CN102206218B - Method for purifying high-purity pemetrexed disodium - Google Patents
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Abstract
The invention provides a method for purifying high-purity pemetrexed disodium. The method is realized by combining a salting-out method with an organic solvent/water mixed solvent crystallization method. The method provided by the invention is carried out at normal temperature; and by using the method, the quantities and contents of organic impurities and inorganic impurities in the purified products can be effectively controlled, the content of the organic impurities satisfies requirements on identification thresholds of the impurities of bulk drugs in China, and the quantity of the organic impurities is obviously reduced.
Description
Technical field
The present invention relates to a kind of purification process of pemetrexed disodium, belong to medical technical field, belong to specifically medicine and make the field.
Background technology
Pemetrexed disodium (Pemetrexed disodium), chemical name are N-[4-[2-(2-amino-4,7-dihydro-4-oxygen-1H-pyrrolo-[2,3-d] pyrimidine-5-alkyl) ethyl] benzoyl]-the Pidolidone disodium.
Pemetrexed disodium is many target spots antifol, be used for the treatment of tumour by Lilly Co., Eli.'s exploitation, combination with cisplatin can be treated the malignant pleural mesothelioma that can't perform the operation, at present, pemetrexed disodium is the medicine of unique treatment malignant pleural mesothelioma (MPM) in the world, is used for simultaneously the Metastatic Nsclc second line treatment.Pemetrexed list medicine or combined chemotherapy have obvious therapeutic action to kinds of tumors, and especially to previously treating failed patient, pemetrexed disodium has brought new chance and hope to them.
The multiple preparation method of pemetrexed disodium is open in patent EP432677, EP589720, WO0011004, EP549886, CN1778797 etc., but the pemetrexed disodium crude product purity that above method obtains is lower, especially organic impurity content does not meet the requirement of medicine registration, can not be directly used in the preparation of pemetrexed disodium preparation, therefore need to carry out purifying to it.
Present disclosed pemetrexed disodium purification process mainly contains two kinds:
The mixed solvent crystallization method of first organic solvent/water:
(the Yi Bixin such as Yi Bixin, Ye Hai etc., synthesizing of pemetrexed disodium. Chinese Journal of Pharmaceuticals .2006,37 (12): 798-800) and (Zhu Gaojun such as Zhu Gaojun, Liu Zenglu etc., synthesizing of pemetrexed disodium. Chinese Journal of Pharmaceuticals .2005,36 (12): 727-729) all openly can adopt in the literature alcohol-water that pemetrexed disodium is carried out recrystallization purifying.
In addition, patent WO0114379 and CN1406238 relate to a kind of preparation method of pemetrexed disodium heptahydrate, disclose the aqueous solution that will comprise pemetrexed disodium and have been heated to 40～60 ℃, are cooled to the method for 0～30 ℃ of crystallization behind the adding acetone.
Patent CN1778797 discloses the aqueous solution that will comprise pemetrexed disodium and has been heated to 50 ℃, adds the method that ethanol is cooled to the room temperature crystallization.
Patent CN1778802 mentions a kind of method for preparing the pemetrexed disodium trihydrate, also relate to pemetrexed disodium from comprise pemetrexed disodium, water and a kind of can with the method that crystallizes out the miscible organic solvent of water, this solvent comprises ethanol, methyl alcohol, Virahol, acetone, tetrahydrofuran (THF), glycol dimethyl ether or their mixture, wherein, the temperature of adding ethanol should be not less than 40 ℃.
Patent WO9916742, CN1271338 and CN1475477 relate to and add the method that 6～7 times of amounts are down to the room temperature crystallization behind the alcohol under 70 ℃ in containing the aqueous solution of pemetrexed disodium.
Above mixed solvent crystallization method, generally be incorporated into after the pemetrexed disodium synthetic method, be used for the preparation of bulk drug crude product, or be used for the preparation of certain specific crystal formation crude product, can not reach the purpose of refining pemetrexed disodium bulk drug, even adopt above method repeatable operation, still have the part organic impurity and surpass limit of identification, the high effective liquid chromatography for measuring result shows, above method is not good to the organic impurity removal effect of strong polarity, and in addition, mixed solvent crystallization method process adopts heating steps, to greatly aggravate the hydrolysis oxidation of product, increase kind and the content of organic impurity.
It two is salting-out process:
CN101417998 discloses a kind of purification process of saltouing of pemetrexed disodium, be specially in the aqueous solution that comprises pemetrexed disodium and add one or more water-soluble salt solids (or its aqueous solution), the pemetrexed disodium crystal is separated out, the method is mainly removed the water-soluble impurity in the pemetrexed disodium raw material, and the method need not heat, and can solve the problem that heats the product hydrolysis oxidation that causes.
But this method of saltouing merely is Shortcomings also, because the method is crystallization in aqueous phase system, therefore can only remove the stronger water-soluble impurity of segment polarity, is difficult to except the organic impurity of depolarization less than pemetrexed disodium.Pemetrexed disodium raw material behind employing this method purifying still have partial impurities content to exceed the limit of impurities that the medicine registration requires, so the CN101417998A method still can not satisfy the preparation requirement of high-purity pemetrexed disodium raw material.
" technical director's principle of chemicals impurity research " of State Food and Drug Administration's issue pointed out, bulk drug for maximum per daily dose≤2g, the limit of identification of organic impurity is 0.1%, if organic impurity exceeds this limit, then tackle the organic impurity that exceeds limit of identification and carry out Structural Identification, analyze its hazardness.In addition, the medicine that adopts this medicinal chemicals to make should carry out with the product of former R ﹠ D Enterprises comprehensive quality comparative study, and its organic impurity kind and content all must not be apparently higher than former R ﹠ D Enterprises.
After measured, more than disclosed method the bulk drug organic impurity is controlled at below 0.1%, and the preparation that the raw material behind above method purifying is made, single organic impurity content and total organic impurity quantity and content all are higher than the import preparation of former research and development company far away.In addition, salting-out process such as condition control are bad, also introduce easily a large amount of inorganic salt impurity, not only reduce the product actual recovery, also might affect product stability.
In sum, lack a kind of excellent process in the prior art, effectively remove the various impurity in the pemetrexed disodium bulk drug, to satisfy the medicine registration to the requirement of bulk drug limit of impurities.
The medicine trade proprietary term that above literal is introduced is explained as follows, wherein:
Term " medicinal chemicals " refers to by chemical synthesis process preparation, and patient can't directly take, and as materials such as the powder of pharmaceutical purpose, crystallizations, comprises activeconstituents and impurity two portions.
Term " medicine registration " refers to various countries Drug Administration mechanism according to legal procedure, the security of intending the list marketing medicine, validity, quality controllability etc. is examined, and determined whether to agree the process of examining of its list marketing.
Term " organic impurity " comprises the impurity introduced in the technique and degraded product etc., may be known or unknown, volatile or non-volatility.Because the chemical structure of this class impurity is general and activeconstituents is similar or have the origin relation, so usually can be referred to as related substance again.
Term " limit of identification (Identification Threshold) ": the impurity that exceeds this limit all should carry out qualitative analysis, determines its chemical structure.
Summary of the invention
The present invention is directed to the salting-out process that exists in the present pemetrexed disodium purification process and mixed solvent crystallization method can't effectively be removed various impurity and heating causes the problems such as degradation impurity generation to be improved, find to utilize to saltout and merge organic solvent under the normal temperature/water mixed solvent crystallization operation, can effectively remove the impurity in the pemetrexed disodium bulk drug, make purified product meet the medicine registration for the general requirement of limit of impurities.
The present invention is achieved through the following technical solutions:
The purification process of the pemetrexed disodium shown in a kind of formula I,
The method may further comprise the steps:
(1) the pemetrexed disodium crude product is added to the water makes it dissolving, regulate pH value to 7.5～8.5 with hydrochloric acid or sodium hydroxide solution, add sodium chloride solution again, stirring until the concentration of sodium chloride solution is 8～20%, is left standstill crystallization;
(2) filter, filter cake washs with 8～20% sodium chloride solution, drains;
(3) filter cake is added to the water and makes it dissolving, adds one or more and the miscible organic solvent of water, and stirring until the organic solvent amount reaches 70～90%, is left standstill crystallization;
(4) filter, the described organic solvent washing of the step with 70～90% (3) is drained drying under reduced pressure.
This purge process can repeat according to purification effect.
Sequencing of saltouing purge process and mixed solvent crystallization purge process of the present invention can be changed, and, carries out first mixed solvent crystallization purifying that is, after the purifying of saltouing, also can reach the object of the invention.
It is pointed out that above operation all carries out at normal temperatures, normal temperature is relatively heating in this patent, refers to 5～39 ℃.
Step (1) is not if middle pH value between 7.5～8.5, then needs to regulate again.
The crystallization time of leaving standstill in the purification step should be in 1～3 hour, and 1 hour crystallization of less than is insufficient, and yield descends, and surpasses hydrolysis aggravation in 3 hours, and impurity increases.
Concentration of sodium chloride solution in the above purification step represents that with weight percentage organic solvent content represents with volumn concentration.
" pemetrexed disodium crude product " in the purification step refers to the mixture of pemetrexed disodium content between 80～99.5%, but is lower than 80% bulk drug for pemetrexed disodium content, repeats according to circumstances above operation and also can realize the purifying purpose.
" water " in the purification step is water for injection.
Be not that all organic solvents all can reach the object of the invention, through contriver's screening, " organic solvent miscible with water " in the purification step is selected from one or more in ethanol, acetonitrile and the dimethyl formamide.
This patent adopts high performance liquid chromatography and muriate test procedure comprehensive evaluation purification effect.
Wherein, high performance liquid chromatography as evaluation index, is investigated pemetrexed disodium content and organic impurity content with product yield, product purity, organic impurity quantity and maximum single organic impurity content.
In addition, the muriate test procedure is take chloride content as evaluation index, and whether the sodium chloride as impurity of investigating the salting-out process introducing exceeds standard.
In the purge process, the crystallization condition of step (1) is that the Chlorine in Solution na concn reaches 8～20%, in this scope, all can realize effect of the present invention, preferred 10～14%, in the preferable range, the purity of separating out pemetrexed disodium is the highest, and yield is the highest, amount of impurities is minimum, and maximum single assorted content is minimum.Sodium chloride concentration is less than 8% the time, and pemetrexed disodium is separated out deficiency, causes yield to descend, and sodium chloride concentration is greater than 20% the time, and solid sodium chloride is separated out in a large number, and product purity descends.
In the purge process, the crystallization condition of step (3) is that organic solvent concentration reaches 70～90% in the solution, in this scope, all can realize effect of the present invention, preferred 75～85%, under the optimum condition, the purity of separating out pemetrexed disodium is the highest, and yield is the highest, amount of impurities is minimum, and maximum single assorted content is minimum.Organic solvent content is less than 70%, and pemetrexed disodium is separated out deficiency, and product yield descends, and organic solvent content is greater than 90%, and foreign matter content increases, and is difficult to reach the removal of impurities requirement.
In the purification step (1), the amount that adds entry should make the raw material crude product dissolve fully, and amount of water is all can realize in 6～10 times of weight ranges of raw material crude product weight; Be to save cost, the concentration of sodium chloride solution of adding should be as far as possible near saturation concentration 26.5%, but the concentration of the sodium chloride solution that adopts is as long as all can realize the present invention greater than 20%;
In the purification step (2), the concentration of sodium chloride solution of washing usefulness, should with step (1) in to add the concentration of the new sodium chloride solution that forms after the sodium chloride solution consistent;
In the purification step (3), the amount that adds entry should make filter cake dissolve fully, and amount of water all can be realized the object of the invention in 10～20 times of weight ranges of filter cake weight; For saving cost, the organic solvent of adding adopts anhydrous or moisture 5% the organic solvent that is no more than as far as possible, but adopts the concentration of organic solvent as long as all can realize the present invention greater than 90%;
In the purification step (4), the concentration of organic solvent of washing usefulness, should with step (3) in to add the concentration of organic solvent in the organic solvent/water mixed system that forms after the organic solvent consistent.
The pemetrexed disodium raw material 1 (content 98.86%) of buying certain factory with market illustrates the invention effect, the total impurities content of this raw material is 1.14%, maximum single foreign matter content 0.18% (exceeding impurity limit of identification (0.1%)), organic impurity adds up to 15.To directly the injection pemetrexed disodium of preparation and the injection pemetrexed disodium of former research and development company import are made comparisons with this raw material, preparation total impurities content and maximum single foreign matter content that the purchase raw material is made are respectively 0.84% and 0.16%, all be higher than import preparation (total impurities content 0.20%, maximum single foreign matter content: 0.06%) far away.
We adopt this patent method that above raw material has been carried out purification refine, so that raw material total impurities content reduces to 0.23% by 1.14%, maximum single foreign matter content is reduced to below 0.07% by 0.18% and (is met 0.1% impurity limit of identification), the organic impurity number drops to 4 by 15, study on the stability shows behind the purifying more stable than the raw material before the purifying, and makes injection pemetrexed disodium preparation and former research and development company quality product approaches.
According to multiple art methods, respectively above raw material is carried out purifying, the raw material total impurities can drop in 0.4～0.8% scope by 1.14%, maximum single impurity drops to (still not meeting the impurity limit of identification requires) in 0.11～0.16% scope by 0.18%, and the organic impurity number drops in 7～8 scopes by 15.And with the injection pemetrexed disodium preparation that art methods is made, its foreign matter content and quantity still have larger gap with former research and development company.
We buy again other producer's raw material 2～5 from market, purification result shows that equally the present invention can realize preparing the purpose of high-purity pemetrexed disodium, but art methods can't realize this purpose.
Therefore, effect of the present invention is effectively to remove the impurity in the pemetrexed disodium raw material crude product, comprise organic impurity and inorganic impurity, be with the remarkable difference of prior art, the operation of employing present method, organic impurity quantity obviously reduces, can be dropped to by 15 before the purifying 4 behind the purifying, maximum single organic impurity can be controlled in the limit of identification of medicine registration requirement below 0.1%, and can significantly reduce the inorganic impurity (sodium-chlor) that salting-out process is introduced, it is approaching with former research and development company imported product quality to adopt the refining pemetrexed disodium bulk drug of the inventive method to make preparation, meets the national registration requirement.In addition, the inventive method is with low cost, and is simple to operate, is easy to industrialization.
Description of drawings
Fig. 1: unpurified crude product high-efficient liquid phase chromatogram.
Fig. 2: by the high-efficient liquid phase chromatogram of Comparative Examples 1 purifying.
Fig. 3: by the high-efficient liquid phase chromatogram of Comparative Examples 3 purifying.
Fig. 4: by the high-efficient liquid phase chromatogram of Comparative Examples 4 purifying.
Fig. 5: the high-efficient liquid phase chromatogram of the inventive method (embodiment 1) purifying.
Embodiment
Further specify the present invention below in conjunction with embodiment, but the scope of protection of present invention is not limited to the following example.
Embodiment 1
Taking by weighing pemetrexed disodium raw material 1 (content 98.86%) 20g under the room temperature adds 8 times of water gagings and makes dissolving, adding 25% sodium chloride solution makes sodium chloride concentration reach 12%, stir, placed crystallization 2 hours, and filtered, filter cake washs with 12% sodium chloride solution, drain, filter cake adds the dissolving of 15 times of water gagings again, adds 95% ethanol and makes and contain the alcohol amount and reach 80%, places 2 hours crystallizatioies after stirring.Filter, filter cake 80% washing with alcohol is drained, and drying under reduced pressure gets pemetrexed disodium.
Embodiment 2
Under the room temperature the wet product before embodiment 1 drying under reduced pressure are dissolved with 15 times of water gagings, adding 25% sodium chloride solution makes sodium chloride concentration reach 12%, stir, crystallization was placed 2 hours, filtered, and filter cake washs with 12% sodium chloride solution, drain, filter cake adds the dissolving of 15 times of water gagings again, adds 95% ethanol and makes and contain the alcohol amount and reach 80%, places 2 hours crystallizatioies after stirring.Filter, filter cake 80% washing with alcohol is drained, and drying under reduced pressure gets pemetrexed disodium.
Embodiment 3
Taking by weighing pemetrexed disodium raw material 1 (content 98.86%) 20g under the room temperature adds 8 times of water gagings and makes dissolving, adding 25% sodium chloride solution makes sodium chloride concentration reach 10%, stir, placed crystallization 2 hours, and filtered, filter cake washs with 10% sodium chloride solution, drain, filter cake adds the dissolving of 15 times of water gagings again, adds 95% ethanol and makes and contain the alcohol amount and reach 75%, places 2 hours crystallizatioies.Filter, filter cake 75% washing with alcohol is drained, and drying under reduced pressure gets pemetrexed disodium.
Embodiment 4
Taking by weighing pemetrexed disodium raw material 1 (content 98.86%) 20g under the room temperature adds 8 times of water gagings and makes dissolving, adding 25% sodium chloride solution makes sodium chloride concentration reach 14%, stir, placed crystallization 2 hours, and filtered, filter cake washs with 14% sodium chloride solution, drain, filter cake adds the dissolving of 15 times of water gagings again, adds 95% ethanol and makes and contain the alcohol amount and reach 85%, places 2 hours crystallizatioies.Filter, filter cake 85% washing with alcohol is drained, and drying under reduced pressure gets pemetrexed disodium.
Embodiment 5
Taking by weighing pemetrexed disodium raw material 1 (content 98.86%) 20g under the room temperature adds 8 times of water gagings and makes dissolving, adding 25% sodium chloride solution makes sodium chloride concentration reach 8%, stir, placed crystallization 2 hours, and filtered, filter cake washs with 8% sodium-chlor, drain, filter cake adds the dissolving of 15 times of water gagings again, adds 95% ethanol and makes and contain the alcohol amount and reach 70%, places 2 hours crystallizatioies.Filter, filter cake 70% washing with alcohol is drained, and drying under reduced pressure gets pemetrexed disodium.
Embodiment 6
Taking by weighing pemetrexed disodium raw material 1 (content 98.86%) 20g under the room temperature adds 8 times of water gagings and makes dissolving, adding 25% sodium chloride solution makes sodium chloride concentration reach 20% to saltout, place 2 hours crystallizatioies, filter, filter cake washs with 20% sodium-chlor, drains, and filter cake adds 15 times of water gagings dissolvings again, add 95% ethanol and make and contain alcohol amount and reach 90%, place 2 hours crystallizatioies.Filter, filter cake 90% washing with alcohol is drained, and drying under reduced pressure gets pemetrexed disodium.
Comparative Examples 1
Purifying is carried out in the operation of embodiment 1 in the patent of employing CN101417998.Concrete operations are: under 20～30 ℃, pemetrexed disodium raw material 1 (content 98.86%) 20.0g is added 25% saturated sodium chloride aqueous solution 200g, transfer pH11～12 molten clear with sodium hydroxide solution, stir the lower half saturated sodium chloride aqueous solution 200g of adding, finish with about hydrochloric acid soln readjustment pH to 8, continue to filter 20～30 ℃ of lower stirrings 1～2 hour, filter cake is drying to obtain pemetrexed disodium with an amount of aqueous ethanol washing.
Comparative Examples 2
Get the purified product 10.0g after saltouing in the above-mentioned Comparative Examples 1, carrying out the 2nd time according to the operation of Comparative Examples 1 saltouts, 25% saturated sodium-chloride water solution and the half saturated sodium chloride aqueous solution consumption that add reduce by half, and other working method namely gets pemetrexed disodium with Comparative Examples 1.
Comparative Examples 3
Take by weighing pemetrexed disodium raw material 1 (content 98.86%) 20g under the room temperature and add 8 times of water gagings and make dissolving, add 95% ethanol and make and contain the alcohol amount and reach 80%, place 2 hours crystallizatioies.Filter, filter cake 80% washing with alcohol is drained, and drying under reduced pressure gets pemetrexed disodium.
Comparative Examples 4
Get the wet product 30.5g (purified product 10.0g is equivalent to saltout) before the salting-out process drying in the above-mentioned Comparative Examples 1, add 15 times of amount dissolvings of water, add again 95% ethanol and make and contain the alcohol amount and reach 80%, be heated to 45 ℃ and moltenly leave standstill clearly, be cooled under the room temperature crystallization 2 hours.Filter, filter cake 80% washing with alcohol, drying gets pemetrexed disodium.
Comparative Examples 5
Technical scheme according to the patent of CN101417998, design following purge process, concrete operations are: under 20～30 ℃, pemetrexed disodium raw material 1 (content 98.86%) 20.0g is added among the 25% saturated sodium chloride aqueous solution 200g, transfer pH11～12 molten clear with sodium hydroxide solution, stir the lower half saturated sodium chloride aqueous solution 200g of adding and dehydrated alcohol 250g, finish with about hydrochloric acid soln readjustment pH to 8, continuation was being stirred 1～2 hour under 20～30 ℃, filter, filter cake is drying to obtain with an amount of aqueous ethanol washing.Measure purity.
Embodiment 7
To the purification effect of above-described embodiment 1～6 and Comparative Examples 1～5, with high performance liquid chromatography (HPLC) method product content and organic impurity content are detected, check sodium chloride content with the muriate test procedure.
(1) high performance liquid chromatography:
Instrument condition: Agilent high performance liquid chromatograph, the reverse-phase chromatographic column take octyl silane group silica gel as weighting agent, UV-detector.
Chromatographic condition: acetonitrile-acetate buffer (is got Glacial acetic acid 1.7ml thin up to 1000ml, regulate pH5.5 with 50% sodium hydroxide solution) (3: 97) be mobile phase A, acetonitrile-acetate buffer (12.5: 87.5) is Mobile phase B, gradient elution.
(2) muriate test procedure: get tested material 0.2g, check (2010 editions appendix VIIIA of Chinese Pharmacopoeia) in accordance with the law, the contrast liquor ratio made from standard sodium chloride solution 10ml must not denseer (0.05%).
The results are shown in following table:
Above detected result shows, embodiment 1～6 all can obviously reduce the detected organic impurity number of HPLC method, successful is better than Comparative Examples 1～5, and the content that can make maximum single organic impurity is controlled at the limit of identification of medicine registration requirement below 0.1%, and can avoid introducing sodium chloride as impurity, meet the basic demand of bulk drug purifying process, illustrate and adopt the inventive method can effectively control impurity number and content.
Comparative Examples 1～2 also can significantly reduce organic impurity quantity, but maximum single organic impurity content does not meet the limit of identification that the medicine registration requires, in addition, because Comparative Examples is not optimized salting-out condition, introduce easily a large amount of inorganic impurities (such as sodium-chlor etc.), cause product purity to descend, inorganic impurity content is difficult to reflect from the measurement result of high performance liquid chromatography, but the muriate check result can embody in this respect defective of Comparative Examples 1～2.
Comparative Examples 3 is for only adopting ethanol water mixed solvent crystallization method that the pemetrexed disodium crude product is carried out purifying, and the result shows that effectively remove portion polarity is less than the organic impurity of pemetrexed disodium according to Comparative Examples 3 operations, and the result is undesirable.
Comparative Examples 4 is except carrying out heating operation in the mixed solvent Crystallization Process, other steps all adopt the operation identical with the present invention, display comparison example 3 can significantly increase its related substances in the product as a result, cause maximum single contaminant to exceed standard, illustrate that the purge process heating is unfavorable for constant product quality.
Comparative Examples 5 according to the CN101417998 Technical Design shows that salting-out process adds ethanol, can only promote pemetrexed disodium to separate out, and increases yield, can not significantly reduce foreign matter content.
Adopt market to buy, different manufacturers, purity is respectively the pemetrexed disodium raw material crude product of 80.26% (raw material 2), 87.35% (raw material 3), 95.28% (raw material 4) and 99.55% (raw material 5), after carrying out purifying according to embodiment 1 operation, detect respectively, detection method is with embodiment 7, and the result is as follows:
Above result shows that the present invention all has purification for the pemetrexed disodium crude product of content in 80～99.5% scopes, can reach the effect of the limit of identification that makes foreign matter content be controlled at medicine registration of the present invention within requiring.
Embodiment 9～14
Press the operation of embodiment 1, only incite somebody to action the following solvent replacing of ethanol wherein, carry out respectively purifying, the high effective liquid chromatography for measuring result who presses embodiment 7 is as follows:
Above result shows that acetonitrile or dimethyl formamide instead of ethanol also can reach desirable purification effect, considers the synthesis result of purification effect, yield and cost, preferred alcohol.
Embodiment 15
Taking by weighing pemetrexed disodium raw material 1 (content 98.86%) 20g under 5 ℃ adds 8 times of water gagings and makes dissolving, adding 25% sodium chloride solution makes sodium chloride concentration reach 20%, stir, placed crystallization 2 hours, and filtered, filter cake washs with 20% sodium chloride solution, drain, filter cake adds the dissolving of 15 times of water gagings again, adds 95% ethanol and makes and contain the alcohol amount and reach 90%, places 2 hours crystallizatioies after stirring.Filter, filter cake 90% washing with alcohol is drained, and drying under reduced pressure gets pemetrexed disodium.
Press the high effective liquid chromatography for measuring of embodiment 7, organic impurity is 5 behind the purifying, and maximum single assorted 0.09%.
Embodiment 16
Taking by weighing pemetrexed disodium raw material 1 (content 98.86%) 20g under 39 ℃ adds 8 times of water gagings and makes dissolving, adding 25% sodium chloride solution makes sodium chloride concentration reach 20%, stir, placed crystallization 2 hours, and filtered, filter cake washs with 20% sodium chloride solution, drain, filter cake adds the dissolving of 15 times of water gagings again, adds 95% ethanol and makes and contain the alcohol amount and reach 90%, places 2 hours crystallizatioies after stirring.Filter, filter cake 90% washing with alcohol is drained, and drying under reduced pressure gets pemetrexed disodium.
Press the high effective liquid chromatography for measuring of embodiment 7, organic impurity is 5 behind the purifying, and maximum single assorted 0.10%.
Above embodiment 15～16 explanations, the present invention can realize in 5～39 ℃ of scopes.
Claims (2)
1. purification process for preparing high-purity pemetrexed disodium is characterized in that comprising following steps:
(1) the pemetrexed disodium crude product is added to the water makes it dissolving, regulate pH value to 7.5～8.5, add sodium chloride solution again, stirring until the concentration of sodium chloride solution is 8～20%, is left standstill crystallization;
(2) filter, filter cake washs with 8～20% sodium chloride solution, drains;
(3) filter cake is added to the water and makes it dissolving, adds the organic solvent miscible with water again, stirs, until the organic solvent amount reaches 70～90%, leaves standstill crystallization;
(4) filter, the described organic solvent washing of the step with 70～90% (3) is drained, drying under reduced pressure,
The organic solvent that above-mentioned steps (3) is described and water is miscible is selected from one or more in ethanol, acetonitrile and the dimethyl formamide.
2. purification process as claimed in claim 1 is characterized in that the method is 5～39 ℃ of lower operations.
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| CN102838602B (en) * | 2011-06-21 | 2016-08-03 | 重庆医药工业研究院有限责任公司 | Pemetrexed oxide and preparation method thereof |
| CN102911176B (en) * | 2012-10-10 | 2015-07-22 | 德州德药制药有限公司 | Preparation method of pemetrexed disodium |
| CN102977107B (en) * | 2012-12-25 | 2015-04-22 | 山西普德药业股份有限公司 | Pemetrexed disodium compound and composition thereof |
| CN104119345B (en) * | 2014-06-18 | 2016-04-27 | 威海昊同医药科技有限公司 | A kind of purification process of injection stage pemetrexed disodium |
| CN104606150B (en) * | 2014-12-31 | 2018-03-16 | 辰欣药业股份有限公司 | A kind of pemetrexed disodium sterile powder injection and preparation method thereof |
| TW202000204A (en) * | 2018-06-20 | 2020-01-01 | 日商日本化藥股份有限公司 | Pemetrexed sodium injection solution formulation and manufacturing method therefor |
| CN115252564A (en) * | 2022-08-30 | 2022-11-01 | 海南锦瑞制药有限公司 | Preparation method of pemetrexed disodium for injection |
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