CN1332962C - Method of synthesizing methanesulfonic acid parzhushaxing intermedinte - Google Patents
Method of synthesizing methanesulfonic acid parzhushaxing intermedinte Download PDFInfo
- Publication number
- CN1332962C CN1332962C CNB2005100190825A CN200510019082A CN1332962C CN 1332962 C CN1332962 C CN 1332962C CN B2005100190825 A CNB2005100190825 A CN B2005100190825A CN 200510019082 A CN200510019082 A CN 200510019082A CN 1332962 C CN1332962 C CN 1332962C
- Authority
- CN
- China
- Prior art keywords
- solution
- methyl
- cooled
- difluoro
- temperature
- 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.)
- Expired - Fee Related
Links
Landscapes
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Abstract
The present invention relates to a method for synthesizing an intermediate body of pazufloxacin mesilate, which relates to a method for synthesizing an intermediate body of pazufloxacin mesilate. The method comprises: NaOH is added to (S)-9, 10-difluoro-3-methyl-7-oxygen-2, 3-dihydro-7H-pyrido [1, 2, 3-d, e][1, 4]benzene oxazine-6-carboxylic acid ethyl ester (difluoro); the (S)-9, 10-difluoro-3-methyl-7-oxygen-2, 3-dihydro-7H-pyrido [1, 2, 3-d, e][1, 4]benzene oxazine-6-carboxylic acid ethyl ester (difluoro) is cooled to a temperature below 0 DEG C by a mixture of ice and salt; PEG200 as a phase transfer catalyst and ethyl cyanoacetate are added to the obtained solution during stirring the solution; a diluted sulfuric acid is used for regulating a pH value of the solution after the solution is stirred, and the solution is slowly heated to a temperature of 25 to 60 DEG C; the reaction lasts for 4 to 10 hours; after air bubbles are overflowed, the solution is cooled to a temperature of 2 to 10 DEG C; the solution is stirred for 2 to 5 hours at a temperature below 0 DEGC, and the temperature is raised to 20 to 25 DEG C; the temperature is preserved, and the reaction lasts for 3 to 8 hours; the solution is refrigerated, and crystals are precipitated; the solution is sucked, filtered and dried, and the product is obtained. The present invention only uses one-step synthesis reaction, and has the advantages of low cost, little investment, simple process, easy operation, high product yield, stable quality, no toxicity, no harmful substances, no substances with high danger and little environmental pollution. The yield of the present invention can reach as high as 93.06%. The present invention adopts the optimal nonionic phase transfer catalyst, and the reaction effects are obvious.
Description
Technical field
The present invention relates to a kind of method of synthesizing methanesulfonic acid Pazufloxacin intermediate.
Background technology
Bibliographical information, synthetic (S)-10-(cyano methyl)-9-fluoro-3-methyl-7-oxo-2, [1,4] benzoxazine-6-carboxylic acid adopts two-step approach to 3-dihydro-7H-pyridine [1,2,3-d, e].The first step, preparation (S)-10-(cyanogen oxyethyl group carbonyl methyl)-9-fluoro-3-methyl-7-oxygen 2,3-dihydro-7H-pyrido [1,2,3-d, e] [1,4] Ben oxazines-6-carbonyl acetoacetic ester, with the NaH 64g (1.6mol) that adds its weight 60% under the cryosel cooling and stirring in-5-0 ℃ 1250ml DMF, dripping concentration at-5 ℃ in reaction solution is 99% ethyl cyanoacetate 300ml, stirs 60 minutes.In reaction solution, add (S)-9,10-two fluoro-3-methyl-7-oxygen-2,3-dihydro-7H-pyrido [1,2,3-d, e] [1,4] benzene oxazine-6-carboxylic acid, ethyl ester 124g (0.4mol) in batches.Slowly be heated to 35 ℃ of reactions after 16 hours, be cooled to 25 ℃, add frozen water 5000ml.HCl with 6N regulates PH=4.Use the 3000ml ethyl acetate extraction.The washing liquid layer is to PH=7.Ethyl acetate is removed in underpressure distillation.Get a reddish-brown oily compound.Add the 150ml ether again, cooling is separated out solid, suction filtration, 55 ℃ of oven dry.Concrete reaction formula is as follows:
Second step, preparation (S)-10-(cyanogen methyl)-9-fluoro-3-methyl-7-oxygen-2,3-dihydro-7H-pyrido [1,2,3-d, e] [1,4] Ben oxazine-6-carboxylic acid,
Get 136.0g (0.33mol) (S)-10-(cyanogen methyl)-9-fluoro-3-methyl-7-oxygen-2, [1,4] Ben oxazine-6-carboxylic acid, ethyl ester at room temperature adds 1100ml dioxane and 200ml water to 3-dihydro-7H-pyrido [1,2,3-d, e], stirs 30 minutes.Add 73.0g (0.38mol) tosic acid in reaction mixture, stirred 60 minutes, reheat refluxes and stirred 48 hours, is cooled to room temperature and separates out crystallization.Crystallization is filtered, and filtrate adds 1100ml water, and restir is separated out crystallization, filters.Merge filter cake, to doing, use the 1000ml water washing with the abundant agitator treating after-filtration of methylene dichloride, with after the ether drip washing again in 55 ℃ of dry products that get.Concrete reaction formula is as follows:
Its yield is 75.68%.
This method has the following disadvantages:
1, used the second kind solvent: diox, the methylene dichloride that limit use; The 3rd kind solvent: dimethyl sulfoxide (DMSO) DMF, ethyl acetate and toxic substance tosic acid, diox and high risk material sodium hydride.Bring difficulty on the one hand transportation, workman's operation; Bring difficulty to wastewater treatment on the one hand, environment is caused irreversible lesion, operator are had great danger;
2, used organic chemical reagent costs an arm and a leg, and has increased cost;
3, use ethyl acetate extraction, though can reuse after heavily steaming, the extraction process loss is bigger, and cost is higher, and it residues in water or volatilization, can reduce the purity of raw material, reduces productive rate;
4, use the concentrated hydrochloric acid and the vitriol oil to come hydrolysis, long reaction time has certain pollution to environment.
Summary of the invention
The purpose of this invention is to provide a kind of needs the one-step synthesis reaction, and cost is low, yield is high, output is high, with short production cycle, the method for a kind of synthesizing methanesulfonic acid Pazufloxacin intermediate that environmental pollution is little.
The implementation of purpose of the present invention is, a kind of method of synthesizing methanesulfonic acid Pazufloxacin intermediate, get 40-160g (S)-9,10-two fluoro-3-methyl-7-oxygen-2,3-dihydro-7H-pyrido [1,2,3-d, e] [1,4] Ben oxazine-6-carboxylic acid, ethyl ester is to wherein adding the NaOH200-700ml that concentration is 20-60%, use ice, the mixture of salt is cooled to below 0 ℃, blending ratio is 5: 1-8: 1, stir adding 10-60g phase-transfer catalyst PEG200 down, the 80-180g ethyl cyanoacetate, stirring the back is the dilute sulphuric acid regulator solution pH value to 6.0 of 6-18% with concentration, slowly be heated to 25-60 ℃ again, reacted 4-10 hour, and after bubble all overflows, be cooled to 2-10 ℃, be cooled to again and slowly stirred below 0 ℃ 2-5 hour, be warming up to 20-25 ℃ then, insulation reaction 3-8 hour, be refrigerated to-10 ℃, visible crystals is separated out, suction filtration, 55 ℃ dry product, the building-up reactions formula is as follows:
The present invention has following advantage:
1, one-step synthesis reaction, less investment, simple, the easy operation of flow process, product yield height, the constant product quality yield is up to 93.06%;
2, poisonous, harmful, high risk materials such as diox useless, methylene dichloride, DMF, tosic acid, diox have reduced environmental pollution, have protected operator's health;
3, do not use ethyl acetate, sodium hydride etc., reduced cost;
4, adopt best non-ionic type phase-transfer catalyst: as various polyoxyethylene glycol PEG etc., and other water-soluble polymers PEG200-6000, tween etc., reaction effect is obvious, and is little to human toxicity;
5, with an organic solvent less, reduce environmental pollution;
6, replace NaH with NaOH, substitution reaction take place, the yield of reaction very high, consuming time short, danger coefficient is low, environmental pollution is little, cost is low.
Embodiment
Method of the present invention is to get (S)-9,10-two fluoro-3-methyl-7-oxygen-2,3-dihydro-7H-pyrido [1,2,3-d, e] [1,4] Ben oxazine-6-carboxylic acid, ethyl ester (difluoro thing) is to wherein adding NaOH, use ice, the mixture of salt is cooled to below 0 ℃, stir and add phase-transfer catalyst PEG200 down, ethyl cyanoacetate stirs the back with dilute sulphuric acid regulator solution pH value to 6.0, slowly is heated to 25-60 ℃ again, reacted 4-10 hour, after bubble all overflows, be cooled to 2-10 ℃, stirring 2-5 hour below 0 ℃ again, be warming up to 20-25 ℃, insulation reaction 3-8 hour, freezing, crystal was separated out, suction filtration, dry product.
The present invention replaces NaH with the NaOH solution of high density, and ethyl cyanacetate with the difluoro thing substitution reaction takes place equally under the catalysis of phase-transfer catalyst; Two ester groups in the product that generates under this condition change carboxylate salt into simultaneously under the NaOH effect; Reaction is finally without separation, and directly with the dilute sulphuric acid acidifying, carboxylate salt changes carboxylic acid into, and 9 carboxyls are also the same with former technology, and decarboxylation has taken place, and obtains target product.
Enumerate the specific embodiment of the invention below:
Example 1, get 140g (S)-9,10-two fluoro-3-methyl-7-oxygen-2,3-dihydro-7H-pyrido [1,2,3-d, e] [1,4] Ben oxazine-6-carboxylic acid, ethyl esters (difluoro thing), 50%NaOH500ml is with the mixture of ice and salt, blending ratio is 5: 1, be cooled to below 0 ℃, stir adding 20g phase-transfer catalyst PEG200 down, the 100g ethyl cyanoacetate, stir, carefully with 6% dilute sulphuric acid regulator solution pH value to 6.0, and slowly be heated to 50 ℃, reacted 4 hours, treat to be chilled to 9 ℃ after bubble all overflows, maintain the temperature at below 0 ℃, slowly stirred 2 hours, be warming up to 20 ℃ then gradually, insulation reaction 4 hours is finished with TLC (tlc) control reaction.Be refrigerated to-10 ℃, crystal is separated out, suction filtration, in 55 ℃ dry the 115.4g product, yield 93.06%.
Reaction formula is as follows:
Example 2, method and reaction formula are with example 1, different is to get 80g (S)-9,10-two fluoro-3-methyl-7-oxygen-2,3-dihydro-7H-pyrido [1,2,3-d, e] [1,4] Ben oxazine-6-carboxylic acid, ethyl esters (difluoro thing), 700ml 20%NaOH, the blending ratio of ice and salt is 6: 1, cooling adds 30g phase-transfer catalyst PEG200,80g ethyl cyanoacetate, dilute sulphuric acid regulator solution pH value to 6.0 with 12%, 60 ℃ of reactions 6 hours, 20 ℃ of insulation reaction 5 hours were refrigerated to-10 ℃, visible crystals is separated out, suction filtration, 55 ℃ dry the 119.48g product, yield 93.87%.
Example 3, method and reaction formula are with example 1, and different is 160g (S)-9,10-two fluoro-3-methyl-7-oxygen-2,3-dihydro-7H-pyrido [1,2,3-d, e] [1,4] Ben oxazine-6-carboxylic acid, ethyl esters (difluoro thing), 200ml 60%NaOH, the blending ratio of ice and salt is 7: 1, cooling adds 60g phase-transfer catalyst PEG2000, the 140g ethyl cyanoacetate, the dilute sulphuric acid regulator solution pH value to 6.0 with 8% was in 25 ℃ of reactions 8 hours, complete 3 hours of 24 ℃ of insulation reaction, be refrigerated to-10 ℃, visible crystals is separated out, suction filtration, 55 ℃ dry the 116.59g product, yield: 93.15%.
Example 4, method and reaction formula are with example 1, and different is 40g (S)-9,10-two fluoro-3-methyl-7-oxygen-2,3-dihydro-7H-pyrido [1,2,3-d, e] [1,4] Ben oxazine-6-carboxylic acid, ethyl esters (difluoro thing), 400ml 40%NaOH, the blending ratio of ice and salt is 8: 1, cooling adds 10g phase-transfer catalyst PEG1000, the 175g ethyl cyanoacetate, the dilute sulphuric acid regulator solution pH value to 6.0 with 18% was in 25 ℃ of reactions 10 hours, complete 8 hours of 24 ℃ of insulation reaction, be refrigerated to-10 ℃, visible crystals is separated out, suction filtration, 55 ℃ dry the 115.01g product, yield: 93.10%.
Claims (1)
1, a kind of method of synthesizing methanesulfonic acid Pazufloxacin intermediate, it is characterized in that a kind of synthetic (S)-10-(cyano methyl)-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyridine [1,2,3-d, e] [1, the method of 4] benzoxazine-6-carboxylic acid, get 40-160g (S)-9,10-two fluoro-3-methyl-7-oxygen-2,3-dihydro-7H-pyrido [1,2,3-d, e] [1,4] Ben oxazine-6-carboxylic acid, ethyl esters, to wherein adding the NaOH200-700ml that concentration is 20-60%, with ice, the mixture of salt is cooled to below 0 ℃, and blending ratio is 5: 1-8: 1, stir and add 10-60g phase-transfer catalyst PEG200 down, the 80-180g ethyl cyanoacetate, stirring the back is the dilute sulphuric acid regulator solution pH value to 6.0 of 6-18% with concentration, slowly is heated to 25-60 ℃ again, reacts 4-10 hour, after bubble all overflows, be cooled to 2-10 ℃, be cooled to again and slowly stirred below 0 ℃ 2-5 hour, be warming up to 20-25 ℃ then, insulation reaction 3-8 hour, be refrigerated to-10 ℃, visible crystals is separated out, suction filtration, 55 ℃ dry product, the building-up reactions formula is as follows:
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2005100190825A CN1332962C (en) | 2005-07-12 | 2005-07-12 | Method of synthesizing methanesulfonic acid parzhushaxing intermedinte |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2005100190825A CN1332962C (en) | 2005-07-12 | 2005-07-12 | Method of synthesizing methanesulfonic acid parzhushaxing intermedinte |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1724537A CN1724537A (en) | 2006-01-25 |
| CN1332962C true CN1332962C (en) | 2007-08-22 |
Family
ID=35924181
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB2005100190825A Expired - Fee Related CN1332962C (en) | 2005-07-12 | 2005-07-12 | Method of synthesizing methanesulfonic acid parzhushaxing intermedinte |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1332962C (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102295652A (en) * | 2011-06-27 | 2011-12-28 | 辽宁海神联盛制药有限公司 | Improvement method for pazufloxacin mesylate synthesis process |
| CN104031064B (en) * | 2014-05-29 | 2016-04-27 | 上海应用技术学院 | A kind of Pazufloxacin impurity and preparation method thereof |
| CN104031063A (en) * | 2014-05-29 | 2014-09-10 | 上海应用技术学院 | Quinolone compound as well as preparation method and application thereof |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4990508A (en) * | 1988-04-23 | 1991-02-05 | Toyama Chemical Co., Ltd. | Pyridone carboxylic acid derivatives and salts thereof, process for producing the same and antibacterial agents comprising the same |
| JPH0543464A (en) * | 1988-04-23 | 1993-02-23 | Toyama Chem Co Ltd | Antibacterial agent containing pyridonecarboxylic acid derivative or its salt |
| WO1996001829A1 (en) * | 1994-07-11 | 1996-01-25 | Bayer Aktiengesellschaft | PYRIDO[3,2,1-i,j][3,1]BENZOXAZINE DERIVATIVES |
| CN1238774A (en) * | 1996-09-27 | 1999-12-15 | 第一制药株式会社 | Pyridobenzoxazine derwatives |
| CN1294592A (en) * | 1999-02-24 | 2001-05-09 | 三星电子株式会社 | Process for preparing (-) pyridobenzoxazine carboxylic acid derivatives |
-
2005
- 2005-07-12 CN CNB2005100190825A patent/CN1332962C/en not_active Expired - Fee Related
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4990508A (en) * | 1988-04-23 | 1991-02-05 | Toyama Chemical Co., Ltd. | Pyridone carboxylic acid derivatives and salts thereof, process for producing the same and antibacterial agents comprising the same |
| JPH0543464A (en) * | 1988-04-23 | 1993-02-23 | Toyama Chem Co Ltd | Antibacterial agent containing pyridonecarboxylic acid derivative or its salt |
| WO1996001829A1 (en) * | 1994-07-11 | 1996-01-25 | Bayer Aktiengesellschaft | PYRIDO[3,2,1-i,j][3,1]BENZOXAZINE DERIVATIVES |
| CN1238774A (en) * | 1996-09-27 | 1999-12-15 | 第一制药株式会社 | Pyridobenzoxazine derwatives |
| CN1294592A (en) * | 1999-02-24 | 2001-05-09 | 三星电子株式会社 | Process for preparing (-) pyridobenzoxazine carboxylic acid derivatives |
Non-Patent Citations (5)
| Title |
|---|
| 帕珠沙星消旋体的合成及HPLC法拆分 史翔等，中国医药工业杂志，第35卷第6期 2004 * |
| 帕珠沙星的合成 张文治等，武汉大学学报（理学版），第49卷第2期 2003 * |
| 抗菌药甲磺酸帕珠沙星的合成与研究 唐传久，安徽化工，第2期 2004 * |
| 甲磺酸帕珠沙星的合成工艺改进 仝春晖，浙江化工，第35卷第10期 2004 * |
| 甲磺酸帕珠沙星的合成工艺改进 仝春晖，浙江化工，第35卷第10期 2004;抗菌药甲磺酸帕珠沙星的合成与研究 唐传久，安徽化工，第2期 2004;帕珠沙星的合成 张文治等，武汉大学学报（理学版），第49卷第2期 2003;帕珠沙星消旋体的合成及HPLC法拆分 史翔等，中国医药工业杂志，第35卷第6期 2004 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1724537A (en) | 2006-01-25 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102603841B (en) | Preparation method of dehydroisoandrosterone | |
| CA2993607A1 (en) | Process for preparing pridopidine | |
| CN1332962C (en) | Method of synthesizing methanesulfonic acid parzhushaxing intermedinte | |
| CN101948437B (en) | Refining method of bendamustine hydrochloride | |
| CN106565616A (en) | Preparation method of antibacterial veterinary drug sulfamonomethoxine sodium | |
| CN101921284A (en) | Preparation method of cefathiamidine | |
| MX2011013946A (en) | Process for producing crystals of polymorphic 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazoleâcaboxylic acid by poor-solvent addition method. | |
| CN102731605A (en) | Purifying method for abiraterone acetate | |
| CN102993032A (en) | Synthetic method of methoxamine hydrochloride | |
| CN105732754A (en) | Synthesis method of alkyl acid testosterone compound | |
| CN102617461A (en) | Novel method for refining aripiprazole | |
| CN106366070A (en) | Preparation method for high-purity sodium esomeprazole | |
| CN103113408B (en) | A kind of novel method preparing phosphonomycin fosfomycin phenylethylamine calt | |
| CN108546278A (en) | The process for purification of Mecobalamin | |
| CN102010439A (en) | Production process for extracting yolk lecithin | |
| CN105646521B (en) | A kind of method for crystallising of moxidectin | |
| CN115215802A (en) | Method for purifying vitamin H intermediate cyclic acid | |
| CN102746295B (en) | Preparation method for 4-substituted-7-azaindole | |
| CN114262331A (en) | Preparation method of sitagliptin phosphate monohydrate | |
| CN103664990A (en) | Preparation method of Vicagrel | |
| CN103408553B (en) | A kind of process for refining of hydromorphone acid salt | |
| CN107382813B (en) | synthesis method of key intermediate of glimepiride | |
| CN101475533B (en) | One-pot clean production method for 3-amino pyrazole-4-pyrazolecarboxamide Hemisulfate | |
| CN107311862B (en) | Preparation method of sitagliptin intermediate | |
| CN106083564B (en) | A kind of synthesis of 2,6- dimethyl phenoxyacetic acid and purification process |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C17 | Cessation of patent right | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20070822 Termination date: 20130712 |