CN101891742B - Preparation method of meropenem trihydrate crystal - Google Patents
Preparation method of meropenem trihydrate crystal Download PDFInfo
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- CN101891742B CN101891742B CN 201010232096 CN201010232096A CN101891742B CN 101891742 B CN101891742 B CN 101891742B CN 201010232096 CN201010232096 CN 201010232096 CN 201010232096 A CN201010232096 A CN 201010232096A CN 101891742 B CN101891742 B CN 101891742B
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Abstract
The invention discloses a preparation method of a meropenem trihydrate crystal, comprising the following steps: dissolving a crude meropenem product in water at 30-70 DEG C to obtain solution I; treating the solution I with active carbon and then filtering the treated solution at 5-30 DEG C to obtain solution II; adding an organic solvent to the solution II and then cooling to -20-0 DEG C to form a crystal nucleus; and melting the crystal nucleus, adding an organic solvent, and then crystallizing to obtain the meropenem trihydrate crystal. The preparation method is simple and feasible; and the obtained meropenem trihydrate crystal has uniform crystallinity, high purity and fast dissolving performance, and the crystal can be used for preparing a meropenem medicinal preparation with good dissolubility.
Description
Technical field
The present invention relates to a kind of preparation method of compound, relate in particular to a kind of preparation method with Meropenem trihydrate crystals of excellent dissolution performance.
Background technology
Carbapenem antibiotic is a kind of novel complete synthesis β-Nei Xiananleikangshengsu, and gram-positive microorganism and negative bacterium, aerophil, anerobes are all had very strong anti-microbial activity.Since 1976 found sulfomycin, the research of carbapenem antibiotic had had very big development.Particularly 1 beta-methyl carbapenem antibiotic has good chemicalstability, stable to β-Nei Xiananmei and kidney dehydrogenation peptide-I enzyme; Be one of choice drug of treating at present severe and multi-drug resistant bacteria infection, obtained application more and more widely clinically.
Commercial at present 1 beta-methyl carbapenem antibiotic has meropenem, biapenem, S-4661 and ertapenem.Meropenem is that first is applied to 1 clinical Beta-methyl carbapenem antibiotic.Meropenem trihydrate (following formula) is the stable existence mode of meropenem, the existing report of its process for purification.
US2009264643 discloses a kind of process for purification of Meropenem trihydrate, wherein relates to successively adding ammoniacal liquor, first acid for adjusting pH value, uses THF crystalline technology then.This method is more loaded down with trivial details, and THF belongs to two kind solvents, should avoid using in the final step of technology.
US2007197781, CN200610083362.7 disclose to adopt acetone to join to contain the meropenem aqueous solution of crude and have forced brilliant method, and its yield can reach more than 80%.
The preparation method of the relevant Meropenem trihydrate crystals of below having reported does not all relate to its solubility property, and in clinical application, solubility property is an index that receives publicity.The solubility property of Meropenem trihydrate is directly connected to the solvability of its preparation.
Summary of the invention
The purpose of this invention is to provide a kind of simple, be easy to control and effectively prepare Meropenem trihydrate crystalline method, products obtained therefrom has uniform crystallinity, high purity and solubility property fast.
The present invention does not use the freeze-drying and the expensive time-consuming column chromatography purifying technique of loaded down with trivial details power consumption, therefore can satisfy the method requirement of making meropenem, is convenient on technical scale, operate.
In order to realize this purpose, the present invention provides following technical scheme: a kind of method for preparing Meropenem trihydrate crystals comprises step:
1) with the meropenem dissolving crude product in water, solution I;
2) solution I is used activated carbon treatment, filter, get filtrate II;
3) in filtrate II, add organic solvent, make solution form nucleus;
4) said nucleus is melted, add organic solvent, crystallization obtains Meropenem trihydrate crystals.
Wherein, in the step 1), the meropenem bullion can be through any method preparation of the prior art.Water temperature can be preheated to 30～70 ℃.Every gram meropenem bullion uses about 20ml～65ml water, is enough to realize effective purification, and need not anyly be used for concentrating and removal process of separated product.
Step 2) in, said activated carbon treatment is to carry out at a lower temperature, and for example between 5～30 ℃, preferably at 5～10 ℃, low temperature helps preventing the sample degraded fast.Activated carbon treatment is used to adsorb impurity, and the insoluble impurity of part can come along with gac and remove, and the filtrate II of gained is generally transparent, colourless solution.
In the step 3), said nucleus forms under-20～0 ℃ temperature usually, for example-20～-5 ℃.Temperature reduces makes solution system be in solid-liquid mixing, forms nucleus.
In the step 4), said nucleus melts usually being lower than under 30 ℃ the temperature and carries out preferred 0～20 ℃.The crystallization process is carried out under 0～5 ℃ of temperature, can be the mode of stirring and crystallizing, for example stirs 3～4 hours.
The organic solvent that uses among the present invention can be a lower alcohol, like methyl alcohol, ethanol, propyl alcohol and Virahol; Or ketone, like acetone, methyl ethyl ketone; Or its mixture.
The solvability measuring method is: take by weighing the 0.5g Meropenem trihydrate crystals, and 0.1g yellow soda ash, the water that 10ml is 25 ℃ mixes 40 times/min of light rolling, observes with the clarity appearance, writes down the not muddy time, is less than 5 particulate times and complete dissolution time.
Utilize the said determination method; Can record the dissolution time of Meropenem trihydrate crystal in water that adopts the inventive method to make is 30～80 seconds; Be superior to adopting the Meropenem trihydrate crystalline dissolution time (about 2 minutes, seeing comparative example) that method makes described in the one Chinese patent application CN200610083362.7.
Method of the present invention freeze drying technology that use cost is not high and expensive time-consuming again hydrophobic resin column chromatography purifying technique; The gained Meropenem trihydrate crystals not only has uniform crystallinity, high purity; And solubility property is fast arranged, can be used for preparing the meropenem pharmaceutical prepn of favorable solubility.
Embodiment
Below in conjunction with specific embodiment, the present invention is further described, used all ingredients among the embodiment, except that the meropenem bullion according to the said method preparation of CN1948312, be commercially available purchase.
Embodiment 1
Under nitrogen atmosphere, zero(ppm) water (200ml) is heated to 45 ℃～50 ℃.Said meropenem bullion (5.0g, check=93%) is added in the zero(ppm) water, stirred 2 minutes down, add gac 1.0g, be cooled to 5 ℃～10 ℃ then rapidly at 45 ℃～50 ℃.Said carbon is filtered.Add acetone (100ml) in the filtrating, be cooled to-20 ℃～-5 ℃, system is frozen.Kept under this temperature vigorous stirring 30 minutes.Then system temperature is increased to 5 ℃～20 ℃, under this temperature, adds acetone (300ml).Being cooled to 0 ℃～5 ℃ then stirred 3～4 hours.Said crystalline solid is filtered, and use washing with acetone, drying is 3～4 hours under 40 ℃ reduced pressure, obtains white Meropenem trihydrate crystal (4.03g, check 99.5%).The clarity not muddy time of test is 30 seconds, and being less than for 5 particle times is 45 seconds, and dissolution time is 60 seconds fully.
The physics characterization data of gained Meropenem trihydrate:
UV
max H2Onm：297
IR(KBr，cm
-1)：1755，1627，1393，1252，1130
NMR(δ，D
2O)：1.25(d，3H)，1.81-1.96(m，1H)，2.96(s，3H)，3.03(s，3H)，3.14-3.20(m，3H)，3.31-3.41(m，2H)，3.62-3.72(m，1H)，3.90-4.00(m，1H)，4.14-4.26(m，2H)，4.63(t，1H)
Embodiment 2
Use meropenem bullion (5.0g, check=80%) to repeat the method for embodiment 1, obtain white Meropenem trihydrate crystal (3.52g, check 98.2%).The clarity not muddy time of test is 30 seconds, and being less than for 5 particle times is 60 seconds, and dissolution time is 75 seconds fully.
Embodiment 3
Under nitrogen atmosphere, zero(ppm) water (100ml) is heated to 65 ℃.Said meropenem bullion (5.0g, check=93%) is added in the zero(ppm) water, stirred 2 minutes down, add gac 1.0g, be cooled to 5 ℃～10 ℃ then rapidly at 65 ℃.Said carbon is filtered.Add acetone (50ml) in the filtrating, be cooled to-20 ℃～-5 ℃, system is frozen.Kept under this temperature vigorous stirring 30 minutes.Then system temperature is increased to 5 ℃～20 ℃, under this temperature, adds acetone (150ml).Being cooled to 0 ℃～5 ℃ then stirred 3～4 hours.Said crystalline solid is filtered, and use washing with acetone, drying is 3～4 hours under 40 ℃ reduced pressure, obtains white Meropenem trihydrate crystal (4.15g, check 99.3%).The clarity not muddy time of test is 30 seconds, and being less than for 5 particle times is 45 seconds, and dissolution time is 60 seconds fully.
Embodiment 4
In crystallisation process, replace acetone with Virahol, repeat embodiment 3, obtain Meropenem trihydrate crystal (3.85g, 99.1%).The clarity not muddy time of test is 30 seconds, and being less than for 5 particle times is 45 seconds, and dissolution time is 60 seconds fully.
Comparative example
Add 75ml cold distilled water (5%) in the 10g meropenem bullion, be added dropwise to ammoniacal liquor and clarify until system.Add gac 2g and handle after-filtration, with formic acid adjust pH to 5～6, add 4 hours after-filtration of 400ml THF crystallization, THF washing, drying obtain 7g Meropenem trihydrate crystal (check 98.8%).The clarity not muddy time of test is 40 seconds, and being less than for 5 particle times is 70 seconds, and dissolution time is 105 seconds fully.
More than the description of preferred embodiment of the present invention is not limited the present invention, those skilled in the art can make various changes and distortion according to the present invention, only otherwise break away from spirit of the present invention, all should belong to the category of accompanying claims of the present invention.
Claims (6)
1. method for preparing Meropenem trihydrate crystals comprises step:
1) with the meropenem dissolving crude product in water, solution I;
2) solution I is used activated carbon treatment, filter, get filtrate II;
3) in filtrate II, add organic solvent, form nucleus;
4) said nucleus is melted, add organic solvent, crystallization obtains Meropenem trihydrate crystals;
Wherein the said nucleus of step 3) is under-20～0 ℃ temperature, to form; The said nucleus of step 4) is under 0～20 ℃ temperature, to melt, and said organic solvent is selected from one or more in methyl alcohol, ethanol, propyl alcohol, Virahol, acetone and the methyl ethyl ketone, and said crystallization is under 0～5 ℃ temperature, to carry out.
2. the method for claim 1, wherein the temperature of the water of step 1) is 30-70 ℃.
3. the method for claim 1, wherein the by weight/volume of the meropenem bullion of step 1) and water is 1g/ (20-65) ml.
4. the method for claim 1, wherein step 2) activated carbon treatment be under 5～30 ℃ temperature, to carry out.
5. the method for claim 1, wherein step 2) activated carbon treatment be under 5～10 ℃ temperature, to carry out.
6. the method for claim 1, wherein the crystallization of step 4) is a stirring and crystallizing.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103570719A (en) * | 2012-07-31 | 2014-02-12 | 深圳市海滨制药有限公司 | Meropenem raw medicine, preparation method thereof and pharmaceutical composition containing same |
| CN103570718A (en) * | 2012-07-31 | 2014-02-12 | 深圳市海滨制药有限公司 | Meropenem raw medicine, preparation method thereof and pharmaceutical composition containing same |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102267997B (en) * | 2011-07-15 | 2013-01-23 | 海南美兰史克制药有限公司 | Meropenem compound and preparation method thereof |
| CN102964348A (en) * | 2012-12-21 | 2013-03-13 | 卫宏远 | New meropenem crystal form and preparation method thereof |
| CN109239233A (en) * | 2018-11-02 | 2019-01-18 | 海口市制药厂有限公司 | The detection method and application of impurity in meropenem for injection |
| CN113185515A (en) * | 2020-01-14 | 2021-07-30 | 重庆圣华曦药业股份有限公司 | Preparation method of meropenem trihydrate |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006035300A2 (en) * | 2004-09-30 | 2006-04-06 | Ranbaxy Laboratories Limited | A process for the preparation of meropenem |
| CN1948312A (en) * | 2006-03-14 | 2007-04-18 | 深圳市海滨制药有限公司 | Preparation method of meluopeinan |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8097719B2 (en) * | 2008-07-15 | 2012-01-17 | Genesen Labs | Meropenem intermediate in novel crystalline form and a method of manufacture of meropenem |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006035300A2 (en) * | 2004-09-30 | 2006-04-06 | Ranbaxy Laboratories Limited | A process for the preparation of meropenem |
| CN1948312A (en) * | 2006-03-14 | 2007-04-18 | 深圳市海滨制药有限公司 | Preparation method of meluopeinan |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103570719A (en) * | 2012-07-31 | 2014-02-12 | 深圳市海滨制药有限公司 | Meropenem raw medicine, preparation method thereof and pharmaceutical composition containing same |
| CN103570718A (en) * | 2012-07-31 | 2014-02-12 | 深圳市海滨制药有限公司 | Meropenem raw medicine, preparation method thereof and pharmaceutical composition containing same |
| CN103570719B (en) * | 2012-07-31 | 2016-03-02 | 深圳市海滨制药有限公司 | A kind of meropenem bulk drug, its preparation method and comprise its pharmaceutical composition |
| CN103570718B (en) * | 2012-07-31 | 2016-06-29 | 深圳市海滨制药有限公司 | A kind of meropenem crude drug, its preparation method and comprise its pharmaceutical composition |
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Effective date of registration: 20180927 Address after: 518057 Jian Kang Yuan Pharmaceutical Group, No. 17, Langshan Road, North Nanshan District high tech Zone, Shenzhen, Guangdong Patentee after: Jiankangyuan Pharmaceutical Group Co., Ltd. Address before: 518081 2003 Sha Yan Road, Yantian District, Shenzhen, Guangdong Patentee before: Shenzhen Haibin Pharmaceutical Co., Ltd. |
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