KR0123414B1 - Novel abscisic acid derivatives with fluorine - Google Patents
Novel abscisic acid derivatives with fluorineInfo
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- KR0123414B1 KR0123414B1 KR1019940015476A KR19940015476A KR0123414B1 KR 0123414 B1 KR0123414 B1 KR 0123414B1 KR 1019940015476 A KR1019940015476 A KR 1019940015476A KR 19940015476 A KR19940015476 A KR 19940015476A KR 0123414 B1 KR0123414 B1 KR 0123414B1
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- C—CHEMISTRY; METALLURGY
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- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/40—Unsaturated compounds
- C07C59/76—Unsaturated compounds containing keto groups
- C07C59/88—Unsaturated compounds containing keto groups containing halogen
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
- C07C57/52—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing halogen
- C07C57/56—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing halogen containing rings other than six-membered aromatic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/40—Unsaturated compounds
- C07C59/42—Unsaturated compounds containing hydroxy or O-metal groups
- C07C59/56—Unsaturated compounds containing hydroxy or O-metal groups containing halogen
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- C—CHEMISTRY; METALLURGY
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/62—Halogen-containing esters
- C07C69/65—Halogen-containing esters of unsaturated acids
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Abstract
Description
본 발명은 신규한 불소치환 아브시스산 유도체에 관한 것이다. 좀 더 구체적으로, 본 발명은 하기 일반식(Ⅰ) 및 (Ⅱ)로 표시되는 신규한 불소치환 아브시스산 유도체와 그의 제조방법 및 식물생장조절제로서의 용도에 관한 것이다.The present invention relates to a novel fluorine-substituted absic acid derivative. More specifically, the present invention relates to novel fluorine-substituted absic acid derivatives represented by the following general formulas (I) and (II), methods for their preparation and use as plant growth regulators.
상기식에서, X는 H2또는 O이고; Y는 H 또는 OH이며; 및, R은 H 또는 탄소수 1 내지 2개의 알킬기이다.Wherein X is H 2 or O; Y is H or OH; And R is H or an alkyl group having 1 to 2 carbon atoms.
아브시스산(Abscisic acid, ABA)은 하기 구조식을 갖는 식물호르몬의 일종으로서, 다른 식물호르몬과는 달리 식물의 생장을 억제하는 생리작용을 나타낸다. 아울러, 여러 가지 스트레스를 받은 식물체 내에 아브시스산의 농도가 증대되는 것으로 보아, 각종 직물의 항 스트레스제로서 이용할 수 있는 가능성이 매우 큰 화합물로 알려지고 있다.Abscisic acid (ABA) is a type of plant hormone having the following structural formula, and unlike other plant hormones, it exhibits a physiological effect of inhibiting plant growth. In addition, since the concentration of abscisic acid is increased in various stressed plants, it is known that the compound has a high possibility of being used as an antistress agent for various textiles.
아브시스산 유도체의 구조 및 활성의 상관관계에 관하여는 수많은 연구가 축적되어 활성발현에 필요한 구조에 관해서도 대략 알려져 있다. 이에 의하면, C-3, C-2' 의 메틸기가 활성발현에 중요하며, 측쇄의 이중결합이 2-cis -4-trans의 구조를 가져야 한다는 것 등으로 요약할 수 있다.Numerous studies have been accumulated about the structure and activity of the absic acid derivatives, and the structure required for the active expression is also known. According to this, it can be summarized that the methyl group of C-3, C-2 'is important for activity expression, and the double bond of the side chain should have the structure of 2-cis-4-trans.
다른 식물호르몬들이 산업적으로 실용화되어진 것과는 달리, 중요한 생리 활성을 나타내면서도 아브시스산은 아직까지 실용화에 이르지 못하고 있으며, 현재에 이르기까지 수많은 아브시스산 유도체가 합성되어졌지만 아직도 아브시스산을 증가하는 활성을 타나내는 화합물은 발견되지 않고 있다. 그 이유로서는 첫째, 천연의 아브시스산은 불안정하여 빛에 의해 쉽게 측쇄의 이중결합이 2-trans-4-trans의 구조로 이성화 되어 불활성화되며; 둘째, 식물체 내에서 쉽게 대사되어 활성을 발현하는데 필요한 농도가 유지되지 않는다는 것 등을 들 수 있다.Unlike other plant hormones that have been industrially used, abscisic acid has not yet been put to practical use, although it exhibits significant physiological activity. To date, numerous absic acid derivatives have been synthesized, but still have activity of increasing abscitic acid. No compound is found. The reason for this is as follows: First, natural abscisic acid is unstable, and the side chain double bond isomerized easily by light to inactivate the structure of 2-trans-4-trans; Second, the concentration necessary for expressing the activity easily metabolized in the plant is not maintained.
한편, 아브시스산의 구조중 일부를 변형하여 상기의 문제점을 극복하려는 여러 가지 시도가 행하여져 왔다: 본 발명의 아스시스산 유도체와 관련이 있는 화합물에 대하여는 일본 공개특허공보 평3-2102, 유럽 공개특허 EP 87,638 및 유럽 공개특허 EP 77,439 등에 공지되어 있다. 그러나, 이들은 불소치환제를 포함하지 있지 않을 뿐만 아니라, 생리활성면에서도 아브시스산에 비하여 현저히 낮은 것으로 판명되었다. 또한, 아브시스산의 측쇄부를 변형한 유도체는 일본 공개 특허공보 평1-254638 및 일본 공개특허공보 평5-97844 등에 공지되어 있다. 그러나, 이들 역시 불소치환제를 포함하고 있지 않을 뿐만 아니라, 생리 활성면에서도 아브시스산에 비하여 현저히 낮은 것으로 판명되었다.On the other hand, various attempts have been made to overcome some of the above problems by modifying some of the structures of absic acid: Japanese Patent Laid-Open No. H3-2102, European Publication, for compounds related to the assis acid derivatives of the present invention; Patent EP 87,638 and European Patent EP 77,439 and the like. However, they did not contain a fluorine-substituent and were found to be significantly lower than abscinic acid in terms of physiological activity. Derivatives in which the side chain moiety of absciic acid are modified are known from Japanese Patent Application Laid-open No. Hei 1-254638, Japanese Patent Application Laid-open No. Hei 5-97844 and the like. However, they also did not contain a fluorine-substituent and were found to be remarkably lower in comparison with absic acid in terms of physiological activity.
이에, 본 발명자들은 아브시스산의 C-2 위치의 수소를 불소로 치환시킨 2-플루오로아브시스산은 2-cis로부터 2-trans로 이성화하는데 아스시스산 보다 많은 에너지가 필요하므로, 아브시스산에 비하여 2-플루오로아브시스산이 보다 안정할 뿐만 아니라 생리활성의 증가와 함께 장기적 발현이 가능할 것이라는 점에 착안하여 예의 연구를 거듭한 결과, 신규한 불소치환 아브시스산 유도체를 1 내지 2단계의 공정을 사용하여 합성하고, 아울러 간편하게 대량으로 제조할 수 있는 방법을 알아내고 본 발명을 완성하게 되었다.Accordingly, the inventors of the present invention have found that 2-fluoroabbisic acid in which hydrogen at the C-2 position of abscisic acid is replaced with fluorine requires more energy than assis acid to isomerize from 2-cis to 2-trans. Compared to the fact that 2-fluoroabsic acid is not only more stable but also long-term expression with increased physiological activity, the results of intensive studies have shown that the novel fluorine-substituted abscides derivatives can The present invention has been accomplished by finding a method that can be synthesized using a process and can be easily produced in large quantities.
결국, 본 발명의 제1목적은 상기 일반식(Ⅰ) 및 (Ⅱ)로 표시되는 불소가 치환된 아브시스산 유도체를 제공하는데 있다.As a result, the first object of the present invention is to provide a fluorine-substituted absic acid derivative represented by the general formulas (I) and (II).
본 발명의 제2목적은 상기 일반식(Ⅰ) 및 (Ⅱ)로 표시되는 불소가 치환된 아브시스산 유초체의 제조방법을 제공하는데 있다.A second object of the present invention is to provide a method for producing an fluoric acid-substituted acetic acid derivative represented by the general formulas (I) and (II).
본 발명의 제3목적은 상기 일반식(Ⅰ) 및 (Ⅱ)로 표시되는 불소가 치환된 아브시스산 유도체를 포함하는 식물생장조절제로서의 용도를 제공하는데 있다.A third object of the present invention is to provide a use as a plant growth regulator comprising a fluorine-substituted absic acid derivative represented by the general formulas (I) and (II).
본 발명의 불소치환된 아브시스산 유도체는 다양한 반응경로를 통해 제조될 수 있으나, 이하에서는, 그중 대표적인-반응경로를 설명한다.Although the fluorine-substituted absic acid derivatives of the present invention can be prepared through various reaction pathways, the following describes a representative-reaction pathway among them.
본 발명에서 상기 일반식(Ⅰ) 및 (Ⅱ)로 표시되는 불소치환 아브시스산 유도체는 하기 구조식(Ⅲ)으로 표시되는 트리메틸 2-플루오로포스포노아세테이트 및 하기 일반식(Ⅳ)로 표시되는 α-요논(α-ionone)유도체의 반응을 포함하는 일련의 반응에 의해 제조한다. 이때, 본 발명에서 출발물질로 사용하는 하기 구조식(Ⅲ)으로 표시되는 트리에틸 2-플루오로포스포노아세테이트는 불소치환 비닐기의 구축에 사용되며 아브시스산의 측쇄에 불소글 도입하는데 유용하게 사용된는 화합물체로서 에틸 2-브로모-2-플루오로아세테이트에 트리에틸포스파이트를 반응시켜 고수율로 얻을 수 있으며, 하기 일반식(Ⅳ)로 표시되는 α-요논유도체는 아브시스산 유도체의 합성에 유용한 중간체로서 α-요논 또는 β-요논을 산화반응시켜 얻을 수 있다.In the present invention, the fluorine-substituted absic acid derivatives represented by the general formulas (I) and (II) are trimethyl 2-fluorophosphonoacetate represented by the following structural formula (III) and α represented by the following general formula (IV). Prepared by a series of reactions involving the reaction of α-ionone derivatives. At this time, triethyl 2-fluorophosphonoacetate represented by the following structural formula (III) used as a starting material in the present invention is used for the construction of a fluorine-substituted vinyl group and usefully used to introduce fluorine into the side chain of absciic acid. Can be obtained in high yield by reacting triethyl phosphite with ethyl 2-bromo-2-fluoroacetate as a compound, α-nonone derivative represented by the general formula (IV) As intermediates useful for the preparation, they can be obtained by oxidation of? -Nonon or? -Nonon.
상기식에서, X는 H2또는 O이고; Y는 H 또는 OH이다.Wherein X is H 2 or O; Y is H or OH.
본 발명의 유도체는 하기의 공정을 통해 제조될 수 있으나, 이들 방법이 본 발명의 제조방법을 한정하는 것은 아니다.Derivatives of the present invention can be prepared through the following process, but these methods do not limit the preparation method of the present invention.
[제1공정 : 트리에틸 2-플루오로포스포노아세테이트의 제조공정][Step 1: Preparation of Triethyl 2-Fluorophosphonoacetate]
상기 일반식(Ⅲ)으로 표시되는 트리에틸 2-플루오로포스포아세테이트는 에틸 2-브로모-2-플루오로아세테이트를 트리에틸 포스파이트와 반응시켜 얻을 수 있다. 이때, 용매로는 벤젠, 톨루엔 및 크실렌 등의 반응에 악영향을 주지 않는 용매를 단독 또는 2종 이상 혼합하여 사용할 수 있다. 반응온도는 특별히 한정된 것은 아니나, 용매의 비점범위의 온도가 적당하며, 반응시간은 20시간이 바람직하다.Triethyl 2-fluorophosphoacetate represented by the above general formula (III) can be obtained by reacting ethyl 2-bromo-2-fluoroacetate with triethyl phosphite. At this time, as the solvent, a solvent which does not adversely affect the reaction of benzene, toluene, xylene and the like may be used alone or in combination of two or more thereof. Although reaction temperature is not specifically limited, The temperature of the boiling point range of a solvent is suitable, and reaction time is preferable 20 hours.
상기의 제1공정을 반응식으로 표시하면 다음과 같다:Representing the first step in the reaction scheme is as follows:
제1공정:First step:
[제2공정 : α-요논 유도체의 제조공정][Second Step: Manufacturing Step of α-Yonon Derivative]
상기 일반식(Ⅳ)로 표시되는 α-요논 유도체는 다음과 같은 방법을 통하여 제조될 수 있다:The α-nonon derivative represented by the general formula (IV) may be prepared by the following method:
하기 구조식(Ⅳ-a)로 표시되는 α-요논 유도체는 하기 구조식(Ⅳ-d)로 표시되는 α-요논을 직접 산화반응시켜 얻을 수 있다. 이때, 용매로는 알콜, 피리딘, 이염화탄소 및 사염화탄소 등과 같은 반응에 악영향을 주지 않는 용매를 단독 또는 2종 이상 혼합항여 사용할 수 있다. 반응온도는 특별히 한정된 것은 아니나, 상온부터 용매의 비점범위 내의 온도가 바람직하며, 반응시간은 2 내지 20시간이 바람직하다. 또한, 산화제로는 t-부틸크로메이트를 비롯하여 크롬산, 존스시약 및 피리딘 클로로크로메이트 등을 사용할 수 있다.The α-nonon derivative represented by the following structural formula (IV-a) can be obtained by directly oxidizing the α-nonon represented by the following structural formula (IV-d). In this case, as the solvent, a solvent which does not adversely affect the reaction such as alcohol, pyridine, carbon dichloride and carbon tetrachloride may be used alone or in combination of two or more thereof. Although reaction temperature is not specifically limited, The temperature in the boiling point range of a solvent is preferable from normal temperature, and the reaction time of 2 to 20 hours is preferable. As the oxidizing agent, t-butyl chromate, chromic acid, Jones reagent, pyridine chlorochromate and the like can be used.
하기 구조식(Ⅳ-b)로 표시되는 α-요논 유도체는 β-요논을 에폭시화한 다음, 개환반응시켜 얻을 수 있다. 이때 에폭시화반응에 사용하는 산화제로는 과산화 수소산, 과산화 아세트산, 과산화 벤조산 및 과산화 메타클로로벤조산 등이 사용될 수 있으며, 용매로는 사염화탄소, 삼염화탄소 및 이염화탄소 등과 같은 반응에 악영향을 주지 않는 용매를 단독 또는 2종 이상 혼합하여 사용할 수 있다. 반응온도는 특별히 한정된 것은 아니다. -78℃부터 용매의 비점범위 내의 온도가 바람직하며, 반응시간은 2 내지 20시간이 바람직하다. 개환반응에 사용하는 염기로는 수산화 나트륨, 페닐 리튬 및 디에틸아민 리튬 등을 사용할 수 있으며, 용매로는 사염화탄소, 삼염화탄소, 이염화탄소 및 테트라히드로후한 등과 같은 반응에 악영향을 주지 않는 용매를 사용할 수 있다. 반응온도는 특별히 한정된 것은 아니다. 상온부터 용매의 비점범위 내의 온도가 바람직하며, 반응시간을 2 내지 20시간이 바람직하다.The α-nonon derivative represented by the following structural formula (IV-b) can be obtained by epoxidizing β-nonon and then ring-opening. At this time, as the oxidizing agent used in the epoxidation reaction, hydrogen peroxide, acetic acid peroxide, benzoic acid peroxide and metachlorobenzoic acid peroxide may be used, and as a solvent, a solvent which does not adversely affect the reaction such as carbon tetrachloride, carbon trichloride, and carbon dichloride may be used alone. Or it can mix and use 2 or more types. The reaction temperature is not particularly limited. The temperature within the boiling point range of the solvent is preferably from -78 ° C, and the reaction time is preferably 2 to 20 hours. Sodium hydroxide, phenyl lithium and diethylamine lithium can be used as the base used for the ring-opening reaction, and a solvent which does not adversely affect the reaction such as carbon tetrachloride, carbon trichloride, carbon dichloride and tetrahydrocarbon can be used as the solvent. have. The reaction temperature is not particularly limited. The temperature within the boiling point range of the solvent is preferred from normal temperature, and the reaction time is preferably 2 to 20 hours.
또한, 하기 구조식(Ⅳ-c)로 표시되는 α-요논 유도체는 α요논(Ⅳ-d)을 산화반응시켜 얻을 수 있다.In addition, the alpha-onon derivative represented by the following structural formula (IV-c) can be obtained by oxidizing α-nonon (IV-d).
이때, 용매로는 알콜, 피리딘, 이염화탄소 및 사염화탄소 등과 같은 반응에 악영향을 주지 않는 용매를 단독 또는 2종 이상 혼합하여 사용할 수 있다. 반응온도는 특별히 한정된 것은 아니나, 상온부터 용매의 비점범위내의 온도가 적당하며, 반응시간은 2 내지 20시간이 바람직하다. 또한, 산화제로는 t-부틸크로메이트를 비롯하여 크롬산, 존스시약 및 피리딘 클로로크로메이트 등을 사용할 수 있다.In this case, as the solvent, a solvent which does not adversely affect the reaction such as alcohol, pyridine, carbon dichloride and carbon tetrachloride may be used alone or in combination of two or more thereof. The reaction temperature is not particularly limited, but a temperature within a boiling point range of the solvent from normal temperature is suitable, and the reaction time is preferably 2 to 20 hours. As the oxidizing agent, t-butyl chromate, chromic acid, Jones reagent, pyridine chlorochromate and the like can be used.
상기의 제2공정을 반응식으로 표시하면 다음과 같다:Representing the second step in the reaction scheme is as follows:
제2공정 :Second Step:
[제3공정 : 불소치환 아브시스산 유도체의 제조공정][Step 3: Preparation of Fluorine-Substituted Absic Acid Derivatives]
상기 일반식(Ⅰ) 및 (Ⅱ)로 표시되는 불소치환 아브시스산 유도체는 다음과 같은 방법을 통하여 제조할 수 있다.:Fluorine-substituted absic acid derivatives represented by formulas (I) and (II) can be prepared by the following method:
제1방법은 상기 일반식(Ⅰ) 및 (Ⅱ)로 표시되는 불소치환 아브시스산 유도체 중 R은 에틸기인 유도체를 제조하는 경우에 적용된다. 이들 유도체는 상기 일반식(Ⅳ)로 표시되는 α-요논 유도체와 상기 일반식(Ⅲ)으로 표시되는 트리에틸 2-플루오로포스로노아세테이트를 비티히 반응(Writting reaction)시켜 얻을 수 있다. 이때, 염기로는 수소화 나트륨(NaH)를 비롯하여 수소화 칼륨 및 아미드화 나트륨 등을 사용할 수 있으며, 용매로는 테느라히드로후란 및 벤젠등과 같은 반응에 악영향을 주지 않는 용매를 단독 또는 2종 이상 혼합하여 사용할 수 있다. 반응온도는 특별히 한정된 것은 아니나, 용매의 비점범위 내의 온도가 바람직하며, 반응시간은 2 내지 20시간이 바람직하다. 반응결과 얻어지는 2-cis-4-trans 유도체(Ⅰ-1)과 2-trans-4-trans 유도체(Ⅱ-1)은 크로마토그래피 등을 이용하여 용이하게 분리할 수 있으며, 이하의 방법에서는 각각의 분리된 이성체를 사용하였다.The first method is applied to the case of producing a derivative in which R is an ethyl group in the fluorine-substituted absic acid derivatives represented by the general formulas (I) and (II). These derivatives can be obtained by the Wittich reaction of the α-yonone derivative represented by the general formula (IV) and triethyl 2-fluorophosphonoacetate represented by the general formula (III). In this case, as the base, sodium hydride (NaH), potassium hydride, sodium amidated, etc. may be used, and as the solvent, one or two or more solvents that do not adversely affect the reactions such as tenerahydrofuran and benzene It can be mixed and used. The reaction temperature is not particularly limited, but a temperature within the boiling point range of the solvent is preferable, and the reaction time is preferably 2 to 20 hours. The 2-cis-4-trans derivative (I-1) and 2-trans-4-trans derivative (II-1) obtained as a result of the reaction can be easily separated by chromatography or the like. Separated isomers were used.
제2방법은 상기 일반식(Ⅰ) 및 (Ⅱ)로 표시되는 불소치환 아브시스산 유도체 중 R은 H인 유도체를 제조하는 경우에 적용된다. 이들 유도체는 상기 제1방법에서 제조한 2-cis-4-trans 유도체(Ⅰ-1)과 2-trans-4-trans 유도체(Ⅱ-1)의 에스테르 화합물을 가수분해하여 얻을 수 있다. 이때, 염기로는 수산화 나트륨, 수산화 칼륨, 소디움 메톡시드 및 소디움 에톡시드 등을 사용할 수 있으며, 용매로는 물 및 알콜 등과 같은 반응에 악영향을 주지 않는 용매를 단독 또는 2종 이상 혼합하여 사용할 수 있다. 반응온도는 특별히 한정된 것은 아니나, 상온부터 용매의 비점범위 내의 온도가 바람직하며, 반응시간은 2 내지 20시간이 바람직하다.The second method is applied to the case of producing a derivative in which R is H in the fluorine-substituted absic acid derivatives represented by the general formulas (I) and (II). These derivatives can be obtained by hydrolyzing ester compounds of 2-cis-4-trans derivative (I-1) and 2-trans-4-trans derivative (II-1) prepared in the first method. In this case, sodium hydroxide, potassium hydroxide, sodium methoxide and sodium ethoxide may be used as the base, and as the solvent, a solvent which does not adversely affect the reaction such as water and alcohol may be used alone or in combination of two or more thereof. . Although reaction temperature is not specifically limited, The temperature in the boiling point range of a solvent is preferable from normal temperature, and the reaction time of 2 to 20 hours is preferable.
제3방법은 상기 일반식(Ⅰ) 및 (Ⅱ)로 표시되는 불소치환 아브시스산 유도체 중 R은 메틸기인 유도체를 제조하는 경우에 적용된다. 이들 유도체는 상기 제2방법에서 제조한 유도체(Ⅰ-2) 및 (Ⅱ-2)를 에스테르화 반응시켜 얻을 수 있다. 이때, 염기로는 수산화 나트륨, 수산화 칼륨, 소디움 매톡시드 및 소디움 에톡시드 등을 혼합하여 사용할 수 있으며, 용매로는 알콜 등과 같은 반응에 악영향을 주지 않는 용매를 단옥 또는 2종 이상 혼합하여 사용할 수 있다. 반응온도는 특별히 한정된 것은 아니나, 상온부터 용매의 비점범위 내의 온도가 바람직하며, 반응시간은 2 내지 20시간이 바람직하다.The third method is applied to the case of producing a derivative in which R is a methyl group in the fluorine-substituted absic acid derivatives represented by the general formulas (I) and (II). These derivatives can be obtained by esterifying the derivatives (I-2) and (II-2) prepared in the second method. In this case, as the base, sodium hydroxide, potassium hydroxide, sodium methoxide and sodium ethoxide may be mixed and used, and as the solvent, a solvent which does not adversely affect the reaction, such as alcohol, may be used alone or in a mixture of two or more thereof. . Although reaction temperature is not specifically limited, The temperature in the boiling point range of a solvent is preferable from normal temperature, and the reaction time of 2 to 20 hours is preferable.
또한, 상기 방법 대신에 에테르 중에서 디아조메틴과 반응시키는 방법을 사용할 수도 있다.It is also possible to use a method of reacting with diazomethine in ether instead of the above method.
상기의 제3공정을 반응식으로 표시하면 다음과 같다:Representing the third step in the reaction scheme is as follows:
제3공정 : (1) 제1방법Third Process: (1) Method 1
(2) 제2방법(2) Second method
(3) 제3방법(3) Third method
상기 식에서, X 및 Y는 이미 정의한 바와 같다.Wherein X and Y are as defined above.
[제4공정 : 광학활성을 지닌 아브시스산 유도체의 제조공정][Step 4: Preparation of Abbic Acid Derivative with Optical Activity]
상기 일반식으로 표시되는 불소치환 아스시스산 유도체 중, X는 O이고, Y는 OH이며, R이 H인 유도체는 광학활성을 지닌다. 이러한 광학활성을 지닌 아브시스산 유도체는 상기 제3공정의 제3방법을 통하여 수득한 유도체 중, X는 O이고, Y는 OH이며, R이 메틸기인 유도체를 광학이성질체의 분리가 가능한 칼럼을 사용한 HPLC 등의 크로마토그래피를 이용하여 분리한 다음, 가수분해하여 얻을 수 있다.Of the fluorine-substituted asisic acid derivatives represented by the above general formula, X is O, Y is OH, and R is H. The derivative has optical activity. Absic acid derivatives having such optical activity are derivatives obtained through the third method of the third step, wherein X is O, Y is OH, and R is a methyl group using a column capable of separating optical isomers. It can be separated by chromatography using HPLC or the like, and then obtained by hydrolysis.
상기의 제4공정을 반응식으로 표시하면 다음과 같다.:The fourth step is represented by the following reaction scheme:
제4공정:4th process:
상기의 제조방법에 있어서 각 공정별로 얻어지는 상기 일반식(Ⅰ) 및 (Ⅱ)로 표시되는 불소가 치환된 아브시스산 유도체는 각 화합물의 물성에 따라 증류, 결정화, 크로마토그래피 등과 같은 당해 분야에서 통상적으로 사용되는 방법에 따라 분리 및 정제되며, 화합물의 동정은1H-NMR 및 질량분석기 등을 사용하여 수행한다.The fluorine-substituted abscides derivatives represented by the general formulas (I) and (II) obtained in each step in the above production method are conventional in the art, such as distillation, crystallization, chromatography, etc., depending on the physical properties of each compound. The mixture is separated and purified according to the method used, and identification of the compound is performed using 1 H-NMR and a mass spectrometer.
본 발명을 통하여 하기 일반식(Ⅰ) 및 (Ⅱ)로 표시되는 불소가 치환된 아브시스산 유도체는 그 자체로서 제초활성을 갖는 농약 및 식물생장조절제의 활성성분으로 이용될 수 있으며, 유효성분을 합성하는 중간체로서도 유용하다.Through the present invention, the fluorine-substituted abscides derivatives represented by the following general formulas (I) and (II) can be used as active ingredients of pesticides and plant growth regulators having herbicidal activity by themselves, It is also useful as an intermediate to synthesize.
이하, 본 발명을 실시예에 의하여 보다 구체적으로 설명하고자 한다. 이들 실시예는 오로지 본 발명을 설명하기 위한 것으로 본 발명의 요지에 따라 본 발명의 범위가 이들 실실예에 국한되지 않는다는 것은 당업계에서 통상의 지식을 가진 자에게 있어서 자명할 것이다.Hereinafter, the present invention will be described in more detail with reference to Examples. These examples are only for illustrating the present invention, and it will be apparent to those skilled in the art that the scope of the present invention is not limited to these examples according to the gist of the present invention.
[합성예 1]Synthesis Example 1
트리에틸-2-플루오로포스포노아세테이트의 합성(제1공정)Synthesis of Triethyl-2-fluorophosphonoacetate (First Step)
에틸 2-브로모-2-플루오로아세테이트 25g(0.135mmol)과 트리에틸 포스파이트 67g(0.4mmol)을 혼합하여 4시간 동안 가열환류시킨 다음, 반응액을 증류하고 초류를 제거하여 얻어진 잔류물을 126℃의 온도 및 3mmHg의 진공도의 조건하에서 진공증류하여 유상물 17g을 얻었다(수율:52g).25 g (0.135 mmol) of ethyl 2-bromo-2-fluoroacetate and 67 g (0.4 mmol) of triethyl phosphite were mixed and heated to reflux for 4 hours, and then the reaction solution was distilled off and the residue was removed. Vacuum distillation was carried out under the conditions of a temperature of 126 DEG C and a vacuum degree of 3 mmHg to obtain 17 g of an oily substance (yield: 52 g).
1H-NMR(CDCl3,TMS)δ:1.39(t,9H), 4.29(q,6H), 5.2(dd,1H,J=12Hz,J=36Hz). 1 H-NMR (CDCl 3 , TMS) δ: 1.39 (t, 9H), 4.29 (q, 6H), 5.2 (dd, 1H, J = 12 Hz, J = 36 Hz).
[합성예 2]Synthesis Example 2
α-요논 유도체의 합성(제2공정)Synthesis of α-yonon Derivatives (Second Step)
[합성예 2-1]Synthesis Example 2-1
4-(1'-히드록시-4'-옥소-2',6',6'-트리메틸-2'-시클로헥센-1'-일)-3-부텐-2-온(Ⅳ-a)의 합성Of 4- (1'-hydroxy-4'-oxo-2 ', 6', 6'-trimethyl-2'-cyclohexene-1'-yl) -3-buten-2-one (IV-a) synthesis
α-요논 25g(0.13mmol)을 t-부틸알콜 100ml에 용해하고 반응액을 가열환류시키면서 t-부틸크로메이트 용액(0.75mmol 용액) 265ml를 20시간 동안 서서히 적가 하였다. 반응액을 5시간 가열환류시킨 후 물 500ml를 가하고 과량의 t-부틸크로메이트를 제거하기 위해 메틸알콜 100ml와 옥살산 20g을 가한 다음, 클로로포름 2L를 사용하여 추출하고 유기층을 무수 황산마그네슘으로 건조시켜 용매를 감압증발시켰다. 잔류물을 칼럼크로마토그래피(용리액:n-헥산:에틸아세테이트=5:1 내지 2:1, v/v)로 정제하여 생성물 4.33g을 얻었다.(수율:15%).25 g (0.13 mmol) of α-ionone was dissolved in 100 ml of t-butyl alcohol, and 265 ml of t-butyl chromate solution (0.75 mmol solution) was slowly added dropwise for 20 hours while refluxing the reaction solution. After the reaction solution was heated to reflux for 5 hours, 500 ml of water was added, 100 ml of methyl alcohol and 20 g of oxalic acid were added to remove excess t-butyl chromate. The mixture was extracted using 2 L of chloroform, and the organic layer was dried over anhydrous magnesium sulfate. Evaporation under reduced pressure. The residue was purified by column chromatography (eluent: n-hexane: ethyl acetate = 5: 1 to 2: 1, v / v) to give 4.33 g of product. (Yield: 15%).
1H-NMR(CDCl3,TMS)δ:1.02(s,3H), 1.11(s,3H), 1.88(d,3H,J=1.4Hz), 2.30(s,3H), 2.31(bs,1H,OH), 2.33(d,1HJ=17.2Hz), 2.51(d,1HJ=17.3Hz), 5.95(s,1H), 6.46(d,1H,J=15.7Hz), 6.84(d,1H,J=15.7Hz). 1 H-NMR (CDCl 3 , TMS) δ: 1.02 (s, 3H), 1.11 (s, 3H), 1.88 (d, 3H, J = 1.4Hz), 2.30 (s, 3H), 2.31 (bs, 1H , OH), 2.33 (d, 1HJ = 17.2Hz), 2.51 (d, 1HJ = 17.3Hz), 5.95 (s, 1H), 6.46 (d, 1H, J = 15.7Hz), 6.84 (d, 1H, J = 15.7 Hz).
[합성예 2-2]Synthesis Example 2-2
4-(1'-히드록시 2',6',6'-트리메틸-2'-시클로헥센-1'-일)-3-부텐-2-온(Ⅳ-6)의 합성Synthesis of 4- (1'-hydroxy 2 ', 6', 6'-trimethyl-2'-cyclohexene-1'-yl) -3-buten-2-one (IV-6)
[합성예 2-2-1]Synthesis Example 2-2-1
4-(1',2'-에폭시-2',6',6'-트리메틸시클로헥센-1'-일)-3-부텐-2-온(Ⅳ-6)의 합성Synthesis of 4- (1 ', 2'-epoxy-2', 6 ', 6'-trimethylcyclohexene-1'-yl) -3-buten-2-one (IV-6)
β-요논 9.62g(0.05mmol)을 건조된 디클로로메탄 100ml에 용해하고 반응액을 0℃로 냉각시킨 다음, 과산화 메타클로로벤조산 17.26g(50%, 0.05mmol)을 가하였다. 반응액을 상온에서 20시간 교반시키고 여과하여 유기층을 포화 탄산수소나트륨 수용액 및 5% 아황산나트륨 수용액으로 세척한 다음, 무수 황산마그네슘으로 건조시켰다. 용매를 감압증발시켜 얻어진 잔류물을 칼럼크로마토그래피(용리액:n-헥산 :아틸아세테이트-1:4,v/v)로 정제하여 생성물 8.84g을 얻었다(수율:85%).9.62 g (0.05 mmol) of β-nonone was dissolved in 100 ml of dried dichloromethane, and the reaction solution was cooled to 0 ° C., followed by addition of 17.26 g (50%, 0.05 mmol) of metachlorobenzoic acid peroxide. The reaction solution was stirred at room temperature for 20 hours, filtered, and the organic layer was washed with saturated aqueous sodium bicarbonate solution and 5% aqueous sodium sulfite solution, and then dried over anhydrous magnesium sulfate. The residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography (eluent: n-hexane: acetylacetate-1: 4, v / v) to obtain 8.84 g of the product (yield: 85%).
1H-NMR(CDCl3,TMS)δ:0.93(s,3H), 1.14(s,6H), 1.38-1.95(m,6H), 2.28(s,3H), 6.28(d,1H,J=15.7Hz), 7.02(d,1H,J=15.7Hz). 1 H-NMR (CDCl 3 , TMS) δ: 0.93 (s, 3H), 1.14 (s, 6H), 1.38-1.95 (m, 6H), 2.28 (s, 3H), 6.28 (d, 1H, J = 15.7 Hz), 7.02 (d, 1H, J = 15.7 Hz).
MS m/e(rel. int.):208(M+,5), 193(13), 135(100), 123(100), 107(51), 95(52), 79(25), 69(30), 43(100).MS m / e (rel. Int.): 208 (M +, 5), 193 (13), 135 (100), 123 (100), 107 (51), 95 (52), 79 (25), 69 ( 30), 43 (100).
[합성예 2-2-2]Synthesis Example 2-2-2
4-(1'-히드록시 2',6',6'-트리메틸-2'-시클로헥센-1'-일)-3-부텐-2-온(Ⅳ-b)의 합성Synthesis of 4- (1'-hydroxy 2 ', 6', 6'-trimethyl-2'-cyclohexene-1'-yl) -3-buten-2-one (IV-b)
질소기류를 통과시키면서 건조된 에테르 100ml와 디에틸아민 4.39g (0.06mmol)을 혼합하여 반응액의 온도을 -78℃로 냉각시켰다. 반응액에 부틸리튬(n-BuLi)용액 (2.5mmol) 25ml(0.0625mmol)를 서서히 적가하고 -20℃까지 서서히 가온시킨 다음, 다시 -78℃로 냉각하고 상기 합성예에서 제조한 4-(1'2'-에폭시-2',6',6'-트리메틸시클로헥산-1'-일)-3-부텐-2-온 4.16g(0.02mmol)을 에테르 10ml에 용해하여 반응액에 서서히 가하였다. 반응액을 상온에서 12시간 교반시킨 다음, 물을 가하고 유기층을 에테르(3x50ml)로 추출하여 무수 황산마그네슘으로 건조시켰다. 용매를 감압증발시켜 얻어진 잔류물을 칼럼크로마토그래피(용리액:n-헥산:에틸아세테이트=1:2,v/v)로 정제하여 생성물 0.957g을 얻었다(수율:23%).100 ml of dried ether and 4.39 g (0.06 mmol) of diethylamine were mixed while passing through a nitrogen stream, and the reaction solution was cooled to -78 ° C. 25 ml (0.0625 mmol) of butyllithium (n-BuLi) solution (2.5 mmol) was slowly added dropwise to the reaction solution, and gradually warmed to −20 ° C., and then cooled to −78 ° C. again to obtain 4- (1). 4.16 g (0.02 mmol) of '2'-epoxy-2', 6 ', 6'-trimethylcyclohexane-1'-yl) -3-buten-2-one was dissolved in 10 ml of ether and slowly added to the reaction solution. . The reaction solution was stirred at room temperature for 12 hours, and then water was added and the organic layer was extracted with ether (3 × 50 ml) and dried over anhydrous magnesium sulfate. The residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography (eluent: n-hexane: ethyl acetate = 1: 2, v / v) to obtain 0.957 g of a product (yield: 23%).
1H-NMR(CDCl3,TMS)δ:0.91(s,3H), 1.01(s,3H), 1.45-1.68(m,2H), 1.59(s,3H), 2.00-2.15(m,3H), 2.29(s,3H), 5.56(bs,1H), 6.35(d,1H), 6.81(d,1H). 1 H-NMR (CDCl 3 , TMS) δ: 0.91 (s, 3H), 1.01 (s, 3H), 1.45-1.68 (m, 2H), 1.59 (s, 3H), 2.00-2.15 (m, 3H) , 2.29 (s, 3H), 5.56 (bs, 1H), 6.35 (d, 1H), 6.81 (d, 1H).
MS m/s(rel. int.):208(M+,4), 193(9), 181(5), 165(21), 152(11), 123(20), 109(100), 81(22), 43(39).MS m / s (rel. Int.): 208 (M + , 4), 193 (9), 181 (5), 165 (21), 152 (11), 123 (20), 109 (100), 81 (22), 43 (39).
[합성예 2-3]Synthesis Example 2-3
4-(4'-옥소-2',6',6'-트리메틸-2'-시클로헥센-1'-일)-3-부텐-2-온(Ⅳ-c)의 합성Synthesis of 4- (4'-oxo-2 ', 6', 6'-trimethyl-2'-cyclohexene-1'-yl) -3-buten-2-one (IV-c)
α-요논 1.5g(7.8mmol)을 아세톤 40mol에 혼합하고 90% 아세톤 수용액 10ml에 크롬산 2g(0.013mmol) 및 진한황산 3ml를 가하여 제조한 존스시약을 반응액에 가한 다음, 상온에서 10시간 동안 교반시켰다. 반응액을 여과하고 용매를 감압증발에 의해 제거하여 얻어진 잔류물을 컬럼크로마토그래피(용리액:n-헥산:에틸아세테이트=1:2,v/v)로 정제하여 생성물 0.45g을 얻었다(수율:28%)Jones reagent prepared by mixing α-ionon 1.5g (7.8 mmol) with 40 mol of acetone and adding 2 g (0.013 mmol) of chromic acid and 3 ml of concentrated sulfuric acid to 10 ml of 90% acetone aqueous solution was added to the reaction solution, followed by stirring at room temperature for 10 hours. I was. The reaction solution was filtered and the solvent was removed by evaporation under reduced pressure. The residue was purified by column chromatography (eluent: n-hexane: ethyl acetate = 1: 2, v / v) to obtain 0.45 g of a product (yield: 28). %)
1H-NMR(CDCl3,TMS)δ:1.01(s,3H), 1.08(s,3H), 1.90(d,3H,J=1Hz), 2.29(s,3H), 2.15-2.41(m,2H), 2.72(d,1H,J=9.5Hz), 5.98(s,1Hz), 6.68(dd,1H,J=15.8Hz,9.5Hz). 1 H-NMR (CDCl 3 , TMS) δ: 1.01 (s, 3H), 1.08 (s, 3H), 1.90 (d, 3H, J = 1 Hz), 2.29 (s, 3H), 2.15-2.41 (m, 2H), 2.72 (d, 1H, J = 9.5 Hz), 5.98 (s, 1 Hz), 6.68 (dd, 1H, J = 15.8 Hz, 9.5 Hz).
MS m/e(rel. int.):206(M+,2), 191(2), 164(2), 150(44), 135(6), 108(100), 43(100).MS m / e (rel. Int.): 206 (M + , 2), 191 (2), 164 (2), 150 (44), 135 (6), 108 (100), 43 (100).
[실시예 1]Example 1
2-플루오로아브시스산 에틸에스테르(Ⅰ-1a) 및 (Ⅱ-1a)의 제조(제3공정 제1방법)Preparation of 2-fluoroabic acid ethyl ester (I-1a) and (II-1a) (3rd process 1st method)
질소기류를 통과시키면서 상기 합성예 1에서 제조한 트리에틸 2-플루오로포스포노아세테이트 1.33g(5.5mmol)을 건조시킨 테트라히드로후관 100ml에 용해시킨 다음, 수소화 나트륨 150mg(5mmol, 80% dispersion in mineral oil)을 가하여 1시간 동안 교반하였다. 반응액에 상기 합성예 2-1에서 제조한 4-(1'-히드록시-4'-옥소-2',6',6'-트리메틸-2'-시클로헥센-1'-일)-3-부텐-2-온(Ⅳ-a)1.10g(5mmol)을 가하고 12시간 동안 가열환류시켰다. 반응액을 상온으로 냉각하여 물로 세척한 다음, 에테르로 추출하고 유기층을 무수 황산마그네슘으로 건조시켜 얻은 잔류물을 컬럼크로마토그래피(용리액:n-헥산:에틸아세테이트=4:1,v/v)로 정제하고, 본 실시예로부터 수득한 두가지 기하학적 이성체를 분리하여 Rf 값이 0.45인 화합물(Ⅰ-1a) 0.62g 및 Rf값이 0.38인 화합물(Ⅱ-1a) 0.63g을 각각 얻었다(수율:80%).While passing through a nitrogen stream, 1.33 g (5.5 mmol) of triethyl 2-fluorophosphonoacetate prepared in Synthesis Example 1 was dissolved in 100 ml of dried tetrahydro tube, followed by 150 mg (5 mmol, 80% dispersion in mineral) of sodium hydride. oil) was added and stirred for 1 hour. 4- (1'-hydroxy-4'-oxo-2 ', 6', 6'-trimethyl-2'-cyclohexene-1'-yl) -3 prepared in Synthesis Example 2-1 to the reaction solution -10 g (5 mmol) of butene-2-one (IV-a) was added and heated to reflux for 12 hours. The reaction solution was cooled to room temperature, washed with water, extracted with ether, and the organic layer was dried over anhydrous magnesium sulfate. The residue obtained was purified by column chromatography (eluent: n-hexane: ethyl acetate = 4: 1, v / v). Purification and separation of the two geometrical isomers obtained in this Example yielded 0.62 g of Compound (I-1a) having an Rf value of 0.45 and 0.63 g of Compound (II-1a) having an Rf value of 0.38, respectively (yield: 80% ).
(2E,4E) 이성체(Ⅰ-1a):(2E, 4E) Isomers (I-1a):
융점:120 내지 122℃Melting Point: 120-122 ° C
(2Z,4E) 이성체(Ⅱ-1a)(2Z, 4E) Isomers (II-1a)
융점:114 내지 115℃Melting Point: 114-115 ° C
[실시예 2 내지 4][Examples 2 to 4]
실시예 2 내지 4는 실시예 1에서 사용한 α-요논 유도체(Ⅳ-a)대신에 α-요논 유도체(Ⅳ-b)(Ⅳ-c) 및 (Ⅳ-d)를 사용한 것을 제외하고는, 실시예 1과 동일한 방법으로 수행하였다. 실시예 1 내지 4에서 제조한 화합물의 화학분석 결과는 하기 표1에 나타내었다.Examples 2 to 4 were carried out except that α-nonon derivatives (IV-b) (IV-c) and (IV-d) were used instead of the α-nonon derivative (IV-a) used in Example 1. It carried out in the same manner as in Example 1. The chemical analysis results of the compounds prepared in Examples 1 to 4 are shown in Table 1 below.
[실시예 5]Example 5
실시예 2 내지 4는 실시예 1에서 사용한 α-요논 유도체(Ⅳ-α)대신에 α-요논 유도체(Ⅳ-b),(Ⅳ-c) 및 (Ⅳ-d)를 사용한 것을 제외하고는, 실시예 1과 동일한 방법으로 수행하였다. 실시예 1 내지 4에서 제조한 화합물의 화학분석 결과는 하기 표 1에 나타내었다.Examples 2 to 4 except that α-nonon derivatives (IV-b), (IV-c) and (IV-d) were used instead of the α-nonon derivative (IV-α) used in Example 1, It was carried out in the same manner as in Example 1. The chemical analysis results of the compounds prepared in Examples 1 to 4 are shown in Table 1 below.
[실시예 5]Example 5
(±)(2E,4E)-2-플루오로아브시스산(Ⅰ-2a)의 제조(제3공정 제2방법)Preparation of (±) (2E, 4E) -2-fluoroabbic acid (I-2a) (third step second method)
실시예 Ⅰ에서 제조한 (±)(2E,4E)-2-플루오로아브시스산 에틸에스테르(Ⅰ-1a) 0.2g(0.645mmol)을 메틸알콜 5ml에 용해한 다음, 수산화칼륨 0.41g을 물 5ml에 용해하여 반응액에 가하고 1시간 동안 가열환류시켰다. 메틸알콜을 감압증발시켜 제거하고 2N-염산 용액으로 산성화시킨 다음, 에틸아세테이트 20ml로 추헥산:에틸아세테이트:포름산=50:50:0.2,v/v)로 정제하여 생성물 0.132g을 얻었으며, 화학분석 결과는 하기 표 1에 나타내었다(수율:72.6%)0.2 g (0.645 mmol) of (±) (2E, 4E) -2-fluoroabbic acid ethyl ester (I-1a) prepared in Example I was dissolved in 5 ml of methyl alcohol, followed by 0.41 g of potassium hydroxide 5 ml of water. Dissolved in the reaction solution and heated to reflux for 1 hour. The methyl alcohol was removed by evaporation under reduced pressure, acidified with 2N hydrochloric acid solution, and purified by 20 ml of ethyl acetate with chuhexane: ethyl acetate: formic acid = 50: 50: 0.2, v / v) to give 0.132 g of product. The analytical results are shown in Table 1 below (yield: 72.6%).
융점:166 내지 168℃Melting Point: 166 to 168 ° C
[실시예 6]Example 6
(±)(2Z,4E)-2-플루오로아브시스산(Ⅱ-2a)의 제조Preparation of (±) (2Z, 4E) -2-fluoroabbic acid (II-2a)
실시예 1에서 제조한 (±)(2Z,4E)-2-플루오로아브시스산 에틸에스테르(Ⅱ-1a) 0.2g(0.645mmol)을 원료로 사용한 것을 제외하고는, 실시예 5와 동일한 방법을 사용하여 생성물을 얻었다(수율:71%)The same method as in Example 5, except that 0.2 g (0.645 mmol) of (±) (2Z, 4E) -2-fluoroabbic acid ethyl ester (II-1a) prepared in Example 1 was used as a raw material. The product was obtained using (yield 71%).
융점:158 내지 160℃Melting Point: 158-160 ° C
[실시예 7 내지 9][Examples 7 to 9]
실시예 7 내지 9는 (±)(2E,4E)-2-플루오로아브시스산 에틸에스테르(Ⅰ-1a) 대신에 실시에 2 내지 4에서 제조한 화합물을 원료로 사용한 것을 제외하고는, 실시예 5와 동일한 방법으로 수행하였다. 실시예 6내지 9에서 제조한 화합물의 화학분석 결과는 하기 표 1에 나타내었다.Examples 7 to 9 were carried out except that the compounds prepared in Examples 2 to 4 were used as raw materials instead of (±) (2E, 4E) -2-fluoroabbic acid ethyl ester (I-1a). It carried out in the same manner as in Example 5. The chemical analysis results of the compounds prepared in Examples 6 to 9 are shown in Table 1 below.
[실시예 10]Example 10
(±)(2E,4E)-2-플루오로아브시스산 메틸에스테르(Ⅰ-3a)의 제조(제3공정 제3방법)Preparation of (±) (2E, 4E) -2-fluoroabdic acid methyl ester (I-3a) (third step third method)
에테르 15ml에 실시예 5에서 제조한 (±)(2E,4E)-2-플루오로아브시스산(Ⅰ-2a) 50mg(0.177mmol)을 가한 반응액에 디아조메탄(0.02mmol 용액) 용액 10ml를 가하여 상온에서 20분간 교반시켰다. 반응액을 감압증발시켜 얻은 잔류물을 칼럼크로마토그래피(용리액:n-헥산:에틸아세테이트=2:1,v/v)로 정제하여 생성물 45mg을 얻었다(수율:86%).10 ml of diazomethane (0.02 mmol solution) solution was added to the reaction solution to which 50 mg (0.177 mmol) of (±) (2E, 4E) -2-fluoroabbic acid (I-2a) prepared in Example 5 was added to 15 ml of ether. It was added and stirred for 20 minutes at room temperature. The residue obtained by evaporation of the reaction solution under reduced pressure was purified by column chromatography (eluent: n-hexane: ethyl acetate = 2: 1, v / v) to give 45 mg of product (yield: 86%).
융점:136 내지 138℃Melting Point: 136-138 ° C
[실시예 11]Example 11
(±)(2Z,4E)-2-플루오로아브시스산 메틸에스테르(Ⅱ-3a)의 제조(제3공정 제3방법)Preparation of (±) (2Z, 4E) -2-fluoroabbic acid methyl ester (II-3a) (third step third method)
실시예 6에서 제조한 (2Z,4E)-2-플루오로아브시스산(Ⅱ-2a) 50mg(0.17 mmol)을 원료로 사용한 것을 제외하고는, 실시예 10과 동일한 방법을 사용하여 생성물 47mg을 얻었다(수율:89%). 실시예 10 내지 11에서 제조한 화합물의 화학분석 결과는 하기 표 1에 나타내었다.47 mg of the product was obtained in the same manner as in Example 10, except that 50 mg (0.17 mmol) of (2Z, 4E) -2-fluoroabbic acid (II-2a) prepared in Example 6 was used as a raw material. Obtained (yield: 89%). The chemical analysis results of the compounds prepared in Examples 10 to 11 are shown in Table 1 below.
융점:135 내지 136℃Melting Point: 135-136 ° C
[실시예 12]Example 12
광학활성을 지닌 아브시스산 유도체의 제조(제4공정)Preparation of Abbic Acid Derivatives with Optical Activity (4th Step)
실시예 10에서 제조한 (±)(2E,4E)-2-플루오로아브시스산 메틸에스테르(Ⅰ-3a)를 하기와 같은 조건하에서 HPLC를 사용하여 광학이성질체를 분리하여 (S)-(+)-2-플루오로아브시스산 메틸에스테르 및 (R)-(+)-2-플루오로아브시스산 메틸에스테르를 각각 분취하였다. 분취한 각각의 광학이성질체를 실시예 5와 동일한 방법으로 가수분해하여 (S)-(+)-2-플루오로아브시스산(Ⅰ-4a) 및 (R)-(-)-2-플루오로아브시스산(Ⅰ-4b)를 제조하였으며, 광학활성도 및 화학분석 결과는 하기 표 1에 나타내었다.(±) (2E, 4E) -2-fluoroabbic acid methyl ester (I-3a) prepared in Example 10 was separated under optical conditions using HPLC under (S)-(+ ) -2-fluoroabic acid methyl ester and (R)-(+)-2-fluoroabic acid methyl ester were respectively fractionated. Each of the optical isomers fractionated was hydrolyzed in the same manner as in Example 5 to give (S)-(+)-2-fluoroabbic acid (I-4a) and (R)-(-)-2-fluoro Abbic acid (I-4b) was prepared, and optical activity and chemical analysis results are shown in Table 1 below.
컬럼:Chiral Cel OD(Daicel Chemical Ind., Japen)(4.6x250mm)Column: Chiral Cel OD (Daicel Chemical Ind., Japen) (4.6x250 mm)
분리조건:용액:3% IPA in hexaneSeparation conditions: Solution: 3% IPA in hexane
용출속도:1ml/minDissolution rate: 1 ml / min
시료농도:10mg/mlSample concentration: 10 mg / ml
검출조건:UV 254nmDetection condition: UV 254nm
[불소치환 아브시스산 유도체를 포함하는 식물생장조절제의 생리활성][Physical Activity of Plant Growth Regulators Containing Fluorine-Substituted Absic Acid Derivatives]
본 발명에 있어서, 식물생장조절제는 식물의 발아저해작용, 생장저해작용, 제초제와 같은 식물생장억제작용 및 왜화제와 같은 식물의 도복방지작용 등의 다양한 식물생장조절작용을 나타내는 약제를 포함한다.In the present invention, the plant growth regulator includes agents that exhibit various plant growth control actions such as germination inhibition, growth inhibition, plant growth inhibition such as herbicides and anti-dock action of plants such as dwarfing agents.
본 발명의 식물생장조절제는 불소치환 아브시스산 유도체를 수용액 등의 형태로 식물 또는 식물종자를 파종한 지상에 살포하는 방법 등으로 사용할 수 있다. 특히, 식물생장조절제 중 제초제의 경우에는 종래의 제초제 성분에 본 발명의 불소치환 아브시스산 유도체를 첨가하여 사용할 수 있다. 또한, 왜화제의 경우에도 종래의 왜화제 성분에 본 발명의 불소치환 아브시스산 유도체를 첨가하여 사용할 수 있다. 아울러, 본 발명의 불소치환 아브시스산 유도체는 종래의 식물용 살균제 및 살충제 등과 혼합하여 사용할 수 있다.The plant growth regulator of the present invention can be used by a method of spraying a fluorine-substituted absic acid derivative in the form of an aqueous solution or the like on the ground planted with plants or plant seeds. In particular, in the case of herbicides among plant growth regulators, the fluorine-substituted absic acid derivative of the present invention can be added to the conventional herbicide component. Moreover, also in the case of a distortion agent, the fluorine-substituted abdic acid derivative of this invention can be added and used for the conventional distortion agent component. In addition, the fluorine-substituted absic acid derivative of the present invention can be used in combination with conventional plant fungicides and insecticides.
이하, 본 발명의 불소치환 아브시스산 유도체를 포함하는 식물생장조절제의 적용대상식물, 처리부위, 처리시기, 처리방법, 처리량 및 제형 등에 대하여 상세히 설명한다.Hereinafter, a plant, a treatment site, a treatment time, a treatment method, a dosage amount, and a formulation of the plant growth regulator comprising the fluorine-substituted absic acid derivative of the present invention will be described in detail.
ⅰ)적용대상식물 : 본 발명의 식물생장조절제를 제초제로서 사용하는 경우에 적용대상식물은 전 초종이며, 왜화제로서 사용하는 경우에는 일년생 식물이 바람직하다.Iii) Plant to be applied: When the plant growth regulator of the present invention is used as a herbicide, the plant to be applied is all herb species, and when used as a dwarfing agent, an annual plant is preferable.
ⅱ)처리부위 : 본 발명의 식물생장조절제의 처리부위로는 식물의 종자 및 경엽부가 바람직하다.Ii) Treatment part: As the treatment part of the plant growth regulator of the present invention, the seed and foliage part of the plant are preferable.
ⅲ)처리시기 : 본 발명의 식물생장조절제의 처리시기로는 제초제로서 사용하는 경우에는 통상적인 제초제의 처리시기와 동일하며, 왜화제로서 사용하는 경우에는 파종기, 유묘기 또는 성숙기가 바람직하다.Iii) Treatment time: The treatment time of the plant growth regulator of the present invention is the same as the treatment time of a conventional herbicide when used as a herbicide, and when used as a dwarfing agent, a planting period, a seedling period or a maturation period is preferable.
ⅳ)처리방법 : 본 발명의 식물생장조절제의 처리방법은 제초제로서 사용하는 경우에는 지상살포이며, 왜화제로서 사용하는 경우에는 지면살포 또는 토양혼합처리가 바람직하다.I) Treatment method: The treatment method of the plant growth regulator of the present invention is ground spraying when used as a herbicide, and ground spraying or soil mixing treatment is preferable when used as a dwarfing agent.
ⅴ)처리량 : 본 발명의 식물생장조절제를 제초제로서 사용하는 경우에는 지면 1㎡당 0.01mg 이상의 유효성분을 사용하는 것이 바람직하며, 왜화제로서 사용하는 경우에는 지면 1㎡당 0.01 내지 1mg의 유효성분을 사용하는 것이 바람직하다.I) Treatment amount: When the plant growth regulator of the present invention is used as a herbicide, it is preferable to use an active ingredient of 0.01 mg or more per 1 m 2 of land, and when used as a dwarfing agent, 0.01 to 1 mg of active ingredient per 1 m 2 of land. Preference is given to using.
ⅵ)제형 : 본 발명의 식물생장조절제는 종래의 농약을 제조하는 방법에 의하여 수화제, 유제 및 분제 등의 제형으로 사용할 수 있다.Iii) Formulation: The plant growth regulator of the present invention can be used in formulations such as hydrating agent, emulsion and powder by the conventional method for producing pesticides.
본 발명의 제조방법에 의해 합성된 불소치환된 아브시스산 유도체 중 (2E,4E)의 배위(configuration)를 지닌 유도체의 발아저해 활성, α-아미라제 유도저해 활상 및 신장저해 활성을 천연의 아브시스산의 경우와 비교하기 위하여 다음과 같은 방법을 사용하였다:The germination inhibitory activity, α-amylase-induced inhibitory activity, and growth inhibitory activity of the derivatives having a configuration of (2E, 4E) among the fluorine-substituted absic acid derivatives synthesized by the preparation method of the present invention were reduced to The following method was used to compare with the cis acid:
1.발아저해 활성시험1. Germination inhibition activity test
본 발명의 아브시스산 유도체에 에틸알콜을 가하여 피검용액을 제조한 다음, 여지를 깔은 페트리 접시(내경 6cm)에 전기 피검용액을 일정량 여지에 균일하게 흡수시킨 후 풍건시켜 용매를 제거하였다. 증류수를 별개의 페트리 접시에 1ml씩 가하고, 여지 위에 크레스(cress : Lepidium sativum) 종자 25립을 균일하게 치상하여 뚜껑을 덮고 25℃의 암조건에서 배양하였다. 그런 다음, 36시간 후에 발아하지 않은 종자의 수를 세어서 대조구의 발아율에 대한 백분율로 계산하여 각각의 화합물에 따른 50% 발아저해율(pi50)을 구하였으며, 상기의 시험을 3회 반복 수행하였다. 이때, 불소치환 아브시스산 유도체의 사용 농도는 0.3 내지 1ppm이었다.Ethyl alcohol was added to the absic acid derivative of the present invention to prepare a test solution. The test solution was then uniformly absorbed by a predetermined amount in a petri dish (6 cm inside diameter), and then air dried to remove the solvent. Distilled water was added to a separate Petri dish 1 ml each, and 25 seeds of cress (cress: Lepidium sativum) were uniformly flocculated, covered with a lid, and incubated at 25 ° C. under dark conditions. Then, after 36 hours, the number of non-germinated seeds was counted and calculated as a percentage of the germination rate of the control to obtain 50% germination inhibition rate (pi50) for each compound, and the test was repeated three times. At this time, the concentration of the fluorine-substituted absic acid derivative was 0.3 to 1 ppm.
2.α-아미라제 유도저해 활성시험2.α-Amirase Inhibition Activity Test
보리(Hordeum vulgare L. var. hexastichon)를 멸균시키고 반절로 잘라서 배유부분 10개를 멸균한 2ml의 배지(1mM 아세테이트 완충용액, pH 5.1, 20μM염화칼슘 함유)에 넣은 다음, 본 발명의 아브시스산 유도체로부터 제조한 피검용액을 가하였다. 대조구로는 지베레린(GA: gibberelic acid)을 사용하여 25에서, 48시간 진동배양시킨 다음, 보리의 반절종자를 조직파쇄기(homogenizer)로 갈아서 배양시 사용한 완충액(3ml)으로 세척하여 모든 배양액을 2000g에서 10분간 원심분리하여 상등액을 채취하였다. 침전물은 배지 3ml에 가하고 재차 원심분리하여 얻은 전기 상등액과 혼합하고, 2회에 걸쳐 얻은 싱등액에 증류수를 가해 10ml로 하여 α-아미라제를 포함하고 있는 시료액으로 사용하였다. 이때, 불소치환 아브시스산 유도체의 사용 농도는 0.3 내지 1ppm이었다.The barium (Hordeum vulgare L. var. Hexastichon) was sterilized, cut in half, and 10 endosperms were placed in sterile 2 ml of medium (containing 1 mM acetate buffer, pH 5.1, 20 μM calcium chloride), and then the absic acid derivative of the present invention. The test solution prepared from the above was added. For control, gibberlic acid (GA: gibberelic acid) was incubated at 25, for 48 hours, then barley half-seeds were changed with a homogenizer and washed with a buffer solution (3 ml) used for incubation. The supernatant was collected by centrifugation at 2000g for 10 minutes. The precipitate was added to 3 ml of the medium, and again mixed with the supernatant obtained by centrifugation. Distilled water was added to 10 ml of the supernatant obtained twice, and 10 ml was used as a sample liquid containing α-amylase. At this time, the concentration of the fluorine-substituted absic acid derivative was 0.3 to 1 ppm.
상기의 과정을 거쳐 얻어진 효소액에 대하여 다음의 α-아미라제 측정법을 사용하여 활성을 측정하고 천연의 아브시스산에 대한 상대치로 활성을 평가하였다:즉, 전분 100mg을 증류수 10ml에 용해시켜 기질로 사용하며 α-아미라제와의 효소반응을 정지시키고 증색하기 위해서 0.05N-염산용액을 포함하는 0.05% 요오드(I2) 용액을 사용하였는데, 이때, 요오드 용액은 10% 요오드와 칼륨을 포함하는 1% 요도드 용액0.5ml와 2N-염산 2.5ml에 증류수를 가하여 100ml로 제조하여 사용하였다. 효소활성의 측정시 기질 0.5ml 및 0.1M 아세테이트 완충용액(pH 5.1, 20mM 염화칼슘 포함)0.5ml를 10ml의 시험관 A,B(바탕용액)에 가한 다음, 30℃로 유지된 항온조에서 5분간 효소반응을 시켰다. 그런 다음, 5분 후 상기의 효소액 1ml를 실험관 A에 가하여 반응을 정지시키는 것과 동시에 냉각시키고, 증류수를 가하여 620nm에서 반응액과 바탕용액의 흡광도(OD) D, D를 측정하였다. 동일한 방법을 피검 화합물에 의해 유도되어진 α-아미라제를 포함하는 시료액에 적용하여 흡광도 D을 측정하고, α-아미라제의 상대량은 효소액의 농도를 변화시켜 측정한 D에 기초하여 얻은 검량선에 의해 구하였다.The enzyme solution obtained through the above procedure was measured for activity using the following α-amylase assay, and the activity was evaluated relative to the natural abstic acid: 100 mg of starch was dissolved in 10 ml of distilled water and used as a substrate. In order to stop and color the enzymatic reaction with α-amylase, 0.05% iodine (I2) solution containing 0.05N hydrochloric acid solution was used, wherein the iodine solution contains 1% urethra containing 10% iodine and potassium. Distilled water was added to 0.5 ml of the solution and 2.5 ml of 2N hydrochloric acid to prepare 100 ml. When measuring enzyme activity, 0.5 ml of substrate and 0.5 ml of 0.1 M acetate buffer (pH 5.1, 20 mM calcium chloride) were added to 10 ml of test tubes A and B (base solution), followed by enzymatic reaction for 5 minutes in a thermostat maintained at 30 ° C. Let. Then, 5 minutes later, 1 ml of the enzyme solution was added to Test Tube A to stop the reaction, and simultaneously cooled. Distilled water was added to measure absorbances (OD) D and D of the reaction solution and the substrate solution at 620 nm. The same method was applied to the sample solution containing α-amylase induced by the test compound, and the absorbance D was measured, and the relative amount of α-amylase was measured on the calibration curve obtained based on D measured by changing the concentration of the enzyme solution. Obtained by
3.신장저해 활성시험3. Kidney inhibition activity test
벼 유묘를 시험용 폿트내의 배지에 10개씩 심은 다음, 본 발명의 아브시스산 유도체를 일정농도의 용액으로 제조하여 지상살포하였다. 수분이 증발되지 않도록 시험용 폿트를 비닐로 봉하고 25 내지 30℃에서 10일간 배양한 다음, 벼 유묘의 일 엽초의 초장의 길이를 측정하여 약제를 살포하지 않은 대구조와 비교하였다. 이때, 불소치환 아브시스산 유도체의 사용 농도는 1 내지 3ppm이었다.Rice seedlings were planted 10 times in a medium in a test pot, and then the absic acid derivative of the present invention was prepared as a solution at a predetermined concentration and ground sprayed. The test pot was sealed with vinyl and incubated for 10 days at 25 to 30 ° C. to prevent evaporation of water, and then the length of the grass length of one vinegar of rice seedlings was measured and compared with the large structure without spraying the drug. At this time, the use concentration of the fluorine-substituted abstic acid derivative was 1 to 3 ppm.
상기 실시예에 의해 합성된 본 발며에 따른 불소치환된 아브시스산 유도체 중 (2E,4E)의 배위를 지닌 유도체의 발아저해 활성, α-아미라제 유도저해 활성 및 신장저해 활성을 천연의 마브시스산의 경우와 비교한 결과를 하기 표 2 내지 4에 나타내었다. 하기 표 2내지 4에서 보듯이, 본 발명의 불소치환 아브시스산 유도체 중 (2E,4E)의 배위를 지닌 유도체는 천연의 아브시스산에 필적한 발아저해 활성을 나타내었고 천연의 아브시스산에 비하여 10분의 1 내지 동등한 정도의 α-아미라제 유도저해 활성을 나타내었으며 10분의 1 정도의 신장저해 활성을 나타내었다. 이와 같이 본 발명의 불소치환된 아브시스산 유도체 중 (2E,4E)의 배위를 지닌 유도체는 아브시스산 보다 훨씬 안정하며, 천연의 아브시스산과 마찬가지로 높은 발아저해 활성, α-아미라제 유도저해 활성 및 신장저해 활성을 가지므로, 제초제 및 왜화제 등과 같은 식물생장조절제로 사용될 수 있음을 확인하였다.Among the fluorine-substituted absic acid derivatives synthesized by the above examples, the germination inhibitory activity, α-amylase-induced inhibitory activity, and renal inhibitory activity of the derivatives having a coordination of (2E, 4E) were naturally induced. The results compared with the case of Susan are shown in Tables 2 to 4 below. As shown in Tables 2 to 4 below, derivatives having a coordination of (2E, 4E) in the fluorine-substituted absic acid derivatives of the present invention showed a germination inhibitory activity comparable to that of natural abscisic acid and Compared with the one-tenth equivalent to α-amylase-induced inhibitory activity, and about one-tenth the kidney inhibitory activity. As described above, derivatives having a coordination of (2E, 4E) among the fluorine-substituted absic acid derivatives of the present invention are much more stable than absic acid, and have high germination inhibitory activity and α-amylase-induced inhibitory activity like natural absicylic acid. And it has been confirmed that it can be used as a plant growth regulator, such as herbicides and dwarfs because it has a renal inhibitory activity.
이상에서 상세히 설명하고 입증하였듯이, 본 발명에 의해 제조된 불소치환된 아브시스산 유도체는 천연의 아브시스산보다 안정하면서도 생리활성면에서도 강력한 아브시스산 활성을 나타내어, 그 자체로서 제초활성을 갖는 농약 및 왜화제 등의 식물생장조절제의 활성성분으로 이용될 수 있으며, 유효성분을 합성하는 중간체로서도 유용할 것으로 밝혀졌다.As described and demonstrated in detail above, the fluorine-substituted abscides derivatives prepared according to the present invention are more stable than natural abscides and exhibit potent abscisdic activity in terms of physiological activity, and thus have pesticides having herbicidal activity as such. And it can be used as an active ingredient of plant growth regulators such as dwarfs, it was found to be useful as an intermediate for synthesizing the active ingredient.
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