(betaR,deltaR,1S,2S)-1,2-二氢-beta,delta,6-三羟基-2-甲基-1-萘庚酸钠盐 | 136590-28-8

• 分子结构分类: 有机化合物 - 苯类化合物 - 萘
• 中文名称: (betaR,deltaR,1S,2S)-1,2-二氢-beta,delta,6-三羟基-2-甲基-1-萘庚酸钠盐
• 中文别名: 普伐他汀杂质G
• 英文名称: R-195
• 英文别名: Desacyl-dehydropravastatin；(3R,5R)-3,5-dihydroxy-7-[(1S,2S)-6-hydroxy-2-methyl-1,2-dihydronaphthalen-1-yl]heptanoic acid
• CAS: 136590-28-8
• 化学式: C₁₈H₂₄O₅
• 分子量: 320.386
• InChiKey: STGSFABFWFDJSQ-SRMUXQRQSA-N

物化性质

• 熔点：
  118-121°C (dec.)
• 溶解度：
  DMSO（少许）、甲醇（少许）、水（少许）

计算性质

• 辛醇/水分配系数(LogP)：
  2.1
• 重原子数：
  23
• 可旋转键数：
  7
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  98
• 氢给体数：
  4
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (betaR,deltaR,1S,2S)-1,2-二氢-beta,delta,6-三羟基-2-甲基-1-萘庚酸钠盐 在 盐酸 、 silica gel 作用下， 以 二氯甲烷 、 水 为溶剂， 以0.48 g的产率得到(4R,6R)-4-hydroxy-6-(2-((1S,2S)-6-hydroxy-2-methyl-1,2-dihydronaphthalen-1-yl)ethyl)tetrahydro-2H-pyran-2-one
  参考文献：
  名称：

  一种降血脂类药物氧化杂质的制备方法

  摘要：

  本发明公开了一种降血脂类药物氧化杂质的制备方法。本发明提供了的如式III所示的苯酚类化合物的制备方法，其包括如下步骤：步骤(1)在溶剂中，在酸存在下，将如式III’所示的苯酚类化合物的钠盐的粗品进行如下所示的环合反应，得到如式IV所示的苯酚类化合物即可；步骤(2)在溶剂中，在碱存在下，将所述的如式IV所示的苯酚类化合物进行如下所示的内酯开环‑成盐反应，得到如式III所示的苯酚类化合物即可。该制备方法可高纯度的得到普伐他汀钠氧化杂质，用于产品的质量控制，提高用药安全性。

  公开号：

  CN112778120A
• 作为产物：
  描述：

  pravastatin sodium salt 在 盐酸 、 水 、 silica gel 、 pyridinium chlorochromate 、 sodium hydroxide 作用下， 以 二氯甲烷 、 水 、 乙酸乙酯 、 丙酮 、 甲苯 为溶剂， 反应 6.0h， 生成 (betaR,deltaR,1S,2S)-1,2-二氢-beta,delta,6-三羟基-2-甲基-1-萘庚酸钠盐
  参考文献：
  名称：

  一种降血脂类药物氧化杂质的制备方法

  摘要：

  本发明公开了一种降血脂类药物氧化杂质的制备方法。本发明提供了的如式III所示的苯酚类化合物的制备方法，其包括如下步骤：步骤(1)在溶剂中，在酸存在下，将如式III’所示的苯酚类化合物的钠盐的粗品进行如下所示的环合反应，得到如式IV所示的苯酚类化合物即可；步骤(2)在溶剂中，在碱存在下，将所述的如式IV所示的苯酚类化合物进行如下所示的内酯开环‑成盐反应，得到如式III所示的苯酚类化合物即可。该制备方法可高纯度的得到普伐他汀钠氧化杂质，用于产品的质量控制，提高用药安全性。

  公开号：

  CN112778120A

文献信息

• Metabolism of Pravastatin Sodium by 3.ALPHA.-Hydroxysteroid Dehydrogenase.
  作者：Shigeki MURAMATSU、Yuko KOMOKATA、Yorihisa TANAKA、Hidekuni TAKAHAGI

  DOI：10.1248/bpb.20.1199

  日期：——

  When incubated with isolated rat hepatocytes, pravastatin sodium (PS) yielded a small amount of a metabolite in addition to two major metabolites that have already been reported. The previously uncharacterized metabolite was found to be formed by at first being enzymatically dehydrogenated to 6'-keto intermediate (R-104), followed by decomposition to give the aromatized metabolite (R-195), through spontaneous deesterification with accompanying aromatization. The PS-6'β-hydroxydehydrogenase activity was localized in cytosolic fraction and required NADP, preferentially over NAD, as a cofactor. The formation of R-195 by rat liver cytosol was strongly inhibited by indomethacin, 3α-hydroxysteroids (but not 3β-isomers) and 3-ketosteroids. The results and high substrate specificity of purified PS-6'β-hydroxydehydrogenase toward 3α-hydroxysteroids suggested that the enzyme is identical to 3α-hydroxysteroid dehydrogenase.

  普伐他汀钠（PS）与离体大鼠肝细胞孵育时，除了已报道的两种主要代谢物外，还产生了少量代谢物。研究发现，先前未定性的代谢物首先是通过酶促脱氢生成 6'- 酮中间体（R-104），然后通过自发脱酯和伴随的芳香化作用分解生成芳香化代谢物（R-195）。PS-6'β-羟基脱氢酶的活性定位于细胞膜部分，需要 NADP（优先于 NAD）作为辅助因子。吲哚美辛、3α-羟基类固醇（但不包括 3β-异构体）和 3-酮类固醇能强烈抑制大鼠肝脏细胞液中 R-195 的形成。这些结果以及纯化的 PS-6'β- 羟基脱氢酶对 3α- 羟基类固醇的高底物特异性表明，该酶与 3α- 羟基类固醇脱氢酶相同。
• Selection of solid dosage form composition through drug–excipient compatibility testing
  作者：Abu T.M. Serajuddin、Ajit B. Thakur、Rabin N. Ghoshal、Michael G. Fakes、Sunanda A. Ranadive、Kenneth R. Morris、Sailesh A. Varia

  DOI：10.1021/js980434g

  日期：1999.7

  A drug-excipient compatibility screening model was developed by which potential stability problems due to interactions of drug substances with excipients in solid dosage forms can be predicted. The model involved storing drug-excipient blends with 20% added water in closed glass vials at 50 degrees C and analyzing them after 1 and 3 weeks for chemical and physical stability. The total weight of drug-excipient blend in a vial was usually kept at about 200 mg. The amount of drug substance in a blend was determined on the basis of the expected drug-to-excipient ratio in the final formulation. Potential roles of several key factors, such as the chemical nature of the excipient, drug-to-excipient ratio, moisture, microenvironmental pH of the drug-excipient mixture, temperature, and light, on dosage farm stability could he identified by using the model. Certain physical changes, such as polymorphic conversion or change from crystalline to amorphous form, that could occur in drug-excipient mixtures were also studied. Selection of dosage form composition by using this model at the outset of a drug development program would lead to reduction of "surprise" problems during long-term stability testing of drug products.
• Process for obtaining HMG-CoA reductase inhibitors of high purity
  申请人：Grahek Rok

  公开号：US20070032549A1

  公开（公告）日：2007-02-08

  Lovastatin, pravastatin, simvastatin, mevastatin, atorvastatin, and derivatives and analogs thereof are known as HMG-CoA reductase inhibitors and are used as antihypercholesterolemic agents. The majority of them are produced by fermentation using microorganisms of different species identified as species belonging to Aspergillus, Monascus, Nocardia, Amycolatopsis, Mucor or Penicillium genus, Streptomyces, Actinomadura, Micromonospora, some are obtained by treating the fermentation products using the method of chemical synthesis or they are the products of total chemical synthesis. The purity of the active ingredient is an important factor for manufacturing the safe and effective pharmaceutical, especially if the pharmaceutical product must be taken on a longer term basis in the treatment or prevention of high plasma cholesterol. The accumulation of the impurities from the pharmaceuticals of lower purity may cause many side effects during the medical treatment. The present invention relates to a new industrial process for the isolation of HMG-CoA reductase inhibitors using so-called displacement chromatography. Use of the invention enables one to obtain HMG-CoA reductase inhibitors of high purity, with high yields, lower production costs and suitable ecological balance.
• 一种降血脂类药物氧化杂质的制备方法
  申请人：上海现代制药股份有限公司

  公开号：CN112778120A

  公开（公告）日：2021-05-11

  本发明公开了一种降血脂类药物氧化杂质的制备方法。本发明提供了的如式III所示的苯酚类化合物的制备方法，其包括如下步骤：步骤(1)在溶剂中，在酸存在下，将如式III’所示的苯酚类化合物的钠盐的粗品进行如下所示的环合反应，得到如式IV所示的苯酚类化合物即可；步骤(2)在溶剂中，在碱存在下，将所述的如式IV所示的苯酚类化合物进行如下所示的内酯开环‑成盐反应，得到如式III所示的苯酚类化合物即可。该制备方法可高纯度的得到普伐他汀钠氧化杂质，用于产品的质量控制，提高用药安全性。