CN104098573A - Pemetrexed salt and preparation method thereof - Google Patents
Pemetrexed salt and preparation method thereof Download PDFInfo
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- CN104098573A CN104098573A CN201310122869.9A CN201310122869A CN104098573A CN 104098573 A CN104098573 A CN 104098573A CN 201310122869 A CN201310122869 A CN 201310122869A CN 104098573 A CN104098573 A CN 104098573A
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- pemetrexed
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- 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
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Abstract
The invention discloses a pemetrexed salt and a preparation method and use thereof, the pemetrexed salt can be dipotassium salt, arginine salt, heme-L-lysinate salt and tromethamine salt of the pemetrexed, and the pemetrexed salt can be used for treatment of various cancers such as mesothelioma, lung cancer and the like.
Description
Technical field
The present invention relates to synthetic organic chemistry and pharmaceutical field, be specifically related to pemetrexed salt and preparation method thereof, and the purposes of pemetrexed salt.
Background technology
Pemetrexed (Pemetrexed) and salt thereof are open relies on as one kind of multiple folic acid the strong inhibitor that enzyme comprises thymidylate synthetase (TS), Tetrahydrofolate dehydrogenase (DHFR) and glycinamide ribonucleotide transformylase (GARFT); as reports such as EP334636, EP432677, CN1552713, CN101033227, there is antitumour activity.
The disodium salt of pemetrexed, be that pemetrexed disodium (formula I compound) goes on the market in states such as China, the U.S., European Union as anticarcinogen, pemetrexed disodium has four indications at approved aspect treatment cancer at present: (1) and cisplatin combined medication, treat inoperable malignant pleural mesothelioma, pemetrexed disodium is that first for the treatment of malignant pleural mesothelioma is also a current unique medicine; (2), separately for local late period of second line treatment or Metastatic Nsclc, due to pemetrexed disodium treatment nonsmall-cell lung cancer determined curative effect, side effect is less, has become the standard drug that this indication is new; (3) with cisplatin combined medication first-line treatment advanced Non-small cell lung; (4) maintain treatment late period or the non-squama cancer of transitivity type nonsmall-cell lung cancer, pemetrexed disodium is first medicine with this indication.In addition, its research that is used for the treatment of intestinal cancer, carcinoma of the pancreas, incidence cancer, cancer of the stomach, bladder cancer, mammary cancer etc. just in II, III phase are clinical, is expected to soon the treatment for these cancers.
In recent years, to pemetrexed disodium, research is found, it can produce impurity by being oxidized and being hydrolyzed two approach in preparation, storage with in using, and in the file that this point is gone on the market at the EMEA of European Union approval pemetrexed disodium, has carried out explaining (http://www.emea.eu.int//humandocs/PDFs/ EPAR/alimta/102004en1.pdf.).Therefore, find the research of better pemetrexed salt shape and carrying out always, CN1552713 discloses magnesium, calcium salt, meglumine and the amido glucosamine salt of pemetrexed; CN101033227 discloses the ethylenediamine salt of pemetrexed; CN101691371 discloses the thiocarbamide salt of pemetrexed.Magnesium in above salt type, calcium salt are water-soluble poor; Meglumine, the very easily moisture absorption of amido glucosamine salt, preserve inconvenience; Ethylenediamine salt toxicity is larger.The inventor passes through the preparation of different pemetrexed salts, screening, comparison, pleasantly surprised discovery pemetrexed di-potassium, arginic acid salt, lysine salt and tromethamine salt, the natrium brine dissolubility that their water-soluble ratio has gone on the market is better, and easily preserve, for the formulation manufacture of pemetrexed provides more choices.
Summary of the invention
The object of the present invention is to provide a kind of di-potassium, arginic acid salt, lysine salt, tromethamine salt of pemetrexed.
For realizing the object of the invention described above, provide following embodiment.
In one embodiment, the invention provides the pemetrexed di-potassium suc as formula II.
In another embodiment, the invention provides as the organic salt of the pemetrexed of formula III, wherein, in formula III, M is arginine, Methionin or Trometamol.
III
In the above-described embodiment, described arginine comprises L-arginine, D-Arg or their mixture, preferred D, and L-arginine, described Methionin comprises 1B, D-Lys or their mixture, preferred D, 1B.
Another object of the present invention has been to provide a kind of preparation method who prepares pemetrexed di-potassium, arginic acid salt, lysine salt and tromethamine salt.
In one embodiment, the method for preparing pemetrexed di-potassium of the present invention, comprises pemetrexed is reacted and made with the basic cpd that contains potassium ion in solvent.
In the above-described embodiment, the described basic cpd containing potassium ion is selected from potassium hydroxide, salt of wormwood, saleratus, isocaprylic acid potassium etc. or their mixture, preferably potassium hydroxide or salt of wormwood.Described solvent includes but not limited to that water, organic solvent are as comprised ketone, ester class, ethers, alcohols, nitrile, halo alkanes, amides, sulfone class, hydro carbons etc., as acetone, ethyl acetate, methyl acetate, tetrahydrofuran (THF), dioxane, ether, sherwood oil, methyl alcohol, ethanol, Virahol, ethylene glycol, acetonitrile, methylene dichloride, trichloromethane, tetrachloromethane, N, dinethylformamide, N,N-dimethylacetamide, methyl-sulphoxide, normal hexane, hexanaphthene, pentamethylene, benzene,toluene,xylene etc. or their mixture.
In yet another embodiment, the present invention prepares the method for arginic acid salt, lysine salt or the tromethamine salt of pemetrexed, comprises the following steps:
(1) pemetrexed is become to solution with solvent;
(2) arginine, Methionin or Trometamol are mixed to reaction with the solution of (1);
(3) separation obtains pemetrexed arginic acid salt, pemetrexed lysine salt or pemetrexed tromethamine salt.
In above-mentioned another embodiment, the arginic acid salt of preparing pemetrexed of the present invention, the method of lysine salt or tromethamine salt, described solvent includes but not limited to water, organic solvent is as comprised ketone, ester class, ethers, alcohols, nitrile, halo alkanes, amides, sulfone class, hydro carbons etc., as acetone, ethyl acetate, methyl acetate, tetrahydrofuran (THF), dioxane, ether, sherwood oil, methyl alcohol, ethanol, Virahol, ethylene glycol, acetonitrile, methylene dichloride, trichloromethane, tetrachloromethane, N, dinethylformamide, N, N-N,N-DIMETHYLACETAMIDE, methyl-sulphoxide, normal hexane, hexanaphthene, pentamethylene, benzene, toluene, dimethylbenzene etc. or their mixture, described arginine comprises L-arginine, D-Arg or their mixture, preferred D, L-arginine, described Methionin comprises 1B, D-Lys or their mixture, preferred D, 1B.
In above-mentioned another embodiment, method of the present invention, the mixing that step (2) is described, its mode can be that arginine, Methionin or Trometamol are added in the solution containing pemetrexed, also can be that the solution that contains pemetrexed is joined in the solution containing potassium hydroxide, arginine, Methionin or Trometamol, arginine, Methionin and Trometamol can be also that solid form participates in reaction.In above-mentioned another embodiment, method of the present invention, the described sepn process of step (3) is conventional post-treating method, as crystallization, filtration, concentrated, lyophilize etc.
Pemetrexed can be prepared by methods such as published US Patent No. 4996206 and US5028608, introduces in full reference of the present invention.
Another object of the present invention has been to provide a kind of pharmaceutical composition, contains pemetrexed di-potassium and pharmaceutical excipient, pemetrexed arginic acid salt and pharmaceutical excipient, pemetrexed lysine salt and pharmaceutical excipient or pemetrexed tromethamine salt and pharmaceutical excipient.
The invention provides a kind of pharmaceutical composition, the pemetrexed di-potassium that comprises effective therapeutic dose, pemetrexed essence ammonia salt, pemetrexed lysine salt or pemetrexed tromethamine salt and pharmaceutical excipient.Be generally that a kind of and one or more pharmaceutical excipients in above-mentioned four kinds of salt for the treatment of significant quantity are made to pharmaceutical composition or preparation, this pharmaceutical composition or preparation are that the mode to know in pharmacy field is prepared.
Said preparation comprises: powder pin, capsule, granule, oral liquid and various tablet are as formulations such as slow releasing tablet, buccal tablet, orally disintegrating tablet, chewable tablet, effervescent tablets.Described composition or the dosage of preparation are adjusted according to the character of disease and seriousness, route of administration and patient's age, body weight etc., change, in single or divided doses in every day between 0.1mg to 1g.
Another object of the present invention has been to provide the application in the various cancer drugs of preparation treatment by pemetrexed di-potassium, pemetrexed arginic acid salt, pemetrexed lysine salt or pemetrexed tromethamine salt, as the application in diseases such as lung cancer, mesothelioma, intestinal cancer, carcinoma of the pancreas, incidence cancer, cancer of the stomach, bladder cancer, mammary cancer.
The technique effect producing in order to further illustrate pemetrexed salt of the present invention, is compared as follows its each salt type base character:
Embodiment
Following examples are explained the present invention for further, but do not limit the scope of the invention.
Embodiment 1
The preparation of pemetrexed di-potassium
In reaction vessel, add 2.0g pemetrexed, add 20ml deionized water to suspend, the potassium hydroxide aqueous solution tune pH9-10 that is added dropwise to 5N under stirring makes molten clear, add 100ml ethanol, stirring and crystallizing, filters, vacuum-drying obtains pemetrexed di-potassium solid 1.9g, yield 80.5%.
Embodiment 2
The preparation of pemetrexed di-potassium
In reaction vessel, add 2.0g pemetrexed, add 30ml DMF molten clear, solution joins containing potassium hydroxide 0.6g, in the acetone 300ml that moisture is 10%, and stirring and crystallizing, filter, vacuum-drying obtains pemetrexed di-potassium solid 1.7g, yield 72.0%.
Embodiment 3
The preparation of pemetrexed di-potassium
In reaction vessel, add 2.0g pemetrexed, add 12ml deionized water to suspend, add 0.6g potassium hydroxide solid under stirring, add 60ml acetonitrile stirring and crystallizing, filter, vacuum-drying obtains pemetrexed di-potassium solid 1.5g, yield 63.6%.
Embodiment 4
The preparation of pemetrexed di-potassium
In reaction vessel, add 2.0g pemetrexed, add 20ml deionized water to suspend, under stirring, being added dropwise to 20% solution of potassium carbonate, to adjust pH9-10 to make molten clear, add 120ml Virahol, stirring and crystallizing, filters, vacuum-drying obtains pemetrexed di-potassium solid 2.0g, yield 84.7%.
Embodiment 5
The preparation of pemetrexed di-potassium
In reaction vessel, add 2.0g pemetrexed, add 20ml deionized water to suspend, add 1.8g isocaprylic acid potassium, then add 100ml acetone under stirring, stirring and crystallizing, filters, and vacuum-drying obtains pemetrexed di-potassium solid 1.5g, yield 63.6%.
Embodiment 6
The preparation of pemetrexed L-arginine salt
In reaction vessel, add 3.0g pemetrexed, add 30ml deionized water, add 2.5g L arginine under stirring, 40 ℃ are evaporated to dryly, obtain 5.7g pemetrexed L-arginine salt, yield 100.0%.
Embodiment 7
The preparation of pemetrexed D-Arg salt
In reaction vessel, add 3.0g pemetrexed, add 30ml deionized water, add 2.5g D arginine under stirring, lyophilize obtains 5.6g pemetrexed D-Arg salt, yield 100.0%.
Embodiment 8
Pemetrexed D, the preparation of L-arginine salt
In reaction vessel, add 3.0g pemetrexed, add 50ml methyl-sulphoxide to dissolve, add 2.5g D, L-arginine, then add 30ml isopropyl ether stirring and crystallizing, and to filter, vacuum-drying obtains pemetrexed dipotassium D, L-arginine salt 4.5g, yield 82.7%.
Embodiment 9
The preparation of pemetrexed 1B salt
In reaction vessel, add 2.0g pemetrexed, add 50ml deionized water, add 1.5g L Methionin under stirring, 40 ℃ are evaporated to dryly, obtain 3.6g pemetrexed 1B salt, yield 100.0%.
Embodiment 10
The preparation of pemetrexed D-Lys salt
In reaction vessel, add 2.0g pemetrexed, add 25ml deionized water, under stirring, add 1.5g D-Lys, lyophilize to obtain 3.7g pemetrexed D-Lys salt, yield 100.0%.
Embodiment 11
Pemetrexed D, the preparation of 1B salt
In reaction vessel, add 2.0g pemetrexed, add 30ml N,N-dimethylacetamide to dissolve, add 1.5g D, 1B, then add 70ml normal heptane stirring and crystallizing, and to filter, vacuum-drying obtains pemetrexed D, 1B salt 2.8g, yield 83.1%.
Embodiment 12
The preparation of pemetrexed tromethamine salt
In reaction vessel, add 2.0g pemetrexed, add 30ml N,N-dimethylacetamide to dissolve, add 0.7 Trometamol, then add 90ml normal heptane stirring and crystallizing, filter, vacuum-drying obtains pemetrexed tromethamine salt 2.2g, yield 85.6%.
Embodiment 13
The preparation of pemetrexed di-potassium tablet
Pemetrexed di-potassium ... 15g
Lactose monohydrate ... 25g
Magnesium Stearate ... 0.5g
W-Gum ... 60g
Maltodextrin ... 2g
Pemetrexed di-potassium and lactose monohydrate, W-Gum, maltodextrin are mixed and made into softwood, sieve, granulate, add Magnesium Stearate, whole grain, mix, compressing tablet.
Embodiment 14
The preparation of pemetrexed di-potassium freeze-dried powder
Pemetrexed di-potassium ... 15g
Dextran ... 60g
Water for injection ... 1500ml
Add water for injection to dissolve pemetrexed di-potassium, add dextran to dissolve and mix again, filtration, bottling, lyophilize, gland.
According to said method can prepare pemetrexed L-arginine salt, D-Arg salt, D, L-arginine salt, 1B salt, D-Lys salt and D, the powder pin of 1B salt.
Embodiment 15
The preparation of pemetrexed di-potassium capsule
Pemetrexed di-potassium ... 15g
Microcrystalline Cellulose ... 80g
Micropowder silica gel ... 3g
Talcum powder ... 3g
Pemetrexed di-potassium and Microcrystalline Cellulose, differential silica gel and talcum powder are mixed, sieve, dress up capsule.
Embodiment 16
The preparation of pemetrexed L-arginine salt oral liquid
Pemetrexed L-arginine salt ... 15g
Asccharin ... 0.3g
Essence ... 0.05g
Purified water ... 1500ml
By pemetrexed L-arginine salt, asccharin, essence add purified water dissolve, mix, again with purified water dilution, packing and get final product.
Embodiment 17
The preparation of pemetrexed 1B salt particle agent
Pemetrexed 1B salt ... 15g
Soluble starch ... 100g
Icing Sugar ... 15g
Essence ... 0.05g
By pemetrexed 1B salt, soluble starch,, Icing Sugar, essence mix, sieve, granulation, packing and get final product.
Embodiment 18
The preparation of pemetrexed tromethamine salt oral liquid
Pemetrexed L-arginine salt ... 10g
Asccharin ... 0.2g
Essence ... 0.04g
Purified water ... 1000ml
By pemetrexed tromethamine salt, asccharin, essence add purified water dissolve, mix, again with purified water dilution, packing and get final product.
Claims (10)
1. suc as formula a pemetrexed di-potassium of II,
。
2. a preparation method for pemetrexed di-potassium, comprises pemetrexed is reacted and made with the basic cpd that contains potassium ion in solvent.
3. method as claimed in claim 2, the described basic cpd containing potassium ion is selected from potassium hydroxide, salt of wormwood, saleratus, isocaprylic acid potassium and their mixture, preferably potassium hydroxide, salt of wormwood or isocaprylic acid potassium.
4. as a pemetrexed organic salt for formula III,
Wherein, M is arginine, Methionin or Trometamol.
5. pemetrexed organic salt as claimed in claim 4, described arginine is the mixture of L-arginine, D-Arg or their arbitrary proportions; Described Methionin is the mixture of 1B, D-Lys or their arbitrary proportions.
6. pemetrexed organic acid salt as claimed in claim 4, described arginine is D, L-arginine, described Methionin is D, 1B.
7. a method of preparing the pemetrexed organic salt of claim 3, comprises pemetrexed is reacted and made with the organic compound that is selected from arginine, Methionin and Trometamol in solvent.
8. method as claimed in claim 7, described arginine is L-arginine, D-Arg or D, the mixture of their arbitrary proportions of L-arginine person; Described Methionin is 1B, D-Lys or D, 1B.
9. a pharmaceutical composition, comprises pemetrexed dipotassium in claim 1 or pemetrexed organic salt and the pharmaceutical excipient of claim 4.
10. the pemetrexed dipotassium of claim 1 and the pemetrexed arginic acid salt of claim 4, lysine salt and the pemetrexed tromethamine salt application in preparation treatment cancer drug.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105726492A (en) * | 2014-12-08 | 2016-07-06 | 博瑞生物医药（苏州）股份有限公司 | Freeze-dried powder injection of pemetrexed dipotassium and preparation method thereof |
| JP2016521732A (en) * | 2013-06-14 | 2016-07-25 | シントン・ベスローテン・フェンノートシャップ | Arginine salt of stable anticancer agent and composition containing the same |
| CN110128427A (en) * | 2018-02-09 | 2019-08-16 | 鲁南制药集团股份有限公司 | Pemetrexed valine salt |
| CN110128428A (en) * | 2018-02-09 | 2019-08-16 | 鲁南制药集团股份有限公司 | Pemetrexed alanine salt |
| CN110128426A (en) * | 2018-02-09 | 2019-08-16 | 鲁南制药集团股份有限公司 | Pemetrexed glutamate |
| US11793813B2 (en) | 2016-02-19 | 2023-10-24 | Eagle Pharmaceuticals, Inc. | Pemetrexed formulations |
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| JP2016521732A (en) * | 2013-06-14 | 2016-07-25 | シントン・ベスローテン・フェンノートシャップ | Arginine salt of stable anticancer agent and composition containing the same |
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Application publication date: 20141015 |