CN108659007B - Preparation method of cylindrical dicloxacillin sodium crystal - Google Patents
Preparation method of cylindrical dicloxacillin sodium crystal Download PDFInfo
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- CN108659007B CN108659007B CN201810812620.3A CN201810812620A CN108659007B CN 108659007 B CN108659007 B CN 108659007B CN 201810812620 A CN201810812620 A CN 201810812620A CN 108659007 B CN108659007 B CN 108659007B
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- C—CHEMISTRY; METALLURGY
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- 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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- 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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- C07—ORGANIC CHEMISTRY
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- C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
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- C07D499/18—Separation; Purification
- C07D499/20—Separation; Purification via salts with organic bases
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- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
The invention provides a preparation method of cylindrical dicloxacillin sodium crystals, which comprises the steps of preparing supersaturated solution of dicloxacillin sodium, and crystallizing in the supersaturated solution to obtain cylindrical dicloxacillin sodium crystals; the organic solvent of the supersaturated solution comprises an alcohol solvent with volume fraction of 74-100% and an auxiliary solvent with volume fraction of 0-26%; the content of impurity water in the organic solvent is less than or equal to 3.5 wt%. The method is simple and easy to implement, the obtained product has excellent performance, good geometric crystallography appearance, higher purity and yield, less impurities, and easy solid-liquid separation in the preparation process, obviously reduces the difficulty of production operation, greatly shortens the production period, and has wide industrial application prospect.
Description
Technical Field
The invention relates to a preparation method of dicloxacillin sodium, in particular to a preparation method of a cylindrical dicloxacillin sodium crystal.
Background
Dicloxacillin sodium, chemical name: (2S,5R,6R) -3, 3-dimethyl-6- [ 5-methyl-3- (2, 6-dichlorophenyl) -4-isoxazolecarboxamido ] -7-oxo-4-thia-1-azabicyclo [3.2.0] heptane-2-carboxylic acid sodium salt having the formula:
dicloxacillin sodium belongs to isoxazole beta lactam antibiotics, has the characteristics of acid resistance, enzyme resistance and the like, and has antibacterial activity on staphylococcus and gram-positive bacteria. As an antibacterial drug, dicloxacillin sodium can be used for treating penicillin G resistant staphylococcus aureus infection.
In a method for preparing dicloxacillin sodium crystals, a dicloxacillin sodium crystal is usually prepared by crystallization using an ester solvent, and for example, patent document CN201180072474.1 discloses a method for preparing an isoxazolyl penicillin sodium salt, which comprises the steps of firstly preparing an ester solution of isoxazolyl penicillin acid (such as cloxacillin acid, dicloxacillin acid, flucloxacillin acid, etc.), washing the ester solution with a saturated sodium chloride solution, then adding the washed ester solution into a 2-ethyl sodium caproate solution, and crystallizing to obtain an isoxazolyl penicillin sodium salt such as cloxacillin sodium, dicloxacillin sodium, flucloxacillin sodium, etc. The crystals prepared by the method using the ester solvent as the main solvent of the crystallization system are mostly irregular sheets, the granularity is small, the filtering time is long, the drying is difficult, the production period of the product is long, the production capacity is low, the ester solvent is easy to wrap the inside of the crystals and is difficult to remove by means of washing, centrifugal drying and the like, and the product quality is unqualified.
Therefore, there is a need to develop a novel method for preparing dicloxacillin sodium crystals, so as to prepare crystals with regular shape, convenient post-treatment such as filtration and drying, and high purity.
Disclosure of Invention
The invention aims to provide a preparation method of cylindrical dicloxacillin sodium crystals, which aims to solve the problems of irregular crystal shape, complex post-treatment process and product quality improvement in the existing synthesis method.
The purpose of the invention is realized as follows:
a method for preparing cylindrical dicloxacillin sodium crystals comprises the steps of preparing supersaturated solution of dicloxacillin sodium, and crystallizing in the supersaturated solution to obtain cylindrical dicloxacillin sodium crystals; the organic solvent of the supersaturated solution comprises an alcohol solvent with volume fraction of 74-100% and an auxiliary solvent with volume fraction of 0-26%; the content of impurity water in the organic solvent is less than or equal to 3.5 wt%.
Preferably, the alcoholic solvent comprises a lower alcohol, more preferably C1~C4An alcohol.
Preferably, the alcohol solvent comprises ethanol, isopropanol or a mixed solvent formed by mutual dissolution of the ethanol and the isopropanol in any proportion; preferably, the alcohol solvent of the supersaturated solution is ethanol or isopropanol; more preferably, the alcoholic solvent of the supersaturated solution is isopropanol.
Preferably, the volume fraction of the alcohol solvent in the supersaturated solution is 74-99.5%; the supersaturated solution contains 0.07-3.5 wt% of water.
The auxiliary solvent comprises a solvent capable of dissolving 3- (2, 6-dichlorophenyl) -5-methylisoxazole-4-formyl chloride; preferably, the auxiliary solvent comprises at least one of dichloromethane, acetone, methyl acetate, more preferably dichloromethane or acetone.
The concentration of the supersaturated solution of dicloxacillin sodium is 0.007-0.11 g/ml.
The supersaturated solution of dicloxacillin sodium can be obtained by adopting the existing preparation method, such as reaction crystallization, recrystallization, evaporative crystallization and the like. The amount of the dicloxacillin sodium comprises the dicloxacillin sodium crystals separated out from the system and the dicloxacillin sodium which is not crystallized and separated out and is in a dissolved state.
Preferably, the supersaturated solution of dicloxacillin sodium is prepared by the following steps:
preparing a dicloxacillin acid solution dissolved in a first solvent; preparing a solution of sodium 2-ethylhexanoate in a second solvent; adding a dicloxacillin acid solution into the 2-sodium ethylhexanoate solution to obtain a supersaturated solution of dicloxacillin sodium;
the first solvent can be selected from an alcohol solvent, an auxiliary solvent or a mixed solvent of the alcohol solvent and the auxiliary solvent, wherein the auxiliary solvent can be at least one of acetone, dichloromethane and methyl acetate; the second solvent can also be selected from an alcohol solvent, an auxiliary solvent or a mixed solvent of the alcohol solvent and the auxiliary solvent, and is preferably an alcohol solvent; the first solvent can be the same as or different from the second solvent, and the organic solvent used in the supersaturated solution of dicloxacillin sodium obtained by mixing the first solvent and the second solvent only needs to comprise an alcohol solvent with a volume fraction of 74-100% and an auxiliary solvent with a volume fraction of 0-26%.
Preferably, the dicloxacillin acid solution is prepared by reacting 6-aminopenicillanic acid and 3- (2, 6-dichlorophenyl) -5-methylisoxazole-4-formyl chloride.
Specifically, the preparation method of the dicloxacillin acid solution comprises the following steps: dissolving 6-aminopenicillanic acid in water to obtain suspension of 6-aminopenicillanic acid; dissolving 3- (2, 6-dichlorophenyl) -5-methylisoxazole-4-formyl chloride in a third solvent, wherein the third solvent is any one of acetone, dichloromethane and methyl acetate; adjusting the pH value of a 6-aminopenicillanic acid aqueous solution to 7-8 until the system is clear, adding a 3- (2, 6-dichlorophenyl) -5-methylisoxazole-4-formyl chloride solution into the aqueous solution for acylation reaction, and controlling the pH value to be = 7-8; after the reaction is finished, adding dichloromethane or methyl acetate into the system, adjusting the pH value to be =2.0 +/-0.2 by adopting acid, carrying out phase separation, and taking down the organic phase of the lower layer to obtain the dicloxacillin acid solution.
Optionally, ethanol, isopropanol or a mixed solvent formed by mutually dissolving the ethanol and the isopropanol in any proportion is added into the dicloxacillin acid solution obtained after phase separation.
Preferably, the process of adding dicloxacillin acid solution to the sodium 2-ethylhexanoate solution comprises: firstly, pre-adding 18-30% of the volume of the dicloxacillin acid solution into the obtained 2-sodium ethylhexanoate solution, and after crystals appear, continuously adding the rest dicloxacillin acid solution.
In the process of preparing the dicloxacillin sodium crystal, crystallization can be carried out at 10-30 ℃ under the standing condition or the stirring condition.
The invention takes an alcohol solvent as a main solvent for preparing the dicloxacillin sodium crystal, prepares the dicloxacillin sodium crystal with cylindrical crystal habit under specific conditions by preparing a supersaturated solution of dicloxacillin acid and controlling various factors in the system, and the obtained crystal has good geometric crystallography appearance, higher yield, lower impurity content, difficult inclusion of residual solvent and easy solid-liquid separation in the preparation process, overcomes the defects of fine dicloxacillin sodium crystal and difficult filtration prepared by the prior art, solves the problem of unqualified residual solvent, can obviously reduce the difficulty of production operation and greatly shorten the production period.
The method is simple and easy to implement, the obtained product has excellent performance, the quality and the yield of the product are effectively improved, the method can be used for preparing the dicloxacillin sodium crystal seeds and standard products, can be popularized and used for small-scale experimental process research of the dicloxacillin sodium, is more beneficial to guiding the industrial production of the dicloxacillin sodium, and has wide industrial application prospect.
Drawings
FIG. 1 is an SEM photograph of the dicloxacillin sodium crystals prepared in example 1.
FIG. 2 is a liquid phase spectrum of the dicloxacillin sodium crystal prepared in example 1.
FIG. 3 is an SEM photograph of the dicloxacillin sodium crystals prepared in example 2.
FIG. 4 is an SEM photograph of the dicloxacillin sodium crystals prepared in example 3.
FIG. 5 is an SEM photograph of the dicloxacillin sodium crystals prepared in example 4.
FIG. 6 is an SEM photograph of the dicloxacillin sodium crystals prepared in example 5.
FIG. 7 is an SEM photograph of the dicloxacillin sodium crystals prepared in example 6.
FIG. 8 is an SEM photograph of the dicloxacillin sodium crystals prepared in example 7.
FIG. 9 is an SEM photograph of the dicloxacillin sodium crystals prepared in example 8.
FIG. 10 is an SEM photograph of the dicloxacillin sodium crystals prepared in example 9.
Fig. 11 is an SEM image of the dicloxacillin sodium crystals prepared in comparative example 1.
Fig. 12 is an SEM image of the dicloxacillin sodium crystals prepared in comparative example 2.
Fig. 13 is an SEM image of the dicloxacillin sodium crystals prepared in comparative example 3.
Detailed Description
The invention is further illustrated by the following examples, which are given by way of illustration only and are not intended to limit the scope of the invention in any way.
The reagents used in the examples are either analytically or chemically pure and are either commercially available or prepared by methods well known to those of ordinary skill in the art. The following examples all achieve the objects of the present invention.
Example 1
At the temperature of 0-5 ℃, 12g of 6-aminopenicillanic acid (6-APA) is put into 60ml of purified water, 20ml of 10wt% NaOH aqueous solution is dripped into the system, and the dripping is finished within 20 min; dissolving 16.2g of 3- (2, 6-dichlorophenyl) -5-methylisoxazole-4-carbonyl chloride in 70ml of acetone to prepare a 3- (2, 6-dichlorophenyl) -5-methylisoxazole-4-carbonyl chloride solution, and adding the 3- (2, 6-dichlorophenyl) -5-methylisoxazole-4-carbonyl chloride solution into the system at 5 ℃ over 1 hour to carry out an acylation reaction while dropping 20ml of a 10wt% aqueous NaOH solution, maintaining pH = 7; after the reaction was completed, 10ml of dichloromethane was added to the system, 10wt% dilute sulfuric acid was added to the system, the pH was adjusted to =2, the mixture was allowed to stand with a separatory funnel, and after separation, the lower organic phase (50 ml in total) was taken out, and 50ml of isopropyl alcohol was added thereto to obtain 100ml of dicloxacillin solution. The dicloxacillin acid solution is detected by liquid phase, the concentration of the dicloxacillin acid is 0.246g/ml, and the moisture content in the dicloxacillin acid solution is 3.2wt% as determined by a moisture determinator.
Dissolving 10.8g of sodium 2-ethylhexanoate in 200ml of isopropanol to prepare a sodium 2-ethylhexanoate solution; adding 18 percent of the volume of the dicloxacillin acid solution into the 2-sodium ethylhexanoate solution at 30 ℃ and 60rpm, after crystal growth, continuing stirring at the rotating speed for 30min, then continuing dropwise adding the rest of the dicloxacillin acid solution at 100rpm for 1h, and obtaining the dicloxacillin sodium crystal. In the crystallization system, the isopropanol accounts for 93 percent of the volume of all the organic solvents, the water content of the crystallization system is 1.0 percent by weight, and the concentration of dicloxacillin sodium is 0.085 g/ml. Then stirring is continued for 1h at 30 ℃ and 100rpm, finally the crystallization liquid is filtered, the filter cake is washed by beating with a mixed solvent of acetone and isopropanol (v/v = 1: 20) for 3 times, the dosage of the washing solvent is 50ml each time, and vacuum drying is carried out for 2h at 80 ℃ to obtain 22.70g of dicloxacillin sodium white solid product with the yield of 80.21%.
SEM representation is carried out on the obtained dicloxacillin sodium crystal, and the result is shown in figure 1. The obtained solid product was detected according to the liquid phase detection method of european pharmacopoeia EP9.0, and the spectrum is shown in fig. 2. As can be seen from the figure, the main peak purity of dicloxacillin sodium in the product is 99.77%, which accords with the relevant standards of pharmacopoeia; the solvent residue content of the product is as follows: 0ppm of acetone, 831ppm of isopropanol and 87ppm of dichloromethane, and meets the ICH industry guide principle standard.
Example 2
Adding 12g of 6-aminopenicillanic acid into 60ml of purified water at 0-5 ℃, dropwise adding 20ml of 10wt% sodium hydroxide aqueous solution into the system under the stirring condition of 300rpm, and finishing dropwise adding within 20 min; 16.2g of 3- (2, 6-dichlorophenyl) -5-methylisoxazole-4-carbonyl chloride was dissolved in 70ml of methyl acetate to give a 3- (2, 6-dichlorophenyl) -5-methylisoxazole-4-carbonyl chloride solution, and the 3- (2, 6-dichlorophenyl) -5-methylisoxazole-4-carbonyl chloride solution was charged into the system at 5 ℃ at 500rpm at a time to conduct acylation, and 20ml of a 10% by weight aqueous sodium hydroxide solution was added dropwise to the system while maintaining pH =7, and the addition was completed for 1 hour. Adding 10wt% of dilute sulfuric acid into the system, adjusting the pH to be =2, then standing the mixture by using a separating funnel, taking a lower-layer organic phase (total 100 ml) after layering, and adding 100ml of ethanol for dilution to obtain 200ml of organic solution of dicloxacillin acid. The dicloxacillin acid solution is detected by liquid phase, the concentration of the dicloxacillin acid is 0.056g/ml, and the moisture content in the dicloxacillin acid solution is 3.6wt% as determined by a moisture tester.
Dissolving 10.8g of sodium 2-ethylhexanoate in 100ml of absolute ethyl alcohol to prepare a sodium 2-ethylhexanoate solution; under the stirring conditions of 25 ℃ and 60rpm, adding 18 percent of the volume of the dicloxacillin acid solution into the 2-sodium ethylhexanoate solution, after crystal formation, continuing to stir at the rotating speed for 30min, then continuing to dropwise add the rest of the dicloxacillin acid solution for crystallization under the stirring condition of 100rpm, and after 1h, ending the dropwise addition to obtain the dicloxacillin sodium crystals. The volume fraction of ethanol in all organic solvents in the crystallization system is 74 percent, the water content of the crystallization system is 2.4 percent by weight, and the concentration of dicloxacillin sodium is 0.039 g/ml. The obtained columnar crystals were subjected to SEM characterization, and the results are shown in fig. 3.
Example 3
At the temperature of 0-5 ℃, 12g of 6-aminopenicillanic acid is added into 60ml of purified water, 20ml of 10wt% sodium hydroxide aqueous solution is dripped into the system at the rpm of 300 until the system is clear, and the dripping is finished within 20 min; a solution of 3- (2, 6-dichlorophenyl) -5-methylisoxazole-4-carbonyl chloride was prepared by dissolving 16.2g of 3- (2, 6-dichlorophenyl) -5-methylisoxazole-4-carbonyl chloride in 70ml of acetone, and then the 3- (2, 6-dichlorophenyl) -5-methylisoxazole-4-carbonyl chloride solution was added to an aqueous 6-aminopenicillanic acid solution at 5 ℃ and 500rpm in one portion for acylation reaction, while 20ml of an aqueous 10wt% NaOH solution was added dropwise to the system over 1 hour, and the pH =8 was maintained. To this system, 10ml of dichloromethane was added, and 10wt% diluted sulfuric acid was added to adjust pH =2, and the mixture was allowed to stand with a separatory funnel, and after separation, the lower organic phase (total 50 ml) was taken out and diluted with 40ml of absolute ethanol to prepare 90ml of dicloxacillin acid solution. The dicloxacillin acid solution is detected by liquid phase, the concentration of the dicloxacillin acid is 0.194g/ml, and the moisture content is 6.5wt% as measured by a moisture tester.
Dissolving 10.8g of sodium 2-ethylhexanoate in 40ml of absolute ethanol to prepare a sodium 2-ethylhexanoate solution; adding 20% of the volume of the dicloxacillin acid solution into the 2-sodium ethylhexanoate solution at 25 ℃ and 60rpm, continuing to stir at the rotating speed for 30min after crystal formation, then adding 80ml of absolute ethyl alcohol into the system, continuing to dropwise add the dicloxacillin acid solution at 100rpm for crystallization, and ending dropwise addition after 1h to obtain the dicloxacillin sodium crystals. Through the analysis of the crystal system determination, the ethanol accounts for 89 percent of the volume of all organic solvents in the crystal system, the water content of the crystal system is 2.6 percent, and the concentration of dicloxacillin sodium is 0.086 g/ml. The SEM image of the resulting columnar crystal is shown in FIG. 4.
Example 4
At the temperature of 0-5 ℃, 12g of 6-aminopenicillanic acid is put into 60ml of purified water, 10wt% of NaOH aqueous solution is fed into the system, and the feeding is finished within 20 min; dissolving 16.2g of 3- (2, 6-dichlorophenyl) -5-methylisoxazole-4-carbonyl chloride in 70ml of acetone to prepare a 3- (2, 6-dichlorophenyl) -5-methylisoxazole-4-carbonyl chloride solution, and then adding the 3- (2, 6-dichlorophenyl) -5-methylisoxazole-4-carbonyl chloride solution in one portion to the system for acylation while feeding 20ml of a 10% by weight aqueous NaOH solution thereto while maintaining pH = 7; after the acylation, 10ml of dichloromethane and 10wt% of dilute sulfuric acid were added, the pH was adjusted to =2, the mixture was allowed to stand with a separatory funnel, and after the layers were separated, the lower organic phase (50 ml in total) was taken out, and 50ml of isopropyl alcohol was added to the organic phase to obtain 100ml of dicloxacillin acid solution. The dicloxacillin acid solution is detected by liquid phase, the concentration of the dicloxacillin acid is 0.213g/ml, and the moisture content in the dicloxacillin acid solution is 5.0wt% as determined by a moisture determinator.
Dissolving 10.8g of sodium 2-ethylhexanoate in 100ml of isopropanol, and adding 100ml of ethanol to prepare a sodium 2-ethylhexanoate solution; adding 18 percent of the dicloxacillin acid solution in volume into 2-sodium ethylhexanoate solution at 25 ℃ and 60rpm, after crystal is formed, continuously stirring at the rotating speed for 30min, then continuously adding the rest of the dicloxacillin acid solution into the system at 100rpm, and after the adding is finished for 1h, obtaining the dicloxacillin sodium crystal. Through the determination and analysis of the crystallization system, the volume fraction of isopropanol, the volume fraction of ethanol, the water content of the crystallization system and the concentration of dicloxacillin sodium in the crystallization system are respectively 37%, 56%, 1.6% and 0.071 g/ml. The SEM picture of the resulting columnar crystal is shown in fig. 5.
Example 5
Water was added to the crystallization system of example 4 to adjust the water content of the system to 3.5%, and an SEM photograph of the resulting columnar crystals is shown in FIG. 6.
Example 6
At the temperature of 0-5 ℃, 12g of 6-aminopenicillanic acid is added into 60ml of purified water, 20ml of NaOH aqueous solution with the concentration of 10wt% is dripped into the system, and the dripping is finished within 20 min; dissolving 16.2g of 3- (2, 6-dichlorophenyl) -5-methylisoxazole-4-carbonyl chloride in 70ml of acetone to prepare a 3- (2, 6-dichlorophenyl) -5-methylisoxazole-4-carbonyl chloride solution, and adding the 3- (2, 6-dichlorophenyl) -5-methylisoxazole-4-carbonyl chloride solution to the system in one portion for acylation while dropping 20ml of a 10% by weight aqueous NaOH solution to maintain pH = 7; adding 10ml of dichloromethane into the system, then adding 10wt% of dilute sulfuric acid, adjusting the pH to be =2, standing by using a separating funnel, taking a lower-layer organic phase after layering, and supplementing 50ml of isopropanol into the organic phase to obtain 100ml of dicloxacillin acid solution. The dicloxacillin acid solution is detected by liquid phase, the concentration of the dicloxacillin acid is 0.26g/ml, and the moisture content in the dicloxacillin acid solution is 4.4wt% as determined by a moisture determinator.
Dissolving 10.8g of sodium 2-ethylhexanoate in 150ml of isopropanol to prepare a sodium 2-ethylhexanoate solution; adding 18% of the dicloxacillin acid solution in volume into 2-sodium ethylhexanoate solution at 10 ℃ and 60rpm, after crystal formation, continuing stirring at the rotating speed for 30min, then dropwise adding the rest of the dicloxacillin acid solution at 100rpm for 1h, and obtaining dicloxacillin sodium crystals, wherein the SEM image of the obtained cylindrical crystals is shown in FIG. 7. According to the determination and analysis of the crystallization system, the isopropanol accounts for 93 percent of the volume of all organic solvents in the crystallization system, the water content of the crystallization system is 1.2 percent by weight, and the concentration of the dicloxacillin sodium is 0.084 g/ml.
Example 7
At the temperature of 0-5 ℃, 12g of 6-aminopenicillanic acid is added into 60ml of purified water, 20ml of NaOH aqueous solution with the concentration of 10wt% is dripped into the system, and the dripping is finished within 20 min; dissolving 16.2g of 3- (2, 6-dichlorophenyl) -5-methylisoxazole-4-carbonyl chloride in 70ml of acetone to prepare a 3- (2, 6-dichlorophenyl) -5-methylisoxazole-4-carbonyl chloride solution, and adding the 3- (2, 6-dichlorophenyl) -5-methylisoxazole-4-carbonyl chloride solution to the system at a time to conduct acylation while dropping 20ml of a 10% by weight aqueous NaOH solution while maintaining pH = 7; adding 10ml of dichloromethane, adding 10wt% of dilute sulfuric acid, adjusting the pH to be =2, standing by using a separating funnel, taking a lower-layer organic phase after layering, and adding 50ml of isopropanol into the lower-layer organic phase to obtain 100ml of dicloxacillin acid solution. The dicloxacillin acid solution is detected by liquid phase, the concentration of the dicloxacillin acid is 0.194g/ml, and the moisture content in the dicloxacillin acid solution is 8.2% as determined by a moisture determinator.
Dissolving 10.8g of sodium 2-ethylhexanoate in 150ml of isopropanol to prepare a sodium 2-ethylhexanoate solution; adding 18% of the dicloxacillin acid solution in volume into 2-sodium ethylhexanoate solution at 30 ℃ and 60rpm, growing crystal for 30min after crystal is generated, then continuously dropwise adding the rest of the dicloxacillin acid solution at 100rpm for 1h to obtain dicloxacillin sodium crystals, wherein the SEM picture of the obtained cylindrical crystals is shown in FIG. 8. According to the analysis of the crystal system measurement, the isopropanol accounts for 91 percent of the volume of all organic solvents in the crystal system, the water content of the crystal system is 1.5 percent by weight, and the concentration of the dicloxacillin sodium is 0.11 g/ml.
Example 8
At the temperature of 0-5 ℃, 1.2g of 6-aminopenicillanic acid is added into 6ml of purified water, 2ml of NaOH aqueous solution with the concentration of 10wt% is dripped into the system, and the dripping is finished within 20 min; dissolving 1.62g of 3- (2, 6-dichlorophenyl) -5-methylisoxazole-4-carbonyl chloride in 7ml of acetone to prepare a 3- (2, 6-dichlorophenyl) -5-methylisoxazole-4-carbonyl chloride solution, and adding the 3- (2, 6-dichlorophenyl) -5-methylisoxazole-4-carbonyl chloride solution to the system at a time to conduct acylation while dropping 2ml of a 10% by weight aqueous NaOH solution to maintain pH = 7; adding 1ml of dichloromethane, adding 10wt% of dilute sulfuric acid into the system, adjusting the pH to be =2, standing the mixture by using a separating funnel, taking a lower-layer organic phase after layering, and adding 5ml of isopropanol into the lower-layer organic phase to obtain 10ml of dicloxacillin acid solution. The dicloxacillin acid solution is detected by liquid phase, the concentration of the dicloxacillin acid is 0.257g/ml, and the moisture content in the dicloxacillin acid solution is 2.6wt% as determined by a moisture determinator.
Dissolving 1.08g of sodium 2-ethylhexanoate in 20ml of isopropanol to prepare a sodium 2-ethylhexanoate solution; adding 18% of the dicloxacillin acid solution in volume into 2-sodium ethylhexanoate solution at 25 ℃ and 60rpm, growing crystals for 30min after crystal emergence, supplementing 380ml of isopropanol into the crystallization system, continuing dropwise adding the rest of the dicloxacillin acid solution at 100rpm for 1h to obtain dicloxacillin sodium crystals, wherein an SEM image of the obtained cylindrical crystals is shown in FIG. 9. According to the determination and analysis of the crystallization system, the isopropanol accounts for 99.5 percent of the volume fraction of all organic solvents in the crystallization system (approximately equal to 100 percent), the water content of the crystallization system is 0.07 percent by weight (approximately equal to 0 percent), and the concentration of dicloxacillin sodium is 0.007 g/ml.
Example 9
Adding 12g of 6-aminopenicillanic acid (6-aminopenicillanic acid) into 60ml of purified water at 0-5 ℃, dropwise adding 20ml of 10wt% NaOH aqueous solution into the system, and finishing dropwise adding within 20 min; dissolving 16.2g of 3- (2, 6-dichlorophenyl) -5-methylisoxazole-4-carbonyl chloride in 70ml of acetone to prepare a 3- (2, 6-dichlorophenyl) -5-methylisoxazole-4-carbonyl chloride solution, and adding the 3- (2, 6-dichlorophenyl) -5-methylisoxazole-4-carbonyl chloride solution into the system at 5 ℃ over 1 hour to conduct acylation reaction while dropping 20ml of a 10wt% aqueous NaOH solution to maintain pH = 7; after the reaction was completed, 10ml of dichloromethane was added to the system, 10wt% dilute sulfuric acid was added to the system, the pH was adjusted to =2, the mixture was allowed to stand with a separatory funnel, and after separation, the lower organic phase (50 ml in total) was taken out, and 50ml of ethanol was added thereto to obtain 100ml of dicloxacillin solution. The dicloxacillin acid solution is detected by liquid phase, the concentration of the dicloxacillin acid is 0.211g/ml, and the moisture content in the dicloxacillin acid solution is 5.6wt% as determined by a moisture determinator.
Dissolving 10.8g of sodium 2-ethylhexanoate in 100ml of isopropanol and 100ml of ethanol to prepare a sodium 2-ethylhexanoate solution; adding 18 percent of the volume of the dicloxacillin acid solution into the 2-sodium ethylhexanoate solution at 30 ℃ and 60rpm, after crystal growth, continuing stirring at the rotating speed for 30min, then continuing dropwise adding the rest of the dicloxacillin acid solution at 100rpm for 1h, and obtaining the dicloxacillin sodium crystal. According to the determination and analysis of the crystallization system, the isopropanol accounts for 37 percent of the volume fraction of the organic solvent in the crystallization system, the volume fraction of the ethanol in the crystallization system is 56 percent, the water content of the crystallization system is 1.9 percent by weight, and the concentration of the dicloxacillin sodium is 0.073 g/ml. SEM representation is carried out on the obtained dicloxacillin sodium crystal, and the result is shown in figure 10.
Comparative example 1
Adding 10g of 6-aminopenicillanic acid into a system containing 16.5ml of acetone and 33.5ml of water for injection, cooling to 0-4 ℃, dropwise adding a 12wt% NaOH aqueous solution under the stirring condition of the rotation speed of 300rpm until the solution is clear and the end point pH =7.5 +/-0.5, and then continuously stirring for 10 min; dissolving 13.5g of 3- (2, 6-dichlorophenyl) -5-methylisoxazole-4-formyl chloride in 50ml of acetone to prepare a 3- (2, 6-dichlorophenyl) -5-methylisoxazole-4-formyl chloride solution, adding the 3- (2, 6-dichlorophenyl) -5-methylisoxazole-4-formyl chloride solution into the reaction system at a time to carry out acylation reaction, and simultaneously adding 12ml of a 12wt% NaOH aqueous solution dropwise to control the pH to be 7.2 +/-0.2; after the acylation reaction is finished, 42ml of butyl acetate is added into the system, 10wt% of dilute sulfuric acid is added, the mixture is acidified to the pH value of 2.0 +/-0.2, a separating funnel is adopted for standing and phase splitting, and the lower-layer water phase is discharged. Adding 12.5ml saturated sodium chloride aqueous solution and 0.42g NaCl into the system, stirring and washing for 15min at 100rpm, standing for 20min, draining the lower aqueous phase, and filtering the upper organic phase to obtain 80ml dicloxacillin acid solution.
Dissolving 9g of sodium 2-ethylhexanoate in a mixed solution of 25ml of acetone and 12.5ml of methanol to prepare a sodium 2-ethylhexanoate solution; adding 2-ethyl caproic acid sodium solution into the dicloxacillin acid solution at 25 deg.C and 100rpm, crystallizing, and stirring at the rotation speed for 15 min; distilling at 25 ℃ under reduced pressure for 1h, evaporating to remove methanol, performing suction filtration, pulping and washing a filter cake with acetone for 3 times, using 40ml of acetone each time, performing suction drying on the filter cake, and performing vacuum drying at 72 ℃ for 2h to obtain a dicloxacillin sodium crystal product with the yield of 72%.
The obtained irregular crystals were subjected to SEM characterization, and the obtained results are shown in fig. 11. Simultaneously, detecting the residual content of solvent in the product, wherein the residual content comprises 8974ppm of butyl acetate, 39941ppm of acetone and 0ppm of methanol; the residual soluble content of butyl acetate and acetone is more than 5000ppm, which does not accord with the guidance principle of ICH industry.
Comparative example 2
Water was added to the crystallization system of example 5 to adjust the water content of the system to 3.9%, and SEM characterization was performed on the obtained crystals, and the results are shown in FIG. 12.
Comparative example 3
At the temperature of 0-5 ℃, 12g of 6-aminopenicillanic acid is added into 60ml of purified water, 20ml of 10wt% NaOH aqueous solution is dripped into the system, and the dripping is finished after 20 min; dissolving 16.2g of 3- (2, 6-dichlorophenyl) -5-methylisoxazole-4-carbonyl chloride in 90ml of acetone to prepare a 3- (2, 6-dichlorophenyl) -5-methylisoxazole-4-carbonyl chloride solution, and adding the 3- (2, 6-dichlorophenyl) -5-methylisoxazole-4-carbonyl chloride solution into the system at 5 ℃ over 1 hour to carry out an acylation reaction while dropping 20ml of a 10wt% aqueous NaOH solution, maintaining pH = 7; after the reaction was completed, 10ml of dichloromethane was added to the system, 10wt% dilute sulfuric acid was added to the system, the pH was adjusted to =2, the mixture was allowed to stand with a separatory funnel, and after separation, the lower organic phase (50 ml in total) was taken out.
Dissolving 10.8g of sodium 2-ethylhexanoate in 50ml of isopropanol to prepare a sodium 2-ethylhexanoate solution; adding 18 percent of the volume of the dicloxacillin acid solution into the 2-sodium ethylhexanoate solution at 30 ℃ and 60rpm, after crystal growth, continuing stirring at the rotating speed for 30min, then continuing dropwise adding the rest of the dicloxacillin acid solution at 100rpm for 1h, and obtaining the irregular crystal of the dicloxacillin sodium. Through the analysis of the crystal system measurement, the volume fraction of isopropanol in the crystal system is 71.4%, the water content in the crystal system is 2.5wt%, and the concentration of dicloxacillin sodium is 0.28 g/ml. The obtained crystal was subjected to SEM characterization, and the results thereof are shown in fig. 13.
Claims (2)
1. A preparation method of cylindrical dicloxacillin sodium crystals is characterized by preparing supersaturated solution of dicloxacillin sodium, and carrying out reaction crystallization in the supersaturated solution to obtain cylindrical dicloxacillin sodium crystals;
the supersaturated solution of dicloxacillin sodium is prepared by the following steps: adding a dicloxacillin acid solution into the 2-sodium ethylhexanoate solution to obtain a supersaturated solution of dicloxacillin sodium; the process of adding dicloxacillin acid solution into sodium 2-ethylhexanoate solution comprises the following steps: firstly, pre-adding 18-30% of the volume of a dicloxacillin acid solution into the obtained 2-sodium ethylhexanoate solution, and after crystals appear, continuously adding the rest dicloxacillin acid solution;
the preparation method of the dicloxacillin acid solution comprises the following steps: putting 6-aminopenicillanic acid into water to obtain suspension of 6-aminopenicillanic acid; dissolving 3- (2, 6-dichlorophenyl) -5-methylisoxazole-4-formyl chloride in a third solvent, wherein the third solvent is any one of acetone, dichloromethane and methyl acetate; adjusting the pH value of a 6-aminopenicillanic acid aqueous solution to 7-8 until the system is clear, adding a 3- (2, 6-dichlorophenyl) -5-methylisoxazole-4-formyl chloride solution into the aqueous solution for acylation reaction, and controlling the pH value to be = 7-8; after the reaction is finished, adding dichloromethane or methyl acetate into the system, adjusting the pH value to be =2.0 +/-0.2 by adopting acid, carrying out phase separation, taking a lower-layer organic phase, and adding ethanol, isopropanol or a mixed solvent formed by mutually dissolving the ethanol and the isopropanol in any proportion into the lower-layer organic phase to obtain a dicloxacillin solution;
the sodium 2-ethylhexanoate solution is prepared by the following steps: dissolving 2-ethyl sodium hexanoate in ethanol, isopropanol or a mixed solvent formed by mutually dissolving the ethanol and the isopropanol in any proportion;
in the supersaturated solution of dicloxacillin sodium, the volume fraction of the third solvent is 0-26%, and the content of impurity water is less than or equal to 3.5 wt%.
2. The method for preparing cylindrical dicloxacillin sodium crystals according to claim 1, wherein the concentration of the supersaturated solution of dicloxacillin sodium is 0.007-0.11 g/ml.
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