CN107311946A - 2‑（The triazol radicals of 1H 1,2,3）The synthetic method of the carboxylic acid ethyl ester compound of 3 xenol 4 - Google Patents

2‑（The triazol radicals of 1H 1,2,3）The synthetic method of the carboxylic acid ethyl ester compound of 3 xenol 4 Download PDF

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CN107311946A
CN107311946A CN201710492115.0A CN201710492115A CN107311946A CN 107311946 A CN107311946 A CN 107311946A CN 201710492115 A CN201710492115 A CN 201710492115A CN 107311946 A CN107311946 A CN 107311946A
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carboxylic acid
xenol
synthetic method
ethyl ester
acid ethyl
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CN107311946B (en
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王强
范云场
张社利
赵新萍
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Henan University of Technology
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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
    • C07D249/06—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles with aryl radicals directly attached to ring atoms

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Abstract

The invention discloses a kind of synthetic method of the carboxylic acid ethyl ester compound of 2 (triazol radicals of 1H 1,2,3) 3 xenol 4, belong to technical field of organic synthesis.Technical scheme main points are：Reaction equation in the synthetic method of the carboxylic acid ethyl ester compound of 2 (triazol radicals of 1H 1,2,3) 3 xenol 4, its building-up process is：

Description

2- (1H-1,2,3- triazol radicals) -3- xenol -4- carboxylic acid ethyl ester compounds Synthetic method
Technical field
The invention belongs to technical field of organic synthesis, and in particular to a kind of 2- (1H-1,2,3- triazol radicals) -3- hydroxyls connection The synthetic method of benzene -4- carboxylic acid ethyl ester compounds.
Background technology
2- (1H-1,2,3- triazol radicals) -3- xenol -4- carboxylic acid ethyl ester compounds are used as a kind of important classics Heterocyclic compound, is widely used in the various fields such as medicine, material and synthesis.It is difficult to obtain yet with raw material, to being at present Only, the synthetic method of such compound is also reported without pertinent literature.
The content of the invention
Present invention solves the technical problem that there is provided a kind of 2- (1H-1,2,3- triazol radicals) -3- xenol -4- carboxylics The synthetic method of acetoacetic ester class compound, the synthetic method there is initiation material simply easily to prepare, without expensive metal catalytic Agent and reagent, environment are the advantages of good, reaction condition is gentle and easy to operate again.
The present invention is to solve above-mentioned technical problem to adopt the following technical scheme that, 2- (1H-1,2,3- triazol radicals) -3- hydroxyls The synthetic method of biphenyl-4-carboxylic acid ethyl ester compound, it is characterised in that specifically building-up process is：With 4- azido acetoacetates Ethyl ester, terminal alkyne class compound and 1,2- connection ketene compounds are reaction raw materials, using copper sulphate and sodium ascorbate to urge Change system, using potassium carbonate, cesium carbonate or sodium hydroxide as alkali, using the mixed solution of the tert-butyl alcohol and water as solvent, passes through in 80 DEG C Target product 2- (1H-1,2,3- triazoles are made in the condensation reaction that the cyclization and alkali or salt of the copper catalysis of series connection promote Base) -3- xenol -4- carboxylic acid ethyl ester compounds, the reaction equation in the synthetic method is：
Wherein R is phenyl, 3,4- Dimethoxyphenyls, the bromo- 5- methoxyphenyls of 2-, 2- bromophenyls, 4- trifluoromethylbenzenes Base or the bromo- 5- fluorophenyls of 2-, R1For phenyl, 3- aminomethyl phenyls, 4- aminomethyl phenyls, 4- fluorophenyls, 4- chlorphenyls, 4- bromophenyls, Benzyl, methylol, 1- hydroxyphenylmethyls or 2- hydroxyls-(1 '-bromophenylethyl), R2For hydrogen or methyl, R3For hydrogen or phenyl.
Further preferably, described 2- (1H-1,2,3- triazol radicals) -3- xenol -4- carboxylic acid ethyl ester compounds Synthetic method, it is characterised in that concretely comprise the following steps：4- azidos ethyl acetoacetate and terminal alkyne class compound are dissolved in In the mixed solution of the tert-butyl alcohol and water, sodium ascorbate and copper-bath are added, obtained mixture is stirred at room temperature 12h, then adds potassium carbonate, cesium carbonate or sodium hydroxide and 1,2- connection ketene compounds, is warming up to 80 DEG C of reactions 3h, TLC Added water terminating reaction after monitoring reaction completely, extracted, dried with dichloromethane, concentrated, the isolated 2- (1H- of rapid column chromatography 1,2,3- triazol radicals) -3- xenol -4- carboxylic acid ethyl ester compounds.
Further preferably, described 4- azidos ethyl acetoacetate, terminal alkyne class compound, 1,2- connection ketenes The molar ratio of compound, sodium ascorbate, cupric sulfate pentahydrate and potassium carbonate or cesium carbonate is 1:1:0.9:0.1:0.05:1.
Further preferably, described 4- azidos ethyl acetoacetate, terminal alkyne class compound, 1,2- connection ketenes Compound, sodium ascorbate, the molar ratio of cupric sulfate pentahydrate and sodium hydroxide are 1:1:0.9:0.1:0.05:2.
Further preferably, the charge ratio of 1 described, 2- connection ketene compounds and solvent is 1mmol:4mL.
Further preferably, the volume ratio of the tert-butyl alcohol and water is 1 in the mixed solution of described solvent tertiary butanol and water:1.
Present invention firstly provides a kind of 2- (1H-1,2,3- triazol radicals) -3- xenol -4- carboxylic acid ethyl ester chemical combination The synthetic method of thing, the synthetic method has advantages below：1st, reaction condition is gentle, technique is simple, it is not necessary to anhydrous and oxygen-free ring Border；2nd, metallic catalyst and special reagent that need not be expensive, solvent environment be friendly；3rd, initiation material 4- azidos acetoacetate The non-ring compounds such as ethyl ester, terminal alkyne class compound and 1,2- connection ketene compounds prepare convenient or easily purchase；4th, should Synthetic method constructs phenyl ring and triazole ring simultaneously；5th, the target product finally synthesized is easily isolated purifying.
Embodiment
The above to the present invention is described in further details by the following examples, but this should not be interpreted as to this The scope for inventing above-mentioned theme is only limitted to following embodiment, and all technologies realized based on the above of the present invention belong to this hair Bright scope.
Embodiment 1
In 10mL round-bottomed flask add 1a (1mmol, 102mg), 4- nitrine ethyl acetoacetate 2 (1mmol, 171mg) and the 4mL tert-butyl alcohols and water mixture (volume ratio is 1/1), then add the cupric sulfate pentahydrate aqueous solution (0.05mmol, 52 μ L, 1M) and sodium ascorbate (0.1mmol, 19.9mg), obtained mixture is stirred at room temperature after 12h, adds 3a (0.9mmol, 129.6mg) and sodium hydroxide (2.0mmol, 80mg), is warming up to 80 DEG C and continues to react 2h.Room temperature is cooled to add 5mL water quenchings are gone out reaction, are extracted with dichloromethane (5mL × 3), saturated common salt water washing, anhydrous sodium sulfate drying.Filtering, is spin-dried for, Cross silica gel post separation (petrol ether/ethyl acetate=5/1) and obtain yellow oil product 5- methyl -2- (4- phenyl -1H-1,2,3- Triazol radical) -3- hydroxyls-(1,1 '-biphenyl) -4- carboxylic acid, ethyl esters 4aa (256mg, 64%).
The characterize data of the compound is as follows：1HNMR(400MHz,CDCl3) δ=12.08 (s, 1H), 7.81-7.78 (m, 2H),7.70(s,1H),7.40-7.37(m,2H),7.32-7.28(m,1H),7.25-7.22(m,3H),7.20-7.16(m, 2H), 6.93 (s, 1H), 4.50 (q, J=7.6Hz, 2H), 2.69 (s, 3H), 1.47 (t, J=7.2Hz, 3H)；13CNMR (100MHz,CDCl3) δ=171.2,158.7,147.1,144.6,143.5,136.5,130.5,128.7,128.5,12 8.1, 128.1,125.8,124.3,122.9,122.0,112.4,62.4,24.3,14.2；HRMS(ESI):calcd for C24H22N3O3[M+H]+:400.1661；found 400.1663.
Embodiment 2
In 10mL round-bottomed flask add 1a (1mmol, 102mg), 4- nitrine ethyl acetoacetate 2 (1mmol, 171mg) and the 4mL tert-butyl alcohols and water mixture (volume ratio is 1/1), then add the cupric sulfate pentahydrate aqueous solution (0.05mmol, 52 μ L, 1M) and sodium ascorbate (0.1mmol, 19.9mg), obtained mixture is stirred at room temperature after 12h, adds 3a (0.9mmol, 129.6mg) and potassium carbonate (1.0mmol, 138mg), is warming up to 80 DEG C and continues to react 2h.Room temperature is cooled to, plus 5mL water quenchings are gone out reaction, are extracted with dichloromethane (5mL × 3), saturated common salt water washing, anhydrous sodium sulfate drying.Filtering, is spin-dried for, Cross silica gel post separation (petrol ether/ethyl acetate=5/1) and obtain yellow oil product 5- methyl -2- (4- phenyl -1H-1,2,3- Triazol radical) -3- hydroxyls-(1,1 '-biphenyl) -4- carboxylic acid, ethyl esters 4aa (200mg, 50%).
Embodiment 3
In 10mL round-bottomed flask add 1a (1mmol, 102mg), 4- nitrine ethyl acetoacetate 2 (1mmol, 171mg) and the 4mL tert-butyl alcohols and water mixture (volume ratio is 1/1), then add the cupric sulfate pentahydrate aqueous solution (0.05mmol, 52 μ L, 1M) and sodium ascorbate (0.1mmol, 19.9mg), obtained mixture is stirred at room temperature after 12h, adds 3a (0.9mmol, 129.6mg) and cesium carbonate (1.0mmol, 325.8mg), is warming up to 80 DEG C and continues to react 2h.Room temperature is cooled to, plus 5mL water quenchings are gone out reaction, are extracted with dichloromethane (5mL × 3), saturated common salt water washing, anhydrous sodium sulfate drying.Filtering, is spin-dried for, Cross silica gel post separation (petrol ether/ethyl acetate=5/1) and obtain yellow oil product 5- methyl -2- (4- phenyl -1H-1,2,3- Triazol radical) -3- hydroxyls-(1,1 '-biphenyl) -4- carboxylic acid, ethyl esters 4aa (204mg, 51%).
Embodiment 4
In 10mL round-bottomed flask add 1a (1mmol, 102mg), 4- nitrine ethyl acetoacetate 2 (1mmol, 171mg) and the 4mL tert-butyl alcohols and water mixture (volume ratio is 1/1), then add the cupric sulfate pentahydrate aqueous solution (0.05mmol, 52 μ L, 1M) and sodium ascorbate (0.1mmol, 19.9mg), obtained mixture is stirred at room temperature after 12h, adds 3b (0.9mmol, 204.2mg) and sodium hydroxide (2.0mmol, 80mg), is warming up to 80 DEG C and continues to react 2h.Room temperature is cooled to, plus 5mL water quenchings are gone out reaction, are extracted with dichloromethane (5mL × 3), saturated common salt water washing, anhydrous sodium sulfate drying.Filtering, is spin-dried for, Cross silica gel post separation (petrol ether/ethyl acetate=3/1) and obtain yellow solid product 5- methyl -2- (4- phenyl -1H-1,2,3- Triazol radical) -3- hydroxyls -3 ', 4 '-dimethoxy-(1,1 '-biphenyl) -4- carboxylic acid, ethyl esters 4ab (299mg, 65%).
The characterize data of the compound is as follows：1HNMR(400MHz,CDCl3) δ=12.08 (s, 1H), 7.78-7.76 (m, 2H), 7.67 (s, 1H), 7.39-7.35 (m, 2H), 7.30-7.26 (m, 2H), 6.93 (s, 1H), 6.82 (dd, J=1.6, 8.4Hz, 1H), 6.74 (d, J=8.4Hz, 1H), 6.59 (d, J=2.4Hz, 1H), 4.47 (q, J=6.8Hz, 2H), 3.79 (s, 3H), (t, J=6.8Hz, the 3H) of 3.65 (s, 3H), 2.67 (s, 3H), 1.4513CNMR(100MHz,CDCl3) δ=171.3, 159.0,149.3,148.7,147.3,144.2,143.6,130.4,128.8,128.8,128.1,125.8,123.9, 122.9,121.7,120.9,111.9,111.0,62.4,55.9,55.8,24.4,14.2.HRMS(ESI):calcd for C26H26N3O5[M+H]+:460.1872；found 460.1877.
Embodiment 5
In 10mL round-bottomed flask add 1b (1mmol, 116mg), 4- nitrine ethyl acetoacetate 2 (1mmol, 171mg) and the 4mL tert-butyl alcohols and water mixture (volume ratio is 1/1), then add the cupric sulfate pentahydrate aqueous solution (0.05mmol, 52 μ L, 1M) and sodium ascorbate (0.1mmol, 19.9mg), obtained mixture is stirred at room temperature after 12h, adds 3c (0.9mmol, 253mg) and sodium hydroxide (2.0mmol, 80mg), is warming up to 80 DEG C and continues to react 2h.It is cooled to room temperature, plus 5mL Water quenching is gone out reaction, is extracted with dichloromethane (5mL × 3), saturated common salt water washing, anhydrous sodium sulfate drying.Filtering, is spin-dried for, mistake Silica gel post separation (petrol ether/ethyl acetate=5/1) obtains yellow solid product 5- methyl -2- (4- (m- methyl) phenyl -1H- 1,2,3- triazol radicals) -5 '-methoxyl group of -3- hydroxyls -2 '-bromo- (1,1 '-biphenyl) -4- carboxylic acid, ethyl esters 4bc (375.8mg, 72%).
The characterize data of the compound is as follows：1HNMR(400MHz,CDCl3) δ=12.09 (s, 1H), 7.90 (s, 1H), 7.65 (s, 1H), 7.55 (d, J=7.6Hz, 1H), 7.32-7.24 (m, 2H), 7.10 (d, J=8.0Hz, 1H), 6.81 (s, 1H), 6.78 (d, J=2.8Hz, 1H), 6.64 (dd, J=3.2,8.8Hz, 1H), 4.49 (q, J=7.6Hz, 2H), 3.67 (s, 3H), (t, J=7.6Hz, the 3H) of 2.68 (s, 3H), 2.36 (s, 3H), 1.4613CNMR(100MHz,CDCl3) δ=171.2, 158.5,158.2,146.7,143.9,143.2,138.4,138.1,133.0,130.4,128.8,128.7,126.4, 124.4,122.9,122.70,122.67,116.5,115.8,113.2,112.1,62.5,55.5,24.3,21.4, 14.2.HRMS(ESI):calcd for C26H25BrN3O4[M+H]+:522.1028；found 522.1033.
Embodiment 6
In 10mL round-bottomed flask add 1c (1mmol, 116mg), 4- nitrine ethyl acetoacetate 2 (1mmol, 171mg) and the 4mL tert-butyl alcohols and water mixture (volume ratio is 1/1), then add the cupric sulfate pentahydrate aqueous solution (0.05mmol, 52 μ L, 1M) and sodium ascorbate (0.1mmol, 19.9mg), obtained mixture is stirred at room temperature after 12h, adds 3d (0.9mmol, 223mg) and sodium hydroxide (2.0mmol, 80mg), is warming up to 80 DEG C and continues to react 2h.It is cooled to room temperature plus 5mL Water quenching is gone out reaction, is extracted with dichloromethane (5mL × 3), saturated common salt water washing, anhydrous sodium sulfate drying.Filtering, is spin-dried for, mistake Silica gel post separation (petrol ether/ethyl acetate=5/1) obtains brown solid 5- methyl -2- (4- (p- aminomethyl phenyls) -1H- 1,2,3- triazol radicals) -3- hydroxyls -2 '-bromo- (1,1 '-biphenyl) -4- carboxylic acid, ethyl esters 4cd (344.4mg, 70%).
The characterize data of the compound is as follows：1HNMR(400MHz,CDCl3) δ=12.09 (s, 1H), 7.85 (s, 1H), 7.66 (d, J=8.4Hz, 2H), 7.46 (d, J=8.4Hz, 1H), 7.22-7.17 (m, 4H), 7.10-7.06 (m, 1H), 6.81 (s, 1H), 4.49 (q, J=7.2Hz, 2H), 2.68 (s, 3H), 2.34 (s, 3H), 1.47 (t, J=7.0Hz, 2H)13CNMR (100MHz,CDCl3) δ=171.2,158.1,146.6,143.9,143.1,137.8,137.4,132.4,130.8,12 9.9, 129.4,127.7,127.2,125.7,124.5,122.8,122.3,121.9,113.2,62.5,24.3,21.3, 14.2.HRMS(ESI):calcdfor C25H23BrN3O3[M+H]+:492.0923；found 492.0929.
Embodiment 7
In 10mL round-bottomed flask add 1d (1mmol, 120mg), 4- nitrine ethyl acetoacetate 2 (1mmol, 171mg) and the 4mL tert-butyl alcohols and water mixture (volume ratio is 1/1), then add the cupric sulfate pentahydrate aqueous solution (0.05mmol, 52 μ L, 1M) and sodium ascorbate (0.1mmol, 19.9mg), obtained mixture is stirred at room temperature after 12h, adds 3a (0.9mmol, 129.6mg) and sodium hydroxide (2.0mmol, 80mg), is warming up to 80 DEG C and continues to react 2h.Room temperature is cooled to add 5mL water quenchings are gone out reaction, are extracted with dichloromethane (5mL × 3), saturated common salt water washing, anhydrous sodium sulfate drying.Filtering, is spin-dried for, Cross silica gel post separation (petrol ether/ethyl acetate=5/1) and obtain yellow solid product 5- methyl -2- (4- (p- fluorophenyls) -1H- 1,2,3- triazol radicals) -3- hydroxyls-(1,1 '-biphenyl) -4- carboxylic acid, ethyl esters 4da (284.3mg, 68%).
The characterize data of the compound is as follows：1HNMR(400MHz,CDCl3) δ=12.10 (s, 1H), 7.76-7.73 (m, 2H),7.66(s,1H),7.24-7.22(m,3H),7.18-7.16(m,2H),7.08-7.04(m,2H),6.92(s,1H), (t, J=7.6Hz, the 2H) of 4.49 (q, J=7.6Hz, 2H), 2.69 (s, 3H), 1.4713CNMR(100MHz,CDCl3) δ= 171.2,163.8,161.4,158.7,146.2,144.6,143.6,136.5,128.5,128.1,127.6,127.5, 126.79,126.76,124.3,122.6,121.9,115.8,115.6,112.4,62.5,24.4,14.2.HRMS(ESI): calcd for C24H21FN3O3[M+H]+:418.1567；found 418.1562.
Embodiment 8
In 10mL round-bottomed flask add 1e (1mmol, 136.6mg), 4- nitrine ethyl acetoacetate 2 (1mmol, 171mg) and the 4mL tert-butyl alcohols and water mixture (volume ratio is 1/1), then add the cupric sulfate pentahydrate aqueous solution (0.05mmol, 52 μ L, 1M) and sodium ascorbate (0.1mmol, 19.9mg), obtained mixture is stirred at room temperature after 12h, adds 3a (0.9mmol, 129.6mg) and sodium hydroxide (2.0mmol, 80mg), is warming up to 80 DEG C and continues to react 2h.Room temperature is cooled to add 5mL water quenchings are gone out reaction, are extracted with dichloromethane (5mL × 3), saturated common salt water washing, anhydrous sodium sulfate drying.Filtering, is spin-dried for, Cross silica gel post separation (petrol ether/ethyl acetate=5/1) and obtain yellow solid product 5- methyl -2- (4- (p- chlorphenyls) -1H- 1,2,3- triazol radicals) -3- hydroxyls-(1,1 '-biphenyl) -4- carboxylic acid, ethyl esters 4ea (299.5mg, 69%).
The characterize data of the compound is as follows：1HNMR(400MHz,CDCl3) δ=12.10 (s, 1H), 7.74-7.70 (m, 2H),7.68(s,1H),7.36-7.33(m,2H),7.25-7.22(m,3H),7.17-7.15(m,2H),6.93(s,1H), (t, J=7.2Hz, the 3H) of 4.50 (q, J=7.2Hz, 2H), 2.69 (s, 3H), 1.4813CNMR(100MHz,CDCl3) δ= 171.2,158.6,146.0,144.6,143.7,136.4,133.8,128.9,128.6,128.5,128.1,127.1, 124.3,122.9,121.9,112.4,62.5,24.4,14.2.HRMS(ESI):calcd for C24H21ClN3O3[M+H]+: 434.1271；found 434.1276.
Embodiment 9
In 10mL round-bottomed flask add 1f (1mmol, 181mg), 4- nitrine ethyl acetoacetate 2 (1mmol, 171mg) and the 4mL tert-butyl alcohols and water mixture (volume ratio is 1/1), then add the cupric sulfate pentahydrate aqueous solution (0.05mmol, 52 μ L, 1M) and sodium ascorbate (0.1mmol, 19.9mg), obtained mixture is stirred at room temperature after 12h, adds 3a (0.9mmol, 129.6mg) and sodium hydroxide (2.0mmol, 80mg), is warming up to 80 DEG C and continues to react 2h.Room temperature is cooled to add 5mL water quenchings are gone out reaction, are extracted with dichloromethane (5mL × 3), saturated common salt water washing, anhydrous sodium sulfate drying.Filtering, is spin-dried for, Cross silica gel post separation (petrol ether/ethyl acetate=5/1) and obtain brown solid 5- methyl -2- (4- (p- bromophenyls) -1H- 1,2,3- triazol radicals) -3- hydroxyls-(1,1 '-biphenyl) -4- carboxylic acid, ethyl esters 4fa (339.4mg, 71%).
The characterize data of the compound is as follows：1HNMR(400MHz,CDCl3) δ=12.11 (s, 1H), 7.70 (s, 1H), 7.64 (d, J=8.8Hz, 2H), 7.48 (d, J=8.0Hz, 2H), 7.24-7.21 (m, 3H), 7.17-7.14 (m, 2H), 6.92 (s, 1H), 4.49 (q, J=7.6Hz, 2H), 2.68 (s, 3H), 1.46 (t, J=7.2Hz, 3H)13CNMR(100MHz,CDCl3) δ=171.2,158.6,146.1,144.6,143.7,136.4,131.9,129.5,128.5,12 8.1,127.3,124.3, 123.0,121.9,112.4,62.5,24.4,14.2.HRMS(ESI):calcd for C24H21BrN3O3[M+H]+: 478.0766；found 478.0770.
Embodiment 10
In 10mL round-bottomed flask add 1f (1mmol, 181mg), 4- nitrine ethyl acetoacetate 2 (1mmol, 171mg) and the 4mL tert-butyl alcohols and water mixture (volume ratio is 1/1), then add the cupric sulfate pentahydrate aqueous solution (0.05mmol, 52 μ L, 1M) and sodium ascorbate (0.1mmol, 19.9mg), obtained mixture is stirred at room temperature after 12h, adds 3b (0.9mmol, 204.2mg) and sodium hydroxide (2.0mmol, 80mg), is warming up to 80 DEG C and continues to react 2h.Room temperature is cooled to add 5mL water quenchings are gone out reaction, are extracted with dichloromethane (5mL × 3), saturated common salt water washing, anhydrous sodium sulfate drying.Filtering, is spin-dried for, Cross silica gel post separation (petrol ether/ethyl acetate=5/1) obtain yellow oil 5- methyl -2- (4- (p- bromophenyls) -1H-1, 2,3- triazol radicals) -3- hydroxyls -2 ', 5 '-dimethoxy-(1,1 '-biphenyl) -4- carboxylic acid, ethyl esters 4fb (376.6mg, 70%).
The characterize data of the compound is as follows：1HNMR(400MHz,CDCl3) δ=12.10 (s, 1H), 7.68 (s, 1H), 7.64-7.61 (m, 2H), 7.48-7.45 (m, 2H), 6.96 (s, 1H), 6.79 (dd, J=2.0,8.4Hz, 1H), 6.73 (d, J =8.4Hz, 1H), 6.57 (d, J=1.6Hz, 1H), 4.46 (q, J=7.2Hz, 2H), 3.78 (s, 3H), 3.63 (s, 3H), 1.44 (t, J=7.2Hz, 3H)13CNMR(100MHz,CDCl3) δ=171.2,158.9,149.3,148.7,146.3, 144.1,143.7,131.9,129.4,128.8,127.3,123.9,123.1,121.9,121.6,120.9,111.9, 110.9,62.4,55.8,55.7,24.4,14.2.HRMS(ESI):calcd for C26H25BrN3O5[M+H]+:538.0978； found 538.0972。
Embodiment 11
In 10mL round-bottomed flask add 1f (1mmol, 181mg), 4- nitrine ethyl acetoacetate 2 (1mmol, 171mg) and the 4mL tert-butyl alcohols and water mixture (volume ratio is 1/1), then add the cupric sulfate pentahydrate aqueous solution (0.05mmol, 52 μ L, 1M) and sodium ascorbate (0.1mmol, 19.9mg), obtained mixture is stirred at room temperature after 12h, adds 3e (0.9mmol, 191mg) and sodium hydroxide (2.0mmol, 80mg), is warming up to 80 DEG C and continues to react 2h.It is cooled to room temperature plus 5mL Water quenching is gone out reaction, is extracted with dichloromethane (5mL × 3), saturated common salt water washing, anhydrous sodium sulfate drying.Filtering, is spin-dried for, mistake Silica gel post separation (petrol ether/ethyl acetate=5/1) obtains yellow solid product 5- -4 '-trifluoromethyls of methyl -2- (4- (p- bromines Phenyl) -1H-1,2,3- triazol radicals) -3- hydroxyls-(1,1 '-biphenyl) -4- carboxylic acid, ethyl esters 4fe (360.4mg, 66%).
The characterize data of the compound is as follows：1HNMR(400MHz,CDCl3) δ=12.14 (s, 1H), 7.80 (s, 1H), 7.86-7.66 (m, 1H), 7.52-7.49 (m, 4H), 7.30 (d, J=8.0Hz, 2H), 6.90 (s, 1H), 4.51 (q, J= 7.2Hz, 2H), 2.70 (s, 3H), 1.48 (t, J=6.8Hz, 3H)13CNMR(100MHz,CDCl3) δ=171.1,158.5, 146.3,144.0,143.0,140.2,131.9,130.7,130.4,129.3,128.6,127.3,125.5,125.4, 125.2,124.2,122.9,122.1,121.9,113.0,62.7,24.4,14.2.HRMS(ESI):calcd for C25H20BrF3N3O3[M+H]+:546.0640；found 546.0635.
Embodiment 12
In 10mL round-bottomed flask add 1g (1mmol, 116.2mg), 4- nitrine ethyl acetoacetate 2 (1mmol, 171mg) and the 4mL tert-butyl alcohols and water mixture (volume ratio is 1/1), then add the cupric sulfate pentahydrate aqueous solution (0.05mmol, 52 μ L, 1M) and sodium ascorbate (0.1mmol, 19.9mg), obtained mixture is stirred at room temperature after 12h, adds 3b (0.9mmol, 204.2mg) and sodium hydroxide (2.0mmol, 80mg), is warming up to 80 DEG C and continues to react 2h.Room temperature is cooled to add 5mL water quenchings are gone out reaction, are extracted with dichloromethane (5mL × 3), saturated common salt water washing, anhydrous sodium sulfate drying.Filtering, is spin-dried for, Cross silica gel post separation (petrol ether/ethyl acetate=3/1) and obtain white solid product 5- methyl -2- (4- benzyls -1H-1,2,3- Triazol radical) -3- hydroxyls -3 ', 4 '-dimethoxy-(1,1 '-biphenyl) -4- carboxylic acid, ethyl esters 4gb (303.4mg, 64%).
The characterize data of the compound is as follows：1HNMR(400MHz,CDCl3) δ=11.95 (s, 1H), 7.23-7.14 (m, 3H), 7.07-7.05 (m, 3H), 6.88 (s, 1H), 6.74 (s, 1H), 6.48 (s, 1H), 4.47 (q, J=7.2Hz, 2H), 4.06 (s, 2H), 3.85 (s, 2H), 2.65 (s, 3H), 1.47 (t, J=7.2Hz, 3H)13CNMR(100MHz,CDCl3) δ=171.2, 158.8,149.3,148.7,144.3,143.3,129.1,128.5,128.4,126.3,124.9,123.8,120.8, 111.0,110.9,62.3,55.82,55.78,31.9,24.3,14.2.HRMS(ESI):calcd for C27H28N3O5[M+H ]+:474.2029；found 474.2035.
Embodiment 13
In 10mL round-bottomed flask add 1h (1mmol, 56.1mg), 4- nitrine ethyl acetoacetate 2 (1mmol, 171mg) and the 4mL tert-butyl alcohols and water mixture (volume ratio is 1/1), then add the cupric sulfate pentahydrate aqueous solution (0.05mmol, 52 μ L, 1M), sodium ascorbate (0.1mmol, 19.9mg), obtained mixture is stirred at room temperature after 12h, adds 3a (0.9mmol, 129.6mg) and sodium hydroxide (2.0mmol, 80mg), is warming up to 80 DEG C and continues to react 2h.Room temperature is cooled to add 5mL water quenchings are gone out reaction, are extracted with dichloromethane (5mL × 3), saturated common salt water washing, anhydrous sodium sulfate drying.Filtering, is spin-dried for, Cross silica gel post separation (petrol ether/ethyl acetate=1/1) obtain yellow solid product 5- methyl -2- (4- methylol -1H-1,2, 3- triazol radicals) -3- hydroxyls-(1,1 '-biphenyl) -4- carboxylic acid, ethyl esters 4ha (276mg, 78%).
The characterize data of the compound is as follows：1HNMR(400MHz,CDCl3) δ=12.08 (s, 1H), 7.46 (s, 1H), 7.25-7.21 (m, 3H), 7.14-7.09 (m, 2H), 6.90 (s, 1H), 4.73 (s, 2H), 4.49 (q, J=7.6Hz, 2H), (t, J=7.2Hz, the 3H) of 2.77 (s, 1H), 2.68 (s, 3H), 1.4713CNMR(100MHz,CDCl3) δ=171.2,158.6, 146.9,144.6,143.6,136.4,128.53,128.51,128.0,125.1,124.3,121.9,112.4,62.4, 56.4,24.3,14.2.HRMS(ESI):calcd for C19H20N3O4[M+H]+:354.1454；found 354.1459.
Embodiment 14
In 10mL round-bottomed flask add 1h (1mmol, 56.1mg), 4- nitrine ethyl acetoacetate 2 (1mmol, 171mg) and the 4mL tert-butyl alcohols and water mixture (volume ratio is 1/1), then add the cupric sulfate pentahydrate aqueous solution (0.05mmol, 52 μ L, 1M) and sodium ascorbate (0.1mmol, 19.9mg), obtained mixture is stirred at room temperature after 12h, adds 3d (0.9mmol, 223mg) and sodium hydroxide (2.0mmol, 80mg), is warming up to 80 DEG C and continues to react 2h.It is cooled to room temperature plus 5mL Water quenching is gone out reaction, is extracted with dichloromethane (5mL × 3), saturated common salt water washing, anhydrous sodium sulfate drying.Filtering, is spin-dried for, mistake Silica gel post separation (petrol ether/ethyl acetate=1/1) obtains yellow solid product 5- methyl -2- (4- methylols -1H-1,2,3- Triazol radical) -3- hydroxyls -2 '-bromo- (1,1 '-biphenyl) -4- carboxylic acid, ethyl esters 4hd (319.7mg, 74%).
The characterize data of the compound is as follows：1HNMR(400MHz,CDCl3) δ=11.97 (s, 1H), 7.61 (s, 1H), 7.45 (d, J=7.6Hz, 1H), 7.17-7.14 (m, 2H), 7.10-7.06 (m, 1H), 6.78 (s, 1H), 4.65 (s, 2H), (t, J=6.8Hz, the 3H) of 4.49 (q, J=6.8Hz, 2H), 2.82 (s, 1H), 2.66 (s, 3H), 1.4613CNMR(100MHz, CDCl3) δ=171.1,158.0,146.5,143.9,143.1,137.3,132.4,130.7,129.9,12 7.1,124.7, 124.5,122.7,121.9,113.3,62.5,56.4,24.2,14.2.HRMS(ESI):calcd for C19H19BrN3O4[M+ H]+:432.0559；found 432.0565.
Embodiment 15
In 10mL round-bottomed flask add 1h (1mmol, 56.1mg), 4- nitrine ethyl acetoacetate 2 (1mmol, 171mg) and the 4mL tert-butyl alcohols and water mixture (volume ratio is 1/1), then add the cupric sulfate pentahydrate aqueous solution (0.05mmol, 52 μ L, 1M) and sodium ascorbate (0.1mmol, 19.9mg), obtained mixture is stirred at room temperature after 12h, adds 3f (0.9mmol, 216.9mg) and sodium hydroxide (2.0mmol, 80mg), is warming up to 80 DEG C and continues to react 2h.Room temperature is cooled to add 5mL water quenchings are gone out reaction, are extracted with dichloromethane (5mL × 3), saturated common salt water washing, anhydrous sodium sulfate drying.Filtering, is spin-dried for, Cross silica gel post separation (petrol ether/ethyl acetate=1/1) obtain white solid product 5- methyl -2- (4- methylol -1H-1,2, 3- triazol radicals) -3- hydroxyls -2 '-bromo- 5 '-fluoro- (1,1 '-biphenyl) -4- carboxylic acid, ethyl esters 4hf (342mg, 76%).
The characterize data of the compound is as follows：1HNMR(400MHz,CDCl3) δ=12.08 (s, 1H), 7.68 (s, 1H), 7.40 (dd, J=4.8,9.2Hz, 1H), 6.95 (dd, J=2.8,8.4Hz, 1H), 6.84 (ddd, J=2.8,8.8,8.8Hz, 1H), 4.71 (s, 2H), 4.50 (q, J=6.8Hz, 1H), 2.70 (s, 1H), 2.67 (s, 3H), 1.47 (t, J=6.8Hz, 1H) .13CNMR(100MHz,CDCl3) δ=171.0,162.5,160.0,157.8,146.5,143.4,142.6,139.3,139.2, 137.8,133.7,124.8,124.1,122.6,118.2,117.9,117.3,117.1,116.33,116.28,113.6, 62.6,56.5,24.2,14.2.HRMS(ESI):calcd for C19H18BrFN3O4[M+H]+:450.0465；found 450.0470。
Embodiment 16
In 10mL round-bottomed flask add 1i (1mmol, 132.2mg), 4- nitrine ethyl acetoacetate 2 (1mmol, 171mg) and the 4mL tert-butyl alcohols and water mixture (volume ratio is 1/1), then add the cupric sulfate pentahydrate aqueous solution (0.05mmol, 52 μ L, 1M) and sodium ascorbate (0.1mmol, 19.9mg), obtained mixture is stirred at room temperature after 12h, adds 3a (0.9mmol, 129.6mg) and sodium hydroxide (2.0mmol, 80mg), is warming up to 80 DEG C and continues to react 2h.Room temperature is cooled to add 5mL water quenchings are gone out reaction, are extracted with dichloromethane (5mL × 3), saturated common salt water washing, anhydrous sodium sulfate drying.Filtering, is spin-dried for, Cross silica gel post separation (petrol ether/ethyl acetate=2/1) obtain white solid product 5- methyl -2- (4- (hydroxy phenyl) methyl - 1H-1,2,3- triazol radicals) -3- hydroxyls-(1,1 '-biphenyl) -4- carboxylic acid, ethyl esters 4ia (301.1mg, 70%).
The characterize data of the compound is as follows：1HNMR(400MHz,CDCl3) δ=11.99 (s, 1H), 7.28-7.18 (m, 8H), 7.14 (s, 1H), 7.04-7.02 (m, 2H), 6.87 (s, 1H), 5.93 (s, 1H), 4.46 (q, J=7.6Hz, 2H), 3.52 (s, 1H), 2.65 (s, 3H), 1.44 (t, J=7.2Hz, 3H)13CNMR(100MHz,CDCl3) δ=171.2,158.5, 150.7,144.6,143.6,141.9,136.4,128.5,128.44,128.36,128.0,127.8,126.7,124.8, 124.0,121.9,112.5,68.9,62.4,24.3,14.2.HRMS(ESI):calcd for C25H24N3O4[M+H]+: 430.1767；found 430.1773.
Embodiment 17
In 10mL round-bottomed flask add 1j (1mmol, 225mg), 4- nitrine ethyl acetoacetate 2 (1mmol, 171mg) and the 4mL tert-butyl alcohols and water mixture (volume ratio is 1/1), then add the cupric sulfate pentahydrate aqueous solution (0.05mmol, 52 μ L, 1M) and sodium ascorbate (0.1mmol, 19.9mg), obtained mixture is stirred at room temperature after 12h, adds 3e (0.9mmol, 191mg) and sodium hydroxide (2.0mmol, 80mg), is warming up to 80 DEG C and continues to react 2h.It is cooled to room temperature plus 5mL Water quenching is gone out reaction, is extracted with dichloromethane (5mL × 3), saturated common salt water washing, anhydrous sodium sulfate drying.Filtering, is spin-dried for, mistake Silica gel post separation (petrol ether/ethyl acetate=3/1) obtains yellow oil product 5- -4 '-trifluoromethyl of methyl -2- (4- (2- (2- bromophenyls) -1- hydroxyls) ethyl -1H-1,2,3- triazol radicals) -3- hydroxyls-(1,1 '-biphenyl) -4- carboxylic acid, ethyl esters 4je (407.1mg, 69%).
The characterize data of the compound is as follows：1HNMR(400MHz,CDCl3) δ=12.07 (s, 1H), 7.49-7.44 (m, 4H), 7.31 (s, 1H), 7.25-7.20 (m, 3H), 7.07 (t, J=7.2Hz, 1H), 6.87 (s, 1H), 5.30 (s, 1H), 4.49 (q, J=7.6Hz, 2H), 3.74 (s, 1H), 3.23 (d, J=14.8Hz, 1H), 2.96 (dd, J=6.8,14.0Hz, 1H), 2.67 (s, 3H), 1.46 (d, J=7.2Hz, 3H)13CNMR(100MHz,CDCl3) δ=171.1,158.5,143.9,142.9, 142.2,140.2,132.5,130.6,130.2,128.8,128.5,127.6,127.5,125.39,125.36,125.23, 124.0,122.5,121.6,113.1,71.9,62.6,33.1,24.3,14.1.HRMS(ESI):calcd for C27H24BrF3N3O4[M+H]+:590.0902；found 590.0910.
Embodiment 18
In 10mL round-bottomed flask add 1b (1mmol, 116.2mg), 4- nitrine ethyl acetoacetate 2 (1mmol, 171mg) and the 4mL tert-butyl alcohols and water mixture (volume ratio is 1/1), then add the cupric sulfate pentahydrate aqueous solution (0.05mmol, 52 μ L, 1M) and sodium ascorbate (0.1mmol, 19.9mg), obtained mixture is stirred at room temperature after 12h, adds 3g (0.9mmol, 142.4mg) and sodium hydroxide (2.0mmol, 80mg), is warming up to 80 DEG C and continues to react 2h.Room temperature is cooled to add 5mL water quenchings are gone out reaction, are extracted with dichloromethane (5mL × 3), saturated common salt water washing, anhydrous sodium sulfate drying.Filtering, is spin-dried for, Cross silica gel post separation (petrol ether/ethyl acetate=8/1) and obtain yellow oil product 5,6- dimethyl -2- (4- (m- methylbenzenes Base) -1H-1,2,3- triazol radicals) -3- hydroxyls-(1,1 '-biphenyl) -4- carboxylic acid, ethyl esters 4bg (239.7mg, 56%).
The characterize data of the compound is as follows：1HNMR(400MHz,CDCl3) δ=10.79 (s, 1H), 7.56 (s, 1H), 7.50 (s, 1H), 7.45 (d, J=7.2Hz, 1H), 7.25-7.19 (m, 4H), 7.09-7.06 (m, 3H), 4.50 (q, J= 7.2Hz, 2H), 2.58 (s, 3H), 2.35 (s, 3H), 2.04 (s, 3H), 1.46 (7, J=7.6Hz, 3H)13CNMR(100MHz, CDCl3) δ=170.6,153.9,146.7,144.7,141.4,138.4,136.3,130.3,128.8,12 8.7,128.6, 128.2,127.9,127.6,126.4,122.8,122.64,122.61,115.4,62.3,21.4,19.4,17.7, 14.2.HRMS(ESI):calcd forC26H26N3O3[M+H]+:428.1974；found 428.1979.
Embodiment 19
In 10mL round-bottomed flask add 1b (1mmol, 116.2mg), 4- nitrine ethyl acetoacetate 2 (1mmol, 171mg) and the 4mL tert-butyl alcohols and water mixture (volume ratio is 1/1), then add the cupric sulfate pentahydrate aqueous solution (0.05mmol, 52 μ L, 1M) and sodium ascorbate (0.1mmol, 19.9mg), obtained mixture is stirred at room temperature after 12h, adds 3h (0.9mmol, 198.3mg) and sodium hydroxide (2.0mmol, 80mg), is warming up to 80 DEG C and continues to react 2h.Room temperature is cooled to add 5mL water quenchings are gone out reaction, are extracted with dichloromethane (5mL × 3), saturated common salt water washing, anhydrous sodium sulfate drying.Filtering, is spin-dried for, Cross silica gel post separation (petrol ether/ethyl acetate=5/1) obtain yellow oil product 5- benzyls -2- (4- (m- aminomethyl phenyls) - 1H-1,2,3- triazol radicals) -3- hydroxyls-(1,1 '-biphenyl) -4- carboxylic acid, ethyl esters 4bh (156.8mg, 32%).
The characterize data of the compound is as follows：1HNMR(400MHz,CDCl3) δ=11.95 (s, 1H), 7.72 (s, 1H), 7.67 (s, 1H), 7.56 (d, J=7.2Hz, 1H), 7.32-7.28 (m, 3H), 7.24-7.21 (m, 4H), 7.17-7.11 (m, 5H), 6.95 (s, 1H), 4.47 (s, 2H), 4.34 (q, J=6.8Hz, 2H), 2.38 (s, 3H), 1.21 (t, J=6.8Hz, 3H) .13CNMR(100MHz,CDCl3) δ=170.6,158.8,147.3,144.7,140.3,138.5,136.4,130.4,128.8, 128.7,128.59,128.56,128.53,128.2,128.1,126.5,126.2,124.9,122.9,122.8,122.7, 62.4,41.9,21.4,13.8.HRMS(ESI):calcd for C31H28N3O3[M+H]+:490.2131；found 490.2136。
Have been shown and described above the general principle of the present invention, principal character and advantage, do not depart from spirit of the invention and On the premise of scope, the present invention also has various changes and modifications, and these changes and improvements both fall within claimed invention Scope.

Claims (6)

  1. The synthetic method of 1.2- (1H-1,2,3- triazol radicals) -3- xenol -4- carboxylic acid ethyl ester compounds, its feature exists It is in specific building-up process：Ketene compounds are joined with 4- azidos ethyl acetoacetate, terminal alkyne class compound and 1,2- For reaction raw materials, using copper sulphate and sodium ascorbate as catalyst system and catalyzing, using potassium carbonate, cesium carbonate or sodium hydroxide as alkali, with uncle The mixed solution of fourth alcohol and water is solvent, the condensation reaction system promoted in 80 DEG C of cyclizations and alkali by the copper catalysis of series connection Obtain in target product 2- (1H-1,2,3- triazol radicals) -3- xenol -4- carboxylic acid ethyl ester compounds, the synthetic method Reaction equation is：
    Wherein R be phenyl, 3,4- Dimethoxyphenyls, the bromo- 5- methoxyphenyls of 2-, 2- bromophenyls, 4- trifluoromethyls or The bromo- 5- fluorophenyls of 2-, R1For phenyl, 3- aminomethyl phenyls, 4- aminomethyl phenyls, 4- fluorophenyls, 4- chlorphenyls, 4- bromophenyls, benzene first Base, methylol, 1- hydroxyphenylmethyls or 2- hydroxyls-(1 '-bromophenylethyl), R2For hydrogen or methyl, R3For hydrogen or phenyl.
  2. 2. 2- (1H-1,2,3- triazol radicals) -3- xenol -4- carboxylic acid ethyl ester compounds according to claim 1 Synthetic method, it is characterised in that concretely comprise the following steps：4- azidos ethyl acetoacetate and terminal alkyne class compound are dissolved in In the mixed solution of the tert-butyl alcohol and water, sodium ascorbate and copper-bath are added, obtained mixture is stirred at room temperature 12h, then adds potassium carbonate, cesium carbonate or sodium hydroxide and 1,2- connection ketene compounds, is warming up to 80 DEG C of reactions 2h, TLC Added water terminating reaction after monitoring reaction completely, extracted, dried with dichloromethane, concentrated, the isolated 2- (1H- of rapid column chromatography 1,2,3- triazol radicals) -3- xenol -4- carboxylic acid ethyl ester compounds.
  3. 3. 2- (1H-1,2,3- triazol radicals) -3- xenol -4- carboxylic acid ethyl ester compounds according to claim 1 Synthetic method, it is characterised in that：Described 4- azidos ethyl acetoacetate, terminal alkyne class compound, 1,2- connection ketenes The molar ratio of class compound, sodium ascorbate, cupric sulfate pentahydrate and potassium carbonate or cesium carbonate is 1:1:0.9:0.1:0.05: 1。
  4. 4. 2- (1H-1,2,3- triazol radicals) -3- xenol -4- carboxylic acid ethyl ester compounds according to claim 1 Synthetic method, it is characterised in that：Described 4- azidos ethyl acetoacetate, terminal alkyne class compound, 1,2- connection ketenes Class compound, sodium ascorbate, the molar ratio of cupric sulfate pentahydrate and sodium hydroxide are 1:1:0.9:0.1:0.05:2.
  5. 5. 2- (1H-1,2,3- triazol radicals) -3- xenol -4- carboxylic acid ethyl ester compounds according to claim 1 Synthetic method, it is characterised in that：It is 1mmol that described 1,2-, which joins ketene compounds and the charge ratio of solvent,:4mL.
  6. 6. 2- (1H-1,2,3- triazol radicals) -3- xenol -4- carboxylic acid ethyl ester compounds according to claim 1 Synthetic method, it is characterised in that：The volume ratio of the tert-butyl alcohol and water is 1 in described solvent tertiary butanol and the mixed solution of water: 1。
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