CN105440020B - 1,2,3- triazole class compounds with anti-tumor activity and preparation method thereof - Google Patents

1,2,3- triazole class compounds with anti-tumor activity and preparation method thereof Download PDF

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CN105440020B
CN105440020B CN201510672486.8A CN201510672486A CN105440020B CN 105440020 B CN105440020 B CN 105440020B CN 201510672486 A CN201510672486 A CN 201510672486A CN 105440020 B CN105440020 B CN 105440020B
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nmr
cdcl
preparation
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triazole
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CN105440020A (en
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陈新
梁翠荣
杨庆鸿
任杰
金桂花
黄倩卉
许园元
胡昆
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T3 Biotechnology Co Ltd
Changzhou University
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Changzhou University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Abstract

The present invention relates to the three kinds of 1,2,3-triazoles class compounds of left side containing heteroaryl structure, general structure is respectively

Description

1,2,3- triazole class compounds with anti-tumor activity and preparation method thereof
The present invention is application No. is 201310669840.2, and the applying date is on December 10th, 2013, entitled " 1,2,3- tri- Azole compounds and its preparation method and application " patent of invention divisional application.
Technical field
The present invention relates to a series of 1,2,3-triazoles class compounds as new anticancer drug, belongs to pharmaceutical synthesis field.
Background technique
Triazole is made of 2 carbon atoms and 3 nitrogen-atoms, it is that 1 carbon atom in imidazole ring is replaced by nitrogen-atoms Obtained five-ring heterocycles.Triazole ring has electronics abundant and armaticity, can be by dredging with metallic ion coordination and generation Water effect forms a variety of non-covalent bonding forces such as hydrogen bond and electrostatic interaction and the intracorporal receptor of biology and enzyme interacting, makes It obtains triazole class compounds and shows the multiple biological activities such as antibacterium, antimycotic, treating tuberculosis, antiviral, anti-inflammatory and antalgic, anticancer. At present had numerous triazole type medicines for agricultural and clinic.
In agriculture field, by the development of more than ten years, triazole pesticide has widened its application range and has prevented object, Mainly as fungicide, have the function of interior suction function, protection and treatment, therefore is widely used in by sub- basidiomycetes, capsule bacterium etc. By the prevention and treatment of fungus-caused multiple diseases.Triazolone was developed in Bayer A.G in 1974, it is first commodity The triazole bactericidal agent product of change.Can be used for preventing and treating fruit tree, vegetables, tobacco, grape, flowers and wheat and barley rust and Powdery mildew, toxicity are low and to honeybee safety.
In medical domain, triazole class compounds are in antibacterial field using always by the weight of medicine drug development worker Depending on.In triazole class compounds, 1,2,3-triazoles class is a kind of important heterocyclic compound, has upper a century to its research. 1993, Kume et al. (Kume M.；Kubota T.；Kimura Y,et al.Synthesis and structure activity relationship of new 7-beta-[(Z)-2-(2-aminothiazol-4-y1)-2- hydroxyminoa cetamido]-phalosporins with 1,2,3-triazole in C-3side chain[J].J Antibiotics.1993,46,177-192. it) is obtained by being connected to 1,2,3- triazole in the mother nucleus structure formula of cephalosporin The cephalosporin analog derivatives of structure novels a series of.Their activity all has good biology compared with original drug Availability.
In addition, triazole class compounds can prevent women by inhibiting activity of aromatizing enzyme as arimedex Internal androgen conversion is estrogen, to reduce estrogen level, reaches the mesh for the treatment of menopausal women breast cancer disease.Third For the Ah Nagqu arimedex (Cuzick J.Anastrozole [J] .Drugs Today, 2005,41,227-239.) Azoles, Vorozole and Letrozole have been used to clinic, have the characteristics that efficient, single-minded, reversible, toxic side effect is small, in some countries Have become the therapeutic agent of a line.
Triazole class compounds are as the novel compound with antitumor potentiality, it has also become the weight of pharmaceutical chemistry research and development Point.1,2,3-triazoles equally shows potential researching value in anti-cancer field as l, the isostere of 2,4- triazoles.
Summary of the invention
The main object of the present invention is to provide a series of 1,2,3-triazoles class compounds and preparation method thereof, and to these changes It closes object and carries out preliminary bioactivity research, find the new anticancer drug that activity is good, selectivity is high.
The general structure of 1,2,3- triazole class compounds of the present invention is as follows:
Wherein in structural formula I, II and Group III, R1, R2For halogen (fluorine, chlorine, bromine), methyl, methoxyl group, hydroxyl, nitro Deng.R3For 3,4- (methine dioxy) benzyl, benzyl, substituted benzyl, thiophene etc..
In structural formula I class, k 0,1.
In formula II, Group III, X is oxygen, nitrogen etc.；R4For hydrogen, straight chain or C1-C5Branched alkyl.
The present invention also provides the synthetic methods of above-mentioned three classes compound:
One, the synthetic method of I class 1,2,3- triazole class compounds
R1,R2=X (F, Cl, Br), Me, MeO, OH, NO2；
The synthetic route of reaction equation 1:I class 1,2,3- triazole class compounds
Specifically carry out as steps described below:
(1) under normal temperature conditions, substituent group aldehyde 1 withIn K2CO3It answers, generates as hair occurs under the conditions of alkali Alkynes, structural formula areWherein aldehyde:K2CO3Molar ratio be 1:1-5:1-200, preferably 1:1.1: 2；Wherein the alkali is potassium carbonate, sodium carbonate, sodium hydride, potassium tert-butoxide, preferably potassium carbonate；Wherein the solvent is first Alcohol, acetone, butanone, preferably methanol；Wherein the reaction temperature is -40 DEG C -80 DEG C, preferably 0 DEG C -25 DEG C；Reaction time is 1- 24 hours, preferably 10 hours；The wherein substituent R for replacing aldehyde1, R2For halogen atom (fluorine, chlorine, bromine), methyl, methoxyl group, Hydroxyl, nitro etc..
(2) alkynes and azide compounds are in CuSO4·5H2Click occurs under the action of O and sodium ascorbate Chemistry reacts to obtain 1,2,3-triazoles class compound 3, and structural formula isAlkynes described in wherein: Nitrine: Cu2SO4·5H2O: the molar ratio of sodium ascorbate is 1:1-3:1-5:1-5, preferably 1:1.2:3:3；The wherein reaction Solvent is dimethyl sulfoxide, water, the tert-butyl alcohol, tetrahydrofuran, the preferably tert-butyl alcohol and water；Wherein the reaction temperature is -40 DEG C -80 DEG C, preferably 0 DEG C -25 DEG C；Reaction time is 1-24 hours, preferably 2 hours；Wherein, R3For 3,4- (methine dioxy) benzyl, benzyl Base, substituted benzyl, thiophene etc..
Two, the synthetic method of II class 1,2,3- triazole class compounds
As X=O
R1,R2=F, Cl, Br, Me, MeO, OH, NO2；R4=H, C1-C5Linear or branched alkyl group；
The synthetic method of reaction equation 2-1:II class 1,2,3- triazole class compounds
Specifically carry out as steps described below:
1. fortified phenol 4 reacts in the presence of potassium carbonate with alpha-brominated ester, α-phenoxy acid methyl esters 5, structural formula are obtained ForThe wherein fortified phenol: alpha-brominated ester: the molar ratio of potassium carbonate is 1:1-5:1-5, preferably 1: 1.1:2；Wherein the alkali is potassium carbonate, sodium carbonate, sodium hydride, preferably potassium carbonate；Wherein the reaction temperature be -40 DEG C - 80 DEG C, preferably 65 DEG C；Reaction time is 1-24 hours, preferably 12 hours；The wherein substituent R for replacing aldehyde1, R2For halogen Atom (fluorine, chlorine, bromine), methyl, methoxyl group, hydroxyl, nitro etc.；R4For hydrogen, straight chain or C1-C5Branched alkyl.
2. α-phenoxy acid methyl esters 5 hydrolyzes under the conditions of lithium hydroxide basic and obtains α-phenoxy acid formic acid 6, structural formula ForThe wherein substitution α-phenoxy acid methyl esters 5: lithium hydroxide molar ratio is 1:1-10, preferably 1:5；Its Described in reaction temperature be -40 DEG C -80 DEG C, preferably 25 DEG C；Reaction time is 1-24 hours, preferably 2 hours.
3. α-phenoxy acid formic acid 6 is condensed under EDC/HOBt effect with dimethyl azanol hydrochloride, α-phenoxy group acyl is obtained Amine 7, structural formula areThe wherein substitution α-phenoxy acid: dimethyl azanol hydrochloride: HOBt:EDC:N- The molar ratio of methylmorpholine is 1:1-5:1-5:1-10, preferably 1:1.1:1.1:1.1:1.5.Wherein the reaction temperature be- 40 DEG C -80 DEG C, preferably 25 DEG C；Reaction time is 1-24 hours, preferably 10 hours.
4. α-phenoxy group amide 7 reacts under the action of Lithium Aluminium Hydride obtains corresponding α-phenoxy group aldehyde 8, structural formula isThe wherein substitution α-phenoxy group amide: the molar ratio of Lithium Aluminium Hydride is 1:1-3, preferably 1:1.8；Wherein The reaction temperature is -80 DEG C -80 DEG C, preferably -78 DEG C；Reaction time is 1-24 hours, preferably 5 hours.
5. under normal temperature conditions, α-phenoxy group aldehyde 8 withIn K2CO3It is answered as hair occurs under the conditions of alkali, raw phase The alkynes 9 answered, structural formula areWherein aldehyde:K2CO3Molar ratio be 1:1-5:1-200, it is excellent Select 1:1.1:12；Wherein the reaction temperature is -40 DEG C -80 DEG C, preferably 0 DEG C -25 DEG C；Reaction time is 1-24 hours, preferably 10 hours.
(6) alkynes 9 and azide compounds are in CuSO4·5H2Click occurs under the action of O and sodium ascorbate Chemistry reacts to obtain 1,2,3-triazoles class compound 10, and structural formula isDescribed in wherein Alkynes 2: nitrine: Cu2SO4·5H2O: the molar ratio of sodium ascorbate is 1:1-3:1-5:1-5, preferably 1:1.2:3:3；It is wherein described Reaction temperature is -40 DEG C -80 DEG C, preferably 0 DEG C -25 DEG C；Reaction time is 1-24 hours, preferably 3 hours；Wherein, R3For 3,4- (methine dioxy) benzyl, benzyl, substituted benzyl, thiophene etc..
As X=N
R1,R2=X (F, Cl, Br), Me, MeO, OH, NO2；R4=H, C1-C5Linear or branched alkyl group；
The synthetic method of reaction equation 2-2:II class 1,2,3- triazole class compounds
Specifically carry out as steps described below:
(1) replace fluorobenzene 11 and amino acid 12 under the action of potassium carbonate, obtain α-anilino- acid formic acid 13, structural formula ForThe wherein substitution fluorobenzene: amino acid: the molar ratio of potassium carbonate is 1:1-5:1-5, preferably 1:1.2: 2；Wherein the alkali is potassium carbonate, sodium carbonate, sodium hydride, preferably potassium carbonate；Wherein the reaction temperature is -40 DEG C -80 DEG C, It is preferred that: 80 DEG C；Reaction time is 1-24 hours, preferably 12 hours；The wherein substituent R for replacing aldehyde1, R2For halogen atom (fluorine, chlorine, bromine), methyl, methoxyl group, hydroxyl, nitro etc.；R4For hydrogen, straight chain or C1-C5Branched alkyl.
(2) synthetic method that synthesizes referring to above compound 6 to 10 of the compound 13 to compound 17.
Three, the synthetic method of Group III 1,2,3- triazole class compounds
R1,R2=F, Cl, Br, Me, MeO, OH, NO2；
R4=H, straight chain or C1-C5Branched alkyl；X=O, N；
The synthetic method of reaction equation 3:III class 1,2,3- triazole class compounds
Specifically carry out as steps described below:
(1) α-benzene oxygen (amine) base acid formic acid 6 is condensed under EDC/HOBt effect with ynamine, obtains corresponding alkynes 18, structure Formula isWherein the substitution α-benzene oxygen (amine) base is sour: ynamine: HOBt:EDC:N, N- diisopropylethylamine Molar ratio be 1:1-5:1-5:1-10, preferably 1:1.1:1.1:1.1:3.Wherein the reaction temperature is -40 DEG C -80 DEG C, excellent Select 25 DEG C；Reaction time is 1-24 hours, preferably 12 hours.The wherein substituent R for replacing acid1, R2For halogen atom (fluorine, Chlorine, bromine), methyl, methoxyl group, hydroxyl, nitro etc.；R4For hydrogen, straight chain or C1-C5Branched alkyl.
(2) compound alkynes 18 is in CuSO4·5H2Click occurs with azide compounds under the action of O and sodium ascorbate Chemistry reacts to obtain 1,2,3-triazoles class compound 19, and structural formula isWherein institute The alkynes 18 stated: nitrine: Cu2SO4·5H2O: the molar ratio of sodium ascorbate is 1:1-3:1-5:1-5, preferably 1:1.2:3:3；Its Described in reaction temperature be -40 DEG C -80 DEG C, preferably 0 DEG C -25 DEG C；Reaction time is 1-24 hours, preferably 2 hours；Wherein, R3 For 3,4- (methine dioxy) benzyl, benzyl, substituted benzyl, thiophene etc..
Advantages of the present invention: a series of 1,2,3- triazole of structure novels has been synthesized by Click Chemistry method Class compound.(nerve is female to DU-145 (Human Prostate Cancer Cells), Hela (cervical cancer cell), SH-SY5Y for these compounds Cell carcinoma cells), K562 (chronic myeloid leukemia cell), K562/ADR (adriamycin-resistant chronic myeloid leukemia cell) Certain inhibiting effect that 5 kinds of cancer cells are shown.
Specific embodiment
The present invention will be described in detail with reference to embodiments, but the present invention is not limited to these embodiments.
Embodiment 1:
The preparation of 1- [3,4- (methylene-dioxy) benzyl]-4-(2,4 dichloro benzene base)-1,2,3- triazoles (3a)
Step 1: the preparation of 2,4 dichloro benzene first alkynes
It weighs 2,4- dichlorobenzaldehyde (202.6mg, 1.2mmol) and solvent methanol (5mL) is added, then weigh potassium carbonate (325.5mg,2.3mmol,2eq)；It is added(256mg, 1.3mmol, 1.2eq) reacts 10 hours.By reactant Concentration removes methanol；H is added2O (15mL) and ethyl acetate (5mL) are dissolved, and are extracted, are had with ethyl acetate (30mL × 3) Machine is mutually with saturation NaHCO3Solution (30mL), H2O (25mL × 2), saturated sodium chloride solution (30mL × 1) washing；And with appropriate nothing Aqueous sodium persulfate dries organic phase.Concentration, then column chromatographic purifying [V (ethyl acetate): V (petroleum ether)=1:50] is carried out, obtain light powder Color solid 146mg, yield 74%.1H NMR(300MHz,CDCl3): δ 7.45 (d, J=10.35Hz, 1H), 7.22 (dd, J= 8.04Hz,1H),3.41(s,1H).
Step 2: the preparation of-4-(2,4 dichloro benzene base)-1,2,3- triazole of 1- [3,4- (methylene-dioxy) benzyl]
Weigh Compound 2.4- dichloro-benzenes first alkynes (81.6mg, 0.5mmol) is put into round-bottomed flask；Weigh Compound 3 again, 4- methylenedioxy benzyl nitrine (120mg, 0.68mmol, 1.4eq) is put into round-bottomed flask；Dimethyl sulfoxide is added (0.2mL)；Measure the solution tert-butyl alcohol (4mL) and H2O (2mL) is instilled in mixture；After weigh catalyst pentahapto brochanite (390mg)；SODIUM ASCORBATE (290mg) is weighed again.Become muddy from clarification, is in yellow.5 hours of stirring at normal temperature, to reality It tests and is post-processed, ice water (15mL) is added under stiring, quenching reaction；It is extracted with ethyl acetate (30mL × 3)；Organic phase is used H2O (25mL × 2), saturated sodium chloride solution (30mL × 2) washing；And organic phase is dried with appropriate anhydrous sodium sulfate；Filtering is simultaneously Concentration is in brown at solid, and column chromatographic purifying [V (methylene chloride): V (petroleum ether)=1:1] obtains white solid 125.0mg, Yield 75%.1H NMR(300MHz,CDCl3): δ 8.20 (d, J=8.52Hz, 1H), 8.09 (d, J=1.98Hz, 1H), 8.08 (s, 1H), 7.44 (d, J=2.04Hz, 1H), 7.34 (dd, J=6.42Hz, 1H), 6.79-6.85 (m, 3H), 5.99 (s, 2H), 5.49(s,2H).13C NMR(75MHz,CDCl3):δ54.82,102.12,109.15,109.31,122.56,123.55, 128.24,128.51,128.75,130.53,131.18,132.23,134.76,148.77,149.01.MS(negative): m/z 347(M-1)。
Step 1: the preparation of 3,4- dichloro-benzenes first alkynes
Method is the same as 1 step 1 of example
Obtain faint yellow solid, yield 58%.1H NMR(300MHz,CDCl3):δ3.14(s,1H),7.26-7.41(m, 2H), 7.57 (d, J=1.17Hz, 1H).
Step 2: the preparation of-4-(3,4- dichlorophenyl)-1,2,3- triazole of 1- [3,4- (methylene-dioxy) benzyl]
Method is the same as 1 step 2 of example
Obtain white solid, yield 82%.1H NMR(300MHz,DMSO-d6):δ5.54(s,2H),6.02(s,2H), 6.88-6.94 (m, 2H), 6.99 (d, J=1.02Hz, 1H), 7.69 (d, J=8.4Hz, 1H), 7.85 (dd, J=6.36Hz, 1H), 8.09 (d, J=1.98Hz, 1H), 8.73 (s, 1H)13C NMR(75MHz,DMSO-d6):δ53.03,101.27, 108.48,108.78,122.15,122.34,125.15,126.78,129.22,130.11,131.20,131.38,131.73, 144.44,147.31,147.58.MS(positive):m/z 349(M+1)。
Step 1: the preparation of 3.4- dimethoxy benzene first alkynes
Method is the same as 1 step 1 of example
Obtain white solid, yield 92%.1H NMR(300MHz,CDCl3): δ 7.26 (s, 1H), 7.11 (dd, J= 1.65Hz, 1H), 6.99 (d, J=1.65Hz, 1H), 6.80 (d, J=8.28Hz, 1H), 3.88 (d, J=3,6Hz, 6H), 3.01 (s, 1H) step 2: the preparation of-4-(3,4- Dimethoxyphenyl)-1,2,3- triazole of 1- [3,4- (methylene-dioxy) benzyl]
Method is the same as 1 step 2 of example
Obtain yellowish solid, yield 96%.1H NMR(300MHz,CDCl3): δ 7.60 (s, 1H), 7.45 (d, J= 1.92Hz, 1H), 7.22-7.25 (m, 1H), 6.88 (d, J=6.72Hz, 1H), 6.81 (dd, J=0.69Hz, 3H), 5.97 (s, 2H),5.45(s,2H),3.94(s,3H),3.89(s,3H).13C NMR(75MHz,CDCl3):δ53.04,54.90,54.96, 100.41,107.53,107.57,107.81,107.81,110.20,117.09,117.64,120.89,122.52,127.30, 147.04,147.10,147.31,148.01,148.22.MS(positive):m/z 340(M+1)。
Embodiment 4:
The preparation of 1- (thiophene -1- methyl) -4- (3,4- Dimethoxyphenyl) -1,2,3- triazole (3d)
Step:
Method is the same as example 3
Obtain white solid, yield 85%.1H NMR(300MHz,CDCl3): δ 7.68 (s, 1H), 7.45 (d, J=1.92Hz, 1H), 7.34 (dd, J=1.2Hz, 1H), 7.25 (dd, J=6.2Hz, 1H), 7.14 (d, J=2.55Hz, 1H) 7.0-7.03 (m, 1H),5.73(s,2H),3.94(s,3H),3.89(s,3H).13C NMR(75MHz,CDCl3):δ49.18,56.53,56.59, 109.45,111.83,118.77,119.20,124.06,127.74,127.97,128.80,136.79,148.71,149.66, 149.83.MS(positive):m/z 301.85(M+1).
Embodiment 5:
The preparation of 1- [3,4- (methylene-dioxy) benzyl]-4-(2- nitrobenzophenone)-1,2,3- triazoles (3e)
Step 1: the preparation of 2- nitrobenzoyl alkynes
It weighs in o-nitrobenzaldehyde (202mg, 1.33mmol) investment round-bottomed flask, is added methanol (10mL)；It weighs again Potassium carbonate (370mg, 2.6mmol, 2eq) is put into mixture, is added(306mg, 1.6mmol, 1.2eq), instead It is concentrated after answering 8 hours；H is added2O (15mL), ethyl acetate (40mL × 3) extraction；Organic phase saturation NaHCO3Solution (40mL)、H2O (40mL × 3), saturated sodium chloride solution (30mL) washing；And it is dry with appropriate anhydrous sodium sulfate；Concentration, then into Row column chromatographic purifying [V (ethyl acetate): V (petroleum ether)=1:15], obtains white solid 160mg, yield 82%.1H NMR (300MHz,CDCl3): δ 8.05 (d, J=8.01Hz, 1H), 7.70 (d, J=7.38Hz, 1H), 7.60 (t, J=7.2Hz), 7.51 (t, J=7.62Hz), 3.53 (s, 1H)
Step 2: the preparation of-4-(2- nitrobenzophenone)-1,2,3- triazole of 1- [3,4- (methylene-dioxy) benzyl]
Weigh 2- nitrobenzoyl alkynes (66mg, 0.45mmol), 3,4- methylenedioxy benzyl nitrine (100mg, 0.56mmol, 1.2eq)；It is added dimethyl sulfoxide (0.5mL), the tert-butyl alcohol (3mL) and H2O (1.5mL) is instilled in mixture；Again It weighs copper sulphate (360mg), SODIUM ASCORBATE (270mg), 6 hours of stirring at normal temperature, experiment is post-processed, is being stirred Lower addition ice water (15mL) is extracted with methylene chloride (30mL × 3)；Organic phase H2O (25mL × 2), saturated sodium chloride solution (30mL × 2) washing；And it is filtered and is concentrated, column chromatographic purifying [V (ethyl acetate): V with the dry organic phase of appropriate anhydrous sodium sulfate (petroleum ether)=1:3], obtain yellowish solid 120mg, yield 82%.1H NMR(300MHz,CDCl3): δ 8.02 (dd, J= 1.29Hz, 1H), 7.80 (dd, J=1.11Hz, 1H), 7.72 (s, 1H), 7.65 (t, J=7.7Hz, 1H), 7.49 (t, J= 7.7Hz,1H),6.82-6.79(m,3H),5.98(s,2H),5.49(s,2H).13C NMR(75MHz,CDCl3):δ54.84, 102.12,109.20,109.33,122.68,123.40,124.70,125.34,128.50,129.60,131.76,133.22, 143.05,148.81,149.01.
Embodiment 6:
The preparation of 1- [3,4- (methylene-dioxy) benzyl] -4- (3- chloro-4-hydroxyl phenyl) -1,2,3- triazole (3g)
Step 1: the preparation of the chloro- 4- benzoxybenzaldehyde of 3-
Weigh 3- chloro-4-hydroxyl benzaldehyde (513.3mg, 3.3mmol), then weigh potassium carbonate (923.2mg, 6.7mmol, It 2eq) puts into three-necked flask, is added solvent acetone (25mL), after 15min, measurement cylite (677.0mg, 3.9mmol, 1.2eq) instill in mixture.It is heated to reflux, reacts 6 hours.Muddy mixture is filtered；Filtrate is carried out dense Contracting；H is added2O (25mL) and ethyl acetate are dissolved；It is extracted with ethyl acetate (40mL × 3)；Organic phase H2O(30mL× 2), saturated sodium chloride solution (30mL × 2) is washed；And organic phase is dried with appropriate anhydrous sodium sulfate；Concentration, at solid；Again into Row column chromatographic purifying [V (ethyl acetate): V (petroleum ether)=1:8].Obtain flocculence white solid 532mg, yield 66%.1H NMR(300MHz,CDCl3): δ 5.26 (s, 2H), 7.08 (d, J=8.46Hz, 1H), 7.48-7.35 (dd, J=6.45Hz, 1H), 7.73 (d, J=2.01Hz, 1H), 9.84 (s, 1H).
Step 2: the preparation of the chloro- 4- benzyloxy benzene first alkynes of 3-
Method is the same as 1 step 1 of example
Obtain faint yellow solid, yield 99%.1H NMR(300MHz,CDCl3):δ3.02(s,1H),5.17(s,2H),6.89 (d, J=8.52Hz, 1H), 7.30-7.46 (m, 6H), 7.52 (d, J=2.04Hz, 1H).
Step 3: 1- [3,4- (methylene-dioxy) benzyl] -4- (the chloro- 4- benzyloxy-phenyl of 3-) -1,2,3- triazole (3f) Preparation
Method is the same as 1 step 2 of example
Obtain white solid, yield 97%.1H NMR(300MHz,DMSO-d6):δ5.24(s,2H),5.51(s,2H),6.01 (s, 2H), 6.87-6.94 (m, 2H), 6.98 (s, 1H), 7.30-7.49 (m, 6H), 7.77 (dd, J=1.71Hz, 1H), 7.91 (d, J=1.74Hz, 1H), 8.58 (s, 1H)13C NMR(75MHz,DMSO-d6):δ52.91,70.06,101.24,108.45, 108.71,114.68,121.04,122.04,124.56,124.93,126.56,127.58,128.02,128.53,129.43, 136.49,145.33,147.25,147.55,153.51.
Step 4: 1- [3,4- (methylene-dioxy) benzyl] -4- (3- chloro-4-hydroxyl phenyl) -1,2,3- triazole (3g) Preparation
Weigh 1- [3,4- (methylene-dioxy) benzyl] -4- (the chloro- 4- benzyloxy-phenyl of 3-) -1,2,3-triazoles (81mg, 0.2mmol), anhydrous methanol (15mL) is added.A few drop concentrated sulfuric acids are added.It weighs in palladium carbon (15mg) investment mixture, plugs hydrogen Balloon.Solution gradually dissolves change clarification after reaction 3 hours.Reaction 24 hours, post-processes experiment, suction filtered through kieselguhr；It is dense Contracting, adds H2O (5mL) is added NaOH (1mol/L) and is adjusted to alkalinity；It is extracted with ethyl acetate (30mL × 3)；Organic phase H2O The washing of (25mL × 2), saturated sodium chloride solution (30mL × 2)；And organic phase is dried with appropriate anhydrous sodium sulfate；Carry out column chromatography It purifies [V (methylene chloride): V (methanol)=150:1], obtains yellowish solid 51.6mg, yield 82%.1H NMR(300MHz, DMSO-d6): δ 5.50 (s, 2H), 6.01 (s, 2H), 6.86-7.02 (m, 4H), 7.62 (t, J=6.6Hz, 1H), 7.79 (d, J =1.53Hz, 1H), 8.51 (s, 1H), 10.38 (s, 1H)13C NMR(75MHz,DMSO-d6):δ52.87,54.97, 101.25,108.45,108.70,116.99,120.10,120.57,122.02,123.01,124.97,126.57,129.52, 145.72,147.24,147.55,152.82.MS(positive):m/z 330(M+1).
Embodiment 7:
4- [(2,4 dichloro benzene oxygroup) propyl- 1- yl] -1- [3,4- (methylene-dioxy) benzyl] 1,2,3- triazole (10a) Preparation
Step 1: the preparation of 2- (2,4 dichloro benzene oxygen)-methyl butyrate
2,4- chlorophenesic acid (815mg, 5mmol) is weighed in 100mL round-bottomed flask, addition Anhydrous potassium carbonate (1.38g, 10.0mmol, 2eq), it is small to be heated to reflux 12 for acetone (30mL) and 2- bromide methyl butyrate (995.6mg, 5.5mmol, 1.1eq) When.Reactant is cooled to room temperature, and filters removal solid, then water (30mL) is added after filtrate is evaporated, and is extracted with ethyl acetate (50mL × 3), combining extraction liquid are washed with water (20mL × 2) and saturated salt solution (20mL) respectively, and anhydrous sodium sulphate is dried Filter concentration, crude product pass through silica gel column chromatography separating purification [V (ethyl acetate): V (petroleum ether)=1:8], obtain 1.22g, yield 93%.1H NMR(400MHz,CDCl3): δ 7.38 (d, J=2.4Hz, 1H), 7.13 (dd, J=2.4,8.8Hz, 1H), 6.72 (d, J=8.8Hz, 1H), 4.56 (q, J=6.0Hz, 1H), 3.76 (s, 3H), 2.08-2.01 (m, 2H), 1.11 (t, J= 7.2Hz,3H).
Step 2: the preparation of 2- (2,4 dichloro benzene oxygen)-butyric acid
Ester 2- (2,4- Dichlorophenoxy)-methyl butyrate (789mg, 3mmol) is dissolved in methanol (10mL) and water (10mL), It is added lithium hydroxide (359.1mg, 15mmol, 5eq), 2h is stirred at room temperature.After methanol is evaporated off, pH value of solution is adjusted to 2- with dilute hydrochloric acid 3, there is solid precipitation, filter, washes, it is dry, obtain white solid, yield 85%；1H NMR(500MHz,CDCl3):δ7.39(d,J =2.5Hz, 1H), 7.16 (dd, J=2.5,9.0Hz, 1H), 6.78 (d, J=8.5Hz, 1H), 4.63 (t, J=6.0Hz, 1H), 2.12-2.06 (m, 2H), 1.14 (t, J=7.5Hz, 3H)
Step 3: the preparation of 2- (2,4 dichloro benzene oxygroup)-N- methoxy-. N-methyl butyramide
It weighs in 2- (2,4- Dichlorophenoxy)-butyric acid (540mg, 2.18mmol) investment three-necked flask, solvent dichloro is added Methane (15mL)；It weighs HOBt (330mg, 2.4mmol, 1.2eq), EDCHCl (511mg, 2.67mmol, 1.2eq), N, O- Dimethyl hydroxyl hydrochloride (266mg, 2.73mmol, 1.2eq), after being stirred at room temperature 30 minutes, ice bath is cooling, adds N- methyl Morpholine (0.8mL, 7.25mmol, 3eq).Reaction is concentrated after 10 hours, obtains weak yellow liquid.1N HCl is added, uses acetic acid Ethyl ester (50mL × 3) extraction；Organic phase 1N HCl (25mL × 2), H2O (25mL × 2), saturated sodium chloride solution (30mL × 2) it washs；And organic phase is dried with appropriate anhydrous sodium sulfate；Column chromatographic purifying [V (ethyl acetate): V (petroleum ether)=1:5], obtains To weak yellow liquid 571mg, yield 90%.1H NMR(300MHz,CDCl3): δ 7.36 (d, J=2.55Hz, 1H), 7.12 (dd, J=2.55Hz, 1H), 6.80 (d, J=8.79Hz, 1H), 4.86 (t, J=5.43Hz, 1H), 3.70 (s, 3H), 3.21 (s, 3H), 1.91-2.12 (m, 2H), 1.12 (t, J=7.44Hz, 1H)
Step 4: the preparation of 2- (2,4 dichloro benzene oxygroup) butyraldehyde
It weighs in Lithium Aluminium Hydride (125mg, 3.29mmol, 1.7eq) investment 50mL round-bottomed flask, tetrahydrofuran is added (20mL)；It weighs 2- (2,4 dichloro benzene oxygroup)-N- methoxy-. N-methyl butyramide (571mg, 1.96mmol) and flask is added In, react 5 hours.1N HCl (20mL) is added into solution, is extracted with ethyl acetate (50mL × 3)；Organic phase saturation Sodium chloride solution (30mL × 2) washing；And organic phase is dried with appropriate anhydrous sodium sulfate；Column chromatographic purifying [V is carried out after concentration (ethyl acetate): V (petroleum ether)=1:5], obtain weak yellow liquid 350mg, yield 77%.1H NMR(300MHz,CDCl3):δ 9.71 (d, J=2.16Hz, 1H), 7.40 (d, J=2.55Hz, 1H), 7.15 (dd, J=2.55Hz, 1H), 4.40-4.45 (m, 1H), 1.92-2.03 (m, 2H), 1.26 (t, J=7.14Hz, 3H)
Step 5: the preparation of 3- (2,4 dichloro benzene oxygroup) pentyne
Weigh Compound 2- (2,4- dichlorophenoxy) butyraldehyde (286mg, 1.2mmol) is dissolved in anhydrous methanol (10mL), Potassium carbonate (345mg, 2.5mmol, 2eq), compound are weighed again(271.6mg, 1.4mmol, 1.1eq) instills bottle In.20 hours of coreaction, reaction is post-processed, mixture is concentrated；H is added2O and ethyl acetate dissolution, are used Ethyl acetate (30mL × 3) extraction；Organic phase saturation NaHCO3Solution (40mL), H2O (40mL × 3), saturated sodium chloride solution (30mL) washing；And organic phase is dried with appropriate anhydrous sodium sulfate；Column chromatographic purifying [V (ethyl acetate): V (stone is carried out after concentration Oily ether)=1:200], obtain weak yellow liquid 152mg, yield 66%..1H NMR(300MHz,CDCl3): δ 7.37 (d, J= 2.49Hz, 1H), 7.18 (dd, J=2.52Hz, 1H), 7.16 (d, J=8.82Hz, 1H), 4.63-4.68 (m, 1H), 2.51 (d, J=2.07Hz, 1H), 1.93-2.12 (m, 2H), 1.15 (t, J=7.44Hz, 3H)
Step 6: 4- [(2,4 dichloro benzene oxygroup) propyl- 1- yl] -1- [3,4- (methylene-dioxy) benzyl] -1,2,3- three The preparation of azoles
It weighs in 3- (2,4- dichlorophenoxy) pentyne (93.0mg, 0.41mmol) investment round-bottomed flask；Chemical combination is weighed again Object 3,4- methylenedioxy benzyl nitrine (88mg, 0.5mmol, 1.2eq) are put into round-bottomed flask；Dimethyl sulfoxide is added (0.2mL)；Measure the solution tert-butyl alcohol (4mL) and H2O (2mL) is instilled in mixture；After weigh catalyst cupric sulfate pentahydrate (402mg), SODIUM ASCORBATE (307mg), 5 hours of stirring at normal temperature.It is added ice water (15mL), quenching reaction；With acetic acid second Ester (30mL × 3) extraction；Organic phase is washed with saturated sodium chloride solution (30mL × 2)；And have with the drying of appropriate anhydrous sodium sulfate Machine phase；It filters and is concentrated, column chromatographic purifying [V (ethyl acetate): V (petroleum ether)=1:5] obtains white solid 145mg, yield 87%.1H NMR(300MHz,CDCl3): δ 7.39 (s, 1H), 7.30 (d, J=2.55Hz, 1H), 7.06 (dd, J=2.55Hz, 1H), 6.91 (d, J=8.88Hz, 1H), 6.66-6.76 (m, 3H), 5.20-5.44 (m, 3H), 1.96-2.15 (m, 2H), 1.03 (t, J=7.38Hz, 3H)13C NMR(75MHz,CDCl3):δ10.31,30.04,54.73,102.10,109.05,109.24, 117.16,121.78,122.50,124.88,126.74,128.19,128.58,130.50,148.71,148.95,149.21, 152.96.MS(positive):m/z 406(M+1).
Embodiment 8:
The preparation of 4- [(2,4 dichloro benzene oxygroup) propyl- 1- yl] -1- (thiophene -1- methyl) 1,2,3- triazole (10b)
Step:
Method is the same as example 7
Obtain white solid, yield 96%.1H NMR(400MHz,CDCl3):δ7.47(s,1H),7.29-7.33(m,2H), 7.03-7.07 (m, 2H), 6.97-7.0 (m, 1H), 6.91 (d, J=8.85Hz, 1H), 5.67 (q, J=15.39Hz, 2H), 5.36 (t, J=6.78Hz, 1H), 2.01-2.18 (m, 2H), 1.02 (t, J=7.38Hz, 3H)13C NMR(75MHz, CDCl3):δ10.23,30.00,49.29,117.18,121.70,124.93,126.78,127.81,127.97,128.19, 128.77,130.52,136.49,149.22,152.96.MS(positive):m/z 367.8(M+1).
Embodiment 9:
4- [(2,4- dibromobenzene oxygroup) propyl- 1- yl] -1- [3,4- (methylene-dioxy) benzyl] 1,2,3- triazole (10c) Preparation
Step 1: the preparation of 2- (2,4- dibromo-phenoxy)-methyl butyrate
Method is the same as 7 step 1 of example
Obtain oily liquids, yield 92%.1H NMR(400MHz,CDCl3): δ 7.68 (d, J=2.4Hz, 1H), 7.31 (dd, J=2.0,6.4Hz, 1H), 6.62 (d, J=8.8Hz, 1H), 4.56 (t, J=6.0Hz, 1H), 3.75 (s, 3H), 2.09-2.02 (m, 2H), 1.11 (t, J=7.6Hz, 3H)
Step 2: the preparation of 2- (2,4- dibromo-phenoxy)-butyric acid
Method is the same as 7 step 2 of example
Obtain white solid, yield 93%；1H NMR(400MHz,CDCl3): δ 7.70 (d, J=2.4Hz, 1H), 7.35 (dd, J=2.4,6.4Hz, 1H), 6.68 (d, J=8.8Hz, 1H), 4.64 (t, J=6.0Hz, 1H), 2.11-2.08 (m, 2H), 1.14 (t, J=7.6Hz, 3H)
Step 3: the preparation of 2- (2,4- dibromobenzene oxygroup)-N- methoxy-. N-methyl butyramide
Method is the same as 7 step 3 of example
Obtain weak yellow liquid, yield 91%.1H NMR(300MHz,CDCl3): δ 7.67 (d, J=2.37Hz, 1H), 7.30 (dd, J=2.4Hz, 1H), 4.85 (bar, 1H), 3.71 (s, 3H), 3.21 (s, 3H), 1.94-2.11 (s, 2H), 1.13 (t, J=7.44Hz, 3H)
Step 4: the preparation of 2- (2,4- dibromobenzene oxygroup) butyraldehyde
Method is the same as 7 step 4 of example
Obtain weak yellow liquid, yield 83%.1H NMR(300MHz,CDCl3): δ 9.70 (d, J=2.19Hz, 1H), 7.71 (d, J=2.37Hz, 1H), 7.33 (dd, J=2.40Hz, 1H), 6.63 (d, J=8.79Hz, 1H), 4.40-4.45 (m, 1H), 1.94-2.05 (m, 2H), 1.10 (t, J=7.44Hz, 3H)
Step 5: the preparation of 3- (2,4- dibromobenzene oxygroup) pentyne
Method is the same as 7 step 5 of example
Obtain weak yellow liquid, yield 89%.1H NMR(300MHz,CDCl3): δ 7.67 (d, J=2.37Hz, 1H), 7.36 (dd, J=2.37Hz, 1H), 7.01 (d, J=8.79Hz, 1H), 4.62-4.67 (m, 1H), 2.51 (d, J=2.04Hz, 1H), 1.98-2.07 (m, 2H), 1.15 (t, J=7.44Hz, 3H)
Step 6: 4- [(2,4- dibromobenzene oxygroup) propyl- 1- yl] -1- [3,4- (methylene-dioxy) benzyl] 1,2,3- triazole Preparation
Method is the same as 7 step 6 of example
Obtain white solid, yield 84%.1H NMR(300MHz,CDCl3): δ 7.60 (d, J=2.4Hz, 1H), 7.38 (s, 1H), 7.24 (dd, J=2.4Hz, 1H), 6.66-6.84 (m, 4H), 5.97 (s, 2H), 5.30-5.44 (m, 3H), 1.96-2.15 (m, 2H), 1.03 (t, J=7.38Hz, 3H)13C NMR(75MHz,CDCl3):δ10.28,30.05,54.75,102.10, 109.05,109.25,114.05,114.32,117.30,121.83,122.49,128.64,131.83,131.83,136.06, 148.74,149.18,154.34.MS(positive):m/z 495.7(M+1).
Embodiment 10:
The preparation of 4- [(2,4- dibromobenzene oxygroup) propyl- 1- yl] -1- benzyl -1,2,3- triazole (10d)
Step:
Method is the same as example 9
Obtain white solid, yield 98%.1H NMR(300MHz,CDCl3): δ 7.60 (d, J=2.4Hz, 1H), 7.40 (s, 1H), 7.33-7.37 (m, 3H), 7.16-7.25 (m, 3H), 6.82-6.85 (d, J=8.85Hz, 1H), 5.36-5.56 (m, 3H), 1.99-2.15 (m, 2H), 1.03 (t, J=7.41Hz, 3H)13C NMR(75MHz,CDCl3):δ10.23,30.01, 54.87,77.09,114.03,114.34,117.31,122.09,128.50,129.42,129.78,131.80,135.08, 136.05,149.17,154.31.MS(positive):m/z 451.70(M+1).
Embodiment 11:
4- [(2,4 difluorobenzene oxygroup) propyl- 1- yl] -1- [3,4- (methylene-dioxy) benzyl] 1,2,3- triazole (10e) Preparation
Step 1: the preparation of 2- (2,4 difluorobenzene oxygen)-methyl butyrate
Method is the same as 7 step 1 of example
Obtain oily liquids, yield 94%.1H NMR(400MHz,CDCl3):δ6.95-6.83(m,2H),6.78-6.72(m, 1H), 4.52 (t, J=6.0Hz, 1H), 3.75 (s, 3H), 2.04-1.97 (m, 2H), 1.10 (t, J=7.2Hz, 3H)
Step 2: the preparation of 2- (2,4 difluorobenzene oxygen)-butyric acid
Method is the same as 7 step 2 of example
Obtain white solid, yield 89%；1H NMR(400MHz,CDCl3):δ7.00-6.95(m,1H),6.90-6.85(m, 1H), 6.78 (t, J=8.8Hz, 1H), 4.58 (t, J=6.0Hz, 1H), 2.08-2.01 (m, 2H), 1.13 (t, J=7.6Hz, 3H).
Step 3: the preparation of 2- (2,4 difluorobenzene oxygroup)-N- methoxy-. N-methyl butyramide
Method is the same as 7 step 3 of example
Obtain weak yellow liquid, yield 87%.1H NMR(300MHz,CDCl3):δ6.93-7.01(m,1H),6.80- 6.87 (m, 1H), 6.70-6.78 (m, 1H), 4.85 (t, J=6.06Hz, 1H), 3.66 (s, 3H), 3.20 (s, 3H), 1.91- 2.00 (m, 2H), 1.10 (t, J=7.44Hz, 3H)
Step 4: the preparation of 2- (2,4 difluorobenzene oxygroup) butyraldehyde
Method is the same as 7 step 4 of example
Obtain weak yellow liquid, yield 68%.1H NMR(300MHz,CDCl3):δ6.83-6.95(m,2H),6.73- 6.83 (m, 1H), 4.32-4.37 (m, 1H), 1.87-1.97 (m, 2H), 1.09 (t, J=7.44Hz, 3H)
Step 5: the preparation of 3- (2,4 difluorobenzene oxygroup) pentyne
Method is the same as 7 step 5 of example
Obtain weak yellow liquid, yield 49%.1H NMR(300MHz,CDCl3):δ7.09-7.16(m,1H),6.75-6.89 (m, 1H), 4.61-4.66 (m, 1H), 2.50 (d, J=2.13Hz, 1H), 1.91-2.06 (m, 2H), 1.13 (t, J=7.41Hz, 3H).
Step 6: 4- [(2,4 difluorobenzene oxygroup) propyl- 1- yl] -1- [3,4- (methylene-dioxy) benzyl] 1,2,3- triazole Preparation
Method is the same as 7 step 6 of example
Obtain white solid, yield 92%.1H NMR(300MHz,CDCl3):δ7.40(s,1H),6.89-6.96(m,1H), 6.64-6.82 (m, 5H), 5.97 (s, 2H), 5.38 (dd, J=14.73Hz, 2H), 5.27 (t, J=6.75Hz, 1H), 1.94- 2.15 (m, 2H), 1.01 (t, J=7.38Hz, 3H)13C NMR(75MHz,CDCl3):δ10.36,29.78,54.69, 102.09,105.08,105.38,105.43,105.73,109.02,109.22,110.98,111.03,111.28,111.33, 119.39,119.42,119.51,119.55,121.85,122.46,128.72,142.77,142.91,142.96,148.72, 148.72,148.98,149.27,152.10,152.26.MS(positive):m/z 373.9(M+1).
Embodiment 12:
The preparation of 4- [(2,4 difluorobenzene oxygroup) propyl- 1- yl] -1- benzyl -1,2,3- triazole (10f)
Step:
Method is the same as example 11
Obtain white solid, yield 97%.1H NMR(300MHz,CDCl3):δ7.41(s,1H),7.33-7.36(m,3H), 7.16-7.21 (m, 2H), 6.88-6.96 (m, 1H), 6.74-6.81 (m, 1H), 6.63-6.70 (m, 1H), 5.50 (q, J= 14.94Hz, 1H), 5.28 (t, J=6.6Hz, 1H), 1.97-2.18 (m, 2H), 1.02 (t, J=7.41Hz, 3H)13C NMR (75MHz,CDCl3):δ10.36,29.80,54.87,105.46,105.76,110.98,111.33,119.47,119.56, 122.09,128.53,129.44,129.79,135.18,149.33.MS(positive):m/z 329.9(M+1).
Embodiment 13:
The preparation of 4- [(2- nitrobenzene) propyl- 1- yl] -1- (thiophene -1- methyl) 1,2,3- triazole (17a)
Step 1: the preparation of 2- (2- nitro-phenylamino)-butyric acid
It weighs C4H9NO2 (1.24g, 12mmol, 1.2eq) to be dissolved in DMF (60mL), adds K2CO3(2.76g, 19.9mmol, 2.0eq), it is eventually adding the fluoro- 2- nitrobenzene (1.41g, 10.0mmol) of 1-, solution is heated to 80 DEG C.It is small to react 12 Shi Hou is added into reaction solution and dilute hydrochloric acid and is extracted with ethyl acetate (80mL × 3), merges organic phase and with dilute hydrochloric acid (50mL × 3) washing, saturated sodium chloride solution (50mL × 2) washing；And organic phase is dried with appropriate anhydrous sodium sulfate；It filters and is concentrated. The yellow-brown solid 1.45g of recrystallize with dichloromethane, yield 65%.1H NMR(300MHz,CDCl3): δ 8.31 (d, J= 7.2Hz, 1H), 8.21 (dd, J=1.8Hz, 1H), 7.44-7.50 (m, 1H), 6.70-6.76 (m, 2H), 4.24 (dd, J= 6.6Hz, 1H), 1.96-2.15 (m, 2H), 1.11 (t, J=7.5Hz, 3H)
Step 2: the preparation of 2- (2- nitro-phenylamino)-N- methoxy-. N-methyl butyramide
Method is the same as 7 step 3 of example
Obtain yellow solid, yield 88%.1H NMR(300MHz,CDCl3): δ 8.47 (d, J=7.47Hz, 1H), 8.19 (dd, J=1.56Hz, 1H), 7.39-7.45 (m, 1H), 6.81 (d, J=8.46Hz, 1H), 6.63-6.69 (m, 1H), 4.62 (q, J=7.14Hz, 1H)), 3.79 (s, 3H), 3.25 (s, 3H), 1.83-2.08 (m, 2H), 1.03 (t, J=7.5Hz, 3H)
Step 3: the preparation of 2- (2- nitro-phenylamino) butyraldehyde
Method is the same as 7 step 4 of example
Obtain yellow liquid, yield 75%.1H NMR(300MHz,CDCl3): δ 9.59 (d, J=2.07Hz, 1H), 8.36 (dd, J=1.56Hz, 1H), 7.41-7.47 (m, 1H), 6.69-6.77 (m, 2H), 4.06-4.13 (m, 1H), 1.88-2.13 (m, 2H), 1.08 (t, J=7.47Hz, 3H)
Step 4: the preparation of 2- (2- nitro-phenylamino) butine
Method is the same as 7 step 5 of example
Obtain yellow liquid, yield 50%.1H NMR(300MHz,CDCl3): δ 8.19 (dd, J=1.59Hz, 1H), 8.06 (d, J=4.98Hz, 1H), 7.46-7.52 (m, 1H), 7.03 (d, J=8.04Hz, 1H), 4.15-4.22 (m, 1H), 2.31 (d, J=2.16Hz, 1H), 1.92-2.03 (m, 2H), 1.17 (t, J=7.44Hz, 3H)
Step 5: the preparation of 4- [(2- nitrobenzene) propyl- 1- yl] -1- (thiophene -1- methyl) 1,2,3- triazole
Method is the same as 7 step 6 of example
Obtain yellow solid, yield 85%.1H NMR(300MHz,CDCl3): δ 8.34 (d, J=6.3Hz, 1H), 8.14 (dd, J=1.53Hz, 1H), 7.39 (s, 1H), 7.27-7.36 (m, 2H), 7.05-7.06 (m, 1H), 6.96-6.99 (m, 1H), 6.83 (d, J=8.43Hz, 1H), 6.60-6.66 (m, 1H), 5.66 (q, J=15.33Hz, 2H), 4.79 (q, J=6.48Hz, 1H), 1.94-2.16 (m, 2H), 1.039 (t, J=7.44Hz, 3H)13C NMR(75MHz,CDCl3):δ10.86,30.16,49.25, 52.42,115.37,116.49,121.03,127.35,127.66,127.90,128.65,132.90,136.63,136.79, 145.13,150.61.
Embodiment 14:
4- { 2- [(2- nitrobenzene amido) butyryl] } methylamino -1- [3,4- (methylene-dioxy) benzyl] -1,2,3- triazole The preparation of (19a)
Step 1: the preparation of 2- (2- nitro-phenylamino)-butyric acid
With 13 step 1 of example
Step 2: the preparation of 1- propine-N- (2- nitro-phenylamino)-butyramide
2- (2- nitro-phenylamino)-butyric acid (303.5mg, 1.35mmol), HOBt (222.7mg, 1.65mmol, 1.2eq), EDCHCl (316mg, 1.65mmol, 1.2eq) is dissolved in DMF (10mL), addition propargylamine (95mg, 1.7mmol, 1.3eq), after being stirred at room temperature 30 minutes, ice bath is cooling, adds diisopropyl ethyl amine (0.7mL, 4.24mmol, 3.0eq), Ice bath is removed after twenty minutes, and that is stirred overnight at room temperature pours into reaction solution saturated ammonium chloride solution (30mL), ethyl acetate extraction (30mL × 3), combined extract liquor are washed respectively with water (30mL × 2) and saturated salt solution (15mL), and anhydrous sodium sulfate is dry, Filtering and concentrating, crude product pass through silica gel column chromatography separating purification [V (ethyl acetate): V (petroleum ether)=1:5], and it is solid to obtain yellow Body 340mg, yield 96%.1H NMR(300MHz,CDCl3): δ 8.23 (d, J=8.55Hz, 1H), 8.13 (s, 1H), 7.49 (t, J=7.38Hz, 1H), 6.82 (t, J=7.56Hz, 1H), 6.71 (d, J=8.52Hz, 1H), 6.56 (s, 1H), 3.97-4.15 (m, 2H), 3.86-3.96 (m, 1H), 2.18 (s, 1H), 1.87-2.14 (m, 2H), 1.12 (t, J=7.47Hz, 3H)
Step 3: 4- { 2- [(2- nitrobenzene amido) butyryl] } methylamino -1- [3,4- (methylene-dioxy) benzyl] -1,2, The preparation of 3- triazole
Weigh Compound 1- propine-N- (2- nitro-phenylamino)-butyramide (84.0mg, 0.32mmol) puts into round bottom and burns In bottle；Weigh Compound 3 again, 4- methylenedioxy benzyl nitrine (69mg, 0.39mmol, 1.2eq) are put into round-bottomed flask；Add Enter dimethyl sulfoxide (0.2mL)；Measure the solution tert-butyl alcohol (4mL) and H2O (2mL) is instilled in mixture；After weigh catalyst five Brochanite (256mg), SODIUM ASCORBATE (194mg), 5 hours of stirring at normal temperature.It is added ice water (15mL), quenching reaction； It is extracted with ethyl acetate (30mL × 3)；Organic phase is washed with saturated sodium chloride solution (30mL × 2)；And with appropriate anhydrous slufuric acid Sodium dries organic phase；It filters and is concentrated, column chromatographic purifying [V (ethyl acetate): V (petroleum ether)=1:1] obtains white solid 116mg, yield 83%.1H NMR(400MHz,CDCl3): δ 8.16 (d, J=6.8Hz, 1H), 8.12 (d, J=2.4Hz, 1H), 7.38 (s, 1H), 7.31 (t, J=6.0Hz, 1H), 6.71-6.79 (m, 3H), 6.68 (s, 1H), 6.61 (d, J=6.8Hz, 1H),5.98(s,2H),5.30-5.38(m,2H),4.41(br,2H),3.87(s,1H),1.86-2.04(m,2H),1.03(t, J=6.0Hz, 3H)13C NMR(100MHz,CDCl3):δ10.39,26.54,34.68,54.08,60.00,101.47, 108.53,108.61,114.39,117.03,122.01,126.87,127.98,133.03,136.32,144.07,148.14, 148.33,172.17.MS(negative):m/z 437(M-1).
Embodiment 15:
The preparation of 4- { 2- [(2- nitrobenzene amido) butyryl] } methylamino -1- benzyl -1,2,3- triazole (19b)
Step:
Method is the same as example 14
Obtain white solid, yield 82%.1H NMR(400MHz,CDCl3): δ 8.15 (d, J=8.4Hz, 1H), 8.12 (d, J =4.0Hz, 1H), 7.24-7.39 (m, 7H), 6.71 (t, J=7.6Hz, 3H), 6.60 (d, J=8.4Hz, 1H), 5.45 (s, 2H), 4.40-4.43 (m, 2H), 38.5-3.89 (m, 1H), 1.86-2.05 (m, 2H), 1.02 (t, J=7.2Hz, 3H)13C NMR(100MHz,CDCl3):δ10.38,26.52,34.68,54.21,59.99,114.36,117.06,122.08,126.86, 128.09,128.85,129.15,133.03,134.42,136.32,144.06,144.76,172.17.MS(positive): m/z 417(M+Na)
Embodiment 16:
4- { 2- [(2- nitrobenzene amido) butyryl] } methylamino -1- [(4- methoxyl group) benzyl] 1,2,3- triazole (19c) Preparation
Step:
Method is the same as example 14
Obtain yellow solid, yield 87%.1H NMR(300MHz,CDCl3): δ 8.12 (d, J=8.61Hz, 2H), 7.67 (br, 1H), 7.38 (s, 1H), 7.17-7.25 (m, 3H), 6.88 (d, J=8.52Hz, 2H), 6.69 (t, J=7.71Hz, 2H), 6.50 (d, J=8.55Hz, 1H), 5.37 (s, 2H), 4.35 (d, J=5.79Hz, 2H), 3.86-3.92 (m, 1H), 3.81 (s, 3H), 1.80-2.07 (m, 2H), 1.01 (t, J=7.44Hz, 3H)13C NMR(75MHz,CDCl3):δ10.99,27.11, 35.15,54.35,55.98,60.41,114.95,115.07,117.44,122.66,126.98,127.40,130.31, 133.48,136.89,144.71,145.32,160.56,172.85.MS(positive):m/z 424.9(M+1).
Embodiment 17:
The preparation of 4- { 2- [(2- nitrobenzene amido) butyryl] } methylamino -1- (4- luorobenzyl) 1,2,3- triazole (19d)
Step:
Method is the same as example 14
Obtain yellow solid, yield 90%.1H NMR(300MHz,CDCl3):δ8.09-8.14(m,2H),7.82(br,1H), 7.44 (s, 1H), 7.21-7.28 (m, 2H), 7.04 (t, J=8.85Hz, 2H), 6.68 (t, J=8.19Hz, 1H), 6.60 (d, J =8.46Hz, 1H), 5.42 (s, 2H), 4.34 (d, J=5.88Hz, 2H), 3.86-3.93 (m, 1H), 1.82-2.06 (m, 2H), 1.00 (t, J=7.47Hz, 3H)13C NMR(75MHz,CDCl3):δ10.94,27.09,35.07,54.01,60.37, 114.92,116.58,116.87,117.40,122.95,127.38,130.56,130.67,130.91,130.95,133.47, 136.84,144.71,145.58,161.82,165.11,172.93.MS(positive):m/z 412.9(M+1).
Embodiment 18:
The system of 4- { 2- [(2- nitrobenzene amido) butyryl] } methylamino -1- (thiophene -1- methyl) -1,2,3- triazole (19e) It is standby
Step:
Method is the same as example 14
Obtain yellow solid, yield 94%.1H NMR(300MHz,CDCl3):δ8.11-8.15(m,2H),7.67(bar, 1H), 7.48 (s, 1H), 7.33 (dd, J=1.17Hz, 1H), 7.24-7.30 (m, 1H), 7.09 (d, J=2.67Hz, 1H), 6.99-7.02 (m, 1H), 6.67-6.72 (m, 1H), 6.60 (d, J=8.37Hz, 1H), 5.63 (s, 2H), 4.36 (d, J= 5.94Hz, 2H), 3.86-3.92 (m, 1H), 1.81-2.10 (m, 2H), 1.02 (t, J=7.47Hz, 3H)13C NMR(75MHz, CDCl3):δ11.02,27.12,35.13,49.11,60.44,114.96,117.50,122.64,127.42,127.83, 128.00,128.93,133.49,136.47,136.95,144.71,145.44.MS(positive):m/z 400.85(M+ 1).
Embodiment 19:
4- { 2- [(2,4 dichloro benzene oxygroup) butyryl] } methylamino -1- [3,4- (methylene-dioxy) benzyl] -1,2,3- three The preparation of azoles (19f)
Step 1: two:
With example 7 Step 1: two
Step 3: the preparation of 1- propine-N-2- (2,4 dichloro benzene oxygen)-butyramide
Method is the same as 14 step 2 of example
It is solid to obtain white, yield 90%.1H NMR(300MHz,CDCl3): δ 7.40 (d, J=2.52Hz, 1H), 7.18 (dd, J=2.52Hz, 1H), 6.82 (d, J=8.85Hz, 2H), 4.60 (t, J=5.52Hz, 1H), 4.01-4.16 (m, 2H), 2.23 (t, J=2.52Hz, 1H), 1.98-2.07 (m, 2H), 1.04 (t, J=7.41Hz, 3H)
Step 4: 4- { 2- [(2,4- dichlorophenoxy) butyryl] } methylamino -1- [3,4- (methylene-dioxy) benzyl] -1, The preparation of 2,3- triazole
Method is the same as 14 step 3 of example
Obtain white solid, yield 92%.1H NMR(300MHz,CDCl3): δ 7.35-7.36 (m, 2H), 7.11 (dd, J= 2.52Hz,1H),6.70-6.80(m,3H),6.70(s,1H),5.97(s,2H),5.37(s,2H),4.52-4.57(m,3H), 1.93-2.04 (m, 2H), 0.97 (t, J=7.44Hz, 3H)13C NMR(75MHz,CDCl3):δ9.51,26.24,35.36, 54.70,81.89,102.10,109.15,109.26,116.36,122.39,122.59,125.10,127.86,128.42, 128.71,130.94,145.38,148.76,148.96,152.30,171.22.MS(positive):m/z 462.85(M+ 1).
Embodiment 20:
4- { 2- [(2,4- dichlorophenoxy) butyryl] } methylamino -1- [(4- methoxyl group) benzyl] -1,2,3-triazoles (19g) Preparation
Step:
Method is the same as example 19
Obtain white solid, yield 92%.1H NMR(300MHz,CDCl3):δ7.34-7.35(m,2H),7.14-7.21(m, 3H), 7.09 (dd, J=2.52Hz, 1H), 6.90 (d, J=1.89Hz, 1H), 6.75 (d, J=8.85Hz, 1H), 5.41 (s, 2H), 4.51-4.56 (m, 3H), 3.80 (s, 3H), 1.95-2.01 (m, 2H), 0.96 (t, J=7.41Hz, 3H)13C NMR (75MHz,CDCl3):δ9.51,26.23,35.34,54.40,55.99,81.87,115.14,116.34,122.34, 125.07,127.07,127.83,128.40,130.29,130.91,145.27,152.29,160.60,171.22.MS (positive):m/z 448.85(M+1).
Embodiment 21:
The system of 4- { 2- [(2,4- dichlorophenoxy) butyryl] } methylamino -1- [(4- fluorine) benzyl] -1,2,3-triazoles (19h) It is standby
Step:
Method is the same as example 19
Obtain white solid, yield 92%.1H NMR(300MHz,CDCl3): δ 7.36 (d, J=4.98Hz, 2H), 7.03- 7.24 (m, 5H), 6.75 (d, J=8.73Hz, 1H), 5.46 (s, 2H), 4.53 (m, 3H), 1.94-1.99 (m, 2H), 0.96 (t, J=7.05Hz, 3H)13C NMR(75MHz,CDCl3):δ9.48,26.19,35.33,54.09,81.80,116.33, 116.68,116.96,122.53,125.07,127.88,128.43,130.53,130.64,130.95,145.56, 152.25.MS(positive):m/z 436.80(M+1).
Embodiment 22:
4- { 2- [(2,4- dichlorophenoxy) butyryl] } methylamino -1- (thiophene -1- methyl) -1,2,3-triazoles (19i) Preparation
Step:
Method is the same as example 19
Obtain white solid, yield 96%.1H NMR(300MHz,CDCl3): δ 7.44 (s, 1H), 7.34 (d, J=5.13Hz, 2H), 7.17 (bar, 1H), 7.01-7.09 (m, 3H), 6.75 (d, J=8.73Hz, 1H), 5.66 (s, 2H), 4.52-4.54 (m, 3H), 1.95-1.99 (m, 2H), 0.97 (t, J=7.17Hz, 3H)13C NMR(75MHz,CDCl3):δ9.54,26.24, 35.31,49.16,81.85,116.29,122.30,125.05,127.86,128.01,128.42,128.90,130.93, 136.52,145.40,152.27,171.26.MS(positive):m/z 434.80(M+1).
Embodiment 23:
4- { 2- [(2,4- dibromobenzene oxygroup) butyryl] } methylamino -1- [3,4- (methylene-dioxy) benzyl] -1,2,3- tri- The preparation of azoles (19j)
Step 1: two:
With example 9 Step 1: two
Step 3: the preparation of 1- propine-N-2- (2,4- dibromo-phenoxy)-butyramide
Method is the same as 14 step 2 of example
It is solid to obtain white, yield 90%.1H NMR(300MHz,CDCl3): δ 7.71 (d, J=2.25Hz, 1H), 7.37 (dd, J=2.25Hz, 1H), 6.84 (bar, 1H), 6.73 (dd, J=8.79Hz, 1H), 4.62 (t.J=5.16Hz, 1H), 4.01-4.17 (m, 2H), 2.23 (t, J=2.37Hz, 1H), 1.98-2.07 (m, 2H), 1.03 (t, J=7.47Hz, 3H)
Step 4: 4- { 2- [(2,4- dibromobenzene oxygroup) butyryl] } methylamino -1- [3,4- (methylene-dioxy) benzyl] -1, The preparation of 2,3- triazole
Method is the same as 14 step 3 of example
It is solid to obtain white, yield 90%.1H NMR(300MHz,CDCl3): δ 7.66 (d, J=2.34Hz, 1H), 7.36 (s, 1H), 7.31 (dd, J=2.34Hz, 1H), 7.16 (bar, 1H), 6.67-6.81 (m, 4H), 5.98 (s, 2H), 5.38 (s, 2H), 4.52-4.59 (m, 3H), 1.93-2.02 (m, 2H), 0.97 (t, J=7.41Hz, 3H)13C NMR(75MHz,CDCl3):δ 9.48,26.11,35.39,54.71,81.61,102.10,109.16,109.27,114.36,115.07,116.27, 122.41,122.60,128.71,132.05,136.47,145.38,148.77,148.99,153.55,171.13.MS (positive):m/z 552.65(M+1).
Embodiment 24:
4- { 2- [(2,4- dibromobenzene oxygroup) butyryl] } methylamino -1- [(4- methoxyl group) benzyl] -1,2,3- triazole (19k) Preparation
Step:
Method is the same as example 23
Obtain white solid, yield 93%.1H NMR(300MHz,CDCl3): δ 7.65 (d, J=2.34Hz, 1H), 7.34 (s, 1H), 7.22-7.30 (dd, J=2.34Hz, 1H), 7.15-7.19 (m, 3H), 6.90 (d, J=8.64Hz, 2H), 6.66 (d, J =8.79Hz, 1H), 5.41 (s, 2H), 4.51-4.58 (m, 3H), 3.81 (s, 3H), 1.95-2.02 (m, 2H), 0.96 (d, J= 2.34Hz,3H).13C NMR(75MHz,CDCl3):δ9.49,26.07,35.36,54.39,55.99,81.54,114.31, 115.01,115.12,116.21,122.35,127.04,130.29,132.01,136.41,145.26,153.50,160.56, 171.09.MS(positive):m/z 538.70(M+1).
Embodiment 25:
The system of 4- { 2- [(2,4- dibromobenzene oxygroup) butyryl] } methylamino -1- [(4- fluorine) benzyl] -1,2,3- triazole (19l) It is standby
Step:
Method is the same as example 23
Obtain white solid, yield 90%.1H NMR(300MHz,CDCl3): δ 7.66 (d, J=2.34Hz, 1H), 7.36 (s, 1H), 7.30 (dd, J=2.3Hz, 1H), 7.22-7.25 (m, 2H), 7.15 (t, J=5.43Hz, 1H), 7.02-7.10 (m, 2H), 6.68 (d, J=8.82Hz, 1H), 5.45 (s, 2H), 4.53-4.60 (m, 3H), 1.93-2.04 (m, 2H), 0.95 (t, J =7.41Hz, 1H)13C NMR(75MHz,CDCl3):δ9.46,26.08,30.36,35.38,54.11,81.57,114.36, 115.10,116.26,116.69,116.98,122.54,130.53,130.64,130.99,131.04,132.05,136.48, 145.56,153.52,161.89,165.18,171.16.
Embodiment 26:
4- { 2- [(2,4 difluorobenzene oxygroup) butyryl] } methylamino -1- [3,4- (methylene-dioxy) benzyl] -1,2,3- three The preparation of azoles (19m)
Step 1: two:
With example 11 Step 1: two
Step 3: the preparation of 1- propine-N-2- (2,4 difluorobenzene oxygen)-butyramide
Method is the same as 14 step 2 of example
It is solid to obtain white, yield 85%.1H NMR(300MHz,CDCl3): δ 6.78-6.97 (m, 4H), 4.50 (t, J= 5.16Hz, 1H), 409-4.11 (m, 2H), 2.24 (s, 1H), 1.94-2.03 (m, 2H), 1.04 (t, J=7.35Hz, 3H)
Step 4: 4- { 2- [(2,4 difluorobenzene oxygroup) butyryl] } methylamino -1- [3,4- (methylene-dioxy) benzyl] -1, The preparation of 2,3- triazole
Method is the same as 14 step 3 of example
It is solid to obtain white, yield 90%.1H NMR(300MHz,CDCl3):δ7.40(s,1H),7.21(br,1H),6.71- 6.91 (m, 6H), 5.97 (s, 2H), 5.37 (s, 2H), 4.54 (d, J=5.85Hz, 2H), 4.46 (t, J=5.34Hz, 1H), 1.89-1.98 (m, 2H), 0.97 (t, J=7.41Hz, 3H)13C NMR(75MHz,CDCl3):δ9.52,26.41,35.25, 54.69,83.30,102.09,105.54,105.84,105.89,106.19,109.15,109.24,111.33,111.38, 111.63,111.68,118.95,118.98,118.07,119.10,122.43,122.61,128.71,145.45,148.75, 148.97,171.60.MS(positive):m/z 430.85(M+1).
Embodiment 27:
4- { 2- [(2,4- difluoro phenoxy group) butyryl] } methylamino -1- [(4- methoxyl group) benzyl] -1,2,3-triazoles (19n) Preparation
Step:
Method is the same as example 26
Obtain white solid, yield 90%.1H NMR(300MHz,CDCl3): δ 7.36 (s, 1H), 7.21 (d, J=8.52Hz, 3H), 6.78-6.90 (m, 4H), 6.68-6.74 (m, 1H), 5.41 (s, 2H), 4.53 (d, J=5.88Hz, 3H), 4.45 (t, J =5.34Hz, 1H), 1.90-1.97 (m, 2H), 0.97 (t, J=7.38Hz, 3H)13C NMR(75MHz,CDCl3):δ9.52, 26.41,35.27,54.40,55.97,83.28,105.53,105.82,105.88,106.18,111.32,111.37, 111.62,111.67,115.13,118.91,119.04,122.36,127.08,130.30,142.55,145.36,152.10, 160.61,171.57.MS(positive):m/z 416.90(M+1).
Embodiment 28:
The system of 4- { 2- [(2,4- difluoro phenoxy group) butyryl] } methylamino -1- [(4- fluorine) benzyl] -1,2,3-triazoles (19o) It is standby
Step:
Method is the same as example 26
Obtain white solid, yield 91%.1H NMR(300MHz,CDCl3):δ7.41(s,1H),7.22-7.27(m,3H), 7.06 (t, J=8.55Hz, 2H), 6.79-6.91 (m, 2H), 6.69-6.75 (m, 1H), 5.46 (s, 2H), 4.54 (d, J= 5.88Hz, 2H), 4.46 (t, J=5.28Hz, 1H), 1.88-1.97 (m, 2H), 0.95 (t, J=7.38Hz, 3H)13C NMR (75MHz,CDCl3):δ9.47,23.33,26.34,30.33,35.23,54.07,83.19,105.53,105.82,105.88, 106.18,111.32,111.38,111.62,111.68,1116.63,116.92,118.90,118.93,119.03, 122.58,130.52,130.63,130.98,131.02,142.30,142.35,142.44,145.62,151.92,152.08, 155.23,155.39,156.37,156.50,159.60,159.74,161.85,165.14,171.62.MS(positive): m/z 404.90(M+1).
Embodiment 29:
4- { 2- [(2,4 difluorobenzene oxygroup) propionyl] } methylamino -1- [(4- methoxyl group) benzyl] -1,2,3- triazole (19p) Preparation
Step:
Method is the same as example 26
Obtain white solid, yield 90%.1H NMR(300MHz,CDCl3): δ 7.38 (s, 1H), 7.22 (d, J=8.55Hz, 2H),6.79-6.92(m,4H),6.70-6.76(m,1H),5.42(s,2H),4.46-4.61(m,3H),3.80(s,3H), 1.53 (d, J=6.75Hz, 3H)13C NMR(75MHz,CDCl3):δ19,35.29,54.39,55.96,78.46,105.53, 105.83,106.18,111.34,111.64,111.69,115.11,119.40,119.53,122.39,127.03,130.33, 141.77,145.24,160.57,172.12.MS(positive):m/z 402.90(M+1).
Embodiment 30:
The system of 4- { 2- [(2,4 dichloro benzene oxygroup) propionyl] } methylamino -1- [(4- fluorine) benzyl] -1,2,3- triazole (19q) It is standby
Step:
Method is the same as example 26
Obtain white solid, yield 96%.1H NMR(300MHz,CDCl3):δ7.42(s,1H),7.23-7.30(m,2H), 7.03-7.09(m,2H),6.80-6.94(m,2H),6.70-6.77(m,1H),5.46(s,2H),4.48-4.62(m,3H), 1.53 (d, J=6.75Hz, 3H)13C NMR(75MHz,CDCl3):δ18.97,30.32,35.27,54.07,78.45, 105.54,105.84,105.89,106.19,111.36,111.41,111.66,111.71,116.63,116.92,119.42, 119.54,122.60,130.56,130.67,130.96,131.00,141.70,141.90,145.53,152.17,152.33, 155.47,155.63,156.55,156.69,159.79,161.86,165.15,172.19.MS(positive):m/z 390.90(M+1).
Embodiment 31:
4- { 2- [(2,4 difluorobenzene oxygroup) isovaleryl] } methylamino -1- [(4- methoxyl group) benzyl] -1,2,3- triazole The preparation of (19r)
Step:
Method is the same as example 26
Obtain white solid, yield 85%.1H NMR(300MHz,CDCl3): δ 7.41 (d, J=29.7Hz, 1H), 7.18- 7.21(m,3H),6.77-6.90(m,3H),6.68-6.70(m,1H),5.41(s,2H),4.51-4.52(m,2H),4.23- 4.27(m,1H),3.81(s,3H),1.92-2.01(m,1H),2.24-2.26(m,1H),0.8-1.03(m,6H).13C NMR (75MHz,CDCl3):δ17.63,19.27,19.39,21.38,30.34,32.47,33.07,35.17,36.14,54.41, 55.97,61.17,87.17,105.45,105.81,106.11,111.32,111.57,115.12,118.45,118.57, 127.06,130.28,160.60,169.12,171.30.MS(positive):m/z 430.90(M+1).
Embodiment 32:
4- { 2- [(2,4 dichloro benzene oxygroup) isovaleryl] } methylamino -1- [(4- fluorine) benzyl] -1,2,3- triazole (19s) Preparation
Step:
Method is the same as example 26
Obtain white solid, yield 90%.1H NMR(300MHz,CDCl3): δ 7.44 (d, J=28.8Hz, 1H), 7.21- 7.25 (m, 2H), 7.15 (bar, 1H), 7.05 (t, J=8.49Hz, 2H), 6.72-6.89 (m, 2H), 6.67-6.70 (m, 1H), 5.46 (d, J=4.5Hz, 2H), 4.44-4.60 (m, 2H), 4.24-4.29 (m, 1H), 2.22-2.38 (m, 1H), 0.90-1.02 (m,6H).13C NMR(75MHz,CDCl3):δ17.60,19.22,19.38,21.39,30.34,32.46,33.07,35.16, 36.15,54.06,61.21,87.13,105.47,105.77,105.83,106.12,111.29,111.34,111.59, 111.65,116.63,116.92,118.47,118.57,118.60,122.58,122.83,130.49,130.53,130.60, 130.64,131.01,131.06,143.13,143.18,143.27,143.32,145.30,145.65,151.68,154.98, 155.14,156.20,156.34,159.43,159.57,161.86,165.15,169.16,171.34.MS(positive): m/z 418.90(M+1).
Embodiment 33:
4- { 2- [(2,4 difluorobenzene oxygroup) valeryl] } methylamino -1- [(4- methoxyl group) benzyl] -1,2,3- triazole (19t) Preparation
Step:
Method is the same as example 26
Obtain white solid, yield 90%.1H NMR(300MHz,CDCl3):δ7.34(s,1H),7.15-7.22(m,3H), 6.78-6.91(m,4H),6.66-6.73(m,1H),5.41(s,2H),4.45-4.53(m,3H),3.80(s,3H),1.82- 1.90 (m, 2H), 1.39-1.51 (m, 2H), 0.90 (t, J=7.41Hz, 3H)13C NMR(75MHz,CDCl3):δ14.38, 18.65,35.25,35.43,54.38,55.95,82.28,105.50,105.80,105.86,106.15,111.28, 111.33,111.58,111.64,115.11,118.58,118.61,118.71,118.74,122.33,127.05,130.30, 142.45,142.50,142.50,142.60,142.64,145.32,151.79,151.95,155.10,155.25,156.29, 156.43,159.52,159.66,160.59,171.83.MS(positive):m/z 430.90(M+1).
Embodiment 34:
The system of 4- { 2- [(2,4 dichloro benzene oxygroup) valeryl] } methylamino -1- [(4- fluorine) benzyl] -1,2,3- triazole (19u) It is standby
Step:
Method is the same as example 26
Obtain white solid, yield 90%.1H NMR(300MHz,CDCl3):δ7.38(s,1H),7.23-7.27(m,2H), 7.21(br,1H),7.03-7.09(m,2H),6.79-6.90(m,2H),6.67-6.75(m,1H),5.46(s,2H),4.46- 4.54 (m, 3H), 1.82-1.90 (m, 2H), 1.38-1.51 (m, 2H), 0.90 (t, J=7.38Hz, 3H)13C NMR(75MHz, CDCl3):δ14.39,18.64,35.25,35.41,54.09,82.28,105.54,105.84,105.89,106.19, 111.32,111.37,111.62,111.67,116.66,116.95,118.63,118.66,118.75,118.78,122.54, 130.54,130.65,130.98,131.02,142.44,142.48,142.63,145.59,151.83,151.99,155.14, 155.29,156.47,159.70,161.88,165.17,171.89.MS(positive):m/z 418.85(M+1).
Embodiment
Anticancer activity measurement
Hela (cervical cancer cell), DU-145 (Human Prostate Cancer Cells), (chronic myelocytic leukemia is thin by K562 Born of the same parents), 5 kinds of K562/ADR (adriamycin-resistant chronic myeloid leukemia cell), SH-SY5Y (neuroblastoma cell) cancer cells For test cell strain, and use normal cell Vero (African MK cells) as control, with mtt assay to synthesized three Azole derivative carries out Anticancer Activity in vitro test, using 5-Fluorouracil as positive control.The cancer cell of logarithmic growth phase, 5 × 10 are diluted to the culture solution of RPMI1640 or DMEM after centrifugation4A/mL is inoculated in 96 orifice plates.37 DEG C of overnight incubations, Then the sample of various concentration is added, then is incubated for 72h, the MTT solution (5mgmL of 10.0 μ L/well is added-1), it is incubated in 37 DEG C After changing 4h, 100 μ L DMSO (dissolution purple formazan crystal) is added in every hole.After ten minutes, first shake for a moment, after orifice plate is placed in On automatic microplate spectrophotometer, measurement absorbs angle value at 570nm and 630nm, and calculates half with Bliss method and effectively press down Concentration (IC processed50), every group of sample carries out 3 parallel testings.
Newly synthesized 35 compounds are determined to DU-145 (Human Prostate Cancer Cells), Hela (cervix cancer with mtt assay Cell), SH-SY5Y (neuroblastoma cell), K562 (chronic myeloid leukemia cell), K562/ADR (adriamycin-resistant Chronic myeloid leukemia cell) 5 kinds of cancer cells inhibited proliferation, the results are shown in Table 1.Test result shows I class 1,2, In 3- triazole class compounds, benzene ring substituents are electron donating group, such as when methoxyl group and hydroxyl, are conducive to improve its anticancer Activity.In class ii 1,2,3-triazoles class compound, when benzene ring substituents are chlorine, bromine, all have to the 5 kinds of cancer cells surveyed The activity of certain anticancer.In group iii 1,2,3-triazoles class compound, when benzene ring substituents are nitro, to SH-SY5Y Cell line has apparent inhibiting effect；When substituent group is chlorine, bromine, to DU-145, Hela, SH-SY5Y and K562, these four are thin Born of the same parents system all has certain inhibiting effect；Benzene ring substituents are fluorine, R4When for isopropyl, to SH-SY5Y cell line have compared with Good anticancer activity.Above-mentioned synthesized triazole class compounds and compound 19v comparison can initial guess, left side heteroaryl structure is 1,2,3- triazole derivative has the necessary structure of anticancer activity.
1 1,2,3- triazole derivative anticancer activity of table tests table

Claims (1)

1. a kind of 1,2,3-triazoles class compound, structure are,
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