(99d) Scientific Bases for Development of Technology of Key Semi-Products in Production of Medicinal Preparations of Piperidine

Derivatives of piperidine-4-ones are the key products for synthesis and search of new vital effective medicinal preparations such as analgetics, anticancer, anti-AIDS, and antidiabetes medicines. Up to the present time on the territory of CIS countries the method of academician I.N. Nazarov realized in the production of analgetic Promedol was of great importance in the field of synthesis of dimethylsubstituted piperidine ketones. The technology of this production has a number of significant disadvantages: mercury salts used as catalyst in this process are higly toxic, and the raw materials are characterized as highly flammable and explosive. Development of new more accessible and safe methods of synthesis of 2,5- dimethyl and N-substituted 2,5-dimethylpiperidine-4-ones and searching for new medicines on their basis is the purpose of these investigations. Creation of modern synthesis technologies of new compounds on the basis of available raw materials requires, first of all, the solution of fundamental problems of organic chemistry, such as conformation of molecule and its reactivity, stereochemical and conformational regularities of the reaction procedure, and the use of quantum-chemical calculations for determination of the energy parameters of the molecule for purposeful synthesis. Systematic investigations carried in the field of synthesis of piperidine ketones and their derivatives allowed us to substantiate theoretically and validate experimentally a scientific approach to creation of new methods and the improvement of the existing methods of synthesis of the key semi-products for production of analgetics, anticancer, anti-AIDS, and antidiabetes medicines. On the basis of the obtained results we have developed new methods of synthesis of 2,5- dimethyl and N-substituted 2,5-dimethylpiperidine-4-ones from acetoacetic ester. We studied general regularities of selective reduction of the olefine bond of intermediate enaminoesters, by catalytic nucleophilic addition of amines to multiple bonds of sterically hindered esters of a, β - uansaturated carbonic acids, cyclization of aminodiesters into 2,5-dimethyl- and N-substituted 2,5- dimethylpiperidine-4-ones. The main parameters of the processes were experimentally founded. We have studied the tautomerism, configuration and conformation isomerism of ethyl ester of 3-amino-2- butene acid of its cis-S- cis, trans-S- cis and trans-S-trans conformers. Quantum-chemical estimation of cis-S-cis, trans-S-cis and trans-S-trans conformers of esters of 3-amino-2-butene acid were carried out. On the base of received results we developed a new industrial method of synthesis of ethyl ester of β β -aminooil acid by selective hydrogenation of ethyl ester of β -aminocrotonic acid on Ni-Re. By condensation of acetoacetic ester with secondary amines we have synthesized tertiary enaminoesters in trans-S-cis conformation, the following reduction of which by sodium borhydride allowed us to develop industrially available methods of obtaining the esters of tertiary β -aminoacids. Also we have developed an alternative method of synthesis of differently substituted esters of secondary and tertiary β -aminoacids by catalytic nucleophilic addition of amines to multiple bonds of esters of a, β - saturated carbonic acids. We have suggested a mechanism of catalysis. Fundamental researches on synthesis, search of the structure and physiological activity of Piperidine derivatives allowed us to develop some original highly-effective preparations: local anesthetics, antibacterial, dermatoprotector, immunocorrector and anti-cancer medicines. Pre-clinical researches of the preparations were carried out at laboratories of Cuban Medical Academy (Russia). Clinical reseaches were carried out in the leading clinical centres of Russian Federation and Republic of Kazakhstan. There were developed various medical forms of pharmaceuticals including prolonged and combined ones. Some of these products are allowed in medical practice and industrial output. The methods of synthesis are successfully approbated on the pilot equipment at Pavlodar Chemical Plant. Medical products on dimethylpiperidine-4-ones basis are noted by higher stability because its particular spatial structure, the lowered toxicity and more valuable therapeutic properties in comparison with piperidone-4, which does not have alkyl radicals in a cycle. Synthesis and search of new derivatives on its basis, in particular, for the treatment of HIV infection has good prospects. Optical active form of the esters of ß-hydroxibutyric acid is a perspective monomer in the manufacture of biodegradabled polymers. They can find application in the reception of plasticizers. The method of production of new hydrogel was developed on the basis of ethyl ester of ß-aminocrotonic and acrylic acids (it lends itself well to an application in biotechnology ? in purification and separation of proteins, immobilization and stabilization of enzymes, fermentative catalysis in pharmaceutics ? as an auxiliary material for prolongation of medical products, in petrochemistry ? as an inhibitor of corrosion of metals in oil production, and as an antidepressant). References 1. RK Patent No. 3119. Richlocaine ? benzoic ester of a-isomer of 1-allyl-2,5-dimethylpiperidol-4 as an anaesthetic. A.Sh. Sharifkanov, Sh.S. Akhmedova, K.B. Murzagulova (RK), Galenko-Jaroshevskiy P.A. (RF). 2. RF Patent No. 2026289. The way of reciept of 2,5-dimethylpiperidin-4-on. Praliev K.D., Murzagulova K.B., Akhmedova Sh. S., Sharifkanov A.Sh.(Kaz), Trubachev V.I. Jablokov S.O. (Russia). 3. RF Patent No. 2148577. The method of synthesis 2,5-dimethyl-4-hydroxipiperidine ? semi-product for production of local anaesthetic Richlocaine. A.Sh. Sharifkanov, Sh.S. Akhmedova, K.B. Murzagulova (RK). 4. Decision of patent distribution on the application: RF Patent No. 2001103068/14 of 09.04.02. Richlocaine ? dermatoprotector and anticonvulsive medicine. Sh. S. Akhmedova, K.B. Murzagulova (RK), P.A. Galenko-Jaroshevskiy (RF). 5. RF Patent No. 2180557 Anaesthetic composition of prolonging effect. Shantyz M.G., Galenko-Jaroshevskiy P.A. (RF), Sharifkanov A.Sh., Akhmedova Sh. S., K.B. Murzagulova (RK). 6. Murzagulova K.B. Makysh G.Sh., Bimendina L., Kudaibergenov S. e. Interaction of richlocaine with some linear and crosslinked polymers// Polymer.-2002.-V.43, No.16, -P. 4349-4353. 7. Makysh G.Sh., Bimendina L., Murzagulova K.B., Kudaibergenov S. Interactions of a new anaesthetic drug richlocain with linear and weakly crosslinked poly-N-vinylpyrrolidone // J. Appl. Polymer Sci., -2003. ?V89.-P.2977-2981.