A method for synthesizing chiral indeneamine
The synthesis of chiral indaneamine via a ruthenium-based chiral bisphosphine catalyst in a hydrogenation reaction solves the problems of low yield and complex process in the synthesis of chiral indaneamine from indazine-flufenoxam in the prior art, achieving high yield and high enantioselectivity, making it suitable for industrial production.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- DALIAN INSTITUTE OF CHEMICAL PHYSICS CHINESE ACADEMY OF SCIENCES
- Filing Date
- 2024-11-25
- Publication Date
- 2026-05-26
AI Technical Summary
Existing methods for synthesizing chiral indane from indazine and fluroxypyr have low yields, complex processes, and are uneconomical, making large-scale production difficult.
Chiral indaneamine was synthesized by hydrogenation using a ruthenium-based chiral bisphosphine catalyst. The asymmetric hydrogenation of N-(2,5-dimethyl-1H-indol-3-yl)acetamide was carried out in a hydrogenation reactor under mild reaction conditions, with readily available catalysts and yields exceeding 90%.
It achieves high yield and high enantioselectivity, and the catalyst is readily available, the operation is simple, and the environmental pollution is minimal, making it suitable for industrial production.
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Figure CN122079792A_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 a broad-spectrum herbicide belonging to the triazole class of compounds. Its chemical structural formula is as follows:
[0003]
[0004] It kills weeds primarily by inhibiting specific enzymes in plants.
[0005] Indazon-flufenican is a deep red crystalline solid with good solubility and stability. It is highly soluble in water and can be rapidly absorbed and transported by plants to the roots, stems, and leaves. Indazon-flufenican has good control effects on a broad spectrum of weeds and shows no significant toxicity to some common cultivated crops. Indazon-flufenican exerts its herbicidal effect by inhibiting the activity of specific enzymes in plants. Specifically, it inhibits the activity of acetolactate synthase (ALS), an important enzyme in plant tissues. ALS is a key enzyme involved in plant molecular biology processes, catalyzing the synthesis of amino acids in plant tissues.
[0006] 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.
[0007] There are two main methods for synthesizing the (1R,2S)-2,3-dihydro-2,6-dimethyl-1H-inden-1-amino (dihydroindenyl) fragment. One method involves enantiomeric resolution of indenamine to obtain (1R,2S)-indenamine. This method is suitable for stereoisomer control experiments, but it is not economically feasible due to the loss of unwanted stereoisomers (CN108794339A). The other suitable method, established by J. M. Assaletta, involves dynamic kinetic resolution followed by nucleophilic substitution to obtain chiral indenamine. This method consists of two steps: In the first step, indenone is hydrogenated to the corresponding indenol in the presence of a ruthenium-based Noyori / Ikariya catalyst. The reducing agent enters from the less sterically hindered side, opposite the methyl group, forming cis-inden. Under the chiral induction of a ruthenium catalyst, only (2S)-indanone was reduced, while the remaining (2R)-indanone underwent an equilibrium reaction to yield (2R / S)-indanone. Therefore, the racemic indanone was completely converted to (1S,2S)-indanol, exhibiting high diastereomeric and enantiomeric selectivity. In the second step, the hydroxyl group was substituted with an azide group (through conversion with diphenylphosphine-phosphated azide), achieving complete configuration inversion. Subsequently, a stoein reduction was performed with triphenylphosphine to obtain the desired (1R,2S)-indanamine. (Tetrahedron (2007), 63(29), 6755-6763)
[0008] Although this method has high stereoselectivity, the two-step yield is only 50%. The process from indanol to indanamine requires a large amount of azide compounds and triphenylphosphine. In industrial production, the process technology is difficult to implement and is not economical, making it difficult to mass-produce on a large scale. Summary of the Invention
[0009] This invention utilizes a ruthenium-based chiral bisphosphine catalyst to hydrogenate N-(2,5-dimethyl-1H-indol-3-yl)acetamide (enamine) to trans-indaneamine, achieving a yield exceeding 90% and an ee of 97%. Compared to methods that generate indanol and then use expensive and highly polluting reactants such as azide compounds to obtain chiral indaneamine, this method is simpler, has milder reaction conditions, higher yield, less environmental pollution, and lower waste, demonstrating promising prospects for industrialization.
[0010] This invention provides a method for synthesizing chiral indeneamine. The method involves adding N-(2,5-dimethyl-1H-indol-3-yl)acetamide (enamine), a solvent, and a chiral catalyst to a hydrogenation reactor. Hydrogen gas is added under a certain pressure, and the mixture is stirred and subjected to a hydrogenation reaction at a specified temperature. After the reaction is complete, the catalyst is recovered and reused by filtration at room temperature. The filtrate is concentrated and acidified to obtain (1R,2S)-2,6-dimethyl-1-indeneamine. The reaction process is as follows:
[0011]
[0012] The catalyst is a ruthenium chiral bisphosphine catalyst with the following structure. Figure 1 As shown:
[0013]
[0014] The weight ratio of the chiral catalyst to the enamine is 1:100-20000, preferably 1:500-10000.
[0015] The solvent is selected from one or more of water, methanol, ethanol, acetonitrile, trifluoroethanol, and tetrahydrofuran; the enamine compound has a mass concentration of 5-30%, preferably 5-20%.
[0016] The hydrogen pressure is 1-8 MPa, preferably 3-6 MPa; the reaction temperature is 25-100℃, preferably 50-80℃.
[0017] The advantages of this invention are: in the asymmetric hydrogenation reaction of enamine, the chiral indane trans isomer content is greater than 97%, 95% ee and yield is greater than 90%, the catalyst is readily available, 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 Figure Description
[0018] Figure 1 The gas chromatogram of (1R,2S)-2,6-dimethyl-1-indeneamine obtained in Example 1;
[0019] Figure 2 The liquid chromatogram of the (1R,2S)-2,6-dimethyl-1-indeneamine derivative obtained in Example 1;
[0020] Figure 3 The NMR spectrum of (1R,2S)-2,6-dimethyl-1-indeneamine is 1H NMR. Detailed Implementation
[0021] The following examples will further illustrate the present invention, but are not intended to limit the invention. The NMR of the products in the examples 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. In the following examples, the chiral catalyst was a ruthenium chiral bisphosphine catalyst with the structure shown in Formula 1 below.
[0022]
[0023] Example 1
[0024] 20.1 g of N-(2,5-dimethyl-1H-indol-3-yl)acetamide, 100.0 g of anhydrous ethanol, and 10 mg of chiral catalyst were added to a hydrogenation reactor. Hydrogen gas was introduced, and the hydrogenation reaction was carried out at 3.5 MPa and 65 °C for 12 hours. The catalyst was recovered by filtration at room temperature, and the filtrate was concentrated to 50 ml. 20 g of 36% concentrated hydrochloric acid was added, and the mixture was refluxed for 12 hours. The solid was filtered at room temperature to obtain (1R,2S)-2,6-dimethyl-1-indoleamine hydrochloride, which was dissolved in 50 g of water. The pH was adjusted to greater than 9 with 10% sodium hydroxide, and 50 ml of toluene was added for extraction. The extract was concentrated to obtain 14.7 g of (1R,2S)-2,6-dimethyl-1-indoleamine, with a yield of 91%.
[0025] Example 2
[0026] 20.1 g of N-(2,5-dimethyl-1H-indol-3-yl)acetamide, 80.0 g of anhydrous ethanol, and 15 mg of chiral catalyst were added to a hydrogenation reactor. Hydrogen gas was introduced, and the hydrogenation reaction was carried out at 4.5 MPa and 75 °C for 10 hours. The catalyst was recovered by filtration at room temperature, and the filtrate was concentrated to 50 ml. 20 g of 36% hydrochloric acid was added, and the mixture was refluxed for 12 hours. The solid was filtered at room temperature to obtain (1R,2S)-2,6-dimethyl-1-indoleamine hydrochloride, which was dissolved in 50 g of water. The pH was adjusted to be greater than 9 by adding 10% sodium hydroxide, and 50 ml of toluene was added for extraction. The extract was concentrated to obtain 13.8 g of (1R,2S)-2,6-dimethyl-1-indoleamine, with a yield of 86%.
[0027] Example 3
[0028] 20.1 g of N-(2,5-dimethyl-1H-indol-3-yl)acetamide, 120.0 g of anhydrous ethanol, and 20 mg of chiral catalyst were added to a hydrogenation reactor. Hydrogen gas was introduced, and the hydrogenation reaction was carried out at 3.5 MPa and 65 °C for 12 hours. The catalyst was recovered by filtration at room temperature, and the filtrate was concentrated to 50 ml. 20 g of 36% concentrated hydrochloric acid was added, and the mixture was refluxed for 12 hours. The solid was filtered at room temperature to obtain (1R,2S)-2,6-dimethyl-1-indoleamine hydrochloride, which was dissolved in 50 g of water. The pH was adjusted to be greater than 9 by adding 10% sodium hydroxide, and 50 ml of toluene was added for extraction. The extract was concentrated to obtain 14.2 g of (1R,2S)-2,6-dimethyl-1-indoleamine, with a yield of 88%.
[0029] Example 4
[0030] 20.1 g of N-(2,5-dimethyl-1H-indol-3-yl)acetamide, 100.0 g of trifluoroethanol, and 25 mg of chiral catalyst were added to a hydrogenation reactor. Hydrogen gas was introduced, and the hydrogenation reaction was carried out at 3.5 MPa and 70 °C for 10 hours. The catalyst was recovered by filtration at room temperature, and the filtrate was concentrated to 50 ml. 20 g of 36% hydrochloric acid was added, and the mixture was refluxed for 12 hours. The solid was filtered at room temperature to obtain (1R,2S)-2,6-dimethyl-1-indoleamine hydrochloride, which was dissolved in 50 g of water. The pH was adjusted to be greater than 9 by adding 10% sodium hydroxide, and 50 ml of toluene was added for extraction. The extract was concentrated to obtain 13.6 g of (1R,2S)-2,6-dimethyl-1-indoleamine, with a yield of 85%.
[0031] Example 5
[0032] 20.1 g of N-(2,5-dimethyl-1H-indol-3-yl)acetamide, 100.0 g of tetrahydrofuran, and 20 mg of chiral catalyst were added to a hydrogenation reactor. Hydrogen gas was introduced, and the hydrogenation reaction was carried out at 4.5 MPa and 50 °C for 12 hours. The catalyst was recovered by filtration at room temperature, and the filtrate was concentrated to 50 ml. 20 g of 36% hydrochloric acid was added, and the mixture was refluxed for 12 hours. The solid was filtered at room temperature to obtain (1R,2S)-2,6-dimethyl-1-indoleamine hydrochloride, which was dissolved in 50 g of water. The pH was adjusted to be greater than 9 by adding 10% sodium hydroxide, and 50 ml of toluene was added for extraction. The extract was concentrated to obtain 12.9 g of (1R,2S)-2,6-dimethyl-1-indoleamine, with a yield of 80%.
[0033] Example 6
[0034] 20.1 g of N-(2,5-dimethyl-1H-indol-3-yl)acetamide, 150.0 g of anhydrous ethanol, and 50 mg of chiral catalyst were added to a hydrogenation reactor. Hydrogen gas was introduced, and the hydrogenation reaction was carried out at 3.0 MPa and 60 °C for 8 hours. The catalyst was recovered by filtration at room temperature, and the filtrate was concentrated to 50 ml. 20 g of 36% hydrochloric acid was added, and the mixture was refluxed for 12 hours. The solid was filtered at room temperature to obtain (1R,2S)-2,6-dimethyl-1-indoleamine hydrochloride, which was dissolved in 50 g of water. The pH was adjusted to be greater than 9 by adding 10% sodium hydroxide, and 50 ml of toluene was added for extraction. The extract was concentrated to obtain 14.0 g of (1R,2S)-2,6-dimethyl-1-indoleamine, with a yield of 87%.
Claims
1. A method for synthesizing chiral indane, characterized in that: The specific process is as follows: N-(2,5-dimethyl-1H-indol-3-yl)acetamide (enamine), solvent and chiral catalyst are added to the hydrogenation reactor, hydrogen is added, hydrogenation reaction is carried out, and after acidification, (1R,2S)-2,6-dimethyl-1-indeneamine is obtained.
2. The method according to claim 1, characterized in that: The catalyst is a ruthenium chiral bisphosphine catalyst, with the structure shown in Formula 1 below:
3. The method according to claim 1, characterized in that: The weight ratio of the chiral catalyst to the enamine is 1:100-20000, preferably 1:500-10000.
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 enamine has a mass concentration of 5-30%, preferably 10-30%.
5. The method according to claim 1, characterized in that: The hydrogen pressure is 1-8 MPa, preferably 3-6 MPa; the reaction temperature is 25-100℃, preferably 50-80℃; and the reaction time is 2-24 hours, preferably 5-14 hours.
6. The method according to claim 1, characterized in that: The acidification process is as follows: add 10-30 g of concentrated hydrochloric acid to 50 ml of reaction solution, reflux for 8-24 hours, filter the solid at room temperature to obtain (1R,2S)-2,6-dimethyl-1-indane hydrochloride, dissolve it in 40-60 g of water, adjust the pH value to be greater than 9 with sodium hydroxide, add 30-60 ml of toluene for extraction to obtain (1R,2S)-2,6-dimethyl-1-indane.
7. The method according to claim 1, characterized in that: The synthesis method uses indanone as a starting material and specifically includes the following steps: The oxime from indanone (CN108794339A) and the enamine from indanone (Organic Letters (2009), 11(2), 481-483) can be synthesized from known literature; then (1R,2S)-2,6-dimethyl-1-indanone is synthesized by the asymmetric hydrogenation reaction of the enamine.