【作者】 臧健；

【导师】 吴怡祖；

【作者基本信息】 南京工业大学 ， 化学工程， 2005， 硕士

【摘要】 在大量的不对称合成医药试剂中,手性化合物扁桃酸及其衍生物α-环己基扁桃酸都是重要的前体合成原料。光学活性的扁桃酸具有很好的生物分解性,是目前最受瞩目的酸性光学拆分剂,它可使多数外消旋体胺类和氨基酸类经非对映体异构盐形成法进行光学拆分;而且它本身又可用于一些药品中间体,如R-(-)-扁桃酸用于头孢菌类系列抗生素-羟苄四唑头孢菌素的侧链修饰剂等。目前国际市场上光学活性的扁桃酸需求约以年均10%以上的速度增长,成为热点的精细化工中间体。手性α-环己基扁桃酸不仅可以用来合成奥昔布宁和脱乙基奥昔布宁等解痉药,还可以用来合成奥芬溴铵和羟苄利明等抗胆碱药;相比较它们的消旋结构,光学活性的药物有更有效的药理作用。因此,单一对映体α-环己基扁桃酸的市场前景非常巨大。在国外,从二十世纪六十年代开始,如何开发出高效、简便的不对称合成路径一直是研究的热点。而国内的研究还未见报道。为协助常州胜杰化工有限公司开发出手性新品,打进国际市场,本论文主要研究了扁桃酸的光学拆分及其衍生物R-(-)-α-环己基扁桃酸的不对称合成。与此同时,也研究了拆分剂D-(-)-苯甘氨酸丁酯及其盐酸盐的制备方法。 扁桃酸的光学拆分主要研究了形成非对映异构体拆分的方法。通过本论文的比较及实验,选用了D-(-)-苯甘氨酸丁酯盐酸盐作为拆分剂,它与消旋扁桃酸的摩尔比为1.0～1.2,两者在10℃下溶于水溶液中,用NaOH滴定,得到好的拆分效率。通过实验知道,形成的非对映异构体盐D-苯甘氨酸丁酯.R-扁桃酸从水溶液中结晶析出,经酸化,用乙醚提取后,得到了R-(-)-扁桃酸,有98.9%的收率和32%的光学纯度。而从酸化后的母液中用乙醚提取了S-(+)-扁桃酸,有90%的收率和67%的光学纯度。另外,作者也回收套用了拆分后的母液,减少了整个拆分成本,提高了收率。 在拆分剂的制备过程中,主要用了D-(-)-苯甘氨酸和正丁醇为起始原料,氯化亚砜为酯化的催化剂。选择在低温下缓慢滴加氯化亚砜,一般在5℃左右进行滴加;滴加完毕后,在室温下反应1小时左右,直至完全生成酰氯盐酸盐。然后进行回流酯化,反应时间最佳为70分钟。为了扩大化生产的需要,可以将母液直接套用,达到节省原料,节约生产成本,提高收率的目的。最终得到了摩尔收率在85%以上,光学纯度为98.1%的产品D-苯甘氨酸丁酯盐酸盐。接着选用10%氢氧化钠溶液作为制备D-苯更多还原

【Abstract】 In the asymmetric synthesis of a variety of medicinal agents, chiral mandelic acid and α-cyclohexyl-mandelic acid are important intermediate compounds. Optically active mandelic acid has a good biology resolvability. It is focused more attention in the acidic resolving agents at present. Most racemic amines or amino acids can be optical resolved by it. In addition, it can be used in intermediate medicament as side-chain. Such as R-(-)-mandelic acid can be used in cefamandole (CMD). The need of single enantiomer of mandelic acid is increased up to 10% every year. So it is a more important intermediate compound in fine chemical now. Chiral a-cyclohexyl-mandelic acid can be used in synthesizing convulsion antagonist medicaments or muscarinic receptor antagonists. For example, oxybutynin and its metabolite desethyloxybutynin, oxyphenonium bromide and oxphencyclimine. They display improved therapeutic profiles compared to theirs racemic counterparts. So it has a long-range foreground in market. In foreign country, it had been a focus how to develop a simple and efficient method of asymmetry synthesis since 1960. On the contrary, there were no more reports in our country. For making the chiral productions to be industrialized and exported, not only the optical resolution of mandelic acid but also the asymmetric synthesis of R-(-)-α-cyclohexyl-mandelic acid was discussed here. At the same time, the synthesis of D-(-)-phenylglycine butyl ester and its hydrochloride were disclosed.The resolution through formation of diastereoisomeric salts was studied here. The author used D-phenylglycine butyl ester hydrochloride as the resolving agent. The mol ratio was 1.0—1.2 to the racemic mandelic acid. Both of them were dissolved in water at 10 ℃ . With stirring, NaOH solution was dripped in them. The diastereoisomeric salt (D-phenylglycine butyl ester.R-mandelic acid) was separated out. After acidification and extraction with ether, R-(-)-mandelic acid was gotten. The yield was 98.9% and the optical purity was 32%. At the same time, S-(+)-mandelic acid was obtained in mother liquor. The yield was 90% and the optical purity was 67%. In addition, the author recycled the mother liquor of the resolution. It increased the overall yield and decreased the whole productioncost.In the synthesis of resolving agents, D-(-)-phenylglycine butyl ester hydrochloride was prepared by D-(-)-phenylglycine and 1-butanol. The catalyst of esterification was SOCI2. With stirring, SOC12 was dripped in them at 5 °C. Then, all of them reacted for about one hour at home temperature. Finally, they were heated up to reflux. The best reflux time was 70 minutes. Reusing the mother liquor made the overall yield over 85% and the optical purity over 98.1%. D-phenylglycine butyl ester was prepared by neutralization of D-phenylglycine butyl ester hydrochloride using NaOH under 5°C. Be careful in accommodating the PH during 7 and 8. Twenty minutes later, it was extracted three times with the mixture of n-hexane and dichloromethane (2/1, V/V). The yield and the optical purity were 74.1% and 98.4%.The raw materials of the asymmetric synthesis of R-(-)-a-cyclohexyl-mandelic acid were R-(-)-mandelic acid and iso-butyraldehyde. The reaction solvent was the mixture of n-hexane and ether (4/1, V/V). The catalyst was methanesulfonic acid. They allowed reflux about 4 hours. The water generated in the reaction was separated with a Dean-Stark trap. Four recrystallization of crude solid from the mixture of n-hexane and ether (4/1, V/V) yielded cis-(2R,5R)-2-isopropyl-5-phenyl-l,3-dioxolan-4-one( I). The yield and the optical purity were 43.6% and 93.6%. To a -78°C solution of lithium bis(trimethylsilyl)-amide in THF was added cis-(2R,5R)-2-isopropyl-5-phenyl-l,3-dioxolan-4-one( I). The reaction mixture was allowed to stir to produce enol under nitrogen, followed by the addition of neat cyclohexanone as electrophilic agent. Then, the reaction solution was added thionyl chloride (SOCI2), followed by pyridine. Sulfur impurity was washed by the addition of saturated NH4CI solution. Next, 5.5N NaOH was added to hydrolyze. After acidification, white solids were precipitated. It was R-cyclohex-1-enyl-hydroxy-phenyl-acetic acid(IV). The yield was 55.2%. After recrystallization, the white solid dissolved in methanol, followed by the addition of 10% Pd/C. The reaction was subjected to 1 atm of hydrogen and was allowed to stir for 14 hours at 50 °C. The yield and the optical purity were 61.2% and 81.1%. After recrystallization from n-hexane, the purity R-(-)-CHPGA was gotten.The method of the synthesis of D-phenylglycine butyl ester and its hydrochloride was successfully found out. It was satisfied with the yield and the optical purity. The process ofthe optical resolution of mandelic acid by D-phenylglycine butyl ester was improved on, and two optical isomers were gained. The yield was increased and the cost was saved through reusing mother liquor. In our actual condition, pilot study of the asymmetric synthesis of R-(-)-CHPGA from cheapness iso-butyraldehyde was experimentized. The final product R-(-)-CHPGA was gotten and some optimized operation conditions were found out. But some aspect of the problem in yield or reaction steps could be improved.更多还原