Synthetic method of indaziflam intermediate 2, 6-dimethyl-indene amine

Abstract

The invention discloses a synthesis method of an indaziflam intermediate 2, 6-dimethyl-indene amine. In the invention, indanone is reduced by using a cheap reducing reagent to prepare indanol, the indanol and sulfonyl chloride are subjected to an elimination reaction to prepare indene, and finally, the indene and an amination reagent are subjected to addition to prepare the 2, 6-dimethyl-indene amine. The route is good in reaction selectivity and few in side reaction, and the total yield of the 2, 6-dimethyl-indene amine can reach 70% or above. The method is mild in reaction condition, easy to control, less in three wastes, simple in whole process operation and easy to industrialize.

Description

Technical Field

[0001] The present invention belongs to the field of organic synthesis, and particularly relates to a method for synthesizing 2,6-dimethyl-indanamine, an intermediate of indaziflam. Background Art

[0002] Indaziflam is a broad-spectrum, highly efficient, novel-structured and excellent-performance long-acting soil treatment triazine herbicide. It is the most effective herbicide that inhibits plant cellulose biosynthesis (CBIs) discovered so far and is a new type of non-selective pre-emergence herbicide. Due to its broad herbicidal spectrum, long residual period and excellent control effect on resistant weeds, indaziflam has a broad market prospect. In recent years, the dominant populations of annual weeds and broad-leaved weeds have changed greatly. In particular, the number of resistant weeds is on the rise and is developing rapidly, which increases the difficulty of weed control. This situation has brought new development opportunities to herbicides led by indaziflam. And 2,6-dimethyl-indanamine is a key intermediate for synthesizing indaziflam. Therefore, studying the synthetic process route of 2,6-dimethyl-indanamine is of great significance.

[0003]

[0004] Currently, the synthetic methods for 2,6-dimethyl-indanamine are all prepared by forming an oxime from indanone and hydroxylamine hydrochloride and then performing reduction. It is mainly the reduction route catalyzed by nickel of Bayer [CN116082166, 2023, A; and WO2015070995A; and J. Chem. Soc., Perkin Trans. 1, 1998, 3459-3462]. And the reduction route catalyzed by palladium [Org. Process Res. Dev. 2014, 18, 1169−1174 and J. Am. Chem. Soc.1966, 88, 10, 2233-2240]. The above synthetic routes have the disadvantages of expensive catalysts, low yields, the need to use special equipment, too high costs, and being unfavorable for industrial production.

[0005] Summary of the Invention

[0006] In view of the problems of the existing synthetic route, such as the need to use expensive noble metal reagents for reduction, low yield, the need to use special equipment, and high cost, the present invention provides a method for synthesizing indaziflam intermediate 2,6-dimethyl-indanamine. In the present invention, indanone is reduced with a cheap reducing reagent to prepare indanol, indanol is then subjected to an elimination reaction with sulfonyl chloride to prepare indene, and finally indene is subjected to an addition reaction with an amination reagent to prepare 2,6-dimethyl-indanamine. This route has good reaction selectivity, few side reactions, and the total yield of 2,6-dimethyl-indanamine can reach more than 70%. The reaction conditions of this method are mild, easy to control, with less three wastes, and the whole process is simple to operate and easy to industrialize.

[0007] The method for synthesizing indaziflam intermediate 2,6-dimethyl-indanamine of the present invention comprises the following steps:

[0008] Step 1: 2,6-dimethyl-indanone undergoes a reduction reaction in the presence of a reducing reagent to form 2,6-dimethyl-indanol;

[0009] Step 2: 2,6-dimethyl-indanol undergoes an elimination reaction in the presence of a sulfonylation reagent to form 2,6-dimethyl-indene;

[0010] Step 3: 2,6-dimethyl-indene undergoes an addition reaction in the presence of an amination reagent, a catalyst, an initiating reagent, and a reducing reagent to form 2,6-dimethyl-indanamine.

[0011] In Step 1, the reducing reagent is selected from lithium aluminum hydride (LiAlH4), sodium borohydride (NaBH4), aluminum isopropoxide, or borane, etc., and preferably sodium borohydride.

[0012] In Step 1, the reaction is carried out in a solvent, and the solvent is selected from methanol, toluene, acetonitrile, tetrahydrofuran, DCE, ethyl acetate, or DMF, etc., and preferably methanol.

[0013] In Step 2, the sulfonylation reagent is selected from methanesulfonyl chloride, trifluoromethanesulfonyl chloride, p-toluenesulfonyl chloride, p-nitrobenzenesulfonyl chloride, or methanesulfonic anhydride, etc., and preferably methanesulfonyl chloride.

[0014] In Step 2, the reaction is carried out in a solvent, and the solvent is selected from toluene, acetonitrile, tetrahydrofuran, DCE, ethyl acetate, or DMF, etc., and preferably toluene.

[0015] In Step 3, the amination reagent is selected from bis(tert-butoxycarbonyl)amine, bis(benzyloxycarbonyl)amine, or bis(9-fluorenylmethoxycarbonyl)amine, etc., and preferably bis(tert-butoxycarbonyl)amine; the molar amount of the amination reagent is 1-5 times the molar amount of 2,6-dimethyl-indene, and preferably 1.2 times.

[0016] In step 3, the catalyst is selected from cobalt chloride, cobalt oxide, copper chloride, copper acetate or manganese chloride, preferably cobalt chloride. The molar amount of the catalyst is 1% to 1 times the molar amount of 2,6-dimethyl-indene, preferably 5%.

[0017] In step 3, the initiating agent is selected from tert-butyl perbenzoate, benzoyl peroxide, di-tert-butyl peroxide, etc., preferably tert-butyl perbenzoate. The molar amount of the initiating agent is 1.3-5 times the molar amount of 2,6-dimethyl-indene, preferably 2 times.

[0018] In step 3, the reducing agent is selected from methyldimethoxysilane, n-butyldimethylsilane, triisopropylsilane, phenylmethylsilane, trivinylsilane or trimethoxysilane, preferably methyldimethoxysilane. The molar amount of the reducing agent is 1.3-5 times the molar amount of 2,6-dimethyl-indene, preferably 2 times.

[0019] In step 3, the reaction is carried out in a solvent selected from toluene, acetonitrile, tetrahydrofuran, DCE, ethyl acetate or DMF, preferably tetrahydrofuran.

[0020] The synthetic route of the present invention is as follows:

[0021]

[0022] The key and special features of the synthetic route of the present invention are the reaction processes of step 2 and step 3. In step 2, no other catalyst is needed to be added, and the elimination of the hydroxyl group in 2,6-dimethyl-indanol by only a sulfonylating agent has not been reported. In the reaction process of step 3, in the reaction system of the aminating agent, catalyst, initiating agent and reducing agent screened by the present invention, the catalyst is firstly generated into a trivalent metal hydride by the initiating agent and the reducing agent in the system, and the trivalent metal hydride is freely added to indene under the initiator, and then replaced by the aminating agent, and hydrolyzed to obtain the target product. The system can achieve a higher product yield with a relatively common and inexpensive catalyst system. Therefore, the synthetic route of the present invention has mild reaction conditions, is easy to control, has less three wastes, and the entire process is simple to operate and easy to industrialize.

[0023] In addition, the method of the present invention has good reaction selectivity, few side reactions, and the total yield of 2,6-dimethyl-indenylamine can reach more than 70%. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 This is the NMR characterization spectrum of 2,6-dimethyl-indanol.

[0025] Figure 2 This is the NMR characterization spectrum of 2,6-dimethyl-indene.

[0026] Figure 3It is the NMR characterization spectrum of 2,6-dimethyl-indanamine. Detailed implementation mode

[0027] The technical solution of the present invention will be further analyzed and described below through specific embodiments.

[0028] Example 1:

[0029] 1. 2,6-Dimethyl-indanone undergoes a reduction reaction to form 2,6-dimethyl-indanol

[0030] Add 10 g of 2,6-dimethyl-indanone and 20 g of MeOH to a 100 ml three-necked flask, cool down to -5 °C, control T < 0 °C, slowly add 4.72 g of NaBH4, and slowly raise the temperature to room temperature after addition. Stir at room temperature for 30 min until the reaction is complete. Filter, distill off the solvent under reduced pressure, then add 20 g of DCM to dissolve, wash with saturated NH4Cl aqueous solution twice, wash the organic phase with water once, and distill off the solvent under reduced pressure to obtain 9.81 g of white solid 2,6-dimethyl-indanol, with a yield of 97% and a purity of 97.3%. Obtain 2,6-dimethyl-indanol, which is a mixture of two configurations of cis-2,6-dimethyl-indanol and trans-2,6-dimethyl-indanol (judged by NMR, cis:trans = 10:1. The mixture sample is measured by NMR, and its data are as follows: cis-2,6-dimethyl-indanol (content approximately 90.9%) 1 1H-NMR(CDCl3): 1.12 (3H, d), 2.34 (3H, s), 2.50 - 2.56 (1H, m), 2.60 - 2.64 (1H, dd), 2.88 - 2.92 (1H, dd), 4.95 (1H, d), 7.05 - 7.06 (1H, d), 7.10 - 7.11 (1H, d), 7.22 (1H, s); trans-2,6-dimethyl-indanol (content approximately 9.1%) 1 1H-NMR(CDCl3) (the nuclear magnetic hydrogen integral area is based on cis-2,6-dimethyl-indanol as the standard): 1.23 (0.42H, d), 2.19 - 2.25 (0.16H, m), 2.38 - 2.43 (0.14H, m), 3.03 - 3.08 (0.12H, m), 4.67 (0.1H, d), 7.18 (0.11H, s).

[0031] 2. The elimination reaction of 2,6-dimethyl-indanol forms 2,6-dimethyl-indene

[0032] Add 7 g of indanol, 4.58 g of triethylamine, and 105 ml of toluene to a 500 ml three-necked flask. Cool the temperature to -10 °C. Weigh 5.18 g of methanesulfonyl chloride, control the temperature T < 0 °C, and add it dropwise to the reaction flask. After the addition is complete, raise the temperature to room temperature and stir for 4 h. Add 20 ml of water, wash with water and separate the layers. Concentrate the organic phase to obtain 6.1 g of white solid 2,6-dimethyl-indene, with a yield of 98% and a purity of 98.2%.

[0033] 1H-NMR data of 2,6-dimethyl-indene 1 1H-NMR(CDCl3): 2.13 (3H, s), 2.35 (3H, s), 3.23(2H, s), 6.42 (1H, s), 6.89 - 6.91 (1H, d), 7.04 (1H, s), 7.22 - 7.23 (1H, d).

[0034] 3. Addition reaction of 2,6-dimethyl-indene to form 2,6-dimethyl-indeneamine

[0035] Add 0.4 g of cobalt chloride to a 500 ml three-necked flask at room temperature, displace with nitrogen three times, add 200 ml of tetrahydrofuran under a nitrogen atmosphere, add 8.9 g of methyldimethoxysilane, add 16.2 g of tert-butyl peroxybenzoate, and stir at room temperature for 20 minutes after the addition is complete. Then add 6 g of 2,6-dimethyl-indene under a nitrogen atmosphere, and stir at room temperature for 20 minutes after the addition is complete. Dropwise add a solution of 10.8 g of bis(tert-butoxycarbonyl)amine in 50 ml of tetrahydrofuran. After the addition is complete, raise the temperature to reflux for 12 hours. After the reaction is completed, add 40 g of 1 mol / L hydrochloric acid solution while it is hot until the pH = 3 - 4, and then reflux for 2 hours. Then continue to add 250 g of DCE for extraction twice to remove impurities. Concentrate and recycle the separated organic phase. Then dropwise add 10% liquid alkali to the acid aqueous phase until the pH = 13 - 14, add 250 g of DCE for extraction twice, combine the organic phases and concentrate to dryness to obtain 5.7 g of yellow liquid 2,6-dimethyl-indeneamine, with a yield of 85%.

[0036] 1H-NMR of 2,6-dimethyl-indeneamine 1 1H-NMR(CDCl3): 1.25 (3H, d), 1.93 - 1.99 (1H, m),2.34 (3H, s), 2.40 - 2.45 (1H, dd), 2.95 - 3.00 (1H, dd), 3.74 (1H,d), 6.98 - 7.00(1H, d), 7.05 - 7.06 (1H, d), 7.12 (1H, s).

[0037] Example 2:

[0038] 1. The reduction reaction of 2,6-dimethyl-indanone produces 2,6-dimethyl-indanol

[0039] Add 10 g of 2,6-dimethyl-indanone and 20 g of MeOH into a 100 ml three-necked flask, cool down to below 0 °C, control T < 0 °C, slowly add 12.7 g of aluminum isopropoxide. After addition, slowly warm up to room temperature and stir at room temperature for 30 min until the reaction is completed. Filter, distill off the solvent under reduced pressure, then add 20 g of DCM to dissolve. Wash with saturated NH4Cl aqueous solution twice and wash the organic phase with water once. Distill off the solvent under reduced pressure to obtain 9.92 g of white solid 2,6-dimethyl-indanol, with a yield of 98%.

[0040] 2. The elimination reaction of 2,6-dimethyl-indanol forms 2,6-dimethyl-indene

[0041] Add 7 g of indanol, 4.58 g of triethylamine and 105 ml of ethyl acetate into a 500 ml three-necked flask, cool down to -10 °C. Weigh 8.63 g of p-toluenesulfonyl chloride, control T < 0 °C, and dropwise add it into the reaction flask. After addition, warm up to room temperature and stir for 4 h. Add 20 ml of water, wash and separate the layers. Concentrate the organic phase to obtain 5.9 g of white solid 2,6-dimethyl-indene, with a yield of 95%.

[0042] 3. The addition reaction of 2,6-dimethyl-indene forms 2,6-dimethyl-indanamine

[0043] Add 0.33 g of copper sulfate into a 500 ml three-necked flask at room temperature, displace with nitrogen three times. Under a nitrogen atmosphere, add 200 ml of tetrahydrofuran and 13.1 g of triisopropylsilane. Then add 16.2 g of tert-butyl peroxybenzoate, and stir at room temperature for 20 minutes after addition. Then, under a nitrogen atmosphere, add 6 g of 2,6-dimethyl-indene, and stir at room temperature for 20 minutes after addition. Dropwise add a 50 ml tetrahydrofuran solution containing 10.8 g of bis(tert-butoxycarbonyl)amine. After addition, heat up to reflux for 12 hours. After the reaction is completed, quickly add 40 g of 1 mol / L hydrochloric acid solution until pH = 3 - 4, and then reflux for 2 hours. Then continue to add 250 g of DCE to extract twice for impurity removal. Concentrate the separated organic phase for recycling. Then dropwise add 10% liquid alkali to the acid aqueous phase until pH = 13 - 14, add 250 g of DCE to extract twice, combine the organic phases and concentrate to dryness to obtain 5.37 g of yellow liquid 2,6-dimethyl-indanamine, with a yield of 80%.

[0044] Example 3:

[0045] 1. The reduction reaction of 2,6-dimethyl-indanone produces 2,6-dimethyl-indanol

[0046] Add 10 g of 2,6-dimethyl-indanone and 20 g of tetrahydrofuran into a 100 ml three-necked flask. Cool the mixture to below 0 °C, control T < 0 °C, and slowly add 4.74 g of lithium aluminum hydride. After addition, slowly warm up to room temperature and stir at room temperature for 30 min until the reaction is completed. Filter, distill off the solvent under reduced pressure, then add 20 g of DCM to dissolve. Wash with saturated aqueous NH4Cl solution twice and wash the organic phase with water once. Distill off the solvent under reduced pressure to obtain 9.32 g of white solid 2,6-dimethyl-indanol with a yield of 92%.

[0047] 2. Elimination reaction of 2,6-dimethyl-indanol to form 2,6-dimethyl-indene

[0048] Add 7 g of indanol, 4.58 g of triethylamine, and 105 ml of tetrahydrofuran into a 500 ml three-necked flask. Cool the mixture to -10 °C, weigh 7.63 g of trifluoromethanesulfonyl chloride, control T < 0 °C, and add dropwise to the reaction flask. After addition, warm up to room temperature and stir for 4 h. Add 20 ml of water, wash and separate the layers. Concentrate the organic phase to obtain 5.97 g of white solid 2,6-dimethyl-indene with a yield of 96%.

[0049] 3. Addition reaction of 2,6-dimethyl-indene to form 2,6-dimethyl-indanamine

[0050] Add 0.28 g of manganese chloride at room temperature into a 500 ml three-necked flask, displace with nitrogen three times, and add 200 ml of tetrahydrofuran and 7.1 g of methyldimethoxysilane under a nitrogen atmosphere. Then add 20.2 g of benzoyl peroxide and stir at room temperature for 20 min after addition. Then add 6 g of 2,6-dimethyl-indene under a nitrogen atmosphere and stir at room temperature for 20 min after addition. Dropwise add a 50 ml solution of bis(tert-butoxycarbonyl)amine (10.8 g) in tetrahydrofuran. After addition, heat up to reflux for 12 h. After the reaction is completed, add 40 g of 1 mol / L hydrochloric acid solution while it is hot until pH = 3 - 4, and then reflux for 2 h. Then continue to add 250 g of DCE for extraction twice to remove impurities. Concentrate the separated organic phase for recycling. Then dropwise add 10% liquid alkali to the acid aqueous phase until pH = 13 - 14, add 250 g of DCE for extraction twice, combine the organic phases and concentrate to dryness to obtain 5.5 g of yellow liquid 2,6-dimethyl-indanamine with a yield of 82%.

Claims

1. A method for synthesizing 2,6-dimethyl-indeneamine, an intermediate of indolepyralid, characterized in that The steps include: Step 1: 2,6-dimethyl-indanone undergoes a reduction reaction in the presence of a reducing agent to generate 2,6-dimethyl-indanol; Step 2: 2,6-dimethyl-indanol undergoes an elimination reaction in the presence of a sulfonylating agent to generate 2,6-dimethyl-indene; Step 3: 2,6-dimethyl-indene undergoes an addition reaction in the presence of an aminating agent, a catalyst, an initiating agent and a reducing agent to form 2,6-dimethyl-indeneamine; The synthetic route is as follows: 。 2. The synthesis method according to claim 1, characterized in that: In step 1, the reducing agent is selected from lithium aluminum hydride, sodium borohydride, aluminum isopropoxide or borane.

3. The synthesis method according to claim 1, characterized in that: In step 2, the sulfonylating agent is selected from methanesulfonyl chloride, trifluoromethanesulfonyl chloride, p-toluenesulfonyl chloride, p-nitrosulfonyl chloride or methanesulfonic anhydride.

4. The synthesis method according to claim 1, characterized in that: In step 3, the amination reagent is selected from bis(tert-butyloxycarbonyl)amine, bis(benzyloxycarbonyl)amine or bis(fluorenylmethoxycarbonyl)amine.

5. The synthesis method according to claim 4, characterized in that: The molar amount of the amination reagent is 1-5 times the molar amount of 2,6-dimethyl-indene.

6. The synthesis method according to claim 1, characterized in that: In step 3, the catalyst is selected from cobalt chloride, cobalt oxide, copper chloride, copper acetate or manganese chloride.

7. The synthesis method according to claim 1, characterized in that: In step 3, the initiating agent is selected from tert-butyl perbenzoate, benzoyl peroxide or di-tert-butyl peroxide.

8. The synthesis method according to claim 7, characterized in that: The molar amount of the initiating agent is 1.3-5 times the molar amount of 2,6-dimethyl-indene.

9. The synthesis method according to claim 1, characterized in that: In step 3, the reducing agent is selected from methyldimethoxysilane, n-butyldimethylsilane, triisopropylsilane, phenylmethylsilane, trivinylsilane or trimethoxysilane.

10. The synthesis method according to claim 9, characterized in that: The molar amount of the reducing agent is 1.3-5 times the molar amount of 2,6-dimethyl-indene.

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