CN1042424C - 将二水合罗拉卡转变成一水合罗拉卡的方法 - Google Patents
将二水合罗拉卡转变成一水合罗拉卡的方法 Download PDFInfo
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Abstract
本发明提供结晶一水合物形式的式(Ⅰ)化合物的制备方法，其中包括将结晶二水合物形式的式(Ⅰ)化合物暴露在温度为大约50-60℃、相对湿度为大约为60%至100%的环境中。
Description
本发明涉及制备结晶罗拉卡一水合物的方法。
式(Ⅰ)β-内酰胺抗菌素是有效的口服活性抗菌素，被称为罗拉卡(Loracarbef)。式(Ⅰ)如下：
该抗菌素被描述于例如1982年6月15日公告的J.Hashimoto等人的美国专利第4,335,211号中。
上述化合物有包括结晶一水合物形式在内的多种形式，它们被公开在1989年4月12日公布的欧洲专利公开0,311,366中。已知的该化合物的其它溶剂化形式公开在Eckrich等人的美国专利第4,977,257号中。罗拉卡的结晶二水合物形式被公开在1990年5月23日公布的欧洲专利公开369,686中。象在EPO申请中所指出的，结晶一水合物可以这样制备：首先将二水合物在水中悬浮，加入酸再加入碱调节pH，或者加入碱再加入酸调节pH来进行溶解。
测定结果表明罗拉卡结晶一水合物是一种“细发”状结晶，过滤非常缓慢。在过滤一水合物时，该结晶易在过滤介质中形成一层隔热物质层，阻碍滤饼的脱水或减低脱水的能力，从而增加了所需的的清洗体积。由于罗拉卡一水合物在水中具有中等溶解度(约10mg/ml)，所以增加清洗体积就会引起收率的损失。随着清洗体积增加，总的过滤时间当然也随着增加。
由于出现上述问题，就需要建立一种更有效地制备结晶罗拉卡一水合物的方法，即避开结晶一水合物的过滤的方法。
本发明提供结晶一水合物形式的式(Ⅰ)化合物的制备方法，其中包括将结晶二水合物形式的式(Ⅰ)化合物曝露于温度为约50至65℃，相对温度为约60至100％环境中。式(Ⅰ)如下：
罗拉卡二水合物是以片状结晶形式存在的，它此结晶一水合物的过滤速度快得多。实验结果表明二水合物的过滤速度是一水合物的二十倍。已经有人尝试将湿块或干固体的二水合物用高温方法转化成一水合物。然而，该途径被证明是行不通的。
已发现除高温外再加高相对温度就可以引起固体状态转化，使二水合物变成一水合物。该发现提供了一种避免通过过滤来分离一水合物的方法。因为可以通过先形成易过滤的二水合物，然后经过固体转换成为一水合物，这样就可分离出一水合物。而且也不需要明象前面所述的那样用酸或碱将一水合物从液体中结晶出来。
二水合物到一水合物的固态转变发生于升温和高相对湿度的环境中，温度为约50至60℃，湿度为60-100％左右。当其它形式的罗拉卡用这种方法转变时，业已发现只有二水合物形式能令人奇怪地转变成一水合物，其它的溶剂化物如二[二甲基甲酰胺(以后简称DMF)]溶剂化物和乙醇化物暴露于各种温湿度条件下时，转变成各种非一水合物形式或各种形式的混合物。所以，本发明也提供了二水合物晶体形式到一水合物晶体形式专一性的转变。
二水合物可以通过本领域熟知的方法制备，诸如先前提及的欧洲专利公开369,686中的方法。二水合物的存在形式有湿块或干粉二种。将二水合物放在敞口容器中，然后置于相对湿度为50-100％，温度为约50-65℃的湿润的箱中。最好湿度范围在约80-90％，温度范围在50-60℃左右。将二水合物在这种条件下放置几小时，已注意到在一些实验中在温度为60℃相对湿度为90％的条件下，8小时内转化生成了一水合物。这种转化可通过显微镜观察来监测，当显微镜上观察到该物质已转化成一水合物后，可以取出样品用于卡尔费休水分测定和X-射衍射图案分析以进行该组分的证实。相信这咱转换是固固转变，而不是溶解后重结晶。令人奇怪的是在湿润环境中也存在脱水现象。
借助显微镜可以看到转变过程中片状的二水合物向针状的一水合物的变化。伴随着二水合物变成一水合物，卡尔费休值(以后简称KF)从9％变成5％。产物的X-射线衍射图案与一水合物参此图案完全一致。而且，没有观察到出现新峰，表明二水合物完全转化成了一水合物。
实验部分
实施例1
将罗拉卡二水合物(5g，初始KF=9.3％)放在陪替氏培养皿中，然后将培养皿放在相对湿度为60％、温度为20℃的湿箱中。放置二十四小时后，通过里微镜观察进行监测。由于没观察到变化发生，所以温度以10℃的梯度向上升高，每次均放置24小时，该过程一直重复到温度达到60℃。直到温度达到50℃才发现产生了一水合物，在60℃可观察到更多得多的一水合物。X-射线图样表明，在50℃大多数二水合物没有转化，但在60℃，图样表明主要为一水合物，只留下痕量的二水合物。KF分析表明二水合物放在60℃温度下，含水量明显下降。
实施例2
将3g罗拉卡二水合物放在陪替氏培养皿中，然后将培养皿放在温度为60℃相对温度为80％的湿箱。2小时后，通过显微镜观察到的物质看起来极似一水合物。X-射线图样证实发生了转换，表明物质大部份为一水合物，少量为残存在二水合。
实施例3
将罗拉卡二水合物(5g，初始KF=8.7％)放在陪替低培养皿中，然后将培养皿放在温度为60℃相对温度为80℃的湿润箱中。通过显微镜观察监测转变过程，72小时后，观察到大多数物质转变成了一水合物。产物的KF为5.5％，总相关物质量为0.51％，效价是9.65％。X-射线图案证实该物质为一水合物。
实施例4
将500ml单颈玻璃帕尔瓶配上橡皮塞和二支同心管。这种管子提供了供应和去除瓶内用水蒸气饱和的氮气的通道。每支管的末端密封好，在管壁上钻一个洞，如果水蒸汽在这些管线中冷凝时，这提供了排水的通道。将罗拉卡二水合物(约0.75g)均匀地置于帕尔瓶底，瓶口用盖盖紧。然后将帕尔瓶浸没于流满水的4升树脂烧瓶中。树脂烧瓶配有加热罩和温度控制器，用对设在65℃。此外，通过烧结金属玻璃料将干燥氮气以100sccm/min的控制速率喷射到水中；这提供了和水与浸没的帕瓶温度相同的水蒸气饱的氮气。树脂烧瓶和帕尔瓶管被密封并相互连通，所以100sccm/min的氮气可以冲到帕尔瓶中。将用卡尔费体滴定测得的含8.9％(重量)水的二水合物置于帕尔瓶中。用光学显微镜观察指示出了二水合物晶体形式的片状晶体特性。将二水合物曝露于65℃和100sccm/min的水蒸气100％相对湿度饱和的氮气流中70小时后，提出帕尔瓶中的物质。用光学显微镜进行观察，出现了一水合物晶体形式的针状结晶特征。卡尔费滴定分析表明晶体含水量为5.5％(重量)。
Claims (3)
1．结晶一水合物形式的式(Ⅰ)化合物的制备方法，其中包括将结晶二水合物形式的式(Ⅰ)化合物暴露于温度为50-65℃相对湿度为60-100℃的环境中。
2．权利要求1的方法，其中所述的相对湿度是80-90％。
3．权利要求2的方法，其中所述的温度是50-60℃。
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US08/071,550 US5374719A (en) | 1993-06-04 | 1993-06-04 | Process for converting loracarbef dihydrate to loracarbef monohydrate |
| US071,550 | 1993-06-04 | ||
| US071550 | 1993-06-04 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1097754A CN1097754A (zh) | 1995-01-25 |
| CN1042424C true CN1042424C (zh) | 1999-03-10 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN94106984A Expired - Fee Related CN1042424C (zh) | 1993-06-04 | 1994-06-03 | 将二水合罗拉卡转变成一水合罗拉卡的方法 |
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| Country | Link |
|---|---|
| US (1) | US5374719A (zh) |
| EP (1) | EP0627430B1 (zh) |
| JP (1) | JP3442479B2 (zh) |
| KR (1) | KR100311699B1 (zh) |
| CN (1) | CN1042424C (zh) |
| AT (1) | ATE146472T1 (zh) |
| AU (1) | AU678000B2 (zh) |
| BR (1) | BR9402149A (zh) |
| CA (1) | CA2125001C (zh) |
| CO (1) | CO4230100A1 (zh) |
| CZ (1) | CZ283468B6 (zh) |
| DE (1) | DE69401163T2 (zh) |
| DK (1) | DK0627430T3 (zh) |
| ES (1) | ES2097002T3 (zh) |
| FI (1) | FI108132B (zh) |
| GR (1) | GR3022111T3 (zh) |
| HU (1) | HU217066B (zh) |
| IL (1) | IL109871A (zh) |
| MY (1) | MY110724A (zh) |
| NO (1) | NO306302B1 (zh) |
| NZ (1) | NZ260653A (zh) |
| PE (1) | PE13195A1 (zh) |
| PH (1) | PH30304A (zh) |
| PL (1) | PL174539B1 (zh) |
| RU (1) | RU2124013C1 (zh) |
| TW (1) | TW252980B (zh) |
| UA (1) | UA27812C2 (zh) |
| YU (1) | YU33394A (zh) |
| ZA (1) | ZA943827B (zh) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5550231A (en) * | 1993-06-15 | 1996-08-27 | Eli Lilly And Company | Loracarbef hydrochloride C1-C3 alcohol solvates and uses thereof |
| US5580977A (en) * | 1995-03-01 | 1996-12-03 | Eli Lilly And Company | Process for preparing loracarbef monohydrate |
| US20070225285A1 (en) * | 2005-11-04 | 2007-09-27 | Amira Pharmaceuticals, Inc. | 5-lipoxygenase-activating protein (flap) inhibitors |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0311366A1 (en) * | 1987-10-06 | 1989-04-12 | Eli Lilly And Company | Crystalline beta-lactam hydrate |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3531481A (en) * | 1969-04-21 | 1970-09-29 | Lilly Co Eli | Method for manufacture of crystalline cephalosporin |
| US3502663A (en) * | 1969-04-21 | 1970-03-24 | Lilly Co Eli | Crystalline cephalosporin,method for its manufacture |
| US4977257A (en) * | 1988-11-14 | 1990-12-11 | Eli Lilly And Company | DMF solvates of a β-lactam antibiotic |
| CA2002596A1 (en) * | 1988-11-14 | 1990-05-14 | Thomas M. Eckrich | Hydrates of b-lactam antibiotic |
-
1993
- 1993-06-04 US US08/071,550 patent/US5374719A/en not_active Expired - Lifetime
-
1994
- 1994-06-01 CZ CZ941342A patent/CZ283468B6/cs not_active IP Right Cessation
- 1994-06-01 DE DE69401163T patent/DE69401163T2/de not_active Expired - Fee Related
- 1994-06-01 DK DK94303945.3T patent/DK0627430T3/da active
- 1994-06-01 TW TW083105006A patent/TW252980B/zh active
- 1994-06-01 PE PE1994243644A patent/PE13195A1/es not_active Application Discontinuation
- 1994-06-01 ZA ZA943827A patent/ZA943827B/xx unknown
- 1994-06-01 EP EP94303945A patent/EP0627430B1/en not_active Expired - Lifetime
- 1994-06-01 BR BR9402149A patent/BR9402149A/pt not_active Application Discontinuation
- 1994-06-01 AT AT94303945T patent/ATE146472T1/de not_active IP Right Cessation
- 1994-06-01 NZ NZ260653A patent/NZ260653A/en unknown
- 1994-06-01 ES ES94303945T patent/ES2097002T3/es not_active Expired - Lifetime
- 1994-06-01 PL PL94303676A patent/PL174539B1/pl not_active IP Right Cessation
- 1994-06-02 UA UA94005241A patent/UA27812C2/uk unknown
- 1994-06-02 IL IL10987194A patent/IL109871A/en not_active IP Right Cessation
- 1994-06-02 KR KR1019940012340A patent/KR100311699B1/ko not_active IP Right Cessation
- 1994-06-02 NO NO942048A patent/NO306302B1/no not_active IP Right Cessation
- 1994-06-02 CO CO94023737A patent/CO4230100A1/es unknown
- 1994-06-02 PH PH48386A patent/PH30304A/en unknown
- 1994-06-02 AU AU64516/94A patent/AU678000B2/en not_active Ceased
- 1994-06-02 CA CA002125001A patent/CA2125001C/en not_active Expired - Fee Related
- 1994-06-02 MY MYPI94001408A patent/MY110724A/en unknown
- 1994-06-03 HU HU9401675A patent/HU217066B/hu not_active IP Right Cessation
- 1994-06-03 CN CN94106984A patent/CN1042424C/zh not_active Expired - Fee Related
- 1994-06-03 FI FI942633A patent/FI108132B/fi not_active IP Right Cessation
- 1994-06-03 JP JP12228394A patent/JP3442479B2/ja not_active Expired - Fee Related
- 1994-06-03 RU RU94019424A patent/RU2124013C1/ru not_active IP Right Cessation
- 1994-06-03 YU YU33394A patent/YU33394A/sh unknown
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- 1996-12-19 GR GR960403422T patent/GR3022111T3/el unknown
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0311366A1 (en) * | 1987-10-06 | 1989-04-12 | Eli Lilly And Company | Crystalline beta-lactam hydrate |
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