KR101533009B1 - Synthesis of 4-hydroxyderricin - Google Patents
Synthesis of 4-hydroxyderricin Download PDFInfo
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- KR101533009B1 KR101533009B1 KR1020130049442A KR20130049442A KR101533009B1 KR 101533009 B1 KR101533009 B1 KR 101533009B1 KR 1020130049442 A KR1020130049442 A KR 1020130049442A KR 20130049442 A KR20130049442 A KR 20130049442A KR 101533009 B1 KR101533009 B1 KR 101533009B1
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- ethoxymethoxyphenyl
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- 230000015572 biosynthetic process Effects 0.000 title claims description 10
- 238000003786 synthesis reaction Methods 0.000 title claims description 10
- XDKYBPGIBVMHHB-KPKJPENVSA-N 4-Hydroxyderricin Chemical compound OC1=C(CC=C(C)C)C(OC)=CC=C1C(=O)\C=C\C1=CC=C(O)C=C1 XDKYBPGIBVMHHB-KPKJPENVSA-N 0.000 title 1
- XDKYBPGIBVMHHB-UHFFFAOYSA-N 4-Hydroxyderricin Natural products OC1=C(CC=C(C)C)C(OC)=CC=C1C(=O)C=CC1=CC=C(O)C=C1 XDKYBPGIBVMHHB-UHFFFAOYSA-N 0.000 title 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 14
- 238000000034 method Methods 0.000 claims abstract description 12
- 238000006462 rearrangement reaction Methods 0.000 claims abstract description 11
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 24
- -1 1, 1-dimethyl-2-propynyloxy Chemical group 0.000 claims description 17
- HGINCPLSRVDWNT-UHFFFAOYSA-N Acrolein Chemical compound C=CC=O HGINCPLSRVDWNT-UHFFFAOYSA-N 0.000 claims description 13
- 239000012046 mixed solvent Substances 0.000 claims description 10
- 150000001875 compounds Chemical class 0.000 claims description 9
- 125000005745 ethoxymethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])* 0.000 claims description 9
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 9
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 9
- UILPJVPSNHJFIK-UHFFFAOYSA-N Paeonol Chemical compound COC1=CC=C(C(C)=O)C(O)=C1 UILPJVPSNHJFIK-UHFFFAOYSA-N 0.000 claims description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 6
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 6
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 claims description 4
- 238000006722 reduction reaction Methods 0.000 claims description 4
- 238000001308 synthesis method Methods 0.000 claims description 4
- 238000005984 hydrogenation reaction Methods 0.000 claims description 3
- 239000011981 lindlar catalyst Substances 0.000 claims description 3
- 230000008707 rearrangement Effects 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 31
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 30
- 238000006243 chemical reaction Methods 0.000 description 12
- 235000019439 ethyl acetate Nutrition 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- DQFBYFPFKXHELB-UHFFFAOYSA-N Chalcone Natural products C=1C=CC=CC=1C(=O)C=CC1=CC=CC=C1 DQFBYFPFKXHELB-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- 235000005513 chalcones Nutrition 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 239000000741 silica gel Substances 0.000 description 5
- 229910002027 silica gel Inorganic materials 0.000 description 5
- DQFBYFPFKXHELB-VAWYXSNFSA-N trans-chalcone Chemical compound C=1C=CC=CC=1C(=O)\C=C\C1=CC=CC=C1 DQFBYFPFKXHELB-VAWYXSNFSA-N 0.000 description 5
- 239000007788 liquid Substances 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000011347 resin Substances 0.000 description 4
- 229920005989 resin Polymers 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- 238000006266 etherification reaction Methods 0.000 description 3
- 229920001467 poly(styrenesulfonates) Polymers 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- QSILYWCNPOLKPN-UHFFFAOYSA-N 3-chloro-3-methylbut-1-yne Chemical compound CC(C)(Cl)C#C QSILYWCNPOLKPN-UHFFFAOYSA-N 0.000 description 2
- RGHHSNMVTDWUBI-UHFFFAOYSA-N 4-hydroxybenzaldehyde Chemical compound OC1=CC=C(C=O)C=C1 RGHHSNMVTDWUBI-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- DCERHCFNWRGHLK-UHFFFAOYSA-N C[Si](C)C Chemical compound C[Si](C)C DCERHCFNWRGHLK-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 238000005882 aldol condensation reaction Methods 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 238000006482 condensation reaction Methods 0.000 description 2
- ZYGHJZDHTFUPRJ-UHFFFAOYSA-N coumarin Chemical compound C1=CC=C2OC(=O)C=CC2=C1 ZYGHJZDHTFUPRJ-UHFFFAOYSA-N 0.000 description 2
- 238000010511 deprotection reaction Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- PVSPTVQNQJFQMP-UHFFFAOYSA-N 1-but-1-ynoxybut-1-yne Chemical compound CCC#COC#CCC PVSPTVQNQJFQMP-UHFFFAOYSA-N 0.000 description 1
- VSTXCZGEEVFJES-UHFFFAOYSA-N 1-cycloundecyl-1,5-diazacycloundec-5-ene Chemical compound C1CCCCCC(CCCC1)N1CCCCCC=NCCC1 VSTXCZGEEVFJES-UHFFFAOYSA-N 0.000 description 1
- WKEOCOHKXRVQEU-UHFFFAOYSA-N 4-(ethoxymethoxy)benzaldehyde Chemical compound CCOCOC1=CC=C(C=O)C=C1 WKEOCOHKXRVQEU-UHFFFAOYSA-N 0.000 description 1
- 241001105098 Angelica keiskei Species 0.000 description 1
- 235000007516 Chrysanthemum Nutrition 0.000 description 1
- 244000189548 Chrysanthemum x morifolium Species 0.000 description 1
- 229910021591 Copper(I) chloride Inorganic materials 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 230000003266 anti-allergic effect Effects 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 230000003579 anti-obesity Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 238000009739 binding Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 description 1
- 229960000956 coumarin Drugs 0.000 description 1
- 235000001671 coumarin Nutrition 0.000 description 1
- 230000006119 deprenylation Effects 0.000 description 1
- GUJOJGAPFQRJSV-UHFFFAOYSA-N dialuminum;dioxosilane;oxygen(2-);hydrate Chemical compound O.[O-2].[O-2].[O-2].[Al+3].[Al+3].O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O GUJOJGAPFQRJSV-UHFFFAOYSA-N 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- ZONYXWQDUYMKFB-UHFFFAOYSA-N flavanone Chemical compound O1C2=CC=CC=C2C(=O)CC1C1=CC=CC=C1 ZONYXWQDUYMKFB-UHFFFAOYSA-N 0.000 description 1
- 235000011981 flavanones Nutrition 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 125000001844 prenyl group Chemical group [H]C([*])([H])C([H])=C(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/78—Separation; Purification; Stabilisation; Use of additives
- C07C45/81—Separation; Purification; Stabilisation; Use of additives by change in the physical state, e.g. crystallisation
- C07C45/82—Separation; Purification; Stabilisation; Use of additives by change in the physical state, e.g. crystallisation by distillation
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
- C07C49/84—Ketones containing a keto group bound to a six-membered aromatic ring containing ether groups, groups, groups, or groups
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2200/00—Function of food ingredients
- A23V2200/30—Foods, ingredients or supplements having a functional effect on health
Abstract
본 발명은 4-하이드록시데리신 합성방법에 관한 것으로서, 좀더 자세히는 다양한 생리활성을 나타내어 건강식품 및 한약재료로 이용되고 있는 신선초의 주요 활성성분 4-하이드록시데리신을 기존의 비효율적인 [1,3]-시그마결합 재배열 (sigmatropic rearrangement) 반응 대신 물에 의해 촉진되는 [3,3]-시그마결합 재배열 (water accelerated [3,3]-sigmatropic rearrangement) 반응을 통하여 효율적으로 전합성하는 방법에 관한 것이다.The present invention relates to a method for synthesizing 4-hydroxydericine. More specifically, the present invention relates to a method for synthesizing 4-hydroxydericine, which comprises 4-hydroxyderisin, (3,3) -sigmatropic rearrangement, which is catalyzed by water instead of the sigmatropic rearrangement reaction. .
Description
본 발명은 4-하이드록시데리신 합성방법에 관한 것으로서, 좀더 자세히는 다양한 생리활성을 나타내어 건강식품 및 한약재료로 이용되고 있는 신선초의 주요 활성성분 4-하이드록시데리신을 기존의 비효율적인 [1,3]-시그마결합 재배열 (sigmatropic rearrangement) 반응 대신 물에 의해 촉진되는 [3,3]-시그마결합 재배열 (water accelerated [3,3]-sigmatropic rearrangement) 반응을 통하여 효율적으로 전합성하는 방법에 관한 것이다.
The present invention relates to a method for synthesizing 4-hydroxydericine. More specifically, the present invention relates to a method for synthesizing 4-hydroxydericine, which comprises 4-hydroxyderisin, (3,3) -sigmatropic rearrangement, which is catalyzed by water instead of the sigmatropic rearrangement reaction. .
4-하이드록시데리신은 항암, 항박테리아, 항알러지, 항비만, 항산화, 항곰팡이, 항바이러스등 다양한 생리활성을 나타내는 물질로서 신선초 (Angelica keiskei)의 주요활성성분이다 [J. Oleo Sci., 2011, 60, 71-77]. 신선초에는 찰콘 (chalcone), 플라바논 (flavanon), 쿠마린 (coumarin) 등의 활성성분들이 존재하며, 찰콘의 종류도 10여 가지가 발견되고 있지만 이중 4-하이드록시데리신이 가장 활성이 뛰어난 것으로 알려져 있다. 4-하이드록시데리신의 중요한 활성이 계속 밝혀지고 있음에도 불구하고 현재까지는 한 가지 전합성 방법만 보고되어 있다 [Tetrahedron Lett., 2008, 49, 6639-6641]. 이 방법의 핵심반응은 몬모릴로나이트 (montmorillonite) K10을 이용한 찰콘 에테르 (chalcone ether)의 [1,3]-시그마결합 재배열 (sigmatropic rearrangement) 반응으로서 46%의 낮은 수율을 나타내고 있을 뿐만 아니라, 탈프레닐화 (deprenylation)로 인한 부생성물도 얻어지는 문제점을 나타낸다.
4- Hydroxydericine is a major active ingredient of Angelica keiskei as a substance exhibiting various physiological activities such as anticancer, antibacterial, antiallergic, anti-obesity, antioxidant, antifungal and antiviral [ J. Oleo Sci. , 2011, 60 , 71-77]. There are active ingredients such as chalcone, flavanon and coumarin in chrysanthemum, and more than 10 kinds of chalcone have been found. Among them, 4-hydroxydericin is known to be most active . Despite the fact that the important activity of 4-hydroxydercin is still being clarified, only one pre-synthesis method has been reported so far [ Tetrahedron Lett. , 2008 , 49 , 6639-6641]. The key reaction of this method is the [1,3] - sigmatropic rearrangement reaction of chalcone ether using montmorillonite K10 as well as showing a low yield of 46% the byproducts due to deprenylation are also obtained.
따라서, 본 발명의 과제는 종래 4-하이드록시데리신 합성방법의 비효율성을 극복하고 효율적 전합성방법을 제공하려는 것이다.
Accordingly, an object of the present invention is to overcome the inefficiency of the conventional 4-hydroxydericine synthesis method and provide an efficient whole-synthesis method.
상기 과제를 해결하기 위해, 본 발명에서는 클라이젠-슈미트 응축 (Claisen-Schmidt condensation) 반응으로 보호된 찰콘 (protected chalcone) 화합물을 합성한 후 물을 첨가한 혼합용매 시스템을 bomb reactor 하에 반응시켜 [3,3]-시그마결합 재배열 반응으로 4-하이드록시데리신만을 합성하는 방법을 제공한다. 클라이젠-슈미트 응축 반응 전에 [3,3]-시그마결합 재배열 반응을 하게 되면 선택성이 떨어져 혼합물이 발생하게 된다.
In order to solve the above problem, in the present invention, a protected chalcone compound protected by a Claisen-Schmidt condensation reaction is synthesized and then a mixed solvent system in which water is added is reacted under a bomb reactor [3 , 3] -sigma bond rearrangement reaction to synthesize 4-hydroxyderiscin alone. When the [3,3] -sigma bond rearrangement reaction is performed prior to the Clagen-Schmidt condensation reaction, the selectivity deteriorates and the mixture is generated.
4-하이드록시데리신의 전합성은 상업적으로 쉽게 구할 수 있는 4-하이드록시-4-메톡시아세토페논 (4-hydroxy-4-methoxyacetophenone) (화학식 1)을 3-클로로-3-메틸-1-부틴 (3-chloro-3-methyl-1-butyne)과 염기를 이용한 에테르화 (etherification) 반응으로 아릴 부티닐 에테르 (aryl butynyl ether) (화학식 2)를 합성한 후 4-(에톡시메톡시)벤즈알데하이드 {4-(ethoxymethoxy)benzaldehyde} (화학식 3)와 KOH, EtOH을 이용한 Claisen-Schmidt 응축반응을 시켜 에톡시메틸 (EOM)기로 보호된 찰콘 (EOM protected chalcone) (화학식 4)을 합성한다. 합성된 부티닐찰콘 (butynylchalcone) (화학식 4)은 Lindlar 촉매를 이용한 수소환원반응으로 부테닐찰콘 (butenylchalcone) (화학식 5)으로 환원시킨다. 전체 반응의 가장 핵심적인 Claisen-type의 [3,3]-시그마결합 반응은 밤 반응기 (bomb reactor)를 이용하여 EtOH/water (4/1, v/v), 70℃, 12 시간 반응시켜 재배열된 찰콘 (화학식 6)을 합성하고 에톡시메틸기의 탈보호 (deprotection)는 메탄올 용매에서 DOWEX 수지 50x2를 이용하여 최종물질인 4-하이드록시데리신 (화학식 7)을 얻는다.
The entire synthesis of 4-hydroxy dececine is carried out by using commercially available 4-hydroxy-4-methoxyacetophenone (Formula 1) with 3-chloro-3-methyl- (Aryl) butynyl ether (Formula 2) was synthesized by an etherification reaction using 3-chloro-3-methyl-1-butyne and a base. Then, 4- (ethoxymethoxy) (EOM) protected chalcone (Formula 4) is synthesized by a Claisen-Schmidt condensation reaction using benzaldehyde {4- (ethoxymethoxy) benzaldehyde} (Formula 3) and KOH and EtOH. The synthesized butynylchalcone (Formula 4) is reduced to butenylchalcone (Formula 5) by hydrogen reduction using Lindlar catalyst. The most critical Claisen-type [3,3] -Sigma binding reaction of the whole reaction was a reaction in EtOH / water (4/1, v / v) using a bomb reactor at 70 ° C for 12 hours Synthesized chalcone (Chemical Formula 6) is synthesized and the deprotection of the ethoxymethyl group is carried out by using DOWEX resin 50x2 in a methanol solvent to obtain the final product 4-hydroxyderecin (Chemical Formula 7).
본 발명은 하기 화학식 1로 표시되는 2-하이드록시-4-메톡시아세토페논으로부터 화학식 7로 표시되는 4-하이드록시데리신을 합성하는 방법에 있어서, The present invention relates to a process for synthesizing 4-hydroxyderissin represented by the formula (7) from 2-hydroxy-4-methoxyacetophenone represented by the following formula (1)
(a) 화학식 1로 표시되는 2-하이드록시-4-메톡시아세토페논을 에테르화하여 화학식 2로 표시되는 화합물인 4-메톡시-2-(1,1-다이메틸-2-프로피닐옥시)아세토페논을 생성하는 단계; (a) etherifying 2-hydroxy-4-methoxyacetophenone represented by the formula (1) to obtain 4-methoxy-2- (1,1- ) Producing acetophenone;
(b) 상기 (a) 단계에서 생성된 화학식 2로 표시되는 화합물인 4-메톡시-2-(1,1-다이메틸-2-프로피닐옥시)아세토페논과 화학식 3으로 표시되는 화합물인 4-(에톡시메톡시)벤즈알데하이드의 클라이젠-슈미트 응축반응으로 화학식 4로 표시되는 화합물인 (E)-3-[4-에톡시메톡시페닐]-1-[4-메톡시-2-(1,1-다이메틸-2-프로피닐옥시)] 프로프-2-엔-1-온 {(E)-3-[4-ethoxymethoxyphenyl]-1-[4-methoxy-2-(1,1-dimethyl-2-propynyloxy)] prop-2-en-1-one}을 합성하는 단계;(b) 4-methoxy-2- (1,1-dimethyl-2-propynyloxy) acetophenone, a compound represented by the general formula (2) ( E ) -3- [4-ethoxymethoxyphenyl] -1- [4-methoxy-2- (ethoxymethoxy) benzaldehyde, which is a compound represented by the
(c) 상기 (b) 단계에서 합성된 화학식 4로 표시되는 화합물인 (E)-3-[4-에톡시메톡시페닐]-1-[4-메톡시-2-(1,1-다이메틸-2-프로페닐옥시)] 프로프-2-엔-1-온으로부터 린드라 촉매 (Lindlar catalyst)를 이용한 수소화 환원반응으로 화학식 5로 표시되는 화합물인 (E)-3-[4-에톡시메톡시페닐]-1-[4-메톡시-2-(1,1-다이메틸-2-프로페닐옥시)] 프로프-2-엔-1-온 {(E)-3-[4-ethoxymethoxyphenyl]-1-[4-methoxy-2-(1,1-dimethyl-2-propenyloxy)] prop-2-en-1-one}을 합성하는 단계; 및 (c) The compound represented by the general formula (4) synthesized in the step (b), ( E ) -3- [4-ethoxymethoxyphenyl] -1- [4-methoxy- Methyl-2-propenyloxy)] prop-2-en-1-one was subjected to a hydrogenation reduction reaction using a Lindlar catalyst to obtain ( E ) -3- [4- Prop-2-en-1-one {( E ) -3- [4- (4-methoxyphenyloxy) -ethoxymethoxyphenyl] -1- [4-methoxy-2- (1,1-dimethyl-2-propenyloxy)] prop-2-en-1-one}; And
(d) 상기 (c) 단계에서 합성된 화학식 5로 표시되는 화합물인 (E)-3-[4-에톡시메톡시페닐]-1-[4-메톡시-2-(1,1-다이메틸-2-프로페닐옥시)] 프로프-2-엔-1-온 {(E)-3-[4-ethoxymethoxyphenyl]-1-[4-methoxy-2-(1,1-dimethyl-2-propenyloxy)] prop-2-en-1-one}을 재배열 및 탈보호기화하여 화학식 7로 표시되는 4-하이드록시데리신을 합성하는 방법에 관한 것이다. (d) Synthesis of ( E ) -3- [4-ethoxymethoxyphenyl] -1- [4-methoxy-2- Methyl-2-propenyloxy)] prop-2-en-1-one {( E ) -3- [4- ethoxymethoxyphenyl] -1- [4- methoxy- 2- propenyloxy)] prop-2-en-1-one} is rearranged and deprotected to synthesize 4-hydroxydericin represented by formula (7).
<화학식 1>≪ Formula 1 >
<화학식 2>(2)
<화학식 3>(3)
<화학식 4>≪ Formula 4 >
<화학식 5>≪ Formula 5 >
<화학식 7>≪ Formula 7 >
{단, 상기 화학식 3, 화학식 4 및 화학식 5에서 상기 R은 알킬기, 시클로알킬기, 벤질기, 테트라하이드록시피라닐 (tetrahydropyranyl; THP)기, 메톡시메틸 (methoxymethyl; MOM)기, 에톡시메틸 (ethoxymethyl; EOM)기, t-부틸다이메틸실릴 (t-buthyldimethylsilyl; TBDMS)기 또는 트리메틸실릴 (trimethylsilyl; TMS)기이다.}(Wherein R represents an alkyl group, a cycloalkyl group, a benzyl group, a tetrahydropyranyl (THP) group, a methoxymethyl (MOM) group, an ethoxymethyl ethoxymethyl (EOM) group, t-buthyldimethylsilyl (TBDMS) group or trimethylsilyl (TMS) group.
또한, 본 발명은 상기 (d) 단계에서 화학식 5로 표시되는 화합물인 (E)-3-[4-에톡시메톡시페닐]-1-[4-메톡시-2-(1,1-다이메틸-2-프로페닐옥시)] 프로프-2-엔-1-온 {(E)-3-[4-ethoxymethoxyphenyl]-1-[4-methoxy-2-(1,1-dimethyl-2-propenyloxy)] prop-2-en-1-one}의 재배열은 물을 첨가한 혼합용매 시스템 (에탄올/물)에서 물에 의해 촉진되는 [3,3]-시그마결합 재배열 반응임을 특징으로 하는 4-하이드록시데리신 합성방법에 관한 것이다. 이때 에탄올/물 혼합용매는 3~5/1 범위가 바람직하다. 에탄올이 너무 적으면 용해도의 문제로 반응이 거의 일어나지 않으며, 물이 너무 적게 되면 반응시간이 아주 길어지게 되는 문제점이 야기되는 동시에 원하지 않는 부반응으로서 비정상 재배열 (abnormal rearrangement) 반응도 일어난다.The present invention also relates to a process for the preparation of ( E ) -3- [4-ethoxymethoxyphenyl] -1- [4-methoxy-2- (1,1- Methyl-2-propenyloxy)] prop-2-en-1-one {( E ) -3- [4- ethoxymethoxyphenyl] -1- [4- methoxy- 2- propenyloxy)] prop-2-en-1-one} is a [3,3] -sigma bond rearrangement reaction promoted by water in a mixed solvent system (ethanol / water) 4-hydroxydericin. ≪ / RTI > At this time, the ethanol / water mixed solvent is preferably in the range of 3 to 5/1. If the amount of ethanol is too small, the reaction hardly occurs due to the solubility problem. If the amount of water is too low, the reaction time becomes very long. At the same time, an abnormal rearrangement reaction occurs as an undesired side reaction.
뿐만 아니라, 본 발명은 상기 물을 첨가한 혼합용매가 에탄올/물 = 4/1 (v/v) 비율인 것임을 특징으로 하는 4-하이드록시데리신 합성방법에 관한 것이다. 혼합용매의 비율이 위와 같을 때 반응이 최적화된다.
In addition, the present invention relates to a method for synthesizing 4-hydroxydercin, wherein the water-added mixed solvent has a ratio of ethanol / water = 4/1 (v / v). The reaction is optimized when the ratio of the mixed solvent is as above.
본 발명은 상업적으로 쉽게 구할 수 있는 화학식 1 화합물로부터 화학식 7의 4-하이드록시데리신을 제조하는데 있어 화학식 2와 화학식 3의 클라이젠-슈미트 응축반응을 거쳐 부티닐찰콘 (butynylchalcone) (화학식 4)을 합성한 후, 이를 부테닐찰콘 (butenylchalcone) (화학식 5)으로 환원하고, 여기에 물을 첨가한 혼합용매 시스템을 밤 반응기 (bomb reactor) 하에 반응시켜 [3,3]-시그마결합 재배열반응만 선택적으로 일어나게 하는 4-하이드록시데리신의 효율적 전합성 방법이므로, 수율이 높고, 부생성물이 적다.
The present invention relates to a process for the production of 4-hydroxyderisin of the formula (7) from a commercially available compound of the formula (1) by subjecting a butynylchalcone (formula (4) After the synthesis, it is reduced with butenylchalcone (Formula 5), and a mixed solvent system in which water is added is reacted under a bomb reactor to produce a [3,3] -sigma bond rearrangement reaction only Hydrolyzedrin is selectively synthesized. Therefore, the yield is high and the number of by-products is low.
도 1은 본 발명의 일 실시예에 의한 반응식을 나타낸다. 1 shows a reaction formula according to an embodiment of the present invention.
이하 구체적인 실시예 및 데이타를 들어 본 발명을 좀 더 자세히 설명한다. 그러나, 본 발명의 범위가 실시예의 기재에 의하여 한정되는 것이 아니며, 실시예의 기재는 본 발명의 구성을 구체화하기 위한 예시임은 본 발명이 속하는 기술분야에서 통상의 지식을 가진 자에게 자명하다.
Hereinafter, the present invention will be described in more detail with reference to specific examples and data. However, it is to be understood that the scope of the present invention is not limited to the description of the embodiments, but the description of the embodiments is for the purpose of embodying the constitution of the present invention to those skilled in the art.
본 발명에서 출발물질로 사용되는 2-하이드록시-4-메톡시아세토페논은 하기 화학식 1로 표시된다:The 2-hydroxy-4-methoxyacetophenone used as a starting material in the present invention is represented by the following Formula 1:
상기 2-하이드록시-4-메톡시아세토페논 (화학식 1)은 알드리치등의 시약회사에서 쉽게 구입할 수 있으며 아세토나이트릴 (acetonitrile) 용매에 녹여서 사용한다.The 2-hydroxy-4-methoxyacetophenone (Formula 1) can be easily obtained from a reagent company such as Aldrich and dissolved in an acetonitrile solvent.
상기 화학식 2의 4-메톡시-2-(1,1-다이메틸-2-프로피닐옥시)아세토페논은 출발물질 (화학식 1)로부터 염기를 이용한 에테르화 (etherification) 반응으로 얻어진다.The 4-methoxy-2- (1,1-dimethyl-2-propynyloxy) acetophenone of the above formula (2) is obtained from the starting material (1) by an etherification reaction with a base.
상기 화학식 3의 4-(에톡시메톡시)벤즈알데하이드는 4-하이드록시벤즈알데하이드로부터 에테르화 반응으로 얻어진다. 상기 R은 알킬, 시클로알킬, 벤질, 테트라하이드로피라닐 (tetrahydropyranyl; THP), 메톡시메틸 (methoxymethyl; MOM), 에톡시메틸 (ethoxymethyl; EOM), t-부틸다이메틸실릴 (t-buthyldimethylsilyl; TBDMS) 또는 트리메틸실릴 (trimethylsilyl; TMS)기 중 선택된 1종일 수 있다.The 4- (ethoxymethoxy) benzaldehyde of
상기 식에서, (E)-3-[4-ethoxymethoxyphenyl]-1-[4-methoxy-2-(1,1-dimethyl-2-propynyloxy)] prop-2-en-1-one은 화학식 2와 화학식 3의 클라이젠-슈미트 응축반응으로 얻어진다. 상기 R은 알킬, 시클로알킬, 벤질, THP (tetrahydropyranyl), MOM (methoxymethyl), EOM (ethoxymethyl), TBDMS (t-buthyldimethylsilyl) 또는 TMS (trimethylsilyl)기 중 선택된 1종일 수 있다.( E ) -3- [4-ethoxymethoxyphenyl] -1- [4-methoxy-2- (1,1-dimethyl- 2- propynyloxy)] prop- 3 by the Clagen-Schmidt condensation reaction. The R may be selected from the group consisting of alkyl, cycloalkyl, benzyl, tetrahydropyranyl, MOM, ethoxymethyl, TBDMS, and trimethylsilyl.
상기식에서 (E)-3-[4-ethoxymethoxyphenyl]-1-[4-methoxy-2-(1,1-dimethyl-2-propenyloxy)] prop-2-en-1-one은 화학식 4의 Lindlar 촉매를 이용한 수소화 환원반응으로 얻어진다. 상기 R은 알킬, 시클로알킬, 벤질, THP (tetrahydropyranyl), MOM (methoxymethyl), EOM (ethoxymethyl), TBDMS (t-buthyldimethylsilyl) 또는 TMS (trimethylsilyl)일 수 있다.( E ) -3- [4-ethoxymethoxyphenyl] -1- [4-methoxy-2- (1,1-dimethyl- 2- propenyloxy)] prop- And a hydrogenation reduction reaction using hydrogen peroxide. The R may be alkyl, cycloalkyl, benzyl, tetrahydropyranyl, MOM, ethoxymethyl, TBDMS, or TMS (trimethylsilyl).
상기 식에서 (E)-3-[4-ethoxymethoxyphenyl]-1-[2-hydroxy-4-methoxy-3-(3-methyl-2-butenyl)] prop-2-en-1-one은 화학식 5에 물을 첨가한 혼합용매 시스템을 bomb reactor, 에탄올/물 (4/1, v/v) 하에 반응시킨 [3,3]-시그마결합 재배열반응으로 얻어진다. 상기 R은 알킬, 시클로알킬, 벤질, THP (tetrahydropyranyl), MOM (methoxymethyl), EOM (ethoxymethyl), TBDMS (t-buthyldimethylsilyl) 또는 TMS (trimethylsilyl)일 수 있다.( E ) -3- [4-ethoxymethoxyphenyl] -1- [2-hydroxy-4-methoxy-3- (3-methyl-2-butenyl)] prop- (3,3] -sigma bond rearrangement reaction in which a water-added mixed solvent system is reacted under a bomb reactor, ethanol / water (4/1, v / v). The R may be alkyl, cycloalkyl, benzyl, tetrahydropyranyl, MOM, ethoxymethyl, TBDMS, or TMS (trimethylsilyl).
상기 화학식 7로 표시되는 화합물인 4-하이드록시데리신은 화학식 6의 DOWEX 수지 50x2를 이용한 탈보호기화 (deprotection) 반응으로 얻어진다.
4-Hydroxyderecin, which is a compound represented by the above formula (7), is obtained by a deprotection reaction using a DOWEX resin 50x2 of the formula (6).
이하 본 발명을 하기 실시예에 의하여 더욱 상세하게 설명하고자 한다. 단, 하기 실시예는 본 발명을 예시하기 위한 것일 뿐, 본 발명의 범위가 실시예의 기재범위 내로 한정되는 것이 아님은 본 발명이 속하는 기술분야에서 통상의 지식을 가진 자에게 자명하다.
Hereinafter, the present invention will be described in more detail with reference to the following examples. It is to be understood, however, that the following examples are illustrative of the present invention only and that the scope of the present invention is not limited to the scope of the present invention.
<실시예 1: 2-하이드록시-4-메톡시아세토페논 (화학식 1)으로부터 화학식 2의 합성>Example 1: Synthesis of
Two-neck flask에 2-하이드록시-4-메톡시아세토페논 (500 ㎎, 3.01 mmol)과 CuCl22H2O (5 ㎎, 0.03 mmol)을 넣어주고 질소를 채운 후 아세토나이트릴 (10 ㎖)에 녹였다. 거기에 1,8-다이아자바이사이클로운덱-7-엔 (1,8-diazabicycloundec-7-ene) (0.49 ㎖, 3.31 mmol)을 넣고 10분간 교반시켜주었다. 그 후 3-클로로-3-메틸-1-부틴 (3-chloro-3-methyl-1-butyne) (0.37 ㎖, 3.31 mmol)을 용매에 희석해서 천천히 넣어주었다. 0 ℃에서 5시간 교반 후 용매를 감압 증류시키고 CH2Cl2로 추출하였다. Na2SO4로 건조시켜 필터하여 에틸아세테이트/헥산 = 1/10 으로 실리카겔 컬럼분리하여 노란색 고체인 화학식 2 화합물을 얻었다.2-Hydroxy-4-methoxyacetophenone (500 mg, 3.01 mmol) and CuCl 2 2H 2 O (5 mg, 0.03 mmol) were added to a two-neck flask and purged with nitrogen. Acetonitrile Respectively. 1,8-diazabicycloundec-7-ene (0.49 ml, 3.31 mmol) was added thereto, followed by stirring for 10 minutes. Then, 3-chloro-3-methyl-1-butyne (0.37 ml, 3.31 mmol) was diluted in a solvent and slowly added. After stirring at 0 ° C for 5 hours, the solvent was distilled off under reduced pressure and extracted with CH 2 Cl 2 . Dried over Na 2 SO 4 , filtered, and separated by silica gel column with ethyl acetate / hexane = 1/10 to obtain a yellow solid compound (2).
수율 : 535 ㎎, 77%Yield: 535 mg, 77%
R f = 0.42 (EtOAc/Hexane = 1/4). 1H NMR (300 MHz, CDCl3) 7.74 (1H, d, J = 9.0 Hz), 7.17 (1H, d, J = 1.8 Hz), 6.58 (1H, dd, J = 9.0, 1.8 Hz), 3.83 (3H, s), 2.67 (1H, s), 2.57 (3H, s), 1.75 (6H, s). 13C NMR (75 MHz, CDCl3) 198.3, 163.1, 156.8, 132.0, 124.6, 107.3, 104.9, 85.3, 75.1, 75.0, 73.1, 55.5, 31.9, 29.7.
Rf = 0.42 (EtOAc / Hexane = 1/4). 1 H NMR (300 MHz, CDCl 3) 7.74 (1H, d, J = 9.0 Hz), 7.17 (1H, d, J = 1.8 Hz), 6.58 (1H, dd, J = 9.0, 1.8 Hz), 3.83 ( 3H, s), 2.67 (1H, s), 2.57 (3H, s), 1.75 (6H, s). 13 C NMR (75 MHz, CDCl 3 ) 198.3, 163.1, 156.8, 132.0, 124.6, 107.3, 104.9, 85.3, 75.1, 75.0, 73.1, 55.5, 31.9, 29.7.
<실시예 2: 화학식 2와 화학식 3으로부터 화학식 4의 합성>≪ Example 2: Synthesis of
Two-neck flask에 화학식 2 (250 ㎎, 1.08 mmol), 화학식 3 (213 ㎎, 1.18 mmol)와 수산화칼륨 (121 ㎎, 2.15 mmol)을 에탄올 (10 ㎖)에 녹이고 실온에서 24시간 동안 교반하였다. 반응이 종결되면 용매를 감압 증류시키고 에틸아세테이트로 추출하고 포화 간수로 한 번 씻어주었다. Na2SO4로 건조시켜 필터 후 에틸아세테이트/헥산 = 1/8 로 실리카겔 컬럼분리하여 노란색 액체인 화학식 4 화합물을 얻었다. Two-neck flask (230 mg, 1.18 mmol) and potassium hydroxide (121 mg, 2.15 mmol) were dissolved in ethanol (10 ml), and the mixture was stirred at room temperature for 24 hours. When the reaction was completed, the solvent was distilled off under reduced pressure, extracted with ethyl acetate, and washed once with saturated sodium chloride. The organic layer was dried over Na 2 SO 4 , filtered, and then subjected to silica gel column separation with ethyl acetate / hexane = 1/8 to obtain a yellow liquid (4).
수율 : 315 ㎎, 74%Yield: 315 mg, 74%
R f = 0.25 (EtOAc/Hexane = 1/6). 1H NMR (300 MHz, CDCl3) 7.69 (1H, d, J = 8.7 Hz), 7.60 (1H, d, J = 15.6 Hz), 7.52 (2H, d, J = 8.4 Hz), 7.39 (1H, d, J = 15.6 Hz), 7.14 (1H, d, J = 2.4 Hz), 7.03 (2H, d, J = 8.4 Hz), 6.67 (1H, dd, J = 8.7, 2.4 Hz), 5.24 (2H, s), 3.85 (3H, s), 3.73 (2H, q, J = 6.9 Hz), 2.63 (1H, s), 1.62 (6H, s), 1.23 (3H, t, J = 6.9 Hz). 13C NMR (75 MHz, CDCl3) 191.1, 162.8, 158.9, 156.0, 141.2, 132.0, 129.7, 128.9, 126.8, 125.7, 116.4, 108.5, 106.7, 93.0, 85.7, 74.7, 73.9, 64.5, 55.5, 29.6, 15.2.
Rf = 0.25 (EtOAc / Hexane = 1/6). 1 H NMR (300 MHz, CDCl 3) 7.69 (1H, d, J = 8.7 Hz), 7.60 (1H, d, J = 15.6 Hz), 7.52 (2H, d, J = 8.4 Hz), 7.39 (1H, d, J = 15.6 Hz), 7.14 (1H, d, J = 2.4 Hz), 7.03 (2H, d, J = 8.4 Hz), 6.67 (1H, dd, J = 8.7, 2.4 Hz), 5.24 (2H, s), 3.85 (3H, s), 3.73 (2H, q, J = 6.9 Hz), 2.63 (1H, s), 1.62 (6H, s), 1.23 (3H, t, J = 6.9 Hz). 13 C NMR (75 MHz, CDCl 3) 191.1, 162.8, 158.9, 156.0, 141.2, 132.0, 129.7, 128.9, 126.8, 125.7, 116.4, 108.5, 106.7, 93.0, 85.7, 74.7, 73.9, 64.5, 55.5, 29.6, 15.2.
<실시예 3: 화학식 4로부터 화학식 5의 합성>≪ Example 3: Synthesis of
Two-neck flask에 화학식 4 (188 ㎎, 0.48 mmol)와 무게비 5%의 Pd-CaCO3 (10 ㎎), 퀴놀린 (2.0 ㎎, 0.02 mmol)을 에탄올 (5 ㎖)에 넣고 수소를 충전한 후 실온에서 5시간 동안 교반시켜주었다. 반응이 끝나면 팔라듐을 메탄올로 씻어 셀라이트 필터 (Celite filter)로 걸러준 후 감압증류 시키고, 에틸아세테이트/헥산 = 1/10 으로 실리카겔 컬럼분리하여 노란색 액체인 화학식 5 화합물을 얻었다. In a two-neck flask, (188 mg, 0.48 mmol), Pd-CaCO 3 (10 mg) and quinoline (2.0 mg, 0.02 mmol) in a weight ratio of 5% were charged in ethanol (5 ml), and the mixture was stirred at room temperature for 5 hours . After the completion of the reaction, the palladium was washed with methanol, filtered through a Celite filter, distilled under reduced pressure, and subjected to silica gel column separation with ethyl acetate / hexane = 1/10 to obtain a yellow liquid (5).
수율 : 107 ㎎, 57%Yield: 107 mg, 57%
R f = 0.29 (EtOAc/Hexane = 1/4). 1H NMR (300 MHz, CDCl3) 7.67 (1H, d, J = 8.1 Hz), 7.61 (1H, d, J = 15.6 Hz), 7.53 (2H, d, J = 8.7 Hz), 7.46 (1H, d, J = 15.6 Hz), 7.03 (2H, d, J = 8.7 Hz), 6.67 (1H, d, J = 2.4 Hz). 6.59 (1H, dd, J = 8.1, 2.4 Hz), 6.14 (1H, dd, J = 17.7, 10.8 Hz), 5.24 (2H, s), 5.19 (1H, d, J = 17.7 Hz), 5.15 (1H, d, J = 10.8 Hz), 3.79 (3H, s), 3.73 (2H, q, J = 6.9 Hz), 1.46 (6H, s), 1.23 (3H, t, J = 6.9 Hz). 13C NMR (75 MHz, CDCl3) 191.4, 162.7, 158.8, 156.8, 143.8, 140.9, 132.0, 129.7, 129.0, 126.5, 125.8, 116.4, 113.9, 107.5, 106.6, 93.0, 81.4, 64.5, 55.4, 27.0, 15.2.
Rf = 0.29 (EtOAc / Hexane = 1/4). 1 H NMR (300 MHz, CDCl 3) 7.67 (1H, d, J = 8.1 Hz), 7.61 (1H, d, J = 15.6 Hz), 7.53 (2H, d, J = 8.7 Hz), 7.46 (1H, d, J = 15.6 Hz), 7.03 ( 2H, d, J = 8.7Hz), 6.67 (1H, d, J = 2.4Hz). 6.59 (1H, dd, J = 8.1, 2.4 Hz), 6.14 (1H, dd, J = 17.7, 10.8 Hz), 5.24 (2H, s), 5.19 (1H, d, J = 17.7 Hz), 5.15 (1H (d, J = 10.8 Hz), 3.79 (3H, s), 3.73 (2H, q, J = 6.9 Hz), 1.46 (6H, s), 1.23 (3H, t, J = 6.9 Hz). 13 C NMR (75 MHz, CDCl 3) 191.4, 162.7, 158.8, 156.8, 143.8, 140.9, 132.0, 129.7, 129.0, 126.5, 125.8, 116.4, 113.9, 107.5, 106.6, 93.0, 81.4, 64.5, 55.4, 27.0, 15.2.
<실시예 4: 화학식 5로부터 화학식 6의 합성>≪ Example 4: Synthesis of
밤 반응기(Bomb reactor)에 화학식 5 (59 ㎎, 0.15 mmol)를 넣고 에탄올/H2O(v/v) = 4/1 혼합용매 4 ㎖를 가하여 70 ℃에서 12시간 동안 물에 의해 촉진되는 [3,3]-시그마결합 재배열반응을 진행하였다. 반응이 끝나면 용매를 감압증류 시키고 에틸아세테이트로 추출 후 Na2SO4로 건조시켜 에틸아세테이트/헥산 = 1/9로 실리카겔 컬럼분리하여 노란색 액체인 화학식 6 화합물을 얻었다.(59 mg, 0.15 mmol) was added to a bomb reactor and 4 mL of a mixed solvent of ethanol / H 2 O (v / v) = 4/1 was added thereto. The mixture was stirred at 70 ° C. for 12 hours, 3,3] -sigma bond rearrangement reaction. After the reaction was completed, the solvent was distilled off under reduced pressure, followed by extraction with ethyl acetate, drying over Na 2 SO 4 and silica gel column separation with ethyl acetate / hexane = 1/9 to obtain a yellow liquid (6).
수율 : 46 ㎎, 78%Yield: 46 mg, 78%
R f = 0.53 (EtOAc/Hexane = 1/4). 1H NMR (300 MHz, CDCl3) 13.47 (1H, s), 7.83 (1H, d, J = 15 Hz), 7.77 (1H, d, J = 8.7 Hz), 7.58 (2H, d, J = 8.7 Hz), 7.47 (1H, d, J = 15 Hz), 7.06 (2H, d, J = 8.7 Hz), 6.48 (1H, d, J = 8.7 Hz), 5.26 (2H, s), 5.22 (1H, br t, J = 6.9 Hz), 3.90 (3H, s), 3.73 (2H, q, J = 6.9 Hz), 3.38 (2H, d, J = 6.9 Hz), 1.80 (3H, br s), 1.68 (3H, br s), 1.23 (3H, t, J = 6.9 Hz). 13C NMR (75 MHz, CDCl3) 192.0, 163.1, 162.9, 159.3, 143.7, 131.7, 130.0, 129.0, 128.5, 122.0, 118.5, 117.5, 116.5, 114.6, 102.0, 92.9, 64.5, 55.8, 25.9, 21.8, 17.9, 15.2.
Rf = 0.53 (EtOAc / Hexane = 1/4). 1 H NMR (300 MHz, CDCl 3) 13.47 (1H, s), 7.83 (1H, d, J = 15 Hz), 7.77 (1H, d, J = 8.7 Hz), 7.58 (2H, d, J = 8.7 Hz), 7.47 (1H, d, J = 15 Hz), 7.06 (2H , d, J = 8.7 Hz), 6.48 (1H, d, J = 8.7 Hz), 5.26 (2H, s), 5.22 (1H, br t, J = 6.9 Hz), 3.90 (3H, s), 3.73 (2H, q, J = 6.9 Hz), 3.38 (2H, d, J = 6.9 Hz), 1.80 t, J = 6.9 Hz). 13 C NMR (75 MHz, CDCl 3) 192.0, 163.1, 162.9, 159.3, 143.7, 131.7, 130.0, 129.0, 128.5, 122.0, 118.5, 117.5, 116.5, 114.6, 102.0, 92.9, 64.5, 55.8, 25.9, 21.8, 17.9, 15.2.
<실시예 5: 화학식 6으로부터 화학식 7의 합성>Example 5: Synthesis of Formula (7) from Formula (6)
Two-neck flask에 화학식 6 (27 ㎎, 0.07 mmol)을 메탄올 (3 ㎖)에 녹여 넣어주고 활성화시킨 DOWEX 수지 50X2 (10 ㎎)를 넣어주고 실온에서 4시간 교반하였다. 반응이 종결되면 수지를 여과한 후 에틸아세테이트/헥산 = 1/3으로 실리카겔 컬럼분리하여 노란색 액체인 화학식 7 화합물을 얻었다.6 (27 mg, 0.07 mmol) was dissolved in methanol (3 mL) and the activated DOWEX resin 50X2 (10 mg) was added to a two-neck flask, followed by stirring at room temperature for 4 hours. When the reaction was completed, the resin was filtered off and the residue was subjected to silica gel column separation with ethyl acetate / hexane = 1/3 to obtain a yellow liquid (7).
수율 : 15 ㎎, 65%Yield: 15 mg, 65%
R f = 0.15 (EtOAc/Hexane = 1/4). 1H NMR (300 MHz, CDCl3) 13.43 (1H, s), 7.80 (1H, d, J = 15.3 Hz), 7.77 (1H, d, J = 8.7 Hz), 7.52 (2H, d, J = 8.7 Hz), 7.44 (1H, d, J = 15.3 Hz), 6.86 (2H, d, J = 8.7 Hz), 6.48 (1H, d, J = 8.7 Hz), 5.90 (1H, br s), 5.22 (1H, br t, J = 7.2 Hz), 3.90 (3H, s), 3.38 (2H, d, J = 7.2 Hz), 1.79 (3H, br s), 1.68 (3H, br s). 13C NMR (75 MHz, CDCl3) 192.2, 163.1, 162.8, 157.9, 143.9, 131.8, 130.4, 129.0, 127.7, 122.0, 118.1, 117.5, 115.9, 114.6, 102.1, 55.8, 25.9, 21.8, 17.9
Rf = 0.15 (EtOAc / Hexane = 1/4). 1 H NMR (300 MHz, CDCl 3) 13.43 (1H, s), 7.80 (1H, d, J = 15.3 Hz), 7.77 (1H, d, J = 8.7 Hz), 7.52 (2H, d, J = 8.7 Hz), 7.44 (1H, d , J = 15.3 Hz), 6.86 (2H, d, J = 8.7 Hz), 6.48 (1H, d, J = 8.7 Hz), 5.90 (1H, br s), 5.22 (1H , br t, J = 7.2 Hz ), 3.90 (3H, s), 3.38 (2H, d, J = 7.2 Hz), 1.79 (3H, br s), 1.68 (3H, br s). 13 C NMR (75 MHz, CDCl 3) 192.2, 163.1, 162.8, 157.9, 143.9, 131.8, 130.4, 129.0, 127.7, 122.0, 118.1, 117.5, 115.9, 114.6, 102.1, 55.8, 25.9, 21.8, 17.9
Claims (3)
(a) 화학식 1로 표시되는 2-하이드록시-4-메톡시아세토페논을 에테르화하여 화학식 2로 표시되는 화합물인 4-메톡시-2-(1,1-다이메틸-2-프로피닐옥시)아세토페논을 생성하는 단계;
(b) 상기 (a) 단계에서 생성된 화학식 2로 표시되는 화합물인 4-메톡시-2-(1,1-다이메틸-2-프로피닐옥시)아세토페논과 화학식 3으로 표시되는 화합물인 4-(에톡시메톡시)벤즈알데하이드의 클라이젠-슈미트 응축반응으로 화학식 4로 표시되는 화합물인 (E)-3-[4-에톡시메톡시페닐]-1-[4-메톡시-2-(1,1-다이메틸-2-프로피닐옥시)] 프로프-2-엔-1-온 {(E)-3-[4-ethoxymethoxyphenyl]-1-[4-methoxy-2-(1,1-dimethyl-2-propynyloxy)] prop-2-en-1-one}을 합성하는 단계;
(c) 상기 (b) 단계에서 합성된 화학식 4로 표시되는 화합물인 (E)-3-[4-에톡시메톡시페닐]-1-[4-메톡시-2-(1,1-다이메틸-2-프로페닐옥시)] 프로프-2-엔-1-온으로부터 린드라 촉매 (Lindlar catalyst)를 이용한 수소화 환원반응으로 화학식 5로 표시되는 화합물인 (E)-3-[4-에톡시메톡시페닐]-1-[4-메톡시-2-(1,1-다이메틸-2-프로페닐옥시)] 프로프-2-엔-1-온 {(E)-3-[4-ethoxymethoxyphenyl]-1-[4-methoxy-2-(1,1-dimethyl-2-propenyloxy)] prop-2-en-1-one}을 합성하는 단계; 및
(d) 상기 (c) 단계에서 합성된 화학식 5로 표시되는 화합물인 (E)-3-[4-에톡시메톡시페닐]-1-[4-메톡시-2-(1,1-다이메틸-2-프로페닐옥시)] 프로프-2-엔-1-온 {(E)-3-[4-ethoxymethoxyphenyl]-1-[4-methoxy-2-(1,1-dimethyl-2-propenyloxy)] prop-2-en-1-one}을 재배열 및 탈보호기화하여 화학식 7로 표시되는 4-하이드록시데리신을 합성하는 방법.
<화학식 1>
<화학식 2>
<화학식 3>
<화학식 4>
<화학식 5>
<화학식 7>
{단, 상기 화학식 3, 화학식 4 및 화학식 5에서 상기 R은 알킬기, 시클로알킬기, 벤질기, 테트라하이드록시피라닐 (tetrahydropyranyl; THP)기, 메톡시메틸 (methoxymethyl; MOM)기, 에톡시메틸 (ethoxymethyl; EOM)기, t-부틸다이메틸실릴 (t-buthyldimethylsilyl; TBDMS)기 또는 트리메틸실릴 (trimethylsilyl; TMS)기이다.}
In the method for synthesizing 4-hydroxyderissin represented by the formula (7) from 2-hydroxy-4-methoxyacetophenone represented by the formula (1)
(a) etherifying 2-hydroxy-4-methoxyacetophenone represented by the formula (1) to obtain 4-methoxy-2- (1,1- ) Producing acetophenone;
(b) 4-methoxy-2- (1,1-dimethyl-2-propynyloxy) acetophenone, a compound represented by the general formula (2) ( E ) -3- [4-ethoxymethoxyphenyl] -1- [4-methoxy-2- (ethoxymethoxy) benzaldehyde, which is a compound represented by the formula 4, by the Clizen- ( E ) -3- [4-ethoxymethoxyphenyl] -1- [4-methoxy-2- (1, 1-dimethyl-2-propynyloxy)] prop-2-en-1-one};
(c) The compound represented by the general formula (4) synthesized in the step (b), ( E ) -3- [4-ethoxymethoxyphenyl] -1- [4-methoxy- Methyl-2-propenyloxy)] prop-2-en-1-one was subjected to a hydrogenation reduction reaction using a Lindlar catalyst to obtain ( E ) -3- [4- Prop-2-en-1-one {( E ) -3- [4- (4-methoxyphenyloxy) -ethoxymethoxyphenyl] -1- [4-methoxy-2- (1,1-dimethyl-2-propenyloxy)] prop-2-en-1-one}; And
(d) Synthesis of ( E ) -3- [4-ethoxymethoxyphenyl] -1- [4-methoxy-2- Methyl-2-propenyloxy)] prop-2-en-1-one {( E ) -3- [4- ethoxymethoxyphenyl] -1- [4- methoxy- 2- propenyloxy)] prop-2-en-1-one} is rearranged and deprotected to synthesize 4-hydroxyderisin represented by the formula (7).
≪ Formula 1 >
(2)
(3)
≪ Formula 4 >
≪ Formula 5 >
≪ Formula 7 >
(Wherein R represents an alkyl group, a cycloalkyl group, a benzyl group, a tetrahydropyranyl (THP) group, a methoxymethyl (MOM) group, an ethoxymethyl ethoxymethyl (EOM) group, t-buthyldimethylsilyl (TBDMS) group or trimethylsilyl (TMS) group.
상기 (d) 단계에서 화학식 5로 표시되는 화합물인 (E)-3-[4-에톡시메톡시페닐]-1-[4-메톡시-2-(1,1-다이메틸-2-프로페닐옥시)] 프로프-2-엔-1-온 {(E)-3-[4-ethoxymethoxyphenyl]-1-[4-methoxy-2-(1,1-dimethyl-2-propenyloxy)] prop-2-en-1-one}의 재배열은 물을 첨가한 혼합용매 시스템 (에탄올/물)에서 물에 의해 촉진되는 [3,3]-시그마결합 재배열 반응임을 특징으로 하는 4-하이드록시데리신 합성방법.
The method according to claim 1,
( E ) -3- [4-ethoxymethoxyphenyl] -1- [4-methoxy-2- (1,1- Phenyloxy)] prop-2-en-1-one {( E ) -3- [4-ethoxymethoxyphenyl] -1- [4- methoxy- 2- (1,1- 2-en-1-one} is a [3,3] -sigma bond rearrangement reaction promoted by water in a mixed solvent system (ethanol / water) New synthesis method.
상기 물을 첨가한 혼합용매는 에탄올/물 = 4/1 (v/v) 비율인 것임을 특징으로 하는 4-하이드록시데리신 합성방법.
The method of claim 2,
Wherein the water-added mixed solvent has a ratio of ethanol / water = 4/1 (v / v).
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