CN105440020A - 1,2,3-triazole compounds with antitumor activity and preparation method for 1,2,3-triazole compounds - Google Patents

1,2,3-triazole compounds with antitumor activity and preparation method for 1,2,3-triazole compounds Download PDF

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CN105440020A
CN105440020A CN201510672486.8A CN201510672486A CN105440020A CN 105440020 A CN105440020 A CN 105440020A CN 201510672486 A CN201510672486 A CN 201510672486A CN 105440020 A CN105440020 A CN 105440020A
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phenoxy
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CN105440020B (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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Us T3 Bio-Science Technology 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

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Abstract

The present invention relates to three 1,2,3-triazole compounds with aryl structures on the left sides, and the general structural formulae thereof are as shown in the specification. The three compounds have good antitumor activity.

Description

1,2,3-triazoles compounds with anti-tumor activity and preparation method thereof
The present invention is application number is 201310669840.2, and the applying date is on December 10th, 2013, the divisional application of the patent of invention that name is called " 1,2,3-triazoles compounds and its production and use ".
Technical field
The present invention relates to a series of 1,2,3-triazoles compounds as new type anticancer medicine, belong to pharmaceutical synthesis field.
Background technology
Triazole is made up of 2 carbon atoms and 3 nitrogen-atoms, it be 1 carbon atom in imidazole ring by nitrogen-atoms replace the five-membered ring that obtains.Triazole ring has abundant electronics and aromaticity, by with metallic ion coordination and hydrophobic interaction occurs, form acceptor in the multiple non-covalent bonding force such as hydrogen bond and electrostatic interaction and organism and enzyme interacting, triazole class compounds is made to show antibacterium, antimycotic, tuberculosis, antiviral, relieving inflammation and relaxing pain, the multiple biological activity such as anticancer.There is numerous triazole type medicine at present for agriculture and clinical.
At agriculture field; through the development of more than ten years, triazole pesticide has been widened its range of application and has been prevented object, and it is mainly as sterilant; there is the effect of interior suction function, protection and treatment, be therefore widely used in by the control by fungus-caused multiple diseases such as sub-basidiomycetes, capsule bacterium.Triazolone develops in Bayer A.G in 1974, and it is first commercial triazole bactericidal agent product.Can be used for preventing and treating fruit tree, vegetables, tobacco, grape, the rust of flowers and Wheat and barley and Powdery Mildew, toxicity is low and to honeybee safety.
At medical field, the application of triazole class compounds in antibacterial field enjoys the attention of medicine drug development worker always.In triazole class compounds, 1,2,3-triazoles class is the important heterogeneous ring compound of a class, existing century-old to its research.1993, the people such as Kume (KumeM.; KubotaT.; KimuraY, etal.Synthesisandstructureactivityrelationshipofnew7-bet a-[(Z)-2-(2-aminothiazol-4-y1)-2-hydroxyminoacetamido]-phalosporinswith1,2,3-triazoleinC-3sidechain [J] .JAntibiotics.1993,46,177-192.) pass through 1, the mother nucleus structure formula that 2,3-triazole is connected to cynnematin obtains the cynnematin analog derivative of a series of novel structure.Their activity all has good bioavailability compared with original medicine.
In addition, triazole class compounds, as arimedex, by suppressing activity of aromatizing enzyme, can stop androgen conversion in human female to be oestrogenic hormon, thus reducing estrogen level, reach the order for the treatment of menopausal women breast cancer disease.Third generation arimedex (CuzickJ.Anastrozole [J] .DrugsToday, 2005,41,227-239.) Anastrozole, vorozole and letrozole are for clinical, there is the features such as efficient, single-minded, reversible, toxic side effect is little, become the medicine of a line in some countries.
Triazole class compounds, as the novel compound with antitumor potentiality, has become the emphasis of pharmaceutical chemistry research and development.1,2,3-triazoles is as l, and the isostere of 2,4-triazole, shows potential researching value at anti-cancer field equally.
Summary of the invention
Main purpose of the present invention is to provide a series of 1,2,3-triazoles compounds and preparation method thereof, and carries out preliminary bioactivity research to these compounds, finds the new type anticancer medicine that activity is good, selectivity is high.
The general structure of 1,2,3-triazoles compounds of the present invention is as follows:
Wherein in structural formula I, II and III class, R 1, R 2for halogen (fluorine, chlorine, bromine), methyl, methoxyl group, hydroxyl, nitro etc.R 3be 3,4-(methyne dioxy) benzyl, benzyl, substituted benzyl, thiophene etc.
In structural formula I class, k is 0,1.
In formula II, III class, X is oxygen, nitrogen etc.; R 4for hydrogen, straight chain or C 1-C 5branched-chain alkyl.
The present invention also provides the synthetic method of above-mentioned three compounds:
One, the synthetic method of I class 1,2,3-triazoles compounds
R 1,R 2＝X(F,Cl,Br),Me,MeO,OH,NO 2；
The synthetic route of reaction formula 1:I class 1,2,3-triazoles compounds
Specifically carry out according to following step:
(1) under normal temperature condition, substituting group aldehyde 1 with at K 2cO 3issue hair tonic as alkali condition to answer, generate alkynes, its structural formula is wherein aldehyde: k 2cO 3mol ratio be 1:1-5:1-200, preferred 1:1.1:2; Wherein said alkali is salt of wormwood, sodium carbonate, sodium hydride, potassium tert.-butoxide, preferred salt of wormwood; Wherein said solvent is methyl alcohol, acetone, butanone, particular methanol; Wherein said temperature of reaction is-40 DEG C-80 DEG C, preferably 0 DEG C-25 DEG C; Reaction times is 1-24 hour, preferably 10 hours; The substituent R of wherein said replacement aldehyde 1, R 2for halogen atom (fluorine, chlorine, bromine), methyl, methoxyl group, hydroxyl, nitro etc.
(2) alkynes and azide compounds are at CuSO 45H 2clickChemistry occurs under the effect of O and sodium ascorbate and is obtained by reacting 1,2,3-triazoles compounds 3, its structural formula is wherein said alkynes: nitrine: Cu 2sO 45H 2o: the mol ratio of sodium ascorbate is 1:1-3:1-5:1-5, preferred 1:1.2:3:3; Wherein said reaction solvent is dimethyl sulfoxide (DMSO), water, the trimethyl carbinol, tetrahydrofuran (THF), preferred tertiary fourth alcohol and water; Wherein said temperature of reaction is-40 DEG C-80 DEG C, preferably 0 DEG C-25 DEG C; Reaction times is 1-24 hour, preferably 2 hours; Wherein, R 3be 3,4-(methyne dioxy) benzyl, benzyl, substituted benzyl, thiophene etc.
Two, the synthetic method of II class 1,2,3-triazoles compounds
As X=O
R 1, R 2=F, Cl, Br, Me, MeO, OH, NO 2;r 4=H, C 1-C 5straight or branched alkyl;
The synthetic method of reaction formula 2-1:II class 1,2,3-triazoles compounds
Specifically carry out according to following step:
1. fortified phenol 4 and alpha-brominated ester react under salt of wormwood exists, and obtain α-phenoxy acid methyl esters 5, its structural formula is wherein said fortified phenol: alpha-brominated ester: the mol ratio of salt of wormwood is 1:1-5:1-5, preferred 1:1.1:2; Wherein said alkali is salt of wormwood, sodium carbonate, sodium hydride, preferred salt of wormwood; Wherein said temperature of reaction is-40 DEG C-80 DEG C, preferably 65 DEG C; Reaction times is 1-24 hour, preferably 12 hours; The substituent R of wherein said replacement aldehyde 1, R 2for halogen atom (fluorine, chlorine, bromine), methyl, methoxyl group, hydroxyl, nitro etc.; R 4for hydrogen, straight chain or C 1-C 5branched-chain alkyl.
2. α-phenoxy acid methyl esters 5 obtains α-phenoxy acid formic acid 6 in lithium hydroxide basic Water Under solution, and its structural formula is wherein said replacement α-phenoxy acid methyl esters 5: lithium hydroxide mol ratio is 1:1-10, preferred 1:5; Wherein said temperature of reaction is-40 DEG C-80 DEG C, preferably 25 DEG C; Reaction times is 1-24 hour, preferably 2 hours.
3. α-phenoxy acid formic acid 6 is with dimethyl azanol hydrochloride condensation under EDC/HOBt effect, and obtain α-phenoxy group acid amides 7, structural formula is wherein said replacement α-phenoxy acid: dimethyl azanol hydrochloride: the mol ratio of HOBt:EDC:N-methylmorpholine is 1:1-5:1-5:1-10, preferred 1:1.1:1.1:1.1:1.5.Wherein said temperature of reaction is-40 DEG C-80 DEG C, preferably 25 DEG C; Reaction times is 1-24 hour, preferably 10 hours.
4. α-phenoxy group acid amides 7 is obtained by reacting corresponding α-phenoxy group aldehyde 8 under the effect of Lithium Aluminium Hydride, and its structural formula is wherein said replacement α-phenoxy group acid amides: the mol ratio of Lithium Aluminium Hydride is 1:1-3, preferred 1:1.8; Wherein said temperature of reaction is-80 DEG C-80 DEG C, preferably-78 DEG C; Reaction times is 1-24 hour, preferably 5 hours.
5. under normal temperature condition, α-phenoxy group aldehyde 8 with at K 2cO 3issue hair tonic as alkali condition to answer, raw corresponding alkynes 9, its structural formula is wherein aldehyde: k 2cO 3mol ratio be 1:1-5:1-200, preferred 1:1.1:12; Wherein said temperature of reaction is-40 DEG C-80 DEG C, preferably 0 DEG C-25 DEG C; Reaction times is 1-24 hour, preferably 10 hours.
(6) alkynes 9 and azide compounds are at CuSO 45H 2clickChemistry occurs under the effect of O and sodium ascorbate and is obtained by reacting 1,2,3-triazoles compounds 10, its structural formula is wherein said alkynes 2: nitrine: Cu 2sO 45H 2o: the mol ratio of sodium ascorbate is 1:1-3:1-5:1-5, preferred 1:1.2:3:3; Wherein said temperature of reaction is-40 DEG C-80 DEG C, preferably 0 DEG C-25 DEG C; Reaction times is 1-24 hour, preferably 3 hours; Wherein, R 3be 3,4-(methyne dioxy) benzyl, benzyl, substituted benzyl, thiophene etc.
As X=N
R 1, R 2=X (F, Cl, Br), Me, MeO, OH, NO 2; R 4=H, C 1-C 5straight or branched alkyl;
The synthetic method of reaction formula 2-2:II class 1,2,3-triazoles compounds
Specifically carry out according to following step:
(1) replace fluorobenzene 11 with amino acid/11 2 under the effect of salt of wormwood, obtain α-anilino acid formic acid 13, its structural formula is wherein said replacement fluorobenzene: amino acid: the mol ratio of salt of wormwood is 1:1-5:1-5, preferred 1:1.2:2; Wherein said alkali is salt of wormwood, sodium carbonate, sodium hydride, preferred salt of wormwood; Wherein said temperature of reaction is-40 DEG C-80 DEG C, preferably: 80 DEG C; Reaction times is 1-24 hour, preferably 12 hours; The substituent R of wherein said replacement aldehyde 1, R 2for halogen atom (fluorine, chlorine, bromine), methyl, methoxyl group, hydroxyl, nitro etc.; R 4for hydrogen, straight chain or C 1-C 5branched-chain alkyl.
(2) compound 13 is to the synthetic method of the synthesis reference above-claimed cpd 6 to 10 of compound 17.
Three, the synthetic method of III class 1,2,3-triazoles compounds
R 1,R 2＝F,Cl,Br,Me,MeO,OH,NO 2；
R 4=H, straight chain or C 1-C 5branched-chain alkyl; X=O, N;
The synthetic method of reaction formula 3:III class 1,2,3-triazoles compounds
Specifically carry out according to following step:
(1) α-benzene oxygen (amine) base acid formic acid 6 is with ynamine condensation under EDC/HOBt effect, and obtain corresponding alkynes 18, structural formula is wherein said replacement α-benzene oxygen (amine) base acid: ynamine: the mol ratio of HOBt:EDC:N, N-diisopropylethylamine is 1:1-5:1-5:1-10, preferred 1:1.1:1.1:1.1:3.Wherein said temperature of reaction is-40 DEG C-80 DEG C, preferably 25 DEG C; Reaction times is 1-24 hour, preferably 12 hours.The substituent R of wherein said replacing acid 1, R 2for halogen atom (fluorine, chlorine, bromine), methyl, methoxyl group, hydroxyl, nitro etc.; R 4for hydrogen, straight chain or C 1-C 5branched-chain alkyl.
(2) compound alkynes 18 is at CuSO 45H 2with azide compounds, ClickChemistry occurs under the effect of O and sodium ascorbate and be obtained by reacting 1,2,3-triazoles compounds 19, its structural formula is wherein said alkynes 18: nitrine: Cu 2sO 45H 2o: the mol ratio of sodium ascorbate is 1:1-3:1-5:1-5, preferred 1:1.2:3:3; Wherein said temperature of reaction is-40 DEG C-80 DEG C, preferably 0 DEG C-25 DEG C; Reaction times is 1-24 hour, preferably 2 hours; Wherein, R 3be 3,4-(methyne dioxy) benzyl, benzyl, substituted benzyl, thiophene etc.
Advantage of the present invention: synthesized the 1,2,3-triazoles compounds of a series of structure novel by ClickChemistry method.Certain restraining effect that these compounds show DU-145 (Human Prostate Cancer Cells), Hela (cervical cancer cell), SH-SY5Y (neuroblastoma cell), K562 (chronic myeloid leukemia cell), K562/ADR (adriamycin-resistant chronic myeloid leukemia cell) 5 kinds of cancer cells.
Embodiment
Describe the present invention below in conjunction with embodiment, 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 one: the preparation of 2,4 dichloro benzene first alkynes
Take 2,4 dichloro benzene formaldehyde (202.6mg, 1.2mmol) and add solvent methanol (5mL), then take salt of wormwood (325.5mg, 2.3mmol, 2eq); Add (256mg, 1.3mmol, 1.2eq), reacts 10 hours.Reactant is concentrated, removing methyl alcohol; Add H 2o (15mL) and ethyl acetate (5mL) are dissolved, with ethyl acetate (30mL × 3) extraction, and the saturated NaHCO of organic phase 3solution (30mL), H 2o (25mL × 2), saturated nacl aqueous solution (30mL × 1) wash; And by appropriate anhydrous sodium sulfate drying organic phase.Concentrated, then carry out column chromatography purification [V (ethyl acetate): V (sherwood oil)=1:50], obtain pale pink solid 146mg, productive rate 74%. 1HNMR(300MHz,CDCl 3):δ7.45(d,J＝10.35Hz,1H),7.22(dd,J＝8.04Hz,1H),3.41(s,1H).
The preparation of step 2: 1-[3,4-(methylene-dioxy) benzyl]-4 – (2,4 dichloro benzene base)-1,2,3-triazoles
Weigh Compound 2.4-dichlorobenzene first alkynes (81.6mg, 0.5mmol) drops in round-bottomed flask; Weigh Compound 3,4-methylenedioxy benzyl nitrine (120mg, 0.68mmol, 1.4eq) drops in round-bottomed flask again; Add dimethyl sulfoxide (DMSO) (0.2mL); Measure the solution trimethyl carbinol (4mL) and H 2o (2mL) instills in mixture; After take catalyzer pentahapto brochantite (390mg); Take SODIUM ASCORBATE (290mg) again.Muddiness is become, in yellow from clarification.Stirring at normal temperature 5 hours, carries out aftertreatment to experiment, under agitation adds frozen water (15mL), and cancellation is reacted; Extract by ethyl acetate (30mL × 3); Organic phase H 2o (25mL × 2), saturated nacl aqueous solution (30mL × 2) wash; And by appropriate anhydrous sodium sulfate drying organic phase; Filter and concentrate, become solid, in brown, column chromatography purification [V (methylene dichloride): V (sherwood oil)=1:1], obtains white solid 125.0mg, productive rate 75%. 1HNMR(300MHz,CDCl 3):δ8.20(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). 13CNMR(75MHz,CDCl 3):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/z347(M-1)。
Step one: the preparation of 3,4-dichlorobenzene first alkynes
Method is with example 1 step one
Obtain faint yellow solid, productive rate 58%. 1HNMR(300MHz,CDCl 3):δ3.14(s,1H),7.26-7.41(m,2H),7.57(d,J＝1.17Hz,1H)。
The preparation of step 2: 1-[3,4-(methylene-dioxy) benzyl]-4 – (3,4-dichlorophenyl)-1,2,3-triazoles
Method is with example 1 step 2
Obtain white solid, productive rate 82%. 1HNMR(300MHz,DMSO-d 6):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). 13CNMR(75MHz,DMSO-d 6):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/z349(M+1)。
Step one: the preparation of 3.4-dimethoxy benzene first alkynes
Method is with example 1 step one
Obtain white solid, productive rate 92%. 1hNMR (300MHz, CDCl 3): 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: 1-[3,4-(methylene-dioxy) benzyl]-4 – (3,4-Dimethoxyphenyl) preparation of-1,2,3-triazoles
Method is with example 1 step 2
Obtain micro-yellow solid, productive rate 96%. 1HNMR(300MHz,CDCl 3):δ7.60(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). 13CNMR(75MHz,CDCl 3):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/z340(M+1)。
Embodiment 4:
The preparation of 1-(thiophene-1-methyl)-4-(3,4-Dimethoxyphenyl)-1,2,3-triazoles (3d)
Step:
Method is with example 3
Obtain white solid, productive rate 85%. 1HNMR(300MHz,CDCl 3):δ7.68(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). 13CNMR(75MHz,CDCl 3):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/z301.85(M+1).
Embodiment 5:
The preparation of 1-[3,4-(methylene-dioxy) benzyl]-4 – (2-nitrophenyl)-1,2,3-triazoles (3e)
Step one: the preparation of 2-nitrobenzoyl alkynes
Taking Ortho Nitro Benzaldehyde (202mg, 1.33mmol) drops in round-bottomed flask, adds methyl alcohol (10mL); Taking salt of wormwood (370mg, 2.6mmol, 2eq) again drops in mixture, adds (306mg, 1.6mmol, 1.2eq), reacts concentrated after 8 hours; Add H 2o (15mL), ethyl acetate (40mL × 3) extracts; The saturated NaHCO of organic phase 3solution (40mL), H 2o (40mL × 3), saturated nacl aqueous solution (30mL) wash; And use appropriate anhydrous sodium sulfate drying; Concentrated, then carry out column chromatography purification [V (ethyl acetate): V (sherwood oil)=1:15], obtain white solid 160mg, productive rate 82%. 1HNMR(300MHz,CDCl 3):δ8.05(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).
The preparation of step 2: 1-[3,4-(methylene-dioxy) benzyl]-4 – (2-nitrophenyl)-1,2,3-triazoles
Take 2-nitrobenzoyl alkynes (66mg, 0.45mmol), 3,4-methylenedioxy benzyl nitrine (100mg, 0.56mmol, 1.2eq); Add dimethyl sulfoxide (DMSO) (0.5mL), the trimethyl carbinol (3mL) and H 2o (1.5mL) instills in mixture; Take copper sulfate (360mg) again, SODIUM ASCORBATE (270mg), stirring at normal temperature 6 hours, carries out aftertreatment to experiment, under agitation adds frozen water (15mL), extracts with methylene dichloride (30mL × 3); Organic phase H 2o (25mL × 2), saturated nacl aqueous solution (30mL × 2) wash; And filter by appropriate anhydrous sodium sulfate drying organic phase and concentrate, column chromatography purification [V (ethyl acetate): V (sherwood oil)=1:3], obtains micro-yellow solid 120mg, productive rate 82%. 1HNMR(300MHz,CDCl 3):δ8.02(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). 13CNMR(75MHz,CDCl 3):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-triazoles (3g)
The preparation of the chloro-4-benzoxybenzaldehyde of step one: 3-
Take 3-chloro-4-hydroxyl phenyl aldehyde (513.3mg, 3.3mmol), take salt of wormwood (923.2mg again, 6.7mmol, 2eq) drop in there-necked flask, add solvent acetone (25mL), after 15min, measure cylite (677.0mg, 3.9mmol, 1.2eq) to instill in mixture.Reflux, reacts 6 hours.The mixture of muddiness is filtered; Filtrate is concentrated; Add H 2o (25mL) and ethyl acetate are dissolved; Extract by ethyl acetate (40mL × 3); Organic phase H 2o (30mL × 2), saturated nacl aqueous solution (30mL × 2) wash; And by appropriate anhydrous sodium sulfate drying organic phase; Concentrated, become solid; Carry out column chromatography purification [V (ethyl acetate): V (sherwood oil)=1:8] again.Obtain flocculence white solid 532mg, productive rate 66%. 1HNMR(300MHz,CDCl 3):δ5.26(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)。
The preparation of step 2: 3-chloro-4-benzyloxy benzene first alkynes
Method is with example 1 step one
Obtain faint yellow solid, productive rate 99%. 1HNMR(300MHz,CDCl 3):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)。
The preparation of step 3: 1-[3,4-(methylene-dioxy) benzyl]-4-(the chloro-4-benzyloxy-phenyl of 3-)-1,2,3-triazoles (3f)
Method is with example 1 step 2
Obtain white solid, productive rate 97%. 1HNMR(300MHz,DMSO-d 6):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). 13CNMR(75MHz,DMSO-d 6):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.
The preparation of step 4: 1-[3,4-(methylene-dioxy) benzyl]-4-(3-chloro-4-hydroxyl phenyl)-1,2,3-triazoles (3g)
Take 1-[3,4-(methylene-dioxy) benzyl]-4-(the chloro-4-benzyloxy-phenyl of 3-)-1,2,3-triazoles (81mg, 0.2mmol), add anhydrous methanol (15mL).Add several vitriol oils.Taking palladium carbon (15mg) drops in mixture, plugs hydrogen balloon.React solution after 3 hours and dissolve change clarification gradually.React 24 hours, aftertreatment is carried out to experiment, suction filtered through kieselguhr; Concentrated, add H 2o (5mL), adds NaOH (1mol/L) and is adjusted to alkalescence; Extract by ethyl acetate (30mL × 3); Organic phase H 2o (25mL × 2), saturated nacl aqueous solution (30mL × 2) wash; And by appropriate anhydrous sodium sulfate drying organic phase; Carry out column chromatography purification [V (methylene dichloride): V (methyl alcohol)=150:1], obtain micro-yellow solid 51.6mg, productive rate 82%. 1HNMR(300MHz,DMSO-d 6):δ5.50(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). 13CNMR(75MHz,DMSO-d 6):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/z330(M+1).
Embodiment 7:
The preparation of 4-[(2,4 dichloro benzene oxygen base) the third-1-base]-1-[3,4-(methylene-dioxy) benzyl] 1,2,3-triazoles (10a)
The preparation of step one: 2-(2,4 dichloro benzene oxygen)-methyl-butyrate
Take 2,4-chlorophenesic acid (815mg, 5mmol) in 100mL round-bottomed flask, add Anhydrous potassium carbonate (1.38g, 10.0mmol, 2eq), acetone (30mL) and 2-bromide methyl butyrate (995.6mg, 5.5mmol, 1.1eq), reflux 12 hours.Reactant is cooled to room temperature, suction filtration removes solid, water (30mL) will be added again after filtrate evaporate to dryness, be extracted with ethyl acetate (50mL × 3), combining extraction liquid uses water (20mL × 2) and saturated aqueous common salt (20mL) washing respectively, and anhydrous sodium sulphate dry filter concentrates, and crude product is through silica gel column chromatography separating purification [V (ethyl acetate): V (sherwood oil)=1:8], obtain 1.22g, productive rate 93%. 1HNMR(400MHz,CDCl 3):δ7.38(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).
The preparation of step 2: 2-(2,4 dichloro benzene oxygen)-butyric acid
Ester 2-(2,4 dichloro benzene oxygen)-methyl-butyrate (789mg, 3mmol) is dissolved in methyl alcohol (10mL) and water (10mL), adds lithium hydroxide (359.1mg, 15mmol, 5eq), stirring at room temperature 2h.Steam except after methyl alcohol, with dilute hydrochloric acid regulator solution pH to 2-3, have solid to separate out, suction filtration, washing, dry, obtain white solid, productive rate 85%; 1hNMR (500MHz, CDCl 3): δ 7.39 (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).
The preparation of step 3: 2-(2,4 dichloro benzene oxygen base)-N-methoxy-. N-methyl butyramide
Take that 2-(2,4 dichloro benzene oxygen)-butyric acid (540mg, 2.18mmol) drops in there-necked flask, add methylene chloride (15mL); Take HOBt (330mg, 2.4mmol, 1.2eq), EDCHCl (511mg, 2.67mmol, 1.2eq), N, O-dimethyl hydroxyl hydrochloride (266mg, 2.73mmol, 1.2eq), stirring at room temperature is after 30 minutes, and ice bath cools, then adds N-methylmorpholine (0.8mL, 7.25mmol, 3eq).React concentrated after 10 hours, obtain weak yellow liquid.Add 1NHCl, extract by ethyl acetate (50mL × 3); Organic phase 1NHCl (25mL × 2), H 2o (25mL × 2), saturated nacl aqueous solution (30mL × 2) wash; And by appropriate anhydrous sodium sulfate drying organic phase; Column chromatography purification [V (ethyl acetate): V (sherwood oil)=1:5], obtains weak yellow liquid 571mg, productive rate 90%. 1HNMR(300MHz,CDCl 3):δ7.36(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).
The preparation of step 4: 2-(2,4 dichloro benzene oxygen base) butyraldehyde
Take Lithium Aluminium Hydride (125mg, 3.29mmol, 1.7eq) to drop in 50mL round-bottomed flask, add tetrahydrofuran (THF) (20mL); Taking 2-(2,4 dichloro benzene oxygen base)-N-methoxy-. N-methyl butyramide (571mg, 1.96mmol) adds in flask, reacts 5 hours.In solution, add 1NHCl (20mL), extract by ethyl acetate (50mL × 3); Organic phase saturated nacl aqueous solution (30mL × 2) washs; And by appropriate anhydrous sodium sulfate drying organic phase; Carry out column chromatography purification [V (ethyl acetate): V (sherwood oil)=1:5] after concentrated, obtain weak yellow liquid 350mg, productive rate 77%. 1HNMR(300MHz,CDCl 3):δ9.71(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).
The preparation of step 5: 3-(2,4 dichloro benzene oxygen base) pentyne
Weigh Compound 2-(2,4 dichloro benzene oxygen base) butyraldehyde (286mg, 1.2mmol) is dissolved in anhydrous methanol (10mL), then takes salt of wormwood (345mg, 2.5mmol, 2eq), compound (271.6mg, 1.4mmol, 1.1eq) instills in bottle.Coreaction 20 hours, carries out aftertreatment to reaction, is concentrated by mixture; Add H 2o and acetic acid ethyl dissolution, extract by ethyl acetate (30mL × 3); The saturated NaHCO of organic phase 3solution (40mL), H 2o (40mL × 3), saturated nacl aqueous solution (30mL) wash; And by appropriate anhydrous sodium sulfate drying organic phase; Column chromatography purification [V (ethyl acetate): V (sherwood oil)=1:200] is carried out after concentrated, obtain weak yellow liquid 152mg, productive rate 66%.. 1HNMR(300MHz,CDCl 3):δ7.37(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).
The preparation of step 6: 4-[(2,4 dichloro benzene oxygen base) the third-1-base]-1-[3,4-(methylene-dioxy) benzyl]-1,2,3-triazoles
Taking 3-(2,4 dichloro benzene oxygen base) pentyne (93.0mg, 0.41mmol) drops in round-bottomed flask; Weigh Compound 3,4-methylenedioxy benzyl nitrine (88mg, 0.5mmol, 1.2eq) drops in round-bottomed flask again; Add dimethyl sulfoxide (DMSO) (0.2mL); Measure the solution trimethyl carbinol (4mL) and H 2o (2mL) instills in mixture; After take catalyzer cupric sulfate pentahydrate (402mg), SODIUM ASCORBATE (307mg), stirring at normal temperature 5 hours.Add frozen water (15mL), cancellation is reacted; Extract by ethyl acetate (30mL × 3); Organic phase saturated nacl aqueous solution (30mL × 2) washs; And by appropriate anhydrous sodium sulfate drying organic phase; Filter and concentrate, column chromatography purification [V (ethyl acetate): V (sherwood oil)=1:5], obtains white solid 145mg, productive rate 87%. 1HNMR(300MHz,CDCl 3):δ7.39(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). 13CNMR(75MHz,CDCl 3):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/z406(M+1).
Embodiment 8:
The preparation of 4-[(2,4 dichloro benzene oxygen base) the third-1-base]-1-(thiophene-1-methyl) 1,2,3-triazoles (10b)
Step:
Method is with example 7
Obtain white solid, productive rate 96%. 1HNMR(400MHz,CDCl 3):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). 13CNMR(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/z367.8(M+1).
Embodiment 9:
The preparation of 4-[(2,4-dibromo-phenoxy base) the third-1-base]-1-[3,4-(methylene-dioxy) benzyl] 1,2,3-triazoles (10c)
The preparation of step one: 2-(2,4-dibromo-phenoxy)-methyl-butyrate
Method is with example 7 step one
Obtain oily liquids, productive rate 92%. 1HNMR(400MHz,CDCl 3):δ7.68(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).
The preparation of step 2: 2-(2,4-dibromo-phenoxy)-butyric acid
Method is with example 7 step 2
Obtain white solid, productive rate 93%; 1hNMR (400MHz, CDCl 3): 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).
The preparation of step 3: 2-(2,4-dibromo-phenoxy base)-N-methoxy-. N-methyl butyramide
Method is with example 7 step 3
Obtain weak yellow liquid, productive rate 91%. 1HNMR(300MHz,CDCl 3):δ7.67(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).
The preparation of step 4: 2-(2,4-dibromo-phenoxy base) butyraldehyde
Method is with example 7 step 4
Obtain weak yellow liquid, productive rate 83%. 1HNMR(300MHz,CDCl 3):δ9.70(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).
The preparation of step 5: 3-(2,4-dibromo-phenoxy base) pentyne
Method is with example 7 step 5
Obtain weak yellow liquid, productive rate 89%. 1HNMR(300MHz,CDCl 3):δ7.67(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).
The preparation of step 6: 4-[(2,4-dibromo-phenoxy base) the third-1-base]-1-[3,4-(methylene-dioxy) benzyl] 1,2,3-triazoles
Method is with example 7 step 6
Obtain white solid, productive rate 84%. 1HNMR(300MHz,CDCl 3):δ7.60(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). 13CNMR(75MHz,CDCl 3):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/z495.7(M+1).
Embodiment 10:
The preparation of 4-[(2,4-dibromo-phenoxy base) the third-1-base]-1-benzyl-1,2,3-triazoles (10d)
Step:
Method is with example 9
Obtain white solid, productive rate 98%. 1HNMR(300MHz,CDCl 3):δ7.60(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). 13CNMR(75MHz,CDCl 3):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/z451.70(M+1).
Embodiment 11:
The preparation of 4-[(2,4 difluorobenzene oxygen base) the third-1-base]-1-[3,4-(methylene-dioxy) benzyl] 1,2,3-triazoles (10e)
The preparation of step one: 2-(2,4 difluorobenzene oxygen)-methyl-butyrate
Method is with example 7 step one
Obtain oily liquids, productive rate 94%. 1HNMR(400MHz,CDCl 3):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).
The preparation of step 2: 2-(2,4 difluorobenzene oxygen)-butyric acid
Method is with example 7 step 2
Obtain white solid, productive rate 89%; 1hNMR (400MHz, CDCl 3): δ 7.00-6.95 (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).
The preparation of step 3: 2-(2,4 difluorobenzene oxygen base)-N-methoxy-. N-methyl butyramide
Method is with example 7 step 3
Obtain weak yellow liquid, productive rate 87%. 1HNMR(300MHz,CDCl 3):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).
The preparation of step 4: 2-(2,4 difluorobenzene oxygen base) butyraldehyde
Method is with example 7 step 4
Obtain weak yellow liquid, productive rate 68%. 1HNMR(300MHz,CDCl 3):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).
The preparation of step 5: 3-(2,4 difluorobenzene oxygen base) pentyne
Method is with example 7 step 5
Obtain weak yellow liquid, productive rate 49%. 1HNMR(300MHz,CDCl 3):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).
The preparation of step 6: 4-[(2,4 difluorobenzene oxygen base) the third-1-base]-1-[3,4-(methylene-dioxy) benzyl] 1,2,3-triazoles
Method is with example 7 step 6
Obtain white solid, productive rate 92%. 1HNMR(300MHz,CDCl 3):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). 13CNMR(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/z373.9(M+1).
Embodiment 12:
The preparation of 4-[(2,4 difluorobenzene oxygen base) the third-1-base]-1-benzyl-1,2,3-triazoles (10f)
Step:
Method is with example 11
Obtain white solid, productive rate 97%. 1HNMR(300MHz,CDCl 3):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). 13CNMR(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/z329.9(M+1).
Embodiment 13:
The preparation of 4-[(2-oil of mirbane) third-1-base]-1-(thiophene-1-methyl) 1,2,3-triazoles (17a)
The preparation of step one: 2-(2-nitro-phenylamino)-butyric acid
Take C4H9NO2 (1.24g, 12mmol, 1.2eq) to be dissolved in DMF (60mL), then add K 2cO 3(2.76g, 19.9mmol, 2.0eq), finally add the fluoro-2-oil of mirbane (1.41g, 10.0mmol) of 1-, solution is heated to 80 DEG C.React after 12 hours, in reaction solution, add dilute hydrochloric acid and be extracted with ethyl acetate (80mL × 3), merge organic phase and wash with dilute hydrochloric acid (50mL × 3) washing, saturated nacl aqueous solution (50mL × 2); And by appropriate anhydrous sodium sulfate drying organic phase; Filter and concentrate.The yellow-brown solid 1.45g of methylene dichloride recrystallization, productive rate 65%. 1HNMR(300MHz,CDCl 3):δ8.31(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).
The preparation of step 2: 2-(2-nitro-phenylamino)-N-methoxy-. N-methyl butyramide
Method is with example 7 step 3
Obtain yellow solid, productive rate 88%. 1HNMR(300MHz,CDCl 3):δ8.47(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).
The preparation of step 3: 2-(2-nitro-phenylamino) butyraldehyde
Method is with example 7 step 4
Obtain yellow liquid, productive rate 75%. 1HNMR(300MHz,CDCl 3):δ9.59(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).
The preparation of step 4: 2-(2-nitro-phenylamino) butine
Method is with example 7 step 5
Obtain yellow liquid, productive rate 50%. 1HNMR(300MHz,CDCl 3):δ8.19(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).
The preparation of step 5: 4-[(2-oil of mirbane) third-1-base]-1-(thiophene-1-methyl) 1,2,3-triazoles
Method is with example 7 step 6
Obtain yellow solid, productive rate 85%. 1HNMR(300MHz,CDCl 3):δ8.34(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). 13CNMR(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-oil of mirbane amido) butyryl] } preparation of methylamino-1-[3,4-(methylene-dioxy) benzyl]-1,2,3-triazoles (19a)
The preparation of step one: 2-(2-nitro-phenylamino)-butyric acid
With example 13 step one
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) be dissolved in DMF (10mL), add propargylamine (95mg, 1.7mmol, 1.3eq), stirring at room temperature is after 30 minutes, ice bath cools, add diisopropyl ethyl amine (0.7mL again, 4.24mmol, 3.0eq), ice bath is removed after 20 minutes, stirred overnight at room temperature. reaction solution is poured into saturated ammonium chloride solution (30mL), extraction into ethyl acetate (30mL × 3), the extraction liquid water (30mL × 2) merged and saturated aqueous common salt (15mL) wash respectively, anhydrous sodium sulfate drying, filtering and concentrating, crude product is through silica gel column chromatography separating purification [V (ethyl acetate): V (sherwood oil)=1:5], obtain yellow solid 340mg, productive rate 96%. 1HNMR(300MHz,CDCl 3):δ8.23(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-oil of mirbane amido) butyryl] } preparation of methylamino-1-[3,4-(methylene-dioxy) benzyl]-1,2,3-triazoles
Weigh Compound 1-propine-N-(2-nitro-phenylamino)-butyramide (84.0mg, 0.32mmol) drops in round-bottomed flask; Weigh Compound 3,4-methylenedioxy benzyl nitrine (69mg, 0.39mmol, 1.2eq) drops in round-bottomed flask again; Add dimethyl sulfoxide (DMSO) (0.2mL); Measure the solution trimethyl carbinol (4mL) and H 2o (2mL) instills in mixture; After take catalyzer cupric sulfate pentahydrate (256mg), SODIUM ASCORBATE (194mg), stirring at normal temperature 5 hours.Add frozen water (15mL), cancellation is reacted; Extract by ethyl acetate (30mL × 3); Organic phase saturated nacl aqueous solution (30mL × 2) washs; And by appropriate anhydrous sodium sulfate drying organic phase; Filter and concentrate, column chromatography purification [V (ethyl acetate): V (sherwood oil)=1:1], obtains white solid 116mg, productive rate 83%. 1HNMR(400MHz,CDCl 3):δ8.16(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). 13CNMR(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/z437(M-1).
Embodiment 15:
4-{2-[(2-oil of mirbane amido) butyryl] } preparation of methylamino-1-benzyl-1,2,3-triazoles (19b)
Step:
Method is with example 14
Obtain white solid, productive rate 82%. 1HNMR(400MHz,CDCl 3):δ8.15(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). 13CNMR(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/z417(M+Na)
Embodiment 16:
4-{2-[(2-oil of mirbane amido) butyryl] } preparation of methylamino-1-[(4-methoxyl group) benzyl] 1,2,3-triazoles (19c)
Step:
Method is with example 14
Obtain yellow solid, productive rate 87%. 1HNMR(300MHz,CDCl 3):δ8.12(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). 13CNMR(75MHz,CDCl 3):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/z424.9(M+1).
Embodiment 17:
4-{2-[(2-oil of mirbane amido) butyryl] } preparation of methylamino-1-(4-luorobenzyl) 1,2,3-triazoles (19d)
Step:
Method is with example 14
Obtain yellow solid, productive rate 90%. 1HNMR(300MHz,CDCl 3):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). 13CNMR(75MHz,CDCl 3):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/z412.9(M+1).
Embodiment 18:
4-{2-[(2-oil of mirbane amido) butyryl] } preparation of methylamino-1-(thiophene-1-methyl)-1,2,3-triazoles (19e)
Step:
Method is with example 14
Obtain yellow solid, productive rate 94%. 1HNMR(300MHz,CDCl 3):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). 13CNMR(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/z400.85(M+1).
Embodiment 19:
4-{2-[(2,4 dichloro benzene oxygen base) butyryl] } preparation of methylamino-1-[3,4-(methylene-dioxy) benzyl]-1,2,3-triazoles (19f)
Step one, two:
With example 7 step one, two
Step 3: the preparation of 1-propine-N-2-(2,4 dichloro benzene oxygen)-butyramide
Method is with example 14 step 2
Obtain white solid, productive rate 90%. 1HNMR(300MHz,CDCl 3):δ7.40(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 dichloro benzene oxygen base) butyryl] } preparation of methylamino-1-[3,4-(methylene-dioxy) benzyl]-1,2,3-triazoles
Method is with example 14 step 3
Obtain white solid, productive rate 92%. 1HNMR(300MHz,CDCl 3):δ7.35-7.36(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). 13CNMR(75MHz,CDCl 3):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/z462.85(M+1).
Embodiment 20:
4-{2-[(2,4 dichloro benzene oxygen base) butyryl] } preparation of methylamino-1-[(4-methoxyl group) benzyl]-1,2,3-triazoles (19g)
Step:
Method is with example 19
Obtain white solid, productive rate 92%. 1HNMR(300MHz,CDCl 3):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). 13CNMR(75MHz,CDCl 3):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/z448.85(M+1).
Embodiment 21:
4-{2-[(2,4 dichloro benzene oxygen base) butyryl] } preparation of methylamino-1-[(4-fluorine) benzyl]-1,2,3-triazoles (19h)
Step:
Method is with example 19
Obtain white solid, productive rate 92%. 1HNMR(300MHz,CDCl 3):δ7.36(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). 13CNMR(75MHz,CDCl 3):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/z436.80(M+1).
Embodiment 22:
4-{2-[(2,4 dichloro benzene oxygen base) butyryl] } preparation of methylamino-1-(thiophene-1-methyl)-1,2,3-triazoles (19i)
Step:
Method is with example 19
Obtain white solid, productive rate 96%. 1HNMR(300MHz,CDCl 3):δ7.44(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). 13CNMR(75MHz,CDCl 3):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/z434.80(M+1).
Embodiment 23:
4-{2-[(2,4-dibromo-phenoxy base) butyryl] } preparation of methylamino-1-[3,4-(methylene-dioxy) benzyl]-1,2,3-triazoles (19j)
Step one, two:
With example 9 step one, two
Step 3: the preparation of 1-propine-N-2-(2,4-dibromo-phenoxy)-butyramide
Method is with example 14 step 2
Obtain white solid, productive rate 90%. 1HNMR(300MHz,CDCl 3):δ7.71(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-dibromo-phenoxy base) butyryl] } preparation of methylamino-1-[3,4-(methylene-dioxy) benzyl]-1,2,3-triazoles
Method is with example 14 step 3
Obtain white solid, productive rate 90%. 1HNMR(300MHz,CDCl 3):δ7.66(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). 13CNMR(75MHz,CDCl 3):δ9.48,26.11,35.39,54.71,81.61,102.10,109.16,109.27,114.36,115.07,116.27,122.41,122.60,128.71,132.05,136.47,145.38,148.77,148.99,153.55,171.13.MS(positive):m/z552.65(M+1).
Embodiment 24:
4-{2-[(2,4-dibromo-phenoxy base) butyryl] } preparation of methylamino-1-[(4-methoxyl group) benzyl]-1,2,3-triazoles (19k)
Step:
Method is with example 23
Obtain white solid, productive rate 93%. 1HNMR(300MHz,CDCl 3):δ7.65(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). 13CNMR(75MHz,CDCl 3):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/z538.70(M+1).
Embodiment 25:
4-{2-[(2,4-dibromo-phenoxy base) butyryl] } preparation of methylamino-1-[(4-fluorine) benzyl]-1,2,3-triazoles (19l)
Step:
Method is with example 23
Obtain white solid, productive rate 90%. 1HNMR(300MHz,CDCl 3):δ7.66(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). 13CNMR(75MHz,CDCl 3):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 oxygen base) butyryl] } preparation of methylamino-1-[3,4-(methylene-dioxy) benzyl]-1,2,3-triazoles (19m)
Step one, two:
With example 11 step one, two
Step 3: the preparation of 1-propine-N-2-(2,4 difluorobenzene oxygen)-butyramide
Method is with example 14 step 2
Obtain white solid, productive rate 85%. 1HNMR(300MHz,CDCl 3):δ6.78-6.97(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 oxygen base) butyryl] } preparation of methylamino-1-[3,4-(methylene-dioxy) benzyl]-1,2,3-triazoles
Method is with example 14 step 3
Obtain white solid, productive rate 90%. 1HNMR(300MHz,CDCl 3):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). 13CNMR(75MHz,CDCl 3):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/z430.85(M+1).
Embodiment 27:
4-{2-[(2,4 difluorobenzene oxygen base) butyryl] } preparation of methylamino-1-[(4-methoxyl group) benzyl]-1,2,3-triazoles (19n)
Step:
Method is with example 26
Obtain white solid, productive rate 90%. 1HNMR(300MHz,CDCl 3):δ7.36(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). 13CNMR(75MHz,CDCl 3):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/z416.90(M+1).
Embodiment 28:
4-{2-[(2,4 difluorobenzene oxygen base) butyryl] } preparation of methylamino-1-[(4-fluorine) benzyl]-1,2,3-triazoles (19o)
Step:
Method is with example 26
Obtain white solid, productive rate 91%. 1HNMR(300MHz,CDCl 3):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). 13CNMR(75MHz,CDCl 3):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/z404.90(M+1).
Embodiment 29:
4-{2-[(2,4 difluorobenzene oxygen base) propionyl] } preparation of methylamino-1-[(4-methoxyl group) benzyl]-1,2,3-triazoles (19p)
Step:
Method is with example 26
Obtain white solid, productive rate 90%. 1HNMR(300MHz,CDCl 3):δ7.38(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). 13CNMR(75MHz,CDCl 3):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/z402.90(M+1).
Embodiment 30:
4-{2-[(2,4 dichloro benzene oxygen base) propionyl] } preparation of methylamino-1-[(4-fluorine) benzyl]-1,2,3-triazoles (19q)
Step:
Method is with example 26
Obtain white solid, productive rate 96%. 1HNMR(300MHz,CDCl 3):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). 13CNMR(75MHz,CDCl 3):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/z390.90(M+1).
Embodiment 31:
4-{2-[(2,4 difluorobenzene oxygen base) isovaleryl] } preparation of methylamino-1-[(4-methoxyl group) benzyl]-1,2,3-triazoles (19r)
Step:
Method is with example 26
Obtain white solid, productive rate 85%. 1HNMR(300MHz,CDCl 3):δ7.41(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). 13CNMR(75MHz,CDCl 3):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/z430.90(M+1).
Embodiment 32:
4-{2-[(2,4 dichloro benzene oxygen base) isovaleryl] } preparation of methylamino-1-[(4-fluorine) benzyl]-1,2,3-triazoles (19s)
Step:
Method is with example 26
Obtain white solid, productive rate 90%. 1HNMR(300MHz,CDCl 3):δ7.44(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). 13CNMR(75MHz,CDCl 3):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/z418.90(M+1).
Embodiment 33:
4-{2-[(2,4 difluorobenzene oxygen base) valeryl] } preparation of methylamino-1-[(4-methoxyl group) benzyl]-1,2,3-triazoles (19t)
Step:
Method is with example 26
Obtain white solid, productive rate 90%. 1HNMR(300MHz,CDCl 3):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). 13CNMR(75MHz,CDCl 3):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/z430.90(M+1).
Embodiment 34:
4-{2-[(2,4 dichloro benzene oxygen base) valeryl] } preparation of methylamino-1-[(4-fluorine) benzyl]-1,2,3-triazoles (19u)
Step:
Method is with example 26
Obtain white solid, productive rate 90%. 1HNMR(300MHz,CDCl 3):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). 13CNMR(75MHz,CDCl 3):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/z418.85(M+1).
Embodiment
Antitumour activity measures
Be test cell strain Hela (cervical cancer cell), DU-145 (Human Prostate Cancer Cells), K562 (chronic myeloid leukemia cell), K562/ADR (adriamycin-resistant chronic myeloid leukemia cell), SH-SY5Y (neuroblastoma cell) 5 kinds of cancer cells, and with a normal cell Vero (African monkey nephrocyte) in contrast, mtt assay is used to carry out Anticancer Activity in vitro test, using 5-Fluorouracil as positive control to synthesized triazole derivative.The cancer cells of taking the logarithm vegetative period, the nutrient solution of centrifugal rear RPMI1640 or DMEM is diluted to 5 × 10 4individual/mL, is inoculated in 96 orifice plates.37 DEG C of overnight incubation, then add the sample of different concns, then hatch 72h, add the MTT solution (5mgmL of 10.0 μ L/well -1), after 37 DEG C of hatching 4h, every hole adds 100 μ LDMSO (dissolve purple formazan crystal).After 10 minutes, first shake for a moment, after orifice plate is placed on automatic microplate spectrophotometer, measure at 570nm and 630nm place and absorb angle value, and with Bliss method calculating half effective inhibition concentration (IC 50), often organize sample and carry out 3 parallel testings.
Determine 35 compounds of new synthesis to the inhibited proliferation of DU-145 (Human Prostate Cancer Cells), Hela (cervical cancer cell), SH-SY5Y (neuroblastoma cell), K562 (chronic myeloid leukemia cell), K562/ADR (adriamycin-resistant chronic myeloid leukemia cell) 5 kinds of cancer cells with mtt assay, the results are shown in Table 1.Test result shows, in I class 1,2,3-triazoles compounds, benzene ring substituents is electron-donating group, such as, when methoxyl group and hydroxyl, is conducive to improving its antitumour activity.In II class 1,2,3-triazoles compounds, when benzene ring substituents is chlorine, bromine, to surveyed 5 kinds of cancer cells, all there is certain anticancer activity.In III class 1,2,3-triazoles compounds, when benzene ring substituents is nitro, there is obvious restraining effect to SH-SY5Y clone; When substituting group is chlorine, bromine, to these four kinds of clones of DU-145, Hela, SH-SY5Y and K562, all there is certain restraining effect; Benzene ring substituents is fluorine, R 4during for sec.-propyl, to SH-SY5Y clone, there is good antitumour activity.Above-mentioned synthesized triazole class compounds and compound 19v contrast can initial guess, and left side heteroaryl structure is the necessary structure that 1,2,3-triazoles analog derivative has antitumour activity.
Table 11,2,3-triazole derivative antitumour activity test chart

Claims (3)

1. a 1,2,3-triazoles compounds, its general structure as shown in formula II,
Wherein R 1, R 2for halogen (chlorine, bromine), methyl, methoxyl group, hydroxyl; R 3be 3,4-(methyne dioxy) benzyl, benzyl, substituted benzyl, thiophene; R 4for hydrogen, straight chain or C 1-C 5branched-chain alkyl; X is oxygen, nitrogen.
2. the synthetic method of 1,2,3-triazoles compounds according to claim 1, is characterized in that carrying out according to following step:
I is as X=O
(1) fortified phenol and alpha-brominated ester react in the presence of a base, and obtain α-phenoxy acid methyl esters, its structural formula is wherein said fortified phenol: alpha-brominated ester: the mol ratio of salt of wormwood is 1:1-5:1-5; Wherein said alkali is salt of wormwood, sodium carbonate, sodium hydride; Wherein said temperature of reaction is-40 DEG C-80 DEG C; Reaction times is 1-24 hour; The substituent R of wherein said replacement aldehyde 1, R 2for halogen atom (fluorine, chlorine, bromine), methyl, methoxyl group, hydroxyl, nitro; R 4for hydrogen, straight chain or C 1-C 5branched-chain alkyl;
(2) α-phenoxy acid methyl esters obtains α-phenoxy acid formic acid in lithium hydroxide basic Water Under solution, and its structural formula is wherein said replacement α-phenoxy acid methyl esters: lithium hydroxide mol ratio is 1:1-10; Wherein said temperature of reaction is-40 DEG C-80 DEG C; Reaction times is 1-24 hour;
(3) α-phenoxy acid formic acid is with dimethyl azanol hydrochloride condensation under EDC/HOBt effect, and obtain α-phenoxy group acid amides, structural formula is wherein said replacement α-phenoxy acid: dimethyl azanol hydrochloride: the mol ratio of HOBt:EDC:N-methylmorpholine is 1:1-5:1-5:1-10; Wherein said temperature of reaction is-40 DEG C-80 DEG C; Reaction times is 1-24 hour.
(4) α-phenoxy group acid amides is obtained by reacting corresponding α-phenoxy group aldehyde under the effect of Lithium Aluminium Hydride, and its structural formula is wherein said replacement α-phenoxy group acid amides: the mol ratio of Lithium Aluminium Hydride is 1:1-3; Wherein said temperature of reaction is-80 DEG C-80 DEG C; Reaction times is 1-24 hour;
(5) under normal temperature condition, α-phenoxy group aldehyde with at K 2cO 3issue hair tonic as alkali condition to answer, raw corresponding α-phenoxy group alkynes, its structural formula is wherein aldehyde: mol ratio be 1:1-5:1-200; Wherein said temperature of reaction is-40 DEG C-80 DEG C; Reaction times is 1-24 hour;
(6) α-phenoxy group alkynes and azide compounds are at CuSO 4 .5H 2clickChemistry occurs under the effect of O and sodium ascorbate and is obtained by reacting Equations of The Second Kind 1,2,3-triazoles compounds, its structural formula is wherein said α-phenoxy group alkynes: nitrine: Cu 2sO 4 .5H 2o: the mol ratio of sodium ascorbate is 1:1-3:1-5:1-5; Wherein said temperature of reaction is-40 DEG C-80 DEG C; Reaction times is 1-24 hour; Wherein, R 3be 3,4-(methyne dioxy) benzyl, benzyl, substituted benzyl, thiophene;
II is as X=N
(1) replacement fluorobenzene and amino acid are under the effect of salt of wormwood, and obtain α-anilino acid formic acid, its structural formula is wherein said replacement fluorobenzene: amino acid: the mol ratio of salt of wormwood is 1:1-5:1-5, and wherein said alkali is salt of wormwood, sodium carbonate, sodium hydride; Wherein said temperature of reaction is-40 DEG C-80 DEG C; Reaction times is 1-24 hour; The substituent R of wherein said replacement aldehyde 1, R 2for halogen atom (fluorine, chlorine, bromine), methyl, methoxyl group, hydroxyl, nitro; R 4for hydrogen, straight chain or C 1-C 5branched-chain alkyl;
(2) α-anilino acid formic acid to the synthesis of Equations of The Second Kind 1,2,3-triazoles compounds with reference to the synthetic method of above-mentioned α-phenoxy acid formic acid to Equations of The Second Kind 1,2,3-triazoles compounds.
3. the synthetic method of 1,2,3-triazoles compounds according to claim 2:
As X=O
It is characterized in that wherein wherein said fortified phenol described in step (1): alpha-brominated ester: the mol ratio of salt of wormwood is 1:1.1:2; Wherein said alkali is salt of wormwood; Wherein said temperature of reaction is 65 DEG C; Reaction times is 12 hours;
α-phenoxy acid methyl esters is replaced: lithium hydroxide mol ratio is 1:5 described in step (2); Wherein said temperature of reaction is 25 DEG C; Reaction times is 2 hours;
Step replaces α-phenoxy acid described in (3): dimethyl azanol hydrochloride: the mol ratio of HOBt:EDC:N-methylmorpholine is 1:1.1:1.1:1.1:1.5; Wherein said temperature of reaction is 25 DEG C; Reaction times is 10 hours;
α-phenoxy group acid amides is replaced: the mol ratio of Lithium Aluminium Hydride is 1:1.8 described in step (4); Wherein said temperature of reaction is-78 DEG C; Reaction times is 5 hours;
α-phenoxy group aldehyde is replaced described in step (5): mol ratio be 1:1.1:12; Wherein said temperature of reaction is 0 DEG C-25 DEG C; Reaction times is 10 hours;
α-phenoxy group alkynes is replaced: nitrine: Cu described in step (6) 2sO 4 .5H 2o: the mol ratio of sodium ascorbate is 1:1.2:3:3; Wherein said temperature of reaction is 0 DEG C-25 DEG C; Reaction times is 3 hours;
As X=N
It is characterized in that the wherein replacement fluorobenzene described in step (1): amino acid: the mol ratio of salt of wormwood is 1:1.2:2; Wherein said alkali is salt of wormwood; Wherein said temperature of reaction is 80 DEG C; Reaction times is 12 hours;
α described in step (2)-anilino acid formic acid to the synthesis of Equations of The Second Kind 1,2,3-triazoles compounds with reference to the synthetic method of above-mentioned α-phenoxy acid formic acid to Equations of The Second Kind 1,2,3-triazoles compounds.
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