头孢地尼侧链酸 | 128438-01-7

• 物质功能分类: 医药中间体 - 杂环化合物
• 分子结构分类: 有机化合物 - 苯类化合物 - 三苯基化合物
• 中文名称: 头孢地尼侧链酸
• 中文别名: (Z)-2-(2-氨基噻唑-4-基)-2-三苯甲氧亚氨基乙酸
• 英文名称: (Z)-2-(2-aminothiazol-4-yl)-2-(triphenylmethoxyimino)acetic acid
• 英文别名: (Z)-(2-Aminothiazol-4-yl) (triphenylmethoxyimino)acetic acid；(Z)-2-(2-amino-4-thiazolyl)-2-trityloxyiminoacetic acid；(Z)-2-(2-aminothiazol-4-yl)-2-trityloxyiminoacetic acid；2-(2-amino-4-thiazolyl)-2-(Z)-trityloxyiminoacetic acid；2-(2-aminothiazol-4-yl)-2(Z)-trityloxyiminoacetic acid；(Z)-2-(2-Aminothiazol-4-yl)-2-((trityloxy)imino)acetic acid；(2Z)-2-(2-amino-1,3-thiazol-4-yl)-2-trityloxyiminoacetic acid
• CAS: 128438-01-7
• 化学式: C₂₄H₁₉N₃O₃S
• 分子量: 429.499
• InChiKey: XEZIFGWTSLOMMT-MEFGMAGPSA-N

物化性质

• 熔点：
  179-182 °C
• 沸点：
  651.5±65.0 °C(Predicted)
• 密度：
  1.29±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  5.6
• 重原子数：
  31
• 可旋转键数：
  7
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.04
• 拓扑面积：
  126
• 氢给体数：
  2
• 氢受体数：
  7

安全信息

• 海关编码：
  2934100090
• 储存条件：
  室温

制备方法与用途

用途：用于制备头孢类药物的中间体。

反应信息

• 作为反应物：
  描述：

  头孢地尼侧链酸 在 盐酸 、 苯磺酰胺 、 甲酸 、 potassium carbonate 、 甲基磺酰氯 、 N,N-二异丙基乙胺 作用下， 以 N,N-二甲基乙酰胺 、 N,N-二甲基甲酰胺 为溶剂， 反应 1.0h， 生成 7β-[2-(Z)-(2-aminothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-[2-(4-pyridyl)ethylthio]-3-cephem-4-carboxylic acid
  参考文献：
  名称：

  Orally active cephalosporins. Part 2: Synthesis, structure–activity relationships and oral absorption of cephalosporins having a C-3 pyridyl side chain

  摘要：

  A series of 7 beta-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]cephalosporins having a pyridine ring connected through various spacer moieties at the C-3 position was designed and synthesized and evaluated for antibacterial activity and oral absorption in rats. All compounds showed potent antibacterial activity against Staphylococcus aureus, whereas antibacterial activity against Gram-negative bacteria was markedly influenced by the spacer moiety between the pyridine and cephem nucleus. Oral absorption was influenced by the position of the pyridine nitrogen as well as by the spacer moiety. Among these compounds, FR86830 (14), having a 4-pyridylmethylthio moiety at the C-3 position, showed the most well balanced activity and moderate oral absorption. (C) 2000 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0968-0896(00)00021-3
• 作为产物：
  描述：

  三苯基甲醇 在 溶剂黄146 三氟化硼乙醚 、 水 、 potassium hydroxide 作用下， 以 乙醇 、 水 、 乙酸乙酯 为溶剂， 反应 25.5h， 生成 头孢地尼侧链酸
  参考文献：
  名称：

  [EN] PROCESS FOR PREPARING 2-AMINOTHIAZOL-4-YL-ACETIC ACID DERIVATES
  [FR] PROCÉDÉ PAR PRÉPARER DES DÉRIVÉS D'ACIDE 2-AMINOTHIAZOL-4-YL ACÉTIQUE

  摘要：

  该发明提供了一种制备式(I)的(2-氨基噻唑-4-基)-三芳基甲氧基-亚氨基乙酸或其酯式(II)的过程，其中R1、R2和R3独立地是可选择取代的苯基，R4是C1-6烷基，通过将式(III)的(2-氨基噻唑-4-基)羟基亚氨基乙酸酯与式R1R2R3COH的醇在BF3存在下反应形成式(II)的(2-氨基噻唑-4-基)三芳基甲氧基亚氨基乙酸酯，可选择地，水解所述的式(II)酯以获得式(I)的酸。

  公开号：

  WO2011029596A1

文献信息

• Studies on Anti-MRSA Parenteral Cephalosporins. I. Synthesis and Antibacterial Activity of 7.BETA.-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2(Z)-hydroxyiminoacetamido]-3-(substituted imidazo [1,2-b]-pyridazinium-1-yl)methyl-3-cephem-4-carboxylates and Related Compounds.
  作者：TOMOYASU ISHIKAWA、YIJJI IIZAWA、KENJI OKONOGI、AKIO MIYAKE

  DOI：10.7164/antibiotics.53.1053

  日期：——

  In order to improve the antibacterial activity of cefozopran (CZOP) against methicillin-resistant Staphylococcus aureus (MRSA), we initiated chemical modification to introduce a 2-(5-amino-1, 2, 4-thiadiazol-3-yl)-2(Z)-hydroxyimino acetyl group at the C-7 position and a 3- or 6-substituted imidazo[1, 2-b]pyridazinium or 5-substituted imidazo[1, 2-a]pyridmium group at the C-3' position. Although this approach successfully enhanced the anti-MRSA activity of CZOP two to eight times, a slight decrease in the activity against Gram-negative bacteria including Pseudomonas aeruginosa was involved. Among the novel derivatives, 3-(6-aminoimidazo[1, 2-b]pyridazinium-1-yl)methyl-7β-[2-(5-amino-1, 2, 4-thiadiazol-3-yl)-2(Z)-hydroxyiminoacetamido]-3-cephem-4-carboxylate (44a) showed an excellent balance of activity against MRSA and Gram-negative bacteria.

  为了提高cefozopran (CZOP) 对耐甲氧西林金黄色葡萄球菌 (MRSA) 的抗菌活性，我们开始了化学修饰，引入一个2-(5-氨基-1, 2, 4-噻二唑-3-基)-2(Z)-羟亚氨基乙酰基团在C-7位，以及一个3位或6位取代的咪唑[1, 2-b]吡啶鎓或5位取代的咪唑[1, 2-a]吡啶鎓基团在C-3'位。尽管这种方法成功地将CZOP对MRSA的抗性提高了两到八倍，但对包括铜绿假单胞菌在内的革兰氏阴性菌的活性略有下降。在这些新衍生物中，3-(6-氨基咪唑[1, 2-b]吡啶鎓-1-基)甲基-7β-[2-(5-氨基-1, 2, 4-噻二唑-3-基)-2(Z)-羟亚氨基乙酰氨基]-3-头孢烯-4-羧酸酯(44a)表现出了对MRSA和革兰氏阴性菌的活性之间的优良平衡。
• Discovery of RWJ-54428 (MC-02,479), a New Cephalosporin Active Against Resistant Gram-positive Bacteria.
  作者：SCOTT J. HECKER、TOMASZ W. GLINKA、AESOP CHO、ZHIJIA J. ZHANG、MARY E. PRICE、SUZANNE CHAMBERLAND、DAVID GRIFFITH、VING J. LEE

  DOI：10.7164/antibiotics.53.1272

  日期：——

  The discovery of RWJ-54428 (MC-02, 479), a new cephalosporin displaying promising activity against sensitive and resistant Gram-positive bacteria, is described. Progressive structural modification from the previously reported 3-phenylthiocephem MC-02, 331 afforded an overall increase in potency against MRSA while retaining other key properties such as acceptable solubility and serum binding. Evaluation of the in vitro potency and in vivo efficacy of a series of closely related compounds resulted in selection of RWJ-54428 (MC-02, 479) for further studies.

  描述了新型头孢菌素RWJ-54428（MC-02, 479）的发现，该药物对敏感和耐药的阳性革兰氏菌表现出良好的活性。通过对之前报道的3-苯基硫头孢MC-02, 331进行渐进式结构修饰，整体提高了对MRSA的效能，同时保持了其他关键特性，如可接受的溶解度和血清结合能力。对一系列密切相关化合物的体外活性和体内疗效进行评估，最终选择了RWJ-54428（MC-02, 479）进行进一步研究。
• Synthesis of HR 916 K: An Efficient Route to the Pure Diastereomers of the 1-(Pivaloyloxy)ethyl Esters of Cephalosporins
  作者：Elisabeth Defoßa、Gerd Fischer、Uwe Gerlach、Rolf Hörlein、Dieter Isert、Norbert Krass、Rudolf Lattrell、Ulrich Stache、Theo Wollmann

  DOI：10.1002/jlac.199619961107

  日期：1996.11

  HR 916 K (5), the 1-(S)-(pivaloyloxy)ethyl prodrug ester of the cephalosporin cefdaloxime, exhibits a significantly higher oral bioavailability than the 1-(R) diastereomer HR 916 J. An efficient synthesis of HR 916 K was developed. The separation of the diastereomers was achieved by precipitation of the 1-(R)-hydrochloride 9 followed by crystallization of the 1-(S)-amine 10 (de > 96%). The 1-(R) diastereomer

  HR 916 K（5）是头孢菌素头孢达肟的1-（S）-（新戊酰氧基）乙基前药酯，其口服生物利用度明显高于1-（R）非对映异构体HR 916J。HR 916 K的有效合成发展了。非对映异构体的分离通过沉淀1-（R）-盐酸盐9，然后结晶1-（S）-胺10（de＞ 96％）来实现。通过酸性皂化或酶促裂解将1-（R）非对映异构体9再循环至AMCA（7）。胺10用巯基苯并噻唑硫酯或由羧酸13和14制备的混合酸酐将其酰化，几乎可以定量收率。肟的脱保护和甲苯磺酸酯的形成是一步进行的。使用硫酯18，我们以42％的收率从AMCA（7）获得了HR 916 K（5）。
• Cephalosporin antibiotics
  申请人：Microcide Pharmaceuticals, Inc.

  公开号：US06087355A1

  公开（公告）日：2000-07-11

  The present invention includes novel compounds of formula ##STR1## where A, B, D, and E are selected from the group consisting of carbon, nitrogen and sulfur, R.sup.99 is selected from the group consisting of sulfur, SO, SO.sub.2, NH, N-alkyl, oxygen, C.dbd.C (cis or trans), and C.tbd.C, and R.sup.12 is NR.sup.13 R.sup.14, ##STR2## The invention also includes the pharmacologically acceptable salts which exhibit antibiotic activity against a wide spectrum of organisms including organisms which are resistant to .beta.-lactam antibiotics and are useful as antibacterial agents. The invention also relates to novel intermediates useful for making the novel compounds of the present invention and to novel methods for producing the novel compounds and intermediate compounds.

  本发明包括以下结构的新化合物：其中A、B、D和E从碳、氮和硫组成的群体中选择，R.sup.99从硫、SO、SO.sub.2、NH、N-烷基、氧、C.dbd.C（顺式或反式）和C.tbd.C组成的群体中选择，R.sup.12是NR.sup.13R.sup.14，本发明还包括表现出抗生素活性的药理学上可接受的盐，对包括对β-内酰胺抗生素产生抗性的广谱生物体具有抗菌活性，并可用作抗菌剂。本发明还涉及用于制备本发明新化合物的新中间体，以及用于生产新化合物和中间化合合物的新方法。
• Novel amino chlorothiazole compounds
  申请人：Microcide Pharmaceuticals, Inc.

  公开号：EP1059293A1

  公开（公告）日：2000-12-13

  The invention relates to novel amino chlorothiazole compounds and to novel methods for producing the novel compounds. The compounds are useful in the production of cephalosporin antiobiotics.

  该发明涉及新型氨基氯噻唑化合物以及生产这些新化合物的新方法。这些化合物在头孢菌素类抗生素的生产中很有用。