A method for synthesizing chiral indolines
By using a chiral ruthenium bisphosphine framework catalyst to directly synthesize chiral indaneamine, the problems of low yield and high pollution in existing technologies have been solved, enabling efficient and environmentally friendly industrial production.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- DALIAN INSTITUTE OF CHEMICAL PHYSICS CHINESE ACADEMY OF SCIENCES
- Filing Date
- 2023-08-11
- Publication Date
- 2026-06-23
AI Technical Summary
Existing methods for synthesizing chiral indaneamine suffer from low yields, complex processes, high costs, and significant pollution, making large-scale industrial production difficult.
Using a chiral ruthenium bisphosphine framework catalyst, cis-indaneamine was directly synthesized from indanone under certain temperature and hydrogen pressure. Trans-indaneamine was then obtained through a transposition reaction. The catalyst and solvent can be recycled, the reaction conditions are mild, and pollution is minimal.
It achieves high yield (over 95%) and high enantioselectivity (98% ee) of chiral indane, simplifies the process, reduces environmental pollution and production costs, and is suitable for industrial production.
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Figure CN119462395B_ABST
Abstract
Description
Technical Field
[0001] This invention belongs to the field of organic synthesis, specifically relating to a method for synthesizing chiral indeneamine. Background Technology
[0002] Indazon-flufenican is an alkylazine herbicide newly developed by Bayer Crop Science in 2010. It is a new member of the plant cellulose biosynthesis inhibitors (CBIs) (Formula 2), possessing a unique resistance-based mode of action. It exhibits broad-spectrum activity at low application rates and also has high lipophilicity (logKow = 2.8) and low water solubility (2.8 mg L⁻¹), thus resulting in increased soil residual activity compared to other commonly used herbicides. Indazon-flufenican is primarily used for weed control in permanent crops such as citrus, grapes, fruit trees, tree nuts, and industrial plantations, as well as for weed control in perennial sugarcane, lawns, golf courses, lawn farms, recreational lawns, ornamental plants, and non-crop areas such as Christmas tree farms and forest areas.
[0003]
[0004] In the structure of indazine-flufenazate, the 1-aminodihydroindene skeleton is the most effective active structure, changing the mode of action (MoA) from inhibition of photosystem II to inhibition of cellulose biosynthesis with minimal impact on photosynthetic electron transport. Furthermore, the halogen atom (Br, Cl < F) is bonded to a 2,4-diamino-1,3,5-triazine containing an alkyl or cycloalkyl group at the 6-position, a structure crucial for its good herbicidal activity. This leads to the introduction of a new chiral center at the 1-position of the ethyl side chain, thus giving the compound three chiral centers. Subsequent studies on the eight synthesized diastereomers revealed that the active compound, indazine-flufenoxam, is the compound formed by the combination of the (1R,2S)-2,3-dihydro-2,6-dimethyl-1H-indene-1-amino(dihydroindene) fragment and the 6-(R)-1-fluoroethyl-substituted 2,4-diamino-1,3,5-triazine fragment. This compound is suitable for weeds resistant to other herbicidal mechanisms such as 5-enolpyruvate 3-phosphate synthase (EPSPS) and acetylhydroxyacetic acid synthase / acetyllactate synthase (AHAS / ALS), and no cross-resistance has been observed to date.
[0005] There are two main methods for synthesizing chiral indane. One method involves enantiomeric resolution of indane to obtain (1R,2S)-indane. This method is suitable for stereoisomer control experiments, but it is economically infeasible due to the loss of unwanted stereoisomers (CN1747939). The other suitable method, established by J. M. S. A ... Therefore, the racemic indanone is completely converted to (1S,2S)-indanol with high diastereoselectivity and enantioselectivity. In the second step, the hydroxyl group is substituted with an azide group (through conversion with diphenylphosphine-phosphated azide), achieving complete configuration inversion. Then, a stoein reduction is performed with triphenylphosphine to obtain the desired (1R,2S)-indanamine. Although this method has high stereoselectivity, the two-step yield is only 50%, and a large amount of azide compound and triphenylphosphine are required in the intermediate alcohol-to-amine process. In industrial production, the process technology is difficult to implement and uneconomical, making large-scale production difficult (Tetrahedron (2007), 63(29), 6755-6763). Summary of the Invention
[0006] This invention utilizes a chiral ruthenium bisphosphine framework catalyst to directly synthesize cis-indane from indanone, achieving a yield exceeding 95%. Further transposition yields trans-indane with 98% ee, also exceeding 97%. Compared to methods that generate alcohols and then use expensive and highly polluting reactants such as azide compounds to obtain chiral amines, this method is simpler, has milder reaction conditions, higher yields, less environmental pollution, and lower waste levels, demonstrating promising prospects for industrialization.
[0007] This invention provides a method for synthesizing chiral indane, comprising the following steps: (1) Ammonium acetate, solvent, catalyst, and 2,6-dimethyl-1-indane are added to a pressure reactor. After the air in the pressure reactor is replaced with an inert gas, the reaction is carried out at a certain temperature and hydrogen pressure. After the reaction is completed, the solvent is removed, water is added, toluene is added for extraction, and the mixture is dried, concentrated, and the solvent is removed to obtain (1S,2S)-2,6-dimethyl-1-indane, i.e., cis-chiral indane. (2) Cis-chiral indane, solvent, and catalyst are added to a hydrogenation reactor. Hydrogen gas at a certain pressure is added, stirring is started, and the transposition reaction is carried out at a specified temperature. After the reaction is completed, the catalyst is filtered at room temperature for recycling. The filtrate is concentrated to obtain (1R,2S)-2,6-dimethyl-1-indane.
[0008] The specific steps are as follows:
[0009]
[0010] The catalyst mentioned in step (1) is a chiral ruthenium bisphosphine framework catalyst, with the structure shown in Formula 1 below:
[0011]
[0012] The weight ratio of the chiral ruthenium bisphosphine framework catalyst to indanone in step (1) is 1:100-5000, preferably 1:500-2000.
[0013] The solvent in step (1) is selected from one or more of water, methanol, ethanol, acetonitrile, trifluoroethanol, and tetrahydrofuran; the indanone compound has a mass concentration of 0.5-30%, preferably 5-20%.
[0014] The molar ratio of ammonium acetate to indanone in step (1) is 0.5-10:1, preferably 1-3:1.
[0015] The hydrogen pressure in step (1) is 0.1-10 MPa, preferably 1-5 MPa; the reaction temperature is 0-200℃, preferably 60-100℃.
[0016] The volume of water added in step (1) is 0.1-3:1 of the volume of the remaining reaction system liquid, preferably 0.2-0.5:1.
[0017] The catalyst mentioned in step (2) is one of palladium sulfate, palladium acetate, and palladium on carbon; the mass ratio of catalyst to substrate is 1:10-1000, preferably 1:20-100.
[0018] The solvent in step (2) is selected from one or more of water, methanol, ethanol, acetonitrile, trifluoroethanol, and tetrahydrofuran; the indoleamine compound has a mass concentration of 0.5-30%, preferably 5-20%.
[0019] The hydrogen pressure in step (2) is 0.1-10 MPa, preferably 2-5 MPa; the reaction temperature is 25-200℃, preferably 50-80℃.
[0020] The advantages of this invention are: the trans-isocyanate content in the product chiral trans-indane is greater than 99%, 98% ee and a total yield of over 90% can be obtained, both the catalyst and solvent can be recycled and reused, the operation is simple, the raw materials are readily available, the pollution from waste is small, and the energy consumption is low, making it suitable for industrial production. Attached image description:
[0021] Figure 1The gas chromatogram of (1R,2S)-2,6-dimethyl-1-indeneamine obtained in Example 1;
[0022] Figure 2 The liquid chromatogram of the (1R,2S)-2,6-dimethyl-1-indeneamine derivative obtained in Example 1;
[0023] Figure 3 The 1H NMR spectrum of chiral (1R,2S)-2,6-dimethyl-1-indeneamine is shown. Detailed Implementation
[0024] The following examples will further illustrate the present invention, but are not intended to limit the invention. In the examples, the NMR of the products was determined using a Bruker 400M NMR spectrometer. The cis-trans ratio analysis of (1R,2S)-2,6-dimethyl-1-indane was performed using an Agilent 7890 series gas chromatograph under the following conditions: column: PEG20M: 30m*320μm*0.25μm, column inlet pressure: 9.8764mp (flow rate 1.5ml / min), injection port temperature: 250°C, detector temperature: 250°C, column temperature: 50°C, hold time: 2 minutes, ramp rate: 10°C / min, stop temperature: 280°C, hold time: 5 minutes. The ee value of (1R,2S)-2,6-dimethyl-1-indane was determined by liquid chromatography under the following conditions: column: CHIRALPAK AD-H isopropanol / water = 97 / 3, 254 nm, 0.8 ml / min, column temperature 40 °C.
[0025] The ruthenium catalyst described in the following examples is a chiral ruthenium bisphosphine framework catalyst. The synthesis method is referenced in Organic Letters (2021), 23(22), 8766-8771 and Organic Metallics (2000), 19(20), 4117-4126. The structure is shown in Formula 1 below:
[0026]
[0027] Example 1
[0028] 32.0 g of 2,6-dimethyl-1-indanone, 31.0 g of ammonium acetate, 200 mL of trifluoroethanol, and 40 mg of ruthenium catalyst were added to a pressure vessel. After stirring and purging with nitrogen three times, 5.0 MPa of hydrogen was added, and the system temperature was raised to 80°C. The reaction was maintained for 20 hours, then cooled to room temperature. The solvent was removed by concentration under reduced pressure. 15.0 g of water was added to 45 mL of the residue, and the mixture was stirred for 10 minutes. Then, 20.0 g of toluene was added, and the mixture was stirred for another 10 minutes. The mixture was allowed to stand and separated, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to remove toluene, yielding 31.3 g of (1S,2S)-2,6-dimethyl-1-aminoindanone, with a yield of 97.5% and an ee of 98.3%.
[0029] The (1S,2S)-2,6-dimethyl-1-aminoindane obtained above was added to a hydrogenation pressure vessel along with 200.0 ml of anhydrous ethanol and 0.35 g of palladium sulfate. After purging with nitrogen three times, 3.0 MPa of hydrogen was added, and the mixture was stirred and heated to 80°C for 20 hours. After cooling, the catalyst was recovered by filtration, and the mother liquor was concentrated under reduced pressure and the solvent was evaporated to dryness to obtain 29.2 g of chiral trans-indane, with a yield of 93.3%. Gas chromatography analysis showed that the trans-indane / cis-indane ratio was 99 / 1, with an ee of 98.2%.
[0030] The 1H NMR data are as follows: 1 H NMR (400MHz, DMSO) δ7.10 (s, 1H), 7.00 (d, J = 7.6Hz, 1H), 6.96–
[0031] 6.87(m,1H),3.56(d,J=8.6Hz,1H),2.86(dd,J=15.1,7.5Hz,1H),2.36–
[0032] 2.28(m,1H),2.27(s,3H),1.90–1.83(m,1H),1.18(d,J=6.7Hz,3H).
[0033] Example 2
[0034] 32.0 g of 2,6-dimethyl-1-indanone, 18.0 g of ammonium acetate, 200 mL of ethanol, and 0.04 g of ruthenium catalyst were added to a pressure vessel. After stirring and purging with nitrogen three times, 5.0 MPa of hydrogen was added, the system temperature was raised to 80°C, and the reaction was maintained for 20 hours. The mixture was then cooled to room temperature, concentrated under reduced pressure to remove the solvent, and 15.0 g of water was added to 35 mL of the residue. After stirring for 10 minutes, 25 g of toluene was added, and the mixture was stirred for 10 minutes. The mixture was allowed to stand and separated, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to remove toluene, yielding 28.3 g of (1S,2S)-2,6-dimethyl-1-aminoindanone, with a yield of 87.9% and an ee of 97.8%.
[0035] The (1S,2S)-2,6-dimethyl-1-aminoindane obtained above was added to a hydrogenation pressure vessel along with 200.0 ml of anhydrous ethanol and 0.3 g of palladium sulfate. After purging with nitrogen three times, 3.0 MPa of hydrogen was added, and the mixture was stirred and heated to 80°C for 20 hours. The mixture was then cooled, filtered to recover the catalyst, and the mother liquor was concentrated under reduced pressure to evaporate the solvent, yielding 27.2 g of chiral trans-indane, with a yield of 96.1%. Gas chromatography analysis showed that the trans-indane / cis-indane ratio was 98 / 2, with an ee of 96.7%.
[0036] Example 3
[0037] 32.0 g of 2,6-dimethyl-1-indanone, 31.0 g of ammonium acetate, 200 mL of acetonitrile, and 0.05 g of ruthenium catalyst were added to a pressure vessel. After stirring and purging with nitrogen three times, 3.5 MPa of hydrogen was added, the system temperature was raised to 80°C, and the reaction was maintained for 20 hours. The mixture was then cooled to room temperature, concentrated under reduced pressure to remove the solvent, and 20.0 g of water was added to 43 mL of the residue. After stirring for 10 minutes, 20 g of toluene was added, and the mixture was stirred for 10 minutes. The mixture was allowed to stand and separated, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to remove toluene, yielding 30.4 g of (1S,2S)-2,6-dimethyl-1-aminoindanone, with a yield of 94.4% and an ee of 95.7%.
[0038] The (1S,2S)-2,6-dimethyl-1-aminoindane obtained above was added to a hydrogenation pressure vessel along with 200.0 ml of anhydrous ethanol and 0.5 g of palladium sulfate. After purging with nitrogen three times, 2.5 MPa of hydrogen was added, and the mixture was stirred and heated to 80°C for 18 hours. The mixture was then cooled, filtered to recover the catalyst, and the mother liquor was concentrated under reduced pressure to evaporate the solvent, yielding 29.8 g of chiral trans-indane, with a yield of 98.0%. Gas chromatography analysis showed that the trans-indane / cis-indane ratio was 99 / 1, with an ee of 95.2%.
[0039] Example 4
[0040] 32.0 g of 2,6-dimethyl-1-indanone, 31.0 g of ammonium acetate, 200 mL of methanol, and 0.06 g of ruthenium catalyst were added to a pressure vessel. After stirring and purging with nitrogen three times, 2.5 MPa of hydrogen was added, the system temperature was raised to 80°C, and the reaction was maintained for 20 hours. The mixture was then cooled to room temperature, concentrated under reduced pressure to remove the solvent, and 20.0 g of water was added to 42 mL of the residue. After stirring for 10 minutes, 30 g of toluene was added, and the mixture was stirred for 10 minutes. The mixture was allowed to stand and separated, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to remove toluene, yielding 30.2 g of (1S,2S)-2,6-dimethyl-1-aminoindanone, with a yield of 93.8% and an ee of 98.0%.
[0041] The (1S,2S)-2,6-dimethyl-1-aminoindane obtained above was added to a hydrogenation pressure vessel along with 200.0 ml of anhydrous ethanol and 0.5 g of palladium sulfate. After purging with nitrogen three times, 3.0 MPa of hydrogen was added, and the mixture was stirred and heated to 60°C for 18 hours. The mixture was then cooled, filtered to recover the catalyst, and the mother liquor was concentrated under reduced pressure to evaporate the solvent, yielding 29.5 g of chiral trans-indane, with a yield of 97.7%. Gas chromatography analysis showed that the trans-indane / cis-indane ratio was 98 / 2, with an ee of 97.8%.
[0042] Example 5
[0043] 32.0 g of 2,6-dimethyl-1-indanone, 25.0 g of ammonium acetate, 200 mL of tetrahydrofuran, and 0.04 g of ruthenium catalyst were added to a pressure vessel. After stirring and purging with nitrogen three times, 5.0 MPa of hydrogen was added, the system temperature was raised to 80°C, and the reaction was maintained for 18 hours. The mixture was then cooled to room temperature, concentrated under reduced pressure to remove the solvent, and 15 g of water was added to 38 mL of the residue. After stirring for 10 minutes, 25 g of toluene was added, and the mixture was stirred for 10 minutes. The mixture was allowed to stand and separated, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to remove toluene, yielding 28.3 g of (1S,2S)-2,6-dimethyl-1-aminoindanone, with a yield of 87.9% and an ee of 95.3%.
[0044] The (1S,2S)-2,6-dimethyl-1-aminoindane obtained above was added to a hydrogenation pressure vessel along with 200.0 ml of anhydrous ethanol and 0.5 g of palladium acetate. After purging with nitrogen three times, 3.0 MPa of hydrogen was added, and the mixture was stirred and heated to 80°C for 24 hours. The mixture was then cooled, filtered to recover the catalyst, and the mother liquor was concentrated under reduced pressure to evaporate the solvent, yielding 27.0 g of chiral trans-indane, with a yield of 95.4%. Gas chromatography analysis showed that the trans / cis ratio was 95 / 5, with an ee of 95.2%.
[0045] Example 6
[0046] 32.0 g of 2,6-dimethyl-1-indanone, 20.0 g of ammonium acetate, 200 mL of trifluoroethanol, and 0.05 g of ruthenium catalyst were added to a pressure vessel. After stirring and purging with nitrogen three times, 4.0 MPa of hydrogen was added, and the system temperature was raised to 60°C. The reaction was maintained for 20 hours, then cooled to room temperature. The solvent was removed by concentration under reduced pressure. 15 g of water was added to 39 mL of the residue, and the mixture was stirred for 10 minutes. Then, 25 g of toluene was added, and the mixture was stirred for 10 minutes. The mixture was allowed to stand and separated, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to remove toluene, yielding 29.4 g of (1S,2S)-2,6-dimethyl-1-aminoindanone, with a yield of 91.3% and an ee of 97.5%. The (1S,2S)-2,6-dimethyl-1-aminoindane obtained above was added to a hydrogenation pressure vessel along with 200.0 ml of anhydrous methanol and 0.3 g of palladium sulfate. After purging with nitrogen three times, 3.0 MPa of hydrogen was added, and the mixture was stirred and heated to 80°C for 24 hours. The mixture was then cooled, filtered to recover the catalyst, and the mother liquor was concentrated under reduced pressure to evaporate the solvent, yielding 29.1 g of chiral trans-indane, with a yield of 99.0%. Gas chromatography analysis showed that the trans-indane / cis-indane ratio was 99 / 1, with an ee of 96.8%.
[0047] Example 7
[0048] 32.0 g of 2,6-dimethyl-1-indanone, 25.0 g of ammonium acetate, 200 mL of trifluoroethanol, and 0.06 g of ruthenium catalyst were added to a pressure vessel. After stirring and purging with nitrogen three times, 4.5 MPa of hydrogen was added, and the system temperature was raised to 60°C. The reaction was maintained for 20 hours, then cooled to room temperature. The solvent was removed by concentration under reduced pressure. 10 g of water was added to 34 mL of the residue, and the mixture was stirred for 10 minutes. Then, 20 g of toluene was added, and the mixture was stirred for 10 minutes. The mixture was allowed to stand and separated. The residue was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to remove toluene, yielding 30.6 g of (1S,2S)-2,6-dimethyl-1-aminoindanone, with a yield of 95.0% and an ee of 98.5%. The (1S,2S)-2,6-dimethyl-1-aminoindane obtained above, 200.0 ml of anhydrous ethanol, and 0.5 g of palladium sulfate (recycled three times) were added to a hydrogenation pressure vessel. After purging with nitrogen three times, 3.0 MPa of hydrogen was added, and the mixture was stirred and heated to 80°C for 24 hours. After cooling, the catalyst was recovered by filtration, and the mother liquor was concentrated under reduced pressure and the solvent was evaporated to dryness to obtain 29.3 g of chiral trans-indane, with a yield of 95.8%. Gas chromatography analysis showed that the trans-indane / cis-indane ratio was 98 / 2, with an ee of 98.1%.
Claims
1. A method for synthesizing chiral indane, characterized in that: The synthesis method uses indanone as a starting material and specifically includes the following steps: ； Step (1): Ammonium acetate, solvent, catalyst and 2,6-dimethyl-1-indanone are added to a pressure reactor. After the air in the pressure reactor is replaced with an inert atmosphere gas, the reaction is carried out at a certain temperature and hydrogen pressure. After the reaction is completed, the product is purified to obtain cis-chiral indanamine. Step (2): Add cis-chiral indaneamine, solvent and catalyst to hydrogenation reactor, add hydrogen gas at a certain pressure, stir, carry out the transposition reaction at a specified temperature, and purify the product after the reaction to obtain (1R,2S)-2,6-dimethyl-1-indaneamine; The catalyst mentioned in step (1) is a chiral ruthenium bisphosphine framework catalyst, with the structure shown in Formula 1 below: Formula 1 The weight ratio of the chiral ruthenium bisphosphine framework catalyst to indanone in step (1) is 1:100-5000; The catalyst mentioned in step (2) is one or more of palladium sulfate, palladium acetate, and palladium on carbon; the mass ratio of the catalyst to the substrate cis-chiral indeneamine is 1:10-1000.
2. The method according to claim 1, characterized in that: The weight ratio of the chiral ruthenium bisphosphine framework catalyst to indanone in step (1) is 1:500-2000; In step (2), the mass ratio of the catalyst to the substrate cis-chiral indeneamine is 1:20-100.
3. The method according to claim 1, characterized in that: The solvent in step (1) is selected from one or more of water, methanol, ethanol, acetonitrile, trifluoroethanol, and tetrahydrofuran; the mass concentration of the 2,6-dimethyl-1-indanone compound in the solvent is 0.1-30%.
4. The method according to claim 3, characterized in that: Step (1) The mass concentration of the 2,6-dimethyl-1-indanone compound in the solvent is 5-20%.
5. The method according to claim 1, characterized in that: The molar ratio of ammonium acetate to indanone in step (1) is 0.5-10:
1.
6. The method according to claim 5, characterized in that: The molar ratio of ammonium acetate to indanone in step (1) is 1-3:
1.
7. The method according to claim 1, characterized in that: The hydrogen pressure in step (1) is 0.1-10 MPa; the reaction temperature is 0-200℃; and the reaction time is 12-24 hours. The inert atmosphere gas is one or more of nitrogen, argon, and helium.
8. The method according to claim 7, characterized in that: The hydrogen pressure in step (1) is 1-5 MPa; the reaction temperature is 60-100℃; and the reaction time is 16-20 hours.
9. The method according to claim 1, characterized in that: The purification process at the end of step (1) is as follows: After the reaction was completed, the solvent was removed, water was added, toluene was extracted, the layers were separated, the toluene layer was washed with saturated brine and dried, and the solvent toluene was removed by concentration to obtain (1S,2S)-2,6-dimethyl-1-indane, i.e. cis-chiral indane. The volume of water added is 0.1-3:1 of the remaining reaction system liquid volume; The mass ratio of toluene to water added is 1-3:
1.
10. The method according to claim 9, characterized in that: In step (1), the volume of water added is 0.2-0.5 times the volume of the remaining reaction system liquid; the mass ratio of toluene to water added is 1-2 times.
11. The method according to claim 1, characterized in that: The solvent in step (2) is selected from one or more of water, methanol, ethanol, acetonitrile, trifluoroethanol, and tetrahydrofuran; the mass concentration of the cis-chiral indaneamine in the solvent is 0.5-30%.
12. The method according to claim 11, characterized in that: The mass concentration of the cis-chiral indaneamine in the solvent in step (2) is 5-20%.
13. The method according to claim 1, characterized in that: The hydrogen pressure in step (2) is 0.1-10 MPa; the reaction temperature is 25-200℃; and the reaction time is 12-36 hours.
14. The method according to claim 13, characterized in that: The hydrogen pressure in step (2) is 2-5 MPa; the reaction temperature is 50-80℃; and the reaction time is 20-30 hours.
15. The method according to claim 1, characterized in that: The purification process of the product after the reaction in step (2) is as follows: After the reaction was completed, the catalyst was recovered and reused by filtration at room temperature. The filtrate was concentrated to obtain (1R,2S)-2,6-dimethyl-1-indeneamine.