CN118005651A - Method for preparing amoxicillin through catalytic method - Google Patents
Method for preparing amoxicillin through catalytic method Download PDFInfo
- Publication number
- CN118005651A CN118005651A CN202410148786.5A CN202410148786A CN118005651A CN 118005651 A CN118005651 A CN 118005651A CN 202410148786 A CN202410148786 A CN 202410148786A CN 118005651 A CN118005651 A CN 118005651A
- Authority
- CN
- China
- Prior art keywords
- reaction
- hydroxyphenylglycine
- acid catalyst
- solid acid
- amoxicillin
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 238000000034 method Methods 0.000 title claims abstract description 55
- LSQZJLSUYDQPKJ-NJBDSQKTSA-N amoxicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=C(O)C=C1 LSQZJLSUYDQPKJ-NJBDSQKTSA-N 0.000 title claims abstract description 41
- 229960003022 amoxicillin Drugs 0.000 title claims abstract description 41
- LSQZJLSUYDQPKJ-UHFFFAOYSA-N p-Hydroxyampicillin Natural products O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)C(N)C1=CC=C(O)C=C1 LSQZJLSUYDQPKJ-UHFFFAOYSA-N 0.000 title claims abstract description 41
- 230000003197 catalytic effect Effects 0.000 title claims abstract description 21
- 239000003054 catalyst Substances 0.000 claims abstract description 72
- 239000011973 solid acid Substances 0.000 claims abstract description 64
- SZBDOFWNZVHVGR-MRVPVSSYSA-N methyl (2r)-2-amino-2-(4-hydroxyphenyl)acetate Chemical compound COC(=O)[C@H](N)C1=CC=C(O)C=C1 SZBDOFWNZVHVGR-MRVPVSSYSA-N 0.000 claims abstract description 48
- 238000005406 washing Methods 0.000 claims abstract description 31
- 238000001035 drying Methods 0.000 claims abstract description 17
- NGHVIOIJCVXTGV-ALEPSDHESA-N 6-aminopenicillanic acid Chemical compound [O-]C(=O)[C@H]1C(C)(C)S[C@@H]2[C@H]([NH3+])C(=O)N21 NGHVIOIJCVXTGV-ALEPSDHESA-N 0.000 claims abstract description 10
- NGHVIOIJCVXTGV-UHFFFAOYSA-N 6beta-amino-penicillanic acid Natural products OC(=O)C1C(C)(C)SC2C(N)C(=O)N21 NGHVIOIJCVXTGV-UHFFFAOYSA-N 0.000 claims abstract description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 129
- 239000013078 crystal Substances 0.000 claims description 37
- 238000006243 chemical reaction Methods 0.000 claims description 34
- 239000000203 mixture Substances 0.000 claims description 33
- 238000002360 preparation method Methods 0.000 claims description 32
- 239000000463 material Substances 0.000 claims description 29
- LJCWONGJFPCTTL-SSDOTTSWSA-N D-4-hydroxyphenylglycine Chemical compound [O-]C(=O)[C@H]([NH3+])C1=CC=C(O)C=C1 LJCWONGJFPCTTL-SSDOTTSWSA-N 0.000 claims description 26
- QCWXUUIWCKQGHC-UHFFFAOYSA-N Zirconium Chemical compound [Zr] QCWXUUIWCKQGHC-UHFFFAOYSA-N 0.000 claims description 26
- 229910052726 zirconium Inorganic materials 0.000 claims description 26
- 238000001816 cooling Methods 0.000 claims description 25
- 239000010902 straw Substances 0.000 claims description 25
- 239000000047 product Substances 0.000 claims description 23
- 238000001914 filtration Methods 0.000 claims description 18
- 239000007787 solid Substances 0.000 claims description 15
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 14
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 14
- YVBOZGOAVJZITM-UHFFFAOYSA-P ammonium phosphomolybdate Chemical compound [NH4+].[NH4+].[NH4+].[NH4+].[O-]P([O-])=O.[O-][Mo]([O-])(=O)=O YVBOZGOAVJZITM-UHFFFAOYSA-P 0.000 claims description 14
- 239000012043 crude product Substances 0.000 claims description 14
- 238000003756 stirring Methods 0.000 claims description 13
- 238000001354 calcination Methods 0.000 claims description 11
- 238000002156 mixing Methods 0.000 claims description 11
- 239000012299 nitrogen atmosphere Substances 0.000 claims description 11
- 108010073038 Penicillin Amidase Proteins 0.000 claims description 10
- 238000003786 synthesis reaction Methods 0.000 claims description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- 108090000790 Enzymes Proteins 0.000 claims description 7
- 102000004190 Enzymes Human genes 0.000 claims description 7
- 239000012141 concentrate Substances 0.000 claims description 6
- 239000002202 Polyethylene glycol Substances 0.000 claims description 5
- 229920001223 polyethylene glycol Polymers 0.000 claims description 5
- 230000002255 enzymatic effect Effects 0.000 claims description 4
- 238000007036 catalytic synthesis reaction Methods 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 7
- 239000002994 raw material Substances 0.000 abstract description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 abstract description 5
- 239000000126 substance Substances 0.000 abstract description 3
- 238000004821 distillation Methods 0.000 abstract description 2
- 239000000843 powder Substances 0.000 description 19
- 239000012295 chemical reaction liquid Substances 0.000 description 18
- 239000002904 solvent Substances 0.000 description 18
- 239000007788 liquid Substances 0.000 description 11
- 238000010438 heat treatment Methods 0.000 description 9
- 229940068918 polyethylene glycol 400 Drugs 0.000 description 9
- 238000010992 reflux Methods 0.000 description 9
- 238000007873 sieving Methods 0.000 description 9
- 238000005886 esterification reaction Methods 0.000 description 7
- 238000004811 liquid chromatography Methods 0.000 description 7
- 238000000926 separation method Methods 0.000 description 7
- 230000000052 comparative effect Effects 0.000 description 6
- 238000006555 catalytic reaction Methods 0.000 description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 5
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- 238000001308 synthesis method Methods 0.000 description 4
- 239000002253 acid Substances 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 230000007547 defect Effects 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000011148 porous material Substances 0.000 description 3
- 238000004064 recycling Methods 0.000 description 3
- 239000004254 Ammonium phosphate Substances 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 229910000148 ammonium phosphate Inorganic materials 0.000 description 2
- 235000019289 ammonium phosphates Nutrition 0.000 description 2
- 230000003115 biocidal effect Effects 0.000 description 2
- 238000003763 carbonization Methods 0.000 description 2
- 239000008367 deionised water Substances 0.000 description 2
- 229910021641 deionized water Inorganic materials 0.000 description 2
- MNNHAPBLZZVQHP-UHFFFAOYSA-N diammonium hydrogen phosphate Chemical compound [NH4+].[NH4+].OP([O-])([O-])=O MNNHAPBLZZVQHP-UHFFFAOYSA-N 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 230000032050 esterification Effects 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- -1 phosphate radical Chemical class 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 238000001179 sorption measurement Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- LJCWONGJFPCTTL-UHFFFAOYSA-N 4-hydroxyphenylglycine Chemical compound OC(=O)C(N)C1=CC=C(O)C=C1 LJCWONGJFPCTTL-UHFFFAOYSA-N 0.000 description 1
- 208000035143 Bacterial infection Diseases 0.000 description 1
- 201000008197 Laryngitis Diseases 0.000 description 1
- ZOKXTWBITQBERF-UHFFFAOYSA-N Molybdenum Chemical compound [Mo] ZOKXTWBITQBERF-UHFFFAOYSA-N 0.000 description 1
- 206010033078 Otitis media Diseases 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 206010035664 Pneumonia Diseases 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 208000022362 bacterial infectious disease Diseases 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 235000019658 bitter taste Nutrition 0.000 description 1
- 210000002421 cell wall Anatomy 0.000 description 1
- 239000013064 chemical raw material Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000007797 corrosion Effects 0.000 description 1
- 238000005260 corrosion Methods 0.000 description 1
- 239000006184 cosolvent Substances 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 208000022760 infectious otitis media Diseases 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 229910052750 molybdenum Inorganic materials 0.000 description 1
- 239000011733 molybdenum Substances 0.000 description 1
- 229910000476 molybdenum oxide Inorganic materials 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- PQQKPALAQIIWST-UHFFFAOYSA-N oxomolybdenum Chemical compound [Mo]=O PQQKPALAQIIWST-UHFFFAOYSA-N 0.000 description 1
- RVTZCBVAJQQJTK-UHFFFAOYSA-N oxygen(2-);zirconium(4+) Chemical compound [O-2].[O-2].[Zr+4] RVTZCBVAJQQJTK-UHFFFAOYSA-N 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 150000002960 penicillins Chemical class 0.000 description 1
- 150000005837 radical ions Chemical class 0.000 description 1
- 206010040872 skin infection Diseases 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 208000019206 urinary tract infection Diseases 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
- 239000002351 wastewater Substances 0.000 description 1
- 229910001928 zirconium oxide Inorganic materials 0.000 description 1
Classifications
-
- 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
- Y02P20/584—Recycling of catalysts
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a method for preparing amoxicillin through a catalytic method, which adopts a solid acid catalyst to catalyze and synthesize D-p-hydroxyphenylglycine methyl ester, and the amoxicillin is synthesized by reacting with 6-APA after atmospheric distillation, so that dangerous chemical raw materials of thionyl chloride are avoided, thereby avoiding generating corrosive gas and improving the safety of a production process; meanwhile, subsequent procedures of washing, separating, drying and the like of D-p-hydroxyphenylglycine methyl ester are saved, the production procedures are simplified, the energy loss and the equipment loss are reduced, the cost is reduced, and the efficiency is improved; in addition, the solid acid catalyst can be reused, and the production cost is further reduced.
Description
Technical Field
The invention relates to the technical field of chemical pharmacy, in particular to a method for preparing amoxicillin through a catalytic method.
Background
Amoxicillin (Amoxicillin) is an organic compound with a chemical formula of C 16H19N3 O5S, is an antibiotic drug, is also called amoxicillin, and belongs to the aminopenicillin class of penicillin families. The white or white-like crystal powder has slightly specific smell and bitter taste, is a main variety of second-generation penicillin, is a broad-spectrum semisynthetic antibiotic, can inhibit the synthesis of bacterial cell walls, has high-efficiency broad-spectrum antibacterial effect, has small toxic and side effects, and is commonly used for treating bacterial infections such as middle ear infection, streptococcal laryngitis, pneumonia, skin infection and urinary tract infection.
The synthesis method of amoxicillin mainly comprises a chemical synthesis method and an enzymatic synthesis method. The enzymatic synthesis method adopts the direct synthesis of amoxicillin under the catalysis of enzyme by adopting the levo-p-hydroxyphenylglycine methyl ester (D-p hydroxyphenylglycine METHYL ESTER) and 6-aminopenicillin acid, has the advantages of mild process conditions, environmental protection and good product quality, and becomes a main method for industrial production of amoxicillin, thereby driving the market rapid development of the raw materials or intermediates of the levo-p-hydroxyphenylglycine methyl ester (D-p-hydroxyphenylglycine methyl ester).
The D-p-hydroxyphenylglycine methyl ester is generally prepared by taking D-p-hydroxyphenylglycine as a starting material and carrying out esterification reaction with methanol in the presence of a proper catalyst. In the early technology, concentrated sulfuric acid or thionyl chloride is adopted as a dehydration catalyst, so that the defects of high raw material consumption, serious equipment corrosion and difficult environmental protection treatment exist, and a plurality of technical improvements are carried out in the later stage.
The Chinese patent document CN114105795B discloses a synthesis method of an amoxicillin production intermediate, which takes DL-p-hydroxyphenylglycine and methanol as raw materials, and solid phosphoric acid is used as a catalyst and a resolving agent to synthesize D-p-hydroxyphenylglycine methyl ester, so that the recycling of the solid phosphoric acid catalyst is avoided, but the process technology is complex and the product yield is not stable enough.
The Chinese patent document CN111153821A discloses a preparation method of D-p-hydroxyphenylglycine methyl ester, which adopts a traditional esterification process, takes a large amount of sulfuric acid as an esterification catalyst and a cosolvent of D-p-hydroxyphenylglycine for methyl esterification reaction, has the synthesis yield as high as 96 percent, and has the defects of large consumption of sulfuric acid, large consumption of deionized water and large amount of waste water generated by removing sodium sulfate salt entrained by the product.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide a method for preparing amoxicillin through a catalytic method, and the solid acid catalyst provided by the invention is applied to the catalytic synthesis of D-p-hydroxyphenylglycine methyl ester and has the characteristics of high yield and good reusability.
In order to achieve the above purpose, the present invention adopts the following technical scheme:
A method for preparing amoxicillin through a catalytic method comprises the following steps:
S1, adding D-p-hydroxyphenylglycine, methanol and a solid acid catalyst into a reaction bottle for reaction, filtering to recover the solid acid catalyst after the reaction is finished, and distilling at normal pressure to recover the methanol to obtain D-p-hydroxyphenylglycine methyl ester concentrate;
s2, adding 6-APA into ammonia water, stirring and dissolving, and then adding D-p-hydroxyphenylglycine methyl ester concentrate and immobilized penicillin acylase into the solution to perform enzyme catalytic synthesis reaction;
S3, after the reaction is finished, separating the immobilized penicillin acylase, adding hydrochloric acid, dissolving the crude product, then adding ammonia water into the crude product solution, adjusting the pH value to be 4.8-5.5, growing crystals for 95-115min, and after the crystal growth is finished, centrifuging, washing and drying to obtain the amoxicillin finished product.
Preferably, in step S1, the preparation method of the solid acid catalyst is as follows:
(1) Crushing straw, adding the crushed straw into ZrO (NO 3)2 solution, adding polyethylene glycol, stirring at room temperature for 1-2h, drying, and calcining at 400-600 ℃ for 3-6h in nitrogen atmosphere to obtain a zirconium-containing biochar material;
(2) And uniformly mixing solid ammonium phosphomolybdate and a zirconium-containing biochar material, then placing the mixture in a muffle furnace, roasting the mixture at 450-600 ℃ for 3-6 hours, and cooling the mixture to room temperature after roasting is finished to obtain the solid acid catalyst.
Preferably, in the step (1), the mass volume ratio of the straw to the ZrO (NO 3)2 solution to the polyethylene glycol is 1g:10-15mL:0.1-0.2mL, and the mass fraction of the ZrO (NO 3)2 solution is 10-15%).
Preferably, in the step (2), the mass ratio of the solid ammonium phosphomolybdate to the zirconium-containing biochar material is 1-3:10.
Preferably, in step S1, the molar ratio of D-hydroxyphenylglycine to methanol is 1:35-45.
Preferably, in the step S1, the mass ratio of the D-hydroxyphenylglycine to the solid acid catalyst is 1:0.5-3.0.
Preferably, in step S1, the reaction temperature is 60-100 ℃ and the reaction time is 4-8h.
Preferably, the molar ratio of D-hydroxyphenylglycine to 6-APA is from 1:0.8 to 1.1.
Preferably, in step S2, the mass ratio of 6-APA to immobilized penicillin acylase is 1:0.5-2.0.
Preferably, in step S2, the specific process of the enzymatic synthesis reaction is: at 13-25 ℃, ammonia water with the weight percent of 5-8% is used for adjusting the pH of the reaction to 6.15-6.35, and the reaction lasts for 40-220min.
Compared with the prior art, the invention has the following beneficial effects:
(1) The invention prepares the zirconium-containing biochar material by taking waste straws as raw materials through carbonization reaction, has the characteristics of easily available raw materials, low price and high resource utilization rate, and in the carbonization process, polyethylene glycol is used as a pore-forming agent, so that the pore structure of the biochar material is enriched, the biochar material has higher specific surface area and pore volume, places are provided for esterification reaction of macromolecules, and meanwhile, the abundant pore structure enables the biochar material to have more active centers, stronger adsorption and mass transfer capacity, thereby effectively avoiding the loss of acid radical ions, improving the catalytic performance and the service life of the solid acid catalyst.
(2) According to the invention, ammonium phosphomolybdate is adopted to activate the biochar material, phosphate radical acts with zirconium and molybdenum in a coordination form, and meanwhile, the biochar has physical adsorption effect on the phosphate radical, so that the acid sites of the solid acid catalyst are enriched, the catalytic activity of the catalyst is improved, and the catalytic performance of the solid acid catalyst is further enhanced; in addition, molybdenum oxide and zirconium oxide can also be used as active centers of the esterification reaction to catalyze the esterification reaction.
(3) According to the invention, the solid acid catalyst is adopted to catalyze and synthesize the D-p-hydroxyphenylglycine methyl ester, and the amoxicillin is synthesized by reacting with the 6-APA after atmospheric distillation, so that the use of dangerous chemical raw material sulfoxide chloride is avoided, thereby avoiding the generation of corrosive gas and improving the safety of the production process; meanwhile, subsequent procedures of washing, separating, drying and the like of D-p-hydroxyphenylglycine methyl ester are saved, the production procedures are simplified, the energy loss and the equipment loss are reduced, the cost is reduced, and the efficiency is improved; in addition, the solid acid catalyst can be reused, and the production cost is further reduced.
Detailed Description
The present invention will be described in further detail with reference to the following preferred examples, but the present invention is not limited to the following examples.
Unless otherwise specified, the chemical reagents involved in the present invention are all commercially available.
Example 1
The preparation method of the D-p-hydroxyphenylglycine methyl ester comprises the following steps:
(1) Preparation of solid acid catalyst
Crushing straw, sieving with a 100-mesh sieve, adding 10g of straw powder into 100mL of 10wt% ZrO (NO 3)2 solution, adding 1mL of polyethylene glycol 400, stirring at room temperature for 1h, drying in a 100 ℃ oven, and calcining at 450 ℃ for 3h in a nitrogen atmosphere to obtain a zirconium-containing biochar material;
Uniformly mixing 1g of solid ammonium phosphomolybdate and 10g of zirconium-containing biochar material, then placing the mixture in a muffle furnace, roasting the mixture at 500 ℃ for 5 hours, and cooling the mixture to room temperature after roasting is finished to obtain the solid acid catalyst.
(2) Preparation of D-p-hydroxyphenylglycine methyl ester
Dispersing 16.72g (0.1 mol) of D-p-hydroxyphenylglycine in 128g of methanol solvent, adding 15.8g of solid acid catalyst, heating and refluxing at 80 ℃ for reaction for 3 hours, fully esterifying suspended D-p-hydroxyphenylglycine powder, dissolving, filtering while the solid acid catalyst is hot, washing the solid acid catalyst with methanol, merging the washing liquid into the reaction liquid, and then distilling to recover the methanol solvent in the reaction liquid;
(3) Separation of D-p-hydroxyphenylglycine methyl ester
Cooling the reaction solution to room temperature, further cooling and crystallizing at 5 ℃, filtering and separating out the separated crystals, washing the crystals with methanol and then airing the crystals to obtain 16.87g of D-p-hydroxyphenylglycine methyl ester crystals, wherein the yield of the product is 93.11%, and the purity of the product is 99.6% measured by a liquid chromatography method.
Example 2
The preparation method of the D-p-hydroxyphenylglycine methyl ester comprises the following steps:
(1) Preparation of solid acid catalyst
Crushing straw, sieving with a 100-mesh sieve, adding 10g of straw powder into 100mL of 15wt% ZrO (NO 3)2 solution, adding 2mL of polyethylene glycol 400, stirring at room temperature for 1h, drying in a 100 ℃ oven, and calcining at 450 ℃ for 3h in a nitrogen atmosphere to obtain a zirconium-containing biochar material;
Uniformly mixing 3g of solid ammonium phosphomolybdate and 10g of zirconium-containing biochar material, then placing the mixture in a muffle furnace, roasting the mixture at 600 ℃ for 3 hours, and cooling the mixture to room temperature after roasting is finished to obtain the solid acid catalyst.
(2) Preparation of D-p-hydroxyphenylglycine methyl ester
Dispersing 16.72g (0.1 mol) of D-p-hydroxyphenylglycine in 128g of methanol solvent, adding 20.2g of solid acid catalyst, heating and refluxing at 80 ℃ for reaction for 3 hours, fully esterifying suspended D-p-hydroxyphenylglycine powder, dissolving, filtering while the solid acid catalyst is hot, washing the solid acid catalyst with methanol, merging the washing liquid into the reaction liquid, and then distilling to recover the methanol solvent in the reaction liquid;
(3) Separation of D-p-hydroxyphenylglycine methyl ester
Cooling the reaction solution to room temperature, further cooling and crystallizing at 5 ℃, filtering and separating out the separated crystals, washing the crystals with methanol and then airing the crystals to obtain 17.21g of D-p-hydroxyphenylglycine methyl ester crystals, wherein the yield of the product is 94.98%, and the purity of the product is 99.7% measured by a liquid chromatography method.
Example 3
The preparation method of the D-p-hydroxyphenylglycine methyl ester comprises the following steps:
(1) Preparation of solid acid catalyst
Crushing straw, sieving with a 100-mesh sieve, adding 10g of straw powder into 100mL of 10wt% ZrO (NO 3)2 solution, adding 1.5mL of polyethylene glycol 400, stirring at room temperature for 1h, drying in a 100 ℃ oven, and calcining at 500 ℃ for 3h in a nitrogen atmosphere to obtain a zirconium-containing biochar material;
Uniformly mixing 2g of solid ammonium phosphomolybdate and 10g of zirconium-containing biochar material, then placing the mixture in a muffle furnace, roasting the mixture at 600 ℃ for 3 hours, and cooling the mixture to room temperature after roasting is finished to obtain the solid acid catalyst.
(2) Preparation of D-p-hydroxyphenylglycine methyl ester
Dispersing 16.72g (0.1 mol) of D-p-hydroxyphenylglycine in 128g of methanol solvent, adding 18.6g of solid acid catalyst, heating and refluxing at 80 ℃ for reaction for 3 hours, fully esterifying suspended D-p-hydroxyphenylglycine powder, dissolving, filtering while the solid acid catalyst is hot, washing the solid acid catalyst with methanol, merging the washing liquid into the reaction liquid, and then distilling to recover the methanol solvent in the reaction liquid;
(3) Separation of D-p-hydroxyphenylglycine methyl ester
Cooling the reaction solution to room temperature, further cooling and crystallizing at 5 ℃, filtering and separating out the separated crystals, washing the crystals with methanol and then airing the crystals to obtain 17.09g of D-p-hydroxyphenylglycine methyl ester crystals, wherein the yield of the product is 94.32%, and the purity of the product is 99.5% measured by a liquid chromatography method.
Example 4
The preparation method of the D-p-hydroxyphenylglycine methyl ester comprises the following steps:
(1) Preparation of solid acid catalyst
Crushing straw, sieving with a 100-mesh sieve, adding 10g of straw powder into 150mL of 10wt% ZrO (NO 3)2 solution, adding 2mL of polyethylene glycol 400, stirring at room temperature for 1h, drying in a 100 ℃ oven, and calcining at 400 ℃ for 6h in a nitrogen atmosphere to obtain a zirconium-containing biochar material;
Uniformly mixing 1.5g of solid ammonium phosphomolybdate and 10g of zirconium-containing biochar material, then placing the mixture in a muffle furnace, roasting the mixture at 600 ℃ for 3 hours, and cooling the mixture to room temperature after roasting is finished to obtain the solid acid catalyst.
(2) Preparation of D-p-hydroxyphenylglycine methyl ester
Dispersing 16.72g (0.1 mol) of D-p-hydroxyphenylglycine in 128g of methanol solvent, adding 17.1g of solid acid catalyst, heating and refluxing at 80 ℃ for reaction for 3 hours, fully esterifying suspended D-p-hydroxyphenylglycine powder, dissolving, filtering while the solid acid catalyst is hot, washing the solid acid catalyst with methanol, merging the washing liquid into the reaction liquid, and then distilling to recover the methanol solvent in the reaction liquid;
(3) Separation of D-p-hydroxyphenylglycine methyl ester
Cooling the reaction solution to room temperature, further cooling and crystallizing at 5 ℃, filtering and separating out the separated crystals, washing the crystals with methanol and then airing the crystals to obtain 16.98g of D-p-hydroxyphenylglycine methyl ester crystals, wherein the yield of the product is 93.71%, and the purity of the product is 99.5% measured by a liquid chromatography method.
Example 5
A method for preparing amoxicillin through a catalytic method comprises the following steps:
(1) Preparation of solid acid catalyst
Crushing straw, sieving with a 100-mesh sieve, adding 10g of straw powder into 100mL of 10wt% ZrO (NO 3)2 solution, adding 1mL of polyethylene glycol 400, stirring at room temperature for 1h, drying in a 100 ℃ oven, and calcining at 450 ℃ for 3h in a nitrogen atmosphere to obtain a zirconium-containing biochar material;
Uniformly mixing 1g of solid ammonium phosphomolybdate and 10g of zirconium-containing biochar material, then placing the mixture in a muffle furnace, roasting the mixture at 500 ℃ for 5 hours, and cooling the mixture to room temperature after roasting is finished to obtain the solid acid catalyst.
(2) Preparation of D-p-hydroxyphenylglycine methyl ester concentrate
Dispersing 16.72g (0.1 mol) of D-p-hydroxyphenylglycine in 128g of methanol solvent, adding 15.8g of solid acid catalyst, heating and refluxing at 80 ℃ for reaction for 3 hours, fully esterifying suspended D-p-hydroxyphenylglycine powder, dissolving, filtering while the solid acid catalyst is hot, washing the solid acid catalyst with methanol, merging the washing liquid into the reaction liquid, and then distilling and recovering the methanol solvent in the reaction liquid to obtain the D-p-hydroxyphenylglycine methyl ester concentrated solution.
(3) Preparation of amoxicillin crude product
21.63G (0.1 mol) of 6-APA is added into 5wt% ammonia water, stirred and dissolved, and then the D-p-hydroxyphenylglycine methyl ester concentrated solution obtained in the step (2) and 30g of immobilized penicillin acylase are added into the ammonia water for enzyme catalysis synthesis reaction, wherein the specific conditions of the enzyme catalysis synthesis reaction are as follows: and (3) regulating the reaction pH to 6.20 by using 5wt% ammonia water at 20 ℃ and reacting for 90min to obtain an amoxicillin crude product.
(4) Preparation of amoxicillin finished product
Separating the immobilized penicillin acylase in the amoxicillin crude product, then adding 20% hydrochloric acid, dissolving the crude product, then adding 5wt% ammonia water into the crude product dissolving liquid, adjusting the pH value to 5.00, growing the crystal for 100min, centrifuging, washing and drying after the crystal growth is finished, thus obtaining 37.90g of amoxicillin finished product, and the amoxicillin yield is 90.37%.
Example 6
A method for preparing amoxicillin through a catalytic method comprises the following steps:
(1) Preparation of solid acid catalyst
Crushing straw, sieving with a 100-mesh sieve, adding 10g of straw powder into 150mL of 10wt% ZrO (NO 3)2 solution, adding 2mL of polyethylene glycol 400, stirring at room temperature for 1h, drying in a 100 ℃ oven, and calcining at 400 ℃ for 6h in a nitrogen atmosphere to obtain a zirconium-containing biochar material;
Uniformly mixing 1.5g of solid ammonium phosphomolybdate and 10g of zirconium-containing biochar material, then placing the mixture in a muffle furnace, roasting the mixture at 600 ℃ for 3 hours, and cooling the mixture to room temperature after roasting is finished to obtain the solid acid catalyst.
(2) Preparation of D-p-hydroxyphenylglycine methyl ester concentrate
Dispersing 16.72g (0.1 mol) of D-p-hydroxyphenylglycine in 128g of methanol solvent, adding 17.1g of solid acid catalyst, heating and refluxing at 80 ℃ for reaction for 3 hours, fully esterifying suspended D-p-hydroxyphenylglycine powder, dissolving, filtering while the solid acid catalyst is hot, washing the solid acid catalyst with methanol, merging the washing liquid into the reaction liquid, and then distilling and recovering the methanol solvent in the reaction liquid to obtain the D-p-hydroxyphenylglycine methyl ester concentrated solution.
(3) Preparation of amoxicillin crude product
21.63G (0.1 mol) of 6-APA is added into 5wt% ammonia water, stirred and dissolved, and then the D-p-hydroxyphenylglycine methyl ester concentrated solution obtained in the step (2) and 35g of immobilized penicillin acylase are added into the ammonia water for enzyme catalysis synthesis reaction, wherein the specific conditions of the enzyme catalysis synthesis reaction are as follows: and (3) regulating the reaction pH to 6.20 by using 5wt% ammonia water at 20 ℃ and reacting for 90min to obtain an amoxicillin crude product.
(4) Preparation of amoxicillin finished product
Separating the immobilized penicillin acylase in the amoxicillin crude product, then adding 20% hydrochloric acid, dissolving the crude product, then adding 5wt% ammonia water into the crude product dissolving liquid, adjusting the pH value to 5.0, growing the crystal for 100min, centrifuging, washing and drying after the crystal growth is finished, thus obtaining 38.24g of amoxicillin finished product, and the amoxicillin yield is 91.18%.
Comparative example 1
The preparation method of the D-p-hydroxyphenylglycine methyl ester comprises the following steps:
(1) Preparation of solid acid catalyst
Crushing straw, sieving with a 100-mesh sieve, adding 10g of straw powder into 100mL of deionized water, adding 1.5mL of polyethylene glycol 400, stirring at room temperature for 1h, drying in a 100 ℃ oven, and calcining at 500 ℃ for 3h in a nitrogen atmosphere to obtain a zirconium-containing biochar material;
Uniformly mixing 2g of solid ammonium phosphomolybdate and 10g of zirconium-containing biochar material, then placing the mixture in a muffle furnace, roasting the mixture at 600 ℃ for 3 hours, and cooling the mixture to room temperature after roasting is finished to obtain the solid acid catalyst.
(2) Preparation of D-p-hydroxyphenylglycine methyl ester
Dispersing 16.72g (0.1 mol) of D-p-hydroxyphenylglycine in 128g of methanol solvent, adding 18.6g of solid acid catalyst, heating and refluxing at 80 ℃ for reaction for 3 hours, fully esterifying suspended D-p-hydroxyphenylglycine powder, dissolving, filtering while the solid acid catalyst is hot, washing the solid acid catalyst with methanol, merging the washing liquid into the reaction liquid, and then distilling to recover the methanol solvent in the reaction liquid;
(3) Separation of D-p-hydroxyphenylglycine methyl ester
Cooling the reaction solution to room temperature, further cooling and crystallizing at 5 ℃, filtering and separating out the separated crystals, washing the crystals with methanol and then airing the crystals to obtain 15.97g of D-p-hydroxyphenylglycine methyl ester crystals, wherein the yield of the product is 88.13%, and the purity of the product is 99.4% measured by a liquid chromatography method.
In this comparative example, no Zr element was introduced as compared with example 3.
Comparative example 2
The preparation method of the D-p-hydroxyphenylglycine methyl ester comprises the following steps:
(1) Preparation of solid acid catalyst
Crushing straw, sieving with a 100-mesh sieve, adding 10g of straw powder into 100mL of 10wt% ZrO (NO 3)2 solution, stirring for 1h at room temperature, drying in a 100 ℃ oven, and calcining for 3h at 500 ℃ in a nitrogen atmosphere to obtain a zirconium-containing biochar material;
Uniformly mixing 2g of solid ammonium phosphomolybdate and 10g of zirconium-containing biochar material, then placing the mixture in a muffle furnace, roasting the mixture at 600 ℃ for 3 hours, and cooling the mixture to room temperature after roasting is finished to obtain the solid acid catalyst.
(2) Preparation of D-p-hydroxyphenylglycine methyl ester
Dispersing 16.72g (0.1 mol) of D-p-hydroxyphenylglycine in 128g of methanol solvent, adding 18.6g of solid acid catalyst, heating and refluxing at 80 ℃ for reaction for 3 hours, fully esterifying suspended D-p-hydroxyphenylglycine powder, dissolving, filtering while the solid acid catalyst is hot, washing the solid acid catalyst with methanol, merging the washing liquid into the reaction liquid, and then distilling to recover the methanol solvent in the reaction liquid;
(3) Separation of D-p-hydroxyphenylglycine methyl ester
Cooling the reaction solution to room temperature, further cooling and crystallizing at 5 ℃, filtering and separating out the separated crystals, washing the crystals with methanol and then airing the crystals to obtain 15.16g of D-p-hydroxyphenylglycine methyl ester crystals, wherein the yield of the product is 83.66%, and the purity of the product is 99.5% measured by a liquid chromatography method.
In this comparative example, polyethylene glycol 400, a pore-forming agent, was not added as compared with example 3.
Comparative example 3
The preparation method of the D-p-hydroxyphenylglycine methyl ester comprises the following steps:
(1) Preparation of solid acid catalyst
Crushing straw, sieving with a 100-mesh sieve, adding 10g of straw powder into 100mL of 10wt% ZrO (NO 3)2 solution, adding 1.5mL of polyethylene glycol 400, stirring at room temperature for 1h, drying in a 100 ℃ oven, and calcining at 500 ℃ for 3h in a nitrogen atmosphere to obtain a zirconium-containing biochar material;
And uniformly mixing 2g of solid ammonium phosphate and 10g of zirconium-containing biochar material, then placing the mixture in a muffle furnace, roasting the mixture at 600 ℃ for 3 hours, and cooling the mixture to room temperature after roasting is finished to obtain the solid acid catalyst.
(2) Preparation of D-p-hydroxyphenylglycine methyl ester
Dispersing 16.72g (0.1 mol) of D-p-hydroxyphenylglycine in 128g of methanol solvent, adding 18.6g of solid acid catalyst, heating and refluxing at 80 ℃ for reaction for 3 hours, fully esterifying suspended D-p-hydroxyphenylglycine powder, dissolving, filtering while the solid acid catalyst is hot, washing the solid acid catalyst with methanol, merging the washing liquid into the reaction liquid, and then distilling to recover the methanol solvent in the reaction liquid;
(3) Separation of D-p-hydroxyphenylglycine methyl ester
Cooling the reaction solution to room temperature, further cooling and crystallizing at 5 ℃, filtering and separating out the separated crystals, washing the crystals with methanol and then airing the crystals to obtain 16.63g of D-p-hydroxyphenylglycine methyl ester crystals, wherein the yield of the product is 91.78%, and the purity of the product is 99.5% measured by a liquid chromatography method.
In this comparative example, ammonium phosphomolybdate was replaced with ammonium phosphate as compared with example 3.
In order to examine the effect of recycling the catalyst, the solid acid catalyst used in example 3 was washed with methanol, dried and used for the next reaction, and the catalyst used for the first time was recorded as the first time, and the recycling result is shown in the following table:
| Number of times | Yield of D-p-hydroxyphenylglycine methyl ester (%) |
| 1 St time | 94.32 |
| 2 Nd time | 94.06 |
| 3 Rd time | 93.87 |
| Fourth time | 93.35 |
| 5 Th time | 91.21 |
Finally, it should be noted that: the above examples are not intended to limit the present invention in any way. Modifications and improvements will readily occur to those skilled in the art upon the basis of the present invention. Accordingly, any modification or improvement made without departing from the spirit of the invention is within the scope of the invention as claimed.
Claims (10)
1. The method for preparing amoxicillin through catalytic method is characterized by comprising the following steps:
S1, adding D-p-hydroxyphenylglycine, methanol and a solid acid catalyst into a reaction bottle for reaction, filtering to recover the solid acid catalyst after the reaction is finished, and distilling at normal pressure to recover the methanol to obtain D-p-hydroxyphenylglycine methyl ester concentrate;
s2, adding 6-APA into ammonia water, stirring and dissolving, and then adding D-p-hydroxyphenylglycine methyl ester concentrate and immobilized penicillin acylase into the solution to perform enzyme catalytic synthesis reaction;
S3, after the reaction is finished, separating the immobilized penicillin acylase, adding hydrochloric acid, dissolving the crude product, then adding ammonia water into the crude product solution, adjusting the pH value to be 4.8-5.5, growing crystals for 95-115min, and after the crystal growth is finished, centrifuging, washing and drying to obtain the amoxicillin finished product.
2. The method for preparing amoxicillin directly by catalytic method according to claim 1, wherein in step S1, the preparation method of the solid acid catalyst is as follows:
(1) Crushing straw, adding the crushed straw into ZrO (NO 3)2 solution, adding polyethylene glycol, stirring at room temperature for 1-2h, drying, and calcining at 400-600 ℃ for 3-6h in nitrogen atmosphere to obtain a zirconium-containing biochar material;
(2) And uniformly mixing solid ammonium phosphomolybdate and a zirconium-containing biochar material, then placing the mixture in a muffle furnace, roasting the mixture at 450-600 ℃ for 3-6 hours, and cooling the mixture to room temperature after roasting is finished to obtain the solid acid catalyst.
3. The method for preparing amoxicillin directly by a catalytic method according to claim 2, wherein in the step (1), the mass-volume ratio of straw, zrO (NO 3)2 solution and polyethylene glycol is 1g:10-15ml:0.1-0.2ml, and the mass fraction of ZrO (NO 3)2 solution is 10-15%).
4. The method for preparing amoxicillin directly by a catalytic method according to claim 2, wherein in the step (2), the mass ratio of the solid ammonium phosphomolybdate to the zirconium-containing biochar material is 1-3:10.
5. The method for preparing amoxicillin directly by a catalytic method according to claim 1, wherein in step S1, the molar ratio of D-p-hydroxyphenylglycine to methanol is 1:35-45.
6. The method for preparing amoxicillin directly by a catalytic method according to claim 1, wherein in step S1, the mass ratio of D-p-hydroxyphenylglycine to solid acid catalyst is 1:0.5-3.0.
7. The method for preparing amoxicillin directly by a catalytic method according to claim 1, wherein in step S1, the reaction temperature is 60-100 ℃ and the reaction time is 4-8h.
8. The method for preparing amoxicillin directly by a catalytic method according to claim 1, wherein the molar ratio of D-p-hydroxyphenylglycine to 6-APA is 1:0.8-1.1.
9. The method for preparing amoxicillin directly by a catalytic method according to claim 1, wherein in step S2, the mass ratio of 6-APA to immobilized penicillin acylase is 1:0.5-2.0.
10. The method for preparing amoxicillin directly by catalytic method according to claim 1, wherein in step S2, the specific process of the enzymatic synthesis reaction is as follows: at 13-25 ℃, ammonia water with the weight percent of 5-8% is used for adjusting the pH of the reaction to 6.15-6.35, and the reaction lasts for 40-220min.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202410148786.5A CN118005651A (en) | 2024-02-02 | 2024-02-02 | Method for preparing amoxicillin through catalytic method |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202410148786.5A CN118005651A (en) | 2024-02-02 | 2024-02-02 | Method for preparing amoxicillin through catalytic method |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN118005651A true CN118005651A (en) | 2024-05-10 |
Family
ID=90943937
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202410148786.5A Pending CN118005651A (en) | 2024-02-02 | 2024-02-02 | Method for preparing amoxicillin through catalytic method |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN118005651A (en) |
-
2024
- 2024-02-02 CN CN202410148786.5A patent/CN118005651A/en active Pending
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN110003151B (en) | Process for the preparation of furanonic acids | |
| CN104356146B (en) | A kind of preparation method of cefotiam chloride | |
| CN112592356A (en) | Method for synthesizing lornoxicam | |
| CN112645912B (en) | Preparation method of high-purity M2 crystal form meclofenol sodium | |
| CN109628541A (en) | A kind of method of enzymatic clarification penicillin V salt | |
| CN111393331B (en) | Preparation method of glycocyamine | |
| CN118005651A (en) | Method for preparing amoxicillin through catalytic method | |
| CN110668977B (en) | Preparation process of lauroyl arginine ethyl ester hydrochloride | |
| CN101125878B (en) | Method for preparing steroid muscle relaxants rocuronium bromide | |
| CN108084213B (en) | Preparation method of cefazedone sodium compound | |
| CN106636241B (en) | Method for preparing esmollin intermediate by enzyme method | |
| CN113025679B (en) | Enzymatic preparation process of cefcapene precursor acid of t-butyloxycarbonyl | |
| CN112110926B (en) | Method for preparing tebipenem pivoxil | |
| CN112552316B (en) | Preparation method of cefotetan disodium raw material medicine | |
| CN115232107A (en) | Preparation method of high-purity Voranolan fumarate | |
| CN110586187B (en) | Supported phosphotungstic acid catalyst, and preparation method and application thereof | |
| CN114436930A (en) | Synthesis method of Boc-L-hydroxyproline | |
| CN102153460B (en) | Method for preparing glycollic acid by glycol | |
| CN111153953A (en) | Efficient synthesis method of nicotinamide riboside chloride | |
| CN111019980B (en) | Biosynthesis method of mono-p-nitrobenzyl malonate | |
| CN115677523B (en) | Preparation method of 2, 6-difluorobenzamide | |
| CN108623598A (en) | A kind of preparation method of Imipenem intermediate and Imipenem | |
| CN103880899A (en) | Demethyl azithromycin synthesis method | |
| CN115677456B (en) | Preparation method of cannabidiol | |
| CN110563750B (en) | Synthesis method of cefazedone |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |