Synthetic methods of aminophenylpyrazole compounds

Abstract

This method, belonging to the field of organic synthesis technology, discloses a synthetic method for aminophenylpyrazole compounds. The method employs a green and environmentally friendly synthetic route: using 4-halo-3-nitroacetophenone as a starting material, it first reacts with DMF-DMA to obtain N,N-dimethylenamine ketone compounds. Then, the obtained N,N-dimethylenamine ketone compounds are condensed with hydrazine compounds to obtain nitrophenylpyrazole compounds. Finally, the obtained nitrophenylpyrazole compounds are reduced to aminophenylpyrazole compounds in a Fe and NH4Cl system. The synthetic process does not require expensive palladium catalysts or ligands, thus avoiding the problems of heavy metal residues or heavy metal toxicity in pharmaceutical products caused by palladium catalysts in pharmaceutical processes. It also eliminates the need to remove trace metal residues from the target product. The raw materials used are abundant, inexpensive, and readily available; the reaction system is green and environmentally friendly; the operation steps and post-processing are simple; and the overall yield is high.

Description

Technical Field

[0001] This scheme belongs to the field of organic synthesis technology, specifically involving a method for synthesizing aminophenylpyrazole compounds. Background Technology

[0002] Pyrazole heterocyclic compounds are widely found in natural products, functional materials, drugs, and related bioactive compounds, and have always been a hot topic in organic synthesis research. For example... Figure 34 Compound (A, BMS-986299) is a candidate drug with anticancer activity, and its structure contains a pyrazole structure (see patent documents WO2017184746A1, 2017; WO2018152396A1, 2018). This pyrazole compound (number: TM) is the first starting material for the synthesis of the candidate drug (A). Therefore, studying the synthesis of this pyrazole compound (TM) or its structural analogues is of great significance. Previous synthetic processes (a, b, c) all used palladium-catalyzed coupling reactions (see patent documents WO2020037094A1, 2020; Org. Process Res.Dev. 2021, 25, 434-441). These palladium-catalyzed coupling reactions are widely used as efficient synthetic tools in organic synthesis. However, its application still has limitations, such as: (1) palladium catalysts are usually very expensive and sensitive to air and moisture, requiring strict operation; (2) in most cases, ligands are needed, which are usually more expensive and sometimes difficult to prepare; (3) palladium catalysts are toxic to heavy metals, and removing trace metal residues from target products is very challenging and therefore expensive in the pharmaceutical industry. Therefore, developing new green synthetic conditions for the preparation of pyrazole compounds (TM) and developing new environmentally friendly and cost-effective solutions is of great significance. Summary of the Invention

[0003] This method aims to overcome at least one deficiency in existing technologies. It provides a novel approach for synthesizing aminophenylpyrazole compounds, which are structural analogs of pharmaceutical intermediates. These structural analogs exhibit the same chemical reactivity when used in pharmaceutical research and development. This method avoids the use of palladium-catalyzed coupling reactions to prepare these analog intermediates.

[0004] The synthetic method of aminophenylpyrazole compounds adopted in this scheme is as follows: using 4-halo-3-nitroacetophenone as a raw material, it is first reacted with N,N-dimethylformamide dimethyl acetal (DMF-DMA) to obtain N,N-dimethylenamine ketone compounds, then the obtained N,N-dimethylenamine ketone compounds are condensed with hydrazine compounds to obtain nitrophenylpyrazole compounds (SM), and finally the obtained nitrophenylpyrazole compounds are reduced to aminophenylpyrazole compounds in iron and ammonium chloride (Fe, NH4Cl).

[0005] Its synthetic route is as follows:

[0006]

[0007] Wherein, formula (S) is 4-halo-3-nitroacetophenone, formula (S-1a) is an N,N-dimethylenamine ketone compound, formula (SM) is a nitrophenylpyrazole compound, formula (TM) is an aminophenylpyrazole compound, and RNHNH2 is a hydrazine compound; in the aforementioned compounds, X represents Cl or Br, R represents H, Bn or PMB, and PG represents THP, Bn or PMB.

[0008] That is, 4-halo-3-nitroacetophenone (S) is selected from 4-chloro-3-nitroacetophenone or 4-bromo-3-nitroacetophenone;

[0009] N,N-dimethylenamino ketones (S-1a) are selected from N,N-dimethyl-1-(2-chloro-nitrobenzyl-5-yl)enamino ketones or N,N-dimethyl-1-(2-bromo-nitrobenzyl-5-yl)enamino ketones;

[0010] Nitrophenylpyrazole compounds (SM) are selected from 1-(tetrahydro-2H-pyran-2-yl)-3-(2-chloro-1-nitrobenzen-5-yl)-1H-pyrazole, 1-(tetrahydro-2H-pyran-2-yl)-3-(2-bromo-1-nitrobenzen-5-yl)-1H-pyrazole, 1-benzyl-3-(2-chloro-1-nitrobenzen-5-yl)-1H-pyrazole, 1-benzyl-3-(2-bromo-1-nitrobenzen-5-yl)-1H-pyrazole, 1-p-methoxybenzyl-3-(2-chloro-1-nitrobenzen-5-yl)-1H-pyrazole, or 1-p-methoxybenzyl-3-(2-bromo-1-nitrobenzen-5-yl)-1H-pyrazole;

[0011] The aminophenylpyrazole compounds (TM) are selected from 1-(tetrahydro-2H-pyran-2-yl)-3-(2-chloro-1-aminophenyl-5-yl)-1H-pyrazole, 1-(tetrahydro-2H-pyran-2-yl)-3-(2-bromo-1-aminophenyl-5-yl)-1H-pyrazole, 1-benzyl-3-(2-chloro-1-aminophenyl-5-yl)-1H-pyrazole, 1-benzyl-3-(2-bromo-1-aminophenyl-5-yl)-1H-pyrazole, 1-p-methoxybenzyl-3-(2-chloro-1-aminophenyl-5-yl)-1H-pyrazole or 1-p-methoxybenzyl-3-(2-bromo-1-aminophenyl-5-yl)-1H-pyrazole. The hydrazine compounds (RNHNH2) are selected from hydrazine, hydrazine hydrates, benzylhydrazine, salts of benzylhydrazine, p-methoxybenzylhydrazine, or salts of p-methoxybenzylhydrazine.

[0012] Preferably, the above synthesis method includes the following steps:

[0013] Synthesis of S1.N,N-dimethylenamine ketones (S-1a)

[0014] This step involves the reaction of 4-halo-3-nitroacetophenone (S) with DMF-DMA to yield N,N-dimethylenamine ketone compounds (S-1a). Specifically, it includes:

[0015] S11. Mix 4-chloro-3-nitroacetophenone, DMF-DMA and N,N-dimethylformamide;

[0016] S12. React the mixture obtained in step S11 at 120±5℃ with stirring until the reaction is complete;

[0017] S13. Quench the mixture obtained in step S12, extract, dry the organic layer solution, concentrate under reduced pressure, and purify.

[0018] The amount of N,N-dimethylformamide dimethyl acetal (DMF-DMA) added was 2.0 ± 0.2 times the molar amount of 4-chloro-3-nitroacetophenone (S). The reaction endpoint was monitored by thin-layer chromatography. After the reaction was completed, the mixture was quenched with water, extracted with ethyl acetate (EtOAc), dried with anhydrous sodium sulfate (Na2SO4), concentrated under reduced pressure, and purified by washing and drying, specifically by washing with cold ethanol (EtOH).

[0019] S2. Synthesis of nitrophenylpyrazole compounds (SM)

[0020] This step involves the condensation of the obtained N,N-dimethylenamine ketone compound (S-1a) with a hydrazine compound (RNHNH2) to yield a nitrophenylpyrazole compound (SM). Specifically:

[0021] If the hydrazine compounds are hydrazine or its hydrates, then specifically they include:

[0022] S211. Mix N,N-dimethylenamine ketone (S-1a), hydrazine (RNHNH2), acetic acid (HOAc), and ethanol (EtOH);

[0023] S212. React the mixture obtained in step S211 under a nitrogen atmosphere, at 80±5℃, with stirring, until the reaction is complete;

[0024] S213. After the mixture obtained in step S212 has cooled to room temperature, concentrate it under reduced pressure and purify it.

[0025] S214. Mix the intermediate product obtained in step S213, the tetrahydrofuran (THF) solution of 3,4-dihydro-2H-pyran (DHP), and p-toluenesulfonic acid monohydrate;

[0026] S215. React the mixture obtained in step S214 under a nitrogen atmosphere, at 80±5℃, with stirring, until the reaction is complete;

[0027] S216. After the mixture obtained in step S215 is cooled to room temperature, it is concentrated under reduced pressure and purified.

[0028] The amount of hydrazine compound (RNHNH2) added is 1.5 ± 0.2 times the molar amount of N,N-dimethylenamino ketone compound (S-1a), and the amount of acetic acid (HOAc) added is 1.0 ± 0.2 times the molar amount of N,N-dimethylenamino ketone compound (S-1a); the amount of 3,4-dihydro-2H-pyran (DHP) added is 3.0 ± 0.5 times the molar amount of the intermediate product; the reaction endpoints of steps S212 and S215 are monitored by thin-layer chromatography; after concentration under reduced pressure in steps S213 and S216, the product is purified by silica gel column chromatography (elution: petroleum ether / ethyl acetate system), and step S213 can also be purified by washing (petroleum ether) and then drying.

[0029] If the hydrazine compound is benzylhydrazine, a salt of benzylhydrazine, p-methoxybenzylhydrazine, or a salt of p-methoxybenzylhydrazine, then specifically it includes:

[0030] S221. Mix N,N-dimethylenamine ketone (S-1a), hydrazine (RNHNH2), acetic acid (HOAc), and ethanol (EtOH);

[0031] S222. React the mixture obtained in step S221 under a nitrogen atmosphere, at 80±5℃, with stirring, until the reaction is complete;

[0032] S223. After the mixture obtained in step S222 has cooled to room temperature, concentrate it under reduced pressure and purify it.

[0033] The amount of hydrazine compound (RNHNH2) added was 1.5 ± 0.2 times the molar amount of N,N-dimethylenamino ketone compound (S-1a), and the amount of acetic acid (HOAc) added was 1.0 ± 0.2 times the molar amount of N,N-dimethylenamino ketone compound (S-1a). The reaction endpoint was monitored by thin-layer chromatography. After concentration under reduced pressure, the mixture was purified by silica gel column chromatography (elution: petroleum ether / ethyl acetate system).

[0034] S3. Synthesis of aminophenylpyrazole compounds (TM)

[0035] This step involves reducing the obtained nitrophenylpyrazole compound (SM) with Fe and NH4Cl to obtain an aminophenylpyrazole compound (TM). Specifically, this includes:

[0036] S31. Mix an aqueous solution of nitrophenylpyrazole compound (SM), Fe, NH4Cl and methanol (MeOH / H2O);

[0037] S32. React the mixture obtained in step S31 under a nitrogen atmosphere at 65±5℃ until the reaction is complete;

[0038] S33. After the mixture obtained in step S32 has cooled to room temperature, filter, extract, dry the organic layer, and concentrate under reduced pressure.

[0039] The amount of iron (Fe) added was 5.0 ± 1.0 times the molar amount of nitrophenylpyrazole compound (SM), and the amount of ammonium chloride (NH4Cl) added was 10.0 ± 2.0 times the molar amount of nitrophenylpyrazole compound (SM). The reaction endpoint was monitored by thin-layer chromatography. After the reaction was completed, the mixture was filtered with diatomaceous earth, the filtrate was extracted with ethyl acetate, and the organic layer was dried with anhydrous sodium sulfate (Na2SO4).

[0040] This scheme designs a route for synthesizing aminophenylpyrazole compounds (TM) from 4-halo-3-nitroacetophenone (S). The synthesis process does not require the use of expensive palladium catalysts or ligands, thus avoiding the problems of heavy metal residues or heavy metal toxicity in drug products caused by palladium catalysts in pharmaceutical processes. There is no need to remove trace metal residues from the target product. The raw materials used are abundant, inexpensive, and readily available. The reaction system is green and environmentally friendly. The operation steps and post-processing are simple, and the overall yield is high.

[0041] Compared with existing technologies, this solution has the following advantages:

[0042] (1) The raw materials used are abundant, inexpensive and readily available; the developed reaction system is green and environmentally friendly; the operation steps and post-processing are simple and the overall yield is high;

[0043] (2) No expensive palladium catalysts or ligands are required, so there is no problem of heavy metal residues or heavy metal toxicity in drug products caused by palladium catalysts in the pharmaceutical process;

[0044] (3) No harsh and strict operating conditions are required;

[0045] (4) There is no problem of expensive industrial heavy metal waste disposal;

[0046] (5) The products have diverse structural selectivity and high overall yield. Attached Figure Description

[0047] Figure 1 It is the nuclear magnetic resonance of compound S2-1a 1 H NMR spectrum.

[0048] Figure 2 It is the nuclear magnetic resonance of compound S2-1a 13 C NMR spectrum.

[0049] Figure 3 It is the NMR of compound 1c 1 H NMR spectrum.

[0050] Figure 4 It is the NMR of compound 1c 13 C NMR spectrum.

[0051] Figure 5 It is the nuclear magnetic resonance of compound SM-3a 1 H NMR spectrum.

[0052] Figure 6 It is the nuclear magnetic resonance of compound SM-3a 13 C NMR spectrum.

[0053] Figure 7 It is the nuclear magnetic resonance of compound TM-3a 1 H NMR spectrum.

[0054] Figure 8 It is the nuclear magnetic resonance of compound TM-3a 13 C NMR spectrum.

[0055] Figure 9 It is the nuclear magnetic resonance of compound SM-4a 1 H NMR spectrum.

[0056] Figure 10 It is the nuclear magnetic resonance of compound SM-4a 13 C NMR spectrum.

[0057] Figure 11 It is the nuclear magnetic resonance of compound TM-4a1 H NMR spectrum.

[0058] Figure 12 It is the nuclear magnetic resonance of compound TM-4a 13 C NMR spectrum.

[0059] Figure 13 It is the nuclear magnetic resonance of compound SM-5a 1 H NMR spectrum.

[0060] Figure 14 It is the nuclear magnetic resonance of compound SM-5a 13 C NMR spectrum.

[0061] Figure 15 It is the nuclear magnetic resonance of compound TM-5a 1 H NMR spectrum.

[0062] Figure 16 It is the nuclear magnetic resonance of compound TM-5a 13 C NMR spectrum.

[0063] Figure 17 It is the nuclear magnetic resonance of compound S3-1a 1 H NMR spectrum.

[0064] Figure 18 It is the nuclear magnetic resonance of compound S3-1a 13 C NMR spectrum.

[0065] Figure 19 It is the nuclear magnetic resonance of compound 1d. 1 H NMR spectrum.

[0066] Figure 20 It is the NMR of compound 1d 13 C NMR spectrum.

[0067] Figure 21 It is the nuclear magnetic resonance of compound SM-6a 1 H NMR spectrum.

[0068] Figure 22 It is the nuclear magnetic resonance of compound SM-6a 13 C NMR spectrum.

[0069] Figure 23 It is the nuclear magnetic resonance of compound TM-6a 1 H NMR spectrum.

[0070] Figure 24 It is the nuclear magnetic resonance of compound TM-6a 13 C NMR spectrum.

[0071] Figure 25It is the nuclear magnetic resonance of compound SM-7a 1 H NMR spectrum.

[0072] Figure 26 It is the nuclear magnetic resonance of compound SM-7a 13 C NMR spectrum.

[0073] Figure 27 It is the NMR of compound TM-7a 1 H NMR spectrum.

[0074] Figure 28 It is the NMR of compound TM-7a 13 C NMR spectrum.

[0075] Figure 29 It is the nuclear magnetic resonance of compound SM-8a 1 H NMR spectrum.

[0076] Figure 30 It is the nuclear magnetic resonance of compound SM-8a 13 C NMR spectrum.

[0077] Figure 31 It is the nuclear magnetic resonance of compound TM-8a 1 H NMR spectrum.

[0078] Figure 32 It is the nuclear magnetic resonance of compound TM-8a 13 C NMR spectrum.

[0079] Figure 33 This is the synthetic route for aminophenylpyrazole compounds in this scheme.

[0080] Figure 34 This is the overall research route for aminophenylpyrazole compounds in the pharmaceutical intermediate structure among candidate drugs (A) with anticancer activity in the existing technology. Detailed Implementation

[0081] This scheme completely abandons the palladium-catalyzed coupling reaction and designs a novel, green, and environmentally friendly synthetic route for aminophenylpyrazole compounds (TM): Using inexpensive commercial reagents 4-chloro-3-nitroacetophenone (S2) or 4-bromo-3-nitroacetophenone (S3), it reacts with N,N-dimethylformamide dimethyl acetal (DMF-DMA) to obtain N,N-dimethylenamine ketone compounds (S2-1a or S3-1a); then, S2-1a or S3-1a is condensed with hydrazine compounds to obtain various nitrophenylpyrazole compounds (SM); finally, the nitro group is reduced to an amino group in iron and ammonium chloride to obtain the target compound TM. The overall route is as follows:

[0082]

[0083] To enable those skilled in the art to better understand this solution, the following detailed description is provided in conjunction with specific embodiments. Unless otherwise specified, the process methods used in the embodiments are conventional methods; and unless otherwise specified, the materials used are commercially available.

[0084] Example 1: Synthesis of a series of aminophenylpyrazole compounds (TM) using 4-chloro-3-nitroacetophenone (S2) as the starting material.

[0085] I. Synthesis of Compound (S2-1a)

[0086]

[0087] In an air atmosphere, 4-chloro-3-nitroacetophenone (S2, 40 mmol, 7984.0 mg), N,N-dimethylformamide dimethyl acetal (DMF-DMA, 2 equivalents, 80 mmol, 10.63 mL), and N,N-dimethylformamide (DMF, 60 mL) were added to a 250 mL round-bottom flask equipped with a magnetic stirrer. The reaction flask was then degassed three times with nitrogen, and the mixture was stirred in an oil bath at 120 °C for 16 h (monitored by TLC). After the reaction was complete, the mixture was quenched with water (150 mL) and extracted with ethyl acetate (EtOAc, 150 mL × 3). The organic layer was dried over anhydrous sodium sulfate (Na2SO4). The dried solution was concentrated under reduced pressure to obtain a dark brown crude solid product. The obtained crude solid product was washed with cold ethanol (EtOH, 50 mL) to obtain the pure product. The pure product was dried under vacuum to give compound S2-1a (yellow solid, 40 mmol, 7345.0 mg, yield 72%).

[0088] Using H respectively 1 -NMR (Bruker FT-NMR) and C 13 The structure of the obtained compound S2-1a was confirmed by FT-NMR (Bruker FT-NMR), and the results are as follows: Figures 1-2 As shown, the obtained compound S2-1a is N,N-dimethyl-1-(2-chloro-nitrobenzene-5-yl)enamine ketone.

[0089] 1H NMR (400MHz, CDCl3): δ8.36(d,J=2.0Hz,1H),,8.06(dd,J=8.4Hz,2.0Hz,1H),7.88(d,J =12.0Hz,1H),7.58(d,J=8.4Hz,1H),5.63(d,J=12.0Hz,1H),3.21(s,3H),2.97(s,3H);

[0090] 13 C{ 1 H}NMR (100MHz, CDCl3): 183.93, 155.41, 147.58, 140.06, 131.81, 131.70, 129.06, 124.42, 90.63, 45.41, 37.54.

[0091] II. Synthesis of a series of target products (TM)

[0092] a. Synthesis of the target product protected by tetrahydropyran (THP)

[0093]

[0094] Under a nitrogen atmosphere, a mixture of hydrazine monohydrate (NH₂NH₂·H₂O, 80% aqueous solution, 1.5 equivalents, 15 mmol, 0.9 mL), compound S2-1a (10 mmol, 2547.0 mg), and acetic acid (HOAc, 1.0 equivalents, 10 mmol, 0.57 mL) was added to a dry 250 mL reaction flask, followed by the addition of ethanol (EtOH, 80 mL). The mixture was then stirred in an oil bath at 80 °C for 15 h (monitored by TLC). After the reaction was complete, it was cooled to room temperature and concentrated under reduced pressure to give a brown crude product solid. Then, 10% Na₂CO₃ (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL × 3), and the organic layer was dried with anhydrous sodium sulfate (Na₂SO₄). The resulting solution was concentrated under reduced pressure to give the desired crude product 1c. Finally, the crude product filter cake was washed with petroleum ether (150 mL) and dried under vacuum to obtain pure compound 1c (yellow solid, 10 mmol, 1900.0 mg, yield 85%).

[0095] Using H respectively 1 -NMR (Bruker FT-NMR) and C 13 The structure of compound 1c obtained above was confirmed by FT-NMR (Bruker FT-NMR), and the results are as follows: Figures 3-4 As shown, it can be seen that the obtained compound 1c is 3-(2-chloro-1-nitrobenzene-5-yl)-1H-pyrazole.

[0096] 1H NMR (400MHz, DMSO-d6): δ13.20(br,s,1H),8.44(d,J=2.0Hz,1H),8.14(dd,J=8 .4Hz,2.0Hz,1H),7.88-7.87(m,1H),7.80(d,J=8.4Hz,1H),6.93-6.92(m,,1H);

[0097] 13 C{ 1 H}NMR (100MHz, DMSO-d6): 148.14, 147.24, 134.37, 131.97, 130.74, 129.88, 122.99, 121.50, 102.88.

[0098] Under a nitrogen atmosphere, a 30 mL solution of 3,4-dihydro-2H-pyran (DHP, 3.0 equivalents, 18 mmol, 1.64 mL) in tetrahydrofuran (THF) was added to a 150 mL reaction flask containing compound 1c (6.0 mmol, 1340.0 mg) and p-toluenesulfonic acid monohydrate (10 mol%, 114.0 mg). The mixture was then stirred in an oil bath at 80 °C for 24 h (monitored by TLC). After the reaction was complete, it was cooled to room temperature. The resulting solution was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5:1, R...). f =0.45), to obtain the desired product SM-3a (yellow solid, 6.0 mmol, 1608.2 mg, yield 87%).

[0099] Using H respectively 1 -NMR (Bruker FT-NMR) and C 13 The structure of the product SM-3a obtained above was confirmed by FT-NMR (Bruker FT-NMR), and the results are as follows: Figures 5-6 As shown, the obtained product SM-3a is 1-(tetrahydro-2H-pyran-2-yl)-3-(2-chloro-1-nitrobenzen-5-yl)-1H-pyrazole.

[0100] 1H NMR (400MHz, CDCl3): δ8.32(d,J=2.0Hz,1H),7.96(dd,J=8.4Hz,2.0Hz,1H),7.68(d,J=2.0Hz,1H),7.54(d,J=8.4Hz,1H),6.64(d,J=2. 2Hz,1H),5.43(dd,J=9.8Hz,2.2Hz,1H),4.12-4.09(m,1H),3.77-3.71(m,1H),2.24-2.14(m,1H),2.11-2.08(m,2H),1.78-1.63(m,3H);

[0101] 13 C{ 1 H}NMR (100MHz, CDCl3): 148.26, 148.07, 133.62, 131.86, 129.90, 129.70, 125.44, 122.45, 103.63, 87.87, 67.97, 30.47, 24.83, 22.35.

[0102] Under a nitrogen atmosphere, an aqueous methanol solution (MeOH / H₂O, 30 mL, v / v = 4 / 1) was added to a 100 mL reaction flask containing compound SM-3a (5.0 mmol, 1540.0 mg), reduced iron powder (Fe, 5.0 equivalent, 25 mmol, 1400.0 mg), and ammonium chloride (NH₄Cl, 10 equivalent, 50 mmol, 2680.0 mg). The reaction was then carried out in an oil bath at 65 °C for 5 h (monitored by TLC). After the reaction was complete, the mixture was cooled to room temperature. The solution was filtered through diatomaceous earth, and the filtrate was extracted with ethyl acetate (50 mL × 3). The organic layer was dried over anhydrous sodium sulfate (Na₂SO₄). The solution was concentrated under reduced pressure to give the desired pure product TM-3a (pale yellow viscous solid, 5.0 mmol, 1195.6 mg, 86% yield).

[0103] Using H respectively 1 -NMR (Bruker FT-NMR) and C 13 The structure of the pure product TM-3a obtained above was confirmed by FT-NMR (Bruker FT-NMR), and the results are as follows: Figures 7-8 As shown, the obtained pure product TM-3a is 1-(tetrahydro-2H-pyran-2-yl)-3-(2-chloro-1-aminophenyl-5-yl)-1H-pyrazole.

[0104] 1H NMR (400MHz, CDCl3): δ7.61(d,J=2.4Hz,1H),7.29(d,J=2.0Hz,1H),7.24(d,J=8.2Hz,1H),7.11(dd,J=8.2Hz,2.0Hz,1H),6.53(d,J=2 .4Hz,1H),5.40(dd,J=9.8Hz,2.4Hz,1H),4.11-4.09(m,1H),4.07(br,s,2H),3.74-3.68(m,1H),2.16-2.03(m,3H),1.73-1.58(m,3H);

[0105] 13 C{ 1 H} NMR (100MHz, CDCl3): 150.82, 142.85, 132.85, 129.34, 128.80, 118.61, 116.70, 112.89, 103.41, 87.76, 67.92, 30.58, 24.86, 22.50.

[0106] b. Synthesis of the target product protected by benzyl (Bn)

[0107]

[0108] Under a nitrogen atmosphere, a mixture of benzylhydrazine hydrochloride (Bn-NHNH2·2HCl, 1.5 equivalent, 7.5 mmol, 1463.0 mg), compound S2-1a (5.0 mmol, 1273.0 mg), and acetic acid (HOAc, 1.0 equivalent, 5.0 mmol, 286 μL) was added to a dry 100 mL reaction flask, followed by the addition of ethanol (EtOH, 30 mL). The mixture was then stirred in an oil bath at 80 °C for 15 h (monitored by TLC). After the reaction was complete, the mixture was cooled to room temperature and concentrated under reduced pressure to give a brown crude solid. Purification was achieved by silica gel column chromatography (elution: petroleum ether / ethyl acetate = 5:1, R...). f =0.50), to obtain the desired product SM-4a (yellow solid, 5.0 mmol, 1350.0 mg, yield 86%).

[0109] Using H respectively 1 -NMR (Bruker FT-NMR) and C 13 The structure of the product SM-4a obtained above was confirmed by FT-NMR (Bruker FT-NMR), and the results are as follows: Figures 9-10 As shown, the obtained product SM-4a is 1-benzyl-3-(2-chloro-1-nitrobenzene-5-yl)-1H-pyrazole.

[0110] 1 H NMR (400MHz, CDCl3): δ7.78(d,J=2.0Hz,1H),7.64(d,J=2.0Hz,1H),7.55(d,J=8.2Hz,1H),7.42(d d,J=8.2Hz,2.0Hz,1H),7.33-7.25(m,3H),7.06-7.04(m,2H),6.44(d,J=2.0Hz,1H),5.36(s,2H);

[0111] 13 C{ 1 H}NMR (100MHz, CDCl3): 147.84,140.21,139.46,136.74,133.00,132.15,130.58,128.89,127.95,127.11,126.57,125.61,107.58,53.70.

[0112] Under a nitrogen atmosphere, an aqueous methanol solution (MeOH / H₂O, 30 mL, v / v = 4 / 1) was added to a 100 mL reaction flask containing compound SM-4a (4.0 mmol, 1255.0 mg), reduced iron powder (Fe, 5.0 equivalent, 20 mmol, 1120.0 mg), and ammonium chloride (NH₄Cl, 10 equivalent, 40 mmol, 2140.0 mg). The mixture was then stirred in an oil bath at 65 °C for 5 h (monitored by TLC). After the reaction was complete, it was cooled to room temperature. The mixture was filtered through diatomaceous earth, and the filtrate was extracted with ethyl acetate (50 mL × 3). The organic layer was dried over anhydrous sodium sulfate (Na₂SO₄). The resulting solution was concentrated under reduced pressure to give the desired pure product TM-4a (yellow solid, 4.0 mmol, 1040.0 mg, yield 92%).

[0113] Using H respectively 1 -NMR (Bruker FT-NMR) and C 13 The structure of the purified product TM-4a obtained above was confirmed by FT-NMR (Bruker FT-NMR), and the results are as follows: Figures 11-12 As shown, the obtained pure product TM-4a is 1-benzyl-3-(2-chloro-1-aminophenyl-5-yl)-1H-pyrazole.

[0114] 1H NMR (400MHz, CDCl3): δ7.58(d,J=2.0Hz,1H),7.32-7.23(m,4H),7.07-7.05(m,2H),6.67(d,J=2 .0Hz,1H),6.63(dd,J=8..2Hz,2.0Hz,1H),6.30(d,J=2.0Hz,1H),5.33(s,2H),4.09(br,s,2H);

[0115] 13 C{ 1 H} NMR (100MHz, CDCl3): 143.30, 142.92, 139.24, 137.60, 130.12, 129.55, 128.63, 127.49, 126.72, 119.52, 119.30, 115.94, 106.31, 53.09.

[0116] c. Synthesis of the target product protected by p-methoxybenzyl (PMB)

[0117]

[0118] Under a nitrogen atmosphere, a mixture of p-methoxybenzylhydrazine hydrochloride (PMB-NHNH2·HCl, 1.5 equivalent, 7.5 mmol, 1415.0 mg), compound S2-1a (5.0 mmol, 1273.0 mg), and acetic acid (HOAc, 1.0 equivalent, 5.0 mmol, 286 μL) was added to a dry 100 mL reaction flask, followed by the addition of ethanol (EtOH, 30 mL). The mixture was then stirred in an oil bath at 80 °C for 15 h (monitored by TLC). After the reaction was complete, the mixture was cooled to room temperature and concentrated under reduced pressure to give a brown crude solid. Purification was achieved by silica gel column chromatography (elution: petroleum ether / ethyl acetate = 5:1, R...). f =0.40), to obtain the desired product SM-5a (yellow solid, 5.0 mmol, 1510.0 mg, yield 88%).

[0119] Using H respectively 1 -NMR (Bruker FT-NMR) and C 13 The structure of the product SM-5a obtained above was confirmed by FT-NMR (Bruker FT-NMR), and the results are as follows: Figures 13-14 As shown, the obtained product SM-5a is 1-p-methoxybenzyl-3-(2-chloro-1-nitrobenzen-5-yl)-1H-pyrazole.

[0120] 1H NMR (400MHz, CDCl3): δ7.79(d,J=2.0Hz,1H),7.62(d,J=2.0Hz,1H),7.56(d,J=8.2Hz,1H),7.43(dd,J=8 .2Hz,2.0Hz,1H),7.02-6.99(m,2H),6.85-6.81(m,2H),6.41(d,J=2.0Hz,1H),5.29(s,2H),3.78(s,3H);

[0121] 13 C{ 1 H} NMR (100MHz, CDCl3): 159.26, 147.86, 140.02, 139.34, 133.10, 132.13, 130.73, 128.72, 127.08, 125.67, 114.23, 107.56, 55.26, 53.30.

[0122] Under a nitrogen atmosphere, an aqueous methanol solution (MeOH / H₂O, 30 mL, v / v = 4 / 1) was added to a 100 mL reaction flask containing compound SM-5a (4.0 mmol, 1375.0 mg), reduced iron powder (Fe, 5.0 equivalent, 20 mmol, 1120.0 mg), and ammonium chloride (NH₄Cl, 10 equivalent, 40 mmol, 2140.0 mg). The mixture was then stirred in an oil bath at 65 °C for 5 h (monitored by TLC). After the reaction was complete, it was cooled to room temperature. The mixture was filtered through diatomaceous earth, and the filtrate was extracted with ethyl acetate (50 mL × 3). The organic layer was dried over anhydrous sodium sulfate (Na₂SO₄). The resulting solution was concentrated under reduced pressure to give the desired pure product TM-5a (yellow solid, 4.0 mmol, 1090.0 mg, yield 87%).

[0123] Using H respectively 1 -NMR (Bruker FT-NMR) and C 13 The structure of the pure product TM-5a obtained above was confirmed by FT-NMR (Bruker FT-NMR), and the results are as follows: Figures 15-16 As shown, the obtained pure product TM-5a is 1-p-methoxybenzyl-3-(2-chloro-1-aminophenyl-5-yl)-1H-pyrazole.

[0124] 1H NMR (400MHz, CDCl3): δ7.56(d,J=2.0Hz,1H),7.25(d,J=8.2Hz,1H),7.02-6.99(m,2H),6.83-6.79(m,2H),6.67( d,J=2.0Hz,1H),6.63(dd,J=8.2Hz,2.0Hz,1H),6.27(d,J=2.0Hz,1H),5.25(s,2H),4.13(br,s,2H),3.76(s,3H);

[0125] 13 C{ 1 H}NMR (100MHz, CDCl3): 158.86,143.04,142.93,139.05,130.17,129.56,128.17,119.41,119.26,115.94,113.91,106.24,55.15,52.56.

[0126] Example 2: Synthesis of a series of aminophenylpyrazole compounds (TM) using 4-bromo-3-nitroacetophenone (S3) as the starting material.

[0127] I. Synthesis of Compounds (S3-1a)

[0128]

[0129] In an air atmosphere, 4-bromo-3-nitroacetophenone (S3, 40 mmol, 9762.0 mg), N,N-dimethylformamide dimethyl acetal (DMF-DMA, 2 equivalents, 80 mmol, 10.63 mL), and N,N-dimethylformamide (DMF, 60 mL) were added to a 250 mL round-bottom flask equipped with a magnetic stirrer. The reaction flask was then degassed three times with nitrogen, and the mixture was stirred in an oil bath at 120 °C for 20 h (monitored by TLC). After the reaction was complete, the mixture was quenched with water (150 mL) and extracted with ethyl acetate (EtOAc, 150 mL × 3). The organic layer was dried over anhydrous sodium sulfate (Na2SO4). The dried solution was concentrated under reduced pressure to obtain a dark brown solid crude product. The crude product solid was washed with cold ethanol (EtOH, 100 mL) to obtain the pure product. The pure product was dried under vacuum to give compound S3-1a (yellow-brown solid, 40 mmol, 7800.0 mg, yield 65%).

[0130] Using H respectively 1 -NMR (Bruker FT-NMR) and C 13 The structure of the obtained compound S3-1a was confirmed by FT-NMR (Bruker FT-NMR), and the results are as follows: Figures 17-18 As shown, the obtained compound S3-1a is N,N-dimethyl-1-(2-bromo-nitrobenzene-5-yl)enamine ketone.

[0131] 1 H NMR (400MHz, CDCl3): δ8.31(d,J=2.0Hz,1H),,7.95(dd,J=8.4Hz,2.0Hz,1H),7.87(d,J =12.0Hz,1H),7.77(d,J=8.4Hz,1H),5.62(d,J=12.0Hz,1H),3.20(s,3H),2.97(s,3H);

[0132] 13 C{ 1 H}NMR (100MHz, CDCl3): 184.01, 155.42, 149.51, 140.73, 134.90, 131.73, 124.36, 116.72, 90.62, 45.41, 37.53.

[0133] II. Synthesis of a series of target products (TM)

[0134] a. Synthesis of the target product protected by tetrahydropyran (THP)

[0135]

[0136] Under a nitrogen atmosphere, a mixture of hydrazine monohydrate (NH₂NH₂·H₂O, 80% aqueous solution, 1.5 equivalents, 15 mmol, 0.9 mL), compound S3-1a (10 mmol, 2990.0 mg), and acetic acid (HOAc, 1.0 equivalents, 10 mmol, 0.57 mL) was added to a dry 250 mL reaction flask, followed by the addition of ethanol (EtOH, 60 mL). The mixture was then stirred in an oil bath at 80 °C for 16 h (monitored by TLC). After the reaction was complete, the mixture was cooled to room temperature and concentrated under reduced pressure to give a brown crude product solid. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 2:1, R...). f =0.40) yielded compound 1d (yellow solid, 10 mmol, 1920.0 mg, yield 72%).

[0137] Using H respectively 1 -NMR (Bruker FT-NMR) and C 13 The structure of the obtained compound 1d was confirmed by FT-NMR (Bruker FT-NMR), and the results are as follows: Figures 19-20 As shown, it can be seen that the obtained compound 1d is 3-(2-bromo-1-nitrobenzene-5-yl)-1H-pyrazole.

[0138] 1 H NMR (400MHz, DMSO-d6): δ13.20(br,s,1H),8.40(d,J=2.0Hz,1H),8.05-8.03(m,1H),7.93-7.91(m,1H),7.87(s,1H),6.92(d,J=2.0Hz,1H);

[0139] 13 C{ 1 H}NMR (100MHz, DMSO-d6): 150.24, 147.30, 135.00, 134.86, 130.72, 129.78, 121.40, 110.96, 102.87.

[0140] Under a nitrogen atmosphere, a 30 mL solution of 3,4-dihydro-2H-pyran (DHP, 3.0 equivalents, 18 mmol, 1.64 mL) in tetrahydrofuran (THF) was added to a 150 mL reaction flask containing compound 1d (6.0 mmol, 1608.0 mg) and p-toluenesulfonic acid monohydrate (10 mol%, 114.0 mg). The mixture was then stirred in an oil bath at 80 °C for 24 h (monitored by TLC). After the reaction was complete, it was cooled to room temperature. The resulting solution was concentrated under reduced pressure. Purification was performed by silica gel column chromatography (elution: petroleum ether / ethyl acetate = 5:1, R...). f =0.45), to obtain the desired product SM-6a (yellow solid, 6.0 mmol, 1965.0 mg, yield 93%).

[0141] Using H respectively 1 -NMR (Bruker FT-NMR) and C 13 The structure of the obtained product SM-6a was confirmed by FT-NMR (Bruker FT-NMR), and the results are as follows: Figures 21-22 As shown, the obtained product SM-6a is 1-(tetrahydro-2H-pyran-2-yl)-3-(2-bromo-1-nitrobenzen-5-yl)-1H-pyrazole.

[0142] 1H NMR (400MHz, CDCl3): δ8.28(d,J=2.0Hz,1H),,7.87(dd,J=8.4Hz,2.0Hz,1H),7.72(d,J=8.4Hz,1H),7.67(d,J=2.4Hz,1H), 6.64(d,J=2. 4Hz,1H),,5.42(dd,J=9.6Hz,2.4Hz,1H),4.12-4.08(m,1H),3.76-3.70(m,1H),2.23-2.14(m,1H),2.13-2.04(m,2H),1.76-1.66(m,3H);

[0143] 13 C{ 1 H} NMR (100MHz, CDCl3): 150.05, 148.36, 135.10, 134.33, 129.99, 129.77, 122.56, 112.80, 103.72, 87.94, 68.04, 30.55, 24.89, 22.42.

[0144] Under a nitrogen atmosphere, an aqueous methanol solution (MeOH / H₂O, 30 mL, v / v = 4 / 1) was added to a 150 mL reaction flask containing compound SM-6a (4.0 mmol, 1410.0 mg), reduced iron powder (Fe, 5.0 equivalent, 20 mmol, 1120.0 mg), and ammonium chloride (NH₄Cl, 10 equivalent, 40 mmol, 2140.0 mg). The mixture was then stirred in an oil bath at 65 °C for 5 h (monitored by TLC). After the reaction was complete, it was cooled to room temperature. The mixture was filtered through diatomaceous earth, and the filtrate was extracted with ethyl acetate (50 mL × 3). The organic layer was dried over anhydrous sodium sulfate (Na₂SO₄). The resulting solution was concentrated under reduced pressure to give the desired pure product TM-6a (pale yellow viscous solid, 4.0 mmol, 1120.0 mg, 87% yield).

[0145] Using H respectively 1 -NMR (Bruker FT-NMR) and C 13 The structure of the pure product TM-6a obtained above was confirmed by FT-NMR (Bruker FT-NMR), and the results are as follows: Figures 23-24 As shown, the obtained pure product TM-6a is 1-(tetrahydro-2H-pyran-2-yl)-3-(2-bromo-1-aminophenyl-5-yl)-1H-pyrazole.

[0146] 1H NMR (400MHz, CDCl3): δ7.61(d,J=2.4Hz,1H),7.40(d,J=8.2Hz,1H),7.29(d,J=2.0Hz,1H),7.04(dd,J=8.2Hz,2.0Hz,1H),6.54(d,J=2.4Hz,1H) ,5.40(dd,J=9.6Hz,2.6Hz,1H),4.11(br,s,2H),4.08-4.07(m,1H),3.7 5-3.68(m,1H),2.19-2.12(m,1H),2.11-2.03(m,2H),1.76-1.58(m,3H);

[0147] 13 C{ 1 H}NMR(100MHz, CDCl3)::150.77,144.03,133.52,132.49,,128.81,117.07,112.71,108.56,103.41,87.75,67.92,30.56,24.84,22.49.

[0148] b. Synthesis of the target product protected by benzyl (Bn)

[0149]

[0150] Under a nitrogen atmosphere, a mixture of benzylhydrazine hydrochloride (Bn-NHNH2·2HCl, 1.5 equivalent, 6.0 mmol, 1170.0 mg), compound S3-1a (4.0 mmol, 1196.0 mg), and acetic acid (HOAc, 1.0 equivalent, 4.0 mmol, 230 μL) was added to a dry 100 mL reaction flask, followed by the addition of ethanol (EtOH, 30 mL). The mixture was then stirred in an oil bath at 80 °C for 16 h (monitored by TLC). After the reaction was complete, the mixture was cooled to room temperature and concentrated under reduced pressure to give a brown crude solid. Purification was achieved by silica gel column chromatography (elution: petroleum ether / ethyl acetate = 5:1, R...). f =0.35), to obtain the desired product SM-7a (yellow solid, 4.0 mmol, 1048.0 mg, yield 73%).

[0151] Using H respectively 1 -NMR (Bruker FT-NMR) and C 13 The structure of the product SM-7a obtained above was confirmed by FT-NMR (Bruker FT-NMR), and the results are as follows: Figures 25-26 As shown, the obtained product SM-7a is 1-benzyl-3-(2-bromo-1-nitrobenzene-5-yl)-1H-pyrazole.

[0152] 1 H NMR (400MHz, CDCl3): δ7.75(s,1H),7.74(d,J=6.2Hz,1H),,7.65(d,J=2.0Hz, 1H),7.34-7.26(m,4H),7.07-7.05(m,2H),6.44(d,J=2.0Hz,1H),5.37(s,2H);

[0153] 13 C{ 1 H} NMR (100MHz, CDCl3): 149.75, 140.27, 139.52, 136.74, 135.37, 132.98, 131.19, 128.91, 127.97, 126.55, 125.61, 114.56, 107.55, 53.68.

[0154] Under a nitrogen atmosphere, an aqueous methanol solution (MeOH / H₂O, 30 mL, v / v = 4 / 1) was added to a 100 mL reaction flask containing compound SM-7a (2.0 mmol, 716.0 mg), reduced iron powder (Fe, 5.0 equivalent, 10 mmol, 560.0 mg), and ammonium chloride (NH₄Cl, 10 equivalent, 20 mmol, 1070.0 mg). The mixture was then stirred in an oil bath at 65 °C for 5 h (monitored by TLC). After the reaction was complete, it was cooled to room temperature. The mixture was filtered through diatomaceous earth, and the filtrate was extracted with ethyl acetate (50 mL × 3). The organic layer was dried over anhydrous sodium sulfate (Na₂SO₄). The solution was concentrated under reduced pressure to give the desired pure product TM-7a (yellow solid, 2.0 mmol, 605.0 mg, yield 92%).

[0155] Using H respectively 1 -NMR (Bruker FT-NMR) and C 13 The structure of the pure product TM-7a obtained above was confirmed by FT-NMR (Bruker FT-NMR), and the results are as follows: Figures 27-28 As shown, the obtained pure product TM-7a is 1-benzyl-3-(2-bromo-1-aminophenyl-5-yl)-1H-pyrazole.

[0156] 1H NMR (400MHz, CDCl3): δ7.58(d,J=2.0Hz,1H),7.41(d,J=8.0Hz,1H),7.32-7.23(m,3H),7.07-7.05(m,2H), 6.66(d,J=2.0Hz,1H),6.57(dd,J=8.0Hz,2.0Hz,1H),6.31(d,J=2.0Hz,1H),5.33(s,2H),4.13(br,s,2H);

[0157] 13 C{ 1 H} NMR (100MHz, CDCl3): 144.12, 143.24, 139.22, 137.53, 132.69, 130.75, 128.59, 127.46, 126.67, 119.53, 115.69, 109.43, 106.25, 53.03.

[0158] c. Synthesis of the target product protected by p-methoxybenzyl (PMB)

[0159]

[0160] Under a nitrogen atmosphere, a mixture of p-methoxybenzylhydrazine hydrochloride (PMB-NHNH2·HCl, 1.5 equivalent, 6.0 mmol, 1132.0 mg), compound S3-1a (4.0 mmol, 1196.0 mg), and acetic acid (HOAc, 1.0 equivalent, 4.0 mmol, 230 μL) was added to a dry 100 mL reaction flask, followed by the addition of ethanol (EtOH, 30 mL). The mixture was then stirred in an oil bath at 80 °C for 16 h (monitored by TLC). After the reaction was complete, the mixture was cooled to room temperature and concentrated under reduced pressure to give a brown crude solid. Purification was achieved by silica gel column chromatography (elution: petroleum ether / ethyl acetate = 5:1, R...). f =0.30), to obtain the desired product SM-8a (yellow solid, 4.0 mmol, 997.0 mg, yield 64%).

[0161] Using H respectively 1 -NMR (Bruker FT-NMR) and C 13 The structure of the product SM-8a obtained above was confirmed by FT-NMR (Bruker FT-NMR), and the results are as follows: Figures 29-30 As shown, the obtained product SM-8a is 1-p-methoxybenzyl-3-(2-bromo-1-nitrobenzene-5-yl)-1H-pyrazole.

[0162] 1H NMR (400MHz, CDCl3): δ7.76 (s, 1H), 7.75 (d, J = 5.0Hz, 1H), 7.62 (d, J = 2.0Hz, 1H), 7.34 (dd, J = 8.2Hz ,2.0Hz,1H),7.01-6.99(m,2H),6.84-6.81(m,2H),6.41(d,J=2.0Hz,1H),5.29(s,2H),3.78(s,3H);

[0163] 13 C{ 1 H} NMR (100MHz, CDCl3): 159.20, 149.74, 140.05, 139.36, 135.33, 133.07, 131.31, 128.68, 128.06, 125.64, 114.49, 114.19, 107.51, 55.25, 53.25.

[0164] Under a nitrogen atmosphere, an aqueous methanol solution (MeOH / H₂O, 30 mL, v / v = 4 / 1) was added to a 100 mL reaction flask containing compound SM-8a (2.0 mmol, 776.0 mg), reduced iron powder (Fe, 5.0 equivalent, 10 mmol, 560.0 mg), and ammonium chloride (NH₄Cl, 10 equivalent, 20 mmol, 1070.0 mg). The mixture was then stirred in an oil bath at 65 °C for 5 h (monitored by TLC). After the reaction was complete, it was cooled to room temperature. The mixture was filtered through diatomaceous earth, and the filtrate was extracted with ethyl acetate (50 mL × 3). The organic layer was dried over anhydrous sodium sulfate (Na₂SO₄). The solution was concentrated under reduced pressure to give the desired pure product TM-8a (yellow solid, 2.0 mmol, 650.0 mg, yield 91%).

[0165] Using H respectively 1 -NMR (Bruker FT-NMR) and C 13 The structure of the purified product TM-8a obtained above was confirmed by FT-NMR (Bruker FT-NMR), and the results are as follows: Figures 31-32 As shown, the obtained pure product TM-8a is 1-p-methoxybenzyl-3-(2-bromo-1-aminophenyl-5-yl)-1H-pyrazole.

[0166] 1H NMR (400MHz, CDCl3): δ7.56(d,J=1.6Hz,1H),7.42(d,J=8.0Hz,1H),7.02-7.00(m,2H),6.83-6.81(m,2H),6.67( d,J=2.0Hz,1H),6.57(dd,J=8.0Hz,2.0Hz,1H),6.28(d,J=1.6Hz,1H),5.26(s,2H),4.15(br,s,2H),3.77(s,3H);

[0167] 13 C{ 1 H}NMR (100MHz, CDCl3): 158.80,144.13,142.99,139.05,132.63,130.81,129.50,128.13,119.53,115.71,113.87,109.34,106.20,55.12,52.51.

[0168] Obviously, the above embodiments of this solution are merely examples for clearly illustrating this solution, and are not intended to limit the implementation of this solution. Those skilled in the art can make other variations or modifications based on the above description. It is neither necessary nor possible to exhaustively list all possible implementations here. Any modifications, equivalent substitutions, and improvements made within the spirit and principles of this solution should be included within the scope of protection of the claims of this solution.

Claims

1. A method for synthesizing an aminophenylpyrazole compound, wherein the aminophenylpyrazole compound is used to synthesize BMS-986299, characterized in that, The synthetic route is as follows: Wherein, formula (S) is 4-halo-3-nitroacetophenone, formula (S-1a) is an N,N-dimethylenamine ketone compound, formula (SM) is a nitrophenylpyrazole compound, formula (TM) is an aminophenylpyrazole compound, and RNHNH2 is a hydrazine compound; in the aforementioned compounds, X represents Cl or Br, R represents H, Bn or PMB, and PG represents THP, Bn or PMB; The synthesis method includes: S1. N,N-dimethylenamine ketones are obtained by reacting 4-halo-3-nitroacetophenone with DMF-DMA; S2. The obtained N,N-dimethylenamine ketone compounds are condensed with hydrazine compounds to obtain nitrophenylpyrazole compounds; S3. The obtained nitrophenylpyrazole compounds were reduced by Fe and NH4Cl to yield aminophenylpyrazole compounds; If the hydrazine compound is hydrazine or its hydrate, then step S2 is as follows: S211. Mix N,N-dimethylenamine ketones, hydrazine compounds, acetic acid, and ethanol; S212. React the mixture obtained in step S211 under a nitrogen atmosphere, at 80±5℃, with stirring, until the reaction is complete; S213. After the mixture obtained in step S212 has cooled to room temperature, concentrate it under reduced pressure and purify it; S214. Mix the intermediate product obtained in step S213, the tetrahydrofuran solution of 3,4-dihydro-2H-pyran, and p-toluenesulfonic acid monohydrate; S215. React the mixture obtained in step S214 under a nitrogen atmosphere, at 80±5℃, with stirring, until the reaction is complete; S216. After the mixture obtained in step S215 has cooled to room temperature, concentrate it under reduced pressure and purify it; If the hydrazine compound is benzylhydrazine, a salt of benzylhydrazine, p-methoxybenzylhydrazine, or a salt of p-methoxybenzylhydrazine, then step S2 specifically involves: S221. Mix N,N-dimethylenamine ketones, hydrazine compounds, acetic acid, and ethanol; S222. React the mixture obtained in step S221 under a nitrogen atmosphere, at 80±5℃, with stirring, until the reaction is complete; S223. After the mixture obtained in step S222 has cooled to room temperature, concentrate it under reduced pressure and purify it; Step S3 is as follows: S31. Mix an aqueous solution of a nitrophenylpyrazole compound, Fe, NH4Cl, and methanol; S32. React the mixture obtained in step S31 under a nitrogen atmosphere at 65±5℃ until the reaction is complete; S33. After the mixture obtained in step S32 has cooled to room temperature, filter, extract, dry the organic layer, and concentrate under reduced pressure.

2. The method for synthesizing aminophenylpyrazole compounds according to claim 1, characterized in that, Step S1 is as follows: S11. Mix 4-chloro-3-nitroacetophenone, DMF-DMA and N,N-dimethylformamide; S12. React the mixture obtained in step S11 at 120±5℃ with stirring until the reaction is complete; S13. Quench the mixture obtained in step S12, extract, dry the organic layer solution, concentrate under reduced pressure, and purify.

3. The method for synthesizing aminophenylpyrazole compounds according to claim 2, characterized in that, In step S11, the amount of DMF-DMA added is 2.0 ± 0.2 times the molar amount of 4-chloro-3-nitroacetophenone; and / or In step S12, the reaction endpoint is monitored by thin-layer chromatography; and / or In step S13, the mixture is quenched with water; and / or the quenched mixture is extracted with ethyl acetate; and / or the organic layer is dried with anhydrous sodium sulfate; and / or purified by washing followed by drying after concentration under reduced pressure.

4. The method for synthesizing aminophenylpyrazole compounds according to claim 1, characterized in that, In steps S211 and / or S221, the amount of hydrazine compound added is 1.5 ± 0.2 times the molar amount of N,N-dimethylenamino ketone compound, and / or the amount of acetic acid added is 1.0 ± 0.2 times the molar amount of N,N-dimethylenamino ketone compound; and / or In steps S212, S215, and / or S222, the reaction endpoint is monitored by thin-layer chromatography; and / or In step S214, the amount of 3,4-dihydro-2H-pyran added is 3.0 ± 0.5 times the molar amount of the intermediate product.

5. The method for synthesizing aminophenylpyrazole compounds according to claim 1, characterized in that, In steps S213, S216 and / or S223, after concentration under reduced pressure, the product is purified by silica gel column chromatography using a mobile phase with petroleum ether / ethyl acetate as the eluent, or by washing and drying.

6. The method for synthesizing aminophenylpyrazole compounds according to claim 1, characterized in that, In step S213, after vacuum concentration, the product is purified by washing followed by drying, with petroleum ether used for washing.

7. The method for synthesizing aminophenylpyrazole compounds according to claim 1, characterized in that, In step S31, the amount of Fe added is 5.0 ± 1.0 times the molar amount of the nitrophenylpyrazole compound, and / or the amount of NH4Cl added is 10.0 ± 2.0 times the molar amount of the nitrophenylpyrazole compound; and / or In step S32, the reaction endpoint is monitored by thin-layer chromatography; and / or In step S33, the mixture is filtered with diatomaceous earth, and / or the filtrate is extracted with ethyl acetate, and / or the organic layer is dried with anhydrous sodium sulfate.

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