Lol And Evil Tzds Chiral Intermediates Mannitol Synthesis Research

The drugs such as Propranolol, Metoprolol and Linezolid have the same structure (2S)-3-amino-2-propanol. The most important problem is how to build this structure in synthesis these drugs. D-mannitol, a hexanehexol with four chiral carbon centre, as well as rich source and low cost, is a high performance -value rate chiral source. D-mannitol will be of great worth in chiral drug production when there is a proper method. Oxidative disconnection of the C-3 and C4 of D-mannitol give two chiral 2- propanol units.This thesis took D-mannitol as chiral resource and several general drug intermediates ofβ-adrenoceptor blocking agents and oxazolones were prepared by simple reactions with common laboratory equipments.The preparation of the intermediates ofβ-adrenoceptor blocking agents: Diisopropylidene-D-mannitol was preparation by acetalization of D-mannitol catalyzed by zinc chloride with yield up to 60% after optimization of the conditions. (R)-Glyceraldehyde acetonide efficiently converted into its imines with a series of amines at presence of 4A Molecular Sieve avoiding light and oxygen. Without further purification, the imines were converted into derivatives of (2S)-3-amido-1, 2-propandiol by hydrolysis after the reduction of these imines with high yields. (2S)-3-isopropylamino-2-propanol was chosen successfully to synthesis the key intermediate N-(1-methylehyl)-1, 3, 2-Dioxathiolane-4-methanaimine-2-oxide. There was no ideal solvent found to resolve the raw material, but the dichloromethane can made it dispersed as oil and that was good for the reaction with sulfoxide chloride. Further more, this method was good for the separation of the product. In this paper the intermediate was used for the preparation of Propranolol and Metoprolol.The preparation of the intermediates of oxazolones: D-mannitol was selectively transformed into 1, 6-di-O- tolylsulfonyl -D-mannitol with p-toluenesulfonyl chloride. The product was dissolved in DMF and then stirred with potassium cyanate at 120℃for 8h gave 1,2;5,6-di-N,O-carbonyl-1,6-diamino-D-mannitol with more than 30% yield.