CN114380723A - 一种对羟基苯磺酸盐化合物及其制备方法和用途 - Google Patents
一种对羟基苯磺酸盐化合物及其制备方法和用途 Download PDFInfo
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Abstract
本发明涉及一种对羟基苯磺酸盐化合物及其用途,所述对羟基苯磺酸盐化合物具体为羟苯磺酸钙及酚磺乙胺杂质,其是在使用对苯二酚为起始物料合成时起始原料中带入的杂质苯酚,在磺化过程中生成的工艺杂质,所述化合物起到在酚磺乙胺原料药和羟苯磺酸钙原料药的杂质对照品的用途。本发明对酚磺乙胺及羟苯磺酸钙原料药质量研究有一定的指导意义。
Description
技术领域
本发明涉及羟基苯磺酸盐化合物的合成领域,尤其涉及一种酚磺乙胺和羟苯磺酸钙杂质及其制备方法和用途。
背景技术
酚磺乙胺(止血敏)是一种人工合成的止血药,具有减少毛细血管通透性,能增强毛细血管抵抗力,使血管收缩,缩短出血时间,能促使血小板循环量增加,增加血小板聚集性与黏附性,促使凝血活性物质从血小板释放,加快血块收缩,是临床上常用的止血药。酚磺乙胺止血作用迅速,能维持4~6h,适用于预防和治疗外科手术出血过多,血小板减少性紫癜或过敏性紫癜以及其他原因引起的出血,如:脑出血、胃肠道出血、泌尿道出血、眼底出血、齿龈出血、鼻出血和皮肤出血等。其结构为:
羟苯磺酸钙化学名称为2,5-二羟基苯磺酸钙,又名多贝斯,国外商品名为Doxium,国际非专利药品名为Calcium dobesilate,是一种用于改善微循环的血管营养剂,主要用于治疗各种原因引起的毛细血管疾病,对急性心肌梗塞也有良好的效果。而且主要是指一水合经苯磺酸钙,其结构式为:
2,5-二羟基苯磺酸钙可降低活性氧诱导的毛细血管通透性增加及毛细血管脆性,增强抵抗力,具有抗氧化性能,改善淋巴液的回流,减少水肿;抑制毛细血管活性物质如组胺、5-羟色胺、透明质酸、血小板激活因子等对微血管的高通透作用,减少血管内膜损伤,改善基底膜胶原的生物合成,阻止毛细血管基底膜增厚;降低血液黏稠度,降低凝血因子Ⅰ和球蛋白水平,纠正清蛋白/球蛋白比值,降低血小板的高聚性,激活纤维蛋白酶活性,增加纤维蛋白的溶解能力,从而防止血栓形成并提高红细胞柔韧性。口服后经胃肠道吸收,血浆半衰期约5h,主要以原型通过大小便***。
目前最简单的合成方法是以对苯二酚为原料合成制得酚磺乙胺和对羟基苯磺酸钙。
中国专利申请CN01131818.X公开了一种羟基苯磺酸钙水合物的合成工艺,采用对苯二酚和浓硫酸进行磺化,加入乙醇水溶解,加入碳酸钙进行中和,调节pH值,过滤,滤液减压浓缩,冷却,结晶抽滤得到粗产品,在进行冷却结晶,无水乙醇和水混合洗涤得到高纯度的羟基苯磺酸钙。
中国专利申请CN201910991493.2公开了一种1/20水,酚磺乙胺化合物的合成,酚磺乙胺化合物纯度高,并具有较好的热稳定性,并且基本不吸湿。
中国专利申请CN201811481951.X公开了一种减少羟苯双磺酸钙杂质含量的羟苯磺酸钙制备方法,包括磺化反应、中和反应、粗品冷却析晶;磺化反应,选用89-91%的硫酸,按硫酸与对苯二酚摩尔比为1:1.38-1.43混合,在78-80℃下保温反应3-3.5小时后,加入对苯二酚二倍水量;中和反应,将磺化反应的物质加碳酸钙进行中和反应,调pH值为4;过滤除去固体产物,收集滤液;将滤液移至减压蒸馏装置中,加热至58-60℃,结晶析出时停止加热,冷却到4℃放至初结晶体析出,加热过程不小于2小时,冷却过程不于小7小时;精制后冷却析晶,将初结晶体与水混合溶解,加热至60℃停止加热,冷却至4℃放至精结晶体析出,干燥得到羟苯磺酸钙,测得羟苯磺酸钙中羟苯双磺酸钙含量小于0.15‰,羟苯磺酸钙纯度达到999.6‰。
中国专利申请CN201811428838.5公开了一种生产高纯度酚磺乙胺的方法,本方法为对苯二酚为起始原料、磺化剂、分散剂、有机溶剂进行磺化反应即得2,5-二羟基苯磺酸,然后冷却反应液至45-70℃,加入二乙胺和水混合溶液成盐,冷却析晶得酚磺乙胺,本方法所用反应体系改善了体系的流动性,提高了三传一反的效率从而使得物料的转化率提高5%~10%;反应结束后待体系冷却至45~70℃时,向体系中直接加入二乙胺和水混合溶液,简化了操作缩短了后处理时间;避免了浓缩水降低了能耗且产品成盐后的收率达到80~85%;产品无需通过重结晶,活性炭除色步骤,纯度直接达到99.5%以上,所有单杂均低于0.05%;另外也避免使用了一类溶剂和含有基因毒性警示结构的试剂,全部改用安全低毒对人和环境更加友好的二类、三类溶剂。
酚磺乙胺与羟苯磺酸钙分子主体一致,只是2,5-二羟基苯磺酸所形成的盐不同。酚磺乙胺为2,5-二羟基苯磺酸的二乙胺盐;羟苯磺酸钙为2,5-二羟基苯磺酸的钙盐水合物。这两种药物临床疗效确切、安全性好,尽管如此酚磺乙胺和羟苯磺酸钙也有潜在的毒副作用,从而引起不良反应,不良反应的产生除与药物本身的药理活性有关外,与其中存在的杂质也有极大的关系。在合成反应中,起始物料的杂质和副反应所产生的杂质,不可避免地会带入到成品中,成为酚磺乙胺及羟苯磺酸钙难以清除的杂质,因此,将酚磺乙胺及羟苯磺酸钙成品中所含有的杂质发现、确证结构并制备出来作为杂质对照品,用于酚磺乙胺及羟苯磺酸钙原料药及制剂的质量控制,对酚磺乙胺及羟苯磺酸钙的质量、安全评价有着重要的意义。但目前酚磺乙胺及羟苯磺酸钙的杂质研究工作比较滞后。
中国专利申请CN201911413121.8公开了4类酚磺乙胺和羟苯磺酸钙杂质及其制备方法,分别为2,5-二羟基-1,4-苯二磺酸化合物、2,4-二羟基-1,5-苯二磺酸化合物、2,5-二羟基苯磺酸酯化合物、2,3-二羟基苯磺酸化合物,本发明所制备得到的化合物纯度均在96%以上,可应用于酚磺乙胺及羟苯磺酸钙原料药及制剂的质量控制。
近年来为加强药物的质量和安全性,国家食品药品监督管理局对药物的杂质质控越来越严格,杂质研究成为人们关注的重点。
发明内容
本发明的目的是提供一种酚磺乙胺和羟苯磺酸钙杂质及其制备方法与用途,即本发明的对羟基苯磺酸盐化合物,其可以为对酚磺乙胺及羟苯磺酸钙原料药及制剂的质量控制提供对照品。
本发明所述的一种对羟基苯磺酸盐化合物,其结构为:
或
本发明还提供了所述的对羟基苯磺酸盐化合物的制备方法,包括如下步骤:
(1)使用苯酚与磺化剂在溶剂中加热至25-95℃,搅拌保温反应4-8h,反应完成后去除溶剂;
(2)步骤(1)得到的产物加入水分散后,向其中加入碱形成盐,趁热过滤,滤液在0-5℃下搅拌析晶6-8小时,经洗涤后得到。
优选地,所述的苯酚与磺化剂的摩尔比为1:1.05-1.7。
优选地,步骤(1)中采用的磺化剂为氯磺酸或硫酸。
更优选地,所采用的磺化剂为硫酸,步骤(1)中苯酚与硫酸的摩尔比为1:1.4-1.7。
优选地,步骤(1)中溶剂为正庚烷、正己烷、三氯甲烷、1,2-二氯乙烷中的一种,溶剂用量为苯酚投料体积的3-5倍;步骤(2)中加入的水的体积为苯酚投料质量的0.6-1.3倍。
优选地,所述的步骤(2)中加入的碱为二乙胺或者碳酸钙,碱与苯酚的摩尔比为0.5-1.2:1。
优选地,还包括在步骤(2)产物洗涤后进行重结晶的步骤,重结晶溶剂为水或者水与异丙醇溶液。
本发明还提供了对羟基苯磺酸盐化合物或前述任一项方法制备得到的对羟基苯磺酸盐化合物作为酚磺乙胺原料药和羟苯磺酸钙原料药的杂质对照品的用途。
酚磺乙胺对应杂质为对羟基苯磺酸二乙胺盐,其结构为:
羟苯磺酸钙对应的杂质为对羟基苯磺酸钙盐,其结构为:
本发明的优点:
本发明公开了酚磺乙胺及羟苯磺酸钙的工艺杂质,为酚磺乙胺、羟苯磺酸钙原料及制剂的质量控制提供了对照品。本发明所合成的杂质对羟基苯磺酸盐主要是由于在酚磺乙胺及羟苯磺酸钙的合成工艺中起始原料对苯二酚中包含的杂质苯酚所生成。
附图说明
图1对羟基苯磺酸二乙胺盐杂质的-核磁氢谱图
图2对羟基苯磺酸二乙胺盐杂质的-核磁碳谱图
图3对羟基苯磺酸二乙胺盐杂质的-红外光谱图
图4对羟基苯磺酸二乙胺盐杂质的-质谱图
图5对羟基苯磺酸钙盐杂质的-核磁氢谱图
图6对羟基苯磺酸钙盐杂质的-核磁碳谱图
图7对羟基苯磺酸钙盐杂质的-红外光谱图
图8对羟基苯磺酸钙盐杂质的-质谱图
具体实施方式
为使本申请实施例的目的、技术方案和优点更加清楚,下面将结合本申请实施例中附图,对本申请实施例中的技术方案进行清楚、完整地描述,显然,所描述的实施例仅仅是本申请一部分实施例,而不是全部的实施例。通常在此处附图中描述和示出的本申请实施例的组件可以以各种不同的配置来布置和设计。因此,以下对在附图中提供的本申请的实施例的详细描述并非旨在限制要求保护的本申请的范围,而是仅仅表示本申请的选定实施例。基于本申请的实施例,本领域技术人员在没有做出创造性劳动的前提下所获得的所有其他实施例,都属于本申请保护的范围。
在本申请实施例的描述中,需要说明的是,术语“上”、“下”、“左”、“右”、“竖直”、“水平”、“内”、“外”等指示的方位或位置关系为基于附图所示的方位或位置关系,或者是该发明产品使用时惯常摆放的方位或位置关系,仅是为了便于描述本申请和简化描述,而不是指示或暗示所指的装置或元件必须具有特定的方位、以特定的方位构造和操作,因此不能理解为对本申请的限制。此外,术语“第一”、“第二”、“第三”等仅用于区分描述,而不能理解为指示或暗示相对重要性。
以下各实施例中的实验方法,如无特殊说明,均为常规方法。下述实施例中所用的试验材料,如无特殊说明,均为从常规供应商处购买得到。
实施例1对羟基苯磺酸二乙胺盐合成
取苯酚94.10g加入282ml正庚烷(3倍苯酚投料质量体积)142.10g硫酸(用量为苯酚的1.45当量),加热搅拌至回流,搅拌保温反应4h。反应毕,倒除溶剂,降温至室温后,加56ml入水(苯酚投料量0.6倍质量体积)分散后,控制50~60℃加入87.68g二乙胺(用量为苯酚的1.2当量)成盐。成盐毕,降温至0~5℃搅拌保温析晶6小时,抽滤,使用150ml异丙醇淋洗滤饼,滤饼60℃真空减压干燥4h得到209.02g类白色粉末状粗品,摩尔收率84.52%。
去200.04g粗品,加入160ml异丙醇水溶液重结晶(异丙醇:水=8:2,按体积比配置),加热至回流溶清。溶清后,自然降温至室温,再降温至内温0~5℃搅拌析晶3h,抽滤过滤,滤饼使用150ml异丙醇淋洗滤饼,收集滤饼60℃减压干燥4h,得到156.91g纯净的目标化合物,精制收率78.45,化合物呈白色粉末状晶体,样品液相纯度99.85%。
其结构经核磁氢谱、核磁碳谱、红外光谱、质谱确认,详见附图1-4。
实施例2对羟基苯磺酸钙盐合成
取94.23g苯酚加入424ml正己烷(用量为苯酚投料量的4.5倍质量体积)及147.51g硫酸(用量为苯酚投料量的1.5当量),加热搅拌至回流,搅拌保温反应8h。反应毕,降温至室温后,倒除溶剂,加122.5ml入水(用量为苯酚投料量的1.3倍质量体积)分散后,分批加入114.13g碳酸钙(加入量为苯酚投料量的1.14当量)调pH值至5成盐。成盐毕,滤除不溶物,滤液50℃真空减压浓缩,至体系微浊,停止浓缩。将浓缩残液降温至0~5℃搅拌析晶8小时,抽滤,并用120ml异丙醇淋洗滤饼。收集滤饼60℃真空减压干燥4h,得到124.75g粗品,摩尔收率64.57%,样品呈类白色粉末。
取115.41g粗品加入126ml(水用量为1.1倍粗品投料体积),加热至回流溶清,再50℃减压浓缩,至体系微浊,停止浓缩,先降温至室温,再降温至内温0~5℃搅拌析晶7h,过滤,100ml异丙醇淋洗滤饼,收集滤饼60℃真空减压干燥5h,得到59.78g目标化合物样品,样品呈类白色粉末,精制收率51.45%,化合物液相纯度99.35%。
其结构经核磁氢谱、核磁碳谱、红外光谱、质谱确认,详见附图5-8。
以上所述实施例仅表达了本申请的具体实施方式,其描述较为具体和详细,但并不能因此而理解为对本申请保护范围的限制。应当指出的是,对于本领域的普通技术人员来说,在不脱离本申请技术方案构思的前提下,还可以做出若干变形和改进,这些都属于本申请的保护范围。
Claims (9)
2.如权利要求1所述的对羟基苯磺酸盐化合物的制备方法,包括如下步骤:
(1)使用苯酚与磺化剂在溶剂中加热至25-95℃,搅拌保温反应4-8h,反应完成后去除溶剂;
(2)步骤(1)得到的产物加入水分散后,向其中加入碱形成盐,趁热过滤,滤液在0-5℃下搅拌析晶6-8小时,经洗涤后得到。
3.如权利要求2所述的一种高纯度羟基苯磺酸盐的制备方法,其特征在于所述的苯酚与磺化剂的摩尔比为1:1.05-1.7。
4.如权利要求2或3所述的一种高纯度羟基苯磺酸盐的制备方法,其特征在于所述的步骤(1)中采用的磺化剂为氯磺酸或硫酸。
5.如权利要求2-4任一项所述的一种高纯度羟基苯磺酸盐的制备方法,其特征在于,所采用的磺化剂为硫酸,步骤(1)中苯酚与硫酸的摩尔比为1:1.4-1.7。
6.如权利要求2-5任一项所述的一种高纯度羟基苯磺酸盐的制备方法,其特征在于所述的步骤(1)中溶剂为正庚烷、正己烷、三氯甲烷、1,2-二氯乙烷中的一种,溶剂用量为苯酚投料体积的3-5倍;步骤(2)中加入的水的体积为苯酚投料质量的0.6-1.3倍。
7.如权利要求2-6任一项所述的一种高纯度羟基苯磺酸盐的制备方法,其特征在于:所述的步骤(2)中加入的碱为二乙胺或者碳酸钙,碱与苯酚的摩尔比为0.5-1.2:1。
8.如权利要求2-7任一项所述的一种高纯度羟基苯磺酸盐的制备方法,其特征在于:还包括在步骤(2)产物洗涤后进行重结晶的步骤,重结晶溶剂为水或者水与异丙醇溶液。
9.如权利要求1所述的对羟基苯磺酸盐化合物或权利要求2-8任一项方法制备得到的对羟基苯磺酸盐化合物作为酚磺乙胺原料药和羟苯磺酸钙原料药的杂质对照品的用途。
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