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

Abstract

The invention discloses a method for preparing (1R, 2S)-2, 6-dimethyl-1H-indene-1-amine, and relates to the technical field of synthesis of herbicide indaziflam. The invention relates to a high-temperature-resistant and high-pressure-resistant polyester resin, which is prepared from the following components in parts by weight: 26.1 to 63.0 parts of Ritter reaction component and 42.0 to 123.5 parts of hydrolysis reaction component, and the Ritter reaction component is prepared from the following components in parts by weight: 10.0 parts of (1S, 2S)-2, 6-dimethyl-1-hydroxyindane, 10.0 to 40.0 parts of cyanide, 0.1 to 2.0 parts of acid catalyst and 5.0 to 10.0 parts of Ritter reaction solvent. According to the method disclosed by the invention, the Ritter reaction and the acid-promoted hydrolysis two-step reaction are matched, and the (1S, 2S)-2, 6-dimethyl-1-hydroxyindane, the cyanide, the preferable acid catalyst NTPA and the L-camphorsulfonic acid are matched; the preparation method solves the problems of difficulty in chiral control, mixing of multi-configuration isomers and low target product yield which is generally lower than 65% in an azide method and a dynamic kinetic resolution method in the existing preparation method, does not generate redundant chiral isomers, can directly meet the requirements of products such as indaziflam and the like as downstream herbicides on high-purity chiral intermediates, avoids a subsequent complex resolution process, and is suitable for industrial production. And the downstream production efficiency is improved.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of herbicide indoxacarb, in particular to a method for preparing (1R, 2S)-2, 6-dimethyl-1H-inden-1-amine. BACKGROUND

[0002] Indoxacarb is developed by Bayer Company in Germany. As a cellulose biosynthesis inhibitor (CBI), indoxacarb has a unique herbicidal mechanism. The molecule can penetrate the plant cell membrane, enter the cell interior, target the cellulose synthase complex, interfere with its normal function, and hinder the assembly of cellulose filaments. Moreover, in the face of weed populations that have developed resistance to traditional herbicides such as glyphosate and ALS inhibitors, indoxacarb still has strong herbicidal activity due to its unique mechanism of action.

[0003] Indoxacarb has a wide range of applications. In the agricultural field, it can effectively control common grass weeds such as Digitaria sanguinalis, Eupatorium odoratum, Echinochloa crus-galli, and Dactyloctenium aegyptium, as well as broadleaf weeds such as Chenopodium album, Amaranthus, Abutilon theophrasti, and Portulaca oleracea in crop planting areas such as sugarcane, corn, soybean, and cotton.

[0004] In orchard areas, it can control the germination and early growth of annual weeds in perennial fruit trees such as citrus, apple, pear, and grape, preventing weeds from entwining around the trees and competing for nutrients, maintaining the cleanliness of the orchard, reducing the cost of manual weeding, and improving fruit quality and yield. For non-agricultural areas such as lawns, golf courses, and landscape green spaces, it can maintain the neatness and beauty of the lawn.

[0005] (1R, 2S)-2, 6-dimethyl-1H-inden-1-amine is one of the key intermediates for the synthesis of indoxacarb.

[0006] Currently, several methods for preparing (1R, 2S)-indoleamine have been reported: Bayer Company uses the dynamic kinetic resolution method established by J.M. Lassaletta, which involves two steps: First, indanone is hydrogenated to the corresponding cis-indanol under the action of a ruthenium-based catalyst. In the second step, the hydroxyl group is replaced by an azido group (through conversion with diphenyl phosphoryl azide), which reverses the configuration. Then, catalytic reduction is performed to obtain the desired (1R, 2S)-indoleamine.

[0007] This method has high catalyst cost, especially involving azide reagents, and the process safety limits its commercial potential.

[0008] CN108794339B reported that the mixture of four isomers (III) obtained by hydrogenation was used as raw material, and the compound of formula (II) enriched with trans isomer was obtained by hydrogenation in the presence of palladium catalyst; then the enantiomer mixture of formula (II) was separated by R-mandelic acid to obtain the enantiomer RS-(I) enriched (1R, 2S)-2, 6-dimethyl-1-indanamine.

[0009] This method cannot achieve single product configuration, and the chemical resolution results in low final yield. It also cannot meet the needs of commercialization.

[0010] CN119462395A reported that chiral indanamine was synthesized by using indenone as raw material, ruthenium chiral bisphosphine catalyst, high yield and high stereoselectivity, and then trans body chiral indanamine was obtained by transposition. The first step catalyst uses Salen skeleton ruthenium catalyst, and the second step uses palladium sulfate as catalyst.

[0011] Here, the chirality of the methyl group is controlled by using chiral catalysts, which is a great improvement over CN108794339B. Similarly, the same method of enriching trans isomer using palladium catalyst is used. The mechanism is not clear. We found that a large amount of 2, 6-dimethyl-1H-indane byproduct was produced by removing the amino group.

[0012] WO2024 / 201469A1 reported that dimethyl indane can react with hydroxylamine compounds in the presence of transition metal and chiral ligand to obtain chiral indanamine.

[0013] This method greatly improves the availability of chiral indanamine. However, the materials involved are too expensive, such as chiral ligand Ph-BPE, chiral dioxazoline ligand, silane, O-Ac-N, N-dibenzylhydroxylamine, etc. These factors result in high cost of chiral indanamine synthesis, which greatly reduces the potential of commercial production.

[0014] CN119661374A reported a method for resolving trans indanamine using amino acid derivatives to obtain (1R, 2S)-2, 6-dimethyl-1-indanamine. This method is not atomically economical and has high cost, which is not suitable for commercial production.

[0015] In view of the shortcomings of the prior art that cannot be commercialized, the characteristics of the group on the chiral carbon in the target product are analyzed, and therefore a method for preparing (1R, 2S)-2, 6-dimethyl-1H-inden-1-amine is now proposed to solve such problems. SUMMARY

[0016] Technical problems solved To address the shortcomings of existing technologies, this invention provides a method for preparing (1R,2S)-2,6-dimethyl-1H-indene-1-amine, which solves the problems mentioned in the background art. Technical solution

[0017] To achieve the above objectives, the present invention is implemented through the following technical solution: a (1R,2S)-2,6-dimethyl-1H-indene-1-amine, composed of 26.1 to 63.0 parts of Ritter reaction component and 42.0 to 123.5 parts of hydrolysis reaction component; The key to selecting the above component ratios is to ensure the synergistic timing of the Ritter reaction and hydrolysis reaction through intermediate generation and conversion, thereby achieving the preparation of the target product. Controlling the Ritter reaction component to 26.1–63.0 parts ensures the complete conversion of the starting material into the amide intermediate, with a yield exceeding 95%. Controlling the hydrolysis reaction component to 42.0–123.5 parts precisely matches the amount of intermediate to achieve complete hydrolysis, with a conversion rate exceeding 98%. An imbalance in the two component ratios can lead to raw material waste or a decrease in product yield. This range balances reaction efficiency and cost while ensuring the optical purity of the target product, with an ee value exceeding 95%.

[0018] The Ritter reaction components include: 10.0 parts of (1S,2S)-2,6-dimethyl-1-hydroxyindene, 10.0 to 40.0 parts of cyanide, 0.1 to 2.0 parts of acid catalyst, and 6.0 to 10.0 parts of Ritter reaction solvent; The purpose of selecting this composition for the Ritter reaction components is to construct the amide intermediate through the synergistic effect of each component. The (1S,2S)-2,6-dimethyl-1-hydroxyindene is fixed at 10.0 parts, serving as the source of the chiral core, with its 1-hydroxyl group (S configuration) being the key reactive site. The cyanide is set at 10.0–40.0 parts; this excess design ensures complete reaction of the starting materials while providing the necessary acyl group for the reaction. The acid catalyst, at 0.1–2.0 parts, activates the protonation of the hydroxyl group, promoting the formation of the carbocation. The Ritter reaction solvent, at 5.0–10.0 parts, maintains the homogeneity of the reaction system. This composition avoids reaction stagnation due to insufficient single components or side reactions such as carbonization of the starting materials and reordering of the intermediate due to excess components.

[0019] The solvent for the Ritter reaction includes at least one of acetonitrile, tetrahydrofuran, and alcohols with 1 to 4 carbon atoms; The solvents mentioned above were chosen because of their excellent compatibility with the Ritter reaction components. Acetonitrile, with its moderate polarity, not only dissolves cyanides and starting materials but also stabilizes the carbocations generated during the reaction and serves as a supplementary source of cyanide. Tetrahydrofuran exhibits good solubility in the starting materials, low toxicity, and a suitable boiling point (66°C), making it suitable for large-scale production. Alcohols with 1–4 carbon atoms (such as methanol and ethanol) can form proton solvent systems with acid catalysts, further enhancing catalytic efficiency. These solvents can be used individually or in mixtures, avoiding the post-processing difficulties caused by using high-boiling-point or highly toxic solvents, ensuring a stable and easily controllable reaction system.

[0020] The hydrolysis reaction components include: (1R,2S)-2,6-dimethyl-1-acylaminoindene 12.0-13.0 parts, hydrolysis acid 5.0-15.0 parts, hydrolysis reaction solvent 12.0-65.0 parts, and water 24.0-130.0 parts; The core objective of this hydrolysis reaction component is the directional cleavage of the amide intermediate. The (1R,2S)-2,6-dimethyl-1-amide indene, at 12.0–13.0 parts, corresponds to the theoretical yield of the Ritter reaction, ensuring sufficient starting material for the hydrolysis reaction. The hydrolysis acid, at 5.0–15.0 parts, provides an acidic environment to activate the amide bond, facilitating its cleavage. The hydrolysis solvent, at 12.0–65.0 parts, ensures complete dissolution of the intermediate, preventing uneven reaction. Water, at 24.0–130.0 parts, serves as the reaction medium, directly participating in the amide bond cleavage process. This composition avoids incomplete hydrolysis due to insufficient acid or excessive dilution due to excessive water, ensuring a target product yield exceeding 90%.

[0021] (1S,2S)-2,6-dimethyl-1-hydroxyindane provides the indane core as the starting material, and cyanide provides the acyl group. Under the catalysis of an acid catalyst and the system maintenance effect of the Ritter reaction solvent, the two undergo the Ritter reaction to generate (1R,2S)-2,6-dimethyl-1-amide indane. Through the mixing of this intermediate product with the hydrolysis reaction components, the hydrolysis reaction occurs under the action of amide bond breaking of the hydrolysis acid, the system stabilization effect of the hydrolysis reaction solvent, and the action of the water reaction medium, finally forming (1R,2S)-2,6-dimethyl-1H-indane-1-amine. The above reaction process is designed based on the synergistic mechanism of the Ritter reaction and hydrolysis reaction. In the Ritter reaction stage, the acid catalyst protonates the hydroxyl group at position 1 of the starting material, promoting the formation of a carbocation. Subsequently, the cyano group of the cyanide attacks the carbocation and undergoes hydrolysis to form an amide group. During this process, the configuration of the carbon at position 1 flips from S to R, ensuring the correct chirality of the intermediate. In the hydrolysis stage, the acid used for hydrolysis activates the carbonyl group of the amide group, and water molecules then attack and break the CN bond, releasing the amino group and ultimately generating the target product. The two-step reaction is tightly linked through an intermediate, avoiding accidental chirality flipping or damage to the indane nucleus, effectively solving the problems of difficult chirality control and numerous side reactions in traditional preparation methods.

[0022] In cyanides, the group R1 attached to the cyano group includes at least one of an alkyl group with 1 to 10 carbon atoms or an aryl group with 1 to 10 carbon atoms; R1 is chosen as an alkyl or aryl group with 1 to 10 carbon atoms because the steric hindrance and electronic effects of this range of groups are suitable for the requirements of the Ritter reaction. Alkyl groups with 1 to 10 carbon atoms (such as methyl and ethyl) have less steric hindrance, allowing them to quickly combine with carbocations and resulting in a faster reaction rate. Although aryl groups with 1 to 10 carbon atoms (such as phenyl and tolyl) have slightly greater steric hindrance, their conjugated structure can stabilize the intermediates formed in the reaction and reduce side reactions. If the number of carbon atoms in R1 exceeds 10, the reaction will be hindered due to excessive steric hindrance; if the number of carbon atoms is too small (such as hydrogen atoms), the cyano group is less stable and prone to decomposition. This range achieves a balance between reaction efficiency and intermediate stability.

[0023] The hydrolysis reaction solvent includes at least one of the following: alcohols with 1 to 4 carbon atoms, tetrahydrofuran, dioxane, PEG, DMF, and methyl tert-butyl ether; The solvents mentioned above for the hydrolysis reaction were chosen because they possess both good water compatibility and intermediate solubility. Alcohols with 1 to 4 carbon atoms (such as methanol) are miscible with water, which improves the homogeneity of the reaction system; tetrahydrofuran has excellent solubility for intermediates and a moderate boiling point (66°C), facilitating subsequent recovery; dioxane can be mixed with water in any proportion, stabilizing the acidic hydrolysis environment and preventing system stratification; PEG and DMF are highly polar and suitable for high-concentration hydrolysis systems; methyl tert-butyl ether can assist in subsequent product extraction. These solvents can be flexibly selected according to specific hydrolysis conditions to ensure complete dissolution of intermediates and uniform reaction.

[0024] The acid catalyst includes at least one of L-camphor sulfonic acid, BPA, NTPA, BALT, IDPi, trifluoromethane sulfonic acid, m-nitrobenzene sulfonic acid, p-benzene sulfonic acid, methanesulfonic acid, tris(pentafluorophenyl)borane, boron trifluoride, fluoroboric acid, hydrochloric acid, sulfuric acid, nitric acid, and trifluoroacetic acid.

[0025] The aforementioned acid catalysts were chosen because they efficiently catalyze the Ritter reaction and are well-suited to the requirements of chiral control. Chiral acids such as L-camphorsulfonic acid and NTPA can induce a configuration inversion at the 1-position carbon through their steric hindrance, improving the chiral purity of the intermediate; strong acids such as trifluoromethanesulfonic acid and sulfuric acid have strong protonation capabilities, which can accelerate the formation of carbocations and increase the reaction rate; Lewis acids such as boron trifluoride can coordinate with hydroxyl groups, enhancing the leaving ability of the hydroxyl group. These catalysts can be used alone or in combination, avoiding the use of inefficient or overly corrosive catalysts and ensuring that the reaction proceeds efficiently under mild conditions.

[0026] The hydrolysis reaction is carried out in a manner that includes at least one of alkaline-promoted hydrolysis and acid-promoted hydrolysis; the acid used for hydrolysis includes at least one of hydrochloric acid, concentrated sulfuric acid, fluoroboric acid, and trifluoroacetic acid.

[0027] Both alkaline and acid-promoted hydrolysis are chosen because they achieve amide bond cleavage through different mechanisms. Acid-promoted hydrolysis is preferred due to its mild reaction conditions (temperature range 60–140°C), which minimizes the risk of indene ring opening and keeps side reaction rates below 3%. While alkaline-promoted hydrolysis has a faster reaction rate, the high-alkalinity environment may cause indene ring cleavage. Hydrochloric acid and concentrated sulfuric acid are selected as the acids for hydrolysis because their acidity is controllable and post-treatment is simple: the amine salt formed by hydrochloric acid and the product can be neutralized by alkali to release the target product; concentrated sulfuric acid has high catalytic efficiency; and fluoroboric acid and trifluoroacetic acid are suitable for applications with low equipment corrosion requirements. This selection achieves a balance between hydrolysis efficiency and product purity.

[0028] A method for preparing (1R,2S)-2,6-dimethyl-1H-indene-1-amine, such as Figure 1 As shown, it includes the following steps: This preparation method employs a two-step design: a Ritter reaction to prepare the intermediate and a hydrolysis reaction to prepare the target product. This allows for precise control of the entire reaction process. The step-by-step operation facilitates the optimization of parameters, such as temperature and time, for each stage of the reaction, avoiding increased side reactions due to conflicting conditions in a single step. Simultaneously, the intermediate can be purified separately, effectively improving the purity of the final product to over 99%. Compared to existing one-pot methods, this method increases the yield by more than 15%, offers superior chirality controllability, and achieves an ee value exceeding 95%.

[0029] Step 1: Mix (1S,2S)-2,6-dimethyl-1-hydroxyindane and cyanide, add acid catalyst and Ritter reaction solvent, react at a set temperature, and after the reaction is completed, purify to obtain (1R,2S)-2,6-dimethyl-1-amide indane; The core design principle of Step 1 is the efficient generation of chiral intermediates. The starting material is first mixed with a cyanide, followed by the addition of an acid catalyst and solvent. This sequence avoids direct contact between the acid and the starting material, preventing localized over-protonation and reducing side reactions such as dehydration. By setting a specific reaction temperature, the stable formation of carbocations and their effective binding with amide groups is ensured. Post-reaction purification removes unreacted materials and catalyst, guaranteeing an intermediate purity exceeding 98%, thus laying a solid foundation for subsequent hydrolysis. This step is highly reproducible and suitable for large-scale production.

[0030] The reaction temperature is -20℃ to 120℃; the reaction time is 4 to 12 hours; the purification process includes at least one of filtration, washing, and drying, and the washing solvent is a mixed solvent of acetonitrile and water in a volume ratio of 2:1. The reaction temperature is controlled between -20℃ and 120℃ because the low-temperature range (-20℃ to 30℃) is suitable for chiral catalyst-induced configuration inversion, which can improve the chiral purity of the intermediate; the high-temperature range (30℃ to 120℃) can accelerate the reaction rate and shorten the reaction time. If the temperature is too high (above 120℃), it will trigger cyanide polymerization; if the temperature is too low (below -20℃), the reaction will stagnate. The reaction time is set to 4 to 12 hours to ensure that the conversion rate of the starting material exceeds 98%. Too short a time will result in raw material residue, while too long a time will easily lead to degradation of the intermediate. The solvent used in the purification process, a 2:1 volume ratio of acetonitrile and water, can dissolve unreacted cyanide and acid catalyst, but not the intermediate (solubility is less than 1g / 100mL), which can efficiently remove impurities. After drying, the water content of the intermediate can be controlled to below 0.5%.

[0031] The molar ratio of cyanide to (1S,2S)-2,6-dimethyl-1-hydroxyindane is 1 to 40:1; the molar ratio of acid catalyst to (1S,2S)-2,6-dimethyl-1-hydroxyindane is 0.1 to 2:1, preferably 0.6 to 1:1; and the mass concentration of acid catalyst is 5% to 100%.

[0032] The molar ratio of cyanide to starting material is set at 1–40:1. An excess ratio ensures complete reaction of the starting material. When the ratio is preferably 20–40:1, the conversion rate can exceed 99%, and the excess cyanide can also act as a reaction solvent. If the ratio is lower than 1:1, more starting material residue will remain. The molar ratio of acid catalyst to starting material is 0.1–2:1, preferably 0.6–1:1. This range achieves a balance between protonation efficiency and side reaction control. Too low a ratio will lead to insufficient catalysis and a slow reaction rate, while too high a ratio can easily cause carbonization of the starting material. The mass concentration of the acid catalyst is 5%–100%. High concentrations (50%–100%) can increase proton density and accelerate the reaction, while low concentrations (5%–50%) are suitable for acid-sensitive starting materials, avoiding over-reaction.

[0033] Step 2: The (1R,2S)-2,6-dimethyl-1-acylaminoindane obtained in Step 1 is mixed with hydrolysis acid, hydrolysis reaction solvent and water, and hydrolysis reaction is carried out at a set temperature. After the reaction is completed, post-treatment is performed to obtain (1R,2S)-2,6-dimethyl-1H-indane-1-amine.

[0034] Step two involves mixing the intermediate with the hydrolysis component to achieve directional cleavage of the amide group at a set temperature. The process involves first mixing the intermediate with solvent and water, then adding the hydrolysis acid. This sequence avoids localized acid excess leading to over-atomization of the product and affecting subsequent separation. Setting the temperature ensures efficient amide bond cleavage, and the post-reaction processing steps achieve the separation and purification of the target product. This step is closely linked to step one; the high purity of the intermediate directly increases the yield of the target product, exceeding 90%, while simultaneously preventing impurities from interfering with the hydrolysis reaction.

[0035] The volume ratio of dioxane to (1R,2S)-2,6-dimethyl-1-acylaminoindane is 1 to 5:1. The volume ratio of dioxane to the intermediate is controlled between 1 and 5:1 because this range ensures complete dissolution of the intermediate (solubility exceeding 20 g / 100 mL). A ratio lower than 1:1 will result in incomplete dissolution of the intermediate and uneven hydrolysis; a ratio higher than 5:1 will dilute the concentration of the hydrolysis acid, prolonging the reaction time. Dioxane has good compatibility, maintaining the homogeneity of the reaction system, avoiding stratification that could lead to localized reaction differences, and ensuring a hydrolysis conversion rate exceeding 98%.

[0036] The post-treatment includes at least one of the following: adjusting the pH to 10-14 with an aqueous sodium carbonate solution, organic solvent extraction, drying with anhydrous sodium sulfate, and rotary concentration, wherein the organic solvent used for extraction is dichloromethane; The post-processing steps are designed for efficient separation of the target product. Adjusting the pH to 10–14 with an aqueous sodium carbonate solution releases the product from its amine salt form into free amine, facilitating subsequent dissolution in organic solvents. Dichloromethane is chosen as the extractant because of its solubility for the product exceeding 50 g / 100 mL, clear separation from the aqueous layer, and extraction efficiency exceeding 98%. Drying with anhydrous sodium sulfate removes trace amounts of water from the extract, reducing the water content to below 0.1%. Rotary concentration using reduced pressure at 40–50 °C gently removes the solvent, preventing product loss due to high-temperature volatilization. This process can improve product purity to over 99%, is simple to operate, and is suitable for industrial production.

[0037] The mass ratio of water to (1R,2S)-2,6-dimethyl-1-acylaminoindane is 2–10:1; the mass concentration of the acid used for hydrolysis is 1%–36.5%; the hydrolysis reaction temperature is 60℃–140℃; and the hydrolysis reaction time is 4–48 hours.

[0038] The water-to-intermediate mass ratio is set at 2–10:1 to ensure sufficient medium for the hydrolysis reaction. A ratio lower than 2:1 will lead to incomplete reaction, while a ratio higher than 10:1 will over-dilute the system and affect the reaction rate. A ratio of 3–5:1 is preferred for the most thorough hydrolysis. The mass concentration of the acid used for hydrolysis is 1%–36.5%, preferably 15%–30%. This range balances the acid's activity and its corrosiveness to the equipment. Too low a concentration will result in a slow reaction rate, while too high a concentration will exacerbate equipment corrosion. The hydrolysis reaction temperature is controlled at 60℃–140℃ to accelerate amide bond breaking. If the temperature is below 60℃, the reaction time needs to be extended to 48 hours; if the temperature is above 140℃, the product is easily oxidized. A reaction time of 4–48 hours ensures complete cleavage of the amide group and avoids intermediate residue due to premature termination of the reaction. Beneficial effects

[0039] The present invention has the following beneficial effects: (1) This method for preparing (1R,2S)-2,6-dimethyl-1H-indene-1-amine, through the combination of a two-step reaction of Ritter reaction and acid-promoted hydrolysis, and the combination of components of (1S,2S)-2,6-dimethyl-1-hydroxyindene, cyanide, preferred acid catalyst NTPA, and L-camphor sulfonic acid, solves the problems of difficult chiral control, mixed polyconfiguration isomers, and low yield of target product (usually less than 65%) in existing preparation methods such as azide method and dynamic kinetic resolution method. It makes the optical purity ee value of target product stable ≥95.5%, the total yield reaches 89.0%~97.0%, and no excess chiral isomers are generated. It can directly meet the demand of downstream herbicides such as indazine and fluroxypyr for high-purity chiral intermediates, avoid subsequent complex resolution processes, and improve downstream production efficiency.

[0040] (2) This method for preparing (1R,2S)-2,6-dimethyl-1H-indene-1-amine avoids the use of azide reagent DPPA, precious metal catalyst ruthenium-based catalyst, and palladium-on-carbon catalyst. It uses readily available industrial-grade cyanide acetonitrile, propionitrile, conventional acid catalyst, and water as the reaction medium. At the same time, it controls the mild conditions of the Ritter reaction at -20℃ to 120℃ and atmospheric pressure and the hydrolysis reaction at 60℃ to 140℃ and atmospheric pressure. This solves the problems of high-risk reagents that are prone to causing safety accidents, high cost of precious metal catalysts, and difficulty in treating waste containing precious metal solid waste that requires special disposal in the existing technology. As a result, each 1kg of target product produced only generates 8.0 to 9.5L of wastewater and 115 to 130g of solid waste, and there is no harmful waste gas emission. The safety protection only requires basic acid corrosion protection, which greatly reduces the safety risks and environmental protection costs of industrial production and meets the national safety and environmental protection requirements of the fine chemical industry.

[0041] (3) This method for preparing (1R,2S)-2,6-dimethyl-1H-indene-1-amine simplifies the process to two core steps: preparation of intermediates via Ritter reaction and preparation of target product via hydrolysis reaction. The reaction parameters, such as the molar ratio of cyanide to indene alcohol, are 1-40:1 and the reaction temperature range is wide. At the same time, the low-cost raw materials and industrial-grade acid catalysts are used, which solve the problems of multiple steps, sensitive and difficult-to-control parameters, and high raw material costs of over 5,000 yuan per kilogram in the existing three-step hydrogenation-azide process. This allows the production cycle of a single batch to be controlled within 8-60 hours, with raw material costs of only 1,850-2,020 yuan / kg. Moreover, the process has strong resistance to fluctuations and still achieves a yield of ≥60% even under non-optimal parameters. It is suitable for industrial production lines of different scales, significantly reducing production costs while ensuring product quality and enhancing product market competitiveness.

[0042] Of course, any product implementing this invention does not necessarily need to achieve all of the advantages described above at the same time. Attached Figure Description

[0043] Figure 1 This is a flowchart of a method for preparing (1R,2S)-2,6-dimethyl-1H-inden-1-amine; Figure 2 The normal-phase liquid chromatography chromatogram of the (1R,2S)-2,6-dimethyl-1H-indene-1-amine derivative obtained in Example 1; Figure 3 The gas chromatography-mass spectrometry chromatogram of (1R,2S)-2,6-dimethyl-1H-inden-1-amine obtained in Example 1; Figure 4 The 1H NMR spectrum of (1R,2S)-2,6-dimethyl-1H-indene-1-amine obtained in Example 1. Detailed Implementation

[0044] 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. Example

[0045] Example 1 provides a preparation method for (1R,2S)-2,6-dimethyl-1H-inden-1-amine, such as... Figures 2-4 As shown, it contains the following components by mass / molarity: Ritter reaction components: 10.0 parts of (1S,2S)-2,6-dimethyl-1-hydroxyindene, 10.0 parts of cyanide (acetonitrile), 0.1 parts of acid catalyst (NTPA), 5% mass concentration of acid catalyst, molar ratio of acid catalyst to (1S,2S)-2,6-dimethyl-1-hydroxyindene of 0.1:1, and 6.0 mL of Ritter reaction solvent (acetonitrile). Hydrolysis reaction components: 12.0 parts of (1R,2S)-2,6-dimethyl-1-acylaminoindene (Ritter reaction product), 5.0 mL of hydrolysis acid (hydrochloric acid), 1% mass concentration of hydrolysis acid, 12.0 mL of hydrolysis reaction solvent (dioxane), with a volume ratio of dioxane to (1R,2S)-2,6-dimethyl-1-acylaminoindene of 1:1, 24.0 g of water, with a mass ratio of water to (1R,2S)-2,6-dimethyl-1-acylaminoindene of 2:1.

[0046] The preparation process is as follows: Step 1: Ritter reaction to prepare (1R,2S)-2,6-dimethyl-1-acylaminoindane. Add 10.0 parts of (1S,2S)-2,6-dimethyl-1-hydroxyindane and 5.0 mL of acetonitrile to a 250 mL three-necked flask, and install a mechanical stirrer and thermometer. Cool to -20℃, slowly add 0.1 part NTPA over 30 min, and keep the reaction at this temperature for 4 h after the addition is complete; after the reaction is complete, slowly add 50 mL water while stirring, precipitate solid, and stir for 1 h. The filter cake was filtered, washed twice with 15 mL of a solvent consisting of acetonitrile and water in a volume ratio of 2:1, and dried under vacuum at 60 °C to obtain 12.0 parts of (1R,2S)-2,6-dimethyl-1-acylaminoindane.

[0047] Step 2: Hydrolysis reaction to prepare (1R,2S)-2,6-dimethyl-1H-indene-1-amine. 12.0 parts of (1R,2S)-2,6-dimethyl-1H-indene obtained in Step 1, 5.0 mL of 1% hydrochloric acid, and 12.0 mL of dioxane were added to a 250 mL three-necked flask, and a mechanical stirrer, thermometer, and spherical condenser were installed. The full volume ratio of dioxane to (1R,2S)-2,6-dimethyl-1-acylaminoindene is 1:1, and the full mass ratio of water to (1R,2S)-2,6-dimethyl-1-acylaminoindene is 2:1. The oil bath was heated to 60°C and refluxed for 4 hours. After the reaction was complete, the pH was adjusted to 10 with sodium carbonate aqueous solution, and 24 mL of dichloromethane was added for extraction twice. The dichloromethane layers were combined and dried with anhydrous sodium sulfate for 4 hours. The solvent was then evaporated using a rotary evaporator at 45°C and -0.09 MPa to obtain 8.9 parts of (1R,2S)-2,6-dimethyl-1H-indene-1-amine. Example

[0048] Example 2 provides a preparation method for (1R,2S)-2,6-dimethyl-1H-inden-1-amine, comprising the following components by mass / molarity: Ritter reaction components: 10.0 parts of (1S,2S)-2,6-dimethyl-1-hydroxyindene, 40.0 parts of cyanide (propionitrile), 2.0 parts of acid catalyst (NTPA), 100% mass concentration of acid catalyst, molar ratio of acid catalyst to (1S,2S)-2,6-dimethyl-1-hydroxyindene of 2:1, and 10.0 mL of Ritter reaction solvent (tetrahydrofuran); Hydrolysis reaction components: 13.0 parts of (1R,2S)-2,6-dimethyl-1-acylaminoindene (Ritter reaction product), 15.0 mL of hydrolysis acid (hydrochloric acid), 36.5% mass concentration of hydrolysis acid, 65.0 mL of hydrolysis reaction solvent (dioxane), with a volume ratio of dioxane to (1R,2S)-2,6-dimethyl-1-acylaminoindene of 5:1, 130.0 g of water, with a mass ratio of water to (1R,2S)-2,6-dimethyl-1-acylaminoindene of 10:1.

[0049] The preparation process is as follows: Step 1: Ritter reaction to prepare (1R,2S)-2,6-dimethyl-1-acylaminoindane. Add 10.0 parts of (1S,2S)-2,6-dimethyl-1-hydroxyindane and 10.0 mL of tetrahydrofuran to a 250 mL three-necked flask and start mechanical stirring. Heat to 120℃, add 2.0 parts of NTPA in 3 portions, 30 min apart, and keep warm for 12 h after the addition is complete; after the reaction is complete, cool to room temperature, add 100 mL of water, and stir for 30 min. The filter cake was filtered, and washed twice with 30 mL of a solvent containing tetrahydrofuran and water at a volume ratio of 2:1. It was then dried under vacuum at 55 °C to obtain 13.0 parts of (1R,2S)-2,6-dimethyl-1-acylaminoindan.

[0050] Step 2: Hydrolysis reaction to prepare (1R,2S)-2,6-dimethyl-1H-indene-1-amine. 13.0 parts of (1R,2S)-2,6-dimethyl-1H-indene obtained in Step 1, 15.0 mL of 36.5% hydrochloric acid, and 65.0 mL of dioxane were added to a 250 mL three-necked flask, and a spherical condenser was installed. The full volume ratio of dioxane to (1R,2S)-2,6-dimethyl-1-acylaminoindene is 5:1, and the full mass ratio of water to (1R,2S)-2,6-dimethyl-1-acylaminoindene is 10:1. The oil bath temperature was raised to 140℃ and refluxed for 48 hours; After the reaction was complete, the pH was adjusted to 14 with sodium hydroxide aqueous solution, and 52 mL of dichloromethane was added for extraction twice. Combine the organic phases and dry with anhydrous magnesium sulfate for 3 h; use a rotary evaporator to evaporate the solvent at 50 °C and -0.09 MPa to obtain 9.7 parts of (1R,2S)-2,6-dimethyl-1H-indene-1-amine.

[0051] II. Comparative Example Comparative Example 1 The difference between Comparative Example 1 and Example 1 is that the acid catalyst in the Ritter reaction is replaced with hydrochloric acid, while the other components, amounts, and preparation processes are completely consistent with Example 1.

[0052] Key replacement component: Acid catalyst (hydrochloric acid) 0.04 mL, with a molar ratio of hydrochloric acid to (1S,2S)-2,6-dimethyl-1-hydroxyindene of 0.1:1, and a hydrochloric acid mass concentration of 36.5%; Results: The Ritter reaction yielded 9.5 parts of (1R,2S)-2,6-dimethyl-1-acylaminoindane, which, after hydrolysis, yielded 6.3 parts of (1R,2S)-2,6-dimethyl-1H-indane-1-amine.

[0053] Comparative Example 2 The difference between Comparative Example 2 and Example 1 is that the amount of cyanide (acetonitrile) used is 5.0 parts, the molar ratio of cyanide to (1S,2S)-2,6-dimethyl-1-hydroxyindene is 0.5:1, and the other components, amounts and preparation processes are completely consistent with Example 1.

[0054] Results: The Ritter reaction yielded 8.2 parts of (1R,2S)-2,6-dimethyl-1-acylaminoindane, which was hydrolyzed to give 5.1 parts of (1R,2S)-2,6-dimethyl-1H-indane-1-amine.

[0055] III. Experimental Examples Experimental Example 1 Test objective: To verify the effects of the examples and comparative examples on the total yield, optical purity (ee value), and chemical purity of (1R,2S)-2,6-dimethyl-1H-indene-1-amine.

[0056] Test items and methods: Overall yield: calculated as actual mass of target product / theoretical mass × 100%, with the theoretical mass derived from the full molar amount of starting material (1S,2S)-2,6-dimethyl-1-hydroxyindene; Optical purity (ee value): determined by high performance liquid chromatography (HPLC) with a CHIRALPAKAD-H column, isopropanol-water = 97:3 mobile phase, detection wavelength 254 nm, flow rate 0.8 mL / min, and column temperature 40 °C. Chemical purity: determined by gas chromatography. The chromatographic column was DB-530m×0.32mm×0.25μm, the injection port temperature was 250℃, the detector temperature was 280℃, and the temperature program was as follows: initial temperature of 80℃ held for 2 min, then increased to 220℃ at 10℃ / min and held for 5 min.

[0057] As shown in the table below:

[0058] In this experimental example, the overall yield of Examples 1 and 2 reached 89.0%~97.0%, the optical purity was 95.5%~96.2%, and the chemical purity was 99.0%~99.5%. Due to the use of a non-preferred catalyst, the overall yield of Comparative Example 1 decreased by 29.0% compared to Example 1, and the optical purity decreased by 8.2% compared to Example 1. Due to insufficient cyanide content, the overall yield of Comparative Example 2 decreased by 42.7% compared to Example 1, and the optical purity decreased by 6.4% compared to Example 1.

[0059] Experiment Example 2 Test objective: To verify the controllability of the reaction and the amount of waste generated in the examples and comparative examples.

[0060] Test items and methods: Complete reaction time: The time when the residual amount of raw materials is ≤1% is monitored by high performance liquid chromatography. The Ritter reaction time and hydrolysis reaction time are recorded separately, in h. Three waste quantities: The volume of wastewater (washing and extraction wastewater) and the mass of solid waste (filter cake and spent catalyst) for each kg of target product prepared are counted, with units of L / kg and g / kg, respectively.

[0061] As shown in the table below:

[0062] In this experiment, Example 1 had a short reaction time, with the Ritter reaction completed in 4 hours and the hydrolysis reaction completed in 4 hours, resulting in less waste. Example 2 had a longer reaction time but a higher product yield. Comparative Example 1 had a 100% longer Ritter reaction time and a 50% longer hydrolysis reaction time compared to Example 1 due to low catalyst activity. Comparative Example 2 had a 75% longer Ritter reaction time and a 25% longer hydrolysis reaction time compared to Example 1 due to insufficient raw materials.

[0063] It should be noted that, in this document, relational terms such as "first" and "second" are used only to distinguish one entity or operation from another, and do not necessarily require or imply any such actual relationship or order between these entities or operations. Furthermore, the terms "comprising," "including," or any other variations thereof are intended to cover non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements includes not only those elements but also other elements not expressly listed, or elements inherent to such process, method, article, or apparatus.

[0064] The preferred embodiments of the present invention disclosed above are merely illustrative of the invention. These preferred embodiments do not exhaustively describe all details, nor do they limit the invention to the specific implementations described. Clearly, many modifications and variations can be made based on the content of this specification. This specification selects and specifically describes these embodiments to better explain the principles and practical applications of the invention, thereby enabling those skilled in the art to better understand and utilize the invention. The invention is limited only by the claims and their full scope and equivalents.

Claims

1. (1 R, 2S)-2,6-dimethyl-1 H-inden-1 -amine, characterized in that, Compositions: The Ritter reaction component includes: (1S, 2S)-2, 6-dimethyl-1-hydroxy indane 10.0 parts, cyanide 10.0-40.0 parts, acid catalyst 0.1-2.0 parts, Ritter reaction solvent 6.0-10.0 parts; The hydrolysis reaction component includes: (1R, 2S)-2, 6-dimethyl-1-amido indane 12.0-13.0 parts, hydrolysis acid 5.0-15.0 parts, hydrolysis reaction solvent 12.0-65.0 parts, water 24.0-130.0 parts; (1S, 2S)-2, 6-dimethyl-1-hydroxy indane provides the indane nucleus as the starting material, and the cyanide provides the acyl source. Under the catalysis of the acid catalyst and the system maintenance of the Ritter reaction solvent, the Ritter reaction occurs to generate (1R, 2S)-2, 6-dimethyl-1-amido indane. Through the mixing of the intermediate product with the hydrolysis reaction component, under the amide bond breaking action of the hydrolysis acid, the system stabilizing action of the hydrolysis reaction solvent and the reaction medium action of water, the hydrolysis reaction occurs to finally form (1R, 2S)-2, 6-dimethyl-1H-inden-1-amine. The group R1 connected to the cyano group in the cyanide at least includes one of an alkyl group with 1-10 carbon atoms and an aryl group with 1-10 carbon atoms.

2. A (1R, 2S)-2,6-dimethyl-1 H-inden-1 -amine according to claim 1, characterized in that: The acid catalyst at least includes one of L-camphorsulfonic acid, BPA, NTPA, BALT, IDPi, trifluoromethanesulfonic acid, m-nitrobenzenesulfonic acid, p-toluene sulfonic acid, methanesulfonic acid, tris(pentafluorophenyl)borane, boron trifluoride, fluoroboric acid, hydrochloric acid, sulfuric acid, nitric acid, and trifluoroacetic acid.

3. A (1R, 2S)-2,6-dimethyl-1 H-inden-1 -amine according to claim 1, characterized in that: The hydrolysis reaction at least includes one of base-promoted hydrolysis and acid-promoted hydrolysis; the hydrolysis acid at least includes one of hydrochloric acid, concentrated sulfuric acid, fluoroboric acid, and trifluoroacetic acid.

4. A (1R, 2S)-2,6-dimethyl-1 H-inden-1 -amine according to claim 1, characterized in that: The Ritter reaction solvent at least includes one of acetonitrile, tetrahydrofuran, and an alcohol with 1-4 carbon atoms; 5. A (1R, 2S)-2,6-dimethyl-1 H-inden-1 -amine according to claim 1, characterized in that: The hydrolysis reaction solvent at least includes one of an alcohol with 1-4 carbon atoms, tetrahydrofuran, dioxane, PEG, DMF, and methyl tert-butyl ether. The method includes the following steps:

6. A process for the preparation of (1R,2S)-2,6-dimethyl-1 H-inden-1 -amine, characterized in that, Step one: mixing (1S, 2S)-2, 6-dimethyl-1-hydroxy indane and cyanide, adding an acid catalyst and a Ritter reaction solvent, and reacting at a set temperature. After the reaction is completed, purification treatment is performed to obtain (1R, 2S)-2, 6-dimethyl-1-amido indane; Step two: mixing (1R, 2S)-2, 6-dimethyl-1-amido indane obtained in step one with a hydrolysis acid, a hydrolysis reaction solvent, and water, and performing a hydrolysis reaction at a set temperature. After the reaction is completed, post-treatment is performed to obtain (1R, 2S)-2, 6-dimethyl-1H-inden-1-amine. ​ 7. A process for the preparation of (1R, 2S)-2,6-dimethyl-1 H-inden-1 -amine according to claim 6, characterized in that: In step one, the molar ratio of cyanide to (1S,2S)-2,6-dimethyl-1-hydroxyindane is 1-40:1; the molar ratio of acid catalyst to (1S,2S)-2,6-dimethyl-1-hydroxyindane is 0.1-2:1, and preferably 0.6-1:1; the mass concentration of acid catalyst is 5%-100%.

8. A process for the preparation of (1R, 2S)-2,6-dimethyl-1 H-inden-1 -amine according to claim 6, characterized in that: In step one, the reaction temperature is -20°C-120°C; the reaction time is 4-12 hours; the purification process at least includes one of filtering, washing, and drying, and the washing solvent is a mixed solvent of acetonitrile and water in a volume ratio of 2:

1.

9. A process for the preparation of (1R, 2S)-2,6-dimethyl-1 H-inden-1 -amine according to claim 6, characterized in that: In step two, the mass ratio of water to (1R,2S)-2,6-dimethyl-1-amidoindane is 2-10:1; the mass concentration of hydrolysis acid is 1%-36.5%; the hydrolysis reaction temperature is 60°C-140°C; and the hydrolysis reaction time is 4-48 hours.

10. A process for the preparation of (1R, 2S)-2,6-dimethyl-1 H-inden-1 -amine according to claim 6, characterized in that: In step two, the volume ratio of dioxane to (1R,2S)-2,6-dimethyl-1-amidoindane is 1-5:

1. The post-treatment at least includes one of adjusting the pH to 10-14 with a sodium carbonate aqueous solution, organic solvent extraction, anhydrous sodium sulfate drying, and rotary concentration, and the extraction organic solvent is dichloromethane.

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