CN113354664A - Preparation method of latamoxef hydroxyl impurities - Google Patents
Preparation method of latamoxef hydroxyl impurities Download PDFInfo
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- CN113354664A CN113354664A CN202110763989.1A CN202110763989A CN113354664A CN 113354664 A CN113354664 A CN 113354664A CN 202110763989 A CN202110763989 A CN 202110763989A CN 113354664 A CN113354664 A CN 113354664A
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- 229960000433 latamoxef Drugs 0.000 title claims abstract description 58
- 239000012535 impurity Substances 0.000 title claims abstract description 48
- 238000002360 preparation method Methods 0.000 title claims abstract description 25
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims abstract description 51
- GRIXGZQULWMCLU-HUTAOCTPSA-L disodium;(6r,7r)-7-[[2-carboxylato-2-(4-hydroxyphenyl)acetyl]amino]-7-methoxy-3-[(1-methyltetrazol-5-yl)sulfanylmethyl]-8-oxo-5-oxa-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate Chemical compound [Na+].[Na+].N([C@]1(OC)C(N2C(=C(CSC=3N(N=NN=3)C)CO[C@@H]21)C([O-])=O)=O)C(=O)C(C([O-])=O)C1=CC=C(O)C=C1 GRIXGZQULWMCLU-HUTAOCTPSA-L 0.000 claims abstract description 38
- 239000011347 resin Substances 0.000 claims abstract description 29
- 229920005989 resin Polymers 0.000 claims abstract description 29
- 238000006243 chemical reaction Methods 0.000 claims abstract description 19
- 239000007864 aqueous solution Substances 0.000 claims abstract description 16
- 238000002156 mixing Methods 0.000 claims abstract description 11
- 238000004108 freeze drying Methods 0.000 claims abstract description 10
- 238000004321 preservation Methods 0.000 claims abstract description 6
- 238000000926 separation method Methods 0.000 claims description 13
- 238000000034 method Methods 0.000 claims description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- 238000001035 drying Methods 0.000 claims description 5
- 238000003756 stirring Methods 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 3
- 239000003480 eluent Substances 0.000 claims description 2
- 238000011534 incubation Methods 0.000 claims 1
- 239000000126 substance Substances 0.000 abstract description 4
- 238000010812 external standard method Methods 0.000 abstract description 3
- 238000011160 research Methods 0.000 abstract description 3
- 239000000243 solution Substances 0.000 description 12
- 230000000844 anti-bacterial effect Effects 0.000 description 8
- 238000001228 spectrum Methods 0.000 description 8
- 239000007788 liquid Substances 0.000 description 7
- 239000008399 tap water Substances 0.000 description 6
- 235000020679 tap water Nutrition 0.000 description 6
- 238000004458 analytical method Methods 0.000 description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- 238000001816 cooling Methods 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 238000012544 monitoring process Methods 0.000 description 3
- 239000008213 purified water Substances 0.000 description 3
- 239000013558 reference substance Substances 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- 241000894006 Bacteria Species 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 241000588653 Neisseria Species 0.000 description 2
- 230000003115 biocidal effect Effects 0.000 description 2
- 229960004261 cefotaxime Drugs 0.000 description 2
- GPRBEKHLDVQUJE-VINNURBNSA-N cefotaxime Chemical compound N([C@@H]1C(N2C(=C(COC(C)=O)CS[C@@H]21)C(O)=O)=O)C(=O)/C(=N/OC)C1=CSC(N)=N1 GPRBEKHLDVQUJE-VINNURBNSA-N 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- 238000004237 preparative chromatography Methods 0.000 description 2
- 238000010183 spectrum analysis Methods 0.000 description 2
- QXNSHVVNEOAAOF-RXMQYKEDSA-N (6R)-4-oxa-5-thia-1-azabicyclo[4.2.0]oct-2-en-8-one Chemical compound S1OC=CN2[C@H]1CC2=O QXNSHVVNEOAAOF-RXMQYKEDSA-N 0.000 description 1
- 241000589291 Acinetobacter Species 0.000 description 1
- 241000606124 Bacteroides fragilis Species 0.000 description 1
- 229930186147 Cephalosporin Natural products 0.000 description 1
- 241000588923 Citrobacter Species 0.000 description 1
- 108090000204 Dipeptidase 1 Proteins 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 241000588914 Enterobacter Species 0.000 description 1
- 241000194033 Enterococcus Species 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- 241000192125 Firmicutes Species 0.000 description 1
- 241000606768 Haemophilus influenzae Species 0.000 description 1
- 241000588748 Klebsiella Species 0.000 description 1
- 241000588769 Proteus <enterobacteria> Species 0.000 description 1
- 241000589516 Pseudomonas Species 0.000 description 1
- 241000607720 Serratia Species 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 229940126575 aminoglycoside Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 102000006635 beta-lactamase Human genes 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 229960004682 cefoperazone Drugs 0.000 description 1
- GCFBRXLSHGKWDP-XCGNWRKASA-N cefoperazone Chemical compound O=C1C(=O)N(CC)CCN1C(=O)N[C@H](C=1C=CC(O)=CC=1)C(=O)N[C@@H]1C(=O)N2C(C(O)=O)=C(CSC=3N(N=NN=3)C)CS[C@@H]21 GCFBRXLSHGKWDP-XCGNWRKASA-N 0.000 description 1
- 229940124587 cephalosporin Drugs 0.000 description 1
- 150000001780 cephalosporins Chemical class 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 238000013375 chromatographic separation Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 229940047650 haemophilus influenzae Drugs 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- IVBHGBMCVLDMKU-GXNBUGAJSA-N piperacillin Chemical compound O=C1C(=O)N(CC)CCN1C(=O)N[C@H](C=1C=CC=CC=1)C(=O)N[C@@H]1C(=O)N2[C@@H](C(O)=O)C(C)(C)S[C@@H]21 IVBHGBMCVLDMKU-GXNBUGAJSA-N 0.000 description 1
- 229960002292 piperacillin Drugs 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 238000013441 quality evaluation Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 241001148471 unidentified anaerobic bacterium Species 0.000 description 1
Images
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D505/00—Heterocyclic compounds containing 5-oxa-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxacephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D505/02—Preparation
- C07D505/06—Preparation from compounds already containing the ring or condensed ring systems, e.g. by dehydrogenation of the ring, by introduction, elimination or modification of substituents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D505/00—Heterocyclic compounds containing 5-oxa-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxacephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D505/10—Heterocyclic compounds containing 5-oxa-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxacephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
- C07D505/12—Heterocyclic compounds containing 5-oxa-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxacephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 substituted in position 7
- C07D505/14—Heterocyclic compounds containing 5-oxa-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxacephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 substituted in position 7 with hetero atoms directly attached in position 7
- C07D505/16—Nitrogen atoms
- C07D505/18—Nitrogen atoms further acylated by radicals derived from carboxylic acids or by nitrogen or sulfur analogues thereof
- C07D505/20—Nitrogen atoms further acylated by radicals derived from carboxylic acids or by nitrogen or sulfur analogues thereof with the acylating radicals further substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Molecular Biology (AREA)
- Investigating, Analyzing Materials By Fluorescence Or Luminescence (AREA)
- Investigating Or Analyzing Non-Biological Materials By The Use Of Chemical Means (AREA)
Abstract
The invention belongs to the technical field of chemical preparation, and particularly relates to a preparation method of latamoxef hydroxyl impurities, which comprises the following steps: mixing the latamoxef sodium aqueous solution with the sodium hydroxide aqueous solution, and carrying out heat preservation reaction to obtain a; and then separating and freeze-drying the alpha by using macroporous resin. The preparation method has the advantages of simple and convenient operation, high purity and large sample acquisition amount. The prepared latamoxef hydroxyl impurities are convenient for the quality research of latamoxef sodium, especially, the external standard method is adopted to quantify the impurity content in the latamoxef sodium, so that a large batch of impurity reference products with uniform quality are provided, the whole quality level of the latamoxef sodium is favorably improved, and a foundation is laid for the variety to reach the quality level of a reference preparation.
Description
Technical Field
The invention belongs to the technical field of chemical preparation, and particularly relates to a preparation method of latamoxef hydroxyl impurities.
Background
Latamoxef sodium is a semi-synthetic oxacephem antibiotic. The basic structure of the compound is similar to that of cephamycins, and only the S at the 1-position of the parent nucleus is replaced by O. The product has broad spectrum and antibacterial effect similar to that of cephalosporin 3 generation. The antibacterial spectrum is similar to that of cefotaxime. Has good antibacterial effect on various gram-negative bacteria, including Escherichia coli, Haemophilus influenzae, Klebsiella, Proteus, Enterobacter, Citrobacter, and Serratia chemical book, etc. with strong antibacterial activity; has good antibacterial activity on anaerobic bacteria such as Bacteroides fragilis; the antibacterial effect on acinetobacter and pseudomonas is worse than that of aminoglycosides or piperacillin; sensitive to gonococcus producing enzyme and gonococcus not producing enzyme, has the antibacterial activity similar to that of cefoperazone, is poorer than cefotaxime, is resistant to enterococcus and is generally weaker in antibacterial activity to gram-positive bacteria. The product has strong stability to beta-lactamase, so bacteria are not easy to generate drug resistance to the product. The latamoxef sodium contains some known or unknown impurities, so that the content of the impurities is indispensable for detecting when the quality evaluation is carried out in the preparation of the latamoxef sodium, and the impurity reference substance meeting the requirements of the reference substance is indispensable.
Latamoxef sodium has an impurity, and only the liquid quality analysis result of the impurity in latamoxef sodium is mentioned in the article "LC/MSn method rapid analysis of impurity spectrum of latamoxef sodium raw material" published by the chinese food and drug certification institute at 7 th volume of 7.44 of 2019, which is a document of antibiotic impurities, because of the poor stability of the impurity, the method of preparative chromatographic separation from the mother liquor is extremely difficult to obtain a sample with higher purity, and is limited by the sample carrying capacity of preparative chromatographic column and the content of the impurity in the mother liquor, although a lot of time is consumed, only a very small number of samples can be obtained. And because the separation principle of preparative chromatography is that the components in the feed liquid are respectively eluted by the mobile phase after entering the chromatographic column under the action of the filler, the separation mode has the disadvantages that the concentration of the obtained target product solution is generally below 1 percent, concentration or extraction and other modes are required for enrichment and then freeze-drying, and because the separation capacity of the preparative chromatographic column is limited, the sample loading quantity in each time cannot be too much, repeated separation is required, and the target product solution is combined for enrichment treatment. No methods are currently available that can be prepared in large quantities.
Disclosure of Invention
In view of the above, the present invention aims to provide a preparation method of latamoxef hydroxyl impurities, which adopts a method of directly passing latamoxef sodium through macroporous resin after degradation to separate, so as to obtain a high-concentration impurity aqueous solution, and freeze-drying the impurity aqueous solution at a low temperature to obtain a latamoxef hydroxyl impurity sample, wherein the reaction formula is as follows:
the latamoxef sodium impurity prepared by the preparation method is convenient for quality research of latamoxef sodium, especially for providing a large batch of impurity reference products with uniform quality by quantifying the impurity content in latamoxef sodium by adopting an external standard method, is favorable for improving the overall quality level of latamoxef sodium, and lays a foundation for the variety to reach the quality level of a reference preparation.
The preparation method of the latamoxef hydroxyl impurity comprises the following steps: mixing the latamoxef sodium aqueous solution with the sodium hydroxide aqueous solution, and carrying out heat preservation reaction to obtain a; then separating and freeze-drying the a by using macroporous resin; the latamoxef hydroxyl impurity has a structural formula shown in formula I,
preferably, in the latamoxef sodium aqueous solution, the solvent water is 0.5 to 20 times, preferably 2 to 3 times of the weight of the latamoxef sodium.
Preferably, the mass percentage concentration of the sodium hydroxide aqueous solution is 1-10%, and the molar ratio of sodium hydroxide to latamoxef sodium is 1-3.
Preferably, the mass percentage concentration of the sodium hydroxide aqueous solution is 1-10%, and the molar ratio of the sodium hydroxide to the latamoxef sodium is 1-1.5.
Preferably, the mass percentage concentration of the sodium hydroxide aqueous solution is 4-6%, and the molar ratio of the sodium hydroxide to the latamoxef sodium is 1-3.
Preferably, the mass percentage concentration of the sodium hydroxide aqueous solution is 4-6%, and the molar ratio of the sodium hydroxide to the latamoxef sodium is 1-1.5.
Preferably, the reaction temperature of the heat preservation reaction is 20-80 ℃.
Preferably, the reaction temperature of the heat preservation reaction is 45-55 ℃.
Preferably, the model of the macroporous resin is DM-2, the column passing temperature for separating the macroporous resin is 2-10 ℃, and the eluent is water.
Preferably, the drying temperature of the lyophilization is 5 ℃.
In certain embodiments, the latamoxef hydroxy impurity is prepared by a method comprising: adding tap water and crystalline latamoxef sodium into a reaction bottle, stirring to dissolve, adding sodium hydroxide/tap water solution, and controlling the temperature at 40 ℃ to react for 5 hours. Cooling to room temperature, passing the reaction solution through DM-2 resin column, controlling temperature of resin column jacket at 2-10 deg.C, washing with purified water after feeding liquid, monitoring bottom effluent with capillary tube until 254nm fluorescence color development, collecting effluent, and lyophilizing at maximum drying temperature of 5 deg.C to obtain light yellow solid.
The invention aims to further provide a preparation system of the latamoxef sodium impurity. The preparation system can be used for preparing latamoxef hydroxyl impurities in large batch, and the chemical structural formula of the impurities is as follows:
the preparation system comprises a mixing reactor, a macroporous resin separation device and a freeze dryer, wherein a discharge hole of the mixing reactor is connected with a feed hole of the macroporous resin separation device, and a discharge hole of the macroporous resin separation device is connected with the freeze dryer.
Preferably, the mixing reactor is provided with a stirring device.
Preferably, the macroporous resin separation device and the freeze dryer are also connected with a storage device for collecting effluent liquid.
Preferably, the resin of the macroporous resin separation device is DM-2.
Specifically, stirring and mixing the latamoxef sodium aqueous solution and the sodium hydroxide solution in the mixing reactor, and carrying out heat preservation reaction; then the effluent is put into a pore resin separation device and passes through a DM-2 resin column, the temperature of a resin column jacket is controlled at 2-10 ℃, and then the effluent is collected by using the storage device and is subjected to low-temperature freeze-drying by using a freeze dryer.
The invention has the beneficial effects that
The preparation method of latamoxef hydroxyl impurities provided by the invention has the advantages of simplicity, convenience, easy operation, high purity and large sample acquisition amount. The prepared latamoxef hydroxyl impurities are convenient for the quality research of latamoxef sodium, especially, the external standard method is adopted to quantify the impurity content in the latamoxef sodium, so that a large batch of impurity reference products with uniform quality are provided, the whole quality level of the latamoxef sodium is favorably improved, and a foundation is laid for the variety to reach the quality level of a reference preparation.
The method for preparing the oxycephalosporane hydroxyl impurities is used for preparing the oxycephalosporane hydroxyl impurities, the concentration of feed liquid passing through macroporous resin can reach 10-20%, and more impurities can be obtained by direct freeze-drying.
Drawings
FIG. 1 is a chart showing the impurity hydrogen spectrum of latamoxef sodium prepared in example 2.
FIG. 2 is a carbon spectrum of impurities in latamoxef sodium prepared in example 2.
FIG. 3 is a mass spectrum of impurities in latamoxef sodium prepared in example 2.
Detailed Description
The examples are given for the purpose of better illustration of the invention, but the invention is not limited to the examples. Therefore, those skilled in the art should make insubstantial modifications and adaptations to the embodiments of the present invention in light of the above teachings and remain within the scope of the invention.
In the embodiment of the invention, the nuclear magnetic hydrogen spectrum/carbon spectrum conditions are as follows: equipment: bruker, solvent D2O.
Example 1
50g of tap water and 20g of crystalline latamoxef sodium are added into a 250ml reaction flask, stirred and dissolved, and then a solution of 2.1g of sodium hydroxide/50 g of tap water is added, and the temperature is controlled at 40 ℃ for reaction for 5 hours. Cooling to room temperature, allowing the reaction solution to pass through DM-2 resin column, controlling temperature of resin column jacket at 2-10 deg.C, washing with purified water, monitoring bottom effluent with capillary tube until 254nm fluorescence color development, collecting effluent 45-50 g, and lyophilizing at maximum drying temperature of 5 deg.C to obtain light yellow solid 5.3g with yield of 32.1%.
Example 2
70g of tap water and 20g of crystalline latamoxef sodium are added into a 250ml reaction bottle, stirred and dissolved, and then a solution of 2.6g of sodium hydroxide/50 g of tap water is added, and the temperature is controlled at 45 ℃ for reaction for 5 hours. Cooling to room temperature, passing the reaction solution through DM-2 resin column, controlling temperature of resin column jacket at 2-10 deg.C, washing with purified water after feeding liquid, monitoring bottom effluent with capillary tube until 254nm fluorescence color development, collecting effluent 45-50 g, and lyophilizing at maximum drying temperature of 5 deg.C to obtain light yellow solid 5.1g with yield of 30.9%.
The preparation method adopts the preparative chromatography to prepare 1 sample, about 2mg of the sample can be obtained after one separation, the concentration of the feed liquid passing through the macroporous resin can reach 10-20 percent, and the impurity can be obtained by direct freeze-drying, and about 5g of the impurity reference substance can be obtained once in the embodiment.
Example 3 sample characterization
The latamoxef hydroxyl impurity prepared in example 2 is subjected to nuclear magnetic hydrogen spectrum analysis, and the analysis hydrogen spectrum is shown in figure 1.
The latamoxef hydroxyl impurities prepared in example 2 were subjected to nuclear magnetic carbon spectrum analysis, and the analysis carbon spectrum is shown in fig. 2.
The latamoxef hydroxyl impurity prepared in example 2 is subjected to mass spectrometry, and the analysis mass spectrogram is shown in fig. 3.
Finally, the above embodiments are only for illustrating the technical solutions of the present invention and not for limiting, although the present invention has been described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications or equivalent substitutions may be made to the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention, and all of them should be covered in the claims of the present invention.
Claims (10)
1. A preparation method of latamoxef hydroxyl impurities is characterized by comprising the following steps: mixing the latamoxef sodium aqueous solution with the sodium hydroxide aqueous solution, and carrying out heat preservation reaction to obtain a; then separating and freeze-drying the a by using macroporous resin; the latamoxef hydroxyl impurity has a structural formula shown in formula I,
2. the process according to claim 1, wherein the aqueous solution of latamoxef sodium is dissolved in water in an amount of 0.5 to 20 times the weight of the latamoxef sodium.
3. The process according to claim 2, wherein the solvent water is 2 to 3 times the weight of said latamoxef sodium.
4. The preparation method according to claim 2, wherein the aqueous solution of sodium hydroxide has a mass percentage concentration of 1-10% and the molar ratio of sodium hydroxide to latamoxef sodium is 1-3.
5. The method according to claim 1, wherein the reaction temperature of the incubation reaction is 20 ℃ to 80 ℃.
6. The preparation method according to claim 1, wherein the macroporous resin is DM-2, the temperature of the column passing through the macroporous resin for separation is 2-10 ℃, and the eluent is water.
7. The method of claim 1, wherein the drying temperature of the lyophilization is 5 ℃.
8. The preparation system of latamoxef hydroxyl impurity, characterized in that, the preparation system includes mixing reactor, macroporous resin separator and freeze dryer, mixing reactor's discharge opening with macroporous resin separator's inlet opening is connected, macroporous resin separator's discharge opening is connected with the freeze dryer.
9. The system of claim 8, wherein the mixing reactor is equipped with a stirring device.
10. The preparation system of claim 8, wherein the latamoxef hydroxy impurities have a structural formula shown in formula I, and the macroporous resin separation device comprises DM-2;
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105037394A (en) * | 2015-08-07 | 2015-11-11 | 浙江新和成股份有限公司 | Preparing method for high-purity latamoxef sodium |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105037394A (en) * | 2015-08-07 | 2015-11-11 | 浙江新和成股份有限公司 | Preparing method for high-purity latamoxef sodium |
Non-Patent Citations (3)
| Title |
|---|
| LULU HE等: "Separation and characterization of unknown impurities in latamoxef sodium by LC-Q-TOF MS and a summary of their positive-ion fragmentation regularities", JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS, vol. 175, pages 112793 * |
| 李进等: "LC/MSn法快速分析拉氧头孢钠原料的杂质谱", 中国抗生素杂志, vol. 44, no. 7, pages 820 - 833 * |
| 董风其;焦红军;: "高效液相色谱法测定拉氧头孢钠的含量", 医药论坛杂志, vol. 32, no. 4, pages 149 - 150 * |
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Application publication date: 20210907 |