CN113912629A - Crystallization method of biapenem - Google Patents
Crystallization method of biapenem Download PDFInfo
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- CN113912629A CN113912629A CN202111283627.9A CN202111283627A CN113912629A CN 113912629 A CN113912629 A CN 113912629A CN 202111283627 A CN202111283627 A CN 202111283627A CN 113912629 A CN113912629 A CN 113912629A
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- Prior art keywords
- biapenem
- water
- activated carbon
- added
- crystallization
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- MRMBZHPJVKCOMA-YJFSRANCSA-N biapenem Chemical compound C1N2C=NC=[N+]2CC1SC([C@@H]1C)=C(C([O-])=O)N2[C@H]1[C@@H]([C@H](O)C)C2=O MRMBZHPJVKCOMA-YJFSRANCSA-N 0.000 title claims abstract description 59
- 229960003169 biapenem Drugs 0.000 title claims abstract description 58
- 238000002425 crystallisation Methods 0.000 title claims abstract description 27
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims abstract description 34
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims abstract description 28
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 24
- 239000012043 crude product Substances 0.000 claims abstract description 12
- 230000008025 crystallization Effects 0.000 claims abstract description 12
- 239000013078 crystal Substances 0.000 claims abstract description 11
- 238000001914 filtration Methods 0.000 claims abstract description 10
- 238000004090 dissolution Methods 0.000 claims abstract description 9
- 238000003756 stirring Methods 0.000 claims abstract description 9
- 239000000706 filtrate Substances 0.000 claims abstract description 8
- 239000012528 membrane Substances 0.000 claims abstract description 8
- 238000001816 cooling Methods 0.000 claims abstract description 6
- 238000010438 heat treatment Methods 0.000 claims abstract description 5
- 238000005262 decarbonization Methods 0.000 claims abstract description 4
- 238000000034 method Methods 0.000 claims description 16
- 230000001376 precipitating effect Effects 0.000 claims description 5
- 238000004042 decolorization Methods 0.000 claims description 4
- 238000005261 decarburization Methods 0.000 claims description 2
- 239000000047 product Substances 0.000 abstract description 9
- 230000007613 environmental effect Effects 0.000 abstract description 5
- 230000000052 comparative effect Effects 0.000 description 5
- 239000000203 mixture Substances 0.000 description 4
- 239000002351 wastewater Substances 0.000 description 4
- WKDDRNSBRWANNC-UHFFFAOYSA-N Thienamycin Natural products C1C(SCCN)=C(C(O)=O)N2C(=O)C(C(O)C)C21 WKDDRNSBRWANNC-UHFFFAOYSA-N 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- ZSKVGTPCRGIANV-ZXFLCMHBSA-N imipenem Chemical compound C1C(SCC\N=C\N)=C(C(O)=O)N2C(=O)[C@H]([C@H](O)C)[C@H]21 ZSKVGTPCRGIANV-ZXFLCMHBSA-N 0.000 description 3
- 229960002182 imipenem Drugs 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- 238000001556 precipitation Methods 0.000 description 3
- 241000894006 Bacteria Species 0.000 description 2
- 241000588769 Proteus <enterobacteria> Species 0.000 description 2
- 241000589517 Pseudomonas aeruginosa Species 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 230000002349 favourable effect Effects 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 241000186046 Actinomyces Species 0.000 description 1
- 241000606125 Bacteroides Species 0.000 description 1
- 208000014085 Chronic respiratory disease Diseases 0.000 description 1
- 241000588923 Citrobacter Species 0.000 description 1
- 241000193403 Clostridium Species 0.000 description 1
- 208000003322 Coinfection Diseases 0.000 description 1
- 241000588914 Enterobacter Species 0.000 description 1
- 241000194033 Enterococcus Species 0.000 description 1
- 241000194031 Enterococcus faecium Species 0.000 description 1
- 241000588722 Escherichia 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
- 241000588621 Moraxella Species 0.000 description 1
- 208000029082 Pelvic Inflammatory Disease Diseases 0.000 description 1
- 241000191992 Peptostreptococcus Species 0.000 description 1
- 206010035664 Pneumonia Diseases 0.000 description 1
- 206010037596 Pyelonephritis Diseases 0.000 description 1
- 206010049677 Salpingo-oophoritis Diseases 0.000 description 1
- 206010040047 Sepsis Diseases 0.000 description 1
- 241000607720 Serratia Species 0.000 description 1
- 241000191940 Staphylococcus Species 0.000 description 1
- 241000194017 Streptococcus Species 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- YZBQHRLRFGPBSL-RXMQYKEDSA-N carbapenem Chemical compound C1C=CN2C(=O)C[C@H]21 YZBQHRLRFGPBSL-RXMQYKEDSA-N 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 201000003146 cystitis Diseases 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 239000002532 enzyme inhibitor Substances 0.000 description 1
- 229940047650 haemophilus influenzae Drugs 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 201000003453 lung abscess Diseases 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229960002260 meropenem Drugs 0.000 description 1
- DMJNNHOOLUXYBV-PQTSNVLCSA-N meropenem Chemical compound C=1([C@H](C)[C@@H]2[C@H](C(N2C=1C(O)=O)=O)[C@H](O)C)S[C@@H]1CN[C@H](C(=O)N(C)C)C1 DMJNNHOOLUXYBV-PQTSNVLCSA-N 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 206010034674 peritonitis Diseases 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 208000013223 septicemia Diseases 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
- C07D519/06—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 containing at least one condensed beta-lactam ring system, provided for by groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00, e.g. a penem or a cepham system
Abstract
The invention discloses a crystallization method of biapenem, which comprises the following steps: (1) dissolving: adding the biapenem crude product into water (the weight ratio of biapenem to water is 1: 10), quickly heating to 40-50 ℃, and stirring to dissolve and brighten; (2) decarbonization: adding 1% of activated carbon for decoloring for 10 minutes, and then filtering by using a 0.45-micrometer filter membrane to obtain a filtrate; (3) and (3) rapidly cooling to 10-20 ℃, separating out biapenem crystals, adding 3 times of acetone, and further carrying out dissolution crystallization to obtain biapenem with better purity and color grade. The crystallization method provided by the invention is simple and convenient to operate, has a short period, has the advantage of environmental protection, improves the purity of the biapenem product, reduces the color grade, has better quality, and is safer to use.
Description
Technical Field
The invention relates to the technical field of crystallization of biapenem, and particularly relates to a crystallization method of biapenem.
Background
Biapenem is a carbapenem synthetic antibiotic, is more stable to renal dehydropeptidase than meropenem, and does not require the use of enzyme inhibitors. The activity against gram-negative bacteria, in particular against pseudomonas aeruginosa, is stronger than that against imipenem; the antibacterial activity to gram-positive bacteria needing positive is slightly lower than that of imipenem; the activity against anaerobes is the same as imipenem.
Among the strains sensitive to biapenem are: staphylococcus, Streptococcus, pneumococcus, enterococcus (except enterococcus faecium), Moraxella, Escherichia, Citrobacter, Klebsiella, Enterobacter, Serratia, Proteus, Haemophilus influenzae, Pseudomonas aeruginosa, Actinomyces, Peptostreptococcus, Bacteroides, Proteus, and Clostridium.
Biapenem is suitable for treating septicemia, pneumonia, lung abscess, secondary infection caused by chronic respiratory diseases, refractory cystitis, pyelonephritis, peritonitis, and gynecological adnexitis caused by sensitive bacteria.
Biapenem is called Biapenem in English, and has the chemical name of (-)6- [ [ (4R,5S,6S) -2-carboxyl-6- [ (1R) -1-hydroxyethyl ] -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-en-3-yl ] thio ] -6, 7-dihydro-5H-pyrazolo [1,2-a ] [1,2,4] triazol-4-ium inner salt, and the chemical structural formula is as follows:
molecular formula C15H18N4O4S, molecular weight: 350.40, inner salt white or white-like powder. Is soluble in water and insoluble in common organic solvents.
The existing crystallization method of biapenem comprises the following steps: at low temperature, a large amount of water is added to dissolve biapenem, and then a large amount of acetone is added for crystallization. Because the low-temperature dissolution is carried out, the water consumption for dissolution is large. Because the dissolution concentration is lower and the precipitation is slower, the crystallization time is long, the acetone dosage is large, the yield is low and the color grade is higher.
How to improve the crystallization method, control the color grade of the product, improve the product quality, reduce the impurity types and directly influence the medication safety, therefore, the research of the biapenem crystallization method has very important significance.
Disclosure of Invention
The technical problem to be solved by the invention is to provide a biapenem crystallization method, which has the advantages of short operation period, less wastewater discharge, less solvent consumption and environmental protection, and the obtained biapenem has high purity, low color grade and 1# and is safer to use.
The invention provides a crystallization method of biapenem, which comprises the following steps:
(1) dissolving: adding the biapenem crude product into water, wherein the weight ratio of biapenem to water is 1: 8-12, heating to 40-50 ℃, and stirring to dissolve until the biapenem crude product is dissolved and clarified;
(2) decarbonization: adding activated carbon for decolorization, and then filtering to obtain a filtrate;
(3) and cooling to 10-20 ℃, precipitating biapenem crystals, and adding acetone for further dissolution and crystallization to obtain biapenem.
Preferably, in the step (1), the weight ratio of biapenem to water in dissolving is 1: 10.
preferably, in the step (2), in the decarbonization process, 1-2% by weight of activated carbon is added, preferably 1.5%.
Preferably, in the step (2), activated carbon is added for decoloring for 10-15 minutes in the decarburization process.
Preferably, in the step (2), the filtration after decolorization is performed by using a 0.45 μm filter membrane.
Preferably, in the step (3), the volume of the acetone added is 3-5 times, preferably 3 times of the volume of the water in the step (1)
The invention provides a crystallization method of biapenem, which comprises the following steps:
adding 10g of biapenem crude product with the purity of 98.2% into 100ml of water, heating to 40-50 ℃ for 10-15 min, stirring for dissolving until the crude product is clear and bright, adding 1g of activated carbon, stirring for decoloring for 10 min, then filtering by using a 0.45 micron filter membrane to obtain filtrate, cooling to 10-20 ℃ within 5 min, precipitating biapenem crystals, adding 300ml of acetone, further dissolving and crystallizing for 2 h to obtain 9.30g of biapenem, wherein the yield is 93.0%, the purity is 99.4%, and the color level is # 1.
Adopt the produced beneficial effect of above-mentioned technical scheme to lie in:
(1) the method has short operation period and shortens the time by 200 percent.
(2) The method has the advantages of reducing water consumption by 50%, reducing acetone by 50%, reducing environmental-friendly discharged wastewater by 20%, and having environmental-friendly advantages.
(3) The method has the advantages of improving the yield by 5 percent, reducing the cost by 10 percent and being beneficial to reducing the material loss.
(4) The method is favorable for the precipitation of products for products difficult to crystallize due to high crystallization concentration, reduces the precipitation in the impurity crystallization process, is favorable for improving the product purity, and simultaneously has better color grade of the products. And the medication safety of the product is improved.
Detailed Description
The present invention will be described in more detail with reference to the following embodiments, which should not be construed as limiting the scope of the present invention.
Example 1
10g of biapenem crude product (with the purity of 98.2%) is added into 100ml of water, the temperature is raised to 40-50 ℃ for 10-15 minutes, and the mixture is stirred and dissolved until the mixture is clear and bright. Adding 1.5g of activated carbon, stirring and decoloring for 10 minutes, and then filtering by using a 0.45-micrometer filter membrane to obtain a filtrate; reducing the temperature to 10-20 ℃ within 5 minutes, separating out biapenem crystals, adding 300ml of acetone, further carrying out dissolution and crystallization for 2 hours to obtain 9.30g of biapenem, wherein the yield is 93.0%, the purity is 99.4%, and the color grade is # 1.
Compared with comparative example 1, the yield is improved by 11%, the purity is improved by 0.5%, and the color grade is reduced from 2# to 1 #.
Example 2
9g of biapenem crude product (with the purity of 98.2%) is added into 100ml of water, the temperature is raised to 40-50 ℃ within 10-15 minutes, and the mixture is stirred, dissolved and brightened. Adding 1.2g of activated carbon, stirring and decoloring for 10 minutes, and then filtering by using a 0.45-micrometer filter membrane to obtain a filtrate; reducing the temperature to 10-20 ℃ within 5 minutes, separating out biapenem crystals, adding 300ml of acetone, and further carrying out dissolution and crystallization to obtain 8.01g of biapenem, wherein the yield is 89.0%, the purity is 99.5%, and the color grade is # 1. Compared with comparative example 1, the yield is improved by 9 percent, the purity is improved by 0.8 percent, and the color grade is reduced by 1 #.
Example 3
11g of biapenem crude product (with the purity of 98.2%) is added into 110ml of water, the temperature is raised to 40-50 ℃ within 10-15 minutes, and the mixture is stirred, dissolved and brightened. Adding 1.5g of activated carbon for decoloring for 10 minutes, and then filtering by using a 0.45-micrometer filter membrane to obtain a filtrate; rapidly cooling to 10-20 ℃ within 5 minutes, precipitating biapenem crystals, adding 300ml of acetone, and further carrying out dissolution and crystallization to obtain 10.1g of biapenem, wherein the yield is 91.9%, the purity is 99.3%, and the color grade is # 1. Compared with comparative example 1, the yield is improved by 11.9%, the purity is improved by 0.6%, and the color grade is reduced by 1 #.
Comparative example 1
At 25 ℃, 10g of biapenem was dissolved in 200ml of water, and then 700ml of acetone was added thereto to conduct crystallization for 6 hours. The yield of biapenem crystal is 80%, the purity is 98.7%, and the color grade is No. 2.
Comparative example 2
At 20 ℃, 10g of biapenem was dissolved in 200ml of water, and then 600ml of acetone was added to crystallize for 6.5 hours. The yield of biapenem crystal is 82%, the purity is 98.5%, and the color grade is No. 2.
The existing crystallization method of biapenem is to dissolve at the temperature of 20-25 ℃, compared with the technical scheme of the invention, the water consumption is about twice more, and in order to separate out crystals, the time is prolonged, and the acetone consumption is also twice more. The operation time is long, the water consumption and the solvent consumption are more, the environmental protection treatment burden is large due to a large amount of waste water generated in the environmental protection process, the operation period is long, and degradation and new impurities are easily generated. The crystallization method of biapenem has the advantages of simple operation, short period, less waste water discharge, environmental protection, high purity of biapenem product, low color level 1# and safe medication.
Claims (9)
1. A crystallization method of biapenem comprises the following steps:
(1) dissolving: adding the biapenem crude product into water, wherein the weight ratio of biapenem to water is 1: 8-12, heating to 40-50 ℃, and stirring to dissolve until the biapenem crude product is dissolved and clarified;
(2) decarbonization: adding activated carbon for decolorization, and then filtering to obtain a filtrate;
(3) and cooling to 10-20 ℃, precipitating biapenem crystals, and adding acetone for further dissolution and crystallization to obtain biapenem.
2. The method of claim 1, wherein in step (1) the weight ratio of biapenem to water is 1: 10.
3. The method of claim 1, wherein in step (2), 1-2% by weight of activated carbon, preferably 1.5% by weight of activated carbon, is added.
4. The method of claim 3, wherein in step (2), 1.5% by weight of activated carbon is added.
5. The method according to claim 1, wherein in the step (2), activated carbon is added for decoloring for 10 to 15 minutes during the decarburization process.
6. The method according to claim 1, wherein in the step (2), the filtration after the decolorization is performed by using a 0.45 μm filter membrane.
7. The method according to claim 1, wherein in step (3), the volume of acetone added is 3 to 5 times the volume of water in step (1).
8. The method of claim 7, wherein in step (3), the volume of acetone added is 3 times the volume of water added in step (1).
9. The invention provides a crystallization method of biapenem, which comprises the following steps: adding 10g of biapenem crude product with the purity of 98.2% into 100ml of water, heating to 40-50 ℃ for 10-15 min, stirring for dissolving until the crude product is clear and bright, adding 1g of activated carbon, stirring for decoloring for 10 min, then filtering by using a 0.45 micron filter membrane to obtain filtrate, cooling to 10-20 ℃ within 5 min, precipitating biapenem crystals, adding 300ml of acetone, further dissolving and crystallizing for 2 h to obtain 9.30g of biapenem, wherein the yield is 93.0%, the purity is 99.4%, and the color level is # 1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111283627.9A CN113912629A (en) | 2021-11-01 | 2021-11-01 | Crystallization method of biapenem |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111283627.9A CN113912629A (en) | 2021-11-01 | 2021-11-01 | Crystallization method of biapenem |
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| CN202111283627.9A Pending CN113912629A (en) | 2021-11-01 | 2021-11-01 | Crystallization method of biapenem |
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2021
- 2021-11-01 CN CN202111283627.9A patent/CN113912629A/en active Pending
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Application publication date: 20220111 |
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