CN105646539B - Cefotiam hydrochloride for reducing anaphylaxis and preparation thereof - Google Patents
Cefotiam hydrochloride for reducing anaphylaxis and preparation thereof Download PDFInfo
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- CN105646539B CN105646539B CN201610149052.4A CN201610149052A CN105646539B CN 105646539 B CN105646539 B CN 105646539B CN 201610149052 A CN201610149052 A CN 201610149052A CN 105646539 B CN105646539 B CN 105646539B
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- HSHGZXNAXBPPDL-UHFFFAOYSA-N CC(OCC(CSC1C2N)=C(C(O)=O)N1C2=O)=O Chemical compound CC(OCC(CSC1C2N)=C(C(O)=O)N1C2=O)=O HSHGZXNAXBPPDL-UHFFFAOYSA-N 0.000 description 1
- WFQGISKXSQATIF-UHFFFAOYSA-N CN(C)CCC[n]1nnnc1S Chemical compound CN(C)CCC[n]1nnnc1S WFQGISKXSQATIF-UHFFFAOYSA-N 0.000 description 1
- ASOCNIXLXRQKRJ-UHFFFAOYSA-O CN(C)CC[NH2+]C(SCC(CSC1C2N)=C(C(O)=O)N1C2=O)=NN(C)N Chemical compound CN(C)CC[NH2+]C(SCC(CSC1C2N)=C(C(O)=O)N1C2=O)=NN(C)N ASOCNIXLXRQKRJ-UHFFFAOYSA-O 0.000 description 1
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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
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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
- C07D501/02—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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- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (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 antibiotic is and in particular to a kind of reduce anaphylactoid cefotiam chloride.
Background technology
Cefotiam is second generation bactericidal properties cephalosporins broad-spectrum antibiotic, effect and the cephalo azoles to gram positive bacteria
Forest form is close, and to gram-negative bacteria, such as haemophilus, EHEC, klebsiella spp, proteus mirabilis etc. act on relatively
By force, also there is antibacterial action to enterobacteria, citrobacter, indole-positive proteus etc..Its mechanism of action is and bacterial cell
PBP (PBPs) on film combines, and so that transpeptidase is acylated, and every the synthesis with cell membrane in suppression bacterium, impact is thin
The cross-connection of cell wall mucopeptide composition, makes cell division and growth be suppressed, ne ar is elongated, finally dissolves and dead.
Cefotiam chloride, chemical entitled (6R- is trans) -7- [[(2- amino -4- thiazolyl) acetyl group] amino] -3-
[[[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 clinically applying wide cynnematin, its structural formula is：
The synthetic route of cefotiam chloride all with 7-aminocephalosporanic acid (7-ACA) as raw material, its 3 and 1-
The thiol reactant of (2- decil) -1,2,3,4 four ammonia azoles -5- mercaptan typically in sodium acid carbonate or dichloro phosphoric acid, three
Chloroacetic 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 acetyl group typically has two methods：
JP52083871 discloses 7-ACA and 4- chloro- 3- oxo butyl chloride and carries out amidation process, after react with thiocarbamide again
Closed loop, this two step total total recovery of reaction is 50-60%, and product also needs that reaction method finally synthesizes cephalo and replaces again with DMMT
Peace.
It is prepared into ATC with the ATA of amido protecting, more acylated 7-ACMT is obtained the Cefotiam with protection group, finally uses acid
Or enzyme sloughs protection group and obtains Cefotiam.US441874 discloses and is acylated 7-ACMT with the ATC-2 that ATA-2 is obtained, and gained produces
The method that thing PA ase Deprotection obtains Cefotiam, synthesizes total receipts of Cefotiam two step reaction with ATC-2
Rate is 48-52%.US6787649 discloses and prepares ATC-1 with ATA-1, is then acylated 7-ACMT, and products therefrom hydrochloric acid hydrolyzes
The method that Deprotection is obtained cefotiam chloride, the total recovery of two step reactions is 74%.
It is stronger that the 4- chloro- 3- oxo butyl chloride that first method uses has a reactivity, is difficult to transport, therefore the method
It is not suitable for industrial production.Second method needs protection group and the operating procedure of Deprotection, leads to high cost, yield
Low.Accordingly, it is desirable to provide new synthesis technique makes improvements.
December calendar year 2001 " the anaphylactoid research of beta-lactam antibiotic " obtains national science progress prize card, wins a prize single
Position：Chinese pharmaceutical biological product research institute (now renames：Chinese food drug inspection research institute).My company in 2015 with China
Food and medicine Inspection Research institute chemistry room is reached in cooperation agreement application " the anaphylactoid research of beta-lactam antibiotic "
Technological improvement generates technique, reduces cephalosporin analog antibiotic impurity, reaches improve product quality reduction cephalosporin analog antibiotic allergy anti-
The purpose answered, is improved to the synthesis technique of cefotiam chloride, it is achieved thereby that the present invention.
Content of the invention
It is an object of the invention to provide a kind of reduce anaphylactoid cefotiam chloride.
It is a further object to provide a kind of preparation method reducing anaphylactoid cefotiam chloride, its
It is characterised by, 7-ACMT is dissolved in organic solvent by (1), add tert-butyl chloro-silicane and organic base to be reacted, preparation
Obtain formula 1 compound；(2) 2- formamido group thiazole -4 chloroacetic chloride is dissolved in organic solution, adds step (1) to prepare
Formula 1 compound is reacted, and prepares formula 2 compound；(3) organic solution of formula 2 compound is reacted with HCl, reacted
Entirely separate out crystal afterwards, filter, washing, it is dried to obtain cefotiam chloride；
Reaction equation is as follows：
The mol ratio of the 7-ACMT, tert-butyl chloro-silicane and organic base of step (1) is 1：2-2.1：2-2.1.
The organic solvent of step (1) is chloroform, dichloromethane, ethyl acetate, oxolane, acetone or methylisobutylketone
One or more.
The organic solvent of step (2) is chloroform, dichloromethane, ethyl acetate, oxolane, acetone or methylisobutylketone
One or more.
The organic solvent of step (3) is chloroform, dichloromethane, ethyl acetate, oxolane, acetone or methylisobutylketone
One or more.
The organic base of step (1) is pyridine or triethylamine.
The HCl of step (3) is aqueous hydrochloric acid solution.
The reaction temperature of step (3) is 35-45 DEG C, and the reaction time is 2-3 hour.
It is a further object to provide a kind of containing the medicine system being reduced anaphylactoid cefotiam chloride
Agent, is prepared by said method and reduces anaphylactoid cefotiam chloride, then mixes with pharmaceutically acceptable carrier
Prepare pharmaceutical preparation.
The consumption of the reaction raw materials of the present invention has no particular limits, and is typically based on chemical reaction metering and carries out.
In the inventive solutions, using tert-butyl chloro-silicane, the amino of 7-ACMT and carboxyl are entered simultaneously
Row protection, is then reacted with acyl chlorides again, is hydrolyzed with to become salt anti-using aqueous hydrochloric acid solution afterwards in step (3) simultaneously
Should, reaction at 35-45 DEG C can optionally hydrolyze formamido.The reaction process of the present invention is simple, and product yield is high, miscellaneous
Matter content is low, and reaction further just need not can obtain highly purified cefotiam chloride by purification step after terminating, very suitable
Together in industrialized production.
Specific embodiment
With reference to embodiment, the present invention is described in further detail, but embodiments of the present invention not limited to this.
In following embodiments, method therefor is conventional method if no special instructions.
Embodiment 1：
(1) 7-ACMT 385g is dissolved in 2L acetone, adds 300g tert-butyl chloro-silicane and 202g triethylamine,
Stirring reaction under room temperature, TLC detection reaction, to complete, is cooled to 0 DEG C, removes solvent and obtains formula 1 compound.
(2) 2- formamido group thiazole -4 chloroacetic chloride 204g is dissolved in 2L dichloromethane, adds the formula that step (1) obtains
1 compound 598g, is stirred at room temperature reaction 3 hours, and to complete, removal of solvent under reduced pressure obtains formula 1 chemical combination for TLC detection reaction
Thing.
(3) formula 2 compound that step (2) prepares is dissolved in 2L acetone, is subsequently adding excessive aqueous hydrochloric acid solution, plus
Heat is reacted 3 hours to 35 DEG C, and reaction separates out crystal, washing completely afterwards, and vacuum drying obtains cefotiam chloride 550kg, receives
Rate is 92%.
Assay：Measure according to molecular exclusion chromatography (Chinese Pharmacopoeia two annex VH of version in 2010).
Chromatographic condition and system suitability：With sephadex G -10, (40-120 μm) is filler, in glass column
Footpath 1.0-1.6cm, pillar height degree 30-45cm.With the 0.04mol/L disodium phosphate soln of pH10.0 as mobile phase A, with water for stream
Dynamic phase B, flow velocity is 0.5ml per minute, and Detection wavelength is 254nm.Measure 0.1mg/ml blue dextran 2000 solution 50 μ l, note
Enter liquid chromatograph, respectively with mobile phase A, B is measured, record chromatogram, press the theoretical plate of blue dextran 2000 peak calculating
Number is all not less than 400, and tailing factor all should be less than 2.0.In two kinds of flow phase system during the reservation at blue dextran 2000 peak
Between ratio should be between 0.93-1.07, contrast solution main peak and polymer peak in need testing solution are blue with corresponding chromatographic system
The ratio of the retention time at color Dextran 200 0 peak all should be between 0.93-1.07.Accurately weighed this product about 0.25g puts 10ml amount
In bottle, add blue dextran 2000 solution of 0.1mg/ml to dissolve and be diluted to scale, shake up.Measure 50 μ l injection liquid phase colors
Spectrometer, is measured with mobile phase A, records chromatogram.Paddy height ratio between the peak height of high polymer and monomer and high polymer should be big
In 2.0.Separately with Mobile phase B as mobile phase, precision measures contrast solution 50 μ l, continuous sample introduction 5 times, and the relative standard of peak area is inclined
Difference should be not more than 5.0%.
According to above-mentioned condition, assay, the wherein content of Cefotiam are carried out to the cefotiam chloride of embodiment 1
For 97.8%, 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-ACMT 385g is dissolved in 2L ethyl acetate, adds 315g tert-butyl chloro-silicane and 212g tri- second
Amine, is stirred at room temperature reaction, and TLC detection reaction to complete, is cooled to -5 DEG C, removes solvent and obtain formula 1 compound.
(2) 2- formamido group thiazole -4 chloroacetic chloride 204g is dissolved in 2L chloroform, adds the formula 1 that step (1) obtains and change
Compound 592g, is stirred at room temperature reaction 2.5 hours, and to complete, removal of solvent under reduced pressure obtains formula 1 compound for TLC detection reaction.
(3) formula 2 compound that step (2) prepares is dissolved in 2L methylisobutylketone, is subsequently adding excessive hydrochloric acid water
Solution, is heated to 40 DEG C and reacts 2.5 hours, and reaction separates out crystal, washing completely afterwards, and vacuum drying obtains cefotiam chloride
545g, yield is 91%.
According to above-mentioned condition, assay, the wherein content of Cefotiam are carried out to the cefotiam chloride of embodiment 2
For 98.0%, the content of impurity 1 is 1.2%, and the content of impurity 2 is 0.8%.
Embodiment 3：
(1) 7-ACMT 385g is dissolved in 2L oxolane, adds 308g tert-butyl chloro-silicane and 207g tri- second
Amine, is stirred at room temperature reaction, and TLC detection reaction to complete, is cooled to 5 DEG C, removes solvent and obtain formula 1 compound.
(2) 2- formamido group thiazole -4 chloroacetic chloride 204g is dissolved in 2L acetone, adds the formula 1 that step (1) obtains and change
Compound 596g, is stirred at room temperature reaction 2.5 hours, and to complete, removal of solvent under reduced pressure obtains formula 1 compound for TLC detection reaction.
(3) formula 2 compound that step (2) prepares is dissolved in 2L acetone, is subsequently adding excessive aqueous hydrochloric acid solution, plus
Heat is reacted 2 hours to 45 DEG C, and reaction separates out crystal, washing completely afterwards, and vacuum drying obtains cefotiam chloride 538g, yield
For 90%.
According to above-mentioned condition, assay, the wherein content of Cefotiam are carried out to the cefotiam chloride of embodiment 3
For 97.6%, 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
100g cefotiam chloride and 30g natrium carbonicum calcinatum are uniformly mixed, carries out point according to every bottle of 1g active ingredient
Dress, prepares cefotiam chloride powder-injection.
The Cefotiam yield that the method for the present invention prepares be can be seen that by embodiment 1-3 and purity is all very high,
Wherein only contain impurity 1 and 2 by analysis, compare with the additive method of prior art, the species and content of impurity are all significantly
Reduce, in terms of the stability of product, the minimizing allergic reaction of preparation and in terms of clinical practice, all there is great progress.
Claims (8)
1. a kind of preparation method of cefotiam chloride it is characterised in that：
(1) 7-ACMT is dissolved in organic solvent, adds tert-butyl chloro-silicane and organic base to be reacted, prepare formula
1 compound；
(2) 2- formamido group thiazole -4- chloroacetic chloride is dissolved in organic solution, adds formula 1 compound that step (1) prepares
Reacted, prepared formula 2 compound；
(3) organic solution of formula 2 compound is reacted with HCl, reaction separates out crystal completely afterwards, filter, washing, it is dried to obtain head
Spore replaces peace hydrochloride；
Reaction equation is as follows：
2. method according to claim 1 it is characterised in that：The 7-ACMT of step (1), tert-butyl chloro-silicane and
The mol ratio of organic base is 1：2-2.1：2-2.1.
3. method according to claim 1 it is characterised in that：The organic solvent of step (1) is chloroform, dichloromethane, second
One or more of acetoacetic ester, oxolane, acetone or methylisobutylketone.
4. method according to claim 1 it is characterised in that：The organic solvent of step (2) is chloroform, dichloromethane, second
One or more of acetoacetic ester, oxolane, acetone or methylisobutylketone.
5. method according to claim 1 it is characterised in that：The organic solvent of step (3) is chloroform, dichloromethane, second
One or more of acetoacetic ester, oxolane, acetone or methylisobutylketone.
6. method according to claim 1 it is characterised in that：The organic base of step (1) is pyridine or triethylamine.
7. method according to claim 1 it is characterised in that：The HCl of step (3) is aqueous hydrochloric acid solution.
8. method according to claim 1 it is characterised in that：The reaction temperature of step (3) is 35-45 DEG C, the reaction time
It is 2-3 hour.
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| CN101648961B (en) * | 2009-08-25 | 2011-06-29 | 哈药集团制药总厂 | Method and equipment for preparing cefotiam hydrochloride |
| CN101633666B (en) * | 2009-08-26 | 2010-08-18 | 海南永田药物研究院有限公司 | Cefotiam hydrochloride compound in new path |
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