KR101822306B1 - Regioselective synthesis of alkyl EGCG derivatives - Google Patents

Regioselective synthesis of alkyl EGCG derivatives Download PDF

Info

Publication number
KR101822306B1
KR101822306B1 KR1020160150006A KR20160150006A KR101822306B1 KR 101822306 B1 KR101822306 B1 KR 101822306B1 KR 1020160150006 A KR1020160150006 A KR 1020160150006A KR 20160150006 A KR20160150006 A KR 20160150006A KR 101822306 B1 KR101822306 B1 KR 101822306B1
Authority
KR
South Korea
Prior art keywords
compound
organic solvent
acetone
egcg
group
Prior art date
Application number
KR1020160150006A
Other languages
Korean (ko)
Inventor
정유훈
김미경
서유진
Original Assignee
건국대학교 산학협력단
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 건국대학교 산학협력단 filed Critical 건국대학교 산학협력단
Priority to KR1020160150006A priority Critical patent/KR101822306B1/en
Application granted granted Critical
Publication of KR101822306B1 publication Critical patent/KR101822306B1/en

Links

Images

Classifications

    • 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
    • C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
    • C07D311/60—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with aryl radicals attached in position 2
    • C07D311/62—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with aryl radicals attached in position 2 with oxygen atoms directly attached in position 3, e.g. anthocyanidins
    • 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
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention relates to a synthesis method for regioselective alkylation of ((-)-epigallocatechin gallate (-)-EGCG), and in the regioselective alkylation of the (-)-EGCG according to the present invention, EGCG is firstly acetylated and alkylated without directly alkylating EGCG, thereby producing 4-alkylated-EGCG with a high yield.

Description

에피갈로카테킨 갈레이트의 위치 선택적 알킬화를 위한 합성방법 {Regioselective synthesis of alkyl EGCG derivatives}Regioselective synthesis of alkyl EGCG derivatives < RTI ID = 0.0 >

본 발명은 에피갈로카테킨 갈레이트 ((-)-epigallocatechin gallate, (-)-EGCG)의 위치 선택적 알킬화를 위한 합성방법에 관한 것이다.The present invention relates to a synthetic method for the selective alkylation of epigallocatechin gallate ((-) - epigallocatechin gallate, (-) - EGCG).

에피갈로카테킨 갈레이트 ((-)-epigallocatechin gallate, (-)-EGCG) (이하 EGCG로 표기)는 녹차에 포함된 대표적인 카테친 화합물 중 하나이다. 카테친 화합물인 EGCG는 생리활성이 높고, 항산화 활성이 높으며, 또한 UV-B에 의해 유발된 과산화물 생성을 저해하며 다양한 효능을 가지고 있다.Epigallocatechin gallate ((-) - EGCG) (hereinafter referred to as EGCG) is one of the representative catechin compounds in green tea. EGCG, a catechin compound, has high physiological activity, high antioxidant activity, and inhibits the generation of peroxides induced by UV-B and has various effects.

하지만, EGCG는 산성 조건에서 대단히 불안정하며 생체 내에서의 대사 속도가 높다. 또한, 매우 친수성이 높아 약물로 개발하는데 많은 제약을 받아왔다.However, EGCG is very unstable in acidic conditions and has a high metabolic rate in vivo. In addition, since it is highly hydrophilic, it has been restricted in development as a drug.

따라서, EGCG의 효능을 유지하면서 안정화 할 수 있는 방법과 약물로써 용이한 물성을 갖도록 하기 위해 EGCG의 다양한 유도체 합성법이 연구 되고 있지만 EGCG의 8개의 하이드록시기 때문에 유기합성시 다루기 힘들뿐만 아니라 하이드록시에 위치 선택적인 알킬화가 어렵다.Therefore, a variety of derivatives of EGCG have been investigated in order to stabilize EGCG while maintaining its physical properties. However, EGCG's eight hydroxyl groups make it difficult to handle in organic synthesis, Position selective alkylation is difficult.

따라서, 아직까지는 EGCG 유도체와 위치 선택적인 알킬화 합성법이 많이 알려지지 않았다. 지금까지 시도된 유기합성 방법으로는 EGCG와 황산다이메틸 (dimethyl sulfate)을 5시간 동안 환류가열 하여 4"-OMe-EGCG을 얻는 방법이다 (Y. Wu, X. Wang and X. Wan, Synthesis of methylated EGCG and its stability in artificial simulation gastric juice and artificial simulation intestinal juice. J. Anhui Agric . Univ. 2010). 하지만, 이 방법은 수득률이 9% 밖에 되지 않기 때문에 효과적이지 않다. Therefore, there is not yet much known how to synthesize EGCG derivatives and position-selective alkylation. EGCG and dimethyl sulfate are refluxed for 5 hours to obtain 4 "-OMe-EGCG (Y. Wu, X. Wang and X. Wan, Synthesis of methylated EGCG and its stability in artificial simulation gastric juice and artificial simulation intestinal juice. J. Anhui Agric . Univ. 2010 ). However, this method is not effective because the yield is only 9%.

또한, 리파아제(lipase)를 이용한 에스테르화를 통해 EGCG 유도체들을 합성하려는 시도도 있었으나, 이 방법 역시 8개의 하이드록시 그룹 때문에 선택적인 알킬화가 어렵고, 수득률이 낮다는 것을 확인할 수 있다 (K. Matsumura, K. Kaigatsu, S. Mori, H. H. Cho, N. Kato and S. H. Hyon, Enganced antitumor activities of (-)-epigallocatechin-3-O-gallate fatty acid monoester derivatives in vitro and in vivo. Biochemical and Biophysical Research Communications. 377 (2008) 1118-1122).In addition, attempts have been made to synthesize EGCG derivatives through esterification with lipase, but it is also confirmed that this method is also difficult to selectively alkylate due to the presence of eight hydroxy groups and low yield (K. Matsumura, K (-) - epigallocatechin-3- O- valerate fatty acid monoester derivatives in vitro and in vivo. Biochemical and Biophysical Research Communications 377 2008 ) 1118-1122).

이 밖에 EGCG 유도체를 만드는 합성법으로 알려진 것은 전합성 방법으로써, EGCG를 출발물질로 사용하지 않고, 에피갈로카테킨 (Epigallocatechin, EGC) 을 출발물질로 사용하여 EGC의 3번 수산화기를 제외한 나머지 수산화기에 보호기를 도입하여 갈릭에시드 (Gallic acid)와 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) coupling을 하여 EGCG 유도체를 얻는 방법이다 (Y. Aihara, A. Yoshida, T. Furuta, T. Wakimoto, T. Akizawa, M. Konishi and T. Kan, Resioselecrive synthesis of methylated epigallocatechin gallate via nitrobenzenesulfonyl (Ns) protecting group. Bioorg . Med . Chem . Lett. 19 (2009) 4171-4174). 그러나 이 방법은 보호기의 도입과 제거가 반복되므로 과정이 복잡하다는 단점을 가지고 있다.In addition, it is known that EGCG derivatives are synthesized by using epigallocatechin (EGC) as a starting material instead of EGCG as a starting material. (Y. Aihara, A. Yoshida, T. Furuta, and T. Wakimoto), which is a method for obtaining EGCG derivatives by coupling gallic acid and 1-ethyl-3- (3- dimethylaminopropyl) carbodiimide , T. Akizawa, M. Konishi and T. Kan, Resioselecrive synthesis of methylated epigallocatechin gallate via nitrobenzenesulfonyl (Ns) protecting group. Bioorg . Med . Chem . Lett. 19 ( 2009 ) 4171-4174). However, this method has the disadvantage that the process is complicated because the introduction and removal of the protecting group are repeated.

[Epigallocatechin, EGC][Epigallocatechin, EGC]

Figure 112016110265141-pat00001
Figure 112016110265141-pat00001

따라서, 본 발명자는 EGCG를 출발물질로 사용하여 간단한 과정을 거쳐 높은 수율로 EGCG 유도체와 위치 선택적 알킬화 방법을 제공하고자 한다.Accordingly, the present inventor intends to provide an EGCG derivative and a method of selective alkylation at a high yield through a simple process using EGCG as a starting material.

Bioorg. Med. Chem. Lett. 19 (2009), 4171-4174.Bioorg. Med. Chem. Lett. 19 (2009), 4171-4174.

본 발명의 목적은 4''-알킬화-에피갈로카테킨 갈레이트의 제조방법을 제공하는 것이다.It is an object of the present invention to provide a process for preparing 4 " -alkylated-epigallocatechin gallate.

상기 목적을 달성하기 위하여,In order to achieve the above object,

본 발명은 하기 반응식 1에 나타난 바와 같이,As shown in the following Reaction Scheme 1,

화합물 2(에피갈로카테킨 갈레이트, EGCG) 및 과량의 아세트산을 유기용매에 첨가하고, 10-40℃에서 4-8시간 반응시켜 화합물 2의 하이드록시기를 모두 아세틸화한 화합물 3을 얻는 단계(단계 1);Compound 3 (epigallocatechin gallate, EGCG) and excess acetic acid are added to an organic solvent and reacted at 10-40 ° C for 4-8 hours to obtain Compound 3 in which all the hydroxy groups of Compound 2 are acetylated Step 1);

화합물 3, 탄산칼륨(K2CO3), 요오드화칼륨(KI) 및 할로겐화알킬(R-X, 여기서 상기 X는 할로겐이고, R은 하기 반응식 1에서 정의한 바와 같다)을 유기용매에 첨가하고 35-65℃에서 2-6시간 반응시켜 화합물 4를 얻는 단계(단계 2); 및Compound 3, potassium carbonate (K 2 CO 3 ), potassium iodide (KI) and alkyl halide (RX, where X is halogen and R is as defined in Scheme 1) For 2 to 6 hours to obtain compound 4 (step 2); And

화합물 4를 유기용매에 녹인 다음, 수소화붕소나트륨(NaBH4)를 0-5℃에서 첨가하고 20-60분 후에, 10-40℃에서 4-8시간 교반하여 탈아세틸화된 화합물 1을 얻는 단계(단계 3);Compound 4 is dissolved in an organic solvent, and sodium borohydride (NaBH 4 ) is added at 0-5 ° C. After 20-60 minutes, stirring is carried out at 10-40 ° C for 4-8 hours to obtain deacetylated compound 1 (Step 3);

를 포함하는 4''-알킬화-에피갈로카테킨 갈레이트의 제조방법을 제공한다.≪ RTI ID = 0.0 > 4 " -alkylated-epigallocatechin gallate. ≪ / RTI >

[반응식 1][Reaction Scheme 1]

Figure 112016110265141-pat00002
Figure 112016110265141-pat00002

상기 반응식 1에서,In the above Reaction Scheme 1,

R은 C1-6의 직쇄 또는 측쇄 알킬, C1-6의 직쇄 또는 측쇄 알케닐, 또는 -R1Ar이고,R is C 1-6 straight or branched chain alkyl, C 1-6 straight or branched alkenyl, or-R 1 Ar,

R1은 C1-6의 직쇄 또는 측쇄 알킬레닐이고,R 1 is C 1-6 linear or branched alkylenyl,

Ar은 C6-10의 아릴이다.Ar is C 6-10 aryl.

바람직하게,Preferably,

상기 R은 C1-3의 직쇄 또는 측쇄 알킬, C1-3의 직쇄 또는 측쇄 알케닐, 또는 -R1Ar이고,Wherein R is C 1-3 linear or branched alkyl, C 1-3 linear or branched alkenyl, or-R 1 Ar,

R1은 C1-3의 직쇄 또는 측쇄 알킬레닐이고,R 1 is C 1-3 linear or branched alkylenyl,

Ar은 C6-8의 아릴일 수 있다.Ar may be C 6-8 aryl.

더욱 바람직하게,More preferably,

상기 R은 메틸, 에틸, 프로필, 프로페닐 또는 페닐메틸일 수 있다.The R may be methyl, ethyl, propyl, propenyl or phenylmethyl.

상기 단계 1의 유기용매는 피리딘, t-부탄올, 에탄올, 테트라하이드로퓨란(THF), 벤젠, KOH/MeOH, MeOH, 톨루엔, CH2Cl2, 헥산, 디메틸포름아미드(DMF), 디이소프로필에테르, 디에틸에테르, 디옥산, 디메틸아세트아미드(DMA), 디메틸설폭사이드(DMSO), 아세톤, 클로로벤젠 등을 단독으로 또는 혼합하여 사용할 수 있고, 바람직하게는 피리딘을 사용할 수 있다.The organic solvent of step 1 may be selected from the group consisting of pyridine, t-butanol, ethanol, tetrahydrofuran (THF), benzene, KOH / MeOH, MeOH, toluene, CH2Cl2, hexane, dimethylformamide Ether, dioxane, dimethylacetamide (DMA), dimethylsulfoxide (DMSO), acetone, chlorobenzene, etc. may be used singly or in combination, preferably pyridine.

상기 단계 2의 유기용매는 아세톤, t-부탄올, 에탄올, 테트라하이드로퓨란(THF), 벤젠, KOH/MeOH, MeOH, 톨루엔, CH2Cl2, 헥산, 디메틸포름아미드(DMF), 디이소프로필에테르, 디에틸에테르, 디옥산, 디메틸아세트아미드(DMA), 디메틸설폭사이드(DMSO), 클로로벤젠 등을 단독으로 또는 혼합하여 사용할 수 있고, 바람직하게는 아세톤을 사용할 수 있다.The organic solvent in step 2 may be selected from the group consisting of acetone, t-butanol, ethanol, tetrahydrofuran (THF), benzene, KOH / MeOH, MeOH, toluene, CH2Cl2, hexane, dimethylformamide Ether, dioxane, dimethylacetamide (DMA), dimethylsulfoxide (DMSO), chlorobenzene, etc. may be used alone or in combination, and acetone may be preferably used.

상기 단계 3의 유기용매는 메탄올, t-부탄올, 에탄올, 테트라하이드로퓨란(THF), 벤젠, KOH/MeOH, 톨루엔, CH2Cl2, 헥산, 디메틸포름아미드(DMF), 디이소프로필에테르, 디에틸에테르, 디옥산, 디메틸아세트아미드(DMA), 디메틸설폭사이드(DMSO), 아세톤, 클로로벤젠 등을 단독으로 또는 혼합하여 사용할 수 있고, 바람직하게는 메탄올을 사용할 수 있다.The organic solvent in step 3 may be selected from the group consisting of methanol, t-butanol, ethanol, tetrahydrofuran (THF), benzene, KOH / MeOH, toluene, CH2Cl2, hexane, dimethylformamide (DMF), diisopropyl ether, (DMA), dimethylsulfoxide (DMSO), acetone, chlorobenzene, and the like can be used alone or in combination. Methanol can be preferably used.

또한, 본 발명은 상기 제조방법으로 제조되는 것을 특징으로 하는 하기 화학식 1로 표시되는 화합물을 제공한다.The present invention also provides a compound represented by the following general formula (1), which is produced by the above process.

[화학식 1][Chemical Formula 1]

Figure 112016110265141-pat00003
Figure 112016110265141-pat00003

상기 화학식 1에서,In Formula 1,

R은 메틸, 에틸, 프로필, 프로페닐 또는 페닐메틸이다.R is methyl, ethyl, propyl, propenyl or phenylmethyl.

본 발명에 따른 EGCG의 위치 선택적인 알킬화 방법은, EGCG를 바로 알킬화하지 않고, EGCG를 먼저 아세틸화한 다음 알킬화를 실시함에 따라서, 4''-알킬화-EGCG를 높은 수득률로 제조할 수 있는 효과가 있다.The positionally selective alkylation method of EGCG according to the present invention has the effect of producing a 4 " -alkylated-EGCG with a high yield by first alkylating EGCG followed by acetylation of EGCG without directly alkylating EGCG have.

도 1은 (-)-epigallocatechin gallate의 화학구조식이다.Figure 1 is a chemical structure of (-) - epigallocatechin gallate.

이하, 본 발명을 하기의 실시예에 의하여 더욱 상세하게 설명한다. 단, 하기의 실시예는 본 발명을 예시하는 것일 뿐, 본 발명의 내용이 하기의 실시예에 의해 한정되는 것은 아니다.Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the following examples are illustrative of the present invention, and the present invention is not limited by the following examples.

이하의 실시예 1 내지 5는 상기의 반응식 1에 나타낸 바와 같이 합성하되, 각 실시예의 치환기 R은 하기와 같다.Examples 1 to 5 below are synthesized as shown in Reaction Scheme 1, wherein the substituent R in each of Examples is as follows.

실시예 1(화합물 1a): R = -CH3 Example 1 (compound 1a): R = -CH 3

실시예 2(화합물 1b): R = -CH2CH3 Example 2 (Compound 1b): R = -CH 2 CH 3

실시예 3(화합물 1c): R = -CH2CH2CH3 Example 3 (compound 1c): R = -CH 2 CH 2 CH 3

실시예 4(화합물 1d): R = -CH2CH=CH2 Example 4 (Compound 1d): R = -CH 2 CH = CH 2

실시예 5(화합물 1e): R = -CH2-PhExample 5 (compound 1e): R = -CH 2 -Ph

<< 실시예Example 1> ( 1> ( 22 RR ,3, 3 RR )-5,7-) -5,7- 디하이드록시Dihydroxy -2-(3,4,5--2- (3,4,5- 트리하이드록시페닐Trihydroxyphenyl )) 크로만Croix -3-일 3,5-디하이드록시-4-메톡시벤조에이트 (화합물 1a)의 제조-3-yl 3,5-dihydroxy-4-methoxybenzoate (Compound 1a)

단계 step 1: 51: 5 -((((- (((( 22 RR ,3, 3 RR )-5,7-) -5,7- 디아세토시Diacetoxy -2-(3,4,5--2- (3,4,5- 트리아세토시페닐Triacetoxyphenyl )) 크로만Croix -3-일)옥시)카보닐)벤젠-1,2,3-트릴 트리아세테이트 (3-yl) oxy) carbonyl) benzene-1,2,3-triyl triacetate ( EGCGEGCG peracetateperacetate , 화합물 , Compound 3)의3) of 제조 Produce

피리딘 (pyrdine) (25 mL)에 EGCG (1 g, 2.2 mmol), 아세트산무수물 (acetic anhydride, Ac2O) (3.1 mL, 32.8 mmol)을 넣고 6 시간 동안 실온에서 교반한다. 6시간 뒤 혼합물을 감압농축 한 후, 농축물을 실리카겔 컬럼크로마토그래피 (헥세인 : 아세톤 = 1 : 1)로 정제하여 하얀색 가루 형태인 화합물 3을 88% 수율로 얻을 수 있다.Pyridine (pyrdine) into the EGCG (1 g, 2.2 mmol) , acetic anhydride (acetic anhydride, Ac 2 O) (3.1 mL, 32.8 mmol) in (25 mL) is stirred at room temperature for 6 hours. After 6 hours, the mixture was concentrated under reduced pressure, and the concentrate was purified by silica gel column chromatography (hexane: acetone = 1: 1) to obtain compound 3 in the form of a white powder in 88% yield.

1H NMR (400 MHz, Acetone-d 6 ) δ 7.62 (s, 2H), 7.40 (s, 2H), 6.73 (d, J = 2.2 Hz, 1H), 6.60 (d, J = 2.2 Hz, 1H), 5.76 (m, 1H), 5.52 (s, 1H), 3.22 (A of ABq, J = 17.9 Hz, 4.4 Hz, 1H), 3.10 (B of ABq, J = 18.0 Hz, 1.6 Hz, 1H), 2.25 (m, 24H). 1 H NMR (400 MHz, Acetone- d 6) δ 7.62 (s, 2H), 7.40 (s, 2H), 6.73 (d, J = 2.2 Hz, 1H), 6.60 (d, J = 2.2 Hz, 1H) , 5.76 (m, 1H), 5.52 (s, 1H), 3.22 (A of ABq, J = 17.9 Hz, 4.4 Hz, 1H), 3.10 (B of ABq, J = 18.0 Hz, 1.6 Hz, 1H) (m, 24H).

단계 2: 5-((2Step 2: 5 - ((2 RR ,3, 3 RR )-5,7-디아세토시-3-((3,5-디아세토시-4-메톡시벤조일)옥시)크로만-2-일)벤젠-1,2,3-트라일 트리아세테이트(화합물 4a)의 제조) -5,7-diacetoxy-3 - ((3,5-diacetoxy-4-methoxybenzoyl) oxy) chroman-2-yl) benzene-1,2,3-trayl triacetate Preparation of compound 4a)

화합물 3 (0.30 g, 0.38 mmol)를 아세톤 (acetone) (5 mL)에 녹인 후 탄산 칼륨 (potassium carbonate, K2CO3) (0.09 g, 0.05 mmol)과 요오드화 칼륨 (potassium iodide, KI) (0.13 g, 0.76 mmol)를 넣어준다. 그런 후 요오드화 메틸 (methyl iodide, MeI) (0.06 mL, 0.76 mmol)를 넣어주고 50 oC에서 4 시간 동안 가열한다. 반응이 끝난 후, 혼합물을 상온에서 냉각 시킨 후, 거름종이로 탄산 칼륨을 여과 후 감압 농축 한다. 농축물을 실리카겔 컬럼크로마토그래피 (헥세인 : 아세톤 = 1 : 1)로 정제하여 하얀색 가루 형태인 화합물 4a를 수율 68%로 얻을 수 있다.Compound 3 (0.30 g, 0.38 mmol) was dissolved in acetone (5 mL), potassium carbonate (K 2 CO 3 ) (0.09 g, 0.05 mmol) and potassium iodide (KI) g, 0.76 mmol). Then, add methyl iodide (MeI) (0.06 mL, 0.76 mmol) and heat at 50 ° C for 4 hours. After the reaction is completed, the mixture is cooled at room temperature, and potassium carbonate is filtered off with filter paper and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (hexane: acetone = 1: 1) to obtain Compound 4a in the form of white powder in a yield of 68%.

1H NMR (400 MHz, Acetone-d 6 ) δ 7.50 (s, 2H), 7.42 (s, 2H), 6.74 (d, J = 2.2 Hz, 1H), 6.61 (d, J = 2.2 Hz, 1H), 5.74 (m, 1H), 5.53 (s, 1H), 3.84 (s, 3H), 3.21 (A of ABq, J = 16.7 Hz, 4.6 Hz, 1H), 3.08 (B of ABq, J = 17.9 Hz, 1.6 Hz, 1H), 2.26 (m, 21H); 1 H NMR (400 MHz, Acetone- d 6) δ 7.50 (s, 2H), 7.42 (s, 2H), 6.74 (d, J = 2.2 Hz, 1H), 6.61 (d, J = 2.2 Hz, 1H) , 5.74 (m, 1H), 5.53 (s, 1H), 3.84 (s, 3H), 3.21 (A of ABq, J = 16.7 Hz, 4.6 Hz, 1H), 3.08 (B of ABq, J = 17.9 Hz, 1.6 Hz, 1 H), 2.26 (m, 21 H);

13C NMR (100 MHz, Acetone-d 6 ) δ 168.03, 167.65, 166.99, 166.18, 163.12, 154.41, 149.69, 149.48, 148.31, 143.52, 141.17, 135.42, 134.22, 123. 95, 121.91, 118.52, 109..62, 108.71, 107.28, 75.97, 67.85, 60.09, 25.13, 19.59, 19.30, 19.27, 19.13, 18.66. 13 C NMR (100 MHz, Acetone- d 6) δ 168.03, 167.65, 166.99, 166.18, 163.12, 154.41, 149.69, 149.48, 148.31, 143.52, 141.17, 135.42, 134.22, 123. 95, 121.91, 118.52, 109 .. 62, 108.71, 107.28, 75.97, 67.85, 60.09, 25.13, 19.59, 19.30, 19.27, 19.13, 18.66.

단계 3: (Step 3: ( 22 RR ,3, 3 RR )-5,7-) -5,7- 디하이드록시Dihydroxy -2-(3,4,5--2- (3,4,5- 트리하이드록시페닐Trihydroxyphenyl )) 크로만Croix -3-일 3,5--3-yl 3,5- 디하이드록시Dihydroxy -4--4- 메톡시벤조에이트Methoxybenzoate (화합물 1a)의 제조 (Compound 1a)

화합물 4a를 메탄올 (methanol, MeOH) (5 mL)에 녹인 후, 수소화붕소나트륨 (sodium borohydride, NaBH4)를 0 oC에서 넣어준다. 30 분 뒤 실온에서 혼합물을 6 시간 동안 교반한다. 반응이 끝난 후, 2 N의 염산 (HCl)과 에틸아세테이트 (ethyl acetate, EtOAc)를 사용하여 혼합물을 축출한다. 유기용매 층을 모아 황산마그네슘 (magnesium sulfate, MgSO4)으로 수분을 제거한 후 감압 농축 한다. 농축물을 실리카겔 컬럼크로마토그래피 (디클로로메테인 : 메탄올 = 10 : 1)로 정제하여 분홍색 가루 형태인 화합물 1a를 수득률 72%로 얻을 수 있다.Compound 4a is dissolved in methanol (MeOH) (5 mL), and sodium borohydride (NaBH 4 ) is added at 0 ° C. After 30 minutes, the mixture is stirred at room temperature for 6 hours. After the reaction is complete, the mixture is evacuated using 2 N hydrochloric acid (HCl) and ethyl acetate (EtOAc). The organic solvent layer was collected, and the water was removed with magnesium sulfate (MgSO 4 ) and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (dichloromethane: methanol = 10: 1) to obtain compound 1a in the form of a pink powder at a yield of 72%.

1H NMR (400 MHz, Acetone-d 6 ) δ 8.32 (br s, 1H), 8.26 (br s, 1H), 8.10 (br s, 1H), 7.81 (br s, 1H), 7.00 (s, 2H), 6.64 (s, 2H), 6.33 (d, J = 2.2 Hz, 1H), 6.03 (d, J = 2.2 Hz, 1H), 5.56 (m, 1H), 5.08 (s, 1H), 3.82 (s, 3H), 3.04 (A of ABq, J = 17.4 Hz, 4.5 Hz, 1H), 2.92 (B of ABq, J = 17.4 Hz, 2.1 Hz, 1H); 1 H NMR (400 MHz, Acetone- d 6 )? 8.32 (br s, 1 H), 8.26 (br s, 1 H), 8.10 ), 6.64 (s, 2H), 6.33 (d, J = 2.2 Hz, 1H), 6.03 (d, J = 2.2 Hz, 1H), 5.56 , 3H), 3.04 (A of ABq, J = 17.4 Hz, 4.5 Hz, 1H), 2.92 (B of ABq, J = 17.4 Hz, 2.1 Hz, 1H);

13C NMR (100 MHz, Acetone-d 6 ) δ 164.44, 156.40, 156.09, 155.68, 149.73, 144.90, 139.05, 131.75, 129.29, 125.10, 108.54, 105.25, 97.53, 95.07, 94.41, 76.55, 68.29, 59.22, 25.24. 13 C NMR (100 MHz, Acetone- d 6) δ 164.44, 156.40, 156.09, 155.68, 149.73, 144.90, 139.05, 131.75, 129.29, 125.10, 108.54, 105.25, 97.53, 95.07, 94.41, 76.55, 68.29, 59.22, 25.24 .

<< 실시예Example 2> ( 2> ( 22 RR ,3, 3 RR )-5,7-) -5,7- 디하이드록시Dihydroxy -2-(3,4,5--2- (3,4,5- 트리하이드록시페닐Trihydroxyphenyl ) ) 크로만Croix -3-일 4--3-yl 4- 에톡시Ethoxy -3,5-디하이드록시벤조에이트 (화합물 1b)의 제조-3,5-dihydroxybenzoate (compound 1b)

단계 1: 화합물 3의 제조Step 1: Preparation of compound 3

상기 실시예 1의 단계 1과 동일하게 실시하여 화합물 3을 제조하였다.Compound 3 was prepared in the same manner as in Step 1 of Example 1.

단계 step 2: 52: 5 -((- (( 22 RR ,3, 3 RR )-5,7-) -5,7- 디아세토시Diacetoxy -3-((3,5--3 - ((3,5- 디아세토시Diacetoxy -4--4- 에톡시벤조일Ethoxybenzoyl ) 옥시)크로만-2-일)벤젠-1,2,3-트라일 트리아세테이트 (화합물 4b)의 제조) Oxy) chroman-2-yl) benzene-1,2,3-trayl triacetate (Compound 4b)

상기 실시예 1의 단계 2에서 '요오드화 메틸' 대신에 '요오드화 에틸'을 사용한 것을 제외하고는 동일하게 실시하여, 하얀색 가루 형태인 화합물 4b를 70% 수율로 얻었다.Compound 4b in the form of a white powder was obtained in a yield of 70%, except that in step 2 of Example 1, 'iodide ethyl' was used instead of 'methyl iodide'.

1H NMR (400 MHz, Acetone-d 6 ) δ 7.49 (s, 2H), 7.41 (s, 2H), 6.74 (d, J = 2.2 Hz, 1H), 6.60 (d, J = 2.2 Hz, 1H), 5.72 (m, 1H), 5.51 (s, 1H), 4.07 (m, 2H), 3.20 (A of ABq, J = 17.9 Hz, 4.4 Hz, 1H), 3.06 (B of ABq, J = 18.1 Hz, 1.5 Hz, 1H), 2.26 (m, 21H), 1.26 (t, J = 7.0 Hz, 3H); 1 H NMR (400 MHz, Acetone- d 6) δ 7.49 (s, 2H), 7.41 (s, 2H), 6.74 (d, J = 2.2 Hz, 1H), 6.60 (d, J = 2.2 Hz, 1H) , 5.72 (m, 1H), 5.51 (s, 1H), 4.07 (m, 2H), 3.20 (A of ABq, J = 17.9 Hz, 4.4 Hz, 1H), 3.06 (B of ABq, J = 18.1 Hz, 1.5 Hz, 1 H), 2.26 (m, 21H), 1.26 (t, J = 7.0 Hz, 3H);

13C NMR (100 MHz, Acetone-d 6 ) δ 168.01, 167.62, 166.97, 166.16, 163.15, 154.42, 149.69, 149.48, 147.54, 143.73, 143.17, 135.42, 134.23, 123.82, 121.85, 118.53, 109.62, 108.70, 107.28, 75.98, 69.10, 67.82, 25.14, 19.59, 19.30, 19.13, 18.66, 14.61. 13 C NMR (100 MHz, Acetone- d 6) δ 168.01, 167.62, 166.97, 166.16, 163.15, 154.42, 149.69, 149.48, 147.54, 143.73, 143.17, 135.42, 134.23, 123.82, 121.85, 118.53, 109.62, 108.70, 107.28 , 75.98, 69.10, 67.82, 25.14, 19.59, 19.30, 19.13, 18.66, 14.61.

단계 3: (Step 3: ( 22 RR ,3, 3 RR )-5,7-) -5,7- 디하이드록시Dihydroxy -2-(3,4,5--2- (3,4,5- 트리하이드록시페닐Trihydroxyphenyl ) ) 크로만Croix -3-일 4-에톡시-3,5-디하이드록시벤조에이트 (화합물 1b)의 제조-3-yl 4-ethoxy-3,5-dihydroxybenzoate (Compound 1b)

상기 실시예 1의 단계 3에서 '화합물 4a' 대신에 '화합물 4b'를 사용한 것을 제외하고는 동일하게 실시하여, 하얀색 가루 형태인 화합물 1b를 70% 수율로 얻었다.Compound 1b in the form of a white powder was obtained in a yield of 70% in the same manner as in the step 1 of Example 1, except that the compound 4b was used instead of the compound 4a.

1H NMR (400 MHz, Acetone-d 6 ) δ 8.28 (br s, 2H), 8.11 (br s, 1H), 7.00 (s, 2H), 6.64 (s, 2H), 6.04 (d, J = 2.2 Hz, 1H), 6.02 (d, J = 2.2 Hz, 1H), 5.55 (m, 1H), 5.07 (s, 1H), 4.12 (q, J = 7.0 Hz, 2H), 3.04 (m, 2H), 1.28 (t, J = 7.0 Hz, 3H); 1 H NMR (400 MHz, Acetone- d 6) δ 8.28 (br s, 2H), 8.11 (br s, 1H), 7.00 (s, 2H), 6.64 (s, 2H), 6.04 (d, J = 2.2 Hz, 1H), 6.02 (d , J = 2.2 Hz, 1H), 5.55 (m, 1H), 5.07 (s, 1H), 4.12 (q, J = 7.0 Hz, 2H), 3.04 (m, 2H), 1.28 (t, J = 7.0 Hz, 3 H);

13C NMR (100 MHz, Acetone-d 6 ) δ 164.49, 156.41, 156.08, 155.68, 149.87, 144.89, 137.62, 131.69, 129.26, 124.93, 108.45, 105.21, 97.49, 94.96, 94.40, 76.59, 68.30, 67.37, 25.21, 14.17. 13 C NMR (100 MHz, Acetone- d 6) δ 164.49, 156.41, 156.08, 155.68, 149.87, 144.89, 137.62, 131.69, 129.26, 124.93, 108.45, 105.21, 97.49, 94.96, 94.40, 76.59, 68.30, 67.37, 25.21 , 14.17.

<< 실시예Example 3> ( 3> ( 22 RR ,3, 3 RR )-5,7-) -5,7- 디하이드록시Dihydroxy -2-(3,4,5--2- (3,4,5- 트리하이드록시페닐Trihydroxyphenyl )) 크로만Croix -3-일 3,5- -3-yl 3,5- 디하이드록시Dihydroxy -4--4- 프로포시벤조에이트Propoxybenzoate (화합물 1c)의 제조 (Compound 1c)

단계 1: 화합물 3의 제조Step 1: Preparation of compound 3

상기 실시예 1의 단계 1과 동일하게 실시하여 화합물 3을 제조하였다.Compound 3 was prepared in the same manner as in Step 1 of Example 1.

단계 2: 5-((2Step 2: 5 - ((2 RR ,3, 3 RR )-5,7-디아세토시-3-((3,5-디아세토시-4-프로포시벤조일) 옥시)크로만-2-일)벤젠-1,2,3-트라일 트리아세테이트 (화합물 4c)의 제조) -5,7-diacetoxy-3 - ((3,5-diacetoxy-4-propoxybenzoyl) oxy) chroman-2-yl) benzene-1,2,3-trayl triacetate Preparation of compound 4c)

상기 실시예 1의 단계 2에서 '요오드화 메틸' 대신에 '요오드화 프로필'을 사용한 것을 제외하고는 동일하게 실시하여, 하얀색 가루 형태인 화합물 4c를 65% 수율로 얻었다.Compound 4c in the form of a white powder was obtained in a yield of 65% in the same manner as in the step 1 of Example 1, except that 'iodide was used in place of' methyl iodide '.

1H NMR (400 MHz, Acetone-d 6 ) δ 7.49 (s, 2H), 7.41 (s, 2H), 6.73 (d, J = 2.2 Hz, 1H), 6.67 (d, J = 2.1 Hz, 1H), 5.73 (m, 1H), 5.52 (s, 1H), 3.87 (m, 2H), 3.20 (A of ABq, J = 17.9 Hz, 4.4 Hz, 1H), 3.07 (B of ABq, J = 17.8 Hz, 1.5 Hz, 1H), 2.26 (m, 21H), 1.68 (m, 2H), 0.97 (t, J = 7.4 Hz, 3H); 1 H NMR (400 MHz, Acetone- d 6) δ 7.49 (s, 2H), 7.41 (s, 2H), 6.73 (d, J = 2.2 Hz, 1H), 6.67 (d, J = 2.1 Hz, 1H) , 5.73 (m, 1H), 5.52 (s, 1H), 3.87 (m, 2H), 3.20 (A of ABq, J = 17.9 Hz, 4.4 Hz, 1H), 3.07 (B of ABq, J = 17.8 Hz, 1.5 Hz, 1H), 2.26 (m, 21H), 1.68 (m, 2H), 0.97 (t, J = 7.4 Hz, 3H);

13C NMR (100 MHz, Acetone-d 6 ) δ 167.99, 167.57, 166.95, 166.13, 163.14, 154.42, 150.83, 149.48, 147.67. 143.68, 143.17, 135.42, 134.22, 123.79, 121.91, 118.52, 109.62, 108.69, 107.27, 75.98, 74.73, 67.82, 25.13, 22.75, 19.57, 19.31, 19.28, 19.12, 18.64, 9.21. 13 C NMR (100 MHz, Acetone- d 6) δ 167.99, 167.57, 166.95, 166.13, 163.14, 154.42, 150.83, 149.48, 147.67. 143.68, 143.17, 135.42, 134.22, 123.79, 121.91, 118.52, 109.62, 108.69, 107.27, 75.98, 74.73, 67.82, 25.13, 22.75, 19.57, 19.31, 19.28, 19.12, 18.64, 9.21.

단계 3: (Step 3: ( 22 RR ,3, 3 RR )-5,7-) -5,7- 디하이드록시Dihydroxy -2-(3,4,5--2- (3,4,5- 트리하이드록시페닐Trihydroxyphenyl )) 크로만Croix -3-일 3,5-디하이드록시-4-프로포시벤조에이트 (화합물 1c)의 제조 -3-yl 3,5-dihydroxy-4-propoxybenzoate (Compound 1c)

상기 실시예 1의 단계 3에서 '화합물 4a' 대신에 '화합물 4c'를 사용한 것을 제외하고는 동일하게 실시하여, 하얀색 가루 형태인 화합물 1c를 80% 수율로 얻었다.Compound 1c in the form of a white powder was obtained in a yield of 80% in the same manner as in the step 3 of Example 1, except that the compound 4c was used instead of the compound 4a.

1H NMR (400 MHz, Acetone-d 6 ) δ 8.24 (br s, 1H), 8.20 (br s, 1H), 8.07 (s, 1H), 7.82 (br s, 2H), 7.03 (s, 2H), 6.64 (s, 2H), 6.04 (d, J = 2.2 Hz, 1H), 6.02 (d, J = 2.2 Hz, 1H), 5.54 (m, 1H), 5.07 (s, 1H), 4.03 (t, J = 6.9 Hz, 2H), 3.04 (A of ABq, J = 17.4 Hz, 4.4 Hz, 1H), 2.91 (B of ABq, J = 17.5 Hz, 2.2 Hz, 1H), 1.72 (m, 21H), 0.94 (t, J = 7.4 Hz, 3H); 1 H NMR (400 MHz, Acetone- d 6) δ 8.24 (br s, 1H), 8.20 (br s, 1H), 8.07 (s, 1H), 7.82 (br s, 2H), 7.03 (s, 2H) 2H), 6.04 (d, J = 2.2 Hz, 1H), 6.02 (d, J = 2.2 Hz, 1H), 5.54 (m, J = 6.9 Hz, 2H), 3.04 (A of ABq, J = 17.4 Hz, 4.4 Hz, 1H), 2.91 (B of ABq, J = 17.5 Hz, 2.2 Hz, 1H) (t, J = 7.4 Hz, 3 H);

13C NMR (100 MHz, Acetone-d 6 ) δ 164.50, 156.43, 156.08, 155.67, 149.71, 144.89, 139.82, 131.24, 129.28, 124.74, 108.54, 105.24, 97.49, 95.08, 94.40, 76.58, 73.51, 68.32, 25.21, 22.42, 9.14. 13 C NMR (100 MHz, Acetone- d 6) δ 164.50, 156.43, 156.08, 155.67, 149.71, 144.89, 139.82, 131.24, 129.28, 124.74, 108.54, 105.24, 97.49, 95.08, 94.40, 76.58, 73.51, 68.32, 25.21 , 22.42, 9.14.

<< 실시예Example 4> ( 4> 22 RR ,3, 3 RR )-5,7-) -5,7- 디하이드록시Dihydroxy -2-(3,4,5--2- (3,4,5- 트리하이드록시페닐Trihydroxyphenyl )) 크로만Croix -3-일 4-( -3-yl 4- ( 알릴록시Allyloxy )-3,5-디하이드록시벤조에이트 (화합물 1d)의 제조) -3,5-dihydroxybenzoate (Compound 1d)

단계 1: 화합물 3의 제조Step 1: Preparation of compound 3

상기 실시예 1의 단계 1과 동일하게 실시하여 화합물 3을 제조하였다.Compound 3 was prepared in the same manner as in Step 1 of Example 1.

단계 step 2: 2: 5-((25 - ((2 RR ,3, 3 RR )-5,7-디아세토시-3-((3,5-디아세토시-4-(알릴옥시) 벤조일)옥시)크로만-2-일)벤젠-1,2,3-트라일 트리아세테이트 (화합물 4d)의 제조) -5,7-diacetoxy-3 - ((3,5-diacetoxy-4- (allyloxy) benzoyl) oxy) chroman- Acetate (Compound 4d)

상기 실시예 1의 단계 2에서 '요오드화 메틸' 대신에 '요오드화 프로페닐'을 사용한 것을 제외하고는 동일하게 실시하여, 하얀색 가루 형태인 화합물 4d를 72% 수율로 얻었다.Compound 4d in the form of white powder was obtained in 72% yield in the same manner as in step 1 of Example 1, except that 'iodide propyl' was used in place of 'methyl iodide'.

1H NMR (400 MHz, Acetone-d 6 ) δ 7.51 (s, 2H), 7.41 (s, 2H), 6.74 (d, J = 2.2 Hz, 1H), 6.60 (d, J = 2.2 Hz, 1H), 5.98 (m, 1H), 5.73 (m, 1H), 5.51 (s, 1H), 5.35 (dd, J = 17.2, 1.4 Hz, 1H), 5.20 (dd, J = 10.0, 0.9 Hz, 1H), 5.18 (dd, J = 3.8, 2.9 Hz, 1H), 3.12 (m, 2H), 2.26 (m, 21H); 1 H NMR (400 MHz, Acetone- d 6) δ 7.51 (s, 2H), 7.41 (s, 2H), 6.74 (d, J = 2.2 Hz, 1H), 6.60 (d, J = 2.2 Hz, 1H) , 5.98 (m, 1H), 5.73 (m, 1H), 5.51 (s, 1H), 5.35 (dd, J = 17.2, 1.4 Hz, 1H), 5.20 (dd, J = 10.0, 0.9 Hz, 1H), 5.18 (dd, J = 3.8, 2.9 Hz, 1H), 3.12 (m, 2H), 2.26 (m, 21H);

13C NMR (100 MHz, Acetone-d 6 ) δ 168.00, 167.59, 166.97, 166.15, 163.11, 154.41, 149.69, 149.48, 147.28, 143.85, 143.17, 135.42, 134.23, 133.09, 124.22, 121.85, 118.52, 116.66, 109.61, 108.70, 107.27, 75.97, 73.72, 67.87, 25.12 19.58, 19.35, 19.29, 19.13, 18.65. 13 C NMR (100 MHz, Acetone- d 6 )? 168.00, 167.59,166.97,166.15,163.11,154.41,149.69,149.48,147.28,143.85,143.17,135.42,134.23,133.09,124.22,121.85,118.52,116.66,109.61 , 108.70, 107.27, 75.97, 73.72, 67.87, 25.12 19.58, 19.35, 19.29, 19.13, 18.65.

단계 3: (Step 3: ( 22 RR ,3, 3 RR )-5,7-) -5,7- 디하이드록시Dihydroxy -2-(3,4,5--2- (3,4,5- 트리하이드록시페닐Trihydroxyphenyl )) 크로만Croix -3-일 4-( -3-yl 4- ( 알릴록시Allyloxy )-3,5-디하이드록시벤조에이트 (화합물 1d)의 제조) -3,5-dihydroxybenzoate (Compound 1d)

상기 실시예 1의 단계 3에서 '화합물 4a' 대신에 '화합물 4d'를 사용한 것을 제외하고는 동일하게 실시하여, 하얀색 가루 형태인 화합물 1d를 82% 수율로 얻었다.Compound 1d in the form of a white powder was obtained in 82% yield in the same manner as in the step 1 of Example 1, except that the compound 4d was used instead of the compound 4a.

1H NMR (400 MHz, Acetone-d 6 ) δ 8.30 (br s, 3H), 8.15 (br s, 1H), 7.84 (br s, 2H), 7.01 (s, 2H), 6.65 (s, 2H), 6.06 (m, 3H), 5.28 (m 1H), 5.26 (dd, J = 17.2 Hz, 1.4 Hz, 1H), 5.11 (m, 2H), 4.61 (d, J = 6.0 Hz, 2H), 3.02 (m, 2H); 1 H NMR (400 MHz, Acetone- d 6) δ 8.30 (br s, 3H), 8.15 (br s, 1H), 7.84 (br s, 2H), 7.01 (s, 2H), 6.65 (s, 2H) , 6.06 (m, 3H), 5.28 (m 1H), 5.26 (dd, J = 17.2 Hz, 1.4 Hz, 1H), 5.11 (m, 2H), 4.61 (d, J = 6.0 Hz, 2H), 3.02 ( m, 2H);

13C NMR (100 MHz, Acetone-d 6 ) δ 164.54, 156.34, 156.06, 155.66, 149.87, 144.88, 137.38, 133.81, 131.73, 129.30, 125.05, 117.21, 108.55, 105.28, 97.55, 95.13, 94.44, 76.52, 72.54, 68.35, 25.24. 13 C NMR (100 MHz, Acetone- d 6) δ 164.54, 156.34, 156.06, 155.66, 149.87, 144.88, 137.38, 133.81, 131.73, 129.30, 125.05, 117.21, 108.55, 105.28, 97.55, 95.13, 94.44, 76.52, 72.54 , 68.35, 25.24.

<< 실시예Example 5> ( 5> 22 RR ,3, 3 RR )-5,7-) -5,7- 디하이드록시Dihydroxy -2-(3,4,5--2- (3,4,5- 트리하이드록시페닐Trihydroxyphenyl )) 크로Crock 만 -3-일 4-(벤질록시)-3,5-디하이드록시벤조에이트 (화합물 1e)의 제조3-yl 4- (benzyloxy) -3,5-dihydroxybenzoate (Compound 1e)

단계 1: 화합물 3의 제조Step 1: Preparation of compound 3

상기 실시예 1의 단계 1과 동일하게 실시하여 화합물 3을 제조하였다.Compound 3 was prepared in the same manner as in Step 1 of Example 1.

단계 step 2: 2: 5-((25 - ((2 RR ,3, 3 RR )-5,7-디아세토시-3-((3,5-디아세토시-4-(벤질록시) 벤조일)옥시)크로만-2-일)벤젠-1,2,3-트라일 트리아세테이트 (화합물 4e)의 제조) -5,7-diacetoxy-3 - ((3,5-diacetoxy-4- (benzyloxy) benzoyl) oxy) Acetate (Compound 4e)

상기 실시예 1의 단계 2에서 '요오드화 메틸' 대신에 '요오드화 페닐메틸'을 사용한 것을 제외하고는 동일하게 실시하여, 하얀색 가루 형태인 화합물 4e를 75% 수율로 얻었다.Compound 4e in the form of a white powder was obtained in a yield of 75% in the same manner as in the step 1 of Example 1, except that phenylmethyl iodide was used instead of methyl iodide.

1H NMR (400 MHz, Acetone-d 6 ) δ 7.53 (s, 2H), 7.40 (m, 7H), 6.74 (d, J = 2.2 Hz, 1H), 6.60 (d, J = 2.2 Hz, 1H), 5.74 (m, 1H), 5.52 (s, 1H), 5.05 (s, 2H), 3.17 (m, 2H), 2.24 (m, 21H); 1 H NMR (400 MHz, Acetone- d 6) δ 7.53 (s, 2H), 7.40 (m, 7H), 6.74 (d, J = 2.2 Hz, 1H), 6.60 (d, J = 2.2 Hz, 1H) , 5.74 (m, IH), 5.52 (s, IH), 5.05 (s, 2H), 3.17 (m, 2H), 2.24 (m, 21H);

13C NMR (100 MHz, Acetone-d 6 ) δ 167.99, 167.59, 166.96, 166.14, 163.11, 154.41, 149.69, 149.48, 147.38, 143.90, 143.18, 136.46, 135.42, 134.23, 127.92, 127.71, 127.48, 124.30, 121.90, 118.52, 109.61, 108.70, 107.27, 75.98, 74.88, 67.90, 25.12, 19.57, 19.30, 19.13, 18.65. 13 C NMR (100 MHz, Acetone- d 6 ) δ 167.99, 167.59, 166.96, 166.14, 163.11, 154.41, 149.69, 149.48, 147.38, 143.90, 143.18, 136.46, 135.42, 134.23, 127.92, 127.71, 127.48, 124.30, 121.90 , 118.52, 109.61, 108.70, 107.27, 75.98, 74.88, 67.90, 25.12, 19.57, 19.30, 19.13, 18.65.

단계 3: (Step 3: ( 22 RR ,3, 3 RR )-5,7-) -5,7- 디하이드록시Dihydroxy -2-(3,4,5--2- (3,4,5- 트리하이드록시페닐Trihydroxyphenyl )) 크로만Croix -3-일 4-( -3-yl 4- ( 벤질록시Benzyloxy )-3,5-디하이드록시벤조에이트 (화합물 1e)의 제조) -3,5-dihydroxybenzoate (Compound 1e)

상기 실시예 1의 단계 3에서 '화합물 4a' 대신에 '화합물 4e'를 사용한 것을 제외하고는 동일하게 실시하여, 하얀색 가루 형태인 화합물 1e를 85% 수율로 얻었다.Compound 1e in the form of a white powder was obtained in 85% yield in the same manner as in the step 1 of Example 1, except that the compound 4e 'was used instead of the compound 4a'.

1H NMR (400 MHz, Acetone-d 6 ) δ 8.39 (s, 2H), 8.29 (s, 1H), 8.13 (s, 1H), 7.82 (s, 1H), 7.48 (d, J = 7.2 Hz, 2H), 7.30 (m, 4H), 7.01 (s, 2H), 6.64 (s, 2H), 6.06 (d, J = 2.0 Hz, 1H), 6.04 (d, J = 2.0 Hz, 1H), 5.57 (m, 1H), 5.13 (s, 2H), 5.08 (s, 1H), 3.05 (A of ABq, J = 17.4 Hz, 4.5 Hz, 1H), 2.93 (B of ABq, J = 16.6 Hz, 1.6 Hz, 1H); 1 H NMR (400 MHz, Acetone- d 6) δ 8.39 (s, 2H), 8.29 (s, 1H), 8.13 (s, 1H), 7.82 (s, 1H), 7.48 (d, J = 7.2 Hz, 2H), 7.30 (m, 4H ), 7.01 (s, 2H), 6.64 (s, 2H), 6.06 (d, J = 2.0 Hz, 1H), 6.04 (d, J = 2.0 Hz, 1H), 5.57 ( m, 1H), 5.13 (s , 2H), 5.08 (s, 1H), 3.05 (A of ABq, J = 17.4 Hz, 4.5 Hz, 1H), 2.93 (B of ABq, J = 16.6 Hz, 1.6 Hz, 1H);

13C NMR (100 MHz, Acetone-d 6 ) δ 164.44, 156.43, 156.10, 155.68, 149.88, 144.91, 137.59, 137.21, 131.74, 129.27, 127.88, 127.61, 127.37, 125.12, 108.60, 105.25, 97.51, 95.08, 94.42, 76.57, 73.14, 68.30, 25.23. 13 C NMR (100 MHz, Acetone- d 6) δ 164.44, 156.43, 156.10, 155.68, 149.88, 144.91, 137.59, 137.21, 131.74, 129.27, 127.88, 127.61, 127.37, 125.12, 108.60, 105.25, 97.51, 95.08, 94.42 , 76.57, 73.14, 68.30, 25.23.

Claims (10)

하기 반응식 1에 나타난 바와 같이,
화합물 2(에피갈로카테킨 갈레이트, EGCG) 및 과량의 아세트산을 유기용매에 첨가하고, 10-40℃에서 4-8시간 반응시켜 화합물 2의 하이드록시기를 모두 아세틸화한 화합물 3을 얻는 단계(Step 1);
화합물 3, 탄산칼륨(K2CO3), 요오드화칼륨(KI) 및 할로겐화알킬(R-X, 여기서 상기 X는 할로겐이고, R은 하기 반응식 1에서 정의한 바와 같다)을 유기용매에 첨가하고 35-65℃에서 2-6시간 반응시켜 화합물 4를 얻는 단계(Step 2); 및
화합물 4를 유기용매에 녹인 다음, 수소화붕소나트륨(NaBH4)를 0-5℃에서 첨가하고 20-60분 후에, 10-40℃에서 4-8시간 교반하여 탈아세틸화된 화합물 1을 얻는 단계(Step 3);
를 포함하는 4''-알킬화-에피갈로카테킨 갈레이트의 제조방법:
[반응식 1]
Figure 112017074505654-pat00004

(상기 반응식 1에서,
R은 C1-6의 직쇄 또는 측쇄 알킬, C1-6의 직쇄 또는 측쇄 알케닐, 또는 -R1Ar이고,
R1은 C1-6의 직쇄 또는 측쇄 알킬레닐이고,
Ar은 C6-10의 아릴이다).
As shown in Scheme 1 below,
Compound 3 (epigallocatechin gallate, EGCG) and excess acetic acid are added to an organic solvent and reacted at 10-40 ° C for 4-8 hours to obtain compound 3 in which all of the hydroxy groups of Compound 2 are acetylated Step 1);
Compound 3, potassium carbonate (K 2 CO 3 ), potassium iodide (KI) and alkyl halide (RX, where X is halogen and R is as defined in Scheme 1) For 2 to 6 hours to obtain Compound 4 (Step 2); And
Compound 4 is dissolved in an organic solvent, and sodium borohydride (NaBH 4 ) is added at 0-5 ° C. After 20-60 minutes, stirring is carried out at 10-40 ° C for 4-8 hours to obtain deacetylated compound 1 (Step 3);
&Lt; RTI ID = 0.0 &gt;4'-alkylation-epigallocatechin gallate &lt;
[Reaction Scheme 1]
Figure 112017074505654-pat00004

(In the above Reaction Scheme 1,
R is C 1-6 straight or branched chain alkyl, C 1-6 straight or branched alkenyl, or-R 1 Ar,
R 1 is C 1-6 linear or branched alkylenyl,
Ar is C 6-10 aryl.
제1항에 있어서,
상기 R은 C1-3의 직쇄 또는 측쇄 알킬, C1-3의 직쇄 또는 측쇄 알케닐, 또는 -R1Ar이고,
R1은 C1-3의 직쇄 또는 측쇄 알킬레닐이고,
Ar은 C6-8의 아릴인 것을 특징으로 하는 제조방법.
The method according to claim 1,
Wherein R is C 1-3 linear or branched alkyl, C 1-3 linear or branched alkenyl, or-R 1 Ar,
R 1 is C 1-3 linear or branched alkylenyl,
And Ar is C 6-8 aryl.
제2항에 있어서,
상기 R은 메틸, 에틸, 프로필, 프로페닐 또는 페닐메틸인 것을 특징으로 하는 제조방법.
3. The method of claim 2,
Wherein R is methyl, ethyl, propyl, propenyl or phenylmethyl.
제1항에 있어서,
상기 단계 1의 유기용매는 피리딘, t-부탄올, 에탄올, 테트라하이드로퓨란(THF), 벤젠, KOH/MeOH, MeOH, 톨루엔, CH2Cl2, 헥산, 디메틸포름아미드(DMF), 디이소프로필에테르, 디에틸에테르, 디옥산, 디메틸아세트아미드(DMA), 디메틸설폭사이드(DMSO), 아세톤 및 클로로벤젠으로 이루어지는 군으로부터 선택되는 1종 이상인 것을 특징으로 하는 제조방법.
The method according to claim 1,
The organic solvent of step 1 may be selected from the group consisting of pyridine, t-butanol, ethanol, tetrahydrofuran (THF), benzene, KOH / MeOH, MeOH, toluene, CH 2 Cl 2 , hexane, dimethylformamide , At least one member selected from the group consisting of diethyl ether, dioxane, dimethylacetamide (DMA), dimethylsulfoxide (DMSO), acetone and chlorobenzene.
제4항에 있어서,
상기 단계 1의 유기용매는 피리딘인 것을 특징으로 하는 제조방법.
5. The method of claim 4,
Wherein the organic solvent in step 1 is pyridine.
제1항에 있어서,
상기 단계 2의 유기용매는 아세톤, t-부탄올, 에탄올, 테트라하이드로퓨란(THF), 벤젠, KOH/MeOH, MeOH, 톨루엔, CH2Cl2, 헥산, 디메틸포름아미드(DMF), 디이소프로필에테르, 디에틸에테르, 디옥산, 디메틸아세트아미드(DMA), 디메틸설폭사이드(DMSO) 및 클로로벤젠으로 이루어지는 군으로부터 선택되는 1종 이상인 것을 특징으로 하는 제조방법.
The method according to claim 1,
The organic solvent of step 2 may be selected from the group consisting of acetone, t-butanol, ethanol, tetrahydrofuran (THF), benzene, KOH / MeOH, MeOH, toluene, CH 2 Cl 2 , hexane, dimethylformamide , At least one member selected from the group consisting of diethyl ether, dioxane, dimethylacetamide (DMA), dimethylsulfoxide (DMSO) and chlorobenzene.
제6항에 있어서,
상기 단계 2의 유기용매는 아세톤인 것을 특징으로 하는 제조방법.
The method according to claim 6,
Wherein the organic solvent in step 2 is acetone.
제1항에 있어서,
상기 단계 3의 유기용매는 메탄올, t-부탄올, 에탄올, 테트라하이드로퓨란(THF), 벤젠, KOH/MeOH, 톨루엔, CH2Cl2, 헥산, 디메틸포름아미드(DMF), 디이소프로필에테르, 디에틸에테르, 디옥산, 디메틸아세트아미드(DMA), 디메틸설폭사이드(DMSO), 아세톤 및 클로로벤젠으로 이루어지는 군으로부터 선택되는 1종 이상인 것을 특징으로 하는 제조방법.
The method according to claim 1,
The organic solvent in step 3 may be selected from the group consisting of methanol, t-butanol, ethanol, tetrahydrofuran (THF), benzene, KOH / MeOH, toluene, CH 2 Cl 2 , hexane, dimethylformamide Wherein the solvent is at least one selected from the group consisting of ethyl ether, dioxane, dimethylacetamide (DMA), dimethylsulfoxide (DMSO), acetone and chlorobenzene.
제8항에 있어서,
상기 단계 3의 유기용매는 메탄올인 것을 특징으로 하는 제조방법.
9. The method of claim 8,
Wherein the organic solvent in step 3 is methanol.
삭제delete
KR1020160150006A 2016-11-11 2016-11-11 Regioselective synthesis of alkyl EGCG derivatives KR101822306B1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
KR1020160150006A KR101822306B1 (en) 2016-11-11 2016-11-11 Regioselective synthesis of alkyl EGCG derivatives

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
KR1020160150006A KR101822306B1 (en) 2016-11-11 2016-11-11 Regioselective synthesis of alkyl EGCG derivatives

Publications (1)

Publication Number Publication Date
KR101822306B1 true KR101822306B1 (en) 2018-01-25

Family

ID=61093891

Family Applications (1)

Application Number Title Priority Date Filing Date
KR1020160150006A KR101822306B1 (en) 2016-11-11 2016-11-11 Regioselective synthesis of alkyl EGCG derivatives

Country Status (1)

Country Link
KR (1) KR101822306B1 (en)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20190114494A (en) 2018-03-30 2019-10-10 건국대학교 산학협력단 Pharmaceutical composition for preventing or treating a Malignant Neoplasms Of Breast comprising (-)-epigallocatechin gallate derivatives
KR20190114500A (en) 2018-03-30 2019-10-10 건국대학교 산학협력단 (-)-epigallocatechin gallate prodrugs , preparation method thereof and composition for mitochondrial biosis
KR20200005886A (en) 2018-07-09 2020-01-17 건국대학교 산학협력단 (-)-epigallocatechin gallate prodrugs, preparation method thereof and composition for inducing autophagy activation
WO2021187569A1 (en) * 2020-03-18 2021-09-23 花王株式会社 Method for producing epigallocatechin gallate conjugate

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
Chemistry of Natural Compounds. 2015. Vol. 51, No. 3, pp. 472-475*
J. Agric. Food Chem. 2005. Vol. 53, pp. 7035-7042*
PLOS ONE. 2014. Vol. 9, Issue 2, e85520*

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20190114494A (en) 2018-03-30 2019-10-10 건국대학교 산학협력단 Pharmaceutical composition for preventing or treating a Malignant Neoplasms Of Breast comprising (-)-epigallocatechin gallate derivatives
KR20190114500A (en) 2018-03-30 2019-10-10 건국대학교 산학협력단 (-)-epigallocatechin gallate prodrugs , preparation method thereof and composition for mitochondrial biosis
KR20200005886A (en) 2018-07-09 2020-01-17 건국대학교 산학협력단 (-)-epigallocatechin gallate prodrugs, preparation method thereof and composition for inducing autophagy activation
WO2021187569A1 (en) * 2020-03-18 2021-09-23 花王株式会社 Method for producing epigallocatechin gallate conjugate
JP2021151997A (en) * 2020-03-18 2021-09-30 花王株式会社 Method for producing epigallocatechin gallate conjugate
JP7041767B2 (en) 2020-03-18 2022-03-24 花王株式会社 Manufacturing method of epigallocatechin gallate conjugate
CN115298171A (en) * 2020-03-18 2022-11-04 花王株式会社 Method for producing epigallocatechin gallate conjugate

Similar Documents

Publication Publication Date Title
KR101822306B1 (en) Regioselective synthesis of alkyl EGCG derivatives
EP1390359B1 (en) Synthesis of cannabinoids
CA2787919A1 (en) Furo [3, 2 -b] pyrane derivatives useful in the synthesis of halichondrin b analogs
JP5547167B2 (en) Composition for the treatment of cancer cells and method of synthesis thereof
NZ539819A (en) Compositions and therapeutic methods involving isoflavones and analogues thereof
ES2636441T3 (en) A novel procedure for the synthesis of polyphenols
JP5781432B2 (en) Method for producing pyripyropene derivative
Xiao et al. Design, synthesis and antitumor activity of a series of novel coumarin–stilbenes hybrids, the 3-arylcoumarins
CN103554122B (en) A kind of containing chromone structure pyrazoles norcantharidin derivative and preparation method thereof and application
JP5717752B2 (en) Method for producing pyripyropene derivative
KR101829102B1 (en) Preparation method of chromanone 2-carboxylic acid or chroman 2-carboxylic acid derivatives
US20120059050A1 (en) Garcinia derivative, its preparing method and medicinal use
Navarrete-Encina et al. On the one pot syntheses of chromeno [4, 3-b] pyridine-3-carboxylate and chromeno [3, 4-c] pyridine-3-carboxylate and dihydropyridines
KR20110064006A (en) A novel quercetin conjugate, pom-q or poc-q and a method for manufacturing the same
IE871984L (en) 1,3-dioxinones
Wang et al. Regioselective sonochemical synthesis of genistein derivatives
HU182227B (en) Process for preparing hexitols containing free carboxyl group
ES2949217T3 (en) Method for synthesizing 2-((6-(hydroxymethyl)chromen-5-yl)oxy)-1-phenylethanone derivative
EP3733656B1 (en) Method for synthesis of lobaric acid and analog thereof
KR101794970B1 (en) Novel derivatives of nucleosides
JP7121986B2 (en) Method for producing alkoxyflavone derivative
KR101350540B1 (en) Process for the preparation of L-3-O-Alkyl ascorbic acid
KR101471943B1 (en) Process for preparing 7-hydroxy-3&#39;,4&#39;,5-trimethoxyflavone
CN104610170B (en) 2, 5-diketopiperazine derivative as well as preparation method and application thereof
KR20220101508A (en) Method of manufacturing fisetin or its derivatives

Legal Events

Date Code Title Description
GRNT Written decision to grant