The Synthesis And Design Of The Tricyclic Benzothiazepine Derivatives Containing Quinoline Moiety

Heterocyclic compounds always play a very important role in pharmaceutical and pesticide fields. Studies on the synthesis of heterocyclic compounds possessing biological activity become a hot topic in the research of pharmacochemistry and have made great contribution to human health and agricultural development in recent years. Considering the combination principles for drug design, the biological activities of the compounds containing different heterocyclic in a single molecular can be visibly increased.1,5-Benzothiazepine is an important seven-membered heterocyclic ring system. It has attracted considerable attention to synthetic and medicinal chemists due to their broad spectrum of biological activities such as regulation of cardiovascular, antihypertensive, anti-HIV, anticancer, antibacterial, anti-ulcer and antispasmodic. Derivatives containing quinoline moiety are always given to attention for pharmacy workers because of the characteristic of high cure effect and broad spectrum of antibacterial activities. Some drugs have been widely used in clinics at the present time, for example, chloroquine, cinchophen, dibucaine and dequalinium chloride as antimalarial, antipyretic analgesics, local anesthetic and antibiotic respectively.1,3-Dipolar and [2+2] cycoladdition reaction are the classic method used for synthesizing the five-membered, four-membered, heterocycles, respectively, such as1,2,4-oxadiazole,1,2,4-triazole and β-lactam.Major work of the thesis is to design and synthesize some new1,5-benzothiazepine derivatives bearing quinoline ring. The C=N amine double bond in the molecule is the major chemical modification position. Consequently, we obtained a series of novel tricyclic1,5-benzothiazepine derivatives via1,3-dipolar and [2+2] cycloaddition reaction with potential biological activities.The thesis includes two major parts:The first part:literature review.This part introduce the important synthetic methods, biology activities and application of drug of the1,5-benzothiazepine and quinoline derivatives, and also elaborate1,3-dipolar and [2+2] cycloaddition reaction.The second part:experimental content—synthesis of the tricyclic1,5-benzothiazepine derivatives containing quinoline moiety.1. Synthesis of the1,5-benzothiazepine containing quinoline moiety. This part synthesis the intermediate compounds2-chloroquinoline-3-aldehyde, chalcone and1,5-benzothiazepine.2. Synthesis of oxadiazolo[1,5]benzothiazepine derivatives via1,3-dipolar cycloaddition.In this part, a series of novel [1,2,4]oxadiazolo[5,4-d][1,5]benzothiazepine derivatives were synthesized via1,3-dipolar cycloaddition. In the presence of Et3N, the nitrile oxide generated in situ and C=N double bond in the benzothiazepine ring forms a cyclic transition state and the σ-bonds of C-N and C-O were formed simultaneously to obtain the1,2,4-oxadiazole ring.3. Synthesis of triazolo[1,5]benzothiazepine derivatives via1,3-dipolar cycload-dition.The [3+2]1,3-dipolar cycloaddition reaction of1,5-benzothiazepine with hydraz-onoyl chlorides in the presence of Et3N gave the [1,2,4]triazolo[3,4-d][1,5]benzothia-zepine derivatives. The reaction condition and mechanism equate with the part2.4. Synthesis of P-lactam derivatives with a-chlor/phenoxy substitute of the1,5-benzothiazepine.The [2+2] cycloaddition of the olefine ketone and C=N double bond in the benzothiazepine ring afforded a series of novel β-lactam derivatives with a-chlor/phenoxy substitute of the1,5-benzothiazepine.The structures of all the new compounds were confirmed by MS, IR,1H NMR and elemental analyses. Also, we give the single crystal discussion to some of the target compounds.