羟基脯氨酸正十二烷基酯的合成及抗氧化研究
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摘要
羟基脯氨酸正十二烷基酯同时含有亲水和疏水两种基团,具有良好的表面活性,改变了羟基脯氨酸与脂不相溶无法通过细胞膜的缺点,可以将羟基脯氨酸顺利带进细胞。同时,由于其含有一个羟基,为进一步反应提供了条件,可以作为其他药物以及化工产品的中间体。
本文以L-羟基脯氨酸和正十二醇为原料,对甲基苯磺酸为催化剂,甲苯为带水剂合成羟基脯氨酸正十二烷基酯。催化剂用量、合成反应时间、反应温度和底物配比均影响羟基脯氨酸转化率。L16(45)正交实验结果指出,合成羟基脯氨酸正十二烷基酯的最佳工艺条件为:反应时间10小时,温度130℃,羟基脯氨酸与正十二醇的摩尔比为1:5,羟基脯氨酸与对甲基苯磺酸的摩尔比为1:1.08。在该最优条件下合成羟基脯氨酸正十二烷基酯,羟基脯氨酸的转化率为85.57%。各因素所选的各水平内,对羟基脯氨酸转化率影响因素的大小顺序为底物配比>反应温度>反应时间>催化剂用量。
分别采用结晶法和硅胶柱层析法对羟基脯氨酸正十二烷基酯进行分离纯化,结晶法的优点就是操作简单,速度较快,在纯度要求不高时可采用该法。硅胶柱层析法所得的产物,不论是纯度还是收得率都比结晶法高,所以柱层析法分离纯化产物是一个较优的方法。结晶获得羟基脯氨酸正十二烷基酯纯度为89.46%,收率为78.62%;硅胶柱层析所得纯度为90.17%,收率为87.34%。将二次层析后的羟基脯氨酸正十二烷基酯制备成冻干粉,进行红外和核磁共振分析和结构表征,确定获得的高纯度产物为羟基脯氨酸正十二烷基酯。
羟基脯氨酸上有羧基,仲羟基和亚氨基三个亲水性基团,极易与水分子形成氢键而溶解在水中。当其成酯后其最强的亲水性基团羧基被长链烷基取代,亲水性降低;同时长链烷基的位阻作用阻碍仲羟基和亚氨基与水分子作用,最终造成在水中的溶解度大幅下降,脂溶性增强。其油/水分配系数从-1增加到0.5。
羟基脯氨酸正十二烷基酯的仲羟基和亚氨基可以作为氢供体,具有提供质子的能力,使强氧化性的超氧阴离子(O2-·)还原,从而终止自由基链式反应,起到清除超氧阴离子(O2-·)的作用;同时,能与金属离子形成螯合物,从而阻止Fenton反应的发生,进而阻止羟基自由基(·OH)产生。当加入酯的浓度为10 mg/mL时,对O2-·的清除率达到了69.3%,对·OH的清除率为67.62%。
Hydroxyproline lauryl alcohol ester comprises hydrophilic and hydrophobic groups both, the surfactivity of which is excellence. The disadvantage that hydroxyproline is indiscerptible in fat and can not get through the cell membrane is changed by esterification to enter the cells favoringly. At the same time, Hydroxyproline lauryl alcohol ester could be used for intermediate of medicament, because of the dissociative hydroxyl.
In this article, L-hydroxyproline and lauryl alcohol were used as materials of esterification, paratoluene sulfonic acid was used as catalyzer, and toluene was used as the water schlepped. Dosage of catalyzer, time and temperature of reaction, scale of materials affecte the reactive rate of hydroxyproline. It is showed by the results of L9 (43) orthogonal tests that the optimum conditions are that the time of reaction was 10 hours; the temperature of esterification is 130℃;the molar scale of hydroxyproline and lauryl alcohol is 1:5; the molar scale of hydroxyproline and paratoluene sulfonic acid is 1:1.08. With the optimum conditions, the reactive rate of hydroxyproline is 85.57%. The effect of these factors is different that the molar scale of hydroxyproline and lauryl alcohol > temperature > time > molar scale of hydroxyproline and paratoluene sulfonic acid.
Crystal and silica gel column chromatography were used for purification of hydroxyproline lauryl alcohol ester. The advangtage of crystal are simply operation and fast separation, because of which crystal is used for getting low purity. Because the purity and the yield by silica gel column chromatography were both higher than crystal, silica gel column chromatography was chose to purify hydroxyproline lauryl alcohol ester in this article. The purity and yield of hydroxyproline lauryl alcohol ester were 89.46% and 78.62% by crystal, and 90.17% and 87.34% by silica gel column chromatography respectively. After silica gel column chromatography twice, hydroxyproline lauryl alcohol ester was prepared to freeze-dried powder, and was characterized the structure by IR and NMR.
There are three hydrophilic group: carboxyl, -OH and–NH2 on the hydroxyproline, which form hydrogen bond with water and dissolve in water. Because of that the carboxyl is replaced with long-chain alkyl, hydrophilic capability of hydroxyproline is reduced; and the steric effect of long-chain alkyl blocks the effect of -OH and–NH- with water, that the solubility reduces significantly in water, but increases in fat. The oil-water partition coefficient increase from -1 to 0.5.
The -OH and -NH- of hydroxyproline lauryl alcohol ester can be used for hydrogen donor, and deoxidize O2-·; hydroxyproline lauryl alcohol ester can form chelate compound with metallic ion, and stops the Fenton reaction, then stops the appearance of·OH. When the concentration of hydroxyproline lauryl alcohol ester is 10 mg/mL, the rate of O2-·elimination is 69.3%, and·OH elimination was 67.62%.
本文以L-羟基脯氨酸和正十二醇为原料,对甲基苯磺酸为催化剂,甲苯为带水剂合成羟基脯氨酸正十二烷基酯。催化剂用量、合成反应时间、反应温度和底物配比均影响羟基脯氨酸转化率。L16(45)正交实验结果指出,合成羟基脯氨酸正十二烷基酯的最佳工艺条件为:反应时间10小时,温度130℃,羟基脯氨酸与正十二醇的摩尔比为1:5,羟基脯氨酸与对甲基苯磺酸的摩尔比为1:1.08。在该最优条件下合成羟基脯氨酸正十二烷基酯,羟基脯氨酸的转化率为85.57%。各因素所选的各水平内,对羟基脯氨酸转化率影响因素的大小顺序为底物配比>反应温度>反应时间>催化剂用量。
分别采用结晶法和硅胶柱层析法对羟基脯氨酸正十二烷基酯进行分离纯化,结晶法的优点就是操作简单,速度较快,在纯度要求不高时可采用该法。硅胶柱层析法所得的产物,不论是纯度还是收得率都比结晶法高,所以柱层析法分离纯化产物是一个较优的方法。结晶获得羟基脯氨酸正十二烷基酯纯度为89.46%,收率为78.62%;硅胶柱层析所得纯度为90.17%,收率为87.34%。将二次层析后的羟基脯氨酸正十二烷基酯制备成冻干粉,进行红外和核磁共振分析和结构表征,确定获得的高纯度产物为羟基脯氨酸正十二烷基酯。
羟基脯氨酸上有羧基,仲羟基和亚氨基三个亲水性基团,极易与水分子形成氢键而溶解在水中。当其成酯后其最强的亲水性基团羧基被长链烷基取代,亲水性降低;同时长链烷基的位阻作用阻碍仲羟基和亚氨基与水分子作用,最终造成在水中的溶解度大幅下降,脂溶性增强。其油/水分配系数从-1增加到0.5。
羟基脯氨酸正十二烷基酯的仲羟基和亚氨基可以作为氢供体,具有提供质子的能力,使强氧化性的超氧阴离子(O2-·)还原,从而终止自由基链式反应,起到清除超氧阴离子(O2-·)的作用;同时,能与金属离子形成螯合物,从而阻止Fenton反应的发生,进而阻止羟基自由基(·OH)产生。当加入酯的浓度为10 mg/mL时,对O2-·的清除率达到了69.3%,对·OH的清除率为67.62%。
Hydroxyproline lauryl alcohol ester comprises hydrophilic and hydrophobic groups both, the surfactivity of which is excellence. The disadvantage that hydroxyproline is indiscerptible in fat and can not get through the cell membrane is changed by esterification to enter the cells favoringly. At the same time, Hydroxyproline lauryl alcohol ester could be used for intermediate of medicament, because of the dissociative hydroxyl.
In this article, L-hydroxyproline and lauryl alcohol were used as materials of esterification, paratoluene sulfonic acid was used as catalyzer, and toluene was used as the water schlepped. Dosage of catalyzer, time and temperature of reaction, scale of materials affecte the reactive rate of hydroxyproline. It is showed by the results of L9 (43) orthogonal tests that the optimum conditions are that the time of reaction was 10 hours; the temperature of esterification is 130℃;the molar scale of hydroxyproline and lauryl alcohol is 1:5; the molar scale of hydroxyproline and paratoluene sulfonic acid is 1:1.08. With the optimum conditions, the reactive rate of hydroxyproline is 85.57%. The effect of these factors is different that the molar scale of hydroxyproline and lauryl alcohol > temperature > time > molar scale of hydroxyproline and paratoluene sulfonic acid.
Crystal and silica gel column chromatography were used for purification of hydroxyproline lauryl alcohol ester. The advangtage of crystal are simply operation and fast separation, because of which crystal is used for getting low purity. Because the purity and the yield by silica gel column chromatography were both higher than crystal, silica gel column chromatography was chose to purify hydroxyproline lauryl alcohol ester in this article. The purity and yield of hydroxyproline lauryl alcohol ester were 89.46% and 78.62% by crystal, and 90.17% and 87.34% by silica gel column chromatography respectively. After silica gel column chromatography twice, hydroxyproline lauryl alcohol ester was prepared to freeze-dried powder, and was characterized the structure by IR and NMR.
There are three hydrophilic group: carboxyl, -OH and–NH2 on the hydroxyproline, which form hydrogen bond with water and dissolve in water. Because of that the carboxyl is replaced with long-chain alkyl, hydrophilic capability of hydroxyproline is reduced; and the steric effect of long-chain alkyl blocks the effect of -OH and–NH- with water, that the solubility reduces significantly in water, but increases in fat. The oil-water partition coefficient increase from -1 to 0.5.
The -OH and -NH- of hydroxyproline lauryl alcohol ester can be used for hydrogen donor, and deoxidize O2-·; hydroxyproline lauryl alcohol ester can form chelate compound with metallic ion, and stops the Fenton reaction, then stops the appearance of·OH. When the concentration of hydroxyproline lauryl alcohol ester is 10 mg/mL, the rate of O2-·elimination is 69.3%, and·OH elimination was 67.62%.
引文
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