CN111732517A - 1-(4-(2-环丁氧基乙基)苯氧基)-3-(异丙基氨基)丙基-2-醇及制备方法 - Google Patents
1-(4-(2-环丁氧基乙基)苯氧基)-3-(异丙基氨基)丙基-2-醇及制备方法 Download PDFInfo
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- -1 4- (2-cyclobutoxyethyl) phenoxy Chemical group 0.000 title claims abstract description 62
- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- CHDPSNLJFOQTRK-UHFFFAOYSA-N betaxolol hydrochloride Chemical compound [Cl-].C1=CC(OCC(O)C[NH2+]C(C)C)=CC=C1CCOCC1CC1 CHDPSNLJFOQTRK-UHFFFAOYSA-N 0.000 claims abstract description 90
- 229960004347 betaxolol hydrochloride Drugs 0.000 claims abstract description 52
- 150000001875 compounds Chemical class 0.000 claims abstract description 20
- 239000003889 eye drop Substances 0.000 claims abstract description 18
- 229940012356 eye drops Drugs 0.000 claims abstract description 17
- 238000001514 detection method Methods 0.000 claims abstract description 11
- 239000000126 substance Substances 0.000 claims abstract description 11
- 239000013558 reference substance Substances 0.000 claims abstract description 10
- 239000000243 solution Substances 0.000 claims description 67
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 claims description 52
- 229960004324 betaxolol Drugs 0.000 claims description 38
- 239000001103 potassium chloride Substances 0.000 claims description 26
- 235000011164 potassium chloride Nutrition 0.000 claims description 26
- 238000006243 chemical reaction Methods 0.000 claims description 24
- 238000007865 diluting Methods 0.000 claims description 20
- 239000000047 product Substances 0.000 claims description 20
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
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- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- 238000004809 thin layer chromatography Methods 0.000 claims description 8
- 230000035945 sensitivity Effects 0.000 claims description 7
- 229940126062 Compound A Drugs 0.000 claims description 6
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 claims description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 6
- 238000010992 reflux Methods 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- 239000012071 phase Substances 0.000 claims description 5
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 claims description 5
- 239000000706 filtrate Substances 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- 239000002994 raw material Substances 0.000 claims description 4
- 238000003756 stirring Methods 0.000 claims description 4
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- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 3
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 3
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 3
- 238000010812 external standard method Methods 0.000 claims description 3
- 230000014759 maintenance of location Effects 0.000 claims description 3
- 239000011259 mixed solution Substances 0.000 claims description 3
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 claims description 3
- 239000008363 phosphate buffer Substances 0.000 claims description 3
- 239000000377 silicon dioxide Substances 0.000 claims description 3
- 239000007787 solid Substances 0.000 claims description 3
- YCCILVSKPBXVIP-UHFFFAOYSA-N 2-(4-hydroxyphenyl)ethanol Chemical compound OCCC1=CC=C(O)C=C1 YCCILVSKPBXVIP-UHFFFAOYSA-N 0.000 claims description 2
- LRWZZZWJMFNZIK-UHFFFAOYSA-N 2-chloro-3-methyloxirane Chemical compound CC1OC1Cl LRWZZZWJMFNZIK-UHFFFAOYSA-N 0.000 claims description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 2
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims description 2
- 125000006278 bromobenzyl group Chemical group 0.000 claims description 2
- KXVUSQIDCZRUKF-UHFFFAOYSA-N bromocyclobutane Chemical compound BrC1CCC1 KXVUSQIDCZRUKF-UHFFFAOYSA-N 0.000 claims description 2
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- 238000004896 high resolution mass spectrometry Methods 0.000 claims description 2
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 claims description 2
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- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 238000006073 displacement reaction Methods 0.000 description 2
- 230000004410 intraocular pressure Effects 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
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- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 2
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- 201000002862 Angle-Closure Glaucoma Diseases 0.000 description 1
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 1
- 208000010412 Glaucoma Diseases 0.000 description 1
- RCEAADKTGXTDOA-UHFFFAOYSA-N OS(O)(=O)=O.CCCCCCCCCCCC[Na] Chemical compound OS(O)(=O)=O.CCCCCCCCCCCC[Na] RCEAADKTGXTDOA-UHFFFAOYSA-N 0.000 description 1
- 206010030043 Ocular hypertension Diseases 0.000 description 1
- 206010030348 Open-Angle Glaucoma Diseases 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 210000001742 aqueous humor Anatomy 0.000 description 1
- 230000004509 aqueous humor production Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 229910001424 calcium ion Inorganic materials 0.000 description 1
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- 230000000694 effects Effects 0.000 description 1
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- 239000012467 final product Substances 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
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- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
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- C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
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- C07C217/30—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines having the oxygen atom of at least one of the etherified hydroxy groups further bound to a carbon atom of a six-membered aromatic ring
- C07C217/32—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines having the oxygen atom of at least one of the etherified hydroxy groups further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring being further substituted
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Abstract
Description
技术领域
本发明属于药物制备技术领域,主要涉及一种新化合物1-(4-(2-环丁氧基乙基)苯氧基)-3-(异丙基氨基)丙基-2-醇及制备方法,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。盐酸倍他洛尔及其滴眼剂中的杂质,同盐酸倍他洛尔临床用药不良反应的发生有很大的关系。倍他洛尔杂质F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F的结构和制备方法均未见国内文献报道。
发明内容
本发明目的在于,提供了倍他洛尔杂质F的全新结构,1-(4-(2-环丁氧基乙基)苯氧基)-3-(异丙基氨基)丙基-2-醇。
本发明另一目的在于提供了1-(4-(2-环丁氧基乙基)苯氧基)-3-(异丙基氨基)丙基-2-醇的制备方法。
本发明还提供了制备得到的1-(4-(2-环丁氧基乙基)苯氧基)-3-(异丙基氨基)丙基-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-(2-环丁氧基乙基)苯氧基)-3-(异丙基氨基)丙基-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:(权利要求书)
本发明提供了一种1-(4-(2-环丁氧基乙基)苯氧基)-3-(异丙基氨基)丙基-2-醇,其结构式如下:
本发明还提供了一种1-(4-(2-环丁氧基乙基)苯氧基)-3-(异丙基氨基)丙基-2-醇的制备方法,反应过程如下所示:
本发明提供的制备方法,具体包括以下步骤:
(1)将10g对羟基苯乙醇加至100ml乙腈中,室温下加入15g碳酸钾,12.63g溴苄,升温至回流反应过夜,将反应液过滤,滤液浓缩干,柱层析得化合物A;
(2)将2g化合物A加至20mlDMF中,加入1.05gNaH,搅拌20min,11.83g环丁基溴,升温至80℃(油温)反应14h,TLC检测,有新点生成,水相PH接近中性,淬灭反应,DCM萃取产品,有机相水洗,饱和盐水洗涤,干燥,过滤,浓缩干,柱层析,得化合物B;
(3)将0.5g化合物B加至30ml无水甲醇中,加入100mg10%Pd/C,氢气置换三次,升温至40℃ 反应6h,TLC检测化合物B反应完,过滤,蒸干得化合物C;
(4)将0.3g化合物C加至5ml乙腈中,升温至40℃全溶,加入0.34g碳酸钾,0.28g环氧氯丙烷,升温至回流反应14h,TLC(DCM:MeOH=10:1)原料基本反应完,原料与产物点很近,降温至室温,过滤,滤液浓缩干得化合物D;
(5)将0.4g化合物D加至5ml异丙胺中,升温至40℃(水浴温度)回流反应16h,TLC检测SM反应完,减压浓缩干,PE打浆得固体,高分辨质谱检测分子量正确,柱层析精制得纯品1-(4-(2-环丁氧基乙基)苯氧基)-3-(异丙基氨基)丙基-2-醇。
进一步的,步骤(1)、(2)、(5)中,所述柱层析的洗脱剂为DCM:MeOH=50:1组成。
本发明还提供了一种采用上述制备方法制备的1-(4-(2-环丁氧基乙基)苯氧基)-3-(异丙基氨基)丙基-2-醇在盐酸倍他洛尔及盐酸倍他洛尔滴眼液有关物质及含量检测中的应用。
进一步的,所述检测包括以下步骤:取1-(4-(2-环丁氧基乙基)苯氧基)-3-(异丙基氨基)丙基-2-醇摇匀,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1-(4-(2-环丁氧基乙基)苯氧基)-3-(异丙基氨基)丙基-2-醇检测过程中,含量测定方法为:取1-(4-(2-环丁氧基乙基)苯氧基)-3-(异丙基氨基)丙基-2-醇,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。
上述液相色谱的色谱条件为:采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。
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-(2-环丁氧基乙基)苯氧基)-3-(异丙基氨基)丙基-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-(2-环丁氧基乙基)苯氧基)-3-(异丙基氨基)丙基-2-醇,分子式为C18H29NO3,分子量为307.43。
本发明的有益效果为:
(1)本发明首次提供了1-(4-(2-环丁氧基乙基)苯氧基)-3-(异丙基氨基)丙基-2-醇的结构式及其制备方法,制备过程简单可控,易操作。
(2)本发明制备得到的1-(4-(2-环丁氧基乙基)苯氧基)-3-(异丙基氨基)丙基-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-(2-环丁氧基乙基)苯氧基)-3-(异丙基氨基)丙基-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。
附图说明
图1为实施例1制备的化合物A的核磁共振氢谱图。
图2为实施例1制备的化合物B的核磁共振氢谱图。
图3为实施例1制备的1-(4-(2-环丁氧基乙基)苯氧基)-3-(异丙基氨基)丙基-2-醇的核磁共振氢谱图。
图4为实施例1制备的1-(4-(2-环丁氧基乙基)苯氧基)-3-(异丙基氨基)丙基-2-醇的质谱图。
图5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
将合成的化合物A进行核磁共振氢谱鉴定,谱图如图1所示,鉴定结构正确。
(2)化合物B合成反应方程式如下:
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B进行核磁共振氢谱鉴定,谱图如图2所示,鉴定结构正确。
(3)化合物C的合成反应方程式如下:
具体反应步骤如表5所示。
表5
合成后直接用于下一步
(4)化合物D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6所示。
表6
具体反应步骤如表7所示。
表7
(5)终产物反应方程式如下:
具体反应步骤如表8所示。
表8
将合成的化合物进行核磁共振氢谱和质谱鉴定,谱图如图3和图4所示,鉴定结构正确,MS也正确,详细请看COA谱图。本发明合成的化合物,同中间产物化合物B相比,终产物环丁基及相连的两个亚甲基的位移没有发生改变,说明上苄基的位置为酚羟基上,苄基脱除后对两个亚甲基及环丁基的位移没影响。
效果实施例本发明合成的倍他洛尔杂质F在盐酸倍他洛尔及滴眼液有关物质检测中的应用盐酸倍他洛尔滴眼液
(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,记录色谱图如图5所示。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9。
表9有关物质检验结果
Claims (9)
3.根据权利要求2所述的制备方法,其特征在于,具体包括以下步骤:
(1)将10g对羟基苯乙醇加至100ml乙腈中,室温下加入15g碳酸钾,12.63g溴苄,升温至回流反应过夜,将反应液过滤,滤液浓缩干,柱层析得化合物A;
(2)将2g化合物A加至20mlDMF中,加入1.05gNaH,搅拌20min,11.83g环丁基溴,升温至80℃(油温)反应14h,TLC检测,有新点生成,水相PH接近中性,淬灭反应,DCM萃取产品,有机相水洗,饱和盐水洗涤,干燥,过滤,浓缩干,柱层析,得化合物B;
(3)将0.5g化合物B加至30ml无水甲醇中,加入100mg10%Pd/C,氢气置换三次,升温至40℃ 反应6h,TLC检测化合物B反应完,过滤,蒸干得化合物C;
(4)将0.3g化合物C加至5ml乙腈中,升温至40℃全溶,加入0.34g碳酸钾,0.28g环氧氯丙烷,升温至回流反应14h,TLC(DCM:MeOH=10:1)原料基本反应完,原料与产物点很近,降温至室温,过滤,滤液浓缩干得化合物D;
(5)将0.4g化合物D加至5ml异丙胺中,升温至40℃(水浴温度)回流反应16h,TLC检测SM反应完,减压浓缩干,PE打浆得固体,高分辨质谱检测分子量正确,柱层析精制得纯品1-(4-(2-环丁氧基乙基)苯氧基)-3-(异丙基氨基)丙基-2-醇。
4.根据权利要求3所述的制备方法,其特征在于,步骤(1)、(2)、(5)中,所述柱层析的洗脱剂为DCM:MeOH=50:1组成。
5.一种如权利要求1或权利要求2-4任一项所述的制备方法制备的1-(4-(2-环丁氧基乙基)苯氧基)-3-(异丙基氨基)丙基-2-醇在盐酸倍他洛尔及盐酸倍他洛尔滴眼液有关物质及含量检测中的应用。
6.根据权利要求5所述的应用,其特征在于,所述检测包括以下步骤:取1-(4-(2-环丁氧基乙基)苯氧基)-3-(异丙基氨基)丙基-2-醇摇匀,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。
7.根据权利要求5所述的应用,其特征在于,所述1-(4-(2-环丁氧基乙基)苯氧基)-3-(异丙基氨基)丙基-2-醇检测过程中,含量测定方法为:取1-(4-(2-环丁氧基乙基)苯氧基)-3-(异丙基氨基)丙基-2-醇,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。
8.根据权利要求6或7所述的应用,其特征在于,所述液相色谱的色谱条件为:采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。
9.根据权利要求8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。
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CN101665441A (zh) * | 2009-09-18 | 2010-03-10 | 安徽省庆云医药化工有限公司 | 左旋盐酸倍他洛尔的制备方法 |
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 |
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2020
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Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA1183455A (en) * | 1982-12-09 | 1985-03-05 | Merck & Co., Inc. | Ophthalmic compositions for treating elevated intraocular pressure |
CN101085742A (zh) * | 2007-07-13 | 2007-12-12 | 郑州大学 | 左旋盐酸倍他洛尔合成工艺 |
CN101665441A (zh) * | 2009-09-18 | 2010-03-10 | 安徽省庆云医药化工有限公司 | 左旋盐酸倍他洛尔的制备方法 |
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 |
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