CN1861608A - 头孢呋辛酸的结晶性溶剂化物 - Google Patents

头孢呋辛酸的结晶性溶剂化物 Download PDF

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CN1861608A
CN1861608A CNA2006100825438A CN200610082543A CN1861608A CN 1861608 A CN1861608 A CN 1861608A CN A2006100825438 A CNA2006100825438 A CN A2006100825438A CN 200610082543 A CN200610082543 A CN 200610082543A CN 1861608 A CN1861608 A CN 1861608A
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solvate
cefuroxime acid
acetonitrile
crystalline
cefuroxime
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M·泽诺尼
A·G·卡塔尼奥
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ACS Dobfar SpA
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D501/14—Compounds having a nitrogen atom directly attached in position 7
    • C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
    • C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
    • C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
    • C07D501/26—Methylene radicals, substituted by oxygen atoms; Lactones thereof with the 2-carboxyl group
    • C07D501/34—Methylene radicals, substituted by oxygen atoms; Lactones thereof with the 2-carboxyl group with the 7-amino radical acylated by carboxylic acids containing hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D501/14—Compounds having a nitrogen atom directly attached in position 7
    • C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
    • C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
    • C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
    • C07D501/26—Methylene radicals, substituted by oxygen atoms; Lactones thereof with the 2-carboxyl group

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
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  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Communicable Diseases (AREA)
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  • Animal Behavior & Ethology (AREA)
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Abstract

头孢呋辛酸的结晶性溶剂化物，可用于制备抗生素的头孢呋辛钠盐。

Description

头孢呋辛酸的结晶性溶剂化物
头孢呋辛是一种重要的抗生素，其已经用于治疗革兰氏阴性细菌感染多年，并由下式表征：
Figure A20061008254300051
它可以作为钠盐通过静脉注射或肌肉注射给药。
上述的式(I)明显衍生于7-ACA核，其在化学合成过程中经受一系列的反应，所述反应修饰其3位和7位。
根据现有技术，前述的钠盐由从上述化学合成过程中分离出的中间体制备成可注射的无菌形式。按照逻辑上的假设，现有技术所用的中间体不是头孢呋辛酸，因为它非常不稳定，其程度可达在真空和+5℃的条件下放置30天后变成可见的有色。因此，迄今为止背景技术还没有使用非无菌的四氢呋喃溶剂化钠盐，例如US 4277601中实施例要求的，以及US 4775750中第1栏第51行提及的。将前述的中间体放进溶液，无菌过滤并再沉淀得到可注射的产品。
在工业实践中，生产大批量的在适宜条件下储藏的中间体再以小批量使用来生产无菌的钠盐是方便的。然而，据观察，四氢呋喃溶剂化钠盐的稳定性即使高于酸本身的稳定性，也不是很高，特别因为含水量通常≥2％，其不能以任何方式降低。因此，显而易见的是中间体无法长期储存而没有观察到影响终产物的收率和质量的着色和降解。
现在，本发明人令人惊奇地发现，用于制备抗生素头孢呋辛钠盐的溶剂化的头孢呋辛和实质上无水的头孢呋辛酸结晶性溶剂化物可以通过用乙腈处理后制得。已经证实，这种溶剂化物的稳定性大大高于四氢呋喃溶剂化钠盐的稳定性。
以这种方式，可以克服中间体的上述稳定性和着色问题，在最终的收率和质量方面具有明显的优点。除了上述的优点，还注意到，与如果同样分离头孢呋辛酸获得的收率相比，分离乙腈酸结晶性溶剂化物导致更高的收率：在这方面，对于相同的合成，就结晶性溶剂化物的活性而言，头孢呋辛酸的收率至少比同样分离的头孢呋辛酸的活性高5％。在任一情况下，通过已知方法，以与制备四氢呋喃溶剂化钠盐相似的方法，将头孢呋辛酸本身或其乙腈结晶性溶剂化物放入溶液，无菌过滤，再沉淀为钠盐。
实施例1
通过已知方式，由278g的7-ACA制得头孢呋辛酸的乙酸乙酯和二氯甲烷混合物的溶液。溶液在真空下浓缩至1100ml，冷却到+15℃，用1000ml的乙腈稀释。加入后，溶液在真空下进一步浓缩，再用1000ml的乙腈进一步稀释。
混合物在缓慢搅拌下冷却到+5℃，持续90分钟，得到头孢呋辛酸的乙腈溶剂化物的沉淀。过滤沉淀，用乙腈洗涤，得到430g的湿产物。在55℃的真空下干燥，得到350g干燥的溶剂化物，K.F.为0.2％，干基(dry basis)浓度为84.0％，乙腈的浓度为13.8％。
产品在室温下储藏，甚至在6个月后没有任何浓度损失和颜色变化。
通过ROGAKU DMAX II衍射仪测定样品产品的衍射光谱，操作条件是Cu-Kα(λ＝1.5405A°)40kV和40mA，基于反射光束的石墨单色仪，以每步长0.02度且每步长1秒进行扫描。
光谱如所附的图1所示，同时下表给出数据：
对阴极：Cu-Kα电压：40kV角：(2-θ)     过滤器：镍电流：40mA相对强度
    6.437.788.909.5411.7812.7913.9615.4816.1717.8418.3918.6819.2419.5720.8721.9422.5022.7322.8323.2624.2224.7825.1225.6126.1726.8426.8027.3427.5028.2328.6428.7928.9929.3429.9730.9431.8332.2032.6233.2833.9433.9534.0834.3635.0935.6437.5338.13     9.5259.465.9449.1945.7321.5148.337.6112.235.8217.887.6124.6831.3120.0739.5617.3017.8216.38100.0013.7820.0115.3427.289.059.118.658.828.3613.907.678.656.407.7923.0712.238.946.9811.536.466.116.526.346.008.256.577.617.96
  38.3038.4538.7639.6140.0740.4740.6440.7841.0041.1942.2346.73     8.077.047.095.829.986.756.067.445.946.117.215.82
。

Claims (3)

1、式(II)的头孢呋辛酸的结晶性溶剂化物：
含有10-16％的乙腈，K.F.为0.2％，干基浓度≤80.0％。
2、根据权利要求1所要求的头孢呋辛酸的结晶性溶剂化物，其特征在于具有下述特征的Xr衍射光谱的结晶结构：   对阴极：Cu-Kα电压：40kV角：(2-θ)   过滤器：镍电流：40mA相对强度   6.437.788.909.5411.7812.7913.9615.4816.1717.8418.3918.6819.2419.5720.8721.94   9.5259.465.9449.1945.7321.5148.337.6112.235.8217.887.6124.6831.3120.0739.56
  22.5022.7322.8323.2624.2224.7825.1225.6126.1726.8426.8027.3427.5028.2328.6428.7928.9929.3429.9730.9431.8332.2032.6233.2833.9433.9534.0834.3635.0935.6437.5338.1338.3038.4538.7639.6140.0740.4740.6440.7841.0041.1942.2346.73   17.3017.8216.38100.0013.7820.0115.3427.289.059.118.658.828.3613.907.678.656.407.7923.0712.238.946.9811.536.466.116.526.346.008.256.577.617.968.077.047.095.829.986.756.067.445.946.117.215.82
3、制备权利要求1所要求的头孢呋辛溶剂化物的方法，其特征在于用乙腈稀释头孢呋辛酸的有机溶剂混合物溶液，所述溶剂混合物至少含乙酸乙酯和二氯甲烷两种溶剂中的一种，然后在真空下浓缩并冷却至0℃-10℃以沉淀该溶剂化物，将其过滤分离，用乙腈洗涤并在低于60℃的真空下干燥。
CNA2006100825438A 2005-05-13 2006-04-28 头孢呋辛酸的结晶性溶剂化物 Pending CN1861608A (zh)

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AT (1) ATE387456T1 (zh)
DE (1) DE602006000578D1 (zh)
ES (1) ES2299144T3 (zh)
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102746323A (zh) * 2012-06-26 2012-10-24 天津大学 一种头孢呋辛酸的新晶型及其结晶制备方法
CN112480146A (zh) * 2020-10-30 2021-03-12 浙江惠迪森药业有限公司 一种头孢呋辛酸混合溶剂化物、晶型及制备方法

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* Cited by examiner, † Cited by third party
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US3985741A (en) * 1972-09-15 1976-10-12 Bristol-Myers Company Production of p-hydroxycephalexin
ZA80844B (en) 1979-02-15 1981-08-26 Glaxo Group Ltd Preparation of sodium cefuroxime
IN190849B (zh) * 2000-07-17 2003-08-23 Ranbaxy Lab Ltd
AT411996B (de) 2000-09-11 2004-08-26 Sandoz Ag Verfahren zur herstellung von cefuroxim in der form seines n-butylammoniumsalzes
US20040092735A1 (en) 2002-11-08 2004-05-13 Orchid Chemicals & Pharmaceuticals Limited Process for the preparation of cefuroxime sodium

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102746323A (zh) * 2012-06-26 2012-10-24 天津大学 一种头孢呋辛酸的新晶型及其结晶制备方法
CN102746323B (zh) * 2012-06-26 2014-05-07 天津大学 一种头孢呋辛酸的新晶型及其结晶制备方法
CN112480146A (zh) * 2020-10-30 2021-03-12 浙江惠迪森药业有限公司 一种头孢呋辛酸混合溶剂化物、晶型及制备方法

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EP1724273A1 (en) 2006-11-22
ES2299144T3 (es) 2008-05-16
KR20060117199A (ko) 2006-11-16
PT1724273E (pt) 2008-04-22
EP1724273B1 (en) 2008-02-27
KR101310618B1 (ko) 2013-09-24
ATE387456T1 (de) 2008-03-15
US20060258636A1 (en) 2006-11-16
US7615631B2 (en) 2009-11-10

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