Method for selective N-2 methylation of 2H-indazole compound
By adding methylation reagents and acidic reagents to the solvent, the temperature control reaction is solved, and the reaction conditions of selective N-2 methylation of 2H-indazole compounds in the prior art are harsh and difficult to control the selectivity of selectivity, so as to achieve Highly efficient and low-cost N-2 selective methylation, high product yield and simple operation.
Patent Information
- Application Number
- CN202411498132.1
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-10-25
- Publication Date
- 2024-12-27
AI Technical Summary
The prior art has problems such as harsh reaction conditions, small substrate range, cumbersome synthesis steps, many side reactions and difficulty in controlling selectivity in the selectivity of 2H-indazole compounds, and it is often expensive to use. Transition metal catalysts and hazardous reagents.
A green and efficient method is adopted to achieve selective N-2 methylation by adding methylation reagents and acidic reagents to the solvent, controlling the temperature reaction, and avoiding the use of transition metal catalysts and photocatalysts. The reaction conditions are safe, and the reagents used are used. and solvents are relatively inexpensive.
It realizes efficient N-2 selective methylation, easy to separate the product, good yield, low material cost, simple process operation, N-2:N-1 methylation selection ratio can reach 40:1~100: 1.
Smart Images
Figure CN119192084A_ABST
Abstract
Description
Technical Field
[0001] The invention belongs to the technical field of compound synthesis, and in particular relates to a method for selective N-2 methylation of 2H-indazole compounds. Background Art
[0002] Indazole is a class of heterocyclic compounds containing adjacent nitrogen atoms. It is an important structural unit of many complex natural products and artificial synthetic molecules, and an important intermediate in organic synthesis. In addition, many indazole derivatives have excellent biological and pharmacological activities, such as anti-cancer, anti-inflammatory, antibacterial, and anti-AIDS. They can also be used as enzyme inhibitors.
[0003] According to the substitution mode of heterocyclic ring, indazole has three isomeric forms such as 1H-indazole, 2H-indazole and 3H-indazole. For many years, researchers have been committed to developing the synthesis technology of indazole derivatives. Because of the important applications of indazole and its derivatives in biology and chemistry, this field remains a research hotspot that chemists continue to pay attention to. Particularly noteworthy is the synthesis of 2H-indazole. As an organic compound, 2H-indazole has a wide range of potential applications and has significant value in synthetic chemistry, drug research and chemical biology. 2H-indazole compounds and their derivatives are widely distributed in various natural active molecules, drug molecules, fluorescent functional materials and anti-tumor active molecules, and are a very important class of molecular skeleton structures. Continuing to explore new technologies and methods to achieve the selective synthesis of 2H-indazole small molecule compounds remains a challenging research task. For example, 6-bromo-2-methyl-2H-indazole plays an indispensable role in inhibitors of prostaglandins and leukocyte production.
[0004] Common synthetic methods for synthesizing 2H-indazole compounds and their derivatives, such as transition metal catalysis and Lewis acid catalysis, have great limitations. Most of these methods use hazardous reagents such as azide compounds to synthesize 2H-indazole (such as CN114920698 A, CN 116120236 A, CN 116589410A), so there are problems such as harsh reaction conditions, small substrate range, cumbersome synthesis steps, and many side reactions. There are few literature reports on the method of selective methylation, which is usually carried out by using sodium hydride and iodomethane or sodium methoxide and iodomethane (such as CN109369506A) for selective methylation. The preparation of N-2 substituted 2H-indazole by conventional N-alkylation methods will inevitably obtain a mixture of N1 and N-2 substituted regional isomers, and the selectivity is difficult to control. To achieve selective alkylation, the existing technology relies on expensive transition metals and other catalysts or hazardous reagents, and the reaction conditions are relatively harsh. Summary of the invention
[0005] In view of this, the present invention aims to overcome the defects in the prior art and proposes a method for selective N-2 methylation of 2H-indazole compounds. The method is green and efficient, does not require the use of photocatalysts and transition metal catalysts, and has good reaction safety.
[0006] To achieve the above object, the technical solution of the present invention is achieved as follows:
[0007] A method for selective N-2 methylation of 2H-indazole compounds comprises the following steps:
[0008] Compound A is used as a raw material, a methylating agent is added to a solvent, an acidic agent is used as an auxiliary agent, and the temperature is controlled to react until the reaction is completed to obtain a selective N-2 methylated product; the compound A is
[0009] Wherein R is selected from any one of H, alkyl, alkoxy, halogen, nitro, and fluorine substituents.
[0010] Preferably, the acidic reagent is any one of p-toluenesulfonic acid, benzenesulfonic acid and trifluoromethanesulfonic acid.
[0011] Preferably, the methylating agent is any one of dimethyl sulfate, methyl iodide, methyl p-toluenesulfonate, and tetrabutylammonium fluoride.
[0012] Preferably, the solvent is any one of acetonitrile, 1,4-dioxane, ethyl acetate, acetone, DMF, and MeCN.
[0013] The molar ratio of the compound A, the methylating agent and the auxiliary agent is 1:(1.2-3.0):(2.0-3.0); preferably 1:2:3.
[0014] Preferably, the reaction temperature is 60-100°C.
[0015] Preferably, the reaction time is 3-24 hours.
[0016] Preferably, the preparation method comprises the following steps:
[0017] 1) dissolving compound A and an auxiliary agent in an organic solvent and mixing them uniformly to obtain a mixed solution I;
[0018] 2) dissolving the methylation reagent in an organic solvent and mixing uniformly to obtain a mixed solution II;
[0019] 3) Add the mixed solution II dropwise to the mixed solution I, keep stirring at 60-100° C. for 3-24 hours, then quench the reaction, perform extraction, separation, organic phase concentration, and purification in sequence to obtain a selective N-2 methylation product.
[0020] Compared with the prior art, the present invention has the following advantages:
[0021] The preparation method of the present invention can obtain a methylated product with high N-2 selectivity for 2H-indazole compounds, and the N-2:N-1 methylation selection ratio can reach 40:1 to 100:1, and N-2 selective methylation can be efficiently achieved. The product is easier to separate and has a better yield. The material cost is relatively low and the process operation is relatively simple. BRIEF DESCRIPTION OF THE DRAWINGS
[0022] Figure 1 This is the IPC spectrum of the methylated product described in Example 1 of the present invention;
[0023] Figure 2 This is the HPLC spectrum of the methylated product described in Example 1 of the present invention;
[0024] Figure 3 This is the HNMR spectrum of the methylated product described in Example 1 of the present invention;
[0025] Figure 4 This is the IPC spectrum of the methylation product described in Example 2 of the present invention.
[0026] Figure 5 This is the IPC spectrum of the methylation product described in Example 3 of the present invention.
[0027] Figure 6 This is the IPC spectrum of the methylation product described in Comparative Example 1 of the present invention. DETAILED DESCRIPTION
[0028] Unless otherwise defined, the technical terms used in the following examples have the same meanings as those generally understood by those skilled in the art to which the present invention belongs. The test reagents used in the following examples, unless otherwise specified, are all conventional biochemical reagents; the experimental methods, unless otherwise specified, are all conventional methods.
[0029] The present invention will be described in detail below with reference to the embodiments.
[0030] Embodiment 1:
[0031]
[0032] Add SM 6-bromo-1H-indazole (2.0 g, 10.2 mmol, 1.0 eq), 1,4-dioxane (20.6 g, 0.23 mol, 10 vol), p-toluenesulfonic acid (3.5 g, 20.3 mmol, 2.0 eq) to a dry and clean 50 mL glass reaction bottle and start stirring. Heat the system to 60-65 °C, dissolve dimethyl sulfate (3.84 g, 30.1 mmol, 3.0 eq) in 1,4-dioxane (10.3 g, 0.12 mol, 5 vol), add dropwise to the system, and stir for 24 hours. Take a sample IPC (see Figure 1 ) showed that the ratio of methylated products N-2:N-1=81.4:0.8 (>100:1). After the reaction was completed, water (30.0 g, 15 vol) was added to quench. The system was extracted with ethyl acetate (15.8 g, 0.18 mol, 10 vol)*4 times. The liquids were separated, the organic phases were combined, and the organic phases were concentrated to dryness under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to obtain 1.58 g of a yellow oily product with a HPLC purity (see Figure 2 ) 98.9%, HNMR structure conforms to (see Figure 3 ), yield 79%.
[0033] Embodiment 2:
[0034]
[0035] Add SM (0.2g, 1.0mmol, 1.0eq), acetonitrile (1.6g, 39.0mol, 10vol), p-toluenesulfonic acid (0.26g, 1.5mmol, 1.5eq) to a dry and clean 25mL glass reaction bottle, and start stirring. Heat the external bath to 95-100℃, dissolve dimethyl sulfate (0.45g, 3.6mmol, 3.5eq) in acetonitrile (0.79g, 19.1mol, 5vol), and add it dropwise to the system. After the addition is complete, keep warm and stir for 3h, and take a sample of IPC (see Figure 4 ) showed that the ratio of methylated products N-2:N-1=79.6:1.3 (>60:1).
[0036] Example 3
[0037]
[0038] SM (0.5 g, 2.3 mmol, 1.0 eq), acetonitrile (3.9 g, 96.0 mmol, 10 vol), p-toluenesulfonic acid (0.26 g, 4.6 mmol, 2.0 eq) were added to a dry and clean 25 mL glass reaction bottle, stirred, and heated to 65-70 ° C in an external bath. Dimethyl sulfate (0.87 g, 6.9 mmol, 3.0 eq) was dissolved in acetonitrile (1.96 g, 48.0 mmol, 5 vol) and added dropwise to the system. After the addition was completed, the mixture was stirred for 3 h at room temperature. Sample IPC (see Figure 5 ) showed that the methylated product N-2:N-1=66.7:1.67 (40:1).
[0039] Comparative Example 1
[0040]
[0041] Add SM (0.5 g, 2.3 mmol, 1.0 eq), acetone (3.9 g, 68.0 mmol, 10 vol), KOH (0.19 g, 3.5 mmol, 1.5 eq) to a 25 ml glass reaction bottle, stir to react, and cool the external bath to 0-5 ° C. Dissolve iodomethane (0.36 g, 2.6 mmol, 1.1 eq) in acetone (1.95 g, 34.0 mmol, 5 vol) and add dropwise to the reaction solution. Stir for 3 hours after the addition is complete. Sample IPC analysis (see Figure 6 ) showed that the ratio of methylated products N-2:N-1 was 32.7:65.5 (1:2).
[0042] In summary, the present invention can realize the N-2 selective methylation reaction of 6-bromo-1H-indazole, and the N-2:N-1 methylation selection ratio can reach 40:1 to 100:1. The process operation is simple, and the N-2 selective methylation can be efficiently realized to obtain the target product 6-bromo-2-methyl-2H-indazole in a high yield. The raw materials and solvents used are relatively cheap, which saves production costs compared with the prior art, and the operation difficulty is relatively low.
[0043] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims
1. A method for selective N-2 methylation of 2H-indazole compounds, characterized in that: The steps include: Compound A is used as a raw material, a methylating agent is added to a solvent, an acidic agent is used as an auxiliary agent, and the temperature is controlled to react until the reaction is completed to obtain a selective N-2 methylated product; the compound A is Wherein R is selected from any one of H, alkyl, alkoxy, halogen, nitro, and fluorine substituents.
2. The method according to claim 1, characterized in that: The acidic reagent is any one of p-toluenesulfonic acid, benzenesulfonic acid and trifluoromethanesulfonic acid.
3. The method according to claim 1, characterized in that: The R is selected from halogen.
4. The method according to claim 1, characterized in that: The R is bromine.
5. The method according to claim 1, characterized in that: The methylating agent is any one of dimethyl sulfate, methyl iodide, methyl p-toluenesulfonate, and tetrabutylammonium fluoride.
6. The method according to claim 1, characterized in that: The solvent is any one of acetonitrile, 1,4-dioxane, ethyl acetate, acetone, DMF, and MeCN.
7. The method according to claim 1, characterized in that: The molar ratio of the compound A, the methylating agent and the auxiliary agent is 1:(1.2-3.0):(2.0-3.0); preferably 1:2:
3.
8. The method according to claim 1, characterized in that: The reaction temperature is 60-100°C.
9. The method according to claim 1, characterized in that: The reaction time is 3-24 hours.
10. The method according to claim 1, characterized in that: The preparation method comprises the following steps: 1) dissolving compound A and an auxiliary agent in an organic solvent and mixing them uniformly to obtain a mixed solution I; 2) dissolving the methylation reagent in an organic solvent and mixing uniformly to obtain a mixed solution II; 3) Add the mixed solution II dropwise to the mixed solution I, stir and react at 60-100° C. for 3-24 hours, then quench the reaction, perform extraction, separation, organic phase concentration and purification in sequence to obtain a selective N-2 methylation product.