CN111689868A - 1-【(4-羟乙基)苯氧基】-3-(异丙基氨基)丙-2-醇的制备方法与应用 - Google Patents
1-【(4-羟乙基)苯氧基】-3-(异丙基氨基)丙-2-醇的制备方法与应用 Download PDFInfo
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Abstract
Description
技术领域
本发明属于药物制备技术领域,主要涉及化合物1-【(4-羟乙基)苯氧基】-3-(异丙基氨基)丙-2-醇的制备方法以及在盐酸倍他洛尔及盐酸倍他洛尔滴眼液有关物质检测中的应用。
背景技术
盐酸倍他洛尔为选择性B1受体阻滞药,几乎不阻断B2受体,并具有钙离子拮抗作用,无内源性拟交感活性,有一定的膜稳定作用,可通过抑制房水产生以及增加房水流出来降低眼压,可降低青光眼或其他眼病引起的眼压升高。临床上基于此机制主要用来治疗开角型青光眼、手术后未完全控制的闭角型青光眼和高眼压症。主要剂型为滴眼剂。目前国内外药品标准对盐酸倍他洛尔及盐酸倍他洛尔滴眼液的有关物质控制较为简单,对其相关杂质研究的文献报道更是少之甚少。为了保证盐酸倍他洛尔滴眼液临床使用的安全性,我们对盐酸倍他洛尔及其滴眼剂的有关物质进行了系统的研究,发现1-【(4-羟乙基)苯氧基】-3-(异丙基氨基)丙-2-醇是盐酸倍他洛尔及其滴眼剂中的主要杂质,与盐酸倍他洛尔临床用药不良反应的发生有很大的关系。
1-【(4-羟乙基)苯氧基】-3-(异丙基氨基)丙-2-醇又称倍他洛尔杂质A,分子式为C14H23NO3,分子量:253.34,化学结构式如下:
倍他洛尔杂质A结构式
倍他洛尔杂质A是一种白色固体粉末,易溶于水,是盐酸倍他洛尔储存过程中产生的降解产物,是影响盐酸倍他洛尔产品质量和安全性的潜在隐患。在盐酸倍他洛尔有关物质研究领域,倍他洛尔杂质A的制备及检测方法均属首次提出,其制备合成方法和应用均未见国内文献报道。
发明内容
本发明目的在于,提供了1-【(4-羟乙基)苯氧基】-3-(异丙基氨基)丙-2-醇的制备方法。
本发明还提供了制备得到的1-【(4-羟乙基)苯氧基】-3-(异丙基氨基)丙-2-醇的应用,可作为对照品,用于检测盐酸倍他洛尔及其滴眼液中的1-【(4-羟乙基)苯氧基】-3-(异丙基氨基)丙-2-醇的含量检测,为盐酸倍他洛尔及其滴眼液质量标准的提升及产品质量的安全性控制提供了技术支撑和物质保障,使盐酸倍他洛尔国家标准处于世界领先水平,具有良好的经济效益和社会效益。
本发明为了实现上述目的所采用的技术方案为:
本发明提供了一种1-【(4-羟乙基)苯氧基】-3-(异丙基氨基)丙-2-醇的制备方法,所述方法合成路线如下所示:
本发明提供的制备方法,具体包括以下步骤:
(1)将50g对羟基苯乙醇加至450ml乙腈中,升温至40℃全溶,加入100g碳酸钾,83.7g环氧氯丙烷,升温至回流反应6h,TLC检测原料不再减少,降温至室温,过滤,滤液浓缩干,甲苯带干一次,得化合物A;
(2)将20g化合物A的粗品加至100ml异丙胺中,回流反应4h,TLC检测原料反应完,将反应液浓缩干,柱层析精制得产物。
进一步的,所述TLC所使用的展开剂为DCM:MeOH=10:1。
本发明还提供了一种通过上述制备方法制备的1-【(4-羟乙基)苯氧基】-3-(异丙基氨基)丙-2-醇的应用,所述应用为在检测盐酸倍他洛尔及其滴眼液中的1-【(4-羟乙基)苯氧基】-3-(异丙基氨基)丙-2-醇作为对照品,进行有关物质成分及含量检测。
进一步的,所述成分检测时,包括以下步骤:取本品,摇匀,用内容量移液管精密量取2ml,置25ml量瓶中,加0.6mol/L氯化钾溶液适量,超声使盐酸倍他洛尔溶解,用0.6mol/L氯化钾溶液稀释至刻度,摇匀,离心,取上清液作为供试品溶液;精密量取1ml,置100ml量瓶中,用0.6mol/L氯化钾溶液稀释至刻度,摇匀,作为对照溶液;精密量取对照溶液5ml,置100ml量瓶中,用0.6mol/L氯化钾溶液稀释至刻度,摇匀,作为灵敏度溶液;取灵敏度溶液20µl注入液相色谱仪,记录色谱图,主成分峰高的信噪比应大于10;再精密量取供试品溶液与对照溶液各20µl,分别注入液相色谱仪,记录色谱图至主成分峰保留时间的5倍。
进一步的,所述含量检测的具体步骤为:取本品,摇匀,用内容量移液管精密量取2ml,置50ml量瓶中,加0.6mol/L氯化钾溶液适量,超声使盐酸倍他洛尔溶解,用0.6mol/L氯化钾溶液稀释至刻度,摇匀,离心,取上清液作为测定总倍他洛尔的供试品溶液;另取本品适量,以每分钟15000转离心30分钟,精密量取上清液2ml,置50ml量瓶中,用0.6mol/L氯化钾溶液稀释至刻度,摇匀,作为测定游离态倍他洛尔的供试品溶液,精密量取20μl注入液相色谱仪,记录色谱图;另取盐酸倍他洛尔对照品适量,用0.6mol/L氯化钾溶液溶解并稀释制成每1ml中约含倍他洛尔0.1mg的对照品溶液,同法测定;按外标法以峰面积分别计算总倍他洛尔与游离态倍他洛尔标示含量,再以总倍他洛尔与游离态倍他洛尔标示含量的差值除以总倍他洛尔的标示含量,计算结合态倍他洛尔相当于总倍他洛尔的百分含量。
所述检测过程中采用液相色谱法色谱条件为:用十八烷基硅烷键合硅胶为填充剂, C18柱,4.6mm×150 mm,3μm;以磷酸盐缓冲液-乙腈(53:47),并含0.3%十二烷基硫酸钠的混合溶液作为流动相;检测波长为220nm;流速为每分钟1.25ml。
本发明所使用的磷酸盐缓冲液具体配置过程为:取磷酸5ml,加水900ml,用浓氨溶液调节pH值至3.0,用水稀释至1000ml,摇匀即可。
本发明的有益效果为:
(1)本发明首次提供了1-【(4-羟乙基)苯氧基】-3-(异丙基氨基)丙-2-醇的制备方法,制备过程简单可控,易操作。
(2)本发明制备的1-【(4-羟乙基)苯氧基】-3-(异丙基氨基)丙-2-醇可作为对照品,用于检测盐酸倍他洛尔及其滴眼液中的1-【(4-羟乙基)苯氧基】-3-(异丙基氨基)丙-2-醇的含量及成分的分析鉴定,为盐酸倍他洛尔及其滴眼液质量标准的提升及产品质量的安全性控制提供了技术支撑和物质保障,使盐酸倍他洛尔国家标准处于世界领先水平,具有良好的经济效益和社会效益。
附图说明
图1为实施例1合成的1-【(4-羟乙基)苯氧基】-3-(异丙基氨基)丙-2-醇的质谱图。
图2为实施例1合成的1-【(4-羟乙基)苯氧基】-3-(异丙基氨基)丙-2-醇的氢谱图。
图3为系统适用性试验液相色谱图。
具体实施方式
下面通过具体的实施例对本发明的技术方案作进一步的解释和说明。
实施例1
(1)化合物A的合成反应方程式如下:
反应中所使用的反应物及产物如表1所示。
表1
具体反应步骤如表2所示。
表2
(2)终产物反应方程式如下:
反应中所使用的反应物及产物如表3所示。
表3
具体反应步骤如表4所示。
表4
将合成的化合物进行核磁共振氢谱和质谱鉴定,谱图如图1和图2所示,鉴定结构正确。
效果实施例 1-【(4-羟乙基)苯氧基】-3-(异丙基氨基)丙-2-醇在盐酸倍他洛尔及滴眼液有关物质检测中的应用
(一)有关物质与含量测定
(1)有关物质 取本品,摇匀,用内容量移液管精密量取2ml,置25ml量瓶中,加0.6mol/L氯化钾溶液适量,超声使盐酸倍他洛尔溶解,用0.6mol/L氯化钾溶液稀释至刻度,摇匀,离心,取上清液作为供试品溶液;精密量取1ml,置100ml量瓶中,用0.6mol/L氯化钾溶液稀释至刻度,摇匀,作为对照溶液;精密量取对照溶液5ml,置100ml量瓶中,用0.6mol/L氯化钾溶液稀释至刻度,摇匀,作为灵敏度溶液。照含量测定项下的色谱条件,取灵敏度溶液20µl注入液相色谱仪,记录色谱图,主成分峰高的信噪比应大于10。再精密量取供试品溶液与对照溶液各20µl,分别注入液相色谱仪,记录色谱图至主成分峰保留时间的5倍。供试品溶液的色谱图中如有杂质峰,杂质A峰面积不得大于对照溶液主峰面积的0.8倍(0.8%),杂质F峰面积不得大于对照溶液主峰面积的0.3倍(0.3%),其他单个杂质峰面积不得大于对照溶液主峰面积的0.5倍(0.5%),各杂质峰面积的和不得大于对照溶液主峰面积的2倍(2.0%)。
(2)含量测定
色谱条件与系统适用性试验 用十八烷基硅烷键合硅胶为填充剂(Thermo BDSHYPERSIL C18柱,4.6mm×150 mm,3μm或效能相当的色谱柱);以磷酸盐缓冲液(取磷酸5ml,加水900ml,用浓氨溶液调节pH值至3.0,用水稀释至1000ml,摇匀)-乙腈(53:47),并含0.3%十二烷基硫酸钠的混合溶液作为流动相;检测波长为220nm;流速为每分钟1.25ml。取盐酸倍他洛尔、杂质A与杂质F对照品各适量,加0.6mol/L氯化钾溶液溶解并稀释制成每1ml中约含倍他洛尔0.2mg、杂质A 8µg与杂质F 3µg的溶液,取20µl注入液相色谱仪,记录色谱图,倍他洛尔峰、杂质A峰与杂质F峰之间的分离度均应符合要求,理论板数按倍他洛尔峰计算应不低于3000。
测定法 取本品,摇匀,用内容量移液管精密量取2ml,置50ml量瓶中,加0.6mol/L氯化钾溶液适量,超声使盐酸倍他洛尔溶解,用0.6mol/L氯化钾溶液稀释至刻度,摇匀,离心,取上清液作为测定总倍他洛尔的供试品溶液;另取本品适量,以每分钟15000转离心30分钟,精密量取上清液2ml,置50ml量瓶中,用0.6mol/L氯化钾溶液稀释至刻度,摇匀,作为测定游离态倍他洛尔的供试品溶液,精密量取20μl注入液相色谱仪,记录色谱图;另取盐酸倍他洛尔对照品适量,用0.6mol/L氯化钾溶液溶解并稀释制成每1ml中约含倍他洛尔0.1mg的对照品溶液,同法测定。按外标法以峰面积分别计算总倍他洛尔与游离态倍他洛尔标示含量,再以总倍他洛尔与游离态倍他洛尔标示含量的差值除以总倍他洛尔的标示含量,计算结合态倍他洛尔相当于总倍他洛尔的百分含量。1mg盐酸倍他洛尔相当于0.894mg的倍他洛尔。
(二)系统适用性典型图谱
系统适用性试验
取盐酸倍他洛尔、杂质A与杂质F各对照品适量,加0.6mol/L氯化钾溶液溶解并稀释制成每1ml中约含倍他洛尔0.2mg、杂质A 8µg与杂质F 3µg的溶液,取20µl注入液相色谱仪,记录色谱图。色谱图见图3。
由试验结果可得,倍他洛尔峰、杂质A峰(RRT0.25)与杂质F峰(RRT1.24)之间的分离度均符合要求。
有关物质结果见表5。
表5 有关物质检验结果
Claims (8)
2.根据权利要求1所述的制备方法,其特征在于,具体包括以下步骤:
(1)将50g对羟基苯乙醇加至450ml乙腈中,升温至40℃全溶,加入100g碳酸钾,83.7g环氧氯丙烷,升温至回流反应6h,TLC检测原料不再减少,降温至室温,过滤,滤液浓缩干,甲苯带干一次,得化合物A;
(2)将20g化合物A的粗品加至100ml异丙胺中,回流反应4h,TLC检测原料反应完,将反应液浓缩干,柱层析精制得产物。
3.根据权利要求2所述的制备方法,其特征在于,所述TLC所使用的展开剂为DCM:MeOH=10:1。
4.一种如权利要求1或权利要求2-3任一项所述的制备方法制备的1-【(4-羟乙基)苯氧基】-3-(异丙基氨基)丙-2-醇的应用,其特征在于,所述应用为在检测盐酸倍他洛尔及其滴眼液中的1-【(4-羟乙基)苯氧基】-3-(异丙基氨基)丙-2-醇作为对照品,进行有关物质成分及含量检测。
5.根据权利要求4的应用,其特征在于,所述成分检测时,包括以下步骤:取本品,摇匀,用内容量移液管精密量取2ml,置25ml量瓶中,加0.6mol/L氯化钾溶液适量,超声使盐酸倍他洛尔溶解,用0.6mol/L氯化钾溶液稀释至刻度,摇匀,离心,取上清液作为供试品溶液;精密量取1ml,置100ml量瓶中,用0.6mol/L氯化钾溶液稀释至刻度,摇匀,作为对照溶液;精密量取对照溶液5ml,置100ml量瓶中,用0.6mol/L氯化钾溶液稀释至刻度,摇匀,作为灵敏度溶液;取灵敏度溶液20µl注入液相色谱仪,记录色谱图,主成分峰高的信噪比应大于10;再精密量取供试品溶液与对照溶液各20µl,分别注入液相色谱仪,记录色谱图至主成分峰保留时间的5倍。
6.根据权利要求4所述的应用,其特征在于,所述含量检测的具体步骤为:取本品,摇匀,用内容量移液管精密量取2ml,置50ml量瓶中,加0.6mol/L氯化钾溶液适量,超声使盐酸倍他洛尔溶解,用0.6mol/L氯化钾溶液稀释至刻度,摇匀,离心,取上清液作为测定总倍他洛尔的供试品溶液;另取本品适量,以每分钟15000转离心30分钟,精密量取上清液2ml,置50ml量瓶中,用0.6mol/L氯化钾溶液稀释至刻度,摇匀,作为测定游离态倍他洛尔的供试品溶液,精密量取20μl注入液相色谱仪,记录色谱图;另取盐酸倍他洛尔对照品适量,用0.6mol/L氯化钾溶液溶解并稀释制成每1ml中约含倍他洛尔0.1mg的对照品溶液,同法测定;按外标法以峰面积分别计算总倍他洛尔与游离态倍他洛尔标示含量,再以总倍他洛尔与游离态倍他洛尔标示含量的差值除以总倍他洛尔的标示含量,计算结合态倍他洛尔相当于总倍他洛尔的百分含量。
7.根据权利要求5或6所述的应用,其特征在于,所述检测过程中采用液相色谱法色谱条件为:用十八烷基硅烷键合硅胶为填充剂, C18柱,4.6mm×150 mm,3μm;以磷酸盐缓冲液-乙腈(53:47),并含0.3%十二烷基硫酸钠的混合溶液作为流动相;检测波长为220nm;流速为每分钟1.25ml。
8.根据权利要求7所述的应用,其特征在于,所述磷酸盐缓冲液具体配置过程为:取磷酸5ml,加水900ml,用浓氨溶液调节pH值至3.0,用水稀释至1000ml,摇匀即可。
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Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4760182A (en) * | 1985-02-07 | 1988-07-26 | Torcan Chemical Ltd. | Process for preparing substituted phenol ethers via oxazolidine-structure intermediates |
CN101632646A (zh) * | 2009-05-31 | 2010-01-27 | 北京四环科宝制药有限公司 | 一种盐酸奥洛他定片及其制备方法和检测方法 |
CN102091048A (zh) * | 2009-12-09 | 2011-06-15 | 汪昌瑞 | 盐酸阿比朵尔片的制备方法及其质量控制方法 |
CN108066283A (zh) * | 2017-12-28 | 2018-05-25 | 兆科药业(广州)有限公司 | 一种盐酸左倍他洛尔滴眼液的制备方法 |
-
2020
- 2020-07-03 CN CN202010637294.4A patent/CN111689868A/zh active Pending
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4760182A (en) * | 1985-02-07 | 1988-07-26 | Torcan Chemical Ltd. | Process for preparing substituted phenol ethers via oxazolidine-structure intermediates |
CN101632646A (zh) * | 2009-05-31 | 2010-01-27 | 北京四环科宝制药有限公司 | 一种盐酸奥洛他定片及其制备方法和检测方法 |
CN102091048A (zh) * | 2009-12-09 | 2011-06-15 | 汪昌瑞 | 盐酸阿比朵尔片的制备方法及其质量控制方法 |
CN108066283A (zh) * | 2017-12-28 | 2018-05-25 | 兆科药业(广州)有限公司 | 一种盐酸左倍他洛尔滴眼液的制备方法 |
Non-Patent Citations (3)
Title |
---|
中国食品药品检定研究院组织编写: "《中国药品检验标准操作规范:2019年版》", 31 August 2019, 中国医药科技出版社 * |
可钰等: "反相高效液相色谱法测定盐酸左旋倍他洛尔含量", 《郑州大学学报(理学版)》 * |
王慧娟等: "盐酸倍他洛尔温敏型眼用原位凝胶的制备及其含量测定", 《山地农业生物学报》 * |
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