CN102796106B - A kind of pemetrexed method of quality control and pemetrexed impurity and the preparation of salt thereof - Google Patents
A kind of pemetrexed method of quality control and pemetrexed impurity and the preparation of salt thereof Download PDFInfo
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Abstract
The present invention provides a kind of pemetrexed method of quality control and pemetrexed impurity and the preparation of salt thereof, in the present invention, pemetrexed impurity is to prepare with N tertbutyloxycarbonyl L glutamic acid 5 benzyl ester for Material synthesis, the pemetrexed impurity that pemetrexed method of quality control is mainly prepared with technology provided by the present invention analyze for detection in standard reference material.The inventive method solve in prior art the acquisition of pemetrexed impurity can only from pemetrexed and sodium salt preparation process thereof the problem of isolated, and the pemetrexed impurity that purity is higher cannot be obtained.This method is simple to operate, and equipment requirements is low, and reaction condition is gentle, and product purity and yield are preferable.
Description
Technical field
The present invention relates to medicinal chemistry art, particularly relate to a kind of pemetrexed method of quality control and pemetrexed impurity
And the preparation of salt.
Background technology
Pemetrexed is a kind of novel many target position folic acid blocker, it is possible to blocks in cancer cell division and hyperplastic process and needs
Multiple enzyme, by destroying the normal metabolic processes of intracellular folate-dependant, suppress cellular replication, thus suppress the life of tumor
Long.Developed by Eli Lilly company of the U.S., in 2004 in U.S.'s Initial Public Offering, be used for treating malignant pleural mesothelioma and non-
Small cell lung cancer, obtains FDA approval in February, 2004 and treats malignant pleural mesothelioma with cisplatin combined medication.
The medicinal forms of pemetrexed is usually its salt, the most common are its disodium salt, due at pemetrexed disodium
Easily producing impurity in building-up process, and be difficult to be removed, the end-product purity causing product is the highest, and residual impurity composition is relatively
Many, this will largely effect on the quality of product.
Prior art discloses the impurity as shown in following formula (D)
。
But the method that in prior art, the openest pemetrexed impurity (D) synthesizes, most of pemetrexed impurity
(D) it is to separate acquisition by target product with the post of repeatedly crossing of impurity during preparing pemetrexed disodium.Such as patent
TW201118098, US5268362 individually disclose a kind of method preparing pemetrexed and the preparation of poly-heterocyclic compound and answer
With, during preparing pemetrexed impurity, the method that all employ column chromatography, prepare by the way of separation.But, training
The impurity of beautiful Qu Sai is numerous, and the retention time between each impurity closely, is difficult to obtain pure list by the way of column chromatography
One impurity.Therefore, in later stage research pemetrexed disodium medicine, impurity is on the stability of medicine and when affecting of drug effect, owing to not having
There is purity better quality preferable single contaminant sterling to compare thing, make the safe and effective Journal of Sex Research of medicine lack and depend on reliably
According to, it is difficult to ensure the control of product quality.So the synthesis side of a kind of highly purified pemetrexed impurity (D) of exigence
Method.
Summary of the invention
It is an object of the invention to provide the pemetrexed impurity shown in a kind of formula (D) or the preparation method of its salt.
The present invention is achieved through the following technical solutions:
The pemetrexed impurity shown in formula (D) shown in a kind of following synthetic route or the preparation method of its salt:
Described method specifically includes:
Step 1) by compound shown in formula (6) at room temperature with dicyclohexylcarbodiimide generation acylation reaction, then pass through
Filter prepares the compound shown in formula (5).
Described reaction is carried out in a solvent, and reaction dissolvent is ether, petroleum ether or dichloromethane solution, preferably dichloromethane
Alkane solution；Response time is 2-6 hour, preferably 4 hours.
Step 2) compound shown in formula (5) is sloughed formula (4) compound that benzyl protecting group prepares in alcoholic solution.
Described alcoholic solution includes C1-C5The alcohol of straight or branched, preferably methanol, ethanol, 1-propanol, 2-propanol, n-butyl alcohol
Or isobutanol, more preferably methanol；Response time is 1-3 hour, preferably 2 hours.
Compound shown in formula (4) is at room temperature reacted by step 3) with glutamate diethyl ester, then through washing, dry system
For obtaining compound shown in formula (3).
Described reaction is carried out in a solvent, and reaction dissolvent is ether, petroleum ether or dichloromethane solution, preferably dichloromethane
Solution；Compound shown in formula (4) and glutamate diethyl ester mass ratio 1:1-5, preferably 1:2.5；Response time is 10-20 hour,
Preferably 12 hours.
Compound shown in formula (3) is sloughed protection group and is prepared compound shown in formula (2) by step 4) in acid condition.
Described reaction is carried out in a solvent, and reaction dissolvent is ether, petroleum ether or dichloromethane solution, preferably dichloromethane
Solution；Acid condition is trifluoroacetic acid；Response time is 1-3 hour, preferably 2 hours.
Compound shown in formula (2) and pemedolac can promoted generation in the presence of the chemical agent that peptide bond is formed by step 5)
Reaction, prepares compound shown in formula (1) through extracting, being dried.
Shown in described pemedolac and formula (2), the consumption mass ratio of compound is 1:1-3, preferably 1:1.Reaction temperature is
Room temperature；Response time is 1-2 hour, preferably 1 hour.
Described can promote that the chemical agent that peptide bond is formed includes CDMT(2-chloro-4,6-dimethoxy-1,3,5-three
Piperazine), DCC(N, N-dicyclohexylcarbodiimide), HOBT(hydroxybenzotriazole) or EDC(1-ethyl-3-(3-dimethylamino
Propyl group) carbodiimide) in one or more, preferably CDMT(2-chlorine-4,6-dimethoxy-1,3,5-triazine).
Step 6) by compound generation hydrolysis shown in formula (1), then through acid adjustment, filter, be dried that to prepare training U.S. bent
Plug impurity D.
Described hydrolysising reacting temperature is 20-30 DEG C；Response time is 1-2 hour, preferably 1 hour；Regulation reaction solution
PH value is between 8-9.Being preferably hydrolyzed under basic conditions, described alkali includes that alkali is alkali metal or alkaline earth metal hydroxide,
It is preferably sodium hydroxide.
Further object is that offer a kind of pemetrexed pharmaceutical product detection is analyzed and the side of quality control
Method, it is characterised in that during finished product detection analysis and control, the contamination levels product used are for as described in claim 1-10
Method prepare gained.
The pemetrexed impurity (D) of present invention offer and the preparation method of salt thereof, reaction condition is gentle, and product purity is high,
Analyze for the detection of pemetrexed pharmaceutical product and the method for quality control provides contamination levels product, thus be pemetrexed medicine
Lmpurities qualitative and quantitative analysis provides contrast；Also for studying kind and content, the impurity of impurity in pemetrexed medicine
The impact of stability and drug effect etc. that medicine is prepared as preparation provides reference frame, is conducive to adding the control of strong impurity, from
And reach to improve the purpose of product quality.
Detailed description of the invention
In order to make technical problem solved by the invention, technical scheme and beneficial effect clearer, below in conjunction with
Specific embodiment, the present invention is further illustrated.
Compound shown in formula (6) be N-tertbutyloxycarbonyl-Pidolidone 5-benzyl ester from commercially available, as being purchased from lark prestige
Science and Technology Ltd., Shanghai Mai Ruier chemical technology company limited or Shanghai De Mo Pharmaceutical Technology Co., Ltd etc..
Embodiment 1:
Compound shown in 7.8g formula (6) is dissolved in 100ml dichloromethane solution, adds 4.8g dicyclohexyl carbon two
Imines, 0.2g DMAP, 5ml dehydrated alcohol, reaction 4 hour is stirred at room temperature, sucking filtration removes solvent and obtains 8.3g formula
(5) compound shown in.MS[M+1]+366。
Compound shown in 8.3g formula (5) being dissolved in 60ml methanol, adds 0.8g palladium carbon, atmospheric pressure at room hydrogenates 2 hours, takes out
Filtering palladium carbon, filtrate decompression removes solvent and obtains the compound shown in 4.6g formula (4).MS[M-1]-274。
Compound shown in 4.6g formula (4) is dissolved in 50ml dichloromethane solution, adds 7.8g N, N-dicyclohexyl carbon
Diimine, 3.3g hydroxybenzotriazole, 11.5g glutamate diethyl ester, reacts while stirring at 0 DEG C 1 hour, is warmed to room temperature limit and stirs
Mixing limit to react 12 hours, add 100ml dchloromethane, 100ml washes, and 100ml saturated common salt is washed, anhydrous sodium sulfate
Being dried, removal of solvent under reduced pressure obtains the compound shown in 6.1g formula (3).
1H NMR (d6-DMSO) δ 1.28(t, 9H), 1.38 (s, 9H), 2.10-2.25 (m, 4H), 2.29 (m, 2H),
2.35 (m, 2H), 4.10-4.23 (m, 6H), 4.52 (m, 2H), 8.10 (br s, 2H).
Compound shown in 6.1g formula (3) adds in 10ml dichloromethane solution, adds 10ml trifluoroacetic acid solution, room
Reacting while stirring under temperature 2 hours, removal of solvent under reduced pressure and trifluoroacetic acid solution obtain the compound shown in 7.7g formula (2).MS[M
+1]+361。
2g pemedolac, 1.3g2-chloro-4,6-dimethoxy-1,3,5-triazine are sequentially added into 15ml dimethylformamide
In solution, it is down to 5 DEG C, then drips 2ml methyl morpholine, stir 1.5 hours at 25 DEG C, then be down to 0 DEG C, add shown in formula (2)
Compound 2g, reacts at 25 DEG C 1 hour while stirring, adds 80ml water, and 150ml dichloromethane extracts 1 time, takes organic layer anhydrous
Sodium sulfate is dried, and removal of solvent under reduced pressure obtains the compound shown in 1.7g formula (1).Efficiently Liquid Detection display purity is more than 98%.
1H NMR(d6-DMSO) δ 1.29(t,6H),2.03(m,2H),2.17(m,3H),2.35(m,2H), 2.67
(s,4H),
4.03(m,1H),4.32(m,1H),6.19(s,1H),7.08(d,2H),7.57(d,2H)。
Compound shown in 1.7g formula (1) is added in 10ml 1N sodium hydroxide solution, at 25 DEG C, reacts 1 while stirring
Hour, it being 8 with 1N hydrochloric acid conditioning solution pH value, then add 80ml ethanol, sucking filtration, filter cake uses a small amount of water, ethanol rinse, decompression successively
It is dried to obtain 0.7g pemetrexed impurity (D).Efficiently Liquid Detection display purity is more than 98%.
1H NMR(D2O) δ 1.82(m,1H),2.01(m,2H),2.18(m,3H),2.38(m,2H), 2.67(s,
4H),
4.04(m,1H),4.31(m,1H),6.19(s,1H),7.07(d,2H),7.57(d,2H)。
Embodiment 2:
Compound shown in 8.2g formula (6) is dissolved in 100ml diethyl ether solution, adds 4.5g dicyclohexyl carbon two sub-
Amine, 0.2g DMAP, 5ml dehydrated alcohol, reaction 2 hour is stirred at room temperature, sucking filtration removes solvent and obtains 8.3g formula (5)
Shown compound.MS[M+1]+366。
Compound shown in 8.2g formula (5) being dissolved in 60ml 2-propanol, adds 0.8g palladium carbon, it is little that atmospheric pressure at room hydrogenates 1
Time, sucking filtration removes palladium carbon, and filtrate decompression removes solvent and obtains the compound shown in 4.5g formula (4).MS[M-1]-274。
Compound shown in 4.5g formula (4) is dissolved in 50ml petroleum ether solution, adds 7.8g N, N-dicyclohexyl carbon two
Imines, 3.3g hydroxybenzotriazole, 4.5g glutamate diethyl ester, reacts while stirring at 0 DEG C 1 hour, is warmed to room temperature limit stirring
Limit is reacted 10 hours, adds 100ml dchloromethane, and 100ml washes, and 100ml saturated common salt is washed, and anhydrous sodium sulfate is done
Dry, removal of solvent under reduced pressure obtains the compound shown in 4.8g formula (3).
1H NMR (d6-DMSO) δ 1.28(t, 9H), 1.38 (s, 9H), 2.10-2.25 (m, 4H), 2.29 (m, 2H),
2.35 (m, 2H), 4.10-4.23 (m, 6H), 4.52 (m, 2H), 8.10 (br s, 2H).
Compound shown in 4.5g formula (3) is added 10ml petroleum ether solution, adds 10ml trifluoroacetic acid solution, room temperature
Under react while stirring 1 hour, removal of solvent under reduced pressure and trifluoroacetic acid solution obtain the compound shown in 5.2g formula (2).MS[M+
1]+361。
By 2g pemedolac, 1.3g N, N-dicyclohexylcarbodiimide is sequentially added in 15ml dimethyl formamide solution,
It is down to 3 DEG C, then drips 2ml methyl morpholine, stir 1.5 hours at 25 DEG C, then be down to 0 DEG C, add the compound shown in formula (2)
4g, reacts at 25 DEG C 1.5 hours while stirring, adds 80ml water, and 150ml dichloromethane extracts 1 time, takes organic layer anhydrous slufuric acid
Sodium is dried, and removal of solvent under reduced pressure obtains the compound shown in 2.5g formula (1).Efficiently Liquid Detection display purity is more than 95%.
1H NMR(d6-DMSO) δ 1.29(t,6H),2.03(m,2H),2.17(m,3H),2.35(m,2H), 2.67
(s,4H),
4.03(m,1H),4.32(m,1H),6.19(s,1H),7.08(d,2H),7.57(d,2H)。
Compound shown in 2.1g formula (1) is added in 10ml 1N potassium hydroxide solution, reacts while stirring at 20 DEG C
1.5 hours, be 9 with 1N hydrochloric acid conditioning solution pH value, then adds 80ml ethanol, sucking filtration, and a small amount of water used successively by filter cake, ethanol rinse,
Drying under reduced pressure obtains 0.9g pemetrexed impurity (D).Efficiently Liquid Detection display purity is more than 97%.
1H NMR(D2O) δ 1.82(m,1H),2.01(m,2H),2.18(m,3H),2.38(m,2H), 2.67(s,
4H),
4.04(m,1H),4.31(m,1H),6.19(s,1H),7.07(d,2H),7.57(d,2H)。
Embodiment 3:
Compound shown in 7.6g formula (6) is dissolved in 100ml petroleum ether solution, adds 4.5g dicyclohexyl carbon two sub-
Amine, 0.2g DMAP, 5ml dehydrated alcohol, reaction 6 hour is stirred at room temperature, sucking filtration removes solvent and obtains 8.3g formula (5)
Shown compound.MS[M+1]+366。
Compound shown in 8.0g formula (5) being dissolved in 60ml isobutanol, adds 0.8g palladium carbon, atmospheric pressure at room hydrogenates 3 hours,
Sucking filtration removes palladium carbon, and filtrate decompression removes solvent and obtains the compound shown in 4.5g formula (4).MS[M-1]-274。
Compound shown in 4.5g formula (4) is dissolved in 50ml diethyl ether solution, adds 7.8g N, N-dicyclohexyl carbon two sub-
Amine, 3.3g hydroxybenzotriazole, 4.5g glutamate diethyl ester, reacts while stirring at 0 DEG C 1 hour, is warmed to room temperature while stirring
Reacting 20 hours, add 100ml dchloromethane, 100ml washes, and 100ml saturated common salt is washed, and anhydrous sodium sulfate is done
Dry, removal of solvent under reduced pressure obtains the compound shown in 4.8g formula (3).
1H NMR (d6-DMSO) δ 1.28(t, 9H), 1.38 (s, 9H), 2.10-2.25 (m, 4H), 2.29 (m, 2H),
2.35 (m, 2H), 4.10-4.23 (m, 6H), 4.52 (m, 2H), 8.10 (br s, 2H).
Compound shown in 4.5g formula (3) is added 10ml diethyl ether solution, adds 10ml trifluoroacetic acid solution, under room temperature
Reaction 3 hours while stirring, removal of solvent under reduced pressure and trifluoroacetic acid solution obtain the compound shown in 5.2g formula (2).MS[M+1]+
361。
By 2g pemedolac, 0.5g hydroxybenzotriazole and 0.8g 1-ethyl-3-(3-dimethylaminopropyl) carbon two Asia
Amine is sequentially added in 15ml dimethyl formamide solution, is down to 5 DEG C, then drips 2ml methyl morpholine, stirs 1 hour at 25 DEG C, then
It is down to 2 DEG C, adds the compound shown in 6g formula (2), react while stirring at 25 DEG C 2 hours, add 80ml water, 150ml dichloro
Methane extracts 1 time, takes organic layer anhydrous sodium sulfate and is dried, and removal of solvent under reduced pressure obtains the compound shown in 2.8g formula (1).High-efficient liquid
Detection display purity is more than 95% mutually.
1H NMR(d6-DMSO) δ 1.29(t,6H),2.03(m,2H),2.17(m,3H),2.35(m,2H), 2.67
(s,4H),
4.03(m,1H),4.32(m,1H),6.19(s,1H),7.08(d,2H),7.57(d,2H)。
Compound shown in 2.5g formula (1) is added in 10ml 1N hydrochloric acid solution, reacts 2 at 30 DEG C while stirring little
Time, it being 8 with 1N hydrochloric acid conditioning solution pH value, then add 80ml ethanol, sucking filtration, filter cake uses a small amount of water, ethanol rinse successively, and decompression is dry
Dry 1.2g pemetrexed impurity (D).Efficiently Liquid Detection display purity is more than 96%.
1H NMR(D2O) δ 1.82(m,1H),2.01(m,2H),2.18(m,3H),2.38(m,2H), 2.67(s,
4H),
4.04(m,1H),4.31(m,1H),6.19(s,1H),7.07(d,2H),7.57(d,2H)。
Use mass spectrograph (MS) that target product pemetrexed impurity (D) in above-described embodiment is detected,
Measurement result such as following table:
The mass spectroscopy result of table 1 pemetrexed impurity
| Mass-to-charge ratio (m/z) | Relative abundance | Remarks |
| 557 | 100 | [M-3Na+4H]+ |
| 579 | 30 | [M-2Na+3H]+ |
| 595 | 20 | [M-Na+2H]+ |
As seen from the above table, ESI(+) record [M-3Na+4H] of target product pemetrexed disodium impurity (D) of the present invention+Peak
Mass-to-charge ratio be 557, the molecular weight of target product pemetrexed disodium impurity (D) of the present invention is 622, with the molecule of sample impurity
Amount is consistent.The molecular weight of target product pemetrexed disodium impurity (D) of the present invention is even number, should contain even number atom N in molecule,
This is consistent with the structure containing 6 atom N in impurity.
It should be noted that, the foregoing is only presently preferred embodiments of the present invention, not in order to limit the present invention, all
Any amendment, equivalent and the improvement etc. made within the spirit and principles in the present invention, should be included in the guarantor of the present invention
Within the scope of protecting.
Claims (1)
1. a pemetrexed pharmaceutical product detection is analyzed and the method for quality control, it is characterised in that the contamination levels used
Product are the compound shown in formula (D), and the preparation method of its Chinese style (D) is as follows:
Wherein, compound shown in formula (5) is by compound shown in formula (6) at room temperature occurs that acylation reaction prepare；
Compound shown in formula (4) is to be sloughed benzyl protecting group in alcoholic solution by compound shown in formula (5) to prepare；
Compound shown in formula (3) is at room temperature to be occurred condensation reaction to prepare by compound shown in formula (4) and glutamate diethyl ester；
Compound shown in formula (2) is to be sloughed protection group in acid condition by compound shown in formula (3) to prepare；
Compound shown in formula (1) is can be promoted depositing of chemical agent that peptide bond is formed by compound shown in formula (2) and pemedolac
Reacting under prepared, the described chemical agent that can promote that peptide bond is formed includes 2-chloro-4,6-dimethoxy-1,3,5-tri-
Piperazine,
In N, N-dicyclohexylcarbodiimide, hydroxybenzotriazole or 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide
One or more；
Compound shown in formula (1) is prepared compound shown in formula (D) through hydrolysis.
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| CN104292232A (en) * | 2014-10-01 | 2015-01-21 | 山东铂源药业有限公司 | Synthesis method for intermediate of impurity A of pemetrexed disodium |
| CN105175423A (en) * | 2015-10-15 | 2015-12-23 | 南京先声东元制药有限公司 | Pemetrexed derivatives and preparation method and application thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0492316A1 (en) * | 1990-12-14 | 1992-07-01 | Takeda Chemical Industries, Ltd. | Condensed heterocyclic oligoglutamate derivatives, their production and pharmaceutical compositions containing them |
| CN101417998A (en) * | 2007-10-24 | 2009-04-29 | 重庆医药工业研究院有限责任公司 | Purification method of pemetrexed salt |
| CN102344452A (en) * | 2010-07-22 | 2012-02-08 | 凯米股份公司 | A novel process for the synthesis of pemetrexed disodium salt |
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| JP5796570B2 (en) * | 2010-03-24 | 2015-10-21 | 味の素株式会社 | Glutamic acid ester derivative or salt thereof |
| WO2012056285A1 (en) * | 2010-10-25 | 2012-05-03 | Fresenius Kabi Oncology Ltd. | An improved process for the preparation of pemetrexed |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0492316A1 (en) * | 1990-12-14 | 1992-07-01 | Takeda Chemical Industries, Ltd. | Condensed heterocyclic oligoglutamate derivatives, their production and pharmaceutical compositions containing them |
| CN101417998A (en) * | 2007-10-24 | 2009-04-29 | 重庆医药工业研究院有限责任公司 | Purification method of pemetrexed salt |
| CN102344452A (en) * | 2010-07-22 | 2012-02-08 | 凯米股份公司 | A novel process for the synthesis of pemetrexed disodium salt |
Non-Patent Citations (1)
| Title |
|---|
| "synthesis of pteroly-γ-glutamyl-γ-glutamylglutamic acid（teropterin）";J. H. Boothe等，;《Transactions of the New York Academy of Sciences》;20120430;第10卷(第3期);第70-71页 * |
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Effective date of registration: 20200310 Address after: 225400 No. 22 Binjiang South Road, Taixing Economic Development Zone, Taizhou City, Jiangsu Province Co-patentee after: Xintai Pharmaceutical (Suzhou) Co., Ltd. Patentee after: Borui Biomedicine Taixing Co., Ltd. Address before: Xinghu Street Industrial Park of Suzhou city in Jiangsu province 215123 No. 218 BioBAY building C27 Patentee before: Xintai Pharmaceutical (Suzhou) Co., Ltd. |
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Address after: 22 Binjiang South Road, Taixing Economic Development Zone, Taizhou City, Jiangsu Province Patentee after: BRIGHTGENE BIO-MEDICAL TECHNOLOGY Co.,Ltd. Patentee after: Borui Pharmaceutical (Suzhou) Co., Ltd Address before: 22 Binjiang South Road, Taixing Economic Development Zone, Taizhou City, Jiangsu Province Patentee before: BRIGHTGENE BIO-MEDICAL TECHNOLOGY Co.,Ltd. Patentee before: XINTAI PHARMACEUTICAL (SUZHOU) Co.,Ltd. |
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