CN116239474B - Preparation method of indacaterol intermediate 5, 6-diethyl-2, 3-dihydro-1H-indene-2-amine hydrochloride - Google Patents
Preparation method of indacaterol intermediate 5, 6-diethyl-2, 3-dihydro-1H-indene-2-amine hydrochloride Download PDFInfo
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Abstract
本发明涉及一种茚达特罗中间体5,6‑二乙基‑2,3‑二氢‑1H‑茚‑2‑胺盐酸盐的制备方法，包括以下步骤：1,3‑二氢‑2H‑茚‑2‑酮和盐酸羟胺经肟化反应得到1,3‑二氢‑2H‑茚‑2‑酮肟；1,3‑二氢‑2H‑茚‑2‑酮肟经溴化反应得到5，6‑二溴‑1,3‑二氢‑2H‑茚‑2‑酮肟；5，6‑二溴‑1,3‑二氢‑2H‑茚‑2‑酮肟与乙烯基正丁醚经Heck反应后水解，得到5，6‑二乙酰基‑1,3‑二氢‑2H‑茚‑2‑酮肟；5，6‑二乙酰基‑1,3‑二氢‑2H‑茚‑2‑酮肟经氢化反应后成盐得到目标产物5,6‑二乙基‑2,3‑二氢‑1H‑茚‑2‑胺盐酸盐。本发明易于工业化放大、成本低。
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
The invention relates to a preparation method of a drug intermediate, belonging to the technical field of preparation of chemical raw material drug intermediates.
Background
5, 6-Diethyl-2, 3-dihydro-1H-indene-2-amine hydrochloride is a key intermediate of indacaterol (Indacaterol), and the structural formula is shown in chemical formula 1. Indantrole, commercially available as runs, is a drug for the treatment of COPD manufactured by North Switzerland. Is an inhaled long-acting beta 2 receptor agonist (LABA) that was first approved by SFDA for maintenance therapy in patients with stable phase Chronic Obstructive Pulmonary Disease (COPD). The structural formula is shown in chemical formula 2.
Chronic Obstructive Pulmonary Disease (COPD) is a chronic bronchitis and/or emphysema characterized by airflow obstruction that can further develop into common chronic diseases of pulmonary heart disease and respiratory failure. The indacaterol is a novel ultra-long acting beta 2 receptor agonist, which is approved by the FDA in the United states on month 1 of 2011 and is used for treating patients with chronic broncho-obstructive disease (COPD) airflow obstruction, including chronic bronchitis and/or emphysema. The 5, 6-diethyl-2, 3-dihydro-1H-indene-2-amine hydrochloride serving as the most critical intermediate of indacaterol has good market prospect and economic benefit.
The preparation methods of the 5, 6-diethyl-2, 3-dihydro-1H-indene-2-amine hydrochloride reported at present mainly comprise the following steps.
MAHAVIR PRASHAD et al, 2006, reported for the first time a commercial synthetic route for this compound (Organic Process Research & Development 2006,10,135-141) as shown in equation one. According to the method, 2-aminoindane is used as a starting material, ethyl trifluoroacetate is used for protecting amino, two-step Friedel-crafts reaction and two-step palladium-carbon reduction reaction are carried out, and finally deprotection salification is carried out, so that a target compound is obtained. Fu Qingquan et al, select the same route, change the trifluoro acetyl protection of the first step into acetyl protection (CN 108752220A) on the basis of this craft, this route is relatively high in price of the initial raw materials, the reaction step is longer, there is a large amount of waste acid water to be produced in the two-step Fu Keshi reaction, unfavorable for industrial production.
Frankois Baur et al 2010 reported the preparation of this compound starting from o-diethylbenzene (j.med. Chem.2010,53, 3675-3684), as shown in chemical equation two. 1, 2-diethylbenzene is used as a starting material, and is subjected to Friedel-crafts reaction, cyclization reaction, oximation reaction, reduction reaction and the like to prepare the 5, 6-diethyl-2, 3-dihydro-1H-indene-2-amine hydrochloride. The raw material o-diethylbenzene of the route is not commercially produced, the price is high, a large amount of isomers are generated in the second-step cyclization reaction, the separation and purification by adopting a conventional method are inconvenient, and the industrialization difficulty of the whole route is high and the cost is high.
Wang Kunpeng et al prepared this compound (CN 110183330A) starting from 2-indenol as shown in equation three. The target compound is prepared by taking 2-indenol as a starting material and performing six-step reactions of acetyl protection, bromination, deprotection, azide and reduction into salt. The route has longer steps, uses azide, has great potential safety hazard, has poor economy and safety of the whole process, and is not beneficial to industrial production.
Disclosure of Invention
The invention aims to provide a preparation method of 5, 6-diethyl-2, 3-dihydro-1H-indene-2-amine hydrochloride, which is easy to realize industrialized amplification and has low cost.
The preparation method of the 5, 6-diethyl-2, 3-dihydro-1H-indene-2-amine hydrochloride has a synthetic route shown in a chemical reaction formula IV:
chemical reaction type IV
The technical scheme adopted by the invention is as follows:
A preparation method of indacaterol intermediate 5, 6-diethyl-2, 3-dihydro-1H-indene-2-amine hydrochloride comprises the following steps:
under the action of a solvent and alkali, carrying out oximation reaction on 1, 3-dihydro-2H-indene-2-one and hydroxylamine hydrochloride to obtain 1, 3-dihydro-2H-indene-2-ketoxime;
Step two, carrying out bromination reaction on the 1, 3-dihydro-2H-indene-2-ketoxime to obtain 5, 6-dibromo-1, 3-dihydro-2H-indene-2-ketoxime;
step three, 5, 6-dibromo-1, 3-dihydro-2H-indene-2-ketoxime is hydrolyzed with vinyl n-butyl ether under the action of a palladium catalyst after Heck reaction to obtain 5, 6-diacetyl-1, 3-dihydro-2H-indene-2-ketoxime;
step four, 5, 6-diacetyl-1, 3-dihydro-2H-indene-2-ketoxime is subjected to hydrogenation reaction under the action of palladium-carbon (10%) catalyst in a hydrogen atmosphere to obtain a target product 5, 6-diethyl-2, 3-dihydro-1H-indene-2-amine hydrochloride. Preferably, the method comprises the steps of,
The solvent used in the first step is ethanol, methanol, tetrahydrofuran or a mixed solvent thereof, and the weight ratio of the solvent to the 1, 3-dihydro-2H-indene-2-ketone is 3:1-10:1.
Preferably, the method comprises the steps of,
The alkali used in the first step is one or more of pyridine, triethylamine, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide and potassium hydroxide, and the molar ratio of the alkali to the 1, 3-dihydro-2H-indene-2-ketone is 1:1-5:1;
The molar ratio of the 1, 3-dihydro-2H-indene-2-one to the hydroxylamine hydrochloride used in the first step is 1:1.2-1:1.4;
The reaction temperature of the first step is 20-80 ℃ and the reaction time is 8 hours.
Preferably, the method comprises the steps of,
The brominating reagent used in the brominating reaction in the step two is N-bromosuccinimide or bromine, and the molar ratio of the brominating reagent to the 1, 3-dihydro-2H-indene-2-ketoxime is 2:1-4:1.
Preferably, the method comprises the steps of,
The solvent used in the second step is acetonitrile, dichloromethane or 1, 2-dichloroethane, and the weight ratio of the solvent to the 1, 3-dihydro-2H-indene-2-ketoxime is 3:1-10:1;
the reaction temperature of the step S2 is 20-55 ℃, and the reaction time of the step S2 is 12h.
Preferably, the method comprises the steps of,
The solvent used in the third step is dimethyl sulfoxide (DMSO), N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, toluene or acetonitrile, and the weight ratio of the solvent to the 5, 6-dibromo-1, 3-dihydro-2H-indene-2-ketoxime is 2:1-10:1.
Preferably, the method comprises the steps of,
The palladium catalyst used in the third step is one or more of bis (triphenylphosphine) palladium dichloride ([ PdCl 2(PPh3)2 ]), 1' -bis (diphenylphosphino) ferrocene palladium dichloride ([ PdCl 2 (dppf) ]), [1, 3-bis (diphenylphosphinopropane) palladium chloride ([ PdCl 2 (dppp) ]), and 1, 2-bis (diphenylphosphino) ethane palladium dichloride ([ PdCl 2 (dppe) ]), and the molar ratio of the 5, 6-dibromo-1, 3-dihydro-2H-inden-2-one oxime to the palladium catalyst is 1000:1-10:1;
In the third step, the mol ratio of the 5, 6-dibromo-1, 3-dihydro-2H-indene-2-ketoxime to the vinyl n-butyl ether is 1:2.2-1:3. Preferably, the method comprises the steps of,
The alkali used in the step three hydrolysis reaction is triethylamine, N, N, N ', N' -tetramethyl ethylenediamine (TMEDA), 1,2, 6-pentamethylpiperidine, N, N-dimethylaniline, 4-dimethylaminopyridine, potassium carbonate or sodium carbonate, and the molar ratio of the alkali to the 5, 6-dibromo-1, 3-dihydro-2H-indene-2-ketoxime is 2:1-1:1;
step three, heck reaction temperature is 80-160 ℃ and reaction time is 36h;
and step three, the hydrolysis reaction temperature is 10-25 ℃ and the reaction time is 1h.
Preferably, the method comprises the steps of,
In the fourth step, the weight ratio of the 5, 6-diacetyl-1, 3-dihydro-2H-indene-2-ketoxime to the palladium carbon is 10:1-100:1, and the mass fraction of the palladium in the palladium carbon is 10%.
Preferably, the method comprises the steps of,
In the fourth step, the solvent used in the 5, 6-diacetyl-1, 3-dihydro-2H-indene-2-ketoxime is ethyl acetate, ethanol, methanol, tetrahydrofuran or 1, 4-dioxane, and the weight ratio of the solvent used to the 5, 6-diacetyl-1, 3-dihydro-2H-indene-2-ketoxime is 4:1-10:1;
the pressure of hydrogen in the fourth step is 5atm to 40atm;
the reaction temperature in the fourth step is 25-100 ℃ and the reaction time is 6h.
The room temperature of the invention is 4-39 ℃.
The invention has the beneficial effects that:
The invention has the advantages of wide sources of the initial raw materials, low production cost, mild reaction conditions, simple operation, easy purification of the product, environmental friendliness and high total yield. The method has the advantages of short reaction steps, less waste water yield and low cost, and is suitable for large-scale industrial production. The invention has no isomer generation, is convenient for separation and purification by adopting a conventional method, and has low industrialization difficulty, low cost and high economic value in the whole route.
Drawings
FIG. 1 is an HPLC chromatogram of 1, 3-dihydro-2H-inden-2-one oxime;
FIG. 2 is an HPLC chromatogram of 5, 6-dibromo-1, 3-dihydro-2H-inden-2-one oxime;
FIG. 3 is an HPLC chromatogram of 5, 6-diethyl-2, 3-dihydro-1H-inden-2-amine hydrochloride;
FIG. 4 is a1, 3-dihydro-2H-inden-2-one oxime 1 H-NMR chart;
FIG. 5 is a 1 H-NMR chart of 5, 6-dibromo-1, 3-dihydro-2H-inden-2-one oxime;
FIG. 6 is a 1 H-NMR chart of 5, 6-diacetyl-1, 3-dihydro-2H-inden-2-one oxime;
FIG. 7 is a 1 H-NMR chart of 5, 6-diethyl-2, 3-dihydro-1H-inden-2-amine hydrochloride.
Detailed Description
The following examples are provided to illustrate the invention, but are not intended to limit the scope of the invention in any way.
Step one preparation of 1, 3-dihydro-2H-indene-2-one oxime
Example 1
1, 3-Dihydro-2H-inden-2-one (132.0 g,1.0 mol), 700ml of absolute ethanol was added to a 2L three-necked flask under nitrogen protection, after stirring at room temperature for 30 minutes, hydroxylamine hydrochloride (104.2 g,1.5 mol) was added to the system, stirring was continued at room temperature for 30 minutes, then sodium hydroxide (80.0 g,2.0 mol) was added to the system, the reaction was kept at 40℃for 8 hours under heating, then distillation was performed under reduced pressure, most of the ethanol was removed, filtration was performed after the temperature was lowered to room temperature, and a solid vacuum oven was dried to obtain 1, 3-dihydro-2H-inden-2-one oxime (138.5 g), purity was 97.5%, yield was 94.2%, see FIG. 1 and FIG. 4.
Example 2
1, 3-Dihydro-2H-inden-2-one (132.0 g,1.0 mol), 700ml of anhydrous methanol was added to a 2L three-port flask under nitrogen protection, after stirring at room temperature for 30 minutes, hydroxylamine hydrochloride (104.2 g,1.5 mol) was added to the system, stirring was continued at room temperature for 30 minutes, triethylamine (202.4 g,2.0 mol) was then added to the system, the reaction was kept at 40℃for 8 hours under heating, then distilled under reduced pressure, most of the ethanol was removed, and after the temperature was lowered to room temperature, the filter cake was rinsed with 1L of water, dried in a solid vacuum oven to give 1, 3-dihydro-2H-inden-2-one oxime (126.5 g), purity was 97.8%, yield 86.0%. Step two, preparation of 5, 6-dibromo-1, 3-dihydro-2H-indene-2-ketoxime
Example 3
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 under nitrogen atmosphere, stirred at room temperature for 12 hours, distilled under reduced pressure to remove acetonitrile, the residue was poured into a mixed solvent composed of 300ml of methylene chloride and 200ml of water, the solution was separated, the organic phase was washed with 100ml of diluted hydrochloric acid, then with 100ml of saturated brine, the organic phase was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give 5, 6-dibromo-1, 3-dihydro-2H-indene-2-one oxime (140.5 g) with a purity of 95.5%, a yield of 92.8%, see FIG. 2 and FIG. 5.
Example 4
1, 2-Dichloroethane (300 ml), 1, 3-dihydro-2H-indene-2-ketoxime (73.5 g,0.5 mol) and N-bromosuccinimide (267.0 g,1.5 mol) were added to a 1L three-necked flask under nitrogen atmosphere, stirred at room temperature for 12 hours, 300ml of diluted hydrochloric acid was added to the reaction system, the mixture was separated after sufficient stirring, the organic phase was washed with 100ml of diluted hydrochloric acid, then with 100ml of saturated brine, the organic phase was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure to give 5, 6-dibromo-1, 3-dihydro-2H-indene-2-ketoxime (142.5 g) in a purity of 96.5% and a yield of 94.1%.
Preparation of 5, 6-diethyl-2, 3-dihydro-1H-indene-2-amine hydrochloride
Example 5
DMSO (300 ml), 5, 6-dibromo-1, 3-dihydro-2H-indene-2-ketoxime (30.3 g,100 mmol), vinyl n-butyl ether (20.0 g,200 mmol) [1, 3-bisdiphenylphosphinopropane ] palladium chloride (5.9 g,10 mmol) and triethylamine (15.2 g,150 mmol) were added to a 500ml four-necked flask under nitrogen protection, the temperature was raised to 115℃for 36 hours, the reaction system was cooled to room temperature, dilute hydrochloric acid was then added to the reaction system, dichloromethane extraction was performed, the organic phase was washed with 100ml saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain crude 5, 6-diacetyl-1, 3-dihydro-2H-indene-2-ketoxime (24.5 g) which was continued to the next reaction without purification.
Methanol (300 ml) was added to the above 5, 6-diacetyl-1, 3-dihydro-2H-indene-2-ketoxime (24.5 g), 10% Pd/C (2 g) was added to a 500ml autoclave under nitrogen atmosphere, nitrogen was replaced three times, hydrogen was replaced three times, the pressure was kept between 10atm and 20atm, the temperature was raised to 80℃for 6 hours, cooled to room temperature, after the hydrogen was purged, the autoclave was opened to remove the material, pd/C was removed by filtration, methanol was distilled off from the filtrate under reduced pressure, 200ml of diluted hydrochloric acid was added to the residue, 2g of activated carbon was heated to reflux, the activated carbon was removed by filtration after stirring for 1 hour, the filtrate was cooled to room temperature and was filtered, and the solid was dried in a vacuum oven to give 5, 6-diethyl-2, 3-dihydro-1H-indene-2-amine hydrochloride (16.5 g), the purity of which was 99.5% and the yield of the two steps was 73.3%, as shown in FIG. 6.
Example 6
DMSO (300 ml), 5, 6-dibromo-1, 3-dihydro-2H-indene-2-ketoxime (30.3 g,100 mmol), vinyl N-butyl ether (20.0 g,200 mmol) [1, 3-bisdiphenylphosphinopropane ] palladium chloride (5.9 g,10 mmol) and N, N, N ', N' -tetramethyl ethylenediamine (17.4 g,150 mmol) were added to a 500ml four-necked flask under nitrogen protection, the temperature was raised to 115℃for 36 hours, the reaction system was cooled to room temperature, dilute hydrochloric acid was then added to the reaction system, dichloromethane extraction was performed, the organic phase was washed with 100ml saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain crude 5, 6-diacetyl-1, 3-dihydro-2H-indene-2-ketoxime (25.4 g) which was continued to react without purification.
Methanol (300 ml) was added to the above 5, 6-diacetyl-1, 3-dihydro-2H-indene-2-ketoxime (25.4 g), 10% Pd/C (2 g) was added to a 500ml autoclave under nitrogen atmosphere, nitrogen was replaced three times, hydrogen was replaced three times, the pressure was maintained between 10atm and 20atm, the temperature was raised to 80℃for 6 hours, cooled to room temperature, after the hydrogen was purged, the autoclave was opened to remove the material, pd/C was removed by filtration, methanol was distilled off from the filtrate under reduced pressure, 200ml of diluted hydrochloric acid was added to the residue, 2g of activated carbon was heated to reflux, activated carbon was removed by filtration after stirring for 1 hour, the filtrate was cooled to room temperature and was filtered, and the solid was dried in a vacuum oven to give 5, 6-diethyl-2, 3-dihydro-1H-indene-2-amine hydrochloride (18.4 g) having a purity of 99.5% and a two-step yield of 81.8%, see FIG. 3 and FIG. 7.
Example 7
DMSO (300 ml), 5, 6-dibromo-1, 3-dihydro-2H-indene-2-ketoxime (30.3 g,100 mmol), vinyl N-butyl ether (20.0 g,200 mmol) 1,1' -bis (diphenylphosphino) ferrocene palladium dichloride (7.3 g,10 mmol) and N, N, N ', N ' -tetramethyl ethylenediamine (17.4 g,150 mmol) were added to a 500ml four-necked flask under nitrogen protection, the temperature was raised to 115℃for 36 hours, the reaction system was cooled to room temperature, then diluted hydrochloric acid was added to the reaction system, dichloromethane extraction was performed, the organic phase was washed with 100ml saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain crude 5, 6-diacetyl-1, 3-dihydro-2H-indene-2-ketoxime (26.8 g) without purification and the next reaction was continued.
Methanol (300 ml) was added to 5, 6-diacetyl-1, 3-dihydro-2H-indene-2-ketoxime (26.8 g), 10% Pd/C (2 g) was added to a 500ml autoclave under nitrogen protection, nitrogen was replaced three times, hydrogen was replaced three times, the pressure was kept between 10atm and 20atm, the temperature was raised to 80 ℃, the reaction was carried out for 6 hours, cooling to room temperature, after the hydrogen was purged, the autoclave was opened to take out the material, pd/C was removed by filtration, methanol was removed by distillation under reduced pressure from the filtrate, 200ml of diluted hydrochloric acid was added to the residue, 2g of activated carbon was heated to reflux, the activated carbon was removed by filtration after stirring for 1 hour, the filtrate was cooled to room temperature and filtered, and dried in a solid vacuum drying oven to give 5, 6-diethyl-2, 3-dihydro-1H-indene-2-amine hydrochloride (18.1 g), the purity was 99.6%, and the yield in two steps was 80.4%.
Claims (10)
1. The preparation method of the indacaterol intermediate 5, 6-diethyl-2, 3-dihydro-1H-indene-2-amine hydrochloride is characterized by comprising the following steps:
under the action of a solvent and alkali, carrying out oximation reaction on 1, 3-dihydro-2H-indene-2-one and hydroxylamine hydrochloride to obtain 1, 3-dihydro-2H-indene-2-ketoxime;
Step two, carrying out bromination reaction on the 1, 3-dihydro-2H-indene-2-ketoxime to obtain 5, 6-dibromo-1, 3-dihydro-2H-indene-2-ketoxime;
step three, 5, 6-dibromo-1, 3-dihydro-2H-indene-2-ketoxime is hydrolyzed with vinyl n-butyl ether under the action of a palladium catalyst after Heck reaction to obtain 5, 6-diacetyl-1, 3-dihydro-2H-indene-2-ketoxime;
Step four, 5, 6-diacetyl-1, 3-dihydro-2H-indene-2-ketoxime is subjected to hydrogenation reaction in the presence of a palladium-carbon catalyst to form salt to obtain a target product 5, 6-diethyl-2, 3-dihydro-1H-indene-2-amine hydrochloride;
the alkali used in the first step 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 the step three is one or more of bis (triphenylphosphine) palladium dichloride, 1' -diphenyl phosphino ferrocene palladium dichloride, 1, 3-bis (diphenylphosphino) propane palladium chloride and 1, 2-diphenyl phosphino ethane palladium dichloride;
the base used in the step three hydrolysis reaction is triethylamine, N, N, N ', N' -tetramethyl ethylenediamine, 1,2, 6-pentamethylpiperidine, N, N-dimethylaniline, 4-dimethylaminopyridine, potassium carbonate or sodium carbonate.
2. The preparation method of the indacaterol intermediate 5, 6-diethyl-2, 3-dihydro-1H-indene-2-amine hydrochloride according to claim 1, which is characterized in that,
The solvent used in the first step is ethanol, methanol, tetrahydrofuran or a mixed solvent thereof, and the weight ratio of the solvent to the 1, 3-dihydro-2H-indene-2-ketone is 3:1-10:1.
3. The preparation method of the indacaterol intermediate 5, 6-diethyl-2, 3-dihydro-1H-indene-2-amine hydrochloride according to claim 1, which is characterized in that,
The molar ratio of the alkali to the 1, 3-dihydro-2H-indene-2-ketone used in the first step is 1:1-5:1;
The molar ratio of the 1, 3-dihydro-2H-indene-2-one to the hydroxylamine hydrochloride used in the first step is 1:1.2-1:1.4;
The reaction temperature of the first step is 20-80 ℃ and the reaction time is 8 hours.
4. The preparation method of the indacaterol intermediate 5, 6-diethyl-2, 3-dihydro-1H-indene-2-amine hydrochloride according to claim 1, which is characterized in that,
The brominating reagent used in the brominating reaction in the step two is N-bromosuccinimide or bromine, and the molar ratio of the brominating reagent to the 1, 3-dihydro-2H-indene-2-ketoxime is 2:1-4:1.
5. The preparation method of the indacaterol intermediate 5, 6-diethyl-2, 3-dihydro-1H-indene-2-amine hydrochloride according to claim 1, which is characterized in that,
The solvent used in the second step is acetonitrile, dichloromethane or 1, 2-dichloroethane, and the weight ratio of the solvent to the 1, 3-dihydro-2H-indene-2-ketoxime is 3:1-10:1;
the reaction temperature of the step S2 is 20-55 ℃, and the reaction time of the step S2 is 12h.
6. The preparation method of the indacaterol intermediate 5, 6-diethyl-2, 3-dihydro-1H-indene-2-amine hydrochloride according to claim 1, which is characterized in that,
The solvent used in the third step is dimethyl sulfoxide, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, toluene or acetonitrile, and the weight ratio of the solvent to the 5, 6-dibromo-1, 3-dihydro-2H-indene-2-ketoxime is 2:1-10:1.
7. The preparation method of the indacaterol intermediate 5, 6-diethyl-2, 3-dihydro-1H-indene-2-amine hydrochloride according to claim 1, which is characterized in that,
In the third step, the molar ratio of the 5, 6-dibromo-1, 3-dihydro-2H-indene-2-ketoxime to the palladium catalyst is 1000:1-10:1;
in the third step, the mol ratio of the 5, 6-dibromo-1, 3-dihydro-2H-indene-2-ketoxime to the vinyl n-butyl ether is 1:2.2-1:3.
8. The preparation method of the indacaterol intermediate 5, 6-diethyl-2, 3-dihydro-1H-indene-2-amine hydrochloride according to claim 1, which is characterized in that,
The molar ratio of the alkali to the 5, 6-dibromo-1, 3-dihydro-2H-indene-2-ketoxime used in the step III is 2:1-1:1;
step three, heck reaction temperature is 80-160 ℃ and reaction time is 36h;
and step three, the hydrolysis reaction temperature is 10-25 ℃ and the reaction time is 1h.
9. The preparation method of the indacaterol intermediate 5, 6-diethyl-2, 3-dihydro-1H-indene-2-amine hydrochloride according to claim 1, which is characterized in that,
In the fourth step, the weight ratio of the 5, 6-diacetyl-1, 3-dihydro-2H-indene-2-ketoxime to the palladium carbon is 10:1-100:1, and the mass fraction of the palladium in the palladium carbon is 10%.
10. The preparation method of the indacaterol intermediate 5, 6-diethyl-2, 3-dihydro-1H-indene-2-amine hydrochloride according to claim 1, which is characterized in that,
The solvent used in the fourth step is ethyl acetate, ethanol, methanol, tetrahydrofuran or 1, 4-dioxane, and the weight ratio of the solvent to the 5, 6-diacetyl-1, 3-dihydro-2H-indene-2-ketoxime is 4:1-10:1;
the pressure of hydrogen in the fourth step is 5atm to 40atm;
the reaction temperature in the fourth step is 25-100 ℃ and the reaction time is 6h.
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