A method for synthesizing 6-chloro-2-methyl-2H-indazol-5-amine

Abstract

A method for synthesizing 6-chloro-2-methyl-2H-indazol-5-amine. In view of the problems of low safety, low selectivity, low yield and difficulty in obtaining high-purity products in the existing synthetic route of 6-chloro-2-methyl-2H-indazol-5-amine, the present invention specifically includes the following reaction steps: 1) The compound of formula A03 is cyclized under the action of sodium nitrite to form the compound of formula A04; 2) A methyl group is added to the compound of formula A04 under the condition of Me3OBF4 to obtain the compound of formula A05; 3) The compound of formula A05 is coupled under the action of a catalyst to obtain the compound of formula B06. 4) The PMB is removed from the compound of formula B06 under the action of trifluoroacetic acid to obtain the final product. Using the synthetic method of the present invention to synthesize 6-chloro-2-methyl-2H-indazol-5-amine, the process route is novel and has the characteristics of short route, high chemical purity, easy production, green safety and environmental protection, etc.

Description

Technical Field

[0001] The present invention belongs to the field of organic chemical synthesis, and specifically relates to a synthesis method of 6-chloro-2-methyl-2H-indazol-5-amine. Background Art

[0002] 6-Chloro-2-methyl-2H-indazol-5-amine is a key intermediate for synthesizing S-217622, a compound for treating COVID-19 developed by Shionogi. Ensitrelvir (S-217622) is the first orally active, non-covalent, non-peptide SARS-CoV-2 3CL protease inhibitor. Shionogi announced the completion of the analysis of the phase IIb clinical trial of the oral COVID-19 drug S-217622 and applied to the Ministry of Health, Labour and Welfare of Japan for production and sales approval based on the phase IIb clinical data.

[0003]

[0004] Structural formula of 6-chloro-2-methyl-2H-indazol-5-amine

[0005] Currently, the main synthetic route for preparing this intermediate, 6-chloro-2-methyl-2H-indazol-5-amine, is as shown in the following figure. This route has a long reaction step, and the second step is a nitration reaction, so the production capacity will be limited during large-scale production. The selectivity is poor during the synthesis of the 6-chloro-5-nitro-2H-indazole compound in the fourth step, and there are great potential safety hazards during the reduction synthesis of the final product, 6-chloro-2-methyl-2H-indazol-5-amine, in the sixth step, making it not suitable for large-scale production.

[0006]

[0007] In summary, the development of COVID-19 drugs requires pharmaceutical intermediates such as 6-chloro-2-methyl-2H-indazol-5-amine, but there is still much room for improvement in its current synthesis methods. Summary of the Invention

[0008] Aiming at the problems of low safety, low selectivity, low yield, and difficulty in obtaining high-purity products in the existing synthetic route of 6-chloro-2-methyl-2H-indazol-5-amine, the present invention provides a new method for synthesizing 6-chloro-2-methyl-2H-indazol-5-amine.

[0009] To improve the problems of the existing long route, low yield, poor green environmental protection, and great potential safety hazards, the present invention provides a new method for synthesizing 6-chloro-2-methyl-2H-indazol-5-amine. Specifically, it includes the following reaction steps:

[0010] 1) The compound of formula A03 undergoes ring closure under the action of sodium nitrite to form the compound of formula A04;

[0011] The specific operation is as follows:

[0012] Add AcOH (10 vol.) and A03 (1.0 eq.) into a three-necked flask, stir until clear, and slowly add dropwise an aqueous solution (0.5 vol.) of sodium nitrite (1.1 eq.) to the reaction solution. Stir at room temperature for 16 h, and take a sample for HPLC in-process control.

[0013] Work-up: Cool the reaction solution to 10 - 15 °C, then slowly add dropwise (2 h) (20 vol.) of ice water to the reaction solution. After the addition, stir for 0.5 h. Filter, wash the filter cake with ice water (2 vol.), then wash with n-heptane (2 vol.), and dry the filter cake to obtain yellow solid A04.

[0014] 2) Add a methyl group to the compound of formula A04 under the condition of Me3OBF4 to obtain the compound of formula A05.

[0015] The specific operation is as follows:

[0016] Add the crude product A04 (1.0 eq.) from Step 1 into a three-necked flask, add EtOAc (12 vol.), and add a chloroform (2 vol.) suspension of Me3OBF4 (1.0 eq.). Stir at room temperature and take a sample for HPLC in-process control.

[0017] Work-up: Filter to obtain a yellow solid. Add the yellow solid into a reaction flask, add EtOAc (20 vol.) and water (10 vol.), and stir until the yellow solid dissolves and becomes clear. After sufficient stirring, filter the insoluble matters with diatomaceous earth, separate the layers, wash the organic phase with saturated brine (5 vol. * 3), separate the layers again, pass the organic phase through flash silica gel, and concentrate under reduced pressure until no distillate is obtained to obtain yellowish-gray solid A05.

[0018] 3) Couple the compound of formula A05 under the action of a catalyst to obtain the compound of formula B06.

[0019] The specific operation is as follows:

[0020] Add A05 (1.0 eq.) into a three-necked flask, add p-methoxybenzylamine (1.2 eq.), add sodium tert-butoxide (3.0 eq.), add catalyst Pd(OAc)2 (0.02 eq.), add ligand BINAP (0.02 eq.), and add dioxane solution (10 vol.). Replace the air with nitrogen for protection, stir the reaction solution at 60 - 110 °C for about 16 h, and take a sample for HPLC in-process control.

[0021] Workup: The reaction solution was cooled to room temperature, filtered through diatomaceous earth, the filter cake was rinsed with EA, the filtrates were combined, and the filtrate was concentrated until no components flowed out. To the concentrated residue was added EtOAc (5 vol.) and water (3 vol.), and the mixture was stirred until clear. The organic phase was separated, concentrated and dried to obtain a purple-black solid B06.

[0022] 4) Compound B06 was deprotected with PMB under the action of trifluoroacetic acid to obtain the final product.

[0023] The specific operation is as follows:

[0024] B06 (1.0 eq.) was placed in a three-necked flask, DCM (5 vol.) was added, stirring was started, and an organic solvent (6.0 eq.) was added. After 16 h, a sample was taken for in-process control.

[0025] Workup: After the raw materials were consumed, the pH of the reaction solution was adjusted to 7 - 8 with saturated aqueous sodium bicarbonate, stirred for 0.5 h, separated, the organic phase was concentrated, and purified by column chromatography to obtain A0.

[0026] Alternatively, a method is provided as follows:

[0027] 1) Compound A03 was cyclized under the action of sodium nitrite to form compound A04;

[0028] The specific operation is as follows:

[0029] AcOH (10 vol.) and A03 (1.0 eq.) were added to a three-necked flask, stirred until clear, and an aqueous solution of sodium nitrite (1.1 eq.) in water (0.5 vol.) was added dropwise to the reaction solution, stirred at room temperature (16 h), and a sample was taken for HPLC in-process control.

[0030] Workup: The reaction solution was cooled to 10 - 15 °C, then ice water (20 vol.) was slowly added dropwise (2 h) to the reaction solution, stirred for 0.5 h after dropping, filtered, the filter cake was rinsed with ice water (2 vol.), then rinsed with n-heptane (2 vol.), and the filter cake was dried to obtain a yellow solid A04;

[0031] 2) Compound A04 was methylated under the condition of Me3OBF4 to obtain compound A05;

[0032] The specific operation is as follows:

[0033] The crude product A04 from Step 1 (1.0 eq.) was added to a three-necked flask, EtOAc (12 vol.) was added, and a chloroform (2 vol.) suspension of Me3OBF4 (1.0 eq.) was added, stirred at room temperature, and a sample was taken for HPLC in-process control.

[0034] Work-up: filtration to obtain a yellow solid. Dissolve the yellow solid in EtOAc (20 vol.) and water (10 vol.). After stirring well, filter the insoluble matter through diatomaceous earth, separate the layers. Wash the organic layer with saturated brine (5 vol. * 3), separate the layers. Pass the organic layer through flash silica gel, collect the eluent and concentrate it under reduced pressure until no distillate is obtained to get a yellowish-gray solid A05.

[0035] 3) Add A05 (2.46 g, 10 mmol, 1.0 eq.), Cu2O (143 mg, 1 mmol, 0.1 eq.), 1,10-phenanthroline (1,10 - o-phenanthroline, 180 mg, 1 mmol, 0.1 eq.), K3PO4 (4.24 g, 20 mmol, 2.0 eq.), 20% aqueous ammonia (15 mL), and DMSO (15 mL) into a high-pressure reactor. Replace the air in the reactor with nitrogen for protection. Place the reactor in an oil bath at 60 - 150 °C and react for 24 hours. After the reaction is completed, cool the reaction solution to room temperature. Add water and EtOAc to the reaction solution, separate the layers. Extract the aqueous layer with EtOAc. Combine the organic layers, wash with saturated brine 4 times, dry over anhydrous sodium sulfate, filter, collect the organic layer and concentrate it under reduced pressure to obtain the crude product. Purify the obtained crude product by column chromatography to obtain the target compound A0 (1.57 g, 87% yield).

[0036] The reaction route is as follows:

[0037]

[0038] A typical reaction route is as follows, where X is bromine and R is H:

[0039]

[0040] Preferred embodiments of the present invention:

[0041] 1) Preferably, in the starting materials of compounds A03, A04, and A05, the X position is iodine or bromine, and it is preferred to use bromo compounds as the starting materials;

[0042] 2) Preferably, the coupling reagent in step 3) is at least one of BocNH2 or p-methoxybenzylamine, and R can be a protecting group such as H, benzyl, p-methoxybenzyl, Boc, Cbz, or Formoc;

[0043] 3) Preferably, the deprotecting reagent in step 4) is at least one of ammonium cerium(IV) nitrate and trifluoroacetic acid.

[0044] Using the synthesis method of the present invention to synthesize 6-chloro-2-methyl-2H-indazol-5-amine, the process route is novel, with the characteristics of short route, high chemical purity, easy production, green, safe, and environmentally friendly, as follows:

[0045] 1) The starting materials are inexpensive, and the ring closure to obtain Compound A04 can be achieved using sodium nitrite, avoiding the use of a nitration reaction route with limited production capacity. The original route consisted of 6 steps, while the route of the present invention is a 3-step or 4-step method, and the overall yield can reach over 63%.

[0046] 2) During the process of obtaining Compound A05 using a methylation reagent from Compound A04, the methylation position on the methyl group is selective. Both positions of the two nitrogens in A04 can be methylated. We choose to use Me3OBF4 as the methylation reagent, and its selectivity is 100%. Description of the Drawings

[0047] Figures 1-3 LC-MS spectrum in the LCMS of A04;

[0048] Figure 4 1H NMR spectrum of A04;

[0049] Figures 5-7 LCMS spectrum of A05;

[0050] Figure 8 1H NMR spectrum of A05;

[0051] Figure 9 2D 1H NMR spectrum of A05;

[0052] Figure 10 LC-MS spectrum of B06;

[0053] Figure 11 Positive signal of the MS spectrum in the LCMS of B06;

[0054] Figure 12 MS spectrum in the LCMS of B06;

[0055] Figure 13 1H NMR spectrum of A0;

[0056] Figures 14-16 LC-MS spectrum of A0. Detailed Embodiments

[0057] Example 1

[0058] Step 1

[0059] Add acetic acid AcOH (400 mL) and A03 (40.0 g, 1.0 eq.) to a three-necked flask, stir until clear, and add dropwise a solution of sodium nitrite (13.77 g, 1.1 eq.) in water (27 mL) to the reaction solution. Stir at room temperature overnight (16 h). After confirming by HPLC that there is no raw material, perform post-treatment. The intermediate control purity of A04 is 75.67%.

[0060] A03 is as follows:

[0061] Post-treatment: Cool the reaction solution to 10 - 15 °C, then slowly add 800 mL of ice water dropwise (over 2 h) to the reaction solution. After dropping, stir for 0.5 h. Filter, wash the filter cake with ice water (100 mL), then wash with n-heptane (100 mL), and dry the filter cake to obtain 33.5 g of yellow solid A04, with a yield of 79.8%.

[0062] Characterization data of A04: 1 H NMR (400 MHz, DMSO): δ 13.35 (s, 1H), 8.25 (s, 1H), 8.10 (s, 1H), 7.87 (s, 1H).

[0063] Figures 1-3 This is the LC-MS spectrum of A04. It can be seen from the figure that the MS positive ion signal of A04 is consistent with the structure.

[0064] Figure 4 This is the HNMR spectrum of A04. It can be seen from the figure that the structure of A04 is correct.

[0065] Step 2

[0066] Add compound A04 (1.0 g, 1.0 eq.) to a three-necked flask, add ethyl acetate EtOAc (20 mL), and add a chloroform suspension of trimethyloxonium tetrafluoroborate Me3OBF4 (1.1 eq.). Stir at room temperature for 0.5 h, take a sample for in-process control inspection. After there is no raw material left, carry out post-treatment.

[0067] Post-treatment: Filter, dissolve the filter cake with EA and water and then separate the layers. Wash the organic layer with saturated brine, separate the layers, and concentrate the organic layer to dryness to obtain 0.96 g of yellow solid A05, with a yield of 90.4% and a selectivity of 100%.

[0068] Characterization data of A05: 1 H NMR (400 MHz, DMSO): δ 8.41 (s, 1H), 8.23 (s, 1H), 7.95 (s, 1H), 4.18 (s, 3H).

[0069] Figures 5-7 This is the LCMS spectrum of A05. It can be seen from the figure that the MS positive ion signal of A05 is consistent with the structure.

[0070] Figure 8 This is the HNMR spectrum of A05 Figure 9 This is the two-dimensional 1H NMR spectrum of A05. From Figures 8-9It can be determined that the structure of A05 is correct, with a methyl group at the 2-position and no isomeric impurities.

[0071] Step 3

[0072] A05 (31.0 g, 1.0 eq.) was added to a three-necked flask, and p-methoxybenzylamine (20.79 g, 1.2 eq.), potassium carbonate (0.34 g, 3.0 eq.), CuI (0.0155 g, 0.1 eq.), DMSO (2 mL), and 1,10-phenanthroline (0.0294 g, 0.2 eq.) were added. Under nitrogen protection, the mixture was refluxed at 100 °C for 16 h, and the reaction was monitored by HPLC sampling. After post-treatment, the target intermediate B06 was obtained in a yield of 85%. B06 is

[0073] Figure 10 The LC-MS spectrum of B06 is shown. It can be seen from the figure that the positive ion signal of B06 is consistent with the structure.

[0074] Figure 11 This is the positive signal in the MS spectrum of B06 in LCMS;

[0075] Figure 12 This is the MS spectrum of B06 in LCMS.

[0076] Step 4

[0077] B06 (45.0 g, 1.0 eq.) was placed in a three-necked flask, DCM (225 mL, 5 vol.) was added, stirring was started, and trifluoroacetic acid (102.01 g, 6.0 eq.) was added. After 16 h, the reaction was monitored by sampling. Post-treatment: After the raw materials were consumed, the pH of the reaction solution was adjusted to 7-8 with saturated aqueous sodium bicarbonate, stirred for 0.5 h, and then separated by liquid-liquid extraction. The organic phase was concentrated to obtain the product of formula A0 in a yield of 95% and a purity of 99.35%.

[0078] Characterization data of A0: 1 H NMR (400 MHz, DMSO): δ 7.98 (s, 1H), 7.58 (s, 1H), 6.88 (s, 1H), 4.94 (s, 2H), 4.06 (s, 3H).

[0079] Figure 13 This is the HNMR spectrum of A0. It can be seen from the figure that the NMR spectrum of A0 is consistent with the structure.

[0080] Figures 14-16 This is the LC-MS spectrum of A0. It can be seen from the figure that the positive ion signal of A0 is consistent with the structure.

[0081] Example 2

[0082] In this embodiment, the method for preparing A05 can be the method in Embodiment 1 or other methods.

[0083] Step 3

[0084] Add A05 (2.46 g, 10 mmol, 1.0 eq.), Cu2O (143 mg, 1 mmol, 0.1 eq.), 1,10-phenanthroline (180 mg, 1 mmol, 0.1 eq.), K3PO4 (4.24 g, 20 mmol, 2.0 eq.), 20% aqueous ammonia (15 mL), and DMSO (15 mL) into a high-pressure reactor. Replace the air in the reactor with nitrogen for protection. Place the reactor in an oil bath at 140 °C and react for 24 hours. After the reaction is completed, cool the reaction solution to room temperature. Add water and EtOAc to the reaction solution, separate the layers, and extract the aqueous layer with EtOAc. Combine the organic layers, wash them 4 times with saturated brine, dry over anhydrous sodium sulfate, filter, and collect the organic layer. Concentrate it under reduced pressure to obtain the crude product. Purify the obtained crude product by column chromatography to obtain the target compound A0 (1.57 g, 87% yield).

[0085] Example 3

[0086] Step 2

[0087] Add compound A04 (1.0 g, 1.0 eq.) into a three-necked flask, add THF (20 mL), add methyl iodide (1.0 eq.), add Cy2NMe (1.0 eq.), stir at room temperature for 0.5 h, take a sample for in-process control inspection. After no raw materials are detected, carry out post-treatment.

[0088] Post-treatment: Filter, dissolve the filter cake with EtOAc and water, separate the layers, wash the organic layer with saturated brine, separate the layers, concentrate the organic layer to dryness to obtain a yellow solid A05, with a yield of 75% and a methylation selectivity of 100%.

[0089] Example 4

[0090] In this embodiment, the method used in Step 2 is as follows, and the other steps are the same as those in Embodiment 1.

[0091] Step 2

[0092] Add compound A04 (1.0 g, 1.0 eq.) into a three-necked flask, add DCM (20 mL), add CCl3CNHOMe (1.0 eq.), add CF3SO3H (1.0 eq.), keep stirring at 30 °C for 0.5 h, take a sample for in-process control inspection. After no raw materials are detected, carry out post-treatment.

[0093] Work-up: filtration. The filter cake was dissolved with EA and water, and then separated by liquid separation. The organic phase was washed with saturated brine, separated by liquid separation, and the organic phase was concentrated to dryness to obtain yellow solid A05 with a yield of 90% and a methylation selectivity of 100%.

[0094] Example 5

[0095] Step 3

[0096] A05 (2.0 g, 1.0 eq.) was added to a three-necked flask, and BocNH2 (1.15 g, 1.2 eq.) was added. Potassium phosphate (5.19 g, 3.0 eq.) was added, catalyst Pd(OAc)2 (0.0366 g, 0.02 eq.) was added, ligand XantPhos (0.1886 g, 0.04 eq.) was added, and dioxane solution (40 mL, 20 vol.) was added. Under nitrogen protection, reflux at 100 °C for 16 h, and HPLC was used for in-process control of the sample. The purity of product A06 was 88.84%.

[0097] A06 is The protecting group of A06 is the Boc protecting group.

[0098] Example 6

[0099] In this example, the method used in Step 3 is as follows, and the other steps are the same as those in Example 1.

[0100] Step 3

[0101] A05 (31.0 g, 1.0 eq.) was added to a three-necked flask, and p-methoxybenzylamine (20.79 g, 1.2 eq.), potassium carbonate (0.34 g, 3.0 eq.), CuI (0.0155 g, 0.1 eq.), DMSO (2 mL), and 1,10-phenanthroline (0.0294 g, 0.2 eq.) were added. Under nitrogen protection, reflux at 100 °C for 16 h, and HPLC was used for in-process control of the sample. After work-up, the target intermediate B06 was obtained with a yield of 85%.

[0102] Example 7

[0103] In this example, the method used in Step 3 is as follows, and the other steps are the same as those in Example 1.

[0104] Step 3

[0105] A05 (31.0 g, 1.0 eq.) was added to a three-necked flask, followed by the addition of PMBNH2 (20.79 g, 1.2 eq.), sodium tert-butoxide (36.40 g, 3.0 eq.), the catalyst Pd(OAc)2 (0.5670 g, 0.02 eq.), the ligand BINAP (3.1491 g, 0.02 eq.), and a dioxane solution (310 mL, 10 vol.). Under nitrogen protection, the mixture was refluxed at 100 °C for 16 h, and HPLC was used for in-process control by sampling.

[0106] Workup: The reaction mixture was cooled to room temperature and filtered through diatomaceous earth. The filter cake was rinsed with EA, and the filtrates were combined and concentrated until no more components flowed out. The residue was dissolved in EA (100 mL) and water (50 mL), and the layers were separated. The organic phase was concentrated to dryness to obtain a purple-black solid B06.

[0107] Example 8

[0108] In this example, the method for preparing B06 can be the method in Example 1 or other methods.

[0109] Step 4

[0110] B06 (1.0 g, 1.0 eq.) was placed in a three-necked flask, and acetonitrile (1 mL, 1 vol.) and water (1 mL, 1 vol.) were added. Stirring was started, and ammonium cerium(IV) nitrate (0.37 g, 2.5 eq.) was added in portions. After stirring at room temperature for 16 h, in-process control was carried out by sampling. Workup: After the raw materials were consumed, the pH of the reaction mixture was adjusted to 7 - 8 with saturated aqueous sodium bicarbonate solution, stirred for 0.5 h, and then the layers were separated. The organic phase was concentrated and purified by column chromatography to obtain A0 with a yield of 70%.

[0111] Example 9

[0112] In this example, the method for preparing B06 can be the method in Example 1 or other methods.

[0113] Step 4

[0114] B06 (45.0 g, 1.0 eq.) was placed in a three-necked flask, DCM (225 mL, 5 vol.) was added, and stirring was started. Trifluoroacetic acid (102.01 g, 6.0 eq.) was added, and in-process control was carried out by sampling after 16 h. Workup: After the raw materials were consumed, the pH of the reaction mixture was adjusted to 7 - 8 with saturated aqueous sodium bicarbonate solution, stirred for 0.5 h, and then the layers were separated. The organic phase was concentrated to obtain the product of formula A0 with a yield of 95%.

[0115] 11H NMR (400 MHz, DMSO): δ 7.98 (s, 1H), 7.58 (s, 1H), 6.88 (s, 1H), 4.94 (s, 2H), 4.06 (s, 3H).

[0116] Example 10

[0117] In this example, the method for preparing A05 can be the method in Example 1 or other methods. In this example, steps 3 and 4 are not used for A05, but step 5 (i.e., step 5 in the reaction roadmap).

[0118] Add A05 (2.46 g, 10 mmol, 1.0 eq.), Cu2O (143 mg, 1 mmol, 0.1 eq.), 1,10-phenanthroline (180 mg, 1 mmol, 0.1 eq.), K3PO4 (4.24 g, 20 mmol, 2.0 eq.), 20% aqueous ammonia (15 mL), and DMSO (15 mL) into a high-pressure reactor. Replace the gas in the reactor with nitrogen for protection. Place the reactor in an oil bath at 140 °C and react for 24 hours. After the reaction is completed, cool the reaction solution to room temperature. Add water and EtOAc to the reaction solution, separate the layers, and extract the aqueous phase with EtOAc. Combine the organic phases, wash them 4 times with saturated brine, dry over anhydrous sodium sulfate, filter, collect the organic phase, and concentrate it under reduced pressure to obtain the crude product. Purify the obtained crude product by column chromatography to obtain the target compound A0 (1.57 g, 87% yield).

Claims

1. A method for synthesizing 6-chloro-2-methyl-2H-indazol-5-amine, characterized in that, The method comprises the following steps: 1) Compound A03 is subjected to ring closure under the action of sodium nitrite to generate compound A04; 2) Compound A04 is treated with Me3OBF4 to add a methyl group to obtain compound A05; 3) Add A05, Cu2O, 1,10-phenanthroline, K3PO4, 20% aqueous ammonia, DMSO into a high-pressure reactor. Replace the gas in the reactor with nitrogen for protection. Place the reactor in an oil bath at 60 - 150 o °C for reaction. After the reaction is completed, cool the reaction solution to room temperature. Add water and EtOAc to the reaction solution, separate the layers, and extract the aqueous phase with EtOAc. Combine the organic phases, wash, dry, filter, collect the organic phase, and concentrate it under reduced pressure to obtain the crude product. Purify the obtained crude product to get the target compound A0; where A03 is , A04 is , A05 is , A0 is ; X is iodine or bromine.

2. The method for synthesizing 6-chloro-2-methyl-2H-indazol-5-amine as claimed in claim 1, wherein The method described is to replace the above step 3) with the following steps: 3.1) Add A05 to the reaction vessel, and then successively add the coupling reagent, sodium tert-butoxide, the catalyst and the ligand BINAP. Then add the dioxane solution, displace the nitrogen for protection, and react at 60 - 110 o °C; The reaction solution was cooled to room temperature, filtered, the filter cake was washed, the filtrate was combined, and the filtrate was concentrated until no component flowed out, and then the filtrate was dissolved with EtOAc and water, separated, and the organic phase was concentrated and dried to obtain B06; The coupling reagent is p-methoxybenzylamine; Among which, B06 is ; The catalyst is Pd(OAc)2; 3.2) Place B06 in a reaction vessel, add DCM, start stirring, add a deprotection reagent, and react; the deprotection reagent is ammonium cerium nitrate or trifluoroacetic acid; After the reaction is completed, the pH of the reaction solution is adjusted to 7-8, the solution is separated after stirring, the organic phase is concentrated, and purified by column to obtain A0.

3. The method for synthesizing 6-chloro-2-methyl-2H-indazol-5-amine according to claim 1, wherein The specific steps of step 1) are: Add AcOH and A03 into the reaction vessel, stir to clarify, add an aqueous solution of sodium nitrite dropwise into the reaction solution, and stir at room temperature until the reaction is complete; The reaction solution was cooled to 10-15°C, and then ice water was slowly added dropwise to the reaction solution. After the addition was completed, stirring was continued, the solution was filtered, the filter cake was rinsed, and the filter cake was dried to obtain a yellow solid A04.

4. The method for synthesizing 6-chloro-2-methyl-2H-indazol-5-amine according to claim 1, characterized in that, The specific steps of step 2) are: Add the crude product A04 from step 1) to a reaction vessel, add EtOAc, add a chloroform suspension of Me3OBF4, and stir at room temperature overnight; The reaction solution was filtered to obtain a yellow solid. The yellow solid was dissolved with EtOAc and water. After sufficient stirring, the insoluble matter was filtered out, the liquids were separated, the organic phase was washed, the liquids were separated, the organic phase was passed through rapid silica gel, and the eluent was concentrated to obtain a yellow-gray solid A05.

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