Research On The Synthesis Of Captopril Intermediates And 2-oxazoline Derivatives

1.Captopril is a drug mainly used for the treatment of hypertension and congestive heart failure.It can reduce the body’s cardiac congestive pressure,control ventricular hypodynamics caused by heart failure,and protect the stability of vital signs in patients with hypertension.plays an important role in treatment.In industrial production,captopril is mostly obtained by combining its important intermediate(S)-3-(acetylthio)-2-methylpropionic acid with L-proline,and then hydrolyzed and acidified.The direct asymmetric synthesis of the intermediate(S)-3-(acetylthio)-2-methylpropionic acid is difficult,and the commonly used method is to use the chiral separation of the racemate to obtain,but the method needs to use a large amount of resolving agent,and the recovery and utilization operation of the resolving agent is more complicated,the loss of the resolving agent is larger in the recovery process,and the production cost is higher.In this paper,3-(acetylthio)-2-methylpropionic acid with S configuration as the main material was synthesized by asymmetric catalysis using α-methacrylic acid and thioacetic acid as raw materials.The system realizes the chirality control of the asymmetric addition-protonation reaction of thioacetic acid and α-methacrylic acid in a metal-catalyzed manner,so that the product has better enantioselectivity.After determining the basic process route,a lot of optimizations were carried out on the reaction solvent,reaction temperature,additives,ligands,metals,etc.,and the optimal reaction system was screened out.In this system,tetraisopropyl titanate is used as metal,L-dimethyl tartrate is used as ligand,and under the combined action of additive sodium trichloroacetate,the product 3-(acetylthio)-2-methylpropionic acid,with the highest enantioselectivity of 67%,provides a new method for the synthesis of captopril intermediates.2.Oxazoline is a five-membered heterocyclic compound containing a double bond in the molecule,and is divided into 2-oxazoline,3-oxazoline and 4-oxazoline according to the position of the double bond.2-oxazoline compounds are widely used because of their active chemical properties.It plays an extremely important role in the fields of organic synthesis,asymmetric catalysis,natural products,materials science and biomedicine.Most of the existing synthetic routes for synthesizing oxazoline and its derivatives have harsh reaction conditions,and some of the synthetic routes require metals to catalyze the reaction.In this paper,we hope to synthesize2-oxazoline compounds through Lewis acid-promoted intramolecular nucleophilic addition heterocyclization of unsaturated amide N-(2-phenylallyl)benzamide.After determining the basic idea,the reaction temperature,solvent and Lewis acid were optimized,and the optimal reaction system was screened out.At 25°C,dichloroethane was used as a solvent,and trimethylsilyl trifluoromethanesulfonate was used to promote the intramolecular nucleophilic cyclization of unsaturated amides.The reaction system has a good range of substrates.A total of 31 2-oxazoline products were isolated in this paper,and the intramolecular nucleophilic addition and cyclization reaction products were isolated in high yields(80-94% yield).The reaction generates 2-oxazoline compounds in one step,and has the advantages of mild reaction conditions,no metal,high efficiency,etc,and provides a new synthetic method for the synthesis of 2-oxazoline and its derivatives.