CN1301254C - Preparation of catifloxacin and purifying method - Google Patents
Preparation of catifloxacin and purifying method Download PDFInfo
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- CN1301254C CN1301254C CNB2004100803139A CN200410080313A CN1301254C CN 1301254 C CN1301254 C CN 1301254C CN B2004100803139 A CNB2004100803139 A CN B2004100803139A CN 200410080313 A CN200410080313 A CN 200410080313A CN 1301254 C CN1301254 C CN 1301254C
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- Prior art keywords
- gatifloxacin
- purifying
- preparation according
- acid
- iib
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Links
- 238000000034 method Methods 0.000 title claims abstract description 27
- 238000002360 preparation method Methods 0.000 title claims abstract description 21
- 238000006243 chemical reaction Methods 0.000 claims abstract description 13
- 239000002253 acid Substances 0.000 claims abstract description 9
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 claims abstract description 7
- 239000002798 polar solvent Substances 0.000 claims abstract description 6
- 239000000843 powder Substances 0.000 claims abstract description 5
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 4
- XUBOMFCQGDBHNK-JTQLQIEISA-N (S)-gatifloxacin Chemical compound FC1=CC(C(C(C(O)=O)=CN2C3CC3)=O)=C2C(OC)=C1N1CCN[C@@H](C)C1 XUBOMFCQGDBHNK-JTQLQIEISA-N 0.000 claims description 34
- 229960003923 gatifloxacin Drugs 0.000 claims description 34
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 21
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 18
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 10
- 150000002148 esters Chemical class 0.000 claims description 10
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- 238000006460 hydrolysis reaction Methods 0.000 claims description 6
- LOAUVZALPPNFOQ-UHFFFAOYSA-N quinaldic acid Chemical compound C1=CC=CC2=NC(C(=O)O)=CC=C21 LOAUVZALPPNFOQ-UHFFFAOYSA-N 0.000 claims description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 4
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 4
- 239000003153 chemical reaction reagent Substances 0.000 claims description 4
- 230000003301 hydrolyzing effect Effects 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- 230000007062 hydrolysis Effects 0.000 claims description 3
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 3
- 238000004128 high performance liquid chromatography Methods 0.000 abstract description 4
- 238000000746 purification Methods 0.000 abstract description 4
- -1 quinolinecarboxylic ester Chemical class 0.000 abstract description 3
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 abstract description 2
- 239000004327 boric acid Substances 0.000 abstract description 2
- 239000013522 chelant Substances 0.000 abstract 2
- 239000003513 alkali Substances 0.000 abstract 1
- 238000009776 industrial production Methods 0.000 abstract 1
- 239000000203 mixture Substances 0.000 abstract 1
- 238000007670 refining Methods 0.000 abstract 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- 229960000935 dehydrated alcohol Drugs 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 2
- JOMNTHCQHJPVAZ-UHFFFAOYSA-N 2-methylpiperazine Chemical compound CC1CNCCN1 JOMNTHCQHJPVAZ-UHFFFAOYSA-N 0.000 description 1
- 244000025254 Cannabis sativa 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
- NBIIXXVUZAFLBC-UHFFFAOYSA-L Phosphate ion(2-) Chemical compound OP([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-L 0.000 description 1
- 206010034972 Photosensitivity reaction Diseases 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- UNXNGGMLCSMSLH-UHFFFAOYSA-N dihydrogen phosphate;triethylazanium Chemical compound OP(O)(O)=O.CCN(CC)CC UNXNGGMLCSMSLH-UHFFFAOYSA-N 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 1
- 208000007578 phototoxic dermatitis Diseases 0.000 description 1
- 231100000018 phototoxicity Toxicity 0.000 description 1
- 150000007660 quinolones Chemical class 0.000 description 1
- 239000013558 reference substance Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention provides a preparation and purification method for catifloxacin. Cyclized quinolinecarboxylic ester (III) firstly reacts with boric acid and generates chelate (IIb), and the chelate reacts with N-methylpiperazine in the presence of a polar solvent at certain temperature for some time. The mixture is hydrolyzed by a deacidification agent and is respectively processed by acid and diluted alkali, and then catifloxacin white powder is obtained. The obtained catifloxacin has the advantages of good appearance, high purity (which is more than 99.5% through HPLC analysis), high reaction yield and simple refining method, and is suitable for industrial production.
Description
Technical field
The present invention relates to i.e. (±)-1-cyclopropyl-6-fluoro-1 of Gatifloxacin, 4-dihydro-8-methoxyl group-7-(3-methyl isophthalic acid-piperazine)-4-oxo-3-quinoline carboxylic acid's preparation and purification process.
Background technology
Gatifloxacin (gatifloxacin, AM-1155,1), i.e. (±)-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxyl group-7-(3-methyl isophthalic acid-piperazine)-4-oxo-3-quinoline carboxylic acid is a kind of new quinolones antiseptic-germicide, has the advantages that spectrum is efficient, phototoxicity is low.
Existing Gatifloxacin preparation technology all will make quinoline carboxylic acid's cyclized ester (III) earlier, makes Gatifloxacin (I) from quinoline carboxylic acid's cyclized ester (III) again.By quinoline carboxylic acid's cyclized ester (III) preparation Gatifloxacin (I) two kinds of approach are arranged: (1) first method is to get quinoline carboxylic acid's cyclocomplex (IIa) by (III) first hydrolysis, obtains Gatifloxacin (I) with the N methyl piperazine condensation again.Since 8 methoxyl groups push away electronic action by force, make 7-position F reduce greatly as the leavings group activity of nucleophilic substitution reaction, when therefore making (I) by (III), yield is the end of than, only about 20% (referring to EP241206).(2) second method is to form inner complex (IIb) (referring to EP241206) with acid reaction earlier by (III), makes Gatifloxacin (I) with the N methyl piperazine reaction again.
Summary of the invention
The object of the present invention is to provide a kind of method of easy and simple to handle, yield is higher, outward appearance good and product purity is high production Gatifloxacin.
Purpose of the present invention can realize by following technical measures:
In the method for preparation of the present invention and purifying Gatifloxacin, form inner complex (IIb) with acid reaction earlier by quinoline carboxylic acid's cyclized ester (III), again with N methyl piperazine in the presence of polar solvent at a certain temperature the reaction (temperature of reaction is preferably 70-80 ℃, more preferably 78 ℃) for some time (being preferably 2-5 hour, more preferably 3 hours).Use de-acidying agent (being hydrolytic reagent) hydrolysis then as triethylamine, pyridine, to dimethylamino pyridine or dimethyl formamide (DMF).The selective hydrolysis reaction times is 7-13 hour, more preferably 10 hours.Handle respectively with acid and diluted alkaline again, obtain the Gatifloxacin white powder.Gained Gatifloxacin outward appearance is good, purity height (HPLC analyze reach more than 99.5%), and reaction yield higher (totally 52.2%), process for purification is easy, is suitable for suitability for industrialized production.
In the method for the invention, described preferred polar solvent is acetonitrile, dimethyl sulfoxide (DMSO) (DMSO), DMF, tetrahydrofuran (THF) or methylene dichloride, more preferably acetonitrile.
In a preferred embodiment of the invention, preferred hydrolytic reagent be triethylamine, pyridine, to dimethylamino pyridine or DMF.
In a preferred embodiment of the invention, preferred acid is hydrochloric acid, sulfuric acid, phosphoric acid or acetic acid, more preferably concentrated hydrochloric acid.
In a preferred embodiment of the invention, preferred diluted alkaline is sodium hydroxide or potassium hydroxide solution, more preferably the solution of 5-8%, most preferably 5% sodium hydroxide solution.
The present invention is simple to operate, and product appearance is good, and yield is higher, especially can obtain the Gatifloxacin of high purity (it is more than 99.5% that HPLC analyzes).
Embodiment
Embodiment 1.
In the 250ml reaction flask, add Zinc Chloride Anhydrous 0.4g, diacetyl oxide 120ml, be heated to 80 ℃, add boric acid 13.2g then, temperature is controlled at 80-110 ℃, finishes in batches, under 110 ℃ of temperature, stirred 1 hour, and be cooled to 80 ℃ then, add compound (III) 60g and reacted 2 hours with 80 ℃.Reaction finishes, the reclaim under reduced pressure diacetyl oxide has solid to separate out to bottle, is cooled to room temperature, add the 350ml absolute ethyl alcohol and stirring, be cooled to below 10 ℃ and make it crystallization, suction filtration, solid is washed till neutrality with frozen water, wash with dehydrated alcohol again, dry that compound (IIb) weighs 55g, yield 70%, outward appearance is a white powder.
Embodiment 2.
In the 250ml reaction flask, add compound (IIb) 55g, acetonitrile 170ml, 2-methylpiperazine 19.5g and triethylamine 56ml, be heated to 60 ℃ of reactions 3 hours, vacuum distillation recovered solvent (the liquid temperature is no more than 60 ℃), debris is diluted with dehydrated alcohol 200ml and is transferred in the reaction flask of 1000ml, add dehydrated alcohol 130ml, water 100ml again, triethylamine 200ml is heated to 76-78 ℃, backflow is arranged, reacted 10 hours, underpressure distillation is to doing, add water 40ml evaporate to dryness again, repeat again once, get grass green liquid.Add dehydrated alcohol 700ml reflux to solid and dissolve fully, cold slightly, add hydrochloric acid to pH=1 under stirring, have solid to separate out, filter, solid is washed back 360ml water heating for dissolving with dehydrated alcohol, the sodium hydroxide of 60 ℃ of Dropwise 5 % makes pH=8.5, there are a large amount of solids to separate out, filter, wash with cold water and dehydrated alcohol respectively, dry that the white powder solid is Gatifloxacin (I), heavy 36.5g, yield is 74.6%, content (HPLC) is 99.6%.
The content assaying method of Gatifloxacin among the present invention:
With octadecylsilane chemically bonded silica is weighting agent; [rare triethylamine solution (1 → 100) is regulated pH to 4.5 with phosphoric acid]-acetonitrile (80: 20) is a moving phase with the triethylamine phosphoric acid solution; 40 ℃ of column temperatures; Flow velocity is 1ml/min; Detect wavelength 325nm.It is an amount of to get the Gatifloxacin reference substance, makes dissolving with an amount of dilute phosphoric acid solution (2 → 1000), adds the biphosphate sodium solution and (gets the NaH of 390mg
2PO
42H
2O is dissolved in water and is diluted to 1000ml) be diluted to the solution that contains 0.5mg among every 1ml approximately, get 20ul and inject liquid chromatograph, the record color atlas; Number of theoretical plate calculates by the Gatifloxacin peak should be not less than 2500.
The reacting flow chart of the inventive method is as follows:
Claims (15)
1. one kind prepares and the method for purifying Gatifloxacin, and this method comprises the following steps: to form inner complex (IIb) with acid reaction earlier by quinoline carboxylic acid's cyclized ester (III),
React for some time at a certain temperature under the condition that polar solvent exists with N methyl piperazine again, use the de-acidying agent hydrolysis then, handle respectively with acid and diluted alkaline again, obtain Gatifloxacin (I) white powder.
2. the method for preparation according to claim 1 and purifying Gatifloxacin is characterized in that described polar solvent is acetonitrile, dimethyl sulfoxide (DMSO), dimethyl formamide, tetrahydrofuran (THF) or methylene dichloride.
3. the method for preparation according to claim 2 and purifying Gatifloxacin is characterized in that described polar solvent is an acetonitrile.
4. the method for preparation according to claim 1 and purifying Gatifloxacin is characterized in that described temperature is 70-80 ℃.
5. the method for preparation according to claim 4 and purifying Gatifloxacin is characterized in that described temperature is 78 ℃.
6. the method for preparation according to claim 1 and purifying Gatifloxacin is characterized in that the inner complex (IIb) and the reaction times of N methyl piperazine are 2-5 hour.
7. the method for preparation according to claim 6 and purifying Gatifloxacin is characterized in that the inner complex (IIb) and the reaction times of N methyl piperazine are 3 hours.
8. the method for preparation according to claim 1 and purifying Gatifloxacin, it is characterized in that described hydrolytic reagent be triethylamine, pyridine, to dimethylamino pyridine or dimethyl formamide.
9. the method for preparation according to claim 1 and purifying Gatifloxacin is characterized in that described hydrolytic reagent is a triethylamine.
10. the method for preparation according to claim 1 and purifying Gatifloxacin, the time that it is characterized in that described hydrolysis reaction is 7-13 hour.
11. the method for preparation according to claim 10 and purifying Gatifloxacin, the time that it is characterized in that described hydrolysis reaction is 10 hours.
12. the method for preparation according to claim 1 and purifying Gatifloxacin is characterized in that described acid is hydrochloric acid, sulfuric acid, phosphoric acid or acetic acid.
13. the method for preparation according to claim 12 and purifying Gatifloxacin is characterized in that described acid is concentrated hydrochloric acid.
14. the method for preparation according to claim 1 and purifying Gatifloxacin is characterized in that described diluted alkaline is the solution of the 5-8% of sodium hydroxide or potassium hydroxide.
15. the method for preparation according to claim 14 and purifying Gatifloxacin is characterized in that described diluted alkaline is 5% sodium hydroxide solution.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2004100803139A CN1301254C (en) | 2004-09-28 | 2004-09-28 | Preparation of catifloxacin and purifying method |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2004100803139A CN1301254C (en) | 2004-09-28 | 2004-09-28 | Preparation of catifloxacin and purifying method |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1616456A CN1616456A (en) | 2005-05-18 |
| CN1301254C true CN1301254C (en) | 2007-02-21 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB2004100803139A Expired - Fee Related CN1301254C (en) | 2004-09-28 | 2004-09-28 | Preparation of catifloxacin and purifying method |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1301254C (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101659654B (en) * | 2008-08-28 | 2013-11-06 | 四川科伦药物研究有限公司 | 2-Methylpiperazine fluoroquinolone compound and preparation method and application thereof |
| CN102351843B (en) * | 2011-08-18 | 2013-07-31 | 张家口市格瑞高新技术有限公司 | Synthesis method of 2-methyl piperazine lomefloxacin |
| CN111777632A (en) * | 2020-07-20 | 2020-10-16 | 浙江国邦药业有限公司 | Preparation method of moxifloxacin hydrochloride chelate |
| CN115819402A (en) * | 2022-12-13 | 2023-03-21 | 无锡福祈制药有限公司 | Preparation method of balofloxacin |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN87103693A (en) * | 1986-03-31 | 1988-03-30 | 三共株式会社 | Quinoline-3-carboxylic acid derivatives and its preparation and application |
-
2004
- 2004-09-28 CN CNB2004100803139A patent/CN1301254C/en not_active Expired - Fee Related
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN87103693A (en) * | 1986-03-31 | 1988-03-30 | 三共株式会社 | Quinoline-3-carboxylic acid derivatives and its preparation and application |
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| Publication number | Publication date |
|---|---|
| CN1616456A (en) | 2005-05-18 |
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