tert-butyl (3R,5S)-6-oxo-3,5-dihydroxy-3,5-O-isopropylidenehexanoate | 123185-87-5

• 物质功能分类: 医药中间体 - 原料药中间体
• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: tert-butyl (3R,5S)-6-oxo-3,5-dihydroxy-3,5-O-isopropylidenehexanoate
• 英文别名: tert-butyl 2-(6-formyl-2,2-dimethyl-1,3-dioxan-4-yl)acetate；tert-butyl cis-2,2-dimethyl-6-formyl-1,3-dioxane-4-acetate；3,5-Dideoxy-2,4-O-(1-methylethylidene)-D-erythro-hexuronic Acid 1,1-Dimethylethyl Ester；tert-butyl 2-[(4S,6R)-6-formyl-2,2-dimethyl-1,3-dioxan-4-yl]acetate
• CAS: 123185-87-5；124752-23-4；125517-63-7
• 化学式: C₁₃H₂₂O₅
• 分子量: 258.315
• InChiKey: JEFQIIXBSQLRTF-VHSXEESVSA-N

物化性质

• 沸点：
  320.3±32.0 °C(Predicted)
• 密度：
  1.073±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.2
• 重原子数：
  18
• 可旋转键数：
  5
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.85
• 拓扑面积：
  61.8
• 氢给体数：
  0
• 氢受体数：
  5

安全信息

• 危险性防范说明：
  P261,P280,P305+P351+P338
• 危险性描述：
  H302,H315,H319,H332,H335

制备方法与用途

性质

(4R-cis)-6-醛基-2,2-二甲基-1,3-二氧己环-4-乙酸叔丁酯(tert-Butyl (4R-cis)-6-formaldehydel-2,2-dimethyl-1,3-dioxane-4-acetate)又名(4R,6S)-6-甲酰基-2,2-二甲基-1,3-二氧六环-4-基]乙酸叔丁酯，其分子式为C13H22O5，分子量为258.31，CAS号为124752-23-4。

应用

(4R-cis)-6-醛基-2,2-二甲基-1,3-二氧己环-4-乙酸叔丁酯是合成降血脂药瑞舒伐他汀钙(RosuvastatinCalcium)的一个重要中间体。瑞舒伐他汀钙是阿斯利康公司于2002年在欧洲获得上市批准的最新他汀类药物，是媒体评价的“超级他汀”，是迄今为止最强效的降脂药物。用于治疗原发性、家族性高胆固醇血症和混合型脂质异常血症。

反应信息

• 作为反应物：
  描述：

  tert-butyl (3R,5S)-6-oxo-3,5-dihydroxy-3,5-O-isopropylidenehexanoate 在 正丁基锂 、 对甲苯磺酸 作用下， 以 四氢呋喃 、 甲醇 为溶剂， 生成 tert-butyl (3S,5R,6E)-9,9-bis(4-fluorophenyl)-3,5-dihydroxy-8-(1-methyltetrazol-5-yl)nona-6,8-dienoate
  参考文献：
  名称：

  HMG-CoA还原酶的有效，组织选择性合成抑制剂。

  摘要：

  DOI：

  10.1021/jm00129a004
• 作为产物：
  描述：

  tert-butyl cis-3,5-dihydroxy-7-phenylhept-6-enoate 在 二甲基硫 、 对甲苯磺酸 、 臭氧 作用下， 以 二氯甲烷 为溶剂， 反应 32.0h， 生成 tert-butyl (3R,5S)-6-oxo-3,5-dihydroxy-3,5-O-isopropylidenehexanoate
  参考文献：
  名称：

  Synthesis, biological profile, and quantitative structure-activity relationship of a series of novel 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors

  摘要：

  A series of 9,9-bis(4-fluorophenyl)-3,5-dihydroxy-8-(alkyltetrazol-5-yl)- 6,8-nonadienoic acid derivatives 1 were synthesized and found to inhibit competitively the enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. The analogues having 1N-methyltetrazol-5-yl attached to the C8-position (3a, 4a, R1 = R2 = F) are the most active in suppressing cholesterol biosynthesis in both in vitro and in vivo models: the IC50 for the chiral form of 3a is 19 nM, Ki = 4.3 x 10(-9)M when Km for HMG-CoA is 28 x 10(-6) M;1 the ED50 (oral) value corresponding to the lactone derivative (4a, BMY 22089) is approximately 0.1 mg/kg. Further, BMY 21950 is nearly 2 orders of magnitude more active in parenchymal heptaocytes, from which most of the serum cholesterol originates, than in other cell preparations (such as spleen, testes, ileum, adrenal, and ocular lens epithelial cells; Table III). This apparent tissue specificity may be highly beneficial since the blocking of cholesterol biosynthesis in other vital organs could eventually lead to undesirable side effects. In addition to the chemical synthesis and biological evaluation, a theoretical study aimed at relating the HMG-CoA reductase inhibitory potency to the three-dimensional structure of the inhibitors was undertaken. With a combination of molecular mapping and 3D-QSAR techniques, it was possible to determine a logical candidate for the conformation of the bound inhibitor and to quantitatively relate inhibitory potency to the shape and size of both the binding site and the C8-substituent.

  DOI：

  10.1021/jm00173a013

文献信息

• Synthesis and Biophysical Studies on 35-Deoxy Amphotericin B Methyl Ester
  作者：Alex M. Szpilman、Damiano M. Cereghetti、Jeffrey M. Manthorpe、Nicholas R. Wurtz、Erick M. Carreira

  DOI：10.1002/chem.200900231

  日期：2009.7.20

  amphotericin B is presented. A modular strategy for the synthesis of amphotericin B and its designed analogues is developed, which relies on an efficient gram‐scale synthesis of various subunits of amphotericin B. A novel method for the coupling of the mycosamine to the aglycone was identified. The implementation of the approach has enabled the preparation of 35‐deoxy amphotericin B methyl ester. Investigation

  介绍了分子编辑在阐明两性霉素B作用机理中的用途。开发了一种用于合成两性霉素B及其设计类似物的模块化策略，该策略依赖于两性霉素B各种亚基的有效克级合成。鉴定了一种将霉菌胺与糖苷配基偶联的新方法。该方法的实施使得能够制备35-脱氧两性霉素B甲酯。对这种两性霉素B同源物的抗真菌活性和外排诱导能力的研究为35-羟基的作用提供了新线索，并且与双桶离子通道参与引起电解质外排的现象是一致的。
• Synthesis of Artificial HMG-CoA Reductase Inhibitors Based on the Olefination Strategy
  作者：Tamejiro Hiyama、Tatsuya Minami、Kyoko Takahashi

  DOI：10.1246/bcsj.68.364

  日期：1995.1

  Synthetic methods were studied for optically active 6-oxo-3,5-isopropylidenedioxyhexanoate esters (4), which could be used as a key precursor of various kinds of artificial analogs of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors. An enantiomer (+)-4 was prepared by asymmetric reduction of β,δ-diketo esters derived from the Taber’s alcohol or l-tartrate followed by a series of chemical transformations, and the desired enantiomer (−)-4 was prepared by the same asymmetric reduction starting from d-tartrate. The key intermediate (−)-4 was finally converted into a highly potent HMG-CoA reductase inhibitor, NK-104.

  研究了合成光学活性6-氧代-3,5-异丙基二氧六酸酯（4）的方法，这些化合物可作为各种人工类3-羟基-3-甲基戊二酸酰辅酶A（HMG-CoA）还原酶抑制剂的关键前体。通过对来自塔贝酒精或l-酒石酸盐的β,δ-二酮酯进行不对称还原，制备了对映异构体(+)-4，随后经过一系列化学转化，最终得到所需的对映异构体(−)-4，并通过相同的不对称还原方法从d-酒石酸盐出发制得。关键中间体(−)-4最终转化为一种高效的HMG-CoA还原酶抑制剂NK-104。
• Novel bifunctional probe for radioisotope-free photoaffinity labeling: compact structure comprised of photospecific ligand ligation and detectable tag anchoring unitsElectronic supplementary information (ESI) available: Photo-decomposition study of phenyl and benzyl azides. Experimental details for photoreactions of 1 and 5. Synthetic procedures and characterization of new compounds. See http://www.rsc.org/suppdata/ob/b3/b316221d/.
  作者：Takamitsu Hosoya、Toshiyuki Hiramatsu、Takaaki Ikemoto、Masayuki Nakanishi、Hiroshi Aoyama、Ayako Hosoya、Tomoya Iwata、Kei Maruyama、Makoto Endo、Masaaki Suzuki

  DOI：10.1039/b316221d

  日期：——

  A novel method for radioisotope-free photoaffinity labeling was developed, in which a bifunctional ligand is connected to a target protein by activation of a photoreactive group, such as an aromatic azido or 3-trifluoromethyl-3H-diazirin-3-yl group, and identification of the ligated product is achieved by anchoring of a detectable tag through the Staudinger-Bertozzi reaction with an alkyl azido moiety

  开发了一种无放射性同位素的光亲和标记的新方法，其中双功能配体通过激活光反应性基团（例如芳族叠氮基或3-三氟甲基-3H-二氮杂-3-基）与靶蛋白连接，并且通过Staudinger-Bertozzi反应与可在光解中幸存的烷基叠氮基部分锚定可检测标签，可实现对连接产物的鉴定。该方法的化学基础已通过使用具有双官能团的模型化合物在光辐射下，存在用于反应性中间体的捕集剂的条件下进行了确认。该方法的实用性已经通过人HMG-CoA还原酶的催化部分的特异性标记得到证明。
• 一种2-((4R, 6S)-6-甲酰基-2,2-二取代 基-1,3-二氧六环-4-基)乙酸酯制备方法
  申请人：新发药业有限公司

  公开号：CN104230879B

  公开（公告）日：2016-08-24

  本发明涉及一种简便的2‑((4R,6S)‑6‑甲酰基‑2,2‑二取代基‑1,3‑二氧六环‑4‑基)乙酸酯的制备方法。2‑((4R,6S)‑6‑甲酰基‑2,2‑二取代基‑1,3‑二氧六环‑4‑基)乙酸酯具有通式Ⅰ的结构。本发明方法利用丁二烯和3,3‑二烷氧基丙酸酯或3‑烷氧基丙烯酸酯为原料，在路易斯酸催化下成环、取代苯甲醛成环保护，再水解后与相应的醛(酮)或其缩二甲醇、缩二乙醇成环反应制备具有通式Ⅵ的2‑((4R,6S)‑6‑乙烯基‑2,2‑二取代基‑1,3‑二氧六环‑4‑基)乙酸酯、然后经乙烯基臭氧化三步反应制备Ⅰ。本发明原料易得，反应流程短，利用六元环椅式结构的平伏键稳定形式构建手性中心，不使用易燃易爆的不对称还原剂，简便且环保，适于他汀类手性侧链的工业化生产。
• 一种他汀类中间体及其衍生物的制备方法
  申请人：江苏阿尔法药业有限公司

  公开号：CN103113357B

  公开（公告）日：2017-02-08

  本发明公开了一种他汀类中间体及其衍生物的制备方法，式（Ⅳ）化合物在碱金属盐催化剂存在下与DMSO和碱进行氧化反应制备得到式（Ⅱ）化合物，式（Ⅱ）化合物再在碱催化下与式（III）化合物缩合即得到式（I）化合物；式中，X为卤素，R为取代或非取代的C1～6的烷基、C3～5的烷环基或芳基，其取代基为芳基；R1选自C1～6的烷基、卤素中的一种或几种。与现有技术相比，式（Ⅳ）化合物不经过酯化和水解制备醇，然后再氧化制备醛（式（Ⅱ）化合物），直接由式（Ⅳ）化合物一步法制备得到式（Ⅱ）化合物，该制备方法步骤简短，操作简单，适宜于工业化大生产。