Study On New Azo-reagent In The Mitsunobu Reaction And The New Synthesis Route Of Penciclovir

The Mitsunobu reaction, discovered by Mitsunobu in the 1967, has become the standard method for the inversions of configuration in secondary alcohols and has wide applications in total synthesis,heterocyclic,medicinal chemistry,biochemistry, and natural product synthesis due to its scope, stereoselectivity, and mild reaction conditions. Though it is a powerful process in organic synthesis, a major drawback of this redox-condensation is the requirement of two reagents, a azo-reagent and a Pâ…¢-reagent, which both produce stoichiometric amounts of byproducts hydrazine compound and PV oxide.Traditional azo-reagents such as diethyl azodicarboxylate (DEAD)and diisopropyl azodicarboxylate (DIAD) are commercially available, but they are sensitive to light, heat and moisture and often be stored under low temperature in dark and dry area. In addition, diethyl and diisopropyl hydrazinedicarboxylates arising from DEAD and DIAD are problematic during the separation of the product and they are difficult to be recycled. Fine chromatography is usually required to isolate the pure target product from the unreacted reagents and byproducts. This situation limits the direct application of the Mitsunobu reaction in combinatorial library syntheses.The thesis focus on friendly-separation in the Mitsunobu reaction to develop some new azo-reagents to solve some of these problem and to apply the Mitsunobu reaction as the key step in the synthesis of penciclovir. The main contents are generalized as follows:1. Dicyclopentyl azodicarboxylate (DCpAD) was readily prepared with two steps' reaction in good yields using cyclopentyl chloroformate and hydrazine hydrate as starting raw material. The structure of DCpAD was confirmed by IR,1H NMR, 13C NMR, ESI-MS, and elemental analysis. The thermal stability of DCpAD was studied by thermal gravimetric analysis (TGA) and differencial scanning calorimetry (DSC) and the influence of illumination and effect of temperature on the stability of it were studied also. DCpAD is more stable and safe than DEAD and is an attractive alternative to azo-reagents in the Mitsunobu reactions. 2. Focusing on friendly-separation in the Mitsunobu reaction di-p-cyanobenzyl azocarboxylate (DCyAD) is prepared in good-to-excellent yield in two steps and purified without resorting to chromatography as yellowish solid. When DCyAD and DIAD were used for various Mitsunobu couplings, these reactions employing DCyAD/PPh3 usually gave higher isolated yields of products and took less time for completion than those with DIAD/PPh3. Moreover, the poor solubilities of DCyADH2 in some solvents such as methylene dichloride, acetonitrile especially in toluene make it easy to be separated from the product and recovered just via filtration after the completion of the Mitsunobu reaction and then recycled by re-exposure to Br2 or NBS.3. We studied the performance di-p-nitrobenzyl azocarboxylate (DNAD) which is the analogue of DCyAD in the Mitsunobu reaction for the first time. The results shown that DNADH2, the precursor of DNAD, has poor solubilities in some common solvents such as DCM, acetonitrile, and toluene ect. So during the Mitsunobu reaction, DNADH2 constantly to separate out and can be recycled via filtration with the similar to DCyADH2. In addition, the stability of DNAD is similar with DCyAD and the performances of it in the Mitsunobu reaction are batter than DCyAD.4. Penciclovir (PCV) is broad-spectrum anti-viral agents against both the herpes simplex virus (HSV),the vari-cella-zoster virus (VZV),hepatitis B virus (HBV) and duck hepatitis B virus (DHBV) activity.2-Amino-6-chloropurine (ACP) was commonly used as a starting material for coupling with alkyl halide side-chain under basic conditions, which was the key step for the synthesis of PCV. But ACP exposed several problems because of its notorious insolubility in organic solvents, along with its polyfunctional nature such as imidazole, amide, and guanidine sub-structures. The basic problem was the selective N-alkylation at the desired site, namely at the N-7 or N-9 position. Normally, alkylation took place at N-9 position as well as at the N-7 position of the purine moiety, and the N-9/N-7 ratio was usually less than 6:1.We developed a new practical and efficient method for the synthesis of penciclovir (PCV) using N,N-ditertbutyloxycarbonyl-2-amino-6-chloropurine coupling with 5-(2-hydroxyethyl)-2,2-dimethyl-1,3-diox under the Mitsunobu conditions as the key step for the first time and gave the complete special N9-selectivity product in high yield. The reaction conditions were especially mild, requiring only 1.2 equiv of each of the side-chain, PPh3 and DNAD within 60 min at room temperature. This was very good advantageous method to afford the higher yield of the N-9 alkylated product and also its purification was to be facilitated. Another advantage was the side chain of 5-(2-hydroxyethyl)-2,2-dimethyl-1,3-diox needn't to be converted to 5-(2-bromoethyl)-2,2-dimethyl-1,3-diox and can be coupled with N,N/-ditertbutyloxycarbonyl-2-amino-6-chloropurine directly and the coupling product needn't to be separated and can be used in the next step of hydrolysis and deprotection in one pot. So the synthetic route for the preparation of the side chain was shorter than the usually way, which increased the overall yield and reduced the cost.In addition, we do some researches on the viscosities and densities of some binary mixture about manufacturing production of cyclopropanecarboxylic acid and to provide important fundamental thermodynamic data for the chemical design and the optimization of chemical process.