CN103159793B - A kind of preparation method of nemonoxacin chelate - Google Patents
A kind of preparation method of nemonoxacin chelate Download PDFInfo
- Publication number
- CN103159793B CN103159793B CN201310090062.1A CN201310090062A CN103159793B CN 103159793 B CN103159793 B CN 103159793B CN 201310090062 A CN201310090062 A CN 201310090062A CN 103159793 B CN103159793 B CN 103159793B
- Authority
- CN
- China
- Prior art keywords
- nemonoxacin
- carboxylic acid
- formula
- chelate
- reaction
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Abstract
The invention discloses a kind of method directly preparing nemonoxacin chelate from nemonoxacin cyclized ester.In existing method, reactions steps is partially long, last handling process is on the high side, causes the overall time preparing nemonoxacin to be obviously prolonged；And it is unfavorable for industrialized production and environmental protection.The present invention, using the mixed solvent of carboxylic acid anhydrides or carboxylic acid anhydrides and carboxylic acid as reaction dissolvent, adds boric acid or boric anhydride reaction；In the reactant liquor obtained, add nemonoxacin cyclized ester, carry out chelatropic reaction, obtain nemonoxacin chelate.The preparation method of the present invention only has a step chelatropic reaction, decreases the process of hydrolysis and filtration thereof, the complicated post-processing operation such as is dried, makes the overall time of preparation nemonoxacin be greatly shortened, beneficially industrialized production；Turn avoid the use of the reagent such as concentrated hydrochloric acid, ethanol simultaneously, economic and environment-friendly.
Description
Technical field
The present invention relates to the preparation of nemonoxacin intermediate, a kind of method directly preparing nemonoxacin chelate from nemonoxacin cyclized ester.
Background technology
Antimicrobial quinolone compounds nemonoxacin (3S, 5S)-7-[3-amino-5-methyl-piperidyl]-1-cyclopropyl-1,4-dihydro-8-methoxyl group-4-oxo-3-quinoline carboxylic acid is disclosed in United States Patent (USP) 6,329,391, its malate and polymorph are disclosed in Chinese patent CN101045725B, and these two references cited therein are for reference.The synthesis of various quinolone compounds has been reported that the most in the literature, such as United States Patent (USP) 6,329,391；United States Patent (USP) 6,803,469；Chinese patent CN101045725B；Chinese patent CN101045695B；" the Non6-FluoroSubstitutedQuinoloneAntibacterials:Structurea ndActivity " of B.Ledoussal et al., J.MedChem., volume 35, page 198 to page 200 (1992)；" the Studieson6-Aminoquinolines:SynthesisandAntibacterialEval uationof6-Amino-8-methylquinolones " of V.Cecchetti et al., MedChem., volume 39, page 436 to page 445 (1996)；" the Potent6-Desfluoro-8-methylquinolonesasNewLeadCompoundsin AntibacterialChemotherapy " of V.Cecchetti et al., J.MedChem., volume 39, page 4952 to page 4957 (1996).But this area needs the improved method for preparing above-mentioned Antimicrobe compound.
Chinese patent CN101045725B discloses the preparation method of the chelate intermediate shown in formula () in nemonoxacin synthesis, and the main purpose preparing this chelate is, strengthens in follow-up condensation reaction 7-position F as the activity of nucleophilic substitution leaving group.
Formula ()
Described method as initiation material, prepares nemonoxacin chelate formula () shown in through hydrolysis, chelating two-step reaction with the nemonoxacin cyclized ester shown in formula (), and synthetic route is as follows:
But, in the method for the nemonoxacin chelate shown in above-mentioned formula (), reactions steps is partially long, last handling process is on the high side, causes the overall time preparing nemonoxacin to be obviously prolonged；The carboxylic acid intermediate shown in formula () that hydrolysis obtains, pressed powder is thinner, it is difficult to solid-liquid separation, is unfavorable for industrialized production；Solvent for use kind is more, such as concentrated hydrochloric acid, ethanol, toluene, TBME etc., is unfavorable for environmental protection.
Summary of the invention
The technical problem to be solved is the defect overcoming above-mentioned prior art to exist, it is provided that a kind of method directly being prepared nemonoxacin chelate through a step chelatropic reaction by nemonoxacin cyclized ester, its simple possible, beneficially industrialized production.
To this end, the present invention adopts the following technical scheme that: the preparation method of a kind of nemonoxacin chelate, the step of the method is as follows: 1) using the mixed solvent of carboxylic acid anhydrides or carboxylic acid anhydrides and carboxylic acid as reaction dissolvent, adds boric acid or boric anhydride reaction；2) in step 1) reactant liquor that obtains adds the nemonoxacin cyclized ester shown in formula (), carry out chelatropic reaction, obtain formula (v) shown in nemonoxacin chelate；
The synthetic route of said method is as follows:
Wherein, the R shown in formula ()1Selected from alkyl, aryl or heteroaryl；The R that formula is (v) shown2For H, alkyl, aryl or heteroaryl, the carboxylic acid anhydrides selected by reaction determine.
Further, step 1) in, the R of described carboxylic acid anhydrides2Group is alkyl than preferably, is more preferably C1～C4Alkyl, optimal for methyl；The consumption of carboxylic acid anhydrides, preferably for 3-20 times of mole of nemonoxacin cyclized ester shown in formula (), is more preferably 4.0～10.0 times, optimal for 5.0～8.0 times；The R of described carboxylic acid2Group is alkyl than preferably, is more preferably C1～C4Alkyl, optimal for methyl；Carboxylic acid is 1-20:1 with the molar ratio of nemonoxacin cyclized ester shown in formula ()；The consumption of described boric acid, preferably for 1～4 times of mole of nemonoxacin cyclized ester shown in formula (), is more preferably 1.0～2.5 times, optimal for 1.2～1.6 times；The consumption of described boric anhydride, preferably for 0.5～2.0 times of mole of nemonoxacin cyclized ester shown in formula (), is more preferably 0.5～1.0 times, optimal for 0.6～0.8 times；The temperature that reaction uses is preferably 90～130 DEG C, is more preferably 110～120 DEG C；Response time is preferably 0.5～5.0h, is more preferably 1.0～3.0h.
Further, step 2) in, the R of described nemonoxacin cyclized ester1Group is preferably alkyl, is more preferably the alkyl of C1～C4, most preferably ethyl；Described reaction temperature is preferably 70～130 DEG C, is more preferably 75～105 DEG C, optimal for 80～90 DEG C；The described response time is preferably 0.5～15.0h, is more preferably 2.0～6.0h, optimal for 3.0～5.0h.After reaction terminates, by step 2) reactant liquor that obtains mix with water, stirring and crystallizing, filters, and drying obtains the nemonoxacin chelate solid that formula is (v) shown.
The preparation method of the present invention only has a step chelatropic reaction, decreases the process of hydrolysis and filtration thereof, the complicated post-processing operation such as is dried, makes the overall time of preparation nemonoxacin be greatly shortened, beneficially industrialized production；Turn avoid the use of the reagent such as concentrated hydrochloric acid, ethanol simultaneously, economic and environment-friendly.
Detailed description of the invention
Further illustrate the present invention below by the mode of embodiment, but the most therefore limit the present invention among described scope of embodiments.
Embodiment 1 does reactant with boric acid, is not added with acetic acid, the nemonoxacin chelate shown in formula ()
Acetic anhydride 40ml(423mmol is added in 100ml there-necked flask), be warming up to 110～115 DEG C, add boric acid 7.2g(116.5mmol), insulated and stirred 1.5h.After insulation, reactant liquor is cooled to 80～90 DEG C, adds the nemonoxacin cyclized ester 22.5g(73.7mmol shown in formula ()), insulated and stirred 3.5h, HPLC or TLC(petroleum ether: ethyl acetate=1:2) monitoring reaction result.After reaction completely, being added to frozen water by reactant liquor, stirring and crystallizing, filter, washing, vacuum drying obtains off-white color solid 28.4g, HPLC purity 99.2%, yield 95.1%.
NMR(CDCl3, 400MHz) and δ (ppm): 9.23 (s, 1H), 8.37-8.33 (m, 1H), 7.55 (t, J=9.8Hz, 1H), 4.43-4.40 (m, 1H), 4.14 (s, 3H), 2.04 (s, 6H), 1.45-1.42 (m, 2H), 1.33-1.30 (m, 2H).
Embodiment 2 does reactant with boric anhydride, adds acetic acid, the nemonoxacin chelate shown in formula ()
Acetic anhydride 45ml(476mmol is added in 250ml there-necked flask), acetic acid 21.6ml(378mmol) it is warming up to 120～125 DEG C, add boric anhydride 2.94g(42.2mmol), insulated and stirred 2.5h.After insulation, reactant liquor is cooled to 80～90 DEG C, adds the nemonoxacin cyclized ester 20.0g(65.5mmol shown in formula ()), insulated and stirred 3.5h, HPLC or TLC(petroleum ether: ethyl acetate=1:2) monitoring reaction result.After reaction completely, being added to frozen water by reactant liquor, stirring and crystallizing, filter, washing, vacuum drying obtains off-white color solid 24.6g, HPLC purity 99.5%, yield 92.7%.Comparing embodiment 1, make reaction dissolvent with acetic acid and acetic anhydride, crystalline particle is thicker, the rate of filtration faster, but yield lower slightly 2～3%.
NMR(CDCl3, 400MHz) and δ (ppm): 9.23 (s, 1H), 8.37-8.33 (m, 1H), 7.55 (t, J=9.8Hz, 1H), 4.43-4.40 (m, 1H), 4.14 (s, 3H), 2.04 (s, 6H), 1.45-1.42 (m, 2H), 1.33-1.30 (m, 2H).
Embodiment 3 does reactant with boric acid, adds acetic acid, the nemonoxacin chelate shown in formula ()
Acetic anhydride 40ml(423mmol is added in 250ml there-necked flask), be warming up to 110～115 DEG C, add boric acid 7.2g(116.5mmol), insulated and stirred 1.0h, add acetic acid 40ml(700mmol) dilution, continue insulated and stirred 0.5h.After insulation, reactant liquor is cooled to 80～90 DEG C, adds the nemonoxacin cyclized ester 22.5g(73.7mmol shown in formula ()), insulated and stirred 3.5h, HPLC or TLC(petroleum ether: ethyl acetate=1:2) monitoring reaction result.After reaction completely, being added to frozen water by reactant liquor, stirring and crystallizing, filter, washing, vacuum drying obtains off-white color solid 27.6g, HPLC purity 99.5%, yield 92.5%.
Chelate shown in cyclized ester formula () shown in comparative example CN101045725 embodiment 1 formula ()
At ambient temperature to the cyclized ester (0.76kg ,～2.5mol ,～1.0 equivalents) shown in reactor loading type (), it is subsequently added the aqueous hydrochloric acid solution (1.1kg, 10mol) of ethanol (5.3kg, 6.8L) and 32 weight %.Reactant mixture rises to reflux temperature (76 DEG C to 80 DEG C), and first this mixture becomes homogeneous during this period, is subsequently changed to heterogeneous.This mixture is heated to reflux at least 5 hours or until analyzes (15%EtOAc/ hexane volume/volume) with TLC and detected.After completing, reaction is cooled to 0 DEG C ± 5 DEG C, and is isolated by filtration the solid of precipitation and washs with ethanol (1.7kg) subsequently with distilled water (1.7kg).Isolated solid is dried the carboxylic acid intermediate (0.65kg ,～95%) obtained shown in formula ().
Boron oxide (2.0kg, 29mol) is loaded reactor, subsequently with glacial acetic acid (8.1L, 142mol) and acetic anhydride (16.2L, 171mol) dilution.Gained mixture is heated to reflux temperature at least 2 hours.Reactant is cooled to 40 DEG C, and the carboxylic acid intermediate (14.2kg, 51mol) shown in formula () is added to reactant mixture.Mixture is again heated to reflux temperature at least 6 hours.Carry out with HPLC and NMR monitoring reaction.Mixture is cooled to about 90 DEG C, and toluene (45L) is added in reaction.Reaction is cooled further to 50 DEG C, and tert-butyl methyl ether (19L) is added in reactant mixture to promote product to precipitate.Then mixture is cooled to 20 DEG C, and is isolated by filtration out the chelate shown in solid type ().Then isolated solid is washed with tert-butyl methyl ether (26L) before being dried in 40 DEG C of vacuum drying ovens (50 torr).The product yield that chelate shown in formula () is obtained in the reaction is 86.4%.
From comparative example, it is the longest that the method for the nemonoxacin chelate shown in original formula () compares the present invention, operation complexity, not environmentally, uneconomical, is unfavorable for industrialized production.
Claims (6)
1. a preparation method for nemonoxacin chelate, the step of the method is as follows: 1) using the mixed solvent of carboxylic acid anhydrides or carboxylic acid anhydrides and carboxylic acid as reaction dissolvent, adds boric acid or boric anhydride reaction, and the temperature that reaction uses is 90～130 DEG C；2) in step 1) reactant liquor that obtains adds the nemonoxacin cyclized ester shown in formula (), carry out chelatropic reaction, obtain the nemonoxacin chelate shown in formula (v)；
The synthetic route of said method is as follows:
Wherein, R2For H, C1～C4Alkyl, is determined by the carboxylic acid anhydrides selected by reaction；
And step 2) in, the R of described nemonoxacin cyclized ester1For C1～C4Alkyl, the temperature of chelatropic reaction is 75～105 DEG C, and the response time is 2～6h.
The preparation method of nemonoxacin chelate the most according to claim 1, it is characterised in that: step 1) in, the R in described carboxylic acid and carboxylic acid anhydrides2For C1～C4Alkyl；The ratio of the mole dosage of nemonoxacin cyclized ester shown in carboxylic acid anhydrides and formula () is for 3-20:1；The ratio of the mole dosage of nemonoxacin cyclized ester shown in carboxylic acid and formula () is for 1-20:1；The consumption of described boric acid is 1～4 times of the mole of nemonoxacin cyclized ester shown in formula ()；Response time is 0.5-5.0h；The consumption of described boric anhydride is 0.5～2.0 times of the mole of nemonoxacin cyclized ester shown in formula ().
The preparation method of nemonoxacin chelate the most according to claim 2, it is characterised in that: step 1) in, the R in described carboxylic acid and carboxylic acid anhydrides2For C1～C4Alkyl；The ratio of the mole dosage of nemonoxacin cyclized ester shown in carboxylic acid anhydrides and formula () is for 4-10:1；The consumption of described boric acid is 1～2.5 times of the mole of nemonoxacin cyclized ester shown in formula ()；The temperature that reaction uses is 110～120 DEG C, and the response time is 1.0-3.0h；The consumption of described boric anhydride is 0.5～1.0 times of the mole of nemonoxacin cyclized ester shown in formula ().
The preparation method of nemonoxacin chelate the most according to claim 3, it is characterised in that: step 1) in, the R in described carboxylic acid and carboxylic acid anhydrides2For methyl；The ratio of the mole dosage of nemonoxacin cyclized ester shown in carboxylic acid anhydrides and formula () is for 5-8:1；The consumption of described boric acid is 1.2～1.6 times of the mole of nemonoxacin cyclized ester shown in formula ()；The consumption of described boric anhydride is 0.6～0.8 times of the mole of nemonoxacin cyclized ester shown in formula ().
The preparation method of nemonoxacin chelate the most according to claim 1, it is characterised in that: step 2) in, the R of described nemonoxacin cyclized ester1For ethyl, the temperature of chelatropic reaction is 80～90 DEG C, and the response time is 3～5h.
The preparation method of nemonoxacin chelate the most according to claim 1, it is characterized in that: step 2) terminate after, by step 2) reactant liquor that obtains mixes with water, stirring and crystallizing, filter, dry and obtain the nemonoxacin chelate solid shown in formula (v).
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310090062.1A CN103159793B (en) | 2013-03-20 | 2013-03-20 | A kind of preparation method of nemonoxacin chelate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310090062.1A CN103159793B (en) | 2013-03-20 | 2013-03-20 | A kind of preparation method of nemonoxacin chelate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103159793A CN103159793A (en) | 2013-06-19 |
| CN103159793B true CN103159793B (en) | 2016-08-03 |
Family
ID=48583358
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310090062.1A Active CN103159793B (en) | 2013-03-20 | 2013-03-20 | A kind of preparation method of nemonoxacin chelate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103159793B (en) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1563004A (en) * | 2004-04-21 | 2005-01-12 | 中国医学科学院医药生物技术研究所 | Compound of quinolone carboxylic acid, preparation method and medicinal usage |
| CN101045695A (en) * | 2006-03-28 | 2007-10-03 | 宝洁公司 | Hydro-reduction method for preparing quinolone intermediate |
| WO2009023473A2 (en) * | 2007-08-09 | 2009-02-19 | Taigen Biotechnology Co., Ltd. | Antimicrobial parenteral formulation |
| CN102351858A (en) * | 2011-09-21 | 2012-02-15 | 浙江新东港药业股份有限公司 | High selectivity method for synthesizing moxifloxacin |
-
2013
- 2013-03-20 CN CN201310090062.1A patent/CN103159793B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1563004A (en) * | 2004-04-21 | 2005-01-12 | 中国医学科学院医药生物技术研究所 | Compound of quinolone carboxylic acid, preparation method and medicinal usage |
| CN101045695A (en) * | 2006-03-28 | 2007-10-03 | 宝洁公司 | Hydro-reduction method for preparing quinolone intermediate |
| WO2009023473A2 (en) * | 2007-08-09 | 2009-02-19 | Taigen Biotechnology Co., Ltd. | Antimicrobial parenteral formulation |
| CN102351858A (en) * | 2011-09-21 | 2012-02-15 | 浙江新东港药业股份有限公司 | High selectivity method for synthesizing moxifloxacin |
Also Published As
| Publication number | Publication date |
|---|---|
| CN103159793A (en) | 2013-06-19 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN105820126B (en) | A kind of preparation method of olaparib | |
| CN113292535B (en) | Method for preparing apaluamide intermediate and apaluamide | |
| CN105330634A (en) | One-pot method for preparing 3-hydroxyphtalic anhydride | |
| CN102617622A (en) | Method for preparing moxifloxacin or its medicinal salt and its intermediate | |
| US6376668B1 (en) | Process for preparing pyridinemethanol compounds | |
| JPH0649009A (en) | Production of 2,5-diphenylaminoterephthalic acid and its derivative | |
| CN109503380A (en) | The synthetic method of 4- alkoxy acetoacetates | |
| CN103724288B (en) | Triethyl orthoformate legal system is for the post-treating method of 1H-tetrazole-1-acetic acid | |
| CN103159793B (en) | A kind of preparation method of nemonoxacin chelate | |
| CN105153013B (en) | The synthetic method of the ketone of 6 bromine isoindoline 1 | |
| CN106187940A (en) | A kind of one kettle way prepares the method for Febustat | |
| CN110818560A (en) | Preparation method of 4-benzyloxy phenyl ethyl n-decanoate | |
| CN105801482B (en) | A kind of preparation method of the bromo- 8- difluoro-methoxies -1,4- dihydroquinoline -3- carboxylic acid, ethyl esters of 1- cyclopropyl -4- oxos -7- | |
| CN105801484A (en) | Preparation method of pyrazolyl acrylonitrile compound | |
| CN102180843A (en) | Preparation method of 2-(2-amino-4-thiazolyl)-2(Z)-triphenylmethoxy imidoacetic acid | |
| CN103333145B (en) | Preparation method of 3-(alpha- methoxyl) methylene benzofuran-2(3H)-ketone | |
| CN103073525A (en) | Method for synthesizing (S)-(3,4-difluorophenyl)hexamethylene oxide | |
| CN102659579A (en) | preparation method of p-chlorine methyl cinnamate | |
| CN108358866B (en) | Preparation method of febuxostat intermediate and application of febuxostat intermediate in preparation of febuxostat | |
| CN105777631B (en) | A kind of synthetic method of the bromo- 8- difluoro-methoxies -1,4- dihydroquinoline -3- carboxylic acid, ethyl esters of 1- cyclopropyl -4- oxos -7- | |
| CN105330525A (en) | Preparation method of 7-hydroxy-1-indanone | |
| EP3224229B1 (en) | Process of production of 7,8-dihydro-c15-aldehyde | |
| CN103145615B (en) | A kind of post-treating method of Nai Nuosha star inner complex | |
| TWI542583B (en) | Oxidation process | |
| CN108658931A (en) | A kind of preparation method of Raltitrexed key intermediate |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C41 | Transfer of patent application or patent right or utility model | ||
| COR | Change of bibliographic data |
Free format text: CORRECT: ADDRESS; FROM: 312500 SHAOXING, ZHEJIANG PROVINCE TO: 310011 HANGZHOU, ZHEJIANG PROVINCE |
|
| TA01 | Transfer of patent application right |
Effective date of registration: 20140522 Address after: Hangzhou City, Zhejiang province 310011 Gongshu District Dengyun Road No. 268 Applicant after: Zhejiang Pharmaceutical Co., Ltd. Address before: 312500, No. 59 East Ring Road, Xinchang County, Shaoxing, Zhejiang Applicant before: Xinchang Pharmaceutical Factory, Zhejiang Medicine Co., Ltd. |
|
| ASS | Succession or assignment of patent right |
Owner name: TAIGEN BIOTECHNOLOGY Free format text: FORMER OWNER: ZHEJIANG PHARMACEUTICAL CO., LTD. Effective date: 20150821 Owner name: ZHEJIANG PHARMACEUTICAL CO., LTD. Effective date: 20150821 |
|
| C41 | Transfer of patent application or patent right or utility model | ||
| TA01 | Transfer of patent application right |
Effective date of registration: 20150821 Address after: Xinming road Taiwan Taipei City Neihu district Chinese No. 138 7 floor Applicant after: Taigen Biotechnology Applicant after: Zhejiang Pharmaceutical Co., Ltd. Address before: Hangzhou City, Zhejiang province 310011 Gongshu District Dengyun Road No. 268 Applicant before: Zhejiang Pharmaceutical Co., Ltd. |
|
| CB03 | Change of inventor or designer information |
Inventor after: Sheng Li Inventor after: Mao Wei Inventor after: Wu Guofeng Inventor after: Jin Qixin Inventor after: Chen Gang Inventor after: Zou Xianyan Inventor after: Zhang Yongjiang Inventor after: Zhang Li Inventor before: Sheng Li Inventor before: Chen Gang Inventor before: Zhang Yongjiang Inventor before: Zhang Li |
|
| COR | Change of bibliographic data | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20210609 Address after: 312500 No. 59 Huancheng East Road, Chengguan Town, Xinchang County, Shaoxing City, Zhejiang Province Patentee after: Zhejiang Medicine Co.,Ltd. Xinchang Pharmaceutical Factory Address before: Xinming road Taiwan Taipei City Neihu district Chinese No. 138 7 floor Patentee before: TaiGen Biotechnology Co.,Ltd. Patentee before: ZHEJIANG MEDICINE Co.,Ltd. |