CN107311946B - Synthesis method of 2-(1H-1,2,3-triazolyl)-3-hydroxybiphenyl-4-carboxylic acid ethyl ester compounds - Google Patents
Synthesis method of 2-(1H-1,2,3-triazolyl)-3-hydroxybiphenyl-4-carboxylic acid ethyl ester compounds Download PDFInfo
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- -1 2-(1H-1,2,3-triazolyl)-3-hydroxybiphenyl-4-carboxylic acid ethyl ester compounds Chemical class 0.000 title claims abstract description 43
- 238000001308 synthesis method Methods 0.000 title claims abstract description 9
- 238000006243 chemical reaction Methods 0.000 claims abstract description 51
- IHTPQJBOGBAEJZ-UHFFFAOYSA-N ethyl 4-azido-3-oxobutanoate Chemical compound CCOC(=O)CC(=O)CN=[N+]=[N-] IHTPQJBOGBAEJZ-UHFFFAOYSA-N 0.000 claims abstract description 24
- 238000000034 method Methods 0.000 claims abstract description 18
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 6
- 239000002904 solvent Substances 0.000 claims abstract description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 66
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 63
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 54
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 48
- 239000000203 mixture Substances 0.000 claims description 40
- 235000010378 sodium ascorbate Nutrition 0.000 claims description 27
- PPASLZSBLFJQEF-RKJRWTFHSA-M sodium ascorbate Substances [Na+].OC[C@@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RKJRWTFHSA-M 0.000 claims description 27
- 229960005055 sodium ascorbate Drugs 0.000 claims description 27
- PPASLZSBLFJQEF-RXSVEWSESA-M sodium-L-ascorbate Chemical compound [Na+].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RXSVEWSESA-M 0.000 claims description 27
- JZCCFEFSEZPSOG-UHFFFAOYSA-L copper(II) sulfate pentahydrate Chemical compound O.O.O.O.O.[Cu+2].[O-]S([O-])(=O)=O JZCCFEFSEZPSOG-UHFFFAOYSA-L 0.000 claims description 14
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 14
- 239000000243 solution Substances 0.000 claims description 13
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 7
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 6
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 6
- 239000011259 mixed solution Substances 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 239000002994 raw material Substances 0.000 claims description 3
- 238000010189 synthetic method Methods 0.000 claims description 3
- 125000006276 2-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000004199 4-trifluoromethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C(F)(F)F 0.000 claims description 2
- 230000003197 catalytic effect Effects 0.000 claims description 2
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 2
- 125000000040 m-tolyl group Chemical group [H]C1=C([H])C(*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 238000012544 monitoring process Methods 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims 1
- 238000004440 column chromatography Methods 0.000 claims 1
- 238000006482 condensation reaction Methods 0.000 claims 1
- 238000001035 drying Methods 0.000 claims 1
- 238000010438 heat treatment Methods 0.000 claims 1
- 238000007363 ring formation reaction Methods 0.000 claims 1
- 238000003756 stirring Methods 0.000 claims 1
- 238000003786 synthesis reaction Methods 0.000 abstract description 6
- 230000015572 biosynthetic process Effects 0.000 abstract description 4
- 239000003054 catalyst Substances 0.000 abstract description 3
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 3
- 229910052751 metal Inorganic materials 0.000 abstract description 3
- 239000002184 metal Substances 0.000 abstract description 3
- 239000007858 starting material Substances 0.000 abstract description 3
- 150000001260 acyclic compounds Chemical group 0.000 abstract 1
- 125000001425 triazolyl group Chemical group 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 57
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 38
- 150000001875 compounds Chemical class 0.000 description 23
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 19
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 19
- 239000003208 petroleum Substances 0.000 description 19
- 238000010791 quenching Methods 0.000 description 19
- 239000000741 silica gel Substances 0.000 description 19
- 229910002027 silica gel Inorganic materials 0.000 description 19
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 19
- 238000012512 characterization method Methods 0.000 description 17
- 238000001816 cooling Methods 0.000 description 15
- 229910000365 copper sulfate Inorganic materials 0.000 description 13
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 description 13
- 239000012265 solid product Substances 0.000 description 12
- 239000000047 product Substances 0.000 description 8
- 235000010290 biphenyl Nutrition 0.000 description 4
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 4
- 125000003762 3,4-dimethoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 description 1
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 description 1
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 1
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 1
- 150000004686 pentahydrates Chemical class 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 150000003852 triazoles Chemical group 0.000 description 1
Classifications
-
- 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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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Medicinal Preparation (AREA)
Abstract
本发明公开了一种2‑(1H‑1,2,3‑三氮唑基)‑3‑羟基联苯‑4‑羧酸乙酯类化合物的合成方法，属于有机合成技术领域。本发明的技术方案要点为：2‑(1H‑1,2,3‑三氮唑基)‑3‑羟基联苯‑4‑羧酸乙酯类化合物的合成方法，其合成过程中的反应方程式为：
Description
技术领域technical field
本发明属于有机合成技术领域，具体涉及一种2-(1H-1,2,3-三氮唑基)-3-羟基联苯-4- 羧酸乙酯类化合物的合成方法。The invention belongs to the technical field of organic synthesis, in particular to a method for synthesizing 2-(1H-1,2,3-triazolyl)-3-hydroxybiphenyl-4-carboxylic acid ethyl ester compounds.
背景技术Background technique
2-(1H-1,2,3-三氮唑基)-3-羟基联苯-4-羧酸乙酯类化合物作为一种重要的经典杂环化合物，广泛应用于医药、材料和合成等众多领域。然而由于原料不易获得，到目前为止，还没有相关文献报道该类化合物的合成方法。2-(1H-1,2,3-triazolyl)-3-hydroxybiphenyl-4-carboxylate ethyl ester is an important classical heterocyclic compound widely used in medicine, materials and synthesis, etc. many fields. However, because the raw materials are not easy to obtain, so far, there is no relevant literature report on the synthesis of such compounds.
发明内容SUMMARY OF THE INVENTION
本发明解决的技术问题是提供了一种2-(1H-1,2,3-三氮唑基)-3-羟基联苯-4-羧酸乙酯类化合物的合成方法，该合成方法具有起始原料简单易制备、无需昂贵的金属催化剂和试剂、环境又好、反应条件温和且操作简便等优点。The technical problem solved by the present invention is to provide a method for synthesizing 2-(1H-1,2,3-triazolyl)-3-hydroxybiphenyl-4-carboxylic acid ethyl ester compounds, the synthesis method has the following characteristics: The starting materials are simple and easy to prepare, no expensive metal catalysts and reagents are required, the environment is good, the reaction conditions are mild, and the operation is simple.
本发明为解决上述技术问题采用如下技术方案，2-(1H-1,2,3-三氮唑基)-3-羟基联苯 -4-羧酸乙酯类化合物的合成方法，其特征在于具体合成过程为：以4-叠氮基乙酰乙酸乙酯、末端炔烃类化合物和1,2-联烯酮类化合物为反应原料，以硫酸铜和抗坏血酸钠为催化体系，以碳酸钾、碳酸铯或氢氧化钠为碱，以叔丁醇和水的混合溶液为溶剂，于80℃通过串联的铜催化的环化反应和碱或盐促进的缩合反应制得目标产物2-(1H-1,2,3-三氮唑基)-3-羟基联苯-4-羧酸乙酯类化合物，该合成方法中的反应方程式为：In order to solve the above-mentioned technical problems, the present invention adopts the following technical scheme, a method for synthesizing 2-(1H-1,2,3-triazolyl)-3-hydroxybiphenyl-4-carboxylic acid ethyl ester compounds, which is characterized in that The specific synthesis process is as follows: using ethyl 4-azido acetoacetate, terminal alkyne compounds and 1,2-diketene compounds as reaction raw materials, copper sulfate and sodium ascorbate as the catalytic system, potassium carbonate, carbonic acid The target product 2-(1H-1, 2-(1H-1, 2-(1H-1, 2-(1H-1, 2,3-triazolyl)-3-hydroxybiphenyl-4-carboxylic acid ethyl ester compound, the reaction equation in this synthetic method is:
其中R为苯基、3,4-二甲氧基苯基、2-溴-5-甲氧基苯基、2-溴苯基、4-三氟甲基苯基或 2-溴-5-氟苯基，R1为苯基、3-甲基苯基、4-甲基苯基、4-氟苯基、4-氯苯基、4-溴苯基、苯甲基、羟甲基、1-羟基苯甲基或2-羟基-(1’-溴苯乙基)，R2为氢或甲基，R3为氢或苯基。where R is phenyl, 3,4-dimethoxyphenyl, 2-bromo-5-methoxyphenyl, 2-bromophenyl, 4-trifluoromethylphenyl or 2-bromo-5- Fluorophenyl, R 1 is phenyl, 3-methylphenyl, 4-methylphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, benzyl, hydroxymethyl, 1-hydroxybenzyl or 2-hydroxy-(1'-bromophenethyl), R 2 is hydrogen or methyl, R 3 is hydrogen or phenyl.
进一步优选，所述的2-(1H-1,2,3-三氮唑基)-3-羟基联苯-4-羧酸乙酯类化合物的合成方法，其特征在于具体步骤为：将4-叠氮基乙酰乙酸乙酯和末端炔烃类化合物溶于叔丁醇和水的混合溶液中，再加入抗坏血酸钠和硫酸铜溶液，得到的混合物于室温搅拌12h，然后加入碳酸钾、碳酸铯或氢氧化钠和1,2-联烯酮类化合物，升温至80℃反应3h，TLC监测反应完全后加水终止反应，用二氯甲烷萃取、干燥、浓缩、快速柱层析分离得到2-(1H-1,2,3- 三氮唑基)-3-羟基联苯-4-羧酸乙酯类化合物。Further preferably, the synthetic method of the 2-(1H-1,2,3-triazolyl)-3-hydroxybiphenyl-4-carboxylic acid ethyl ester compound is characterized in that the specific steps are: 4 - Ethyl acetoacetate and terminal alkyne compounds are dissolved in a mixed solution of tert-butanol and water, then sodium ascorbate and copper sulfate solution are added, the resulting mixture is stirred at room temperature for 12h, and then potassium carbonate, cesium carbonate or Sodium hydroxide and 1,2-alienone compounds were heated to 80 °C and reacted for 3 h. After monitoring the completion of the reaction by TLC, water was added to terminate the reaction, extracted with dichloromethane, dried, concentrated, and separated by flash column chromatography to obtain 2-(1H -1,2,3-Triazolyl)-3-hydroxybiphenyl-4-carboxylic acid ethyl ester compound.
进一步优选，所述的4-叠氮基乙酰乙酸乙酯、末端炔烃类化合物、1,2-联烯酮类化合物、抗坏血酸钠、五水硫酸铜和碳酸钾或碳酸铯的投料摩尔比为1:1:0.9:0.1:0.05:1。Further preferably, the molar ratio of described ethyl 4-azido acetoacetate, terminal alkyne compounds, 1,2-alienone compounds, sodium ascorbate, copper sulfate pentahydrate and potassium carbonate or cesium carbonate is 1:1:0.9:0.1:0.05:1.
进一步优选，所述的4-叠氮基乙酰乙酸乙酯、末端炔烃类化合物、1,2-联烯酮类化合物、抗坏血酸钠、五水硫酸铜和氢氧化钠的投料摩尔比为1:1:0.9:0.1:0.05:2。Further preferably, the molar ratio of described ethyl 4-azido acetoacetate, terminal alkyne compound, 1,2-alienone compound, sodium ascorbate, copper sulfate pentahydrate and sodium hydroxide is 1: 1:0.9:0.1:0.05:2.
进一步优选，所述的1,2-联烯酮类化合物与溶剂的投料配比为1mmol:4mL。Further preferably, the charging ratio of the 1,2-alienone compound and the solvent is 1 mmol: 4 mL.
进一步优选，所述的溶剂叔丁醇和水的混合溶液中叔丁醇与水的体积比为1:1。Further preferably, the volume ratio of tert-butyl alcohol to water in the mixed solution of the solvent tert-butyl alcohol and water is 1:1.
本发明首次提出了一种2-(1H-1,2,3-三氮唑基)-3-羟基联苯-4-羧酸乙酯类化合物的合成方法，该合成方法具有以下优点：1、反应条件温和、工艺简单，不需要无水无氧环境； 2、不需要昂贵的金属催化剂和特殊试剂，溶剂环境友好；3、起始原料4-叠氮基乙酰乙酸乙酯、末端炔烃类化合物和1,2-联烯酮类化合物等非环化合物制备方便或容易购买；4、该合成方法同时构造苯环和三氮唑环；5、最终合成的目标产物易于分离纯化。The present invention proposes for the first time a method for synthesizing 2-(1H-1,2,3-triazolyl)-3-hydroxybiphenyl-4-carboxylic acid ethyl ester compounds, and the synthesis method has the following advantages: 1 , The reaction conditions are mild, the process is simple, and no water and oxygen-free environment is required; 2. No expensive metal catalysts and special reagents are required, and the solvent environment is friendly; 3. The starting material 4-azido ethyl acetoacetate, terminal alkyne Acyclic compounds such as 1,2-diketene compounds and 1,2-alienone compounds are easy to prepare or buy; 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.
具体实施方式Detailed ways
以下通过实施例对本发明的上述内容做进一步详细说明，但不应该将此理解为本发明上述主题的范围仅限于以下的实施例，凡基于本发明上述内容实现的技术均属于本发明的范围。The above-mentioned content of the present invention is described in further detail below through the examples, but it should not be understood that the scope of the above-mentioned subject matter of the present invention is limited to the following examples, and all technologies realized based on the above-mentioned content of the present invention belong to the scope of the present invention.
实施例1Example 1
在10mL的圆底烧瓶中加入1a(1mmol,102mg)、4-叠氮乙酰乙酸乙酯2(1mmol,171mg) 和4mL叔丁醇与水的混合物(体积比为1/1)，然后加入五水硫酸铜水溶液(0.05mmol,52μL, 1M)和抗坏血酸钠(0.1mmol,19.9mg)，得到的混合物于室温搅拌12h后，加入3a(0.9mmol, 129.6mg)和氢氧化钠(2.0mmol,80mg)，升温至80℃继续反应2h。冷却至室温加5mL水淬灭反应，用二氯甲烷萃取(5mL×3)，饱和食盐水洗涤，无水硫酸钠干燥。过滤，旋干，过硅胶柱分离(石油醚/乙酸乙酯＝5/1)得到黄色油状产物5-甲基-2-(4-苯基-1H-1,2,3-三氮唑基)-3-羟基-(1,1’-联苯)-4-羧酸乙酯4aa(256mg,64％)。In a 10 mL round-bottomed flask, add 1a (1 mmol, 102 mg), ethyl 4-azido acetoacetate 2 (1 mmol, 171 mg) and 4 mL of a mixture of tert-butanol and water (1/1 by volume), then add five Aqueous copper sulfate solution (0.05mmol, 52μL, 1M) and sodium ascorbate (0.1mmol, 19.9mg), 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 temperature was raised to 80 °C and the reaction was continued for 2 h. After cooling to room temperature, 5 mL of water was added to quench the reaction, extracted with dichloromethane (5 mL×3), washed with saturated brine, and dried over anhydrous sodium sulfate. Filter, spin dry, and separate through silica gel column (petroleum ether/ethyl acetate=5/1) to obtain 5-methyl-2-(4-phenyl-1H-1,2,3-triazolyl as a yellow oily product) )-3-hydroxy-(1,1'-biphenyl)-4-carboxylic acid ethyl ester 4aa (256 mg, 64%).
该化合物的表征数据如下：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＝171.2,158.7,147.1,144.6,143.5,136.5,130.5,128.7,128.5,128.1,128.1, 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。The characterization data for this compound are as follows: 1 HNMR (400 MHz, CDCl 3 ) 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); 13 CNMR (100MHz, CDCl 3 )δ=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 for C 24 H 22 N 3 O 3 [M+H] + : 400.1661; found 400.1663.
实施例2Example 2
在10mL的圆底烧瓶中加入1a(1mmol,102mg)、4-叠氮乙酰乙酸乙酯2(1mmol,171mg) 和4mL叔丁醇与水的混合物(体积比为1/1)，然后加入五水硫酸铜水溶液(0.05mmol,52μL, 1M)和抗坏血酸钠(0.1mmol,19.9mg)，得到的混合物于室温搅拌12h后，加入3a(0.9mmol, 129.6mg)和碳酸钾(1.0mmol,138mg)，升温至80℃继续反应2h。冷却至室温，加5mL 水淬灭反应，用二氯甲烷萃取(5mL×3)，饱和食盐水洗涤，无水硫酸钠干燥。过滤，旋干，过硅胶柱分离(石油醚/乙酸乙酯＝5/1)得到黄色油状产物5-甲基-2-(4-苯基-1H-1,2,3-三氮唑基)-3-羟基-(1,1’-联苯)-4-羧酸乙酯4aa(200mg,50％)。In a 10 mL round-bottomed flask, add 1a (1 mmol, 102 mg), ethyl 4-azido acetoacetate 2 (1 mmol, 171 mg) and 4 mL of a mixture of tert-butanol and water (1/1 by volume), then add five Aqueous copper sulfate solution (0.05mmol, 52μL, 1M) and sodium ascorbate (0.1mmol, 19.9mg), the resulting mixture was stirred at room temperature for 12h, then 3a (0.9mmol, 129.6mg) and potassium carbonate (1.0mmol, 138mg) were added , the temperature was raised to 80 °C and the reaction was continued for 2 h. Cool to room temperature, add 5 mL of water to quench the reaction, extract with dichloromethane (5 mL×3), wash with saturated brine, and dry over anhydrous sodium sulfate. Filter, spin dry, and separate through silica gel column (petroleum ether/ethyl acetate=5/1) to obtain 5-methyl-2-(4-phenyl-1H-1,2,3-triazolyl as a yellow oily product) )-3-hydroxy-(1,1'-biphenyl)-4-carboxylic acid ethyl ester 4aa (200 mg, 50%).
实施例3Example 3
在10mL的圆底烧瓶中加入1a(1mmol,102mg)、4-叠氮乙酰乙酸乙酯2(1mmol,171mg) 和4mL叔丁醇与水的混合物(体积比为1/1)，然后加入五水硫酸铜水溶液(0.05mmol,52μL, 1M)和抗坏血酸钠(0.1mmol,19.9mg)，得到的混合物于室温搅拌12h后，加入3a(0.9mmol, 129.6mg)和碳酸铯(1.0mmol,325.8mg)，升温至80℃继续反应2h。冷却至室温，加5mL 水淬灭反应，用二氯甲烷萃取(5mL×3)，饱和食盐水洗涤，无水硫酸钠干燥。过滤，旋干，过硅胶柱分离(石油醚/乙酸乙酯＝5/1)得到黄色油状产物5-甲基-2-(4-苯基-1H-1,2,3-三氮唑基)-3-羟基-(1,1’-联苯)-4-羧酸乙酯4aa(204mg,51％)。In a 10 mL round-bottomed flask, add 1a (1 mmol, 102 mg), ethyl 4-azido acetoacetate 2 (1 mmol, 171 mg) and 4 mL of a mixture of tert-butanol and water (1/1 by volume), then add five Aqueous copper sulfate solution (0.05mmol, 52μL, 1M) and sodium ascorbate (0.1mmol, 19.9mg), after the resulting mixture was stirred at room temperature for 12h, 3a (0.9mmol, 129.6mg) and cesium carbonate (1.0mmol, 325.8mg) were added ), the temperature was raised to 80 °C and the reaction was continued for 2 h. Cool to room temperature, add 5 mL of water to quench the reaction, extract with dichloromethane (5 mL×3), wash with saturated brine, and dry over anhydrous sodium sulfate. Filter, spin dry, and separate through silica gel column (petroleum ether/ethyl acetate=5/1) to obtain 5-methyl-2-(4-phenyl-1H-1,2,3-triazolyl as a yellow oily product) )-3-hydroxy-(1,1'-biphenyl)-4-carboxylic acid ethyl ester 4aa (204 mg, 51%).
实施例4Example 4
在10mL的圆底烧瓶中加入1a(1mmol,102mg)、4-叠氮乙酰乙酸乙酯2(1mmol,171mg) 和4mL叔丁醇和水的混合物(体积比为1/1)，然后加入五水硫酸铜水溶液(0.05mmol,52μL, 1M)和抗坏血酸钠(0.1mmol,19.9mg)，得到的混合物于室温搅拌12h后，加入3b(0.9mmol, 204.2mg)和氢氧化钠(2.0mmol,80mg)，升温至80℃继续反应2h。冷却至室温，加5mL 水淬灭反应，用二氯甲烷萃取(5mL×3)，饱和食盐水洗涤，无水硫酸钠干燥。过滤，旋干，过硅胶柱分离(石油醚/乙酸乙酯＝3/1)得到黄色固体产物5-甲基-2-(4-苯基-1H-1,2,3-三氮唑基)-3-羟基-3’,4’-二甲氧基-(1,1’-联苯)-4-羧酸乙酯4ab(299mg,65％)。In a 10 mL round-bottomed flask, add 1a (1 mmol, 102 mg), ethyl 4-azido acetoacetate 2 (1 mmol, 171 mg) and 4 mL of a mixture of tert-butanol and water (1/1 by volume), then add pentahydrate Aqueous copper sulfate (0.05mmol, 52μL, 1M) and sodium ascorbate (0.1mmol, 19.9mg), the resulting mixture was stirred at room temperature for 12h, then 3b (0.9mmol, 204.2mg) and sodium hydroxide (2.0mmol, 80mg) were added , the temperature was raised to 80 °C and the reaction was continued for 2 h. Cool to room temperature, add 5 mL of water to quench the reaction, extract with dichloromethane (5 mL×3), wash with saturated brine, and dry over anhydrous sodium sulfate. Filter, spin dry, and separate through silica gel column (petroleum ether/ethyl acetate=3/1) to obtain 5-methyl-2-(4-phenyl-1H-1,2,3-triazolyl as a yellow solid product) )-3-hydroxy-3',4'-dimethoxy-(1,1'-biphenyl)-4-carboxylate ethyl ester 4ab (299 mg, 65%).
该化合物的表征数据如下：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), 3.65(s,3H),2.67(s,3H),1.45(t,J＝6.8Hz,3H).13CNMR(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):calcdfor C26H26N3O5[M+H]+:460.1872； found460.1877。The characterization data for this compound are as follows: 1 HNMR (400 MHz, CDCl 3 ) 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), 3.65(s, 3H), 2.67(s, 3H), 1.45(t, J=6.8Hz, 3H). 13 CNMR (100MHz, CDCl 3 )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, 111.5.8, 62 24.4, 14.2. HRMS (ESI): calcd for C 26 H 26 N 3 O 5 [M+H] + : 460.1872; found460.1877.
实施例5Example 5
在10mL的圆底烧瓶中加入1b(1mmol,116mg)、4-叠氮乙酰乙酸乙酯2(1mmol,171mg) 和4mL叔丁醇与水的混合物(体积比为1/1)，然后加入五水硫酸铜水溶液(0.05mmol,52μL, 1M)和抗坏血酸钠(0.1mmol,19.9mg)，得到的混合物于室温搅拌12h后，加入3c(0.9mmol, 253mg)和氢氧化钠(2.0mmol,80mg)，升温至80℃继续反应2h。冷却至室温，加5mL 水淬灭反应，用二氯甲烷萃取(5mL×3)，饱和食盐水洗涤，无水硫酸钠干燥。过滤，旋干，过硅胶柱分离(石油醚/乙酸乙酯＝5/1)得到黄色固体产物5-甲基-2-(4-(m-甲基)苯基 -1H-1,2,3-三氮唑基)-3-羟基-5’-甲氧基-2’-溴-(1,1’-联苯)-4-羧酸乙酯4bc(375.8mg,72％)。In a 10 mL round-bottomed flask, add 1b (1 mmol, 116 mg), ethyl 4-azido acetoacetate 2 (1 mmol, 171 mg) and 4 mL of a mixture of tert-butanol and water (1/1 by volume), then add five Aqueous copper sulfate solution (0.05mmol, 52μL, 1M) and sodium ascorbate (0.1mmol, 19.9mg), the resulting mixture was stirred at room temperature for 12h, then 3c (0.9mmol, 253mg) and sodium hydroxide (2.0mmol, 80mg) were added , the temperature was raised to 80 °C and the reaction was continued for 2 h. Cool to room temperature, add 5 mL of water to quench the reaction, extract with dichloromethane (5 mL×3), wash with saturated brine, and dry over anhydrous sodium sulfate. Filter, spin dry, and separate through silica gel column (petroleum ether/ethyl acetate=5/1) to obtain a yellow solid product 5-methyl-2-(4-(m-methyl)phenyl-1H-1,2, 3-Triazolyl)-3-hydroxy-5'-methoxy-2'-bromo-(1,1'-biphenyl)-4-carboxylate ethyl ester 4bc (375.8 mg, 72%).
该化合物的表征数据如下：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),2.68(s, 3H),2.36(s,3H),1.46(t,J＝7.6Hz,3H).13CNMR(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。The characterization data of this compound are as follows: 1 HNMR (400 MHz, CDCl 3 ) δ=12.09 (s, 1H), 7.90 (s, 1H), 7.65 (s, 1H), 7.55 (d, J=7.6 Hz, 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). 13 CNMR (100MHz, CDCl 3 )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, 113.2.5. , 62.5, 55.5, 24.3, 21.4, 14.2. HRMS(ESI): calcd for C 26 H 25 BrN 3 O 4 [M+H] + : 522.1028; found 522.1033.
实施例6Example 6
在10mL的圆底烧瓶中加入1c(1mmol,116mg)、4-叠氮乙酰乙酸乙酯2(1mmol,171mg) 和4mL叔丁醇与水的混合物(体积比为1/1)，然后加入五水硫酸铜水溶液(0.05mmol,52μL, 1M)和抗坏血酸钠(0.1mmol,19.9mg)，得到的混合物于室温搅拌12h后，加入3d(0.9mmol, 223mg)和氢氧化钠(2.0mmol,80mg)，升温至80℃继续反应2h。冷却至室温加5mL水淬灭反应，用二氯甲烷萃取(5mL×3)，饱和食盐水洗涤，无水硫酸钠干燥。过滤，旋干，过硅胶柱分离(石油醚/乙酸乙酯＝5/1)得到棕色固体产物5-甲基-2-(4-(p-甲基苯基) -1H-1,2,3-三氮唑基)-3-羟基-2’-溴-(1,1’-联苯)-4-羧酸乙酯4cd(344.4mg,70％)。In a 10 mL round-bottomed flask, add 1c (1 mmol, 116 mg), ethyl 4-azido acetoacetate 2 (1 mmol, 171 mg) and 4 mL of a mixture of tert-butanol and water (1/1 by volume), then add five Aqueous copper sulfate solution (0.05mmol, 52μL, 1M) and sodium ascorbate (0.1mmol, 19.9mg), the resulting mixture was stirred at room temperature for 12h, then 3d (0.9mmol, 223mg) and sodium hydroxide (2.0mmol, 80mg) were added , the temperature was raised to 80 °C and the reaction was continued for 2 h. After cooling to room temperature, 5 mL of water was added to quench the reaction, extracted with dichloromethane (5 mL×3), washed with saturated brine, and dried over anhydrous sodium sulfate. Filter, spin dry, and separate through silica gel column (petroleum ether/ethyl acetate=5/1) to obtain a brown solid product 5-methyl-2-(4-(p-methylphenyl)-1H-1,2, 3-Triazolyl)-3-hydroxy-2'-bromo-(1,1'-biphenyl)-4-carboxylate ethyl ester 4cd (344.4 mg, 70%).
该化合物的表征数据如下：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＝171.2,158.1,146.6,143.9,143.1,137.8,137.4,132.4,130.8,129.9,129.4, 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。The characterization data for this compound are as follows: 1 HNMR (400 MHz, CDCl 3 ) δ=12.09 (s, 1H), 7.85 (s, 1H), 7.66 (d, J=8.4 Hz, 2H), 7.46 (d, J=8.4 Hz, 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=7.0 Hz, 2H). 13 CNMR (100 MHz, CDCl 3 ) δ=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 C 25 H 23 BrN 3 O 3 [M+H] + :492.0923; found 492.0929 .
实施例7Example 7
在10mL的圆底烧瓶中加入1d(1mmol,120mg)、4-叠氮乙酰乙酸乙酯2(1mmol,171mg)和4mL叔丁醇与水的混合物(体积比为1/1)，然后加入五水硫酸铜水溶液(0.05mmol,52μL,1M)和抗坏血酸钠(0.1mmol,19.9mg)，得到的混合物于室温搅拌12h后，加入3a(0.9mmol,129.6mg)和氢氧化钠(2.0mmol,80mg)，升温至80℃继续反应2h。冷却至室温加5mL水淬灭反应，用二氯甲烷萃取(5mL×3)，饱和食盐水洗涤，无水硫酸钠干燥。过滤，旋干，过硅胶柱分离(石油醚/乙酸乙酯＝5/1)得到黄色固体产物5-甲基-2-(4-(p- 氟苯基)-1H-1,2,3-三氮唑基)-3-羟基-(1,1’-联苯)-4-羧酸乙酯4da(284.3mg,68％)。In a 10 mL round-bottomed flask, add 1d (1 mmol, 120 mg), ethyl 4-azido acetoacetate 2 (1 mmol, 171 mg) and 4 mL of a mixture of tert-butanol and water (1/1 by volume), then add five Aqueous copper sulfate solution (0.05mmol, 52μL, 1M) and sodium ascorbate (0.1mmol, 19.9mg), the resulting mixture was stirred at room temperature for 12h, 3a (0.9mmol, 129.6mg) and sodium hydroxide (2.0mmol, 80mg) were added ), the temperature was raised to 80 °C and the reaction was continued for 2 h. After cooling to room temperature, 5 mL of water was added to quench the reaction, extracted with dichloromethane (5 mL×3), washed with saturated brine, and dried over anhydrous sodium sulfate. Filter, spin dry, and separate through silica gel column (petroleum ether/ethyl acetate=5/1) to obtain a yellow solid product 5-methyl-2-(4-(p-fluorophenyl)-1H-1,2,3 -Triazolyl)-3-hydroxy-(1,1'-biphenyl)-4-carboxylic acid ethyl ester 4da (284.3 mg, 68%).
该化合物的表征数据如下：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),4.49(q, J＝7.6Hz,2H),2.69(s,3H),1.47(t,J＝7.6Hz,2H).13CNMR(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。The characterization data for this compound are as follows: 1 HNMR (400 MHz, CDCl 3 ) 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), 4.49(q, J=7.6Hz, 2H), 2.69(s, 3H), 1.47(t, J=7.6 Hz, 2H). 13 CNMR (100MHz, CDCl 3 )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, 121.3, 122.6, 12 , 115.6, 112.4, 62.5, 24.4, 14.2. HRMS(ESI): calcd for C 24 H 21 FN 3 O 3 [M+H] + : 418.1567; found 418.1562.
实施例8Example 8
在10mL的圆底烧瓶中加入1e(1mmol,136.6mg)、4-叠氮乙酰乙酸乙酯2(1mmol,171mg)和4mL叔丁醇与水的混合物(体积比为1/1)，然后加入五水硫酸铜水溶液(0.05mmol,52μL,1M)和抗坏血酸钠(0.1mmol,19.9mg)，得到的混合物于室温搅拌12h后，加入3a(0.9mmol,129.6mg)和氢氧化钠(2.0mmol,80mg)，升温至80℃继续反应2h。冷却至室温加5mL水淬灭反应，用二氯甲烷萃取(5mL×3)，饱和食盐水洗涤，无水硫酸钠干燥。过滤，旋干，过硅胶柱分离(石油醚/乙酸乙酯＝5/1)得到黄色固体产物5-甲基-2-(4-(p- 氯苯基)-1H-1,2,3-三氮唑基)-3-羟基-(1,1’-联苯)-4-羧酸乙酯4ea(299.5mg,69％)。In a 10 mL round-bottomed flask were added 1e (1 mmol, 136.6 mg), ethyl 4-azido acetoacetate 2 (1 mmol, 171 mg) and 4 mL of a mixture of tert-butanol and water (1/1 by volume), then added Aqueous copper sulfate pentahydrate (0.05mmol, 52μL, 1M) and sodium ascorbate (0.1mmol, 19.9mg), the resulting mixture was stirred at room temperature for 12h, then 3a (0.9mmol, 129.6mg) and sodium hydroxide (2.0mmol, 129.6mg) were added. 80 mg), the temperature was raised to 80 °C and the reaction was continued for 2 h. After cooling to room temperature, 5 mL of water was added to quench the reaction, extracted with dichloromethane (5 mL×3), washed with saturated brine, and dried over anhydrous sodium sulfate. Filter, spin dry, and separate through silica gel column (petroleum ether/ethyl acetate=5/1) to obtain a yellow solid product 5-methyl-2-(4-(p-chlorophenyl)-1H-1,2,3 -Triazolyl)-3-hydroxy-(1,1'-biphenyl)-4-carboxylic acid ethyl ester 4ea (299.5 mg, 69%).
该化合物的表征数据如下：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),4.50(q, J＝7.2Hz,2H),2.69(s,3H),1.48(t,J＝7.2Hz,3H).13CNMR(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。The characterization data for this compound are as follows: 1 HNMR (400 MHz, CDCl 3 ) 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), 4.50(q, J=7.2Hz, 2H), 2.69(s, 3H), 1.48(t, J=7.2 Hz, 3H). 13 CNMR(100MHz, CDCl 3 )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 , 14.2. HRMS (ESI): calcd for C 24 H 21 ClN 3 O 3 [M+H] + : 434.1271; found 434.1276.
实施例9Example 9
在10mL的圆底烧瓶中加入1f(1mmol,181mg)、4-叠氮乙酰乙酸乙酯2(1mmol,171mg) 和4mL叔丁醇与水的混合物(体积比为1/1)，然后加入五水硫酸铜水溶液(0.05mmol,52μL, 1M)和抗坏血酸钠(0.1mmol,19.9mg)，得到的混合物于室温搅拌12h后，加入3a(0.9mmol, 129.6mg)和氢氧化钠(2.0mmol,80mg)，升温至80℃继续反应2h。冷却至室温加5mL水淬灭反应，用二氯甲烷萃取(5mL×3)，饱和食盐水洗涤，无水硫酸钠干燥。过滤，旋干，过硅胶柱分离(石油醚/乙酸乙酯＝5/1)得到棕色固体产物5-甲基-2-(4-(p-溴苯基)-1H-1,2,3- 三氮唑基)-3-羟基-(1,1’-联苯)-4-羧酸乙酯4fa(339.4mg,71％)。In a 10 mL round-bottomed flask, add 1f (1 mmol, 181 mg), ethyl 4-azido acetoacetate 2 (1 mmol, 171 mg) and 4 mL of a mixture of tert-butanol and water (1/1 by volume), then add five Aqueous copper sulfate solution (0.05mmol, 52μL, 1M) and sodium ascorbate (0.1mmol, 19.9mg), 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 temperature was raised to 80 °C and the reaction was continued for 2 h. After cooling to room temperature, 5 mL of water was added to quench the reaction, extracted with dichloromethane (5 mL×3), washed with saturated brine, and dried over anhydrous sodium sulfate. Filter, spin dry, and separate through silica gel column (petroleum ether/ethyl acetate=5/1) to obtain a brown solid product 5-methyl-2-(4-(p-bromophenyl)-1H-1,2,3 - Triazolyl)-3-hydroxy-(1,1'-biphenyl)-4-carboxylic acid ethyl ester 4fa (339.4 mg, 71%).
该化合物的表征数据如下：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＝ 171.2,158.6,146.1,144.6,143.7,136.4,131.9,129.5,128.5,128.1,127.3,124.3,123.0,121.9, 112.4,62.5,24.4,14.2.HRMS(ESI):calcd for C24H21BrN3O3[M+H]+:478.0766；found 478.0770。Characterization data for this compound are as follows: 1 HNMR (400 MHz, CDCl 3 ) δ=12.11 (s, 1H), 7.70 (s, 1H), 7.64 (d, J=8.8 Hz, 2H), 7.48 (d, J=8.0 Hz, 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=7.2 Hz, 3H). 13 CNMR (100 MHz, CDCl 3 ) δ= 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 C 24 H 21 BrN 3 O 3 [M+H] + : 478.0766; found 478.0770.
实施例10Example 10
在10mL的圆底烧瓶中加入1f(1mmol,181mg)、4-叠氮乙酰乙酸乙酯2(1mmol,171mg) 和4mL叔丁醇与水的混合物(体积比为1/1)，然后加入五水硫酸铜水溶液(0.05mmol,52μL, 1M)和抗坏血酸钠(0.1mmol,19.9mg)，得到的混合物于室温搅拌12h后，加入3b(0.9mmol, 204.2mg)和氢氧化钠(2.0mmol,80mg)，升温至80℃继续反应2h。冷却至室温加5mL水淬灭反应，用二氯甲烷萃取(5mL×3)，饱和食盐水洗涤，无水硫酸钠干燥。过滤，旋干，过硅胶柱分离(石油醚/乙酸乙酯＝5/1)得到黄色油状物5-甲基-2-(4-(p-溴苯基)-1H-1,2,3- 三氮唑基)-3-羟基-2’,5’-二甲氧基-(1,1’-联苯)-4-羧酸乙酯4fb(376.6mg,70％)。In a 10 mL round-bottomed flask, add 1f (1 mmol, 181 mg), ethyl 4-azido acetoacetate 2 (1 mmol, 171 mg) and 4 mL of a mixture of tert-butanol and water (1/1 by volume), then add five Aqueous copper sulfate solution (0.05mmol, 52μL, 1M) and sodium ascorbate (0.1mmol, 19.9mg), the obtained mixture was stirred at room temperature for 12h, 3b (0.9mmol, 204.2mg) and sodium hydroxide (2.0mmol, 80mg) were added ), the temperature was raised to 80 °C and the reaction was continued for 2 h. After cooling to room temperature, 5 mL of water was added to quench the reaction, extracted with dichloromethane (5 mL×3), washed with saturated brine, and dried over anhydrous sodium sulfate. Filter, spin dry, and separate through silica gel column (petroleum ether/ethyl acetate=5/1) to obtain a yellow oily substance 5-methyl-2-(4-(p-bromophenyl)-1H-1,2,3 - Triazolyl)-3-hydroxy-2',5'-dimethoxy-(1,1'-biphenyl)-4-carboxylic acid ethyl ester 4fb (376.6 mg, 70%).
该化合物的表征数据如下：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。The characterization data for this compound are as follows: 1 HNMR (400 MHz, CDCl 3 ) 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). 13 CNMR (100MHz, CDCl 3 )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 C 26 3O5 [M+H] + : 538.0978 ; found 538.0972.
实施例11Example 11
在10mL的圆底烧瓶中加入1f(1mmol,181mg)、4-叠氮乙酰乙酸乙酯2(1mmol,171mg) 和4mL叔丁醇与水的混合物(体积比为1/1)，然后加入五水硫酸铜水溶液(0.05mmol,52μL, 1M)和抗坏血酸钠(0.1mmol,19.9mg)，得到的混合物于室温搅拌12h后，加入3e(0.9mmol, 191mg)和氢氧化钠(2.0mmol,80mg)，升温至80℃继续反应2h。冷却至室温加5mL水淬灭反应，用二氯甲烷萃取(5mL×3)，饱和食盐水洗涤，无水硫酸钠干燥。过滤，旋干，过硅胶柱分离(石油醚/乙酸乙酯＝5/1)得到黄色固体产物5-甲基-4’-三氟甲基-2-(4-(p- 溴苯基)-1H-1,2,3-三氮唑基)-3-羟基-(1,1’-联苯)-4-羧酸乙酯4fe(360.4mg,66％)。In a 10 mL round-bottomed flask, add 1f (1 mmol, 181 mg), ethyl 4-azido acetoacetate 2 (1 mmol, 171 mg) and 4 mL of a mixture of tert-butanol and water (1/1 by volume), then add five Aqueous copper sulfate solution (0.05mmol, 52μL, 1M) and sodium ascorbate (0.1mmol, 19.9mg), the resulting mixture was stirred at room temperature for 12h, then 3e (0.9mmol, 191mg) and sodium hydroxide (2.0mmol, 80mg) were added , the temperature was raised to 80 °C and the reaction was continued for 2 h. After cooling to room temperature, 5 mL of water was added to quench the reaction, extracted with dichloromethane (5 mL×3), washed with saturated brine, and dried over anhydrous sodium sulfate. Filter, spin dry, and separate through silica gel column (petroleum ether/ethyl acetate = 5/1) to obtain a yellow solid product 5-methyl-4'-trifluoromethyl-2-(4-(p-bromophenyl) -1H-1,2,3-Triazolyl)-3-hydroxy-(1,1'-biphenyl)-4-carboxylate ethyl ester 4fe (360.4 mg, 66%).
该化合物的表征数据如下：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 forC25H20BrF3N3O3[M+H]+: 546.0640；found 546.0635。The characterization data for this compound are as follows: 1 HNMR (400 MHz, CDCl 3 ) 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). 13 CNMR (100MHz, CDCl 3 )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, 122.0, 62. , 24.4, 14.2. HRMS(ESI): calcd for C 25 H 20 BrF 3 N 3 O 3 [M+H] + : 546.0640; found 546.0635.
实施例12Example 12
在10mL的圆底烧瓶中加入1g(1mmol,116.2mg)、4-叠氮乙酰乙酸乙酯2(1mmol,171mg)和4mL叔丁醇与水的混合物(体积比为1/1)，然后加入五水硫酸铜水溶液(0.05mmol,52μL,1M)和抗坏血酸钠(0.1mmol,19.9mg)，得到的混合物于室温搅拌12h后，加入3b(0.9mmol,204.2mg)和氢氧化钠(2.0mmol,80mg)，升温至80℃继续反应2h。冷却至室温加5mL水淬灭反应，用二氯甲烷萃取(5mL×3)，饱和食盐水洗涤，无水硫酸钠干燥。过滤，旋干，过硅胶柱分离(石油醚/乙酸乙酯＝3/1)得到白色固体产物5-甲基-2-(4-苄基 -1H-1,2,3-三氮唑基)-3-羟基-3’,4’-二甲氧基-(1,1’-联苯)-4-羧酸乙酯4gb(303.4mg,64％)。Into a 10 mL round-bottomed flask was added 1 g (1 mmol, 116.2 mg), ethyl 4-azido acetoacetate 2 (1 mmol, 171 mg) and 4 mL of a mixture of tert-butanol and water (1/1 by volume), and then added Aqueous copper sulfate pentahydrate (0.05mmol, 52μL, 1M) and sodium ascorbate (0.1mmol, 19.9mg), the resulting mixture was stirred at room temperature for 12h, 3b (0.9mmol, 204.2mg) and sodium hydroxide (2.0mmol, 204.2mg) were added. 80 mg), the temperature was raised to 80 °C and the reaction was continued for 2 h. After cooling to room temperature, 5 mL of water was added to quench the reaction, extracted with dichloromethane (5 mL×3), washed with saturated brine, and dried over anhydrous sodium sulfate. Filter, spin dry, and separate through silica gel column (petroleum ether/ethyl acetate=3/1) to obtain 5-methyl-2-(4-benzyl-1H-1,2,3-triazolyl as a white solid product) )-3-hydroxy-3',4'-dimethoxy-(1,1'-biphenyl)-4-carboxylic acid ethyl ester 4gb (303.4 mg, 64%).
该化合物的表征数据如下：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 forC27H28N3O5[M+H]+:474.2029； found 474.2035。The characterization data for this compound are as follows: 1 HNMR (400 MHz, CDCl 3 ) 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). 13 CNMR (100MHz, CDCl 3 )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 .
实施例13Example 13
在10mL的圆底烧瓶中加入1h(1mmol,56.1mg)、4-叠氮乙酰乙酸乙酯2(1mmol,171mg)和4mL叔丁醇与水的混合物(体积比为1/1)，然后加入五水硫酸铜水溶液(0.05mmol,52μL,1M)，抗坏血酸钠(0.1mmol,19.9mg)，得到的混合物于室温搅拌12h后，加入3a(0.9mmol,129.6mg)和氢氧化钠(2.0mmol,80mg)，升温至80℃继续反应2h。冷却至室温加5mL水淬灭反应，用二氯甲烷萃取(5mL×3)，饱和食盐水洗涤，无水硫酸钠干燥。过滤，旋干，过硅胶柱分离(石油醚/乙酸乙酯＝1/1)得到黄色固体产物5-甲基-2-(4-羟甲基-1H-1,2,3-三氮唑基)-3-羟基-(1,1’-联苯)-4-羧酸乙酯4ha(276mg,78％)。In a 10 mL round-bottomed flask, add 1 h (1 mmol, 56.1 mg), ethyl 4-azido acetoacetate 2 (1 mmol, 171 mg) and 4 mL of a mixture of tert-butanol and water (1/1 by volume), then add Aqueous copper sulfate pentahydrate (0.05mmol, 52μL, 1M), sodium ascorbate (0.1mmol, 19.9mg), after the resulting mixture was stirred at room temperature for 12h, 3a (0.9mmol, 129.6mg) and sodium hydroxide (2.0mmol, 129.6mg) were added. 80 mg), the temperature was raised to 80 °C and the reaction was continued for 2 h. After cooling to room temperature, 5 mL of water was added to quench the reaction, extracted with dichloromethane (5 mL×3), washed with saturated brine, and dried over anhydrous sodium sulfate. Filter, spin dry, and separate through silica gel column (petroleum ether/ethyl acetate=1/1) to obtain 5-methyl-2-(4-hydroxymethyl-1H-1,2,3-triazole as a yellow solid product) yl)-3-hydroxy-(1,1'-biphenyl)-4-carboxylic acid ethyl ester 4ha (276 mg, 78%).
该化合物的表征数据如下：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),2.77(s, 1H),2.68(s,3H),1.47(t,J＝7.2Hz,3H).13CNMR(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。The characterization data for this compound are as follows: 1 HNMR (400 MHz, CDCl 3 ) 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), 2.77(s, 1H), 2.68(s, 3H), 1.47(t, J=7.2Hz, 3H) . 13 CNMR (100MHz, CDCl 3 )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 C 19 H 20 N 3 O 4 [M+H] + : 354.1454; found 354.1459.
实施例14Example 14
在10mL的圆底烧瓶中加入1h(1mmol,56.1mg)、4-叠氮乙酰乙酸乙酯2(1mmol,171mg)和4mL叔丁醇与水的混合物(体积比为1/1)，然后加入五水硫酸铜水溶液(0.05mmol,52μL,1M)和抗坏血酸钠(0.1mmol,19.9mg)，得到的混合物于室温搅拌12h后，加入3d(0.9mmol,223mg)和氢氧化钠(2.0mmol,80mg)，升温至80℃继续反应2h。冷却至室温加5mL水淬灭反应，用二氯甲烷萃取(5mL×3)，饱和食盐水洗涤，无水硫酸钠干燥。过滤，旋干，过硅胶柱分离(石油醚/乙酸乙酯＝1/1)得到黄色固体产物5-甲基-2-(4-羟甲基 -1H-1,2,3-三氮唑基)-3-羟基-2’-溴-(1,1’-联苯)-4-羧酸乙酯4hd(319.7mg,74％)。In a 10 mL round-bottomed flask, add 1 h (1 mmol, 56.1 mg), ethyl 4-azido acetoacetate 2 (1 mmol, 171 mg) and 4 mL of a mixture of tert-butanol and water (1/1 by volume), then add Aqueous copper sulfate pentahydrate (0.05mmol, 52μL, 1M) and sodium ascorbate (0.1mmol, 19.9mg), the resulting mixture was stirred at room temperature for 12h, 3d (0.9mmol, 223mg) and sodium hydroxide (2.0mmol, 80mg) were added ), the temperature was raised to 80 °C and the reaction was continued for 2 h. After cooling to room temperature, 5 mL of water was added to quench the reaction, extracted with dichloromethane (5 mL×3), washed with saturated brine, and dried over anhydrous sodium sulfate. Filter, spin dry, and separate through silica gel column (petroleum ether/ethyl acetate=1/1) to obtain 5-methyl-2-(4-hydroxymethyl-1H-1,2,3-triazole as a yellow solid product) yl)-3-hydroxy-2'-bromo-(1,1'-biphenyl)-4-carboxylic acid ethyl ester 4hd (319.7 mg, 74%).
该化合物的表征数据如下：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),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) δ＝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。The characterization data for this compound are as follows: 1 HNMR (400 MHz, CDCl 3 ) δ=11.97 (s, 1H), 7.61 (s, 1H), 7.45 (d, J=7.6 Hz, 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). 13 CNMR (100MHz, CDCl 3 ) δ=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 C 19 H 19 BrN 3 O 4 [M+H] + : 432.0559; found 432.0565.
实施例15Example 15
在10mL的圆底烧瓶中加入1h(1mmol,56.1mg)、4-叠氮乙酰乙酸乙酯2(1mmol,171mg)和4mL叔丁醇与水的混合物(体积比为1/1)，然后加入五水硫酸铜水溶液(0.05mmol,52μL,1M)和抗坏血酸钠(0.1mmol,19.9mg)，得到的混合物于室温搅拌12h后，加入3f(0.9mmol,216.9mg)和氢氧化钠(2.0mmol,80mg)，升温至80℃继续反应2h。冷却至室温加5mL水淬灭反应，用二氯甲烷萃取(5mL×3)，饱和食盐水洗涤，无水硫酸钠干燥。过滤，旋干，过硅胶柱分离(石油醚/乙酸乙酯＝1/1)得到白色固体产物5-甲基-2-(4-羟甲基-1H-1,2,3-三氮唑基)-3-羟基-2’-溴-5’-氟-(1,1’-联苯)-4-羧酸乙酯4hf(342mg,76％)。In a 10 mL round-bottomed flask, add 1 h (1 mmol, 56.1 mg), ethyl 4-azido acetoacetate 2 (1 mmol, 171 mg) and 4 mL of a mixture of tert-butanol and water (1/1 by volume), then add Aqueous copper sulfate pentahydrate (0.05mmol, 52μL, 1M) and sodium ascorbate (0.1mmol, 19.9mg), the resulting mixture was stirred at room temperature for 12h, then 3f (0.9mmol, 216.9mg) and sodium hydroxide (2.0mmol, 216.9mg) were added. 80 mg), the temperature was raised to 80 °C and the reaction was continued for 2 h. After cooling to room temperature, 5 mL of water was added to quench the reaction, extracted with dichloromethane (5 mL×3), washed with saturated brine, and dried over anhydrous sodium sulfate. Filter, spin dry, and separate through silica gel column (petroleum ether/ethyl acetate=1/1) to obtain 5-methyl-2-(4-hydroxymethyl-1H-1,2,3-triazole as a white solid product) yl)-3-hydroxy-2'-bromo-5'-fluoro-(1,1'-biphenyl)-4-carboxylate ethyl ester 4hf (342 mg, 76%).
该化合物的表征数据如下：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；found450.0470。The characterization data for this compound are as follows: 1 HNMR (400 MHz, CDCl 3 ) δ=12.08 (s, 1H), 7.68 (s, 1H), 7.40 (dd, J=4.8, 9.2 Hz, 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). 13 CNMR (100MHz, CDCl 3 )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 C 19 H 18 BrFN 3 O 4 [M+H] + :450.0465; found450.0470.
实施例16Example 16
在10mL的圆底烧瓶中加入1i(1mmol,132.2mg)、4-叠氮乙酰乙酸乙酯2(1mmol,171mg)和4mL叔丁醇与水的混合物(体积比为1/1)，然后加入五水硫酸铜水溶液(0.05mmol,52μL,1M)和抗坏血酸钠(0.1mmol,19.9mg)，得到的混合物于室温搅拌12h后，加入3a(0.9mmol,129.6mg)和氢氧化钠(2.0mmol,80mg)，升温至80℃继续反应2h。冷却至室温加5mL水淬灭反应，用二氯甲烷萃取(5mL×3)，饱和食盐水洗涤，无水硫酸钠干燥。过滤，旋干，过硅胶柱分离(石油醚/乙酸乙酯＝2/1)得到白色固体产物5-甲基-2-(4-(羟基苯基)甲基-1H-1,2,3-三氮唑基)-3-羟基-(1,1’-联苯)-4-羧酸乙酯4ia(301.1mg,70％)。In a 10 mL round-bottomed flask, 1i (1 mmol, 132.2 mg), ethyl 4-azido acetoacetate 2 (1 mmol, 171 mg) and 4 mL of a mixture of tert-butanol and water (1/1 by volume) were added, followed by Aqueous copper sulfate pentahydrate (0.05mmol, 52μL, 1M) and sodium ascorbate (0.1mmol, 19.9mg), the resulting mixture was stirred at room temperature for 12h, then 3a (0.9mmol, 129.6mg) and sodium hydroxide (2.0mmol, 129.6mg) were added. 80 mg), the temperature was raised to 80 °C and the reaction was continued for 2 h. After cooling to room temperature, 5 mL of water was added to quench the reaction, extracted with dichloromethane (5 mL×3), washed with saturated brine, and dried over anhydrous sodium sulfate. Filter, spin dry, and separate through silica gel column (petroleum ether/ethyl acetate=2/1) to obtain a white solid product 5-methyl-2-(4-(hydroxyphenyl)methyl-1H-1,2,3 -Triazolyl)-3-hydroxy-(1,1'-biphenyl)-4-carboxylic acid ethyl ester 4ia (301.1 mg, 70%).
该化合物的表征数据如下：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；found430.1773。The characterization data for this compound are as follows: 1 HNMR (400 MHz, CDCl 3 ) 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) . 13 CNMR (100MHz, CDCl 3 )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. , 14.2. HRMS(ESI): calcd for C 25 H 24 N 3 O 4 [M+H] + : 430.1767; found430.1773.
实施例17Example 17
在10mL的圆底烧瓶中加入1j(1mmol,225mg)、4-叠氮乙酰乙酸乙酯2(1mmol,171mg) 和4mL叔丁醇与水的混合物(体积比为1/1)，然后加入五水硫酸铜水溶液(0.05mmol,52μL, 1M)和抗坏血酸钠(0.1mmol,19.9mg)，得到的混合物于室温搅拌12h后，加入3e(0.9mmol, 191mg)和氢氧化钠(2.0mmol,80mg)，升温至80℃继续反应2h。冷却至室温加5mL水淬灭反应，用二氯甲烷萃取(5mL×3)，饱和食盐水洗涤，无水硫酸钠干燥。过滤，旋干，过硅胶柱分离(石油醚/乙酸乙酯＝3/1)得到黄色油状产物5-甲基-4’-三氟甲基-2-(4-(2- (2-溴苯基)-1-羟基)乙基-1H-1,2,3-三氮唑基)-3-羟基-(1,1’-联苯)-4-羧酸乙酯4je(407.1mg, 69％)。In a 10 mL round-bottomed flask, add 1j (1 mmol, 225 mg), ethyl 4-azido acetoacetate 2 (1 mmol, 171 mg) and 4 mL of a mixture of tert-butanol and water (1/1 by volume), then add five Aqueous copper sulfate solution (0.05mmol, 52μL, 1M) and sodium ascorbate (0.1mmol, 19.9mg), the resulting mixture was stirred at room temperature for 12h, then 3e (0.9mmol, 191mg) and sodium hydroxide (2.0mmol, 80mg) were added , the temperature was raised to 80 °C and the reaction was continued for 2 h. After cooling to room temperature, 5 mL of water was added to quench the reaction, extracted with dichloromethane (5 mL×3), washed with saturated brine, and dried over anhydrous sodium sulfate. Filter, spin dry, and separate through silica gel column (petroleum ether/ethyl acetate=3/1) to obtain 5-methyl-4'-trifluoromethyl-2-(4-(2-(2-bromo) as a yellow oily product Phenyl)-1-hydroxy)ethyl-1H-1,2,3-triazolyl)-3-hydroxy-(1,1'-biphenyl)-4-carboxylate ethyl ester 4je (407.1 mg, 69%).
该化合物的表征数据如下：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 forC27H24BrF3N3O4[M+H]+: 590.0902；found 590.0910。The characterization data for this compound are as follows: 1 HNMR (400 MHz, CDCl 3 ) 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). 13 CNMR (100MHz, CDCl 3 )δ=171.1 HRMS (ESI): calcd for C27H24BrF3N3O4 [ M + H] + : 590.0902 ; found 590.0910.
实施例18Example 18
在10mL的圆底烧瓶中加入1b(1mmol,116.2mg)、4-叠氮乙酰乙酸乙酯2(1mmol,171mg)和4mL叔丁醇与水的混合物(体积比为1/1)，然后加入五水硫酸铜水溶液(0.05mmol,52μL,1M)和抗坏血酸钠(0.1mmol,19.9mg)，得到的混合物于室温搅拌12h后，加入3g(0.9mmol,142.4mg)和氢氧化钠(2.0mmol,80mg)，升温至80℃继续反应2h。冷却至室温加5mL水淬灭反应，用二氯甲烷萃取(5mL×3)，饱和食盐水洗涤，无水硫酸钠干燥。过滤，旋干，过硅胶柱分离(石油醚/乙酸乙酯＝8/1)得到黄色油状产物5,6-二甲基-2-(4- (m-甲基苯基)-1H-1,2,3-三氮唑基)-3-羟基-(1,1’-联苯)-4-羧酸乙酯4bg(239.7mg,56％)。In a 10 mL round-bottomed flask, 1b (1 mmol, 116.2 mg), ethyl 4-azido acetoacetate 2 (1 mmol, 171 mg) and 4 mL of a mixture of tert-butanol and water (1/1 by volume) were added, followed by Aqueous copper sulfate pentahydrate (0.05mmol, 52μL, 1M) and sodium ascorbate (0.1mmol, 19.9mg), the resulting mixture was stirred at room temperature for 12h, 3g (0.9mmol, 142.4mg) and sodium hydroxide (2.0mmol, 142.4mg) were added. 80 mg), the temperature was raised to 80 °C and the reaction was continued for 2 h. After cooling to room temperature, 5 mL of water was added to quench the reaction, extracted with dichloromethane (5 mL×3), washed with saturated brine, and dried over anhydrous sodium sulfate. Filter, spin dry, and separate through silica gel column (petroleum ether/ethyl acetate=8/1) to obtain a yellow oily product 5,6-dimethyl-2-(4-(m-methylphenyl)-1H-1 , 2,3-Triazolyl)-3-hydroxy-(1,1'-biphenyl)-4-carboxylic acid ethyl ester 4bg (239.7 mg, 56%).
该化合物的表征数据如下：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＝170.6,153.9,146.7,144.7,141.4,138.4,136.3,130.3,128.8,128.7,128.6,128.2,127.9, 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。The characterization data of this compound are as follows: 1 HNMR (400 MHz, CDCl 3 ) δ=10.79 (s, 1H), 7.56 (s, 1H), 7.50 (s, 1H), 7.45 (d, J=7.2 Hz, 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=7.6 Hz, 3H). 13 CNMR (100 MHz, CDCl 3 ) δ=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 C 26 H 26 N 3 O 3 [M+H] + :428.1974; found428.1979.
实施例19Example 19
在10mL的圆底烧瓶中加入1b(1mmol,116.2mg)、4-叠氮乙酰乙酸乙酯2(1mmol,171mg)和4mL叔丁醇与水的混合物(体积比为1/1)，然后加入五水硫酸铜水溶液(0.05mmol,52μL,1M)和抗坏血酸钠(0.1mmol,19.9mg)，得到的混合物室温搅拌12h后，加入3h(0.9mmol,198.3mg)和氢氧化钠(2.0mmol,80mg)，升温至80℃继续反应2h。冷却至室温加5mL水淬灭反应，用二氯甲烷萃取(5mL×3)，饱和食盐水洗涤，无水硫酸钠干燥。过滤，旋干，过硅胶柱分离(石油醚/乙酸乙酯＝5/1)得到黄色油状产物5-苄基-2-(4-(m- 甲基苯基)-1H-1,2,3-三氮唑基)-3-羟基-(1,1’-联苯)-4-羧酸乙酯4bh(156.8mg,32％)。In a 10 mL round-bottomed flask, 1b (1 mmol, 116.2 mg), ethyl 4-azido acetoacetate 2 (1 mmol, 171 mg) and 4 mL of a mixture of tert-butanol and water (1/1 by volume) were added, followed by Aqueous copper sulfate pentahydrate (0.05mmol, 52μL, 1M) and sodium ascorbate (0.1mmol, 19.9mg), the resulting mixture was stirred at room temperature for 12h, and then added for 3h (0.9mmol, 198.3mg) and sodium hydroxide (2.0mmol, 80mg) ), the temperature was raised to 80 °C and the reaction was continued for 2 h. After cooling to room temperature, 5 mL of water was added to quench the reaction, extracted with dichloromethane (5 mL×3), washed with saturated brine, and dried over anhydrous sodium sulfate. Filter, spin dry, and separate through silica gel column (petroleum ether/ethyl acetate = 5/1) to obtain a yellow oily product 5-benzyl-2-(4-(m-methylphenyl)-1H-1,2, 3-Triazolyl)-3-hydroxy-(1,1'-biphenyl)-4-carboxylate ethyl ester 4bh (156.8 mg, 32%).
该化合物的表征数据如下：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；found490.2136。The characterization data of this compound are as follows: 1 HNMR (400 MHz, CDCl 3 ) δ=11.95 (s, 1H), 7.72 (s, 1H), 7.67 (s, 1H), 7.56 (d, J=7.2 Hz, 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). 13 CNMR (100MHz, CDCl 3 )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. H] + :490.2131;found490.2136.
以上显示和描述了本发明的基本原理，主要特征和优点，在不脱离本发明精神和范围的前提下，本发明还有各种变化和改进，这些变化和改进都落入要求保护的本发明的范围。The basic principles, main features and advantages of the present invention have been shown and described above. Without departing from the spirit and scope of the present invention, the present invention has various changes and improvements, which all fall into the claimed invention. range.
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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