KR100812499B1 - Anticonvulsant - Google Patents
Anticonvulsant Download PDFInfo
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- KR100812499B1 KR100812499B1 KR1020060100124A KR20060100124A KR100812499B1 KR 100812499 B1 KR100812499 B1 KR 100812499B1 KR 1020060100124 A KR1020060100124 A KR 1020060100124A KR 20060100124 A KR20060100124 A KR 20060100124A KR 100812499 B1 KR100812499 B1 KR 100812499B1
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- octan
- aza
- bicyclo
- onyl
- pyrrol
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
Abstract
Description
생리활성 및 구조적 특이성을 가진 8-aza-bicyclo[3,2,1]octan-3-one 합성을 위해, 다양한 아민(diaminoalkane or diaminobenzene)을 2,5-dimethoxytetrahydrofuran과 1,3-acetonedicarboxylic acid와 함께 반응시켜 di-(8-aza-bicyclo[3,2,1]octan-3-onyl)alkanes, di-(8-aza-bicyclo[3,2,1]octan-3-onyl)-benzenes 및 그들의 유도체의 합성에 관한 것이다.For the synthesis of 8-aza-bicyclo [3,2,1] octan-3-one with bioactive and structural specificities, various amines (diaminoalkane or diaminobenzene) were combined with 2,5-dimethoxytetrahydrofuran and 1,3-acetonedicarboxylic acid. Reacted with di- (8-aza-bicyclo [3,2,1] octan-3-onyl) alkanes, di- (8-aza-bicyclo [3,2,1] octan-3-onyl) -benzenes and their It relates to the synthesis of derivatives.
트로판 알칼로이드(tropane alkaloid)인 아트로핀(atropine), 코카인(cocaine), 스코폴아민(scopolamine), 유사트로핀(pseudotropine)은 여러 식물에 존재한다. 고리 화합물인 트로판 유도체들은 약리학적으로 매우 흥로로운 연구과제로 지목되어 최근에 그들의 합성법, 입체적 구조분석, 및 약학적인 연구가 활발히 진행되고 있다.Tropan alkaloids such as atropine, cocaine, cocaine, scopolamine and pseudotropine are present in many plants. Tropan derivatives, which are cyclic compounds, have been pointed out as pharmacologically very interesting researches, and their synthesis, stereoscopic structural analysis, and pharmaceutical research have recently been actively conducted.
주변에서 흔히 볼 수 있는 피페리딘 고리를 갖고 있는 알칼로이드는 독당근에 들어 있으며, 그 종류로는 무기력증, 혐오감, 호흡장애와 마비, 심지어 사망까지 초래할 수 있는 코닌(coniine), 맹독성이지만 묽혀서 (0.5-1.0%) 안과진찰을 할 때 눈의 동공을 확장시키는데 사용하는 아트로핀과 아트로핀 유도체들 그리고 마약 으로 알려져 있는 코카인등이 있다.Alkaloids with a piperidine ring commonly found in the periphery are found in hemlocks, which include coniine, a highly toxic but dilute (which can cause lethargy, aversion, respiratory failure and paralysis, and even death). 0.5-1.0%) Ophthalmic examinations include atropine and atropine derivatives, which are used to dilate the pupils of the eye, and cocaine, also known as a drug.
특히, 아트로핀은 신경절후 콜린성 섬유(postganglionic cholineigic fibers)로 분류된 콜린성 수용체에서 아세틸콜린(acetylcholine)의 작용을 선잭적으로 차단한다. 1897년 빌슈테터(Willstatter, R)에 의해 시클로헵타논(cycloheptanone)을 전화시켜 처음으로 8-aza-bicyclo[3,2,1]octan-3-one을 합성하였다. 이것은 식물내에서만 합성되는 것으로 생각했던 8-aza-bicyclo[3,2,1]octan-3-one의 최초의 합성이라고 볼 수 있다. 또한, 1988년에 이즈퀴어르(Izquier, M. L) 등이 N-alkyl 8-aza-bicylo[3,2,1]octan-3-one의 합성과 구조분석에 관한 연구를 발표하였으며, aliphatic hydroxy amine과 2,5-dimethoxytetrahydrofuran을 1,3-acetonedicarboxylic acid과 함께 반응시켜 N-alkyl 8-aza-bicyclo[3,2,1]octan-3-one을 합성하였다.In particular, atropine preemptively blocks the action of acetylcholine at cholinergic receptors classified as postganglionic cholineigic fibers. In 1897, cycloheptanone was converted by Willstatter (R) to synthesize 8-aza-bicyclo [3,2,1] octan-3-one for the first time. This is the first synthesis of 8-aza-bicyclo [3,2,1] octan-3-one, which was thought to be synthesized only in plants. In 1988, Izquier (M. L) and others published a study on the synthesis and structural analysis of N-alkyl 8-aza-bicylo [3,2,1] octan-3-one. N-alkyl 8-aza-bicyclo [3,2,1] octan-3-one was synthesized by reacting hydroxy amine with 2,5-dimethoxytetrahydrofuran with 1,3-acetonedicarboxylic acid.
지금까지, 여러 가지 약리효과와 입체구조분석의 대상이 되고 있는 8-aza-bicyclo[3,2,1]octan-3-one 유도체의 합성은 주로 8-위치에 알킬기가 치환된 경우만 보고되었다.Until now, the synthesis of 8-aza-bicyclo [3,2,1] octan-3-one derivatives, which have been subject to various pharmacological effects and stereostructure analysis, has been reported mainly when the alkyl group is substituted at the 8-position. .
따라서, 항 경련 연구의 주된 영역으로서 보다 효율적이고 다양한 경련증상을 모두 통제할 수 있는 임상적 적용범위가 넓은 항 경련제 개발에 대한 필요성이 대두되고 있다. 많은 항 경련제가 개발되고 있지만, 다양한 증상에 모두 효과를 보이는 것은 아니므로, 각 증상에 따라 (Generalized tonic-clonic, Absense, Status epilepticus, Complex partial seizures) 적당한 약물을 선택해야 한다.Therefore, there is a need to develop an anticonvulsant with a wide range of clinical applications that can control all of the more effective and various convulsive symptoms as a main area of anticonvulsation research. Many anticonvulsants are being developed, but not all are effective against a variety of symptoms, so be sure to choose the right drug for each condition (Generalized tonic-clonic, Absense, Status epilepticus, Complex partial seizures).
본 발명은 항 경련 연구의 주된 영역으로서 보다 효과적이고 다양한 경련증상을 모두 통제할 수 있는 임상적 적용범위가 넓은 항 경련제 개발에 목적을 두고 있다.The present invention aims to develop an anticonvulsant with a wide range of clinical applications that can control all of the more effective and various convulsive symptoms as a main area of anticonvulsion research.
본 발명은 항 경련 활성을 보이는 8-aza-bicyclo[3,2,1]octan-3-one구조를 모체로 하여 새로운 항 경련 화합물의 합성을 제공하는 데 그 목적이 있다.An object of the present invention is to provide a synthesis of a new anti-convulsant compound based on the 8-aza-bicyclo [3,2,1] octan-3-one structure exhibiting anti-convulsive activity.
또한, 본 발명은 생리활성 및 구조적 특이성을 가진 8-aza-bicylo[3,2,1]octan-3-one을 합성하기 위하여, 다양한 아민(예를 들어, diaminoalkane, diaminobenzene)을 2,5-dimethoxytetrahydrofuran과 1,3-acetonedicarboxylic acid와 함께 반응시켜 di-(8-aza-bicylo[3,2,1]octan-3-onyl)alkanes, di-(8-aza-bicyclo[3,2,1]octan-3-onyl)-benzenes, 및 그들의 유도체를 합성을 제공하는 데 그 목적이 있다.In addition, the present invention, in order to synthesize 8-aza-bicylo [3,2,1] octan-3-one having physiological activity and structural specificity, various amines (for example, diaminoalkane, diaminobenzene) 2,5- reacted with dimethoxytetrahydrofuran and 1,3-acetonedicarboxylic acid to di- (8-aza-bicylo [3,2,1] octan-3-onyl) alkanes, di- (8-aza-bicyclo [3,2,1] Its purpose is to provide synthesis of octan-3-onyl) -benzenes, and derivatives thereof.
1. 시약 및 기기1. Reagents and Instruments
본 발명에서 사용되는 시약은 모두 특급 시약이며, 대부분의 반응은 KOH, CaCl2, 분자체(molecular sieves 3Å) 및 실리카겔 블루(silica gel blue)를 통과하여 얻은 건조 질소하에서 수행한다.The reagents used in the present invention are all special reagents, and most of the reactions are carried out under dry nitrogen obtained through KOH, CaCl 2 , molecular sieves (3 ′) and silica gel blue.
녹는점 측정은 Buchi 510 녹는점 측정기기, 전열 (electrothermal) 디지털 녹는점 측정기기 , General V4. IC DuPont 2200을 이용하여 보정없이 사용한다. IR spectra는 Bruker IFS 55 FT-IR 분광광도계를 사용한다. H NMR spectra는 (CH3)4Si (TMS)를 내부 표준물질로 사용하고, DMSO-d6, CDCl3와 Acetone-d6를 용매로 사용하며, Bruker AC 200 (200 MHz)와 Varian Gemini (200 또는 300 MHz) FT-NMR 분광계를 이용하여 ppm 단위로 측정한다. 질량분석 spectra는 HP (Hewlett Packard 5890 II GC/MSD [Column ; HP-1 (crosslinked Methyl Silicone Gum, 30 m × 0.25 mm × 0.3 μm), Detector ; 5972A mass detector 70 eV, EI]를 사용하여 얻었다. 얇은 막 크로마토그래피(TLC)는 E. Merck사 (60F-254, 두께 0.25 mm)의 precoated silica-gel 판을 사용하였고, 전개된 spot은 UV 램프와 visualizing agent (CH3COOH ; Ethyl alcohol : H2SO4 : Anisaldehyde = 3 : 337 : 12 : 9, v/v/v/v 또는 5% NaOH : H2O : K2CO3 : KMnO4 = 5 : 300 : 20 : 3, v/v/v/v)로 발색시켜 확인하였으며, 컬럼 크로마토그래피(column chromatography)는 실리카겔 1000 (70-230 mesh, ASTM, Merck)과 실리카겔 9385 (230-410 mesh, E. Merck)를 사용하였다.Melting point measuring instruments are Buchi 510 melting point measuring instruments, electrothermal digital melting point measuring instruments, General V4. Use without correction using IC DuPont 2200. IR spectra uses a Bruker IFS 55 FT-IR spectrophotometer. The H NMR spectra uses (CH 3 ) 4 Si (TMS) as an internal standard, DMSO-d 6 , CDCl 3 and Acetone-d 6 as solvents, Bruker AC 200 (200 MHz) and Varian Gemini ( 200 or 300 MHz), measured in ppm using an FT-NMR spectrometer. Mass spectrometric spectra were obtained using Hewlett Packard 5890 II GC / MSD [Column; HP-1 (crosslinked Methyl Silicone Gum, 30 m × 0.25 mm × 0.3 μm), Detector; 5972A mass detector 70 eV, EI]. Thin layer chromatography (TLC) was a precoated silica-gel plate of E. Merck (60F-254, 0.25 mm thick), and the developed spot was UV lamp and visualizing agent (CH 3 COOH; Ethyl alcohol: H 2). SO 4 : Anisaldehyde = 3: 337: 12: 9, v / v / v / v or 5% NaOH: H 2 O: K 2 CO 3 : KMnO 4 = 5: 300: 20: 3, v / v / v / v) was confirmed by color development, column chromatography (column chromatography) using silica gel 1000 (70-230 mesh, ASTM, Merck) and silica gel 9385 (230-410 mesh, E. Merck).
2. 실험방법2. Experimental method
(1) 2,5-Dimethoxytetrahydrofuran과 1,3-Acetonedicarboxylic acid에 의한 Ethylenediamine 1의 반응(1) Reaction of Ethylenediamine 1 with 2,5-Dimethoxytetrahydrofuran and 1,3-Acetonedicarboxylic Acid
실온에서 잘 건조시킨 100 ml 이구 둥근바닥플라스크에 2,5-dimethoxytetrahydrofuran (6.6 g, 0.05 mol)과 1,3-acetonedicarboxylic acid (5.84 g, 0.04 mol)과 증류수 20 ml, 그리고 HCl 0.5 ml를 넣고 30분간 교반한 후, 증류수 10 ml에 녹인 ethylenediamine 1 (1.2 g, 0.02 mol)을 ice-bath상에서 적하 깔대기(dropping funnel)를 사용하여 천천히 적가하였다. 실온에서 24시간 동안 교반한 후, TLC로 반응의 완결을 확인하고, 포화 NaHCO3 수용액 100 ml로 중화하였다. 이 때 생기는 고체는 여과하여 증류수로 여러번 씻어주고, 여액은 dichloromethane으로 추출한 후 분리한 dichloromethane층을 무수 MaSO4로 건조시킨 다음 진공회전 증발기를 이용하여 완전히 제거하였다. 얻어진 전사를 플래시 컬럼 크로마토그래피(flash column chromatography) (eluent ; CH2Cl2 : n-Hexane : MeOH = 10 : 10 : 1, v/v/v)하여 연한 황토색의 고체인 8-(2-pyrrol-1-y1-ethyl)-8-aza-bicyclo[3,2,1]octan-3-one 2 (0.218 g, yield ; 5.0%)과 1,2-di-(8-aza-bicyclo[3,2,1]octan-3-onyl)ethane 3 (0.93 g, yield : 17.0%)를 얻었다.In a 100 ml two-necked round-bottom flask, dried at room temperature, add 2,5-dimethoxytetrahydrofuran (6.6 g, 0.05 mol), 1,3-acetonedicarboxylic acid (5.84 g, 0.04 mol), 20 ml of distilled water, and 0.5 ml of HCl. After stirring for 1 minute, ethylenediamine 1 (1.2 g, 0.02 mol) dissolved in 10 ml of distilled water was slowly added dropwise using a dropping funnel on an ice-bath. After stirring for 24 hours at room temperature, the reaction was confirmed complete by TLC and neutralized with 100 ml of saturated aqueous NaHCO 3 solution. The solid produced at this time was filtered and washed several times with distilled water. The filtrate was extracted with dichloromethane and the separated dichloromethane layer was dried over anhydrous MaSO 4 and completely removed using a vacuum rotary evaporator. The obtained transcription was subjected to flash column chromatography (eluent; CH 2 Cl 2 : n-Hexane: MeOH = 10: 10: 1, v / v / v) to give 8- (2-pyrrol) as a pale yellow solid. -1-y1-ethyl) -8-aza-bicyclo [3,2,1] octan-3-one 2 (0.218 g, yield; 5.0%) and 1,2-di- (8-aza-bicyclo [3 , 2,1] octan-3-onyl) ethane 3 (0.93 g, yield: 17.0%) was obtained.
8-(2-Pyrrol-1-yl-ethyl)-8-aza-bicyclo[3,2,1]octan-3-one 2 : yield ; 5.0%. Rf ; 0.51 (TLC eluent ; CH2Cl2 : n-Hexane : MeOH = 5 : 5 : 1, v/v/v). Mass (70 eV), m/z (rel. Int. %) ; 218(100), 205(39), 191(30), 152(36), 138(73), 94(48), 82(45), 68(40). 1H NMR (CDCl3, 200 MHz) ; δ 6.64(s, 2H), 6.12(s, 2H), 3.82～3.89(t, 2H), 3.54 (s, 2H), 2.52～2.69(dd, 4H), 2.21(s, 2H), 2.13～2.16(d, 2H), 1.56～1.59(d, 2H). C NMR (CDCl3, 50 MHz) ; δ 210.09(1C), 120.39(2C), 107.70(2C), 58.45(2C), 50.06(1C), 49.54(1C), 47.10(2C), 29.11(2C).8- (2-Pyrrol-1-yl-ethyl) -8-aza-bicyclo [3,2,1] octan-3-one 2: yield; 5.0%. R f ; 0.51 (TLC eluent; CH 2 Cl 2 : n-Hexane: MeOH = 5: 5: 1, v / v / v). Mass (70 eV), m / z (rel. Int.%); 218 (100), 205 (39), 191 (30), 152 (36), 138 (73), 94 (48), 82 (45), 68 (40). 1 H NMR (CDCl 3 , 200 MHz); δ 6.64 (s, 2H), 6.12 (s, 2H), 3.82 to 3.89 (t, 2H), 3.54 (s, 2H), 2.52 to 2.69 (dd, 4H), 2.21 (s, 2H), 2.13-2.16 (d, 2H), 1.56-1.59 (d, 2H). C NMR (CDCl 3 , 50 MHz); δ 210.09 (1C), 120.39 (2C), 107.70 (2C), 58.45 (2C), 50.06 (1C), 49.54 (1C), 47.10 (2C), 29.11 (2C).
1,2-Di-(8-aza-bicyclo[3,2,1]octan-3-onyl)ethane 3 : yield ; 17.0%.mp ; 140 ～ 142℃. Rf ; 0.25 (TLC eluent ; CH2Cl2 : n-Hexane : MeOH = 5 : 5 : 1, v/v/v). Mass (70 eV), m/z (rel. Int. %) ; 276(2), 138(100), 96(13), 54(8). IR (ν, KBr, ㎝-1) ; 3030, 2920, 2905, 1725 (C=O). 1H NMR (CDCl3, 200 MHz) ; δ 3.55(s, 4H), 2.77(s, 4H), 2.58～2.68(dd, 4H), 2.12～2.20(d, 4H), 1.99～2.04(m, 4H), 1.55～1.59(m, 4H). 13C NMR (CDCl3, 50 MHz) ; δ 209.61(2C), 59.24(4C), 50.25(2C), 47.37(4C), 27.83(4C).1,2-Di- (8-aza-bicyclo [3,2,1] octan-3-onyl) ethane 3: yield; 17.0% .mp; 140 to 142 ° C. R f ; 0.25 (TLC eluent; CH 2 Cl 2 : n-Hexane: MeOH = 5: 5: 1, v / v / v). Mass (70 eV), m / z (rel. Int.%); 276 (2), 138 (100), 96 (13), 54 (8). IR (ν, KBr, cm −1 ); 3030, 2920, 2905, 1725 (C = O). 1 H NMR (CDCl 3 , 200 MHz); δ 3.55 (s, 4H), 2.77 (s, 4H), 2.58 to 2.68 (dd, 4H), 2.12 to 2.20 (d, 4H), 1.99 to 2.04 (m, 4H), 1.55 to 1.59 (m, 4H) . 13 C NMR (CDCl 3 , 50 MHz); δ 209.61 (2C), 59.24 (4C), 50.25 (2C), 47.37 (4C), 27.83 (4C).
(2) 2,5-Dimethoxytetrahydrofuran과 1,3-Acetonedicarboxylic acid에 의한 1,3-Diaminopropane 4의 반응(2) Reaction of 1,3-Diaminopropane 4 with 2,5-Dimethoxytetrahydrofuran and 1,3-Acetonedicarboxylic acid
실온에서 잘 건조시킨 100 ml 이구 둥근바닥플라스크에 2,5-dimethoxytetrahydrofuran (6.6 g, 0.05 mol)과 1,3-acetonedicarboxylic acid (5.84 g, 0.04 mol)과 증류수 20 ml, 그리고 HCl 0.5 ml를 넣고 30분간 교반한 후, 1,3-diaminopropane 4 (1.48 g, 0.02 mol)을 ice-bath상에서 적하깔대기를 사용하여 천천히 적가하였다. 실온에서 27시간 동안 교반한 후, TLC로 반응의 완결을 확인하고, 포화 NaHCO3 수용액 100 ml로 중화하였다. 이 혼합용액을 dichloromethane으로 추출한 후 분리한 dichloromethane층을 진공회전 증발기를 이용하여 완전히 제거하였다. 얻어진 잔사를 플래시 컬럼 크로마토그래피 (eluent ; EtOAc : n- Hexane = 3 : 1, v/v) 하여 진한 갈색의 액체인 8-(3-pyrrol-1-yl-propyl)-8-aza-bicyclo-[3,2,1]octan-3-one 5 (0.32 g, yield ; 6.0%)과 1,3-di-(8-aza-bicyclo[3,2,1]octan-3-onyl)propane 6 (1.27 g, yield ; 21.0%)을 얻었다.2,5-dimethoxytetrahydrofuran in a 100 ml double-bottomed flask, dried well at room temperature (6.6 g, 0.05 mol), 1,3-acetonedicarboxylic acid (5.84 g, 0.04 mol), 20 ml of distilled water, and 0.5 ml of HCl were stirred for 30 minutes, and then 1,3-diaminopropane 4 (1.48 g, 0.02 mol) was slowly added dropwise using an ice funnel on an ice-bath. After stirring for 27 hours at room temperature, the reaction was confirmed complete by TLC and neutralized with 100 ml of saturated aqueous NaHCO 3 solution. The mixed solution was extracted with dichloromethane and the separated dichloromethane layer was completely removed using a vacuum rotary evaporator. The obtained residue was subjected to flash column chromatography (eluent; EtOAc: n-Hexane = 3: 1, v / v) to give a dark brown liquid, 8- (3-pyrrol-1-yl-propyl) -8-aza-bicyclo- [3,2,1] octan-3-one 5 (0.32 g, yield; 6.0%) and 1,3-di- (8-aza-bicyclo [3,2,1] octan-3-onyl) propane 6 (1.27 g, yield; 21.0%) was obtained.
8-(3-Pyrrol-1-yl-propyl)-8-aza-bicyclo[3,2,1]octan-3-one 5 : yield ; 6.0%. Rf ; 0.38 (TLC eluent ; EtOAc). Mass (70 eV), m/z (rel. Int. %) ; 232(25.9), 175(8.3), 152(7.4), 138(22.2), 106 (13), 94 (13.9), 81(100), 68(7.4), 53(10.2). 1H NMR (CDCl3, 300 MHz) ; δ 6.67～6.68(d, 2H), 6.14～6.15(t, 2H), 3.57(s, 2H), 2.74(s, 4H), 2.64～2.71(dd, 2H), 2.17～2.23(dd, 2H), 2.03～2.07(m, 2H), 1.78～1.87(m, 2H), 1.57～1.64(m, 2H). 13C NMR (CDCl3, 125 MHz) ; δ 210.33(1C), 121.01(2C), 108.41(2C), 59.07(2C), 47.94(2C), 47.42(1C), 47.32(1C), 30.36(1C), 28.26(2C).8- (3-Pyrrol-1-yl-propyl) -8-aza-bicyclo [3,2,1] octan-3-one 5: yield; 6.0%. R f ; 0.38 (TLC eluent; EtOAc). Mass (70 eV), m / z (rel. Int.%); 232 (25.9), 175 (8.3), 152 (7.4), 138 (22.2), 106 (13), 94 (13.9), 81 (100), 68 (7.4), 53 (10.2). 1 H NMR (CDCl 3 , 300 MHz); δ 6.67 to 6.68 (d, 2H), 6.14 to 6.15 (t, 2H), 3.57 (s, 2H), 2.74 (s, 4H), 2.64 to 2.71 (dd, 2H), 2.17 to 2.23 (dd, 2H) , 2.03-2.07 (m, 2H), 1.78-1.87 (m, 2H), 1.57-1.64 (m, 2H). 13 C NMR (CDCl 3 , 125 MHz); δ 210.33 (1C), 121.01 (2C), 108.41 (2C), 59.07 (2C), 47.94 (2C), 47.42 (1C), 47.32 (1C), 30.36 (1C), 28.26 (2C).
1,3-Di-(8-aza-bicyclo[3,2,1]octan-3-onyl)propane 6 : yield ; 21.0%. Rf ; 0.1 (TLC eluent ; EtOAc). Mass (70 eV), m/z (rel. Int. %) ; 290(10.3), 165(11.2), 152(20.6), 138(100), 122(44.9), 108(16.8), 96(22.4), 81(16.8), 68(15), 55(16.8). IR (ν, KBr, ㎝-1) ; 3035, 2920, 2909, 1723 (C=O). 1H NMR (CDCl3, 300 MHz) ; δ 3.57(s, 4H), 2.74(s, 4H), 2.64～2.71(dd, 4H, J = 10 Hz), 2.17～2.23(dd, 4H, J = 4 Hz), 2.03～2.07(m, 4H), 1.78～1.87(m, 2H), 1.57～ 1.64(m, 4H). 13C NMR (CDCl3, 125 MHz) ; δ 210.31(2C), 58.98(4C), 48.51(2C), 47.63(4C), 28.85(1C), 28.25(4C).1,3-Di- (8-aza-bicyclo [3,2,1] octan-3-onyl) propane 6: yield; 21.0%. R f ; 0.1 (TLC eluent; EtOAc). Mass (70 eV), m / z (rel. Int.%); 290 (10.3), 165 (11.2), 152 (20.6), 138 (100), 122 (44.9), 108 (16.8), 96 (22.4), 81 (16.8), 68 (15), 55 (16.8). IR (ν, KBr, cm −1 ); 3035, 2920, 2909, 1723 (C = O). 1 H NMR (CDCl 3 , 300 MHz); δ 3.57 (s, 4H), 2.74 (s, 4H), 2.64 to 2.71 (dd, 4H, J = 10 Hz), 2.17 to 2.23 (dd, 4H, J = 4 Hz), 2.03 to 2.07 (m, 4H ), 1.78-1.87 (m, 2H), 1.57-1.64 (m, 4H). 13 C NMR (CDCl 3 , 125 MHz); δ 210.31 (2C), 58.98 (4C), 48.51 (2C), 47.63 (4C), 28.85 (1C), 28.25 (4C).
(3) 2,5-Dimethoxytetrahydrofuran과 1,3-Acetonedicarboxylic acid에 의한 1,8-Diaminooctane 7의 반응(3) Reaction of 1,8-Diaminooctane 7 with 2,5-Dimethoxytetrahydrofuran and 1,3-Acetonedicarboxylic acid
실온에서 잘 건조시킨 100 ml 이구 둥근바닥플라스크에 2,5-dimethoxytetrahydrofuran (6.6 g, 0.05 mol)과 1,3-acetonedicarboxylic acid (5.84 g, 0.04 mol)과 증류수 20 ml, 그리고 HCl 0.5 ml를 넣고 30분간 교반한 후, 증류수 10 ml에 녹인 1,8-diaminooctane 7 (2.88 g, 0.02 mol)을 ice-bath상에서 적하깔대기를 사용하여 천천히 적가하였다. 실온에서 67시간 동안 교반한 후, TLC로 반응의 완결을 확인하고, 포화 NaHCO3 수용액 100 ml로 중화하였다. 이때 생기는 고체는 여과하여 증류수로 여러번 씻어주고, 여액은 dichloromethane으로 추출한 후 분리한 dichloromethane층을 진공회전 증발기를 이용하여 완전히 제거하였다. 얻어진 잔사를 플래시 컬럼 그로마토그래피 (eluent ; EtOAc : CH2Cl2 = 1 : 1, v/v) 하여 갈색의 oil인 8-(8-pyrrol-1-yl-octyl)-8-aza-bicyclo[3,2,1]octan-3-one 8 (0.19 g, yield ; 2.6%)과 1,8-di-(8-aza-bicyclo[3,2,1]octan-3-onyl)octane 9 (1.79 g, yield ; 24.9%)을 얻었다.2,5-dimethoxytetrahydrofuran in a 100 ml double-bottomed flask, dried well at room temperature (6.6 g, 0.05 mol) and 1,3-acetonedicarboxylic acid (5.84 g, 0.04 mol), 20 ml of distilled water, and 0.5 ml of HCl were stirred for 30 minutes, and then dissolved in 10 ml of distilled water, 1,8-diaminooctane 7 (2.88 g, 0.02 mol) was slowly added dropwise using an ice funnel on an ice-bath. After stirring for 67 hours at room temperature, the reaction was confirmed complete by TLC and neutralized with 100 ml of saturated aqueous NaHCO 3 solution. The resulting solids were filtered and washed several times with distilled water, the filtrate was extracted with dichloromethane and the separated dichloromethane layer was completely removed using a vacuum rotary evaporator. The obtained residue was subjected to flash column chromatography (eluent; EtOAc: CH 2 Cl 2 = 1: 1, v / v) to give a brown oil, 8- (8-pyrrol-1-yl-octyl) -8-aza-bicyclo. [3,2,1] octan-3-one 8 (0.19 g, yield; 2.6%) and 1,8-di- (8-aza-bicyclo [3,2,1] octan-3-onyl) octane 9 (1.79 g, yield; 24.9%) was obtained.
8-(8-Pyrrol-1-yl-octyl)-8-aza-bicyclo[3,2,1]octan-3-one 8 : yield ; 2.6%. Rf ; 0.48 (TLC eluent ; EtOAc : CH2Cl2 = 1 : 1, v/v). Mass (70 eV), m/z (rel. Int. %) ; 302(47.7), 273(14.7), 245(100), 138(98.2), 96(17.4), 80(44), 68(17.4), 55(18.3). 1H NMR (CDCl3, 200 MHz) ; δ 6.64(s, 2H), 6.12(s, 2H), 3.82～3.89(t, 2H), 3.54(s, 2H), 2.52～2.69(dd, 4H), 2.21(s, 2H), 2.13～2.16(d, 2H), 2.02(t, 2H), 1.75(t, 2H), 1.56～1.59(d, 2H), 1.25～1.31(d, 8H). 13C NMR (CDCl3, 50 MHz) ; δ 210.09(1C), 130.82(2C), 120.39(2C), 58.45(2C), 50.06(1C), 49.54(1C), 47.10(2C), 31.49(1C), 29.35(1C), 28.95(1C), 27.83(2C), 27.37(1C), 26.65(1C).8- (8-Pyrrol-1-yl-octyl) -8-aza-bicyclo [3,2,1] octan-3-one 8: yield; 2.6%. R f ; 0.48 (TLC eluent; EtOAc: CH 2 Cl 2 = 1: 1, v / v). Mass (70 eV), m / z (rel. Int.%); 302 (47.7), 273 (14.7), 245 (100), 138 (98.2), 96 (17.4), 80 (44), 68 (17.4), 55 (18.3). 1 H NMR (CDCl 3 , 200 MHz); δ 6.64 (s, 2H), 6.12 (s, 2H), 3.82 to 3.89 (t, 2H), 3.54 (s, 2H), 2.52 to 2.69 (dd, 4H), 2.21 (s, 2H), 2.13 to 2.16 (d, 2H), 2.02 (t, 2H), 1.75 (t, 2H), 1.56 to 1.59 (d, 2H), 1.25 to 1.31 (d, 8H). 13 C NMR (CDCl 3 , 50 MHz); δ 210.09 (1C), 130.82 (2C), 120.39 (2C), 58.45 (2C), 50.06 (1C), 49.54 (1C), 47.10 (2C), 31.49 (1C), 29.35 (1C), 28.95 (1C) , 27.83 (2C), 27.37 (1C), 26.65 (1C).
1,8-Di-(8-aza-bicyclo[3,2,1]octan-3-onyl)octane 9 : yield ; 24.9%. Rf ; 0.15 (TLC eluent ; EtOAc : CH2Cl2 = 1 : 1, v/v). Mass (70 eV), m/z (rel.Int. %) ; 360(12.9), 303(100), 275(9.3), 245(7.4), 138(68.5), 96(13.8), 68(11.1), 55(12.9). IR (ν, KBr, ㎝-1) ; 3035, 2925, 2910, 1726 (C=O). 1H NMR (CDCl3, 200 MHz) ; δ 3.52(s, 4H), 2.67(d, 4H), 2.54(t, 4H), 2.15(d, 4H), 2.00(d, 4H), 1.53(d, 4H), 1.33(s, 12H). 13C NMR (CDCl3, 50 MHz) ; δ 210.23(2C), 58.42(4C), 50.08(2C), 47.10(4C), 29.48(2C), 29.07(2C), 27.88(4C), 27.46(2C).1,8-Di- (8-aza-bicyclo [3,2,1] octan-3-onyl) octane 9 : yield; 24.9%. R f ; 0.15 (TLC eluent; EtOAc: CH 2 Cl 2 = 1: 1, v / v). Mass (70 eV), m / z (rel. Int.%); 360 (12.9), 303 (100), 275 (9.3), 245 (7.4), 138 (68.5), 96 (13.8), 68 (11.1), 55 (12.9). IR (ν, KBr, cm −1 ); 3035, 2925, 2910, 1726 (C = O). 1 H NMR (CDCl 3 , 200 MHz); δ 3.52 (s, 4H), 2.67 (d, 4H), 2.54 (t, 4H), 2.15 (d, 4H), 2.00 (d, 4H), 1.53 (d, 4H), 1.33 (s, 12H). 13 C NMR (CDCl 3 , 50 MHz); δ 210.23 (2C), 58.42 (4C), 50.08 (2C), 47.10 (4C), 29.48 (2C), 29.07 (2C), 27.88 (4C), 27.46 (2C).
(4) 2,5-Dimethoxytetrahydrofuran과 1,3-Acetonedicarboxylic acid에 의한 p-Phenylenediamine 10의 반응(4) by 2,5-Dimethoxytetrahydrofuran and 1,3-Acetonedicarboxylic acid Reaction of p-Phenylenediamine 10
실온에서 잘 건조시킨 250 ml 이구 둥근바닥플라스크에 2,5-dimethoxytetrahydrofuran (6.6 g, 0.05 mol)과 1,3-acetonedicarboxylic acid (5.84 g, 0.04 mol)과 증류수 20 ml, 그리고 HCl 0.5 ml를 넣고 30분간 교반한 후, 증류수 10 ml에 녹인 p-phenylenediamine 10 (2.16 g, 0.02 mol)을 ice-bath상에서 적하깔대기를 사용하여 천천히 적가하였다. 실온에서 22시간 동안 교반한 후, TLC로 반응의 완결을 확인하고, 포화 NaHCO3 수용액 500 ㎖로 중화하였다. 이때 생기는 고체는 여과하여 증류수로 여러번 씻어주고, 여액은 dichloromethane으로 추출한 후 분리한 dichloromethane층을 진공회전 증발기를 이용하여 완전히 제거하였다. 얻어진 잔사를 n-hexane과 dichloromethane로 재결정시킨 후 생긴 고체를 소량의 dichloromethane에 녹인 후, 플래시 컬럼 크로마토그래피 (eluent ; EtOAc : n-Hexane = 3 : 1, v/v) 하여 진한 갈색의 고체인 p-dipyrrolylbenzene 11 (0.166 g, yield ; 4.0%)과 8-(4-pyrrol-1-yl-phenyl)-8-aza-bicyclo[3.2.1]octan-3-one 12 (0.638 g, yield ; 12.0%)과 1,4-di-(8-aza-bicyclo[3,2,1]-octan-3-onyl)benzene 13 (3.83 g, yield ; 59.0%)을 얻었다.2,5-dimethoxytetrahydrofuran in a 250 ml double-bottomed flask (6.6 g, 0.05 mol) and 1,3-acetonedicarboxylic acid (5.84 g, 0.04 mol), 20 ml of distilled water, and 0.5 ml of HCl were stirred for 30 minutes, and then p-phenylenediamine 10 dissolved in 10 ml of distilled water. (2.16 g, 0.02 mol) was slowly added dropwise using an ice funnel on an ice-bath. After stirring for 22 hours at room temperature, the reaction was completed by TLC and neutralized with 500 mL of saturated NaHCO 3 aqueous solution. The resulting solids were filtered and washed several times with distilled water, the filtrate was extracted with dichloromethane and the separated dichloromethane layer was completely removed using a vacuum rotary evaporator. The obtained residue was recrystallized with n-hexane and dichloromethane, and the resulting solid was dissolved in a small amount of dichloromethane. Then, flash column chromatography (eluent; EtOAc: n -Hexane = 3: 1, v / v) was carried out to give a dark brown solid p. -dipyrrolylbenzene 11 (0.166 g, yield; 4.0%) and 8- (4-pyrrol-1-yl-phenyl) -8-aza-bicyclo [3.2.1] octan-3-one 12 (0.638 g, yield; 12.0 %) And 1,4-di- (8-aza-bicyclo [3,2,1] -octan-3-onyl) benzene 13 (3.83 g, yield; 59.0%).
p-Dipyrrolylbenzene 11 : yield ; 4.0%. mp ; 213 ～ 214℃. Rf ; 0.48 (TLC eluent ; n-Hexane : EtOAc : CH2Cl2 = 2 : 1 : 1, v/v/v). Mass (70 eV), m/z (rel. Int. %) ; 208(100), 180(32), 152(7.2), 115(11.5), 28(36.1). 1H NMR (CDCl3, 200 MHz) ; δ 7.36(m, 4H), 6.89～6.96(m, 4H), 6.17～6.22(t, 4H).p-Dipyrrolylbenzene 11: yield; 4.0%. mp; 213-214 ° C. R f ; 0.48 (TLC eluent; n-Hexane: EtOAc: CH 2 Cl 2 = 2: 1: 1, v / v / v). Mass (70 eV), m / z (rel. Int.%); 208 (100), 180 (32), 152 (7.2), 115 (11.5), 28 (36.1). 1 H NMR (CDCl 3 , 200 MHz); δ 7.36 (m, 4H), 6.89 to 6.96 (m, 4H), 6.17 to 6.22 (t, 4H).
8-(4-Pyrrol-1-yl-phenyl)-8-aza-bicyclo[3.2.1]octan-3-one 12 : yield ; 12%. mp ; 230 ～ 231℃. 8- (4-Pyrrol-1-yl-phenyl) -8-aza-bicyclo [3.2.1] octan-3-one 12: yield; 12%. mp; 230 to 231 ° C.
Rf ; 0.35 (TLC eluent ; n-Hexane : EtOAc : CH2Cl2 = 2 : 1 : 1, v/v/v). Mass (70 eV), m/z (rel. Int. %) ; 266(100), 209(93.1), 169(32), 142(25), 115(38.2), 68(57.4). 1H NMR (CDCl3, 200 MHz) ; δ 7.31～7.35(m, 2H), 6.90～7.01(m, 4H), 6.30～6.33(t, 2H), 4.50(s, 2H), 2.66～2.76(dd, 2H), 2.18～2.37(m, 4H), 1.80～1.87(m, 2H).R f ; 0.35 (TLC eluent; n- Hexane: EtOAc: CH 2 Cl 2 = 2: 1: 1, v / v / v). Mass (70 eV), m / z (rel. Int.%); 266 (100), 209 (93.1), 169 (32), 142 (25), 115 (38.2), 68 (57.4). 1 H NMR (CDCl 3 , 200 MHz); δ 7.31 to 7.35 (m, 2H), 6.90 to 7.01 (m, 4H), 6.30 to 6.63 (t, 2H), 4.50 (s, 2H), 2.66 to 2.76 (dd, 2H), 2.18 to 2.37 (m, 4H), 1.80-1.87 (m, 2H).
1,4-Di-(8-aza-bicyclo[3,2,1]octan-3-onyl)benzene 13 : yield ; 59.0%. mp ; 246 ～ 247℃. Rf ; 0.45 (TLC eluent ; EtOAc). Mass (70 eV), m/z (rel. Int. %) ; 324(100), 267(58.3), 214(27.8), 117(13.9), 68(14.8). IR (ν, KBr, ㎝-1) ; 3037, 2923, 1730 (C=O), 1590. 1H NMR (CDCl3, 300 MHz) ; δ 6.31～7.44(m, 4H), 4.49(s, 4H), 2.67～2.73(d, 4H, J = 10 Hz), 2.26～2.36(d, 4H, J = 3 Hz), 2.16～2.19(d, 4H), 1.77～1.87(d, 4H). 13C NMR (CDCl3, 125 MHz) ; δ 208.93(2C), 138.05(2C), 117.18(4C), 55.08～55.35(4C), 45.76(4C), 29.20(4C).1,4-Di- (8-aza-bicyclo [3,2,1] octan-3-onyl) benzene 13: yield; 59.0%. mp; 246-247 ° C. R f ; 0.45 (TLC eluent; EtOAc). Mass (70 eV), m / z (rel. Int.%); 324 (100), 267 (58.3), 214 (27.8), 117 (13.9), 68 (14.8). IR (ν, KBr, cm −1 ); 3037, 2923, 1730 (C = O), 1590. 1 H NMR (CDCl 3 , 300 MHz); δ 6.31 to 7.44 (m, 4H), 4.49 (s, 4H), 2.67 to 2.63 (d, 4H, J = 10 Hz), 2.26 to 2.36 (d, 4H, J = 3 Hz), 2.16 to 2.19 (d , 4H), 1.77-1.87 (d, 4H). 13 C NMR (CDCl 3 , 125 MHz); 208.93 (2C), 138.05 (2C), 117.18 (4C), 55.08-55.35 (4C), 45.76 (4C), 29.20 (4C).
(5) 2,5-Dimethoxytetrahydrofuran과 1,3-Acetonedicarboxylic acid에 의한 m-Phenylenediamine 14의 반응(5) Reaction of m-Phenylenediamine 14 with 2,5-Dimethoxytetrahydrofuran and 1,3-Acetonedicarboxylic acid
실온에서 잘 건조시킨 250 ml 이구 둥근바닥플라스크에 2,5-dimethoxytetrahydrofuran (6.6 g, 0.05 mol)과 1,3-acetonedicarboxylic acid (5.84 g, 0.04 mol)과 증류수 20 ml, 그리고 HCl 0.5 ml를 넣고 30분간 교반한 후, 증류수 10 ml에 녹인 m-phenylenediamine 14 (2.16 g, 0.02 mol)을 ice-bath상에서 적하깔때기를 사용하여 천천히 적가하였다. 실온에서 31시간 동안 교반한 후, TLC로 반응의 완결을 확인하고, 포화 NaHCO3 수용액 500 ㎖로 중화하였다. 이때 생기는 고체는 여과하여 증류수로 여러번 씻어주고, 여액은 dichloromethane으로 추출한 후 분리한 dichloromethane층을 진공회전 증발기를 이용하여 완전히 제거하였다. 얻어진 잔사를 flash column chromatography (eluent ; EtOAc : n-Hexane = 1 : 5, v/v) 하여 옅은 황토색의 고체인 8-(3-pyrrol-1-yl-phenyl)-8-aza-bicyclo[3.2.1]octan-3-one 15 (0.081 g, yield ; 2.0%)과 1,3-di-(8-aza-bicyclo[3,2,1]octan-3-onyl)benzene 16 (1.83 g, yield ; 28.0%)을 얻었다.2,5-dimethoxytetrahydrofuran (6.6 g, 0.05 mol), 1,3-acetonedicarboxylic acid (5.84 g, 0.04 mol), 20 ml of distilled water, and 0.5 ml of HCl were added to a 250 ml two-necked round bottom flask, which was dried well at room temperature. After stirring for a minute, m-phenylenediamine 14 (2.16 g, 0.02 mol) dissolved in 10 ml of distilled water was slowly added dropwise using an ice dropping funnel. After stirring for 31 h at room temperature, the reaction was complete by TLC and neutralized with 500 mL of saturated NaHCO 3 aqueous solution. The resulting solids were filtered and washed several times with distilled water, the filtrate was extracted with dichloromethane and the separated dichloromethane layer was completely removed using a vacuum rotary evaporator. The obtained residue was subjected to flash column chromatography (eluent; EtOAc: n-Hexane = 1: 5, v / v) to give 8- (3-pyrrol-1-yl-phenyl) -8-aza-bicyclo [3.2] as a pale yellow solid. .1] octan-3-one 15 (0.081 g, yield; 2.0%) and 1,3-di- (8-aza-bicyclo [3,2,1] octan-3-onyl) benzene 16 (1.83 g, yield; 28.0%) was obtained.
8-(3-pyrrol-1-yl-phenyl)-8-aza-bicyclo[3.2.1]octan-3-one 15 : yield ; 2.0%. mp ; 163 ～ 164℃. Rf ; 0.69 (TLC eluent ; EtOAc : n-Hexane = 1 : 2, v/v). Mass (70 eV), m/z (rel. Int. %) ; 266(100), 209(92.7), 169(29.5), 142(22.3), 115(47), 68(58). 1H NMR (CDCl3, 200 MHz) ; δ 7.38～7.45(m, 2H), 7.15～7.27(m, 4H), 6.32～6.36(t, 2H), 4.49(s, 4H), 2.72～2.79(d, 4H), 2.30～2.37(d, 4H), 2.17～2.21(d, 4H), 1.78～1.83(d, 4H).8- (3-pyrrol-1-yl-phenyl) -8-aza-bicyclo [3.2.1] octan-3-one 15: yield; 2.0%. mp; 163-164 캜. R f ; 0.69 (TLC eluent; EtOAc: n-Hexane = 1: 2, v / v). Mass (70 eV), m / z (rel. Int.%); 266 (100), 209 (92.7), 169 (29.5), 142 (22.3), 115 (47), 68 (58). 1 H NMR (CDCl 3 , 200 MHz); δ 7.38 to 7.45 (m, 2H), 7.15 to 7.27 (m, 4H), 6.32 to 6.63 (t, 2H), 4.49 (s, 4H), 2.72 to 2.79 (d, 4H), 2.30 to 2.37 (d, 4H), 2.17-2.21 (d, 4H), 1.78-1.83 (d, 4H).
1,3-Di-(8-aza-bicyclo[3,2,1]octan-3-onyl)benzene 16 : yield ; 28.0%. mp ; 176 ～ 178℃. Rf ; 0.41 (TLC eluent ; EtOAc : n-Hexane = 1 : 2, v/v). Mass (70 eV), m/z (rel. Int. %) ; 324(100), 281(21.3), 267(51.9), 225(14.8), 209(51.9), 143(15.7), 117(16.7), 68(15.7). IR (ν, KBr, ㎝-1) ; 3040, 2920, 1728 (C=O), 1595. 1H NMR (CDCl3, 300 MHz) ; δ 7.19～7.29(m, 4H), 4.49(s, 4H), 2.70～2.77(d, 4H), 2.29～2.34(d, 4H), 2.17～2.20(d, 4H), 1.78～1.83(d, 4H). 13C NMR (CDCl3, 125 MHz) ; δ 208.69(2C), 147.06(2C), 131.54(1C), 106.17(2C), 101.79(1C), 54.90(4C), 46.11(4C), 29.16(4C).1,3-Di- (8-aza-bicyclo [3,2,1] octan-3-onyl) benzene 16: yield; 28.0%. mp; 176-178 캜. R f ; 0.41 (TLC eluent; EtOAc: n-Hexane = 1: 2, v / v). Mass (70 eV), m / z (rel. Int.%); 324 (100), 281 (21.3), 267 (51.9), 225 (14.8), 209 (51.9), 143 (15.7), 117 (16.7), 68 (15.7). IR (ν, KBr, cm −1 ); 3040, 2920, 1728 (C = O), 1595. 1 H NMR (CDCl 3 , 300 MHz); δ 7.19 to 7.29 (m, 4H), 4.49 (s, 4H), 2.70 to 2.77 (d, 4H), 2.29 to 2.24 (d, 4H), 2.17 to 2.20 (d, 4H), 1.78 to 1.83 (d, 4H). 13 C NMR (CDCl 3 , 125 MHz); 208.69 (2C), 147.06 (2C), 131.54 (1C), 106.17 (2C), 101.79 (1C), 54.90 (4C), 46.11 (4C), 29.16 (4C).
(6) 2,5-Dimethoxytetrahydrofuran과 1,3-Acetonedicarboxylic acid에 의한 o-Phenylenediamine 17의 반응(6) Reaction of o-Phenylenediamine 17 with 2,5-Dimethoxytetrahydrofuran and 1,3-Acetonedicarboxylic acid
실온에서 잘 건조시킨 250 ml 이구 둥근바닥플라스크에 2,5-dimethoxytetrahydrofuran (6.6 g, 0.05 mol)과 1,3-acetonedicarboxylic acid (5.84 g, 0.04 mol)과 증류수 20 ml, 그리고 HCl 0.5 ml를 넣고 30분간 교반한 후, 증류수 10 ml에 녹인 o-phenylenediamine 17 (2.16 g, 0.02 mol)을 ice-bath상에서 적하깔대기를 사용하여 천천히 적가하였다. 적가가 완료된 후 30분 정도 교반을 한 다음 계속해서 역류시키면서 TLC와 GC-MASS로 확인을 하였으나 1,2-di-(8-aza-bicyclo[3,2,1]octan-3-onyl)benzene 18은 흔적량만 나타날 뿐 더 이상의 반응은 진행되지 않았다.2,5-dimethoxytetrahydrofuran (6.6 g, 0.05 mol), 1,3-acetonedicarboxylic acid (5.84 g, 0.04 mol), 20 ml of distilled water, and 0.5 ml of HCl were added to a 250 ml two-necked round bottom flask, which was dried well at room temperature. After stirring for 10 minutes, o- phenylenediamine 17 (2.16 g, 0.02 mol) dissolved in 10 ml of distilled water was slowly added dropwise using a dropping funnel. After the addition was completed, the mixture was stirred for about 30 minutes, and the result was confirmed by TLC and GC-MASS while refluxing continuously. However, 1,2-di- (8-aza-bicyclo [3,2,1] octan-3-onyl) benzene 18 showed only trace amounts and no further reactions proceeded.
합성된 알칸 유도체의 구조는 아래 화학식과 같다.The structure of the synthesized alkan derivatives is shown in the formula below.
합성된 벤젠 유도체의 구조는 아래 화학식과 같다.The structure of the synthesized benzene derivative is represented by the following formula.
합성된 생성물의 실험결과는 아래 표 1과 같다.Experimental results of the synthesized product are shown in Table 1 below.
이와 같이 1,3-acetonedicarboxylic acid 존재하의 아민과 2,5-dimethoxytetrahydrofuran과의 실온에서의 반응은 주생성물로 di-(8-aza-bicyclo[3,2,1]octan-3-onyl)alkanes와 di-(8-aza-bicyclo[3,2,1]octan-3-onyl)benzenes와 부생성물인 N-치환된 pyrrolylalkanes와 N-치환된 phenylpyrroles가 합성되어 졌다. 8-aza-bicyclo[3,2,1]octan-3-one과 pyrrole 합성의 반응 메커니즘은 각각 아래 화학식 3과 화학식 4와 같다.The reaction of amine in the presence of 1,3-acetonedicarboxylic acid with 2,5-dimethoxytetrahydrofuran at room temperature is the main product of di- (8-aza-bicyclo [3,2,1] octan-3-onyl) alkanes. Di- (8-aza-bicyclo [3,2,1] octan-3-onyl) benzenes and byproducts N-substituted pyrrolylalkanes and N-substituted phenylpyrroles were synthesized. The reaction mechanism of 8-aza-bicyclo [3,2,1] octan-3-one and pyrrole synthesis is shown in the following formulas (3) and (4), respectively.
앞서 언급한 두 반응을 비교할 때 8-aza-bicyclo[3,2,1]octan-3-one 유도체의 합성은 실온에서 실시하여야 하며, 1,3-acetonedicarboxylic acid가 중간체 p와 같이 존재하여 중간체 b와 반응할 수 있는 시간적 여유가 필요하다. 그러나 가온환 류 시켰을 때는 1,3-acetonedicarboxylic acid가 중간체 p를 형성치 못하고 다만 산의 역할로 반응하여 중간체 b를 형성한 뒤 바로 안정한 pyrrole 유도체가 형성된다.When comparing the two reactions mentioned above, the synthesis of the 8-aza-bicyclo [3,2,1] octan-3-one derivatives should be carried out at room temperature, and the intermediate b has 1,3-acetonedicarboxylic acid present as intermediate p. You need time to react. However, when heated to reflux, 1,3-acetonedicarboxylic acid does not form intermediate p but reacts as an acid to form intermediate b, which forms a stable pyrrole derivative.
또한 화학식 3을 살펴보면 1,3-acetonedicarboxylic acid가 산 용매(c-HCl, H2O)에서 CO2가 달아나는 추진력에 의해 중간체 p로 전환된 다음 중간체 b를 공격하여 중간체 c가 되고 중간체 d를 거쳐 다시 CO2가 달아나는 추진력에 의해 중간체 e가 형성되어 N-치환된 8-aza-bicyclo[3,2,1]octan-3-one이 된다.In addition, in the formula (3), 1,3-acetonedicarboxylic acid is converted to intermediate p by the driving force of the CO 2 escape from the acid solvent (c-HCl, H 2 O) and then attacked intermediate b to become intermediate c and intermediate d Intermediate e is formed by the driving force of CO 2 escape and becomes N-substituted 8-aza-bicyclo [3,2,1] octan-3-one.
표 1에서 나타난 데이터와 같이 본 연구는 실온에서 반응을 진행시켰기에 pyrrole 유도체보다는 8-aza-bicyclo[3,2,1]octan-3-one 유도체의 합성이 더 유리하다는 결과를 얻을 수 있다. 또한, diaminoalkanes(1, 4, 7)의 반응에서는 탄소 체인이 길어질수록 N원자에 전자를 더 잘 밀어주므로 활성이 더 크며, 탄소 입체효과(steric effect)도 작기 때문에 생성물의 수율이 더 높다. Diaminobenzenes(10, 14, 17)의 반응에서는 8-aza-bicyclo[3,2,1]octan-3-one 링(ring)들의 입체효과 방해의 영향으로 p-위치의 생성물의 수율이 m-위치의 생성물의 수율보다 더 높고, o-위치의 경우는 반응이 거의 진행되지 않았다.As shown in the data shown in Table 1, the present study proceeded with the reaction at room temperature, and thus the synthesis of 8-aza-bicyclo [3,2,1] octan-3-one derivatives was more advantageous than pyrrole derivatives. In addition, in the reaction of diaminoalkanes (1, 4, 7), the longer the carbon chain, the better the activity of the electrons to N atoms, because the greater the activity, the lower the carbon steric effect (steric effect), the higher the yield of the product. In the reaction of diaminobenzenes (10, 14, 17), the yield of the product in the p-position is m-position due to the interference of steric effect of 8-aza-bicyclo [3,2,1] octan-3-one rings. It was higher than the yield of the product, and in the o-position, the reaction hardly proceeded.
본 발명은 항 경련 활성을 보이는 8-aza-bicyclo[3,2,1]octan-3-one구조를 모체로 하여 새로운 항 경련 화합물의 합성을 제공함으로써, 항 경련 연구의 주된 영역으로서 보다 효과적이고 다양한 경련증상을 모두 통제할 수 있는 임상적 적용범위가 넓은 항 경련제를 제공할 수 있다.The present invention provides a synthesis of new anticonvulsant compounds based on the 8-aza-bicyclo [3,2,1] octan-3-one structure exhibiting anticonvulsant activity, thereby making it more effective as a main area of anticonvulsant research. Anticonvulsants with a wide range of clinical applications can be provided that can control all of the various convulsive symptoms.
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| JPH02237920A (en) * | 1984-12-20 | 1990-09-20 | Sandoz Ag | Gastroenteric cisorder treating agent |
| JPH04264085A (en) * | 1990-10-26 | 1992-09-18 | Hoechst Roussel Pharmaceut Inc | 8-azabicyclo (3.2.1) octylalkylthiazolidinone |
| KR19990063651A (en) * | 1995-10-13 | 1999-07-26 | 페더 벨링 | Method and use of 8-azabicyclo [3,2,1] oct-2-ene derivative |
| KR20060132727A (en) * | 2004-02-18 | 2006-12-21 | 세라밴스 인코포레이티드 | Indazole-carboxamide compounds as 5-ht4 receptor agonists |
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| JPH02237920A (en) * | 1984-12-20 | 1990-09-20 | Sandoz Ag | Gastroenteric cisorder treating agent |
| JPH04264085A (en) * | 1990-10-26 | 1992-09-18 | Hoechst Roussel Pharmaceut Inc | 8-azabicyclo (3.2.1) octylalkylthiazolidinone |
| KR19990063651A (en) * | 1995-10-13 | 1999-07-26 | 페더 벨링 | Method and use of 8-azabicyclo [3,2,1] oct-2-ene derivative |
| KR20060132727A (en) * | 2004-02-18 | 2006-12-21 | 세라밴스 인코포레이티드 | Indazole-carboxamide compounds as 5-ht4 receptor agonists |
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