The Second Generation Of Dutch Resolution With Cyphos Family

Cyphos are strongly acidic resolving agents with rigidity structure. And they play an important role in the resolution of strong bases and weak bases. Dutch resolution with better resolution effect than classical resolution, is a new chemical resolution method developed in recent years.Three Cyphos racemates were prepared through Aldol-Cannizzaro,cyclophosph-oric acylation, hydrolysis from starting materials such as isobutyraldehyde, benzald-ehyde, o-chlorobenzaldehyde,o-methoxybenzaldehyde, POCl3 and so on.Theα-Phen-ylethylamine and (-)-p-hydroxypenylglycine were used to resolve Cyphos racemates to get the chiral Cyphos family agents. The three racemates were 4-Phenyl-2-hy-droxy-5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorinane(PhenCyphos,CP1), 4-(2-chloroPhe-nyl)-2-hydroxy-5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorinane(chloCyphos,CP2), and 4-(2-methoxyPhenyl)-2-hydro-xy-5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorinane(aniCyph-os,CP3).The emphasis of this paper is to study the second family of Dutch resolution by using the chiral Cyphos family. Several different family agents with different molar ratios were chosen to resolve p-hydroxyPhenylglycine and Phenylalanine by using chiral CP2 or chiral CP3 as parent resolving agent, CP1, CP2 and CP3 as additive agent in methanol/water and ethanol/water as solvents.In most cases, Dutch resolution of p-hydroxyPhenylglycine and Phenylalanine by using chiral CP2 or chiral CP3 as parent resolving agent got higher optical purity than those of classical resolution.Among the Dutch resolution experiments, levorotatory p-hydroxyPhenylglycine with the highest optical purity 99.76 % was got by using chiral CP3 as parent resolving agent with additive CP2 in ethanol/water. And the ratio of CP3 to CP2 is 99:1. The optical purity value in this experiment is apparently higher than the optical purity value in classical resolution of p-hydroxyPhenylglycine (90.65 %.o.p.).Dextrorotatory Phenylalanine with the highest optical purity 99.81% o.p. was got by using chiral CP2 as parent resolving agent with additive CP3 in ethanol/water. And the ratio of CP2 to CP3 is 99:1. The optical purity value in this experiment is apparently higher than the optical purity value in classical resolution of Phenylalanine(91.13 %.o.p.).Among the Dutch resolution experiments by using the chiral CP2 or chiral CP3 as parent resolving agent, the nucleation tempreture of the less soluble diastereomer is lower than the nucleation tempreture of classical resolution. The metastable zone width in Dutch resolution is larger than the metastable zone width in the classical resolution. This Phenomenon is similar with the resolution mechanism of the literature.Many experiments were also done to optimize the synthesis process of racemic CP1, CP2 and CP3. The higher yield condition was obtained and the total yield was 75 %, which is higher than the yield 67 % in the literature.