WO2023277587A1 - Procédé de préparation d'un dérivé de n-acyle, composition et produit pharmaceutique ou agricole le contenant - Google Patents

Procédé de préparation d'un dérivé de n-acyle, composition et produit pharmaceutique ou agricole le contenant Download PDF

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Publication number
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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English (en)
Korean (ko)
Inventor
강명구
김지원
안병훈
이경원
이원재
정대연
조재하
Original Assignee
주식회사 엘지화학
주식회사 팜한농
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Priority to CN202280014397.2A priority Critical patent/CN116829531A/zh
Publication of WO2023277587A1 publication Critical patent/WO2023277587A1/fr

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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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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Agronomy & Crop Science (AREA)
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  • Emergency Medicine (AREA)
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  • Engineering & Computer Science (AREA)
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  • Wood Science & Technology (AREA)
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  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention concerne un procédé de préparation d'un dérivé de N-acyle par distillation d'une première composition comprenant un composé de formule chimique 1 et d'utilisation de la première composition distillée, un dérivé de N-acyle préparé par celui-ci, et un produit pharmaceutique ou agricole le comprenant.
PCT/KR2022/009352 2021-06-29 2022-06-29 Procédé de préparation d'un dérivé de n-acyle, composition et produit pharmaceutique ou agricole le contenant WO2023277587A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202280014397.2A CN116829531A (zh) 2021-06-29 2022-06-29 制备n-酰基衍生物的方法、组合物和包含其的药物或农产品

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KR10-2021-0084509 2021-06-29
KR20210084509 2021-06-29

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WO2023277587A1 true WO2023277587A1 (fr) 2023-01-05

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WO (1) WO2023277587A1 (fr)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996001559A1 (fr) * 1994-07-11 1996-01-25 Ciba-Geigy Ag Composition fongicide et procede de lutte contre une infestation par des champignons
WO1998026654A2 (fr) * 1996-12-19 1998-06-25 Isagro S.P.A. Compositions fongicides a base de (n-phenylacetyl-n-2,6-xylyl)methyl alaninate
WO2000076960A1 (fr) * 1999-06-15 2000-12-21 Isagro S.P.A. Processus de preparation de derives optiquement actifs de n-acyles de methyle n- (2,6-dimethylephenyle) -d-alaninate
WO2014125020A1 (fr) * 2013-02-14 2014-08-21 Purac Biochem Bv Procédé de préparation de lactate de méthyle

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996001559A1 (fr) * 1994-07-11 1996-01-25 Ciba-Geigy Ag Composition fongicide et procede de lutte contre une infestation par des champignons
WO1998026654A2 (fr) * 1996-12-19 1998-06-25 Isagro S.P.A. Compositions fongicides a base de (n-phenylacetyl-n-2,6-xylyl)methyl alaninate
WO2000076960A1 (fr) * 1999-06-15 2000-12-21 Isagro S.P.A. Processus de preparation de derives optiquement actifs de n-acyles de methyle n- (2,6-dimethylephenyle) -d-alaninate
WO2014125020A1 (fr) * 2013-02-14 2014-08-21 Purac Biochem Bv Procédé de préparation de lactate de méthyle

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
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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KR20230002110A (ko) 2023-01-05

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