Improved synthesis method of indaziflam intermediate
By improving the synthesis process of the indazine fluazifop intermediate, adopting addition, enamination, catalytic hydrogenation and hydrolysis reactions, and using AgSbF6, [RhCl(nbd)]2 and phosphine ligand L catalyst, the problems of lengthy routes and low yields in the existing technology are solved, and efficient industrial production is achieved.
Patent Information
- Application Number
- CN202510859282.9
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-06-25
- Publication Date
- 2025-09-19
AI Technical Summary
The existing synthetic route for the indazine fluazifop intermediate is lengthy, has a low yield, and wastes a large amount of non-target chiral indamine after splitting, making it unsuitable for industrial production.
A new synthetic process route is adopted, including four steps of addition, enamination, catalytic hydrogenation and hydrolysis. A composite catalyst of AgSbF6, [RhCl(nbd)]2 and phosphine ligand L is used to avoid sodium borohydride and DPPA, and the configuration transformation is controlled by a large sterically hindered ligand.
The synthesis route is shortened, the reaction yield is improved, and the complex isomer separation is avoided, making it suitable for industrial production.
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Figure CN120664973A_ABST
Abstract
Description
Technical Field
[0001] The invention belongs to the field of organic synthesis, and particularly relates to an improved synthesis method of an indazine fluazifop intermediate. Background Art
[0002] Indaziflam is a triazine herbicide developed by Bayer AG in Germany. As a cellulose biosynthesis inhibitor, indaziflam effectively inhibits plant cell membrane biosynthesis, thereby affecting the normal growth of plant meristems, thereby achieving weed control. Its unique cellulose biosynthesis inhibition mechanism, broad spectrum of weed control, long-lasting weed control, and low dosage make indaziflam a promising herbicide for broad application in agriculture.
[0003] 2,6-Dimethyl-2,3-dihydro-1H-inden-1-amine is a key intermediate in the synthesis of indazine fluazifop. The general synthesis method uses the compound 2,6-dimethyl-1-indanone as the starting material, which is reduced to 2,6-dimethyl-1-indanol via sodium borohydride. The indanol is then reacted with dppa and DBU Mitsunobu to generate 2,6-dimethyl-1-inden azide. The inden azide is reduced with stannous chloride to finally generate 2,6-dimethyl-2,3-dihydro-1H-inden-1-amine. The racemic indenamine is then resolved, usually using NoVozym435 enzyme to obtain (1R, 2S)-2,3-dihydro-2,6-dimethylindenamine. This method has a lengthy route, and only a small portion of the chiral indeneamine with the desired configuration is obtained after splitting, while most of the chiral indeneamine with the remaining configuration is wasted, resulting in a low yield, and is not suitable for industrial production.
[0004] Summary of the Invention
[0005] The present invention addresses the shortcomings of the prior art and provides an improved synthesis method for an indazine fluazifop intermediate. By modifying the synthetic process, the present invention shortens the experimental route and avoids the use of hazardous reagents such as sodium borohydride and DPPA. Furthermore, a novel catalyst system is designed, significantly improving the reaction yield and making it more suitable for industrial production.
[0006] The improved synthesis method of the indazine fluazifop intermediate of the present invention comprises the following steps:
[0007] Step 1: Addition reaction
[0008] The starting material 2,6-dimethyl-2,3-dihydro-indanone reacts with hydroxylamine hydrochloride to generate 2,3-dihydro-2,6-dimethyl-1H-indan-1-one oxime.
[0009] In step 1, the feed equivalent ratio of 2,6-dimethyl-2,3-dihydro-indanone to hydroxylamine hydrochloride is 1:1.05-1:1.2; the reaction solvent can be selected from methanol, ethanol, isopropanol, etc.; and the reaction temperature is 50-70°C.
[0010] Step 2: Enamination
[0011] 2,3-Dihydro-2,6-dimethyl-1H-inden-1-one oxime is reduced with iron powder in the presence of acetic anhydride and acetic acid to give N-(2,6-dimethyl-1H-inden-3-yl)acetamide.
[0012] In step 2, the molar ratio of 2,3-dihydro-2,6-dimethyl-1H-inden-1-one oxime to acetic anhydride and acetic acid is 1:1.2:1.2~1:3:3; the reducing agent includes iron powder, sodium bisulfite, sodium sulfite, etc.; the reaction temperature is 110-130 o C, the reaction time is 8-12 hours.
[0013] Step 3: Catalytic hydrogenation
[0014] N-[(1R,2S)-2,3-dihydro-2,6-dimethyl-1H-inden-3-yl]-2-methoxyacetamide was obtained by asymmetric hydrogenation reduction using N-(2,6-dimethyl-1H-inden-3-yl)acetamide as the starting material and a complex reaction product of AgSbF6 (silver hexafluoroantimonate), [RhCl(nbd)]2 (chloronorbornadiene rhodium(I) dimer) and phosphine ligand L as the catalyst.
[0015] In step 3, the molar ratio of AgSbF6 (silver hexafluoroantimonate), [RhCl(nbd)]2 (chloronorbornadiene rhodium (I) dimer) and phosphine ligand L is 1.5:0.5:1.
[0016] In step 3, the molar ratio of the phosphine ligand L to N-(2,6-dimethyl-1H-inden-3-yl)acetamide is 1:100 to 10:100; the reaction solvent is ethyl acetate, ethanol, methanol, etc., and the reaction time is 8-12 hours.
[0017] Step 4: Hydrolysis reaction
[0018] Chiral N-[(1R,2S)-2,3-dihydro-2,6-dimethyl-1H-inden-1-yl]-2-methoxyacetamide is hydrolyzed under acidic conditions to generate (1R,2S)-2,3-dihydro-2,6-dimethylindenamine.
[0019] In step 4, the acid added to the reaction system is hydrochloric acid, sulfuric acid, hydrobromic acid, etc.; the reaction solvent is isopropanol, isopropanol water, ethanol water, methanol water, etc., and the reaction temperature is 90-110°C.
[0020] The synthetic route is as follows:
[0021]
[0022] The general structural formula of the ligand L is:
[0023] .
[0024] Wherein the R substituent of the phosphine ligand L = -C6H5, -C6H4OMe or -C6H4OCF3, preferably R = -C6H5.
[0025]
[0026] The synthesis route of the phosphine ligand L is as follows:
[0027] .
[0028] The method of the present invention uses 2,6-dimethyl-2,3-dihydro-indanone as the starting material, and sequentially carries out four-step reactions of addition, enamination, catalytic hydrogenation, and hydrolysis to prepare the target product. Compared with the existing process, the method avoids the complicated isomer separation. By using a designed large sterically hindered ligand, the enamination intermediate is catalytically hydrogenated after being compounded with metal rhodium, and the configuration transformation can be efficiently and accurately controlled to obtain (1R, 2S)-2,3-dihydro-2,6-dimethyl-1H-indene-1-amine with a high ee value, thereby greatly improving the yield. In addition, the raw materials in this process route are easily available and the reaction conditions are mild, which is more suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS
[0029] Figure 1 is the NMR spectrum of phosphine ligand L.
[0030] Figure 2 This is the nuclear magnetic spectrum of (1R,2S)-2,3-dihydro-2,6-dimethyl-1H-inden-1-amine. DETAILED DESCRIPTION
[0031] The technical solution of the present invention is further analyzed and explained below through specific embodiments.
[0032] Example 1:
[0033] In a 100 ml three-necked flask, 2,6-dimethyl-2,3-dihydro-indanone (100 mmol), sodium acetate (120 mmol), hydroxylamine hydrochloride (120 mmol), and 50 ml of methanol were added. The temperature was raised to 60°C and the reaction was carried out for 2 hours. After the reaction, the temperature was lowered to room temperature, 100 ml of water was added, and the mixture was extracted twice with 50 ml of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated to obtain the dry product 2,3-dihydro-2,6-dimethyl-1H-indan-1-one oxime with a yield of 90%.
[0034] Example 2:
[0035] To a 500 ml three-necked flask, add 2,3-dihydro-2,6-dimethyl-1H-inden-1-one oxime (90 mmol) and 180 ml of toluene. The atmosphere was replaced with nitrogen three times, and acetic anhydride (270 mmol), acetic acid (270 mmol), and iron powder (200 mmol) were added. After addition, the reaction solution was heated to reflux for 10 hours. After the reaction was completed, the solution was cooled to room temperature, 100 ml of ethyl acetate was added, filtered, and washed twice with 100 ml of water. Then, 1 mmol / ml sodium hydroxide solution was added until alkaline. The organic phase was dried over anhydrous sodium sulfate. Filtered and concentrated to yield N-(2,6-dimethyl-1H-inden-3-yl)acetamide in a yield of 78%.
[0036] Example 3: Synthesis of Phosphine Ligand L
[0037] Triethylamine (1 mmol, 0.5 mL) and phosphorus trichloride (1 mmol, 100 μL) were mixed in THF (1 mL) and stirred at room temperature under a nitrogen atmosphere. A solution of (R)-bis((R)-1-phenylethyl)amine in THF (1 mmol) was slowly added, and the reaction mixture was stirred at 70°C for 3-5 hours. R-3,3'-diphenylbinaphthol (1 mmol) was then added to the reaction mixture at -78°C, and the suspension was stirred at room temperature overnight. The reaction was monitored for completion by TLC. The reaction was quenched with water and extracted with DCM (10 mL x 3). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by flash silica gel column chromatography (petroleum ether / ethyl acetate = 10:1) to obtain a white solid in a 71.8% yield, namely, phosphine ligand L.
[0038] Example 4: Catalytic hydrogenation
[0039] To a 100 ml three-necked flask, add AgSbF6 (silver hexafluoroantimonate) (0.015 mmol) and [RhCl(nbd)]2 (chlorobornadiene rhodium (I) dimer) (0.005 mmol). The atmosphere was replaced with nitrogen three times. Acetone (5 V) was added. After the addition was complete, the mixture was stirred for 30 min. The phosphine ligand L (0.01 mmol) was added and stirred at 20-25°C for 0.5 h. The reaction solution was transferred to a hydrogenation reactor, evacuated, and replaced with nitrogen three times. N-(2,6-dimethyl-1H-inden-3-yl)acetamide (1 mmol) was added. The mixture was evacuated, and replaced with hydrogen three times. The hydrogen pressure was adjusted to 20 atm. The reaction was carried out under the same conditions for 10 h. After the reaction was completed, the reaction solution was concentrated to dryness and purified by silica gel column to obtain N-[(1R,2S)-2,3-dihydro-2,6-dimethyl-1H-inden-1-yl]-2-methoxyacetamide with a yield of 81.3% and dr=95:1.
[0040] Example 5:
[0041] N-[(1R,2S)-2,3-dihydro-2,6-dimethyl-1H-inden-1-yl]-2-methoxyacetamide (10 mmol), 25 ml of concentrated hydrochloric acid, and 90 ml of isopropanol were added, and the temperature was raised to 100°C for 16 hours. The reaction was then cooled to room temperature and concentrated under reduced pressure to remove isopropanol. 50 ml of a 1N aqueous sodium hydroxide solution was added, and the mixture was extracted twice with 100 ml of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered to obtain (1R,2S)-2,3-dihydro-2,6-dimethyl-1H-inden-1-amine with a dr ratio of 95:1 and a yield of 92.3%.
Claims
1. An improved synthesis method of an indazine fluazifop intermediate, characterized in that The steps include: Step 1: Addition reaction The starting material 2,6-dimethyl-2,3-dihydro-indanone reacts with hydroxylamine hydrochloride to generate 2,3-dihydro-2,6-dimethyl-1H-indan-1-one oxime; Step 2: Enamination 2,3-Dihydro-2,6-dimethyl-1H-inden-1-one oxime is reduced with a reducing agent in the presence of acetic anhydride and acetic acid to obtain N-(2,6-dimethyl-1H-inden-3-yl)acetamide; Step 3: Catalytic hydrogenation N-(2,6-dimethyl-1H-inden-3-yl)acetamide is used as a raw material, and a complex reaction product of silver hexafluoroantimonate, chloronorbornadiene rhodium (I) dimer and phosphine ligand L is used as a catalyst to obtain N-[(1R,2S)-2,3-dihydro-2,6-dimethyl-1H-inden-1-yl]-2-methoxyacetamide through asymmetric hydrogenation reduction; Step 4: Hydrolysis reaction Chiral N-[(1R,2S)-2,3-dihydro-2,6-dimethyl-1H-inden-1-yl]-2-methoxyacetamide is hydrolyzed under acidic conditions to generate (1R,2S)-2,3-dihydro-2,6-dimethylindenamine; The synthetic route is as follows: 。 2. The synthesis method according to claim 1, wherein: In step 1, the feed equivalent ratio of 2,6-dimethyl-2,3-dihydro-indanone to hydroxylamine hydrochloride is 1:1.05 to 1:1.2; and the reaction temperature is 50-70°C.
3. The synthesis method according to claim 1, wherein: In step 2, the reducing agent includes iron powder, sodium bisulfite or sodium sulfite.
4. The synthesis method according to claim 1, wherein: In step 2, the molar ratio of 2,3-dihydro-2,6-dimethyl-1H-inden-1-one oxime to acetic anhydride and acetic acid is 1:1.2:1.2 to 1:3:
3.
5. The synthesis method according to claim 1, wherein: The general structural formula of the phosphine ligand L is: ； wherein R is selected from -C6H5, -C6H4OMe or -C6H4OCF3.
6. The synthesis method according to claim 1 or 5, characterized in that: In step 3, the molar ratio of silver hexafluoroantimonate, chlorobornadiene rhodium (I) dimer and phosphine ligand L is 1.5:0.5:
1.
7. The synthesis method according to claim 6, characterized in that: In step 3, the molar ratio of the phosphine ligand L to N-(2,6-dimethyl-1H-inden-3-yl)acetamide is 1:100 to 10:
100.
8. The synthesis method according to claim 1, wherein: In step 4, the acidic condition is achieved by adding hydrochloric acid, sulfuric acid or hydrobromic acid.