Synthesis Of The Asymmetric Catalytic Reduction Of The Preparation Of The Substrate And Chiral Ligand Intermediates

The chiral aromatic alcohols are of great importance which are used as intermediates of many effective medicines widely .So it is very useful to study its synthesis in the field of pharmaceutical chemistry. (R)-Salbutamol sulfate is an antihasthma, for us studying its synthetical method has greatly practical value.Herein the value of chiral aromatic alcohols and various preparation methods of the chiral aromatic alcohols were reviewed. There are two main methods to obtain chiral aromatic alcohols from prochiral aromatic carbonyl compounds .One is asymmetric addition reaction, the other is asymmetric reduction reaction.In the dissertation we design the synthetical route of racemic Salbutamol and (R)-Salbutamol. The reaction substrate 5 - [[(1,1-dimethylethyl)amino]acetyl]-2 -hydroxybenzaldehyde was prepared by the convenient materials Salicylic aldehyde and Chloroscetyl chloride, which is the precursor of (R)-Salbutamol. The synthesis of reaction substrate can be reduced to two steps from initial three steps ,in which we has gained the higher yield than the value reported in the literature.The synthetical methods of the chiral ligand intermediate spiro[4,4] nonane -1,6- dione were studied in the dissertation. Spiro[4,4]nonane-l,6-dione was prepared by two different methods, and optimized and improved reaction condition has been given by a series of experiments,which can be produced substantially by easily abtained nonoptical pure compound. It is indicated in the experiment that we can directly hydrolyse instead of puring the second and third product. In this way,it can be avoided of the loss of product in the condition of reduced pressure and the overall yield is added up to 43% from the initial 38%. In the second reaction step ,we choose potassium carbonate to replace potassium hydride to seize active hydrogen in the a -position,which simplied the experiment procedure. In the last step ,it is important that having TLC to monitor reaction proceeding to avoid producing byproduct and lowing the yield .Chiral resolution agent named 5-(α-phenylethyl)semioxamazide is synthesized successfully by easily obtained compound,which is used to resolve spiro[4,4]nonane -1,6-dione. The resoving condition in the experiment is discussed with chiral resolution agent 5-(α -phenylethyl)semioxamazide and BINOL .