CN106220634B - The related substances F and G of pemetrexed disodium and its preparation and detection method - Google Patents
The related substances F and G of pemetrexed disodium and its preparation and detection method Download PDFInfo
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- CN106220634B CN106220634B CN201610629115.6A CN201610629115A CN106220634B CN 106220634 B CN106220634 B CN 106220634B CN 201610629115 A CN201610629115 A CN 201610629115A CN 106220634 B CN106220634 B CN 106220634B
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- related substances
- pemetrexed disodium
- detection method
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- 12mmol
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- 0 *CC[C@](*=C*)NC(c1ccc(CCc2c[n]c(NC(N)=N3)c2C3O)cc1)=O Chemical compound *CC[C@](*=C*)NC(c1ccc(CCc2c[n]c(NC(N)=N3)c2C3O)cc1)=O 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/62—Detectors specially adapted therefor
- G01N30/74—Optical detectors
Abstract
Present invention is disclosed the related substances F and G of a kind of antineoplastic pemetrexed disodium, and to described two substances carried out prepare and detect study, this for improve pemetrexed disodium drug quality and safety, have significant economic and technical benefit.The chemical formula of wherein described two substances is as follows：
Description
Technical field
The invention belongs to organic synthetic route design and its bulk pharmaceutical chemicals and intermediate preparing technical field, more particularly to a kind of
The related substances of pemetrexed disodium and its preparation and detection method.
Background technology
Pemetrexed disodium (Pemetrexed disodium) is a kind of novel more target position leaves containing pyrrolopyrimidine group
Sour retarding agent.Required a variety of enzymes in cancer cell division and hyperplastic process can be blocked, it is antitumor to achieve the effect that.It should
Medicine is developed by Lilly (Eli Lilly) company, in 2004 in U.S.'s Initial Public Offering, is approved for treating with Cisplatin
Malignant pleural mesothelioma and non-small cell lung cancer, trade name Alimta (Alimta).In December, 2005 medicine in Discussion on Chinese Listed,
The indication of approval is malignant pleural mesothelioma.
[[(2- amino -4,7- dihydro -4- oxygen -1H- pyrroles [2,3-d] is phonetic by 2- by 4- by the entitled N- of chemistry of pemetrexed disodium
Pyridine -5- bases) ethyl] benzoyl]-Pidolidone disodium salt, chemical formula is：
Pemetrexed disodium bulk pharmaceutical chemicals have listed, and United States drug approval (USP) and European Union's drug standards (EP) etc. are carried
And the known related substances of the drug include five kinds of related substances A, B, C, D and E etc., respectively process contaminants (A and D), alkali
Property degradation impurity (B and C) and optical isomer impurity E.Respectively chemical formula is as follows for its：
From above-mentioned five kinds of related substances and its mechanism of production analysis having disclosed, research is not directed to oxidation process institute
The impurity of generation, however oxidative factors are inevitable influence factor during bulk pharmaceutical chemicals storage and use.
Therefore, it is necessory to be conducted further research with regard to its oxidation process, result of study trains antineoplastic beautiful
Song plug disodium product quality and the safety is improved have realistic meaning, can be better achieved the drug economy and society effect
Benefit.
Invention content
It is an object of the invention on the basis of existing pemetrexed disodium quality standard, with regard to its oxidation process into traveling
The research of one step, proposes new issuable related substances, and the related substances new to this detached, purified, prepare with
And detection.The research result has realistic meaning for the product quality and safety that improve pemetrexed disodium, can promote
The economic technology of the bulk pharmaceutical chemicals develops.
To achieve the goals above, main technical schemes provided by the present invention are as follows：
A kind of the related substances F and G of pemetrexed disodium, chemical name are respectively (5R)-N- [4- [2- (2- amino-
4,5,6,7- tetrahydrochysene -4,6- dioxy -1H- pyrroles [2,3-d] pyrimidine -5- bases) ethyl] benzoyl]-Pidolidone, and (5S) -
N- [4- [2- (2- amino -4,5,6,7- tetrahydrochysene -4,6- dioxy -1H- pyrroles [2,3-d] pyrimidine -5- bases) ethyl] benzoyl]-L-
The chemical formula difference of glutamic acid, the two is as follows：
Further, another embodiment of the invention additionally provides a kind of pemetrexed two of the present invention
The preparation method of related substances two kinds of substances of F and G of sodium, step be using pemetrexed disodium as raw material, by with hydrogen peroxide
Oxidation reaction obtain related substances F and related substances G.Its synthetic route is as follows：
Further, in different embodiments, wherein the solvent of the oxidation reaction is water.
Further, in different embodiments, wherein the solvent of the oxidation reaction is water and ethyl alcohol, methanol, second
One kind in nitrile or tetrahydrofuran.It is preferred that water and tetrahydrofuran.
Further, in different embodiments, wherein the temperature of the oxidation reaction is 0~30 DEG C.It is preferred that 15-25
℃。
Further, another embodiment of the invention additionally provides a kind of pemetrexed two of the present invention
The detection method of related substances two kinds of substances of F and G of sodium detects for high performance liquid chromatography (HPLC), includes the following steps：
(1) select and determine chromatographic column be column/150 C8 × 4.6mm/3.5 μm, column temperature is 20~50 DEG C, wavelength be 245~
260nm and flow velocity are 0.5~1.5mL/min；
(2) acetonitrile of the ammonium formate solution and 10~1% volumes of the 12mmol/L that mobile phase A is 90~99% volumes is prepared
With formic acid tune pH value to 3.5 after mixing；Prepare the ammonium formate solution of the 12mmol/L that Mobile phase B is 50~90% volumes with 50~
With first acid for adjusting pH to 3.5 after the acetonitrile mixing of 10% volume；And determine mobile phase gradient timetable program be 100%~0%/
0~55min；
(3) it measures and records chromatogram.
Further, in different embodiments, wherein the column temperature of the chromatographic column is 25 DEG C, wavelength 250nm, flow velocity
For 1.0mL/min.
Further, in different embodiments, wherein the mobile phase A is the ammonium formate of the 12mmol/L of 95% volume
Solution mixed with the acetonitrile of 5% volume after with formic acid tune pH value to 3.5；The Mobile phase B is the 12mmol/L's of 70% volume
Ammonium formate solution uses first acid for adjusting pH to 3.5 after being mixed with the acetonitrile of 30% volume.
A kind of antitumor drug pemetrexed disodium that the present invention discloses in an oxidizing environment caused by related substances F and
Related substances G, and the oxidation impurities isolate and purify, structural identification and preparation and detection are studied.It studies knot
The quality control of pemetrexed disodium, quality are improved fruit and drug safety all has realistic meaning, promotes the medicine
The further development of the economic and technical of product.
Description of the drawings
Fig. 1 is the high-efficient liquid phase chromatogram of the related substances F and G of pemetrexed disodium of the present invention.
Specific implementation mode
Below with reference to preferred embodiment to the related substances F and G of pemetrexed disodium of the present invention and its preparation
It is further non-limitingly described in detail with the technical solution of detection method.
Embodiment one：The preparation of pemetrexed disodium related substances F and related substances G
At room temperature, pemetrexed disodium (4.7g, 10mmol) and water 50mL are added in reaction bulb, stirring adds to dissolving
Enter 18% hydrogen peroxide 3.5mL, kept for 20~30 DEG C, stir 3~5 hours, TLC detections, reaction is completed.
Dichloromethane 50mL is added, is used in combination salt acid for adjusting pH to 3~4, stirs 30 minutes, layering concentrates organic phase, gained
Grease is detached through column chromatography (ethyl acetate/methanol=5/1), obtains pemetrexed disodium related substances F's and related substances G
Off-white powder 3.1g, yield 70.0%.1H NMR(DMSO-d6)δ8.43(s,4H,),8.16(m,1H),7.73(m,2H),
7.54 (s, 2H), 7.25 (d, J=6.8Hz, 2H), 4.17 (m, 1H), 3.30 (m, 1H), 2.68 (m, 2H), 2.20 (m, 2H),
2.02(m,2H),1.94(m,2H)；EI-MS m/z 443(M+H).
The synthetic route being directed to is as follows：
Embodiment two：The high-efficiency liquid chromatography method for detecting of pemetrexed disodium related substances F and related substances G
Using high performance liquid chromatography (HPLC), to pemetrexed disodium related substances F of the present invention and related substances G
It is detected comprising following steps：
(1) C8/150 × 4.6mm/3.5 μm of chromatographic column, 25 DEG C of column temperature, wavelength 250nm and flow velocity are 1.0mL/min；
(2) it prepares after mobile phase A mixes for the ammonium formate solution of the 12mmol/L of 95% volume with the acetonitrile of 5% volume and uses
Formic acid tune pH value is to 3.5；The acetonitrile of the ammonium formate solution for preparing the 12mmol/L that Mobile phase B is 70% volume and 30% volume is mixed
With first acid for adjusting pH to 3.5 after conjunction；Determine that the gradient timetable program of mobile phase is 100%~0%/0~55min；
Detailed gradient design is：
(3) chromatogram is measured and records, testing result please refers to Fig.1 shown.
A kind of antitumor drug pemetrexed disodium that the present invention discloses in an oxidizing environment caused by related substances F and
Related substances G, and the oxidation impurities isolate and purify, structural identification and preparation and detection are studied.It studies knot
The quality control of pemetrexed disodium, quality are improved fruit and drug safety all has realistic meaning, promotes the medicine
The further development of the economic and technical of product.
It is pointed out that the technical concepts and features of above-mentioned preferred embodiment only to illustrate the invention, its object is to
Those skilled in the art can understand the contents of the present invention and implements according to this, and the protection of the present invention can not be limited with this
Range.Any equivalent change or modification in accordance with the spirit of the invention should be covered by the protection scope of the present invention.
Claims (4)
1. the detection method of the related substances F and G of a kind of pemetrexed disodium, wherein the chemical name of the related substances F is
(5R)-N- [4- [2- (2- amino -4,5,6,7- tetrahydrochysene -4,6- dioxy -1H- pyrroles [2,3-d] pyrimidine -5- bases) ethyl] benzene first
Acyl] chemical name of-Pidolidone and the related substances G is (5S)-N- [4- [2- (2- amino -4,5,6,7- tetrahydrochysenes -
4,6- dioxy -1H- pyrroles [2,3-d] pyrimidine -5- bases) ethyl] benzoyl]-Pidolidone；The chemical formula of the two distinguishes following institute
Show：
It is characterized in that the detection method is high performance liquid chromatography detection；Include the following steps：
(1) select and determine chromatographic column be column/150 C8 × 4.6mm/3.5 μm, column temperature is 20~50 DEG C, wavelength be 245~
260nm and flow velocity are 0.5~1.5mL/min；
(2) ammonium formate solution for preparing the 12mmol/L that mobile phase A is 90~99% volumes is mixed with the acetonitrile of 10~1% volumes
Afterwards with formic acid tune pH value to 3.5；Prepare the ammonium formate solution and 50~10% for the 12mmol/L that Mobile phase B is 50~90% volumes
With first acid for adjusting pH to 3.5 after the acetonitrile mixing of volume；And determine mobile phase gradient timetable program be 100%~0%/0~
55min；
(3) it measures and records chromatogram.
2. the detection method of the related substances F and G of pemetrexed disodium as described in claim 1, it is characterised in that：Wherein institute
The column temperature for stating chromatographic column is 25 DEG C, wavelength 250nm, flow velocity 1.0mL/min.
3. the detection method of the related substances F and G of pemetrexed disodium as described in claim 1, it is characterised in that：Wherein institute
State mobile phase A be 95% volume 12mmol/L ammonium formate solution mixed with the acetonitrile of 5% volume after with formic acid tune pH value extremely
3.5。
4. the detection method of the related substances F and G of pemetrexed disodium as described in claim 1, it is characterised in that：The stream
Dynamic phase B is after the ammonium formate solution of the 12mmol/L of 70% volume is mixed with the acetonitrile of 30% volume with first acid for adjusting pH to 3.5.
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| CN201610629115.6A CN106220634B (en) | 2016-08-03 | 2016-08-03 | The related substances F and G of pemetrexed disodium and its preparation and detection method |
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| CN111592547B (en) * | 2020-06-01 | 2023-08-04 | 江苏海洋大学 | Preparation method of pemetrexed and related substances of pharmaceutically acceptable salts thereof |
| CN111521714B (en) * | 2020-06-08 | 2022-08-19 | 重庆三圣实业股份有限公司 | Method for separating and measuring capecitabine and impurities thereof |
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| CN101560206B (en) * | 2009-05-21 | 2011-06-22 | 苏州立新制药有限公司 | Intermediate of pemetrexed disodium, preparation method thereof and method for preparing pemetrexed disodium thereby |
| CN102827168A (en) * | 2012-09-24 | 2012-12-19 | 苏州立新制药有限公司 | Preparation method of pemetrexed intermediate |
| WO2014122109A1 (en) * | 2013-02-05 | 2014-08-14 | Novozymes A/S | Enzymatic preparation of indigo dyes and intermediates |
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