CN1045604C - 棒酸盐的制备方法 - Google Patents
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Abstract
在生产药学上可接受的棒酸盐时,用2-氨基-2,4,4-三甲基戊烷棒酸盐作为中间产物。
Description
本发明涉及一种药学上可接受的棒酸盐的新生产方法。
棒酸由于对β-内酰胺酶具抑制活性,因而作为添加剂对β-内酰胺类抗菌素生产具有特殊的影响。β-内酰胺酶是这样一类酶:它能将青霉素和头孢菌素的β-内酰胺环打开,从而使它们的抗菌活性丧失。许多细菌能产生β-内酰胺酶,这就是它们对青霉素和头孢菌素产生抗性的原因。因此证明将β-内酰胺类抗菌素与棒酸或其药学上可接受的盐混合使用是有益的,这样,即使在能产生β-内酰胺酶的细菌存在下也能完全保持β-内酰胺的效力。这样的例子有:可商购的羟氨苄青霉素与棒酸钾盐的合剂广泛用于传染病的控制。
棒酸可由链霉菌(Streptomyces clavuligerus)发酵获得,经复杂的分离和纯化处理,如文献DOS251716所述。分离出细胞群后,将滤液酸化,用有机溶剂,例如正丁醇提取棒酸。再将提取物用水抽提,经下述工艺复杂但经济的纯化处理,例如:离子交换树脂层析或凝胶层析。EP-B-0026044描述了在该分离过程中用棒酸的叔丁胺盐作为中间产物。该盐的丙酮溶剂化物的形式从含丙酮的混合有机溶剂中结晶出来。当将棒酸的叔丁基胺盐转化成药学上可接受的棒酸盐时,丙酮进入反应混合物中,从而给溶剂的回收和再利用带来麻烦。
EP-A0387178描述了用有机胺盐分离棒酸。该胺可以是伯、仲或叔胺且可以被不超过七个碳原子的脂烃基或芳基取代。公开了不同的棒酸的结晶性胺盐的实施例。然而除仲丁基胺和苄基叔丁基胺这两个碱外,我们以结晶形式再生这些胺盐的尝试没有成功。而由前者生产棒酸的胺盐时却慢且结晶困难,这样会影响该盐的纯度;后者不易得且很贵。
就活性物质的药学上的应用而言,上述棒酸的胺盐最好是转化成药学上可以接受的碱金属盐类,尤其是钾盐。该转化可按下述方法完成:将该胺盐溶于无水或加水的溶剂中,然后加入易溶的碱金属盐,如2-乙基己酸钠或2-乙基己酸钾的溶液,这样棒酸的碱金属盐由于难溶而结晶出来得以分离。由于所述胺盐在适宜的有机溶剂中的溶解性差,加水是必要的,从而改善其溶解性。然而加水过多也会增加已沉淀析出的棒酸的碱金属盐的溶解度,因而使产率降低。
改进药学上可接受的棒酸盐的生产方法仍是一个急待解决的问题。可喜的是,用棒酸的特殊的胺盐可以达到这个目的。
本发明提供一个药学上可接受的棒酸盐的生产方法,它包括:生成2-氨基-2,4,4-三甲基戊烷棒酸盐和将该盐转化成药学上可接受的棒酸盐。
将棒酸以其2-氨基-2,4,4-三甲基戊烷盐的形式从不纯的棒酸有机溶液中分离出来很有利于高产率和高纯度。该不纯的棒酸有机溶液由用有机溶剂提取发酵液或其滤液而得。该2-氨基-2,4,4-三甲基戊烷棒酸盐已在美国专利4650795号中公开,但仅涉及其在药用制剂中的应用,而未提及棒酸的分离和纯化。
本发明特别地提供了一种药学上可接受的棒酸盐的生产方法,它包括:
a)用2-氨基-2,4,4-三甲基戊烷处理溶有棒酸的有机溶液,该溶液可得自发酵液或其滤液的提取;
b)分离出2-氨基-2,4,4-三甲基戊烷棒酸盐,并可将其重结晶;和
c)将获得的2-氨基-2,4,4-三甲基戊烷棒酸盐转化成药学上可接受的棒酸盐。
同时,本发明提出在药学上可接受的棒酸盐的生产中可用2-氨基-2,4,4-三甲基戊烷棒酸盐作为中间产物。
尤其适合于药学上可接受的棒酸的盐有碱金属盐和碱土金属盐,例如钠、钾、钙或镁盐。钠盐和钾盐是最合适的,钾盐更好。
本发明方法可按下例进行:
用有机溶剂从发酵液或其滤液中提取棒酸,仔细除去该提取液中的残留水分,例如通过真空共沸干燥或加入诸如硫酸镁这样的脱水剂。提取所用的有机溶剂最好是与水不互溶或只部分互溶的酮、醇或酯,例如二乙基酮、甲基异丁基酮、环己酮、正丁醇、环己醇、乙酸乙酯、乙酸正丁酯,甲基异丁基酮或乙酸乙酯更好。然后,加入2-氨基-2,4,4-三甲基戊烷纯品或溶液,相应的棒酸的胺盐以结晶性固体分出。该方法在常温下进行,温度一般在0℃到35℃间为宜,例如从0℃到25℃。沉淀出来的盐,洗涤,干燥后做进一步处理。
如果需要,2-氨-2,4,4-三甲基戊烷棒酸盐可以用重结晶法纯化。该步骤是将2-氨-2,4,4-三甲基戊烷棒酸盐溶于适宜的单一溶剂或混合溶剂中。溶剂可以是醇,例如甲醇、乙醇或异丙醇,水,或水和与水互溶的有机溶剂的混合物,这样的有机溶剂如异丙醇、四氢呋喃或丙酮。该重结晶是通过加入一种2-氨基-2,4,4-三甲基戊烷棒酸盐在其中溶解度很小的溶剂来完成的,这样的溶剂如:四氢呋喃,丙酮,二乙基酮,甲基异丁基酮,甲基叔丁基醚或乙酸正丁酯。
就将2-氨基-2,4,4-三甲基戊烷棒酸盐转化成药学上可接受的棒酸盐而言,是将作为中间产物分出的胺盐溶于有机溶剂中,最好是醇,例如乙醇,异丙醇或丁醇,这样就不必为改善溶解性而加水。加入所需的有机羧酸盐形式的碱金属或碱土金属盐溶液,适宜的羧酸盐如:乙酸盐、丙酸盐或2-乙基己酸盐,2-乙基己酸盐最好。该酸既有利于生成易溶性的碱金属盐,有又利于2-氨基-2,4,4-三甲基戊烷盐溶于所用的溶剂。理想的药学上可接受的棒酸盐,例如碱金属或碱土金属盐,如棒酸的钾盐,这样,沉淀产率高,纯度好。滤出沉淀,洗涤和干燥。
本发明所用的2-氨基2,4,4-三甲基戊烷盐十分优于EP-B-0026044和EP-A-0387178中分离和纯化棒酸所用的棒酸的胺盐。本发明中棒酸的胺盐的一个突出优点在于,该盐可以结晶的形式从含适于提取的溶剂的溶液中析出,不加丙酮。固此使溶剂回收相当简便。由于经济原因,溶剂回收变得更重要了。如果用单一溶剂提取,则溶剂回收简便。本发明一另一优点在于,2-氨基-2,4,4-三甲基戊烷棒的盐结晶迅速,产率高,纯度好,而且该2-氨基-2,4,4-三甲基戊烷已有市售。
所述盐的更优越的方面在于,它在酸的药学上可接受的盐的转化时所用的有机溶剂中有极好的溶解性。因而可避免当用棒酸的其它胺盐时需要加水这个问题。
本发明方法适于工业生产。
下列实施例仅意在进一步详述本发明,对本发明决无限制,给出的所有温度均为摄氏温度。
实施例1:
将2.5ml 2-氨基-2,4,4-三甲基戊烷在搅拌下与100ml含棒酸(30g/l)的无水甲基异丁基酮溶液混合,室温搅拌30分钟,冷却到5℃,并在该温度下搅拌2小时,滤出沉淀,以甲基异丁基酮洗涤,30℃下真空干燥,得到4.7g(产率95%)2-氨基-2,4,4-三甲基戊烷棒酸盐的结晶。
实施例2:
将2-氨基-2,4,4-三甲基戊烷(3.0ml)的乙酸乙酯(25ml)溶液在搅拌下与130ml含棒酸(26g/l)的无水乙酸乙酯溶液混合,室温搅拌30分钟,冷却到15℃,并在该温度下搅拌3小时,滤出沉淀产物,以乙酸乙酯洗涤,30℃下真空干燥,得到5.2g(产率93%)2-氨基-2,4,4-三甲基戊烷棒酸盐的结晶。
实施例3:
将235ml 2-氨基-2,4,4-三甲基戊烷加到4.0l棒酸的无水乙酸乙酯溶液中,该溶液是由用乙酸乙酯提取发酵液,真空浓缩提取液后所得;室温搅拌2小时,冷却到5℃,并在此温度下搅拌过夜,滤出沉淀,以乙酸乙酯洗涤,30℃下真空干燥,得到232g 2-氨基-2,4,4-三甲基戊烷棒酸盐的结晶。
实施例4:
将得自实施例1或2的4.0g 2-氨基-2,4,4-三甲基戊烷棒酸盐在20℃下溶于150ml异丙醇中,加入6.7ml 2M 2-乙基己酸钾的异丙醇溶液,20℃下搅拌30分钟,然后,在0-5℃下冷却2小时,滤出沉淀,以异丙醇洗涤,30℃下真空干燥,得到2.7g(产率95%)棒酸钾的结晶。
Claims (3)
1.药学上可接受的棒酸盐的生产方法,该方法包括:
a)用2-氨基-2,4,4-三甲基戊烷处理可从发酵液或其滤液中提取的含棒酸的有机溶液,以形成2-氨基-2,4,4-三甲基戊烷棒酸盐,
b)分离出2-氨基-2,4,4-三甲基戊烷棒酸盐;和
c)将得到的2-氨基-2,4,4-三甲基戊烷棒酸盐转化成药学上可接受的棒酸盐。
2.按权利要求1所述的方法,其中药学上可接受的盐为棒酸的钾盐。
3.按照权利要求1所述的方法,其中,该有机溶剂选自:二乙基酮、环已酮、甲基异丁基酮、环己醇、正丁醇、乙酸乙酯和乙酸正丁酯。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AT0047292A AT400033B (de) | 1992-03-10 | 1992-03-10 | Neues verfahren zur isolierung und reinigung von clavulansäure und zur herstellung von pharmakologisch verträglichen salzen derselben |
ATA472/92 | 1992-03-10 |
Related Child Applications (2)
Application Number | Title | Priority Date | Filing Date |
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CN96108276A Division CN1145906A (zh) | 1992-03-10 | 1996-06-29 | 药用棒酸盐的制造方法 |
CN96108278A Division CN1150153A (zh) | 1992-03-10 | 1996-06-29 | 2-氨基-2,4,4-三甲基戊烷棒酸盐的应用 |
Publications (2)
Publication Number | Publication Date |
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CN1079743A CN1079743A (zh) | 1993-12-22 |
CN1045604C true CN1045604C (zh) | 1999-10-13 |
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CN93102897A Expired - Fee Related CN1045604C (zh) | 1992-03-10 | 1993-03-09 | 棒酸盐的制备方法 |
CN96108276A Pending CN1145906A (zh) | 1992-03-10 | 1996-06-29 | 药用棒酸盐的制造方法 |
CN96108278A Pending CN1150153A (zh) | 1992-03-10 | 1996-06-29 | 2-氨基-2,4,4-三甲基戊烷棒酸盐的应用 |
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CN96108276A Pending CN1145906A (zh) | 1992-03-10 | 1996-06-29 | 药用棒酸盐的制造方法 |
CN96108278A Pending CN1150153A (zh) | 1992-03-10 | 1996-06-29 | 2-氨基-2,4,4-三甲基戊烷棒酸盐的应用 |
Country Status (21)
Country | Link |
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US (4) | US20010036940A1 (zh) |
JP (2) | JP2817563B2 (zh) |
CN (3) | CN1045604C (zh) |
AT (1) | AT400033B (zh) |
AU (1) | AU659282B2 (zh) |
CH (1) | CH685054A5 (zh) |
CY (1) | CY1995A (zh) |
DE (1) | DE4307422B4 (zh) |
DK (1) | DK26093A (zh) |
ES (1) | ES2058029B1 (zh) |
FI (1) | FI101965B1 (zh) |
FR (1) | FR2688506B1 (zh) |
GB (1) | GB2264944B (zh) |
GR (1) | GR1002329B (zh) |
HK (1) | HK42696A (zh) |
IE (1) | IE70926B1 (zh) |
IT (1) | IT1261213B (zh) |
NL (1) | NL9300430A (zh) |
NO (1) | NO301372B1 (zh) |
SE (1) | SE508043C2 (zh) |
TW (1) | TW364907B (zh) |
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AT403375B (de) * | 1995-11-15 | 1998-01-26 | Biochemie Gmbh | Verfahren zur fällung von alkalisalzen der clavulansäure |
EP1095046A1 (en) * | 1998-07-16 | 2001-05-02 | Dsm N.V. | Improved process for the preparation of salts and esters of clavulanic acid |
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AT399155B (de) | 1992-03-26 | 1995-03-27 | Lek Tovarna Farmacevtskih | Neue alkylendiammonium-diclavulanat-derivate, verfahren zu deren herstellung sowie deren verwendung |
SI9300296B (sl) | 1992-06-11 | 1998-06-30 | Smithkline Beecham P.L.C. | Postopek in intermedianti za pripravo klavulanske kisline |
SI9200139A (en) | 1992-07-08 | 1994-03-31 | Lek Tovarna Farmacevtskih | New inclusion complex of clavulanic acid with hydrophylyc and hydropholyc beta-cyclodextrin derivates for production of them |
KR100200239B1 (ko) | 1992-10-21 | 1999-06-15 | 김충환 | 클라불란산 칼륨염의 제조방법 |
GB9401969D0 (en) | 1994-02-02 | 1994-03-30 | Smithkline Beecham Plc | Process |
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. |
GB2298201B (en) | 1995-02-25 | 1997-05-28 | Spurcourt Ltd | Clavulanic acid salts |
EP0729961B1 (en) | 1995-02-25 | 2001-12-19 | Spurcourt Limited | Clavulanic acid salt |
SI9500074A (en) | 1995-03-10 | 1996-10-31 | Lek Tovarna Farmacevtskih | Process for preparation of alkani salts of clavulanic acid. |
SI9500134B (sl) | 1995-04-20 | 2004-04-30 | Lek, | Postopek za pripravo čistih alkalijskih soli klavulanske kisline |
KR100200242B1 (ko) | 1995-05-16 | 1999-06-15 | 김충환 | 클라불란산염의 제조 방법 |
GB9515809D0 (en) | 1995-08-02 | 1995-10-04 | Smithkline Beecham Plc | Process |
SI9500265A1 (en) | 1995-08-28 | 1997-02-28 | Lek Tovarna Farmacevtskih | Process for purification of the aqueous fermented broth filtrate of streptomyces sp. p 6621 ferm p 2804 by ultrafiltration |
ZA975198B (en) | 1996-06-13 | 1997-12-15 | Smithkline Beecham Corp | Improved process for preparing potassium clavulanate. |
PL333247A1 (en) | 1996-11-11 | 1999-11-22 | Gist Brocades Bv | Method of manufacturing of salts and esters of clavulan acid |
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1992
- 1992-03-10 AT AT0047292A patent/AT400033B/de not_active IP Right Cessation
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1993
- 1993-03-05 CH CH670/93A patent/CH685054A5/de not_active IP Right Cessation
- 1993-03-08 JP JP5046691A patent/JP2817563B2/ja not_active Expired - Fee Related
- 1993-03-08 SE SE9300758A patent/SE508043C2/sv not_active IP Right Cessation
- 1993-03-08 NO NO930829A patent/NO301372B1/no unknown
- 1993-03-08 GB GB9304704A patent/GB2264944B/en not_active Expired - Fee Related
- 1993-03-09 CN CN93102897A patent/CN1045604C/zh not_active Expired - Fee Related
- 1993-03-09 IE IE930172A patent/IE70926B1/en not_active IP Right Cessation
- 1993-03-09 DE DE4307422A patent/DE4307422B4/de not_active Expired - Fee Related
- 1993-03-09 FR FR9302720A patent/FR2688506B1/fr not_active Expired - Fee Related
- 1993-03-09 DK DK026093A patent/DK26093A/da not_active Application Discontinuation
- 1993-03-09 GR GR930100090A patent/GR1002329B/el not_active IP Right Cessation
- 1993-03-09 AU AU34070/93A patent/AU659282B2/en not_active Ceased
- 1993-03-09 FI FI931032A patent/FI101965B1/fi active
- 1993-03-10 ES ES09300483A patent/ES2058029B1/es not_active Expired - Fee Related
- 1993-03-10 IT ITRM930147A patent/IT1261213B/it active IP Right Grant
- 1993-03-10 NL NL9300430A patent/NL9300430A/nl active Search and Examination
- 1993-05-04 TW TW082103491A patent/TW364907B/zh not_active IP Right Cessation
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1996
- 1996-03-14 HK HK42696A patent/HK42696A/xx not_active IP Right Cessation
- 1996-06-29 CN CN96108276A patent/CN1145906A/zh active Pending
- 1996-06-29 CN CN96108278A patent/CN1150153A/zh active Pending
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1997
- 1997-08-13 JP JP9218732A patent/JPH1067785A/ja active Pending
- 1997-09-05 CY CY199597A patent/CY1995A/xx unknown
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2001
- 2001-06-26 US US09/892,179 patent/US20010036940A1/en not_active Abandoned
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2002
- 2002-02-08 US US10/071,364 patent/US20020072513A1/en not_active Abandoned
- 2002-09-20 US US10/251,948 patent/US20030022882A1/en not_active Abandoned
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2003
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