CN114349769B - Preparation method of cefcapene pivoxil E-isomer - Google Patents
Preparation method of cefcapene pivoxil E-isomer Download PDFInfo
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- CN114349769B CN114349769B CN202111600274.0A CN202111600274A CN114349769B CN 114349769 B CN114349769 B CN 114349769B CN 202111600274 A CN202111600274 A CN 202111600274A CN 114349769 B CN114349769 B CN 114349769B
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- WVPAABNYMHNFJG-QDVBXLKVSA-N 2,2-dimethylpropanoyloxymethyl (6r,7r)-7-[[(z)-2-(2-amino-1,3-thiazol-4-yl)pent-2-enoyl]amino]-3-(carbamoyloxymethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate Chemical compound N([C@@H]1C(N2C(=C(COC(N)=O)CS[C@@H]21)C(=O)OCOC(=O)C(C)(C)C)=O)C(=O)\C(=C/CC)C1=CSC(N)=N1 WVPAABNYMHNFJG-QDVBXLKVSA-N 0.000 title claims abstract description 106
- 229950004627 cefcapene pivoxil Drugs 0.000 title claims abstract description 105
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- 239000002994 raw material Substances 0.000 claims abstract description 25
- 238000010438 heat treatment Methods 0.000 claims abstract description 24
- 238000010992 reflux Methods 0.000 claims abstract description 19
- 229910017053 inorganic salt Inorganic materials 0.000 claims abstract description 6
- 238000004321 preservation Methods 0.000 claims abstract description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 57
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 53
- 239000000243 solution Substances 0.000 claims description 44
- 239000012265 solid product Substances 0.000 claims description 26
- 239000007864 aqueous solution Substances 0.000 claims description 20
- 239000012074 organic phase Substances 0.000 claims description 18
- 239000003960 organic solvent Substances 0.000 claims description 18
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 15
- 238000000034 method Methods 0.000 claims description 14
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 13
- 238000000746 purification Methods 0.000 claims description 13
- 239000012071 phase Substances 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 11
- 238000000605 extraction Methods 0.000 claims description 10
- -1 cefcapene ester Chemical class 0.000 claims description 9
- 239000012043 crude product Substances 0.000 claims description 9
- 238000000926 separation method Methods 0.000 claims description 8
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- 238000004440 column chromatography Methods 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 5
- 238000002156 mixing Methods 0.000 claims description 4
- 239000012266 salt solution Substances 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 17
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- 238000003756 stirring Methods 0.000 description 27
- 238000001035 drying Methods 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- 238000006243 chemical reaction Methods 0.000 description 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 229940079593 drug Drugs 0.000 description 12
- 239000007788 liquid Substances 0.000 description 11
- 239000000047 product Substances 0.000 description 11
- 239000007787 solid Substances 0.000 description 10
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 7
- 239000012535 impurity Substances 0.000 description 7
- 239000000741 silica gel Substances 0.000 description 7
- 229910002027 silica gel Inorganic materials 0.000 description 7
- 238000004809 thin layer chromatography Methods 0.000 description 7
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 238000005191 phase separation Methods 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- 238000004090 dissolution Methods 0.000 description 5
- 238000006317 isomerization reaction Methods 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 238000012544 monitoring process Methods 0.000 description 5
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- 230000000630 rising effect Effects 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 239000012295 chemical reaction liquid Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 239000012670 alkaline solution Substances 0.000 description 2
- 239000002274 desiccant Substances 0.000 description 2
- 238000004811 liquid chromatography Methods 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- BQIMPGFMMOZASS-CLZZGJSISA-N (6r,7r)-7-amino-3-(hydroxymethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid Chemical compound S1CC(CO)=C(C(O)=O)N2C(=O)[C@@H](N)[C@H]21 BQIMPGFMMOZASS-CLZZGJSISA-N 0.000 description 1
- DIOSHTLNZVXJOF-UHFFFAOYSA-N 2,5-bis(3-oxobutanoylamino)benzenesulfonic acid Chemical compound CC(=O)CC(=O)NC1=CC=C(NC(=O)CC(C)=O)C(S(O)(=O)=O)=C1 DIOSHTLNZVXJOF-UHFFFAOYSA-N 0.000 description 1
- XIXNSLABECPEMI-UHFFFAOYSA-N 2-[2-[(2-methylpropan-2-yl)oxycarbonylamino]-1,3-thiazol-4-yl]pent-2-enoic acid Chemical group CCC=C(C(O)=O)C1=CSC(NC(=O)OC(C)(C)C)=N1 XIXNSLABECPEMI-UHFFFAOYSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 206010061695 Biliary tract infection Diseases 0.000 description 1
- 206010018612 Gonorrhoea Diseases 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical group [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- 206010033078 Otitis media Diseases 0.000 description 1
- 206010035664 Pneumonia Diseases 0.000 description 1
- 206010037596 Pyelonephritis Diseases 0.000 description 1
- 206010057190 Respiratory tract infections Diseases 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 1
- 150000008041 alkali metal carbonates Chemical class 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 206010006451 bronchitis Diseases 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 208000003167 cholangitis Diseases 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 201000003146 cystitis Diseases 0.000 description 1
- 208000001786 gonorrhea Diseases 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 229940124588 oral cephalosporin Drugs 0.000 description 1
- LARRNBYMHFLZKK-UHFFFAOYSA-N pent-3-enamide Chemical compound CC=CCC(N)=O LARRNBYMHFLZKK-UHFFFAOYSA-N 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 239000013558 reference substance Substances 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 201000009890 sinusitis Diseases 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 206010044008 tonsillitis Diseases 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
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
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Cephalosporin Compounds (AREA)
Abstract
The invention relates to the technical field of medicine synthesis, in particular to a preparation method of cefcapene pivoxil E-type isomer. The preparation method provided by the invention is characterized in that an organic solution of a cefcapene pivoxil raw material is heated and refluxed to obtain a cefcapene pivoxil E isomer, the cefcapene pivoxil raw material comprises cefcapene pivoxil and/or inorganic salt of the cefcapene pivoxil, and the heat preservation temperature of the heated and refluxed cefcapene pivoxil is more than or equal to 40 ℃. According to the preparation method provided by the invention, the cefcapene pivoxil E-isomer is successfully prepared by heating and refluxing the cefcapene pivoxil solution at the temperature of not less than 40 ℃, and the yield of the cefcapene pivoxil E-isomer is high.
Description
Technical Field
The invention relates to the technical field of medicine synthesis, in particular to a preparation method of cefcapene pivoxil E-type isomer.
Background
Cefcapene pivoxil hydrochloride (Cefcapene Pivoxil Hydrochloride), the chemical name of which is 7- [2- (2-amino-1, 3-thiazol-4-yl) pent-3-enamide ] -3- (carbamoyloxymethyl) -8-oxo-5-thio-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid 2, 2-dimethylpropionyloxymethyl ester hydrochloride, the chemical structure of which is shown in formula 1:
cefcapene pivoxil hydrochloride is a third generation oral cephalosporin antibiotic developed by the japanese salt wild company and marketed under the trade name Flomox for the first time in 1997. Pharmacological research results show that the cefcapene pivoxil hydrochloride has the characteristics of stronger antibacterial activity and small dosage compared with the traditional oral cefcapene pivoxil hydrochloride. Is mainly applicable to respiratory tract infection such as pneumonia, bronchitis, sphagitis, tonsillitis and the like caused by sensitive bacteria; otitis media; sinusitis; urinary tract infections such as gonorrhea, pyelonephritis, and cystitis; skin and skin tissue infections, etc.; biliary tract infection, and the like.
In the research and development process of new drugs, the quality of the drugs is an important standard for measuring the quality of the drugs, the content of active ingredients of the drugs is an important sign reflecting the purity of the drugs, and impurities in the drugs directly influence the curative effect of the drugs and possibly cause toxic and side effects. The impurities of the medicine refer to substances which exist in the medicine and have no therapeutic effect or influence on the stability and curative effect of the medicine and possibly have harm to human health. The presence of these substances not only affects the quality of the drug but also exposes problems that occur during production and storage. For safe and effective use of the drug, the quality standard of the drug has strict regulations on the purity of the active ingredient of the drug and the limit of impurities, and generally, more than 0.1% of the impurities of the drug should be identified and quantified by a selective method.
Cefcapene pivoxil hydrochloride is a high-purity sample obtained by taking mother nucleus D-7-ACA (hydroxymethyl-7-aminocephalosporanic acid) and BAPA (2- (2-tert-butoxycarbonyl aminothiazole-4-yl) -2-pentenoic acid) side chains as starting materials, obtaining a carboester precursor acid (BCN) through condensation and carbamation, and then esterifying and removing tert-butoxycarbonyl protecting groups. The cefcapene pivoxil E-isomer is a reaction byproduct generated in the production process of cefcapene pivoxil hydrochloride, is a key impurity in raw material medicines of cefcapene pivoxil hydrochloride, and is not introduced in the prior art at present.
Disclosure of Invention
In view of the above, the invention provides a preparation method of cefcapene pivoxil E isomer, and the preparation method can prepare the cefcapene pivoxil E isomer with high yield.
In order to achieve the above object, the present invention provides the following technical solutions:
the invention provides a preparation method of cefcapene pivoxil E-type isomer, which comprises the following steps:
and heating and refluxing an organic solution of a cefcapene pivoxil raw material to obtain a cefcapene pivoxil E isomer, wherein the cefcapene pivoxil raw material comprises cefcapene pivoxil and/or inorganic salt of cefcapene pivoxil, and the heat preservation temperature of the heating and refluxing is more than or equal to 40 ℃.
Preferably, the heat preservation temperature of the heating reflux is 40-60 ℃.
Preferably, the organic solution of the cefcapene pivoxil raw material comprises the cefcapene pivoxil raw material and an organic solvent, wherein the organic solvent comprises one or more of ethyl acetate, lower alcohol, dichloromethane and N, N-dimethylformamide.
Preferably, the concentration of the organic solution of the cefcapene pivoxil hydrochloride raw material is 0.1-0.125 g/mL.
Preferably, the method comprises the steps of heating and refluxing to obtain an isomerised solid product, wherein the isomerised solid product contains cefcapene pivoxil E-isomer, dissolving the isomerised solid product in an organic solvent to obtain an isomerised solid product organic solution, mixing and extracting an alkaline aqueous solution and the isomerised solid product organic solution, and taking an organic phase after extraction to obtain the cefcapene pivoxil E-isomer.
Preferably, the pH value of the alkaline aqueous solution is 6-8.
Preferably, the aqueous alkaline solution comprises an aqueous inorganic strong alkaline solution and/or an aqueous strong and weak acid solution.
Preferably, the ratio of the mass of the isomerized solid product to the volume of the organic solvent in the organic solution of the isomerized solid product is 1g (8-10) mL.
Preferably, the volume ratio of the organic solution and the alkaline aqueous solution of the isomerized solid product is (1.3-2): 1.
Preferably, the organic phase is cefcapene ester E-isomer crude product, and the method further comprises dissolving the cefcapene ester E-isomer crude product in a mobile phase for column chromatography separation and purification to obtain the cefcapene ester E-isomer, wherein the mobile phase is dichloromethane and methanol, and the volume ratio of the dichloromethane to the methanol is (20-40): 1.
The invention provides a preparation method of cefcapene pivoxil E-type isomer, which comprises the following steps: and heating and refluxing an organic solution of a cefcapene pivoxil raw material to obtain a cefcapene pivoxil E isomer, wherein the cefcapene pivoxil raw material comprises cefcapene pivoxil and/or inorganic salt of cefcapene pivoxil, and the heat preservation temperature of the heating and refluxing is more than or equal to 40 ℃. According to the preparation method provided by the invention, the cefcapene pivoxil E-isomer is successfully prepared by heating and refluxing the cefcapene pivoxil solution at the temperature of not less than 40 ℃, and the yield of the cefcapene pivoxil E-isomer is high. The preparation method provided by the invention is simple and effective, and the results of the examples show that the yield of the cefcapene pivoxil E isomer obtained by the preparation method provided by the invention is more than 50% and the purity is more than 90%. The preparation method provided by the invention can provide a qualified reference substance for the impurity research of the cefcapene pivoxil hydrochloride, and has great significance for the stable control in the production process of the cefcapene pivoxil hydrochloride.
Drawings
FIG. 1 is a HPLC chart of cefcapene pivoxil E isomer prepared in example 1 of the present invention.
Detailed Description
The invention provides a preparation method of cefcapene pivoxil E-type isomer, which comprises the following steps:
and heating and refluxing an organic solution of a cefcapene pivoxil raw material to obtain a cefcapene pivoxil E isomer, wherein the cefcapene pivoxil raw material comprises cefcapene pivoxil and/or inorganic salt of cefcapene pivoxil, and the heat preservation temperature of the heating and refluxing is more than or equal to 40 ℃.
In the present invention, the raw materials used are commercially available products well known to those skilled in the art unless specified otherwise.
In the present invention, the organic solution of the cefcapene pivoxil raw material preferably includes the cefcapene pivoxil raw material and an organic solvent (hereinafter referred to as a first organic solvent).
In the present invention, the cefcapene pivoxil raw material preferably comprises an inorganic salt of cefcapene pivoxil.
In a specific embodiment of the present invention, the cefcapene pivoxil raw material is specifically preferably cefcapene pivoxil hydrochloride.
In the present invention, the first organic solvent preferably includes one or more of ethyl acetate, lower alcohol, methylene chloride and N, N-dimethylformamide.
In the present invention, the lower alcohol preferably includes methanol and/or ethanol.
In a specific embodiment of the present invention, the first organic solvent is preferably methanol.
In the present invention, the ratio of the mass of the cefcapene pivoxil hydrochloride raw material to the volume of the first organic solvent is preferably 1g (8-10) mL, more preferably 1g (8.5-9.5) mL.
The cefcapene pivoxil raw material is first dissolved in the first organic solvent to obtain an organic solution of the cefcapene pivoxil raw material.
In the present invention, the temperature of the first dissolution is preferably 20 to 25 ℃.
In the present invention, the first dissolution is preferably performed under stirring, and there is no particular requirement for the specific implementation of the stirring.
In the present invention, the heat retaining temperature of the heating reflux is preferably 40 to 60 ℃, more preferably 50 ℃.
In the present invention, the heating reflux is preferably performed under stirring conditions, and the present invention has no particular requirement for the specific implementation of the stirring.
In the process of heating reflux, the cefcapene pivoxil in the cefcapene pivoxil solution is heated in the solution to generate isomerization reaction to obtain the cefcapene pivoxil E-type isomer, and the reaction equation is shown in the formula 2:
the isomerization reaction is preferably detected by thin layer chromatography and/or high-phase liquid chromatography, and the reaction is ended when the mass white rice content of the cefcapene pivoxil E-isomer product in the isomerization reaction liquid is detected not to be increased by the thin layer chromatography and/or the high-phase liquid chromatography.
In a specific embodiment of the present invention, the heating reflux is performed for 3 to 4 hours.
In the present invention, the method further preferably includes dissolving (hereinafter referred to as a second dissolution) the isomerized solid product in an organic solvent (hereinafter referred to as a second organic solvent) to obtain an isomerized solid product organic solution, mixing and extracting an alkaline aqueous solution and the isomerized solid product organic solution, and taking an organic phase after extraction to obtain the cefcapene pivoxil E isomer.
In the present invention, it is preferable that the isomerization reaction liquid is obtained after the heating and refluxing, and the present invention preferably further comprises concentrating the isomerization reaction liquid under reduced pressure to obtain the isomerized solid product.
In the present invention, the temperature of the reduced pressure concentration is preferably 40 to 45 ℃.
The invention has no special requirements on the specific implementation process of the reduced pressure concentration.
In the present invention, the isomerized solid product is a yellow solid.
In the present invention, the second organic solvent preferably includes one or more of ethyl acetate, methylene chloride, ethanol, and N, N-dimethylformamide.
In the present invention, the second dissolution is preferably under stirring, and the present invention has no special requirement for the specific implementation of the stirring.
In the present invention, the ratio of the mass of the isomerized solid product to the volume of the second organic solvent in the isomerized solid product organic solution is preferably 1g (8 to 10) mL, more preferably 1g (8.5 to 9) mL.
In the present invention, the alkaline aqueous solution preferably includes an inorganic strong alkaline aqueous solution and/or a strong alkali weak acid aqueous solution.
In the present invention, the aqueous alkali weak acid salt solution is preferably an aqueous alkali metal carbonate solution and/or an aqueous alkali metal bicarbonate solution.
In a specific embodiment of the present invention, the alkaline aqueous solution is specifically preferably an aqueous sodium hydroxide solution or an aqueous sodium bicarbonate solution.
In the present invention, the pH of the alkaline aqueous solution is preferably 6 to 8, more preferably 6.5 to 7.5.
In the present invention, the volume ratio of the isomerized solid product organic solution to the basic aqueous solution is preferably (1.3 to 2): 1, more preferably (1.5 to 1.95): 1.
In the present invention, the mixing is preferably: adding water into the organic solution of the isomerized solid product to form an initial organic phase and a water phase, and dropwise adding a pH reagent into the initial water phase to obtain an alkaline aqueous solution to form an initial organic phase and a water phase extraction phase, wherein the pH reagent is preferably a high-concentration alkaline aqueous solution, and the mass percentage of the high-concentration alkaline aqueous solution is preferably 7-10 percent. The solute component in the high-concentration alkaline aqueous solution is the same as the solute component in the alkaline aqueous solution.
In the present invention, the extraction is preferably performed under stirring.
In the present invention, the extraction time is preferably 30 to 35 minutes.
In the present invention, during the extraction process, water-soluble impurities in the isomerized solid product organic solution pass from the organic phase to the aqueous phase.
In the present invention, the extraction system is obtained after the extraction, and the present invention preferably performs a post-treatment on the extraction system to obtain an organic phase. In the present invention, the post-treatment preferably includes: sequentially separating organic phase, drying organic phase, solid-liquid separating and concentrating under reduced pressure. The organic phase separation is not particularly required in the present invention, and in the present invention, the organic phase is preferably mixed with a drying agent, and in the present invention, the drying agent is preferably anhydrous magnesium sulfate. The present invention has no special requirement for the amount of the dry reagent. In the present invention, the solid-liquid separation preferably separates the dried organic phase from the dried reagent. In the present invention, the solid-liquid separation is preferably filtration. The dried organic phase is preferably concentrated under reduced pressure, and the solvent in the organic phase is preferably removed by concentration. In the present invention, the temperature of the reduced pressure concentration is preferably 35 to 40 ℃. The invention has no special requirements on the specific implementation process of the reduced pressure concentration.
In the present invention, the organic phase is preferably a crude cefcapene pivoxil E isomer, and after the organic phase is obtained, the present invention preferably further comprises dissolving (hereinafter referred to as third dissolving) the crude cefcapene pivoxil E isomer in a mobile phase, and performing column chromatography separation and purification to obtain the cefcapene pivoxil E isomer, wherein the mobile phase is dichloromethane and methanol, and the volume ratio of dichloromethane to methanol is (20-40): 1.
The present invention has no special requirement for the third dissolution.
In the present invention, the volume ratio of methylene chloride to methanol is preferably (25 to 35): 1.
In the present invention, the column chromatography separation and purification is preferably performed using a silica gel column.
In the present invention, the silica gel column is preferably packed by a wet method.
The invention adopts column chromatography separation and purification, and uses the difference of retention time of cefcapene pivoxil and cefcapene pivoxil E isomer to separate and purify.
In the invention, the purification liquid is obtained after the separation and purification by column chromatography, and the cefcapene pivoxil E isomer is obtained by carrying out post-treatment on the purification liquid with the preference of the invention.
In the present invention, the post-treatment preferably includes: concentrating under reduced pressure and drying. The solvent in the purified liquid is preferably removed by concentrating under reduced pressure, the solvent in the purified solid product after concentrating under reduced pressure is preferably further removed by drying, in the present invention, the drying temperature is preferably 30-35 ℃, and the drying time is not particularly required, and the weight is constant.
The technical solutions of the present invention will be clearly and completely described in the following in connection with the embodiments of the present invention.
Example 1
Adding 10g of cefcapene pivoxil hydrochloride and 100mL of methanol into a 500mL flask at 20 ℃, stirring until the system is dissolved, heating to 50 ℃ in water bath, stirring for 3-4 h, stopping the reaction after monitoring that the content of the cefcapene pivoxil E-type isomer is not rising any more through thin layer chromatography and HPLC, concentrating the reaction solution at 40 ℃ under reduced pressure until the yellow solid is obtained, dissolving the yellow solid in 100mL of ethyl acetate, stirring uniformly, adding 50mL of pure water, dripping 10% sodium hydroxide solution to adjust the pH to be=6, stirring for 30min, layering, drying anhydrous sodium sulfate, filtering, concentrating to dryness at 30-45 ℃ under reduced pressure to obtain a crude product of the cefcapene pivoxil E-type isomer; wet packing silica gel column with dichloromethane: the mobile phase separation and purification sample of methanol=35:1 (v: v), the concentration under reduced pressure and the drying of the material at 30 ℃ gave 6.0g of dry product, the yield of cefcapene pivoxil E isomer was 60%, the purity of the product was 92.4%, the liquid chromatogram was as shown in fig. 1, and the retention time of cefcapene pivoxil E isomer was 34.055min.
Example 2
Adding 10g of cefcapene pivoxil hydrochloride and 90mL of methanol into a 500mL flask at 20 ℃, stirring until the system is dissolved, heating to 50 ℃ in water bath, stirring for 3-4 h, stopping the reaction after monitoring that the content of the cefcapene pivoxil E-type isomer is not rising any more through thin layer chromatography and HPLC, concentrating the reaction solution at 40 ℃ under reduced pressure until the yellow solid is obtained, dissolving the yellow solid in 90mL of dichloromethane, stirring uniformly, adding 50mL of pure water, dripping 10% sodium hydroxide solution to adjust the pH to be=6, stirring for 30min, layering, drying with anhydrous sodium sulfate, filtering, concentrating to dryness at 30-45 ℃ under reduced pressure to obtain a crude product of the cefcapene pivoxil E-type isomer; wet packing silica gel column with dichloromethane: the mobile phase separation and purification sample of methanol=40:1 (v: v), concentration under reduced pressure and drying of the material at 30 ℃ gave 5.8g of dry product, 58% yield of cefcapene pivoxil E isomer, 91.8% purity of product, liquid chromatogram similar to fig. 1.
Example 3
Adding 10g of cefcapene pivoxil hydrochloride and 90mL of methanol into a 500mL flask at 20 ℃, stirring until the system is dissolved, heating to 50 ℃ in water bath, stirring for 3-4 h, stopping the reaction after monitoring that the content of the cefcapene pivoxil E-type isomer is not rising any more through thin layer chromatography and HPLC, concentrating the reaction solution at 40 ℃ under reduced pressure until the yellow solid is obtained, dissolving the yellow solid in 80mL of dichloromethane, stirring uniformly, adding 50mL of pure water, dripping 7% sodium bicarbonate solution to adjust the pH to 8, stirring for 30min, layering, drying with anhydrous sodium sulfate, filtering, concentrating to dryness at 30-45 ℃ under reduced pressure to obtain a crude product of the cefcapene pivoxil E-type isomer; wet packing silica gel column with dichloromethane: the mobile phase separation and purification sample of methanol=30:1 (v: v), concentration under reduced pressure and drying of the material at 30 ℃ gave 5.1g of dry product, with a yield of cefcapene pivoxil E isomer of 51%, a purity of 90.4% and a liquid chromatogram similar to that of fig. 1.
Example 4
Adding 10g of cefcapene pivoxil hydrochloride and 100mL of methanol into a 500mL flask at 20 ℃, stirring until the system is dissolved, heating to 50 ℃ in water bath, stirring for 3-4 h, stopping the reaction after monitoring that the content of the cefcapene pivoxil E-type isomer is not rising any more through thin layer chromatography and HPLC, concentrating the reaction solution at 40 ℃ under reduced pressure until the yellow solid is dissolved in 100mL of ethanol, stirring uniformly, adding 50mL of pure water, dripping 7% sodium bicarbonate solution to adjust the pH to be 7, stirring for 30min, layering, drying with anhydrous sodium sulfate, filtering, concentrating to dryness at 30-45 ℃ under reduced pressure to obtain a crude product of the cefcapene pivoxil E-type isomer; wet packing silica gel column with dichloromethane: the mobile phase separation and purification sample of methanol=40:1 (v: v), concentration under reduced pressure and drying of the material at 30 ℃ gave 5.3g of dry product, 53% yield of cefcapene pivoxil E isomer, 93.1% purity of product, liquid chromatogram similar to fig. 1.
Example 5
Adding 10g of cefcapene pivoxil hydrochloride and 100mL of methanol into a 500mL flask at 20 ℃, stirring until the system is dissolved, heating to 50 ℃ in a water bath, stirring for 3-4 h, stopping the reaction by monitoring that the content of the cefcapene pivoxil E-type isomer is not rising any more through thin layer chromatography and HPLC, concentrating the reaction solution to yellow solid under reduced pressure at 40 ℃, dissolving the yellow solid in 100mLN, stirring uniformly after N-dimethylformamide, adding 50mL of pure water, dripping 10% sodium hydroxide solution to adjust the pH to 7, stirring for 30min, layering, drying with anhydrous sodium sulfate, filtering, concentrating to dryness under reduced pressure at 30-45 ℃ to obtain a crude product of the cefcapene pivoxil E-type isomer; wet packing silica gel column with dichloromethane: the mobile phase separation and purification sample of methanol=25:1 (v: v), concentration under reduced pressure and drying of the material at 30 ℃ gave 5.7g of dry product, 57% yield of cefcapene pivoxil E isomer, 90.7% purity of product, liquid chromatogram similar to fig. 1.
The foregoing is merely a preferred embodiment of the present invention and it should be noted that modifications and adaptations to those skilled in the art may be made without departing from the principles of the present invention, which are intended to be comprehended within the scope of the present invention.
Claims (5)
1. The preparation method of the cefcapene pivoxil E isomer is characterized by comprising the following steps:
heating and refluxing an organic solution of a cefcapene pivoxil raw material to obtain a cefcapene pivoxil E isomer, wherein the cefcapene pivoxil raw material is cefcapene pivoxil and/or inorganic salt of cefcapene pivoxil, and the heat preservation temperature of the heating and refluxing is 40-60 ℃; the organic solution of the cefcapene pivoxil raw material is prepared from the cefcapene pivoxil raw material and an organic solvent, wherein the organic solvent is one or more of ethyl acetate, low-carbon alcohol, methylene dichloride and N, N-dimethylformamide;
the method comprises the steps of heating and refluxing to obtain an isomerized solid product, wherein the isomerized solid product contains cefcapene pivoxil E isomer, the heating and refluxing step further comprises the steps of dissolving the isomerized solid product in an organic solvent to obtain an isomerized solid product organic solution, and the ratio of the mass of the isomerized solid product to the volume of the organic solvent in the isomerized solid product organic solution is 1g (8-10) mL; mixing and extracting an alkaline aqueous solution and the organic solution of the isomerized solid product, and taking an organic phase after extraction; the organic phase is cefcapene ester E-type isomer crude product, the method further comprises the steps of dissolving the cefcapene ester E-type isomer crude product in a mobile phase, and performing column chromatography separation and purification to obtain the cefcapene ester E-type isomer, wherein the mobile phase is dichloromethane and methanol, and the volume ratio of the dichloromethane to the methanol is (20-40): 1.
2. The preparation method of claim 1, wherein the concentration of the organic solution of the cefcapene pivoxil hydrochloride raw material is 0.1-0.125 g/mL.
3. The method according to claim 1, wherein the pH of the alkaline aqueous solution is 6 to 8.
4. The method according to claim 1, wherein the alkaline aqueous solution is an inorganic strong alkaline aqueous solution and/or a strong base weak acid aqueous salt solution.
5. The method according to claim 1, wherein the volume ratio of the organic solution to the alkaline aqueous solution is 1.3-2.
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Denomination of invention: A preparation method for the E-type isomer of ceftriaxone Granted publication date: 20230822 Pledgee: Agricultural Bank of China Limited Xiangyang High tech Zone Branch Pledgor: Hubei Lingsheng Pharmaceutical Co.,Ltd. Registration number: Y2024980002009 |
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