CN102838602B - Pemetrexed oxide and preparation method thereof - Google Patents
Pemetrexed oxide and preparation method thereof Download PDFInfo
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Abstract
The present invention relates to the oxidation impurities compound of a kind of pemetrexed or its disodium salt, i.e. pemetrexed oxide A and disodium salt compound thereof and U.S. song plug oxide B and disodium salt thereof, and their preparation and purposes in pemetrexed disodium quality control.
Description
Technical field
The present invention relates to synthetic organic chemistry and pharmaceutical field, be specifically related to a kind of pemetrexed oxidation impurities i.e. pemetrexed oxide and preparation thereof and the purposes in pemetrexed disodium quality control.
Background technology
(compound of formula I works as M for pemetrexed (Pemetrexed) and salt thereof1 +And M2 +It is H+Time be pemetrexed) open include thymidylate synthetase (TS), dihydrofolate reductase (DHFR) and the strong inhibitor of glycinamide ribonucleotide transformylase (GARFT) as one kind of multiple folate-dependant enzymes; such as EP334636; EP432677; CN1552713; CN101033227 etc. report, have active anticancer.
In formula:
M1 +And M2 +Can be monovalent cation, such as: H+、Li+、Na+、K+Or monoamine cation is (such as NH4 +, dimethylamine ion, diethylamine ion, meglumine ion, amido glucose ion etc.) etc., M1 +And M2 +Can be identical or different；M1 +And M2 +Can also join together to represent bivalent cation, such as: Ca2+、Mg2+、Zn2+Or diamino cation (such as ethylenediamine ion, propane diamine ion) etc..
The disodium salt of pemetrexed, i.e. pemetrexed disodium (Formula II compound) as anticarcinogen in China, the U.S., European Union etc.
State lists, at present, pemetrexed disodium approved in terms for the treatment of cancer has four indications: (1) and cisplatin combined medication, treats inoperable malignant pleural mesothelioma, and it is also only one medicine that pemetrexed disodium is first for the treatment of malignant pleural mesothelioma；(2) being individually used for second line treatment Locally Advanced or Metastatic Nsclc, owing to pemetrexed disodium treats nonsmall-cell lung cancer determined curative effect, side effect is less, it has also become the standard drug that this indication is new；(3) with cisplatin combined medication first-line treatment advanced Non-small cell lung；(4) maintaining treatment late period or transitivity non-scale cancer type nonsmall-cell lung cancer, pemetrexed disodium is first medicine with this indication.It addition, it is for treating the research of intestinal cancer, cancer of pancreas, incidence cancer, gastric cancer, bladder cancer, breast carcinoma etc. just in II, III phase clinic, it is expected to soon for the treatment of these cancers.
Impurity research is an important content of medicament research and development, it is directly connected to quality control and the safety of medicine, as is known to persons skilled in the art, by impurity structure in identification of pharmaceutical active composition or pharmaceutical end product and the amount determining impurity, the control to product quality and safety can be greatly reinforced.Pemetrexed and pharmaceutical salts major impurity in preparing, storing and use thereof are to be produced by oxidation and two approach of hydrolysis, and this point also has carried out stating (http://www.emea.eu.int//humandocs/PDFs/EPAR/alimta/102004enl.pd f.) in the file that European Union EMEA approval pemetrexed disodium lists.But, the not open pemetrexed of existing report or its salt oxidized after create which kind of impurity (by-product or catabolite), do not have document to disclose chemical constitution and the title of its oxidation impurities yet.Identify the most further, separate and oxidation impurities in chemical characterization pemetrexed disodium is to improving pemetrexed disodium quality control level further and safety has great significance.
Summary of the invention
Object of the present invention is to provide the oxidation impurities compound in pemetrexed and salt thereof, described impurity compound is the compound of formula III and/or the compound of formula IV and their chiral isomer thereof or its salt, wherein, in formula, A-1, A-2, A-3, B-1, B-2, B-3 are chiral centre.
These impurity be pemetrexed and pharmaceutical salts thereof preparation, store and use in produced by oxidation and/or two approach of hydrolysis, these impurity are presented in acid or salt.
Chiral centre A-1, A-2 of formula III compound of the present invention lays respectively at 5 and 6 of its pyrrolo-[2,3-d] pyrimidine radicals, and chiral centre B-1, B-2 of described IV formula compound lays respectively at 5 and 6 of its pyrrolo-[2,3-d] pyrimidine radicals.
For realizing the purpose of the invention described above, it is provided that following specific embodiments:
In one embodiment, the compound of a kind of formula III and chiral isomer thereof or their salt,
In formula, chiral centre (A-1, A-2) is (R, R) type, (S, S) type or their mixed type, chiral centre A-3 be S type, R type or their mixed type, preferably chiral centre A-3 be S type (i.e. Pidolidone).
Above-mentioned formula III compound is the oxidation impurities of pemetrexed and salt thereof; its chemistry is entitled: N-[4-[2-[2-amino-4; 7-dihydro-5; 6-epoxy-1-hydroxyl-4-oxo-1H-pyrrolo-[2; 3-d] pyrimidine-5-base] ethyl] benzoyl]-glutamic acid (hereinafter referred to as " oxide A "); wherein, described salt includes alkali formula addition salts and acid addition salt.
Alkali formula addition salts for oxide A includes monovalent cation salt and divalent cation salt etc., wherein, monovalent cation salt includes sodium salt, potassium salt, lithium salts, monoamine cationic salts (such as ammonia salt, dimethylamine salt, diethylamine energy, meglumine salt, amido glucosamine salt etc.) etc. or their salt-mixture；Wherein farther include the double ion salt of these monovalent cations, isolated alite, three ion salt or their mixture.In these monovalent cation salt, particular certain cancers, potassium salt, the double ion salt of lithium salts, i.e. disodium salt, di-potassium and dilithium salt, more preferably disodium salt；Divalent cation salt includes calcium salt, magnesium salt, zinc salt, and diamino salt (such as ethylenediamine salt, propane diamine salt etc.) etc., preferred salt is sodium salt, more preferably disodium salt.
Acid addition salt for oxide A includes hydrochlorate, sulfate, hydrobromate, hydriodate, mesylate, tosilate etc..
The formula III compound or its salt of the invention described above, specifically includes following compound:
N-[4-[2-[2-amino-4; 7-dihydro-5; 6-epoxy-1-hydroxyl-4-oxo-1H-pyrrolo-[2,3-d] pyrimidine-5-base] ethyl] benzoyl]-Pidolidone (i.e. chiral centre A-3 is S configuration, referred to as " pemetrexed oxide A ")
N-[4-[2-[2-amino-4,7-dihydro-5,6-epoxy-1-hydroxyl-4-oxo-1H-pyrrolo-[2,3-d] pyrimidine-5-base] ethyl] benzoyl]-D-Glu (i.e. chiral centre A-3 is R configuration)
(5R; 6R)-N-[4-[2-[2-amino-4,7-dihydro-5,6-epoxy-1-hydroxyl-4-oxo-1H-pyrrolo-[2; 3-d] pyrimidine-5-base] ethyl] benzoyl]-Pidolidone (referred to as " (5R, 6R)-pemetrexed oxide A ")
(5S; 6S)-N-[4-[2-[2-amino-4,7-dihydro-5,6-epoxy-1-hydroxyl-4-oxo-1H-pyrrolo-[2; 3-d] pyrimidine-5-base] ethyl] benzoyl]-Pidolidone (referred to as " (5S, 6S)-pemetrexed oxide A ")
N-[4-[2-[2-amino-4,7-dihydro-5,6-epoxy-1-hydroxyl-4-oxo-1H-pyrrolo-[2,3-d] pyrimidine-5-base] ethyl] benzoyl]-Pidolidone disodium salt (referred to as " pemetrexed oxide A disodium salt ")
N-[4-[2-[2-amino-4,7-dihydro-5,6-epoxy-1-hydroxyl-4-oxo-1H-pyrrolo-[2,3-d] pyrimidine-5-base] ethyl] benzoyl]-D-Glu disodium salt (i.e. chiral centre A-3 is R configuration)
(5R; 6R)-N-[4-[2-[2-amino-4; 7-dihydro-5; 6-epoxy-1-hydroxyl-4-oxo-1H-pyrrolo-[2; 3-d] pyrimidine-5-base] ethyl] benzoyl]-Pidolidone disodium salt (referred to as " (5R, 6R)-pemetrexed oxide A disodium salt ")
(5S; 6S)-N-[4-[2-[2-amino-4; 7-dihydro-5; 6-epoxy-1-hydroxyl-4-oxo-1H-pyrrolo-[2; 3-d] pyrimidine-5-base] ethyl] benzoyl]-Pidolidone disodium salt (referred to as " (5S, 6S)-pemetrexed oxide A disodium salt ")
N-[4-[2-[2-amino-4,7-dihydro-5,6-epoxy-1-hydroxyl-4-oxo-1H-pyrrolo-[2,3-d] pyrimidine-5-base] ethyl] benzoyl]-Pidolidone di-potassium (referred to as " pemetrexed oxide A di-potassium ")
N-[4-[2-[2-amino-4,7-dihydro-5,6-epoxy-1-hydroxyl-4-oxo-1H-pyrrolo-[2,3-d] pyrimidine-5-base] ethyl] benzoyl]-D-Glu di-potassium
(5R; 6R)-N-[4-[2-[2-amino-4; 7-dihydro-5; 6-epoxy-1-hydroxyl-4-oxo-1H-pyrrolo-[2; 3-d] pyrimidine-5-base] ethyl] benzoyl]-Pidolidone di-potassium (referred to as " (5R, 6R)-pemetrexed oxide A di-potassium ")
(5S; 6S)-N-[4-[2-[2-amino-4; 7-dihydro-5; 6-epoxy-1-hydroxyl-4-oxo-1H-pyrrolo-[2; 3-d] pyrimidine-5-base] ethyl] benzoyl]-Pidolidone di-potassium (referred to as " (5S, 6S)-pemetrexed oxide A di-potassium ")
N-[4-[2-[2-amino-4,7-dihydro-5,6-epoxy-1-hydroxyl-4-oxo-1H-pyrrolo-[2,3-d] pyrimidine-5-base] ethyl] benzoyl]-Pidolidone dilithium salt (referred to as " pemetrexed oxide A dilithium salt ")
N-[4-[2-[2-amino-4,7-dihydro-5,6-epoxy-1-hydroxyl-4-oxo-1H-pyrrolo-[2,3-d] pyrimidine-5-base] ethyl] benzoyl]-D-Glu dilithium salt
(5R; 6R)-N-[4-[2-[2-amino-4; 7-dihydro-5; 6-epoxy-1-hydroxyl-4-oxo-1H-pyrrolo-[2; 3-d] pyrimidine-5-base] ethyl] benzoyl]-Pidolidone dilithium salt (referred to as " (5R, 6R)-pemetrexed oxide A dilithium salt ")
(5S; 6S)-N-[4-[2-[2-amino-4; 7-dihydro-5; 6-epoxy-1-hydroxyl-4-oxo-1H-pyrrolo-[2; 3-d] pyrimidine-5-base] ethyl] benzoyl]-Pidolidone dilithium salt (referred to as " (5S, 6S)-pemetrexed oxide A dilithium salt ")
At another specific embodiments, the compound of a kind of formula IV and chiral isomer, raceme or their salt,
In formula, chiral centre B-1, B-2 and B-3 all include S type, R type or their mixed type.
The compound of above-mentioned formula IV is the oxidation impurities of pemetrexed and salt thereof; its chemistry is entitled: N-[4-[2-[2-amino-4; 7-dihydro-4-oxo-1,5,6-trihydroxy-1H-pyrrolo-es [2; 3-d] pyrimidine-5-base] ethyl] benzoyl]-glutamic acid (hereinafter referred to as thing " oxide B "); or its salt, wherein, for salt; owing to having acidic-group and basic group in formula IV compound simultaneously, therefore this salt includes alkali formula addition salts and acid addition salt.
Alkali formula addition salts for oxide B includes monovalent cation salt and divalent cation salt etc., wherein, monovalent cation salt includes sodium salt, potassium salt, lithium salts, monoamine cationic salts (such as ammonia salt, dimethylamine salt, diethylamine salt, meglumine salt, amido glucosamine salt etc.) etc. or their salt-mixture；Wherein farther include the double ion salt of these monovalent cations, isolated alite and three ion salt.In these monovalent cation salt, particular certain cancers, potassium salt, the double ion salt of lithium salts, i.e. disodium salt, di-potassium and dilithium salt, more preferably disodium salt；Divalent cation salt includes calcium salt, magnesium salt, zinc salt, and diamino salt (such as ethylenediamine salt, propane diamine salt etc.) etc., preferred salt is sodium salt, more preferably disodium salt.
Acid addition salt for oxide B includes hydrochlorate, sulfate, hydrobromate, hydriodate, mesylate, tosilate etc..
The compound or its salt of the formula IV that the present invention is above-mentioned, including following compound or its salt:
N-[4-[2-[2-amino-4,7-dihydro-4-oxo-1,5,6-trihydroxy-1H-pyrrolo-[2,3-d] pyrimidine-5-bases] ethyl] benzoyl]-Pidolidone (referred to as " pemetrexed oxide B ")
N-[4-[2-[2-amino-4,7-dihydro-4-oxo-1,5,6-trihydroxy-1H-pyrrolo-[2,3-d] pyrimidine-5-bases] ethyl] benzoyl]-D-Glu (i.e. chiral centre B-3 is R configuration)
(5S, 6S)-N-[4-[2-[2-amino-4,7-dihydro-4-oxo-1; 5; 6-trihydroxy-1H-pyrrolo-[2,3-d] pyrimidine-5-base] ethyl] benzoyl]-Pidolidone (referred to as " (5S, 6S)-pemetrexed oxide B ")
(5S, 6R)-N-[4-[2-[2-amino-4,7-dihydro-4-oxo-1; 5; 6-trihydroxy-1H-pyrrolo-[2,3-d] pyrimidine-5-base] ethyl] benzoyl]-Pidolidone (referred to as " (5S, 6R)-pemetrexed oxide B ")
(5R, 6S)-N-[4-[2-[2-amino-4,7-dihydro-4-oxo-1; 5; 6-trihydroxy-1H-pyrrolo-[2,3-d] pyrimidine-5-base] ethyl] benzoyl]-Pidolidone (referred to as " (5R, 6S)-pemetrexed oxide B ")
(5R, 6R)-N-[4-[2-[2-amino-4,7-dihydro-4-oxo-1; 5; 6-trihydroxy-1H-pyrrolo-[2,3-d] pyrimidine-5-base] ethyl] benzoyl]-Pidolidone (referred to as " (5R, 6R)-pemetrexed oxide B ")
N-[4-[2-[2-amino-4,7-dihydro-4-oxo-1,5,6-trihydroxy-1H-pyrrolo-[2,3-d] pyrimidine-5-bases] ethyl] benzoyl]-Pidolidone disodium salt (referred to as " pemetrexed oxide B disodium salt ")
N-[4-[2-[2-amino-4,7-dihydro-4-oxo-1,5,6-trihydroxy-1H-pyrrolo-[2,3-d] pyrimidine-5-bases] ethyl] benzoyl]-D-Glu disodium salt
(5S; 6S)-N-[4-[2-[2-amino-4; 7-dihydro-4-oxo-1; 5; 6-trihydroxy-1H-pyrrolo-[2; 3-d] pyrimidine-5-base] ethyl] benzoyl]-Pidolidone disodium salt (referred to as " (5S, 6S)-pemetrexed oxide B disodium salt ")
(5S; 6R)-N-[4-[2-[2-amino-4; 7-dihydro-4-oxo-1; 5; 6-trihydroxy-1H-pyrrolo-[2; 3-d] pyrimidine-5-base] ethyl] benzoyl]-Pidolidone disodium salt (referred to as " (5S, 6R)-pemetrexed oxide B disodium salt ")
(5R; 6S)-N-[4-[2-[2-amino-4; 7-dihydro-4-oxo-1; 5; 6-trihydroxy-1H-pyrrolo-[2; 3-d] pyrimidine-5-base] ethyl] benzoyl]-Pidolidone disodium salt (referred to as " (5R, 6S)-pemetrexed oxide B disodium salt ")
(5R; 6R)-N-[4-[2-[2-amino-4; 7-dihydro-4-oxo-1; 5; 6-trihydroxy-1H-pyrrolo-[2; 3-d] pyrimidine-5-base] ethyl] benzoyl]-Pidolidone disodium salt (referred to as " (5R, 6R)-pemetrexed oxide B disodium salt ")
N-[4-[2-[2-amino-4,7-dihydro-4-oxo-1,5,6-trihydroxy-1H-pyrrolo-[2,3-d] pyrimidine-5-bases] ethyl] benzoyl]-Pidolidone di-potassium (referred to as " pemetrexed oxide B di-potassium ")
N-[4-[2-[2-amino-4,7-dihydro-4-oxo-1,5,6-trihydroxy-1H-pyrrolo-[2,3-d] pyrimidine-5-bases] ethyl] benzoyl]-D-Glu di-potassium
(5S; 6S)-N-[4-[2-[2-amino-4; 7-dihydro-4-oxo-1; 5; 6-trihydroxy-1H-pyrrolo-[2; 3-d] pyrimidine-5-base] ethyl] benzoyl]-Pidolidone di-potassium (referred to as " (5S, 6S)-pemetrexed oxide B di-potassium ")
(5S; 6R)-N-[4-[2-[2-amino-4; 7-dihydro-4-oxo-1; 5; 6-trihydroxy-1H-pyrrolo-[2; 3-d] pyrimidine-5-base] ethyl] benzoyl]-Pidolidone di-potassium (referred to as " (5S, 6R)-pemetrexed oxide B di-potassium ")
(5R; 6S)-N-[4-[2-[2-amino-4; 7-dihydro-4-oxo-1; 5; 6-trihydroxy-1H-pyrrolo-[2; 3-d] pyrimidine-5-base] ethyl] benzoyl]-Pidolidone di-potassium (referred to as " (5R, 6S)-pemetrexed oxide B di-potassium ")
(5R; 6R)-N-[4-[2-[2-amino-4; 7-dihydro-4-oxo-1; 5; 6-trihydroxy-1H-pyrrolo-[2; 3-d] pyrimidine-5-base] ethyl] benzoyl]-Pidolidone di-potassium (referred to as " (5R, 6R)-pemetrexed oxide B di-potassium ")
N-[4-[2-[2-amino-4,7-dihydro-4-oxo-1,5,6-trihydroxy-1H-pyrrolo-[2,3-d] pyrimidine-5-bases] ethyl] benzoyl]-Pidolidone dilithium salt (referred to as " pemetrexed oxide B dilithium salt ")
N-[4-[2-[2-amino-4,7-dihydro-4-oxo-1,5,6-trihydroxy-1H-pyrrolo-[2,3-d] pyrimidine-5-bases] ethyl] benzoyl]-D-Glu dilithium salt
(5S; 6S)-N-[4-[2-[2-amino-4; 7-dihydro-4-oxo-1; 5; 6-trihydroxy-1H-pyrrolo-[2; 3-d] pyrimidine-5-base] ethyl] benzoyl]-Pidolidone dilithium salt (referred to as " (5S, 6S)-pemetrexed oxide B dilithium salt ")
(5S; 6R)-N-[4-[2-[2-amino-4; 7-dihydro-4-oxo-1; 5; 6-trihydroxy-1H-pyrrolo-[2; 3-d] pyrimidine-5-base] ethyl] benzoyl]-Pidolidone dilithium salt (referred to as " (5S, 6R)-pemetrexed oxide B dilithium salt ")
(5R; 6S)-N-[4-[2-[2-amino-4; 7-dihydro-4-oxo-1; 5; 6-trihydroxy-1H-pyrrolo-[2; 3-d] pyrimidine-5-base] ethyl] benzoyl]-Pidolidone dilithium salt (referred to as " (5R, 6S)-pemetrexed oxide B dilithium salt ")
(5R; 6R)-N-[4-[2-[2-amino-4; 7-dihydro-4-oxo-1; 5; 6-trihydroxy-1H-pyrrolo-[2; 3-d] pyrimidine-5-base] ethyl] benzoyl]-Pidolidone dilithium salt (referred to as " (5R, 6R)-pemetrexed oxide B dilithium salt ")
Said structure is the compound of formula III or formula IV, each compound may exist with the equilibrium mixture form of its tautomer, following partial structurtes formula represents and carries out tautomeric part structure in molecule, therefore, the compound of the present invention includes the forms such as corresponding change " 1-oxo; 4-oxo ", " 1-oxo, 4-hydroxyl ".
The formula III compound of the present invention and salt thereof or formula IV compound and salt thereof, it is separated into the purity with at least 0.01% in some embodiments, or the purity of at least 0.1%, or the purity of at least 1%, or the purity of at least 5%, or the purity of at least 10%, or the purity of at least 15%, or the purity of at least 25%, or the purity of at least 50%, or the purity of at least 75%, or the purity of at least 95%.This purity is generally the purity of HPLC area normalization method.
Above-mentioned oxide A or its salt (i.e. formula III compound) or oxide B or its salt (i.e. formula IV compound) can be presented in solids or solution.If but when oxide A or its salt (i.e. formula III compound) are present in aqueous solution, it can be converted into corresponding oxide B or its salt (i.e. formula IV compound), i.e.
It is a further object of the present invention to provide a kind of pemetrexed and the compositions of salt (compound of formula I) thereof, it is characterized in that: the content of compound of formula I is not less than 98%HPLC percent area, the total content of formula III compound is not more than 0.5%HPLC percent area, or/and the total content of formula IV compound is not more than 0.5%HPLC percent area.
Preferably, the pemetrexed of the present invention and the compositions of salt (compound of formula I) thereof, it is characterised in that: the content of compound of formula I is not less than 98%HPLC percent area, and the total content of formula III compound is not more than 0.5%HPLC percent area.
Preferably, the pemetrexed of the present invention and the compositions of salt (compound of formula I) thereof, it is characterised in that: the content of compound of formula I is not less than 98%HPLC percent area, and the total content of formula IV compound is not more than 0.5%HPLC percent area.
The compositions of the invention described above, wherein " total content of formula III compound " refers to occur in the composition, and belongs to the summation of the compounds content that formula III represents；Equally, " total content of formula IV compound " refers to occur in the composition, and belongs to the summation of the compounds content that formula IV represents.
In a specific embodiment, the pemetrexed (M in compound of formula I of the present invention1 +And M2 +It is all H+null) or the compositions of its salt，It is characterized in that: the content of pemetrexed is not less than 98%，Impurity N-[4-[2-[2-amino-4，7-dihydro-5，6-epoxy-1-hydroxyl-4-oxo-1H-pyrrolo-[2，3-d] pyrimidine-5-base] ethyl] benzoyl]-Pidolidone，And chiral centre A-3 is S type (pemetrexed oxide A)，Its total content is not more than 0.5%，N-[4-[2-[2-amino-4，7-dihydro-4-oxo-1，5，6-trihydroxy-1H-pyrrolo-[2，3-d] pyrimidine-5-base] ethyl] benzoyl]-Pidolidone，And the total content that chiral centre B-3 is S type (referred to as " pemetrexed oxide B ") is not more than 0.5%，Its content is all in terms of HPLC percent area.
In the above-described embodiment, the pemetrexed of the present invention or the compositions of its salt, farther include:
The HPLC percent area of pemetrexed not less than 98.5%, the HPLC percent area of pemetrexed oxide A total content be not more than 0.5%, 0.4%, 0.3%, 0.2%, 0.15%, 0.1% or 0.05%, and/or the HPLC percent area of pemetrexed oxide B total content is not more than 0.5%, 0.4%, 0.3%, 0.2%, 0.15%, 0.1% or 0.05%.
Preferably, the pemetrexed of the present invention or the compositions of its salt, the HPLC percent area of pemetrexed not less than 99.0%, the HPLC percent area of pemetrexed oxide A total content be not more than 0.5%, 0.4%, 0.3%, 0.2%, 0.15%, 0.1% or 0.05%, and/or the HPLC percent area of pemetrexed oxide B total content is not more than 0.5%, 0.4%, 0.3%, 0.2%, 0.15%, 0.1% or 0.05%.
Preferably, the pemetrexed of the present invention or the compositions of its salt, the HPLC percent area of pemetrexed not less than 99.5%, the HPLC percent area of pemetrexed oxide A total content be not more than 0.5%, 0.4%, 0.3%, 0.2%, 0.15%, 0.1% or 0.05%, and/or the HPLC percent area of pemetrexed oxide B total content is not more than 0.5%, 0.4%, 0.3%, 0.2%, 0.15%, 0.1% or 0.05%.
Preferably, the pemetrexed of the present invention or the compositions of its salt, the HPLC percent area of pemetrexed not less than 99.5%, the HPLC percent area of pemetrexed oxide A total content be not more than 0.25%, 0.2%, 0.15%, 0.1% or 0.05%, and/or the HPLC percent area of pemetrexed oxide B total content is not more than 0.25%, 0.2%, 0.15%, 0.1% or 0.05%.
Above-mentioned " pemetrexed oxide A total content " refers to occur (5R, 6R)-pemetrexed oxide A in the composition or/and the summation of (5S, 6S)-pemetrexed oxide A content；" pemetrexed oxide B total content " refers to (5S occurred in the composition, 6S)-pemetrexed oxide B, (5S, 6R)-pemetrexed oxide B, (5R, 6S)-pemetrexed oxide B is or/and the summation of (5R, 6R)-pemetrexed oxide B content.
nullOn the other hand，The invention provides the compositions of a kind of pemetrexed disodium，It is characterized in that: the content of pemetrexed disodium is not less than 98%HPLC percent area，N-[4-[2-[2-amino-4，7-dihydro-5，6-epoxy-1-hydroxyl-4-oxo-1H-pyrrolo-[2，3-d] pyrimidine-5-base] ethyl] benzoyl]-Pidolidone disodium (the disodium salt of formula III compound，And chiral centre A-3 is S type，Referred to as " pemetrexed oxide A disodium salt ") total content is not more than 0.5%HPLC percent area，And/or N-[4-[2-[2-amino-4，7-dihydro-4-oxo-1，5，6-trihydroxy-1H-pyrrolo-[2，3-d] pyrimidine-5-base] ethyl] benzoyl]-Pidolidone disodium (the disodium salt of formula IV compound，And chiral centre B-3 is S type，Total content referred to as " pemetrexed oxide B disodium salt ") is not more than 0.5%HPLC percent area.
Preferably, the pemetrexed disodium high-purity composition of the present invention, including: the HPLC percent area of pemetrexed disodium not less than 98.5%, the HPLC percent area of pemetrexed oxide A disodium salt total content be not more than 0.5%, 0.4%, 0.3%, 0.2%, 0.15%, 0.1% or 0.05%, and/or the HPLC percent area of pemetrexed oxide B disodium salt total content is not more than 0.5%, 0.4%, 0.3%, 0.2%, 0.15%, 0.1% or 0.05%.
Preferably, the pemetrexed disodium high-purity composition of the present invention, including: the HPLC percent area of pemetrexed disodium not less than 99.0%, the HPLC percent area of pemetrexed oxide A disodium salt total content be not more than 0.5%, 0.4%, 0.3%, 0.2%, 0.15%, 0.1% or 0.05%, and/or the HPLC percent area of pemetrexed oxide B disodium salt total content is not more than 0.5%, 0.4%, 0.3%, 0.2%, 0.15%, 0.1% or 0.05%.
Preferably, the pemetrexed disodium high-purity composition of the present invention, including: the HPLC percent area of pemetrexed disodium not less than 99.5%, the HPLC percent area of pemetrexed oxide A disodium salt total content be not more than 0.5%, 0.4%, 0.3%, 0.2%, 0.15%, 0.1% or 0.05%, and/or the HPLC percent area of pemetrexed oxide B disodium salt total content is not more than 0.5%, 0.4%, 0.3%, 0.2%, 0.15%, 0.1% or 0.05%.
Preferably, the pemetrexed disodium high-purity composition of the present invention, including: the HPLC percent area of pemetrexed disodium not less than 99.5%, the HPLC percent area of pemetrexed oxide A disodium salt total content be not more than 0.3%, 0.2%, 0.15%, 0.1% or 0.05%, and/or the HPLC percent area of pemetrexed oxide B disodium salt total content is not more than 0.3%, 0.2%, 0.15%, 0.1% or 0.05%.
More preferably, the pemetrexed disodium high-purity composition of the present invention, including: the HPLC percent area of pemetrexed disodium not less than 99.5%, the HPLC percent area of pemetrexed oxide A disodium salt total content be not more than 0.5%, 0.4%, 0.3%, 0.2%, 0.15%, 0.1% or 0.05%.
More preferably, the pemetrexed disodium high-purity composition of the present invention, including: the HPLC percent area of pemetrexed disodium not less than 99.5%, the HPLC percent area of pemetrexed oxide B disodium salt total content be not more than 0.5%, 0.4%, 0.3%, 0.2%, 0.15%, 0.1% or 0.05%.
Above-mentioned " pemetrexed oxide A disodium salt total content " refers to occur (5R, 6R)-pemetrexed oxide A disodium salt in the composition or/and the summation of (5S, 6S)-pemetrexed oxide A disodium salt content；" pemetrexed oxide B disodium salt total content " refers to (5S occurred in the composition, 6S)-pemetrexed oxide B disodium salt, (5S, 6R)-pemetrexed oxide B disodium salt, (5R, 6S)-pemetrexed oxide B disodium salt is or/and the summation of (5R, 6R)-pemetrexed oxide B disodium salt content.
Above-mentioned " HPLC percent area " refers to the purity of product, is to measure with high performance liquid chromatography (HPLC) area normalization method, and the concentration of the detection limit of each component is less than 0.02%.The numerical value of content or purity is to round up gained through measurement data.
The invention provides the preparation method of formula III compound or its salt, the method includes by Formula V compound in anhydrous conditions with oxidizing and obtain,
In formula, chiral centre * includes S type, R type or their mixed type, at random addition salts.
Salt described in said method includes alkali formula addition salts and acid addition salt, wherein, alkali formula addition salts includes monovalent cation salt and divalent cation salt etc., monovalent cation salt includes sodium salt, potassium salt, lithium salts, monoamine cationic salts (such as ammonia salt, dimethylamine salt, diethylamine salt, meglumine salt, amido glucosamine salt etc.) etc. or their salt-mixture；Wherein farther include the double ion salt of these monovalent cations, isolated son energy, three ion salt or their mixture.In these monovalent cation salt, particular certain cancers, potassium salt, the double ion salt of lithium salts, i.e. disodium salt, di-potassium and dilithium salt, more preferably disodium salt；Divalent cation salt includes calcium salt, magnesium salt, zinc salt, and diamino salt (such as ethylenediamine salt, propane diamine salt etc.) etc., acid addition salt includes hydrochlorate, sulfate, hydrobromate, hydriodate, mesylate, tosilate etc..
Oxidant described in said method includes inorganic oxidizer and organic oxidizing agent.Wherein inorganic oxidizer includes but not limited to oxygen, hydrogen peroxide, sulphuric acid, nitric acid, perchloric acid and salt thereof, hypochlorous acid and salt, potassium permanganate etc.；Organic oxidizing agent includes but not limited to tert-butyl hydroperoxide, benzoyl hydroperoxide, metachloroperbenzoic acid etc., preferably hydrogen peroxide, oxygen.The consumption of oxidant is generally 0.01～100 times of Formula V compound mole, preferably 0.1～50 times, more preferably 1～30 times.
" anhydrous condition " described in said method is included in anhydrous solution or reacts under condition of no solvent." " referring to the mixed solution being made up of Formula V compound, oxidant, solvent etc., wherein wet weight is less than 1% to anhydrous solution.Wherein solvent includes conventional organic solvent, such as alcohols (methanol, ethanol, butanol, isopropanol, normal propyl alcohol, n-butyl alcohol etc.), esters (ethyl acetate, methyl acetate, butyl acetate etc.), ethers (diisopropyl ether, petroleum ether, methyl tertiary butyl ether(MTBE), glycol dimethyl ether, oxolane, dioxane etc.), nitrile (acetonitrile, succinonitrile etc.), ketone (acetone, 2-butanone etc.), amide-type (N, dinethylformamide, N,N-dimethylacetamide etc.), sulfone class (dimethyl sulfoxide etc.) and their mixture；Wherein preferred methanol, ethanol and DMF.Solvent volume consumption is generally 0.5～50 times of Formula V compound quality, preferably 1～25 times, more preferably 5～10 times.
The method of the present invention still further comprises and carries out isolated and purified by prepared oxide A or its salt (formula III compound), and isolation and purification method can adopt the method into routine in the art, such as: recrystallization, chromatographic isolation, lyophilization etc..
In a specific embodiment, the invention provides a kind of pemetrexed oxide A (i.e. formula III compound, and chiral centre A-3 is S type) preparation method, the method includes being dissolved in organic solvent pemetrexed, it is passed through hydrogen peroxide gas to aoxidize, controls this solution system wet weight less than 1%.Wherein, organic solvent is selected from methanol, ethanol, oxolane, acetonitrile, acetone, DMF, N,N-dimethylacetamide, dimethyl sulfoxide etc. and their mixture, wherein preferred methanol, ethanol and DMF；The volume of solvent is 0.5～100 times of pemetrexed quality, preferably 1～50 times, more preferably 5～30 times.Hydrogen peroxide use is 0.1～50 times of Formula V compound mole, preferably 1～30 times.Reaction temperature generally-20 DEG C to solvent boiling point temperature, preferably-10～50 DEG C, more preferably 0～30 DEG C.
Obtained pemetrexed oxide A purity be have at least 0.1% purity, or the purity of at least 0.5%, or the purity of at least 1%, or the purity of at least 5%, or the purity of at least 10%, or the purity of at least 15%, or the purity of at least 25%, or the purity of at least 50%, or the purity of at least 75%, or the purity of at least 95%.This purity is generally the purity of HPLC area normalization method.
In another specific embodiment, the invention provides a kind of pemetrexed oxide A disodium salt, di-potassium or dilithium salt (i.e. disodium salt, di-potassium or dilithium salt in formula III compound, and chiral centre A-3 is S type) preparation method, the method includes pemetrexed disodium, di-potassium or dilithium salt (i.e. disodium salt, di-potassium or dilithium salt in Formula V compound, and chiral centre * is S type) under condition of no solvent, i.e. it is passed through air or oxygen under solid state and processes.Temperature is generally 20～100 DEG C, preferably 60～80 DEG C.Obtained pemetrexed oxide A disodium salt, di-potassium or dilithium salt be separated into the purity with at least 0.1% in some embodiments, or the purity of at least 0.5%, or the purity of at least 1%, or the purity of at least 5%, or the purity of at least 10%, or the purity of at least 15%, or the purity of at least 25%, or the purity of at least 50%, or the purity of at least 75%, or the purity of at least 95%.This purity is generally the purity of HPLC area normalization method.
The invention provides a kind of oxide B or the preparation method of its salt (formula IV compound), the method include by Formula V compound under aqueous conditions with oxidizing and obtain, or oxide A or its salt (formula III compound) hydrolysis are obtained.
Formula V
In formula, chiral centre * includes S type, R type or their mixed type, and its salt includes alkali formula addition salts and acid addition salt.
" alkali formula addition salts " in the method compound of formula V includes monovalent cation salt and divalent cation salt etc..Wherein monovalent cation salt includes sodium salt, potassium salt, lithium salts, monoamine cationic salts (such as ammonia salt, dimethylamine salt, diethylamine salt, meglumine salt, amido glucosamine salt etc.) etc. or their salt-mixture；Wherein farther include the double ion salt of these monovalent cations, isolated alite, three ion salt or their mixture.In these monovalent cation salt, particular certain cancers, potassium salt, the double ion salt of lithium salts, i.e. disodium salt, di-potassium and dilithium salt, more preferably disodium salt.Wherein divalent cation salt includes calcium salt, magnesium salt, zinc salt, diamino salt (such as ethylenediamine salt, propane diamine salt etc.) etc..
" acid addition salt " in the method compound of formula V includes hydrochlorate, sulfate, hydrobromate, hydriodate, mesylate, tosilate etc..
In said method, " oxidant " includes inorganic oxidizer and organic oxidizing agent.Wherein inorganic oxidizer includes but not limited to oxygen, hydrogen peroxide, sulphuric acid, nitric acid, perchloric acid and salt thereof, hypochlorous acid and salt, potassium permanganate etc.；Organic oxidizing agent includes but not limited to tert-butyl hydroperoxide, benzoyl hydroperoxide, metachloroperbenzoic acid etc..Wherein preferred hydrogen peroxide.The consumption of oxidant is generally 0.01～100 times of Formula V compound mole, preferably 0.1～50 times, more preferably 1～30 times.
In the method, " " referring to the mixed aqueous solution being made up of Formula V compound, oxidant, water and optional organic solvent etc., wherein wet weight is more than 5%, preferably greater than 20%, more preferably greater than 50% to aqueous conditions.Can include such as alcohols (methanol, ethanol, butanol, isopropanol, normal propyl alcohol, n-butyl alcohol etc.), esters (ethyl acetate, methyl acetate, butyl acetate etc.), ethers (diisopropyl ether, petroleum ether, methyl tertiary butyl ether(MTBE) for organic solvent, glycol dimethyl ether, oxolane, dioxane etc.), nitrile (acetonitrile, succinonitrile etc.), ketone (acetone, 2-butanone etc.), amide-type (N, dinethylformamide, N,N-dimethylacetamide etc.), sulfone class (dimethyl sulfoxide etc.) and their mixture.The solvent volume of water or water and ORGANIC SOLVENT MIXTURES is generally 0.5～100 times of Formula V compound quality, preferably 1～50 times, more preferably 5～30 times.
In the method, oxidizing reaction temperature generally-20 DEG C is to solvent boiling point temperature, preferably-10～50 DEG C, more preferably 0～30 DEG C.
Can further include in the method and carry out isolated and purified by prepared oxide B or its salt (formula III compound), isolation and purification method can adopt the method into routine in the art, such as: recrystallization, chromatographic isolation, lyophilization etc..
In the method, oxide B or its salt are separated into the purity with at least 0.1% in some embodiments, or the purity of at least 0.5%, or the purity of at least 1%, or the purity of at least 5%, or the purity of at least 10%, or the purity of at least 15%, or the purity of at least 25%, or the purity of at least 50%, or the purity of at least 75%, or the purity of at least 95%.This purity is generally the purity of HPLC area normalization method.
In a specific embodiment, the invention provides a kind of pemetrexed oxide B (i.e. oxide part B in formula IV compound, and chiral centre B-3 is S type) preparation method, the method includes pemetrexed (i.e. acid moieties in Formula V compound, and chiral centre * is S type) it is dissolved in water or water and selected from methanol, ethanol, oxolane, acetonitrile, acetone, N, dinethylformamide, N, N-dimethyl acetylamide, the mixed solvent of the composition such as dimethyl sulfoxide, add hydrogen peroxide to aoxidize, wherein control this solution system wet weight more than 5%, preferably greater than 20%, more preferably greater than 50%.Wherein mixed solvent volume is 1～50 times of pemetrexed quality, preferably 5～30 times.Hydrogen peroxide use is 0.1～50 times of Formula V compound mole, preferably 1～30 times.Oxidizing reaction temperature generally-10～50 DEG C, preferably 0～30 DEG C.Obtained pemetrexed oxide B is separated into the purity with at least 0.1% in some embodiments, or the purity of at least 0.5%, or the purity of at least 1%, or the purity of at least 5%, or the purity of at least 10%, or the purity of at least 15%, or the purity of at least 25%, or the purity of at least 50%, or the purity of at least 75%, or the purity of at least 95%.This purity is generally the purity of HPLC area normalization method.
In another specific embodiment, the invention provides a kind of pemetrexed oxide B disodium salt, di-potassium or dilithium salt (i.e. disodium salt, di-potassium or dilithium salt in formula IV compound, and chiral centre A-3 is S type) preparation method, the method includes pemetrexed disodium, di-potassium or dilithium salt (i.e. disodium salt, di-potassium or dilithium salt in Formula V compound, and chiral centre * is S type) it is dissolved in the water, add hydrogen peroxide and aoxidize.Wherein water volume is 1～50 times of pemetrexed disodium, di-potassium or dilithium salt quality, preferably 5～30 times.Hydrogen peroxide use is 0.1～50 times of Formula V compound mole, preferably 1～30 times.Oxidizing reaction temperature generally-10～50 DEG C, preferably 0～30 DEG C.Obtained pemetrexed oxide B disodium salt, di-potassium or dilithium salt are separated into the purity with at least 0.1% in some embodiments, or the purity of at least 0.5%, or the purity of at least 1%, or the purity of at least 5%, or the purity of at least 10%, or the purity of at least 15%, or the purity of at least 25%, or the purity of at least 50%, or the purity of at least 75%, or the purity of at least 95%.This purity is generally the purity of HPLC area normalization method.This pemetrexed oxide B disodium salt, di-potassium or dilithium salt are carried out the most isolated and purified by the method that available preparative liquid chromatography, lyophilization etc. combine, and obtain solids.
In another specific embodiment, the invention provides a kind of pemetrexed oxide B disodium salt, di-potassium or dilithium salt (i.e. disodium salt, di-potassium or dilithium salt in formula IV compound, and chiral centre A-3 is S type) preparation method, the method includes being dissolved in the water pemetrexed oxide A disodium salt, di-potassium or dilithium salt.Temperature generally-10～50 DEG C, preferably 0～30 DEG C.Obtained pemetrexed oxide B disodium salt, di-potassium or dilithium salt are separated into the purity with at least 0.1% in some embodiments, or the purity of at least 0.5%, or the purity of at least 1%, or the purity of at least 5%, or the purity of at least 10%, or the purity of at least 15%, or the purity of at least 25%, or the purity of at least 50%, or the purity of at least 75%, or the purity of at least 95%.This purity is generally the purity of HPLC area normalization method.This U.S. bent plug oxide B disodium salt, di-potassium or dilithium salt are carried out the most isolated and purified by the method that available preparative liquid chromatography, lyophilization etc. combine, and obtain solids.
In another specific embodiment, pemetrexed oxide B or its salt (i.e. disodium salt, di-potassium or dilithium salt in formula IV compound, and chiral centre A-3 is S type) with preparative liquid chromatography isolated and purified time, it may occur that the change of in the following manner:
Tautomeride I
Control (such as separation temperature, disengaging time etc.) according to different separation conditions, the mass percent of pemetrexed oxide B shared by tautomeride I or its salt has certain change, and generally less than 50%, preferably smaller than 40%, more preferably 30%.Obtained pemetrexed oxide B or its tautomeride, or their mixture (including their disodium salt, di-potassium or dilithium salt) is separated into the purity with at least 0.1% in some embodiments, or the purity of at least 0.5%, or the purity of at least 1%, or the purity of at least 5%, or the purity of at least 10%, or the purity of at least 15%, or the purity of at least 25%, or the purity of at least 50%, or the purity of at least 75%, or the purity of at least 95%.This purity is generally the purity of HPLC area normalization method.
Another object of the present invention is, by formula III compound or/and formula IV compound is used for pemetrexed and the purposes of energy (compound of formula I) quality control reference substance thereof.Specifically formula III compound (the preferably U.S. oxide A of training and disodium salt) or/and formula IV compound (preferably pemetrexed oxide B and disodium salt) for pemetrexed and the preparation of disodium salt, store and use during quality control reference substance and impurity test.
A kind of method that the invention provides impurity measuring pemetrexed and salt thereof, the method includes:
(1) the formula III compound (the preferably U.S. oxide A of training and disodium salt) of a kind of known quantity and/or characteristic is provided or/and formula IV compound (preferably pemetrexed oxide B and disodium salt) with reference to sample；
(2) a kind of pemetrexed or its salt (preferably disodium salt) sample are provided；
(3) measure with reference to the III compound or its salt in sample and pemetrexed or its salt (preferably disodium salt) sample with HPLC, or/and the content of formula IV compound or its salt.
In above-mentioned method of testing, III compound or its salt in pemetrexed or its salt sample is or/and the content of formula IV compound or its salt is not more than 0.5%, and preferred content is no more than 0.5%, 0.4%, 0.3%, 0.2%, 0.15%, 0.1% or 0.05%.
Described HPLC method generally comprises external standard method, internal standard method, relative retention time and corrector factor method etc..
External standard method may include that a kind of formula III compound of offer or/and formula IV is made, with reference to sample, to test with HPLC；There is provided one containing pemetrexed or its salt sample, test with HPLC under the same conditions；According to test result calculations formula III compound or/and formula IV compound amount in pemetrexed or its salt sample.
In the specific embodiments of an external standard method, the present invention measures the method for pemetrexed or its salt, and the method comprises the following steps:
A) quantitatively preparing containing formula III compound or/and the reference solution of formula IV compound or its salt, inject HPLC column under a set of conditions, it is thus achieved that HPLC collection of illustrative plates, wherein reference solution compound of formula III is or/and the amount of formula IV compound and/or characteristic are known；
B) quantitatively preparation, containing pemetrexed or the test solution of its salt, injects HPLC column, it is thus achieved that HPLC collection of illustrative plates under identical set condition；
C) by the HPLC collection of illustrative plates of contrast step a) and step b) chromatographic peak retention time or relative retention time and peak area/or peak height calculates formula III compound or/and formula IV compound content in pemetrexed or its salt test sample.
Internal standard method includes: provide a kind of formula III compound or/and formula IV is made with reference to sample, with pemetrexed or its salt as internal standard substance, draws relative retention time and correction factor by HPLC test；There is provided a kind of pemetrexed or its salt sample, with the test of the same terms HPLC；Formula III compound is calculated or/and the existence in pemetrexed or its salt sample of the formula IV compound and/or amount according to test result and relative retention time and correction factor.
In the specific embodiments of an internal standard method, the method of the impurity measuring pemetrexed and salt thereof of the present invention, the method includes: quantitatively preparation containing formula III compound (the preferably U.S. oxide A of training and disodium salt) or/and formula IV compound (preferably pemetrexed oxide B and disodium salt) and containing pemetrexed or its salt (preferably disodium salt) as the reference solution of internal standard substance, inject HPLC column under a set of conditions, (this collection of illustrative plates can be one to obtain a HPLC collection of illustrative plates, it can also be one group), wherein reference solution compound of formula III (the preferably U.S. oxide A of training and disodium salt) is or/and formula IV compound (the preferably U.S. oxide B of training and disodium salt) and pemetrexed or the amount of its salt (preferably disodium salt) and/or characteristic are known；Quantitatively preparation is containing pemetrexed or the test solution of its salt (preferably disodium salt), injects HPLC column, it is thus achieved that the 2nd HPLC collection of illustrative plates (this collection of illustrative plates can be, it is also possible to is a group) under identical set condition；Calculated relative retention time and the correction factor of chromatographic peak by a HPLC collection of illustrative plates, on contrast the 2nd HPLC collection of illustrative plates, the relative retention time of chromatographic peak and peak area/or peak height calculate formula III compound or/and the existence in pemetrexed or its salt test sample of the formula IV compound and/or amount.
Above-mentioned corrector factor method, the method includes providing a kind of formula III compound or/and formula IV is made with reference to sample, by drawing correction factor with the contrast test of pemetrexed or its salt HPLC；There is provided a kind of pemetrexed or its salt sample, with the test of the same terms HPLC；With formula III compound or/and the corresponding impurity in pemetrexed or its salt sample is positioned by formula IV compound；Formula III compound is calculated or/and the existence in pemetrexed or its salt sample of the formula IV compound and/or amount according to test result and correction factor.
In the specific embodiments of a corrector factor method, the method of the impurity measuring pemetrexed and energy thereof of the present invention, the method includes: quantitatively preparation containing formula III compound or/and the reference solution of formula IV compound and containing pemetrexed or the reference solution of its salt, both reference solutions can with mixed preparing (i.e. containing formula III compound or/and formula IV compound and containing pemetrexed or the reference solution of its salt), can also be individually to prepare, inject HPLC column under a set of conditions, (this collection of illustrative plates can be one to obtain a HPLC collection of illustrative plates, it can also be one group), wherein reference solution compound of formula III is or/and formula IV compound and pemetrexed or the amount of its salt and/or characteristic are known；Quantitatively preparation is containing pemetrexed or the test solution of its salt, injects HPLC column, it is thus achieved that the 2nd HPLC collection of illustrative plates (this collection of illustrative plates can be, it is also possible to is a group) under identical set condition；Add in the test solution containing pemetrexed or its salt a certain amount of containing formula III compound or/and the solution of formula IV compound, HPLC column is injected, it is thus achieved that the 3rd HPLC collection of illustrative plates (this collection of illustrative plates for formula III compound or/and the location of formula IV compound) under identical set condition；The correction factor of chromatographic peak is calculated by a HPLC collection of illustrative plates, by the location of the 3rd HPLC collection of illustrative plates, by III compound on the 2nd HPLC collection of illustrative plates or/and the calculated by peak area of formula IV compound chromatographic peak goes out formula III compound or/and the existence in pemetrexed or its salt test sample of the formula IV compound and/or amount.
Above-mentioned relative retention time method, the method includes: provide a kind of formula III compound or/and formula IV is made, with reference to sample, to test with HPLC；There is provided a kind of pemetrexed or its salt sample, with the test of the same terms HPLC；It is quantitatively adding formula III compound or/and formula IV compound, with the test of the same terms HPLC in pemetrexed or its salt sample；According to test result calculations formula III compound or/and the existence in pemetrexed or its salt sample of the formula IV compound and/or amount.
In the specific embodiments of a relative retention time method, the method of the impurity measuring pemetrexed and salt thereof of the present invention, the method includes: quantitatively preparation containing formula III compound or/and the reference solution of formula IV compound, inject HPLC column under a set of conditions, (this collection of illustrative plates can be one to obtain a HPLC collection of illustrative plates, can also be one group), wherein reference solution compound of formula III is or/and the amount of formula IV compound and/or characteristic are known；Quantitatively preparation is containing pemetrexed or the test solution of its salt, injects HPLC column, it is thus achieved that the 2nd HPLC collection of illustrative plates (this collection of illustrative plates can be, it is also possible to is a group) under identical set condition；Add in the test solution containing pemetrexed or its salt quantitative containing formula III compound or/and the reference solution of formula IV compound, under identical set condition, inject HPLC column, it is thus achieved that the 3rd HPLC collection of illustrative plates (this collection of illustrative plates can be, it is also possible to is a group)；Formula III compound is gone out or/and the existence in pemetrexed or its salt test sample of the formula IV compound and/or amount by the retention time on HPLC collection of illustrative plates and/or calculated by peak area.
The method of said determination may also include further, and III compound of putting on record in writing is or/and the chemical characteristic of formula IV compound is or/and it is as impurity existence in pemetrexed or its salt test sample and/or amount.
The method of the impurity measuring pemetrexed and salt thereof of the above-mentioned present invention, wherein said pemetrexed or the preferred pemetrexed of its salt or pemetrexed disodium；Described III compound or its salt preferred pemetrexed oxide A, (5R, 6R)-pemetrexed oxide A, (5S, 6S)-pemetrexed oxide A, pemetrexed oxide A disodium salt, (5R, 6R)-pemetrexed oxide A disodium salt or (5S, 6S)-pemetrexed oxide A disodium salt；Described IV compound or its salt preferred pemetrexed oxide B, (5S, 6S)-pemetrexed oxide B, (5S, 6R)-pemetrexed oxide B, (5R, 6S)-pemetrexed oxide B, (5R, 6R)-pemetrexed oxide B, pemetrexed oxide B disodium salt, (5S, 6S)-pemetrexed oxide B disodium salt, (5S, 6R)-pemetrexed oxide B disodium salt, (5R, 6S)-pemetrexed oxide B disodium salt or (5R, 6R)-pemetrexed oxide B disodium salt.
The method of the impurity measuring pemetrexed and salt thereof of the above-mentioned present invention, III compound or its salt in pemetrexed or its disodium salt sample is or/and the content of formula IV compound or its salt is not more than 0.5%, and preferred content is no more than 0.5%, 0.4%, 0.3%, 0.2%, 0.15%, 0.1% or 0.05%.
In said method HPLC column can be reversed-phase column can also be normal phase column, wherein preferably reversed-phase HPLC post, the most anti-phase C18HPLC post；Flowing can use the solution with aqueous, acetonitrile, ammonium formate solution, phosphate solution etc. or its mixture to carry out eluting mutually；Detection wavelength is 226～300nm, preferably 254nm.
In one embodiment, the method for the impurity measuring pemetrexed of the present invention, the method includes:
(1) the III compound of a kind of known quantity and/or characteristic is provided or/and formula IV compound is made with reference to sample；
(2) a kind of pemetrexed sample is provided；
(3) pemetrexed oxide A, (5R in pemetrexed sample are determined by HPLC method, 6R)-pemetrexed oxide A, (5S, 6S)-pemetrexed oxide A, pemetrexed oxide B, (5S, 6S)-pemetrexed oxide B, (5S, 6R)-pemetrexed oxide B, (5R, 6S)-pemetrexed oxide B is or/and the amount of (5R, 6R)-pemetrexed oxide B
Wherein, formula III compound is selected from pemetrexed oxide A, (5R, 6R)-pemetrexed oxide A, (5S, 6S)-pemetrexed oxide A, pemetrexed oxide A disodium salt, (5R, 6R)-pemetrexed oxide A disodium salt or (5S, 6S)-pemetrexed oxide A disodium salt；Formula IV compound is selected from pemetrexed oxide B, (5S, 6S)-pemetrexed oxide B, (5S, 6R)-pemetrexed oxide B, (5R, 6S)-pemetrexed oxide B, (5R, 6R)-pemetrexed oxide B, pemetrexed oxide B disodium salt, (5S, 6S)-pemetrexed oxide B disodium salt, (5S, 6R)-pemetrexed oxide B disodium salt, (5R, 6S)-pemetrexed oxide B disodium salt or (5R, 6R)-pemetrexed oxide B disodium salt.
Said method concrete operations are as follows:
Quantitatively preparation containing formula III compound or/and the reference solution of formula IV compound, inject HPLC column under a set of conditions, (this collection of illustrative plates can be one to obtain a HPLC collection of illustrative plates, can also be one group), wherein reference solution compound of formula III is or/and the amount of formula IV compound and/or characteristic are known；The quantitatively preparation test solution containing pemetrexed, injects HPLC column, it is thus achieved that the 2nd HPLC collection of illustrative plates (this collection of illustrative plates can be, it is also possible to is a group) under identical set condition；By contrasting the retention time of chromatographic peak on the first and second HPLC collection of illustrative plates or relative retention time and peak area/or peak height calculates formula III compound or/and the existence in pemetrexed test sample of the formula IV compound and/or amount.
In such scheme, formula III compound or its salt preferred pemetrexed oxide A, pemetrexed oxide A disodium salt；Formula IV compound or its salt preferred pemetrexed oxide B, pemetrexed oxide B disodium salt.
In another embodiment, the method for the impurity measuring pemetrexed disodium that the invention provides, the method includes:
(1) the formula III compound or its salt of a kind of known quantity and/or characteristic is provided or/and formula IV compound or its salt with reference to sample；
(2) a kind of pemetrexed disodium sample is provided；
(3) pemetrexed oxide A disodium salt, (5R in pemetrexed disodium sample are determined by HPLC method, 6R)-pemetrexed oxide A disodium salt, (5S, 6S)-pemetrexed oxide A disodium salt, pemetrexed oxide B disodium salt, (5S, 6S)-pemetrexed oxide B disodium salt, (5S, 6R)-pemetrexed oxide B disodium salt, (5R, 6S)-pemetrexed oxide B disodium salt is or/and (5R, the existence of 6R)-pemetrexed oxide B disodium salt is or/and measure
Wherein, formula III compound is selected from pemetrexed oxide A, (5R, 6R)-pemetrexed oxide A, (5S, 6S)-pemetrexed oxide A, pemetrexed oxide A disodium salt, (5R, 6R)-pemetrexed oxide A disodium energy or (5S, 6S)-pemetrexed oxide A disodium salt；Formula IV compound is selected from pemetrexed oxide B, (5S, 6S)-pemetrexed oxide B, (5S, 6R)-pemetrexed oxide B, (5R, 6S)-pemetrexed oxide B, (5R, 6R)-pemetrexed oxide B, pemetrexed oxide B disodium salt, (5S, 6S)-pemetrexed oxide B disodium salt, (5S, 6R)-pemetrexed oxide B disodium salt, (5R, 6S)-pemetrexed oxide B disodium salt or (5R, 6R)-pemetrexed oxide B disodium salt.
The method concrete operations are as follows:
Quantitatively preparation containing formula III compound or/and the reference solution of formula IV compound, inject HPLC column under a set of conditions, (this collection of illustrative plates can be one to obtain a HPLC collection of illustrative plates, can also be one group), wherein reference solution compound of formula III is or/and the amount of formula IV compound and/or characteristic are known；The quantitatively preparation test solution containing pemetrexed disodium, injects HPLC column, it is thus achieved that the 2nd HPLC collection of illustrative plates (this collection of illustrative plates can be, it is also possible to is a group) under identical set condition；By contrasting the retention time of chromatographic peak on the first and second HPLC collection of illustrative plates or relative retention time and peak area/or peak height calculates formula III compound or/and the existence in pemetrexed disodium test sample of the formula IV compound and/or amount.
Such scheme compound of formula III or its salt preferred pemetrexed oxide A, pemetrexed oxide A disodium salt；Formula IV compound or its salt preferred pemetrexed oxide B, pemetrexed oxide B disodium salt.
In an exemplary embodiment scheme, the method of the impurity measuring pemetrexed disodium of the present invention, the method includes: take a certain amount of pemetrexed oxide A disodium salt or/and pemetrexed oxide B disodium salt, accurately weighed, add flowing and the most quantitatively dissolve (0.03mol/L ammonium formate solution-acetonitrile volume ratio is 94: 6), obtain reference solution, take reference solution and quantitatively inject the HPLC chromatogram instrument with octadecylsilane chemically bonded silica reversed-phase column as chromatographic column, carry out eluting mutually with this flowing, record HPLC collection of illustrative plates；Take a certain amount of pemetrexed disodium, accurately weighed, the most quantitatively dissolve with above-mentioned flowing and i.e. obtain test solution, take test solution and quantitatively inject the HPLC chromatogram instrument of same test condition, record HPLC collection of illustrative plates；By the retention time in contrast reference solution HPLC collection of illustrative plates and test solution HPLC collection of illustrative plates and/or peak area, calculate impurity pemetrexed oxide A disodium salt in pemetrexed disodium test solution or/and the content of pemetrexed oxide B disodium salt.It is of course also possible to reach same purpose by the method such as relative retention time, correction factor.
It is conventional method in the art that HPLC above by reference solution and test solution tests and calculate the method for the content of impurity in test solution.As improved the accuracy of test further, method of testing can be carried out the Method validation of necessity.
Additionally; present invention also offers minimizing Formula V compound process in storage and be converted into formula III compound or/and the method for formula IV compound; the method includes: Formula V compound carries out evacuation storage or stores Formula V compound nitrogen filled protection, storage temperature generally-40～40 DEG C.
In a specific embodiment; a kind of pemetrexed process in storage that reduces is converted into pemetrexed oxide A or/and the method for pemetrexed oxide B; the method carries out evacuation storage to pemetrexed or nitrogen filled protection stores, storage temperature generally-40～40 DEG C, preferably-20～30 DEG C.
In a specific embodiment; a kind of pemetrexed disodium process in storage that reduces is converted into pemetrexed oxide A disodium salt or/and the method for pemetrexed oxide B disodium salt; the method includes that pemetrexed disodium carries out evacuation storage or nitrogen filled protection stores; storage temperature generally-40～40 DEG C, preferably-30～10 DEG C.
In said method, " evacuation " and " nitrogen filled protection " is conventional method in the art, as completed evacuation packaging in vacuum packaging machine, carries out evacuation in vacuum packaging machine successively, and inflated with nitrogen can complete to take out nitrogen gas packing.Packaging material internal layer can use one or more layers polyethylene plastic bag, and outer layer can use one or more layers Aluminum-plastic composite bag.
The method of the impurity measuring pemetrexed and salt thereof of above-mentioned all present invention, III compound or its salt in pemetrexed or its disodium salt sample is or/and the content of formula IV compound or its salt is not more than 0.5%, preferred content is no more than 0.5%, 0.4%, 0.3%, 0.2%, 0.15%, 0.1% or 0.05%, wherein, formula III compound or its salt is selected from pemetrexed oxide A, (5R, 6R)-pemetrexed oxide A, (5S, 6S)-pemetrexed oxide A, pemetrexed oxide A disodium salt, (5R, 6R)-pemetrexed oxide A disodium salt, (5S, 6S)-pemetrexed oxide A disodium salt and their mixture；Formula IV compound or its salt is selected from pemetrexed oxide B, (5S, 6S)-pemetrexed oxide B, (5S, 6R)-pemetrexed oxide B, (5R, 6S)-pemetrexed oxide B, (5R, 6R)-pemetrexed oxide B, pemetrexed oxide B disodium salt, (5S, 6S)-pemetrexed oxide B disodium salt, (5S, 6R)-pemetrexed oxide B disodium salt, (5R, 6S)-pemetrexed oxide B disodium salt, (5R, 6R)-pemetrexed oxide B disodium salt and their mixture, preferred version, formula III compound or its salt preferred pemetrexed oxide A, pemetrexed oxide A disodium salt and their mixture；Formula IV compound or its salt preferred pemetrexed oxide B, pemetrexed oxide B disodium salt and their mixture.
Detailed description of the invention
Below in conjunction with embodiment, the invention will be further described, professional and technical personnel in the field can be made to be more completely understood by the present invention, but limit the scope of the present invention never in any form.The term and the abbreviation that use in embodiment have common implication.As " DEG C ", " g ", " mg ", " ml ", "1HNMR”、“13CNMR ", " HPLC " refer respectively to degree Celsius, gram, milligram, milliliter, proton magnetic resonance (PMR), carbon-13 magnetic resonance, high performance liquid chromatography.In nuclear magnetic resonance data, " s " represents unimodal, and " d " represents bimodal, and " m " represents multiplet.
Embodiment 1
The synthesis of N-[4-[2-[2-amino-4,7-dihydro-5,6-epoxy-1-hydroxyl-4-oxo-1H-pyrrolo-[2,3-d] pyrimidine-5-base] ethyl] benzoyl]-Pidolidone (referred to as " pemetrexed oxide A ")
Pemetrexed 2g, adds methanol 10ml (recording water content is 0.2%), is passed through hydrogen peroxide gas about 0.3g, and in keeping, temperature 0～5 DEG C stirring reaction 10 hours, obtain containing pemetrexed oxide A methanol solution.
HPLC:7.0%
(+) ESI-MS:460.1
Embodiment 2
N-[4-[2-[2-amino-4; 7-dihydro-5; 6-epoxy-1-hydroxyl-4-oxo-1H-pyrrolo-[2,3-d] pyrimidine-5-base] ethyl] benzoyl] synthesis of-D-Glu (i.e. formula III compound chirality center A-3 is R configuration)
N-[4-[2-(2-amino-4, 7-dihydro-4-oxo-1H-pyrrolo-[2, 3-d] pyrimidine-5-base) ethyl] benzoyl]-D-Glu (i.e. Formula V compound chirality center is R configuration) 0.5g, add N, dinethylformamide 8ml (recording water content is 0.9%), it is passed through oxygen about 0.1g, temperature 25～30 DEG C stirring reaction 50 hours in keeping, obtain containing N-[4-[2-[2-amino-4, 7-dihydro-5, 6-epoxy-1-hydroxyl-4-oxo-1H-pyrrolo-[2, 3-d] pyrimidine-5-base] ethyl] benzoyl] N of-D-Glu, dinethylformamide solution.
HPLC:0.9%
(+) ESI-MS:460.1
Embodiment 3
N-[4-[2-[2-amino-4; 7-dihydro-5; 6-epoxy-1-hydroxyl-4-oxo-1H-pyrrolo-[2,3-d] pyrimidine-5-base] ethyl] benzoyl] synthesis of-Pidolidone disodium (referred to as " pemetrexed oxide A disodium salt ")
Pemetrexed disodium 0.5g, is passed directly into oxygen about 0.6g, and in keeping, temperature 70～80 DEG C stirring reaction 72 hours, obtain the pemetrexed disodium containing pemetrexed oxide A disodium salt.
HPLC:0.2%
(+) ESI-MS:460.1
According to said method change the salt of different pemetrexed and do other salt that reaction raw materials can prepare following pemetrexed oxide A:
N-[4-[2-[2-amino-4,7-dihydro-5,6-epoxy-1-hydroxyl-4-oxo-1H-pyrrolo-[2,3-d] pyrimidine-5-base] ethyl] benzoyl]-Pidolidone di-potassium (referred to as " pemetrexed oxide A di-potassium ")
N-[4-[2-[2-amino-4,7-dihydro-5,6-epoxy-1-hydroxyl-4-oxo-1H-pyrrolo-[2,3-d] pyrimidine-5-base] ethyl] benzoyl]-Pidolidone dilithium salt (referred to as " pemetrexed oxide A dilithium salt ")
Embodiment 4
N-[4-[2-[2-amino-4; 7-dihydro-5; 6-epoxy-1-hydroxyl-4-oxo-1H-pyrrolo-[2,3-d] pyrimidine-5-base] ethyl] benzoyl] synthesis of-D-Glu disodium (i.e. formula III compound chirality center A-3 is R configuration)
N-[4-[2-(2-amino-4, 7-dihydro-4-oxo-1H-pyrrolo-[2, 3-d] pyrimidine-5-base) ethyl] benzoyl]-D-Glu disodium (i.e. Formula V compound chirality center is the disodium salt of R configuration) 1g, add N, dinethylformamide 8ml (recording water content is 0.5%), it is passed through hydrogen peroxide gas about 0.1g, temperature 15～20 DEG C stirring reaction 48 hours in keeping, obtain containing N-[4-[2-[2-amino-4, 7-dihydro-5, 6-epoxy-1-hydroxyl-4-oxo-1H-pyrrolo-[2, 3-d] pyrimidine-5-base] ethyl] benzoyl] N of-D-Glu disodium, dinethylformamide solution.
HPLC:1.3%
(+) ESI-MS:460.1
According to said method change the salt that different Formula V compound chirality center is R configuration to do reaction raw materials and can prepare other salt of following formula III compound:
N-[4-[2-[2-amino-4,7-dihydro-5,6-epoxy-1-hydroxyl-4-oxo-1H-pyrrolo-[2,3-d] pyrimidine-5-base] ethyl] benzoyl]-D-Glu disodium salt
N-[4-[2-[2-amino-4,7-dihydro-5,6-epoxy-1-hydroxyl-4-oxo-1H-pyrrolo-[2,3-d] pyrimidine-5-base] ethyl] benzoyl]-D-Glu di-potassium
N-[4-[2-[2-amino-4,7-dihydro-5,6-epoxy-1-hydroxyl-4-oxo-1H-pyrrolo-[2,3-d] pyrimidine-5-base] ethyl] benzoyl]-D-Glu dilithium salt
Embodiment 5
The synthesis of N-[4-[2-[2-amino-4,7-dihydro-4-oxo-1,5,6-trihydroxy-1H-pyrrolo-[2,3-d] pyrimidine-5-bases] ethyl] benzoyl]-Pidolidone (referred to as " pemetrexed oxide B ")
Pemetrexed 1.5g, adds DMF 25ml, the aqueous hydrogen peroxide solution 8ml of 30%, temperature 10～15 DEG C stirring reaction 32 hours in keeping.Must be containing the DMF solution of pemetrexed oxide B.
HPLC:13.2%
(+) ESI-MS:478.1
Embodiment 6
The synthesis of N-[4-[2-[2-amino-4,7-dihydro-4-oxo-1,5,6-trihydroxy-1H-pyrrolo-[2,3-d] pyrimidine-5-bases] ethyl] benzoyl]-D-Glu (i.e. formula IV compound chirality center B-3 is R configuration)
N-[4-[2-(2-amino-4; 7-dihydro-4-oxo-1H-pyrrolo-[2; 3-d] pyrimidine-5-base) ethyl] benzoyl]-D-Glu (i.e. Formula V compound chirality center is R configuration) 0.8g; add dimethyl sulfoxide 15ml; the aqueous hydrogen peroxide solution 5.5ml of 30%; temperature 25～30 DEG C stirring reaction 72 hours in keeping; obtain containing N-[4-[2-[2-amino-4; 7-dihydro-4-oxo-1; 5; 6-trihydroxy-1H-pyrrolo-[2,3-d] pyrimidine-5-base] ethyl] benzoyl] solution of-D-Glu.
HPLC:35%
(+) ESI-MS:478.1
Embodiment 7
N-[4-[2-[2-amino-4; 7-dihydro-4-oxo-1; 5,6-trihydroxy-1H-pyrrolo-[2,3-d] pyrimidine-5-bases] ethyl] benzoyl] synthesis of-Pidolidone disodium (referred to as " pemetrexed oxide B disodium salt ")
Take pemetrexed disodium 0.3g, add 2ml water dissolution, add the aqueous hydrogen peroxide solution 2ml of 30%, 5～10 DEG C of stirrings are reacted 48 hours, obtain the aqueous solution containing pemetrexed oxide B disodium salt.
HPLC:70.8%
(+) ESI-MS:478.1
According to said method change the salt of different pemetrexed and do other salt that reaction raw materials can prepare following pemetrexed oxide B:
N-[4-[2-[2-amino-4,7-dihydro-4-oxo-1,5,6-trihydroxy-1H-pyrrolo-[2,3-d] pyrimidine-5-bases] ethyl] benzoyl]-Pidolidone di-potassium (referred to as " pemetrexed oxide B di-potassium ")
N-[4-[2-[2-amino-4,7-dihydro-4-oxo-1,5,6-trihydroxy-1H-pyrrolo-[2,3-d] pyrimidine-5-bases] ethyl] benzoyl]-Pidolidone dilithium salt (referred to as " pemetrexed oxide B dilithium salt ")
Embodiment 8
N-[4-[2-[2-amino-4; 7-dihydro-4-oxo-1; 5,6-trihydroxy-1H-pyrrolo-[2,3-d] pyrimidine-5-bases] ethyl] benzoyl] synthesis of-D-Glu disodium (i.e. formula IV compound chirality center B-3 is the disodium salt of R configuration)
N-[4-[2-(2-amino-4; 7-dihydro-4-oxo-1H-pyrrolo-[2; 3-d] pyrimidine-5-base) ethyl] benzoyl]-D-Glu disodium (i.e. Formula V compound chirality center is the disodium salt of R configuration) 3g; add water 15ml; the aqueous hydrogen peroxide solution 18ml of 30%; temperature 5～10 DEG C stirring reaction 30 hours in keeping; obtain containing N-[4-[2-[2-amino-4; 7-dihydro-4-oxo-1; 5; 6-trihydroxy-1H-pyrrolo-[2,3-d] pyrimidine-5-base] ethyl] benzoyl] aqueous solution of-D disodium glutamate.
HPLC:45.5%
(+) ESI-MS:478.1
According to said method change the salt that different Formula V compound chirality center is R configuration to do reaction raw materials and can prepare other salt of following formula IV compound:
N-[4-[2-[2-amino-4,7-dihydro-4-oxo-1,5,6-trihydroxy-1H-pyrrolo-[2,3-d] pyrimidine-5-bases] ethyl] benzoyl]-D-Glu disodium salt
N-[4-[2-[2-amino-4,7-dihydro-4-oxo-1,5,6-trihydroxy-1H-pyrrolo-[2,3-d] pyrimidine-5-bases] ethyl] benzoyl]-D-Glu di-potassium
N-[4-[2-[2-amino-4,7-dihydro-4-oxo-1,5,6-trihydroxy-1H-pyrrolo-[2,3-d] pyrimidine-5-bases] ethyl] benzoyl]-D-Glu dilithium salt
Embodiment 9
N-[4-[2-[2-amino-4; 7-dihydro-4-oxo-1; 5,6-trihydroxy-1H-pyrrolo-[2,3-d] pyrimidine-5-bases] ethyl] benzoyl] synthesis of-Pidolidone disodium (referred to as " pemetrexed oxide B disodium salt ")
Taking pemetrexed impurity A disodium salt 0.1g, add 10ml aqueous solution, 2～8 DEG C of stirrings are reacted 12 hours, and obtaining the impurity B disodium salt HPLC containing pemetrexed is the aqueous solution of 70%.
HPLC:68.5%
(+) ESI-MS:478.1
Embodiment 10
N-[4-[2-[2-amino-4,7-dihydro-4-oxo-1,5,6-trihydroxy-1H-pyrrolo-[2,3-d] pyrimidine-5-bases] ethyl] benzoyl]-Pidolidone (referred to as " pemetrexed oxide B ") isolated and purified
Pemetrexed disodium solid 2g, add water 10ml, the aqueous hydrogen peroxide solution 15ml of 30%, temperature 0～10 DEG C stirring reaction 24 hours in keeping, reactant liquor high-pressure liquid phase column chromatography carries out separating (flowing is mutually for water: acetonitrile: formic acid volume ratio is 9: 1: 0.001), and collecting retention time is 38～40min fractions.Gained fraction is lyophilization 48 hours at-50～-40 DEG C, obtain pemetrexed oxide B80mg.
HPLC:96%
(+) ESI-MS:478.1
1HNMR (500MHz, DMSO-d6) δ (ppm): 9.18 (2H, s), 8.67 (1H, s), 8.45 (1H, s), 7.79～7.81 (2H, d), 7.22～7.31 (2H, d), 7.39 (1H, s), 6.30 (1H, s), 3～4 (1H, s), 5.16 (1H, s), 4.33～4.37 (1H, m), 2.85 (2H, m), 2.30～2.37 (2H, m), 2.00～2.12 (1H, m), 2.00～2.12 (1H, m), 1.92～1.97 (1H, m).
1HNMR (500MHz, D2O) δ (ppm): 7.74～7.75 (2H, d), 7.40～7.45 (2H, d), 5.31 (1H, s), 4.35 (1H, s), 2.87～3.002.85 (2H, m), 2.19～2.30 (1H, m), 2.36 (2H, m), 2.19～2.30 (1H, m), 2.04～2.04 (1H, m).
13CNMR (400MHz, DMSO-d6) δ (ppm): 178.7,170.2,168,164.1,163.6,145.5/145.3,128.6,131.2,128.8,127.5,127.5,79.9/79.6,72.9,69.1,64.6,54.5,31.1,30.6,29.8,28.1,26.7,
Embodiment 11
Impurity pemetrexed oxide A disodium salt and the mensuration (external standard method) of pemetrexed oxide B disodium salt in pemetrexed disodium
Take pemetrexed oxide A disodium salt and oxide B disodium salt about 5mg respectively, accurately weighed, add flowing phased soln and be diluted to 10ml, obtaining the reference solution containing about 0.5mg in every 1ml.According to high effective liquid chromatography for measuring, it is filler (4.6mm × 250mm, 5 μm, ACEC18 post) with octadecylsilane chemically bonded silica；0.03mol/L ammonium formate solution-acetonitrile is flowing phase, and uses following condition to carry out gradient elution；Detection wavelength is 254nm；Column temperature is 25 DEG C；Flow velocity is 1.5ml/min.Precision measures reference solution 25 μ l, injects chromatograph of liquid, records disodium salt peak area or the peak height of oxide A and oxide B respectively.
Take pemetrexed disodium about 5mg, accurately weighed, add flowing phased soln and be diluted to 10ml, obtaining the test solution containing about 0.5mg in every 1ml.According to high effective liquid chromatography for measuring, it is filler (4.6mm × 250mm, 5 μm, ACEC18 post) with octadecylsilane chemically bonded silica；0.03mol/L ammonium formate solution-acetonitrile is flowing phase, and uses following condition to carry out gradient elution；Detection wavelength is 254nm；Column temperature is 25 DEG C；Flow velocity is 1.5ml/min.Precision measures test solution 25 μ l, injects chromatograph of liquid, records peak area or the peak height of the disodium salt of pemetrexed oxide A and oxide B in test solution chromatogram.
This test sample is calculated containing pemetrexed oxide A and the amount of oxide B disodium energy by pemetrexed oxide A and the peak area of oxide B disodium salt or peak height in contrast reference solution and test solution.
Pemetrexed oxide A disodium salt: 0.25%
Pemetrexed oxide B disodium salt: 0.13%
Instrument: Agilent chromatograph of liquid
Chromatographic column: ACEC18 post (4.6mm × 250mm, 5 μm)
Column temperature: 25 DEG C
Detection wavelength: 254nm
Flow velocity: 1.5ml/min
Sampling volume: 25 μ l
Flowing phase: 0.03mol/L ammonium formate solution-acetonitrile (94: 6), and use following condition to carry out gradient elution
| Time (minute) | 0.03mol/L ammonium formate solution (%) | Acetonitrile (%) |
| 0 | 94 | 6 20 --> |
| 3 | 90 | 10 |
| 6 | 90 | 10 |
| 8 | 87.5 | 12.5 |
| 21 | 87.5 | 12.5 |
| 30 | 45 | 55 |
| 35 | 35 | 65 |
| 38 | 94 | 6 |
| 50 | 94 | 6 |
According to said method can test pemetrexed oxide A or B and the content of their dilithium salt and di-potassium, magnesium salt, calcium salt, zinc salt and diamino salt etc. in pemetrexed and salt thereof.
Embodiment 12
Impurity pemetrexed oxide A disodium salt and the mensuration (internal standard method) of pemetrexed oxide B disodium salt in pemetrexed disodium
Take the disodium salt about 12.5mg of pemetrexed oxide A and B respectively, accurately weighed, add flowing phased soln be diluted to 25ml, shake up, obtain the reference substance solution of disodium salt containing pemetrexed oxide A and B.Separately take pemetrexed disodium reference substance about 12.5mg, accurately weighed, add flowing phased soln and be diluted to 25ml, shaking up, obtain pemetrexed disodium reference substance solution.Accurate reference substance solution and each 0.5ml of pemetrexed disodium reference substance solution measuring pemetrexed oxide A respectively, adds flowing phase dilution to 100ml, shakes up, obtain concentration and be respectively the mixing reference substance solution 1 of 2.5 μ g/ml；The most accurate disodium salt and each 0.5ml of pemetrexed disodium reference substance solution measuring pemetrexed oxide B, adds flowing phase dilution to 100ml, shakes up, obtain concentration and be respectively the mixing reference substance solution 2 of 2.5 μ g/ml.According to high effective liquid chromatography for measuring, it is filler (4.6mm × 250mm, 5 μm, ACEC18 post) with octadecylsilane chemically bonded silica；0.03mol/L ammonium formate solution-acetonitrile is flowing phase, and uses following condition to carry out gradient elution；Detection wavelength is 254nm；Column temperature is 25 DEG C；Flow velocity is 1.5ml/min.Precision measures the above-mentioned 1 and 2 mixing each 25 μ l of reference substance solution respectively, injects chromatograph of liquid, records chromatogram.The correction factor of the disodium salt of pemetrexed oxide A and B is calculated respectively according to concentration and peak area or peak height.
Separately take pemetrexed disodium test sample about 12.5mg, accurately weighed, add flowing phased soln and be diluted to 25ml, obtaining the test solution containing about 0.5mg in every 1ml.According to high effective liquid chromatography for measuring, it is filler (4.6mm × 250mm, 5 μm, ACEC18 post) with octadecylsilane chemically bonded silica；0.03mol/L ammonium formate solution-acetonitrile is flowing phase, and uses following condition to carry out gradient elution；Detection wavelength is 254nm；Column temperature is 25 DEG C；Flow velocity is 1.5ml/min.Precision measures need testing solution 25 μ l, injects chromatograph of liquid, records peak area or the peak height of the disodium salt of pemetrexed oxide A and oxide B in test solution chromatogram.
This test sample is calculated containing pemetrexed oxide A and the amount of oxide B disodium salt by pemetrexed oxide A in the correction factor calculated and test solution and the peak area of oxide B disodium salt or peak height.
Pemetrexed oxide A disodium salt: 0.42%
Pemetrexed oxide B disodium salt: 0.58%
Instrument: Agilent chromatograph of liquid
Chromatographic column: ACEC18 post (4.6mm × 250mm, 5 μm)
Column temperature: 25 DEG C
Detection wavelength: 254nm
Flow velocity: 1.5ml/min
Sampling volume: 25 μ l
Flowing phase: 0.03mol/L ammonium formate solution-acetonitrile (94: 6), and use following condition to carry out gradient elution
| Time (minute) | 0.03mol/L ammonium formate solution (%) | Acetonitrile (%) |
| 0 | 94 | 6 |
| 3 | 90 | 10 |
| 6 | 90 | 10 |
| 8 | 87.5 | 12.5 |
| 21 | 87.5 | 12.5 |
| 30 | 45 | 55 |
| 35 | 35 | 65 |
| 38 | 94 | 6 |
| 50 | 94 | 6 |
Embodiment 13
The preservation of pemetrexed disodium
Take respectively with a collection of pemetrexed disodium 2g, pack as follows:
A, internal layer polyethylene plastic bag, outer layer can be packed with Aluminum-plastic composite bag；
B, internal layer vacuum packaging machine carry out evacuation, and outer layer Aluminum-plastic composite bag is packed；
C, internal layer vacuum packaging machine evacuation, then inflated with nitrogen, outer layer Aluminum-plastic composite bag is packed.
Three above packaging carries out oxide A after 24 months and oxide B disodium salt content measures 2～8 DEG C of cold preservations respectively, and measurement result is as follows:
Above HPLC test condition is with embodiment 11
As can be known from the above table, saving under the conditions of B, C, pemetrexed disodium stability is substantially better than the preservation under the conditions of A.
Claims (11)
1. a compound or its salt shown in formula III,
In formula, A-1, A-2, A-3 are chiral centre.
2. the compound described in claim 1, chiral centre A-3 is S type.
3. the compound described in claim 1, described salt is disodium salt.
4. a preparation method for the compound or its salt described in claim 1, the method includes by Formula V compound or its salt in anhydrous conditions with oxidizing and obtain,
In formula, chiral centre * is S type, R type or their mixed type, and described oxidant is hydrogen peroxide gas or oxygen.
5. method as claimed in claim 4, the consumption of oxidant is generally 0.01～100 times of Formula V compound mole.
6. method as claimed in claim 5, the consumption of oxidant is generally 0.1～50 times of Formula V compound mole.
7. method as claimed in claim 6, the consumption of oxidant is generally 1～30 times of Formula V compound mole.
8. measuring a method for impurity in pemetrexed and salt thereof, the method includes:
(1) the reference sample of the formula III compound or its salt of a kind of claim 1 containing known quantity is provided；
(2) sample of a kind of pemetrexed or its salt is provided；
(3) pemetrexed or the sample of its salt and the amount with reference to the formula III compound in sample are measured with HPLC.
9. the method described in claim 8, described formula III compound or its salt, its chiral centre A-3 is S type.
10. the method described in claim 8, described salt is disodium salt.
The compound described in 11. any one of claim 1-3 purposes in detection pemetrexed disodium quality.
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| CN103884784B (en) * | 2013-09-29 | 2015-07-22 | 山东新时代药业有限公司 | Method for analyzing and detecting pemetrexed disodium intermediate |
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