盐酸头孢吡肟 | 107648-80-6

• 物质功能分类: 原料药 - 抗生素类药物 - 头孢菌素类药
• 分子结构分类: 有机化合物 - 有机杂环化合物 - 内酰胺类
• 中文名称: 盐酸头孢吡肟
• 中文别名: (6R,7R)-7-[[(2E)-2-(2-氨基-1,3-噻唑-4-基)-2-甲氧基亚氨乙酰]氨基]-3-[(1-甲基吡咯烷-1-基)甲基]-8-氧代-5-硫杂-1-氮杂双环[4.2.0]辛-2-烯-2-甲酸二盐酸盐；头孢吡肟精氨酸混粉；氨噻肟酸苯并三唑酯(活性氧酯)；(6R,7R)-7-[(Z)-2-(2-氨基-4-噻唑基)-2-甲氧亚胺]乙酰胺基-3-[1-(1-甲基吡咯烷基)甲基]-8-氧-5-硫杂-1-氮杂双环[4.2.0]辛-2-烯-2-羧酸盐酸盐
• 英文名称: 1-[[(6R,7R)-7-[[(2Z)-(2-amino-4-thiazolyl)(methoxyimino)acetyl]amino]-2-carboxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]methyl]-1-methyl-pyrrolidinium chloride hydrochloride
• 英文别名: cefepime hydrochloride；cefepime dihydrochloride；1-[[(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-methoxyimino)-acetamido]-2-carboxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]methyl]-1-methyl-pyrrolidinium chloride monohydrochloride；Cefeprime dihydrochloride；(6R,7R)-7-[[(2Z)-2-(2-amino-1,3-thiazol-4-yl)-2-methoxyiminoacetyl]amino]-3-[(1-methylpyrrolidin-1-ium-1-yl)methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate;dihydrochloride
• CAS: 107648-80-6
• 化学式: C₁₉H₂₅N₆O₅S₂*ClH*Cl
• 分子量: 553.491
• InChiKey: XQQAUWFZBOTKFQ-MHRNPJSASA-N

物化性质

• 熔点：
  230 °C (decomp)
• 溶解度：
  水:10.0(最大浓度 mg/mL);17.5(最大浓度 mM)DMSO:6.0(最大浓度 mg/mL);10.5(最大浓度 mM)

计算性质

• 辛醇/水分配系数(LogP)：
  -2.52
• 重原子数：
  34
• 可旋转键数：
  7
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.53
• 拓扑面积：
  201
• 氢给体数：
  4
• 氢受体数：
  11

ADMET

毒理性

• 在妊娠和哺乳期间的影响

◉ 母乳喂养期间使用概述：尽管没有关于母乳喂养期间使用头孢匹姆的信息，但母乳中的水平似乎较低，通常不期望头孢菌素对哺乳婴儿产生不良影响。偶尔报道头孢菌素会破坏婴儿的胃肠道菌群，导致腹泻或鹅口疮，但这些影响尚未得到充分评估。头孢匹姆对哺乳母亲是可接受的。 ◉ 对哺乳婴儿的影响：截至修订日期，未找到相关的已发布信息。 ◉ 对泌乳和母乳的影响：截至修订日期，未找到相关的已发布信息。

◉ Summary of Use during Lactation:Although no information is available on the use of cefepime during breastfeeding, the levels in breastmilk appear to be low and cephalosporins are generally not be expected to cause adverse effects in breastfed infants. Occasionally disruption of the infant's gastrointestinal flora, resulting in diarrhea or thrush have been reported with cephalosporins, but these effects have not been adequately evaluated. Cefepime is acceptable in nursing mothers. ◉ Effects in Breastfed Infants:Relevant published information was not found as of the revision date. ◉ Effects on Lactation and Breastmilk:Relevant published information was not found as of the revision date.

来源:Drugs and Lactation Database (LactMed)

安全信息

• 海关编码：
  2941905990

制备方法与用途

用途：用于治疗多种细菌感染，包括重症感染。

反应信息

• 作为产物：
  描述：

  5-氯-3-[(1,5-二羟基-2-萘)偶氮]-2-羟基苯磺酸钠 、 1-[((6R,7R)-7-amino-2-carboxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl)methyl]-1-methylpyrrolidinium chloride hydrochloride 在 三乙胺 作用下， 以 水 、 丙酮 为溶剂， 以80%的产率得到盐酸头孢吡肟
  参考文献：
  名称：

  [EN] PROCESS FOR THE DIRECT PREPARATION OF CEFEPIME FOR INJECTABLE USE
  [FR] PROCÉDÉ DE PRÉPARATION DIRECTE DE CÉFÉPIME POUR UTILISATION PAR VOIE INJECTABLE

  摘要：

  本发明涉及一种直接工艺，无需分离任何中间体，用于制备注射用的Cefepime双氯化物一水合物的无菌质量，包括以下步骤：在水中存在碱或酸的情况下，对式（II）化合物进行预处理脱色步骤；在至少一种可溶于水的溶剂存在下，使用MAEM进行酰化步骤；在与水不相溶的溶剂存在下进行萃取步骤；对含有溶解产品的富水溶液进行脱色步骤；最后，在盐酸存在下，使用丙酮结晶步骤对产品进行结晶。

  公开号：

  WO2013114319A1

文献信息

• [EN] PROCESS FOR PREPARING PURE CEPHALOSPORINE INTERMEDIATES<br/>[FR] PROCEDE DE PREPARATION D'INTERMEDIAIRES DE CEPHALOSPORINE PURES
  申请人：HETERO DRUGS LTD

  公开号：WO2006008749A1

  公开（公告）日：2006-01-26

  The present invention relates to a process for preparing key intermediates for cephalosporin antibiotics substantially free of undesired delta A2 isomer. Thus, 7-aminocephalosporanic acid (7-ACA) is silylated with hexamethyldisilazane in cyclohexane at reflux temperature. (6R,7R)-3-[(Acetyloxy)methyl]-7-(trimethylsilyl)aminoceph-3-em-4-oic acid obtained is reacted with the mixture of N-methylpyrrolidine and trimethylsilyliodide in cyclohexane, desilylated with isopropyl alcohol and treated with hydrochloric acid to obtain [6R-(6a,7b)]-1-[[7-Amino-2-carboxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]methyl]-1-methylpyrrolidinium inner salt hydrochloride. [6R-(6a,7b)]-1-[[7-Amino-2-carboxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]methyl]-1-methylpyrrolidinium inner salt hydrochloride is N-acylated with syn-2-(2-aminothiazol-4-yl)-2-methoxyimino acetic acid 2-benzothiazolyl thioester (MAEM) followed by treatment with hydrochloric acid to give cefepime dihydrochloride monohydrate.

  本发明涉及一种制备头孢菌素抗生素的关键中间体的方法，该方法基本上不含不需要的δA2异构体。因此，7-氨基头孢菌酸（7-ACA）在环己烷中与六甲基二硅氮烷在回流温度下硅化。得到的（6R,7R）-3-[(乙酰氧)甲基]-7-(三甲基硅基)氨基头孢-3-烯-4-酸与N-甲基吡咯烷和三甲基硅碘酸酯的混合物在环己烷中反应，用异丙醇脱硅，然后用盐酸处理，得到[6R-(6a,7b)]-1-[[7-氨基-2-羧基-8-氧代-5-硫代-1-氮杂双环[4.2.0]辛-2-烯-3-基]甲基]-1-甲基吡咯烷内盐盐酸盐。[6R-(6a,7b)]-1-[[7-氨基-2-羧基-8-氧代-5-硫代-1-氮杂双环[4.2.0]辛-2-烯-3-基]甲基]-1-甲基吡咯烷内盐盐酸盐与syn-2-(2-氨基噻唑-4-基)-2-甲氧基亚氨基乙酸2-苯并噻唑基硫酯（MAEM）N-酰化，然后用盐酸处理，得到头孢哌酮二盐酸盐一水合物。
• [EN] PROCESS FOR PREPARATION OF CEFEPIME DIHYDROCHLORIDE MONOHYDRATE<br/>[FR] PROCÉDÉ POUR LA PRÉPARATION DE DICHLORHYDRATE DE CÉFÉPIME MONOHYDRATÉ
  申请人：NECTAR LIFESCIENCES LTD

  公开号：WO2011121389A1

  公开（公告）日：2011-10-06

  A process for preparation of cefepime dihydrochloride monohydrate is provided. The process comprises condensing 7-amino-3-[(l -methyl- 1 -pyrrolidino)methyl]-3-cephem-4-carboxylate monohydrochloride dihydrate and 2-mercaptobenzothiazolyl-(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetate in the presence of a base in an alcohol solvent.

  提供一种制备头孢匹罗啉二盐酸盐一水合物的方法。该方法包括在醇溶剂中，在碱的存在下，将7-氨基-3-[(l-甲基-1-吡咯啉基)甲基]-3-头孢-4-羧酸单盐酸盐二水合物和2-巯基苯并噻唑基-(Z)-2-(2-氨基噻唑-4-基)-2-甲氧基亚胺乙酸酯进行缩合。
• Processes for the preparations of cefepime
  申请人：Sandoz AG

  公开号：EP2218723A2

  公开（公告）日：2010-08-18

  The invention relates to new processes for the preparation of 1-[[(6R,7R)-7-[[(2Z)-(2-amino-4-thiazolyl)methoxyimino)acetyl]amino]-2-carboxy-8-oxo-5-thia-azabicyclo[4.2.0]oct-2-en-3-yl]methyl]-1-methyl-pyrrolidinium dihydrochloride hydrate (cefepime dihydrochloride monohydrate).

  本发明涉及制备头孢吡肟二盐酸盐一水合物（cefepime dihydrochloride monohydrate）的新工艺。
• Process for preparing pure cephalosporine intermediates
  申请人：Parthasaradhi Reddy Bandi

  公开号：US20070111980A1

  公开（公告）日：2007-05-17

  The present invention relates to a process for preparing key intermediates for cephalosporin antibiotics substantially free of undesired Δ 2 isomer. Thus, 7-aminocephalosporanic acid (7-ACA) is silylated with hexamethyldisilazane in cyclohexane at reflux temperature. (6R,7R)-3-[(Acetyloxy)methyl]-7-(trimethylsilyl)aminoceph-3-em-4-oic acid obtained is reacted with the mixture of N-methylpyrrolidine and trimethylsilyl iodide in cyclohexane, desilylated with isopropyl alcohol and treated with hydrochloric acid to obtain [6R-(6α,7β)]-1-[[7-Amino-2-carboxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]methyl]-1-methylpyrrolidinium inner salt hydrochloride. [6R-(6α,7β)]-1-[[7-Amino-2-carboxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]methyl]-1-methylpyrrolidinium inner salt hydrochloride is N-acylated with syn-2-(2-aminothiazol-4-yl)-2-methoxyimino acetic acid 2-benzothiazolyl thioester (MAEM) followed by treatment with hydrochloric acid to give cefepime dihydrochloride monohydrate.

  本发明涉及一种制备头孢菌素抗生素关键中间体的方法，该方法基本上不含不需要的Δ2异构体。因此，将7-氨基头孢烷酸（7-ACA）在环己烷中回流温度下与六甲基二硅氮烷硅化，得到（6R，7R）-3-[(乙酰氧)甲基]-7-(三甲基硅基)氨基头孢-3-烯-4-酸，然后将其与N-甲基吡咯烷和三甲基硅基碘混合物在环己烷中反应，用异丙醇去除硅基，再用盐酸处理，得到[6R-(6α,7β)]-1-[[7-氨基-2-羧基-8-氧代-5-硫-1-氮杂双环[4.2.0]辛-2-烯-3-基]甲基]-1-甲基吡咯烷内盐盐酸盐。然后，用syn-2-(2-氨基噻唑-4-基)-2-甲氧基亚硝基乙酸2-苯并噻唑基硫酯（MAEM）对[6R-(6α,7β)]-1-[[7-氨基-2-羧基-8-氧代-5-硫-1-氮杂双环[4.2.0]辛-2-烯-3-基]甲基]-1-甲基吡咯烷内盐盐酸盐进行N-酰化，然后用盐酸处理，得到头孢哌酮二盐酸盐一水合物。
• Crystalline dihydrate of a cephalosporin dihydrochloride salt and injectable compositions thereof
  申请人：Bristol-Myers Squibb Company

  公开号：EP0587121A1

  公开（公告）日：1994-03-16

  The present invention relates to a new crystalline dihydrochloride dihydrate salt of the cephalosporin antibiotic, cefepime. In particular, this invention provides a temperature and moisture stable crystalline dihydrochloride dihydrate form of cefepime having enhanced stability and a specific x-ray powder diffraction pattern as described herein. The present invention also provides physical admixtures of the new crystalline dihydrochloride dihydrate salt of cefepime with a pharmaceutically acceptable non-toxic organic or inorganic base. In particular, this invention provides physical admixtures of a temperature and moisture stable crystalline dihydrochloride dihydrate form of cefepime having a specific X-ray powder diffraction pattern as described herein with L(+) arginine.

  本发明涉及头孢菌素类抗生素头孢吡肟的一种新的结晶二盐酸盐二水合物。特别是，本发明提供了一种温度和湿度稳定的头孢吡肟二盐酸盐二水合物结晶形式，具有更高的稳定性和本文所述的特定 X 射线粉末衍射图样。本发明还提供了头孢吡肟的新型结晶二盐酸盐二水合物与药学上可接受的无毒有机或无机碱的物理混合物。特别是，本发明提供了具有本文所述特定 X 射线粉末衍射图样的头孢吡肟二盐酸盐二水合物晶体的温度和湿度稳定型与 L（+）精氨酸的物理混合物。