CN113549111A - 一种富马酸替诺福韦艾拉酚胺杂质的制备方法 - Google Patents
一种富马酸替诺福韦艾拉酚胺杂质的制备方法 Download PDFInfo
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Abstract
Description
技术领域
本发明属于药物化学领域,具体涉及富马酸替诺福韦艾拉酚胺杂质的制备方法。
背景技术
富马酸替诺福韦艾拉酚胺(tenofovir alafenamide fumarate)缩写TAF,其结构式为:
该化合物是由美国Gilead Sciences公司研发,美国食品药品管理局(FDA)于2016年11月10日批准在美国用于慢性乙型肝炎成人感染者的治疗,是创新型、靶向性抗乙肝病毒,是近十年内被批准用于治疗慢性乙型肝炎的首个药物。TAF作为替诺福韦磷酰胺酯的前体药,其经血流入肝,经肝细胞膜上的有机阴离子转运多肽1B1和1B3主动转运进入人原代肝细胞。TAF进入肝细胞后,再经过羧酸酯酶水解转化为TFV,TFV在细胞激酶的作用下磷酸化,随后生成具有药物活性的二磷酸替诺福韦。二磷酸替诺福韦再经过乙肝病毒逆转录酶,进入乙肝病毒的DNA链之中,终止乙肝病毒DNA链的扩展,最终抑制乙肝病毒复制。在临床试验中,TAF已被证明在低于吉利德已上市药物替诺福韦酯(TDF)十分之一剂量时,具有非常高的抗病毒疗效,并在三期临床试验中表现出很好的抗HBV疗效。TAF大大减弱了长期服用TDF所带来的严重不良反应,可改善肾功能和骨骼安全参数,具有广阔的应用前景。
专利文献CN201510943798.8中公开了富马酸替诺福韦艾拉酚胺的以下三个杂质的合成方法:替诺福韦艾拉酚胺异丙酯杂质(TAF-impurity H),替诺福韦艾拉酚胺二苯酯杂质(TAF-impurity I),替诺福韦艾拉酚胺二酰胺酯杂质(TAF impurity J)。
专利文献CN110099912A和WO2017100108A1中披露了制备式Ⅰ类型化合物的合成方法,采用一步法使用DBU等有机碱水解方式,但是所述方法所得到的产品极其不稳定,也没有报道相关的收率、纯度以及核磁谱图等结构确证信息,更没有得到该杂质的标准品,而是作为中间态直接用于其他化合物的合成,所以按照上述方式合成,得不到标准对照杂质,无法作为商品满足市场需求,严重影响申报进度,有待改进。
至今仍未见文献报道式Ⅰ的杂质的合成方法:
发明内容
本发明的目的是提供富马酸替诺福韦艾拉酚胺生产工艺中降解杂质的制备方法,对改进富马酸替诺福韦艾拉酚胺的生产工艺、提高产品质量具有指导意义。
本发明提供了一种式(I)化合物的制备方法,其包括以下步骤:向含有API即替诺福韦艾拉酚胺的溶液中,加入碱,反应后得到式(I)的化合物:
在式(I)的化合物中,M为金属离子;优选为碱金属离子,如Li+、Na+或K+;更优选为Li+。
本发明还提供一种式(II)化合物的制备方法,其包括以下步骤:向含有API-替诺福韦艾拉酚胺的溶液中,加入碱,反应后得到式(II)的化合物:
在式(II)的化合物中,M为金属离子;优选为碱金属离子,如Li+、Na+或K+;更优选为Na+或K+。
根据本发明,所述含有API的溶液采用的溶剂可以选自水、乙醇、甲醇、四氢呋喃和1,4-二氧六环中的一种、或者两种或更多种溶剂的混合物;其中溶剂与API的体积质量比可以为(1~100ml):1g,例如(5~90ml):1g,(10~80ml):1g,(10~70ml):1g,(10~60ml):1g,(10~50ml):1g,(10~40ml):1g,(10~30ml):1g。
根据本发明,所述反应的温度可以为0~80℃,例如5~70℃,10~60℃,15~50℃,15~40℃,15~35℃,20~30℃。
根据本发明,在式(I)化合物的制备方法中,所述碱选自一水氢氧化锂、氢氧化钠或氢氧化钾,优选为一水氢氧化锂;所述碱与API的摩尔比可以为(0.5~1):1,例如(0.6~1):1,(0.7~1):1,(0.8~1):1,(0.85~0.95):1,如0.9:1。
根据本发明,在式(II)化合物的制备方法中,所述碱选自一水氢氧化锂、氢氧化钠或氢氧化钾,优选为氢氧化钠或氢氧化钾;所述碱与API的摩尔比可以为(1~10):1,例如(1.2~9):1,(1.4~8.5):1,(1.5~8):1,(1.6~7.5):1,(1.8~7):1,(2~6.5):1,(2~6):1。
根据本发明,式(I)的化合物为如下的式(I-1)化合物:
根据本发明,其中制备式(I-1)的化合物所使用的碱为一水氢氧化锂。
根据本发明,式(II)的化合物为如下的式(II-1)或式(II-2)化合物:
根据本发明,其中制备式(II-1)的化合物所使用的碱为氢氧化钠,制备式(II-2)的化合物所使用的碱为氢氧化钾。
有益效果
与现有技术相比,本发明通过定向合成法,以替诺福韦艾拉酚胺为原料,采用一步法直接用无机碱水解制备得到式(I)或式(II)的化合物,所得产物以金属盐的形式保存,完全解决了所述化合物的稳定性问题。并且本发明的制备方法反应条件温和,产物的收率高且纯度高。所得式(I)或式(II)的化合物可作为富马酸替诺福韦艾拉酚胺有关物质检测的对照品,对改进生产工艺、提高产品内控质量具有指导意义,有助于富马酸替诺福韦艾拉酚胺质量控制以及制剂纯度的控制。
附图说明
图1为实施例1制备的式(I-1)化合物的质谱图。
图2为实施例1制备的式(I-1)化合物的核磁谱图。
图3为实施例1制备的式(I-1)化合物的有关物质。
图4为实施例2制备的式(II-1)化合物的质谱图。
图5为实施例2制备的式(II-1)化合物的核磁谱图。
图6为实施例2制备的式(II-1)化合物的有关物质。
具体实施方式
下文将结合具体实施例对本发明的技术方案做更进一步的详细说明。应当理解,下列实施例仅为示例性地说明和解释本发明,而不应被解释为对本发明保护范围的限制。凡基于本发明上述内容所实现的技术均涵盖在本发明旨在保护的范围内。
除非另有说明,以下实施例中使用的原料和试剂均为市售商品,或者可以通过已知方法制备。本申请中API指替诺福韦艾拉酚胺。
实施例1式(I-1)化合物的制备
将API(15.0g,31.5mmol,1.0eq)和四氢呋喃(50ml)在室温条件下加入250ml单口瓶中,将一水合氢氧化锂(1.19g,28.35mmol,1.0eq)溶于60ml水中,然后加入上述体系,室温下搅拌反应12小时,体系呈蓝紫色,TLC监测(加甲醇,展开剂:DCM:(MeOH:NH3H2O(10:1))=10:1-2:1)。原料剩余少许,反应体系用二氯甲烷(100ml*2)萃取两次,保留水相,水相减压浓缩,然后冻干,加入80ml乙腈打浆1小时,过滤,得白色固体12g,其为标题化合物。HPLC纯度:98.75%,收率:93.81%,其质谱图如图1所示,核磁表征结果如图2所示,有关物质纯度表征结果如图3所示。
实施例2式(II-1)化合物的制备
将API(15.0g,31.5mmol,1.0eq)和四氢呋喃(60ml)在室温条件下加入250ml单口瓶中,然后将氢氧化钠(6.3g,157.5mmol,5.0eq)溶于100ml水中,加入上述体系,在室温下搅拌15小时,体系澄清,TLC监测(加甲醇,展开剂:DCM:(MeOH:NH3H2O(10:1))=10:1-2:1)。原料完全消失,反应体系用二氯甲烷(100ml*2)萃取两次,保留水相,水相减压浓缩,然后冻干,加入200ml甲醇搅拌1小时基本溶解,过滤,保留甲醇相,向甲醇相中滴加乙腈200ml,析出固体,搅拌至少1小时,过滤,乙腈淋洗,得白色固体10g,其为标题化合物。HPLC纯度:98.71%,收率:78.96%,其质谱图如图4所示,核磁表征结果如图5所示,有关物质纯度表征结果如图6所示。
以上,对本发明的实施方式进行了说明。但是,本发明不限定于上述实施方式。凡在本发明的精神和原则之内,所做的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。
Claims (9)
3.根据权利要求1或2所述的方法,其中所述含有API的溶液采用的溶剂选自水、乙醇、甲醇、四氢呋喃和1,4-二氧六环中的一种、或者两种或更多种溶剂的混合物。
4.根据权利要求3所述的方法,其中所述溶剂与API的体积质量比为(1~100ml):1g,例如(5~90ml):1g,(10~80ml):1g,(10~70ml):1g,(10~60ml):1g,(10~50ml):1g,(10~40ml):1g,(10~30ml):1g。
5.根据权利要求1-4中任一项所述的方法,其中,在式(I)化合物的制备方法中,所述碱选自一水氢氧化锂、氢氧化钠或氢氧化钾,优选为一水氢氧化锂;所述碱与API的摩尔比可以为(0.5~1):1,例如(0.6~1):1,(0.7~1):1,(0.8~1):1,(0.85~0.95):1,如0.9:1。
6.根据权利要求1-4中任一项所述的方法,其中,在式(II)化合物的制备方法中,所述碱选自一水氢氧化锂、氢氧化钠或氢氧化钾,优选为氢氧化钠或氢氧化钾;所述碱与API的摩尔比可以为(1~10):1,例如(1.2~9):1,(1.4~8.5):1,(1.5~8):1,(1.6~7.5):1,(1.8~7):1,(2~6.5):1,(2~6):1。
7.根据权利要求1-6中任一项所述的方法,其中反应温度为0~80℃。
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