1.The Synthesis Of BCX4430 2.The Research Of The Compound Of Diaziridine

BCX4430 is a new kind of broad-spectrum of drug protection against filovirus diseases, which is developed by the scientific research team of Biocryst, a pharmaceuticals company. The mechanism of BCX4430 is that BCX4430 can effectively inhibit viral RNA polymerase function, acting as a non-obligate RNA chain terminator. The chemical name of BCX4430 is that (2S,3S,4R,5R)-2-(4-amino-5H-pyrrolo[3,2-d] pyrimidin-7-yl)-5-(hydroxymethyl)pyrrolidine-3,4-diol dihydrochloride.The research work of this thesis is divided into two parts:one is the optimization of synthesis process of BCX4430; second is the design and exploration the new synthesis route of BCX4430.In process of optimization, establish the D-ribose as the starting material, eventually after protection, esterification, cyclization, coupling, hydrogenation, hydrolysis etc.29 steps, successfully synthesized the target product BCX4430. Product is confirmed by1H NMR.In the process of optimization, mainly solved the following questions:1. In the synthesis of (3aR,4R,6aS)-4-(((tert-butyldimethysilyl) oxy)methyl)-2,2-dimethyl-4,6a-dihydro-3aH-[1,3]dioxolo[4,5-c]pyrrole, we contrast PhMe/KOH system and anhydrous THF/Li-TMP system on the formation of imine and find that the latter is better. The yield increases to 72.5% after purification.2. On the reaction of chlorine substitution of carbonyl group, filtration followed by ammonia neutralization is beneficial to improve the yield and purity of product.3. It is better for the reaction to control temperature from-55℃ to 0℃ during docking reaction.4. The best purification method is thatcrude product is dissolved by H2O and EtOH on the ratio of 1:5 at 50℃, then cool to room temperature to precipitate solid.5. Optimization of each step.In the exploration of the new route of BCX4430, use the method of inverse synthetic analysis to design a new synthesis route and do the relevant experiments. We successfully synthetize the key intermediate N-Benzyl-5-(benzyloxymethyl)-7-bromo-5H-pyrrolo[3,2-d]pyrimidin-4-a mine and do various explorations to docking reaction.6,6,7b-trimethyl-1,3,4,7b-tetrahydro[1,2]-diazireno[3,1-a]cyclopropa [2,3-c]pyridine-5-one(compound 1) is one of the components in swertia. The compound has the structure ofdiaziridine, which may have antiviral activity when happeningring-opening reaction. Because of the difficulty in separation, we need to use the method of chemical synthesis, so that pharmacological study can be carried out.So far, synthesis of compound 1 has not been reported in the literature, it has important theoretical and practical significance to find a suitable synthetic route. Repeated previous work, and on this basis of inverse synthetic analysis of compound 1, design a new synthetic route and carry out the related experiments.In the repetition of the previous work, we successfully synthesized theintermediate 5,5-Dimethyl-2-cyclopentenone (4) and 3-nitroethyl-5,5--Dimethyl-cyclopentanone(5). We have tried a variety of solvents and catalysts, but failed to find the method of double bond isomerization.In the exploration of the new synthetic route, We successfully get thekey intermediate2-Bromo-5,5-Dimethyl-2-cyclopentenoneEthylene- -Ketal(14) from intermediate 4 by bromization and thylene glycol protectionof carbonyl. In the exploration of synhthesis of 2-amimoethyl-5,5-Dimethyl-2-CyclopentenoneEthylene Ketal(15a), Sequentially try the effect of THF/n-BuLi system, THF/HMPA/n-BuLi and THF/CuI/n-BuLi system in coupling reaction, getting primary results.