CN113563181B - 吉非罗齐杂质的去除方法 - Google Patents
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- HEMJJKBWTPKOJG-UHFFFAOYSA-N Gemfibrozil Chemical compound CC1=CC=C(C)C(OCCCC(C)(C)C(O)=O)=C1 HEMJJKBWTPKOJG-UHFFFAOYSA-N 0.000 title claims abstract description 74
- 229960003627 gemfibrozil Drugs 0.000 title claims abstract description 73
- 238000000034 method Methods 0.000 title claims abstract description 20
- 239000012535 impurity Substances 0.000 claims abstract description 79
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 45
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 26
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 claims abstract description 15
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 claims abstract description 15
- 238000003756 stirring Methods 0.000 claims abstract description 13
- 239000012065 filter cake Substances 0.000 claims abstract description 11
- 238000001035 drying Methods 0.000 claims abstract description 8
- 239000004289 sodium hydrogen sulphite Substances 0.000 claims abstract description 6
- 238000002386 leaching Methods 0.000 claims abstract description 3
- 239000000047 product Substances 0.000 claims description 6
- 238000000967 suction filtration Methods 0.000 claims description 5
- 238000010438 heat treatment Methods 0.000 claims description 3
- 239000005411 L01XE02 - Gefitinib Substances 0.000 abstract description 8
- 229960002584 gefitinib Drugs 0.000 abstract description 8
- XGALLCVXEZPNRQ-UHFFFAOYSA-N gefitinib Chemical compound C=12C=C(OCCCN3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 XGALLCVXEZPNRQ-UHFFFAOYSA-N 0.000 abstract description 7
- 238000001914 filtration Methods 0.000 abstract description 3
- 238000000746 purification Methods 0.000 abstract description 2
- 239000000243 solution Substances 0.000 description 14
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 8
- 229940079827 sodium hydrogen sulfite Drugs 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 208000031226 Hyperlipidaemia Diseases 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000002699 waste material Substances 0.000 description 3
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 239000003741 agents affecting lipid metabolism Substances 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000005265 energy consumption Methods 0.000 description 2
- 208000020346 hyperlipoproteinemia Diseases 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- NMFQPFSIPWZZMR-UHFFFAOYSA-N 1,1,1,2,3,3-hexafluoropropan-2-ol Chemical compound FC(F)C(F)(O)C(F)(F)F NMFQPFSIPWZZMR-UHFFFAOYSA-N 0.000 description 1
- OHVLMTFVQDZYHP-UHFFFAOYSA-N 1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)-2-[4-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]piperazin-1-yl]ethanone Chemical compound N1N=NC=2CN(CCC=21)C(CN1CCN(CC1)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)=O OHVLMTFVQDZYHP-UHFFFAOYSA-N 0.000 description 1
- WZFUQSJFWNHZHM-UHFFFAOYSA-N 2-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)CC(=O)N1CC2=C(CC1)NN=N2 WZFUQSJFWNHZHM-UHFFFAOYSA-N 0.000 description 1
- CFMZSMGAMPBRBE-UHFFFAOYSA-N 2-hydroxyisoindole-1,3-dione Chemical compound C1=CC=C2C(=O)N(O)C(=O)C2=C1 CFMZSMGAMPBRBE-UHFFFAOYSA-N 0.000 description 1
- 206010003210 Arteriosclerosis Diseases 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 101000777206 Homo sapiens Ubiquitin carboxyl-terminal hydrolase 40 Proteins 0.000 description 1
- 102100031284 Ubiquitin carboxyl-terminal hydrolase 40 Human genes 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 208000011775 arteriosclerosis disease Diseases 0.000 description 1
- 150000003935 benzaldehydes Chemical class 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- QAHREYKOYSIQPH-UHFFFAOYSA-L cobalt(II) acetate Chemical compound [Co+2].CC([O-])=O.CC([O-])=O QAHREYKOYSIQPH-UHFFFAOYSA-L 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 208000029078 coronary artery disease Diseases 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- -1 gefitinib isobutyl ester Chemical class 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 238000010587 phase diagram Methods 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
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Abstract
本发明公开了一种吉非罗齐杂质的去除方法,针对的是含有杂质Ⅰ和杂质Ⅱ的吉非罗齐,包括以下步骤:将吉非罗齐溶解在乙醇中,再加入质量浓度20~40%的亚硫酸氢钠溶液,于20~30℃搅拌1±0.5小时;然后滴加纯水,纯水滴加完毕后,再搅拌1~2小时,然后过滤,滤饼用纯水淋洗,再干燥,得到纯化后吉非罗齐。纯化后吉非罗齐中,杂质Ⅰ和杂质Ⅱ的含量均分别≤0.10%。
Description
技术领域
本发明属于医药化学技术领域,涉及吉非罗齐产品中杂质的去除方法。
背景技术
吉非罗齐(Gemfibrozil),化学名2,2-二甲基-5-(2,5-二甲基苯基氧基)-戊酸,结构如下:
吉非罗齐是氯贝丁酸脂类血脂调节药,美国在1982年上市,临床用于治疗高脂血症,适用于严重Ⅳ或Ⅴ型高脂蛋白血症、冠心病、Ⅱb型高脂蛋白血症及其它血脂调节药物治疗无效者,也可用于防止动脉硬化,且有助于减少心肌梗塞的发生率。
吉非罗齐合成方面有多种工艺路线报导,US3674838、US 5456476、CN105693504等报导了合成方法,这些方法在实际生产中往往会产生副产物(杂质),对于药品来说,其中含有的杂质有可能带来与治疗无关的副作用,因此,需对其中的杂质进行严格控制,多数杂质要求在0.10%以下,当然杂质越少越好。
CN105669368B的发明《高纯低色度吉非罗齐的制备方法》是申请人早期申请的专利:在吉非异丁酯粗品中加入碱液Ⅱ,直至所得体系的pH值为10.0~12,然后减压精馏,得吉非罗齐异丁酯;吉非罗齐异丁酯经回流碱水解、调酸,得吉非罗齐粗品;粗品精制:在吉非罗齐粗品中加入醇水溶液,升温至回流并保温0.5~1小时,冷却降温至0~5℃并保温搅拌1.5~2.5小时,过滤,所得的滤饼烘干,得高纯度、低色度的吉非罗齐。
当生产过程中出现异常等情况而导致吉非罗齐中含有杂质Ⅰ和杂质Ⅱ时,需要有特定的方法来去除杂质,而目前的现有技术难以解决该问题。
杂质Ⅰ为:杂质Ⅱ为:/>
杂质Ⅰ:
1H-NMR(600MHz,CDCl3),δ(ppm),10.43(s,1H),7.72(d,1H)6.82(d,1H),6.74(s,1H),4.05(t,2H),3.01(s,3H),1.86(m,2H),1.76(q,2H),1.26(s,6H),13C-NMR(150MHz,CDCl3),δ(ppm),189.62,189.53,184.21,161.46,147.47,128.27,122.61,121.64,112.96,68.44,41.92,36.73,25.02,24.89,22.33.MS[M]-263.1.
杂质Ⅱ:
1H-NMR(600MHz,CDCl3),δ(ppm),9.90(s,1H),7.32-7.27(3H,Ar-H),4.02(t,2H),2.29(s,3H),1.84(m,2H),1.77(q,2H),1.26(s,6H),13C-NMR(150MHz,CDCl3),δ(ppm),192.16,192.12,184.46,157.59,135.76,135.04,130.85,124.32,108.76,68.13,41.94,36.74,24.97,24.92,16.82.MS[M]-263.1.
式Ⅰ所述物在专利CN109232238中被提及;
式Ⅱ所述物在Selective Aerobic Oxidation of Methylarenes toBenzaldehydes Catalyzed by N-Hydroxyphthalimide and Cobalt(II)Acetate inHexafluoropropan-2-ol(Eden Gaster,Dr.Sebastian Kozuch,Prof.Dr.Doron Pappo,First published:24April 2017)有告知。
目前针对吉非罗齐的国内外药典标准中均没有明确列出上述二个杂质,即,标准中均将其作为未知杂质进行控制。例如,欧州药典9.0版标准及美国药典USP40中,要求未知杂质低于0.10%。
发明内容
本发明要解决的技术问题是提供一种去除吉非罗齐中的杂质Ⅰ、杂质Ⅱ的方法,采用该方法可以确保吉非罗齐中的此二个杂质的含量符合标准,去除这二个杂质过程的收率可达95%以上。
为解决上述技术问题,本发明提供一种吉非罗齐杂质的去除方法,针对的是含有杂质Ⅰ和杂质Ⅱ的吉非罗齐,包括以下步骤:
1)、将吉非罗齐溶解乙醇中,吉非罗齐与乙醇的重量比为1:2.0~4.0,溶解温度为20~30℃;再加入质量浓度20~40%的亚硫酸氢钠溶液,于20~30℃搅拌1±0.5小时;
所述乙醇为质量浓度≥90%的乙醇水溶液、或纯乙醇;即为90~100%的乙醇;
吉非罗齐中所含有的杂质Ⅰ和杂质Ⅱ之和称为杂质,
亚硫酸氢钠:吉非罗齐中的杂质=20~35:1的摩尔比;
所述杂质Ⅰ为:
所述杂质Ⅱ为:
2)、在步骤1)所得物中滴加纯水,纯水:步骤1)中的乙醇=1.0~2.0:1的重量比;
纯水滴加完毕后,再搅拌1~2小时,然后过滤,滤饼用纯水淋洗,再干燥(减压干燥),得到纯化后吉非罗齐。
所述纯化后吉非罗齐中,杂质Ⅰ和杂质Ⅱ的含量均分别≤0.10%。
含量代表仪器(高效液相色谱仪)所显示的面积百分数。
作为本发明的吉非罗齐杂质的去除方法的改进,所述步骤2)中:
纯水的滴加时间为30~90分钟;
干燥为40℃真空干燥。
作为本发明的吉非罗齐杂质的去除方法的进一步改进,所述步骤2)中,滤饼用纯水淋洗时,纯水的用量为吉非罗齐质量的1~1.5倍。
作为本发明的吉非罗齐杂质的去除方法的进一步改进:
取100g吉非罗齐,加入到250g 95%的乙醇中,加热升温至30℃,搅拌至吉非罗齐溶解,得吉非罗齐乙醇溶液;
加入浓度为29~30%的亚硫酸氢钠溶液,30℃保温搅拌1小时;亚硫酸氢钠:吉非罗齐中的杂质=29~29.5:1的摩尔比;
再滴加(滴加时间为30分钟)350g纯水,滴加完毕后,搅拌1小时,抽滤,滤饼用100g纯水淋洗,再干燥,得到纯化后吉非罗齐。
在本发明中,没有明确说明的%均为质量%,没有明确告知温度的均为20~30℃。
本发明是利用杂质与亚硫酸氢钠反应形成的加成合物,在水中的溶解度大大增加,从而确保吉非罗齐结晶析出时杂质不会析出,达到吉非罗齐与杂质分离,提高吉非罗齐的纯度。
本发明所用的检测方法如下:
色谱柱:Waters Spherisob ODS2 4.6×250mm,0.3μm;
将作为待测样品的吉非罗齐配成10mg/ml的溶液,进行上样,上样量为10μl。
流动相:量取490ml乙腈到1000ml容量瓶中,加入10ml冰醋酸,用纯水定容至1000ml。
柱温:35℃
检测波长:276nm
流速:1ml/min
洗脱时间为60min;
处理前的吉非罗齐样品中的杂质Ⅰ、杂质Ⅱ、吉非罗齐的出峰如图1所示;
仪器(高效液相色谱仪)中生成的图谱能自动给出杂质Ⅰ、杂质Ⅱ、吉非罗齐的面积%;
杂质Ⅰ的摩尔数=待测吉非罗齐质量×杂质Ⅰ面积百分比/杂质Ⅰ分子量(264.3);
杂质Ⅱ的摩尔数=待测吉非罗齐质量×杂质Ⅱ面积百分比/杂质Ⅱ分子量(264.3)。
本发明具有如下技术优势:
本发明采用的方法可有效降低吉非罗齐中杂质Ⅰ和杂质Ⅱ的含量,且收率高;本方法基本在室温下进行,能耗少;通过杂质与无机盐类反应去除,易进行,安全可靠;所用溶剂为乙醇、水,其产生的废液可回收,三废处理成本低。采用本方法纯化吉非罗齐,其杂质式Ⅰ、式Ⅱ明显低,能耗少,三废处理简单,有较明显的经济效益。
附图说明
下面结合附图对本发明的具体实施方式作进一步详细说明。
图1为使用本发明方法前的吉非罗齐的液相图谱。
图2为使用本发明方法(实施例2)去除杂质后的吉非罗齐图谱。
具体实施方式
下面结合具体实施例对本发明进行进一步描述,但本发明的保护范围并不仅限于此:
下文中:
数据进行常规的四舍五入处理。没有明确告知的均为质量%,没有明确告知温度的均为20~30℃,搅拌的转速为150~250转/分。
实施例1
取100g吉非罗齐,此吉非罗齐中,含杂质Ⅰ0.24%(0.91mmol),杂质Ⅱ0.24%(0.91mmol),将吉非罗齐加入到250g 95%的乙醇中,加热升温至30℃,搅拌至吉非罗齐溶解,得吉非罗齐乙醇溶液。
向上述溶液中加入18.5g亚硫酸氢钠溶液,此溶液由5.5g(52.9mmol)亚硫酸氢钠+13g纯水溶解组成,30℃保温搅拌1小时。然后再滴加350g纯水,滴加时间为30分钟,滴加完毕后,搅拌1小时,抽滤,滤饼用100g纯水淋洗,抽干,得湿品约132g,真空40℃干燥(至恒重)得吉非罗齐96g。收率为96.0%,HPLC纯度100.0%,杂质Ⅰ、杂质式Ⅱ均未检出。
实施例2、
取100g吉非罗齐,其含式Ⅰ杂质0.24%(0.91mmol),式Ⅱ杂质0.24%(0.91mmol),加入到200g 95%的乙醇中,加热升温至25℃,搅拌至吉非罗齐溶解,得吉非罗齐乙醇溶液。
向上述溶液中加入19.0g亚硫酸氢钠溶液,此溶液由6.0g(57.7mmol)亚硫酸氢钠+13g纯水溶解组成,30℃保温搅拌1小时。然后再滴加400g纯水,搅拌1小时,抽滤,滤饼用100g纯水洗涤,抽干,得湿品约138g,真空40℃干燥得吉非罗齐96.7g。收率96.7%,HPLC纯度99.89%,杂质式Ⅰ0.05%、式Ⅱ0.06%。
实施例3
取100g吉非罗齐,其含式Ⅰ杂质0.24%(0.91mmol),式Ⅱ杂质0.24%(0.91mmol),加入到300g 95%的乙醇中,加热升温至25℃,搅拌至吉非罗齐溶解,得吉非罗齐乙醇溶液。
向上述溶液中加入19.5g亚硫酸氢钠溶液,此溶液由6.5g(62.5mmol)亚硫酸氢钠+13g纯水溶解组成,25℃保温搅拌1小时。然后再滴加400g纯水,搅拌1小时,抽滤,滤饼用100g纯水洗涤,抽干,得湿品约133g,真空40℃干燥得吉非罗齐95.6g。收率95.6%,HPLC纯度99.90%,杂质式Ⅰ0.05%、式Ⅱ0.05%。
实施例4-1、将实施例1中的“95%的乙醇”改成100%乙醇,质量保持不变,其余等同于实施例1。处理完毕后的吉非罗齐中杂质Ⅰ、杂质式Ⅱ的含量均约为0.02~0.04%。
实施例4-2、将实施例1中的“95%的乙醇”改成90%乙醇,质量保持不变,其余等同于实施例1。处理完毕的吉非罗齐中杂质Ⅰ、杂质式Ⅱ的含量均约为0.03%。
对比例1、将实施例1中的亚硫酸氢钠改成碳酸钠、碳酸钾,摩尔用量保持不变;处理完毕后的吉非罗齐中杂质Ⅰ、杂质式Ⅱ的含量基本同吉非罗齐处理前。
最后,还需要注意的是,以上列举的仅是本发明的若干个具体实施例。显然,本发明不限于以上实施例,还可以有许多变形。本领域的普通技术人员能从本发明公开的内容直接导出或联想到的所有变形,均应认为是本发明的保护范围。
Claims (1)
1.吉非罗齐杂质的去除方法,针对的是含有杂质Ⅰ和杂质Ⅱ的吉非罗齐,其特征在于包括以下步骤:
1)、取100g吉非罗齐,加入到250g 95%的乙醇中,加热升温至30℃,搅拌至吉非罗齐溶解,得吉非罗齐乙醇溶液;
加入浓度为29~30%的亚硫酸氢钠溶液,30℃保温搅拌1小时;亚硫酸氢钠:吉非罗齐中的杂质=29~29.5:1的摩尔比;
吉非罗齐中所含有的杂质Ⅰ和杂质Ⅱ之和称为杂质;
所述杂质Ⅰ为:
所述杂质Ⅱ为:
2)、在步骤1)所得物中再滴加350g纯水,滴加时间为30分钟,滴加完毕后,搅拌1小时,抽滤,滤饼用100g纯水淋洗,再干燥,得到纯化后吉非罗齐。
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