KR101542300B1 - Synthesis method of pyranocarbazole derivatives - Google Patents
Synthesis method of pyranocarbazole derivatives Download PDFInfo
- Publication number
- KR101542300B1 KR101542300B1 KR1020130069023A KR20130069023A KR101542300B1 KR 101542300 B1 KR101542300 B1 KR 101542300B1 KR 1020130069023 A KR1020130069023 A KR 1020130069023A KR 20130069023 A KR20130069023 A KR 20130069023A KR 101542300 B1 KR101542300 B1 KR 101542300B1
- Authority
- KR
- South Korea
- Prior art keywords
- carbazole
- dihydropyrano
- compound
- tetrahydropyrano
- trans
- Prior art date
Links
- 0 *C1(*)Oc2ccc(c3ccccc3[n]3)c3c2C=C1 Chemical compound *C1(*)Oc2ccc(c3ccccc3[n]3)c3c2C=C1 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
Abstract
본 발명은 피라노카바졸 유도체의 합성방법에 관한 것으로, 보다 상세하게는 항종양 활성 등을 포함한 다양한 생리활성을 나타내는 피라노카바졸 유도체를 보다 높은 수율로 간편하게 합성할 수 있는 합성방법에 관한 것이다.The present invention relates to a method for synthesizing a pyranocarbazole derivative, and more particularly, to a method for synthesizing a pyranocarbazole derivative having various physiological activities, including antitumor activity, at a higher yield .
Description
본 발명은 다양한 생리활성을 나타내는 피라노카바졸 유도체를 좋은 수율로 얻는 간편한 합성방법에 관한 것이다.The present invention relates to a simple synthesis method of obtaining a pyranocarbazole derivative exhibiting various physiological activities in good yield.
피라노카바졸 그룹을 갖는 화합물은 천연에서 많이 발견되며, 이러한 화합물은 다양한 생리학 및 약학적 특성을 가진다. 그 중 기리님빈(Girinimbine), 머라이아신(murrayacine) 및 O-메틸머라이아민 A(O-methylmurrayamine A)는 카레나무(Murraya koenigii)에서 분리되었고, 기리님빈은 항종양 활성이 알려져 있다.Compounds having a pyranocarbazole group are found in many natural sources, and these compounds have various physiological and pharmacological properties. Giri's of the blank (Girinimbine), meorayi Aisin (murrayacine) and O- methyl meorayi amine A (O -methylmurrayamine A) was separated from the curry tree (Murraya koenigii), Giri's bin is known the anti-tumor activity.
천연에서 발견되는 마하님빈(mahanimbine), 마하닌(mahanine) 및 마하님비신(mahanimbicine)도 카레나무(Murraya koenigii)에서 분리되었고, 이들 화합물들은 항비만, 항당뇨, 항산화, 항종양 등 다양한 활성을 나타내는 것으로 알려져 있다. Mahanimbine, mahanine and mahanimbicine found in nature have also been isolated from the currants ( Murraya koenigii), and these compounds have been shown to have various activities such as anti-obesity, antidiabetic, antioxidant, ≪ / RTI >
피라노카바졸 유도체 합성과 관련하여 몇가지 합성 방법이 알려져 있다. 즉, 1-하이드록시카바졸과 말로노니트릴과 아릴알데히드를 Na2CO3 촉매 하에서 반응시켜 합성하거나(Synth. Commun. 2012, 42, 1330), 팔라듐 촉매 하에서 1-하이드록시-7-메틸카바졸의 분자 내 C-O 및 C-C 가교 커플링 반응을 수행하거나(Synlett 2011, 1835), 철 매개 산화적 고리화 반응을 수행하거나(Org. Biomol. Chem. 2011, 9, 2057), H2O2/NaOH 하에서 2-시나모일-1-하이드록시카바졸의 반응(Naturforsc. B. 2008, 63, 1112)을 통해 합성할 수 있다. Several synthetic methods are known for the synthesis of pyranocarbazole derivatives. Namely, synthesis of 1-hydroxycarbazole with malononitrile and arylaldehyde by reaction with Na 2 CO 3 catalyst ( Synth. Commun ., 2012, 42 , 1330) or 1-hydroxy-7- performing a sol of intramolecular CO and CC cross-coupling reaction, or (Synlett 2011, 1835), performing the iron-mediated oxidative cyclization, or (Org. Biomol. Chem. 2011 , 9, 2057), H 2 O 2 / B , 2008, 63 , 1112). ≪ RTI ID = 0.0 > 2- Cyano -1-hydroxycarbazole < / RTI >
그러나, 이러한 합성방법은 가혹한 반응 조건, 낮은 수율 및 사용된 촉매 양 등의 문제로 인하여 합성에 한계가 있다. 따라서, 여전히 수율이 좋고 간편한 피라노카바졸 유도체의 합성 방법의 개발이 필요한 실정이다.However, such a synthesis method has limitations in synthesis due to problems such as severe reaction conditions, low yield and amount of catalyst used. Therefore, it is necessary to develop a method for synthesizing pyranocarbazole derivatives, which still yields a good yield.
본 발명의 목적은 피라노카바졸 유도체를 좋은 수율로 간편하게 합성할 수 있는 새로운 합성방법을 제공하는 데에 있다.It is an object of the present invention to provide a novel synthesis method capable of easily synthesizing a pyranocarbazole derivative with good yield.
상기 목적을 달성하기 위하여, 본 발명은 에틸렌디아민 디아세테이트(EDDA)의 촉매와 자일렌 용매 하에서 하이드록시카바졸과 α,β-불포화 알데히드를 환류 반응시켜 화학식 1 또는 화학식 2의 화합물을 합성하는 것을 특징으로 하는 피라노카바졸 유도체의 합성방법을 제공한다: In order to achieve the above object, the present invention provides a process for preparing a compound represented by the formula (1) or (2) by reacting a hydroxycarbazole with an α, β-unsaturated aldehyde in the presence of a catalyst of ethylenediamine diacetate (EDDA) Wherein R < 1 > and R < 2 >
[화학식 1][Chemical Formula 1]
[화학식 2](2)
상기 화학식 1 및 화학식 2에서, R1 내지 R4는 각각 동일하거나 다를 수 있으며, 수소, C1 내지 C4 알킬, C1 내지 C4의 알콕시, 하이드록시, 4-메틸펜트-3-에닐, 4,8-디메틸노나-3,7-디에닐, 페닐 및 할로겐으로 이루어진 군에서 선택될 수 있다.In Formula 1 and Formula 2, R 1 to R 4 may be the same or different and each represents hydrogen, C1 to C4 alkyl, C1 to C4 alkoxy, hydroxy, 4-methylpent-3-enyl, Dimethylnona-3,7-dienyl, phenyl, and halogen.
상기 하이드록시카바졸은 2-하이드록시카바졸 또는 4-하이드록시카바졸 중 어느 하나일 수 있다.The hydroxycarbazole may be either a 2-hydroxycarbazole or a 4-hydroxycarbazole.
상기 α,β-불포화 알데히드는 3-메틸부트-2-에날, 트랜스-크로톤알데히드, 시트랄, 트랜스,트랜스-파네살 및 트랜스-신남알데히드로 이루어진 군에서 선택된 어느 하나일 수 있다.The alpha, beta -unsaturated aldehydes may be any one selected from the group consisting of 3-methylbut-2-ene, trans-croton aldehyde, citral, trans, trans-panesal and trans-cinnamaldehyde.
상기 화학식 1의 화합물은 3,3-디메틸-3,11-디하이드로피라노[3,2-a]카바졸(11a); 3-메틸-3,11-디하이드로피라노[3,2-a]카바졸(11b); 3-메틸-3-(4-메틸펜트-3-엔-1-일)-3,11-디하이드로피라노[3,2-a]카바졸(11c); 3-(4,8-디메틸노나-3,7-디엔-1-일)-3-메틸-3,11-디하이드로피라노[3,2-a]카바졸(11d); 및 3-페닐-3,11-디하이드로피라노[3,2-a]카바졸(11e)로 이루어진 군에서 선택된 어느 하나일 수 있다.The compound of Formula 1 is 3,3-dimethyl-3,11-dihydropyrano [3,2- a ] carbazole (11a); 3-methyl-3,11-dihydropyrano [3,2- a ] carbazole (11b); 3-methyl-3- (4-methylpent-3-en-1-yl) -3,11-dihydropyrano [3,2- a ] carbazole (11c); 3- (4,8-dimethylnona-3,7-dien-1-yl) -3-methyl-3,11-dihydropyrano [3,2- a ] carbazole (11d); And 3-phenyl-3,11-dihydropyrano [3,2- a ] carbazole (11e).
상기 화학식 2의 화합물은 2,2-디메틸-2,7-디하이드로피라노[3,2-c]카바졸(11f); 2-메틸-2,7-디하이드로피라노[3,2-c]카바졸(11g); 2-메틸-2-(4-메틸펜트-3-엔-1-일)-2,7-디하이드로피라노[3,2-c]카바졸(11h); 2-(4,8-디메틸노나-3,7-디엔-1-일)-2-메틸-2,7-디하이드로피라노[3,2-c]카바졸(11i); 및 2-페닐-2,7-디하이드로피라노[3,2-c]카바졸(11j)로 이루어진 군에서 선택된 어느 하나일 수 있다.The compound of Formula 2 is 2,2-dimethyl-2,7-dihydropyrano [3,2- c ] carbazole (11f); 2-methyl-2,7-dihydropyrano [3,2- c ] carbazole (11 g); 2-methyl-2- (4-methylpent-3-en-1-yl) -2,7-dihydropyrano [3,2- c ] carbazole (11h); 2- (4,8-dimethylnona-3,7-dien-1-yl) -2-methyl-2,7-dihydropyrano [3,2- c ] carbazole (11i); And 2-phenyl-2,7-dihydropyrano [3,2- c ] carbazole (11j).
또한, 본 발명은 에틸렌디아민 디아세테이트(EDDA)의 촉매와 자일렌 용매 하에서 하이드록시카바졸과 α,β-불포화 알데히드를 환류 반응시켜 화학식 1 또는 화학식 2의 화합물을 합성하는 단계; 및 상기 화학식 1 또는 화학식 2의 화합물을 디옥산, 아세톤, 디메틸포름아마이드 또는 t-BuOH-테트라하이드로퓨란(THF)-H2O에서 선택된 용매 하에서 N-브로모숙신이미드, 물, 오스뮴 테트록사이드, 4-메틸모폴린 N-옥사이드, 디메틸디옥시란, NaH 및 메틸 아이오다이드로 이루어진 군에서 선택된 하나 이상의 화합물을 첨가하여 교반시키는 단계를 포함하여 이루어지는 것을 특징으로 하는 피라노카바졸 유도체의 합성방법을 제공한다. The present invention also relates to a process for preparing a compound represented by the formula (1) or (2) by reacting a hydroxycarbazole with an α, β-unsaturated aldehyde in the presence of a catalyst of ethylenediamine diacetate (EDDA) And the compound of formula (1) or (2) dioxane, acetone, dimethylformamide or t-BuOH- tetrahydrofuran (THF), a solvent selected from -H 2 O N- bromosuccinimide, water, osmium lock Tet And a step of adding and stirring at least one compound selected from the group consisting of N, N'-dideoxy-4-methylmorpholine N-oxide, dimethyldioxirane, NaH and methyl iodide, and stirring the resulting mixture to prepare a pyranocarbazole derivative ≪ / RTI >
[화학식 1][Chemical Formula 1]
[화학식 2](2)
상기 화학식 1 및 화학식 2에서, R1 내지 R4는 각각 동일하거나 다를 수 있으며, 수소, C1 내지 C4 알킬, C1 내지 C4의 알콕시, 하이드록시, 4-메틸펜트-3-에닐, 4,8-디메틸노나-3,7-디에닐, 페닐 및 할로겐으로 이루어진 군에서 선택될 수 있다.In Formula 1 and Formula 2, R 1 to R 4 may be the same or different and each represents hydrogen, C1 to C4 alkyl, C1 to C4 alkoxy, hydroxy, 4-methylpent-3-enyl, Dimethylnona-3,7-dienyl, phenyl, and halogen.
본 발명에 따르면, 항종양 활성 등 다양한 생리활성을 나타내는 피라노카바졸 유도체를 보다 좋은 수율로 간편하게 합성할 수 있다.According to the present invention, pyranocarbazole derivatives showing various physiological activities such as antitumor activity can be easily synthesized with better yield.
이하, 일실시예를 통해 본 발명을 보다 상세하게 설명한다.Hereinafter, the present invention will be described in more detail with reference to an embodiment.
본 발명자는 다양한 용매와 다양한 촉매 하에서 2-하이드록시카바졸과 3-메틸-2-부테날을 이용하여 피라노카바졸을 합성한 결과, 용매로서 자일렌을, 촉매로서 에틸렌디아민 디아세테이트(EDDA)를 사용한 경우 가장 높은 수율을 나타냄을 확인하여 본 발명을 완성하였다.The present inventors have synthesized pyranocarbazole using 2-hydroxycarbazole and 3-methyl-2-butenal in various solvents and various catalysts. As a result, it has been found that xylene is used as a solvent and ethylenediamine diacetate (EDDA ), It was confirmed that the highest yield was obtained. Thus, the present invention was completed.
보다 상세하게는, 본 발명에서는 에틸렌디아민 디아세테이트(EDDA)의 촉매와 자일렌 용매 하에서 하기 표 1과 같이 다양한 하이드록시카바졸과 α,β-불포화 알데히드를 환류 반응시켜 피라노카바졸 유도체를 제조할 수 있다. More specifically, in the present invention, various hydroxycarbazole and α, β-unsaturated aldehydes are subjected to a reflux reaction in the presence of a catalyst of ethylenediamine diacetate (EDDA) and a xylene solvent as shown in Table 1 below to prepare a pyranocarbazole derivative can do.
[표 1][Table 1]
또한, 본 발명에서는 에틸렌디아민 디아세테이트(EDDA)의 촉매와 자일렌 용매 하에서 하기 반응식 1 및 반응식 2와 같이 3,3-디메틸-3,11-디하이드로피라노[3,2-a]카바졸(11a) 또는 2,2-디메틸-2,7-디하이드로피라노[3,2-c]카바졸(11f)과 같은 하이드록시카바졸과 다양한 α,β-불포화 알데히드를 환류 반응시켜 피라노카바졸 유도체를 제조할 수 있다. In the present invention, a catalyst of ethylenediamine diacetate (EDDA) is reacted with a 3,3-dimethyl-3,11-dihydropyrano [3,2- a ] carbazole (11a) or 2,2-dimethyl-2,7-dihydropyrano [3,2- c ] carbazole (11f) and various?,? -Unsaturated aldehydes, Carbazole derivatives can be prepared.
[반응식 1][Reaction Scheme 1]
[반응식 2][Reaction Scheme 2]
이하, 하기 실시예를 통해 본 발명을 보다 상세하게 설명한다. 다만, 이러한 실시예에 의해 본 발명이 한정되는 것은 아니다.Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the present invention is not limited by these examples.
이하 모든 실험은 질소 분위기 하에서 수행되었다. 분석용 TLC를 측정하기 위하여 머크사의 형광지시약을 지닌 pre-coated silica gel plates (Art. 5554)를 사용하였다. 실리카겔 9385 (Merck)를 이용하여 플래쉬 컬럼 크로마토그래피를 수행하였다. 그리고, 1H NMR 및 13C NMR 분석은 용매 화학적 시프트로서 CDCl3, DMSO-d 6 , 아세톤-d 6 에서 Bruker Model ARX (300 및 75 MHz) 분광분석기를 통해 기록하였다. IR 분석은 Jasco FTIR 5300 분광분석기를 이용하여 측정하였다. HRMS 분석은 한국기초과학지원연구원을 통해 수행하였다.
All experiments were carried out under nitrogen atmosphere. For the TLC analysis, pre-coated silica gel plates (Art. 5554) with fluorescence indicator from Merck are used. Flash column chromatography was performed using silica gel 9385 (Merck). And 1 H NMR and 13 C NMR analyzes were recorded via a Bruker Model ARX (300 and 75 MHz) spectrometer in CDCl 3, DMSO- d 6 , acetone- d 6 as solvent chemical shifts. IR analysis was performed using a Jasco FTIR 5300 spectrometer. HRMS analysis was carried out through Korea Basic Science Research Institute.
<실시예 1> 최적 합성 조건 규명Example 1: Identification of optimal synthesis conditions
2-하이드록시카바졸(10a)과 3-메틸-2-부테날을 이용한 피라노카바졸 합성반응에서 몇가지 촉매와 용매를 변화시켜 최적 조건을 규명하였다. 즉, 2-하이드록시카바졸(10a)(1.0 mmol)와 3-메틸-2-부테날(2.0 mmol)을 다양한 용매(10 mL)에 용해시킨 혼합물에 다양한 촉매(40 mg, 20 mol%)를 첨가하여 얻어진 반응혼합물을 질소 분위기 하에서 15-24 시간 동안 환류시켰다. 반응 완료를 TLC로 확인한 후, 감압 하에서 용매를 제거하였다. 남은 잔사는 헥산/EtOAc (20:1)을 이용한 컬럼 크로마토그래피를 통해 정제하여 최종 생성물을 얻었다.In the synthesis of pyranocarbazole using 2-hydroxycarbazole (10a) and 3-methyl-2-butenal, several catalysts and solvents were changed to determine optimum conditions. (40 mg, 20 mol%) was added to a mixture of 2-hydroxycarbazole (10a) (1.0 mmol) and 3-methyl-2-butenal (2.0 mmol) in various solvents Was added and the resulting reaction mixture was refluxed under a nitrogen atmosphere for 15-24 hours. After completion of the reaction was confirmed by TLC, the solvent was removed under reduced pressure. The remaining residue was purified by column chromatography using hexane / EtOAc (20: 1) to give the final product.
그 결과, 하기 표 1과 같이 촉매로서 EDDA를 사용하고 용매로서 자일렌을 사용한 경우 가장 높은 수율을 나타내었기 때문에 이후 실험에서는 촉매로서 EDDA를, 용매로서 자일렌을 사용하여 합성하였다.As a result, as shown in Table 1, EDDA was used as a catalyst and xylene was used as a solvent. Thus, EDDA was used as a catalyst and xylene was used as a solvent in the subsequent experiments.
<실시예 2> 3,3-디메틸-3,11-디하이드로피라노[3,2-Example 2 Synthesis of 3,3-dimethyl-3,11-dihydropyrano [3,2- aa ]카바졸(11a) 합성] Carbazole (11a) Synthesis
화합물 10a(182 mg, 1.0 mmol)와 3-메틸-2-부테날(168 mg, 2.0 mmol)을 p-자일렌(10 mL)에 용해시킨 혼합물에 EDDA(40 mg, 20 mol%)를 첨가하여 얻어진 반응혼합물을 질소 분위기 하에서 15 시간 동안 환류시켰다. 반응 완료를 TLC로 확인한 후, 감압 하에서 용매를 제거하였다. 남은 잔사는 헥산/EtOAc (20:1)을 이용한 컬럼 크로마토그래피를 통해 정제하여 붉은 오일인 화합물 11a(179 mg, 72%)을 얻었다. To the mixture of compound 10a (182 mg, 1.0 mmol) and 3-methyl-2-butenal (168 mg, 2.0 mmol) in p -xylene (10 mL) was added EDDA (40 mg, 20 mol%) The resulting reaction mixture was refluxed under a nitrogen atmosphere for 15 hours. After completion of the reaction was confirmed by TLC, the solvent was removed under reduced pressure. The remaining residue was purified by column chromatography using hexane / EtOAc (20: 1) to give compound 11a (179 mg, 72%) as a red oil.
1H NMR (300 MHz, CDCl3): δ7.95(1H,s,br,NH), 7.92(1H,d,J = 7.8 Hz), 7.77 (1H, d, J = 8.4 Hz), 7.38-7.15 (3H, m), 6.72 (1H, d, J = 8.4 Hz), 6.61 (1H, d, J = 9.9 Hz), 5.69 (1H, d, J = 9.9 Hz), 1.47 (6H, s); 1 H NMR (300 MHz, CDCl 3): δ7.95 (1H, s, br, NH), 7.92 (1H, d, J = 7.8 Hz), 7.77 (1H, d, J = 8.4 Hz), 7.38- D, J = 9.9 Hz), 1.47 (3H, m), 6.72 (1H, d, J = 8.4 Hz), 6.61 (1H, d, J = 9.9 Hz).
13CNMR (75MHz,CDCl3): δ151.6, 139.8, 136.6, 129.5, 124.5, 123.9, 120.5, 119.6, 119.4, 117.7, 117.3, 110.7, 109.6, 104.9, 76.1, 27.7, 27.7; 13 CNMR (75 MHz, CDCl 3 ):? 151.6, 139.8, 136.6, 129.5, 124.5, 123.9, 120.5, 119.6, 119.4, 117.7, 117.3, 110.7, 109.6, 104.9, 76.1, 27.7, 27.7;
IR(neat) 3355, 3050, 2973, 1709, 1635, 1450, 1349, 1218, 1159, 743cm-1;IR (neat) 3355, 3050, 2973, 1709, 1635, 1450, 1349, 1218, 1159, 743 cm < -1 & gt ;;
HRMS(EI) m/z (M+) calcd for C17H15NO: 249.1154. Found: 249.1151.
HRMS (EI) m / z ( M +) calcd for C 17 H 15 NO: 249.1154. Found: 249.1151.
<실시예 3> 3-메틸-3,11-디하이드로피라노[3,2-Example 3: Synthesis of 3-methyl-3,11-dihydropyrano [3,2- aa ]카바졸(11b) 합성] Carbazole (11b) Synthesis
화합물 10a(182 mg, 1.0 mmol)와 트랜스-크로톤알데히드(140 mg, 2.0 mmol)을 p-자일렌(10 mL)에 용해시킨 혼합물에 EDDA(40 mg, 20 mol%)를 첨가하여 얻어진 반응혼합물을 질소 분위기 하에서 15 시간 동안 환류시켰다. 반응 완료를 TLC로 확인한 후, 감압 하에서 용매를 제거하였다. 남은 잔사는 헥산/EtOAc (20:1)을 이용한 컬럼 크로마토그래피를 통해 정제하여 초록색 고상인 화합물 11b(119 mg, 51%)을 얻었다. To a mixture of compound 10a (182 mg, 1.0 mmol) and trans-crotonaldehyde (140 mg, 2.0 mmol) in p -xylene (10 mL) was added EDDA (40 mg, 20 mol% Was refluxed under a nitrogen atmosphere for 15 hours. After completion of the reaction was confirmed by TLC, the solvent was removed under reduced pressure. The remaining residue was purified by column chromatography using hexane / EtOAc (20: 1) to give compound 11b (119 mg, 51%) as a green solid.
Mp 120-122℃;Mp 120-122 DEG C;
1H NMR (300 MHz, CDCl3): δ7.99(1H,s,br,NH), 7.85(1H,d,J = 7.8 Hz), 7.70 (1H, d, J = 8.4 Hz), 7.32-7.21 (2H, m), 7.14-7.09 (1H, m), 6.67 (1H, d, J = 8.4 Hz), 6.62 (1H, d, J = 9.3 Hz), 5.67 (1H, dd, J = 9.6, 3 Hz), 4.98-4.94 (1H, m), 1.43 (3H, d, J = 6.6 Hz); 1 H NMR (300 MHz, CDCl 3): δ7.99 (1H, s, br, NH), 7.85 (1H, d, J = 7.8 Hz), 7.70 (1H, d, J = 8.4 Hz), 7.32- 7.21 (2H, m), 7.14-7.09 (1H, m), 6.67 (1H, d, J = 8.4 Hz), 6.62 (1H, d, J = 9.3 Hz), 5.67 (1H, dd, J = 9.6, 3 Hz), 4.98-4.94 (1H, m), 1.43 (3H, d, J = 6.6 Hz);
13C NMR (75MHz,CDCl3): δ152.1, 139.2, 126.2, 125.7, 124.5, 123.7, 120.5, 119.6, 119.4, 118.5, 110.4, 109.2, 105.4, 71.3, 29.6, 20.7; 13 C NMR (75 MHz, CDCl 3 ):? 152.1, 139.2, 126.2, 125.7, 124.5, 123.7, 120.5, 119.6, 119.4, 118.5, 110.4, 109.2, 105.4, 71.3, 29.6, 20.7;
IR (KBr) 3358, 3054, 2928, 1707, 1628, 1450, 1325, 1217, 1102, 744cm-1;IR (KBr) 3358, 3054, 2928, 1707, 1628, 1450, 1325, 1217, 1102, 744 cm -1 ;
HRMS (EI) m/z (M+) calcd for C16H13NO: 235.0997. Found: 235.0999.
HRMS (EI) m / z ( M +) calcd for C 16 H 13 NO: 235.0997. Found: 235.0999.
<실시예 4> 3-메틸-3-(4-메틸펜트-3-엔-1-일)-3,11-디하이드로피라노[3,2-Example 4 Synthesis of 3-methyl-3- (4-methylpent-3-en-1-yl) -3,11-dihydropyrano [3,2- aa ]카바졸(11c) 합성] Carbazole (11c) Synthesis
화합물 10a(182 mg, 1.0 mmol)와 시트랄(304 mg, 2.0 mmol)을 p-자일렌(10 mL)에 용해시킨 혼합물에 EDDA(40 mg, 20 mol%)를 첨가하여 얻어진 반응혼합물을 질소 분위기 하에서 15 시간 동안 환류시켰다. 반응 완료를 TLC로 확인한 후, 감압 하에서 용매를 제거하였다. 남은 잔사는 헥산/EtOAc (20:1)을 이용한 컬럼 크로마토그래피를 통해 정제하여 초록색 오일인 화합물 11c(253 mg, 80%)을 얻었다. To the mixture of compound 10a (182 mg, 1.0 mmol) and citral (304 mg, 2.0 mmol) in p -xylene (10 mL) was added EDDA (40 mg, 20 mol% Under reflux for 15 hours. After completion of the reaction was confirmed by TLC, the solvent was removed under reduced pressure. The remaining residue was purified by column chromatography using hexane / EtOAc (20: 1) to give compound 11c (253 mg, 80%) as a green oil.
1H NMR (300 MHz, CDCl3): δ7.96(1H,s,br,NH), 7.91(1H,d,J = 8.1 Hz), 7.76 (1H, d, J = 8.4 Hz), 7.38-7.27 (2H, m), 7.20-7.15 (1H, m), 6.72 (1H, d, J = 8.4 Hz), 6.64 (1H, d, J = 9.9 Hz), 5.65 (1H, d, J = 9.9 Hz), 5.09 (1H, t, J = 6.9 Hz), 2.17-2.10 (2H, m), 1.79-1.70 (2H, m), 1.64 (3H, s), 1.56 (3H, s), 1.43 (3H, s); 1 H NMR (300 MHz, CDCl 3): δ7.96 (1H, s, br, NH), 7.91 (1H, d, J = 8.1 Hz), 7.76 (1H, d, J = 8.4 Hz), 7.38- 7.27 (2H, m), 7.20-7.15 (1H, m), 6.72 (1H, d, J = 8.4 Hz), 6.64 (1H, d, J = 9.9 Hz), 5.65 (1H, d, J = 9.9 Hz ), 5.09 (1H, t, J = 6.9 Hz), 2.17-2.10 (2H, m), 1.79-1.70 (2H, m), 1.64 (3H, s) s);
13C NMR (75 MHz, CDCl3): δ151.9, 139.7, 136.5, 131.8, 128.8, 124.6, 124.3, 124.1, 120.6, 119.8, 119.5, 117.6, 117.5, 110.6, 109.7, 104.7, 78.5, 40.9, 26.1, 25.8, 22.9, 17.8; 13 C NMR (75 MHz, CDCl 3 ): δ 151.9, 139.7, 136.5, 131.8, 128.8, 124.6, 124.3, 124.1, 120.6, 119.8, 119.5, 117.6, 117.5, 110.6, 109.7, 104.7, 78.5, 40.9, 26.1 , 25.8, 22.9, 17.8;
IR (neat) 3353, 2921, 1708, 1627, 1443, 1355, 1216, 1092, 910, 811, 742cm-1;IR (neat) 3353, 2921, 1708, 1627, 1443, 1355, 1216, 1092, 910, 811, 742 cm -1 ;
HRMS (EI) m/z (M+) calcd for C22H23NO: 317.1780. Found: 317.1778.
HRMS (EI) m / z ( M +) calcd for C 22 H 23 NO: 317.1780. Found: 317.1778.
<실시예 5> 3-(4,8-디메틸노나-3,7-디엔-1-일)-3-메틸-3,11-디하이드로피라노[3,2-Example 5 Synthesis of 3- (4,8-dimethylnona-3,7-dien-1-yl) -3-methyl-3,11-dihydropyrano [3,2- aa ]카바졸(11d) 합성] Carbazole (11d) Synthesis
화합물 10a(182 mg, 1.0 mmol)와 트랜스,트랜스-파네살(220 mg, 2.0 mmol)을 p-자일렌(10 mL)에 용해시킨 혼합물에 EDDA(40 mg, 20 mol%)를 첨가하여 얻어진 반응혼합물을 질소 분위기 하에서 15 시간 동안 환류시켰다. 반응 완료를 TLC로 확인한 후, 감압 하에서 용매를 제거하였다. 남은 잔사는 헥산/EtOAc (20:1)을 이용한 컬럼 크로마토그래피를 통해 정제하여 노란색 오일인 화합물 11d(566 mg, 83%)을 얻었다. To a mixture of compound 10a (182 mg, 1.0 mmol) and trans, trans-panesar (220 mg, 2.0 mmol) in p -xylene (10 mL) was added EDDA (40 mg, 20 mol% The reaction mixture was refluxed under a nitrogen atmosphere for 15 hours. After completion of the reaction was confirmed by TLC, the solvent was removed under reduced pressure. The remaining residue was purified by column chromatography using hexane / EtOAc (20: 1) to give compound 11d (566 mg, 83%) as a yellow oil.
1H NMR (300 MHz, CDCl3): δ7.89(1H,s,1H,NH), 7.86(1H,d,J = 7.8 Hz), 7.70 (1H, d, J = 8.1 Hz), 7.32-7.09 (3H, m), 6.66 (1H, d, J = 8.4 Hz), 6.58 (1H, d, J = 9.9 Hz), 5.60 (1H, d, J = 9.9 Hz), 5.07-5.00 (2H, m), 2.11-2.06 (2H, m), 1.98-1.88 (4H, m), 1.74-1.68 (2H, m), 1.59 (3H, s), 1.50 (6H, s), 1.39 (3H, s); 1 H NMR (300 MHz, CDCl 3): δ7.89 (1H, s, 1H, NH), 7.86 (1H, d, J = 7.8 Hz), 7.70 (1H, d, J = 8.1 Hz), 7.32- 7.09 (3H, m), 6.66 (1H, d, J = 8.4 Hz), 6.58 (1H, d, J = 9.9 Hz), 5.60 (1H, d, J = 9.9 Hz), 5.07-5.00 (2H, m ), 2.11-2.06 (2H, m), 1.98-1.88 (4H, m), 1.74-1.68 (2H, m), 1.59 (3H, s), 1.50 (6H, s), 1.39 (3H, s);
13C NMR (75 MHz, CDCl3): δ151.9, 139.6, 136.4, 135.5, 131.5, 128.8, 124.6, 124.5, 124.1, 124.0, 120.6, 119.8, 119.5, 117.6, 117.4, 110.6, 109.7, 104.7, 78.5, 40.9, 39.8, 26.8, 26.1, 25.8, 22.8, 17.8, 16.1; 13 C NMR (75 MHz, CDCl 3): δ151.9, 139.6, 136.4, 135.5, 131.5, 128.8, 124.6, 124.5, 124.1, 124.0, 120.6, 119.8, 119.5, 117.6, 117.4, 110.6, 109.7, 104.7, 78.5 , 40.9, 39.8, 26.8, 26.1, 25.8, 22.8, 17.8, 16.1;
IR (neat) 3415, 2920, 2346, 1707, 1633, 1447, 1323, 1216, 1091, 811, 743cm-1;IR (neat) 3415, 2920, 2346, 1707, 1633, 1447, 1323, 1216, 1091, 811, 743 cm < -1 & gt ;;
HRMS (EI) m/z (M+) calcd for C27H31NO: 385.2406. Found: 385.2403.
HRMS (EI) m / z (M + ) calcd for C 27 H 31 NO: 385.2406. Found: 385.2403.
<실시예 6> 3-페닐-3,11-디하이드로피라노[3,2-Example 6 Synthesis of 3-phenyl-3,11-dihydropyrano [3,2- aa ]카바졸(11e) 합성] Carbazole (11e) Synthesis
화합물 10a(182 mg, 1.0 mmol)와 신남알데히드(132 mg, 2.0 mmol)을 p-자일렌(10 mL)에 용해시킨 혼합물에 EDDA(40 mg, 20 mol%)를 첨가하여 얻어진 반응혼합물을 질소 분위기 하에서 8 시간 동안 환류시켰다. 반응 완료를 TLC로 확인한 후, 감압 하에서 용매를 제거하였다. 남은 잔사는 헥산/EtOAc (20:1)을 이용한 컬럼 크로마토그래피를 통해 정제하여 검은색 고상인 화합물 11e(181 mg, 61%)을 얻었다. EDA (40 mg, 20 mol%) was added to a mixture of compound 10a (182 mg, 1.0 mmol) and cinnamaldehyde (132 mg, 2.0 mmol) dissolved in p -xylene (10 mL) Under reflux for 8 hours. After completion of the reaction was confirmed by TLC, the solvent was removed under reduced pressure. The remaining residue was purified by column chromatography using hexane / EtOAc (20: 1) to give compound 11e (181 mg, 61%) as a black solid.
Mp 175-177℃;Mp 175-177 [deg.] C;
1H NMR (300 MHz, CDCl3) :δ8.01(1H,s,br,NH), 7.93(1H,d,J = 7.8 Hz), 7.78 (1H, d, J = 8.4 Hz), 7.50-7.48 (1H, m), 7.40-7.30 (5H, m), 7.21-7.16 (2H, m), 6.83 (1H, d, J = 8.7 Hz), 6.76 (1H, d, J = 8.7 Hz), 5.94-5.88 (2H, m); 1 H NMR (300 MHz, CDCl 3): δ8.01 (1H, s, br, NH), 7.93 (1H, d, J = 7.8 Hz), 7.78 (1H, d, J = 8.4 Hz), 7.50- (2H, m), 6.83 (1H, d, J = 8.7Hz), 6.76 (1H, d, J = 8.7Hz), 5.94 -5.88 (2 H, m);
13C NMR (75 MHz, CDCl3): δ151.8, 140.8, 140.0, 136.7, 128.6, 128.6, 128.3, 127.1, 127.1, 124.6, 123.7, 123.3, 120.8, 119.5, 119.4, 118.0, 110.7, 108.9, 105.2; 13 C NMR (75 MHz, CDCl 3 ): δ 151.8, 140.8, 140.0, 136.7, 128.6, 128.6, 128.3, 127.1, 127.1, 124.6, 123.7, 123.3, 120.8, 119.5, 119.4, 118.0, 110.7, 108.9, 105.2 ;
IR (KBr) 3412, 3046, 2832, 1666, 1643, 1446, 1321, 1216, 1130, 1061, 743, 696 cm-1; IR (KBr) 3412, 3046, 2832, 1666, 1643, 1446, 1321, 1216, 1130, 1061, 743, 696 cm -1 ;
HRMS (EI) m/z (M+) calcd for C21H15NO: 297.1154. Found: 297.1156.
HRMS (EI) m / z ( M +) calcd for C 21 H 15 NO: 297.1154. Found: 297.1156.
<실시예 7> 2,2-디메틸-2,7-디하이드로피라노[3,2-Example 7 Synthesis of 2,2-dimethyl-2,7-dihydropyrano [3,2- cc ]카바졸(11f) 합성] Carbazole (11f) Synthesis
화합물 10b(182 mg, 1.0 mmol)와 3-메틸-2-부테날(168 mg, 2.0 mmol)을 p-자일렌(10 mL)에 용해시킨 혼합물에 EDDA(40 mg, 20 mol%)를 첨가하여 얻어진 반응혼합물을 질소 분위기 하에서 15 시간 동안 환류시켰다. 반응 완료를 TLC로 확인한 후, 감압 하에서 용매를 제거하였다. 남은 잔사는 헥산/EtOAc (20:1)을 이용한 컬럼 크로마토그래피를 통해 정제하여 노란색 고상인 화합물 11f(159 mg, 64%)을 얻었다. To the mixture of compound 10b (182 mg, 1.0 mmol) and 3-methyl-2-butenal (168 mg, 2.0 mmol) in p -xylene (10 mL) was added EDDA (40 mg, 20 mol%) The resulting reaction mixture was refluxed under a nitrogen atmosphere for 15 hours. After completion of the reaction was confirmed by TLC, the solvent was removed under reduced pressure. The remaining residue was purified by column chromatography using hexane / EtOAc (20: 1) to give compound 11f (159 mg, 64%) as a yellow solid.
Mp 128-130℃;Mp 128-130 DEG C;
1H NMR (300 MHz, CDCl3): δ8.24(1H,d,J = 7.8 Hz), 7.85 (1H, s, br, NH), 7.31-7.23 (2H, m), 7.16-7.11 (1H, m), 6.95 (1H, d, J = 8.1 Hz), 6.76 (1H, d, J = 7.8 Hz), 6.37 (1H, d, J = 9.6 Hz), 5.43 (1H, d, J = 9.6 Hz), 1.49 (6H, s); 1 H NMR (300 MHz, CDCl 3): δ8.24 (1H, d, J = 7.8 Hz), 7.85 (1H, s, br, NH), 7.31-7.23 (2H, m), 7.16-7.11 (1H , m), 6.95 (1H, d, J = 8.1 Hz), 6.76 (1H, d, J = 7.8 Hz), 6.37 (1H, d, J = 9.6 Hz), 5.43 (1H, d, J = 9.6 Hz ), 1.49 (6H, s);
13C NMR (75 MHz, CDCl3): δ149.4, 141.3, 139.3, 126.5, 125.2, 124.6, 123.1, 122.9, 122.6, 119.6, 112.4, 112.3, 110.1, 102.5, 77.6, 28.5, 28.5; 13 C NMR (75 MHz, CDCl 3 ):? 149.4, 141.3, 139.3, 126.5, 125.2, 124.6, 123.1, 122.9, 122.6, 119.6, 112.4, 112.3, 110.1, 102.5, 77.6, 28.5, 28.5;
IR (KBr) 3388, 3044, 2768, 1611, 1448, 1389, 1324, 1207, 948, 790, 738, 647 cm-1;IR (KBr) 3388, 3044, 2768, 1611, 1448, 1389, 1324, 1207, 948, 790, 738, 647 cm -1 ;
HRMS (EI) m/z (M+) calcd for C17H15NO: 249.1154. Found: 249.1153.
HRMS (EI) m / z ( M +) calcd for C 17 H 15 NO: 249.1154. Found: 249.1153.
<실시예 8> 2-메틸-2,7-디하이드로피라노[3,2-Example 8: Synthesis of 2-methyl-2,7-dihydropyrano [3,2- cc ]카바졸(11g) 합성] Carbazole (11 g) Synthesis
화합물 10b(182 mg, 1.0 mmol)와 트랜스-크로톤알데히드(140 mg, 2.0 mmol)을 p-자일렌(10 mL)에 용해시킨 혼합물에 EDDA(40 mg, 20 mol%)를 첨가하여 얻어진 반응혼합물을 질소 분위기 하에서 15 시간 동안 환류시켰다. 반응 완료를 TLC로 확인한 후, 감압 하에서 용매를 제거하였다. 남은 잔사는 헥산/EtOAc (20:1)을 이용한 컬럼 크로마토그래피를 통해 정제하여 초록색 고상인 화합물 11g(139 mg, 59%)을 얻었다. To a mixture of compound 10b (182 mg, 1.0 mmol) and trans-crotonaldehyde (140 mg, 2.0 mmol) in p -xylene (10 mL) was added EDDA (40 mg, 20 mol% Was refluxed under a nitrogen atmosphere for 15 hours. After completion of the reaction was confirmed by TLC, the solvent was removed under reduced pressure. The remaining residue was purified by column chromatography using hexane / EtOAc (20: 1) to give 11 g (139 mg, 59%) of the compound as a green solid.
Mp 150-152℃;Mp 150-152 C;
1H NMR (300 MHz, CDCl3):δ8.20(1H,d,J = 7.5 Hz), 7.79 (1H, s, br, NH), 7.30- 7.19 (2H, m), 7.13 (1H, dd, J = 7.2, 6.9 Hz), 6.92 (1H, d, J = 8.1 Hz), 6.74 (1H, d, J = 8.1 Hz), 6.41 (1H, d, J = 9.6 Hz), 5.47 (1H, dd, J = 9.9, 3 Hz), 5.16-5.14 (1H, m), 1.49 (3H, d, J = 6.3 Hz); 1 H NMR (300 MHz, CDCl 3): δ8.20 (1H, d, J = 7.5 Hz), 7.79 (1H, s, br, NH), 7.30- 7.19 (2H, m), 7.13 (1H, dd , J = 7.2, 6.9 Hz) , 6.92 (1H, d, J = 8.1 Hz), 6.74 (1H, d, J = 8.1 Hz), 6.41 (1H, d, J = 9.6 Hz), 5.47 (1H, dd , J = 9.9,3 Hz), 5.16-5.14 (1H, m), 1.49 (3H, d, J = 6.3 Hz);
13C NMR (75 MHz, CDCl3) δ149.7, 141.2, 139.1, 125.1, 124.6, 124.3, 123.0, 122.4, 122.3, 119.5, 112.9, 111.9, 109.9, 102.6, 71.9, 21.6; 13 C NMR (75 MHz, CDCl 3 ) δ 149.7, 141.2, 139.1, 125.1, 124.6, 124.3, 123.0, 122.4, 122.3, 119.5, 112.9, 111.9, 109.9, 102.6, 71.9, 21.6;
IR (KBr) 3360, 2958, 1704, 1620, 1446, 1358, 1223, 747 cm-1;IR (KBr) 3360, 2958, 1704, 1620, 1446, 1358, 1223, 747 cm < -1 & gt ;;
HRMS (EI) m/z (M+) calcd for C16H13NO: 235.0997 Found: 235.0995.
HRMS (EI) m / z ( M +) calcd for C 16 H 13 NO: 235.0997 Found: 235.0995.
<실시예 9> 2-메틸-2-(4-메틸펜트-3-엔-1-일)-2,7-디하이드로피라노[3,2-Example 9 Synthesis of 2-methyl-2- (4-methylpent-3-en-1-yl) -2,7-dihydropyrano [3,2- cc ]카바졸(11h) 합성] Carbazole (11h) Synthesis
화합물 10b(182 mg, 1.0 mmol)와 시트랄(304 mg, 2.0 mmol)을 p-자일렌(10 mL)에 용해시킨 혼합물에 EDDA(40 mg, 20 mol%)를 첨가하여 얻어진 반응혼합물을 질소 분위기 하에서 15 시간 동안 환류시켰다. 반응 완료를 TLC로 확인한 후, 감압 하에서 용매를 제거하였다. 남은 잔사는 헥산/EtOAc (20:1)을 이용한 컬럼 크로마토그래피를 통해 정제하여 붉은색 오일인 화합물 11h(250 mg, 79%)을 얻었다. EDA (40 mg, 20 mol%) was added to a mixture of compound 10b (182 mg, 1.0 mmol) and citral (304 mg, 2.0 mmol) dissolved in p -xylene (10 mL) Under reflux for 15 hours. After completion of the reaction was confirmed by TLC, the solvent was removed under reduced pressure. The remaining residue was purified by column chromatography using hexane / EtOAc (20: 1) to give compound 11h (250 mg, 79%) as a red oil.
1H NMR (300 MHz, CDCl3): δ8.22(1H,d,J = 7.8 Hz), 7.90 (1H, s, br, NH), 7.29-7.27 (2H, m), 7.18-7.11 (1H, m), 6.94 (1H, d, J = 7.8 Hz), 6.77 (1H, d, J = 8.1 Hz), 6.40 (1H, d, J = 10.2 Hz), 5.39 (1H, d, J = 9.9 Hz), 5.06 (1H, t, J = 7.2 Hz), 2.20-2.14 (2H, m), 1.83-1.73 (2H, m), 1.54 (3H, s), 1.46 (6H, s); 1 H NMR (300 MHz, CDCl 3): δ8.22 (1H, d, J = 7.8 Hz), 7.90 (1H, s, br, NH), 7.29-7.27 (2H, m), 7.18-7.11 (1H , m), 6.94 (1H, d, J = 7.8 Hz), 6.77 (1H, d, J = 8.1 Hz), 6.40 (1H, d, J = 10.2 Hz), 5.39 (1H, d, J = 9.9 Hz ), 5.06 (1H, t, J = 7.2 Hz), 2.20-2.14 (2H, m), 1.83-1.73 (2H, m), 1.54 (3H, s), 1.46 (6H, s);
13C NMR (75 MHz, CDCl3): δ149.3, 141.1, 139.1, 131.5, 125.3, 124.9, 124.4, 124.1, 123.2, 122.9, 122.4, 119.3, 112.0, 111.9, 109.9, 102.2, 79.0, 41.5, 26.6, 25.5, 22.7, 17.4; 13 C NMR (75 MHz, CDCl 3): δ149.3, 141.1, 139.1, 131.5, 125.3, 124.9, 124.4, 124.1, 123.2, 122.9, 122.4, 119.3, 112.0, 111.9, 109.9, 102.2, 79.0, 41.5, 26.6 , 25.5, 22.7, 17.4;
IR (neat) 3408, 2962, 2921, 1619, 1447, 1388, 1334, 1272, 1216, 1106, 913, 798, 744 cm-1;IR (neat) 3408, 2962, 2921, 1619, 1447, 1388, 1334, 1272, 1216, 1106, 913, 798, 744 cm -1 ;
HRMS (EI) m/z (M+) calcd for C22H23NO: 317.1780. Found: 317.1776.
HRMS (EI) m / z ( M +) calcd for C 22 H 23 NO: 317.1780. Found: 317.1776.
<실시예 10> 2-(4,8-디메틸노나-3,7-디엔-1-일)-2-메틸-2,7-디하이드로피라노[3,2-Example 10 Synthesis of 2- (4,8-dimethylnona-3,7-dien-1-yl) -2-methyl-2,7-dihydropyrano [3,2- cc ]카바졸(11i) 합성] Carbazole (11i) Synthesis
화합물 10b(182 mg, 1.0 mmol)와 트랜스,트랜스-파네살(220 mg, 2.0 mmol)을 p-자일렌(10 mL)에 용해시킨 혼합물에 EDDA(40 mg, 20 mol%)를 첨가하여 얻어진 반응혼합물을 질소 분위기 하에서 15 시간 동안 환류시켰다. 반응 완료를 TLC로 확인한 후, 감압 하에서 용매를 제거하였다. 남은 잔사는 헥산/EtOAc (20:1)을 이용한 컬럼 크로마토그래피를 통해 정제하여 붉은색 오일인 화합물 11i(327 mg, 85%)을 얻었다. To a mixture of compound 10b (182 mg, 1.0 mmol) and trans, trans-panesar (220 mg, 2.0 mmol) in p -xylene (10 mL) was added EDDA (40 mg, 20 mol% The reaction mixture was refluxed under a nitrogen atmosphere for 15 hours. After completion of the reaction was confirmed by TLC, the solvent was removed under reduced pressure. The residue was purified by column chromatography using hexane / EtOAc (20: 1) to give compound 11i (327 mg, 85%) as a red oil.
1H NMR (300 MHz, CDCl3) :δ8.30(1H,d,J = 7.8 Hz), 7.92 (1H, s, br, NH), 7.36-7.32 (2H, m), 7.24-7.18 (1H, m), 7.01 (1H, d, J = 7.8 Hz), 6.84 (1H, dd, J = 8.1, 1.5 Hz), 6. 47 (1H, d, J = 9.9 Hz), 5.47 (1H, d, J = 10.2 Hz), 5.14 (1H, t, J = 7.2 Hz), 5.05 (1H, t, J = 6.9 Hz), 2.27 (2H, t, J = 5.4 Hz), 2.00 (2H, t, J = 6.6 Hz), 1.94-1.83 (4H, m), 1.65 (3H, s), 1.56 (3H, s), 1.53 (6H, s); 1 H NMR (300 MHz, CDCl 3): δ8.30 (1H, d, J = 7.8 Hz), 7.92 (1H, s, br, NH), 7.36-7.32 (2H, m), 7.24-7.18 (1H , m), 7.01 (1H, d, J = 7.8 Hz), 6.84 (1H, dd, J = 8.1, 1.5 Hz), 6. 47 (1H, d, J = 9.9 Hz), 5.47 (1H, d, J = 10.2 Hz), 5.14 ( 1H, t, J = 7.2 Hz), 5.05 (1H, t, J = 6.9 Hz), 2.27 (2H, t, J = 5.4 Hz), 2.00 (2H, t, J = 6.6 Hz), 1.94-1.83 (4H, m), 1.65 (3H, s), 1.56 (3H, s), 1.53 (6H, s);
13C NMR (75 MHz, CDCl3): δ149.6, 141.3, 139.3, 135.4, 131.4, 125.6, 125.2, 124.7, 124.5, 124.2, 123.4, 123.1, 122.6, 119.7, 112.3, 112.2, 110.1, 102.4, 79.3, 41.7, 39.8, 26.9, 26.8, 25.8, 22.8, 17.8, 16.0; 13 C NMR (75 MHz, CDCl 3 ):? 149.6, 141.3, 139.3, 135.4, 131.4, 125.6, 125.2, 124.7, 124.5, 124.2, 123.4, 123.1, 122.6, 119.7, 112.3, 112.2, 110.1, 102.4, 79.3 , 41.7, 39.8, 26.9, 26.8, 25.8, 22.8, 17.8, 16.0;
IR (neat) 3405, 3039, 2957, 2920, 1709, 1618, 1444, 1347, 1218, 1099, 914, 798, 745, 658 cm-1; IR (neat) 3405, 3039, 2957, 2920, 1709, 1618, 1444, 1347, 1218, 1099, 914, 798, 745, 658 cm -1 ;
HRMS (EI) m/z (M+) calcd for C27H31NO: 385.2406. Found:385.2403.
HRMS (EI) m / z (M + ) calcd for C 27 H 31 NO: 385.2406. Found: 385.2403.
<실시예 11> 2-페닐-2,7-디하이드로피라노[3,2-Example 11: Synthesis of 2-phenyl-2,7-dihydropyrano [3,2- cc ]카바졸(11j) 합성] Carbazole (11j) Synthesis
화합물 10a(182 mg, 1.0 mmol)와 신남알데히드(132 mg, 2.0 mmol)을 p-자일렌(10 mL)에 용해시킨 혼합물에 EDDA(40 mg, 20 mol%)를 첨가하여 얻어진 반응혼합물을 질소 분위기 하에서 8 시간 동안 환류시켰다. 반응 완료를 TLC로 확인한 후, 감압 하에서 용매를 제거하였다. 남은 잔사는 헥산/EtOAc (20:1)을 이용한 컬럼 크로마토그래피를 통해 정제하여 갈색 고상인 화합물 11j(181 mg, 61%)을 얻었다. EDA (40 mg, 20 mol%) was added to a mixture of compound 10a (182 mg, 1.0 mmol) and cinnamaldehyde (132 mg, 2.0 mmol) dissolved in p -xylene (10 mL) Under reflux for 8 hours. After completion of the reaction was confirmed by TLC, the solvent was removed under reduced pressure. The remaining residue was purified by column chromatography using hexane / EtOAc (20: 1) to obtain a brown solid compound 11j (181 mg, 61%).
Mp 110-112℃;Mp 110-112 DEG C;
1H NMR (300 MHz, CDCl3): δ8.28(1H,d,J = 7.8Hz), 8.00 (1H, s, br, NH), 7.62 (2H, d, J = 7.5 Hz), 7.43-7.29 (5H, m), 7.24-7.19 (1H, m), 7.10 (1H, d, J = 8.1 Hz), 6.94 (1H, d, J = 8.1 Hz), 6.70 (1H, d, J = Hz 9.6 Hz), 6.23 (1H, s), 5.80 (1H, dd, J = 9.9, 3.6 Hz ); 1 H NMR (300 MHz, CDCl 3): δ8.28 (1H, d, J = 7.8Hz), 8.00 (1H, s, br, NH), 7.62 (2H, d, J = 7.5 Hz), 7.43- 7.29 (5H, m), 7.24-7.19 (1H, m), 7.10 (1H, d, J = 8.1 Hz), 6.94 (1H, d, J = 8.1 Hz), 6.70 (1H, d, J = Hz 9.6 Hz), 6.23 (1H, s), 5.80 (1H, dd, J = 9.9, 3.6 Hz);
13C NMR (75 MHz, CDCl3): δ149.4, 141.7, 141.5, 139.3, 129.1, 128.7, 128.7, 128.1, 126.7, 126.7, 125.3, 124.9, 124.6, 123.2, 122.3, 120.5, 119.8, 112.6, 111.9, 110.2, 103.1; 13 C NMR (75 MHz, CDCl 3): δ149.4, 141.7, 141.5, 139.3, 129.1, 128.7, 128.7, 128.1, 126.7, 126.7, 125.3, 124.9, 124.6, 123.2, 122.3, 120.5, 119.8, 112.6, 111.9 , 110.2, 103.1;
IR (KBr) 3384, 3034, 2909, 1612, 1489, 1448, 1395, 1334, 1269, 1210, 1100, 956, 803, 742;IR (KBr) 3384, 3034, 2909, 1612, 1489, 1448, 1395, 1334, 1269, 1210, 1100, 956, 803, 742;
HRMS (EI) m/z (M+) calcd for C21H15NO: 297.1154. Found: 297.1151.
HRMS (EI) m / z ( M +) calcd for C 21 H 15 NO: 297.1154. Found: 297.1151.
<실시예 12> 트랜스-2-브로모-3,3-디메틸-1,2,3,11-테트라하이드로피라노[3,2-a]카바졸-1-올(14) 합성Example 12 Synthesis of trans-2-bromo-3,3-dimethyl-1,2,3,11-tetrahydropyrano [3,2-a]
다이옥산(5 mL)에 용해시킨 화합물 11a 용액(125 mg, 0.5 mmol)에 NBS(N-bromosuccinimide, 133 mg, 0.75 mmol)를 첨가하였다. 실온에서 3시간 동안 교반한 후, 진공 하에서 과량의 용매를 제거하였다. 상기 반응혼합물을 EtOAc (10 mL x 3)로 추출하고 염수(10 mL) 및 물(10 mL)로 세정하였다. 이렇게 얻어진 유기층을 무수 Na2SO4로 건조시켰다. 상기 용매를 진공 하에서 제거한 후 얻은 조산물은 헥산/EtOAc (7:1)을 이용한 실리카겔 컬럼 크로마토그래피를 통해 정제하여 황백색 고상인 화합물 14(95 mg, 55%)를 얻었다. N-bromosuccinimide (133 mg, 0.75 mmol) was added to a solution of Compound 11a (125 mg, 0.5 mmol) dissolved in dioxane (5 mL). After stirring at room temperature for 3 hours, excess solvent was removed under vacuum. The reaction mixture was extracted with EtOAc (10 mL x 3) and washed with brine (10 mL) and water (10 mL). The organic layer thus obtained was dried with anhydrous Na 2 SO 4 . The solvent was removed in vacuo and the obtained crude product was purified by silica gel column chromatography using hexane / EtOAc (7: 1) to give Compound 14 (95 mg, 55%) as a pale yellow solid.
Mp 180-182℃;Mp 180-182 DEG C;
1H NMR (300 MHz, CDCl3): δ7.90(1H,d,J = 7.8 Hz), 7.84 (1H, d, J = 8.4 Hz), 7.80 (1H, s, NH), 7.36-7.27 (2H, m), 7.23-7.16 (1H, m), 6.78 (1H, d, J = 8.4 Hz), 5.83 (1H, d, J = 9.6 Hz), 5.26 (1H, d, J = 9.6 Hz), 2.92 (1H, br, s, OH), 1.67 (3H, s), 1.42 (3H, s); 1 H NMR (300 MHz, CDCl 3): δ7.90 (1H, d, J = 7.8 Hz), 7.84 (1H, d, J = 8.4 Hz), 7.80 (1H, s, NH), 7.36-7.27 ( 2H, m), 7.23-7.16 (1H , m), 6.78 (1H, d, J = 8.4 Hz), 5.83 (1H, d, J = 9.6 Hz), 5.26 (1H, d, J = 9.6 Hz), 2.92 (1H, br, s, OH), 1.67 (3H, s), 1.42 (3H, s);
13C NMR (75 MHz, DMSO-d 6 ): δ 151.5, 140.1, 136.6, 124.4, 122.7, 120.9, 119.4, 119.0, 117.3, 111.9, 109.9, 101.5, 77.9, 55.3, 50.6, 28.0, 19.5; 13 C NMR (75 MHz, DMSO- d 6): δ 151.5, 140.1, 136.6, 124.4, 122.7, 120.9, 119.4, 119.0, 117.3, 111.9, 109.9, 101.5, 77.9, 55.3, 50.6, 28.0, 19.5;
IR (KBr) 3457, 3416, 2986, 1776, 1696, 1606, 1459, 1386, 1163, 744 cm-1;IR (KBr) 3457, 3416, 2986, 1776, 1696, 1606, 1459, 1386, 1163, 744 cm < -1 & gt ;;
FAB-HRMS m/z (M-H2O+H)+calcd for C17H16BrNO2: 328.0337. Found:328.0334.
FAB-HRMS m / z (MH 2 O + H) + calcd for C 17 H 16 BrNO 2 : 328.0337. Found: 328.0334.
<실시예 13> 시스-3,3-디메틸-1,2,3,11-테트라하이드로피라노[3,2-a]카바졸-1,2-디올(15) 합성Example 13 Synthesis of cis-3,3-dimethyl-1,2,3,11-tetrahydropyrano [3,2-a] carbazole-1,2-diol (15)
다이옥산(5 mL)에 용해시킨 화합물 11a 용액(125 mg, 0.5 mmol)을 0℃에서 오스뮴 테트록사이드(OsO4, 4% in water, 0.31 mL, 10 mol%)와 4-메틸모폴린 N-옥사이드(NMO, 117 mg, 2.0 mmol)를 t-BuOH/THF/H2O(10:3:1,10mL)에서 용해시킨 교반 용액에 첨가하였다. 상기 반응혼합물을 실온에서 데운 후, 5시간 동안 교반하였다. NaHSO3 수용액의 포화 용액(10 mL)을 첨가하고, 반응혼합물을 추가적으로 1시간 더 교반한 후, EtOAc (10 mL x 3)로 추출하였다. 상기 얻어진 유기층을 염수(30 mL)로 세정하고, 무수 Na2SO4로 건조시키고, 감압 하에서 농축시켰다. 상기 용매를 진공 하에서 제거한 후 얻은 조산물은 헥산/EtOAc (4:1)을 이용한 실리카겔 컬럼 크로마토그래피를 통해 정제하여 황백색 고상인 화합물 15(99 mg, 70%)를 얻었다. (OsO 4 , 4% in water, 0.31 mL, 10 mol%) and 4-methylmorpholine N -methylpyrrolidone were dissolved at 0 ° C in a solution of compound 11a (125 mg, 0.5 mmol) Oxide (NMO, 117 mg, 2.0 mmol) was added to a stirred solution of t- BuOH / THF / H 2 O (10: 3: 1, 10 mL). The reaction mixture was warmed to room temperature and then stirred for 5 hours. After addition of a saturated solution (10 mL) of NaHSO 3 aqueous solution, and further stirred for 1 hours the reaction mixture was extracted with EtOAc (10 mL x 3). The obtained organic layer was washed with brine (30 mL), dried over anhydrous Na 2 SO 4 , and concentrated under reduced pressure. The solvent was removed in vacuo and the obtained crude product was purified by silica gel column chromatography using hexane / EtOAc (4: 1) to give compound 15 (99 mg, 70%) as a yellowish white solid.
Mp 160-162℃;Mp 160-162 DEG C;
1H NMR (300 MHz, acetone-d 6): δ9.89(1H,s,NH), 7.95(1H,d,J = 7.8 Hz), 7.84 (1H, d, J = 8.4 Hz), 7.55 (1H, d, J = 8.1 Hz), 7.29-7.24 (1H, m), 7.13-7.08 (1H, m), 6.61 (1H, d, J = 8.1 Hz), 5.20 (1H, dd, J = 8.1, 4.8 Hz), 4.23 (1H, d, J = 6.3 Hz, OH), 4.14 (1H, d, J = 8.4 Hz, OH), 3.83 (1H, dd, J = 5.4, 5.1 Hz), 1.48 (3H, s), 1.32 (3H, s); 1 H NMR (300 MHz, acetone- d 6): δ9.89 (1H, s, NH), 7.95 (1H, d, J = 7.8 Hz), 7.84 (1H, d, J = 8.4 Hz), 7.55 ( 1H, d, J = 8.1 Hz ), 7.29-7.24 (1H, m), 7.13-7.08 (1H, m), 6.61 (1H, d, J = 8.1 Hz), 5.20 (1H, dd, J = 8.1, 4.8 Hz), 4.23 (1H, d, J = 6.3 Hz, OH), 4.14 (1H, d, J = 8.4 Hz, OH), 3.83 (1H, dd, J = 5.4, 5.1 Hz), 1.48 (3H, s), 1.32 (3H, s);
13C NMR (75 MHz, actone-d 6 ): δ 152.6, 141.0, 124.8, 124.8, 124.3, 121.0, 119.8, 119.7, 117.5, 111.8, 110.2, 106.1, 78.5, 72.0, 65.1, 24.5, 24.3; 13 C NMR (75 MHz, actone- d 6 ):? 152.6, 141.0, 124.8, 124.8, 124.3, 121.0, 119.8, 119.7, 117.5, 111.8, 110.2, 106.1, 78.5, 72.0, 65.1, 24.5, 24.3;
IR (KBr) 3309, 3056, 2924, 1706, 1609, 1451, 1346, 1255, 1146, 1087, 922, 793, 738 cm-1;IR (KBr) 3309, 3056, 2924, 1706, 1609, 1451, 1346, 1255, 1146, 1087, 922, 793, 738 cm -1 ;
HRMS (EI) m/z (M+) calcd for C17H17NO3: 283.1208. Found: 283.1207.
HRMS (EI) m / z ( M +) calcd for C 17 H 17 NO 3: 283.1208. Found: 283.1207.
<실시예 14> 시스-3,3-디메틸-1,2,3,11-테트라하이드로피라노[3,2-a]카바졸-1,2-디올(15) 및 트랜스-3,3-디메틸-1,2,3,11-테트라하이드로피라노[3,2-a]카바졸-1,2-디올(16) 합성Example 14 Synthesis of cis-3,3-dimethyl-1,2,3,11-tetrahydropyrano [3,2-a] carbazole-1,2-diol (15) Dimethyl-1,2,3,11-tetrahydropyrano [3,2-a] carbazole-1,2-diol (16)
실온에서 디메틸디옥시란(DMDO, 2.8 mL, 0.052 M, 1.0 mmol)을 습윤 아세톤(5 mL)에 용해시킨 화합물 11a 용액(125 mg, 0.5 mmol)에 첨가하였다. 상기 반응혼합물을 실온에서 4시간 동안 교반하고 감압 하에서 농축하였다. 얻어진 잔사를 헥산/EtOAc (3:1)을 이용한 실리카겔 플래쉬 컬럼 크로마토그래피를 통해 정제하여 시스-디올인 화합물 15(73 mg, 52%)와 트랜스-디올인 고상 화합물 16(40 mg, 28%)을 얻었다. (DMDO, 2.8 mL, 0.052 M, 1.0 mmol) was added to a solution of compound 11a (125 mg, 0.5 mmol) dissolved in wet acetone (5 mL) at room temperature. The reaction mixture was stirred at room temperature for 4 hours and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel using hexane / EtOAc (3: 1) to obtain 40 mg (28%) of cis-diol phosphorus compound 15 (73 mg, 52% ≪ / RTI >
트랜스-디올 (화합물 16)Trans-diol (Compound 16)
Mp 70-72℃;Mp 70-72 DEG C;
1H NMR (300 MHz, acetone-d 6): δ 9.77 (1H,s,NH), 7.82 (1H,d,J = 7.8 Hz), 7.71 (1H, d, J = 8.7 Hz), 7.40 (1H, d, J = 8.1 Hz), 7.13 (1H, t, J = 8.1 Hz, 1H), 6.97 (1H, dd, J = 8.1, 7.8 Hz), 6.49 (1H, d, J = 8.4 Hz), 4.79 (1H, d, J = 8.1 Hz), 4.60 (1H, br, s, OH), 4.34 (1H, br, s, OH), 3.63 (1H, d, J = 8.1 Hz), 1.34 (3H, s), 1.10 (3H, s); 1 H NMR (300 MHz, acetone- d 6): δ 9.77 (1H, s, NH), 7.82 (1H, d, J = 7.8 Hz), 7.71 (1H, d, J = 8.7 Hz), 7.40 (1H , d, J = 8.1 Hz) , 7.13 (1H, t, J = 8.1 Hz, 1H), 6.97 (1H, dd, J = 8.1, 7.8 Hz), 6.49 (1H, d, J = 8.4 Hz), 4.79 (1H, d, J = 8.1 Hz), 4.60 (1H, br, s, OH), 4.34 (1H, br, s, OH), 3.63 (1H, d, J = 8.1 Hz), 1.34 (3H, s ), 1.10 (3H, s);
13C NMR (75 MHz, acetone-d 6 ): δ 152.2, 141.0, 140.5, 124.8, 124.1, 121.1, 119.8, 119.7, 117.6, 111.8, 110.1, 107.5, 79.6, 77.4, 69.8, 27.2, 19.2; 13 C NMR (75 MHz, acetone- d 6): δ 152.2, 141.0, 140.5, 124.8, 124.1, 121.1, 119.8, 119.7, 117.6, 111.8, 110.1, 107.5, 79.6, 77.4, 69.8, 27.2, 19.2;
IR (KBr) 3436, 2961, 2926, 1711, 1613, 1459, 1308, 1221, 1021, 745 cm-1;IR (KBr) 3436, 2961, 2926, 1711, 1613, 1459, 1308, 1221, 1021, 745 cm -1 ;
HRMS (EI) m/z (M+) calcd for C17H17NO3: 283.1208. Found: 283.1205.
HRMS (EI) m / z ( M +) calcd for C 17 H 17 NO 3: 283.1208. Found: 283.1205.
<실시예 15> 3,3,11-트리메틸-3,11-디하이드로피라노[3,2-a]카바졸(17) 합성Example 15 Synthesis of 3,3,11-trimethyl-3,11-dihydropyrano [3,2-a] carbazole (17)
0℃에서 NaH(60% dispersion in mineral oil, 300 mg 7.5 mmol)를 DMF(디메틸포름아마이드, 5 mL)에 용해시킨 화합물 11a 용액(1.245 g, 5.0 mmol)에 첨가하고 30분 동안 교반한 후 메틸 아이오다이드(0.34 mL, 5.5 mmol)를 몇 방울 적가하였다. 상기 반응혼합물을 30분 더 교반한 후, 빙수(30 mL)로 식혔다. 상기 반응혼합물을 EtOAc (30 mL x 3)로 추출하고 염화암모늄 포화 용액(50 mL)과 물(30 mL)로 세정하였다. 얻어진 유기층을 무수 Na2SO4로 건조시켰다. 상기 용매를 진공 하에서 제거한 후 얻은 조산물은 헥산/EtOAc (20:1)을 이용한 실리카겔 컬럼 크로마토그래피를 통해 정제하여 황백색 고상인 화합물 17(1.249 g, 95%)을 얻었다. Was added to a solution of compound 11a (1.245 g, 5.0 mmol) in which NaH (60% dispersion in mineral oil, 300 mg, 7.5 mmol) was dissolved in DMF (dimethylformamide, 5 mL) at 0 ° C, stirred for 30 minutes, A few drops of iodide (0.34 mL, 5.5 mmol) were added. The reaction mixture was stirred for an additional 30 minutes and then chilled with ice water (30 mL). The reaction mixture was extracted with EtOAc (30 mL x 3) and washed with saturated aqueous ammonium chloride (50 mL) and water (30 mL). The obtained organic layer was dried over anhydrous Na 2 SO 4 . The solvent was removed in vacuo and the obtained crude product was purified by silica gel column chromatography using hexane / EtOAc (20: 1) to give compound 17 as a yellowish white solid (1.249 g, 95%).
Mp 160-162℃;Mp 160-162 DEG C;
1H NMR (300 MHz, CDCl3): δ 7.92 (1H,d,J = 7.5 Hz), 7.80 (1H, d, J = 8.4 Hz), 7.39-7.29 (2H, m), 7.20-7.12 (2H, m), 6.74 (1H, d, J = 8.1 Hz), 5.66 (1H, d, J = 9.9 Hz), 4.01 (3H, s), 1.48 (6H, s); 1 H NMR (300 MHz, CDCl 3): δ 7.92 (1H, d, J = 7.5 Hz), 7.80 (1H, d, J = 8.4 Hz), 7.39-7.29 (2H, m), 7.20-7.12 (2H (1H, m), 6.74 (1H, d, J = 8.1 Hz), 5.66 (1H, d, J = 9.9 Hz), 4.01 (3H, s), 1.48 (6H, s);
13C NMR (75 MHz, CDCl3): δ 152.7, 141.8, 137.6, 128.7, 124.6, 123.2, 120.6, 119.4, 119.2, 118.7, 118.1, 109.8, 108.4, 106.3, 75.1, 33.0, 27.2, 27.2; 13 C NMR (75 MHz, CDCl 3 ):? 152.7, 141.8, 137.6, 128.7, 124.6, 123.2, 120.6, 119.4, 119.2, 118.7, 118.1, 109.8, 108.4, 106.3, 75.1, 33.0, 27.2, 27.2;
IR(KBr) 3051, 2970, 2928, 1632, 1584, 1463, 1401, 1342, 1213, 1114, 1012, 820, 736 cm-1; IR (KBr) 3051, 2970, 2928, 1632, 1584, 1463, 1401, 1342, 1213, 1114, 1012, 820, 736 cm -1 ;
HRMS (EI) m/z (M+) calcd for C18H17NO: 263.1310. Found: 263.1309.
HRMS (EI) m / z ( M +) calcd for C 18 H 17 NO: 263.1310. Found: 263.1309.
<실시예 16> 트랜스-2-브로모-3,3,11--트리메틸-1,2,3,11-테트라하이드로피라노[3,2-a]카바졸-1-올(18) 합성Example 16 Synthesis of trans-2-bromo-3,3,11-trimethyl-1,2,3,11-tetrahydropyrano [3,2-a]
다이옥산(5 mL)에 용해시킨 화합물 17 용액(132 mg, 0.5 mmol)에 NBS(133 mg, 0.75 mmol)를 첨가하였다. 실온에서 3시간 동안 교반한 후, 과량의 용매를 진공 하에서 제거하였다. 상기 반응혼합물을 EtOAc (10 mL x 3)로 추출하고 염수(10 mL) 및 물(10 mL)로 세정하였다. 상기 얻어진 유기층을 Na2SO4로 건조시켰다. 상기 용매를 진공 하에서 제거한 후 얻은 조산물은 헥산/EtOAc (7:1)을 이용한 실리카겔 컬럼 크로마토그래피를 통해 정제하여 황백색 고상인 화합물 18(99 mg, 55%)를 얻었다. NBS (133 mg, 0.75 mmol) was added to a solution of Compound 17 (132 mg, 0.5 mmol) dissolved in dioxane (5 mL). After stirring at room temperature for 3 hours, the excess solvent was removed in vacuo. The reaction mixture was extracted with EtOAc (10 mL x 3) and washed with brine (10 mL) and water (10 mL). The obtained organic layer was dried with Na 2 SO 4. The solvent was removed in vacuo and the crude product was purified by silica gel column chromatography using hexane / EtOAc (7: 1) to give compound 18 (99 mg, 55%) as a pale yellow solid.
Mp 228-230℃;Mp 228-230 C;
1H NMR (300 MHz, acetone-d 6): δ 7.97-7.92 (2H,m), 7.38-7.33 (2H,m), 7.14-7.20 (1H,m), 6.72 (1H,d,J = 8.4 Hz), 6.26 (1H, d, J = 9.3 Hz), 4.70 (1H, d, J = 9.3 Hz), 3.72(3H, s), 2.80 (1H, br, s, OH), 1.62 (3H, s), 1.58 (3H, s); 1 H NMR (300 MHz, acetone- d 6): δ 7.97-7.92 (2H, m), 7.38-7.33 (2H, m), 7.14-7.20 (1H, m), 6.72 (1H, d, J = 8.4 Hz), 6.26 (1H, d , J = 9.3 Hz), 4.70 (1H, d, J = 9.3 Hz), 3.72 (3H, s), 2.80 (1H, br, s, OH), 1.62 (3H, s ), 1.58 (3H, s);
13C NMR (75 MHz, acetone-d 6): δ 177.6, 154.8, 144.1, 125.4, 121.9, 121.0, 120.6, 120.0, 119.7, 119.5, 111.4, 110.6, 103.9, 78.5, 57.6, 53.0, 34.5, 18.3, 18.1; 13 C NMR (75 MHz, acetone- d 6): δ 177.6, 154.8, 144.1, 125.4, 121.9, 121.0, 120.6, 120.0, 119.7, 119.5, 111.4, 110.6, 103.9, 78.5, 57.6, 53.0, 34.5, 18.3, 18.1;
IR(KBr) 3469, 2982, 2935, 1710, 1591, 1452, 1354, 1212, 1154, 1007, 815, 752 cm-1;IR (KBr) 3469, 2982, 2935, 1710, 1591, 1452, 1354, 1212, 1154, 1007, 815, 752 cm -1 ;
FAB-HRMS m/z (M-H2O+H)+calcd for C18H18BrNO2: 342.0494. Found: 342.0493. FAB-HRMS m / z (MH 2 O + H) + calcd for C 18 H 18 BrNO 2 : 342.0494. Found: 342.0493.
<실시예 17> 시스-3,3,11-트리메틸-1,2,3,11-테트라하이드로피라노[3,2-a]카바졸-1,2-디올(19) 합성Example 17 Synthesis of cis-3,3,11-trimethyl-1,2,3,11-tetrahydropyrano [3,2-a] carbazole-1,2-diol (19)
화합물 17 용액(132 mg, 0.5 mmol)을 0℃에서 오스뮴 테트록사이드(4% in water, 0.31 mL, 10 mol%)와 4-메틸모폴린 N-옥사이드(NMO, 117 mg, 2.0 mmol)를 t-BuOH/THF/H2O(10:3:1,10mL)에서 용해시킨 교반 용액에 첨가하였다. 상기 반응혼합물을 실온에서 데운 후, 5시간 동안 교반하였다. NaHSO3 수용액의 포화 용액(10 mL)을 첨가하고, 반응혼합물을 추가적으로 1시간 더 교반한 후, EtOAc (10 mL x 3)로 추출하였다. 상기 얻어진 유기층을 염수(30 mL)로 세정하고, 무수 Na2SO4로 건조시키고, 감압 하에서 농축시켰다. 상기 용매를 진공 하에서 제거한 후 얻은 조산물은 헥산/EtOAc (4:1)을 이용한 실리카겔 컬럼 크로마토그래피를 통해 정제하여 시스-디올인 화합물 19(110 mg, 74%)를 얻었다. (NMO, 117 mg, 2.0 mmol) was added to a solution of compound 17 (132 mg, 0.5 mmol) at 0 < 0 > C and treated with osmium tetroxide (4% in water, 0.31 mL, 10 mol%) and 4-methylmorpholine N- t- BuOH / THF / H 2 O (10: 3: 1, 10 mL). The reaction mixture was warmed to room temperature and then stirred for 5 hours. After addition of a saturated solution (10 mL) of NaHSO 3 aqueous solution, and further stirred for 1 hours the reaction mixture was extracted with EtOAc (10 mL x 3). The obtained organic layer was washed with brine (30 mL), dried over anhydrous Na 2 SO 4 , and concentrated under reduced pressure. The solvent was removed in vacuo, and the obtained crude product was purified by silica gel column chromatography using hexane / EtOAc (4: 1) to obtain cis-diol compound 19 (110 mg, 74%).
Mp 178-180℃;Mp 178-180 DEG C;
1H NMR (300 MHz, acetone-d 6): δ 7.97(1H,d,J = 7.5 Hz), 7.92 (1H, d, J = 8.4 Hz), 7.47 (1H, d, J = 8.1 Hz), 7.35 (1H, dd, J = 8.1, 7.2 Hz), 7.15 (1H, dd, J = 7.8, 7.2 Hz), 6.64 (1H, d, J = 8.4 Hz), 5.39 (1H, t, J = 4.5 Hz), 4.66 (1H, d, J = 6.3 Hz), 4.24 (3H, s), 4.21 (1H, d, J = 4.2 Hz), 3.94 (1H, dd, J = 6.0, 5.1 Hz), 1.46 (3H, s), 1.45 (3H, s); 1 H NMR (300 MHz, acetone- d 6): δ 7.97 (1H, d, J = 7.5 Hz), 7.92 (1H, d, J = 8.4 Hz), 7.47 (1H, d, J = 8.1 Hz), 7.35 (1H, dd, J = 8.1, 7.2 Hz), 7.15 (1H, dd, J = 7.8, 7.2 Hz), 6.64 (1H, d, J = 8.4 Hz), 5.39 (1H, t, J = 4.5 Hz ), 4.66 (1H, d, J = 6.3 Hz), 4.24 (3H, s), 4.21 (1H, d, J = 4.2 Hz), 3.94 (1H, dd, J = 6.0, 5.1 Hz), 1.46 (3H , < / RTI > s), 1.45 (3H, s);
13C NMR (75 MHz, acetone-d 6): δ 153.4, 142.9, 125.3, 125.3, 124.2, 122.0, 120.2, 119.8, 119.7, 118.3, 111.3, 109.9, 77.7, 73.3, 63.7, 32.0, 27.5, 21.9, 21.9; 13 C NMR (75 MHz, acetone- d 6): δ 153.4, 142.9, 125.3, 125.3, 124.2, 122.0, 120.2, 119.8, 119.7, 118.3, 111.3, 109.9, 77.7, 73.3, 63.7, 32.0, 27.5, 21.9, 21.9;
IR (KBr) 3424, 2930, 2882, 1590, 1452, 1336, 1217, 1114, 1070, 997, 739 cm-1;IR (KBr) 3424, 2930, 2882, 1590, 1452, 1336, 1217, 1114, 1070, 997, 739 cm < -1 & gt ;;
HRMS (EI) m/z (M+) calcd for C18H19NO3: 297.1365. Found: 297.1361.
HRMS (EI) m / z ( M +) calcd for C 18 H 19 NO 3: 297.1365. Found: 297.1361.
<실시예 18> 트랜스-3-브로모-2,2-디메틸-2,3,4,7-테트라하이드로피라노[3,2-c]카바졸-4-올(20) 합성Example 18 Synthesis of trans-3-bromo-2,2-dimethyl-2,3,4,7-tetrahydropyrano [3,2-c]
다이옥산(5 mL)에 용해시킨 화합물 11f 용액(125 mg, 0.5 mmol)에 NBS(N-bromosuccinimide, 133 mg, 0.75 mmol)를 첨가하였다. 실온에서 3시간 동안 교반한 후, 진공 하에서 과량의 용매를 제거하였다. 상기 반응혼합물을 EtOAc (10 mL x 3)로 추출하고 염수(10 mL) 및 물(10 mL)로 세정하였다. 이렇게 얻어진 유기층을 무수 Na2SO4로 건조시켰다. 상기 용매를 진공 하에서 제거한 후 얻은 조산물은 헥산/EtOAc (7:1)을 이용한 실리카겔 컬럼 크로마토그래피를 통해 정제하여 황백색 고상인 화합물 20(102 mg, 59%)을 얻었다. NBS (N-bromosuccinimide, 133 mg, 0.75 mmol) was added to a solution of Compound 11f (125 mg, 0.5 mmol) dissolved in dioxane (5 mL). After stirring at room temperature for 3 hours, excess solvent was removed under vacuum. The reaction mixture was extracted with EtOAc (10 mL x 3) and washed with brine (10 mL) and water (10 mL). The organic layer thus obtained was dried with anhydrous Na 2 SO 4 . The solvent was removed in vacuo and the obtained crude product was purified by silica gel column chromatography using hexane / EtOAc (7: 1) to give compound 20 (102 mg, 59%) as a pale yellow solid.
Mp 172-174℃;Mp 172-174 DEG C;
1H NMR (300 MHz, CDCl3): δ 8.11 (1H,d,J = 7.8 Hz), 7.99 (1H, s, NH), 7.25-7.22 (2H, m), 7.14-7.08 (1H, m), 6.76 (1H, d, J = 8.1 Hz), 6.64 (1H, d, J = 8.4 Hz), 5.63 (1H, d, J = 10.8 Hz), 5.14 (1H, d, J = 10.8 Hz), 2.80 (1H, br, s, OH), 1.73 (3H, s), 1.44 (3H, s); 1 H NMR (300 MHz, CDCl 3): δ 8.11 (1H, d, J = 7.8 Hz), 7.99 (1H, s, NH), 7.25-7.22 (2H, m), 7.14-7.08 (1H, m) , 6.76 (1H, d, J = 8.1 Hz), 6.64 (1H, d, J = 8.4 Hz), 5.63 (1H, d, J = 10.8 Hz), 5.14 (1H, d, J = 10.8 Hz), 2.80 (1H, br, s, OH), 1.73 (3H, s), 1.44 (3H, s);
13C NMR (75 MHz, CDCl3): δ 148.9, 140.5, 138.9, 125.2, 122.9, 122.6, 122.1, 119.6, 112.3, 110.0, 108.4, 104.0, 79.5, 53.4, 53.0, 29.1, 19.1; 13 C NMR (75 MHz, CDCl 3 ):? 148.9, 140.5, 138.9, 125.2, 122.9, 122.6, 122.1, 119.6, 112.3, 110.0, 108.4, 104.0, 79.5, 53.4, 53.0, 29.1, 19.1;
IR (KBr) 3402, 2982, 1776, 1705, 1612, 1497, 1450, 1374, 1157,733 cm-1;IR (KBr) 3402, 2982, 1776, 1705, 1612, 1497, 1450, 1374, 1157, 733 cm < -1 & gt ;;
FAB-HRMS m/z (M-H2O+H)+calcd for C17H16BrNO2: 328.0337 Found: 328.0334.
FAB-HRMS m / z (MH 2 O + H) + calcd for C 17 H 16 BrNO 2 : 328.0337 Found: 328.0334.
<실시예 19> 시스-2,2-디메틸-2,3,4,7-테트라하이드로피라노[3,2-c]카바졸-3,4-디올(21) 합성Example 19 Synthesis of cis-2,2-dimethyl-2,3,4,7-tetrahydropyrano [3,2-c] carbazole-3,4-diol (21)
화합물 11f(125 mg, 0.5 mmol)을 0℃에서 오스뮴 테트록사이드(4% in water, 0.31 mL, 10 mol%)와 4-메틸모폴린 N-옥사이드(NMO, 117 mg, 2.0 mmol)를 t-BuOH/THF/H2O(10:3:1,10mL)에서 용해시킨 교반 용액에 첨가하였다. 상기 반응혼합물을 실온에서 데운 후, 5시간 동안 교반하였다. NaHSO3 수용액의 포화 용액(10 mL)을 첨가하고, 반응혼합물을 추가적으로 1시간 더 교반한 후, EtOAc (10 mL x 3)로 추출하였다. 상기 얻어진 유기층을 염수(30 mL)로 세정하고, 무수 Na2SO4로 건조시키고, 감압 하에서 농축시켰다. 얻은 조산물은 헥산/EtOAc (4:1)을 이용한 실리카겔 컬럼 크로마토그래피를 통해 정제하여 시스-디올인 화합물 21(95 mg, 67%)을 얻었다. Compound 11f (125 mg, 0.5 mmol) in a 0 ℃ osmium tetroxide (4% in water, 0.31 mL , 10 mol%) and 4-methylmorpholine N - oxide (NMO, 117 mg, 2.0 mmol ) to t -BuOH / THF / H 2 O ( 10: 3: 1,10mL) was added to a stirred solution of from. The reaction mixture was warmed to room temperature and then stirred for 5 hours. After addition of a saturated solution (10 mL) of NaHSO 3 aqueous solution, and further stirred for 1 hours the reaction mixture was extracted with EtOAc (10 mL x 3). The obtained organic layer was washed with brine (30 mL), dried over anhydrous Na 2 SO 4 , and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography using hexane / EtOAc (4: 1) to obtain cis-diol compound 21 (95 mg, 67%).
Mp 100-112℃;Mp 100-112 DEG C;
1H NMR (300 MHz, acetone-d 6): δ 10.2 (1H,s,NH), 8.24 (1H,d,J = 7.5 Hz), 7.47-7.42 (2H, m), 7.33-7.27 (1H, m), 7.16-7.10 (1H, m), 7.05 (1H, d, J = 8.4 Hz), 4.96 (1H, dd, J = 6.6, 4.5 Hz ), 4.15 (1H, d, J = 7.5 Hz, OH), 4.00 (1H, d, J = 5.7 Hz, OH), 3.85 (1H, dd, J = 5.7, 4.5 Hz), 1.61 (3H, s), 1.45 (3H, s); 1 H NMR (300 MHz, acetone- d 6): δ 10.2 (1H, s, NH), 8.24 (1H, d, J = 7.5 Hz), 7.47-7.42 (2H, m), 7.33-7.27 (1H, m), 7.16-7.10 (1H, m ), 7.05 (1H, d, J = 8.4 Hz), 4.96 (1H, dd, J = 6.6, 4.5 Hz), 4.15 (1H, d, J = 7.5 Hz, OH ), 4.00 (1H, d, J = 5.7 Hz, OH), 3.85 (1H, dd, J = 5.7, 4.5 Hz), 1.61 (3H, s), 1.45 (3H, s);
13C NMR (75 MHz, acetone-d 6 ): δ 149.8, 142.0, 140.4, 127.6, 125.2, 123.6, 123.6, 119.5, 113.5, 112.2, 111.0, 104.1, 78.8, 72.4, 65.8, 25.3, 24.5; 13 C NMR (75 MHz, acetone- d 6): δ 149.8, 142.0, 140.4, 127.6, 125.2, 123.6, 123.6, 119.5, 113.5, 112.2, 111.0, 104.1, 78.8, 72.4, 65.8, 25.3, 24.5;
IR (KBr) 3429, 2979, 1694, 1468, 1338, 1253, 1145, 1109, 750 cm-1;IR (KBr) 3429, 2979, 1694, 1468, 1338, 1253, 1145, 1109, 750 cm < -1 & gt ;;
HRMS (EI) m/z (M+) calcd for C17H17NO3: 283.1208. Found: 283.1205.
HRMS (EI) m / z ( M +) calcd for C 17 H 17 NO 3: 283.1208. Found: 283.1205.
<실시예 20> 시스-2,2-디메틸-2,3,4,7-테트라하이드로피라노[3,2-c]카바졸-3,4-디올(21) 및 트랜스-2,2-디메틸-2,3,4,7-테트라하이드로피라노[3,2-c]카바졸-3,4-디올(22) 합성Example 20 Synthesis of cis-2,2-dimethyl-2,3,4,7-tetrahydropyrano [3,2-c] carbazole-3,4-diol (21) Dimethyl-2,3,4,7-tetrahydropyrano [3,2-c] carbazole-3,4-diol (22)
실온에서 디메틸디옥시란(2.8 mL, 0.052 M, 1.0 mmol)을 습윤 아세톤(5 mL)에 용해시킨 화합물 11f 용액(125 mg, 0.5 mmol)에 첨가하였다. 상기 반응혼합물을 실온에서 4시간 동안 교반하고 감압 하에서 농축하였다. 얻어진 잔사를 헥산/EtOAc (3:1)을 이용한 실리카겔 플래쉬 컬럼 크로마토그래피를 통해 정제하여 시스-디올인 화합물 21(73 mg, 52%)와 트랜스-디올인 황백색 고상 화합물 22(36 mg, 26%)을 얻었다. Was added to a solution of compound 11f (125 mg, 0.5 mmol) in which dimethyldioxirane (2.8 mL, 0.052 M, 1.0 mmol) was dissolved in wet acetone (5 mL) at room temperature. The reaction mixture was stirred at room temperature for 4 hours and concentrated under reduced pressure. The obtained residue was purified by flash column chromatography on silica gel using hexane / EtOAc (3: 1) to obtain 36 mg (26%) of cis-diol phosphorus compound 21 (73 mg, 52%) and trans- ).
트랜스-디올 (화합물 22) Trans-diol (Compound 22 )
Mp 122-125℃; Mp 122-125 DEG C;
1H NMR (300 MHz, acetone-d 6): δ 10.24 (1H,s,NH), 8.24 (1H,d,J = 7.8 Hz), 7.50-7.43 (2H, m), 7.31 (1H, dd, J = 9.3, 7.2 Hz), 7.13 (1H, t, J = 8.1 Hz), 7.06 (1H, d, J = 8.4 Hz), 4.68 (1H, d, J = 7.8 Hz), 4.56 (1H, br, s, OH), 4.36 (1H, br, s, OH), 3.70 (1H, d, J = 8.1 Hz), 1.64 (3H, s), 1.34 (3H, s); 1 H NMR (300 MHz, acetone- d 6): δ 10.24 (1H, s, NH), 8.24 (1H, d, J = 7.8 Hz), 7.50-7.43 (2H, m), 7.31 (1H, dd, J = 9.3, 7.2 Hz), 7.13 (1H, t, J = 8.1 Hz), 7.06 (1H, d, J = 8.4 Hz), 4.68 (1H, d, J = 7.8 Hz), 4.56 (1H, br, s, OH), 4.36 (1H, br, s, OH), 3.70 (1H, d, J = 8.1 Hz), 1.64 (3H, s), 1.34 (3H, s);
13C NMR (75 MHz, actone-d 6 ): δ 149.2, 141.9, 140.4, 126.5, 125.2, 123.4, 123.4, 119.4, 115.1, 112.1, 111.0, 104.0, 79.7, 77.1, 70.1, 27.4, 19.9 cm-1; 13 C NMR (75 MHz, actone- d 6): δ 149.2, 141.9, 140.4, 126.5, 125.2, 123.4, 123.4, 119.4, 115.1, 112.1, 111.0, 104.0, 79.7, 77.1, 70.1, 27.4, 19.9 cm -1 ;
HRMS (EI) m/z (M+) calcd for C17H17NO3: 283.1208. Found: 283.1207.
HRMS (EI) m / z ( M +) calcd for C 17 H 17 NO 3: 283.1208. Found: 283.1207.
<실시예 21> 2,2,7-트리메틸-2,7-디하이드로피라노[3,2-c]카바졸(23) 합성Example 21 Synthesis of 2,2,7-trimethyl-2,7-dihydropyrano [3,2-c] carbazole (23)
0℃에서 NaH(60% dispersion in mineral oil, 300 mg 7.5 mmol)를 DMF(디메틸포름알마이드, 5 mL)에 용해시킨 화합물 11f 용액(1.245 g, 5.0 mmol)에 첨가하고 30분 동안 교반한 후 메틸 아이오다이드(0.34 mL, 5.5 mmol)를 몇 방울 적가하였다. 상기 반응혼합물을 30분 더 교반한 후, 빙수(30 mL)로 식혔다. 상기 반응혼합물을 EtOAc (30 mL x 3)로 추출하고 염화암모늄 포화 용액(50 mL)과 물(30 mL)로 세정하였다. 얻어진 유기층을 무수 Na2SO4로 건조시켰다. 상기 용매를 진공 하에서 제거한 후 얻은 조산물은 헥산/EtOAc (20:1)을 이용한 실리카겔 컬럼 크로마토그래피를 통해 정제하여 황백색 고상인 화합물 23(1.279 g, 97%)을 얻었다. Was added to a solution of compound 11f (1.245 g, 5.0 mmol) in which NaH (60% dispersion in mineral oil, 300 mg, 7.5 mmol) was dissolved in DMF (dimethylformamide, 5 mL) at 0 ° C and stirred for 30 minutes A few drops of methyl iodide (0.34 mL, 5.5 mmol) were added. The reaction mixture was stirred for an additional 30 minutes and then chilled with ice water (30 mL). The reaction mixture was extracted with EtOAc (30 mL x 3) and washed with saturated aqueous ammonium chloride (50 mL) and water (30 mL). The obtained organic layer was dried over anhydrous Na 2 SO 4 . The solvent was removed in vacuo, and the obtained crude product was purified by silica gel column chromatography using hexane / EtOAc (20: 1) to obtain Compound 23 (1.279 g, 97%) as a yellowish white solid.
Mp 50-52℃;Mp 50-52 DEG C;
1H NMR (300 MHz, CDCl3): δ 8.24 (1H,d,J = 7.5 Hz), 7.30 (1H, t, J = 8.4 Hz), 7.19-7.07 (2H, m), 6.96 (1H, d, J = 8.1 Hz), 6.70 (1H, d, J = 8.1 Hz), 6.35 (1H, d, J = 9.9 Hz), 5.39 (1H, d, J = 9.9 Hz), 3.60 (3H, s), 1.46 (6H, s); 1 H NMR (300 MHz, CDCl 3): δ 8.24 (1H, d, J = 7.5 Hz), 7.30 (1H, t, J = 8.4 Hz), 7.19-7.07 (2H, m), 6.96 (1H, d , J = 8.1 Hz), 6.70 (1H, d, J = 8.1 Hz), 6.35 (1H, d, J = 9.9 Hz), 5.39 (1H, d, J = 9.9 Hz), 3.60 (3H, s), 1.46 (6H, s);
13C NMR (75 MHz, CDCl3): δ 149.8, 143.1, 141.1, 126.7, 125.3, 124.7, 123.4, 123.3, 122.5, 119.4, 112.4, 111.9, 108.2, 100.7, 77.8, 29.5, 28.8, 28.8; 13 C NMR (75 MHz, CDCl 3 ):? 149.8, 143.1, 141.1, 126.7, 125.3, 124.7, 123.4, 123.3, 122.5, 119.4, 112.4, 111.9, 108.2, 100.7, 77.8, 29.5, 28.8, 28.8;
IR (KBr) 3042, 2971, 2927, 1711, 1626, 1465, 1331, 1292, 1125, 995, 789, 744 cm-1;IR (KBr) 3042, 2971, 2927, 1711, 1626, 1465, 1331, 1292, 1125, 995, 789, 744 cm -1 ;
HRMS (EI) m/z (M+) calcd for C18H17NO: 263.1310. Found: 263.1308.
HRMS (EI) m / z ( M +) calcd for C 18 H 17 NO: 263.1310. Found: 263.1308.
<실시예 22> 3-브로모-2,2,7-트리메틸-2,3,4,7-테트라하이드로피라노[3,2-c]카바졸-4-올(24) 합성Example 22 Synthesis of 3-bromo-2,2,7-trimethyl-2,3,4,7-tetrahydropyrano [3,2-c]
다이옥산(5 mL)에 용해시킨 화합물 23 용액(132 mg, 0.5 mmol)에 NBS(133 mg, 0.75 mmol)를 첨가하였다. 실온에서 3시간 동안 교반한 후, 과량의 용매를 진공 하에서 제거하였다. 상기 반응혼합물을 EtOAc (10 mL x 3)로 추출하고 염수(10 mL) 및 물(10 mL)로 세정하였다. 상기 얻어진 유기층을 Na2SO4로 건조시켰다. 상기 용매를 진공 하에서 제거한 후 얻은 조산물은 헥산/EtOAc (7:1)을 이용한 실리카겔 컬럼 크로마토그래피를 통해 정제하여 황백색 고상인 화합물 24(83 mg, 46%)를 얻었다. NBS (133 mg, 0.75 mmol) was added to a solution of Compound 23 (132 mg, 0.5 mmol) dissolved in dioxane (5 mL). After stirring at room temperature for 3 hours, the excess solvent was removed in vacuo. The reaction mixture was extracted with EtOAc (10 mL x 3) and washed with brine (10 mL) and water (10 mL). The obtained organic layer was dried with Na 2 SO 4. The solvent was removed in vacuo, and the obtained crude product was purified by silica gel column chromatography using hexane / EtOAc (7: 1) to give compound 24 (83 mg, 46%) as a yellowish white solid.
Mp 205-207℃;Mp 205-207 DEG C;
1H NMR (300 MHz, acetone-d 6): δ 8.26 (1H,d,J = 7.8 Hz), 7.51-7.40 (2H, m), 7.20 (1H, t, J = 7.5 Hz), 7.07-7.02 (2H, m), 5.71 (1H, d, J = 10.8 Hz), 5.31 (1H, d, J = 10.8 Hz), 3.85 (3H, s), 2.95 (1H, br, s, OH), 1.86 (3H, s), 1.58 (3H, s); 1 H NMR (300 MHz, acetone- d 6): δ 8.26 (1H, d, J = 7.8 Hz), 7.51-7.40 (2H, m), 7.20 (1H, t, J = 7.5 Hz), 7.07-7.02 (2H, m), 5.71 (1H, d, J = 10.8 Hz), 5.31 (1H, d, J = 10.8 Hz), 3.85 3H, s), 1.58 (3H, s);
13C NMR (75 MHz, acetone-d 6 ): δ 149.9, 143.3, 141.9, 126.2, 124.4, 123.8, 122.7, 120.2, 112.4, 110.1, 109.6, 103.5, 80.5, 54.6, 54.0, 29.0, 29.0, 19.6; 13 C NMR (75 MHz, acetone- d 6): δ 149.9, 143.3, 141.9, 126.2, 124.4, 123.8, 122.7, 120.2, 112.4, 110.1, 109.6, 103.5, 80.5, 54.6, 54.0, 29.0, 29.0, 19.6;
IR (KBr) 3471, 2979, 1711, 1601, 1488, 1368, 1283, 1155, 998, 801, 746 cm-1;IR (KBr) 3471, 2979, 1711, 1601, 1488, 1368, 1283, 1155, 998, 801, 746 cm -1 ;
FAB-HRMS m/z (M-H2O+H)+ calcd for C18H18BrNO2: 342.0494. Found: 342.0492.
FAB-HRMS m / z (MH 2 O + H) + calcd for C 18 H 18 BrNO 2 : 342.0494. Found: 342.0492.
<실시예 23> 2,2,7-트리메틸-2,3,4,7-테트라하이드로피라노[3,2-c]카바졸-3,4-디올(25) 합성Example 23 Synthesis of 2,2,7-trimethyl-2,3,4,7-tetrahydropyrano [3,2-c] carbazole-3,4-diol (25)
화합물 23(132 mg, 0.5 mmol)을 0℃에서 오스뮴 테트록사이드(4% in water, 0.31 mL, 10 mol%)와 4-메틸모폴린 N-옥사이드(NMO, 117 mg, 2.0 mmol)를 t-BuOH/THF/H2O(10:3:1,10mL)에서 용해시킨 교반 용액에 첨가하였다. 상기 반응혼합물을 실온에서 데운 후, 5시간 동안 교반하였다. NaHSO3 수용액의 포화 용액(10 mL)을 첨가하고, 반응혼합물을 추가적으로 1시간 더 교반한 후, EtOAc (10 mL x 3)로 추출하였다. 상기 얻어진 유기층을 염수(30 mL)로 세정하고, 무수 Na2SO4로 건조시키고, 감압 하에서 농축시켰다. 얻은 조산물은 헥산/EtOAc (4:1)을 이용한 실리카겔 컬럼 크로마토그래피를 통해 정제하여 시스-디올인 화합물 25(101 mg, 68%)을 얻었다. Compound 23 (132 mg, 0.5 mmol) in a 0 ℃ osmium tetroxide (4% in water, 0.31 mL , 10 mol%) and 4-methylmorpholine N - oxide (NMO, 117 mg, 2.0 mmol ) to t -BuOH / THF / H 2 O ( 10: 3: 1,10mL) was added to a stirred solution of from. The reaction mixture was warmed to room temperature and then stirred for 5 hours. After addition of a saturated solution (10 mL) of NaHSO 3 aqueous solution, and further stirred for 1 hours the reaction mixture was extracted with EtOAc (10 mL x 3). The obtained organic layer was washed with brine (30 mL), dried over anhydrous Na 2 SO 4 , and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography using hexane / EtOAc (4: 1) to obtain cis-diol compound 25 (101 mg, 68%).
Mp 140-142℃;Mp 140-142 DEG C;
1H NMR (300 MHz, CDCl3): δ 8.28 (1H,d,J = 7.8 Hz), 7.55 (1H, d, J = 8.4 Hz), 7.47-7.36 (2H, m), 7.20-7.14 (1H, m), 4.98 (1H, d, J = 3.3 Hz), 4.23 (1H, br, s, OH), 4.05 (1H, br, s, OH), 3.85 (sd, J = 7.2 Hz, 4H), 1.62 (3H, s), 1.44 (3H, s); 1 H NMR (300 MHz, CDCl 3): δ 8.28 (1H, d, J = 7.8 Hz), 7.55 (1H, d, J = 8.4 Hz), 7.47-7.36 (2H, m), 7.20-7.14 (1H br s, OH), 3.85 (sd, J = 7.2 Hz, 4H), 4.08 (1H, br, 1.62 (3H, s), 1.44 (3H, s);
13C NMR (75 MHz, acetone-d 6 ): δ 149.9, 143.1, 141.4, 127.7, 125.3, 123.6, 123.2, 119.6, 113.8, 111.5, 109.0, 102.0, 78.9, 72.4, 65.8, 25.3, 25.3, 24.4; 13 C NMR (75 MHz, acetone- d 6): δ 149.9, 143.1, 141.4, 127.7, 125.3, 123.6, 123.2, 119.6, 113.8, 111.5, 109.0, 102.0, 78.9, 72.4, 65.8, 25.3, 25.3, 24.4;
IR (KBr) 3429, 2979, 2930, 1694, 1633, 1605, 1468, 1338, 1253, 1145, 1109, 1041, 788, 750 cm-1;IR (KBr) 3429, 2979, 2930, 1694, 1633, 1605, 1468, 1338, 1253, 1145, 1109, 1041, 788, 750 cm -1 ;
HRMS (EI) m/z (M+) calcd for C18H19NO3: 297.1365. Found: 297.1363.
HRMS (EI) m / z ( M +) calcd for C 18 H 19 NO 3: 297.1365. Found: 297.1363.
이상으로 본 발명 내용의 특정한 부분을 상세히 기술하였는 바, 당업계의 통상의 지식을 가진 자에게 있어서, 이러한 구체적 기술은 단지 바람직한 실시양태일 뿐이며, 이에 의해 본 발명의 범위가 제한되는 것이 아닌 점은 명백할 것이다. 따라서 본 발명의 실질적인 범위는 첨부된 청구항들과 그것들의 등가물에 의하여 정의된다고 할 것이다. While the present invention has been particularly shown and described with reference to specific embodiments thereof, those skilled in the art will appreciate that such specific embodiments are merely preferred embodiments and that the scope of the present invention is not limited thereby. something to do. It is therefore intended that the scope of the invention be defined by the claims appended hereto and their equivalents.
Claims (7)
[화학식 1]
[화학식 2]
상기 화학식 1 및 화학식 2에서, R1 내지 R4는 각각 동일하거나 다를 수 있으며, 수소, C1 내지 C4 알킬, C1 내지 C4의 알콕시, 하이드록시, 4-메틸펜트-3-에닐, 4,8-디메틸노나-3,7-디에닐, 페닐 및 할로겐으로 이루어진 군에서 선택됨.Characterized in that a compound of formula (1) or (2) is synthesized by refluxing a hydroxycarbazole and an alpha, beta -unsaturated aldehyde for 15 hours in the presence of a catalyst of ethylene diamine diacetate (EDDA) Synthesis of derivatives:
[Chemical Formula 1]
(2)
In Formula 1 and Formula 2, R 1 to R 4 may be the same or different and each represents hydrogen, C1 to C4 alkyl, C1 to C4 alkoxy, hydroxy, 4-methylpent-3-enyl, Dimethylnona-3,7-dienyl, phenyl, and halogen.
상기 화학식 1 또는 화학식 2의 화합물을 디옥산, 아세톤, 디메틸포름아마이드 또는 t-BuOH-테트라하이드로퓨란(THF)-H2O에서 선택된 용매 하에서 N-브로모숙신이미드, 물, 오스뮴 테트록사이드, 4-메틸모폴린 N-옥사이드, 디메틸디옥시란, NaH 및 메틸 아이오다이드로 이루어진 군에서 선택된 하나 이상의 화합물을 첨가하여 교반시켜 피라노카바졸 유도체를 합성하는 단계를 포함하여 이루어지며,
상기 피라노카바졸 유도체는 트랜스-2-브로모-3,3-디메틸-1,2,3,11-테트라하이드로피라노[3,2-a]카바졸-1-올(14); 시스-3,3-디메틸-1,2,3,11-테트라하이드로피라노[3,2-a]카바졸-1,2-디올(15); 트랜스-3,3-디메틸-1,2,3,11-테트라하이드로피라노[3,2-a]카바졸-1,2-디올(16); 3,3,11-트리메틸-3,11-디하이드로피라노[3,2-a]카바졸(17); 트랜스-2-브로모-3,3,11--트리메틸-1,2,3,11-테트라하이드로피라노[3,2-a]카바졸-1-올(18); 시스-3,3,11-트리메틸-1,2,3,11-테트라하이드로피라노[3,2-a]카바졸-1,2-디올(19); 트랜스-3-브로모-2,2-디메틸-2,3,4,7-테트라하이드로피라노[3,2-c]카바졸-4-올(20); 시스-2,2-디메틸-2,3,4,7-테트라하이드로피라노[3,2-c]카바졸-3,4-디올(21); 트랜스-2,2-디메틸-2,3,4,7-테트라하이드로피라노[3,2-c]카바졸-3,4-디올(22); 2,2,7-트리메틸-2,7-디하이드로피라노[3,2-c]카바졸(23); 3-브로모-2,2,7-트리메틸-2,3,4,7-테트라하이드로피라노[3,2-c]카바졸-4-올(24); 및 2,2,7-트리메틸-2,3,4,7-테트라하이드로피라노[3,2-c]카바졸-3,4-디올(25)로 이루어진 군에서 선택된 어느 하나인 것을 특징으로 하는 피라노카바졸 유도체의 합성방법:
[화학식 1]
[화학식 2]
상기 화학식 1 및 화학식 2에서, R1 내지 R4는 각각 동일하거나 다를 수 있으며, 수소, C1 내지 C4 알킬, C1 내지 C4의 알콕시, 하이드록시, 4-메틸펜트-3-에닐, 4,8-디메틸노나-3,7-디에닐, 페닐 및 할로겐으로 이루어진 군에서 선택됨.
Reacting a hydroxycarbazole with an α, β-unsaturated aldehyde in the presence of a catalyst of ethylene diamine diacetate (EDDA) and a xylene solvent under reflux for 15 hours to synthesize a compound of Formula 1 or 2; And
The compound of formula (1) or (2) dioxane, acetone, dimethylformamide or a solvent selected from amide-t BuOH- tetrahydrofuran (THF) -H 2 O N- bromosuccinimide, water, osmium tetroxide , 4-methylmorpholine N-oxide, dimethyldioxirane, NaH, and methyl iodide, and stirring the mixture to synthesize a pyranocarbazole derivative,
The pyranocarbazole derivative is a trans-2-bromo-3,3-dimethyl-1,2,3,11-tetrahydropyrano [3,2-a] carbazol-1-ol (14); Cis-3,3-dimethyl-1,2,3,11-tetrahydropyrano [3,2-a] carbazole-1,2-diol (15); Trans-3,3-dimethyl-1,2,3,11-tetrahydropyrano [3,2-a] carbazole-1,2-diol (16); 3,3,11-trimethyl-3,11-dihydropyrano [3,2-a] carbazole (17); Trans-2-bromo-3,3,11-trimethyl-1,2,3,11-tetrahydropyrano [3,2-a] carbazol-1-ol (18); Cis-3,3,11-trimethyl-1,2,3,11-tetrahydropyrano [3,2-a] carbazole-1,2-diol (19); Trans-3-bromo-2,2-dimethyl-2,3,4,7-tetrahydropyrano [3,2-c] carbazol-4-ol (20); Cis-2,2-dimethyl-2,3,4,7-tetrahydropyrano [3,2-c] carbazole-3,4-diol (21); Trans-2,2-dimethyl-2,3,4,7-tetrahydropyrano [3,2-c] carbazole-3,4-diol (22); 2,2,7-trimethyl-2,7-dihydropyrano [3,2-c] carbazole (23); 3-Bromo-2,2,7-trimethyl-2,3,4,7-tetrahydropyrano [3,2-c] carbazol-4-ol (24); And 2,2,7-trimethyl-2,3,4,7-tetrahydropyrano [3,2-c] carbazole-3,4-diol (25) Synthesis of pyranocarbazole derivatives:
[Chemical Formula 1]
(2)
In Formula 1 and Formula 2, R 1 to R 4 may be the same or different and each represents hydrogen, C1 to C4 alkyl, C1 to C4 alkoxy, hydroxy, 4-methylpent-3-enyl, Dimethylnona-3,7-dienyl, phenyl, and halogen.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1020130069023A KR101542300B1 (en) | 2013-06-17 | 2013-06-17 | Synthesis method of pyranocarbazole derivatives |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1020130069023A KR101542300B1 (en) | 2013-06-17 | 2013-06-17 | Synthesis method of pyranocarbazole derivatives |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| KR20140146392A KR20140146392A (en) | 2014-12-26 |
| KR101542300B1 true KR101542300B1 (en) | 2015-08-06 |
Family
ID=52675655
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| KR1020130069023A KR101542300B1 (en) | 2013-06-17 | 2013-06-17 | Synthesis method of pyranocarbazole derivatives |
Country Status (1)
| Country | Link |
|---|---|
| KR (1) | KR101542300B1 (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111825688B (en) * | 2019-04-18 | 2022-07-19 | 中国医学科学院药物研究所 | Preparation method of 6-tert-butyl-3 ', 3', 3-trimethylpyrano [3,2-a ] carbazole |
| CN112961165B (en) * | 2021-02-18 | 2022-02-01 | 同济大学 | Carbazole benzopyran compound and application thereof |
-
2013
- 2013-06-17 KR KR1020130069023A patent/KR101542300B1/en active IP Right Grant
Non-Patent Citations (2)
| Title |
|---|
| Bull. Korean Chem. Soc., 2010, 31(8), pages 2406-2409 |
| International Journal of Photoenergy, 2006, pages 1-7 |
Also Published As
| Publication number | Publication date |
|---|---|
| KR20140146392A (en) | 2014-12-26 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Reddy et al. | PEG-SO3H catalyzed synthesis and cytotoxicity of α-aminophosphonates | |
| CA2903797C (en) | Processes for the preparation of an apoptosis-inducing agent | |
| Gui et al. | A cinchona alkaloid catalyzed enantioselective sulfa-Michael/aldol cascade reaction of isoindigos: construction of chiral bispirooxindole tetrahydrothiophenes with vicinal quaternary spirocenters | |
| Kudale et al. | Intramolecular Povarov reactions involving 3-aminocoumarins | |
| US9096626B2 (en) | Monophosphorus ligands and their use in cross-coupling reactions | |
| JP5584709B2 (en) | Method for producing 5- (2-{[6- (2,2-difluoro-2-phenylethoxy) hexyl] amino} -1-hydroxyethyl) -8-hydroxyquinolin-2 (1H) -one | |
| Su et al. | An enantioselective strategy for the total synthesis of (S)-tylophorine via catalytic asymmetric allylation and a one-pot DMAP-promoted isocyanate formation/Lewis acid catalyzed cyclization sequence | |
| KR101542300B1 (en) | Synthesis method of pyranocarbazole derivatives | |
| US9624221B2 (en) | Key intermediates and impurities of the synthesis of Apixaban: Apixaban glycol esters | |
| KR101598179B1 (en) | Improved preparing method of oxindole dimers and oxindole dimers made by the same | |
| Wang et al. | Synthesis of phostones via DABCO-catalyzed bromocyclization of alkenylphosphonic acid monoesters | |
| US8399706B2 (en) | Chiral tetraaminophosphonium salts, catalyst for asymmetric synthesis and method for producing chiral β-nitroalcohol | |
| CN111087394A (en) | Synthetic method of 2, 9-substituted 4-halo-1, 10-phenanthroline | |
| JP5207516B2 (en) | Method for producing 2,3-dicyanonaphthalene derivative | |
| KR101668908B1 (en) | Method for producing n-substituted-2-amino-4-(hydroxymethylphosphinyl)-2-butenoic acid | |
| KR101453413B1 (en) | Method for preparation of alpha-carboline derivatives | |
| US11866393B2 (en) | 7,7′-dihalo-3,3,3′,3′-tetramethyl-1,1′-spirobiindane and preparation method thereof | |
| KR102271982B1 (en) | Method for synthesizing (z)-aurone and derivative compounds thereof | |
| CN110343083B (en) | Method for preparing coumarin fluorescent agent by copper acetate catalysis | |
| KR101262468B1 (en) | Synthesis method of acronycine, noracronycine or derivatives thereof | |
| Venkateswarlu et al. | Synthesis and spectral characterization of N‐[2‐(4‐halophenoxy)‐3‐(3‐chlorophenyl)‐3, 4‐dihydro‐2H‐1, 3, 2‐λ5‐benzoxazaphosphinin‐2‐yliden]‐N‐substituted amines by the Staudinger reaction | |
| KR101840518B1 (en) | New Carbazoles and Preparation method thereof | |
| KR102110059B1 (en) | Phenacene compound, manufacturing method of phenacene compound, and organic light emitting device | |
| RU2632673C1 (en) | Method for producing (1,11-dioxa-4,8-dithia-6-azacyclothrenedecan-6-yl) -quinolines | |
| KR102399991B1 (en) | Methods and systems for camptothecin analog synthesis |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| E902 | Notification of reason for refusal | ||
| E701 | Decision to grant or registration of patent right | ||
| FPAY | Annual fee payment |
Payment date: 20180703 Year of fee payment: 4 |
|
| FPAY | Annual fee payment |
Payment date: 20190708 Year of fee payment: 5 |