A process for the preparation of trans-aminoindan

Abstract

The present application relates to the technical field of pharmaceutical intermediates, and in particular to a preparation method of trans-aminoindane, which comprises the following steps: taking indanone as a raw material, and reacting ammonium salt, a drying agent and a palladium-carbon catalyst in a hydrogen environment to generate trans-aminoindane; the present application has the advantages that: the content of the product, trans-aminoindane, is greater than 99%, the catalyst and the solvent can be recycled and reused, the operation is simple, the raw material is easy to obtain, the three-waste pollution is small, the energy consumption is low, and the present application is suitable for industrial production.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of organic synthesis, and particularly relates to a method for preparing trans-aminoindane. BACKGROUND

[0002] Aminoindane is an important pharmaceutical intermediate, which can be used to synthesize various drug compounds, and has the effects of anti-tumor, anti-hypertension, regulating endocrine and metabolic disorders, and improving abnormal heart rate. Trans-aminoindane is an important chiral pharmaceutical intermediate. The new drug rasagiline is mainly used for the treatment of Parkinson's disease, and is currently undergoing clinical research for the treatment of Alzheimer's disease (AD), depression, and hyperactivity in children. Trans-aminoindane is also one of the key intermediates for the synthesis of indaziflam. Indaziflam is a new herbicide developed by Bayer CropScience, which is mainly used for preventing annual weeds (such as horse pond, Chinese alpine, bluegrass, etc.) and 65 species of grass weeds and broadleaf weeds in lawns, flowers, and vegetation.

[0003] There are few reported methods for the synthesis of trans-aminoindane. Indenone is reacted with hydroxylamine hydrochloride / sodium acetate to form an intermediate oxime, and then trans-aminoindane is obtained by hydrogenation with palladium-carbon. This method has low efficiency in the synthesis of oxime, requires a large amount of solvent and generates a large amount of waste water, and the content of trans-aminoindane obtained at one time is only 60%, which needs recrystallization to obtain the trans-isomer, resulting in high production cost (CN108794339 A). Indenone is reduced to indane by sodium cyanoborohydride, which is a slow reaction that requires prolonged reaction time to obtain relatively pure product (Journal of Separation Science (2013), 36(23), 3682-3687). There is also a report that 2,6-dimethyl-1-indenone is used as a raw material, and asymmetric hydrogenation is carried out in the presence of a chiral catalyst based on rhodium or ruthenium to obtain cis-hydroxyindane. Then, Mitsunobu reaction is used to replace the hydroxyl group with azide in DPPA, and then LiAlH4 is used for reduction to obtain trans-aminoindane. Although this scheme does not produce waste isomers, the reactions used are complex, the chiral catalyst used in asymmetric hydrogenation and the reagents used in Mitsunobu and reduction reactions are expensive, and can only be prepared in the laboratory, which is not suitable for process scale-up (Tetrahedron 2007, 63(29), 6755-6763). The patent CN106414420A of Bayer CropScience also discloses its synthesis scheme. This method uses a phthaloyl-protected bromide as a raw material, and cyclizes under the catalysis of Pd(PPh3)4 to obtain an intermediate. The intermediate is deprotected with hydrazine hydrate to obtain a racemic trans-isomer. SUMMARY

[0004] The present application aims to use indanone as raw material, through ammonium salt, drying agent and palladium-carbon catalyst to react in hydrogen environment to generate trans-aminoindane. The present application has the advantages of directly synthesizing trans-aminoindane through cheap and easily available indanone in one step, which is more convenient than the method of generating oxime from indanone and then catalytic hydrogenation, has mild reaction conditions, high yield, small environmental pollution, low three wastes, and good industrialization prospect.

[0005] The present application provides a preparation method of trans-aminoindane, which comprises the following steps: (1) adding indanone compound (I), solvent, ammonium salt and drying agent into a hydrogenation kettle, replacing with inert gas (such as nitrogen) for three times, then adding hydrogen gas with a certain pressure, stirring and reacting at a specified temperature; (2) cooling the system to room temperature after the reaction is completed, removing the solvent by concentration, adding water, extracting with toluene, drying and removing the solvent by concentration to obtain trans-aminoindane. The specific steps are as follows:

[0006]

[0007] In the step (1), the substituent R1 in the indanone compound (I) is one of hydrogen, methyl, ethyl, isopropyl, methoxy and halogen, and R2 is one of methyl, ethyl, isopropyl, phenyl and halogen;

[0008] In the step (1), the weight ratio of the palladium-carbon catalyst to indanone is 1:10-1000, preferably 1:20-100;

[0009] In the step (1), the solvent is one or more of water, methanol, ethanol, acetonitrile, trifluoroethanol and tetrahydrofuran; the mass concentration of the indanone compound (I) in the solvent is 0.1-30%, preferably 5-20%;

[0010] In the step (1), the ammonium salt is one of ammonium acetate, ammonium chloride and ammonium sulfate; the molar ratio of the ammonium salt to indanone is 0.5-10:1, preferably 1-3:1;

[0011] In the step (1), the drying agent is one of anhydrous magnesium sulfate, anhydrous calcium chloride and 4A molecular sieve; the mass ratio of the drying agent to indanone is 0.05-5:1, preferably 0.1-0.5:1;

[0012] In the step (1), the hydrogen pressure is 0.1-10 MPa, preferably 1-3 MPa; the reaction temperature is 0-200°C, preferably 50-80°C;

[0013] In the step (2), the volume of water added is 0.1-2:1, preferably 0.2-0.5:1, of the volume of the remaining reaction system liquid;

[0014] In the step (2), the weight ratio of the amount of toluene added to water is 2-1:1;

[0015] The present application has the advantages that the content of the product aminoindan trans-form is greater than 99%, the catalyst and solvent can be recycled, the operation is simple, the raw materials are easy to obtain, the pollution of three wastes is small, the energy consumption is low, and the industrial production is suitable. BRIEF DESCRIPTION OF DRAWINGS

[0016] Figure 1 Gas chromatogram of 2,6-dimethyl-1-aminoinandan obtained from Example 1;

[0017] Figure 2 NMR hydrogen spectrum of 2,6-dimethyl-1-aminoinandan obtained from Example 1. DETAILED DESCRIPTION

[0018] The following examples will further illustrate the present application, but are not intended to limit the present application. The nuclear magnetic resonance of the product in the examples is determined by a Bruker 400M nuclear magnetic resonance instrument. The analysis of 2,6-dimethyl-1-aminoinandan is determined by an Agilent 7890 series gas chromatograph, and the conditions are as follows: chromatographic column: PEG20M: 30m*320μm*0.25μm, pre-column pressure: 9.8764mp (flow rate 1.5ml / min) injection port temperature: 250 degrees, detector temperature: 250 degrees, column temperature: 50 degrees, hold for 2 minutes, program rise speed 10 degrees / min, final temperature 280 degrees, hold for 5 minutes.

[0019] Example 1

[0020] In a pressure kettle (hydrogenation kettle, hydrogenation reaction kettle), 2,6-dimethyl-1-indanone 32.0 grams, ammonium acetate 31.0 grams, anhydrous ethanol 200 milliliters, 5% palladium on carbon (5% represents that the mass content of palladium in the catalyst is 5%, and the meaning of 5% palladium on carbon in the following examples is the same as here) 0.45 grams, 4A molecular sieve powder (d<50μm) 3.5 grams, under stirring, nitrogen replacement 3 times, 2.0MP hydrogen gas is added, the system temperature is raised to 80 degrees Celsius, and the reaction is maintained for 20 hours, and then the temperature is lowered to room temperature, filtered, and the catalyst is washed with ethanol and then recycled, the mother liquor is concentrated under reduced pressure, 55ml of residue is added, water 20.0 grams, stirred for 10 minutes, then toluene 35.0 grams is added, stirred for 10 minutes, and then separated by standing, the organic layer is washed with saturated brine, dried with anhydrous sodium sulfate, and then toluene is removed by concentration to obtain 2,6-dimethyl-1-aminoinandan 31.5 grams, with a yield of 97.8%. The gas chromatographic analysis of the product shows that the molar ratio of trans-form / cis-form is 99 / 1. The nuclear magnetic hydrogen spectrum data are as follows:

[0021] 1H NMR (400 MHz, DMSO) δ 7.11 (s, 1H), 7.00 (d, J = 7.5 Hz, 1H), 6.92 (d, J = 7.7 Hz, 1H), 3.56 (d, J = 8.6 Hz, 1H), 2.86 (dd, J = 15.1, 7.5 Hz, 1H), 2.27 (s, 3H), 1.99 - 1.82 (m, 1H), 1.78 (s, 2H), 1.18 (d, J = 6.6 Hz, 3H).

[0022] Example 2

[0023] In a pressure vessel, 2,6-dimethyl-1-indanone 32.0 g, ammonium acetate 31.0 g, trifluoroethanol 200 ml, 5% palladium on carbon 0.32 g, anhydrous calcium chloride 3.5 g, under stirring, nitrogen was replaced for 3 times, then 2.0 MP hydrogen was added, the system temperature was raised to 80 degree Celsius, the reaction was kept for 20 hours, then the temperature was lowered to room temperature, filtration was carried out, the catalyst was washed with ethanol, then it was recycled, the mother liquor was concentrated under reduced pressure, 45 ml remained, then water 20 g was added, stirring was carried out for 10 minutes, then toluene 30.0 g was added, stirring was carried out for 10 minutes, then it was left to stand, the liquid was separated, the organic layer was washed with saturated brine, then it was dried over anhydrous sodium sulfate, then toluene was removed by concentration, then 2,6-dimethyl-1- aminoindeane 30.3 g was obtained, the yield was 94.1%, gas chromatography analysis showed that the trans / cis was 99 / 1.

[0024] Example 3

[0025] In a pressure vessel, 2-methyl-1-indanone 29.2 g, ammonium acetate 28.0 g, anhydrous methanol 200 ml, 5% palladium on carbon 0.3 g, anhydrous magnesium sulfate 3.0 g, under stirring, nitrogen was replaced for 3 times, then 2.5 MP hydrogen was added, the system temperature was raised to 65 degree Celsius, the reaction was kept for 20 hours, then the temperature was lowered to room temperature, filtration was carried out, the catalyst was washed with methanol, then it was recycled, the mother liquor was concentrated under reduced pressure, 44 ml remained, then water 20.0 g was added, stirring was carried out for 10 minutes, then toluene 30.0 g was added, stirring was carried out for 10 minutes, then it was left to stand, the liquid was separated, the organic layer was washed with saturated brine, then it was dried over anhydrous sodium sulfate, then toluene was removed by concentration, then 2-methyl-1- aminoindeane 28 g was obtained, the yield was 95.2%, gas chromatography analysis showed that the trans / cis was 98 / 2.

[0026] Example 4

[0027] In a pressure vessel, add 2-methyl-6-ethyl-1-indanone 34.8 g, ammonium sulfate 35.0 g, absolute ethanol 200 ml, 5% palladium on carbon 0.5 g, 4A molecular sieves (powder) 4.0 g, stir under nitrogen for 3 times, then add 3.0 MP hydrogen gas, raise the temperature to 80 °C, keep the reaction for 20 hours, cool to room temperature, filter, wash the catalyst with ethanol, then recycle, concentrate the mother liquor under reduced pressure, add water 20.0 g to the 52 ml residue, stir for 10 minutes, then add toluene 30.0 g, stir for 10 minutes, stand to separate, wash the organic layer with saturated brine, dry over anhydrous sodium sulfate, concentrate to remove toluene, then get 2-methyl-6-ethyl-1- aminoinadan 33.6 g, yield 96.0%. Gas chromatography analysis shows that the trans / cis ratio is 99 / 1.

[0028] Example 5

[0029] In a pressure vessel, add 2-methyl-6-ethyl-1-indanone 34.8 g, ammonium sulfate 35.0 g, absolute ethanol 200 ml, 5% palladium on carbon 0.5 g, 4A molecular sieves (powder) 4.0 g, stir under nitrogen for 3 times, then add 3.0 MP hydrogen gas, raise the temperature to 80 °C, keep the reaction for 20 hours, cool to room temperature, filter, wash the catalyst with ethanol, then recycle, concentrate the mother liquor under reduced pressure, add water 20.0 g to the 52 ml residue, stir for 10 minutes, then add toluene 30.0 g, stir for 10 minutes, stand to separate, wash the organic layer with saturated brine, dry over anhydrous sodium sulfate, concentrate to remove toluene, then get 2-methyl-6-ethyl-1- aminoinadan 33.6 g, yield 96.0%. Gas chromatography analysis shows that the trans / cis ratio is 99 / 1.

[0030] Example 6

[0031] In a pressure vessel, add 2-methyl-6-ethyl-1-indanone 34.8 g, ammonium sulfate 35.0 g, absolute ethanol 200 ml, 5% palladium on carbon 0.5 g, 4A molecular sieves (powder) 4.0 g, stir under nitrogen for 3 times, then add 3.0 MP hydrogen gas, raise the temperature to 80 °C, keep the reaction for 20 hours, cool to room temperature, filter, wash the catalyst with ethanol, then recycle, concentrate the mother liquor under reduced pressure, add water 20.0 g to the 52 ml residue, stir for 10 minutes, then add toluene 30.0 g, stir for 10 minutes, stand to separate, wash the organic layer with saturated brine, dry over anhydrous sodium sulfate, concentrate to remove toluene, then get 2-methyl-6-ethyl-1- aminoinadan 33.6 g, yield 96.0%. Gas chromatography analysis shows that the trans / cis ratio is 99 / 1.

[0032] Example 7

[0033] In a pressure vessel was charged 2-methyl-6-chloro-1-indanone 36.1 g, ammonium acetate 31.0 g, acetonitrile 200 ml, 5% palladium on carbon 0.6 g, 4A molecular sieves (powder) 35.0 g, stirred, purged with nitrogen 3 times, charged with 2.0 MP hydrogen, the temperature of the system was raised to 80°C, the reaction was maintained for 20 hours, the temperature was lowered to room temperature, filtered, the catalyst was washed with acetonitrile and recycled, the mother liquor was concentrated under reduced pressure, 48 ml of residue was charged with water 20.0 g, stirred for 10 minutes, charged with toluene 30.0 g, stirred for 10 minutes, allowed to stand and separated, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated to remove toluene, 2-methyl-6-chloro-1- aminoindeane 30.7 g was obtained, the yield was 84.6%. The analysis of gas chromatography showed that the trans / cis ratio was 95 / 5.

[0034] Example 8

[0035] In a pressure vessel was charged 2-methyl-6-chloro-1-indanone 36.1 g, ammonium acetate 31.0 g, acetonitrile 200 ml, 5% palladium on carbon 0.6 g, 4A molecular sieves (powder) 35.0 g, stirred, purged with nitrogen 3 times, charged with 2.0 MP hydrogen, the temperature of the system was raised to 80°C, the reaction was maintained for 20 hours, the temperature was lowered to room temperature, filtered, the catalyst was washed with acetonitrile and recycled, the mother liquor was concentrated under reduced pressure, 48 ml of residue was charged with water 20.0 g, stirred for 10 minutes, charged with toluene 30.0 g, stirred for 10 minutes, allowed to stand and separated, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated to remove toluene, 2-methyl-6-chloro-1- aminoindeane 30.7 g was obtained, the yield was 84.6%. The analysis of gas chromatography showed that the trans / cis ratio was 95 / 5.

[0036] Example 9

[0037] In a pressure vessel was charged 2-methyl-6-chloro-1-indanone 36.1 g, ammonium acetate 31.0 g, acetonitrile 200 ml, 5% palladium on carbon 0.6 g, 4A molecular sieves (powder) 35.0 g, stirred, purged with nitrogen 3 times, charged with 2.0 MP hydrogen, the temperature of the system was raised to 80°C, the reaction was maintained for 20 hours, the temperature was lowered to room temperature, filtered, the catalyst was washed with acetonitrile and recycled, the mother liquor was concentrated under reduced pressure, 48 ml of residue was charged with water 20.0 g, stirred for 10 minutes, charged with toluene 30.0 g, stirred for 10 minutes, allowed to stand and separated, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated to remove toluene, 2-methyl-6-chloro-1- aminoindeane 30.7 g was obtained, the yield was 84.6%. The analysis of gas chromatography showed that the trans / cis ratio was 95 / 5.

[0038] Example 10

[0039] In a pressure vessel was charged 2-methyl-1-indanone 29.2 g, ammonium acetate 31.0 g, absolute ethanol 200 ml, after 5 cycles of recovery, palladium on carbon 0.5 g, 4A molecular sieve (powder) 35.0 g, under stirring, nitrogen was replaced for 3 times, then 2.0 MP hydrogen was added, the system temperature was raised to 80 degree Celsius, the reaction was maintained for 20 hours, the temperature was lowered to room temperature, filtration was performed, the catalyst was washed with ethanol and then recycled, the mother liquor was concentrated under reduced pressure, 38 ml remained, water 15.0 g was added, stirring was performed for 10 minutes, then toluene 20.0 g was added, stirring was performed for 10 minutes, standing was performed for liquid separation, saturated brine was used for washing, anhydrous sodium sulfate was used for drying, toluene was removed by concentration, 2-methyl-1-aminoindeane 28.5 g was obtained, the yield was 96.9%, gas chromatography analysis showed that the trans / cis ratio was 98 / 2.

[0040] Example 11

[0041] In a pressure vessel was charged 6-chloro-2-methoxy-1-indanone 39.3 g, ammonium chloride 15.0 g, absolute methanol 200 ml, 5% palladium on carbon 0.5 g, 4A molecular sieve (powder) 35.0 g, under stirring, nitrogen was replaced for 3 times, then 1.8 MP hydrogen was added, the system temperature was raised to 60 degree Celsius, the reaction was maintained for 20 hours, the temperature was lowered to room temperature, filtration was performed, the catalyst was washed with methanol and then recycled, the mother liquor was concentrated under reduced pressure, 40 ml remained, water 15.0 g was added, stirring was performed for 10 minutes, then toluene 20.0 g was added, stirring was performed for 10 minutes, standing was performed for liquid separation, saturated brine was used for washing, anhydrous sodium sulfate was used for drying, toluene was removed by concentration, 2,6-dimethyl-1-aminoindeane 27.9 g was obtained, the yield was 86.6%, gas chromatography analysis showed that the trans / cis ratio was 97 / 3.

[0042] Comparative Example 1 (CN108794339A)

[0043] 200.0 g of 2,6-dimethyl-1-indanone was dissolved in 1000 ml of an ethanol solution, and 307 g of a sodium acetate aqueous solution was quickly added dropwise to the reaction system. Refluxing was performed, TLC detection showed that the reaction was complete after 2-3 hours. The ethanol was concentrated, the reaction liquid was extracted with ethyl acetate, the combined organic phase was dried and concentrated to obtain a yellowish oil of a crude product.

[0044] In a 1000 ml hydrogenation kettle, the above-mentioned 240.0 g of a crude product was dissolved in 600.0 ml of methanol, 24 g of 10% Pd / C, 24 ml of acetic acid were added, and the hydrogen pressure was 2.0 MP. The temperature was heated to about 55 degree Celsius, and the reaction was carried out overnight. The Pd / C catalyst was removed by filtration, the methanol was recovered by concentration, and the crude product was recrystallized with methanol to obtain white solid 2,6-dimethyl-1-aminoindeane acetate 270 g, the yield was 98%, HPLC detection showed that the trans and cis isomers in 2,6-dimethyl-1-aminoindeane acetate were in a ratio of 60:40.

Claims

1. A method for preparing trans-aminoindane, characterized in that: The preparation method uses indanone as a starting material and specifically includes the following steps: ； Indene compound (I), ammonium salt, solvent, palladium on carbon catalyst, and desiccant were added to a hydrogenation reactor. After the atmosphere inside the hydrogenation reactor was replaced with an inert atmosphere, hydrogen was added and the reaction was stirred to obtain trans-aminoindene. In the indanone compound (Ⅰ), the substituent R1 is one or more of hydrogen, methyl, ethyl, isopropyl, methoxy, F, Cl, Br, and I, and R2 is one or more of methyl, ethyl, isopropyl, phenyl, F, Cl, Br, and I. The ammonium salt is one or more of ammonium acetate, ammonium chloride, and ammonium sulfate; The desiccant is one or more of anhydrous magnesium sulfate, anhydrous calcium chloride, and 4A molecular sieve. The hydrogen pressure in the hydrogenation reactor is 0.1-10 MPa, the reaction temperature is 0-200℃, and the reaction time is 12-48 hours. After the reaction is completed, the system is cooled to room temperature, solid-liquid separation is performed, the liquid is concentrated to remove the solvent, water is added, toluene is extracted, and the system is dried and concentrated to remove the solvent.

2. The method according to claim 1, characterized in that: The palladium content in the palladium-on-carbon catalyst is 3%-10% by mass; the weight ratio of the palladium-on-carbon catalyst to the indanone compound (Ⅰ) is 1:10-1000.

3. The method according to claim 2, characterized in that: The weight ratio of palladium on carbon catalyst to indanone compound (Ⅰ) is 1:20-100.

4. The method according to claim 1, characterized in that: The solvent is selected from one or more of water, methanol, ethanol, acetonitrile, trifluoroethanol, and tetrahydrofuran; the indanone compound (Ⅰ) is present in the solvent at a mass concentration of 0.1-30%.

5. The method according to claim 4, characterized in that: The indanone compound (Ⅰ) is present in a concentration of 5-20% by mass.

6. The method according to claim 1, characterized in that: The molar ratio of the ammonium salt to indanone is 0.5-10:

1.

7. The method according to claim 6, characterized in that: The molar ratio of the ammonium salt to indanone is 1-3:

1.

8. The method according to claim 1, characterized in that: The mass ratio of the desiccant to indanone is 0.05-5:

1.

9. The method according to claim 8, characterized in that: The mass ratio of the desiccant to indanone is 0.1-0.5:

1.

10. The method according to claim 1, characterized in that: The hydrogen pressure in the hydrogenation reactor is 1-3 MPa; the reaction temperature is 50-80℃; and the reaction time is 18-24 hours.

11. The method according to claim 1, characterized in that: The volume of water added is 0.1-2 times the volume of the remaining reaction system liquid.

12. The method according to claim 11, characterized in that: The volume of water added is 0.2-0.5 times the volume of the remaining reaction system liquid.

13. The method according to claim 1, characterized in that: The weight ratio of the added toluene to water is 2-1:1.

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