CN113527269A - 一种匹伐他汀钙氧化杂质的制备方法 - Google Patents
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- RHGYHLPFVJEAOC-FFNUKLMVSA-L pitavastatin calcium Chemical compound [Ca+2].[O-]C(=O)C[C@H](O)C[C@H](O)\C=C\C1=C(C2CC2)N=C2C=CC=CC2=C1C1=CC=C(F)C=C1.[O-]C(=O)C[C@H](O)C[C@H](O)\C=C\C1=C(C2CC2)N=C2C=CC=CC2=C1C1=CC=C(F)C=C1 RHGYHLPFVJEAOC-FFNUKLMVSA-L 0.000 title claims abstract description 20
- 229960003296 pitavastatin calcium Drugs 0.000 title claims abstract description 19
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- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
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- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 3
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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 claims description 2
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/58—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems with hetero atoms directly attached to the ring nitrogen atom
- C07D215/60—N-oxides
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Abstract
本发明涉及一种匹伐他汀钙氧化杂质的制备方法,包括以下步骤:以匹伐他汀酯为原料,与氧化剂在有机溶剂中反应获得匹伐他汀酯的氧化物,与无机碱水溶液反应进一步水解得到氧化物的盐,该合成方法,操作简单且产物纯度高,可用于杂质的定性和定量检测,利于匹伐他汀的质量控制和用药安全性。
Description
技术领域
本发明属于医药合成技术领域,具体涉及一种匹伐他汀钙氧化杂质的制备方法。
背景技术
近年来,随着人们生活水平的日益提高和工作节奏的不断加快,心血管疾病的发病率和死亡率都呈明显上升态势,西方发达国家中老年人的高血脂症发病率高达60%,我国高脂血症的患病率在7%以上,约有高血脂症患者9000万人,总体趋势是北方大于南方,城市大于农村,高血脂症已成为威胁人类健康的头号杀手。早期医药界防治心血管类疾病侧重在降压药的开发上,后来逐步认识到血浆胆固醇浓度,特别是低密度脂蛋白(LDL)、胆固醇的浓度升高是引起动脉粥样硬化和缺血性心脑疾病的重要危险因素,于是降血脂药物的开发就成为心血管类疾病防治的重点。80年代后期开始崭露头角的他汀类药物,以其卓越的临床疗效,在全球医药市场上赢得了巨大的成功。全球他汀类药物的总销售额超过了100亿美元。占据降血脂药物市场的60%。在我国,约有3600万的患者在使用降脂药物。
匹伐他汀钙是日本日产化学工业株式会社研制开发,由日产化学工业株式会社等申请,2003年7月匹伐他汀钙片在日本获准上市用于高胆固醇血症的治疗。匹伐他汀钙对HMG-CoA还原酶的抑制活性强于已上市的他汀类药物,其临床有效剂量为1-2mg/d,明显低于其他已上市的他汀类药物。而且匹伐他汀钙与其他他汀类药物相比,一个重要的优点在于:匹伐他汀钙在体内不经CYP3A4代谢,引发不良的药物相互作用的可能性较小。匹伐他汀钙的问世,为高脂血症的临床治疗提供一种新的更好的选择,而在研究匹伐他汀钙中发现其在专属性氧化降解试验下会产生较多氧化降解杂质,需提供氧化杂质标准品用以保证样品质量研究,提高匹伐他汀钙的质量控制和用药安全性,目前匹伐他汀钙氧化杂质制备主要有以下两条合成路线:。
路线1:CN109020962A报道了以下合成路线:
用匹伐他汀钙加有机酸酐,用过氧化脲为氧化剂的方法制备环氧酸及N氧化物钠盐的方法。但是实际实验结果却是大部分内酯化,无法得到氧化产物。
路线2:Indian Pat.Appl,2014MU02014,01Jan 2016报道以下合成路线:
以mCPBA为氧化剂,乙酸乙酯为溶剂,5-10℃反应,然后升至室温,反应18-20h,但收率非常低,大部分为未反应的匹伐他汀钙盐。
因此本领域迫切需要一种收率高,操作简单,且产物纯度高,易于分离的氧化杂质的制备方法。
发明内容
本发明提供一种匹伐他汀钙氧化杂质的制备方法,以克服现有技术上存在的不足。
一种匹伐他汀钙氧化杂质的制备方法,包括以下步骤:以匹伐他汀酯为原料,经氧化,获得匹伐他汀酯的氧化物,与无机碱水溶液反应进一步水解得到氧化物的盐。
化学反应式如下:
其中,所述匹伐他汀酯选自1-5个碳的烷基酯或苄基酯,优选叔丁基酯;
在一种实施方式中,所述步骤1)中所选溶剂包括DCM、甲苯、乙酸异丙酯、2-甲基四氢呋喃,乙醇,甲醇或乙睛中的一种或多种,反应温度0-50℃;
优选地所述步骤1)中反应溶剂包括二氯甲烷、乙酸异丙酯中一种或多种;反应温度为20-50℃;
在一种实施方式中,所述步骤1)中氧化剂为过氧化物,
优选地所述步骤1)中过氧化物包括过氧乙酸,间氯过氧苯甲酸,过氧化脲,H2O2中一种或多种;
更优选地所述步骤1)中过氧化物为间氯过氧苯甲酸;
在一种实施方式中,所述步骤1)中氧化剂与匹伐他汀酯的摩尔比0.8:1~4.0:1,
优选地所述步骤1)中氧化剂与匹伐他汀酯的摩尔比为1.0:1~2.5:1
在一种实施方式中,所述步骤2)中impK-1,impO-1,impL-1,imp-1在无机碱水溶液中水解为氧化物的盐,
进一步地,步骤2中所述无机碱包括氢氧化锂、氢氧化钠、氢氧化钾等的一种或多种,优选氢氧化钠。
本发明中,所述两步反应优选按下述方式进行:
匹伐他汀叔丁酯,溶于有机溶剂中,在20-30度搅拌,1小时内滴加10%质量浓度的同种有机溶剂中的间氯过氧苯甲酸溶液,滴毕,室温搅拌4小时,加入碳酸氢钠溶液淬灭,分得油相用碳酸氢钠再洗1次,旋干,得粗品,加1%碱溶液,20-25度搅拌过夜,用EA洗涤水相,水相冻干得氧化物的盐impK-2,impO-2,impL-2,impP-2。
本发明中,所述mCPBA为间氯过氧苯甲酸。
本发明中,按本领域常识,在这些所述的反应完成后,可进行本领域常规的纯化和分离方法对产物进行纯化和分离,包括但不限于过滤、重结晶、柱层析等方式或方法。
本发明中,所述的室温温度为本领域常规意义上的室温温度,一般为10-30℃。
本发明所用试剂和原料除特殊说明外,均市售可得。
本发明的积极进步效果在于:本发明的制备方法简单,得到的杂质可以用于定性和定量的分析,从而提高匹伐他汀的质量控制和用药安全性。在符合本领域常识的基础上,上述各条件,可任意组合,即得本发明各较佳实例。
具体实施方式
本文的实施例中,如果对于反应温度或操作温度没有做出具体说明,则该温度通常指室温(15-30℃)。
以下通过实施例进一步阐述本发明。应理解,这些实施例仅用于举例说明目的,而不是对本发明的限制。本领域技术人员根据本发明构思对其作出的各种改变或调整,均应落入本发明的保护范围内。
本文中涉及到多种物质的添加量、含量及浓度,其中所述的百分含量,除特别说明外,皆指质量百分含量。
本文所述的纯度一般是指HPLC纯度。
检测仪器:Agilent 1200,Bruker NMR 400MHz。
试剂:本发明实施例中使用的有机溶剂等均为工业级,直接使用。
实施例
实施例1:ImpK-1,ImpL-1,ImpO-1,ImpP-1的制备
取匹伐他汀酯10克,溶于50mL有机溶剂中,在一定温度下搅拌,1小时内滴加10%质量浓度的氧化剂的有机溶剂溶液,滴毕,室温搅拌4小时,加入碳酸氢钠溶液淬灭,分得油相用碳酸氢钠再洗1次,旋干,得粗品,用LCMS检测匹伐他汀酯反应彻底,目标物MS+510.35(ImpP-1)、494.35(ImpL-1)、494.35(ImpO-1+ImpK-1)分别为18.62%、14.08%、47.26%。通过制备色谱分离,得ImpK-1、ImpL-1、ImpO-1、impP-1。
具体结果见下表1:
表1
实施例2:ImpK-2,ImpL-2,ImpO-2,ImpP-2的制备
分别取impK-1、impL-1、impO-1、impP-1各100mg,加1%碱水溶液,20-25度搅拌过夜,用EA洗涤水相,水相冻干,分别得到ImpK-2、ImpL-2、ImpO-2、ImpP-2。
各方案具体结果见下表2:
表2
impK-2:
1H NMR(400MHz,DMSO-d6)δ7.881(d,J=8.0Hz,1H),7.698-7.660(m,1H),7.467-7.300(m,6H),4.95(s,)4.20(d,J=2.4Hz,1H),3.67(m,1H),,3.250-3.239(m,1H),2.688-2.651(m,2H),2.012-1.965(m,1H),1.801-1.631(m,1H),1.378–1.056(m,5H),1.108-1.031(m,1H)
13C NMR(101MHz,DMSO-d6)δ176.619,163.706,,161.272,162.629,146.896,145.620,132.740,132.429,132.352,131.885,131.805,129.806,128.862,127.785,126.230,125.879,125.573,116.153,115.941,115.852,115.640,67.459,66.509,64.398,53.387,43.756,40.833,15.154,11.563,10.787;m/z:[M+H+]=438.2
impL-2:
1H NMR(400MHz,DMSO-d6)δδ8.582(d,J=8.4Hz,1H),7.754-7.713(m,1H),7.570-7.530(m,1H),7.339-7.299(m,5H),6.398-6.356(m,1H),5.605-5.551(m,1H),5.06,,4.124(d,J=6.4Hz,1H),3.594-3.542(m,1H),2.167(tt,1H),2.058-1.990(m,1H),1.870-1.849(dd,1H),1.39(dt,1H),1.308(td 2H),1.294-1.039(m,4H)。
13C NMR(101MHz,DMSO-d6)δ177.20,163.33,160.90,146.53,142.93,140.22,133.53,133.18,133.12,133.02,132.90,132.82,129.97,128.53,128.20,126.94,122.89,119.37,115.87,115.66,69.03,66.20,45.05,44.02,25.61,13.14,8.96,8.29,8.24;m/z:[M+H+]=438.2
impO-2:
1H NMR(400MHz,DMSO-d6)δ7.874(d,J=8.0Hz,1H),7.687-7.652(m,1H),7.455-7.289(m,6H),4.224(d,J=2.0Hz,1H),3.76–3.65(m,1H),3.509-3.418(m,1H),2.757–2.729(m,2H),2.044-2.007(m,1H),1.848-1.827(m,1H),1.301-1.071(m,6H).
13C NMR(101MHz,DMSO-d6)δ7.884 7.864 7.690 7.687 7.673 7.670 7.6667.652 7.4557.431 7.429 7.414 7.411 7.407 7.394 7.390 7.381 7.374 7.367 7.3617.358 7.309 7.308 7.2894.226 4.221 3.509 3.500 3.487 3.478 3.418 2.757 2.7432.736 2.729 2.522 2.044 2.0172.007 1.848 1.827,1.161 1.100 1.091 1.079 1.071;m/z:[M+H+]=438.2
ImpP-2:
1H NMR(400MHz,DMSO-d6)δ8.609 8.587 7.810 7.792 7.788 7.771 7.6237.606 7.6027.585 7.491 7.475 7.462 7.402 7.381 7.358 7.324 7.318 7.300 4.2394.234 4.209 4.204 3.6683.660 3.393 2.711 2.679 2.673 2.671 2.665 2.522 2.5172.513 2.509 2.504 1.997 1.991 1.9861.963 1.954 1.790 1.768 1.752 1.625 1.2391.119 1.107 1.098 1.086 1.070
13C NMR(101MHz,DMSO-d6)δ176.757,176.697,163.799,161.360,147.887,147.760,140.875,134.735,134.630,133.150,132.488,132.195,131.775,130.513,128.750,127.802,126.704,119.370,116.215,116.005,115.795,66.951,66.579,64.553,64.047,53.597,43.742,43.597,25.775,12.860,7.196,7.071;m/z:[M+H+]=454.3
对比实施例1(CN109020962A实施例1):
100ml单口烧瓶中加入30ml三氯甲烷,4.41g匹伐他汀钙,缓慢加入2.10g三氟乙酸酐,放热剧烈,搅拌,降温至0℃。2.76g过氧化脲中加入10ml乙醇,不溶,0℃下以悬浊液形式滴加到上述反应体系中,滴加完毕,保持0℃~5℃反应5h,TLC检测,大部分为匹伐他汀酸。剧烈搅拌下取反应液,加水,取清液层,用乙腈溶解后进LCMS检测,大部分为匹伐他汀酸,无目标产物。
对比实施例2(参比IN2014MUM2014):
将9克匹伐他汀游离酸溶于60毫升乙酸乙酯中,冷却至5-10℃,用滴液漏斗缓慢加入由6.7克(1摩尔当量)间氯过氧苯甲酸在30ml乙酸乙酯中的浑浊溶液。将反应物料升至室温并搅拌18-20小时,体系仍为白色悬浮液。取样,加饱和碳酸氢钠溶液,取油层,用LCMS检测,目标峰MS+454、438、438分别为2.58%、13.39%、9.6%,未反应的匹伐他汀酸为62.82%。
Claims (9)
2.如权利要求1所述制备方法,其特征在于,匹伐他汀酯为1-5个碳的烷基酯或苄基酯。
3.如权利要求1所述制备方法,其特征在于,步骤1中所选溶剂为DCM、甲苯、乙酸异丙酯、2-甲基四氢呋喃,乙醇,甲醇或乙睛一种或多种。
4.如权利要求1所述制备方法,其特征在于氧化剂为过氧化物。
5.如权利要求4所述,其特征在于,过氧化物为过氧乙酸,间氯过氧苯甲酸(mCPBA),过氧化脲,H2O2中的一种或多种。
6.如权利要求1所述制备方法,其特征在于氧化剂与匹伐他汀酯的摩尔比为0.8:1~4.0:1。
7.如权利要求1所述制备方法,其特征在于步骤1中反应温度为0~50度。
8.如权利要求1所述制备方法,其特征在于步骤2中在无机碱性水溶液条件下进一步水解得到氧化物的盐。
9.如权利要求8所述,其特征在于无机碱为氢氧化锂、氢氧化钠、氢氧化钾的一种或多种。
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