5-羟基-1,3,4-噻二唑[3,2-a]并嘧啶-7-酮衍生物的绿色合成

为了寻找干扰嘌呤核酸代谢的抗肿瘤新药,设计和合成了嘌呤生物碱的类似物。以2-氨基-1,3,4-噻二唑、丙二酸与三氯氧磷为原料,经过关环,偶合等反应合成了9种5-羟基-1,3,4-噻二唑[3,2-a]并嘧啶-7-酮衍生物,通过元素分析、IR、1 H NMR和质谱分析确定了其结构。     

环烯烃并[b]吡啶-2-酮的合成

以环己酮为原料,经Michael加成、环化反应获得2,3-环己烯并吡啶-2-酮2,总收率为41.8%。以环戊酮和乙酰乙酸乙酯为原料,经Aldol缩合、环化反应获得4-甲基-2,3-环戊烯并吡啶-2-酮3b,总收率为21.5%。以环庚酮、甲酸乙酯与氰基乙酰胺为原料,经串联的Aldol反应、关环、酸水解、脱羧反应获得2,3-环庚烯并吡啶-2-酮4,总收率为40%。化合物通过熔点和1H-NMR进行了表征。     

Reactions with β-ketodianilides. I. New synthesis of Pyrido[3,4-c]pyridine Derivatives

Acetonedicarboxylic acid dianiline reacted with malononitrile, ethyl cyanoacetate or benzoylacetonitrile to give (6-amino-5-cyano-1,2-dihydro-2-oxo-1-phenylpyrid-4-yl)-acetanilide ( 3 ), (3-cyano-2,6-dioxo-1-phenyl-1,2,5,6-tetrahydropyrid-4-yl)acetanilide ( 8 ) or (3-cyano-1,6-dihydro-1,2-diphenyl-6-oxopyrid-4-yl)acetanilide ( 9 ). Compounds 3 and 8 could be cyclised into 8-amino-1,6-diphenyl-1,2,4,5,6,7-hexahydro-7-iminopyrido[3,4-c]pyridine-2,5-dione ( 4 ) and 7-amino-1,2,3,5,6,8-hexahydro-1,6-diphenylpyrido[3,4-c]pyridine-2,5,8-trione ( 10 ) respectively by heating their solutions in dimethylformamide in the presence of triethylamine. Each of 3 and 4 coupled with arenediazonium chlorides to give the corresponding arylhydrazone derivatives ( 5a–d ) and ( 6a–c ), respectively. Condensation of 4 with p-nitrosodimethylaniline yielded 8-amino-4- (p-dimethylaminophenylimino)-1,6-diphenyl-1,2,4,5,6,7-hexahydro-7-iminopyrido[3,4-c]pyridine2,5-dione ( 7 ).     

One-Pot Multicomponent Synthesis of Pyrazolo[3,4-d]pyrimidine-6-one Derivatives

An environmentally benign, simple, and efficient procedure has been developed for the one-pot multicomponent synthesis of pyrazolo[3,4-d]pyrimidine-6-one derivatives by the reaction of the variety of aryl-aldehydes, 5-methyl-2-phenyl-2,4-dihydro-3H-pyrazol-3-one, and urea in the presence of catalytic amount of poly(N-vinylpyridinium) hydrogen sulfate in glycerol. The present method affords non-toxic and non-corrosive medium, short reaction times, high yield of the products, mild reaction conditions as well as simple experimental and isolation procedures. The catalyst can be recycled by simple filtration and reused without any significant reduction in its activity.     

6，7-二氢-5H-环戊烷并[b]吡啶

6,7-二氢-5H-环戊烷并[b]吡啶主要用于药物、杀菌剂和抗菌剂的研究,也被广泛应用于制备植物保护剂和合成树脂、防老剂以及塑料制品等。目前因其被作为第四代抗生素头孢匹罗的侧链而成为研究者竞相开发的热点。6,7-二氢-5H-环戊烷并[b]吡啶有实用价值的合成方法主要有N-羟基邻苯二甲酰胺法、丙烯醛法和己二酸二乙酯法。丙烯醛法中6,7-二氢-5H-环戊烷并[b]吡啶的收率为87.4%,具有较好的开发前景。     

5-氨基-1,4-苯并二恶烷盐酸盐的合成

以2,3-二羟基苯甲酸为原料,经酚羟基烷基化保护、羧酸叠氮化、Curtius重排、水解成盐四步反应以35%的总收率合成了5-氨基-1,4-苯并二恶烷盐酸盐,其结构经1H-NMR确认。由于合理的反应溶剂选择和反应温度控制,减少了副反应的发生、简化了工艺操作、降低了分离难度、提高了收率和产品纯度,使得该路线适合于工业化生产。     

脱羧串联式反应合成2-磺酰基苯并[b]呋喃

以3-烯丙基-2-羟基肉桂酸或4-二乙氨基-2-羟基肉桂酸为起始原料,分别与对甲苯亚磺酸钠,在Cu/Ag双金属体系作用下,经脱羧串联式反应得到2个2-磺酰基苯并[b]呋喃化合物。其结构经1H NMR和~(13)C NMR确证。     

6,7-二氢苯并菲咯啉的衍生物合成

以1,2-环己二酮和邻氨基苯甲酰类衍生物为原料,经Friedlander缩合反应合成系列菲咯啉衍生物-6,7-二氢苯并菲咯啉(A-D)。研究表明:以硝酸铈铵为催化剂,乙醇为溶剂的合成工艺收率较高,后处理方法简捷,底物普适性好,具有良好的应用前景。     

MANNICH reaction on 5-hydroxybenzo[b]thiophene

The reaction of 5-hydroxybenzo[b]thiophene 1 with formaldehyde and some primary and secondary amines has been investigated. Whereas secondary amines give always the corresponding 4-aminomethyl-derivatives 2 , the products with primary amines depend largely on the experimental conditions. The products, so obtained, have been characterized using micro- and spectral analyses.     

Reaction of hydrazonoyl halides 49 1: Synthesis and antimicrobial activity of some new pyrimido[1,2-b][1,2,4,5]tetrazin-6-one,tetrazino[3,2-b]quinazolin-5-one,pyrimidino[1,2-b]1,2,4,5-tetrazin-5-one and triazolo[4,3-a]pyrimidine derivatives

Pyrimido[1,2-b][1,2,4,5]tetrazin-6-one, tetrazino[3,2-b]quinazolin-5-one, pyrimidino[1,2-b]1,2,4,5-tetrazin-5-one and triazolo[4,3-a]pyrimidine derivatives were synthesized from C-(4-methyl-2-phenyl)thiazol-5-oyl-N-phenyl-hydrazonoyl bromide and different pyrimidine-2-thiones. New compounds had their structures confirmed by elemental and spectral analysis and were screened antimicrobial activity.     

Efficient Synthesis of Chiral Isoquinoline and Pyrido[1,2‐b]‐isoquinoline Derivatives via Intramolecular Heck Reactions

The palladium(0)‐catalyzed reaction of derivatives of γ‐amino‐α,β‐unsaturated esters bearing an N‐(2‐iodobenzoyl) substituent results in an intramolecular Heck reaction, the outcome of which depends on the structure of the substrate as well as on the experimental conditions. The methodology developed has been applied to the efficient syntheses of chiral isoquinoline and pyrido[1,2‐b]–isoquinoline derivatives.     

Reactions with 5,6-Diphenyl-2,3-dihydro-imidazo[2,1-b]thiazol-3-ones and 6,7-Diphenyl-2,3-dihydro-4H-imidazo[2,1-b]1,3-thiazin-4-one

2-Methyl-5,6-diphenyl-2,3-dihydro-imidazo[2,1-b]thiazol-3-one 5 and 6,7-diphenyl-2,3-dihydro-4H-imidazo[2,1-b]1,3-thiazin-4-one 6 are prepared from 4,5-diphenyl-2-mercapto-imidazole 1 . Compounds 5 and 6 react with amines or hydrazines to give the 2-(4,5-diphenyl-imidazol-2-ylthio)acet(or propan) amides (hydrazides) 7a – g and the 3-(4,5-diphenyl-imidazol-2 ylthio) propanamides(hydrazides) 8a – e , respectively. The hydrazides 7a, 7b and 8a are condensed with aromatic aldehydes to the hydrazones 9a – h and 10a – d . Compound 5 couples with aryldiazonium salts to give 2-arylazo-2-methyl-5,6-diphenyl-2,3-dihydro-imidazo[2,1-b]thiazol-3-ones 11a – d .     

Spectroscopic and In Silico Studies on the Interaction of Substituted Pyrazolo[1,2-a]benzo[1,2,3,4]tetrazine-3-one Derivatives with c-Myc G4-DNA

Herein we describe a combined experimental and in silico study of the interaction of a series of pyrazolo[1,2-a]benzo[1,2,3,4]tetrazin-3-one derivatives (PBTs) with parallel G-quadruplex (GQ) DNA aimed at correlating their previously reported anticancer activities and the stabilizing effects observed by us on c-myc oncogene promoter GQ structure. Circular dichroism (CD) melting experiments were performed to characterize the effect of the studied PBTs on the GQ thermal stability. CD measurements indicate that two out of the eight compounds under investigation induced a slight stabilizing effect (2–4 °C) on GQ depending on the nature and position of the substituents. Molecular docking results allowed us to verify the modes of interaction of the ligands with the GQ and estimate the binding affinities. The highest binding affinity was observed for ligands with the experimental melting temperatures (T_ms). However, both stabilizing and destabilizing ligands showed similar scores, whilst Molecular Dynamics (MD) simulations, performed across a wide range of temperatures on the GQ in water solution, either unliganded or complexed with two model PBT ligands with the opposite effect on the T_ms, consistently confirmed their stabilizing or destabilizing ability ascertained by CD. Clues about a relation between the reported anticancer activity of some PBTs and their ability to stabilize the GQ structure of c-myc emerged from our study. Furthermore, Molecular Dynamics simulations at high temperatures are herein proposed for the first time as a means to verify the stabilizing or destabilizing effect of ligands on the GQ, also disclosing predictive potential in GQ-targeting drug discovery.     

5-硝基-2-磺酰基苯并呋喃的合成研究

以5-硝基水杨醛为起始原料,经Horner-Wittig反应、水解得到5-硝基-2-羟基肉桂酸。该中间体分别与不同电性基团取代的苯亚磺酸钠,在Cu(OAc)_2和Ag OAc双金属体系作用下,经串联式反应得到2个5-硝基-2-磺酰基苯并呋喃化合物。其结构经~1H NMR、~(13)C NMR确证。     

11H-Benzo[4,5]imidazo[1,2-a]indol-11-one as a New Precursor of Azomethine Ylides: 1,3-Dipolar Cycloaddition Reactions with Cyclopropenes and Maleimides

The possibility of generating azomethine ylides from 11H-benzo[4,5]imidazo[1,2-a]indol-11-one and amino acids is shown for the first time. Based on the cycloaddition reactions of these azomethine ylides with cyclopropenes and maleimides, cyclopropa[a]pyrrolizines, 3-azabicyclo[3.1.0]hexanes, and pyrrolo[3,4-a]pyrrolizines spiro-fused with a benzo[4,5]imidazo[1,2-a]indole fragment were synthesized. Spirocyclic compounds were obtained in moderate to good yields, albeit with poor diastereoselectivity. Density functional theory calculations were performed to obtain an insight into the mechanism of the 1,3-dipolar cycloaddition of 11H-benzo[4,5]imidazo[1,2-a]indol-11-one-derived azomethine ylides to cyclopropenes. The cytotoxic activity of some of the obtained cycloadducts against the human erythroleukemia (K562) cell line was evaluated in vitro by MTS-assay.     

5-氨基苯[b]并噻吩-2-甲酸乙酯的合成

以2-氯-5-硝基苯甲醛为原料,与巯基乙酸乙酯发生环合,得到5-硝基苯[b]并噻吩-2-甲酸乙酯,再在Pd/C和甲酸铵作用下,经过氢化还原得到5-氨基苯[b]并噻吩-2-甲酸乙酯,总产率89.4%。