Synthesis method of compound 4-bromo-5-methoxy-1-methyl-1H-pyrazole

Abstract

The invention discloses a synthetic method of a compound 4-bromo-5-methoxy-1-methyl-1H-pyrazole, and belongs to the technical field of organic synthesis. The synthetic method provided by the invention comprises the following steps: under the action of a condensing agent and triphenylphosphine, 1-methyl-5-hydroxypyrazole reacts with methanol to obtain a compound 5-methoxyl-1-methyl-1H-pyrazole, and the compound 5-methoxyl-1-methyl-1H-pyrazole is further converted into a compound 4-bromo-5-methoxyl-1-methyl-1H-pyrazole. By optimizing the raw materials, the synthesis method of the compound 4-bromo-5-methoxy-1-methyl-1H-pyrazole provided by the invention has the advantages of low cost, high yield, short steps, easiness in operation, relatively mild reaction conditions, low potential safety hazard and ideal yield.

Description

Technical Field

[0001] The invention relates to the technical field of organic synthesis, and in particular to a method for synthesizing a compound 4-bromo-5-methoxy-1-methyl-1H-pyrazole. Background Art

[0002] Pyrazole compounds have a wide range of biological activities in the fields of medicine and pesticides, including antibacterial, antiviral, antitumor, anti-inflammatory, antidepressant, insecticidal, and weed control. In the field of medicine, pyrazole compounds can be used to treat diseases such as hypertension, diabetes, depression, pain, and inflammation. In the field of pesticides, pyrazole compounds are used as insecticides, fungicides, and herbicides. For example, pyrazole sulfonate is a highly active herbicide based on the pyrazole structure, which is used to control dicotyledonous weeds in cereal crops.

[0003] The compound 4-bromo-5-methoxy-1-methyl-1H-pyrazole is an important pyrazole compound and an important molecular building block. As a key intermediate and building block of drug molecules, it is used in the synthesis of EGFR inhibitors in patent WO2022 / 187363, which can be used to treat or prevent kinase-mediated diseases, including cancer and other proliferative diseases; and in patent US2011 / 281888, it is used in the synthesis of fusion bicyclic kinase inhibitors.

[0004] Therefore, it is of great significance to continuously explore new synthetic methods for the compound 4-bromo-5-methoxy-1-methyl-1H-pyrazole. Summary of the invention

[0005] In view of the deficiencies of the prior art, the present invention provides a method for synthesizing a compound 4-bromo-5-methoxy-1-methyl-1H-pyrazole. The present invention optimizes the raw materials to provide a method for synthesizing a compound 4-bromo-5-methoxy-1-methyl-1H-pyrazole, which has the advantages of low cost, short steps, easy operation, relatively mild reaction conditions, low safety risks and ideal yield.

[0006] The technical solution of the present invention is as follows:

[0007] The invention provides a method for synthesizing a compound 4-bromo-5-methoxy-1-methyl-1H-pyrazole. The method comprises the following steps: under the action of a condensing agent and a phosphine ligand, 1-methyl-5-hydroxypyrazole reacts with methanol to obtain a compound 5-methoxy-1-methyl-1H-pyrazole, which is then further converted into the compound 4-bromo-5-methoxy-1-methyl-1H-pyrazole.

[0008] Preferably, the condensing agent includes one or more of diisopropyl azodicarboxylate, dimethyl azodicarboxylate, and diethyl azodicarboxylate.

[0009] Preferably, the phosphine ligand includes at least one of triphenylphosphine and tributylphosphine.

[0010] Preferably, the compound 5-methoxy-1-methyl-1H-pyrazole is synthesized by the following method:

[0011] 1-Methyl-5-hydroxypyrazole, phosphine ligand and methanol are added to organic solvent I. Under the protection of inert gas, after cooling, a condensing agent solution is added, the mixture is stirred at a constant temperature, the temperature is naturally raised to room temperature, and the reaction is continued for 10 h to 20 h to obtain a reaction solution. The reaction solution is post-treated to obtain 5-methoxy-1-methyl-1H-pyrazole.

[0012] Preferably, the molar ratio of the 1-methyl-5-hydroxypyrazole to the phosphine ligand is 1:1.0-1.5; the phosphine ligand includes at least one of triphenylphosphine and tributylphosphine; the molar ratio of the 1-methyl-5-hydroxypyrazole to the methanol is 1:1.0-1.5.

[0013] Preferably, the organic solvent I comprises one or more of tetrahydrofuran, ether, dichloromethane, toluene, and ethyl acetate; and the mass volume ratio of the 1-methyl-5-hydroxypyrazole to the organic solvent I is 1:5-40 g / mL.

[0014] Preferably, the inert gas is selected from one or more of nitrogen or argon; and the cooling refers to cooling to -80°C to -50°C.

[0015] Preferably, the condensing agent solution is obtained by adding an organic solvent II to a condensing agent; the condensing agent includes one or more of diisopropyl azodicarboxylate, dimethyl azodicarboxylate, and diethyl azodicarboxylate; the organic solvent II includes one or more of tetrahydrofuran, ether, dichloromethane, toluene, and ethyl acetate; the molar ratio of the 1-methyl-5-hydroxypyrazole to the condensing agent is 1:1.0-2.0; the mass volume ratio of the 1-methyl-5-hydroxypyrazole to the organic solvent II is g / mL 1:1-5; and the constant temperature stirring reaction time is 3h-5h.

[0016] Preferably, the further transformation comprises: adding an organic solvent III to the compound 5-methoxy-1-methyl-1H-pyrazole, cooling, adding pyridinium tribromide, reacting at a constant temperature, naturally heating to room temperature, continuing the reaction for 10 h to 30 h, and post-treating the obtained reaction solution to obtain the compound 4-bromo-5-methoxy-1-methyl-1H-pyrazole.

[0017] Preferably, the organic solvent III includes at least one of methanol, ethanol, n-propanol, isopropanol, n-butanol and sec-butanol; and / or the cooling refers to cooling to -5°C to 5°C; and / or the mass volume ratio of the 5-methoxy-1-methyl-1H-pyrazole to the organic solvent III is 1:5 to 40 g / mL; the molar ratio of the 5-methoxy-1-methyl-1H-pyrazole to the pyridinium tribromide is 1:1 to 1.5; and / or the isothermal reaction time is 1h to 2h.

[0018] The beneficial technical effects of the present invention are:

[0019] The present invention provides a method for synthesizing a compound 4-bromo-5-methoxy-1-methyl-1H-pyrazole. Under the action of triphenylphosphine and a condensing agent, a raw material 1-methyl-5-hydroxypyrazole reacts with methanol to obtain 5-methoxy-1-methyl-1H-pyrazole, and compound 2 is further converted into a target compound 4-bromo-5-methoxy-1-methyl-1H-pyrazole. The synthetic route of the present invention is a breakthrough in converting the raw material 1-methyl-5-hydroxypyrazole into an intermediate compound 5-methoxy-1-methyl-1H-pyrazole in a simple method and with an ideal yield; ultimately, a synthetic route for the compound 4-bromo-5-methoxy-1-methyl-1H-pyrazole is obtained, which has the advantages of high yield, low cost, relatively mild reaction conditions, and suitability for process amplification. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1 This is the H NMR spectrum of compound 2 (5-methoxy-1-methyl-1H-pyrazole) in Example 1 of the present invention.

[0021] Figure 2 This is the H NMR spectrum of compound 3 (4-bromo-5-methoxy-1-methyl-1H-pyrazole) in Example 1 of the present invention. DETAILED DESCRIPTION

[0022] The present invention is described in detail below in conjunction with the accompanying drawings and embodiments.

[0023] The invention provides a method for synthesizing 4-bromo-5-methoxy-1-methyl-1H-pyrazole, comprising: reacting 1-methyl-5-hydroxypyrazole with methanol under the action of a condensing agent and a phosphine ligand to obtain a compound 5-methoxy-1-methyl-1H-pyrazole, and further converting the compound into a compound 4-bromo-5-methoxy-1-methyl-1H-pyrazole.

[0024] In some embodiments of the present invention, the synthesis route of the compound 4-bromo-5-methoxy-1-methyl-1H-pyrazole is as follows:

[0025]

[0026] In some embodiments, the condensing agent includes one or more of diisopropyl azodicarboxylate (DIAD), dimethyl azodicarboxylate, or diethyl azodicarboxylate (DEAD).

[0027] In some embodiments, the phosphine ligand includes at least one of triphenylphosphine (PPh3), or tributylphosphine (P(n-Bu)3).

[0028] In some embodiments, the compound 5-methoxy-1-methyl-1H-pyrazole is specifically synthesized by the following method:

[0029] 1-Methyl-5-hydroxypyrazole, phosphine ligand and methanol are added to organic solvent I. Under the protection of inert gas, after cooling, a condensing agent solution is added, the mixture is stirred at a constant temperature, the temperature is naturally raised to room temperature, and the reaction is continued for 10 h to 20 h to obtain a reaction solution. The reaction solution is post-treated to obtain 5-methoxy-1-methyl-1H-pyrazole.

[0030] In some embodiments, the molar ratio of the 1-methyl-5-hydroxypyrazole to the phosphine ligand is 1:1.0-1.5; and the phosphine ligand includes at least one of triphenylphosphine and tributylphosphine.

[0031] In some embodiments, the molar ratio of the 1-methyl-5-hydroxypyrazole to the methanol is 1:1.0-1.5.

[0032] It is understandable that, in the present invention, methanol can condense with the hydroxyl group of 1-methyl-5-hydroxypyrazole to remove a molecule of water and generate a methoxy group.

[0033] In some embodiments, the organic solvent I includes one or more of tetrahydrofuran, diethyl ether, dichloromethane, toluene, and ethyl acetate.

[0034] In some embodiments, the mass volume ratio of the 1-methyl-5-hydroxypyrazole to the organic solvent I is 1:5-40 g / mL.

[0035] In some embodiments, the inert gas is selected from one or more of nitrogen or argon; and the cooling refers to cooling to -80°C to -50°C.

[0036] In some embodiments, the condensing agent solution is obtained by adding an organic solvent II to a condensing agent.

[0037] In some embodiments, the condensing agent includes one or more of diisopropyl azodicarboxylate, dimethyl azodicarboxylate, and diethyl azodicarboxylate.

[0038] In some embodiments, the organic solvent II includes one or more of tetrahydrofuran, diethyl ether, dichloromethane, toluene, and ethyl acetate.

[0039] In some embodiments, the molar ratio of the 1-methyl-5-hydroxypyrazole to the condensing agent is 1:1.0-2.0.

[0040] In some embodiments, the mass volume ratio of the 1-methyl-5-hydroxypyrazole to the organic solvent II is 1:1-5 g / mL.

[0041] In some embodiments, the constant temperature stirring reaction time is 3h to 5h.

[0042] In some embodiments, the further transformation includes: adding organic solvent III to the compound 5-methoxy-1-methyl-1H-pyrazole, cooling, adding pyridinium tribromide, reacting at a constant temperature, naturally heating to room temperature, continuing the reaction for 10 hours to 30 hours, and post-treating the obtained reaction solution to obtain the compound 4-bromo-5-methoxy-1-methyl-1H-pyrazole.

[0043] In some embodiments, the organic solvent III includes at least one of methanol, ethanol, n-propanol, isopropanol, n-butanol, and sec-butanol;

[0044] In some embodiments, the cooling refers to cooling to -5°C to 5°C;

[0045] In some embodiments, the mass volume ratio of the 5-methoxy-1-methyl-1H-pyrazole to the organic solvent III is 1:5-40 g / mL.

[0046] In some embodiments, the molar ratio of the 5-methoxy-1-methyl-1H-pyrazole to the pyridinium tribromide is 1:1 to 1.5.

[0047] In some embodiments, the isothermal reaction time is 1 h to 2 h.

[0048] Unless otherwise specified in the following examples, all reagents and materials used were commercially available.

[0049] The technical solution of the present invention is further explained below by way of embodiments.

[0050] Example 1

[0051] The synthesis steps of the compound 4-bromo-5-methoxy-1-methyl-1H-pyrazole are as follows:

[0052] (1) Compound 1, i.e., 1-methyl-5-hydroxypyrazole (100.00 g, 1.02 mol, 1.00 eq), triphenylphosphine (320.83 g, 1.22 mol, 1.20 eq) and methanol (35.93 g, 1.12 mol, 1.10 eq) were sequentially added to anhydrous tetrahydrofuran (2.0 L) as a solvent. Under the protection of inert gas nitrogen, the temperature was lowered to -60°C, and a solution of diisopropyl azodicarboxylate (267.95 g, 1.33 mol, 1.30 eq) in anhydrous tetrahydrofuran (200 mL) was slowly added dropwise. After the addition was completed, the mixture was stirred at -60°C for 4 hours, and then naturally heated to room temperature for 12 hours. After the reaction is complete, tetrahydrofuran is removed by concentration under reduced pressure, and then water (1.0 L) is added and extracted with ethyl acetate (1.0 L). The organic phase is washed with saturated brine (400 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product is purified by distillation to obtain compound 2, i.e., 5-methoxy-1-methyl-1H-pyrazole (light yellow liquid, weight 112.00 g, purity 98%, yield 96%).

[0053] The H NMR spectrum of the obtained compound 2 (5-methoxy-1-methyl-1H-pyrazole) is as follows Figure 1 The characterization data are as follows:

[0054] 1 H NMR (600MHz, MeOD) δ7.26 (d, J = 2.1 Hz, 1H), 5.63 (d, J = 2.1 Hz, 1H), 3.91 (s, 3H), 3.58 (s, 3H).

[0055] (2) Compound 2 (100.00 g, 891.81 mmol, 1.00 eq) was added to methanol (1.0 L), cooled to 0°C, and pyridinium tribromide (285.22 g, 891.81 mmol, 1.00 eq) was slowly added in batches. After the addition was complete, the mixture was kept at 0°C for 1 hour, and then naturally warmed to room temperature for 12 hours. After the reaction was completed, a saturated sodium thiosulfate aqueous solution (750 mL) was added, followed by water (1.0 L), and stirred for 30 minutes. Ethyl acetate (2.5 L) was then added, and the organic phase was separated. The organic phase was washed with saturated brine (400 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 3, i.e., 4-bromo-5-methoxy-1-methyl-1H-pyrazole (weight 159.80 g, purity 98%, yield 92%).

[0056] The H NMR spectrum of the obtained compound 3 (4-bromo-5-methoxy-1-methyl-1H-pyrazole) is as follows: Figure 2 The characterization data are as follows:

[0057] 1H NMR (400MHz, CDCl3) δ7.29(s,1H),4.08(s,3H),3.68(s,3H).

[0058] Example 2-13

[0059] Example 2-13 is basically the same as Example 1, except that the condensing agent, methanol, triphenylphosphine and organic solvent I used in step (1) are adjusted, as shown in Table 1.

[0060] Through Examples 1-13, the effects of various reaction conditions on the reaction yield in the synthesis of intermediate compound 2 (5-methoxy-1-methyl-1H-pyrazole) were verified. The results are shown in Table 1.

[0061] Embodiment 14

[0062] The method is basically the same as Example 1, except that in step (1), after the diisopropyl azodicarboxylate solution is added dropwise, the stirring reaction temperature of the mixed solution is adjusted from -60°C to -20°C.

[0063] Embodiment 15

[0064] The method is basically the same as Example 1, except that in step (1), after the diisopropyl azodicarboxylate solution is added dropwise, the stirring reaction temperature of the mixed solution is adjusted from -60°C to -78°C.

[0065] Table 1: Synthesis conditions and results of the examples

[0066]

[0067] The experiment found that the purity of compound 2 obtained in Examples 1-15 was around 98%. At the same time, combined with Table 1, it can be seen that: compared with Examples 1-3, diisopropyl azodicarboxylate, dimethyl azodicarboxylate and diethyl azodicarboxylate were used as condensing agents, and the reaction could be carried out, among which diisopropyl azodicarboxylate was more effective as a condensing agent. Comparing Examples 1, 4-5, when the molar ratio of raw material 1 to methanol was 1.0:1.1, the reaction effect was already better. Comparing Examples 1, 6-7, when the molar ratio of raw material 1: condensing agent was 1.0:1.3, the reaction effect was already better. Comparing Examples 1, 8-9, when the molar ratio of raw material 1: triphenylphosphine was 1.0:1.2, the reaction effect was already better. Comparing Examples 1, 10-13, tetrahydrofuran, ether, dichloromethane, toluene and ethyl acetate were used as reaction solvents, and the reaction could be carried out, among which tetrahydrofuran was more effective as a solvent. Comparing Example 1 with Examples 14-15, it can be seen that when the cooling temperature is -20°C, the yield is lower.

[0068] 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 synthesizing the compound 4-bromo-5-methoxy-1-methyl-1H-pyrazole, characterized in that: The synthesis method comprises the following steps: under the action of a condensing agent and a phosphine ligand, 1-methyl-5-hydroxypyrazole reacts with methanol to obtain a compound 5-methoxy-1-methyl-1H-pyrazole, which is then further converted into a compound 4-bromo-5-methoxy-1-methyl-1H-pyrazole.

2. The synthesis method according to claim 1, characterized in that The condensing agent includes one or more of diisopropyl azodicarboxylate, dimethyl azodicarboxylate, and diethyl azodicarboxylate.

3. The synthesis method according to claim 1, characterized in that The phosphine ligand includes at least one of triphenylphosphine and tributylphosphine.

4. The synthesis method according to claim 1, characterized in that The compound 5-methoxy-1-methyl-1H-pyrazole is specifically synthesized by the following method: 1-Methyl-5-hydroxypyrazole, phosphine ligand and methanol are added to organic solvent I. Under the protection of inert gas, after cooling, a condensing agent solution is added, the mixture is stirred at a constant temperature, the temperature is naturally raised to room temperature, and the reaction is continued for 10 h to 20 h to obtain a reaction solution. The reaction solution is post-treated to obtain 5-methoxy-1-methyl-1H-pyrazole.

5. The synthesis method according to claim 4, characterized in that The molar ratio of the 1-methyl-5-hydroxypyrazole to the phosphine ligand is 1:1.0-1.5; the phosphine ligand includes at least one of triphenylphosphine and tributylphosphine; The molar ratio of the 1-methyl-5-hydroxypyrazole to the methanol is 1:1.0-1.

5.

6. The synthesis method according to claim 4, characterized in that The organic solvent I includes one or more of tetrahydrofuran, ether, dichloromethane, toluene, and ethyl acetate; The mass volume ratio of the 1-methyl-5-hydroxypyrazole to the organic solvent I is 1:5-40 g / mL.

7. The synthesis method according to claim 4, characterized in that The inert gas is selected from one or more of nitrogen and argon; the cooling refers to cooling to -80°C to -50°C.

8. The synthesis method according to claim 4, characterized in that The condensing agent solution is obtained by adding an organic solvent II to the condensing agent; The condensing agent includes one or more of diisopropyl azodicarboxylate, dimethyl azodicarboxylate, and diethyl azodicarboxylate; The organic solvent II includes one or more of tetrahydrofuran, ether, dichloromethane, toluene, and ethyl acetate; The molar ratio of the 1-methyl-5-hydroxypyrazole to the condensing agent is 1:1.0-2.0; The mass volume ratio of the 1-methyl-5-hydroxypyrazole to the organic solvent II is 1:1 to 5 g / mL; The constant temperature stirring reaction time is 3h to 5h.

9. The synthesis method according to claim 1, characterized in that The further transformation includes: adding organic solvent III to the compound 5-methoxy-1-methyl-1H-pyrazole, cooling down, adding pyridinium tribromide, reacting at a constant temperature, naturally heating up to room temperature, continuing the reaction for 10 hours to 30 hours, and post-treating the obtained reaction solution to obtain the compound 4-bromo-5-methoxy-1-methyl-1H-pyrazole.

10. The synthesis method according to claim 1, characterized in that The organic solvent III includes at least one of methanol, ethanol, n-propanol, isopropanol, n-butanol, and sec-butanol; And / or, the cooling refers to cooling to -5°C to 5°C; and / or, the mass volume ratio g / mL of the 5-methoxy-1-methyl-1H-pyrazole to the organic solvent III is 1:5 to 40; The molar ratio of the 5-methoxy-1-methyl-1H-pyrazole to the pyridinium tribromide is 1:1 to 1.5; And / or, the isothermal reaction time is 1 h to 2 h.

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