CN104788439A - 2,4-Dihalobiphenyl group-containing novel azole compound, and synthetic method and use thereof - Google Patents
2,4-Dihalobiphenyl group-containing novel azole compound, and synthetic method and use thereof Download PDFInfo
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Abstract
The invention discloses a 2,4-dihalobiphenyl group-containing novel azole compound, and a synthetic method and a use thereof, and belongs to the field of chemistry. The novel azole compound is 2,4-dihalobiphenyl group-containing imidazole or a 1,2,4-triazole compound, and the synthetic method of the compound comprises the steps of intermediate preparation and target product synthesis. An antifungal activity test result of the novel azole compound shows that the antifungal activity of the compound is better than or reaches the antifungal effect of an antifungal drug ketoconazole clinically used at present.
Description
Technical field
The present invention relates to a kind of novel oxazole compound and preparation method and use thereof, particularly one contains novel oxazole compound and the preparation method and use thereof of 2,4-dihalobiphenyl base, belongs to chemical field.
Background technology
Fungi exists in a large number at nature, and numerous fungi can cause vegeto-animal multiple diseases, not only harms the crops, the growth of economic animal produces, more importantly affect human health, threaten human life's safety.Many fungies can cause human skin, mucous membrane, the infection of subcutis and internal organ, wherein the fungi infestation such as skin, mucous membrane, subcutis, hair and nail is Superficial mycoses, and encroach on the mucous membrane depths of human body, internal organ, urinary system, brain and bone etc. fungi infestation be called deep mycosis.Superficial mycoses infectivity is strong, though deep fungal infection is general not as superficial fungal infection, hazardness is large, often can cause death.In recent years, due to immunocompromised persons, comprise the increasing fast of the morbidities such as malignant tumour, malignant hematologic disease, acquired immune deficiency syndrome (AIDS), SARS, diabetes, autoimmune disease, serious burn, and the widely using of Broad spectrum antibiotics, corticosteroid hormone and immunosuppressor, carrying out of the new technologies such as conduit, intubate and organ transplantation, make the fungi infestation sickness rate of opportunistic deep internal organs more and more higher, also more and more serious.Document [Liu Zhengyin, Wang Aixia, Sheng Ruiyuan, etc. the new trend [J] of ward infection viewed from 99 routine septicemia.
china's internal medicine is mixed, 1998,
37 (5):323-326] report, by to the eighties in last century to the nineties nosocomial bacteria and fungi infestation cause the analysis of statistical results of septicemia to show, wherein fungi infestation causes the sickness rate of septicemia obviously cumulative, and the case fatality rate of fungal septicemia is the highest, up to 71.43%.Equally, document [Liu Zhengyin, Sheng Ruiyuan, Li Xuli, etc. Nosocomial fungus infection 149 example analyzes [J].
chinese Medical Journal, 2003,
83 (5): 399-403] report, by show the analysis of 149 routine fungi infestations, fungi infestation is ascendant trend year by year.Therefore, the research and development of antifungal drug more and more comes into one's own, current investigator has developed the different antifungal drug of different kinds of molecules structure, but the disease of the fungi infestation caused due to many reasons is also increasing, and also there is certain toxic side effect in existing antifungal drug, especially the increase of Antifungal resistance, all these brings difficulty to the treatment of fungal infection disease.The antifungal drug of current application still can not meet clinical treatment needs, therefore clinical in researching and developing new and effective, low toxicity, wide spectrum antifungal drug [Sheng C.; Zhang W.; Ji H., Zhang M.; Song Y.; Xu H.; Zhu J.; Miao Z.; Jiang Q.; Yao J.; Zhou Y.; Zhu J.; Lu J. Structure-based optimization of azole antifungal agents by CoMFA, CoMSIA, and molecular docking [J].
j Med Chem. 2006,
49: 2512 – 2525].And the microbiotic anti-fungus spectra of current newfound most of anti-animal fungal is narrow, or activity in vivo is faint, or cytotoxicity is stronger etc., have DEVELOPMENT PROSPECT person few [Zhang Zhiping. Progress in Research of Antifungal Agents [J].
china's prescription drugs, 2006,
3:28-32], and the diversity of organic synthesis, make the method utilizing organic synthesis, synthesize of a great variety, the compound with potential anti-mycotic activity of novel structure, and then develop efficient, low toxicity, wide spectrum antifungal drug on this basis and just become possibility, from the practice of current synthetic antifunguses thing exploitation, the compound of the novel texture of some non-azoles of the design and synthesis of pharmaceutical chemistry investigator exploration, and its anti-mycotic activity is tested, but the real rarely seen report dropping into clinical application.And the current complete synthesis antifungal drug of a most widely used line and be in complete synthesis antimycotic (CYP51) inhibitor of clinical investigation phase clinically, be mainly azole compounds.Therefore it is realistic for continuing in azole compounds, find safer, effective antifungal drug.、，
The triazole antifungal agent of current clinical application, be mostly contain between the azole derivative (halogen is fluorine or chlorine) of phenyl-dihalide.As: Triaconazole, fluconazole, KETOKONAZOL, clotrimazole, itraconazole, miconazole [Robert A.; Fromtling. Overview of medically important antifungal azole derivatives [J].
clin Microbiol Rev. 1988,
1 (2): 187-217].But have no report based on the nitrogen azole derivative of 2,4-dihalobiphenyl base.
Summary of the invention
The object of the present invention is to provide a kind of the novel oxazole compound and the preparation method and use thereof that contain 2,4-dihalobiphenyl base.
The novel oxazole compound containing 2,4-dihalobiphenyl base provided by the present invention, described novel oxazole compound T has following structural formula:
Wherein: X is chlorine or fluorine, Y is imidazoles or 1,2,4-triazole, and A is phenyl or substituted-phenyl or fragrant heterocyclic radical, and described substituted-phenyl is 4-chloro-phenyl-or 4-aminomethyl phenyl, and described fragrant heterocyclic radical is 2-furyl or 2-thienyl.
The synthetic method of the novel oxazole compound containing 2,4-dihalobiphenyl base, described synthetic method adopts following synthesis route, and reaction scheme is as follows:
Wherein X is chlorine or fluorine, and Y is imidazoles or 1,2,4-triazole, A is phenyl or substituted-phenyl or fragrant heterocyclic radical, and described substituted-phenyl is 4-chloro-phenyl-or 4-aminomethyl phenyl, described fragrant heterocyclic radical is 2-furyl or 2-thienyl, and synthesis route comprises the following steps:
(a) with 2,4-dihalobiphenyl, 4-chloro-benzoyl chloride or 4-methyl benzoyl chloride or 2 furoyl chloride or 2-thiophene chloride for starting raw material, under Using Aluminium Trichloride as Catalyst, in carbon disulfide solvent, temperature control, at 40-45 DEG C of heating reflux reaction 4-5h, after reaction terminates, is hydrolyzed with dilute hydrochloric acid under cooling, again through separatory, washing, dry, boil off solvent, crude product hexanaphthene recrystallization, obtains intermediate a;
B () intermediate a and sodium borohydride be heating reflux reaction 1.5-2.5 h in dehydrated alcohol, after reaction terminates, boil off solvent, and residue with ethyl acetate dissolves, and washing is dry, boils off ethyl acetate, obtains reduzate intermediate b;
C () intermediate b and diazole sulfoxide be stirring reaction 11-13 h in acetonitrile solvent, evaporation of solvent acetonitrile, residue with ethyl acetate dissolves, with distilled water wash, finally use anhydrous magnesium sulfate drying, obtain faint yellow sticky mass after steaming desolventizes, cross chromatographic column with eluent petroleum ether: ethyl acetate=1:1 (V/V), obtain target product T.
The purposes of the novel oxazole compound containing 2,4-dihalobiphenyl base, described novel oxazole compound is used for antifungal drug.
Advantageous Effects of the present invention is: the invention provides a kind of novel oxazole compound and synthetic method thereof and antifungal application thereof, this novel oxazole compound T is after anti-mycotic activity test, test result shows, its anti-mycotic activity is better than or reaches the anti-mycotic efficiency being applied to antifungal drug KETOKONAZOL clinically at present, as there being 7 in the compound of 11 in the present invention, the MIC value of positive control KETOKONAZOL is all less than to the minimum inhibitory concentration value of Candida albicans, described novel oxazole compound is used for antifungal drug or the development research for antifungal drug, the development research that this novel cpd is used for antifungal drug has good development prospect.
Embodiment
In order to better understand and implement technical scheme of the present invention, provide some embodiments of the present invention at this, these embodiments, in order to better explain technical solutions according to the invention, are not formed any form restriction of the present invention.
The novel oxazole compound containing 2,4-dihalobiphenyl base provided by the present invention, described novel oxazole compound T has following structural formula:
Wherein: X is chlorine or fluorine, Y is imidazoles or 1,2,4-triazole, A is phenyl or substituted-phenyl or fragrant heterocyclic radical, and described substituted-phenyl is 4-chloro-phenyl-or 4-aminomethyl phenyl, and described fragrant heterocyclic radical is 2-furyl or 2-thienyl, as shown in table 1 according to the particular compound of each product of the present invention after above substituting group combination
Novel oxazole compound of the present invention and synthetic method thereof and antifungal application thereof are set forth in synthesis below in conjunction with each particular compound, containing 2, the synthetic method of the novel oxazole compound of 4-dihalobiphenyl base, described synthetic method adopts following synthesis route, and reaction formula is as follows:
Wherein X is chlorine or fluorine, and Y is imidazoles or 1,2,4-triazole, A is phenyl or substituted-phenyl or fragrant heterocyclic radical, and described substituted-phenyl is 4-chloro-phenyl-or 4-aminomethyl phenyl, described fragrant heterocyclic radical is 2-furyl or 2-thienyl, and synthesis route comprises the following steps:
(a) with 2,4-dihalobiphenyl, 4-chloro-benzoyl chloride or 4-methyl benzoyl chloride or 2 furoyl chloride or 2-thiophene chloride for starting raw material, under Using Aluminium Trichloride as Catalyst, in carbon disulfide solvent, temperature control, at 40-45 DEG C of heating reflux reaction 4-5h, after reaction terminates, is hydrolyzed with dilute hydrochloric acid under cooling, again through separatory, washing, dry, boil off solvent, crude product hexanaphthene recrystallization, obtains intermediate a;
B () intermediate a and sodium borohydride be heating reflux reaction 1.5-2.5 h in dehydrated alcohol, after reaction terminates, boil off solvent, and residue with ethyl acetate dissolves, and washing is dry, boils off ethyl acetate, obtains reduzate intermediate b;
C () intermediate b and diazole sulfoxide be stirring reaction 11-13 h in acetonitrile solvent, evaporation of solvent acetonitrile, residue with ethyl acetate dissolves, with distilled water wash, finally use anhydrous magnesium sulfate drying, obtain faint yellow sticky mass after steaming desolventizes, cross chromatographic column with eluent petroleum ether/ethyl acetate=1:1 (V/V), obtain target product T.
Below in conjunction with each embodiment, the present invention is further elaborated, and below the present invention in all embodiments, fusing point X-5 micro-meldometer measures, infrared spectrum Varian-800-FT-IR determination of infrared spectroscopy; High resolution mass spectrum Waters ACQUITY
tMuPLC/LCT Premier XE liquid phase mass spectrograph measures;
1h-NMR Bruker Am-400 type nuclear magnetic resonance analyser (solvent C DCl
3), TMS is interior mark, and chemical shift is with d(ppm) represent; Column chromatography silica gel (Haiyang Chemical Plant, Qingdao) 200-300 order.PetroChina Company Limited. of the present invention ether/ethyl acetate refers to sherwood oil: ethyl acetate.Two-1-imidazoles sulfoxides used in the present invention are prepared by following methods:
4.14 g(60 mmol are added successively in 100 mL Erlenmeyer flasks) imidazoles and the dried acetonitrile of 30 mL, under normal temperature magnetic agitation, 1.1 mL(1.79g are slowly dripped by constant pressure funnel, 15.0 mmol) mixed solution of thionyl chloride and 5 mL acetonitriles, after dropwising, continue stirring reaction 2h.Suction filtration, to remove imidazole hydrochloride, obtains the acetonitrile solution of compound two-1-imidazoles sulfoxide, is directly used in next step reaction.Preparation feedback formula is as follows:
。
Embodiment 1:1-[2 ＇, 4 ＇-two fluoro-(1,1 ＇-biphenyl)-4-base-2-thienyl methyl]-imidazoles (being expressed as T-1 in the present invention) and synthesis
(a) intermediate 2', 4'-bis-fluoro-(1,1'-biphenyl) synthesis of-4-base-2-thienyl ketone (being expressed as a-1 in the present invention): in three-necked bottle, add 11.4 g (60 mmol) 2 successively, the dithiocarbonic anhydride of 4-DfBP and 45 mL dryings, treat to add 9.3 g (70 mmol) AlCl again after 2,4-DfBP dissolves completely
3, under cooling and stirring condition, in reaction flask, slowly drip 9.93 g(68 mmol by constant pressure funnel) and the mixed solution of newly steamed 2-thiophene chloride and the dried dithiocarbonic anhydride of 15 mL, after dripping off, be heated to 45 DEG C of back flow reaction 4.5 h.Reaction terminates to add dilute hydrochloric acid in backward reaction flask makes reaction mixture be hydrolyzed, and has solid to separate out; In the mixed solution after hydrolysis, add 40 mL ether, the solids of precipitation is dissolved.Branch vibration layer, organic layer first washs with the sodium hydroxide solution of 10%, then is washed with distilled water to neutrality, finally uses anhydrous magnesium sulfate drying.Boil off solvent, excess hexanaphthene recrystallization, obtain 8.2 g intermediate a-1, productive rate 45.6%.Obtain white solid, measure: fusing point: 98-100 DEG C, IR (KBr, cm
-1): 3084,1626,1519,1491,1294,1267,1142,1095,856,808.
1H-NMR(CDCl
3, 400MHz):d 6.939-7.030 (m, 2H); 7.186-7.207 (m, 1H);7.440-7.444 (m, 1H); 7.633-7.658 (m, 2H); 7.708-7.761(m, 2H); 7.959 (t, J = 4.2Hz, 2H)。HMRS: m/z [M+H] calcd. for C
17H
11F
2OS: 301.0499; found: 301.0490
This step reaction formula is as follows:
(b) intermediate 2', 4' bis-fluoro-(1,1'-biphenyl) preparation of-4-base-2-thienylmethanol (in the present invention b-1): in round-bottomed flask, add 1.0 g(3.4 mmol successively) compound a-1,0.14 g (3.5 mmol) sodium borohydride and 30 mL dehydrated alcohols, magnetic agitation, after oil bath reflux 2 h, TLC (petrol ether/ethyl acetate=2:1, V/V) monitoring reaction, show that intermediate a-1 is converted into intermediate b-1 completely.Rotary evaporation removing ethanol.Excess 15mL water and 15 mL acetic acid ethyl dissolutions, separatory removing water layer, organic layer 15 mL × 2 distilled water washs, finally use anhydrous magnesium sulfate drying.Rotary evaporation removing solvent ethyl acetate, obtains 1.0 g intermediate b-1(faint yellow thick), quantitative reaction, is directly used in next step reaction;
This step reaction formula is as follows:
The synthesis of (c) target compound 1-[2 ＇, 4 ＇-two fluoro-(1,1 ＇-biphenyl)-4-base-2-thienyl methyl]-imidazoles (T-1)
In round-bottomed flask, add 1 g(3.39 mmol) intermediate b-1 and 20 mL containing acetonitrile solution stirring heating back flow reaction 12 h of 15.0 mmol bis--1-imidazoles sulfoxides, rotary evaporation removing solvent acetonitrile.Excess 20mL acetic acid ethyl dissolution, with 15 mL × 3 distilled water washs, finally uses anhydrous magnesium sulfate drying.Obtain faint yellow sticky mass after distillation, cross chromatographic column with eluent petroleum ether/ethyl acetate=1:1 (V/V).Obtain pure target compound (T-1) 0.87 g(2.5 mmol), orange-yellow sticky mass, productive rate is 73.7%, measures: IR (KBr, cm
-1): 3700-2600 (the imidazole ring charateristic avsorption band spreaded), 1617,1495,1142,1101,851,817,782.
1H-NMR (CDCl
3, 400 MHz):d 6.220-6.517(m, 1H); 6.745(s, 1H); 6.906-7.006(m, 5H); 7.113(s, 1H); 7.192-7.249(m, 2H); 7.351-7.400(m, 1H); 7.465-7.544(m, 3H)。HMRS: m/z [M+H] calcd. for C
20H
15N
2F
2S: 353.0924; found: 353.0911。This step reaction formula is as follows:
。
Embodiment 2:1-[2 ＇, 4 ＇-two fluoro-(1,1 ＇-biphenyl)-4-base-2-thienyl methyl]-1,2,4-triazoles (the present invention is expressed as T-2) and synthesis:
Two-the 1-(1s of intermediate b-1 in 1.02 g (3.4 mmol) embodiment 1 and 20 mL containing 15.0 mmol are added successively, 2,4-triazol radical in round-bottomed flask) acetonitrile solution of sulfoxide, magnetic agitation heating reflux reaction 12 h.Then distillation removing solvent acetonitrile, excess 20 mL acetic acid ethyl dissolutions, with 15 mL × 2 distilled water washs, finally use anhydrous magnesium sulfate drying.Obtain faint yellow solid after distillation, cross silica gel chromatographic column (eluent petroleum ether/ethyl acetate=1:1, V/V).Obtain pure target compound (T-2) 0.89 g, productive rate is 73.5%.Faint yellow solid, measures: fusing point: 85-87 DEG C.IR(KBr，cm
-1): 3139 ，3069，3105，1597，1494，1140，1102，854，802。
1H-NMR (CDCl
3, 400 MHz):d6.901-6.949 (m, 2H); 6.980(t, J = 7.6Hz, 2H); 7.046 (t, J = 4.4Hz, 1H); 7.286 (d, J = 8.4Hz, 2H); 7.368-7.427 (m, 2H); 7.526 (t, J= 4Hz, 3H); 8.052(s, 1H); 8.107 (s, 1H)。HMRS: m/z [M+H] calcd. for C
19H
14N
3F
2S: 354.0876; found: 354.0872
Reaction formula is as follows:
Two-1-(1,2,4-triazol radical in the present embodiment and this patent) synthesis of sulfoxide can adopt following methods:
4.14 g(60 mmol are added successively in Erlenmeyer flask) 1,2,4,-triazole and the dried acetonitrile of 30 mL, and with constant pressure funnel by 1.1 mL(1.79g, 15.0 mmol) mixed solution of thionyl chloride and 5 mL acetonitriles slowly instills in reaction flask, normal temperature magnetic agitation, reaction backflow 2h.The hydrochloride of 1,2,4-triazole removes by suction filtration, obtains two-1-(1,2,4-triazol radical) acetonitrile solution of sulfoxide, crude product is directly used in next step reaction without separation.The synthesis of all 1,2,4-triazole class target compounds two-1-(1,2,4-triazol radical used in the application) preparation of sulfoxide all can use this method.Preparation feedback formula is as follows:
。
Embodiment 3:1-[2 ＇, 4 ＇-two fluoro-(1,1 ＇-biphenyl)-4-base-2-furyl methyl]-imidazoles (T-3)
The synthesis of (a) intermediate 2 ', 4 '-two fluoro-(1,1 '-biphenyl)-4-base-2-furyl ketone (being expressed as a-3 in the present invention)
In three-necked bottle, add the dithiocarbonic anhydride of 11.40 g (60 mmol) 2,4-DfBPs and 45 mL dryings successively, treat to add 9.30 g (70 mmol) AlCl again after 2,4-DfBP dissolves completely
3, under cooling and stirring condition, in reaction flask, slowly drip 11.88 g(91mmol by constant pressure funnel) and the mixed solution of newly steamed 2 furoyl chloride and the dried dithiocarbonic anhydride of 20 mL.After dripping off, be heated to 45 DEG C of back flow reaction 4.5 h.Reaction terminates to add dilute hydrochloric acid in backward reaction flask makes reaction mixture be hydrolyzed, and has solid to separate out; In the mixed solution after hydrolysis, add 40 mL ether, the solids of precipitation is dissolved.Branch vibration layer, organic layer first washs with the sodium hydroxide solution of 10%, then is washed with distilled water to neutrality, finally uses anhydrous magnesium sulfate drying.Boil off solvent, excess hexanaphthene recrystallization, obtain 7.80 g intermediate a-3, productive rate 45.8%.White solid, fusing point: 127-128 DEG C.IR(KBr，cm
-1): 3128 ，3096，1647，1621，1520，1396，1256，964，846。
1H-NMR (CDCl
3, 400 MHz):d6.630-6.638(m, 1H); 6.941-7.029(m, 2H); 7.272-7.315(m, 1H); 7.442-7.502(m, 1H); 7.642-7.662(m, 2H); 7.739(s, 1H); 8.083(d, J = 8Hz, 2H)。Reaction formula is as follows:
B () intermediate 2 ', 4 '-two fluoro-(1,1 '-biphenyl)-4-base-2-furyl alcohol (being expressed as b-3 in the present invention) synthesizes:
1.42 g(5 mmol) intermediate a-3 and 0.3 g (8 mmol) sodium borohydride and 30 mL dehydrated alcohols, water-bath 80-85 DEG C, backflow about 2 h, TLC (petrol ether/ethyl acetate=2:1, V/V) monitoring reaction, show that intermediate a-3 is converted into b-3 completely, rotary evaporation removing ethanol, excess 15mL water and 15 mL acetic acid ethyl dissolutions, separatory removing water layer, organic layer distilled water wash twice, anhydrous magnesium sulfate drying, filter, rotary evaporation is except desolventizing.Obtain 1.43 g intermediate b-3, white waxy solid, be directly used in next step reaction.Reaction formula is:
The synthesis of (c) target compound 1-[2 ＇, 4 ＇-two fluoro-(1,1 ＇-biphenyl)-4-base-2-furyl methyl]-imidazoles (T-3):
1.34 g (4.7 mmol) intermediate b-3 and 20 mL is containing acetonitrile solution stirring heating back flow reaction 12 h of 15.0 mmol bis--1-imidazoles sulfoxides, and rotary evaporation, removes acetonitrile.Excess 15 mL acetic acid ethyl dissolutions, 15 mL × 2 distilled water washs, then use anhydrous magnesium sulfate drying.Rotary evaporation is except desolventizing, and excess crosses silica gel chromatographic column, eluent: petrol ether/ethyl acetate=1/1 (V/V).Obtain the pure target compound T-3 of 0.88 g, yellow, viscous material.Productive rate is 55.7 %.Measure: IR (KBr, cm
-1): 3600-2650 (the imidazole ring charateristic avsorption band spreaded), 1618,1495,1405,1275,1147,953,782.
1H-NMR (CDCl
3, 400 MHz):d6.236(s, 1H); 6.402(s, 1H); 6.521(s, 1H); 6.895-6.978(m, 3H); 7.120(s, 1H); 7.199-7.273(m, 2H); 7.378-7.421(m, 1H); 7.479-7.517(m, 4H);
HMRS: m/z [M+H] calcd. for C
20H
15N
2F
2O: 337.1152; found: 337.1173。Reaction formula is:
。
Embodiment 4:1-[2 ＇, 4 ＇-two fluoro-(1,1 ＇-biphenyl)-4-base-2-furyl methyl]-1,2,4-triazoles (T-4) and synthesis
Intermediate b-3 in 1.40 g (4.9 mmol) above embodiment and 20 mL is containing 15.0 mmol bis--1-(1,2,4-triazole) acetonitrile solution stirring heating back flow reaction 12 h of sulfoxide, rotary evaporation, removing acetonitrile, excess 15 mL acetic acid ethyl dissolutions, with 15 mL × 2 distilled water washs twice, then use anhydrous magnesium sulfate drying.Rotary evaporation is except desolventizing, and excess crosses silica gel chromatographic column, eluent: petrol ether/ethyl acetate=1/1 (V/V).Obtain pure target compound (T-4) 0.92 g, productive rate is 55.8%.For faint yellow needle-like crystal, fusing point: 71-72 DEG C.IR(KBr，cm
-1): 3129 ，3071，1598，1496，1405，1274，1142，966，855。
1H-NMR (CDCl
3, 400 MHz):d6.308 (d, J=3.2Hz, 1H); 6.432(t, J = 1.6Hz, 1H); 6.772(s,1H); 6.896-6.984(m, 2H); 7.286(t, J = 5Hz, 2H); 7.363-7.423(m, 1H); 7.526(t, J = 4.2Hz, 3H); 8.033(s, 1H); 8.074(s, 1H)。HMRS: m/z [M+H] calcd. for C
19H
14N
3F
2O: 338.1105; found: 338.1121。Reaction formula is as follows:
Embodiment 5:1-[2 ', 4 '-two fluoro-(1,1-biphenyl)-4-base-toluene-4-ylmethyl]-imidazoles (being expressed as T-5 in the present invention) and synthesis
(a) intermediate 4-(2 ', 4 '-difluoro biphenyl) synthesis to methylbenzophenone (a-5):
7.60 g (40 mmol) 2,4-DfBPs and the dried dithiocarbonic anhydride of 20 ml are added in three-necked bottle, and electric stirring makes solid dissolve completely.Then add the aluminum chloride that 6.80 g (51.7 mmol) are dry, then stirring at normal temperature drips 5.0 mL dithiocarbonic anhydride and 6.18 g (40 mmol) mixed solution to methyl benzoyl chloride.Post-heating to 45 to be dropwised DEG C backflow 3 h, stop heating, ice-water bath is cooled to less than 10 DEG C.Start to drip the mixed solution that 25 g trash ices and 25 mL hydrochloric acid are made under stirring, after being hydrolyzed, add 20 mL anhydrous diethyl ethers and make dissolution of solid, separate organic layer, wash once by 10% NaOH solution, then be washed till neutrality with distilled water, steam organic solvent with after anhydrous magnesium sulfate drying, excess hexanaphthene recrystallization obtains 3.25 g intermediate a-5, and productive rate is 26.38%.White crystal, fusing point is 120-121 DEG C.IR(KBr，cm
-1): 3093，2963, 2874，1642，1618，1510，1394，1183, 1167, 852, 813。
1H NMR (CDCl
3, 400 MHz) d7.882（d, J=8.8, 2H）; 7.777(d, J=8.4, 2H); 7.641-7.616(m, 2H); 7.505-7.446(m.1H); 7.321(d, J=7.6, 2H); 7.037-6.939(m, 2H); 2.471(s, 3H) 。HMRS: m/z [M+H] calcd. for C
20H
15F
2O: 309.1091; found: 309.1091。Reaction formula is:
；
(b) intermediate 4-(2 ', 4 '-difluoro biphenyl) synthesis to methylbenzyl alcohol (b-5):
By 2.0 g (6.5 mmol) intermediate a-5 with 50 mL anhydrous alcohol solutions in the round-bottomed flask of 100 mL, magnetic agitation adds 0.40 g sodium borohydride heating reflux reaction 3 h after dissolving, TLC (petrol ether/ethyl acetate=2:1, V/V) monitoring reaction, show that intermediate a-5 is converted into b-5 completely.Revolve and steam except desolventizing, obtain white solid.Add 25 mL water and 25 mL ethyl acetate make it dissolve, with 25 mL × 2 distilled water washs twice, finally use anhydrous magnesium sulfate drying.Revolve and steam except desolventizing, obtain water white transparency sticky mass b-5, quality 2.0 g, be directly used in next step reaction.Reaction formula is as follows:
；
The synthesis of (c) target compound 1-[2 ', 4 '-two fluoro-(1,1-biphenyl)-4-base-toluene-4-ylmethyl]-imidazoles (T-5):
1 .77 g(5.69 mmol is added in round-bottomed flask) intermediate b-5 and 20 mL is containing acetonitrile solution stirring heating back flow reaction 20 h of 15.0 mmol bis--1-imidazoles sulfoxides, rotary evaporation removing solvent acetonitrile, excess 30 mL acetic acid ethyl dissolutions, 20 mL × 3 distilled water washs, anhydrous magnesium sulfate drying.Rotary evaporation is except desolventizing, and excess crosses silica gel chromatographic column, eluent: petrol ether/ethyl acetate=2/1 (V/V).Obtain straight product 0.65 g(1.74 mmol) T-5, be orange-yellow sticky mass, productive rate is 30.58%.IR (KBr, cm
-1): 3600-2700 (the imidazole ring charateristic avsorption band spreaded), 3096,2965,2879,1615,1510,1394,1183,1167,855,816.
1H-NMR(CDCl
3, 400M): d2.382(s, 3H); 6.542(s, 1H); 6.905-7.989(m, 3H); 7.061(d, J = 8Hz, 2H); 7.166-7.213(m, 4H); 7.278-7.330(m, 1H); 7.376-7.436(m, 1H); 7.467-7.509(m, 3H)。HMRS: m/z [M+H] calcd. for C
23H
19F
2N
2: 361.1516; found: 361.1522。Reaction formula is:
The synthesis of embodiment 6:1-[2 ', 4 '-two fluoro-(1,1-biphenyl)-4-base-toluene-4-ylmethyl]-1,2,4-triazoles (being expressed as T-6 in the present invention)
1.5 g (4.84 mmol) intermediate b-5 and 20 mL is added successively containing 15.0 mmol bis--1-(1 in round-bottomed flask, 2,4-triazole) acetonitrile solution stirring heating back flow reaction 12 h of sulfoxide, rotary evaporation, removing acetonitrile, excess 20 mL acetic acid ethyl dissolutions, 15 mL × 3 distilled water washs, anhydrous magnesium sulfate drying.Revolve and steam except desolventizing, excess crosses silica gel chromatographic column, eluent: petrol ether/ethyl acetate=1/1 (V/V).Obtain target compound T-6 1.21 g, faint yellow sticky mass, productive rate is 66.48%.IR(KBr，cm
-1): 3124 ，3094，2962, 2875， 1616，1512，1394，1185, 1166, 857, 817。
1H-NMR (CDCl
3, 400 MHz):d2.325(s, 3H); 6.786(s, 1H); 6.839-6.922(m, 2H); 7.096 (d, J = 8Hz, 2H); 7.161-7.198(m, 4H); 7.320-7.379(m, 1H); 7.480(d, J = 8Hz, 2H); 8.018(s, 1H); 8.036(s, 1H)。HMRS: m/z [M+H] calcd. for C
22H
18N
3F
2: 362.1469; found: 362.1452。Reaction formula is:
Embodiment 7:1-[2 ', 4 '-two fluoro-(1,1-biphenyl)-4-base-chlorobenzene-4-ylmethyl]-1,2,4-triazoles (being expressed as T-7 in the present invention)
(a) intermediate 4-(2 ', 4 '-difluoro biphenyl)-chlormezanone (a-7) is synthesized
Weigh 5.76 g (40 mmol) 2,4-DfBP is dissolved in the reaction flask filling 30 mL dithiocarbonic anhydride, the aluminum chloride that 9.60 g (73 mmol) are dry is added after solid dissolves completely, after aluminum chloride has dissolved, the mixed solution of agitation and dropping 20 mL dithiocarbonic anhydride and 7.35 g (42mmol) parachlorobenzoyl chloride under normal temperature, after dropwising, be heated to 45 DEG C of back flow reaction 3h.Under ice-water bath cooling, the mixed solution that agitation and dropping 25 g trash ice and 25 mL concentrated hydrochloric acids are made into, add 50 mL anhydrous diethyl ethers after dripping off and make dissolution of solid, separate organic layer, wash once by 10% NaOH solution, then be washed till neutrality with distilled water, with anhydrous magnesium sulfate drying, steam except organic solvent, obtain 4.98 g intermediate a-7 with hexanaphthene recrystallization, productive rate is 38.04%.White solid, fusing point: 189-192 DEG C of .IR (KBr, cm
-1): 3076,1650,1621,1587,1578,1191,1174,857,815
1H NMR (CDCl
3, 400 MHz) d 7.873（d, J=8.4Hz, 2H）; 7.836(d, J=8.4, 2H); 7.658-7.633(m, 2H); 7.512-7.444(m, 3H); 7.043-6.945(m, 2H); HMRS: m/z [M+H] calcd. for C
19H
12ClF
2O: 329.0545; found: 329.0541。Reaction formula is:
；
(b) intermediate 4-(2 ', 4 '-DCBP base)-synthesis to chlorobenzene methanol (b-7)
By 1.00 g intermediate a-7,0.13 g sodium borohydride, 30 mL dehydrated alcohols join in flask, magnetic agitation heating reflux reaction 3 h, TLC (petrol ether/ethyl acetate=2:1, V/V) monitors reaction, shows that intermediate a-7 is converted into b-7 completely, except desolventizing, obtain white solid.Add 15 mL distilled water and 15 mL ethyl acetate make it dissolve rear separatory.Organic layer uses 15 mL × 2 to distill washing again, finally uses anhydrous magnesium sulfate drying.Revolve and steam except desolventizing, obtain intermediate (b-7) 1.01 g.Be directly used in next step reaction.Reaction formula is:
C () target is the synthesis of 1-[2 ', 4 '-two fluoro-(1,1-biphenyl)-4-base-chlorobenzene-4-ylmethyl]-1,2,4-triazoles (T-7)
1.54 g (4.73 mmol) intermediate b-7 and 20 mL is containing 15.0 mmol bis--1-(1,2,4-triazole) acetonitrile solution stirring heating back flow reaction 12 h of sulfoxide, rotary evaporation, removing acetonitrile, excess 15 mL acetic acid ethyl dissolutions, with distilled water wash twice, then use anhydrous magnesium sulfate drying.Rotary evaporation is except desolventizing, and excess crosses silica gel chromatographic column, eluent: petrol ether/ethyl acetate=1/1 (V/V=1/1).Rotary evaporation is except desolventizing, and obtain 0.94 g target product T-7, productive rate is 54.3%.For pale yellow colored solid thing, fusing point: 189-192 DEG C.IR(KBr，cm
-1): 3125，3082，1621，1584, 1575, 1192, 1176, 859, 817。
1H-NMR (CDCl
3, 400 MHz):d6.798(s, 1H); 6.910-6.993(m, 2H); 7.137(d, J = 8.4Hz, 2H); 7.219(d, J = 8Hz, 2H); 7.380-7.410(m, 3H); 7.534(d, J = 7.2Hz, 2H); 8.041(s, 1H); 8.098(s, 1H)。HMRS: m/z [M+H] calcd. for C
21H
15N
3F
2Cl: 382.0923; found: 382.0917。Reaction formula is:
Embodiment 8:1-[2 ＇, 4 ＇-two chloro-(1,1 ＇-biphenyl)-4-base-phenyl methyl]-imidazoles (being expressed as T-8 in the present invention)
(a) intermediate 4-(2 ', 4 '-DCBP base) synthesis of phenyl ketone (a-8)
Reaction formula is:
8.92 g(40 mmol) 2,4-DCBP is dissolved in the reaction flask filling 30 mL dithiocarbonic anhydride, the aluminum chloride that 9.60 g (73 mmol) are dry is added after dissolving completely, after aluminum chloride has dissolved, stir the mixed solution of lower dropping 20 mL dithiocarbonic anhydride and 5.62 g (40mmol) Benzoyl chloride, be heated to 45 DEG C of back flow reaction 3 h.Under ice-water bath cooling, the mixed solution that agitation and dropping 25 g trash ice and 25 mL concentrated hydrochloric acids are made into, add 50 mL anhydrous diethyl ethers after dripping off and make dissolution of solid, separate organic layer, wash once by 10% NaOH solution, then be washed till neutrality with distilled water, with anhydrous magnesium sulfate drying, steam except organic solvent, obtain 6.05 g intermediate a-8 with hexanaphthene recrystallization, productive rate is 46.25%.White solid, fusing point: 108.5-109.5 DEG C
IR(KBr ,cm
-1): 3029，3081，1711，1653，1177，1147，1104，858，820。
1H-NMR (CDCl
3, 400 MHz): d7.312-7.374(m, 2H); 7.506-7.559(m, 5H); 7.607-7.647(m, 1H); 7.858-7.907(m, 4H);
HMRS: m/z [M+H] calcd. for C
19H
13Cl
2O: 327.0343; found: 327.0335；
(b) intermediate 4-(2 ', 4 '-DCBP base) synthesis of phenyl methanol (b-8)
Reaction formula is:
By 1.00 g (3.06 mmol) intermediate a-8,0.13 g (3.17 mmol) sodium borohydride, 30 mL dehydrated alcohols join in flask, magnetic agitation heating reflux reaction 3 h, TLC (ether/ethyl acetate=2:1, V/V) monitors reaction, shows that intermediate a-8 is converted into b-8 completely, except desolventizing, obtain white solid.Add 15 mL distilled water and 15 mL ethyl acetate make it dissolve rear separatory.Organic layer uses 15 mL × 2 to distill washing again, and finally use anhydrous magnesium sulfate drying, rotary evaporation obtains water white transparency sticky mass b-8, quality 1.00 g.Be directly used in next step reaction;
The synthesis of (c) target compound 1-[2 ＇, 4 ＇-two chloro-(1,1 ＇-biphenyl)-4-base-phenyl methyl]-imidazoles (T-8)
Reaction formula is:
Get 1.00 g (3.04 mmol) intermediate b-8,10 mL are containing stirring heating back flow reaction 12 h in the acetonitrile solution of 7.5 mmol bis--1-imidazoles sulfoxides and reaction flask, rotary evaporation removing solvent acetonitrile, excess 15 mL water and 15 mL acetic acid ethyl dissolutions, separatory, organic layer 15 mL × 2 distilled water washs, anhydrous magnesium sulfate drying.Rotary evaporation is except desolventizing, and excess crosses silica gel chromatographic column, eluent: petrol ether/ethyl acetate=2/ 1 (V/V).Obtain straight product 0.65g T-8, productive rate is 56.5%.For white solid matter, fusing point: 87.5-88.5 DEG C.IR (KBr, cm
-1): 3550-2650 (the imidazole ring charateristic avsorption band spreaded), 1638,1586,1494,1469,868,812.
1H-NMR (CDCl
3, 400 MHz): d6.578(s, 1H); 6.898(s, 1H); 7.122-7.174(m, 5H); 7.250-7.290(m, 2H); 7.370-7.414(m, 5H); 7.475(d, J = 8Hz, 2H)。HMRS: m/z [M+H] calcd. for C
22H
17N
2Cl
2: 379.0769; found: 379.0784。
Embodiment 9:1-[2 ＇, 4 ＇-two chloro-(1,1 ＇-biphenyl)-4-base-phenyl methyl]-1,2,4-triazoles (the present invention is expressed as T-9):
Preparation feedback formula is as follows:
1.50 g (4.56 mmol) intermediate b-8 and 20 mL is containing 15.0 mmol bis--1-(1,2,4-triazole) acetonitrile solution stirring heating back flow reaction 12 h of sulfoxide, rotary evaporation, removing acetonitrile, excess 20 mL water and 20 mL acetic acid ethyl dissolutions, separatory, organic layer 20 mL × 2 distilled water washs, anhydrous magnesium sulfate drying.Rotary evaporation is except desolventizing, and excess crosses silica gel chromatographic column, eluent: petrol ether/ethyl acetate=1/1 (V/V=1/1).Rotary evaporation is except desolventizing, and obtain 1.15 g target product T-9, productive rate is 66.5%.For faint yellow solid, fusing point: 88-89 DEG C.IR(KBr,cm-1): 3132，3061，1629，1584，1497，1471，861，815。
1H-NMR (CDCl
3, 400 MHz):d6.824(s,1H); 7.189-7.209(m, 5H); 7.244-7.311(m, 2H); 7.388-7.488(m, 5H); 8.004(s, 1H); 8.057(s, 1H)。HMRS: m/z [M+H] calcd. for C
21H
16N
3Cl
2: 380.0721; found: 380.0726。
Embodiment 10:1-[2 ＇, 4 ＇-two chloro-(1,1 ＇-biphenyl)-4-base-2-thienyl methyl]-imidazoles (T-10)
(a-10) synthesis of (a) intermediate 2', 4'-bis-chloro-(1,1'-biphenyl)-4-base-2-thienyl ketone
Reaction formula is as follows:
18.33 g(82 mmol are added successively in reaction flask) dithiocarbonic anhydride of 2,4-DCBPs and 30 mL dryings, treat to add 16 g (121 mmol) AlCl again after 2,4-DCBP dissolves completely
3, under cooling and stirring condition, in reaction flask, slowly drip 14.65g(100 mmol by constant pressure funnel) and the mixed solution of newly steamed 2-thiophene chloride and the dried dithiocarbonic anhydride of 12 mL.Drip off rear slow heating, temperature control 40 ~ 42 DEG C reaction 4.5 h.After reaction terminates, under cooling and stirring, in reaction flask, add the mixed solution of 50 g ice and 50 mL concentrated hydrochloric acids.Proceeded in separating funnel after hydrolysis terminates, separate lower organic layer, upper strata anhydrous diethyl ether extracts, and merges organic layer, uses the sodium hydroxide of 5%, saturated common salt water washing successively, add appropriate anhydrous magnesium sulfate drying.Revolve steaming, excess hexanaphthene recrystallization, obtain 8g intermediate a-10, productive rate is 29.33%.Pale solid, fusing point: 144.4 ~ 145.9 DEG C.IR (KBr，cm
-1): 3083 ，1633，1514，1466，1105，1056， 1001，855，816。
1H-NMR (CDCl
3, 400 MHz):d6.626-6.639(m，1H)； 7.300-7.365(m, 3H); 7.532-7.567(m, 3H); 7.400(s, 1H ); 8.068(d, J = 8.4Hz, 2H)。HMRS: m/z [M+H] calcd. for C
27H
11Cl
2OS: 332.9908; found: 332.9884；
The synthesis of (b) intermediate 2', 4' bis-chloro-(1,1'-biphenyl)-4-base-2-thienylmethanol (b-10)
Reaction formula is as follows:
1.95 g (5.87 mmol) intermediate a-10 is added successively in reaction flask, 0.4 g (11.74 mmol) sodium borohydride and 50 mL dehydrated alcohols, magnetic agitation heating reflux reaction 3 h, TLC (petrol ether/ethyl acetate=2:1, V/V) monitors reaction, shows that intermediate a-10 is converted into b-10 completely, revolve and steam except desolventizing, obtain white solid.Add 20 mL distilled water and 30 mL ethyl acetate make it dissolve rear separatory.Organic layer uses 15 mL × 2 to distill washing again, and finally use anhydrous magnesium sulfate drying, rotary evaporation obtains faint yellow sticky mass b-10, quality 1.90 g.Be directly used in next step reaction;
The preparation of (c) target compound 1-[2', 4'-bis-chloro-(1,1'-biphenyl)-4-base-2-thienyl methyl] imidazoles (T-10):
Reaction formula is:
1 .9 g(5.69 mmol is added in round-bottomed flask) intermediate b-10 and 20 mL is containing acetonitrile solution stirring heating back flow reaction 15 h of 10.0 mmol bis--1-imidazoles sulfoxides, rotary evaporation removing solvent acetonitrile, excess 30 mL acetic acid ethyl dissolutions, use 20 mL × 2 distilled water washs more successively, finally use anhydrous magnesium sulfate drying.Rotary evaporation is except desolventizing, and excess crosses silica gel chromatographic column, eluent: petrol ether/ethyl acetate=2/1 (V/V).Obtain straight product 0.67 g T-10, be orange-yellow sticky mass, productive rate is 63.7%.IR (KBr, cm
-1): 3600-26500 (the imidazole ring charateristic avsorption band spreaded), 1587,1471,1102,1075,862,818.
1H-NMR (CDCl
3, 400 MHz):d6.753(s, 1H)； 6.913-7.031(m, 3H); 7.125(s, 1H); 7.218-7.324(m, 4H); 7.365-7.426(m, 3H); 7.493-7.553(m, 2H)。HMRS: m/z [M+H]
+calcd. for C
20H
15N
2SCl
2: 385.0333; found: 385.0346。
Embodiment 11:1-[2 ＇, 4 ＇-two chloro-(1,1 ＇-biphenyl)-4-base-2-thienyl methyl]-1,2,4-triazoles (T-11)
Reaction formula is as follows:
1.37 g(4.1 mmol are added successively in round-bottomed flask) intermediate b-10 and 20 mL is containing acetonitrile solution stirring heating back flow reaction 15 h of 10.0 mmol bis--1-imidazoles sulfoxides, rotary evaporation removing solvent acetonitrile, excess 30 mL acetic acid ethyl dissolutions, use 20 mL × 2 distilled water washs more successively, finally use anhydrous magnesium sulfate drying.Rotary evaporation is except desolventizing, and excess crosses silica gel chromatographic column, eluent: petrol ether/ethyl acetate=4/1 (V/V).Obtain straight product 1.02g T-11, be faint yellow waxy solid, productive rate is 64.6%.IR(KBr，cm
-1): 3135，3110，2927，2859，1587，1500，1469，1107，1074，862，801，707。
1H-NMR (CDCl
3, 400 MHz):d6.983-7.042(m, 3H)； 7.235-7.306(m, 4H); 7.383-7.432(m, 3H); 7.482(d, J = 2Hz, 1H); 8.045(s, 1H); 8.110(s, 1H)。HMRS: m/z [M+H] calcd. for C
19H
14N
3SCl
2: 386.0285; found: 386.0258。
Antifungal property test example:
1. in The National Center for Drug Screening's his-and-hers watches 1, compound 1,2,3,4 anti-mycotic activity test result is as shown in table 2
Antibacterial activity in vitro measures:
Screening model: anti-mycotic activity
Test system: external
Measuring method: agar method, with minimum inhibitory concentration MIC(μ g/mL) value judgement
Table 2
As shown in Table 2, test-compound in table, to the anti-mycotic activity of trichophyton purpureatum and trichophyton gypseum with to contrast medicine amphotericin B suitable, more weak to the anti-mycotic activity of saccharomyces albicans and saccharomyces sake bacterium.
In order to explore the antibacterial activity of this compounds, compound 1 in The National Center for Drug Screening's his-and-hers watches 1,2,3,4 antibacterial activities have also carried out preliminary test, and test result is as shown in table 3
Screening model: antibacterial activity
Test system: external
Measuring method: trace liquid diluting method (streptococcus aureus), with minimum inhibitory concentration MIC(μ g/mL) value judgement
Table 3: the MIC value of the 1st to the 4th kind of compound and contrast Ofloxacine USP 23
As shown in Table 3, test-compound in table, to the anti-microbial activity of streptococcus aureus with contrast medicine Ofloxacine USP 23 and compare, the minimum inhibitory concentration value of compound 1 pair of streptococcus aureus is less than the MIC value of positive control Ofloxacine USP 23.
Compound 1 in our unit's his-and-hers watches 1,2,3,4,5,6,7,8,9,10,11 anti-mycotic activity test results are as shown in table 4
Extracorporeal antifungal activity measures:
Test method: with reference to U.S. NCCLS M27-A2 scheme, adopts trace liquid diluting method to measure series compound of the present invention and positive control medicine KETOKONAZOL to the minimum inhibitory concentration (MIC) of tested bacterial strain.By concentration about 1.16
candida albicans (ATCC 10231) the liquid 40 μ L of 106 CFU/mL, after even according to 1:100 dilution mixture with RPMI.1640 substratum, then get in 96 orifice plates that 150 μ L are inoculated in containing different pharmaceutical concentration according to after 1:20 dilution again, cultivate after 24 hours for 35 DEG C, flat board is placed in microplate reader, measure the OD value of liquid under 630 nm wavelength in every hole, with growth control boring ratio comparatively, 80 % grow the compound concentration be suppressed and are namely judged to be MIC value.
2.2 test strains: the experimental strain used is ATCC 10231, after ordinary method qualification, adopt dull and stereotyped continuous method of scoring by strain inoculation on sabouraud culture medium, in 37 DEG C of incubators, constant temperature culture 24 h is for subsequent use.Test-compound dissolve with ethanol, is made into the concentration of 500,250,62.5,31.25,15.62,7.81,3.91,1.95 μ g/mL respectively, according to the method for parallel three groups, respectively gets 20 μ L and adds in 96 orifice plates.On Bechtop, uviolizing 30 minutes, cultivate 24 hours in 35 degree of constant incubators after adding bacterium liquid, positive controls is KETOKONAZOL (MIC=2.28 μ g/mL), wherein 11 compounds have carried out external activity test, the MIC of this series compound to Candida albicans (ATCC 10231) the results are shown in Table 4, as shown in Table 4, compound 2, 3, 5, 6, 8, 9, the minimum inhibitory concentration value of 11 pairs of Candida albicanss is all less than the MIC value of positive control KETOKONAZOL, illustrate its molecular skeleton of the triazole antifungal agent of current clinical application by 2, 4-dihalogenated phenyl is converted to 2, 4-dihalobiphenyl base, the anti-mycotic activity of some compound improves.
Table 4: the MIC value of the 1st to the 11st kind of compound and contrast KETOKONAZOL
After describing various specific embodiment of the present invention above in detail, those of ordinary skill in the art should be well understood to, according to the various common practise of this area, can carry out various equivalent variations, equivalent replacement according to thinking of the present invention or simply revise, these all should belong to the scope of technical solution of the present invention.
Claims (3)
1. the novel oxazole compound containing 2,4-dihalobiphenyl base, is characterized in that: described novel oxazole compound T has following structural formula:
Wherein: X is chlorine or fluorine, Y is imidazoles or 1,2,4-triazole, and A is phenyl or substituted-phenyl or fragrant heterocyclic radical, and described substituted-phenyl is 4-chloro-phenyl-or 4-aminomethyl phenyl, and described fragrant heterocyclic radical is 2-furyl or 2-thienyl.
2. the synthetic method containing the novel oxazole compound of 2,4-dihalobiphenyl base according to claim 1, is characterized in that: described synthetic method adopts following synthesis route, and reaction scheme is as follows:
Wherein X is chlorine or fluorine, and Y is imidazoles or 1,2,4-triazole, A is phenyl or substituted-phenyl or fragrant heterocyclic radical, and described substituted-phenyl is 4-chloro-phenyl-or 4-aminomethyl phenyl, described fragrant heterocyclic radical is 2-furyl or 2-thienyl, and synthesis route comprises the following steps:
(a) with 2,4-dihalobiphenyl, 4-chloro-benzoyl chloride or 4-methyl benzoyl chloride or 2 furoyl chloride or 2-thiophene chloride for starting raw material, under Using Aluminium Trichloride as Catalyst, in carbon disulfide solvent, temperature control, at 40-45 DEG C of heating reflux reaction 4-5h, after reaction terminates, is hydrolyzed with dilute hydrochloric acid under cooling, again through separatory, washing, dry, boil off solvent, crude product hexanaphthene recrystallization, obtains intermediate a;
B () intermediate a and sodium borohydride be heating reflux reaction 1.5-2.5 h in dehydrated alcohol, after reaction terminates, boil off solvent, and residue with ethyl acetate dissolves, and washing is dry, boils off ethyl acetate, obtains reduzate intermediate b;
C () intermediate b and diazole sulfoxide be stirring reaction 11-13 h in acetonitrile solvent, evaporation of solvent acetonitrile, residue with ethyl acetate dissolves, with distilled water wash, finally use anhydrous magnesium sulfate drying, obtain faint yellow sticky mass after steaming desolventizes, cross chromatographic column with eluent petroleum ether: ethyl acetate=1:1 (V/V), obtain target product T.
3. the purposes containing the novel oxazole compound of 2,4-dihalobiphenyl base according to claim 1, is characterized in that: described novel oxazole compound is used for antifungal drug.
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| CN (1) | CN104788439A (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4118487A (en) * | 1974-12-24 | 1978-10-03 | Bayer Aktiengesellschaft | Substituted azol-1-ylmethanes |
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2014
- 2014-01-21 CN CN201410026101.6A patent/CN104788439A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4118487A (en) * | 1974-12-24 | 1978-10-03 | Bayer Aktiengesellschaft | Substituted azol-1-ylmethanes |
Non-Patent Citations (3)
| Title |
|---|
| 俞庆森，等: "《药物设计》", 31 July 2005 * |
| 陈勇，等: ""１’[２’，４’-二氟-(１，１’-联苯)-４-基苯基甲基]-１，２，４-三氮唑的合成与表征"", 《华中师范大学学报（自然科学版）》 * |
| 陈勇，等: ""１’[２’，４’-二氟-(１，１’-联苯)-４-基苯基甲基]-咪唑的合成"", 《合成化学》 * |
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