Chiral Salen-co Catalysts In The Asymmetric Ring Opening Reaction And Drug Synthesis

The value of Salen metal complexes as a catalyst is gradually being revealed, not only research on asymmetric catalysis methodologies, but also on the synthesis of natural products. The research and application of Salen-Co catalyst is developed in recent years. Because of effective use value, high catalytic activity, it has been extensively studies.In this paper, the process of preparing the chiral-Salen-Co(III) complex was described concisely according to the literature. Highly enantioenriched (R)-epichlorohydrin and (S)-3-chloro-1,2-propanediol were obtained through the hydrolytic kinetic resolution (HKR) of racemic epichlorohydrin catalyzed by the (S,S)- Salen-Co(III) complex. Aβ-adrenergic blocking agent [(S)-metoprolol] was finally prepared from the (R)-epichlorohydrin and (S)-3-chloro-1,2-propanediol with stereoconvergent synthesis, and a novel synthetic technology of 4-(2-methoxyethyl)phenol, which was the key intermediate of metoprolol was reported. At the same time, the first example of enantioselective kinetic resolution of racemic terminal epoxides using phthalimide as the nucleophile catalyzed by (R,R)- Salen-Co(III) complex was described.The hydrolytic kinetic resolution(HKR) of racemic epichlorohydrin catalyzed by the (S,S)- Salen-Co(III) complex was investigated in detail, and the appropriate reaction conditions for preparing highly optical purity (R)-epichlorohydrin were given as follows: reaction temperature 5℃, with a reaction time of 60h,and the molar ratio between the (S,S)- Salen-Co(III) complex, racemic epichlorohydrin and water is 0.1%:1:0.55. When the molar ratio between the chiral Salen-CoIII complex, racemic epichlorohydrin and water is 0.1%:1:0.45, with a reaction time of 48h and reaction temperature of 5℃, highly enantioenriched (S)-3-chloro-1,2-propanediol was prepared.4-(2-methoxyethyl)phenol was prepared from p-hydroxybenzaldehyde via benzyl protection, Darzen condensation, rearrangement reaction, addition reaction with sodium bisulfite, reduction of Potassium borohydride, methylation, deprotection overall yield of 46%. The Darzen condensation was investigated in detail, and the appropriate reaction conditions were given as follows: the molar ratio between p-hydroxybenzaldehyde, ethyl chloroacetate and sodium methoxide is 1:1.2:1.2, with a reaction temperature of 25℃.The asymmetric synthetic routes for (S)-metoprolol were proposed. In these synthsis, (S)-metoprolol was prepared from prepared from 4-(2-methoxyethyl)phenol via reaction with (S)-3-chloro-1,2-propanediol and further amination reaction with isopropyl amine to give an optical purity of higher than 99%. Modest enantioenriched (R)-epichlorohydrin was also used as chiral reagent to synthesize (S)-metoprolol with an optical purity of greater than 92%. The procedure is effective, simple and high utilization ratio of raw material, total yield of 53.9%. The process may be suitable for industrial applications.The aminolysis kinetic resolution (AKR) of racemic terminal epoxides using phthalimide as the nucleophile catalyzed by (R,R)- Salen-Co(III) complex was researched in detail, and the appropriate reaction conditions for AKR were given as follows: reaction temperature 0℃, with a reaction time of 45h,and the molar ratio between the (R,R)- Salen-Co(III) complex, racemic terminal epoxides and phthalimide is 2.5%: 1: 0.55. In this reaction conditions, high enantiomeric excess(ee) of chrial terminal epoxides and moderate enantiomeric excess N-protected amino alcohols were obtained.The structures of the target compounds and key intermediates were confirmed by IR, 1^H NMR, ¹³C NMR and MS.