CN114671890B - 一种高效稳定的依维莫司制备方法 - Google Patents
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Abstract
本发明属于医药化工领域,具体涉及一种高效稳定的依维莫司制备方法。本发明以西罗莫司为起始原料,通过固体酸催化剂直接将西罗莫司与乙二醇缩合得到依维莫司。该方法使用了固体酸催化剂可以选择性活化西罗莫司42位羟基,而31位羟基不发生反应,转化率更高,工艺条件更温和,操作步骤更简便,成本更低,可得到高收率的产品,更适合工业放大。
Description
技术领域
本发明属于医药化工领域,具体涉及一种高效稳定的依维莫司制备方法。
背景技术
依维莫司(everolimus,figure1,RAD-001),是由瑞士诺华公司(Novartis)最先研制开发的一种mTOR抑制剂,为雷帕霉素的40-O-(2-羟乙基)衍生物。其作用机理为:依维莫司是一种mTOR的抑制剂(雷帕霉素哺乳动物靶点),PI3K/AKT通路下游的一种丝氨酸苏氨酸激酶。在几种人癌中mTOR失调控。依维莫司结合至细胞内蛋白,FKBP-12,导致一种抑制剂性复合物形成和mTOR激酶活性的抑制。依维莫司减低S6核糖体蛋白激酶(S6K1)的活性和真核生物延伸因子4E-结合蛋白(4E-BP),mTOR的下游效应器,涉及蛋白质合成。此外,依维莫司抑制缺氧-可诱导因子的表达(如,HIF-1)和减低血管内皮生长因子(VEGF)的表达。在体外和/或体内研究中通过依维莫司mTOR的抑制作用曾显示减低细胞增殖,血管生成和葡萄糖摄取。依维莫司可用于晚期肾细胞癌(RCC):适用于用舒尼替尼或索拉非尼治疗失败后晚期肾细胞癌患者的治疗;室管膜下巨细胞性星形细胞瘤:适用于有SEGA伴随结节性脑硬化(TS)需要治疗性干预但不是手术切除备选患者的治疗。相较于雷帕霉素,依维莫司的羟乙基结构增加了水溶性,提高了口服生物利用度,药理学性质明显改善,减少了不良反应,具有更高的治疗指数和人体耐受性,其结构式如下:
文献报道合成依维莫司的方法主要有以下几条路线:
方法一:中国专利申请CN102127092A、CN104592254A等文献报道,在有机碱的作用下,以雷帕霉素和单保护的乙二醇三氟甲磺酸酯为反应物,在一定的有机溶剂中,反应得到中间体,再在酸性条件下脱去硅醚保护,分离纯化得到产物依维莫司,合成路线如下:
方法二:中国专利申请CN102268015A、CN103848849A、CN105254646A等文献报道,以雷帕霉素或者雷帕霉素的衍生物为原料,与三氟甲磺酸酐反应,将42位羟基活化,再与单保护的乙二醇反应分离得到中间体,再通过脱去硅醚保护,分离纯化得到产品依维莫司,合成路线如下:
方法三:中国专利申请CN1402731等文献报道以雷帕霉素为原料,先与三甲基氯化硅反应对31位羟基进行保护,酸性水解生成单保护的雷帕霉素,再与单保护的乙二醇三氟甲磺酸酯在碱性条件下进行硅醚化反应,再脱保护分离纯化得到产品依维莫司,路线如下:
以上合成路线的存在以下不足:
1、方法一直接使用雷帕霉素和单保护的乙二醇三氟甲磺酸酯进行醚化反应,该方法选择性差,无法避免31-位羟基参与反应,生成的31-位取代副产物极性与目标产物物化性质相近,难以与目标产物分离,导致主产物收率较低。
2、方法二将雷帕霉素42位羟基直接用三氟甲磺酸酐活化,该方法易导致42位羟基异构化,难以分离去除,并且会有较多小杂质产生,收率较低。
3、方法三利用硅醚化保护基得到31-位硅醚保护雷帕霉素,再与单保护的乙二醇三氟甲磺酸酯醚化反应,脱保护分离纯化得到产品。该方法虽然有效提高了42位羟基反应的选择性,但醚化反应温度较高,而单保护的乙二醇三氟甲磺酸酯高温下稳定性很差,转化率较低,杂质多,路线较长,成本高,收率较低;以上各路线总收率在35%~72%之间,因此,本发明路线无论从目标产物的转化率还是产品的纯化角度都是优选的合成路线。
根据目前已有的文献资料,依维莫司合成的总收率在20~75%之间,无论从目标产物的转化率还是产品的纯化角度,都需要进一步优化依维莫司的合成工艺,以期获得更简便、低成本、高收率的依维莫司合成工艺。因此,需采用一种新型的依维莫司合成方法,能够更简单稳定、高质量低成本工业化的合成依维莫司。
发明内容
本发明提供了一种高效稳定的依维莫司制备方法,该方法使用了固体酸催化剂可以选择性活化42位羟基,而31位羟基不发生反应,转化率更高,工艺条件更温和,操作步骤更简便,成本更低,可得到高收率的产品,更适合工业放大。
本发明具体通过如下技术方案实现:
化合物I的制备包括如下步骤:将化合物SM-1即西罗莫司加入有机溶剂A中,搅拌溶清后,加入乙二醇,加入固体酸催化剂,控温搅拌反应,反应结束后反应液过滤减压浓缩,加入有机溶剂B溶解,再控温加入有机溶剂C精制得到依维莫司。
优选地,所述有机溶剂A选自三氯甲烷、四氢呋喃、1,4-二氧六环、乙腈、丙酮、二氯甲烷中的一种或其组合,其中特别优选三氯甲烷。
优选地,所述的固体酸催化剂选自Amberlyst-15、Cycat4045、-Al2O3中的一种,其中特别优选Amberlyst-15。
优选地,所述的化合物SM-1、乙二醇的投料摩尔比为1:1.0~1.5,其中特别优选1:1.1。
优选地,所述的化合物SM-1、催化剂的投料质量比为1:0.05~0.2,特别优选1:0.12。
优选地,所述的反应温度为-10~50℃,优选35~40℃。
优选地,所述有机溶剂B选自乙酸乙酯、无水乙醇、无水乙醚、丙酮、二氯甲烷、三氯甲烷中的一种或其组合,其中特别优选乙酸乙酯。
优选地,所述有机溶剂C选自正庚烷、正己烷、环己烷中的一种或其组合,其中特别优选正庚烷。
优选地,所述有机溶剂C体积用量为有机溶剂B体积用量的1~10倍,其中特别优选有机溶剂B的4倍。
优选地,所述滴加有机溶剂C的温度为0~40℃,优选30℃。
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的新方法,通过固体酸催化剂直接将西罗莫司与乙二醇缩合得到依维莫司,该发明相较于已有的合成工艺,具有以下特点:
(1)反应路线更短,操作更简单
(2)无腐蚀性,对设备无任何的伤害。
(3)可重复使用,尤其适合于连续化装置。
(4)产品易分离,反应完成后,只需过滤即可使产品和催化剂进行分离。
(5)没有废水排放,无需要中和水洗,经济环保。
(6)低温活性好,选择性强,副反应少。
2、提供了一种高选择性及高收率、高纯度的依维莫司的合成工艺,用于依维莫司的工业生产。
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=975.77[M+NH4]+;1H-NMR(400MHz,DMSO-d6):0.63(d,J=11.6Hz,1H),0.72(d,J=6.4Hz,3H),0.79(d,J=6.8Hz,3H),0.84(d,J=6.4Hz,3H),0.89(d,J=6.8Hz,3H),0.94~0.98(m,6H),1.03~1.08(m,3H),1.22~1.29(m,4H),1.34~1.41(m,2H),1.51~1.68(m,10H),1.74(s,3H),1.82~1.92(m,4H),1.99~2.04(m,2H),2.08~2.10(m,1H),2.38~2.43(m,2H),2.70~2.76(m,1H),2.95~2.97(m,1H),2.99~3.03(m,1H),3.06(s,3H),3.09~3.13(m,1H),3.16(s,3H),3.25~3.29(m,1H),3.33(s,4H),3.45~3.48(m,2H,C53-CH2),3.51~3.53(m,2H,C54-CH2),3.62~3.65(m,1H).3.94~3.96(m,1H),4.04(t,J=6.8Hz,2H),4.44(t,J=5.6Hz,1H),4.95(d,J=4.8Hz,1H),4.97~4.99(m,1H),5.11(d,J=10Hz,1H),5.27(d,J=4.8Hz,1H),5.43~5.50(m,1H),6.10~6.25(m,3H),6.37~6.40(m,1H),6.45(s,1H);
13C NMR(100MHz,DMSO-d6):10.3,13.2,13.5,14.1,14.8,15.6,20.4,21.7,24.5,26.7,26.5,29.6,29.8,30.9,32.3,33.3,34.8,35.3,36.0,38.1,38.9,39.1,43.5,45.2,50.8,55.4,56.9,57.0,60.9(C54),61.2,66.2,71.0(C53),73.6,75.7,82.3,82.3,82.5,85.6,99.0,125.0,127.0,130.4,132.3,137.1,137.8,139.3,167.0,169.2,198.8,207.4,210.4.
实施例1
室温下,将西罗莫司(18.28g,0.02mmol)加入三氯甲烷(183mL)中搅拌溶解,溶清后加入乙二醇(1.37mg,0.022mmol)及Amberlyst-15(2.19g),加毕升温至35℃搅拌反应1h。检测反应完毕后,反应液抽滤,用三氯甲烷(20mL)淋洗滤饼,滤液减压浓缩至干得粗品。向粗品中加入乙酸乙酯(92mL)搅拌溶清后加热至30℃,开始缓慢滴加正庚烷(368mL),滴加完毕,保温搅拌析晶得依维莫司,收率96.8%,HPLC纯度99.98%。
实施例2
室温下,将西罗莫司(18.28g,0.02mmol)加入二氯甲烷(183mL)中搅拌溶解,溶清后加入乙二醇(1.24mg,0.02mmol)及Cycat4045(2.19g),加毕控温至-10℃搅拌反应1h。检测反应完毕后,反应液抽滤,用二氯甲烷(20mL)淋洗滤饼,滤液减压浓缩至干得粗品。向粗品中加入二氯甲烷(92mL)搅拌溶清后控温至0℃,开始缓慢滴加正庚烷(92mL),滴加完毕,保温搅拌析晶得依维莫司,收率92.2%,HPLC纯度99.62%。
实施例3
室温下,将西罗莫司(18.28g,0.02mmol)加入四氢呋喃(183mL)中搅拌溶解,溶清后加入乙二醇(1.86mg,0.03mmol)及-Al2O3(2.19g),加毕控温至50℃搅拌反应1h。检测反应完毕后,反应液抽滤,用三氯甲烷(20mL)淋洗滤饼,滤液减压浓缩至干得粗品。向粗品中加入三氯甲烷(92mL)搅拌溶清后加热至40℃,开始缓慢滴加正庚烷(920mL),滴加完毕,保温搅拌析晶得依维莫司,收率93.5%,HPLC纯度99.58%。
实施例4
室温下,将西罗莫司(18.28g,0.02mmol)加入四氢呋喃(183mL)中搅拌溶解,溶清后加入乙二醇(2.11mg,0.034mmol)及-Al2O3(2.19g),加毕控温至45℃搅拌反应1h。检测反应完毕后,反应液抽滤,用三氯甲烷(20mL)淋洗滤饼,滤液减压浓缩至干得粗品。向粗品中加入三氯甲烷(92mL)搅拌溶清后加热至45℃,开始缓慢滴加正庚烷(85mL),滴加完毕,保温搅拌析晶得依维莫司,收率87.7%,HPLC纯度98.88%。
实施例5
室温下,将西罗莫司(18.28g,0.02mmol)加入1,4-二氧六环(183mL)中搅拌溶解,溶清后加入乙二醇(1.37mg,0.022mmol)及Amberlyst-15(0.92g),加毕升温至35℃搅拌反应1h。检测反应完毕后,反应液抽滤,用1,4-二氧六环(20mL)淋洗滤饼,滤液减压浓缩至干得粗品。向粗品中加入无水乙醇(92mL)搅拌溶清后加热至30℃,开始缓慢滴加正己烷(368mL),滴加完毕,保温搅拌析晶得依维莫司,收率93.1%,HPLC纯度99.66%。
实施例6
室温下,将西罗莫司(18.28g,0.02mmol)加入乙腈(183mL)中搅拌溶解,溶清后加入乙二醇(1.37mg,0.022mmol)及Amberlyst-15(3.66g),加毕升温至35℃搅拌反应1h。检测反应完毕后,反应液抽滤,用乙腈(20mL)淋洗滤饼,滤液减压浓缩至干得粗品。向粗品中加入无水乙醚(92mL)搅拌溶清后控温至0℃,开始缓慢滴加环己烷(368mL),滴加完毕,保温搅拌析晶得依维莫司,收率92.6%,HPLC纯度99.58%。
实施例7
室温下,将西罗莫司(18.28g,0.02mmol)加入丙酮(183mL)中搅拌溶解,溶清后加入乙二醇(1.37mg,0.022mmol)及Amberlyst-15(0.55g),控温至-15℃搅拌反应1h。检测反应完毕后,反应液抽滤,用丙酮(20mL)淋洗滤饼,滤液减压浓缩至干得粗品。向粗品中加入丙酮(92mL)搅拌溶清后控温至-5℃,开始缓慢滴加环己烷(368mL),滴加完毕,保温搅拌析晶得依维莫司,收率87.7%,HPLC纯度99.02%。
实施例8
室温下,将西罗莫司(18.28g,0.02mmol)加入三氯甲烷(183mL)中搅拌溶解,溶清后加入乙二醇(1.37mg,0.022mmol)及Amberlyst-15(4.02g),控温至55℃搅拌反应1h。检测反应完毕后,反应液抽滤,用三氯甲烷(20mL)淋洗滤饼,滤液减压浓缩至干得粗品。向粗品中加入三氯甲烷(92mL)搅拌溶清后控温至45℃,开始缓慢滴加环己烷(368mL),滴加完毕,保温搅拌析晶得依维莫司,收率86.8%,HPLC纯度98.92%。
Claims (6)
1.一种依维莫司的制备方法,其特征在于,制备方法包括如下步骤:室温下,将化合物SM-1加入有机溶剂A中,搅拌溶清后,加入乙二醇,加入固体酸催化剂,控温搅拌反应,反应结束后反应液过滤减压浓缩,加入有机溶剂B溶解,再控温加入有机溶剂C精制得到依维莫司,合成路线如下:
,
所述有机溶剂A选自三氯甲烷、四氢呋喃、二氧六环、乙腈、丙酮、二氯甲烷中的一种或其组合;
固体酸催化剂选自Amberlyst-15、Cycat4045、中的一种;
所述有机溶剂B选自乙酸乙酯、无水乙醇、无水乙醚、丙酮、二氯甲烷、三氯甲烷中的一种或其组合;
所述有机溶剂C选自正庚烷、正己烷、环己烷中的一种或其组合。
2.根据权利要求1所述的制备方法,其特征在于,所述的化合物SM-1、固体酸催化剂的投料摩尔比为1:1.0~1.5。
3.根据权利要求1所述的制备方法,其特征在于,所述的化合物SM-1、催化剂的投料质量比为1:0.05~0.2。
4.根据权利要求1所述的制备方法,其特征在于,所述有机溶剂C体积用量为有机溶剂B体积用量的1~10倍。
5.根据权利要求1所述的制备方法,其特征在于,所述反应温度为-10~50℃。
6.根据权利要求1所述的制备方法,其特征在于,反应结束后滴加有机溶剂C的温度为0~40℃。
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