Process for the preparation of 2,6-dimethyl-2,3-dihydro-1-indenone

Abstract

The application discloses a method for preparing 2,6-dimethyl-2,3-dihydro-1-indanone or a mixture of any proportion isomer thereof, comprising the following steps: 1) reacting 2,6-dimethyl-2,3-dihydro-1H-inden-1-amine or a mixture of any proportion isomer thereof with a halogenated reagent to obtain a mixture containing an intermediate; 2) separating or not separating the intermediate, and reacting the intermediate with a reducing agent to obtain 2,6-dimethyl-2,3-dihydro-1-indanone. The application can convert 2,6-dimethyl-2,3-dihydro-1H-inden-1-amine from an amine into a ketone, especially convert an indanamine isomer which cannot be catalyzed by a lipase to be acylated into a ketone, realizes recycling of raw materials, and greatly reduces raw material cost. The halogenated reagent can be synthesized in situ or used, a process is saved, activity of the halogenated reagent is improved, and meanwhile, raw material cost is also lower.

Description

Technical Field

[0001] This invention relates to the field of pesticides and herbicides, specifically to a method for preparing 2,6-dimethyl-2,3-dihydro-1-indanone (CAS No.: 66309-83-9). Background Technology

[0002] Indaziflam was developed by Bayer in 2004 and first launched in the United States in 2010. This herbicide belongs to the cellulose synthesis inhibitor (CBI) class. It achieves highly effective weed control by inhibiting cell membrane biosynthesis and acting on the growth of plant meristematic cells. After soil application, the herbicide is absorbed through the hypocotyl of the plant, inhibiting the growth of new roots and leaves, causing yellowing of the weed stems and leaves, and ultimately leading to weed death. Currently, it is mainly used internationally for weed control in 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, and ornamental plants.

[0003] The key intermediate for indazin-flufenican is (1R,2S)-2,6-dimethyl-2,3-dihydro-1H-indene-1-amine (CAS No.: 752984-24-0). Its synthetic methods include: The literature Tetrahedron (2007), 63(29), 6755-6763 reports the preparation of (1R,2S)-2,6-dimethyl-2,3-dihydro-1H-indene-1-amine from 2,6-dimethyl-2,3-dihydro-1-indene ketone via asymmetric hydrogenation, Mitsunobu reaction, azidation, and reduction. Although this route can selectively yield the target chiral indeneamine product, it requires the use of azides and generates azide intermediates, posing certain safety risks. Furthermore, it uses reagents such as DPPA and DBU, which are difficult to recycle, resulting in a large amount of hazardous organic waste.

[0004] Patent application CN119768531A discloses that a mixture of four stereoisomers of 2,6-dimethyl-1-aminoindenhydride is reacted with an acylation or carboxylation agent under the catalysis of lipase to convert the 1R2S configuration into the corresponding amide or carbamate, but the remaining three configurations are basically unreacted and have no utilization value.

[0005] Publication No. CN119768530A discloses a reaction of a mixture of four stereoisomers of 2,6-dimethyl-1-aminoindenhydride with an acylation or carboxylation agent under lipase catalysis to convert the 1R2S configuration to the corresponding amide or carbamate. Simultaneously, the unreacted configuration is racemized under the action of a metal catalyst to obtain the lipase-catalyzed 1R2S configuration, which is further converted to the corresponding amide or carbamate. Although theoretically this dynamic kinetic resolution (DKR) can achieve a high yield, dimers and deamination products are inevitably generated during the metal-catalyzed racemization process, resulting in a low yield. Furthermore, the simultaneous use of a heterogeneous metal catalyst and enzyme complicates the recovery and reuse of the reaction system.

[0006] In view of the drawbacks of the above technical solutions, it is of great significance to develop a method for recycling 2,6-dimethyl-2,3-dihydro-1-indoleamine and further reduce the production cost of its technical grade. Summary of the Invention

[0007] For the sake of brevity, the term “compound of formula (N) (such as compound of formula (II))” as used below may also encompass any optical isomer, geometric isomer, tautomer or mixture of isomers of compound of formula (N), or an agriculturally acceptable salt.

[0008] The term "optical isomer" refers to the various isomers formed when a compound has one or more chiral centers, each of which can exist in either an R or S configuration. Optical isomers include all diastereomers, enantiomers, meso compounds, racemates, or mixtures thereof. For example, optical isomers can be separated by chiral chromatography or by chiral synthesis.

[0009] The term "geometric isomer" refers to the fact that when a compound contains a double bond, it can exist as cis isomers, trans isomers, E-isomers, and Z-isomers. Geometric isomers include cis isomers, trans isomers, E-isomers, Z-isomers, or mixtures thereof.

[0010] The term "tautomer" refers to an isomer that results from the rapid movement of an atom in a molecule to two different positions. Those skilled in the art will understand that tautomers can interconvert and may coexist in an equilibrium state under certain conditions.

[0011] Unless otherwise specified, the reference herein to “compound of formula (N) (such as compound of formula (II))” also includes isotopically labeled compounds obtained by replacing any one atom of that compound with its isotopic atom. That is, the present invention includes all agriculturally acceptable isotopically labeled compounds of formula (N), wherein one or more atoms are replaced by atoms having the same atomic number as atoms commonly found in nature but with different atomic masses or mass numbers.

[0012] Examples of isotopes suitable for inclusion in the compounds of this invention include isotopes of hydrogen, such as... 2 H(D) and 3 H(T), isotopes of carbon, such as 11 C 13 C and 14 C, isotopes of chlorine, such as 37 Cl, an isotope of fluorine, such as 18 F, an isotope of iodine, such as 123 I and 125 I, isotopes of nitrogen, such as 13 N and 15 N, an isotope of oxygen, such as 15 O、 17 O and 18 O, and isotopes of sulfur, such as 35 S.

[0013] Isotope-labeled compounds of formula (N) can generally be prepared by conventional techniques known to those skilled in the art or by using a suitable isotope-labeling reagent instead of the previously used unlabeled reagent, in a manner similar to that described in the examples and preparations appended herein.

[0014] Compounds of formula (N) may exist in the form of agriculturally acceptable salts, such as acid addition salts and / or base addition salts of compounds of formula (N). Unless otherwise specified, “agriculturally acceptable salts” as used herein includes acid addition salts or base addition salts that may appear in compounds of formula (N).

[0015] Agriculturally acceptable salts of compounds of formula (N) include their acid addition salts and base addition salts. Suitable acid addition salts are formed from acids that form non-toxic salts. Examples include, but are not limited to: acetates, adipates, aspartates, benzoates, benzenesulfonates, bicarbonates / carbonates, hydrogen sulfates / sulfates, borates, camphorsulfonates, citrates, cyclohexylamine sulfonates, ethanedisulfonates, formates, fumarates, gluconate, glucuronide, glucuronide, hexafluorophosphate, 2-(4-hydroxybenzyl)benzoate, hydrochlorides / chlorides, hydrobromides / bromines, hydroiodides / iodides, 2-hydroxyethanesulfonates, lactates, malates, maleates, malonates, methanesulfonates, methyl sulfates, naphthalates, 2-naphthalenesulfonates, nicotinates, nitrates, orotates, oxalates, hexadecates, phosphates / hydrogen phosphates / dihydrogen phosphates, pyroglutamates, gluconate, stearates, salicylates, tannins, tartrates, toluenesulfonates, and trifluoroacetates. Suitable base addition salts are formed by bases that form non-toxic salts. Examples include, but are not limited to: ammonium salts, aluminum, arginine, calcium, choline, diethylamine, diethanolamine, glycine, lysine, magnesium, meglumine, ethanolamine, potassium, sodium, lithium, tromethamine, and zinc salts. They can also form acid and base hemisalts, such as hemisulfates and hemicalcium salts. Methods for preparing agriculturally acceptable salts of the compounds described herein are known to those skilled in the art.

[0016] Some compounds of the present invention may exist in both unsolvated and solvated forms (including hydrated forms). Generally, compounds of formula (N) are included within the scope of the present invention, whether they exist in solvated or unsolvated forms.

[0017] Some compounds of the present invention may exist in different crystal forms or amorphous forms. Regardless of the form in which they exist, compounds of formula (N) are included within the scope of the present invention.

[0018] In a first aspect, this application provides a method for preparing a mixture of 2,6-dimethyl-2,3-dihydro-1-indanone or any proportion of its isomers represented by formula (I), comprising the following steps: 1) React a mixture of compound (II) or any proportion of its isomers with a halogenating agent to obtain a mixture containing an intermediate; 2) With or without separating the intermediate, react the intermediate with a reducing agent to obtain compound (I).

[0019] In the preparation method of the first aspect of the present invention, the compound of formula (II) may exist in the form of a single isomer. For example, in one embodiment of the present invention, the compound of formula (II) may be a pure form of formula (II-1), formula (II-2), formula (II-3), or formula (II-4). Alternatively, the compound of formula (II) may also exist in the form of a mixture of two or more of formulas (II-1), (II-2), (II-3), and (II-4) in any proportion. Optionally, the compound of formula (II) in step 1) exists in the form of a mixture. In one embodiment of the present invention, the halogenated reagent includes at least one selected from chlorinated and brominated reagents. Optionally, the chlorinated reagent includes chlorine gas and hypochlorite M(ClO). n At least one of trichloroisocyanuric acid (TCCA), dichloroisocyanuric acid (DCCA), N-chlorosuccinimide (NCS), and dichlorohydantoin (DCDMH), and hypochlorite M(ClO). n M can be selected from Na, K, Ca, and Mg, and n is 1 or 2. Further optionally, the chlorinating agent includes at least one of chlorine, sodium hypochlorite, and trichloroisocyanuric acid (TCCA); optionally, the brominating agent includes liquid bromine and hypobromite M(BrO). n At least one of the following, hypobromite M(BrO) n M can be selected from Na, K, Ca, and Mg, and n is 1 or 2. Further optional brominating reagents include at least one of liquid bromine and sodium hypobromite.

[0020] In one embodiment of the present invention, the halogenated reagent can be used directly, generated in situ before participating in the reaction, or generated in situ and participating in the reaction simultaneously. For example, sodium hypochlorite can be used directly for the reaction; chlorine gas can be passed through a sodium hydroxide solution to prepare a sodium hypochlorite solution for use; or the compound of formula (II) can be mixed with a sodium hydroxide solution, and then chlorine gas can be passed through, i.e., sodium hypochlorite is generated in situ and reacts with the compound of formula (II) simultaneously.

[0021] In one embodiment of the present invention, the halogenated reagent is generated in situ before participating in the reaction, or the in situ generation and participation in the reaction occur simultaneously. For example, when the chlorination reagent includes trichloroisocyanuric acid (TCCA), it can be generated in situ by passing chlorine gas through a sodium hydroxide solution with dichloroisocyanuric acid and / or monochloroisocyanuric acid and / or isocyanuric acid, and then participate in the reaction or react simultaneously; when the chlorination reagent includes dichloroisocyanuric acid (DCCA), it can be generated in situ by passing chlorine gas through a sodium hydroxide solution with monochloroisocyanuric acid and / or isocyanuric acid, and then participate in the reaction or react simultaneously; when the chlorination reagent includes N-chlorosuccinimide (NCS), it can be generated in situ by passing chlorine gas through a sodium hydroxide solution with N-chlorosuccinimide, and then participate in the reaction or react simultaneously; when the chlorination reagent includes dichlorohydantoin (DCDMH), it can be generated in situ by passing chlorine gas through a sodium hydroxide solution with DCDMH, and then participate in the reaction or react simultaneously.

[0022] In some embodiments, the in-situ generation takes place in an alkaline solution. The alkaline solution may be one or a mixture of two or more of the following: sodium hydroxide solution, potassium hydroxide solution, calcium hydroxide solution, magnesium hydroxide solution, etc.

[0023] In one embodiment of the present invention, the molar ratio of the halogenated reagent to the compound of formula (II) or any proportion of its isomers is 0.6:1 to 5:1, for example 1:1, 1.5:1, 2:1, 2.5:1, 3:1, 3.5:1, 4:1, 4.5:1, etc., preferably 1:1 to 3:1.

[0024] In one embodiment of the present invention, the reaction temperature of step 1) is -10 to 60°C, for example -5°C, 0°C, 5°C, 10°C, 15°C, 20°C, 25°C, 30°C, 35°C, 40°C, 45°C, 50°C, 55°C, etc., and optionally 0 to 30°C.

[0025] In one embodiment of the present invention, the reaction time of step 1) is 1 to 10 hours, for example 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, etc.

[0026] In one embodiment of the present invention, step 1) is carried out in an aqueous system, which may be a pure aqueous phase or a mixed system containing water and organic solvent. Optionally, the organic solvent includes at least one of aromatic solvents (e.g., benzene, xylene, trimethylbenzene, ethylbenzene, diethylbenzene, isopropylbenzene, diisopropylbenzene, halobenzene, dihalobenzene, etc.), alkane solvents (e.g., at least one of n-hexane, cyclohexane, n-heptane, methylcyclohexane, ethylcyclohexane, etc.), halocarbon solvents (e.g., at least one of dichloromethane, dichloroethane, chloroform, carbon tetrachloride, etc.), ether solvents (e.g., at least one of tetrahydrofuran, methyltetrahydrofuran, methyl tert-butyl ether, diisopropyl ether, methylcyclopentyl ether, ethylene glycol dimethyl ether, dioxane, diethylene glycol dimethyl ether, etc.), and ester solvents (e.g., at least one of ethyl acetate, isopropyl acetate, butyl acetate, etc.), and further optionally includes at least one of toluene, chlorobenzene, dichloroethane, and dichloromethane.

[0027] In one embodiment of the present invention, in step 1), the mixture containing the intermediate is a mixture containing a compound of formula (IV): .

[0028] The intermediate includes a compound of formula (Ⅳ).

[0029] In one embodiment of the present invention, the compound of formula (Ⅳ) may exist as a single isomer. For example, the compound of formula (IV) may be a pure form of formula (Ⅳ-1), formula (Ⅳ-2), formula (Ⅳ-3), or formula (Ⅳ-4); or, the compound of formula (IV) may exist as a mixture comprising two or more of formulas (Ⅳ-1), (Ⅳ-2), (Ⅳ-3), and (Ⅳ-4) in any proportion. Optionally, in step 1), the compound of formula (Ⅳ) exists as a mixture. In one embodiment of the present invention, the reducing agent comprises one or more of the following: sulfite compounds, bisulfite compounds, dithionite compounds, thiosulfate compounds, metabisulfite compounds, and thiourea dioxide, wherein the cation of the salt compound may be selected from Na+. + K + Ca 2+ and Mg 2+ Optionally, the reducing agent includes at least one of sodium sulfite, potassium sulfite, sodium bisulfite, potassium bisulfite, sodium dithionite (sodium hydrosulfite), potassium dithionite, sodium thiosulfate, potassium thiosulfate, sodium metabisulfite, and thiourea dioxide.

[0030] In one embodiment of the present invention, the molar ratio of the reducing agent to the compound of formula (II) or any proportion of its isomers is from 0.3:1 to 5:1, for example 0.5:1, 1:1, 1.5:1, 2:1, 2.5:1, 3:1, 3.5:1, 4:1, 4.5:1, etc., preferably from 0.5:1 to 3:1.

[0031] In one embodiment of the present invention, the reaction temperature of step 2) can be from -10 to 70°C, for example -5°C, 0°C, 5°C, 10°C, 15°C, 20°C, 25°C, 30°C, 35°C, 40°C, 45°C, 50°C, 55°C, 60°C, 65°C, etc., preferably from 10 to 50°C.

[0032] In one embodiment of the present invention, the reaction time of step 2) is 1 to 10 hours, such as 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, etc., and optionally 3 to 5 hours.

[0033] In one embodiment of the present invention, step 2) is carried out in an aqueous system, which may be a pure aqueous phase or a mixed system containing water and organic solvent. The organic solvents include at least one of the following: aromatic solvents (e.g., benzene, xylene, trimethylbenzene, ethylbenzene, diethylbenzene, isopropylbenzene, diisopropylbenzene, halobenzene, dihalobenzene, etc.), alkane solvents (e.g., at least one of n-hexane, cyclohexane, n-heptane, methylcyclohexane, ethylcyclohexane, etc.), halocarbon solvents (e.g., at least one of dichloromethane, dichloroethane, chloroform, carbon tetrachloride, etc.), ether solvents (e.g., at least one of tetrahydrofuran, methyltetrahydrofuran, methyl tert-butyl ether, diisopropyl ether, methylcyclopentyl ether, ethylene glycol dimethyl ether, dioxane, diethylene glycol dimethyl ether, etc.), and ester solvents (e.g., at least one of ethyl acetate, isopropyl acetate, butyl acetate, etc.). Preferably, the organic solvents include at least one of toluene, chlorobenzene, dichloroethane, and dichloromethane.

[0034] In a second aspect, this application provides a mixture of a compound of formula (IV) or its isomers. .

[0035] Compound (Ⅳ) may exist as a single isomer; for example, compound (I) may be a pure form of formula (Ⅳ-1), formula (Ⅳ-2), formula (Ⅳ-3), or formula (Ⅳ-4). Alternatively, compound (IV) may exist as a mixture of two or more of formulas (Ⅳ-1), (Ⅳ-2), (Ⅳ-3), and (Ⅳ-4) in any proportion. Preferably, the compound of formula (IV) can be prepared with reference to the first aspect of the present invention.

[0036] In a third aspect, this application provides a method for preparing a mixture of compounds of formula (IV) or isomers thereof, comprising: Reacting a compound of formula (II) or a mixture of its (arbitrary) isomers with a halogenating reagent yields a compound of formula (IV); .

[0037] Preferably, the compound of formula (IV) can be prepared with reference to the first aspect of the present invention.

[0038] In a fourth aspect, this application provides a method for preparing a mixture of 2,6-dimethyl-2,3-dihydro-1-indanone or any proportion of its isomers represented by formula (I), comprising: A mixture of compounds of formula (IV) or their isomers is reacted with a reducing agent in an aqueous system to give a compound of formula (I). .

[0039] Preferably, the compound of formula (IV) can be prepared with reference to the first aspect of the present invention.

[0040] The preparation methods described in the third and fourth aspects can be further selected and optimized with reference to the first aspect.

[0041] Those skilled in the art will understand that the definitions and preferences described in one aspect of this application also apply to other aspects. Those skilled in the art will appreciate that embodiments of various aspects of this application can be combined in various ways without departing from the subject matter and spirit of this application, and these combinations are also included within the scope of this application.

[0042] Compared with the prior art, the beneficial effects of this invention are as follows: 1. This application can convert the compound represented by formula (II) from an amine to a ketone, especially converting the indamine isomer that cannot be catalyzed by lipase to a ketone, thereby realizing the recycling of raw materials and greatly reducing the cost of raw materials.

[0043] 2. Halogenated reagents (chlorinated reagents) can be synthesized or used in situ, saving process steps, improving the activity of halogenated reagents (chlorinated reagents), and also making the raw material cost lower. Detailed Implementation

[0044] The present invention will be further illustrated below with reference to embodiments; however, these embodiments do not limit the scope of the invention. Unless otherwise stated, all reactants used in the embodiments are obtained commercially or according to existing technology; the instruments and equipment used in the synthesis experiments and product analysis are conventional instruments and equipment commonly used in organic synthesis.

[0045] Example 1: Synthesis of compound (I).

[0046] Sodium hypochlorite solution (10.6% available chlorine, 2000g) was added to the reaction flask and cooled to 5°C. A toluene solution (400g) containing compound (II) (200g, 98.5% purity, where (II-1):(II-2):(II-3):(II-4) = 33:32:17:16) was slowly added dropwise while maintaining the system temperature at 5-10°C. After the addition was complete, the temperature was naturally raised to room temperature and maintained for 10 hours. The reaction was considered complete when the reactant concentration in the gas phase was less than 0.5%. After standing and separating the layers, the organic phase was washed twice with water to obtain a toluene solution of compound (IV) with a GC-normalized purity of 95%. This toluene solution could be used directly in the next reaction without further purification. GC-MS analysis of this toluene solution showed m / z (ESI) 194.07 ([M+1)). + , 100 %).

[0047] The toluene solution obtained above was added to a reaction flask, followed by 500g of water. At 10-15°C, sodium hydrosulfite (480g) was added in batches. After the addition was complete, the temperature was raised to 35-40°C and maintained for 5 hours. The reaction was considered complete when the raw material concentration was less than 0.5%. The mixture was allowed to stand and separate into layers. The organic phase was washed twice with water, dissolved under reduced pressure, and distilled to obtain 177.4g of compound (I) with a purity of 98.2% and a yield of 90%.

[0048] m / z (ESI) 161.07 ([M+1] + , 100 %).

[0049] 1 H NMR (CDCl3, 400 MHz): δ1.29(d, J =7.3 Hz,3H),2.39 (s,3H), 2.63-2.75(m,2H), 3.34 (dd, J =7.9, 17.1 Hz, 1H), 7.32 (d, J =7.8Hz, 1H), 7.39 (d, J =7.8Hz, 1H), 7.55 (s, 1H).

[0050] Example 2: Synthesis of compound (I).

[0051] Add sodium hypochlorite solution (10.6% available chlorine, 2000g) to the reaction flask, cool to 5°C, and slowly add 400g of toluene solution containing compound (II) (200g, 98.0% purity, where (II-1):(II-2):(II-3):(II-4) = 0.8:52.2:22:25), while maintaining the system temperature at 5-10°C. After the addition is complete, allow the temperature to rise naturally to room temperature and maintain the reaction for 10 hours. The reaction is complete when the reactant concentration in the gas phase is less than 0.5%. Allow the mixture to stand and separate into layers. Wash the organic phase twice with water to obtain a toluene solution of compound (IV), which can be used directly in the next reaction without purification.

[0052] The toluene solution obtained above was added to a reaction flask, followed by 500g of water. Sodium hydrosulfite (480g) was added in batches at 10-15°C. After the addition was complete, the temperature was raised to 35-40°C and maintained for 5 hours. The reaction was considered complete when the raw material concentration was less than 0.5%. The mixture was allowed to stand and separate into layers. The organic phase was washed twice with water, dissolved under reduced pressure, and distilled to obtain 178.6g of compound (I) with a purity of 98.3% and a yield of 91.2%.

[0053] Example 3: Synthesis of compound (I).

[0054] Add 31% sodium hydroxide solution (364g) to the reaction flask, then add 400g of toluene solution containing compound (II) (200g, 98.5% purity). Cool to 5°C, slowly introduce chlorine gas while maintaining the system temperature at 5-10°C. After introducing 195.2g of chlorine gas, stop the gas flow and allow the system to naturally warm to room temperature for 10 hours. The reaction is complete when the reactant concentration in the gas phase is less than 0.5%. Allow the mixture to stand and separate into layers. Wash the organic phase twice with water to obtain a toluene solution of compound (IV), which can be used directly in the next reaction without purification.

[0055] The toluene solution obtained above was added to a reaction flask, followed by 500g of water. Sodium hydrosulfite (480g) was added in batches at 10-15°C. After the addition was complete, the temperature was raised to 35-40°C and maintained for 5 hours. The reaction was considered complete when the raw material concentration was less than 0.5%. The mixture was allowed to stand and separate into layers. The organic phase was washed twice with water, dissolved under reduced pressure, and distilled to obtain 185.9g of compound (I) with a purity of 98.5% and a yield of 94.6%.

[0056] Example 4: Synthesis of compound (I).

[0057] Add 31% sodium hydroxide solution (364g) to the reaction flask, then add 400g of dichloromethane solution containing compound (II) (200g, 98.5% purity). Cool to 5°C, slowly introduce chlorine gas while maintaining the system temperature at 5-10°C. After introducing 194g of chlorine gas, stop the gas flow and allow the system to naturally warm to room temperature for 10 hours. The reaction is complete when the reactant concentration in the gas phase is less than 0.5%. Allow the mixture to stand and separate into layers. Wash the organic phase twice with water to obtain a dichloromethane solution of compound (IV), which can be used directly in the next reaction without purification.

[0058] The above-mentioned dichloromethane solution was added to a reaction flask, followed by 500g of water. At 10-15°C, sodium hydrosulfite (480g) was added in batches. After the addition was complete, the temperature was raised to 35-40°C and maintained for 5 hours. The reaction was considered complete when the raw material concentration was less than 0.5%. The mixture was allowed to stand and separate into layers. The organic phase was washed twice with water, dissolved under reduced pressure, and distilled to obtain 172.4g of compound (I) with a purity of 96.1% and a yield of 85.6%.

[0059] Example 5: Synthesis of compound (I).

[0060] Add 31% sodium hydroxide solution (364g) to the reaction flask, then add 400g of toluene solution containing compound (II) (200g, 98.5% purity). Cool to 5°C, slowly introduce chlorine gas while maintaining the system temperature at 5-10°C. After introducing 194g of chlorine gas, stop the gas flow and allow the system to naturally warm to room temperature for 10 hours. The reaction is complete when the reactant concentration in the gas phase is less than 0.5%. Allow the mixture to stand and separate into layers. Wash the organic phase twice with water to obtain a toluene solution of compound (IV), which can be used directly in the next reaction without purification.

[0061] The toluene solution obtained above was added to a reaction flask, followed by 500g of water. Sodium hydrosulfite (270g) was added in batches at 10-15°C. After the addition was complete, the temperature was raised to 35-40°C and maintained for 5 hours. The reaction was considered complete when the raw material concentration was less than 0.5%. The mixture was allowed to stand and separate into layers. The organic phase was washed twice with water, dissolved under reduced pressure, and distilled to obtain 182.7g of compound (I) with a purity of 98.1% and a yield of 92.6%.

[0062] Example 6: Synthesis of compound (I).

[0063] Add toluene (400g) to the reaction flask, followed by trichloroisocyanuric acid (209.3g). Stir until homogeneous and cool to 5°C. Slowly add compound (II) (200g, 98.5% purity) dropwise while maintaining the system temperature at 5-10°C. Allow the mixture to naturally warm to room temperature and maintain the reaction for 10 hours. The reaction is complete when the reactant concentration in the gas phase is less than 0.5%. The filtrate obtained is a toluene solution of compound (IV), which can be used directly in the next reaction without purification.

[0064] The toluene solution obtained above was added to a reaction flask, followed by 500g of water. Thiourea dioxide (266.9g) was added in portions at 10-15°C. After the addition was complete, the temperature was raised to 35-40°C and maintained for 5 hours. The reaction was considered complete when the initial reactant concentration was less than 0.5%. The mixture was allowed to stand and separate into layers. The organic phase was washed twice with water, dissolved under reduced pressure, and distilled to obtain 171.7g of compound (I) with a purity of 97.6% and a yield of 86.6%.

[0065] The preferred embodiments of the present invention have been described in detail above. However, the present invention is not limited to the specific details in the above embodiments. Within the scope of the technical concept of the present invention, various simple modifications can be made to the technical solution of the present invention, and these simple modifications all fall within the protection scope of the present invention.

[0066] It should also be noted that the various specific technical features described in the above specific embodiments can be combined in any suitable manner without contradiction. In order to avoid unnecessary repetition, the present invention will not describe the various possible combinations separately.

[0067] Furthermore, various different embodiments of the present invention can be combined in any way, as long as they do not violate the spirit of the present invention, they should also be regarded as the content disclosed by the present invention.

Claims

1. A method for preparing a mixture of 2,6-dimethyl-2,3-dihydro-1-indanone or any proportion of its isomers represented by formula (I), characterized in that, Includes the following steps: 1) React a mixture of compound (II) or any proportion of its isomers with a halogenating agent to obtain a mixture containing the intermediate; 2) With or without separating the intermediate, react the intermediate with a reducing agent to obtain compound (I).

2. The method according to claim 1, characterized in that, The halogenated reagent includes at least one of the chlorinated reagent and the brominated reagent; Optionally, the chlorinating reagent includes chlorine gas and hypochlorite M(ClO). n At least one of trichloroisocyanuric acid, dichloroisocyanuric acid, N-chlorosuccinimide, and dichlorohydantoin, and hypochlorite M(ClO). n M is selected from Na, K, Ca, and Mg, and n is 1 or 2; Optionally, the chlorination reagent includes at least one of chlorine gas, sodium hypochlorite, and trichloroisocyanuric acid; Optionally, the brominating reagent includes liquid bromine or hypobromite M(BrO). n At least one of the following, hypobromite M(BrO) n M is selected from Na, K, Ca, and Mg, and n is 1 or 2; Optionally, the brominating agent includes at least one of liquid bromine and sodium hypobromite; And / or, the halogenated reagent may be used directly, or generated in situ before participating in the reaction, or generated in situ and participated in the reaction simultaneously; Optionally, the in-situ generation is carried out in an alkaline solution. More preferably, the alkaline solution is one or a mixture of two or more of sodium hydroxide solution, potassium hydroxide solution, calcium hydroxide solution, and magnesium hydroxide solution. And / or, the molar ratio of the halogenated reagent to a mixture of the compound of formula (II) or any proportion of its isomers is 0.6:1 to 5:1, preferably 1:1 to 3:

1.

3. The method according to claim 1, characterized in that, The reaction temperature for step 1) is -10 to 60°C, optionally 0 to 30°C; And / or, the reaction time for step 1) is 1 to 10 hours; And / or, the reaction temperature in step 2) is -10 to 70°C, preferably 10 to 50°C; And / or, the reaction time for step 2) is 1 to 10 hours, optionally 3 to 5 hours.

4. The method according to claim 1, characterized in that, Steps 1) and 2) are carried out in an aqueous system; Optionally, the aqueous system is a pure aqueous phase or a mixed system containing water and organic solvents; Optionally, the organic solvent includes at least one of aromatic solvents, alkane solvents, halogenated hydrocarbon solvents, ether solvents, and ester solvents; Optionally, the aromatic solvent includes at least one of benzene, xylene, trimethylbenzene, ethylbenzene, diethylbenzene, isopropylbenzene, diisopropylbenzene, halobenzene, and dihalobenzene; Optionally, the alkane solvent includes at least one selected from n-hexane, cyclohexane, n-heptane, methylcyclohexane, and ethylcyclohexane; Optionally, the halocarbon solvent includes at least one of dichloromethane, dichloroethane, chloroform, and carbon tetrachloride; Optionally, the ether solvent includes at least one of tetrahydrofuran, methyltetrahydrofuran, methyl tert-butyl ether, diisopropyl ether, methyl cyclopentyl ether, ethylene glycol dimethyl ether, dioxane, and diethylene glycol dimethyl ether; Optionally, the ester solvent includes at least one of ethyl acetate, isopropyl acetate, and butyl acetate; Optionally, the organic solvent includes at least one of toluene, chlorobenzene, dichloroethane, and dichloromethane.

5. The method according to claim 1, characterized in that, The mixture containing the intermediate is a mixture containing compounds of formula (IV): ； The intermediate includes a compound of formula (Ⅳ).

6. The method according to claim 1, characterized in that, The reducing agent comprises one or more of the following: sulfite compounds, bisulfite compounds, dithionite compounds, thiosulfate compounds, metabisulfite compounds, and thiourea dioxide, wherein the cation of the salt compound is selected from Na. + K + Ca 2+ and Mg 2+ ; Optionally, the reducing agent includes at least one of sodium sulfite, potassium sulfite, sodium bisulfite, potassium bisulfite, sodium dithionite, potassium dithionite, sodium thiosulfate, potassium thiosulfate, sodium metabisulfite, and thiourea dioxide. And / or, the molar ratio of the reducing agent to a mixture of the compound of formula (II) or any proportion of its isomers is 0.3:1 to 5:1, preferably 0.5:1 to 3:

1.

7. A compound of formula (IV) or a mixture of its isomers, 。 8. A method for preparing a mixture of a compound of formula (IV) or its isomers, characterized in that, include: A mixture of compounds of formula (II) or their isomers is reacted with a halogenating reagent to give compounds of formula (IV); 。 9. A method for preparing a mixture of 2,6-dimethyl-2,3-dihydro-1-indanone or any proportion of its isomers represented by formula (I), characterized in that, include: A mixture of compounds of formula (IV) or their isomers is reacted with a reducing agent in an aqueous system to give a compound of formula (I). 。 10. The preparation method according to claim 9, characterized in that, The reaction temperature is -10 to 70°C, preferably 10 to 50°C; And / or, the reaction time is 1 to 10 hours, optionally 3 to 5 hours; And / or, the aqueous system is a pure aqueous phase, or a mixed system containing water and organic solvents; Optionally, the organic solvent includes at least one of aromatic solvents, alkane solvents, halogenated hydrocarbon solvents, ether solvents, and ester solvents; Optionally, the aromatic solvent includes at least one of benzene, xylene, trimethylbenzene, ethylbenzene, diethylbenzene, isopropylbenzene, diisopropylbenzene, halobenzene, and dihalobenzene; Optionally, the alkane solvent includes at least one selected from n-hexane, cyclohexane, n-heptane, methylcyclohexane, and ethylcyclohexane; Optionally, the halocarbon solvent includes at least one of dichloromethane, dichloroethane, chloroform, and carbon tetrachloride; Optionally, the ether solvent includes at least one of tetrahydrofuran, methyltetrahydrofuran, methyl tert-butyl ether, diisopropyl ether, methyl cyclopentyl ether, ethylene glycol dimethyl ether, dioxane, and diethylene glycol dimethyl ether; Optionally, the ester solvent includes at least one of ethyl acetate, isopropyl acetate, and butyl acetate; And / or, the reducing agent comprises one or more of the following: sulfite compounds, bisulfite compounds, dithionite compounds, thiosulfate compounds, metabisulfite compounds, and thiourea dioxide, wherein the cation of the salt compound is selected from Na. + K + Ca 2+ and Mg 2+ ; Optionally, the reducing agent includes at least one of sodium sulfite, potassium sulfite, sodium bisulfite, potassium bisulfite, sodium dithionite, potassium dithionite, sodium thiosulfate, potassium thiosulfate, sodium metabisulfite, and thiourea dioxide. And / or, the molar ratio of the reducing agent to a mixture of the compound of formula (II) or any proportion of its isomers is 0.3:1 to 5:1, preferably 0.5:1 to 3:1.

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