CN101475539B - Refining method for preparing high-purity oteracil potassium - Google Patents
Refining method for preparing high-purity oteracil potassium Download PDFInfo
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- CN101475539B CN101475539B CN2009100086656A CN200910008665A CN101475539B CN 101475539 B CN101475539 B CN 101475539B CN 2009100086656 A CN2009100086656 A CN 2009100086656A CN 200910008665 A CN200910008665 A CN 200910008665A CN 101475539 B CN101475539 B CN 101475539B
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Abstract
The invention provides a method for refining high-purity potassium oxonate. The method is characterized by comprising the following steps: adding an potassium oxonate crude product into water; adding alkali into the water until the crude product is completely dissolved; adding a polar solvent into the solution; adjusting the pH of the solution to neutrality by acid; filtering and separating out crystal; and drying the crystal so as to obtain the high-purity potassium oxonate. The method has the advantages of simple operation, mild reaction condition, high yield, pure product and the like, andhas yield over 90 percent, purity over 99.95 percent (detected by HPLC), and a single impurity peak reduced from 0.5 percent to below 0.05 percent.
Description
Technical field
The present invention relates to the synthetic field of medicine, relate in particular to a kind of process for purification of medical compounds Oteracil Potassium.
Background technology
Oteracil Potassium (Potassium oxonate) has another name called oteracil potassium (Oteracil Potassium), chemical name: 1,4,5, and 6-tetrahydrochysene-4,6-dioxy-1,3,5-triazines-2-carboxylic acid potassium, chemical structural formula is as follows:
As one of major ingredient of a kind of compound anti-cancer medicine TS-1 (TS-1), though self does not show as anti-tumor activity, but it is retained in the gi tract, can suppress the activation of 5-fluor-uracil (5-FU) in this position, thereby the toxic side effect that suppresses the antitumor drug Tegafur, Oteracil Potassium can optionally act on orotate phosphoribosyl-transferase at gi tract, blocking-up Ro 2-9757 phosphorylation, reduce toxic side effecties such as consequent gi tract, Oteracil Potassium can also suppress the minimizing of animal subject food ration, thereby improves the symptom that the weight of animals descends.
Find by retrieval, document is the argumentation for Oteracil Potassium pharmacological action and preparation mostly, about the synthetic method bibliographical information of Oteracil Potassium seldom, ubiquity preparation process complexity in the prior art, yield is low, the many purity of product impurity do not reach problems such as quality standard, some document only is to have done some discussions from reaction mechanism, specifically do not provide more complete, detailed preparation technology, especially do not provide and how to remove impurity, improve the process for purification of purity, because Oteracil Potassium is used strong oxidizer in the process of Cheng Huan, on the piperazine interannular position two more active hydrogen are arranged simultaneously, because hydrogen ion and nitrogen is in conjunction with slow, and and oxygen in conjunction with very fast, form unsettled enol easily, be converted into carbonyl stably then, side reaction takes place in balanced body easily that have an enol and carbonyl in salifiable process, introduce other impurity, impurity and product property difference are little, and conventional recrystallization method is difficult to remove.
Britain document Tetrahedron, vol.44.No.21, PP.6723-8.1988 provides a kind of method of synthetic Oteracil Potassium, respectively with 2, it is starting raw material that 2-two urea groups propanedioic acid or its take off a carboxyl product allantoic acid (allantoic acid), and salify makes under ring, the alkaline condition through being oxidized to, and crude product is without refining, yield only 48%, not mentioned purity.
Same author is at Britain document Tetrahedron, vol.42.No.2, PP.747-51.1986 provide in addition two kinds of methods that prepare Oteracil Potassium, and one is for being that starting raw material prepares Oteracil Potassium through steps such as oxidation open loop, salifies with the uric acid, crude product is without making with extra care not mentioned purity.
Reaction formula is as follows:
Other method is for being salify in the raw material alkaline aqueous solution with the wallantoin, and reaction formula is as follows:
Bibliographical information yield 82%, recrystallization gets needle-like crystal twice in 80～90 ℃ of hot water of gained crude product, ℃ m.p.＞300, not mentioned purity, contriver's high-efficient liquid phase analysis is found, though take on a new look two impurity peaks that occur about 4～5 minutes to some extent by the refining color of this method, not only do not make with extra care on the contrary and to strengthen, may since Oteracil Potassium in 80～90 ℃ of hot water due to the decomposes.
EP0957096A1 provides a kind of method, is starting raw material with the wallantoin, changes into six-ring by five-ring under liquid bromine, KI effect, and salify in the KOH aqueous solution obtains Oteracil Potassium again, and yield 70% does not provide process for purification, and product purity is not described yet.
Reaction formula is as follows:
Summary of the invention
The object of the present invention is to provide a kind of process for purification of effective purifying Oteracil Potassium.
Many at resulting Oteracil Potassium product impurity in the prior art, purity is low, do not reach relevant criterion, can't satisfy the requirement of pharmaceutical preparation, the contriver by high performance liquid phase-mass spectroscopy (chromatographic condition: with between octadecylsilane and silica gel be weighting agent, transfer pH value to 9 to make moving phase with acetonitrile-0.010mol/l bromohexadecane base trimethylamine solution (65: 35) with triethylamine, the detection wavelength is 264nm, number of theoretical plate calculates by the Oteracil Potassium peak and is not less than 5000) discovery impurity, determine and according to the structure of impurity, physico-chemical property is formulated the purification refine scheme, this invention can be removed impurity effectively, the preparation high-purity oteracil potassium, have simple to operation, the reaction conditions gentleness, the yield advantages of higher, yield is more than 90%, and purity is (HPLC detection) more than 99.95%, and single impurity peaks is reduced to below 0.05% by 0.5%.
The contriver carries out HPLC to the Oteracil Potassium by prior art for preparing by the chromatographic condition of carrying above and analyzes and find, two bigger impurity peaks appearred about 4～5 minutes, the area of single impurity peaks reaches 0.5%, the constructional feature of serious analysis impurity and the character of functional group, surprised discovery is because solvent effect, impurity can interact with polar solvent, show the solvability different with product, especially more obvious with some protic polar solvent effects, as containing hydroxyl or amino organic compound solvent in the molecule, protic solvent can provide proton that impurity molecule is exerted an influence, form stronger hydrogen chain with foreign ion, thereby the impurity combination is removed.
Oteracil Potassium is water insoluble, adds behind the alkali because alkali acts on the hydrogen on the piperazine interannular position, makes Oteracil Potassium well soluble in water, adds polar solvent then, uses sour neutralization bases again, and impurity is stayed in the mother liquor, and purified product is separated out, thereby plays refining effect.
The present invention is achieved through the following technical solutions:
The Oteracil Potassium crude product is added in the entry, and it is molten entirely to crude product to add alkali, adds polar solvent again, transfers PH to neutral with acid again, filters, dry highly purified Oteracil Potassium.
In the technique scheme, polar solvent is protic polar solvent or non-proton property polar solvent, for example: acetone, methyl-sulphoxide, methyl alcohol, ethanol, propyl alcohol, butanols, ethylene glycol, Virahol, N, dinethylformamide, N, the N-N,N-DIMETHYLACETAMIDE, acetonitrile, tetrahydrofuran (THF), methylethylketone, the mixture of one or more in ethyl acetate and the hexamethylphosphoramide, the protic polar solvent is significantly better than non-proton property polar solvent, especially contain hydroxyl, amido or amino protic polar solvent, particular methanol, ethanol, propyl alcohol, ethylene glycol, acetone, N, one or more mixture in dinethylformamide and the Virahol; More preferably acetone, methyl alcohol, N, in dinethylformamide, the ethanol in one or more mixture.
Alkali in the technique scheme comprises sylvite class, metal alkylide lithium compound, the amido lithium compound of organic bases such as alcohol and contains the potassium mineral alkali, is specially one or more the mixture in potassium methylate, potassium ethylate, salt of wormwood, saleratus, potassium tert.-butoxide, n-Butyl Lithium, phenyl lithium, potassium hydroxide, potassium hydride KH, lithium diisopropyl amido and the hexamethyldisilazane lithium; The mixture of one or more in particular methanol potassium, n-Butyl Lithium, potassium ethylate, salt of wormwood, potassium hydroxide and the potassium hydride KH; The more preferably mixture of one or more in salt of wormwood, potassium ethylate, the potassium hydroxide.
Acid in the technique scheme comprises organic acid such as carboxylic acid, sulfonic acid and mineral acid, is specially one or more the mixture in formic acid, acetate, propanedioic acid, Phenylsulfonic acid, sulfuric acid, hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, toxilic acid and the phosphoric acid; The mixture of one or more in preferable formic acid, acetate, sulfuric acid and the hydrochloric acid.
Service temperature of the present invention is-10～60 ℃, preferred 10 ℃～40 ℃; Feed ratio is: Oteracil Potassium: alkali: acid=1mol: 1～1.05mol: 1～1.05mol, Oteracil Potassium: water: polar solvent=1g: 6～14ml: 0.6～1.4ml.
Beneficial effect of the present invention is there is not complicated reaction process, can carry out at normal temperatures, and is workable, is difficult for causing side reaction, yield 〉=90%, and purity is (HPLC detection) more than 99.95%, and single impurity peaks is reduced to below 0.05% by 0.5%.
Specific embodiment
Now further describe beneficial effect of the present invention by following examples, be interpreted as these embodiment and only be used for the purpose of illustration, do not limit the scope of the invention, conspicuous change and modification that while those of ordinary skills are made according to the present invention are also contained within the scope of the invention.
Embodiment 1
10g Oteracil Potassium crude product is added in the 90ml water, adding 10% potassium hydroxide solution under stirring, to transfer to crude product molten entirely, add acetone 8.5ml again, 25 ℃ are stirred half an hour, stir down and transfer PH to 6.9-7.2 with 10% hydrochloric acid, the adularescent crystal is separated out, crystallization finish filtration, use the washing with acetone filter cake, filter cake vacuum-drying, weigh highly purified Oteracil Potassium 9.2g, yield 92%, purity 99.98% (HPLC detection).
Embodiment 2
10g Oteracil Potassium crude product is added in the 70ml water, adding 15% solution of potassium carbonate under stirring, to transfer to crude product molten entirely, add methyl alcohol 7ml again, 10 ℃ are stirred half an hour, stir down and transfer PH to 6.9-7.2 with 8% sulfuric acid, the adularescent crystal is separated out, crystallization finish filtration, use the methanol wash filter cake, filter cake vacuum-drying, weigh highly purified Oteracil Potassium 9.5g, yield 95%, purity 99.96% (HPLC detection).
Embodiment 3
10g Oteracil Potassium crude product is added in the 100ml water, adding 10% potassium hydroxide solution under stirring, to transfer to crude product molten entirely, add ethanol 10ml again, 35 ℃ are stirred half an hour, stir down and transfer PH to 6.9-7.2 with 15% formic acid, the adularescent crystal is separated out, crystallization finish filtration, use the washing with alcohol filter cake, filter cake vacuum-drying, weigh highly purified Oteracil Potassium 9.3g, yield 93%, purity 99.95% (HPLC detection).
Embodiment 4
10g Oteracil Potassium crude product is added in the 110ml water, and adding 10% potassium methylate solution under stirring, to transfer to crude product molten entirely, adds N again, dinethylformamide 10ml, 15 ℃ are stirred half an hour, stir down and transfer PH to 6.9-7.2 with 15% hydrochloric acid, and the adularescent crystal is separated out, crystallization finish filtration, use N, the dinethylformamide washing leaching cake, filter cake vacuum-drying, weigh highly purified Oteracil Potassium 9.25g, yield 92.5%, purity 99.97% (HPLC detection).
Embodiment 5
10g Oteracil Potassium crude product is added in the 120ml water, adding 10% potassium hydride KH solution under stirring, to transfer to crude product molten entirely, add acetonitrile 12ml again, 25 ℃ are stirred half an hour, stir down and transfer PH to 6.9-7.2 with 15% formic acid, the adularescent crystal is separated out, crystallization finish filtration, use the acetonitrile washing leaching cake, filter cake vacuum-drying, weigh highly purified Oteracil Potassium 9.3g, yield 93%, purity 99.96% (HPLC detection).
Embodiment 6
10g Oteracil Potassium crude product is added in the 140ml water, adding 10% potassium hydroxide solution under stirring, to transfer to crude product molten entirely, add ethanol 10ml again, 30 ℃ are stirred half an hour, stir down and transfer PH to 6.9-7.2 with 15% hydrochloric acid, the adularescent crystal is separated out, crystallization finish filtration, use the washing with alcohol filter cake, filter cake vacuum-drying, weigh highly purified Oteracil Potassium 9.15g, yield 91.5%, purity 99.97% (HPLC detection).
Embodiment 7
10g Oteracil Potassium crude product is added in the 100ml water, adding 10% potassium ethylate solution under stirring, to transfer to crude product molten entirely, add acetone 10ml again, 25 ℃ are stirred half an hour, stir down and transfer PH to 6.9-7.2 with 15% acetate, the adularescent crystal is separated out, crystallization finish filtration, use the washing with acetone filter cake, filter cake vacuum-drying, weigh highly purified Oteracil Potassium 9.6g, yield 96%, purity 99.98% (HPLC detection).
Claims (8)
1. the process for purification of a high-purity oteracil potassium, this method comprises following process:
The Oteracil Potassium crude product is added in the entry, it is molten entirely to crude product to add alkali, add polar solvent again, transfer PH to neutral with acid, crystal, the dry high-purity oteracil potassium that gets are separated out in filtration, wherein polar solvent is acetone, methyl alcohol, N, one or more mixture in dinethylformamide, ethanol and the acetonitrile.
2. method according to claim 1 is characterized in that refining used alkali is one or more the mixture in potassium methylate, potassium ethylate, salt of wormwood, saleratus, potassium tert.-butoxide, n-Butyl Lithium, phenyl lithium, potassium hydroxide, potassium hydride KH, lithium diisopropyl amido and the hexamethyldisilazane lithium.
3. method according to claim 1 is characterized in that refining used alkali is one or more the mixture in potassium methylate, n-Butyl Lithium, potassium ethylate, salt of wormwood, potassium hydroxide and the potassium hydride KH.
4. method according to claim 1 is characterized in that refining used alkali is one or more the mixture in salt of wormwood, potassium ethylate, the potassium hydroxide.
5. method according to claim 1 is characterized in that refining used acid is one or more the mixture in formic acid, acetate, propanedioic acid, Phenylsulfonic acid, sulfuric acid, hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, toxilic acid and the phosphoric acid.
6. method according to claim 1 is characterized in that refining used acid is one or more the mixture in formic acid, acetate, sulfuric acid and the hydrochloric acid.
7. method according to claim 1 is characterized in that refining feed ratio is an Oteracil Potassium: alkali: acid=1mol: 1～1.05mol: 1～1.05mol, Oteracil Potassium: water: polar solvent=1g: 6～14ml: 0.6～1.4ml.
8. method according to claim 1 is characterized in that extraction temperature is 10 ℃～40 ℃.
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| CN102250025B (en) * | 2011-05-18 | 2013-11-13 | 深圳万乐药业有限公司 | Preparation method suitable for industrially producing oteracil potassium |
| CN102746244B (en) * | 2012-07-27 | 2014-06-25 | 南京正大天晴制药有限公司 | Refining method of oteracil potassium |
| CN103435566A (en) * | 2013-08-22 | 2013-12-11 | 江苏正大清江制药有限公司 | Synthesis technology for preparing oteracil potassium |
| CN103739560A (en) * | 2013-09-24 | 2014-04-23 | 国药一心制药有限公司 | Method for refining Oteracil Potassium |
| CN103694184B (en) * | 2013-12-02 | 2015-08-05 | 山东永泰集团有限公司 | A kind of process for purification of oteracil potassium |
| CN103833641B (en) * | 2014-03-20 | 2016-03-02 | 鲁南新时代生物技术有限公司 | Impurity compound of a kind of oteracil potassium and its production and use |
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Assignee: Shandong Xinshidai Pharmaceutical Industry Co., Ltd. Assignor: Lunan Pharmaceutical Group Co., Ltd. Contract record no.: 2010370000508 Denomination of invention: Refining method for preparing high-purity oteracil potassium License type: Exclusive License Open date: 20090708 Record date: 20100908 |
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Application publication date: 20090708 Assignee: Lunan New Era Biological Technology Co., Ltd. Assignor: Lunan Pharmaceutical Group Co., Ltd. Contract record no.: 2012370000304 Denomination of invention: Refining method for preparing high-purity oteracil potassium Granted publication date: 20101020 License type: Exclusive License Record date: 20121226 |
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