CN1522255A - 结晶亚胺培南的分离方法 - Google Patents
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Abstract
本发明涉及制备高纯度亚胺培南的方法，该方法费用低且在工业上是有利的。
Description
发明领域
本发明涉及制备高纯度亚胺培南的方法，该方法费用低且在工业上是有利的。
发明背景
亚胺培南一水合物是沙纳霉素的N-亚胺甲基衍生物，具有结构式I所示的结构。
式I
这是第一个在临床上可用的一类新的具有碳青霉烯环系统的β-内酰胺抗生素。亚胺培南对革兰氏阳性和革兰氏阴性好氧菌和厌氧菌有非常广的抗菌活性，这部分是由于它对β-内酰胺酶的高稳定性。
亚胺培南首先揭示在美国专利4,194,047中，它是通过冻干技术获得的。用冻干法获得的产品大部份是无定形的且是热力学不稳定的。该方法还包括用疏水树脂通过柱层析进行初步纯化。
美国专利4,260,543揭示了热力学稳定的晶体一水合物形式的亚胺培南，它是通过将冻干的亚胺培南样品结晶获得的。然而，该方法在商业领域不尽如人意，因为它需要通过柱层析、冻干再结晶以分离产品。此外，分离最终产物的冗长过程会导致亚胺培南降解，从而影响产品的纯度。
美国专利4,292,436揭示了通过柱层析纯化粗制产品获得的晶体亚胺培南。此外，Crocker等在J.Pharm.Sci.84，226(1995)中报道了冻干参数的改变，导致改变了分离出的亚胺培南样品的结晶度。另一种采用了Connolly等在J.Pharm.Sci.85，174(1996)中报道的冷冻结晶法的经过变化的制造亚胺培南的方法有非常高的结晶度。然而，这些方法都很麻烦、笨重且不适合工业应用。
发明概要
本发明的目的是提供一种简单的、易于实践的且有效的制造晶体亚胺培南一水合物的方法，该产品对热稳定、有均匀的结晶度和高纯度。
本发明涉及从含有亚胺培南的溶液中分离纯净的晶体亚胺培南一水合物的方法。所述方法没有使用资金密集的冻干或冷冻结晶技术，且无需花费使用昂贵疏水树脂的柱层析进行纯化所需耗费的时间。因此本发明实现了在商业领域易于操作的方法的需要。
因此，本发明提供了分离式I的纯净的晶体亚胺培南一水合物的方法。
式I
所述方法包括从其溶液中结晶出亚胺培南一水合物，所述溶液含有有机溶剂、含水溶剂或它们的混合物，该方法无需采用冻干、冷冻干燥或层析技术。
可从可与水混溶的有机溶剂中选择可从中结晶出产品的溶剂系统，所述有机溶剂可单独使用或与水混合。
所述可与水混溶的有机溶剂的例子包括低级醇，如甲醇、乙醇、丙醇和异丙醇；酮类，如丙酮；乙二醇醚类如 单乙二醇；酰胺类，如N，N-二甲基甲酰胺，N，N-二甲基乙酰胺；内酰胺类，如N-甲基吡咯烷酮以及环醚类如四氢呋喃、二噁烷或它们的混合物。
所述结晶步骤应在低温下进行，如约0℃-约15℃，同时需要调整用来进行结晶的溶液中亚胺培南的浓度，例如可蒸发溶剂或进行稀释以使它既不太稀也不太浓。
所述结晶可包括至最后一个或多个形成亚胺培南的反应阶段。形成亚胺培南的反应可按照现有技术的合成路线，即美国专利4,194,047；4,292,436；或4,894,450，在此将其并入以供参考，所述的任何反应规则进行，但优选按照这里公开本发明所述的方法进行，该方法如本发明实施例1所示。
在进行结晶之前，可用在水中具有有限溶混性的有机溶剂洗涤含有亚胺培南的溶液以除去有机杂质。
同时，如果需要的话，在洗涤之前可将亚胺培南溶液的pH调至约7-8以便于除去杂质。
在本发明中，术语“有限溶混性”也包括不与水混溶的溶剂。这种有机溶剂的例子包括羧酸酯如乙酸乙酯，高级烷酮如甲基异丁酮，氯化烃如二氯甲烷，醚类如二乙醚，芳烃如甲苯，以及它们的混合物。
发明详述
通过以下实施例阐述了本发明，这些实施例不能理解为以任何方式限制本发明的有效范围。
亚胺培南的制备
实施例1
步骤(a)-制备烯醇磷酸酯中间体
将p-硝基苄基(3R，5R，6S)-2-氧代-6-[(1R)-1-羟乙基)]碳青霉烯-3-羧酸酯(30g)溶于N，N-二甲基乙酰胺(300ml)和二氯甲烷(150ml)的混合物。将溶液冷却至-55℃，并加入二甲基氨基吡啶(0.17g)，然后加入二异丙基乙胺(26.7g)。将混合物在约-55℃下搅拌5分钟，然后在-55至-45℃下逐滴加入溶于二氯甲烷(30ml)的二苯基氯代磷酸酯(25.4g)溶液。将反应物再搅拌30分钟以得到烯醇磷酸酯中间体。
步骤(b)-制备沙纳霉素酯
将步骤(a)的反应混合物再冷却至-70至-75℃，并在-75至-60℃下在10分钟内加入溶于N，N-二甲基乙胺(60ml)的2-氨基乙硫醇盐酸盐(12g)溶液。将反应混合物再搅拌60分钟以得到沙纳霉素的p-硝基苄基酯。
步骤(c)-制备亚胺培南的p-硝基苄基酯
在-50至-55℃下，在上述步骤(b)的反应混合物中加入二异丙基乙胺(16.0g)和苄基亚胺甲酸酯盐酸盐(20.0g)。将反应混合物在相同的温度下继续进行约一个半小时。然后将温度升高至-20℃并在此温度下将反应混合物搅拌20-30分钟以得到澄清的亚胺培南酯的溶液。
步骤(d)-制备亚胺培南
将上述步骤(c)所得的澄清溶液倒进保持在5-10℃的水(300ml)、异丙醇(150ml)和N-甲基吗啉(26g)的混合物，并将溶液的pH调至7.0-7.5。10-25℃下，将此溶液在钯-碳上以3-4kg的压力氢化2.5小时。将混合物过滤并检测亚胺培南(80％，用HPLC测定)。
晶体亚胺培南一水合物的分离
实施例2
将实施例1步骤(d)所得的含有亚胺培南的反应混合物和二氯甲烷(900ml)一起搅拌，将pH保持在7.0和8.0之间，有含水层分离出来。将含水层脱气以除去二氯甲烷，并进行活性碳处理。将滤得的含水溶液与异丙醇(400ml)混合并在5-10℃下搅拌3小时。将所得晶体产物过滤，用异丙醇(isopropropanol)洗涤，再用丙酮洗涤，并在35-40℃下干燥1小时以得到晶体亚胺培南一水合物(9.0g，HPLC测得的纯度为99％)。
实施例3
在结晶时用丙酮(400ml)而不是异丙醇重复实施例2的过程。得到了纯度为99％(用HPLC测得)的晶体亚胺培南一水合物(8.0g)。
实施例4
将实施例2所得的含水部分浓缩至200ml。在5-10℃下用碳处理所得含水溶液，并在5-10℃将滤得的溶液和丙酮(400ml)一起搅拌3小时以在过滤和干燥后得到晶体亚胺培南一水合物(12.0g，HPLC测得的纯度为98-99％)。
由于用特定的实施方案描述了本发明，精通这一技术的技术人员可以对它进行修改和等效改变，这应理解为包括在本发明的范围之内。
Claims (13)
1.分离如式I所示的纯净的晶体亚胺培南一水合物的方法，
式I
所述方法包括从其溶液中结晶出亚胺培南一水合物，所述溶液含有有机溶剂、含水溶剂或它们的混合物，所述方法无需采用冻干、冷冻干燥或层析技术。
2.如权利要求1所述的方法，其中，所述有机溶剂包括可与水混溶的有机溶剂。
3.如权利要求1所述的方法，其中，所述溶液包含和水混合的可与水混溶的有机溶剂。
4.如权利要求2所述的方法，其中，所述可与水混溶的有机溶剂包括低级醇、酮、乙二醇醚、酰胺、内酰胺、环醚或它们的混合物。
5.如权利要求4所述的方法，其中，所述可与水混溶的有机溶剂选择甲醇、乙醇、丙醇、异丙醇、丙酮、单乙二醇、N，N-二甲基甲酰胺、N，N-二甲基乙酰胺、N-甲基吡咯烷酮、四氢呋喃、二噁烷或它们的混合物。
6.如权利要求1所述的方法，其中，所述结晶是在低温下进行的。
7.如权利要求7所述的方法，其中，所述温度约为0℃至约15℃。
8.如权利要求1所述的方法，其中，所述含有亚胺培南的溶液直接从反应混合物中获得。
9.如权利要求1所述的方法，其中，所述含有亚胺培南的溶液在结晶前用在水中具有有限溶混性的有机溶剂洗涤。
10.如权利要求9所述的方法，其中，所述在水中具有有限溶混性的有机溶剂包括不与水混溶的溶剂。
11.如权利要求9所述的方法，其中，所述在水中具有有限溶混性的有机溶剂包括羧酸酯、高级烷酮、氯化烃、醚类、芳烃或它们的混合物。
12.如权利要求11所述的方法，其中，所述在水中具有有限溶混性的有机溶剂选自乙酸乙酯、甲基异丁酮、二氯甲烷、二乙醚、甲苯以及它们的混合物。
13.如权利要求9所述的方法，其中，在进行洗涤前所述溶液的pH被调至约7-8。
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN595/DEL/01 | 2001-05-18 | ||
| IN595DE2001 | 2001-05-18 |
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| CN1522255A true CN1522255A (zh) | 2004-08-18 |
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| CNA028131207A Pending CN1522255A (zh) | 2001-05-18 | 2002-05-20 | 结晶亚胺培南的分离方法 |
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| Country | Link |
|---|---|
| US (1) | US7241885B2 (zh) |
| EP (1) | EP1395588A4 (zh) |
| JP (1) | JP2005514323A (zh) |
| KR (1) | KR20040010649A (zh) |
| CN (1) | CN1522255A (zh) |
| AR (1) | AR036018A1 (zh) |
| BR (1) | BR0209844A (zh) |
| CA (1) | CA2447673A1 (zh) |
| CZ (1) | CZ20033351A3 (zh) |
| HU (1) | HUP0501093A2 (zh) |
| MX (1) | MXPA03010548A (zh) |
| NO (1) | NO20035137D0 (zh) |
| OA (1) | OA12608A (zh) |
| PL (1) | PL373527A1 (zh) |
| SK (1) | SK15092003A3 (zh) |
| WO (1) | WO2002094773A2 (zh) |
| ZA (1) | ZA200309288B (zh) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103524508A (zh) * | 2013-09-02 | 2014-01-22 | 上海龙翔生物医药开发有限公司 | 一种亚胺培南一水合物的结晶方法 |
| CN108623598A (zh) * | 2018-05-21 | 2018-10-09 | 重庆天地药业有限责任公司 | 一种亚胺培南中间体及亚胺培南的制备方法 |
| CN113135916A (zh) * | 2020-01-20 | 2021-07-20 | 鲁南制药集团股份有限公司 | 一种亚胺培南制备工艺的除钯方法 |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ATE437879T1 (de) * | 2001-05-18 | 2009-08-15 | Ranbaxy Lab Ltd | Verfahren zur herstellung von imipenem |
| WO2003016312A1 (fr) * | 2001-08-13 | 2003-02-27 | Eisai Co., Ltd. | Procede de preparation d'antibiotiques a base de carbapenem |
| PL368984A1 (en) * | 2001-11-16 | 2005-04-04 | Ranbaxy Laboratories Limited | Process for the preparation of crystalline imipenem |
| US8293924B2 (en) | 2007-10-08 | 2012-10-23 | Orchid Chemicals & Pharmaceuticals Limited | Process for the preparation of carbapenem antibiotic |
Family Cites Families (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4138433A (en) * | 1975-06-26 | 1979-02-06 | Hoechst Aktiengesellschaft | Process for preparing 1,2-oxa-phospholanes |
| US4194047A (en) | 1975-11-21 | 1980-03-18 | Merck & Co., Inc. | Substituted N-methylene derivatives of thienamycin |
| US4081455A (en) * | 1976-06-02 | 1978-03-28 | Pfizer Inc. | 6-Amino-2,2-dimethyl-3-cyanopenams |
| US4260543A (en) | 1978-07-03 | 1981-04-07 | Merck & Co., Inc. | Crystalline N-formimidoyl thienamycin |
| US4292436A (en) | 1980-06-25 | 1981-09-29 | Merck & Co., Inc. | Process for the preparation of N-protected N-formimidoyl 2-aminoethanethiol |
| US4374772A (en) | 1981-03-19 | 1983-02-22 | Merck & Co., Inc. | Process for the preparation of N-formimidoyl thienamycin and reagents therefor |
| US4894450A (en) | 1987-05-11 | 1990-01-16 | Merck & Co., Inc. | Process for 2-(aminoalkylthio) carbapenems |
| US5245069A (en) * | 1992-10-27 | 1993-09-14 | Merck & Co., Inc. | Process for the preparation of bis(aryl)-phosphorohalidates |
| IN191798B (zh) | 2000-11-03 | 2004-01-03 | Ranbaxy Lab Ltd | |
| PL368984A1 (en) * | 2001-11-16 | 2005-04-04 | Ranbaxy Laboratories Limited | Process for the preparation of crystalline imipenem |
-
2002
- 2002-05-20 SK SK1509-2003A patent/SK15092003A3/sk not_active Application Discontinuation
- 2002-05-20 WO PCT/IB2002/001718 patent/WO2002094773A2/en not_active Application Discontinuation
- 2002-05-20 KR KR10-2003-7015043A patent/KR20040010649A/ko not_active Application Discontinuation
- 2002-05-20 AR ARP020101854A patent/AR036018A1/es not_active Application Discontinuation
- 2002-05-20 JP JP2002591446A patent/JP2005514323A/ja not_active Withdrawn
- 2002-05-20 CN CNA028131207A patent/CN1522255A/zh active Pending
- 2002-05-20 HU HU0501093A patent/HUP0501093A2/hu unknown
- 2002-05-20 PL PL02373527A patent/PL373527A1/xx not_active Application Discontinuation
- 2002-05-20 CZ CZ20033351A patent/CZ20033351A3/cs unknown
- 2002-05-20 BR BR0209844-0A patent/BR0209844A/pt not_active IP Right Cessation
- 2002-05-20 OA OA1200300302A patent/OA12608A/en unknown
- 2002-05-20 EP EP02730574A patent/EP1395588A4/en active Pending
- 2002-05-20 MX MXPA03010548A patent/MXPA03010548A/es unknown
- 2002-05-20 CA CA002447673A patent/CA2447673A1/en not_active Abandoned
- 2002-05-20 US US10/478,624 patent/US7241885B2/en not_active Expired - Fee Related
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2003
- 2003-11-18 NO NO20035137A patent/NO20035137D0/no not_active Application Discontinuation
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103524508A (zh) * | 2013-09-02 | 2014-01-22 | 上海龙翔生物医药开发有限公司 | 一种亚胺培南一水合物的结晶方法 |
| CN103524508B (zh) * | 2013-09-02 | 2016-03-30 | 上海龙翔生物医药开发有限公司 | 一种亚胺培南一水合物的结晶方法 |
| CN108623598A (zh) * | 2018-05-21 | 2018-10-09 | 重庆天地药业有限责任公司 | 一种亚胺培南中间体及亚胺培南的制备方法 |
| CN113135916A (zh) * | 2020-01-20 | 2021-07-20 | 鲁南制药集团股份有限公司 | 一种亚胺培南制备工艺的除钯方法 |
Also Published As
| Publication number | Publication date |
|---|---|
| KR20040010649A (ko) | 2004-01-31 |
| PL373527A1 (en) | 2005-09-05 |
| US7241885B2 (en) | 2007-07-10 |
| WO2002094773A3 (en) | 2003-10-16 |
| WO2002094773A2 (en) | 2002-11-28 |
| BR0209844A (pt) | 2005-04-05 |
| EP1395588A4 (en) | 2004-09-15 |
| ZA200309288B (en) | 2005-02-28 |
| AR036018A1 (es) | 2004-08-04 |
| SK15092003A3 (sk) | 2004-09-08 |
| CA2447673A1 (en) | 2002-11-28 |
| NO20035137D0 (no) | 2003-11-18 |
| MXPA03010548A (es) | 2004-05-27 |
| US20040242865A1 (en) | 2004-12-02 |
| CZ20033351A3 (cs) | 2007-12-27 |
| HUP0501093A2 (en) | 2006-03-28 |
| OA12608A (en) | 2006-06-08 |
| JP2005514323A (ja) | 2005-05-19 |
| EP1395588A2 (en) | 2004-03-10 |
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