Study On Diversity-oriented Synthesis Applied In The Synthesis Of Some Heterocyclic Compounds

Diversity-oriented synthesis (DOS) concept was first put forward by Schreiber in 2000, the synthesis from simple starting materials start with simple method for synthesis of structure diversity, complex structure of natural product-like. Its synthesis strategy follows forward-synthetic analysis, try to introduce a variety of functional groups in the process of synthesis, build different molecular skeleton, and hope to eventually build a small molecule compound library covers the chemical diversity of as much as possible (including the concentration of chiral functional groups, the rich stereochemistry and three-dimensional structure, and the diversity of compounds skeleton). Then they are screened by "high throughput" in biology, screening of DOS target is not aimed at one kind of specific biological targets, but looking for new ligands for various targets, cells and the function of the organism is analyzed, found that macromolecular interactions "wiring diagram". Around the diversity-oriented synthesis of heterocyclic compounds, this thesis is divided into the following five chapters.1. The research progress of diversity-oriented synthesis:It is briefly reviewed in this chapter by the complex structural diversity, structure of natural product-like from simple starting materials was synthesized by the Friedel-Crafts, Diels-Alder (D-A), cycloaddition, conjugate addition or free radicals reaction and so on. And diversity-oriented synthesis strategy was applied in synthesis of a-amino acid derivatives, polypeptide compound, natural products, biological active drug molecules, aromatic or fat heterocyclic compounds and chemical genetics. The research progress is reviewed with 120 references in this chapter.2. The synthesis of piperazine skeleton compounds by three components domino reaction: piperazine is one of the most important structures in the heterocyclic compound, and the skeleton exists in many natural products. Piperazine skeleton derivatives has extensive pharmacological activities, therefore, the synthesis of its skeleton derivatives is favored by a lot of drug synthesis workers. In the summary about the progress in the synthesis of piperazine skeleton in recent years, on the basis of diversity-oriented synthesis strategy, we developed the synthesis methods of disubstituted piperazine skeleton derivatives. The tri-component domino reactions were applied in a synthesis method, which makes this method has the characteristics of the operation is simple, convenient and atomic economy, and synthesis method is also suitable for the scale synthesis application. Applicability is wide and its substrates. For using this method, 58 new disubstituted piperazine derivatives were synthesized, and one crystal structure of the compounds vas determined by X-ray diffraction.3. Diversity-oriented synthesis thiadiazolopyrimidinone:In this chapter,2-amino-1,3,4-thiadiazole was synthesized by reaction of thiosemicarbazide and aromatic carboxylic acid as the material in POCl3. The target product, skeleton structure of thiadiazolopyrimidin-5-one derivatives was synthesized through the assembly structure by reaction of 2-amino-1,3,4-thiadiazole derivatives under the formic acid-phosphorus pentoxide catalyzed and cyanide ethyl acetate. The one-pot synthesis method is novel and efficient, and is set [3 + 3] cycloaddition, reduction of imines, taking off the amino series of cascade reaction. The target product, skeleton structure of thiadiazolopyrimidin-7-one derivatives was synthesized by the reaction of 2-amino-1,3,4-thiadiazole derivatives and propiolic acid ester skeleton structure in the ethanol. A total of 25 kinds of new compounds were synthesized, including three kinds crystal structure of compounds was determined by X-ray diffraction.4. Diversity-oriented synthesis thiadiazolopyrimidine carboxylic acid derivatives: In this chapter, 2-amino-1,3,4-thiadiazole was synthesized by reaction of thiosemicarbazide and aromatic carboxylic acid as the material in POCl3. Then, some methyl 7-oxo-2-substituted-7H-[1,3,4]thiadiazolo[3,2-a]pyrimidine-5-carboxylate was synthesized by the reacton of various kinds 2-amino-5-substituted-1,3,4-thiadiazole, dimethyl acetylene dicarboxylate (DMAD), under the condition of the reaction of 1,2-dimethoxyethane as solvent, using ultrasonic cleaning machine ultrasonic radiation reaction. However, methyl 5-oxo-2-substituted-5H-[1,3,4]thiadiazolo[3,2-a] pyrimidine-7-carboxylate was not synthesized just like reaction of pyridin-2-amine. 17 new compounds are synthesized, and two crystal structure of these compounds was determined by X-ray diffraction.5. Diversity-oriented synthesis of biscarbonyl compounds and dimethyl acetylene dicarboxylate: In this chapter, several (2*S,5*R)-dimethyl 4,5-diaryl-2,5-dihydrofuran-2,3-dicarboxylate was given by the reaction of benzoin-typ compounds and dimethyl acetylene dicarboxylate (DMAD) under the catalyst of triphenylphosphine; Use of dicarbonyl compounds as raw materials, and DMAD, under DABCO as catalyst condition, when promote with ultrasonic. A series of multisubstituted benzene derivatives were obtained by the reaction of dicarbonyl compounds and DMAD, 1,4-diazabicyclo[2.2.2]octane (DABCO) as catalyst under the condition of ultrasound to promote the reaction. When the reaction of dicarbonyl compounds and DMAD was carried out under DABCO and sodium methoxide as catalyst, use ultrasound to promote the reaction, some pyrone derivatives are obtained. In this part,26 kinds of new compounds were synthesized. Three kinds crystal structure of compounds were determined by X-ray diffraction.