阅读说明：本技术 一种3-甲基-4-溴-7-（三氟甲基）-1h-吲唑的合成方法 (Synthetic method of 3-methyl-4-bromo-7- (trifluoromethyl) -1H-indazole ) 是由 史建云 刘超 戴红升 顾云龙 周超 江云青 于 2019-12-27 设计创作，主要内容包括：本发明公开了一种3-甲基-4-溴-7-(三氟甲基)-1H-吲唑的合成方法,属于有机化学合成领域。该方法以6-溴-2-氟-3-(三氟甲基)苯甲醛为原料,在氮气保护下,与甲基格氏试剂加成,再用二氧化锰氧化,最后和水合肼关环,得到目标产物3-甲基-4-溴-7-(三氟甲基)-1H-吲唑。本发明所述的合成方法选择性高,实验操作简单,易于实现,得到的产物收率较高。(The invention discloses a synthesis method of 3-methyl-4-bromo-7- (trifluoromethyl) -1H-indazole, belonging to the field of organic chemical synthesis. The method comprises the steps of taking 6-bromo-2-fluoro-3- (trifluoromethyl) benzaldehyde as a raw material, adding the raw material with a methyl Grignard reagent under the protection of nitrogen, oxidizing the obtained product with manganese dioxide, and finally closing a ring with hydrazine hydrate to obtain the target product 3-methyl-4-bromo-7- (trifluoromethyl) -1H-indazole. The synthesis method provided by the invention has the advantages of high selectivity, simple experimental operation, easiness in realization and higher yield of the obtained product.)

1. A synthetic method of 3-methyl-4-bromo-7- (trifluoromethyl) -1H-indazole is characterized by comprising the following steps:

the method comprises the following steps:

(1) dissolving the compound A in an organic solvent, and reacting with a methyl Grignard reagent under the protection of nitrogen to obtain a compound B;

(2) dissolving the compound B in an organic solvent, and oxidizing with manganese dioxide to obtain a compound C;

(3) and reacting the compound C with hydrazine hydrate to obtain a compound D.

2. The method for synthesizing 3-methyl-4-bromo-7- (trifluoromethyl) -1H-indazole according to claim 1, wherein the organic solvent in step (1) is anhydrous tetrahydrofuran, the reaction temperature is-78-0 ℃, and the reaction time is 0.5 hour.

3. The method of synthesizing 3-methyl-4-bromo-7- (trifluoromethyl) -1H-indazole of claim 1, wherein the molar ratio of compound a to methyl grignard reagent in step (1) is 1: 1.2.

4. the method for synthesizing 3-methyl-4-bromo-7- (trifluoromethyl) -1H-indazole according to any one of claims 1 to 3, wherein the methyl Grignard reagent in step (1) is methyl magnesium bromide or methyl magnesium chloride.

5. The method for synthesizing 3-methyl-4-bromo-7- (trifluoromethyl) -1H-indazole according to claim 4, wherein the concentration of methyl magnesium bromide or methyl magnesium chloride in step (1) is 1 mol/L.

6. The method for synthesizing 3-methyl-4-bromo-7- (trifluoromethyl) -1H-indazole according to claim 1, wherein the organic solvent in step (2) is dichloromethane, the reaction temperature is 15-40 ℃, and the reaction time is 6-24 hours.

7. The method of synthesizing 3-methyl-4-bromo-7- (trifluoromethyl) -1H-indazole of claim 1, wherein the molar ratio of compound B to manganese dioxide in step (2) is 1: 10.

8. the method for synthesizing 3-methyl-4-bromo-7- (trifluoromethyl) -1H-indazole according to claim 1, wherein the reaction temperature in step (3) is 50-100 ℃, and the reaction time is 3-12 hours.

9. The method for synthesizing 3-methyl-4-bromo-7- (trifluoromethyl) -1H-indazole according to claim 1, wherein hydrazine hydrate in step (3) is an aqueous solution with a mass fraction of 80%.

Technical Field

The invention relates to the field of organic chemical synthesis, in particular to a synthetic method of 3-methyl-4-bromo-7- (trifluoromethyl) -1H-indazole.

Background

In recent years, more and more fluorine-containing organic compounds have attracted attention with the development of biology and medicinal chemistry. Trifluoromethyl has the general commonality of fluoride, i.e., biological activity, and has wide applications in medicine, pesticides, life sciences, and the like. Trifluoromethyl is one of the hot spots of new drug research and development in the research aspect of fluorine-containing drugs as a novel fluorine-containing group.

The indazole compound with the pharmaceutical activities of resisting tumor, easing pain, diminishing inflammation and the like is generated by taking a simple trifluoromethyl benzene compound as a raw material and introducing a heterocyclic ring through ring closure with hydrazine hydrate. The introduction of heterocyclic ring with high cost by ring closure is an important means for designing new medicine and an important research direction in the future.

Disclosure of Invention

The invention aims to provide a synthesis method of 3-methyl-4-bromo-7- (trifluoromethyl) -1H-indazole. Mainly solves the technical problem that no literature reports the synthesis method of the compound.

In order to realize the purpose of the invention, the invention adopts the following technical scheme:

a synthetic method of 3-methyl-4-bromo-7- (trifluoromethyl) -1H-indazole comprises the following steps:

the synthesis method is realized by the following steps:

(1) dissolving the compound A in an organic solvent, and reacting with a methyl Grignard reagent under the protection of nitrogen to obtain a compound B;

(2) dissolving the compound B in an organic solvent, and oxidizing with manganese dioxide to obtain a compound C;

(3) and reacting the compound C with hydrazine hydrate to obtain a compound D.

Preferably, the organic solvent in the step (1) is anhydrous tetrahydrofuran, the reaction temperature is-78-0 ℃, and the reaction time is 0.5 hour.

Preferably, the molar ratio of compound a to methyl grignard reagent in step (1) is 1: 1.2.

preferably, the methyl grignard reagent in step (1) is methyl magnesium bromide or methyl magnesium chloride.

Preferably, the concentration of methyl magnesium bromide or methyl magnesium chloride in step (1) is 1 mol/L.

Preferably, the organic solvent in the step (2) is dichloromethane, the reaction temperature is 15-40 ℃, and the reaction time is 6-24 hours.

Preferably, the molar ratio of the compound B to the manganese dioxide in the step (2) is 1: 10.

preferably, the reaction temperature in the step (3) is 50-100 ℃, and the reaction time is 3-12 hours.

Preferably, the hydrazine hydrate in the step (3) is an aqueous solution with the mass fraction of 80%.

The invention has the beneficial effects that:

the invention provides a synthetic method of 3-methyl-4-bromo-7- (trifluoromethyl) -1H-indazole for the first time, and provides theoretical basis and experimental data for preparing the 3-methyl-4-bromo-7- (trifluoromethyl) -1H-indazole; the synthesis method provided by the invention has the advantages of high selectivity, simple experimental operation, easiness in realization and higher yield of the obtained product.

Detailed Description

The invention is further illustrated by the following examples, without restricting its scope to these examples. Numerous other changes and modifications can be made by those skilled in the art without departing from the spirit and scope of the invention. In particular, certain agents which are both chemically and structurally related may be substituted for the agents described herein to achieve the same or similar results, and reactions may be carried out under conditions outside the preferred ranges, albeit less than optimally. Accordingly, such obvious substitutions and modifications are intended to be included within the scope of the appended claims.