Preparation method of 1-(3-bromo-4-methoxyphenyl)-3-(trifluoromethyl)-1, 2, 4-triazole
By carrying out three-step nucleophilic substitution reaction, ring-closing reaction and bromination reaction under alkaline conditions, 1-(3-bromo-4-methoxyphenyl)-3-(trifluoromethyl)-1,2,4-triazole was successfully prepared, which solved the problem of lack of effective preparation methods in the prior art and achieved efficient and pure compound preparation.
Patent Information
- Application Number
- CN202411749949.1
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-12-02
- Publication Date
- 2025-03-07
AI Technical Summary
There is a lack of effective preparation methods in the prior art to synthesize 1-(3-bromo-4-methoxyphenyl)-3-(trifluoromethyl)-1,2,4-triazole. This compound has important uses in pharmaceuticals and pesticides, but its preparation method has not been reported.
A three-step preparation method is adopted: first, 4-methoxyphenylhydrazine hydrochloride and trifluoroacetamid are nucleophilic substitution reaction under alkaline conditions, followed by ring-closed reaction, and finally the target compound is obtained by bromination reaction. This method is simple to operate, has high yield, and the post-processing and purification process is also relatively simple.
The efficient preparation of 1-(3-bromo-4-methoxyphenyl)-3-(trifluoromethyl)-1,2,4-triazole was achieved. The total yield of the three-step reaction reached 80%, and there was no by-product production throughout the process, and the product purity was as high as 95%.
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Figure CN119569663A_ABST
Abstract
Description
Technical Field
[0001] The invention relates to the technical field of pharmaceutical intermediate synthesis, and in particular to a method for preparing 1-(3-bromo-4-methoxyphenyl)-3-(trifluoromethyl)-1,2,4-triazole. Background Art
[0002] Drug molecular building blocks are important fragments that make up drug molecules, just like Lego blocks, and are the raw materials for the synthesis of drug molecules. 1,2,4-Triazole is an important intermediate for the synthesis of pesticide fungicides, plant growth regulators such as paclobutrazol, diniconazole, triadimefon, and fenadone. It can be used as an intermediate for a variety of pesticides, medicines, and dyes, and its demand is increasing as the scope of application expands. 1,2,4-Triazole, as a very valuable five-membered nitrogen-containing heterocyclic skeleton, is widely present in many functional molecules and is used in organic catalysis, materials science and other fields. In addition, the 1,2,4-triazole skeleton also appears in many biologically active molecules.
[0003] The 1-(3-bromo-4-methoxyphenyl)-3-(trifluoromethyl)-1,2,4-triazole synthesized by the method has important uses in the pharmaceutical industry and pesticides because it contains a 1,2,4-triazole functional group. The bromine group contained in this type of compound is a very valuable synthetic building block in synthesis. At present, there is no report on the compound and preparation method of 1-(3-bromo-4-methoxyphenyl)-3-(trifluoromethyl)-1,2,4-triazole. Summary of the invention
[0004] In view of the deficiencies of the prior art, the present invention provides a method for preparing 1-(3-bromo-4-methoxyphenyl)-3-(trifluoromethyl)-1,2,4-triazole. The preparation method provided by the present invention is simple to operate, has a high yield, a simple post-processing and purification process, and is easy to realize industrialization.
[0005] The technical solution of the present invention is as follows:
[0006] A method for preparing 1-(3-bromo-4-methoxyphenyl)-3-(trifluoromethyl)-1,2,4-triazole, wherein the preparation method is carried out according to the following process:
[0007]
[0008] The specific steps are:
[0009] (1) Using compound 1 as the starting material, compound 1 and a base are dissolved in solvent 1, and then compound 2 is added to carry out a nucleophilic substitution reaction to obtain compound 3;
[0010] (2) Compound 3 is mixed with triethyl orthoformate, and the mixture is heated to reflux to undergo a ring-closing reaction to obtain compound 4;
[0011] (3) Compound 4 is dissolved in solvent II, NBS is added, and the mixture is heated to cause a bromination reaction to obtain 1-(3-bromo-4-methoxyphenyl)-3-(trifluoromethyl)-1,2,4-triazole.
[0012] Furthermore, in step (1), the molar ratio of compound 1 to compound 2 is 1:1 to 20.0.
[0013] Furthermore, in step (1), the molar ratio of compound 1 to triethylamine is 1:1.5-20.0.
[0014] Furthermore, in step (1), the base is selected from any one of trimethylamine, triethylamine, tripropylamine, triisopropylamine, and diisopropylethylamine; the solvent I is selected from any one of methanol, ethanol, isopropanol, propanol, and n-butanol; and the concentration of the compound 1 in the solvent I is 0.1 to 2 mol / L.
[0015] Furthermore, in step (1), the temperature of the nucleophilic substitution reaction is 20 to 40° C., and the time is 12 to 48 hours.
[0016] Furthermore, in step (2), the molar ratio of compound 3 to triethyl orthoformate is 1:10 to 20.0.
[0017] Furthermore, in step (2), the temperature of the ring-closure reaction is 100 to 110° C., and the time is 12 to 48 hours.
[0018] Furthermore, in step (3), the molar ratio of compound 4 to NBS is 1:1 to 20.0.
[0019] Furthermore, in step (3), the solvent II is selected from any one of acetonitrile, dichloromethane, methanol, N,N-dimethylformamide, N,N-dimethylacetamide, and tetrahydrofuran; and the concentration of the compound 4 in the solvent II is 0.01 to 1 mol / L.
[0020] Furthermore, in step (3), the temperature of the bromination reaction is 80 to 100° C., and the time is 12 to 48 hours.
[0021] The beneficial technical effects of the present invention are:
[0022] The invention firstly causes 4-methoxyphenylhydrazine hydrochloride and trifluoroacetamidine to undergo nucleophilic substitution reaction under alkaline conditions, and then undergoes ring-closing reaction and bromination reaction to obtain the target compound, wherein the reaction is carried out toward the target product by optimizing the conditions of the bromination reaction. The whole operation process of the invention does not produce other byproducts, has a single position, has no other isomers, is simple to operate, and has a three-step yield of up to 80%. BRIEF DESCRIPTION OF THE DRAWINGS
[0023] Figure 1 This is the H NMR spectrum of 1-(4-methoxyphenyl)-3-(trifluoromethyl)-1,2,4-triazole prepared in Example 1 of the present invention.
[0024] Figure 2 This is the H NMR spectrum of 1-(3-bromo-4-methoxyphenyl)-3-(trifluoromethyl)-1,2,4-triazole prepared in Example 1 of the present invention.
[0025] Figure 3 This is the hydrogen nuclear magnetic spectrum of 5-bromo-1-(4-methoxyphenyl)-3-(trifluoromethyl)-1,2,4-triazole prepared in Comparative Example 1 of the present invention. DETAILED DESCRIPTION
[0026] The present invention is described in detail below in conjunction with the accompanying drawings and embodiments.
[0027] Example 1
[0028] A method for preparing 1-(3-bromo-4-methoxyphenyl)-3-(trifluoromethyl)-1,2,4-triazole, the method comprising the following steps:
[0029] (1) Preparation of 2,2,2-trifluoro-N'-(4-methoxyphenyl)acetylhydrazone
[0030] Compound 1 4-methoxyphenylhydrazine hydrochloride (1.8 g, 0.01 mol) and triethylamine (1.57 g, 0.015 mol) were dissolved in methanol (50 mL), and compound 2 trifluoroacetamidine (1.3 g, 0.011 mol) was slowly added in batches, and the reaction mixture was stirred at 40°C for 12 h. The reaction was complete as detected by LCMS control, and the mixture was poured into ice water and extracted with EA. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by vacuum distillation to obtain a brown oil, namely compound 3 2,2,2-trifluoro-N'-(4-methoxyphenyl)acetylhydrazone amide 2.8 g, which was directly used in the next step.
[0031] (2) Preparation of 1-(4-methoxyphenyl)-3-(trifluoromethyl)-1,2,4-triazole
[0032] Compound 3 2,2,2-trifluoro-N'-(4-methoxyphenyl)acetylhydrazone (1.8 g, 0.0077 mol) and triethyl orthoformate (16.6 mL, 0.10 mol) were mixed evenly, and the reaction was heated to 100°C and stirred for 48 h. The reaction was complete by TLC control, and the mixture was poured into ice water and extracted with EA. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by vacuum distillation to obtain a crude product, which was purified by flash column chromatography (PE / EA=6 / 1) to obtain a brown oil, i.e., compound 4 1-(4-methoxyphenyl)-3-(trifluoromethyl)-1,2,4-triazole 1.36 g, with a two-step yield of 88% and a purity of 95%.
[0033] The NMR spectrum of the product is shown in Figure 1 As shown, 1 H NMR (400MHz, CDCl3): δ8.50(s,1H),7.69–7.51(m,2H),7.09–6.97(m,2H),3.88(s,3H).
[0034] (3) Preparation of 1-(3-bromo-4-methoxyphenyl)-3-(trifluoromethyl)-1,2,4-triazole
[0035] Compound 4 1-(4-methoxyphenyl)-3-(trifluoromethyl)-1,2,4-triazole (0.92 g, 0.004 mol) was dissolved in acetonitrile (10 mL), and then NBS (1.0 g, 0.006 mmol) was slowly added in batches, and then heated to 80°C and stirred for 48 h. The reaction was detected to be complete by TLC control, and the mixture was poured into an ice-saturated NH4Cl aqueous solution and extracted with EA. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by reduced pressure distillation. The crude product was purified by flash column chromatography (PE / EA=6 / 1) to obtain a yellow solid, i.e., 1.09 g of the 1-(3-bromo-4-methoxyphenyl)-3-(trifluoromethyl)-1,2,4-triazole, with a yield of 90% and a purity of 95%.
[0036] The NMR spectrum of the product is shown in Figure 2 As shown, 1 H NMR (400MHz, CDCl3): δ8.52 (d, J = 0.9 Hz, 1H), 7.91 (d, J = 2.7 Hz, 1H), 7.61 (dd, J = 8.8, 2.7 Hz, 1H), 7.02 (d, J = 8.9 Hz, 1H), 3.97 (s, 3H).
[0037] Example 2
[0038] A method for preparing 1-(3-bromo-4-methoxyphenyl)-3-(trifluoromethyl)-1,2,4-triazole, the method comprising the following steps:
[0039] Compound 1 4-methoxyphenylhydrazine hydrochloride (1.8 g, 0.01 mol) and triethylamine (6.28 g, 0.06 mol) were dissolved in methanol (10 mL), and compound 2 trifluoroacetamidine (13.0 g, 0.11 mol) was slowly added in batches, and the reaction mixture was stirred at 30° C. for 24 h. The reaction was complete as detected by LCMS control, and the mixture was poured into ice water and extracted with EA. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by vacuum distillation to obtain a brown oil, i.e., compound 3 2,2,2-trifluoro-N'-(4-methoxyphenyl)acetylhydrazone amide 2.9 g, which was directly used in the next step.
[0040] Compound 3 2,2,2-trifluoro-N'-(4-methoxyphenyl)acetylhydrazone (1.8 g, 0.0077 mol) and triethyl orthoformate (19.2 mL, 0.12 mol) were mixed evenly, and the reaction was heated to 105°C and stirred for 24 h. The reaction was complete by TLC control, and the mixture was poured into ice water and extracted with EA. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by vacuum distillation to obtain a crude product, which was purified by flash column chromatography (PE / EA=6 / 1) to obtain a brown oil, i.e., compound 4 1-(4-methoxyphenyl)-3-(trifluoromethyl)-1,2,4-triazole 1.3 g, with a two-step yield of 84% and a purity of 95%.
[0041] Compound 4 1-(4-methoxyphenyl)-3-(trifluoromethyl)-1,2,4-triazole (0.92 g, 0.004 mol) was dissolved in acetonitrile (4 mL), and then NBS (10 g, 0.06 mmol) was slowly added in batches, and then heated to 100°C and stirred for 12 h. The reaction was detected to be complete by TLC control, and the mixture was poured into an ice-saturated NH4Cl aqueous solution and extracted with EA. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by vacuum distillation to obtain a crude product, which was then purified by flash column chromatography (PE / EA=6 / 1) to obtain a yellow solid, i.e., 1.1 g of the 1-(3-bromo-4-methoxyphenyl)-3-(trifluoromethyl)-1,2,4-triazole, with a yield of 91% and a purity of 95%.
[0042] Example 3
[0043] A method for preparing 1-(3-bromo-4-methoxyphenyl)-3-(trifluoromethyl)-1,2,4-triazole, the method comprising the following steps:
[0044] Compound 1 4-methoxyphenylhydrazine hydrochloride (1.8 g, 0.01 mol) and triethylamine (18.84 g, 0.18 mol) were dissolved in methanol (100 mL), and compound 2 trifluoroacetamidine (26.0 g, 0.2 mol) was slowly added in batches, and the reaction mixture was stirred at 20° C. for 48 h. The reaction was complete as detected by LCMS control, and the mixture was poured into ice water and extracted with EA. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by vacuum distillation to obtain a brown oil, i.e., compound 3 2,2,2-trifluoro-N'-(4-methoxyphenyl)acetylhydrazone amide 2.95 g, which was directly used in the next step reaction.
[0045] Compound 3 2,2,2-trifluoro-N'-(4-methoxyphenyl)acetylhydrazone (1.8 g, 0.0077 mol) and triethyl orthoformate (25.6 mL, 0.15 mol) were mixed evenly, and the reaction was heated to 110°C and stirred for 12 h. The reaction was complete by TLC control, and the mixture was poured into ice water and extracted with EA. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by vacuum distillation to obtain a crude product, which was purified by flash column chromatography (PE / EA=6 / 1) to obtain a brown oil, i.e., compound 4 1-(4-methoxyphenyl)-3-(trifluoromethyl)-1,2,4-triazole 1.40 g, with a two-step yield of 90% and a purity of 95%.
[0046] Compound 4 1-(4-methoxyphenyl)-3-(trifluoromethyl)-1,2,4-triazole (0.92 g, 0.004 mol) was dissolved in acetonitrile (200 mL), and then NBS (6.7 g, 0.04 mmol) was slowly added in batches, and then heated to 90°C and stirred for 24 h. The reaction was detected to be complete by TLC control, and the mixture was poured into an ice-saturated NH4Cl aqueous solution and extracted with EA. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by vacuum distillation to obtain a crude product, which was then purified by flash column chromatography (PE / EA=6 / 1) to obtain a yellow solid, i.e., 1.09 g of the 1-(3-bromo-4-methoxyphenyl)-3-(trifluoromethyl)-1,2,4-triazole, with a yield of 90% and a purity of 95%.
[0047] Comparative Example 1
[0048] The preparation method of Comparative Example 1 is basically the same as that of Example 2, except that the reaction conditions in step (3) are adjusted. The specific process of the bromination reaction in step (3) of this comparative example is as follows:
[0049] Compound 4 1-(4-methoxyphenyl)-3-(trifluoromethyl)-1,2,4-triazole (0.46 g, 0.002 mol) was dissolved in tetrahydrofuran (5 mL), and then the temperature was lowered to -70 °C, and n-butyl lithium (2 mL, 0.004 mol, 2.5 M hexane solution) was slowly added dropwise. After stirring for 1 hour, NBS (0.5 g, 0.003 mmol) was added in batches, and the temperature was raised to 25 °C and stirred for 2 hours. The reaction was complete when the TLC control was detected. The mixture was poured into an ice-saturated NH4Cl aqueous solution and extracted with EA. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by vacuum distillation. The crude product was purified by flash column chromatography (PE / EA=6 / 1) to obtain a yellow solid, i.e., 0.5 g of the isomer 5-bromo-1-(4-methoxyphenyl)-3-(trifluoromethyl)-1,2,4-triazole, with a yield of 82% and a purity of 95%.
[0050] The NMR spectrum of the product is shown in Figure 3 As shown, 1 H NMR (400MHz, CDCl3): δ7.52–7.39(m,2H),7.08–6.98(m,2H),3.89(s,3H).
[0051] The above is only a preferred embodiment of the present invention, and the present invention is not limited to the above embodiments. It is understood that other improvements and changes directly derived or associated by those skilled in the art without departing from the spirit and concept of the present invention should be considered to be included in the protection scope of the present invention.
Claims
1. A method for preparing 1-(3-bromo-4-methoxyphenyl)-3-(trifluoromethyl)-1,2,4-triazole, characterized in that: The preparation method is carried out according to the following process: The specific steps are: (1) Using compound 1 as the starting material, compound 1 and a base are dissolved in solvent 1, and then compound 2 is added to carry out a nucleophilic substitution reaction to obtain compound 3; (2) Compound 3 is mixed with triethyl orthoformate, and the mixture is heated to reflux to undergo a ring-closing reaction to obtain compound 4; (3) Compound 4 is dissolved in solvent II, NBS is added, and the mixture is heated to cause a bromination reaction to obtain 1-(3-bromo-4-methoxyphenyl)-3-(trifluoromethyl)-1,2,4-triazole.
2. The preparation method according to claim 1, characterized in that: In step (1), the molar ratio of compound 1 to compound 2 is 1:1 to 20.
0.
3. The preparation method according to claim 1, characterized in that: In step (1), the molar ratio of compound 1 to triethylamine is 1:1.5-20.
0.
4. The preparation method according to claim 1, characterized in that: In step (1), the base is selected from any one of trimethylamine, triethylamine, tripropylamine, triisopropylamine, and diisopropylethylamine; the solvent I is selected from any one of methanol, ethanol, isopropanol, propanol, and n-butanol; and the concentration of the compound 1 in the solvent I is 0.1 to 2 mol / L.
5. The preparation method according to claim 1, characterized in that: In step (1), the temperature of the nucleophilic substitution reaction is 20 to 40° C. and the time is 12 to 48 hours.
6. The preparation method according to claim 1, characterized in that: In step (2), the molar ratio of compound 3 to triethyl orthoformate is 1:10 to 20.
0.
7. The preparation method according to claim 1, characterized in that: In step (2), the temperature of the ring-closure reaction is 100 to 110° C., and the time is 12 to 48 hours.
8. The preparation method according to claim 1, characterized in that: In step (3), the molar ratio of compound 4 to NBS is 1:1 to 20.
0.
9. The preparation method according to claim 1, characterized in that: In step (3), the solvent II is selected from any one of acetonitrile, dichloromethane, methanol, N,N-dimethylformamide, N,N-dimethylacetamide, and tetrahydrofuran; and the concentration of the compound 4 in the solvent II is 0.01 to 1 mol / L.
10. The preparation method according to claim 1, characterized in that: In step (3), the temperature of the bromination reaction is 80 to 100° C. and the time is 12 to 48 hours.