【作者】 张旭；

【导师】 于奕峰；

【作者基本信息】 河北科技大学 ， 药物化学， 2010， 硕士

【摘要】 Cyphos是一类具有刚性结构的强酸性拆分试剂,在拆分碱性及弱碱性的有机物方面具有重要的作用。族拆分是近几年发展起来的一种新的化学拆分方法,与经典拆分相比具有更加有效的拆分行为。本课题以异丁醛、苯甲醛、邻氯苯甲醛、邻甲氧基苯甲醛、三氯氧磷等为起始原料,经Aldol-Cannizzaro、环磷酰化、水解三步反应,合成了3种Cyphos消旋体。以光活α-苯乙胺和(-)-对羟基苯甘氨酸作拆分剂对Cyphos进行拆分,制备了手性Cyphos族拆分试剂,分别是4-苯基-2-羟基-5,5-二甲基-2-氧代-1,3,2-二氧磷杂环己烷(Phencyphos,CP1)、4-(2-氯苯基)-2-羟基-5,5-二甲基-2-氧代-1,3,2-二氧磷杂环己烷(chlocyphos,CP2)和4-(2-甲氧基苯基)-2-羟基-5,5-二甲基-2-氧代-1,3,2-二氧磷杂环己烷(anicyphos,CP3)。本论文重点研究以光活Cyphos作拆分剂进行的第二代族拆分研究。采用光活的CP2或CP3作主拆分剂,以光活或消旋的CP1、CP2或CP3作助拆分剂,通过改变两者的摩尔比组成不同组合的族拆分试剂,分别选用甲醇/水和乙醇/水作溶剂,拆分对羟基苯甘氨酸和苯丙氨酸。以(-)-CP2或(-)-CP3作主拆分剂时的族拆分得到的光活性对羟基苯甘氨酸和光活性苯丙氨酸的光学纯度多数大于(-)-CP2或(-)-CP3的经典拆分得到的光学纯度。其中以(-)-CP3为主拆分试剂,(-)-CP2为助拆分剂,摩尔比为99:1,乙醇/水作溶剂拆分对羟基苯甘氨酸,得(-)-对羟基苯甘氨酸光学纯度为99.76 %o.p.,明显高于(-)-CP3为拆分试剂的经典拆分的光学纯度90.65 %o.p.。以(-)-CP2为主拆分剂,(+)-CP3为助拆分剂,摩尔比为99:1,乙醇/水作溶剂拆分苯丙氨酸时,(+)-苯丙氨酸的光学纯度最高为99.81 %o.p.,高于(-)-CP2为拆分试剂的经典拆分的光学纯度91.13 %o.p.。采用(-)-CP2或(-)-CP3作主拆分剂时开展的族拆分中,溶解度较小的非对映异构体的析晶温度低于经典拆分时的析晶温度,也即族拆分中溶解度较小的非对映异构体的亚稳区宽度明显大于经典拆分时的亚稳区宽度,这与文献报道的有关族拆分的机理一致。本论文还对消旋体的合成工艺进行了优化,确定了提高消旋体合成收率的较优路线,最终产品总收率最高达75 %,高于文献值67 %。更多还原

【Abstract】 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.更多还原