CN115043853A - Preparation method of cefalexin sodium - Google Patents
Preparation method of cefalexin sodium Download PDFInfo
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- CN115043853A CN115043853A CN202210977764.0A CN202210977764A CN115043853A CN 115043853 A CN115043853 A CN 115043853A CN 202210977764 A CN202210977764 A CN 202210977764A CN 115043853 A CN115043853 A CN 115043853A
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/02—Preparation
- C07D501/04—Preparation from compounds already containing the ring or condensed ring systems, e.g. by dehydrogenation of the ring, by introduction, elimination or modification of substituents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/02—Preparation
- C07D501/12—Separation; Purification
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
- C07D501/22—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with radicals containing only hydrogen and carbon atoms, attached in position 3
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Abstract
The invention belongs to the technical field of drug synthesis, and particularly relates to a preparation method of veterinary cefalexin sodium. The cefalexin sodium powder crystal prepared by the method contains acetone and acetone glycerol in a certain proportion in a crystallization system for preparing cefalexin sodium, so that the growth of the cefalexin sodium crystal in an irregular polyhedral shape is facilitated, and the flowability of the obtained cefalexin sodium powder crystal is remarkably improved in a closed material transfer process; different solvents are matched with each other in a reaction system to obtain high-yield and high-purity cefalexin sodium; the preparation method disclosed by the invention is mild in reaction conditions, simple in post-treatment operation, high in product fluidity in the closed material transferring process and beneficial to workshop production.
Description
Technical Field
The invention belongs to the technical field of drug synthesis, relates to a preparation method of a cephalosporin antibiotic for livestock, and particularly relates to a preparation method of cefalexin sodium.
Background
Cephalexin is a broad-spectrum antibiotic, has antibacterial action on both gram-negative bacteria and gram-positive bacteria, belongs to the first generation of cephalosporin antibiotics, and is approved as veterinary use in 2014 in China. Cefalexin is not easy to dissolve in water, and the current veterinary cefalexin preparations only comprise cefalexin tablets and cefalexin suspension for injection. Because the animal has higher oral administration difficulty, and the strong pain of the animal is easily caused when the suspension is injected into the animal, and the drug absorption rate is poor, the two preparation forms of the cefalexin are not favorable for the animal administration. The cefalexin sodium is sodium salt of cefalexin, is easy to dissolve in water, and can improve the drug absorption efficiency and facilitate the administration of animals when being used for preparing cefalexin sodium preparation powder injection. At present, the domestic market lacks the development of cefalexin sodium powder injection.
U.S. Pat. No. 3,3822256 (A) discloses a preparation method of cefalexin sodium, which comprises the following specific steps: adding triethylamine and distilled water into an isopropanol solution of cefalexin monohydrate at room temperature to prepare a clear solution; adding isopropanol into the clear solution, adding a sodium salt solution, and stirring for reaction; after a certain time, adding isopropanol again, and stirring at 0 ℃ for reaction; finally, the reaction mixture was filtered, washed and dried to obtain white crystalline powder.
Although the yield of the cefalexin sodium prepared by the method is high (more than or equal to 89%), the cefalexin sodium crystal is in a needle shape, a rod shape or a spherical-needle mixed type, and the powder flowability of the crystal shapes is poor in the industrial production process.
Disclosure of Invention
Aiming at the problems that the cefalexin sodium prepared by the existing method has poor crystal form, poor powder flowability and is not beneficial to industrial production, the invention provides the preparation method of cefalexin sodium.
In order to achieve the purpose, the invention adopts the following technical scheme:
the invention provides a preparation method of cefalexin sodium, which is characterized by comprising the following steps of:
(1) adding a sodium supply agent into the cefalexin solution for reaction, or simultaneously adding the cefalexin solution and the sodium supply agent into a base solution for reaction; after the reaction is finished, adding a crystallization solvent for crystal growth to obtain a solution to be separated;
(2) sequentially filtering, washing and drying the liquid to be separated in the step (1) to finally obtain cefalexin sodium;
the liquid to be separated in the step (1) contains acetone and acetone glycerol acetal, and the total volume of the acetone and the acetone glycerol acetal accounts for 60-75% of the volume of the liquid to be separated.
The acetone in the liquid to be separated in the step (1) is from a cefalexin solution and/or a sodium supply agent and/or a crystallization solvent; the acetone condensed glycerol in the liquid to be separated in the step (1) is from a cefalexin solution and/or a sodium supply agent and/or a crystallization solvent.
Preferably, the mass fraction of the cefalexin in the cefalexin solution in the step (1) is 8-11%.
Preferably, the preparation of the cefalexin solution in the step (1) comprises the following steps: adding cefalexin monohydrate into an organic solvent, adding organic alkali, and stirring to dissolve the cefalexin monohydrate to obtain a clear solution.
Further preferably, the organic solvent is at least one selected from acetonitrile, acetone, acetonide, methanol, ethanol, isopropanol, dichloromethane, and ethyl acetate.
Further preferably, the mass volume ratio of the cefalexin monohydrate to the organic solvent is 1 (10-15) g/m 3 。
The organic base is capable of adjusting the system to a pH =8.0-10.0 and promoting the conversion of cephalexin monohydrate to cephalexin sodium.
Further preferably, the organic base is one or more selected from ethylenediamine, triethylamine, triethanolamine and N, N-dimethylethanolamine.
Further preferably, the solution obtained after dissolving the cefalexin monohydrate is subjected to adsorption decoloration treatment by using activated carbon and filtered.
Preferably, the preparation of the cefalexin solution is carried out at 25-35 ℃; too low a temperature will affect dissolution and too high a temperature will result in higher impurities.
The reaction formula in the step (1) is shown as a formula I:
formula I
In order to control the reaction rate and optimize the crystallization state, it is necessary to ensure that the sodium salt is added to the reaction system in step (1) in a more dispersed state, and therefore, the sodium salt is generally added to a dispersant to prepare a solution or a suspension to improve the dispersibility.
Preferably, the ratio of the amount of cefalexin in the cefalexin solution in the step (1) to the amount of the substance of sodium element in the sodium supplying agent is 1: (1.1-1.6).
Preferably, the volume ratio of the acetone to the acetonide in the liquid to be separated in the step (1) is 1 (1-2).
Preferably, the sodium supplying agent in the step (1) is any one of a sodium salt, a sodium salt solution prepared from the sodium salt and a dispersing agent, or a sodium salt suspension.
Further preferably, the mass fraction of the sodium salt in the sodium salt solution or sodium salt suspension is 15-30%.
More preferably, the sodium salt is selected from one of sodium acetate, sodium lactate, sodium carbonate and sodium isooctanoate; the dispersing agent is at least one selected from acetonitrile, acetone condensed glycerol, dimethyl carbonate, methyl ethyl ketone, methanol, ethanol, isopropanol, dichloromethane and ethyl acetate.
Still further preferably, the dispersant of the sodium salt solution is selected from: acetonitrile, acetone glycerol, methanol, ethanol, methyl ethyl ketone and isopropanol; the dispersant of the sodium salt suspension is selected from: dichloromethane, ethyl acetate.
Preferably, the base solution in step (1) is at least one of acetonitrile, acetone-glycerol, methanol, ethanol, isopropanol, dichloromethane and ethyl acetate.
Preferably, the reaction temperature in the step (1) is 25-35 ℃, and the reaction time is 1-2 h.
Preferably, the volume ratio of the crystallization solvent in the step (1) to the liquid to be separated is (0.4-0.7): 1.
Preferably, the crystallization solvent of step (1) is at least one selected from acetonitrile, acetone acetal, dimethyl carbonate, methyl ethyl ketone, methanol, ethanol, isopropanol, dichloromethane and ethyl acetate.
Preferably, after the crystallization solvent is added in the step (1), slowly growing crystals for 1-2 hours to obtain the liquid to be separated.
The crystal form of the product obtained by the method that the cefalexin solution and the sodium supplying agent are simultaneously added into the base solution in the step (2) is more excellent.
Preferably, the washing agent used in the step (2) is at least one selected from acetonitrile, acetone acetal, dimethyl carbonate, methyl ethyl ketone, methanol, ethanol, isopropanol, dichloromethane and ethyl acetate.
Preferably, the drying in the step (2) is vacuum drying at 30-50 ℃.
And (2) selecting the organic solvent of the cefalexin solution in the step (1), the dispersing agent of a sodium supply agent, the base solution, the crystallization solvent and the washing agent in the step (2) from the same solvent so as to facilitate the recovery and treatment of mother liquor.
Generally, the size and shape of drug crystals affect the quality and production efficiency of products, and the size and shape of drug crystals are susceptible to the production process, in which the solvent for the reaction process and the crystallization process is one of the important factors for controlling the size and shape of crystals.
The cefalexin sodium crystal prepared by the method is mainly in an irregular polyhedral shape, the medicine powder in the crystal shape is generally high in filtering speed, thorough in washing, short in drying time and good in fluidity, and the operations such as large-scale production closed material transfer and the like are easy to realize because: irregular polyhedrons generally comprise tens to tens of faces, and their irregularities result in less interparticle contact and imbalance in forces, resulting in a reduction in interparticle adhesion, which has a greater dispersion angle under the action of gravity, i.e., fluidity.
One or more technical schemes provided by the invention at least have the following technical effects:
1. the preparation method comprises acetone and acetone glycerol in a certain proportion in a crystallization system, so that the growth of the cefalexin sodium crystal in an irregular polyhedral shape is facilitated, and the flowability of the obtained cefalexin sodium powder crystal is remarkably improved in a closed material transferring process.
2. According to the preparation method, different solvents are matched with each other in a reaction system, so that high-yield and high-purity cefalexin sodium is obtained.
3. The preparation method disclosed by the invention is mild in reaction conditions, simple in post-treatment operation, high in product fluidity in the closed material transferring process and beneficial to workshop production.
Drawings
FIG. 1 is a picture of the crystal form of cefalexin sodium in example 1;
FIG. 2 shows the DSC/TG measurement of cefalexin sodium in example 1;
FIG. 3 shows the XRD detection result of cefalexin sodium in example 1;
FIG. 4 is a picture of the crystal shape of cefalexin sodium in example 2;
FIG. 5 is a photograph showing the crystal shape of cefalexin sodium in example 3;
FIG. 6 is a photograph showing the crystal shape of cefalexin sodium in example 4;
FIG. 7 is a photograph showing the crystal shape of cefalexin sodium in example 5;
FIG. 8 is a photograph showing the crystal shape of cefalexin sodium in example 6;
FIG. 9 is a photograph showing the crystal shape of cefalexin sodium in comparative example 1;
FIG. 10 is a photograph showing the crystal shape of cefalexin sodium in comparative example 2;
FIG. 11 is a picture of the crystal shape of cefalexin sodium in comparative example 3;
FIG. 12 is a photograph showing the crystal shape of cefalexin sodium in comparative example 4;
FIG. 13 is a photograph showing the crystal shape of cefalexin sodium in comparative example 5;
FIG. 14 is a photograph showing the crystal shape of cefalexin sodium in comparative example 6;
FIG. 15 is a photograph showing the crystal shape of cefalexin sodium in comparative example 7;
FIG. 16 is a picture of the crystal shape of cefalexin sodium in comparative example 8;
FIG. 17 is a photograph showing the crystal shape of cefalexin sodium in comparative example 9;
FIG. 18 is a photograph showing the crystal shape of cefalexin sodium in comparative example 10;
fig. 19 is a picture of the crystal shape of cefalexin sodium in comparative example 11.
Detailed Description
The following description will further describe a process for preparing cefalexin sodium by way of specific examples in conjunction with the accompanying drawings.
The crystal form of the product was determined in all examples and comparative examples using a Mettler on-line particle image Analyzer EasyViewer 100 System.
Moisture content: the water in the medicine includes crystal water and adsorbed water. The amount of water content has an influence on the stability, physical and chemical properties, and medicinal effects. The standard of the water content in the medicine powder injection is as follows: 4-6%.
The pH standard of the medicine powder injection is as follows: 8.5 to 10.0.
Total vehicle residue: namely the residue of organic volatile compounds used in the production of bulk drugs or excipients, and in the preparation process of the formulations; the total solvent residue in the present invention was detected by high performance gas chromatography.
Example 1
A preparation method of cefalexin sodium comprises the following steps:
(1) adding 50mL of mixed solution of acetone and acetone glycerol in a volume ratio of 1:1 into a 250mL three-necked bottle, adding 5g (0.0137mol) of cefalexin monohydrate, controlling the temperature to be 25 ℃, dropwise adding triethanolamine, stirring until the solution is clear, adding 0.5g of activated carbon, stirring and decoloring for 30min, and filtering to obtain a cefalexin solution with the mass fraction of 9%; controlling the temperature to be 25-35 ℃, adding a sodium lactate solution (2.3g of 0.0205mol of sodium lactate is dissolved in 10mL of a mixed solution of acetone and acetone-glycerol in a volume ratio of 1: 1) into the cephalexin solution, stirring for 20min, dropwise adding 100mL of the mixed solution of acetone and acetone-glycerol in a volume ratio of 1:1, slowly stirring for growing crystals for 1 h to obtain a liquid to be separated, wherein the total volume of acetone and acetone-glycerol in the liquid to be separated accounts for 70% of the volume of the liquid to be separated, and the volume ratio of acetone to acetone-glycerol in the liquid to be separated is 1: 1;
(2) after the separated liquid is filtered by suction, crystals are obtained, 50mL of mixed liquid of acetone and acetone glycerol with the volume ratio of 1:1 is used for washing the crystals, and the crystals are dried for 2 hours at the temperature of 40 ℃ in vacuum, so that 4.62g (0.0125 mol) of cefalexin sodium is obtained, and the yield is 91.2%.
The product is tested and analyzed, the result is shown in table 1, the crystal shape is shown in figure 1 of the specification, the crystal is in an irregular polyhedron shape, the medicine powder in the shape has good fluidity in the closed material transferring process, and workshop production is facilitated; DSC/TG analysis is carried out on the product, and the result is shown in the specification and figure 2, the product does not contain crystal water and starts to decompose at 270 ℃; XRD analysis of the product showed that the product had a crystalline form as shown in FIG. 3 of the specification and diffraction peaks at 2 theta =5.73,8.57,9.00,9.40,11.45,15.01,17.31,18.52,19.22,20.57,22.20,22.88,23.96,25.21,27.39,28.64,29.51,31.03,32.94,36.73 and 38.90.
Example 2
A preparation method of cefalexin sodium comprises the following steps:
(1) adding 50mL of mixed solution of acetone and acetone glycerol in a volume ratio of 1:1 into a 250mL three-necked bottle, adding 5g (0.0137 mmol) of cefalexin monohydrate, controlling the temperature to be 25 ℃, dropwise adding triethylamine, stirring until the solution is clear, adding 0.5g of activated carbon, stirring and decoloring for 30min, and filtering to obtain a cefalexin solution with the mass fraction of 9%; controlling the temperature to be 25-35 ℃, simultaneously adding the cefalexin solution and the sodium acetate solution (1.68 g of 0.0205mol of sodium acetate dissolved in 10mL of a mixed solution of acetone and acetone-glycerol acetal with a volume ratio of 1: 1) into 50mL of ethanol (base solution), stirring for 20min after the addition, dropwise adding 100mL of isopropanol, slowly stirring and growing crystals for 1 h to obtain a liquid to be separated, wherein the total volume of acetone and acetone-glycerol acetal in the liquid to be separated accounts for 70% of the volume of the liquid to be separated, and the volume ratio of acetone to acetone-glycerol acetal in the liquid to be separated is 1: 1;
(2) and (3) filtering the separated liquid to obtain crystals, washing the crystals by using 50mL of mixed liquid of acetone and acetone glycerol in a volume ratio of 1:1, and drying at 40 ℃ in vacuum for 2 hours to obtain 4.45g (0.012 mmol) of cefalexin sodium, wherein the yield is 87.6%.
The product is tested and analyzed, and the result is shown in table 1, the crystal shape is shown in figure 4 of the specification, the crystal is in a crushed particle shape, and the flowability is good in the closed material transferring process. The broken granular products are easy to block the micropores of a filter medium during filtering, so that the filtering effect is poor, but because the broken granular products are granular, the contact surface among granules is few, the stress is unbalanced, the adhesion force is weakened, and the flowability is better under the influence of external force.
Example 3
A preparation method of cefalexin sodium comprises the following steps:
(1) adding 50mL of acetone into a 250mL three-necked bottle, adding 5g (0.0137mol) of cefalexin monohydrate, controlling the temperature to be 25 ℃, dropwise adding triethylamine, stirring until the solution is clear, adding 0.5g of activated carbon, stirring and decoloring for 30min, and filtering to obtain a cefalexin solution with the mass fraction of 10%; controlling the temperature to be 25-35 ℃, adding an acetone solution of sodium lactate (2.3g of 0.0205mol of sodium lactate dissolved in 10mL of acetone) into the cephalexin solution, stirring for 20min after adding, dropwise adding 120mL of a mixed solution of acetone and acetone glycerol in a volume ratio of 1:3, and slowly stirring for growing crystals for 1 h to obtain a liquid to be separated, wherein the volume of the acetone in the liquid to be separated accounts for 70% of the volume of the liquid to be separated; the volume ratio of acetone to acetone glycerol in the liquid to be separated is 1: 1;
(2) after the separated liquid was filtered by suction, crystals were obtained, which were washed with 50mL of acetone and dried at 40 ℃ for 2 hours under vacuum to obtain 4.55g (0.0123mmol) of cefalexin, with a yield of 89.8%.
The test analysis of the product shows that the crystal shape is shown in figure 5, the irregular polyhedron shape is shown in the specification, and the medicine powder has better fluidity in the closed material transferring process.
Example 4
A preparation method of cefalexin sodium comprises the following steps:
(1) adding 100mL of acetone glycerol into a 500mL three-necked bottle, adding 10g (0.0274mol) of cefalexin monohydrate, controlling the temperature to be 25 ℃, dropwise adding ethylenediamine, stirring until the solution is clear, adding 1g of activated carbon, stirring and decoloring for 30min, and filtering to obtain a cefalexin solution with the mass fraction of 8%; controlling the temperature to be 25-35 ℃, adding an acetone solution of sodium iso-octoate (5.4g of sodium iso-octoate 0.0325mol dissolved in 20mL of acetone) into the cephalexin solution, stirring for 20min after adding, dropwise adding 180mL of a mixed solution of acetone and acetone glycerol (the volume ratio is 2:1), slowly stirring for growing crystals for 1 h to obtain a liquid to be separated, wherein the total volume of the acetone and the acetone glycerol in the liquid to be separated accounts for 70% of the volume of the liquid to be separated, and the volume ratio of the acetone and the acetone glycerol in the liquid to be separated is 1: 1.14;
(2) after the separated liquid is filtered by suction to obtain crystals, the crystals are washed by 100mL of acetone and dried for 2 hours at the temperature of 40 ℃ in vacuum, and 9.03g (0.0244mmol) of cefalexin sodium is obtained with the yield of 89.1 percent.
The product was analyzed and found to have the crystal shape shown in fig. 6, which is irregular polyhedron shape, and the powder of the drug was flowable in the process of sealed material transfer as shown in table 1.
Example 5
A preparation method of cefalexin sodium comprises the following steps:
(1) adding 60mL of acetone-glycerol mixture with the volume ratio of 2:1 into a 250mL three-necked bottle, adding 5g (0.0137mol) of cefalexin monohydrate, controlling the temperature to be 25 ℃, dropwise adding triethylamine, stirring until the solution is clear, adding 0.5g of activated carbon, stirring and decoloring for 30min, and filtering to obtain a cefalexin solution with the mass fraction of 8%; controlling the temperature to be 25-35 ℃, adding an acetone solution of sodium lactate (2.3g of 0.0205mol of sodium lactate dissolved in 10mL of acetone) into the cephalexin solution, stirring for 20min after adding, dropwise adding 60mL of acetone-glycerol, slowly stirring for growing crystals for 1 h to obtain a liquid to be separated, wherein the total volume of the acetone and the acetone-glycerol in the liquid to be separated accounts for 75% of the volume of the liquid to be separated;
(2) and (3) carrying out suction filtration on a solution to be separated (the volume ratio of acetone to acetonide in the solution to be separated is 1: 1.6) to obtain crystals, washing the crystals with 50mL of acetone, and drying at 40 ℃ in vacuum for 2 hours to obtain 4.58g (0.0124mmol) of cefalexin sodium with the yield of 90.5%.
The product was analyzed and found to have the crystal shape shown in fig. 7 of the specification, which is irregular polyhedron shape, and the powder of the drug was flowable in the closed transferring process, as shown in table 1.
Example 6
A preparation method of cefalexin sodium comprises the following steps:
the difference from example 1 is that the volume ratio of acetone to acetonide in the mixture of acetone and acetonide in steps (1) to (2) was 1:2, and that 4.58g (0.0124mol) of cefalexin sodium was obtained, with a yield of 90.5%.
The product is tested and analyzed, the analysis result is shown in table 1, the crystal shape is shown in figure 8 of the specification, the crystal is in an irregular polyhedron shape, and the medicine powder has good fluidity in the closed material transferring process.
Comparative example 1
A preparation method of cefalexin sodium comprises the following steps:
(1) adding 50mL of acetone into a 250mL three-necked bottle, adding 5g (0.0137mol) of cefalexin monohydrate, controlling the temperature to be 25 ℃, dropwise adding ethylenediamine, stirring until the solution is clear, adding 0.5g of activated carbon, stirring and decoloring for 30min, and filtering to obtain a cefalexin solution; controlling the temperature to be 25-35 ℃, adding a methanol solution of sodium acetate (1.68 g of 0.0205mol of sodium acetate is dissolved in 5mL of methanol) into the cephalexin solution, stirring for 20min after adding, dropwise adding 100mL of acetone, slowly stirring for crystal growth for 1 hour to obtain a to-be-separated liquid, wherein the to-be-separated liquid does not contain acetone glycerol;
(2) and (3) filtering the separated liquid to obtain crystals, washing the crystals with 50mL of acetone, and drying the crystals for 2 hours at the temperature of 40 ℃ in vacuum to obtain 4.3g (0.0116 mol) of cefalexin sodium with the yield of 84.7%.
The product was subjected to test analysis, and the analysis results are shown in table 1, and the crystal shape is shown in fig. 9 of the specification, and is rod-shaped, and the crystal powder with the shape has poor fluidity in the closed material transferring process.
Comparative example 2
A preparation method of cefalexin sodium comprises the following steps:
(1) adding 50mL of methyl ethyl ketone into a 250mL three-neck flask, adding 5g (0.0137mol) of cefalexin monohydrate, controlling the temperature to be 25 ℃, dropwise adding triethylamine, stirring until the solution is clear, adding 0.5g of activated carbon, stirring and decoloring for 30min, and filtering to obtain a cefalexin solution; controlling the temperature to be 25-35 ℃, adding a methyl ethyl ketone solution of sodium acetate (1.68 g of 0.0205mol of sodium acetate is dissolved in 5mL of methyl ethyl ketone) into the cephalexin solution, stirring for 20min after adding, dropwise adding 100mL of methyl ethyl ketone, slowly stirring for crystal growth for 1 hour to obtain a liquid to be separated, wherein the liquid to be separated does not contain acetone and acetone glycerol;
(2) after the separated liquid was filtered by suction to obtain crystals, 50mL of methyl ethyl ketone was used to wash the crystals, which were dried at 40 ℃ for 2 hours under vacuum to obtain 4.5g (0.0122mol) of cefalexin, with a yield of 89.1%.
The product was subjected to test analysis, and the analysis results are shown in Table 1, and the crystal shape is shown in FIG. 10 of the specification, and is needle-like, and the powder of the crystal with this shape has poor fluidity in the closed transferring process.
Comparative example 3
A preparation method of cefalexin sodium comprises the following steps:
(1) adding 50mL of dimethyl carbonate and 50mL of acetone into a 500mL three-necked bottle, adding 10g (0.0274mol) of cefalexin monohydrate, controlling the temperature to be 25 ℃, dropwise adding ethylenediamine, stirring until the solution is clear, adding 1g of activated carbon, stirring and decoloring for 30min, and filtering to obtain a cefalexin solution; controlling the temperature to be 25-35 ℃, adding an acetone solution of sodium iso-octoate (5.4g of sodium iso-octoate is dissolved in 10mL of acetone by 0.0325 mol) into the cephalexin solution, stirring for 20min after adding, dropwise adding 100mL (50 mL each) of a mixed solution of acetone and dimethyl carbonate, slowly stirring and growing crystals for 1 hour to obtain a to-be-separated liquid, wherein the to-be-separated liquid does not contain acetone glycidol;
(2) after the separated liquid was filtered by suction to obtain crystals, the crystals were washed with 50mL of ethanol and dried at 40 ℃ for 2 hours under vacuum to obtain 8.9g (0.0241 mol) of cefalexin sodium in 88.0% yield.
The product was subjected to test analysis, and the analysis results are shown in table 1, and the crystal shape is shown in fig. 11 of the specification, and is rod-shaped, and the crystal powder with this shape has poor fluidity in the closed material transfer process.
Comparative example 4
A preparation method of cefalexin sodium comprises the following steps:
(1) adding 50mL of isopropanol into a 250mL three-necked bottle, adding 5g (0.0137mol) of cefalexin monohydrate, controlling the temperature to be 25 ℃, dropwise adding N, N-dimethylethanolamine, stirring until the solution is clear, adding 0.5g of activated carbon, stirring and decoloring for 30min, and filtering to obtain a cefalexin solution; controlling the temperature to be 25-35 ℃, adding an isopropanol solution of sodium isooctanoate (2.7 g of 0.0162mol of sodium isooctanoate is dissolved in 10mL of isopropanol) into the cephalexin solution, stirring for 20min after the addition is finished, dropwise adding 100mL of isopropanol, slowly stirring for growing crystals for 1 h to obtain a liquid to be separated, wherein the liquid to be separated does not contain acetone and acetone glycidol;
(2) after the separated liquid was filtered by suction to obtain crystals, 50mL of isopropanol was used to wash the crystals, which were dried at 40 ℃ for 2 hours under vacuum to obtain 4.6g (0.0125 mol) of cefalexin in 91.2% yield.
The product was subjected to test analysis, and the analysis results are shown in table 1, and the crystal shape is shown in fig. 12 of the specification, and is needle-like, and the crystal powder of this shape has poor fluidity in the closed material transfer process.
Comparative example 5
A preparation method of cefalexin sodium comprises the following steps:
(1) adding 50mL of ethanol into a 250mL three-necked bottle, adding 5g (0.0137mol) of cefalexin monohydrate, controlling the temperature to be 25 ℃, dropwise adding triethylamine, stirring until the solution is clear, adding 0.5g of activated carbon, stirring and decoloring for 30min, and filtering to obtain a cefalexin solution; controlling the temperature to be 25-35 ℃, simultaneously adding the cefalexin solution and the ethanol solution of sodium acetate (1.68 g of 0.0205mol of sodium acetate is dissolved in 5mL of ethanol) into 50mL of ethanol (base solution), stirring for 20min after the addition is finished, dropwise adding 100mL of isopropanol, slowly stirring for growing crystals for 1 h to obtain a liquid to be separated, wherein the liquid to be separated does not contain acetone and acetone glycidol;
(2) and (3) filtering the separated liquid to obtain crystals, washing the crystals with 50mL of isopropanol, and drying at 40 ℃ in vacuum for 2 hours to obtain 4.3g (0.0116 mol) of cefalexin sodium with the yield of 84.7%.
The product was subjected to test analysis, and the analysis results are shown in table 1, and the crystal shape is shown in fig. 13 of the specification, and is rod-like, and the crystal powder of this shape has poor fluidity in the process of closed material transfer.
Comparative example 6
A preparation method of cefalexin sodium comprises the following steps:
the difference from example 1 was that, by replacing all the acetone/acetone-glycerol mixture in steps (1) to (2) with ethanol of the same volume, cefalexin sodium (4.30 g, 0.0116 mol) was obtained with a yield of 84.7%.
The product was analyzed by detection, and the analysis results are shown in table 1, and the crystal shape is shown in fig. 14 of the specification, and is rod-like, and the crystal powder with this shape has poor fluidity in the process of closed material transfer.
Comparative example 7
The difference from example 1 is that in the mixture of acetone and acetonide in steps (1) to (2), the volume ratio of acetone to acetonide was 1:0.5, and that cefalexin sodium was obtained at 4.57g (0.0124mol) with a yield of 90.5%.
The product was subjected to test analysis, and the analysis results are shown in table 1, and the crystal shape is shown in fig. 15 of the specification, and is rod-shaped, and the crystal powder with the shape has poor fluidity in the closed material transfer process.
Comparative example 8
The difference from example 1 is that in the mixture of acetone and acetonide in steps (1) to (2), the volume ratio of acetone to acetonide was 1:4, and that 4.59g (0.0124mol) of cefalexin sodium was obtained, with a yield of 90.5%.
The product was subjected to test analysis, and the analysis results are shown in table 1, and the crystal shape is shown in fig. 16 of the specification, and is rod-shaped, and the crystal powder in such a shape has poor fluidity in the closed material transfer process.
Comparative example 9
Compared with the example 1, the difference is that in the acetone and acetone-glycerol mixture in the steps (1) to (2), the acetone is replaced by isopropanol with the same volume, so that the obtained cefalexin sodium is 4.55g (0.0123mol), the yield is 89.8%, the product is subjected to test analysis, the analysis result is shown in the table 1, the crystal shape is shown in the specification and attached figure 17 and is a rod, and the flowability of the crystal powder with the shape in the closed material transferring process is poor.
Comparative example 10
The difference from example 1 was that in the mixture of acetone and acetonide in steps (1) to (2), 4.50g (0.0122mol) of cefalexin sodium was obtained by replacing the acetonide with isopropanol of the same volume, and the yield was 89.1%.
The product was subjected to test analysis, and the analysis results are shown in table 1, and the crystal shape is shown in fig. 18 of the specification, and is rod-shaped, and the crystal powder in such a shape has poor fluidity in the closed material transfer process.
Comparative example 11
Compared with the example 1, the difference is that the mixture of acetone and acetone condensed glycerol in the steps (1) to (2) is replaced by the mixture of isopropanol and ethanol with the volume ratio of 1:1, so that the obtained cefalexin sodium is 4.45g (0.012mol), and the yield is 87.6%.
The product was subjected to test analysis, and the analysis results are shown in table 1, and the crystal shape of the product is shown in fig. 19 of the specification, and is rod-shaped, and the crystal powder in such a shape has poor fluidity in the closed material transfer process.
TABLE 1 test results of various indexes of cefalexin sodium in examples and comparative examples
| Examples or comparative examples | Moisture content | pH | Sodium content | Optical rotation | Total solvent residue | Yield/% |
| Example 1 | 4.5% | 9.6 | 5.7% | 142° | 0.45% | 91.2 |
| Example 2 | 3.9% | 8.7 | 5.5% | 141° | 0.35% | 87.6 |
| Example 3 | 4.6% | 9.3 | 5.1% | 141° | 0.43% | 89.8 |
| Example 4 | 4.1% | 9.5 | 5.5% | 141° | 0.27% | 89.1 |
| Example 5 | 4.3% | 9.4 | 5.6% | 143° | 0.38% | 90.5 |
| Example 6 | 4.8% | 9.1 | 5.2% | 143° | 0.40% | 90.5 |
| Comparative example 1 | 4.6% | 9.3 | 5.1% | 141° | 0.43% | 84.7 |
| Comparative example 2 | 4.1% | 9.5 | 5.5% | 141° | 0.27% | 89.1 |
| Comparative example 3 | 4.3% | 9.4 | 5.3% | 143° | 0.38% | 88.0 |
| Comparative example 4 | 3.7% | 9.7 | 5.9% | 142° | 0.35% | 91.2 |
| Comparative example 5 | 4.2% | 9.7 | 5.4% | 142° | 0.23% | 84.7 |
| Comparative example 6 | 4.5% | 8.9 | 5.5% | 142° | 0.27% | 84.7 |
| Comparative example 7 | 4.6% | 9.1 | 5.4% | 142° | 0.28% | 90.5 |
| Comparative example 8 | 5.0% | 9.2 | 5.2% | 142° | 0.25% | 90.5 |
| Comparative example 9 | 3.9% | 8.6 | 5.4% | 142° | 0.45% | 89.8 |
| Comparative example 10 | 4.3% | 9.1 | 5.1% | 141° | 0.33% | 89.1 |
| Comparative example 11 | 4.5% | 9.2 | 5.3% | 142° | 0.38% | 87.6 |
And (4) analyzing results: comparative examples 1-6 and 9-11 in comparison with examples 1-6, the liquid to be separated contained neither acetone nor acetone-glycerol, and the crystals of cefalexin sodium obtained were needle-like or rod-like in shape, and the crystal powder was inferior in fluidity in the closed transfer process.
Comparative example 7, comparative example 8 compared with examples 1-6, the volume ratio of acetone to acetonide in the liquid to be separated was too large (2: 1) or too small (1: 4) to facilitate the formation of polyhedral crystals, and the resulting cefalexin sodium crystals mostly had rod-like shapes and had poor flowability during the closed transfer process.
Claims (11)
1. A preparation method of cefalexin sodium is characterized by comprising the following steps:
(1) adding a sodium supply agent into the cefalexin solution for reaction, or simultaneously adding the cefalexin solution and the sodium supply agent into the base solution for reaction; after the reaction is finished, adding a crystallization solvent, and growing crystals to obtain a solution to be separated;
(2) filtering, washing and drying the liquid to be separated in the step (1) to obtain cefalexin sodium;
the liquid to be separated in the step (1) contains acetone and acetone glycerol acetal, and the total volume of the acetone and the acetone glycerol acetal accounts for 60-75% of the volume of the liquid to be separated;
the volume ratio of acetone to acetone condensed glycerol in the liquid to be separated in the step (1) is 1 (1-2).
2. The preparation method of cefalexin sodium according to claim 1, characterized in that the mass fraction of cefalexin in the cefalexin solution of step (1) is 8-11%, and the solvent of the cefalexin solution is an organic solvent.
3. The process according to claim 2, wherein the preparation of the cephalexin solution in step (1) comprises: adding cefalexin monohydrate into an organic solvent, adding organic alkali, and stirring to dissolve the cefalexin monohydrate to obtain a clear solution; the organic alkali is selected from any one of ethylenediamine, triethylamine, triethanolamine and N, N-dimethylethanolamine.
4. The process according to claim 2, wherein the organic solvent in the cephalexin solution of step (1) is at least one of acetonitrile, acetone, acetonide, methanol, ethanol, isopropanol, dichloromethane, and ethyl acetate.
5. The process according to claim 1, wherein the ratio of the amount of cefalexin in the cefalexin solution to the amount of sodium in the sodium donor in step (1) is 1: (1.1-1.6).
6. The process for preparing cefalexin sodium according to claim 1, wherein the sodium supplying agent in step (1) is any one of a sodium salt, a sodium salt solution containing the sodium salt and a dispersing agent, and a sodium salt suspension containing the sodium salt and the dispersing agent;
the sodium salt is selected from one of sodium acetate, sodium lactate, sodium carbonate and sodium isooctanoate.
7. The process of claim 6, wherein the dispersant is at least one selected from the group consisting of acetonitrile, acetone, acetonide, dimethyl carbonate, methyl ethyl ketone, methanol, ethanol, isopropanol, dichloromethane, and ethyl acetate.
8. The process of claim 1, wherein the base solution in step (1) is at least one of acetonitrile, acetone, acetonide, methanol, ethanol, isopropanol, dichloromethane, and ethyl acetate.
9. The preparation method of cefalexin sodium according to claim 1, characterized in that the reaction temperature in the step (1) is 25-35 ℃, and the reaction time is 1-2 h;
the crystallization solvent in the step (1) is at least one selected from acetonitrile, acetone condensed glycerol, dimethyl carbonate, methyl ethyl ketone, methanol, ethanol, isopropanol, dichloromethane and ethyl acetate.
10. The preparation method of cefalexin sodium according to claim 1, characterized in that the volume ratio of the crystallization solvent in the step (1) to the liquid to be separated is (0.4-0.7): 1.
11. The process of claim 1, wherein the washing in step (2) is performed with a detergent selected from at least one of acetonitrile, acetone, acetonide, dimethyl carbonate, methyl ethyl ketone, methanol, ethanol, isopropanol, dichloromethane, and ethyl acetate; the drying method in the step (2) is vacuum drying at 30-50 ℃.
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|---|---|---|---|---|
| FR2187303A1 (en) * | 1972-06-08 | 1974-01-18 | Bristol Myers Co | |
| ES526971A0 (en) * | 1983-11-02 | 1986-02-01 | Gema Sa | PROCEDURE FOR THE PREPARATION OF SODIC SALTS OF BETA-LACTAMIC ANTIBIOTICS |
| US5908929A (en) * | 1996-12-05 | 1999-06-01 | Vitara Chemicals Limited | Process for the manufacture of the antibiotic 7-(D-α-amino-α-phenylacetamido)-3-methyl-3-cephem-4-carboxylic acid (cephalexin) and pharmaceutically acceptable salts thereof |
| CN104940207A (en) * | 2015-05-26 | 2015-09-30 | 青岛海之星生物科技有限公司 | Cefalexin and probenecid compound sustained-release capsule and preparation method thereof |
| CN109134505A (en) * | 2017-07-19 | 2019-01-04 | 陶灵刚 | 1/2 water cefoperazone sodium compound of one kind and its drug combination preparation |
| CN109651401A (en) * | 2018-12-12 | 2019-04-19 | 淄博鑫泉医药技术服务有限公司 | The preparation method of Cefuroxime Sodium |
| CN111909179A (en) * | 2020-08-13 | 2020-11-10 | 天津大学 | Preparation method for improving morphological index of cefalexin crystal |
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- 2022-08-16 CN CN202210977764.0A patent/CN115043853A/en active Pending
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2187303A1 (en) * | 1972-06-08 | 1974-01-18 | Bristol Myers Co | |
| ES526971A0 (en) * | 1983-11-02 | 1986-02-01 | Gema Sa | PROCEDURE FOR THE PREPARATION OF SODIC SALTS OF BETA-LACTAMIC ANTIBIOTICS |
| US5908929A (en) * | 1996-12-05 | 1999-06-01 | Vitara Chemicals Limited | Process for the manufacture of the antibiotic 7-(D-α-amino-α-phenylacetamido)-3-methyl-3-cephem-4-carboxylic acid (cephalexin) and pharmaceutically acceptable salts thereof |
| CN104940207A (en) * | 2015-05-26 | 2015-09-30 | 青岛海之星生物科技有限公司 | Cefalexin and probenecid compound sustained-release capsule and preparation method thereof |
| CN109134505A (en) * | 2017-07-19 | 2019-01-04 | 陶灵刚 | 1/2 water cefoperazone sodium compound of one kind and its drug combination preparation |
| CN109651401A (en) * | 2018-12-12 | 2019-04-19 | 淄博鑫泉医药技术服务有限公司 | The preparation method of Cefuroxime Sodium |
| CN111909179A (en) * | 2020-08-13 | 2020-11-10 | 天津大学 | Preparation method for improving morphological index of cefalexin crystal |
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