Method for preparing high-purity 1-aminoindan and (R)-(-)-1-aminoindan

Abstract

The invention belongs to the field of medical chemistry, and particularly relates to a preparation and resolution method of (R)-(-)-1-aminoindan. According to the method, 1-indanone is used as a raw material, a 1-aminoindane racemate is prepared through addition and reduction, (R)-(-)-1-aminoindane is prepared through R-3-cyclohexenecarboxylic acid resolution, the resolution selectivity is high, and the yield and the purity are both suitable for large-scale industrial production.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical chemistry, and specifically provides a method for preparing 1-aminoindane and (R)-(-)-1-aminoindane. Background Technology

[0002] Rasagiline is an irreversible selective monoamine oxidase inhibitor jointly developed by Teva Pharmaceutical Industries of Israel and Lundbeck Pharmaceuticals of Denmark. It is a novel and potent second-generation selective MAo-B inhibitor. The drug was first approved for marketing in Israel in January 2005, followed by approval in the European Union in February 2005, and its initial launch in the UK in June 2005. In 2006, the FDA approved rasagiline for marketing in the United States for initial monotherapy of early-stage Parkinson's disease and as a supplement to levodopa for later-stage patients. Compared to the first-generation MAo-B inhibitor selegiline, it offers better efficacy and fewer side effects.

[0003] 1-Aminoindane racemate and (R)-(-)-1-aminoindane are important intermediates in the preparation of rasagiline mesylate. The structural formulas of 1-aminoindane racemate (shown in Formula IV) and (R)-(-)-1-aminoindane (shown in Formula I) are as follows:

[0004]

[0005] According to literature reports, the main methods for preparing 1-aminoindane racemic mixtures and (R)-(-)-1-aminoindane are as follows:

[0006] (I) Chinese Journal of New Drugs, 2003, 12(6)

[0007] This literature reports a method for synthesizing 1-aminoindane, which uses 2,3-dihydro-1H-indane-1-one oxime as a raw material and reduces it in ethylene glycol dimethyl ether solvent with titanium tetrachloride and sodium borohydride to obtain the racemic 1-aminoindane. This method uses titanium tetrachloride and sodium borohydride, which are relatively expensive reagents, complicated to operate, and have high costs, making it unsuitable for industrial-scale production.

[0008] (ii) CN101062897A and CN116082166A

[0009] CN101062897A and CN116082166A both disclose a method of using 1-indanone as a raw material, reacting it with hydroxylamine hydrochloride to generate 2,3-dihydro-1H-indanone oxime, and then adding an aluminum-nickel alloy and sodium hydroxide to the 2,3-dihydro-1H-indanone oxime to reduce it to a 1-aminoindanone racemic mixture. This method uses an aluminum-nickel alloy to reduce 2,3-dihydro-1H-indanone oxime to a 1-aminoindanone racemic mixture in the presence of sodium hydroxide. The amount of aluminum-nickel alloy used is relatively large, and the production process requires first dissolving aluminum in a high-concentration sodium hydroxide solution. The reaction during dissolution is violent, releasing a large amount of hydrogen and heat. Then, active nickel is prepared through multiple water washing and filtration. During the filtration process, the active nickel is highly flammable, posing a safety hazard and making it unsuitable for industrial-scale production.

[0010] (III) China Pharmaceutical Industry Magazine, 2011, 42(1), 4-6

[0011]

[0012] This route involves the condensation of 1-indanone with the chiral auxiliary reagent (R)-phenylethylamine, followed by asymmetric reduction with sodium borohydride and debenzylation via hydrogenation to yield (R)-aminoindanone hydrochloride. Steps 1 and 2 yield 44.6%, while step 3, using palladium reduction on carbon, yields 36.9% via hydrogenation, resulting in an overall yield of 16.45%. This route has a low overall yield and utilizes two regulated reduction reactions involving sodium borohydride and palladium on carbon, making it unsuitable for industrial production.

[0013] (iv) WO2012116752A1

[0014] This patent uses 1-aminoindene racemic mixture as raw material and discloses three resolving agents: L-(+)-aspartic acid, L-(-)-malic acid, and L-(+)-tartaric acid. The yields (theoretical yield and actual yield) and optical purity after resolving are shown in the table below:

[0015] Resolving reagents Theoretical yield (%) Actual yield (%) Optical purity (%) L-(+)-Aspartic acid 66 33 91.9 L-(-)-malic acid 47 23.5 99.75 L-(+)-tartaric acid 66 33 93.7

[0016] The three resolving reagents mentioned above have the highest optical purity for L-(-)-malic acid, but the yield is low, resulting in high cost and failing to meet the product demand for rasagiline mesylate.

[0017] In view of the defects in the existing preparation methods of 1-aminoindane and (R)-(-)-1-aminoindane, the aim is to develop a new preparation or resolution method that can improve the general existing production technology, increase product purity, make it more practical for production, and make it more competitive in the market to meet the growing market demand. Summary of the Invention

[0018] The purpose of this invention is to provide a simple method for preparing 1-aminoindane and (R)-(-)-1-aminoindane, so as to overcome the defects of the prior art, use inexpensive raw materials, have low cost, and stable reaction, thus making it more suitable for industrial production and having great industrial application value.

[0019] The technical problem to be solved by the present invention is to provide a method for preparing 1-aminoindenyne, comprising the following steps:

[0020]

[0021] Compound III was reacted with reduced zinc powder in a protic solvent under acidic conditions to prepare compound IV, 1-aminoindane.

[0022] In a further preferred embodiment of the present invention, the protic solvent is any one or a combination of methanol, ethanol, and isopropanol; the acidic conditions are provided by ammonium chloride, ammonium acetate, and acetic acid.

[0023] In a further preferred embodiment of the present invention, the molar ratio of the compound of formula III to the reduced zinc powder is in the range of 1:(1.0-10.0), preferably 1:(2.0-8.0), more preferably 1:(3.0-7.0), more preferably 1:(4.0-6.0), and even more preferably 1:(5.0-6.0).

[0024] In a further preferred embodiment of the present invention, the zinc powder reduction reaction temperature is above 30°C, preferably above 40°C, preferably above 50°C, preferably above 60°C, and more preferably carried out under reflux conditions.

[0025] In a further preferred embodiment of the present invention, the reaction time is 20-100h, preferably 30-90h, and more preferably 40-80h.

[0026] Another aspect of the present invention is to provide a method for purifying 1-aminoindenine, comprising the following steps:

[0027] The reaction solution containing 1-aminoindane was filtered to remove zinc powder. Organic solvent and water were added and stirred. The mixture was allowed to stand and separate into layers. The organic solvent extract was then concentrated to obtain purified 1-aminoindane.

[0028] In a further preferred embodiment of the present invention, the filtered filter cake is first washed with a protic solvent, wherein the protic solvent is any one or a combination of methanol, ethanol, and isopropanol.

[0029] In a further preferred embodiment of the present invention, after standing and separating, the upper solution can be extracted with organic solvent 1-5 times, preferably 2-3 times, and the organic solvent extracts are combined and concentrated.

[0030] In a further preferred embodiment of the present invention, the upper layer solution after standing and separating is adjusted to a pH of 12-14 with sodium hydroxide or potassium hydroxide before being extracted with an organic solvent; preferably a sodium hydroxide solution, the concentration of which is 5%-50%, more preferably a 10-15% sodium hydroxide solution.

[0031] In a further preferred embodiment of the present invention, the organic solvent is one or a combination of chloromethane, dichloromethane, trichloromethane, carbon tetrachloride, dichloroethane, dichloropropane, trichloroethane, and chloroform, preferably dichloromethane.

[0032] In a further preferred embodiment of the present invention, the mixed solution of organic solvent and water is adjusted to pH 1-2 with concentrated hydrochloric acid and stirred for 0.1-1 h, preferably for 20-40 min.

[0033] Another aspect of the present invention is to provide a method for preparing (R)-(-)-1-aminoindenymium, comprising the following steps:

[0034]

[0035] Compound IV was prepared by salt formation, crystallization, and release in a solvent using a resolving agent to obtain compound I (R)-(-)-1-aminoindane.

[0036] In a further preferred embodiment of the present invention, the resolving agent is R-3-cyclohexenecarboxylic acid.

[0037] In a further preferred embodiment of the present invention, the molar ratio of R-3-cyclohexenic acid to compound IV is in the range of 1:(0.1-2.0), preferably 1:(0.2-1.0), more preferably 1:(0.3-7.0), and even more preferably 1:(0.40-0.50).

[0038] In a further preferred embodiment of the present invention, the solvent is selected from any one or a combination of methanol, ethanol, isopropanol, ethyl acetate, isopropyl acetate, and n-butyl acetate, preferably a mixed solvent of isopropanol and isopropyl acetate.

[0039] Another aspect of the present invention is to provide a method for preparing (R)-(-)-1-aminoindenymium, comprising the following steps:

[0040]

[0041] (1) Compound III is reacted with reduced zinc powder in a protic solvent under acidic conditions to prepare compound IV;

[0042] (2) Compound IV was prepared by salt formation, crystallization and freeing in a solvent using a resolving agent to prepare (R)-(-)-1-aminoindane.

[0043] In a further preferred embodiment of the present invention, the protic solvent in step (1) is any one or a combination of methanol, ethanol, and isopropanol; the acidic condition in step (2) is provided by ammonium chloride, ammonium acetate, and acetic acid.

[0044] In a further preferred embodiment of the present invention, the molar ratio of compound III to reduced zinc powder in step (1) is in the range of 1:(1.0-10.0), preferably 1:(2.0-8.0), preferably 1:(3.0-7.0), more preferably 1:(4.0-6.0), and even more preferably 1:(5.0-6.0).

[0045] In a further preferred embodiment of the present invention, the zinc powder reduction reaction temperature in step (1) is above 30°C, preferably above 40°C, preferably above 50°C, preferably above 60°C, and more preferably carried out under reflux conditions.

[0046] In a further preferred embodiment of the present invention, the reaction time in step (1) is 20-100h, preferably 30-90h, and more preferably 40-80h.

[0047] In a further preferred embodiment of the present invention, in step (1), the reaction solution containing 1-aminoindane after the reaction is filtered to remove zinc powder, an organic solvent and water are added and stirred, allowed to stand and separate into layers, and the organic solvent extract is concentrated to obtain purified 1-aminoindane.

[0048] In a further preferred embodiment of the present invention, the filter cake after filtration in step (1) is first washed with a protic solvent, wherein the protic solvent is any one or a combination of methanol, ethanol, and isopropanol.

[0049] In a further preferred embodiment of the present invention, after the upper layer solution is allowed to stand and separate into layers in step (1), the upper layer solution can be extracted with organic solvent 1-5 times, preferably 2-3 times, and the organic solvent extracts are combined and concentrated.

[0050] In a further preferred embodiment of the present invention, in step (1), the upper layer solution after standing and separating is adjusted to pH 12-14 with sodium hydroxide or potassium hydroxide, and then an organic solvent is added for extraction; preferably sodium hydroxide solution, the concentration of the sodium hydroxide solution used is 5%-50%, more preferably 10-15% sodium hydroxide solution.

[0051] In a further preferred embodiment of the present invention, the organic solvent in step (1) is one or a combination of chloromethane, dichloromethane, trichloromethane, carbon tetrachloride, dichloroethane, dichloropropane, trichloroethane, and chloroform, preferably dichloromethane.

[0052] In a further preferred embodiment of the present invention, in step (1), the mixed solution of organic solvent and water is adjusted to pH 1-2 with concentrated hydrochloric acid and stirred for 0.1-1 h, preferably for 20-40 min.

[0053] In a further preferred embodiment of the present invention, the resolving agent in step (2) is R-3-cyclohexenecarboxylic acid.

[0054] In a further preferred embodiment of the present invention, the molar ratio of R-3-cyclohexenecarboxylic acid to compound IV in step (2) is in the range of 1:(0.1-2.0), preferably 1:(0.2-1.0), more preferably 1:(0.3-7.0), and even more preferably 1:(0.40-0.50).

[0055] In a further preferred embodiment of the present invention, the solvent in step (2) is selected from any one or a combination of methanol, ethanol, isopropanol, ethyl acetate, isopropyl acetate, and n-butyl acetate, preferably a mixed solvent of isopropanol and isopropyl acetate.

[0056] Another aspect of the present invention is to provide a method for preparing (R)-(-)-1-aminoindenymium, comprising the following steps:

[0057]

[0058] (1) Compound II and hydroxylamine hydrochloride are reacted in a solvent with an alkaline solution to prepare compound III;

[0059] (2) Compound III is reacted with reduced zinc powder in a protic solvent under acidic conditions to prepare compound IV;

[0060] (3) Compound IV was prepared by salt formation, crystallization and freeing in a solvent using a resolving agent to prepare (R)-(-)-1-aminoindane.

[0061] In a further preferred embodiment of the present invention, the solvent in step (1) is any one or a combination of methanol, ethanol, isopropanol, and water; the alkaline solution is any one or a combination of lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium acetate, potassium acetate, basic carbonate, and basic bicarbonate aqueous solution, preferably sodium hydroxide solution, and the concentration of the sodium hydroxide solution used is 5%-50%, more preferably 10-15% sodium hydroxide solution.

[0062] In a further preferred embodiment of the present invention, the molar ratio of compound II to hydroxylamine hydrochloride in step (1) is in the range of 1:(0.5-5.0), preferably 1:(0.8-4.0), more preferably 1:(1.0-3.0), and even more preferably 1:(1.5-2.0).

[0063] In a further preferred embodiment of the present invention, the reaction temperature in step (1) is 20-50°C, preferably 25-45°C; the reaction time is 1-5 hours, preferably 2-4 hours, and more preferably 3 hours.

[0064] In a further preferred embodiment of the present invention, the protic solvent in step (2) is any one or a combination of methanol, ethanol, and isopropanol; the acidic condition in step (2) is provided by ammonium chloride and ammonium acetate.

[0065] In a further preferred embodiment of the present invention, the molar ratio of compound III to reduced zinc powder in step (2) is in the range of 1:(1.0-10.0), preferably 1:(2.0-8.0), preferably 1:(3.0-7.0), more preferably 1:(4.0-6.0), and even more preferably 1:(5.0-6.0).

[0066] In a further preferred embodiment of the present invention, the zinc powder reduction reaction temperature in step (2) is above 30°C, preferably above 40°C, preferably above 50°C, preferably above 60°C, and more preferably carried out under reflux conditions.

[0067] In a further preferred embodiment of the present invention, the reaction time in step (2) is 20-100h, preferably 30-90h, and more preferably 40-80h.

[0068] In a further preferred embodiment of the present invention, in step (2), the reaction solution containing 1-aminoindane after the reaction is filtered to remove zinc powder, an organic solvent and water are added and stirred, allowed to stand and separate into layers, and the organic solvent extract is concentrated to obtain purified 1-aminoindane.

[0069] In a further preferred embodiment of the present invention, the filter cake after filtration in step (2) is first washed with a protic solvent, wherein the protic solvent is any one or a combination of methanol, ethanol, and isopropanol.

[0070] In a further preferred embodiment of the present invention, after the upper layer solution is allowed to stand and separate into layers in step (2), the upper layer solution can be extracted with organic solvent 1-5 times, preferably 2-3 times, and the organic solvent extracts are combined and concentrated.

[0071] In a further preferred embodiment of the present invention, in step (2), the upper layer solution after standing and separating is adjusted to pH 12-14 with sodium hydroxide or potassium hydroxide, and then an organic solvent is added for extraction; preferably sodium hydroxide solution, the concentration of the sodium hydroxide solution used is 5%-50%, more preferably 10-15% sodium hydroxide solution.

[0072] In a further preferred embodiment of the present invention, the organic solvent in step (2) is one or a combination of chloromethane, dichloromethane, trichloromethane, carbon tetrachloride, dichloroethane, dichloropropane, trichloroethane, and chloroform, preferably dichloromethane.

[0073] In a further preferred embodiment of the present invention, in step (2), the pH value of the mixed solution of organic solvent and water is adjusted to 1-2 using concentrated hydrochloric acid, and stirred for 0.1-1h, preferably 20-40min.

[0074] In a further preferred embodiment of the present invention, the resolving agent in step (3) is R-3-cyclohexenecarboxylic acid.

[0075] In a further preferred embodiment of the present invention, the molar ratio of R-3-cyclohexenecarboxylic acid to compound IV in step (3) is in the range of 1:(0.1-2.0), preferably 1:(0.2-1.0), more preferably 1:(0.3-7.0), and even more preferably 1:(0.40-0.50).

[0076] In a further preferred embodiment of the present invention, the solvent in step (3) is selected from any one or a combination of methanol, ethanol, isopropanol, ethyl acetate, isopropyl acetate, and n-butyl acetate, preferably a mixed solvent of isopropanol and isopropyl acetate.

[0077] Compared with the prior art, the present invention has the following advantages:

[0078] 1. In the preparation of 1-aminoindane, the present invention uses a zinc powder, ammonium chloride and alcohol reduction system, or a zinc powder, acetic acid and alcohol reduction system. This system does not add water, and the purity of the obtained 1-aminoindane can reach more than 86%. This avoids the problems of violent reaction, need for batch feeding, high safety risks and inability to be industrialized caused by using aluminum-nickel alloy system.

[0079] 2. In this invention, R-3-cyclohexenic acid is used to resolve 1-aminoindane. The salt formation of R-3-cyclohexenic acid and aminoindane is thermodynamically controlled. Under heating conditions, the salt formation of R-3-cyclohexenic acid and R-aminoindane is more stable. Therefore, the resolved R-aminoindane has better selectivity and higher yield.

[0080] 3. In the preparation process of (R)-(-)-1-aminoindenman in this invention, the overall reaction conditions are mild, the product purity is high, the quality of the finished drug is improved, and it is suitable for large-scale industrial production. Detailed Implementation

[0081] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Furthermore, it should be understood that after reading the teachings of this invention, those skilled in the art can make various alterations or modifications to the invention, and these equivalent forms also fall within the scope defined by the appended claims. Where specific conditions are not specified in the embodiments, conventional conditions or conditions recommended by the manufacturer are followed. Reagents or instruments whose manufacturers are not specified are all commercially available conventional products.

[0082] Example 1:

[0083] In a 20L reactor, 1-indanone (1.0 kg), hydroxylamine hydrochloride (0.8 kg), methanol (4.0 kg), and water (4.0 kg) were added and stirred until dissolved. Sodium hydroxide (0.6 kg) was dissolved in water (8.0 kg) and added dropwise after cooling to room temperature, controlling the temperature not to exceed 45℃. The reaction was stirred at 25-45℃ for 3 hours. The reaction was completed under TLC control. The mixture was then filtered, and the filter cake was washed with water until neutral. It was then dried at 50-70℃ to constant weight to obtain 1.05 kg of 2,3-dihydro-1H-indanone oxime (Formula III), with a yield of 94.29% and a purity of 99.215%.

[0084] Example 2:

[0085] In a 500 mL reaction flask, 1-indanone (20.0 g), hydroxylamine hydrochloride (21.03 g), ethanol (200.0 g), and sodium acetate (14.6 g) were added. The mixture was refluxed for 5 hours. After the reaction was completed under TLC, the ethanol was removed by concentration. 300 mL of water was added, and the mixture was cooled to room temperature and stirred for 2 hours. The mixture was then filtered, and the filter cake was washed with water until neutral. It was then dried at 50-70 °C to constant weight to obtain 21.3 g of 2,3-dihydro-1H-indan-1-one oxime (Formula III), with a yield of 95.63% and a purity of 98.637%.

[0086] Example 3:

[0087] In a 50L reactor, methanol (12.0 kg), reduced zinc powder (2.5 kg), ammonium chloride (3.0 kg), and 2,3-dihydro-1H-inden-1-one oxime (1.0 kg) were added, and the mixture was heated to reflux for 32 hours. The mixture was then cooled to room temperature, and the zinc powder was removed by filtration. The filter cake was soaked once in methanol (4.0 kg) and then filtered again. The combined filtrates were concentrated until no more distillate was obtained. Dichloromethane (8.0 kg), water (6.0 kg), and concentrated hydrochloric acid were added to adjust the pH to 1-2. (Approximately 500 mL of concentrated hydrochloric acid was used); the mixture was stirred for 30 minutes, and the lower layer of dichloromethane was separated and discarded; the pH of the aqueous phase was adjusted to 12-14 with 10% sodium hydroxide, and dichloromethane was added for extraction twice (5.0 kg / extraction). The dichloromethane extracts were combined and concentrated until no fraction was obtained, yielding 764.1 g of 1-aminoindene racemic mixture (Formula IV), a pale yellow oily liquid with a yield of 84.42% and a purity of 93.481%. No further purification was required, and the mixture was directly proceeded to the next step of resolution.

[0088] Example 4:

[0089] In a 500 mL reaction flask, add 240 mL of ethanol, 75.6 g of reduced zinc powder, 60 mL of acetic acid, and 30.0 g of 2,3-dihydro-1H-inden-1-one oxime. React at 35-45 °C for 80 hours. Filter to remove the zinc powder, and soak the filter cake once in 100 mL of ethanol and filter under vacuum. Combine the filtrates and concentrate until no more distillate is produced. Add 200 mL of dichloromethane and 200 mL of water, and adjust the pH to 1 with concentrated hydrochloric acid. 1-2. Stir for 30 minutes, separate and discard the lower layer of dichloromethane; adjust the pH of the aqueous phase to 12-14 with 10% sodium hydroxide, extract twice with dichloromethane (200 mL / time), combine the dichloromethane extracts, concentrate until no fraction is produced, and obtain 23.50 g of 1-aminoindene racemic mixture (formula IV), a pale yellow oily liquid with a yield of 85.56% and a purity of 87.707%. No further purification is required, proceed directly to the next step of separation.

[0090] Comparative Example 1:

[0091] In a 250 mL reaction flask, add 80 mL of ethanol, 9.5 g of reduced iron powder, 9.1 g of ammonium chloride, and 5.0 g of 2,3-dihydro-1H-indene-1-one oxime. Heat to 55-65 °C and react for 20 hours. Take 2 mL of the reaction solution, filter to remove the iron powder, and perform HPLC control. The results show that the content of 2,3-dihydro-1H-indene-1-one oxime in the reaction system is 63.712%, and the content of 1-aminoindene racemic mixture is 4.128%.

[0092] Comparative Example 2:

[0093] In a 250 mL reaction flask, add drinking water (50 mL), reduced zinc powder (11.1 g), concentrated hydrochloric acid (10.0 mL), and 2,3-dihydro-1H-indene-1-one oxime (5.0 g). Heat to 75-85 °C and react for 12 hours. Take 2 mL of the reaction solution, filter to remove zinc powder, and perform HPLC control. The results show that the content of 1-aminoindene racemic mixture in the reaction system is 21.874%.

[0094] Comparative Example 3:

[0095] In a 250 mL reaction flask, add 80 mL of ethanol, 11.1 g of reduced zinc powder, 14.2 mL of concentrated hydrochloric acid, and 5.0 g of 2,3-dihydro-1H-indene-1-one oxime. Heat to 55-65 °C and react for 20 hours. Take 2 mL of the reaction solution, filter to remove the zinc powder, and perform HPLC control. The results show that the content of 1-aminoindene racemic mixture in the reaction system is 67.693%.

[0096] Example 5:

[0097] In a 100 mL reaction flask, 5.0 g of 1-aminoindane racemic mixture from Example 3, 15 mL of isopropanol, 20 mL of isopropyl acetate, and 2.2 g (0.5 eq) of R-3-cyclohexenecarboxylic acid were added. The mixture was heated to 80-90 °C and stirred for 5 h, then cooled to 10-20 °C and stirred for 2 h. The mixture was filtered, and the filter cake was dried at 50-60 °C to constant weight to obtain 3.0 g of (R)-(-)-1-aminoindanecyclohexenecarboxylic acid salt, with a yield of 35.13%, a purity of 99.940%, and an optical purity of 99.681%.

[0098]

[0099] Example 6:

[0100] In a 100 mL reaction flask, add 5.0 g of the 1-aminoindane racemic mixture from Example 3, a mixed solvent of isopropanol / isopropyl acetate, and 2.2 g (0.5 eq) of R-3-cyclohexenecarboxylic acid. Heat to 80-90 °C and stir for 5 h, then cool to 10-20 °C and stir for 2 h. Filter and dry the filter cake at 50-60 °C to constant weight to obtain (R)-(-)-1-aminoindanecyclohexenecarboxylic acid salt.

[0101] Comparative Example 4:

[0102] In a 100 mL reaction flask, add 2.0 g of the racemic 1-aminoindene from Example 3 and 20.0 mL of methanol. Add the optically active organic acids listed in the table below to this solution. Heat the mixture to reflux and stir for 30 min, then cool to 20 ± 5 °C and stir for 3 h. Filter and dry the precipitated crystals. Determine the purity and optical purity of R-1-aminoindene. The results are shown in the table below:

[0103]

[0104] Although the present invention has been described in detail above, those skilled in the art will understand that various modifications and improvements can be made to the present invention without departing from the spirit and scope thereof.

Claims

1. A method for preparing 1-aminoindenyne, comprising the following steps: Compound III was reacted with reduced zinc powder in a protic solvent under acidic conditions to prepare compound IV, 1-aminoindane.

2. The method of claim 1, wherein the protic solvent is any one or a combination of methanol, ethanol, and isopropanol; and the acidic conditions are provided by ammonium chloride, ammonium acetate, and acetic acid.

3. The method according to claim 1 or 2, wherein the molar ratio of the compound of formula III to the reduced zinc powder is in the range of 1:(1.0-10.0), preferably 1:(2.0-8.0), more preferably 1:(3.0-7.0), more preferably 1:(4.0-6.0), and even more preferably 1:(5.0-6.0).

4. The method according to any one of claims 1-3, wherein the zinc powder reduction reaction temperature is above 30°C, preferably above 40°C, preferably above 50°C, preferably above 60°C, and more preferably carried out under reflux conditions; and the reaction time is 20-100h, preferably 30-90h, and more preferably 40-80h.

5. A method for purifying 1-aminoindenine obtained by the method according to any one of claims 1-4, comprising the following steps: The reaction solution containing 1-aminoindane was filtered to remove zinc powder. Organic solvent and water were added and stirred. The mixture was allowed to stand and separate into layers. The organic solvent extract was then concentrated to obtain purified 1-aminoindane.

6. The method as described in claim 5, wherein the filtered filter cake is first washed with a protic solvent, wherein the protic solvent is any one or a combination of methanol, ethanol, and isopropanol; after standing and separating, the upper layer solution can be further extracted with an organic solvent 1-5 times, preferably 2-3 times, and the organic solvent extracts are combined and concentrated.

7. The method of claim 6, wherein the upper layer solution after standing and separating is optionally adjusted to pH 12-14 with sodium hydroxide or potassium hydroxide before being extracted with an organic solvent; preferably a sodium hydroxide solution, wherein the concentration of the sodium hydroxide solution used is 5%-50%, more preferably a 10-15% sodium hydroxide solution; the organic solvent is one or a combination of chloromethane, dichloromethane, trichloromethane, carbon tetrachloride, dichloroethane, dichloropropane, trichloroethane, and chloroform, preferably dichloromethane.

8. A method for preparing (R)-(-)-1-aminoindenman, comprising the following steps: (1) The method according to any one of claims 1-7 is used to prepare compound of formula IV; (2) Compound IV was prepared by salt formation, crystallization and freeing in a solvent using a resolving agent to prepare (R)-(-)-1-aminoindane.

9. The method according to claim 8, wherein the resolving agent in step (3) is R-3-cyclohexenic acid; the molar ratio of R-3-cyclohexenic acid to compound IV in step (3) is in the range of 1:(0.1-2.0), preferably 1:(0.2-1.0), more preferably 1:(0.3-7.0), and more preferably 1:(0.40-0.50); ​​the solvent in step (3) is selected from any one or a combination of methanol, ethanol, isopropanol, ethyl acetate, isopropyl acetate, and n-butyl acetate, preferably a mixed solvent of isopropanol and isopropyl acetate.

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