CN111961066B - Preparation method of antibacterial drug - Google Patents
Preparation method of antibacterial drug Download PDFInfo
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- CN111961066B CN111961066B CN202010809910.XA CN202010809910A CN111961066B CN 111961066 B CN111961066 B CN 111961066B CN 202010809910 A CN202010809910 A CN 202010809910A CN 111961066 B CN111961066 B CN 111961066B
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- acid
- cefmetazole
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- sodium
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- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- 229940124350 antibacterial drug Drugs 0.000 title claims abstract description 8
- SNBUBQHDYVFSQF-HIFRSBDPSA-N cefmetazole Chemical compound S([C@@H]1[C@@](C(N1C=1C(O)=O)=O)(NC(=O)CSCC#N)OC)CC=1CSC1=NN=NN1C SNBUBQHDYVFSQF-HIFRSBDPSA-N 0.000 claims abstract description 81
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 52
- 239000002904 solvent Substances 0.000 claims abstract description 52
- 229960002676 cefmetazole sodium Drugs 0.000 claims abstract description 46
- 239000002253 acid Substances 0.000 claims abstract description 42
- 238000003756 stirring Methods 0.000 claims abstract description 38
- 229960003585 cefmetazole Drugs 0.000 claims abstract description 36
- 238000001816 cooling Methods 0.000 claims abstract description 36
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 26
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims abstract description 23
- 239000003513 alkali Substances 0.000 claims abstract description 5
- 238000007664 blowing Methods 0.000 claims abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 93
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 74
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 69
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 38
- 238000006243 chemical reaction Methods 0.000 claims description 38
- 239000013078 crystal Substances 0.000 claims description 32
- 238000002425 crystallisation Methods 0.000 claims description 26
- 230000008025 crystallization Effects 0.000 claims description 26
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- 230000001276 controlling effect Effects 0.000 claims description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 18
- 229910052799 carbon Inorganic materials 0.000 claims description 17
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 claims description 16
- OEOIWYCWCDBOPA-UHFFFAOYSA-N 6-methyl-heptanoic acid Chemical compound CC(C)CCCCC(O)=O OEOIWYCWCDBOPA-UHFFFAOYSA-N 0.000 claims description 14
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 14
- 239000011734 sodium Substances 0.000 claims description 14
- 229910052708 sodium Inorganic materials 0.000 claims description 14
- 238000000034 method Methods 0.000 claims description 12
- 238000001035 drying Methods 0.000 claims description 11
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 6
- 230000001105 regulatory effect Effects 0.000 claims description 5
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 4
- 150000007530 organic bases Chemical class 0.000 claims description 4
- 239000001632 sodium acetate Substances 0.000 claims description 4
- 235000017281 sodium acetate Nutrition 0.000 claims description 4
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 3
- 238000000967 suction filtration Methods 0.000 claims description 3
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 2
- 239000003242 anti bacterial agent Substances 0.000 claims 2
- 238000001914 filtration Methods 0.000 abstract description 16
- 239000000047 product Substances 0.000 abstract description 15
- 238000001291 vacuum drying Methods 0.000 abstract description 8
- 238000005406 washing Methods 0.000 abstract 2
- 238000004042 decolorization Methods 0.000 abstract 1
- 238000007599 discharging Methods 0.000 abstract 1
- 239000012065 filter cake Substances 0.000 abstract 1
- 239000007788 liquid Substances 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 34
- 239000012535 impurity Substances 0.000 description 19
- 150000003536 tetrazoles Chemical class 0.000 description 17
- 150000002596 lactones Chemical class 0.000 description 16
- 238000002386 leaching Methods 0.000 description 14
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 14
- 238000010926 purge Methods 0.000 description 13
- 230000000052 comparative effect Effects 0.000 description 10
- 239000000843 powder Substances 0.000 description 8
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 239000003814 drug Substances 0.000 description 3
- 230000009286 beneficial effect Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000007857 degradation product Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 235000006408 oxalic acid Nutrition 0.000 description 2
- 238000007670 refining Methods 0.000 description 2
- 238000001179 sorption measurement Methods 0.000 description 2
- XOHZHMUQBFJTNH-UHFFFAOYSA-N 1-methyl-2h-tetrazole-5-thione Chemical compound CN1N=NN=C1S XOHZHMUQBFJTNH-UHFFFAOYSA-N 0.000 description 1
- 238000010669 acid-base reaction Methods 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 238000010923 batch production Methods 0.000 description 1
- -1 cefmetazole lactone Chemical class 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000005352 clarification Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
Classifications
-
- 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
- C07D501/57—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with a further substituent in position 7, e.g. cephamycines
-
- 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
- C07D501/04—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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Cephalosporin Compounds (AREA)
Abstract
The invention discloses a preparation method of an antibacterial drug, which comprises the following steps: (1) Dissolving cefmetazole acid in a good solvent, cooling to 10 ℃, and stirring to dissolve; (2) Adding an organic alkali solution into the solution, stirring, adding acid to adjust the pH, and adding activated carbon for decolorization; (3) dropping a poor solvent to separate out a product; (4) after the dripping is finished, cooling to 0 ℃, stirring for 2 hours, and filtering; (5) Filtering, washing a filter cake with washing liquid, carrying out nitrogen humidification and blowing on the product, then carrying out vacuum drying, and discharging to obtain a cefmetazole sodium finished product; the yield reaches more than 90%, the purity of the obtained product is more than 99.8%, the content is more than 98%, and the product meets the requirements of medicinal quality.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a preparation method of an antibacterial medicine.
Background
Cefmetazole sodium is unstable to light and heat, and generates degradation products in high-temperature or humid environments or after being damaged by acid, alkali, heat and oxidation. The main degradation product is cefmetazole lactone and 1-methyl-5-mercapto-1, 2,3, 4-tetrazole.
The cefmetazole sodium medicine sold in the market at present is cefmetazole sodium sterile powder for injection, and the sterile freeze-dried powder prepared by using the ultralow temperature freeze-forming technology has the following defects: the freeze-dried powder is uneven, the color is poor, the split charging amount is different, the clarity is problematic, the purity of the prepared product is low, the stability problem of substances is not completely solved, the product is not easy to store for a long time, and the like, and the freeze-dried powder injection has complex process and high cost. The prior patent literature reports that the above technical problems are solved by solvent crystallization technology.
Patent document CN102627660a discloses a preparation method of cefmetazole sodium sterile powder, which adopts a mixed solvent to recrystallize the cefmetazole sodium, and vacuum-dries to obtain the cefmetazole sodium sterile powder, wherein the purity of the cefmetazole sodium sterile powder is 94% to more than 99.3%, but no impurity data is given, and no technical scheme for reducing solvent residues is given.
Patent document CN104844627a discloses a cefmetazole sodium compound and a preparation method thereof, wherein after cefmetazole sodium is dissolved in a good solvent, a poor solvent is dripped to separate out, the purity of the product after vacuum drying is more than 99.6%, but the yield is only 82%, and the product can be obtained only by further refining after cefmetazole acid is prepared into cefmetazole sodium.
Patent document CN101787039a discloses a preparation method of cefmetazole sodium compound, which comprises the steps of acid-base reaction, macroporous adsorption resin and active carbon adsorption, crystallization, suction filtration and reduced pressure drying to obtain the high-purity cefmetazole sodium compound, wherein the purity of the refined product is more than 99.6%. The process needs to prepare cefmetazole sodium into cefmetazole acid and then prepare the cefmetazole sodium, and the process has complicated steps and is not beneficial to batch production.
The prior art researches have been developed to a certain extent to obtain the cefmetazole sodium sterile powder with high purity, but the method is to prepare cefmetazole sodium by one-step or even two-step refining after preparing cefmetazole acid into cefmetazole sodium, and no patent is given to a technical scheme for preparing cefmetazole sodium from cefmetazole acid by one-step solvent crystallization and solving the problems of impurities, solvent residues and the like.
Disclosure of Invention
The invention provides a preparation method of an antibacterial drug, which enables cefmetazole acid to be prepared through one-step solvent crystallization to obtain high-purity cefmetazole sodium, is suitable for mass production, reduces production cost, shortens production period and improves production efficiency.
The technical problems to be solved by the invention are realized by the following technical scheme:
a method for preparing an antibacterial drug, comprising the following steps:
(1) Dissolving cefmetazole acid in a good solvent under the protection of nitrogen, cooling, dissolving, adding another solvent, slowly dripping a solution prepared by organic alkali and the good solvent, controlling the temperature to be-10-15 ℃ for reaction, adding acid to adjust the pH after the reaction is finished, adding active carbon, stirring and decarbonizing;
(2) And (3) dropwise adding a poor solvent into the solution for crystallization, cooling, crystallizing, performing suction filtration, leaching the obtained crystal with a solvent, humidifying and blowing nitrogen, and performing vacuum drying to obtain cefmetazole sodium.
The reaction route is as follows:
in the step (1), the good solvent is one or two of acetone and methanol, and the volume mass ratio of the good solvent to cefmetazole acid is 5-18: 1, the other solvent is one or more of acetic acid, citric acid and n-butyric acid, and the mol ratio of the other solvent to cefmetazole acid is 0.1-0.5:1;
the organic base in the step (1) is one or more of sodium isooctanoate, sodium acetate, sodium methoxide and sodium ethoxide, and the molar ratio of the organic base to cefmetazole acid is 1.2-1.8:1, the volume mass ratio of a good solvent for dissolving organic alkali to cefmetazole acid is 2-4:1;
the acid used for regulating the pH in the step (1) is one or more of acetic acid, citric acid and n-butyric acid, and the pH is regulated to 5.0-6.0;
in the step (2), the poor solvent is one or two of isopropanol and ethyl acetate, and the volume mass ratio of the poor solvent to cefmetazole acid is 10-36: 1, the crystal growing temperature is-5-5 ℃;
the nitrogen in the step (2) contains 2 to 12 percent of water vapor, and is discharged after being purged for 1 to 6 hours and vacuum dried for 2 to 10 hours at the temperature of 10 to 35 ℃.
The technical scheme of the invention has the following beneficial effects:
(1) In the salt formation process of cefmetazole acid, another acid solvent is added besides the organic solvent, and the proton concentration is regulated, so that the reaction is milder and controllable, a good environment is provided for crystallization, and the product does not need to be refined.
(2) After the reaction is finished, the pH is strictly regulated, a good environment is provided for the crystallization process, the generation of impurities in the cefmetazole sodium synthesis process is effectively reduced, the yield of the obtained product reaches more than 90%, the purity is more than 99.8%, tetrazole is not more than 0.08%, lactone is not more than 0.05%, other maximum single impurities are not more than 0.07%, and the content is more than 98% calculated according to anhydrous matters.
(3) The solvent is adopted to humidify and sweep after the solvent is leached, the water vapor content in the nitrogen is strictly controlled, the solvent residue is rapidly reduced to below the limit, and the solvent residue problem is solved.
The specific embodiment is as follows:
specific embodiments of the invention will be described in detail below to facilitate a further understanding of the invention. All experimental methods used in the following examples are conventional methods unless otherwise specified. Materials, reagents, etc. used in the following examples, unless otherwise specified, were commercially available, and the purity of cefmetazole acid used in the following examples was: 99.4%.
EXAMPLE 1 preparation of cefmetazole sodium
Dissolving 47.15g of cefmetazole acid in 240mL of acetone under the protection of nitrogen, cooling to-10 ℃, stirring to dissolve, adding 0.6g of acetic acid, slowly dropwise adding a solution prepared from 19.9g of sodium isooctanoate and 95mL of acetone, controlling the temperature to-10-15 ℃ for reaction, adding acetic acid to adjust the pH to 5.0 after the reaction is finished for 30min, adding 4.7g of active carbon, stirring and decarbonizing;
dropwise adding 472mL of isopropanol into the solution for crystallization, cooling to-5 ℃ for crystal growth for 2 hours, filtering, leaching the obtained crystal by using isopropanol, continuously purging for 1 hour by using wet nitrogen containing 2% of water vapor at 25 ℃, and then drying for 4 hours in vacuum at 20 ℃ to obtain 44.86g of cefmetazole sodium, wherein the yield is 90.8%, the purity is 99.8%, the content is 98.5%, the tetrazole content is 0.06%, the lactone content is 0.03%, the maximum single impurity content is 0.08%, and the solvent is remained: 0.10% of isopropanol.
EXAMPLE 2 preparation of cefmetazole sodium
Dissolving 47.15g of cefmetazole acid in 377mL of methanol under the protection of nitrogen, cooling to-5 ℃, stirring to dissolve, adding 3.8g of citric acid, slowly dropwise adding a solution prepared from 12.3g of sodium acetate and 141mL of methanol, controlling the temperature to-10-15 ℃ for reaction, adding citric acid to adjust the pH to 6.0 after the reaction is finished for 30min, adding 4.7g of activated carbon, stirring and decarbonizing;
adding 943mL of ethyl acetate dropwise into the solution for crystallization, cooling to 0 ℃ for crystal growth for 2 hours, filtering, leaching the obtained crystal by using ethyl acetate, continuously purging by using wet nitrogen containing 4% of water vapor at 25 ℃ for 2 hours, and then drying in vacuum at 20 ℃ for 4 hours to obtain 44.66g of cefmetazole sodium, wherein the yield is 90.5%, the purity is 99.8%, the content is 98.8%, the tetrazole content is 0.06%, the tetrazole content is 0.08%, the lactone content is 0.02%, and the maximum single impurity content is 0.05%, and the solvent is remained: ethyl acetate 0.15%.
EXAMPLE 3 preparation of cefmetazole sodium
Dissolving 47.15g of cefmetazole acid in 472ml of acetone under the protection of nitrogen, cooling to 5 ℃, stirring for clarification, adding 2.64g of n-butyric acid, slowly dropwise adding a solution prepared from 9.72g of sodium methoxide and 189ml of acetone, controlling the temperature to-10-15 ℃ for reaction, adding n-butyric acid after 30min to adjust the pH to 5.2, adding 4.7g of activated carbon, stirring and decarburizing;
and (3) dropwise adding 1415ml of isopropanol into the solution for crystallization, cooling to 5 ℃, stirring for 2 hours, and filtering. The obtained crystal is leached by isopropanol, continuously blown for 3 hours at 25 ℃ with 6% wet nitrogen, vacuum dried for 3 hours at 20 ℃, and discharged to obtain 45.0g of cefmetazole sodium finished product, the yield is 91.2%, the product purity is 99.8%, the content is 99.0%, tetrazole is 0.08%, lactone is 0.03%, the maximum single impurity is 0.07%, and the solvent is remained: 0.15% of isopropanol.
EXAMPLE 4 preparation of cefmetazole sodium
Dissolving 47.15g of cefmetazole acid in 707mL of methanol under the protection of nitrogen, cooling to 10 ℃, stirring to dissolve, adding 2.4g of acetic acid, slowly dropwise adding a solution prepared from 10.9g of sodium ethoxide and 141mL of methanol, controlling the temperature to-10-15 ℃ for reaction, adding acetic acid to adjust the pH to 5.4 after the reaction is finished for 30min, adding 4.7g of active carbon, stirring and decarbonizing;
dripping 1697mL of ethyl acetate into the solution for crystallization, cooling to-5 ℃ for crystal growth for 2 hours, filtering, leaching the obtained crystal by using ethyl acetate, continuously purging by using wet nitrogen containing 8% of water vapor at 25 ℃ for 4 hours, and then vacuum drying at 20 ℃ for 4 hours to obtain 44.37g of cefmetazole sodium, wherein the yield is 89.9%, the purity is 99.9%, the content is 100.1%, the tetrazole content is 0.02%, the lactone content is 0.03%, the maximum single impurity content is 0.05%, and the solvent is remained: ethyl acetate 0.06%.
EXAMPLE 5 preparation of cefmetazole sodium
Dissolving 47.15g of cefmetazole acid in 849mL of acetone under the protection of nitrogen, cooling to 15 ℃, stirring to dissolve, adding 9.6g of citric acid, slowly dripping a solution prepared from 28.3g of sodium isooctanoate and 189mL of acetone, controlling the temperature to-10-15 ℃ for reaction, adding citric acid to adjust the pH to 5.6 after the reaction is finished for 30min, adding 4.7g of active carbon, stirring and decarbonizing;
707mL of isopropanol is added dropwise into the solution for crystallization, the temperature is reduced to 0 ℃ for crystallization for 2 hours, the obtained crystal is leached by isopropanol, wet nitrogen containing 10% of water vapor is continuously purged for 5 hours at 25 ℃, then the cefmetazole sodium is obtained after vacuum drying for 4 hours at 20 ℃ and 44.91g of cefmetazole sodium is obtained, the yield is 91.0%, the purity is 99.9%, the content is 99.8%, the tetrazole is 0.04%, the lactone is 0.02%, the maximum single impurity is 0.04%, and the solvent is remained: 0.08% of isopropanol.
EXAMPLE 6 preparation of cefmetazole sodium
Dissolving 47.15g of cefmetazole acid in 566mL of methanol under the protection of nitrogen, cooling to 0 ℃, stirring to dissolve, adding 4.4g of n-butyric acid, slowly dropwise adding a solution prepared from 10.66g of sodium acetate and 141mL of acetone, controlling the temperature to-10-15 ℃ for reaction, adding n-butyric acid to adjust the pH to 5.8 after the reaction is finished for 30min, adding 4.7g of active carbon, stirring and decarbonizing;
707mL of isopropanol is added dropwise into the solution for crystallization, the temperature is reduced to 0 ℃ for crystallization for 2 hours, the obtained crystal is leached by isopropanol, wet nitrogen containing 10% of water vapor is continuously purged for 5 hours at 25 ℃, then the cefmetazole sodium is obtained after vacuum drying for 4 hours at 20 ℃ and 44.91g of cefmetazole sodium is obtained, the yield is 91.0%, the purity is 99.9%, the content is 99.8%, the tetrazole is 0.04%, the lactone is 0.02%, the maximum single impurity is 0.04%, and the solvent is remained: 0.08% of isopropanol.
Comparative example 1
Dissolving 47.15g of cefmetazole acid in 240mL of acetone under the protection of nitrogen, cooling to-10 ℃, stirring to dissolve, slowly dripping a solution prepared from 19.9g of sodium isooctanoate and 95mL of acetone, controlling the temperature to-10-15 ℃ for reaction, adding acetic acid to adjust the pH to 5.0 after the reaction is finished for 30min, adding 4.7g of active carbon, stirring and decarbonizing;
dropwise adding 472mL of ethyl acetate into the solution for crystallization, cooling to-5 ℃ for crystal growth for 2 hours, filtering, leaching the obtained crystal by using ethyl acetate, continuously purging for 1 hour by using wet nitrogen containing 2% of water vapor at 25 ℃, and then drying for 4 hours at 20 ℃ in vacuum to obtain 42.74g of cefmetazole sodium, wherein the yield is 86.6%, the purity is 97.8%, the content is 91.5%, the tetrazole content is 0.30%, the lactone content is 0.21%, the maximum single impurity content is 0.35%, and the solvent is remained: ethyl acetate 0.15%.
Comparative example 2
Dissolving 47.15g of cefmetazole acid in 240mL of acetone under the protection of nitrogen, cooling to-10 ℃, stirring to dissolve, adding 2.7g of oxalic acid, slowly dropwise adding a solution prepared from 19.9g of sodium isooctanoate and 95mL of acetone, controlling the temperature to-10-15 ℃ for reaction, adding acetic acid to adjust the pH to 5.0 after the reaction is finished for 30min, adding 4.7g of active carbon, stirring and decarbonizing;
dropwise adding 472mL of isopropanol into the solution for crystallization, cooling to-5 ℃ for crystal growth for 2 hours, filtering, leaching the obtained crystal by using isopropanol, continuously purging by using wet nitrogen containing 4% of water vapor at 25 ℃ for 1 hour, and then vacuum drying at 20 ℃ for 4 hours to obtain 44.42g of cefmetazole sodium, wherein the yield is 90.0%, the product purity is 98.6%, the content is 91.8%, the tetrazole content is 0.14%, the lactone content is 0.18%, the maximum single impurity content is 0.27%, and the solvent is remained: acetone 0.08% and isopropanol 0.17%.
Comparative example 3
Dissolving 47.15g of cefmetazole acid in 240mL of acetone under the protection of nitrogen, cooling to-10 ℃, stirring to dissolve, adding 1.44g of concentrated hydrochloric acid, slowly dropwise adding a solution prepared from 19.9g of sodium isooctanoate and 95mL of acetone, controlling the temperature to-10-15 ℃ for reaction, adding acetic acid to adjust the pH to 5.0 after the reaction is finished for 30min, adding 4.7g of active carbon, stirring and decarbonizing;
and adding 472mL of isopropanol dropwise into the solution for crystallization, cooling to-5 ℃ for crystal growth for 2 hours, filtering, leaching the obtained crystal by using isopropanol, continuously purging for 1 hour by using wet nitrogen containing 4% of water vapor at 25 ℃, and then drying in vacuum at 20 ℃ for 4 hours to obtain 43.45g of cefmetazole sodium. Yield 88.05%, purity 97.3%, content 90.5%, tetrazole 0.61%, lactone 0.32%, maximum single impurity 0.32%, solvent residue: acetone 0.08% and isopropanol 0.13%.
Comparative example 4
Dissolving 47.15g of cefmetazole acid in 240mL of acetone under the protection of nitrogen, cooling to-10 ℃, stirring to dissolve, adding 0.6g of acetic acid, slowly dropwise adding a solution prepared from 19.9g of sodium isooctanoate and 95mL of acetone, controlling the temperature to-10-15 ℃ for reaction, adding acetic acid to adjust the pH to 4.5 after the reaction is finished for 30min, adding 4.7g of active carbon, stirring and decarbonizing;
and (3) dropwise adding 472mL of ethyl acetate into the solution for crystallization, cooling to-5 ℃ for crystal growth for 2 hours, filtering, leaching the obtained crystal by using ethyl acetate, continuously purging for 1 hour by using wet nitrogen containing 4% of water vapor at 25 ℃, and then drying for 4 hours at 20 ℃ in vacuum to obtain 44.07g of cefmetazole sodium. Yield 89.3%, purity 99.05%, content 93.5%, tetrazole 0.15%, lactone 0.12%, other maximum single impurity 0.13%, solvent residue: acetone 0.04%, ethyl acetate 0.15%.
Comparative example 5
Dissolving 47.15g of cefmetazole acid in 240mL of acetone under the protection of nitrogen, cooling to-10 ℃, stirring to dissolve, adding 0.6g of acetic acid, slowly dropwise adding a solution prepared from 19.9g of sodium isooctanoate and 95mL of acetone, controlling the temperature to-10-15 ℃ for reaction, adding acetic acid to adjust the pH to 6.5 after the reaction is finished for 30min, adding 4.7g of active carbon, stirring and decarbonizing;
and (3) dropwise adding 472mL of ethyl acetate into the solution for crystallization, cooling to-5 ℃ for crystal growth for 2 hours, filtering, leaching the obtained crystal by using ethyl acetate, continuously purging for 1 hour by using wet nitrogen containing 4% of water vapor at 25 ℃, and then drying for 4 hours at 20 ℃ in vacuum to obtain 43.13g of cefmetazole sodium. Yield 87.4%, purity 94.3%, content 93.8%, tetrazole 1.91%, lactone 0.34%, other maximum single impurity 1.21%, solvent residue: acetone 0.07% and ethyl acetate 0.14%.
Comparative example 6
Dissolving 47.15g of cefmetazole acid in 240mL of acetone under the protection of nitrogen, cooling to-10 ℃, stirring to dissolve, adding 0.6g of acetic acid, slowly dropwise adding a solution prepared from 19.9g of sodium isooctanoate and 95mL of acetone, controlling the temperature to-10-15 ℃ for reaction, adding oxalic acid to adjust the pH to 5.0 after the reaction is finished for 30min, adding 4.7g of active carbon, stirring and decarbonizing;
dropwise adding 472mL of ethyl acetate into the solution for crystallization, cooling to-5 ℃ for crystal growth for 2 hours, filtering, leaching the obtained crystal by using ethyl acetate, continuously purging with wet nitrogen containing 2% of water vapor at 25 ℃ for 1 hour, and then vacuum drying at 20 ℃ for 4 hours to obtain 41.90g of cefmetazole sodium, wherein the yield is 84.9%, the purity is 99.1%, the content is 98.5%, the tetrazole content is 0.27%, the lactone content is 0.12%, the maximum single impurity content is 0.21%, and the solvent is remained: acetone 0.03%, ethyl acetate 0.11%.
Comparative example 7
Dissolving 47.15g of cefmetazole acid in 240mL of acetone under the protection of nitrogen, cooling to-10 ℃, stirring to dissolve, adding 0.6g of acetic acid, slowly dropwise adding a solution prepared from 19.9g of sodium isooctanoate and 95mL of acetone, controlling the temperature to-10-15 ℃ for reaction, adding concentrated hydrochloric acid to adjust the pH to 5.0 after the reaction is finished for 30min, adding 4.7g of active carbon, stirring and decarbonizing;
and (3) dropwise adding 472mL of ethyl acetate into the solution for crystallization, cooling to-5 ℃ for crystal growth for 2 hours, filtering, leaching the obtained crystal by using ethyl acetate, continuously purging for 1 hour by using wet nitrogen containing 2% of water vapor at 25 ℃, and then drying for 4 hours at 20 ℃ in vacuum to obtain 43.33g of cefmetazole sodium. Yield 87.8%, purity 99.05%, tetrazole 0.12%, lactone 0.08%, other maximum single impurity 0.11%, solvent residue: acetone 0.06%, ethyl acetate 0.17%.
Comparative example 8
Dissolving 47.15g of cefmetazole acid in 240mL of acetone under the protection of nitrogen, cooling to-10 ℃, stirring to dissolve, adding 0.6g of acetic acid, slowly dropwise adding a solution prepared from 19.9g of sodium isooctanoate and 95mL of acetone, controlling the temperature to-10-15 ℃ for reaction, adding acetic acid to adjust the pH to 5.0 after the reaction is finished for 30min, adding 4.7g of active carbon, stirring and decarbonizing;
and (3) dropwise adding 472mL of ethyl acetate into the solution for crystallization, cooling to-5 ℃ for crystal growth for 2 hours, filtering, leaching the obtained crystal by using ethyl acetate, continuously purging for 2 hours by using nitrogen at 25 ℃, and then drying in vacuum at 20 ℃ for 4 hours to obtain 45.16g of cefmetazole sodium. Yield 91.5%, purity 99.3%, tetrazole 0.17%, lactone 0.06%, other maximum single impurity 0.13%, solvent residue: acetone 0.6% and ethyl acetate 2.8%.
Comparative example 9
Dissolving 47.15g of cefmetazole acid in 240mL of acetone under the protection of nitrogen, cooling to-10 ℃, stirring to dissolve, adding 0.6g of acetic acid, slowly dropwise adding a solution prepared from 19.9g of sodium isooctanoate and 95mL of acetone, controlling the temperature to-10-15 ℃ for reaction, adding acetic acid to adjust the pH to 5.0 after the reaction is finished for 30min, adding 4.7g of active carbon, stirring and decarbonizing;
and (3) dropwise adding 472mL of ethyl acetate into the solution for crystallization, cooling to-5 ℃ for crystal growth for 2 hours, filtering, leaching the obtained crystal by using ethyl acetate, continuously purging for 2 hours at 25 ℃ by using nitrogen containing 1% of water vapor, and then drying for 4 hours at 20 ℃ in vacuum to obtain 44.66g of cefmetazole sodium. Yield 90.5%, purity 99.3%, content 91.5%, tetrazole 0.14%, lactone 0.11%, other maximum single impurity 0.17%, solvent residue: acetone 0.8% ethyl acetate 2.1%.
Comparative example 10
Dissolving 47.15g of cefmetazole acid in 240mL of acetone under the protection of nitrogen, cooling to-10 ℃, stirring to dissolve, adding 0.6g of acetic acid, slowly dropwise adding a solution prepared from 19.9g of sodium isooctanoate and 95mL of acetone, controlling the temperature to-10-15 ℃ for reaction, adding acetic acid to adjust the pH to 5.0 after the reaction is finished for 30min, adding 4.7g of active carbon, stirring and decarbonizing;
and (3) dropwise adding 472mL of ethyl acetate into the solution for crystallization, cooling to-5 ℃ for crystal growth for 2 hours, filtering, leaching the obtained crystal by using ethyl acetate, continuously purging for 2 hours by using nitrogen containing 15% of water vapor at 25 ℃, absorbing water by the material, melting and agglomerating, and discarding for inspection.
Claims (5)
1. The preparation method of the antibacterial drug is characterized by comprising the following steps:
(1) Dissolving cefmetazole acid in a good solvent under the protection of nitrogen, cooling, dissolving, adding another solvent, slowly dripping a solution prepared by organic alkali and the good solvent, controlling the temperature to be-10-15 ℃ for reaction, adding acid to adjust the pH value to 5.0-6.0 after the reaction is finished, adding active carbon, stirring and decarbonizing; the good solvent is one or two of acetone and methanol, the other solvent is one or more of acetic acid, citric acid and n-butyric acid, and the organic base is one or more of sodium isooctanoate, sodium acetate, sodium methoxide and sodium ethoxide; the acid used for regulating the pH is one or more of acetic acid, citric acid and n-butyric acid;
(2) And (3) dropwise adding a poor solvent into the solution for crystallization, cooling, crystallizing, performing suction filtration, eluting the obtained crystal by using a solvent, humidifying and blowing nitrogen, and drying in vacuum to obtain cefmetazole sodium, wherein the poor solvent is one or two of isopropanol and ethyl acetate, and the nitrogen contains 2% -12% of water vapor.
2. The method for preparing an antibacterial drug according to claim 1, wherein the volume mass ratio of the good solvent to cefmetazole acid in the step (1) is 5-18: 1.
3. the method for preparing an antibacterial agent according to claim 1, wherein the molar ratio of the other solvent added in the step (1) to cefmetazole acid is 0.1 to 0.5:1.
4. The method for preparing an antibacterial agent according to claim 1, wherein the molar ratio of the organic base to cefmetazole acid in step (1) is 1.2 to 1.8:1.
5. the method for preparing an antibacterial drug according to claim 1, wherein the volume-mass ratio of the poor solvent to cefmetazole acid in the step (2) is 10-36: 1.
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