CN118530136A - Aminoadamantane compound, preparation method and application thereof - Google Patents
Aminoadamantane compound, preparation method and application thereof Download PDFInfo
- Publication number
- CN118530136A CN118530136A CN202310152161.1A CN202310152161A CN118530136A CN 118530136 A CN118530136 A CN 118530136A CN 202310152161 A CN202310152161 A CN 202310152161A CN 118530136 A CN118530136 A CN 118530136A
- Authority
- CN
- China
- Prior art keywords
- compound
- formula
- aminoadamantane
- preparation
- reaction
- 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
- -1 Aminoadamantane compound Chemical class 0.000 title claims abstract description 32
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- 239000012535 impurity Substances 0.000 claims abstract description 13
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 30
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 28
- 150000001875 compounds Chemical class 0.000 claims description 23
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 20
- 238000006243 chemical reaction Methods 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 11
- 230000008569 process Effects 0.000 claims description 7
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 3
- 238000004440 column chromatography Methods 0.000 claims description 3
- 239000012074 organic phase Substances 0.000 claims description 3
- 239000007787 solid Substances 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 2
- 239000011230 binding agent Substances 0.000 claims description 2
- 239000003054 catalyst Substances 0.000 claims description 2
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims 2
- 238000003756 stirring Methods 0.000 claims 2
- 238000001035 drying Methods 0.000 claims 1
- 238000005406 washing Methods 0.000 claims 1
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 abstract description 9
- 239000013558 reference substance Substances 0.000 abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 16
- 239000003814 drug Substances 0.000 description 8
- 229960004640 memantine Drugs 0.000 description 7
- BUGYDGFZZOZRHP-UHFFFAOYSA-N memantine Chemical compound C1C(C2)CC3(C)CC1(C)CC2(N)C3 BUGYDGFZZOZRHP-UHFFFAOYSA-N 0.000 description 6
- 102000004868 N-Methyl-D-Aspartate Receptors Human genes 0.000 description 4
- 108090001041 N-Methyl-D-Aspartate Receptors Proteins 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 150000003254 radicals Chemical class 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 229960003805 amantadine Drugs 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 208000024827 Alzheimer disease Diseases 0.000 description 2
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 229910002651 NO3 Inorganic materials 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 229910001424 calcium ion Inorganic materials 0.000 description 2
- 210000003710 cerebral cortex Anatomy 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000004896 high resolution mass spectrometry Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- CWNOIUTVJRWADX-UHFFFAOYSA-N 1,3-dimethyladamantane Chemical compound C1C(C2)CC3CC1(C)CC2(C)C3 CWNOIUTVJRWADX-UHFFFAOYSA-N 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- 108091006146 Channels Proteins 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 108010078321 Guanylate Cyclase Proteins 0.000 description 1
- 102000014469 Guanylate cyclase Human genes 0.000 description 1
- 229940127523 NMDA Receptor Antagonists Drugs 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- SNIOPGDIGTZGOP-UHFFFAOYSA-N Nitroglycerin Chemical compound [O-][N+](=O)OCC(O[N+]([O-])=O)CO[N+]([O-])=O SNIOPGDIGTZGOP-UHFFFAOYSA-N 0.000 description 1
- 239000000006 Nitroglycerin Substances 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- DKNWSYNQZKUICI-UHFFFAOYSA-N amantadine Chemical compound C1C(C2)CC3CC2CC1(N)C3 DKNWSYNQZKUICI-UHFFFAOYSA-N 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 238000012925 biological evaluation Methods 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000003205 diastolic effect Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- XEYBHCRIKKKOSS-UHFFFAOYSA-N disodium;azanylidyneoxidanium;iron(2+);pentacyanide Chemical compound [Na+].[Na+].[Fe+2].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].[O+]#N XEYBHCRIKKKOSS-UHFFFAOYSA-N 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 210000003989 endothelium vascular Anatomy 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 229960003711 glyceryl trinitrate Drugs 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- YWXYYJSYQOXTPL-SLPGGIOYSA-N isosorbide mononitrate Chemical compound [O-][N+](=O)O[C@@H]1CO[C@@H]2[C@@H](O)CO[C@@H]21 YWXYYJSYQOXTPL-SLPGGIOYSA-N 0.000 description 1
- 229960003827 isosorbide mononitrate Drugs 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000004770 neurodegeneration Effects 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 230000004112 neuroprotection Effects 0.000 description 1
- 230000036963 noncompetitive effect Effects 0.000 description 1
- 230000004792 oxidative damage Effects 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229940083618 sodium nitroprusside Drugs 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 210000004509 vascular smooth muscle cell Anatomy 0.000 description 1
- 230000000304 vasodilatating effect Effects 0.000 description 1
- 230000024883 vasodilation Effects 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides an aminoadamantane compound, a preparation method and application thereof. The aminoadamantane compound provided by the invention is (3-acetamido-5-ethyladamantan-1-yl) methyl acetate, and provides a preparation method of the (3-acetamido-5-ethyladamantan-1-yl) methyl acetate and application of the (3-acetamido-5-ethyladamantan-1-yl) methyl acetate as an impurity reference substance.
Description
Technical Field
The invention belongs to the technical field of biological medicines, and particularly relates to a novel aminoadamantane compound, a preparation method and application thereof.
Background
Amantadine and its derivatives have various biological activities and have wide application in the medical field. Memantine (1, 3-dimethyladamantane) is a non-competitive antagonist of the NMDA receptor and is currently mainly used for the treatment of moderate to severe alzheimer's disease. Through binding with the binding site in the NMDA receptor ion channel, memantine can block the inflow of K +,Ca2+ plasma, thereby playing a role in neuroprotection. Memantine is reversible in binding to NMDA receptor and has moderate dissociation rate, which not only ensures pharmacological action, but also ensures that memantine does not accumulate in the channel and affects normal physiological function of the receptor (Chen HS,Lipton SA.The chemical biology of clinically tolerated NMDA receptor antagonists.J Neurochem.2006Jun;97(6):1611-26.).
Nitric Oxide (NO) has a variety of biological activities in vivo. As a free radical gas, NO has an unpaired electron, is extremely unstable in chemical property and is very easy to combine with free radicals, so that the number of the free radicals is reduced, and the damage to organism tissues caused by oxidative damage is reduced. Meanwhile, NO plays a multiple role in the cardiovascular and cerebrovascular systems as a signal molecule. Endogenous NO is a vasodilating factor that promotes vasodilation by acting on guanylate cyclase in vascular smooth muscle cells, lowering blood pressure. At the same time, it can enter platelet cells to reduce their activity, so as to inhibit their aggregation and adhesion to vascular endothelium, prevent thrombosis and prevent atherosclerosis. The small molecular drugs capable of releasing NO, such as nitroglycerin, sodium nitroprusside, isosorbide mononitrate and the like, are widely applied to the treatment of various clinical diseases.
Pharmacological researches show that the amantadine nitrate compound MN08 can play a role similar to memantine, effectively antagonize excessive activation of NMDA receptors caused by glutamic acid, inhibit the inflow of calcium ions, and remove free radicals in cerebral cortex, so that cerebral cortex neurons are effectively protected; meanwhile, the novel high-efficiency release of NO can also be realized, and the diastolic arterial blood vessel (Liu Z,Yang S,Jin X,Zhang G,Guo B,Chen H,Yu P,Sun Y,Zhang Z,Wang Y.Synthesis and biological evaluation of memantine nitrates as a potential treatment for neurodegenerative diseases.Medchemcomm.2016Oct 20;8(1):135-147.).MN-08 is currently in the pulmonary arterial high-pressure clinical II phase and the Alzheimer disease clinical II phase, so that the novel high-efficiency release of NO has wide development prospect and great practical and economic significance.
Memantine and amantadine nitrate compound MN08 have the following structural formula:
The quality, safety and efficacy of the medicines must be evaluated scientifically before the medicines are marketed, the medicine impurities are closely related to the medicine quality and the medicine safety, the impurity reference substances can help to determine the reasonable limit of the impurities, and the establishment of medicine inspection methods and quality standards can be greatly promoted.
Disclosure of Invention
The invention aims to provide an aminoadamantane compound, a preparation method and application thereof.
In order to achieve the above purpose, the technical scheme of the invention is as follows:
The inventors have found that the MN08 compound prepared using the method disclosed in CN105294450a has an impurity which is different from the impurity of the presently disclosed MN08 compound and is necessary to identify the impurity for the purposes of pharmaceutical quality control and clinical safety detection. However, the impurity content is low, the chemical property of the compound is close to that of the MN08 compound, and the separation is very difficult. By theoretical deduction, a large number of compound controls are synthesized, and the impurity is different from adamantan amino nitrate compound and is actually (3-acetamido-5-ethyl adamantan-1-yl) methyl acetate (the compound of the formula I).
In a first aspect, the present invention provides an aminoadamantane compound having a structure according to formula I:
in a second aspect, the present invention provides a process for the preparation of the above-described aminoadamantane compound.
The preparation method of the aminoadamantane compound comprises the steps of reacting a compound shown in a formula II with acetic anhydride to obtain a compound shown in a formula I; the reaction route is as follows:
Preferably, in the above process for obtaining the compound of formula I from the reaction of the compound of formula II with acetic anhydride, triethylamine (TEA) is used as the acid-binding agent and 4-Dimethylaminopyridine (DMAP) is used as the catalyst.
Preferably, in the above method for obtaining the compound of formula I by reacting the compound of formula II with acetic anhydride, the molar ratio of the compound of formula II, acetic anhydride, TEA, DMAP is 1:2-4:2-4:0.05-0.15.
Preferably, in the preparation process, the compound of the formula II, acetic anhydride, TEA and DMAP are dissolved by using a solvent DCM, stirred at room temperature for reaction, water is added into the reaction liquid after the reaction is completed, the mixture is stirred and layered, an organic phase is washed by water, anhydrous sodium sulfate is dried, and the white solid compound of the formula I is obtained after column chromatography purification.
In a third aspect, the present invention provides the use of the above-described aminoadamantane compound as a compound MN08 impurity control.
Advantageous effects
The invention provides an aminoadamantane compound, a preparation method and application thereof. The aminoadamantane compound provided by the invention is (3-acetamido-5-ethyladamantan-1-yl) methyl acetate (a compound shown in a formula I), and provides a preparation method of the (3-acetamido-5-ethyladamantan-1-yl) methyl acetate and application of the (3-acetamido-5-ethyladamantan-1-yl) methyl acetate as an impurity reference substance. The preparation method of the (3-acetamido-5-ethyl adamantan-1-yl) methyl acetate has the advantages of simple route, mild reaction conditions, simple post-treatment process, and high purity of the prepared (3-acetamido-5-ethyl adamantan-1-yl) methyl acetate, and is suitable for being used as an impurity standard.
Drawings
FIG. 1 is a mass spectrum of methyl (3-acetamido-5-ethyl adamantan-1-yl) acetate.
Detailed Description
The following description of the embodiments of the present invention will clearly and fully describe the technical aspects of the present invention in conjunction with the specific embodiments of the present invention, and it is apparent that the described embodiments are only some embodiments of the present invention, but not all embodiments. It will be appreciated by those skilled in the art that modifications to the specific embodiments of the invention or equivalent replacement of parts of the technical features may be made without departing from the spirit of the technical solution of the invention, and are intended to be covered in the scope of the invention.
The reagents and materials used in the present invention are commercially available. The compounds of formula II may be prepared by the methods disclosed in CN105294450 a. The solvent PE used in the column chromatography is petroleum ether, and EA is ethyl acetate.
Except special description, the proportion of the invention is mass ratio, the parts are weight parts, and the percentages are mass percentages.
Example 1
Preparation of Compounds of formula I
| Material name | Molecular weight | Feeding amount |
| Compounds of formula II | 251.36 | 10g |
| Acetic anhydride | 102.09 | 12.2g |
| Triethylamine (TEA) | 101.19 | 12.1g |
| 4-Dimethylaminopyridine (DMAP) | 112.17 | 0.45g |
| Dichloromethane (DCM) | / | 50mL |
The preparation process comprises the following steps: the compound of formula II (10 g), DCM (50 mL), acetic anhydride (12.2 g), TEA (12.1 g), DMAP (0.45 g,0.1 eq.) were added to a 250mL single-necked flask and stirred at room temperature. TLC detection reaction was complete.
Post-treatment: 100mL of water and 50mL of DCM were added to the reaction flask, the layers were stirred, the aqueous phase was extracted once with DCM (50 mL), the organic phases were combined, washed once with water (50 mL), dried over anhydrous sodium sulfate, and applied to a column (PE: EA=3:1) to give 8.4g of a white solid compound of formula I (HPLC purity: 99.22%).
High Resolution Mass Spectrometry (HRMS), instrument model: agilent 6210 mass spectrometer; measurement results: as shown in FIG. 1, the measured molecular weight 294.2069 (M+1) corresponds to the theoretical molecular weight 294.2064 (M+1).
Nuclear magnetic structure confirmation: instrument model: bruker AVANCE III MHz nuclear magnetic resonance spectrometer; sample preparation: about 30mg of the compound of formula I was dissolved in 0.60mL CDCl 3.
Note that: s=single peak, br=broad peak, d=double peak, dd=split double peak, t=triplet-peak, q=four-fold peak, m=multiple peaks.
Claims (6)
1. An aminoadamantane compound having a structure according to formula I:
2. the process for the preparation of an aminoadamantane compound of claim 1, wherein the compound of formula I is obtained by reacting a compound of formula II with acetic anhydride; the reaction route is as follows:
3. A process for the preparation of an aminoadamantane compound according to claim 2, wherein: triethylamine is an acid binding agent; 4-dimethylaminopyridine is used as a catalyst.
4. A process for producing an aminoadamantane compound according to claim 3, wherein: the molar ratio of the compound of formula II, acetic anhydride, TEA, DMAP to the reaction charge is 1:2-4:2-4:0.05-0.15.
5. The process for producing an aminoadamantane compound, according to claim 4, wherein: dissolving the compound of the formula II, acetic anhydride, TEA and DMAP with a solvent DCM, stirring at room temperature for reaction, adding water into the reaction solution after the reaction is completed, stirring for layering, washing an organic phase with water, drying by anhydrous sodium sulfate, and purifying by column chromatography to obtain a white solid compound of the formula I.
6. Use of an aminoadamantane compound of claim 1 as a compound MN08 impurity control.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310152161.1A CN118530136A (en) | 2023-02-22 | 2023-02-22 | Aminoadamantane compound, preparation method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310152161.1A CN118530136A (en) | 2023-02-22 | 2023-02-22 | Aminoadamantane compound, preparation method and application thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN118530136A true CN118530136A (en) | 2024-08-23 |
Family
ID=92385069
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202310152161.1A Pending CN118530136A (en) | 2023-02-22 | 2023-02-22 | Aminoadamantane compound, preparation method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN118530136A (en) |
-
2023
- 2023-02-22 CN CN202310152161.1A patent/CN118530136A/en active Pending
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102816085B (en) | Preparation method of iohexol impurity | |
| CN118530136A (en) | Aminoadamantane compound, preparation method and application thereof | |
| CN113956266A (en) | Method for synthesizing tetrodotoxin on large scale | |
| EP2851363A1 (en) | Agomelatine acid radical composite, and preparation method and application thereof | |
| CN102746184B (en) | Preparation method of iohexol impurity | |
| CN108210933B (en) | Conjugate of dezocine and polyethylene glycol | |
| CN111362962B (en) | Tetrafluorobenzyl norcantharidin carboxylate and synthesis method thereof | |
| CN116970027A (en) | Dumbbell amphiphilic peptide dendrimer, synthesis and application thereof as drug delivery system | |
| CN111253415B (en) | Norcantharidin carboxylic acid trifluoro benzyl ester and synthetic method and application thereof | |
| CN113788796A (en) | Spilt derivative of moleplant diterpene alkane molecule, preparation method and application thereof | |
| EP4163271A1 (en) | Method for preparing methyl (s)-2-amino-3-(4-(2,3-dimethylpyridin-4-yl)phenylpropionate and salt thereof | |
| CN109320500B (en) | A kind of18F-labeled benzimidazole compound and preparation method and application thereof | |
| CN105175352A (en) | Preparation method of nitazoxanide | |
| CN107540640A (en) | A kind of reductive modification agent and its preparation method and application | |
| CN111269242A (en) | Norcantharidin carboxylic acid monofluorobenzyl ester and synthesis method and anti-tumor application thereof | |
| CN118271175A (en) | Adamantane nitrate compound and preparation method and application thereof | |
| CN101362746A (en) | Separation method of argatroban single stereoisomers and polymorph | |
| CN116715706B (en) | Chemical modification method for prolonging in-vivo half-life of theanine | |
| CN110128500A (en) | Prepare α-amide groups amide substance Ugi mixed solvent method | |
| CN114940695B (en) | Androstanol derivative with anti-tumor activity and preparation method and application thereof | |
| CN114907228B (en) | Colchicine and magnolol compound, synthesis method thereof and application thereof in resisting new coronaviruses | |
| CN102020602B (en) | Crystal form of lercanidipine hydrochloride and preparation method thereof and crystal form-containing medicinal composition | |
| CN113527141B (en) | Synthetic method of spiro [2,5] octane derivative | |
| CN108912201B (en) | Preparation method of ornithine phytosterol ester hydrochloride | |
| CN114213381B (en) | 4-chromanone derivative, preparation method and medical application thereof |
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 |