CN114349769A - Preparation method of cefcapene pivoxil E-type isomer - Google Patents
Preparation method of cefcapene pivoxil E-type isomer Download PDFInfo
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- CN114349769A CN114349769A CN202111600274.0A CN202111600274A CN114349769A CN 114349769 A CN114349769 A CN 114349769A CN 202111600274 A CN202111600274 A CN 202111600274A CN 114349769 A CN114349769 A CN 114349769A
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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 114
- 229950004627 cefcapene pivoxil Drugs 0.000 title claims abstract description 112
- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- 238000010438 heat treatment Methods 0.000 claims abstract description 28
- 238000010992 reflux Methods 0.000 claims abstract description 23
- 239000002994 raw material Substances 0.000 claims abstract description 19
- 238000004321 preservation Methods 0.000 claims abstract description 9
- 229910017053 inorganic salt Inorganic materials 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 54
- 239000000243 solution Substances 0.000 claims description 39
- 239000012265 solid product Substances 0.000 claims description 28
- 239000007864 aqueous solution Substances 0.000 claims description 23
- 239000012074 organic phase Substances 0.000 claims description 20
- 238000000034 method Methods 0.000 claims description 17
- 239000003960 organic solvent Substances 0.000 claims description 17
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 15
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 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
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- 238000000746 purification Methods 0.000 claims description 7
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- 238000003756 stirring Methods 0.000 description 27
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- 238000001035 drying Methods 0.000 description 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 239000000047 product Substances 0.000 description 12
- 238000004128 high performance liquid chromatography Methods 0.000 description 11
- 239000007787 solid Substances 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- 238000006243 chemical reaction Methods 0.000 description 9
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- 239000007788 liquid Substances 0.000 description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 7
- 239000012295 chemical reaction liquid Substances 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
- 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
- 238000012544 monitoring process Methods 0.000 description 5
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- -1 2-amino-1, 3-thiazole-4-yl Chemical group 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000000463 material Substances 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
- 238000005034 decoration Methods 0.000 description 2
- 239000002274 desiccant Substances 0.000 description 2
- 238000004811 liquid chromatography Methods 0.000 description 2
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- 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
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 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
- 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
- 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
- 239000002585 base Substances 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 206010006451 bronchitis Diseases 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 230000021235 carbamoylation Effects 0.000 description 1
- HJJRIJDTIPFROI-NVKITGPLSA-N cefcapene Chemical compound N([C@@H]1C(N2C(=C(COC(N)=O)CS[C@@H]21)C(O)=O)=O)C(=O)\C(=C/CC)C1=CSC(N)=N1 HJJRIJDTIPFROI-NVKITGPLSA-N 0.000 description 1
- 229960002966 cefcapene Drugs 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
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 208000001786 gonorrhea Diseases 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 229940124588 oral cephalosporin Drugs 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
- 201000009890 sinusitis Diseases 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 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
- 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
Images
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
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- Cephalosporin Compounds (AREA)
Abstract
The invention relates to the technical field of drug synthesis, in particular to a preparation method of cefcapene pivoxil E-type isomer. The preparation method provided by the invention heats and reflows the organic solution of cefcapene pivoxil raw material to obtain the E-type isomer of cefcapene pivoxil, 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 reflowing is more than or equal to 40 ℃. The preparation method provided by the invention successfully prepares the cefcapene pivoxil E-type isomer by heating and refluxing the cefcapene pivoxil solution at the heat preservation temperature of more than or equal to 40 ℃, and the yield of the cefcapene pivoxil E-type isomer is high.
Description
Technical Field
The invention relates to the technical field of drug synthesis, in particular to a preparation method of cefcapene pivoxil E-type isomer.
Background
Cefcapene Pivoxil Hydrochloride (Cefcapene Pivoxil Hydrochloride) with the chemical name of 7- [2- (2-amino-1, 3-thiazole-4-yl) pent-3-enamido ] -3- (carbamoyloxymethyl) -8-oxo-5-thio-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid 2, 2-dimethylpropionyloxymethyl ester Hydrochloride and the chemical structure is shown as formula 1:
cefcapene pivoxil hydrochloride is a third-generation oral cephalosporin antibiotic, developed by Japan salt wild-meaning company, and first marketed under the trade name Flomox in 1997. Pharmacological research results show that the cefcapene pivoxil hydrochloride has the characteristics of stronger antibacterial activity and small dosage compared with the existing oral cefcapene varieties. Is mainly suitable for respiratory tract infection caused by sensitive bacteria, such as pneumonia, bronchitis, pharyngolaryngitis, tonsillitis and the like; otitis media; sinusitis; urinary tract infections such as gonorrhea, pyelonephritis, and cystitis; skin and skin tissue infections, etc.; biliary tract infections, and the like.
In the process of research and development 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 mark for reflecting the purity of the drugs, and impurities in the drugs directly influence the curative effect of the drugs and can cause toxic and side effects. The impurities of the drug mean substances which have no treatment effect or influence the stability and the curative effect of the drug and are possibly harmful to the human health. The presence of these substances not only affects the quality of the drug, but also exposes problems during production and storage. For safe and effective use of drugs, the quality standards of drugs have strict requirements on the purity of active ingredients of drugs and the limits of impurities, and generally, more than 0.1% of drug impurities should be identified and quantified by a selective method.
The 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-butoxycarbonylaminothiazole-4-yl) -2-pentenoic acid) side chains as starting materials, carrying out condensation and carbamylation to obtain a precursor acid (BCN) of the cefcapene pivoxil hydrochloride, and carrying out esterification and tert-butoxycarbonyl protecting group removal. The cefcapene pivoxil E-type isomer is a reaction byproduct generated in the production process of cefcapene pivoxil hydrochloride and is a key impurity in a cefcapene pivoxil hydrochloride raw material drug, and at present, no introduction aiming at a method for synthesizing the cefcapene pivoxil E-type isomer exists in the prior art.
Disclosure of Invention
In view of the above, the present invention provides a method for preparing cefcapene pivoxil E-type isomer, and the method provided by the present invention can prepare cefcapene pivoxil E-type 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:
heating and refluxing an organic solution of a cefcapene pivoxil raw material to obtain an E-type isomer of cefcapene pivoxil, 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 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, a 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 isomerization solid product is obtained after the heating reflux, the isomerization solid product contains cefcapene pivoxil E-type isomer, the isomerization solid product is dissolved in an organic solvent to obtain an isomerization solid product organic solution after the heating reflux, an alkaline aqueous solution and the isomerization solid product organic solution are mixed and extracted, and an organic phase is taken after the extraction to obtain the cefcapene pivoxil E-type isomer.
Preferably, the pH value of the alkaline aqueous solution is 6-8.
Preferably, the alkaline aqueous solution comprises an inorganic strong alkali aqueous solution and/or a strong alkali weak acid salt aqueous solution.
Preferably, the ratio of the mass of the isomerized solid product in the isomerized solid product organic solution to the volume of the organic solvent is 1g (8-10) mL.
Preferably, the volume ratio of the isomerization solid product organic solution to the alkaline aqueous solution is (1.3-2): 1.
Preferably, the organic phase is a crude product of the E-type isomer of cefcapene pivoxil, the step of obtaining the organic phase further comprises the step of dissolving the crude product of the E-type isomer of cefcapene pivoxil in a mobile phase for column chromatography separation and purification to obtain the E-type isomer of cefcapene pivoxil, 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: heating and refluxing an organic solution of a cefcapene pivoxil raw material to obtain an E-type isomer of cefcapene pivoxil, 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 ℃. The preparation method provided by the invention successfully prepares the cefcapene pivoxil E-type isomer by heating and refluxing the cefcapene pivoxil solution at the heat preservation temperature of more than or equal to 40 ℃, and the yield of the cefcapene pivoxil E-type isomer is high. The preparation method provided by the invention is simple and effective, and the results of the embodiment show that the mass yield of the E-type isomer of cefcapene pivoxil 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 impurity research of cefcapene pivoxil hydrochloride, and has great significance for stable control in the production process of cefcapene pivoxil hydrochloride.
Drawings
FIG. 1 is an HPLC chromatogram of cefcapene pivoxil isomer E obtained 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:
heating and refluxing an organic solution of a cefcapene pivoxil raw material to obtain an E-type isomer of cefcapene pivoxil, 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 starting materials are all commercially available products known to those skilled in the art, unless otherwise specified.
In the present invention, the organic solution of cefcapene pivoxil starting material preferably comprises cefcapene pivoxil starting material and an organic solvent (hereinafter referred to as the first organic solvent).
In the present invention, the cefcapene pivoxil starting 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, a lower alcohol, dichloromethane, 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 specifically preferably methanol.
In the 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, and more preferably 1g (8.5-9.5) mL.
The cefcapene pivoxil raw material is firstly dissolved in the first organic solvent to obtain the 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 carried out under stirring, and the present invention has no particular requirement for the specific implementation of the stirring.
In the invention, the heat preservation temperature of the heating reflux is preferably 40-60 ℃, and more preferably 50 ℃.
In the present invention, the heating reflux is preferably carried out under stirring, and the present invention has no special requirement for the specific implementation process of the stirring.
In the invention, in the process of heating reflux, cefcapene pivoxil in the cefcapene pivoxil solution is heated in the solution to generate an isomerization reaction to obtain an E-type isomer of cefcapene pivoxil, and the reaction equation is shown as formula 2:
the isomerization reaction is preferably detected by adopting thin layer chromatography and/or high-phase liquid chromatography, and the reaction is finished when the thin layer chromatography and/or high-phase liquid chromatography are adopted to detect that the quality of the cefcapene pivoxil E-type isomer product in the isomerization reaction liquid is not increased any more.
In a specific embodiment of the invention, the time for the isomerization reaction under heating and refluxing is preferably 3 to 4 hours.
In the present invention, after the heating reflux, an isomerized solid product is obtained, wherein the isomerized solid product contains cefcapene pivoxil E-type isomer, and after the heating reflux, the present invention preferably further comprises dissolving (hereinafter referred to as second dissolving) the isomerized solid product in an organic solvent (hereinafter referred to as 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 the extraction to obtain the cefcapene pivoxil E-type isomer.
In the present invention, the isomerization reaction liquid is preferably obtained after the heating reflux, and the present invention preferably further comprises concentrating the isomerization reaction liquid under reduced pressure to obtain the isomerization 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, dichloromethane, ethanol, and N, N-dimethylformamide.
In the present invention, the second dissolution is preferably carried out under stirring, and the present invention has no particular requirement on the specific implementation process of the stirring.
In the 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 (8-10) mL, and more preferably 1g (8.5-9) mL.
In the present invention, the alkaline aqueous solution preferably includes an inorganic strong alkali aqueous solution and/or a strong alkali weak acid salt aqueous solution.
In the present invention, the aqueous solution of a strong base and a weak acid carbonate is preferably an aqueous solution of an alkali metal carbonate and/or an aqueous solution of an alkali metal bicarbonate.
In a specific embodiment of the present invention, the basic aqueous solution is particularly preferably an aqueous sodium hydroxide solution or an aqueous sodium bicarbonate solution.
In the invention, the pH value of the alkaline aqueous solution is preferably 6-8, and more preferably 6.5-7.5.
In the invention, the volume ratio of the isomerization solid product organic solution to the alkaline aqueous solution is preferably (1.3-2): 1, and more preferably (1.5-1.95): 1.
In the present invention, the mixing is preferably: adding water into the isomerized solid product organic solution to form an initial organic phase and an aqueous phase, and dropwise adding a pH reagent into the initial aqueous phase to obtain an alkaline aqueous solution to form an initial organic phase and an aqueous 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%. The solute component in the high-concentration aqueous alkaline solution is the same as the solute component in the aqueous alkaline solution.
In the present invention, the extraction is preferably performed under stirring.
In the invention, the extraction time is preferably 30-35 min.
In the present invention, during the extraction process, water-soluble impurities in the organic solution of the isomerized solid product pass from the organic phase into the aqueous phase.
In the invention, an extraction system is obtained after the extraction, and the invention preferably carries out post-treatment on the extraction system to obtain an organic phase. In the present invention, the post-treatment preferably comprises: sequentially carrying out organic phase separation, organic phase drying, solid-liquid separation and reduced pressure concentration. The present invention does not require any particular phase separation, and in the present invention, the organic phase is dried, preferably by mixing the organic phase with a drying agent, and in the present invention, the drying agent is preferably anhydrous magnesium sulfate. The invention has no special requirement on the dosage of the dry reagent. In the present invention, the solid-liquid separation is preferably performed by separating the dried organic phase and the dried reagent. In the present invention, the solid-liquid separation is preferably performed by filtration. The organic phase after drying is preferably concentrated under reduced pressure in the present invention, and the solvent in the organic phase is preferably removed by concentration in the present invention. 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 invention, the organic phase is preferably a crude product of an E-type isomer of cefcapene pivoxil, and after the organic phase is obtained, the invention preferably further comprises the step of dissolving the crude product of the E-type isomer of cefcapene pivoxil (hereinafter referred to as third dissolution) in a mobile phase for column chromatography separation and purification to obtain the E-type isomer of cefcapene pivoxil, wherein the mobile phase is dichloromethane and methanol, and the volume ratio of the dichloromethane to the methanol is (20-40): 1.
The present invention has no particular requirement for the third dissolution.
In the invention, the volume ratio of the dichloromethane to the methanol is preferably (25-35): 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 filled by a wet method.
The invention adopts column chromatography for separation and purification, and the separation and purification are carried out by utilizing the difference of the retention time of the cefcapene pivoxil and the E-type isomer of the cefcapene pivoxil.
In the invention, after the column chromatography separation and purification, a purified solution is obtained, and the purified solution is preferably subjected to post-treatment to obtain the cefcapene pivoxil E-type isomer.
In the present invention, the post-treatment preferably comprises: vacuum concentrating and drying sequentially. In the invention, the solvent in the purified liquid is preferably removed by vacuum concentration, and the solvent in the purified solid product after vacuum concentration is preferably further removed by drying, wherein the drying temperature is preferably 30-35 ℃, and the drying time is not particularly required, and the constant weight is only required.
The technical solution of the present invention will be clearly and completely described below with reference to the embodiments of the present invention.
Example 1
Adding 10g of cefcapene pivoxil hydrochloride and 100mL of methanol into a 500mL flask at the temperature of 20 ℃, stirring until the system is clear, heating in a water bath to 50 ℃, stirring for 3-4 h, monitoring the content of the E-type isomer of cefcapene pivoxil by thin-layer chromatography and HPLC (high performance liquid chromatography), stopping the reaction, concentrating the reaction liquid at 40 ℃ under reduced pressure to obtain a yellow solid, dissolving the yellow solid in 100mL of ethyl acetate, uniformly stirring, adding 50mL of pure water, dropwise adding a 10% sodium hydroxide solution, adjusting the pH value to 6, stirring for 30min, layering, drying with anhydrous sodium sulfate, filtering, and concentrating at 30-45 ℃ under reduced pressure to obtain a crude product of the E-type isomer of cefcapene pivoxil; wet packing a silica gel column with dichloromethane: a mobile phase separation of methanol 35:1(v: v) purified sample, reduced pressure concentration, and drying at 30 ℃ to obtain dry product 6.0g, cefcapene pivoxil E isomer yield of 60%, product purity of 92.4%, liquid chromatogram as shown in figure 1, and retention time of cefcapene pivoxil E isomer of 34.055 min.
Example 2
Adding 10g of cefcapene pivoxil hydrochloride and 90mL of methanol into a 500mL flask at the temperature of 20 ℃, stirring until the system is clear, heating in a water bath to 50 ℃, stirring for 3-4 h, monitoring the content of the E-type isomer of cefcapene pivoxil by thin-layer chromatography and HPLC (high performance liquid chromatography), stopping the reaction, concentrating the reaction liquid at 40 ℃ under reduced pressure to obtain a yellow solid, dissolving the yellow solid in 90mL of dichloromethane, uniformly stirring, adding 50mL of pure water, dropwise adding a 10% sodium hydroxide solution, adjusting the pH value to 6, stirring for 30min, layering, drying with anhydrous sodium sulfate, filtering, and concentrating at 30-45 ℃ under reduced pressure to obtain a crude product of the E-type isomer of cefcapene pivoxil; wet packing a silica gel column with dichloromethane: a mobile phase of 40:1(v: v) methanol was separated to purify the sample, concentrated under reduced pressure, and the material was dried at 30 ℃ to obtain 5.8g of dry product, yield of cefcapene pivoxil E-isomer was 58%, purity of the product was 91.8%, and liquid chromatogram was similar to that of fig. 1.
Example 3
Adding 10g of cefcapene pivoxil hydrochloride and 90mL of methanol into a 500mL flask at the temperature of 20 ℃, stirring until the system is clear, heating in a water bath to 50 ℃, stirring for 3-4 h, monitoring the content of the E-type isomer of cefcapene pivoxil by thin-layer chromatography and HPLC (high performance liquid chromatography), stopping the reaction, concentrating the reaction liquid at 40 ℃ under reduced pressure to obtain a yellow solid, dissolving the yellow solid in 80mL of dichloromethane, stirring uniformly, adding 50mL of pure water, dropwise adding a 7% sodium bicarbonate solution, adjusting the pH value to 8, stirring for 30min, layering, drying with anhydrous sodium sulfate, filtering, and concentrating at 30-45 ℃ under reduced pressure to obtain a crude product of the E-type isomer of cefcapene pivoxil; wet packing a silica gel column with dichloromethane: mobile phase separation of methanol 30:1(v: v) purified sample, reduced pressure concentration, and drying at 30 ℃ to obtain dry product 5.1g, cefcapene pivoxil E isomer yield of 51%, product purity of 90.4%, and liquid chromatogram similar to fig. 1.
Example 4
Adding 10g of cefcapene pivoxil hydrochloride and 100mL of methanol into a 500mL flask at the temperature of 20 ℃, stirring until the system is clear, heating in a water bath to 50 ℃, stirring for 3-4 h, monitoring the content of the E-type isomer of cefcapene pivoxil by thin-layer chromatography and HPLC (high performance liquid chromatography), stopping the reaction, concentrating the reaction liquid at 40 ℃ under reduced pressure to obtain a yellow solid, dissolving the yellow solid in 100mL of ethanol, stirring uniformly, adding 50mL of pure water, dropwise adding a 7% sodium bicarbonate solution, adjusting the pH to 7, stirring for 30min, layering, drying with anhydrous sodium sulfate, filtering, and concentrating at 30-45 ℃ under reduced pressure to obtain a crude product of the E-type isomer of cefcapene pivoxil; wet packing a silica gel column with dichloromethane: a mobile phase of 40:1(v: v) methanol was separated to purify the sample, concentrated under reduced pressure, and the material was dried at 30 ℃ to obtain 5.3g of dry product, yield of cefcapene pivoxil E-isomer was 53%, purity of the product was 93.1%, and liquid chromatogram was similar to that of fig. 1.
Example 5
Adding 10g of cefcapene pivoxil hydrochloride and 100mL of methanol into a 500mL flask at the temperature of 20 ℃, stirring until the system is clear, heating in a water bath to 50 ℃, stirring for 3-4 h, monitoring the content of the E-type isomer of cefcapene pivoxil by using a thin layer chromatography and HPLC (high performance liquid chromatography), stopping the reaction, concentrating the reaction solution at 40 ℃ under reduced pressure to obtain a yellow solid, dissolving the yellow solid in 100mLN and N-dimethylformamide, uniformly stirring, adding 50mL of pure water, dropwise adding a 10% sodium hydroxide solution, adjusting the pH value to 7, stirring for 30min, layering, drying with anhydrous sodium sulfate, filtering, and concentrating at 30-45 ℃ under reduced pressure to obtain a crude product of the E-type isomer of cefcapene pivoxil; wet packing a silica gel column with dichloromethane: a mobile phase of methanol 25:1(v: v) was separated and the sample was purified, concentrated under reduced pressure, and the material was dried at 30 ℃ to obtain 5.7g of dry product, yield of cefcapene pivoxil E-isomer was 57%, purity of the product was 90.7%, and liquid chromatogram was similar to that of fig. 1.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.
Claims (10)
1. A preparation method of cefcapene pivoxil E-type isomer is characterized by comprising the following steps:
heating and refluxing an organic solution of a cefcapene pivoxil raw material to obtain an E-type isomer of cefcapene pivoxil, 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 ℃.
2. The method according to claim 1, wherein the temperature of the heated reflux is 40 to 60 ℃.
3. The process according to claim 1, wherein the organic solution of cefcapene pivoxil starting material comprises cefcapene pivoxil starting material and an organic solvent comprising one or more of ethyl acetate, a lower alcohol, dichloromethane and N, N-dimethylformamide.
4. The preparation method according to claim 1 or 3, wherein the concentration of the organic solution of the cefcapene pivoxil hydrochloride raw material is 0.1-0.125 g/mL.
5. The preparation method according to claim 1, wherein the heating reflux is performed to obtain an isomerized solid product containing cefcapene pivoxil E-type isomer, the heating reflux further comprises dissolving the isomerized solid product in an 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 extracting an organic phase to obtain the cefcapene pivoxil E-type isomer.
6. The method according to claim 5, wherein the pH of the aqueous alkaline solution is 6 to 8.
7. The method of claim 5, wherein the aqueous alkaline solution comprises an aqueous solution of an inorganic strong base and/or an aqueous solution of a strong base and a weak acid salt.
8. The preparation method of claim 5, wherein 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.
9. The method according to any one of claims 6 to 8, wherein the volume ratio of the isomerized solid product organic solution to the basic aqueous solution is (1.3-2): 1.
10. The preparation method according to claim 5, wherein the organic phase is a crude product of E-type isomer of cefcapene pivoxil, and after the organic phase is obtained, the method further comprises the step of dissolving the crude product of E-type isomer of cefcapene pivoxil in a mobile phase for column chromatography separation and purification to obtain the E-type isomer of cefcapene pivoxil, wherein the mobile phase is dichloromethane and methanol, and the volume ratio of dichloromethane to methanol is (20-40): 1.
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Address after: 441048 Xiangcheng Economic Development Zone, Xiangcheng District, Xiangyang City, Hubei Province Patentee after: Hubei Lingsheng Pharmaceutical Co.,Ltd. Address before: 441141 Xiangcheng Economic Development Zone, Xiangcheng District, Xiangyang City, Hubei Province Patentee before: HUBEI LINGSHENG PHARMACEUTICAL CO.,LTD. |
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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 |