Method for synthesizing (1R, 2S)-2, 6-dimethyl-1H-indene-1-amine

Abstract

The invention discloses a method for synthesizing (1R, 2S)-2, 6-dimethyl-1H-indene-1-amine, which comprises the following steps: step 1, condensation of a substrate and a chiral prothetic group; step 2, hydrogenation amination; 3, recycling the catalyst; step 4, separating and purifying a product; according to the invention, hydrogenation amination and chiral prothetic group removal processes are synchronously carried out, so that the synthesis process is greatly simplified; the reaction conditions do not need extreme environments such as extreme temperature and high pressure, so that the requirements on production equipment and the operation difficulty are reduced; by means of precise induction and 1, 3-position stereo control of a chiral prothetic group, the stereo selectivity can reach 95% ee or above; the reaction yield is high, the configuration is single, the discharge amount of three wastes in the reaction process is small, the development requirement of green chemical industry is met, the palladium-carbon catalyst can be recycled and reused for many times, and the catalyst cost is remarkably reduced; the method has the advantages of efficient and simple process, mild reaction conditions, excellent product quality, environmental protection and low production cost.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, specifically to a method for synthesizing (1R,2S)-2,6-dimethyl-1H-indene-1-amine. Background Technology

[0002] Indazon-flufenican, developed by Bayer AG of Germany, is a cellulose biosynthesis inhibitor with a unique herbicidal mechanism. Due to its special chemical structure and physicochemical properties, the molecule can penetrate the plant cell membrane, enter the cell interior, target the cellulose synthase complex, interfere with its normal function, and inhibit the assembly of cellulose microfibrils. Furthermore, even against weed populations that have developed resistance to traditional herbicides such as glyphosate and ALS inhibitors, indazon-flufenican, thanks to its unique mechanism of action, still exhibits strong herbicidal activity.

[0003] In the existing technology, there are various methods for preparing indazine-flufenoxam, but they still have the following drawbacks: 1. The dynamic kinetic resolution method used by Bayer involves two steps: First, indanone is hydrogenated to the corresponding cis-indanol in the presence of a ruthenium-based catalyst; second, the hydroxyl group is replaced by an azide group, achieving configuration inversion; then catalytic reduction is carried out to obtain the desired (1R,2S)-indanamine. This method has high catalyst costs, especially involving azide reagents, and process safety limits its commercialization potential. Limited; 2. Invention patent CN108794339B reports a method for preparing (1R,2S)-2,6-dimethyl-1-aminoindenhydride, using a mixture of four isomers (III) obtained by hydrogenation as a raw material, and hydrogenating it in the presence of a palladium catalyst to obtain a compound of formula (II) enriched in the trans isomer; then resolving the enantiomer mixture of formula (II) with R-mandelic acid to obtain (1R,2S)-2,6-dimethyl-1-aminoindenhydride enriched in the enantiomer RS-(I). 6-Dimethyl-1-indane; however, this method cannot achieve a single product configuration, and chemical resolution leads to a low final yield, which cannot meet commercial needs; 3. Invention patent CN119462395A reports a method for synthesizing chiral indane, using indanone as a raw material, through a ruthenium chiral bisphosphine catalyst, to synthesize cis-chiral indane in high yield and high stereoselectivity, and then trans-chiral indane through transposition; wherein the catalyst in the first step uses Salen The first step uses a ruthenium catalyst with a framework, and the second step uses palladium sulfate as a catalyst. Although this method improves the accessibility of chiral indane to some extent, it produces a large number of deamination byproducts during the reaction. 4. The invention patent with announcement number WO2024 / 201469Al reported that dimethyl indane can react with hydroxylamine compounds in the presence of transition metals and chiral ligands to obtain chiral indane. The materials involved in this method, such as chiral ligands Ph-BPE and silanes, are too expensive, resulting in high synthesis costs. Summary of the Invention

[0004] The purpose of this invention is to provide a method for synthesizing (1R,2S)-2,6-dimethyl-1H-indene-1-amine to solve the problems mentioned in the background art.

[0005] To achieve the above objectives, the present invention provides the following technical solution: a method for synthesizing (1R,2S)-2,6-dimethyl-1H-indene-1-amine, comprising the following steps: step one, condensation of substrate and chiral cofactor; step two, hydrogenation amination; step three, catalyst recovery; and step four, separation and purification of the product.

[0006] In step one above, 2,6-dimethyl-1-indanone, chiral cofactor, additive and solvent are weighed according to the formula ratio and set aside. The weighed 2,6-dimethyl-1-indanone, chiral cofactor and additive are added to the reaction vessel in sequence, and stirred at 100-200 rpm for 3-5 min at 20-25℃. Then the solvent is added and the reaction is continued to be stirred for 40-48 h to obtain reaction solution A.

[0007] In step two above, the reaction solution A obtained in step one is transferred to an autoclave, a catalyst is added, and the mixture is stirred at 150-250 rpm for 3-5 minutes at 20-25℃. Nitrogen gas is introduced into the autoclave to replace the air inside once, and then hydrogen gas is introduced to replace the air inside twice. Hydrogen gas is introduced into the autoclave until the pressure inside the autoclave reaches 0.5 MPa, and the mixture is heated and stirred to obtain reaction solution B.

[0008] In step three above, the hydrogen valve of the autoclave is closed, the temperature is lowered to room temperature and the pressure is released to atmospheric pressure, the reaction solution B is taken out and filtered, and the catalyst is recovered.

[0009] In step four above, the filtrate obtained from filtering reaction solution B in step three is distilled under reduced pressure and purified to obtain (1R,2S)-2,6-dimethyl-1H-indene-1-amine.

[0010] Preferably, in step one, the mass percentage content of each component in the formulation is as follows: 5-20% of 2,6-dimethyl-1-indanone, 8-20% of chiral cofactor, 0.1-2% of additives and 60-90% of solvent.

[0011] Preferably, the chiral prosthetic group is an α-amino acid or its derivative, wherein Ar is a C6-C2 amino acid. 20 Aromatic groups; R is H, C1-C 20 . group.

[0012] Preferably, the additive is one of potassium carbonate, triethylamine, DBU, potassium acetate, and pyridine p-toluenesulfonate, and the solvent is one or a mixture of methanol, ethanol, acetonitrile, toluene, and THF.

[0013] Preferably, in step two, the catalyst is one of Pd / C, Pt / C, or Raney nickel, and the amount of catalyst used is 0.5-1% of the mass of reaction solution A.

[0014] Preferably, in step two, the specific method for introducing nitrogen gas into the autoclave to replace the air inside the autoclave once, and then introducing hydrogen gas to replace it twice, is as follows: connect the autoclave to the nitrogen cylinder, open the nitrogen valve, introduce nitrogen gas until the pressure inside the autoclave reaches 0.3 MPa, then close the valve, maintain the pressure for 5 minutes, then open the pressure relief valve to reduce the pressure inside the autoclave to 0.02 MPa, completing one nitrogen replacement. Finally, use hydrogen gas to replace it twice to ensure that the residual oxygen content inside the autoclave is ≤0.1%.

[0015] Preferably, in step two, the heating and stirring are carried out at a heating rate of 5℃ / min to raise the temperature inside the vessel to 80-85℃, and the reaction is carried out at 100-250rpm for 40-48h.

[0016] Preferably, in step two, during the heating and stirring process, the hydrogen pressure is recorded every 2 hours. If the pressure drops below 0.3 MPa, hydrogen is added to bring the pressure up to 0.5 MPa.

[0017] Preferably, step three specifically involves: closing the autoclave, stopping heating and stirring, closing the hydrogen valve, opening the pressure relief valve, reducing the pressure inside the autoclave to atmospheric pressure for ≥30 minutes, waiting for the temperature inside the autoclave to drop to 20-35°C, opening the autoclave, transferring the reaction solution B to a filtration device for filtration, rinsing the inner wall of the autoclave and the filter cake with solvent, collecting the washing liquid and adding it to the filtrate, transferring the filter cake to a vacuum drying oven, and drying it at 60°C and -0.09 MPa for 4 hours to complete the catalyst recovery.

[0018] Preferably, in step four, the purification specifically involves: transferring the crude product obtained by vacuum distillation to a crystallization device, adding 10 times the amount of n-hexane to the crude product, stirring at 40-60 rpm for 5-10 min, cooling to 3-5℃ and standing for 2-4 h to precipitate crystals, filtering the crystallization solution and washing it twice with n-hexane at 0-5℃, transferring the washed crystals to a vacuum drying oven and drying at 30℃ for 2 h to obtain (1R,2S)-2,6-dimethyl-1H-indene-1-amine.

[0019] Compared with the prior art, the beneficial effects of the present invention are as follows: The present invention simplifies the synthesis process by simultaneously carrying out hydrogenation and amination with the removal of chiral cofactors; the reaction conditions do not require extreme environments such as extreme temperature and high pressure, reducing the requirements for production equipment and the difficulty of operation; through the precise induction of chiral cofactors and stereoselectivity at the 1,3-position, the stereoselectivity can reach more than 95% ee; the reaction yield is high and the configuration is simple, the emission of waste gas, wastewater, and solid waste during the reaction process is low, which meets the development needs of green chemical industry; the palladium-on-carbon catalyst can be recycled and reused multiple times, significantly reducing the cost of catalysts; it has the advantages of efficient and simple process, mild reaction conditions, excellent product quality, green environmental protection, and low production cost. Attached Figure Description

[0020] Figure 1 This is a flowchart of the method of the present invention;

[0021] Figure 2 The 1H NMR spectrum of chiral (1R,2S)-2,6-dimethyl-1-indeneamine is shown.

[0022] Figure 3 The liquid chromatogram of 2,6-dimethyl-1-indoleamine;

[0023] Figure 4 The liquid chromatogram of (1R,2S)-2,6-dimethyl-1-indoleamine. Detailed Implementation

[0024] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0025] Please see the appendix Figure 1 - Appendix Figure 4 The present invention provides an embodiment of a method for synthesizing (1R,2S)-2,6-dimethyl-1H-indene-1-amine, comprising the following steps: Step 1, condensation of substrate and chiral cofactor; Step 2, hydrogenation amination; Step 3, catalyst recovery; Step 4, separation and purification of product;

[0026] In step one above, 2,6-dimethyl-1-indanone, a chiral cofactor, an additive, and a solvent are weighed according to the formula ratio and set aside. The weighed 2,6-dimethyl-1-indanone, chiral cofactor, and additive are added sequentially to a reaction vessel and stirred at 100-200 rpm for 3-5 minutes at 20-25°C. Then, the solvent is added, and the reaction is continued for 40-48 hours to obtain reaction solution A. The mass percentage content of each component in the formula is as follows: 5-20% of 2,6-dimethyl-1-indanone, 8-20% of the chiral cofactor, 0.1-2% of the additive, and 60-90% of the solvent. The chiral cofactor is an α-amino acid or its derivative, wherein Ar is a C6-C2 amino acid. 20 Aromatic groups; R is H, C1-C 20 The additive is one of potassium carbonate, triethylamine, DBU, potassium acetate, and p-pyridine toluenesulfonate, and the solvent is one or a mixture of methanol, ethanol, acetonitrile, toluene, and THF.

[0027] In step two above, the reaction solution A obtained in step one is transferred to an autoclave, a catalyst is added, and the mixture is stirred at 150-250 rpm for 3-5 minutes at 20-25°C. The autoclave is then connected to a nitrogen cylinder, the nitrogen valve is opened, and nitrogen is introduced until the pressure inside the autoclave reaches 0.3 MPa. The valve is then closed, and the pressure is maintained for 5 minutes. The pressure relief valve is then opened to reduce the pressure inside the autoclave to 0.02 MPa, completing one nitrogen purging. Finally, hydrogen is used for two purgings to ensure that the residual oxygen content inside the autoclave is ≤0.1%. Hydrogen gas was introduced into the autoclave until the pressure inside the autoclave reached 0.5 MPa. The temperature inside the autoclave was raised to 80-85℃ at a heating rate of 5℃ / min, and the reaction was stirred at 100-250 rpm for 40-48 hours. The hydrogen pressure was recorded every 2 hours. If the pressure dropped below 0.3 MPa, hydrogen gas was added to bring the pressure back up to 0.5 MPa. After the reaction was completed, reaction solution B was obtained. The catalyst was one of Pd / C, Pt / C, or Raney nickel, and the amount of catalyst was 0.5-1% of the mass of reaction solution A.

[0028] In step three above, the hydrogen valve of the high-pressure reactor is closed, the temperature is lowered to room temperature and the pressure is released to atmospheric pressure, the reaction solution B is taken out and filtered, and the catalyst is recovered. Specifically, the high-pressure reactor is closed, heating and stirring are stopped, the hydrogen valve is closed, the pressure relief valve is opened, the pressure inside the reactor is reduced to atmospheric pressure, the pressure relief time is ≥30min, and the temperature inside the reactor is lowered to 20-35℃. The high-pressure reactor is opened, the reaction solution B is transferred to the filtration device for filtration, the inner wall of the high-pressure reactor and the filter cake are washed with solvent, the washing liquid is collected and added to the filtrate, and the filter cake is transferred to the vacuum drying oven and dried at 60℃ and -0.09MPa for 4h to complete the recovery of the catalyst.

[0029] In step four above, the filtrate obtained from filtering reaction solution B in step three is purified by vacuum distillation to obtain (1R,2S)-2,6-dimethyl-1H-indene-1-amine. Specifically, the purification process involves: transferring the crude product obtained by vacuum distillation to a crystallization device, adding 10 times the amount of n-hexane to the crude product, stirring at 40-60 rpm for 5-10 min, cooling to 3-5℃ and allowing it to stand for 2-4 h to precipitate crystals, filtering the crystallization solution and washing it twice with n-hexane at 0-5℃, transferring the washed crystals to a vacuum drying oven and drying at 30℃ for 2 h to obtain (1R,2S)-2,6-dimethyl-1H-indene-1-amine.

[0030] Experimental Example 1:

[0031] Following the method described in the examples, 160.0 g of 2,6-dimethyl-1-indanone, 214.0 g of (αR)-α-Amino-N-methylnaphthaleneacetamide, 2.0 g of potassium acetate, and 1500 mL of isopropanol were added to a reaction vessel. The mixture was stirred at room temperature for 48 hours. The reaction solution was then transferred to an autoclave, and 4.0 g of 5% palladium on carbon was added. After purging with nitrogen once and hydrogen twice, hydrogen gas at 0.5 M pressure was introduced, and the reaction was carried out at 85 degrees Celsius for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, the pressure was released, the catalyst was recovered by filtration, and the filtrate was concentrated to obtain 131.2 g of chiral (1R,2S)-indanamine, with a yield of 81.0%. Gas chromatography analysis showed that the trans / cis formulation was 98 / 2, 99.0% ee. The 1H NMR data are as follows: NMR (400MHz, DMSO) δ7.11 (s, 1H), 7.01 (d, J = 7.6Hz, 1H), 6.92 (d, J = 7.6Hz, 1H), 3.57 (d, J = 8.8Hz, 1H), 2 .86 (dd, J=15.1, 7.5Hz, 1H), 2.36–2.28 (m, 1H), 2.27 (s, 3H), 1.90–1.83 (m, 1H), 1.18 (d, J=6.7Hz, 3H).

[0032] Experimental Example 2:

[0033] Following the method described in the examples, 160.0 g of 2,6-dimethyl-1-indanone, 150.0 g of αR-Amino-3,5-benzeneacetamide, 2.0 g of pyridine p-toluenesulfonate, and 1000 mL of toluene were added to a reaction vessel. The mixture was stirred at room temperature for 48 hours. The reaction solution was then transferred to a high-pressure reactor, and 4.0 g of palladium on carbon and 500 mL of methanol were added. The mixture was purged with nitrogen once and hydrogen twice. Hydrogen gas at 0.5 M pressure was then introduced, and the reaction was carried out at 80 degrees Celsius for 48 hours. After the reaction was completed, the mixture was cooled to room temperature, the pressure was released, the catalyst was recovered by filtration, and the filtrate was concentrated to obtain 134.9 g of chiral (1R,2S)-indanamine, with a yield of 83.3%. Gas chromatography analysis showed that the trans / cis form was 97 / 3, with an ee of 95.2%.

[0034] Comparative Example 1:

[0035] 16.0 g of 2,6-dimethyl-1-indanone, 7.0 g of hydroxylamine hydrochloride, 13.8 g of potassium carbonate, and 150 mL of isopropanol were added to a reaction vessel and stirred at room temperature for 48 hours. The reaction solution was then transferred to a high-pressure reactor, and 0.3 g of palladium on carbon was added. After purging with nitrogen once and hydrogen twice, hydrogen gas at 0.5 M pressure was introduced, and the reaction was carried out at 80 degrees Celsius for 13 hours. After the reaction was completed, the temperature was lowered to room temperature, the pressure was released, the catalyst was recovered by filtration, and the filtrate was concentrated to obtain 13.5 g of racemic 2,6-dimethyl-1-indanone, with a yield of 83.3%. Gas chromatography analysis showed that the trans / cis formulation was 35 / 65.

[0036] Based on the above, the advantages of this invention are as follows: When using this invention, an amine chiral cofactor is first used as an inducing reagent to undergo a condensation reaction with indanone to generate an imine intermediate. Under alkaline conditions, this intermediate undergoes an imine-enamine rearrangement process, preferentially forming a stable chiral methyl intermediate through thermodynamic selection. Subsequently, with the help of the 1,3-position stereocontrol of the chiral cofactor, a chiral amine structure is directionally constructed. Finally, in a hydrogen atmosphere, the hydrogenation-amination reaction and the deprotection process of the chiral cofactor are simultaneously completed to obtain the target product, chiral indanone. The simultaneous hydrogenation-amination and cofactor removal significantly simplifies the process steps, achieving highly efficient synthesis. The reaction conditions are mild, the product yield is high, and the stereoselectivity can reach over 95% ee. Waste emissions are low, meeting the requirements of green chemistry. Furthermore, the palladium-on-carbon catalyst used can be recycled and reused multiple times, effectively reducing production costs and possessing good prospects for industrial application.

[0037] It will be apparent to those skilled in the art that the present invention is not limited to the details of the exemplary embodiments described above, and that the invention can be implemented in other specific forms without departing from its spirit or essential characteristics. Therefore, the embodiments should be considered in all respects as exemplary and non-limiting, and the scope of the invention is defined by the appended claims rather than the foregoing description. Thus, all variations falling within the meaning and scope of equivalents of the claims are intended to be included within the present invention. No reference numerals in the claims should be construed as limiting the scope of the claims.

Claims

1. A method for synthesizing (1R,2S)-2,6-dimethyl-1H-indene-1-amine, comprising the following steps: Step 1, condensation of substrate and chiral cofactor; Step 2, hydrogenation and amination; Step 3, catalyst recovery; Step 4, separation and purification of product; characterized in that: In step one above, 2,6-dimethyl-1-indanone, chiral cofactor, additive and solvent are weighed according to the formula ratio and set aside. The weighed 2,6-dimethyl-1-indanone, chiral cofactor and additive are added to the reaction vessel in sequence, and stirred at 100-200 rpm for 3-5 min at 20-25℃. Then the solvent is added and the reaction is continued to be stirred for 40-48 h to obtain reaction solution A. In step two above, the reaction solution A obtained in step one is transferred to an autoclave, a catalyst is added, and the mixture is stirred at 150-250 rpm for 3-5 minutes at 20-25℃. Nitrogen gas is introduced into the autoclave to replace the air inside once, and then hydrogen gas is introduced to replace the air inside twice. Hydrogen gas is introduced into the autoclave until the pressure inside the autoclave reaches 0.5 MPa, and the mixture is heated and stirred to obtain reaction solution B. In step three above, the hydrogen valve of the autoclave is closed, the temperature is lowered to room temperature and the pressure is released to atmospheric pressure, the reaction solution B is taken out and filtered, and the catalyst is recovered. In step four above, the filtrate obtained from filtering reaction solution B in step three is distilled under reduced pressure and purified to obtain (1R,2S)-2,6-dimethyl-1H-indene-1-amine.

2. The method for synthesizing (1R,2S)-2,6-dimethyl-1H-indene-1-amine according to claim 1, characterized in that: In step one, the mass percentage content of each component in the formulation is as follows: 5-20% of 2,6-dimethyl-1-indanone, 8-20% of chiral cofactor, 0.1-2% of additives, and 60-90% of solvent.

3. The method for synthesizing (1R,2S)-2,6-dimethyl-1H-inden-1-amine according to claim 2, characterized in that: The chiral prosthetic group is an α-amino acid or its derivative, wherein Ar is a C6-C-containing amino acid. 20 Aromatic groups; R is H, C1-C 20 . group.

4. The method for synthesizing (1R,2S)-2,6-dimethyl-1H-inden-1-amine according to claim 2, characterized in that: The additive is one of potassium carbonate, triethylamine, DBU, potassium acetate, and pyridine p-toluenesulfonate, and the solvent is one or a mixture of methanol, ethanol, acetonitrile, toluene, and THF.

5. The method for synthesizing (1R,2S)-2,6-dimethyl-1H-indene-1-amine according to claim 1, characterized in that: In step two, the catalyst is one of Pd / C, Pt / C, or Raney nickel, and the amount of catalyst used is 0.5-1% of the mass of reaction solution A.

6. The method for synthesizing (1R,2S)-2,6-dimethyl-1H-indene-1-amine according to claim 1, characterized in that: In step two, the specific method for introducing nitrogen gas into the autoclave to replace the air inside the autoclave once, and then introducing hydrogen gas to replace it twice, is as follows: Connect the autoclave to the nitrogen cylinder, open the nitrogen valve, introduce nitrogen gas until the pressure inside the autoclave reaches 0.3 MPa, then close the valve, maintain the pressure for 5 minutes, then open the pressure relief valve to reduce the pressure inside the autoclave to 0.02 MPa, completing one nitrogen replacement. Finally, use hydrogen gas to replace it twice to ensure that the residual oxygen content inside the autoclave is ≤0.1%.

7. The method for synthesizing (1R,2S)-2,6-dimethyl-1H-indene-1-amine according to claim 1, characterized in that: In step two, the heating and stirring are carried out at a heating rate of 5℃ / min to raise the temperature inside the vessel to 80-85℃, and the reaction is carried out at 100-250rpm for 40-48h.

8. The method for synthesizing (1R,2S)-2,6-dimethyl-1H-indene-1-amine according to claim 1, characterized in that: In step two, during the heating and stirring process, the hydrogen pressure is recorded every 2 hours. If the pressure drops below 0.3 MPa, hydrogen is added to bring the pressure up to 0.5 MPa.

9. The method for synthesizing (1R,2S)-2,6-dimethyl-1H-inden-1-amine according to claim 1, characterized in that: Step three specifically involves: closing the autoclave, stopping heating and stirring, closing the hydrogen valve, opening the pressure relief valve, reducing the pressure inside the autoclave to atmospheric pressure for ≥30 minutes, waiting for the temperature inside the autoclave to drop to 20-35℃, opening the autoclave, transferring reaction solution B to a filtration device for filtration, rinsing the inner wall of the autoclave and the filter cake with solvent, collecting the washing liquid and adding it to the filtrate, transferring the filter cake to a vacuum drying oven, and drying it at 60℃ and -0.09MPa for 4 hours to complete the catalyst recovery.

10. The method for synthesizing (1R,2S)-2,6-dimethyl-1H-inden-1-amine according to claim 1, characterized in that: In step four, the purification process is as follows: the crude product obtained by vacuum distillation is transported to a crystallization device, 10 times the amount of n-hexane is added to the crude product, and the mixture is stirred at 40-60 rpm for 5-10 min. After cooling to 3-5℃, the mixture is allowed to stand for 2-4 h to precipitate crystals. The crystallization solution is filtered and washed twice with n-hexane at 0-5℃. The washed crystals are then transferred to a vacuum drying oven and dried at 30℃ for 2 h to obtain (1R,2S)-2,6-dimethyl-1H-indene-1-amine.

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