CN104513227A - Production method for imatinib mesylate alpha crystal form - Google Patents
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- CN104513227A CN104513227A CN201310453062.3A CN201310453062A CN104513227A CN 104513227 A CN104513227 A CN 104513227A CN 201310453062 A CN201310453062 A CN 201310453062A CN 104513227 A CN104513227 A CN 104513227A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Abstract
The invention belongs to the technical field of medicines, and concretely relates to a production method for imatinib mesylate alpha crystal form. The production method helps to improve the quality of a purified matinib mesylate product by optimizing all steps and technological parameters. The crystal form of a crude product is not considered in the production process, and regardless of product refining or transformation of other known crystal forms of imatinib mesylate into the alpha crystal form, the alpha-crystal-form product with high quality and purity can be obtained. The production method is simple and easy to operate, the yield is high, and the technology is stable and mature, is suitable for laboratory-scale preparation and is relatively suitable for industrialized large-scale production of the medicinal raw material. The purity of the product obtained in the large-scale production process reaches 99.8% or more, the yield is substantially improved, the yields from laboratory-scale preparation to large-scale production all reach 90% or more, and the highest yield reaches 93.6%.
Description
Technical field
The invention belongs to medical art, be specifically related to a kind of production method of imatinib mesylate alfa crystal form.
Background technology
Imatinib mesylate is the derivative of aniline pyrimidine, is a specific tyrosine kinase inhibitor (tyrosinekinases inhibitors, TKI).May calendar year 2001 is used for the treatment of chronic myelocytic leukemia by FDA approval.Within 2003, be used for the treatment of gastrointestinal stromal tumor (GIST) by FDA approval.
Universal Chinese character name: imatinib mesylate
English popular name: Imatinib Mesylate
Chemical structural formula:
As first the tumour generation coherent signal conduction depressant drug got the Green Light in the whole world, the consistent favorable comment of each side of international medicine sector has been won in the listing of imatinib mesylate: the antitumor drug that it not only represents a class mechanism of action brand-new formally enters into clinical application thus, and itself is just predictive of the direction that a kind of disease therapeuticing medicine develops, namely drug target day by day will tend to molecular level, and this improves medication effect just and reduce its poison, side reaction effective way.
Imatinib mesylate compound is open by Xi Ba-Geiz stock Corp (Novartis Co., Ltd) the earliest, and China Patent No. is CN93103566.X.Novartis Co., Ltd successively discloses α, β, F, G, H, I, K, δ, ε and the armorphous form (CN98807303.X, CN200680044007.7, CN200880018651.6, CN201010586080.5) of this compound, and setting forth other crystal formations at normal temperatures, especially easily having changed beta crystal into when having water, alcohol, ketone to exist.
Subsequently, NATCO PHARMA LTD successively discloses α 2 type crystalline form and I and II type crystal formation (US2008255138, WO2006054314); HETERO DRUGS LTD discloses H1 type crystal formation (US2005234069); Nanjing Cavan Dixu Biologicgal Enginnering Technology Co., Ltd, Yan Rong apply for imatinib mesylate polymorph I and II(CN201110032923.1, CN201110141335.1); Jiangsu Haosen Pharmaceutical Co., Ltd, Jiangsu Hansoh Medical Research Institute Co., Ltd. disclose crystal form A (CN201010176726.2); Polymorphic form N, polymorphic form Y, polymorphic form Z are open by WO2011108953, WO2011100282, WO2011100282 respectively.
The preparation method of imatinib mesylate has: the method in (1) patent WO99/03854 is: by suspending imatinib base in ethanol, then the ethanolic soln of methylsulfonic acid is instilled, after heating reflux reaction, solvent is steamed clean, in residue, add decrease temperature crystalline after a large amount of ethanol and a small amount of water rising temperature for dissolving again; (2) method of patent WO2006/024863 is: by suspending imatinib base in Virahol, then instills the aqueous isopropanol of methylsulfonic acid, crystallization of lowering the temperature after temperature rising reflux; (3) method of patent WO2006/0223816 is: by suspending imatinib base in asymmetric ketone (as methyl ethyl ketone, methyl isopropyl Ketone etc.), after heating for dissolving, start the solution of the unsymmetrical ketone dripping methylsulfonic acid, before separating out solid, the crystal seed of appropriate α type product is added in dropping process, continue to dropwise and reacted rear cooling crystallization, or the variation before and after above working order is carried out.The α type imatinib mesylate fusing point prepared due to method (1) is on the low side, and also there is a small amount of β type product in α type imatinib mesylate prepared by method (2), although method (3) makes moderate progress to above situation, but the price of the various ketone used in preparation process is higher, cause cost in production process higher.Chinese invention patent application CN102190649A discloses a kind of method preparing α imatinib mesylate, in this technical scheme it first by suspending imatinib base in water and organic solvent, be added dropwise to after methylsulfonic acid being dissolved in organic solvent reaction feed liquid in; Add α type imatinib mesylate crystal seed, through crystallization, filtration, drying, obtain product.But to there is crystal seed in technical scheme of the present invention easily dissolved and be not easy to the problem that operates after amplifying.
According to document and patent report, the method for synthesis α type imatinib mesylate mainly contains two kinds: the first is reacted at imatinib alkali and methylsulfonic acid, and the second changes into alpha-crystal form from other crystal formations of imatinib mesylate.First method is all generally that imatinib alkali is added methylsulfonic acid, dissolves in a solvent, adds the solvent turning crystalline substance again and carry out turning brilliant after concentrated.The system adopted mainly contains: anhydrous methanol-Virahol (synthesis of imatinib mesylate), dehydrated alcohol-Virahol (research of tyrosine kinase inhibitor imatinib mesylate new synthetic process).In above two kinds of systems, what obtain after concentrated is amorphous imatinib mesylate, through turning brilliant, the normally mixed crystal obtained or beta crystal.And equipment required in production is more, and step is more.The system adopted in second method mainly contains: dehydrated alcohol (imatinib mesylate new synthetic process), dehydrated alcohol-Virahol (research of tyrosine kinase inhibitor imatinib mesylate new synthetic process), dehydrated alcohol-ethyl acetate (US7732601), Virahol (US20070265288), propyl carbinol (US20070265288) and methanol-water (WO2006048890A), in these systems, all need heating or backflow a few hours, or it is concentrated, required equipment relative complex, the time of consumption is also many.Disclosed two kinds of crystallization method are all the crystallized forms directly obtained with methylsulfonic acid salify in organic solvent by suspending imatinib base above; Or imatinib mesylate suspension is added or do not add crystal seed in a solvent under certain temperature to be obtained.
But the above-mentioned method about preparing α type imatinib mesylate is be applicable to bench scale mostly, the problem of operating aspect is often there is after amplification, and these methods existing to there is technique loaded down with trivial details, circulation ratio is bad, technical scheme cannot be guaranteed effectively to remove physical impurity, can cause remaining in product to there is genetoxic impurity risk, be not suitable for a series of shortcoming such as suitability for industrialized production and product purity difference.Seldom report about the large maturation process produced in present stage.
Summary of the invention
In order to overcome defect of the prior art, the invention discloses a kind of production method of imatinib mesylate alfa crystal form.
Technical scheme of the present invention is: by water-soluble for imatinib mesylate crude product with in the mixed solvent of alcohol organic solvent, 60 ~ 65 DEG C are incubated 0.5 ~ 1.0 hour, then this mixing solutions is added drop-wise in the alcohol organic solvent being suspended with imatinib mesylate alfa crystal form crystal seed, 20 ~ 30 DEG C of crystallizatioies, centrifugal rejection filter, drying, obtains product.
Technical scheme of the present invention is preferably:
Step one, by the mixed solvent of the water-soluble and alcohol organic solvent of imatinib mesylate crude product heat, 60 ~ 65 DEG C of insulations 0.5 ~ 1.0 hour; The charging capacity of described water is 0.3 ~ 0.6ml/g imatinib mesylate crude product; The charging capacity of described alcohol organic solvent is 1 ~ 4ml/g imatinib mesylate crude product;
Step 2, above-mentioned solution after filtration, after filtering insoluble impurities, are added drop-wise in the alcohol organic solvent adding imatinib mesylate alfa crystal form crystal seed in advance, drip process temperature at 20 ~ 30 DEG C; The amount of described imatinib mesylate alfa crystal form crystal seed is 0.1% ~ 0.2% of imatinib mesylate crude product weight; The charging capacity of described alcohol organic solvent is 10 ~ 15ml/g imatinib mesylate crude product;
Step 3,20 ~ 30 DEG C of crystallizatioies 4 ~ 6 hours, rejection filter, 60 ~ 65 DEG C of dryings 6 ~ 8 hours, obtain product.
The amount of the present invention to above-mentioned steps one water used is carried out preferably, and preferably, the amount of above-mentioned steps one water used is 0.4 ~ 0.5ml/g imatinib mesylate crude product; More preferably, the amount of above-mentioned steps one water used is 0.45ml/g imatinib mesylate crude product.
The present invention's alcohol used to above-mentioned steps one carries out preferably, preferably, above-mentioned steps one alcohol organic solvent used is the alcohol of the straight or branched of 1 ~ 5 carbon, more preferably, the alcohol organic solvent that above-mentioned steps one is used is the one in methyl alcohol, ethanol, Virahol, propyl carbinol or the trimethyl carbinol; Most preferably, the alcohol organic solvent that above-mentioned steps one is used is methyl alcohol, Virahol.
The amount of the present invention to above-mentioned steps one alcohol used is carried out preferably, preferably, the amount of above-mentioned steps one alcohol organic solvent used is 2 ~ 3ml/g imatinib mesylate crude product, and more preferably, the amount of above-mentioned steps one alcohol organic solvent used is 2.5ml/g imatinib mesylate crude product.
Filter method in above-mentioned steps two of the present invention carries out preferably, preferably, and what above-mentioned filter method was used is millipore filtration and 0.5 μm-2 μm precise microfiltration devices of 0.22 μm; More preferably, what above-mentioned filter method was used is 0.5 μm of precise microfiltration device.
The amount of the present invention to above-mentioned steps two crystal seed used is carried out preferably, and preferably, the amount of above-mentioned steps two crystal seed used is 0.15% of imatinib mesylate crude product weight.
The present invention's alcohol organic solvent used to above-mentioned steps two is carried out preferably, preferably, above-mentioned steps two alcohol organic solvent used is the alcohol of the straight or branched of 1 ~ 5 carbon, more preferably, the alcohol organic solvent that above-mentioned steps two is used is the one in ethanol, Virahol, propyl carbinol or the trimethyl carbinol; Most preferably, the alcohol organic solvent that above-mentioned steps two is used is ethanol, Virahol.
The amount of the present invention to above-mentioned steps two alcohol organic solvent used is carried out preferably, and preferably, the amount of above-mentioned steps two alcohol organic solvent used is 12 ~ 14ml/g imatinib mesylate crude product.
Contriver collects data in process of the test repeatedly, selects to optimize each step and processing parameter thereof, has summed up the technical scheme described in this invention.The present invention compared with prior art, there is following clear superiority: production method purifying of the present invention improves the quality of imatinib mesylate product, without the need to considering the crystal formation of crude product in its production process, no matter be the refining of product, or brilliant to turning of alpha-crystal form to other crystal formation imatinib mesylate existing, all can obtain quality and the high alpha-crystal form of purity.In addition, the simple easy handling of production method of the present invention, yield is high, process stabilizing and ripe, is not only suitable for lab scale, is more suitable for the industrialized production of medical material, and the purity of products obtained therefrom all reaches more than 99.8% when large production, yield is also significantly improved, and all reaches more than 90%, be up to 93.6% from lab scale to large yield of producing.
Specific embodiment
Embodiment below in conjunction with embodiment is described in further detail the present invention, but does not therefore limit the present invention among described scope of embodiments.
Embodiment 1
Step one, by 1g imatinib mesylate crude product thermosol in the mixed solvent of 0.5ml water and 3ml Virahol, 65 DEG C of insulations 0.5 hour;
Step 2, by above-mentioned solution through 0.22 μm of filtering with microporous membrane, after filtering insoluble impurities, be added drop-wise in the 12ml Virahol adding 1.5mg imatinib mesylate alfa crystal form crystal seed in advance, drip process temperature at 20 DEG C;
Step 3,20 DEG C of crystallizatioies 6 hours, rejection filter, 65 DEG C of dryings 7 hours, obtain off-white color solid phase prod 0.92g, detection is learnt, the purity 99.84% of products obtained therefrom, yield 92.0%.
Embodiment 2
Step one, by 100g imatinib mesylate crude product thermosol in the mixed solvent of 50ml water and 250ml propyl carbinol, 60 DEG C of insulations 1.0 hours;
Step 2, by above-mentioned solution through 0.22 μm of filtering with microporous membrane, after filtering insoluble impurities, be added drop-wise in the 1300ml propyl carbinol adding 0.15g imatinib mesylate alfa crystal form crystal seed in advance, drip process temperature at 25 DEG C;
Step 3,25 DEG C of crystallizatioies 6 hours, rejection filter, 60 DEG C of dryings 8 hours, obtain off-white color solid phase prod 93.5g, detection is learnt, the purity of products obtained therefrom is 99.92%, yield 93.5%.
Embodiment 3
Step one, by 2.0kg imatinib mesylate crude product thermosol in the mixed solvent of 600ml water and the 4L trimethyl carbinol, 60 DEG C of insulations 1.0 hours;
Step 2, by above-mentioned solution through 2 μm of precise microfiltration devices, after filtering insoluble impurities, be added drop-wise in the 20L trimethyl carbinol adding 2.0g imatinib mesylate alfa crystal form crystal seed in advance, drip process temperature at 30 DEG C;
Step 3,30 DEG C of crystallizatioies 5 hours, rejection filter, 65 DEG C of dryings 6 hours, obtain off-white color solid phase prod 1.83kg, detection is learnt, the purity of products obtained therefrom is 99.88%, yield 91.5%.
Embodiment 4
Step one, by 20.0kg imatinib mesylate crude product thermosol in the mixed solvent of 6L water and 60L Virahol, 62 DEG C of insulations 0.8 hour;
Step 2, above-mentioned solution to be filtered through 0.5 μm of millipore filter, after filtering insoluble impurities, be added drop-wise in the 280L Virahol adding 20g imatinib mesylate alfa crystal form crystal seed in advance, drip process temperature at 21 DEG C;
Step 3,21 DEG C of crystallizatioies 5 hours, rejection filter, 61 DEG C of dryings 8 hours, obtain off-white color solid phase prod 18.40kg, detection is learnt, the purity of products obtained therefrom is 99.86%, yield 92.0%.
Embodiment 5
Step one, by 25.0kg imatinib mesylate crude product thermosol in the mixed solvent of 10L water and 100L methyl alcohol, 64 DEG C of insulations 0.6 hour;
Step 2, above-mentioned solution to be filtered through 0.5 μm of millipore filter, after filtering insoluble impurities, be added drop-wise in the 300L ethanol adding 50g imatinib mesylate alfa crystal form crystal seed in advance, drip process temperature at 28 DEG C;
Step 3,28 DEG C of crystallizatioies 4 hours, rejection filter, 60 ~ 65 DEG C of dryings 7 hours, obtain off-white color solid phase prod 23.16kg, detection is learnt, the purity of products obtained therefrom is 99.84%, yield 92.6%.
Embodiment 6
Step one, by 25.0kg imatinib mesylate crude product thermosol in the mixed solvent of 15L water and 25L ethanol, 63 DEG C of insulations 1.0 hours;
Step 2, above-mentioned solution to be filtered through 1 μm of millipore filter, after filtering insoluble impurities, be added drop-wise in the 250L Virahol adding 25g imatinib mesylate alfa crystal form crystal seed in advance, drip process temperature at 22 DEG C;
Step 3,22 DEG C of crystallizatioies 6 hours, rejection filter, 60 DEG C of dryings 8 hours, obtain off-white color solid phase prod 22.55kg, detection is learnt, the purity of products obtained therefrom is 99.87%, yield 90.2%.
Embodiment 7
Step one, by 25.0kg imatinib mesylate crude product thermosol in the mixed solvent of 10L water and 50L Virahol, 61 DEG C of insulations 0.5 hour;
Step 2, above-mentioned solution to be filtered through 0.5 μm of millipore filter, after filtering insoluble impurities, be added drop-wise in the 300L ethanol adding 37.5g imatinib mesylate alfa crystal form crystal seed in advance, drip process temperature at 30 DEG C;
Step 3,30 DEG C of crystallizatioies 5 hours, rejection filter, 62 DEG C of dryings 7 hours, obtain off-white color solid phase prod 23.05kg, detection is learnt, the purity of products obtained therefrom is 99.88%, yield 92.2%.
Embodiment 8
Step one, by 25.0kg imatinib mesylate crude product thermosol in the mixed solvent of 11.2L water and 62.5L Virahol, 62 DEG C of insulations 1 hour;
Step 2, above-mentioned solution to be filtered through 0.5 μm of millipore filter, after filtering insoluble impurities, be added drop-wise in the 325L Virahol adding 37.5g imatinib mesylate alfa crystal form crystal seed in advance, drip process temperature at 25 DEG C;
Step 3,25 DEG C of crystallizatioies 6 hours, rejection filter, 62 DEG C of dryings 7 hours, obtain off-white color solid phase prod 23.4kg, detection is learnt, the purity of products obtained therefrom is 99.91%, yield 93.6%.
Claims (8)
1. a production method for imatinib mesylate alfa crystal form, is characterized in that, it comprises following steps:
Step one, by the mixed solvent of the water-soluble and alcohol organic solvent of imatinib mesylate crude product heat, 60 ~ 65 DEG C of insulations 0.5 ~ 1.0 hour; The charging capacity of described water is 0.3 ~ 0.6ml/g imatinib mesylate crude product; Described alcohol organic solvent is the alcohol of the straight or branched of 1 ~ 5 carbon, and its charging capacity is 1 ~ 4ml/g imatinib mesylate crude product;
Step 2, above-mentioned solution after filtration, after filtering insoluble impurities, are added drop-wise in the alcohol organic solvent adding imatinib mesylate alfa crystal form crystal seed in advance, drip process temperature at 20 ~ 30 DEG C; The charging capacity of described crystal seed is 0.1% ~ 0.2% of imatinib mesylate crude product weight; Described alcohol organic solvent is the alcohol of the straight or branched of 1 ~ 5 carbon, and its charging capacity is 10 ~ 15ml/g imatinib mesylate crude product;
Step 3,20 ~ 30 DEG C of crystallizatioies 4 ~ 6 hours, rejection filter, 60 ~ 65 DEG C of dryings 6 ~ 8 hours, obtain product.
2. production method according to claim 1, is characterized in that, the charging capacity of described step one water used is 0.4 ~ 0.5ml/g imatinib mesylate crude product.
3. production method according to claim 1, is characterized in that, described step one alcohol organic solvent used is the one in methyl alcohol, ethanol, Virahol, propyl carbinol or the trimethyl carbinol.
4. production method according to claim 3, is characterized in that, the charging capacity of described step one alcohol organic solvent used is 2 ~ 3ml/g imatinib mesylate crude product.
5. production method according to claim 1, is characterized in that, in described step 2 filter adopt be the filtering with microporous membrane of 0.22 μm, 0.5 μm ~ 2 μm of filter cores precise microfiltration device filter.
6. production method according to claim 1, is characterized in that, the charging capacity of described step 2 crystal seed used is 0.15% of imatinib mesylate crude product weight.
7. production method according to claim 1, is characterized in that, described step 2 alcohol organic solvent used is the one in ethanol, Virahol, propyl carbinol or the trimethyl carbinol.
8. production method according to claim 6, is characterized in that, the charging capacity of described step 2 alcohol organic solvent used is 12 ~ 14ml/g imatinib mesylate crude product.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20060223816A1 (en) * | 2006-05-08 | 2006-10-05 | Chemagis Ltd. | Imatinib mesylate alpha form and production process therefor |
| CN102190649A (en) * | 2011-03-28 | 2011-09-21 | 齐鲁天和惠世制药有限公司 | Method for preparing alpha-imatinib mesylate |
| CN102250063A (en) * | 2010-05-19 | 2011-11-23 | 江苏豪森药业股份有限公司 | Crystal form of imatinib mesylate and preparation method thereof |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20060223816A1 (en) * | 2006-05-08 | 2006-10-05 | Chemagis Ltd. | Imatinib mesylate alpha form and production process therefor |
| CN102250063A (en) * | 2010-05-19 | 2011-11-23 | 江苏豪森药业股份有限公司 | Crystal form of imatinib mesylate and preparation method thereof |
| CN102190649A (en) * | 2011-03-28 | 2011-09-21 | 齐鲁天和惠世制药有限公司 | Method for preparing alpha-imatinib mesylate |
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