KR102220170B1 - Ketide compounds, method for manufacturing, and use for treating diabetes thereof - Google Patents

Ketide compounds, method for manufacturing, and use for treating diabetes thereof Download PDF

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KR102220170B1
KR102220170B1 KR1020180006151A KR20180006151A KR102220170B1 KR 102220170 B1 KR102220170 B1 KR 102220170B1 KR 1020180006151 A KR1020180006151 A KR 1020180006151A KR 20180006151 A KR20180006151 A KR 20180006151A KR 102220170 B1 KR102220170 B1 KR 102220170B1
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acetate
ethyl
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methoxy
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김인수
김형식
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성균관대학교산학협력단
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/475—Preparation of carboxylic acid esters by splitting of carbon-to-carbon bonds and redistribution, e.g. disproportionation or migration of groups between different molecules
    • 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
    • A61K31/12—Ketones
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
    • A61K31/37—Coumarins, e.g. psoralen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
    • B01J31/22—Organic complexes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
    • C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
    • C07C69/738—Esters of keto-carboxylic acids or aldehydo-carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/06—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
    • B01J2531/80—Complexes comprising metals of Group VIII as the central metal
    • B01J2531/82—Metals of the platinum group
    • B01J2531/827—Iridium

Abstract

본 발명은 케타이드 화합물, 이의 제조방법, 및 이의 당뇨병 치료용도에 관한 것으로, 본 발명에 따른 케타이드 화합물의 제조방법은, 다양한 항 당뇨성 TMPA 유도체 디자인을 유도하는 데 유용할 수 있으며, 기존의 다단계 합성에 비해 효율적이라는 장점이 있다. 또한, 본 발명에 따른 케타이드 화합물들은 강력한 AMPK 활성을 가져 당뇨병 치료제로 유용하게 사용될 수 있을 것으로 기대된다.The present invention relates to a ketide compound, a method for preparing the same, and a use for treating diabetes thereof, and the method for preparing a ketide compound according to the present invention may be useful for inducing a variety of anti-diabetic TMPA derivative designs. It has the advantage of being efficient compared to multi-step synthesis. In addition, the ketide compounds according to the present invention are expected to have strong AMPK activity and thus be usefully used as diabetes treatments.

Description

케타이드 화합물, 이의 제조방법, 및 이의 당뇨병 치료용도 {Ketide compounds, method for manufacturing, and use for treating diabetes thereof} Ketide compounds, method for manufacturing, and use for treating diabetes thereof {Ketide compounds, method for manufacturing, and use for treating diabetes thereof}

본 발명은 케타이드 화합물, 이의 제조방법, 및 이의 당뇨병 치료용도에 관한 것이다.The present invention relates to a ketide compound, a method for preparing the same, and use thereof for treating diabetes.

당뇨병 치료제는 고혈당으로 인한 대사 장애 치료에 혁명을 일으켰다. 예를 들어, 글루카곤 유사 펩타이드 (GLP) 작용제, 포타슘 채널 억제제, AMP- 활성 단백질 키나아제 (AMPK) 신호 활성제, α- 글루코시다아제 억제제 및 PPAR-γ 억제제와 같은 항 당뇨병 제제는 효과적인 의약품 제재로 주목받고 있다. 특히, 메트포민은 AMPK 신호 전달 향상을 통해 인슐린 저항성을 감소시키는 치료제로 가장 많이 처방되고 있다. Diabetes treatments revolutionized the treatment of metabolic disorders caused by hyperglycemia. For example, antidiabetic agents such as glucagon-like peptide (GLP) agonists, potassium channel inhibitors, AMP-activated protein kinase (AMPK) signal activators, α-glucosidase inhibitors, and PPAR-γ inhibitors are attracting attention as effective pharmaceutical formulations. have. In particular, metformin is most often prescribed as a therapeutic agent for reducing insulin resistance through improved AMPK signaling.

2000년에 천연 옥타케타이드 대사 산물인 사이토스포론 A와 B가 기생균류 인 Cytospora sp. CR200 및 Diaporthe sp. CR146 두 종류에서 분리되었다. 특히 사이토스포론 B는 LKB1 매개 AMPK 활성화 제어를 자극 할 수 있는 핵 고아 수용체 77(Nur77)의 리간드 결합 도메인과 직접 상호 작용하는 것으로 입증된 바 있다. In 2000, the natural octaketide metabolites, cytosporons A and B, were parasitic fungi Cytospora sp. CR200 and Diaporthe sp. CR146 was separated from two types. In particular, cytosporon B has been demonstrated to directly interact with the ligand binding domain of nuclear orphan receptor 77 (Nur77), which can stimulate the control of LKB1-mediated AMPK activation.

또한, 비천연물인 TMPA(에틸 2-[2,3,4-트리메톡시-6-(1-옥타노일)페닐]아세테이트) 역시 Nur77-LKB1 상호 작용을 차단함으로써 AMPK 인산화를 향상시키는 것으로 밝혀졌다.In addition, non-natural TMPA (ethyl 2-[2,3,4-trimethoxy-6-(1-octanoyl)phenyl]acetate) was also found to enhance AMPK phosphorylation by blocking Nur77-LKB1 interaction. .

강력한 항 당뇨병 활성과 비교적 단순한 TMPA 구조에도 불구하고 TMPA의 제조를 위한 합성 전략이 연구된 바 있다. 그러나, 이러한 합성 전략은 Friedel-Craft 분자 내 아실화, OsO4- 매개 디 히드록시화 및 Pinick 산화와 같은 다단계 합성과 가혹한 반응 조건이라는 단점을 가지고 있다(도 1). 따라서, 합성 단계가 짧은 다양한 TMPA 유도체를 합성하는 보다 효율적인 방법의 개발이 필요한 실정이었다.Synthetic strategies for the production of TMPA have been studied despite its strong antidiabetic activity and relatively simple TMPA structure. However, this synthesis strategy has the disadvantages of multi-step synthesis and harsh reaction conditions such as acylation, OsO4-mediated dihydroxylation, and Pinick oxidation in the Friedel-Craft molecule (Fig. 1). Therefore, there is a need to develop a more efficient method for synthesizing various TMPA derivatives with short synthesis steps.

최근 촉매성 탄소-수소 관능화는 생물학적으로 적절한 유기 분자의 합성을 위한 온화하고 경제적인 경로로서 인식되어왔다. Recently, catalytic carbon-hydrogen functionalization has been recognized as a gentle and economical route for the synthesis of biologically suitable organic molecules.

앞서 W. Chan, S.-F. Lo, Z. Zhou, W.-Y. Yu, J. Am. Chem . Soc . 2012, 134, 13565. 에서 발표된 탄소-수소 관능화에 대한 촉매 카베노이드 삽입 반응에 대한 연구로부터, 탄소-수소 알킬화 및 헤테로 사이클 형성을 위해 디아조 화합물을 사용하는 유도 보조 탄소(sp2)-수소 관능화가 집중적으로 연구되었다. 특히, 멜드럼 디아조 화합물은 상응하는 알킬화 및/또는 고리화된 부가물을 제공하는 새로운 종류의 α-디아조 시약으로서 이용되었다. Earlier, W. Chan, S.-F. Lo, Z. Zhou, W.-Y. Yu, J. Am. Chem . Soc . 2012 , 134 , 13565. From the study of the catalytic carbenoid insertion reaction for carbon-hydrogen functionalization, published in 2012, 134, 13565. Inducible auxiliary carbon (sp2)-hydrogen using diazo compounds for carbon-hydrogen alkylation and heterocycle formation. Functionalization has been studied intensively. In particular, Meldrum diazo compounds have been used as a new class of α-diazo reagents providing the corresponding alkylated and/or cyclized adducts.

한편, 촉매 탄소-수소 관능화에 기반한 생물학적 활성 화합물에 대한 연구에서 본 발명자는 알코올을 이용한 아세토페논의 이리듐(III) 촉매 α-알킬화와, 아세트페논과 멜드럼 디아조 에스터의 케톤-유도 이리듐(III) 및 로듐(III) 촉매의 오르토-탄소-수소 알킬화 반응을 밝혀냈다.On the other hand, in the study of biologically active compounds based on catalytic carbon-hydrogen functionalization, the present inventors have studied the iridium (III) catalytic α-alkylation of acetophenone using alcohol, and ketone-derived iridium of acetophenone and meldrum diazo ester ( III) and the ortho-carbon-hydrogen alkylation reaction of the rhodium(III) catalyst was found.

본 발명은 케타이드 화합물, 이의 제조방법을 제공함으로써 효율적 제조방법, 및 당뇨병 치료에 사용할 수 있는 화합물들을 제공하는 것이다.The present invention provides a ketide compound and a method for preparing the same, thereby providing an efficient method for preparing and compounds that can be used in diabetes treatment.

본 발명은 하기 화학식 1 또는 화학식 2로 표시되는 화합물, 이의 이성질체, 또는 이의 약학적으로 허용가능한 염을 제공할 수 있다 :The present invention can provide a compound represented by the following Formula 1 or Formula 2, an isomer thereof, or a pharmaceutically acceptable salt thereof:

[화학식 1][Formula 1]

Figure 112018005760933-pat00001
Figure 112018005760933-pat00001

[화학식 2][Formula 2]

Figure 112018005760933-pat00002
Figure 112018005760933-pat00002

상기 화학식 1 또는 2에서,In Formula 1 or 2,

R1 내지 R4는 각각 독립적으로 수소, 히드록시, 또는 알콕시이고, R 1 to R 4 are each independently hydrogen, hydroxy, or alkoxy,

R5는 C1-C10의 직쇄 또는 분지쇄 알킬이며, R 5 is C 1 -C 10 straight or branched chain alkyl,

R6는 히드록시 또는 알콕시이다,R 6 is hydroxy or alkoxy,

그리고, 상기 화학식 1 또는 2에서, R1 내지 R4는 각각 독립적으로 수소, 히드록시, 또는 메톡시 이고, R5는 메틸, 에틸, 프로필, 부틸, 펜틸, 헥실, 헵틸, 또는 옥틸 이며, R6는 히드록시, 메톡시, 에톡시, OiPr, OnBu, 또는 OBn 일 수 있다.And, in Formula 1 or 2, R 1 to R 4 are each independently hydrogen, hydroxy, or methoxy, R 5 is methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, or octyl, and R 6 may be hydroxy, methoxy, ethoxy, O i Pr, O n Bu, or OBn.

또한, 상기 화합물은 하기 화합물들로 이루어진 군으로부터 선택될 수 있다 :In addition, the compound may be selected from the group consisting of the following compounds:

Ethyl 2-(6-hexanoyl-2,3,4-trimethoxyphenyl)acetate (화합물 5aa),Ethyl 2-(6-hexanoyl-2,3,4-trimethoxyphenyl)acetate (compound 5aa),

Ethyl 2-(6-heptanoyl-2,3,4-trimethoxyphenyl)acetate (화합물 5ab),Ethyl 2-(6-heptanoyl-2,3,4-trimethoxyphenyl)acetate (compound 5ab),

Ethyl 2-(2,3,4-trimethoxy-6-octanoylphenyl)acetate (화합물 5ac),Ethyl 2-(2,3,4-trimethoxy-6-octanoylphenyl)acetate (compound 5ac),

Ethyl 2-(2,3,4-trimethoxy-6-nonanoylphenyl)acetate (화합물 5ad),Ethyl 2-(2,3,4-trimethoxy-6-nonanoylphenyl)acetate (compound 5ad),

Ethyl 2-(2-hexanoyl-3-methoxyphenyl)acetate (화합물 5ba),Ethyl 2-(2-hexanoyl-3-methoxyphenyl)acetate (compound 5ba),

Ethyl 2-(2-heptanoyl-3-methoxyphenyl)acetate (화합물 5bb),Ethyl 2-(2-heptanoyl-3-methoxyphenyl)acetate (compound 5bb),

Ethyl 2-(3-methoxy-2-octanoylphenyl)acetate (화합물 5bc),Ethyl 2-(3-methoxy-2-octanoylphenyl)acetate (compound 5bc),

Ethyl 2-(3-methoxy-2-nonanoylphenyl)acetate (화합물 5bd),Ethyl 2-(3-methoxy-2-nonanoylphenyl)acetate (compound 5bd),

Ethyl 2-(2-hexanoyl-3,5-dimethoxyphenyl)acetate (화합물 5ca),Ethyl 2-(2-hexanoyl-3,5-dimethoxyphenyl)acetate (compound 5ca),

Ethyl 2-(2-heptanoyl-3,5-dimethoxyphenyl)acetate (화합물 5cb),Ethyl 2-(2-heptanoyl-3,5-dimethoxyphenyl)acetate (compound 5cb),

Ethyl 2-(3,5-dimethoxy-2-octanoylphenyl)acetate (화합물 5cc),Ethyl 2-(3,5-dimethoxy-2-octanoylphenyl)acetate (compound 5cc),

Ethyl 2-(3,5-dimethoxy-2-nonanoylphenyl)acetate (화합물 5cd),Ethyl 2-(3,5-dimethoxy-2-nonanoylphenyl)acetate (compound 5cd),

Ethyl 2-(2-hexanoyl-5-methoxyphenyl)acetate (화합물 5da),Ethyl 2-(2-hexanoyl-5-methoxyphenyl)acetate (compound 5da),

Ethyl 2-(2-heptanoyl-5-methoxyphenyl)acetate (화합물 5db),Ethyl 2-(2-heptanoyl-5-methoxyphenyl)acetate (compound 5db),

Ehyl 2-(5-methoxy-2-octanoylphenyl)acetate (화합물 5dc),Ehyl 2-(5-methoxy-2-octanoylphenyl)acetate (compound 5dc),

Ethyl 2-(5-methoxy-2-nonanoylphenyl)acetate (화합물 5dd),Ethyl 2-(5-methoxy-2-nonanoylphenyl)acetate (compound 5dd),

Ethyl 2-(2-hexanoyl-4-methoxyphenyl)acetate (화합물 5ea),Ethyl 2-(2-hexanoyl-4-methoxyphenyl)acetate (compound 5ea),

Ethyl 2-(2-hexanoyl-6-methoxyphenyl)acetate (화합물 5ea'),Ethyl 2-(2-hexanoyl-6-methoxyphenyl)acetate (compound 5ea'),

Ethyl 2-(2-heptanoyl-4-methoxyphenyl)acetate (화합물 5eb),Ethyl 2-(2-heptanoyl-4-methoxyphenyl)acetate (compound 5eb),

Ethyl 2-(2-heptanoyl-6-methoxyphenyl)acetate (화합물 5eb'),Ethyl 2-(2-heptanoyl-6-methoxyphenyl)acetate (compound 5eb'),

Ethyl 2-(4-methoxy-2-octanoylphenyl)acetate (화합물 5ec),Ethyl 2-(4-methoxy-2-octanoylphenyl)acetate (compound 5ec),

Ethyl 2-(2-methoxy-6-octanoylphenyl)acetate (화합물 5ec'),Ethyl 2-(2-methoxy-6-octanoylphenyl)acetate (compound 5ec'),

Ethyl 2-(4-methoxy-2-nonanoylphenyl)acetate (화합물 5ed),Ethyl 2-(4-methoxy-2-nonanoylphenyl)acetate (compound 5ed),

Ethyl 2-(2-methoxy-6-nonanoylphenyl)acetate (화합물 5ed'),Ethyl 2-(2-methoxy-6-nonanoylphenyl)acetate (compound 5ed'),

Methyl 2-(2,3,4-trimethoxy-6-octanoylphenyl)acetate (화합물 6aa),Methyl 2-(2,3,4-trimethoxy-6-octanoylphenyl)acetate (compound 6aa),

Isopropyl 2-(2,3,4-trimethoxy-6-octanoylphenyl)acetate (화합물 6ab),Isopropyl 2-(2,3,4-trimethoxy-6-octanoylphenyl)acetate (compound 6ab),

Butyl 2-(2,3,4-trimethoxy-6-octanoylphenyl)acetate (화합물 6ac),Butyl 2-(2,3,4-trimethoxy-6-octanoylphenyl)acetate (compound 6ac),

Benzyl 2-(2,3,4-trimethoxy-6-octanoylphenyl)acetate (화합물 6ad),Benzyl 2-(2,3,4-trimethoxy-6-octanoylphenyl)acetate (compound 6ad),

Ethyl 2-(3-hydroxy-5-methoxy-2-octanoylphenyl)acetate (화합물 7a),Ethyl 2-(3-hydroxy-5-methoxy-2-octanoylphenyl)acetate (compound 7a),

2-(3,5-Dimethoxy-2-octanoylphenyl)acetic acid (화합물 7b), 및2-(3,5-Dimethoxy-2-octanoylphenyl)acetic acid (compound 7b), and

1-Heptyl-6,8-dimethoxyisochromane (화합물 7c).1-Heptyl-6,8-dimethoxyisochromane (Compound 7c).

한편, 본 발명은 이리듐 촉매 또는 로듐 촉매 존재 하에서, 하기 화학식 3로 표시되는 화합물을 하기 화학식 4로 표시되는 화합물과 반응시키는 단계를 포함하는, 하기 화학식 1 또는 화학식 2로 표시되는 화합물의 제조방법을 제공할 수 있다.On the other hand, the present invention provides a method for preparing a compound represented by Formula 1 or Formula 2, comprising reacting a compound represented by Formula 3 with a compound represented by Formula 4 in the presence of an iridium catalyst or a rhodium catalyst. Can provide.

[화학식 1][Formula 1]

Figure 112018005760933-pat00003
Figure 112018005760933-pat00003

[화학식 2][Formula 2]

Figure 112018005760933-pat00004
Figure 112018005760933-pat00004

[화학식 3] [Formula 3]

Figure 112018005760933-pat00005
Figure 112018005760933-pat00005

[화학식 4][Formula 4]

Figure 112018005760933-pat00006
Figure 112018005760933-pat00006

상기 화학식 1 또는 2에서,In Formula 1 or 2,

R1 내지 R4는 각각 독립적으로 수소, 히드록시, 또는 알콕시이고, R 1 to R 4 are each independently hydrogen, hydroxy, or alkoxy,

R5는 C1-C10의 직쇄 또는 분지쇄 알킬이며, R 5 is C 1 -C 10 straight or branched chain alkyl,

R6는 히드록시 또는 알콕시이다,R 6 is hydroxy or alkoxy,

또한, 상기 이리듐 촉매는 이리듐(III)-촉매 [IrCp*Cl2]2 일 수 있으며, 상기 로듐 촉매는 로듐(III)-촉매 [RhCp*Cl2]2 일 수 있고, 상기 화학식 3로 표시되는 화합물을 화학식 4로 표시되는 화합물과 반응시키는 단계는 첨가제 존재 하에서 반응시킬 수 있다. In addition, the iridium catalyst may be an iridium (III)-catalyst [IrCp*Cl 2 ] 2 , and the rhodium catalyst may be a rhodium (III)-catalyst [RhCp*Cl 2 ] 2 , and represented by Formula 3 The step of reacting the compound with the compound represented by Formula 4 may be reacted in the presence of an additive.

상기 첨가제는 알코올 및 실버아세테이트(AgOAc)일 수 있으며, 상기 화학식 3로 표시되는 화합물을 화학식 4로 표시되는 화합물과 반응시키는 단계는 Dichloroethylene(DCE) 용매 하에서 반응할 수 있다.The additive may be alcohol and silver acetate (AgOAc), and the step of reacting the compound represented by Formula 3 with the compound represented by Formula 4 may be reacted in a dichloroethylene (DCE) solvent.

한편, 본 발명은 상기 화합물들, 이의 이성질체, 또는 이의 약학적으로 허용가능한 염을 유효성분으로 포함하는 당뇨병 치료용 약학적 조성물을 제공할 수 있다.On the other hand, the present invention can provide a pharmaceutical composition for treating diabetes comprising the compounds, isomers thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

또한, 본 발명은 상기 화합물들, 이의 이성질체, 또는 이의 약학적으로 허용가능한 염을 유효성분으로 포함하는 조성물을 개체에 투여하는 단계를 포함하는 당뇨병 치료방법을 제공할 수 있다.In addition, the present invention can provide a method for treating diabetes comprising administering to a subject a composition comprising the compounds, isomers thereof, or pharmaceutically acceptable salts thereof as an active ingredient.

그리고, 본 발명은 상기 화합물들, 이의 이성질체, 또는 이의 약학적으로 허용가능한 염의 당뇨병 치료용도를 제공할 수 있다.Further, the present invention can provide the use of the compounds, isomers thereof, or pharmaceutically acceptable salts thereof for the treatment of diabetes.

본 발명에 따른 케타이드 화합물의 제조방법은, 아세토페논과 알콜의 이리듐(III) 촉매를 통한 α-알킬화와, 멜드럼 다이아조 물질을 사용한 α-알킬화된 아세토페논의 케톤으로 유도된 이리듐(III) 또는 로듐(III) 촉매의 산화 환원 중립적인 탄소-수소 알킬화 반응으로만 제조될 수 있고, 이러한 제조방법은 위치 선택성과 기능기 호환성을 가진 TMPA 유도체의 범위를 효과적으로 제공할 수 있으며, TMPA 유도체의 위치 선택적인 탈 메틸화는 천연물인 포모신C를 좋은 수율로 제공할 수 있다는 효과를 가진다.The method for preparing a ketide compound according to the present invention includes α-alkylation of acetophenone and alcohol through an iridium (III) catalyst, and iridium (III) derived from a ketone of α-alkylated acetophenone using a Meldrum diazo material. ) Or rhodium (III) catalyst can be prepared only by a redox-neutral carbon-hydrogen alkylation reaction, and this production method can effectively provide a range of TMPA derivatives with site selectivity and functional group compatibility, and Regio-selective demethylation has the effect that it can provide the natural product, formosin C, in good yield.

아울러, 이러한 제조방법은 다양한 항 당뇨성 TMPA 유도체 디자인을 유도하는 데 유용할 수 있으며, 기존의 다단계 합성에 비해 효율적이라는 장점이 있다.In addition, this manufacturing method can be useful in inducing the design of various anti-diabetic TMPA derivatives, and has the advantage of being efficient compared to the existing multi-step synthesis.

그리고, 본 발명에 따른 케타이드 화합물들은 강력한 AMPK 활성을 가져 당뇨병 치료제로 유용하게 사용될 수 있을 것으로 기대된다.In addition, the ketide compounds according to the present invention are expected to have strong AMPK activity and thus be usefully used as diabetes treatments.

도 1은, 종래 TMPA의 제조방법과 본 발명에 따른 TMPA의 제조방법을 도시한 반응식이다.
도 2는, 본 발명에 따른 α-알킬화된 아세토페논의 제조방법을 도시한 반응식이다.
도 3은, α-알킬화 아세토페논 화합물 3ab-3ed를 멜드럼 디아조에스터(4a)와 반응시켜 화합물 5aa 내지 5ed'를 수득하는 반응식이다.
도 4는, 본 발명에 따른 화합물 6ab-6ad를 수득하는 반응식이다.
도 5는, 본 발명에 따른 화합물 7a-7c를 수득하는 반응식이다.
도 6은, AMPK 활성화에 대한 본 발명에 따른 화합물들의 효능을 대조군과 비교한 그래프이다.
도 7은, AMPK 활성화에 대한 in vitro 결과를 바탕으로, streptozotocin 유도 당뇨병 동물 모델을 사용하여 화합물 5ac와 화합물 5cd의 생체 내 항당뇨성을 평가한 그래프이다.1 is a reaction scheme showing a conventional method for preparing TMPA and a method for preparing TMPA according to the present invention.
2 is a reaction scheme showing a method for preparing α-alkylated acetophenone according to the present invention.
3 is a reaction scheme for obtaining compounds 5aa to 5ed' by reacting α-alkylated acetophenone compound 3ab-3ed with a meldrum diazoester (4a).
4 is a reaction scheme for obtaining compound 6ab-6ad according to the present invention.
5 is a reaction scheme for obtaining compounds 7a-7c according to the present invention.
6 is a graph comparing the efficacy of the compounds according to the present invention on AMPK activation with a control group.
7 is a graph for evaluating in vivo antidiabetic properties of compound 5ac and compound 5cd using a streptozotocin-induced diabetes animal model based on in vitro results for AMPK activation.

본 발명은 다양한 변환을 가할 수 있고 여러 가지 실시예를 가질 수 있는 바, 특정 실시예들을 도면에 예시하고 상세한 설명에 상세하게 설명하고자 한다. 그러나, 이는 본 발명을 특정한 실시 형태에 대해 한정하려는 것이 아니며, 본 발명의 사상 및 기술 범위에 포함되는 모든 변환, 균등물 내지 대체물을 포함하는 것으로 이해되어야 한다. 본 발명을 설명함에 있어서 관련된 공지 기술에 대한 구체적인 설명이 본 발명의 요지를 흐릴 수 있다고 판단되는 경우 그 상세한 설명을 생략한다.Since the present invention can apply various transformations and have various embodiments, specific embodiments are illustrated in the drawings and will be described in detail in the detailed description. However, this is not intended to limit the present invention to a specific embodiment, it is to be understood to include all conversions, equivalents, and substitutes included in the spirit and scope of the present invention. In describing the present invention, when it is determined that a detailed description of a related known technology may obscure the subject matter of the present invention, a detailed description thereof will be omitted.

본 발명은, 하기 화학식 1 또는 화학식 2로 표시되는 화합물, 이의 이성질체, 또는 이의 약학적으로 허용가능한 염을 제공한다.The present invention provides a compound represented by the following Formula 1 or Formula 2, an isomer thereof, or a pharmaceutically acceptable salt thereof.

[화학식 1][Formula 1]

Figure 112018005760933-pat00007
Figure 112018005760933-pat00007

[화학식 2][Formula 2]

Figure 112018005760933-pat00008
Figure 112018005760933-pat00008

상기 화학식 1 또는 2에서,In Formula 1 or 2,

R1 내지 R4는 각각 독립적으로 수소, 히드록시, 또는 알콕시이고, R 1 to R 4 are each independently hydrogen, hydroxy, or alkoxy,

R5는 C1-C10의 직쇄 또는 분지쇄 알킬이며, R 5 is C 1 -C 10 straight or branched chain alkyl,

R6는 히드록시 또는 알콕시이다,R 6 is hydroxy or alkoxy,

또한, 본 발명의 다른 측면에 따르면 이리듐 촉매 또는 로듐 촉매 존재 하에서, 하기 화학식 3로 표시되는 화합물을 하기 화학식 4로 표시되는 화합물과 반응시키는 단계를 포함하는, 하기 화학식 1 또는 화학식 2로 표시되는 화합물의 제조방법을 제공한다.In addition, according to another aspect of the present invention, in the presence of an iridium catalyst or a rhodium catalyst, a compound represented by the following Formula 1 or Formula 2 comprising the step of reacting a compound represented by the following Formula 3 with a compound represented by the following Formula 4 It provides a method of manufacturing.

[화학식 1][Formula 1]

Figure 112018005760933-pat00009
Figure 112018005760933-pat00009

[화학식 2][Formula 2]

Figure 112018005760933-pat00010
Figure 112018005760933-pat00010

[화학식 3][Formula 3]

Figure 112018005760933-pat00011
Figure 112018005760933-pat00011

[화학식 4][Formula 4]

Figure 112018005760933-pat00012
Figure 112018005760933-pat00012

상기 화학식 1 또는 2에서,In Formula 1 or 2,

R1 내지 R4는 각각 독립적으로 수소, 히드록시, 또는 알콕시이고, R 1 to R 4 are each independently hydrogen, hydroxy, or alkoxy,

R5는 C1-C10의 직쇄 또는 분지쇄 알킬이며, R 5 is C 1 -C 10 straight or branched chain alkyl,

R6는 히드록시 또는 알콕시이다,R 6 is hydroxy or alkoxy,

종래 TMPA의 합성 방법은 Friedel-Craft 분자 내 아실화, OsO4- 매개 디 히드록시화 및 Pinick 산화와 같은 다단계 합성과 가혹한 반응 조건을 필요로 한다는 문제점이 있었다.Conventional methods for synthesizing TMPA have a problem in that it requires multi-step synthesis and severe reaction conditions such as acylation in Friedel-Craft molecules, OsO4-mediated dihydroxylation, and Pinick oxidation.

이에 본 발명자들은, 아세토페논과 알콜의 이리듐(III) 촉매를 통한 α-알킬화 반응과, 멜드럼 다이아조 물질을 사용한 α-알킬화된 아세토페논의 케톤으로 유도된 이리듐(III) 또는 로듐(III) 촉매의 산화 환원 중립적인 탄소-수소 알킬화 반응을 거치는 경우, 효율적으로 TMPA 유도체들의 제조가 가능하다는 점을 실험을 통하여 확인하고 발명을 완성하였다.Therefore, the present inventors, iridium (III) or rhodium (III) derived from the ketone of α-alkylated acetophenone using a meldrum diazo material and α-alkylation reaction through an iridium (III) catalyst of acetophenone and alcohol When the catalyst undergoes an oxidation-reduction neutral carbon-hydrogen alkylation reaction, it was confirmed through an experiment that TMPA derivatives can be efficiently produced, and the invention was completed.

이하 발명의 구체적인 구현예에 따른 케타이드 화합물, 이의 제조방법, 및 이의 당뇨병 치료용도에 관하여 보다 상세하게 설명하기로 한다.Hereinafter, a ketide compound according to a specific embodiment of the present invention, a method for preparing the same, and a use for treating diabetes thereof will be described in more detail.

아세토페논과 Acetophenone 알콜의Alcoholic 이리듐(III) 촉매를 통한 α-알킬화 반응 Α-alkylation reaction through iridium(III) catalyst

TMPA 유도체의 합성은 α-알킬화된 아세토페논의 제조부터 시작할 수 있다. 도 2에서와 같이, 아세토페논(1a)를 우선 1차알콜(2a-2d)와 결합시켜 이리듐(III) 촉매 하에서 중간 정도의 수율로 α-알킬화된 아세토페논(화합물 3aa 내지 3ed)를 수득할 수 있다.Synthesis of TMPA derivatives can begin with the production of α-alkylated acetophenone. As shown in Figure 2, acetophenone (1a) is first combined with a primary alcohol (2a-2d) to obtain α-alkylated acetophenone (compounds 3aa to 3ed) in an intermediate yield under an iridium (III) catalyst. I can.

또한, 상기 방법은 오르토-, 메타- 및 파라- 위치에 메톡시기를 함유하는 아세토페논(1b-1e)의 범위에 추가로 적용하여, 화학식 3ba-3bd, 3ca-3cd, 3da-3dd 및 3ea -3ed를 중간에서부터 높은 수율까지 얻을 수 있다.In addition, the method is further applied to the range of acetophenone (1b-1e) containing a methoxy group in the ortho-, meta- and para- positions, and formulas 3ba-3bd, 3ca-3cd, 3da-3dd and 3ea- 3ed can be obtained from medium to high yield.

멜드럼Meldrum 다이아조Diazo 물질을 사용한 α-알킬화된 아세토페논의 케톤으로 유도된 이리듐(III) 또는 로듐(III) 촉매의 탄소-수소 알킬화 반응 Carbon-hydrogen alkylation reaction of iridium (III) or rhodium (III) catalysts induced with ketones of α-alkylated acetophenone using material

하기 반응식 1 및 표 1에 나타낸 바와 같이 멜드럼 디아조 에스터(4a)를 모델 기질로 사용하여 아세톤페논(화합물 3aa)의 케톤-유도된 이리듐(III)-촉매 오르토-알킬화를 수행할 수 있다. Ketone-derived iridium (III)-catalyzed ortho-alkylation of acetonephenone (Compound 3aa) can be performed using Meldrum diazo ester (4a) as a model substrate as shown in Scheme 1 and Table 1 below.

에탄올 용매의 존재 하에서 양이온성 이리듐(III) 촉매화를 통한 화합물 3aa와 4a 사이의 커플링 반응은 관찰되지 않았다 (표 1, entry 1). 한편, 에탄올이 DCE 용매에서 첨가제로 사용될 때, 오르토-알킬화 생성물(화합물 5aa)가 22 %의 수율로 얻어졌다(표 1, entry 2). 또한, 아세트산 공급원으로서의 소듐 아세테이트의 처리는 효과적이라는 것이 밝혀졌다(표 1, entry 3). No coupling reaction between compounds 3aa and 4a via cationic iridium (III) catalyzed in the presence of an ethanol solvent was observed (Table 1, entry 1). On the other hand, when ethanol was used as an additive in the DCE solvent, an ortho-alkylated product (compound 5aa) was obtained in a yield of 22% (Table 1, entry 2). In addition, it was found that treatment of sodium acetate as an acetic acid source was effective (Table 1, entry 3).

아울러, 실버 아세테이트 첨가제는 높은 수준의 전환율로 이 반응에서 71 %의 수율로 원하는 생성물(화합물 5aa)를 합성하는 데 매우 중요하다는 것을 알 수 있었다(표 1, entry 4-7). 또한, 상대 음이온 인 AgSbF6 및 AgPF6은 덜 효과적(표 1, entry 8 및 9)이었으며, 로듐(III), 코발트(III) 및 루테늄(II)와 같은 다른 양이온성 전이금속 촉매는 이 커플링 반응에서 효과가 없는 것으로 밝혀졌다(표 1, entry 10-12). In addition, it was found that the silver acetate additive was very important in synthesizing the desired product (compound 5aa) in a yield of 71% in this reaction with a high level of conversion (Table 1, entry 4-7). In addition, the counter anions AgSbF6 and AgPF6 were less effective (Table 1, entries 8 and 9), and other cationic transition metal catalysts such as rhodium (III), cobalt (III) and ruthenium (II) were used in this coupling reaction. It was found to have no effect (Table 1, entry 10-12).

한편, 용매로는 DCE가 THF, 아세토나이트릴 및 톨루엔과 같은 다른 용매보다 우수함을 알 수 있었다(표 1, entry 13-15). Meanwhile, it was found that DCE was superior to other solvents such as THF, acetonitrile, and toluene as a solvent (Table 1, entry 13-15).

또한, 반응 온도는 실온보다는 100℃에서 수율이 높아 높은 수율로 화합물 5aa를 제공하는 알킬화 반응에 온도가 중요하다는 것도 알 수 있었다(표 1, entry 16 및 17).In addition, it was found that the reaction temperature was higher at 100°C than room temperature, so that the temperature was important for the alkylation reaction to provide compound 5aa in high yield (Table 1, entries 16 and 17).

[반응식 1][Scheme 1]

Figure 112018005760933-pat00013
Figure 112018005760933-pat00013

EntryEntry Catalyst (mol %)Catalyst (mol %) Additive (mol %)Additive (mol %) SolventSolvent Yield (%) b Yield (%) b 1One [IrCp*Cl2]2 (2)[IrCp*Cl 2 ] 2 (2) AgNTf2 (8)AgNTf 2 (8) EtOHEtOH N.R.N.R. 22 [IrCp*Cl2]2 (2)[IrCp*Cl 2 ] 2 (2) AgNTf2 (8), EtOH (2 equiv.)AgNTf 2 (8), EtOH (2 equiv.) DCEDCE 2222 33 [IrCp*Cl2]2 (2)[IrCp*Cl 2 ] 2 (2) AgNTf2 (8), NaOAc (8 mol %), EtOH (2 equiv.)AgNTf 2 (8), NaOAc (8 mol %), EtOH (2 equiv.) DCEDCE 4242 44 [IrCp*Cl2]2 (2)[IrCp*Cl 2 ] 2 (2) AgNTf2 (8), CsOAc (8 mol %), EtOH (2 equiv.)AgNTf 2 (8), CsOAc (8 mol %), EtOH (2 equiv.) DCEDCE 5959 55 [IrCp*Cl2]2 (2)[IrCp*Cl 2 ] 2 (2) AgNTf2 (8), LiOAc (8 mol %), EtOH (2 equiv.)AgNTf 2 (8), LiOAc (8 mol %), EtOH (2 equiv.) DCEDCE N.R.N.R. 66 [IrCp*Cl2]2 (2)[IrCp*Cl 2 ] 2 (2) AgNTf2 (8), Cu(OAc)2 (8 mol %), EtOH (2 equiv.)AgNTf 2 (8), Cu(OAc) 2 (8 mol %), EtOH (2 equiv.) DCEDCE 6464 77 [[ IrCpIrCp ** ClCl 22 ]] 22 (2) (2) AgNTfAgNTf 22 (8), (8), AgOAcAgOAc ( ( 8 mol8 mol %% ), ), EtOHEtOH (2 (2 equivequiv .).) DCEDCE 7171 88 [IrCp*Cl2]2 (2)[IrCp*Cl 2 ] 2 (2) AgSbF6 (8), AgOAc (8 mol %), EtOH (2 equiv.)AgSbF 6 (8), AgOAc (8 mol %), EtOH (2 equiv.) DCEDCE 6262 99 [IrCp*Cl2]2 (2)[IrCp*Cl 2 ] 2 (2) AgPF6 (8), AgOAc (8 mol %), EtOH (2 equiv.)AgPF 6 (8), AgOAc (8 mol %), EtOH (2 equiv.) DCEDCE 4343 1010 [RhCp*Cl2]2 (2)[RhCp*Cl 2 ] 2 (2) AgSbF6 (8), AgOAc (8 mol %), EtOH (2 equiv.)AgSbF 6 (8), AgOAc (8 mol %), EtOH (2 equiv.) DCEDCE 88 1111 [CoCp*(CO)I2] (5)[CoCp*(CO)I 2 ] (5) AgNTf2 (10), AgOAc (8 mol %), EtOH (2 equiv.)AgNTf 2 (10), AgOAc (8 mol %), EtOH (2 equiv.) DCEDCE N.R.N.R. 1212 [Ru(p-cymene)Cl2]2 (5)[Ru( p- cymene)Cl 2 ] 2 (5) AgNTf2 (10), AgOAc (8 mol %), EtOH (2 equiv.)AgNTf 2 (10), AgOAc (8 mol %), EtOH (2 equiv.) DCEDCE N.R.N.R. 1313 [IrCp*Cl2]2 (2)[IrCp*Cl 2 ] 2 (2) AgNTf2 (8), AgOAc (8 mol %), EtOH (2 equiv.)AgNTf 2 (8), AgOAc (8 mol %), EtOH (2 equiv.) THFTHF tracetrace 1414 [IrCp*Cl2]2 (2)[IrCp*Cl 2 ] 2 (2) AgNTf2 (8), AgOAc (8 mol %), EtOH (2 equiv.)AgNTf 2 (8), AgOAc (8 mol %), EtOH (2 equiv.) MeCNMeCN N.R.N.R. 1515 [IrCp*Cl2]2 (2)[IrCp*Cl 2 ] 2 (2) AgNTf2 (8), AgOAc (8 mol %), EtOH (2 equiv.)AgNTf 2 (8), AgOAc (8 mol %), EtOH (2 equiv.) toluenetoluene tracetrace 16 c 16 c [IrCp*Cl2]2 (2)[IrCp*Cl 2 ] 2 (2) AgNTf2 (8), AgOAc (8 mol %), EtOH (2 equiv.)AgNTf 2 (8), AgOAc (8 mol %), EtOH (2 equiv.) DCEDCE 5353 17 d 17 d [IrCp*Cl2]2 (2)[IrCp*Cl 2 ] 2 (2) AgNTf2 (8), AgOAc (8 mol %), EtOH (2 equiv.)AgNTf 2 (8), AgOAc (8 mol %), EtOH (2 equiv.) DCEDCE N.R.N.R.

aa 반응 조건: Reaction conditions: 3aa3aa ( ( 0.2 mmol0.2 mmol ), ), 4a4a ( ( 0.24 mmol0.24 mmol ), 용매 (), solvent ( 1 mL1 mL ), ), 공기 하에서Under air 압력 튜브에 20시간 동안 60℃에서 반응. Reaction at 60°C for 20 hours in a pressure tube. bb flash column chromatography에 의한 수율. Yield by flash column chromatography. cc 100 100 oo C에서In C 반응. reaction. dd 실온에서 반응. Reaction at room temperature.

상기에서 도출한 최적의 반응 조건을 이용하여 다양한 α-알킬화 아세토페논 화합물 3ab-3ed를 멜드럼 디아조에스터(4a)와 반응시켰다(도 3). Using the optimum reaction conditions derived above, various α-alkylated acetophenone compounds 3ab-3ed were reacted with Meldrum diazoester (4a) (Fig. 3).

화합물 3ab-3ad는 오르토-알킬화된 TMPA 유도체 화합물 5ab-5ad를 제공하여 우수한 반응성을 나타내는 것으로 나타났다. 특히, TMPA(화합물 5ac, 에틸 2-[2,3,4-트리메톡시-6-(1-옥타노일)페닐]아세테이트)는 아세토페논(1a)와 1차알콜(2c)의 이리듐(III)-촉매된 탄소(sp3)-수소 알킬화 반응에 이어 멜드럼 디아조에스터를 이용한 연속적인 이리듐(III)촉매 오르토-탄소(sp2)-수소 알킬화 반응을 거치는 2단계 반응을 통해 최종 31%의 수율을 얻었다. Compound 3ab-3ad was shown to exhibit excellent reactivity by providing the ortho-alkylated TMPA derivative compound 5ab-5ad. In particular, TMPA (compound 5ac, ethyl 2-[2,3,4-trimethoxy-6-(1-octanoyl)phenyl]acetate) is acetophenone (1a) and iridium (III) of primary alcohol (2c). )-Catalyzed carbon (sp3)-hydrogen alkylation reaction followed by a continuous iridium (III) catalyst ortho-carbon (sp2)-hydrogen alkylation reaction using Meldrum diazoester, resulting in a final 31% yield Got it.

그러나, 오르토 치환된 아세토페논 화합물 3ba의 경우, 목적하는 생성물 화합물 5ba의 현저한 감소가 관찰되었다. 또한, 2,4- 디메톡시-치환된 아세토페논 화합물 3ca는 반응 조건 하에서 어떠한 커플링 생성물도 생성되지 않았다. However, in the case of the ortho-substituted acetophenone compound 3ba, a significant decrease in the desired product compound 5ba was observed. In addition, 2,4-dimethoxy-substituted acetophenone compound 3ca did not produce any coupling product under the reaction conditions.

따라서, 본 발명자는 3ba와 4a 사이의 부위 선택적 알킬화를 달성하기 위해 반응 조건을 탐색하였다. Thus, the inventors have explored the reaction conditions to achieve site-selective alkylation between 3ba and 4a.

그 결과, 다른 반응 조건에서 양이온성 Rh (III) 촉매는 원하는 생성물 화합물 5ba를 좋은 수율 (86 %)로 전달하는데 더 효과적이라는 것이 발견되었다. As a result, it was found that under different reaction conditions the cationic Rh (III) catalyst was more effective in delivering the desired product compound 5ba in good yield (86%).

변형된 반응 조건은 오르토 치환된 아세토페논 화합물 3bb-3bd 및 화합물 3ca-3cd에 적용하여 중간 정도 내지 양호한 수율로 상응하는 생성물을 생성할 수 있다. Modified reaction conditions can be applied to ortho-substituted acetophenone compound 3bb-3bd and compound 3ca-3cd to produce the corresponding product in medium to good yield.

또한, 파라 메톡시로 치환된 아세토페논 화합물 3da-3dd는 Ir (III) 촉매 하에서 4a와 결합하여 적당한 수율로 목적한 생성물 화합물 5da-5dd를 제공하는 것으로 밝혀졌다. In addition, it was found that the acetophenone compound 3da-3dd substituted with para-methoxy was combined with 4a under an Ir (III) catalyst to give the desired product compound 5da-5dd in an appropriate yield.

또한, 메타-메톡시로 치환된 아세토페논 화합물 3ea-3ed는 C-6 및 C-2 위치에서 화합물 5ea-5ed 및 화합물 5ea'-5ed'의 위치 이성질체 혼합물을 1 : 2 비율로 제공하였다. 이러한 결과로부터 cyclorhodated 중간체의 형성이 주로 입체 효과 대신 전자 효과에 의해 지배 될 수 있음을 알 수 있었다.In addition, meta-methoxy substituted acetophenone compound 3ea-3ed provided a mixture of positional isomers of compound 5ea-5ed and compound 5ea'-5ed' at positions C-6 and C-2 in a ratio of 1:2. From these results, it was found that the formation of cyclorhodated intermediates could be mainly dominated by electronic effects instead of steric effects.

한편, TMPA에서 에스터 부분의 유도체화에 알코올을 사용할 수 있다. 메탄올의 존재하에서 멜드럼 디아조에스터(4a)와 TMPA 전구체 화합물 3ac의 반응을 동일한 반응 조건으로 수행하여 메틸 에스터 화합물 6aa가 39 %의 수율로 형성될 수 있었다(도 4). 이 과정은 다른 알코올에도 적용되어 상응하는 에스터 유도체 화합물 6ab-6ad를 56-65 %의 수율로 얻을 수 있었다(도 4).On the other hand, alcohol can be used for derivatization of the ester moiety in TMPA. In the presence of methanol, the reaction between the Meldrum diazoester (4a) and the TMPA precursor compound 3ac was performed under the same reaction conditions, so that the methyl ester compound 6aa could be formed in a yield of 39% (FIG. 4). This process was also applied to other alcohols to obtain the corresponding ester derivative compound 6ab-6ad in a yield of 56-65% (FIG. 4).

한편, 0℃ 디클로로메탄 조건에서 BBr3(4 당량)를 사용하여 5cc의 부위-선택적인 탈 메틸화를 수행하여, 맹그로브 기생균류인 Phomopsis sp. ZSU-H76에서 분리된 포모신 C (화합물 7a)를 76 % 수율로 유도하였다(도 5). 또한, 화합물 5cc에 대한 에스터 잔기의 염기성 가수 분해를 시도하여 카르복시산 화합물 7b를 고수율로 수득 하였다(도 5). 또한, NaBH4를 사용하여 케톤을 환원 시킨 후 분자 내 고리화를 통해 유기 합성에서 중요한 합성 중간체로 알려져 있는 3-이소크로마논 화합물 7c의 제조를 수행할 수 있었다(도 5).Meanwhile, 5cc of site-selective demethylation was performed using BBr 3 (4 equivalents) in dichloromethane conditions at 0° C., and the mangrove parasitic fungus Phomopsis sp. Formosine C (compound 7a) isolated from ZSU-H76 was induced in 76% yield (FIG. 5). In addition, basic hydrolysis of the ester residue was attempted with respect to compound 5cc to obtain a carboxylic acid compound 7b in high yield (FIG. 5). In addition, it was possible to prepare 3-isochromanone compound 7c, which is known as an important synthetic intermediate in organic synthesis, through intramolecular cyclization after ketone reduction using NaBH4 (FIG. 5).

본 발명에 따른 화학식 1 또는 화학식 2로 표시되는 화합물은 바람직하게는, 화학식 1 또는 2에서, R1 내지 R4는 각각 독립적으로 수소, 히드록시, 또는 메톡시 이고, R5는 메틸, 에틸, 프로필, 부틸, 펜틸, 헥실, 헵틸, 또는 옥틸 이며, R6는 히드록시, 메톡시, 에톡시, OiPr, OnBu, 또는 OBn 일 수 있으나 이에 제한되지는 아니한다.The compound represented by Formula 1 or Formula 2 according to the present invention is preferably, in Formula 1 or 2, R 1 to R 4 are each independently hydrogen, hydroxy, or methoxy, and R 5 is methyl, ethyl, Propyl, butyl, pentyl, hexyl, heptyl, or octyl, and R 6 may be hydroxy, methoxy, ethoxy, O i Pr, O n Bu, or OBn, but is not limited thereto.

또한, 상기 화합물은 하기 화합물들로 이루어진 군으로부터 선택될 수 있다 :In addition, the compound may be selected from the group consisting of the following compounds:

Ethyl 2-(6-hexanoyl-2,3,4-trimethoxyphenyl)acetate (화합물 5aa),Ethyl 2-(6-hexanoyl-2,3,4-trimethoxyphenyl)acetate (compound 5aa),

Ethyl 2-(6-heptanoyl-2,3,4-trimethoxyphenyl)acetate (화합물 5ab),Ethyl 2-(6-heptanoyl-2,3,4-trimethoxyphenyl)acetate (compound 5ab),

Ethyl 2-(2,3,4-trimethoxy-6-octanoylphenyl)acetate (화합물 5ac),Ethyl 2-(2,3,4-trimethoxy-6-octanoylphenyl)acetate (compound 5ac),

Ethyl 2-(2,3,4-trimethoxy-6-nonanoylphenyl)acetate (화합물 5ad),Ethyl 2-(2,3,4-trimethoxy-6-nonanoylphenyl)acetate (compound 5ad),

Ethyl 2-(2-hexanoyl-3-methoxyphenyl)acetate (화합물 5ba),Ethyl 2-(2-hexanoyl-3-methoxyphenyl)acetate (compound 5ba),

Ethyl 2-(2-heptanoyl-3-methoxyphenyl)acetate (화합물 5bb),Ethyl 2-(2-heptanoyl-3-methoxyphenyl)acetate (compound 5bb),

Ethyl 2-(3-methoxy-2-octanoylphenyl)acetate (화합물 5bc),Ethyl 2-(3-methoxy-2-octanoylphenyl)acetate (compound 5bc),

Ethyl 2-(3-methoxy-2-nonanoylphenyl)acetate (화합물 5bd),Ethyl 2-(3-methoxy-2-nonanoylphenyl)acetate (compound 5bd),

Ethyl 2-(2-hexanoyl-3,5-dimethoxyphenyl)acetate (화합물 5ca),Ethyl 2-(2-hexanoyl-3,5-dimethoxyphenyl)acetate (compound 5ca),

Ethyl 2-(2-heptanoyl-3,5-dimethoxyphenyl)acetate (화합물 5cb),Ethyl 2-(2-heptanoyl-3,5-dimethoxyphenyl)acetate (compound 5cb),

Ethyl 2-(3,5-dimethoxy-2-octanoylphenyl)acetate (화합물 5cc),Ethyl 2-(3,5-dimethoxy-2-octanoylphenyl)acetate (compound 5cc),

Ethyl 2-(3,5-dimethoxy-2-nonanoylphenyl)acetate (화합물 5cd),Ethyl 2-(3,5-dimethoxy-2-nonanoylphenyl)acetate (compound 5cd),

Ethyl 2-(2-hexanoyl-5-methoxyphenyl)acetate (화합물 5da),Ethyl 2-(2-hexanoyl-5-methoxyphenyl)acetate (compound 5da),

Ethyl 2-(2-heptanoyl-5-methoxyphenyl)acetate (화합물 5db),Ethyl 2-(2-heptanoyl-5-methoxyphenyl)acetate (compound 5db),

Ehyl 2-(5-methoxy-2-octanoylphenyl)acetate (화합물 5dc),Ehyl 2-(5-methoxy-2-octanoylphenyl)acetate (compound 5dc),

Ethyl 2-(5-methoxy-2-nonanoylphenyl)acetate (화합물 5dd),Ethyl 2-(5-methoxy-2-nonanoylphenyl)acetate (compound 5dd),

Ethyl 2-(2-hexanoyl-4-methoxyphenyl)acetate (화합물 5ea),Ethyl 2-(2-hexanoyl-4-methoxyphenyl)acetate (compound 5ea),

Ethyl 2-(2-hexanoyl-6-methoxyphenyl)acetate (화합물 5ea'),Ethyl 2-(2-hexanoyl-6-methoxyphenyl)acetate (compound 5ea'),

Ethyl 2-(2-heptanoyl-4-methoxyphenyl)acetate (화합물 5eb),Ethyl 2-(2-heptanoyl-4-methoxyphenyl)acetate (compound 5eb),

Ethyl 2-(2-heptanoyl-6-methoxyphenyl)acetate (화합물 5eb'),Ethyl 2-(2-heptanoyl-6-methoxyphenyl)acetate (compound 5eb'),

Ethyl 2-(4-methoxy-2-octanoylphenyl)acetate (화합물 5ec),Ethyl 2-(4-methoxy-2-octanoylphenyl)acetate (compound 5ec),

Ethyl 2-(2-methoxy-6-octanoylphenyl)acetate (화합물 5ec'),Ethyl 2-(2-methoxy-6-octanoylphenyl)acetate (compound 5ec'),

Ethyl 2-(4-methoxy-2-nonanoylphenyl)acetate (화합물 5ed),Ethyl 2-(4-methoxy-2-nonanoylphenyl)acetate (compound 5ed),

Ethyl 2-(2-methoxy-6-nonanoylphenyl)acetate (화합물 5ed'),Ethyl 2-(2-methoxy-6-nonanoylphenyl)acetate (compound 5ed'),

Methyl 2-(2,3,4-trimethoxy-6-octanoylphenyl)acetate (화합물 6aa),Methyl 2-(2,3,4-trimethoxy-6-octanoylphenyl)acetate (compound 6aa),

Isopropyl 2-(2,3,4-trimethoxy-6-octanoylphenyl)acetate (화합물 6ab),Isopropyl 2-(2,3,4-trimethoxy-6-octanoylphenyl)acetate (compound 6ab),

Butyl 2-(2,3,4-trimethoxy-6-octanoylphenyl)acetate (화합물 6ac),Butyl 2-(2,3,4-trimethoxy-6-octanoylphenyl)acetate (compound 6ac),

Benzyl 2-(2,3,4-trimethoxy-6-octanoylphenyl)acetate (화합물 6ad),Benzyl 2-(2,3,4-trimethoxy-6-octanoylphenyl)acetate (compound 6ad),

Ethyl 2-(3-hydroxy-5-methoxy-2-octanoylphenyl)acetate (화합물 7a),Ethyl 2-(3-hydroxy-5-methoxy-2-octanoylphenyl)acetate (compound 7a),

2-(3,5-Dimethoxy-2-octanoylphenyl)acetic acid (화합물 7b), 및2-(3,5-Dimethoxy-2-octanoylphenyl)acetic acid (compound 7b), and

1-Heptyl-6,8-dimethoxyisochromane (화합물 7c).1-Heptyl-6,8-dimethoxyisochromane (Compound 7c).

한편, 상술한 바와 같이 본 발명은 이리듐 촉매 또는 로듐 촉매 존재 하에서, 하기 화학식 3로 표시되는 화합물을 하기 화학식 4로 표시되는 화합물과 반응시키는 단계를 포함하는, 하기 화학식 1 또는 화학식 2로 표시되는 화합물의 제조방법을 제공할 수 있다.Meanwhile, as described above, the present invention comprises the step of reacting a compound represented by the following formula 3 with a compound represented by the following formula 4 in the presence of an iridium catalyst or a rhodium catalyst, a compound represented by the following formula 1 or formula 2 It can provide a manufacturing method of.

[화학식 3][Formula 3]

Figure 112018005760933-pat00014
Figure 112018005760933-pat00014

[화학식 4][Formula 4]

Figure 112018005760933-pat00015
Figure 112018005760933-pat00015

상기 화학식에서,In the above formula,

R1 내지 R4는 각각 독립적으로 수소, 히드록시, 또는 알콕시이고, R 1 to R 4 are each independently hydrogen, hydroxy, or alkoxy,

R5는 C1-C10의 직쇄 또는 분지쇄 알킬이다.R 5 is C 1 -C 10 straight or branched chain alkyl.

이하, 본 발명의 바람직한 실시예를 첨부도면을 참조하여 상세히 설명하기로 한다. 다만, 이들 실시예는 오로지 본 발명을 예시하기 위한 것으로서, 본 발명의 범위가 이들 실시예에 의해 제한되는 것으로 해석되지는 않는다 할 것이다.Hereinafter, preferred embodiments of the present invention will be described in detail with reference to the accompanying drawings. However, these examples are for illustrative purposes only, and the scope of the present invention will not be construed as being limited by these examples.

제조예Manufacturing example 1 : α- 1: α- alkylatedalkylated acetophenonesacetophenones (화합물 (compound 3aa3aa -- 3ed3ed )의 제조) Of manufacture

1-(3,4,5-트리메톡시페닐)에탄-1-온(1a) (1.1 g, 5 mmol, 100 mol %), [IrCp*Cl2]2 (39.8 mg, 0.05 mmol, 1 mol %) 및 NaOH pellets (0.2 g, 5 mmol, 100 mol %)으로 충전된 오븐-건조된 밀봉 튜브에 n-부틸 알코올(2a) (0.41 g, 5.5 mmol, 110 mol %) 및 톨루엔 (0.5mol)을 실온에서 공기 중에서 첨가하였다.1-(3,4,5-trimethoxyphenyl)ethan-1-one (1a) (1.1 g, 5 mmol, 100 mol %), [IrCp*Cl 2 ] 2 (39.8 mg, 0.05 mmol, 1 mol %) and NaOH pellets (0.2 g, 5 mmol, 100 mol %) in an oven-dried sealed tube filled with n-butyl alcohol (2a) (0.41 g, 5.5 mmol, 110 mol %) and toluene (0.5 mol) in air at room temperature. Added.

반응 혼합물을 110 ℃에서 17 시간 동안 교반 하였다. 반응 혼합물을 실온으로 냉각시키고 EtOAc (2 x 15 mL)로 추출 하였다. 유기층을 염수 용액 (2 x 60 mL)으로 세척하고, MgSO4로 건조시키고, 여과하고, 진공에서 농축시켰다. 잔류물을 플래시 컬럼 크로마토그래피 (n- 헥산 / EtOAc = 200 : 1)로 정제하여 3aa (0.67 g, 50 %)를 황색 오일로서 수득하였다.The reaction mixture was stirred at 110° C. for 17 hours. The reaction mixture was cooled to room temperature and extracted with EtOAc (2 x 15 mL). The organic layer was washed with brine solution (2 x 60 mL), dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (n-hexane / EtOAc = 200: 1) to give 3aa (0.67 g, 50%) as a yellow oil.

상기와 같이 같은 방식으로 화합물 3ab-3ed 를 제조하였고, 하기에 특성을 나타내었다.Compound 3ab-3ed was prepared in the same manner as described above, and the properties were shown below.

1-(3,4,5-1-(3,4,5- TrimethoxyphenylTrimethoxyphenyl )) hexanhexan -1-one (-1-one ( 3aa3aa ))

Figure 112018005760933-pat00016
Figure 112018005760933-pat00016

0.67 g (50%); yellowish oil; 1H NMR (400 MHz, CDCl3) δ 7.21 (s, 2H), 3.92 (s, 6H), 3.91 (s, 3H), 2.92 (t, J = 7.2 Hz, 2H), 1.76-1.70 (m, 2H), 1.38-1.34 (m, 4H), 0.91 (t, J = 6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 199.3, 153.0, 142.4, 132.4, 105.6, 60.9, 56.3, 38.3, 31.5, 24.2, 22.5, 13.9; IR (KBr) υ 2933, 2871, 1679, 1583, 1504, 1455, 1411, 1329, 1230, 1158, 1123, 1003, 865, 824 cm-1; HRMS (quadrupole, EI) calcd for C15H22O4 [M]+ 266.1518, found 266.1516. 0.67 g (50%); yellowish oil;OneH NMR (400 MHz, CDCl3) δ 7.21 (s, 2H), 3.92 (s, 6H), 3.91 (s, 3H), 2.92 (t,J = 7.2 Hz, 2H), 1.76-1.70 (m, 2H), 1.38-1.34 (m, 4H), 0.91 (t,J = 6.4 Hz, 3H);13C NMR (100 MHz, CDCl3) δ 199.3, 153.0, 142.4, 132.4, 105.6, 60.9, 56.3, 38.3, 31.5, 24.2, 22.5, 13.9; IR (KBr) υ 2933, 2871, 1679, 1583, 1504, 1455, 1411, 1329, 1230, 1158, 1123, 1003, 865, 824 cm-One; HRMS (quadrupole, EI) calcd for C15H22O4 [M]+ 266.1518, found 266.1516.

1-(3,4,5-1-(3,4,5- TrimethoxyphenylTrimethoxyphenyl )) heptanheptan -1-one (-1-one ( 3ab3ab ))

Figure 112018005760933-pat00017
Figure 112018005760933-pat00017

0.69 g (49%); yellowish oil; 1H NMR (400 MHz, CDCl3) δ 7.21 2 (s, 2H), 3.92 (s, 6H), 3.91 (s, 3H), 2.92 (t, J = 7.2 Hz, 2H), 1.76-1.69 (m, 2H), 1.40-1.30 (m, 6H), 0.89 (t, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 199.3, 153.0, 142.4, 132.4, 105.5, 60.9, 56.3, 38.4, 31.6, 29.0, 24.5, 22.5, 14.0; IR (KBr) υ 2931, 2587, 1679, 1583, 1504, 1455, 1411, 1321, 1229, 1156, 1123, 1003, 854, 831 cm-1; HRMS (quadrupole, EI) calcd for C16H24O4 [M]+ 280.1675, found 280.1678. 0.69 g (49%); yellowish oil;OneH NMR (400 MHz, CDCl3) δ 7.21 2 (s, 2H), 3.92 (s, 6H), 3.91 (s, 3H), 2.92 (t,J = 7.2 Hz, 2H), 1.76-1.69 (m, 2H), 1.40-1.30 (m, 6H), 0.89 (t,J = 6.8 Hz, 3H);13C NMR (100 MHz, CDCl3) δ 199.3, 153.0, 142.4, 132.4, 105.5, 60.9, 56.3, 38.4, 31.6, 29.0, 24.5, 22.5, 14.0; IR (KBr) υ 2931, 2587, 1679, 1583, 1504, 1455, 1411, 1321, 1229, 1156, 1123, 1003, 854, 831 cm-One; HRMS (quadrupole, EI) calcd for C16H24O4 [M]+ 280.1675, found 280.1678.

1-(3,4,5-1-(3,4,5- TrimethoxyphenylTrimethoxyphenyl )) octanoctan -1-one (-1-one ( 3ac3ac ))

Figure 112018005760933-pat00018
Figure 112018005760933-pat00018

0.76 g (52%); yellowish oil; 1H NMR (400 MHz, CDCl3) δ 7.21 (s, 2H), 3.92 (s, 6H), 3.91 (s, 3H), 2.92 (t, J = 7.2 Hz, 2H), 1.76-1.69 (m, 2H), 1.37-1.27 (m, 8H), 0.88 (t, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 199.3, 153.0, 142.4, 132.4, 105.5, 60.9, 56.3, 38.3, 31.7, 29.3, 29.1, 24.5, 22.6, 14.0; IR (KBr) υ 2926, 2854, 1678, 1583, 1504, 1455, 1411, 1322, 1230, 1156, 1123, 1004, 859, 823 cm-1; HRMS (quadrupole, EI) calcd for C17H26O4 [M]+ 294.1831, found 294.1833. 0.76 g (52%); yellowish oil;OneH NMR (400 MHz, CDCl3) δ 7.21 (s, 2H), 3.92 (s, 6H), 3.91 (s, 3H), 2.92 (t,J = 7.2 Hz, 2H), 1.76-1.69 (m, 2H), 1.37-1.27 (m, 8H), 0.88 (t,J = 6.8 Hz, 3H);13C NMR (100 MHz, CDCl3) δ 199.3, 153.0, 142.4, 132.4, 105.5, 60.9, 56.3, 38.3, 31.7, 29.3, 29.1, 24.5, 22.6, 14.0; IR (KBr) υ 2926, 2854, 1678, 1583, 1504, 1455, 1411, 1322, 1230, 1156, 1123, 1004, 859, 823 cm-One; HRMS (quadrupole, EI) calcd for C17H26O4 [M]+ 294.1831, found 294.1833.

1-(3,4,5-1-(3,4,5- TrimethoxyphenylTrimethoxyphenyl )) nonannonan -1-one (-1-one ( 3ad3ad ))

Figure 112018005760933-pat00019
Figure 112018005760933-pat00019

0.77 g (50%); yellowish oil; 1H NMR (400 MHz, CDCl3) δ 7.21 (s, 2H), 3.92 (s, 6H), 3.91 (s, 3H), 2.92 (t, J = 7.2 Hz, 2H), 1.74-1.69 (m, 2H), 1.38-1.27 (m, 10H), 0.88 (t, J = 6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 199.3, 153.0, 142.4, 132.4, 105.5, 60.9, 56.3, 38.4, 31.8, 29.4, 29.1, 24.5, 22.6, 14.1; IR (KBr) υ 2925, 2853, 1679, 1583, 1504, 1455, 1411, 1322, 1230, 1155, 1124, 1004, 854, 829 cm-1; HRMS (quadrupole, EI) calcd for C18H28O4 [M]+ 308.1988, found 308.1987. 0.77 g (50%); yellowish oil;OneH NMR (400 MHz, CDCl3) δ 7.21 (s, 2H), 3.92 (s, 6H), 3.91 (s, 3H), 2.92 (t,J = 7.2 Hz, 2H), 1.74-1.69 (m, 2H), 1.38-1.27 (m, 10H), 0.88 (t,J = 6.4 Hz, 3H);13C NMR (100 MHz, CDCl3) δ 199.3, 153.0, 142.4, 132.4, 105.5, 60.9, 56.3, 38.4, 31.8, 29.4, 29.1, 24.5, 22.6, 14.1; IR (KBr) υ 2925, 2853, 1679, 1583, 1504, 1455, 1411, 1322, 1230, 1155, 1124, 1004, 854, 829 cm-One; HRMS (quadrupole, EI) calcd for C18H28O4 [M]+ 308.1988, found 308.1987.

1-(2-1-(2- MethoxyphenylMethoxyphenyl )) hexanhexan -1-one (-1-one ( 3ba3ba ))

Figure 112018005760933-pat00020
Figure 112018005760933-pat00020

0.54 g (52%); light brown oil; 1H NMR (400 MHz, CDCl3) δ 7.64 (d, J = 7.6 Hz, 1H), 7.43 (t, J = 7.6 Hz, 1H), 6.99 (t, J = 7.2 Hz, 1H), 6.95 (d, J = 8.4 Hz, 1H), 3.89 (s, 3H), 2.95 (t, J = 7.2 Hz, 2H), 1.69-1.63 (m, 2H), 1.36-1.30 (m, 4H), 0.89 (t, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 203.3, 158.2, 133.0, 130.1, 128.8, 120.6, 111.4, 55.4, 43.7, 31.6, 24.1, 22.5, 14.0; IR (KBr) υ 2955, 2929, 2860, 1673, 1597, 1485, 1464, 1436, 1282, 1243, 1180, 1162, 1023, 754 cm-1; HRMS (quadrupole, EI) calcd for C13H18O2 [M]+ 206.1307, found 206.1305. 0.54 g (52%); light brown oil;OneH NMR (400 MHz, CDCl3) δ 7.64 (d,J = 7.6 Hz, 1H), 7.43 (t,J = 7.6 Hz, 1H), 6.99 (t,J = 7.2 Hz, 1H), 6.95 (d,J = 8.4 Hz, 1H), 3.89 (s, 3H), 2.95 (t,J = 7.2 Hz, 2H), 1.69-1.63 (m, 2H), 1.36-1.30 (m, 4H), 0.89 (t,J = 6.8 Hz, 3H);13C NMR (100 MHz, CDCl3) δ 203.3, 158.2, 133.0, 130.1, 128.8, 120.6, 111.4, 55.4, 43.7, 31.6, 24.1, 22.5, 14.0; IR (KBr) υ 2955, 2929, 2860, 1673, 1597, 1485, 1464, 1436, 1282, 1243, 1180, 1162, 1023, 754 cm-One; HRMS (quadrupole, EI) calcd for C13H18O2 [M]+ 206.1307, found 206.1305.

1-(2-1-(2- MethoxyphenylMethoxyphenyl )) heptanheptan -1-one (-1-one ( 3bb3bb ))

Figure 112018005760933-pat00021
Figure 112018005760933-pat00021

0.72 g (65%); light brown oil; 1H NMR (400 MHz, CDCl3) δ 7.63 (dd, J = 7.6, 1.6 Hz, 1H), 7.45-7.41 (m, 1H), 6.99 (td, J = 8.4, 1.0 Hz, 1H), 6.95 (d, J = 8.4 Hz, 1H), 3.89 (s, 3H), 2.95 (t, J = 7.2 Hz, 2H), 1.70-1.62 (m, 2H), 1.37-1.27 (m, 6H), 0.88 (t, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 203.4, 158.3, 133.0, 130.1, 128.9, 120.6, 111.4, 55.4, 43.8, 31.7, 29.1, 24.4, 22.5, 14.0; IR (KBr) υ 2954, 2927, 2857, 1472, 1597, 1484, 1464, 1436, 1284, 1241, 1180, 1162, 1023, 753 cm-1; HRMS (quadrupole, EI) calcd for C14H20O2 [M]+ 220.1463, found 220.1464. 0.72 g (65%); light brown oil;OneH NMR (400 MHz, CDCl3) δ 7.63 (dd,J = 7.6, 1.6 Hz, 1H), 7.45-7.41 (m, 1H), 6.99 (td,J = 8.4, 1.0 Hz, 1H), 6.95 (d,J = 8.4 Hz, 1H), 3.89 (s, 3H), 2.95 (t,J = 7.2 Hz, 2H), 1.70-1.62 (m, 2H), 1.37-1.27 (m, 6H), 0.88 (t,J = 6.8 Hz, 3H);13C NMR (100 MHz, CDCl3) δ 203.4, 158.3, 133.0, 130.1, 128.9, 120.6, 111.4, 55.4, 43.8, 31.7, 29.1, 24.4, 22.5, 14.0; IR (KBr) υ 2954, 2927, 2857, 1472, 1597, 1484, 1464, 1436, 1284, 1241, 1180, 1162, 1023, 753 cm-One; HRMS (quadrupole, EI) calcd for C14H20O2 [M]+ 220.1463, found 220.1464.

1-(2-1-(2- MethoxyphenylMethoxyphenyl )) octanoctan -1-one (-1-one ( 3bc3bc ))

Figure 112018005760933-pat00022
Figure 112018005760933-pat00022

0.66 g (56%); yellowish oil; 1H NMR (400 MHz, CDCl3) δ 7.62 (dd, J = 7.6, 2.0 Hz, 1H), 7.45-7.41 (m, 1H), 6.98 (td, J = 8.4, 1.0 Hz, 1H), 6.95 (d, J = 8.4 Hz, 1H), 3.89 (s, 3H), 2.94 (t, J = 7.6 Hz, 2H), 1.70-1.62 (m, 2H), 1.35-1.26 (m, 8H), 0.87 (t, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 203.4, 158.2, 133.0, 130.1, 128.8, 120.6, 111.4, 55.4, 43.7, 31.7, 29.3, 29.1, 24.4, 22.6, 14.0; IR (KBr) υ 2953, 2925, 2854, 1673, 1597, 1484, 1464, 1436, 1283, 1242, 1179, 1161, 1024, 753 cm-1; HRMS (quadrupole, EI) calcd for C15H22O2 [M]+ 234.1620, found 234.1621. 0.66 g (56%); yellowish oil;OneH NMR (400 MHz, CDCl3) δ 7.62 (dd,J = 7.6, 2.0 Hz, 1H), 7.45-7.41 (m, 1H), 6.98 (td,J = 8.4, 1.0 Hz, 1H), 6.95 (d,J = 8.4 Hz, 1H), 3.89 (s, 3H), 2.94 (t,J = 7.6 Hz, 2H), 1.70-1.62 (m, 2H), 1.35-1.26 (m, 8H), 0.87 (t,J = 6.8 Hz, 3H);13C NMR (100 MHz, CDCl3) δ 203.4, 158.2, 133.0, 130.1, 128.8, 120.6, 111.4, 55.4, 43.7, 31.7, 29.3, 29.1, 24.4, 22.6, 14.0; IR (KBr) υ 2953, 2925, 2854, 1673, 1597, 1484, 1464, 1436, 1283, 1242, 1179, 1161, 1024, 753 cm-One; HRMS (quadrupole, EI) calcd for C15H22O2 [M]+ 234.1620, found 234.1621.

1-(2-1-(2- MethoxyphenylMethoxyphenyl )) nonannonan -1-one (-1-one ( 3bd3bd ))

Figure 112018005760933-pat00023
Figure 112018005760933-pat00023

0.62 g (50%); yellowish oil; 1H NMR (400 MHz, CDCl3) δ 7.63 (dd, J = 8.0, 2.0 Hz, 1H), 7.45-7.41 (m, 1H), 6.99 (td, J = 8.4, 1.0 Hz, 1H), 6.95 (d, J = 8.4 Hz, 1H), 3.89 (s, 3H), 2.94 (t, J = 7.2 Hz, 2H), 1.70-1.62 (m, 2H), 1.35-1.26 (m, 10H), 0.87 (t, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 203.4, 158.2, 133.0, 130.1, 128.8, 120.6, 111.4, 55.4, 43.8, 31.8, 29.5, 29.4, 29.2, 24.4, 22.6, 14.1; IR (KBr) υ 2924, 2853, 1673, 1597, 1484, 1464, 1436, 1283, 1242, 1180, 1162, 1024, 753 cm-1; HRMS (quadrupole, EI) calcd for C16H24O2 [M]+ 248.1776, found 248.1773. 0.62 g (50%); yellowish oil;OneH NMR (400 MHz, CDCl3) δ 7.63 (dd,J = 8.0, 2.0 Hz, 1H), 7.45-7.41 (m, 1H), 6.99 (td,J = 8.4, 1.0 Hz, 1H), 6.95 (d,J = 8.4 Hz, 1H), 3.89 (s, 3H), 2.94 (t,J = 7.2 Hz, 2H), 1.70-1.62 (m, 2H), 1.35-1.26 (m, 10H), 0.87 (t,J = 6.8 Hz, 3H);13C NMR (100 MHz, CDCl3) δ 203.4, 158.2, 133.0, 130.1, 128.8, 120.6, 111.4, 55.4, 43.8, 31.8, 29.5, 29.4, 29.2, 24.4, 22.6, 14.1; IR (KBr) υ 2924, 2853, 1673, 1597, 1484, 1464, 1436, 1283, 1242, 1180, 1162, 1024, 753 cm-One; HRMS (quadrupole, EI) calcd for C16H24O2[M]+ 248.1776, found 248.1773.

1-(2,4-1-(2,4- DimethoxyphenylDimethoxyphenyl )) hexanhexan -1-one (-1-one ( 3ca3ca ))

Figure 112018005760933-pat00024
Figure 112018005760933-pat00024

0.58 g (49%); yellowish oil; 1H NMR (400 MHz, CDCl3) δ 7.77 (d, J = 8.8 Hz, 1H), 6.51 (dd, J = 8.8, 2.0 Hz, 1H), 6.44 (d, J = 2.4 Hz, 1H), 3.87 (s, 3H), 3.84 (s, 3H), 2.91 (t, J = 7.6 Hz, 2H), 1.69-1.62 (m, 2H), 1.36-1.30 (m, 4H), 0.89 (t, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 201.0, 164.1, 160.5, 132.6, 121.5, 104.9, 98.4, 55.5, 55.4, 43.6, 31.7, 24.3, 22.5, 14.0; IR (KBr) υ 2954, 2931, 2859, 1662, 1598, 1573, 1463, 1416, 1253, 1210, 1161, 1130, 1103, 1027, 826 cm-1; HRMS (quadrupole, EI) calcd for C14H20O3 [M]+ 236.1412, found 236.1413. 0.58 g (49%); yellowish oil;OneH NMR (400 MHz, CDCl3) δ 7.77 (d,J = 8.8 Hz, 1H), 6.51 (dd,J = 8.8, 2.0 Hz, 1H), 6.44 (d,J = 2.4 Hz, 1H), 3.87 (s, 3H), 3.84 (s, 3H), 2.91 (t,J = 7.6 Hz, 2H), 1.69-1.62 (m, 2H), 1.36-1.30 (m, 4H), 0.89 (t,J = 6.8 Hz, 3H);13C NMR (100 MHz, CDCl3) δ 201.0, 164.1, 160.5, 132.6, 121.5, 104.9, 98.4, 55.5, 55.4, 43.6, 31.7, 24.3, 22.5, 14.0; IR (KBr) υ 2954, 2931, 2859, 1662, 1598, 1573, 1463, 1416, 1253, 1210, 1161, 1130, 1103, 1027, 826 cm-One; HRMS (quadrupole, EI) calcd for C14H20O3 [M]+ 236.1412, found 236.1413.

1-(2,4-1-(2,4- DimethoxyphenylDimethoxyphenyl )) heptanheptan -1-one (-1-one ( 3cb3cb ))

Figure 112018005760933-pat00025
Figure 112018005760933-pat00025

0.71 g (57%); yellowish oil; 1H NMR (400 MHz, CDCl3) δ 7.77 (d, J = 8.0 Hz, 1H), 6.51 (dd, J = 8.0, 4.0 Hz, 1H), 6.44 (d, J = 4.0 Hz, 1H), 3.88 (s, 3H), 3.84 (s, 3H), 2.91 (t, J = 8.0 Hz, 2H), 1.68-1.61 (m, 2H), 1.37-1.30 (m, 6H), 0.88 (t, J = 8.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 201.0, 164.1, 160.5, 132.5, 121.5, 104.9, 98.3, 55.5, 55.4, 43.6, 31.7, 29.2, 24.6, 22.5, 14.0; IR (KBr) υ 2953, 2926, 2855, 1662, 1598, 1574, 1463, 1416, 1253, 1209, 1161, 1130, 1027, 834 cm-1; HRMS (quadrupole, EI) calcd for C15H22O3 [M]+ 250.1569, found 250.1568. 0.71 g (57%); yellowish oil;OneH NMR (400 MHz, CDCl3) δ 7.77 (d,J = 8.0 Hz, 1H), 6.51 (dd,J = 8.0, 4.0 Hz, 1H), 6.44 (d,J = 4.0 Hz, 1H), 3.88 (s, 3H), 3.84 (s, 3H), 2.91 (t,J = 8.0 Hz, 2H), 1.68-1.61 (m, 2H), 1.37-1.30 (m, 6H), 0.88 (t,J = 8.0 Hz, 3H);13C NMR (100 MHz, CDCl3) δ 201.0, 164.1, 160.5, 132.5, 121.5, 104.9, 98.3, 55.5, 55.4, 43.6, 31.7, 29.2, 24.6, 22.5, 14.0; IR (KBr) υ 2953, 2926, 2855, 1662, 1598, 1574, 1463, 1416, 1253, 1209, 1161, 1130, 1027, 834 cm-One; HRMS (quadrupole, EI) calcd for C15H22O3 [M]+ 250.1569, found 250.1568.

1-(2,4-1-(2,4- DimethoxyphenylDimethoxyphenyl )) octanoctan -1-one (3cc)-1-one (3cc)

Figure 112018005760933-pat00026
Figure 112018005760933-pat00026

0.71 g (54%); yellowish oil; 1H NMR (400 MHz, CDCl3) δ 7.77 (d, J = 8.8 Hz, 1H), 6.51 (dd, J = 8.4, 2.0 Hz, 1H), 6.44 (d, J = 2.4 Hz, 1H), 3.87 (s, 3H), 3.84 (s, 3H), 2.91 (t, J = 7.2 Hz, 2H), 1.68-1.61 (m, 2H), 1.33-1.26 (m, 8H), 0.87 (t, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 201.0, 164.1, 160.5, 132.5, 121.5, 104.9, 98.4, 55.5, 55.4, 43.6, 31.7, 29.4, 29.2, 24.6, 22.6, 14.1; IR (KBr) υ 2925, 2854, 1663, 1598, 1574, 1463, 1416, 1254, 1209, 1161, 1130, 1027, 834 cm-1; HRMS (quadrupole, EI) calcd for C16H24O3 [M]+ 264.1725, found 264.1725. 0.71 g (54%); yellowish oil;OneH NMR (400 MHz, CDCl3) δ 7.77 (d,J = 8.8 Hz, 1H), 6.51 (dd,J = 8.4, 2.0 Hz, 1H), 6.44 (d,J = 2.4 Hz, 1H), 3.87 (s, 3H), 3.84 (s, 3H), 2.91 (t,J = 7.2 Hz, 2H), 1.68-1.61 (m, 2H), 1.33-1.26 (m, 8H), 0.87 (t,J = 6.8 Hz, 3H);13C NMR (100 MHz, CDCl3) δ 201.0, 164.1, 160.5, 132.5, 121.5, 104.9, 98.4, 55.5, 55.4, 43.6, 31.7, 29.4, 29.2, 24.6, 22.6, 14.1; IR (KBr) υ 2925, 2854, 1663, 1598, 1574, 1463, 1416, 1254, 1209, 1161, 1130, 1027, 834 cm-One; HRMS (quadrupole, EI) calcd for C16H24O3 [M]+ 264.1725, found 264.1725.

1-(2,4-1-(2,4- DimethoxyphenylDimethoxyphenyl )) nonannonan -1-one (3cd)-1-one (3cd)

Figure 112018005760933-pat00027
Figure 112018005760933-pat00027

0.74 g (53%); yellowish oil; 1H NMR (400 MHz, CDCl3) δ 7.77 (d, J = 8.0 Hz, 1H), 6.51 (dd, J = 8.8, 1.6 Hz, 1H), 6.44 (d, J = 2.0 Hz, 1H), 3.87 (s, 3H), 3.84 (s, 3H), 2.91 (t, J = 7.6 Hz, 2H), 1.68-1.61 (m, 2H), 1.34-1.26 (m, 10H), 0.87 (t, J = 6.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 201.0, 164.1, 160.5, 132.5, 121.5, 104.9, 98.3, 55.5, 55.4, 43.6, 31.8, 29.5, 29.2, 24.6, 22.6, 14.1; IR (KBr) υ 2924, 2853, 1663, 1598, 1574, 1463, 1416, 1254, 1209, 1161, 1028, 834 cm-1; HRMS (quadrupole, EI) calcd for C17H26O3 [M]+ 278.1882, found 278.1881. 0.74 g (53%); yellowish oil;OneH NMR (400 MHz, CDCl3) δ 7.77 (d,J = 8.0 Hz, 1H), 6.51 (dd,J = 8.8, 1.6 Hz, 1H), 6.44 (d,J = 2.0 Hz, 1H), 3.87 (s, 3H), 3.84 (s, 3H), 2.91 (t,J = 7.6 Hz, 2H), 1.68-1.61 (m, 2H), 1.34-1.26 (m, 10H), 0.87 (t,J = 6.0 Hz, 3H);13C NMR (100 MHz, CDCl3) δ 201.0, 164.1, 160.5, 132.5, 121.5, 104.9, 98.3, 55.5, 55.4, 43.6, 31.8, 29.5, 29.2, 24.6, 22.6, 14.1; IR (KBr) υ 2924, 2853, 1663, 1598, 1574, 1463, 1416, 1254, 1209, 1161, 1028, 834 cm-One; HRMS (quadrupole, EI) calcd for C17H26O3 [M]+ 278.1882, found 278.1881.

1-(4-1-(4- MethoxyphenylMethoxyphenyl )) hexanhexan -1-one (-1-one ( 3da3da ))

Figure 112018005760933-pat00028
Figure 112018005760933-pat00028

0.57 g (55%); white solid; mp = 42.4-44.1 oC; 1H NMR (400 MHz, CDCl3) δ 7.95-7.92 (m, 2H), 6.94-6.91 (m, 2H), 3.86 (s, 3H), 2.90 (t, J = 7.6 Hz, 2H), 1.76-1.68 (m, 2H), 1.37-1.33 (m, 4H), 0.90 (t, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 199.2, 163.3, 130.3, 130.2, 113.6, 55.4, 38.3, 31.6, 24.3, 22.5, 13.9; IR (KBr) υ 2955, 2931, 2860, 1674, 1597, 1509, 1461, 1417, 1308, 1252, 1168, 1030, 828 cm-1; HRMS (quadrupole, EI) calcd for C13H18O2 [M]+ 206.1307, found 206.1305. 0.57 g (55%); white solid; mp = 42.4-44.1oC;OneH NMR (400 MHz, CDCl3) δ 7.95-7.92 (m, 2H), 6.94-6.91 (m, 2H), 3.86 (s, 3H), 2.90 (t,J = 7.6 Hz, 2H), 1.76-1.68 (m, 2H), 1.37-1.33 (m, 4H), 0.90 (t,J = 6.8 Hz, 3H);13C NMR (100 MHz, CDCl3) δ 199.2, 163.3, 130.3, 130.2, 113.6, 55.4, 38.3, 31.6, 24.3, 22.5, 13.9; IR (KBr) υ 2955, 2931, 2860, 1674, 1597, 1509, 1461, 1417, 1308, 1252, 1168, 1030, 828 cm-One; HRMS (quadrupole, EI) calcd for C13H18O2 [M]+ 206.1307, found 206.1305.

1-(4-1-(4- MethoxyphenylMethoxyphenyl )) heptanheptan -1-one (-1-one ( 3db3db ))

Figure 112018005760933-pat00029
Figure 112018005760933-pat00029

0.90 g (82%); white solid; mp = 44.2-46.7 oC; 1H NMR (400 MHz, CDCl3) δ 7.96-7.92 (m, 2H), 6.95-6.90 (m, 2H), 3.86 (s, 3H), 2.90 (t, J = 7.6 Hz, 2H), 1.75-1.67 (m, 2H), 1.40-1.29 (m, 6H), 0.88 (t, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 199.2, 163.3, 130.3, 130.2, 113.6, 55.4, 38.3, 31.6, 29.1, 24.6, 22.5, 14.0; IR (KBr) υ 2954, 2929, 2856, 1675, 1597, 1509, 1460, 1417, 1308, 1255, 1467, 1029, 835 cm-1; HRMS (quadrupole, EI) calcd for C14H20O2 [M]+ 220.1463, found 220.1460. 0.90 g (82%); white solid; mp = 44.2-46.7oC;OneH NMR (400 MHz, CDCl3) δ 7.96-7.92 (m, 2H), 6.95-6.90 (m, 2H), 3.86 (s, 3H), 2.90 (t,J = 7.6 Hz, 2H), 1.75-1.67 (m, 2H), 1.40-1.29 (m, 6H), 0.88 (t,J = 6.8 Hz, 3H);13C NMR (100 MHz, CDCl3) δ 199.2, 163.3, 130.3, 130.2, 113.6, 55.4, 38.3, 31.6, 29.1, 24.6, 22.5, 14.0; IR (KBr) υ 2954, 2929, 2856, 1675, 1597, 1509, 1460, 1417, 1308, 1255, 1467, 1029, 835 cm-One; HRMS (quadrupole, EI) calcd for C14H20O2 [M]+ 220.1463, found 220.1460.

1-(4-1-(4- MethoxyphenylMethoxyphenyl )) octanoctan -1-one (-1-one ( 3dc3dc ))

Figure 112018005760933-pat00030
Figure 112018005760933-pat00030

0.99 g (84%); white solid; mp = 53.2-55.9 oC; 1H NMR (400 MHz, CDCl3) δ 7.94 (dt, J = 10.0, 3.2 Hz, 2H), 6.92 (dt, J = 9.6, 2.8 Hz, 2H), 3.86 (s, 3H), 2.90 (t, J = 7.2 Hz, 2H), 1.75-1.68 (m, 2H), 1.37-1.27 (m, 8H), 0.88 (t, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 199.2, 163.2, 130.3, 130.2, 113.6, 55.4, 38.3, 31.7, 29.4, 29.1, 24.6, 22.6, 14.0; IR (KBr) υ 2954, 2925, 2854, 1675, 1599, 1509, 1462, 1417, 1308, 1255, 1168, 1030, 829 cm-1; HRMS (quadrupole, EI) calcd for C15H22O2 [M]+ 234.1620, found 234.1618. 0.99 g (84%); white solid; mp = 53.2-55.9oC;OneH NMR (400 MHz, CDCl3) δ 7.94 (dt,J = 10.0, 3.2 Hz, 2H), 6.92 (dt,J = 9.6, 2.8 Hz, 2H), 3.86 (s, 3H), 2.90 (t,J = 7.2 Hz, 2H), 1.75-1.68 (m, 2H), 1.37-1.27 (m, 8H), 0.88 (t,J = 6.8 Hz, 3H);13C NMR (100 MHz, CDCl3) δ 199.2, 163.2, 130.3, 130.2, 113.6, 55.4, 38.3, 31.7, 29.4, 29.1, 24.6, 22.6, 14.0; IR (KBr) υ 2954, 2925, 2854, 1675, 1599, 1509, 1462, 1417, 1308, 1255, 1168, 1030, 829 cm-One; HRMS (quadrupole, EI) calcd for C15H22O2 [M]+ 234.1620, found 234.1618.

1-(4-1-(4- MethoxyphenylMethoxyphenyl )) nonannonan -1-one (-1-one ( 3dd3dd ))

Figure 112018005760933-pat00031
Figure 112018005760933-pat00031

0.96 g (77%); white solid; mp = 53.8-55.2 oC; 1H NMR (400 MHz, CDCl3) δ 7.93 (dt, J = 9.6, 2.8 Hz, 2H), 6.92 (dt, J = 9.6, 2.8 Hz, 2H), 3.86 (s, 3H), 2.90 (t, J = 7.2 Hz, 2H), 1.75-1.67 (m, 2H), 1.38-1.25 (m, 10H), 0.87 (t, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 199.2, 163.2, 130.3, 130.2, 113.6, 55.4, 38.3, 31.8, 29.4, 29.1, 24.6, 22.6, 14.1; IR (KBr) υ 2954, 2924, 2853, 1676, 1599, 1509, 1463, 1417, 1307, 1254, 1168, 1031, 833 cm-1; HRMS (quadrupole, EI) calcd for C16H24O2 [M]+ 248.1776, found 248.1776. 0.96 g (77%); white solid; mp = 53.8-55.2oC;OneH NMR (400 MHz, CDCl3) δ 7.93 (dt,J = 9.6, 2.8 Hz, 2H), 6.92 (dt,J = 9.6, 2.8 Hz, 2H), 3.86 (s, 3H), 2.90 (t,J = 7.2 Hz, 2H), 1.75-1.67 (m, 2H), 1.38-1.25 (m, 10H), 0.87 (t,J = 6.8 Hz, 3H);13C NMR (100 MHz, CDCl3) δ 199.2, 163.2, 130.3, 130.2, 113.6, 55.4, 38.3, 31.8, 29.4, 29.1, 24.6, 22.6, 14.1; IR (KBr) υ 2954, 2924, 2853, 1676, 1599, 1509, 1463, 1417, 1307, 1254, 1168, 1031, 833 cm-One; HRMS (quadrupole, EI) calcd for C16H24O2 [M]+ 248.1776, found 248.1776.

1-(3-1-(3- MethoxyphenylMethoxyphenyl )) hexanhexan -1-one (-1-one ( 3ea3ea ))

Figure 112018005760933-pat00032
Figure 112018005760933-pat00032

0.61 g (59%); yellowish oil; 1H NMR (400 MHz, CDCl3) δ 7.53 (d, J = 7.6 Hz, 1H), 7.49 (s, 1H), 7.36 (t, J = 8.0 Hz, 1H), 7.09 (dd, J = 8.0, 2.4 Hz, 1H), 3.85 (s, 3H), 2.94 (t, J = 7.6 Hz, 2H), 1.77-1.70 (m, 2H), 1.37-1.34 (m, 4H), 0.91 (t, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 200.5, 159.9, 138.6, 129.6, 120.8, 119.4, 112.4, 55.5, 38.8, 31.6, 24.2, 22.6, 14.1; IR (KBr) υ 2955, 2930, 2860, 1683, 1597, 1582, 1485, 1463, 1428, 1287, 1266, 1169, 1040, 784 cm-1; HRMS (quadrupole, EI) calcd for C13H18O2 [M]+ 206.1307, found 206.1308. 0.61 g (59%); yellowish oil;OneH NMR (400 MHz, CDCl3) δ 7.53 (d,J = 7.6 Hz, 1H), 7.49 (s, 1H), 7.36 (t,J = 8.0 Hz, 1H), 7.09 (dd,J = 8.0, 2.4 Hz, 1H), 3.85 (s, 3H), 2.94 (t,J = 7.6 Hz, 2H), 1.77-1.70 (m, 2H), 1.37-1.34 (m, 4H), 0.91 (t,J = 6.8 Hz, 3H);13C NMR (100 MHz, CDCl3) δ 200.5, 159.9, 138.6, 129.6, 120.8, 119.4, 112.4, 55.5, 38.8, 31.6, 24.2, 22.6, 14.1; IR (KBr) υ 2955, 2930, 2860, 1683, 1597, 1582, 1485, 1463, 1428, 1287, 1266, 1169, 1040, 784 cm-One; HRMS (quadrupole, EI) calcd for C13H18O2 [M]+ 206.1307, found 206.1308.

1-(3-1-(3- MethoxyphenylMethoxyphenyl )) heptanheptan -1-one (-1-one ( 3eb3eb ))

Figure 112018005760933-pat00033
Figure 112018005760933-pat00033

0.63 g (57%); yellowish oil; 1H NMR (400 MHz, CDCl3) δ 7.53 (dt, J = 7.6, 1.6 Hz, 1H), 7.49-7.48 (m, 1H), 7.36 (t, J = 8.0 Hz, 1H), 7.09 (ddd, J = 8.4, 2.8, 1.0 Hz, 1H), 3.85 (s, 3H), 2.94 (t, J = 7.2 Hz, 2H), 1.76-1.68 (m, 2H), 1.41-1.29 (m, 6H), 0.89 (t, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 200.4, 159.8, 138.5, 129.5, 120.7, 119.3, 112.3, 55.4, 38.7, 31.6, 29.0, 24.4, 22.5, 14.0; IR (KBr) υ 2954, 2928, 2857, 1684, 1597, 1582, 1486, 1463, 1428, 1254, 1167, 1044, 783 cm-1; HRMS (quadrupole, EI) calcd for C14H20O2 [M]+ 220.1463, found 220.1460. 0.63 g (57%); yellowish oil;OneH NMR (400 MHz, CDCl3) δ 7.53 (dt,J = 7.6, 1.6 Hz, 1H), 7.49-7.48 (m, 1H), 7.36 (t,J = 8.0 Hz, 1H), 7.09 (ddd,J = 8.4, 2.8, 1.0 Hz, 1H), 3.85 (s, 3H), 2.94 (t,J = 7.2 Hz, 2H), 1.76-1.68 (m, 2H), 1.41-1.29 (m, 6H), 0.89 (t,J = 6.8 Hz, 3H);13C NMR (100 MHz, CDCl3) δ 200.4, 159.8, 138.5, 129.5, 120.7, 119.3, 112.3, 55.4, 38.7, 31.6, 29.0, 24.4, 22.5, 14.0; IR (KBr) υ 2954, 2928, 2857, 1684, 1597, 1582, 1486, 1463, 1428, 1254, 1167, 1044, 783 cm-One; HRMS (quadrupole, EI) calcd for C14H20O2 [M]+ 220.1463, found 220.1460.

1-(3-1-(3- MethoxyphenylMethoxyphenyl )) octanoctan -1-one (-1-one ( 3ec3ec ))

Figure 112018005760933-pat00034
Figure 112018005760933-pat00034

0.65 g (55%); yellowish oil; 1H NMR (400 MHz, CDCl3) δ 7.54 (dt, J = 7.6, 1.2 Hz, 1H), 7.49-7.48 (m, 1H), 7.36 (t, J = 8.0 Hz, 1H), 7.10 (ddd, J = 8.0, 2.8, 1.0 Hz, 1H), 3.85 (s, 3H), 2.94 (t, J = 7.2 Hz, 2H), 1.76-1.69 (m, 2H), 1.39-1.27 (m, 8H), 0.88 (t, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 200.4, 159.8, 138.5, 129.5, 120.7, 119.3, 112.3, 55.4, 38.7, 31.6, 29.3, 29.1, 24.4, 22.6, 14.1; IR (KBr) υ 2954, 2925, 2855, 1683, 1597, 1582, 1485, 1463, 1428, 1252, 1167, 1040, 783 cm-1; HRMS (quadrupole, EI) calcd for C15H22O2 [M]+ 234.1620, found 234.1619. 0.65 g (55%); yellowish oil;OneH NMR (400 MHz, CDCl3) δ 7.54 (dt,J = 7.6, 1.2 Hz, 1H), 7.49-7.48 (m, 1H), 7.36 (t,J = 8.0 Hz, 1H), 7.10 (ddd,J = 8.0, 2.8, 1.0 Hz, 1H), 3.85 (s, 3H), 2.94 (t,J = 7.2 Hz, 2H), 1.76-1.69 (m, 2H), 1.39-1.27 (m, 8H), 0.88 (t,J = 6.8 Hz, 3H);13C NMR (100 MHz, CDCl3) δ 200.4, 159.8, 138.5, 129.5, 120.7, 119.3, 112.3, 55.4, 38.7, 31.6, 29.3, 29.1, 24.4, 22.6, 14.1; IR (KBr) υ 2954, 2925, 2855, 1683, 1597, 1582, 1485, 1463, 1428, 1252, 1167, 1040, 783 cm-One; HRMS (quadrupole, EI) calcd for C15H22O2 [M]+ 234.1620, found 234.1619.

1-(3-1-(3- MethoxyphenylMethoxyphenyl )) nonannonan -1-one (-1-one ( 3ed3ed ))

Figure 112018005760933-pat00035
Figure 112018005760933-pat00035

0.73 g (59%); light yellow oil; 1H NMR (400 MHz, CDCl3) δ 7.54 (dt, J = 7.6, 1.6 Hz, 1H), 7.49-7.48 (m, 1H), 7.36 (t, J = 8.0 Hz, 1H), 7.10 (ddd, J = 8.4, 2.8, 1.0 Hz, 1H), 3.85 (s, 3H), 2.94 (t, J = 7.2 Hz, 2H), 1.76-1.68 (m, 2H), 1.39-1.27 (m, 10H), 0.87 (t, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 200.4, 159.8, 138.5, 129.5, 120.7, 119.3, 112.3, 55.4, 38.7, 31.8, 29.4, 29.3, 29.2, 24.4, 22.6, 14.1; IR (KBr) υ 2954, 2924, 2853, 1683, 1597, 1582, 1486, 1463, 1428, 1259, 1166, 1043, 783 cm-1; HRMS (quadrupole, EI) calcd for C16H24O2 [M]+ 248.1776, found 248.1775. 0.73 g (59%); light yellow oil;OneH NMR (400 MHz, CDCl3) δ 7.54 (dt,J = 7.6, 1.6 Hz, 1H), 7.49-7.48 (m, 1H), 7.36 (t,J = 8.0 Hz, 1H), 7.10 (ddd,J = 8.4, 2.8, 1.0 Hz, 1H), 3.85 (s, 3H), 2.94 (t,J = 7.2 Hz, 2H), 1.76-1.68 (m, 2H), 1.39-1.27 (m, 10H), 0.87 (t,J = 6.8 Hz, 3H);13C NMR (100 MHz, CDCl3) δ 200.4, 159.8, 138.5, 129.5, 120.7, 119.3, 112.3, 55.4, 38.7, 31.8, 29.4, 29.3, 29.2, 24.4, 22.6, 14.1; IR (KBr) υ 2954, 2924, 2853, 1683, 1597, 1582, 1486, 1463, 1428, 1259, 1166, 1043, 783 cm-One; HRMS (quadrupole, EI) calcd for C16H24O2[M]+ 248.1776, found 248.1775.

제조예Manufacturing example 2 : 2 : orthoortho -- alkylatedalkylated derivatives 화합물 derivatives compounds 5aa5aa -- 5ed5ed ' 및 'And 6aa6aa -- 6ad의6ad 제조 Produce

1-(3,4,5-trimethoxyphenyl)hexan-1-one (3aa) (53.3 mg, 0.2 mmol, 100 mol %), [IrCp*Cl2]2 (3.2 mg, 0.004 mmol, 2 mol %) 또는 [RhCp*Cl2]2 (2.5 mg, 0.004 mmol, 2 mol %), AgNTf2 (6.2 mg, 0.016 mmol, 8 mol %), AgOAc (2.6 mg, 0.016 mmol, 8 mol %) 및 5-diazo-2,2-dimethyl-1,3-dioxane-4,6-dione (4a) (40.8 mg, 0.24 mmol, 120 mol %) 으로 충전된 오븐-건조된 밀봉 튜브에 EtOH (18.4 mg, 0.4 mmol, 200 mol %) 및 DCE (1 mL) 을 실온에서 공기 중에서 첨가하였다.1- (3,4,5-trimethoxyphenyl) hexan- 1-one (3aa) (53.3 mg, 0.2 mmol, 100 mol%), [IrCp * Cl 2] 2 (3.2 mg, 0.004 mmol, 2 mol %) or [RhCp*Cl 2 ] 2 (2.5 mg, 0.004 mmol, 2 mol %), AgNTf 2 (6.2 mg, 0.016 mmol, 8 mol %), AgOAc (2.6 mg, 0.016 mmol, 8 mol %) and 5-diazo-2,2-dimethyl-1,3-dioxane-4,6-dione ( 4a ) (40.8 mg, 0.24 mmol, 120 mol %) filled with oven-dried To a sealed tube EtOH (18.4 mg, 0.4 mmol, 200 mol %) and DCE (1 mL) were added in air at room temperature.

반응 혼합물을 60 ℃에서 20 시간 동안 교반 하였다. 반응 혼합물을 실온으로 냉각시키고, EtOAc (3 mL)로 희석시키고, 진공에서 농축시켰다. 잔류물을 플래시 컬럼 크로마토그래피 (n- 헥산 / EtOAc = 12 : 1)로 정제하여 5aa (50.2 mg, 71 %)를 황색 고체로서 수득 하였다.The reaction mixture was stirred at 60° C. for 20 hours. The reaction mixture was cooled to room temperature, diluted with EtOAc (3 mL) and concentrated in vacuo. The residue was purified by flash column chromatography (n-hexane/EtOAc = 12:1) to give 5aa (50.2 mg, 71%) as a yellow solid.

상기와 같이 같은 방식으로 화합물 5ab-6ad 를 제조하였고, 하기에 특성을 나타내었다. Compound 5ab-6ad was prepared in the same manner as described above, and the properties were shown below.

Ethyl 2-(6-Ethyl 2-(6- hexanoylhexanoyl -2,3,4--2,3,4- trimethoxyphenyltrimethoxyphenyl )acetate ()acetate ( 5aa5aa ))

Figure 112018005760933-pat00036
Figure 112018005760933-pat00036

50.2 mg (71%); yellowish solid; mp = 66.0-68.2 oC; 1H NMR (400 MHz, CDCl3) δ 7.02 (s, 1H), 4.14 (q, J = 7.2 Hz, 2H), 3.90 (s, 3H), 3.89 (s, 3H), 3.87 (s, 2H), 3.82 (s, 3H), 2.84 (t, J = 7.2 Hz, 2H), 1.70-1.62 (m, 2H), 1.33-1.28 (m, 4H), 1.25 (t, J = 7.2 Hz, 3H), 0.88 (t, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 202.9, 172.0, 152.7, 151.7, 145.0, 133.5, 121.7, 108.4, 61.0, 60.7, 60.5, 56.1, 40.9, 31.8, 31.4, 24.0, 22.4, 14.2, 13.8; IR (KBr) υ 2939, 2871, 1733, 1682, 1595, 1568, 1495, 1453, 1403, 1331, 1172, 1137, 1113, 1028, 966, 918, 831cm-1; HRMS (quadrupole, EI) calcd for C19H28O6 [M]+ 352.1886, found 352.1884. 50.2 mg (71%); yellowish solid; mp = 66.0-68.2oC;OneH NMR (400 MHz, CDCl3) δ 7.02 (s, 1H), 4.14 (q,J = 7.2 Hz, 2H), 3.90 (s, 3H), 3.89 (s, 3H), 3.87 (s, 2H), 3.82 (s, 3H), 2.84 (t,J = 7.2 Hz, 2H), 1.70-1.62 (m, 2H), 1.33-1.28 (m, 4H), 1.25 (t,J = 7.2 Hz, 3H), 0.88 (t,J = 6.8 Hz, 3H);13C NMR (100 MHz, CDCl3) δ 202.9, 172.0, 152.7, 151.7, 145.0, 133.5, 121.7, 108.4, 61.0, 60.7, 60.5, 56.1, 40.9, 31.8, 31.4, 24.0, 22.4, 14.2, 13.8; IR (KBr) υ 2939, 2871, 1733, 1682, 1595, 1568, 1495, 1453, 1403, 1331, 1172, 1137, 1113, 1028, 966, 918, 831cm-One; HRMS (quadrupole, EI) calcd for C19H28O6 [M]+ 352.1886, found 352.1884.

Ethyl 2-(6-Ethyl 2-(6- heptanoylheptanoyl -2,3,4--2,3,4- trimethoxyphenyltrimethoxyphenyl )acetate ()acetate ( 5ab5ab ))

Figure 112018005760933-pat00037
Figure 112018005760933-pat00037

44.9 mg (61%); yellowish oil; 1H NMR (400 MHz, CDCl3) δ 7.02 (s, 1H), 4.13 (q, J = 7.2 Hz, 2H), 3.90 (s, 3H), 3.89 (s, 3H), 3.88 (s, 2H), 3.82 (s, 3H), 2.85 (t, J = 7.6 Hz, 2H), 1.70-1.62 (m, 2H), 1.35-1.28 (m, 6H), 1.25 (t, J = 6.8 Hz, 3H), 0.87 (t, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 203.0, 172.0, 152.7, 151.8, 145.1, 133.6, 121.8, 108.4, 61.0, 60.7, 60.5, 56.2, 41.0, 31.8, 31.6, 28.9, 24.3, 22.4, 14.2, 13.9; IR (KBr) υ 2933, 2857, 1735, 1683, 1593, 1568, 1495, 1454, 1403, 1335, 1230, 1174, 1138, 1116, 1029, 966, 920, 841 cm-1; HRMS (quadrupole, EI) calcd for C20H30O6 [M]+ 366.2042, found 366.2044. 44.9 mg (61%); yellowish oil;OneH NMR (400 MHz, CDCl3) δ 7.02 (s, 1H), 4.13 (q,J = 7.2 Hz, 2H), 3.90 (s, 3H), 3.89 (s, 3H), 3.88 (s, 2H), 3.82 (s, 3H), 2.85 (t,J = 7.6 Hz, 2H), 1.70-1.62 (m, 2H), 1.35-1.28 (m, 6H), 1.25 (t,J = 6.8 Hz, 3H), 0.87 (t,J = 6.8 Hz, 3H);13C NMR (100 MHz, CDCl3) δ 203.0, 172.0, 152.7, 151.8, 145.1, 133.6, 121.8, 108.4, 61.0, 60.7, 60.5, 56.2, 41.0, 31.8, 31.6, 28.9, 24.3, 22.4, 14.2, 13.9; IR (KBr) υ 2933, 2857, 1735, 1683, 1593, 1568, 1495, 1454, 1403, 1335, 1230, 1174, 1138, 1116, 1029, 966, 920, 841 cm-One; HRMS (quadrupole, EI) calcd for C20H30O6 [M]+ 366.2042, found 366.2044.

Ethyl 2-(2,3,4-Ethyl 2-(2,3,4- trimethoxytrimethoxy -6--6- octanoylphenyloctanoylphenyl )acetate ()acetate ( 5ac5ac ))

Figure 112018005760933-pat00038
Figure 112018005760933-pat00038

45.1 mg (59%); yellowish oil; 1H NMR (400 MHz, CDCl3) δ 7.02 (s, 1H), 4.13 (q, J = 7.2 Hz, 2H), 3.90 (s, 3H), 3.89 (s, 3H), 3.87 (s, 2H), 3.82 (s, 3H), 2.85 (t, J = 7.2 Hz, 2H), 1.70-1.62 (m, 2H), 1.31-1.23 (m, 11H), 0.86 (t, J = 6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 203.0, 172.0, 152.7, 151.7, 145.0, 133.5, 121.7, 108.4, 61.0, 60.7, 60.5, 56.2, 41.0, 31.8, 31.6, 29.2, 29.0, 24.3, 22.5, 14.2, 14.0; IR (KBr) υ 2927, 2854, 1736, 1683, 1593, 1568, 1495, 1454, 1403, 1333, 1251, 1162, 1137, 1116, 1029, 1006, 966, 920, 838 cm-1; HRMS (quadrupole, EI) calcd for C21H32O6 [M]+ 380.2199, found 380.2202. 45.1 mg (59%); yellowish oil;OneH NMR (400 MHz, CDCl3) δ 7.02 (s, 1H), 4.13 (q,J = 7.2 Hz, 2H), 3.90 (s, 3H), 3.89 (s, 3H), 3.87 (s, 2H), 3.82 (s, 3H), 2.85 (t,J = 7.2 Hz, 2H), 1.70-1.62 (m, 2H), 1.31-1.23 (m, 11H), 0.86 (t,J = 6.4 Hz, 3H);13C NMR (100 MHz, CDCl3) δ 203.0, 172.0, 152.7, 151.7, 145.0, 133.5, 121.7, 108.4, 61.0, 60.7, 60.5, 56.2, 41.0, 31.8, 31.6, 29.2, 29.0, 24.3, 22.5, 14.2, 14.0; IR (KBr) υ 2927, 2854, 1736, 1683, 1593, 1568, 1495, 1454, 1403, 1333, 1251, 1162, 1137, 1116, 1029, 1006, 966, 920, 838 cm-One; HRMS (quadrupole, EI) calcd for C21H32O6 [M]+ 380.2199, found 380.2202.

Ethyl 2-(2,3,4-Ethyl 2-(2,3,4- trimethoxytrimethoxy -6--6- nonanoylphenylnonanoylphenyl )acetate ()acetate ( 5ad5ad ))

Figure 112018005760933-pat00039
Figure 112018005760933-pat00039

49.1 mg (62%); yellowish oil; 1H NMR (400 MHz, CDCl3) δ 7.02 (s, 1H), 4.14 (q, J = 7.2 Hz, 2H), 3.90 (s, 3H), 3.89 (s, 3H), 3.87 (s, 2H), 3.82 (s, 3H), 2.84 (t, J = 7.6 Hz, 2H), 1.69-1.62 (m, 2H), 1.32-1.23 (m, 13H), 0.86 (t, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 203.0, 172.0, 152.8, 151.8, 145.1, 133.6, 121.8, 108.5, 61.0, 60.7, 60.5, 56.2, 41.0, 31.8, 31.7, 29.4, 29.2, 29.1, 24.3, 22.6, 14.2, 14.0; IR (KBr) υ 2925, 2853, 1735, 1663, 1593, 1568, 1495, 1454, 1403, 1367, 1333, 1229, 1161, 1136, 1115, 1028, 1007, 966, 917, 838 cm-1; HRMS (quadrupole, EI) calcd for C22H34O6 [M]+ 394.2355, found 394.2358. 49.1 mg (62%); yellowish oil;OneH NMR (400 MHz, CDCl3) δ 7.02 (s, 1H), 4.14 (q,J = 7.2 Hz, 2H), 3.90 (s, 3H), 3.89 (s, 3H), 3.87 (s, 2H), 3.82 (s, 3H), 2.84 (t,J = 7.6 Hz, 2H), 1.69-1.62 (m, 2H), 1.32-1.23 (m, 13H), 0.86 (t,J = 6.8 Hz, 3H);13C NMR (100 MHz, CDCl3) δ 203.0, 172.0, 152.8, 151.8, 145.1, 133.6, 121.8, 108.5, 61.0, 60.7, 60.5, 56.2, 41.0, 31.8, 31.7, 29.4, 29.2, 29.1, 24.3, 22.6, 14.2, 14.0; IR (KBr) υ 2925, 2853, 1735, 1663, 1593, 1568, 1495, 1454, 1403, 1367, 1333, 1229, 1161, 1136, 1115, 1028, 1007, 966, 917, 838 cm-One; HRMS (quadrupole, EI) calcd for C22H34O6 [M]+ 394.2355, found 394.2358.

Ethyl 2-(2-Ethyl 2-(2- hexanoylhexanoyl -3--3- methoxyphenylmethoxyphenyl )acetate ()acetate ( 5ba5ba ))

Figure 112018005760933-pat00040
Figure 112018005760933-pat00040

50.3 mg (86%); light yellow oil; 1H NMR (400 MHz, CDCl3) δ 7.27 (t, J = 8.0 Hz, 1H), 6.87-6.85 (m, 2H), 4.12 (q, J = 7.2 Hz, 2H), 3.81 (s, 3H), 3.59 (s, 2H), 2.84 (t, J = 7.2 Hz, 2H), 1.71-1.63 (m, 2H), 1.34-1.30 (m, 4H), 1.24 (t, J = 7.2 Hz, 3H), 0.90 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 207.8, 171.2, 156.7, 132.3, 131.5, 130.2, 123.2, 109.9, 60.9, 55.6, 44.4, 38.2, 31.4, 23.3, 22.5, 14.1, 13.9; IR (KBr) υ 2955, 2927, 2856, 1734, 1691, 1597, 1581, 1469, 1438, 1367, 1336, 1259, 1181, 1159, 1073, 1030, 950, 768 cm-1; HRMS (quadrupole, EI) calcd for C17H24O4 [M]+ 292.1675, found 292.1675. 50.3 mg (86%); light yellow oil;OneH NMR (400 MHz, CDCl3) δ 7.27 (t,J = 8.0 Hz, 1H), 6.87-6.85 (m, 2H), 4.12 (q,J = 7.2 Hz, 2H), 3.81 (s, 3H), 3.59 (s, 2H), 2.84 (t,J = 7.2 Hz, 2H), 1.71-1.63 (m, 2H), 1.34-1.30 (m, 4H), 1.24 (t,J = 7.2 Hz, 3H), 0.90 (t,J = 7.2 Hz, 3H);13C NMR (100 MHz, CDCl3) δ 207.8, 171.2, 156.7, 132.3, 131.5, 130.2, 123.2, 109.9, 60.9, 55.6, 44.4, 38.2, 31.4, 23.3, 22.5, 14.1, 13.9; IR (KBr) υ 2955, 2927, 2856, 1734, 1691, 1597, 1581, 1469, 1438, 1367, 1336, 1259, 1181, 1159, 1073, 1030, 950, 768 cm-One; HRMS (quadrupole, EI) calcd for C17H24O4 [M]+ 292.1675, found 292.1675.

Ethyl 2-(2-Ethyl 2-(2- heptanoylheptanoyl -3--3- methoxyphenylmethoxyphenyl )acetate ()acetate ( 5bb5bb ))

Figure 112018005760933-pat00041
Figure 112018005760933-pat00041

54.1 mg (88%); light yellow oil; 1H NMR (400 MHz, CDCl3) δ 7.27 (t, J = 8.0 Hz, 1H), 6.87-6.83 (m, 2H), 4.12 (q, J = 6.8 Hz, 2H), 3.81 (s, 3H), 3.58 (s, 2H), 2.84 (t, J = 7.2 Hz, 2H), 1.70-1.62 (m, 2H), 1.36-1.27 (m, 6H), 1.24 (t, J = 7.2 Hz, 3H), 0.88 (t, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 207.8, 171.2, 156.7, 132.3, 131.5, 130.2, 123.2, 109.9, 60.8, 55.5, 44.4, 38.2, 31.6, 28.9, 23.5, 22.5, 14.1, 14.0; IR (KBr) υ 2955, 2928, 2856, 1735, 1691, 1598, 1582, 1469, 1438, 1367, 1297, 1262, 1181, 1160, 1074, 1030, 949, 760 cm-1; HRMS (quadrupole, EI) calcd for C18H26O4 [M]+ 306.1831, found 306.1832. 54.1 mg (88%); light yellow oil;OneH NMR (400 MHz, CDCl3) δ 7.27 (t,J = 8.0 Hz, 1H), 6.87-6.83 (m, 2H), 4.12 (q,J = 6.8 Hz, 2H), 3.81 (s, 3H), 3.58 (s, 2H), 2.84 (t,J = 7.2 Hz, 2H), 1.70-1.62 (m, 2H), 1.36-1.27 (m, 6H), 1.24 (t,J = 7.2 Hz, 3H), 0.88 (t,J = 6.8 Hz, 3H);13C NMR (100 MHz, CDCl3) δ 207.8, 171.2, 156.7, 132.3, 131.5, 130.2, 123.2, 109.9, 60.8, 55.5, 44.4, 38.2, 31.6, 28.9, 23.5, 22.5, 14.1, 14.0; IR (KBr) υ 2955, 2928, 2856, 1735, 1691, 1598, 1582, 1469, 1438, 1367, 1297, 1262, 1181, 1160, 1074, 1030, 949, 760 cm-One; HRMS (quadrupole, EI) calcd for C18H26O4 [M]+ 306.1831, found 306.1832.

Ethyl 2-(3-Ethyl 2-(3- methoxymethoxy -2--2- octanoylphenyloctanoylphenyl )acetate ()acetate ( 5bc5bc ))

Figure 112018005760933-pat00042
Figure 112018005760933-pat00042

58.9 mg (92%); light yellow oil; 1H NMR (400 MHz, CDCl3) δ 7.27 (t, J = 8.0 Hz, 1H), 6.87-6.83 (m, 2H), 4.12 (q, J = 7.2 Hz, 2H), 3.81 (s, 3H), 3.59 (s, 2H), 2.84 (t, J = 7.6 Hz, 2H), 1.70-1.62 (m, 2H), 1.34-1.26 (m, 8H), 1.24 (t, J = 7.2 Hz, 3H), 0.88 (t, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 207.9, 171.2, 156.7, 132.3, 131.5, 130.2, 123.2, 109.9, 60.9, 55.6, 44.4, 38.2, 31.7, 29.2, 29.1, 23.6, 22.6, 14.1, 14.0; IR (KBr) υ 2955, 2925, 2854, 1735, 1691, 1597, 1581, 1469, 1438, 1367, 1297, 1260, 1180, 1158, 1074, 1029, 952, 754 cm-1; HRMS (quadrupole, EI) calcd for C19H28O4 [M]+ 320.1988, found 320.1987. 58.9 mg (92%); light yellow oil;OneH NMR (400 MHz, CDCl3) δ 7.27 (t,J = 8.0 Hz, 1H), 6.87-6.83 (m, 2H), 4.12 (q,J = 7.2 Hz, 2H), 3.81 (s, 3H), 3.59 (s, 2H), 2.84 (t,J = 7.6 Hz, 2H), 1.70-1.62 (m, 2H), 1.34-1.26 (m, 8H), 1.24 (t,J = 7.2 Hz, 3H), 0.88 (t,J = 6.8 Hz, 3H);13C NMR (100 MHz, CDCl3) δ 207.9, 171.2, 156.7, 132.3, 131.5, 130.2, 123.2, 109.9, 60.9, 55.6, 44.4, 38.2, 31.7, 29.2, 29.1, 23.6, 22.6, 14.1, 14.0; IR (KBr) υ 2955, 2925, 2854, 1735, 1691, 1597, 1581, 1469, 1438, 1367, 1297, 1260, 1180, 1158, 1074, 1029, 952, 754 cm-One; HRMS (quadrupole, EI) calcd for C19H28O4 [M]+ 320.1988, found 320.1987.

Ethyl 2-(3-Ethyl 2-(3- methoxymethoxy -2--2- nonanoylphenylnonanoylphenyl )acetate ()acetate ( 5bd5bd ))

Figure 112018005760933-pat00043
Figure 112018005760933-pat00043

47.5 mg (71%); light yellow oil; 1H NMR (400 MHz, CDCl3) δ 7.28 (t, J = 8.0 Hz, 1H), 6.87-6.83 (m, 2H), 4.12 (q, J = 7.2 Hz, 2H), 3.81 (s, 3H), 3.59 (s, 2H), 2.84 (t, J = 7.2 Hz, 2H), 1.70-1.62 (m, 2H), 1.35-1.22 (m, 13H), 0.87 (t, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 207.9, 171.2, 156.7, 132.3, 131.5, 130.2, 123.2, 109.9, 60.9, 55.6, 44.4, 38.2, 31.8, 29.4, 29.3, 29.2, 23.6, 22.6, 14.2, 14.1; IR (KBr) υ 2954, 2925, 2853, 1735, 1691, 1597, 1581, 1468, 1438, 1367, 1297, 1259, 1180, 1158, 1075, 1030, 952 cm-1; HRMS (quadrupole, EI) calcd for C20H30O4 [M]+ 334.2144, found 334.2143. 47.5 mg (71%); light yellow oil;OneH NMR (400 MHz, CDCl3) δ 7.28 (t,J = 8.0 Hz, 1H), 6.87-6.83 (m, 2H), 4.12 (q,J = 7.2 Hz, 2H), 3.81 (s, 3H), 3.59 (s, 2H), 2.84 (t,J = 7.2 Hz, 2H), 1.70-1.62 (m, 2H), 1.35-1.22 (m, 13H), 0.87 (t,J = 6.8 Hz, 3H);13C NMR (100 MHz, CDCl3) δ 207.9, 171.2, 156.7, 132.3, 131.5, 130.2, 123.2, 109.9, 60.9, 55.6, 44.4, 38.2, 31.8, 29.4, 29.3, 29.2, 23.6, 22.6, 14.2, 14.1; IR (KBr) υ 2954, 2925, 2853, 1735, 1691, 1597, 1581, 1468, 1438, 1367, 1297, 1259, 1180, 1158, 1075, 1030, 952 cm-One; HRMS (quadrupole, EI) calcd for C20H30O4 [M]+ 334.2144, found 334.2143.

Ethyl 2-(2-Ethyl 2-(2- hexanoylhexanoyl -3,5--3,5- dimethoxyphenyldimethoxyphenyl )acetate ()acetate ( 5ca5ca ))

Figure 112018005760933-pat00044
Figure 112018005760933-pat00044

24.5 mg (38%); yellowish oil; 1H NMR (400 MHz, CDCl3) δ 6.38 (s, 1H), 6.37 (s, 1H), 4.12 (q, J = 7.2 Hz, 2H), 3.81 (s, 3H), 3.80 (s, 3H), 3.61 (s, 2H), 2.81 (t, J = 7.2 Hz, 2H), 1.66-1.60 (m, 2H), 1.32-1.30 (m, 4H), 1.24 (t, J = 7.2 Hz, 3H), 0.87 (t, J = 6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 207.0, 171.2, 161.2, 158.7, 134.4, 124.2, 107.7, 97.5, 60.8, 55.5, 55.3, 44.4, 38.8, 31.5, 23.7, 22.5, 14.1, 13.9; IR (KBr) υ 2955, 2929, 2857, 1734, 1682, 1601, 1580, 1457, 1423, 1315, 1290, 1254, 1202, 1152, 1084, 1029, 950, 834 cm-1; HRMS (quadrupole, EI) calcd for C18H26O5 [M]+ 322.1780, found 322.1781. 24.5 mg (38%); yellowish oil;OneH NMR (400 MHz, CDCl3) δ 6.38 (s, 1H), 6.37 (s, 1H), 4.12 (q,J = 7.2 Hz, 2H), 3.81 (s, 3H), 3.80 (s, 3H), 3.61 (s, 2H), 2.81 (t,J = 7.2 Hz, 2H), 1.66-1.60 (m, 2H), 1.32-1.30 (m, 4H), 1.24 (t,J = 7.2 Hz, 3H), 0.87 (t,J = 6.4 Hz, 3H);13C NMR (100 MHz, CDCl3) δ 207.0, 171.2, 161.2, 158.7, 134.4, 124.2, 107.7, 97.5, 60.8, 55.5, 55.3, 44.4, 38.8, 31.5, 23.7, 22.5, 14.1, 13.9; IR (KBr) υ 2955, 2929, 2857, 1734, 1682, 1601, 1580, 1457, 1423, 1315, 1290, 1254, 1202, 1152, 1084, 1029, 950, 834 cm-One; HRMS (quadrupole, EI) calcd for C18H26O5 [M]+ 322.1780, found 322.1781.

Ethyl 2-(2-Ethyl 2-(2- heptanoylheptanoyl -3,5--3,5- dimethoxyphenyldimethoxyphenyl )acetate ()acetate ( 5cb5cb ))

Figure 112018005760933-pat00045
Figure 112018005760933-pat00045

30.4 mg (45%); yellowish oil; 1H NMR (400 MHz, CDCl3) δ 6.38 (s, 1H), 6.37 (s, 1H), 4.11 (q, J = 6.8 Hz, 2H), 3.81 (s, 3H), 3.80 (s, 3H), 3.60 (s, 2H), 2.81 (t, J = 7.6 Hz, 2H), 1.67-1.59 (m, 2H), 1.35-1.29 (m, 6H), 1.24 (t, J = 7.2 Hz, 3H), 0.87 (t, J = 6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 207.0, 171.2, 161.2, 158.7, 134.4, 124.2, 107.7, 97.5, 60.8, 55.5, 55.3, 44.5, 38.8, 31.7, 29.0, 24.0, 22.5, 14.1, 14.0; IR (KBr) υ 2955, 2930, 2856, 1734, 1682, 1601, 1580, 1457, 1423, 1367, 1315, 1254, 1202, 1151, 1085, 1029, 950, 834 cm-1; HRMS (quadrupole, EI) calcd for C19H28O5 [M]+ 336.1937, found 336.1939. 30.4 mg (45%); yellowish oil;OneH NMR (400 MHz, CDCl3) δ 6.38 (s, 1H), 6.37 (s, 1H), 4.11 (q,J = 6.8 Hz, 2H), 3.81 (s, 3H), 3.80 (s, 3H), 3.60 (s, 2H), 2.81 (t,J = 7.6 Hz, 2H), 1.67-1.59 (m, 2H), 1.35-1.29 (m, 6H), 1.24 (t,J = 7.2 Hz, 3H), 0.87 (t,J = 6.4 Hz, 3H);13C NMR (100 MHz, CDCl3) δ 207.0, 171.2, 161.2, 158.7, 134.4, 124.2, 107.7, 97.5, 60.8, 55.5, 55.3, 44.5, 38.8, 31.7, 29.0, 24.0, 22.5, 14.1, 14.0; IR (KBr) υ 2955, 2930, 2856, 1734, 1682, 1601, 1580, 1457, 1423, 1367, 1315, 1254, 1202, 1151, 1085, 1029, 950, 834 cm-One; HRMS (quadrupole, EI) calcd for C19H28O5 [M]+ 336.1937, found 336.1939.

Ethyl 2-(3,5-Ethyl 2-(3,5- dimethoxydimethoxy -2--2- octanoylphenyloctanoylphenyl )acetate (5cc))acetate (5cc)

Figure 112018005760933-pat00046
Figure 112018005760933-pat00046

33.7 mg (48%); yellowish oil; 1H NMR (400 MHz, CDCl3) δ 6.39 (br s, 1H), 6.37 (br s, 1H), 4.13 (q, J = 8.0 Hz, 2H), 3.81 (s, 3H), 3.80 (s, 3H), 3.61 (s, 2H), 2.82 (t, J = 8.0 Hz, 2H), 1.67-1.60 (m, 2H), 1.32-1.23 (m, 11H), 0.87 (t, J = 8.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 207.0, 171.3, 161.2, 158.7, 134.4, 124.3, 107.7, 97.5, 60.8, 55.5, 55.4, 44.5, 38.9, 31.7, 29.3, 29.1, 24.0, 22.6, 14.2, 14.1; IR (KBr) υ 2954, 2927, 2854, 1734, 1682, 1601, 1580, 1457, 1423, 1366, 1315, 1260, 1201, 1151, 1086, 1030, 951, 833 cm-1; HRMS (quadrupole, EI) calcd for C20H30O5 [M]+ 350.2093, found 350.2096. 33.7 mg (48%); yellowish oil;OneH NMR (400 MHz, CDCl3) δ 6.39 (br s, 1H), 6.37 (br s, 1H), 4.13 (q,J = 8.0 Hz, 2H), 3.81 (s, 3H), 3.80 (s, 3H), 3.61 (s, 2H), 2.82 (t,J = 8.0 Hz, 2H), 1.67-1.60 (m, 2H), 1.32-1.23 (m, 11H), 0.87 (t,J = 8.0 Hz, 3H);13C NMR (100 MHz, CDCl3) δ 207.0, 171.3, 161.2, 158.7, 134.4, 124.3, 107.7, 97.5, 60.8, 55.5, 55.4, 44.5, 38.9, 31.7, 29.3, 29.1, 24.0, 22.6, 14.2, 14.1; IR (KBr) υ 2954, 2927, 2854, 1734, 1682, 1601, 1580, 1457, 1423, 1366, 1315, 1260, 1201, 1151, 1086, 1030, 951, 833 cm-One; HRMS (quadrupole, EI) calcd for C20H30O5 [M]+ 350.2093, found 350.2096.

Ethyl 2-(3,5-Ethyl 2-(3,5- dimethoxydimethoxy -2--2- nonanoylphenylnonanoylphenyl )acetate (5cd))acetate (5cd)

Figure 112018005760933-pat00047
Figure 112018005760933-pat00047

38.1 mg (52%); yellowish oil; 1H NMR (400 MHz, CDCl3) δ 6.38 (s, 1H), 6.37 (s, 1H), 4.12 (q, J = 7.2 Hz, 2H), 3.80 (s, 3H), 3.79 (s, 3H), 3.60 (s, 2H), 2.81 (t, J = 7.2 Hz, 2H), 1.65-1.59 (m, 2H), 1.29-1.22 (m, 13H), 0.87 (t, J = 6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 207.0, 171.2, 161.2, 158.7, 134.4, 124.2, 107.7, 97.5, 60.8, 55.5, 55.3, 44.5, 38.8, 31.7, 29.4, 29.3, 29.1, 24.0, 22.6, 14.1, 14.0; IR (KBr) υ 2925, 2853, 1735, 1682, 1602, 1580, 1457, 1423, 1367, 1315, 1256, 1201, 1151, 1087, 1030, 952, 834 cm-1; HRMS (quadrupole, EI) calcd for C21H32O5 [M]+ 364.2250, found 364.2247. 38.1 mg (52%); yellowish oil;OneH NMR (400 MHz, CDCl3) δ 6.38 (s, 1H), 6.37 (s, 1H), 4.12 (q,J = 7.2 Hz, 2H), 3.80 (s, 3H), 3.79 (s, 3H), 3.60 (s, 2H), 2.81 (t,J = 7.2 Hz, 2H), 1.65-1.59 (m, 2H), 1.29-1.22 (m, 13H), 0.87 (t,J = 6.4 Hz, 3H);13C NMR (100 MHz, CDCl3) δ 207.0, 171.2, 161.2, 158.7, 134.4, 124.2, 107.7, 97.5, 60.8, 55.5, 55.3, 44.5, 38.8, 31.7, 29.4, 29.3, 29.1, 24.0, 22.6, 14.1, 14.0; IR (KBr) υ 2925, 2853, 1735, 1682, 1602, 1580, 1457, 1423, 1367, 1315, 1256, 1201, 1151, 1087, 1030, 952, 834 cm-One; HRMS (quadrupole, EI) calcd for C21H32O5 [M]+ 364.2250, found 364.2247.

Ethyl 2-(2-Ethyl 2-(2- hexanoylhexanoyl -5--5- methoxyphenylmethoxyphenyl )acetate ()acetate ( 5da5da ))

Figure 112018005760933-pat00048
Figure 112018005760933-pat00048

24.1 mg (41%); yellowish oil; 1H NMR (400 MHz, CDCl3) δ 7.81 (d, J = 8.8 Hz, 1H), 6.84 (dd, J = 8.4, 2.4 Hz, 1H), 6.74 (d, J = 2.4 Hz, 1H), 4.15 (q, J = 7.2 Hz, 2H), 3.91 (s, 2H), 3.85 (s, 3H), 2.88 (t, J = 7.2 Hz, 2H), 1.71-1.63 (m, 2H), 1.34-1.31 (m, 4H), 1.26 (t, J = 7.2 Hz, 3H), 0.89 (t, J = 6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 201.8, 171.5, 161.9, 137.5, 131.9, 129.7, 118.5, 111.8, 60.6, 55.3, 40.9, 40.2, 31.5, 24.3, 22.5, 14.2, 13.9; IR (KBr) υ 2956, 2928, 2858, 1733, 1673, 1603, 1569, 1464, 1428, 1367, 1336, 1315, 1291, 1244, 1211, 1159, 1131, 1031, 977, 877 cm-1; HRMS (quadrupole, EI) calcd for C17H24O4 [M]+ 292.1675, found 292.1674. 24.1 mg (41%); yellowish oil;OneH NMR (400 MHz, CDCl3) δ 7.81 (d,J = 8.8 Hz, 1H), 6.84 (dd,J = 8.4, 2.4 Hz, 1H), 6.74 (d,J = 2.4 Hz, 1H), 4.15 (q,J = 7.2 Hz, 2H), 3.91 (s, 2H), 3.85 (s, 3H), 2.88 (t,J = 7.2 Hz, 2H), 1.71-1.63 (m, 2H), 1.34-1.31 (m, 4H), 1.26 (t,J = 7.2 Hz, 3H), 0.89 (t,J = 6.4 Hz, 3H);13C NMR (100 MHz, CDCl3) δ 201.8, 171.5, 161.9, 137.5, 131.9, 129.7, 118.5, 111.8, 60.6, 55.3, 40.9, 40.2, 31.5, 24.3, 22.5, 14.2, 13.9; IR (KBr) υ 2956, 2928, 2858, 1733, 1673, 1603, 1569, 1464, 1428, 1367, 1336, 1315, 1291, 1244, 1211, 1159, 1131, 1031, 977, 877 cm-One; HRMS (quadrupole, EI) calcd for C17H24O4 [M]+ 292.1675, found 292.1674.

Ethyl 2-(2-Ethyl 2-(2- heptanoylheptanoyl -5--5- methoxyphenylmethoxyphenyl )acetate ()acetate ( 5db5db ))

Figure 112018005760933-pat00049
Figure 112018005760933-pat00049

24.5 mg (40%); yellowish oil; 1H NMR (400 MHz, CDCl3) δ 7.81 (d, J = 8.8 Hz, 1H), 6.84 (dd, J = 8.4, 2.4 Hz, 1H), 6.74 (d, J = 2.4 Hz, 1H), 4.14 (q, J = 7.2 Hz, 2H), 3.91 (s, 2H), 3.85 (s, 3H), 2.88 (t, J = 7.2 Hz, 2H), 1.70-1.63 (m, 2H), 1.38-1.30 (m, 6H), 1.26 (t, J = 7.2 Hz, 3H), 0.88 (t, J = 6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 201.8, 171.5, 161.9, 137.5, 131.9, 129.7, 118.5, 111.8, 60.6, 55.3, 40.9, 40.3, 31.6, 29.0, 24.6, 22.5, 14.2, 14.0; IR (KBr) υ 2955, 2929, 2856, 1734, 1673, 1603, 1569, 1464, 1367, 1336, 1315, 1291, 1255, 1230, 1208, 1159, 1131, 1031, 980, 877, 814 cm-1; HRMS (quadrupole, EI) calcd for C18H26O4 [M]+ 306.1831, found 306.1831. 24.5 mg (40%); yellowish oil;OneH NMR (400 MHz, CDCl3) δ 7.81 (d,J = 8.8 Hz, 1H), 6.84 (dd,J = 8.4, 2.4 Hz, 1H), 6.74 (d,J = 2.4 Hz, 1H), 4.14 (q,J = 7.2 Hz, 2H), 3.91 (s, 2H), 3.85 (s, 3H), 2.88 (t,J = 7.2 Hz, 2H), 1.70-1.63 (m, 2H), 1.38-1.30 (m, 6H), 1.26 (t,J = 7.2 Hz, 3H), 0.88 (t,J = 6.4 Hz, 3H);13C NMR (100 MHz, CDCl3) δ 201.8, 171.5, 161.9, 137.5, 131.9, 129.7, 118.5, 111.8, 60.6, 55.3, 40.9, 40.3, 31.6, 29.0, 24.6, 22.5, 14.2, 14.0; IR (KBr) υ 2955, 2929, 2856, 1734, 1673, 1603, 1569, 1464, 1367, 1336, 1315, 1291, 1255, 1230, 1208, 1159, 1131, 1031, 980, 877, 814 cm-One; HRMS (quadrupole, EI) calcd for C18H26O4 [M]+ 306.1831, found 306.1831.

EhylEhyl 2-(5- 2-(5- methoxymethoxy -2--2- octanoylphenyloctanoylphenyl )acetate ()acetate ( 5dc5dc ))

Figure 112018005760933-pat00050
Figure 112018005760933-pat00050

25.1 mg (39%); yellowish oil; 1H NMR (400 MHz, CDCl3) δ 7.81 (d, J = 8.8 Hz, 1H), 6.84 (dd, J = 8.4, 2.4 Hz, 1H), 6.74 (d, J = 2.8 Hz, 1H), 4.15 (q, J = 7.2 Hz, 2H), 3.91 (s, 2H), 3.84 (s, 3H), 2.87 (t, J = 7.2 Hz, 2H), 1.68-1.62 (m, 2H), 1.33-1.24 (m, 11H), 0.87 (t, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 201.8, 171.5, 161.9, 137.5, 131.9, 129.7, 118.5, 111.8, 60.6, 55.3, 40.9, 40.3, 31.7, 29.3, 29.1, 24.6, 22.6, 14.2, 14.1; IR (KBr) υ 2954, 2925, 2853, 1735, 1674, 1604, 1569, 1464, 1367, 1315, 1254, 1225, 1159, 1131, 1031, 983, 877, 815 cm-1; HRMS (quadrupole, EI) calcd for C19H28O4 [M]+ 320.1988, found 320.1987. 25.1 mg (39%); yellowish oil;OneH NMR (400 MHz, CDCl3) δ 7.81 (d,J = 8.8 Hz, 1H), 6.84 (dd,J = 8.4, 2.4 Hz, 1H), 6.74 (d,J = 2.8 Hz, 1H), 4.15 (q,J = 7.2 Hz, 2H), 3.91 (s, 2H), 3.84 (s, 3H), 2.87 (t,J = 7.2 Hz, 2H), 1.68-1.62 (m, 2H), 1.33-1.24 (m, 11H), 0.87 (t,J = 6.8 Hz, 3H);13C NMR (100 MHz, CDCl3) δ 201.8, 171.5, 161.9, 137.5, 131.9, 129.7, 118.5, 111.8, 60.6, 55.3, 40.9, 40.3, 31.7, 29.3, 29.1, 24.6, 22.6, 14.2, 14.1; IR (KBr) υ 2954, 2925, 2853, 1735, 1674, 1604, 1569, 1464, 1367, 1315, 1254, 1225, 1159, 1131, 1031, 983, 877, 815 cm-One; HRMS (quadrupole, EI) calcd for C19H28O4 [M]+ 320.1988, found 320.1987.

Ethyl 2-(5-Ethyl 2-(5- methoxymethoxy -2--2- nonanoylphenylnonanoylphenyl )acetate ()acetate ( 5dd5dd ))

Figure 112018005760933-pat00051
Figure 112018005760933-pat00051

26.8 mg (40%); white solid; mp = 51.2-53.8 oC; 1H NMR (400 MHz, CDCl3) δ 7.81 (d, J = 8.8 Hz, 1H), 6.84 (dd, J = 8.8, 2.4 Hz, 1H), 6.74 (d, J = 2.4 Hz, 1H), 4.15 (q, J = 7.2 Hz, 2H), 3.91 (s, 2H), 3.84 (s, 3H), 2.87 (t, J = 7.2 Hz, 2H), 1.70-1.63 (m, 2H), 1.33-1.24 (m, 13H), 0.87 (t, J = 6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 201.8, 171.5, 161.9, 137.5, 131.9, 129.7, 118.5, 111.8, 60.6, 55.3, 40.9, 40.2, 31.8, 29.4, 29.3, 29.2, 24.6, 22.6, 14.2, 14.0; IR (KBr) υ 2925, 2854, 1736, 1675, 1604, 1569, 1463, 1367, 1315, 1254, 1160, 1132, 1032, 877, 816 cm-1; HRMS (quadrupole, EI) calcd for C20H30O4 [M]+ 334.2144, found 334.2147. 26.8 mg (40%); white solid; mp = 51.2-53.8oC;OneH NMR (400 MHz, CDCl3) δ 7.81 (d,J = 8.8 Hz, 1H), 6.84 (dd,J = 8.8, 2.4 Hz, 1H), 6.74 (d,J = 2.4 Hz, 1H), 4.15 (q,J = 7.2 Hz, 2H), 3.91 (s, 2H), 3.84 (s, 3H), 2.87 (t,J = 7.2 Hz, 2H), 1.70-1.63 (m, 2H), 1.33-1.24 (m, 13H), 0.87 (t,J = 6.4 Hz, 3H);13C NMR (100 MHz, CDCl3) δ 201.8, 171.5, 161.9, 137.5, 131.9, 129.7, 118.5, 111.8, 60.6, 55.3, 40.9, 40.2, 31.8, 29.4, 29.3, 29.2, 24.6, 22.6, 14.2, 14.0; IR (KBr) υ 2925, 2854, 1736, 1675, 1604, 1569, 1463, 1367, 1315, 1254, 1160, 1132, 1032, 877, 816 cm-One; HRMS (quadrupole, EI) calcd for C20H30O4 [M]+ 334.2144, found 334.2147.

Ethyl 2-(2-Ethyl 2-(2- hexanoylhexanoyl -4--4- methoxyphenylmethoxyphenyl )acetate ()acetate ( 5ea5ea ))

Figure 112018005760933-pat00052
Figure 112018005760933-pat00052

8.9 mg (15%); light yellow oil; 1H NMR (400 MHz, CDCl3) δ 7.26 (s, 1H), 7.16 (d, J = 8.4 Hz, 1H), 6.96 (dd, J = 8.4, 2.8 Hz, 1H), 4.15 (q, J = 7.2 Hz, 2H), 3.84 (s, 3H), 3.82 (s, 2H), 2.89 (t, J = 7.6 Hz, 2H), 1.72-1.64 (m, 2H), 1.35-1.31 (m, 4H), 1.25 (t, J = 7.2 Hz, 3H), 0.90 (t, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 203.8, 171.9, 158.5, 138.8, 133.4, 126.0, 115.9, 115.5, 60.6, 55.5, 40.8, 39.1, 31.5, 23.9, 22.5, 14.2, 13.9; IR (KBr) υ 2955, 2929, 2857, 1734, 1686, 1607, 1573, 1502, 1463, 1418, 1368, 1338, 1288, 1256, 1160, 1032, 984, 928, 875 cm-1; HRMS (quadrupole, EI) calcd for C17H24O4 [M]+ 292.1675, found 292.1673. 8.9 mg (15%); light yellow oil;OneH NMR (400 MHz, CDCl3) δ 7.26 (s, 1H), 7.16 (d,J = 8.4 Hz, 1H), 6.96 (dd,J = 8.4, 2.8 Hz, 1H), 4.15 (q,J = 7.2 Hz, 2H), 3.84 (s, 3H), 3.82 (s, 2H), 2.89 (t,J = 7.6 Hz, 2H), 1.72-1.64 (m, 2H), 1.35-1.31 (m, 4H), 1.25 (t,J = 7.2 Hz, 3H), 0.90 (t,J = 6.8 Hz, 3H);13C NMR (100 MHz, CDCl3) δ 203.8, 171.9, 158.5, 138.8, 133.4, 126.0, 115.9, 115.5, 60.6, 55.5, 40.8, 39.1, 31.5, 23.9, 22.5, 14.2, 13.9; IR (KBr) υ 2955, 2929, 2857, 1734, 1686, 1607, 1573, 1502, 1463, 1418, 1368, 1338, 1288, 1256, 1160, 1032, 984, 928, 875 cm-One; HRMS (quadrupole, EI) calcd for C17H24O4 [M]+ 292.1675, found 292.1673.

Ethyl 2-(2-Ethyl 2-(2- hexanoylhexanoyl -6--6- methoxyphenylmethoxyphenyl )acetate ()acetate ( 5ea5ea ')')

Figure 112018005760933-pat00053
Figure 112018005760933-pat00053

22.3 mg (38%); light yellow oil; 1H NMR (400 MHz, CDCl3) δ 7.32 (t, J = 8.0 Hz, 1H), 7.27 (d, J = 7.2 Hz, 1H), 7.01 (d, J = 8.0 Hz, 1H), 4.14 (q, J = 7.2 Hz, 2H), 3.93 (s, 2H), 3.83 (s, 3H), 2.88 (t, J = 7.6 Hz, 2H), 1.71-1.64 (m, 2H), 1.34-1.30 (m, 4H), 1.25 (t, J = 6.8 Hz, 3H), 0.89 (t, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 204.8, 171.8, 158.2, 139.9, 127.8, 122.5, 120.3, 113.4, 60.5, 55.9, 41.6, 31.5, 31.4, 23.9, 22.5, 14.2, 13.9; IR (KBr) υ 2955, 2932, 2871, 1734, 1685, 1580, 1459, 1439, 1409, 1367, 1335, 1265, 1205, 1158, 1030, 930, 883 cm-1; HRMS (quadrupole, EI) calcd for C17H24O4 [M]+ 292.1675, found 292.1674. 22.3 mg (38%); light yellow oil;OneH NMR (400 MHz, CDCl3) δ 7.32 (t,J = 8.0 Hz, 1H), 7.27 (d,J = 7.2 Hz, 1H), 7.01 (d,J = 8.0 Hz, 1H), 4.14 (q,J = 7.2 Hz, 2H), 3.93 (s, 2H), 3.83 (s, 3H), 2.88 (t,J = 7.6 Hz, 2H), 1.71-1.64 (m, 2H), 1.34-1.30 (m, 4H), 1.25 (t,J = 6.8 Hz, 3H), 0.89 (t,J = 6.8 Hz, 3H);13C NMR (100 MHz, CDCl3) δ 204.8, 171.8, 158.2, 139.9, 127.8, 122.5, 120.3, 113.4, 60.5, 55.9, 41.6, 31.5, 31.4, 23.9, 22.5, 14.2, 13.9; IR (KBr) υ 2955, 2932, 2871, 1734, 1685, 1580, 1459, 1439, 1409, 1367, 1335, 1265, 1205, 1158, 1030, 930, 883 cm-One; HRMS (quadrupole, EI) calcd for C17H24O4 [M]+ 292.1675, found 292.1674.

Ethyl 2-(2-Ethyl 2-(2- heptanoylheptanoyl -4--4- methoxyphenylmethoxyphenyl )acetate ()acetate ( 5eb5eb ))

Figure 112018005760933-pat00054
Figure 112018005760933-pat00054

8.7 mg (14%); light yellow oil; 1H NMR (400 MHz, CDCl3) δ 7.26 (s, 1H), 7.16 (d, J = 8.4 Hz, 1H), 6.96 (dd, J = 8.4, 2.4 Hz, 1H), 4.13 (q, J = 7.2 Hz, 2H), 3.84 (s, 3H), 3.82 (s, 2H), 2.89 (t, J = 7.2 Hz, 2H), 1.71-1.64 (m, 2H), 1.38-1.28 (m, 6H), 1.25 (t, J = 7.2 Hz, 3H), 0.88 (t, J = 6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 203.8, 171.9, 158.5, 138.8, 133.4, 126.0, 115.9, 115.5, 60.6, 55.5, 40.8, 39.1, 31.6, 28.9, 24.1, 22.5, 14.2, 14.0; IR (KBr) υ 2955, 2930, 2857, 1734, 1685, 1608, 1574, 1501, 1463, 1418, 1367, 1337, 1254, 1213, 1159, 1031, 984, 929, 873 cm-1; HRMS (quadrupole, EI) calcd for C18H26O4 [M]+ 306.1831, found 306.1828. 8.7 mg (14%); light yellow oil;OneH NMR (400 MHz, CDCl3) δ 7.26 (s, 1H), 7.16 (d,J = 8.4 Hz, 1H), 6.96 (dd,J = 8.4, 2.4 Hz, 1H), 4.13 (q,J = 7.2 Hz, 2H), 3.84 (s, 3H), 3.82 (s, 2H), 2.89 (t,J = 7.2 Hz, 2H), 1.71-1.64 (m, 2H), 1.38-1.28 (m, 6H), 1.25 (t,J = 7.2 Hz, 3H), 0.88 (t,J = 6.4 Hz, 3H);13C NMR (100 MHz, CDCl3) δ 203.8, 171.9, 158.5, 138.8, 133.4, 126.0, 115.9, 115.5, 60.6, 55.5, 40.8, 39.1, 31.6, 28.9, 24.1, 22.5, 14.2, 14.0; IR (KBr) υ 2955, 2930, 2857, 1734, 1685, 1608, 1574, 1501, 1463, 1418, 1367, 1337, 1254, 1213, 1159, 1031, 984, 929, 873 cm-One; HRMS (quadrupole, EI) calcd for C18H26O4 [M]+ 306.1831, found 306.1828.

Ethyl 2-(2-Ethyl 2-(2- heptanoylheptanoyl -6--6- methoxyphenylmethoxyphenyl )acetate ()acetate ( 5eb5eb ')')

Figure 112018005760933-pat00055
Figure 112018005760933-pat00055

21.7 mg (35%); light yellow oil; 1H NMR (400 MHz, CDCl3) δ 7.32 (t, J = 8.0 Hz, 1H), 7.27 (d, J = 7.6 Hz, 1H), 7.01 (d, J = 8.0 Hz, 1H), 4.13 (q, J = 7.2 Hz, 2H), 3.93 (s, 2H), 3.83 (s, 3H), 2.88 (t, J = 7.6 Hz, 2H), 1.70-1.63 (m, 2H), 1.37-1.30 (m, 6H), 1.25 (t, J = 7.2 Hz, 3H), 0.87 (t, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 204.8, 171.8, 158.1, 139.9, 127.8, 122.5, 120.3, 113.4, 60.5, 55.9, 41.6, 31.6, 31.5, 28.9, 24.2, 22.5, 14.2, 14.0; IR (KBr) υ 2954, 2930, 2857, 1734, 1685, 1580, 1459, 1439, 1367, 1335, 1265, 1238, 1205, 1159, 1030, 931 cm-1; HRMS (quadrupole, EI) calcd for C18H26O4 [M]+ 306.1831, found 306.1834. 21.7 mg (35%); light yellow oil;OneH NMR (400 MHz, CDCl3) δ 7.32 (t,J = 8.0 Hz, 1H), 7.27 (d,J = 7.6 Hz, 1H), 7.01 (d,J = 8.0 Hz, 1H), 4.13 (q,J = 7.2 Hz, 2H), 3.93 (s, 2H), 3.83 (s, 3H), 2.88 (t,J = 7.6 Hz, 2H), 1.70-1.63 (m, 2H), 1.37-1.30 (m, 6H), 1.25 (t,J = 7.2 Hz, 3H), 0.87 (t,J = 6.8 Hz, 3H);13C NMR (100 MHz, CDCl3) δ 204.8, 171.8, 158.1, 139.9, 127.8, 122.5, 120.3, 113.4, 60.5, 55.9, 41.6, 31.6, 31.5, 28.9, 24.2, 22.5, 14.2, 14.0; IR (KBr) υ 2954, 2930, 2857, 1734, 1685, 1580, 1459, 1439, 1367, 1335, 1265, 1238, 1205, 1159, 1030, 931 cm-One; HRMS (quadrupole, EI) calcd for C18H26O4 [M]+ 306.1831, found 306.1834.

Ethyl 2-(4-Ethyl 2-(4- methoxymethoxy -2--2- octanoylphenyloctanoylphenyl )acetate ()acetate ( 5ec5ec ))

Figure 112018005760933-pat00056
Figure 112018005760933-pat00056

8.4 mg (13%); light yellow oil; 1H NMR (400 MHz, CDCl3) δ 7.26 (br s, 1H), 7.16 (d, J = 8.0 Hz, 1H), 6.96 (dd, J = 8.0, 4.0 Hz, 1H), 4.12 (q, J = 8.0 Hz, 2H), 3.84 (s, 3H), 3.82 (s, 2H), 2.89 (t, J = 8.0 Hz, 2H), 1.69-1.64 (m, 2H), 1.33-1.23 (m, 11H), 0.87 (t, J = 8.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 203.8, 171.9, 158.5, 138.8, 133.4, 126.0, 115.9, 115.4, 60.6, 55.5, 40.8, 39.1, 31.7, 29.2, 29.1, 24.2, 22.6, 14.2, 14.0; IR (KBr) υ 2954, 2925, 2854, 1735, 1686, 1608, 1574, 1501, 1464, 1418, 1368, 1252, 1213, 1159, 1032, 987, 928, 874 cm-1; HRMS (quadrupole, EI) calcd for C19H28O4 [M]+ 320.1988, found 320.1990. 8.4 mg (13%); light yellow oil;OneH NMR (400 MHz, CDCl3) δ 7.26 (br s, 1H), 7.16 (d,J = 8.0 Hz, 1H), 6.96 (dd,J = 8.0, 4.0 Hz, 1H), 4.12 (q,J = 8.0 Hz, 2H), 3.84 (s, 3H), 3.82 (s, 2H), 2.89 (t,J = 8.0 Hz, 2H), 1.69-1.64 (m, 2H), 1.33-1.23 (m, 11H), 0.87 (t,J = 8.0 Hz, 3H);13C NMR (100 MHz, CDCl3) δ 203.8, 171.9, 158.5, 138.8, 133.4, 126.0, 115.9, 115.4, 60.6, 55.5, 40.8, 39.1, 31.7, 29.2, 29.1, 24.2, 22.6, 14.2, 14.0; IR (KBr) υ 2954, 2925, 2854, 1735, 1686, 1608, 1574, 1501, 1464, 1418, 1368, 1252, 1213, 1159, 1032, 987, 928, 874 cm-One; HRMS (quadrupole, EI) calcd for C19H28O4 [M]+ 320.1988, found 320.1990.

Ethyl 2-(2-Ethyl 2-(2- methoxymethoxy -6--6- octanoylphenyloctanoylphenyl )acetate ()acetate ( 5ec5ec ')')

Figure 112018005760933-pat00057
Figure 112018005760933-pat00057

21.9 mg (34%); light yellow oil; 1H NMR (400 MHz, CDCl3) δ 7.32 (t, J = 8.0 Hz, 1H), 7.26 (d, J = 8.0 Hz, 1H), 7.01 (d, J = 8.0 Hz, 1H), 4.14 (q, J = 8.0 Hz, 2H), 3.93 (s, 2H), 3.83 (s, 3H), 2.88 (t, J = 8.0 Hz, 2H), 1.70-1.63 (m, 2H), 1.33-1.23 (m, 11H), 0.87 (t, J = 8.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 204.9, 171.8, 158.2, 139.9, 127.8, 122.6, 120.3, 113.3, 60.5, 55.9, 41.7, 31.7, 31.5, 29.2, 29.1, 24.3, 22.6, 14.2, 14.0; IR (KBr) υ 2953, 2926, 2855, 1735, 1686, 1580, 1459, 1439, 1367, 1335, 1266, 1236, 1204, 1158, 1031, 1009, 930, 833 cm-1; HRMS (quadrupole, EI) calcd for C19H28O4 [M]+ 320.1988, found 320.1989. 21.9 mg (34%); light yellow oil;OneH NMR (400 MHz, CDCl3) δ 7.32 (t,J = 8.0 Hz, 1H), 7.26 (d,J = 8.0 Hz, 1H), 7.01 (d,J = 8.0 Hz, 1H), 4.14 (q,J = 8.0 Hz, 2H), 3.93 (s, 2H), 3.83 (s, 3H), 2.88 (t,J = 8.0 Hz, 2H), 1.70-1.63 (m, 2H), 1.33-1.23 (m, 11H), 0.87 (t,J = 8.0 Hz, 3H);13C NMR (100 MHz, CDCl3) δ 204.9, 171.8, 158.2, 139.9, 127.8, 122.6, 120.3, 113.3, 60.5, 55.9, 41.7, 31.7, 31.5, 29.2, 29.1, 24.3, 22.6, 14.2, 14.0; IR (KBr) υ 2953, 2926, 2855, 1735, 1686, 1580, 1459, 1439, 1367, 1335, 1266, 1236, 1204, 1158, 1031, 1009, 930, 833 cm-One; HRMS (quadrupole, EI) calcd for C19H28O4 [M]+ 320.1988, found 320.1989.

Ethyl 2-(4-Ethyl 2-(4- methoxymethoxy -2--2- nonanoylphenylnonanoylphenyl )acetate ()acetate ( 5ed5ed ))

Figure 112018005760933-pat00058
Figure 112018005760933-pat00058

8.7 mg (13%); light yellow oil; 1H NMR (400 MHz, CDCl3) δ 7.26 (s, 1H), 7.16 (d, J = 8.4 Hz, 1H), 6.96 (dd, J = 8.4, 2.8 Hz, 1H), 4.13 (q, J = 7.2 Hz, 2H), 3.84 (s, 3H), 3.82 (s, 2H), 2.89 (t, J = 7.6 Hz, 2H), 1.71-1.64 (m, 2H), 1.34-1.23 (m, 13H), 0.87 (t, J = 6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 203.8, 171.9, 158.5, 138.8, 133.4, 126.0, 115.9, 115.5, 60.6, 55.5, 40.8, 39.1, 31.8, 29.4, 29.3, 29.1, 24.2, 22.6, 14.2, 14.1; IR (KBr) υ 2954, 2925, 2854, 1735, 1686, 1608, 1574, 1501, 1463, 1418, 1368, 1258, 1213, 1159, 1031, 985, 928, 874 cm-1; HRMS (quadrupole, EI) calcd for C20H30O4 [M]+ 334.2144, found 334.2144. 8.7 mg (13%); light yellow oil;OneH NMR (400 MHz, CDCl3) δ 7.26 (s, 1H), 7.16 (d,J = 8.4 Hz, 1H), 6.96 (dd,J = 8.4, 2.8 Hz, 1H), 4.13 (q,J = 7.2 Hz, 2H), 3.84 (s, 3H), 3.82 (s, 2H), 2.89 (t,J = 7.6 Hz, 2H), 1.71-1.64 (m, 2H), 1.34-1.23 (m, 13H), 0.87 (t,J = 6.4 Hz, 3H);13C NMR (100 MHz, CDCl3) δ 203.8, 171.9, 158.5, 138.8, 133.4, 126.0, 115.9, 115.5, 60.6, 55.5, 40.8, 39.1, 31.8, 29.4, 29.3, 29.1, 24.2, 22.6, 14.2, 14.1; IR (KBr) υ 2954, 2925, 2854, 1735, 1686, 1608, 1574, 1501, 1463, 1418, 1368, 1258, 1213, 1159, 1031, 985, 928, 874 cm-One; HRMS (quadrupole, EI) calcd for C20H30O4 [M]+ 334.2144, found 334.2144.

Ethyl 2-(2-Ethyl 2-(2- methoxymethoxy -6--6- nonanoylphenylnonanoylphenyl )acetate ()acetate ( 5ed5ed ')')

Figure 112018005760933-pat00059
Figure 112018005760933-pat00059

22.2 mg (33%); light yellow oil; 1H NMR (400 MHz, CDCl3) δ 7.32 (t, J = 8.0 Hz, 1H), 7.26 (d, J = 8.0 Hz, 1H), 7.01 (d, J = 8.0 Hz, 1H), 4.14 (q, J = 8.0 Hz, 2H), 3.93 (s, 2H), 3.83 (s, 3H), 2.88 (t, J = 8.0 Hz, 2H), 1.70-1.63 (m, 2H), 1.35-1.23 (m, 13H), 0.87 (t, J = 8.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 204.9, 171.8, 158.2, 139.9, 127.8, 122.5, 120.3, 113.3, 60.5, 55.9, 41.7, 31.8, 31.5, 29.4, 29.2, 29.1, 24.2, 22.6, 14.2, 14.0; IR (KBr) υ 2952, 2926, 2853, 1737, 1606, 1596, 1489, 1462, 1425, 1340, 1304, 1262, 1207, 1148, 1098, 1053, 950, 827 cm-1; HRMS (quadrupole, EI) calcd for C20H30O4 [M]+ 334.2144, found 334.2144. 22.2 mg (33%); light yellow oil;OneH NMR (400 MHz, CDCl3) δ 7.32 (t,J = 8.0 Hz, 1H), 7.26 (d,J = 8.0 Hz, 1H), 7.01 (d,J = 8.0 Hz, 1H), 4.14 (q,J = 8.0 Hz, 2H), 3.93 (s, 2H), 3.83 (s, 3H), 2.88 (t,J = 8.0 Hz, 2H), 1.70-1.63 (m, 2H), 1.35-1.23 (m, 13H), 0.87 (t,J = 8.0 Hz, 3H);13C NMR (100 MHz, CDCl3) δ 204.9, 171.8, 158.2, 139.9, 127.8, 122.5, 120.3, 113.3, 60.5, 55.9, 41.7, 31.8, 31.5, 29.4, 29.2, 29.1, 24.2, 22.6, 14.2, 14.0; IR (KBr) υ 2952, 2926, 2853, 1737, 1606, 1596, 1489, 1462, 1425, 1340, 1304, 1262, 1207, 1148, 1098, 1053, 950, 827 cm-One; HRMS (quadrupole, EI) calcd for C20H30O4 [M]+ 334.2144, found 334.2144.

Methyl 2-(2,3,4-Methyl 2-(2,3,4- trimethoxytrimethoxy -6--6- octanoylphenyloctanoylphenyl )acetate ()acetate ( 6aa6aa ))

Figure 112018005760933-pat00060
Figure 112018005760933-pat00060

29.7 mg (39%); yellowish oil; 1H NMR (400 MHz, CDCl3) δ 7.04 (s, 1H), 3.91 (s, 3H), 3.90 (s, 3H), 3.89 (s, 2H), 3.83 (s, 3H), 3.68 (s, 3H), 2.85 (t, J = 7.2 Hz, 2H), 1.70-1.63 (m, 2H), 1.32-1.24 (m, 8H), 0.86 (t, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 202.9, 172.5, 152.8, 151.8, 145.1, 133.4, 121.7, 108.5, 61.0, 60.7, 56.2, 51.8, 40.9, 31.7, 31.6, 29.2, 29.1, 24.3, 22.5, 14.0; IR (KBr) υ 2929, 2854, 1738, 1682, 1593, 1568, 1495, 1454, 1403, 1333, 1290, 1194, 1164, 1136, 1115, 1048, 1004, 962, 919, 841 cm-1; HRMS (quadrupole, EI) calcd for C20H30O6 [M]+ 366.2042, found 366.2045. 29.7 mg (39%); yellowish oil;OneH NMR (400 MHz, CDCl3) δ 7.04 (s, 1H), 3.91 (s, 3H), 3.90 (s, 3H), 3.89 (s, 2H), 3.83 (s, 3H), 3.68 (s, 3H), 2.85 (t,J = 7.2 Hz, 2H), 1.70-1.63 (m, 2H), 1.32-1.24 (m, 8H), 0.86 (t,J = 6.8 Hz, 3H);13C NMR (100 MHz, CDCl3) δ 202.9, 172.5, 152.8, 151.8, 145.1, 133.4, 121.7, 108.5, 61.0, 60.7, 56.2, 51.8, 40.9, 31.7, 31.6, 29.2, 29.1, 24.3, 22.5, 14.0; IR (KBr) υ 2929, 2854, 1738, 1682, 1593, 1568, 1495, 1454, 1403, 1333, 1290, 1194, 1164, 1136, 1115, 1048, 1004, 962, 919, 841 cm-One; HRMS (quadrupole, EI) calcd for C20H30O6 [M]+ 366.2042, found 366.2045.

Isopropyl 2-(2,3,4-Isopropyl 2-(2,3,4- trimethoxytrimethoxy -6--6- octanoylphenyloctanoylphenyl )acetate ()acetate ( 6ab6ab ))

Figure 112018005760933-pat00061
Figure 112018005760933-pat00061

44.3 mg (56%); yellow oil; 1H NMR (400 MHz, CDCl3) δ 7.04 (s, 1H), 5.05-4.99 (m, 1H), 3.93 (s, 3H), 3.92 (s, 3H), 3.88 (s, 2H), 3.85 (s, 3H), 2.87 (t, J = 7.6 Hz, 2H), 1.72-1.65 (m, 2H), 1.35-1.25 (m, 8H), 1.27 (s, 3H), 1.25 (s, 3H), 0.89 (t, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 203.6, 171.5, 152.8, 151.7, 144.9, 133.7, 121.8, 108.4, 67.8, 61.0, 60.7, 56.2, 41.1, 32.1, 31.6, 29.2, 29.1, 24.3, 22.5, 21.8, 14.0; IR (KBr) υ 2929, 2854, 1731, 1683, 1593, 1568, 1495, 1454, 1403, 1325, 1289, 1229, 1173, 1136, 1108, 1047, 1005, 970, 919, 830 cm-1; HRMS (quadrupole, EI) calcd for C22H34O6 [M]+ 394.2355, found 394.2358. 44.3 mg (56%); yellow oil;OneH NMR (400 MHz, CDCl3) δ 7.04 (s, 1H), 5.05-4.99 (m, 1H), 3.93 (s, 3H), 3.92 (s, 3H), 3.88 (s, 2H), 3.85 (s, 3H), 2.87 (t,J = 7.6 Hz, 2H), 1.72-1.65 (m, 2H), 1.35-1.25 (m, 8H), 1.27 (s, 3H), 1.25 (s, 3H), 0.89 (t,J = 6.8 Hz, 3H);13C NMR (100 MHz, CDCl3) δ 203.6, 171.5, 152.8, 151.7, 144.9, 133.7, 121.8, 108.4, 67.8, 61.0, 60.7, 56.2, 41.1, 32.1, 31.6, 29.2, 29.1, 24.3, 22.5, 21.8, 14.0; IR (KBr) υ 2929, 2854, 1731, 1683, 1593, 1568, 1495, 1454, 1403, 1325, 1289, 1229, 1173, 1136, 1108, 1047, 1005, 970, 919, 830 cm-One; HRMS (quadrupole, EI) calcd for C22H34O6 [M]+ 394.2355, found 394.2358.

Butyl 2-(2,3,4-Butyl 2-(2,3,4- trimethoxytrimethoxy -6--6- octanoylphenyloctanoylphenyl )acetate ()acetate ( 6ac6ac ))

Figure 112018005760933-pat00062
Figure 112018005760933-pat00062

53.1 mg (65%); yellowish oil; 1H NMR (400 MHz, CDCl3) δ 7.02 (s, 1H), 4.08 (t, J = 6.8 Hz, 2H), 3.90 (s, 3H), 3.89 (s, 3H), 3.88 (s, 2H), 3.82 (s, 3H), 2.85 (t, J = 7.2 Hz, 2H), 1.68-1.57 (m, 4H), 1.41-1.24 (m, 10H), 0.91 (t, J = 7.2 Hz, 3H), 0.86 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 203.0, 172.1, 152.8, 151.8, 145.0, 133.6, 121.8, 108.4, 64.5, 61.0, 60.7, 56.2, 41.1, 31.8, 31.6, 30.6, 29.2, 29.1, 24.3, 22.5, 19.1, 14.0, 13.6; IR (KBr) υ 2955, 2930, 2855, 1735, 1683, 1593, 1568, 1495, 1454, 1403, 1332, 1289, 1164, 1136, 1115, 1047, 1005, 967, 918, 837 cm-1; HRMS (quadrupole, EI) calcd for C23H36O6 [M]+ 408.2512, found 408.2509. 53.1 mg (65%); yellowish oil;OneH NMR (400 MHz, CDCl3) δ 7.02 (s, 1H), 4.08 (t,J = 6.8 Hz, 2H), 3.90 (s, 3H), 3.89 (s, 3H), 3.88 (s, 2H), 3.82 (s, 3H), 2.85 (t,J = 7.2 Hz, 2H), 1.68-1.57 (m, 4H), 1.41-1.24 (m, 10H), 0.91 (t,J = 7.2 Hz, 3H), 0.86 (t,J = 7.2 Hz, 3H);13C NMR (100 MHz, CDCl3) δ 203.0, 172.1, 152.8, 151.8, 145.0, 133.6, 121.8, 108.4, 64.5, 61.0, 60.7, 56.2, 41.1, 31.8, 31.6, 30.6, 29.2, 29.1, 24.3, 22.5, 19.1, 14.0, 13.6; IR (KBr) υ 2955, 2930, 2855, 1735, 1683, 1593, 1568, 1495, 1454, 1403, 1332, 1289, 1164, 1136, 1115, 1047, 1005, 967, 918, 837 cm-One; HRMS (quadrupole, EI) calcd for C23H36O6 [M]+ 408.2512, found 408.2509.

Benzyl 2-(2,3,4-Benzyl 2-(2,3,4- trimethoxytrimethoxy -6--6- octanoylphenyloctanoylphenyl )acetate ()acetate ( 6ad6ad ))

Figure 112018005760933-pat00063
Figure 112018005760933-pat00063

45.1 mg (51%); light yellow solid; mp = 64.8-66.7 oC; 1H NMR (400 MHz, CDCl3) δ 7.37-7.29 (m, 5H), 7.04 (s, 1H), 5.15 (s, 2H), 3.97 (s, 2H), 3.91 (s, 6H), 3.79 (s, 3H), 2.84 (t, J = 7.2 Hz, 2H), 1.69-1.61 (m, 2H), 1.31-1.25 (m, 8H), 0.88 (t, J = 6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 202.9, 171.9, 152.8, 151.7, 145.1, 136.2, 133.5, 128.3, 128.1, 127.9, 121.6, 108.4, 66.3, 61.0, 60.7, 56.2, 41.0, 31.8, 31.6, 29.2, 29.1, 24.3, 22.6, 14.0; IR (KBr) υ 2955, 2930, 2855, 1735, 1683, 1593, 1568, 1495, 1454, 1403, 1333, 1165, 1136, 1115, 1048, 1006, 968, 919, 834 cm-1; HRMS (quadrupole, EI) calcd for C26H34O6 [M]+ 442.2355, found 442.2354. 45.1 mg (51%); light yellow solid; mp = 64.8-66.7oC;OneH NMR (400 MHz, CDCl3) δ 7.37-7.29 (m, 5H), 7.04 (s, 1H), 5.15 (s, 2H), 3.97 (s, 2H), 3.91 (s, 6H), 3.79 (s, 3H), 2.84 (t,J = 7.2 Hz, 2H), 1.69-1.61 (m, 2H), 1.31-1.25 (m, 8H), 0.88 (t,J = 6.4 Hz, 3H);13C NMR (100 MHz, CDCl3) δ 202.9, 171.9, 152.8, 151.7, 145.1, 136.2, 133.5, 128.3, 128.1, 127.9, 121.6, 108.4, 66.3, 61.0, 60.7, 56.2, 41.0, 31.8, 31.6, 29.2, 29.1, 24.3, 22.6, 14.0; IR (KBr) υ 2955, 2930, 2855, 1735, 1683, 1593, 1568, 1495, 1454, 1403, 1333, 1165, 1136, 1115, 1048, 1006, 968, 919, 834 cm-One; HRMS (quadrupole, EI) calcd for C26H34O6 [M]+ 442.2355, found 442.2354.

제조예Manufacturing example 3 : 3: phomopsinphomopsin C 화합물 7a의 제조 Preparation of C compound 7a

CH2Cl2 (1 mL) 중 ethyl 2-(3,5-dimethoxy-2-octanoylphenyl)acetate (5cc) (70.1 mg, 0.2 mmol, 100 mol %)가 충전된 오븐-건조 밀봉된 튜브에 보론 트리 브로마이드(디클로로메탄에 1 M 용액, 0.8 mL, 0.8 mmol, 400 mol %)을 -78 ℃에서 아르곤 하에 첨가 하였다. In an oven-dried sealed tube filled with ethyl 2-(3,5-dimethoxy-2-octanoylphenyl)acetate (5cc) (70.1 mg, 0.2 mmol, 100 mol %) in CH2Cl2 (1 mL), boron tribromide (dichloro A 1 M solution, 0.8 mL, 0.8 mmol, 400 mol%) in methane was added at -78 °C under argon.

반응 혼합물을 0 ℃에서 2 시간 동안 교반 하였다. 반응 혼합물을 실온으로 냉각시키고, H2O 및 포화 NaHCO3 용액으로 ??칭시켜 반응 혼합물의 pH 7로 만든 다음 EtOAc (3x20mL)로 추출하였다. 유기층을 MgSO4상에서 건조시키고, 여과하고, 진공에서 농축시켰다. 잔류물을 플래시 컬럼 크로마토그래피 (n- 헥산 / EtOAc = 5 : 1)로 정제하여 7a (51.1 mg)를 76 % 수율로 수득하였고, 이의 특성을 하기에 나타내었다.The reaction mixture was stirred at 0 °C for 2 hours. The reaction mixture was cooled to room temperature, quenched with H2O and saturated NaHCO3 solution to bring the reaction mixture to pH 7 and then extracted with EtOAc (3x20mL). The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (n-hexane/EtOAc = 5: 1) to give 7a (51.1 mg) in 76% yield, and its properties are shown below.

Ethyl 2-(3-Ethyl 2-(3- hydroxyhydroxy -5--5- methoxymethoxy -2--2- octanoylphenyloctanoylphenyl )acetate (7a))acetate (7a)

Figure 112018005760933-pat00064
Figure 112018005760933-pat00064

51.1 mg (76%); brown solid; mp = 75.6-77.8 oC; 1H NMR (400 MHz, CDCl3) δ 12.4 (s, 1H), 6.36 (d, J = 2.0 Hz, 1H), 6.31 (d, J = 2.0 Hz, 1H), 4.17 (q, J = 7.2 Hz, 2H), 3.84 (s, 2H), 3.79 (s, 3H), 2.82 (t, J = 7.6 Hz, 2H), 1.72-1.65 (m, 2H), 1.30-1.23 (m, 8H), 1.25 (t, J = 7.2 Hz, 3H), 0.86 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 206.5, 170.8, 165.1, 163.6, 136.2, 115.9, 112.5, 100.4, 61.3, 55.3, 43.2, 41.9, 31.6, 29.1, 29.0, 24.9, 22.5, 14.1, 14.0; IR (KBr) υ 3228, 2954, 2925, 2854, 1736, 1710, 1608, 1588, 1464, 1438, 1368, 1305, 1197, 1153, 1022, 962, 844 cm-1; HRMS (orbitrap, ESI) calcd for C19H28O5 [M+H]+ 336.1937, found 336.1939. 51.1 mg (76%); brown solid; mp = 75.6-77.8oC;OneH NMR (400 MHz, CDCl3) δ 12.4 (s, 1H), 6.36 (d,J = 2.0 Hz, 1H), 6.31 (d,J = 2.0 Hz, 1H), 4.17 (q,J = 7.2 Hz, 2H), 3.84 (s, 2H), 3.79 (s, 3H), 2.82 (t,J = 7.6 Hz, 2H), 1.72-1.65 (m, 2H), 1.30-1.23 (m, 8H), 1.25 (t,J = 7.2 Hz, 3H), 0.86 (t,J = 7.2 Hz, 3H);13C NMR (100 MHz, CDCl3) δ 206.5, 170.8, 165.1, 163.6, 136.2, 115.9, 112.5, 100.4, 61.3, 55.3, 43.2, 41.9, 31.6, 29.1, 29.0, 24.9, 22.5, 14.1, 14.0; IR (KBr) υ 3228, 2954, 2925, 2854, 1736, 1710, 1608, 1588, 1464, 1438, 1368, 1305, 1197, 1153, 1022, 962, 844 cm-One; HRMS (orbitrap, ESI) calcd for C19H28O5 [M+H]+ 336.1937, found 336.1939.

제조예Manufacturing example 4 : 화합물 7b의 제조 4: Preparation of compound 7b

2-(3,5-dimethoxy-2-octanoylphenyl)acetate(5cc) (70.1 mg, 0.2 mmol, 100 mol %)로 충전된 오븐- 건조 밀봉된 튜브에 1 M NaOH (1 mL) 및 THF(1 mL)을 실온에서 공기 중에서 첨가 하였다.1 M NaOH (1 mL) and THF (1 mL) in an oven-dried sealed tube filled with 2-(3,5-dimethoxy-2-octanoylphenyl)acetate(5cc) (70.1 mg, 0.2 mmol, 100 mol %) ) Was added in air at room temperature.

반응 혼합물을 실온에서 14 시간 동안 교반 하였다. 반응 혼합물을 1M HCl (1 mL)로 ??칭시켜 pH 7로 만들고 CH2Cl2 (3 x 20 mL)로 추출 하였다. 유기층을 MgSO4상에서 건조시키고, 여과하고, 진공에서 농축시켰다. 잔류물을 플래시 컬럼 크로마토그래피 (n- 헥산 / EtOAc = 1 : 2)로 정제하여 7b (46.3 mg)를 72 % 수율로 수득하였고, 이의 특성을 하기에 나타내었다.The reaction mixture was stirred at room temperature for 14 hours. The reaction mixture was quenched with 1M HCl (1 mL) to pH 7 and extracted with CH2Cl2 (3 x 20 mL). The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (n-hexane/EtOAc=1:2) to give 7b (46.3 mg) in 72% yield, and its properties are shown below.

2-(3,5-2-(3,5- DimethoxyDimethoxy -2--2- octanoylphenyloctanoylphenyl )acetic acid (7b))acetic acid (7b)

Figure 112018005760933-pat00065
Figure 112018005760933-pat00065

46.3 mg (72%); light brown solid; mp = 80.8-82.3 oC; 1H NMR (400 MHz, CDCl3) δ 6.48 (d, J = 1.6 Hz, 1H), 6.40 (d, J = 2.0 Hz, 1H), 3.84 (s, 3H), 3.82 (s, 3H), 3.51 (s, 2H), 2.91 (t, J = 7.6 Hz, 2H), 1.68-1.61 (m, 2H), 1.28-1.26 (m, 8H), 0.86 (t, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 210.1, 172.1, 162.6, 159.9, 135.4, 122.6, 107.5, 98.2, 55.7, 55.6, 44.2, 41.4, 31.6, 29.3, 29.0, 24.7, 22.5, 14.0; IR (KBr) υ 2925, 2853, 1738, 1711, 1600, 1580, 1457, 1423, 1324, 1290, 1203, 1153, 1084, 1059, 950, 835 cm-1; HRMS (orbitrap, ESI) calcd for C18H26O5 [M+H]+ 322.1780, found 322.1779. 46.3 mg (72%); light brown solid; mp = 80.8-82.3oC;OneH NMR (400 MHz, CDCl3) δ 6.48 (d,J = 1.6 Hz, 1H), 6.40 (d,J = 2.0 Hz, 1H), 3.84 (s, 3H), 3.82 (s, 3H), 3.51 (s, 2H), 2.91 (t,J = 7.6 Hz, 2H), 1.68-1.61 (m, 2H), 1.28-1.26 (m, 8H), 0.86 (t,J = 6.8 Hz, 3H);13C NMR (100 MHz, CDCl3) δ 210.1, 172.1, 162.6, 159.9, 135.4, 122.6, 107.5, 98.2, 55.7, 55.6, 44.2, 41.4, 31.6, 29.3, 29.0, 24.7, 22.5, 14.0; IR (KBr) υ 2925, 2853, 1738, 1711, 1600, 1580, 1457, 1423, 1324, 1290, 1203, 1153, 1084, 1059, 950, 835 cm-One; HRMS (orbitrap, ESI) calcd for C18H26O5 [M+H]+ 322.1780, found 322.1779.

제조예Manufacturing example 5 : 15: 1 -- heptylheptyl -6,8--6,8- dimethoxyisochromanedimethoxyisochromane 화합물 7c의 제조 Preparation of compound 7c

2-(3,5-dimethoxy-2-octanoylphenyl)acetate (5cc) (70.1 mg, 0.2 mmol, 100 mol %)로 충전 된 오븐 건조 밀봉 된 튜브에 실온에서 공기 중에서 NaBH4 (15.1 mg, 0.4 mmol, 200 mol % ) 및 EtOH (1 mL)를 첨가하였다.In an oven-dried sealed tube filled with 2-(3,5-dimethoxy-2-octanoylphenyl)acetate (5cc) (70.1 mg, 0.2 mmol, 100 mol%) in air at room temperature NaBH4 (15.1 mg, 0.4 mmol, 200 mol%) and EtOH (1 mL) were added.

반응 혼합물을 60 ℃에서 4 시간 동안 교반 하였다. 반응 혼합물을 실온으로 냉각시키고, H2O 및 포화 NH4Cl 용액으로 ??칭시켜 반응 혼합물의 pH 7로 만든 다음 CH2Cl2 (3 x 20 mL)로 추출 하였다. 유기층을 MgSO4상에서 건조시키고, 여과하고, 진공에서 농축시켰다. 잔류 물을 플래시 컬럼 크로마토 그래피 (n- 헥산 / EtOAc = 15 : 1)로 정제하여 7c (23.4 mg)를 40 % 수율로 수득하였고, 이의 특성을 하기에 나타내었다.The reaction mixture was stirred at 60° C. for 4 hours. The reaction mixture was cooled to room temperature, quenched with H2O and saturated NH4Cl solution to bring the reaction mixture to pH 7 and then extracted with CH2Cl2 (3 x 20 mL). The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (n-hexane/EtOAc = 15:1) to give 7c (23.4 mg) in 40% yield, and its properties are shown below.

1-One- HeptylHeptyl -6,8--6,8- dimethoxyisochromanedimethoxyisochromane (7c) (7c)

Figure 112018005760933-pat00066
Figure 112018005760933-pat00066

23.4 mg (40%); yellowish oil; 1H NMR (400 MHz, CD3OD) δ 6.29 (s, 1H), 6.24 (s, 1H), 4.80 (dd, J = 8.8, 2.0 Hz, 1H), 4.02-3.96 (m, 1H), 3.78 (s, 3H), 3.77 (s, 3H), 3.76-3.72 (m, 1H), 2.84-2.76 (m, 1H), 2.69 (dt, J = 16.4, 4.8 Hz, 1H), 1.86-1.69 (m, 2H), 1.46-1.43 (m, 2H), 1.35-1.26 (m, 8H), 0.88 (t, J = 6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 158.7, 156.7, 135.6, 120.1, 104.1, 96.5, 72.0, 59.5, 55.2, 55.1, 33.2, 31.9, 29.5, 29.4, 29.3, 25.8, 22.7, 14.1; IR (KBr) υ 2952, 2923, 2853, 1736, 1605, 1595, 1489, 1463, 1425, 1340, 1304, 1261, 1207, 1148, 1098, 1054, 951, 827 cm-1; HRMS (orbitrap, ESI) calcd for C18H28O3 [M+H]+ 292.2038, found 292.2040. 23.4 mg (40%); yellowish oil;OneH NMR (400 MHz, CD3OD) δ 6.29 (s, 1H), 6.24 (s, 1H), 4.80 (dd,J = 8.8, 2.0 Hz, 1H), 4.02-3.96 (m, 1H), 3.78 (s, 3H), 3.77 (s, 3H), 3.76-3.72 (m, 1H), 2.84-2.76 (m, 1H), 2.69 (dt,J = 16.4, 4.8 Hz, 1H), 1.86-1.69 (m, 2H), 1.46-1.43 (m, 2H), 1.35-1.26 (m, 8H), 0.88 (t,J = 6.4 Hz, 3H);13C NMR (100 MHz, CDCl3) δ 158.7, 156.7, 135.6, 120.1, 104.1, 96.5, 72.0, 59.5, 55.2, 55.1, 33.2, 31.9, 29.5, 29.4, 29.3, 25.8, 22.7, 14.1; IR (KBr) υ 2952, 2923, 2853, 1736, 1605, 1595, 1489, 1463, 1425, 1340, 1304, 1261, 1207, 1148, 1098, 1054, 951, 827 cm-One; HRMS (orbitrap, ESI) calcd for C18H28O3 [M+H]+ 292.2038, found 292.2040.

실험예Experimental example 1 : One : AMPKAMPK 활성 효과 측정 Measuring active effect

AMPK는 진핵 생물에서 포도당 및 지질 대사의 주요 세포 조절 인자로 알려져 있으며, AMPK는 세포 내 ATP 수준이 낮을 때 자동으로 활성화 될 수 있다. AMPK 활성화 효과는 골격근에서의 포도당 흡수 및 지질 산화의 증가를 통한 인슐린 감수성의 증가뿐만 아니라 간에서의 글루코스 및 지질 형성의 억제와 관련된다. 따라서 AMPK는 제 2 형 당뇨병, 비만 및 암과 같은 대사성 질병을 조절하는 주요 분자이다.AMPK is known as a major cellular regulator of glucose and lipid metabolism in eukaryotes, and AMPK can be automatically activated when the intracellular ATP level is low. The AMPK activation effect is associated with the inhibition of glucose and lipid formation in the liver as well as the increase in insulin sensitivity through increased glucose uptake and lipid oxidation in skeletal muscle. Thus, AMPK is a major molecule regulating metabolic diseases such as type 2 diabetes, obesity and cancer.

이전에 보고된 사이토스포론 및 TMPA의 간접 AMPK 활성에 대한 데이터를 바탕으로 본 발명의 TMPA 유도체의 in vitro AMPK 활성을 평가하였다.Based on previously reported data on the indirect AMPK activity of cytosporone and TMPA, the in vitro AMPK activity of the TMPA derivatives of the present invention was evaluated.

구체적으로, HepG2 세포를 합성 화합물로 처리하고 인산화된 AMPK (p-AMPK) 발현 수준을 웨스턴 블랏팅 분석으로 결정하였다. AMPK 활성화에 대한 화합물의 효능을 대조군과 비교하여 도 6에 나타낸 바와 같이 상대 백분율 값으로 나타내었다(공지된 AMPK 활성제인 메트포민을 양성 대조군으로 선택). Specifically, HepG2 cells were treated with a synthetic compound and the level of phosphorylated AMPK (p-AMPK) expression was determined by Western blotting analysis. The efficacy of the compound on AMPK activation was shown as a relative percentage value as shown in FIG. 6 compared to the control (meetformin, a known AMPK activator, was selected as a positive control).

그 결과, 본 발명의 화합물 5ac, 5bd, 5cd, 5dd, 6ac 및 6ad 은 메트포민과 유사한 활성을 보였고, 특히 TMPA 화합물 5ac 및 5cd는 가장 강력한 AMPK 활성을 보였으며, 이는 양성 대조군보다 더 강한 활성이었다.As a result, the compounds 5ac, 5bd, 5cd, 5dd, 6ac and 6ad of the present invention showed similar activity to metformin, and in particular, TMPA compounds 5ac and 5cd showed the strongest AMPK activity, which was stronger than the positive control.

한편, 화합물 5cd는 신규 AMPK 활성제이며, 화합물 5bd, 5cd 및 5dd 사이의 구조-활성도 관계(SAR)는 아세토페논 상의 α-알킬 사슬의 길이 및 방향족 메톡시- 치환체의 위치가 AMPK의 활성화에 중요한 역할을 한다는 것을 나타냄을 알 수 있었다. On the other hand, compound 5cd is a novel AMPK activator, and the structure-activity relationship (SAR) between compounds 5bd, 5cd and 5dd shows that the length of the α-alkyl chain on acetophenone and the position of the aromatic methoxy-substituent play an important role in the activation of AMPK. I could see that it indicates that I am doing.

또한, TMPA 화합물 5ac 상의 에틸 카르복실레이트 작용기는 화합물 6aa-6ad와 비교하여 관찰 했을 때 AMPK 활성에 매우 중요하다는 것을 알 수 있었다.In addition, it was found that the ethyl carboxylate functional group on TMPA compound 5ac is very important for AMPK activity when observed compared to compound 6aa-6ad.

실험예Experimental example 2 : ( 2 : ( 5ac5ac )와 5cd의 in ) And 5cd in vivovivo 항당뇨성Antidiabetic 평가 evaluation

상기 AMPK 활성화에 대한 in vitro 결과를 바탕으로, streptozotocin 유도 당뇨병 동물 모델을 사용하여 화합물 5ac와 화합물 5cd의 생체 내 항당뇨성 평가를 수행하고 도 7에 결과를 나타내었다.Based on the in vitro results of AMPK activation, in vivo antidiabetic evaluation of compound 5ac and compound 5cd was performed using a streptozotocin-induced diabetes animal model, and the results are shown in FIG. 7.

실험 결과, 화합물 5ac는 혈당치를 점차적으로 감소시키는 것으로 밝혀졌으며, 이는 메트포민과 유사한 효과를 나타냈다. 또한, 화합물 5cd는 메트포민보다 약 13 % 강한 가장 강력한 항 당뇨 효과를 나타냄을 알 수 있었다.As a result of the experiment, it was found that compound 5ac gradually decreased blood sugar levels, which showed a similar effect to metformin. In addition, it was found that compound 5cd exhibited the strongest antidiabetic effect, which was about 13% stronger than metformin.

이상으로 본 발명 내용의 특정한 부분을 상세히 기술하였는바, 당업계의 통상의 지식을 가진 자에게 있어서, 이러한 구체적 기술은 단지 바람직한 실시 양태일 뿐이며, 이에 의해 본 발명의 범위가 제한되는 것이 아닌 점은 명백할 것이다. 따라서 본 발명의 실질적인 범위는 첨부된 청구항들과 그것들의 등가물에 의하여 정의된다고 할 것이다.As described above, specific parts of the present invention have been described in detail, and for those of ordinary skill in the art, it is obvious that these specific techniques are only preferred embodiments, and the scope of the present invention is not limited thereby. something to do. Therefore, it will be said that the practical scope of the present invention is defined by the appended claims and their equivalents.

Claims (11)

하기 화학식 1 또는 화학식 2로 표시되는 화합물, 이의 이성질체, 또는 이의 약학적으로 허용가능한 염 :
[화학식 1]
Figure 112020064658533-pat00067

[화학식 2]
Figure 112020064658533-pat00068

상기 화학식 1 또는 2에서,
R1 내지 R4 는 각각 독립적으로 수소, 히드록시, 또는 알콕시이고,
R5 는 C1-C5 또는 C8의 직쇄 또는 분지쇄 알킬이며,
R6 는 히드록시 또는 알콕시이다,
단, R1 내지 R4 중 하나 이상 셋 이하가 알콕시며,
R1 내지 R4 중 셋이 알콕시인 경우에 R6 는 OBn 이다.
A compound represented by the following Formula 1 or Formula 2, an isomer thereof, or a pharmaceutically acceptable salt thereof:
[Formula 1]
Figure 112020064658533-pat00067

[Formula 2]
Figure 112020064658533-pat00068

In Formula 1 or 2,
R 1 to R 4 are each independently hydrogen, hydroxy, or alkoxy,
R 5 is C 1 -C 5 or C 8 straight or branched chain alkyl,
R 6 is hydroxy or alkoxy,
Provided that at least one of R 1 to R 4 is alkoxy,
When three of R 1 to R 4 are alkoxy, R 6 is OBn.
 제1항에 있어서,
상기 화학식 1 또는 2에서,
R 1 내지 R4 는 각각 독립적으로 수소, 히드록시, 또는 메톡시 이고,
R5 는 메틸, 에틸, 프로필, 부틸, 펜틸, 또는 옥틸 이며,
R6 는 히드록시, 메톡시, 에톡시, OiPr, OnBu, 또는 OBn 인 것을 특징으로 하 는 화합물, 이의 이성질체 또는 이의 약학적으로 허용 가능한 염,
단, R1 내지 R4 중 하나 이상 셋 이하가 메톡시이며,
R1 내지 R4 중 셋이 메톡시인 경우에 R6 는 OBn 이다.
The method of claim 1,
In Formula 1 or 2,
R 1 to R 4 are each independently hydrogen, hydroxy, or methoxy,
R 5 is methyl, ethyl, propyl, butyl, pentyl, or octyl,
R 6 is a compound characterized in that it is hydroxy, methoxy, ethoxy, O i Pr, O n Bu, or OBn, isomers thereof or pharmaceutically acceptable salts thereof,
However, at least one of R 1 to R 4 is methoxy,
When three of R 1 to R 4 are methoxy, R 6 is OBn.
 하기 화합물들로 이루어진 군으로부터 선택되는 것을 특징으로 하는 화합물, 이의 이성질체, 또는 이의 약학적으로 허용가능한 염 :
Ethyl 2-(2-hexanoyl-3-methoxyphenyl)acetate (화합물 5ba),
Ethyl 2-(2-heptanoyl-3-methoxyphenyl)acetate (화합물 5bb),
Ethyl 2-(3-methoxy-2-octano ylphenyl)acetate (화합물 5bc),
Ethyl 2-(3-methoxy-2-nonanoylphenyl)acetate (화합물 5bd),
Eth yl 2-(2-hexanoyl-3,5-dimethoxyphenyl)acetate (화합물 5ca),
Ethyl 2-(2-heptanoyl-3,5-dimethoxyphe nyl)acetate (화합물 5cb),
Ethy l 2-(3,5-dimethoxy-2-nonanoylphenyl)acetate (화합물 5cd),
Ethyl 2-(2-hexanoyl-5-methoxyphenyl)ac etate (화합물 5da),
Ethyl 2-(5-methoxy-2-nonanoylphenyl)acetate (화합물 5dd),
Ethyl 2-(2-hexanoyl-4-methoxyphenyl)acetate (화합물 5ea),
Ethyl 2-(2-hexanoyl-6-methox yphenyl)acetate (화합물 5ea'),
Ethyl 2-(2-methoxy-6-octanoylphenyl)acetate (화합물 5ec'),
Ethyl 2-(4-me thoxy-2-nonanoylphenyl)acetate (화합물 5ed),
Ethyl 2-(2-methoxy-6-nonanoylphenyl)acetate (화합물 5ed'),
Benzyl 2-(2,3,4-trimethoxy-6-octanoylphenyl)acetate (화합물 6ad), 및
1-Heptyl-6,8-dimethoxyisochromane (화합물 7c).
A compound, isomer thereof, or pharmaceutically acceptable salt thereof, characterized in that it is selected from the group consisting of the following compounds:
Ethyl 2-(2-hexanoyl-3-methoxyphenyl)acetate (compound 5ba),
Ethyl 2-(2-heptanoyl-3-methoxyphenyl)acetate (compound 5bb),
Ethyl 2-(3-methoxy-2-octano ylphenyl)acetate (compound 5bc),
Ethyl 2-(3-methoxy-2-nonanoylphenyl)acetate (compound 5bd),
Eth yl 2-(2-hexanoyl-3,5-dimethoxyphenyl)acetate (compound 5ca),
Ethyl 2-(2-heptanoyl-3,5-dimethoxyphe nyl)acetate (compound 5cb),
Ethy l 2-(3,5-dimethoxy-2-nonanoylphenyl)acetate (compound 5cd),
Ethyl 2-(2-hexanoyl-5-methoxyphenyl)ac etate (compound 5da),
Ethyl 2-(5-methoxy-2-nonanoylphenyl)acetate (compound 5dd),
Ethyl 2-(2-hexanoyl-4-methoxyphenyl)acetate (compound 5ea),
Ethyl 2-(2-hexanoyl-6-methox yphenyl)acetate (compound 5ea'),
Ethyl 2-(2-methoxy-6-octanoylphenyl)acetate (compound 5ec'),
Ethyl 2-(4-me thoxy-2-nonanoylphenyl)acetate (compound 5ed),
Ethyl 2-(2-methoxy-6-nonanoylphenyl)acetate (compound 5ed'),
Benzyl 2-(2,3,4-trimethoxy-6-octanoylphenyl)acetate (compound 6ad), and
1-Heptyl-6,8-dimethoxyisochromane (Compound 7c).
 이리듐 촉매 또는 로듐 촉매 존재 하에서, 하기 화학식 3로 표시되는 화합물을 하기 화학식 4로 표시되는 화합물과 반응시키는 단계를 포함하는, 하기 화학식 1 또는 화학식 2로 표시되는 화합물의 제조방법.
[화학식 1]
Figure 112018005760933-pat00069

[화학식 2]
Figure 112018005760933-pat00070

[화학식 3]
Figure 112018005760933-pat00071

[화학식 4]
Figure 112018005760933-pat00072

상기 화학식 1 또는 2에서,
R1 내지 R4는 각각 독립적으로 수소, 히드록시, 또는 알콕시이고,
R5는 C1-C10의 직쇄 또는 분지쇄 알킬이며,
R6는 히드록시 또는 알콕시이다,
In the presence of an iridium catalyst or a rhodium catalyst, a method for producing a compound represented by the following Formula 1 or Formula 2, comprising reacting a compound represented by the following Formula 3 with a compound represented by the following Formula 4.
[Formula 1]
Figure 112018005760933-pat00069

[Formula 2]
Figure 112018005760933-pat00070

[Formula 3]
Figure 112018005760933-pat00071

[Formula 4]
Figure 112018005760933-pat00072

In Formula 1 or 2,
R 1 to R 4 are each independently hydrogen, hydroxy, or alkoxy,
R 5 is C 1 -C 10 straight or branched chain alkyl,
R 6 is hydroxy or alkoxy,
 제4항에 있어서,
상기 화학식 1, 2, 또는 3에서,
R1 내지 R4는 각각 독립적으로 수소, 히드록시, 또는 메톡시 이고,
R5는 메틸, 에틸, 프로필, 부틸, 펜틸, 헥실, 헵틸, 또는 옥틸 이며,
R6는 히드록시, 메톡시, 에톡시, OiPr, OnBu, 또는 OBn 인 것을 특징으로 하는 화합물의 제조방법.
The method of claim 4,
In Formula 1, 2, or 3,
R 1 to R 4 are each independently hydrogen, hydroxy, or methoxy,
R 5 is methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, or octyl,
R 6 is hydroxy, methoxy, ethoxy, O i Pr, O n Bu, or a method for producing a compound, characterized in that OBn.
 제4항에 있어서,
상기 이리듐 촉매는 이리듐(III)-촉매 [IrCp*Cl2]2 이며, 상기 로듐 촉매는 로듐(III)-촉매 [RhCp*Cl2]2 인 것을 특징으로 하는 화합물의 제조방법.
The method of claim 4,
The iridium catalyst is iridium (III)-catalyst [IrCp*Cl 2 ] 2 , and the rhodium catalyst is rhodium (III)-catalyst [RhCp*Cl 2 ] 2 .
 제4항에 있어서,
상기 화학식 3로 표시되는 화합물을 화학식 4로 표시되는 화합물과 반응시키는 단계는
첨가제 존재 하에서 반응시키는 것을 특징으로 하는 화합물의 제조방법.
The method of claim 4,
The step of reacting the compound represented by Formula 3 with the compound represented by Formula 4
Method for producing a compound, characterized in that the reaction in the presence of an additive.
 제7항에 있어서,
상기 첨가제는 알코올 및 실버아세테이트(AgOAc) 인 것을 특징으로 하는 화합물의 제조방법.
The method of claim 7,
The additive is a method for producing a compound, characterized in that alcohol and silver acetate (AgOAc).
 제4항에 있어서,
상기 화학식 3로 표시되는 화합물을 화학식 4로 표시되는 화합물과 반응시키는 단계는 Dichloroethylene(DCE) 용매 하에서 반응시키는 것을 특징으로 하는 화합물의 제조방법.
The method of claim 4,
The step of reacting the compound represented by Formula 3 with the compound represented by Formula 4 is a method for producing a compound, characterized in that the reaction is performed in a dichloroethylene (DCE) solvent.
 제1항 내지 제3항 중 어느 한 항의 화합물, Ethyl 2-(3,5-dimethoxy-2-octanoylphenyl)acetate (화합물 5cc), Ethyl 2-(3-hydroxy-5-methoxy-2-octanoylphenyl)acetate (화합물 7a), 이의 이성질체, 또는 이의 약학적으로 허용가능한 염을 유효성분으로 포함하는 당뇨병 치료용 약학적 조성물.
The compound of any one of claims 1 to 3, Ethyl 2-(3,5-dimethoxy-2-octanoylphenyl)acetate (compound 5cc), Ethyl 2-(3-hydroxy-5-methoxy-2-octanoylphenyl)acetate (Compound 7a), its isomer, or a pharmaceutical composition for the treatment of diabetes, comprising as an active ingredient a pharmaceutically acceptable salt thereof.
 제10항에 있어서,
상기 화합물은,
Ethyl 2-(3-m ethoxy-2-nonanoylphenyl)acetate (화합물 5bd),
Ethyl 2-(3,5-dimethoxy-2-nonanoylphenyl)acetate (화합물 5cd),
Ethyl 2-(5-methoxy-2-nonanoylphenyl)acetate (화합물 5dd), 및
Benzyl 2-(2,3,4-trimethoxy-6-octanoylphenyl)acetate (화합물 6ad)로 이루어지는 군으로부터 선택되는 것을 특징으로 하는 당뇨병 치료용 약학적 조성물.The method of claim 10,
The compound is
Ethyl 2-(3-m ethoxy-2-nonanoylphenyl)acetate (compound 5bd),
Ethyl 2-(3,5-dimethoxy-2-nonanoylphenyl)acetate (compound 5cd),
Ethyl 2-(5-methoxy-2-nonanoylphenyl)acetate (compound 5dd), and
Benzyl 2-(2,3,4-trimethoxy-6-octanoylphenyl)acetate (Compound 6ad) A pharmaceutical composition for treating diabetes, characterized in that selected from the group consisting of.
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