Intermediate of N, N-diisobutyl-1H-indazole-4-amine and preparation method

Abstract

The invention relates to the field of organic synthesis, in particular to an intermediate for synthesizing N, N-diisobutyl-1H-indazole-4-amine and a preparation method thereof.4-nitro-1-H-indazole serves as a reaction raw material, benzyl protecting groups are introduced, and then a reduction reaction, continuous substitution and a debenzylation reaction are conducted to obtain the compound N, N-diisobutyl-1H-indazole-4-amine. The invention relates to an intermediate of N, N-diisobutyl-1H-indazole-4-amine and a novel preparation method. According to the method, the total reaction yield is increased to 23%, and the method is simple in technological operation, mild in reaction condition, few in by-products, high in substrate universality and high in economic benefit.

Description

Technical Field

[0001] The present invention relates to the field of organic chemistry, and in particular to an intermediate of N,N-diisobutyl-1H-indazole-4-amine and a preparation method thereof. Background Art

[0002] Functionalization of nitrogen-containing heterocyclic compounds has a wide range of applications in dye preparation, medicinal chemistry, and materials science, and is an important research field in organic chemistry. Among them, indazole is a class of heterocyclic compounds containing adjacent nitrogen atoms, which is widely present in dye molecules and has a unique chemical structure and good dyeing properties. And because it can be used as a precursor of many cutting-edge dyes such as squarylium salts, it has a bright development prospect. Squarylium pigments have excellent blocking properties for near-infrared light and high transmittance for visible light. Therefore, as a cutting-edge dye, they are widely used in dye-sensitized solar cells, optical filters, and camera devices. After years of development, a variety of commercial squarylium salt dyes have been synthesized, and the market still needs to improve newer and better structures to further improve the transmittance of visible light and improve optical performance. For example, A1-10 reported in the patent (CN 108603038 A) is an excellent squarylium pigment, which has good compatibility in transparent resins, and even a thinner absorption layer has good spectral characteristics, thereby further reducing the volume of optical filters. The preparation method includes taking 2,6-difluorobenzaldehyde as a raw material, reacting it with diisobutylamine for nucleophilic substitution, and then cyclizing it with ammonia water. After purification by a chromatographic column, the yield of N,N-diisobutyl-1H-indazole-4-amine is only 13%. Finally, it is condensed with square acid to generate A1-10, and the total yield is 0.94%.

[0003]

[0004] N,N-diisobutyl-1H-indazole-4-amine is the key precursor of A1-10. Although its preparation process has only two steps, the reaction time is too long and many by-products are produced, resulting in a very low single-step yield (13%) and difficulty in product purification. Therefore, it is necessary to develop a new process that is simple to operate, easy to purify the product, and has a higher total yield. Summary of the invention

[0005] In order to solve the above defects in the prior art, the technical solution provided by the present invention is as follows: First, the present invention provides a compound of formula (I), the structural formula of which is: , in: A is a 4-7 membered unsaturated heterocyclic ring containing 1-2 heteroatoms N and O; n is an integer from 1 to 6; R1 is a substituent, including H or alkyl, alkoxy, wherein the alkyl can be methyl, ethyl, propyl, isopropyl; Q is independent of HR 3 or R 2 , R 3 and R 2 Can be one or more -CH 2 -C 1-6 Alkyl, -CH 2 -C 1-6 Alkoxy, halo-CH 2 -C 1-6 alkyl.

[0006] When Q in the above compound of formula (I) is defined as HR 3 , the compound of formula (1) has the structure of the following formula (Ia): , When Q in the above compound of formula (I) is defined as R 2 , and one or more -CH 2 -C 1-6 When the alkyl group is an alkyl group, the compound of formula (1) has the structure of the following formula (Ib): , Wherein, A is a 5-membered unsaturated heterocyclic ring containing 1 to 2 heteroatoms N and O; n, p are integers from 1 to 2; R 1 is H or alkyl.

[0007] In a preferred embodiment of the present invention, A is preferably a 5- to 6-membered unsaturated heterocycle containing 1 to 2 heteroatoms N, O, and further preferably a 5-membered unsaturated heterocycle containing 1 to 2 heteroatoms N, O. Furthermore, A is preferably the following groups: , , , , The two connecting bonds on the left side of the preferred group A connect the benzene rings adjacent to A in the structure of formula (I), and actually form a structure of A and benzo rings. The connecting bonds on the right or bottom side of the group A connect the benzene rings in formula (I). Group.

[0008] n is preferably an integer of 1-3, and more preferably an integer of 1-2.

[0009] R 1 It is preferably H or alkyl, and preferably H.

[0010] Q is preferably HR3 or R 2 , R 3 and R 2 Preferably one or more -CH 2 -C 1-6 Alkyl, -CH 2 -C 1-6 Alkoxy, halo-CH 2 -C 1-6 Alkyl, more preferably 1 to 2 CH 2 -C 1-3 Alkyl, -CH 2 -C 1-3 Alkoxy, more preferably 1 to 2 -CH 2 -C 1-3 Alkyl, more preferably 1 to 2 -CH 2 -C 1-3 alkyl.

[0011] The present invention provides the following preferred compounds of general formula (I), specifically: , , .

[0012] Furthermore, the compound of the general formula (I) provided by the present invention can be prepared by the synthesis method shown below, which comprises subjecting the compound of the formula (III) to a reduction reaction to obtain the compound of the formula (II), and subjecting the compound of the formula (II) to a continuous substitution reaction to obtain the compound of the general formula (I), and the reaction equation is as follows: , where A, n, R 1 , the definition of Q is the same as in the above definition.

[0013] The above preparation method further includes the following reaction equation, , Wherein, A is a 5-membered unsaturated heterocyclic ring containing 2 heteroatoms N; n is 1, R 1 H, R 3 and R 2 One or more -CH 2 -C 1-6 alkyl.

[0014] Or the following reaction equation, , wherein A is a 5-membered unsaturated heterocyclic ring containing 2 heteroatoms N; n, p are 1, R 1 For H.

[0015] A preferred embodiment of the present invention is: , Or as shown below, .

[0016] The present invention provides a preparation method for synthesizing N,N-diisobutyl-1H-indazole-4-amine (a5) and its intermediates. A preferred embodiment has an overall reaction equation as follows: .

[0017] The specific implementation methods are as follows: Method 1, comprising subjecting compound (A3-1) to a continuous substitution reaction in a solvent under alkaline conditions to obtain compound (A5-1); Method 2, comprising step (i) subjecting compound (A2-2) to a reduction reaction in an acidic environment in the presence of a reducing agent to obtain compound (A3-2); step (ii) subjecting compound (A3-2) to a halogenated hydrocarbon substitution to obtain compound (A4-2); step (iii) subjecting compound (A4-2) to a halogenated hydrocarbon substitution to obtain compound (A5-2).

[0018] In some specific embodiments, the compound (A3-1) or compound (A2-2) involved in the above method 1 and method 2 can be prepared from compound A. The compound N,N-diisobutyl-1H-indazole-4-amine can be prepared from the intermediate (A5-1) or intermediate (A5-2).

[0019] In the method of the present invention, the method one is a nucleophilic substitution reaction. The base can be one of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium phosphate (including monobasic potassium phosphate, dibasic potassium phosphate and tribasic potassium phosphate), sodium phosphate (including monobasic sodium phosphate, dibasic sodium phosphate and tribasic sodium phosphate), preferably potassium carbonate. The base can be 1.0~1.3 eq, preferably 1.0~1.1 eq, preferably 1.05 eq. The reaction can be carried out in the presence of one or more solvents, and the one or more solvents are selected from N,N-dimethylformamide, tetrahydrofuran, dichloromethane, N-methylpyrrolidone, hexamethylphosphoramide, dimethyl ether, dimethyl sulfoxide. Preferably, the solvent can be N,N-dimethylformamide, tetrahydrofuran or dichloromethane. More preferably, the solvent can be N,N-dimethylformamide.

[0020] In the method of the present invention, the reaction step (i) in the method 2 is a reduction reaction. The reducing agent may be iron powder or zinc powder, preferably iron powder. The acidic condition may be ammonium chloride, hydrochloric acid, or sulfuric acid, preferably ammonium chloride. The amount of iron powder used is 1.0 to 2.5 eq, preferably 1.7 eq. The solvent in the reaction is selected from tetrahydrofuran, hexamethylphosphoramide, C1 to C5 alcohols, dimethyl ether, diethyl ether, diisopropyl ether, ethyl acetate, dimethoxyethane, and toluene. Preferably, the solvent may be water, tetrahydrofuran, or C1 to C5 alcohols (such as methanol, ethanol, propanol, isopropanol, butanol, etc.). More preferably, the solvent may be a mixed solvent of ethanol and water, with a dosage ratio of 5:1, 4:1, 1:2, preferably 4:1.

[0021] In the method of the present invention, the reaction step (ii) in the method 2 is a substitution reaction. The base can be one of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium phosphate (including monobasic potassium phosphate, dibasic potassium phosphate and tribasic potassium phosphate), sodium phosphate (including monobasic sodium phosphate, dibasic sodium phosphate and tribasic sodium phosphate), preferably potassium carbonate. The base can be 1.0~1.3 eq, preferably 1.0~1.1 eq, preferably 1.05 eq. The reaction solvent is selected from N,N-dimethylformamide, tetrahydrofuran, dichloromethane, N-methylpyrrolidone, hexamethylphosphoramide, dimethyl ether, dimethyl sulfoxide. Preferably, the solvent can be N,N-dimethylformamide, tetrahydrofuran or dichloromethane. More preferably, the solvent can be N,N-dimethylformamide.

[0022] In the method of the present invention, the reaction step (iii) in the method 2 is a substitution reaction. The base can be any one of lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, sodium amide, and sodium hydride, preferably lithium bis(trimethylsilyl)amide. The base can be 1.0 to 1.3 eq, preferably 1.0 to 1.1 eq, preferably 1.05 eq. The solvent in the reaction is selected from tetrahydrofuran, toluene, dimethyl ether, diethyl ether, and diisopropyl ether. Preferably, the solvent can be tetrahydrofuran or dimethyl ether. More preferably, the solvent is tetrahydrofuran.

[0023] In the method of the present invention, the compound (A3-1) or compound (A2-2) is prepared from compound (A) under alkaline conditions in a solvent. The alkali can be one of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium phosphate (including monobasic potassium phosphate, dibasic potassium phosphate and tribasic potassium phosphate), sodium phosphate (including monobasic sodium phosphate, dibasic sodium phosphate and tribasic sodium phosphate), preferably potassium carbonate. The reaction solvent is selected from N,N-dimethylformamide, tetrahydrofuran, dichloromethane, N-methylpyrrolidone, hexamethylphosphoramide, dimethyl ether, dimethyl sulfoxide. Preferably, the solvent can be N,N-dimethylformamide, tetrahydrofuran or dichloromethane. More preferably, the solvent can be N,N-dimethylformamide.

[0024] In the method of the present invention, the compound N,N-diisobutyl-1H-indazole-4-amine is prepared from the intermediate (A5-1) or the intermediate (A5-2) under alkaline conditions in a solvent. The alkalinity can be one of potassium tert-butoxide, sodium tert-butoxide, and sodium hydride, preferably potassium tert-butoxide. The reaction can be carried out in the presence of one or more solvents, and the one or more solvents are selected from N,N-dimethylformamide, tetrahydrofuran, N-methylpyrrolidone, hexamethylphosphoramide, dimethyl ether, and dimethyl sulfoxide. Preferably, the solvent can be N,N-dimethylformamide, tetrahydrofuran, and dimethyl sulfoxide. More preferably, the solvent can be tetrahydrofuran or dimethyl sulfoxide.

[0025] Compared with the prior art, the present invention has the following beneficial effects: the present invention uses 4-nitro-1-H-indazole as a reaction raw material, introduces a benzyl protecting group, and then performs a reduction reaction, a continuous substitution and a debenzylation reaction to prepare an intermediate of the compound N,N-diisobutyl-1H-indazole-4-amine and a new preparation method, the method increases the total reaction yield to 23%, and the process operation is simple, the reaction conditions are mild, the by-products are small, the substrate universality is high, and the economic benefits are high. DETAILED DESCRIPTION

[0026] The following is a detailed description of the preferred embodiments of the present invention so that the advantages and features of the present invention can be more easily understood by those skilled in the art, thereby making a clearer and more definite definition of the protection scope of the present invention.

[0027] Example 1

[0028] Compound A (9.95 g, 61 mmol) and potassium carbonate (16.86 g, 122 mmol) were added to a 250 mL three-necked round-bottom flask at 18 °C under nitrogen, and ultra-dry N,N-dimethylformamide (120 mL) was quickly added to dissolve and stir. After 10 minutes, benzyl bromide (11.48 g, 67 mmol) was added dropwise. The reaction lasted for 17 hours. The sampling point plate was tested. The results showed that the raw material disappeared, the target product was generated, and there were many impurities. 300 mL of water was added to quench and stir, and the mixture was extracted with a large amount of water and ethyl acetate for 3 times (50 mL*3). The organic phase was collected and washed with a large amount of brine for 3 times. The organic phase was collected and dried over anhydrous sodium sulfate. The filtrate was dried at 43 °C to obtain a black solid. Ethyl acetate was added to dissolve it, and an appropriate amount of silica gel powder was added. The mixture was dried to powder. The sample was loaded by dry method. The eluent was n-hexane:ethyl acetate = 30:1~10:1. The two product points were collected and dried separately. A golden solid compound A2-1 (7.43 g, 48.1%). 1 H NMR (400 MHz, Chloroform-d) d 8.67 (s, 1H), 8.13 (d, J = 7.6 Hz,1H), 7.69 (d, J = 8.4 Hz, 1H), 7.44 (t, J = 8.0 Hz, 1H), 7.34 – 7.29 (m, 3H), 7.21 – 7.19 (m, 2H), 5.69 (s, 2H). An orange-yellow solid compound A2-2 (6.95 g, 45.0%) was obtained. 1 HNMR (400 MHz, Chloroform-d) d 8.58 (s, 1H), 8.19 (d, J = 7.6 Hz, 1H), 8.12(d, J = 8.4 Hz, 1H), 7.43-7.35 (m, 6H), 5.68 (s, 2H).

[0029] Example 2

[0030] At 24°C (room temperature), compound A2-1 (7.43 g, 29.3 mmol), iron powder (16.4 g, 293 mmol) and ammonium chloride (785 mg, 14.7 mmol) were weighed into a 500 mL three-necked flask; 196 mL of ethanol and 49 mL of water were added under nitrogen at 24°C and stirred; the mixture was transferred to a 98°C oil bath and heated under reflux for 1 hour; a sample was taken and quenched with potassium carbonate solution, and the plate was extracted with ethyl acetate. It was found that the raw material disappeared and the target product was generated; the mixture was removed from the oil bath and cooled, filtered with a funnel and silica gel, washed with ethanol, and the filtrate was collected; after removing the ethanol by vacuum rotary evaporation at 50°C, the mixture was dissolved in ethyl acetate and potassium carbonate solution was added to adjust the pH to 8 for extraction, washed with ethyl acetate 3 times (75 mL*3), the organic phase was collected, washed once with saturated brine, and the collected organic phase was dried over anhydrous sodium sulfate; the organic phase was vacuum rotary evaporated at 43°C to obtain a crude orange-brown solid compound A3-1 (6.41 g, 98%). 1 HNMR (400 MHz, Chloroform-d) d 7.98 (d, J = 1.0 Hz, 1H), 7.30 – 7.26 (m, 3H), 7.20 – 7.18 (m, 2H), 7.15 – 7.11 (m, 1H), 6.75 (d, J = 8.3 Hz, 1H), 6.33 (d, J = 7.4 Hz, 1H), 5.54 (s, 2H), 4.15-4.10 (m, 2H).

[0031]

[0032] At 24°C (room temperature), weigh A2-2 (6.95 g, 27.5 mmol), iron powder (15.18 g, 275 mmol) and ammonium chloride (738 mg, 13.8 mmol) in a 500 mL three-necked flask; add 164 mL ethanol and 41 mL water at 24°C under nitrogen and stir; move to 78°C oil bath and heat under reflux for 2 hours; take a sample and quench with potassium carbonate solution, extract with ethyl acetate and spot plate, it is found that the raw material disappears, the target product is generated, and there are many impurities; remove from the oil bath to cool, filter with a funnel and silica gel, wash with ethanol, and collect the filtrate; after removing ethanol by vacuum rotary evaporation at 50°C, dissolve with ethyl acetate and add potassium carbonate solution to adjust pH = 8, extract, wash 3 times with ethyl acetate (75 mL*3), collect the organic phase, wash once with saturated brine, collect the organic phase and dry with anhydrous sodium sulfate; vacuum rotary evaporation of the organic phase at 43°C gives gray-green solid compound A3-2 (5.65 g, 92%).1 HNMR (400 MHz, Chloroform-d) d 7.82 (s, 1H), 7.40-7.35 (m, 3H), 7.31-7.29 (m,2H), 7.21 – 7.19 (m, 1H), 7.12 (dd, J = 8.7, 7.0 Hz, 1H), 6.29 – 6.27 (m,1H), 5.59 (s, 2H), 3.61 (s, 2H).

[0033] Example 3 ,

[0034] At 22°C (room temperature), compound A3-1 (6.41 g, 28.7 mmol) and potassium carbonate (11.9 g, 86.0 mmol) were weighed into a 500 mL three-necked flask; under nitrogen, 65 mL of N,N-dimethylformamide was added to dissolve and stirred for 10 minutes; iodine isobutane (10.5 g, 57.4 mmol) was slowly added, and the mixture was moved to a 130°C oil bath for heating and reaction for 12 hours, cooled to room temperature, and the sample was quenched with water. The ethyl acetate extraction spot plate showed that the raw material reaction was complete and the target product was generated; the oil bath was removed, cooled to room temperature, and potassium carbonate was removed by filtering with a sand core funnel, and washed with ethyl acetate; the filtrate was collected, extracted with a large amount of water and ethyl acetate 3 times (50 mL*3), the organic phase was collected, washed three times with saturated brine, the organic phase was collected, anhydrous sodium sulfate was added to dry, and the organic phase was evaporated under reduced pressure at 43°C to obtain a crude product, which was then separated by column separation (ethyl acetate: n-hexane = 1:30 ~1:10), to give compound A4-1 as an off-white solid (4.24 g, 53%). 1 H NMR (400 MHz, Chloroform-d) d 8.01 (d, J = 1.0 Hz, 1H), 7.34 – 7.27 (m, 3H), 7.24 – 7.19 (m, 3H), 6.70 (d, J = 8.4 Hz, 1H), 6.22 (d, J = 7.6 Hz, 1H), 5.56 (s, 2H), 4.31 (s, 1H), 3.14(d, J = 6.8 Hz, 2H), 2.04 (dp, J = 13.4, 6.7 Hz, 1H), 1.07 (d,J = 6.7 Hz,6H). 13 C NMR (100 MHz, Chloroform-d) d 142.29, 141.10, 137.14, 130.10, 128.67, 128.31, 127.62, 127.20, 114.45, 98.96, 97.91, 52.96, 51.60, 28.09, 20.58. Compound A5-1 was obtained as a light yellow liquid (385 mg, 4%). 1 H NMR (400 MHz, Chloroform-d) d 8.10 (d, J =1.0 Hz, 1H), 7.40 – 7.31 (m, 2H), 7.30 – 7.25 (m, 3H), 7.20 (t, J = 8.0 Hz,1H), 6.72 (d, J = 8.2 Hz, 1H), 6.30 (d, J = 7.8 Hz, 1H), 5.54 (s, 2H), 3.38(d, J = 7.2 Hz, 4H), 2.19 – 2.12 (m, 2H), 0.96 (d, J = 6.6 Hz, 12H). 13 C NMR (100 MHz, Chloroform-d) d : 144.16, 142.04, 137.12, 133.36, 128.69, 127.66,127.62, 127.33, 115.46, 103.93, 97.68, 61.56, 52.84, 26.74, 20.46.

[0035] ,

[0036] At 22°C (room temperature), compound A3-2 (5.65 g, 25.3 mmol) and potassium carbonate (13.99 g, 101.2 mmol) were weighed into a 500 mL three-necked flask. Under nitrogen, 63 mL of N,N-dimethylformamide was added to dissolve and stirred for 10 minutes. Isobutyl iodide (18.6 g, 101.2 mmol) was slowly added. The mixture was moved to a 130°C oil bath and heated for 4 hours. The mixture was cooled to room temperature and quenched with water. The ethyl acetate extraction spot plate showed that the raw material reaction was complete and the target product was generated. The mixture was removed from the oil bath and cooled to room temperature. The potassium carbonate was removed by filtering with a sand core funnel and washed with ethyl acetate. The filtrate was collected and extracted with a large amount of water and ethyl acetate for 3 times (50 mL*3). The organic phase was collected and washed with saturated brine for 3 times. The organic phase was collected and dried by adding anhydrous sodium sulfate. The organic phase was evaporated under reduced pressure at 43°C to obtain a crude product, which was then separated by column separation (ethyl acetate: n-hexane = 1:30). ~1:5), to give compound A4-2 as an off-white solid (2.97 g, 42%). 1 H NMR (400 MHz, Chloroform-d) d 7.78 (s, 1H), 7.35 – 7.30 (m, 3H), 7.26 – 7.24 (m, 2H), 7.17-7.13 (m, 1H),7.08 (d, J = 8.6 Hz, 1H), 6.07 (d, J = 7.1 Hz, 1H), 5.52 (s, 2H), 3.90 (s,1H), 3.03 (d, J = 6.8 Hz, 2H), 1.95 (dp, J = 13.4, 6.7 Hz, 1H), 1.00 (d, J =6.7 Hz, 6H). 13 C NMR (100 MHz, Chloroform-d) d The compound A5-2 was obtained as an orange-red solid (1.23 g, 14.5%). 1 H NMR (400 MHz, Chloroform-d) d7.86 (s, 1H), 7.37 – 7.27 (m, 5H), 7.14 – 7.13 (m, 2H), 6.23 – 6.18 (m, 1H), 5.55 (s, 2H), 3.16 (d, J J = 7.2 Hz, 4H), 2.04 – 1.97 (m, 2H), 0.85 (d, J J = 6.7Hz, 12H). 13 C NMR (100 MHz, Chloroform-d) d 151.22, 143.58, 135.93, 128.93, 128.32, 128.03, 127.10, 122.83, 116.34, 106.99, 104.51, 61.24, 57.31, 26.70, 20.56。

[0037] Example 4

[0038] At 18 °C (room temperature) under nitrogen protection, 45 mL of tetrahydrofuran was used to transfer compound A4-1 (4.24 g, 15.18 mmol) to a 250 mL three-necked reaction flask, stirred and dissolved, and lithium bis(trimethylsilyl)amide (45.5 ml, 1 moL / L) was added dropwise at 18 °C; stirred for 1 hour, and isobutyl iodide (3.52 mL, 30.4 mmol) was slowly added, and stirred for 1 hour; sampling and TLC showed that the raw materials were not completely reacted (extended time, no change in the product), the target product was formed, the reaction was stopped, quenched with water, extracted 3 times with water and ethyl acetate (50 mL * 3), the combined organic phases were washed once with saturated brine, dried over anhydrous sodium sulfate, and the organic phase was rotary evaporated under reduced pressure at 43 °C to obtain a crude product, which was then separated by column chromatography (ethyl acetate: n-hexane = 1:20 ~ 1:5). The raw material beige solid compound A4-1 was recovered to obtain a yellow oily liquid compound A5-1 (2.14 g, 42%).

[0039]

[0040] At 18°C ​​(room temperature), under nitrogen protection, compound A4-2 (2.97 g, 10.6 mmol) was transferred to a 250 mL three-necked reaction bottle with tetrahydrofuran (32 mL) and stirred to dissolve; at 18°C, lithium bis(trimethylsilyl)amide (21.2 mL, 1 moL / L) was added dropwise, and the yellow liquid gradually became turbid; after stirring for 1 hour, isobutyl iodide (3.7 mL, 31.8 mmol) was slowly added and stirred for 1 hour (the yellow turbid system gradually became a brown clear liquid); the sampling point plate showed that the raw material was not completely reacted (the product did not change with extended time), and the target product was generated; the reaction was stopped, quenched with water, extracted with water and ethyl acetate 3 times (50 mL*3), the organic phases were combined, washed once with saturated brine, and dried over anhydrous sodium sulfate; the organic phase was evaporated under reduced pressure at 43°C to obtain a crude product, which was then separated by column (ethyl acetate: n-hexane = 1:30 ~ 1:5). Beige solid compound A4-2 was recovered, and yellow oily liquid compound A5-2 (1.89 g, 53%) was obtained.

[0041] Example 5

[0042] At 17°C (room temperature), potassium tert-butoxide (8.43 g, 75 mmol) was transferred to a 500 ml round-bottom flask, and dimethyl sulfoxide (15.9 mL) was added under oxygen protection, and compound A5-1 (2.52 g, 7.5 mmol) dissolved in 59 mL of tetrahydrofuran was added, and stirred for 12 hours. The sampling point plate showed: no starting material, and new product was generated; the reaction was stopped, 250 mL of saturated sodium chloride aqueous solution was added, and extracted with ethyl acetate (4*60 mL); the organic phases were combined, washed once with saturated brine, and dried over anhydrous sodium sulfate; the organic phase was evaporated under reduced pressure at 45°C to obtain a crude product, and then separated by column (ethyl acetate: n-hexane = 1:10~1:5) to obtain yellow solid compound a5 (1.51 g, 82%). 1 H NMR (400 MHz, Chloroform-d) d 8.16(d, J = 1.1 Hz, 1H), 7.28 – 7.22 (m, 1H), 6.85 (d, J = 8.1 Hz, 1H), 6.33 (d, J = 7.8 Hz, 1H), 3.37 (d, J = 7.3 Hz, 4H), 2.17 – 2.08 (m, 2H), 0.95 (d, J =6.7 Hz, 12H).13 C NMR (100 MHz, Chloroform-d) d 144.06, 142.60, 134.73,128.09, 114.74, 104.47, 98.23, 61.52, 26.73, 20.45.

[0043] Example 6

[0044] At 17°C (room temperature), potassium tert-butoxide (10.44 g, 93 mmol) was transferred to a 500 ml round-bottom flask, and dimethyl sulfoxide (19.8 mL) was added under oxygen protection, and compound A5-2 (3.12 g, 9.3 mmol) dissolved in 72 mL of tetrahydrofuran was added, and stirred for 12 hours. The sampling point plate showed: no starting material, and new product was generated; the reaction was stopped, 250 mL of saturated sodium chloride aqueous solution was added, and extracted with ethyl acetate (4*60 mL); the organic phases were combined, washed once with saturated brine, and dried over anhydrous sodium sulfate; the organic phase was evaporated under reduced pressure at 45°C to obtain a crude product, and then separated by column (ethyl acetate: n-hexane = 1:10 ~ 1:5) to obtain yellow solid compound a5 (1.78 g, 78%). 1 H NMR (400 MHz, Chloroform-d) d 8.16 (s, 1H), 7.29 – 7.22 (m, 1H), 6.85 (d, J = 8.1 Hz,1H), 6.34 (d, J = 7.8Hz, 1H), 3.38 (d, J = 7.2 Hz, 4H), 2.17 – 2.10 (m, 2H), 0.95 (d, J = 6.6 Hz,12H). 13 C NMR (100 MHz, Chloroform-d) d 144.06, 142.61, 134.72, 128.09,114.74, 104.45, 98.23, 61.52, 26.73, 20.45.

[0045] The above descriptions are merely embodiments of the present invention and are not intended to limit the patent scope of the present invention. Any equivalent structure or equivalent process transformation made using the contents of the present invention specification, or directly or indirectly applied in other related technical fields, are also included in the patent protection scope of the present invention.

Claims

1. A compound having the following general formula (I), the structural formula of which is: ， in: A is a 4-7 membered unsaturated heterocyclic ring containing 1-2 heteroatoms N and O; n is an integer from 1 to 3; R1 is a substituent, including H or alkyl, alkoxy, wherein the alkyl can be methyl, ethyl, propyl, isopropyl; Q is independently HR3 or R2, R3 and R2 can be one or more -CH2-C 1-6 Alkyl, -CH2-C 1-6 Alkoxy, halo-CH2-C 1-6 alkyl.

2. The compound of formula (I) according to claim 1, characterized in that When Q is independently HR3, R3 represents one or more -CH2-C as defined in claim 1 1-6 When the alkyl group is an alkyl group, the compound of formula (1) has the following structure of formula (Ia): ， When Q is independently R2, R2 represents one or more -CH2-C as defined in claim 1 1-6 When the alkyl group is an alkyl group, the compound of formula (1) has the structure of the following formula (Ib): ， Wherein, A is a 5-membered unsaturated heterocyclic ring containing 1 to 2 heteroatoms N and O; n, p are integers from 1 to 2; R1 is H or alkyl.

3. The compound of formula (I) according to claim 2, characterized in that in, A is selected from the following groups: ， ， ， ， 。 4. The compound of formula (I) according to any one of claims 1 to 3, characterized in that The structural formula of the compound of formula (I) is: ， ， 。 5. A method for preparing a compound of formula (I), characterized in that: The compound of formula (III) is reduced with a reducing agent to prepare the compound of formula (II), and then the compound of formula (II) is subjected to a continuous substitution reaction under alkaline conditions to prepare the compound of formula (I). The reaction equation is as follows: , wherein the definitions of A, n, R1, and Q are the same as those in the above definition.

6. The preparation method according to claim 5, characterized in that: The compound of formula (Ib-2) is prepared by continuous substitution reaction of the compound of formula (II-2) under alkaline conditions. The reaction equation is as follows: , wherein A is a 5-membered unsaturated heterocyclic ring containing 2 heteroatoms N, n, p are 1, and R1 is H.

7. The preparation method according to claim 5, characterized in that: The reducing agent is iron powder; the acidic conditions are ammonium chloride, hydrochloric acid, and sulfuric acid; the amount of iron powder used is 1.0-2.5 eq; and the solvent is selected from a variety of water, tetrahydrofuran, methanol, ethanol, propanol, isopropanol, butanol, hexamethylphosphoramide, dimethyl ether, diethyl ether, diisopropyl ether, ethyl acetate, and dimethoxyethane.

8. The preparation method according to claim 5, characterized in that: The base is any one of lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, sodium amide, and sodium hydride, preferably lithium bis(trimethylsilyl)amide; the base can be 1.0-1.3 eq; the solvent is selected from one of tetrahydrofuran, toluene, dimethyl ether, diethyl ether, and diisopropyl ether.

9. The preparation method according to claim 6, characterized in that: The base is one of sodium carbonate, sodium bicarbonate, potassium carbonate, monobasic potassium phosphate, dibasic potassium phosphate, tribasic potassium phosphate, monobasic sodium phosphate, dibasic sodium phosphate, and tribasic sodium phosphate; the base is 1.0~1.3 eq; the solvent is selected from one or more of N,N-dimethylformamide, tetrahydrofuran, dichloromethane, N-methylpyrrolidone, hexamethylphosphoramide, dimethyl ether, and dimethyl sulfoxide.

10. The preparation method according to claim 5 or 6, characterized in that: The compound of formula (III) is prepared by the following method: 。 11. The preparation method according to claim 5 or 6, characterized in that: Further preparing the compound N,N-diisobutyl-1H-indazol-4-amine (a5) comprises the following steps: Compound (A5-1) or (A5-2) is subjected to a deprotection reaction with benzyl bromide to obtain compound N,N-diisobutyl-1H-indazol-4-amine (a5): 。 12. The preparation method according to claim 5 or 6, characterized in that: The steps include: Or the following steps, 。

Images