CN103570702A - Method for industrial preparation of raltitrexed and novel raltitrexed crystal form for pharmacy - Google Patents
Method for industrial preparation of raltitrexed and novel raltitrexed crystal form for pharmacy Download PDFInfo
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Abstract
The invention discloses a synthesis preparation technology of raltitrexed as an antitumor drug and a specific raltitrexed crystal form. The synthesis preparation technology comprises that N-(5-methylamino-2-thenoyl)-L-glutamate diethyl ester and 6-bromomethyl-3,4-dihydro-2-methyl-quinazoline-4-one undergo base catalysis and acid-binding synthesis reactions in the presence of an organic solvent to produce a C-N coupling product N-[5-[N-(3,4-dihydro-2-methyl-4-oxo-6-quinazoline)-methyl]-N-methyl]-2-thenoyl-L-glutamate diethyl ester; the C-N coupling product undergoes a hydrolysis reaction under the alkaline condition and the hydrolysis product is subjected to acid precipitation so that a raltitrexed crude product is obtained; and the raltitrexed crude product is subjected to recrystallization and the crystals are dried so that a high-purity raltitrexed raw drug in the specific crystal form is obtained. The specific crystal form is characterized definitely by an X-ray diffraction technology. The synthesis preparation technology utilizes extraction and crystallization processes to purify an intermediate and a product, is simple, economic and efficient, and is suitable for large-scale industrial preparation of raltitrexed.
Description
Technical field
Present technique invention belongs to a kind of preparation technology of chemical synthetic drug, particularly relates to the synthesis preparation method of a kind of antitumor drug Raltitrexed (Raltitrexed) and comprises the new Technology that crystal formation is studied.
Background technology
Raltitrexed is a kind of quinazoline antifol, it is to suppress thymidylate synthase (Thymidylate synthase by specificity, TS) produce antitumor action, because this enzyme is one of key enzyme in DNA biosynthetic process, and Raltitrexed is metabolised to very soon the form of multiple polyglutamic acid in cell and bring into play this powerful enzyme inhibition, thereby the growth and breeding of inhibition tumor cell, in to the treatment of colorectal cancer, its curative effect is better than or share similar in appearance to 5 FU 5 fluorouracil and folinic acid, but the toxic side effect of having avoided 5 FU 5 fluorouracil to produce, and easy to use, patient compliance is high, now become the first-line treatment medicine for the treatment of advanced colorectal cancer.This medicine also has certain curative effect to other cancers as tumor of head and neck, prostate cancer, lung cancer, soft tissue sarcoma and leukemia etc.
The chemical structural formula of Raltitrexed is as follows:
Raltitrexed is mainly by quinazolinone, thiophene and Pidolidone three parts form, document (Quinazoline Antifolate Thymidylate Synthase Inhibitors:Heterocyclic Benzoyl Ring Modifications, J.Med.Chem.1991, 34, 1594-1605) with United States Patent (USP) (US4992550, 1991) and Chinese patent (CN102127063A) and Chinese patent (CN1216883C) etc. all at length report and described main synthesis route and the preparation method of Raltitrexed, so I repeat no more at this, its synthetic intermediate is all easily buied on market, we are with commercially available Raltitrexed intermediate N (5-methylamino-2-thenoyl)-Pidolidone diethyl ester (hereinafter to be referred as LTS1) and 6-brooethyl-3, 4-dihydro-2-methyl-quinazoline-4-one (hereinafter to be referred as LTS2) in organic solvent through base catalysis with tie up the synthetic C-N coupled product N-[5-[N-(3 that obtains of acid, 4-dihydro-2-methyl-4-oxo-6-quinazolyl)-methyl]-N-methyl]-2-Thenoyl-Pidolidone diethyl ester (hereinafter to be referred as LT12), this product is hydrolyzed under alkaline condition to also acid out and obtains Raltitrexed crude product, crude product recrystallization is also dried and obtains highly purified Raltitrexed bulk drug.This technique has obtained highly purified Raltitrexed through two step building-up reactionss and refining step, and quality meets medicinal standard requirement completely, and the raw material that we adopt and the chemical structural formula of intermediate are as follows:
In patent in the past and other documents and materials report, all adopt circulation preparative chromatograph or column chromatography to obtain LT12, so not only consume a large amount of eluting solvents but also need to use specific installation, and be difficult for a large amount of preparation Raltitrexed, these methods the production Raltitrexed that is not suitable for industrial mass, but global tumor incidence is all generally the situation raising year by year in recent years, data presentation according to statistics, the existing colorectal cancer patients of Jin China is more than 100 ten thousand people nearly, add other tumor diseases patient's medication demand, Raltitrexed is as the treatment first-line treatment medicine of advanced colorectal cancer effective to kinds cancer, therefore can be necessary by a large amount of its bulk drugs of producing in industrialization ground.
Summary of the invention
Deficiency for conventional art, main purpose of the present invention is to obtain LT12 by the alternative original column chromatography method of purification of method of crystallization purifying, make Raltitrexed more easily obtain in large quantity to meet the need of clinical application, the present invention not only has breakthrough innovation on aftertreatment technology, and on synthetic technological condition, also have larger improvement, product is more easily separated out and purifying.
For realizing the present invention, I take following process program, and this process program comprises following three steps:
Step 1, be first intermediate LTS1 and LTS2 in organic solvent with sodium bicarbonate or 2, dehalogenation ammonification under the catalysis of the alkaline matters such as 6-lutidine, obtain C-N coupled product LT12, this product crude product after treatment recrystallization obtains purity at more than 95% LT12.
Operational path illustrates as follows:
In step 1, organic solvent used adopts aprotic polar solvent as N conventionally, dinethylformamide (DMF), N-Methyl pyrrolidone (NMP) and acetonitrile, also can adopt the methyl-sulphoxide that polarity is less (DMSO), dioxane, ethyl acetate, ether, tetrahydrofuran (THF) and toluene, even adopt the halogenated alkane that polarity is less, as methylene dichloride and chloroform etc., adopt one or more in above-mentioned solvent, or use them to using mixed solvent that arbitrary proportion was formed as solvent, preferably adopt DMF, NMP and acetonitrile are made reaction solvent, selected solvent should be used after fully dry.The catalyzer of this reaction and acid binding agent adopt mineral alkali as sodium bicarbonate, sodium carbonate, salt of wormwood, tertiary sodium phosphate, Sodium phosphate dibasic, dipotassium hydrogen phosphate etc., preferred sodium bicarbonate and dipotassium hydrogen phosphate, also can adopt organic bases, as triethylamine, diisopropylethylamine, DMAP (DMAP), 2,6-lutidine etc., preferably adopt 2,6-lutidine as catalyzer and the acid binding agent of this reaction.Material equivalent proportioning is LTS1: LTS2=1: 0.1-10, is preferably 1: 0.8-1.2, preferred proportioning is 1: 0.9, catalyst levels is LTS1 0.1 times to 100 times, preferably 5-10 is doubly.Temperature of reaction is 0-120 ℃, is preferably controlled at 20-60 ℃, and preferably 35-40 ℃, obviously increases higher than 40 ℃ of impurity that reaction produces, and lower than 35 ℃, speed of response is obviously slack-off.Reaction times is 12-72 hour, preferred 24-48 hour, and reaction end is confirmed with thin-layer chromatography.This reaction can be carried out under protection of inert gas, also can not add protection of inert gas, and reaction still can be carried out; but reaction solution color is darker, and impurity is more, therefore preferably under nitrogen protection, carry out this reaction; with starvation and the intrusion that prevents moisture, avoid this reaction to cause adverse influence.At LTS1, feed intake excessive in the situation that, when finding only to have micro-LTS2 remaining, thin layer monitoring reaction can carry out aftertreatment by stopped reaction, first to the methylene dichloride that adds reaction solution volume 3-5 doubly to measure in reaction solution, salt is separated out and filtering, then the salt solution that adopts about 10-15% is wash filtrate dry repeatedly, then solvent evaporated obtains oily matter crude product or solid, then this crude product is dissolved in to recrystallization in ethyl acetate obtains purity at more than 95% LT12.These professional personnel are to be understood that, here not refer to and can only adopt re-crystallizing in ethyl acetate, can make the recrystallisation solvent that product LT12 separates out should have many kinds all can adopt, or even mixed solvent also should be all right, the technical characterstic of this technique does not also lie in and adopts which kind of solvent that LT12 is separated out, and what adopt is the scheme of crystallization purifying LT12, so that large-scale industrial production Raltitrexed becomes possibility.
In step 2, the aqueous solution of the preferred sodium hydroxide of alkali used or potassium hydroxide, LT12 hydrolysis is not exclusively as sodium carbonate or sodium bicarbonate to adopt weak alkali, even reaction is difficult to carry out, conventionally adopt the alkali lye that concentration is 1N, the too dense reaction impurities of alkali lye increases, and the too rare speed of response of alkali lye is slack-off, and substrate LT12 likely can not be hydrolyzed and affects yield and quality product completely.Temperature of reaction can not be too high, general control between-10-10 ℃, preferred 0-5 ℃.Be hydrolyzed organic solvent that rear employing and water do not dissolve each other mutually as methylene dichloride and the ethyl acetate impurity in extractive reaction liquid several times, can have made like this impurity be down to lower level.After in question response liquid, most of impurity is extracted and removes, (10 ℃ following) at a lower temperature, pH value with acid-conditioning solution, until pH value drops at 3 o'clock, at this moment there is a large amount of Raltitrexed solids to separate out from reaction solution, then filter, adopt deionized water repetitive scrubbing filter cake, drain, without dry, direct crystallization is refining as far as possible.The acid solution of the general 1N of employing takes the mode dripping to regulate pH value, and acid used can be the mineral acids such as hydrochloric acid, sulfuric acid or phosphoric acid, can be also the organic acids such as Glacial acetic acid, preferably hydrochloric acid.Can adopt pH meter or pH test paper to judge the terminal of adjusting.
In step 3, the crude product of undried can at room temperature directly dissolve with 40-100 methyl alcohol doubly, then concentrating under reduced pressure at 28-35 ℃, until there is crystal, separate out, putting 4 ℃ of refrigerator and cooled Tibetan spends the night, several subalbous crystal that filtration is separated out, we are surprised to find the gained Raltitrexed crystal gloss that glimmering under illumination, then put and in vacuum drying oven, be no more than 35 ℃ of drying under reduced pressure (Vanadium Pentoxide in FLAKES is made drying aid) a few hours, obtain Raltitrexed finished product, high performance liquid phase detects purity more than 99.8% (referring to accompanying drawing 1), in following table, having listed a collection of Raltitrexed HPLC prepared by technique of the present invention, to detect data as shown in table 1: (table 1)
Adopting area normalization method to obtain Raltitrexed purity is 99.8453%, there is no to surpass 0.1% impurity, and maximum single mixing only has 0.0453%.
We carry out the detection of X diffraction to analyze its crystal formation (referring to accompanying drawing 2) to it subsequently, and this crystal formation has no bibliographical information, and it has distinctive diffraction 2 θ angles and is: 8.066,10.059,10.389,12.751,13.129,14.810,15.390,17.032,17.486,19.141,20.930,24.047,25.647,26.867,28.276,33.369.Gained Raltitrexed crystal is close to white, and stable in properties, easily stores.
Be below that examples of implementation with indefiniteness further illustrate technical characterstic of the present invention, so that this professional personage can more clearly understand the present invention particularly, but should not be understood as limitation of the present invention:
Embodiment
Embodiment 1
(1), N-[5-[N-(3,4-dihydro-2-methyl-4-oxo-6-quinazolyl)-methyl]-N-methyl]-2-Thenoyl-Pidolidone diethyl ester (LT12) synthetic
I, reaction formula:
II, table feeds intake: (table 2)
III, operation:
5.1g (20.2mmol) LTS2 is suspended in to 40ml with in 4A molecular sieve drying DMF later, separately by sodium bicarbonate 12g (142.9mmol), add thermometer is housed, in the 500ml there-necked flask stirring, stir 15 minutes, then the LTS1 of the 7.6g (22.2mmol) dissolving with 40ml DMF is in advance added in reaction flask, under nitrogen protection, be warming up to 40 ℃, react 24 hours, add sodium bicarbonate 6g, under nitrogen protection, continue reaction approximately 12 hours, (a basic complete reaction of plate bromo-derivative of take is basis for estimation, TLC detects developping agent condition: ethyl acetate/methanol=10/l), stopped reaction, be cooled to room temperature, add methylene chloride 240 milliliters, stir half an hour, solids removed by filtration material, with methylene dichloride repetitive scrubbing filter cake (40 milliliters * 3 times), filtrate merges, with the washing of 200ml purified water once, while there is emulsification, standing promotion layering after the jolting of appropriate interpolation saturated sodium-chloride water solution, and then wash (200ml * 3 time) with the sodium chloride aqueous solution of 10-15%.Organic phase stirs dry more than 1 hour with anhydrous magnesium sulfate, filter, washed with dichloromethane filter cake, in filtrate, add 1 gram of gac, stirring at room 1 hour, filters washed with dichloromethane filter cake, 40 ℃ of left and right are evaporated to dry brown color solid or the about 12g of oily matter crude product, add 300 milliliters of dissolvings of ethyl acetate, 30 ℃ revolve steaming to separating out solid, put 4 ℃ of refrigerator and cooled and hide more than 3 hours, filter, ethyl acetate washing, room temperature forced air drying, obtains approximately 4.8 grams, off-white color LT12 intermediate, it is 97.3% that high performance liquid phase detects purity, and molar yield is about 46%.
(2), N-[5-[N-methyl-N-(2-methyl-4-oxo-3,4-dihydroquinazoline base-6-methyl) amino] thiophene-2-formyl radical]-Pidolidone (Raltitrexed) synthetic
I, reaction equation:
II, table feeds intake: (table 3)
III, operation:
Under condition of ice bath (temperature is 0 ℃), in 480ml 1N NaOH solution, add gradation to add 52.8g (about 0.1mol) purity at the LT12 of 97% left and right, continue to stir 2 hours, filter.Filtrate is fallen organic phase impurity with methylene dichloride (500ml * 2) extraction, use again ethyl acetate (500ml * 2) to extract again and fall remaining organic phase impurity, under agitation (0--5 ℃) water layer, with 1N hydrochloric acid adjust pH to 3.0 left and right, has a large amount of solids to separate out.At 0 ℃, stir 1 hour, filter, product washs by purified water, is washed till filtrate without Cl
-(use 0.1NAgNO
3measure), drain as far as possible, obtain 138 grams of the thick wet products of Raltitrexed, this crude product detects purity through HPLC and is about 99% left and right.
Hydrolysis terminal and production quality control: by tlc, detect
TLC condition: developping agent: Glacial acetic acid: methyl alcohol=1: 5
Silica gel G F
254plate
R
f＝0.50
Under 254nm ultraviolet lamp, inspect LT12 hydrolysis completely, inclusion-free spot produces.
(3) Raltitrexed is refining
Getting above-mentioned Raltitrexed crude product 13.8g joins in 600ml anhydrous methanol, stirring at room 0.5 hour, preproduction has a small amount of insolubles, under room temperature, filter, concentrated crystallization at filtrate 28-35 ℃, puts 4 ℃ of refrigerator and cooled and hides 3 hours, filter, product washs by a small amount of purified water, and room temperature vacuum-drying 10 hours obtains several subalbous crystalline solid 3.2g.Second step yield 70% after refining.171～183 ℃ of fusing points, this product starts incipient melting in the time of 171 ℃, simultaneously color generation considerable change, in the time of 176 ℃, volume starts to expand, during to 183 ℃ volumetric expansion complete, without fine melt phenomenon (two appendix VIC melting point determinations of Chinese Pharmacopoeia version in 2010).[α
20 d26.2 ° of]=+, HPLC method is measured related substance and is all less than 0.1%, purity 99.86%.
Residue crude product is through refining with method, by vacuum drying at room temperature 24 hours, obtains finished product 31.2g, yield 75.6%, and mp171～183 ℃, purity 99.85%, always assorted < 0.2%, not have the impurity over 0.1%.
Change the catalyzer of the first step reaction into 2,6-lutidine, use 5 times that equivalent is LTS2, all the other operations are substantially the same manner as Example 1, obtain purity and be 95.7% LT12, and yield reaches 61%.Adopt the LT12 of this purity, through basic hydrolysis and acid out, obtain Raltitrexed, operation, with embodiment 1, finally obtains Raltitrexed finished product, and the total recovery of second step reaction and the 3rd one-step refining is 76%, and product purity reaches 99.81%, is not greater than 0.1% impurity.
(4) Raltitrexed crystal formation determines
By X diffraction analysis, by the known gained Raltitrexed of collection of illustrative plates, be crystalline compounds, there are distinctive diffraction 2 θ angle numerical value to be: 8.066,10.059,10.389,12.751,13.129,14.810,15.390,17.032,17.486,19.141,20.930,24.047,25.647,26.867,28.276,33.369.This Raltitrexed crystalline powder has stable in properties, easily stores, and purity is high, and colourity is shallow, is applicable to medicinal feature.Adopt different X diffraction instruments and/or at different environment, even same personnel are not in different timings, likely can make its diffracted intensity and 2 θ angular datas produce the difference of a little, but in the scope of allowing in error, can assert that these crystal formation data are reliable and stable, particularly: 8.066, 10.389, 14.810, 17.486, 20.930, 24.047 and 28.276 1 groups of data have good circulation ratio, can be defined as the X diffraction 2 θ angular datas of the tool feature of this crystal formation, therefore anyone without patentee's express authorization of the present invention in the situation that, prepare there is above-mentioned X diffractive features Raltitrexed crystal all by the behavior that is regarded as invading our intellecture property to pending.
Accompanying drawing explanation
Fig. 1: technique gained Raltitrexed HPLC of the present invention detects collection of illustrative plates;
Fig. 2: technique gained Raltitrexed crystal powder X diffracting spectrum of the present invention.
Claims (9)
1. synthesize the new process program of preparation Raltitrexed, this scheme comprises the content of the following aspects:
This process technology scheme is through two step building-up reactionss and refining step, to have obtained meeting the Raltitrexed of medicinal standard, be in particular: Raltitrexed intermediate N (5-methylamino-2-thenoyl)-Pidolidone diethyl ester (hereinafter to be referred as LTS1) and 6-brooethyl-3, 4-dihydro-2-methyl-quinazoline-4-one (hereinafter to be referred as LTS2) in organic solvent through base catalysis with tie up the synthetic C-N coupled product N-[5-[N-(3 that obtains of acid, 4-dihydro-2-methyl-4-oxo-6-quinazolyl)-methyl]-N-methyl]-2-Thenoyl-Pidolidone diethyl ester (hereinafter to be referred as LT12), by this product recrystallization purifying, then under alkaline condition, hydrolysis acid out obtain Raltitrexed crude product, crude product recrystallization is also dried and obtains highly purified Raltitrexed bulk drug.The raw material adopting and the chemical structural formula of intermediate are as follows:
2. as claimed in claim 1, the reaction solvent adopting is that aprotic polar solvent is as N, dinethylformamide (DMF), N-Methyl pyrrolidone (NMP) and acetonitrile, also adopt the methyl-sulphoxide that polarity is less (DMSO), dioxane, ethyl acetate, ether, tetrahydrofuran (THF) and toluene, even adopt the halogenated alkane that polarity is less, as methylene dichloride and chloroform etc., adopt one or more in above-mentioned solvent, or use them to using mixed solvent that arbitrary proportion was formed as solvent, preferably adopt DMF, NMP and acetonitrile are made reaction solvent, selected solvent should be used after fully dry.
3. as claimed in claim 1, the catalyzer of the first step reaction and acid binding agent adopt mineral alkali as sodium bicarbonate, sodium carbonate, salt of wormwood, tertiary sodium phosphate, Sodium phosphate dibasic, dipotassium hydrogen phosphate etc., preferred sodium bicarbonate and dipotassium hydrogen phosphate, also can adopt organic bases, as triethylamine, diisopropylethylamine, DMAP (DMAP), 2,6-lutidine etc., preferably adopt 2, and 6-lutidine is as catalyzer and the acid binding agent of this reaction.
4. as claimed in claim 1, the material equivalent proportioning of the first step reaction is LTS1: LTS2=1: 0.1-10, is preferably 1: 0.8-1.2, preferred proportioning is 1: 0.9, catalyst levels is LTS1 0.1 times to 100 times, preferably 5-10 is doubly.Temperature of reaction is 0-120 ℃, is preferably controlled at 20-60 ℃, and preferably 35-40 ℃, obviously increases higher than 40 ℃ of impurity that reaction produces, and lower than 35 ℃, speed of response is obviously slack-off.
5. as claimed in claim 1, the first step temperature of reaction is 0-120 ℃, is preferably controlled at 20-60 ℃, and preferably 35-40 ℃, obviously increases higher than 40 ℃ of impurity that reaction produces, and lower than 35 ℃, speed of response is obviously slack-off.Reaction times is 12-72 hour, preferred 24-48 hour, and reaction end is confirmed with thin-layer chromatography.This reaction is preferably carried out under protection of inert gas, with starvation and the intrusion that prevents moisture, avoids this reaction to cause adverse influence.
6. as claimed in claim 1, at LTS1, feed intake excessive in the situation that, when finding only to have micro-LTS2 remaining, thin layer monitoring reaction can carry out aftertreatment by stopped reaction, first to the methylene dichloride that adds reaction solution volume 3-5 doubly to measure in reaction solution, salt is separated out and filtering, then the salt solution that adopts about 10-15% is wash filtrate dry repeatedly, and then solvent evaporated obtains oily matter crude product or solid, then this crude product is dissolved in to recrystallization in ethyl acetate obtains purity at more than 95% LT12.The technical scheme of this technique is characterised in that the method purifying LT12 that adopts crystallization so that large-scale industrial production Raltitrexed becomes possibility, and and not lie in what adopt on earth be the recrystallization purifying which kind of solvent carries out LT12.
7. as claimed in claim 1, the preferred sodium hydroxide of alkali that second step reacts used or the aqueous solution of potassium hydroxide, conventionally adopt the alkali lye that concentration is 1N, the too dense reaction impurities of alkali lye increases, the too rare speed of response of alkali lye is slack-off, and substrate LT12 likely can not be hydrolyzed completely and affects yield and quality product.Temperature of reaction can not be too high, general control between-10-10 ℃, preferred 0-5 ℃.Be hydrolyzed rear employing organic solvent as methylene dichloride and the ethyl acetate impurity in extractive reaction liquid several times, can have made like this impurity be down to lower level.After in question response liquid, most of impurity is extracted and removes, (10 ℃ following) at a lower temperature, pH value with acid-conditioning solution, until pH value drops at 3 o'clock, at this moment there is a large amount of Raltitrexed solids to separate out from reaction solution, then filter, adopt deionized water repetitive scrubbing filter cake, drain, without dry, direct crystallization is refining as far as possible.The acid solution of the general 1N of employing takes the mode dripping to regulate pH value, and acid used can be the mineral acids such as hydrochloric acid, sulfuric acid or phosphoric acid, can be also the organic acids such as Glacial acetic acid, preferably hydrochloric acid.Can adopt pH meter or pH test paper to judge the terminal of adjusting.In this step, adopting the impurity of the organic solvent extracting not dissolving each other mutually with water in extracting reaction solution that Raltitrexed can higher purity be separated out is one of important technology feature of this technique.
8. as claimed in claim 1, in third step treating process, the crude product of undried can at room temperature directly dissolve with 40-100 methyl alcohol doubly, then concentrating under reduced pressure at 28-35 ℃, until there is crystal, separate out, putting 4 ℃ of refrigerator and cooled Tibetan spends the night, several subalbous crystal that filtration is separated out, the gained Raltitrexed crystal gloss that glimmering under illumination, then put and in vacuum drying oven, be no more than 35 ℃ of drying under reduced pressure (Vanadium Pentoxide in FLAKES is made drying aid) a few hours, obtain Raltitrexed finished product, high performance liquid phase detects purity more than 99.8% (referring to accompanying drawing 1).
9. by the known gained Raltitrexed of X diffraction analysis collection of illustrative plates, be crystalline compounds, there are distinctive diffraction 2 θ angle numerical value to be: 8.066,10.059,10.389,12.751,13.129,14.810,15.390,17.032,17.486,19.141,20.930,24.047,25.647,26.867,28.276,33.369 (referring to accompanying drawings 2).This Raltitrexed crystalline powder has stable in properties, easily stores, and purity is high, and colourity is shallow, is applicable to medicinal feature.In the scope of allowing in error, can assert that these crystal formation data are reliable and stable, particularly: 8.066,10.389,14.810,17.486,20.930,24.047 and 28.276 1 group of 2 θ angular data has good circulation ratio, can be defined as the X diffraction 2 θ angular datas of the tool feature of this crystal formation, so anyone prepares the Raltitrexed crystal with above-mentioned X diffractive features and all the behavior that is regarded as invading our intellecture property is carried out pending without patentee's express authorization of the present invention in the situation that.
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN106957311A (en) * | 2016-12-29 | 2017-07-18 | 南京正大天晴制药有限公司 | Solvate of Raltitrexed and preparation method thereof |
| CN107129492A (en) * | 2017-07-19 | 2017-09-05 | 南京普氟生物检测技术有限公司 | A kind of Raltitrexed is condensed the preparation method of impurity |
| CN107616976A (en) * | 2017-09-11 | 2018-01-23 | 南京正大天晴制药有限公司 | A kind of pharmaceutical composition of Raltitrexed and preparation method thereof |
| CN109283263A (en) * | 2017-07-21 | 2019-01-29 | 南京正大天晴制药有限公司 | Determination method for Raltitrexed synthesis quality control |
| 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 |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101088997A (en) * | 2006-06-16 | 2007-12-19 | 魏秀华 | Improved process of preparing Raltitrexed |
| CN102424679A (en) * | 2011-11-15 | 2012-04-25 | 扬子江药业集团有限公司 | Preparation method of Raltitrexed |
-
2012
- 2012-07-26 CN CN201210260633.7A patent/CN103570702A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101088997A (en) * | 2006-06-16 | 2007-12-19 | 魏秀华 | Improved process of preparing Raltitrexed |
| CN102424679A (en) * | 2011-11-15 | 2012-04-25 | 扬子江药业集团有限公司 | Preparation method of Raltitrexed |
Non-Patent Citations (1)
| Title |
|---|
| PETER R. MARSHAM ET AL.: "Quinazoline Antifolate Thymidylate Synthase Inhibitors: Heterocyclic Benzoyl Ring Modifications", 《JOURNAL OF MEDICINAL CHEMISTRY》 * |
Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN105111197B (en) * | 2015-08-26 | 2021-05-04 | 上海鼎雅药物化学科技有限公司 | Synthesis method of raltitrexed |
| CN106957311A (en) * | 2016-12-29 | 2017-07-18 | 南京正大天晴制药有限公司 | Solvate of Raltitrexed and preparation method thereof |
| CN106957311B (en) * | 2016-12-29 | 2020-03-31 | 南京正大天晴制药有限公司 | Solvate of raltitrexed and preparation method thereof |
| CN107129492A (en) * | 2017-07-19 | 2017-09-05 | 南京普氟生物检测技术有限公司 | A kind of Raltitrexed is condensed the preparation method of impurity |
| CN109283263A (en) * | 2017-07-21 | 2019-01-29 | 南京正大天晴制药有限公司 | Determination method for Raltitrexed synthesis quality control |
| 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 |
| CN109283263B (en) * | 2017-07-21 | 2019-06-25 | 南京正大天晴制药有限公司 | Determination method for Raltitrexed synthesis quality control |
| 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 |
| CN107616976A (en) * | 2017-09-11 | 2018-01-23 | 南京正大天晴制药有限公司 | A kind of pharmaceutical composition of Raltitrexed and preparation method thereof |
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