FK520的分离及其衍生物的合成
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摘要
免疫抑制剂是一类具有免疫抑制作用的药物,又称为抗排斥药物。目前在临床上主要用于治疗自身免疫性疾病和防止脏器移植排斥。国外对免疫抑制剂的研究自1954年人类第一例同卵双生子间肾脏移植手术取得成功后,医学家在器官移植方面的研究取得了许多重大进展。自20世纪80年代初环孢素A(CsA)应用于临床,器官移植取得巨大成就以来,FK506、MMF又先后获得美国FDA认证并上市。免疫抑制剂在器官移植方面起着越来越重要的作用;免疫抑制剂除了被用来防止器官排斥,也可用来治疗严重的皮肤病如牛皮癣,类风湿关节炎,克罗恩氏病(慢性炎症的消化道)和片状脱发(斑秃)等其他疾病,其中一些疾病属于“自身免疫”性疾病。随着对移植免疫学、分子生物学技术和理论的认识与掌握,人们相继发现并研制出许多新药,其中一些现已进入临床试验及评估阶段。近年来,国内学者也正积极致力于免疫抑制剂的研究与开发。但是由于起步较晚,研发成本较高,目前只有少数几家国内公司涉足,而且主要以仿制国外新药为主。
吡美莫司(pimecrolimus)[商品名]Elidel,为新一代免疫抑制类药物。由瑞士诺华公司开发,于2002年在英国率先上市,主要用做免疫抑制药物和特应性皮炎的治疗药物,其作为抗牛皮癣药物和治疗哮喘药物已进入临床二期试验阶段,作为抗关节炎药物和治疗胃肠道炎症药物即将进入临床试验。吡美莫司是大环内酯类抗菌药物子囊霉素(ascomycin, FK520)的一种衍生物,国内目前尚未有厂家生产,因此,研究该药物的合成方法对新药开发具有一定的应用价值。
目的
1建立从FK506尾液中分离纯化FK506与FK520的方法,得到FK506和FK520的纯品。
2以FK520为原料,建立吡美莫司的制备方法,优化合成工艺。
3初步建立吡美莫司的含量测定方法并对其异构体现象进行初步研究。
方法
1建立了FK506与FK520的分离方法,首先对两者的混合溶液进行粗提,除去混合液中的油状物质和其他杂质;然后采用硝酸银硅胶柱层析法分离得到二者的纯品。
2以FK520为原料,合成目标产物吡美莫司。
2.1①以FK520为原料,采用叔丁基二甲基硅烷基三氟甲烷磺酸酯(TBDMS Trifluoromethanesulfonate)对FK520的C-24和C-33位羟基进行保护,生成Ⅰ;②Ⅰ在对甲基苯磺酸条件下脱去C-33位保护基,生成Ⅱ;③Ⅱ在DMAP催化条件下,经邻硝基苯磺酰氯活化生成Ⅲ;④以氯化锂做氯化试剂,将Ⅲ氯化,生成Ⅳ;⑤Ⅳ在HF酸中水解脱去C-24位保护基,得到目标产物Ⅴ。其中Ⅱ可以不经过活化而直接氯化生成Ⅳ。
2.2我们参阅最新文献,发现FK520 C-24位羟基活性较低,可以不必进行特殊保护直接氯化,我们分别采用了三苯基膦与BTC氯化试剂、三苯基膦与NCS氯化试剂和三苯基膦与四氯化碳氯化试剂,取得了理想的结果,并对工艺进行改进,减少了操作步骤,降低了成本,减少了污染。
3初步建立了吡美莫司的含量测定方法,并初步考察了吡美莫司的异构现象。
结果
1成功分离得到了FK506和FK520的纯品,纯度均大于98%。
2得到了FK520的衍生物吡美莫司,经核磁共振氢谱、核磁共振碳谱、质谱分析符合其结构特征。
对专利文献方法进行了改进,提高了收率,降低了成本;吡美莫司的总收率42.1%,纯度>96%,熔点为135.2-136.1℃,与文献报道相符。
3初步确立了吡美莫司的含量测定方法,初步考察了吡美莫司的异构现象。
结论
1成功分离了FK506和FK520的混合物,所采用的硝酸银硅胶柱层析法分离效果好,两者性质稳定,产品纯度高。
2在吡美莫司的制备中,改进了专利方法,同时制备了优良的氯化试剂,尝试多种新型路线,缩短了反应周期,降低了成本,提高产品纯度,并且研究了反应原料的最佳配比。
3初步建立了吡美莫司HPLC含量测定方法,初步考察了吡美莫司的异构体情况,为吡美莫司的开发打下了一定基础。
Immunosuppressant drugs, also called anti-rejection drugs, are a kind of drug which have immunosuppressive effects. Mainly used to treat the autoimmune diseases and to prevent organ transplant rejection in clinic. The study on immunosuppressive agents abroad, after the success of the first human case between twins with the egg of kidney transplant since 1954, doctors in the study of organ transplant have made a number of major breakthroughs. Since the early 1980s, cyclosporine A (CsA) are used in clinic, organ transplant has made tremendous achievements, FK506 and MMF have been certified by the United States FDA and listed. Immunosuppressants in organ transplant play an increasingly important role; In addition to being used to prevent organ rejection, immunosuppressant drugs are also used to treat such severe skin disorders as psoriasis and such other diseases as rheumatoid arthritis, Crohn's disease (chronic inflammation of the digestive tract) and patchy hair loss (alopecia areata). Some of these conditions are termed "autoimmune" diseases. With the mastering and understanding of the theory of transplantation immunology and molecular biology technology, People discovered and developed many new drugs, some of which have entered clinical trials and evaluation phase. In recent years, domestic scholars are also actively engaged in the research and development of immunosuppressant. However, due to a late start, and the high cost of research and development, at present, only a handful of domestic companies involved, mainly in generic drug abroad.
Pimecrolimus [commodity name] Elidel, a new generation of immunosuppressant drugs developed by Novartis company, and in 2002 the first listing in the United Kingdom. mainly used as immunosuppressive drugs and the treatment of atopic dermatitis, as an antipsoriasis drugs and the treatment of asthma drugs have entered Phase II clinical trial stage, as an anti-arthritis drug and treatment of G1 inflammatory drugs will soon enter clinical trials. Pimecrolimus is a derivative of antibacterials ascomycin (FK520) which belongs to macrolide antibiotic drug, Domestic manufacturers are not yet available, Therefore, the study of the drug synthesis method for the development of new drugs have some value.
Objective
1 Isolation and Purification of the FK506 and FK520 from the end of the FK506, FK506 and FK520 are pure materials.
2 Using FK520 as a raw material, established the preparation methods of pimecrolimus, optimized synthesis process.
3 The HPLC determination of pimecrolimus was researched, made initial research on isomer.
Methods
1 Established a method for isolation of FK520 and FK506, firstly purified the mixed solution of FK520 and FK506, removed the oily mixture of substances and other impurities and then obtained pure FK520 and FK506 using silver nitrate silica gel column chromatography .
2 Using FK520 as a raw material, prepared the target product pimecrolimus.
2.1①The intermediate I was prepared from FK520 by using TBDMS Trifluoromethanesulfonate to protect the C-24 and C-33 hydroxyl.②Under the conditions of the p-toluenesulfonate, I deprotection of the C-33 base, generated II;③II in DMAP catalytic conditions, the o-nitrophenyl activated chloride generated III;④Using chloride lithium as chloride agent, III generated IV;⑤IV in HF acid conditions, deprotection of the C-24 base, obtained the final product V. In addition, II can be Chlorided directly without using activating agent, generated IV.
2.2 According to the latest literature, we found C-24 hydroxy group of FK520 lower activity and it can be conducted without special protection, we have adopted triphenylphosphine-BTC as chlorine agent, triphenylphosphine-NCS as chlorine agent and triphenylphosphine-carbon tetrachloride as chlorine agent, and achieved the desired results. We also made some reasonable improvement to simplify the working steps, to save the cost and to reduce pollution.
Results
1 Successfully separated and obtained the pure FK520 and FK506, the purity of both are greater than 98%.
2 Obtained FK520 derivative pimecrolimus, the 1H-NMR, 13C NMR spectroscopy, mass spectrometry consistent with its structural characteristics.
According to the patent literature, we improved and simplified the response route, and reduce costs; pimecrolimus yield: 42.1%, the purity > 96%, mp 135.2-136.1℃, according to the data above, the product is confirmed to be pimecrolimus.
Conclusion
1 successfully separated the mixture of FK506 and FK520 using silver nitrate silica gel column chromatography. The separation method has good effect, the nature of both are stable, product purity is high.
2 In the preparation of compound pimecrolimus, we have improved the patented process, prepared excellent chloride reagents, tried a variety of new routes, shorted the cycle of reaction, reduced the cost, increased the purity of the product, and researched the best ratio among the raw materials.
3 Researched the HPLC determination of pimecrolimus, and made initial research on isomer, the work has great significance for the futrue research of pimecrolimus.
吡美莫司(pimecrolimus)[商品名]Elidel,为新一代免疫抑制类药物。由瑞士诺华公司开发,于2002年在英国率先上市,主要用做免疫抑制药物和特应性皮炎的治疗药物,其作为抗牛皮癣药物和治疗哮喘药物已进入临床二期试验阶段,作为抗关节炎药物和治疗胃肠道炎症药物即将进入临床试验。吡美莫司是大环内酯类抗菌药物子囊霉素(ascomycin, FK520)的一种衍生物,国内目前尚未有厂家生产,因此,研究该药物的合成方法对新药开发具有一定的应用价值。
目的
1建立从FK506尾液中分离纯化FK506与FK520的方法,得到FK506和FK520的纯品。
2以FK520为原料,建立吡美莫司的制备方法,优化合成工艺。
3初步建立吡美莫司的含量测定方法并对其异构体现象进行初步研究。
方法
1建立了FK506与FK520的分离方法,首先对两者的混合溶液进行粗提,除去混合液中的油状物质和其他杂质;然后采用硝酸银硅胶柱层析法分离得到二者的纯品。
2以FK520为原料,合成目标产物吡美莫司。
2.1①以FK520为原料,采用叔丁基二甲基硅烷基三氟甲烷磺酸酯(TBDMS Trifluoromethanesulfonate)对FK520的C-24和C-33位羟基进行保护,生成Ⅰ;②Ⅰ在对甲基苯磺酸条件下脱去C-33位保护基,生成Ⅱ;③Ⅱ在DMAP催化条件下,经邻硝基苯磺酰氯活化生成Ⅲ;④以氯化锂做氯化试剂,将Ⅲ氯化,生成Ⅳ;⑤Ⅳ在HF酸中水解脱去C-24位保护基,得到目标产物Ⅴ。其中Ⅱ可以不经过活化而直接氯化生成Ⅳ。
2.2我们参阅最新文献,发现FK520 C-24位羟基活性较低,可以不必进行特殊保护直接氯化,我们分别采用了三苯基膦与BTC氯化试剂、三苯基膦与NCS氯化试剂和三苯基膦与四氯化碳氯化试剂,取得了理想的结果,并对工艺进行改进,减少了操作步骤,降低了成本,减少了污染。
3初步建立了吡美莫司的含量测定方法,并初步考察了吡美莫司的异构现象。
结果
1成功分离得到了FK506和FK520的纯品,纯度均大于98%。
2得到了FK520的衍生物吡美莫司,经核磁共振氢谱、核磁共振碳谱、质谱分析符合其结构特征。
对专利文献方法进行了改进,提高了收率,降低了成本;吡美莫司的总收率42.1%,纯度>96%,熔点为135.2-136.1℃,与文献报道相符。
3初步确立了吡美莫司的含量测定方法,初步考察了吡美莫司的异构现象。
结论
1成功分离了FK506和FK520的混合物,所采用的硝酸银硅胶柱层析法分离效果好,两者性质稳定,产品纯度高。
2在吡美莫司的制备中,改进了专利方法,同时制备了优良的氯化试剂,尝试多种新型路线,缩短了反应周期,降低了成本,提高产品纯度,并且研究了反应原料的最佳配比。
3初步建立了吡美莫司HPLC含量测定方法,初步考察了吡美莫司的异构体情况,为吡美莫司的开发打下了一定基础。
Immunosuppressant drugs, also called anti-rejection drugs, are a kind of drug which have immunosuppressive effects. Mainly used to treat the autoimmune diseases and to prevent organ transplant rejection in clinic. The study on immunosuppressive agents abroad, after the success of the first human case between twins with the egg of kidney transplant since 1954, doctors in the study of organ transplant have made a number of major breakthroughs. Since the early 1980s, cyclosporine A (CsA) are used in clinic, organ transplant has made tremendous achievements, FK506 and MMF have been certified by the United States FDA and listed. Immunosuppressants in organ transplant play an increasingly important role; In addition to being used to prevent organ rejection, immunosuppressant drugs are also used to treat such severe skin disorders as psoriasis and such other diseases as rheumatoid arthritis, Crohn's disease (chronic inflammation of the digestive tract) and patchy hair loss (alopecia areata). Some of these conditions are termed "autoimmune" diseases. With the mastering and understanding of the theory of transplantation immunology and molecular biology technology, People discovered and developed many new drugs, some of which have entered clinical trials and evaluation phase. In recent years, domestic scholars are also actively engaged in the research and development of immunosuppressant. However, due to a late start, and the high cost of research and development, at present, only a handful of domestic companies involved, mainly in generic drug abroad.
Pimecrolimus [commodity name] Elidel, a new generation of immunosuppressant drugs developed by Novartis company, and in 2002 the first listing in the United Kingdom. mainly used as immunosuppressive drugs and the treatment of atopic dermatitis, as an antipsoriasis drugs and the treatment of asthma drugs have entered Phase II clinical trial stage, as an anti-arthritis drug and treatment of G1 inflammatory drugs will soon enter clinical trials. Pimecrolimus is a derivative of antibacterials ascomycin (FK520) which belongs to macrolide antibiotic drug, Domestic manufacturers are not yet available, Therefore, the study of the drug synthesis method for the development of new drugs have some value.
Objective
1 Isolation and Purification of the FK506 and FK520 from the end of the FK506, FK506 and FK520 are pure materials.
2 Using FK520 as a raw material, established the preparation methods of pimecrolimus, optimized synthesis process.
3 The HPLC determination of pimecrolimus was researched, made initial research on isomer.
Methods
1 Established a method for isolation of FK520 and FK506, firstly purified the mixed solution of FK520 and FK506, removed the oily mixture of substances and other impurities and then obtained pure FK520 and FK506 using silver nitrate silica gel column chromatography .
2 Using FK520 as a raw material, prepared the target product pimecrolimus.
2.1①The intermediate I was prepared from FK520 by using TBDMS Trifluoromethanesulfonate to protect the C-24 and C-33 hydroxyl.②Under the conditions of the p-toluenesulfonate, I deprotection of the C-33 base, generated II;③II in DMAP catalytic conditions, the o-nitrophenyl activated chloride generated III;④Using chloride lithium as chloride agent, III generated IV;⑤IV in HF acid conditions, deprotection of the C-24 base, obtained the final product V. In addition, II can be Chlorided directly without using activating agent, generated IV.
2.2 According to the latest literature, we found C-24 hydroxy group of FK520 lower activity and it can be conducted without special protection, we have adopted triphenylphosphine-BTC as chlorine agent, triphenylphosphine-NCS as chlorine agent and triphenylphosphine-carbon tetrachloride as chlorine agent, and achieved the desired results. We also made some reasonable improvement to simplify the working steps, to save the cost and to reduce pollution.
Results
1 Successfully separated and obtained the pure FK520 and FK506, the purity of both are greater than 98%.
2 Obtained FK520 derivative pimecrolimus, the 1H-NMR, 13C NMR spectroscopy, mass spectrometry consistent with its structural characteristics.
According to the patent literature, we improved and simplified the response route, and reduce costs; pimecrolimus yield: 42.1%, the purity > 96%, mp 135.2-136.1℃, according to the data above, the product is confirmed to be pimecrolimus.
Conclusion
1 successfully separated the mixture of FK506 and FK520 using silver nitrate silica gel column chromatography. The separation method has good effect, the nature of both are stable, product purity is high.
2 In the preparation of compound pimecrolimus, we have improved the patented process, prepared excellent chloride reagents, tried a variety of new routes, shorted the cycle of reaction, reduced the cost, increased the purity of the product, and researched the best ratio among the raw materials.
3 Researched the HPLC determination of pimecrolimus, and made initial research on isomer, the work has great significance for the futrue research of pimecrolimus.
引文
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29 秦凤华. 雷公藤总甙对细胞免疫应答的抑制作用及抗移植排斥作用[J]. 中国药理学通报, 1994, 10(2): 123
30 邓文龙, 聂仁吉, 刘家玉. 中草药, 1981, 12(8): 22~26
31 邓文龙, 刘家玉, 聂仁吉. 中草药, 1981, 12(10): 26~30
32 万屏, 王红兵, 吕昭萍, 等中国皮肤性病学杂志, 2001, 15(4): 238~239
33 Pirsch JD, Miller J, Deierhoi MH, et al. A comparison of tacrolimus (FK506) and cyclosporine for immunosupper- ssion after cadaveric renal transplantation, FK506 Kidney Transplant Study Group. Transplantation, 1997, 63: 977~983
34 Mayer AD, Dmitrewski J, Squifflet J P, et al. Multicenter randomized trial comparing tacrolimus(FK506) and cyclos- porine in the prevention of renal allograft rejection: a report of the European Tacrolimus Multicenter Renal Study Group. Transplantation , 1997, 64: 436~443
35 Paul LC. The future of new immunosuppressive drugs. Transplant Proc, 1999, 31(Suppl 7A): 16s~18s
36 Sintchak MD, Fleming MA, Futer O, et al. Structure and mechanism of inosin monophosphate dehydrogenase in complex with theimmunosuppressant mycophenolic acid. Cell, 1996, 85: 921~930
37 Anonymous. Frontiers in immunobiology and immunosu- ppression, Proceedings of a symposium, Minneapolis, Minnesota, August 26~27, 1995. Clin Transplant, 1996, 10(1 pt2): 77~145
38 Davis JP, Cain GA, Pitts WJ, et al. The immunosuppres- sive metabolite of leflunomide is a potent inhibitor of human dihydroorotate dehydrogenase Biochemistry, 1996, 35: 1270~1273
39 Kahan BD. Renaissance of immunosuppressive therapy in the new millennium. Transplant Proc, 1998, 30: 2493~ 2496
40 Kaplan B, Meier Kriesche HU, Napoli KL, et al. The effects of relative timing of sirolimus and cyclosporine microemulsion formulation coadministration on the pharmacokinetics of each agent. Clin Pharmacol Ther, 1998, 63: 48~53
41 Nashan B, Moore R, Amlot P, et al. Randomised trial of basiliximab versus placebo for control of acute cellular rejection in renal allograft recipients, CHIB 201 Internatio- nal Study Group. Lancet, 1997, 350: 1193~1198
42 Yanagawa Y, Hoshino Y, Kataoka H, et al. FTY-720, anovelimmunosuppressant, prolongs rat skin allograft survival by decreasing T-cell infiltration into grafts. Transplant Proc, 1999, 31: 1227~1229
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27 李志杰, 李辰. 雷公藤多甙防治角膜移植免疫排斥反应的实验研究[J]. 眼科研究, 1996, 14(2): 76~78
28 吴京. 雷公藤对异位角膜移植抗排斥反应的研究[J]. 眼科新进展, 1998, 18(2): 63
29 秦凤华. 雷公藤总甙对细胞免疫应答的抑制作用及抗移植排斥作用[J]. 中国药理学通报, 1994, 10(2): 123
30 邓文龙, 聂仁吉, 刘家玉. 中草药, 1981, 12(8): 22~26
31 邓文龙, 刘家玉, 聂仁吉. 中草药, 1981, 12(10): 26~30
32 万屏, 王红兵, 吕昭萍, 等中国皮肤性病学杂志, 2001, 15(4): 238~239
33 Pirsch JD, Miller J, Deierhoi MH, et al. A comparison of tacrolimus (FK506) and cyclosporine for immunosupper- ssion after cadaveric renal transplantation, FK506 Kidney Transplant Study Group. Transplantation, 1997, 63: 977~983
34 Mayer AD, Dmitrewski J, Squifflet J P, et al. Multicenter randomized trial comparing tacrolimus(FK506) and cyclos- porine in the prevention of renal allograft rejection: a report of the European Tacrolimus Multicenter Renal Study Group. Transplantation , 1997, 64: 436~443
35 Paul LC. The future of new immunosuppressive drugs. Transplant Proc, 1999, 31(Suppl 7A): 16s~18s
36 Sintchak MD, Fleming MA, Futer O, et al. Structure and mechanism of inosin monophosphate dehydrogenase in complex with theimmunosuppressant mycophenolic acid. Cell, 1996, 85: 921~930
37 Anonymous. Frontiers in immunobiology and immunosu- ppression, Proceedings of a symposium, Minneapolis, Minnesota, August 26~27, 1995. Clin Transplant, 1996, 10(1 pt2): 77~145
38 Davis JP, Cain GA, Pitts WJ, et al. The immunosuppres- sive metabolite of leflunomide is a potent inhibitor of human dihydroorotate dehydrogenase Biochemistry, 1996, 35: 1270~1273
39 Kahan BD. Renaissance of immunosuppressive therapy in the new millennium. Transplant Proc, 1998, 30: 2493~ 2496
40 Kaplan B, Meier Kriesche HU, Napoli KL, et al. The effects of relative timing of sirolimus and cyclosporine microemulsion formulation coadministration on the pharmacokinetics of each agent. Clin Pharmacol Ther, 1998, 63: 48~53
41 Nashan B, Moore R, Amlot P, et al. Randomised trial of basiliximab versus placebo for control of acute cellular rejection in renal allograft recipients, CHIB 201 Internatio- nal Study Group. Lancet, 1997, 350: 1193~1198
42 Yanagawa Y, Hoshino Y, Kataoka H, et al. FTY-720, anovelimmunosuppressant, prolongs rat skin allograft survival by decreasing T-cell infiltration into grafts. Transplant Proc, 1999, 31: 1227~1229
43 李晓玉. 免疫调节药. 见: 杨藻宸, 姚明辉. 医用药理学[M].第 4 版. 北京: 人民卫生出版社, 2005, 352~366