CN104774155B - A kind of 1,3-indandione derivative and crystal formation thereof - Google Patents
A kind of 1,3-indandione derivative and crystal formation thereof Download PDFInfo
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Abstract
The invention discloses shown in a kind of formula I 1,3-indandione derivative and crystal formation thereof, this crystal formation belongs to monoclinic system, and space group is C2, and cell parameter is a=26.781 (9)，b＝7.497(3)，c＝10.095(4)，β＝90.227(11)°，V＝2027.0(13) 3，ρcalc＝1.296g/cm3. The present invention also provides their preparation method and purposes. The crystal formation of formula I compound of the present invention, preparation technology is simple, has certain antibacterial activity, has good stability, and can effectively avoid compound moisture absorption deliquescence, for later stage Product transport, storage or preparation process provide very big facility.
Description
Technical field
The present invention relates to a kind of 1,3-indandione derivative and crystal formation thereof.
Background technology
1,3-indandione derivative is a kind of important anticoagulant raticide, current business-like kindComprise diphacinone, Duocide, Valone and chloradion etc. The representational patent in this aspect has:
Patent CN107489A discloses a kind of 1,3-indandione derivative, and this compound is two replacementAryl acetyl group 1,3-indandione compound.
Patent CN1083752A disclose a kind of pair of chlorophacinone and ammonium (or sodium) thereof preparation method and shouldWith, in this rat poison, indandione compounds is also two substituted aryl acetyl group 1,3-indandioneCompound.
In addition, 1,3-indandione derivative also has many application in optical material field.
Patent CN1376661A discloses a kind of 1,3-indandione derivative, and this compound is indaneDihydroxy cyclohexadione compounds, can be used as photic magnetic and photochromic material.
But at present, the report there are no 1,3-indandione derivative for anti-bacterial drug, not yetSee that to have 2 disubstituted 1 by ester group and acyl group, the report of 3-indandione derivative. Visible, at presentNew purposes and new construction to 1,3-indandione derivative lack new exploration.
In addition, for same compound, conventionally have two or more different crystalline states,Different crystal formations can show different bioavilabilities, dissolution rate, rate of dissolution, stable conventionallyProperty, fusing point, color, filtrability, density and mobility etc. Therefore,, for medicine, developThe better crystal formation of dissolubility and stability has very important significance equally.
Summary of the invention
In order to explore the new purposes of 1,3-indandione derivative, the object of the present invention is to provide onePlant 1,3-indandione derivative and crystal formation thereof. Another object of the present invention is to provide a kind of this chemical combinationThe preparation method of thing and crystal formation thereof.
The present invention compound shown in formula I is provided:
Wherein R1 is selected from the alkyl of C1-C8, and R2 is selected from phenyl or substituted-phenyl.
The alkyl of above-mentioned C1-C8 refers to the alkyl of the straight or branched with 1-8 carbon atom, for example firstBase, ethyl, propyl group, isopropyl, butyl, the tert-butyl group, amyl group, neopentyl, hexyl, heptyl and pungentBase etc.
Preferably, described R1 is methyl, and R2 is phenyl, and structure is suc as formula shown in II:
The present invention also provides the method for compound shown in a kind of preparation formula II, and it comprises the following steps:
The method of preparing compound described in claim 2, comprises the following steps:
(1), taking ninhydrin and beta-nitrostyrene as raw material, obtain formula IV compound through MBH reaction;The solvent of described MBH reaction comprises acetonitrile, oxolane, carrene etc. Wherein, the receipts of acetonitrileRate is higher, and the yield of carrene is lower. The catalyst of described MBH reaction comprises 4-dimethylamino pyrroleThe catalyst of pyridine and following chemical constitution:
(2) taking formula IV compound as raw material, under the existence of acid binding agent, anti-with acylating agent generation acetylationShould obtain formula V compound; The solvent of described reaction comprises acetonitrile, carrene etc., and wherein acetonitrile is better;Described acid binding agent comprises triethylamine, piperidines, sodium acetate or potash etc., and wherein potash effect is better; InstituteState acylating agent and comprise chloroacetic chloride, acetic anhydride, glacial acetic acid etc., wherein acetic anhydride is better.
(3), taking formula V compound and propionic aldehyde as raw material, under the existence of acid and catalyst, react the formula that obtainsV compound; Described acid comprises glacial acetic acid, trifluoroacetic acid, benzoic acid etc., and wherein glacial acetic acid effect is better;Described catalyst comprises (2S)-2-[diphenyl [(trimethylsilyl group) oxygen base] methyl]-pyrrolidines and followingizationLearn the catalyst of structure:
(4) formula III compound is dissolved in solvent, reacts completely at 70-80 DEG C, separation and purification obtains formulaII compound.
The present invention does not represent the restriction that the present invention is selected to illustrating of the selected scope of various reagent
Further preferably, in described step (1), described MBH reacts with DMAPFor catalyst, taking acetonitrile as solvent, the temperature of reaction is 20-25 DEG C.
Further preferably, in described step (2), reaction temperature is 0-25 DEG C; Acylating agent is vinegarAcid anhydrides; Acid binding agent is potash.
Further preferably, in described step (3), reaction temperature is 20-25 DEG C; Described acid is iceAcetic acid, catalyst is (2S)-2-[diphenyl [(trimethylsilyl group) oxygen base] methyl]-pyrrolidines; Reaction dissolvent isAcetonitrile.
Further preferably, in described step (4), the temperature of reaction is 70 DEG C; Described solvent choosingFrom toluene.
The present invention also provides the crystal formation of compound shown in formula II, it is characterized in that:
This crystal formation belongs to monoclinic system, and space group is C2, and cell parameter is β＝90.227(11)°，ρcalc＝1.296g/cm3。
Further preferably, the fusing point of described crystal formation is 174-176 DEG C; Described crystal formation Chinese style II compoundEe value > 98%.
The present invention also provides a kind of method of preparing described crystal formation, and it comprises the following steps: by formula IIizationCompound is dissolved in crystallization in methylene chloride-methanol system, isolates crystal and get final product; Described carrene-firstIn alcohol system, carrene content is 96-98%v/v.
Further preferably, described crystallization is volatilization crystallization.
Further preferably, described volatilization crystallization is the slow crystallization of volatilization naturally under normal temperature.
The present invention also provides described compound or the purposes of crystal formation in preparation antibacterials.
Further preferably, described antibacterials refer to having a liking for Fructus Hordei Germinatus monad, the luxuriant and rich with fragrance acinetobacter calcoaceticus of promise, goldAny one in staphylococcus aureus, MRSE or the multiple antibacterials with antibacterial activity.
Further preferably, described in, have a liking for Fructus Hordei Germinatus monad for having a liking for Fructus Hordei Germinatus monad S1; Not lever of described promise phenanthreneBacterium is the luxuriant and rich with fragrance acinetobacter calcoaceticus N2 of promise or the luxuriant and rich with fragrance acinetobacter calcoaceticus N3 of promise; Described staphylococcus aureus is golden yellow PortugalGrape coccus J4; Described MRSE is MRSE BP8 or MRSE BP4.
The present invention also provides a kind of pharmaceutical composition, and it is that described compound or crystal formation becomes as activityPoint, add the preparation that acceptable auxiliary material pharmaceutically or complementary composition are prepared from.
MBH reaction of the present invention refers to the reaction of gloomy field-Belize-Harry Hillman(Morita – Baylis – Hillmanreaction), is α, β-unsaturated compound and electrophilic reagent (aldehyde, ketone)Under suitable catalyst action, generate the reaction of alkene alpha-position addition compound product.
Key intermediate in the present invention separates and purifying with compound, and the mode using is organicIn chemistry, conventional Isolation and purification method and the example of described method comprise filtration, extract, are dried, revolveDo and various types of chromatograms. Selectively, can make that intermediate is not purified carries out next step reaction.
In some embodiments, one or more compounds of the present invention use that can combine with one another. AlsoCan select compound of the present invention to be combined with any other active agent, thin for the preparation of regulation and controlMedicine or the pharmaceutical composition of born of the same parents' function or treatment disease. If what use is one group of compound, can be byThese compounds simultaneously, carry out administration to study subject respectively or in an orderly manner.
The method of application of the compounds of this invention or pharmaceutical composition is not particularly limited, the representational side of usingFormula comprises (but being not limited to): oral, parenteral (in intravenous, muscle or subcutaneous) and topical.
Solid dosage forms for oral administration comprises capsule, tablet, pill, powder and granule. ?In these solid dosage forms, reactive compound mixes with at least one conventional inert excipient (or carrier), asNatrium citricum or Dicalcium Phosphate, or mix with following compositions: (a) filler or bulking agent, for example, starch,Lactose, sucrose, glucose, sweet mellow wine and silicic acid; (b) adhesive, for example, CMC,Alginates, gelatin, PVP, sucrose and Arabic gum; (c) NMF, for example,Glycerine; (d) disintegrant, for example, agar, calcium carbonate, farina or tapioca, alginic acid,Some composition silicate and sodium carbonate; (e) retarding solvent, for example paraffin; (f) absorb accelerator, for example,Quaternary ammonium compound; (g) wetting agent, for example cetanol and glycerin monostearate; (h) adsorbent, for example,Kaolin; (i) lubricant, for example, talcum, calcium stearate, dolomol, solid polyethylene glycol,Lauryl sodium sulfate, or its mixture. In capsule, tablet and pill, formulation also can comprise bufferingAgent.
Solid dosage forms is prepared as tablet, sugar-pill, capsule, pill and granule can adopt dressing and shell material,As casing and other material well known in the art. They can comprise opacifying agent, and, this compositionIn the mode that the release of middle reactive compound or compound can postpone certain part in alimentary canal, releasePut. The example of adoptable embedding component is polymeric material and Wax. If desired, reactive compoundAlso can with above-mentioned excipient in one or more form microencapsulation form.
Liquid dosage form for oral administration comprises pharmaceutically acceptable emulsion, solution, suspension, sugarSlurry or tincture. Except active ingredient beyond the region of objective existence, it is rare that liquid dosage form can comprise the inertia of conventional employing in this areaRelease agent, as water or other solvent, solubilizer and emulsifying agent, example knows, ethanol, isopropyl alcohol, ethyl carbonate,Ethyl acetate, propane diols, 1,3-BDO, dimethyl formamide and oil, particularly cottonseed oil, flowerThe mixture of oil generation, maize germ, olive oil, castor oil and sesame oil or these materials etc.
Except these inert diluents, composition also can comprise auxiliary agent, as wetting agent, emulsifying agent and outstandingFloating agent, sweetener, flavouring and spices.
Except active ingredient beyond the region of objective existence, suspension can comprise suspending agent, for example, ethoxylation isooctadecane alcohol,Polyoxyethylene sorbitol and Isosorbide Dinitrate, microcrystalline cellulose, aluminium methoxide and agar or these materialsMixture etc.
For the composition of parenteral injection can comprise physiologically acceptable aseptic moisture or anhydrous solution,Dispersion liquid, suspension or emulsion, and for being again dissolved into the nothing of aseptic Injectable solution or dispersion liquidBacterium powder. Suitable moisture and nonaqueous carrier, diluent, solvent or excipient comprises water, ethanol, manyUnit's alcohol and suitable mixture thereof.
The formulation that is used for the compounds of this invention of topical comprises ointment, powder, patch, propellantAnd inhalant. Active component under aseptic condition with physiologically acceptable carrier and any anticorrisive agent, slowElectuary, or the propellant that may need is if desired mixed together.
Pharmaceutically acceptable auxiliary material of the present invention, refers to except active component and is included in formulationMaterial.
Pharmaceutically acceptable complementary composition of the present invention, it has certain physiologically active, but this one-tenthAdding of dividing can not change the leading position of aforementioned pharmaceutical compositions in disease treatment process, and only sends outWave auxiliary effect, these auxiliary effects are only the utilizations to this composition known activity, are that field of medicaments is used toWith supplemental treatment mode. If above-mentioned complementary composition and pharmaceutical composition of the present invention are used in conjunction with, stillSo should belong to the scope of protection of the invention.
Obviously, according to foregoing of the present invention, according to ordinary skill knowledge and the customary means of this area,Do not departing under the above-mentioned basic fundamental thought of the present invention prerequisite, can also make other various ways amendment,Replace or change.
The detailed description of the invention of form by the following examples, remakes further foregoing of the present inventionDetailed description. But this should be interpreted as to the scope of the above-mentioned theme of the present invention only limits to following example.All technology realizing based on foregoing of the present invention all belong to scope of the present invention.
Brief description of the drawings
The molecule stereo structure figure that Fig. 1 crystal formation of the present invention obtains by Advances in crystal X-ray diffraction analysis.
Detailed description of the invention
The raw material, the equipment that in the specific embodiment of the invention, use are known product, commercially available by buyingProduct obtains.
The preparation of embodiment 1 formula III of the present invention compound
(1) molten to the acetonitrile 6mL that is dissolved with ninhydrin (1mmol) and nitroolefin (1.1mmol)In liquid, drip the DMAP (0.2mmol) after 3mL dilution in acetonitrile, normal temperature (20～25 DEG C)Lower stirring 2～4 hours, thin-layer chromatography is monitored until react complete;
(2) dissolve containing in the acetonitrile 10mL solution of formula IV compound (1mmol) and add successively acetic anhydride3mmol and potash 0.5mmol, stir (20～25 DEG C) 2～4 hours under normal temperature, thin-layer chromatography monitoringUntil react completely;
(3) get 10mL reaction tube, add formula IV compound 409.4mg (1mmol), propionic aldehyde 116.0(2mmol), (2S)-2-[diphenyl [(trimethylsilyl group) oxygen base] methyl]-pyrrolidines 48.8m (0.15mmol,No. CAS: 848821-58-9), glacial acetic acid 12.0mg (0.2mmol), using acetonitrile 4mL as solvent,(20 DEG C～25 DEG C) reaction under normal temperature, after thin-layer chromatography monitoring reacts completely, obtains reactant liquor;
The solvent in reactant liquor is removed in decompression, obtains residue; Silicagel column on residue, washes through eluant, eluentDe-(eluant, eluent is benzinum: ethyl acetate=4:1, volume ratio), thin layer is followed the tracks of, and merges eluent,Except desolventizing, obtain salt derivative white solid in indone shown in formula III, productive rate 90%. Indenes shown in formula IIIIn ketone, the detection data of salt derivative are as follows: fusing point (mp): 144 DEG C～146 DEG C, and [α] D20:+43,ESIHRMS：432.1057(+Na)。
The preparation of embodiment 2 formula II of the present invention compound
(1) molten to the acetonitrile 8mL that is dissolved with ninhydrin (1mmol) and nitroolefin (1.1mmol)In liquid, drip the DMAP (0.2mmol) after 3mL dilution in acetonitrile, normal temperature (20～25 DEG C)Lower stirring 2～4 hours, thin-layer chromatography is monitored until react complete;
(2) dissolve containing in acetonitrile (10～12mL) solution of formula IV compound (1mmol) and add successivelyAcetic anhydride 2mmol and potash 0.8mmol, stir (20～25 DEG C) 2～4 hours under normal temperature, thin layer lookSpectrum monitoring is until react completely;
(3) get 10mL reaction tube, add formula IV compound 409.4mg (1mmol), propionic aldehyde 116.0(2mmol), (2S)-2-[diphenyl [(trimethylsilyl group) oxygen base] methyl]-pyrrolidines 48.8m (0.15mmol,No. CAS: 848821-58-9), glacial acetic acid 12.0mg (0.2mmol), using acetonitrile 6mL as solvent,(20 DEG C～25 DEG C) reaction under normal temperature, after thin-layer chromatography monitoring reacts completely, obtains reactant liquor;
The solvent in reactant liquor is removed in decompression, obtains residue; Silicagel column on residue, washes through eluant, eluentDe-(eluant, eluent is benzinum: ethyl acetate=4:1, volume ratio), thin layer is followed the tracks of, and merges eluent,Except desolventizing, obtain salt derivative white solid in indone shown in formula III.
The preparation of embodiment 3 formula II of the present invention compound
Get 10mL reaction tube, add the indone inner salt product 204.5mg (0.5mmol) shown in formula III,Taking toluene (4mL) as solvent, reaction at 70 DEG C of oil baths, after question response finishes, decompression except dereaction moltenAgent, silicagel column on residue, benzinum: ethyl acetate=5:1 wash-out, thin-layer chromatography is followed the tracks of, and mergesEluent, except desolventizing, gained purified is formula II compound, yield 70%, white solid. InspectionSurvey result is as follows: mp:174-176 DEG C, [α]D 20：+50，ESI-HRMS:418.0901(+Na)。
The preparation of embodiment 4 crystal formations of the present invention
Get formula II compound prepared by embodiment 3, normal in methylene chloride-methanol (96%:4%v/v)Temperature is slowly volatilization crystallization down, obtains the crystal formation of compound shown in formula I of the present invention, ee value > 98%, this crystal formationBy X-ray single crystal diffraction, its molecule stereo structure figure as shown in Figure 1, proves the molecule knot of compoundStructure and steric configuration do not change in crystal formation preparation, and its crystal structure data are as follows:
Single Crystal X-ray diffraction conditions are: the X-ray diffraction of collecting these monocrystalline at the temperature of 296KData, wavelength isResult is as shown in table 1.
The single crystal diffraction data of table 1 crystal formation of the present invention
The preparation of embodiment 5 crystal formations of the present invention
Get formula II compound prepared by embodiment 3, normal in methylene chloride-methanol (98%:2%v/v)The lower slowly volatilization of temperature crystallization, obtains crystal formation of the present invention.
Below by the mode of test example, beneficial effect of the present invention is described:
The antibacterial activity of test example 1 crystal formation of the present invention
Adopt coubling dilution to measure the antibacterial activity of crystal formation of the present invention.
The acquisition of experimental strain:
Experimental strain of the present invention is all for being identified by People's Hospital, Sichuan Prov., the collection of healthcare hospital for women & children of Sichuan ProvinceClinical separation pathogenic bacteria. Sample is mainly derived from blood, phlegm, urine etc., is collecting unit through French plumIn dust (BioMeriruk) VITEK-32, VITEK-60 automatic microbe identification and analysis instrument identify,And through Biolog Bacteria analyzer (U.S.) API20E, 20NE for Sichuan Industrial Institute of Antibiotics,Staph series and conventional method are identified again, distinguish called after: have a liking for Fructus Hordei Germinatus monad S1, promise phenanthrene is motionlessBacillus N2, the luxuriant and rich with fragrance acinetobacter calcoaceticus N3 of promise, staphylococcus aureus J4, MRSE BP8, epidermisStaphylococcus BP4, for antibacterial tests.
First by the crystal formation of the present invention of accurate weighing for 30mg 2mLDMSO (dimethyl sulfoxide (DMSO)) dissolve,Do respectively 10 concentration gradients by coubling dilution, each gradient is to MH (caseinhydrolysate Mueller-Hinton) in culture dish, add 1mL to contain drug solns, and mix with 14mLMH solid medium, doBecome the different culture dish of pastille. Then be inoculated in training with the bacterium liquid that the card punch in 27 holes is 106 by bacteria containing amountWhether support on ware, put into the constant incubator of 37 DEG C, cultivate 18-24h, observing inoculation position has bacterium rawLong, to judge its fungistatic effect. Result is as shown in table 2, using lavo-ofloxacin as reference.
Antibacterial activity refers to that antimicrobial suppresses or the ability of pathogenic microbe killing; Available extracorporeal bacteria inhibitor testMeasure with experimental therapy method in body; In Vitro Bacteriostasis experiment has important references meaning to clinical application. CanThe least concentration that suppresses bacterial growth in culture medium is minimal inhibitory concentration MIC (minimalinhibitoryConcentration). The bacteriostasis of antimicrobial is relative with bactericidal action, and some antimicrobial is low denseWhile spending, be bacteriostasis, and high concentration is bactericidal action.
The mensuration of the antibacterial activity MIC (mg/mL) of table 2 crystal formation of the present invention
As shown in Table 2, crystal formation provided by the invention can suppress to have a liking for Fructus Hordei Germinatus monad, Nuo Fei notThe growth of lever bacterium, staphylococcus aureus and MRSE, has certain antibacterial activity.
Stability and the hygroscopicity of test example 2 crystal formations of the present invention
1, stability:
The crystal formation 30mg of formula II compound of the present invention is put into stability test case and carries out accelerated test,Experimental condition is: temperature, 40 DEG C ± 2 DEG C; Humidity, RH75% ± 5%, the time is 3 months. Result:Adopt TLC (thin-layer chromatography) and HPLC (high performance liquid chromatography) to measure, all find this compound notThere is significant change, illustrate that stable crystal form of the present invention is good.
2, hygroscopicity:
Adopt 2010 editions second annex XIXJ medicine of Pharmacopoeia of People's Republic of China to draw moist test directionPrinciple, measurement result is as follows:
Table 3 stability and hygroscopicity are investigated
| Used time (my god) | 0 | 5 | 10 | 15 |
| Compound draws wet weightening finish | 0.0％ | 1.3％ | 1.3％ | 1.3％ |
The result of table 3 shows, crystal formation of the present invention is placed 15 days under wet environment, and it draws the wet rate of body weight gain utmost pointLow, illustrate that crystal formation of the present invention can effectively avoid compound moisture absorption deliquescence.
In sum, of the present invention 1,3-indandione derivative can prepare has pharmaceutically activeCrystal formation, expanded the purposes of 1,3-indandione derivative. Preparation technology is simple for this crystal formation, hasCertain antibacterial activity, can be used for the preparation of antibacterials; Have good stability, can effectively avoid chemical combinationThing moisture absorption deliquescence, for later stage Product transport, storage or preparation process provide very big facility.
Claims (12)
1. suc as formula the compound shown in I:
Wherein R1Be selected from C1-C8Alkyl, R2Be selected from phenyl.
2. compound according to claim 1, is characterized in that: described R1For methyl, R2For phenyl, structure is suc as formula shown in II:
。
3. the method for preparing compound described in claim 2, comprises the following steps:
(1), taking ninhydrin and beta-nitrostyrene as raw material, obtain formula IV compound through MBH reaction;
(2), taking formula IV compound as raw material, under the existence of acid binding agent, obtain formula V compound with acylating agent generation acetylization reaction;
(3), taking formula V compound and propionic aldehyde as raw material, under the existence of acid and catalyst, react and obtain formula III compound;
(4) formula III compound is dissolved in solvent, reacts completely at 70-80 DEG C, separation and purification obtains formula II compound.
4. preparation method according to claim 3, is characterized in that: in described step (1), described MBH reacts taking DMAP as catalyst, and taking acetonitrile as solvent, the temperature of reaction is 20-25 DEG C.
5. preparation method according to claim 3, is characterized in that: in described step (2), reaction temperature is 0-25 DEG C; Acylating agent is acetic anhydride; Acid binding agent is potash.
6. preparation method according to claim 3, is characterized in that: in described step (3), reaction temperature is 20-25 DEG C; Described acid is glacial acetic acid, and catalyst is (2S)-2-[diphenyl [(trimethylsilyl group) oxygen base] methyl]-pyrrolidines; Reaction dissolvent is acetonitrile.
7. preparation method according to claim 3, is characterized in that: in described step (4), the temperature of reaction is 70 DEG C; Described solvent is selected from toluene.
8. the crystal formation of compound shown in formula II described in claim 2, is characterized in that:
This crystal formation belongs to monoclinic system, and space group is C2, and cell parameter is β＝90.227(11)°，ρcalc＝1.296g/cm3。
9. crystal formation according to claim 8, is characterized in that: the fusing point of described crystal formation is 174-176 DEG C; The ee value of described crystal formation Chinese style II compound > 98%.
10. the method for preparing crystal formation described in claim 8 or 9, is characterized in that: it comprises the following steps: formula II compound is dissolved in to crystallization in methylene chloride-methanol system, isolates crystal and get final product; In described methylene chloride-methanol system, carrene content is 96-98%v/v.
Compound described in 11. claim 1 or 2 or 8 or 9 any one or the crystal formation purposes in preparation antibacterials.
12. purposes according to claim 11, is characterized in that: described antibacterials refer to having a liking for any one or the multiple antibacterials with antibacterial activity in the luxuriant and rich with fragrance acinetobacter calcoaceticus of Fructus Hordei Germinatus monad, promise, staphylococcus aureus, MRSE.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1074897A (en) * | 1992-01-29 | 1993-08-04 | 辽宁省化工研究院 | The synthetic method of indandione raticide |
| CN1245013A (en) * | 1999-04-09 | 2000-02-23 | 单承仪 | Process for synthesizing refined diphacinone |
| CN103342686A (en) * | 2013-07-02 | 2013-10-09 | 扬州大学 | New epoxidation method of 2-benzylidene-1,3-indan diketone double bond |
-
2015
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1074897A (en) * | 1992-01-29 | 1993-08-04 | 辽宁省化工研究院 | The synthetic method of indandione raticide |
| CN1245013A (en) * | 1999-04-09 | 2000-02-23 | 单承仪 | Process for synthesizing refined diphacinone |
| CN103342686A (en) * | 2013-07-02 | 2013-10-09 | 扬州大学 | New epoxidation method of 2-benzylidene-1,3-indan diketone double bond |
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