CN105566226B - 盐酸苯达莫司汀二聚体的制备方法与应用 - Google Patents
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Abstract
本发明涉及一种式III所示的盐酸苯达莫司汀二聚体的制备方法与应用。其制备方法是将盐酸苯达莫司汀与单羟基苯达莫司汀盐酸盐在催化剂和缩合剂的条件下反应，得到盐酸苯达莫司汀二聚体(式III所示)。式III化合物可作为盐酸苯达莫司汀有关物质检测用对照品，用于盐酸苯达莫司汀原料或制剂的纯度控制。
Description
技术领域
本发明涉及4-[1-甲基-5-[2-[4-[1-甲基-5-双(2-氯乙基)胺基-2-苯并咪唑基]丁酰氧乙基]-2-氯乙基]胺基-2-苯并咪唑基]丁酸二盐酸盐(即盐酸苯达莫司汀二聚体)的制备方法与应用，盐酸苯达莫司汀二聚体是盐酸苯达莫司汀原料或制剂工艺中的重要杂质。
背景技术
盐酸苯达莫司汀最早于1963年在德国耶拿的微生物试验协会研制获得，是一种双功能基烷化剂。1993年后，Ribosepharm GmbH公司首次完成盐酸苯达莫司汀的大规模临床验证试验，被统一后的德国正式批准上市，商品名主要用于霍奇金病、非霍奇金淋巴瘤、浆细胞瘤(多发性骨髓瘤)、慢性淋巴细胞白血病(CLL)及乳腺癌的治疗。2008年3月20日，FDA批准Cephalon公司开发的注射用盐酸苯达莫司汀在美国上市，用于“慢性淋巴细胞白血病(CLL)”的治疗，商品名同年10月31日，FDA又批准该药用于“接受美罗华或含美罗华方案6个月内进展的惰性B细胞非霍奇金淋巴瘤(NHL)”的治疗。2010年7月，Mundipharma公司以商品名在欧洲上市用于治疗NHL，CLL和多发性骨髓瘤(MM)，2010年12月日本Eisai公司以商品名上市用于治疗NHL和套细胞淋巴瘤(MCL)。盐酸苯达莫司汀的化学结构式如式I所示：
单羟基苯达莫司汀盐酸盐(HP1，式II所示)与盐酸苯达莫司汀二聚体(BM1，式III所示)均为盐酸苯达莫司汀原料及制剂工艺中常见的杂质。
关于盐酸苯达莫司汀二聚体(式III所示)，化学名为4-[1-甲基-5-[2-[4-[1-甲基-5-双(2-氯乙基)胺基-2-苯并咪唑基]丁酰氧乙基]-2-氯乙基]胺基-2-苯并咪唑基]丁酸二盐酸盐，目前相关的文献报道很少，且均未涉及该二聚体的制备，如专利WO2010063476对其分析检测进行了报道。因此，有必要开发该二聚体的制备方法，用于盐酸苯达莫司汀原料和制剂的质量控制。
对盐酸苯达莫司汀原料和制剂的质量控制，必须有质量合格的杂质对照品。本发明的4-[1-甲基-5-[2-[4-[1-甲基-5-双(2-氯乙基)胺基-2-苯并咪唑基]丁酰氧乙基]-2-氯乙基]胺基-2-苯并咪唑基]丁酸二盐酸盐为盐酸苯达莫司汀杂质，可以作为杂质对照品控制盐酸苯达莫司汀原料或制剂的纯度。
发明内容
本发明一方面提供了盐酸苯达莫司汀二聚体的制备方法，其化学结构式如式III所示，化学名称为：4-[1-甲基-5-[2-[4-[1-甲基-5-双(2-氯乙基)胺基-2-苯并咪唑基]丁酰氧乙基]-2-氯乙基]胺基-2-苯并咪唑基]丁酸二盐酸盐。
本发明是参考文献“盐酸苯达莫司汀的合成研究”(海峡药学，2011，23(11)，227-229)制备得到盐酸苯达莫司汀，通过将盐酸苯达莫司汀与单羟基苯达莫司汀盐酸盐(式II所示)反应，开发出的盐酸苯达莫司汀二聚体(式III所示)的合成新方法。具体合成路线如下：
本发明的盐酸苯达莫司汀二聚体的制备步骤：(1)在缩合剂和催化剂作用下，将盐酸苯达莫司汀和单羟基苯达莫司汀盐酸盐在有机溶剂中进行反应；(2)然后通过柱层析方法分离得到盐酸苯达莫司汀二聚体。
进一步地，步骤(1)中所述的有机溶剂选自N,N-二甲基甲酰胺(DMF)、N-甲基吡咯烷酮(NMP)、二甲亚砜(DMSO)或四氢呋喃(THF)中的一种或几种；催化剂选自4-二甲氨基吡啶(DMAP)、三乙胺(TEA)或二异丙基乙胺(DIPEA)；缩合剂选自1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI)、2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(HATU)、N,N’-羰基二咪唑(CDI)或O-苯并三氮唑-N,N,N',N'-四甲基脲四氟硼酸(TBTU)。
进一步地，步骤(2)中柱层析方法使用十八烷基硅烷键合硅胶(ODS-C18)进行分离，流动相为乙腈和稀盐酸的混合液。
更进一步地，稀盐酸的pH值为1～5。
更进一步地，稀盐酸的pH值为2～3。
另一方面，本发明提供了制备的化合物4-[1-甲基-5-[2-[4-[1-甲基-5-双(2-氯乙基)胺基-2-苯并咪唑基]丁酰氧乙基]-2-氯乙基]胺基-2-苯并咪唑基]丁酸二盐酸盐的用途，其可作为盐酸苯达莫司汀的有关物质检测用对照品，用于盐酸苯达莫司汀及其相关制剂的质量控制。
本发明中所述的稀盐酸为浓盐酸和水混合后所得到的氯化氢水溶液，浓盐酸的摩尔浓度不大于12mol/L，本发明中稀盐酸浓度控制在10-1～10-5mol/L之间，其pH值为1～5。
本发明采用的技术方案的优点在于：其一，提供了一种操作便捷，反应条件温和可控的盐酸苯达莫司汀二聚体的制备方法；其二，大大提高反应的稳定性，反应产物纯度高。
式III化合物结构经核磁共振谱和质谱确证，具体数据为：质谱(MS)：m/z＝679[M+H]+，m/z＝677[M-H]+；高分辨质谱(HRMS)：m/z＝679.2335[M+H]+，m/z＝677.2178[M-H]+；1HNMR(DMSO-d6)δ15.20(br,2H),8.00-7.00(br,1H),7.73(d,1H),7.72(d,1H),7.12(d,2H),6.94(d,1H),6.93(d,1H),4.19(t,2H),3.90(s,6H),3.81(t,4H),3.77(m,6H),3.76(m,2H),3.71(t,2H),3.17(t,4H),2.51(t,2H),2.41(t,2H),2.04(m,2H),2.03(m,2H)；13C-NMR(DMSO-d6)δ173.5,172.1,151.5,151.4,146.1,145.7,131.5,124.7,124.5,113.4,113.3,112.4,112.3,94.7,94.6,61.1,52.4,52.3,49.3,41.0,32.5,32.3,31.0,30.9,23.9,23.8,21.6,21.4。
附图说明
图1为盐酸苯达莫司汀二聚体的合成路线图。
具体实施方式
本发明将于下文通过实施例更加详细的描述，这些实施例示例性地用于进一步说明，且不应当视为对本发明的限制。
实施例中式I化合物(盐酸苯达莫司汀)是按照文献“盐酸苯达莫司汀的合成研究”(海峡药学，2011，23(11)，227-229)报道的盐酸苯达莫司汀的合成方法，以2,4-二硝基氯苯为起始原料，经取代、还原、酰化、环合、还原、取代、氯代和水解制备得到盐酸苯达莫司汀的。其他材料与试剂均为市售可得。
实施例1：式II化合物的制备
盐酸苯达莫司汀(式I化合物，1g)和5％K2CO35ml混合搅拌，加热至25℃，反应1小时，用3mol/L的盐酸溶液调节pH到5，加入乙腈，过滤，母液采用柱层析方法纯化。具体柱层析条件：硅胶为十八烷基硅烷键合硅胶(ODS-C18)，流动相为稀盐酸(pH为5)：乙腈＝3:1(体积比)，流速为2ml/分钟，收集相应的组分，在10℃以下减压浓缩后冷冻干燥，得0.35g化合物II，HPLC纯度99.5％。
实施例2：式III化合物的制备
将盐酸苯达莫司汀(式I化合物，70mg)、单羟基苯达莫司汀盐酸盐(式II化合物，50mg)、THF(4ml)、EDCI(100mg)和DMAP(38mg)加入反应瓶，室温下反应4小时，采用柱层析方法纯化。具体柱层析条件：硅胶为十八烷基硅烷键合硅胶(ODS-C18)，流动相为稀盐酸(pH为5)：乙腈＝10:1(体积比)，流速为3ml/分钟，收集相应的组分，在5℃以下浓缩，冷冻干燥，得25mg化合物III，HPLC纯度97.6％。
实施例3：式III化合物的制备
将盐酸苯达莫司汀(式I化合物，60mg)、单羟基苯达莫司汀盐酸盐(式II化合物，50mg)、NMP(4ml)、TBTU(150mg)和DIPEA(41mg)加入反应瓶，室温下反应4小时，采用柱层析方法纯化。具体柱层析条件：硅胶为十八烷基硅烷键合硅胶(ODS-C18)，流动相为稀盐酸(pH为3)：乙腈＝10:1(体积比)，流速为3ml/分钟，收集相应的组分，在5℃以下浓缩，冷冻干燥，得30mg化合物III，HPLC纯度97.5％。
实施例4：式III化合物的制备
将盐酸苯达莫司汀(式I化合物，43mg)、单羟基苯达莫司汀盐酸盐(式II化合物，33mg)、DMF(4ml)、HATU(150mg)和TEA(35mg)加入反应瓶，室温下反应3小时，采用柱层析方法纯化。具体柱层析条件：硅胶为十八烷基硅烷键合硅胶(ODS-C18)，流动相为稀盐酸(pH为1)：乙腈＝10:1(体积比)，流速为3ml/分钟，收集相应的组分，在5℃以下浓缩，冷冻干燥，得28mg化合物III，HPLC纯度98.3％。
实施例5：式III化合物的制备
将盐酸苯达莫司汀(式I化合物，506mg)、单羟基苯达莫司汀盐酸盐(式II化合物，508mg)、DMSO(5ml)、EDCI(503mg)和DMAP(254mg)加入反应瓶，室温下反应3小时，采用柱层析方法纯化。具体柱层析条件：硅胶为十八烷基硅烷键合硅胶(ODS-C18)，流动相为稀盐酸(pH为2)：乙腈＝10:1(体积比)，流速为5ml/分钟，收集相应的组分，在5℃以下浓缩，冷冻干燥，得236mg化合物III，HPLC纯度98.6％。
Claims (6)
1.一种式III的盐酸苯达莫司汀二聚体的制备方法，其特征在于包括如下步骤：
(1)在2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯和三乙胺作用下，将式II的单羟基苯达莫司汀盐酸盐和式I的盐酸苯达莫司汀在有机溶剂中进行反应；
(2)然后通过柱层析方法分离得到盐酸苯达莫司汀二聚体；
2.根据权利要求1所述的制备方法，其特征在于：步骤(1)中所述的有机溶剂选自N,N-二甲基甲酰胺、N-甲基吡咯烷酮、二甲亚砜或四氢呋喃中的一种或几种。
3.根据权利要求1所述的制备方法，其特征在于：步骤(1)中所述的有机溶剂选择N,N-二甲基甲酰胺。
4.根据权利要求1所述的制备方法，其特征在于：步骤(2)中所述柱层析方法使用十八烷基硅烷键合硅胶进行分离，流动相为乙腈和稀盐酸的混合液。
5.根据权利要求4所述的制备方法，其特征在于：所述稀盐酸的pH值为1～5。
6.根据权利要求4所述的制备方法，其特征在于：所述稀盐酸的pH值为2～3。
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| CN102292073A (zh) * | 2008-12-03 | 2011-12-21 | 安斯泰来德国有限公司 | 苯达莫司汀的固体剂型 |
| CN103351346A (zh) * | 2013-07-29 | 2013-10-16 | 东南大学 | 盐酸苯达莫司汀杂质hp1的制备方法 |
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| CN102292073A (zh) * | 2008-12-03 | 2011-12-21 | 安斯泰来德国有限公司 | 苯达莫司汀的固体剂型 |
| CN103351346A (zh) * | 2013-07-29 | 2013-10-16 | 东南大学 | 盐酸苯达莫司汀杂质hp1的制备方法 |
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