CN112174984A - Preparation method of ceftezole acid and sodium salt thereof - Google Patents
Preparation method of ceftezole acid and sodium salt thereof Download PDFInfo
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- CN112174984A CN112174984A CN202011163150.6A CN202011163150A CN112174984A CN 112174984 A CN112174984 A CN 112174984A CN 202011163150 A CN202011163150 A CN 202011163150A CN 112174984 A CN112174984 A CN 112174984A
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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
- C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
- C07D501/36—Methylene radicals, substituted by sulfur atoms
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Abstract
The invention relates to the technical field of medicines, and particularly discloses a preparation method of ceftezole acid and a sodium salt thereof. The preparation method comprises the following steps: the method comprises the following steps: adding MTD and 7-ACA into a dimethyl carbonate, boron trifluoride dimethyl carbonate complex and formic acid system, and reacting at 18-22 ℃ to obtain an intermediate 7-ACT; reacting 7-ACT with a mixed anhydride solution prepared from TAA and TCL at-11 to-14 ℃, decoloring, crystallizing, centrifuging and drying to obtain the ceftezole acid. Adding ceftezole acid into water, adjusting the pH value to 4.9-5.5 by using sodium bicarbonate, primarily growing crystals in a methanol-ethanol mixed solvent, and supplementing ethanol for further growing crystals to obtain ceftezole sodium. The preparation method provided by the invention has the advantages of simple process, mild reaction conditions, less pollution, capability of reducing cost and effectively improving the yield of ceftezole acid, the yield of ceftezole sodium prepared from ceftezole acid is more than or equal to 98%, and the purity of the obtained ceftezole sodium is more than 99.8%.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a preparation method of ceftezole acid and a sodium salt thereof.
Background
Ceftezole acid, chemical name (6R) -8-oxo-7- [ (1H-1-tetrazolylacetyl) amino ] -3- [ [2- (1,3, 4-thiadiazolyl) thio ] methyl ] -5-thia-1-azabicyclo [4,2,0] oct-2-ene-2-carboxylic acid, is a semi-synthetic cephalosporin antibiotic synthesized and developed by Nippon Teuzolk drug company. The ceftezole acid is the main raw material for preparing the ceftezole sodium, and the quality of the ceftezole acid directly influences the quality of the ceftezole sodium.
At present, the literature on the synthesis process of ceftezole acid is less, and the ceftezole acid is mainly synthesized by taking tetrazole acetic acid as an initial raw material, preparing acyl chloride, reacting with 7-ACA to prepare an intermediate 7-tetrazole acetamido cephalosporanic acid, and then reacting with 2-mercapto-1, 3, 4-thiadiazole. The method has the advantages of easy environmental pollution, high cost and low yield, and the 7-bit acylation reaction is carried out firstly, needs to be carried out under the condition of low temperature, increases the cost and has high equipment requirement. In addition, 7-ACA is used as an initial raw material and reacts with tetrazole acetic acid under the catalysis of DCC to produce 7-tetrazole acetamido cephalosporanic acid, and then the 7-tetrazole acetamido cephalosporanic acid reacts with 2-mercapto-1, 3, 4-thiadiazole to produce ceftezole acid.
Disclosure of Invention
Aiming at the technical problems in the existing synthesis process of ceftezole acid, the invention provides a preparation method of ceftezole acid and a sodium salt thereof.
In order to achieve the purpose of the invention, the embodiment of the invention adopts the following technical scheme:
a preparation method of ceftezole acid comprises the following steps:
s1: sequentially adding dimethyl carbonate, boron trifluoride dimethyl carbonate complex and formic acid into a reaction kettle, stirring and cooling to 0-5 ℃, adding 2-mercapto-1, 3, 4-thiadiazole and 7-ACA under the protection of nitrogen and at the temperature of less than 10 ℃, heating to 18-22 ℃, reacting for 25-35 min to obtain reaction liquid containing 7-ACT, and crystallizing, centrifuging, washing and drying to obtain an intermediate 7-ACT;
s2: adding acetone and tetrazoleacetic acid into a reaction kettle, cooling to 0 ℃ under the protection of nitrogen, slowly adding triethylamine to adjust the pH value to 7.5-8.0, cooling to-12-10 ℃, slowly adding terephthaloyl chloride, heating to 0 ℃ for reacting for 50-70 min to obtain a mixed anhydride solution, and cooling to-18-20 ℃; adding 7-ACT into an acetone-water mixed solvent, cooling to-11-14 ℃, adding triethylamine until 7-ACT is completely dissolved to obtain a 7-ACT solution, cooling to-18-20 ℃, mixing with the mixed anhydride solution, reacting for 30-45 min at-11-14 ℃, transferring into an aqueous solution with the mass concentration of sodium metabisulfite and disodium ethylene diamine tetraacetate of 0.01-0.1%, and decolorizing, crystallizing, centrifuging and drying to obtain ceftezole acid.
Compared with the prior art, the preparation method of ceftezole acid provided by the invention has the advantages that 2-mercapto-1, 3, 4-thiadiazole and 7-ACA are adopted as raw materials, boron trifluoride dimethyl carbonate complex is used as a catalyst to synthesize an intermediate 7-ACT ((6R,7R) -3- [ (1,3, 4-thiadiazole-2-yl) thiomethyl ] -7-amino-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-formic acid), the yield of the intermediate is improved, and the final yield of ceftezole acid is increased; and the tetrazole acetic acid and the terephthaloyl chloride react to form mixed anhydride, 4-methylpyridine is not needed to be added, the reaction temperature is improved while pollution is reduced, the cost is reduced, the reaction activity with an intermediate 7-ACT is provided, the reaction time is shortened, and the final yield of the ceftezole acid is further ensured. The preparation method provided by the invention adopts a two-step method, has simple process flow, mild reaction conditions and low cost, can effectively improve the yield, and is suitable for large-scale popularization and application.
Further, in step S1, the mass ratio of the 2-mercapto-1, 3, 4-thiadiazole to the 7-ACA is 0.45 to 0.5: 1, the mass ratio of the boron trifluoride dimethyl carbonate complex to the 7-ACA is 3.35-3.40: 1; the mass ratio of the dimethyl carbonate to the 7-ACA is 3.0-3.5: 1; the mass ratio of the formic acid to the 7-ACA is 0.4-0.6: 1, promoting the reaction to be full and ensuring the yield of the intermediate 7-ACT.
Further, in step S1, the specific method of crystallization is: adding a reaction solution containing 7-ACT into an aqueous solution with the mass concentration of 0.01-0.1% of sodium metabisulfite and disodium ethylene diamine tetraacetate, adjusting the pH value to 0.5-1 at the temperature of 0-5 ℃, stirring for crystal growth for 40-60 min, and ensuring the yield of 7-ACT.
Further, in step S1, after centrifugation, washing with hydrochloric acid solution with pH of 0.5-1, then washing with acetone, combining acetone washing solution with the centrifuged mother solution, recycling reagent, and reducing 7-ACT loss.
Further, in the step S2, the mass ratio of the terephthaloyl chloride to the tetrazoleacetic acid is 0.9-1.1: 1, so that the synthesis of mixed anhydride is ensured; the mass ratio of the 7-ACT to the tetrazoleacetic acid is 1.5-1.7: 1, and the 7-ACT is promoted to be fully subjected to acylation reaction and converted into ceftezole acid.
Further, in step S2, the specific method of decoloring is: adjusting the pH value of the system to 4.5-5.5 by using acetic acid, adding medicinal adsorption alumina, stirring for 30-45 min at 10-15 ℃, decoloring and filtering, washing filter cakes by using water, collecting filtrate, ensuring the decoloring effect, improving the product purity and facilitating subsequent crystallization treatment.
Further, in step S2, the specific method of crystallization is: and cooling the obtained filtrate to 0-5 ℃, adjusting the pH value to 1-1.5 by using hydrochloric acid, stirring for crystal growth for 50-60 min, and fully crystallizing to ensure the yield of the ceftezole acid.
Further, in step S2, the method further includes a refining process after the crystallization, and the refining process includes: and transferring the crystallized crude product of the ceftezole acid into an aqueous solution with the mass concentration of 0.01-0.1% of sodium metabisulfite and disodium ethylene diamine tetraacetate, adjusting the pH value to 5.5-5.8 by using sodium bicarbonate to completely dissolve the ceftezole acid, adding activated carbon, stirring, filtering, washing the activated carbon by using deionized water, combining filtrate, cooling to 0-5 ℃, adjusting the pH value to 1-1.5 by using hydrochloric acid, stirring and crystallizing for 50-60 min, and further improving the purity of the product.
Further, in step S2, after the centrifugation, the mixture was washed with deionized water and then with ethanol.
Further, in the step S1, the drying temperature is 30-40 ℃, the drying vacuum degree is more than or equal to-0.090 Mpa, and the drying time is 5-6 h; in the step S2, the drying temperature is 30-40 ℃, the drying vacuum degree is more than or equal to-0.090 Mpa, and the drying time is 4-5 h.
The invention also provides a preparation method of ceftezole sodium, which comprises the following steps:
adding ceftezole acid into water, adjusting the pH value to 4.9-5.5 by using sodium bicarbonate at the temperature of 10-15 ℃ to completely dissolve the ceftezole acid, adding sodium metabisulfite and disodium edetate, wherein the mass concentration of the sodium metabisulfite and the disodium edetate is 0.01-0.1%, and decolorizing and filtering to obtain a solution;
step two, dripping the obtained dissolved solution into a methanol-ethanol mixed solvent with a volume ratio of 0.6-1: 1, growing crystals for 25-35 min at 10-15 ℃, supplementing 50-60% of ethanol of the volume of the initial mixed solvent, growing crystals for 25-35 min at 5-10 ℃, supplementing 40-50% of ethanol of the volume of the initial mixed solvent, growing crystals for 45-60 min at 0-5 ℃, filtering, washing a filter cake with 0-5 ℃ of ethanol, and drying to obtain ceftezole sodium.
Compared with the prior art, the preparation method of ceftezole sodium provided by the invention has the advantages that ceftezole acid is dissolved in the aqueous solution containing sodium metabisulfite and disodium ethylene diamine tetraacetate, primary crystal growth is carried out in the methanol-ethanol mixed solvent, and finally, further crystal growth is carried out by supplementing ethanol, so that high-yield and high-purity ceftezole sodium is obtained, the process is simple, and the operation is convenient.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to the following embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
The embodiment of the invention provides a preparation method of ceftezole acid, which comprises the following steps:
s1: 2-mercapto-1, 3, 4-thiadiazole and 7-ACA are used as raw materials, and a boron trifluoride dimethyl carbonate complex is used as a catalyst to synthesize an intermediate 7-ACT, wherein the related reaction formula is as follows;
s2: the tetrazole acetic acid and the paraphthaloyl chloride react to form mixed anhydride, and the mixed anhydride reacts with an intermediate 7-ACT to synthesize the ceftezole acid, and the related reaction formula is as follows.
In order to better illustrate the preparation method of ceftezole acid provided by the embodiment of the invention, the following examples further illustrate the preparation method.
The quality specifications of the main substances used in the examples of the present invention are shown in table 1.
TABLE 1
Example 1
A preparation method of ceftezole acid comprises the following steps:
s1: adding 300L dimethyl carbonate into a reaction kettle, adding 337.5kg boron trifluoride dimethyl carbonate complex and 50kg formic acid under the protection of nitrogen, stirring and cooling to 4 ℃, adding 48kg MTD and 100kg 7-ACA under the protection of nitrogen and at the temperature of less than 10 ℃, flushing a container pipeline with 30L dimethyl carbonate, leading the system to start to be turbid, quickly becoming clear to obtain a light yellow clear solution, heating to 18 ℃ for reacting for 35min to obtain a reaction solution containing 7-ACT, sampling and testing by HPLC that the content of 7-ACA is less than 3%,
adding 800L of deionized water into a crystallizing tank, adding 0.5kg of sodium metabisulfite and 0.5kg of disodium ethylene diamine tetraacetate, stirring and adjusting the temperature to 4 ℃, adding the obtained reaction solution, adjusting the pH to 0.8 by using sodium hydroxide within 70min under the condition of 4 ℃, slowly stirring for growing crystals for 50min, washing by using hydrochloric acid solution with the pH of 0.8 after centrifuging until the content of 7-ACT is more than 97% in a sampling HPLC test, then washing by using 200L of acetone, combining acetone washing liquid and mother liquor after centrifuging to obtain 160kg of 7-ACT wet product, drying for 5.5h by using a double-cone drier under the conditions that the temperature is 35 ℃ and the vacuum degree is more than or equal to-0.090 Mpa, sampling for measuring the moisture content, wherein the yield is 94.7%, and the purity of HPLC is more than or equal to 97%;
s2: adding 140L of acetone and 31.75kg of tetrazoleacetic acid into a reaction kettle, cooling to 0 ℃ under the protection of nitrogen, slowly adding triethylamine (25.45kg) to adjust the pH value to 7.9, cooling to-11 ℃, slowly adding 29.2kg of terephthaloyl chloride, finishing the addition within 15min, heating to 0 ℃ for reaction for 60min to obtain a mixed anhydride solution, and cooling to-19 ℃; adding 50kg of 7-ACT into an acetone-water mixed solvent (40L of acetone and 60L of deionized water), cooling to-12 ℃, adding triethylamine (28.4kg) to adjust the pH value to 7-ACT to be completely dissolved to obtain a 7-ACT solution, cooling to-19 ℃, mixing with the mixed anhydride solution, reacting at-12 ℃, sampling every 15min until the 7-ACT content is lower than 3mg/ml (or the ceftezole acid content is more than 94% as measured by sampling HPLC and the 7-ACT content is less than 0.5%), finishing the reaction after 45min,
adding the reaction solution into a solution prepared from 0.5kg of sodium metabisulfite, 0.25kg of disodium ethylene diamine tetraacetate and 500L of deionized water, adjusting pH of the system to 5.0 with acetic acid, adding 30kg medicinal adsorption alumina, stirring at 12 deg.C for 40min, decolorizing, filtering, washing filter cake with water, collecting filtrate, cooling the filtrate to 4 deg.C, adjusting pH to 1.2 with hydrochloric acid, stirring for crystallizing for 55min, filtering to obtain 90kg wet product of ceftezole acid, further centrifuging, washing with deionized water until the content of ceftezole acid is more than 98.5% by HPLC, washing with 100L ethanol to obtain 80kg wet ceftezole acid, drying with a double-cone dryer, drying at 35 deg.C under vacuum degree of not less than-0.090 Mpa for 4.5h, sampling to measure water content, and obtaining ceftezole acid (56.2kg, yield of 84.0%, HPLC purity of not less than 99%).
The method for preparing ceftezole sodium by using the obtained ceftezole acid specifically comprises the following steps:
step one, adding 40kg of ceftezole acid into 200L of water, adjusting the pH value to 5.0 by using sodium bicarbonate at the temperature of 10 ℃ to completely dissolve the ceftezole acid, adding 200g of sodium metabisulfite, 200g of disodium ethylene diamine tetraacetate and 2.5kg of activated carbon, stirring, decoloring, performing suction filtration, and washing the activated carbon by using water to obtain a dissolved solution;
and step two, dropwise adding the obtained dissolved solution into a mixed solvent composed of 320L of methanol and 400L of ethanol, growing crystals for 30min at 12 ℃, supplementing 400L of ethanol, growing crystals for 30min at 8 ℃, supplementing 320L of ethanol, growing crystals for 50min at 4 ℃, filtering, washing a filter cake with ethanol at 4 ℃, and drying to obtain 41.2kg of ceftezole sodium (the yield is 97.8%, and the HPLC purity is more than 99.8%).
Example 2
A preparation method of ceftezole acid comprises the following steps:
s1: adding 300L dimethyl carbonate into a reaction kettle, adding 335kg boron trifluoride dimethyl carbonate complex and 40kg formic acid under the protection of nitrogen, stirring and cooling to 5 ℃, adding 45kg MTD and 100kg 7-ACA under the protection of nitrogen and at the temperature of less than 10 ℃, leading the system to start to be turbid, quickly becoming clear to obtain a light yellow clear solution, heating to 20 ℃, reacting for 30min to obtain a reaction solution containing 7-ACT, sampling and testing by HPLC that the content of the 7-ACA is less than 3%,
adding 800L of deionized water into a crystallization tank, adding 0.5kg of sodium metabisulfite and 0.5kg of disodium ethylene diamine tetraacetate, stirring and adjusting the temperature to 5 ℃, adding the obtained reaction solution, adjusting the pH to 0.5 by using sodium hydroxide within 60min under the condition of 5 ℃, slowly stirring for growing crystals for 40min, washing by using hydrochloric acid solution with the pH of 0.5 after centrifuging until the content of 7-ACT is more than 97% in a sampling HPLC test, then washing by using 200L of acetone, combining acetone washing liquid and mother liquor after centrifuging to obtain a 7-ACT wet product, drying for 6h by using a double-cone dryer under the conditions that the temperature is 30 ℃ and the vacuum degree is more than or equal to-0.090 Mpa, sampling for measuring the moisture content, and obtaining 7-ACT (116kg, the yield is 95.6%, and the purity of HPLC is more than or equal to 97%);
s2: adding 140L of acetone and 31.75kg of tetrazoleacetic acid into a reaction kettle, cooling to 0 ℃ under the protection of nitrogen, slowly adding triethylamine to adjust the pH value to 7.5, cooling to-12 ℃, slowly adding 34.9kg of terephthaloyl chloride, finishing the addition within 15min, heating to 0 ℃ for reaction for 50min to obtain a mixed anhydride solution, and cooling to-18 ℃; adding 50kg of 7-ACT into an acetone-water mixed solvent (40L of acetone and 60L of deionized water), cooling to-11 ℃, adding triethylamine to adjust the pH value to 7-ACT to be completely dissolved to obtain a 7-ACT solution, cooling to-18 ℃, mixing with a mixed anhydride solution, reacting at the temperature of-11 ℃, sampling every 15min until the 7-ACT content is lower than 3mg/ml (or the ceftezole acid content is more than 94% and the 7-ACT content is less than 0.5% in a sampling HPLC test), finishing the reaction after 30min,
adding the reaction solution into a solution prepared from 0.5kg of sodium metabisulfite, 0.25kg of disodium ethylene diamine tetraacetate and 500L of deionized water, adjusting pH of the system to 4.5 with acetic acid, adding 30kg medicinal adsorption alumina, stirring at 10 deg.C for 30min, decolorizing, filtering, washing filter cake with water, collecting filtrate, cooling the filtrate to 0 deg.C, adjusting pH to 1 with hydrochloric acid, stirring for crystal growth for 50min, filtering to obtain wet product of ceftezole acid, further centrifuging, washing with deionized water until the content of ceftezole acid is more than 98.5% by HPLC (high performance liquid chromatography) test, washing with 100L of ethanol to obtain 82kg of ceftezole acid wet product, adopting a double-cone dryer, drying at 30 deg.C under vacuum degree of not less than-0.090 Mpa for 4h, sampling to measure water content, and obtaining ceftezole acid (57.3kg, yield of 85.7%, HPLC purity of not less than 99%) with water content of less than 0.5%.
The method for preparing ceftezole sodium by using the obtained ceftezole acid specifically comprises the following steps:
step one, adding 40kg of ceftezole acid into 200L of water, adjusting the pH value to 4.9 by using sodium bicarbonate at 15 ℃ to completely dissolve the ceftezole acid, adding 200g of sodium metabisulfite, 200g of disodium ethylene diamine tetraacetate and 2.5kg of activated carbon, stirring, decolorizing, performing suction filtration, and washing the activated carbon by using water to obtain a dissolved solution;
and step two, dropwise adding the obtained dissolved solution into a mixed solvent composed of 320L of methanol and 400L of ethanol, growing the crystals for 25min at 10 ℃, supplementing 400L of ethanol, growing the crystals for 25min at 5 ℃, supplementing 320L of ethanol, growing the crystals for 45min at 0 ℃, filtering, washing a filter cake with 0 ℃ of ethanol, and drying to obtain 41.3kg of ceftezole sodium (the yield is 98.3%, and the HPLC purity is more than 99.8%).
Example 3
A preparation method of ceftezole acid comprises the following steps:
s1: adding 300L dimethyl carbonate into a reaction kettle, adding 340kg boron trifluoride dimethyl carbonate complex and 50kg formic acid under the protection of nitrogen, stirring and cooling to 0 ℃, adding 50kg MTD and 100kg 7-ACA under the protection of nitrogen and at the temperature of less than 10 ℃, leading the system to start to be turbid, quickly becoming clear to obtain a light yellow clear solution, heating to 22 ℃, reacting for 35min to obtain a reaction solution containing 7-ACT, sampling and testing by HPLC that the content of the 7-ACA is less than 3%,
adding 800L of deionized water into a crystallization tank, adding 0.5kg of sodium metabisulfite and 0.5kg of disodium ethylene diamine tetraacetate, stirring and adjusting the temperature to 0 ℃, adding the obtained reaction solution, adjusting the pH to 1 with sodium hydroxide within 60min under the condition of 0 ℃, slowly stirring for growing crystals for 60min, washing with a hydrochloric acid solution with the pH of 1 after centrifugation till the content of 7-ACT is more than 97% in a sampling HPLC test, then washing with 200L of acetone, combining an acetone washing solution with a mother solution after centrifugation to obtain a 7-ACT wet product, drying for 6h by using a double-cone dryer under the conditions that the temperature is 40 ℃ and the vacuum degree is more than or equal to-0.090 Mpa, sampling for measuring the moisture content, and obtaining 7-ACT (117kg, the yield is 96.5% and the purity is more than or equal to 97%);
s2: adding 140L of acetone and 31.75kg of tetrazoleacetic acid into a reaction kettle, cooling to 0 ℃ under the protection of nitrogen, slowly adding triethylamine to adjust the pH value to 8.0, cooling to-10 ℃, slowly adding 29.2kg of terephthaloyl chloride, finishing the addition within 15min, heating to 0 ℃ for reaction for 70min to obtain a mixed anhydride solution, and cooling to-20 ℃; adding 54kg of 7-ACT into an acetone-water mixed solvent (40L of acetone and 60L of deionized water), cooling to-14 ℃, adding triethylamine to adjust the pH value to 7-ACT to be completely dissolved to obtain a 7-ACT solution, cooling to-18 to-20 ℃, mixing with the mixed anhydride solution, reacting at-14 ℃, sampling every 15min until the 7-ACT content is lower than 3mg/ml (or the ceftezole acid content is more than 94% and the 7-ACT content is less than 0.5% in a sampling HPLC test), finishing the reaction after 40min,
adding the reaction solution into a solution prepared from 0.5kg of sodium metabisulfite, 0.25kg of disodium ethylene diamine tetraacetate and 500L of deionized water, adjusting pH of the system to 5.5 with acetic acid, adding 30kg medicinal adsorption alumina, stirring at 15 deg.C for 45min, decolorizing, filtering, washing filter cake with water, collecting filtrate, cooling the filtrate to 5 deg.C, adjusting pH to 1.5 with hydrochloric acid, stirring for crystal growth for 60min, filtering to obtain wet ceftezole acid, further centrifuging, washing with deionized water until the content of ceftezole acid is more than 98.5% by HPLC (high performance liquid chromatography) test, washing with 100L of ethanol to obtain 84kg of ceftezole acid wet product, adopting a double-cone dryer, drying at 40 deg.C under vacuum degree of not less than-0.090 Mpa for 5h, sampling to measure water content, and obtaining ceftezole acid (57.0kg, yield of 85.2%, HPLC purity of not less than 99%).
The method for preparing ceftezole sodium by using the obtained ceftezole acid specifically comprises the following steps:
step one, adding 40kg of ceftezole acid into 200L of water, adjusting the pH value to 5.5 by using sodium bicarbonate at the temperature of 12 ℃ to completely dissolve the ceftezole acid, adding 200g of sodium metabisulfite, 200g of disodium ethylene diamine tetraacetate and 2.5kg of activated carbon, stirring, decoloring, performing suction filtration, and washing the activated carbon by using water to obtain a dissolved solution;
and step two, dropwise adding the obtained dissolved solution into a mixed solvent composed of 320L of methanol and 400L of ethanol, growing crystals for 35min at 15 ℃, supplementing 400L of ethanol, growing crystals for 35min at 10 ℃, supplementing 320L of ethanol, growing crystals for 60min at 5 ℃, filtering, washing a filter cake with 5 ℃ of ethanol, and drying to obtain 41.4kg of ceftezole sodium (the yield is 98.5%, and the HPLC purity is more than 99.8%).
From the data, the preparation method of ceftezole acid and the ceftezole sodium salt thereof provided by the invention has the advantages of simple process, mild reaction conditions, little pollution, capability of reducing the cost and effectively improving the yield of ceftezole acid, wherein the yield of ceftezole acid is more than or equal to 84%, the yield of ceftezole sodium prepared from ceftezole acid is more than or equal to 98%, and the purity of the obtained ceftezole sodium is more than 99.8%.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents or improvements made within the spirit and principle of the present invention should be included in the scope of the present invention.
Claims (10)
1. A preparation method of ceftezole acid is characterized by comprising the following steps:
s1: sequentially adding dimethyl carbonate, boron trifluoride dimethyl carbonate complex and formic acid into a reaction kettle, stirring and cooling to 0-5 ℃, adding 2-mercapto-1, 3, 4-thiadiazole and 7-ACA under the protection of nitrogen and at the temperature of less than 10 ℃, heating to 18-22 ℃, reacting for 25-35 min to obtain reaction liquid containing 7-ACT, and crystallizing, centrifuging, washing and drying to obtain an intermediate 7-ACT;
s2: adding acetone and tetrazoleacetic acid into a reaction kettle, cooling to 0 ℃ under the protection of nitrogen, slowly adding triethylamine to adjust the pH value to 7.5-8.0, cooling to-12-10 ℃, slowly adding terephthaloyl chloride, heating to 0 ℃ for reacting for 50-70 min to obtain a mixed anhydride solution, and cooling to-18-20 ℃; adding 7-ACT into an acetone-water mixed solvent, cooling to-11-14 ℃, adding triethylamine until 7-ACT is completely dissolved to obtain a 7-ACT solution, cooling to-18-20 ℃, mixing with the mixed anhydride solution, reacting for 30-45 min at-11-14 ℃, transferring into an aqueous solution with the mass concentration of sodium metabisulfite and disodium ethylene diamine tetraacetate of 0.01-0.1%, and decolorizing, crystallizing, centrifuging and drying to obtain ceftezole acid.
2. A process for the preparation of ceftezole acid as claimed in claim 1, wherein: in the step S1, the mass ratio of the 2-mercapto-1, 3, 4-thiadiazole to the 7-ACA is 0.45-0.5: 1, the mass ratio of the boron trifluoride dimethyl carbonate complex to the 7-ACA is 3.35-3.40: 1; the mass ratio of the dimethyl carbonate to the 7-ACA is 3.0-3.5: 1; the mass ratio of the formic acid to the 7-ACA is 0.4-0.6: 1.
3. a process for the preparation of ceftezole acid as claimed in claim 1, wherein: in step S1, the specific method of crystallization is: adding a reaction solution containing 7-ACT into an aqueous solution with the mass concentration of 0.01-0.1% of sodium metabisulfite and disodium ethylene diamine tetraacetate, adjusting the pH value to 0.5-1 at the temperature of 0-5 ℃, and stirring for crystal growth for 40-60 min.
4. A process for the preparation of ceftezole acid as claimed in claim 1, wherein: in step S1, after centrifugation, washing with hydrochloric acid solution with pH of 0.5-1, then washing with acetone, combining acetone washing liquid with centrifuged mother liquor, and recycling.
5. A process for the preparation of ceftezole acid as claimed in claim 1, wherein: in the step S2, the mass ratio of the terephthaloyl chloride to the tetrazoleacetic acid is 0.9-1.1: 1; the mass ratio of the 7-ACT to the tetrazoleacetic acid is 1.5-1.7: 1.
6. A process for the preparation of ceftezole acid as claimed in claim 1, wherein: in step S2, the specific method of decoloring is: adjusting the pH value of the system to 4.5-5.5 by using acetic acid, adding medicinal adsorption alumina, stirring for 30-45 min at 10-15 ℃, decoloring and filtering, washing filter cakes by using water, and collecting filtrate.
7. A process for preparing ceftezole acid according to claim 6, wherein: in step S2, the specific method of crystallization is: and cooling the obtained filtrate to 0-5 ℃, adjusting the pH to 1-1.5 by using hydrochloric acid, and stirring for crystal growth for 50-60 min.
8. A process for the preparation of ceftezole acid as claimed in claim 1, wherein: in step S2, after centrifugation, the mixture was washed with deionized water and then with ethanol.
9. A process for the preparation of ceftezole acid as claimed in claim 1, wherein: in the step S1, the drying temperature is 30-40 ℃, the drying vacuum degree is more than or equal to-0.090 Mpa, and the drying time is 5-6 h; in the step S2, the drying temperature is 30-40 ℃, the drying vacuum degree is more than or equal to-0.090 Mpa, and the drying time is 4-5 h.
10. A preparation method of ceftezole sodium is characterized by comprising the following steps:
adding ceftezole acid into water, adjusting the pH value to 4.9-5.5 by using sodium bicarbonate to completely dissolve the ceftezole acid, adding sodium metabisulfite and disodium ethylene diamine tetraacetate, wherein the mass concentration of the sodium metabisulfite and the disodium ethylene diamine tetraacetate is 0.01-0.1%, and decoloring and filtering to obtain a dissolved solution;
step two, dripping the obtained dissolved solution into a methanol-ethanol mixed solvent with a volume ratio of 0.6-1: 1, growing crystals for 25-35 min at 10-15 ℃, supplementing 50-60% of ethanol of the volume of the initial mixed solvent, growing crystals for 25-35 min at 5-10 ℃, supplementing 40-50% of ethanol of the volume of the initial mixed solvent, growing crystals for 45-60 min at 0-5 ℃, filtering, washing a filter cake with 0-5 ℃ of ethanol, and drying to obtain ceftezole sodium.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102219795A (en) * | 2011-07-28 | 2011-10-19 | 哈药集团制药总厂 | Method for preparing ceftezole sodium |
| CN102617606A (en) * | 2012-03-31 | 2012-08-01 | 哈药集团制药总厂 | Method for preparing ceftezole sodium compound |
| CN102775426A (en) * | 2012-08-10 | 2012-11-14 | 天津新丰制药有限公司 | Crystallization method of ceftezole sodium |
| CN109336907A (en) * | 2018-11-21 | 2019-02-15 | 山东罗欣药业集团股份有限公司 | A kind of preparation method of cefobutazine sodium |
| CN109824697A (en) * | 2019-02-28 | 2019-05-31 | 广西科伦制药有限公司 | A kind of preparation method of ceftezole acid |
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102219795A (en) * | 2011-07-28 | 2011-10-19 | 哈药集团制药总厂 | Method for preparing ceftezole sodium |
| CN102617606A (en) * | 2012-03-31 | 2012-08-01 | 哈药集团制药总厂 | Method for preparing ceftezole sodium compound |
| CN102775426A (en) * | 2012-08-10 | 2012-11-14 | 天津新丰制药有限公司 | Crystallization method of ceftezole sodium |
| CN109336907A (en) * | 2018-11-21 | 2019-02-15 | 山东罗欣药业集团股份有限公司 | A kind of preparation method of cefobutazine sodium |
| CN109824697A (en) * | 2019-02-28 | 2019-05-31 | 广西科伦制药有限公司 | A kind of preparation method of ceftezole acid |
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