CN113801071B - 一种钆特酸葡甲胺的精制方法 - Google Patents
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Abstract
本发明提供了一种钆特酸葡甲胺的制备工艺以及纯化工艺,制备工艺包括将纯化的DOTA加入纯水中,在室温条件下搅拌溶解,加入氧化钆和微孔硅酸钙颗粒,再加入葡甲胺直至溶液PH=7‑9,超声震荡后,过滤,滤液加热至40‑50℃搅拌,反应2‑4h,过滤沉淀物,真空干燥即得,本发明纯化方法包括将粗品钆特酸葡甲胺溶于100ml的甲醇中,搅拌下加热至溶解,搅拌下加入50ml水,停止搅拌,自然降温,缓慢析出细小晶体,3小时后降温至5‑10℃,搅拌下再加入30ml水,加完停止搅拌,放置析晶,抽滤析出的白色晶体,少量甲醇洗涤,60°C下真空干燥,得到晶状粉末。
Description
技术领域
本发明属于造影剂制备方法领域,特别是涉及钆特酸葡甲胺的制备及纯化。
背景技术
钆特酸葡甲胺,化学名1,4,7,10-四氮杂十二烷-1,4,7,10-四乙酸钆葡甲胺,是由Guerbet开发和上市,用作核磁共振成像造影剂。
钆特酸葡胺为离子环形钆制剂,可用于中枢、全身和血管造影,目前,技术公开的钆特酸葡胺的制备方法通常先合成配体轮环藤宁四乙酸(DOTA),然后络合钆离子,再与葡甲胺成盐即得分如下几种:
采用轮环藤宁和溴乙酸叔丁酯为原料,在碳酸钾为碱,氯仿为溶剂条件下发生N-烃化反应、再用三氟乙酸发生酯水解反应得轮环藤宁四乙酸,合成路线如图3所示;该方法虽然工艺上直接解决了除盐的问题,但是所用溶剂毒性较大,溴乙酸叔丁酯和三氟乙酸的用量大,价格高,且反应收率低,所以该方法不建议采用。
路线二采用轮环藤宁和氯乙酸为原料,氢氧化钠为碱,水为溶剂,经N-烃化反应得轮环藤宁四乙酸钠,再用浓盐酸经酯水解反应得轮环藤宁四乙酸,滴加无水乙醇析出,再通过离子交换树脂除盐。合成路线如图4所示;该方法原料氢氧化钠廉价易得,反应时间短,收率高,所得成品纯度高,但是要通过离子交换树脂除盐,设备成本投入大,考虑到离子交换树脂可重复利用,如果生产量大,可考虑该方法。
路线三采用轮环藤宁和氯乙酸为原料,氢氧化锂为碱,水为溶剂,经N-烃化反应得轮环藤宁四乙酸锂,再用浓盐酸经酯水解反应得轮环藤宁四乙酸,滴加无水乙醇析出,再通过水-乙醇重结晶除盐。合成路线如图5所示;
钆特酸葡胺的合成路线如图6所示;现有技术中对钆特酸葡甲胺的纯化方法可以概况为阴阳离子树脂和结晶法,需要频繁操作,交替使用清洗离子交换树脂,并且Gd对比剂在体内循环时间增加,逐渐释放 Gd3+的概率增加,会导致严重的毒性问题,例如肾脏损伤,肾系统纤维化等,脑部沉积则严重影响神经系统。这些给钆特醇造影剂的带来了制备和纯化上更高的要求和技术难题。造影剂的毒性效应给肾脏造成的损伤往往是急性炎症性的,仅仅有在数小时或数天内的窗口期可以治愈,游离金属离子难于从体内排出往往带来的都是不可逆的神经毒性和肾毒性。
发明内容
本发明通过改进制备操作可以获得较为纯净的钆特酸葡甲胺产品,经高效液相和质谱分析,杂质限量和产品纯度符合药典规定,可简略纯化步骤。同时本发明发现改进的析晶步骤,可以稳定钆的螯合状态,药物肾毒性显著降低。
本发明制备方法简单易于操作,加入适量吸附剂,结合超声震荡步骤,可以获的符合规定的纯净的产品,避免了后续的纯化步骤。同时,本发明也改进了常规的析晶工艺,在第二溶剂中分批次加入水,产物析晶后,发现其获得了更稳定的螯合Gd,显著降低肾毒性。
具体步骤包括:
将纯化的DOTA加入纯水溶解,室温下搅拌溶解,加入氧化钆和微孔硅酸钙颗粒,加入葡甲胺直至溶液PH为8-9,超声震荡后过滤除去硅酸钙颗粒,滤液加热至40-50℃搅拌反应2-4h,过滤沉淀物,真空干燥即得。
其中各成分重量比优选为,DOTA:氧化钆为2-4:1-3,氧化钆:葡甲胺为1:1-2,DOTA:微孔硅酸钙颗粒为1:4-5。
优选地,将纯化的DOTA3.75g,加入纯水,在室温条件下搅拌溶解,加入氧化钆(2.15g)和微孔硅酸钙颗粒15g,再加入葡甲胺(2.2-3g)直至溶液PH=8-9,超声震荡1h后,过滤,滤液加热至40-50℃以 80r/min的速度搅拌,反应2-4h,过滤沉淀物,真空干燥后即得。
微孔硅酸钙颗粒优选为20-50nm的平均孔径。
本发明制备得到的钆特酸葡甲胺纯度≥99.6%,单杂含量低于0.02%,游离钆含量<0.001%。
本发明还涉及一种钆特酸葡甲胺的纯化方法,其特征在于,将粗品钆特酸葡甲胺2g溶于100ml的甲醇中,搅拌下加热至溶解,搅拌下加入50ml水,停止搅拌,自然降温,缓慢析出细小晶体,3小时后降温至5-10℃,搅拌下再加入30ml水,加完停止搅拌,放置析晶,抽滤析出的白色晶体,少量甲醇洗涤,60℃下真空干燥,得到晶状粉末。
术语“DOTA”是大环螯合剂1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸的常规缩写,且指DOTA本身或其盐:
术语“葡甲胺”具有其常规含义,且指N-甲基葡糖胺。
纯化的DOTA购自齐岳生物有限公司,纯度99.8%。
附图说明
图1:实施例2制备的钆特酸葡甲胺质谱;
图2:实施例2制备的钆特酸葡甲胺分析图谱;
图3:背景技术中采用轮环藤宁和溴乙酸叔丁酯为原料的合成路线图;
图4:背景技术中采用轮环藤宁和氯乙酸为原料的合成路线图;
图5:背景技术中采用采用轮环藤宁和氯乙酸为原料合成路线图;
图6:背景技术中钆特酸葡胺的合成路线图。
具体实施方式
钆特酸葡甲胺制备
对比实施例1:
反应瓶中加入纯化的DOTA3.75g,加入纯水,在室温条件下搅拌溶解,加入氧化钆2.15g和葡甲胺2.2-3g,调节葡甲胺用量直至溶液PH=7-9,加热至40-50℃以80r/min的速度搅拌,反应2-4h,过滤沉淀物,真空干燥后即得。HPLC分析产品纯度94.1%。
实施例2:
反应瓶中加入纯化的DOTA3.75g,加入纯水,在室温条件下搅拌溶解,加入氧化钆(2.15g)和微孔硅酸钙颗粒15g,再加入葡甲胺2.2-3g直至溶液PH=7-9,超声震荡1h后,过滤,滤液加热至40-50℃以 80r/min的速度搅拌,反应2-4h,过滤沉淀物,真空干燥后即得。
微孔硅酸钙颗粒为20-50nm的平均孔径,超声频率20-50KHZ,功率150W。
本发明制备得到的钆特酸葡甲胺纯度≥99.6%,单杂含量低于0.02%,游离钆含量<0.001%。
实施例3:
反应瓶中加入纯化的DOTA3.75g,加入纯水,在室温条件下搅拌溶解,加入氧化钆(2.15g)和微孔硅酸钙颗粒15g,再加入葡甲胺2.2-3g直至溶液PH=8-9,超声震荡1h后,过滤,滤液加热至40-50℃以 80r/min的速度搅拌,反应2-4h,过滤沉淀物,真空干燥后即得。
微孔硅酸钙颗粒为20-50nm的平均孔径,超声频率20-50KHZ,功率150W。
本发明制备得到的钆特酸葡甲胺纯度≥99.6%,单杂含量低于0.02%,游离钆含量<0.001%。
将上述钆特酸葡甲胺2g溶于100ml的甲醇中,搅拌下加热至溶解,搅拌下加入50ml水,停止搅拌,自然降温,缓慢析出细小晶体,3小时后降温至5-10℃,搅拌下再加入30ml水,加完停止搅拌,放置析晶,抽滤析出的白色晶体,少量甲醇洗涤,60℃下真空干燥,得到晶状粉末,HPLC分析纯度99.8%。
实施例4:
将对比实施例1获得的钆特酸葡甲胺2g溶于100ml的甲醇中,搅拌下加热至溶解,搅拌下加入50ml 水,停止搅拌,自然降温,缓慢析出细小晶体,3小时后降温至5-10℃,搅拌下再加入30ml水,加完停止搅拌,放置析晶,抽滤析出的白色晶体,少量甲醇洗涤,60℃下真空干燥,得到晶状粉末,HPLC分析纯度99.6%。
实施例5:
将实施例2获得的钆特酸葡甲胺2g溶于100ml的甲醇中,搅拌下加热至溶解,搅拌下加入50ml丙酮,停止搅拌,自然降温,缓慢析出细小晶体,3小时后降温至5-10℃,搅拌下再加入30ml丙酮,加完停止搅拌,放置析晶,抽滤析出的白色晶体,少量丙酮洗涤,60℃下真空干燥,得到晶状粉末,HPLC分析纯度99.8%。
试验1:肾毒性检测
肾功能损伤检测中,采用KIM-1指标,这是一种比表型更早发生变化的指标,作为一种I型跨膜糖蛋白,在正常的肾组织中几乎不表达,在鼠造影剂肾毒性的肾组织明显增高。本实验采用ELISA方法,取 120只健康小鼠,分成6组,分别以Gd3+浓度均为0.1mmol/kg剂量尾静脉注射,对比例1,实施例2-5样品,注射前,注射后12h,注射后24h取尿液检测KIM-1值,每组小鼠获得的数值取平均值,,试剂盒为美国R&D公司产尿液原样检测试剂盒;采用全自动分析仪检测。采用SPSS20.0统计软件进行分析,采用t检验比较组间差异,以P<0.05为差异有统计学意义。如表1所示,三组之间比较差异有统计学意义 (P<0.05)
表1小鼠注射造影剂前后肾损伤指标变化
由表1结果可以看出,对比例1的钆造影剂具有较高的肾毒性,并且可能需要更长时间排出,对肾脏损伤的可能性更大。实施例3-5都经过了析晶纯化步骤,实施例5的析晶溶剂采用的甲醇-丙酮,并不比没有经过析晶纯化的实施例2具有更明显的肾毒性的降低,而实施例3,具有显著降低的肾毒性,实施例4 虽然是以对比实施例1获得的纯度较低的钆特酸甲葡胺粗品为原料,但获得的产品仍然具有降低的肾毒性。可见该纯化工艺具有显著难于预期的效果。
综上试验,通过优化制备工艺,得到了纯度较高的产品,可以省纯化步骤,同时本发明也给出了单独的纯化工艺,可显著降低肾毒性,其溶剂不同,特别是将水作为第二溶剂,第一溶剂:第二溶剂=10:8,这些技术步骤产生预料不到的技术效果,可能和化合物结晶水合状态有关。
上述具体实施例并不构成对本发明的保护范围的限定,本领域技术人员可以根据上述说明对本发明进行各种变化和应用。
Claims (3)
1.一种降低钆特酸葡甲胺肾毒性的精制方法,其特征在于,步骤如下:
1)将纯化的DOTA加入纯水中,在室温条件下搅拌溶解,加入氧化钆和微孔硅酸钙颗粒,再加入葡甲胺直至溶液PH=7-9,超声震荡后,过滤,滤液加热至40-50℃搅拌,反应2-4h,过滤沉淀物,真空干燥后即得钆特酸葡甲胺粉末;其中各成分重量比分别为,DOTA:氧化钆为2-4:1-3,氧化钆:葡甲胺为1:1-2,DOTA:微孔硅酸钙颗粒为1:4-5;微孔硅酸钙颗粒为20-50nm的平均孔径;
2)将上述钆特酸葡甲胺溶于甲醇中,搅拌下加热至溶解,搅拌下加入水,停止搅拌,自然降温,析出晶体,3小时后降温至5-10℃,搅拌下再加入水,加完停止搅拌,放置析晶,上述甲醇与水的重量比为1:0.5-1;抽滤析出的白色晶体,少量甲醇洗涤,60 °C下真空干燥,得到晶状粉末。
2.权利要求1所述制备方法,其特征在于步骤1)中搅拌速度为80r/min,超声震荡时间为1h。
3.权利要求1所述制备方法,其特征在于超声频率20-50KHZ, 功率150W。
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