CN105646539A - Cefotiam hydrochloride for reducing anaphylaxis and preparation thereof - Google Patents
Cefotiam hydrochloride for reducing anaphylaxis and preparation thereof Download PDFInfo
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- CN105646539A CN105646539A CN201610149052.4A CN201610149052A CN105646539A CN 105646539 A CN105646539 A CN 105646539A CN 201610149052 A CN201610149052 A CN 201610149052A CN 105646539 A CN105646539 A CN 105646539A
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- anaphylaxis
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
- C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
- C07D501/36—Methylene radicals, substituted by sulfur atoms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
- A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
- A61K31/546—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine containing further heterocyclic rings, e.g. cephalothin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/143—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with inorganic compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/02—Preparation
- C07D501/04—Preparation from compounds already containing the ring or condensed ring systems, e.g. by dehydrogenation of the ring, by introduction, elimination or modification of substituents
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Inorganic Chemistry (AREA)
- Dermatology (AREA)
- Cephalosporin Compounds (AREA)
Abstract
The invention relates to an antibiotic drug, in particular to cefotiam hydrochloride for reducing anaphylaxis. The compound has the advantages of high yield, high purity and the like, and is suitable for industrial production, and product stability and anaphylaxis reducing and clinic application of a preparation are all obviously improved.
Description
Technical field
The present invention relates to a kind of microbiotic, it is specifically related to a kind of cefotiam chloride reducing anaphylaxis.
Background technology
Cefotiam is s-generation bactericidal properties cephalosporins Broad spectrum antibiotics, effect and Cephazolin to gram positive organism are close, and to gram-negative bacteria, as the effects such as influenzae, escherichia coli, klebsiella spp, Proteus mirabilis are relatively strong, enterobacteria, citrobacter, indole-positive Bacillus proteus etc. also there is anti-microbial effect. Its mechanism of action is combine with the penicillin-binding protein (PBPs) on bacterial cell membrane; make transpeptidase acidylate; every the synthesis with cell walls in anti-bacteria; the intersection affecting cell wall mucopeptide composition links; cell fission and growth are suppressed; ne ar is elongated, finally dissolves and death.
Cefotiam chloride; chemistry (6R-is trans)-7-[[(2-amino-4-thiazolyl) ethanoyl] amino]-3-by name [[[1-[(2-(dimethylamino) ethyl]-1H-TETRAZOLE-5-base] sulphomethyl]-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid dihydrochloride; for clinical upper application cynnematin more widely, its structural formula is:
The synthetic route of cefotiam chloride is all taking 7-aminocephalosporanic acid (7-ACA) as raw material, its 3 with the thiol reactant of 1-(2-dimethylamine ethyl)-1,2,3,4 four ammonia azoles-5-mercaptan generally at sodium bicarbonate or two chlorine phosphoric acid, Tricholroacetic Acid, can synthesize 7-ACMT under the catalysis such as boron trifluoride.
The acylation reaction that its 7 bit amino introduces 2-amino 4-thiazole ethanoyl generally has two kinds of methods:
JP52083871 discloses the chloro-3-oxo butyryl chloride of 7-ACA and 4-and carries out amidate action, after again with thiocarbamide react closed loop, the total recovery that this two step reacts total is 50-60%, reaction product also need with DMMT again reaction method finally synthesize cefotiam.
It is prepared into ATC with the ATA of amido protecting, then the cefotiam of the obtained band protecting group of acidylate 7-ACMT, finally slough protecting group with acid or enzyme and obtain cefotiam. US441874 discloses the ATC-2 acidylate 7-ACMT obtained with ATA-2, and products therefrom penicillin acylase Deprotection obtains the method for cefotiam, and the total recovery synthesizing the reaction of cefotiam two step with ATC-2 is 48-52%. US6787649 discloses and prepares ATC-1 with ATA-1, then acidylate 7-ACMT, the products therefrom method of the obtained cefotiam chloride of hydrochloric acid hydrolysis Deprotection, and the total recovery of two step reactions is 74%.
It is relatively strong that the chloro-3-oxo butyryl chloride of 4-that the first method uses has reactive behavior, not easily transports, and therefore the method is not suitable for industrial production. 2nd kind of method needs the operation steps of protecting group and Deprotection, causes cost height, and receipts rate is low. It is thus desirable to provide new synthesis technique makes improvements.
Obtain national science progress prize card in December, 2001 " research of ��-lactam antibitics anaphylaxis ", prize-winning unit: pharmaceutical biological product institute of China (now rename: Chinese food drug inspection research institute). My company reached the technological improvement in cooperation agreement application " research of ��-lactam antibitics anaphylaxis " in 2015 with Chinese food drug inspection research institute's chemistry room and generates technique, reduce cephalosporin analog antibiotic impurity, reaching improves the quality of products reduces the object of cephalosporin analog antibiotic anaphylaxis, the synthesis technique of cefotiam chloride is improved, thus has achieved the present invention.
Summary of the invention
It is an object of the invention to provide a kind of cefotiam chloride reducing anaphylaxis.
It is a further object to provide the preparation method of a kind of cefotiam chloride reducing anaphylaxis, it is characterized in that, (1) 7-ACMT is dissolved in organic solvent, adds TERT-BUTYL DIMETHYL CHLORO SILANE and organic bases reacts, prepare formula 1 compound; (2) 2-formamido group thiazole-4 Acetyl Chloride 98Min. is dissolved in organic solution, adds formula 1 compound that step (1) prepares and react, prepare formula 2 compound; (3) organic solution of formula 2 compound and HCl being reacted, crystallize out after reacting completely, filter, washing, drying obtains cefotiam chloride;
Reaction formula is as follows:
The mol ratio of the 7-ACMT of step (1), TERT-BUTYL DIMETHYL CHLORO SILANE and organic bases is 1:2-2.1:2-2.1.
The organic solvent of step (1) is one or more of chloroform, methylene dichloride, ethyl acetate, tetrahydrofuran (THF), acetone or mibk.
The organic solvent of step (2) is one or more of chloroform, methylene dichloride, ethyl acetate, tetrahydrofuran (THF), acetone or mibk.
The organic solvent of step (3) is one or more of chloroform, methylene dichloride, ethyl acetate, tetrahydrofuran (THF), acetone or mibk.
The organic bases of step (1) is pyridine or triethylamine.
The HCl of step (3) is aqueous hydrochloric acid.
The temperature of reaction of step (3) is 35-45 DEG C, and the reaction times is 2-3 hour.
It is a further object to provide the pharmaceutical preparation of a kind of cefotiam chloride containing reducing anaphylaxis, reduced the cefotiam chloride of anaphylaxis by aforesaid method preparation, then mix useful in preparing drug formulations with pharmaceutically acceptable carrier.
The consumption of the reaction raw materials of the present invention has no particular limits, and generally carries out according to chemical reaction metering.
In the inventive solutions; adopt TERT-BUTYL DIMETHYL CHLORO SILANE the amino of 7-ACMT and carboxyl to be protected simultaneously; and then react with acyl chlorides; using aqueous hydrochloric acid to be hydrolyzed and salt-forming reaction afterwards in step (3), at 35-45 DEG C, reaction can optionally be hydrolyzed formamido-simultaneously. The reaction process of the present invention is simple, and product yield height, foreign matter content are low, reacts the cefotiam chloride that just can obtain high purity after terminating without the need to further purification step, is very suitable for the production of industrialization.
Embodiment
Below in conjunction with embodiment, the present invention is described in further detail, but embodiments of the present invention are not limited to this. In following embodiment, method therefor is ordinary method if no special instructions.
Embodiment 1:
(1) 7-ACMT385g being dissolved in 2L acetone, add 300g TERT-BUTYL DIMETHYL CHLORO SILANE and 202g triethylamine, at room temperature stirring reaction, TLC detection reaction, to completely, is cooled to 0 DEG C, except desolventizing obtains formula 1 compound.
(2) 2-formamido group thiazole-4 Acetyl Chloride 98Min. 204g is dissolved in 2L methylene dichloride, add the formula 1 compound 598g that step (1) obtains again, at room temperature stirring reaction 3 hours, TLC detection reaction is to completely, removal of solvent under reduced pressure obtains formula 1 compound.
(3) formula 2 compound that step (2) prepares is dissolved in 2L acetone, then adds excessive aqueous hydrochloric acid, be heated to 35 DEG C of reactions 3 hours, crystallize out after reacting completely, washing, vacuum-drying obtains cefotiam chloride 550kg, and receipts rate is 92%.
Assay: measure according to size exclusive chromatography (Chinese Pharmacopoeia version in 2010 two annex VH).
Chromatographic condition and system suitability: be weighting agent with dextrane gel G-10 (40-120 ��m), glass column internal diameter 1.0-1.6cm, post height 30-45cm. Taking the 0.04mol/L disodium phosphate soln of pH10.0 as mobile phase A, taking water as Mobile phase B, flow velocity is every minute 0.5ml, and determined wavelength is 254nm. Measuring 0.1mg/ml blue dextran 2000 solution 50 �� l, injection liquid chromatography, respectively with mobile phase A, B measures, and records color atlas, is all not less than 400 by the theoretical plate number of blue dextran 2000 peak calculating, and tailing factor all should be less than 2.0. In two kinds of flow phase system, the retention time ratio at blue dextran 2000 peak should between 0.93-1.07, contrast solution main peak and polymkeric substance peak in need testing solution and in corresponding chromatographic system, the ratio of the retention time at blue dextran 2000 peak all should between 0.93-1.07. Accurately weighed this product is about 0.25g and puts in 10ml measuring bottle, adds blue dextran 2000 solubilize of 0.1mg/ml and is diluted to scale, shakes even. Measure 50 �� l injection liquid chromatographies, measure by mobile phase A, record color atlas. The peak height of high polymer and the paddy height ratio between monomer and high polymer should be greater than 2.0. Another is moving phase taking Mobile phase B, and precision measures contrast solution 50 �� l, and continuous sample introduction 5 times, the relative standard deviation of peak area should be not more than 5.0%.
According to above-mentioned condition, the cefotiam chloride of embodiment 1 is carried out assay, and wherein the content of cefotiam is 97.8%, and the content of impurity 1 is 1.3%, and the content of impurity 2 is 0.9%.
The structure of impurity 1 and impurity 2 is as follows:
Embodiment 2:
(1) 7-ACMT385g being dissolved in 2L ethyl acetate, add 315g TERT-BUTYL DIMETHYL CHLORO SILANE and 212g triethylamine, at room temperature stirring reaction, TLC detection reaction, to completely, is cooled to-5 DEG C, except desolventizing obtains formula 1 compound.
(2) 2-formamido group thiazole-4 Acetyl Chloride 98Min. 204g is dissolved in 2L chloroform, add the formula 1 compound 592g that step (1) obtains again, at room temperature stirring reaction 2.5 hours, TLC detection reaction is to completely, removal of solvent under reduced pressure obtains formula 1 compound.
(3) formula 2 compound that step (2) prepares is dissolved in 2L mibk, then adds excessive aqueous hydrochloric acid, be heated to 40 DEG C of reactions 2.5 hours, crystallize out after reacting completely, washing, vacuum-drying obtains cefotiam chloride 545g, and receipts rate is 91%.
According to above-mentioned condition, the cefotiam chloride of embodiment 2 is carried out assay, and wherein the content of cefotiam is 98.0%, and the content of impurity 1 is 1.2%, and the content of impurity 2 is 0.8%.
Embodiment 3:
(1) 7-ACMT385g being dissolved in 2L tetrahydrofuran (THF), add 308g TERT-BUTYL DIMETHYL CHLORO SILANE and 207g triethylamine, at room temperature stirring reaction, TLC detection reaction, to completely, is cooled to 5 DEG C, except desolventizing obtains formula 1 compound.
(2) 2-formamido group thiazole-4 Acetyl Chloride 98Min. 204g is dissolved in 2L acetone, add the formula 1 compound 596g that step (1) obtains again, at room temperature stirring reaction 2.5 hours, TLC detection reaction is to completely, removal of solvent under reduced pressure obtains formula 1 compound.
(3) formula 2 compound that step (2) prepares is dissolved in 2L acetone, then adds excessive aqueous hydrochloric acid, be heated to 45 DEG C of reactions 2 hours, crystallize out after reacting completely, washing, vacuum-drying obtains cefotiam chloride 538g, and receipts rate is 90%.
According to above-mentioned condition, the cefotiam chloride of embodiment 3 is carried out assay, and wherein the content of cefotiam is 97.6%, and the content of impurity 1 is 0.8%, and the content of impurity 2 is 1.6%.
Embodiment 4: the preparation of injection cefotiam chloride powder injection
By 100g cefotiam chloride and 30g anhydrous sodium carbonate Homogeneous phase mixing, carry out packing according to every bottle of 1g effective constituent, prepare cefotiam chloride powder injection.
Can be found out by embodiment 1-3, cefotiam receipts rate and purity that the method for the present invention prepares are all very high, by analysis wherein only containing impurity 1 and 2, compare with the additive method of prior art, kind and the content of impurity reduce all greatly, in the stability of product, the minimizing anaphylaxis of preparation and all have great progress in clinical application.
Claims (10)
1. one kind is reduced the cefotiam chloride of anaphylaxis.
2. one kind is reduced the preparation method of the cefotiam chloride of anaphylaxis as claimed in claim 1, it is characterised in that:
(1) 7-ACMT is dissolved in organic solvent, adds TERT-BUTYL DIMETHYL CHLORO SILANE and organic bases reacts, prepare formula 1 compound;
(2) 2-formamido group thiazole-4 Acetyl Chloride 98Min. is dissolved in organic solution, adds formula 1 compound that step (1) prepares and react, prepare formula 2 compound;
(3) organic solution of formula 2 compound and HCl being reacted, crystallize out after reacting completely, filter, washing, drying obtains cefotiam chloride;
Reaction formula is as follows:
3. method according to claim 2, it is characterised in that: the mol ratio of the 7-ACMT of step (1), TERT-BUTYL DIMETHYL CHLORO SILANE and organic bases is 1:2-2.1:2-2.1.
4. method according to claim 2, it is characterised in that: the organic solvent of step (1) is one or more of chloroform, methylene dichloride, ethyl acetate, tetrahydrofuran (THF), acetone or mibk.
5. method according to claim 2, it is characterised in that: the organic solvent of step (2) is one or more of chloroform, methylene dichloride, ethyl acetate, tetrahydrofuran (THF), acetone or mibk.
6. method according to claim 2, it is characterised in that: the organic solvent of step (3) is one or more of chloroform, methylene dichloride, ethyl acetate, tetrahydrofuran (THF), acetone or mibk.
7. method according to claim 2, it is characterised in that: the organic bases of step (1) is pyridine or triethylamine.
8. method according to claim 2, it is characterised in that: the HCl of step (3) is aqueous hydrochloric acid.
9. method according to claim 2, it is characterised in that: the temperature of reaction of step (3) is 35-45 DEG C, and the reaction times is 2-3 hour.
10. contain a pharmaceutical preparation for the cefotiam chloride reducing anaphylaxis, reduced the cefotiam chloride of anaphylaxis by the preparation of the method for claim 2-9 arbitrary, then mix useful in preparing drug formulations with pharmaceutically acceptable carrier.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201610149052.4A CN105646539B (en) | 2016-03-16 | 2016-03-16 | Cefotiam hydrochloride for reducing anaphylaxis and preparation thereof |
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| CN201610149052.4A CN105646539B (en) | 2016-03-16 | 2016-03-16 | Cefotiam hydrochloride for reducing anaphylaxis and preparation thereof |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107519172A (en) * | 2017-09-11 | 2017-12-29 | 浙江永宁药业股份有限公司 | A kind of cefotiam chloride organic base combination thing and preparation method thereof |
| CN107722041A (en) * | 2017-11-12 | 2018-02-23 | 王龙 | The preparation method of cefmetazole acid |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101108856A (en) * | 2007-07-27 | 2008-01-23 | 苏州中联化学制药有限公司 | Method of synthesizing antibiotics cefamandole nafate |
| CN101633666A (en) * | 2009-08-26 | 2010-01-27 | 海南永田药物研究院有限公司 | Cefotiam hydrochloride compound in new path |
| CN101648961A (en) * | 2009-08-25 | 2010-02-17 | 哈药集团制药总厂 | Method and equipment for preparing cefotiam hydrochloride |
-
2016
- 2016-03-16 CN CN201610149052.4A patent/CN105646539B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101108856A (en) * | 2007-07-27 | 2008-01-23 | 苏州中联化学制药有限公司 | Method of synthesizing antibiotics cefamandole nafate |
| CN101648961A (en) * | 2009-08-25 | 2010-02-17 | 哈药集团制药总厂 | Method and equipment for preparing cefotiam hydrochloride |
| CN101633666A (en) * | 2009-08-26 | 2010-01-27 | 海南永田药物研究院有限公司 | Cefotiam hydrochloride compound in new path |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107519172A (en) * | 2017-09-11 | 2017-12-29 | 浙江永宁药业股份有限公司 | A kind of cefotiam chloride organic base combination thing and preparation method thereof |
| CN107722041A (en) * | 2017-11-12 | 2018-02-23 | 王龙 | The preparation method of cefmetazole acid |
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| CN105646539B (en) | 2017-02-15 |
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