麦角钙化醇类似物的合成研究
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摘要
1981年,日本科学家首次证实活性麦角钙化醇类似物具有诱导细胞分化和抑制细胞增殖的功能活性钙化醇受体,其不仅存在于小肠、骨胳和肾脏,还存在于人体的各种组织以及各种癌细胞中。如今,麦角钙化醇类药物可作用于多种靶组织,生理作用也多种多样,因此,广泛用于治疗骨质疏松、甲状旁腺亢进(肾衰)、牛皮癣、癌症以及免疫疾病等。然而,由于麦角钙化醇类药物在治疗中常常引起高钙血症和高磷血症,使其应用受到了限制,而19位缺失的麦角钙化醇化合物在动物实验及临床研究中显示具有相对选择性的药理作用,能安全有效地抑制甲状旁腺激素的分泌及甲状旁腺的增生而很少引起高钙血症和高磷血症,本论文在合成阿法骨化醇,度骨化醇,19-nor麦角钙化醇的基础上,初步合成了化合物la-OH-19-nor麦角钙化醇,并对合成中的关键反应进行了研究。
1.合成了阿法骨化醇,并且以麦角钙化醇为原料,与合成阿法骨化醇相似的方法合成了度骨化醇。
2.用高锰酸钾双羟基化的方法合成了19-nor麦角钙化醇,以此为模式反应,在生成3,5环合麦角钙化醇后,通过烯丙位氧化,生成1a-OH,后经过酯保护,再加入高锰酸钾氧化生成二醇,用四醋酸铅代替高碘酸钠生成la-OAc-10-oxo化合物,其后反应与19-nor麦角钙化醇相类似,初步得到目标产物粗品,合成路线复杂,且收率较低。我们又尝试在生成10-oxo麦角钙化醇后,通过Triflating Reagent生成了10-OTf-1-烯麦角钙化醇,经醋酸钯还原,用9-BBN进行硼羟基化,生成了1a-OH化合物,最后通过水解来得到目标产物。
3.在对3,5环合麦角钙化醇双羟化研究中,通过大量试验,使用高锰酸钾代替剧毒且昂贵的四氧化锇作为氧化剂,取得了较好的效果。
4.分别考察了2,6-二甲基吡啶(2,6-Lutidine)、氢化钠(Sodium Hydride)二异丙基胺基锂(LDA)、六甲基二硅基胺基锂(LiHMDS)等作为强碱用于10-oxo-3,5环合麦角钙化醇反应中,初步确定该反应中使用LiHMDS作为强碱副产物少,产率高。
In the past, people think the analogues of ergocalciferol were only nutrient that regulated the balance of calcium metabolism; in 1981, Japanese scientists confirmed that analogues of ergocalciferol had the function that inducted cell differentiation and cell proliferation. Analogues of ergocalciferol receptor, not only exists in small intestine, bone and kidney, but also in various organizations as well as a variety of human cancer cells. Today, the drugs of ergocalciferol analogues can target tissue, physiological role is diversity, it is widely used to treat osteoporosis, parathyroid (ARF), psoriasis, cancer and immune diseases. However, Because ergocalciferol analogues in the treatment of hypercalcemia often lead to hypercalcemia and hyperphosphatemia, its application was limited, and 19-methylene missing ergocalciferol analogues compounds in animal experiments and clinical studies have shown the pharmacological effects of relatively selective were safe and effective for its inhibition the secretion of parathyroid hormone and parathyroid gland hyperplasia and rarely cause hypercalcemia and hyperphosphatemia.
This paper concentrates on studing the synthesis of ergocalciferol analogues and the key steps of synthesis. New 19-nor ergocalciferol analogues were synthesized by two routines, The content included as following:
1. Using similar synthetic method, alfacalcidol and doxercalciferol were synthesized.
2. As a model reaction,19-nor ergocalciferol was synthesized. After the synthesis of 3, 5-cycle ergocalciferol, la-OH formed by allylic oxidation, protected through ester, then used potassium permanganate oxidation to generate diol, with lead tetraacetate instead of sodium periodate generated la-OAc-10-oxo compound, followed by reaction with similar to 19-nor ergocalciferol, final crude product was obtained. This route was complex, low yield. Therefore, we attempted another synthesis, starting from 10-oxo ergocalciferol, by triflating reagent to obtain 10-OTf-l-alene ergotcalciferol, reduced to get 1-alene ergotcalciferol by Pd(OAc)2, then by 9-BBN to obtain la-OH compound, and finally through the hydrolysis method to get target product.
3. On the research of dihydroxylation of the 3,5-cycle ergocalciferol, we employed potassium permanganate as the oxidant instead of osmium tetroxide which is toxic and expensive, and achieved good and similar result.
4. Respectively investigated the synthesis condition on the triflate of 10-oxo-3,5-cycle ergocalciferol by employing different alkali including 2,6-Lutidine、Sodium Hydride、LDA、LiHMDS, experiment showed the best reagent was LiHMDS, it got the less by-product and higher yield.
1.合成了阿法骨化醇,并且以麦角钙化醇为原料,与合成阿法骨化醇相似的方法合成了度骨化醇。
2.用高锰酸钾双羟基化的方法合成了19-nor麦角钙化醇,以此为模式反应,在生成3,5环合麦角钙化醇后,通过烯丙位氧化,生成1a-OH,后经过酯保护,再加入高锰酸钾氧化生成二醇,用四醋酸铅代替高碘酸钠生成la-OAc-10-oxo化合物,其后反应与19-nor麦角钙化醇相类似,初步得到目标产物粗品,合成路线复杂,且收率较低。我们又尝试在生成10-oxo麦角钙化醇后,通过Triflating Reagent生成了10-OTf-1-烯麦角钙化醇,经醋酸钯还原,用9-BBN进行硼羟基化,生成了1a-OH化合物,最后通过水解来得到目标产物。
3.在对3,5环合麦角钙化醇双羟化研究中,通过大量试验,使用高锰酸钾代替剧毒且昂贵的四氧化锇作为氧化剂,取得了较好的效果。
4.分别考察了2,6-二甲基吡啶(2,6-Lutidine)、氢化钠(Sodium Hydride)二异丙基胺基锂(LDA)、六甲基二硅基胺基锂(LiHMDS)等作为强碱用于10-oxo-3,5环合麦角钙化醇反应中,初步确定该反应中使用LiHMDS作为强碱副产物少,产率高。
In the past, people think the analogues of ergocalciferol were only nutrient that regulated the balance of calcium metabolism; in 1981, Japanese scientists confirmed that analogues of ergocalciferol had the function that inducted cell differentiation and cell proliferation. Analogues of ergocalciferol receptor, not only exists in small intestine, bone and kidney, but also in various organizations as well as a variety of human cancer cells. Today, the drugs of ergocalciferol analogues can target tissue, physiological role is diversity, it is widely used to treat osteoporosis, parathyroid (ARF), psoriasis, cancer and immune diseases. However, Because ergocalciferol analogues in the treatment of hypercalcemia often lead to hypercalcemia and hyperphosphatemia, its application was limited, and 19-methylene missing ergocalciferol analogues compounds in animal experiments and clinical studies have shown the pharmacological effects of relatively selective were safe and effective for its inhibition the secretion of parathyroid hormone and parathyroid gland hyperplasia and rarely cause hypercalcemia and hyperphosphatemia.
This paper concentrates on studing the synthesis of ergocalciferol analogues and the key steps of synthesis. New 19-nor ergocalciferol analogues were synthesized by two routines, The content included as following:
1. Using similar synthetic method, alfacalcidol and doxercalciferol were synthesized.
2. As a model reaction,19-nor ergocalciferol was synthesized. After the synthesis of 3, 5-cycle ergocalciferol, la-OH formed by allylic oxidation, protected through ester, then used potassium permanganate oxidation to generate diol, with lead tetraacetate instead of sodium periodate generated la-OAc-10-oxo compound, followed by reaction with similar to 19-nor ergocalciferol, final crude product was obtained. This route was complex, low yield. Therefore, we attempted another synthesis, starting from 10-oxo ergocalciferol, by triflating reagent to obtain 10-OTf-l-alene ergotcalciferol, reduced to get 1-alene ergotcalciferol by Pd(OAc)2, then by 9-BBN to obtain la-OH compound, and finally through the hydrolysis method to get target product.
3. On the research of dihydroxylation of the 3,5-cycle ergocalciferol, we employed potassium permanganate as the oxidant instead of osmium tetroxide which is toxic and expensive, and achieved good and similar result.
4. Respectively investigated the synthesis condition on the triflate of 10-oxo-3,5-cycle ergocalciferol by employing different alkali including 2,6-Lutidine、Sodium Hydride、LDA、LiHMDS, experiment showed the best reagent was LiHMDS, it got the less by-product and higher yield.
引文
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[2]Hussein MR. Ult raviolet radiation and skin cancer: molecular mechanisms [J]. J Cutan Pat hol,2005,32(3):191-205.
[3]Robyn BL, Mike HR,Ant hony JM. Is the current public health message on UV exposure correct [J]. Bulletin of the World Health Organization,2006,84(4):485-491.
[4]杨春华.维生素D简介[J].中国实用医药,2009,4(3):243-244.
[5]彭雯,唐伟,刘超.维生素D对胰岛p细胞功能及胰岛素敏感性的影响[J].国际内科学杂志,2008,35(6)：333-336.
[6]杨宽民,蒋宗勇.维生素D生物功能的新进展[J].广东畜牧兽医科技,2009,34(4):8-10.
[7]Bikle D. Nonclassicactions of vitamin D[J]. ClinEndocrinol Metab,2009,94(1):26-34. [8] Ustianowski A, Shaffer R, Collin S, etal. Prevalence and associations of vitamin D deficiency in foreign-born persons with tuber culosisin London[J]. J Infect,2005,(50): 432-437.
[9]Luciano A, Giuseppe Penna. Control of autoimmune Diseases by the vitamin D endocrine system[J]. Nature Clinical Practice Rheumatology,2008,(4):404-412.
[10]周文娣,张佩斌.维生素D受体及维生素D作用进展[J].中国儿童保健杂志,2008,16(5)：560-562.
[11]蒋艳敏,张克勤.维生素D在糖尿病发病机制中的作用[J].医学研究生学报,2007,20(11)：1202-1205.
[12]Gregori S, Giarratana N, Smiroldo S, et al. A lα,25-Dihydroxyvitamin D3 analog enhances regulatory T2 Cells and arrests autoimmune diabetes in NOD mice[J]. Diabetes, 2002,51(5):1367-1374.
[13]阙凤连,黄国良.维生素D与2型糖尿病[J].中国现代医生,2008,46(11):32-34.
[14]杜平.降钙素联合骨化三醇治疗骨质疏松症的疗效观察[J].实用临床医学,2006,7(9)：60-61.
[15]Zinser GM, McEleney K, Welsh J. Characterization of mammary tumor cell lines from wild type and vitamin D3 receptor knockoutmice[J]. Mol Cell Endocrinol,2003,200 (122):67-80.
[16]Song LN. J Steroid. Biochem Mol Biol [J].1996,57:267.
[17]黄玫,杜娟.阿法骨化醇对老年慢性肾衰血液透析患者血清PTH的影响及意义[J].中 国老年学杂志,2009,29:1637-1638.
[18]易伟.阿法骨化醇联合碳酸钙治疗血液透析患者继发甲状旁腺功能亢进的临床观察[J].实用临床医学,2009,10(10):23-24.
[19]杨舜娟,甘惠贞,黄晓梅.阿法骨化醇治疗肾性佝偻病1例疗效观察[J].基层医学论坛,2009,13(35)：1158.
[20]陈阳生,李明娟.骨化三醇的分离及结构测定[J].中国医疗前沿,2009,4(3):105-106.
[21]曾芍,苏玉文,严开林.维生素D受体与肿瘤的研究进展[J].实用预防医学,2007,14(3)：957-959.
[22]Cozzolino M, Brancaccio D. Emerging role for the vitamin D receptor activator (VDRA), paricalcitol, in the treatment of secondary hyperparathyroidism[J]. Expert Opinion on Pharmacotherapy,2008,9(6):947-954.
[23]Rameshraja Palaparthy, Rajendra S. Pradhan, Jenny Chan, et al. Effect of Omeprazole on the Pharmacokinetics of Paricalcitol in Healthy Subjects[J]. Biopharm Drug Dispos, 2007,28(3):65-71.
[24]George R, Bailie, Curtis A, et al. Comparative Review of the Pharmacokinetics of Vitamin D Analogues[J]. Seminars in Dialysis,2002,15(5):352-357.
[25]郑秉杰,范亚平Paricalcitol治疗尿毒症继发性甲状旁腺功能亢进[J].国外医学泌尿系统分册,2003,23(4):435-437.
[26]Martin KJ, Gonzalez EA, Gellens M, et al.19-Nor-la,25-dihydroxyvitamin D2 (paricalcitol) safely and effectively reduces the levels of intact parathyroid hormone in patients on hemodialysis[J]. J Am Soc Nephrol,1998,9(14):27-32.
[27]Istvan Molnar, Timothy Kute, Mark C. Willingham,etal.19-Nor-1a,25dihydroxy-vitamin D2 (paricalcitol):effects on clonal proliferation, differentiation, and apoptosis in human leukemic cell lines[J]. J Cancer Res Clin Oncol,2003,129(2):35-42.
[28]Alagbala AA, Johnson CS. Antitumor Effects of Two Less-Calcemic Vitamin D Analogs (Paricalcitol and QW-1624F2-2) in Squamous Cell Carcinoma Cells[J]. Oncology,2006, 70(1):483-492.
[29]Tai C, Chen Michael F. Evaluation of Vitamin D Analogs as Therapeutic Agents for Prostate Cancer[J]. Recent Results in Cancer Research,2003,164(4):273-288.
[30]陈阳生,任莉,翟翠云.阿法骨化醇合成的新方法[J].中国新药杂志,2005,14(12):1441-1443.
[31]Moriarty RM, Penmasta RA, Guo L, et al. SYNTHESIS OF la-HYDROXY VITAMIN D:US,5869472[P].1999-02-09.
[32]陈阳生,翟翠云,任莉.骨化三醇的合成[J].中国新药杂志,2005,14(1):69-72.
[33]Chze Siong Ng, Ching-Peng Wei. PROCESS FOR PREPARATION OF PARICALCITOL AND INTERMEDIATES THEREOF:US,7491712 B1[P].2009-02-17.
[34]Hector F. Deluca, Heinrich K. Schnoes. et al.19-NOR VITAMIN D COMPOUNDS: US,5710294[P].1998-01-20.
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