CN1081640C - 二氨基醚的二克拉维酸盐及其制备方法 - Google Patents
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Abstract
一种由克拉维酸和式(I)的二氨基醚制备的二克拉维酸盐。其中R1是一个亚烷基，任选有一个或多个惰性取代基；R2和R3各自是氢原子或烷基，任选有一个或多个惰性取代基，或R2和R3一起形成有4-7个碳原子的杂环，再任选有一个或多个惰性取代基。使二(2-烷基氨基亚烷基)醚(或其盐)与克拉维酸在有机溶剂中反应，分离产生的盐。与药学可接受的载体和任选的β-内酰胺抗菌素一起，该克拉维酸盐可用于药物制剂，并且是制备钾盐的有用中间体。
Description
本发明涉及克拉维酸盐及其制备和含克拉维酸盐的药物组合物。
克拉维酸由于其能抑制多种β-内酰胺酶而在抗菌素配方中具有活性，β-内酰胺能分裂如青霉素和头孢菌素的抗菌剂的β-内酰胺环。所以克拉维酸能改善这些抗菌剂的抗菌作用。克拉维酸具有下面的分子结构：
GB-A-1578739揭示了一类克拉维酸胺盐和制备克拉维酸的方法，用这种方法更易配制这类盐，得到比以前所述的克拉维酸盐更稳定的药物组合物。例如，在GB-A-2264944；Wo93/25557和WO94/22873；EP-A-0026044，EP-A-0387178和EP-A-0562583中所揭示的其他克拉维酸胺盐。
一般，这样的克拉维酸胺盐或者不结晶或者需要加入大量的溶剂，如丙酮，才能引起结晶，或以很细的针状晶体结晶，这样的晶体不易沉降并难以过滤、清洗和干燥。
因此，本发明的目的就是解决这些困难，提供易于结晶或以易于过滤的瓣状晶体结晶的高度稳定的纯克拉维酸盐。
根据本发明的一个方面，提供了由克拉维酸和下式的二氨基醚制备的二克拉维酸盐
其中R1是一个亚烷基(术语亚烷基包括亚环烷基和烷基取代的亚环烷基)，任选有一个或多个惰性取代基；R2和R3各自是氢原子或烷基(术语烷基包括环烷基和烷基取代的环烷基)，任选有一个或多个惰性取代基，或R2和R3一起形成有4-7个碳原子的杂环，再任选有一个或多个惰性取代基。当R2和R3代表烷基时，每个最好都不超过8个碳原子；最好R2和R3相同。
优选的R1不超过4个碳原子，R2和R3一起含有不超过4个碳原子。最好二氨基醚包括二(2-二甲基氨基乙基)醚，其有利于形成高纯度的克拉维酸盐，并且通过加入合适的溶剂如丙酮或异丙醇，可以从水溶液中结晶。已发现用二(2-二甲基氨基乙基)醚，未离析出单价克拉维酸盐晶体，这将有利于使基本为均一的二克拉维酸盐离析。而且，二(2-二甲基氨基乙基)醚的二克拉维酸盐一般不会形成一种特殊的溶剂化物；这一特性可防止任何溶剂的夹带，因此得以基本上避免了以后加工步骤的污染。
本发明的盐其本身可作为药物，因此在药物配方中可以与载体、稀释剂或赋形剂一起使用。或者，也可将这种盐作为制备药物学可接受的进一步的克拉维酸盐，如钾盐，和作为含有这样盐的药物组合物的中间体。
本发明的第二方面，提供了上面定义的克拉维酸二氨基醚盐的制备方法，它包括在一种有机溶剂中，使二胺基醚与克拉维酸反应，分离产生的盐。最好有机溶剂包括脂族羧酸酯或一种基本上与水不混溶的脂族酮；优选的溶剂是乙酸乙酯。该溶剂还可以包括共溶剂如丙酮、乙腈或四氢呋喃，共溶剂有利于改善结晶特性和所获得的盐的质量。
获得的上述盐可进一步转化为药物可接受的其他克拉维酸盐，如钾盐，然后可适用于药物配方中。
本发明的再一个方面，提供了一种药物组合物，组合物包括基本上由上述方法制备的药学可接受的克拉维酸盐和药学可接受的载体、稀释剂或赋形剂。组合物最好还包括β-内酰胺抗菌素。因此，当和本发明的药学可接受的盐一起服用时，β-内酰胺抗菌素的效果得以保持。一般所使用的抗菌素包含青霉素和/或头孢菌素。
本发明还有一方面，提供了制备克拉维酸二氨基醚盐的方法，这种盐具有新颖的结晶习性，该方法包括制备克拉维酸或其盐在有机溶剂中的基本无水的溶液，该溶液保持在约0-15℃，最好低于10℃，与有机溶剂中的二氨基醚反应。这种方法有利于使克拉维酸二氨基醚盐以基本为瓣状晶体结晶，即从一个晶核点发散出几个针状晶体的晶体。据信这是这种胺盐的独特性质，对克拉维酸胺盐以前没有描述这样的结晶习性。这种结晶习性具有明显的优势，能使晶体在溶剂中迅速沉降、过滤和清洗，干燥后的产品具有改进的加工性能。
较好的有机溶剂包括脂族羧酸酯或基本水不混溶的脂族酮；优选的溶剂是乙酸乙酯。该溶剂还可以包括共溶剂如丙酮、乙腈或四氢呋喃，共溶剂有利于改善结晶特性和所获得的盐的质量。
从科学文献中了解到，某些克拉维酸的胺盐能形成水合物和溶剂化物。一般这样的化合物是不确定的，具有变化的成份。也就是在一些情况，为了证实它们的存在，有必要设计一些在回收和提纯克拉维酸的方法中一般不采用的条件。在任何情况下，溶剂化物的形成是相当麻烦的事情，因为不可避免地会把溶剂带到以后的步骤中去。克拉维酸的醚二胺盐通常不会与克拉维酸萃取和提纯中常用的溶剂形成溶剂化物。但是，作为松散结合了溶剂的暂时的/或低水平的中间物，其存在也不能完全忽视。因此，克拉维酸的醚二胺盐其中存在少量溶剂或水，也应考虑为是符合本发明的范围的。
由下面的实施例能更清楚地理解本发明，实施例仅用于说明；实施例中，参考了附图1-3，其中：
图1是实施例1的结晶产品的红外光谱图；
图2说明了实施例1获得的晶体形状；
图3说明了实施例2获得的瓣状晶体。
实施例1
二(2-二甲基氨基乙基)醚的二克拉维酸盐的制备
由现有技术制备硫酸镁和活性炭脱色处理的克拉维酸的乙酸乙酯溶液。在100毫升含有3.0％w/v克拉维酸的这种溶液中加人100毫升丙酮，在室温搅拌产生的混合物。随后，继续搅拌下加入在8.0毫升丙酮中2.0克的二(2-二甲基氨基乙基)醚(商品名为“Jeffcat ZF-20”的产品)的溶液，达到由于形成油滴的细小悬浮物，而使溶液变为浑浊。在试管中移入少量这一悬浮液样品并加入略过量的胺，随后加入丙酮使悬浮液清澈。短时间后就观察到结晶。将晶体悬浮液加回到原来的混合物中，使其作为晶种，继续加入剩余的胺溶液。在室温下搅拌30分钟，混合物完全结晶，然后在0-3℃继续搅拌2小时。过滤出白色晶体产物，用少量丙酮清洗，在真空下干燥一夜，得到3.5克盐(产率为83％)。获得的晶体形状如图2所示，图2为一批晶体放大100倍的显微照片。
获得的晶体产品的分析结果如下：
计算值
碳(％m/m) 51.79 51.61
氢(％m/m) 6.85 6.86
氮(％m/m) 10.09 10.03
熔点(℃)152-154℃熔化并分解
FT-IR示于图1。
实施例2
瓣状晶体的二(2-二甲基氨基乙基)醚的二克拉维酸盐的制备
按常规制备活性炭脱色处理的克拉维酸(0.25％w/v克拉维酸)的乙酸乙酯溶液。用旋转蒸发器将1立升该溶液浓缩到100毫升。在此溶液中加入100毫升丙酮(水含量小于0.2％v/v)，在5-10℃搅拌产生的混合物。然后剧烈搅拌下，迅速加入在6.0毫升丙酮中的1.5克二(2-二甲基氨基乙基)醚溶液。迅速形成晶体，之后搅拌速度减到最小。在5-10℃搅拌30分钟然后在0-3℃继续搅拌2小时，完成混合物的结晶。过滤“瓣状”和针状晶体混合物形态的白色结晶产物，用少量丙酮清洗，在真空下干燥一夜，得到2.8克盐(产率为80％)。获得的晶体形状示于图3，图3是晶体放大100倍后的显微照片。
实施例3
克拉维酸钾盐的制备
室温搅拌下将1.0克二(2-二甲基氨基乙基)醚的二克拉维酸盐溶解在75毫升含2.2％v/v水的异丙醇中。连续搅拌下，在此溶液中加入2.5毫升2N 2-乙基己酸钾的异丙醇溶液。添加完成后，在室温搅拌30分钟，然后在0-3℃继续搅拌2小时。过滤产物，用异丙醇和丙酮清洗，并在真空下干燥一夜，得到0.64克盐(产率为75％)。
Claims (12)
1.一种由克拉维酸盐和下式的二氨基醚制备的二克拉维酸盐，
其中R2和R3各自是氢原子或C1-8烷基。
2.如权利要求1所述的盐，其特征还在于R2和R3一起含有不超过4个的碳原子。
3.如权利要求1或2所述的盐，其特征还在于二氨基醚包括二(2-二甲基氨基乙基)醚。
4.如权利要求1-3中任一权利要求所述的克拉维酸盐的制备方法，其特征在于所述的方法包括使克拉维酸或其盐与二氨基醚在有机溶剂中反应，分离产生的盐。
5.如权利要求4所述的制备方法，其中所述的克拉维酸盐基本为瓣状晶体，其特征在于该方法包括制备克拉维酸或其盐在有机溶剂中的基本无水的溶液，在0-15℃下保持该溶液，使所述的克拉维酸或其盐与所述的二氨基醚在有机溶剂中反应。
6.如权利要求5所述的方法，其特征还在于该溶液在低于10℃下保持。
7.如权利要求4-6任一权利要求所述的方法，其中所述的溶剂进一步包含共溶剂。
8.如权利要求7所述的方法，其特征在于所述的共溶剂包括丙酮、乙腈或四氢呋喃。
9.如权利要求4-6任一权利要求所述的方法，其特征还在于有机溶剂包括脂族羧酸酯或基本与水不溶混的脂族酮。
10.如权利要求9所述的方法，其特征还在于所述羧酸酯是乙酸乙酯，和/或溶剂进一步包含共溶剂。
11.如权利要求10所述的方法，其特征还在于所述的共溶剂包括丙酮、乙腈或四氢呋喃。
12.一种药物组合物，它包括权利要求1得到的克拉维酸药学上可接受的盐和药学上可接受的载体、稀释剂或赋形剂。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9426261.5 | 1994-12-24 | ||
| GBGB9426261.5A GB9426261D0 (en) | 1994-12-24 | 1994-12-24 | Clavulanic acid salts |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1171111A CN1171111A (zh) | 1998-01-21 |
| CN1081640C true CN1081640C (zh) | 2002-03-27 |
Family
ID=10766624
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN95197032A Expired - Fee Related CN1081640C (zh) | 1994-12-24 | 1995-12-22 | 二氨基醚的二克拉维酸盐及其制备方法 |
Country Status (40)
| Country | Link |
|---|---|
| US (1) | US5786351A (zh) |
| EP (1) | EP0799233B1 (zh) |
| JP (1) | JPH10511386A (zh) |
| KR (1) | KR100416946B1 (zh) |
| CN (1) | CN1081640C (zh) |
| AP (1) | AP670A (zh) |
| AR (1) | AR004165A1 (zh) |
| AT (1) | ATE178606T1 (zh) |
| AU (1) | AU702968B2 (zh) |
| BG (1) | BG62971B1 (zh) |
| BR (1) | BR9510250A (zh) |
| CA (1) | CA2208520C (zh) |
| CZ (1) | CZ289287B6 (zh) |
| DE (1) | DE69508962T2 (zh) |
| DK (1) | DK0799233T3 (zh) |
| EE (1) | EE9700139A (zh) |
| ES (1) | ES2132756T3 (zh) |
| FI (1) | FI972464A (zh) |
| GB (1) | GB9426261D0 (zh) |
| GE (1) | GEP20002212B (zh) |
| GR (1) | GR3030629T3 (zh) |
| HU (1) | HUT77090A (zh) |
| IL (1) | IL116498A (zh) |
| IS (1) | IS4501A (zh) |
| MD (1) | MD1738F2 (zh) |
| MY (1) | MY114213A (zh) |
| NO (1) | NO313200B1 (zh) |
| NZ (1) | NZ297857A (zh) |
| OA (1) | OA10861A (zh) |
| PL (1) | PL182364B1 (zh) |
| RO (1) | RO118429B1 (zh) |
| RU (1) | RU2152948C1 (zh) |
| SE (1) | SE520665C2 (zh) |
| SI (2) | SI9520145A (zh) |
| SK (1) | SK282663B6 (zh) |
| TJ (1) | TJ269B (zh) |
| TR (1) | TR199501675A2 (zh) |
| TW (1) | TW401409B (zh) |
| WO (1) | WO1996020199A2 (zh) |
| ZA (1) | ZA9510880B (zh) |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SI9400107A (en) | 1994-03-02 | 1995-10-31 | Lek Tovarna Farmacevtskih | New process of the isolation of clavulanic acid and its pharmaceutical salts from fermented broth of streptomyces sp.p 6621 ferm p 2804. |
| GB9426261D0 (en) * | 1994-12-24 | 1995-02-22 | Spurcourt Ltd | Clavulanic acid salts |
| SI9500134B (sl) | 1995-04-20 | 2004-04-30 | Lek, | Postopek za pripravo čistih alkalijskih soli klavulanske kisline |
| EP0937084A1 (en) * | 1996-11-11 | 1999-08-25 | Gist-Brocades B.V. | Process for the preparation of salts and esters of clavulanic acid |
| AT404728B (de) * | 1996-11-27 | 1999-02-25 | Biochemie Gmbh | Verfahren zur herstellung von clavulansäure-aminsalzen |
| EP1284978B2 (en) | 2000-05-13 | 2008-09-10 | Smithkline Beecham Plc | Process for the purification of a salt of clavulanic acid |
| US8461327B2 (en) * | 2008-04-02 | 2013-06-11 | Dsm Sinochem Pharmaceuticals Netherlands B.V. | Diamine salts of carboxylic acids |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0562583A1 (de) * | 1992-03-26 | 1993-09-29 | LEK, tovarna farmacevtskih in kemicnih izdelkov, d.d. | Neue Alkylendiammonium-diclavulanat-Derivate, Verfahren zu deren Herstellung sowie deren Verwendung |
| WO1993025557A1 (en) * | 1992-06-11 | 1993-12-23 | Smithkline Beecham Plc | Process for the preparation of clavulanic acid |
| WO1994021647A1 (en) * | 1993-03-18 | 1994-09-29 | Smithkline Beecham Plc | Diclavulanate salt with a diamine and process of preparation |
Family Cites Families (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4144242A (en) * | 1975-02-07 | 1979-03-13 | Glaxo Laboratories Limited | Process for the purification of clavulanic acid |
| GB1578739A (en) * | 1976-07-23 | 1980-11-05 | Beecham Group Ltd | Amine salts of clavulanic acid methods for their preparation and compositions containing them |
| US4255332A (en) * | 1977-09-01 | 1981-03-10 | Beecham Group Limited | Process for the preparation of potassium clavulanate from lithium clavulanate |
| US4454069A (en) * | 1979-08-24 | 1984-06-12 | Beecham Group Limited | Clavulanic acid salts and their preparation from the tertiary butyl amine salt |
| DE3063683D1 (en) * | 1979-08-24 | 1983-07-14 | Beecham Group Plc | Amine salt of clavulanic acid, its preparation and use |
| EP0277008B1 (en) | 1987-01-29 | 1995-06-14 | Beecham Group Plc | Process for crystallization of potassium clavulanate |
| US5288861A (en) | 1987-01-29 | 1994-02-22 | Beecham Group Plc | Potassium clavulanate in rosette form |
| ES2010143A6 (es) | 1989-03-01 | 1989-10-16 | Pharma Mar S A Pharmar | Un nuevo procedimiento de obtencion del acido z(2r,5r)-3-(2-hiadroxietiliden)-7- oxo-4-oxa-1-azabiciclo(3,2,0) -heptano-2-carboxilico y de sales estares farmaceutiacamente aceptables del mismo,a partir de caldos de fermentacion de streptomyces, sp. |
| AT400033B (de) * | 1992-03-10 | 1995-09-25 | Biochemie Gmbh | Neues verfahren zur isolierung und reinigung von clavulansäure und zur herstellung von pharmakologisch verträglichen salzen derselben |
| SK279918B6 (sk) | 1993-03-26 | 1999-05-07 | Gist-Brocades N.V. | Soli kyseliny klavulánovej s diamínmi, spôsob ich |
| GB9426261D0 (en) * | 1994-12-24 | 1995-02-22 | Spurcourt Ltd | Clavulanic acid salts |
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1994
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- 1995-12-22 BR BR9510250A patent/BR9510250A/pt not_active IP Right Cessation
- 1995-12-22 CN CN95197032A patent/CN1081640C/zh not_active Expired - Fee Related
- 1995-12-22 AT AT95941809T patent/ATE178606T1/de not_active IP Right Cessation
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- 1995-12-22 KR KR1019970704332A patent/KR100416946B1/ko not_active IP Right Cessation
- 1995-12-22 SK SK776-97A patent/SK282663B6/sk unknown
- 1995-12-22 HU HU9701685A patent/HUT77090A/hu not_active Application Discontinuation
- 1995-12-22 RO RO97-01119A patent/RO118429B1/ro unknown
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- 1995-12-22 GE GEAP19953795A patent/GEP20002212B/en unknown
- 1995-12-22 AU AU43110/96A patent/AU702968B2/en not_active Ceased
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1996
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1997
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0562583A1 (de) * | 1992-03-26 | 1993-09-29 | LEK, tovarna farmacevtskih in kemicnih izdelkov, d.d. | Neue Alkylendiammonium-diclavulanat-Derivate, Verfahren zu deren Herstellung sowie deren Verwendung |
| WO1993025557A1 (en) * | 1992-06-11 | 1993-12-23 | Smithkline Beecham Plc | Process for the preparation of clavulanic acid |
| WO1994021647A1 (en) * | 1993-03-18 | 1994-09-29 | Smithkline Beecham Plc | Diclavulanate salt with a diamine and process of preparation |
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