CN1042535C - 在酶催酰化反应后分离头孢克罗的改进方法 - Google Patents
在酶催酰化反应后分离头孢克罗的改进方法 Download PDFInfo
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- 238000002955 isolation Methods 0.000 title abstract 2
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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
-
- 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
- C07D501/02—Preparation
- C07D501/12—Separation; Purification
-
- 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Cephalosporin Compounds (AREA)
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明提供了一种通过把蒽醌-1，5-二磺酸加到酰化反应混合物中以从该酰化反应混合物中分离头孢克罗的方法。该酸与头孢克罗高选择性地形成沉淀，所以简化了分离和回收步骤。
Description
发明领域
本发明涉及由酶催酰化反应混合物中分离头孢克罗的工业便利方法，其是通过使头孢克罗与蒽醌二磺酸以2∶1盐的形式从混合物中沉淀出来。
发明背景
在美国专利3,816,253中公开了一种通过将氨基酸衍生物与7-氨基头孢菌素核缩合制备头孢菌素类化合物的酶催方法。在美国专利申请号07/874,257(1992年4月24日提交)(X-8505)中公开了一种制备头孢菌素类的改进的酶催方法，特别涉及的是将相应的7-氨基头孢菌素核与氨基酸缩合制备头孢菌素的改进的酶催方法。迄今，在这种酶催酰化反应之后，有价值的化合物，即头孢克罗是处于复杂的环境中，该环境中不仅含有头孢菌素核而且含有苯基甘氨酸、D-苯基甘氨酸甲酯及其盐。根据这种混合物的复杂性，采用了一系列分离柱来分离头孢克罗，当然，这既造成产物损失也花费时间。
由以上看出，在本技术领域中需要的是从复杂的酰化反应混合物中选择性分离头孢克罗的方法。本发明概述
现已发现通过将酶催酰化反应混合物用蒽醌-1,5-二磺酸或其碱金属盐处理，可以从该酶催酰化反应混合物中选择性分离头孢克罗或其盐，该酶催酰化反应混合物包括头孢菌素核、苯基甘氨酸和D-苯基甘氨酸甲酯和其盐。当蒽醌二磺酸与以上所列的其他化合物形成盐的同时，该酸的加入选择性地从酶催反应混合物中沉淀出头孢克罗与蒽醌-1,5-二磺酸生成的2∶1的盐，这样就提供了一种有效的、花时间少的从酶催酰化反应混合物中分离头孢克罗的方法。令人惊奇的是，从该混合物中沉淀出头孢克罗/酸盐具有高的选择性。在1989年11月15日公开的欧洲专利申请341,991中描述了头孢克罗/酸盐本身。
本发明的描述
本发明的方法可用于分离下式(Ⅰ)的头孢克罗或其盐：
该酶催方法按流程Ⅰ所概括的方式进行：
用于该酶催方法中的酰基转移酶可以从任何已知的微生物源衍生得到，其中，有如下的微生物：黄单胞菌属(Xanthomonas)、假单胞菌属(Pseudomonas)、气单胞菌属(Aeromonas)、埃希氏杆菌属(Escherichia)、节细菌属(Arthrobacter)、棒状杆菌属(Corynebacterium)和杆菌属(Bacillus genera)。优选的是使用从大肠埃希氏杆菌(EscherichiaColi)ATCC 9637衍生得到的青霉素酰基转移酶。
酶催酰化反应和其后的分离是在一个含水的体系中进行的。然而，可以使用适宜的有机溶剂，它们包括乙二醇、低级醇(例如甲醇、乙醇、异丙醇、2-丁醇)、丙酮等。酶催酰化反应可以在本技术领域中所述的温度下进行，其后的沉淀/分离步骤可以在约0°-约25℃的温度下进行，优选的温度范围是0°-10℃。
以每摩尔待分离的头孢克罗需要约0.5摩尔-约2摩尔的量将蒽醌-1,5-二磺酸加入到酰化反应混合物中。该酸的优选摩尔用量是每摩尔待分离的头孢克罗需要0.5-0.7摩尔。该酸可以是碱金属盐(钠或钾)的形式。
沉淀/分离步骤可以在pH约1.0-约4.0的条件下进行，优选的pH范围为约1.3-约1.7。该pH可以通过加入适宜的酸如盐酸和/或碱如三乙胺来控制。
在头孢克罗/酸盐分离之后，可以用已知方法形成头孢克罗-水合物。例如，可以将该盐溶解在DMF/水混合物中，该混合物的pH可以提高到约5.7，从中结晶出头孢克罗DMF溶剂化物。然后，可将该DMF溶剂化物加入低pH(0.5-1.0)的水中，以溶解该混合物，在pH 3.5时头孢克罗-水合物从中结晶出来。
下面举例说明本发明。
制备例1
7-(D-2-铵-2-苯基乙酰氨基)-3-氯-3-
头孢烯-4-羧酸盐，内盐
在烧杯中，将7-ACCA(1)(0.9388g,4.0007m mol)和96.0ml水混合，pH是4.12。将3mol NH3(1.78ml)加到该烧杯中，pH是7.57。将D-苯基甘氨酸甲酯盐酸盐(2)(4.7594g,23.602m mol)加到该烧杯中，pH是5.68。把该混合物冷却到5℃，向该混合物中加入3mol NH3(1.90ml)使pH升到7.00。加入酶(6.1442g,940 IU/g的核)。由HPLC分析，得到下面的反应速度数据：
| 时间(分钟) | pH | 温度(℃) | 化合物1剩余的％ | 化合物2剩余的％ | 化合物3形成的％ |
| 085120180200 | 7.006.286.165.975.91 | 6544.54.5 | 1009.29.18.98.8 | 10067.164.363.765.3 | -91.491.591.893.0 |
在时间=200分钟时，过滤该混合物(除去固定化酶)，就地得产率为93％的标题产物。
实施例1
7-(D-2-铵-2-苯基乙酰氨基)-3-氯-3-
头孢烯-4-羧酸盐，内盐
A．酰化反应
(1)将7-ACCA(1)(4.8338g,20m mol)和150ml水在烧杯中混合，pH是3.67。把3mol NH3(8.40ml)加入该烧杯中，pH是8.20。把D-苯基甘氨酸甲酯盐酸盐(2)(23.0g,114m mol)加到该烧杯中，pH是5.29。用白色硅藻土载体过滤器(hyflofilter)过滤该混合物，并用10.0ml水洗涤。该混合物的体积是310ml。将该混合物转移到较大的烧杯中，并用5ml水冲洗。把该混合物冷却到1℃，向该混合物中加入3mol NH3(16.6ml)，使pH升到7.28。加入酶(15,34g,500IU/g的核)。145分钟后过滤该反应混合物除去酶，就地得到(3)的产率是89.8％。
B．分离
将该反应混合物冷却到5℃，其pH是6.65。把蒽醌-1,5-二磺酸2Na(纯度72.3％,10m mol)加入，并搅拌该混合物5分钟，该混合物的温度是4℃,pH是6.72。加浓盐酸(2.3ml)使pH为2.4，并用头孢克罗/蒽醌-1,5-二磺酸盐接种该混合物，再搅拌该混合物2分钟，其pH是3.3。加入浓盐酸(3.9ml)，混合物的pH是1.5，再搅拌该混合物30分钟，混合物的温度是1℃,pH是1.4。过滤出该固体沉淀物并用75ml水洗涤，然后用50ml丙酮洗涤。滤液中含有苯基甘氨酸和化合物(1)和(2)。该沉淀物即(3)和蒽醌-1,5-二磺酸的2∶1盐含就地产生的(3)量为99.8％。
实施例2
以DMF溶剂化物形式的头孢克罗的分离
把头孢克罗/蒽醌-1,5-二磺酸盐(11.06/18.5m mol)放入250ml烧杯中，并加123ml为85/15的DMF/水溶液，其pH是3.85。用头孢克罗/酸盐接种该混合物，并在15分钟内加入三乙胺，使pH约为5.7。把该混合物冷却到18℃，加入三乙胺，搅拌混合物，温度保持在约20℃。过滤混合物，用35ml为85/15的DMF/水溶液洗涤固体，然后用20ml丙酮洗涤，接着在30℃真空下干燥该固体。
实施例3
头孢克罗一水合物的形成
把实施例2的头孢克罗溶剂化物加到含有39ml水、0.07g乙二胺四乙酸钠的1.88ml浓盐酸的溶液中，该溶液预先被冷却到15-20℃的温度。加入浓盐酸，接着加入三乙胺。用头孢克罗-水合物接种该混合物并搅拌。如果需要，加入三乙胺，把混合物冷却到0-5℃并搅拌。然后过滤混合物，并用20ml冷水洗涤固体，在通风橱中，使该固体经空气干燥，得到头孢克罗一水合物。
Claims (6)
1．一种从包括下式的化合物、苯基甘氨酸或其盐和D-苯基甘氨酸甲酯或其盐的酰化反应混合物中分离头孢克罗或其盐的方法，该方法包括把蒽醌-1,5-二磺酸或其碱金属盐加到所述混合物中以形成2∶1头孢克罗/蒽醌-1,5-二磺酸盐的步骤，
2．如权利要求1所述的方法，其中所述的蒽醌-1,5-二磺酸的加入量为每摩尔头孢克罗需要0.5mol-2mol。
3．如权利要求1所述的方法，其中加入步骤是在pH为1.0-4.0，温度为0°-25℃的条件下进行的。
4．如权利要求1所述的方法，还包括分离所述的头孢克罗/蒽醌二磺酸盐的步骤。
5．如权利要求2所述的方法，其中酸的加入量为每摩尔头孢克罗需要0.5-0.7mol。
6．如权利要求3所述的方法，其中pH为1.3-1.7，温度为0°-10℃。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US08/014,015 | 1993-02-05 | ||
| US08/014,015 US5434259A (en) | 1993-02-05 | 1993-02-05 | Process for isolation of cefaclor after enzymatic acylation |
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| Publication Number | Publication Date |
|---|---|
| CN1119439A CN1119439A (zh) | 1996-03-27 |
| CN1042535C true CN1042535C (zh) | 1999-03-17 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN94191513A Expired - Fee Related CN1042535C (zh) | 1993-02-05 | 1994-02-07 | 在酶催酰化反应后分离头孢克罗的改进方法 |
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| Country | Link |
|---|---|
| US (1) | US5434259A (zh) |
| EP (1) | EP0682669A4 (zh) |
| JP (1) | JPH08506814A (zh) |
| KR (1) | KR960701062A (zh) |
| CN (1) | CN1042535C (zh) |
| AU (1) | AU679209B2 (zh) |
| BR (1) | BR9405684A (zh) |
| CA (1) | CA2155530A1 (zh) |
| CZ (1) | CZ285380B6 (zh) |
| FI (1) | FI953728A (zh) |
| HU (1) | HU219601B (zh) |
| NO (1) | NO953060L (zh) |
| NZ (1) | NZ262290A (zh) |
| PL (1) | PL174952B1 (zh) |
| RU (1) | RU2126411C1 (zh) |
| UA (1) | UA41910C2 (zh) |
| WO (1) | WO1994018209A1 (zh) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006117616A1 (en) * | 2005-05-03 | 2006-11-09 | Ranbaxy Laboratories Limited | Polymorphic form i of lumefantrine and processes for its preparation |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111057072A (zh) * | 2019-12-16 | 2020-04-24 | 广州维奥康药业科技有限公司 | 一种头孢克洛杂质去除方法 |
| CN112574233A (zh) * | 2020-12-30 | 2021-03-30 | 苏州盛达药业有限公司 | 头孢克洛原料药 |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3676434A (en) * | 1970-07-29 | 1972-07-11 | Lilly Co Eli | Cephalosporin salts |
| JPS5548797B1 (zh) * | 1971-04-02 | 1980-12-08 | ||
| EP0341991A3 (en) * | 1988-05-13 | 1991-08-28 | Eli Lilly And Company | Method for recovery of antibiotics from mother liquors and novel pharmaceutically-acceptable salts thereof |
-
1993
- 1993-02-05 US US08/014,015 patent/US5434259A/en not_active Expired - Fee Related
-
1994
- 1994-02-07 AU AU61717/94A patent/AU679209B2/en not_active Ceased
- 1994-02-07 KR KR1019950703233A patent/KR960701062A/ko active IP Right Grant
- 1994-02-07 PL PL94310113A patent/PL174952B1/pl unknown
- 1994-02-07 WO PCT/US1994/001375 patent/WO1994018209A1/en not_active Application Discontinuation
- 1994-02-07 EP EP94908733A patent/EP0682669A4/en not_active Ceased
- 1994-02-07 CZ CZ952006A patent/CZ285380B6/cs not_active IP Right Cessation
- 1994-02-07 CA CA002155530A patent/CA2155530A1/en not_active Abandoned
- 1994-02-07 UA UA95083663A patent/UA41910C2/uk unknown
- 1994-02-07 BR BR9405684A patent/BR9405684A/pt not_active Application Discontinuation
- 1994-02-07 NZ NZ262290A patent/NZ262290A/en unknown
- 1994-02-07 CN CN94191513A patent/CN1042535C/zh not_active Expired - Fee Related
- 1994-02-07 RU RU95118294A patent/RU2126411C1/ru active
- 1994-02-07 HU HU9502321A patent/HU219601B/hu not_active IP Right Cessation
- 1994-02-07 JP JP6518295A patent/JPH08506814A/ja not_active Ceased
-
1995
- 1995-08-03 NO NO953060A patent/NO953060L/no not_active Application Discontinuation
- 1995-08-04 FI FI953728A patent/FI953728A/fi unknown
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006117616A1 (en) * | 2005-05-03 | 2006-11-09 | Ranbaxy Laboratories Limited | Polymorphic form i of lumefantrine and processes for its preparation |
Also Published As
| Publication number | Publication date |
|---|---|
| BR9405684A (pt) | 1995-11-21 |
| CZ9502006A3 (en) | 1995-12-13 |
| KR960701062A (ko) | 1996-02-24 |
| AU679209B2 (en) | 1997-06-26 |
| US5434259A (en) | 1995-07-18 |
| JPH08506814A (ja) | 1996-07-23 |
| WO1994018209A1 (en) | 1994-08-18 |
| PL174952B1 (pl) | 1998-10-30 |
| EP0682669A1 (en) | 1995-11-22 |
| NO953060D0 (no) | 1995-08-03 |
| CA2155530A1 (en) | 1994-08-18 |
| HU219601B (hu) | 2001-05-28 |
| FI953728A (fi) | 1995-09-12 |
| NO953060L (no) | 1995-08-03 |
| CN1119439A (zh) | 1996-03-27 |
| PL310113A1 (en) | 1995-11-27 |
| EP0682669A4 (en) | 1996-04-10 |
| AU6171794A (en) | 1994-08-29 |
| NZ262290A (en) | 1998-08-26 |
| CZ285380B6 (cs) | 1999-07-14 |
| FI953728A0 (fi) | 1995-08-04 |
| RU2126411C1 (ru) | 1999-02-20 |
| UA41910C2 (uk) | 2001-10-15 |
| HUT72402A (en) | 1996-04-29 |
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