CN102408386B - Preparation method of 2,4-disubstituted-2H-1, 2, 3-triazole derivatives - Google Patents

Preparation method of 2,4-disubstituted-2H-1, 2, 3-triazole derivatives Download PDF

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CN102408386B
CN102408386B CN201110212052.1A CN201110212052A CN102408386B CN 102408386 B CN102408386 B CN 102408386B CN 201110212052 A CN201110212052 A CN 201110212052A CN 102408386 B CN102408386 B CN 102408386B
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benzyl
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triazole
propyl
bis
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CN102408386A (en
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江岳恒
阙利民
蔡彤�
林志刚
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ABA Chemicals Corp
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—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
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic System
    • C07F5/02—Boron compounds
    • C07F5/025—Boronic and borinic acid compounds

Abstract

The invention discloses a preparation method of 2,4-disubstituted-2H-1,2,3-triazole derivatives and particularly relates to a preparation method of 2-substituted-2H-1,2,3-triazole-4-carboxylic acid compounds and 2-substituted-2H-1,2,3-triazole-4-boric acid compounds. The preparation method is simple and feasible and the obtained compounds have high yield.

Description

Replace-2H-1 of 2,4-bis-, the preparation method of 2,3-triazole derivatives
Technical field
The present invention relates to organic synthesis intermediate preparing technical field, relate in particular to new compound 2, replace-2H-1 of 4-bis-, 2,3-triazole derivatives and preparation method thereof.Further, the present invention relates to new compound 2-replacement-2H-1,2,3-triazole-4-carboxylic acid and 2-replacement-2H-1,2,3-triazole-4-boric acid and preparation method thereof.
Background technology
Replace-2H-1 of 2,4-bis-, 2,3-triazole derivatives is the novel compound with huge exploitation value of a class.Compound take triazole as parent nucleus has potential using value widely, is the important intermediate of current many medicines, weedicide and agrochemical compound, is also pharmacophoric group main in a lot of drug molecules.
2-replacement-2H-1,2,3-triazole-4-carboxylic acid and 2-replacement-2H-1,2,3-triazole-4-boric acid is novel active intermediate, can be used as very important active precursor, in organic synthesis, is applied.
Summary of the invention
Goal of the invention: the object of the present invention is to provide a kind of novel 2, replace-2H-1 of 4-bis-, the preparation method of 2,3-triazole derivatives, further, the invention provides 2-replacement-2H-1,2,3-triazole-4-carboxylic acid and 2-replacement-2H-1, the preparation method of 2,3-triazole-4-boric acid.
Technical scheme: in order to realize foregoing invention object, the technical solution used in the present invention is as follows:
Replace-2H-1 of 2,4-bis-, the preparation method of 2,3-triazole derivatives, is characterized in that: replace-2H-1 of 2,4-bis-, 2,3-triazole derivatives has following structure:
Formula I
Wherein, R1 represents alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, Heterocyclylalkyl; R2 represents carboxyl or boronate.
When R2 is carboxyl, described 2, replace-2H-1 of 4-bis-, 2,3-triazole derivatives is 2-replacement-2H-1,2,3-triazole-4-carboxylic acid (formula II);
Formula II
Wherein, R1 represents alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, Heterocyclylalkyl.
When R2 is boronate, described 2, replace-2H-1 of 4-bis-, 2,3-triazole derivatives is 2-replacement-2H-1,2,3-triazole-4-boric acid (formula III).
Figure BDA0000078974510000022
Formula III
Wherein, R1 represents alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, Heterocyclylalkyl.
Compound formula II of the present invention can be prepared by compound formula VIII.
Figure BDA0000078974510000023
Formula VIII
Wherein, R1 represents alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, Heterocyclylalkyl.
The preparation method of compound formula VIII is described later in detail in applicant's No. 201110166067.9 patent application.
Compound formula VIII of the present invention is dissolved in mass volume ratio 1: 1～100, in preferably 1: 5～20 organic solvent, adds 0.1～50%, the preferably metal catalyst of 0.5～10% weight ratio, pass into hydrogen, maintain pressure 1～100atm, preferably 1～10atm, at 0～200 ℃, preferably 10～50 ℃, react 1～50 hour, at room temperature filter, be evaporated to dryly, enriched material obtains compound formula II through recrystallization;
Described organic solvent is the mixing of one or more arbitrary proportions in alcohols or fatty acid ester, comprise the mixing of one or more arbitrary proportions in methyl alcohol, ethanol, propyl alcohol, Virahol, propyl carbinol, the trimethyl carbinol, Pentyl alcohol, primary isoamyl alcohol, ethyl formate, propyl formate, butyl formate, methyl acetate, ethyl acetate, propyl acetate, butylacetate, isopropyl acetate, isobutyl acetate, pentyl acetate, Isoamyl Acetate FCC, methyl propionate, ethyl propionate, propyl propionate, butyl propionate and amyl propionate, ethyl acetate, methyl alcohol;
Described metal catalyst is that one or more in palladium metal, ruthenium, platinum are carried on to the catalyzer that the charge capacity made on gac, aluminum oxide or Zeolite support is 1～10%, preferably 5～10% palladium charcoal.
Reaction formula is as follows:
Figure BDA0000078974510000031
Compound formula I of the present invention can also be prepared by compound formula VI.
Figure BDA0000078974510000032
Formula VI
Wherein, R1 represents alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, Heterocyclylalkyl.
Compound formula VI of the present invention is dissolved in mass volume ratio 1: 2～20 ether, tetrahydrofuran (THF) or 1,4-dioxane, be cooled to-20～30 ℃, add isopropylmagnesium chloride-lithium chloride mixture, stir 0.5～5 hour, be cooled to-50～20 ℃, pass into carbon dioxide approximately 10～30 minutes, be warming up to room temperature, regulate behind pH=1～5 with hydrochloric acid, with organic solvent extraction, through anhydrous sodium sulphate or anhydrous magnesium sulfate drying, be evaporated to dryly, enriched material obtains compound formula II through recrystallization;
Compound formula VI of the present invention is dissolved in mass volume ratio 1: 2～20 ether, tetrahydrofuran (THF) or 1,4-dioxane, be cooled to-20～30 ℃, add isopropylmagnesium chloride-lithium chloride mixture, stir 0.5～5 hour, be cooled to-50～20 ℃, add compound boric acid ester (formula IX), stir 0.1～2 hour, be warming up to room temperature, regulate behind pH=1～5 with hydrochloric acid, with organic solvent extraction, through anhydrous sodium sulphate or anhydrous magnesium sulfate drying, be evaporated to dryly, enriched material obtains compound formula III through recrystallization;
Figure BDA0000078974510000041
Formula IX
Wherein, R3 represents the straight or branched alkyl of C1～C5, comprises methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, n-pentyl, isopentyl.
The mol ratio of compound formula VI of the present invention and isopropylmagnesium chloride-lithium chloride mixture is 1: 0.8～2.0, preferably 1: 1.2～1.5; The mol ratio of compound formula VI and boric acid ester (formula IX) or carbonic acid gas is 1: 1～10, preferably 1: 1.2～2; Described organic solvent is the mixing of one or more arbitrary proportions in fatty acid ester or ethers, comprise the mixing of one or more arbitrary proportions in ethyl formate, propyl formate, butyl formate, methyl acetate, ethyl acetate, propyl acetate, butylacetate, isopropyl acetate, isobutyl acetate, pentyl acetate, Isoamyl Acetate FCC, methyl propionate, ethyl propionate, propyl propionate, butyl propionate and amyl propionate, ether, propyl ether, isopropyl ether, methyl tertiary butyl ether, ethyl acetate, methyl tertiary butyl ether.
Compound formula VI reacts with grignard reagent isopropylmagnesium chloride-lithium chloride mixture generation format exchange, generates compound formula VII.
Compound formula VII does not need to separate, and directly formats and reacts with carbonic acid gas or boric acid ester again, generates compound formula II or compound formula III.
Reaction formula is as follows:
Figure BDA0000078974510000051
Isopropylmagnesium chloride-lithium chloride mixture of the present invention is the tetrahydrofuran solution of its different volumetric molar concentrations, and commercially available concentration is generally 1.0～1.3 mol/L.
Compound formula VI of the present invention is prepared by compound formula IV.
Figure BDA0000078974510000052
Formula IV
Wherein, R1 represents alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, Heterocyclylalkyl.
The preparation method of compound formula IV is described later in detail in applicant's No. 201110166067.9 patent application.
Compound formula IV of the present invention is dissolved in mass volume ratio 1: 2～20 ether, tetrahydrofuran (THF) or 1,4-dioxane, be cooled to-78～0 ℃, add isopropylmagnesium chloride, stir 0.1～2 hour, add mass ratio 1: 1～20 water, regulate behind pH=1～5 with hydrochloric acid, with organic solvent extraction, through anhydrous sodium sulphate or anhydrous magnesium sulfate drying, be evaporated to dryly, obtain compound formula VI.
The mol ratio of compound formula IV of the present invention and isopropylmagnesium chloride is 1: 0.8～1.2, preferably 1: 1～1.1; Described organic solvent is the mixing of one or more arbitrary proportions in fatty acid ester or ethers, comprise the mixing of one or more arbitrary proportions in ethyl formate, propyl formate, butyl formate, methyl acetate, ethyl acetate, propyl acetate, butylacetate, isopropyl acetate, isobutyl acetate, pentyl acetate, Isoamyl Acetate FCC, methyl propionate, ethyl propionate, propyl propionate, butyl propionate and amyl propionate, ether, propyl ether, isopropyl ether, methyl tertiary butyl ether, ethyl acetate, methyl tertiary butyl ether.
Compound formula IV reacts with grignard reagent isopropylmagnesium chloride generation format exchange, generates compound formula V.Compound formula V, directly reacts with water, through aftertreatment, obtains compound VI.
Reaction formula is as follows:
Isopropylmagnesium chloride of the present invention is tetrahydrofuran solution, 2-methyltetrahydrofuran solution or the diethyl ether solution of its different volumetric molar concentrations, and commercially available concentration is generally 1.0～2.0 mol/L.
Compound formula I of the present invention also can be prepared by compound formula IV one kettle way, and midbody compound formula VI does not need to separate.Operation steps is as follows: compound formula IV is dissolved in mass volume ratio 1: 2～20 ether, tetrahydrofuran (THF) or 1, 4-dioxane, be cooled to-78～0 ℃, add isopropylmagnesium chloride, stir 0.1～2 hour, slowly add C1～C4 lower alcohol, stir 0.5～1 hour, at-20～30 ℃, add isopropylmagnesium chloride-lithium chloride mixture, stir 0.5～5 hour, be cooled to-50～20 ℃, pass into carbon dioxide approximately 10～30 minutes or add compound boric acid ester (formula IX), stir 0.1～2 hour, be warming up to room temperature, regulate behind pH=1～5 with hydrochloric acid, with organic solvent extraction, through anhydrous sodium sulphate or anhydrous magnesium sulfate drying, be evaporated to dry, enriched material obtains compound formula I through recrystallization.
The mol ratio of compound formula IV of the present invention and C1～C4 lower alcohol is 1: 0.8～1.2, preferably 1: 1～1.1; The lower alcohol of described C1～C4 comprises methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol or the trimethyl carbinol; The mol ratio of described compound formula IV and 1.3M isopropylmagnesium chloride-lithium chloride tetrahydrofuran solution is 1: 0.8～2.0, preferably 1: 1.2～1.5; The mol ratio of compound formula IV and boric acid ester (formula IX) or carbonic acid gas is 1: 1～10, preferably 1: 1.2～2; Described organic solvent is the mixing of one or more arbitrary proportions in fatty acid ester or ethers, comprise the mixing of one or more arbitrary proportions in ethyl formate, propyl formate, butyl formate, methyl acetate, ethyl acetate, propyl acetate, butylacetate, isopropyl acetate, isobutyl acetate, pentyl acetate, Isoamyl Acetate FCC, methyl propionate, ethyl propionate, propyl propionate, butyl propionate and amyl propionate, ether, propyl ether, isopropyl ether, methyl tertiary butyl ether, ethyl acetate, methyl tertiary butyl ether.
One kettle way of the present invention is prepared compound formula I, and compared with the method for fractional steps, total recovery can improve 3～10%.
The method of recrystallization of the present invention comprises the following steps, and by mass volume ratio 1: 1～100, preferably 1: 2～20 add enriched material in organic solvent, and at-20～50 ℃, preferably 0～25 ℃ is stirred 0.5～24 hour, filters, and vacuum-drying, obtains sterling.
Recrystallization of the present invention organic solvent used is fatty acid ester, ketone, the mixing of one or more arbitrary proportions in ethers and hydro carbons, comprise ethyl formate, propyl formate, butyl formate, methyl acetate, ethyl acetate, propyl acetate, butylacetate, isopropyl acetate, isobutyl acetate, pentyl acetate, Isoamyl Acetate FCC, methyl propionate, ethyl propionate, propyl propionate, butyl propionate and amyl propionate, acetone, 2-butanone, cyclopentanone and pimelinketone, ether, propyl ether, isopropyl ether, methyl tertiary butyl ether and tetrahydrofuran (THF), 1, 4-dioxane, sherwood oil, normal hexane, hexanaphthene, the mixing of one or more arbitrary proportions in methylcyclohexane and normal heptane, the mixed solvent of ethyl acetate or methyl tertiary butyl ether and normal hexane arbitrary proportion.
Of the present invention 2, replace-2H-1 of 4-bis-, the preparation method of 2,3-triazole derivatives is simple, and the compound yield of acquisition is high.
Embodiment
Below in conjunction with specific embodiment, the present invention will be further explained.
Embodiment 1:
Figure BDA0000078974510000071
By 10g (41.5mmol) 2-methyl-4, the bromo-2H-1 of 5-bis-, 2,3-triazole is dissolved in 100ml tetrahydrofuran (THF), is cooled to-15～-5 ℃, slowly adds 22.4ml (44.8mmol) 2M isopropylmagnesium chloride tetrahydrofuran solution, finish, continue reaction 0.5 hour.Slowly add 10ml water, temperature <-10 ℃,, then extract with 100ml methyl tertiary butyl ether to pH=1～2 with 1.0M hcl acidifying, organic layer is through anhydrous sodium sulfate drying, is evaporated to dryly, obtains the bromo-2-methyl-2H-1 of 4-, 2,3-triazole 5.85g, yield 87%. 1H?NMR(CDCl 3，500MHz)：δ7.52(s，1H)，4.18(s，3H)；? 13C?NMR(CDCl 3，500MHz)：δ135.4，42.3。
Embodiment 2:
Working method is with embodiment 1, by 2-methyl-4, and the bromo-2H-1 of 5-bis-, 2,3-triazole replaces with 10.6g (41.5mmol) 2-ethyl-4, the bromo-2H-1 of 5-bis-, 2,3-triazole.Obtain the bromo-2-ethyl-2H-1 of 4-, 2,3-triazole 6.94g, yield 95%. 1H?NMR(CDCl 3，400MHz)：δ7.52(s，1H)，4.44(t，J＝7.2Hz，2H)，1.55(t，J＝7.2Hz，3H)； 13C?NMR(CDCl 3，400MHz)：δ135.1，121.4，50.8，14.7。
Embodiment 3:
Figure BDA0000078974510000082
Working method is with embodiment 1, by 2-methyl-4, and the bromo-2H-1 of 5-bis-, 2,3-triazole replaces with 11.16g (41.5mmol) 2-n-propyl-4, the bromo-2H-1 of 5-bis-, 2,3-triazole.Obtain the bromo-2-n-propyl-2H-1 of 4-, 2,3-triazole 7.57g, yield 96%. 1H?NMR(CDCl 3，400MHz)：δ7.52(s，1H)，4.35(t，J＝7.2Hz，2H)，2.01-1.92(m，2H)，0.92(t，J＝7.4Hz，3H)； 13CNMR(CDCl 3，400MHz)：δ135.0，121.4，57.3，23.0，11.0。
Embodiment 4:
Figure BDA0000078974510000091
Working method is with embodiment 1, by 2-methyl-4, and the bromo-2H-1 of 5-bis-, 2,3-triazole replaces with 12.24g (41.5mmol) 2-cyclopentyl-4, the bromo-2H-1 of 5-bis-, 2,3-triazole.Obtain the bromo-2-cyclopentyl-2H-1 of 4-, 2,3-triazole 8.6g, yield 96%. 1H?NMR(CDCl 3，400MHz)：δ7.50(s，1H)，4.99-4.93(m，1H)，2.18-2.13(m，4H)，1.90-1.86(m，2H)，1.71-1.68(m，2H)； 13C?NMR(CDCl 3，400MHz)：δ134.7，121.1，66.9，32.7，24.3。
Embodiment 5:
Figure BDA0000078974510000092
Working method is with embodiment 1, by 2-methyl-4, and the bromo-2H-1 of 5-bis-, 2,3-triazole replaces with 13.1g (41.5mmol) 2-phenmethyl-4, the bromo-2H-1 of 5-bis-, 2,3-triazole.Obtain the bromo-2-phenmethyl-2H-1 of 4-, 2,3-triazole 9.48g, yield 96%. 1H?NMR(CDCl 3，400MHz)：δ7.56(s，1H)，7.267.38-7.32(m，5H)，5.55(s，2H)； 13C?NMR(CDCl 3，400MHz)：δ135.8，134.5，128.9，128.6，128.2，122.2，59.4。
Embodiment 6:
Working method is with embodiment 1, by 2-methyl-4, and the bromo-2H-1 of 5-bis-, 2,3-triazole replaces with 13.7g (41.5mmol) 2-to methylbenzyl-4, the bromo-2H-1 of 5-bis-, 2,3-triazole.Obtain the bromo-2-of 4-to methylbenzyl-2H-1,2,3-triazole 10.25g, yield 98%. 1H?NMR(CDCl 3，400MHz)：δ7.53(s，1H)，7.23(ABq，J＝8.0Hz，2H)，7.15(ABq，J＝8.0Hz，2H)，5.69(s，2H)，2.32(s，3H)； 13C?NMR(CDCl 3，400MHz)：δ138.5，135.7，131.5，129.6，128.3，?122.0，59.2，21.2。
Embodiment 7:
Figure BDA0000078974510000101
Working method is with embodiment 1, by 2-methyl-4, and the bromo-2H-1 of 5-bis-, 2,3-triazole replaces with 14.4g (41.5mmol) 2-meta-methoxy phenmethyl-4, the bromo-2H-1 of 5-bis-, 2,3-triazole.Obtain the bromo-2-meta-methoxy of 4-phenmethyl-2H-1,2,3-triazole 10.78g, yield 97%. 1H?NMR(CDCl 3，400MHz)：δ7.56(s，1H)，7.26(t，J＝8.0Hz，1H)，6.92-6.87(m，2H)，6.85(s，1H)，5.52(s，2H)，3.79(s，3H)； 13C?NMR(CDCl 3，400MHz)：δ159.9，135.9，135.8，130.0，122.2，120.4，114.1，113.7，59.3，55.3。
Embodiment 8:
Working method is with embodiment 1, by 2-methyl-4, and the bromo-2H-1 of 5-bis-, 2,3-triazole replaces with 14.4g (41.5mmol) 2-to mehtoxybenzyl-4, the bromo-2H-1 of 5-bis-, 2,3-triazole.Obtain the bromo-2-of 4-to mehtoxybenzyl-2H-1,2,3-triazole 10.78g, yield 97%. 1H?NMR(CDCl 3，500MHz)：δ7.54(s，1H)，7.30(ABq，J＝8.2Hz，2H)，6.88(ABq，J＝8.2Hz，2H)，5.48(s，2H)，3.79(s，3H)； 13C?NMR(CDCl 3，500MHz)：δ159.9，135.6，129.8，126.6，122.0，114.2，59.0，55.3。
Embodiment 9:
Figure BDA0000078974510000103
Working method is with embodiment 1, by 2-methyl-4, and the bromo-2H-1 of 5-bis-, 2,3-triazole replaces with 13.9g (41.5mmol) 2-to fluorobenzene methyl-4, the bromo-2H-1 of 5-bis-, 2,3-triazole.Obtain the bromo-2-of 4-to fluorobenzene methyl-2H-1,2,3-triazole 10.2g, yield 96%. 1H?NMR(CDCl 3，500MHz)：δ7.56(s，1H)，7.33(dd，J＝5.7，8.2Hz，2H)，7.03(dd，J＝8.2，9.0Hz，2H)，5.51(s，2H)； 13C?NMR(CDCl 3，500MHz)：δ162.8(d，J＝246.0Hz)，135.9，130.3(d，J＝3.3Hz)，130.2(d，J＝8.3Hz)，122.3，115.9(d，J＝21.6Hz)，58.6。
Embodiment 10:
Figure BDA0000078974510000111
Working method is with embodiment 1, by 2-methyl-4, and the bromo-2H-1 of 5-bis-, 2,3-triazole replaces with 14.58g (41.5mmol) 2-to chlorophenylmethyl-4, the bromo-2H-1 of 5-bis-, 2,3-triazole.Obtain the bromo-2-of 4-to chlorophenylmethyl-2H-1,2,3-triazole 10.5g, yield 93%. 1H?NMR(CDCl 3，400MHz)：δ7.56(s，1H)，7.32(ABq，J＝8.8Hz，2H)，7.26(ABq，J＝8.8Hz，2H)，5.51(s，2H)； 13C?NMR(CDCl 3，400MHz)：δ136.0，135.2，132.9，129.6，129.1，122.4，58.6。
Embodiment 11:
Working method is with embodiment 1, by 2-methyl-4, and the bromo-2H-1 of 5-bis-, 2,3-triazole replaces with 16.64g (41.5mmol) 2-to trifluoromethoxy phenmethyl-4, the bromo-2H-1 of 5-bis-, 2,3-triazole.Obtain the bromo-2-of 4-to trifluoromethoxy phenmethyl-2H-1,2,3-triazole 12.8g, yield 96%. 1H?NMR(CDCl 3，400MHz)：δ7.58(s，1H)，7.36(ABq，J＝8.6Hz，2H)，7.20(ABq，J＝8.6Hz，2H)，5.55(s，2H)； 13C?NMR(CDCl 3，400MHz)：δ149.4，136.0，133.1，129.8，122.5，121.3，120.4(q，J＝256.0Hz)，58.5。
Embodiment 12:
Figure BDA0000078974510000121
By the bromo-2-methyl-2H-1 of 3.24g (20mmol) 4-, 2,3-triazole is dissolved in 50ml tetrahydrofuran (THF), at 10～20 ℃, slowly adds 18.5ml (24mmol) 1.3M isopropylmagnesium chloride-lithium chloride tetrahydrofuran solution.Finish, continue reaction 2 hours.Be cooled to below 0 ℃, pass into carbon dioxide approximately 10～30 minutes, 15 ℃ of temperature <.At room temperature, with 1.0M hcl acidifying, to pH=1～2, then extract with 100ml methyl tertiary butyl ether, organic layer, through anhydrous sodium sulfate drying, is evaporated to dry.Residual solid is dissolved in to 5ml ethyl acetate, drips 20ml normal hexane under room temperature, continue to stir 1 hour, filter, room temperature vacuum-drying, obtains 2-methyl-2H-1,2,3-triazole-4-carboxylic acid 1.78g, yield 70%. 1H?NMR(CD 3COCD 3，500MHz)：δ8.07(s，1H)，4.26(s，3H)； 13CNMR(CD 3COCD 3，500MHz)：δ161.7，141.0，137.4，42.6。
Embodiment 13:
Figure BDA0000078974510000122
Working method is with embodiment 12, and by bromo-4-2-methyl-2H-1,2,3-triazole replaces with the bromo-2-ethyl-2H-1 of 3.52g (20mmol) 4-, 2,3-triazole.Obtain 2-ethyl-2H-1,2,3-triazole-4-carboxylic acid 2.1g, yield 74%. 1H?NMR(CDCl 3，400MHz)：δ11.57(bs，1H)，8.17(s，1H)，4.62(t，J＝7.2Hz，2H)，1.64(t，J＝7.2Hz，2H)； 13C?NMR(CDCl 3，400MHz)δ165.3，138.9，137.4，51.1，14.6。
Embodiment 14:
Figure BDA0000078974510000123
Working method is with embodiment 12, and by bromo-4-2-methyl-2H-1,2,3-triazole replaces with the bromo-2-n-propyl-2H-1 of 3.8g (20mmol) 4-, 2,3-triazole.Obtain 2-n-propyl-2H-1,2,3-triazole-4-carboxylic acid 2.45g, yield 79%. 1H?NMR(CD 3COCD 3，400MHz)：δ8.12(s，1H)，4.49?(t，J＝7.0Hz，2H)，2.03-1.96(m，2H)，0.92(t，J＝7.4Hz，3H)； 13C?NMR(CD 3COCD 3，400MHz)δ161.9，140.8，137.6，57.7，23.6，11.2。
Embodiment 15:
Figure BDA0000078974510000131
Working method is with embodiment 12, and by bromo-4-2-methyl-2H-1,2,3-triazole replaces with the bromo-2-cyclopentyl-2H-1 of 4.3g (20mmol) 4-, 2,3-triazole.Obtain 2-cyclopentyl-2H-1,2,3-triazole-4-carboxylic acid 3.1g, yield 85%. 1H?NMR(CD 3COCD 3，400MHz)：δ8.09(s，1H)，5.15-5.09(m，1H)，2.24-2.14(m，4H)，1.90-1.86(m，2H)，1.78-1.74(m，2H)；? 13C?NMR(CD 3COCD 3，400MHz)：δ161.9，140.5，137.4，67.5，33.4，24.9。
Embodiment 16:
Figure BDA0000078974510000132
Working method is with embodiment 12, and by bromo-4-2-methyl-2H-1,2,3-triazole replaces with the bromo-2-phenmethyl-2H-1 of 4.76g (20mmol) 4-, 2,3-triazole.Obtain 2-phenmethyl-2H-1,2,3-triazole-4-carboxylic acid 3.7g, yield 91%. 1H?NMR(CD 3COCD 3，400MHz)：δ8.14(s，1H)，7.39-7.33(m，5H)，5.67(s，2H)； 13C?NMR(CD 3COCD 3，400MHz)：δ165.3，139.3，138.1，133.9，129.0，128.8，128.4，59.7。
Embodiment 17:
Figure BDA0000078974510000133
Working method is with embodiment 12, and by bromo-4-2-methyl-2H-1,2,3-triazole replaces with the bromo-2-of 5.06g (20mmol) 4-to methylbenzyl-2H-1,2,3-triazole.Obtain 2-to methylbenzyl-2H-1,2,3-triazole-4-carboxylic acid 3.82g, yield 88%. 1H?NMR(CD 3COCD 3，400MHz)：?δ8.11(s，1H)，7.28(ABq，J＝8.0Hz，2H)，7.19(ABq，J＝8.0Hz，2H)，5.66(s，2H)，2.30(s，3H)； 13C?NMR(CD 3COCD 3，400MHz)：δ161.7，141.3，139.0，138.0，133.1，130.2，129.1，59.6，21.1。
Embodiment 18:
Working method is with embodiment 12, and by bromo-4-2-methyl-2H-1,2,3-triazole replaces with the bromo-2-meta-methoxy of 5.4g (20mmol) 4-phenmethyl-2H-1,2,3-triazole.Obtain 2-meta-methoxy phenmethyl-2H-1,2,3-triazole-4-carboxylic acid 3.82g, yield 82%. 1H?NMR(CD 3COCD 3，400MHz)：δ8.13(s，1H)，7.29(t，J＝8.0Hz，1H)，6.95-6.90(m，3H)，5.69(s，2H)，3.78(s，3H)； 13C?NMR(CD 3COCD 3，400MHz)：δ161.7，160.9，141.4，138.1，137.5，130.7，121.1，114.8，114.5，59.7，55.6。
Embodiment 19:
Figure BDA0000078974510000142
Working method is with embodiment 12, and by bromo-4-2-methyl-2H-1,2,3-triazole replaces with the bromo-2-of 5.4g (20mmol) 4-to mehtoxybenzyl-2H-1,2,3-triazole.Obtain 2-to mehtoxybenzyl-2H-1,2,3-triazole-4-carboxylic acid 4.2g, yield 90%. 1H?NMR(CD 3COCD 3，500MHz)：δ8.10(s，1H)，7.35(ABq，J＝8.5Hz，2H)，6.92(ABq，J＝8.5Hz，2H)，5.63(s，2H)，3.78(s，3H)； 13C?NMR(CD 3COCD 3，500MHz)：δ161.7，160.8，141.2，138.0，130.7，128.0，114.9，59.4，55.6。
Embodiment 20:
Figure BDA0000078974510000143
Working method is with embodiment 12, and by bromo-4-2-methyl-2H-1,2,3-triazole replaces with the bromo-2-of 5.1g (20mmol) 4-to fluorobenzene methyl-2H-1,2,3-triazole.Obtain 2-to fluorobenzene methyl-2H-1,2,3-triazole-4-carboxylic acid 3.76g, yield 85%. 1H?NMR(CD 3COCD 3，400MHz)：δ8.13(s，1H)，7.46(dd，J＝5.7，8.2Hz，2H)，7.16(dd，J＝8.2，9.0Hz，2H)，5.72(s，2H)；? 13C?NMR(CD 3COCD 3，400MHz)：δ163.6(d，J＝244.0Hz)，141.4，138.1，132.3(d，J＝3.0Hz)，131.4(d，J＝8.0Hz)，122.3，116.3(d，J＝21.0Hz)，59.0。
Embodiment 21:
Figure BDA0000078974510000151
Working method is with embodiment 12, and by bromo-4-2-methyl-2H-1,2,3-triazole replaces with the bromo-2-of 5.45g (20mmol) 4-to chlorophenylmethyl-2H-1,2,3-triazole.Obtain 2-to chlorophenylmethyl-2H-1,2,3-triazole-4-carboxylic acid 2.62g, yield 55%. 1H?NMR(CD 3COCD 3，400MHz)：δ8.14(s，1H)，7.42(s，4H)，5.74(s，2H)； 13C?NMR(CD 3COCD 3，400MHz)：δ165.9，145.8，142.6，142.4，139.3，135.2，134.0，63.2。
Embodiment 22:
Figure BDA0000078974510000152
Working method is with embodiment 12, and by bromo-4-2-methyl-2H-1,2,3-triazole replaces with the bromo-2-of 6.45g (20mmol) 4-to trifluoromethyl phenmethyl-2H-1,2,3-triazole.Obtain 2-to trifluoromethyl phenmethyl-2H-1,2,3-triazole-4-carboxylic acid 4.65g, yield 81%. 1H?NMR(CD 3COCD 3，400MHz)：δ8.15(s，1H)，7.54(ABq，J＝8.4Hz，2H)，7.36(ABq，J＝8.4Hz，2H)，5.79(s，2H)； 13C?NMR(CD 3COCD 3，400MHz)：δ161.6，149.9，141.6，138.2，135.4，131.1，122.2，121.4(q，J＝254.0Hz)，58.8。
Embodiment 23:
By the bromo-2-methyl-2H-1 of 3.24g (20mmol) 4-, 2,3-triazole is dissolved in 50ml tetrahydrofuran (THF), at 10～20 ℃, slowly add 18.5ml (24mmol) 1.3M isopropylmagnesium chloride-lithium chloride tetrahydrofuran solution, finish, continue reaction 2 hours.Be cooled to below-20 ℃, add trimethyl borate 3.5ml (30mmol), continue reaction 0.5～2 hour.At room temperature, with 1.0M hcl acidifying, to pH=1～2, then extract by 100ml ethyl acetate, organic layer, through anhydrous sodium sulfate drying, is evaporated to dry.Resistates is dissolved in 20ml methyl tertiary butyl ether, drips 30ml normal hexane under room temperature, is cooled to 0～5 ℃, stirs 1 hour, and filtration, room temperature vacuum-drying, obtain 2-methyl-2H-1,2,3-triazole-4-boric acid 1.6g, yield 63%. 1H?NMR(DMSO-d6，400MHz)：δ7.93(s，1H)，4.19(s，3H)； 13C?NMR(DMSO-d6，400MHz)：δ142.0，41.0。
Embodiment 24:
Figure BDA0000078974510000162
Working method is with embodiment 23, and by bromo-4-2-methyl-2H-1,2,3-triazole replaces with the bromo-2-ethyl-2H-1 of 3.52g (20mmol) 4-, 2,3-triazole.Obtain 2-ethyl-2H-1,2,3-triazole-4-boric acid 1.0g, yield 72%. 1H?NMR(DMSO-d6，400MHz)：δ7.92(s，1H)，4.46(t，J＝7.2Hz，2H)，1.45(t，J＝7.2Hz，3H)； 13C?NMR(DMSO-d6，400MHz)δ140.6，49.0，14.7。
Embodiment 25:
Figure BDA0000078974510000163
Working method is with embodiment 23, and by bromo-4-2-methyl-2H-1,2,3-triazole replaces with the bromo-2-n-propyl-2H-1 of 3.8g (20mmol) 4-, 2,3-triazole.Obtain 2-n-propyl-2H-1,2,3-triazole-4-boric acid 2.66g, yield 86%. 1H?NMR(DMSO-d6，400MHz)：δ7.94(s，1H)，4.40(t，J＝6.8Hz，2H)，1.92-1.86(m，2H)，0.83(t，J＝7.4Hz，3H)； 13C?NMR?(DMSO-d6，400MHz)δ141.6，140.6，55.4，22.7，10.9。
Embodiment 26:
Figure BDA0000078974510000171
Working method is with embodiment 23, and by bromo-4-2-methyl-2H-1,2,3-triazole replaces with the bromo-2-cyclopentyl-2H-1 of 4.3g (20mmol) 4-, 2,3-triazole.Obtain 2-cyclopentyl-2H-1,2,3-triazole-4-boric acid 3.08g, yield 85%. 1H?NMR(DMSO-d6，400MHz)：δ7.92(s，1H)，5.09-5.02(m，1H)，2.14-2.03(m，4H)，1.984-1.78(m，2H)，1.69-1.66(m，2H)；? 13C?NMR(DMSO-d6，400MHz)：δ141.5(bs)，140.4，64.9，32.4，23.9。
Embodiment 27:
Figure BDA0000078974510000172
Working method is with embodiment 23, and by bromo-4-2-methyl-2H-1,2,3-triazole replaces with the bromo-2-phenmethyl-2H-1 of 4.76g (20mmol) 4-, 2,3-triazole.Obtain 2-phenmethyl-2H-1,2,3-triazole-4-boric acid 3.53g, yield 87%. 1H?NMR(DMSO-d6，400MHz)：δ7.99(s，1H)，7.37-7.24(m，5H)，5.68(s，2H)； 13C?NMR(DMSO-d6，400MHz)：δ142.1，141.1，137.1，133.0，129.0，127.6，57.2，20.6。
Embodiment 28:
Working method is with embodiment 23, and by bromo-4-2-methyl-2H-1,2,3-triazole replaces with the bromo-2-of 5.06g (20mmol) 4-to methylbenzyl-2H-1,2,3-triazole.Obtain 2-to methylbenzyl-2H-1,2,3-triazole-4-boric acid 3.81g, yield 88%. 1H?NMR(DMSO-d6，400MHz)：δ7.96(s，1H)，7.15(s，4H)，5.62(s，2H)，2.27(s，3H)； 13C?NMR(DMSO-d6，?400MHz)：δ142.0，141.1?136.0，128.5，127.8，127.6，57.4。
Embodiment 29:
Figure BDA0000078974510000181
Working method is with embodiment 23, and by bromo-4-2-methyl-2H-1,2,3-triazole replaces with the bromo-2-meta-methoxy of 5.4g (20mmol) 4-phenmethyl-2H-1,2,3-triazole.Obtain 2-meta-methoxy phenmethyl-2H-1,2,3-triazole-4-boric acid 3.82g, yield 82%. 1H?NMR(DMSO-d6，400MHz)：δ8.37(bs，2H)，7.96(s，1H)，7.26(t，J＝8.0Hz，1H)，6.87(d，J＝8.0Hz，1H)，6.80(s，1H)，6.79(d，J＝8.0Hz，1H)，5.63(s，2H)，3.72(s，3H)； 13C?NMR(DMSO-d6，400MHz)：δ159.2，141.1，138.1，137.5，129.6，119.6，113.3，113.1，57.2，55.0。
Embodiment 30:
Working method is with embodiment 23, and by bromo-4-2-methyl-2H-1,2,3-triazole replaces with the bromo-2-of 5.4g (20mmol) 4-to mehtoxybenzyl-2H-1,2,3-triazole.Obtain 2-to mehtoxybenzyl-2H-1,2,3-triazole-4-boric acid 3.77g, yield 81%. 1H?NMR(CD 3COCD 3，400MHz)：δ7.90(s，1H)，7.27(ABq，J＝8.6Hz，2H)，6.89(ABq，J＝8.6Hz，2H)，5.58(s，2H)，3.77(s，3H)； 13C?NMR(CD 3COCD 3，400MHz)：δ160.5，141.7，130.3，129.0，114.8，58.4，55.6。
Embodiment 31:
Figure BDA0000078974510000183
Working method is with embodiment 23, and by bromo-4-2-methyl-2H-1,2,3-triazole replaces with the bromo-2-of 5.1g (20 mmol) 4-to fluorobenzene methyl-2H-1,2,3-triazole.Obtain 2-to fluorobenzene methyl-2H-1,2,3-triazole-4-boric acid 3.1g, yield 70%. 1H?NMR(DMSO-d6，400MHz)：δ7.97(s，1H)，7.46(dd，J＝5.7，8.6Hz，2H)，7.19(dd，J＝8.6，9.0Hz，2H)，5.67(s，2H)；? 13C?NMR(DMSO-d6，400MHz)：δ161.7(d，J＝243.0Hz)，141.1，132.2(d，J＝3.0Hz)，129.9(d，J＝9.0Hz)，115.4(d，J＝22.0Hz)，56.5。
Embodiment 32:
Working method is with embodiment 23, and by bromo-4-2-methyl-2H-1,2,3-triazole replaces with the bromo-2-of 5.45g (20mmol) 4-to chlorophenylmethyl-2H-1,2,3-triazole.Obtain 2-to chlorophenylmethyl-2H-1,2,3-triazole-4-boric acid 2.45g, yield 52%. 1H?NMR(DMSO-d6，400MHz)：δ7.99(s，1H)，7.42(ABq，J＝8.4Hz，2H)，7.27(ABq，J＝8.4Hz，2H)，5.69(s，2H)； 13C?NMR(DMSO-d6，400MHz)δ141.2，135.0，132.5，129.5，128.5，128.4，56.6。
Embodiment 33:
Figure BDA0000078974510000192
Working method is with embodiment 23, and by bromo-4-2-methyl-2H-1,2,3-triazole replaces with the bromo-2-of 6.45g (20mmol) 4-to trifluoromethyl phenmethyl-2H-1,2,3-triazole.Obtain 2-to trifluoromethyl phenmethyl-2H-1,2,3-triazole-4-boric acid 3.79g, yield 66%. 1H?NMR(DMSO-d6，400MHz)：δ8.00(s，1H)，7.39(ABq，J＝9.2Hz，2H)，7.36(ABq，J＝9.2Hz，2H)，5.74(s，2H)； 13C?NMR(DMSO-d6，400MHz)：δ147.9(d，J＝2.0Hz)，141.3，135.5，129.7，121.3，119.9(q，J＝245.0Hz)，56.5。
Embodiment 34:
Figure BDA0000078974510000201
By 5g (20.7mmol) 2-methyl-4, the bromo-2H-1 of 5-bis-, 2,3-triazole is dissolved in 40ml tetrahydrofuran (THF), is cooled to-15～-5 ℃, slowly adds 11.2ml (22.4mmol) 2M isopropylmagnesium chloride tetrahydrofuran solution, finish, continue reaction 0.5 hour.Slowly add 0.88ml (21.74mmol) methyl alcohol, be warming up to 5～15 ℃, add 17.3ml (22.4mmol) 1.3M isopropylmagnesium chloride-lithium chloride tetrahydrofuran solution, finish, under room temperature, continue reaction 2 hours.Be cooled to below 0 ℃, pass into carbon dioxide approximately 10～30 minutes, 15 ℃ of temperature <, with 1.0M hcl acidifying, to pH=1～2, then with 100ml methyl tertiary butyl ether extraction, organic layer is through anhydrous sodium sulfate drying, be evaporated to dryly, residual solid is dissolved in to 5ml ethyl acetate, under room temperature, drip 20ml normal hexane, continue to stir 1 hour, filter room temperature vacuum-drying, obtain 2-methyl-2H-1,2,3-triazole-4-carboxylic acid 1.74g, yield 66%.
Embodiment 35:
Figure BDA0000078974510000202
Working method is with embodiment 34, by 2-methyl-4, and the bromo-2H-1 of 5-bis-, 2,3-triazole replaces with 5.28g (20.7mmol) 2-ethyl-4, the bromo-2H-1 of 5-bis-, 2,3-triazole.Obtain 2-ethyl-2H-1,2,3-triazole-4-carboxylic acid 2.34g, yield 80%.
Embodiment 36:
Figure BDA0000078974510000203
Working method is with embodiment 34, by 2-methyl-4, and the bromo-2H-1 of 5-bis-, 2,3-triazole replaces with 5.57g (20.7mmol) 2-n-propyl-4, the bromo-2H-1 of 5-bis-, 2,3-triazole.Obtain 2-n-propyl-2H-1,2,3-triazole-4-carboxylic acid 2.66g, yield 83%.
Embodiment 37:
Working method is with embodiment 34, by 2-methyl-4, and the bromo-2H-1 of 5-bis-, 2,3-triazole replaces with 6.11g (20.7mmol) 2-cyclopentyl-4, the bromo-2H-1 of 5-bis-, 2,3-triazole.Obtain 2-cyclopentyl-2H-1,2,3-triazole-4-carboxylic acid 3.3g, yield 88%.
Embodiment 38:
Figure BDA0000078974510000212
By 5g (20.7mmol) 2-methyl-4, the bromo-2H-1 of 5-bis-, 2,3-triazole is dissolved in 40ml tetrahydrofuran (THF), is cooled to-15～-5 ℃, slowly adds 11.2ml (22.4mmol) 2M isopropylmagnesium chloride tetrahydrofuran solution, finish, continue reaction 0.5 hour.Slowly add 0.88ml (21.74mmol) methyl alcohol, be warming up to 5～15 ℃, add 17.3ml (22.4mmol) 1.3M isopropylmagnesium chloride-lithium chloride tetrahydrofuran solution, finish, under room temperature, continue reaction 2 hours.Be cooled to below-20 ℃, add trimethyl borate 3.6ml (31mmol), continue reaction 0.5～2 hour, with 1.0M hcl acidifying to pH=1～2,15 ℃ of temperature <, then with 100ml ethyl acetate extraction, organic layer is through anhydrous sodium sulfate drying, be evaporated to dry, resistates is dissolved in 10ml methyl tertiary butyl ether, drips 30ml normal hexane under room temperature, is cooled to 0～5 ℃, stir 1 hour, filtration, room temperature vacuum-drying, obtain 2-methyl-2H-1,2,3-triazole-4-boric acid 1.97g, yield 75%.
Embodiment 39:
Figure BDA0000078974510000213
Working method is with embodiment 38, by 2-methyl-4, and the bromo-2H-1 of 5-bis-, 2,3-triazole replaces with 5.28g (20.7mmol) 2-ethyl-4, the bromo-2H-1 of 5-bis-, 2,3-triazole.Obtain 2-ethyl-2H-1,2,3-triazole-4-boric acid 2.54g, yield 87%.
Embodiment 40:
Figure BDA0000078974510000221
Working method is with embodiment 38, by 2-methyl-4, and the bromo-2H-1 of 5-bis-, 2,3-triazole replaces with 5.57g (20.7mmol) 2-n-propyl-4, the bromo-2H-1 of 5-bis-, 2,3-triazole.Obtain 2-n-propyl-2H-1,2,3-triazole-4-boric acid 2.95g, yield 92%.
Embodiment 41:
Figure BDA0000078974510000222
Working method is with embodiment 38, by 2-methyl-4, and the bromo-2H-1 of 5-bis-, 2,3-triazole replaces with 6.11g (20.7mmol) 2-cyclopentyl-4, the bromo-2H-1 of 5-bis-, 2,3-triazole.Obtain 2-cyclopentyl-2H-1,2,3-triazole-4-boric acid 3.37g, yield 90%.
Embodiment 42:
Figure BDA0000078974510000223
By the bromo-2-methyl-2H-1 of 5g (24.27mmol) 5-, 2,3-triazole-4-carboxylic acid is dissolved in 100ml ethyl acetate, adds 0.25g 5% palladium charcoal, passes into hydrogen, maintains pressure 1～3atm, room temperature reaction 20～24 hours.React complete, filter, filtrate decompression is concentrated into dry.Residual solid is dissolved in to 10ml ethyl acetate, drips 50ml normal hexane under room temperature, continue to stir 1 hour, filter, room temperature vacuum-drying, obtains 2-methyl-2H-1,2,3-triazole-4-carboxylic acid 2.9g, yield 95%.

Claims (15)

  1. Replace-2H-1 of 1.2,4-bis-, the preparation method of 2,3-triazole derivatives, this 2, replace-2H-1 of 4-bis-, 2,3-triazole derivatives has following structure:
    Figure FDA0000463529090000011
    Wherein, R1 represents methyl, ethyl, n-propyl, pentamethylene base, benzyl, 4-methyl-benzyl, 3-methoxy-benzyl, 4-methoxy-benzyl, 4-luorobenzyl, 4-chlorobenzyl or 4-trifluoro-methoxybenzyl; R2 represents carboxyl or boronate;
    It is characterized in that, comprise step:
    Formula IV compound is dissolved in to the ether of mass volume ratio 1:2～20, tetrahydrofuran (THF) or 1, 4-dioxane, be cooled to-78～0 ℃, add isopropylmagnesium chloride, stir 0.1～2 hour, slowly add C1～C4 lower alcohol, stir 0.5～1 hour, at-20～30 ℃, add isopropylmagnesium chloride-lithium chloride mixture, stir 0.5～5 hour, be cooled to-50～20 ℃, pass into carbon dioxide 10～30 minutes or add the compound boric acid ester of formula IX, stir 0.1～2 hour, be warming up to room temperature, regulate behind pH=1～5 with hydrochloric acid, with organic solvent extraction, through anhydrous sodium sulphate or anhydrous magnesium sulfate drying, be evaporated to dry, enriched material obtains 2 of formula I through recrystallization, replace-2H-1 of 4-bis-, 2, 3-triazole derivatives,
    Figure FDA0000463529090000012
    Wherein, R1 represents methyl, ethyl, n-propyl, pentamethylene base, benzyl, 4-methyl-benzyl, 3-methoxy-benzyl, 4-methoxy-benzyl, 4-luorobenzyl, 4-chlorobenzyl or 4-trifluoro-methoxybenzyl;
    Figure FDA0000463529090000013
    Figure FDA0000463529090000021
    Wherein, R3 represents the straight or branched alkyl of C1～C5.
  2. 2. according to claim 12, replace-2H-1 of 4-bis-, the preparation method of 2,3-triazole derivatives, is characterized in that, described formula IV compound and the mol ratio of lower alcohol are 1:0.8～1.2; The lower alcohol of described C1～C4 is methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol or the trimethyl carbinol; The mol ratio of described compound formula IV and 1.3M isopropylmagnesium chloride-lithium chloride tetrahydrofuran solution is 1:0.8～2.0; The mol ratio of formula IV compound and formula IX boric acid ester or carbonic acid gas is 1:1～10; Described organic solvent is the mixing of one or more arbitrary proportions in fatty acid ester or ethers.
  3. Replace-2H-1 of 3.2,4-bis-, the preparation method of 2,3-triazole derivatives, this 2, replace-2H-1 of 4-bis-, 2,3-triazole derivatives has following structure:
    Wherein, R1 represents methyl, ethyl, n-propyl, pentamethylene base, benzyl, 4-methyl-benzyl, 3-methoxy-benzyl, 4-methoxy-benzyl, 4-luorobenzyl, 4-chlorobenzyl or 4-trifluoro-methoxybenzyl; R2 represents carboxyl or boronate;
    It is characterized in that, comprise step:
    Formula IV compound is dissolved in to the ether of mass volume ratio 1:2～20, tetrahydrofuran (THF) or 1, 4-dioxane, be cooled to-78～0 ℃, add isopropylmagnesium chloride, stir 0.1～2 hour, add the water of mass ratio 1:1～20, regulate behind pH=1～5 with hydrochloric acid, with organic solvent extraction, through anhydrous sodium sulphate or anhydrous magnesium sulfate drying, be evaporated to dry, obtain formula VI compound, formula VI compound reacts with the compound boric acid ester of carbonic acid gas or formula IX under isopropylmagnesium chloride-lithium chloride exists, further be converted to 2 of formula I, replace-2H-1 of 4-bis-, 2, 3-triazole derivatives,
    Figure FDA0000463529090000023
    Figure FDA0000463529090000031
    Wherein, R1 represents methyl, ethyl, n-propyl, pentamethylene base, benzyl, 4-methyl-benzyl, 3-methoxy-benzyl, 4-methoxy-benzyl, 4-luorobenzyl, 4-chlorobenzyl or 4-trifluoro-methoxybenzyl; Wherein, R3 represents the straight or branched alkyl of C1～C5;
    Figure FDA0000463529090000032
    Wherein, R1 represents methyl, ethyl, n-propyl, pentamethylene base, benzyl, 4-methyl-benzyl, 3-methoxy-benzyl, 4-methoxy-benzyl, 4-luorobenzyl, 4-chlorobenzyl or 4-trifluoro-methoxybenzyl.
  4. 4. according to claim 32, replace-2H-1 of 4-bis-, the preparation method of 2,3-triazole derivatives, is characterized in that, the mol ratio of described formula IV compound and isopropylmagnesium chloride is 1:0.8～1.2; Described organic solvent is the mixing of one or more arbitrary proportions in fatty acid ester or ethers.
  5. 5. according to claim 32, replace-2H-1 of 4-bis-, the preparation method of 2,3-triazole derivatives, it is characterized in that, when R2 is carboxyl, described 2 in formula I, replace-2H-1 of 4-bis-, 2,3-triazole derivatives is 2-replacement-2H-1 of formula II, 2,3-triazole-4-carboxylic acid;
    Figure FDA0000463529090000033
    Wherein, R1 represents methyl, ethyl, n-propyl, pentamethylene base, benzyl, 4-methyl-benzyl, 3-methoxy-benzyl, 4-methoxy-benzyl, 4-luorobenzyl, 4-chlorobenzyl or 4-trifluoro-methoxybenzyl;
    Described 2-replacement-2H-1, 2, 3-triazole-4-carboxylic acid is prepared by following method: the ether that described formula VI compound formula is dissolved in to mass volume ratio 1:2～20, tetrahydrofuran (THF) or 1, 4-dioxane, be cooled to-20～30 ℃, add isopropylmagnesium chloride-lithium chloride mixture, stir 0.5～5 hour, be cooled to-50～20 ℃, pass into carbon dioxide 10～30 minutes, be warming up to room temperature, regulate behind pH=1～5 with hydrochloric acid, with organic solvent extraction, through anhydrous sodium sulphate or anhydrous magnesium sulfate drying, be evaporated to dry, enriched material obtains described 2-replacement-2H-1 through recrystallization, 2, 3-triazole-4-carboxylic acid.
  6. 6. according to claim 32, replace-2H-1 of 4-bis-, the preparation method of 2,3-triazole derivatives, it is characterized in that: when R2 is boronate, described 2 in formula I, replace-2H-1 of 4-bis-, 2,3-triazole derivatives is the 2-replacement-2H-1 of formula III, 2,3-triazole-4-boric acid
    Figure FDA0000463529090000041
    Wherein, R1 represents methyl, ethyl, n-propyl, pentamethylene base, benzyl, 4-methyl-benzyl, 3-methoxy-benzyl, 4-methoxy-benzyl, 4-luorobenzyl, 4-chlorobenzyl or 4-trifluoro-methoxybenzyl;
    Described 2-replacement-2H-1, 2, 3-triazole-4-boric acid is prepared by following method: the ether that described compound formula VI is dissolved in to mass volume ratio 1:2～20, tetrahydrofuran (THF) or 1, 4-dioxane, be cooled to-20～30 ℃, add isopropylmagnesium chloride-lithium chloride mixture, stir 0.5～5 hour, be cooled to-50～20 ℃, add formula IX compound boric acid ester, stir 0.1～2 hour, be warming up to room temperature, regulate behind pH=1～5 with hydrochloric acid, with organic solvent extraction, through anhydrous sodium sulphate or anhydrous magnesium sulfate drying, be evaporated to dry, enriched material obtains described 2-replacement-2H-1 through recrystallization, 2, 3-triazole-4-boric acid.
  7. 7. according to claim 62, replace-2H-1 of 4-bis-, the preparation method of 2,3-triazole derivatives, is characterized in that, the mol ratio of described compound formula VI and isopropylmagnesium chloride-lithium chloride mixture is 1:0.8～2.0; The mol ratio of formula VI compound and formula IX boric acid ester is 1:1～10; Described organic solvent is the mixing of one or more arbitrary proportions in fatty acid ester or ethers.
  8. Replace-2H-1 of 8.2,4-bis-, the preparation method of 2,3-triazole derivatives, is characterized in that, described 2, replace-2H-1 of 4-bis-, 2,3-triazole derivatives is 2-replacement-2H-1 of formula II, 2,3-triazole-4-carboxylic acid;
    Figure FDA0000463529090000051
    Wherein, R1 represents methyl, ethyl, n-propyl, pentamethylene base, benzyl, 4-methyl-benzyl, 3-methoxy-benzyl, 4-methoxy-benzyl, 4-luorobenzyl, 4-chlorobenzyl or 4-trifluoro-methoxybenzyl;
    Described 2-replacement-2H-1,2,3-triazole-4-carboxylic acid is prepared by following method: formula VIII compound is dissolved in the organic solvent of mass volume ratio 1:1～100, the metal catalyst that adds 0.1～50% weight ratio, passes into hydrogen, maintains pressure 1～100atm, at 0～200 ℃, react 1～50 hour, at room temperature filter, be evaporated to dry, enriched material obtains described 2-replacement-2H-1 through recrystallization, 2,3-triazole-4-carboxylic acid
    Figure FDA0000463529090000052
    Wherein, R1 represents methyl, ethyl, n-propyl, pentamethylene base, benzyl, 4-methyl-benzyl, 3-methoxy-benzyl, 4-methoxy-benzyl, 4-luorobenzyl, 4-chlorobenzyl or 4-trifluoro-methoxybenzyl.
  9. 9. according to claim 82, replace-2H-1 of 4-bis-, 2, the preparation method of 3-triazole derivatives, it is characterized in that, described organic solvent is the mixing of one or more arbitrary proportions in alcohols or fatty acid ester, and described metal catalyst is that one or more in palladium metal, ruthenium, platinum are carried on to the catalyzer that the charge capacity made on gac, aluminum oxide or Zeolite support is 1～10%.
  10. 10. according to 2 described in any one in claim 1,5,6,8, replace-2H-1 of 4-bis-, the preparation method of 2,3-triazole derivatives, is characterized in that, the method of described recrystallization comprises the following steps, by mass volume ratio 1:1～100, enriched material is added in organic solvent, at-20～50 ℃, stir 0.5～24 hour, filter, vacuum-drying, obtains sterling.
  11. 11. is according to claim 10 2, replace-2H-1 of 4-bis-, and the preparation method of 2,3-triazole derivatives, is characterized in that, described organic solvent is the mixing of one or more arbitrary proportions in fatty acid ester, ketone, ethers and hydro carbons.
  12. 12. according to 2 described in claim 1 or 3, replace-2H-1 of 4-bis-, and the preparation method of 2,3-triazole derivatives, is characterized in that, R3 represents methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, n-pentyl or isopentyl.
  13. 13. according to 2 described in any one in claim 2,4,7, replace-2H-1 of 4-bis-, 2, the preparation method of 3-triazole derivatives, it is characterized in that, described organic solvent is the mixing of one or more arbitrary proportions in ethyl formate, propyl formate, butyl formate, methyl acetate, ethyl acetate, propyl acetate, butylacetate, isopropyl acetate, isobutyl acetate, pentyl acetate, Isoamyl Acetate FCC, methyl propionate, ethyl propionate, propyl propionate, butyl propionate and amyl propionate, ether, propyl ether, isopropyl ether, methyl tertiary butyl ether.
  14. 14. according to claim 92, replace-2H-1 of 4-bis-, 2, the preparation method of 3-triazole derivatives, it is characterized in that, described organic solvent is methyl alcohol, ethanol, propyl alcohol, Virahol, propyl carbinol, the trimethyl carbinol, Pentyl alcohol, primary isoamyl alcohol, ethyl formate, propyl formate, butyl formate, methyl acetate, ethyl acetate, propyl acetate, butylacetate, isopropyl acetate, isobutyl acetate, pentyl acetate, Isoamyl Acetate FCC, methyl propionate, ethyl propionate, propyl propionate, the mixing of one or more arbitrary proportions in butyl propionate and amyl propionate.
  15. 15. according to claim 11 2, replace-2H-1 of 4-bis-, 2, the preparation method of 3-triazole derivatives, it is characterized in that, described organic solvent is ethyl formate, propyl formate, butyl formate, methyl acetate, ethyl acetate, propyl acetate, butylacetate, isopropyl acetate, isobutyl acetate, pentyl acetate, Isoamyl Acetate FCC, methyl propionate, ethyl propionate, propyl propionate, butyl propionate and amyl propionate, acetone, 2-butanone, cyclopentanone and pimelinketone, ether, propyl ether, isopropyl ether, methyl tertiary butyl ether and tetrahydrofuran (THF), 1, 4-dioxane, sherwood oil, normal hexane, hexanaphthene, the mixing of one or more arbitrary proportions in methylcyclohexane and normal heptane.
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