CN104292172A - Benzotriazole derivative and preparation method thereof - Google Patents

Benzotriazole derivative and preparation method thereof Download PDF

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CN104292172A
CN104292172A CN201410466706.7A CN201410466706A CN104292172A CN 104292172 A CN104292172 A CN 104292172A CN 201410466706 A CN201410466706 A CN 201410466706A CN 104292172 A CN104292172 A CN 104292172A
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triazole
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oil
isobutyl
benzotriazole
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CN104292172B (en
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金甲
吕正兵
张文平
舒建洪
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Zhejiang Sci Tech University ZSTU
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/16—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms condensed with carbocyclic rings or ring systems
    • C07D249/18—Benzotriazoles
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Abstract

The invention provides a benzotriazole derivative and a preparation method thereof, and particularly relates to a new skeleton compound of the benzotriazole derivative and a preparation method of the new skeleton compound. The benzotriazole derivative is prepared from the raw material benzotriazole by the steps of nitration, condensation with 1-bromo-2-methyl propane, reduction with stannous chloride dihydrate, and acylation with benzoyl chloride, benzene sulfonyl chloride, C1-C6 alkyl substituted benzoyl chloride or benzene sulfonyl chloride, halogen substituted benzoyl chloride or benzene sulfonyl chloride. The benzotriazole derivative serving as a mild mitochondrial membrane potential inhibitor has high cell safety and good druggability, and can be used for preparing human metabolic treatment medicines and weight-reducing health products.

Description

A kind of benzotriazole analog derivative and preparation method thereof
Technical field
The present invention relates to and a kind ofly can be used for preparing Benzotriazole Derivative of body metabolism class medicine and fat-reducing class healthcare products and preparation method thereof.
Background technology
Plastosome is Cellular Oxidation phosphorylation and the main place forming ATP, is called as cell " power factory " (power plant).In plastosome, the energy produced through electron transfer system is used to the synthesis of ATP, but some compound can regulate proton concentration gradient or the potential gradient of adventitia in cross-line plastochondria, and we are referred to as mitochondrial membrane potential conditioning agent.
Various a large amount of compound is found and turns out to be mitochondrial membrane potential conditioning agent.Wherein typical representative is the uncoupling agents of proton type.Proton strides across inner membrance and makes intermembrane space have accumulated a large amount of protons to the transhipment of intermembrane space, establishes proton gradient.Due to the foundation of intermembrane space proton gradient, make inner membrance both sides that two changes significantly occur: one is that mitochondrial membrane space produces a large amount of positive charges, and mitochondrial matrix produces a large amount of negative charges, makes inner membrance both sides form potential difference; Two are the difference of both sides hydrogen ion concentration and produce pH poor (Δ pH), and these two kinds of gradients are collectively referred to as electrochemical gradient (electrochemical gradient).The foundation of mitochondrial inner membrane both sides electrochemical gradient, can form proton motive force (proton-motive force, Δ p).According to the hypothesis (Mitchell of the explanation oxidative phosphorylation coupling mechanism that Britain biochemist P.Mitchell proposed in 1961, P., Coupling of phosphorylation to electron and hydrogen transfer by a chemi-osmotic type of mechanism. Nature 1961,191,144-8.), this electrochemical gradient just ATP synthesis DIRECT ENERGY power.And proton type uncoupling agents eliminate or reduces this electrochemical gradient, thus the many-sides such as body metabolism are had an impact.
At present, study hotspot is become to the research of mitochondrial membrane potential conditioning agent, have been reported and specify that mitochondrial uncoupler is relevant with numerous disease, comprise (the Wallace such as metabolic syndrome, nerve degenerative diseases, cancer, aging, D. C., A mitochondrial paradigm of metabolic and degenerative diseases, aging, and cancer:a dawn for evolutionary medicine. Annu Rev Genet 2005,39,359-407.).
Summary of the invention
An object of the present invention is to provide the benzotriazole analog derivative of a kind of formula (I) structure, it is characterized in that, described compound has as the structure shown in following formula (I):
，
The benzoyl that the benzoyl that wherein substituent R is selected from benzoyl, benzenesulfonyl, C1-C6 alkyl replace or benzenesulfonyl, the benzoyl of halogen substiuted or benzenesulfonyl, C1-C6 alkoxyl group replace or benzenesulfonyl.
Described substituent R is the benzoyl that replaces of the benzoyl that replaces of the benzoyl that replaces of benzoyl, benzenesulfonyl, C1-3 alkyl or benzenesulfonyl, bromine or chlorine or fluorine atom or benzenesulfonyl, C1-3 alkoxyl group or benzenesulfonyl more preferably.
Described substituent R can also more preferably benzoyl, benzenesulfonyl, p-toluenesulfonyl or toluoyl base.
Another object of the present invention is the preparation method of the benzotriazole analog derivative providing a kind of formula (I) structure, it is characterized in that, step (i): first benzo nitrogen triazole is dissolved in the 10-15ml vitriol oil, the nitration mixture be made into nitrosonitric acid and the vitriol oil adds and is dissolved with in the concentrated sulfuric acid solution of benzotriazole, carry out nitration reaction, generate 4-oil of mirbane triazole;
Step (ii): by the 4-oil of mirbane triazole that obtains in step (i) and the bromo-2-methylpropane of 1-at N, in dinethylformamide, under the existence of condensing agent salt of wormwood and potassiumiodide, carry out condensation reaction, generate 1-isobutyl--4-oil of mirbane triazole; Described temperature of reaction slowly rises to reflux temperature and under reflux conditions reacts 2 hours;
Step (iii): the 1-isobutyl--4-oil of mirbane triazole obtained in step (ii) and two hydrated stannous chlorides are carried out reduction reaction, reflux 4 h in alcoholic solvent, uses K after being cooled by reactant 2cO 3system pH is transferred to 8, obtains 1-isobutyl--4-amino-benzene triazole; Described alcoholic solvent is selected from ethanol or propyl alcohol.
Step (iv): at catalyst n; under the effect of dinethylformamide and under the existence of acid binding agent, the Benzoyl chloride of the Benzoyl chloride replace the 1-isobutyl--4-amino-benzene triazole obtained in step (iii) and acylating reagent Benzoyl chloride, benzene sulfonyl chloride, C1-C6 alkyl or benzene sulfonyl chloride, halogen substiuted or benzene sulfonyl acyl chlorides carry out acylation reaction and obtain the Benzotriazole Derivative shown in target compounds of formula (I) in methylene dichloride.
Its reaction process is:
Described preparation method, is characterized in that, described step (i) in nitration mixture proportioning be nitrosonitric acid and vitriol oil volume ratio be 1:3 ~ 1:7, prepare temperature control and carry out below 15 DEG C; Nitration mixture is not only as reactant but also as solvent, and usage quantity calculates with nitrosonitric acid, is 4 ~ 10:1 with the mol ratio of described benzotriazole.
Described step (ii) in condensing agent be salt of wormwood and potassiumiodide; The mass ratio of 4-oil of mirbane triazole, salt of wormwood, potassiumiodide is 1:4-5:1-2, and wherein the bromo-2-methylpropane of 1-is 1-2:1g/ml relative to the quality of 4-oil of mirbane triazole and the ratio of volume; After reinforced end, temperature of reaction slowly rises to reflux temperature and under reflux conditions reacts 2 hours.
Described step (iii) middle reductive agent two hydrated stannous chloride is 3-4:1, described reduction reaction reflux 4 h with the molar weight ratio of 1-isobutyl--4-oil of mirbane triazole, uses K after being cooled by reactant 2cO 3system pH is transferred to 8, washing, each three times of extraction into ethyl acetate, merges organic phase, then with saturated common salt washing, dry, obtain reduzate; Wherein reductive agent and the molar weight of 1-isobutyl--4-oil of mirbane triazole are than being preferably 4:1.
Described step (iv), under nitrogen protection ice-water bath condition, slowly adds acid binding agent, reacts 4 hours, concentrated by the reactant after reacting completely after naturally rising to room temperature, with 5% rare HCl washing, finally obtains product with 95% EtOH recrystallization; Described acid binding agent is pyridine; The mol ratio of acid binding agent, catalyzer and acylating reagent and described 1-isobutyl--4-amino-benzene triazole is 1.0 ~ 2.5:0.005 ~ 0.1:1-2:1, and being preferably acid binding agent, catalyzer, acylating reagent and 1-isobutyl--4-amino-benzene triazole mol ratio is 1.5:0.025:1.25:1.
Compared with prior art, the benzo nitrogen triazole derivative that the present invention relates to and prepare tool and have the following advantages:
1, the benzotriazole analog derivative of Chinese style of the present invention (I) structure has different structure as mitochondrial membrane potential inhibitor and prior art, the further category expanded as mitochondrial membrane potential inhibitor compound, and it is better to have good inhibit activities, higher cell security and druggability, can be used for preparing body metabolism class medicine and fat-reducing class healthcare products;
2, the preparation method of the benzotriazole compound of formula (I) structure is related in the present invention, its preparation process have simple and easy to operate, reaction conditions is gentle, cost is low, yield advantages of higher, and step (ii) in need the method for two-step reaction to be reduced to a step to carry out by similar in prior art, while improving reaction yield, go back Reaction time shorten.
Accompanying drawing explanation
Accompanying drawing 1-7: compound K-1-K-7 on a cellular level to the suppression test result of mitochondrial membrane potential (MMP).
Embodiment
Embodiment 1 compd B (4-nitro-1H-benzo [ d] [1,2,3] triazole) and synthesis
Under condition of ice bath, first 4.3 g benzo nitrogen triazoles are dissolved in the vitriol oil (15mL), again nitrosonitric acid (6mL) is joined in the vitriol oil (20mL) and be made into nitration mixture control temperature below 15 DEG C, again nitration mixture is added drop-wise in the vitriol oil system containing benzotriazole, and keeps nitrated system temperature at 10-15 DEG C.Reinforced complete, question response thing rises to room temperature post-heating reaction 1h naturally, then reaction solution slowly to be poured in the trash ice in stirring and control temperature below 20 DEG C.Crude product filters in Büchner funnel, after drying, filter cake frozen water is washed (temperature control less than 20 DEG C), drying 3 times repeatedly, then obtains product (productive rate 81%) with acetone recrystallization.
1H?NMR?(400?MHz,?DMSO)?δ?8.60?(d,? J?=?8.2?Hz,?1H),?8.48?(d,? J?=?7.8?Hz,?1H),?7.65?(t,? J?=?8.0?Hz,?1H).
Embodiment 2 Compound C (1-isobutyl--4-nitro-1H-benzo [ d] [1,2,3] triazole) and synthesis
By compd B, (61 mmol, 10 g), anhydrous K 2cO 3(32 mmol, 4.5 g), and (1.2 g) are dissolved in DMF (100 mL) with dry 2-methyl isophthalic acid-N-PROPYLE BROMIDE (15 mL) KI.Due to containing lower boiling halides in reactant, temperature of reaction slowly rises to reflux temperature and under reflux conditions reacts 2 hours.After reaction terminates, by in reactant impouring cold water (500 mL), then filter, 2% NaOH washing, washing (200 mL), dried thick product uses column chromatography (petrol/EtOAc=6:1) and obtains brownish black oily compound (productive rate 65%).
1H?NMR?(400?MHz,?CDCl 3)?δ?8.40?(d,? J?=?7.6?Hz,?1H),?8.28?(d,? J?=?8.5?Hz,?1H),?7.54?(t,? J?=?8.1?Hz,?1H),?4.68?(d,? J?=?7.4?Hz,?2H),?2.69?–?2.51?(m,?1H),?1.01?(d,? J?=?6.7?Hz,?6H).
Embodiment 3 Compound D (1-isobutyl--4-amino-1H-benzo [ d] [1,2,3] triazole) and synthesis
By Compound C, (30.0 mmol, 4.9 g), SnCl 22H 2(120.0 mmol, 27 g) are dissolved in reflux 4 h in EtOH (50 mL) to O, use K after being cooled by reactant 2cO 3system pH is transferred to 8, is then washed with water by mixture, each three times of EtOAc extraction, merges organic phase, then washes with saturated common salt, anhydrous MgSO 4drying, obtains product (productive rate 88%) after concentrated.
1H?NMR?(400?MHz,?CDCl 3)?δ?7.20?(t,? J?=?8.3?Hz,?1H),?7.18?–?7.10?(m,?1H),?6.48?(d,? J?=?7.1?Hz,?1H),?4.47?(t,? J?=?7.9?Hz,?2H),?4.36?(br,?2H),?2.66?–?2.42?(m,?1H),?0.97?(d,? J?=?6.7?Hz,?6H).
Embodiment 4 compound K-1 (N-(1-isobutyl--1H-benzo [ d] [1,2,3] triazole-4 base) benzamide) synthesis
By Benzoyl chloride (2.5 mmol of brand-new; 350 mg); catalytic amount DMF (0.05mmol) and Compound D (2 mmol; 328 mg) be dissolved in DCM (10 mL); under nitrogen protection ice-water bath condition; slowly add pyridine (0.16 mL), react 4 hours after naturally rising to room temperature.After reactant is concentrated, with 5% rare HCl washing, after being filtered by mixture, obtain product with 95% EtOH recrystallization.
Yield,?69%;?mp?71–?72℃;? 1H?NMR?(400?MHz,?CDCl 3)?δ?8.79?(s,?1H),?8.42?(d,? J?=?7.4?Hz,?1H),?7.99?(d,? J?=?7.3?Hz,?2H),?7.69?–?7.52?(m,?4H),?7.42?(dd,? J?=?11.6,?4.5?Hz,?1H),?4.63?–?4.42?(m,?2H),?2.65?–?2.44?(m,?1H),?0.99?(dd,? J?=?6.6,?1.7?Hz,?6H);? 13C?NMR?(100?MHz,?CDCl 3)?δ?165.6,?144.6,?134.7,?132.1,?130.2,?128.9(2C),?128.5,?127.4,?127.2(2C),?113.6,?112.9,?63.8,?29.9,?19.9(2C);?HRMS?(ESI):?Calcd?for?C 17H 18N 4NaO?[M+Na] +,?317.1373;?Found,?317.1377.
Embodiment 5 compound K-2 (N-(1-isobutyl--1H-benzo [ d] [1,2,3] triazole-4-yl) benzsulfamide) synthesis
The synthetic method of compound K-2 is similar to K-1, just changes brand-new Benzoyl chloride into benzene sulfonyl chloride.
Yield,?64%;?mp?94.3?–?94.9℃;? 1H?NMR?(400?MHz,?CDCl 3)?δ?8.01?–?7.83?(m,?2H),?7.62?–?7.44?(m,?3H),?7.44?–?7.34?(m,?3H),?7.30?–?7.27?(m,?1H),?4.42?(dd,? J?=?7.3,?2.9?Hz,?2H),?2.51?–?2.31?(m,?1H),?1.04?–?0.85?(m,?6H);? 13C?NMR?(100?MHz,?CDCl 3)?δ?144.7,?139.1,?137.8,?133.1,?128.9(2C),?127.3(2C),?126.8,?126.7,?113.7,?113.6,?63.8,?29.8,?19.9(2C);?HRMS?(ESI):?Calcd?for?C 16H 18N 4NaO 2S?[M+Na] +,?353.1043;?Found,?353.1053.
Embodiment 6 compound K-3 (N-(1-isobutyl--1H-benzo [ d] [1,2,3] triazole-4-yl) para toluene sulfonamide) synthesis
The synthetic method of compound K-3 is similar to K-1, just changes brand-new Benzoyl chloride into p-methyl benzene sulfonic chloride.
Yield,?65%;?mp?117?–?118℃;? 1H?NMR?(400?MHz,?CDCl 3)?δ?7.76?(d,? J?=?8.3?Hz,?2H),?7.51?(d,? J?=?8.6?Hz,?1H),?7.43?(d,? J?=?5.3?Hz,?1H),?7.39?(d,? J?=?7.4?Hz,?1H),?7.30?–?7.27?(m,?1H),?7.17?(d,? J?=?8.0?Hz,?2H),?4.43?(d,? J?=?7.3?Hz,?2H),?2.51?–?2.35?(m,?1H),?2.32?(s,?3H),?0.91?(d,? J?=?6.7?Hz,?6H);? 13C?NMR?(100?MHz,?CDCl 3)?δ?144.7,?144.0,?137.8,?136.2,?129.6(2C),?127.4(2C),?126.9,?126.8,?113.5,?113.3,?63.8,?29.8,?21.5,?19.8(2C);?HRMS?(ESI):?Calcd?for?C 17H 20N 4NaO 2S?[M+Na] +,?367.1199;?Found,?367.1200.
Embodiment 7-10
Embodiment 7-10 relate to the synthetic method of compound K-4-K-7 and K-1 similar, just acylating reagent is correspondingly replaced, specifically as shown in table 1:
Embodiment Substituent R Acylating reagent [M+Na] + Productive rate
Embodiment 7 To ethylamino benzonitrile acyl group P-ethylbenzoyl chloride 345.1389 67%
Embodiment 8 To chlorobenzene formacyl Parachlorobenzoyl chloride 351.6188 71%
Embodiment 9 To chlorobenzenesulfonyl Parachloroben-zenesulfonyl chloride 401.6381 61%
Embodiment 10 To anisoyl Anisoyl chloride 347.1372 64%
Table 1: embodiment 7-10 compound
Embodiment 1-10 raw material used is commercially available analytical pure chemical.
Embodiment 11: the MMP inhibit activities test of compound K-1-K-7 on cell levels
Instrument and reagent
1) instrument:
CO 2saturated humidity incubator is Thermo Forma company (Marietta, OH, U.S.A.) product; Biomek FX automatization sample adding system purchased from Beckman Coulter Inc.(Fullerton, CA, U.S.A.); Fluorescence microplate microplate reader Flexstation 2000, Flexstation II 384 and common microplate reader SpectraMAX 340 purchased from Molecular Devices Corporation(Sunnyvale, CA, U.S.A.);
2) reagent, material:
Cell strain and cell culture fluid
L6 rat myoblasts, myotubes is purchased from Chinese Academy of Sciences's cell bank; Human liver cancer cell HepG2 is purchased from ATCC company; DMEM in high glucose substratum is purchased from GIBCO company; Foetal calf serum is purchased from Hyclone company.
Compound and other reagent
Carbonylcyanide-m-chlorophenylhydrazone(CCCP), for the specific dye 5 that mitochondrial membrane potential detects, 5 ', 6,6 '-Tetrachloro-1,1 ', 3,3 '-tetraethyl-imidacarbocyanine iodide(JC-1), Sulforhodamine B is purchased from Sigma company (St Louis, MO, U.S.A.).
Methyl alcohol, SODIUM PHOSPHATE, MONOBASIC, sodium-chlor, glucose, MgCl 2, CaCl 2etc. general chemistry reagent system domestic analytical pure (AR) reagent.
Main consumptive material
Attached cell Tissue Culture Dish used, Tissue Culture Plate are purchased from Corning or Greiner company.
Cell cultures
L6 myotubes (L6 myotube) is containing 10% foetal calf serum, and 100 kU/L penicillin, in the DMEM in high glucose substratum of 100 mg/L Streptomycin sulphates, are placed in CO 2incubator (37 DEG C, 5% CO 2, 95% air) cultivate, go down to posterity to density about 60%.With 6 × 10 4/ mL concentration accesses (first day) in corresponding Tissue Culture Plate or Tissue Culture Dish, cultivates 24 h to 80% adherent.Cell breaks up in the DMEM in high glucose substratum containing 2% foetal calf serum, penicillin 100 kU/L, Streptomycin sulphate 100 mg/L, and every 48 h change liquid once.Muscle cell is divided into the 7th day sarcoplast more than 70%.
Mitochondrial membrane potential detects
1) L6 myotubes 6000/well(HG-DMEM, 10% foetal calf serum), be inoculated in blackboard clear bottom 96 orifice plate, when density reaches 70%, change liquid differentiation (HG-DMEM, 2 % foetal calf serums), break up after five days and can be used for experiment;
2) in the HG-DMEM of 100 μ L containing 2% foetal calf serum, add corresponding compound according to 100x, discard the old substratum in 96 orifice plates, add the above-mentioned medium treatment certain hour (according to requirement of experiment) containing compound;
3) after compound treatment terminates, add HG-DMEM (containing 2 % foetal calf serums) the 100 μ L containing JC-1.96 orifice plate lucifuges are placed in 37 DEG C of incubator reaction required times;
4) nutrient solution in 96 orifice plates all being dried, a moment is placed by thieving paper, then uses Krebs-Ringer phosphate HEPES(KRPH) solution washes three times, each 200 μ L.After last drying solution, 96 orifice plates are inverted in thieving paper and pat several times, it is to be detected to add 100 μ L KRPH solution;
5) detecting instrument Flexstation II 384, red fluorescence ex/em 530 nm/580 nm, green fluorescence ex/em 485 nm/530 nm, reads plate mode well scan, reads 9 regions altogether.
6) data processing, derive the mean value of red fluorescence and green fluorescence respectively, deduct corresponding blank value, the ratio of last red fluorescence and green fluorescence can represent the state of mitochondrial membrane potential.
7) positive control CCCP, working concentration is 10 μMs, and action time is 30 minutes.
Concrete experimental result is see Figure of description 1-7, and in embodiment 4-10, compound K 1-K7 can reduce mitochondrial membrane potential 0.026 μm of concentration.
Embodiment 12
The toxotest of compound on cell levels
Experimental technique
SRB(Sulforhodamine B) cytotoxicity of method detection compound
1) L6 myofibroblasts (differentiation), 3000/ hole is inoculated in 96 hole transparent panels, within second day, adds compound (100x), is placed in CO 2incubator (37 DEG C, 5% CO 2, 95% air) and cultivate 72 h; Rats'liver primary cell (hepatocytes), 50000/ hole is connected in 96 hole transparent panels, and compound treatment is identical with L6, cultivates 24 h; The L6 myocyte broken up processes 24 h equally.
2) do not remove cell culture medium, in every hole, add 50 μ L 10%(wt/vol) trichoroacetic acid(TCA) (trichloroacetic acid, TCA), make TCA final concentration be 3.3%(wt/vol), be then placed in 4 DEG C and fix 1 h;
3) wash cell 4 times with deionized water, with thieving paper, water is blotted only, be then put in room temperature air-dry (20 ~ 25 DEG C).100 μ L 0.057%(wt/vol are added in each hole) SRB solution, be placed in room temperature and dye 30 min;
4) with 1%(vol/vol) glacial acetic acid (acetic acid) gets 4 times express developed, with remove not with the dyestuff of Cell binding, be then put in room temperature air-dry;
5) in every hole, add 100 μ L 10 mM Tris base solution (pH 10.5), then shake 5 min with vibrator, the dyestuff combined with soluble protein;
6) 510 nm survey OD value, calculate cell mortality.
Toxotest IC on L6 cell strain 50value is all greater than 80.Concrete data are as following table 2.
Compounds L6 myoblast, IC 50 (μM) Compounds L6 myoblast, IC 50 (μM)
K-1 >80 K-5 >80
K-2 >80 K-6 >80
K-3 >80 K-7 >80
K-4 >80 CCCP b 6.98±0.77
Cell strain in compound effects after 72 hours, with SRB analytical test IC 50value assessment cell growth inhibitory effect.
asRB analytical procedure is tested with 3 groups of Duplicate Samples, IC 50value gets three groups of experimental data mean values;
buncoupling agents carbonyl cyanide m-chloro phenylhydrazone (CCCP) is as positive control.
From the activity data of above embodiment 11 and embodiment 12, the falling liquid film current potential effect of compound K-1, K-2 is gentle compared with positive control uncoupling agents CCCP, the onset concentration of falling liquid film current potential is low just can show active effect at 25.6 nmol, and does not also significantly reduce mitochondrial membrane potential in high density.The not fairly obvious relative the first two compound of compound falling liquid film current potential activity of K-4 to K-7.In cytotoxicity experiment, the cell security that all compounds are all done well, IC 50value is all greater than 80, apparently higher than Classical Solutions coupling agent CCCP(IC 50=6.98 ± 0.77), illustrate that the compound described in the present invention has good application prospect, has expanded the category of uncoupling agents with hypotoxicity, greater activity further thus.
These are only the preferred embodiment of the present invention; protection scope of the present invention is not limited thereto; any those skilled in the art are in technical scope disclosed by the invention; the change carried out can be easy to or change is all encompassed within protection scope of the present invention; therefore, protection scope of the present invention should be as the criterion with the protection domain of claims.

Claims (10)

1. a benzotriazole analog derivative, is characterized in that, described compound is respectively as shown in following formula (I):
，
The benzoyl that the benzoyl of the benzoyl that wherein substituent R is selected from unsubstituted benzoyl or benzenesulfonyl, C1-C6 alkyl replaces or benzenesulfonyl, halogen substiuted or benzenesulfonyl, C1-C6 alkoxyl group replace or benzenesulfonyl.
2. the benzotriazole analog derivative of formula according to claim 1 (I) structure, is characterized in that, described substituent R is selected from benzoyl, benzenesulfonyl, p-toluenesulfonyl or toluoyl base.
3. the preparation method of the benzotriazole analog derivative of formula (I) structure described in claim 1 or 2, is characterized in that:
Step (i): first benzo nitrogen triazole is dissolved in the 10-15 mL vitriol oil, the nitration mixture be made into nitrosonitric acid and the vitriol oil adds and is dissolved with in the concentrated sulfuric acid solution of benzotriazole, carries out nitration reaction, generates 4-oil of mirbane triazole;
Step (ii): the 4-oil of mirbane triazole obtained in step (i) and the bromo-2-methylpropane of 1-are existed n, nin-dimethyl formamide, under the existence of condensing agent salt of wormwood and potassiumiodide, carry out condensation reaction, generate 1-isobutyl--4-oil of mirbane triazole; Described temperature of reaction slowly rises to reflux temperature and under reflux conditions reacts 2 hours;
Step (iii): the 1-isobutyl--4-oil of mirbane triazole obtained in step (ii) and two hydrated stannous chlorides are carried out reduction reaction, reflux 4 h in alcoholic solvent, uses K after being cooled by reactant 2cO 3system pH is transferred to 8, obtains 1-isobutyl--4-amino-benzene triazole; Described alcoholic solvent is selected from ethanol or propyl alcohol;
Step (iv): at catalyst n; under the effect of dinethylformamide and under the existence of acid binding agent, the Benzoyl chloride of the Benzoyl chloride replace the 1-isobutyl--4-amino-benzene triazole obtained in step (iii) and acylating reagent Benzoyl chloride, benzene sulfonyl chloride, C1-C6 alkyl or benzene sulfonyl chloride, halogen substiuted or benzene sulfonyl acyl chlorides carry out acylation reaction and obtain the Benzotriazole Derivative shown in target compounds of formula (I) in methylene dichloride.
4. preparation method according to claim 3, is characterized in that, described step (i) described in nitration mixture proportioning be nitrosonitric acid and vitriol oil volume ratio be 1:3 ~ 1:7, preferred 1:4, preparation temperature control carries out below 15 DEG C; Nitration mixture is not only as reactant but also as solvent, and usage quantity calculates with nitrosonitric acid, is 4 ~ 10:1 with the mol ratio of described benzotriazole.
5. preparation method according to claim 3, described step (ii) in condensing agent be salt of wormwood and potassiumiodide; The mass ratio of 4-oil of mirbane triazole, salt of wormwood, potassiumiodide is 1:4-5:1-2, and wherein the bromo-2-methylpropane of 1-is 1-2:1 g/mL relative to the quality of 4-oil of mirbane triazole and the ratio of volume.
6. preparation method according to claim 3, described step (iii) middle reductive agent two hydrated stannous chloride is 3-4:1, described reduction reaction reflux 4 h with the molar weight ratio of 1-isobutyl--4-oil of mirbane triazole, uses K after being cooled by reactant 2cO 3system pH is transferred to 8, washing, each three times of extraction into ethyl acetate, merges organic phase, then with saturated common salt washing, dry, obtain reduzate.
7. preparation method according to claim 6, described reductive agent is 4:1 with the molar weight ratio of 1-isobutyl--4-oil of mirbane triazole.
8. preparation method according to claim 3, described step (iv) under nitrogen protection ice-water bath condition, slowly add acid binding agent, naturally react 4 hours after rising to room temperature, reactant after reacting completely is concentrated, with 5% rare HCl washing, finally obtains product with 95%EtOH recrystallization; Described acid binding agent is pyridine; The mol ratio of acid binding agent, catalyzer and acylating reagent and described 1-isobutyl--4-amino-benzene triazole is 1.0 ~ 2.5:0.005 ~ 0.1:1-2:1.
9. preparation method according to claim 8, described acid binding agent, catalyzer, acylating reagent and 1-isobutyl--4-amino-benzene triazole mol ratio are 1.5:0.025:1.25:1.
10. the benzotriazole analog derivative of formula according to claim 1 and 2 (I) structure is as mitochondrial uncoupler, the purposes preparing body metabolism class medicine and fat-reducing class healthcare products.
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