같다. In the reaction scheme, the definitions of R1 to R5 are the same as those in Chemical Formulas 1 to 7.
본 명세서에서는 화학식 1을 반응에 참여시키기 전에 증류를 통해 상기 화학식 8의 일부 제거하여 불순물이 생성될 확률을 낮추어, 최종 N-아실 유도체를 합성했을 때 분리하기 힘든 상기 화학식 10의 화합물의 함량을 줄일 수 있다. In the present specification, by removing some of Formula 8 through distillation before participating in the reaction of Formula 1, the probability of impurity generation is reduced to reduce the content of the compound of Formula 10, which is difficult to separate when synthesizing the final N-acyl derivative. can
본 명세서의 일 실시상태에 있어서, 상기 제1 조성물을 증류하는 단계는, 상기 제1 조성물의 전체 GC 면적을 기준으로, 하기 화학식 8의 화합물의 함량이 0.05 면적% 이하인 제1 조성물을 제조하는 단계이다. 구체적으로, 상기 화학식 1의 화합물과 하기 화학식 8의 화합물을 함께 포함하는 제1 조성물을 증류하여, 제1 조성물로부터 하기 화학식 8의 화합물을 제거하여 제1 조성물 내 화학식 8의 화합물의 함량을 감소시켰다.In one embodiment of the present specification, the step of distilling the first composition is a step of preparing a first composition in which the content of the compound represented by Formula 8 is 0.05 area% or less based on the total GC area of the first composition to be. Specifically, the first composition containing the compound of Formula 1 and the compound of Formula 8 was distilled to remove the compound of Formula 8 from the first composition to reduce the content of the compound of Formula 8 in the first composition. .
[화학식 8][Formula 8]
Figure PCTKR2022009352-appb-img-000021
Figure PCTKR2022009352-appb-img-000021
본 명세서의 일 실시상태에 있어서, 상기 제1 조성물을 증류하는 단계에서 증류는 1회 이상 수행될 수 있으며, 구체적으로 1회 이상, 2회 이상, 또는 3회 이상으로 수회 수행될 수 있다. In one embodiment of the present specification, in the step of distilling the first composition, the distillation may be performed one or more times, specifically, one or more times, two or more times, or three or more times.
본 명세서의 일 실시상태에 있어서, 상기 제1 조성물의 증류를 통해, 상기 제1 조성물의 전체 GC 면적을 기준으로, 상기 화학식 8의 화합물의 함량이 0.05 면적% 이하, 0.04 면적% 이하 또는 0.03 면적% 이하일 수 있으며, 상기 화학식 8의 화합물의 함량은 낮으면 낮을수록 좋으므로 하한치를 특별히 한정하지 않는다.In one embodiment of the present specification, through distillation of the first composition, the content of the compound of Formula 8 is 0.05 area% or less, 0.04 area% or less, or 0.03 area% based on the total GC area of the first composition % or less, and the lower the content of the compound of Formula 8, the better, so the lower limit is not particularly limited.
본 명세서의 일 실시상태에 있어서, 상기 제1 조성물을 증류하는 단계는, 40 torr 내지 60torr의 압력과, 70℃ 내지 100℃의 온도의 온도에서 상기 제1 조성물을 증류한다. 이 경우 다음 증류 단계에서 제거 대상인 화학식 9의 생성량이 감소되므로 화학식 5의 함량이 더욱 높은 제2 조성물을 얻을 수 있다는 장점이 있다. 또한, 상기 제1 조성물의 증류조건이 대량생산에 적합하지 않는 고온이거나 너무 낮은 진공 압력 조건이 아니기 때문에, 대량생산 공정에서도 쉽게 적용이 가능한 장점이 있다. In one embodiment of the present specification, in the step of distilling the first composition, the first composition is distilled at a pressure of 40 torr to 60 torr and a temperature of 70 ° C to 100 ° C. In this case, since the production amount of Chemical Formula 9 to be removed in the next distillation step is reduced, there is an advantage in that a second composition having a higher content of Chemical Formula 5 can be obtained. In addition, since the distillation conditions of the first composition are not high temperature or too low vacuum pressure conditions that are not suitable for mass production, there is an advantage that it can be easily applied even in mass production processes.
본 명세서에서는 화학식 5를 반응에 참여시키기 전에 증류를 통해 상기 화학식 9의 일부 제거하여 불순물이 생성될 확률을 낮추어, 최종물을 합성했을 때 분리하기 힘든 상기 화학식 10의 화합물의 함량을 줄일 수 있다. In the present specification, the content of the compound of Formula 10, which is difficult to separate when synthesizing the final product, can be reduced by removing some of Formula 9 through distillation before participating in the reaction of Formula 5 to lower the probability of impurities being generated.
본 명세서의 일 실시상태에 있어서, 상기 제2 조성물을 증류하는 단계는, 상기 제2 조성물의 전체 GC 면적을 기준으로, 하기 화학식 9의 화합물의 함량이 0.05 면적% 이하인 제2 조성물을 제조하는 단계이다. 구체적으로, 상기 화학식 5의 화합물과 하기 화학식 9의 화합물을 함께 포함하는 제2 조성물을 증류하여, 제2 조성물로부터 하기 화학식 9의 화합물을 제거하여 제2 조성물 내 화학식 9의 화합물의 함량을 감소시켰다.In one embodiment of the present specification, the step of distilling the second composition is a step of preparing a second composition in which the content of the compound represented by Formula 9 is 0.05 area% or less based on the total GC area of the second composition to be. Specifically, the second composition containing the compound of Formula 5 and the compound of Formula 9 was distilled to remove the compound of Formula 9 from the second composition to reduce the content of the compound of Formula 9 in the second composition. .
[화학식 9][Formula 9]
Figure PCTKR2022009352-appb-img-000022
Figure PCTKR2022009352-appb-img-000022
상기 화학식 9에서, R2 및 R3은 서로 같거나 상이하고, 각각 독립적으로 수소; 중수소; 또는 메틸기이고, R4는 메틸기이다.In Formula 9, R2 and R3 are the same as or different from each other, and each independently hydrogen; heavy hydrogen; or a methyl group, and R4 is a methyl group.
본 명세서의 일 실시상태에 있어서, 상기 제2 조성물을 증류하는 단계에서 증류는 1회 이상 수행될 수 있으며, 구체적으로 1회 이상, 2회 이상, 또는 3회 이상으로 수회 수행될 수 있다. In one embodiment of the present specification, in the step of distilling the second composition, distillation may be performed one or more times, specifically, one or more times, two or more times, or three or more times.
본 명세서의 일 실시상태에 있어서, 상기 제2 조성물의 증류를 통해, 상기 제2 조성물의 전체 GC 면적을 기준으로, 상기 화학식 9의 화합물의 함량이 0.05 면적% 이하, 0.04 면적% 이하 또는 0.03 면적% 이하일 수 있으며, 상기 화학식 8의 화합물의 함량은 낮으면 낮을수록 좋으므로 하한치를 특별히 한정하지 않는다.In one embodiment of the present specification, through distillation of the second composition, the content of the compound of Formula 9 is 0.05 area% or less, 0.04 area% or less, or 0.03 area% based on the total GC area of the second composition % or less, and the lower the content of the compound of Formula 8, the better, so the lower limit is not particularly limited.
본 명세서의 일 실시상태에 있어서, 상기 제2 조성물을 증류하는 단계는, 2 torr 내지 20torr의 압력과, 130℃ 내지 200℃의 온도의 온도에서 상기 제2 조성물을 증류한다. 이 경우 다음 증류 단계에서 제거 대상인 화학식 10의 생성량이 감소되므로 화학식 7의 함량이 더욱 높은 제3 조성물을 얻을 수 있다는 장점이 있다.In one embodiment of the present specification, in the step of distilling the second composition, the second composition is distilled at a pressure of 2 torr to 20 torr and a temperature of 130 ° C to 200 ° C. In this case, since the production amount of Chemical Formula 10 to be removed in the next distillation step is reduced, there is an advantage in that a third composition having a higher content of Chemical Formula 7 can be obtained.
본 명세서의 일 실시상태에 있어서, 상기 화학식 1의 화합물을 기준으로, 상기 화학식 2의 화합물의 함량은 1.0 당량 내지 2.0 당량이다. In one embodiment of the present specification, based on the compound of Formula 1, the content of the compound of Formula 2 is 1.0 equivalent to 2.0 equivalent.
본 명세서의 일 실시상태에 있어서, 상기 화학식 3의 화합물을 기준으로, 상기 화학식 4의 화합물의 함량은 2.0 당량 내지 10.0 당량이다. 이 경우, 상기 화학식 4의 사용 당량이 적절하여 반응속도는 빨라지면서 부반응을 제어할 수 있는 장점이 있다.In one embodiment of the present specification, based on the compound of Formula 3, the content of the compound of Formula 4 is 2.0 equivalent to 10.0 equivalent. In this case, there is an advantage in that side reactions can be controlled while the reaction rate is increased because the equivalent amount of Chemical Formula 4 is appropriate.
본 명세서의 일 실시상태에 있어서, 상기 화학식 5의 화합물을 기준으로, 상기 화학식 6의 화합물의 함량은 1.0 당량 내지 2.0 당량이다. In one embodiment of the present specification, based on the compound of Formula 5, the content of the compound of Formula 6 is 1.0 equivalent to 2.0 equivalent.
본 명세서의 일 실시상태에 있어서, 상기 화학식 7의 화합물을 포함하는 제3 조성물의 전체 GC 면적을 기준으로, 하기 화학식 10의 화합물의 함량이 0.05 면적% 이하이다. 전체 반응스킴 중 화학식 1의 화합물과 화학식 5의 화합물을 각각 반응참여 전에 증류를 통해 불순물인 화학식 8과 9의 화합물을 제거하여 최종합성된 최종물에서 하기 화학식 10의 화합물의 함량이 감소했다. 구체적으로 상기 제3 조성물의 전체 GC 면적을 기준으로, 하기 화학식 10의 화합물의 함량은 0.05 면적% 이하, 0.04 면적% 이하, 0.03 면적% 이하 또는 0.02 면적% 이하이다.In one embodiment of the present specification, the content of the compound of Formula 10 is 0.05 area% or less based on the total GC area of the third composition including the compound of Formula 7. In the overall reaction scheme, the compound of formula 1 and the compound of formula 5 were distilled before participating in the reaction, respectively, to remove impurities of the compounds of formulas 8 and 9, and the content of the compound of formula 10 in the final product was reduced. Specifically, based on the total GC area of the third composition, the content of the compound represented by Formula 10 is 0.05 area % or less, 0.04 area % or less, 0.03 area % or less, or 0.02 area % or less.
[화학식 10][Formula 10]
Figure PCTKR2022009352-appb-img-000023
Figure PCTKR2022009352-appb-img-000023
상기 화학식 10에서,In Formula 10,
R2 및 R3은 서로 같거나 상이하고, 각각 독립적으로 수소; 중수소; 또는 메틸기이고, R2 and R3 are the same as or different from each other, and each independently hydrogen; heavy hydrogen; or a methyl group;
R4 및 R5는 메틸기이다.R4 and R5 are methyl groups.
본 명세서의 다른 실시상태는 하기 화학식 1의 화합물을 포함하는 제1 조성물의 전체 GC 면적을 기준으로, 하기 화학식 8의 화합물의 함량이 0.05 면적% 이하인 제1 조성물에 하기 화학식 2의 화합물을 첨가하여 하기 화학식 3의 화합물을 합성하는 단계; 상기 화학식 3의 화합물을 하기 화학식 4의 화합물과 반응시켜 하기 화학식 5의 화합물을 합성하는 단계; 및 상기 화학식 5의 화합물을 하기 화학식 6의 화합물과 반응시켜 하기 화학식 7의 화합물을 합성하는 단계를 포함하는 N-아실 유도체의 제조방법을 제공한다.Another embodiment of the present specification is based on the total GC area of the first composition containing the compound of Formula 1 below, by adding the compound of Formula 2 to the first composition in which the content of the compound of Formula 8 is 0.05 area% or less Synthesizing a compound represented by Chemical Formula 3; synthesizing a compound of Formula 5 by reacting the compound of Formula 3 with a compound of Formula 4; and reacting the compound of Formula 5 with a compound of Formula 6 to synthesize a compound of Formula 7 below.
본 명세서의 또 다른 실시상태는 하기 화학식 1의 화합물을 포함하는 제1 조성물의 전체 GC 면적을 기준으로, 하기 화학식 8의 화합물의 함량이 0.05 면적% 이하인 제1 조성물에 하기 화학식 2의 화합물을 첨가하여 하기 화학식 3의 화합물을 합성하는 단계; 상기 화학식 3의 화합물을 하기 화학식 4의 화합물과 반응시켜 하기 화학식 5의 화합물을 합성하는 단계; 및 상기 화학식 5의 화합물을 포함하는 제2 조성물의 전체 GC 면적을 기준으로, 하기 화학식 9의 화합물의 함량이 0.05 면적% 이하인 제2 조성물에 하기 화학식 6의 화합물을 첨가하여 하기 화학식 7의 화합물을 합성하는 단계를 포함하는 N-아실 유도체의 제조방법을 제공한다.In another embodiment of the present specification, the compound of Formula 2 is added to the first composition in which the content of the compound of Formula 8 is 0.05 area% or less based on the total GC area of the first composition including the compound of Formula 1 below to synthesize a compound represented by Formula 3; synthesizing a compound of Formula 5 by reacting the compound of Formula 3 with a compound of Formula 4; And the compound of Formula 6 is added to a second composition in which the content of the compound of Formula 9 is 0.05 area% or less based on the total GC area of the second composition including the compound of Formula 5, to obtain a compound of Formula 7 It provides a method for producing an N-acyl derivative comprising the step of synthesizing.
[화학식 1][Formula 1]
Figure PCTKR2022009352-appb-img-000024
Figure PCTKR2022009352-appb-img-000024
[화학식 2][Formula 2]
Figure PCTKR2022009352-appb-img-000025
Figure PCTKR2022009352-appb-img-000025
[화학식 3][Formula 3]
Figure PCTKR2022009352-appb-img-000026
Figure PCTKR2022009352-appb-img-000026
[화학식 4][Formula 4]
Figure PCTKR2022009352-appb-img-000027
Figure PCTKR2022009352-appb-img-000027
[화학식 5][Formula 5]
Figure PCTKR2022009352-appb-img-000028
Figure PCTKR2022009352-appb-img-000028
[화학식 6][Formula 6]
Figure PCTKR2022009352-appb-img-000029
Figure PCTKR2022009352-appb-img-000029
[화학식 7][Formula 7]
Figure PCTKR2022009352-appb-img-000030
Figure PCTKR2022009352-appb-img-000030
[화학식 8][Formula 8]
Figure PCTKR2022009352-appb-img-000031
Figure PCTKR2022009352-appb-img-000031
[화학식 9][Formula 9]
Figure PCTKR2022009352-appb-img-000032
Figure PCTKR2022009352-appb-img-000032
상기 화학식 1 내지 7 및 9에서, R1은 메틸기 또는 메틸기로 치환된 아릴기이며, R2 및 R3은 서로 같거나 상이하고, 각각 독립적으로 수소; 중수소; 또는 메틸기이고, R4 및 R5는 메틸기이다.In Formulas 1 to 7 and 9, 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 independently hydrogen; heavy hydrogen; or a methyl group, and R4 and R5 are methyl groups.
본 명세서의 다른 하기 화학식 7의 화합물과, 하기 화학식 10의 화합물을 포함하는 조성물에서, 상기 조성물의 전체 GC 면적을 기준으로, 하기 화학식 10의 화합물의 함량이 0.05 면적% 이하인 조성물을 제공한다. In the composition including the other compound of Formula 7 and the compound of Formula 10 of the present specification, the content of the compound of Formula 10 is 0.05 area% or less based on the total GC area of the composition.
[화학식 7][Formula 7]
Figure PCTKR2022009352-appb-img-000033
Figure PCTKR2022009352-appb-img-000033
[화학식 10][Formula 10]
Figure PCTKR2022009352-appb-img-000034
Figure PCTKR2022009352-appb-img-000034
상기 화학식 7 및 10에서,In Formulas 7 and 10,
R2 및 R3은 서로 같거나 상이하고, 각각 독립적으로 수소; 중수소; 또는 메틸기이고, R2 and R3 are the same as or different from each other, and each independently hydrogen; heavy hydrogen; or a methyl group;
R4 및 R5는 메틸기이다.R4 and R5 are methyl groups.
여기서, N-아실 유도체의 설명은 앞서 설명한 N-아실 유도체의 제조방법의 설명을 인용할 수 있다. Here, the description of the N-acyl derivative may refer to the description of the method for preparing the N-acyl derivative described above.
본 명세서에서 상기 아릴기가 단환식 아릴기인 경우 탄소수는 특별히 한정되지 않으나, 탄소수 6 내지 25인 것이 바람직하다. 구체적으로 단환식 아릴기로는 페닐기, 비페닐기, 터페닐기 등이 될 수 있으나, 이에 한정되는 것은 아니다. In the present specification, when the aryl group is a monocyclic aryl group, the number of carbon atoms is not particularly limited, but preferably has 6 to 25 carbon atoms. Specifically, the monocyclic aryl group may be a phenyl group, a biphenyl group, a terphenyl group, and the like, but is not limited thereto.
상기 아릴기가 다환식 아릴기인 경우 탄소수는 특별히 한정되지 않으나. 탄소수 10 내지 24인 것이 바람직하다. 구체적으로 다환식 아릴기로는 나프틸기, 안트라세닐기, 페난트릴기, 파이레닐기, 페릴레닐기, 크라이세닐기, 플루오레닐기 등이 될 수 있으나, 이에 한정되는 것은 아니다.When the aryl group is a polycyclic aryl group, the number of carbon atoms is not particularly limited. It is preferable that it is carbon number 10-24. Specifically, the polycyclic aryl group may be a naphthyl group, anthracenyl group, phenanthryl group, pyrenyl group, perylenyl group, chrysenyl group, fluorenyl group, and the like, but is not limited thereto.
본 명세서에 있어서, 상기 플루오레닐기는 치환될 수 있으며, 인접한 치환기들이 서로 결합하여 고리를 형성할 수 있다.In the present specification, the fluorenyl group may be substituted, and adjacent substituents may bond to each other to form a ring.
본 명세서의 일 실시상태에 있어서, R1은 메틸기; 또는 메틸기로 치환된 페닐기이다. In one embodiment of the present specification, R1 is a methyl group; or a phenyl group substituted with a methyl group.
본 명세서의 일 실시상태에 있어서, R1은 메틸기; 또는
Figure PCTKR2022009352-appb-img-000035
이며,
Figure PCTKR2022009352-appb-img-000036
는 결합위치이다. In one embodiment of the present specification, R1 is a methyl group; or
Figure PCTKR2022009352-appb-img-000035
is,
Figure PCTKR2022009352-appb-img-000036
is the binding position.
본 명세서의 일 실시상태에 있어서, R2 및 R3는 서로 같거나 상이하고, 각각 독립적으로 수소; 또는 메틸기이다. In one embodiment of the present specification, R2 and R3 are the same as or different from each other, and each independently hydrogen; or a methyl group.
본 명세서의 일 실시상태에 있어서, R2 및 R3는 메틸기이다.In one embodiment of the present specification, R2 and R3 are methyl groups.
본 명세서는 상술한 조성물을 포함하는 의약품 또는 농업용품을 제공한다. 이때, 조성물 내 N-아실 유도체를 그대로 포함하는 상태뿐 아니라, 각각의 용도에 맞게 변경된, 즉 필수적인 화학반응을 통해 변경된 유도체를 포함하는 의약품 또는 농업용품도 포함된다. The present specification provides a pharmaceutical or agricultural product containing the above-described composition. At this time, not only the state containing the N-acyl derivative in the composition as it is, but also pharmaceuticals or agricultural products containing derivatives modified for each use, that is, modified through an essential chemical reaction, are included.
본 명세서에 있어서, 상기 농업용품은 제초제, 작물보호제, 살균제 등 다양한 농업용 화학물품일 수 있다.In the present specification, the agricultural products may be various agricultural chemicals such as herbicides, crop protection agents, and fungicides.
이하에서, 실시예를 통하여 본 명세서를 더욱 상세하게 설명한다. 그러나, 이하의 실시예는 본 명세서를 예시하기 위한 것일 뿐, 본 명세서를 한정하기 위한 것은 아니다.Hereinafter, the present specification will be described in more detail through examples. However, the following examples are only for exemplifying the present specification, and are not intended to limit the present specification.
[실시예][Example]
[실시예 1][Example 1]
메틸 L-락테이트(Methyl L-lactate) 100g(TCI 제조, 순도 98%up(GC), 0.96mol)를 포함하는 용액을 플라스크에 주입하고, 내부 압력을 60 torr로 조절하고, 온도를 70℃로 승온하였다.A solution containing 100 g of methyl L-lactate (manufactured by TCI, purity 98% up (GC), 0.96 mol) was injected into the flask, the internal pressure was adjusted to 60 torr, and the temperature was 70 ° C. was heated to
내부 압력을 다시 60 torr에서 40 torr로 낮추면서 온도는 70℃에서 100℃로 승온 조절하여 메틸 L-락테이트를 증류했다. 그 결과, 증류가 완료된 용액의 전체 GC 면적을 기준으로, L-젖산(L-Lactic acid)이 0.05 면적%로 포함되도록 증류하여 수율 95%의 메틸 L-락테이트를 수득했다.While the internal pressure was again lowered from 60 torr to 40 torr, the temperature was raised from 70°C to 100°C to distill methyl L-lactate. As a result, methyl L-lactate was obtained in a yield of 95% by distillation such that 0.05 area% of L-lactic acid was included based on the total GC area of the distilled solution.
상온에서 디클로로메탄(Dichloromethane) 400 mL가 들어있는 반응기에 증류된 메틸-L-락테이트(104.11g, 1.0 mol) 및 트리에틸아민(Triethylamine) (154.60mL, 111.31g, 1.1 mol)을 첨가하고, 내부 온도를 0℃로 냉각하였다. 내부온도를 0℃ 내지 5℃로 유지하면서 p-톨루엔술포닐 클로라이드(p-Toluenesulfonyl chloride) (209.70g, 1.1 mol)를 천천히 첨가하고, 첨가가 완료된 후 내부 온도를 0℃ 내지 5℃로 유지하면서 4시간 동안 교반하였다. 반응 혼합물 내에 잔류한 미반응 메틸-L-락테이트가 1.0 면적%(GC분석 결과)이하임을 확인한 후 반응 혼합물 내부 온도를 15℃ 내지 20℃로 유지하면서 1N 염산(HCl) 수용액 400mL를 첨가하여 교반한 뒤, 층분리하여 얻은 유기층에 1% 탄산수소나트륨(NaHCO3) 수용액 400 mL를 첨가하고 교반하였다. 그 후, 유기층을 분리하고 감압농축하여 메틸 (s)-2-(p-톨루엔설포닐록시)프로파노에이트(Methyl (s)-2-(p-Toluenesulfonyloxy)propanoate)를 순도 98.40 GC면적%, 수율 79%(204.05g, 0.79mol)로 얻었다.Distilled methyl-L-lactate (104.11g, 1.0 mol) and triethylamine (154.60mL, 111.31g, 1.1 mol) were added to a reactor containing 400 mL of dichloromethane at room temperature, The internal temperature was cooled to 0 °C. While maintaining the internal temperature at 0 ° C to 5 ° C, p-Toluenesulfonyl chloride (209.70 g, 1.1 mol) was slowly added, and after the addition was completed, while maintaining the internal temperature at 0 ° C to 5 ° C Stir for 4 hours. After confirming that the unreacted methyl-L-lactate remaining in the reaction mixture is less than 1.0 area% (GC analysis result), while maintaining the internal temperature of the reaction mixture at 15 ° C to 20 ° C, 400 mL of 1N hydrochloric acid (HCl) aqueous solution is added and stirred After that, 400 mL of 1% sodium bicarbonate (NaHCO 3 ) aqueous solution was added to the organic layer obtained by layer separation and stirred. Then, the organic layer was separated and concentrated under reduced pressure to obtain methyl (s)-2-(p-Toluenesulfonyloxy)propanoate with a purity of 98.40 GC area%, It was obtained in a yield of 79% (204.05 g, 0.79 mol).
제조된 메틸 (s)-2-(p-톨루엔설포닐록시)프로파노에이트 (20.00 g, 77.43 mmol)에 2,6-디메틸아닐린(2,6-Dimethylaniline)(56.30 g, 464.58 mmol)을 첨가하고, 내부 온도를 120℃~130℃로 승온하여 교반했다. 반응 혼합물 내에 잔류한 미반응 메틸 (s)-2-(p-톨루엔설포닐록시)프로파노에이트가 1.0면적%(GC 분석 결과) 이하임을 확인 후 내부 압력을 20 torr로 서서히 낮추면서 잔류한 2,6-디메틸아닐린을 증류로 분리하여 폐기했다. 이후로 내부 압력을 20torr에서 2 torr로 낮추면서 온도는 130℃에서 200℃로 승온 조절하여 불순물을 증류로 분리하여 Crude 메틸 N-(2,6-디메틸페닐)-D-알라니네이트를 순도 95.22 GC면적%, 수율 85%(13.64g, 65.82 mmol)로 얻었다.To the prepared methyl (s)-2-(p-toluenesulfonyloxy)propanoate (20.00 g, 77.43 mmol) was added 2,6-dimethylaniline (2,6-Dimethylaniline) (56.30 g, 464.58 mmol). And, the internal temperature was raised to 120 ° C. to 130 ° C. and stirred. After confirming that the unreacted methyl (s)-2-(p-toluenesulfonyloxy)propanoate remaining in the reaction mixture was less than 1.0 area% (GC analysis result), the internal pressure was gradually lowered to 20 torr, and the remaining 2 ,6-Dimethylaniline was isolated by distillation and discarded. Thereafter, while lowering the internal pressure from 20 torr to 2 torr, the temperature was raised from 130 ° C to 200 ° C to separate impurities by distillation to obtain crude methyl N- (2,6-dimethylphenyl) -D-alaninate with a purity of 95.22 It was obtained in GC area%, yield 85% (13.64 g, 65.82 mmol).
증류하여 수득한 메틸 N-(2,6-디메틸페닐)-D-알라니네이트를 그대로 톨루엔(100 mL)에 희석 후 1N HCl 수용액(20 mL)으로 1회 수세하여 얻어진 유기층을 증류수(30 mL)로 1회 수세한 다음에 감압농축하여 메틸 N-(2,6-디메틸페닐)-D-알라니네이트를 순도 98.52 GC면적%, 수율 81%(13.00 g, 62.72 mmol)로 얻었다. Methyl N- (2,6-dimethylphenyl) -D-alaninate obtained by distillation was diluted in toluene (100 mL) as it is, washed once with 1N HCl aqueous solution (20 mL), and the obtained organic layer was distilled water (30 mL). ) and then concentrated under reduced pressure to obtain methyl N-(2,6-dimethylphenyl)-D-alaninate with a purity of 98.52 GC area% and a yield of 81% (13.00 g, 62.72 mmol).
여기에 NaHCO3(6.85 g, 81.54 mmol)과 톨루엔(52 mL)을 첨가한 후 -5℃ ~ 0℃로 냉각한 다음에 메톡시아세틸 클로라이드(8.85 g, 81.54 mmol)를 적가했다. 적가 완료 후 내부온도 10℃ ~ 15℃를 유지하도록 3시간 동안 교반했다. 반응 혼합물 내에 잔류한 미반응 메틸 N-(2,6-디메틸페닐)-D-알라니네이트가 1.0면적%(GC 분석 결과) 이하를 확인 후 H2O(52 mL)를 첨가한 뒤에, 1N NaOH를 적가하여 pH 7~8을 확인 후 층분리하여, 수층은 폐기했다. 분리된 유기층에 H2O(26 mL)를 첨가하고, 교반 후 층분리하여, 수층을 다시 폐기했다. 분리된 유기층을 여과하여 이물질을 제거한 후에 감압농축하여 메틸 N-(2,6-디메틸페닐)-N-(메톡시아세틸)-D-알라니네이트를 순도 98.82 GC면적%, 수율 84%(14.72 g, 52.68 mmol)로 얻었다. 이때, 수득된 메틸 N-(2,6-디메틸페닐)-N-(메톡시아세틸)-D-알라니네이트의 전체 GC 면적을 기준으로, 유전독성 물질은 0.02면적%였다.After adding NaHCO 3 (6.85 g, 81.54 mmol) and toluene (52 mL), the mixture was cooled to -5°C to 0°C and then methoxyacetyl chloride (8.85 g, 81.54 mmol) was added dropwise. After completion of the dropwise addition, the mixture was stirred for 3 hours to maintain an internal temperature of 10°C to 15°C. After confirming that the unreacted methyl N-(2,6-dimethylphenyl)-D-alaninate remaining in the reaction mixture was less than 1.0 area% (GC analysis result), H 2 O (52 mL) was added, and then 1N NaOH was added dropwise to confirm pH 7-8, and then the layers were separated and the aqueous layer was discarded. H 2 O (26 mL) was added to the separated organic layer, the layers were separated after stirring, and the aqueous layer was discarded again. After filtering the separated organic layer to remove foreign substances, it was concentrated under reduced pressure to obtain methyl N-(2,6-dimethylphenyl)-N-(methoxyacetyl)-D-alaninate with a purity of 98.82 GC area% and a yield of 84% (14.72%). g, 52.68 mmol). At this time, the genotoxic substance was 0.02 area% based on the total GC area of the obtained methyl N-(2,6-dimethylphenyl)-N-(methoxyacetyl)-D-alaninate.
[실시예 2] [Example 2]
메틸 L-락테이트 100g(TCI 제조, 순도 98%up(GC), 0.96mol)를 포함하는 용액을 플라스크에 주입하고, 내부 압력을 60 torr로 조절하고, 온도를 70℃로 승온하였다.A solution containing 100 g of methyl L-lactate (manufactured by TCI, purity 98% up (GC), 0.96 mol) was injected into the flask, the internal pressure was adjusted to 60 torr, and the temperature was raised to 70°C.
내부 압력을 다시 60torr에서 40 torr로 낮추면서 온도는 70℃에서 100℃로 승온 조절하여 메틸 L-락테이트를 증류했다. 그 결과, 증류가 완료된 용액의 전체 GC 면적을 기준으로, L-젖산이 0.05 면적%로 포함되도록 증류로 얻어진 메틸 L-락테이트(104.11 g, 1.0 mol)를 상온에서 디클로로메탄 400 mL가 들어있는 반응기에 투입했다. 여기에 트리에틸아민 (154.60mL, 111.31g, 1.1 mol)을 더 첨가하고, 내부 온도를 0℃로 냉각하였다. 내부온도를 0℃ 내지 5℃로 유지하면서 p-톨루엔술포닐 클로라이드 (209.70g, 1.1 mol)를 천천히 첨가하고, 첨가가 완료된 후 내부 온도를 0℃ 내지 5℃로 유지하면서 4시간 동안 교반하였다. 반응 혼합물 내에 잔류한 미반응 메틸-L-락테이트가 1.0 면적%(GC분석 결과)이하임을 확인한 후 반응 혼합물 내부 온도를 15℃ 내지 20℃로 유지하면서 1N 염산(HCl) 수용액 400mL를 첨가하여 교반한 뒤, 층분리하여 얻은 유기층에 1% 탄산수소나트륨(NaHCO3) 수용액 400 mL를 첨가하고 교반하였다. 그 후, 유기층을 분리하고 감압농축하여 메틸 (s)-2-(p-톨루엔설포닐록시)프로파노에이트를 순도 98.36 GC면적%, 수율 79%(204.44g, 0.79mol)로 얻었다.While the internal pressure was again lowered from 60 torr to 40 torr, the temperature was raised from 70° C. to 100° C. to distill methyl L-lactate. As a result, based on the total GC area of the distilled solution, methyl L-lactate (104.11 g, 1.0 mol) obtained by distillation to contain 0.05 area% of L-lactic acid was mixed with 400 mL of dichloromethane at room temperature. was put into the reactor. Triethylamine (154.60 mL, 111.31 g, 1.1 mol) was further added thereto, and the internal temperature was cooled to 0°C. While maintaining the internal temperature at 0 ° C to 5 ° C, p-toluenesulfonyl chloride (209.70 g, 1.1 mol) was slowly added, and after the addition was completed, the mixture was stirred for 4 hours while maintaining the internal temperature at 0 ° C to 5 ° C. After confirming that the unreacted methyl-L-lactate remaining in the reaction mixture is less than 1.0 area% (GC analysis result), while maintaining the internal temperature of the reaction mixture at 15 ° C to 20 ° C, 400 mL of 1N hydrochloric acid (HCl) aqueous solution is added and stirred After that, 400 mL of 1% sodium hydrogen carbonate (NaHCO 3 ) aqueous solution was added to the organic layer obtained by layer separation, followed by stirring. Thereafter, the organic layer was separated and concentrated under reduced pressure to obtain methyl (s)-2-(p-toluenesulfonyloxy)propanoate with a purity of 98.36 GC area% and a yield of 79% (204.44 g, 0.79 mol).
제조된 메틸 (s)-2-(p-톨루엔설포닐록시)프로파노에이트(20.00 g, 77.43 mmol)에 2,6-디메틸아닐린(56.30 g, 464.58 mmol)을 첨가하고, 내부 온도를 120℃ ~ 130℃로 승온하여 교반했다. To the prepared methyl (s)-2-(p-toluenesulfonyloxy)propanoate (20.00 g, 77.43 mmol) was added 2,6-dimethylaniline (56.30 g, 464.58 mmol), and the internal temperature was raised to 120°C. The temperature was raised to ~ 130° C. and stirred.
반응 혼합물 내에 잔류한 미반응 메틸 (s)-2-(p-톨루엔설포닐록시)프로파노에이트가 1.0면적%(GC 분석 결과) 이하를 확인 후 내부온도를 상온(RT, Room Temperature)으로 냉각하고, 톨루엔(100 mL)을 첨가한 뒤에 다시 0℃로 냉각하여 1시간 동안 교반 후 여과했다. 이 여액을 1N HCl 수용액(20 mL)로 2회 수세하여 얻어진 유기층을 증류수(30 mL)로 1회 수세한 다음에 감압농축하여 메틸 N-(2,6-디메틸페닐)-D-알라니네이트를 순도 97.42 GC면적%, 수율 63%(10.11 g, 48.78 mmol)로 얻었다. After confirming that the unreacted methyl (s)-2-(p-toluenesulfonyloxy)propanoate remaining in the reaction mixture is less than 1.0 area% (GC analysis result), the internal temperature is cooled to room temperature (RT, Room Temperature) After adding toluene (100 mL), the mixture was cooled to 0° C., stirred for 1 hour, and filtered. This filtrate was washed twice with 1N HCl aqueous solution (20 mL), and the resulting organic layer was washed once with distilled water (30 mL) and then concentrated under reduced pressure to obtain methyl N-(2,6-dimethylphenyl)-D-alaninate was obtained with a purity of 97.42 GC area% and a yield of 63% (10.11 g, 48.78 mmol).
여기에 NaHCO3(5.33 g, 63.41 mmol)과 톨루엔(40 mL)을 첨가 후 -5℃ ~ 0℃로 냉각한 다음에 메톡시아세틸 클로라이드(6.88 g, 63.41 mmol)를 적가했다. 적가 완료 후 내부온도 10℃ ~ 15℃를 유지하도록 3시간 교반했다. 반응 혼합물 내에 잔류한 미반응 메틸 N-(2,6-디메틸페닐)-D-알라니네이트가 1.0면적%(GC 분석 결과) 이하를 확인 후 H2O(40 mL)를 첨가한 뒤에, 1N NaOH를 적가하여 pH 7~8을 확인 후 층분리하여, 수층을 폐기했다. 분리된 유기층에 H2O(20 mL)를 첨가하고, 교반 후 층분리 하여, 수층을 폐기했다. 분리된 유기층을 여과하여 이물질을 제거한 후에 감압농축하여 메틸 N-(2,6-디메틸페닐)-N-(메톡시아세틸)-D-알라니네이트를 순도 97.62 GC면적%, 수율 84%(11.45 g, 40.98 mmol)로 얻었다. 이때, 수득된 메틸 N-(2,6-디메틸페닐)-N-(메톡시아세틸)-D-알라니네이트의 전체 GC 면적을 기준으로, 유전독성 물질은 0.11면적%였다.After adding NaHCO 3 (5.33 g, 63.41 mmol) and toluene (40 mL), the mixture was cooled to -5°C to 0°C, and then methoxyacetyl chloride (6.88 g, 63.41 mmol) was added dropwise. After completion of the dropwise addition, the mixture was stirred for 3 hours to maintain an internal temperature of 10 ° C to 15 ° C. After confirming that the unreacted methyl N-(2,6-dimethylphenyl)-D-alaninate remaining in the reaction mixture was 1.0 area% or less (GC analysis result), H 2 O (40 mL) was added, and then 1N NaOH was added dropwise to confirm pH 7-8, and then the layers were separated and the aqueous layer was discarded. H 2 O (20 mL) was added to the separated organic layer, and the layers were separated after stirring, and the aqueous layer was discarded. After filtering the separated organic layer to remove foreign substances, it was concentrated under reduced pressure to obtain methyl N-(2,6-dimethylphenyl)-N-(methoxyacetyl)-D-alaninate with a purity of 97.62 GC area% and a yield of 84% (11.45%). g, 40.98 mmol). At this time, based on the total GC area of the obtained methyl N-(2,6-dimethylphenyl)-N-(methoxyacetyl)-D-alaninate, the genotoxic substance was 0.11 area%.
[비교예 1][Comparative Example 1]
증류를 거치지 않아 전체 GC 면적 중 L-젖산을 0.20 면적%로 포함하고 있는 메틸 L-락테이트(104.11g, 1.0 mol)를 상온에서 디클로로메탄 400mL가 들어있는 반응기에 투입 후 트리에틸아민(154 mL, 111.31 g, 1.1 mol)을 첨가하고, 내부 온도를 0℃로 냉각하였다. 내부온도를 0℃ 내지 5℃로 유지하면서 p-톨루엔술포닐 클로라이드 (209.70g, 1.1 mol)를 천천히 첨가하고, 첨가가 완료된 후 내부 온도를 0℃ 내지 5℃로 유지하면서 4시간 동안 교반하였다. 반응 혼합물 내에 잔류한 미반응 메틸-L-락테이트가 1.0 면적%(GC분석 결과)이하임을 확인한 후 반응 혼합물 내부 온도를 15℃ 내지 20℃로 유지하면서 1N 염산(HCl) 수용액 400mL를 첨가하여 교반한 뒤, 층분리하여 얻은 유기층에 1% 탄산수소나트륨(NaHCO3) 수용액 400 mL를 첨가하고 교반하였다. 그 후, 유기층을 분리하고 감압농축하여 메틸 (s)-2-(p-톨루엔설포닐록시)프로파노에이트를 순도 98.23 GC면적%, 수율 79%(204.38g, 0.79mol)로 얻었다.Methyl L-lactate (104.11 g, 1.0 mol) containing 0.20 area% of L-lactic acid out of the total GC area without distillation was introduced into a reactor containing 400 mL of dichloromethane at room temperature, and then triethylamine (154 mL) was added. , 111.31 g, 1.1 mol) was added and the internal temperature was cooled to 0 °C. While maintaining the internal temperature at 0 ° C to 5 ° C, p-toluenesulfonyl chloride (209.70 g, 1.1 mol) was slowly added, and after the addition was completed, the mixture was stirred for 4 hours while maintaining the internal temperature at 0 ° C to 5 ° C. After confirming that the unreacted methyl-L-lactate remaining in the reaction mixture is less than 1.0 area% (GC analysis result), while maintaining the internal temperature of the reaction mixture at 15 ° C to 20 ° C, 400 mL of 1N hydrochloric acid (HCl) aqueous solution is added and stirred After that, 400 mL of 1% sodium bicarbonate (NaHCO 3 ) aqueous solution was added to the organic layer obtained by layer separation and stirred. Thereafter, the organic layer was separated and concentrated under reduced pressure to obtain methyl (s)-2-(p-toluenesulfonyloxy)propanoate with a purity of 98.23 GC area% and a yield of 79% (204.38 g, 0.79 mol).
제조된 메틸 (s)-2-(p-톨루엔설포닐록시)프로파노에이트 (20.00 g, 77.43 mmol)에 2,6-디메틸아닐린 (56.30 g, 464.58 mmol)를 첨가하고, 내부 온도를 120℃ ~ 130℃로 승온하여 교반했다.To the prepared methyl (s)-2-(p-toluenesulfonyloxy)propanoate (20.00 g, 77.43 mmol) was added 2,6-dimethylaniline (56.30 g, 464.58 mmol), and the internal temperature was raised to 120°C. The temperature was raised to ~ 130° C. and stirred.
반응 혼합물 내에 잔류한 미반응 메틸 (s)-2-(p-톨루엔설포닐록시)프로파노에이트가 1.0면적%(GC 분석 결과) 이하를 확인 후 내부온도를 상온(RT, Room Temperature)으로 냉각하고, 톨루엔(100 mL)을 첨가한 뒤에 다시 0℃로 냉각하여 1시간 동안 교반 후 여과했다. 이 여액을 1N HCl 수용액(20 mL)로 2회 수세하여 얻어진 유기층을 증류수(30 mL)로 1회 수세한 다음에 감압농축하여 메틸 N-(2,6-디메틸페닐)-D-알라니네이트를 순도 97.40 GC면적%, 수율 64%(10.27 g, 49.56 mmol)로 얻었다. After confirming that the unreacted methyl (s)-2-(p-toluenesulfonyloxy)propanoate remaining in the reaction mixture is less than 1.0 area% (GC analysis result), the internal temperature is cooled to room temperature (RT, Room Temperature) After adding toluene (100 mL), the mixture was cooled to 0° C., stirred for 1 hour, and filtered. This filtrate was washed twice with 1N HCl aqueous solution (20 mL), and the resulting organic layer was washed once with distilled water (30 mL) and then concentrated under reduced pressure to obtain methyl N-(2,6-dimethylphenyl)-D-alaninate was obtained with a purity of 97.40 GC area% and a yield of 64% (10.27 g, 49.56 mmol).
여기에 NaHCO3(5.41 g, 64.43 mmol)과 톨루엔 (40 mL)을 첨가 후 -5℃ ~ 0℃로 냉각한 다음에 메톡시아세틸 클로라이드(6.99 g, 64.43 mmol)를 적가했다. 적가 완료 후 내부온도 10℃ ~ 15℃를 유지하도록 3시간 교반했다. 반응 혼합물 내에 잔류한 미반응 메틸 N-(2,6-디메틸페닐)-D-알라니네이트가 1.0면적%(GC 분석 결과) 이하를 확인 후 H2O(40 mL)를 첨가한 뒤에, 1N NaOH를 적가하여 pH 7~8을 확인 후 층분리하여, 수층을 폐기했다. 분리된 유기층에 H2O(20 mL)를 첨가하고, 교반 후 층분리하여, 수층을 폐기했다. 분리된 유기층을 여과하여 이물질을 제거한 후에 감압농축하여 메틸 N-(2,6-디메틸페닐)-N-(메톡시아세틸)-D-알라니네이트를 순도 97.57 GC면적%, 수율 83%(11.49 g, 41.13 mmol)로 얻었다. 이때, 수득된 메틸 N-(2,6-디메틸페닐)-N-(메톡시아세틸)-D-알라니네이트의 전체 GC 면적을 기준으로, 유전독성 물질은 0.19 면적%였다.After adding NaHCO 3 (5.41 g, 64.43 mmol) and toluene (40 mL), the mixture was cooled to -5°C to 0°C, and then methoxyacetyl chloride (6.99 g, 64.43 mmol) was added dropwise. After completion of the dropwise addition, the mixture was stirred for 3 hours to maintain an internal temperature of 10 ° C to 15 ° C. After confirming that the unreacted methyl N-(2,6-dimethylphenyl)-D-alaninate remaining in the reaction mixture was 1.0 area% or less (GC analysis result), H 2 O (40 mL) was added, and then 1N NaOH was added dropwise to confirm pH 7-8, and then the layers were separated and the aqueous layer was discarded. H 2 O (20 mL) was added to the separated organic layer, and the layers were separated after stirring, and the aqueous layer was discarded. After filtering the separated organic layer to remove foreign substances, it was concentrated under reduced pressure to obtain methyl N-(2,6-dimethylphenyl)-N-(methoxyacetyl)-D-alaninate with a purity of 97.57 GC area% and a yield of 83% (11.49 g, 41.13 mmol). At this time, based on the total GC area of the obtained methyl N-(2,6-dimethylphenyl)-N-(methoxyacetyl)-D-alaninate, the genotoxic substance was 0.19 area%.
[실험예 1][Experimental Example 1]
실시예 1, 2 및 비교예 1의 합성의 각단계에서 시료를 채취했고, GC / FID(Gas Chromatography with Flame Ionization Detector)분석은 Shimadzu, GC-2030을 이용하여 하기 조건으로 측정했다. 그 결과를 하기 표 1에 정리했다. 이때, 각 순도 및 함량은 GC/FID로 전체 GC area를 기준으로 GC area%를 의미한다.Samples were taken at each step of the synthesis of Examples 1 and 2 and Comparative Example 1, and GC / FID (Gas Chromatography with Flame Ionization Detector) analysis was measured using Shimadzu, GC-2030 under the following conditions. The results are summarized in Table 1 below. At this time, each purity and content is GC / FID, which means GC area% based on the entire GC area.
Column: [HP-5 ] (0.25 mm ID × 30 m L, 0.25 μm d.f. capillary)Column: [HP-5 ] (0.25 mm ID × 30 m L, 0.25 μm d.f. capillary)
Oven temperatureOven temperature
Initial Value & Hold Time: 50℃ 5minInitial Value & Hold Time: 50℃ 5min
Program Rate: 10℃/minProgram Rate: 10℃/min
Final Value & Hold Time: 320℃, 18 minFinal Value & Hold Time: 320℃, 18min
Injector temperature: 340℃Injector temperature: 340℃
Detector temperature: 340℃Detector temperature: 340℃
Gas Flow rate: Column(N2): 1 mL/minGas Flow rate: Column (N 2 ): 1 mL/min
Split ratio: 1/20Split ratio: 1/20
Injection volume: 1.0 uLInjection volume: 1.0 uL
화학식 1의
L-lactic acid 함유량of Formula 1
L-lactic acid content 		화학식 5
증류여부Formula 5
distillation 		화학식 7
순도(GC면적%)Formula 7
Purity (GC area%) 		화학식 10의
함량(면적%)of Formula 10
Content (area %)
비교예 1Comparative Example 1 0.20 면적%
(증류 X)0.20 area %
(Distillation X) 		증류 XDistillation X 97.5797.57 0.190.19
실시예 1Example 1 0.05 면적%
(증류 O)0.05 area %
(distilled O) 		증류 ODistillation O 98.8298.82 0.020.02
실시예 2Example 2 0.05 면적%
(증류 O)0.05 area %
(distilled O) 		증류 XDistillation X 97.6297.62 0.110.11
상기 표 1을 통해, 증류를 한번도 수행하지 않은 비교예 1은 최종 화합물의 순도도 낮고, 화학식 10의 불순물의 함량이 높은 것을 알 수 있다. 화학식 1의 화합물만 증류한 실시예 2와 비교하더라도, 화학식 1 및 5의 화합물에 대해 모두 증류를 수행한 실시예 1이 더 높은 순도와 화학식 10의 불순물의 함량이 낮은 것을 확인할 수 있다.From Table 1, it can be seen that Comparative Example 1, in which no distillation was performed, had a low purity of the final compound and a high content of impurities represented by Chemical Formula 10. Even when compared with Example 2 in which only the compound of Formula 1 was distilled, Example 1 in which distillation was performed on both the compounds of Formulas 1 and 5 showed higher purity and a lower content of impurities of Formula 10.

Claims (12)

  1. 하기 화학식 1의 화합물을 포함하는 제1 조성물을 증류하는 단계;distilling a first composition comprising a compound represented by Formula 1;
    상기 증류된 제1 조성물에 하기 화학식 2의 화합물을 첨가하여 하기 화학식 3의 화합물을 합성하는 단계;synthesizing a compound of Formula 3 below by adding a compound of Formula 2 to the distilled first composition;
    상기 화학식 3의 화합물을 하기 화학식 4의 화합물과 반응시켜 하기 화학식 5의 화합물을 합성하는 단계; 및synthesizing a compound of Formula 5 by reacting the compound of Formula 3 with a compound of Formula 4; and
    상기 화학식 5의 화합물을 하기 화학식 6의 화합물과 반응시켜 하기 화학식 7의 화합물을 합성하는 단계를 포함하는 N-아실 유도체의 제조방법:A method for preparing an N-acyl derivative comprising synthesizing a compound of Formula 7 by reacting the compound of Formula 5 with a compound of Formula 6:
    [화학식 1][Formula 1]
    Figure PCTKR2022009352-appb-img-000037
    Figure PCTKR2022009352-appb-img-000037
    [화학식 2][Formula 2]
    Figure PCTKR2022009352-appb-img-000038
    Figure PCTKR2022009352-appb-img-000038
    [화학식 3][Formula 3]
    Figure PCTKR2022009352-appb-img-000039
    Figure PCTKR2022009352-appb-img-000039
    [화학식 4][Formula 4]
    Figure PCTKR2022009352-appb-img-000040
    Figure PCTKR2022009352-appb-img-000040
    [화학식 5][Formula 5]
    Figure PCTKR2022009352-appb-img-000041
    Figure PCTKR2022009352-appb-img-000041
    [화학식 6][Formula 6]
    Figure PCTKR2022009352-appb-img-000042
    Figure PCTKR2022009352-appb-img-000042
    [화학식 7][Formula 7]
    Figure PCTKR2022009352-appb-img-000043
    Figure PCTKR2022009352-appb-img-000043
    상기 화학식 1 내지 7에서, In Formulas 1 to 7,
    R1은 메틸기 또는 메틸기로 치환된 아릴기이며, R1 is a methyl group or an aryl group substituted with a methyl group;
    R2 및 R3은 서로 같거나 상이하고, 각각 독립적으로 수소; 중수소; 또는 메틸기이고, R2 and R3 are the same as or different from each other, and each independently hydrogen; heavy hydrogen; or a methyl group;
    R4 및 R5는 메틸기이다.R4 and R5 are methyl groups.
  2. 청구항 1에 있어서, 상기 화학식 5의 화합물을 포함하는 제2 조성물을 증류하는 단계를 더 포함하고, The method according to claim 1, further comprising the step of distilling the second composition containing the compound of Formula 5,
    상기 화학식 7의 화합물을 합성하는 단계는 상기 증류된 제2 조성물에 하기 화학식 6의 화합물을 첨가하여 상기 화학식 7의 화합물을 합성하는 단계인 것인 N-아실 유도체의 제조방법.The step of synthesizing the compound of Formula 7 is a step of synthesizing the compound of Formula 7 by adding the compound of Formula 6 to the distilled second composition.
  3. 하기 화학식 1의 화합물을 포함하는 제1 조성물의 전체 GC 면적을 기준으로, 하기 화학식 8의 화합물의 함량이 0.05 면적% 이하인 제1 조성물에 하기 화학식 2의 화합물을 첨가하여 하기 화학식 3의 화합물을 합성하는 단계;Based on the total GC area of the first composition containing the compound of Formula 1, the compound of Formula 2 is added to the first composition in which the content of the compound of Formula 8 is 0.05 area% or less to synthesize a compound of Formula 3 below doing;
    상기 화학식 3의 화합물을 하기 화학식 4의 화합물과 반응시켜 하기 화학식 5의 화합물을 합성하는 단계; 및synthesizing a compound of Formula 5 by reacting the compound of Formula 3 with a compound of Formula 4; and
    상기 화학식 5의 화합물을 하기 화학식 6의 화합물과 반응시켜 하기 화학식 7의 화합물을 합성하는 단계를 포함하는 N-아실 유도체의 제조방법:A method for preparing an N-acyl derivative comprising synthesizing a compound of Formula 7 by reacting the compound of Formula 5 with a compound of Formula 6:
    [화학식 1][Formula 1]
    Figure PCTKR2022009352-appb-img-000044
    Figure PCTKR2022009352-appb-img-000044
    [화학식 2][Formula 2]
    Figure PCTKR2022009352-appb-img-000045
    Figure PCTKR2022009352-appb-img-000045
    [화학식 3][Formula 3]
    Figure PCTKR2022009352-appb-img-000046
    Figure PCTKR2022009352-appb-img-000046
    [화학식 4][Formula 4]
    Figure PCTKR2022009352-appb-img-000047
    Figure PCTKR2022009352-appb-img-000047
    [화학식 5][Formula 5]
    Figure PCTKR2022009352-appb-img-000048
    Figure PCTKR2022009352-appb-img-000048
    [화학식 6][Formula 6]
    Figure PCTKR2022009352-appb-img-000049
    Figure PCTKR2022009352-appb-img-000049
    [화학식 7][Formula 7]
    Figure PCTKR2022009352-appb-img-000050
    Figure PCTKR2022009352-appb-img-000050
    [화학식 8][Formula 8]
    Figure PCTKR2022009352-appb-img-000051
    Figure PCTKR2022009352-appb-img-000051
    상기 화학식 1 내지 7에서, In Formulas 1 to 7,
    R1은 메틸기 또는 메틸기로 치환된 아릴기이며, R1 is a methyl group or an aryl group substituted with a methyl group;
    R2 및 R3은 서로 같거나 상이하고, 각각 독립적으로 수소; 중수소; 또는 메틸기이고, R2 and R3 are the same as or different from each other, and each independently hydrogen; heavy hydrogen; or a methyl group;
    R4 및 R5는 메틸기이다.R4 and R5 are methyl groups.
  4. 청구항 3에 있어서, 상기 화학식 7의 화합물을 합성하는 단계는,The method according to claim 3, wherein synthesizing the compound of Formula 7 comprises:
    상기 화학식 5의 화합물을 포함하는 제2 조성물의 전체 GC 면적을 기준으로, 하기 화학식 9의 화합물의 함량이 0.05 면적% 이하인 제2 조성물에 상기 화학식 6의 화합물을 첨가하여 상기 화학식 7의 화합물을 합성하는 것인 N-아실 유도체의 제조방법:Synthesis of the compound of Formula 7 by adding the compound of Formula 6 to a second composition in which the content of the compound of Formula 9 is 0.05 area% or less based on the total GC area of the second composition containing the compound of Formula 5 Method for producing an N-acyl derivative that is to:
    [화학식 9][Formula 9]
    Figure PCTKR2022009352-appb-img-000052
    Figure PCTKR2022009352-appb-img-000052
    상기 화학식 9에서, In Formula 9,
    R2 및 R3은 서로 같거나 상이하고, 각각 독립적으로 수소; 중수소; 또는 메틸기이고, R2 and R3 are the same as or different from each other, and each independently hydrogen; heavy hydrogen; or a methyl group;
    R4는 메틸기이다.R4 is a methyl group.
  5. 청구항 1에 있어서, 상기 제1 조성물을 증류하는 단계는, 40 torr 내지 60 torr의 압력과, 70℃ 내지 100℃의 온도에서 상기 제1 조성물을 증류하는 것인 N-아실 유도체의 제조방법.The method of claim 1, wherein the distilling of the first composition is distilling the first composition at a pressure of 40 torr to 60 torr and a temperature of 70°C to 100°C.
  6. 청구항 2에 있어서, 상기 제2 조성물을 증류하는 단계는, 2 torr 내지 20 torr의 압력과, 130℃ 내지 200℃의 온도에서 상기 조성물을 증류하는 것인 N-아실 유도체의 제조방법.The method for preparing an N-acyl derivative according to claim 2, wherein the distilling of the second composition is distilling the composition at a pressure of 2 torr to 20 torr and a temperature of 130°C to 200°C.
  7. 청구항 1에 있어서, 상기 제1 조성물을 증류하는 단계는, 상기 제1 조성물의 전체 GC 면적을 기준으로, 하기 화학식 8의 화합물의 함량이 0.05 면적% 이하인 제1 조성물을 제조하는 단계인 것인 N-아실 유도체의 제조방법:The method according to claim 1, wherein the step of distilling the first composition is a step of preparing a first composition in which the content of the compound of Formula 8 is 0.05 area% or less based on the total GC area of the first composition N -Method for preparing acyl derivatives:
    [화학식 8][Formula 8]
    Figure PCTKR2022009352-appb-img-000053
    Figure PCTKR2022009352-appb-img-000053
  8. 청구항 2에 있어서, 상기 제2 조성물을 증류하는 단계는, 상기 조성물의 전체 GC 면적을 기준으로, 하기 화학식 9의 화합물의 함량이 0.05 면적% 이하인 제2 조성물을 제조하는 단계인 것인 N-아실 유도체의 제조방법:The N-acyl of claim 2, wherein the step of distilling the second composition is a step of preparing a second composition in which the content of the compound of Formula 9 is 0.05 area% or less based on the total GC area of the composition. Method for preparing the derivative:
    [화학식 9][Formula 9]
    Figure PCTKR2022009352-appb-img-000054
    Figure PCTKR2022009352-appb-img-000054
    상기 화학식 9에서, In Formula 9,
    R2 및 R3은 서로 같거나 상이하고, 각각 독립적으로 수소; 중수소; 또는 메틸기이고, R2 and R3 are the same as or different from each other, and each independently hydrogen; heavy hydrogen; or a methyl group;
    R4는 메틸기이다.R4 is a methyl group.
  9. 청구항 1 또는 3에 있어서, 상기 합성된 화학식 7의 화합물을 정제하는 단계를 더 포함하고, The method according to claim 1 or 3, further comprising purifying the synthesized compound of Formula 7,
    상기 정제된 화학식 7의 화합물을 포함하는 제3 조성물의 전체 GC 면적을 기준으로, 하기 화학식 10의 화합물의 함량이 0.05 면적% 이하인 것인 N-아실 유도체의 제조방법:A method for preparing an N-acyl derivative wherein the content of the compound of Formula 10 is 0.05 area% or less based on the total GC area of the third composition containing the purified compound of Formula 7:
    [화학식 10][Formula 10]
    Figure PCTKR2022009352-appb-img-000055
    Figure PCTKR2022009352-appb-img-000055
    상기 화학식 10에서,In Formula 10,
    R2 및 R3은 서로 같거나 상이하고, 각각 독립적으로 수소; 중수소; 또는 메틸기이고, R2 and R3 are the same as or different from each other, and each independently hydrogen; heavy hydrogen; or a methyl group;
    R4 및 R5는 메틸기이다.R4 and R5 are methyl groups.
  10. 하기 화학식 7의 화합물과, 하기 화학식 10의 화합물을 포함하는 조성물에서,In a composition comprising a compound of Formula 7 and a compound of Formula 10 below,
    상기 조성물의 전체 GC 면적을 기준으로, 하기 화학식 10의 화합물의 함량이 0.05 면적% 이하인 조성물:A composition in which the content of the compound of Formula 10 is 0.05 area% or less based on the total GC area of the composition:
    [화학식 7][Formula 7]
    Figure PCTKR2022009352-appb-img-000056
    Figure PCTKR2022009352-appb-img-000056
    [화학식 10][Formula 10]
    Figure PCTKR2022009352-appb-img-000057
    Figure PCTKR2022009352-appb-img-000057
    상기 화학식 7 및 10에서,In Formulas 7 and 10,
    R2 및 R3은 서로 같거나 상이하고, 각각 독립적으로 수소; 중수소; 또는 메틸기이고, R2 and R3 are the same as or different from each other, and each independently hydrogen; heavy hydrogen; or a methyl group;
    R4 및 R5는 메틸기이다.R4 and R5 are methyl groups.
  11. 청구항 10의 조성물을 포함하는 의약품.A pharmaceutical comprising the composition of claim 10.
  12. 청구항 10의 조성물을 포함하는 농업용품.An agricultural product comprising the composition of claim 10.
PCT/KR2022/009352 2021-06-29 2022-06-29 Method for preparing n-acyl derivative, composition, and pharmaceutical or agricultural product containing same WO2023277587A1 (en)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996001559A1 (en) * 1994-07-11 1996-01-25 Ciba-Geigy Ag Fungicidal composition and method of controlling fungus infestation
WO1998026654A2 (en) * 1996-12-19 1998-06-25 Isagro S.P.A. Fungicidal compositions based on (n-phenylacetyl-n-2,6-xylyl)methyl alaninate
WO2000076960A1 (en) * 1999-06-15 2000-12-21 Isagro S.P.A. Process for the preparation of optically active n-acyl derivatives of methyl n-(2,6-dimethylphenyl)-d-alaninate
WO2014125020A1 (en) * 2013-02-14 2014-08-21 Purac Biochem Bv Method for preparing methyl lactate

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996001559A1 (en) * 1994-07-11 1996-01-25 Ciba-Geigy Ag Fungicidal composition and method of controlling fungus infestation
WO1998026654A2 (en) * 1996-12-19 1998-06-25 Isagro S.P.A. Fungicidal compositions based on (n-phenylacetyl-n-2,6-xylyl)methyl alaninate
WO2000076960A1 (en) * 1999-06-15 2000-12-21 Isagro S.P.A. Process for the preparation of optically active n-acyl derivatives of methyl n-(2,6-dimethylphenyl)-d-alaninate
WO2014125020A1 (en) * 2013-02-14 2014-08-21 Purac Biochem Bv Method for preparing methyl lactate

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Title
GOZZO F., ET AL.: "RECENT PROGRESS IN THE FIELD OF N-ACYLALANINES AS SYSTEMIC FUNGICIDES.", PESTICIDE SCIENCE., ELSEVIER APPLIED SCIENCE PUBLISHER. BARKING., GB, vol. 16., 1 January 1985 (1985-01-01), GB , pages 277 - 286., XP002064239, ISSN: 0031-613X *

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