【作者】 任国宾；

【导师】 郭士岭； 詹予忠；

【作者基本信息】 郑州大学 ， 化学工艺， 2002， 硕士

【摘要】 D-对羟基苯甘氨酸(D-p-hydroxyphenylglycine、D-p-HPG)可用于合成广谱抗生素阿莫西林(amoxicillin)、头孢哌酮(cefoperazone)、头孢罗奇(cefoprozil)等，是一种重要的药物中间体。本文深入研究了DL-对羟基苯甘氨酸(DL-p-hydroxyphenylglycine、DL-p-HPG)及其硫酸盐在水-丙酮溶液中固液相平衡问题，并在此基础之上提出了以价廉易得的浓硫酸代替昂贵的手性试剂作拆分剂，以水-丙酮溶液作溶剂拆分DL-对羟基苯甘氨酸及其硫酸盐的新方法；对DL-对羟基苯甘氨酸及其硫酸盐的拆分工艺进行了优化，取得了最优反应条件：混合溶剂中水的百分比为18.18％，氢离子浓度为2 mol／l，晶种加入点(温度)30℃，此时D-p-HPG的单程收率为40.63％，光学纯度(O.P.)＞98％。 建立了一套由激光监视系统、精确控温系统组成的实验装置，对DL-对羟基苯甘氨酸及其硫酸盐在水-丙酮溶液中的溶解度、超溶解度、介稳区宽度等热力学数据进行测定，共测得253组数据，大部分为首次测定。分别利用lnx=A+B|T与lnx=A+B|T+C ln T对溶解度数据进行关联，后者相关性较好，相关系数在0.995以上，平均相对误差小于0.5％；并进一步利用后者对溶解度进行预测，也取得较好结果，平均相对误差在1％以下。 在测得DL-对羟基苯甘氨酸及其硫酸盐在水-丙酮溶液中的溶解度、超溶解度、介稳区宽度等热力学数据基础之上，提出了将结晶过程控制在介稳区之内是优先结晶法成功的关键的观点，并考查了温度、混合溶剂组成、溶液中氢离子浓度、搅拌速度、冷却速度对介稳区宽度的影响：同一物系，超溶解度曲线基本与溶解度曲线平行，温度越高，介稳区越窄，并且溶解度曲线与超溶解度曲线有明显的交汇趋势；随温度、混合溶剂中水的百分比的升高，介稳区均变窄；同一物系，同一组成的混合溶剂，随氢离子浓度的增加，介稳区宽度急剧下降；上述溶解度、超溶解度、介稳区宽度的均是在固定的搅拌速度与冷却速度下得到的。由经典成核理论知，搅拌速 郑州大学硕士学位论文度与冷却速度对介稳区宽度的影响也较大。随搅拌速度的增加，同一饱和温度下的超溶解度降低，介稳区域变窄；这可以由经典成核理论得到解释：晶体的成核速率B’可用式： B’＝ K。凸C品 N”（I）式中：凸乙。—一最大过饱和浓度 N一搅拌速率 K。一成核速率常数 。，n一分别为最大过饱和度和搅拌速率影响的动力学参数 当过饱和度是由冷却结晶产生时，成核速率可以由过饱和度的产生速率来表示，当冷却速率一定时，式（I）可简化为 i A T＿．＝K，一 ：4 In N（11） m 式中：K；为常数。 由式（11）可知，当冷却速率一定时，In凸 T。。与 InN呈线性关系；随搅拌速度的升高，介稳区宽度减小。 随冷却速度的加快，介稳区宽度也在增加。这同样可以由经典的结晶理论进行解释。当搅拌速率一定时，式（l）可简化为： In A T＿＿．．＝K、＋d－ n b（ill） m式中：K；为常数b冷却速率 由式（ill）知，当搅拌速度一定时，In凸 T。与 Inb呈线性关系；随冷却速度的加快，介稳区宽度增加。更多还原

【Abstract】 Optically active D-p-hydroxyphenylglycine (D-p-HPG) is useful as a intermediate for the preparation of semisynthetic amoxicillin , ceforperazone and cefoprozil . Today preferential crystallization procedure is widely used as the method of preparation of D-p-HPG. On the basis of studying the S-L-E of DL-p-HPG and its sulfate in the solution of water-acetone , a new resolution method of DL-p-HPG and its sulfate was put forward hi which costly chiral reagents are taken place by concentrated sulfic acid and the solution of water-acetone is used as the solvent . The effects of constitute of mixing solvent, concentration of H+ and the temperature of solution when crystal is seeded on product yields are discussed . Suitable operating parameters for resolution are defined .- the constitute of mixing solvent is 18.18% , concentration of FT is 2 mol/1 , the temperature of solution when crystal is seeded is 30C and product yields > 40% , O.R>98%Laser monitoring observation system and programmed heating apparatus are set up to determine the solubilities; super solubilities and the width of metasable zone by synthetic method. The solubilities; supersolubilities and the width of metasable zone of DL-p-HPG and its sulfate are determined. Totally 253 sets of data are obtained , most of which are determined at first. Experiential equation In x = A + B / T andlnx = A + B/T+C ln T are used to collete the data. It wasfound that the latter is the best collection equation , and on the basis of the determination of the solubilities x supersolubilities and the width of metasable zone of DL-p-HPG and its sulfate , the viewpoint that crystallization in the metasable zone is the key to the success of preferential crystallization procedure are put forwad and effects on the width of metasable zone of temperature , constitute of mixing solvent, concentration of H+, velocity ofagitation and speed of cooling are studied . Conclusion are obtained : in the same system , the solubility curve and the supersolubility curve are basically parallel . With the increase of temperature , the width of metasable zone of DL-p-HPG and its sulfate is becoming narrow and there is a significant converging trend of the solubility curve and the supersolubility curve. In the same system and the same constitution of mixing solvent ,with the increase of concentration of H4", the width of metasable zone of DL-p-HPG and its sulfate is becoming narrow rapidly . The above-mintioned data of the solubilities , supersolubilities and the width of metasable zone of DL-p-HPG and its sulfate are obtained with fixed cooling speed and agitiation velocity , and according to the classic theories of nucleation , cooling speed and agitiation velocity also have great effects on the width of metasable zone . With the increase of agitiation velocity , the width of metasable zone is becoming narrow when the cooling speed is fixed . This conclusion can be explained by the classic theories of nucleation :B0: nuclear rateΔCmax : the maximal conecrtration of supersaturationN : agitation velocitym , n : dynamical parametersWhen the superation is resulted from cooling crystallization , and the cooling velocity is fixed , the equation ( n ) will be obtained as followsln ΔTmax=K1-n/m lnN (II)K1: constantAccording to (II) ,when cooling speed is fixed ,the realation of In ΔTmax and In N is linear , that is, with the increase of agitation velocity,the width of metasable zone of DL-p-HPG and its sulfate is becoming narrow .With the increase of cooling velocity , the width of metasable zone of DL-p-HPG and its sulfate is becoming wide. This can be also explained according to the classic theories of nucleation . When the agitation velocity is fixed , (EG) will be obtained from ( I )K2: constantAccording to (EH) , when agitation speed is fixed ,the realation of In ΔTmax and ln b is linear , that is , with the increase of cooling velocity , the width of metasable zone of DL-p-HPG and its sulfate更多还原