CN113979961A - Linezolid impurity and preparation method thereof - Google Patents
Linezolid impurity and preparation method thereof Download PDFInfo
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- CN113979961A CN113979961A CN202111312957.6A CN202111312957A CN113979961A CN 113979961 A CN113979961 A CN 113979961A CN 202111312957 A CN202111312957 A CN 202111312957A CN 113979961 A CN113979961 A CN 113979961A
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- 229960003907 linezolid Drugs 0.000 title claims abstract description 40
- TYZROVQLWOKYKF-ZDUSSCGKSA-N linezolid Chemical compound O=C1O[C@@H](CNC(=O)C)CN1C(C=C1F)=CC=C1N1CCOCC1 TYZROVQLWOKYKF-ZDUSSCGKSA-N 0.000 title claims abstract description 40
- 239000012535 impurity Substances 0.000 title claims abstract description 35
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 63
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims abstract description 60
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims abstract description 45
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims abstract description 21
- WYVAMUWZEOHJOQ-UHFFFAOYSA-N propionic anhydride Chemical compound CCC(=O)OC(=O)CC WYVAMUWZEOHJOQ-UHFFFAOYSA-N 0.000 claims abstract description 14
- 238000004440 column chromatography Methods 0.000 claims abstract description 13
- 238000000034 method Methods 0.000 claims abstract description 8
- 238000001035 drying Methods 0.000 claims abstract description 7
- 239000007788 liquid Substances 0.000 claims abstract description 7
- 239000012074 organic phase Substances 0.000 claims abstract description 7
- 238000006243 chemical reaction Methods 0.000 claims abstract description 3
- 229940087646 methanolamine Drugs 0.000 claims abstract 2
- 238000001816 cooling Methods 0.000 claims description 10
- 239000003480 eluent Substances 0.000 claims description 8
- 150000001875 compounds Chemical class 0.000 claims description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 4
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 2
- 238000000605 extraction Methods 0.000 claims description 2
- 235000019253 formic acid Nutrition 0.000 claims description 2
- 239000003208 petroleum Substances 0.000 claims description 2
- 239000003814 drug Substances 0.000 description 5
- 206010059866 Drug resistance Diseases 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 238000005303 weighing Methods 0.000 description 4
- 229940079593 drug Drugs 0.000 description 3
- 230000014616 translation Effects 0.000 description 3
- 108010077805 Bacterial Proteins Proteins 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 230000000845 anti-microbial effect Effects 0.000 description 2
- 230000001580 bacterial effect Effects 0.000 description 2
- 210000001124 body fluid Anatomy 0.000 description 2
- 239000010839 body fluid Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 230000000977 initiatory effect Effects 0.000 description 2
- 238000001243 protein synthesis Methods 0.000 description 2
- 238000003908 quality control method Methods 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical compound O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 241000192125 Firmicutes Species 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 108090000279 Peptidyltransferases Proteins 0.000 description 1
- 229940123573 Protein synthesis inhibitor Drugs 0.000 description 1
- 244000052616 bacterial pathogen Species 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 108020004999 messenger RNA Proteins 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000010587 phase diagram Methods 0.000 description 1
- 239000000007 protein synthesis inhibitor Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 210000004708 ribosome subunit Anatomy 0.000 description 1
- 238000013519 translation Methods 0.000 description 1
Images
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D263/18—Oxygen atoms
- C07D263/20—Oxygen atoms attached in position 2
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention discloses a linezolid impurity 2 as shown in a formula I and a preparation method thereof, wherein the preparation method comprises the following steps: taking linezolid impurity 1, adding dichloromethane, methanol and triethylamine, wherein the mass of the linezolid impurity, the mass of the dichloromethane and the mass of the methanol are as follows: volume: volume: volume = 1: 10-40: 5-10: 2-5, mass: volume: volume: volume = 1: 20: 5: 3, when the mass is g, the volume is ml; adding methyl acetic anhydride after the step I, wherein the mass ratio of the methyl acetic anhydride to the linezolid impurity 1 is 0.4-1.6: 1, preferably 0.8: 1; extracting, separating liquid, drying organic phase and concentrating; step four, column chromatography is carried out, and the reaction is carried out by using ethyl acetate: methanol = 7: 1, eluting to obtain the product. The linezolid impurity 2 prepared by the method has good purity and high yield.
Description
Technical Field
The invention relates to the field of medicines, and particularly relates to linezolid impurity 2 and a preparation method thereof.
Background
Linezolid is an artificially synthesized oxazolidinone antibacterial, has good antibacterial activity on most gram-positive pathogenic bacteria, has no cross-drug resistance with other antibacterial agents, and has wide tissue and body fluid distribution and convenient administration method, so that the linezolid has good effectiveness and safety in treating the infection of the multi-drug-resistant gram-positive bacteria, and is widely concerned clinically. Linezolid has a unique antimicrobial spectrum and antimicrobial activity, and its good tissue and body fluid distribution characteristics make it clinically important.
Linezolid is a bacterial protein synthesis inhibitor, acting on the bacterial 50S ribosomal subunit and closest to the site of action. Unlike other drugs, linezolid does not affect peptidyl transferase activity, but acts on the initiation stage of the translation system to inhibit mRNA binding to the ribosome and prevent the formation of 70S initiation complexes, thereby inhibiting bacterial protein synthesis. The linezolid has unique action site and mode, so that the linezolid is not easy to generate cross drug resistance with other antibacterial agents for inhibiting protein synthesis in positive bacteria with intrinsic or acquired drug resistance characteristics, and is not easy to induce the generation of bacterial drug resistance in vitro.
The pharmaceutical impurities are closely related to the quality, safety and efficacy of the medicine, and the importance of impurity control in the development and research of the medicine is more and more emphasized.
In the prior art, impurity 2 in linezolid is not found, and a preparation method is not available, so that the requirements of the pharmaceutical industry on quality control, safety and the like of linezolid cannot be met. Therefore, the invention provides linezolid impurity 2 and a preparation method thereof.
Disclosure of Invention
The invention mainly solves the technical problems that the prior art does not find that the linezolid contains the impurity 2 and does not have a preparation method of the impurity 2, so that the requirements of the pharmaceutical industry on the quality control, safety and the like of the linezolid cannot be met.
In order to solve the technical problem, the technical scheme is as follows: provides a linezolid impurity 2 which is a compound shown as a formula I:
formula I
The inventors discovered impurity 2 accidentally in the experiment, and the existence of the compound of formula I is not reported at present, and even nobody finds that the compound of formula I exists in linezolid.
A method for preparing linezolid impurity 2, comprising the steps of:
taking linezolid impurity 1, adding dichloromethane l and triethylamine, wherein the linezolid impurity, dichloromethane and mass are as follows: volume: volume: volume = 1: 10-40: 5-10: 2-5, preferably, the mass: volume: volume: volume = 1: 20: 5: 3, cooling, wherein when the mass is g, the volume is ml;
adding methyl acetic anhydride after the step I, wherein the mass ratio of the methyl acetic anhydride to the linezolid impurity 1 is 0.4-1.6: 1, preferably 0.8: 1;
extracting, separating liquid, drying organic phase and concentrating;
step four, column chromatography is carried out, and the reaction is carried out by using ethyl acetate: methanol = 7: 1, eluting to obtain the product.
Further, in the step I, cooling is carried out, wherein the cooling temperature is 0-5 ℃.
Further, the step (II) of adding the methyl acetic anhydride is to dropwise add the methyl acetic anhydride, and the dropwise addition is completed within 5min in the embodiment of the invention.
Further, the extractant extracted in the third step comprises: dichloromethane, formic acid, ethyl acetate, preferably dichloromethane.
Further, in the step (iv), the column chromatography is performed, and an eluent includes: one or more of ethyl acetate, methanol, petroleum ether, and methylene chloride … …, in one embodiment of the invention, ethyl acetate and methanol.
Further, the extraction in the third step is repeated for 2 times, the dosage of the extracting agent is that the volume-to-mass ratio of the extracting agent to the linezolid impurity 1 is 50-100, preferably 100:1, when the volume is ml, the mass is g
Further, in the step (iv), the eluent is ethyl acetate: methanol =5 to 10: 1, preferably 7: 1.
the method has the beneficial effects that the linezolid impurity 2 prepared by the method has good purity and high yield.
Drawings
FIG. 1 is a hydrogen spectrum of the compound of formula (I) obtained in example 1;
FIG. 2 is a mass spectrum of the compound of formula (I) obtained in example 1;
FIG. 3 is a liquid phase diagram of the compound of formula (I) obtained in example 1.
Detailed Description
Example 1
Linezolid impurity 1 Linezolid impurity 2
Weighing 1g of linezolid impurity 1, adding 10ml of dichloromethane, 5ml of methanol and 2ml of triethylamine, cooling to 0-5 ℃, dropwise adding 0.4g of methyl acetic anhydride, continuously stirring for 30min after dropwise adding within 5min, extracting and separating liquid, extracting with 2X 50 dichloromethane, drying an organic phase, concentrating under reduced pressure to obtain a light yellow oily substance, performing column chromatography, and performing column chromatography by using ethyl acetate: methanol = 7: 1, collecting the eluent, and concentrating under reduced pressure to obtain 0.62g of white solid.
Example 2
Weighing 1g of linezolid impurity 1, adding dichloromethane 20ml, methanol 5ml and triethylamine 3ml, cooling to 0-5 ℃, dropwise adding 0.8g of methyl acetic anhydride, stirring for 30min continuously, extracting and separating liquid, extracting with 2 x 70 dichloromethane, drying organic phase, concentrating under reduced pressure to obtain light yellow oily substance, performing column chromatography, and performing column chromatography with ethyl acetate: methanol = 7: 1, collecting the eluent, and concentrating under reduced pressure to obtain 0.71g of white solid.
Example 3
Weighing 1g of linezolid impurity 1, adding dichloromethane 30ml, methanol 10ml and triethylamine 4ml, cooling to 0-5 ℃, dropwise adding 1.2g of methyl acetic anhydride, completing dropwise adding within 5min, continuing stirring for 30min, extracting and separating liquid, extracting with 2X 100 dichloromethane, drying organic phase, concentrating under reduced pressure to obtain light yellow oily substance, performing column chromatography, and performing column chromatography by using ethyl acetate: methanol = 7: 1, collecting the eluent, and concentrating under reduced pressure to obtain 0.65g of white solid.
Example 4
Weighing 1g of linezolid impurity 1, adding 40ml of dichloromethane, 10ml of methanol and 5ml of triethylamine, cooling to 0-5 ℃, dropwise adding 1.6g of methyl acetic anhydride, stirring for 30min continuously after dropwise adding within 5min, extracting and separating liquid, extracting with 2 x 80 dichloromethane, drying organic phase, concentrating under reduced pressure to obtain light yellow oily substance, performing column chromatography, and performing column chromatography by using ethyl acetate: methanol = 7: 1, collecting the eluent, and concentrating under reduced pressure to obtain 0.51g of white solid.
The above description is only an embodiment of the present invention, and not intended to limit the scope of the present invention, and all modifications of equivalent structures and equivalent processes, which are made by the present specification, or directly or indirectly applied to other related technical fields, are included in the scope of the present invention.
Claims (8)
1. Linezolid impurity 2 is characterized in that the impurity 2 is a compound shown as a formula I,
formula I.
2. A preparation method of linezolid impurity 2 is characterized by comprising the following steps:
taking linezolid impurity 1, adding dichloromethane, methanol and triethylamine, wherein the mass of the linezolid impurity, the mass of the dichloromethane and the mass of the methanol are as follows: volume: volume: volume = 1: 10-40: 5-10: 2-5, preferably, the mass: volume: volume: volume = 1: 20: 5: 3, cooling, wherein when the mass is g, the volume is ml;
cooling, and adding methyl acetic anhydride, wherein the mass ratio of the methyl acetic anhydride to the linezolid impurity 1 is 0.4-1.6: 1, preferably 0.8: 1;
extracting, separating liquid, drying organic phase and concentrating;
step four, column chromatography is carried out, and the reaction is carried out by using ethyl acetate: methanol = 7: 1, eluting to obtain the product.
3. The method according to claim 2, wherein the cooling in step (i) is carried out at a temperature of 0 to 5 ℃.
4. The method according to claim 2, wherein the step of adding methyl acetic anhydride is dropwise adding methyl acetic anhydride.
5. The preparation method of claim 2, wherein the extractant extracted in step (c) comprises: dichloromethane, formic acid, ethyl acetate, preferably dichloromethane.
6. The preparation method according to claim 2, wherein the extraction in the step (c) is repeated for 2 times, and the dosage of the extractant is such that the volume-to-mass ratio of the extractant to linezolid impurity 1 is 50-100, preferably 100:1, and the mass is g when the volume is ml.
7. The preparation method according to claim 2, wherein in the step (iv), the column chromatography is performed, and an eluent comprises: one or more of ethyl acetate, methanol, petroleum ether and dichloromethane, preferably ethyl acetate and methanol.
8. The preparation method according to claim 6, wherein in the step (iv), the volume ratio of the eluent is ethyl acetate: 5-10% of methanol: 1, preferably 7: 1.
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| Application Number | Priority Date | Filing Date | Title |
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| CN202111312957.6A CN113979961A (en) | 2021-11-08 | 2021-11-08 | Linezolid impurity and preparation method thereof |
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| CN202111312957.6A CN113979961A (en) | 2021-11-08 | 2021-11-08 | Linezolid impurity and preparation method thereof |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103570639A (en) * | 2012-08-08 | 2014-02-12 | 成都国弘医药有限公司 | Synthetic method of linezolid |
| CN105111160A (en) * | 2015-09-11 | 2015-12-02 | 浙江新东港药业股份有限公司 | Linezolid preparation method |
| CN110015969A (en) * | 2019-04-28 | 2019-07-16 | 梯尔希（南京）药物研发有限公司 | A kind of synthetic method of Linezolid impurity |
| CN110256372A (en) * | 2019-07-16 | 2019-09-20 | 威海迪素制药有限公司 | A kind of Linezolid impurity and preparation method |
-
2021
- 2021-11-08 CN CN202111312957.6A patent/CN113979961A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103570639A (en) * | 2012-08-08 | 2014-02-12 | 成都国弘医药有限公司 | Synthetic method of linezolid |
| CN105111160A (en) * | 2015-09-11 | 2015-12-02 | 浙江新东港药业股份有限公司 | Linezolid preparation method |
| CN110015969A (en) * | 2019-04-28 | 2019-07-16 | 梯尔希（南京）药物研发有限公司 | A kind of synthetic method of Linezolid impurity |
| CN110256372A (en) * | 2019-07-16 | 2019-09-20 | 威海迪素制药有限公司 | A kind of Linezolid impurity and preparation method |
Non-Patent Citations (1)
| Title |
|---|
| 美国化学会: ""RN 908095-06-7"", 《STN ON THE WEB》 * |
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Application publication date: 20220128 |
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