CN107311946B - Synthetic method of 2- (1H-1,2, 3-triazolyl) -3-hydroxybiphenyl-4-carboxylic acid ethyl ester compound - Google Patents
Synthetic method of 2- (1H-1,2, 3-triazolyl) -3-hydroxybiphenyl-4-carboxylic acid ethyl ester compound Download PDFInfo
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Abstract
The invention discloses a synthetic method of a 2- (1H-1,2, 3-triazolyl) -3-hydroxybiphenyl-4-carboxylic acid ethyl ester compound, belonging to the technical field of organic synthesis. The technical scheme provided by the invention has the key points that: the synthesis method of the 2- (1H-1,2, 3-triazolyl) -3-hydroxybiphenyl-4-carboxylic acid ethyl ester compound comprises the following reaction equation in the synthesis process:
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a synthetic method of a 2- (1H-1,2, 3-triazolyl) -3-hydroxybiphenyl-4-carboxylic acid ethyl ester compound.
Background
The 2- (1H-1,2, 3-triazolyl) -3-hydroxybiphenyl-4-carboxylic acid ethyl ester compound is used as an important classical heterocyclic compound and is widely applied to a plurality of fields such as medicine, materials, synthesis and the like. However, as the raw materials are not easily available, no relevant literature reports the synthesis method of the compound.
Disclosure of Invention
The invention solves the technical problem of providing a synthetic method of 2- (1H-1,2, 3-triazolyl) -3-hydroxybiphenyl-4-carboxylic acid ethyl ester compounds, which has the advantages of simple and easy preparation of starting materials, no need of expensive metal catalysts and reagents, good environment, mild reaction conditions, simple and convenient operation and the like.
The invention adopts the following technical scheme for solving the technical problems, and the synthesis method of the 2- (1H-1,2, 3-triazolyl) -3-hydroxybiphenyl-4-carboxylic acid ethyl ester compound is characterized by comprising the following specific synthesis processes: the method comprises the following steps of taking 4-azido ethyl acetoacetate, terminal alkyne compounds and 1, 2-allene compounds as reaction raw materials, copper sulfate and sodium ascorbate as a catalytic system, potassium carbonate, cesium carbonate or sodium hydroxide as alkali, a mixed solution of tert-butyl alcohol and water as a solvent, and preparing a target product, namely 2- (1H-1,2, 3-triazolyl) -3-hydroxybiphenyl-4-carboxylic acid ethyl ester compounds through a series copper-catalyzed cyclization reaction and a condensation reaction promoted by alkali or salt at 80 ℃, wherein the reaction equation in the synthetic method is as follows:
wherein R is phenyl, 3, 4-dimethoxyphenyl, 2-bromo-5-methoxyphenyl, 2-bromophenyl, 4-trifluoromethylphenyl or 2-bromo-5-fluorophenyl, R1Is phenyl, 3-methylphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, benzyl, hydroxymethyl, 1-hydroxybenzyl or 2-hydroxy- (1' -bromophenylethyl), R2Is hydrogen or methyl, R3Is hydrogen or phenyl.
Further preferably, the synthesis method of the 2- (1H-1,2, 3-triazolyl) -3-hydroxybiphenyl-4-carboxylic acid ethyl ester compound is characterized by comprising the following steps of dissolving 4-azido ethyl acetoacetate and a terminal alkyne compound in a mixed solution of tert-butyl alcohol and water, adding sodium ascorbate and a copper sulfate solution, stirring the obtained mixture at room temperature for 12 hours, adding potassium carbonate, cesium carbonate or sodium hydroxide and a 1, 2-allene compound, heating to 80 ℃ for reaction for 3 hours, monitoring by T L C, adding water to stop the reaction after the reaction is completed, extracting by using dichloromethane, drying, concentrating, and performing rapid column chromatography separation to obtain the 2- (1H-1,2, 3-triazolyl) -3-hydroxybiphenyl-4-carboxylic acid ethyl ester compound.
More preferably, the feeding molar ratio of the 4-azidoacetoacetic acid ethyl ester, the terminal alkyne compound, the 1, 2-allene compound, the sodium ascorbate, the copper sulfate pentahydrate and the potassium carbonate or the cesium carbonate is 1:1:0.9:0.1:0.05: 1.
More preferably, the feeding molar ratio of the 4-azidoacetoacetic acid ethyl ester, the terminal alkyne compound, the 1, 2-allene compound, the sodium ascorbate, the copper sulfate pentahydrate and the sodium hydroxide is 1:1:0.9:0.1:0.05: 2.
Further preferably, the feeding ratio of the 1, 2-allene compound to the solvent is 1mmol:4m L.
More preferably, the volume ratio of the tertiary butanol to the water in the mixed solution of the tertiary butanol and the water as the solvent is 1: 1.
The invention provides a synthetic method of 2- (1H-1,2, 3-triazolyl) -3-hydroxybiphenyl-4-carboxylic acid ethyl ester compounds for the first time, and the synthetic method has the following advantages: 1. the reaction condition is mild, the process is simple, and an anhydrous and oxygen-free environment is not needed; 2. Expensive metal catalysts and special reagents are not needed, and the solvent is environment-friendly; 3. non-cyclic compounds such as starting materials of ethyl 4-azidoacetoacetate, terminal alkyne compounds, 1, 2-allene compounds and the like are convenient to prepare or easy to purchase; 4. the synthesis method simultaneously constructs a benzene ring and a triazole ring; 5. the final synthesized target product is easy to separate and purify.
Detailed Description
The present invention is described in further detail below with reference to examples, but it should not be construed that the scope of the above subject matter of the present invention is limited to the following examples, and that all the technologies realized based on the above subject matter of the present invention belong to the scope of the present invention.
Example 1
After 1a (1mmol,102mg), 4-azido ethyl acetoacetate 2(1mmol,171mg) and a mixture of 4M L tert-butanol and water (1/1 by volume) were added to a 10M L round bottom flask, an aqueous solution of copper sulfate pentahydrate (0.05mmol, 52. mu. L, 1M) and sodium ascorbate (0.1mmol,19.9mg) were added, the resulting mixture was stirred at room temperature for 12 hours, 3a (0.9mmol,129.6mg) and sodium hydroxide (2.0mmol,80mg) were added, the reaction was continued at 80 ℃ for 2 hours, the mixture was cooled to room temperature and quenched with 5M L water, extracted with dichloromethane (5M L× 3), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, rotary dried, and separated on a silica gel column (petroleum ether/ethyl acetate ═ 5/1) to give 5-methyl-2- (4-phenyl-1H-1, 2, 3-triazolyl) -3-hydroxy-biphenyl-carboxylic acid ethyl ester (64 mg ).
The characterization data for this compound are as follows:1HNMR(400MHz,CDCl3)＝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)＝171.2,158.7,147.1,144.6,143.5,136.5,130.5,128.7,128.5,128.1,128.1, 125.8,124.3,122.9,122.0,112.4,62.4,24.3,14.2；HRMS(ESI):calcd forC24H22N3O3[M+H]+: 400.1661；found 400.1663。
example 2
After 1a (1mmol,102mg), 4-azido ethyl acetoacetate 2(1mmol,171mg) and a mixture of 4M L tert-butanol and water (1/1 vol%) were added to a 10M L round bottom flask, an aqueous solution of copper sulfate pentahydrate (0.05mmol, 52. mu. L, 1M) and sodium ascorbate (0.1mmol,19.9mg) were added and the resulting mixture was stirred at room temperature for 12H, 3a (0.9mmol,129.6mg) and potassium carbonate (1.0mmol,138mg) were added, the reaction was allowed to continue at 80 ℃ for 2H, cooled to room temperature, quenched with 5M L water, extracted with dichloromethane (5M L× 3), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, rotary dried, and separated on a silica gel column (petroleum ether/ethyl acetate ═ 5/1) to give 5-methyl-2- (4-phenyl-1H-1, 2, 3-triazoyl) -3-hydroxy-biphenyl-carboxylic acid ethyl ester (200mg, aa-50%).
Example 3
After 1a (1mmol,102mg), 4-azido ethyl acetoacetate 2(1mmol,171mg) and a mixture of 4M L tert-butanol and water (1/1 vol%) were added to a 10M L round bottom flask, aqueous copper sulfate pentahydrate (0.05mmol, 52. mu. L, 1M) and sodium ascorbate (0.1mmol,19.9mg) were added and the resulting mixture was stirred at room temperature for 12H, 3a (0.9mmol,129.6mg) and cesium carbonate (1.0mmol,325.8mg) were added and the reaction was continued at 80 ℃ for 2H, cooled to room temperature, quenched with 5M L water, extracted with dichloromethane (5M L× 3), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, spin-dried, and separated on a silica gel column (petroleum ether/ethyl acetate ═ 5/1) to give 5-methyl-2- (4-phenyl-1H-1, 2, 3-triazoyl) -3-hydroxy biphenyl-carboxylic acid ethyl ester (51 mg, 204 aa-51%).
Example 4
After stirring a 10M L round bottom flask with a mixture of 1a (1mmol,102mg), ethyl 4-azidoacetoacetate 2(1mmol,171mg) and 4M L tert-butanol and water (1/1 vol.), aqueous copper sulfate pentahydrate (0.05mmol, 52. mu. L, 1M) and sodium ascorbate (0.1mmol,19.9mg) were added, the resulting mixture was stirred at room temperature for 12H, 3b (0.9mmol,204.2mg) and sodium hydroxide (2.0mmol,80mg) were added, the reaction was allowed to continue at 80 ℃ for 2H, cooled to room temperature, quenched with 5M L water, extracted with dichloromethane (5M L× 3), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, rotary dried, and separated on a silica gel column (petroleum ether/ethyl acetate ═ 3/1) to give the product 5-methyl-2- (4-phenyl-1H-1, 2, 3-triazoyl) -3-dimethoxy-3 ', biphenyl-4 ' -carboxylic acid ethyl ester (65 mg, 4 ' -biphenyl-4-carboxylic acid ethyl ester).
The characterization data for this compound are as follows:1HNMR(400MHz,CDCl3)＝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), 3.65(s,3H),2.67(s,3H),1.45(t,J＝6.8Hz,3H).13CNMR(100MHz,CDCl3)＝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):calcdfor C26H26N3O5[M+H]+:460.1872； found460.1877。
example 5
After stirring a 10M L round bottom flask with a mixture of 1b (1mmol,116mg), ethyl 4-azidoacetoacetate 2(1mmol,171mg) and 4M L tert-butanol and water (1/1 vol.), aqueous copper sulfate pentahydrate (0.05mmol, 52. mu. L, 1M) and sodium ascorbate (0.1mmol,19.9mg) were added and the resulting mixture was stirred at room temperature for 12H, 3c (0.9mmol, 253mg) and sodium hydroxide (2.0mmol,80mg) were added and the reaction was allowed to proceed at 80 ℃ for 2H, cooled to room temperature, quenched with 5M L water, extracted with dichloromethane (5M L× 3), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, dried, and separated on a silica gel column (petroleum ether/ethyl acetate ═ 5/1) to give 5-methyl-2- (4- (M-methyl) phenyl-1H-1, 2, 3-triazoyl) -3-hydroxy-biphenyl-2- (4' -carboxylic acid ethyl ester-1-bromo-2-375 mg,72 mg).
The characterization data for this compound are as follows:1HNMR(400MHz,CDCl3)＝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),2.68(s, 3H),2.36(s,3H),1.46(t,J＝7.6Hz,3H).13CNMR(100MHz,CDCl3)＝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。
example 6
After 1c (1mmol,116mg), 4-azido ethyl acetoacetate 2(1mmol,171mg) and a mixture of 4M L tert-butanol and water (1/1 vol.%) were added to a 10M L round bottom flask, an aqueous solution of copper sulfate pentahydrate (0.05mmol, 52. mu. L, 1M) and sodium ascorbate (0.1mmol,19.9mg) were added and the resulting mixture was stirred at room temperature for 12H, 3d (0.9mmol,223mg) and sodium hydroxide (2.0mmol,80mg) were added and the reaction was continued at 80 ℃ for 2H, cooled to room temperature and quenched with 5M L water, extracted with dichloromethane (5M L× 3), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, dried, and separated on a silica gel column (petroleum ether/ethyl acetate ═ 5/1) to give 5-methyl-2- (4- (p-methylphenyl) -1H-1,2, 3-triazolyl) -3-hydroxy-2- (1' -biphenyl-carboxylic acid ethyl ester (70 mg, 4.344%).
The characterization data for this compound are as follows:1HNMR(400MHz,CDCl3)＝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)＝171.2,158.1,146.6,143.9,143.1,137.8,137.4,132.4,130.8,129.9,129.4, 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):calcd for C25H23BrN3O3[M+H]+:492.0923；found 492.0929。
example 7
1d (1mmol,120mg), ethyl 4-azidoacetoacetate 2(1mmol,171mg) and a mixture of 4M L tert-butanol and water (1/1 by volume) were added to a 10M L round bottom flask, then aqueous copper sulfate pentahydrate (0.05mmol, 52. mu. L, 1M) and sodium ascorbate (0.1mmol,19.9mg) were added and the resulting mixture was stirred at room temperature for 12H, then 3a (0.9mmol,129.6mg) and sodium hydroxide (2.0mmol,80mg) were added and the reaction was continued for 2H while cooling to 80 ℃ and quenching was added with 5M L water to room temperature, followed by extraction with dichloromethane (5M L× 3), washing with saturated brine, drying over anhydrous sodium sulfate, filtration, spin drying, separation on a silica gel column (petroleum ether/ethyl acetate ═ 5/1) to give the product 5-methyl-2- (4- (p-fluorophenyl) -1H-1,2, 3-triazoyl) -3-hydroxy biphenyl-1- (4' -carboxylic acid ethyl ester-284-68% as a yellow solid.
The characterization data for this compound are as follows:1HNMR(400MHz,CDCl3)＝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),4.49(q, J＝7.6Hz,2H),2.69(s,3H),1.47(t,J＝7.6Hz,2H).13CNMR(100MHz,CDCl3)＝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。
example 8
After 1e (1mmol,136.6mg), ethyl 4-azidoacetoacetate 2(1mmol,171mg) and a mixture of 4M L tert-butanol and water (1/1 vol.%) were added to a 10M L round bottom flask, an aqueous solution of copper sulfate pentahydrate (0.05mmol, 52. mu. L, 1M) and sodium ascorbate (0.1mmol,19.9mg) were added and the resulting mixture was stirred at room temperature for 12H, 3a (0.9mmol,129.6mg) and sodium hydroxide (2.0mmol,80mg) were added, the reaction was continued at 80 ℃ for 2H, cooled to room temperature and quenched with 5M L water, extracted with dichloromethane (5M L× 3), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, rotary dried, and isolated on a silica gel column (petroleum ether/ethyl acetate ═ 5/1) to give the product 5-methyl-2- (4- (p-chlorophenyl) -1H-1,2, 3-triazoyl) -3-hydroxy biphenyl-1- (4-carboxylic acid ethyl ester) as a yellow solid product (364 mg, 299.5%).
The characterization data for this compound are as follows:1HNMR(400MHz,CDCl3)＝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),4.50(q, J＝7.2Hz,2H),2.69(s,3H),1.48(t,J＝7.2Hz,3H).13CNMR(100MHz,CDCl3)＝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。
example 9
1f (1mmol,181mg), 4-azidoacetoacetic acid ethyl ester 2(1mmol,171mg) and 4M L mixture of tert-butanol and water (1/1 vol%) were added to a 10M L round bottom flask, then aqueous copper sulfate pentahydrate (0.05mmol, 52. mu. L, 1M) and sodium ascorbate (0.1mmol,19.9mg) were added and the resulting mixture was stirred at room temperature for 12H, then 3a (0.9mmol,129.6mg) and sodium hydroxide (2.0mmol,80mg) were added, the reaction was continued for 2H while heating to 80 ℃ and cooling to room temperature, 5M L water was added to quench the reaction, dichloromethane was used for extraction (5M 3873), saturated brine was washed with anhydrous sodium sulfate, filtered, dried, fa was isolated on silica gel column (petroleum ether/ethyl acetate ═ 5/1) to give 5-methyl-2- (4- (p-bromophenyl) -1H-1,2, 3-triazoyl) -3-hydroxy biphenyl-carboxylic acid ethyl ester (339.4mg, 3971%).
The characterization data for this compound are as follows:1HNMR(400MHz,CDCl3)＝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)＝ 171.2,158.6,146.1,144.6,143.7,136.4,131.9,129.5,128.5,128.1,127.3,124.3,123.0,121.9, 112.4,62.5,24.4,14.2.HRMS(ESI):calcd for C24H21BrN3O3[M+H]+:478.0766；found 478.0770。
example 10
1f (1mmol,181mg), ethyl 4-azidoacetoacetate 2(1mmol,171mg) and a mixture of 4M L tert-butanol and water (1/1 by volume) were added to a 10M L round bottom flask, then aqueous copper sulfate pentahydrate (0.05mmol, 52. mu. L, 1M) and sodium ascorbate (0.1mmol,19.9mg) were added, the resulting mixture was stirred at room temperature for 12H, 3b (0.9mmol,204.2mg) and sodium hydroxide (2.0mmol,80mg) were added, the reaction was continued at 80 ℃ for 2H, cooled to room temperature and quenched with 5M L water, extracted with dichloromethane (5M L× 3), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, rotary dried, and separated on a silica gel column (petroleum ether/ethyl acetate ═ 5/1) to give 5-methyl-2- (4- (p-bromophenyl) -1H-1,2, 3-triazoyl) -3-hydroxy-biphenyl-2- (4-bromophenyl) -1H-1,2, 3-triazolyl) -3-hydroxy-biphenyl-2 ', 376, 4' -carboxylic acid ethyl ester (70 mg, 6-6 mg).
The characterization data for this compound are as follows:1HNMR(400MHz,CDCl3)＝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)＝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。
example 11
After 1f (1mmol,181mg), 4-azidoacetoacetic acid ethyl ester 2(1mmol,171mg) and a mixture of 4M L tert-butanol and water (1/1 by volume) were added to a 10M L round bottom flask, then aqueous copper sulfate pentahydrate (0.05mmol,52 μ L, 1M) and sodium ascorbate (0.1mmol,19.9mg) were added and the resulting mixture was stirred at room temperature for 12H, 3e (0.9mmol, 191mg) and sodium hydroxide (2.0mmol,80mg) were added and the reaction was continued for 2H while heating to 80 ℃ and cooling to room temperature and quenching with 5M L water was added and the reaction was quenched, extracted with dichloromethane (5M L× 3), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, dried, separated on a silica gel column (petroleum ether/ethyl acetate ═ 5/1) to give 5-methyl-4' -trifluoromethyl-2- (4- (p-bromophenyl) -1H-1, 3-triazoyl) -3-hydroxy biphenyl-carboxylic acid ethyl ester (66 mg, 360%) as a yellow solid product.
The characterization data for this compound are as follows:1HNMR(400MHz,CDCl3)＝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)＝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 forC25H20BrF3N3O3[M+H]+: 546.0640；found 546.0635。
example 12
1g (1mmol,116.2mg), ethyl 4-azidoacetoacetate 2(1mmol,171mg) and a mixture of 4M L tert-butanol and water (volume ratio 1/1) are added to a 10M L round-bottom flask, then aqueous copper sulfate pentahydrate (0.05mmol, 52. mu. L, 1M) and sodium ascorbate (0.1mmol,19.9mg) are added, the resulting mixture is stirred at room temperature for 12H, 3b (0.9mmol,204.2mg) and sodium hydroxide (2.0mmol,80mg) are added, the reaction is continued for 2H while heating to 80 ℃ and cooling to room temperature, 5M L of water are added to quench the reaction, dichloromethane is used for extraction (5M L×), saturated brine is washed, anhydrous sodium sulfate is dried, filtered, dried, and separated by a silica gel column (petroleum ether/ethyl acetate ═ 3/1) to give the product 5-methyl-2- (4-benzyl-1H-1, 2, 3-triazoyl) -3-hydroxy-3' -biphenyl-carboxylic acid ethyl ester (4 g, 303.4 mg).
The characterization data for this compound are as follows:1HNMR(400MHz,CDCl3)＝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)＝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 forC27H28N3O5[M+H]+:474.2029； found 474.2035。
example 13
1H (1mmol,56.1mg), ethyl 4-azidoacetoacetate 2(1mmol,171mg) and a mixture of 4M L tert-butanol and water (1/1 vol.%) are added to a 10M L round-bottomed flask, then aqueous copper sulfate pentahydrate (0.05mmol, 52. mu. L, 1M), sodium ascorbate (0.1mmol,19.9mg) are added and the resulting mixture is stirred at room temperature for 12H, 3a (0.9mmol,129.6mg) and sodium hydroxide (2.0mmol,80mg) are added and the reaction is continued for 2H while heating to 80 ℃ and cooling to room temperature and 5M L water is added to quench the reaction and extraction is carried out with dichloromethane (5M L× 3), washing with saturated brine, drying over anhydrous sodium sulfate, filtration, spin-drying, separation on a silica gel column (petroleum ether/ethyl acetate ═ 1/1) gives the product 5-methyl-2- (4-hydroxymethyl-1H-1, 2, 3-triazoyl) -3-hydroxybiphenyl-1- (4' -carboxylic acid ethyl ester as a yellow solid product.
The characterization data for this compound are as follows:1HNMR(400MHz,CDCl3)＝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),2.77(s, 1H),2.68(s,3H),1.47(t,J＝7.2Hz,3H).13CNMR(100MHz,CDCl3)＝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。
example 14
1H (1mmol,56.1mg), ethyl 4-azidoacetoacetate 2(1mmol,171mg) and a mixture of 4M L tert-butanol and water (volume ratio 1/1) are added to a 10M L round-bottom flask, then aqueous copper sulfate pentahydrate (0.05mmol, 52. mu. L, 1M) and sodium ascorbate (0.1mmol,19.9mg) are added, the resulting mixture is stirred at room temperature for 12H, 3d (0.9mmol,223mg) and sodium hydroxide (2.0mmol,80mg) are added, the reaction is continued for 2H while the temperature is raised to 80 ℃, the reaction is quenched by cooling to room temperature and 5M L water is added, dichloromethane is used for extraction (5M 3873), saturated brine is washed with anhydrous sodium sulfate, filtered, dried, and separated by silica gel column (petroleum ether/ethyl acetate ═ 1/1) to obtain 5-methyl-2- (4-hydroxymethyl-1H-1, 2, 3-triazolyl) -3-hydroxy-2- (1H-1,2, 3-oxazolyl) -3-hydroxy-2' -carboxylic acid ethyl ester (319.7mg, 4-H) as a yellow solid product.
The characterization data for this compound are as follows:1HNMR(400MHz,CDCl3)＝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),4.49(q, J＝6.8Hz,2H),2.82(s,1H),2.66(s,3H),1.46(t,J＝6.8Hz,3H).13CNMR(100MHz,CDCl3) ＝171.1,158.0,146.5,143.9,143.1,137.3,132.4,130.7,129.9,127.1,124.7,124.5,122.7, 121.9,113.3,62.5,56.4,24.2,14.2.HRMS(ESI):calcd for C19H19BrN3O4[M+H]+:432.0559； found432.0565。
example 15
1H (1mmol,56.1mg), ethyl 4-azidoacetoacetate 2(1mmol,171mg) and a mixture of 4M L tert-butanol and water (1/1 vol.) were added to a 10M L round bottom flask, then aqueous copper sulfate pentahydrate (0.05mmol, 52. mu. L, 1M) and sodium ascorbate (0.1mmol,19.9mg) were added, the resulting mixture was stirred at room temperature for 12H, 3f (0.9mmol,216.9mg) and sodium hydroxide (2.0mmol,80mg) were added, the reaction was continued at 80 ℃ for 2H, cooled to room temperature and quenched with 5M L water, extracted with dichloromethane (5M L× 3), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, rotary dried, and isolated on a silica gel column (petroleum ether/ethyl acetate ═ 1/1) to give the product 5-methyl-2- (4-hydroxymethyl-1H-1, 2, 3-triazoyl) -3-hydroxy-2 '-biphenyl-carboxylic acid ethyl 5' -bromide (76 mg, 342%).
The characterization data for this compound are as follows:1HNMR(400MHz,CDCl3)＝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)＝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；found450.0470。
example 16
1i (1mmol,132.2mg), ethyl 4-azidoacetoacetate 2(1mmol,171mg) and a mixture of 4M L tert-butanol and water (1/1 vol.) were added to a 10M L round bottom flask, then aqueous copper sulfate pentahydrate (0.05mmol, 52. mu. L, 1M) and sodium ascorbate (0.1mmol,19.9mg) were added, the resulting mixture was stirred at room temperature for 12H, 3a (0.9mmol,129.6mg) and sodium hydroxide (2.0mmol,80mg) were added, the reaction was continued at 80 ℃ for 2H, cooled to room temperature and quenched with 5M L water, extracted with dichloromethane (5M L× 3), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, rotary dried, and separated on a silica gel column (petroleum ether/ethyl acetate ═ 2/1) to give the product 5-methyl-2- (4- (hydroxyphenyl) methyl-1H-1, 2, 3-triazoyl) -3-hydroxy biphenyl-1- (4-carboxylic acid ethyl ester) (301.70 mg).
The characterization data for this compound are as follows:1HNMR(400MHz,CDCl3)＝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)＝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；found430.1773。
example 17
1j (1mmol,225mg), 4-azido ethyl acetoacetate 2(1mmol,171mg) and a mixture of 4M L tert-butanol and water (volume ratio is 1/1) are added into a 10M L round-bottom flask, then aqueous copper sulfate pentahydrate (0.05mmol, 52. mu. L, 1M) and sodium ascorbate (0.1mmol,19.9mg) are added, the mixture obtained is stirred at room temperature for 12H, 3e (0.9mmol, 191mg) and sodium hydroxide (2.0mmol,80mg) are added, the reaction is continued for 2H by heating to 80 ℃, the reaction is quenched by cooling to room temperature and adding 5M L water, the reaction product is extracted with dichloromethane (387m 2), washed with saturated saline, dried over anhydrous sodium sulfate, filtered, dried, separated by silica gel column (petroleum ether/ethyl acetate ═ 3/1) to obtain 5-methyl-4' -trifluoromethyl-2- (4- (2- (2-bromophenyl) -1-hydroxy) ethyl-1H-1, 3-oxazolyl-2- (3-biphenyl) -4- (1-carboxylic acid ethyl ester 69, 64 mg) as yellow oily product.
The characterization data for this compound are as follows:1HNMR(400MHz,CDCl3)＝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)＝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 forC27H24BrF3N3O4[M+H]+: 590.0902；found 590.0910。
example 18
1b (1mmol,116.2mg), ethyl 4-azidoacetoacetate 2(1mmol,171mg) and a mixture of 4M L tert-butanol and water (1/1 vol.) were added to a 10M L round-bottomed flask, then aqueous copper sulfate pentahydrate (0.05mmol, 52. mu. L, 1M) and sodium ascorbate (0.1mmol,19.9mg) were added, the resulting mixture was stirred at room temperature for 12H, 3g (0.9mmol,142.4mg) and sodium hydroxide (2.0mmol,80mg) were added, the reaction was continued at 80 ℃ for 2H, the reaction was quenched by cooling to room temperature with 5M L water, extracted with dichloromethane (5M L× 3), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, rotary dried, and separated on a silica gel column (petroleum ether/ethyl acetate ═ 8/1) to give 5, 6-dimethyl-2- (4- (M-methylphenyl) -1H-1,2, 3-triazoyl) -3-hydroxy-biphenyl-carboxylic acid ethyl ester (56 mg, 239.7%).
The characterization data for this compound are as follows:1HNMR(400MHz,CDCl3)＝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) ＝170.6,153.9,146.7,144.7,141.4,138.4,136.3,130.3,128.8,128.7,128.6,128.2,127.9, 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 for C26H26N3O3[M+H]+:428.1974；found428.1979。
example 19
1b (1mmol,116.2mg), ethyl 4-azidoacetoacetate 2(1mmol,171mg) and a mixture of 4M L tert-butanol and water (1/1 vol.) were added to a 10M L round-bottomed flask, then aqueous copper sulfate pentahydrate (0.05mmol, 52. mu. L, 1M) and sodium ascorbate (0.1mmol,19.9mg) were added and the resulting mixture was stirred at room temperature for 12H, then 3H (0.9mmol,198.3mg) and sodium hydroxide (2.0mmol,80mg) were added and the reaction was continued for 2H while heating to 80 ℃ and cooling to room temperature and quenching with 5M L water was added and extraction was performed with dichloromethane (5M L× 3), washing with saturated brine, drying with anhydrous sodium sulfate, filtration, spin-drying, separation on a silica gel column (petroleum ether/ethyl acetate ═ 5/1) gave 5-benzyl-2- (4- (M-methylphenyl) -1H-1,2, 3-triazoyl) -3-hydroxy biphenyl-carboxylic acid ethyl ester (4-156H-32%).
The characterization data for this compound are as follows:1HNMR(400MHz,CDCl3)＝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)＝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；found490.2136。
while there have been shown and described what are at present considered the fundamental principles of the invention, its essential features and advantages, the invention further resides in various changes and modifications which fall within the scope of the invention as claimed.
Claims (6)
- A synthetic method of 2- (1H-1,2, 3-triazolyl) -3-hydroxybiphenyl-4-carboxylic acid ethyl ester compounds is characterized by comprising the following specific synthetic processes: the method comprises the following steps of taking 4-azido ethyl acetoacetate, terminal alkyne compounds and 1, 2-allene compounds as reaction raw materials, taking copper sulfate pentahydrate and sodium ascorbate as a catalytic system, taking potassium carbonate, cesium carbonate or sodium hydroxide as alkali, taking a mixed solution of tert-butyl alcohol and water as a solvent, and preparing a target product, namely the 2- (1H-1,2, 3-triazolyl) -3-hydroxybiphenyl-4-carboxylic acid ethyl ester compound, through a series copper-catalyzed cyclization reaction and an alkali-promoted condensation reaction at 80 ℃, wherein the reaction equation in the synthesis method is as follows:wherein R is 2-bromo-5-methoxyphenyl, phenyl, 2-bromophenyl or 4-trifluoromethylphenyl, R1Is 3-methylphenyl, hydroxymethyl or 2-hydroxy- (1' -bromophenylethyl), R2Is hydrogen or methyl, R3Is hydrogen.
- 2. The synthesis method of the ethyl 2- (1H-1,2, 3-triazolyl) -3-hydroxybiphenyl-4-carboxylate compound according to claim 1 is characterized by comprising the following specific steps of dissolving ethyl 4-azidoacetoacetate and a terminal alkyne compound in a mixed solution of tert-butyl alcohol and water, adding a sodium ascorbate solution and a copper sulfate pentahydrate solution, stirring the obtained mixture at room temperature for 12 hours, adding potassium carbonate, cesium carbonate or sodium hydroxide and a 1, 2-allene compound, heating to 80 ℃ for reaction for 2 hours, monitoring by T L C, adding water to stop the reaction after the reaction is completed, extracting by using dichloromethane, drying, concentrating, and separating by fast column chromatography to obtain the ethyl 2- (1H-1,2, 3-triazolyl) -3-hydroxybiphenyl-4-carboxylate compound.
- 3. The method for synthesizing the ethyl 2- (1H-1,2, 3-triazolyl) -3-hydroxybiphenyl-4-carboxylate compound according to claim 1, wherein the method comprises the following steps: the feeding molar ratio of the 4-azido ethyl acetoacetate, the terminal alkyne compound, the 1, 2-allene compound, the sodium ascorbate, the copper sulfate pentahydrate and the potassium carbonate or the cesium carbonate is 1:1:0.9:0.1:0.05: 1.
- 4. The method for synthesizing the ethyl 2- (1H-1,2, 3-triazolyl) -3-hydroxybiphenyl-4-carboxylate compound according to claim 1, wherein the method comprises the following steps: the feeding molar ratio of the 4-azido ethyl acetoacetate, the terminal alkyne compound, the 1, 2-allene compound, the sodium ascorbate, the copper sulfate pentahydrate and the sodium hydroxide is 1:1:0.9:0.1:0.05: 2.
- 5. The synthesis method of the 2- (1H-1,2, 3-triazolyl) -3-hydroxybiphenyl-4-carboxylic acid ethyl ester compound according to claim 1, wherein the feeding ratio of the 1, 2-allene compound to the solvent is 1mmol:4m L.
- 6. The method for synthesizing the ethyl 2- (1H-1,2, 3-triazolyl) -3-hydroxybiphenyl-4-carboxylate compound according to claim 1, wherein the method comprises the following steps: the volume ratio of the tertiary butanol to the water in the mixed solution of the tertiary butanol and the water is 1: 1.
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