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

Abstract

The invention discloses a method for synthesizing (1R, 2S)-2, 6-dimethyl-1H-indene-1-amine, which comprises the following steps: step 1, carrying out condensation reaction on substituted propionyl benzene and carbonic ester, and then carrying out ammonification reaction and amidation reaction to generate an enamine intermediate; 2, in the presence of a rhodium catalyst and a chiral ligand, carrying out asymmetric hydrogenation double bond on the enamine intermediate obtained in the step 1 to obtain 2-methyl-3-amino-ester; 3, 2-methyl-3-amino-ester obtained in the step 2 is subjected to a cyclization reaction under the catalysis of acid, and indanone is obtained; 4, performing catalytic hydrogenation on the indanone obtained in the step 3 by adopting a palladium catalyst, removing keto carbonyl and positioning halogen substituent; and step 5, carrying out hydrolysis on the product obtained in the step 4 to remove the protecting group so as to obtain the target product (1R, 2S)-2, 6-dimethyl-1H-indene-1-amine. According to the invention, chiral control of a cyclic trans-substituent, which is difficult to realize by a conventional method, is ingeniously converted into central control of conventional chain double bonds, and finally, the target central chirality is obtained by cyclization.

Description

TECHNICAL FIELD

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

[0002] Indanofan is developed by Bayer Company in Germany. As a cellulose biosynthesis inhibitor (CBI), indanofan 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 microfibrils. Moreover, in the face of weed populations that have developed resistance to traditional herbicides such as glyphosate and ALS inhibitors, indanofan still has strong herbicidal activity due to its unique mechanism of action.

[0003] Indanofan 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]

[0006] (1R, 2S)-2, 6-dimethyl-1H-inden-1-amine is one of the key intermediates for synthesizing triazine indanofan.

[0007]

[0008] Currently, several methods for preparing (1R, 2S)-indanamine have been reported:

[0009] 1) Bayer Company uses the dynamic kinetic resolution method established by J.M. Lassaletta, which consists of two steps:

[0010] In the first step, 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 inverts the configuration. Then, catalytic reduction is performed to obtain the desired (1R, 2S)-indanamine.

[0011]

[0012] The method has high catalyst cost, especially involving azide reagent, and the process safety limits its commercialization potential.

[0013] CN108794339B reports that a mixture of four isomers (III) obtained by hydrogenation is used as a raw material to obtain a compound of formula (II) enriched with trans isomer by a method of hydrogenation in the presence of a palladium catalyst; then the enantiomer mixture of formula (II) is resolved with R-mandelic acid to obtain (1R,2S)-2,6-dimethyl-1-indanamine enriched with enantiomer RS-(I).

[0014]

[0015] This method cannot achieve single product configuration, and the chemical resolution results in low final yield. It also cannot meet the needs of commercialization.

[0016] CN119462395 A reports that chiral indanamine of cis body is synthesized in high yield and high stereoselectivity from indanone as a raw material by using a chiral bisphosphine catalyst of ruthenium, and then trans body chiral indanamine is obtained by translocation. The first step catalyst uses a ruthenium catalyst with Salen skeleton, and the second step uses palladium sulfate as catalyst.

[0017]

[0018] Here, the chirality of the methyl group is controlled using a chiral catalyst, which is a great improvement over CN108794339B. Similarly, the same method of enriching the trans isomer using a palladium catalyst is used. The mechanism is not clear here. We found that a large amount of 2,6-dimethyl-1H-indane byproduct with removed amino group was produced in the repeated process.

[0019] WO2024 / 201469Al reports that dimethyl indane can react with hydroxylamine compounds in the presence of transition metals and chiral ligands to obtain chiral indanamine.

[0020]

[0021] This method greatly improves the accessibility of chiral indanamine. However, the materials involved in it 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 its commercialization potential.

[0022] CN119661374A reports a method for resolving trans indanamine using amino acid derivatives to obtain (1R,2S)-2,6-dimethyl-1-indanamine. This method has poor atom economy and high cost, and is not suitable for commercial production.

[0023] In view of the shortcomings of the prior art, the relationship between the two carbon chiral centers in the target product is analyzed, and a method of asymmetric hydrogenation followed by cyclization is proposed, which is a very efficient method for controlling the two chiral centers. SUMMARY

[0024] The present application aims to provide a method for synthesizing (1R,2S)-2,6-dimethyl-1H-inden-1-amine to solve the problems raised in the background art.

[0025] To achieve the above object, the present application provides the following technical solution: a method for synthesizing (1R,2S)-2,6-dimethyl-1H-inden-1-amine, comprising the following steps:

[0026] Step 1: condensation reaction of substituted propionyl benzene and carbonate, followed by amination reaction and amidation reaction to generate an enamine intermediate;

[0027] Step 2: asymmetric hydrogenation of the double bond of the enamine intermediate obtained in Step 1 in the presence of a rhodium catalyst and a chiral ligand to obtain 2-methyl-3-amino-ester;

[0028] Step 3: cyclization of the 2-methyl-3-amino-ester obtained in Step 2 under acid catalysis to obtain an indenone;

[0029] Step 4: catalytic hydrogenation of the indenone obtained in Step 3 using a palladium catalyst to remove the ketone carbonyl group and position the halogen substituent;

[0030] Step 5: hydrolysis of the product obtained in Step 4 to remove the protecting group to obtain the target product (1R,2S)-2,6-dimethyl-1H-inden-1-amine;

[0031] The reaction equation is:

[0032]

[0033] In the substituted propionyl benzene, the substituent is halogen X, and X is Cl, Br or I;

[0034] The protecting group PG introduced in the amidation reaction is carboxyl, sulfonyl, phosphonyl or carbonic acyl;

[0035] The substituent R of the ester group in the 2-methyl-3-amino-ester is H, C1-C20 alkane or aromatic substituent group.

[0036] Preferably, in step 1, the base used in the condensation reaction is one or more of NaH, sodium alkoxide or LDA, preferably NaH; the ammonia source used in the amination reaction is one of ammonium acetate, ammonium chloride or ammonium carbonate, preferably ammonium acetate; and the acid binding agent used in the amidation reaction is one or more of triethylamine, DIPEA, pyridine or lutidine, preferably pyridine.

[0037] Preferably, in step 2, the solvent used in the reaction is one or more of methanol, ethanol, acetonitrile, toluene, THF or dichloromethane; the chiral ligand is a facially chiral ferrocenyl phosphine ligand, preferably Josiphos; the reaction temperature is 10-50℃, the hydrogen pressure is 10-200 bar, and the reaction time is 5-30 h.

[0038] Preferably, in step 3, the solvent used in the reaction is one or more of acetonitrile, toluene, dichloromethane or dichloroethane, or no solvent is used; the acid is one or more of sulfuric acid, phosphoric acid, methanesulfonic acid, trifluoromethanesulfonic acid, substituted benzenesulfonic acid, ZnCl2, AlCl3 or FeCl3; the reaction temperature is 40-100℃, and the reaction time is 0.5-24 h.

[0039] Preferably, in step 4, the solvent used in the reaction is one or more of methanol, ethanol, acetonitrile, toluene or THF; the palladium catalyst is one or more of Pd / C, Pd black, Pd(OH)2, Pt / C or Raney nickel, and the additive added in the reaction is pyridine p-toluenesulfonate or triethylamine p-toluenesulfonate; the reaction temperature is 10-100℃, and the reaction time is 5-30 h.

[0040] Preferably, in step 5, the solvent used in the reaction is one or more of methanol, ethanol, acetonitrile, toluene, THF or water; the reagent used for deprotection is one or more of hydrochloric acid, sulfuric acid, nitric acid, NaOH, KOH or LiOH; the reaction temperature is 10-150℃, and the reaction time is 0.5-24 h.

[0041] Compared with the prior art, the present application has the following beneficial effects:

[0042] The present application ingeniously converts the chiral control of the cyclic trans-substituted group, which is difficult to achieve by conventional methods, into the central control of the conventional chain double bond, and finally obtains the target central chirality by ring closure; the substrates and catalysts used in the process are simple and easy to obtain, the reaction is a classical and mature conversion, and is easy to operate; no chiral separation is required, and no dangerous reagent is used; the three-waste pollution is small, the energy consumption is low, and the process is suitable for industrial production. BRIEF DESCRIPTION OF DRAWINGS

[0043] Fig. 1Liquid chromatogram of (1R,2S)-2,6-dimethyl-1-indanamine obtained from Example 1;

[0044] Fig. 2 Liquid chromatogram of (1R,2S)-2,6-dimethyl-1-indanamine obtained from Example 1;

[0045] Fig. 3 NMR hydrogen spectrum of chiral (1R,2S)-2,6-dimethyl-1-indanamine. DETAILED DESCRIPTION

[0046] The technical solutions in the embodiments of the present application will be clearly and completely described below in conjunction with the embodiments of the present application. Obviously, the described embodiments are only part of the embodiments of the present application, rather than all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by those skilled in the art without creative work fall within the scope of protection of the present application.

[0047] Please refer to Figs. 1-3 The present application provides a method for synthesizing (1R,2S)-2,6-dimethyl-1H-inden-1-amine, comprising the following steps:

[0048] Step 1: condensation reaction of substituted propionyl benzene and carbonate, followed by amination reaction and amidation reaction to generate an enamine intermediate; the base used in the condensation reaction is one or more of NaH, sodium alkoxide or LDA, preferably NaH; the ammonia source used in the amination reaction is one of ammonium acetate, ammonium chloride or ammonium carbonate, preferably ammonium acetate; the acid binding agent used in the amidation reaction is one or more of triethylamine, DIPEA, pyridine or lutidine, preferably pyridine;

[0049] Step 2: asymmetric hydrogenation of the double bond of the enamine intermediate obtained in Step 1 in the presence of a rhodium catalyst and a chiral ligand to obtain 2-methyl-3-amino-ester; the solvent used in the reaction is one or more of methanol, ethanol, acetonitrile, toluene, THF or dichloromethane mixed solvents; the chiral ligand is a facially chiral ferrocenyl phosphine ligand, preferably Josiphos; the reaction temperature is 10-50°C, the hydrogen pressure is 10-200 bar, and the reaction time is 5-30 h;

[0050] Step 3: ring-closing reaction of 2-methyl-3-amino-ester obtained in Step 2 under acid catalysis to obtain an indenone; the solvent used in the reaction is one or more of acetonitrile, toluene, dichloromethane or dichloroethane mixed solvents, or no solvent is used; the acid is one or more of sulfuric acid, phosphoric acid, methanesulfonic acid, trifluoromethanesulfonic acid, substituted benzene sulfonic acid, ZnCl2, AlCl3 or FeCl3 mixed acid reagent; the reaction temperature is 40-100°C, and the reaction time is 0.5-24 h;

[0051] Step 4: Catalytic hydrogenation of the indanone obtained in Step 3 using a palladium catalyst to remove the ketone carbonyl group and orient the halogen substituent; the solvent used in the reaction is one or a mixture of more than one of methanol, ethanol, acetonitrile, toluene or THF; the palladium catalyst used is one or a mixture of more than one of Pd / C, Pd black, Pd(OH)2, Pt / C or Raney nickel, and the additive added in the reaction is pyridine p-toluenesulfonate or triethylamine p-toluenesulfonate; the reaction temperature is 10-100°C, and the reaction time is 5-30h;

[0052] Step 5: Hydrolysis of the product obtained in Step 4 to remove the protecting group to obtain the target product (1R, 2S)-2, 6-dimethyl-1H-inden-1-amine; the solvent used in the reaction is one or a mixture of more than one of methanol, ethanol, acetonitrile, toluene, THF or water; the reagent used to remove the protecting group is one or a mixture of more than one of hydrochloric acid, sulfuric acid, nitric acid, NaOH, KOH or LiOH; the reaction temperature is 10-150°C, and the reaction time is 0.5-24h;

[0053] The reaction equation is:

[0054]

[0055] In the substituted propionyl benzene, the substituent is halogen X, and X is Cl, Br or I.

[0056] The protecting group PG introduced in the amidation reaction is a carboxyl group, a sulfonyl group, a phosphonyl group or a carbonic acyl group.

[0057] In the 2-methyl-3-amino-ester, the substituent R of the ester group is H, a C1-C20 alkyl group or an aromatic substituent group.

[0058] Example 1:

[0059] In a glass reaction flask, add 50 mL of toluene, add sodium hydride (60%, 10.0 g, 2.5 eq) and diethyl carbonate (24.4 mL, 2.0 eq) sequentially, heat the reaction to 80°C, then add 2-chloro-3-methylpropionylbenzene (18.2, 1.0 eq) dropwise, and allow the reaction to cool to room temperature naturally. Quench the reaction with aqueous hydrochloric acid, extract with toluene, and concentrate to give a light yellow liquid. Add 300 mL of methanol to the liquid obtained above, and add ammonium acetate 77 g (10.0 eq) under reflux in nitrogen for 16 hours. After the reaction is complete, quench the reaction with water, extract with toluene, add pyridine 19.8 mL to the toluene phase, and add acetyl chloride (7.8 g, 1.0 eq.) dropwise at 0°C. Allow the reaction to proceed for 3 hours, quench the reaction with dilute hydrochloric acid, concentrate the toluene, and purify by column chromatography to give the product YA-1 (24.2 g, 82% yield).1H-NMR of Z-3 (CDCI3, 300 MHz) δ = 1.28 (t, 3H, J = 7.2 Hz), 1.59 (s, 3H), 1.97 (s, 3H), 2.31 (s, 3H), 4.19 (q, 2H, J = 7.2 Hz), 7.16-7.23 (m, 3H), 11.1 (bs, 1H) ppm.

[0060] Example 2:

[0061] Add Rh(COD)2BF4(4.0 mg, 10 μmol) and (S)-1-{(Sp)-2-[2-(diphenylphosphino)- phenyl]ferrocenyl}-ethyldicyclohexylphosphine (Walphos-003-1; 7.6 mg, 11 μmol) to a reaction flask, add solvent DCM (0.5 mL), and stir at room temperature for 15 minutes under a nitrogen atmosphere. Add YA-1 (20.0 g) to a pressure vessel, add DCM (150 mL), and add the previously prepared catalyst; replace with H2three times, pressurize with H2to 50 Bar, and react at 60°C for 24 hours. After the reaction is complete, wash with water to remove the catalyst, and concentrate to give YA-2 (29.98 g, 99% yield).

[0062] Example 3:

[0063] Add YA-2 (18.0 g, 1.0 eq.) to a reaction flask, and add trifluoromethanesulfonic acid (90.0 g, 10 equivalents) dropwise at 0°C. Allow the reaction to warm to room temperature naturally, and stir at room temperature for 24 hours. After the reaction is complete, recover the trifluoromethanesulfonic acid, then quench with ice-salt water, extract the reaction with toluene, concentrate the toluene, and purify by column chromatography to give the target product YA-3 (13.5 g, 88% yield).

[0064] Example 4:

[0065] In a reaction flask, add YA-3 (12.0 g, 1.0 eq.), PPTS (13.0 g), Pd / Ti02(3 wt%, 120 mg) and methanol (100 mL), replace with hydrogen for 3 times, stir at 60 degree under 10 Bar for 8 hours. After reaction, filter the catalyst, concentrate the methanol, add water, extract with toluene, concentrate the toluene to get YA-4 (9.6 g, 100% yield).

[0066] Example 5:

[0067] In a reaction flask, add YA-4 (10.0 g, 1.0 eq.) and 6N HC1 (30 mL), reflux the reaction for 12 hours. After reaction, extract the impurities with toluene, neutralize the water phase with NaOH to pH > 11, extract with toluene for 3 times, combine the toluene phase, wash with water once, concentrate the toluene to get the target product (1R, 2S)-2,6-dimethyl-1H-inden-1-amine (7.5 g, 95% yield). The 1H NMR (400 MHz, DMSO) of the target product is as follows: 7.11 (s, 1H), 7.01 (d, J = 7.6 Hz, 1H), 6.92 (d, J = 7.6 Hz, 1H), 3.57 (d, J = 8.8 Hz, 1H), 2.86 (dd, J = 15.1, 7.5 Hz, 1H), 2.36 - 2.28 (m, 1H), 2.27 (s, 3H), 1.90 - 1.83 (m, 1H), 1.18 (d, J = 6.7 Hz, 3H).

[0068] Although the present application has been described in detail with reference to the foregoing embodiments, the technical solutions recorded in the foregoing embodiments can be modified by those skilled in the art, or some technical features can be replaced by equivalent features, and any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present application shall be included in the protection scope of the present application.

Claims

1. A method for synthesizing (1R,2S)-2,6-dimethyl-1H-inden-1-amine, characterized in that, Includes the following steps: Step 1: The substituted propionylbenzene and carbonate undergo a condensation reaction, followed by an ammoniation and amidation reaction to generate an enamine intermediate; Step 2: In the presence of a rhodium catalyst and a chiral ligand, the enamine intermediate obtained in Step 1 is subjected to an asymmetric hydrogenation double bond reaction to obtain 2-methyl-3-amino-ester; Step 3: The 2-methyl-3-amino-ester obtained in Step 2 undergoes a cyclization reaction under acid catalysis to give indanone; Step 4: Catalytic hydrogenation of the indanone obtained in step 3 is carried out using a palladium-based catalyst to remove the ketone carbonyl group and the localized halogen substituent; Step 5: The product obtained in Step 4 is subjected to hydrolysis to remove the protecting group, yielding the target product (1R,2S)-2,6-dimethyl-1H-indene-1-amine; The reaction equation is: Wherein, the substituent in the substituted propionylbenzene is a halogen X, where X is Cl, Br or I; The protecting group PG introduced in the amidation reaction is a carboxyl group, a sulfonyl group, a phosphonyl group, or a carbonic acyl group; The ester group in the 2-methyl-3-amino-ester has a substituent R that is H, a C1-C20 alkane, or an aromatic substituent.

2. The method for synthesizing (1R,2S)-2,6-dimethyl-1H-indene-1-amine according to claim 1, characterized in that, In step 1, the base used in the condensation reaction is one or more of NaH, sodium alkoxide, or LDA, preferably NaH; the ammonia source used in the ammoniation reaction is one of ammonium acetate, ammonium chloride, or ammonium carbonate, preferably ammonium acetate; the acid-binding agent used in the amidation reaction is one or more of triethylamine, DIPEA, pyridine, or lutidine, preferably pyridine.

3. The method for synthesizing (1R,2S)-2,6-dimethyl-1H-indene-1-amine according to claim 1, characterized in that, In step 2, the solvent used for the reaction is one or more mixed solvents selected from methanol, ethanol, acetonitrile, toluene, THF, or dichloromethane; the chiral ligand is a facet-chiral ferrocene phosphine ligand, preferably Josiphos; the reaction temperature is 10-50℃, the hydrogen pressure is 10-200 bar, and the reaction time is 5-30 h.

4. The method for synthesizing (1R,2S)-2,6-dimethyl-1H-indene-1-amine according to claim 1, characterized in that, In step 3, the solvent used in the reaction is one or more mixed solvents selected from acetonitrile, toluene, dichloromethane, or dichloroethane, or no solvent is used; the acid is one or more mixed acid reagents selected from sulfuric acid, phosphoric acid, methanesulfonic acid, trifluoromethanesulfonic acid, substituted benzenesulfonic acid, ZnCl2, AlCl3, or FeCl3; the reaction temperature is 40-100℃, and the reaction time is 0.5-24h.

5. The method for synthesizing (1R,2S)-2,6-dimethyl-1H-indene-1-amine according to claim 1, characterized in that, In step 4, the solvent used in the reaction is one or more mixed solvents selected from methanol, ethanol, acetonitrile, toluene, or THF; the palladium catalyst is one or more mixed catalysts selected from Pd / C, Pd black, Pd(OH)2, Pt / C, or Raney nickel; and the additive added in the reaction is pyridine p-toluenesulfonate or triethylamine p-toluenesulfonate; the reaction temperature is 10-100℃, and the reaction time is 5-30h.

6. The method for synthesizing (1R,2S)-2,6-dimethyl-1H-inden-1-amine according to claim 1, characterized in that, In step 5, the solvent used for the reaction is one or more mixed solvents selected from methanol, ethanol, acetonitrile, toluene, THF, or water; the reagent used for deprotection is one or more mixed reagents selected from hydrochloric acid, sulfuric acid, nitric acid, NaOH, KOH, or LiOH; the reaction temperature is 10-150℃, and the reaction time is 0.5-24h.

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