CN87106308A - 稳定的青霉素衍生物的水合物及其制备方法 - Google Patents
稳定的青霉素衍生物的水合物及其制备方法 Download PDFInfo
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D499/04—Preparation
- C07D499/18—Separation; Purification
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
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- C07D499/21—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a nitrogen atom directly attached in position 6 and a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
- C07D499/44—Compounds with an amino radical acylated by carboxylic acids, attached in position 6
- C07D499/48—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with a carbon chain, substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, attached to the carboxamido radical
- C07D499/58—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with a carbon chain, substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, attached to the carboxamido radical substituted in alpha-position to the carboxamido radical
- C07D499/64—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with a carbon chain, substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, attached to the carboxamido radical substituted in alpha-position to the carboxamido radical by nitrogen atoms
- C07D499/68—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with a carbon chain, substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, attached to the carboxamido radical substituted in alpha-position to the carboxamido radical by nitrogen atoms with aromatic rings as additional substituents on the carbon chain
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Abstract
揭示了一种(2S，5R，6R)-6-{(2R)-2-[(2R)-2-氨基-3-(N-甲基氨基甲酰基)丙酰氨基]-2-(对-羟基苯基)乙酰氨基}-3，3-二甲基-7-氧代-4-硫杂-1-氮杂-1-氮杂双环[3，2，0]庚烷-2-羧酸的稳定的三水合物及其制备方法。
Description
本发明涉及一种稳定的青霉素衍生物的水合物及其制备方法，具体地说，本发明涉及（2S，5R，6R）-6-｛（2R）-2-[（2R）-2-氨基-3-（N-甲基氨基甲酰基）丙酰氨基]-2-（对-羟基苯基）乙酰氨基｝3，3-二甲基-7-氧代-4-硫杂-1-氮杂双环[3，2，0]庚烷-2-羧酸三水合物〔下面指为“N4-甲基-D-天冬酰胺酰基羟氨苄青霉素”（N4-methyl-D-asparaginylamoxicillin）]，其分子式为：
N4-甲基-D-天冬酰胺酰基羟氨苄青霉素是用作化学治疗剂的，因为无论是对于革兰阳性的还是对于革兰阴性的微生物它都显示出有效的抗微生物活性。众所周知，N4-甲基-D-天冬酰胺酰基羟氨苄青霉素的制备既可（ⅰ）通过使6-氨基青霉烷酸与D-2-（D-2-氨基-3-N-甲基氨基甲酰基-丙酰氨基）-2-对-羟基苯乙酸缩合也可以（ⅱ）通过使羟氨苄青霉素与D-2-氨基-3-N-甲基氨基甲酰基-丙酸缩合的途径进行（美国专利No.4，053，609）。这一点也是众所周知的，即通过使N4-甲基-D-天冬酰胺酰基羟氨苄青霉素粗制品的水溶液与一种非极性的大孔吸收附树脂接触、解吸出被吸附产物并将含有所需的产物的解吸液进行冷冻干燥（liophilizing）（美国专利No.4，313，875）的途径得到以无定形无水物形式的纯N4-甲基-D-天冬酰胺酰基羟氨苄青霉素。但是，用已知方法得到的无定形N4-甲基-D-天冬酰胺酰基羟氨苄青霉素无水物会在环境大气中逐渐吸潮而且它是不稳定的，除非把它避潮避光保存。
现在发现了可以以一种结晶态三水合物形式得到N4-甲基-D-天冬酰胺酰基羟氨苄青霉素。这种新的三水合物从其结晶性和稳定性来说具有优越的性能。尤其是，发现该新的三水合物具有确定的晶体结构并具有显著的贮存稳定性。这些性质给N4-甲基-D-天冬酰胺酰基羟氨苄青霉素提供了在药用中的价值。
根据本发明，可以通过调节N4-甲基-D-天冬酰胺酰基羟氨苄青霉素溶液或在含水介质中的N4-甲基-D-天冬酰胺酰基羟氨苄青霉素盐的pH到3至6以制备所需的三水合物结晶。N4-甲基-D-天冬酰胺酰基羟氨苄青霉素三水合物。在本发明中所用的N4-甲基-D-天冬酰胺酰基羟氨苄青霉素可以采用美国专利No 4，053，609中描述的方法制备的粗产物，也可以采用在美国专利No.4，313，875中描述的方法制备的无定形无水物。N4-甲基-D-天冬酰胺酰基羟氨苄青霉素的盐的例子包括碱金属盐（如钠盐或钾盐），碱土金属（如钙盐或镁盐），氨基酸盐（如L-赖氨酸、L-精氨酸、L-组氨酸或L-鸟氨酸盐）或有机碱盐（如三乙胺、三丁胺或N-甲基-吗啉）。水、含水低级链烷醇（如含水甲醇、含水乙醇或含水丙醇）和含水低级链烷酮（如含水丙酮或含水甲乙酮）适宜于作为含水介质。从工业观点出发，水作为含水介质最好。
在实施本发明的方法中，首先调节N4-甲基-D-天冬酰胺酰基羟氨苄青霉素的溶液或其盐在含水介质溶液的pH到3至6，pH为3.5至5.5更好。例如，当N4-甲基-D-天冬酰胺酰基羟氨苄青霉素被以其游离态形式应用时，则通过向所说化合物的溶液中加入一种酸或一种碱来调节pH。当N4-甲基-D-天冬酰胺酰基羟氨苄青霉素以其盐的形式被应用时，可通过向所述盐的溶液中加入一种酸来调节pH。用于调节pH的酸的例子包括一种无机酸，如盐酸或硫酸或一种有机酸，如柠檬酸;而碱的例子包括一种碱金属氢氧化物如氢氧化钠或氢氧化钾。在调节N4-甲基-D-天冬酰胺酰基羟氨苄青霉素或其盐类的溶液至上述的pH后，所需的三水合物就从所说的溶液中结晶出来。所需的三水合物的结晶可通过该溶液冷却或浓缩，或可通过加入一种可与水互溶的有机溶液或通过上述两种方法的一种结合方法来进行则更为有效。例如，当通过使该溶液冷却来进行结晶时，最好把先前被加热到30至70℃的该溶液冷却到0至10℃。当通过浓缩来进行结晶时，最好把N4-甲基-D-天冬酰胺酰基羟氨苄青霉素或其盐的溶液浓缩至所说化合物的浓度达10～45%（重量），特别是达约30～40%（重量）。还有，当通过加入一种可与水互溶的有机溶液进行结晶时，所说的可与水溶混的有机溶剂可被间歇地或连续地加入到N4-甲基-D-天冬酰胺酰基羟氨苄青霉素或其盐的溶液中。这种可与水互溶的有机溶剂的例子包括一种低级链烷醇，如甲醇、乙醇或丙醇，和一种低级链烷酮，如丙酮或甲乙酮。很容易用一种常用的固液分离技术，如过滤或离心分离，来分离沉淀出来的三水合物。
如在此之前所指出的那样，本发明的N4-甲基-D-天冬酰胺酰基羟氨苄青霉素三水合物在环境大气中不易吸潮并在贮存过程中是稳定的。因此，作为大量的药用物质所说的三水合物比已知的无定形无水物优越。而且，本发明的三水合物易于处理，因为它的松（堆）密度和带静电性小于已知的无定形脱水物的松（堆）密度和带静电性。进一步说，本发明的三水合物的特征在于由于它有良好的结晶性而易于被用以工业规模生产。
实验
（稳定性试验）
分别把本发明的结晶态N4-甲基-D-天冬酰胺酰基羟氨苄青霉素三水合物和无定形N4-甲基-D-天冬酰胺酰基羟氨苄青霉素无水物（按照在美国专利No.4，313，875中描述的方法制备）在一个封闷的管中于40℃下放置5、10、15或30天，用测定每种化合物的N4-甲基-D-天冬酰胺酰基羟氨苄青霉素的含量来计算它的稳定性。结果示于下面的表1中。
在下面所指出的条件下，用高效液相色谱（HPLC）测定了N4-甲基-D-天冬酰胺酰基羟氨苄青霉素的含量。
柱子：十八烷基硅烷（4.6mmφ×150mm）
流动相：磷酸盐 缓冲剂-乙腈（87∶13）（pH：3.0）
流速：1.0毫升/分钟
柱温：40℃
被试验的化合物
1.结晶态N4-甲基-D-天冬酰胺酰基羟氨苄青霉素三水合物（本发明的化合物）
2.N4-甲基-D-天冬酰胺酰基羟氨苄青霉素的无定形无水物（按照美国专利No.4，313，875制备的）。
例1
把10克无定形N4-甲基-D-天冬酰胺酰基羟氨苄青霉素脱水物于40℃下溶于50毫升水中。用稀盐酸调节该溶液的pH为4.0并在30℃下搅拌一小时，然后冷却到5℃。通过过滤收集产生的沉淀，用水洗之并使之干燥，从而得到8克N4-甲基-D-天冬酰胺酰基羟氨苄青霉素白色结晶态固体。
水含量（卡尔.菲希尔法）：
10.05%（相当于3摩尔）
产物的含量（用高效液相法测定）（HPLC）：99.7%
[α]20 D+179.5°（C＝1.0，水）
红外波谱：示于图1
X-射线粉末衍射图：示于下面表2
（电源：Cu：Ni，40Kv，35m A，λ＝1.5405）
无定形N4-甲基-D-天冬酰胺酰基羟氨苄青霉素无水物的X-射线粉末衍射图也示于表2中，仅供参考。
表2
＊相对强度是通过把线的强度与一组标准相比较而估计出来的
vs＝很强，s＝强，m＝中等。w＝弱，vw＝很弱
例2
把10克无定形N4-甲基-D-天冬酰胺酰基羟氨苄青霉素无水物溶于500毫升水中[溶液的pH值为4.3]。把该溶液在减压下浓缩至250克，并往里加入250克乙醇。通过过滤收集产生的沉淀并干燥之，从而得到5克N4-甲基-D-天冬酰胺酰基羟氨苄青霉素白色结晶态固体。
水含量（卡尔.菲希尔法）：
10.74%（相当于3摩尔）
产物的含量（用高效液相法测定）（HPLC）：99.3%
[α]20 D+179.3°（C＝1.0，水）
例3
把70毫升水加至22.2克无定形N4-甲基-D-天冬酰胺酰基羟氨苄青霉素无水物中，并把5.4毫升的20%氢氧化钠水溶液逐滴加于其中以溶解所说的无水物。把活性炭加入溶液中，并过滤该混合物。用20%的盐酸（约5.5毫升）调节滤液到pH3.5。通过过滤收集产生的沉淀并干燥之，从而得到了17克N4-甲基-D-天冬酰胺酰基羟氨苄青霉素白色结晶态固体。
水含量（卡尔.菲希尔法）：
10.21%（相当于3摩尔）
产物的含量（用高效液相法测定）（HPLC）：99.7%
[α]20 D+179.9°（C＝1.0，水）
例4
把20.5克硫代苯甲酰胺溶于290毫升乙醇中，并往里加入32.21克（2S，5R，6R）-6-｛（2R）-2-[（2R）-2-（邻-硝基苯基亚磺酰基）-氨基-3-（N-甲基氨基甲酰基）丙酰氨基]-2-（对-羟基苯基）-乙酰氨基]-3，3-二甲基-7-氧代-4-硫杂-1-氮杂双环[3，2，0]庚烷-2-羧酸三水合物。将该混合物在15到20℃下搅拌17小时以除去氨基-保护基（即，邻-硝基苯基亚磺酰基）。用过滤法收集沉淀物（即N4-甲基-D-天冬酰胺酰基羟氨苄青霉素）并干燥之，然后加入到3克活性炭在50克毫升水中的悬浮液中去。用约3毫升的1%的盐酸调节该悬浮液至pH5.5，并在室温下搅拌一小时。把不溶物滤去，并在减压下浓缩滤液至N4-甲基-D-天冬酰胺酰基羟氨苄青霉素的浓度为40%（重量）。在30℃下搅拌浓缩后的溶液一小时，然后使之冷却至5℃。通过过滤收集产生的沉淀并干燥之，从而得到12.5克N4-甲基-D-天冬酰胺酰基羟氨苄青霉素白色结晶态固体。
水含量（卡尔.菲希尔法）：
10.1%（相当于3摩尔）
产物的含量（用高效液相法测定）（HPLC）：99.7%
[α]20 D+180.0°（C＝1.0，水）
Claims (5)
1、(2S，5R，6R)-6-{(2R)-2-[(2 R)-2-氨基-3-(N-甲基氨基甲酰基)丙酰氨基]-2-(对-羟基苯基)乙酰氨基}-3，3-二甲基-7-氧代-4-硫杂-1-氮杂-1-氮杂双环[3，2，0]庚烷-2-羧酸三水合物。
2、一种制备（2S，5R，6R）-6-｛（2R）-2-[（2R）-2-氨基-3-（N-甲基氨基甲酰基）丙酰氨基]-2-（对-羟基苯基）乙酰氨基｝-3，3-二甲基-7-氧代-4-硫杂-1-氮杂双环[3，2，0]庚烷-2-羧酸三水合物的方法，包括调节（2S，5R，6R）-6-｛（2R）-2-[（2R）-2-氨基-3-（N-甲基氨基甲酰基）丙酰氨基]-2-（对-羟基苯基）乙酰氨基｝-3，3-二甲基-7-氧代-4-硫杂-1-氮杂双环[3，2，0]庚烷-2-羧酸或其盐在含水介质溶液的pH到3至6并使所需要的三水合物结晶。
3、根据权利要求2的一种方法，其中pH被调节到3.5至5.5。
4、根据权利要求2或3的一种方法，其中含水介质是水，一种含水低级链烷醇或一种含水低级链烷酮。
5、根据权利要求4的一种方法，其中结晶是通过使该溶液冷却或浓缩或加入一种可与水互混的有机溶剂的途径进行的。
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2264/86 | 1986-09-24 | ||
| JP61226423A JPS6379888A (ja) | 1986-09-24 | 1986-09-24 | ペニシリン誘導体の安定型水和物 |
| JP226423/86 | 1986-09-24 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN87106308A true CN87106308A (zh) | 1988-04-13 |
| CN1021225C CN1021225C (zh) | 1993-06-16 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN87106308A Expired - Fee Related CN1021225C (zh) | 1986-09-24 | 1987-09-12 | 稳定的青霉素衍生物的水合物的制备方法 |
Country Status (24)
| Country | Link |
|---|---|
| US (1) | US4866170A (zh) |
| EP (1) | EP0261823B1 (zh) |
| JP (1) | JPS6379888A (zh) |
| KR (1) | KR920003902B1 (zh) |
| CN (1) | CN1021225C (zh) |
| AT (2) | ATE59655T1 (zh) |
| AU (1) | AU592467B2 (zh) |
| CA (1) | CA1286285C (zh) |
| DE (1) | DE3766921D1 (zh) |
| DK (1) | DK167319B1 (zh) |
| ES (1) | ES2026545T3 (zh) |
| FI (1) | FI86853C (zh) |
| GR (1) | GR3001274T3 (zh) |
| HK (1) | HK42093A (zh) |
| HU (1) | HU196810B (zh) |
| IE (1) | IE60042B1 (zh) |
| IL (1) | IL83786A (zh) |
| MY (1) | MY102553A (zh) |
| NO (1) | NO169717C (zh) |
| PH (1) | PH23644A (zh) |
| PT (1) | PT85773B (zh) |
| SG (1) | SG15393G (zh) |
| SU (1) | SU1517764A3 (zh) |
| ZA (1) | ZA876739B (zh) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5375123A (en) * | 1993-02-05 | 1994-12-20 | Telefonakitebolaget L. M. Ericsson | Allocation of channels using interference estimation |
| US6473602B1 (en) | 1996-10-28 | 2002-10-29 | Ericsson Inc. | Mobile assisted handoff in radiocommunication systems |
| PE20000879A1 (es) * | 1998-04-29 | 2000-09-23 | Dsm Nv | METODO PARA CRISTALIZAR UN ANTIBIOTICO ß-LACTAMICO |
| KR101879756B1 (ko) * | 2016-11-30 | 2018-08-17 | 주식회사 지앤지비 | 욕실용 난방기 |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NL6705789A (zh) * | 1967-03-08 | 1968-09-09 | ||
| GB1241844A (en) * | 1968-08-23 | 1971-08-04 | Beecham Group Ltd | Penicillins |
| US4053609A (en) * | 1975-09-12 | 1977-10-11 | Tanabe Seiyaku Co., Ltd. | Penicillins and processes for preparing the same |
| JPS5640686A (en) * | 1979-09-11 | 1981-04-16 | Tanabe Seiyaku Co Ltd | Purification of penicillin derivative |
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- 1986-09-24 JP JP61226423A patent/JPS6379888A/ja active Granted
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- 1987-09-03 DE DE8787307794T patent/DE3766921D1/de not_active Expired - Fee Related
- 1987-09-04 IL IL83786A patent/IL83786A/xx not_active IP Right Cessation
- 1987-09-09 ZA ZA876739A patent/ZA876739B/xx unknown
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- 1987-09-12 CN CN87106308A patent/CN1021225C/zh not_active Expired - Fee Related
- 1987-09-18 US US07/098,364 patent/US4866170A/en not_active Expired - Fee Related
- 1987-09-22 AU AU78827/87A patent/AU592467B2/en not_active Ceased
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- 1987-09-23 PT PT85773A patent/PT85773B/pt not_active IP Right Cessation
- 1987-09-23 NO NO873969A patent/NO169717C/no not_active IP Right Cessation
- 1987-09-24 KR KR1019870010566A patent/KR920003902B1/ko not_active IP Right Cessation
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