CN103145629A - Synthetic process of tandutinib for treating solid tumors - Google Patents
Synthetic process of tandutinib for treating solid tumors Download PDFInfo
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- CN103145629A CN103145629A CN 201310112708 CN201310112708A CN103145629A CN 103145629 A CN103145629 A CN 103145629A CN 201310112708 CN201310112708 CN 201310112708 CN 201310112708 A CN201310112708 A CN 201310112708A CN 103145629 A CN103145629 A CN 103145629A
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Abstract
The invention relates to a synthetic process of tandutinib for treating solid tumors. According to the synthetic process, tandutinib is synthesized from 3-methoxy-4-phenol methyl formate serving as an initial material by etherifying, nitrifying, replacing, palladium carbon hydrogenation reduction, trimethyl orthoformate or triethyl orthoformate cyclizing, chloridizing and substitution reaction. The synthetic process is short in synthetic route, low in time consumption, high in yield, and low in cost. The pure tandutinib product of which the purity exceeds 99.8% is obtained in a way of recrystallizing the reaction produce.
Description
Technical field
The present invention relates to the synthesis technique of pharmaceutical compound, is a kind of new synthetic process for the treatment of the Tandutinib of noumenal tumour, belongs to the technical field of original new drug preparation and technique.
Background technology
In recent years, molecular weight tumor is learned, the development of molecular pharmacology is progressively illustrated tumorigenic essence, the invention of the modern techniquies such as extensive rapid screening, combinatorial chemistry, genetically engineered and application acceleration the drug development process, the research and development of antitumor drug have entered the brand-new epoch.Tyrosylprotein kinase is modal growth factor receptors, can tumoricidal signal transmission by the blocking-up Tyrosylprotein kinase, thus reach antineoplastic purpose.Receptor tyrosine kinase inhibitors comprises single target spot tyrosine kinase inhibitor and multiple receptor tyrosine kinases inhibitor.Conventional targeted therapy is attempted to block certain acceptor by single target drug and is blocked all signal transductions of tumour cell, and curative effect may be objective not, also likely causes resistance.In recent years the research of relevant many target spots receptor tyrosine kinase inhibitors is very active, for the door of hope has been opened in oncotherapy.
n-(4-isopropoxyphenyl)-4-(6-methoxy-7-(3-morpholinopropoxy) quinazolin-4-yl) piperazine-1-carboxamide, 4-(6-methoxyl group-7-(3-piperidines-1 base propoxy-) quinazoline-4-yl)-N-(4-isopropyl phenyl)-piperazine-1-methane amide (Tandutinib, Tandutinib) be a kind of many target spots of new oral small molecules acceptor Urogastron (EGFR) tyrosine kinase inhibitor that Millennium drugmaker develops, belong to a kind of synthetic clonidine compounds, the acute myeloid lineage leukemia of primary treatment is also attempted the targeted therapy for other multiple noumenal tumour.Tandutinib has restraining effect to receptor tyrosine kinase, comprises FMS sample Tyrosylprotein kinase-3 (FLT-3), PDGFR and STEM CELL FACTOR acceptor (c-KitR).Tandutinib suppresses the phosphorylation of FLT-3.The clinical study of stages shows, Tandutinib to Leukemia Patients has good antitumour activity, for treatment, improve patients ' life quality, extends survival time and brought hope.
At present the technology of Tandutinib mainly adopts the disclosed preparation method of patent WO2010/59239 (A2) of U.S. Millenium drugmaker: take vanillic acid as raw material, replace, remove benzyl protection, etherificate, piperidines through two benzyl protections, nitrated, reduction, cyclisation, chlorination and piperazine and replace, remove the Boc protection, introduce the steps such as aniline and obtain Tandutinib.This route reacts through 11 steps, comprises the process that protection is conciliate in a plurality of protections, and route is tediously long, complex operation, is not suitable for suitability for industrialized production fully.An improved method is to take the vanillic acid methyl esters as raw material, through steps such as etherificate, nitrated, replacement, reduction, cyclisation, chlorination and replacements, obtains Tandutinib.But this method still has following problem: (1) etherification reaction needs for a long time, and energy consumption is high; (2) nitration reaction need to reach the reaction times of 1 day; (3) the long time of piperidines substitution reaction needs, and product needs silica gel column chromatography to remove impurity, otherwise impurity may poison expensive platinum dioxide catalyzer; (4) adopt expensive platinum dioxide to make catalyzer, cost is high; (5) the crude product purity that chlorination reaction obtains is low, needs silica gel column chromatography to purify; (6) substitution reaction obtains a lot of by products, and the purification of product needs column chromatography.Such technique still is not suitable for industrialization.
Summary of the invention
The technical issues that need to address of the present invention are to provide a kind of 4-(6-methoxyl group-7-(3-piperidines-1 base propoxy-) quinazoline-4-yl)-
nthe new synthetic process of-(4-isopropyl phenyl)-piperazine-1-methane amide, to solve defect of the prior art.
The invention provides a kind of production 4-(6-methoxyl group-7-(3-piperidines-1 base propoxy-) quinazoline-4-yl)-
nthe novel process of-(4-isopropyl phenyl)-piperazine-1-methane amide, this processing method comprises the steps:
1. take vanillic acid methyl esters 1 as raw material, and the reaction of 1,3-dibromopropane is converted into ether compound 2
2. compound 2 nitrated compound 3 that obtains in nitration mixture;
3. nitro-compound reacts with piperidines and obtains compound 4, and crude product filters purification by the mixture of silica gel, diatomite and gac, to remove the impurity that may poison palladium-carbon catalyst;
4. compound 4 catalytic hydrogenations obtain amino-complex 5;
5. compound 5 reacts the compound 6 that obtains high yield with trimethyl orthoformate or triethyl orthoformate/ammonium acetate;
6. compound 6 and thionyl chloride or oxalyl chloride or phosphorus oxychloride reaction obtain compound 7;
7. in polar solvent, compound 7 and 10 reactions obtain the Tandutinib crude product;
8. intermediate 10 is obtained by substituted aniline 9 and triphosgene, piperazine reaction;
9. crude product 8 is purified by recrystallization, obtains purity and surpasses 99.8% sterling Tandutinib.
Step 1. in, the solvent of reaction is acetone, tetrahydrofuran (THF), acetonitrile, toluene, dimethyl formamide; The raw material for alkylation of reaction is 1,3-dibromopropane or 1,3-propylene dichloride.
Step 2. in, the ratio of concentrated nitric acid, the vitriol oil and acetate solvate is that 1:1:10 and temperature of reaction are controlled at the 50-60 degree.
Step 3. in, piperidines reacts and obtains 4 with 3 under iodate 4-butyl amine catalyzer exists.Product 4 filters purification by silica gel, diatomite and the active carbon filler of accurately allotment, removes most impurity, particularly may poison the impurity of palladium-carbon catalyst; The ratio of silica gel, diatomite and gac is 1:1:1.
Step 4. in, adopt palladium-carbon catalyst, and avoid using platinum dioxide, reduce costs.
Step 5. in, reaction is made solvent with alcohol, raw material react pass and encircles and to obtain highly purified compound 6 with trimethyl orthoformate, triethyl orthoformate/amine acetate.
Step 6. in, chlorination reagent is thionyl chloride or oxalyl chloride or phosphorus oxychloride, solvent is methylene dichloride, trichloromethane or 1,2-ethylene dichloride; Crude product 7 can be filtered and be purified by the mixed fillers with silica gel, diatomite and gac; The ratio of silica gel, diatomite and gac is 1:1:1.
Step 7. in, the alcohol that solvent is 2-5 carbon, dimethyl formamide, acetonitrile, dimethyl sulfoxide (DMSO).
Step 8. in, compound 10 obtains by substituted aniline 9 and triphosgene, piperazine reaction.
Step 9. in, recrystallization solvent is that reaction solvent is ethyl acetate, ether, tetrahydrofuran (THF), sherwood oil or mixed solvent.
In the tradition synthetic route, 1. step adopts 1,3-propylene dichloride, and reaction needed reaches even 1 ~ 2 day a few hours.Man-hour is long, and energy consumption is large.After using 1,3-dibromopropane instead, reaction substantially completed in 2 hours.
In the tradition synthetic route, 2. step adopts acetic acid to make solvent, and concentrated nitric acid is made nitrating agent, under 0 ~ 20 degree, within 10 ~ tens of hours consuming time, completes nitration reaction.The present invention adds a certain amount of vitriol oil, and the rising temperature of reaction, impels reaction to complete within half an hour, and efficiency is high, and energy consumption is low.
In the tradition synthetic route, 3. step is the bromo-3-chloropropane of 1,3-propylene dichloride or 1-due to what adopt in the first step, causes the piperidines reaction very slow.After the present invention uses bromide instead, the reaction times shortens, and yield improves.The product that traditional method obtains need to be purified by silica gel column chromatography, otherwise impurity easily poisons the platinum dioxide catalyzer.The present invention has simplified method of purification: the solution of thick product, by silica gel, diatomite, activated carbon filtration, can be removed most of impurity, and the purity of the compound 4 obtained can adapt to step catalytic reduction 4..
Step 4. in, adopt relatively inexpensive palladium-carbon catalyst to replace platinum dioxide, and catalyzer can recycle, the decrease cost.
Step 5. in, adopt trimethyl orthoformate or triethyl orthoformate encircles in 60 degree ShiShimonoseki, yield is over 95%.
The invention has the advantages that:
One, to use vanillic acid methyl esters cheap and easy to get be raw material in the present invention, avoided loaded down with trivial details protection in the patented method to conciliate the protection step, shortened synthetic route;
Two, the present invention, by adding a small amount of vitriol oil to allocate nitration mixture, shortened to 0.5 ~ 1 hour to the nitrated reaction times by 24 hours, and the decrease energy consumption, improved efficiency;
Three, the present invention, with by the Methods For Purification intermediate 4 of silica gel, diatomite or activated carbon filtration, has avoided loaded down with trivial details column chromatography process, shortens man-hour, reduces costs, and also significantly reduces the solvent usage quantity, thereby reduces the harm to environment;
Four, the catalyzer of catalytic reduction reaction changes cheap palladium carbon into by expensive platinum dioxide, and catalyzer realizes recycling, the decrease cost;
Five, adopt trimethyl orthoformate or triethyl orthoformate to replace methane amide, make the temperature of reaction of synthetic compound 6 be reduced to the 50-60 degree by being greater than 200 degree, reaction times shortened to 0.5 hour by 12 hours, the Energy Intensity Reduction of ring closure reaction is more than 80%, product purity is greater than 95%, and three waste discharge seldom;
Six, synthetic 7 steps altogether of system-wide line, each step all need only washing, concentrates, recrystallization or filtration can obtain highly purified intermediate or product, without tediously long purification process;
Seven, processing condition gentleness of the present invention, the temperature of all operations is all between normal temperature ~ 100 degree, and energy consumption is little;
Eight, operational path of the present invention is simple, yield is high, easy and simple to handle, discharge less, repeatability is high, those skilled in the art, according to technique scheme, in conjunction with specific embodiments, both can realize the present invention without creative work, were convenient to suitability for industrialized production.
Embodiment:
Following embodiment is just for the present invention is described, and unrestricted the present invention.
Embodiment 1, compound 2(methyl 4-(3-bromopropoxy)-3-methoxybenzoate) synthetic:
Add 182 grams (1 mol) vanillic acid methyl esters, 520 grams (2.57mol) 1,3-dibromopropane, 700 gram salt of wormwood, 20 gram tetrabutylammonium iodides and 2 liters of acetone in 10 liters of four-hole bottles.Reaction mixture under agitation refluxes 2 hours.The reaction mixture cool to room temperature, filter.1 liter of washing with acetone for filter cake, the concentrated yellow solid that obtains 264 gram thickness of filtrate.Yield 264 grams, 87%.
Embodiment 2, compound 3(methyl 4-(3-bromopropoxy)-5-methoxy-2-nitrobenzoate) synthetic:
151 digest compound 2 is dissolved in 3 liters of acetic acid, in solution, adds 400 milliliters of concentrated nitric acids.Under agitation slowly add 400 milliliters of vitriol oils.Reaction mixture at room temperature stirs 5 minutes, then under the 50-60 degree, stirs 30 minutes.The reaction mixture cool to room temperature, remove most of acetic acid by rotary evaporation.Remaining mixture is poured in 10 premium on currency.Methylene dichloride for water (10 liters * 3) extraction.The extraction liquid anhydrous sodium sulfate drying, filter.The concentrated 148 gram light yellow solids that obtain of filtrate.Yield 85%.
Embodiment 3, compound 4(methyl 5-methoxy-2-nitro-4-(3-(piperidin-1-yl) propoxy) benzoate) synthetic:
In the flask of 10 liters, add 87 to digest compound 3,200 gram salt of wormwood, 10 gram iodate 4-butyl amines and 3 liters of acetonitriles.Reaction mixture stirs half an hour, in flask, adds 80 gram piperidines.Reaction solution refluxes 2 hours under vigorous stirring.Cool to room temperature, filter, and filter cake washs with acetonitrile.Filtrate is concentrated dry, the crude product acetic acid ethyl dissolution.Add silica gel, diatomite and gac (ratio, 10:1:1,20 centimetres of height) in the funnel that is 80 centimetres at a diameter.The ethyl acetate solution of compound 4 is by silica gel-diatomite-activated carbon filtration, and filtrate concentrates the dry lurid oily matter of 80 gram, the yield 91% of obtaining.
Embodiment 4, compound 5(methyl 2-amino-5-methoxy-4-(3-(piperidin-1-yl) propoxy) benzoate) synthetic:
The palladium carbon that adds 3 grams 5% in 35.2 digest 3 liters of ethanolic solns of compound 4.Reaction vessel is used hydrogen exchange repeatedly, and at room temperature stirs in hydrogen atmosphere and spend the night until TLC shows that raw material all is exhausted.Reaction mixture is by double-deck filter paper filtering, the catalyzer washing with alcohol on filter paper.Filtrate again the diatomite filtration by 5 centimetres of thickness to remove a small amount of palladium carbon.Filtrate is not done purification, can be directly used in next step reaction.Palladium carbon on filter paper can recycle 3-10 time.
Embodiment 5, compound 6 (methyl 2-amino-5-methoxy-4-(3-(piperidin-1-yl) propoxy) benzoate) synthetic:
Add 42 gram trimethyl orthoformates and 28 gram ammonium acetates in the ethanolic soln of the compound 5 obtained to embodiment 4.Reaction mixture is enclosed within the hydrothermal reaction kettle of 5 liters and heating 1 hour under 60 degree.The reaction mixture cool to room temperature.Be concentrated to 300 milliliters, filter, solid spends the night at air drying, obtains 30.7 gram white solids, yield 95%.Thick product can be dissolved in (2 liters) in hot ethyl acetate, and cool to room temperature filters.Ethyl acetate, ether washing for solid.Yield 28 grams, 88%, purity 99% (HPLC).
Embodiment 6, compound 7(4-chloro-6-methoxy-7-(3-(piperidin-1-yl) propoxy) quinazoline) synthetic:
To compound 6(32 gram) methylene dichloride (1 liter) solution in add 1 milliliter of dimethyl formamide and 20 milliliters of thionyl chlorides.Reaction mixture is mechanical stirring half an hour at room temperature, then refluxes 1 day.Reaction mixture is cooling, concentrated.Remaining oily matter is dissolved in 1 liter of methylene dichloride and 200 milliliters of ethyl acetate.(ratio: 1:1:1), the solution of reacting coarse product is by silica gel, diatomite, activated carbon filtration, 500 milliliters of washed with dichloromethane for filter cake to add the silica gel, diatomite, gac of 20 centimetres of thickness in the sand core funnel that is 80 centimetres at a diameter.Filtrate concentrates dry 30.8 gram light yellow oil, the yield 92% of obtaining.
Embodiment 7, compound 10(N-(4-isopropoxyphenyl) piperazine-1-carboxamide) synthetic:
In 5 liters of flasks, add 100 to digest compound 9 and toluene (1 liter), in flask, slowly drip the toluene solution (1 liter) of triphosgene (130 gram), control temperature in reaction flask during dropping and do not surpass 20 degree.Reaction mixture stirs half an hour, then under 90 degree, stirs 2 hours.The reaction solution cool to room temperature, by saturated sodium bicarbonate washing, sodium bicarbonate washings extracted with diethyl ether.The diethyl ether solution of extraction and toluene solution merge, the concentrated ether of removing.The resistates obtained joins in toluene (2 liters) solution of piperazine (280 gram).Mixture stirs 5 hours under 100 degree.Cooling, concentrate, obtain the crude product of compound 10.Yield: 90 grams, 51%.
Embodiment 8, compound 8(N-(4-isopropoxyphenyl)-4-(6-methoxy-7-(3-(piperidin-1-yl) propoxy) quinazolin-4-yl) piperazine-1-carboxamide) synthetic:
In 500 milliliters of dimethyl formamides, add 70 to digest compound 10 and 136 gram salt of wormwood.Mixture at room temperature stirs 1 hour.In mixture, add 80 to digest compound 7.Reaction mixture stirs and spends the night under 60 degree.Reaction solution is cooling, water (2 liters) dilution, dichloromethane extraction (5 liters).The extraction liquid dried over sodium sulfate, the concentrated solid that obtains yellow thickness.Product is dissolved in hot ethyl acetate, in solution, slowly adds sherwood oil until solution starts to occur muddy.Mixture is immersed in ice-water bath to spend the night and goes out more voluminous thing with crystallization.Mixture filters, petroleum ether, and drying, obtain 125 gram products 8.1H-NMR collection of illustrative plates and document coincide.
Claims (9)
1. the new synthetic process of a Tandutinib is characterized in that this technique comprises following steps:
1. take vanillic acid methyl esters 1 as raw material, and the reaction of 1,3-dibromopropane is converted into ether compound 2;
2. compound 2 nitrated compound 3 that obtains in nitration mixture;
3. nitro-compound reacts with piperidines and obtains compound 4, and crude product filters purification by the mixture of silica gel, diatomite and gac, to remove the impurity that may poison palladium-carbon catalyst;
4. compound 4 catalytic hydrogenations obtain amino-complex 5;
5. compound 5 reacts the compound 6 that obtains high yield with trimethyl orthoformate or triethyl orthoformate/ammonium acetate;
6. compound 6 and thionyl chloride or oxalyl chloride or phosphorus oxychloride reaction obtain compound 7;
7. in polar solvent, compound 7 and 10 reactions obtain the Tandutinib crude product;
8. intermediate 10 is obtained by substituted aniline 9 and triphosgene, piperazine reaction;
9. crude product 8 is purified by recrystallization, obtains purity and surpasses 99.8% sterling Tandutinib.
2. processing method according to claim 1, is characterized in that step 1., and the solvent of reaction is acetone, tetrahydrofuran (THF), acetonitrile, toluene, dimethyl formamide; The raw material for alkylation of reaction is 1,3-dibromopropane or 1,3-propylene dichloride.
3. processing method according to claim 1, is characterized in that step 2., and the ratio of concentrated nitric acid, the vitriol oil and acetate solvate is that 1:1:10 and temperature of reaction are controlled at the 50-60 degree.
4. processing method according to claim 1, is characterized in that step 3., and piperidines reacts and obtain 4 with 3 under iodate 4-butyl amine catalyzer exists; Product 4 filters purification by silica gel, diatomite and the active carbon filler of accurately allotment, removes the impurity that major part may poison palladium-carbon catalyst; The ratio of silica gel, diatomite and gac is 1:1:1.
5. processing method according to claim 1, is characterized in that step 4., adopts palladium-carbon catalyst.
6. processing method according to claim 1, is characterized in that step 5., and reaction makes solvent with alcohol, and raw material reacts with trimethyl orthoformate, triethyl orthoformate/amine acetate and obtains highly purified compound 6.
7. processing method according to claim 1, is characterized in that step 6., and chlorination reagent is thionyl chloride or oxalyl chloride or phosphorus oxychloride, and solvent is methylene dichloride, trichloromethane or 1,2-ethylene dichloride; The mixed fillers of silica gel, diatomite and gac that crude product 7 can passing ratio is 1:1:1 is filtered purifies.
8. processing method according to claim 1, is characterized in that step 7., the alcohol that solvent is 2-5 carbon, dimethyl formamide, acetonitrile, dimethyl sulfoxide (DMSO).
9. preparation method according to claim 1, is characterized in that step 9., the mixing that recrystallization solvent is ethyl acetate, ether, tetrahydrofuran (THF), sherwood oil or several solvents.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104945332A (en) * | 2014-03-31 | 2015-09-30 | 中国科学院广州生物医药与健康研究院 | Preparation method of erlotinib |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104945332A (en) * | 2014-03-31 | 2015-09-30 | 中国科学院广州生物医药与健康研究院 | Preparation method of erlotinib |
| CN104945332B (en) * | 2014-03-31 | 2017-10-17 | 中国科学院广州生物医药与健康研究院 | The preparation method of Erlotinib |
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Application publication date: 20130612 |