CN105198904B - 左氧氟沙星及氧氟沙星的制备方法 - Google Patents
左氧氟沙星及氧氟沙星的制备方法 Download PDFInfo
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- CN105198904B CN105198904B CN201410290425.0A CN201410290425A CN105198904B CN 105198904 B CN105198904 B CN 105198904B CN 201410290425 A CN201410290425 A CN 201410290425A CN 105198904 B CN105198904 B CN 105198904B
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- ofloxacin
- lavo
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- water
- organic solvent
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- 229960001699 ofloxacin Drugs 0.000 title claims abstract description 120
- GSDSWSVVBLHKDQ-UHFFFAOYSA-N 9-fluoro-3-methyl-10-(4-methylpiperazin-1-yl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acid Chemical compound FC1=CC(C(C(C(O)=O)=C2)=O)=C3N2C(C)COC3=C1N1CCN(C)CC1 GSDSWSVVBLHKDQ-UHFFFAOYSA-N 0.000 title claims abstract description 53
- 238000002360 preparation method Methods 0.000 title claims abstract description 52
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims abstract description 54
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 54
- 239000003960 organic solvent Substances 0.000 claims abstract description 39
- 238000006243 chemical reaction Methods 0.000 claims abstract description 38
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims abstract description 35
- 125000004494 ethyl ester group Chemical group 0.000 claims abstract description 30
- 150000004893 oxazines Chemical class 0.000 claims abstract description 28
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical class CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 claims abstract description 27
- 239000002253 acid Substances 0.000 claims abstract description 17
- 239000012046 mixed solvent Substances 0.000 claims abstract description 16
- 239000000203 mixture Substances 0.000 claims abstract description 14
- 239000002994 raw material Substances 0.000 claims abstract description 8
- 230000007062 hydrolysis Effects 0.000 claims description 24
- 238000006460 hydrolysis reaction Methods 0.000 claims description 24
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 21
- 239000003513 alkali Substances 0.000 claims description 21
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 20
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 12
- 239000001257 hydrogen Substances 0.000 claims description 11
- 229910052739 hydrogen Inorganic materials 0.000 claims description 11
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 9
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 8
- 239000001301 oxygen Substances 0.000 claims description 5
- 229910052760 oxygen Inorganic materials 0.000 claims description 5
- GSDSWSVVBLHKDQ-JTQLQIEISA-N Levofloxacin Chemical compound C([C@@H](N1C2=C(C(C(C(O)=O)=C1)=O)C=C1F)C)OC2=C1N1CCN(C)CC1 GSDSWSVVBLHKDQ-JTQLQIEISA-N 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
- 239000002585 base Substances 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 229960003376 levofloxacin Drugs 0.000 claims description 2
- -1 Hydrogen furans Chemical class 0.000 claims 2
- 229960004273 floxacillin Drugs 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract description 6
- 150000001735 carboxylic acids Chemical class 0.000 abstract 2
- OEHYGCZCGGEXKX-LBPRGKRZSA-N levofloxacin ethyl ester Chemical compound C([C@H](C)N1C=C(C(C(=C11)C=C2F)=O)C(=O)OCC)OC1=C2N1CCN(C)CC1 OEHYGCZCGGEXKX-LBPRGKRZSA-N 0.000 abstract 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 abstract 2
- PQIOSYKVBBWRRI-UHFFFAOYSA-N methylphosphonyl difluoride Chemical group CP(F)(F)=O PQIOSYKVBBWRRI-UHFFFAOYSA-N 0.000 abstract 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
- 238000006467 substitution reaction Methods 0.000 description 10
- 238000002425 crystallisation Methods 0.000 description 8
- 230000008025 crystallization Effects 0.000 description 8
- 238000000605 extraction Methods 0.000 description 8
- 238000009413 insulation Methods 0.000 description 8
- 150000004965 peroxy acids Chemical class 0.000 description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 8
- 238000005406 washing Methods 0.000 description 8
- 230000000844 anti-bacterial effect Effects 0.000 description 7
- 241000894006 Bacteria Species 0.000 description 6
- UOBPHQJGWSVXFS-UHFFFAOYSA-N [O].[F] Chemical compound [O].[F] UOBPHQJGWSVXFS-UHFFFAOYSA-N 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- 238000010792 warming Methods 0.000 description 6
- 229960000583 acetic acid Drugs 0.000 description 5
- 208000015181 infectious disease Diseases 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 239000002351 wastewater Substances 0.000 description 4
- 239000012362 glacial acetic acid Substances 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 241000202934 Mycoplasma pneumoniae Species 0.000 description 2
- 241000191967 Staphylococcus aureus Species 0.000 description 2
- 238000005903 acid hydrolysis reaction Methods 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 150000007942 carboxylates Chemical class 0.000 description 2
- 230000007812 deficiency Effects 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 150000003222 pyridines Chemical class 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 241001148471 unidentified anaerobic bacterium Species 0.000 description 2
- 241000193830 Bacillus <bacterium> Species 0.000 description 1
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 description 1
- 241000588921 Enterobacteriaceae Species 0.000 description 1
- 241000192125 Firmicutes Species 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 1
- 241000606768 Haemophilus influenzae Species 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 241000589248 Legionella Species 0.000 description 1
- 208000007764 Legionnaires' Disease Diseases 0.000 description 1
- RJQXTJLFIWVMTO-TYNCELHUSA-N Methicillin Chemical compound COC1=CC=CC(OC)=C1C(=O)N[C@@H]1C(=O)N2[C@@H](C(O)=O)C(C)(C)S[C@@H]21 RJQXTJLFIWVMTO-TYNCELHUSA-N 0.000 description 1
- TZJKHERXIDPDTK-UHFFFAOYSA-N N1=CC=CC2=CC=CC=C12.[F] Chemical compound N1=CC=CC2=CC=CC=C12.[F] TZJKHERXIDPDTK-UHFFFAOYSA-N 0.000 description 1
- ABOLPUDOABZSNW-UHFFFAOYSA-N N1CCNCC1.CC1=C(C=C(C(=O)O)C=C1)C(=O)O Chemical compound N1CCNCC1.CC1=C(C=C(C(=O)O)C=C1)C(=O)O ABOLPUDOABZSNW-UHFFFAOYSA-N 0.000 description 1
- 241000588653 Neisseria Species 0.000 description 1
- 241000588652 Neisseria gonorrhoeae Species 0.000 description 1
- NVKWWNNJFKZNJO-YFKPBYRVSA-N Ofloxacin impurity a Chemical compound N1([C@@H](C)CO2)C=C(C(O)=O)C(=O)C3=C1C2=C(F)C(F)=C3 NVKWWNNJFKZNJO-YFKPBYRVSA-N 0.000 description 1
- 241000588769 Proteus <enterobacteria> Species 0.000 description 1
- 241000589516 Pseudomonas Species 0.000 description 1
- 241000589517 Pseudomonas aeruginosa Species 0.000 description 1
- 206010057190 Respiratory tract infections Diseases 0.000 description 1
- 241000607142 Salmonella Species 0.000 description 1
- 208000019802 Sexually transmitted disease Diseases 0.000 description 1
- 241000607768 Shigella Species 0.000 description 1
- 206010062255 Soft tissue infection Diseases 0.000 description 1
- 201000005010 Streptococcus pneumonia Diseases 0.000 description 1
- 241000193998 Streptococcus pneumoniae Species 0.000 description 1
- 241000193996 Streptococcus pyogenes Species 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- 230000002421 anti-septic effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 210000003445 biliary tract Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 150000001733 carboxylic acid esters Chemical class 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000007797 corrosion Effects 0.000 description 1
- 238000005260 corrosion Methods 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- HPYNZHMRTTWQTB-UHFFFAOYSA-N dimethylpyridine Natural products CC1=CC=CN=C1C HPYNZHMRTTWQTB-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000009513 drug distribution Methods 0.000 description 1
- 238000010931 ester hydrolysis Methods 0.000 description 1
- 229940047650 haemophilus influenzae Drugs 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 239000010985 leather Substances 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 229960003085 meticillin Drugs 0.000 description 1
- JKQOBWVOAYFWKG-UHFFFAOYSA-N molybdenum trioxide Chemical compound O=[Mo](=O)=O JKQOBWVOAYFWKG-UHFFFAOYSA-N 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 238000012805 post-processing Methods 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000004576 sand Substances 0.000 description 1
- 206010040872 skin infection Diseases 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- KKCBUQHMOMHUOY-UHFFFAOYSA-N sodium oxide Chemical compound [O-2].[Na+].[Na+] KKCBUQHMOMHUOY-UHFFFAOYSA-N 0.000 description 1
- 229910001948 sodium oxide Inorganic materials 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000007039 two-step reaction Methods 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
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- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Abstract
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CN201410290425.0A CN105198904B (zh) | 2014-06-25 | 2014-06-25 | 左氧氟沙星及氧氟沙星的制备方法 |
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CN201410290425.0A CN105198904B (zh) | 2014-06-25 | 2014-06-25 | 左氧氟沙星及氧氟沙星的制备方法 |
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CN105198904A CN105198904A (zh) | 2015-12-30 |
CN105198904B true CN105198904B (zh) | 2017-08-15 |
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Families Citing this family (3)
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CN107216342A (zh) * | 2017-06-08 | 2017-09-29 | 武汉励合生物医药科技有限公司 | 一种氧氟沙星的合成工艺 |
CN113493466A (zh) * | 2020-03-20 | 2021-10-12 | 上海安谱实验科技股份有限公司 | 一种稳定同位素标记的氧氟沙星及其合成方法 |
CN114478573A (zh) * | 2022-01-26 | 2022-05-13 | 上虞京新药业有限公司 | 一种左氧氟沙星的合成方法 |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN85101662A (zh) * | 1985-03-20 | 1987-01-17 | 杏林制药株式会社 | 制备喹啉羧酸衍生物的工艺 |
CN1496409A (zh) * | 2001-03-07 | 2004-05-12 | ��һ��������ҩ��ʽ���� | 光学活性的丙氧基苯胺衍生物的制备方法 |
CN1594320A (zh) * | 2004-06-22 | 2005-03-16 | 浙江医药股份有限公司新昌制药厂 | 左旋氧氟沙星和氧氟沙星的制备方法 |
CN101307060A (zh) * | 2008-07-04 | 2008-11-19 | 浙江京新药业股份有限公司 | 左氧氟沙星半水化合物的制备工艺 |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20100029938A1 (en) * | 2006-12-22 | 2010-02-04 | Farmaprojects, S. A. | Process for the preparation of an antibacterial quinolone compound |
-
2014
- 2014-06-25 CN CN201410290425.0A patent/CN105198904B/zh active Active
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN85101662A (zh) * | 1985-03-20 | 1987-01-17 | 杏林制药株式会社 | 制备喹啉羧酸衍生物的工艺 |
CN1496409A (zh) * | 2001-03-07 | 2004-05-12 | ��һ��������ҩ��ʽ���� | 光学活性的丙氧基苯胺衍生物的制备方法 |
CN1594320A (zh) * | 2004-06-22 | 2005-03-16 | 浙江医药股份有限公司新昌制药厂 | 左旋氧氟沙星和氧氟沙星的制备方法 |
CN101307060A (zh) * | 2008-07-04 | 2008-11-19 | 浙江京新药业股份有限公司 | 左氧氟沙星半水化合物的制备工艺 |
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Address after: 31 Weisan Road, Shangyu Economic and Technological Development Zone, Hangzhou Bay, Shangyu City, Shaoxing City, Zhejiang Province, China, 312369 Patentee after: Shaoxing Jingxin Pharmaceutical Co.,Ltd. Address before: 31 Weisan Road, Shangyu Industrial Park, Hangzhou Bay, Shaoxing City, Zhejiang Province, China Patentee before: SHANGYU JINGXIN PHARMACEUTICAL Co.,Ltd. |
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Address after: 312369 No.31, Weisan Road, Shangyu economic and Technological Development Zone, Hangzhou Bay, Shaoxing City, Zhejiang Province Patentee after: Shaoxing Jingxin Pharmaceutical Co.,Ltd. Country or region after: China Address before: 31 Weisan Road, Shangyu Economic and Technological Development Zone, Hangzhou Bay, Shangyu City, Shaoxing City, Zhejiang Province, China, 312369 Patentee before: Shaoxing Jingxin Pharmaceutical Co.,Ltd. Country or region before: China |