CN105294693A - Novel meropenem refining method - Google Patents
Novel meropenem refining method Download PDFInfo
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- CN105294693A CN105294693A CN201510844938.6A CN201510844938A CN105294693A CN 105294693 A CN105294693 A CN 105294693A CN 201510844938 A CN201510844938 A CN 201510844938A CN 105294693 A CN105294693 A CN 105294693A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D477/00—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring
- C07D477/10—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with 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
- C07D477/12—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with 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 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6
- C07D477/16—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with 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 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6 with hetero atoms or carbon atoms 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 3
- C07D477/20—Sulfur atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
The invention relates to a meropenem refining method. The method provided by the invention comprises the following specific steps: (A) dissolving a crude meropenem product in dimethyl sulfoxide to obtain a meropenem dimethyl sulfoxide solution; (B) adding a crystallization agent into the meropenem dimethyl sulfoxide solution obtained in the step A, and stirring for crystallization; and (C) separating, washing and drying the crystals crystallized in the step B, so as to obtain a refined meropenem product. According to the method provided by the invention, the used dissolving agent and crystallization agent in the preparation of meropenem are greatly reduced, the yield is increased, and the obtained meropenem is low in preparation cost, good in crystallization morphology, high in purity and fewer in impurity, so that the method is applicable to industrial large-scale production.
Description
Technical field
The invention belongs to medicinal chemistry art, relate to a kind of process for purification of bulk drug, particularly a kind of process for purification of meropenem.
Background technology
β-lactam antibitics (Beta-lactamantibiotic) is a class microbiotic in chemical structure with beta-lactam nucleus.β-lactam antibitics is a most popular class in current antibiotic, comprises penicillin, cynnematin, monoamide lopps, carbapenems, cephamycin-type, sulfomycin class, monobactams etc.The mechanism of action of β-lactam antibitics to suppress cell wall mucopeptide synthetic enzyme, and then the synthesis of T suppression cell wall mucopeptide, makes bacterial cell wall defect, cause bacterolysis, thus play the effect of sterilization.
Carbapenem antibiotic is a kind of novel β-lactam antibitics, has the features such as stable to β-lactamase, toxicity is low, side effect is little.And carbapenem antibiotic has a broad antifungal spectrum, anti-microbial activity are strong, are one of antibacterials of current main use, have very strong anti-microbial activity to gram-positive microorganism and negative bacterium, aerophil, anerobe.The carbapenem antibiotic of current domestic listing has imipenum, ertapenem, meropenem, Faropenem, panipenem and biapenem.
Meropenem (Meropenem), be translated into Meropenem again, it is the important a member in carbapenem antibiotic family, it has good chemical stability, stablizes β-lactamase and dehydropeptidase of kidney, be one of choice drug for the treatment of severe and multi-drug resistant bacteria infection at present, be widely used clinical.
In prior art, the process for purification about meropenem has Patents bibliographical information:
Patent US2009264643 discloses a kind of process for purification of meropenem, wherein relates to and successively adds ammoniacal liquor, formic acid adjust ph, then use tetrahydrofuran (THF) crystallization.This processing step is various, and process is loaded down with trivial details, and causes production cost higher.
Patent US2007197781 and CN200610083362.7 discloses and adopts acetone to join the method for carrying out crystallization in the meropenem crude product aqueous solution.The method is lower due to the solubleness of meropenem in water, needs to adopt a large amount of water to dissolve, and thus needs to consume a large amount of acetone and carries out crystallization, so there is the high problem of manufacturing cost.
Patent CN101921276 discloses by meropenem dissolving crude product in methyl alcohol, and the mixed solution then adding water and acetone makes meropenem separate out from solution.Because meropenem crude product is unstable in methanol solution, and easy methanol solvate, thus it is on the low side to make this method there is yield, the problem of product contaminant overstandard.
Meropenem solubleness in thumping majority solvent is less, therefore causes in prior art, and meropenem process for purification exists that solvent-oil ratio is large, yield is low, thus causes the production cost of meropenem high.
Invention summary
The present inventor studies and finds that meropenem is very easily dissolved in dimethyl sulfoxide (DMSO), and by dmso solution meropenem crude product, then adding crystallization agent is a kind of process for purification that can obtain high quality meropenem.
According to an aspect of the application, the process for purification of meropenem provided by the invention, said method comprising the steps of:
A. by meropenem dissolving crude product in dimethyl sulfoxide (DMSO), obtain meropenem dimethyl sulphoxide solution;
B. crystallization agent is added, stirring and crystallizing in the meropenem dimethyl sulphoxide solution obtained in steps A; With
C. the crystal separation separated out in step B, washing, drying are obtained meropenem highly finished product.
According to the preferred implementation of the application, carry out desolventing technology in described steps A and filter, preferably using gac to carry out desolventing technology.
According to the preferred implementation of the application, in described steps A, the mass ratio of dimethyl sulfoxide (DMSO) and meropenem crude product is 1.0 ~ 6.0:1; More preferably, the mass ratio of dimethyl sulfoxide (DMSO) and meropenem crude product is 2.0 ~ 5.0:1.
According to the preferred implementation of the application, in described steps A, the temperature of described dissolving is 20 ~ 45 DEG C; More preferably, the temperature of described dissolving is 20 ~ 25 DEG C.
According to the preferred implementation of the application, in described step B, described crystallization agent is the mixed solution of organic solvent and water.
According to the preferred implementation of the application, described organic solvent is one or more the mixture in ethanol, Virahol, acetone, tetrahydrofuran (THF).
According to the preferred implementation of the application, in described crystallization agent, the mass ratio of organic solvent and water is 15.0 ~ 3.0:1.
According to the preferred implementation of the application, in described step B, the mass ratio of described crystallization agent and meropenem crude product is 6.0 ~ 20.0:1; More preferably, the mass ratio of described crystallization agent and meropenem crude product is 8.0 ~ 10.0:1.
According to the preferred implementation of the application, in described step B, the temperature of described crystallization is-10 ~ 20 DEG C; More preferably, the temperature of described crystallization is 0-10 DEG C, more preferably 0 ~ 5 DEG C.
According to the preferred implementation of the application, in described step B, the feed postition of described crystallization agent can adopt and once add or repeatedly add.More preferably, described crystallization agent adds in the mode dripped.
According to the preferred implementation of the application, in described step B, the time of described crystallization is 1.0 ~ 4.0 hours.
According to the preferred implementation of the application, in described step C, described separation is by the crystal of precipitation and solution separating.
According to the preferred implementation of the application, in described step C, use cleaning solvent to wash, described cleaning solvent is the mixed solution of organic solvent and water.
According to the preferred implementation of the application, described organic solvent is one or more the mixture in ethanol, Virahol, acetone, tetrahydrofuran (THF).
According to the preferred implementation of the application, the mass ratio of described organic solvent and water is 15.0 ~ 3.0:1.
Detailed Description Of The Invention
The application relates to a kind of process for purification of meropenem.Specifically, the method for the application comprises the following steps: meropenem dissolving crude product in dimethyl sulfoxide (DMSO), is obtained meropenem dimethyl sulphoxide solution by (A); (B) crystallization agent is added, stirring and crystallizing in the described meropenem dimethyl sulphoxide solution obtained in described steps A; (C) crystal separation separated out in described step B, washing, drying are obtained meropenem highly finished product.
Compared with prior art, the advantage of process for purification of the present invention is: one is overcome the shortcomings such as existing process for purification production efficiency is low, solvent-oil ratio is large, yield is low, preparation method's production efficiency of the application is high, solvating agent, crystallization agent and solvent-oil ratio are little, wherein solvating agent and crystallization agent usage quantity are only about 1/2nd of solvating agent and crystallization agent usage quantity in prior art, and meropenem yield high (>=85%).Such as, (refer to CN101921276) in prior art for 10g meropenem use solvating agent be about 40ml, the amount of the crystallization agent of use is about 200ml; And the solvating agent that the meropenem measured for same 10g in the method for the application uses only needs about 20mL, the consumption of crystallization agent is about 100mL.Therefore compared to existing technology, the method for the application reduces due to the consumption of solvating agent and crystallization agent, makes manufacturing cost reduce 10-15%, is more suitable for industrialized production.Two is because the application employs the dimethyl sulfoxide (DMSO) of very easily dissolving meropenem, more stable in the solvent that meropenem uses in present method, thus meropenem good product quality, impurity are low, meropenem content >=98% in last meropenem highly finished product, and content≤0.03% of major impurity.USP standard requires content≤0.03% of major impurity (open loop meropenem impurity and dimer impurity).Therefore, the meropenem quality using the application's this law to prepare reaches USP standard requirement.
Definition
Meropenem; chemical name (-)-(4R; 5S; 6S)-3-[(3S; 5S)-5-(dimethylin formyl radical)-3-tetramethyleneimine] sulphur-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo [3,2,0] hept-2-ene"-2-carboxylic acid, molecular formula: C
17h
25n
3o
5s, molecular weight 383.5.The solubleness of meropenem in thumping majority solvent is all smaller.The chemical formula of meropenem is
Meropenem has anti-microbial activity to multiple-microorganism, includes but not limited to: gram positive aerobic bacteria, such as streptococcus pneumoniae; Gram negative aerobic bacteria, such as intestinal bacteria, Pseudomonas aeruginosa, hemophilus influenzae; And anerobe: such as peptostreptococcus.
Meropenem is applicable to, by one or more bacterial infection to meropenem sensitivity, include but not limited to pneumonia; Meningitis; Skin soft-tissue infection; Gynecological infection, such as endometritis; Urinary tract infections; Septicemia etc.Meropenem for adult and children all applicable.
The application's term used " anti-microbial activity " refers to that microbiotic suppresses or kills the ability of pathogenetic bacteria.Can the minimum concentration of bacteria growing inhibiting be minimal inhibitory concentration (minimalinhibitoryconcentration, MIC).The minimum concentration can killing more than 99% or 99.5% bacterium is minimal bactericidal concentration (minimalbactericidalconcentration, MBC).
Dimethyl sulfoxide (DMSO) (dimethylsulfoxide, DMSO), molecular formula is (CH
3)
2sO is transparent liquid under normal temperature, and no color or smell, boiling point is high, good stability.
In this application, contriver finds that meropenem is very easily dissolved in dimethyl sulfoxide (DMSO), thus dimethyl sulfoxide (DMSO) is mixed to dissolve meropenem with meropenem crude product.In the preferred implementation of the application, the mass ratio of dimethyl sulfoxide (DMSO) and meropenem crude product is 1.0 ~ 6.0:1, such as 1.5 ~ 6.0:1,2.0 ~ 6.0:1,2.5 ~ 6.0:1,3.0 ~ 6.0:1,3.5 ~ 6.0:1,4.0 ~ 6.0:1,4.5 ~ 6.0:1,5.0 ~ 6.0:1,5.5 ~ 6.0:1,1.0 ~ 5.5:1,1.0 ~ 5.0:1,1..0 ~ 4.5:1,1.0 ~ 4.0:1,1.0 ~ 3.5:1,1.0 ~ 3.0:1,1.0 ~ 2.5:1,1..0 ~ 2.0:1 or 1.0 ~ 1.5:1.In the more preferably embodiment of the application, the mass ratio of dimethyl sulfoxide (DMSO) and meropenem crude product is 2.0 ~ 5.0:1, such as 2.5 ~ 5.0:1,3.0 ~ 5.0:1,3.5 ~ 5.0:1,4.0 ~ 5.0:1,4.5 ~ 5.0:1,2.0 ~ 4.5:1,2.0 ~ 4.0:1,2.0 ~ 3.5:1,2.0 ~ 3.0:1 or 2.0 ~ 2.5:1.In the preferred implementation of the application, the mass ratio of dimethyl sulfoxide (DMSO) and meropenem crude product is 1.0:1,1.5:1,2.0:1,2.5:1,3.0:1,3.5:1,4.0:1,4.5:1,5.0:1,5.5:1 or 6.0:1.
In the preferred implementation of the application, when dimethyl sulfoxide (DMSO) is mixed with meropenem crude product to dissolve meropenem, the temperature of dissolving is 20 ~ 45 DEG C, such as 20 ~ 45 DEG C, 20 ~ 40 DEG C, 20 ~ 35 DEG C, 20 ~ 30 DEG C, 25 ~ 45 DEG C, 30 ~ 45 DEG C, 35 ~ 45 DEG C, 40 ~ 45 DEG C, 25 ~ 40 DEG C, 30 ~ 40 DEG C, 35 ~ 40 DEG C, 25 ~ 35 DEG C or 30 ~ 35 DEG C.In the preferred implementation of the application, the temperature of described dissolving is 20 ~ 25 DEG C, such as 21 ~ 25 DEG C, 22 ~ 25 DEG C, 23 ~ 25 DEG C, 24 ~ 25 DEG C, 21 ~ 24 DEG C, 21 ~ 23 DEG C or 21 ~ 22 DEG C.In the preferred implementation of the application, the temperature of described dissolving is 20 DEG C, 21 DEG C, 22 DEG C, 23 DEG C, 24 DEG C, 25 DEG C, 30 DEG C, 31 DEG C, 32 DEG C, 33 DEG C, 34 DEG C, 35 DEG C, 36 DEG C, 37 DEG C, 38 DEG C, 39 DEG C, 40 DEG C, 41 DEG C, 42 DEG C, 43 DEG C, 44 DEG C or 45 DEG C.
The application's term used " crude product " refers to the head product without purification in production process.Containing a certain amount of impurity in usual crude product.In the application's meropenem crude product used, the ratio of Metro penem compound can be 50 ~ 100%, such as 60 ~ 100%, 70 ~ 100%, 80 ~ 100%, 90 ~ 100%, 95 ~ 100%, 99 ~ 100% etc.
The application's term used " desolventing technology " generally uses physical decolorization process, by solution and adsorbent contact being carried out.Conventional sorbent material includes but not limited to gac, molecular sieve, diatomite, polymeric adsorbent etc.Can pass through after desolventing technology to filter sorbent material.In the preferred implementation of the application, gac is used to carry out desolventing technology and filter.In the embodiment of the application, described filtration can adopt the filter method of any routine known in the art.
In the preferred implementation of the application, the time of desolventing technology is 2-20 minute, such as 3-20,4-20,5-20,8-20,10-20,12-20,15-20,5-18,5-15,5-10,8-15,8-18,10-15 minute.In the more preferably embodiment of the application, the time of desolventing technology is 8-12 minute, more preferably 8,9,10,11 or 12 minutes.
When applying for that term used " crystallization " refers to that material is in nonequilibrium state, material is precipitated from solution with the form of crystal.The application's term used " crystallization agent " is the material of instigating solute to be precipitated from solution with the form of crystal.In the embodiment of the application, described crystallization agent is the mixed solution of organic solvent and water.In the preferred implementation of the application, the organic solvent in described crystallization agent is one or more the mixture in ethanol, Virahol, acetone, tetrahydrofuran (THF).In the preferred implementation of the application, the organic solvent in described crystallization agent is the one in ethanol, Virahol, acetone, tetrahydrofuran (THF).In the preferred implementation of the application, the organic solvent in described crystallization agent is the multiple mixture in ethanol, Virahol, acetone, tetrahydrofuran (THF).
In the preferred implementation of the application, in described crystallization agent, the mass ratio of described organic solvent and water is 15.0 ~ 3.0:1, such as 14.0 ~ 3.0:1, 13.0 ~ 3.0:1, 12.0 ~ 3.0:1, 11.0 ~ 3.0:1, 10.0 ~ 3.0:1, 9.0 ~ 3.0:1, 8.0 ~ 3.0:1, 7.0 ~ 3.0:1, 6.0 ~ 3.0:1, 5.0 ~ 3.0:1, 4.0 ~ 3.0:1, 15.0 ~ 4.0:1, 15.0 ~ 5.0:1, 15.0 ~ 6.0:1, 15.0 ~ 7.0:1, 15.0 ~ 8.0:1, 15.0 ~ 9.0:1, 15.0 ~ 10.0:1, 15.0 ~ 11.0:1, 15.0 ~ 12.0:1, 15.0 ~ 13.0:1, 15.0 ~ 14.0:1, 14.0 ~ 4.0:1, 13.0 ~ 5.0:1, 12.0 ~ 6.0:1, 11.0 ~ 7.0:1, or 10.0 ~ 8.0:1.In the preferred implementation of the application, in described crystallization agent, the mass ratio of described organic solvent and water is 15.0:1,14.0:1,13.0:1,12.0:1,11.0:1,10.0:1,9.0:1,8.0:1,7.0:1,6.0:1,5.0:1,4.0:1 or 3.0:1.
In the preferred implementation of the application, the mass ratio of described crystallization agent and meropenem crude product is 6.0 ~ 20.0:1, such as 6.0 ~ 19.0:1, 6.0 ~ 18.0:1, 6.0 ~ 17.0:1, 6.0 ~ 16.0:1, 6.0 ~ 15.0:1, 6.0 ~ 14.0:1, 6.0 ~ 13.0:1, 6.0 ~ 12.0:1, 6.0 ~ 11.0:1, 6.0 ~ 10.0:1, 6.0 ~ 9.0:1, 6.0 ~ 8.0:1, 6.0 ~ 7.0:1, 7.0 ~ 20.0:1, 9.0 ~ 20.0:1, 9.0 ~ 20.0:1, 10.0 ~ 20.0:1, 11.0 ~ 20.0:1, 12.0 ~ 20.0:1, 13.0 ~ 20.0:1, 14.0 ~ 20.0:1, 15.0 ~ 20.0:1, 16.0 ~ 20.0:1, 17.0 ~ 20.0:1, 18.0 ~ 20.0:1, 19.0 ~ 20.0:1, 7.0 ~ 19.0:1, 8.0 ~ 19.0:1, 9.0 ~ 19.0:1, 10.0 ~ 19.0:1, 10.0 ~ 18.0:1, 10.0 ~ 17.0:1, 10.0 ~ 16.0:1, 10.0 ~ 15.0:1, 10.0 ~ 14.0:1, 10.0 ~ 13.0:1, 10.0 ~ 12.0:1, 10.0 ~ 11.0:1, 11.0 ~ 19.0:1, 12.0 ~ 19.0:1, 13.0 ~ 19.0:1, 14.0 ~ 19.0:1, 15.0 ~ 19.0:1, 16.0 ~ 19.0:1, 17.0 ~ 19.0:1, 18.0 ~ 19.0:1, 7.0 ~ 18.0:1, 7.0 ~ 17.0:1, 7.0 ~ 16.0:1, 7.0 ~ 15.0:1, 7.0 ~ 14.0:1, 7.0 ~ 13.0:1, 7.0 ~ 12.0:1, 7.0 ~ 11.0:1, 7.0 ~ 10.0:1, 7.0 ~ 9.0:1, 7.0 ~ 8.0:1, 8.0 ~ 18.0:1, 8.0 ~ 17.0:1, 8.0 ~ 16.0:1, 8.0 ~ 15.0:1, 8.0 ~ 14.0:1, 8.0 ~ 13.0:1, 8.0 ~ 12.0:1, 8.0 ~ 11.0:1, 8.0 ~ 10.0:1, 8.0 ~ 9.0:1, 9.0 ~ 18.0:1, 9.0 ~ 17.0:1, 9.0 ~ 16.0:1, 9.0 ~ 15.0:1, 9.0 ~ 14.0:1, 9.0 ~ 13.0:1, 9.0 ~ 12.0:1, 9.0 ~ 11.0:1, 9.0 ~ 10.0:1, 11.0 ~ 18.0:1, 12.0 ~ 17.0:1, 13.0 ~ 16.0:1, or 12.0 ~ 16.0:1.In the preferred implementation of the application, the mass ratio of described crystallization agent and meropenem crude product is 8.0 ~ 10.0:1, such as 8.5 ~ 10.0:1,9.0 ~ 10.0:1,9.5 ~ 10.0:1,8.0 ~ 9.5:1,8.0 ~ 9.0:1,8.0 ~ 8.5:1,8.5 ~ 9.5:1,8.5 ~ 9.0:1 or 9.0 ~ 9.5:1.In the preferred implementation of the application, the mass ratio of described crystallization agent and meropenem crude product is 6.0:1,7.0:1,8.0:1,9.0:1,10.0:1,11.0:1,12.0:1,13.0:1,14.0:1,15.0:1,16.0:1,17.0:1,18.0:1,19.0:1 or 20.0:1.
In the preferred implementation of the application, the temperature Wei of described crystallization ?10 ~ 20 DEG C, Li Ru ?5 ~ 20 DEG C, 0 ~ 20 DEG C, 5 ~ 20 DEG C, 10 ~ 20 DEG C, 15 ~ 20 DEG C, ?10 ~ 15 DEG C, ?10 ~ 10 DEG C, ?10 ~ 5 DEG C, ?10 ~ 0 DEG C, ?10～?5 DEG C, ?5 ~ 15 DEG C, ?5 ~ 10 DEG C, ?5 ~ 5 DEG C, ?5 ~ 0 DEG C, 0 ~ 15 DEG C, 5 ~ 15 DEG C or 10 ~ 15 DEG C.In the preferred implementation of the application, the temperature of described crystallization is 0 ~ 10 DEG C, such as 1 ~ 10 DEG C, 2 ~ 10 DEG C, 3 ~ 10 DEG C, 4 ~ 10 DEG C, 5 ~ 10 DEG C, 6 ~ 10 DEG C, 7 ~ 10 DEG C, 8 ~ 10 DEG C, 9 ~ 10 DEG C, 1 ~ 9 DEG C, 1 ~ 8 DEG C, 1 ~ 7 DEG C, 1 ~ 6 DEG C, 1 ~ 5 DEG C, 1 ~ 4 DEG C, 1 ~ 3 DEG C, 1 ~ 2 DEG C, 2 ~ 9 DEG C, 3 ~ 8 DEG C, 4 ~ 7 DEG C, 5 ~ 6 DEG C.In the preferred implementation of the application, the temperature Wei of described crystallization ?10 DEG C, ?9 DEG C, ?8 DEG C, ?7 DEG C, ?6 DEG C, ?5 DEG C, ?4 DEG C, ?3 DEG C, ?2 DEG C, ?1 DEG C, 0 DEG C, 1 DEG C, 2 DEG C, 3 DEG C, 4 DEG C, 5 DEG C, 6 DEG C, 7 DEG C, 8 DEG C, 9 DEG C, 10 DEG C, 11 DEG C, 12 DEG C, 13 DEG C, 14 DEG C, 15 DEG C, 16 DEG C, 17 DEG C, 18 DEG C, 19 DEG C or 20 DEG C.
In the preferred implementation of the application, the feed postition of described crystallization agent can adopt and once add or repeatedly add.In the preferred implementation of the application, the feed postition of described crystallization agent can adopt and once add.In the preferred implementation of the application, the feed postition of described crystallization agent can adopt and repeatedly add, such as, include but not limited to 2 times, 3 times, 4 times, 5 times, 6 times, 7 times, 8 times, 9 times or 10 times and add.In the preferred implementation of the application, the feed postition of described crystallization agent can adopt any feed postition known in the art.In the preferred implementation of the application, the feed postition of described crystallization agent is that the mode dripped adds.
In the preferred implementation of the application, the time of described crystallization is 1.0 ~ 4.0 hours, such as 1.0 ~ 3.5 hours, 1.0 ~ 3.0 hours, 1.0 ~ 2.5 hours, 1.0 ~ 2.0 hours, 1.0 ~ 1.5 hours, 1.5 ~ 4.0 hours, 2.0 ~ 4.0 hours, 2.5 ~ 4.0 hours, 3.0 ~ 4.0 hours, 3.5 ~ 4.0 hours, 1.5 ~ 3.5 hours, 1.5 ~ 3.0 hours, 1.5 ~ 2.5 hours, 1.5 ~ 2.0 hours, 2.0 ~ 3.5 hours, 2.0 ~ 3.0 hours, 2.0 ~ 2.5 hours, 2.5 ~ 3.5 hours, 2.5 ~ 3.0 hours or 3.0 ~ 3.5 hours.In the preferred implementation of the application, the time of described crystallization is 1.0 hours, 1.5 hours, 2.0 hours, 2.5 hours, 3.0 hours, 3.5 hours or 4.0 hours.
In the preferred implementation of the application, in described step C, described separation is by the crystal of precipitation and solution separating.Described separation can adopt the separation method of any routine known in the art, such as filtration or centrifugal.In the preferred implementation of the application, described separation adopts filter method to be separated.In the preferred implementation of the application, described separation adopts centrifugal method to be separated.
In the preferred implementation of the application, the solids wash obtained will be separated in step C.In the preferred implementation of the application, cleaning solvent is selected within the scope of the solvent of crystallization agent.In the preferred implementation of the application, cleaning solvent is the mixed solution of organic solvent and water, and described organic solvent is one or more the mixture in ethanol, Virahol, acetone, tetrahydrofuran (THF).In the preferred implementation of the application, the organic solvent in described cleaning solvent is the one in ethanol, Virahol, acetone, tetrahydrofuran (THF).In the preferred implementation of the application, the organic solvent in described cleaning solvent is the multiple mixture in ethanol, Virahol, acetone, tetrahydrofuran (THF).
In the preferred implementation of the application, described cleaning solvent can be identical or different from the composition of described crystallization agent.In the preferred implementation of the application, described cleaning solvent can be identical with the composition of described crystallization agent, and such as described crystallization agent is acetone and water, and described cleaning solvent is also acetone and water.In the preferred implementation of the application, described cleaning solvent can be different from the composition of described crystallization agent, and such as described crystallization agent is tetrahydrofuran (THF) and water, and described cleaning solvent can be acetone and water, also can be tetrahydrofuran (THF), acetone and water.
In the preferred implementation of the application, in described cleaning solvent, the mass ratio of described organic solvent and water is 15.0 ~ 3.0:1, such as 14.0 ~ 3.0:1, 13.0 ~ 3.0:1, 12.0 ~ 3.0:1, 11.0 ~ 3.0:1, 10.0 ~ 3.0:1, 9.0 ~ 3.0:1, 8.0 ~ 3.0:1, 7.0 ~ 3.0:1, 6.0 ~ 3.0:1, 5.0 ~ 3.0:1, 4.0 ~ 3.0:1, 15.0 ~ 4.0:1, 15.0 ~ 5.0:1, 15.0 ~ 6.0:1, 15.0 ~ 7.0:1, 15.0 ~ 8.0:1, 15.0 ~ 9.0:1, 15.0 ~ 10.0:1, 15.0 ~ 11.0:1, 15.0 ~ 12.0:1, 15.0 ~ 13.0:1, 15.0 ~ 14.0:1, 14.0 ~ 4.0:1, 13.0 ~ 5.0:1, 12.0 ~ 6.0:1, 11.0 ~ 7.0:1, or 10.0 ~ 8.0:1.In the preferred implementation of the application, in described cleaning solvent, the mass ratio of described organic solvent and water is 15.0:1,14.0:1,13.0:1,12.0:1,11.0:1,10.0:1,9.0:1,8.0:1,7.0:1,6.0:1,5.0:1,4.0:1 or 3.0:1.
In the preferred implementation of the application, carry out drying after wash by being separated the solid obtained in step C.In the preferred implementation of the application, described drying can adopt the drying means of any routine known in the art, such as vacuum-drying.
In the preferred implementation of the application, described drying temperature is 10 ~ 40 DEG C, such as 15 ~ 40 DEG C, 20 ~ 40 DEG C, 25 ~ 40 DEG C, 30 ~ 40 DEG C, 35 ~ 40 DEG C, 10 ~ 35 DEG C, 10 ~ 30 DEG C, 10 ~ 25 DEG C, 10 ~ 20 DEG C, 10 ~ 15 DEG C, 15 ~ 35 DEG C, 15 ~ 30 DEG C, 15 ~ 25 DEG C, 15 ~ 20 DEG C, 20 ~ 35 DEG C, 20 ~ 30 DEG C, 20 ~ 25 DEG C, 25 ~ 35 DEG C, 25 ~ 30 DEG C or 30 ~ 35 DEG C.In the preferred implementation of the application, described drying temperature is 10 DEG C, 11 DEG C, 12 DEG C, 13 DEG C, 14 DEG C, 15 DEG C, 16 DEG C, 17 DEG C, 18 DEG C, 19 DEG C, 20 DEG C, 21 DEG C, 22 DEG C, 23 DEG C, 24 DEG C, 25 DEG C, 26 DEG C, 27 DEG C, 28 DEG C, 29 DEG C, 30 DEG C, 31 DEG C, 32 DEG C, 33 DEG C, 34 DEG C, 35 DEG C, 36 DEG C, 37 DEG C, 38 DEG C, 39 DEG C or 40 DEG C.
In the preferred implementation of the application, described time of drying is 2 ~ 10 hours, such as 3 ~ 10 hours, 4 ~ 10 hours, 5 ~ 10 hours, 6 ~ 10 hours, 7 ~ 10 hours, 8 ~ 10 hours, 9 ~ 10 hours, 2 ~ 9 hours, 2 ~ 8 hours, 2 ~ 7 hours, 2 ~ 6 hours, 2 ~ 5 hours, 2 ~ 4 hours, 2 ~ 3 hours, 3 ~ 9 hours, 3 ~ 8 hours, 3 ~ 7 hours, 3 ~ 6 hours, 3 ~ 5 hours, 3 ~ 4 hours, 4 ~ 9 hours, 4 ~ 8 hours, 4 ~ 7 hours, 4 ~ 6 hours, 4 ~ 5 hours, 5 ~ 9 hours, 5 ~ 8 hours, 5 ~ 7 hours, 5 ~ 6 hours, 6 ~ 9 hours, 6 ~ 8 hours, 6 ~ 7 hours, 7 ~ 9 hours, 7 ~ 8 hours, or 8 ~ 9 hours.In the preferred implementation of the application, described time of drying is 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours or 10 hours.
In the embodiment of the application, in step C, by separation, washing, drying, meropenem highly finished product can be obtained, wherein meropenem content >=98%, such as 98.1%, 98.2%, 98.3%, 98.4%, 98.5%, 98.6%, 98.7%, 98.8%, 98.9%, 99.0%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, 99.9%, 100%.
The application's term used " impurity " refers to the impure composition be mingled with in material.In the embodiment of the application, the impurity in meropenem highly finished product is the composition not belonging to meropenem be mingled with in these highly finished product.In the embodiment of the application, the impurity in meropenem highly finished product includes but not limited to, open loop meropenem impurity, dimer impurity etc.These impurity can affect the anti-microbial activity of Metro penem compound in highly finished product.In this area, according to " American Pharmacopeia " standard (USP32-NF27), when major impurity (being open loop meropenem impurity and dimer impurity in the application) content is no more than 0.03%, can be considered as this impurity does not affect.In other words, the meropenem quality using the application's method to prepare reaches USP standard requirement.
Directly can be prepared into pharmaceutical composition or various medicament according to meropenem prepared by the application's method, also may be used for next step and produce, such as, mix with pharmaceutical adjunct.Medicament described in the application can be tablet, pill, capsule, granule, pulvis, suppository, powder, paste, patch, injection liquid, solution, suspension, sprays, lotion, drops, liniment.Described medicament also can be made into dry powder form, and mixes to make solution form with sterilized water or damping fluid before administration.The pH of described damping fluid is generally 3-11, preferred 5-9, more preferably 7-8.
In the preferred implementation of the application, according to weight yield >=85% of meropenem prepared by the application's method, such as >=86%, >=87%, >=88%, >=89%, >=90%, >=91%, >=92%, >=93%, >=94%, >=95%, >=96%, >=97%, >=98%, >=99% or 100%.
The meropenem compound that the application provides also can be included in all isotropic substances of the atom existed in intermediate or product.In compound described in the application, isotopic example includes but not limited to the isotropic substance of the elements such as hydrogen, carbon, nitrogen, fluorine, chlorine, oxygen, sulphur or phosphorus, such as
2h (deuterium),
3h (tritium),
13c,
11c,
14c,
15n,
18f,
36cl,
18o,
17o,
35s,
31p or
32p etc.
Compound described in the application also comprises the tautomeric forms of this compound, such as keto-enol tautomerism body.
Compound described in the application comprises anhydrate form and the non solvate form of this compound, also comprises hydrate and the solvate form thereof of this compound.In the application, term " solvate " refers to the molecule comprising described compound and one or more pharmaceutically acceptable solvent molecule (as ethanol).According to some embodiment of the application, such as 1-8 solvent molecule in described solvate, can be comprised, as 1-6,1-4,1-3,1-2,2-6,2-4,2-3,3-6 or 3-4.When wherein solvent is water, described solvate is hydrate.
The meropenem compound prepared by the application's method can give object by suitable administering mode.Term " administration ", " giving " or " bestowing " refer to and give object by the compound of doses or pharmaceutical composition by suitable administering mode.
Described " administering mode " includes but not limited to any administering modes known in the art such as administration in oral administration, intravenous administration, respiratory tract, sublingual administration, topical, intramuscular adminstration, eye drops, Transdermal absorption, parenteral admin, Intraperitoneal medication, vagina administration, Buccal administration, per rectum administration.The administering mode that those skilled in the art should understand object depends on multiple factor, and described factor comprises the composition etc. of the position of disease, the age of object, the severity of disease and pharmaceutical composition.
Meropenem compound described in the application or pharmaceutical composition can administrations at any time.Such as described compound or pharmaceutical composition can before object seizure of disease, outbreak time or outbreak after administration, such as can before seizure of disease or postictal about 1 hour, about 2 hours, about 4 hours, about 5 hours, about 8 hours, about 12 hours, about 24 hours, about 2 days, about 4 days, about 8 days, about 16 days, about 30 days or 1 month, about 2 months, about 4 months, about administration in 6 months.
Meropenem compound described in the application or pharmaceutical composition can single administrations, also can multiple dosing.When multiple dosing, can in the mode of interval random time, such as subsequent dose and preceding dosage be spaced apart about 8 weeks, about 4 weeks, about 2 weeks, about 1 week, about 5 days, about 3 days, about 2 days, about 24 hours, about 12 hours, about 8 hours, about 6 hours, about 4 hours, about 3 hours, about 2 hours, about 1 hour, about 30 minutes or less time.
Meropenem compound described in the application or pharmaceutical composition can be individually dosed, administered in combination that also can be suitable with other.Described Combined Preparation can be such as with other drug simultaneously administration or consecutive administration.When consecutive administration, can in the mode of interval random time.
After object administration is pointed in term " treatment " or " process ", can " prevent ", " control ", " suppression ", the disease of " improvement " or " healing " object, disorder or disease condition.
In the application, term " object ", " experimenter " or " patient " can exchange use, and have implication widely, comprise people or non-human mammal, such as dog, cat, mouse, rat, sheep, pig, goat, milk cow, non-human primate; Or bird, such as chicken, duck, goose; Comprise other vertebratess, spinal animal, also comprise external tissue, prokaryotic cell prokaryocyte or eukaryotic cell etc.According to some embodiment of the application, described to liking Mammals.According to some embodiment of the application, described to liking primate.According to some embodiment of the application, described to liking people.
When to as if people time, the usual amounts be administered systemically includes but not limited to 10ng/kg-100mg/kg, such as 10-100ng/kg, 10-500ng/kg, 10-1000ng/kg, 50-500ng/kg, 50-1000ng/kg, 1-10 μ g/kg, 5-50 μ g/kg, 10-100 μ g/kg, 100-500 μ g/kg, 250-750 μ g/kg, 10-1000 μ g/kg, 100-1000 μ g/kg, 500-1000 μ g/kg, 1-10mg/kg, 5-50mg/kg, 20-50mg/kg, 25-75mg/kg, 1-100mg/kg, 20-100mg/kg, 50-100mg/kg, 75-100mg/kg, 1mg/kg, 5mg/kg, 10mg/kg, 20mg/kg, 30mg/kg, 40mg/kg, 50mg/kg, 75mg/kg, 100mg/kg etc.
Term used herein " pharmaceutical adjunct " is pharmaceutically acceptable composition or medium, includes but not limited to solvent, vehicle, thinner, adjuvant, weighting agent etc.Common pharmaceutical adjunct comprises physiological saline, buffer reagent, carbohydrate, gelatin, starch, Ringer's solution, Mierocrystalline cellulose etc.The pH of described pharmaceutical adjunct is generally 3-11, preferred 5-9, more preferably 7-8.
In this application when " about " is for modifying certain numerical value, refer to described numerical value can fluctuate ± 10%, ± 9%, ± 8%, ± 7%, ± 6%, ± 5%, ± 4%, ± 3%, in ± the scope of 2% or ± 1%.
Unless be otherwise noted in this application or contradiction obvious with context, in the context describing the application, (comprising in the context of claim) term " one ", " one ", " described ", " being somebody's turn to do " and " at least one " and similar referring to of using is interpreted as covering odd number and plural number.Unless be otherwise noted in this application or contradiction obvious with context, the term used in the application " comprise ", " having ", " comprising " and " containing " be interpreted as open-ended term (namely " including but not limited to ").Unless be otherwise noted in this application or contradiction obvious with context, all methods described in the application according to the understanding of those skilled in the art, can be carried out with any suitable order.
The all patents quoted in the application, patent application and reference are incorporated to the application all by way of reference in full, and its incorporated extent is just quoted separately as a reference as each section of document.If there is conflict between the application and document provided herein, should be as the criterion with the content in the application.
This application describes preferred embodiment and embodiment, those skilled in the art, on the basis of reading the application, can carry out suitable change to the embodiment described in the application and embodiment.Therefore, the application comprises all equivalent modifications and variations to theme in the application's claims in law allowed band.
Embodiment
Unless otherwise defined, all technical terms used herein or proprietary vocabulary have usual the understood implication of those of ordinary skill in the technology of the present invention field.
Below with reference to embodiment, the present invention is described.Those having ordinary skill in the art will appreciate that, following embodiment is for illustrative purposes, should not be interpreted as limitation of the present invention by any way.Protection scope of the present invention limited by accompanying claim.
embodiment 1
Take 20.0ml dimethyl sulfoxide (DMSO), put into flask, temperature 20 ~ 25 DEG C, add 10.0 grams of meropenem crude products, clearly molten.Add 0.2 gram of gac, stir 10 minutes, filter, obtain meropenem dimethyl sulphoxide solution.Then 100ml crystallization agent (acetone: water=4:1) is dripped, time for adding 30 minutes.Drip off rear cooling 0 ~ 5 DEG C, stir 2 hours.Filter, filter cake proper amount of acetone is washed.Filter cake 30 DEG C of vacuum-dryings 3 hours, obtain 9.5 grams of meropenem highly finished product (weight yield 95%).Gained meropenem highly finished product are as follows by HPLC analytical results: meropenem content >=98%, content≤0.01% of open loop meropenem foreign matter content≤0.03%, dimer impurity content≤0.03%, maximum unknown single contaminant.
embodiment 2
Take 20.0ml dimethyl sulfoxide (DMSO), put into flask, temperature 20 ~ 25 DEG C, add 10.0 grams of meropenem crude products, clearly molten.Add 0.2 gram of gac, stir 10 minutes, filter, obtain meropenem dimethyl sulphoxide solution.Then 90ml crystallization agent (acetone: water=5:1) is dripped, time for adding 30 minutes.After dripping off, 0 ~ 5 DEG C is stirred 2 hours.Filter, filter cake proper amount of acetone is washed.Filter cake 30 DEG C of vacuum-dryings 3 hours, obtain 9.2 grams of meropenem highly finished product (weight yield 92%).Gained meropenem highly finished product are as follows by HPLC analytical results: meropenem content >=98%, content≤0.01% of open loop meropenem foreign matter content≤0.03%, dimer impurity content≤0.03%, maximum unknown single contaminant.
embodiment 3
Take 20.0ml dimethyl sulfoxide (DMSO), put into flask, temperature 20 ~ 25 DEG C, add 10.0 grams of meropenem crude products, clearly molten.Add 0.2 gram of gac, stir 10 minutes, filter, obtain meropenem dimethyl sulphoxide solution.Then 100ml crystallization agent (acetone: water=3:1) is dripped, time for adding 30 minutes.After dripping off, 0 ~ 5 DEG C is stirred 2 hours.Filter, filter cake proper amount of acetone is washed.Filter cake 30 DEG C of vacuum-dryings 3 hours, obtain 9.1 grams of meropenem highly finished product (weight yield 91%).Gained meropenem highly finished product are as follows by HPLC analytical results: meropenem content >=98%, content≤0.01% of open loop meropenem foreign matter content≤0.03%, dimer impurity content≤0.03%, maximum unknown single contaminant.
embodiment 4
Take 20.0ml dimethyl sulfoxide (DMSO), put into flask, temperature 20 ~ 25 DEG C, add 10.0 grams of meropenem crude products, clearly molten.Add 0.2 gram of gac, stir 10 minutes, filter, obtain meropenem dimethyl sulphoxide solution.Then 90ml crystallization agent (acetone: tetrahydrofuran (THF): water=4:1:1) is dripped, time for adding 30 minutes.After dripping off, 0 ~ 5 DEG C is stirred 2 hours.Filter, filter cake proper amount of acetone is washed.Filter cake 30 DEG C of vacuum-dryings 3 hours, obtain 9.3 grams of meropenem highly finished product (weight yield 93%).Gained meropenem highly finished product are as follows by HPLC analytical results: meropenem content >=98%, content≤0.01% of open loop meropenem foreign matter content≤0.03%, dimer impurity content≤0.03%, maximum unknown single contaminant.
embodiment 5
Take 20.0ml dimethyl sulfoxide (DMSO), put into flask, temperature 20 ~ 25 DEG C, add 10.0 grams of meropenem crude products, clearly molten.Add 0.2 gram of gac, stir 10 minutes, filter, obtain meropenem dimethyl sulphoxide solution.Then 100ml gram of crystallization agent (acetone: Virahol: water=3:1:1) is dripped, time for adding 30 minutes.After dripping off, 0 ~ 5 DEG C is stirred 2 hours.Filter, filter cake proper amount of acetone is washed.Filter cake 30 DEG C of vacuum-dryings 3 hours, obtain 9.0 grams of meropenem highly finished product (weight yield 90%).Gained meropenem highly finished product are as follows by HPLC analytical results: meropenem content >=98%, content≤0.01% of open loop meropenem foreign matter content≤0.03%, dimer impurity content≤0.03%, maximum unknown single contaminant.
embodiment 6
Take 20.0ml dimethyl sulfoxide (DMSO), put into flask, temperature 20 ~ 25 DEG C, add 10.0 grams of meropenem crude products, clearly molten.Add 0.2 gram of gac, stir 10 minutes, filter, obtain meropenem dimethyl sulphoxide solution.Then 90ml crystallization agent (acetone: Virahol: ethanol: water=3:1:1:1) is dripped, time for adding 30 minutes.After dripping off, 0 ~ 5 DEG C is stirred 2 hours.Filter, filter cake proper amount of acetone is washed.Filter cake 30 DEG C of vacuum-dryings 3 hours, obtain 8.8 grams of meropenem highly finished product (weight yield 88%).Gained meropenem highly finished product are as follows by HPLC analytical results: meropenem content >=98%, content≤0.01% of open loop meropenem foreign matter content≤0.03%, dimer impurity content≤0.03%, maximum unknown single contaminant.
embodiment 7
Take 20.0ml dimethyl sulfoxide (DMSO), put into flask, temperature 20 ~ 25 DEG C, add 10.0 grams of meropenem crude products, clearly molten.Add 0.2 gram of gac, stir 10 minutes, filter, obtain meropenem dimethyl sulphoxide solution.Then 90ml crystallization agent (acetone: Virahol: ethanol: tetrahydrofuran (THF): water=2:1:1:1:1) is dripped, time for adding 30 minutes.After dripping off, 0 ~ 5 DEG C is stirred 2 hours.Filter, filter cake proper amount of acetone is washed.Filter cake 30 DEG C of vacuum-dryings 3 hours, obtain 8.5 grams of meropenem highly finished product (weight yield 85%).Gained meropenem highly finished product are as follows by HPLC analytical results: meropenem content >=98%, content≤0.01% of open loop meropenem foreign matter content≤0.03%, dimer impurity content≤0.03%, maximum unknown single contaminant.
Be explained above each embodiment of the application.Those skilled in the art's content disclosed in this specification sheets can be expected easily, can suitably adjust each embodiment according to actual needs and reconfigure, and can not depart from the spirit of the application.The protection domain of the application is as the criterion with claims of the application.
Claims (10)
1. a process for purification for meropenem, said method comprising the steps of:
A. by meropenem dissolving crude product in dimethyl sulfoxide (DMSO), obtain meropenem dimethyl sulphoxide solution;
B. crystallization agent is added, stirring and crystallizing in the described meropenem dimethyl sulphoxide solution obtained in described steps A;
C. the crystal separation separated out in described step B, washing, drying are obtained meropenem highly finished product.
2. the process for purification of meropenem according to claim 1, is characterized in that: also carry out desolventing technology in described steps A and filter, and preferably uses gac to carry out desolventing technology.
3. the process for purification of meropenem according to claim 1, is characterized in that: in described steps A, and the mass ratio of dimethyl sulfoxide (DMSO) and meropenem crude product is 1.0 ~ 6.0:1; Preferably, the mass ratio of dimethyl sulfoxide (DMSO) and meropenem crude product is 2.0 ~ 5.0:1.
4. the process for purification of meropenem according to claim 1, is characterized in that: in described steps A, and the temperature of described dissolving is 20 ~ 45 DEG C; Preferably, the temperature of described dissolving is 20 ~ 25 DEG C.
5. the process for purification of meropenem according to claim 1, it is characterized in that: in described step B, described crystallization agent is the mixed solution of organic solvent and water, preferably, described organic solvent is one or more the mixture in ethanol, Virahol, acetone, tetrahydrofuran (THF), preferably, in described crystallization agent, the mass ratio of organic solvent and water is 15.0 ~ 3.0:1.
6. the process for purification of meropenem according to claim 1, is characterized in that: in described step B, and the mass ratio of described crystallization agent and meropenem crude product is 6.0 ~ 20.0:1; Preferably, the mass ratio of described crystallization agent and meropenem crude product is 8.0 ~ 10.0:1.
7. the process for purification of meropenem according to claim 1, is characterized in that: in described step B, and the temperature of described crystallization is-10 ~ 20 DEG C; Preferably, the temperature of described crystallization is 0 ~ 10 DEG C.
8. the process for purification of meropenem according to claim 1, is characterized in that: in described step B, and the feed postition of described crystallization agent can adopt and once add or repeatedly add; Preferably, add in the mode dripped.
9. the process for purification of meropenem according to claim 1, is characterized in that: in described step B, and the time of described crystallization is 1.0 ~ 4.0 hours.
10. the process for purification of meropenem according to claim 1, it is characterized in that: in described step C, cleaning solvent is used to wash, described cleaning solvent is the mixed solution of organic solvent and water, preferably, described organic solvent is one or more the mixture in ethanol, Virahol, acetone, tetrahydrofuran (THF), and preferably, the mass ratio of described organic solvent and water is 15.0 ~ 3.0:1.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101921276A (en) * | 2010-09-07 | 2010-12-22 | 江苏天禾迪赛诺制药有限公司 | Crystallization refining method of Meropenem |
| CN102702203A (en) * | 2012-06-19 | 2012-10-03 | 浙江海翔药业股份有限公司 | Meropenem refining method |
| CN103570720A (en) * | 2012-07-31 | 2014-02-12 | 新乡海滨药业有限公司 | Meropenem raw medicine, preparation method thereof and pharmaceutical composition containing same |
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2015
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101921276A (en) * | 2010-09-07 | 2010-12-22 | 江苏天禾迪赛诺制药有限公司 | Crystallization refining method of Meropenem |
| CN102702203A (en) * | 2012-06-19 | 2012-10-03 | 浙江海翔药业股份有限公司 | Meropenem refining method |
| CN103570720A (en) * | 2012-07-31 | 2014-02-12 | 新乡海滨药业有限公司 | Meropenem raw medicine, preparation method thereof and pharmaceutical composition containing same |
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Application publication date: 20160203 |