CN101648961A - Method and equipment for preparing cefotiam hydrochloride - Google Patents
Method and equipment for preparing cefotiam hydrochloride Download PDFInfo
- Publication number
- CN101648961A CN101648961A CN200910194561A CN200910194561A CN101648961A CN 101648961 A CN101648961 A CN 101648961A CN 200910194561 A CN200910194561 A CN 200910194561A CN 200910194561 A CN200910194561 A CN 200910194561A CN 101648961 A CN101648961 A CN 101648961A
- Authority
- CN
- China
- Prior art keywords
- solvent
- reaction
- hcl
- acmt
- mass ratio
- 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.)
- Granted
Links
Images
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a preparation method and equipment of cefotiam hydrochloride. The preparation method comprises the following steps: (1) after adding a solvent into raw materials of ATA.HCl, dripping a chlorinating agent, then adding a catalyst, reacting for 2-4h at the temperature of -15-0 DEG C and filtering out ATC.HCl crystals after finishing the reaction; (2) mixing 7-ACA and DMMT into the solvent, adding a boron trifluoride complex compound, reacting for 1-2h at the temperature of 0-65 DEG C, adding water for hydrolyzing after finishing the reaction, adding an antioxidant, then dripping alkali, cooling, stirring and obtaining 7-ACMT fluorborate; and (3) alkalizing the 7-ACMT, dissolving into a water-contained solvent, adding the ATC.HCl to carry out an acidylating reaction, reacting for 1-2h at the temperature of -30--10 DEG C, separating out an organic phase after finishing the reaction, adding concentrated hydrochloric acid into a water phase, adding a hydrophilic solvent and precipitating cefotiam hydrochloride crystals. The preparation method has the advantages of the yield of 87.6%, low cost, the product purity of 99.9% and the like and is suitable for industrialized production.
Description
Technical field
The invention belongs to the preparation field of antibiotic medicine, particularly relate to a kind of method and apparatus for preparing cefotiam chloride.
Background technology
Cefotiam chloride is a s-generation injection microbiotic, and its dihydrochloride of clinical use (CefotiamDihydrochloride) mixes powder preparation (trade(brand)name Pansporin) with buffer reagent yellow soda ash.This product is close to the effect and the Kefzol of gram-positive microorganism, to intestinal bacteria, and the Ke Shi pulmonitis strain, proteus mirabilis, influenzae has very strong anti-microbial effect.To citric acid bacillus, enterobacteria, the positive mycetozoan of indoles also has anti-microbial effect.
The synthetic route of cefotiam chloride is a raw material with 7-amino-cephalosporanic acid (7-ACA) all, its 3 with 1-(2-decil)-1,2,3,4---the strong reaction of mercaptan of four ammonia azoles-5-mercaptan (DMMT) is generally at sodium bicarbonate or dichloro phosphoric acid (dichloro phosphoric anhydride), Tricholroacetic Acid can synthesize 7-ACMT under the catalysis such as boron trifluoride.
The acylation reaction that its 7 bit amino is introduced 2-amino-4-thiazole ethanoyl generally has following several method:
Method one: earlier carry out amidate action with 4-chloro-3-oxo butyryl chloride (COBC), after again with thiocarbamide reaction closed loop.JP52083871 has reported this method, and the total total recovery of two step reactions is 50-60%, and reaction product also needs the finally synthetic cefotiam of reaction method again with DMMT, because COBC is very unstable, be difficult for transportation, so this method is not suitable for industrial production.
Method two: the ATA with amido protecting is prepared into ATC, and acidylate 7-ACMT makes the cefotiam of band protecting group again, sloughs protecting group with acid or enzyme at last and obtains cefotiam.USP441874 has reported the ATC-2 acidylate 7-ACMT that makes with ATA-2, and products therefrom obtains the method for cefotiam with penicillin acylase deprotection base, is 48-52% with the total recovery of the synthetic cefotiam two steps reaction of ATC-2.USP6787649 has reported with ATA-1 and has prepared ATC-1, acidylate 7-ACMT then, and products therefrom makes the method for cefotiam chloride with hydrochloric acid hydrolysis deprotection base, and the total recoverys of two steps reaction are 74%.
Two kinds of methods comparison shows that, though method two ratio method one is reasonable, connect protecting group and the deprotection base has all increased operation steps, have reduced yield and have improved production cost again.
The 3rd, Chinese patent CN2007100368831 discloses a kind of preparation method of cefotiam chloride, thereby this method is feedstock production ATC.HCL crystal with ATA further synthesizes cefotiam chloride, in this process, need to feed hydrogen chloride gas, therefore conversion unit there is very high airtight requirement, has very big potential safety hazard, in case equipment goes wrong, will cause corresponding pollution and harm to environment and operator, and improve production cost.
Above-mentioned three kinds of synthetic methods all exist certain defective, also do not adopt the liquid chlorizating agent to prepare the equipment and the method for cefotiam chloride up to now.
Summary of the invention
Technical problem to be solved by this invention provides a kind of method and apparatus for preparing cefotiam chloride, and this preparation method has yield up to 87.6%, and cost is low, and product purity reaches 99.9%, is applicable to advantages such as suitability for industrialized production; Chemical equation of the present invention is as follows:
(cefotiam dihydrochloride)
A kind of method for preparing cefotiam chloride of the present invention comprises:
(1) raw material A TC.HCl's is synthetic
Raw material A TA.HCl is fed intake in encloses container, behind the adding solvent, be cooled to-10～10 ℃, to wherein splashing into chlorizating agent, add catalyzer then, in-15～0 ℃ of reaction 2～4h, reaction leaches the ATC.HCl crystallization after finishing;
Wherein, the mass ratio of ATA.HCl and solvent is 1: 5～8; The mol ratio of ATA.HCl and chlorizating agent is 1: 1～3; The mol ratio of ATA.HCl and catalyzer is 1: 1～2;
(2) raw material 7-ACMT's is synthetic
7-ACA and DMMT 1: 1 in molar ratio～1.5 are mixed in the solvent, add boron trifluoride complex, in 0～65 ℃ of reaction 1～2h, reaction finishes the back cooling and adds the water hydrolysis for 20～25 ℃, adds antioxidant, drip alkali then and regulate pH to 2.5～3.0, lower the temperature 10～15 ℃, stir growing the grain 2～3h, filter, washing obtains the 7-ACMT fluoroborate;
Wherein, the mass ratio of 7-ACA and solvent is 1: 1.5～2.5; The mass ratio 3～5: 1 of boron trifluoride complex and 7-ACA; The mass ratio of 7-ACA and antioxidant is 45～70: 1;
(3) cefotiam chloride is synthetic
Above-mentioned 7-ACMT is added alkali be dissolved in the water-containing solvent, add ATC.HCl and carry out acylation reaction, in-30～-10 ℃ of reaction 1～2h, reaction is told organic phase after finishing, and adds concentrated hydrochloric acid at aqueous phase, adds hydrophilic solvent, separates out the cefotiam chloride crystallization;
Wherein, 7-ACMT and alkali mass ratio be 1.5～4: 1; The mass ratio of alkali and water-containing solvent is 1: 10～15; The mass ratio of 7-ACMT and ATC.HCl is 1: 0.6～1.5.
Encloses container in the described step (1) is a glass-lined reactor;
Solvent in the described step (1) is methylene dichloride, trichloromethane, tetracol phenixin, ethylene dichloride etc.;
Chlorizating agent in the described step (1) is thionyl chloride, phosphorus pentachloride, phosphorus oxychloride, oxalyl chloride etc.;
Catalyzer in the described step (1) is N, dinethylformamide, N, dinethylformamide, methane amide etc.;
Solvent in the described step (2) is acetonitrile, methylene dichloride, ethyl acetate etc.;
Boron trifluoride complex in the described step (2) is boron trifluoride acetonitrile, boron trifluoride diethyl etherate, boron trifluoride dimethyl ester etc.;
Antioxidant in the described step (2) is vat powder, Sodium Pyrosulfite, sulfurous acid etc.;
Alkali in the described step (2) is ammoniacal liquor, sodium bicarbonate, yellow soda ash etc.;
Temperature of reaction in the described step (2) is 30～35 ℃;
Water-containing solvent in the described step (3) is the mixed solvent of organic solvent and water; Wherein, organic solvent is selected from methylene dichloride, trichloromethane, ethylene dichloride, the acetonitrile one or both mixture, and the mass ratio of organic solvent and water is 1～2.5: 1;
Alkali in the described step (3) is yellow soda ash, sodium bicarbonate, triethylamine or Tributylamine;
Hydrophilic solvent in the described step (3) is ethanol, Virahol or acetone;
Temperature of reaction in the described step (3) is-25～-20 ℃.
A kind of equipment for preparing cefotiam chloride of the present invention, its structure is: by retort, first header tank, second header tank, solvent pipe, valve tube, the jar mouth, vomit pipe and electric mixer, first header tank, solvent pipe, in retort top ligation jar, described jar of mouth is positioned at retort top successively for valve tube, second header tank, described electric mixer is fixed in the positive top of retort and it stirs in the end insertion reaction jar jar, and described vomit pipe is connected in retort bottom drain hole.
This retort is the lass lining of special substance, and this lass lining matrix is a soft steel, and glaze consists of 60～70%SiO
2And other auxiliary materials such as the B that add
2O
3, Al
2O
3, TiO
2, ZrO
2, V
2O
5Deng, adopt maximum sintering temperature to be lower than 870 ℃, the acid and alkali-resistance lass lining cover-coat enamel retort that obtains.Reaction solvent (methylene dichloride) is by the direct vacuum suction of pipeline, and solid material (ATA.HCl) adds from the jar mouth, after the chuck cooling, add chlorizating agent (thionyl chloride) by header tank, add catalyzer (N, dinethylformamide) by another header tank then, the reaction beginning; Enter the crystal filter of inner liner polytetrafluoroethylene after reaction finishes by blowing jar blowing at the bottom of the jar, suction filtration gets product A TC.HCl.
Based on the stronger character of the acidity of reaction mass, conversion unit is selected the glass-lined reactor of special substance for use, and this retort has the characteristic of utmost point strong alkali-acid resistance, and meets the demand of reaction than the low reaction temperatures condition; Finished product ATC.HCl also has strongly-acid, adopts the teflon-lined crystal filter to filter when filtering, and this strainer has anti-strong acid, corrosion resistant characteristics, meets product requirement; And the building-up reactions that gas participates in requires equipment that very strong stopping property is arranged, otherwise in case the meeting of leakage produces very big danger; Feed the bad control of amount of gas, liquid participates in reacting directly weighing or measures by liquidometer; Gas enters reaction, because main reaction is liquid, the mutual reaction of gas and liquid is insufficient, needs gas excessive much just passable, certainly will cause very big waste like this, and cost can corresponding raising; Feed gas in addition and participate in reaction, unnecessary gas must add a cover device for absorbing tail gas, and waste liquid also will be handled in addition.
Cefotiam chloride synthetic method of the present invention is by raw material A TA.HCl direct chlorination output ATC.HCl.ATA.HCl and chlorizating agent directly generate ATC.HCl under the effect of catalyzer, response behaviour is the solid-liquid mixed phase, stir and fully react very complete, reaction vessel uses glass-lined reactor, can be airtight, liquid material directly adds by header tank or vacuum, and the safety and the feature of environmental protection strengthen.One step and secondary product all do not need drying, directly wet product feed intake and enter next reaction, (expense of drying plant belongs to disposable input with regard to greatly reducing production cost on equipment input and labour cost for this, ATC.HCl belongs to the strongly-acid material, and it is had relatively high expectations to drying plant, needs the titanium alloy moisture eliminator, about 1,000,000 yuan/platform, if output is bigger, just need four such moisture eliminators, about 400～5,000,000 yuan; The character of 7-ACMT is gentle, and common loft drier gets final product, and about 100,000 yuan/platform with same four calculating, needs to drop into about 400,000 yuan.For drying in requisition for labour cost about 10 yuan/kilogram for peace, for peace, need many labor intensive take about 30,000 yuan by three tons of monthly outputs, and there are not problems such as dust pollution in wet product, greatly protected environmental health.
Beneficial effect
With prior art particularly Chinese patent CN2007100368831 compare, cefotiam chloride synthetic method of the present invention is owing to optimized reaction parameter, adopted improved equipment, so improved the yield of end product significantly, its yield is up to 87.6%.And, brought bigger cost to reduce thus, reduced noxious gas emission, environmentally friendly.What is more important adopts the method and apparatus after improving, and the product purity of acquisition reaches 99.9%, is applicable to suitability for industrialized production more.
Description of drawings
Fig. 1 is the structural representation of glass-lined reactor;
Fig. 2 is the structural representation of gas-phase reaction container.
Embodiment
Below in conjunction with specific embodiment, further set forth the present invention.Should be understood that these embodiment only to be used to the present invention is described and be not used in and limit the scope of the invention.Should be understood that in addition those skilled in the art can make various changes or modifications the present invention after the content of having read the present invention's instruction, these equivalent form of values fall within the application's appended claims institute restricted portion equally.
Embodiment 1
(1) raw material A TC.HCl's is synthetic
ATA.HCl23.4g (0.12mol) is suspended in the 128.0g trichloromethane, cool to-5 ℃, add thionyl chloride 14.3g (0.12mol), keep temperature to add catalyst n, N-N,N-DIMETHYLACETAMIDE 10.5g (0.12mol) ,-15 ℃ of stirring reaction 2h lower the temperature, filter, cold trichloromethane 150g washs at twice, gets white ATC.HCl crystallization, and product 35.4g must wet;
(2) raw material 7-ACMT's is synthetic
7-ACA27.2g (0.1mol), DMMT17.30.g (0.1mol) is suspended in the 60g acetonitrile, stirs to add boron trifluoride diethyl etherate 90g down 30 ℃ of reaction 2h.Reaction Bi Jiangwen adds water 110g for 20 ℃, adds Sodium Pyrosulfite 0.4g, and dropping ammonia is lowered the temperature 10 ℃ and stirred growing the grain 2 hours to pH value 2.5, filter, and acetone 150g washing, product 7-ACTM49.5g must wet.
(3) cefotiam chloride is synthetic
Wet product 7-ACTM 49.5g is suspended in 95g water with above-mentioned gained, the 95g acetonitrile, the 70g methylene dichloride, lower the temperature 0～5 ℃, add the 19.6g triethylamine, cool to-20 ℃ after the dissolving fully, add the wet product 35.4g of a step gained,-5～-20 ℃ were reacted 1 hour, adding 90g methylene dichloride is finished in reaction, the 15g concentrated hydrochloric acid, stirred 10 minutes, static layering, water layer adds the 26g concentrated hydrochloric acid, control 25～27 ℃, add 650g acetone, 0～5 ℃ of growing the grain 2 hours filters, 150g acetone is wash crystallization at twice, 45 ℃ of vacuum-dryings got 51.1g white cefotiam dihydrochloride crystalline powder (HPLC purity 98.8%, moisture content 5.2% in 8.5 hours, acetone 0.67%), yield 85.6% (in 7-ACA).
Embodiment 2
(1) raw material A TC.HCl's is synthetic
ATA.HCl23.4g (0.12mol) is suspended in the 187.2g methylene dichloride, cool to 10 ℃, add oxalyl chloride 31.8g (0.26mol), keep temperature to add catalyst n, N-N,N-DIMETHYLACETAMIDE 13.1g (0.15mol), the 0 ℃ of stirring reaction 4h that lowers the temperature filters, cold methylene dichloride 155g washs at twice, gets the wet product 38g of white ATC.HCl.
(2) raw material 7-ACMT's is synthetic
7-ACA27.2g (0.1mol), DMMT25.95g (0.15mol) is suspended in the 68.0g acetonitrile, stirs to add boron trifluoride acetonitrile 108.8g down 55 ℃ of reaction 1h.Reaction Bi Jiangwen adds water 120g for 25 ℃, the powder 0.55g that takes a policy, and dropping ammonia is lowered the temperature 15 ℃ and was stirred growing the grain 3 hours to pH value 3.0, filters acetone 200g washing.Product 48g must wet.
(3) cefotiam chloride is synthetic
Wet product 48g is suspended in 95g water, 196g acetonitrile with above-mentioned gained, lowers the temperature 0～5 ℃, adds the 27g Tributylamine, cool to-20 ℃ after dissolving fully, add the wet product 38g of a step gained, 5～-15 ℃ were reacted 2 hours, adding 90g methylene dichloride, 15g concentrated hydrochloric acid are finished in reaction, stir static layering 10 minutes, water layer adds the 26g concentrated hydrochloric acid, control 25～27 ℃, add 650g acetone, 0～5 ℃ of growing the grain 2 hours, filter, 150g acetone is wash crystallization at twice.45 ℃ of vacuum-dryings got 52.3g white cefotiam dihydrochloride crystalline powder (HPLC purity 99.0%, moisture content 5.86%, acetone 0.30%), yield 87.6% (in 7-ACA) in 6.5 hours.
(1) raw material A TC.HCl's is synthetic
ATA.HCl23.4g (0.12mol) is suspended in the 150.6g methylene dichloride, cool to 5 ℃, add phosphorus oxychloride 27.6g (0.18mol), keep temperature to add catalyst n, dinethylformamide 14.5g (0.20mol) ,-10 ℃ of stirring reaction 3h that lower the temperature filter, cold methylene dichloride 120g washs at twice, gets the wet product 34g of white ATC.HCl;
(2) raw material 7-ACMT's is synthetic
7-ACA27.2g (0.1mol), DMMT18.16g (0.105mol) is suspended in the 50g acetonitrile, stirs to add boron trifluoride acetonitrile 130g down 35 ℃ of reaction 1.5h.Reaction Bi Jiangwen adds water 120g for 20 ℃, the powder 0.6g that takes a policy, and dropping ammonia is lowered the temperature 10 ℃ and was stirred growing the grain 2 hours to pH value 2.8, filters acetone 150g washing.Get faint yellow wet product 51g;
(3) cefotiam chloride is synthetic
The wet product of above-mentioned gained 51g are suspended in 98g water, 155g acetonitrile, lower the temperature 0～5 ℃, add the 17.2g triethylamine, cool to-20 ℃ after dissolving fully, add the wet product 34g of a step gained ,-20～-25 ℃ were reacted 1 hour, adding 90g methylene dichloride, 15g concentrated hydrochloric acid are finished in reaction, stir static layering 10 minutes, water layer adds the 26g concentrated hydrochloric acid, control 25～27 ℃, add 650g acetone, 0～5 ℃ of growing the grain 2 hours, filter, 150g acetone is wash crystallization at twice.45 ℃ of vacuum-dryings got 51.7g white cefotiam dihydrochloride crystalline powder (HPLC purity 99.9%), moisture content 5.40%, acetone 0.5% in 7 hours) yield 86.6% (in 7-ACA).
Claims (9)
1. method for preparing cefotiam chloride comprises:
(1) raw material A TC.HCl's is synthetic
Raw material A TA.HCl is fed intake in encloses container, behind the adding solvent, be cooled to-10～10 ℃, to wherein splashing into chlorizating agent, add catalyzer then, in-15～0 ℃ of reaction 2～4h, reaction leaches the ATC.HCl crystallization after finishing;
Wherein, the mass ratio of ATA.HCl and solvent is 1: 5～8; The mol ratio of ATA.HCl and chlorizating agent is 1: 1～3; The mol ratio of ATA.HCl and catalyzer is 1: 1～2;
(2) raw material 7-ACMT's is synthetic
7-ACA and DMMT 1: 1 in molar ratio～1.5 are mixed in the solvent, add boron trifluoride complex, in 0～65 ℃ of reaction 1～2h, reaction finishes the back cooling and adds the water hydrolysis for 20～25 ℃, adds antioxidant, drip alkali then and regulate pH to 2.5～3.0, lower the temperature 10～15 ℃, stir growing the grain 2～3h, filter, washing obtains the 7-ACMT fluoroborate;
Wherein, the mass ratio of 7-ACA and solvent is 1: 1.5～2.5; The mass ratio 3～5: 1 of boron trifluoride complex and 7-ACA; The mass ratio of 7-ACA and antioxidant is 45～70: 1;
(3) cefotiam chloride is synthetic
Above-mentioned 7-ACMT is added alkali be dissolved in the water-containing solvent, add ATC.HCl and carry out acylation reaction, in-30～-10 ℃ of reaction 1～2h, reaction is told organic phase after finishing, and adds concentrated hydrochloric acid at aqueous phase, adds hydrophilic solvent, separates out the cefotiam chloride crystallization;
Wherein, 7-ACMT and alkali mass ratio be 1.5～4: 1; The mass ratio of alkali and water-containing solvent is 1: 10～15; The mass ratio of 7-ACMT and ATC.HCl is 1: 0.6～1.5.
2. a kind of method for preparing cefotiam chloride according to claim 1 is characterized in that: the encloses container in the described step (1) is a glass-lined reactor.
3. a kind of method for preparing cefotiam chloride according to claim 1 is characterized in that: the solvent in the described step (1) is methylene dichloride, trichloromethane, tetracol phenixin or ethylene dichloride; Chlorizating agent is thionyl chloride, phosphorus pentachloride, phosphorus oxychloride, oxalyl chloride; Catalyzer is N, dinethylformamide, N,N-dimethylacetamide or methane amide.
4. a kind of method for preparing cefotiam chloride according to claim 1 is characterized in that: the solvent in the described step (2) is acetonitrile, methylene dichloride or ethyl acetate; Boron trifluoride complex is boron trifluoride acetonitrile, boron trifluoride diethyl etherate or boron trifluoride dimethyl ester; Antioxidant is vat powder, Sodium Pyrosulfite or sulfurous acid; Alkali is ammoniacal liquor, sodium bicarbonate or yellow soda ash.
5. a kind of method for preparing cefotiam chloride according to claim 1 is characterized in that: the temperature of reaction in the described step (2) is 30～35 ℃.
6. a kind of method for preparing cefotiam chloride according to claim 1 is characterized in that: the water-containing solvent in the described step (3) is the mixed solvent of organic solvent and water; Wherein, organic solvent is selected from one or both the mixture in methylene dichloride, trichloromethane, ethylene dichloride, the acetonitrile, and the mass ratio of organic solvent and water is 1～2.5: 1.
7. a kind of method for preparing cefotiam chloride according to claim 1 is characterized in that: the alkali in the described step (3) is yellow soda ash, sodium bicarbonate, triethylamine or Tributylamine; Hydrophilic solvent is ethanol, Virahol or acetone.
8. a kind of method for preparing cefotiam chloride according to claim 1 is characterized in that: the temperature of reaction in the described step (3) is-25～-20 ℃.
9. equipment for preparing cefotiam chloride, by glass-lined reactor (1), first header tank (2), second header tank (6), solvent pipe (3), valve tube (4), jar mouthful (7), vomit pipe (8) and electric mixer (5), it is characterized in that: described first header tank (2), solvent pipe (3), valve tube (4), second header tank (6) connect glass-lined reactor (1) in glass-lined reactor (1) top successively, and described jar mouthful (7) are positioned at glass-lined reactor (1) top, described electric mixer (5) is fixed in the positive top of glass-lined reactor (1) and it stirs in end insertion glass-lined reactor (1) jar, and described vomit pipe (8) is connected in glass-lined reactor (1) bottom drain hole.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2009101945619A CN101648961B (en) | 2009-08-25 | 2009-08-25 | Method and equipment for preparing cefotiam hydrochloride |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2009101945619A CN101648961B (en) | 2009-08-25 | 2009-08-25 | Method and equipment for preparing cefotiam hydrochloride |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101648961A true CN101648961A (en) | 2010-02-17 |
| CN101648961B CN101648961B (en) | 2011-06-29 |
Family
ID=41671307
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2009101945619A Ceased CN101648961B (en) | 2009-08-25 | 2009-08-25 | Method and equipment for preparing cefotiam hydrochloride |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101648961B (en) |
Cited By (16)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102190667A (en) * | 2011-03-24 | 2011-09-21 | 海南灵康制药有限公司 | New method for purifying cefotiam hydrochloride |
| CN102850381A (en) * | 2012-10-10 | 2013-01-02 | 山东金城医药化工股份有限公司 | Preparation method of cefotiam hydrochloride crude product |
| CN103012432A (en) * | 2012-12-04 | 2013-04-03 | 山东鑫泉医药有限公司 | Method for preparing hydrochloride of high purity cefotiam midbody |
| CN103232476A (en) * | 2013-04-25 | 2013-08-07 | 四川海思科制药有限公司 | Antibacterial compound |
| CN103601737A (en) * | 2013-12-04 | 2014-02-26 | 哈药集团制药总厂 | Method for preparing cefotiam hydrochloride |
| CN103910749A (en) * | 2014-03-14 | 2014-07-09 | 烟台万润精细化工股份有限公司 | A preparation method of cefotiam hydrochloride |
| CN104356146A (en) * | 2014-11-14 | 2015-02-18 | 浙江浙邦制药有限公司 | Method for preparing cefotiam hydrochloride |
| CN105646539A (en) * | 2016-03-16 | 2016-06-08 | 重庆福安药业集团庆余堂制药有限公司 | Cefotiam hydrochloride for reducing anaphylaxis and preparation thereof |
| CN106967091A (en) * | 2017-05-13 | 2017-07-21 | 山西千岫制药有限公司 | A kind of preparation method of Cefotiam parent nucleus |
| CN107987091A (en) * | 2017-11-07 | 2018-05-04 | 河北九派制药股份有限公司 | A kind of preparation method of cefotiam hydrochloride impurity 3- methyl cefotiam chlorides |
| CN108299469A (en) * | 2017-01-12 | 2018-07-20 | 重庆常捷医药有限公司 | A kind of preparation method of cefotiam chloride |
| CN109134508A (en) * | 2018-08-10 | 2019-01-04 | 齐鲁安替制药有限公司 | A kind of preparation method of the high yield high quality cefotiam hydrochloride suitable for industrialized production |
| CN109336906A (en) * | 2018-11-21 | 2019-02-15 | 山东罗欣药业集团股份有限公司 | A kind of cefotiam chloride drying process |
| CN109517001A (en) * | 2018-11-19 | 2019-03-26 | 山东罗欣药业集团股份有限公司 | A kind of preparation method of cefotiam hydrochloride |
| CN109517002A (en) * | 2018-11-21 | 2019-03-26 | 山东罗欣药业集团股份有限公司 | A kind of synthetic method of cefotiam hydrochloride |
| CN110003238A (en) * | 2018-07-25 | 2019-07-12 | 上海上药新亚药业有限公司 | A kind of preparation method of cefotiam |
-
2009
- 2009-08-25 CN CN2009101945619A patent/CN101648961B/en not_active Ceased
Cited By (22)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012126148A1 (en) * | 2011-03-24 | 2012-09-27 | 海南灵康制药有限公司 | New method for purifying cefotiam hydrochloride |
| CN102190667B (en) * | 2011-03-24 | 2013-05-29 | 海南灵康制药有限公司 | New method for purifying cefotiam hydrochloride |
| CN102190667A (en) * | 2011-03-24 | 2011-09-21 | 海南灵康制药有限公司 | New method for purifying cefotiam hydrochloride |
| CN102850381A (en) * | 2012-10-10 | 2013-01-02 | 山东金城医药化工股份有限公司 | Preparation method of cefotiam hydrochloride crude product |
| CN103012432B (en) * | 2012-12-04 | 2015-06-03 | 山东鑫泉医药有限公司 | Method for preparing hydrochloride of high purity cefotiam midbody |
| CN103012432A (en) * | 2012-12-04 | 2013-04-03 | 山东鑫泉医药有限公司 | Method for preparing hydrochloride of high purity cefotiam midbody |
| CN103232476A (en) * | 2013-04-25 | 2013-08-07 | 四川海思科制药有限公司 | Antibacterial compound |
| CN103601737B (en) * | 2013-12-04 | 2016-02-03 | 哈药集团制药总厂 | A kind of preparation method of cefotiam hydrochloride |
| CN103601737A (en) * | 2013-12-04 | 2014-02-26 | 哈药集团制药总厂 | Method for preparing cefotiam hydrochloride |
| CN103910749A (en) * | 2014-03-14 | 2014-07-09 | 烟台万润精细化工股份有限公司 | A preparation method of cefotiam hydrochloride |
| CN104356146A (en) * | 2014-11-14 | 2015-02-18 | 浙江浙邦制药有限公司 | Method for preparing cefotiam hydrochloride |
| CN105646539A (en) * | 2016-03-16 | 2016-06-08 | 重庆福安药业集团庆余堂制药有限公司 | Cefotiam hydrochloride for reducing anaphylaxis and preparation thereof |
| CN108299469A (en) * | 2017-01-12 | 2018-07-20 | 重庆常捷医药有限公司 | A kind of preparation method of cefotiam chloride |
| CN106967091A (en) * | 2017-05-13 | 2017-07-21 | 山西千岫制药有限公司 | A kind of preparation method of Cefotiam parent nucleus |
| CN107987091A (en) * | 2017-11-07 | 2018-05-04 | 河北九派制药股份有限公司 | A kind of preparation method of cefotiam hydrochloride impurity 3- methyl cefotiam chlorides |
| CN110003238A (en) * | 2018-07-25 | 2019-07-12 | 上海上药新亚药业有限公司 | A kind of preparation method of cefotiam |
| CN109134508A (en) * | 2018-08-10 | 2019-01-04 | 齐鲁安替制药有限公司 | A kind of preparation method of the high yield high quality cefotiam hydrochloride suitable for industrialized production |
| CN109517001A (en) * | 2018-11-19 | 2019-03-26 | 山东罗欣药业集团股份有限公司 | A kind of preparation method of cefotiam hydrochloride |
| CN109517001B (en) * | 2018-11-19 | 2020-06-09 | 山东罗欣药业集团股份有限公司 | Preparation method of cefotiam hydrochloride |
| CN109336906A (en) * | 2018-11-21 | 2019-02-15 | 山东罗欣药业集团股份有限公司 | A kind of cefotiam chloride drying process |
| CN109517002A (en) * | 2018-11-21 | 2019-03-26 | 山东罗欣药业集团股份有限公司 | A kind of synthetic method of cefotiam hydrochloride |
| CN109517002B (en) * | 2018-11-21 | 2020-06-09 | 山东罗欣药业集团股份有限公司 | Synthesis method of cefotiam hydrochloride |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101648961B (en) | 2011-06-29 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101648961B (en) | Method and equipment for preparing cefotiam hydrochloride | |
| CN101045733B (en) | Preparation method of cefotiam chloride | |
| CN101928292B (en) | Method for preparing cefuroxime acid | |
| CN104356146B (en) | A kind of preparation method of cefotiam chloride | |
| CN101747344B (en) | Synthesis Method of cefcapene pivoxil hydrochloride | |
| CN105399768B (en) | A kind of process for cleanly preparing for preparing N normal-butyl thiophosphoryl triamines | |
| CN102391291B (en) | Cefmetazole acid preparation method | |
| CN101781315A (en) | Synthesizing method of nafcillin sodium-hydrate | |
| CN104193765B (en) | A kind of synthetic method of cefixime | |
| CN103880773A (en) | Isothiazolinone derivative production method | |
| CN101428860B (en) | Method for producing high purity MnOOH | |
| CN109942598A (en) | A kind of preparation method of trans- cefuroxime derivative | |
| CN109485658A (en) | A kind of preparation method of ceftezole acid | |
| CN101704827A (en) | Novel route for cefathiamidine compounds | |
| CN101643477B (en) | Synthesis method of cefradine | |
| CN109535071B (en) | 2-amino-3-hydroxypyridine and preparation method and refining method thereof | |
| CN101778824A (en) | Process for producing toluidine compound | |
| CN103058956A (en) | Preparation method of 5-amino-1,2,3-thiadiazole | |
| CN103333180B (en) | Preparation method of aspoxicillin | |
| DE60104380T2 (en) | Process for the preparation of N- [1- (S) -ethoxycarbonyl-3-phenylpropyl] -L-alanine-N-carboxyanhydride | |
| CN113025679B (en) | Enzymatic preparation process of cefcapene precursor acid of t-butyloxycarbonyl | |
| CN108047299A (en) | The preparation method of canrenone important intermediate | |
| CN102633594A (en) | Method for synthesizing triphenylchloromethane by using triphenylmethyl alkyl ether | |
| CN112940022B (en) | Preparation method of dimethylamine borane | |
| CN101357928A (en) | Novel technique for synthesizing cefoselis sulfate |
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 | ||
| C35 | Partial or whole invalidation of patent or utility model | ||
| IW01 | Full invalidation of patent right |
Decision date of declaring invalidation: 20140129 Decision number of declaring invalidation: 22060 Granted publication date: 20110629 |