CN103265525A - Substituted thieno-quinone compounds, and preparation method and application thereof - Google Patents
Substituted thieno-quinone compounds, and preparation method and application thereof Download PDFInfo
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Abstract
The invention relates to the technical field of medicine, and provides substituted thieno-quinone compounds and pharmaceutically acceptable salts thereof. The structural general formula of the substituted thieno-quinone compounds is disclosed in the specification. The invention also provides a preparation method of the compounds and application of the compounds in preparation of antifungal drugs.
Description
Technical field
The present invention relates to medical technical field, be specifically related to a kind of new substituted thiophene and benzoquinone compound and preparation method, and as the application of antifungal drug.
Background technology
In recent years, factors such as the abuse of antibiotic, tumor chemoradiotherapy and organ transplantation cause immunosuppression, the AIDS patient increases rapidly in addition, read bacterium, aspergillus fumigatus, Pneumocystis carinii and cryptococcus neoformans deep infection in vain and rise significantly, deep fungal infection has now become major disease main causes of death such as acquired immune deficiency syndrome (AIDS) and tumour.Yet desirable clinically antifungal drug extremely lacks.The polyene antibiotics (for example amphotericin B) that acts on fungal cell's membrane lipid is first-selected curative, but toxic side effect is big, and clinical application is seriously limited.The azole drug (for example fluconazole, itraconazole and voriconazole) that acts on lanosterol 14 α-demethylase (CYP51) is to use maximum a kind of antifungal drugs at present, but such medicine is owing to the restraining effect to cytochrome P 450 enzymes system, can cause tangible drug-drug interactions, and invalid to Resistant strain.There are problems such as expensive, that bioavailability is lower again in the lipopeptid class medicine (for example Caspofungin and Mi Kafen are clean) that acts on fungal cell wall β-1,3 glucan synthase.
Reported first such as Rao in 1986 new bio bases antifungal compound sampangine (J.U.M.Rao.Sampangine, a New Alkaloid from Cananga Odorata, J.Nat.Prod.1986,346-347) .Sampangine extracts in Asia ylang-ylang Cananga odorata (Lamk) Hook.F.et Thoms. stem skin; Reported first such as nineteen ninety Liu.S. extract 3-methoxy sampangine(8 in the root skin of West Africa Cleistophathis patens tree).The two is to the IC of Candida albicans (Candida albicans)
50Value is respectively 3.0 and 0.15 μ g/mL.Because sampangine is Fourth Ring condensed ring structure, poor solubility; The carbonyl of while molecule and pyridine exist resonant, and it is less to cause further modifying the space of transforming, and difficulty is bigger.
Therefore, except the structure and preparation of optimizing the existing medicine of improvement, seek the important directions that tool brand new type and brand-new mechanism of action lead compound have become antifungal drug research.
Summary of the invention
The object of the present invention is to provide a kind of substituted thiophene and benzoquinone compound.Another object of the present invention is to provide the preparation method of described substituted thiophene and benzoquinone compound.The 3rd purpose of the present invention is to provide described substituted thiophene and the application of benzoquinone compound in the preparation antifungal drug.
Technical scheme of the present invention is, using the designs simplification strategy is thieno-benzoquinones parent nucleus with Fourth Ring designs simplification complicated among the antimycotic natural product Sampangine, and at the various substituting groups of skeleton introducing, found that novel structure, molecular weight are low, the substituted thiophene that solvability is good and benzoquinone compound have not yet to see the report of the synthetic and anti-mycotic activity of this compounds.
A first aspect of the present invention provides a kind of substituted thiophene and benzoquinone compound and pharmacy acceptable salt thereof, described substituted thiophene and benzoquinone compound, and its general structure is as follows:
Wherein:
R
1Group, represent the substituting group on the thiophene, substituting group is positioned at each position on the thiphene ring, it is single replacement or polysubstituted, substituting group is nitro, amido, hydrogen, cyano group, methyl, ethyl, propyl group, sec.-propyl, butyl, the tertiary butyl, methoxyl group, oxyethyl group, propoxy-, trifluoromethyl, fluorine, chlorine, bromine, or iodine;
The A group represents the substituting group on the benzoquinones ring, and substituting group is selected from following a) to c) arbitrary:
A) hydrogen, fluorine, chlorine, bromine, iodine;
B) substituted triazole base, namely
Wherein the R group is phenyl, 4-bromophenyl, group-4 ethyl formate, methoxymethyl, hydroxypropyl;
C) substituted amido, be pyrrolidyl, piperazinyl, 4-methylpiperazine base, 4-ethyl piperazidine base, 4-Phenylpiperazinyl, 4-benzyl diethylenediamine base, piperidyl, morpholinyl, N, the N-dimethyl ,-NHCH
3,-NHCH
2CH
3,-NHCH
2CF
3,-NHCH
2CH
2CH
3,-NHCH (CH
3)
2,
The B group represents the substituting group on the benzoquinones ring, and substituting group is selected from following d) to e) arbitrary:
D) hydrogen, fluorine, chlorine, bromine, iodine;
E) substituted amido, i.e. pyrrolidyl, piperazinyl, 4-methylpiperazine base, 4-ethyl piperazidine base, 4-Phenylpiperazinyl, 4-benzyl diethylenediamine base, piperidyl, morpholinyl, N, the N-dimethyl ,-NHCH
3,-NHCH
2CH
3,-NHCH
2CF
3,-NHCH
2CH
2CH
3,-NHCH (CH
3)
2,
Through testing anti-mycotic efficiency part preferred compound preferably, its R
1, A and B group combination be respectively as follows:
Its R of table 1 part preferred compound
1, A and B group combination
The present invention also provides optical isomer, racemic modification, cis-trans-isomer of above-claimed cpd etc.
Some compound of the present invention can be prepared as the form of pharmaceutical salts according to ordinary method.Comprise its organic acid salt and inorganic acid salt: mineral acid includes, but is not limited to hydrochloric acid, sulfuric acid, phosphoric acid, bisphosphate, Hydrogen bromide, nitric acid etc., and organic acid includes, but is not limited to acetic acid, toxilic acid, fumaric acid, tartrate, succsinic acid, lactic acid, tosic acid, Whitfield's ointment, oxalic acid etc.
A second aspect of the present invention provides the preparation method of above-mentioned substituted thiophene and benzoquinone compound and pharmacy acceptable salt thereof.
The building-up reactions flow process of The compounds of this invention is as follows:
Concrete steps are:
(A) preparation 5-azido--2-nitro benzo [b] thiophene-4,7-diketone (1)
At methyl alcohol, in methylene dichloride and the water mixed solvent, sodiumazide is with very high yield substitution compound 2-nitro-5-bromo-benzo [b] thiophene-4, and the bromine atoms in the 7-diketone obtains 5-azido--2-nitro benzo [b] thiophene-4,7-diketone (1);
(B) preparation 5-methoxyl group-2-nitro benzo [b] thiophene-4,7-diketone (2)
Toluene is solvent, and cesium carbonate is alkali, and 5-azido--2-nitro benzo [b] thiophene-4,7-diketone and methyl alcohol react at normal temperatures and obtain 5-methoxyl group-2-nitro benzo [b] thiophene-4 that methoxyl group replaces, 7-diketone (2);
(C) preparation 5 – oxyethyl group-2-nitro benzo [b] thiophene-4,7-diketone (3)
Synthetic method with reference to similar compound 2;
(D) preparation 5-azido--benzo [b] thiophene-4,7-diketone (III)
The synthetic method of reference compound 1;
(E) preparation 5-(4-phenyl-1H-1,2,3-triazol-1-yl) benzo [b] thiophene-4,7-diketone (4)
Acetonitrile is done solvent double as part, and cuprous iodide is catalyzer, 5-azido--benzo [b] thiophene-4, the click cycloaddition reaction takes place and obtains triazole ring 5-(4-phenyl-1H-1 in 7-diketone and phenylacetylene, 2,3-triazol-1-yl) benzo [b] thiophene-4,7-diketone (4);
Compound 5-9 is with reference to the synthetic method of similar compound 4.
(F) preparation 2-nitro-5-((2,2,2-trifluoroethyl) amino) benzo [b] thiophene-4,7-diketone (10)
In alcohol solvent, make alkali with salt of wormwood, the bromine atoms in the compound ii can be obtained 2-nitro-5-((2,2,2-trifluoroethyl by the replacement of 2,2,2-trifluoro ethamine) amino) and benzo [b] thiophene-4, the 7-diketone;
Compound 11-22 is with reference to the synthetic method of similar compound 4; Wherein, the tetramethyleneimine substitution reaction obtains two isomeric compounds 15 and 16 simultaneously; Wherein compound 17 is to prepare by the bromine atoms that trans 4-hydroxy-cyclohexyl amine replaces in the raw material.
(G) benzo [b] thiophene-4 preparation 6-chloro-2-nitro-5-(third amino), 7-diketone (23)
In dichloromethane solvent, be chlorinating agent with NCS, 35 degree reactions are spent the night and are obtained 6-chloro-2-nitro-5-(third amino) and benzo [b] thiophene-4,7-diketone (23);
Compound 24 and 25 reference classes are 23 synthetic method seemingly.
A third aspect of the present invention provides the application in the preparation antifungal drug of described substituted thiophene and benzoquinone compound and pharmacy acceptable salt thereof.
Compound of the present invention proves that through external bacteriostatic experiment majority of compounds has anti-mycotic activity and wider antimicrobial spectrum preferably, illustrates that this compounds can be used for preparing the medicine for the treatment of anti-fungal infection.
Compound of the present invention is the antimycotic lead compound of a class brand new type, has broad-spectrum antifungal activity, has opened up new approach for furtheing investigate and develop new texture type antifungal drug, can be used for preparing the medicine for the treatment of anti-fungal infection.
Embodiment
Below in conjunction with specific embodiment, the invention will be further described.Should be understood that following examples are only for explanation the present invention but not for limiting scope of the present invention.
Embodiment 1:5-azido--2-nitro benzo [b] thiophene-4, the preparation of 7-diketone (1)
Get 5-bromo-2-nitro benzo [b] thiophene-4, the 7-diketone (1.43g 5mmol) is dissolved in 15mL methyl alcohol, in methylene dichloride and the water mixed liquid (volume ratio is 9:2:2), add then the solid sodiumazide (812mg, 2.5eq) and continued stirring at room 2 hours.Add dichloromethane extraction in reaction solution, water transfers to pH=11 with 10% sodium hydroxide solution, adds the excessive sodiumazide of NaClO solution cancellation then.After the organic phase drying, be spin-dried for obtain the brown solid powder (1.13g, yield: 90.2%).
1H NMR (400MHz, CDCl
3) δ ppm:8.25 (s, 1H), 6.46 (s, 1H).
Embodiment 2:5-methoxyl group-2-nitro benzo [b] thiophene-4, the preparation of 7-diketone (2)
Add raw material 5-bromo-2-nitro benzo [b] thiophene-4 in toluene (5mL) and methyl alcohol (0.5mL) mixed solvent, the 7-diketone (27.4mg, 0.1mmol), add then the cesium carbonate solid (47mg, 0.14mmol, 1.50eq), stirring at room 1 hour.Reaction solution is through ethyl acetate extraction, and solvent is removed in dry back, and resistates separates (developping agent: 70% sherwood oil, 30% ethyl acetate), obtain yellow solid 17.8mg, yield 77.3%. through silicagel column
1H NMR (400MHz, CDCl
3) δ ppm:3.95 (s, 3H) 6.18 (s, 1H) 8.28 (s, 1H).
Compound 3 can obtain through repeating embodiment 2 steps.
Embodiment 3:5-azido--benzo [b] thiophene-4, the preparation of 7-diketone (III)
Get 5-bromo-benzo [b] thiophene-4, the 7-diketone (1.21g 5mmol) is dissolved in 20mL methyl alcohol, in methylene dichloride and the water mixed liquid (volume ratio is 9:2:2), add then the solid sodiumazide (812mg, 2.5eq) and continued stirring at room 2 hours.Add dichloromethane extraction in reaction solution, water transfers to pH=11 with 10% sodium hydroxide solution, adds the excessive sodiumazide of NaClO solution cancellation then.After the organic phase drying, be spin-dried for obtain the brown solid powder (0.91g, yield: 88.8%).
1H NMR (400MHz, CDCl
3) δ ppm:7.67 (d, J=4.8Hz, 1H), 7.58 (d, J=4.8Hz, 1H), 6.34 (s, 1H).
Embodiment 4:5-(4-phenyl-1H-1,2,3-triazol-1-yl) benzo [b] thiophene-4, the preparation of 7-diketone (4)
With phenylacetylene (204mg, 2mmol) and CuI(38mg, 0.2mmol, (205mg is in acetonitrile solution 1mmol) (3mL), and with this mixture stirring at room (30 ℃) 20 hours under protection under the argon gas 10mol%) to join trinitride.Then with mixture ethyl acetate (3 * 10mL) extractions that obtain.With the organic layer that merges through dried over sodium sulfate, vacuum concentration.The crude product that obtains column chromatography purifying obtains the 246mg yellow solid, yield: 80%.
1H?NMR(400MHz,DMSO-d
6) δppm:9.05(s,1H),8.27(d,J=4.77Hz,1H),7.99(d,J=7.53Hz,2H),7.73(d,J=5.02Hz,1H),7.49-7.55(m,2H),7.39-7.49(m,2H).MS(ESI)m/z:308.3(M+1).
The step that compound 5-9 can repeat embodiment 4 obtains.
Embodiment 5:2-nitro-5-((2,2,2-trifluoroethyl) amino) benzo [b] thiophene-4, the preparation of 7-diketone (10)
(45mg 0.16mmol) is dissolved in the anhydrous 5mL ethanol, is cooled to-25 ℃, and the back drips 2,2,2-trifluoro ethamine, and (17mg 1.1eq), continued to keep this thermotonus 30 minutes to get the raw material bromo-derivative.Mixture is concentrated in a vacuum dried, resistates separates through preparation HPLC and obtains purple solid 17.4mg, yield 36.1%.
1H NMR (400MHz, CD
3OD) δ ppm:8.23 (s, 1H), 4.61 (q, J=8.87Hz, 2H) .MS (ESI) m/z:307.3 (M+1).
The step that compound 11-22 can repeat embodiment 5 obtains; Wherein, the tetramethyleneimine substitution reaction obtains two isomeric compounds 15 and 16 simultaneously; Wherein compound 17 is to prepare by the bromine atoms that trans 4-hydroxy-cyclohexyl amine replaces in the raw material.
Embodiment 6:6-chloro-2-nitro-5-(third amino) benzo [b] thiophene-4, the preparation of 7-diketone (23)
In a 50mL round-bottomed flask, add 2-nitro-5-(third amino) benzo [b] thiophene-4, (26.6mg is 0.1mmol) with the 3mL anhydrous methylene chloride for the 7-diketone.Add NCS(16mg then, 1.2eq) in batches.This suspension is heated to 35 degree reactions to spend the night.The intact back of raw material reaction adds 2 ml waters, the layering extraction.With the organic phase drying, be concentrated into dried.Resistates obtains red-purple powder 14mg, yield 45.2%. through column chromatography
1H NMR (400MHz, CD
3OD) δ 8.27 (s, 1H), 3.83 (br s, 2H), 1.71-1.78 (m, 2H), 1.01 (t, J=7.53Hz, 3H) .MS (ESI) m/z:301.1 (M+1).
The step that compound 24-25 can repeat embodiment 6 obtains.
The chemical structure of the part preferred compound that the present invention is synthetic and
1The H-NMR data see Table 2, and table 2 is consistent with table 1 compound number.
The chemical structure of table 2 part preferred compound and
1The H-NMR data
Embodiment 7: the substituted thiophene that the present invention synthesizes and the antifungic action of benzoquinone compound
(1) experimental technique: adopt conventional external bacteriostatic experiment method (to see for details: Antimicrob Agents Chemother 1995,39 (5): 1169)
1. materials and methods
(1) experimental strain
This experiment has selected for use following 8 kinds of important human body cause illness's standard fungal bacterial strains as the screening object, and fungal bacterial strain is provided by Changhai hospital of The 2nd Army Medical College Mycology Lab (or available from medicine institute of the Chinese Academy of Sciences).
1) Candida albicans (Candida albicans, type strain SC5314);
2) Candida albicans (Candida albicans, type strain Y0109);
3) Candida parapsilosis (Candida parapsilosis, ATCC 22019)
4) Cryptococcus neoformans (Cryptococcus neoformans, type strain 56992);
5) Candida glabrata (Candida glabrata, 537);
6) aspergillus fumigatus (Aspergillus fumigatus, 0796);
7) trichophyton (Trichophyton rubrum, Cmccftla)
8) gypsum shape sporidiole bacteria (Microsporum gypseum, Cmccfmza).
(2) test method
The bacteria suspension preparation: a. Cryptococcus neoformans and candidiasis were cultivated 16 hours for 35 ℃ through the YEPD liquid nutrient medium, and twice activation with the blood cell counting plate counting, adjusted concentration to 1 * 10 with the RPM1640 liquid nutrient medium
3～5 * 10
3Individual/mL.B. thread fungus (aspergillus fumigatus and trichophyton, gypsum shape sporidiole bacteria) is cultivated (35 ℃) week and (28 ℃) two weeks respectively through the SDA inclined-plane, twice activation, add the RPM1640 liquid nutrient medium and blow and beat with suction pipe, spore is free in the RPM1640 liquid, through four layers of filtered through gauze, counting is adjusted concentration to 1 * 10
3～5 * 10
3Individual/mL.
Soup preparation: get testing compound of the present invention and be dissolved in methyl-sulphoxide, be made into the medicine storage liquid of 8.0mg/ml, be diluted to 640 μ g/ml with RPM1640 before the experiment.
Inoculation: No. 1 hole of 96 orifice plates adds RPM1640 100 μ l and makes blank, the 3-12 hole respectively adds bacteria suspension 120 μ l, No. 2 the hole adds bacteria suspension 160 μ l and soup 1.6 μ l, the drug level in 2-11 hole is made 10 grade of 4 doubling dilution, and each hole drug level is respectively 64,16,4,1,0.25,0.0625,0.0156,0.0039,0.00097,0.00024 μ g/mL.No. 12 the hole does not add soup, makes positive control.The medicine contrast is fluconazole.
Cultivate and detect: establishing positive control hole optical density value (OD value) is 100%, and being lower than 80% lowest drug concentration with optical density value than positive control hole is minimal inhibitory concentration value (MIC).
(2) experimental result
External bacteriostatic experiment the results are shown in Table 3, and table 3 and table 1, table 2 compound number are consistent.
Table 3: the external antimycotic minimal inhibitory concentration value of part selected objective target compound (MIC, μ g/mL)
Above-mentioned experimental result shows, compares with positive control drug, and major part has anti-mycotic activity and wider antimicrobial spectrum preferably in the compound of the present invention, illustrates that this compounds can be used for preparing the medicine for the treatment of anti-fungal infection.
More than show and described ultimate principle of the present invention, principal character and advantage of the present invention.The technician of the industry should understand; the present invention is not restricted to the described embodiments; that describes in above-described embodiment and the specification sheets just illustrates principle of the present invention; the present invention also has various changes and modifications without departing from the spirit and scope of the present invention, and these changes and improvements all fall in the claimed scope of the invention.The claimed scope of the present invention is defined by appending claims and equivalent thereof.
Claims (4)
1. a substituted thiophene and benzoquinone compound comprise its optical isomer, racemic modification, cis-trans-isomer and pharmacy acceptable salt thereof, described substituted thiophene and benzoquinone compound, and its general structure is as follows:
Wherein:
R
1Group, represent the substituting group on the thiophene, substituting group is positioned at each position on the thiphene ring, it is single replacement or polysubstituted, substituting group is nitro, amido, hydrogen, cyano group, methyl, ethyl, propyl group, sec.-propyl, butyl, the tertiary butyl, methoxyl group, oxyethyl group, propoxy-, trifluoromethyl, fluorine, chlorine, bromine, or iodine;
The A group represents the substituting group on the benzoquinones ring, and substituting group is selected from following a) to c) arbitrary:
A) hydrogen, fluorine, chlorine, bromine, iodine;
B) substituted triazole base, namely
Wherein the R group is phenyl, 4-bromophenyl, group-4 ethyl formate, methoxymethyl, or hydroxypropyl;
C) substituted amido, i.e. pyrrolidyl, piperazinyl, 4-methylpiperazine base, 4-ethyl piperazidine base, 4-Phenylpiperazinyl, 4-benzyl diethylenediamine base, piperidyl, morpholinyl, N, the N-dimethyl ,-NHCH
3,-NHCH
2CH
3,-NHCH
2CF
3,-NHCH
2CH
2CH
3,-NHCH (CH
3)
2,
The B group represents the substituting group on the benzoquinones ring, and substituting group is selected from following d) to e) arbitrary:
D) hydrogen, fluorine, chlorine, bromine, iodine;
E) substituted amido, i.e. pyrrolidyl, piperazinyl, 4-methylpiperazine base, 4-ethyl piperazidine base, 4-Phenylpiperazinyl, 4-benzyl diethylenediamine base, piperidyl, morpholinyl, N, the N-dimethyl ,-NHCH
3,-NHCH
2CH
3,-NHCH
2CF
3,-NHCH
2CH
2CH
3,-NHCH (CH
3)
2,
2. a kind of substituted thiophene according to claim 1 and benzoquinone compound comprise its optical isomer, racemic modification, cis-trans-isomer and pharmacy acceptable salt thereof, it is characterized in that, described substituted thiophene and benzoquinone compound are:
5-azido--2-nitro benzo [b] thiophene-4, the 7-diketone,
5-methoxyl group-2-nitro benzo [b] thiophene-4, the 7-diketone,
5 – oxyethyl group-2-nitro benzo [b] thiophene-4, the 7-diketone,
5-(4-phenyl-1H-1,2,3-triazol-1-yl) benzo [b] thiophene-4, the 7-diketone,
5-(4-(1-hydroxyethyl)-1H-1,2,3-triazol-1-yl) benzo [b] thiophene-4, the 7-diketone,
The 5-(4-(4-bromophenyl)-and 1H-1,2,3-triazol-1-yl) benzo [b] thiophene-4, the 7-diketone,
1-(4,7-dioxo-4,7-dihydrobenzo [b] thiophene-5-yl)-1H-1,2,3-triazole-4-carboxylic acid, ethyl ester,
5-(4-(methoxymethyl)-1H-1,2,3-triazol-1-yl) benzo [b] thiophene-4, the 7-diketone,
The 5-(4-(3-hydroxypropyl)-and 1H-1,2,3-triazol-1-yl) benzo [b] thiophene-4, the 7-diketone,
2-nitro-5-((2,2,2-trifluoroethyl) amino) benzo [b] thiophene-4, the 7-diketone,
2-nitro-5-(n-propylamine base) benzo [b] thiophene-4, the 7-diketone,
The 5-((2-ethoxyethyl group) amino)-2-nitro benzo [b] thiophene-4, the 7-diketone,
5-(sec.-propyl amino)-2-nitro benzo [b] thiophene-4, the 7-diketone,
The 5-(dimethylamino)-2-nitro benzo [b] thiophene-4, the 7-diketone,
2-nitro-5-(tetramethyleneimine-1-yl) benzo [b] thiophene-4, the 7-diketone,
2-nitro-6-(tetramethyleneimine-1-yl) benzo [b] thiophene-4, the 7-diketone,
5-(((is trans)-the 4-hydroxy-cyclohexyl) amino)-2-nitro benzo [b] thiophene-4, the 7-diketone,
The 5-((4-p-methoxy-phenyl) amino)-2-nitro benzo [b] thiophene-4, the 7-diketone,
5-morpholino-2-nitro benzo [b] thiophene-4, the 7-diketone,
2-nitro-5-((3-(2-oxo-pyrrolidine-1-yl) benzo [b] thiophene-4 amino propyl group)), the 7-diketone,
5-((1-methoxyl group fourth-2-yl) amino)-2-nitro benzo [b] thiophene-4, the 7-diketone,
2-nitro-5-(((tetrahydrofuran (THF)-2-yl) benzo [b] thiophene-4 amino methyl)), the 7-diketone,
6-chloro-2-nitro-5-(third amino) benzo [b] thiophene-4, the 7-diketone,
5-bromo-2-nitro-6-(tetramethyleneimine-1-yl) benzo [b] thiophene-4, the 7-diketone, or
5-chloro-2-nitro-6-(tetramethyleneimine-1-yl) benzo [b] thiophene-4, the 7-diketone.
3. a substituted thiophene as claimed in claim 1 or 2 and benzoquinone compound comprise the preparation method of its optical isomer, racemic modification, cis-trans-isomer and pharmacy acceptable salt thereof it is characterized in that the reaction process of this method is as follows:
Concrete steps are:
(A) preparation 5-azido--2-nitro benzo [b] thiophene-4,7-diketone (1)
At methyl alcohol, in methylene dichloride and the water mixed solvent, sodiumazide substitution compound 2-nitro-5-bromo-benzo [b] thiophene-4, the bromine atoms in the 7-diketone obtains 5-azido--2-nitro benzo [b] thiophene-4,7-diketone (1);
(B) preparation 5-methoxyl group-2-nitro benzo [b] thiophene-4,7-diketone (2)
Toluene is solvent, and cesium carbonate is alkali, and 5-azido--2-nitro benzo [b] thiophene-4,7-diketone and methyl alcohol react at normal temperatures and obtain 5-methoxyl group-2-nitro benzo [b] thiophene-4 that methoxyl group replaces, 7-diketone (2);
(C) synthetic method of reference compound 2 prepares 5 – oxyethyl group-2-nitro benzo [b] thiophene-4,7-diketone (3);
(D) synthetic method of reference compound 1, preparation 5-azido--benzo [b] thiophene-4,7-diketone (III);
(E) preparation 5-(4-phenyl-1H-1,2,3-triazol-1-yl) benzo [b] thiophene-4,7-diketone (4)
Acetonitrile is done solvent double as part, and cuprous iodide is catalyzer, 5-azido--benzo [b] thiophene-4, the click cycloaddition reaction takes place and obtains triazole ring 5-(4-phenyl-1H-1 in 7-diketone and phenylacetylene, 2,3-triazol-1-yl) benzo [b] thiophene-4,7-diketone (4);
The synthetic method of compound 5-9 reference compound 4;
(F) preparation 2-nitro-5-((2,2,2-trifluoroethyl) amino) benzo [b] thiophene-4,7-diketone (10)
In alcohol solvent, make alkali with salt of wormwood, the bromine atoms in the compound ii can be obtained 2-nitro-5-((2,2,2-trifluoroethyl by the replacement of 2,2,2-trifluoro ethamine) amino) and benzo [b] thiophene-4, the 7-diketone;
The synthetic method of compound 11-22 reference compound 4; Wherein, the tetramethyleneimine substitution reaction obtains two isomeric compounds 15 and 16 simultaneously; Wherein compound 17 is to prepare by the bromine atoms that trans 4-hydroxy-cyclohexyl amine replaces in the raw material;
(G) benzo [b] thiophene-4 preparation 6-chloro-2-nitro-5-(third amino), 7-diketone (23)
In dichloromethane solvent, be chlorinating agent with NCS, 35 degree reactions are spent the night and are obtained 6-chloro-2-nitro-5-(third amino) and benzo [b] thiophene-4,7-diketone (23);
The synthetic method of compound 24 and 25 reference compounds 23.
4. a substituted thiophene as claimed in claim 1 or 2 and benzoquinone compound comprise the application in the preparation antifungal drug of its optical isomer, racemic modification, cis-trans-isomer and pharmacy acceptable salt thereof.
Priority Applications (1)
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN109092356A (en) * | 2018-09-12 | 2018-12-28 | 安徽大学 | Preparation method of ethylenediamine-induced penta-benzoquinone assembly loaded nano-silver composite catalyst |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1534275A (en) * | 1976-01-30 | 1978-11-29 | Shell Int Research | Herbicidal compositions containing 1,4-quinones or derivatives thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| GB1534275A (en) * | 1976-01-30 | 1978-11-29 | Shell Int Research | Herbicidal compositions containing 1,4-quinones or derivatives thereof |
Non-Patent Citations (5)
| Title |
|---|
| CHUNG-KYU RYU ET AL.: "Synthesis and antifungal activity of 5-arylamino-4,7-dioxobenzo[b]thiophenes", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 * |
| JAIME VALDERRAMA ET AL.: "Synthesis and in vitro antiprotozoal activity of thiophene ring-containing quinones", 《CHEMICAL & PHARMACEUTICAL BULLETIN》 * |
| LOUIS F. FIESER ET AL.: "A Comparison of Heterocyclic Systems with Benzene. IV. Thionaphthenequinones", 《JOURNAL OF THE AMERICAN CHEMICAL SOCIETY》 * |
| MARIO DE ROSA ET AL.: "Caldariellaquinone, a unique benzo[b]thiophene-4,7-quinone from Caldariella acidophila, an extremely thermophilic and acidiphilic bacterium", 《JOURNAL OF THE CHEMICAL SOCIETY, PERKIN TRANSACTIONS 1》 * |
| N. B. CHAPMAN ET AL.: "Some Reactions of 7-hydroxy- and 7-mercapto-3-methylbenzo[b]thiophene", 《JOURNAL OF THE CHEMICAL SOCIETY, PERKIN TRANSACTIONS 1》 * |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109092356A (en) * | 2018-09-12 | 2018-12-28 | 安徽大学 | Preparation method of ethylenediamine-induced penta-benzoquinone assembly loaded nano-silver composite catalyst |
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