Synthetic method of indaziflam intermediate

Abstract

The invention discloses a synthetic method of an indaziflam intermediate, which comprises the following steps: by taking (1S, 2S)-2, 6-dimethyl-1-hydroxyindane and phthalimide as initial raw materials, firstly carrying out Mitsunobu reaction in the presence of an azo reagent and a phosphine reagent to obtain the intermediate; the preparation method comprises the following steps: (1) preparing an intermediate, namely (1R, 2S)-2, 6-dimethyl-1-aminoindane, removing phthalimide from the intermediate obtained in the step (1) by hydrazine hydrate to obtain (1R, 2S)-2, 6-dimethyl-1-aminoindane, and finally salifying to obtain the indaziflam intermediate (1R, 2S)-2, 6-dimethyl-1-aminoindane hydrochloride. The synthesis method has the advantages of cheap and easily available initial raw materials and reaction reagents, low production cost, simple reaction operation, mild reaction conditions, high reaction safety, especially high reaction selectivity and resolution selectivity, two-step reaction yield of more than 70%, ee value of more than 98%, and suitableness for industrial mass production.

Description

Technical Field

[0001] The present invention belongs to the technical field of herbicide intermediate synthesis, and specifically relates to a method for synthesizing an indaziflam intermediate. Background Art

[0002] Indaziflam [also known as triazine indaziflam, CAS No. 950782-86-2, English name: Indaziflam] is a cellulose biosynthesis inhibiting (CBI) herbicide. By inhibiting cellulose biosynthesis, differentiated cells are used to construct their own key components without being affected by the inhibitor. Indaziflam has the advantages of diverse modes of action, broad herbicidal spectrum, long duration, low dosage, and low resistance.

[0003] The structural formula of indaziflam is as follows: .

[0004] (1R,2S)-2,6-Dimethyl-1-aminoindan [also known as (1R,2S)-2,6-dimethyl-2,3-dihydro-1H-indene-1-amine, CAS No. 752984-24-0] and its hydrochloride are key intermediates for synthesizing indaziflam. The structural formula of (1R,2S)-2,6-dimethyl-1-aminoindan hydrochloride is as follows: .

[0005] The existing methods for synthesizing (1R,2S)-2,6-dimethyl-1-aminoindan are as follows: (1) Using 2,6-dimethyl-1-indanone as the starting material, first performing asymmetric hydrogenation in the presence of a chiral catalyst to obtain (1S,2S)-2,6-dimethyl-1-hydroxyindan, then substituting the hydroxyl group with azide in the azide reagent DPPA (diphenylphosphoryl azide) to obtain an azide intermediate, and finally reducing it with LiAlH4 to obtain (1R,2S)-2,6-dimethyl-1-aminoindan [see the literature Tetrahedron 2007, 63(29), 6755-6763].

[0006] The synthesis route is as follows: .

[0007] The disadvantages of this method are that both the azide reagent and the azide intermediate have certain safety hazards and are not suitable for large-scale industrial production.

[0008] (2)Starting from 2,6-dimethyl-1-indanone, it first reacts with hydroxylamine hydrochloride to obtain an oxime intermediate, and then undergoes hydrogenation reduction to obtain 2,6-dimethyl-1-aminoindane. Subsequently, palladium-catalyzed hydrogenation and / or salt formation crystallization methods are first used to obtain trans-2,6-dimethyl-1-aminoindane, and finally, (1R,2S)-2,6-dimethyl-1-aminoindane is obtained by chiral resolution using R-mandelic acid [see Chinese Patent Document CN108794339A].

[0009] The synthetic route is as follows: 。

[0010] The disadvantages of this method are: the synthetic route is long, and two resolutions are required, with a low resolution yield, and it is also not suitable for large-scale industrial production.

[0011] (3)Starting from 2,6-dimethyl-1-indanone, it is first reduced with sodium borohydride to obtain 2,6-dimethyl-1-indanol, and then catalytic dehydration is carried out to obtain 2,5-dimethylindene. Subsequently, 2,5-dimethylindene and benzoxazole are subjected to reductive amination under copper catalysis to obtain an imine compound, and finally, the imine is hydrolyzed with hydroxylamine hydrochloride to obtain (1R,2S)-2,6-dimethyl-1-aminoindane [see International Patent Document WO2024201469A].

[0012] The synthetic route is as follows: 。

[0013] The disadvantages of this method are: the synthetic route is long, and the cost of catalytic amination is high, and it is also not suitable for large-scale industrial production.

[0014] (4)Starting from 2-[1-(2-bromo-5-methylphenyl)-2-methylpropyl]-1H-isoindole-1,3(2H)-dione, it first undergoes a cyclization reaction in the presence of Pd(PPh3)4 to obtain 2-[(1R,2S-2,6-dimethyl-2,3-dihydro-1H-inden-1-yl]-1H-isoindole-1,3(2H)-dione, and then the protecting group is removed with hydrazine hydrate to obtain (1R,2S)-2,6-dimethylindan-1-amine [see Example 12 of Chinese Patent Document CN106414420A].

[0015] The synthetic route is as follows: 。

[0016] The disadvantages of this method are: the starting material is expensive and difficult to obtain, and the yield of the cyclization reaction is low, only 55%. Summary of the Invention

[0017] The object of the present invention is to solve the above problems and provide a method for synthesizing an indazine fluazifop intermediate which has high reaction safety, low production cost, high reaction yield and is suitable for large-scale industrial production.

[0018] The technical solution for achieving the purpose of the present invention is: a method for synthesizing an indoxazine fluazifop intermediate, comprising the following steps: ① Using (1S,2S)-2,6-dimethyl-1-hydroxyindane and phthalimide as starting materials, a Mitsunobu reaction is first carried out in the presence of an azo reagent and a phosphine reagent to obtain the intermediate 2-[(1R,2S-2,6-dimethyl-2,3-dihydro-1H-inden-1-yl]-1H-isoindole-1,3(2H)-dione; ② The intermediate obtained in step ① is used to remove phthalimide with hydrazine hydrate to obtain (1R, 2S)-2,6-dimethyl-1-aminoindane, and finally salified to obtain the indoxazine fluazifop intermediate (1R, 2S)-2,6-dimethyl-1-aminoindane hydrochloride.

[0019] The synthetic route is as follows: .

[0020] In the above step ①, the molar ratio of the (1S, 2S)-2,6-dimethyl-1-hydroxyindane to the phthalimide is 1:1 to 1:2.

[0021] In the above step ①, the molar ratio of the (1S, 2S)-2,6-dimethyl-1-hydroxyindane to the azo reagent is 1:1 to 1:2; the azo reagent is diethyl azodicarboxylate or diisopropyl azodicarboxylate.

[0022] In the above step ①, the molar ratio of the (1S, 2S)-2,6-dimethyl-1-hydroxyindane to the phosphine reagent is 1:1 to 1:2; the phosphine reagent is triphenylphosphine or tri-tert-butylphosphine.

[0023] The reaction in step ① is carried out in the presence of an organic solvent; the organic solvent is tetrahydrofuran, toluene, dichloromethane or dichloroethane, preferably dichloromethane.

[0024] The molar ratio of (1S,2S)-2,6-dimethyl-1-hydroxyindane in the above step ① to the hydrazine hydrate in the above step ② is 1:2 to 1:5.

[0025] In the above step ②, the reaction of removing phthalimide by hydrazine hydrate is carried out in the presence of an organic solvent; the organic solvent is methanol and / or tetrahydrofuran.

[0026] In the above step ②, the reaction temperature for hydrazine hydrate to remove phthalimide is 10 - 70 °C.

[0027] The positive effects of the present invention are as follows: The starting materials and reaction reagents of the method of the present invention are cheap and easily available, the production cost is relatively low, the reaction operation is simple, the reaction conditions are mild, and the reaction safety is relatively high. In particular, both the reaction selectivity and the resolution selectivity are relatively high. The total reaction yield can reach more than 70%, and the ee value can reach more than 98%, which is suitable for large-scale industrial production. Specific Embodiments

[0028] (Example 1) The synthesis method of the indaziflam intermediate in this example is specifically as follows: ① Add 13.1 g of triphenylphosphine (0.05 mol) and 120 g of dichloromethane into a 500 mL four-necked flask, cool down to 0 °C, dropwise add 10.1 g of diisopropyl azodicarboxylate (0.05 mol), stir for 30 min after dropping, then add 7.4 g of phthalimide (0.05 mol), stir for 10 min, and then add 8.1 g of (1S,2S)-2,6-dimethyl-1-hydroxyindane (0.05 mol), stir at 20 °C for 16 h, and take a sample for in-process control until the reaction is complete.

[0029] ② After the reaction is completed, first evaporate the solvent, then add 7.8 g of 80 wt% hydrazine hydrate (0.125 mol) and 100 g of methanol, heat up to reflux for reaction for 3 h, take a sample for in-process control until the reaction is complete, cool down to 10 °C, stir for 30 min, filter, evaporate the filtrate to dryness, add 50 g of dichloromethane, then introduce hydrogen chloride gas, precipitate white solid, filter, and dry under vacuum to obtain 7.8 g of white solid, with a yield of 79.0%, an HPLC purity of 99.0%, and an ee value of 99.0%.

[0030] (Examples 2 - 3) The synthesis methods of the indaziflam intermediates in each example are basically the same as that in Example 1, except for the types of solvents. The specific details are shown in Table 1.

[0031] Table 1 Example 1 Example 2 Example 3 Organic solvent Dichloromethane Tetrahydrofuran Toluene Product weight 7.8g 7.6g 7.1g Reaction yield 79.0% 77.0% 71.9% HPLC purity 99.0% 98.0% 96.0% ee value 99.0% 98.5% 98.0%

[0032] (Examples 4 - 8) The synthesis methods of the indaziflam intermediates in each example are basically the same as that in Example 1, except for the types and dosages of the azo reagent and the phosphine reagent. The specific details are shown in Table 2.

[0033] Table 2 Example 1 Example 4 Example 5 Example 6 Example 7 Example 8 Azide reagent type Diisopropyl azodicarboxylate Diisopropyl azodicarboxylate Diisopropyl azodicarboxylate Diisopropyl azodicarboxylate Diethyl azodicarboxylate Diethyl azodicarboxylate Azide reagent dosage 0.05 mol 0.07 mol 0.10 mol 0.05 mol 0.05 mol 0.05 mol Phosphine reagent type Triphenylphosphine Triphenylphosphine Triphenylphosphine Tri-tert-butylphosphine Triphenylphosphine Tri-tert-butylphosphine Phosphine reagent dosage 0.05 mol 0.07 mol 0.10 mol 0.05 mol 0.05 mol 0.05 mol Product weight 7.8g 8.0g 7.6g 7.5g 7.5g 7.3g Reaction yield 79.0% 81.0% 77.0% 75.9% 75.9% 73.9% HPLC purity 99.0% 99.2% 98.7% 98.3% 98.5% 97.7% ee value 99.0% 98.8% 98.5% 98.6% 98.8% 98.3%

Claims

1. A method for synthesizing an indaziflam intermediate, characterized in that The following steps are involved: ① Using (1S,2S)-2,6-dimethyl-1-hydroxyindane and phthalimide as starting materials, a Mitsunobu reaction is first carried out in the presence of an azo reagent and a phosphine reagent to obtain the intermediate 2-[(1R,2S-2,6-dimethyl-2,3-dihydro-1H-inden-1-yl]-1H-isoindole-1,3(2H)-dione; ② The intermediate obtained in step ① is used to remove phthalimide with hydrazine hydrate to obtain (1R, 2S)-2,6-dimethyl-1-aminoindane, and finally salified to obtain the indoxazine fluazifop intermediate (1R, 2S)-2,6-dimethyl-1-aminoindane hydrochloride.

2. The synthetic method of the indaziflam intermediate according to claim 1, characterized in that: In the above step ①, the molar ratio of the (1S, 2S)-2,6-dimethyl-1-hydroxyindane to the phthalimide is 1:1 to 1:

2.

3. The synthesis method of the indaziflam intermediate according to claim 1, characterized in that: In the above step ①, the molar ratio of the (1S, 2S)-2,6-dimethyl-1-hydroxyindane to the azo reagent is 1:1 to 1:

2.

4. The synthetic method of the indaziflam intermediate according to claim 1 or 3, characterized in that: The azo reagent is diethyl azodicarboxylate or diisopropyl azodicarboxylate.

5. The synthetic method of the indaziflam intermediate according to claim 1, wherein: In the above step ①, the molar ratio of the (1S,2S)-2,6-dimethyl-1-hydroxyindane to the phosphine reagent is 1:1 to 1:

2.

6. The synthesis method of the indaziflam intermediate according to claim 1 or 5, characterized in that: The phosphine reagent is triphenylphosphine or tri-tert-butylphosphine.

7. The synthetic method of the indaziflam intermediate according to claim 1, wherein: The reaction in step ① is carried out in the presence of an organic solvent; the organic solvent is tetrahydrofuran, toluene, dichloromethane or dichloroethane.

8. The synthesis method of the indaziflam intermediate according to claim 1, characterized in that: The molar ratio of (1S,2S)-2,6-dimethyl-1-hydroxyindane in the above step ① to the hydrazine hydrate in the above step ② is 1:2 to 1:

5.

9. The synthesis method of the indaziflam intermediate according to claim 1, characterized in that: In the above step ②, the reaction of removing phthalimide by hydrazine hydrate is carried out in the presence of an organic solvent; the organic solvent is methanol and / or tetrahydrofuran.

10. The synthesis method of the indaziflam intermediate according to claim 1 or 9, characterized in that: In the above step ②, the reaction temperature for removing phthalimide by hydrazine hydrate is the reflux temperature.