CN108659007A - A kind of preparation method of dicloxacillin sodium pillar-shaped crystal - Google Patents
A kind of preparation method of dicloxacillin sodium pillar-shaped crystal Download PDFInfo
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- CN108659007A CN108659007A CN201810812620.3A CN201810812620A CN108659007A CN 108659007 A CN108659007 A CN 108659007A CN 201810812620 A CN201810812620 A CN 201810812620A CN 108659007 A CN108659007 A CN 108659007A
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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
- C07D499/86—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 only atoms other than nitrogen atoms 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
- C07D499/865—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 only atoms other than nitrogen atoms 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 with hetero atoms or with 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 6
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- C—CHEMISTRY; METALLURGY
- 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
- C07D499/04—Preparation
- C07D499/10—Modification of an amino radical directly attached in position 6
- C07D499/12—Acylation
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- C07D499/18—Separation; Purification
- C07D499/20—Separation; Purification via salts with organic bases
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Abstract
The present invention provides a kind of preparation methods of dicloxacillin sodium pillar-shaped crystal, prepare the supersaturated solution of dicloxacillin sodium, are crystallized in the supersaturated solution, obtain dicloxacillin sodium pillar-shaped crystal；The secondary solvent that the organic solvent of the supersaturated solution includes the alcohols solvent that volume fraction is 74 ~ 100% and volume fraction is 0 ~ 26%；Content≤3.5wt% of water impurity in the organic solvent.The method of the present invention is simple and practicable, products obtained therefrom function admirable, with good geometric crystallography appearance, purity and yield are higher, impurity is few, and is easy to be separated by solid-liquid separation in preparation process, hence it is evident that reduces the difficulty of production operation, the production cycle is greatly shortened, there is extensive prospects for commercial application.
Description
Technical field
The present invention relates to a kind of preparation methods of dicloxacillin sodium, and it is brilliant to concretely relate to a kind of dicloxacillin sodium cylindricality
The preparation method of body.
Background technology
Dicloxacillin sodium, chemical name are：(2S, 5R, 6R) -3,3- dimethyl -6- [5- methyl -3- (2,6- dichloro-benzenes
Base) -4- isoxazoles formamido group] -7- oxos -4- thia -1- azabicyclos [3.2.0] heptane -2- sodium formates, structural formula is such as
Shown in lower：
。
Dicloxacillin sodium belongs to isoxazole beta-lactam class antibiotic, has the characteristics that acidproof, resistance to enzyme, to staphylococcus and
Gram positive bacteria has antibacterial activity.As antimicrobial DP finish, dicloxacillin sodium can be used for infecting the drug resistant S. aureus L-forms of benzyl penicillin
Treatment.
In the crystallization preparation method of dicloxacillin sodium, generally use esters solvent is crystallized, and double chlorine west are prepared
Woods sodium crystal, if patent document CN201180072474.1 discloses a kind of preparation method of isoxazolyl penicillin sodium salt,
It is that isoxazolyl penicillin acid is prepared first（Such as Cloxacillin acid, dicloxacillin acid, flucloxacillin acid）Esters solution,
The esters solution is washed with saturated nacl aqueous solution, 2 ethyl hexanoic acid sodium then is added in the esters solution after the washing
Isoxazolyl penicillin sodium salt such as Cloxacillin Sodium, dicloxacillin sodium, flucloxacillin sodium etc. is obtained in solution, after crystallization.Using
The crystal being prepared in the method for esters solvent as crystallizing system primary solvent is mostly irregular sheet, and granularity is smaller, leads
Cause filtration time long, it is difficult to which dry, life cycle of the product is long, and production capacity is low, and esters solvent is easy to wrap in crystal
Portion, it is difficult to be removed by means such as washing, centrifugal dryings, product quality is unqualified.
Therefore, there is an urgent need for develop the novel processing step of dicloxacillin sodium crystal regular shape is prepared to be convenient for
Post-processings and the higher crystal of purity such as filter, dry.
Invention content
It is an object of the invention to provide a kind of preparation methods of dicloxacillin sodium pillar-shaped crystal, to solve existing synthesis side
The problem of crystal shape is irregular in method, and last handling process is complicated, and product quality is to be improved.
The object of the present invention is achieved like this：
A kind of preparation method of dicloxacillin sodium pillar-shaped crystal, prepares the supersaturated solution of dicloxacillin sodium, in the supersaturation
It is crystallized in solution, obtains dicloxacillin sodium pillar-shaped crystal；The organic solvent of the supersaturated solution includes that volume fraction is
The secondary solvent that 74 ~ 100% alcohols solvent and volume fraction is 0 ~ 26%；The content of water impurity in the organic solvent≤
3.5wt%。
Preferably, the alcohols solvent includes lower alcohol, more preferably includes C1~C4Alcohol.
Preferably, the alcohols solvent includes that ethyl alcohol, isopropanol or both are dissolved each other the mixed solvent to be formed with arbitrary proportion；
Preferably, the alcohols solvent of the supersaturated solution is ethyl alcohol or isopropanol；It is highly preferred that the alcohols of the supersaturated solution is molten
Agent is isopropanol.
Preferably, the volume fraction of the alcohols solvent of the supersaturated solution is 74 ~ 99.5%；In the supersaturated solution
The content of water is 0.07 ~ 3.5wt%.
The secondary solvent includes the solvent that can dissolve 3- (2,6- dichlorophenyls) -5- methyl isoxazole-4-formyl chlorides；
Preferably, the secondary solvent includes at least one of dichloromethane, acetone, methyl acetate, more preferable dichloromethane or third
Ketone.
A concentration of 0.007 ~ 0.11g/ml of the supersaturated solution of the dicloxacillin sodium.
The supersaturated solution of the dicloxacillin sodium can be used existing preparation method and obtain, such as reactive crystallization, recrystallization
With evaporative crystallization etc..The amount of dicloxacillin sodium includes the dicloxacillin sodium crystal being precipitated in system, further includes not crystallizing analysis
The dicloxacillin sodium in dissolved state gone out.
Preferably, the supersaturated solution of the dicloxacillin sodium is made according to the following steps：
Prepare the dicloxacillin acid solution being dissolved in the first solvent；Prepare the 2 ethyl hexanoic acid sodium solution being dissolved in the second solvent；
Dicloxacillin acid solution is added into 2 ethyl hexanoic acid sodium solution, you can obtain the supersaturated solution of dicloxacillin sodium；
The mixing that first solvent can be selected from alcohols solvent, secondary solvent or the alcohols solvent and the secondary solvent is molten
Agent, wherein the secondary solvent can be at least one of acetone, dichloromethane, methyl acetate；Second solvent also may be used
Mixed solvent selected from alcohols solvent, secondary solvent or the alcohols solvent and the secondary solvent, preferably alcohols solvent；Institute
Stating the first solvent can be identical as the second solvent, can also be different, the mistake of obtained dicloxacillin sodium after the two need to only mixed
Organic solvent used includes the alcohols solvent that volume fraction is 74 ~ 100% and the auxiliary that volume fraction is 0 ~ 26% in saturated solution
Solvent.
Preferably, the dicloxacillin acid solution is using 6-amino-penicillanic acid, 3- (2,6- dichlorophenyl) -5- methyl
The reaction of isoxazole -4- formyl chlorides is prepared.
Specifically, the preparation method of the dicloxacillin acid solution includes：6-amino-penicillanic acid is soluble in water, it obtains
The suspension of 6-amino-penicillanic acid；3- (2,6- dichlorophenyls) -5- methyl isoxazole-4-formyl chlorides are dissolved in third solvent
In, the third solvent is selected from any one of acetone, dichloromethane, methyl acetate；Adjust 6-amino-penicillanic acid aqueous solution
PH be 7 ~ 8, until system clarify, then thereto be added 3- (2,6- dichlorophenyl) -5- methyl isoxazole-4-formyl chloride solution,
Acylation reaction is carried out, pH=7 ~ 8 are controlled；After reaction, dichloromethane or methyl acetate are added into system, and is adjusted using acid
For section to pH=2.0 ± 0.2, split-phase removes a layer organic phase, obtains dicloxacillin acid solution.
Optionally, ethyl alcohol, isopropanol or both are added into the dicloxacillin acid solution of gained after split-phase with arbitrary proportion
Dissolve each other the mixed solvent to be formed.
Preferably, into 2 ethyl hexanoic acid sodium solution, the process of addition dicloxacillin acid solution includes：First to gained
The 18 ~ 30% of pre-add dicloxacillin acid solution volume in 2 ethyl hexanoic acid sodium solution after crystal to appear, are further continued for being added remaining
Dicloxacillin acid solution.
During preparing dicloxacillin sodium crystal, it can be tied in 10 ~ 30 DEG C under static conditions or stirring condition
It is brilliant.
The present invention is using alcohols solvent as the primary solvent for preparing dicloxacillin sodium crystal, by preparing dicloxacillin acid
The double chlorine west practised with cylindricality crystalline substance has been prepared in supersaturated solution, while many factors in control system under given conditions
Woods sodium crystal, obtained crystal have good geometric crystallography appearance, and yield is higher, and impurity content is relatively low, it is not easy to press from both sides
Miscellaneous residual solvent, and be easy to be separated by solid-liquid separation in preparation process, the dicloxacillin sodium for overcoming prior art preparation is brilliant
Body is tiny, is difficult to the defect filtered, and solves the problems, such as that residual solvent is underproof, can obviously reduce the difficulty of production operation,
Substantially shorten the production cycle.
The method of the present invention is simple and practicable, products obtained therefrom function admirable, effectively increases the quality and yield of product, both can be used
In the preparation of dicloxacillin sodium crystal seed and standard items, the lab scale craft research for dicloxacillin sodium can be also promoted, is more conducively referred to
The industrialized production of dicloxacillin sodium is led, there is extensive prospects for commercial application.
Description of the drawings
Fig. 1 is the SEM figures of the dicloxacillin sodium crystal prepared by embodiment 1.
Fig. 2 is the liquid phase spectrogram of the dicloxacillin sodium crystal prepared by embodiment 1.
Fig. 3 is the SEM figures of the dicloxacillin sodium crystal prepared by embodiment 2.
Fig. 4 is the SEM figures of the dicloxacillin sodium crystal prepared by embodiment 3.
Fig. 5 is the SEM figures of the dicloxacillin sodium crystal prepared by embodiment 4.
Fig. 6 is the SEM figures of the dicloxacillin sodium crystal prepared by embodiment 5.
Fig. 7 is the SEM figures of the dicloxacillin sodium crystal prepared by embodiment 6.
Fig. 8 is the SEM figures of the dicloxacillin sodium crystal prepared by embodiment 7.
Fig. 9 is the SEM figures of the dicloxacillin sodium crystal prepared by embodiment 8.
Figure 10 is the SEM figures of the dicloxacillin sodium crystal prepared by embodiment 9.
Figure 11 is the SEM figures of the dicloxacillin sodium crystal prepared by comparative example 1.
Figure 12 is the SEM figures of the dicloxacillin sodium crystal prepared by comparative example 2.
Figure 13 is the SEM figures of the dicloxacillin sodium crystal prepared by comparative example 3.
Specific implementation mode
With reference to embodiment, the present invention is further elaborated, and following embodiments are only as explanation, not with any
Mode limits the scope of the invention.
Agents useful for same is to analyze pure or chemical pure and commercially available or pass through those of ordinary skill in the art in embodiment
It is prepared by well known method.Following embodiments realize the purpose of the present invention.
Embodiment 1
At 0 ~ 5 DEG C, 12g 6-amino-penicillanic acids are put into 60ml purified waters（6-APA）, 10wt% is added dropwise into system
NaOH aqueous solutions 20ml, 20min are added dropwise；With the different evil of 70ml acetone solution 16.2g 3- (2,6- dichlorophenyls) -5- methyl
Azoles -4- formyl chlorides are configured to 3- (2,6- dichlorophenyl) -5- methyl isoxazole-4-formyl chloride solution, at 5 DEG C, should in 1h
3- (2,6- dichlorophenyl) -5- methyl isoxazole-4-formyl chloride solution streams, which are added in system, carries out acylation reaction, is added dropwise simultaneously
The NaOH aqueous solutions of a concentration of 10wt% of 20ml maintain pH=7；After reaction, 10ml dichloromethane is added into system, to
10wt% dilute sulfuric acids are added in the system, is adjusted to pH=2, is stood with separatory funnel, after being layered, remove a layer organic phase（Totally 50
ml）, 50ml isopropanols are added thereto, obtain dicloxacillin acid solution 100ml.The dicloxacillin acid solution is examined by liquid phase
It surveys, a concentration of 0.246g/ml of dicloxacillin acid, it is 3.2wt% that moisture teller, which measures moisture therein,.
10.8g 2 ethyl hexanoic acid sodium is dissolved with 200ml isopropanols, prepares 2 ethyl hexanoic acid sodium solution；In 30 DEG C, 60rpm
Under, the 18% of dicloxacillin acid solution volume is added into 2 ethyl hexanoic acid sodium solution, after going out crystalline substance, continues to stir under the rotating speed
30min is mixed, then continues that remaining dicloxacillin acid solution is added dropwise at 100 rpm, 1h is added dropwise, and obtains dicloxacillin sodium
Crystal.Isopropanol accounts for all organic solvent volume scores 93%, crystallizing system moisture 1.0wt%, dicloxacillin sodium in crystallizing system
Concentration 0.085g/ml.Then continue to stir 1h at 30 DEG C, 100rpm, finally filter crystal solution, with acetone: isopropanol（v/
v=1∶20）3 times, each above-mentioned cleaning solvent dosage 50ml, 80 DEG C vacuum drying 2h of mixed solvent mashing washing filter cake, obtain double
Chlorine XiLin sodium white solid product 22.70g, yield 80.21%.
SEM characterizations are carried out to gained dicloxacillin sodium crystal, the results are shown in Figure 1.According to the liquid of European Pharmacopoeia EP9.0
Phase detection method is detected obtained solid product, and spectrogram is as shown in Figure 2.It can be seen from the figure that double chlorine in product
The main peak purity 99.77% of XiLin sodium, meets pharmacopeia relevant criterion；Product solvent residual content：Acetone 0ppm, isopropanol
831ppm, dichloromethane 87ppm meet ICH industry guideline standards.
Embodiment 2
At 0 ~ 5 DEG C, 12g 6-amino-penicillanic acids, under the stirring condition of 300rpm, Xiang Ti are added into 60ml purified waters
The sodium hydrate aqueous solution of a concentration of 10wt% of 20ml is added dropwise in system, 20min completes to be added dropwise；16.2g is dissolved with 70ml methyl acetates
3- (2,6- dichlorophenyl) -5- methyl isoxazole-4-formyl chlorides obtain 3- (2,6- dichlorophenyl) -5- methylisoxazole -4- first
Solution of acid chloride, at 5 DEG C, 500rpm, disposably by 3- (2,6- the dichlorophenyl) -5- methyl isoxazole-4-formyl chloride solution
It is acylated in input system, while the sodium hydrate aqueous solution of a concentration of 10wt% of 20ml being added dropwise into system, maintain pH=7,
1h is added dropwise.The dilute sulfuric acid of 10wt% is added into the system, is adjusted to pH=2, is then stood with separatory funnel, wait being layered
Afterwards, a layer organic phase is removed（Total 100ml）, the dilution of 100ml ethyl alcohol is added, obtains the organic solution 200ml of dicloxacillin acid.It should
Dicloxacillin acid solution is detected by liquid phase, and dicloxacillin acid concentration is 0.056g/ml, and moisture teller measures moisture therein
Content is 3.6wt%.
10.8g 2 ethyl hexanoic acid sodium is dissolved with 100ml absolute ethyl alcohols, prepares 2 ethyl hexanoic acid sodium solution；25 DEG C,
Under 60rpm stirring conditions, the 18% of dicloxacillin acid solution volume is added in 2 ethyl hexanoic acid sodium solution, after going out crystalline substance, is continued
30min is stirred under the rotating speed, then under 100rpm stirring conditions, is continued remaining dicloxacillin acid solution is added dropwise and be tied
Crystalline substance, completion of dropwise addition after 1h, obtains dicloxacillin sodium crystal.Ethyl alcohol accounts for all organic solvent volume scores 74% in crystallizing system, knot
Crystal system moisture 2.4wt%, dicloxacillin na concn 0.039g/ml.SEM characterizations are carried out to gained pillar-shaped crystal, result is as schemed
Shown in 3.
Embodiment 3
At 0 ~ 5 DEG C, 12g 6-amino-penicillanic acids are put into 60ml purified waters, are added dropwise at 300 rpm into the system
The sodium hydrate aqueous solution of a concentration of 10wt% of 20ml, until system dissolved clarification, 20min are added dropwise；With 70ml acetone solutions
16.2g3- (2,6- dichlorophenyl) -5- methyl isoxazole-4-formyl chlorides prepare the different evil of 3- (2,6- dichlorophenyl) -5- methyl
Azoles -4- formyl solutions of chlorine, then at 5 DEG C, 500rpm, by 3- (2,6- the dichlorophenyl) -5- methyl isoxazole-4-formyl chlorides
Solution, which is added at one time in 6-amino-penicillanic acid aqueous solution, carries out acylation reaction, while dropwise addition 20ml is a concentration of into system
The NaOH aqueous solutions of 10wt%, 1h are added dropwise, and maintain pH=8.10ml dichloromethane is added into the system, and 10wt% is added
Dilute sulfuric acid, be adjusted to pH=2, stood with separatory funnel, after being layered, remove a layer organic phase（Total 50ml）, it is anhydrous that 40ml is added
Ethyl alcohol dilutes, and dicloxacillin acid solution 90ml is prepared.The dicloxacillin acid solution is detected by liquid phase, dicloxacillin acid
A concentration of 0.194g/ml, it is 6.5wt% that moisture teller, which measures moisture,.
10.8g 2 ethyl hexanoic acid sodium is dissolved with 40ml absolute ethyl alcohols, prepares 2 ethyl hexanoic acid sodium solution；25 DEG C,
Under 60rpm, the 20% of dicloxacillin acid solution volume is added into 2 ethyl hexanoic acid sodium solution, after going out crystalline substance, is continued in the rotating speed
Lower stirring 30min, then into the system be added 80ml absolute ethyl alcohols, continue at 100 rpm be added dropwise dicloxacillin acid solution into
Row crystallizes, and completion of dropwise addition after 1h obtains dicloxacillin sodium crystal.It is analyzed by being measured to crystallizing system, ethyl alcohol accounts for crystallizing system
In all organic solvent volume scores 89%, crystallizing system moisture 2.6%, dicloxacillin na concn 0.086g/ml.Gained cylindricality is brilliant
The SEM figures of body are as shown in Figure 4.
Embodiment 4
At 0 ~ 5 DEG C, 12g 6-amino-penicillanic acids are put into 60ml purified waters, stream plus 10wt% NaOH are water-soluble into system
Liquid, 20min streams add complete；With 70ml acetone solutions 16.2g3- (2,6- dichlorophenyl) -5- methyl isoxazole-4-formyl chlorides, match
3- (2,6- dichlorophenyl) -5- methyl isoxazole-4-formyl chloride solution is made, then by 3- (2,6- the dichlorophenyl) -5- first
Base isoxazole -4- formyls solutions of chlorine is disposably acylated in input system, while being flowed plus the NaOH of a concentration of 10wt% of 20ml
Aqueous solution maintains pH=7；After acylation, 10ml dichloromethane is added, and 10wt% dilute sulfuric acids are added, is adjusted to pH=2, with point
Liquid funnel is stood, and after being layered, removes a layer organic phase（Total 50ml）, 50ml isopropanols are added into the organic phase, obtain double chlorine
XiLin acid solution 100ml.The dicloxacillin acid solution is detected by liquid phase, and dicloxacillin acid concentration is 0.213g/ml, and moisture is surveyed
Determine instrument to measure moisture therein to be 5.0wt%.
10.8g 2 ethyl hexanoic acid sodium is dissolved with 100ml isopropanols, ethyl alcohol 100ml is added, it is molten to prepare 2 ethyl hexanoic acid sodium
Liquid；At 25 DEG C, 60rpm, the 18% of above-mentioned dicloxacillin acid solution volume is added into 2 ethyl hexanoic acid sodium solution, is waited for out
After crystalline substance, continue to stir 30min under the rotating speed, it is molten then to continue stream plus remaining dicloxacillin acid into system at 100 rpm
Liquid, 1h streams add complete, obtain dicloxacillin sodium crystal.It is analyzed by being measured to crystallizing system, isopropanol volume in crystallizing system
Score 37%, volume fraction of ethanol 56%, crystallizing system moisture 1.6%, dicloxacillin na concn 0.071g/ml.Gained pillar-shaped crystal
SEM pictures it is as shown in Figure 5.
Embodiment 5
Add water, regulation system moisture to 3.5%, SEM pictures such as Fig. 6 institutes of gained pillar-shaped crystal into the crystallizing system of embodiment 4
Show.
Embodiment 6
At 0 ~ 5 DEG C, 12g 6-amino-penicillanic acids are put into 60ml purified waters, and it is a concentration of that 20ml is added dropwise into system
The NaOH aqueous solutions of 10wt%, 20min are added dropwise；It is different with 70ml acetone solutions 16.2g3- (2,6- dichlorophenyls) -5- methyl
Oxazole -4- formyl chlorides are configured to 3- (2,6- dichlorophenyl) -5- methyl isoxazole-4-formyl chloride solution, by the 3- (2,6- bis-
Chlorphenyl) -5- methyl isoxazole-4-formyl chlorides solution is disposably acylated in input system, while it is a concentration of that 20ml is added dropwise
The NaOH aqueous solutions of 10wt% maintain pH=7；10ml dichloromethane is added into system, 10wt% dilute sulfuric acids are then added, adjusts
It to pH=2, is stood with separatory funnel, after being layered, removes a layer organic phase, 50ml isopropanols are added into the organic phase, obtained double
Chlorine XiLin acid solution 100ml.The dicloxacillin acid solution is detected by liquid phase, dicloxacillin acid concentration is 0.26g/ml, water
It is 4.4wt% to divide analyzer to measure moisture therein.
10.8g 2 ethyl hexanoic acid sodium is dissolved with 150ml isopropanols, prepares 2 ethyl hexanoic acid sodium solution；In 10 DEG C, 60rpm
Under, the 18% of above-mentioned dicloxacillin acid solution volume is added into 2 ethyl hexanoic acid sodium solution, after going out crystalline substance, under the rotating speed after
Continuous stirring 30min, is then added dropwise remaining dicloxacillin acid solution, 1h is added dropwise, and obtains dicloxacillin sodium at 100 rpm
The SEM figures of crystal, gained pillar-shaped crystal are as shown in Figure 7.It is analyzed by being measured to crystallizing system, isopropanol accounts for institute in crystallizing system
There are organic solvent volume score 93%, crystallizing system moisture 1.2wt%, dicloxacillin na concn 0.084g/ml.
Embodiment 7
At 0 ~ 5 DEG C, 12g 6-amino-penicillanic acids are put into 60ml purified waters, and it is a concentration of that 20ml is added dropwise into system
The NaOH aqueous solutions of 10wt%, 20min are added dropwise；It is different with 70ml acetone solution 16.2g 3- (2,6- dichlorophenyls) -5- methyl
Oxazole -4- formyl chlorides are configured to 3- (2,6- dichlorophenyl) -5- methyl isoxazole-4-formyl chloride solution, by the 3- (2,6- bis-
Chlorphenyl) -5- methyl isoxazole-4-formyl chlorides solution is disposably acylated in input system, while it is a concentration of that 20ml is added dropwise
The NaOH aqueous solutions of 10wt% maintain pH=7；10ml dichloromethane is added into system, and 10wt% dilute sulfuric acids are added, is adjusted to
PH=2 are stood with separatory funnel, after being layered, remove a layer organic phase, and 50ml isopropanols are added thereto, obtain dicloxacillin acid
Solution 100ml.The dicloxacillin acid solution is detected by liquid phase, and dicloxacillin acid concentration is 0.194g/ml, and moisture teller is surveyed
Fixed moisture therein is 8.2%.
10.8g 2 ethyl hexanoic acid sodium is dissolved with 150ml isopropanols, prepares 2 ethyl hexanoic acid sodium solution；In 30 DEG C, 60rpm
Under, the 18% of above-mentioned dicloxacillin acid solution volume is added into 2 ethyl hexanoic acid sodium solution, after going out crystalline substance, growing the grain 30min, so
Continue that remaining dicloxacillin acid solution is added dropwise at 100 rpm afterwards, 1h is added dropwise, and obtains dicloxacillin sodium crystal, gained column
The SEM figures of shape crystal are as shown in Figure 8.It is analyzed by being measured to crystallizing system, isopropanol accounts for all organic solvents in crystallizing system
Volume fraction 91%, crystallizing system moisture 1.5wt%, dicloxacillin na concn 0.11g/ml.
Embodiment 8
At 0 ~ 5 DEG C, 1.2g 6-amino-penicillanic acids are put into 6ml purified waters, and a concentration of 10wt% of 2ml are added dropwise into system
NaOH aqueous solutions, 20min is added dropwise；With 7ml acetone solution 1.62g 3- (2,6- dichlorophenyls) -5- methylisoxazoles -
4- formyl chlorides are configured to 3- (2,6- dichlorophenyl) -5- methyl isoxazole-4-formyl chloride solution, by 3- (2, the 6- dichloro-benzenes
Base) -5- methyl isoxazole-4-formyl chlorides solution is disposably acylated in input system, while a concentration of 10wt% of 2ml are added dropwise
NaOH aqueous solutions, maintain pH=7；1ml dichloromethane is added into system, and 10wt% dilute sulfuric acids are added, is adjusted to pH=2, uses
Separatory funnel is stood, and after being layered, removes a layer organic phase, and 5ml isopropanols are added thereto, obtain dicloxacillin acid solution
10ml.The dicloxacillin acid solution is detected by liquid phase, dicloxacillin acid concentration is 0.257g/ml, and moisture teller measures
Moisture therein is 2.6wt%.
1.08g 2 ethyl hexanoic acid sodium is dissolved with 20ml isopropanols, prepares 2 ethyl hexanoic acid sodium solution；In 25 DEG C, 60rpm
Under, the 18% of above-mentioned dicloxacillin acid solution volume is added into 2 ethyl hexanoic acid sodium solution, after going out crystalline substance, growing the grain 30min, to
Isopropanol 380ml is added in the crystallizing system, then continues that remaining dicloxacillin acid solution is added dropwise at 100 rpm, 1h is added dropwise
It finishes, obtains dicloxacillin sodium crystal, the SEM figures of gained pillar-shaped crystal are as shown in Figure 9.It is analyzed by being measured to crystallizing system,
Isopropanol accounts for all organic solvent volume scores 99.5% in crystallizing system（≈100%）, crystallizing system moisture 0.07wt%（≈
0%）, dicloxacillin na concn 0.007g/ml.
Embodiment 9
At 0 ~ 5 DEG C, 12g 6-amino-penicillanic acids are put into 60ml purified waters（6-amino-penicillanic acid）, dripped into system
10wt%NaOH aqueous solutions 20ml, 20min is added to be added dropwise；With 70ml acetone solutions 16.2g3- (2,6- dichlorophenyls) -5- first
Base isoxazole -4- formyl chlorides are configured to 3- (2,6- dichlorophenyl) -5- methyl isoxazole-4-formyl chloride solution, at 5 DEG C, 1h
Interior 3- (2,6- the dichlorophenyl) -5- methyl isoxazole-4-formyl chloride solution streams are added in system carries out acylation reaction, simultaneously
The NaOH aqueous solutions of a concentration of 10wt% of 20ml are added dropwise, maintain pH=7；After reaction, 10ml dichloromethanes are added into system
10wt% dilute sulfuric acids are added into the system, is adjusted to pH=2, is stood with separatory funnel, after being layered, remove a layer organic phase for alkane
（Totally 50 ml）, 50ml ethyl alcohol is added thereto, obtains dicloxacillin acid solution 100ml.The dicloxacillin acid solution is passed through into liquid
It mutually detects, dicloxacillin acid concentration is 0.211g/ml, and it is 5.6wt% that moisture teller, which measures moisture therein,.
10.8g 2 ethyl hexanoic acid sodium is dissolved with 100ml isopropanol+100ml ethyl alcohol, prepares 2 ethyl hexanoic acid sodium solution；
30 DEG C, under 60rpm, the 18% of dicloxacillin acid solution volume is added into 2 ethyl hexanoic acid sodium solution, after going out crystalline substance, in this turn
Continue to stir 30min under speed, then continues that remaining dicloxacillin acid solution is added dropwise at 100 rpm, 1h is added dropwise, obtains
Dicloxacillin sodium crystal.It is analyzed by being measured to crystallizing system, isopropanol accounts for organic solvent volume score 37% in crystallizing system,
Volume fraction 56% in alcohol crystal system, crystallizing system moisture 1.9wt%, dicloxacillin na concn 0.073g/ml.It is double to gained
Chlorine XiLin sodium crystal carries out SEM characterizations, and the results are shown in Figure 10.
Comparative example 1
10g 6-amino-penicillanic acids are added into the system containing 16.5ml acetone and 33.5ml waters for injection, are cooled to 0 ~ 4
DEG C, 12wt% NaOH aqueous solutions are added dropwise in the case where rotating speed is the stirring condition of 300rpm, until solution clarification, terminal pH=7.5 ± 0.5,
Continue to stir 10min later；With 50ml acetone solutions 13.5g3- (2,6- dichlorophenyl) -5- methyl isoxazole-4-formyl chlorides,
It is configured to 3- (2,6- dichlorophenyl) -5- methyl isoxazole-4-formyl chloride solution, the 3- is added at one time into reaction system
(2,6- dichlorophenyl) -5- methyl isoxazole-4-formyl chloride solution carries out acylation reaction, while a concentration of 12wt% of 12ml are added dropwise
NaOH aqueous solutions, control pH=7.2 ± 0.2；After acylation reaction, 42ml butyl acetates are added into system, and be added
10wt% dilute sulfuric acids are acidified to pH value 2.0 ± 0.2, stand split-phase using separatory funnel, exhaust lower layer's water phase.It is added into system
12.5ml saturated sodium-chloride water solutions and 0.42gNaCl, agitator treating 15min, stands 20min, exhausts lower layer at 100 rpm
Water phase obtains dicloxacillin acid solution 80ml after being filtered to upper organic phase.
9g 2 ethyl hexanoic acid sodium is dissolved with the mixed solution of 25ml acetone and 12.5ml methanol, prepares 2 ethyl hexanoic acid sodium
Solution；At 25 DEG C, 100rpm, 2 ethyl hexanoic acid sodium solution is added into above-mentioned dicloxacillin acid solution, after going out crystalline substance, in this turn
Continue to stir 15min under speed；At 25 DEG C, it is evaporated under reduced pressure 1h, methanol is evaporated off, filtered, filter cake mashing is washed 3 times with acetone,
Acetone 40ml is used every time, filter cake is drained, and 72 DEG C of vacuum drying 2h obtain dicloxacillin sodium crystal product, yield 72%.
SEM characterizations are carried out to gained irregular crystal, acquired results are as shown in figure 11.Meanwhile detecting product solvent residual
Content, wherein butyl acetate 8974ppm, acetone 39941ppm, methanol 0ppm；Butyl acetate and the residual molten content of acetone are more than
5000ppm does not meet ICH industry guidelines.
Comparative example 2
Water is added into the crystallizing system of embodiment 5, regulation system moisture to 3.9% carries out SEM characterizations, knot to gained crystal
Fruit is as shown in figure 12.
Comparative example 3
At 0 ~ 5 DEG C, 12g 6-amino-penicillanic acids are put into 60ml purified waters, and it is water-soluble that 10wt%NaOH is added dropwise into system
Liquid 20ml, 20min are added dropwise；With 90ml acetone solution 16.2g 3- (2,6- dichlorophenyls) -5- methylisoxazole -4- formyls
Chlorine is configured to 3- (2,6- dichlorophenyl) -5- methyl isoxazole-4-formyl chloride solution, at 5 DEG C, by the 3- (2,6- bis- in 1h
Chlorphenyl) -5- methyl isoxazole-4-formyl chloride solution streams are added in system and carry out acylation reaction, while it is a concentration of that 20ml is added dropwise
The NaOH aqueous solutions of 10wt% maintain pH=7；After reaction, 10ml dichloromethane is added into system, is added into the system
10wt% dilute sulfuric acids, are adjusted to pH=2, are stood with separatory funnel, after being layered, remove a layer organic phase（Totally 50 ml）.
10.8g 2 ethyl hexanoic acid sodium is dissolved with 50ml isopropanols, prepares 2 ethyl hexanoic acid sodium solution；In 30 DEG C, 60rpm
Under, the 18% of dicloxacillin acid solution volume is added into 2 ethyl hexanoic acid sodium solution, after going out crystalline substance, continues to stir under the rotating speed
30min is mixed, then continues that remaining dicloxacillin acid solution is added dropwise at 100 rpm, 1h is added dropwise, and obtains dicloxacillin sodium
Irregular crystal.It is analyzed by being measured to crystallizing system, isopropanol volume fraction 71.4% in crystallizing system, crystallizing system water
Divide 2.5wt%, dicloxacillin na concn 0.28g/ml.SEM characterizations are carried out to gained crystal, result is as shown in figure 13.
Claims (10)
1. a kind of preparation method of dicloxacillin sodium pillar-shaped crystal, which is characterized in that the supersaturated solution of dicloxacillin sodium is prepared,
It is crystallized in the supersaturated solution, obtains dicloxacillin sodium pillar-shaped crystal；The organic solvent packet of the supersaturated solution
Include the alcohols solvent that volume fraction is 74 ~ 100% and the secondary solvent that volume fraction is 0 ~ 26%；Water impurity in the organic solvent
Content≤3.5wt%.
2. the preparation method of dicloxacillin sodium pillar-shaped crystal according to claim 1, which is characterized in that the alcohols solvent
Including lower alcohol.
3. the preparation method of dicloxacillin sodium pillar-shaped crystal according to claim 2, which is characterized in that the alcohols solvent
It is dissolved each other with arbitrary proportion the mixed solvent to be formed including ethyl alcohol, isopropanol or both.
4. the preparation method of dicloxacillin sodium pillar-shaped crystal according to claim 1, which is characterized in that the secondary solvent
Including at least one of dichloromethane, acetone, methyl acetate.
5. the preparation method of dicloxacillin sodium pillar-shaped crystal according to claim 1, which is characterized in that the dicloxacillin
A concentration of 0.007 ~ 0.11g/ml of the supersaturated solution of sodium.
6. the preparation method of dicloxacillin sodium pillar-shaped crystal according to claim 1, which is characterized in that the dicloxacillin
The supersaturated solution of sodium is made according to the following steps：
Prepare the dicloxacillin acid solution being dissolved in the first solvent；Prepare the 2 ethyl hexanoic acid sodium solution being dissolved in the second solvent；
Dicloxacillin acid solution is added into 2 ethyl hexanoic acid sodium solution, you can obtain the supersaturated solution of dicloxacillin sodium；
First solvent is the mixed solvent of alcohols solvent, secondary solvent or the alcohols solvent and the secondary solvent, institute
State the mixed solvent that the second solvent is alcohols solvent, secondary solvent or the alcohols solvent and the secondary solvent, the two mixing
Afterwards the organic solvent in the supersaturated solution of obtained dicloxacillin sodium include volume fraction be 74 ~ 100% alcohols solvent and
The secondary solvent that volume fraction is 0 ~ 26%.
7. the preparation method of dicloxacillin sodium pillar-shaped crystal according to claim 6, which is characterized in that the dicloxacillin
Acid solution is prepared into using 6-amino-penicillanic acid and the reaction of 3- (2,6- dichlorophenyls) -5- methyl isoxazole-4-formyl chlorides
It arrives.
8. the preparation method of dicloxacillin sodium pillar-shaped crystal according to claim 7, which is characterized in that the dicloxacillin
The preparation method of acid solution includes：6-amino-penicillanic acid is soluble in water, obtain the suspension of 6-amino-penicillanic acid；By 3-
(2,6- dichlorophenyl) -5- methyl isoxazole-4-formyl chlorides are dissolved in third solvent, and the third solvent is selected from acetone, two
Any one of chloromethanes, methyl acetate；Adjust 6-amino-penicillanic acid aqueous solution pH be 7 ~ 8, until system clarify, then to its
Middle addition 3- (2,6- dichlorophenyl) -5- methyl isoxazole-4-formyl chloride solution carries out acylation reaction, controls pH=7 ~ 8；Reaction
After, dichloromethane or methyl acetate are added into system, and pH=2.0 ± 0.2 is adjusted to using acid, split-phase, removing layer has
Machine phase, you can obtain dicloxacillin acid solution.
9. the preparation method of dicloxacillin sodium pillar-shaped crystal according to claim 8, which is characterized in that gained after to split-phase
Dicloxacillin acid solution in ethyl alcohol, isopropanol or both the mixed solvent to be formed that dissolves each other with arbitrary proportion is added.
10. the preparation method of dicloxacillin sodium pillar-shaped crystal according to claim 6, which is characterized in that 2- ethyl hexyls
The process of addition dicloxacillin acid solution includes in acid sodium solution：The double chlorine of pre-add first into the 2 ethyl hexanoic acid sodium solution of gained
The 18 ~ 30% of XiLin acid solution volume after crystal to appear, are further continued for that remaining dicloxacillin acid solution is added.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0273156A2 (en) * | 1986-12-23 | 1988-07-06 | Giovanni Bonfanti | Method for producing pure crystalline products |
| CN102086213A (en) * | 2010-12-23 | 2011-06-08 | 天津大学 | Crystallization preparation method of cloxacillin sodium |
| CN102702227A (en) * | 2012-06-12 | 2012-10-03 | 河北华日药业有限公司 | Preparation method for flucloxacillin sodium |
| CN103687862A (en) * | 2011-05-27 | 2014-03-26 | 瓦尔德曼化学科技股份有限公司 | Improved process for preparing penicillins and intermediate compounds |
| WO2014072843A1 (en) * | 2012-11-07 | 2014-05-15 | Vardhman Chemtech Limited | Process for preparing isoxazolyl penicillins |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0273156A2 (en) * | 1986-12-23 | 1988-07-06 | Giovanni Bonfanti | Method for producing pure crystalline products |
| CN102086213A (en) * | 2010-12-23 | 2011-06-08 | 天津大学 | Crystallization preparation method of cloxacillin sodium |
| CN103687862A (en) * | 2011-05-27 | 2014-03-26 | 瓦尔德曼化学科技股份有限公司 | Improved process for preparing penicillins and intermediate compounds |
| CN102702227A (en) * | 2012-06-12 | 2012-10-03 | 河北华日药业有限公司 | Preparation method for flucloxacillin sodium |
| WO2014072843A1 (en) * | 2012-11-07 | 2014-05-15 | Vardhman Chemtech Limited | Process for preparing isoxazolyl penicillins |
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