CN106957312A - Raltitrexed hydrate crystal forms and preparation method thereof - Google Patents
Raltitrexed hydrate crystal forms and preparation method thereof Download PDFInfo
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- CN106957312A CN106957312A CN201611245842.9A CN201611245842A CN106957312A CN 106957312 A CN106957312 A CN 106957312A CN 201611245842 A CN201611245842 A CN 201611245842A CN 106957312 A CN106957312 A CN 106957312A
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract
The invention belongs to pharmaceutical synthesis field, and in particular to crystal formation of Raltitrexed and preparation method thereof.The Raltitrexed crystal formation of the present invention is hydrate, and the mol ratio of Raltitrexed and water is 1：0.5~3.The present invention is used and is dissolved in Raltitrexed in the mixed solvent of water and organic solvent, then the method for dropwise addition anti-solvent water prepares Raltitrexed novel crystal forms thereto, and the organic solvent is tetrahydrofuran, Isosorbide-5-Nitrae dioxane.The crystal formation of the present invention can keep good storage stability, it is easy to industrialized production, and nothing draws moist, it is to avoid water suction, provide convenient for transport, production, pharmaceutical preparation, possess certain prospect in medicine.
Description
Technical field
The invention belongs to pharmaceutical synthesis field, and in particular to novel crystal forms, its preparation method and the purposes of Raltitrexed.
Background technology
Raltitrexed is cooperated development with Zeneca by the cancer research administration of the Royal Marsden hospitals of Britain
Medicine.It is a kind of thymus gland synthetase inhibitors, belongs to the derivative of folic acid, for treating late period carcinoma of the colon and rectum patient.
Listed in Britain's Initial Public Offering, trade name Tomudex, the same year in the country such as France within 1996.It is used as advanced colorectal cancer
First-line treatment medicine, has the advantages that small toxic and side effect, convenient drug administration, cheap, big in the demand of China.
Raltitrexed physicochemical properties are unstable, to light, wet, hot more sensitive.
Synthetic method, process for purification etc. are concentrated on to the report of Raltitrexed at present, to the research report of Raltitrexed crystal formation
Road is less.
Disclosed in United States Patent (USP) US4992550B and Raltitrexed monohydrate obtained by the process for purification of alkali-soluble acid analysis,
Fusing point is 180-184 DEG C (hereinafter referred to as crystal formation I), and this method can produce a large amount of sodium chloride, cause sodium chloride to remain, post-processed
Cheng Zhongxu could be removed by repeatedly mashing.Chinese patent CN103570702A is disclosed rotates crystallization preparation by absolute methanol
Raltitrexed crystalline solid, fusing point is 171-183 DEG C.Chinese patent CN102424679B is disclosed is dissolved in methanol by crude product, then
The process for purification that purified water obtains faint yellow solid is added thereto.Chinese patent CN102127063A disclose using methanol-
The method of absolute ether recrystallization.
The inventors discovered that Raltitrexed or the thunder by commercially available purchase that the method recorded using current document is obtained
Draw moist strong for Qu Sai, easily the moisture absorption, cause its character to change and purity reduction, to transport, storage and pharmaceutical preparation
Make troubles.
The content of the invention
The technical problem to be solved in the present invention is the easy moisture absorption of Raltitrexed, the stability difference for overcoming prior art to prepare
Defect there is provided a kind of Raltitrexed crystal formation of stabilization with and its preparation method and application.
The invention provides the Raltitrexed hydrate with following structure, hereinafter referred to as crystal formation II：
Wherein, n=0.5~3, preferably n=0.5~1.
The crystal formation II of the present invention is radiated by Cu-Ka, the X-ray powder diffraction represented using 2 θ angles 2 θ values as 6.0 ±
0.2°、7.1±0.2°、8.1±0.2°、13.5±0.2°、14.3±0.2°、16.3±0.2°、18.4±0.2°、19.2±
There is characteristic peak at 0.2 °, 20.6 ± 0.2 °, 26.5 ± 0.2 °；Preferably, X-ray powder diffraction 2 θ values be 6.0 ± 0.2 °,
7.1±0.2°、8.1±0.2°、13.5±0.2°、14.3±0.2°、15.2±0.2°、16.3±0.2°、17.7±0.2°、
18.4±0.2°、19.2±0.2°、20.6±0.2°、21.8±0.2°、24.2±0.2°、26.5±0.2°、28.0±0.2°、
There is characteristic peak at 31.0 ± 0.2 °；It is highly preferred that it has X-ray powder diffraction pattern as shown in Figure 1.
Understand that weight loss, weight occurs in the range of 50~150 DEG C in crystal formation II of the invention through thermogravimetric analysis (TGA)
The mass fraction of loss is 1.7%~4.4%；In a preferred embodiment of the invention, the TGA collection of illustrative plates of the crystal formation II is such as
Shown in Fig. 2；In another preferred embodiment of the invention, the TGA collection of illustrative plates of the crystal formation II is as shown in Figure 5.
Determined through differential scanning calorimetric analysis (DSC), its DSC collection of illustrative plates of crystal formation II of the invention respectively 100~110 DEG C,
There is endothermic peak in the range of 170~185 DEG C；In a preferred embodiment of the invention, the DSC collection of illustrative plates of the crystal formation II is as schemed
Shown in 3；In another preferred embodiment of the invention, the DSC collection of illustrative plates of the crystal formation II is as shown in Figure 6.
In addition, present invention also offers the monocrystalline of Raltitrexed trihydrate, X-ray single crystal diffraction as shown by data, it is
Monoclinic system, axial lengthCrystal face angle α=90.00 °, β=
90.00 °, γ=90.00 °, X single crystal diffraction collection of illustrative plates is as shown in Figure 7.One of water is to combine water as seen from the figure, in addition 2 water
For passage water.
On the other hand, the invention provides crystal formation II preparation method, the method includes the steps of：(a) by thunder for song
Crude product heating for dissolving is filled in water and the mixed solvent of organic solvent；(b) 0~10 DEG C is cooled to, crystallization is stood；(c) separate, dry
Produce.Wherein described organic solvent is selected from tetrahydrofuran, Isosorbide-5-Nitrae-dioxane.
In step (a), the mass ratio of water and organic solvent is 1：0.25~4.
In step (b), optionally, anti-solvent water is added into system, the amount of anti-solvent water is the quality proportion for adding to water
For 80~90%.
In step (c), drying mode is preferably dried in vacuo, and preferably drying temperature is 30~60 DEG C.Drying temperature and time
Difference, can obtain the hydrate of different molar contents, as shown in the table：
(1) screening of recrystallization solvent
Experiment shows that Raltitrexed is insoluble in water, is also insoluble in the organic solvents such as tetrahydrofuran, but inventor is surprised
Ground is found, in the suspension of Raltitrexed tetrahydrofuran suspension or Isosorbide-5-Nitrae-dioxane, is added after a certain proportion of water,
Raltitrexed dissolubility strengthens.Recrystallization can obtain Raltitrexed crystal in the mixed system of water and organic solvent.Following table
It is specific screening process, is 1 by mass ratio：1 water and organic solvent is carried out as recrystallization solvent to crude product Raltitrexed
Recrystallization, it is as a result as follows：
| Solvent | Dissolving crude product | Recrystallize result |
| Water/THF | Dissolving | Crystal formation II |
| Water/Isosorbide-5-Nitrae-dioxane | Dissolving | Crystal formation II |
| Water/isopropanol | It is partly dissolved | It is unformed |
| Water/1-METHYLPYRROLIDONE | It is partly dissolved | It is unformed |
Upper table shows, can obtain crystal formation II in water/THF, water/Isosorbide-5-Nitrae-dioxane, and water/isopropanol or water/
Obtained in 1-METHYLPYRROLIDONE mixed system to be unformed.
(2) research of mixed solvent ratio
Inventor also found and be produced in the water of different proportion and the mixed solvent of above-mentioned two kinds of organic solvents obtained by recrystallization
The crystal formation of product is different, and the crystal formation II of the present invention can be just obtained only in the mixed solvent of special ratios.With water and tetrahydrofuran
Exemplified by, shown in table specific as follows：
Above-mentioned result of the test shows, is 1 in water and tetrahydrofuran mass ratio：When 0.25~4, crystal formation II can be obtained.Hair
A person of good sense has also investigated the ratio of water and Isosorbide-5-Nitrae-dioxane, equally, and crystal formation II can be obtained in the proportion.
Beneficial effects of the present invention：Inventors unexpectedly discovered that with the mixed of the poor solvent composition of two kinds of Raltitrexeds
Bonding solvent (water/organic solvent) can prepare the novel crystal forms of Raltitrexed for recrystallization solvent, by X-ray powder diffraction
Collection of illustrative plates, DSC collection of illustrative plates and TGA collection of illustrative plates are characterized, and the novel crystal forms are different from the crystal formation of current document report.And the novel crystal forms have
Amazing advantage, the crystal formation of current document report or commercially available crystal formation draw moist extremely strong, even if placing at room temperature
The easy moisture absorption, and the crystal formation II of the present invention successfully overcomes this defect, crystal formation II of the invention is moist without drawing, to storage, fortune
Defeated and preparation brings great convenience.Meanwhile, crystal formation II of the invention is compared with crystal formation prepared by existing literature, in dissolubility
Also possesses unexpected advantage with terms of photostability.In terms of dissolubility, crystal formation II is in disodium hydrogen phosphate/hydroxide
It can faster be dissolved compared with crystal formation I in the cushioning liquid of sodium, advantage had more on preparation；In terms of photostability, crystalline substance of the invention
Type II also increases significantly compared with crystal formation I.
Brief description of the drawings
Fig. 1 is the crystal formation II of embodiment 1 X-ray powder diffraction pattern
Fig. 2 is the crystal formation II of embodiment 1 thermogravimetric analysis collection of illustrative plates
Fig. 3 is the crystal formation II of embodiment 1 DSC collection of illustrative plates
Fig. 4 is the crystal formation II of embodiment 4 X-ray powder diffraction pattern
Fig. 5 is the crystal formation II of embodiment 4 thermogravimetric analysis collection of illustrative plates
Fig. 6 is the crystal formation II of embodiment 4 DSC collection of illustrative plates
Fig. 7 is the mono-crystalline structures figure of the trihydrate of embodiment 5
Fig. 8 is the crystal formation I of comparative example 1 X-ray powder diffraction pattern
Fig. 9 is the crystal formation I of comparative example 1 thermogravimetric analysis collection of illustrative plates
Figure 10 is the crystal formation I of comparative example 1 DSC collection of illustrative plates
Embodiment
Technical scheme is further illustrated with reference to specific embodiment, but does not limit the present invention.
Raltitrexed crude product can be used with N- [5- (N- methylaminos) -2- Thenoyls]-Pidolidone diethylesters and 2-
Methyl -6- bromomethyls -3- hydrogen-quinazoline-4-one is raw material, is prepared through condensation, hydrolysis, acid out.
1. powder diffractometer is produced by Arl Inc. of Switzerland of manufacturer, INSTRUMENT MODEL：X'TRA, Tube voltage 40KV, tube current 30mA, 8 °/min of sweep speed.
2. differential scanning calorimeter and thermogravimetric analyzer are produced by PerKinElmer companies of the U.S., INSTRUMENT MODEL：Pyris
1DSC, using nitrogen atmosphere, 10 DEG C/min of heating rate.
3. karl Fischer moisture tester model：Mettler Toledo V30Volumetric KF Titrator
Embodiment 1：Crystal formation II preparation (n=1)
10g Raltitrexed crude products are dissolved in water (280g) and THF (150g) mixed solvent, heating for dissolving is filtered, at room temperature
Water 620g is slowly added dropwise, is cooled to 5 DEG C, stands overnight, crystal is separated out, separation, 30 DEG C of vacuum drying 3h obtain light yellow crystal
9.2g, HPLC purity 99.8%.
XRPD collection of illustrative plates is as shown in Figure 1；
Thermogravimetric analysis collection of illustrative plates by Thermogravimetric Data as shown in Fig. 2 when being heated to 155 DEG C, with 4.12% weightlessness, analyzed
Get a point in sub- Raltitrexed containing a hydrone；
DSC collection of illustrative plates at 109 DEG C, 178 DEG C as shown in figure 3, have endothermic peak, and in 109 DEG C of sons that dry out, 178 DEG C are molten
Change peak.
It is 4.00% that karl Fischer Moisture Meter, which measures moisture,.
Embodiment 2：Crystal formation II preparation (n=1)
10g Raltitrexed crude products are dissolved in water (250g) and tetrahydrofuran (250g) mixed solvent, stirring and dissolving is filtered,
0.05g crystal formations II crystal seed is added at room temperature, water 1000g is added dropwise, is cooled to 10 DEG C, stands overnight, and separates out crystal, separation, 40
DEG C vacuum drying 3h, obtains light yellow crystal 8.9g, HPLC purity for 99.8%.
XRPD collection of illustrative plates, thermogravimetric analysis collection of illustrative plates, DSC collection of illustrative plates are consistent with the gained crystal formation of embodiment 1.
Embodiment 3：Crystal formation II preparation (n=1)
10g Raltitrexed crude products are dissolved in water (100g) and Isosorbide-5-Nitrae-dioxane (300g) mixed solvent, heating for dissolving, mistake
Filter, adds water 1100g at room temperature, separates out crystal, and separation, 40 DEG C of vacuum drying 3h obtain light yellow crystal 8.8g, HPLC purity
For 99.7%.
XRPD collection of illustrative plates, thermogravimetric analysis collection of illustrative plates, DSC collection of illustrative plates are consistent with the gained crystal formation of embodiment 1.
Embodiment 4：Crystal formation II preparation (n=0.5)
10g Raltitrexed crude products are dissolved in water (100g) and tetrahydrofuran (400g) mixed solvent, stirring and dissolving is filtered,
Water 1500g is added at room temperature, crystal is separated out, separated, and 8h is dried at 60 DEG C, obtaining light yellow crystal 9.1g, HPLC purity is
99.8%.
Sample is taken to carry out X-ray powder diffraction, TG, dsc analysis.
X-ray powder diffraction pattern is as shown in figure 4, consistent with Fig. 1.
Thermogravimetric analysis is as shown in figure 5, when being heated to 150 DEG C, with 1.98% weightlessness, by Thermogravimetric Data analyze one
Contain 0.5 hydrone in molecule Raltitrexed；
DSC collection of illustrative plates at 110 DEG C, 178 DEG C as shown in fig. 6, have endothermic peak, and in 110 DEG C of sons that dry out, 178 DEG C are molten
Change peak.
It is 2.00% that karl Fischer Moisture Meter, which measures moisture,.
Embodiment 5：The preparation of trihydrate monocrystalline
200mg Raltitrexeds are dissolved in water：Tetrahydrofuran (mass ratio=1：1) in mixed solvent, 0.45 μm is passed through
Filter paper filters out undissolved solid, and obtained saturation filtrate is sealed with the film for pricking hole, slowly evaporates into solid precipitation,
Filtering, vacuum drying collects solid and produces trihydrate crystal formation.X-ray single crystal diffraction is carried out to single crystal, as a result such as Fig. 7
It is shown.
Comparative example 1：It is prepared by reference literature US4992550B method
By N- [5- [N- (3,4- dihydro -2- methyl -4- oxo -6- quinazolyls)-methyl]-N- methyl] -2- thiophene first
Acyl group-Pidolidone diethylester (1g), NaOH (1.2g) are added in water (10mL) and ethanol (10mL), are stirred at room temperature.Reaction
After the completion of be concentrated under reduced pressure, adjust pH to 3 with 2N hydrochloric acid solutions, separate out white solid, filter, washing, dry Raltitrexed is brilliant
Type I.
XRPD characterizes collection of illustrative plates as shown in figure 8, its XRPD collection of illustrative plates with the gained crystal formation of embodiment 1~4 is significantly different；
Thermogravimetric analysis collection of illustrative plates by Thermogravimetric Data as shown in figure 9, when being heated to 50 DEG C, with 4.17% weightlessness, analyzed
Get a point in sub- Raltitrexed containing a hydrone；
Differential Scanning Calorimetry as shown in Figure 10, has endothermic peak at 80 DEG C, 179 DEG C, in 80 DEG C of sons that dry out,
179 DEG C are melting hump.
Comparative example 2：It is prepared by reference literature CN103570702A method
Take the wet crude product 13.8g of undried Raltitrexed to be added in 600ml methanol, 0.5 hour, room temperature is stirred at room temperature
Crystallization is concentrated at lower filtering, 28-35 DEG C of filtrate, puts in 4 DEG C of refrigerators and refrigerates 3 hours, filtering, product purifies water washing with a small amount of,
Room temperature in vacuo is dried 10 hours, obtains faint yellow solid 2.7g.
Comparative example 3：It is prepared by reference literature CN102424679B method
Take Raltitrexed crude product 10g to be placed in reaction bulb, add 500mL methanol and be heated to reflux to clarification, filtering, filtrate are cold
But to 5-10 DEG C, about 4200mL purified water stirring and crystallizings are slowly added into, are filtered, solid purifying water washing, 40 DEG C of vacuum drying
24 hours, faint yellow solid 3.5g is obtained, is analyzed through X-ray powder diffraction, be unformed.
Comparative example 4：It is prepared by reference literature CN102127063A method
Take 0.2gN- [5- [N- (3,4- dihydro -2- methyl -4- oxo -6- quinazolyls)-methyl]-N- methyl] -2- thiophenes
Fen formoxyl-Pidolidone diethylester is dissolved in 10mL ethanol and 10mL acetone, adds 3N sodium hydrate aqueous solution 14mL, room temperature
Stirring reaction 3h.Ethanol and acetone is evaporated off in vacuum distillation, with 2N salt acid for adjusting pH to 4, filters to obtain faint yellow solid, with methanol-
Absolute ether is recrystallized, and is obtained faint yellow solid, is analyzed through X-ray powder diffraction, is unformed.
The draws moist test of embodiment 6
According to the method for 2015 editions medicine draws moist test guidelines of Chinese Pharmacopoeia to embodiment 1, embodiment 4, contrast
The sample of example 1~4 carries out draws moist test.As a result it is as follows：
The above results show that crystal formation II of the invention hardly draws wet, and the sample obtained by comparative example 1~4 have compared with
Strong draws moist.
The dissolubility comparative test of embodiment 7
The Raltitrexed clinically ratified at present is freeze-dried powder, is needed bulk drug Raltitrexed in production process first
It is added in the cushioning liquid of disodium hydrogen phosphate/NaOH and dissolves, is being freezed.Therefore bulk drug is molten in cushioning liquid
Solution property is particularly significant for preparation process.
Example 1, embodiment 4, comparative example 1, the sample of comparative example 2 carry out dissolubility comparative test.
Respectively Example 1, embodiment 4, comparative example 1, comparative example 2 sample 100mg in be placed at 25 DEG C 100mL buffering
In solution, with identical magnetic stirring speed, observation dissolving speed situation is to be considered as completely such as without visual visible particles of solute
Dissolving.Buffer preparation：Weigh 2g disodium hydrogen phosphates to be dissolved in 800mL distilled water, adjusted with 0.1M sodium hydrate aqueous solutions
The pH value of solution adds water to 7.6 and is settled to 1L.
As a result such as following table：
The stability test of embodiment 8
By embodiment 1, embodiment 4, the sample opening of comparative example 1~4 be placed on 25 DEG C, humidity be 40% in the environment of, put
Put 30 days, sampled in the 15th day and the 30th day, investigate outward appearance and the change of relevant material, as a result see the table below：
The above results show, place one month at ambient temperature, crystal formation II of the invention no matter in outward appearance, water content also
In terms of being relevant material, unchanged, with good storage stability, and the sample of comparative example 1~4 is appearance color first
Change, next to that the easily moisture absorption, while HPLC detection chemical purities find also to raise about the content of material.With existing text
Offer obtained Raltitrexed sterling to compare, crystal formation II of the invention possesses significant advantage.
The exposure experiments to light of embodiment 9
Presently commercially available Raltitrexed and the Raltitrexed prepared according to existing literature, which exist, asks light sensitive
Topic, the present inventor has investigated stability problems of the crystal formation II under illumination condition.
Embodiment 1, embodiment 4, the sample opening of comparative example 1~4 are placed in the lighting box equipped with fluorescent lamp, in illumination
To be placed 10 days under conditions of 4500lx ± 500lx, sampled in the 5th day and the 10th day, investigate outward appearance and the change of relevant material.
To the description of appearance color in upper table, faint yellow, yellow, pale brown, yellowish-brown represent that color is deepened successively.
Exposure experiments to light shows that crystal formation II prepared by embodiment 1,4 is compared with the crystal formation I of comparative example 1, and stability has increased
Plus, be conducive to the storage of bulk drug.
Claims (10)
1. Raltitrexed hydrate, it is characterised in that with following structure：
Wherein, n=0.5~3.
2. hydrate according to claim 1, it is characterised in that radiated using Cu-Ka, the X-ray represented with 2 θ angles
Powder diffraction 2 θ values be 6.0 ± 0.2 °, 7.1 ± 0.2 °, 8.1 ± 0.2 °, 13.5 ± 0.2 °, 14.3 ± 0.2 °, 16.3 ±
There is stronger characteristic peak, it is preferable that its X is penetrated at 0.2 °, 18.4 ± 0.2 ° 19.2 ± 0.2 °, 20.6 ± 0.2 °, 26.5 ± 0.2 °
Line powder diffraction spectrum is as shown in Figure 1.
3. hydrate according to claim 2, it is characterised in that n=1, and it has thermogravimetric analysis as shown in Figure 2
Collection of illustrative plates and DSC collection of illustrative plates as shown in Figure 3.
4. hydrate according to claim 2, it is characterised in that n=0.5, and it has thermogravimetric as shown in Figure 5 point
Analyse collection of illustrative plates and DSC collection of illustrative plates as shown in Figure 6.
5. hydrate according to claim 1, it is characterised in that n=3, its mono-crystalline structures are monoclinic system, axial length Crystal face angle α=90.00 °, β=90.00 °, γ=
90.00 °, it has X-ray single crystal diffraction collection of illustrative plates as shown in Figure 7.
6. a kind of method for preparing any one of the claim 1-4 hydrates, it is characterised in that comprise the steps of：(a) will
Raltitrexed is dissolved in the mixed solvent of water and organic solvent；(b) 0~10 DEG C is cooled to, crystallization is stood；(c) separate, drying is
；Wherein described organic solvent is selected from tetrahydrofuran, Isosorbide-5-Nitrae-dioxane.
7. method according to claim 6, it is characterised in that the mass ratio of step (a) reclaimed water and organic solvent is 1：
0.25~4.
8. method according to claim 6, it is characterised in that also comprised the steps of in step (b):Before cooling
Anti-solvent water is added into system.
9. method according to claim 8, it is characterised in that the amount of anti-solvent water is the quality for adding to water in step (b)
Proportion is 80~90%.
10. method according to claim 6, it is characterised in that dried in step (c) to be dried in vacuo, drying temperature is
40~60 DEG C.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109283262A (en) * | 2017-07-21 | 2019-01-29 | 南京正大天晴制药有限公司 | Pass through the method for high efficiency liquid chromatography for separating and determining Raltitrexed and its impurity |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4992550A (en) * | 1986-03-27 | 1991-02-12 | Imperial Chemical Industries Plc | Anti-tumour agents |
| CN102127063A (en) * | 2011-01-06 | 2011-07-20 | 深圳市普迈达科技有限公司 | New synthesis technology of anti-cancer drug Raltitrexed |
| CN104447724A (en) * | 2014-12-31 | 2015-03-25 | 四川峨嵋山药业股份有限公司 | Refining method of raltitrexed |
| CN105111197A (en) * | 2015-08-26 | 2015-12-02 | 上海鼎雅药物化学科技有限公司 | Synthesis methods of raltitrexed |
-
2016
- 2016-12-29 CN CN201611245842.9A patent/CN106957312B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4992550A (en) * | 1986-03-27 | 1991-02-12 | Imperial Chemical Industries Plc | Anti-tumour agents |
| CN102127063A (en) * | 2011-01-06 | 2011-07-20 | 深圳市普迈达科技有限公司 | New synthesis technology of anti-cancer drug Raltitrexed |
| CN104447724A (en) * | 2014-12-31 | 2015-03-25 | 四川峨嵋山药业股份有限公司 | Refining method of raltitrexed |
| CN105111197A (en) * | 2015-08-26 | 2015-12-02 | 上海鼎雅药物化学科技有限公司 | Synthesis methods of raltitrexed |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109283262A (en) * | 2017-07-21 | 2019-01-29 | 南京正大天晴制药有限公司 | Pass through the method for high efficiency liquid chromatography for separating and determining Raltitrexed and its impurity |
| CN109283262B (en) * | 2017-07-21 | 2019-08-06 | 南京正大天晴制药有限公司 | Pass through the method for high efficiency liquid chromatography for separating and determining Raltitrexed and its impurity |
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