KR102389570B1 - Synthesis method of nectandrin - Google Patents
Synthesis method of nectandrin Download PDFInfo
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- KR102389570B1 KR102389570B1 KR1020200126574A KR20200126574A KR102389570B1 KR 102389570 B1 KR102389570 B1 KR 102389570B1 KR 1020200126574 A KR1020200126574 A KR 1020200126574A KR 20200126574 A KR20200126574 A KR 20200126574A KR 102389570 B1 KR102389570 B1 KR 102389570B1
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- 238000001308 synthesis method Methods 0.000 title abstract 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 47
- 238000000034 method Methods 0.000 claims abstract description 36
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 29
- 238000006243 chemical reaction Methods 0.000 claims description 20
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 claims description 13
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 claims description 12
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- 125000003172 aldehyde group Chemical group 0.000 claims description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 7
- DCFKHNIGBAHNSS-UHFFFAOYSA-N chloro(triethyl)silane Chemical compound CC[Si](Cl)(CC)CC DCFKHNIGBAHNSS-UHFFFAOYSA-N 0.000 claims description 6
- KQIADDMXRMTWHZ-UHFFFAOYSA-N chloro-tri(propan-2-yl)silane Chemical compound CC(C)[Si](Cl)(C(C)C)C(C)C KQIADDMXRMTWHZ-UHFFFAOYSA-N 0.000 claims description 6
- FRIJBUGBVQZNTB-UHFFFAOYSA-M magnesium;ethane;bromide Chemical compound [Mg+2].[Br-].[CH2-]C FRIJBUGBVQZNTB-UHFFFAOYSA-M 0.000 claims description 6
- 230000001590 oxidative effect Effects 0.000 claims description 6
- 239000002841 Lewis acid Substances 0.000 claims description 5
- 229910010082 LiAlH Inorganic materials 0.000 claims description 5
- 239000003153 chemical reaction reagent Substances 0.000 claims description 5
- 150000007517 lewis acids Chemical class 0.000 claims description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- YCCXQARVHOPWFJ-UHFFFAOYSA-M magnesium;ethane;chloride Chemical compound [Mg+2].[Cl-].[CH2-]C YCCXQARVHOPWFJ-UHFFFAOYSA-M 0.000 claims description 4
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 claims description 4
- 230000000379 polymerizing effect Effects 0.000 claims description 4
- 239000012027 Collins reagent Substances 0.000 claims description 3
- ACTAPAGNZPZLEF-UHFFFAOYSA-N chloro(tripropyl)silane Chemical compound CCC[Si](Cl)(CCC)CCC ACTAPAGNZPZLEF-UHFFFAOYSA-N 0.000 claims description 3
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 claims description 3
- 230000018044 dehydration Effects 0.000 claims description 3
- 238000006297 dehydration reaction Methods 0.000 claims description 3
- QBZXOWQOWPHHRA-UHFFFAOYSA-N lithium;ethane Chemical compound [Li+].[CH2-]C QBZXOWQOWPHHRA-UHFFFAOYSA-N 0.000 claims description 3
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 claims description 3
- NPRDHMWYZHSAHR-UHFFFAOYSA-N pyridine;trioxochromium Chemical compound O=[Cr](=O)=O.C1=CC=NC=C1.C1=CC=NC=C1 NPRDHMWYZHSAHR-UHFFFAOYSA-N 0.000 claims description 3
- MNWBNISUBARLIT-UHFFFAOYSA-N sodium cyanide Chemical compound [Na+].N#[C-] MNWBNISUBARLIT-UHFFFAOYSA-N 0.000 claims description 3
- MHYGQXWCZAYSLJ-UHFFFAOYSA-N tert-butyl-chloro-diphenylsilane Chemical compound C=1C=CC=CC=1[Si](Cl)(C(C)(C)C)C1=CC=CC=C1 MHYGQXWCZAYSLJ-UHFFFAOYSA-N 0.000 claims description 3
- 238000007254 oxidation reaction Methods 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 3
- KOPOQZFJUQMUML-UHFFFAOYSA-N chlorosilane Chemical compound Cl[SiH3] KOPOQZFJUQMUML-UHFFFAOYSA-N 0.000 claims 1
- 238000006722 reduction reaction Methods 0.000 claims 1
- 241000498779 Myristica Species 0.000 abstract description 5
- 235000009421 Myristica fragrans Nutrition 0.000 abstract description 5
- 239000001702 nutmeg Substances 0.000 abstract description 5
- 238000000605 extraction Methods 0.000 abstract description 3
- 230000002194 synthesizing effect Effects 0.000 abstract description 3
- 239000006227 byproduct Substances 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 45
- 239000000047 product Substances 0.000 description 29
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 23
- 238000003786 synthesis reaction Methods 0.000 description 11
- 230000015572 biosynthetic process Effects 0.000 description 9
- -1 triethylsilyl Chemical group 0.000 description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 7
- 239000012267 brine Substances 0.000 description 7
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 239000012043 crude product Substances 0.000 description 6
- 239000011259 mixed solution Substances 0.000 description 6
- 239000012044 organic layer Substances 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 239000012230 colorless oil Substances 0.000 description 4
- 238000007363 ring formation reaction Methods 0.000 description 4
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 238000006116 polymerization reaction Methods 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- KSHJDJYDVMQLCK-UHFFFAOYSA-N 1-[4-[tert-butyl(dimethyl)silyl]oxy-3-methoxyphenyl]propan-1-ol Chemical compound CCC(O)C1=CC=C(O[Si](C)(C)C(C)(C)C)C(OC)=C1 KSHJDJYDVMQLCK-UHFFFAOYSA-N 0.000 description 2
- CUQJRZAVTBUOLI-UHFFFAOYSA-N 1-[4-[tert-butyl(dimethyl)silyl]oxy-3-methoxyphenyl]propan-1-one Chemical compound CCC(=O)C1=CC=C(O[Si](C)(C)C(C)(C)C)C(OC)=C1 CUQJRZAVTBUOLI-UHFFFAOYSA-N 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- UBTYFBWZRXUZFF-UHFFFAOYSA-N 4-[tert-butyl(dimethyl)silyl]oxy-3-methoxybenzaldehyde Chemical compound COC1=CC(C=O)=CC=C1O[Si](C)(C)C(C)(C)C UBTYFBWZRXUZFF-UHFFFAOYSA-N 0.000 description 2
- SLQRXDKTUPUDOP-SZPZYZBQSA-N C[C@H]([C@H](C)C(C(C=C1)=CC(OC)=C1O[Si](C)(C)C(C)(C)C)=O)C(C(C=C1)=CC(OC)=C1O[Si](C)(C)C(C)(C)C)=O Chemical compound C[C@H]([C@H](C)C(C(C=C1)=CC(OC)=C1O[Si](C)(C)C(C)(C)C)=O)C(C(C=C1)=CC(OC)=C1O[Si](C)(C)C(C)(C)C)=O SLQRXDKTUPUDOP-SZPZYZBQSA-N 0.000 description 2
- HUDVIPZHIPEVQZ-CFZTZQJTSA-N C[C@H]([C@H](C)[C@@H](C(C=C1)=CC(OC)=C1O[Si](C)(C)C(C)(C)C)O)C(C(C=C1)=CC(OC)=C1O[Si](C)(C)C(C)(C)C)O Chemical compound C[C@H]([C@H](C)[C@@H](C(C=C1)=CC(OC)=C1O[Si](C)(C)C(C)(C)C)O)C(C(C=C1)=CC(OC)=C1O[Si](C)(C)C(C)(C)C)O HUDVIPZHIPEVQZ-CFZTZQJTSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 238000010511 deprotection reaction Methods 0.000 description 2
- NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- BNWJOHGLIBDBOB-UHFFFAOYSA-N myristicin Chemical compound COC1=CC(CC=C)=CC2=C1OCO2 BNWJOHGLIBDBOB-UHFFFAOYSA-N 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 2
- CUGPIXZSVKEBRY-UHFFFAOYSA-N CC(C(C)C(C(C=CC=C1OC)=C1O[Si](C)(C)C(C)(C)C)=O)C=O Chemical compound CC(C(C)C(C(C=CC=C1OC)=C1O[Si](C)(C)C(C)(C)C)=O)C=O CUGPIXZSVKEBRY-UHFFFAOYSA-N 0.000 description 1
- 238000006646 Dess-Martin oxidation reaction Methods 0.000 description 1
- BPLQKQKXWHCZSS-UHFFFAOYSA-N Elemicin Chemical compound COC1=CC(CC=C)=CC(OC)=C1OC BPLQKQKXWHCZSS-UHFFFAOYSA-N 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
- NBBJYMSMWIIQGU-UHFFFAOYSA-N Propionic aldehyde Chemical compound CCC=O NBBJYMSMWIIQGU-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 150000003935 benzaldehydes Chemical class 0.000 description 1
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzenecarboxaldehyde Natural products O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 1
- 230000000711 cancerogenic effect Effects 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- YGHUUVGIRWMJGE-UHFFFAOYSA-N chlorodimethylsilane Chemical compound C[SiH](C)Cl YGHUUVGIRWMJGE-UHFFFAOYSA-N 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 229940043279 diisopropylamine Drugs 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000004817 gas chromatography Methods 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 230000003400 hallucinatory effect Effects 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hcl hcl Chemical compound Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 1
- 239000012038 nucleophile Substances 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 150000003333 secondary alcohols Chemical class 0.000 description 1
- 229910052709 silver Inorganic materials 0.000 description 1
- 239000004332 silver Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 1
- DKZBBWMURDFHNE-UHFFFAOYSA-N trans-coniferylaldehyde Natural products COC1=CC(C=CC=O)=CC=C1O DKZBBWMURDFHNE-UHFFFAOYSA-N 0.000 description 1
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- MWOOGOJBHIARFG-UHFFFAOYSA-N vanillin Chemical compound COC1=CC(C=O)=CC=C1O MWOOGOJBHIARFG-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D307/10—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D307/12—Radicals substituted by oxygen atoms
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
Abstract
본 발명은 넥탄드린 화합물의 합성 방법에 관한 것으로, 기존에는 합성이 아닌 육두구로부터 넥탄드린 화합물을 추출하는 방법을 사용하여 단일한 순수 화합물로 획득하기 어렵고 추출 과정에서 유해한 부산물이 추출되는 문제가 있었으나, 본 발명에 의한 합성 방법으로는 넥탄드린 화합물만을 합성할 수 있다는 장점이 있다. The present invention relates to a method for synthesizing a nectandrine compound. In the past, it was difficult to obtain a single pure compound using a method of extracting a nectandrine compound from nutmeg, not synthetic, and there was a problem that harmful by-products were extracted during the extraction process. The synthesis method according to the present invention has the advantage that only the nectandrine compound can be synthesized.
Description
본 발명은 넥탄드린의 합성 방법에 관한 것이다. The present invention relates to a method for the synthesis of nectandrine.
넥탄드린 B 화합물은 육두구로부터 에탄올 수용액 추출로 얻을 수 있는 화합물로서 다양한 생리활성을 나타낼 수 있다. 기존에는 일반적으로 육두구로부터 유기용매를 사용하여 넥탄드린 B 화합물을 추출하는 방법을 사용하고 있다.The nectandrine B compound is a compound that can be obtained by extracting an aqueous ethanol solution from nutmeg and may exhibit various physiological activities. Conventionally, in general, a method of extracting the nectandrine B compound from nutmeg using an organic solvent is used.
다만, 이 때에 육두구 내에 존재하며 환각효과 및 발암효과를 보이는 것으로 알려진 엘레미신(elemicine), 미리스티신(myristicin) 등의 물질이 함께 추출되어 상기 육두구로부터 추출하는 방법으로는 넥탄드린B 화합물을 단일 순수 화합물로 얻기 어려운 상황이다.However, at this time, substances such as elemicine and myristicin, which are present in nutmeg and which are known to have hallucinogenic and carcinogenic effects, are extracted together, and the nectandrine B compound is extracted from the nutmeg as a single method. It is difficult to obtain as a pure compound.
본 발명은 넥탄드린의 합성 방법을 제공하는 것을 목적으로 한다.An object of the present invention is to provide a method for synthesizing nectandrine.
1. 화학식 1로 표시되는 화합물에서 히드록시기를 보호화하는 제1 단계; 상기 제1 단계의 생성물의 알데히드기에 에틸기를 첨가하는 제2 단계; 상기 제2 단계의 생성물의 히드록시기를 산화시키는 제3 단계; 상기 제3 단계의 생성물을 2당량 중합하는 제4 단계; 상기 제4 단계의 생성물의 카보닐기를 환원시키는 제5 단계; 상기 제5 단계의 생성물을 탈수시켜 고리화하는 제6 단계; 및 상기 제6 단계의 생성물의 히드록시기를 탈보호화하는 제7 단계;를 포함하는 화학식 2로 표시되는 화합물의 제조 방법:1. A first step of protecting a hydroxyl group in the compound represented by Formula 1; a second step of adding an ethyl group to the aldehyde group of the product of the first step; a third step of oxidizing the hydroxyl group of the product of the second step; a fourth step of polymerizing 2 equivalents of the product of the third step; a fifth step of reducing the carbonyl group of the product of the fourth step; a sixth step of cyclizing the product of the fifth step by dehydration; and a seventh step of deprotecting the hydroxyl group of the product of the sixth step;
[화학식 1] [Formula 1]
[화학식 2][Formula 2]
2. 위 1에 있어서, 상기 제1 단계에서 보호화는 화학식 1로 표시되는 화합물을 트리메틸실릴 클로라이드, 트리에틸실릴 클로라이드, 트리-n-프로필실릴 클로라이드, 트리-iso-프로필 실릴 클로라이드, t-부틸다이메틸실릴 클로라이드, 토실클로라이드 또는 t-부틸다이페닐실릴 클로라이드와 반응시켜 수행되는 것인, 화학식 2로 표시되는 화합물의 제조 방법.2. The method of 1 above, wherein the protection in the first step is performed by converting the compound represented by
3. 위 1에 있어서, 상기 제2 단계에서 상기 에틸기의 첨가는 제1 단계의 생성물을 EtLi, EtMgCl, EtMgBr 또는 EtMgI와 반응시켜 수행되는 것인, 화학식 2로 표시되는 화합물의 제조 방법.3. The method according to the above 1, wherein the addition of the ethyl group in the second step is performed by reacting the product of the first step with EtLi, EtMgCl, EtMgBr or EtMgI, the method for preparing a compound represented by
4. 위 1에 있어서, 상기 제3 단계는 Na2Cr2O7, K2Cr2O7, CrO3, H2SO4, H2CrO4, Collins 시약, PCC, Dess-Maritin 시약 또는 KMnO4/Ag2O 존재 하에 수행되는 것인, 화학식 2로 표시되는 화합물의 제조 방법.4. The above 1, wherein the third step is Na 2 Cr 2 O 7 , K 2 Cr 2 O 7 , CrO 3 , H 2 SO 4 , H 2 CrO 4 , Collins reagent, PCC, Dess-Maritin reagent or KMnO 4 /Ag 2 O A method for preparing a compound represented by
5. 위 1에 있어서, 상기 제4 단계는 루이스 산의 존재 하에 수행되는 것인, 화학식 2로 표시되는 화합물의 제조 방법.5. The method according to 1 above, wherein the fourth step is carried out in the presence of a Lewis acid, a method for preparing a compound represented by formula (2).
6. 위 5에 있어서, 상기 루이스 산은 Cu(OTf)2 또는 Cu(OAc)2인, 화학식 2로 표시되는 화합물의 제조 방법.6. The method of 5 above, wherein the Lewis acid is Cu(OTf) 2 or Cu(OAc) 2 .
7. 위 1에 있어서, 상기 제5 단계는 LiAlH4 또는 NaBH4 첨가 하에 수행되는 것인, 화학식 2로 표시되는 화합물의 제조 방법.7. The method of 1 above, wherein the fifth step is carried out under the addition of LiAlH 4 or NaBH 4 , the method for preparing a compound represented by Formula 2
8. 위 1에 있어서, 상기 제6 단계는 MsCl 또는 TsCl 첨가 하에 5각 고리가 형성되는 것인, 화학식 2로 표시되는 화합물의 제조 방법.8. The method for preparing a compound represented by Formula 2 according to the above 1, wherein in the sixth step, a five-membered ring is formed under the addition of MsCl or TsCl.
9. 위 1에 있어서, 상기 제7 단계는 TBAF(tetrabutylammonium fluoride), 염산, 아세트산, NaCN 또는 KCN 첨가 하에 히드록시기가 탈보호화되는 것인, 화학식 2로 표시되는 화합물의 제조 방법.9. The method of 1 above, wherein in the seventh step, the hydroxyl group is deprotected by the addition of tetrabutylammonium fluoride (TBAF), hydrochloric acid, acetic acid, NaCN or KCN.
본 발명은 특정의 유기 합성 반응 경로를 통해 불순물이 포함되지 않은 단일 순수한 넥탄드린 화합물을 제조하고, 합성 과정에서 넥탄드린 화합물의 입체 이성질체 화합물도 함께 합성할 수 있는 방법으로, 벤즈알데히드의 기본 골격을 유지하면서 다양한 치환기가 도입된 출발물질을 사용하여 넥탄드린 B 화합물 유도체를 쉽게 합성할 수 있다. The present invention is a method that can prepare a single pure nectandrine compound without impurities through a specific organic synthesis reaction route and also synthesize a stereoisomeric compound of the nectandrine compound during the synthesis process, maintaining the basic skeleton of benzaldehyde It is possible to easily synthesize nectandrine B compound derivatives using starting materials in which various substituents are introduced.
도 1은 본 발명의 실시예에서 넥탄드린 B 화합물을 합성한 방법을 대략적으로 나타낸 도이다.
도 2는 넥탄드린 B의 1H NMR 결과를 나타낸 것이다.
도 3은 넥탄드린 B의 13C NMR 결과를 나타낸 것이다.
도 4는 넥탄드린 B의 GC-MASS 결과를 나타낸 것으로, 도 4a는 가스크로마토그래피 분석 결과이며, 도 4b는 질량분석 분석 결과를 나타낸 것으로, 넥탄드린 B를 확인한 것이다. 1 is a diagram schematically showing a method for synthesizing a nectandrine B compound in an embodiment of the present invention.
Figure 2 shows the 1H NMR result of nectandrine B.
Figure 3 shows the 13C NMR result of nectandrine B.
4 shows the GC-MASS results of nectandrine B, FIG. 4a shows the gas chromatography analysis results, and FIG. 4b shows the mass spectrometry analysis results, confirming nectandrine B.
이하 본 발명을 상세히 설명한다.Hereinafter, the present invention will be described in detail.
본 발명에서 사용되는 모든 기술용어는, 달리 정의되지 않는 이상, 본 발명의 관련 분야에서 통상의 당업자가 일반적으로 이해하는 바와 같은 의미로 사용된다. 또한, 본 명세서에는 바람직한 방법이나 시료가 기재되나, 이와 유사하거나 동등한 것들도 본 발명의 범주에 포함된다.All technical terms used in the present invention, unless otherwise defined, have the meanings commonly understood by one of ordinary skill in the art of the present invention. In addition, although preferred methods and samples are described herein, similar or equivalent ones are also included in the scope of the present invention.
본 발명은 화학식 1로 표시되는 화합물에서 히드록시기를 보호화하는 제1 단계; 상기 제1 단계의 생성물의 알데히드기에 에틸기를 첨가하는 제2 단계; 상기 제2 단계의 생성물의 히드록시기를 산화시키는 제3 단계; 상기 제3 단계의 생성물을 2당량 중합하는 제4 단계; 상기 제4 단계의 생성물의 카보닐기를 환원시키는 제5 단계; 상기 제5 단계의 생성물을 탈수시켜 고리화하는 제6 단계; 및 상기 제6 단계의 생성물의 히드록시기를 탈보호화하는 제7 단계;를 포함하는 화학식 2로 표시되는 화합물의 제조 방법에 관한 것이다. The present invention provides a first step of protecting a hydroxyl group in a compound represented by Formula 1; a second step of adding an ethyl group to the aldehyde group of the product of the first step; a third step of oxidizing a hydroxyl group of the product of the second step; a fourth step of polymerizing 2 equivalents of the product of the third step; a fifth step of reducing the carbonyl group of the product of the fourth step; a sixth step of cyclizing the product of the fifth step by dehydration; and a seventh step of deprotecting the hydroxyl group of the product of the sixth step;
[화학식 1][Formula 1]
[화학식 2][Formula 2]
상기 1단계에서 히드록시기 보호화는 히드록시기가 2 내지 6단계에서 반응에 참여하지 않도록 하기 위함이며, 일반적인 히드록시기 또는 산소 보호기가 모두 사용될 수 있으며, 구체적으로 상기 보호화는 화학식 1의 화합물을 트리메틸실릴 클로라이드, 트리에틸실릴 클로라이드, 트리-n-프로필실릴 클로라이드, 트리-iso-프로필 실릴 클로라이드, t-부틸다이메틸실릴 클로라이드, 토실클로라이드 또는 t-부틸다이페닐실릴 클로라이드와 반응시켜 수행될 수 있으며, 더 구체적으로는 t-부틸디메틸실릴 클로라이드와 반응시켜 수행될 수 있다. The hydroxyl group protection in
상기 제1 단계에서 보호화는 히드록시기에서만 일어나고, 알콕시기 또는 알데히드기의 산소에서는 일어나지 않을 수 있다.In the first step, protection may occur only in the hydroxyl group, and may not occur in the oxygen of the alkoxy group or the aldehyde group.
상기 제1 단계의 보호화에 의해 하기 화학식 3의 화합물이 생성될 수 있다.By the protection in the first step, a compound of Formula 3 may be produced.
[화학식 3][Formula 3]
(식 중, R1은 트리메틸실릴, 트리에틸실릴, 트리-n-프로필실릴, 트리-iso-프로필실릴, t-부틸다이메틸실릴, 토실 또는 t-부틸다이페닐실릴기임).(Wherein, R 1 is a trimethylsilyl, triethylsilyl, tri-n-propylsilyl, tri-iso-propylsilyl, t-butyldimethylsilyl, tosyl or t-butyldiphenylsilyl group).
상기 제2 단계는 제1 단계의 생성물의 알데히드기에 에틸기를 첨가하는 단계이며, 일반적으로 알데히드기에 에틸기를 첨가하는 방법이라면 모두 가능하고, 구체적으로 EtLi, EtMgCl, EtMgBr 또는 EtMgI 첨가에 의할 수 있고, 더 구체적으로는 EtMgCl, EtMgBr 또는 EtMgI 첨가에 의할 수 있고, 가장 구체적으로는 EtMgBr 첨가에 의할 수 있으나, 이에 제한되는 것은 아니다.The second step is a step of adding an ethyl group to the aldehyde group of the product of the first step, and in general, any method of adding an ethyl group to the aldehyde group is possible. Specifically, EtLi, EtMgCl, EtMgBr or EtMgI can be added by addition, More specifically, it may be by addition of EtMgCl, EtMgBr or EtMgI, and most specifically, it may be by addition of EtMgBr, but is not limited thereto.
상기 제2 단계 반응에 의해 알데히드기는 히드록시기로 환원될 수 있으며, 구체적으로 상기 히드록시기를 포함하는 화합물은 2차 알코올에 해당할 수 있다.The aldehyde group may be reduced to a hydroxyl group by the second step reaction, and specifically, the compound including the hydroxyl group may correspond to a secondary alcohol.
제2 단계의 반응에 의해 하기 화학식 4로 표시되는 화합물이 생성될 수 있다.A compound represented by the following formula (4) may be produced by the reaction of the second step.
[화학식 4][Formula 4]
(상기 R1은 화학식 3의 R1과 같음).(The R 1 is the same as R 1 of Formula 3).
상기 제3 단계는 상기 제2 단계의 생성물의 히드록시기를 산화시키는 단계로, 히드록시기가 카보닐기로 산화되는 단계를 포함하며, 상기 산화는 일반적으로 히드록시기를 카보닐기로 산화시키는 반응에 의할 수 있고, 구체적으로 Na2Cr2O7, K2Cr2O7, CrO3, H2SO4, H2CrO4, Collins 시약, PCC, Dess-Maritin 시약 또는 KMnO4/Ag2O 등에 의할 수 있고, 더 구체적으로 Dess-Martin 시약에 의할 수 있으나, 이에 제한되는 것은 아니다. The third step is a step of oxidizing the hydroxyl group of the product of the second step, and includes a step of oxidizing the hydroxyl group to a carbonyl group, and the oxidation is generally performed by a reaction of oxidizing the hydroxyl group to a carbonyl group, Specifically, Na 2 Cr 2 O 7 , K 2 Cr 2 O 7 , CrO 3 , H 2 SO 4 , H 2 CrO 4 , Collins reagent, PCC, Dess-Maritin reagent, or KMnO 4 /Ag 2 O and the like. , More specifically, it may be by the Dess-Martin reagent, but is not limited thereto.
제3 단계의 반응에 의해 화학식 5의 화합물이 생성될 수 있다.A compound of Formula 5 may be produced by the reaction of the third step.
[화학식 5][Formula 5]
(상기 R1은 화학식 3의 R1과 같음).(The R 1 is the same as R 1 of Formula 3).
상기 제4 단계는 제3 단계의 생성물을 2당량 중합하는 단계로, 각 화합물의 알파탄소 자리에서 중합 반응이 진행될 수 있다. 상기 알파탄소는 카보닐기의 바로 옆자리 탄소를 지칭한다.The fourth step is a step of polymerizing 2 equivalents of the product of the third step, and the polymerization reaction may proceed at the alpha carbon site of each compound. The alpha carbon refers to the carbon immediately adjacent to the carbonyl group.
또한, 상기 중합은 루이스산 존재 하에 진행될 수 있고, 구체적으로 Cu(OTf)2 또는 Cu(OAc)2 첨가 하에 진행될 수 있으나, 이에 제한되는 것은 아니다. In addition, the polymerization may be carried out in the presence of a Lewis acid, specifically, Cu(OTf) 2 or Cu(OAc) 2 may be carried out under addition, but is not limited thereto.
상기 제4 단계의 생성물은 화학식 6으로 표시되는 화합물을 의미하고, (R, R) 또는 (R, S)의 두 가지 입체 이성질체로 얻어질 수 있다.The product of the fourth step refers to a compound represented by Formula 6, and may be obtained as two stereoisomers of (R, R) or (R, S).
[화학식 6][Formula 6]
(상기 R1은 화학식 3의 R1과 같고, 별(*)표시된 탄소는 입체중심을 나타낸 것임).(The R 1 is the same as R 1 in Formula 3, and the star (*) represents a stereocenter).
또한, 상기 제4 단계의 생성물은 반응 단계에서 카보닐기가 반응에 참여하지 않으므로 중합에 의해 화합물 당 2개의 카보닐기가 유지된다.In addition, in the product of the fourth step, since the carbonyl group does not participate in the reaction in the reaction step, two carbonyl groups are maintained per compound by polymerization.
상기 제5 단계는 상기 제4 단계의 생성물의 카보닐기를 히드록시기로 환원시키는 단계로, 제4 단계의 생성물이 포함하는 2개의 카보닐기가 모두 히드록시기로 환원될 때까지 반응을 진행시킨다. 상기 2개의 카보닐기는 동시에 환원될 수 있고, 1개씩 차례로 환원될 수 있으나, 이에 제한되는 것은 아니다. 상기 제5 단계에 의해 화학식 7로 표시되는 화합물이 생성될 수 있다. The fifth step is a step of reducing the carbonyl group of the product of the fourth step to a hydroxyl group, and the reaction proceeds until both carbonyl groups included in the fourth step product are reduced to a hydroxyl group. The two carbonyl groups may be reduced simultaneously and may be reduced one by one in turn, but is not limited thereto. The compound represented by
[화학식 7][Formula 7]
(상기 R1은 화학식 3의 R1과 같음).(The R 1 is the same as R 1 of Formula 3).
상기 제5 단계는 일반적으로 카보닐기를 히드록시기로 환원시키는 방법이라면 모두 가능하고, 구체적으로 LiAlH4, NaBH4 또는 H2/Ni 첨가 하에 수행될 수 있고, 더 구체적으로 LiAlH4 또는 NaBH4 첨가 하에 수행될 수 있으나, 이에 제한되는 것은 아니다.In general, the fifth step can be any method of reducing a carbonyl group to a hydroxy group, specifically LiAlH 4 , NaBH 4 or H 2 /Ni can be added, and more specifically, LiAlH 4 or NaBH 4 is added. may be, but is not limited thereto.
상기 제6 단계는 두 벤젠고리 사이의 히드록시기에서 친핵체의 첨가에 의해 Sn2 반응이 일어나 5각 고리가 형성되는 고리화 반응을 포함하는 단계로, 상기 제6 단계에 의해 화학식 8로 표시되는 화합물이 생성될 수 있다. The sixth step includes a cyclization reaction in which a pentacyclic ring is formed by Sn2 reaction by the addition of a nucleophile in the hydroxyl group between the two benzene rings, and the compound represented by
[화학식 8][Formula 8]
(상기 R1은 화학식 3의 R1과 같고, 별(*)표시된 탄소는 입체중심을 나타낸 것임).(The R 1 is the same as R 1 in
상기 제 6단계는 일반적인 Sn2 반응에 의해 히드록시기가 이탈될 수 있는 형태로 바뀌고, 이후 다른 하나의 히드록시기에 의한 Sn2 반응에 의해 이탈되며 5각 고리를 형성하는 반응을 포함하는 단계로서, 상기 고리화 반응은 히드록시기가 이탈될 수 있는 형태로 바뀔 수 있는 시약의 첨가에 의해 수행될 수 있고, 구체적으로는 MsCl 또는 TsCl 첨가에 의해 수행될 수 있으나, 이에 제한되는 것은 아니다.The sixth step is a step including a reaction in which a hydroxyl group is changed into a form from which a hydroxyl group can be released by a general Sn2 reaction, and then is released by a Sn2 reaction by another hydroxyl group to form a pentagonal ring, the cyclization reaction Silver may be carried out by addition of a reagent that can be changed into a form from which a hydroxyl group can be released, and specifically, it may be carried out by addition of MsCl or TsCl, but is not limited thereto.
상기 고리화 반응에 의해 예를 들어, MsOH 또는 TsOH가 생성될 수 있으나, 이에 제한되는 것은 아니다. For example, MsOH or TsOH may be produced by the cyclization reaction, but is not limited thereto.
상기 제6 단계의 생성물은 고리화에 따라 (2S,3R,4S,5S) 또는 (2R,3R,4S,5S)의 입체이성질체를 가질 수 있으나, 이에 제한되는 것은 아니다.The product of the sixth step may have a stereoisomer of (2S,3R,4S,5S) or (2R,3R,4S,5S) depending on cyclization, but is not limited thereto.
상기 제7 단계는 상기 제1 단계에서 보호화된 히드록시기를 탈보호화하는 단계로, 일반적으로 탈보호화에 쓰이는 방법이라면 모두 가능하고, 구체적으로 TBAF(tetrabutylammonium fluoride) 등의 할로겐화물이나, 염산(HCl) 또는 아세트산 등의 산 또는 NaCN 또는 KCN 등의 염기 첨가에 의해 수행될 수 있고, 더 구체적으로는 TBAF에 의해 수행될 수 있으나, 이에 제한되는 것은 아니다. 상기 탈보호화는 2개의 보호화된 치환기가 동시에 탈보호될 수 있고, 1개씩 차례로 탈보호화될 수 있으나, 순서에 제한되는 것은 아니다. 보호기의 사용은 "Protective Groups in Organic Synthesis" 3rd edition, T.W. Greene & P.G.M. Wutz, Wiley-Interscience (1999)에 상세히 기술되어 있다.The seventh step is a step of deprotecting the hydroxyl group protected in the first step. In general, any method used for deprotection is possible, and specifically, a halide such as tetrabutylammonium fluoride (TBAF) or hydrochloric acid (HCl) Alternatively, it may be performed by addition of an acid such as acetic acid or a base such as NaCN or KCN, and more specifically, TBAF may be performed, but is not limited thereto. In the deprotection, two protected substituents may be deprotected simultaneously, and may be deprotected one by one in turn, but the order is not limited. The use of protecting groups is described in "Protective Groups in Organic Synthesis" 3rd edition, T.W. Greene & P.G.M. It is described in detail in Wutz, Wiley-Interscience (1999).
상기 제7 단계의 생성물 화학식 2로 표시되는 화합물을 의미하며, 구체적으로 (2S,3R,4S,5S) 또는 (2R,3R,4S,5S)의 입체이성질체를 가질 수 있고, (2R,3R,4S,5S)의 입체이성질체를 갖는 화합물이 넥탄드린 B 화합물에 해당한다.The product of the seventh step refers to a compound represented by
이하, 본 발명을 구체적으로 설명하기 위해 실시예를 들어 상세하게 설명하기로 한다.Hereinafter, in order to describe the present invention in detail, examples will be described in detail.
실시예. 화합물의 제조Example. Preparation of compounds
1단계: 4-((tert-부틸디메틸실릴)옥시)-3-메톡시벤즈알데히드의 합성Step 1: Synthesis of 4-((tert-butyldimethylsilyl)oxy)-3-methoxybenzaldehyde
THF(5 mL)와 4-히드록시-3-메톡시벤즈알데히드(1.5g, 9.9mmol, 1당량) 및 이미다졸(1.0g, 14.8mmol, 1.5당량)의 혼합용액에 t-BuMe2SiCl(TBSCl)(1.78g, 11.8mmol, 1.2당량)을 첨가하여, 생성물을 상온에서 밤새도록 교반시켰다. 물(30mL)을 첨가하여 반응을 종결하고, 에틸아세테이트(30mL x3)로 추출했다. 혼합된 유기층은 브라인으로 세척하고 무수화물 MgS04로 건조시킨 후, 여과하고 진공 상태에서 농축하였다. 정제되지 않은 생성물은 헥산에 에틸아세테이트를 넣은 용액(농도 0 부피% 내지 30 부피%)의 플래시 칼럼에 의해 정제되어, 무색 오일 상태의 4-((tert-부틸디메틸실릴)옥시)-3-메톡시벤즈알데히드(2.34g, 89%)를 얻었다. In a mixed solution of THF (5 mL), 4-hydroxy-3-methoxybenzaldehyde (1.5 g, 9.9 mmol, 1 equiv) and imidazole (1.0 g, 14.8 mmol, 1.5 equiv), t-BuMe 2 SiCl (TBSCl) ) (1.78 g, 11.8 mmol, 1.2 eq) was added and the product was stirred at room temperature overnight. The reaction was terminated by adding water (30 mL), followed by extraction with ethyl acetate (30 mL x 3). The combined organic layer was washed with brine, dried over anhydrous MgSO 4 , filtered and concentrated in vacuo. The crude product was purified by flash column of a solution of ethyl acetate in hexane (concentration: 0% by volume to 30% by volume), and 4-((tert-butyldimethylsilyl)oxy)-3-methyl as a colorless oil Toxibenzaldehyde (2.34 g, 89%) was obtained.
2단계:1-(4-((tert-부틸디메틸실릴)옥시)-3-메톡시페닐)프로판-1-올의 합성Step 2: Synthesis of 1-(4-((tert-butyldimethylsilyl)oxy)-3-methoxyphenyl)propan-1-ol
4-((tert-부틸디메틸실릴)옥시)-3-메톡시벤즈알데히드(2.34g, 8.75mmol, 1당량)와 THF(10ml)의 혼합용액을 에틸마그네슘 브로마이드(9.6 mL, 9.62 mmol, 1.1당량, THF 에서 1M농도)에 질소 조건, 0℃에서 한 방울씩 떨어트리고, 생성물을 0℃에서 1시간 동안 교반시켰다. 포화 NH4Cl(30mL)을 첨가하여 반응을 종결하고 에틸아세테이트(30mL x3)로 추출했다. 혼합된 유기층은 브라인으로 세척하고 무수화물 MgSO4로 건조시킨 후, 여과하고 진공 상태에서 농축했다. 정제되지 않은 생성물을 헥산에 에틸아세테이트를 넣은 용액(농도 0 부피% 내지 30 부피%)의 플래시 칼럼에 의해 정제되어 무색 오일 상태의 1-(4-((tert-부틸디메틸실릴)옥시)-3-메톡시페닐)프로판-l-올 (2.315g, 89%)을 얻었다.A mixed solution of 4-((tert-butyldimethylsilyl)oxy)-3-methoxybenzaldehyde (2.34 g, 8.75 mmol, 1 equiv) and THF (10 ml) was mixed with ethylmagnesium bromide (9.6 mL, 9.62 mmol, 1.1 equiv; 1M concentration in THF) was dropped dropwise at 0°C under nitrogen conditions, and the product was stirred at 0°C for 1 hour. Saturated NH 4 Cl (30 mL) was added to terminate the reaction, and the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic layer was washed with brine, dried over anhydrous MgSO 4 , filtered and concentrated in vacuo. The crude product was purified by flash column with a solution of ethyl acetate in hexane (concentration 0 to 30% by volume) to form 1-(4-((tert-butyldimethylsilyl)oxy)-3 as a colorless oil. -Methoxyphenyl) propan-l-ol (2.315 g, 89%) was obtained.
3단계:1-(4-((tert-부틸디메틸실릴)옥시)-3-메톡시페닐)프로판-1-온의 합성Step 3: Synthesis of 1-(4-((tert-butyldimethylsilyl)oxy)-3-methoxyphenyl)propan-1-one
디클로로메탄(60mL) 및 1-(4-((tert-부틸디메틸실릴)옥시)-3-메톡시페닐)프로판-l-올(1.67g, 5.63mmol, 1당량)의 혼합용액에 Dess-Martin 시약(2.63g, 6.2mmol, 1.1당량)을 조금씩 첨가하여, 생성물을 15분 동안 교반시켰다. 포화 NaHC03(30mL)을 첨가하여 반응을 종결시키고, 에틸아세테이트(30mL x3)로 추출하였다. 혼합된 유기층은 브라인으로 세척하고, 무수화물 MgS04로 건조시킨 후, 진공 상태에서 여과하고 농축했다. 정제되지 않은 생성물은 헥산에 에틸아세테이트를 넣은 용액(농도 0 부피% 내지 15 부피%)의 플래시 칼럼에 의해 정제되어, 무색 오일 상태의 1-(4-((tert-부틸디메틸)옥시)-3-메톡시페닐)프로판-l-온 (1.56g, 94%)을 얻었다.Dess-Martin in a mixed solution of dichloromethane (60 mL) and 1-(4-((tert-butyldimethylsilyl)oxy)-3-methoxyphenyl)propan-l-ol (1.67 g, 5.63 mmol, 1 equiv) Reagent (2.63 g, 6.2 mmol, 1.1 eq) was added in portions and the product was stirred for 15 min. The reaction was terminated by addition of saturated NaHCO 3 (30 mL), followed by extraction with ethyl acetate (30 mL x 3). The combined organic layer was washed with brine, dried over anhydrous MgSO 4 , filtered in vacuo, and concentrated. The crude product was purified by flash column of a solution of ethyl acetate in hexane (concentration: 0% by volume to 15% by volume), and 1-(4-((tert-butyldimethyl)oxy)-3 as a colorless oil -Methoxyphenyl) propan-l-one (1.56 g, 94%) was obtained.
4단계:(2R,3S)-1,4-비스(4-((tert-부틸디메틸실릴)옥시)-3-메톡시페닐)-2,3-디메틸부탄-1,4-디온의 합성Step 4: Synthesis of (2R,3S)-1,4-bis(4-((tert-butyldimethylsilyl)oxy)-3-methoxyphenyl)-2,3-dimethylbutane-1,4-dione
디이소프로필아민(278mg, 2.75mmol, 1.1당량)과 THF(5mL)의 혼합용액에 n-BuLi(1.2 mL, 3.0mmol, 1.2당량, 헥산에서 2.5M농도)를 질소 조건, 0℃에서 한 방울씩 떨어뜨렸다. 20분 후, 1-(4-((tert-부틸디메틸실릴)옥시)-3-메톡시페닐)프로판-1-온(734mg, 2.5mmol, 1.0당량)과 THF(3ml) 혼합용액을 LDA의 결과 생성물에 0℃조건에서 한방울씩 떨어뜨렸다. 20분 후, Cu(OTF)2 (1.0g, 2.75mmol, 1.1당량, 150℃에서 진공 감압 상태에서 15분간 건조됨)을 i-PrCN(3mL)에 용해시켜 케톤 에놀레이트의 THF 혼합용액에 0℃에서 한방울씩 떨어뜨렸다. 반응은 2시간 동안 0℃ 내지 상온 조건에서 교반시켰다. 포화 NH4Cl(30mL)에 반응 생성물을 붓고, 에틸아세테이트(30ml x3)로 추출했다. 혼합된 유기층은 브라인으로 세척하고, 무수화물 MgSO4로 건조시켜, 여과하여 진공 상태에서 농축시켰다. 정제되지 않은 생성물은 헥산에 에틸아세테이트를 넣은 용액(농도 5 부피%)의 긴 칼럼에 의해 정제되어 무색 오일 상태의 (2R,3S)-1,4-비스(4-((tert-부틸디메틸실릴)옥시)-3-메톡시페닐)-2,3-디메틸부탄-l,4-디온(100mg, 13.6%, TLC에서 극성이 덜한 지점) 및 (2R,3R)-l,4-비스(4-((tert-부틸디메틸실릴)옥시-3-메톡시페닐)-2,3-디메틸부탄-1,4-디온(327mg, 에틸 아세테이트를 넣은 헥산에서 44% 더 많은 극성을 띠는, TLC에서 더 극성인 지점)을 얻었다.In a mixed solution of diisopropylamine (278 mg, 2.75 mmol, 1.1 equiv) and THF (5 mL), n-BuLi (1.2 mL, 3.0 mmol, 1.2 equiv, 2.5M concentration in hexane) was added dropwise at 0 °C under nitrogen condition. dropped one by one After 20 minutes, a mixed solution of 1-(4-((tert-butyldimethylsilyl)oxy)-3-methoxyphenyl)propan-1-one (734 mg, 2.5 mmol, 1.0 equiv) and THF (3 ml) was mixed with LDA. The resulting product was dropped dropwise at 0°C. After 20 minutes, Cu(OTF) 2 (1.0 g, 2.75 mmol, 1.1 equivalents, dried for 15 minutes under vacuum at 150 ° C.) was dissolved in i-PrCN (3 mL) and 0 in a THF mixed solution of ketone enolate It was dropped drop by drop at ℃. The reaction was stirred at 0° C. to room temperature for 2 hours. The reaction product was poured into saturated NH 4 Cl (30 mL), and extracted with ethyl acetate (30 mL x 3). The combined organic layer was washed with brine, dried over anhydrous MgSO 4 , filtered, and concentrated in vacuo. The crude product is purified by a long column of a solution of ethyl acetate in hexane (concentration of 5% by volume) to form (2R,3S)-1,4-bis(4-((tert-butyldimethylsilyl) as a colorless oil. )oxy)-3-methoxyphenyl)-2,3-dimethylbutane-l,4-dione (100 mg, 13.6%, less polar point on TLC) and (2R,3R)-l,4-bis(4 -((tert-butyldimethylsilyl)oxy-3-methoxyphenyl)-2,3-dimethylbutane-1,4-dione (327 mg, 44% more polar in hexanes with ethyl acetate, in TLC more polar points).
5단계:(2R,3S,4S)-l,4-비스(4-((tert-부틸디메틸실릴)옥시)-3-메톡시페닐)-2,3-디메틸부탄-1,4-디올의 합성Step 5: (2R,3S,4S)-1,4-bis(4-((tert-butyldimethylsilyl)oxy)-3-methoxyphenyl)-2,3-dimethylbutane-1,4-diol synthesis
(2R,3S)-1,4-비스(4-((tert-부틸디메틸실릴)옥시)-3-메톡시페닐)-2,3-디메틸부탄-1,4-디온(50mg, 0.085mmol, 1.0당량)에 질소 조건하에 0℃에서 LiAlH4(13 mg, 4.0당량)를 조금씩 첨가 하였다. 결과 생성물은 15 분 동안 0℃에서 교반시켰다(TLC로 확인하여, 시작 물질이 남아있다면 LiAlH4를 더 첨가함). 에틸 아세테이트(1ml)를 첨가하여 반응을 종결시키고, 에틸 아세테이트(50ml)로 희석하고, 브라인(20ml)으로 세척한 후, 무수물 MgSO4로 건조시키고, 여과하여 진공 조건에서 농축시켰다. 정제되지 않은 원료물질(60 mg)은 다음 단계에 직접 사용되었다.(2R,3S)-1,4-bis(4-((tert-butyldimethylsilyl)oxy)-3-methoxyphenyl)-2,3-dimethylbutane-1,4-dione (50 mg, 0.085 mmol; 1.0 equiv.) was added little by little at 0° C. under nitrogen condition (13 mg, 4.0 equiv). The resulting product was stirred at 0° C. for 15 minutes (additional LiAlH 4 was added if starting material remained as confirmed by TLC). The reaction was quenched by the addition of ethyl acetate (1 ml), diluted with ethyl acetate (50 ml), washed with brine (20 ml), dried over anhydrous MgSO 4 , filtered, and concentrated in vacuo. The crude raw material (60 mg) was used directly in the next step.
6단계:((((2R,3R,4S,5S)-3,4-디메틸테트라히드로퓨란-2,5-디일)비스(2-메톡시-4,1-페닐렌))비스(옥시))비스(tert-부틸디메틸실란)의 합성Step 6:((((2R,3R,4S,5S)-3,4-dimethyltetrahydrofuran-2,5-diyl)bis(2-methoxy-4,1-phenylene))bis(oxy) ) Synthesis of bis(tert-butyldimethylsilane)
(2R,3S,4S)-1,4-비스(4-((tert-부틸디메틸실릴)옥시)-3-메톡시페닐)-2,3-디메틸부탄-1,4-디올(60 mg, 정제되지 않은) 및 DCM(1mL)와 Et3N(55.5mg, 0.55mmol, 5.0당량)을 0℃에서 메탄설포닐 클로라이드(14.6mg, 0.128mmol, 1.5당량. 1mL DCM에 용해)를 한방울씩 떨어뜨렸다. 결과 생성물은 0℃ 내지 상온에서 2시간 동안 교반시켰다. 반응을 물(5mL)을 첨가하여 종결시키고 에틸 아세테이트(50mL)로 추출하였다. 유기층을 브라인으로 세척하고, 무수물 MgSO4로 건조시켜 여과하고 진공 조건에서 농축시켰다. 정제되지 않은 생성물은 헥산에 에틸아세테이트를 넣은 용액(농도 0 부피% 내지 10 부피%)의 플래쉬칼럼에 의해 정제되어 ((((2R,3R,4S,5S)-3,4-디메틸테트라히드로퓨란-2,5-디일)비스(2-메톡시-4,1-페닐렌))비스(옥시))비스(tert-부틸디메틸실란)(39mg, TLC에서 68% 더 극성인 지점) 및 부분 입체 이성질체(18mg. 32%, TLC에서 덜 극성인 지점)을 연노란색의 오일 상태로 얻었다.(2R,3S,4S)-1,4-bis(4-((tert-butyldimethylsilyl)oxy)-3-methoxyphenyl)-2,3-dimethylbutane-1,4-diol (60 mg, Crude) and DCM (1 mL) and Et 3 N (55.5 mg, 0.55 mmol, 5.0 equiv) were added dropwise at 0 °C to methanesulfonyl chloride (14.6 mg, 0.128 mmol, 1.5 equiv. dissolved in 1 mL DCM). knocked out The resulting product was stirred at 0° C. to room temperature for 2 hours. The reaction was quenched by addition of water (5 mL) and extracted with ethyl acetate (50 mL). The organic layer was washed with brine, dried over anhydrous MgSO 4 , filtered and concentrated in vacuo. The crude product is purified by flash column of a solution of ethyl acetate in hexane (concentration: 0% by volume to 10% by volume) ((((2R,3R,4S,5S)-3,4-dimethyltetrahydrofuran) -2,5-diyl)bis(2-methoxy-4,1-phenylene))bis(oxy))bis(tert-butyldimethylsilane) (39 mg, 68% more polar point in TLC) and diastereomers The isomer (18 mg. 32%, less polar point in TLC) was obtained as a pale yellow oil.
7단계: 넥탄드린 B의 합성Step 7: Synthesis of nectandrine B
((((2R,3R,4S,5S)-3,4-디메틸테트라히드로퓨란-2,5-디일)비스(2-메톡시-4,1-페닐렌))비스(옥시))비스(tert-부틸디메틸실란)(39mg, 0.068mmol)와 THF(1mL)의 혼합물에 TBAF(0.5mmol, THF에서 1M 농도)를 첨가했다. 결과 생성물은 1시간 동안 40℃에서 교반시켰다. 에틸아세테이트(30mL)로 희석하고, 물(10mL) 및 브라인(10mL)으로 세척하였다. 유기층을 무수물 MgSO4로 건조시키고, 여과하고, 진공 조건에서 농축시켰다. 정제되지 않은 생성물을 에틸아세테이트를 첨가한 헥산으로 prep-TLC를 이용하여 정제하여 연노란색 고체 상태의 넥탄드린 B(9.7mg, 3단계 동안 41%의 수율) 화합물을 얻었다.((((2R,3R,4S,5S)-3,4-dimethyltetrahydrofuran-2,5-diyl)bis(2-methoxy-4,1-phenylene))bis(oxy))bis( To a mixture of tert-butyldimethylsilane) (39 mg, 0.068 mmol) and THF (1 mL) was added TBAF (0.5 mmol, 1M concentration in THF). The resulting product was stirred at 40° C. for 1 hour. It was diluted with ethyl acetate (30 mL) and washed with water (10 mL) and brine (10 mL). The organic layer was dried over anhydrous MgSO 4 , filtered and concentrated in vacuo. The crude product was purified using prep-TLC with hexane to which ethyl acetate was added to obtain a pale yellow solid nectandrine B (9.7 mg, yield of 41% in 3 steps) as a compound.
실험 결과. 넥탄드린 B 화합물의 확인Experiment result. Identification of nectandrine B compound
상기 단계를 거쳐 획득한 넥탄드린 B 화합물을 하기와 같이 NMR 데이터로 확인하였다.The nectandrine B compound obtained through the above steps was confirmed by NMR data as follows.
1. 1H NMR 결과(도 1)1. 1H NMR result (Fig. 1)
1H NMR (500 MHz, CDCl3), 6.97(s, 2H), 6.95-6.89 (m, 4H), 5.60 (s, 2H), 4.50 (d, J = 6.4 Hz, 2H), 3.89 (s, 6H), 2.38-2.29 (m, 2H), 1.04 (d, J = 6.5 Hz, 6H); 1 H NMR (500 MHz, CDCl 3 ), 6.97(s, 2H), 6.95-6.89 (m, 4H), 5.60 (s, 2H), 4.50 (d, J = 6.4 Hz, 2H), 3.89 (s, 6H), 2.38-2.29 (m, 2H), 1.04 (d, J = 6.5 Hz, 6H);
2. 13C NMR 결과(도 2)2. 13C NMR result (Fig. 2)
13C NMR (125 MHz, CDCl3) 146.43, 145.01, 134.17, 119.26, 114.08, 109.14, 87.33, 55.85, 44.30, 12.94. 13 C NMR (125 MHz, CDCl 3 ) 146.43, 145.01, 134.17, 119.26, 114.08, 109.14, 87.33, 55.85, 44.30, 12.94.
Claims (9)
상기 제1 단계의 생성물의 알데히드기에 에틸기를 첨가하는 제2 단계;
상기 제2 단계의 생성물의 히드록시기를 산화시키는 제3 단계;
상기 제3 단계의 생성물을 2당량 중합하는 제4 단계;
상기 제4 단계의 생성물의 카보닐기를 환원시키는 제5 단계;
상기 제5 단계의 생성물을 탈수시켜 고리화하는 제6 단계; 및
상기 제6 단계의 생성물의 히드록시기를 탈보호화하는 제7 단계;를 포함하는 화학식 2로 표시되는 화합물의 제조 방법:
[화학식 1]
[화학식 2]
A first step of protecting a hydroxyl group in the compound represented by Formula 1;
a second step of adding an ethyl group to the aldehyde group of the product of the first step;
a third step of oxidizing the hydroxyl group of the product of the second step;
a fourth step of polymerizing 2 equivalents of the product of the third step;
a fifth step of reducing the carbonyl group of the product of the fourth step;
a sixth step of cyclizing the product of the fifth step by dehydration; and
A method for preparing a compound represented by Formula 2, including a seventh step of deprotecting the hydroxyl group of the product of the sixth step:
[Formula 1]
[Formula 2]
The method according to claim 1, wherein the protection in the first step is trimethylsilyl chloride, triethylsilyl chloride, tri-n-propylsilyl chloride, tri-iso-propyl silyl chloride, t-butyldimethyl A method for preparing a compound represented by Formula 2, which is carried out by reaction with silyl chloride, tosyl chloride or t-butyldiphenylsilyl chloride.
The method according to claim 1, wherein the addition of the ethyl group in the second step is performed by reacting the product of the first step with EtLi, EtMgCl, EtMgBr or EtMgI.
The method according to claim 1, wherein the third step is Na 2 Cr 2 O 7 , K 2 Cr 2 O 7 , CrO 3 , H 2 SO 4 , H 2 CrO 4 , Collins reagent, PCC, Dess-Maritin reagent or KMnO 4 / Ag 2 O A method for producing a compound represented by Formula 2, wherein the oxidation reaction is carried out in the presence.
The method according to claim 1, wherein the fourth step is carried out in the presence of a Lewis acid, the method for producing a compound represented by Formula 2.
The method of claim 5, wherein the Lewis acid is Cu(OTf) 2 or Cu(OAc) 2 .
The method according to claim 1, wherein in the fifth step, the reduction reaction is performed under the addition of LiAlH 4 or NaBH 4 , the method for preparing a compound represented by Formula 2
The method according to claim 1, wherein in the sixth step, a five-membered ring is formed under the addition of MsCl or TsCl, the method for producing a compound represented by formula (2).
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