A preparation method of indacaterol intermediate 5,6-diethyl-2,3-dihydro-1H-inden-2-amine hydrochloride

Abstract

The invention relates to a method for preparing an indacaterol intermediate 5,6-diethyl-2,3-dihydro-1H-inden-2-amine hydrochloride, comprising the following steps: 1,3-dihydro-2H-inden-2-one and hydroxylamine hydrochloride are subjected to an oximation reaction to obtain 1,3-dihydro-2H-inden-2-ketone oxime; 1,3-dihydro-2H-inden-2-ketone oxime is subjected to a bromination reaction to obtain 5,6-dibromo-1,3-dihydro-2H-inden- 2-ketoxime; 5,6-dibromo-1,3-dihydro-2H-indene-2-ketoxime and vinyl n-butyl ether are subjected to Heck reaction and then hydrolyzed to obtain 5,6-diacetyl-1,3-dihydro-2H-indene-2-ketoxime; 5,6-diacetyl-1,3-dihydro-2H-indene-2-ketoxime is subjected to hydrogenation reaction and then salted to obtain the target product 5,6-diethyl-2,3-dihydro-1H-indene-2-amine hydrochloride. The invention is easy to scale up industrially and has low cost.

Description

Technical Field

[0001] The invention relates to a method for preparing a drug intermediate, and belongs to the technical field of preparation of chemical raw material drug intermediates. Background Art

[0002] 5,6-Diethyl-2,3-dihydro-1H-indene-2-amine hydrochloride is a key intermediate of Indacaterol, and its structural formula is shown in Chemical Formula 1. Indacaterol, whose trade name is Onrun, is a drug produced by Novartis Pharmaceuticals in Switzerland for the treatment of COPD. It is the first inhaled long-acting β2 receptor agonist (LABA) approved by SFDA in China for the maintenance treatment of patients with stable chronic obstructive pulmonary disease (COPD). The structural formula is shown in Chemical Formula 2.

[0003]

[0004] Chronic obstructive pulmonary disease (COPD) is a common chronic disease characterized by chronic bronchitis and / or emphysema with airflow obstruction, which can further develop into cor pulmonale and respiratory failure. It is related to abnormal inflammatory response to harmful gases and particles, with high disability and mortality rates. The global incidence rate of people over 40 years old has reached 9% to 10%. Indacaterol is a new ultra-long-acting β2 receptor agonist. The drug was approved by the US FDA on July 1, 2011 for the treatment of patients with chronic bronchial obstructive disease (COPD) airflow obstruction, including chronic bronchitis and / or emphysema. As the most critical intermediate of indacaterol, 5,6-diethyl-2,3-dihydro-1H-indene-2-amine hydrochloride has good market prospects and economic benefits.

[0005] The currently reported preparation methods of 5,6-diethyl-2,3-dihydro-1H-inden-2-amine hydrochloride are mainly the following.

[0006] Mahavir Prashad et al. first reported the commercial synthesis route of the compound in 2006 (Organic Process Research & Development 2006, 10, 135-141), as shown in chemical reaction formula 1. The method uses 2-aminoindan as the starting material, uses trifluoroacetic acid ethyl to protect the amino group, undergoes two-step Friedel-Crafts reaction, two-step palladium carbon reduction reaction, and finally deprotects the salt to obtain the target compound. Fu Qingquan et al. used the same route, and based on the process, changed the first step of trifluoroacetyl protection to acetyl protection (CN108752220A). The starting material price of this route is relatively high, the reaction steps are relatively long, and a large amount of waste acid water is generated in the two-step Friedel-Crafts reaction, which is not conducive to industrial production.

[0007]

[0008] Francois Baur et al. reported in 2010 that o-diethylbenzene was used as the starting material to prepare the compound (J. Med. Chem. 2010, 53, 3675-3684), as shown in chemical reaction formula 2. 1,2-diethylbenzene was used as the starting material, and 5,6-diethyl-2,3-dihydro-1H-indene-2-amine hydrochloride was obtained through Friedel-Crafts, cyclization, oximation, reduction and other reactions. The starting material o-diethylbenzene of this route is not commercially produced and is expensive. In addition, a large number of isomers are generated in the second step of the cyclization reaction, which is not convenient for separation and purification by conventional methods. The entire route is difficult to industrialize and the cost is high.

[0009]

[0010]

[0011] Wang Kunpeng et al. prepared the compound (CN110183330A) using 2-indanol as the starting material, as shown in chemical reaction formula 3. Using 2-indanol as the starting material, the target compound was prepared through six steps of acetyl protection, bromination, deprotection, azidation and reduction to salt. This route has a long number of steps and uses azide, which poses a great safety hazard. The economy and safety of the entire process are not good, which is not conducive to industrial production.

[0012] Summary of the invention

[0013] The object of the present invention is to provide a method for preparing 5,6-diethyl-2,3-dihydro-1H-indene-2-amine hydrochloride which is easy to scale up industrially and has low cost.

[0014] The preparation method of 5,6-diethyl-2,3-dihydro-1H-inden-2-amine hydrochloride, the synthesis route of which is shown in chemical reaction formula 4:

[0015]

[0016] Chemical reaction formula 4

[0017] The technical solution adopted by the present invention is:

[0018] A method for preparing an indacaterol intermediate 5,6-diethyl-2,3-dihydro-1H-inden-2-amine hydrochloride comprises the following steps:

[0019] Step 1: Under the action of a solvent and a base, 1,3-dihydro-2H-inden-2-one and hydroxylamine hydrochloride undergo an oximation reaction to obtain 1,3-dihydro-2H-inden-2-one oxime;

[0020] Step 2: 1,3-dihydro-2H-indene-2-one oxime is subjected to bromination reaction to obtain 5,6-dibromo-1,3-dihydro-2H-indene-2-one oxime;

[0021] Step 3: 5,6-dibromo-1,3-dihydro-2H-inden-2-one oxime is reacted with vinyl n-butyl ether under the action of palladium catalyst and then hydrolyzed by Heck reaction to obtain 5,6-diacetyl-1,3-dihydro-2H-inden-2-one oxime;

[0022] Step 4: 5,6-diacetyl-1,3-dihydro-2H-inden-2-one oxime is subjected to hydrogenation reaction in a hydrogen atmosphere under the action of palladium carbon (10%) catalyst to obtain the target product 5,6-diethyl-2,3-dihydro-1H-inden-2-amine hydrochloride. Preferably,

[0023] The solvent used in step 1 is ethanol, methanol, tetrahydrofuran or a mixed solvent thereof; the weight ratio of the solvent used to 1,3-dihydro-2H-indene-2-one is 3:1-10:1.

[0024] Preferably,

[0025] The base used in step 1 is one or more of pyridine, triethylamine, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide and potassium hydroxide; the molar ratio of the base used to 1,3-dihydro-2H-inden-2-one is 1:1-5:1;

[0026] The molar ratio of 1,3-dihydro-2H-inden-2-one to hydroxylamine hydrochloride used in step 1 is 1:1.2-1:1.4;

[0027] Step 1: The reaction temperature is 20°C-80°C; the reaction time is 8h.

[0028] Preferably,

[0029] The bromination reagent used in the bromination reaction in step 2 is N-bromosuccinimide or bromine; the molar ratio of the bromination reagent to 1,3-dihydro-2H-indene-2-one oxime is 2:1-4:1.

[0030] Preferably,

[0031] The solvent used in step 2 is acetonitrile, dichloromethane or 1,2-dichloroethane; the weight ratio of the solvent to 1,3-dihydro-2H-indene-2-one oxime is 3:1-10:1;

[0032] The reaction temperature of step S2 is 20°C-55°C; the reaction time of step S2 is 12h.

[0033] Preferably,

[0034] The solvent used in step 3 is dimethyl sulfoxide (DMSO), N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, toluene or acetonitrile; the weight ratio of the solvent used to 5,6-dibromo-1,3-dihydro-2H-indene-2-one oxime is 2:1-10:1.

[0035] Preferably,

[0036] The palladium catalyst used in step 3 is one or more of bistriphenylphosphine palladium dichloride ([PdCl2(PPh3)2]), 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride ([PdCl2(dppf)]), [1,3-bis(diphenylphosphino)propane]palladium chloride ([PdCl2(dppp)]), and 1,2-bis(diphenylphosphino)ethane palladium dichloride ([PdCl2(dppe)]); the molar ratio of 5,6-dibromo-1,3-dihydro-2H-inden-2-one oxime to the palladium catalyst is 1000:1-10:1;

[0037] In step 3, the molar ratio of 5,6-dibromo-1,3-dihydro-2H-indene-2-one oxime to vinyl n-butyl ether is 1:2.2-1:3. Preferably,

[0038] Step 3: The base used in the hydrolysis reaction is triethylamine, N,N,N',N'-tetramethylethylenediamine (TMEDA), 1,2,2,6,6-pentamethylpiperidine, N,N-dimethylaniline, 4-dimethylaminopyridine, potassium carbonate or sodium carbonate; the molar ratio of the base used to 5,6-dibromo-1,3-dihydro-2H-inden-2-one oxime is 2:1-1:1;

[0039] Step 3 Heck reaction: the reaction temperature is 80°C-160°C, and the reaction time is 36h;

[0040] Step 3: Hydrolysis reaction: The reaction temperature is 10-25°C and the reaction time is 1h.

[0041] Preferably,

[0042] In step 4, the weight ratio of 5,6-diacetyl-1,3-dihydro-2H-indene-2-one oxime to palladium carbon is 10:1-100:1, and the mass fraction of palladium in palladium carbon is 10%.

[0043] Preferably,

[0044] In step 4, the solvent used for 5,6-diacetyl-1,3-dihydro-2H-indene-2-one oxime is ethyl acetate, ethanol, methanol, tetrahydrofuran or 1,4-dioxane; the weight ratio of the solvent used to 5,6-diacetyl-1,3-dihydro-2H-indene-2-one oxime is 4:1-10:1;

[0045] In step 4, the pressure of hydrogen is 5 atm-40 atm;

[0046] The reaction temperature of step 4 is 25°C-100°C; the reaction time is 6h.

[0047] The room temperature of the present invention is 4-39°C.

[0048] Beneficial effects of the present invention:

[0049] The route of the present invention has a wide range of starting raw materials, low production cost, mild reaction conditions, simple operation, easy purification of products, environmental friendliness, and high total yield. The present invention has a short reaction step, generates less wastewater, has low cost, and is suitable for large-scale industrial production. The present invention does not generate isomers, is easy to separate and purify using conventional methods, and the whole route has low industrial difficulty, low cost, and high economic value. BRIEF DESCRIPTION OF THE DRAWINGS

[0050] Figure 1 is the HPLC chromatogram of 1,3-dihydro-2H-indene-2-one oxime;

[0051] Figure 2 is the HPLC chromatogram of 5,6-dibromo-1,3-dihydro-2H-indene-2-one oxime;

[0052] Figure 3 is the HPLC chromatogram of 5,6-diethyl-2,3-dihydro-1H-inden-2-amine hydrochloride;

[0053] Figure 4 1,3-Dihydro-2H-indene-2-one oxime 1 H-NMR spectrum;

[0054] Figure 5 5,6-dibromo-1,3-dihydro-2H-inden-2-one oxime 1 H-NMR spectrum;

[0055] Figure 6 5,6-diacetyl-1,3-dihydro-2H-inden-2-one oxime 1 H-NMR spectrum;

[0056] Figure 7 5,6-diethyl-2,3-dihydro-1H-inden-2-amine hydrochloride 1 H-NMR spectrum. DETAILED DESCRIPTION

[0057] The following examples are used to illustrate the present invention. However, these examples are only limited to the purpose of illustrating the present invention and are not intended to limit the scope of the present invention in any form.

[0058] Step 1: Preparation of 1,3-dihydro-2H-indene-2-one oxime

[0059] Example 1

[0060] Under nitrogen protection, 1,3-dihydro-2H-indene-2-one (132.0 g, 1.0 mol) and 700 ml of anhydrous ethanol were added to a 2L three-necked flask. After stirring at room temperature for 30 minutes, hydroxylamine hydrochloride (104.2 g, 1.5 mol) was added to the system. Stirring at room temperature for 30 minutes, sodium hydroxide (80.0 g, 2.0 mol) was added to the system, and the reaction body was heated to 40°C for 8 hours. Then, most of the ethanol was removed by distillation under reduced pressure. After the temperature dropped to room temperature, it was filtered and the solid was dried in a vacuum drying oven to obtain 1,3-dihydro-2H-indene-2-one oxime (138.5 g) with a purity of 97.5% and a yield of 94.2%. Figure 1 and Figure 4 .

[0061] Example 2

[0062] Under nitrogen protection, 1,3-dihydro-2H-indene-2-one (132.0 g, 1.0 mol) and 700 ml of anhydrous methanol were added to a 2L three-necked flask. After stirring at room temperature for 30 minutes, hydroxylamine hydrochloride (104.2 g, 1.5 mol) was added to the system. Stirring at room temperature for 30 minutes, triethylamine (202.4 g, 2.0 mol) was added to the system, and the reaction body was heated to 40°C for 8 hours. Then, most of the ethanol was removed by vacuum distillation. After the temperature dropped to room temperature, the filter cake was rinsed with 1L of water and the solid was dried in a vacuum drying oven to obtain 1,3-dihydro-2H-indene-2-one oxime (126.5 g) with a purity of 97.8% and a yield of 86.0%. Step 2: Preparation of 5,6-dibromo-1,3-dihydro-2H-indene-2-one oxime

[0063] Example 3

[0064] Under nitrogen protection, acetonitrile (300 ml), 1,3-dihydro-2H-indene-2-one oxime (73.5 g, 0.5 mol) and N-bromosuccinimide (267.0 g, 1.5 mol) were added to a 1L three-necked flask, stirred at room temperature for 12 hours, and distilled under reduced pressure to remove acetonitrile. The residue was poured into a mixed solvent consisting of 300 ml of dichloromethane and 200 ml of water, separated, the organic phase was washed with 100 ml of dilute hydrochloric acid, then washed with 100 ml of saturated brine, the organic phase was dried over anhydrous sodium sulfate, and the solvent was distilled under reduced pressure to obtain 5,6-dibromo-1,3-dihydro-2H-indene-2-one oxime (140.5 g) with a purity of 95.5% and a yield of 92.8%. Figure 2 and Figure 5 .

[0065] Example 4

[0066] Under nitrogen protection, 1,2-dichloroethane (300 ml), 1,3-dihydro-2H-indene-2-one oxime (73.5 g, 0.5 mol) and N-bromosuccinimide (267.0 g, 1.5 mol) were added to a 1L three-necked flask and stirred at room temperature for 12 hours. 300 ml of dilute hydrochloric acid was added to the reaction system, and the mixture was fully stirred and separated. The organic phase was washed with 100 ml of dilute hydrochloric acid and then with 100 ml of saturated brine. The organic phase was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure to obtain 5,6-dibromo-1,3-dihydro-2H-indene-2-one oxime (142.5 g) with a purity of 96.5% and a yield of 94.1%.

[0067] Step 3 and Step 4: Preparation of 5,6-diethyl-2,3-dihydro-1H-inden-2-amine hydrochloride

[0068] Example 5

[0069] Under nitrogen protection, DMSO (300 ml), 5,6-dibromo-1,3-dihydro-2H-indene-2-one oxime (30.3 g, 100 mmol), vinyl n-butyl ether (20.0 g, 200 mmol), [1,3-bis(diphenylphosphino)propane]palladium chloride (5.9 g, 10 mmol) and triethylamine (15.2 g, 150 mmol) were added to a 500 ml four-necked flask, heated to 115 ° C, reacted for 36 hours, the reaction system was cooled to room temperature, and then dilute hydrochloric acid was added to the reaction system, extracted with dichloromethane, the organic phase was washed with 100 ml of saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain a crude product of 5,6-diacetyl-1,3-dihydro-2H-indene-2-one oxime (24.5 g), which was continued to the next step without purification.

[0070] Under nitrogen protection, methanol (300 ml) was added to the 5,6-diacetyl-1,3-dihydro-2H-inden-2-one oxime (24.5 g) in the previous step, and 10% Pd / C (2 g) was added to a 500 ml autoclave, replaced with nitrogen three times, replaced with hydrogen three times, and the pressure was maintained between 10 atm-20 atm. The temperature was raised to 80°C, reacted for 6 hours, cooled to room temperature, emptied the hydrogen, replaced with nitrogen three times, opened the autoclave to take out the material, filtered to remove Pd / C, and the filtrate was distilled under reduced pressure to remove methanol. 200 ml of dilute hydrochloric acid and 2 g of activated carbon were added to the residue, heated to reflux, stirred for 1 hour, and then filtered to remove the activated carbon. The filtrate was cooled to room temperature and filtered, and the solid was dried in a vacuum drying oven to obtain 5,6-diethyl-2,3-dihydro-1H-inden-2-amine hydrochloride (16.5 g) with a purity of 99.5% and a two-step yield of 73.3%. Figure 6 .

[0071] Example 6

[0072] Under nitrogen protection, DMSO (300 ml), 5,6-dibromo-1,3-dihydro-2H-indene-2-one oxime (30.3 g, 100 mmol), vinyl n-butyl ether (20.0 g, 200 mmol), [1,3-bis(diphenylphosphino)propane]palladium chloride (5.9 g, 10 mmol) and N,N,N',N'-tetramethylethylenediamine (17.4 g, 150 mmol) were added to a 500 ml four-necked flask, the temperature was raised to 115 ° C, the reaction was carried out for 36 hours, the reaction system was cooled to room temperature, and then dilute hydrochloric acid was added to the reaction system, extracted with dichloromethane, the organic phase was washed with 100 ml of saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain a crude product of 5,6-diacetyl-1,3-dihydro-2H-indene-2-one oxime (25.4 g), which was continued to the next step without purification.

[0073] Under nitrogen protection, methanol (300 ml) was added to the 5,6-diacetyl-1,3-dihydro-2H-indene-2-one oxime (25.4 g) in the previous step, and 10% Pd / C (2 g) was added to a 500 ml autoclave, replaced with nitrogen three times, replaced with hydrogen three times, and the pressure was maintained between 10 atm-20 atm. The temperature was raised to 80°C, reacted for 6 hours, cooled to room temperature, emptied the hydrogen, replaced with nitrogen three times, opened the autoclave to take out the material, filtered to remove Pd / C, and the filtrate was distilled under reduced pressure to remove methanol. 200 ml of dilute hydrochloric acid and 2 g of activated carbon were added to the residue, heated to reflux, stirred for 1 hour, filtered to remove the activated carbon, the filtrate was cooled to room temperature and filtered, and the solid was dried in a vacuum drying oven to obtain 5,6-diethyl-2,3-dihydro-1H-indene-2-amine hydrochloride (18.4 g) with a purity of 99.5% and a two-step yield of 81.8%. Figure 3 and Figure 7 .

[0074] Example 7

[0075] Under nitrogen protection, DMSO (300 ml), 5,6-dibromo-1,3-dihydro-2H-indene-2-one oxime (30.3 g, 100 mmol), vinyl n-butyl ether (20.0 g, 200 mmol), 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride (7.3 g, 10 mmol) and N,N,N',N'-tetramethylethylenediamine (17.4 g, 150 mmol) were added to a 500 ml four-necked bottle, the temperature was raised to 115 ° C, the reaction was carried out for 36 hours, the reaction system was cooled to room temperature, and then dilute hydrochloric acid was added to the reaction system, extracted with dichloromethane, the organic phase was washed with 100 ml of saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain a crude product of 5,6-diacetyl-1,3-dihydro-2H-indene-2-one oxime (26.8 g), which was continued to the next step without purification.

[0076] Under nitrogen protection, methanol (300 ml) was added to 5,6-diacetyl-1,3-dihydro-2H-indene-2-one oxime (26.8 g) and 10% Pd / C (2 g) in a 500 ml autoclave, and the mixture was replaced with nitrogen three times and hydrogen three times. The pressure was maintained between 10 atm and 20 atm. The mixture was heated to 80°C and reacted for 6 hours. The mixture was cooled to room temperature. After the hydrogen was evacuated, the mixture was replaced with nitrogen three times. The autoclave was opened to take out the material, and the Pd / C was removed by filtration. The filtrate was distilled under reduced pressure to remove methanol. 200 ml of dilute hydrochloric acid and 2 g of activated carbon were added to the residue. The mixture was heated to reflux and stirred for 1 hour before being filtered to remove the activated carbon. The filtrate was cooled to room temperature and then filtered. The solid was dried in a vacuum drying oven to obtain 5,6-diethyl-2,3-dihydro-1H-indene-2-amine hydrochloride (18.1 g) with a purity of 99.6% and a two-step yield of 80.4%.

Claims

1. A method for preparing an indacaterol intermediate 5,6-diethyl-2,3-dihydro-1H-inden-2-amine hydrochloride, characterized in that: The following steps are involved: Step 1: Under the action of a solvent and a base, 1,3-dihydro-2H-inden-2-one and hydroxylamine hydrochloride undergo an oximation reaction to obtain 1,3-dihydro-2H-inden-2-one oxime; Step 2: 1,3-dihydro-2H-inden-2-one oxime is subjected to bromination reaction to obtain 5,6-dibromo-1,3-dihydro-2H-inden-2-one oxime; Step 3: 5,6-dibromo-1,3-dihydro-2H-inden-2-one oxime is reacted with vinyl n-butyl ether in the presence of palladium catalyst via Heck reaction and then hydrolyzed to obtain 5,6-diacetyl-1,3-dihydro-2H-inden-2-one oxime; Step 4: 5,6-diacetyl-1,3-dihydro-2H-inden-2-one oxime is subjected to hydrogenation reaction in a hydrogen atmosphere under the action of palladium-carbon catalyst to form a salt to obtain the target product 5,6-diethyl-2,3-dihydro-1H-inden-2-amine hydrochloride; The base used in step 1 is one or more of pyridine, triethylamine, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide and potassium hydroxide; The palladium catalyst used in step 3 is one or more of bistriphenylphosphine palladium dichloride, 1,1'-diphenylphosphinoferrocene palladium dichloride, 1,3-bisdiphenylphosphinopropane palladium chloride, and 1,2-diphenylphosphinoethane palladium dichloride; The base used in the hydrolysis reaction of step 3 is triethylamine, N,N,N',N'-tetramethylethylenediamine, 1,2,2,6,6-pentamethylpiperidine, N,N-dimethylaniline, 4-dimethylaminopyridine, potassium carbonate or sodium carbonate.

2. The method for preparing an indacaterol intermediate 5,6-diethyl-2,3-dihydro-1H-inden-2-amine hydrochloride according to claim 1, characterized in that: The solvent used in step 1 is ethanol, methanol, tetrahydrofuran or a mixed solvent thereof; the weight ratio of the solvent used to 1,3-dihydro-2H-inden-2-one is 3:1-10:

1.

3. The method for preparing an indacaterol intermediate 5,6-diethyl-2,3-dihydro-1H-inden-2-amine hydrochloride according to claim 1, characterized in that: The molar ratio of the base to 1,3-dihydro-2H-inden-2-one used in step 1 is 1:1-5:1; The molar ratio of 1,3-dihydro-2H-inden-2-one and hydroxylamine hydrochloride used in step 1 is 1:1.2-1:1.4; The reaction temperature of step 1 is 20°C-80°C; the reaction time is 8h.

4. The method for preparing an indacaterol intermediate 5,6-diethyl-2,3-dihydro-1H-inden-2-amine hydrochloride according to claim 1, characterized in that: The bromination reagent used in the bromination reaction in step 2 is N-bromosuccinimide or bromine; the molar ratio of the bromination reagent to 1,3-dihydro-2H-inden-2-one oxime is 2:1-4:

1.

5. The method for preparing an indacaterol intermediate 5,6-diethyl-2,3-dihydro-1H-inden-2-amine hydrochloride according to claim 1, characterized in that: The solvent used in step 2 is acetonitrile, dichloromethane or 1,2-dichloroethane; the weight ratio of the solvent to 1,3-dihydro-2H-inden-2-one oxime is 3:1-10:1; The reaction temperature of step S2 is 20°C-55°C; the reaction time of step S2 is 12h.

6. The method for preparing an indacaterol intermediate 5,6-diethyl-2,3-dihydro-1H-inden-2-amine hydrochloride according to claim 1, characterized in that: The solvent used in step 3 is dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, toluene or acetonitrile; the weight ratio of the solvent used to 5,6-dibromo-1,3-dihydro-2H-inden-2-one oxime is 2:1-10:

1.

7. The method for preparing an indacaterol intermediate 5,6-diethyl-2,3-dihydro-1H-inden-2-amine hydrochloride according to claim 1, characterized in that: In step 3, the molar ratio of 5,6-dibromo-1,3-dihydro-2H-inden-2-one oxime to the palladium catalyst is 1000:1-10:1; In step 3, the molar ratio of 5,6-dibromo-1,3-dihydro-2H-inden-2-one oxime to vinyl n-butyl ether is 1:2.2-1:

3.

8. The method for preparing an indacaterol intermediate 5,6-diethyl-2,3-dihydro-1H-inden-2-amine hydrochloride according to claim 1, characterized in that: The molar ratio of the base used in step 3 to 5,6-dibromo-1,3-dihydro-2H-inden-2-one oxime is 2:1-1:1; Step 3: Heck reaction: the reaction temperature is 80-160°C, and the reaction time is 36 hours; Step 3: Hydrolysis reaction: The reaction temperature is 10-25°C and the reaction time is 1h.

9. The method for preparing an indacaterol intermediate 5,6-diethyl-2,3-dihydro-1H-inden-2-amine hydrochloride according to claim 1, characterized in that: In step 4, the weight ratio of 5,6-diacetyl-1,3-dihydro-2H-inden-2-one oxime to palladium on carbon is 10:1-100:1, and the mass fraction of palladium on carbon is 10%.

10. The method for preparing an indacaterol intermediate 5,6-diethyl-2,3-dihydro-1H-inden-2-amine hydrochloride according to claim 1, characterized in that: The solvent used in step 4 is ethyl acetate, ethanol, methanol, tetrahydrofuran or 1,4-dioxane; the weight ratio of the solvent used to 5,6-diacetyl-1,3-dihydro-2H-inden-2-one oxime is 4:1-10:1; The pressure of hydrogen in step 4 is 5 atm-40 atm; The reaction temperature of step 4 is 25°C-100°C; the reaction time is 6h.

Images