CN110283208A - 一种替诺福韦艾拉酚胺的手性拆分方法 - Google Patents
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Abstract
本发明公开了一种替诺福韦艾拉酚胺的手性拆分方法,属于药物合成领域。本发明方案为消旋体替诺福韦艾拉酚胺(TAF‑2)与D‑酒石酸成盐后,经过弱碱水解,再经晶种诱导析晶得到S构型替诺福韦艾拉酚胺(TAF‑3)。该方法采用常规试剂,毒性较小,适合工业化生产,同时能够得到高纯度的TAF‑3,纯度在97%以上,具有很好的拆分效果。
Description
技术领域
本发明属于医药技术领域,涉及药物合成技术,具体为替诺福韦艾拉酚胺的制备方法。
背景技术
全球范围内乙肝患者大约有4亿人。乙肝是一种威胁生命的疾病,可导致肝硬化,是全 球80%原发性肝癌的直接病因,而且乙肝目前尚无法完全治愈,严重威胁人类健康。
市面上的乙肝治疗药物主要有注射用的干扰素α、聚乙二醇干扰素α,以及口服用的拉 米夫定、替比夫定、阿德福韦酯、替诺福韦二吡呋酯、恩替卡韦等常见核苷类似物。不过干 扰素类具有价格高、不良反应多等缺点,口服核苷类药物具有易耐药、停药易复发等缺点。
2016年11月10日,Gilead宣布FDA批准Vemlidy(替诺福韦艾拉酚胺,TAF)25mg 每日1次用于治疗伴有代偿性肝病的慢性乙肝病毒(HBV)感染患者。
替诺福韦艾拉芬胺是一种具有淋巴细胞和组织富集性的替诺福韦前药。体外活性测试显 示GS-7340的抗病毒活性是替诺福韦二吡呋酯的10倍,替诺福韦的100倍,血浆中的稳定性 是替诺福韦二吡呋酯的200倍,该药的临床用剂量仅为替诺福韦二吡呋酯十分之一或更低。 替诺福韦艾拉酚胺作为一种亲脂性细胞-渗透化合物通过被动扩散和通过肝摄取转运蛋白 OATP1B1和OATP1B3进入原代肝细胞。然后替诺福韦艾拉酚胺通过主要地被在原代肝细胞 内羧酸酯酶(CES1)水解转化为替诺福韦。细胞内替诺福韦随后地被细胞激酶磷酸化至药理学 上活性代谢物二磷酸替诺福韦。二磷酸替诺福韦通过HBV逆转录酶被掺入至病毒DNA抑制 HBV复制,它导致DNA链终止。二磷酸替诺福韦是哺乳动物DNA聚合酶的弱抑制剂,其 中包括线粒体DNA聚合酶γ和在细胞培养中对线粒体几乎无毒性。
替诺福韦艾拉酚胺半富马酸盐(Tenofovir alafenamide,GS-7340,TAF)具有式(I)所示 的结构,化学名称为{9-[(R)-2-[[(S)-[[(S)-1-(异丙氧基羰基)乙基]氨基]苯氧基氧膦基]甲氧 基]丙基]腺嘌呤}的半反丁烯二酸盐。
替诺福韦艾拉酚胺本身含有3个手性中心,在其制备过程中对于其手性的控制极为重要, 现有文献报道的制备方法中对于手性拆分、异构体杂质控制并无详细报道,无法得到纯度较 高的S构型的替诺福韦艾拉酚胺。
发明内容
为了制备得到纯度较高的S构型的替诺福韦艾拉酚胺,本发明提供了一种替诺福韦艾拉 酚胺消旋体先经D-酒石酸拆分再经诱导析晶方法,该方法能够获得S构型的替诺福韦艾拉酚 胺,且纯度超过97%。
本发明反应方程式如下:
本发明的技术方案如下:
消旋体替诺福韦艾拉酚胺(TAF-2)与D-酒石酸成盐后,经过弱碱水解,再经晶种诱导 析晶得到S构型替诺福韦艾拉酚胺(TAF-3)。
具体的:
步骤1)TAF-2与D-酒石酸在乙腈与乙醇的混合溶剂中回流反应,冷却后抽滤保留滤液;
步骤2)滤液加入弱碱水溶液,及有机溶剂,充分搅拌,萃取后得到粗产品;
步骤3)粗产品溶解于乙腈,并加入TAF-3晶种诱导析晶,在室温下搅拌后,置于冰水浴 中搅拌析晶,得到TAF-3产品。
优选的,所述步骤1)中所述乙腈与乙醇的体积比为:7~9:1,所述反应温度为60-82℃, 所述反应时间为0.5-4h。
优选的,所述步骤2)中所述弱碱水溶液为碳酸氢钠饱和溶液,所述有机溶剂为二氯甲烷。
优选的,所述步骤3)中晶种比例为碱水解粗产品的5~15%,进一步优选5~10%。步骤3) 中所述冰水浴的温度为-7~0℃,所述冰水浴中搅拌反应2-4h。
相比于现有技术,本发明的优点在于:
本发明拆分方法使用试剂简单,为常规试剂,毒性较小,适合工业化生产。另外本发明 的披露的方法能够得到高纯度的TAF-3,纯度在97%以上,后续进一步成盐后,能够有效控 制药物替诺福韦艾拉酚胺半富马酸盐的原料药的纯度,降低成药后产品的毒副作用,提高成 药后产品的联系。
附图说明
图1为本发明的实施例1中晶种比例为5%情况下TAF-3产品HPLC检测图(1为TAF-3异构体,2为TAF-3);
图2为本发明的实施例1中晶种比例为0.5%情况下TAF-3产品HPLC检测图(1为TAF-3 异构体,2为TAF-3);
图3为本发明的实施例1中晶种比例为2%情况下TAF-3产品HPLC检测图(1为TAF-3异构体,2为TAF-3);
图4为本发明的实施例1中晶种比例为10%情况下TAF-3产品HPLC检测图(1为TAF-3 异构体,2为TAF-3);
图5为本发明的实施例1中晶种比例为15%情况下TAF-3产品HPLC检测图(1为TAF-3 异构体,2为TAF-3);
图6为本发明的实施例2中TAF-3产品HPLC检测图(1为TAF-3异构体,2为TAF-3)。
具体实施方式
下面结合说明书附图和具体的实施例,对本发明作详细描述。
实施例1
反应方程式如下:
步骤1)
在100mL三口瓶中加入TAF-2 10.0g,乙腈50mL,乙醇6.25mL,搅拌下加入D-(-)酒石酸1.51g,升温加热回流反应1h。停止加热,自然冷却后在冰水浴中搅拌30min。抽滤, 滤饼用少量冷乙腈洗涤,保留滤液。
步骤2)
滤液加入50mL饱和NaHCO3,和50mL二氯甲烷,充分搅拌30min。分液,水相用二 氯甲烷萃取,合并有机相,干燥,得到棕红色油状物5.3g。
步骤3)
红色油状物5.3g,加入20mL乙腈溶解,再加入0.43g TAF-3晶种(5%)诱导析晶,在室温下搅拌1h后,置于-5℃冰水浴中搅拌3h,抽滤干燥得到黄色固体TAF-3 4.7g,产率为42.7%,HPLC检测纯度为结果如图1所示。(其中TAF-3晶种为采购的纯品或者是自制检验纯度大于99%的纯品)
制备多批红色油状物,对于诱导析晶晶种加入比例进行研究。每批使用红色油状物5.3g, 加入不同比例晶种诱导析晶,在室温下搅拌1h后,置于-5℃冰水浴中搅拌3h,抽滤干燥得到 黄色固体TAF-3。产品纯度通过HPLC检测得到,产率按照TAF-2投料量10.0g计算。各组 试验结果汇总如表1所示,结果表明晶种在0.5%~2%的比例范围内产率较低,0.5%~5%比例 随着晶种比例增加产率增加,5-15%左右范围内增加晶种比例后,产率变化不明显。晶种投 料比例变化,其析出晶体纯度变化不大,经过D-酒石酸拆分再经诱导析晶都能得到纯度较高 的产品。最终确定优选的晶种比例范围为4.5~15%。
序号 | 晶种投料比例% | 产率% | 纯度% | 附图编号 |
1 | 0.5 | 11.3 | 97.56 | 图2 |
2 | 2 | 35.6 | 98.16 | 图3 |
3 | 5 | 42.7 | 99.17 | 图1 |
4 | 10 | 45.1 | 99.68 | 图4 |
5 | 15 | 43.5 | 97.59 | 图5 |
实施例2
步骤1)
在2L反应瓶中加入TAF-2 300.g,乙腈1.5L,乙醇187.5mL,搅拌下加入D-(-)酒石酸 45g,升温加热回流反应2h。停止加热,自然冷却后在冰水浴中搅拌1h。抽滤,滤饼用少量冷乙腈洗涤,保留滤液。
步骤2)
滤液加入200mL饱和NaHCO3,和50mL二氯甲烷,充分搅拌1h。分液,水相用二氯 甲烷萃取,合并有机相,干燥,得到棕红色油状物175g。
步骤3)
红色油状物175g用150mL乙腈溶解,加入14g(8.0%)TAF-3晶种诱导析晶,在室温下搅拌1h后,置于-5℃冰水浴中搅拌3h,抽滤干燥得到黄色固体TAF-3 143.3g,HPLC检测纯度为结果如图6所示,纯度为98.64%,产率为43.1%。
Claims (9)
1.一种替诺福韦艾拉酚胺的手性拆分方法,其特征在于,所述消旋体替诺福韦艾拉酚胺与D-酒石酸成盐后,经过弱碱水解,再经晶种诱导析晶得到S构型替诺福韦艾拉酚胺。
2.根据权利要求1所述的手性拆分方法,其特征在于,具体的步骤如下:
步骤1)消旋体替诺福韦艾拉酚胺与D-酒石酸在乙腈与乙醇的混合溶剂中回流反应,冷却后抽滤保留滤液;
步骤2)滤液加入弱碱水溶液,及有机溶剂,充分搅拌,萃取后得到粗产品;
步骤3)粗产品溶解于乙腈,并加入晶种诱导析晶,在室温下搅拌后,置于冰水浴中搅拌析晶,得到S构型替诺福韦艾拉酚胺产品。
3.根据权利要求2所述的手性拆分方法,其特征在于,所述步骤1)中所述乙腈与乙醇的体积比为:7~9:1。
4.根据权利要求2所述的手性拆分方法,其特征在于,所述步骤1)中所述反应温度为60-82℃。
5.根据权利要求2所述的手性拆分方法,其特征在于,所述步骤2)中所述弱碱水溶液为碳酸氢钠饱和溶液。
6.根据权利要求2所述的手性拆分方法,其特征在于,所述步骤2)所述有机溶剂为二氯甲烷。
7.根据权利要求2所述的手性拆分方法,其特征在于,所述步骤3)所述晶种比例为步骤2)中粗产品的5~15%。
8.根据权利要求7所述的手性拆分方法,其特征在于,所述步骤3)所述晶种比例为步骤2)中粗产品的5~10%。
9.根据权利要求2所述的手性拆分方法,其特征在于,所述步骤3)所述冰水浴的温度为-7~0℃。
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