CN113493461A - 一种七元杂环化合物或其盐、其制备方法及应用 - Google Patents
一种七元杂环化合物或其盐、其制备方法及应用 Download PDFInfo
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- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 22
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- HEMYPJHWBDDJGB-UHFFFAOYSA-N 1-[6-[(2,4-diaminopyrimidin-5-yl)methyl]-2,3,4-trimethoxyphenyl]ethanone Chemical compound NC1=NC=C(C(=N1)N)CC1=C(C(=C(C(=C1)OC)OC)OC)C(C)=O HEMYPJHWBDDJGB-UHFFFAOYSA-N 0.000 description 1
- LEDWOUJPDAFDRJ-UHFFFAOYSA-N 1-[6-[(2,4-diaminopyrimidin-5-yl)methyl]-2-hydroxy-3,4-dimethoxyphenyl]ethanone Chemical compound NC1=NC=C(C(=N1)N)CC1=C(C(=C(C(=C1)OC)OC)O)C(C)=O LEDWOUJPDAFDRJ-UHFFFAOYSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
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- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
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- 238000010200 validation analysis Methods 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
- C07D491/16—Peri-condensed systems
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/04—Preparation or injection of sample to be analysed
- G01N2030/042—Standards
- G01N2030/047—Standards external
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Physics & Mathematics (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Analytical Chemistry (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- General Physics & Mathematics (AREA)
- Immunology (AREA)
- Pathology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了一种七元杂环化合物或其盐、其制备方法及应用。本发明提供了一种如式7a所示的七元杂环化合物或其盐。本发明还提供了如式7a所示的七元杂环化合物或其盐作为艾拉普林的杂质标准品的应用。通过本发明的如式7a所示的七元杂环化合物作为对照品,来建立艾拉普林质量控制的分析方法,从而可提高艾拉普林临床应用的安全性和有效性。
Description
技术领域
本发明涉及一种七元杂环化合物或其盐、其制备方法及应用。
背景技术
艾拉普林(Iclaprim)是Motif Bio公司开发的一种二氢叶酸还原酶抑制剂,在2018年,其作为急性细菌性皮肤和皮肤结构感染(ABSSSI)适应症治疗药物向美国FDA提出上市申请。Iclaprim作为治疗医院获得性细菌性肺炎(HABP)药物目前处于II期临床试验阶段。此外,还作为治疗囊性纤维化患者金黄色葡萄球菌肺部感染药物目前处于临床前开发阶段。监管方面,Iclaprim已被美国FDA授予合格传染病产品资格(QIDP)和快速通道地位。此外,FDA还授予Iclaprim治疗囊性纤维化患者金黄色葡萄球菌肺部肺部感染的孤儿药地位。其化学名为:5-[(2-环丙基-7,8-二甲氧基-2H-1-苯并吡喃-5-基)甲基]-2,4-嘧啶-二胺,结构式如化合物7所示:
发明专利CN 2019111264400中提供了一种艾拉普林合成方法:
在对发明专利CN2019111264400所报道的艾拉普林合成方法进行HPLC纯度检测的方法优化中,发现了一个新的含量较高的杂质峰。
本领域技术人员已知的是,在药物开发过程中,有关物质的研究是非常重要的环节。
鉴于CN2019111264400中并未发现该杂质,更未做进一步的分离和结构鉴定。为了更好的对Iclaprim进行质量研究和把控,非常有必要确认其生产过程中产生的有关物质的结构,并制备有关物质,以得到相应的标准品,从而规范的对有关物质进行研究,并将其控制在合理的限度范围之内,这不仅有利于原料药合成工艺的理解,产品质量的研究,及原辅料、中间体和成品质量标准的建立,更直接关系到Iclaprim的质量及安全性。
发明内容
本发明所要解决的问题就是克服现有技术中的艾拉普林产品中的杂质来源、结构存在不确定、缺乏制备方法的缺陷,而提供了一种七元杂环化合物或其盐、其制备方法及应用;本发明提供的七元杂环化合物的合成方法步骤简单,反应条件温和,可操作性强,经简单纯化即可得到较高纯度的产品;其可作为Iclaprim有关物质,有利于Iclaprim工艺研究及质量标准的制定,有效降低了研发成本,对药品开发具有重要意义。
本发明是通过下述技术方案来解决上述技术问题的。
本发明提供了一种如式7a所示的七元杂环化合物或其盐,
本发明还提供了一种所述的如式7a所示的七元杂环化合物的制备方法,包括下述步骤:将含有所述的如式7a所示的七元杂环化合物或其盐的艾拉普林或其盐进行色谱分离,即可;所述色谱分离的色谱柱为反相硅胶柱;所述色谱分离的流动相为磷酸二氢钾缓冲液和乙腈。
所述色谱分离的色谱柱可为本领域常规的反相硅胶柱,例如为十八烷基硅烷键合硅胶;较佳地,型号为YMC-pack ODS-AQ,150×3.0mm,3μm silica。
所述色谱分离的流动相,较佳地为流动相A:2mmol/L的磷酸二氢钾缓冲液;流动相B:乙腈;
更佳地,所述的流动相A与所述的流动相B,按下表进行线性梯度洗脱;
时间(分钟) | A相(%) | B相(%) |
0 | 95 | 5 |
5 | 95 | 5 |
6 | 75 | 25 |
14 | 75 | 25 |
15 | 95 | 5 |
25 | 95 | 5 |
所述百分比为占总体积的体积百分比。
所述制备方法中,除流动相和色谱柱外,其他色谱条件可为本领域常规的色谱条件,本发明优选下列色谱条件:检测波长为220nm;柱温为25~40℃(例如30~40℃);流速为0.1mL/min~2.0mL/min(优选0.6mL/min~1.0mL/min);进样体积为1~120μL(优选3-10μL)。
所述的艾拉普林或其盐可为本领域常规的方法制备,例如按照CN 2019111264400的方法制备。
本发明还提供了一种所述的如式7a所示的七元杂环化合物或其盐作为艾拉普林或其盐的杂质标准品的应用。
本发明还提供了一种艾拉普林或其盐的原料药,其含有含量百分比为0.01%~1.0%的如上所述如式7a所示的七元杂环化合物或其盐(例如0.02%、0.03%、0.04%、0.05%、0.06%、0.07%、0.08%、0.09%、0.1%、0.2%、0.3%、0.4%、0.5%、0.6%、0.7%、0.8%和0.9%)。所述的含量百分比为HPLC测定,通过峰面积计算得到。
所述的HPLC检测方法,具体如下:检测波长为220nm;柱温为25~40℃(例如30~40℃);流速为0.1mL/min~2.0mL/min(优选0.6mL/min~1.0mL/min);进样体积为1~120μL(优选3-10μL)。色谱柱型号为YMC-pack ODS-AQ 150×3.0mm,3μm silica。
流动相A:2mmol/L的磷酸二氢钾缓冲液;流动相B:乙腈;更佳地所述的流动相A与所述的流动相B以如下比例进行梯度洗脱:
时间(分钟) | A相(%) | B相(%) |
0 | 95 | 5 |
5 | 95 | 5 |
6 | 75 | 25 |
14 | 75 | 25 |
15 | 95 | 5 |
25 | 95 | 5 |
所述百分比为占总体积的体积百分比。
本发明还提供了一种艾拉普林或其盐的制剂,其包括如上所述的艾拉普林或其盐的原料药和药用辅料。
所述的“艾拉普林或其盐”中的“盐”,与所述的“如式7a所示的七元杂环化合物或其盐”中的盐相同,例如为三氟乙酸、对甲苯磺酸和硫酸。
术语“盐”表示由适宜的有机酸、无机酸、有机碱或无机碱与化合物形成的盐。所述的有机酸可为本领域常规的能成盐的各种有机酸,例如甲磺酸、对甲苯磺酸、马来酸、富马酸、柠檬酸、酒石酸、苹果酸、乳酸、甲酸、乙酸、丙酸、三氟乙酸、草酸、丁二酸、苯甲酸、羟乙基磺酸、萘磺酸和水杨酸中的一种或多种。所述的无机酸可为本领域常规的能成盐的各种无机酸,例如盐酸、硫酸和磷酸中的一种或多种。较佳地为三氟乙酸、对甲苯磺酸一水合物和硫酸中的一种或多种。
术语“原料药”表示由主要药物活性成分,以及含量可控的杂质组成。
术语“制剂”表示由主要药物活性成分,以及含量可控的杂质和/或辅料组成的,根据药典或药品监督部门批准的标准,为满足临床治疗或预防的需要而制备的药物应用形式(剂型)的具体品种。
术语“杂质”表示任何影响药物纯度的物质。所述杂质按其理化性质一般分为三类:有机杂质、无机杂质及残留溶剂。按照其来源,杂质可以分为工艺杂质(包括合成中未反应完全的反应物及试剂、中间体、副产物等)、降解产物、从反应物及试剂中混入的杂质等。
在不违背本领域常识的基础上,上述各优选条件,可任意组合,即得本发明各较佳实例。
本发明所用试剂和原料均市售可得。
本发明的积极进步效果在于:通过本发明的艾拉普林七元环杂质的对照品,可建立艾拉普林质量控制的分析方法,从而可提高艾拉普林临床应用的安全性和有效性。
具体实施方式
下面通过实施例的方式进一步说明本发明,但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法,按照常规方法和条件,或按照商品说明书选择。
实施例1(5-[(2-环丙基-7,8-二甲氧基-2H-1-苯并吡喃-5-基)甲基]-2,4-嘧啶-二胺)的制备
步骤(1)(N,N'-(5-(2-乙酰基-3,4,5-三甲氧基苄基)嘧啶-2,4-二基)二乙酰胺)的制备
向250ml反应瓶中加入化合物1(甲氧苄啶)(10.02g,34.52mmol)、乙酸酐(17.06g,167.11mmol)和100ml氯仿,搅拌下加入四氯化锡(8.00ml,68.36mmol),回流反应1h,TLC检测原料基本消失,降温至室温,将反应液倒入50ml冰水中,搅拌6mins,分液,5ml水洗有机相3次,合并水相,5ml氯仿萃取水相3次,合并有机相,饱和碳酸钠水溶液调pH至7~8,分液,5ml水洗有机相1次,无水硫酸钠干燥,过滤,真空浓缩,乙二醇单甲醚重结晶得到13.30g产品,收率92.63%。mp.203-205℃;HPLC检测其纯度为96.72%。1H-NMR(300MHz,CDCl3)δ(ppm):10.03(s,1H),9.20(s,1H),8.41,(s,1H),6.34(s,1H),3.95(s,3H),3.84(s,3H),3.76(s,2H),3.68(s,3H),2.60(s,3H),2.48(s,3H),2.19(s,3H);MS(ESI+):m/z,417([M+H]+).
步骤(2)(1-(6-((2,4-二氨基嘧啶-5-基)甲基)-2,3,4-三甲氧基苯基)乙酮)的制备
向反应瓶中加入化合物2(65.00g,156.25mmol)、碳酸钾(15.090g,109.35mmol)和600ml甲醇搅拌回流1.5h,停止加热,降至室温后置于冰浴下搅拌慢慢搅拌析晶,抽滤,水洗后烘干得到47.00g白色固体化合物3,收率90.5%,mp.121-123℃;HPLC检测其纯度为97.22%。1H-NMR(400MHz,CDCl3)δ(ppm):7.28(s,1H),6.66(s,1H),6.12,(s,2H),5.70(s,2H),3.82(s,3H),3.75(d,6H,4Hz),3.42(s,2H),2.29(s,3H).
步骤(3)(1-(6-((2,4-二氨基嘧啶-5-基)甲基)-2-羟基-3,4-二甲氧基苯基)乙酮)的制备
向1L反应瓶中加入化合物3(30.00g,90.36mmol)和600ml二氯甲烷,冰盐浴降温至-6℃,缓慢滴加1mol/L的三溴化硼二氯甲烷溶液135.5ml,加毕升至室温反应5h。降温至0℃,300ml甲醇淬灭,搅拌1h,真空浓缩干溶剂,乙醇重结晶得到25.50g白色固体化合物4,收率88.74%。mp.217℃;HPLC检测其纯度为96.10%。1H-NMR(300MHz,CDCl3)δ(ppm):9.66(s,1H),8.31(s,1H),7.91(s,1H),7.54(s,2H),7.14(s,1H),6.46(s,1H),3.77(s,3H),3.69(s,3H),3.48(s,2H),2.42(s,3H);MS(ESI+):m/z,319([M+H]+).
步骤(4)(2-环丙基-5-((2,4-二氨基嘧啶-5-基)甲基)-7,8-二甲氧基苯并二氢吡喃-4-酮)的制备
向100ml反应瓶中加入化合物4(4.01g,12.58mmol)、环丙甲醛(1.07g,15.29mmol)和40ml乙腈,搅拌下缓慢滴加吡咯烷(1.34g,18.87mol)和醋酸(1.13g,18.83mmol),于室温下搅拌36h,抽滤,烘干,得到4.57g类白色固体化合物5的醋酸盐,收率84.28%,mp168-171℃。1H-NMR(400MHz,CDCl3)δ(ppm):7.13(s,1H),6.49(s,1H),6.31(s,2H),5.92(s,2H),3.89-4.00(m,2H),3.78-3.86(m,4H),3.71(s,3H),2.78-2.85(m,1H),2.64-2.69(m,1H),1.89(s,3H),1.19-1.25(m,1H)0.53-0.63(m,2H),0.45-0.51(m,1H),0.37-0.43(m,1H);MS(ESI+):m/z,373([M+H]+).
步骤(5)(2-环丙基-5-((2,4-二氨基嘧啶-5-基)甲基)-7,8-二甲氧基苯并二氢吡喃-4-醇)的制备
向反应瓶中加入化合物5(4.00g,10.81mmol)和80ml甲醇,冰浴降温至4℃,加入硼氢化钠(0.21g,5.56mmol),室温下反应2.5h,蒸干甲醇,加入40ml水,搅拌10mins,抽滤,滤饼加甲醇回流3h,真空浓缩,乙醇和水(乙醇和水的体积比为5:1)重结晶得到3.88g白色固体化合物6,收率96.48%。mp.211-213℃;HPLC检测其纯度为99.23%;1H-NMR(400MHz,CDCl3).δ(ppm):7.49(s,1H),6.17-6.2(d,3H),5.58-5.64(m,3H),4.93-4.94(d,1H),3.78-3.82(d,1H),3.63(s,3H),3.62(s,3H),3.53-3.57(m,1H),2.24-2.28(m,1H),1.96-2.02(m,1H),1.34-1.37(m,1H),0.49-0.1(d,2H),0.31-0.36(m,2H);MS(ESI+):m/z,373([M+H]+)。
步骤(6)(5-[(2-环丙基-7,8-二甲氧基-2H-1-苯并吡喃-5-基)甲基]-2,4-嘧啶-二胺)的制备
向反应瓶中加入化合物6(2.01g,5.40mmol,HPLC纯度为99.23%)与20ml四氢呋喃,搅拌下加入对甲苯磺酸一水合物(1.54g,8.10mmol),加热回流反应1h,TLC检测基本无原料剩余,降至室温,析出大量白色固体,过滤,烘干,得到2.54g白色固体化合物7的对甲苯磺酸盐,收率89.27%;mp.208℃;HPLC检测其纯度为99.91%;1H-NMR(400MHz,CDCl3).δ(ppm):8.06(b,2H),7.45-7.49(m,3H),7.10-7.12(d,2H),6.85(s,1H),6.47(s,1H),6.39-6.42(m,1H),5.75-5.78(m,1H),4.24-4.27(m,1H),3.74(s,3H),-3.72(s,3H),3.57(b,2H),2.28(s,3H),1.12-1.20(m,1H),0.29-0.54(m,4H),MS(ESI+):m/z,355([M+H]+)。化合物7的对甲苯磺酸盐(2.54g,4.83mmol)于饱和碳酸钠溶液中搅拌1h,抽滤,烘干,得到1.71g白色固体化合物7,总收率89.40%。mp.215℃。HPLC检测其纯度为99.96%;1H-NMR(400MHz,CDCl3).δ(ppm):7.07(s,1H),6.45-6.46(d,1H),6.42(s,1H),6.19(s,2H),5.70-5.72(m,1H),5.68(s,2H),4.24-4.26(m,1H),3.70(s,3H),3.71(s,3H),3.52(d,2H),1.11-1.15(m,1H),0.43-0.51(m,2H),0.35-0.39(m,1H),0.30-0.33(m,1H);MS(ESI+):m/z,355([M+H]+)。
上述HPLC检测采用如下方法1:高效液相色谱柱的型号为YMC-pack ODS-AQ(150×3.0mm,3μm silica);以0.1%的甲酸缓冲液为流动相A,以乙腈为流动相B,按下表进行线性梯度洗脱;检测波长220nm;流速:0.6mL/min;进样体积:3-10μL;柱温40℃。
时间(分钟) | A相(%) | B相(%) |
0 | 95 | 5 |
5 | 95 | 5 |
6 | 75 | 25 |
16 | 75 | 25 |
17 | 95 | 5 |
27 | 95 | 5 |
所述百分比为占总体积的体积百分比。
表1 HPLC检测结果如下表所示:
我方研究人员在对上述Iclaprim产品的HPLC分析方法的优化中发现一新的含量较高的杂质峰。
具体HPLC检测采用如下方法2:高效液相色谱柱的型号为YMC-pack ODS-AQ(150×3.0mm,3μm silica);以2mmol/L的磷酸二氢钾缓冲液为流动相A,以乙腈为流动相B,按下表进行线性梯度洗脱;检测波长220nm;流速:0.6mL/min;进样体积:3-10μL;柱温40℃。
时间(分钟) | A相(%) | B相(%) |
0 | 95 | 5 |
5 | 95 | 5 |
6 | 75 | 25 |
14 | 75 | 25 |
15 | 95 | 5 |
25 | 95 | 5 |
所述百分比为占总体积的体积百分比。
表2优化的HPLC检测结果如下表所示:
杂质7a出峰时间13.009mins,Iclaprim出峰时间为12.212mins。杂质7a相对药物Iclaprim的出峰时间为1.07。该液相方法能够有效分离药物与该杂质。
鉴于通过上述新开发的HPLC方法,Iclaprim产品中上述杂质7a含量较高,会超过药典规定的标准,严重影响其质量,对患者的安全用药带来了极大的风险。
本领域技术人员已知的是,在药物开发过程中,有关物质的研究是非常重要的环节,为了更好的对Iclaprim进行质量研究和把控,非常有必要确认其生产过程中产生的有关物质,并研究这些有关物质的制备方法,以得到相应的标准品,从而规范的对有关物质进行研究,并将其控制在合理的限度范围之内,这不仅有利于原料药合成工艺的理解,产品质量的研究,及原辅料、中间体和成品质量标准的建立,更直接关系到Iclaprim的质量及安全性。
因此,我方采用上述优化的HPLC条件通过制备色谱柱富集分离,对该杂质的结构确证进行了研究。
其结构鉴定数据如下:mp.202-204℃;MS(ESI+):m/z,355([M+H]+)。
1H-NMR(600MHz,DMSO-d6).δ(ppm):7.51(s,1H),6.90(s,1H),6.52(s,1H),5.55(s,2H),5.06-5.05(d,1H),4.40-4.38(d,1H),3.74(s,3H),3.63(s,3H),3.32-3.30(m,1H),3.16-3.13(d,2H),2.27-2.24(d,1H),1.87-1.82(m,1H),1.10-1.03(m,1H),0.63-0.58(m,2H),0.52-0.48(m,1H),0.46-0.42(m,1H);13C NMR(100MHz,DMSO-d6)δ162.05,161.73,155.43,151.87,147.58,135.81,135.16,115.35,103.96,103.71,75.10,59.90,55.81,42.87,33.44,32.22,15.06,3.40,1.25.
通过上述分析数据,确定该杂质的化学结构为如下式7a所示的化合物:
但是由于目前还没有上述杂质的相关研究,缺少标准品,对于杂质的药理毒理无法进行进一步的研究,对于产品中该杂质的含量及检测方法也缺少更精确合理的标准。因此,为保证Iclaprim的安全性和有效性,根据上述结构,我方进行了上述杂质7a的合成研究。具体如下实施例所示。
实施例2
向反应瓶中加入化合物6(1.69g,4.54mmol)与20ml四氢呋喃,搅拌下加入三氟乙酸(1.56g,13.68mmol),加热回流反应15h,TLC检测基本无原料剩余,饱和碳酸钠调pH至7左右,蒸掉四氢呋喃,有机相用饱和碳酸钠溶液调pH至10,搅拌1h,抽滤,烘干得到1.59g化合物7,粗品收率98.87%。HPLC检测(同实施例1)化合物7纯度为97.01%,其中HPLC显示该杂质含量为2.10%,我们通过制备色谱柱富集分离得到0.021g。
其结构鉴定数据如下:
mp.202-204℃;1H-NMR(600MHz,DMSO-d6).δ(ppm):7.50(s,1H),6.91(s,1H),6.53(s,1H),5.56(s,2H),5.05-5.04(d,1H),4.41-4.39(d,1H),3.73(s,3H),3.64(s,3H),3.33-3.30(m,1H),3.17-3.13(d,2H),2.26-2.23(d,1H),1.86-1.82(m,1H),1.11-1.03(m,1H),0.64-0.59(m,2H),0.52-0.48(m,1H),0.45-0.41(m,1H);MS(ESI+):m/z,355([M+H]+)。
在此基础上,进一步通过HPLC验证(HPLC方法2)。
表3实施例2中制备得到的7a的HPLC结果数据
可见出峰时间也与上述实施例1相同。
实施例3
向反应瓶中加入化合物6(2.00g,5.38mmol)与20ml四氢呋喃,搅拌下加入对甲苯磺酸一水合物(1.54g,8.10mmol),加热回流反应1h,TLC检测基本无原料剩余,降至室温,饱和碳酸钠调pH至7左右,蒸掉四氢呋喃,饱和碳酸钠溶液调pH至10,搅拌1h,抽滤,烘干,得到1.81g粗品化合物7,总收率95.10%。HPLC检测(HPLC方法2)化合物7其纯度为98.25%,杂质7a含量为1.02%。
分析鉴定数据(包括HPLC的出峰时间)均与上述实施例1相同。
实施例4:
向反应瓶中加入化合物6(2.00g,5.38mmol)与20ml四氢呋喃,搅拌下加入浓硫酸(0.63g,6.43mmol),加热回流反应4h,降至室温,饱和碳酸钠溶液调pH至7左右,蒸干溶剂,饱和碳酸钠水溶液调pH至10左右后搅拌1h,抽滤,烘干,得到1.88g白色固体化合物7,总收率98.78%。mp.215℃;HPLC检测(HPLC方法2)化合物7含量为97.10%,杂质7a含量为1.53%。
分析鉴定数据(包括HPLC的出峰时间)均与上述实施例1相同。
因此,采用上述色谱方法可制备得到杂质7a,其可作为杂质标准品,进一步提高艾拉普林的质量,真正保证艾拉普林的安全性和有效性,降低使用风险。
Claims (10)
2.一种如权利要求1所述的如式7a所示的七元杂环化合物的制备方法,其特征在于,其包括下述步骤:
将含有如权利要求1所述的如式7a所示的七元杂环化合物或其盐的艾拉普林或其盐进行色谱分离,即可;所述色谱分离的色谱柱为反相硅胶柱;所述色谱分离的流动相为磷酸二氢钾缓冲液和乙腈。
3.如权利要求2所述的制备方法,其特征在于,
所述色谱分离的色谱柱为十八烷基硅烷键合硅胶;
和/或,所述色谱分离的流动相中,流动相A:2mmol/L的磷酸二氢钾缓冲液;流动相B:乙腈;
和/或,所述色谱分离的检测波长为220nm;
和/或,所述色谱分离的柱温为25~40℃;
和/或,所述色谱分离的流速为0.1mL/min~2.0mL/min;
和/或,所述色谱分离的进样体积为1~120μL。
5.一种如权利要求1所述的如式7a所示的七元杂环化合物或其盐作为艾拉普林或其盐的杂质标准品的应用。
6.一种艾拉普林或其盐的原料药,其特征在于,其含有含量百分比为0.01%~1.0%的如权利要求1所述如式7a所示的七元杂环化合物或其盐。
7.如权利要求6所述的应用,其特征在于,所述的含量百分比采用HPLC检测,所述的HPLC的色谱柱为反相硅胶柱;所述色谱分离的流动相为磷酸二氢钾缓冲液和乙腈。
8.如权利要求7所述的制备方法,其特征在于,
所述色谱分离的色谱柱为十八烷基硅烷键合硅胶;
和/或,所述色谱分离的流动相中,流动相A:2mmol/L的磷酸二氢钾缓冲液;流动相B:乙腈;
和/或,所述色谱分离的检测波长为220nm;
和/或,所述色谱分离的柱温为25~40℃;
和/或,所述色谱分离的流速为0.1mL/min~2.0mL/min;
和/或,所述色谱分离的进样体积为1~120μL。
10.一种艾拉普林或其盐的制剂,其特征在于,包括如权利要求6所述的艾拉普林或其盐的原料药和药用辅料。
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