喷司他汀的合成与质量控制研究
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摘要
喷司他汀是从链霉素茵发酵液中分离出来的拟嘌呤类物质,对治疗毛细胞白血病、低度恶性淋巴瘤、慢性淋巴细胞白血病等方面具有特殊疗效。1998年美国FDA正式批准喷司他汀为治疗白血病的药物。对于喷司他汀的合成研究,相关的文献报道不多,且报道的路线多停留在实验室试探阶段,反应收率很低。国内迄今未见相关的合成文献报道,也未见生产厂家申报原料药的生产。本论文围绕喷司他汀的合成和质量控制,主要进行以下三方面的工作。一、喷司他汀合成路线的选择和工艺研究
1. 6,7二氢咪唑并[4,5-d][1,3]二氮杂草-8-酮七元杂环的合成。对3条合成路线进行了初步的对比,其中选择以5-硝基咪唑为起始原料,经8步反应的合成路线作为研究重点。并对其中的硝基甲烷化、硝基还原、环合等反应步骤进行了工艺优化,解决了环合产物后处理过程中产品不稳定的问题。
2. 3-(2-脱氧-β-D-赤-戊呋喃糖基)-6,7二氢咪唑并[4,5-d][1,3]二氮杂草-8-酮的合成。以2-脱氧-D-核糖为原料,经过甲基化,对甲苯甲酰氯保护,甲氧基转化为氯等3步反应合成1-氯-2-脱氧-3,5-二-O-对甲苯甲酰基-D-核糖片段。该糖基片段和6,7二氢咪唑并[4,5-d][1,3]二氮杂草-8-酮七元杂环在SnCl4路易斯酸的作用下,进行糖基化反应,得到α和β两种构型的糖基化产物,经过多次重结晶和过柱纯化后得到单一的β构型的糖基化产物。采用SnCl4路易斯酸催化剂使糖基化反应的收率比文献报道的提高了20%。
3.喷司他汀的合成。从p构型的糖基化产物通过以下两条路线反应得到目标产物：一是羰基经NaBH4还原,得到1:1的R/S手性醇,经制备色谱分离得到目标产物喷司他汀。二是采用不对称氢转移反应,以二氯(p-甲基异丙苯)钌(Ⅱ)与(1R,2R)-(-)-N-(对甲基苯磺酰基)-1,2-苯基乙二胺形成的钌配位物,对羰基进行还原,反应得到R/S手性醇比例超过99:1。后一路线很好地解决了手性醇的立体选择性问题,收率比前一路线提高70%,且极大简化了工艺过程。
二、喷司他汀的质量控制研究
针对目前喷司他汀还没有被任何药典收录的现状,建立了喷司他汀的质量标准和检测方法,以更好地控制喷司他汀产品质量,并对其中的高效液相色谱方法和顶空气相方法进行了详细的方法学验证。同时对喷司他汀的异构体杂质进行了结构鉴定。
三、中试工艺研究
在一系列小试数据的基础上,进行选择经济可行的合成路线,进行中试放大。在放大过程中,对工艺进行了调整,以更好地适应实际操作的需要,12步主反应的摩尔总收率达到1.3%。
Pentostatin is a kind of purine analog which was originally isolated from the species of bacteria Streptomyces antibioticus. Pentostatin has shown dramatic antitumor effects to hairycell leukemia, lymphoma and chromic lymphocytic leutemia. In 1998, FDA approved pentostatin as the anti-tumor drug used to treat acute leukaemia. There are a few literatures about the pentostatin synthesis, but most of them focus on the laboratory trial with lower yield. And there is no record about Pentostatin synthesis and no API production record in SFDA in China. Pentostatin synthesis and quality control research work is discussed on the following three parts.
The first part is study on Pentostatin synthesis route and process parameters.
1. Three synthesis routes of 6,7-Dihydro-3H-imidazo[4,5-d][l,3]diazepin-8-one were compared.Much effort was placed on one of the synthesis route,which was accomplished in 8 steps started from 5-nitroimidazole.The process of nitromethane, nitrate deduction and coupling steps are optimized. The instability issue of 6,7-Dihydro-3H-imidazo[4,5-d][1,3]diazepin-8-one was resolved by optimized process procedure.
2. The synthesis of the aglycon fragment,2-deoxy-3,5-di-O-p-Toluoyl-pento-furanosyl, was achieved in 3 steps from 2-deoxy-D-ribose,which underwent methylation, toluyl protection and chloronation. The 6,7-Dihydro-3H-imidazo [4,5-d][1,3]diazepin-8-one heterocyclic moiety is glycosylated by aglycon with Tin(IV) chloride to get the mixture ofβand a ketone. The mixture ofβand a ketone was purified by crystallization and column purification to get the pureβ-ketone. Tin(IV) chloride as Lewwis acid catalyst improved the glycoslation yield more than 20% than that reported on the literature.
3. The final product Pentostatin was synthesized fromβ-ketone by two synthesis routes. One isβ-ketone hydrogenated by NaBH4 to get 1:1 R/S chiral alcohol, then purified by pre-HPLC to get the Pentostatin. Another route is asymmetric transfer hydrogenation. A new catalyst, di-μ-chloro-bis [(p-cymene)chlororuthenium(II) coordinated with (1R,2R)-N-(p-Toluenefulfonyl)-1,2-diphenylethanediamene, was used forβ-ketone hydrogenation with 99:1 R/S chiral alcohol. One of the challenges, a chiral alcoholic center in the C-8 is successfully achieved by this catalyst. The yield of 2nd route increased 70% than the 1st route and the process is simplified dramatically.
The second part is Pentostatin quality control study.
Pentostain has not been recorded by any pharmacopeial yet. So it is necessary to set up the final product specification to control the quality. Also the intermediate and final product test methods were developed. Meanwhile the HPLC and HS-GC method validation were performed. Furthermore, The main known impurities, Pentostatin isomers were identified.
The third part is Pentostatin pilot scale production.
Based on the trial data, the economic and practical synthesis route is used to pilot production. During the pilot, some process parameters were adjusted. Pentostatin was produced in a total 12 steps with 1.3% yield.
1. 6,7二氢咪唑并[4,5-d][1,3]二氮杂草-8-酮七元杂环的合成。对3条合成路线进行了初步的对比,其中选择以5-硝基咪唑为起始原料,经8步反应的合成路线作为研究重点。并对其中的硝基甲烷化、硝基还原、环合等反应步骤进行了工艺优化,解决了环合产物后处理过程中产品不稳定的问题。
2. 3-(2-脱氧-β-D-赤-戊呋喃糖基)-6,7二氢咪唑并[4,5-d][1,3]二氮杂草-8-酮的合成。以2-脱氧-D-核糖为原料,经过甲基化,对甲苯甲酰氯保护,甲氧基转化为氯等3步反应合成1-氯-2-脱氧-3,5-二-O-对甲苯甲酰基-D-核糖片段。该糖基片段和6,7二氢咪唑并[4,5-d][1,3]二氮杂草-8-酮七元杂环在SnCl4路易斯酸的作用下,进行糖基化反应,得到α和β两种构型的糖基化产物,经过多次重结晶和过柱纯化后得到单一的β构型的糖基化产物。采用SnCl4路易斯酸催化剂使糖基化反应的收率比文献报道的提高了20%。
3.喷司他汀的合成。从p构型的糖基化产物通过以下两条路线反应得到目标产物：一是羰基经NaBH4还原,得到1:1的R/S手性醇,经制备色谱分离得到目标产物喷司他汀。二是采用不对称氢转移反应,以二氯(p-甲基异丙苯)钌(Ⅱ)与(1R,2R)-(-)-N-(对甲基苯磺酰基)-1,2-苯基乙二胺形成的钌配位物,对羰基进行还原,反应得到R/S手性醇比例超过99:1。后一路线很好地解决了手性醇的立体选择性问题,收率比前一路线提高70%,且极大简化了工艺过程。
二、喷司他汀的质量控制研究
针对目前喷司他汀还没有被任何药典收录的现状,建立了喷司他汀的质量标准和检测方法,以更好地控制喷司他汀产品质量,并对其中的高效液相色谱方法和顶空气相方法进行了详细的方法学验证。同时对喷司他汀的异构体杂质进行了结构鉴定。
三、中试工艺研究
在一系列小试数据的基础上,进行选择经济可行的合成路线,进行中试放大。在放大过程中,对工艺进行了调整,以更好地适应实际操作的需要,12步主反应的摩尔总收率达到1.3%。
Pentostatin is a kind of purine analog which was originally isolated from the species of bacteria Streptomyces antibioticus. Pentostatin has shown dramatic antitumor effects to hairycell leukemia, lymphoma and chromic lymphocytic leutemia. In 1998, FDA approved pentostatin as the anti-tumor drug used to treat acute leukaemia. There are a few literatures about the pentostatin synthesis, but most of them focus on the laboratory trial with lower yield. And there is no record about Pentostatin synthesis and no API production record in SFDA in China. Pentostatin synthesis and quality control research work is discussed on the following three parts.
The first part is study on Pentostatin synthesis route and process parameters.
1. Three synthesis routes of 6,7-Dihydro-3H-imidazo[4,5-d][l,3]diazepin-8-one were compared.Much effort was placed on one of the synthesis route,which was accomplished in 8 steps started from 5-nitroimidazole.The process of nitromethane, nitrate deduction and coupling steps are optimized. The instability issue of 6,7-Dihydro-3H-imidazo[4,5-d][1,3]diazepin-8-one was resolved by optimized process procedure.
2. The synthesis of the aglycon fragment,2-deoxy-3,5-di-O-p-Toluoyl-pento-furanosyl, was achieved in 3 steps from 2-deoxy-D-ribose,which underwent methylation, toluyl protection and chloronation. The 6,7-Dihydro-3H-imidazo [4,5-d][1,3]diazepin-8-one heterocyclic moiety is glycosylated by aglycon with Tin(IV) chloride to get the mixture ofβand a ketone. The mixture ofβand a ketone was purified by crystallization and column purification to get the pureβ-ketone. Tin(IV) chloride as Lewwis acid catalyst improved the glycoslation yield more than 20% than that reported on the literature.
3. The final product Pentostatin was synthesized fromβ-ketone by two synthesis routes. One isβ-ketone hydrogenated by NaBH4 to get 1:1 R/S chiral alcohol, then purified by pre-HPLC to get the Pentostatin. Another route is asymmetric transfer hydrogenation. A new catalyst, di-μ-chloro-bis [(p-cymene)chlororuthenium(II) coordinated with (1R,2R)-N-(p-Toluenefulfonyl)-1,2-diphenylethanediamene, was used forβ-ketone hydrogenation with 99:1 R/S chiral alcohol. One of the challenges, a chiral alcoholic center in the C-8 is successfully achieved by this catalyst. The yield of 2nd route increased 70% than the 1st route and the process is simplified dramatically.
The second part is Pentostatin quality control study.
Pentostain has not been recorded by any pharmacopeial yet. So it is necessary to set up the final product specification to control the quality. Also the intermediate and final product test methods were developed. Meanwhile the HPLC and HS-GC method validation were performed. Furthermore, The main known impurities, Pentostatin isomers were identified.
The third part is Pentostatin pilot scale production.
Based on the trial data, the economic and practical synthesis route is used to pilot production. During the pilot, some process parameters were adjusted. Pentostatin was produced in a total 12 steps with 1.3% yield.
引文
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