5-羟色胺3拮抗剂盐酸帕洛诺司琼的合成与分析
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摘要
盐酸帕洛诺司琼(Palonosetron Hydrochloride),商品名为:Aloxi,化学名为2-(1-氮杂双环[2,2,2]辛-3S-基-2,3,3aS,4,5,6-六氢-1H-苯并[de]异喹啉-1-酮盐酸盐,是由瑞士Helsinn公司研制开发的一种高效、选择性、竞争性5-羟色胺3受体拮抗剂。用于预防中、高度致吐性化疗(CT)开始和重复疗程中相关的急性和迟发性恶心和呕吐,也是唯一用于迟发性CINA(化疗引发的恶心呕吐)的选择性5-羟色胺受体阻断剂,是第4个获FDA批准的5-HT3拮抗剂。由于美国专利合成与提纯方法复杂且条件苛刻,本学位论文对盐酸帕洛诺司琼的合成及精制尝试了多种改进方法,简化了反应条件与提纯技术并提高了产率。在此基础上,为了控制该原料药的生产质量,本论文还结合具体的工艺路线及盐酸帕洛诺司琼本身的性质,建立了盐酸帕洛诺司琼原料药的质量控制标准。因此,本论文主要由以下两部分组成:(1)盐酸帕洛诺司琼的合成和结构确证;(2)盐酸帕洛诺司琼原料药的分析质量标准研究。
本论文在专利文献的基础上对盐酸帕洛诺司琼的合成方法进行了显著的改进,以1,2,3,4-四氢萘为起始原料,经五步反应得到目标产物,总收率达到40.28%,大副度降低了生产成本,具有一定的经济效益与应用价值。通过HPLC内标法检测其含量达99.5%,并对其化学结构进行了初步分析和归属确认。
为了控制盐酸帕洛诺司琼的光学纯度,提高产品的质量,本文首先选用柱前衍生高效液相色谱法,用常见的异硫氰酸酯类手性衍生试剂(2,3,4,6-四-O-乙酰基-β-D-葡萄糖异硫氰酸酯),对重要手性中间体1-氮杂双环[2,2,2]辛-3-基胺进行了手性分离分析,实现了较好的分离效果。其次,用HPLC手性固定相法完成了目标产物盐酸帕洛诺司琼两非对映异构体(S胺,S酸)型与(S胺,R酸)型的分离分析。根据中国药典2005年版二部和指导原则对原料药的一般要求,结合本论文制定的合成路线的特点,本文对盐酸帕洛诺司琼性状、鉴别、溶解度、比旋度、酸碱度、溶液的澄清度、有关物质、干燥失重、炽灼残渣、重金属、硫酸盐、有机残留溶剂及含量进行了研究,制定了盐酸帕洛诺司琼原料药生产的质量控制标准。其中有机残留溶剂的测定,使用了较新的顶空进样毛细管气相色谱分离方法,得到了较好的结果,建立了简便、灵敏且稳定的检测方法。由于该药在我国目前尚未批准进口,按我国《药品注册管理办法》的有关规定,应属化学药品注册3类第1项新药。因此本文所做工作具有较高的实用价值。
The main of this thesis include two parts:1)synthesis and configurable corroboration of palonosetron hydrochloride as an 5-HT3 antagonist ;2)study on the analysis quality control standard of palonosetron hydrochloride.
Palonosetron hydrochloride,commercially named Aloxi,chemically called 2-[1-Azabicyclo[2,2,2]oct-3(S)-yl]-2,3,3a(S),4,5,6-hexahydro-1H-benz[de]isoquinolin-1-one hydrochloride.It is a high effective,high elective and high emulative 5-hydroxytrptamin3(5-HT3) antagonist,developed by Helsinn Corp. in Swizerland. This drug is used to prevent the emesis witch is caused by chemical therapy in the beginning course,and to treat the cute and delayed nausea and vomiting in repetitive period of treatment.It is the only drug witch can act on delayed nausea and vomiting.And it’s the fourth 5-HT3 antagonist approved by FDA.Synthesis of palonosetron hydrochloride was done according to newly developed pathways based on many patents.Target compound was synthesized using 1,2,3,4-tetrahydro naphthylin as starting material.By five steps,total yield reaches 40.28%,and purity reaches 99.5% detected by high performance liquid chromatography(HPLC).Finally the target molecular structure is in perfect agreement with those of the reference standards by HPLC,uv-vis spectrophotometry(UV-VIS),infrared spectroscopy(IR),mass spectroscopy(MS),nuclear magnetic resonance spectroscopy(NMR),and so on.
For the sake of controlling the optical purity of the target compound , a pre-column derivatization high-performance liquid chromatographic method was developed to separate and analyse 1-azabicyclo[2.2.2]octan-3-amine,witch is an important intermediate for the preparation of palonosetron hydrochloride. The results show that the enantiomers can be separated with 2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl isothiocyanate(GITC) as the derivatization reagent. Then a HPLC chiral stationary phase method was developed to separate two diastereoisomers of palonosetron hydrochloride.
According to the Chinese pharmacopoeia 2005 and the synthetical technics of this thesis ,the quality control standard of palonosetron hydrochloride was established.And the description,identification , solubility,specific rotation,pH value,clarify, relational substances,weight loss of drying,residue on ignition,heavy metal, sulphate, the residual organic volalile solvents,and the contence of palonosetron hydrochloride were detected. Thereinto, a headspace sampling GC method was developed to detect the residual organic volalile solvents.It is proved that the study of this thesis have high applied value.
本论文在专利文献的基础上对盐酸帕洛诺司琼的合成方法进行了显著的改进,以1,2,3,4-四氢萘为起始原料,经五步反应得到目标产物,总收率达到40.28%,大副度降低了生产成本,具有一定的经济效益与应用价值。通过HPLC内标法检测其含量达99.5%,并对其化学结构进行了初步分析和归属确认。
为了控制盐酸帕洛诺司琼的光学纯度,提高产品的质量,本文首先选用柱前衍生高效液相色谱法,用常见的异硫氰酸酯类手性衍生试剂(2,3,4,6-四-O-乙酰基-β-D-葡萄糖异硫氰酸酯),对重要手性中间体1-氮杂双环[2,2,2]辛-3-基胺进行了手性分离分析,实现了较好的分离效果。其次,用HPLC手性固定相法完成了目标产物盐酸帕洛诺司琼两非对映异构体(S胺,S酸)型与(S胺,R酸)型的分离分析。根据中国药典2005年版二部和指导原则对原料药的一般要求,结合本论文制定的合成路线的特点,本文对盐酸帕洛诺司琼性状、鉴别、溶解度、比旋度、酸碱度、溶液的澄清度、有关物质、干燥失重、炽灼残渣、重金属、硫酸盐、有机残留溶剂及含量进行了研究,制定了盐酸帕洛诺司琼原料药生产的质量控制标准。其中有机残留溶剂的测定,使用了较新的顶空进样毛细管气相色谱分离方法,得到了较好的结果,建立了简便、灵敏且稳定的检测方法。由于该药在我国目前尚未批准进口,按我国《药品注册管理办法》的有关规定,应属化学药品注册3类第1项新药。因此本文所做工作具有较高的实用价值。
The main of this thesis include two parts:1)synthesis and configurable corroboration of palonosetron hydrochloride as an 5-HT3 antagonist ;2)study on the analysis quality control standard of palonosetron hydrochloride.
Palonosetron hydrochloride,commercially named Aloxi,chemically called 2-[1-Azabicyclo[2,2,2]oct-3(S)-yl]-2,3,3a(S),4,5,6-hexahydro-1H-benz[de]isoquinolin-1-one hydrochloride.It is a high effective,high elective and high emulative 5-hydroxytrptamin3(5-HT3) antagonist,developed by Helsinn Corp. in Swizerland. This drug is used to prevent the emesis witch is caused by chemical therapy in the beginning course,and to treat the cute and delayed nausea and vomiting in repetitive period of treatment.It is the only drug witch can act on delayed nausea and vomiting.And it’s the fourth 5-HT3 antagonist approved by FDA.Synthesis of palonosetron hydrochloride was done according to newly developed pathways based on many patents.Target compound was synthesized using 1,2,3,4-tetrahydro naphthylin as starting material.By five steps,total yield reaches 40.28%,and purity reaches 99.5% detected by high performance liquid chromatography(HPLC).Finally the target molecular structure is in perfect agreement with those of the reference standards by HPLC,uv-vis spectrophotometry(UV-VIS),infrared spectroscopy(IR),mass spectroscopy(MS),nuclear magnetic resonance spectroscopy(NMR),and so on.
For the sake of controlling the optical purity of the target compound , a pre-column derivatization high-performance liquid chromatographic method was developed to separate and analyse 1-azabicyclo[2.2.2]octan-3-amine,witch is an important intermediate for the preparation of palonosetron hydrochloride. The results show that the enantiomers can be separated with 2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl isothiocyanate(GITC) as the derivatization reagent. Then a HPLC chiral stationary phase method was developed to separate two diastereoisomers of palonosetron hydrochloride.
According to the Chinese pharmacopoeia 2005 and the synthetical technics of this thesis ,the quality control standard of palonosetron hydrochloride was established.And the description,identification , solubility,specific rotation,pH value,clarify, relational substances,weight loss of drying,residue on ignition,heavy metal, sulphate, the residual organic volalile solvents,and the contence of palonosetron hydrochloride were detected. Thereinto, a headspace sampling GC method was developed to detect the residual organic volalile solvents.It is proved that the study of this thesis have high applied value.
引文
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