CN106565772A - 一种新型双氨基的磷酰胆碱化合物Lys‑EG‑PC及其制备方法 - Google Patents
一种新型双氨基的磷酰胆碱化合物Lys‑EG‑PC及其制备方法 Download PDFInfo
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Abstract
本发明公开了一种新型双氨基的磷酰胆碱化合物Lys‑EG‑PC及其制备方法。本发明的目的在于提供一种可用于表面处理剂或表面处理剂原料物质的磷酰胆碱化合物,该类化合物还可直接作为修饰剂、扩链剂或交联剂用来对各种基材表面进行修饰或对基材进行改性,从而提高高分子材料的血液相容性,降低蛋白质吸附,减少细胞沉淀,将在组织工程,药物控释,基因治疗,化妆品等领域具有巨大的学术价值和广阔的应用前景。步骤简单、操作方便、实用性强。
Description
技术领域
本发明属于磷酰胆碱衍生物制备领域,特别涉及一种新型双氨基的磷酰胆碱化合物Lys-EG-PC及其制备方法。
背景技术
磷酰胆碱是组成细胞膜结构单元软磷脂的亲水端基,是细胞外层膜中的外层官能团,同时带有正、负异种电荷,具有较强的结合水的能力和亲水性能,这种结构和组成的表面与生理环境相互作用不仅不会吸附和沉积蛋白质,也不会引发血小板激活,导致凝血等不良反应,具有良好生物相容性。近几年来的研究表明,采用磷酰胆碱基团及其聚合物在材料表面构建具有防细胞外层膜结构,能减少纤维蛋白原的吸附,并通过减少血小板的黏附和活化来增加基体材料的生物相容性。
因此近年来,为了提高改善材料的生物相容性、保水性、吸水性等各种功能,人们正积极地开发导入了可与各种基材表面进行反应的反应性基团的、作为修饰剂的含有磷酰胆碱类似基团的化合物。例如,专利文献1(CN201310106363.9)公开了一种含羟基的磷酰胆碱L-α-甘油磷酰胆碱晶型化合物,专利文献2(CN200580040742.6)公开了一种含羧基的磷酰胆碱的化合物,专利文献3(CN201310251000.4)公开了一种含醛基的磷酰胆碱化合物。
上述专利文献中所公开的化合物虽导入了各种功能团,但在与基材表面处理剂进行化学键合时,在现有的技术条件下,基材表面还必须存在与其互补的官能团,如需要存在氨基。这些化合物若没有氨基的帮助,其反应率会非常低,因此需要长时间且高温的反应条件,或不能进行接枝处理。
因此专利文献4(CN201180062050.7)公开了一种含有单氨基的磷酰胆碱化合物及其制备方法,但是这类化合物应用仍然有局限性。这类化合物只有单氨基官能团,仅能作为表面处理剂用于基材表面的接枝,且反应活性较低,不能长期稳定的存在,另外由于单氨基的局限性这类化合物不能作为扩链剂或交联剂,从而不能从材料本体提高生物亲和性。
发明内容
为了克服上述不足,本发明提供了一种新的磷酰胆碱化合物可以直接作为材料的表面处理剂,可提供比专利文献4的单氨基磷酰胆碱化合物更理想,接枝更稳定的双氨基磷酰胆碱化合物,并且该双氨基的磷酰胆碱化合物可作为扩链剂和交联剂直接引入到基体材料。含有磷酰胆碱的材料伪装成周围的天然成分,能减少纤维蛋白原的吸附,并通过减少血小板的黏附和活化来增加基体材料的生物相容性。
为了实现上述目的,本发明采用如下技术方案:
一种新型双氨基的磷酰胆碱化合物(简称为Lys-EG-PC),其结构式如下:
这里双氨基的磷酰胆碱化合物的合成,选用蛋白质氨基酸中的L-赖氨酸作为起始原料,L-赖氨酸相比D-赖氨酸和其他含多氨基的氨基酸,其原料易得,成本更低;另外L-赖氨酸相对于其他含有双氨基的氨基酸,如天冬酰胺,谷氨酰胺,瓜氨酸等,其水溶解性和有机物溶解性更好,结构更简单,而且其他多氨基氨基酸中,第二个含有氨基的基团大都为酰胺基,酰胺基活性比氨基小的多,很难通过化学方法将酰胺基转变为氨基,因此它们并不是合成这类双氨基磷酰胆碱化合物的最佳选择。
本发明还提供了一种新型双氨基的磷酰胆碱化合物的制备方法,包括:
以L-赖氨酸为原料,在催化剂存在的条件下,与乙二醇进行酯化反应,得化合物(1);
对化合物(1)的两个氨基进行保护;得化合物(2);
使化合物(2)与2-氧代-1,3,2-二氧磷杂环戊烷(COP)在低温下反应,得到的化合物(3);
将化合物(3)在钯炭催化剂存在条件下氢化,脱掉氨基保护基团,即得新型双氨基的磷酰胆碱化合物。
优选的,所述氨基保护基团为苄氧羰基。
优选的,所述催化剂为二氯亚砜。
合成路线如下:
1.以L-赖氨酸为起始原料,选用四氢呋喃或二氯甲烷作为溶剂,三乙胺做缚酸剂,保持温度-10℃—-20℃,在二氯亚砜或三氯氧磷的作用下(与赖氨酸的摩尔比控制在2:1—3:1)反应;反应结束后,反应温度升至室温再与乙二醇反应(与赖氨酸的摩尔比控制在1.1:1—1.5:1),提纯后得到化合物(1);
2.化合物(1)以10%-20%的碳酸钠水溶液作为溶剂,优选氯甲酸苄酯(Cbz-Cl)保护剂对赖氨酸上的两个氨基进行保护。这里保护氨基的官能团还有叔丁氧羰基(Boc),对甲苯磺酰基(Tosyl),芴甲氧羰基(Fmoc)等;得到的目标化合物,选用二氯甲烷,三氯甲烷,二甲基亚砜等有机溶剂进行萃取可以得到纯度更高的产物:
3.用第二步得到的化合物(2)溶于无水四氢呋喃,将2-氧代-1,3,2-二氧磷杂环戊烷(COP)滴加至其中,化合物(2)与COP的物质的量投料比控制在1:1~1:1.9;保持温度-10℃—-25℃反应1-3h,过滤副产物三乙胺盐酸盐,得到的化合物(3)可通过静止,乙腈重结晶,丙酮重结晶的方法纯化:
4.将步骤3中得到的产物溶于乙腈,在反应瓶中保持温度-20℃,快速加入三甲胺,在50-70℃进行开环反应16-30h,再氢解脱掉Cbz基团得到最终产物化合物(Lys-EG-PC)含双氨基的磷酰胆碱化合物,所用氢解方法溴化氢(HBr)酸解,钯炭(Pd/C)催化氢化(钯炭含量5%—20%)等,这里由于溴化氢酸解的反应有副产物产生,最终产物有染色,因此我们选用催化氢化的方法。
本发明还提供了任一上述的方法制备的新型双氨基的磷酰胆碱化合物。
本发明还提供了一种表面处理剂,包括:任一上述的新型双氨基的磷酰胆碱化合物。
本发明还提供了一种扩链剂或交联剂,包括:任一上述的新型双氨基的磷酰胆碱化合物。
本发明还提供了任一上述的含有新型双氨基的磷酰胆碱化合物、表面处理剂、扩链接或交联剂在制备化妆品,以及组织工程、药物控释、基因治疗中的应用。
本发明的有益效果
(1)本发明的新型化合物是具有双氨基结构的磷酰胆碱化合物,是应用性极高的化合物。其本身可以用作表面处理剂,可以作为与各种基材表面进行反应的修饰剂,由于含有双氨基,因而提高了反应的活性及稳定性,在材料表面上极大程度地发挥以生物体适应为代表的磷酰胆碱基的表面改性功能。例如抑制蛋白质吸附和减少凝血等防污性。
(2)利用本发明的新型化合物双氨基的优越性,结合氨基反应特性(例如亲核取代反应、加成反应、共轭取代反应等),可作为交联剂或扩链剂制备新型的基体材料。从材料本身提高了生物相容性,使磷酰胆碱基团长时间稳定地存在,最大程度地发挥磷酰胆碱基团的功能。
(3)本发明的制备方法是采用无毒害的L-赖氨酸作为起始原料,保证了该化合物应用于医用材料中无毒害性,即使材料发生降解在人体内赖氨酸也不会对人体产生损害。
(4)本发明反应原料易得,定量进行,收率高,步骤虽然较多,但提纯步骤简便。
具体实施方式
以下通过实施例对本发明特征及其它相关特征作进一步详细说明,以便于同行业技术人员的理解:
实施例1
步骤1、0.132mol的Cbz-Cl溶于100mL的二乙醚溶液中,滴加入200mL含0.055molL-赖氨酸的10%NaCO3水溶液,滴加完后保持温度0℃反应5h,得到的产物用适量10%柠檬酸酸化后用三氯甲烷萃取,产物水洗后,蒸干得到大量N,N'-双苄氧羰基-L-赖氨酸,产率约93%。
步骤2、将0.055mol的N,N'-双苄氧羰基-L-赖氨酸加入干燥的500mL三口瓶中,加入0.11mol三乙胺缚酸剂和200mL无水四氢呋喃,混合均匀后,把0.145mol的二氯亚砜溶于50mL丙酮,放入恒压滴液漏斗中,-15℃下机械搅拌器,控制二氯亚砜滴加速度,约2h滴加完毕,反应结束约2h,升至室温,2h内滴加完0.08mol乙二醇,反应6小时,将反应液倒出抽滤得到淡黄色溶液,乙醚洗涤3次,蒸干溶剂,得到产物,纯度为98%,产率约93.3%。
步骤3、取上一步所得的产物0.389mol,倒入500mL三口瓶中,用250mL无水四氢呋喃溶解,加入0.389moL三乙胺后,保持反应温度-15℃,机械搅拌下用恒压漏斗滴加0.389mol COP的50mL四氢呋喃溶液,0.5h内滴加完后,再继续反应1.5h,减压抽滤蒸干得到亮黄色粘稠状物质。产率约81.8%。
步骤4、向耐温、耐压的反应瓶中加入0.05mol步骤3中的产物,60mL干乙睛和磁子,将其放入冰箱冷冻室中,使反应液冷却至-20℃后迅速向其中加入三甲胺(0.075mol),适当过量,密封放置,使反应液温度恢复至室温。磁力搅拌下,置于60℃油浴中反应。反应24h后倒出黄色溶液,至于冰箱下层冷却慢慢析出结晶,粗产物用干乙腈重结晶,产率约90%。
步骤5、取0.05mol步骤4所得的产物溶于250mL无水甲醇,在氢气保护下搅拌15min后,加入过量15%Pd/C,室温下反应结束后,过滤除去固体,得到滤液,旋转蒸发除去溶剂,用干乙腈重结晶,得最终产物化合物(1)Lys-EG-PC产率约87%。1H NMR(DMSO,TMS,400MHz,ppm)δ:5.11(4H,NH2—);4.31-4.42(br,4H,—COOCH2CH2O—);3.45(t,H,—CH(NH2)—);2.90(s,9H,—N+(CH3)3);2.65(q,2H,NH2CH2—);1.47-1.7(br,6H,—CH2CH2CH2—)。
具体案例2:
步骤1、取0.055mol的L-赖氨酸和0.11mol三乙胺加入到500毫升的干燥三口瓶中,优选200mL四氢呋喃溶解,保持-15℃的反应温度,在机械搅拌下,缓慢滴加溶于丙酮的0.145mol二氯亚砜,2h内滴加完毕,保持该温度继续反应2h;将温度升至室温后,缓慢滴加0.08mol乙二醇,反应6小时,将反应液倒出抽滤得到淡黄色溶液,乙醚3次,蒸干溶剂,得到产物,产率约96%。
步骤2、0.155mol的Cbz-Cl溶于100mL的二乙醚溶液中,滴加入200mL含0.0645mol化合物(2)的10%NaCO3水溶液,保持温度0℃,反应5h,得到的产物用适量10%柠檬酸酸化后用三氯甲烷萃取,产物水洗后,蒸干得到大量粉末,产率约95%。
步骤3、取上一步所得的产物0.389mol,倒入500mL三口瓶中,用250mL无水四氢呋喃溶解,加入0.389moL三乙胺后,保持反应温度-15℃,机械搅拌下用恒压漏斗滴加50mL含0.389mol COP四氢呋喃溶液,0.5h内滴加完后,再继续反应1.5h,减压抽滤蒸干得到亮黄色粘稠状物质。产率约81.8%。
步骤4、向耐温、耐压的反应瓶中加入0.05mol步骤3中的产物,60mL干乙睛和磁子,将其放入冰箱冷冻室中,使反应液冷却至-20℃后迅速向其中加入三甲胺(0.075mol),适当过量,密封放置,使反应液温度恢复至室温。磁力搅拌下,置于60℃油浴中反应。反应24h后倒出黄色溶液,至于冰箱下层冷却慢慢析出白色结晶,粗产物用干乙腈重结晶,产率约90%。
步骤5、取0.05mol步骤4所得的产物溶于250mL无水甲醇,在氢气保护下搅拌15min后,加入过量15%Pd/C,室温下反应结束后,过滤除去固体,得到滤液,旋转蒸发除去溶剂,用干乙腈重结晶,得最终产物化合物(1)Lys-EG-PC,产率约88%。1H NMR(DMSO,TMS,400MHz,ppm)δ:5.11(4H,NH2—);4.31-4.42(br,4H,—COOCH2CH2O—);3.45(t,H,—CH(NH2)—);2.90(s,9H,—N+(CH3)3);2.65(q,2H,NH2CH2—);1.47-1.7(br,6H,—CH2CH2CH2—)。
最后应该说明的是,以上所述仅为本发明的优选实施例而已,并不用于限制本发明,尽管参照前述实施例对本发明进行了详细的说明,对于本领域的技术人员来说,其依然可以对前述实施例所记载的技术方案进行修改,或者对其中部分进行等同替换。凡在本发明的精神和原则之内,所作的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。上述虽然对本发明的具体实施方式进行了描述,但并非对本发明保护范围的限制,所属领域技术人员应该明白,在本发明的技术方案的基础上,本领域技术人员不需要付出创造性劳动即可做出的各种修改或变形仍在本发明的保护范围以内。
Claims (8)
1.一种新型双氨基的磷酰胆碱化合物Lys-EG-PC,其特征在于,结构式如下:
2.一种新型双氨基的磷酰胆碱化合物的制备方法,其特征在于,包括:
以L-赖氨酸为原料,对赖氨酸上的两个氨基进行保护,得化合物(1);
在催化剂存在的条件下,将化合物(1)与乙二醇进行酯化反应;得化合物(2);
使化合物(2)与2-氧代-1,3,2-二氧磷杂环戊烷(COP)在低温下反应,得到的化合物(3);
将化合物(3)在钯炭催化剂存在条件下氢化,脱掉氨基保护基团,即得新型双氨基的磷酰胆碱化合物。
3.如权利要求2所述的方法,其特征在于,所述氨基保护基团为苄氧羰基。
4.如权利要求2所述的方法,其特征在于,所述催化剂为二氯亚砜。
5.权利要求2-4任一项所述的方法制备的新型双氨基的磷酰胆碱化合物。
6.一种表面处理剂,其特征在于,包括:权利要求1或5所述的新型双氨基的磷酰胆碱化合物。
7.一种扩链剂或交联剂,其特征在于,包括权利要求1或5所述的新型双氨基的磷酰胆碱化合物。
8.权利要求1或5所述的含有新型双氨基的磷酰胆碱化合物、权利要求6所述的表面处理剂、权利要求7所述的扩链接或交联剂在制备化妆品,以及组织工程、药物控释、基因治疗中的应用。
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