CN113999101A - 一种蒽醌类衍生物sz-685c的合成方法 - Google Patents
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Abstract
本发明公开了一种蒽醌类衍生物SZ‑685C的合成方法,属于有机化学合成技术领域,其技术方案要点是:包括如下步骤:S1、以邻苯二甲酸为原料,并向邻苯二甲酸中加入溴素,进而被转化成羟基和甲氧基获得前驱体苯酐衍生物;S2、以乙二醛和丙酮为原料,通过醛酮缩合反应、取代反应、水解、羟醛缩合反应和McMurry偶联反应能够获得环己烯衍生物;S3、以步骤S1中的前驱体苯酐衍生物和步骤S2中的环戊烯衍生物为底物,以固熔体为催化剂一步合成最终的目标分子SZ‑685C。本发明主要用于通过全合成的方式,经9步反应即可制得目标分子SZ‑685C,该方法工艺简便、产物分离难度低、目标化合物产率高且生产周期短,能够为后期进行药理检测、临床试验和规模化生产奠定基础。
Description
技术领域
本发明涉及有机化学合成技术领域,尤其涉及一种蒽醌类衍生物SZ-685C的合成方法。
背景技术
海洋是生命之源,海洋环境的特殊性造就了巨大的生物多样性和独特的化学多样性,由此形成的代谢产物具有复杂、独特的结构和特异、高效的活性。引起了化学家、生物学家及药理学家的广泛关注和极大兴趣,海洋生物资源已成为创新药物发现的重要源泉。
SZ-685C是一种新型的海洋蒽醌类衍生物,分子结构如图1所示,是从中国南海红树林的内生真菌Halorosellinia sp.(No.1403)的次生代谢产物中分离得到的。最近的研究发现,该化合物可以抑制多种肿瘤细胞的生长,包括人脑胶质瘤、肝癌、前列腺癌、乳腺癌和鼻咽癌等癌细胞。中山大学佘志刚课题组的最新研究更是显示该物质能诱导垂体瘤细胞的凋亡。可见,该物质在治疗肿瘤细胞方面具有很高的活性,显示出了极为可观的应用潜力。2016年,广州市已经通过了该化合物作为抗肿瘤候选药物的药性评估,并验收通过了该化合物在鼻咽癌治疗中的应用研究。
目前,获得该物质只能通过生物发酵法来培养内生真菌Halorosellinia sp.(No.1403),并对其次生代谢产物进行分离、纯化得到,然而该工艺操作繁琐、产物分离难度大、目标化合物产率低且生产周期较长。
为了解决上述问题,在现有技术的基础上提供了一种蒽醌类衍生物SZ-685C的全化学合成方法。
发明内容
本发明的目的是提供一种蒽醌类衍生物SZ-685C的合成方法,本发明以简单易得的邻苯二甲酸作为起始反应原料,通过全合成的方式,经9步反应即可制得目标分子SZ-685C,该方法工艺操作简便、产物分离难度低、目标化合物产率高且生产周期短,能够为后期进行更充分的药理检测、临床试验和规模化生产奠定基础。
本发明的上述技术目的是通过以下技术方案得以实现的:
一种蒽醌类衍生物SZ-685C的合成方法,包括如下步骤:
S1、邻苯二甲酸酐衍生物的合成
A.以邻苯二甲酸为原料,并向所述邻苯二甲酸中加入溴素,所述邻苯二甲酸和溴素反应生成中间产物Ⅰ;
B.使所述中间产物Ⅰ在碱性条件下水解,获得中间产物Ⅱ;
C.向所述中间产物Ⅱ中加入甲基化试剂,使中间产物Ⅱ和甲基化试剂反应获得前驱体苯酐衍生物。
S2、环己烯衍生物的合成
a.以乙二醛和丙酮为原料,使乙二醛和丙酮在碱性条件下反应生成中间产物Ⅲ;
b.向中间产物Ⅲ中加入溴素,中间产物Ⅲ和溴素反应生成中间产物Ⅳ;
c.中间产物Ⅳ在碱性条件发生水解,获得中间产物Ⅴ;
d.使中间产物Ⅴ和乙醛在碱性条件下发生羟醛缩合反应生成中间产物Ⅵ;
e.使中间产物Ⅵ在使中间产物Ⅵ在含有四氯化钛和锌粉的四氢呋喃溶液中发生McMurry偶联反应,能够获得环己烯衍生物。
S3、目标分子SZ-685C的合成
以步骤S1中的前驱体苯酐衍生物和步骤S2中的环戊烯衍生物为底物,以固熔体为催化剂一步合成最终的目标分子SZ-685C。
通过采用上述技术方案,以邻苯二甲酸为原料,并向所述邻苯二甲酸中加入溴素,发生取代反应获得含有溴取代基的中间产物Ⅰ;中间产物Ⅰ能够在碱性条件下水解为中间产物Ⅱ,将中间产物Ⅰ中的溴取代基转化为羟基;向所述中间产物Ⅱ中加入甲基化试剂,将中间产物Ⅱ中的一个羟基转变为甲氧基,获得前驱体苯酐衍生物,以便能完成目标分子的合成。
以乙二醛和丙酮为原料,使乙二醛和丙酮在碱性条件下发生醛酮缩合反应生成中间产物Ⅲ;使中间产物Ⅲ和溴素发生取代反应,能够获得含有溴取代基的中间产物Ⅳ;中间产物Ⅳ在碱性条件发生水解,将溴取代基转化为羟基,获得中间产物Ⅴ;使中间产物Ⅴ和乙醛在碱性条件下发生羟醛缩合反应生成中间产物Ⅵ;使中间产物Ⅵ在含有四氯化钛和锌粉的四氢呋喃溶液中发生McMurry偶联反应,能够获得环己烯衍生物。前驱体苯酐衍生物和环戊烯衍生物能够在固熔体的催化作用下,一步合成最终的目标分子SZ-685C。
采用本方案能够以简单易得的邻苯二甲酸作为起始反应原料,通过全合成的方式,经9步反应即可制得目标分子SZ-685C,该方法工艺操作简便、产物分离难度低、目标化合物产率高且生产周期短,能够为后期进行更充分的药理检测、临床试验和规模化生产奠定基础。
进一步地,步骤S1中,所述中间产物Ⅰ中包含有4,5,7-三溴-1,3-二氢-2-苯并呋喃-1,3-二酮;所述中间产物Ⅱ中包含有4,5,7-三羟基-1,3-二氢-2-苯并呋喃-1,3-二酮。
进一步地,步骤S2中,所述中间产物Ⅲ中包含有2-羟基-4-氧代戊烷醛;所述中间产物Ⅳ中包含有3-溴-2-羟基-4-氧代戊烷醛;所述中间产物Ⅴ中包含有2,3-二羟基-4-氧戊烯醛;所述中间产物Ⅵ中包括有2,3,4-三羟基-4-甲基己二醛。
进一步地,步骤S3中,所述固熔体为明矾、氧化铝和氯化钠的固熔体系。
综上所述,本发明具有以下有益效果:本发明以简单易得的邻苯二甲酸酐作为起始反应原料,通过全合成的方式,经9步反应即可制得目标分子SZ-685C,该方法工艺操作简便、产物分离难度低、目标化合物产率高且生产周期短,能够为后期进行更充分的药理检测、临床试验和规模化生产奠定基础。
附图说明
图1是本发明实施例的SZ-685C合成路线示意图;
图2是本发明实施例的步骤S1的反应过程示意图;
图3是本发明实施例的步骤S2的反应过程示意图;
图4是本发明实施例的步骤S3的反应过程示意图。
具体实施方式
下面结合附图和实施方式对本发明作进一步的详细说明:
实施例:一种蒽醌类衍生物SZ-685C的合成方法,如图1至图4所示,合成步骤如下:
S1、邻苯二甲酸酐衍生物的合成
A.将0.1mol邻苯二甲酸溶于100mL 0.2mol/L的NaOH溶液中,升温至80℃,逐滴加入溴素3.5mol,滴毕,TLC监测反应至底物反应完全后继续反应4h,将反应液倒入6mol/L盐酸冰水中,搅拌,硝基苯萃取,合并有机相,无水硫酸镁干燥,旋蒸除去溶剂即得中间产物Ⅰ。
B.使中间产物Ⅰ在碱性条件下水解,获得中间产物Ⅱ:将0.1mol中间产物Ⅰ溶于150mL 3mol/L氢氧化钠溶液中,加入0.01mol活化铜粉,将反应液转移至带有压力计的反应釜中,200℃下反应4h,冷却后倒入100mL预冷浓盐酸中,乙醚萃取,合并有机相,无水硫酸镁干燥,旋蒸除去溶剂,得棕黄色三羟基邻苯二甲酸中间体粗品,向粗品中加入100mL乙酸酐,加热至回流,反应3h,反应结束后蒸除溶剂,产品过200目硅胶柱(以乙醇:乙醚:水:醋酸=7:2:0.5:0.5为洗脱剂),得中间体Ⅱ。
C.向中间产物Ⅱ中加入甲基化试剂,使中间产物Ⅱ和甲基化试剂CH3I反应获得前驱体苯酐衍生物:将0.1mol中间体Ⅱ溶解于100mL0.2mol/L氢氧化钠溶液中,冰水浴条件下加入0.1mol甲基化试剂(硫酸二甲酯或碘甲烷),回流反应,TLC检测至无底物即结束反应,乙醚萃取,合并有机相,无水硫酸镁干燥,旋蒸除去溶剂,即得前驱体苯酐衍生物。
S2、环己烯衍生物的合成
a.以乙二醛和丙酮为原料,使乙二醛和丙酮在碱性条件下反应生成中间产物Ⅲ:室温下将0.1mol乙二醛和0.1mol丙酮溶于200mL乙醇中,搅拌下逐滴加入4mL 10%的乙醇钠或氢氧化钠或氢氧化钾乙醇溶液,滴毕,室温反应10h,反应结束后将反应液倒入冰水中,用盐酸调节pH至中性,乙酸乙酯萃取,合并有机相,无水硫酸镁干燥,旋蒸除去溶剂,产物经200目硅胶层析(乙酸乙酯:石油醚=2:8),得中间产物Ⅲ。
b.向中间产物Ⅲ中加入溴素,中间产物Ⅲ和溴素反应生成中间产物Ⅳ:将0.1mol中间产物Ⅲ溶于50mL乙醇中,室温下逐滴加入逐滴加入0.1mol溴素,滴毕,TLC监测至无底物,结束反应,用氢氧化钠调节pH至中性,乙酸乙酯萃取,合并有机相,无水硫酸镁干燥,旋蒸除去溶剂即得中间产物Ⅳ。
c.中间产物Ⅳ在碱性条件发生水解,获得中间产物Ⅴ:将0.1mol中间产物Ⅳ溶于100mL 70%乙醇水溶液中,逐滴加入10mL 10%氢氧化钠溶液,TLC监测至无底物,反应结束,用盐酸调节反应液pH至6左右,乙醚萃取,合并有机相,无水硫酸镁干燥,旋蒸除去溶剂,即得中间产物Ⅴ。
d.使中间产物Ⅴ和乙醛在碱性条件下发生羟醛缩合反应生成中间产物Ⅵ:向含有0.1mol中间产物Ⅴ和0.1mol乙醛的200mL乙醇溶液中逐滴加入4mL 10%乙醇钠或氢氧化钠或氢氧化钾乙醇溶液,滴毕,室温反应,TLC监测至无底物,结束反应,将反应液倒入冰水中,盐酸调节pH至中性,乙醚萃取,合并有机相,无水硫酸镁干燥,旋蒸除去溶剂,40℃下真空干燥至恒重,即得中间产物Ⅵ。
e.使中间产物Ⅵ在含有四氯化钛和锌粉的四氢呋喃溶液中发生Mcmurry偶联反应,能够获得环己烯衍生物:氮气保护且-20℃下,将2mL四氯化钛逐滴加入到含有3.6g活化锌粉的500mL无水四氢呋喃溶液中,搅拌均匀得黄绿色悬浮液,加热回流1h,冷却至室温后加入0.1mol中间产物Ⅵ,回流反应,TLC监测至无底物结束反应,冷却至室温后倒入300mL10%碳酸钾水溶液,产生大量絮状物,抽滤,滤饼用乙醚洗涤,合并滤液,滤液用乙醚萃取,合并有机相,无水硫酸镁干燥,过滤,旋蒸除去溶剂,以乙醚:石油醚:醋酸=3:6.5:0.5为洗脱剂过柱层析硅胶柱,得环己烯衍生物。
S3、目标分子SZ-685C的合成
以步骤S1中的前驱体苯酐衍生物和步骤S2中的环戊烯衍生物为底物,以固熔体为催化剂一步合成最终的目标分子SZ-685C。
其中,步骤S3的反应过程如下:向单口反应烧瓶中分别加入4.7g明矾、0.5g氧化铝、1.24g氯化钠,机械搅拌逐渐升温使物料完全融化,继续升温至100℃后,依次加入0.1mol前驱体苯酐衍生物和0.1mol环戊烯衍生物,搅拌均匀后继续升温至120℃,TLC监测至无底物后继续反应1h,反应结束后,乙醚萃取,合并有机相,无水硫酸镁干燥、过滤、旋蒸除去溶剂,得粗品,用石油醚:乙酸乙酯=5:1为洗脱剂,经硅胶柱层析纯化,得SZ-685C纯品。经质谱及核磁氢谱表征,数据如下:MS(ESI)m/z:335.08{[M-H]-};1H NMRδ:13.07(s,1H),12.86(s,1H),6.68(s,1H),5.81(s,1H),5.22(s,1H),4.21(s,1H),3.99(d,1H),3.83(s,3H),3.68(d,1H),2.01(s,1H),1.52(s,3H)。
在本发明的上述实施例中,本发明以简单易得的邻苯二甲酸酐作为起始反应原料,通过全合成的方式,经9步反应即可制得目标分子SZ-685C,该方法工艺操作简便、产物分离难度低、目标化合物产率高且生产周期短,能够为后期进行更充分的药理检测、临床试验和规模化生产奠定基础。
本具体实施例仅仅是对本发明的解释,其并不是对本发明的限制,本领域技术人员在阅读完本说明书后可以根据需要对本实施例做出没有创造性贡献的修改,但只要在本发明的权利要求范围内都受到专利法的保护。
Claims (4)
1.一种蒽醌类衍生物SZ-685C的合成方法,其特征是,包括如下步骤:
S1、邻苯二甲酸酐衍生物的合成
A.以邻苯二甲酸为原料,并向所述邻苯二甲酸中加入溴素,所述邻苯二甲酸和溴素反应生成中间产物Ⅰ;
B.使所述中间产物Ⅰ在碱性条件下水解,获得中间产物Ⅱ;
C.向所述中间产物Ⅱ中加入甲基化试剂,使中间产物Ⅱ和甲基化试剂反应获得前驱体苯酐衍生物;
S2、环己烯衍生物的合成
a.以乙二醛和丙酮为原料,使乙二醛和丙酮在碱性条件下反应生成中间产物Ⅲ;
b.向中间产物Ⅲ中加入溴素,中间产物Ⅲ和溴素反应生成中间产物Ⅳ;
c.中间产物Ⅳ在碱性条件发生水解,获得中间产物Ⅴ;
d.使中间产物Ⅴ和乙醛在碱性条件下发生羟醛缩合反应生成中间产物Ⅵ;
e.使中间产物Ⅵ在使中间产物Ⅵ在含有四氯化钛和锌粉的四氢呋喃溶液中发生McMurry偶联反应,能够获得环己烯衍生物;
S3、目标分子SZ-685C的合成
以步骤S1中的前驱体苯酐衍生物和步骤S2中的环戊烯衍生物为底物,以固熔体为催化剂一步合成最终的目标分子SZ-685C。
2.根据权利要求1所述的一种蒽醌类衍生物SZ-685C的合成方法,其特征是:步骤S1中,所述中间产物Ⅰ中包含有4,5,7-三溴-1,3-二氢-2-苯并呋喃-1,3-二酮;所述中间产物Ⅱ中包含有4,5,7-三羟基-1,3-二氢-2-苯并呋喃-1,3-二酮。
3.根据权利要求1所述的一种蒽醌类衍生物SZ-685C的合成方法,其特征是:步骤S2中,所述中间产物Ⅲ中包含有2-羟基-4-氧代戊烷醛;所述中间产物Ⅳ中包含有3-溴-2-羟基-4-氧代戊烷醛;所述中间产物Ⅴ中包含有2,3-二羟基-4-氧戊烯醛;所述中间产物Ⅵ中包括有2,3,4-三羟基-4-甲基己二醛。
4.根据权利要求1所述的一种蒽醌类衍生物SZ-685C的合成方法,其特征是:步骤S3中,所述固熔体为明矾、氧化铝和氯化钠的固熔体系。
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