CN105037269B - Substituted pyrazolecarboxylic ketone secretory protease inhibitors and preparation method thereof - Google Patents
Substituted pyrazolecarboxylic ketone secretory protease inhibitors and preparation method thereof Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D231/18—One oxygen or sulfur atom
- C07D231/20—One oxygen atom attached in position 3 or 5
- C07D231/22—One oxygen atom attached in position 3 or 5 with aryl radicals attached to ring nitrogen atoms
- C07D231/26—1-Phenyl-3-methyl-5- pyrazolones, unsubstituted or substituted on the phenyl ring
Abstract
Application the present invention relates to a kind of substituted pyrazolecarboxylic ketone compounds and preparation method thereof and in pharmacy, belongs to pharmaceutical technology field.Substituted pyrazolecarboxylic ketone compounds are newfound a kind of fungi Sap2 inhibitor, have certain antifungal activity.The invention provides a kind of substituted pyrazolecarboxylic ketone compounds, the structure following structure formula of the compound：Substituted pyrazolecarboxylic ketone compounds of the present invention have preferable Sap2 Inhibiting enzyme activities, and this class compound can be used for the medicine for preparing treatment anti-fungal infection, new approach is opened to further investigate and developing new antifungal drug.
Description
Technical field
The present invention relates to pharmaceutical technology field, is a kind of new substituted pyrazolecarboxylic ketone secretory protease suppression
Preparation --- 4- [(substitution) benzene alkenylene] -3- phenyl -1- [(substitution) phenyl] -1H- pyrazolidines -5 (4H) -one class compounds with
And preparation method.
Background technology
Fungal infection is the common disease and frequently-occurring disease of long-standing problem human health.Epidemiology survey shows, all over the world
The incidence of disease and the death rate of invasive fungal infection are in increase trend year by year.Reason can be divided into following several respects, as wide spectrum class resists
The abuse of rhzomorph；Tumor chemoradiotherapy and organ transplant antirejection therapy etc. cause immunity of organism low；The Chinese mugwort of immune deficiency
Growing patient rapidly increases.It is white read the pathogenic bacteria such as bacterium, Cryptococcus neoformans and aspergillus fumigatus caused by deep fungal infection into
For tumour and the main cause of AIDS patients death, reading bacterium in vain also turns into the fourth-largest the main pathogenic fungi.So, effectively control fungi sense
Dye is to reduce the key of these mortalities.Clinically preferably anti-deep fungal medicine still compares shortage, existing medicine
Generally existing narrow antimicrobial spectrum, side effect are strong, poor bioavailability, are also easy to produce the shortcomings of drug resistance, have been difficult to meet clinical use
Medicine demand.Therefore, the research and development of antifungal drug are still one of focus of drug research, are based especially on new target spot and carry out medicine
Thing designs and new drug discovery seems very urgent and important, and this also becomes the important directions of antifungal drug research and development.
Secretory protease (Secreted aspartic protease, Sap) is a kind of aspartic acid egg
The acidic hydrolysis protease of white enzyme family, it is secreted into the extracellular catalyzing hydrolysis that played to protein peptide bond and acts on.Sap2 by
Confirmation has various biological function, such as provides nutrition, attachment and invasion host cell, the protection for destroying host for own cells
Barrier, infringement host immune stress reaction etc..The research of Sap2 micromolecular inhibitors is still at an early stage.
In order to find the new Sap2 micromolecular inhibitors with brand new type, pass through structure-based virtual screening
With further structure optimization, 4- [(substitution) benzene alkenylene] -3- phenyl -1- [(substitution) phenyl] -1H- pyrazolidines -5 are obtained
(4H) -one class compound, it has reads bacterium Sap2 Inhibiting enzyme activities in vain, has not yet to see synthesis and its Sap2 of such compound
The report of Inhibiting enzyme activity.
The content of the invention
The purpose of the present invention is to be directed to deficiency of the prior art, there is provided a kind of new substituted pyrazolecarboxylic ketone secreting type day
Winter serine protease inhibitor, including 4- [(substitution) benzene alkenylene] -3- phenyl -1- [(substitution) phenyl] -1H- pyrazolidines -5
(4H) -one class compound and its salt.
Another purpose of the present invention is to provide a kind of new substituted pyrazolecarboxylic ketone secretory protease suppression
The application of preparation.
Another purpose of the present invention is to provide a kind of new substituted pyrazolecarboxylic ketone secretory protease suppression
The preparation method of preparation.
To achieve the above object, the present invention adopts the technical scheme that：A kind of substituted pyrazolone antifungal compound,
Characterized in that, the general structure of described compound is：
Wherein：
(1)R1Other any positions of link position are removed on A rings, are monosubstituted or polysubstituted, substitution on A rings
Base refers to：Hydrogen, hydroxyl, amino, methyl, ethyl, methoxyl group, ethyoxyl, nitro, cyano group, trifluoromethyl or halogen, wherein, halogen
Including F, Cl, Br, I；
(2)R2Other any positions of link position are removed on B rings, are monosubstituted or polysubstituted, substitution on B rings
Base refers to：-OCH2COOH。
Preferably, R1、R2The substituent and the position of substitution of representative are as follows：
(1)R1Group is H, R2Group is 2-OCH2COOH；
(2)R1Group is 3-Cl, R2Group is 2-OCH2COOH；
(3)R1Group is 4-Cl, R2Group is 2-OCH2COOH；
(4)R1Group is 4-F, R2Group is 2-OCH2COOH；
(5)R1Group is 4-Me, R2Group is 2-OCH2COOH；
(6)R1Group is 4-OMe, R2Group is 2-OCH2COOH；
(7)R1Group is H, R2Group is 4-OCH2COOH；
(8)R1Group is 3-Cl, R2Group is 4-OCH2COOH；
(9)R1Group is 4-Cl, R2Group is 4-OCH2COOH；
(10)R1Group is 4-F, R2Group is 4-OCH2COOH；
(11)R1Group is 4-Me, R2Group is 4-OCH2COOH；
(12)R1Group is 4-OMe, R2Group is 4-OCH2COOH；
(13)R1Group is H, R2Group is 2,4-diOCH2COOH；
(14)R1Group is 3-Cl, R2Group is 2,4-diOCH2COOH；
(15)R1Group is 4-Cl, R2Group is 2,4-diOCH2COOH；
(16)R1Group is 4-F, R2Group is 2,4-diOCH2COOH；
(17)R1Group is 4-Me, R2Group is 2,4-diOCH2COOH；
(18)R1Group is 4-OMe, R2Group is 2,4-diOCH2COOH；
(19)R1Group is 2,4-diF, R2Group is 2,4-diOCH2COOH；
(20)R1Group is H, R2Group is 2,4-diOCH2COOH；
(21)R1Group is 3-Cl, R2Group is 2,4-diOCH2COOH；
(22)R1Group is 4-Cl, R2Group is 2,4-diOCH2COOH；
(23)R1Group is 4-F, R2Group is 2,4-diOCH2COOH；
(24)R1Group is 4-Me, R2Group is 2,4-diOCH2COOH；
(25)R1Group is 4-OMe, R2Group is 2,4-diOCH2COOH。
To realize above-mentioned second purpose, the present invention adopts the technical scheme that：Above-mentioned pyrazolone compound can be according to
Conventional method is prepared as the form of pharmaceutical salts.Including its organic alkali salt and inorganic base salts：Inorganic base includes but is not limited to hydrogen-oxygen
Change potassium, sodium hydroxide, potassium carbonate, sodium carbonate etc., organic base includes but is not limited to methylamine, ethamine etc..
To realize above-mentioned 3rd purpose, the synthetic reaction flow of the compounds of this invention is as follows：
Concretely comprise the following steps：
(1) (4H) -one (II) of 1- (substitution) phenyl -3- phenyl -1H- pyrazoles -5 is prepared
In acetic acid, return stirring reacts 6 hours for ethyl benzoylacetate (I) and (substitution) hydrazinobenzene hydrochloride salt, generation
(4H) -one (II) of 1- (substitution) phenyl -3- phenyl -1H- pyrazoles -5；
(2) 4- [(substitution) benzene alkenylene] -3- phenyl -1- [(substitution) phenyl] -1H- pyrazolidines -5 (4H) -one is prepared
(III, R2=-OCH2COOEt)
Compound 1,3- bis- (substitution) phenylthiourea, anhydrous sodium acetate and ethyl chloroacetate are heated to reflux in absolute ethyl alcohol
Reaction 6 hours, ethyl alcohol recrystallization obtains 4- [(substitution) benzene alkenylene] -3- phenyl -1- [(substitution) phenyl] -1H- pyrazolidines -5
(4H) -one (III, R2=-OCH2COOEt)；
(3) 4- [(substitution) benzene alkenylene] -3- phenyl -1- [(substitution) phenyl] -1H- pyrazolidines -5 (4H) -one is prepared
(IV, R2=-OCH2COOH)
4- [(substitution) benzene alkenylene] -3- phenyl -1- [(substitution) phenyl] (4H) -one of -1H- pyrazolidines -5 (III, R2=-
OCH2) and LiOHH COOEt2O is in mixed solvent (THF:MeOH:H2O=3:2:1) in, reaction 0.5 hour is stirred at room temperature, obtains
To 4- [(substitution) benzene alkenylene] -3- phenyl -1- [(substitution) phenyl] (4H) -one of -1H- pyrazolidines -5 (IV, R2=-
OCH2COOH)。
The invention has the advantages that：
Compound of the present invention is the fungi Sap2 inhibitor of a kind of brand new type, has preferably suppression enzyme activity
Property, new approach is opened to further investigate and developing new construction type antifungal drug, antimycotic sense is treated available for preparing
The medicine of dye and with existing combined antimicrobial agents medicine.
Brief description of the drawings
Accompanying drawing 1 is the SDS-PAGE (SDS-PAGE of Sap2 refolding) of rear Sap2 before purification.M roads：Mark egg
In vain；1：Non- inducible protein；2：Inducible protein；3：Purification of recombinant proteins.
Embodiment
Embodiment provided by the invention is elaborated below in conjunction with the accompanying drawings.
The chemical constitution of currently preferred pyrazolone compound and1H-NMR and MS data are as shown in table 1.
The chemical constitution of the preferred compound of table 1 and1H-NMR and MS data
Compound of the present invention is the fungi Sap2 inhibitor of a kind of brand new type, has preferably suppression enzyme activity
Property, new approach is opened to further investigate and developing new construction type antifungal drug, antimycotic sense is treated available for preparing
The medicine of dye and with existing combined antimicrobial agents medicine.
Embodiment 1：2,4- dihydro -2,5- diphenyl -3H- pyrazoline -3- ketone (II, R1=H) preparation
Weigh ethyl benzoylacetate (9.61g, 50mmol, 1.0equiv), phenylhydrazine hydrochloride (8.00g, 55mmol,
1.1equiv), acetic acid 2.0mL is in 100mL eggplant-shape bottles, mixture back flow reaction 3h, each small time point plate monitoring.Reaction finishes
Afterwards, reaction solution adds ether 20mL, and 30min is stirred under ice bath, filters precipitate, and (a small amount of multiple) is washed with ether 30mL,
Dry, ethyl alcohol recrystallization 3 times, obtain white solid 5.1g, yield:43%.1H-NMR(600MHz,DMSO-d6)δ:7.98(d,
1H, J=8.26Hz), 7.85 (d, 2H, J=7.60Hz), 7.50 (d, 2H, J=7.73Hz), 7.45-7.47 (m, 1H), 7.36-
7.41 (t, 2H, J=7.52Hz), 7.31-7.35 (t, 2H, J=7.50Hz), 6.46 (s, 1H), 3.87 (s, 1H) .ESI-MS
(m/z):237.43[M+1].
Embodiment 2：2- (2- { [(the 5H)-alkenylene of 5- oxygen -1,3- diphenyl -1H- pyrazolidines -4] methyl } phenoxy group) second
Acetoacetic ester (III, R1=H, R2=2-OCH2COOEt preparation)
Weigh 2,4- dihydro -2,5- diphenyl -3H- pyrazoline -3- ketone (0.47g, 0.2mmol, 1.0equiv), 2- formyls
Phenoxyl ethyl acetate (0.49g, 0.24mmol, 1.2equiv) adds the dissolving of 15mL absolute ethyl alcohols in 25mL eggplant-shape bottles,
Piperidinyl-1 00 μ L, 60 DEG C of stirring reaction 6h are added, there is solid precipitation, precipitate is filtered, ethyl alcohol recrystallization, obtains orange solids
0.53g, yield:62%.1H-NMR(300MHz,DMSO-d6)δ:8.28 (s, 1), 7.95 (d, 2H, J=7.76Hz), 7.70-
7.79 (m, 2H), 7.54-7.66 (m, 4H), 7.46 (t, 2H, J=7.70Hz), 7.07-7.31 (m, 4H), 4.90 (s, 2H),
4.11 (dd, 2H, J=7.10,14.24Hz), 1.13 (t, 3H, J=7.15Hz) .ESI-MS (m/z):427.41[M+1].
Embodiment 3：2- (2- { [(the 5H)-alkenylene of 5- oxygen -1,3- diphenyl -1H- pyrazolidines -4] methyl } phenoxy group) second
Acid (IV, R1=H, R2=2-OCH2COOH preparation)
Weigh 2- (2- { [(the 5H)-alkenylene of 5- oxygen -1,3- diphenyl -1H- pyrazolidines -4] methyl } phenoxy group) acetic acid second
Ester (0.2g, 0.47mmol, 1equiv) and LiOHH2O (0.030g, 0.71mmol, 1.5equiv) is in 5mL mixed solvents
(THF:MeOH:H2O=3:2:1) in, reaction 0.5h. evaporated under reduced pressure solvents are stirred at room temperature, add water (20mL), 1M HCl regulations
PH to 2.0-3.0, there is precipitation to generate.Filtering precipitation, is washed, ethyl alcohol recrystallization with cold water, obtains Orange red solid 0.12g, is received
Rate:64%, m.p.:113-114℃.1H-NMR(300MHz,DMSO-d6)δ:13.09 (br s, 1H), 7.85 (d, 2H, J=
7.95Hz),7.73-7.55(m,2H),7.33-7.52(m,4H),7.20-7.30(m,5H),7.08-7.18(m,2H),4.89
(s,2H).ESI-MS(m/z):399.42[M+1].
Agents useful for same is that commercially available analysis is pure in embodiment.
Compound 2-25 repeats the step in embodiment 3, just can using different (substitution) benzaldehydes as synthesis material in table
Different substituted thiazole ketone compounds needed for synthesis.
Embodiment 4：5- [(substitution of 2- Oxoacetic Acids) benzene Asia alkene methyl] -3- [(substitution) phenyl] -2- that the present invention synthesizes
The Sap2 Inhibiting enzyme activities of [(substitution) phenylimino] thiazolidin-4-one class compound
(1) general principle
This experiment be based on fluorescence radiation method measure enzymatic activity, Sap2 can specific for hydrolysis amino acid peptide bond, such peptide fragment
(H2N-Dabcyl-Arg-Lys-Pro-Ala-Leu-Phe-┆-Phe-Arg-Leu-Glu(EDANS)–Arg-CO2H) two phenylpropyl alcohols
Propylhomoserin is connected peptide bond can be by its specific for hydrolysis.Above-mentioned peptide fragment is FRET-pair-labeled substrates
The substrate of (fluorescence resonance energy transfer) FRET base group modification, substrate
One end is modified by Dabcyl (4,4-dimethyl aminoazobenzene-4 '-carboxylic acid), and the other end has
EDANS (5- [(2-aminoethyl) amino] naphthalene-1-sulfonic acid) base group modification, when EDANS groups
After being excited, its emission band can be fully absorbed by Dabcyl groups, therefore, when two groups are located on same substrate,
Fluorescence radiation is absorbed；When substrate is hydrolyzed, the hydrolysis substrate with EDANS groups will send very strong fluorescence.
(2) test material
Substrate：H2N-Dabcyl-Arg-Lys-Pro-Ala-Leu-Phe-Phe-Arg-Leu-Glu(EDANS)-Arg-
CO2H (customization of gill biochemical industry company), Sap2 enzymes (Nanjing bronze object Bioisystech Co., Ltd prokaryotic expression)
(3) other materials
Sodium citrate buffer solution (50mM, pH 4.5,50mM containing NaCl, autogamy)
Positive drug：Pepstatin A(Sigma)
DMSO：Sigma
Black does not combine flat 96 orifice plate：Corning, model 3650.
(4) instrument
Instrument：The multi-function microplate readers of Bioteck Synergy 2, Gen5 operation softwares.
(5) sample preparation
Substrate is configured to the stand-by solution of 18.75 μM of concentration with DMSO (Sigma)；Positive drug PepA is with DMSO (Sigma)
Dissolving, is configured to series concentration：10 μM~0.001nM；Other testing samples DMSO (Sigma) dissolves, and it is dense to be configured to series
Degree：100 μM~0.01 μM.Experimental unit：Totally 200 μ L, the μ L bottoms of+5 μ L inhibitor (DMSO solution) of+5 μ L enzymes of 185 μ L buffer solutions+5
Thing (DMSO solution), each concentration unit are duplicate hole.The Sap2 enzymes sodium citrate buffer solutions of pH 4.5 dilute 10 times, and room temperature is lived
Change 2h.By hydrolyzing the substrate of 18.75 μM of concentration, enzyme is diluted to 100units/min concentration, now fluorescence intensity is at any time
Between linear growth, the dilution of enzyme is stand-by.
(6) test method
A) 185 μ L sodium citrate buffer solutions, 5 μ L Sap2 enzymes, 5 μ L inhibitor are sequentially added into the orifice plate of black 96, set double
Multiple holes, PepA do positive control, and the DMSO for not adding inhibitor does blank.Solution system is sufficiently mixed vibration, 30 DEG C of incubations
30min。
B) 18.75 μM of μ L of substrate 5 are added, vibration plate is well mixed, as time point, the measure compound fluorescence per 10min
Luminous (λ ex=340/30nm, λ em=485/20nm).
C) according to the increase degree of unit interval fluorescence radiation, the inhibiting rate % of inhibitor under each concentration is calculated.
D) inhibiting rate of each concentration and the log values of sample concentration are carried out nonlinear fitting, obtains activity and dosage
Dependence, IC is directly obtained by software50Value.Software Graphpad prism 5.0, fitting module：log(inhibitor)
Vs response--varible slop, matched curve bottom and top are set to 0 and 100%.
(7) Sap2 Inhibiting enzyme activities
Inhibiting enzyme activity of the pyrazolone compound of table 2 to Sap2
Nd=not determined
It is above-mentioned test result indicates that, pyrazolone compound has preferable Sap2 Inhibiting enzyme activities, and this class compound can use
In the medicine for preparing treatment anti-fungal infection.
Substituted pyrazolecarboxylic ketone compounds of the present invention are the Sap2 inhibitor and antifungal activity of a kind of new construction type
Compound, the present invention open new approach to further investigate and developing new antifungal drug.
Described above is only the preferred embodiment of the present invention, it is noted that for the ordinary skill people of the art
Member, on the premise of the inventive method is not departed from, can also make some improvement and supplement, and these are improved and supplement also should be regarded as
Protection scope of the present invention.
Claims (7)
1. a kind of substituted pyrazolone antifungal compound, it is characterised in that the general structure of described compound is：
Wherein：
(1)R1Other any positions of link position are removed on A rings, are monosubstituted or polysubstituted on A rings, substituent refers to：
Hydrogen, methyl, ethyl, methoxyl group, ethyoxyl or halogen, wherein, halogen F, Cl or Br；
(2)R2Other any positions of link position are removed on B rings, are monosubstituted or polysubstituted, substituent on B rings
Refer to：-OCH2COOH。
2. pyrazolone antifungal compound according to claim 1, it is characterised in that R1、R2The substituent of representative and take
Subrogate put it is as follows：
(1)R1Group is H, R2Group is 2-OCH2COOH；
(2)R1Group is 3-Cl, R2Group is 2-OCH2COOH；
(3)R1Group is 4-Cl, R2Group is 2-OCH2COOH；
(4)R1Group is 4-F, R2Group is 2-OCH2COOH；
(5)R1Group is 4-Me, R2Group is 2-OCH2COOH；
(6)R1Group is 4-OMe, R2Group is 2-OCH2COOH；
(7)R1Group is H, R2Group is 4-OCH2COOH；
(8)R1Group is 3-Cl, R2Group is 4-OCH2COOH；
(9)R1Group is 4-Cl, R2Group is 4-OCH2COOH；
(10)R1Group is 4-F, R2Group is 4-OCH2COOH；
(11)R1Group is 4-Me, R2Group is 4-OCH2COOH；
(12)R1Group is 4-OMe, R2Group is 4-OCH2COOH；
(13)R1Group is H, R2Group is 2,4-diOCH2COOH；
(14)R1Group is 3-Cl, R2Group is 2,4-diOCH2COOH；
(15)R1Group is 4-Cl, R2Group is 2,4-diOCH2COOH；
(16)R1Group is 4-F, R2Group is 2,4-diOCH2COOH；
(17)R1Group is 4-Me, R2Group is 2,4-diOCH2COOH；
(18)R1Group is 4-OMe, R2Group is 2,4-diOCH2COOH；
(19)R1Group is 2,4-diF, R2Group is 2,4-diOCH2COOH；
(20)R1Group is H, R2Group is 2,4-diOCH2COOH；
(21)R1Group is 3-Cl, R2Group is 2,4-diOCH2COOH；
(22)R1Group is 4-Cl, R2Group is 2,4-diOCH2COOH；
(23)R1Group is 4-F, R2Group is 2,4-diOCH2COOH；
(24)R1Group is 4-Me, R2Group is 2,4-diOCH2COOH；
(25)R1Group is 4-OMe, R2Group is 2,4-diOCH2COOH。
3. according to the pharmaceutical salts of any described pyrazolone antifungal compound of claim 1,2.
4. pharmaceutical salts according to claim 3, it is characterised in that described pharmaceutical salts are organic alkali salt or inorganic base salts.
5. pharmaceutical salts according to claim 4, it is characterised in that described inorganic base is potassium hydroxide, sodium hydroxide, carbon
Sour potassium or sodium carbonate, described organic base are methylamine or ethamine.
6. antifungal drug is being prepared according to any described pyrazolone antifungal compounds of claim 1-5 or its pharmaceutical salts
In application.
7. the preparation method of pyrazolone antifungal compound according to claim 2, it is characterised in that described preparation
Method comprises the following steps：
(1) preparation of 2,4- dihydros -2,5- diphenyl -3H- pyrazoline -3- ketone
50mmol ethyl benzoylacetates, 55mmol phenylhydrazine hydrochlorides, 2.0mL vinegar stock back flow reaction 3h, each hour
Point plate monitoring, after completion of the reaction, reaction solution adds ether 20mL, and 30min is stirred under ice bath, filters precipitate, uses ether
30mL is washed, and is dried, ethyl alcohol recrystallization 3 times, is obtained white solid；
(2) system of 2- (2- { [(the 5H)-alkenylene of 5- oxygen -1,3- diphenyl -1H- pyrazolidines -4] methyl } phenoxy group) ethyl acetate
It is standby
0.2mmol 2,4- dihydro -2,5- diphenyl -3H- pyrazoline -3- ketone, 0.24mmol 2- formvlphenoxv acetic acid second
Ester, the dissolving of 15mL absolute ethyl alcohols is added, adds piperidinyl-1 00 μ L, 60 DEG C of stirring reaction 6h, there is solid precipitation, filters precipitate,
Ethyl alcohol recrystallization, obtain orange solids；
(3) preparation of 2- (2- { [(the 5H)-alkenylene of 5- oxygen -1,3- diphenyl -1H- pyrazolidines -4] methyl } phenoxy group) acetic acid
0.47mmol 2- (2- { [(the 5H)-alkenylene of 5- oxygen -1,3- diphenyl -1H- pyrazolidines -4] methyl } phenoxy group) acetic acid second
Ester, 0.71mmol LiOHH2O is in 5mL THF:MeOH:H2O=3:2:1 in the mixed solvent, reaction 0.5h is stirred at room temperature, subtracts
Solvent evaporated is pressed, water is added, 1M HCl regulation pH to 2.0-3.0, has precipitation to generate, filtering precipitation, washed with cold water, ethanol weight
Crystallization, obtains Orange red solid.
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| CN1377346A (en) * | 1999-07-30 | 2002-10-30 | Basf公司 | Z-pyrazoline-5-ones |
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| CN1377346A (en) * | 1999-07-30 | 2002-10-30 | Basf公司 | Z-pyrazoline-5-ones |
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