CN110284181A - The method for preparing single crystal of diltiazem AB isomers - Google Patents
The method for preparing single crystal of diltiazem AB isomers Download PDFInfo
- Publication number
- CN110284181A CN110284181A CN201910725707.1A CN201910725707A CN110284181A CN 110284181 A CN110284181 A CN 110284181A CN 201910725707 A CN201910725707 A CN 201910725707A CN 110284181 A CN110284181 A CN 110284181A
- Authority
- CN
- China
- Prior art keywords
- diltiazem
- single crystal
- preparing single
- isomers
- solvent
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- HSUGRBWQSSZJOP-RTWAWAEBSA-N diltiazem Chemical compound C1=CC(OC)=CC=C1[C@H]1[C@@H](OC(C)=O)C(=O)N(CCN(C)C)C2=CC=CC=C2S1 HSUGRBWQSSZJOP-RTWAWAEBSA-N 0.000 title claims abstract description 49
- 229960004166 diltiazem Drugs 0.000 title claims abstract description 49
- 239000013078 crystal Substances 0.000 title claims abstract description 29
- 238000000034 method Methods 0.000 title claims abstract description 28
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims abstract description 17
- 239000002904 solvent Substances 0.000 claims abstract description 13
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 8
- 238000002425 crystallisation Methods 0.000 claims abstract description 3
- 230000008025 crystallization Effects 0.000 claims abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 33
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 16
- 235000019441 ethanol Nutrition 0.000 claims description 11
- 239000012046 mixed solvent Substances 0.000 claims description 8
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- 238000001914 filtration Methods 0.000 claims description 5
- 238000004061 bleaching Methods 0.000 claims description 3
- 238000004090 dissolution Methods 0.000 claims 1
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 claims 1
- 238000001819 mass spectrum Methods 0.000 abstract description 3
- 238000012790 confirmation Methods 0.000 abstract description 2
- 230000000630 rising effect Effects 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 5
- 238000002447 crystallographic data Methods 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 239000012535 impurity Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000002526 effect on cardiovascular system Effects 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- QNRATNLHPGXHMA-XZHTYLCXSA-N (r)-(6-ethoxyquinolin-4-yl)-[(2s,4s,5r)-5-ethyl-1-azabicyclo[2.2.2]octan-2-yl]methanol;hydrochloride Chemical compound Cl.C([C@H]([C@H](C1)CC)C2)CN1[C@@H]2[C@H](O)C1=CC=NC2=CC=C(OCC)C=C21 QNRATNLHPGXHMA-XZHTYLCXSA-N 0.000 description 1
- YNGDWRXWKFWCJY-UHFFFAOYSA-N 1,4-Dihydropyridine Chemical compound C1C=CNC=C1 YNGDWRXWKFWCJY-UHFFFAOYSA-N 0.000 description 1
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- 230000005260 alpha ray Effects 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 210000001992 atrioventricular node Anatomy 0.000 description 1
- 229910001424 calcium ion Inorganic materials 0.000 description 1
- 210000004351 coronary vessel Anatomy 0.000 description 1
- 238000012937 correction Methods 0.000 description 1
- 229940127292 dihydropyridine calcium channel blocker Drugs 0.000 description 1
- 125000004925 dihydropyridyl group Chemical group N1(CC=CC=C1)* 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 229910002804 graphite Inorganic materials 0.000 description 1
- 239000010439 graphite Substances 0.000 description 1
- 230000000004 hemodynamic effect Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 208000031225 myocardial ischemia Diseases 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000013558 reference substance Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000003340 retarding agent Substances 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 230000024883 vasodilation Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C30—CRYSTAL GROWTH
- C30B—SINGLE-CRYSTAL GROWTH; UNIDIRECTIONAL SOLIDIFICATION OF EUTECTIC MATERIAL OR UNIDIRECTIONAL DEMIXING OF EUTECTOID MATERIAL; REFINING BY ZONE-MELTING OF MATERIAL; PRODUCTION OF A HOMOGENEOUS POLYCRYSTALLINE MATERIAL WITH DEFINED STRUCTURE; SINGLE CRYSTALS OR HOMOGENEOUS POLYCRYSTALLINE MATERIAL WITH DEFINED STRUCTURE; AFTER-TREATMENT OF SINGLE CRYSTALS OR A HOMOGENEOUS POLYCRYSTALLINE MATERIAL WITH DEFINED STRUCTURE; APPARATUS THEREFOR
- C30B29/00—Single crystals or homogeneous polycrystalline material with defined structure characterised by the material or by their shape
- C30B29/54—Organic compounds
-
- C—CHEMISTRY; METALLURGY
- C30—CRYSTAL GROWTH
- C30B—SINGLE-CRYSTAL GROWTH; UNIDIRECTIONAL SOLIDIFICATION OF EUTECTIC MATERIAL OR UNIDIRECTIONAL DEMIXING OF EUTECTOID MATERIAL; REFINING BY ZONE-MELTING OF MATERIAL; PRODUCTION OF A HOMOGENEOUS POLYCRYSTALLINE MATERIAL WITH DEFINED STRUCTURE; SINGLE CRYSTALS OR HOMOGENEOUS POLYCRYSTALLINE MATERIAL WITH DEFINED STRUCTURE; AFTER-TREATMENT OF SINGLE CRYSTALS OR A HOMOGENEOUS POLYCRYSTALLINE MATERIAL WITH DEFINED STRUCTURE; APPARATUS THEREFOR
- C30B7/00—Single-crystal growth from solutions using solvents which are liquid at normal temperature, e.g. aqueous solutions
- C30B7/02—Single-crystal growth from solutions using solvents which are liquid at normal temperature, e.g. aqueous solutions by evaporation of the solvent
- C30B7/06—Single-crystal growth from solutions using solvents which are liquid at normal temperature, e.g. aqueous solutions by evaporation of the solvent using non-aqueous solvents
Landscapes
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Crystallography & Structural Chemistry (AREA)
- Materials Engineering (AREA)
- Metallurgy (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention provides a kind of method for preparing single crystal of diltiazem AB isomers: diltiazem is uniformly mixed, then rising temperature for dissolving with solvent, active carbon is added, filtered, crystallization；The present invention solves the problems, such as the confirmation parsing of diltiazem product structure, and the present invention selects more intuitive method for preparing single crystal to carry out structural identification, to improve the miscellaneous Mass Spectra of diltiazem.
Description
Technical field
The present invention is the method for preparing single crystal of diltiazem AB isomers, belongs to technical field of medicine synthesis.
Background technique
Diltiazem is the representative drug of non-dihydropyridine calcium ion antagonist, to cardiovascular effect between benzene alkanamine
Between class and dihydropyridines, it with light DEG C of peripheral vasodilation effect and can increase coronary artery and renal hemodynamic, be widely used in
The treatment of ischemic heart disease and hypertension.Diltiazem and other atrioventricular node retarding agents are used as in most patient at present controls
The first-line drug of room rate uses.Diltiazem is more effective compared with dihydropyridine type calcium antagonists in terms of reducing cardiovascular complication.
Diltiazem AB isomer structure formula
Present internal sources medicine is all carrying out Conformance Assessment, and diltiazem bulk pharmaceutical chemicals Conformance Assessment is being declared by my company
When, evaluation expert, which proposes, needs the isomers for carrying out diltiazem to carry out methodological study.Diltiazem either which work
Skill route carries out industrialized production, it is necessary to by the synthesis of cis and trans diastereoisomer, including diltiazem
With its enantiomter impurity A B, there are also other diastereoisomer impurity A and AA, the present invention only studies pair of diltiazem
Reflect isomer impurities AB.But since market has no the sale of this reference substance, so we need to prepare target product ourselves, still
AB isomers due to diltiazem is doing hydrogen spectrum and spectral data is substantially identical as diltiazem when mass spectrum, so that sulphur over the ground
Tall and erect AB isomers carries out the simple structures such as hydrogen spectrum and mass spectrum and confirms no convincingness.In order to solve to deposit in above structure confirmation parsing
The problem of, the present invention selects more intuitive method for preparing single crystal to carry out structural identification, to improve the impurity of diltiazem
Spectrum research.
Currently, the method for preparing single crystal of diltiazem AB isomers is not yet reported that.
Summary of the invention
The present invention is to be attained in that by following technical solution
The present invention provides a kind of method for preparing single crystal of diltiazem AB isomers: diltiazem is mixed with solvent
Even, then rising temperature for dissolving, is added active carbon, filters, crystallization.
The method for preparing single crystal of the diltiazem AB isomers, it is characterized in that: selected solvent is ethyl acetate, dichloro
Methane, ethyl alcohol, one of acetone or its mixed solvent.
The method for preparing single crystal of the diltiazem AB isomers, it is characterized in that: selected solvent is methylene chloride and second
The mixed solvent of alcohol.
The method for preparing single crystal of the diltiazem AB isomers, it is characterized in that: selected methylene chloride and ethyl alcohol
Mixed solvent volume ratio is 1:1.0-1.4.
The method for preparing single crystal of the diltiazem AB isomers, it is characterized in that: selected methylene chloride and ethyl alcohol
Mixed solvent volume ratio is 1:1.2.
The method for preparing single crystal of the diltiazem AB isomers, it is characterized in that: filtration temperature is 20-60 DEG C；Decoloration
Time is 0.5-1.5h.
The method for preparing single crystal of the diltiazem AB isomers, it is characterized in that: filtration temperature is 40 DEG C；Bleaching time
For 1h.
The method for preparing single crystal of the diltiazem AB isomers, it is characterized in that: activated carbon dosage is solvent quality
1-5%.
The method for preparing single crystal of the diltiazem AB isomers, it is characterized in that: activated carbon dosage is solvent quality
3%.
Detailed description of the invention
Fig. 1 are as follows: the monocrystalline figure of diltiazem AB isomers
Specific embodiment
Embodiment below is only used for further describing the present invention, is not intended to limit the present invention.
Embodiment 1
Diltiazem AB isomers (0.45g, 0.01mol) is added in ethyl acetate (20mL), is stirred evenly at 20 DEG C,
It is added active carbon (0.16g, 1%), 20 DEG C of insulated and stirred 0.5h.Filtering, filtrate are volatilized naturally, finally there is no target list
It is brilliant.
Embodiment 2
Diltiazem AB isomers (0.45g, 0.01mol) is added into methylene chloride and alcohol mixeding liquid (1:1,20mL)
In, it stirs evenly, is added active carbon (0.16g, 1%), 20 DEG C of insulated and stirred 0.5h at 20 DEG C.Heat filter, filtrate are volatilized naturally, point
From obtaining monocrystalline 0.25g.
Embodiment 3
Diltiazem AB isomers (0.45g, 0.01mol) is added into methylene chloride and alcohol mixeding liquid (1:1.2,20mL)
In, it stirs evenly, is added active carbon (0.48g, 3%), 40 DEG C of insulated and stirred 1h at 40 DEG C.Heat filter, filtrate are volatilized naturally, separate
Obtain monocrystalline 0.32g.
The test method of monocrystalline: the complex monocrystal of suitable size is mounted on II CCD monocrystalline X of Bruker APEX and is penetrated
On line diffractometer, using the Mo K alpha ray (073nm of λ=0.071) through graphite monochromator monochromatization, set with ω scanning mode
Diffraction data is collected within the scope of the 2 fixed angles DEG C θ.Diffraction data carries out empirical absorption correction with program SADABS；Crystal structure
SHELXS-97 program is solved by direct method, to all non-hydrogen atom coordinates and its anisotropy temperature DEG C factor SHELXL-97 journey
Sequence carries out complete matrix least square method and corrects to convergence.Hydrogen atom is theoretical plus hydrogen.The crystallographic data of complex is listed in
Main bond distance's bond angle data of table 1, complex are listed in table 2 and table 3.
The single crystal diffraction data of 1 diltiazem AB isomers of table
Bond distance's data of 2 diltiazem AB isomers monocrystalline of table
The bond angle data of 3 diltiazem AB isomers monocrystalline of table
Conclusion: crystal structure C22H27ClN2O4S (M=450.96g/mol): belonging to rhombic system, p212121 space group,
Unit cell dimension are as follows:Z=4, matter
Measure absorption coefficient μ (MoK α)=0.287mm-1, close DEG C of D (calculating)=1.302g/cm3 have collected 21779 point diffractions
(3.868 °≤2 Θ≤55.21 °) have 5301 independent point diffractions (Rint=0.0643, Rsigma=0.0595), final
R1 is 0.0466 (σ of I > 2 (I)), and wR2 is 0.1471 (all data).
Embodiment 4
Diltiazem AB isomers (0.45g, 0.01mol) is added into methylene chloride and alcohol mixeding liquid (1:1.4,20mL)
In, it stirs evenly, is added active carbon (0.80g, 5%), 60 DEG C of insulated and stirred 1.5h at 60 DEG C.Heat filter, filtrate are volatilized naturally, point
From obtaining monocrystalline 0.22g.
Embodiment 5
Diltiazem AB isomers (0.45g, 0.01mol) is added in acetone (20mL), stirring and dissolving at 50 DEG C, is added
Active carbon (0.64g, 4%), 50 DEG C of insulated and stirred 1.5h.Heat filter, filtrate are volatilized naturally, finally there is no aimed single crystal.
Claims (9)
1. then the method for preparing single crystal of diltiazem AB isomers rises it is characterized in that: diltiazem is uniformly mixed with solvent
Temperature dissolution, is added active carbon, filters, crystallization.
2. the method for preparing single crystal of diltiazem AB isomers according to claim 1, it is characterized in that: selected solvent is second
Acetoacetic ester, methylene chloride, ethyl alcohol, one of acetone or its mixed solvent.
3. the method for preparing single crystal of diltiazem AB isomers according to claim 1 or 2, it is characterized in that: selected solvent
For the mixed solvent of methylene chloride and ethyl alcohol.
4. the method for preparing single crystal of diltiazem AB isomers according to claim 1 or 2, it is characterized in that: selected solvent
Methylene chloride and alcohol mixed solvent volume ratio are 1:1.0-1.4.
5. the method for preparing single crystal of diltiazem AB isomers according to claim 1 or 2, it is characterized in that: selected solvent
Methylene chloride and alcohol mixed solvent volume ratio are 1:1.2.
6. the method for preparing single crystal of diltiazem AB isomers according to claim 1, it is characterized in that: filtration temperature is
20-60℃；Bleaching time is 0.5-1.5h.
7. the method for preparing single crystal of diltiazem AB isomers according to claim 1 or 6, it is characterized in that: filtration temperature
It is 40 DEG C；Bleaching time is 1h.
8. the method for preparing single crystal of diltiazem AB isomers according to claim 1, it is characterized in that: activated carbon dosage is
The 1-5% of solvent quality.
9. the method for preparing single crystal of diltiazem AB isomers according to claim 1, it is characterized in that: activated carbon dosage is
The 3% of solvent quality.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910725707.1A CN110284181A (en) | 2019-08-07 | 2019-08-07 | The method for preparing single crystal of diltiazem AB isomers |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910725707.1A CN110284181A (en) | 2019-08-07 | 2019-08-07 | The method for preparing single crystal of diltiazem AB isomers |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN110284181A true CN110284181A (en) | 2019-09-27 |
Family
ID=68024893
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910725707.1A Pending CN110284181A (en) | 2019-08-07 | 2019-08-07 | The method for preparing single crystal of diltiazem AB isomers |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN110284181A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111910256A (en) * | 2020-08-13 | 2020-11-10 | 山东新华制药股份有限公司 | Single crystal preparation method of caffeine impurity II |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5102999A (en) * | 1989-12-06 | 1992-04-07 | Zambon Group S.P.A. | Process for the preparation of an intermediate of diltiazem |
| CN1271340A (en) * | 1997-10-22 | 2000-10-25 | 萨宝集团公司 | Process for recycle of waste product of diltiazem synthesis |
| CN106892881A (en) * | 2017-03-01 | 2017-06-27 | 郭彦超 | A kind of method of selectivity synthesis diltiazem chiral intermediate |
-
2019
- 2019-08-07 CN CN201910725707.1A patent/CN110284181A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5102999A (en) * | 1989-12-06 | 1992-04-07 | Zambon Group S.P.A. | Process for the preparation of an intermediate of diltiazem |
| CN1271340A (en) * | 1997-10-22 | 2000-10-25 | 萨宝集团公司 | Process for recycle of waste product of diltiazem synthesis |
| CN106892881A (en) * | 2017-03-01 | 2017-06-27 | 郭彦超 | A kind of method of selectivity synthesis diltiazem chiral intermediate |
Non-Patent Citations (2)
| Title |
|---|
| MARTHI,K ET AL.: "Enantiomer associations in the crystal structures of racemic and (2S,3R)-(-)-3-hydroxy-2(4-methoxyphenyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one", 《ACTA CHEMICA SCANDINAVICA》 * |
| 姚思等: "地尔硫卓的合成工艺改进", 《合成化学》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111910256A (en) * | 2020-08-13 | 2020-11-10 | 山东新华制药股份有限公司 | Single crystal preparation method of caffeine impurity II |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103974949B (en) | A kind of I type crystallization of 2-maleate of tyrosine kinase inhibitor and preparation method | |
| CN102702008B (en) | Agomelatine sulfuric acid composition and preparation method thereof | |
| CN105566327A (en) | JAK kinase inhibitor bisulfate crystal type I and preparation method thereof | |
| CN110284181A (en) | The method for preparing single crystal of diltiazem AB isomers | |
| CN103476742A (en) | New crystal form VII of agomelatine, preparation method and use thereof and pharmaceutical composition containing same | |
| CN107674035A (en) | A kind of preparation, structure and the photoluminescent property of benzimidazole hydrochloride | |
| CN109020997B (en) | 3-benzimidazole-6, 7-piperonyl-2 (1H) -quinolinone-zinc complex and preparation method and application thereof | |
| CN111087415B (en) | Europium-doped organic framework material and preparation method and application thereof | |
| WO2017177781A1 (en) | Ahu377 crystal forms, and preparation method therefor and use thereof | |
| CN111138681B (en) | Fluorescent material based on rare earth metal organic framework structure and preparation method thereof | |
| CN102336818B (en) | Peptide substance crystal B and preparation method and use thereof | |
| Fanwick et al. | Multiply bonded octahalodiosmate (III) anions. 3. Synthesis and characterization of the octahalodiosmate (III) anion [Os2X8] 2-(X= Cl, Br). Crystal structure determinations of two forms of (PPN) 2Os2Cl8 (PPN= bis (triphenylphosphine) nitrogen (1+) | |
| CN111393454A (en) | Novel crystalline form of midostaurin and process for its preparation | |
| CN110372575A (en) | A kind of dihydropyridine calcium antagonist eutectic and its preparation method and application | |
| CN113735781B (en) | Copper complex and preparation method and application thereof | |
| CN109516991A (en) | A kind of citric acid tropsch imatinib crystal-form compound and preparation method thereof | |
| CN104961774B (en) | A kind of nickel cluster compound and preparation method thereof | |
| CN107698496A (en) | A kind of phthalic acid and the crystal formation of Etoricoxib forming salt and preparation method thereof | |
| CN110128452B (en) | Gold complex and synthesis method and application thereof | |
| CN103755707B (en) | Lixivaptan crystal form II and its production and use | |
| CN110078679A (en) | A kind of lamotrigine pharmaceutical co-crystal and its preparation method and application | |
| CN105367445B (en) | Preparation, structure and application of benzyl dihydrazone-N-mono-(2-hydroxy-4-diethylin-1-formyl benzene) | |
| CN106010504B (en) | A kind of green fluorescent material based on rare earth metal organic framework | |
| CN112094312B (en) | Crystal form A of cyclovirobuxine D dihydrochloride | |
| CN106916102A (en) | A kind of metal organic complex with antitumor activity |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20190927 |