CN1639169A - 改进的头孢噻夫中间体合成 - Google Patents
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Classifications
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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
- C07D501/18—7-Aminocephalosporanic or substituted 7-aminocephalosporanic acids
-
- 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Cephalosporin Compounds (AREA)
- Steroid Compounds (AREA)
Abstract
本发明涉及通过7－氨基头孢烷酸(II)与呋喃基－2－羰基硫醇(III)在三氟化硼或其复合物的存在下，于0－50℃下，在一种有机溶剂或溶剂混合物中缩合而制备7－氨基－3－[2－(呋喃基羰基)硫甲基]－3－头孢烯－4－羧酸(I)的方法。
Description
技术领域
本发明公开了使用三氟化硼或其复合物作为缩合剂，通过式(II)表示的7-氨基头孢烷酸(7-amino cephalosporanic acid，7-ACA)与式(III)表示的呋喃基-2-羰基硫醇缩合而制备式(I)表示的7-氨基-3-[2-(呋喃基羰基)硫甲基]-3-头孢烯(cephem)-4-羧酸的改进方法。
背景技术
头孢噻夫是式(IV)的化合物的通用名
美国专利4,464,367首次报道了头孢噻夫酸，其碱金属盐、碱土金属盐和铵盐。头孢噻夫是7-ACA与呋喃基-2-羰基硫醇和2-(2-氨基噻唑-4-基)-2-甲氧基亚氨基)乙酸分别在3位和7位缩合的产物。式(I)表示的7-氨基-3-[2-(呋喃基羰基)硫甲基]-3-头孢烯-4-羧酸是关键的中间体，它决定制备头孢噻呋的方法的质量和总收率。
令我们意外的是，在文献中报道的式(I)的7-氨基-3-[2-(呋喃基羰基)硫甲基]-3-头孢烯-4-羧酸的合成方法非常少。该中间体的合成的首次报道出现于美国专利4,464,367，其中用于缩合的方法取自于参考文献Journal of Antibiotics 27，573-8，(1974)。这些参考文献是关于使用磷酸盐缓冲液，在pH6.4下进行的缩合。按照该方法的反应时间很长，并且报道的反应收率为47％。这些限制使该方法不利于商业开发。
WO专利87/01117公开了另一种方法，该专利也仅是先前提到的专利的延伸。缩合通过噻吩钠和7-ACA于65℃和pH为6.4下在含水介质中反应而实现。已知头孢菌素在高温下分解，而且使用该方法，反应不完全，收率也非常低(约45％，而且反应时间也较长，例如，即使数小时后反应也不完全)。
考虑到这些问题，美国专利5,387,679报道了在非水条件下缩合的方法，其中7-ACA与杂环硫醇在三氟化硼与碳酸二烷基酯的复合物的存在下进行缩合，提供用于头孢菌素类抗生素合成的中间体。当该方法应用于7-ACA和呋喃基-2-羰基硫醇的缩合时，反应混合物与几种杂质缔合，其即使在最后的纯化步骤中也无法得到分离。后来，在几次实验之后，我们发现固体形式的呋喃基-2-羰基硫醇的稳定性不好，因为呋喃基-2-羰基硫醇属于杂环硫羰酸而不是杂环硫醇类。硫羰酸的反应行为与硫醇不相似，因此不能将美国专利5,387,679的条件用于本发明。
为了解决该问题，本申请的申请人首次提供缩合7-ACA与呋喃基-2-羰基硫醇以获得式(I)的化合物的方法，所述呋喃基-2-羰基硫醇在气态三氟化硼或其在有机溶剂中的溶液的存在下产生并原位使用。该方法以极好的收率(90-95％)和高纯度(98-99％)给出期望的式(I)的化合物。
发明目的
本发明的首要目的是提供一种改进的和商业上可行的制备作为头孢噻呋中间体的式(I)表示的7-氨基-3-[2-(呋喃基羰基)硫甲基]-3-头孢烯-4-羧酸的方法。
本发明的另一目的是不分离之而原位使用呋喃基-2-羰基硫醇。
本发明的再一目的是提供给出高产品收率和极好的产品纯度的方法。
本发明的又一目的是提供气态三氟化硼或其在有机溶剂中的溶液或三氟化硼复合物于低温下用于进行缩合反应的用途，其便于商业生产。
发明内容
因此，本发明提供通过7-氨基头孢烷酸(II)与呋喃基-2-羰基硫醇(III)在三氟化硼或其复合物的存在下，于0-50℃下，在一种有机溶剂或溶剂混合物中缩合而制备7-氨基-3-[2-(呋喃基羰基)硫甲基]-3-头孢烯-4-羧酸(I)的方法。
反应顺序如下所示：
具体实施方式
在一个实施方案中，用于缩合的有机溶剂选自四氢呋喃、乙酸甲酯、乙酸乙酯、乙酸正丙酯、乙酸异丙酯、乙酸正丁酯、二氯甲烷、甲苯、乙醚、二异丙醚、乙腈、乙酸或它们的混合物。
在另一个实施方案中，在诸如乙腈、乙酸乙酯和其他相容的溶剂中使用气态三氟化硼，以及其与乙醚的复合物。1.0mol的7-ACA使用4-8mol当量的三氟化硼。
在另一个实施方案中，反应优选在30-40℃的温度范围进行。通过测定反应混合物中7-ACA的含量来监测反应的完成。7-ACA的含量应低于1％。在3-5小时内，7-ACA的含量达到低于1％。在反应完成后，将物料(mass)倾入水中，通过添加碱将pH调节至3-4。使用的碱选自氨水、氢氧化铵、氢氧化钠、碳酸钠、三乙胺、三丁基胺。将固体产物过滤并用溶剂和水混合物洗涤。所用的溶剂选自四氢呋喃基、乙酸甲酯、乙酸乙酯、乙酸正丙酯、乙酸异丙酯、乙酸正丁酯、二氯甲烷、甲苯、乙醚、二异丙醚、乙腈、乙酸或它们的混合物。
在再一个实施方案中，提供了使用由上述方法制备的式(I)表示的3-[2-(呋喃基羰基)硫甲基]-3-头孢烯-4-羧酸通过常规方法制备头孢噻夫的方法。
在又一个实施方案中，由呋喃基-2-羰酰氯/硫化钠或呋喃基-2-羰酰氯/硫氢化钠原位制备呋喃基-2-羰基硫醇。
用下列实施例说明本发明，这些实施例只是说明性的，不应被解释为限制本发明的范围。
实施例-I
7-氨基-3-(2-呋喃基羰基)硫甲基]-3-头孢烯-4-羧酸
将硫化钠(54.6g)添加到水(600ml)中，于20℃的温度下，在1.0小时内加入呋喃基-2-羰酰氯(50.0g)。向其中加入乙酸乙酯，用盐酸将物料的pH调节至1.0。将有机层分离，用无水硫酸钠干燥，过滤，得到在乙酸乙酯中的呋喃基-2-羰基硫醇。
在另一个烧瓶中添加乙酸乙酯(350ml)，向其中通入三氟化硼气体(124.0g)。于10.0℃下将7-氨基-头孢烷酸(91.0g)加入该三氟化硼溶液中，随后加入呋喃基-2-羰基硫醇在乙酸乙酯中的溶液(以上制备的)。于30-40℃下搅拌4-5小时之后，反应完成。在反应完成后，将混合物倾入冰冷水中。加氨水将溶液的pH调节至3.45-3.55。将沉淀的固体过滤并用乙酸乙酯混合物洗涤，得到7-氨基-3-(2-呋喃基羰基)硫甲基]-3-头孢烯-4-羧酸(110.0g)，其HPLC纯度为98-99％。
实施例-II
7-氨基-3-(2-呋喃基羰基)硫甲基]-3-头孢烯-4-羧酸
将硫化钠(36.4g)添加到水(400ml)中，于20℃的温度下，在1.0小时内加入呋喃基-2-羰酰氯(33.3.0g)。向其中加入乙酸乙酯，用盐酸将物料的pH调节至1.0。将有机层分离，用无水硫酸钠干燥，过滤，得到在乙酸乙酯中的呋喃基-2-羰基硫醇。
在另一个含有乙腈(350ml)的烧瓶中通入三氟化硼气体(85.0g)。于10.0℃下将7-氨基-头孢烷酸(60.6g)加入该三氟化硼溶液中，随后加入呋喃基-2-羰基硫醇在乙酸乙酯中的溶液(以上制备的)。于30-40℃下搅拌4-5小时之后，反应完成。在反应完成后，将物料倾入冰冷水中。加氨水将溶液的pH调节至3.45-3.55。将沉淀的固体过滤并用水和乙腈的混合物洗涤，得到7-氨基-3-(2-呋喃基羰基)硫甲基]-3-头孢烯-4-羧酸(69.0g)，其HPLC纯度为97-98％。
实施例-III
7-氨基-3-(2-呋喃基羰基)硫甲基]-3-头孢烯-4-羧酸
将硫化钠(54.6g)添加到水(600ml)中，于20℃的温度下，在1.0小时内加入呋喃基-2-羰酰氯(50.0g)。向其中加入乙酸乙酯，用盐酸将物料的pH调节至1.0。将有机层分离，用无水硫酸钠干燥，过滤，得到在乙酸乙酯中的呋喃基-2-羰基硫醇。
于室温下向另一个含有乙腈(350ml)的烧瓶中加入7-氨基-头孢烷酸(91.0g)，随后于10.0℃下加入45-48％醚合三氟化硼(275.5ml)。向其中加入呋喃基-2-羰基硫醇在乙酸乙酯中的溶液(以上制备的)。于40-50℃下搅拌4-5小时之后，反应完成。在反应完成后，将反应混合物倾入冰冷水中。加碳酸钠溶液将溶液的pH调节至3.45-3.55。将沉淀的固体过滤并用水和乙酸乙酯的混合物洗涤，得到7-氨基-3-(2-呋喃基羰基硫甲基]-3-头孢烯-4-羧酸(104.0g)，其HPLC纯度为97-98％。
实施例-IV
7-氨基-3-(2-呋喃基羰基)硫甲基]-3-头孢烯-4-羧酸
于18-25℃下将30.0g硫氢化钠溶解在350ml水中。于18-25℃下，在40-45分钟内缓慢加入27.5g 2-呋喃甲酰氯，并在相同温度下搅拌10分钟。加入乙酸乙酯(250ml)，用盐酸将反应物料的pH保持在1.0以下。将有机层分离，加入水(175ml)，用碳酸氢钠(19g)将pH调节至7.0-7.5。将水层分离并加入乙酸乙酯(100ml)。用盐酸将pH调节至0.9-1.0并搅拌15分钟，分离有机层。
在另一个烧瓶中加入200ml乙酸乙酯并冷却至0℃。向其中通入68.5g三氟化硼气体。向反应物料中加入EDTA(1.0g)，将温度升至15℃，并搅拌10min。于10℃下向该三氟化硼溶液中加入50.0g 7-氨基头孢烷酸，随后再加入呋喃基-2-羰基硫醇在乙酸乙酯中的溶液(先前制备的)。于30-40℃下搅拌3-4小时后，反应完成。然后将混合物冷却至15℃，加入285ml冷水，随后添加新制备的在50ml水中的1g偏亚硫酸氢钠和在50ml水中的0.3g EDTA二钠。加氨水将溶液的pH调节至3.45-3.55。将沉淀的固体过滤，并用乙酸乙酯(50ml)洗涤，得到7-氨基-3-(2-呋喃基羰基)硫甲基]-3-头孢烯-4-羧酸，其HPLC纯度为98-99％。
Claims (4)
1.通过7-氨基头孢烷酸(II)与呋喃基-2-羰基硫醇(III)在三氟化硼或其复合物的存在下，于0-50℃下，在一种有机溶剂或溶剂混合物中缩合而制备式(I)表示的3-[2-(呋喃基羰基)硫甲基]-3-头孢烯-4-羧酸的方法
2.根据权利要求1所述的方法，其中进行缩合反应使用的有机溶剂选自四氢呋喃、乙酸甲酯、乙酸乙酯、乙酸正丙酯、乙酸异丙酯、乙酸正丁酯、二氯甲烷、甲苯、乙醚、二异丙醚、乙腈或它们的混合物。
3.根据权利要求1所述的方法，其中三氟化硼复合物是醚合三氟化硼。
4.使用由前述权利要求之任一项所述的方法制备的式(I)表示的3-[2-(呋喃基羰基)硫甲基]-3-头孢烯-4-羧酸制备头孢噻夫的方法。
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| US10/035,178 | 2002-01-04 | ||
| US10/035,178 US20030135041A1 (en) | 2002-01-04 | 2002-01-04 | Synthesis of ceftiofur intermediate |
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| KR (1) | KR100847339B1 (zh) |
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| AT (1) | ATE294183T1 (zh) |
| AU (1) | AU2002367103A1 (zh) |
| BR (1) | BR0215473A (zh) |
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| DE (1) | DE60203944T2 (zh) |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102234289A (zh) * | 2010-05-02 | 2011-11-09 | 青岛科技大学 | 一种头孢噻呋中间体新的制备方法 |
| CN103804394A (zh) * | 2014-01-24 | 2014-05-21 | 瑞普（天津）生物药业有限公司 | 一种头孢噻呋中间体的制备方法 |
| CN108623617A (zh) * | 2017-03-22 | 2018-10-09 | 蒋辉 | 一种头孢噻呋中间体的制备方法 |
| CN114409676A (zh) * | 2021-12-24 | 2022-04-29 | 河南立诺制药有限公司 | 一种7-acf的制备方法 |
| CN116535421A (zh) * | 2023-07-04 | 2023-08-04 | 齐鲁晟华制药有限公司 | 头孢噻呋钠的合成方法 |
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| KR100502390B1 (ko) * | 2001-09-07 | 2005-07-19 | 주식회사 엘지생명과학 | 세팔로스포린산 유도체의 제조방법 |
| CA2503885A1 (en) * | 2002-10-29 | 2004-05-13 | Lupin Limited | A method for manufacture of ceftiofur |
| US8470809B2 (en) * | 2005-10-12 | 2013-06-25 | Orchid Chemicals & Pharmaceuticals Limited | Crystalline sodium salt of cephalosporin antibiotic |
| US8212024B2 (en) * | 2005-10-12 | 2012-07-03 | Orchid Chemicals & Pharmaceuticals Ltd. | Crystalline sodium salt of cephalosporin antibiotic |
| WO2010020871A2 (en) * | 2008-08-22 | 2010-02-25 | Orchid Chemicals & Pharmaceuticals Limited | Crystalline sodium salt of cephalosporin antibiotic |
| CN112645965B (zh) * | 2020-12-22 | 2022-03-25 | 浙江华尔成生物药业股份有限公司 | 一种真空冻干注射用头孢噻呋钠的制备工艺 |
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| GB1565941A (en) * | 1977-02-08 | 1980-04-23 | Toyama Chemical Co Ltd | Process for producing 7-(substituted)amino-3-substituted thiomethyl cephem carboxylic acids |
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| FR2472574A1 (fr) | 1979-12-24 | 1981-07-03 | Ici Pharma | Derives de cephalosporine et composition pharmaceutique les contenant |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102234289A (zh) * | 2010-05-02 | 2011-11-09 | 青岛科技大学 | 一种头孢噻呋中间体新的制备方法 |
| CN102234289B (zh) * | 2010-05-02 | 2013-07-10 | 青岛科技大学 | 一种头孢噻呋中间体新的制备方法 |
| CN103804394A (zh) * | 2014-01-24 | 2014-05-21 | 瑞普（天津）生物药业有限公司 | 一种头孢噻呋中间体的制备方法 |
| CN108623617A (zh) * | 2017-03-22 | 2018-10-09 | 蒋辉 | 一种头孢噻呋中间体的制备方法 |
| CN108623617B (zh) * | 2017-03-22 | 2021-04-02 | 蒋辉 | 一种头孢噻呋中间体的制备方法 |
| CN114409676A (zh) * | 2021-12-24 | 2022-04-29 | 河南立诺制药有限公司 | 一种7-acf的制备方法 |
| CN116535421A (zh) * | 2023-07-04 | 2023-08-04 | 齐鲁晟华制药有限公司 | 头孢噻呋钠的合成方法 |
Also Published As
| Publication number | Publication date |
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| ES2242044T3 (es) | 2005-11-01 |
| CA2471310C (en) | 2011-02-22 |
| WO2003055893A1 (en) | 2003-07-10 |
| KR100847339B1 (ko) | 2008-07-21 |
| CN1310923C (zh) | 2007-04-18 |
| AU2002367103A1 (en) | 2003-07-15 |
| DE60203944T2 (de) | 2006-02-23 |
| US20030135041A1 (en) | 2003-07-17 |
| DE60203944D1 (de) | 2005-06-02 |
| CA2471310A1 (en) | 2003-07-10 |
| US6803461B2 (en) | 2004-10-12 |
| EP1463734A1 (en) | 2004-10-06 |
| BR0215473A (pt) | 2004-11-30 |
| ATE294183T1 (de) | 2005-05-15 |
| EP1463734B1 (en) | 2005-04-27 |
| US20030130502A1 (en) | 2003-07-10 |
| KR20040098628A (ko) | 2004-11-20 |
| MXPA04006587A (es) | 2005-07-13 |
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