【作者】 石晓华；

【导师】 陈新志；

【作者基本信息】 浙江大学 ， 化学工程与技术， 2005， 博士

【摘要】 西司他丁是一种肾脱氢二肽酶抑制剂,其与亚胺培南复配的抗菌药物——泰能在临床上应用广泛。我国目前还没有西司他丁的工业化生产工艺,开发其高效率低污染的合成工艺十分必要。本文对西司他丁的全合成工艺进行了研究,在设计并研究了西司他丁的两个关键中间体——S-（+）-2,2-二甲基环丙烷甲酰胺和7-氯-2-氧代庚酸的合成路线的基础上,优化了西司他丁的合成过程。 采用新工艺合成了2,2-二甲基环丙烷甲酸。以异戊烯酸为起始原料,经酯化、环丙烷化、水解得到2,2-二甲基环丙烷甲酸,三步总收率为48%。此路线避免使用氰化物,反应时间短,可降低生产成本。其中,采用超声波—乙酰氯协同催化,具有酯基的贫电子烯烃与活性较低的二溴甲烷也可以顺利进行环丙烷化反应。将这个催化体系用于其他烯烃的环丙烷化,结果表明,协同催化效果优于单一催化体系。 改进了2,2-二甲基环丙烷甲酸的拆分及S-（+）-2,2-二甲基环丙烷甲酰胺的合成。首先,用L-肉碱盐酸盐拆分2,2-二甲基环丙烷甲酸,单次拆分收率21.4%,产物的比旋光度为[α]_D²⁰+139.5°（c=0.85,CHCl₃）。S-（+）-2,2-二甲基环丙烷甲酸酰化后与氨水反应,得到S-（+）-2,2-二甲基环丙烷甲酰胺,收率76%。其次,在改进的拆分工艺中,直接用L-肉碱草酸盐拆分2,2-二甲基环丙烷甲酸。经酰化、酯化、部分结晶与氨解,得到s-（+）-2,2-二甲基环丙烷甲酰胺,熔点135.5～137.5℃,[α]_D²⁰+95.5°（c=1.0,CHCl₃）,总收率为19.5%。 L-肉碱草酸盐拆分法与L-肉碱盐酸盐拆分法相比,减少了离子交换与成盐两步,简化了工艺。最后,R-（-）-2,2-二甲基环丙烷甲酸酰化后进行消旋,收率86%,对提高对映体利用率有重要意义。 用动态法和激光监视技术测定了S-（+）-2,2-二甲基环丙烷甲酰胺在甲苯、二氯甲烷、三氯甲烷、乙酸乙酯、乙醇与水六种溶剂中的溶解度,并用半经验模型法对实验数据进行拟合,模型计算值与实验值吻合良好。根据溶解度数据对S-（+）-2,2-二甲基环丙烷甲酰胺的重结晶过程进行了优化,结果表明对于经手性草酸盐直接氨解制得的酰胺,用70%乙醇水溶液重结晶,结晶收率80%;经酰化、氨解制得的酰胺,乙酸乙酯的结晶效果较好,结晶收率78%。 改进了7-氯-2-氧代庚酸的合成。以二氯乙酸、1,3-丙二硫醇与1-溴-5-氯-戊烷为起更多还原

【Abstract】 Cilastatin is an important inhibitor of dehydropeptidase-I, which can enhance the antibacterial activity of Imipenem and has widely clinic applications. In our country, there has not been the industrial procedure for Cilastatin, and it is necessary to research the synthesis route with high efficiency and low pollution. This thesis is mainly about the total synthesis of Cilastatin. On the base of design and study for the synthesis of S-（+）-2,2-dimethylcycloproprane carboxamide and 7-chloro-2-oxoheptanoic acid, which are the key intermediates of Cilastatin, the total synthesis procedure of Cilastatin was optimized.Using 2-methylbutenoic acid as starting material, 2,2-dimethylcyclopropane carboxylic acid was synthesized via esterification, cyclopropanantion and hydrolysis, with 48% yield. This route had advantages such as avoiding cyanide, short reaction time and lower cost. Especially, using ultrasonic-acetyl chloride catalyst system, cyclopropanation of alkenes with withdrawing-electron group and low active dibromomethane could proceed smoothly. This catalyst system was applied in the cyclopropanation of other alkenes, and the results indicated that the catalyst system excelled mono-catalyst.The chiral resolution of 2,2-dimethylcyclopropane carboxylic acid and the synthesis of S-（+）-2,2-dimethylcycloproprane carboxamide were improved. Firstly,2,2-dimethylcyclopropane carboxylic acid was resolved by L-carnitine hydrochloride with21.4% yield, [α]_D²⁰ + 139.5° （c=0.85, CHCl₃）. The product S- （+）-2,2-dimethylcyclopropranecarboxylic acid was converted to S-（+）-2,2-dimethylcycloproprane carboxamide with 76% yield. Then, L-carnitine oxalate was used in the improved chiral resolution of 2,2-dimethylcyclopropane carboxylic acid. In the improved procedure, S-（+）-2,2-dimethylcycloproprane carboxamide was obtained with 19.5% yield via four steps: converted to acid chloride, formed oxalate, fractional crystallization and hydrolysis. Themelting point of product was 135.5¹37.5℃, [α]_D²⁰ +95.5° （c=1.0, CHCl₃）. Comparing two chiral resolutions, the steps of ion exchange and oxalate formation was omitted by using L-carnitine oxalate as the resolution reagent. At last, R-（-）-2,2-dimethylcyclopropranecarboxylic acid was converted to acid chloride and racemized with the yield was 86%, which is important for the utilization of enantiomer.The solubilities of S-（+）-2,2-dimethylcycloproprane carboxamide in toluene, dichloromethane, trichloromethane, ethyl acetate, ethanol and water were measured experimentally using a synthetic method with a laser monitoring observation technique. The solubility data were correlated with a semi-empirical correlation, and the calculated values were in good agreement with those of the experimental. The re-crystallization process of S-（+）-2,2-dimethylcycloproprane carboxamide was optimized according to the solubility data. The result indicated that the carboxamide produced through different process needed different crystallization solvents. To the carboxamide obtained from the ammonolysis of chiral oxalate, 70% ethanol-water solution was good re-crystallization solvent, and could get 80% yield. But ethyl acetate obtained good result to the carboxamide produced from S-（+）-2,2-dimethylcycloproprane carboxylic acid via ammonolysis, 78% yield.The synthesis of 7-chloro-2-oxoheptanonic acid was improved. Using dichloroacetic acid, 1,3-propanedithiol and l-bromo-5-chloro-pentane as starting materials, 7-chloro-2-oxoheptanoic acid was produced via five steps with 31% yield: esterification, cyclization, alkylation* oxidation and transesterification. In the alkylation, l-bromo-5-chloro-pentane was used instead of 1,5-dibromopentane, which increased the conversion rate of l,3-dithiane-2-carboxylate and deceased the byproduct of di-alkylation. Then, the oxidation mechanism of 2-（5-chloropentane）-l,3-dithiane-2-carboxylate by NBS was induced. The HOBr produced by NBS and H2O is considered the main oxidant, and the bromine produced by NBS and HBr is subsidiary oxidant.In addition, the new synthesis techniques of 7-chloro-2-oxoheptanoic acid using Grignard method was studied. The ethyl 7-chloro-2-oxoheptanoate was synthesized from the addition of mono-Grignard reagent of l-bromo-5-chloro-pentane to diethyl oxalate, then, the transesterification was carried out between the ester and formic acid to give 7-chloro-2-oxoheptanoic acid. The total yield was 43%. After that, the techniques conditions were optimized. Using the addition of NaHSO3 to ketones, the enol form of a -keto esters could be transformed to the keto form.Finally, Cilastatin was synthesized via two steps. First step was the reaction of S-（+）-2,2-dimethylcycloproprane carboxamide and 7-chloro-2-oxoheptanoic acid, which gave （+）-（Z）-7-chloro-2-（2,2-dimethylcyclopropanecarboxamido）-2-heptenoic acid. In this reaction, dimethylbenzene was used as solvent to increase the ratio of Z- product and E-product. Consequently, the yield was improved to 35% （literature value 28%）. Second step produced the aim product Cilastatin from the reaction of heptenoic acid and L-cysteine hydrochloride anhydrous, which needed following process: preparation of the sodium L-cysteine, thiolation, ion exchange and column chromatography. The yield was 61%,[aj° +17.9° （c=0.51, CH3OH）. The product was characterized by *H NMR and 13C NMR.Especially, L-cysteine hydrochloride anhydrous was used instead of L-cystine used in the literature, so the reaction could carry out under mild condition.更多还原