Preparation method of trans-aminoindan

Abstract

The invention relates to the technical field of drug intermediates, in particular to a preparation method of trans-aminoindane, which comprises the following steps: by taking indanone as a raw material, reacting with ammonium salt, a drying agent and a palladium-carbon catalyst in a hydrogen environment to generate trans-aminoindane; the method has the advantages that the content of the product aminoindane trans-form is more than 99%, the catalyst and the 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 method is suitable for industrial production.

Description

Technical Field

[0001] The invention belongs to the field of organic synthesis, and in particular relates to a method for preparing trans-aminoindane. Background Art

[0002] Aminoids are an important class of pharmaceutical intermediates that can be used to synthesize a variety of API compounds. They have anti-tumor, anti-hypertensive, endocrine and metabolic disorder regulating, and heart rate improvement effects. Among them, trans-aminoindanes are important chiral drug intermediates. The new drug rasagiline is mainly used for the treatment of Parkinson's disease. Currently, clinical studies are underway for the treatment of Alzheimer's disease (AD), depression, and childhood hyperactivity disorder. Trans-aminoindanes are also one of the key intermediates for the synthesis of triaziflan. Triaziflan is a new herbicide developed by Bayer CropScience. It is mainly used to control annual weeds (such as horsetails, goosegrass, bluegrass, etc.) in lawns, flowers, and vegetation, as well as 65 species of grass-based weeds and broadleaf weeds.

[0003] There are not many methods reported for the synthesis of trans-aminoindanes. Indanone is reacted with hydroxylamine hydrochloride / sodium acetate to generate an intermediate product oxime, which is then hydrogenated with palladium carbon to obtain trans-aminoindanes. This method is inefficient in synthesizing oximes, requires a large amount of solvent and generates a large amount of wastewater, and the content of trans-aminoindan obtained at one time is only 60%. Recrystallization is required to obtain the trans isomer, and the production cost is high (CN108794339 A); indanone is reduced to indamine by sodium cyanoborohydride, and the reaction is slow and the reaction time needs to be extended to obtain a relatively pure product (Journal of Separation Science (2013), 36 (23), 3682-3687); There are also reports that 2,6-dimethyl-1-indanone is used as a raw material, asymmetric hydrogenation is carried out in the presence of a rhodium or ruthenium-based chiral catalyst to obtain a cis-hydroxyindane, and then the hydroxyl group is replaced by the azide in DPPA by the Mitsunobu reaction, and then reduced with LiAlH4 to obtain a trans-aminoindane. Although this scheme does not produce waste isomers, the reaction used is complicated, the chiral catalyst in the asymmetric hydrogenation and the reagents used in the Mitsunobu and reduction reactions are expensive, and can only be prepared in the laboratory, which is not suitable for process-scale production (Tetrahedron 2007, 63 (29), 6755-6763). Bayer CropScience's patent CNl06414420A also discloses its synthesis scheme, which uses a phthaloyl-protected bromide raw material to undergo cyclization under the catalysis of Pd(PPh3)4 to obtain an intermediate, and the intermediate is then deprotected with hydrazine hydrate to obtain a racemic trans isomer. Summary of the invention

[0004] The purpose of the present invention is to use indanone as a raw material, and to generate trans-aminoindan through the reaction of ammonium salt, desiccant and palladium carbon catalyst in a hydrogen environment. The advantage of the invention is that the indanone is cheap and easy to obtain, and the trans-aminoindan is directly synthesized in one step. Compared with the method of generating oxime through indanone, the method of catalytic hydrogenation is simpler, the reaction conditions are mild, the yield is high, the environmental pollution is small, the three wastes are low, and it has good industrialization prospects.

[0005] The present invention provides a method for preparing trans-aminoindan, which comprises the following steps: step (1) adding an indanone compound (I), a solvent, an ammonium salt and a desiccant to a hydrogenation kettle, replacing the inert atmosphere gas (such as nitrogen) three times, adding hydrogen gas under a certain pressure, stirring, and reacting at a specified temperature; step (2) after the reaction is completed, cooling the system to room temperature, concentrating to remove the solvent, adding water, extracting with toluene, drying, concentrating to remove the solvent, and obtaining trans-aminoindan. The specific steps are:

[0006]

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

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

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

[0010] The ammonium salt in step (1) 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] The desiccant in step (1) is one of anhydrous magnesium sulfate, anhydrous calcium chloride, and 4A molecular sieve; the mass ratio of the desiccant to indanone is 0.05-5:1, preferably 0.1-0.5:1;

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

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

[0014] The weight ratio of toluene added to water in step (2) is 2-1:1;

[0015] The invention has the advantages that the content of the aminoindan trans isomer in the product is greater than 99%, the catalyst and the solvent can be recycled, the operation is simple, the raw materials are easily available, the three wastes pollution is small, the energy consumption is low, and it is suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0016] Figure 1 The gas chromatogram of 2,6-dimethyl-1-aminoindane obtained in Example 1;

[0017] Figure 2 This is the H NMR spectrum of 2,6-dimethyl-1-aminoindane obtained in Example 1. DETAILED DESCRIPTION

[0018] The following examples will further illustrate the present invention, but the present invention is not limited thereto. The nuclear magnetic resonance of the product in the example is measured by a Bruker 400M nuclear magnetic resonance instrument. The analysis of 2,6-dimethyl-1-aminoindan is determined by an Agilent 7890 series gas chromatograph, and the conditions are as follows: chromatographic column: PEG20M: 30m*320μm*0.25μm, column front 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, ramp rate 10 degrees / minute, end temperature 280 degrees, hold for 5 minutes.

[0019] Example 1

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

[0021] 1H NMR (400MHz, DMSO) δ7.11(s,1H),7.00(d,J=7.5Hz,1H),6.92(d,J=7.7Hz,1H),3.56(d,J=8.6Hz,1H ),2.86(dd,J=15.1,7.5Hz,1H),2.27(s,3H),1.99–1.82(m,1H),1.78(s,2H),1.18(d,J=6.6Hz,3H).

[0022] Example 2

[0023] 32.0 g of 2,6-dimethyl-1-indanone, 31.0 g of ammonium acetate, 200 ml of trifluoroethanol, 0.32 g of 5% palladium carbon, and 3.5 g of anhydrous calcium chloride were added to the autoclave under stirring. After nitrogen replacement for 3 times, 2.0 MP of hydrogen was added. The system temperature was raised to 80 degrees Celsius, and the reaction was maintained for 20 hours. The temperature was lowered to room temperature, filtered, the catalyst was washed with ethanol, and recycled. The mother liquor was concentrated under reduced pressure, 20 g of water was added to 45 ml of the residue, stirred for 10 minutes, and 30.0 g of toluene was added. Stirred for 10 minutes, the liquid was separated by standing, the organic layer was washed with saturated salt water, dried with anhydrous sodium sulfate, and concentrated to remove toluene to obtain 30.3 g of 2,6-dimethyl-1-aminoindan, with a yield of 94.1%. Gas chromatography analysis showed that the trans-isomer / cis-isomer was 99 / 1.

[0024] Example 3

[0025] Add 29.2 g of 2-methyl-1-indanone, 28.0 g of ammonium acetate, 200 ml of anhydrous methanol, 0.3 g of 5% palladium carbon, and 3.0 g of anhydrous magnesium sulfate to the autoclave, and replace the nitrogen three times under stirring. Then add 2.5 MP hydrogen and raise the system temperature to 65 degrees Celsius. Keep the reaction for 20 hours, cool to room temperature, filter, wash the catalyst with methanol, recycle and reuse, concentrate the mother liquor under reduced pressure, add 20.0 g of water to the 44 ml residue, stir for 10 minutes, add 30.0 g of toluene, stir for 10 minutes, stand for separation, wash the organic layer with saturated salt water, dry with anhydrous sodium sulfate, and concentrate to remove toluene to obtain 28 g of 2-methyl-1-aminoindan, with a yield of 95.2%. Gas chromatography analysis shows that the trans isomer / cis isomer is 98 / 2.

[0026] Example 4

[0027] 34.8 g of 2-methyl-6-ethyl-1-indanone, 35.0 g of ammonium sulfate, 200 ml of anhydrous ethanol, 0.5 g of 5% palladium carbon, and 4.0 g of 4A molecular sieve (powder) were added to the autoclave under stirring. After nitrogen replacement for 3 times, 3.0 MP of hydrogen was added. The system temperature was raised to 80 degrees Celsius, and the reaction was maintained for 20 hours. The temperature was lowered to room temperature, filtered, and the catalyst was washed with ethanol, recycled and reused, and the mother liquor was concentrated under reduced pressure. 20.0 g of water was added to 52 ml of the residue, and after stirring for 10 minutes, 30.0 g of toluene was added, and stirred for 10 minutes. The liquid was separated by standing, and the organic layer was washed with saturated salt water, dried over anhydrous sodium sulfate, and concentrated to remove toluene to obtain 33.6 g of 2-methyl-6-ethyl-1-aminoindan, with a yield of 96.0%. Gas chromatography analysis showed that the trans isomer / cis isomer was 99 / 1.

[0028] Example 5

[0029] 43.2 g of 2,6-diisopropyl-1-indanone, 31.0 g of ammonium acetate, 200 ml of anhydrous methanol, and 0.8 g of 5% palladium carbon were added to the autoclave under stirring. After nitrogen replacement for 3 times, 2.0 MP hydrogen was added. The system temperature was raised to 80 degrees Celsius, and the reaction was maintained for 20 hours. The temperature was lowered to room temperature, filtered, the catalyst was washed with ethanol, and recycled. The mother liquor was concentrated under reduced pressure, 25.0 g of water was added to 55 ml of the residue, stirred for 10 minutes, and 30.0 g of toluene was added. Stirred for 10 minutes, the liquid was separated by standing, the organic layer was washed with saturated salt water, dried with anhydrous sodium sulfate, and concentrated to remove toluene to obtain 42.5 g of 2,6-diisopropyl-1-aminoindan, with a yield of 97.8%. Gas chromatography analysis showed that the trans-isomer / cis-isomer was 99 / 1.

[0030] Example 6

[0031] 32.0 g of 2,6-dimethyl-1-indanone, 20.0 g of ammonium chloride, 200 ml of anhydrous methanol, 0.5 g of 5% palladium carbon, and 35.0 g of 4A molecular sieve (powder) were added to the autoclave, and the nitrogen was replaced 3 times under stirring. Then 1.8 MP hydrogen was added, and the system temperature was raised to 60 degrees Celsius. The reaction was maintained for 20 hours, and the temperature was lowered to room temperature, filtered, and the catalyst was washed with methanol, recycled and reused, and the mother liquor was concentrated under reduced pressure. 15.0 g of water was added to 40 ml of the residue, and after stirring for 10 minutes, 20.0 g of toluene was added, and stirred for 10 minutes. The liquid was separated by standing, and the organic layer was washed with saturated salt water, dried with anhydrous sodium sulfate, and concentrated to remove toluene to obtain 27.9 g of 2,6-dimethyl-1-aminoindan, with a yield of 86.6%. Gas chromatography analysis showed that the trans isomer / cis isomer was 97 / 3.

[0032] Example 7

[0033] 36.1 g of 2-methyl-6-chloro-1-indanone, 31.0 g of ammonium acetate, 200 ml of acetonitrile, 0.6 g of 5% palladium carbon, and 35.0 g of 4A molecular sieve (powder) were added to the autoclave under stirring. After nitrogen replacement for 3 times, 2.0 MP of hydrogen was added. The system temperature was raised to 80 degrees Celsius, and 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, 20.0 g of water was added to 48 ml of the residue, and after stirring for 10 minutes, 30.0 g of toluene was added, and the mixture was stirred for 10 minutes. The mixture was allowed to stand for separation, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to remove toluene to obtain 30.7 g of 2-methyl-6-chloro-1-aminoindan, with a yield of 84.6%. The trans-isomer / cis-isomer ratio was 95 / 5 by gas chromatography analysis.

[0034] Example 8

[0035] 37.6 g of 2-methyl-6-isopropyl-1-indanone, 31.0 g of ammonium acetate, 250 ml of anhydrous methanol, 0.66 g of 5% palladium carbon, and 35.0 g of 4A molecular sieve (powder) were added to the autoclave under stirring. After nitrogen replacement for 3 times, 2.0 MP hydrogen was added. The system temperature was raised to 80 degrees Celsius, and the reaction was maintained for 20 hours. The temperature was lowered to room temperature, filtered, the catalyst was washed with methanol, and recycled, the mother liquor was concentrated under reduced pressure, 20.0 g of water was added to 45 ml of the residue, stirred for 10 minutes, 20.0 g of toluene was added, stirred for 10 minutes, and the liquid was separated by standing. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to remove toluene to obtain 35.5 g of 2-methyl-6-isopropyl-1-aminoindan, with a yield of 93.9%. Gas chromatography analysis showed that the trans isomer / cis isomer was 98 / 2.

[0036] Example 9

[0037] Add 32.0 g of 2,6-dimethyl-1-indanone, 31.0 g of ammonium acetate, 200 ml of anhydrous ethanol, 0.32 g of palladium carbon, 35.0 g of 4A molecular sieve (powder) to the autoclave, and replace with nitrogen three times under stirring. Then add 2.0 MP hydrogen, raise the system temperature to 80 degrees Celsius, keep the reaction for 20 hours, cool to room temperature, filter, wash the catalyst with ethanol, recycle and reuse, concentrate the mother liquor under reduced pressure, add 15.0 g of water to 40 ml of the residue, stir for 10 minutes, add 25.0 g of toluene, stir for 10 minutes, stand for separation, wash with saturated brine, dry with anhydrous sodium sulfate, concentrate and remove toluene, and obtain 31.8 g of 2,6-dimethyl-1-aminoindan, with a yield of 98.8%. Gas chromatography analysis shows that the trans isomer / cis isomer is 99 / 1.

[0038] Example 10

[0039] Add 29.2 g of 2-methyl-1-indanone, 31.0 g of ammonium acetate, 200 ml of anhydrous ethanol to the autoclave, recycle 5 times, add 0.5 g of palladium carbon, 35.0 g of 4A molecular sieve (powder), stir, replace with nitrogen 3 times, add 2.0 MP hydrogen, raise the system temperature to 80 degrees Celsius, keep the reaction for 20 hours, cool to room temperature, filter, wash the catalyst with ethanol, recycle and reuse, concentrate the mother liquor under reduced pressure, add 15.0 g of water to 38 ml of the residue, stir for 10 minutes, add 20.0 g of toluene, stir for 10 minutes, stand for separation, wash with saturated brine, dry with anhydrous sodium sulfate, concentrate and remove toluene, and obtain 28.5 g of 2-methyl-1-aminoindan, with a yield of 96.9%. Gas chromatography analysis shows that the trans isomer / cis isomer is 98 / 2.

[0040] Implementation 11

[0041] 39.3 g of 6-chloro-2-methoxy-1-indanone, 15.0 g of ammonium chloride, 200 ml of anhydrous methanol, 0.5 g of 5% palladium carbon, and 35.0 g of 4A molecular sieve (powder) were added to the autoclave, and the nitrogen was replaced 3 times under stirring. Then 1.8 MP hydrogen was added, and the system temperature was raised to 60 degrees Celsius. The reaction was maintained for 20 hours, and the temperature was lowered to room temperature, filtered, and the catalyst was washed with methanol, recycled and reused, and the mother liquor was concentrated under reduced pressure. 15.0 g of water was added to 40 ml of the residue, and after stirring for 10 minutes, 20.0 g of toluene was added, and stirred for 10 minutes. The liquid was separated by standing, and the organic layer was washed with saturated brine, dried with anhydrous sodium sulfate, and concentrated to remove toluene to obtain 27.9 g of 2,6-dimethyl-1-aminoindan, with a yield of 86.6%. Gas chromatography analysis showed that the trans isomer / cis isomer was 97 / 3.

[0042] Comparative Example 1 (CN108794339A)

[0043] Dissolve 200.0g of 2,6-dimethyl-1-indanone in 1000ml of ethanol solution, and then quickly drop 307g of sodium acetate in 2000ml of aqueous solution into the reaction system. Heat to reflux, and the reaction is complete after 2-3 hours of TLC detection. Concentrate the ethanol, extract the reaction solution with ethyl acetate, combine the organic phases, dry them, and concentrate to obtain a pale yellow oily crude product.

[0044] In a 1000ml hydrogenation reactor, the above 240.0g crude product was dissolved in 600.0ml methanol, and then 24g of 10% Pd / C and 24ml acetic acid were added, and the hydrogen pressure was increased to 2.0MP, and the mixture was heated to about 55 degrees Celsius and reacted overnight. The Pd / C catalyst was removed by filtration, and the methanol was recovered by concentration. The crude product was recrystallized with methanol to obtain 270g of white solid 2,6-dimethyl-1-aminoindan acetate with a yield of 98%. According to HPLC, the ratio of trans-isomer to cis-isomer in 2,6-dimethyl-1-aminoindan acetate was 60:40.

Claims

1. A method for preparing trans-aminoindan, characterized in that: The synthesis method uses indanone as a starting material and specifically comprises the following steps: Indane compound (I), ammonium salt, solvent, palladium carbon catalyst and desiccant are added to a reaction kettle (hydrogenation kettle). After replacing the atmosphere in the hydrogenation kettle with inert gas, hydrogen is added and stirred to react; trans-aminoindane is obtained.

2. The method according to claim 1, characterized in that: In the indanone compound (I), the substituent R1 is one or more of hydrogen, methyl, ethyl, isopropyl, methoxy, and halogen (F, Cl, Br, I), and R2 is one or more of methyl, ethyl, isopropyl, phenyl, and halogen (F, Cl, Br, I).

3. The method according to claim 1, characterized in that: The mass content of palladium in the palladium-carbon catalyst is 3%-10%; the weight ratio of the palladium-carbon catalyst to the indanone compound (I) is 1:10-1000, preferably 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 mass concentration of the indanone compound (I) therein is 0.1-30%, preferably 5-20%.

5. The method according to claim 1, characterized in that: The ammonium salt is one or more 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.

6. The method according to claim 1, characterized in that: The desiccant is one or more of anhydrous magnesium sulfate, anhydrous calcium chloride, and 4A molecular sieve; the mass ratio of the desiccant to indanone is 0.05-5:1, preferably 0.1-0.5:

1.

7. The method according to claim 1, characterized in that: The hydrogen pressure in the reactor is 0.1-10 MPa, preferably 1-3 MPa; The reaction temperature is 0-200°C, preferably 50-80°C; the reaction time is 12-48°C hours, preferably 18-24°C hours.

8. The method according to claim 1, characterized in that: After the reaction is completed, the system is cooled to room temperature, the solid and liquid are separated, the liquid is concentrated to remove the solvent, water is added, toluene is extracted, dried, concentrated to remove the solvent, and trans-aminoindane is obtained.

9. The method according to claim 8, characterized in that: The volume of the added water is 0.1-2 times, preferably 0.2-0.5 times, the volume of the remaining reaction system feed liquid (concentrated feed liquid).

10. The method according to claim 8, characterized in that: The weight ratio of the added toluene to the water is 2-1:1.

Images