CN113801104B - 一种依维莫司大环内酯水解杂质的制备方法 - Google Patents
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Abstract
本发明属于医药化工领域,具体涉及一种依维莫司大环内酯水解杂质的制备方法。本发明提供的依维莫司水解杂质的制备方法包括:将依维莫司即42‑O‑(2‑羟基)乙基雷帕霉素溶于有机溶剂,加入酸或碱,得到开环水解杂质。本发明提供的合成方法路线短,操作简单所得依维莫司杂质收率高,纯度高该杂质化合物可作为依维莫司成品检测标准中的杂质对照。
Description
技术领域
本发明属于医药化工领域,具体涉及一种依维莫司大环内酯水解杂质的制备方法。
背景技术
依维莫司(Everolimus)是诺华(Novartis)公司研发的新一代的大环内酯类免疫抑制剂及抗肿瘤药物,其由雷帕霉素的42-OH衍生为42-O-(2-羟乙基)而成,故依维莫司又称42-O-(2-羟乙基)-雷帕霉素。主要适用于舒尼替尼(sunitinib)或索拉非尼(sorafenib)治疗失败后晚期肾癌细胞癌患者的治疗,结构式如下:
美国专利US5665772最早报道了依维莫司及其合成工艺。该方法以雷帕霉素为原料经两步反应得到依维莫司:先将雷帕霉素与三氟甲磺酸2-(叔丁基二甲基硅氧基)乙酯在甲苯中且在2,6-二甲基吡啶存在下反应得到中间体,再脱保护基到目标产物。但是该方法中第一步反应收率仅有5~15%,大部分原料未转化;第二步反应又极易产生降解产物及异构化,所得产物纯度较低,并不适合于放大生产。
中国专利申请CN105254646、CN1038448849、CN1402731及国际申请WO0123395等进一步优化依维莫司合成工艺,结合已有的相关专利文献,比较好的合成路线主要是以31位单保护西罗莫司在碱性条件下与单保护的乙二醇单三氟甲磺酸酯反应合成中间体,再酸性条件下脱保护从而得到依维莫司:
但按照此工艺方法,发现有大量大环内脂脱水开环的降解杂质产生:
药物的质量是衡量药物品质的一个重要标准,药物的质量标准对药物有效成分的纯度和杂质的限度都有较为严格的规定,一般而言,超过0.1%的药物杂质应通过选择性方法来鉴定并定量,对于药物研发人员来说,开发高效的杂质合成路线定向合成工艺中所产生的杂质,以便获得杂质对照品,保证每批原料药质量检测工作的开展(如,杂质HPLC定位、杂质含量测定等)也是十分重要的工作。
目前对于依维莫司该脱水杂质的制备方法未见文献报道,文献Studies on thechemistry of rapamycin:Novel transforma-tionnsunder Lewis-Acid Catalysis[J].Tetrahedron Letters,1993,34,6:991-994.中有报道西罗莫司开环水解产物的有关合成方法,是以西罗莫司为原料,溶于四氢呋喃中降温至-10℃~0℃,加入DBU后搅拌反应,再用酸处理反应液制备纯化得到目标产物。但按照其报道的方法在制备依维莫司开环杂质时得到45%分子量为591.34的化合物,经分析判断,在DBU作用脱水完全得如下结构杂质化合物:
因此,为依维莫司开环脱水杂质探究一条操作简单、高效、低成本、高质量的合成工艺是目前需要解决的问题。
发明内容
为优化依维莫司合成工艺,明确依维莫司合成过程中生成的杂质及质量研究,本发明涉及了一种依维莫司开环脱水杂质及其制备方法,该方法反应条件温和、路线短、操作简单,可以高收率、高纯度、定向的合成目标杂质化合物,该杂质化合物可作为依维莫司检测标准中的杂质对照品,用于依维莫司生产过程中的杂质定性及定量分析的质量控制环节。
本发明具体通过如下技术方案实现:
一种依维莫司开环水解杂质的制备方法,包括如下步骤:室温下,将依维莫司即42-O-(2-羟基)乙基雷帕霉素溶于有机溶剂,加入催化剂,得到目标化合物。
优选方案,所述的催化剂可以为酸或者碱的水溶液,其中所述酸可以选自盐酸、硫酸、冰醋酸中的一种或其组合;碱可以选氢氧化钠、氢氧化钾、氢氧化锂、碳酸钠中的一种或其组合,其中特别优选氢氧化钠。
优选方案,所述的酸的浓度为0.08mol/L~0.12mol/L,其中特别优选0.1mol/L。
优选方案,所述的碱的浓度为0.8mol/L~1.5mol/L,其中特别优选1.0mol/L。
优选方案,所述的依维莫司、催化剂的投料摩尔比为1:1.0~1.5,其中特别优1:1.2。
优选方案,所述的有机溶剂为四氢呋喃、甲醇、乙醇、二氯甲烷、乙腈、二氧六环中的一种或其组合,其中特别优选四氢呋喃。
在一优选方案中,反应结束后需进行后处理操作,具体的为:以酸为催化剂:反应完毕后向反应液加入二氯甲烷,震荡摇匀,合并后浓缩有机层,经柱纯化(洗脱剂开始用乙酸乙酯:石油醚=1:1,小极性杂质洗脱完毕后,改用乙酸乙酯洗脱)得依维莫司开环脱水杂质;
以碱为催化剂:反应完毕后调节反应液pH=6~7,向反应液加入去离子水和二氯甲烷,搅拌分液,浓缩有机层得依维莫司开环脱水杂质。
与现有技术相比,本发明取得的技术效果是:
1、本发明提供了一种制备依维莫司开环水解杂质的新方法,通过控制催化剂酸或碱的浓度,既可以避免水解过度而生成其他开环杂质,又可以避开现有类似工艺苛刻的反应条件,整个合成方法路线短,操作步骤简单,反应收率高,产品纯度高。
2、提供了一种高纯度的依维莫司开环水解杂质化合物,其可作为杂质对照品,用于生产过程中的依维莫司的质量控制。
具体实施方式
下面通过实施例来进一步说明本发明。应该正确理解的是:本发明的实施例仅仅是用于说明本发明,而不是对本发明的限制,所以,在本发明的方法前提下对本发明的简单改进均属本发明要求保护的范围。
对本发明得到的新化合物结构确证:
化合物I结构表征
化合物I的高分辨质谱:ESI-HRMS:m/z=975.57[M+NH4]+;1H-NMR(400MHz,DMSO-d6):0.60(d,J=11.6Hz,1H),0.78(d,J=6.4Hz,3H),0.83(d,J=6.8Hz,3H),0.87(d,J=6.4Hz,3H),0.91(d,J=6.8Hz,3H),0.98~1.04(m,6H),1.06~1.11(m,3H),1.33~1.39(m,4H),1.44~1.53(m,2H),1.60~1.72(m,10H),1.85(s,3H),1.93~2.06(m,4H),2.10~2.14(m,2H),2.21~2.26(m,1H),2.39~2.45(m,2H),3.00~3.04(m,1H),3.12(s,3H),3.16~3.20(m,1H),3.27(s,3H),3.31~3.35(m,1H),3.42(s,4H),3.47~3.53(m,2H),3.59~3.64(m,2H),3.73~3.76(m,1H).3.92~3.93(m,1H),4.06(t,J=6.8Hz,2H),4.51(t,J=5.6Hz,1H),4.66(d,J=4.8Hz,1H),4.94~4.97(m,1H),5.16(d,J=8Hz,1H),5.31(d,J=4.8Hz,1H),5.48~5.52(m,1H),5.99~6.11(m,3H),6.21(d,J=6.8Hz,1H),6.34~6.39(m,1H),6.48(s,1H),6.93(d,J=6.8Hz,1H);13C-NMR(100MHz,DMSO-d6):9.99,13.1,13.2,13.9,14.7,15.4,20.5,21.8,23.9,26.2,26.3,29.1,29.8,31.1,32.4,33.6,34.9,35.5,36.7,38.8,39.1,39.5,42.9,46.0,51.7,54.4,57.3,57.4,60.7,60.9,67.1,71.8,82.2,82.2,82.4,86.5,101.0,119.9,125.3,130.8,131.2,132.4,138.2,138.3,141.3,173.1,180.3,198.6,198.8,212.1.
实施例1
室温下,将化合物42-O-(2-羟基)乙基雷帕霉素(10.00g,0.01mol)加入50mL四氢呋喃中搅拌溶解,溶清后滴加NaOH溶液(12.0mL,0.012mol,1mol/L),滴毕搅拌反应1h,反应完毕后将反应液调节pH=6~7,向反应液加入50mL去离子水和50mL二氯甲烷,震荡摇匀,合并后浓缩有机层,干燥后得依维莫司开环脱水杂质,收率98.7%,HPLC纯度99.88%。
实施例2
室温下,将化合物42-O-(2-羟基)乙基雷帕霉素(10.00g,0.01mol)加入50mL二氯甲烷中搅拌溶解,溶清后滴加NaOH溶液(10.0mL,0.01mol,1mol/L),滴毕搅拌反应1h,反应完毕后将反应液调节pH=6~7,向反应液加入50mL去离子水和50mL二氯甲烷,震荡摇匀,合并后浓缩有机层,干燥后得依维莫司开环脱水杂质,收率94.7%,HPLC纯度99.76%。
实施例3
室温下,将化合物42-O-(2-羟基)乙基雷帕霉素(10.00g,0.01mol)加入50mL甲醇中搅拌溶解,溶清后滴加NaOH溶液(15.0mL,0.015mol,1mol/L),滴毕搅拌反应1h,反应完毕后将反应液调节pH=6~7,向反应液加入50mL去离子水和50mL二氯甲烷,震荡摇匀,合并后浓缩有机层,干燥后得依维莫司开环脱水杂质,收率92.1%,HPLC纯度99.69%。
实施例4
室温下,将化合物42-O-(2-羟基)乙基雷帕霉素(10.00g,0.01mol)加入50mL乙腈中搅拌溶解,溶清后滴加NaOH溶液(17.0mL,0.017mol,1mol/L),滴毕搅拌反应1h,反应完毕后将反应液调节pH=6~7,向反应液加入50mL去离子水和50mL二氯甲烷,震荡摇匀,合并后浓缩有机层,干燥后得依维莫司开环脱水杂质,收率85.1%,HPLC纯度98.20%。
实施例5
室温下,将化合物42-O-(2-羟基)乙基雷帕霉素(10.00g,0.01mol)加入50mL四氢呋喃中搅拌溶解,溶清后滴加HCl溶液(100.0mL,0.01mol,0.1mol/L),滴毕搅拌反应1.5h,反应完毕后向反应液加入50mL二氯甲烷,震荡摇匀,合并后浓缩有机层,经柱纯化(洗脱剂开始用乙酸乙酯:石油醚=1:1,小极性杂质洗脱完毕后,改用乙酸乙酯洗脱)得依维莫司开环脱水杂质,收率95.2%,HPLC纯度99.89%。
实施例6
室温下,将化合物42-O-(2-羟基)乙基雷帕霉素(10.00g,0.01mol)加入50mL四氢呋喃中搅拌溶解,溶清后滴加HCl(150.0mL,0.015mol,0.1mol/L),滴毕搅拌反应1.5h,反应完毕后向反应液加入50mL二氯甲烷,震荡摇匀,合并后浓缩有机层,经柱纯化(洗脱剂开始用乙酸乙酯:石油醚=1:1,小极性杂质洗脱完毕后,改用乙酸乙酯洗脱)得依维莫司开环脱水杂质,收率90.3%,HPLC纯度98.96%。
实施例7
室温下,将化合物42-O-(2-羟基)乙基雷帕霉素(10.00g,0.01mol)加入50mL四氢呋喃中搅拌溶解,溶清后滴加HCl(180.0mL,0.018mol,0.1mol/L),滴毕搅拌反应1.5h,反应完毕后向反应液加入50mL二氯甲烷,震荡摇匀,合并后浓缩有机层,经柱纯化(洗脱剂开始用乙酸乙酯:石油醚=1:1,小极性杂质洗脱完毕后,改用乙酸乙酯洗脱)得依维莫司开环脱水杂质,收率75.8%,HPLC纯度89.66%。
实施例8
室温下,将化合物42-O-(2-羟基)乙基雷帕霉素(10.00g,0.01mol)加入50mL四氢呋喃中搅拌溶解,溶清后滴加KOH溶液(15.0mL,0.012mol,0.8mol/L),滴毕搅拌反应1h,反应完毕后将反应液调节PH=6~7,向反应液加入50mL去离子水和50mL二氯甲烷,震荡摇匀,合并后浓缩有机层,干燥后得依维莫司开环脱水杂质,收率94.4%,HPLC纯度99.75%。
实施例9
室温下,将化合物42-O-(2-羟基)乙基雷帕霉素(10.00g,0.01mol)加入50mL四氢呋喃中搅拌溶解,溶清后滴加K2CO3溶液(8.0mL,0.012mol,1.5mol/L),滴毕搅拌反应1h,反应完毕后将反应液调节PH=6~7,向反应液加入50mL去离子水和50mL二氯甲烷,震荡摇匀,合并后浓缩有机层,干燥后得依维莫司开环脱水杂质,收率87.4%,HPLC纯度98.55%。
实施例10
室温下,将化合物42-O-(2-羟基)乙基雷帕霉素(10.00g,0.01mol)加入50mL二氧六环中搅拌溶解,溶清后滴加LiOH溶液(24.0mL,0.012mol,0.5mol/L),滴毕搅拌反应1h,反应完毕后将反应液调节PH=6~7,向反应液加入50mL去离子水和50mL二氯甲烷,震荡摇匀,合并后浓缩有机层,干燥后得依维莫司开环脱水杂质,收率83.8%,HPLC纯度95.45%。
实施例11
室温下,将化合物42-O-(2-羟基)乙基雷帕霉素(10.00g,0.01mol)加入50mL四氢呋喃中搅拌溶解,溶清后滴加LiOH溶液(6.7mL,0.012mol,1.8mol/L),滴毕搅拌反应1h,反应完毕后将反应液调节PH=6~7,向反应液加入50mL去离子水和50mL二氯甲烷,震荡摇匀,合并后浓缩有机层,干燥后得依维莫司开环脱水杂质,收率78.6%,HPLC纯度85.32%。
实施例12
室温下,将化合物42-O-(2-羟基)乙基雷帕霉素(10.00g,0.01mol)加入50mL四氢呋喃中搅拌溶解,溶清后滴加HCl(150.0mL,0.012mol,0.08mol/L),滴毕搅拌反应1h,反应完毕后向反应液加入50mL二氯甲烷,震荡摇匀,合并后浓缩有机层,经柱纯化(洗脱剂开始用乙酸乙酯:石油醚=1:1,小极性杂质洗脱完毕后,改用乙酸乙酯洗脱)得依维莫司开环脱水杂质,收率90.3%,HPLC纯度99.43%。
实施例13
室温下,将化合物42-O-(2-羟基)乙基雷帕霉素(10.00g,0.01mol)加入50mL四氢呋喃中搅拌溶解,溶清后滴加HCl(100.0mL,0.012mol,0.12mol/L),滴毕搅拌反应1h,反应完毕后向反应液加入50mL二氯甲烷,震荡摇匀,合并后浓缩有机层,经柱纯化(洗脱剂开始用乙酸乙酯:石油醚=1:1,小极性杂质洗脱完毕后,改用乙酸乙酯洗脱)得依维莫司开环脱水杂质,收率79.5%,HPLC纯度98.21%。
实施例14
室温下,将化合物42-O-(2-羟基)乙基雷帕霉素(10.00g,0.01mol)加入50mL四氢呋喃中搅拌溶解,溶清后滴加硫酸(240.0mL,0.012mol,0.05mol/L),滴毕搅拌反应1h,反应完毕后向反应液加入50mL二氯甲烷,震荡摇匀,合并后浓缩有机层,干燥后得依维莫司开环脱水杂质,收率75.5%,HPLC纯度87.78%。
实施例15
室温下,将化合物42-O-(2-羟基)乙基雷帕霉素(10.00g,0.01mol)加入50mL四氢呋喃中搅拌溶解,溶清后滴加冰醋酸(80.0mL,0.012mol,0.15mol/L),滴毕搅拌反应1h,反应完毕后向反应液加入50mL去离子水和50mL二氯甲烷,震荡摇匀,合并后浓缩有机层,干燥后得依维莫司开环脱水杂质,收率63.2%,HPLC纯度75.23%。
对比实施例
室温下,将化合物42-O-(2-羟基)乙基雷帕霉素(10.00g,0.01mol)加入50mL四氢呋喃中搅拌溶解,溶清后加DBU(1.83g,0.012mol),滴毕搅拌反应1h,向反应液加入50mL去离子水和50mL二氯甲烷,震荡摇匀,合并后浓缩有机层,干燥后得依维莫司开环脱水杂质,收率55.7%,HPLC纯度72.88%。
Claims (1)
1.一种依维莫司大环内酯水解杂质的制备方法,其特征在于,在催化剂作用下依维莫司酯基脱水成羧酸得到目标化合物,制备方法包括如下步骤:室温下将化合物42-O-(2-羟基)乙基雷帕霉素加入有机溶剂中溶解,加入催化剂,搅拌反应得依维莫司开环脱水杂质,其合成路线如下:
,
所述的催化剂为酸或者碱的水溶液,其中所述酸选自盐酸、硫酸、冰醋酸中的一种;碱选自氢氧化钠、氢氧化钾、氢氧化锂、碳酸钠中的一种;
所述酸的浓度为0.08mol/L~0.12mol/L;
所述的碱的浓度为0.8~1.5mol/L;
所述的依维莫司、催化剂的投料摩尔比为1:1.0~1.5;
所述的有机溶剂为四氢呋喃、甲醇、乙醇、二氯甲烷、乙腈、二氧六环中的一种或其组合。
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