CN102321029A - Ornidazole compound and novel preparation method thereof - Google Patents
Ornidazole compound and novel preparation method thereof Download PDFInfo
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- CN102321029A CN102321029A CN201110198551A CN201110198551A CN102321029A CN 102321029 A CN102321029 A CN 102321029A CN 201110198551 A CN201110198551 A CN 201110198551A CN 201110198551 A CN201110198551 A CN 201110198551A CN 102321029 A CN102321029 A CN 102321029A
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- 229960002313 ornidazole Drugs 0.000 title claims abstract description 102
- 238000002360 preparation method Methods 0.000 title claims abstract description 25
- -1 Ornidazole compound Chemical class 0.000 title claims abstract description 10
- IPWKIXLWTCNBKN-UHFFFAOYSA-N Madelen Chemical compound CC1=NC=C([N+]([O-])=O)N1CC(O)CCl IPWKIXLWTCNBKN-UHFFFAOYSA-N 0.000 claims abstract description 92
- 238000000034 method Methods 0.000 claims abstract description 43
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 29
- 239000003814 drug Substances 0.000 claims abstract description 21
- 238000002425 crystallisation Methods 0.000 claims abstract description 16
- 230000008025 crystallization Effects 0.000 claims abstract description 16
- 239000003960 organic solvent Substances 0.000 claims abstract description 11
- 239000013078 crystal Substances 0.000 claims abstract description 6
- 238000000746 purification Methods 0.000 claims description 41
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 33
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 27
- 230000007935 neutral effect Effects 0.000 claims description 19
- 238000000926 separation method Methods 0.000 claims description 18
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 claims description 17
- 239000007788 liquid Substances 0.000 claims description 14
- 239000002245 particle Substances 0.000 claims description 14
- 239000012043 crude product Substances 0.000 claims description 13
- 238000004587 chromatography analysis Methods 0.000 claims description 11
- 238000005261 decarburization Methods 0.000 claims description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- 238000002156 mixing Methods 0.000 claims description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- 238000005406 washing Methods 0.000 claims description 6
- 238000010521 absorption reaction Methods 0.000 claims description 4
- 239000003610 charcoal Substances 0.000 claims description 4
- 239000011148 porous material Substances 0.000 claims description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 4
- 239000007787 solid Substances 0.000 claims description 4
- 230000001572 anti-trichomonad Effects 0.000 claims description 3
- 238000001035 drying Methods 0.000 claims description 3
- ALRHLSYJTWAHJZ-UHFFFAOYSA-N 3-hydroxypropionic acid Chemical compound OCCC(O)=O ALRHLSYJTWAHJZ-UHFFFAOYSA-N 0.000 claims description 2
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 claims description 2
- 230000000694 effects Effects 0.000 abstract description 9
- 239000000047 product Substances 0.000 abstract description 6
- 238000004519 manufacturing process Methods 0.000 abstract description 5
- 231100000331 toxic Toxicity 0.000 abstract description 5
- 230000002588 toxic effect Effects 0.000 abstract description 5
- 229940079593 drug Drugs 0.000 abstract description 3
- 238000001914 filtration Methods 0.000 abstract description 2
- 238000001179 sorption measurement Methods 0.000 abstract description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 abstract 1
- 241001502500 Trichomonadida Species 0.000 abstract 1
- 229910052799 carbon Inorganic materials 0.000 abstract 1
- 239000003480 eluent Substances 0.000 abstract 1
- 239000000706 filtrate Substances 0.000 abstract 1
- 241001148471 unidentified anaerobic bacterium Species 0.000 abstract 1
- 238000003756 stirring Methods 0.000 description 17
- 239000000243 solution Substances 0.000 description 13
- 239000000843 powder Substances 0.000 description 12
- 239000002904 solvent Substances 0.000 description 12
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 10
- 239000001110 calcium chloride Substances 0.000 description 10
- 229910001628 calcium chloride Inorganic materials 0.000 description 10
- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 description 10
- 150000001875 compounds Chemical class 0.000 description 9
- 239000012535 impurity Substances 0.000 description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 7
- 239000011347 resin Substances 0.000 description 7
- 229920005989 resin Polymers 0.000 description 7
- 239000000741 silica gel Substances 0.000 description 7
- 229910002027 silica gel Inorganic materials 0.000 description 7
- FFYTTYVSDVWNMY-UHFFFAOYSA-N 2-Methyl-5-nitroimidazole Chemical class CC1=NC=C([N+]([O-])=O)N1 FFYTTYVSDVWNMY-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 230000000052 comparative effect Effects 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- LRWZZZWJMFNZIK-UHFFFAOYSA-N 2-chloro-3-methyloxirane Chemical compound CC1OC1Cl LRWZZZWJMFNZIK-UHFFFAOYSA-N 0.000 description 2
- 241000193830 Bacillus <bacterium> Species 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 2
- 241000606125 Bacteroides Species 0.000 description 2
- 241000606123 Bacteroides thetaiotaomicron Species 0.000 description 2
- 241000606215 Bacteroides vulgatus Species 0.000 description 2
- 241000193403 Clostridium Species 0.000 description 2
- 102000002322 Egg Proteins Human genes 0.000 description 2
- 108010000912 Egg Proteins Proteins 0.000 description 2
- 241000186394 Eubacterium Species 0.000 description 2
- 241000605909 Fusobacterium Species 0.000 description 2
- 241000590002 Helicobacter pylori Species 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 241000191992 Peptostreptococcus Species 0.000 description 2
- 241001135219 Prevotella disiens Species 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 2
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical compound ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 2
- 239000000470 constituent Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 229940037467 helicobacter pylori Drugs 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 239000013067 intermediate product Substances 0.000 description 2
- 238000009940 knitting Methods 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 210000004681 ovum Anatomy 0.000 description 2
- 239000012264 purified product Substances 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- BRLQWZUYTZBJKN-UHFFFAOYSA-N Epichlorohydrin Chemical compound ClCC1CO1 BRLQWZUYTZBJKN-UHFFFAOYSA-N 0.000 description 1
- 239000004593 Epoxy Substances 0.000 description 1
- 230000005526 G1 to G0 transition Effects 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- HJLSLZFTEKNLFI-UHFFFAOYSA-N Tinidazole Chemical compound CCS(=O)(=O)CCN1C(C)=NC=C1[N+]([O-])=O HJLSLZFTEKNLFI-UHFFFAOYSA-N 0.000 description 1
- 238000007171 acid catalysis Methods 0.000 description 1
- 239000003463 adsorbent Substances 0.000 description 1
- 230000000274 adsorptive effect Effects 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000001175 calcium sulphate Substances 0.000 description 1
- 235000011132 calcium sulphate Nutrition 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000004040 coloring Methods 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000003113 dilution method Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000002158 endotoxin Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 229910001385 heavy metal Inorganic materials 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 239000002932 luster Substances 0.000 description 1
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 1
- 229940050176 methyl chloride Drugs 0.000 description 1
- 229960000282 metronidazole Drugs 0.000 description 1
- VAOCPAMSLUNLGC-UHFFFAOYSA-N metronidazole Chemical compound CC1=NC=C([N+]([O-])=O)N1CCO VAOCPAMSLUNLGC-UHFFFAOYSA-N 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 229960005053 tinidazole Drugs 0.000 description 1
Landscapes
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to an ornidazole compound which is prepared in a method comprising the following steps: (1) a certain amount of ornidazole crude is dissolved in an organic solvent, active carbon is added for adsorption and filtration, filtrate is collected, pressure is reduced for concentration, and then primarily purified ornidazole is obtained; (2) the primarily purified ornidazole is separated and purified by a preparation type chromatographic column, eluent is collected, pressure is reduced for concentration, and then secondarily purified ornidazole is obtained; and (3) pure water is added into a concentrated solution, crystallization is carried out, and precipitated crystals are centrifugally washed and dried to obtain thirdly purified ornidazole. The ornidazole prepared in the method has high purity, the toxic and side effects of anaerobic bacteria and trichomonad resisting drugs are reduced, the product quality of preparations is improved, and the method is suitable for industrial mass production.
Description
Technical field
The present invention relates to a kind of ornidazole compound, can obtain highly purified ornidazole, belong to medical technical field through its method for making.
Background technology
Ornidazole (Ornidazole), white or little yellow crystalline powder, chemical name: 1-(3-chloro-2-hydroxypropyl)-2-methyl-5-nitro imidazoles, molecular formula: C
7H
10ClN
3O
3, molecular weight: 219.63, structural formula is:
Ornidazole is behind metronidazole and tinidazole; The anerobes and the anti-trichomonal medicine that went on the market in Germany first by Switzerland Roche Holding Ag in 1977; Mechanism of its performance anti-microbial effect possibly be: in oxygen-free environment, be reduced into amino or formation through radical and cellular constituent interaction through the nitro in its molecule, thereby cause the death of mikrobe; Ornidazole is used for treatment and bites the caused multiple infection of responsive anerobes such as knitting dimension bacterium, gum genera bacillus by bacteroide fragilis, bacteroides disiens, ovum garden bacterioide, bacteroides thetaiotaomicron, bacteroides vulgatus, clostridium, Eubacterium, dyspepsiacoccus and peptostreptococcus, helicobacter pylori, bacaeroides melaninogenicus, fusobacterium, CO2 clinically.
US3435049A at first discloses the ornidazole by the toluene recrystallization; Mainly contain 3 synthetic routes at present: route 1 with 2-methyl-5-nitro imidazoles and two (3-chloro-2-hydroxypropyl) sulfuric ester reactions, obtains 1-(2; The 3-epoxypropyl)-2-methyl-5-nitro imidazoles; After open loop under the concentrated hydrochloric acid effect, obtain the ornidazole bullion then, use the toluene recrystallization, but raw material is not easy to obtain; Route 2, with 2-methyl-5-nitro imidazoles and epoxy methyl chloride at AlCl
3Effect reaction down obtains, re-crystallizing in ethyl acetate, but reaction must be strict anhydrous; Route 3 reacts in formic acid with 2-methyl-5-nitro imidazoles and epoxy chloropropane and to obtain.
The compound method of the ornidazole of " Chinese Journal of Pharmaceuticals " 2004,35 (II) report, yield has only 51%.The preparation method of a kind of ornidazole optical enantiomorph of introducing among the Chinese patent CN1651415A accomplishes through the experiment of six steps, and comparatively complicated, agents useful for same is more, and cost is high, and yield is lower.Chinese patent CN1800166A provides the preparation and the purification process of ornidazole optical enantiomorph; With 2-methyl-5-nitro imidazoles with have optically active epichlorohydrin reaction; Get intermediate product hydrolysis again, acidifying, neutralization; Promptly get optically active ornidazole, repurity gets pure article S-(-)-ornidazole or R-(+)-ornidazole.
Chinese patent CN1923817A discloses the compound method of ornidazole, uses the lewis acid catalysis, and its productive rate is generally less than 60%.CN101633643A provides a kind of ornidazole compound of variation route, through 2-methyl-5-nitro imidazoles and epoxy chloropropane are reacted in solvent, adds mixture of ice and water, regulates the pH value, and recrystallization obtains ornidazole.
Can find out that the method or the step of prior art are various, are not suitable for industrial production; Perhaps yield is lower, has expended a large amount of raw materials, causes the high enterprise of cost, or has used toxic solvents, causes the toxic residue of medicine, has influenced the formulation products quality.
In addition, deposit improper or shelf-time when long at compound, can cause active constituents of medicine content to reduce, color and luster is strengthened, and the related substance for example content of 2-methyl-5-nitro imidazoles raises.In some cases, because controlling of production process is improper, cause pharmaceutical purity also undesirable.Therefore prior art does not disclose special purification process to this, be necessary underproof product or slightly further carry out purifying, with high yield highly purified compound is provided.This area presses for the compound method that works out a kind of low cost, yield height, is applicable to the ornidazole of big production, to overcome above-mentioned shortcoming.
The technical issues that need to address of the present invention are the deficiencies that overcome prior art, and a kind of purification process of ornidazole compound is provided, and this method is simple, and product purity is high, and yield is high, is easy to suitability for industrialized production.
Summary of the invention
In order to overcome the defective of above-mentioned prior art, improve ornidazole purity, reduce the residual of toxic solvents; The invention provides a kind of purification process of ornidazole compound; Preparing method of the present invention can improve the formulation products quality, reduces toxic side effect, is suitable for industrialized production.
Aspect separation and purification; Know in the specificity owing to compound aspect the high yield compound of acquisition high purity with those skilled in the art know that and face all difficulties; All these just can be expected by the theory of existing general separation and purification absolutely not solution need overcome many difficult problems.
Generally speaking, conventional separation method has, and for example comprises the cooling of reaction mixture, then through filtering the crystalline method of collecting; Comprise adding thermal crystalline, and with for example methyl alcohol or the washing of its analogue of alcohol, distillation is except that desolvating and cooling off the crystalline method that obtains then; Solvent extration; Dilution method; Recrystallization method; Column chromatography; Methods such as preparation thin-layer chromatography.
The applicant is on the basis of a large amount of existing documents; Experiment through a large amount of screenings; Find above-mentioned document and general method for purifying and separating for example method such as crystallization be difficult to obtain the compound of high purity high yield, and various separation purification method and multiple conditional parameter possibly exist varied associativity and unpredictability.The inventor is through long-term conscientious research, and after Combination application specific method and parameters optimization, accident has been found a kind of purification process of ornidazole compound, has obtained the highly purified product of high yield astoundingly.
The ornidazole that process for purification provided by the invention was directed against is prepared ornidazole bullion of present known compound method or commercially available ornidazole bulk drug, below is referred to as the ornidazole bullion that the present invention adopts.
The inventor through comprising the preparation method of following treatment step, can increase substantially the purity of raw material ornidazole through discovering:
(1) with a certain amount of ornidazole dissolving crude product in organic solvent, add charcoal absorption, filter, collect filtrating, concentrating under reduced pressure obtains the ornidazole of elementary purification;
(2) above-mentioned liquid concentrator is carried out separation and purification with the preparative scale chromatography post, collect elutriant, concentrating under reduced pressure obtains the ornidazole that secondary is purified;
(3) in liquid concentrator, add pure water, stir, carry out crystallization, with the crystal centrifuge washing of separating out, drying, the ornidazole of three grades of purifications of acquisition.
The following specifically describes the present invention.
Step 1
In organic solvent, charcoal absorption is filtered with a certain amount of ornidazole dissolving crude product, collects filtrating, and concentrating under reduced pressure obtains the ornidazole of elementary purification.
The organic solvent that with water dissolve each other of described organic solvent for dissolving ornidazole.
Said organic solvent is selected from the lower alcohol or the non-alcohols polar solvent that can make the ornidazole homogenizing, is selected from one or more the mixture in methyl alcohol, ethanol, propyl alcohol, acetone, acetonitrile, tetramethylene sulfone, hydroxy-propionic acid, the terepthaloyl moietie, is preferably ethanol.
In one aspect of the invention, the separation and the purification process of medicine comprise adsorption method, as using gac.Unfortunately, except removing color and other unwanted material, gac also irreversibly adsorbs medicine, and this causes productive rate obviously to reduce.The present invention confirms that gac can be used for the preparation method of ornidazole, and the amount of wherein said adding gac is the 0.1-0.5% (g/ml) of overall solution volume.
Above-mentioned described preparation method, the temperature of wherein said whip attachment are 40-50 ℃, and the time of whip attachment is 10-15 minute.
The possible reason of effect that step 1 of the present invention adopts charcoal absorption why can reach purification is: the larger molecular organicses such as coloring matter of gac molecule in can adsorbent solution.
Step 2
Carry out separation and purification with the preparative scale chromatography post, collect elutriant, concentrating under reduced pressure obtains the ornidazole that secondary is purified.
Generally speaking, contain the solvent of introducing in the preparation process, various raw material, intermediate product in the ornidazole, owing to drawing the moist moisture of bringing into; Bacterial endotoxin; And various inorganicss and heavy metal etc., these materials exist with the form of impurity, have influenced the purity of ornidazole.The present invention uses the separation and purification function of preparative scale chromatography post, and the part of the ornidazole in the solution is partly separated with impurity, reaches the purpose of purification ornidazole.
The applicant is through long-term conscientious big quantity research; In the separation and purification process; Screened various filler chromatographic columns such as silica gel, aluminum oxide or macroporous resin, for example the particle diameter of silica gel is 45-250 μ m, the silica gel of aperture for
; Aluminum oxide or neutral alumina particle diameter are aluminum oxide or the neutral alumina of 18-200 μ m; The macroporous resin model is macroporous resins such as AmberliteXAD-6, AmberliteXAD-7, AmberliteXAD-8, Diaion HP2MG, GDX-501, HPD400, HPD450, HPD750, AmberliteXAD-9, AmberliteXAD-10, GDX-401, GDX-601, AB-8; The unexpected application macroporous resin of finding of the inventor does not have clear improvement to product gas purity; Silica gel is also undesirable; And special-purpose neutral alumina not only can fully adsorb composition impurity and other pigment in the upper prop thing; Also these article purifying is had original windfall effect, and operation is simpler and easy.
In one aspect of the invention, said stationary phase is that particle diameter is 18-200 μ m, and the aperture is 50-200 μ m for pore neutral alumina or the particle diameter of about 6nm, and the aperture is 6nm, the column chromatography special neutral aluminum oxide of pH 7.0 or pH 7.5.
In one aspect of the invention, neutral alumina can be for example for the ICNallumina N preferable particle size of supplier ICN be 18-63 μ m, and the aperture is the pore neutral alumina of 6nm; PH 7.5; Preferable particle size is 18-32 μ m, and the aperture is the pore neutral alumina of 6nm, and pH 7.5.Perhaps, neutral alumina for example is a supplier Baker column chromatography special neutral aluminum oxide, and particle diameter is 50-200 μ m, and the aperture is 6nm, pH 7.0 or pH 7.5.
In one aspect of the invention, as preferably, the quality of each purifying medicine is 1 with the ratio of the quality of chromatographic column filler: 10-200, the preferred mass ratio is 1: 15-100.The consumption of moving phase is as long as satisfy the complete basically wash-out of medicine; Flow point Fractional Collections behind the wash-out; The content of the flow point Chinese traditional medicine of different sections is different, in order to obtain highly purified medicine (for example purity is greater than 99.5%), needs medicament contg is merged greater than 85% flow point; Preferably medicament contg is incorporated in one aspect of the present invention greater than 90% flow point, the required purity that obtains in the methods of the invention depends on the amount of impurity and the operating environment of chromatographic column to a certain extent.The selection of organic solvent and consumption must be controlled in moving phase, make can not come out the impurity wash-out prematurely.Generally speaking, the chromatographic column of the used chromatographic column of the present invention comprises that diameter is about 0.1 to about 20cm, is preferably 3cm at least.The chromatogram column length scope is preferably about 10 centimetres to about 100 centimetres in this method, and more preferably length range is about 20 centimetres to about 30 centimetres, and most preferred length is 25 centimetres.
Preparing method of the present invention, wherein the moving phase used of chromatographic column is 3: 7 the acetonitrile and the mixing solutions of water as volume ratio, and fixed phase stuffing is selected from neutral alumina, and flow velocity 0.1-2ml/min, column temperature are room temperature, wavelength 312nm.
Preparing method of the present invention, wherein the temperature of concentrating under reduced pressure is 50 ℃.
Step 3
In liquid concentrator, add pure water, stir, carry out crystallization, with the crystal centrifuge washing of separating out, drying makes ornidazole.
Preparing method of the present invention, wherein said ornidazole crystallization is dry with solid drier.Preparing method of the present invention, wherein said solid drier is selected from a kind of in anhydrous magnesium sulfate, Calcium Chloride Powder Anhydrous, anhydrous calciumsulphate and the activated alumina, preferred Calcium Chloride Powder Anhydrous.
In view of the powder flowbility of ornidazole, intrinsic dissolution rate, Pickering property and preparation operability huge to the influence of its active performance and the preparation prepared, and the ornidazole that purity is largely increased dissolution rate, the property prepared and stable aspect also corresponding obvious improvement.
Therefore, be fit to fully be mixed with according to the inventive method purified ornidazole and be used to treat the medicine of biting the caused multiple infection of responsive anerobes such as knitting dimension bacterium, gum genera bacillus by bacteroide fragilis, bacteroides disiens, ovum garden bacterioide, bacteroides thetaiotaomicron, bacteroides vulgatus, clostridium, Eubacterium, dyspepsiacoccus and peptostreptococcus, helicobacter pylori, bacaeroides melaninogenicus, fusobacterium, CO2.
The present invention has fundamentally changed the lower present situation of domestic and international ornidazole material purity, has solved the difficult problem that rough ornidazole and ornidazole bulk drug face, and has improved because a series of clinical adverse of the more initiation of impurity.
In addition, the inventive method purity is high, obtains purity and is not less than 99.6%.Its method for detecting purity is known in the art, but High performance liquid chromatography, for example referring to Liang Xiaoqing etc., " Chinese Journal of Pharmaceuticals " 2002,33 (02), the HPL C assay method of ornidazole injection liquid.Adopting Lichrospher-C1 8 chromatographic columns, is moving phase with methanol-water (30: 70), detects wavelength 312nm.
Each reference that the application quoted is incorporated herein by reference at this in full.
As preferably, the present invention provides a kind of process for purification of ornidazole, it is characterized in that this method comprises the steps:
(1) with a certain amount of ornidazole dissolving crude product in the organic solvent that dissolves each other with water of 4-10 times of weight, add the gac that accounts for overall solution volume 0.1-0.5% (g/ml), 40-50 ℃ whip attachment 10-15 minute; Filter decarburization; Collect filtrating, concentrating under reduced pressure obtains the ornidazole of elementary purification;
(2) mix the ornidazole of above-mentioned elementary purification thoroughly back with an amount of fixed phase stuffing and go up appearance, carry out separation and purification with preparation type neutral alumina chromatographic column, collect the ornidazole elutriant, 40～60 ℃ of concentrating under reduced pressure obtain the ornidazole that secondary is purified;
(3) in above-mentioned liquid concentrator, add pure water, carry out crystallization, the crystal centrifuge washing of separating out is dry through solid drier, the ornidazole of three grades of purifications of acquisition.
The ornidazole that relates in one aspect to the inventive method preparation of the present invention is used for the purposes of anaerobe resistant and anti-trichomonal medicine in preparation.
Embodiment
Below come further to explain or explanation content of the present invention through embodiment.But the embodiment that is provided should not be understood that protection domain of the present invention is constituted restriction.
Making with extra care of embodiment 1 ornidazole
The ornidazole dissolving crude product of 10g purity 96.52% in 40ml ethanol, is stirred, it is dissolved fully, add the gac of 0.2g then, 40 ℃ of whip attachment 15 minutes are filtered decarburization, collect filtrating; Add the 10g aluminum oxide again after concentrating and stir, fling to the chromatographic column upper end that is added to preparation behind the solvent, with the preparative scale chromatography post filtrating is carried out separation and purification then; Wherein the moving phase used of chromatographic column is 3: 7 the acetonitrile and the mixing solutions of water as volume ratio, and flow velocity 0.1ml/min, fixed phase stuffing are that particle diameter is that 18-32 μ m, aperture are the ICN allumina N neutral alumina of 6nm; Column temperature is a room temperature; Wavelength 312nm collects elutriant, 50 ℃ of concentrating under reduced pressure; In liquid concentrator, add pure water, stir, crystallization, 500rpm is centrifugal, and Calcium Chloride Powder Anhydrous is dry, gets ornidazole 9.23g, yield 95.63%, purity 99.63%, 77.5 ℃ of mp.
Making with extra care of comparative example's 1 ornidazole
The ornidazole dissolving crude product of 10g purity 96.52% in 40ml ethanol, is stirred, it is dissolved fully, add the gac of 0.2g then, 40 ℃ of whip attachment 15 minutes are filtered decarburization, collect filtrating; Add 10g silica gel again after concentrating and stir, fling to the chromatographic column upper end that is added to preparation behind the solvent, with the preparative scale chromatography post filtrating is carried out separation and purification then; Wherein the moving phase used of chromatographic column is 3: 7 the acetonitrile and the mixing solutions of water as volume ratio, and flow velocity 0.1ml/min, fixed phase stuffing are that particle diameter is that 18-32 μ m, aperture are that the AmberliteXAD-6 type macroporous resin model of 6nm does; Column temperature is a room temperature; Wavelength 312nm collects elutriant, 50 ℃ of concentrating under reduced pressure; In liquid concentrator, add pure water, stir, crystallization, 500rpm is centrifugal, and Calcium Chloride Powder Anhydrous is dry, gets ornidazole 8.93g, yield 92.52%, purity 98.63%, mp 77-78 ℃.
Making with extra care of embodiment 2 ornidazoles
The ornidazole dissolving crude product of 10g purity 96.52% in 100ml ethanol, is stirred, it is dissolved fully, add the gac of 0.1g then, 50 ℃ of whip attachment 10 minutes are filtered decarburization, collect filtrating; Add the 10g aluminum oxide again after concentrating and stir, fling to the chromatographic column upper end that is added to preparation behind the solvent, with the preparative scale chromatography post filtrating is carried out separation and purification then; Wherein the moving phase used of chromatographic column is 3: 7 the acetonitrile and the mixing solutions of water as volume ratio, and flow velocity 2ml/min, fixed phase stuffing are particle diameter 50-200 μ m; The Baker column chromatography special neutral aluminum oxide of aperture 6nm, column temperature is a room temperature, wavelength 312nm; Collect elutriant, 50 ℃ of concentrating under reduced pressure; In liquid concentrator, add pure water, stir, crystallization, 500rpm is centrifugal, and Calcium Chloride Powder Anhydrous is dry, gets ornidazole 9.27g, yield 96.04%, purity 99.7%, 78 ℃ of mp.
Making with extra care of comparative example's 2 ornidazoles
The ornidazole dissolving crude product of 10g purity 96.52% in 100ml ethanol, is stirred, it is dissolved fully, add the gac of 0.1g then, 50 ℃ of whip attachment 10 minutes are filtered decarburization, collect filtrating; Add 10g silica gel again after concentrating and stir, fling to the chromatographic column upper end that is added to preparation behind the solvent, with the preparative scale chromatography post filtrating is carried out separation and purification then; Wherein the moving phase used of chromatographic column is 3: 7 the acetonitrile and the mixing solutions of water as volume ratio, and flow velocity 2ml/min, fixed phase stuffing are particle diameter 50-200 μ m; The silica gel of aperture 6nm, column temperature are room temperature, wavelength 312nm; Collect elutriant, 50 ℃ of concentrating under reduced pressure; In liquid concentrator, add pure water, stir, crystallization, 500rpm is centrifugal, and Calcium Chloride Powder Anhydrous is dry, gets ornidazole 8.57g, yield 88.79%, purity 98.97%, mp 77-78 ℃.
Making with extra care of embodiment 3 ornidazoles
The ornidazole dissolving crude product of 15g purity 96.52% in 120ml ethanol, is stirred, it is dissolved fully, add the gac of 0.4g then, 45 ℃ of whip attachment 10 minutes are filtered decarburization, collect filtrating; Add the 15g aluminum oxide again after concentrating and stir, fling to the chromatographic column upper end that is added to preparation behind the solvent, with the preparative scale chromatography post filtrating is carried out separation and purification then; Wherein the moving phase used of chromatographic column is 3: 7 the acetonitrile and the mixing solutions of water as volume ratio, and flow velocity 1ml/min, fixed phase stuffing are that particle diameter is that 18-32 μ m, aperture are the ICN allumina N neutral alumina of 6nm; Column temperature is a room temperature; Wavelength 312nm collects elutriant, 50 ℃ of concentrating under reduced pressure; In liquid concentrator, add pure water, stir, crystallization, 500rpm is centrifugal, and Calcium Chloride Powder Anhydrous is dry, gets ornidazole 9.36g, yield 96.97%, purity 99.78%, mp77.5 ℃.
Making with extra care of comparative example's 3 ornidazoles
The ornidazole dissolving crude product of 15g purity 96.52% in 120ml ethanol, is stirred, it is dissolved fully, add the gac of 0.4g then, 45 ℃ of whip attachment 10 minutes are filtered decarburization, collect filtrating; Add 15g after concentrating again and stir, be added to the macroporous adsorptive resins upper end after flinging to solvent, water, 3: 7 acetonitrile and the mixing solutions wash-out of water successively, flow velocity 1ml/min, collection elutriant, 50 ℃ of concentrating under reduced pressure through pretreated AB-8 resin; In liquid concentrator, add pure water, stir, crystallization, 500rpm is centrifugal, and Calcium Chloride Powder Anhydrous is dry, gets ornidazole 8.36g, yield 86.61%, purity 99.15%, mp 77-78 ℃.
Making with extra care of embodiment 4 ornidazoles
The ornidazole dissolving crude product of 15g purity 96.52% in 120ml ethanol, is stirred, it is dissolved fully, add the gac of 0.3g then, 45 ℃ of whip attachment 15 minutes are filtered decarburization, collect filtrating; Add the 15g aluminum oxide again after concentrating and stir, fling to the chromatographic column upper end that is added to preparation behind the solvent, with the preparative scale chromatography post filtrating is carried out separation and purification then; Wherein the moving phase used of chromatographic column is 3: 7 the acetonitrile and the mixing solutions of water as volume ratio, and flow velocity 1.5ml/min, fixed phase stuffing are that particle diameter is that 18-32 μ m, aperture are the ICN allumina N neutral alumina of 6nm; Column temperature is a room temperature; Wavelength 312nm collects elutriant, 50 ℃ of concentrating under reduced pressure; In liquid concentrator, add pure water, stir, crystallization, 500rpm is centrifugal, and Calcium Chloride Powder Anhydrous is dry, gets ornidazole 9.40g, yield 97.39%, purity 99.65%.
Making with extra care of comparative example's 4 ornidazoles
The ornidazole dissolving crude product of 15g purity 96.52% in 120ml ethanol, is stirred, it is dissolved fully, add the gac of 0.3g then, 45 ℃ of whip attachment 15 minutes are filtered decarburization, collect filtrating; Concentrated back adds pure water, stirs, and crystallization, 500rpm is centrifugal, and Calcium Chloride Powder Anhydrous is dry, gets ornidazole 9.42g, yield 97.60%, purity 97.28%.
The foregoing description and Comparative Examples have proved absolutely the meliority of particular combination method of the present invention from different aspects, especially comprise the chromatographic condition and the optimum parameters of preparative scale chromatography post, have brought beyond thought effect, are in theory can't rational expectation.Bound by theory not; What possibly be various purification process to different impurities in the medicine removes the effect difference; The purification process of the present invention's combination has collaborative centrifugation to the impurity in the medicine; Process for purification provided by the invention has the characteristics and the obvious improvement of essence, and the beyond thought technique effect of obtaining has obtained the highly purified product of high yield.
According to the above embodiments the present invention has been made detailed description, and the present invention confirms that through relevant with it comparative example the present invention has obtained unexpected excellent effect.What need explanation is that above embodiment is just to illustrating the present invention.Under the prerequisite that does not depart from spirit of the present invention and essence, those skilled in the art can design multiple alternative of the present invention and improvement project, and it all should be understood to be within protection scope of the present invention.
Claims (7)
1. the ornidazole compound shown in the formula (I) is characterized in that its method for making may further comprise the steps:
(1) with a certain amount of ornidazole dissolving crude product in organic solvent, add charcoal absorption, filter, collect filtrating, concentrating under reduced pressure obtains the ornidazole of elementary purification;
(2) ornidazole with above-mentioned elementary purification carries out separation and purification with the preparative scale chromatography post, collects elutriant, and concentrating under reduced pressure obtains the ornidazole that secondary is purified;
(3) in above-mentioned liquid concentrator, add pure water, carry out crystallization, with the crystal centrifuge washing of separating out, drying, the ornidazole of three grades of purifications of acquisition.
2. the method for making of ornidazole according to claim 1 is characterized in that this method comprises the steps:
(1) with a certain amount of ornidazole dissolving crude product in the organic solvent that dissolves each other with water of 4-10 times of weight, add the gac that accounts for overall solution volume 0.1-0.5% (g/ml), 40-50 ℃ whip attachment 10-15 minute; Filter decarburization; Collect filtrating, concentrating under reduced pressure obtains the ornidazole of elementary purification;
(2) ornidazole with above-mentioned elementary purification carries out separation and purification with preparation type neutral alumina chromatographic column, collects the ornidazole elutriant, and 40～60 ℃ of concentrating under reduced pressure obtain the ornidazole that secondary is purified;
(3) in above-mentioned liquid concentrator, add pure water, carry out crystallization, the crystal centrifuge washing of separating out is dry through solid drier, the ornidazole of three grades of purifications of acquisition.
3. method for making according to claim 2 is characterized in that the organic solvent that dissolves each other with water described in the step (1) is selected from one or more in methyl alcohol, ethanol, propyl alcohol, acetone, acetonitrile, tetramethylene sulfone, hydroxy-propionic acid, the terepthaloyl moietie, is preferably ethanol.
4. according to the method for making of the ornidazole of one of claim 1-3; It is characterized in that the moving phase that chromatographic column is used in the step (2) is 3: 7 the acetonitrile and the mixing solutions of water as volume ratio, fixed phase stuffing is selected from neutral alumina, flow velocity 0.1-2ml/min; Column temperature is a room temperature, wavelength 312nm.
5. according to the method for making of the ornidazole of one of claim 1-4, it is characterized in that 50 ℃ of concentrating under reduced pressure in the step (2).
6. according to the method for making of the ornidazole of one of claim 1-5, it is characterized in that: said fixed phase stuffing is that particle diameter is 18-200 μ m, and the aperture is the pore neutral alumina of about 6nm.
7. the purposes that is used for anaerobe resistant and anti-trichomonal medicine according to the ornidazole of one of claim 1-6 method preparation in preparation.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102391188A (en) * | 2011-09-30 | 2012-03-28 | 山东罗欣药业股份有限公司 | Ornidazole hydrate crystal, preparation method thereof and crystal-containing composition tablets |
| CN103073501A (en) * | 2012-12-07 | 2013-05-01 | 西安万隆制药股份有限公司 | Ornidazole crystal compound |
| CN105585532A (en) * | 2014-10-24 | 2016-05-18 | 山东齐都药业有限公司 | After-treatment method for levornidazole reaction liquid |
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| CN1651415A (en) * | 2004-11-29 | 2005-08-10 | 南京圣和药业有限公司 | Preparation and purification method of ornidazole optical antipode |
| CN101143849A (en) * | 2007-10-12 | 2008-03-19 | 西安新安医药科技有限公司 | Preparation and purification method for optical enantiomer of ornidaxole |
| CN101633643A (en) * | 2009-08-14 | 2010-01-27 | 海南美大制药有限公司 | Ornidazole compound in new path |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1651415A (en) * | 2004-11-29 | 2005-08-10 | 南京圣和药业有限公司 | Preparation and purification method of ornidazole optical antipode |
| CN101143849A (en) * | 2007-10-12 | 2008-03-19 | 西安新安医药科技有限公司 | Preparation and purification method for optical enantiomer of ornidaxole |
| CN101633643A (en) * | 2009-08-14 | 2010-01-27 | 海南美大制药有限公司 | Ornidazole compound in new path |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102391188A (en) * | 2011-09-30 | 2012-03-28 | 山东罗欣药业股份有限公司 | Ornidazole hydrate crystal, preparation method thereof and crystal-containing composition tablets |
| CN103073501A (en) * | 2012-12-07 | 2013-05-01 | 西安万隆制药股份有限公司 | Ornidazole crystal compound |
| CN105585532A (en) * | 2014-10-24 | 2016-05-18 | 山东齐都药业有限公司 | After-treatment method for levornidazole reaction liquid |
| CN105585532B (en) * | 2014-10-24 | 2018-05-01 | 山东齐都药业有限公司 | The post-processing approach of l-ornidazole reaction solution |
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