CN111662234A - 一种盐酸苯达莫司汀多取代杂质化合物的合成方法及应用 - Google Patents
一种盐酸苯达莫司汀多取代杂质化合物的合成方法及应用 Download PDFInfo
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Abstract
本发明公开了一种盐酸苯达莫司汀多取代杂质化合物的合成方法及应用,所要制备的多取代杂质为4‑(5‑((2‑(2‑氯乙氧基)乙基)(2‑氯乙氧基)胺基)‑1‑甲基‑1H‑苯[d]咪唑‑2‑基)丁酸盐酸盐,该制备方法是以4‑(5‑氨基‑1‑甲基苯并咪唑‑2‑基)丁酸乙酯为原料,经两步取代反应、一步氯代反应、一步水解反应,得到目标产物盐酸苯达莫司汀多取代杂质。盐酸苯达莫司汀多取代杂质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药和制剂纯度控制。
Description
技术领域
本发明涉及医药领域,具体涉及盐酸苯达莫司汀多取代杂质化合物的合成方法及应用。
背景技术
盐酸苯达莫司汀是一种含有氮芥基团和苯并咪唑环的双功能氮芥衍生物,其药理作用是通过烷化作用使DNA单链和双链交联,干扰DNA的合成与功能,从而发挥抗肿瘤作用。适应症为慢性淋巴细胞白血病和用于治疗使用利妥昔单抗无效的复发难治性B细胞非霍奇金淋巴瘤。
盐酸苯达莫司汀化学结构式如下图所示,化学名称为4-(5-(双(2-氯乙基)氨基)-1-甲基苯并咪唑-2-基)丁酸盐酸盐,其结构式如下所示:
关于盐酸苯达莫司汀的合成,国内外已有大量的文献报道,最常见的合成方法是以2,4-二硝基氯苯为起始原料,经甲胺化、还原、与戊二酸酐酰胺化、关环形成苯并咪唑环、还原、与环氧乙烷发生取代、氯代、水解与成盐等共8步反应,得盐酸苯达莫司汀。路线如下所示:
由合成路线可知,第6步反应过程中生成的中间体可与环氧乙烷进一步反应生成副产物,该副产物经氯代、水解、成盐即可转化为盐酸苯达莫司汀多取代杂质,引入到盐酸苯达莫司汀原料药。盐酸苯达莫司汀多取代杂质在盐酸苯达莫司汀原料药和制剂中的含量对药品的安全性、有效性有重要影响,现有技术中通过杂质对照品比对的方式对杂质含量进行控制是最有效的方式。
目前无相关文献报道盐酸苯达莫司汀多取代杂质的合成方法,因此亟需一种合成盐酸苯达莫司汀多取代杂质的方法,其多取代杂质作为盐酸苯达莫司汀有关物质检测对照品,用于盐酸苯达莫司汀原料药和制剂纯度控制。
发明内容
本发明为了解决上述问题,提供了一种盐酸苯达莫司汀多取代杂质化合物的合成方法及应用,该合成方法操作简单,得到的杂质对照品纯度高,并且该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药和制剂纯度控制。
本发明的目的之一在于提供一种盐酸苯达莫司汀多取代杂质化合物的合成方法,具体的,盐酸苯达莫司汀多取代杂质化合物的结构式如式I所示,合成方法包括如下步骤:
(1)化合物式Ⅳ与亲核试剂A于有机溶剂中,在傅酸剂作用下发生反应,得到化合物式Ⅲ;
(2)步骤(1)得到化合物式Ⅲ与亲核试剂B反应,得到化合物式Ⅱ;
(3)步骤(2)得到化合物式Ⅱ与氯代试剂反应后在盐酸中水解,得到盐酸苯达莫司汀多取代杂质化合物式I。
进一步地,步骤(1)中所述的有机溶剂为二甲基甲酰胺、二甲基乙酰胺、二甲亚砜、乙醇、异丙醇、甲醇、丁醇、乙腈中的一种或多种。
进一步地,步骤(1)中所述的傅酸剂为氢氧化钠、氢氧化钾、碳酸钾、碳酸钠、乙醇钠、甲醇钠中的一种或多种。
进一步地,步骤(2)中所述的亲核试剂B为2-溴乙醇、环氧乙烷、2-氯乙醇中的一种或多种。
进一步地,步骤(3)中所述的氯代试剂为二氯亚砜、草酰氯、三氯氧磷、三氯化磷、五氯化磷中的一种或多种。
进一步地,步骤(3)中所述化合物式Ⅱ与氯代试剂的反应温度为35-50℃。
本发明的目的之二在于提供一种组合物,具体的,所述组合物由盐酸苯达莫司汀和结构式如式I所示的化合物组成。
本发明的目的之三在于提供一种由盐酸苯达莫司汀和结构式如式I所示的化合物组成的组合物在制备盐酸苯达莫司汀杂质对照剂中的应用。
本发明的目的之四在于提供一种盐酸苯达莫司汀多取代杂质化合物在制备盐酸苯达莫司汀杂质对照剂中的应用。
本发明的有益之处在于:本发明通过控制氯乙氧乙基和氯乙基的引入顺序,很好地控制反应过程中副产物的生成,能高纯度、操作简单地合成出盐酸苯达莫司汀多取代杂质,并且该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药和制剂纯度控制。
附图说明
图1为本发明的盐酸苯达莫司汀多取代杂质化合物的合成方法路线图。
具体实施方式
下面通过实施例和附图,对本发明进行进一步详细说明,应当理解,此处所描述的具体实施例仅用以解释本发明,并不用于限定本发明,本领域技术人员应该理解的是,在不偏离本发明的结构思路、使用范围下可以对本发明技术方案的细节和形式进行修改或替换,但这些修改和替换均落入本发明的保护范围内。
实施例1:
盐酸苯达莫司汀多取代杂质化合物结构经核磁共振和质谱确证,具体数据为:质谱(MS):m/z=402、404、406[M+H]+(氯原子同位素峰强度约为9:6:1);
1H-NMR(600MHz,DMSO-d6):δ7.70~7.72(d,1H),7.10~7.11(dd,1H),6.89(s,1H),3.90(s,3H),3.79(bs,4H),3.71~3.76(m,2H),3.64~3.68(m,6H),3.15~3.18(t,2H),2.41~2.43(t,2H),2.01~2.04(m,2H);
13C-NMR(600MHz,DMSO-d6):173.68,151.49,146.17,131.59,124.39,113.33,112.27,94.24,70.62,67.70,52.77,50.75,43.69,40.82,32.57,30.96,24.00,21.61。
实施例2
方法一:
反应式:
将26.1g化合物式IV、6.35g碳酸钠、0.2g碘化钾、100ml二甲基甲酰胺、14.9g 2-氯乙氧基乙醇加入反应瓶中,搅拌,升温至80℃反应过夜;次日,加水淬灭反应后用二氯甲烷提取,水洗,干燥,浓缩,得油状物,过柱纯化(甲醇:二氯甲烷=1:25~1:20),得16.5g化合物式Ⅲ,收率47.3%,HPLC纯度94.5%,质谱:m/z=350([M+H]+)。方法二:
反应式:
将35g化合物式Ⅳ、37g碳酸钾、4.7g碘化钾、350ml二甲基甲酰胺、34g 2-溴乙氧基乙醇加入反应瓶中,搅拌,升温至85℃反应过夜;次日,减压浓缩除去二甲基甲酰胺,加入水和二氯甲烷溶解后,分出二氯甲烷层,再用二氯甲烷提取水层,合并有机层,水洗,干燥,浓缩,得油状物,过柱纯化(甲醇:二氯甲烷=1:25~1:20),得30.9g化合物式III,收率66.0%,HPLC纯度97.3%。
实施例3:
方法一:
反应式:
将8.0g化合物式Ⅲ、31.5g溴乙醇、160ml乙醇加入反应瓶,搅拌,降温至0~10℃,滴加165g质量浓度为8.5%乙醇钠的乙醇溶液,滴毕,密封反应瓶,自然升温至室温反应2天后浓缩除去乙醇,加入水,用二氯甲烷提取,水洗,干燥,浓缩至干后用64ml乙酸乙酯结晶,得6.9g化合物式Ⅱ,收率76.7%,HPLC纯度95.6%,质谱:m/z=394([M+H]+)。
方法二:
反应式:
将17.2g化合物式Ⅲ、170ml冰乙酸加入反应瓶,搅拌,降温至5~10℃,加入含有13g环氧乙烷的水溶液,加毕,密封反应瓶,自然升温至室温反应1天后浓缩除去冰乙酸,加入水,用氨水调节pH至8~9后,用二氯甲烷提取,水洗,干燥,浓缩至干后用136ml乙酸乙酯结晶,得17.2g化合物式Ⅱ,收率88.6%,HPLC纯度97.9%。
实施例4:
反应式:
方法一:将5.4g化合物式Ⅱ、80ml三氯甲烷加入反应瓶,搅拌溶清,降温至0~10℃,滴加5.7g二氯亚砜与10ml三氯甲烷的混合液,滴毕,升温至40~50℃反应1.0~1.5小时,反应液减压浓缩至干,加入20g盐酸,于80℃水浴下反应30分钟后自然降温反应过夜;反应液用0.5g活性炭脱色一次后减压浓缩除去盐酸,残留物中加入36g纯化水与1.2g盐酸配制的酸水,降温至0~5℃,析出固体,保温搅拌2小时,抽滤,干燥,得4.3g化合物式I,收率71.7%,HPLC纯度98.1%。
方法二:将2.5g化合物式Ⅱ、50ml三氯甲烷加入反应瓶,搅拌溶清,降温至0~10℃,滴加3.0g三氯氧磷与10ml三氯甲烷的混合液,滴毕,升温至35~45℃反应45分钟,反应液减压浓缩至干,加入15g盐酸,于80℃水浴下反应30分钟后自然降温反应过夜;反应液用0.5g活性炭脱色一次后减压浓缩除去盐酸,残留物中加入18g纯化水与0.6g盐酸配制的酸水,降温至10~15℃,析出固体,保温搅拌1.5小时,抽滤,干燥,得1.3g化合物式I,收率46.4%,HPLC纯度97.1%。
以上所述仅为本发明的较佳实施例,并不用以限制本发明,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。
Claims (10)
3.根据权利要求1所述的制备方法,其特征在于,步骤(1)中所述的有机溶剂为二甲基甲酰胺、二甲基乙酰胺、二甲亚砜、乙醇、异丙醇、甲醇、丁醇、乙腈中的一种或多种。
4.根据权利要求1所述的制备方法,其特征在于,步骤(1)中所述的傅酸剂为氢氧化钠、氢氧化钾、碳酸钾、碳酸钠、乙醇钠、甲醇钠中的一种或多种。
5.根据权利要求1所述的制备方法,其特征在于,步骤(2)中所述的亲核试剂B为2-溴乙醇、环氧乙烷、2-氯乙醇中的一种或多种。
6.根据权利要求1所述的制备方法,其特征在于,步骤(3)中所述的氯代试剂为二氯亚砜、草酰氯、三氯氧磷、三氯化磷、五氯化磷中的一种或多种。
7.根据权利要求1所述的制备方法,其特征在于,步骤(3)中所述化合物式Ⅱ与氯代试剂的反应温度为35-50℃。
8.一种包含盐酸苯达莫司汀的组合物,其特征在于,所述组合物由盐酸苯达莫司汀和结构式如式I所示的化合物组成。
9.权利要求8所述的组合物在制备盐酸苯达莫司汀杂质对照剂中的应用。
10.权利要求1所述的盐酸苯达莫司汀多取代杂质化合物在制备盐酸苯达莫司汀杂质对照剂中的应用。
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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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US20140275566A1 (en) * | 2013-03-14 | 2014-09-18 | Johnson Matthey Plc | Process for drying bendamustine hydrochloride monohydrate |
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