CN104119345A - Purification method of injection grade pemetrexed disodium - Google Patents
Purification method of injection grade pemetrexed disodium Download PDFInfo
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- CN104119345A CN104119345A CN201410270585.9A CN201410270585A CN104119345A CN 104119345 A CN104119345 A CN 104119345A CN 201410270585 A CN201410270585 A CN 201410270585A CN 104119345 A CN104119345 A CN 104119345A
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- pemetrexed disodium
- aqueous solution
- crude product
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- sodium chloride
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Abstract
The invention provides a purification method of injection grade pemetrexed disodium. The method comprises the following steps: dissolving a pemetrexed disodium crude product in a sodium chloride aqueous solution, adding an organic solvent for extracting the aqueous solution, collecting the aqueous solution, adding active carbon, filtering, adding the organic solvent, separating out crystals, washing and drying. With the adoption of the purification method, the turbid phenomenon during a re-dissolution test can be effectively solved; more surprisingly, the purification method is capable of effectively removing impurities in the raw material medicine of pemetrexed disodium and simply and efficiently carrying out purification.
Description
Technical field
The present invention relates to a kind of purification process of injection stage pemetrexed disodium, belong to medical technical field.
Background technology
Pemetrexed disodium is a kind of many target spots antifol, can suppress the multiple folic acid such as thymidylate synthetase (TS), Tetrahydrofolate dehydrogenase (DHFR) and glycinamide ribonucleotide transformylase (GARFT) and rely on enzyme.Clinical trial shows that pemetrexed disodium is effective to multiple solid tumor, and at present state's listing such as the Yi U.S., European Union, China, for first-line treatment malignant pleural mesothelioma and second line treatment part late period and Metastatic Nsclc.Pemetrexed disodium (Pemetrexed disodium, structural formula is as follows), chemistry is by name: N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo-[2,3-d] pyrimidine-5-yl) ethyl] benzoyl]-Pidolidone disodium salt.
The preparation method of pemetrexed disodium is open in patent CN 1087910, CN 1271338, WO0011004, EP549886, CN1778797 etc., but the pemetrexed disodium crude product purity that above method obtains is lower, do 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.
Purifying is one of important procedure in bulk drug preparation technology, and it directly has influence on quality and the cost of finished product.Current disclosed pemetrexed disodium purification process comprises mixed solvent crystallization method and the salt crystallization method of organic solvent/water.
The mixed solvent crystallization method of organic solvent/water, is heated to 60～70 ℃ of crystallizatioies as disclosed in CN 1271338, WO0114379 with 3A ethanol/water mixed solvent; In CN1778802, disclose with ethanol/water mixed solvent heat to 45～50 ℃ crystallization; In CN1406238, disclose with acetone/water mixed solvent and be heated to 45～50 ℃ of crystallizatioies; In WO0114379, also disclose with isopropanol/water mixed solvent and be heated to 60～65 ℃ of crystallizatioies in addition.Above mixed solvent crystallization method, or prepare for bulk drug crude product, or for the preparation of certain specific crystal formation crude product, above method is not good to the strong organic impurity removal effect of polarity, in addition, mixed solvent crystallization method process adopts higher heating steps, will greatly aggravate the oxidation of product, increases kind and the content of organic impurity.
Salt crystallization method, as 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), pemetrexed disodium crystal is separated out, the method is mainly removed the water-soluble impurity in pemetrexed disodium raw material, and the method does not need heating, can solve the problem that heats the product oxidation causing.But this method of saltouing is merely Shortcomings also, because the method is crystallization in aqueous phase system, therefore can only remove the water-soluble impurity that segment polarity is stronger, be difficult to be less than except depolarization the organic impurity of pemetrexed disodium.
The preparation prescription that contriver uses qualified after testing raw material to carry out pemetrexed disodium is studied, and while redissolving test, unexpected discovery occurs turbid phenomenon in solution, and placement occurs throw out after spending the night, and HPLC detects and also has no obvious degraded product.Through overtesting, got rid of the impact of auxiliary material, and then considered it is to introduce from raw material.
In sum, in prior art, lack a kind of excellent process, effectively remove the various impurity in pemetrexed disodium bulk drug, to meet the requirement of medicine registration to bulk drug limit of impurities.
Summary of the invention
The invention provides a kind of purification process of injection stage pemetrexed disodium, use this purification process can effectively solve the turbid phenomenon of redissolving while testing, more amazingly be, this purification process can effectively be removed the impurity in pemetrexed disodium bulk drug, makes purifying work become simple efficient.
The present invention is achieved through the following technical solutions:
A purification process for injection stage pemetrexed disodium, the method comprises the steps:
(1) pemetrexed disodium crude product is dissolved in sodium chloride aqueous solution;
(2) solution that organic solvent extraction step (1) forms;
(3) collect the aqueous solution that step (2) forms;
(4), to the aqueous solution of step (3), add gac, filtration;
(5) in the filtrate of step (4), add organic solvent, crystallization, washing, dry.
[0010]above-mentioned this purge process can repeat according to purification effect.
" pemetrexed disodium crude product " in above-mentioned purification step refers to the mixture of pemetrexed disodium content between 90～99.5%, but for pemetrexed disodium content lower than 90% bulk drug, optionally repeat above operation and also can realize purifying object; " aqueous solution " described in above-mentioned purification step is the aqueous solution of purified water; The concentration of the sodium chloride aqueous solution in above-mentioned purification step represents with weight percentage, and " gac " in above-mentioned purification step is needle-use activated carbon.
In above-mentioned purification step (1), the concentration of sodium chloride aqueous solution is 0.1-20%, concentration surpasses 20%, and the volume that dissolves the required sodium chloride aqueous solution of pemetrexed disodium crude product is larger, and in the extraction process of above-mentioned purification step (2), have sodium-chlor and separate out, product loss is more; Concentration is lower than 0.1%, its ability of removing impurity can reduce greatly, when the massfraction of sodium chloride aqueous solution is 0.3-5.0%, effect is better, and the concentration that best effect appears at sodium chloride aqueous solution is 0.9-2.0%, now, the consumption of organic solvent of the consumption of sodium chloride aqueous solution and step (2), step (5) is reasonable, cost is best, and preferably, in above-mentioned purification step (1), the concentration of sodium chloride aqueous solution is 0.3-5.0%; Most preferably, in above-mentioned purification step (1), the concentration of sodium chloride aqueous solution is 0.9-2.0%.
The add-on of sodium chloride aqueous solution in above-mentioned purification step (1), should be able to make pemetrexed disodium crude product dissolve completely, the volume of sodium chloride aqueous solution used is that the 2-10 of pemetrexed disodium crude product quality doubly can realize, though too much volume can be realized the object of dissolving, but step (2), the consumption of organic solvent of step (5) is larger, cost is higher, it is better when the volume of sodium chloride aqueous solution is 2-6 times of pemetrexed disodium crude product quality, the volume of best sodium chloride aqueous solution is 3-4 times of crude product quality, preferably, in above-mentioned purification step (1) volume of sodium chloride aqueous solution used be pemetrexed disodium crude product quality 2-6 doubly, most preferably, in above-mentioned purification step (1) volume of sodium chloride aqueous solution used be pemetrexed disodium crude product quality 3-4 doubly.
It is not the object that all solvents can be realized extraction in above-mentioned purification step (2), through contriver, screen, organic solvent described in above-mentioned purification step (2) is one or more in methylene dichloride, methyl acetate, ethyl acetate, propyl acetate, through considering the factors such as character of cost, recovering state, product impurity, the effect of finding methylene dichloride is best, preferably, the organic solvent described in above-mentioned purification step (2) is methylene dichloride.
In above-mentioned purification step (4), the consumption of gac can be the 0.1-10% of pemetrexed disodium crude product quality, the consumption of gac is less than 0.1%, do not reach decolouring, absorption, the effect of removal of impurities, the consumption of gac is greater than 10% can adsorb pemetrexed disodium, through contriver, screen, in above-mentioned purification step (4), when the consumption of gac is the 1-5% of pemetrexed disodium crude product quality, decolouring, absorption, the effect of removal of impurities is best, the pemetrexed disodium crude product of absorption is minimum, preferably, in above-mentioned purification step (4), the consumption of gac is the 1-5% of pemetrexed disodium crude product quality.
Higher temperature in above-mentioned purification step (4), has certain promoter action for the absorption of gac, but has accelerated the oxidation of pemetrexed disodium simultaneously, and temperature is at 20-60
oduring C, both can promote the maximization of charcoal absorption, reduce the oxidation of pemetrexed disodium simultaneously, preferably, in above-mentioned purification step (4), temperature is 30-40
oc.
Organic solvent in above-mentioned purification step (5), should be able to be miscible with water, through contriver, screen, organic solvent described in above-mentioned purification step (5) is one or more in methyl alcohol, ethanol, Virahol, acetonitrile, tetrahydrofuran (THF), acetone, and the volume of organic solvent used is 1-10 times of pemetrexed disodium crude product quality.Through considering the use cost of organic solvent, impurity-eliminating effect, contriver finds, organic solvent in above-mentioned purification step (5) is ethanol, when its volume is 2-4 times of pemetrexed disodium crude product quality, best results, preferably the organic solvent in above-mentioned purification step (5) is ethanol, its volume is 2-4 times of pemetrexed disodium crude product quality.
accompanying drawing explanation
Fig. 1: unpurified crude product high performance liquid chromatography;
Fig. 2: the high-efficient liquid phase chromatogram of the inventive method (embodiment 1) purifying.
Embodiment
Below in conjunction with embodiment, further illustrate the present invention, but the scope of protection of present invention is not limited to the following example.
embodiment 1
Take pemetrexed disodium crude product (HPLC purity 97.68%) 10g, adding 20mL concentration is that 0.9% sodium chloride aqueous solution dissolves, if any muddiness, can add a little a bit to dissolving completely, the dichloromethane extraction twice of 30mL, stratification, collect combining water layer, heating water layer is to 30-40
oc, adds 5% gac, stirs 10-30 minute, filters, and in filtrate, adds 20mL ethanol, stirs and keeps temperature 30-40
oc, places 1-2 hour crystallization, and for filter cake, 50% washing with alcohol, dry, obtains pemetrexed disodium 8.78g, purity 99.73, maximum single assorted 0.08%.
embodiment 2
Take pemetrexed disodium crude product (HPLC purity 97.68%) 10g, adding 30mL concentration is that 1.0% sodium chloride aqueous solution dissolves, if any muddiness, can add a little a bit to dissolving completely, the dichloromethane extraction twice of 30mL, stratification, collect combining water layer, heating water layer is to 30-40
oc, adds 3% gac, stirs 10-30 minute, filters, and in filtrate, adds 20mL ethanol, stirs and keeps temperature 30-40
oc, places 1-2 hour crystallization, and for filter cake, 50% washing with alcohol, dry, obtains pemetrexed disodium 8.56g, purity 99.78, maximum single assorted 0.07%.
embodiment 3
Take pemetrexed disodium crude product (HPLC purity 97.68%) 10g, adding 40mL concentration is that 2.0% sodium chloride aqueous solution dissolves, if any muddiness, can add a little a bit to dissolving completely, the dichloromethane extraction twice of 40mL, stratification, collect combining water layer, heating water layer is to 30-40
oc, adds 1% gac, stirs 10-30 minute, filters, and in filtrate, adds 30mL ethanol, stirs and keeps temperature 30-40
oc, places 1-2 hour crystallization, and for filter cake, 50% washing with alcohol, dry, obtains pemetrexed disodium 8.64g, purity 99.89, maximum single assorted 0.05%.
embodiment 4
Take pemetrexed disodium crude product (HPLC purity 97.68%) 10g, adding 30mL concentration is that 2.0% sodium chloride aqueous solution dissolves, if any muddiness, can add a little a bit to dissolving completely, the dichloromethane extraction twice of 30mL, stratification, collect combining water layer, heating water layer is to 30-40
oc, adds 1% gac, stirs 10-30 minute, filters, and in filtrate, adds 30mL ethanol, stirs and keeps temperature 30-40
oc, places 1-2 hour crystallization, and for filter cake, 50% washing with alcohol, dry, obtains pemetrexed disodium 8.35g, purity 99.87, maximum single assorted 0.05%.
embodiment 5
Take pemetrexed disodium crude product (HPLC purity 97.68%) 10g, adding 40mL concentration is that 2.0% sodium chloride aqueous solution dissolves, if any muddiness, can add a little a bit to dissolving completely, the dichloromethane extraction twice of 40mL, stratification, collect combining water layer, heating water layer is to 30-40
oc, adds 5% gac, stirs 10-30 minute, filters, and in filtrate, adds 40mL ethanol, stirs and keeps temperature 30-40
oc, places 1-2 hour crystallization, and for filter cake, 50% washing with alcohol, dry, obtains pemetrexed disodium 7.83g, purity 99.91, maximum single assorted 0.03%.
Claims (4)
1. a purification process for injection stage pemetrexed disodium, is characterized in that the method comprises the steps:
(1) pemetrexed disodium crude product is dissolved in sodium chloride aqueous solution;
(2) solution that organic solvent extraction step (1) forms;
(3) collect the aqueous solution that step (2) forms;
(4) aqueous solution to step (3) adds gac, filtration,
(5) in the filtrate of step (4), add organic solvent, crystallization, washing, dry.
2. the purification process of injection stage pemetrexed disodium as claimed in claim 1, is characterized in that:
In step (1), the concentration of sodium chloride aqueous solution is 0.1-20%, and the volume of sodium chloride aqueous solution used is 2-10 times of pemetrexed disodium crude product quality;
Organic solvent in step (2) is one or more in methylene dichloride, methyl acetate, ethyl acetate, propyl acetate;
Temperature in step (4) is 20-60
oc, the consumption of gac is the 0.1-10% of pemetrexed disodium crude product quality, in step (5), organic solvent is one or more in methyl alcohol, ethanol, Virahol, acetonitrile, tetrahydrofuran (THF), acetone, and the volume of organic solvent is 1-10 times of pemetrexed disodium crude product quality.
3. the purification process of a kind of injection stage pemetrexed disodium as claimed in claim 2, is characterized in that:
In step (1), the concentration of sodium chloride aqueous solution is 0.3-3.0%, and the volume of sodium chloride aqueous solution used is 2-6 times of pemetrexed disodium crude product quality;
Organic solvent in step (2) is methylene dichloride;
Temperature in step (4) is 30-40
oc, the consumption of gac is the 1-5% of pemetrexed disodium crude product quality, and in step (5), organic solvent is ethanol, and the volume of organic solvent is 2-4 times of pemetrexed disodium crude product quality.
4. the purification process of a kind of injection stage pemetrexed disodium as claimed in claim 3, is characterized in that:
In step (1), the concentration of sodium chloride aqueous solution is 0.9-2.0%, and the volume of sodium chloride aqueous solution used is 2-4 times of pemetrexed disodium crude product quality.
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| JPWO2019244965A1 (en) * | 2018-06-20 | 2020-06-25 | 日本化薬株式会社 | Pemetrexed sodium injection solution formulation and method for producing the same |
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