3，4-二氢异喹啉-1-酮类衍生物的合成研究
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摘要
本论文报道一种合成3,4-二氢异喹啉-1-酮类衍生物的新路线。以异香草醛为原料,用氧化银将其氧化成异香草酸(2),然后酯化生成异香草酸甲酯(3),化合物(3)与烯丙基溴在碳酸钾催化下于丙酮中回流得烯丙基醚(4),然后化合物(4)在N,N-二甲基苯胺中回流发生Claisen重排得邻位产物(5),用四氧化锇/高碘酸钠将(5)氧化成关键中间体(6),化合物(6)与伯胺反应发生加成消除反应生成Schiff碱中间体,然后用三乙酰氧基硼氢化钠还原为仲胺,后者发生分子内的胺解反应生成目标化合物。本路线经八步反应合成了目标化合物,其中,Schiff碱的制备、还原、分子内酯的胺解三步反应在“一锅”内完成,反应条件温和、不需分离中间体,操作简单、反应总收率高。利用该方法合成出了9个目标化合物(1a～li),当伯胺中取代基R′为芳香取代基时,三步反应不能在“一锅”内完成,故本文采用其他方法合成了3个目标化合物(1j～1l)。化合物(1a～1l)均未见文献报道,其结构经~1H NMR、~(13)CNMR、MS、元素分析确认。对化合物(1g～1j)进行了体外抗肿瘤活性初步研究,实验结果表明,化合物(1g～li)对ECV-304/人脐静脉内皮细胞系有抑制作用,具有潜在的抗肿瘤活性,有进一步研究开发的价值。其它化合物活性有待进一步研究。
本论文主要包括以下三部分:
第一章综述了近年来异喹啉酮类衍生物的研究进展。主要分为两个方面:1)合成方法研究进展。合成异喹啉酮类衍生物的主要方法有:Dieckman缩合法、Bischler-Napieralski环化法、重排法、Pd-催化法等。但上述方法普遍存在原料试剂昂贵、条件苛刻、总收率不高等不足,不适合放大。2)药理活性研究概述。异喹啉酮类衍生物具有多种药理活性:如杀菌活性、抗组织胺活性、降血压作用、抗糖尿病活性、抗痉挛和利尿作用、消炎作用等。
第二章利用新路线合成出了12个目标化合物:2-苄基-5-羟基-6-甲氧-3,4-二氢异喹啉-1-酮(1a)、2.乙基-5-羟基-6-甲氧-3,4-二氢异喹啉-1-酮(1b)、(R)-2-(1-苯乙基)-5-羟基-6-甲氧基-3,4-二氢异喹啉-1-酮(1c)、2-(5-羟基-6-甲氧-1-氧代-3,4-二氢异喹啉-2(1H)-基)乙酸乙酯(1d)、2-十六烷基-5-羟基-6-甲氧-3,4-二氢异喹啉-1-酮(1e)、2-(5-羟基-6-甲氧-1-氧代-3,4-二氢异喹啉-2(1H)-基)-3-苯丙酸乙酯(1f)、5-羟基-6-甲氧-2-(2-(二乙基胺)乙基)-3,4-二氢异喹啉-1-酮(1g)、5-羟基-6-甲氧基-2-(2-吗啉乙基)-3,4-二氢异喹啉-1-酮(1h)、5-羟基-6-甲氧基-2-(2-哌啶-1-基)乙基-3,4-二氢异喹啉-1-酮(1i)、2-对甲苯基-5-羟基-6-甲氧-3,4-二氢异喹啉-1-酮(1j)、2-(3-氯-4-氟-苯基)-5-羟基-6-甲氧-3,4-二氢异喹啉-1-酮(1k)、2-苯基-5-羟基-6-甲氧-3,4-二氢异喹啉-1-酮(1l)。12个目标化合物(1a～1l),其结构经~1HNMR、~(13)CNMR、MS、元素分析确认,均未见文献报道。
参考文献方法合成出了5个中间体化合物:3-羟基-4-甲氧基苯甲酸(2)、3-羟基-4-甲氧基苯甲酸甲酯(3)、3-烯丙氧基-4-甲氧基苯甲酸甲酯(4)、2-烯丙基-3-羟基-4-甲氧基苯甲酸甲酯(5)、2-氧乙基-3-羟基-4-甲氧基苯甲酸甲酯(6)。其中3个中间体化合物(4～6)未见文献报道,其结构经IR、~1H NMR确认。
第三章化合物(1g～1i)体外抗肿瘤活性初步研究。本文采用MTT法考察了12个目标化合物中的(1g～1i)对ECV-304/人脐静脉内皮细胞系的生长抑制作用,其半数抑制浓度分别为:(1g),33.74μM;(1h),32.784μM;(1i),41.03μM。说明化合物(1g～1i)对ECV-304/人脐静脉内皮细胞系有抑制作用,具有潜在的抗肿瘤活性,有进一步研究开发的价值。其它化合物活性有待进一步研究。
A novel method for the synthesis of 3,4-dihydro-1(2H)-isoquinolinones from isovanillin was reported.Isovanillin was oxidized into 3-hydroxy-4-Methoxybenzoate(2) with Ag_2O and(2) was esterificated to produce(3).Then the compound(3) and allyl bromide together was refluxed in acetone under the presence of K_2CO_3 to give allyl ether(4).The compound(4) was taken play Claisen rearrangement reaction in N,N-dimethylaniline to produce mainly the ortho-position product (5).Then(5) was oxidized with OsO_4/NaIO_4 to give aldehyde(6),The compound(6) was a key intermediate for the synthesis of target compounds.The addition-elimination reaction of(6) with primary amines gave Schiff-base intermediate,then it was reduced with NaBH(OAc)_3 to produce second amines,the later was converted to target compounds by intermolecular amidation of ester.In this novel method,target compounds were synthesized via eight steps.Actually,the three steps imine-forming,reductive and intermolecular amidation,were completed in one-pot at room temperature.This synthetic method was mild,simple in operation,higher yield in overall.Nine target compounds(1a～1i) were synthesized by this novel method.Because when R' is aryl group, the three steps were not completed in one-pot at room temperature.So other three compounds(1j～1l) were synthesized by another method.All of these compounds(1a～1l) have never reported so far and were confirmed by ~1H NMR,~(13)C NMR,MS,elemental analysis.A pilot evaluation on their anti-tumor activities in vitro was given and the results indicated that compounds(1g～1i) have inhibition on ECV-304/Human Umbilical Vein Endothelial Cell Line.Which have a potential anti-tumor activity,the value of further research and development.The anti-tumor activity of other compounds will be further investigated.This paper is consisted of three parts as follows:
In the first part,the researching progress in the derivatives of isoquinolinones was described. There are mainly involving two aspects:The section one is researching progress in synthetic methods.For example,Dieckman condensation,Bischler-Napieralski cyclization,the rearrangement method,Pd-catalysted method et al.But the above methods have many disadvantages such as the expensive starting materials and reagents,the harsh conditions,the lower total yield and not suit the enlargement.The section two is researching progress in the pharmacological effects of isoquinolinones such as disinfection,antitissue form,Antihypertensive,Anti-diabetes,Diuretic and anti-spasm,inflammation et al.
In the second part,twelve target compounds were synthesized by this novel route.2-benzyl-5-hydroxy-6-methoxy-3,4-dihydroisoquinolin-1(2H)-one(1a),2-ethyl-5-hydroxy-6-methoxy-3,4-dih ydroisoquinolin-1(2H)-one(1b),(R)-5-hydroxy-6-methoxy-2-(1-phenylethyl)-3,4-dihydroisoquinoli n-1(2H)-one(1c),ethyl 2-(5-hydroxy-6-methoxy-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl) acetate(1 d),2-hexadecyl-5-hydroxy-6-methoxy-3,4-dihydroisoquinolin-1(2H)-one(1e),ethyl2-(5-hydroxy-6 -methoxy-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)-3-phenylpropanoate(1f),2-(2-(diethylamino) eth yl)-5-hydroxy-6-methoxy-3,4-dihydroisoquinolin-1(2H)-one(1g),5-hydroxy-6-methoxy-2-(2-morph olinoethyl)-3,4-dihydroisoquinolin-1(2H)-one(1h),5-hydroxy-6-methoxy-2-(2-(piperidin-1-yl)ethy 1)-3,4-dihydroisoquinolin-1(2H)-one(1i),5-hydroxy-6-methoxy-2-p-tolyl-3,4-dihydroisoquinolin-1-(2H)-one(1j), 2-(3-chloro-4-fluorophenyl)-5-hydroxy-6-methoxy-3,4-dihydroisoquinolin-1(2H)-one (1k),5-hydroxy-6-methoxy-2-phenyl-3,4-dihydroisoquinolin-1(2H)-One(1l).All of these target com pounds were never reported so far and were confirmed by ~1H NMR,~(13)C NMR,MS,elemental analys is.Five intermediates were synthesized according to the references.3-hydroxy-4-methoxybenzoic ac id(2),methyl 3-hydroxy-4-methoxybenzoate(3),methyl 3-(allyloxy)-4-methoxybenzoate(4),methyl 2-allyl-3-hydroxy-4-methoxybenzoate(5),methyl 3-hydroxy-4-methoxy-2-(2-oxoethyl) benzoate (6).Three of these were never reported so far and were confirmed by IR,~1H NMR.
In the last part,a pilot evaluation on their anti-tumor activities in vitro of compounds(1g～1i) was investigated by MTT method.The IC_(50) of these compounds were:(1g),33.74μM;(1h),32.78μM;(1i),41.03μM.This results indicate that compounds(1g～1i) have inhibition onECV-304/Hu man Umbilical Vein Endothelial Cell Line which have a potential anti-tumor activity,the value of further research and development.The anti-tumor activity of other compounds will be further investiga ted.
本论文主要包括以下三部分:
第一章综述了近年来异喹啉酮类衍生物的研究进展。主要分为两个方面:1)合成方法研究进展。合成异喹啉酮类衍生物的主要方法有:Dieckman缩合法、Bischler-Napieralski环化法、重排法、Pd-催化法等。但上述方法普遍存在原料试剂昂贵、条件苛刻、总收率不高等不足,不适合放大。2)药理活性研究概述。异喹啉酮类衍生物具有多种药理活性:如杀菌活性、抗组织胺活性、降血压作用、抗糖尿病活性、抗痉挛和利尿作用、消炎作用等。
第二章利用新路线合成出了12个目标化合物:2-苄基-5-羟基-6-甲氧-3,4-二氢异喹啉-1-酮(1a)、2.乙基-5-羟基-6-甲氧-3,4-二氢异喹啉-1-酮(1b)、(R)-2-(1-苯乙基)-5-羟基-6-甲氧基-3,4-二氢异喹啉-1-酮(1c)、2-(5-羟基-6-甲氧-1-氧代-3,4-二氢异喹啉-2(1H)-基)乙酸乙酯(1d)、2-十六烷基-5-羟基-6-甲氧-3,4-二氢异喹啉-1-酮(1e)、2-(5-羟基-6-甲氧-1-氧代-3,4-二氢异喹啉-2(1H)-基)-3-苯丙酸乙酯(1f)、5-羟基-6-甲氧-2-(2-(二乙基胺)乙基)-3,4-二氢异喹啉-1-酮(1g)、5-羟基-6-甲氧基-2-(2-吗啉乙基)-3,4-二氢异喹啉-1-酮(1h)、5-羟基-6-甲氧基-2-(2-哌啶-1-基)乙基-3,4-二氢异喹啉-1-酮(1i)、2-对甲苯基-5-羟基-6-甲氧-3,4-二氢异喹啉-1-酮(1j)、2-(3-氯-4-氟-苯基)-5-羟基-6-甲氧-3,4-二氢异喹啉-1-酮(1k)、2-苯基-5-羟基-6-甲氧-3,4-二氢异喹啉-1-酮(1l)。12个目标化合物(1a～1l),其结构经~1HNMR、~(13)CNMR、MS、元素分析确认,均未见文献报道。
参考文献方法合成出了5个中间体化合物:3-羟基-4-甲氧基苯甲酸(2)、3-羟基-4-甲氧基苯甲酸甲酯(3)、3-烯丙氧基-4-甲氧基苯甲酸甲酯(4)、2-烯丙基-3-羟基-4-甲氧基苯甲酸甲酯(5)、2-氧乙基-3-羟基-4-甲氧基苯甲酸甲酯(6)。其中3个中间体化合物(4～6)未见文献报道,其结构经IR、~1H NMR确认。
第三章化合物(1g～1i)体外抗肿瘤活性初步研究。本文采用MTT法考察了12个目标化合物中的(1g～1i)对ECV-304/人脐静脉内皮细胞系的生长抑制作用,其半数抑制浓度分别为:(1g),33.74μM;(1h),32.784μM;(1i),41.03μM。说明化合物(1g～1i)对ECV-304/人脐静脉内皮细胞系有抑制作用,具有潜在的抗肿瘤活性,有进一步研究开发的价值。其它化合物活性有待进一步研究。
A novel method for the synthesis of 3,4-dihydro-1(2H)-isoquinolinones from isovanillin was reported.Isovanillin was oxidized into 3-hydroxy-4-Methoxybenzoate(2) with Ag_2O and(2) was esterificated to produce(3).Then the compound(3) and allyl bromide together was refluxed in acetone under the presence of K_2CO_3 to give allyl ether(4).The compound(4) was taken play Claisen rearrangement reaction in N,N-dimethylaniline to produce mainly the ortho-position product (5).Then(5) was oxidized with OsO_4/NaIO_4 to give aldehyde(6),The compound(6) was a key intermediate for the synthesis of target compounds.The addition-elimination reaction of(6) with primary amines gave Schiff-base intermediate,then it was reduced with NaBH(OAc)_3 to produce second amines,the later was converted to target compounds by intermolecular amidation of ester.In this novel method,target compounds were synthesized via eight steps.Actually,the three steps imine-forming,reductive and intermolecular amidation,were completed in one-pot at room temperature.This synthetic method was mild,simple in operation,higher yield in overall.Nine target compounds(1a～1i) were synthesized by this novel method.Because when R' is aryl group, the three steps were not completed in one-pot at room temperature.So other three compounds(1j～1l) were synthesized by another method.All of these compounds(1a～1l) have never reported so far and were confirmed by ~1H NMR,~(13)C NMR,MS,elemental analysis.A pilot evaluation on their anti-tumor activities in vitro was given and the results indicated that compounds(1g～1i) have inhibition on ECV-304/Human Umbilical Vein Endothelial Cell Line.Which have a potential anti-tumor activity,the value of further research and development.The anti-tumor activity of other compounds will be further investigated.This paper is consisted of three parts as follows:
In the first part,the researching progress in the derivatives of isoquinolinones was described. There are mainly involving two aspects:The section one is researching progress in synthetic methods.For example,Dieckman condensation,Bischler-Napieralski cyclization,the rearrangement method,Pd-catalysted method et al.But the above methods have many disadvantages such as the expensive starting materials and reagents,the harsh conditions,the lower total yield and not suit the enlargement.The section two is researching progress in the pharmacological effects of isoquinolinones such as disinfection,antitissue form,Antihypertensive,Anti-diabetes,Diuretic and anti-spasm,inflammation et al.
In the second part,twelve target compounds were synthesized by this novel route.2-benzyl-5-hydroxy-6-methoxy-3,4-dihydroisoquinolin-1(2H)-one(1a),2-ethyl-5-hydroxy-6-methoxy-3,4-dih ydroisoquinolin-1(2H)-one(1b),(R)-5-hydroxy-6-methoxy-2-(1-phenylethyl)-3,4-dihydroisoquinoli n-1(2H)-one(1c),ethyl 2-(5-hydroxy-6-methoxy-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl) acetate(1 d),2-hexadecyl-5-hydroxy-6-methoxy-3,4-dihydroisoquinolin-1(2H)-one(1e),ethyl2-(5-hydroxy-6 -methoxy-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)-3-phenylpropanoate(1f),2-(2-(diethylamino) eth yl)-5-hydroxy-6-methoxy-3,4-dihydroisoquinolin-1(2H)-one(1g),5-hydroxy-6-methoxy-2-(2-morph olinoethyl)-3,4-dihydroisoquinolin-1(2H)-one(1h),5-hydroxy-6-methoxy-2-(2-(piperidin-1-yl)ethy 1)-3,4-dihydroisoquinolin-1(2H)-one(1i),5-hydroxy-6-methoxy-2-p-tolyl-3,4-dihydroisoquinolin-1-(2H)-one(1j), 2-(3-chloro-4-fluorophenyl)-5-hydroxy-6-methoxy-3,4-dihydroisoquinolin-1(2H)-one (1k),5-hydroxy-6-methoxy-2-phenyl-3,4-dihydroisoquinolin-1(2H)-One(1l).All of these target com pounds were never reported so far and were confirmed by ~1H NMR,~(13)C NMR,MS,elemental analys is.Five intermediates were synthesized according to the references.3-hydroxy-4-methoxybenzoic ac id(2),methyl 3-hydroxy-4-methoxybenzoate(3),methyl 3-(allyloxy)-4-methoxybenzoate(4),methyl 2-allyl-3-hydroxy-4-methoxybenzoate(5),methyl 3-hydroxy-4-methoxy-2-(2-oxoethyl) benzoate (6).Three of these were never reported so far and were confirmed by IR,~1H NMR.
In the last part,a pilot evaluation on their anti-tumor activities in vitro of compounds(1g～1i) was investigated by MTT method.The IC_(50) of these compounds were:(1g),33.74μM;(1h),32.78μM;(1i),41.03μM.This results indicate that compounds(1g～1i) have inhibition onECV-304/Hu man Umbilical Vein Endothelial Cell Line which have a potential anti-tumor activity,the value of further research and development.The anti-tumor activity of other compounds will be further investiga ted.
引文
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