CN115353524A - Synthesis method of cefuroxime sodium - Google Patents
Synthesis method of cefuroxime sodium Download PDFInfo
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- CN115353524A CN115353524A CN202211022211.6A CN202211022211A CN115353524A CN 115353524 A CN115353524 A CN 115353524A CN 202211022211 A CN202211022211 A CN 202211022211A CN 115353524 A CN115353524 A CN 115353524A
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- URDOHUPGIOGTKV-JTBFTWTJSA-M Cefuroxime sodium Chemical compound [Na+].N([C@@H]1C(N2C(=C(COC(N)=O)CS[C@@H]21)C([O-])=O)=O)C(=O)\C(=N/OC)C1=CC=CO1 URDOHUPGIOGTKV-JTBFTWTJSA-M 0.000 title claims abstract description 54
- 229960000534 cefuroxime sodium Drugs 0.000 title claims abstract description 54
- 238000001308 synthesis method Methods 0.000 title abstract description 4
- 239000000243 solution Substances 0.000 claims abstract description 51
- 239000011734 sodium Substances 0.000 claims abstract description 36
- 229910052708 sodium Inorganic materials 0.000 claims abstract description 36
- 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 abstract description 33
- 238000000034 method Methods 0.000 claims abstract description 31
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 29
- 238000002425 crystallisation Methods 0.000 claims abstract description 25
- 230000008025 crystallization Effects 0.000 claims abstract description 25
- 229960001668 cefuroxime Drugs 0.000 claims abstract description 21
- JFPVXVDWJQMJEE-IZRZKJBUSA-N cefuroxime Chemical compound N([C@@H]1C(N2C(=C(COC(N)=O)CS[C@@H]21)C(O)=O)=O)C(=O)\C(=N/OC)C1=CC=CO1 JFPVXVDWJQMJEE-IZRZKJBUSA-N 0.000 claims abstract description 18
- 238000006243 chemical reaction Methods 0.000 claims abstract description 18
- 150000003839 salts Chemical class 0.000 claims abstract description 16
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 15
- 239000012043 crude product Substances 0.000 claims abstract description 14
- -1 chlorinated N-methoxyimino furan acetamido ammonium salt Chemical class 0.000 claims abstract description 11
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 11
- 230000021235 carbamoylation Effects 0.000 claims abstract description 10
- 230000007062 hydrolysis Effects 0.000 claims abstract description 9
- 230000006181 N-acylation Effects 0.000 claims abstract description 8
- 238000005917 acylation reaction Methods 0.000 claims abstract description 8
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 7
- 238000005185 salting out Methods 0.000 claims abstract description 7
- 239000000758 substrate Substances 0.000 claims abstract description 7
- 239000008156 Ringer's lactate solution Substances 0.000 claims abstract description 5
- 239000000126 substance Substances 0.000 claims abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 49
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 34
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 27
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 27
- 238000005406 washing Methods 0.000 claims description 20
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 16
- 230000002194 synthesizing effect Effects 0.000 claims description 12
- 239000008213 purified water Substances 0.000 claims description 11
- 239000002994 raw material Substances 0.000 claims description 10
- 238000003756 stirring Methods 0.000 claims description 9
- CYDQOEWLBCCFJZ-UHFFFAOYSA-N 4-(4-fluorophenyl)oxane-4-carboxylic acid Chemical compound C=1C=C(F)C=CC=1C1(C(=O)O)CCOCC1 CYDQOEWLBCCFJZ-UHFFFAOYSA-N 0.000 claims description 8
- 239000012074 organic phase Substances 0.000 claims description 8
- 239000001540 sodium lactate Substances 0.000 claims description 8
- 229940005581 sodium lactate Drugs 0.000 claims description 8
- 235000011088 sodium lactate Nutrition 0.000 claims description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
- XHNHGEUDHDUCGM-UHFFFAOYSA-N ethyl acetate;6-methylheptanoic acid Chemical compound CCOC(C)=O.CC(C)CCCCC(O)=O XHNHGEUDHDUCGM-UHFFFAOYSA-N 0.000 claims description 7
- MWAQUBCZSGTPMK-UHFFFAOYSA-N C(C)(=O)[O-].[NH4+].CON=C1OC=CC1 Chemical compound C(C)(=O)[O-].[NH4+].CON=C1OC=CC1 MWAQUBCZSGTPMK-UHFFFAOYSA-N 0.000 claims description 6
- IRFJEJVSVPRPDV-UHFFFAOYSA-N ethanol 6-methylheptanoic acid Chemical compound C(C)O.C(CCCCC(C)C)(=O)O IRFJEJVSVPRPDV-UHFFFAOYSA-N 0.000 claims description 6
- 230000035484 reaction time Effects 0.000 claims description 6
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 5
- WRJWRGBVPUUDLA-UHFFFAOYSA-N chlorosulfonyl isocyanate Chemical group ClS(=O)(=O)N=C=O WRJWRGBVPUUDLA-UHFFFAOYSA-N 0.000 claims description 5
- 238000001816 cooling Methods 0.000 claims description 5
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 claims description 5
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 4
- 235000019441 ethanol Nutrition 0.000 claims description 3
- 238000013329 compounding Methods 0.000 claims description 2
- 239000004310 lactic acid Substances 0.000 claims description 2
- 235000014655 lactic acid Nutrition 0.000 claims description 2
- 239000000047 product Substances 0.000 abstract description 34
- 239000013078 crystal Substances 0.000 abstract description 11
- 239000012535 impurity Substances 0.000 abstract description 7
- 150000002391 heterocyclic compounds Chemical class 0.000 abstract description 2
- 239000007858 starting material Substances 0.000 abstract 1
- 238000002360 preparation method Methods 0.000 description 12
- 238000001914 filtration Methods 0.000 description 11
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 239000012065 filter cake Substances 0.000 description 7
- 239000000706 filtrate Substances 0.000 description 7
- OEOIWYCWCDBOPA-UHFFFAOYSA-N 6-methyl-heptanoic acid Chemical compound CC(C)CCCCC(O)=O OEOIWYCWCDBOPA-UHFFFAOYSA-N 0.000 description 6
- HSHGZXNAXBPPDL-HZGVNTEJSA-N 7beta-aminocephalosporanic acid Chemical compound S1CC(COC(=O)C)=C(C([O-])=O)N2C(=O)[C@@H]([NH3+])[C@@H]12 HSHGZXNAXBPPDL-HZGVNTEJSA-N 0.000 description 5
- 239000003513 alkali Substances 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 238000007112 amidation reaction Methods 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000006228 supernatant Substances 0.000 description 4
- 230000006378 damage Effects 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 238000001291 vacuum drying Methods 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 229930186147 Cephalosporin Natural products 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 229940124587 cephalosporin Drugs 0.000 description 2
- 150000001780 cephalosporins Chemical class 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 239000011549 crystallization solution Substances 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000011345 viscous material Substances 0.000 description 2
- XOIDCKIHZGVJAS-SQFISAMPSA-N CC1=CC=C(C=C1)S(=O)(=O)OC(\C(=N/OC)\C=1OC=CC=1)=O Chemical compound CC1=CC=C(C=C1)S(=O)(=O)OC(\C(=N/OC)\C=1OC=CC=1)=O XOIDCKIHZGVJAS-SQFISAMPSA-N 0.000 description 1
- 108090000204 Dipeptidase 1 Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- ZOEGQXCAXOUFHN-UHFFFAOYSA-N Furosin Natural products OC1C2OC(=O)C(C=3C4C5(O)O)=CC(O)=C(O)C=3OC5(O)C(=O)C=C4C(=O)OC1C(CO)OC2OC(=O)C1=CC(O)=C(O)C(O)=C1 ZOEGQXCAXOUFHN-UHFFFAOYSA-N 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 230000009435 amidation Effects 0.000 description 1
- 230000006229 amino acid addition Effects 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 239000012296 anti-solvent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 244000052616 bacterial pathogen Species 0.000 description 1
- 102000006635 beta-lactamase Human genes 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 238000004042 decolorization Methods 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- CXTMLIMZRPKULL-YXYYPBJFSA-N dnc013643 Chemical compound O([C@@H]1O[C@@H]([C@H]2OC(=O)C=3[C@@H]4C(C(C(=O)C=3)(O)O)(O)OC=3C(O)=C(O)C=C(C4=3)C(=O)O[C@@H]1[C@H]2O)CO)C(=O)C1=CC(O)=C(O)C(O)=C1 CXTMLIMZRPKULL-YXYYPBJFSA-N 0.000 description 1
- 230000000797 effect on infection Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 239000003999 initiator Substances 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 238000005935 nucleophilic addition reaction Methods 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
Images
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
- C07D501/24—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
- C07D501/26—Methylene radicals, substituted by oxygen atoms; Lactones thereof with the 2-carboxyl group
- C07D501/34—Methylene radicals, substituted by oxygen atoms; Lactones thereof with the 2-carboxyl group with the 7-amino radical acylated by carboxylic acids containing hetero rings
-
- 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
-
- 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
- C07D501/06—Acylation of 7-aminocephalosporanic acid
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Organic Chemistry (AREA)
- Cephalosporin Compounds (AREA)
Abstract
The application provides a synthesis method of cefuroxime sodium, belonging to the technical field of heterocyclic compounds. Taking D-7ACA as a starting material, firstly carrying out N-acylation reaction with chlorinated N-methoxyimino furan acetamido ammonium salt to obtain 3-decarbamoyl cefuroxime acid, then carrying out reaction and hydrolysis with a strong carbamylation reagent, adding a salt forming agent, crystallizing to obtain a cefuroxime sodium crude product, taking a sodium lactate solution as a substrate, simultaneously dropwise adding a sodium lactate-alcohol solution and a crude product water soluble substance into the substrate, and carrying out salting out crystallization. The cefuroxime sodium synthesized by the method has the advantages of light product color, few impurities, uniform crystal form, good stability and the like.
Description
Technical Field
The application relates to a synthesis method of cefuroxime sodium, belonging to the technical field of heterocyclic compounds.
Background
Cefuroxime sodium, english name is Cefuroxime sodium, developed successfully by Kuransu Schker company, belongs to the second-generation semi-synthetic cephalosporin, has good curative effect on infection caused by most pathogenic bacteria producing beta-lactamase, and is one of the most widely used cephalosporin antibiotics in clinical application at present. The structural formula of cefuroxime sodium is:
the existing synthetic route of cefuroxime sodium mainly comprises the following steps:
route one, based on CN 1351605A:
using 7-glutamyl-deacetyl-ACA as an initial reactant, carbamylating at the 3-position, removing glutamic acid at the 7-position under the action of enzyme catalysis, performing aminoacylation reaction to obtain cefuroxime acid, and performing sodium conversion to obtain cefuroxime sodium. The synthetic route is shown as a reaction formula (1).
Route one uses 7-glutamyl-deacetyl-ACA as an initiator, and the raw material source is relatively non-extensive, so route one is not generally adopted.
Route two, with CN101289456B as the main:
taking 7-ACA and methoxyimino furan ammonium acetate as raw materials, firstly carrying out N-acylation reaction, then hydrolyzing 3-acetyl of a reaction product to obtain 3-decarbamoyl cefuroxime acid, and finally carrying out 3-carbamylation reaction to obtain cefuroxime acid, and salifying the cefuroxime acid and a salt forming agent to obtain cefuroxime sodium. The synthetic route is shown as a reaction formula (2).
In the second route, 7-ACA is amidated at the 7-position, then hydrolyzed at the 3-position and carbamylated, and finally sodium conversion is performed. However, in this route, after the 7-position amide bond is formed, it may be hydrolyzed into an amino group again in the subsequent 3-position hydrolysis process, so the formed 7-position amide bond needs to be protected first, and then the subsequent steps of operations are performed, and the protecting group is removed after the reaction is completed, which increases the complexity of the operation steps and experiments, and therefore, such an operation sequence is not generally adopted.
Route three, based on CN 109456339A:
dropping alkali solution into 7-aminocephalosporanic acid water solution for hydrolysis reaction, and then carrying out amidation reaction with (Z) -2-furyl-2-methoxyimino acetic acid p-toluenesulfonic anhydride to obtain 3-decarbamoyl cefuroxime acid; dissolving the cefuroxime sodium in an organic solvent, sequentially carrying out nucleophilic addition and hydrolysis reaction with chlorosulfonyl isocyanate, adding a sodium isooctanoate solution, and carrying out crystallization, filtration, washing and drying treatment to obtain the cefuroxime sodium. The synthetic route is shown as a reaction formula (3).
And the third route is to take 7-ACA as a raw material, firstly carry out 3-position hydrolysis to obtain D-7ACA, then carry out 7-position amidation and 3-position hydrolysis to obtain 3-decarbamoyl cefuroxime acid, and then carry out 3-position carbamoylation reaction on the 3-decarbamoyl cefuroxime acid, and then dropwise add sodium isooctanoate to form salt to obtain a cefuroxime sodium finished product. However, in this route, 7-ACA hydrolysis is liable to cause alkali damage and degradation impurities, and the color grade and liquid phase results of cefuroxime sodium prepared by direct salification after 3-position carbamylation are both biased.
Route four, mainly CN 101613359B:
d-7ACA is used as an initial raw material to perform 7-amidation reaction with methoxyimino furan ammonium salt to obtain 3-decarbamoyl cefuroxime acid, then the carbamylation transformation of 3-hydroxymethyl is performed to obtain cefuroxime acid, and finally the operation of converting acid into sodium is performed to obtain cefuroxime sodium. The synthetic route is shown as a reaction formula (4).
In the fourth route, D-7ACA is used for 7-amidation, then 3-carbamylation is carried out, and finally, the operation sequence of acid-to-sodium conversion is carried out for experiment to obtain the cefuroxime sodium finished product. In the step of converting acid into sodium, alkali is required to be added to dissolve cefuroxime acid to form a solution, a certain alkali destruction effect is achieved, and the salt formation adopts an anti-solvent method for crystallization, so that the obtained product has a non-uniform crystal form and poor product stability.
Disclosure of Invention
In view of the above, the present application provides a method for synthesizing high quality cefuroxime sodium, wherein the obtained cefuroxime sodium has the advantages of light color, less impurities, uniform crystal form, good stability, etc.
Specifically, the method is realized through the following scheme:
a method for synthesizing cefuroxime sodium comprises the following steps:
(1) Using D-7ACA as initial raw material, firstly carrying out N-acylation reaction with chlorinated N-methoxyimino furan acetyl ammonium salt to obtain 3-decarbamoyl cefuroxime acid,
(2) 3-decarbamoyl cefuroxime acid reacts with strong carbamylation reagent, is hydrolyzed, is added with salt forming agent and is crystallized to obtain cefuroxime sodium crude product,
(3) And (3) taking a sodium lactate solution as a substrate, simultaneously dropwise adding a sodium lactate-alcohol solution and a water soluble substance of the cefuroxime sodium crude product into the substrate, and performing salting-out crystallization.
In the scheme, the D-7ACA is introduced as a raw material, and the raw material D-7ACA has wide sources and is easy to obtain; in the process of obtaining the finished product, a sodium-to-sodium route is adopted, alkali damage does not exist, and the high-quality cefuroxime sodium finished product with light color, less impurities, uniform crystal form and good stability can be obtained by salting out and crystallizing after water dissolving.
Further, as preferable:
in the step (1), the preparation process of the chlorinated n-methoxyimino furan acetamido ammonium salt is as follows: uniformly stirring dichloromethane and phosphorus pentachloride, cooling to-20 to-15 ℃, adding N, N-dimethylacetamide and methoxyimino furan ammonium acetate (SMIA), reacting at-12 to-10 ℃ for 60 to 90min, purifying water, and washing an organic phase for multiple times, wherein the obtained organic phase is chlorinated N-methoxyimino furan acetoacetammonium salt. In the process, the feeding molar ratio of dichloromethane, phosphorus pentachloride, N-dimethylacetamide and methoxyimino furan ammonium acetate meets 22-35: 1 to 1.8:3 to 6:1 to 1.8.
In the step (1), the temperature of the N-acylation reaction is 0-10 ℃, the reaction time is 1-5 h, and the pH value of the reaction system is 6.7-7.6. And (2) after the N-acylation reaction product is layered, adding organic phase water for extraction and washing, separating out a water phase, adding methanol and dichloromethane, adjusting the pH to be 1-3, stirring and filtering at 10-20 ℃, rinsing and filtering with pure water and dichloromethane, draining, and drying in vacuum at 45 ℃ to obtain a dry product, namely the DCC.
In the step (2), the strong carbamylation reagent is chlorosulfonyl isocyanate, the addition amount of the relative DCC is 30-60% of the mass of the DCC, the reaction temperature is-70-40 ℃, and the reaction time is 30-50 min.
In the step (2), the hydrolysis temperature is-5-0 ℃, and the reaction time is 30-50 min.
In the step (2), the salt forming agent is sodium isooctanoate-ethyl acetate solution, sodium isooctanoate-ethanol solution or sodium isooctanoate-methanol ethanol solution, and the addition amount of the salt forming agent is 1.5 to 3 times of the mass excess of DCC.
In the step (2), the crystallization system is composed of at least one of tetrahydrofuran/absolute ethyl alcohol and water and absolute ethyl alcohol/ethyl acetate, and the volume ratio of the absolute ethyl alcohol/ethyl acetate to the tetrahydrofuran/absolute ethyl alcohol to the water is 6-8.
The crude sodium product with high purity and good crystallinity can be obtained by preparing a salt agent from a sodium iso-octoate-ethyl acetate solution or a sodium iso-octoate-ethanol solution and matching the crystallization system, and the subsequent filtration and drying are facilitated. More preferably, in the crystallization process, the crystallization product is washed for a plurality of times by using the extracted supernatant of the crystal system (ethanol or ethyl acetate) to remove the isooctanoic acid, and the crystallization temperature is 35-45 ℃. The sodium isooctanoate-ethyl acetate solution or the sodium isooctanoate-ethanol solution is used for salifying crystallization, a large amount of yellow isooctanoate byproducts are generated in the crystallization, the appearance of the product is influenced, and the product is sticky, and the supernatant of the cefuroxime crude sodium crystal system is extracted for many times, so that the viscous substance isooctanoate in the mother liquor does not pass through the product during filtration, the residue of the viscous substance isooctanoate in the product is effectively reduced, and the filtration is facilitated.
In the step (3), the lactic acid-alcohol solution is prepared by compounding any one of methanol-containing absolute ethyl alcohol solution and absolute ethyl alcohol with sodium lactate, the volume ratio of lactic acid to alcohol is 1.3-3, the sodium lactate concentration is 25-50% (both when used as a substrate and as a component of the lactic acid-alcohol solution), and the methanol content in the methanol-containing absolute ethyl alcohol solution is 5-10%, so that the obtained cefuroxime sodium product has light color, less impurities, uniform crystal form and good stability.
In the step (3), the salting-out crystallization temperature is 35-45 ℃, and the dripping time is 1-3 h.
Compared with the prior art, the technical scheme of the invention has the following advantages:
(1) D-7ACA is taken as an initial raw material, and is firstly subjected to N-acylation reaction with chlorinated N-methoxyimino furan acetyl ammonium salt to obtain the 3-decarbamoyl cefuroxime acid, and the raw material D-7ACA has wide sources and is easy to obtain.
(2) 3-decarbamoyl cefuroxime acid reacts with a strong carbamylation reagent chlorosulfonyl isocyanate, hydrolyzes, adds sodium isooctanoate ethyl acetate salt forming agent to crystallize to obtain a cefuroxime sodium crude product, and prepares a cefuroxime sodium finished product by a sodium-to-sodium process route.
(3) After the cefuroxime sodium crude product is dissolved in water, sodium lactate-alcohol solution is used as a salifying agent to carry out salting-out crystallization to obtain a high-quality cefuroxime sodium finished product with light color, less impurities, uniform crystal form and good stability.
Drawings
FIG. 1 is a graph of particle size distribution for the product produced in the present application.
Detailed Description
Example 1
The synthesis of cefuroxime sodium in this example comprises the following steps:
(1) Preparation of DCC (3-descarbamoyl cefuroxime acid):
adding 300 mL of dichloromethane and 48.5 g of phosphorus pentachloride into a 1000 mL four-mouth bottle, uniformly stirring, cooling to-20 ℃, adding 71 mL of N, N-dimethylacetamide and 40 g of SMIA (methoxyimino furan ammonium acetate), reacting at-12 ℃ for 80 min, washing an organic phase for three times by using 420 mL of purified water, and keeping the organic phase for later use; in another 1000 mL four-necked flask, 220 mL of purified water and 40 g of D-7ACA were put in, and a sodium hydroxide solution was added dropwise to dissolve the mixture until it was clear, and the temperature was controlled at 5 ℃. Adding the acyl chloride into the mixture twice to perform condensation reaction, adding sodium hydroxide solution in the process to control the pH of the system to be = 6.6, reacting for 3 hours, and controlling the temperature to be 7 ℃; separating layers, extracting and washing organic phase with 60 ml water, separating out water phase, combining with the previous water phase, adding 100 ml methanol and 200 ml dichloromethane, dropwise adding hydrochloric acid to adjust pH =2.0, stirring at 15 deg.C for 30 min, filtering, rinsing filter cake with 100X 2 purified water and 100X 2 dichloromethane, draining, vacuum drying at 45 deg.C until water content is less than 2.0%, to obtain dried product 61.2 g, purity 99.3%, and yield 153%.
(2) Preparation of cefuroxime sodium crude product:
adding 150 ml of tetrahydrofuran into a four-mouth bottle, adding 30 g of DCC, stirring until the mixture is completely dissolved, cooling to the temperature of less than or equal to-70 ℃, adding 14.46 g of chlorosulfonyl isocyanate, maintaining the temperature of less than or equal to-40 ℃, and reacting for 40 +/-5 min. Adding 30 ml of purified water into the other four-mouth bottle, cooling to 5 ℃, transferring the reaction solution into a hydrolysis tank, and controlling the temperature to be-5 ℃ to react for 40 +/-5 min. After hydrolysis, adding 12.5% sodium hydroxide solution for neutralization, and adjusting the pH value to 6.3; after the adjustment, adding 120 ml of ethyl acetate, stirring, adjusting the pH to 2.0 +/-0.2 by using concentrated hydrochloric acid, stirring, standing and layering; 60 mL of ethyl acetate was added to the aqueous layer, the mixture was stirred and allowed to stand for separation, the aqueous layer was separated, and the organic layer was retained. The organic phases are combined, 3 g of activated carbon is added for decolorization and filtration, a little ethyl acetate is used for washing a filter cake, and the filtrate and the washing liquid are combined. To the filtrate and the washing solution, 80 ml of absolute ethanol, 40 ml of tetrahydrofuran, 10 ml of purified water, 60 g of sodium isooctanoate-ethanol solution was added for crystallization, T =40 ℃. After crystallization is finished, crystal growth is carried out for 1 h, supernatant fluid is extracted, 100 ml of absolute ethyl alcohol is added and stirred for 30 min, standing and layer falling are carried out, supernatant fluid is extracted, 100 ml of absolute ethyl alcohol is added and stirred for 30 min, feed liquid is filtered out to obtain solid, 100 ml of absolute ethyl alcohol is used for washing filter cakes, and the filter cakes are drained. 45. Vacuum drying to water content of less than 3.0% to obtain dried product 32.8 g, purity of 99.6%, and yield of 109.3%.
(3) Preparation of cefuroxime sodium finished product:
70 ml of purified water and 10 g of crude furosin sodium are added into a four-mouth bottle, stirred, dissolved and cleaned, filtered, and replaced and washed by 10 ml of purified water to obtain a solution for later use. 80 ml of 50% sodium lactate solution and 30 ml of absolute ethyl alcohol solution are taken and mixed evenly to obtain a salifying agent for later use. Another four-mouth bottle is taken, 20 ml of 50% sodium lactate solution is added as base solution, and the temperature is controlled at 40 ℃ by stirring. And (3) dripping the crude sodium dissolving solution and the salt forming agent into the base solution simultaneously for 1 h, and controlling the temperature of 40 ℃ in the whole dripping process. After dripping, keeping the temperature for growing the crystal for 30 min. Filtering, washing with anhydrous ethanol solution for several times, and draining. 45. Vacuum drying at temperature below 3.0% to obtain dried product 9.02 g with purity of 99.82% and yield of 90.2%.
Example 2
This example is the same as the arrangement of example 1, except that: in the preparation of the cefuroxime sodium crude product in the step (2), 60 ml of ethyl acetate, 35 ml of tetrahydrofuran, 15 ml of purified water, 70 g of sodium isooctanoate-ethyl acetate solution are added to the filtrate and the washing solution for crystallization, and the washing treatment is carried out by using ethyl acetate; in the preparation of the cefuroxime sodium finished product, the concentration of sodium lactate is 25%, and the solvent is an absolute ethyl alcohol solution containing 5% of methanol. 8.93 g of dry product is obtained, the purity is 99.80 percent, and the yield is 89.3 percent.
Example 3
This example is the same as the arrangement of example 1, except that: in the step (2) of preparing cefuroxime sodium crude product, adding 60 ml of ethyl acetate, 40 ml of absolute ethyl alcohol, 10 ml of purified water, 60 g of sodium isooctanoate-ethanol solution for crystallization into the filtrate and the washing solution, filtering the crystallization solution, and washing the filter cake with 3 x 100 ml of absolute ethyl alcohol; in the preparation of the cefuroxime sodium finished product, the concentration of sodium lactate is 25%, and the solvent is absolute ethyl alcohol solution containing 10% of methanol. 8.81 g of dry product is obtained, the purity is 99.85 percent, and the yield is 88.1 percent.
Example 4
This example is the same as the arrangement of example 1, except that: in the preparation of the cefuroxime sodium crude product of step (2), 60 ml of ethyl acetate, 10 ml of purified water, 70 g of sodium isooctanoate-ethyl acetate solution for crystallization, and the filtrate and the washing solution are added to wash the filter cake with 3 x 100 ml of ethyl acetate; in the preparation of the cefuroxime sodium finished product, the concentration of sodium lactate is 50 percent, the solvent is absolute ethyl alcohol solution containing 10 percent of methanol, and the salt forming agent is dripped into the sodium dissolved solution for crystallization for 1 hour. 8.75 g of dry product is obtained, the purity is 99.79 percent, and the yield is 87.5 percent.
Example 5
This example is the same as the arrangement of example 1, except that: in the step (2) of preparing cefuroxime sodium crude product, adding 60 ml of ethyl acetate, 40 ml of absolute ethyl alcohol, 60 g of sodium isooctanoate-ethanol solution into the filtrate and the washing solution for crystallization, filtering the crystallization solution, and washing the filter cake with 3 x 100 ml of absolute ethyl alcohol; in the preparation of the cefuroxime sodium finished product, the concentration of sodium lactate is 25 percent, the solvent is absolute ethyl alcohol, and the salt forming agent is dripped into the sodium dissolving solution for crystallization for 2 hours. 9.08 g of dry product is obtained, the purity is 99.79 percent, and the yield is 90.8 percent.
Example 6
This example is the same as the arrangement of example 1, except that: in the preparation of the cefuroxime sodium crude product in the step (2), 60 ml of ethyl acetate, 40 ml of tetrahydrofuran and 70 g of sodium isooctanoate-ethyl acetate solution are added into the filtrate and the washing solution for crystallization, and the washing treatment is carried out by using ethyl acetate; in the preparation of the cefuroxime sodium finished product, the concentration of sodium lactate is 50%, the solvent is absolute ethyl alcohol, and the dripping time is 3 h. 8.95 g of dry product is obtained, the purity is 99.84 percent, and the yield is 89.5 percent.
The above experimental process shows that: the product obtained by adopting the technical scheme has the advantages of light color, uniform crystal form, stable finished product purity of about 99.8 percent, low impurity content and high yield of over 85 percent.
Claims (10)
1. A method for synthesizing cefuroxime sodium is characterized by comprising the following steps:
(1) Using D-7ACA as initial raw material, firstly carrying out N-acylation reaction with chlorinated N-methoxyimino furan acetyl ammonium salt to obtain 3-decarbamoyl cefuroxime acid,
(2) 3-decarbamoyl cefuroxime acid reacts with strong carbamylation reagent, is hydrolyzed, is added with salt forming agent, is crystallized to obtain cefuroxime sodium crude product,
(3) And (3) taking a sodium lactate solution as a substrate, dripping a sodium lactate-alcohol solution and a water-soluble substance of the cefuroxime sodium crude product into the substrate simultaneously, and carrying out salting-out crystallization.
2. The method for synthesizing cefuroxime sodium according to claim 1, wherein in the step (1), the chlorinated n-methoxyimino furan acetamido ammonium salt is prepared by the following steps: uniformly stirring dichloromethane and phosphorus pentachloride, cooling to-20 to-15 ℃, adding N, N-dimethylacetamide and methoxyimino furan ammonium acetate, reacting at-12 to-10 ℃ for 60 to 90min, and washing an organic phase obtained by the reaction for multiple times by purified water to obtain the chlorinated N-methoxyimino furan acetoacetammonium salt.
3. The method for synthesizing cefuroxime sodium according to claim 2, wherein the method comprises the following steps: dichloromethane, phosphorus pentachloride, N-dimethylacetamide and methoxyimino furan ammonium acetate are added in a molar ratio of 22 to 35:1 to 1.8:3 to 6:1 to 1.8.
4. The method for synthesizing cefuroxime sodium according to claim 1, wherein the method comprises the following steps: in the step (1), the temperature of the N-acylation reaction is 0-10 ℃, the reaction time is 1-5 h, and the pH value of the reaction system is 6.7-7.6.
5. The method for synthesizing cefuroxime sodium according to claim 1, wherein the method comprises the following steps: in the step (2), the strong carbamylation reagent is chlorosulfonyl isocyanate, the addition amount of the strong carbamylation reagent relative to the 3-descarbamoyl cefuroxime acid is 30-60 percent of the mass of the 3-descarbamoyl cefuroxime acid, the reaction temperature is-70 to-40 ℃, and the reaction time is 30-50 min.
6. The method for synthesizing cefuroxime sodium according to claim 1, wherein the method comprises the following steps: in the step (2), the hydrolysis temperature is-5-0 ℃, and the reaction time is 30-50 min.
7. The method for synthesizing cefuroxime sodium according to claim 1, wherein the method comprises the following steps: in the step (2), the salt forming agent is sodium isooctanoate-ethyl acetate solution, sodium isooctanoate-ethanol solution or sodium isooctanoate-methanol ethanol solution, and the addition amount of the salt forming agent is excessive relative to the mass of DCC.
8. The method for synthesizing cefuroxime sodium according to claim 1, wherein the method comprises the following steps: in the step (2), the crystallization system is composed of at least one of tetrahydrofuran/absolute ethyl alcohol and water and absolute ethyl alcohol/ethyl acetate, the volume ratio of the absolute ethyl alcohol/ethyl acetate to the tetrahydrofuran/absolute ethyl alcohol to the water is 6-8.
9. The method for synthesizing cefuroxime sodium according to claim 1, wherein the method comprises the following steps: in the step (3), the lactic acid-alcohol solution is prepared by compounding any one of methanol-containing absolute ethyl alcohol solution and absolute ethyl alcohol with sodium lactate, the volume ratio of lactic acid to alcohol satisfies 1.3-3.
10. The method for synthesizing cefuroxime sodium according to claim 1, wherein the method comprises the following steps: in the step (3), the salting-out crystallization temperature is 35-45 ℃, and the dripping time is 1-3 h.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101613359A (en) * | 2009-08-07 | 2009-12-30 | 哈药集团制药总厂 | Method for synthesizing cefuroxime sodium |
| CN101812076A (en) * | 2009-02-24 | 2010-08-25 | 丽珠医药集团股份有限公司 | Cefuroxime sodium and preparation method thereof |
| CN109456339A (en) * | 2018-09-27 | 2019-03-12 | 湖北凌晟药业有限公司 | A kind of synthetic method of Cefuroxime Sodium |
| 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 |
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| CN101812076A (en) * | 2009-02-24 | 2010-08-25 | 丽珠医药集团股份有限公司 | Cefuroxime sodium and preparation method thereof |
| CN101613359A (en) * | 2009-08-07 | 2009-12-30 | 哈药集团制药总厂 | Method for synthesizing cefuroxime sodium |
| CN109456339A (en) * | 2018-09-27 | 2019-03-12 | 湖北凌晟药业有限公司 | A kind of synthetic method of Cefuroxime Sodium |
| 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 |
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