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Publication numberCN1894221 B
Publication typeGrant
Application numberCN 200480035922
PCT numberPCT/US2004/040329
Publication date8 Aug 2012
Filing date2 Dec 2004
Priority date2 Dec 2003
Also published asCA2546894A1, CA2546894C, CN1894221A, DE602004032465D1, EP1689723A1, EP1689723B1, US7244844, US7692008, US7692009, US7692010, US7741482, US8487097, US20050187234, US20070244321, US20070249830, US20070249831, US20070255059, US20090188305, WO2005056534A1
Publication number200480035922.0, CN 1894221 B, CN 1894221B, CN 200480035922, CN-B-1894221, CN1894221 B, CN1894221B, CN200480035922, CN200480035922.0, PCT/2004/40329, PCT/US/2004/040329, PCT/US/2004/40329, PCT/US/4/040329, PCT/US/4/40329, PCT/US2004/040329, PCT/US2004/40329, PCT/US2004040329, PCT/US200440329, PCT/US4/040329, PCT/US4/40329, PCT/US4040329, PCT/US440329
InventorsN芬克尔斯坦
Applicant特瓦制药工业有限公司
Export CitationBiBTeX, EndNote, RefMan
External Links: SIPO, Espacenet
Reference standard for characterization of rosuvastatin
CN 1894221 B
Abstract
Provided are rosuvastatin degradation products and their use as a reference standard (including reference marker) for analysis of rosuvastatin.
Claims(39)  translated from Chinese
1.具有以下结构的罗苏伐他汀降解产物: 、私'a Rosuvastatin degradation product 1 with the following structure: private 'a
2.具有以下结构的罗苏伐他汀降解产物:OH OH 0 、体 2. having the structure rosuvastatin degradation product: OH OH 0, body
3.具有以下结构的罗苏伐他汀降解产物: 'ユ^^C '其中M是碱金属或碱土金属。 3 having the following structure rosuvastatin degradation product: 'Uni ^^ C' wherein M is an alkali metal or alkaline earth metal.
4.具有以下结构的罗苏伐他汀降解产物: 4. having the structure rosuvastatin degradation product:
Figure CN1894221BC00031
其中M是碱金属或碱土金属。 Wherein M is an alkali metal or alkaline earth metal.
5.权利要求3或4的罗苏伐他汀降解产物,其中M是钙。 3 or 4 of rosuvastatin degradation product of claim 1, wherein M is calcium.
6. 一种将权利要求5的钙盐转化为内酯形式的方法,包括将こ腈、盐酸和所述钙盐混合以得到所述的内酷。 6. A method as claimed in claim 5 the calcium salt is converted to the lactone form, comprising a nitrile ko, hydrochloric acid and mixed to obtain the calcium salt of the inner cool.
7. 一种将权利要求5的钙盐转化为游离酸的方法,包括将所述钙盐溶于こ腈和水的混合物以得到溶液,并将所述溶液和ニ氧化硅柱接触。 A calcium salt as claimed in claim 5 for the conversion of the free acid, comprising the calcium salt is dissolved in a mixture of water and a nitrile ko to obtain a solution, and the solution in contact with Ni silica column.
8.权利要求7的方法,还包括从ニ氧化硅柱获得游离酸。 The method of claim 7, further comprising obtaining a free acid from the silica column ni.
9.具有以下结构的罗苏伐他汀降解产物的内酷形式: 9. having the structure rosuvastatin degradation product within the cool form:
Figure CN1894221BC00032
其中C1和C5形成内酷。 C1 and C5 which formed in the cool.
10.具有以下结构的罗苏伐他汀降解产物的内酷形式: 10. With the structure of rosuvastatin degradation product within the cool form:
Figure CN1894221BC00033
其中C1和C5形成内酷。 C1 and C5 which formed in the cool.
11. 一种将权利要求9或10的内酯转化为钙盐的方法,包括在碱性水溶液条件下水解所述内酷,并且将水解的内酯与钙源反应。 Lactone 9 or 10 is converted to a calcium salt comprising hydrolyzing cool the inner solution under alkaline conditions, and the hydrolysis reaction of the lactone with the calcium source 11. A method according to claim.
12.权利要求11的方法,其中碱性水溶液与内酯的こ腈溶液混合,接着除去こ腈并加入钙源,然后回收所述钙盐。 12. The method of claim 11, wherein the alkaline aqueous solution is mixed with a solution of the lactone nitrile ko, followed by removal and addition of calcium sources ko nitrile, and then recovering the calcium salt.
13.权利要求12的方法,其中所述方法包括将所述内酯溶于こ腈和氢氧化钠水溶液的混合物,蒸发こ腈,井向剰余的水中加入氯化钙以沉淀所述钙盐。 13. The method of claim 12, wherein said method comprises the lactone nitrile ko and dissolved in a mixture of aqueous sodium hydroxide solution and evaporated ko nitrile, well water was added to 剰 than calcium chloride to precipitate the calcium salt.
14. 一种将权利要求9或10的内酯转化为游离酸形式的方法,包括在碱性水溶液条件下水解所述内酯以得到盐,并且将所述的盐与ニ氧化硅柱接触以得到所述的游离酸。 14. A method of the lactone of claim 9 or 10, converted to the free acid form, comprising an aqueous solution of hydrolyzed under basic conditions to give the lactone salt, and the salt with a silica column ni contacting get the free acid.
15.罗苏伐他汀降解产物的混合物,其由以下结构的化合物和其相应的6位立体异构体组成: 15. A mixture of rosuvastatin degradation product, which consists of compounds and their corresponding six stereoisomers of the following structure consists of:
Figure CN1894221BC00041
其中所述的化合物以重量计95%不含其相应的6位立体异构体。 Wherein said compound by weight 95% free of its corresponding stereoisomer 6.
16.权利要求15的混合物,其中所述的罗苏伐他汀降解产物是已分离或纯化的。 Mixture of claim 15, wherein said rosuvastatin degradation product is already isolated or purified.
17.罗苏伐他汀降解产物的混合物,其由以下结构的化合物和其相应的6位立体异构体组成: 17. A mixture of rosuvastatin degradation product, which consists of compounds and their corresponding six stereoisomers of the following structure consists of:
Figure CN1894221BC00042
其中所述的化合物以重量计95%不含其相应的6位立体异构体。 Wherein said compound by weight 95% free of its corresponding stereoisomer 6.
18.权利要求17的混合物,其中所述的罗苏伐他汀降解产物是已分离或纯化的。 18. The mixture of claim 17, wherein said rosuvastatin degradation product is already isolated or purified.
19.罗苏伐他汀降解产物的混合物,其由以下结构的化合物和其相应的6位立体异构体组成: 19. mixture rosuvastatin degradation product, which consists of compounds and their corresponding six stereoisomers of the following structure consists of:
Figure CN1894221BC00051
其中所述的化合物以重量计95%不含其相应的6位立体异构体。 Wherein said compound by weight 95% free of its corresponding stereoisomer 6.
20.权利要求19的混合物,其中所述的罗苏伐他汀降解产物是已分离或纯化的。 Mixture of claim 19, wherein said rosuvastatin degradation product is already isolated or purified.
21.罗苏伐他汀降解产物的混合物,其由以下结构的化合物和其相应的6位立体异构体组成: 21. A mixture of rosuvastatin degradation product, which consists of compounds and their corresponding six stereoisomers of the following structure consists of:
Figure CN1894221BC00052
其中所述的化合物以重量计95%不含其相应的6位立体异构体。 Wherein said compound by weight 95% free of its corresponding stereoisomer 6.
22.权利要求21的混合物,其中所述的罗苏伐他汀降解产物是已分离或纯化的。 22. The mixture of claim 21, wherein said rosuvastatin degradation product is already isolated or purified.
23.如权利要求9所述的罗苏伐他汀降解产物的内酷形式的混合物,其由以下结构的内酯形式和其相应的6位立体异构体组成: Mixture rosuvastatin degradation product forms within 23. Cool claim 9, which is a lactone form of the structure and its corresponding six stereoisomer:
Figure CN1894221BC00053
其中び和び形成内酷, 其中所述的内酯形式以重量计95%不含其相应的6位立体异构体。 Lactone form and び び which formed in the cool, wherein said weight 95% free of its corresponding six stereoisomers.
24.权利要求23的混合物,其中所述的罗苏伐他汀降解产物是已分离或纯化的。 24. The mixture of claim 23, wherein said rosuvastatin degradation product is already isolated or purified.
25.权利要求10的罗苏伐他汀降解产物的内酷形式的混合物,其由以下结构的内酯形式和其相应的6位立体异构体组成: Mixture rosuvastatin degradation product within the cool form of claim 25. 10, which is a lactone form of the structure and its corresponding six stereoisomer:
Figure CN1894221BC00061
其中所述的内酯形式以重量计95%不含其相应的6位立体异构体。 Wherein the lactone form of 95% by weight of 6 free of its corresponding stereoisomers.
26.权利要求25的混合物,其中所述的罗苏伐他汀降解产物是已分离或纯化的。 26. The mixture of claim 25, wherein said rosuvastatin degradation product is already isolated or purified.
27. 一种用于分析罗苏伐他汀样品的方法,包括以下步骤: a)对样品进行色谱法以得到数据;和b)将所述数据与权利要求1、2、3、4、9或10的降解产物的色谱数据比较。 27. A method for rosuvastatin method for analyzing a sample, comprising the following steps: a) the sample was subjected to chromatography to obtain data; and b) the data claims 1,2,3,4,9 or Chromatography Data 10 Comparison of degradation products.
28.权利要求27的方法,其中所述方法包括以下步骤: (a)制备含有所述降解产物的罗苏伐他汀溶液; (b)使所述溶液经过高压液相色谱以得到色谱图;和(c)将所述色谱图中得到的峰与所述降解产物产生的峰进行比较。 28. The method of claim 27, wherein the method comprises the steps of: (a) preparing the degradation product comprising rosuvastatin solution; (b) so that the solution was subjected to high pressure liquid chromatography to obtain a chromatogram; and (c) the peaks in the chromatogram obtained with the peak of degradation products compared.
29.权利要求27的方法,其中所述方法包括以下步骤: (a)制备含有所述降解产物的罗苏伐他汀溶液; (b)使所述溶液经过薄层色谱以得到色谱图;和(c)将所述色谱图中得到的带或斑点与所述降解产物产生的峰或带进行比较。 29. The method of claim 27, wherein the method comprises the steps of: (a) preparing the degradation product comprising rosuvastatin solution; (b) so that the solution was subjected to thin layer chromatography to obtain a chromatogram; and ( c) will peak in the chromatogram obtained with the band or spots or degradation products produced with the comparison.
30. ー种制备权利要求1、2、3、4、9或10的降解产物的方法,包括用可见光照射罗苏伐他汀酸、罗苏伐他汀碱金属盐或碱土金属盐或罗苏伐他汀内酯的步骤。 30. A process for the preparation ー kinds of degradation products of the method 1,2,3,4,9 or 10, including irradiated with visible light rosuvastatin acid, rosuvastatin alkali or alkaline earth metal salt or rosuvastatin Step lactone.
31. 一种用于制备下列化合物的方法: 31. A method for the preparation of the following compounds:
Figure CN1894221BC00071
其中M是钙,包括用可见光照射在有机溶剂和水的混合物溶液中的罗苏伐他汀钙。 Where M is calcium, including irradiated with visible light in a solution of organic solvent and water mixture in the rosuvastatin calcium.
32.权利要求31的方法,其中所述有机溶剂是こ腈。 32. The method of claim 31, wherein said organic solvent is a nitrile ko.
33.权利要求31的方法,其中所述可见光照射在35C为750w。 33. The method of claim 31, wherein said visible light at 35 C to 750w.
34. 一种用于制备下列化合物的内酯形式的方法: 34. A method for preparing lactone form of the compound for the following:
Figure CN1894221BC00072
其中C1和C5形成内酷,或 C1 and C5 which formed in the cool, or
Figure CN1894221BC00081
其中C1和C5形成内酯; 包括用可见光照射溶剂中的罗苏伐他汀内酷。 Where C1 and C5 form a lactone; includes visible light solvent rosuvastatin inside cool.
35.权利要求34的方法,其中所述可见光照射在20C至100C。 35. The method of claim 34, wherein said visible light at 20 C to 100 C.
36.权利要求34的方法,其中所述溶剂是こ腈。 36. The method of claim 34, wherein said solvent is a nitrile ko.
37. 一种用于測定罗苏伐他汀在色谱柱中的保留时间的方法,包括用以下化合物作为參照标准品进行色谱法的步骤: 37. A method for determining rosuvastatin retention time in the column, comprising the steps of these compounds as a reference standard chromatographic method:
Figure CN1894221BC00082
其中R1和R2独立地是氢或可水解的保护基团;R3是氢、C1-C4烷基、或者碱金属或碱土金属;或其中C1和C5形成内酷。 Wherein R1 and R2 are independently hydrogen or a hydrolyzable protecting group; R3 is hydrogen, C1-C4 alkyl, or an alkali metal or alkaline earth metal; or where C1 and C5 formed in the cool.
38.权利要求37的方法,其中所述參照标准品是參照标记物。 38. The method of claim 37, wherein the reference standard is a reference marker.
39.权利要求37的方法,其中所述參照标准品是权利要求1、2、3、4、9或10的降解产物。 39. The method of claim 37, wherein the reference standard is the degradation product of claim 1,2,3,4,9 or 10.
Description  translated from Chinese

用于表征罗苏伐他汀的参照标准品 Rosuvastatin used to characterize the reference standard

[0001] 交叉引用的相关串请 [0001] Cross-Reference to Related string please

[0002] 本申请要求享有2003年12月2日申请的美国临时申请No. 60/526, 449的权益,在此引入该申请公开的全部内容作为参考。 [0002] This application claims the benefit of December 2, 2003 filed U.S. Provisional Application No. 60/526, 449, the entire contents of which are hereby incorporated by reference disclosed.

发明领域 Field of the Invention

[0003] 本发明涉及罗苏伐他汀(rosuvastatin)降解产物和它们作为分析罗苏伐他汀的参照标准品的用途。 [0003] The present invention relates to rosuvastatin (rosuvastatin) degradation products and their use as analytical uses of rosuvastatin reference standard.

[0004] 发明背景 [0004] Background of the Invention

[0005] 抑制素(statins)是目前用于减少有心血管疾病危险的患者血流中低密度脂蛋白(LDL)颗粒浓度最有效的治疗药物。 [0005] inhibin (statins) are currently used to reduce the risk of cardiovascular disease in patients with blood low-density lipoprotein (LDL) particle concentration of the most effective treatments. 因此,抑制素被用于高胆固醇血症、高脂蛋白血症和动脉粥样硬化的治疗。 Thus, inhibin be used hypercholesterolemia, hyperlipoproteinemia and atherosclerosis treatment. 血流中高水平的LDL与冠状损害的形成有关,冠状损害阻碍血液的流动并且可破裂和促进血栓形成。 The formation of LDL and coronary blood flow in a high level of damage related coronary damage impairing blood flow and can rupture and promote thrombosis. Goodman和Gilman, The PharmacologicalBasis ofTherapeutics, 879 页(第9 版,1996 年)。 Goodman and Gilman, The PharmacologicalBasis ofTherapeutics, 879 pages (9th edition, 1996).

[0006] 抑制素通过竞争地抑制3-羟基-3-甲基-戊二酰基-辅酶A (“HMG-CoA”)还原酶来抑制人类胆固醇生物合成。 [0006] 3-hydroxy-3-methyl-inhibin inhibited by competition - glutaryl - coenzyme A ("HMG-CoA") reductase to inhibit human cholesterol biosynthesis. HMG-CoA还原酶催化HMG到甲羟戊酸的转化,这一转化是胆固醇生物合成中的决速步骤。 HMG-CoA reductase catalytic conversion of HMG to mevalonate, the conversion of cholesterol biosynthesis rate-determining step. 减少胆固醇的产生会引起LDL受体数目的增加并相应地减少血流中LDL颗粒的浓度。 Reducing the production of cholesterol causes an increase in the number of LDL receptors and corresponding reduction in the concentration of LDL particles in the bloodstream. 血流中LDL水平的降低会减少冠状动脉疾病的危险。 Reduce LDL levels in the bloodstream can reduce the risk of coronary artery disease. JA Μ. A. 1984,251,351-74。 JA Μ. A. 1984,251,351-74.

[0007]目前可用的抑制素包括洛伐他汀、辛伐他汀、帕伐他汀、氟伐他汀、西立伐他汀和阿伐他汀。 [0007] Currently available statins include lovastatin, simvastatin, pravastatin, fluvastatin, cerivastatin and atorvastatin statins. 洛伐他汀(公开于美国专利No. 4,231,938)和辛伐他汀(公开于美国专利No. 4,444,784)是以内酯形式给药的。 Lovastatin (disclosed in U.S. Patent No. 4,231,938) and simvastatin (disclosed in U.S. Patent No. 4,444,784) is administered in the form of lactone. 吸收后,通过化学或酶水解将内酯环在肝脏中打开,从而产生活性的羟基酸。 After absorption, through chemical or enzymatic hydrolysis in the liver lactone ring opens to generate active hydroxy acid. 帕伐他汀(公开于美国专利No. 4,346,227)是以钠盐的形式给药的。 Pravastatin (disclosed in U.S. Patent No. 4,346,227) is administered in the form of sodium salt. 氟伐他汀(公开于美国专利No. 4,739,073)和西立伐他汀(公开于美国专利No. 5,006, 530和5,177,080),也是以钠盐的形式给药的,是在结构上部分不同于包含六氢萘环这种类型的真菌衍生物的全合成化合物。 Fluvastatin (disclosed in U.S. Patent No. 4,739,073) and West cerivastatin (disclosed 5,006, 530 and 5,177,080 in U.S. Patent No.), also administered as the sodium salt form , is structurally different from the part containing the total synthesis of hexahydro naphthalene ring compound fungal derivatives of this type. 阿伐他汀和两个新的“高效抑制素(superstatins) ” (罗苏伐他汀和匹伐他汀)是以I丐盐的形式给药的。 Atorvastatin and two new "high inhibin (superstatins)" (rosuvastatin and pitavastatin) in the form of a salt I beggar administration.

[0008] 罗苏伐他汀钙(双(+)7-[4-(4-氟苯基)-6_异丙基-2-(N-甲基-N-甲磺酰基氨基嘧啶)-5-基]-(3R,5S) - 二羟基-(E) -6-庚烯酸单钙盐)是HMG-CoA还原酶抑制剂,由盐野义(Shionogi)开发为每日一次口服治疗高脂血症(Ann Rep, Shionogi, 1996 ;Directcommunications, Shionogi, 8Feb 1999 & 25Feb 2000)。 [0008] rosuvastatin calcium (bis (+) 7- [4- (4-fluorophenyl) -6_ isopropyl -2- (N- methyl-pyrimidin -N- methyl sulfonylamino) -5 - yl] - (3R, 5S) - dihydroxy - (E) -6- heptenoic acid calcium salt alone) is a HMG-CoA reductase inhibitors, high Shionogi (Shionogi) was developed by a once-daily oral therapy hyperlipidemia (Ann Rep, Shionogi, 1996; Directcommunications, Shionogi, 8Feb 1999 & 25Feb 2000). 罗苏伐他汀|丐是高效抑制素,其可 Rosuvastatin | beggar efficient inhibin, which may

以比第一代药物更有效地降低LDL-胆固醇和甘油三酯。 Than the first generation of drugs more effective in reducing LDL- cholesterol and triglycerides. 罗苏伐他汀钙具有以下化学式: Rosuvastatin calcium has the following chemical formula:

[0009] [0009]

Figure CN1894221BD00101

[0010] 罗苏伐他汀钙以CRESTOR名称销售用于哺乳动物(例如人)的治疗。 [0010] Rosuvastatin calcium is marketed under the name CRESTOR for a mammal (such as man) treatment. 按照CREST0R的制造者,它是以大约5mg至大约40mg的日剂量给药的。 According CREST0R maker, which is based on a daily dose of about 5mg to about 40mg of administration. 对于需要较小攻击性的LDL-C减少或具有肌病的素因性因素(pre-disposing factors)的患者,建议5毫克剂量,而10毫克剂量推荐给中度的患者,20毫克剂量用于显著的高胆固醇血症和攻击性的脂类指标(>190毫克/dL)的患者,而40毫克剂量用于对较低剂量无反应的患者。 For applications requiring less aggressive LDL-C reduction or vegetarian because of factors have myopathy (pre-disposing factors) patients recommended dose of 5 mg and 10 mg dose recommended for patients with moderate and 20 mg dosages for significant patients with hypercholesterolemia and aggressive lipid index (> 190 mg / dL), and 40 mg doses for unresponsive patients lower doses.

[0011] 美国专利No. 5,260,440公开和要求专利保护罗苏伐他汀,它的钙盐(2 : 1),和它的内酯形式。 [0011] US Patent No. 5,260,440 discloses and claims of patent protection rosuvastatin, its calcium salt (2: 1), and its lactone form. 美国专利No. 5,260,440的方法是通过4-(4-氟苯基)-6-异丙基-2-(N-甲基-N-甲磺酰基氨基)-5-嘧啶甲醛与(3R)-3-(叔丁基二甲基甲硅烷氧基)-5-氧-6-三苯基亚膦基(phosphoranylidene)己酸甲酯在乙腈中回流反应来制备罗苏伐他汀。 U.S. Patent No. 5,260,440 a method is by reaction of 4- (4-fluorophenyl) -6-isopropyl -2- (N- methyl -N- methylsulfonyl) -5- pyrimidine carbaldehyde and prepared rosuvastatin (3R) -3- (tert-butyldimethylsilyloxy) -5-oxo-6-yl triphenyl phosphine (phosphoranylidene) hexanoate reflux in acetonitrile. 然后用氟化氢断裂甲硅烷基,接着用NaBH4和二乙基甲氧基硼烷在THF中还原以得到罗苏伐他汀的甲酯。 Then break with hydrogen fluoride silyl, followed by NaBH4 and diethyl-methoxy-borane to give the methyl ester of rosuvastatin in THF.

[0012] 然后在室温下将所述的酯用氢氧化钠在乙醇中水解,接着除去乙醇并加入醚,以得到罗苏伐他汀的钠盐。 [0012] and then at room temperature for the ester hydrolysis with sodium hydroxide in ethanol, followed by removal of ethanol and ether was added, to obtain a sodium salt of rosuvastatin. 然后将钠盐转变为钙盐。 Then into a calcium salt. 将所述钠盐溶于水并保持在氮气气氛中。 The sodium salt was dissolved in water and maintained under a nitrogen atmosphere. 然后将氯化钙加入该溶液,产生罗苏伐他汀钙(2 : I)的沉淀。 Calcium chloride is then added to the solution, resulting in rosuvastatin calcium (2: I) of precipitation. 中间体的制备方法公开于'440专利,在此将其引入作为参考。 Preparation of intermediates disclosed in the '440 patent, which is incorporated herein by reference.

[0013] 美国专利No. 6,316,460公开了罗苏伐他汀的药物组合物。 [0013] US Patent No. 6,316,460 discloses a rosuvastatin pharmaceutical compositions. 所述药物组合物包含罗苏伐他汀或其盐以及多价的三元磷酸盐。 The pharmaceutical composition comprising rosuvastatin or a salt thereof and a polyvalent ternary phosphate.

[0014] 所述的反应产物混合物很少是纯度足以符合制药标准的单一化合物。 The reaction product mixture [0014], wherein a single compound is rarely pure enough to comply with pharmaceutical standards. 在大多数情况下,会存在所述反应的次要产物和副产物以及用于反应的附加试剂。 In most cases, there will be minor product and by-product of the reaction and additional reagents for reactions. 在把包含在产物混合物中的罗苏伐他汀变成活性药物成分(“API”)的加工期间的某些阶段,必须分析罗苏伐他汀的纯度,通常通过HPLC或GC分析,以确定是否适于连续加工或最终用于药品。 At some stage to be included in the product mixture of rosuvastatin become active pharmaceutical ingredient ("API") during processing, it must be analyzed rosuvastatin purity, typically by HPLC or GC analysis to determine the suitability of in continuous processing or ultimately used drugs. 罗苏伐他汀不需要是绝对纯的。 Rosuvastatin need not be absolutely pure. 绝对纯度是难以达到的理论上的理想。 Absolute purity is unattainable ideal theoretical. 相反地,纯度标准意在确保API不会由于杂质的存在而降低临床使用的安全性。 Rather, purity standards intended to ensure that API is not due to the presence of impurities and reduce the security of clinical use. 在美国,食品和药物管理局指南建议申请人将一些杂质限制在低于0. 1%。 In the United States, the Food and Drug Administration guidelines recommend that applicants limit some impurities less than 0.1%.

[0015] 通常,利用光谱方法和通过其它物理方法识别次要产物、副产物和附加试剂(总称为“杂质”),于是杂质与色谱中的峰位置(或薄层色谱板上的斑点)有关。 [0015] Generally, the use of spectroscopic methods and identification of secondary products, byproducts and additional agents (collectively referred to as "impurities") by other physical methods, so the impurities in the chromatogram peak position (or spot TLC plate) About . (StrobelP.953) (Strobel, HA ;Heineman, ff. R. , Chemical Instrumentation :A SystematicApproach, 3rd dd. (Wiley & Sons :New York 1989))。 (StrobelP.953) (Strobel, HA; Heineman, ff R., Chemical Instrumentation:. A SystematicApproach, 3rd dd (Wiley & Sons: New York 1989).). 此后,杂质可以通过其在所述色谱中的位置被识别出来,色谱中的位置通常用样品注射到柱上和特定的组分经检测器流出之间的时间以分钟计算,被称为“保留时间”。 Thereafter, the impurity can be identified by its position in the chromatogram, the chromatogram of the sample position is usually injected into the time column and specific components between the detected outflow in minutes, known as the "reservations time. " 这一时间段基于使用仪器的条件和许多其它因素每天变化。 This time period is based on the use of the instrument conditions and many other factors can vary daily. 为减轻这样变化对杂质准确鉴别的影响,专业人员使用“相对保留时间”(“RRT”)来鉴别杂质。 To mitigate the impact of such changes on the accurate identification of impurities and professional use "relative retention time" ("RRT") to identify impurities. (Strobel p. 922)。 (Strobel p. 922). 杂质的RRT是其保留时间除以一些参考标记物的保留时间。 RRT of an impurity is its retention time divided by the retention time of some reference marker. 理论上,罗苏伐他汀本身能被用作参照标记物,但实际上罗苏伐他汀在混合物中占有压倒性比例,使其趋向于饱和柱子,导致不能再现保留时间,即相对于罗苏伐他汀的峰的最大值趋向漂移(Strobel Fig. 24.8 (b)p. 879,该页包含当色谱柱过载时所观察到的不对称峰的分类说明。)。 In theory, rosuvastatin itself could be used as a reference marker, but actually rosuvastatin an overwhelming proportion in the mixture, it tends to saturation column, resulting in the retention time can not be reproduced, namely with respect to rosuvastatin maximum peak of statins tend to drift (Strobel Fig. 24.8 (b) p. 879, the page contains columns overload when observed asymmetric peaks Category Description.). 因此,往往希望选择一种替代化合物,将其以足以可检测但不会饱和柱子的足够低的量加入或存在于所述混合物中,并且将该化合物作为参照标记物使用。 Thus, often desirable to select an alternative compound which may be sufficient to detect but not sufficiently low amount of saturated column is added or present in the mixture, and the compound was used as a reference marker.

[0016] 药物生产的研究人员和开发者知道,相对纯状态的化合物能被用作“参照标准品(“参照标记物”类似于参照标准品,但它用来做定性分析)以确定化合物在未知混合物中的数量。当所述化合物用作“外标物”时,以与未知混合物相同的技术来分析所述化合物的已知浓度的溶液。(Strobel p. 924, Snyder p. 549) (Snyder, LR ;Kirkland,JJ Introduction to Modern Liquid Chromatography,2nd ed. (Johnffiley & Sons :NewYork 1979))。所述化合物在混合物中的数量可以通过比较检测器响应值的大小来确定。参见US. 6,333,198,在此引入作为参考。 [0016] Drug production of researchers and developers know relatively pure state of compounds can be used as a "reference standard (" reference marker "is similar to a reference standard, but it used to do qualitative analysis) to determine the compound mixture of unknown quantities. When the compound is used as an "external standard", with the same mixture of unknown technology to analyze solutions of known concentration of the compound. (Strobel p. 924, Snyder p. 549) ( Snyder, LR; Kirkland, JJ Introduction to Modern Liquid Chromatography, 2nd ed (Johnffiley & Sons: NewYork 1979)) the number of compounds in the mixture can be determined by comparing the size of the detector response value, see US 6.... , 333,198, which is incorporated herein by reference.

[0017] 如果已经预先确定出弥补检测器对两种化合物灵敏度差别的“响应因子”,那么所述参照标准品化合物也可以用于确定混合物中另一化合物的数量。 [0017] If you have a pre-determined to make up for detector sensitivity difference between the two compounds "response factor", then the standard reference compound mixture can also be used to determine the number of another compound. (Strobel p. 894)。 (Strobel p. 894). 为此目的,可以将所述参照标准品化合物直接加入到混合物,而在这样情况下它被称作“内标物” (Strobelp. 925, Snyder p. 552)。 For this purpose, the reference standard compound added directly to the mixture, and in this case it is called "internal standard" (Strobelp. 925, Snyder p. 552).

[0018] 通过使用称作“标准品添加”技术,其中至少两种样品是通过加入已知的和不同量的内标物制备的,使未知混合物包含一些参照标准品化合物时,所述参照标准品化合物甚至可以用作内标物。 When [0018] using known as "standard addition" technique, wherein the at least two samples by adding known and varying amounts of the internal standard was prepared so that the unknown mixture contains some of the reference standard compounds, the reference standard product compounds can even be used as an internal standard. (Strobelpp. 391-393,Snyder pp. 571,572) 0最初在混合物中的参照标准品化合物对应的检测器响应值的比例,可以通过将检测器响应值对加入到各个样品中的参照标准品化合物的量所作的图外推至零来确定。 (Strobelpp. 391-393, Snyder pp. 571,572) 0 initially in the reference standard mixture of compounds corresponding proportion of detector response value, the detector response for each sample was added to the reference standard compound may be adopted FIG amount taken extrapolated to zero to determine. (例如,Strobel, Fig. 11. 4p. 392)。 (For example, Strobel, Fig. 11. 4p. 392).

[0019] 本发明提供罗苏伐他汀降解产物,其可用作分析罗苏伐他汀的参照标准品。 [0019] The present invention provides a rosuvastatin degradation product, which is used as the analysis of rosuvastatin reference standards.

[0020] 发明简述 [0020] SUMMARY

[0021] 一方面,本发明提供一种具有以下结构的罗苏伐他汀降解产物: [0021] In one aspect, the present invention provides a method having the following structure rosuvastatin degradation product:

[0022] [0022]

Figure CN1894221BD00111

[0023] 另一方面,本发明提供一种具有以下结构的罗苏伐他汀降解产物:[0024] [0023] another aspect, the present invention provides a structure having the rosuvastatin degradation product: [0024]

Figure CN1894221BD00121

[0025] 另一方面,本发明提供一种具有以下结构的罗苏伐他汀降解产物: [0025] another aspect, the present invention provides a structure having the rosuvastatin degradation product:

[0026] [0026]

Figure CN1894221BD00122

[0027] 其中M是碱金属或碱土金属。 [0027] wherein M is an alkali metal or alkaline earth metal.

[0028] 另一方面,本发明提供一种具有以下结构的罗苏伐他汀降解产物: [0028] another aspect, the present invention provides a structure having the rosuvastatin degradation product:

[0029] [0029]

Figure CN1894221BD00123

[0030] 其中M是碱金属或碱土金属。 [0030] wherein M is an alkali metal or alkaline earth metal. 优选地M是钙。 Preferably M is calcium. 所述钙盐可以转变为内酯形式,通过混合乙腈、盐酸和所述钙盐以得到所述内酯;或者转变为游离酸,包括将所述钙盐溶于乙腈和水的混合物,并将钙盐与二氧化硅柱接触。 The calcium salt may be converted to lactone form by combining acetonitrile, hydrochloric acid and the calcium salt to obtain the lactone; or converted to the free acid, the calcium salt comprising dissolved in acetonitrile and water mixture, and contacts calcium and silica column.

[0031] 另一方面,本发明提供一种具有以下结构的罗苏伐他汀降解产物的内酯形式: [0031] On the other hand, the present invention provides a method having the following structure rosuvastatin degradation product lactone form:

[0032] [0032]

Figure CN1894221BD00131

[0033] 另一方面,本发明提供一种具有以下结构的罗苏伐他汀降解产物的内酯形式: [0033] On the other hand, the present invention provides a method having the following structure rosuvastatin degradation product lactone form:

[0034] [0034]

Figure CN1894221BD00132

[0035] 另一方面,本发明提供一种将所述内酯转化为钙盐的方法,该方法包括在碱性水溶液条件下水解所述内酯,并且将水解的内酯与钙源反应。 [0035] another aspect, the present invention provides a method of lactone is converted to calcium salt, which process comprises hydrolysis under alkaline conditions the lactone solution and the hydrolysis reaction of the lactone with the calcium source.

[0036] 另一方面,本发明提供一种将所述内酯转化为游离酸形式的方法,该方法包括在碱性水溶液条件下水解所述内酯以得到金属盐并且将所述金属盐与二氧化硅柱接触。 [0036] another aspect, the present invention provides a lactone converted to the free acid form, the method comprising hydrolyzing the lactone under aqueous basic conditions to obtain a metal salt and the metal salt contacting silica column.

[0037] 优选地,降解产物以重量计大约95%不含其相应的6位立体异构体。 [0037] Preferably, the degradation products to about 95% by weight of 6 free of its corresponding stereoisomers. 可以将所述罗苏伐他汀降解产物分离或纯化。 The rosuvastatin degradation product can be isolated or purified.

[0038] 另一方面,本发明提供一种分析罗苏伐他汀样品的方法,包括以下步骤: [0038] another aspect, the present invention provides a rosuvastatin method for analyzing a sample, comprising the steps of:

[0039] a)对样品进行色谱法以得到数据;和 [0039] a) The sample was subjected to chromatography to obtain data; and

[0040] b)将数据与降解产物的色谱数据比较。 [0040] b) comparing chromatographic data and degradation products.

[0041] 另一方面,本发明提供一种制备所述降解产物的方法,该方法包括用可见光照射罗苏伐他汀酸、罗苏伐他汀碱或碱土金属盐或罗苏伐他汀内酯的步骤。 [0041] On the other hand, the present invention provides a method of preparing the degradation product, the method comprising the steps of irradiation with visible light rosuvastatin acid, rosuvastatin alkali or alkaline earth metal salt or rosuvastatin lactone .

[0042] 另一方面,本发明提供一种测定罗苏伐他汀在色谱柱中的保留时间的方法,该方法包括用以下化合物作为标准品进行色谱法的步骤: [0042] On the other hand, the present invention provides a method of rosuvastatin in the column retention time measurement, the method comprising the steps of these compounds as standard chromatographic method:

[0043] [0043]

Figure CN1894221BD00141

[0044] 其中R1和R2独立地是氢或可水解的保护基团;R3是氢、C1-C4烷基、或者碱金属或碱土金属;或其中C1和C5形成内酯。 [0044] wherein R1 and R2 are independently hydrogen or a hydrolyzable protecting group; R3 is hydrogen, C1-C4 alkyl, or an alkali metal or alkaline earth metal; or wherein the C1 and C5 form a lactone.

[0045] 附图简述 [0045] Brief Description

[0046] 图I是化合物VI的HPLC色谱图。 [0046] Figure I is a HPLC chromatogram of Compound VI.

[0047] 图2是化合物VII的HPLC色谱图。 [0047] FIG 2 is a HPLC chromatogram of Compound VII.

[0048] 图3是罗苏伐他汀、化合物VI和化合物VII的混合物的HPLC色谱图。 [0048] FIG. 3 is rosuvastatin, compounds VI and VII of the mixture of compounds HPLC chromatograms.

[0049] 发明详述 [0049] DETAILED DESCRIPTION

[0050] 在此使用的术语“参照标准品”是指可用于活性药物成分的定量和定性分析的化合物。 [0050] As used herein, the term "reference standard" refers to a compound that can be used both quantitative and qualitative analysis of active pharmaceutical ingredients. 例如,将所述化合物在HPLC中的保留时间设置为相对保留时间,从而使定性分析成为可能。 For example, the compound retention time in HPLC relative retention time is set, so that qualitative analysis possible. 将注入HPLC柱前所述化合物在溶液中的浓度用于比较HPLC色谱图中峰下的面积,从而使定量分析成为可能。 HPLC column prior to injection of the compound in the solution concentration for HPLC chromatogram comparing the area under the peak, making quantitative analysis possible.

[0051] “参照标记物”用于定性分析是根据它们在例如色谱图中或薄层层析(TLC)板上的位置来鉴定混合物中的组分(Strobel pp. 921,922,953) 0为此目的,如果所述化合物存在于混合物中,则不必将该化合物加入混合物。 [0051] "reference marker" is used for qualitative analysis, for example according to their position in the chromatogram, or thin layer chromatography (TLC) plates to identify the components of a mixture (Strobel pp. 921,922,953) 0 for that purpose, If the compound is present in the mixture, the mixture was added the compound is not necessary. “参照标记物”只用于定性分析,但参照标准品可用于定量或定性分析,或两者。 "Reference marker" is used only for qualitative analysis, but the reference standard may be used for quantitative or qualitative analysis, or both. 因此,参照标记物是参照标准品的子集,并且包括在参照标准品的定义内。 Accordingly, reference marker is a subset of a reference standard, and included within the definition of the reference standard.

[0052] 虽然到目前为止已经概括地描述了本领域关于参照标准品的一些知识,但是本领域的技术人员同样理解所述检测器响应值可以是,例如从HPLC体系的洗脱剂,通过UV或折射指数检测,或者,例如从气相色谱仪的洗脱剂,通过火焰电离检测或热导检测,得到的色谱图的峰高或积分峰面积,或其它检测器响应值,例如荧光薄层色谱板上斑点的UV吸收率。 [0052] Although so far has been generally described in the art some knowledge about the reference standard, but is also skilled in the art to understand the response of the detector may be, for example, from the eluent HPLC system, by UV or refractive index detector, or, for example, from a gas chromatograph eluent through a flame ionization detector or a thermal conductivity detector, resulting chromatogram peak height or peak area integration, or other detector response, such as a fluorescent TLC UV absorbance board spots. 参照标准品的位置可用于计算罗苏伐他汀和其它杂质的相对保留时间。 Reference standard positions used to calculate the relative retention times rosuvastatin and other impurities.

[0053] 当罗苏伐他汀钙在可见光下照射时,得到罗苏伐他汀的降解产物,该降解产物能用作参照标准品。 [0053] When rosuvastatin calcium under visible light irradiation to obtain rosuvastatin degradation product of the degradation products can be used as a reference standard. 两种降解产物是如下在6位的附加不对称中心产生的非对映环状产物 Two degradation products are diastereomeric cyclic products are in six additional asymmetric center created

(II)和(III): (II) and (III):

[0054] [0054]

Figure CN1894221BD00151

[0055] 除罗苏伐他汀钙之外,可以照射罗苏伐他汀的其它形式,包括其内酯、游离酸和盐类,例如钠盐。 [0055] In addition to rosuvastatin calcium, other forms may be irradiated rosuvastatin, including its lactone, free acid and salts such as sodium salt.

[0056] 照射可在溶液中或固态中进行。 [0056] The irradiation can be carried out in solution or in the solid state. 在照射溶液时,照射优选在大约室温至大约回流温度下进行。 When the solution is irradiated, the irradiation is preferably at about room temperature to about reflux temperature. 用于溶解的有机溶剂可以是极性质子性溶剂(C1-CJ?,如甲醇或乙醇)或者非质子溶剂(乙腈、四氢呋喃)和水的混合物。 The organic solvent may be used to dissolve a polar protic solvent (C1-CJ ?, such as methanol or ethanol) or a mixture of an aprotic solvent (acetonitrile, tetrahydrofuran) water. 大约750W的可见光照射大约35C的罗苏伐他汀钙乙腈水溶液大约7小时,得到I : I比例的化合物(II和III)的混合物。 Rosuvastatin calcium aqueous acetonitrile visible light irradiation of about 750W to about 35 C in about 7 hours to give I: I mixture ratio of the compound (II and III) of. 在照射固态时,温度优选从大约20EC至100EC。 When irradiated solid, the temperature is preferably from about 20EC to 100EC. 本领域的技术人员还可以在这些谱或各种谱的混合中选择窄谱。 Those skilled in the art can also choose a narrow spectrum in mixing the spectrum or various spectrum of. 基于结构的指导在此提供各种降解产物,本领域的技术人员可以制定合成路线以得到所述降解产物。 Based on the guidance provided herein various structures degradation products, one skilled in the art may develop synthetic route to obtain the degradation products.

[0057] 在另一实施方案中,得到相应的内酯,通过照射罗苏伐他汀的内酯形式或通过从化合物II和III制备所述内酯以得到能被用作参照标准品的相应的化合物IV和V。 [0057] In another embodiment, the corresponding lactone, by irradiating the lactone form of rosuvastatin or by preparing from the compounds II and III can be used as the lactone to give the corresponding reference standard Compound IV and V. 化合物IV 具有以下1H NMR(300MHz, CDCl3) δ (ppm) :1. 24,I. 34,I. 68,2. 47,2. 53,2. 64,3. 15,3. 35,3. 46,3. 56,3. 60,4. 28,4. 45,6. 99,7. 14,8. 31 ;13C NMR(75MHz, CDCl3) δ (ppm):20. 87,21. 26,23. 29,31. 41,33. 26,34. 03,38. 23,42. 07,43. 00,62. 23,74. 53,115. 61, Compound IV has the following 1H NMR (300MHz, CDCl3) δ (ppm):. 1 24, I 34, I 68,2 47,2 53,2 64,3 15,3 35,3........ ....... 46,3 56,3 60,4 28,4 45,6 99,7 14,8 31; 13C NMR (75MHz, CDCl3) δ (ppm):.. 20 87,21 26, 23. 29,31. 41,33. 26,34. 03,38. 23,42. 07,43. 00,62. 23,74. 53,115. 61,

116. 08(J = 26Hz),116. 25(J = 22Hz),129. 08,128. 91(J = 9Hz),139. 28(J = 8Hz),157. 64,157. 86,163. 96 (J = 253Hz),169. 47,174. 48 ;FAB+m/z (MH+) :464。 116. 08 (J = 26Hz), 116. 25 (J = 22Hz), 129. 08,128. 91 (J = 9Hz), 139. 28 (J = 8Hz), 157. 64,157. 86,163. 96 ( J = 253Hz), 169 47,174 48; FAB + m / z (MH +):.. 464. 化合物V 具有以下1H NMR(300MHz, CDCl3) δ (ppm) :1. 24,I. 29,I. 52,I. 70,2. 58,3. 02,3. 21,3. 27,3. 41,3. 55,3. 60,4. 26,4. 78,7. 05,7. 12,8. 34 ;FAB+m/z (MH+) :464。 Compound V has the following 1H NMR (300MHz, CDCl3) δ (ppm):. 1 24, I 29, I 52, I 70,2 58,3 02,3 21,3 27,3........ ....... 41,3 55,3 60,4 26,4 78,7 05,7 12,8 34; FAB + m / z (MH +): 464.

[0058] 从化合物II和III制备相应的内酯化合物IV和V,包括将化合物II和III溶于合适的溶剂,并且例如用盐酸水溶液形成内酯环。 [0058] The preparation of the corresponding lactone compounds IV and V from compound II and III, including the compounds II and III is dissolved in a suitable solvent, e.g., with aqueous hydrochloric acid and a lactone ring is formed. 其它酸类也可以用来形成内酯。 Other acids may also be used to form a lactone. 从化合物II或III制备所述内酯的合适溶剂是二氯甲烷、氯仿、乙腈或四氢呋喃。 From compound II or III suitable for preparing the lactone solvent is methylene chloride, chloroform, acetonitrile or tetrahydrofuran. 优选地,合适的溶剂是乙腈。 Preferably, the suitable solvent is acetonitrile. 为回收产物,可以通过任何常规方法(例如,蒸发)除去所述溶剂。 The product is recovered, the solvent may be removed by any conventional method (e.g., evaporation). 得到的化合物IV和V可以通过例如柱色谱和结晶的方法分离。 The resulting compound IV and V can be separated by column chromatography and crystallization, for example of the method.

[0059] 从罗苏伐他汀内酯制备相应的内酯化合物IV和V还可以在相同的溶剂中通过可见光照射进行。 [0059] preparation of the corresponding lactone compounds IV and V from rosuvastatin lactone may also be illuminated by visible light in the same solvent. 所述照射特征如上所述。 The irradiation characteristics described above. 所述内酯化合物IV和V在溶剂存在下可以用当量的碱性水溶液(例如氢氧化钠或氢氧化钙)水解以获得相应的盐。 The lactone compounds IV and V in the presence of a solvent with an alkaline aqueous solution can equivalents (e.g., sodium hydroxide or calcium hydroxide) is hydrolyzed to obtain the corresponding salt. 优选地,所述溶剂是乙腈。 Preferably, the solvent is acetonitrile. 在一个实施方案中,所述内酯用氢氧化钠水溶液在乙腈中水解,接着除去乙腈并加入钙源,例如氯化钙。 In one embodiment, the lactone hydrolysis with aqueous sodium hydroxide in acetonitrile, followed by removal of acetonitrile and addition of calcium sources, such as calcium chloride.

[0060] 所述内酯形式IV和V可以用碱水解以得到盐类,之后分别转化为能用作参照标准品的酸形式的VI和VII。 [0060] The lactone form IV and V can be used alkaline hydrolysis to obtain salt, then are converted to be used as a reference standard acid form of VI and VII. 所述内酯到盐的转化可以通过使用碱性水溶液进行。 The conversion of the lactone to a salt by using an alkaline aqueous solution. 在一个实施方案中,所述内酯溶于乙腈和NaOH水溶液的混合物。 In one embodiment, the lactone is dissolved in a mixture of acetonitrile and aqueous NaOH. 然后除去乙腈并加入例如氯化钙的钙源以沉淀所述钙盐。 Then remove the acetonitrile and added calcium source such as calcium chloride to precipitate the calcium salt.

[0061] 通过硅胶柱色谱纯化所述的盐产物后得到酸形式(如实施例I中所述)。 [0061] through the salt product was purified according to silica gel column chromatography to give the acid form (as described in Example I embodiment). 相信二氧化硅柱的酸性对所述转化起作用。 I believe acidic silica column of the conversion work. 化合物VI具有以下1H NMR ^OOMHz,⑶Cl3+ra30D 5 : I)δ (ppm) :1. 25,1. 33, I. 39,1. 58,2. 22,2. 80,2. 89,3. 36,3. 52,3. 58,3. 61,3. 95,7. 01,7 09,8 26 ;13C NMR(150MHz,CDC13+CD30D 5 : I) δ (ppm) :21. 14,21. 31,23. 32,31. 56,33. 47,40. 15,42. 16,42. 97,44. 62,68. 99,71. 45,115. 17(J = 21Hz),116. 32 (J = 22Hz), Compound VI has the following 1H NMR ^ OOMHz, ⑶Cl3 + ra30D 5: I) δ (ppm):.. 1 25,1 33, I. 39,1 58,2 22,2 80,2 89,3.... ...... 36,3 52,3 58,3 61,3 95,7 01,7 09,8 26; 13C NMR (150MHz, CDC13 + CD30D 5: I) δ (ppm): 21. 14,21. 31,23. 32,31. 56,33. 47,40. 15,42. 16,42. 97,44. 62,68. 99,71. 45,115. 17 (J = 21Hz), 116 . 32 (J = 22Hz),

117. 77,128. 87 (J = 9Hz),129. 20,142. 34 (J = 8Hz),157. 71,158. 57,164.26 (J = 251Hz),174. 30 ;Cl+m/z (MH+) :482。 . 117. 77,128 87 (J = 9Hz), 129 20,142 34 (J = 8Hz), 157 71,158 57,164.26 (J = 251Hz), 174 30;..... Cl + m / z (MH +): 482. 化合物VII 具有以下1H NMR(600MHz,CDC13+CD30D 5 : I)δ (ppm) :1. 24,I. 31, I. 43,2. 25,2. 95,3. 05,3. 19,3. 30,3. 56,3. 60,3. 85,4. 03,7. 02,7. 08,7. 31 ;13C NMR(150MHz,CDC13+CD30D 5 : I) δ (ppm) :21. 15,21. 23,22. 98,31. 22,33. 36,38. 83,42. 08,43. 45,68. 82,73. 86,114. 95 (J = 21Hz),116. 31 (J = 21Hz),117. 41, 128. 56(J = 8Hz),128. 91,142. 02(J = 8Hz),157. 58,158. 45,164. 28 (J = 252Hz),173. 19,178 ;Cl+m/z (MH+) :482。 Compound VII has the following 1H NMR (600MHz, CDC13 + CD30D 5: I) δ (ppm):...... 1 24, I 31, I. 43,2 25,2 95,3 05,3 19,3 ........ 30,3 56,3 60,3 85,4 03,7 02,7 08,7 31; 13C NMR (150MHz, CDC13 + CD30D 5: I) δ (ppm): 21. 15,21. 23,22. 98,31. 22,33. 36,38. 83,42. 08,43. 45,68. 82,73. 86,114. 95 (J = 21Hz), 116. 31 (J = 21Hz), 117. 41, 128. 56 (J = 8Hz), 128. 91,142. 02 (J = 8Hz), 157. 58,158. 45,164. 28 (J = 252Hz), 173. 19 , 178; Cl + m / z (MH +): 482.

[0062] 可以纯化各种形式的降解产物,使得只存在一种立体异构体。 [0062] may be purified in various forms of degradation products, so that there is only one stereoisomer. 6位R立体异构体以重量计优选为至少大约95%不含S立体异构体。 6 R stereoisomer by weight, preferably at least about 95% free S stereoisomers. 相反,6位S立体异构体以重量计优选为至少大约95%不含R立体异构体。 In contrast, 6 S stereoisomer by weight preferably at least about 95% free of its R stereoisomer. 纯化可以通过柱色谱、TLC、HPLC,或其它已知的纯化方法进行。 Purification by column chromatography, TLC, HPLC, or other known purification methods were.

[0063] 仪器 [0063] Instruments

[0064] 对于色谱法,可以使用氧化铝或优选硅胶来装柱。 [0064] For the chromatography can use alumina or silica preferably packed. 至于洗脱剂,可以使用不同的有机溶剂或其混合物。 As an eluent, different organic solvents or mixtures thereof. 优选乙酸乙酯。 Preferably ethyl acetate.

[0065] 可以用1H NMR^13C NMR,COSY NMR和质谱分析来研究以相应的酸(VI和VII)、内酯(IV和V)形式分离的化合物II和III以确定它们的结构。 [0065] can be used 1H NMR ^ 13C NMR, COSY NMR and mass spectrometry to study the corresponding acid (VI and VII), lactones (IV and V) in the form of isolated compounds II and III in order to determine their structure.

[0066] 实施例 [0066] Example

[0067] 实施例I通过照射罗苏伐他汀(Ca盐)制备罗苏伐他汀降解产物I、将罗苏伐他汀(Ca-盐)(4. Og)溶于乙腈-水(380ml-140ml)混合物并用可见光(750w,35C )照射7小时。 [0067] Example I irradiated rosuvastatin (Ca salt) Preparation of rosuvastatin degradation product by I, the rosuvastatin (Ca- salt) (4 Og.) Was dissolved in acetonitrile - water (380ml-140ml) mixture and irradiated with visible light (750w, 35 C) 7 hours. 在真空下蒸发乙腈和水。 In the vacuum evaporation of acetonitrile and water. 2、将得到的固体溶于40ml乙腈并加入40mllN盐酸。 2 and the resulting solid was dissolved in 40ml of acetonitrile and hydrochloric acid was added 40mllN. 所述混合物在室温下搅拌过夜。 The mixture was stirred at room temperature overnight. 将乙腈和水蒸发后,在真空下干燥,将得到的产物通过硅胶柱色谱(洗脱剂为己烷-乙酸乙酯I : 2)分离,得到内酯IV(O. Sg)和内酯V(0.6g)。 After evaporation of acetonitrile and water, dried under vacuum, the product was purified by silica gel column chromatography (hexane - ethyl acetate I: 2) to obtain the lactone IV (. O Sg) and lactone V (0.6g). 在硅胶薄层色谱上用己烷-乙酸乙酯(I : 2)洗脱,化合物IV的Rf = O. 30,化合物V的Rf = O. 25。 (: 2 I) elution of the compound IV Rf = O. 30, Compound V of ethyl acetate Rf = O. 25 - thin layer chromatography on silica gel with hexane.

[0068] 化合物IV [0068] Compound IV

Figure CN1894221BD00171

[0070] 化合物V [0070] The compound V

[0071] [0071]

Figure CN1894221BD00172
Figure CN1894221BD00181

[0072] 3、将内酯IV(O. Sg)溶于乙腈,并加入IN氢氧化钠水溶液(4ml)。 [0072] 3, the lactone IV (O. Sg) was dissolved in acetonitrile and adding IN aqueous sodium hydroxide (4ml). 在室温下将混合物搅拌过夜。 The mixture was stirred at room temperature overnight. 乙腈和水蒸发后,在真空下干燥,用硅胶柱色谱(洗脱剂为二氯甲烷-甲醇65ml : IOml)纯化得到的产物,得到纯的化合物VI (O. 4g)。 After evaporation of acetonitrile and water, dried under vacuum, purified by silica gel column chromatography (eluent methylene chloride - methanol 65ml: IOml) was purified to give the pure compound VI (O. 4g).

[0073] 化合物VI (化合物IV相应的酸) [0073] Compound VI (Compound IV corresponding acids)

Figure CN1894221BD00191

[0075] 4、类似地,从内酯V得到化合物VII (O. 3g)。 [0075] 4, similarly, to give Compound VII (O. 3g) from lactone V.

[0076] 化合物VII (化合物V相应的酸) [0076] Compound VII (Compound V corresponding acids)

Figure CN1894221BD00201

[0078] 实施例2通过照射罗苏伐他汀内酯制备罗苏伐他汀降解产物 [0078] Example 2 by irradiation of rosuvastatin lactone prepared rosuvastatin degradation product

[0079] I、将罗苏伐他汀内酯(2. Og)溶于200ml乙腈并用可见光(750w,35C )照射7小时。 [0079] I, will rosuvastatin lactone (2. Og) was dissolved in 200ml of acetonitrile and irradiated with visible light (750w, 35 C) 7 hours. 将乙腈蒸发后,在真空下干燥,将得到的产物通过硅胶柱色谱(洗脱剂为己烷-乙酸乙酯I : 2)分离,得到内酯IV (I. Ig)和内酯V (O. 6g)。 After evaporation of acetonitrile, and dried under vacuum, the product was purified by silica gel column chromatography (hexane - ethyl acetate I: 2) to obtain the lactone IV (I. Ig) and lactone V (O . 6g).

[0080] 2、将内酯IV(l.Og)溶于5ml乙腈并加入2ml IN NaOH水溶液。 [0080] 2, the lactone IV (l.Og) was dissolved in 5ml of acetonitrile and added 2ml IN NaOH solution. 所述混合物在室温下搅拌4小、时。 The mixture was stirred at room temperature for 4 hours, when. 将乙腈蒸发后,加入Iml 2N CaCl2水溶液,在室温下将所述混合物搅拌I小时。 After evaporation of the acetonitrile, Iml 2N CaCl2 aqueous solution was added, at room temperature the mixture was stirred for I h. 将沉淀过滤并在真空下干燥得到化合物II。 The precipitate was filtered and dried under vacuum to give compound II.

[0081] 3、类似地,从内酯V得到化合物III。 [0081] 3, similarly, obtained from a lactone compound III V.

[0082] 实施例3罗苏伐他汀钙的HPLC杂质分布测定 3 HPLC impurity profile determination of rosuvastatin calcium [0082] Example

[0083] 通过HPLC分析确定化合物IV、V、VI和VII的纯度。 [0083] By HPLC analysis to determine the compound IV, V, VI and VII of purity.

[0084] HPLC [0084] HPLC

[0085]柱:Cl8 [0085] Column: Cl8

[0086] 洗脱剂:甲酸盐缓冲液和乙腈的梯度洗脱剂 [0086] eluent: formate buffer and acetonitrile gradient elution

[0087] 流速:1ml/分钟 [0087] flow rate: 1ml / min

[0088]检测器:245nm [0088] Detector: 245nm

[0089] 样品体积:IOuI [0089] Sample volume: IOuI

[0090] 稀释剂:乙腈:水=50 : 50 [0090] Thinner: acetonitrile: water = 50: 50

[0091] 为了达到所需要的系统适合性,可以改变流动相的组成和流速。 [0091] In order to achieve the required system suitability, and can change the flow rate of the mobile phase composition. [0092] 样品制各 [0092] A sample was prepared for each

[0093] 将大约IOmg罗苏伐他汀钙样品在20ml琥珀色容量瓶中称重。 [0093] Approximately IOmg rosuvastatin calcium sample is weighed in a 20ml amber volumetric flask. 用IOml乙腈溶解样品并用水稀释至容量。 The sample is dissolved in acetonitrile with IOml and diluted with water to capacity.

[0094] 标准品制各 [0094] Standard system each

[0095] 将化合物IV、V、VI和VII各大约IOmg在20ml琥珀色容量瓶中称重,用IOml乙腈溶解并用水稀释至容量。 [0095] The compounds IV, V, VI and VII each about IOmg in 20ml amber volumetric flask weighed IOml dissolved in acetonitrile and diluted with water to capacity. 用稀释剂将Iml制备好的溶液稀释至100ml。 With a diluent solution Iml good preparation diluted to 100ml.

[0096] 方法 [0096] Method

[0097] 将新制备的样品溶液注入色谱仪,并将样品的色谱连续进行至梯度的末尾。 [0097] The freshly prepared sample solution into the chromatograph, and the chromatogram of the sample continuously to the end of the gradient. 使用合适的积分仪确定各溶液中的各个峰面积。 Using a suitable integrator determine the solution of each peak area.

[0098] 至此已参考具体的优选实施方案描述了本发明并用实施例进行了举例说明,本领域的技术人员可以对描述和举例说明的本发明做适当的改进而不背离说明书中所公开的本发明的精神和范围。 [0098] Thus with reference to specific preferred embodiments of the invention has been described with illustrative embodiments thereof, those skilled in the art can describe and illustrate the present invention to make the appropriate improvements without departing from the invention disclosed in the specification the spirit and scope of the invention. 阐述实施例是为帮助理解本发明,但不想并且不应视为是以任何方式限制本发明的范围。 Examples are set forth to assist in understanding the invention, but does not want and should not be considered in any way to limit the scope of the invention. 实施例不包括常规方法的详细说明。 Examples do not include a detailed description of conventional methods. 将在本文中提到的所有参考文献以其全部引入。 All references cited herein referred to in its entirety.

Patent Citations
Cited PatentFiling datePublication dateApplicantTitle
CN1543468A16 Aug 20023 Nov 2004特瓦制药工业有限公司Processes for preparing calcium salt forms of statins
WO2004014872A17 Aug 200319 Feb 2004Astrazeneca Uk LimitedProcess for preparing the calcium salt of rosuvastatin
Non-Patent Citations
Reference
1HULL C K ET AL.QUANTIFICATION OF ROSUVASTATIN IN HUMANPLASMA BY AUTOMATED SOLID-PHASE EXTRACTIONUSING TANDEM MASS SPECTROMETRIC DETECTION.JOURNAL OF CHROMATOGRAPHY B:BIOMEDICAL SCIENCES & APPLICATIONS772 2.2002,772(2),219-228.
Classifications
International ClassificationA61K31/519, C07D239/70
Cooperative ClassificationC07D239/70
European ClassificationC07D239/70
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