A method for preparing indaziflam

Abstract

The application provides a preparation method of indaziflam, which uses indamine and dicyandiamide as reactants, and magnesium-aluminum hydrotalcite as a catalyst to react in an organic solvent to obtain a biguanide intermediate, wherein the magnesium-aluminum hydrotalcite has a molar ratio of Mg / Al of 3:1-4:1 and is activated by calcination at 400-500 DEG C; and the biguanide intermediate is reacted with R-2-fluoropropyl methyl ester to generate indaziflam. The application uses the activated magnesium-aluminum hydrotalcite as a catalyst to prepare indaziflam, which can avoid the generation of aluminum-containing wastewater, the biguanide intermediate generated in the reaction has relatively stable properties, and the prepared indaziflam has relatively high purity and yield.

Description

Technical Field

[0001] This application relates to the field of indazine-fluoxam preparation, and more particularly to a method for preparing indazine-fluoxam. Background Technology

[0002] Indaziflam is a triazine herbicide. Its chemical name is N-[(1R,2S)-2,3-dihydro-2,6-dimethyl-1H-indene-1-yl]-6-[(1RS)-1-fluoroethyl]-1,3,5-triazine-2,4-diamine. There are several production processes for indaziflam. One process uses diethyl methylmalonate as a starting material, first synthesizing indene ketone, then indeneamine. Subsequently, in the presence of aluminum isopropoxide, it is converted by dicyandiamide to the corresponding biguanide and stabilized by an aluminum chelate. Finally, the cyclization with methyl R-2-fluoropropionate synthesizes indaziflam.

[0003] Currently, the problems with this process are: aluminum isopropoxide is a Lewis acid, and the aluminum salt formed after the reaction needs to be quenched with acid, which generates a large amount of aluminum-containing wastewater; moreover, isopropanol in the system is miscible with water, resulting in high energy consumption for recovery. The stability of the generated biguanide aluminum chelate is greatly affected by temperature; it is prone to decomposition at temperatures above 80℃, leading to an increase in byproducts. Summary of the Invention

[0004] In view of the problems with the use of aluminum isopropoxide in the above-mentioned indazin-flutamide production process, this application proposes a method for preparing indazin-flutamide that does not use aluminum isopropoxide, but instead uses magnesium aluminum hydrotalcite as a catalyst. The specific scheme is as follows.

[0005] A method for preparing indazine-flufenoxam involves reacting indazine and dicyandiamide as reactants and magnesium aluminum hydrotalcite as a catalyst in an organic solvent to obtain a biguanide intermediate. The magnesium aluminum hydrotalcite has a Mg / Al molar ratio of 3:1 to 4:1 and is activated by calcination at 400 to 500 °C.

[0006] The biguanide intermediate then reacts with methyl R-2-fluoropropionate to generate indazine-fluoxane.

[0007] The technical advantages of this application are as follows: using activated magnesium aluminum hydrotalcite as a catalyst to prepare indazine fluroxypyr can avoid the generation of aluminum-containing wastewater, the biguanide intermediate generated in the reaction is relatively stable, and the prepared indazine fluroxypyr has high purity and yield. Detailed Implementation

[0008] The embodiments of the technical solution of this application will be described in detail below. The following embodiments are only used to illustrate the technical solution of this application more clearly, and are therefore only examples, and should not be used to limit the scope of protection of this application.

[0009] A method for preparing indazine-flufenoxam involves reacting indazine and dicyandiamide as reactants and magnesium aluminum hydrotalcite as a catalyst in an organic solvent to obtain a biguanide intermediate. The magnesium aluminum hydrotalcite has a Mg / Al molar ratio of 3:1 to 4:1 and is activated by calcination at 400 to 500 °C.

[0010] The biguanide intermediate then reacts with methyl R-2-fluoropropionate to generate indazine-fluoxane.

[0011] The structural formula of indanamine described in this application is:

[0012] When the Mg / Al molar ratio is <3:1, the aluminum content is too high, the density of surface alkaline sites is low, dicyandiamide activation is insufficient, and the biguanide synthesis yield is <70%.

[0013] When the Mg / Al molar ratio is >4:1, the magnesium content is too high, the layered structure of hydrotalcite is unstable, and structural collapse is likely to occur during high-temperature reactions, resulting in a rapid decrease in catalytic activity and a limited number of applications (<5 times).

[0014] When the Mg / Al molar ratio is in the range of 3:1 to 4:1, the layered structure of hydrotalcite is relatively stable, the biguanide synthesis selectivity is ≥97%, and the catalyst can be stably reused more than 20 times.

[0015] Testing and experiments revealed that uncalcined raw hydrotalcite contained a large amount of water of crystallization and carbonate ions in the interlayer, resulting in low catalytic activity. At calcination temperatures below 400℃, interlayer impurities were not completely removed, leading to insufficient activity; at temperatures above 500℃, the hydrotalcite underwent sintering, resulting in a smaller specific surface area and lower activity. After calcination at 400-500℃, magnesium aluminum hydrotalcite exhibited a more significant catalytic effect.

[0016] In a preferred embodiment, the calcination and activation process of the magnesium-aluminum hydrotalcite is as follows:

[0017] Magnesium aluminum hydrotalcite powder was placed in a muffle furnace and heated to 400–500°C at a rate of 4–7°C / min. It was then calcined at a constant temperature for 3.5–4.5 hours to remove interlayer water of crystallization and some carbonate ions, forming a magnesium aluminum composite oxide with a mesoporous structure. The powder was then cooled to room temperature.

[0018] In a preferred embodiment, the magnesium-aluminum hydrotalcite has a specific surface area greater than 15 m². 2 / g. The specific surface area of ​​magnesium aluminum layered double hydroxide (MLD) has a significant impact on its catalytic effect. If the specific surface area is too small, the internal active potential is less exposed and unevenly distributed, resulting in a slower reaction rate and more side reactions, leading to a decrease in the yield of the final product. Experiments have shown that when the specific surface area of ​​magnesium aluminum layered double hydroxide is greater than 15 m², the catalytic effect is significantly improved. 2 / g is more in line with the requirements of this application.

[0019] The specific surface area of ​​the magnesium aluminum hydrotalcite described in this application was determined in accordance with the standard GB / T 19587-2017, "Determination of Specific Surface Area of ​​Solid Substances by Gas Adsorption BET Method".

[0020] In a preferred embodiment, the average particle size of the magnesium aluminum hydrotalcite is 200–300 nm.

[0021] In a preferred embodiment, the amount of magnesium aluminum hydrotalcite used is 30-35% of the mass of indaneamine.

[0022] The organic solvent described in this application can be a conventional solvent in the art, such as isopropanol. In a preferred embodiment, the organic solvent is toluene and isopropanol, and the volume ratio of toluene to isopropanol is 4:1 to 3.5:1.

[0023] In a preferred embodiment, the preparation process of indazine-fluoxadecan is as follows:

[0024] The toluene / isopropanol mixed solvent, magnesium aluminum hydrotalcite, and dicyandiamide were premixed to ensure uniform dispersion of the magnesium aluminum hydrotalcite.

[0025] Add indaneamine dropwise, and after the addition is complete, raise the temperature to 110-120°C and react for 4-4.5 hours. Terminate the reaction when the residual amount of indaneamine is <0.5%, and filter to obtain the biguanide reaction solution.

[0026] Add methyl R-2-fluoropropionate dropwise to the biguanide reaction solution, react at a temperature of 70-80℃ for a time of less than 1 hour, and maintain a volume ratio of biguanide reaction solution to methyl R-2-fluoropropionate of 1:1.15-1:1.25.

[0027] After the addition is complete, the temperature is raised to 130-135℃ and kept at this temperature for 4.5-5 hours. The reaction is terminated when the residual amount of biguanide intermediate is <1%.

[0028] Distillation separates the toluene / isopropanol mixed solvent and the reaction solution.

[0029] Add dilute hydrochloric acid to the reaction solution, stir to neutralize the residual alkaline impurities, let stand to separate the layers, and separate the aqueous phase.

[0030] The organic phase was washed with a saturated sodium chloride aqueous solution until neutral, dried with anhydrous sodium sulfate, and then toluene was recovered by vacuum distillation to obtain indazine-flufenoxam.

[0031] In a preferred embodiment, when the biguanide intermediate reacts with methyl R-2-fluoropropionate, 0.5% to 0.6% molar ratio of tetrabutylammonium bromide is added to the solvent to shorten the reaction time. It should be understood that the amount of tetrabutylammonium bromide used as a phase transfer catalyst is relative to the biguanide intermediate; the 0.5% to 0.6% molar ratio indicates that the molar amount of tetrabutylammonium bromide is 0.5% to 0.6% of the molar amount of the biguanide intermediate.

[0032] The effects of this application will be illustrated below through examples and comparative examples.

[0033] Example 1: Magnesium-aluminum based hydrotalcite process

[0034] Magnesium aluminum hydrotalcite pretreatment: Hydrotalcite powder with a Mg / Al molar ratio of 3.5:1 was placed in a muffle furnace and heated to 450℃ at a rate of 5℃ / min. It was then calcined at a constant temperature for 4 hours and allowed to cool naturally to room temperature for later use. The specific surface area was 16.2 m² / g and the average particle size was 241nm.

[0035] Biguanide synthesis: 1200 L of toluene / isopropanol mixed solvent (volume ratio 4:1), 48 kg of the above activated hydrotalcite (30% of the mass of indaneamine), and 109 kg of dicyandiamide were added to the reactor. After nitrogen purging, the temperature was raised to 80 °C and stirred for 30 minutes. 161 kg of indaneamine was added dropwise over 1 hour. After the addition was completed, the temperature was raised to 115 °C and the reaction was maintained for 4 hours. The residual amount of indaneamine was measured to be 0.42%. The catalyst was recovered by hot pressure filtration.

[0036] Ring-closing reaction: 123 kg of methyl R-2-fluoropropionate (1.15 equivalents) was added dropwise to the filtered biguanide reaction solution at a temperature controlled at 75°C over 1 hour; the temperature was then raised to 130°C and the reaction was maintained for 5 hours. The residual amount of biguanide was found to be 0.78%.

[0037] Post-processing: 80% of the mixed solvent was recovered by atmospheric distillation, cooled to 30°C, and neutralized by adding an equal volume of 1% dilute hydrochloric acid. The mixture was allowed to stand and separate into layers. The organic phase was washed with saturated brine until neutral, dried with anhydrous sodium sulfate, and then distilled under reduced pressure to recover toluene. The crude product was recrystallized once with ethanol / water (volume ratio 3:1) and dried under vacuum at 80°C to obtain indazine-flufenoxam.

[0038] Example 2

[0039] The Mg / Al molar ratio of the magnesium aluminum hydrotalcite was 3:1, and the other pretreatment and reaction conditions were the same as in Example 1.

[0040] Example 3

[0041] The Mg / Al molar ratio of the magnesium aluminum hydrotalcite was 4:1, and the other pretreatment and reaction conditions were the same as in Example 1.

[0042] Example 4

[0043] The magnesium-aluminum hydrotalcite was calcined at 400°C, and the other conditions were the same as in Example 1.

[0044] Example 5

[0045] The magnesium-aluminum hydrotalcite was calcined at 500°C, and the other conditions were the same as in Example 1.

[0046] Example 6

[0047] During the ring-closing reaction stage, 0.5% tetrabutylammonium bromide was added, and the remaining conditions were the same as in Example 1.

[0048] Example 7

[0049] The volume ratio of toluene to isopropanol in the mixed solvent was 3.5:1, and the other conditions were the same as in Example 1.

[0050] Example 8

[0051] The ring-closing reaction temperature was 135°C, the holding time was 4.5 hours, and the other conditions were the same as in Example 1.

[0052] Comparative Example 1

[0053] The Mg / Al molar ratio of the magnesium aluminum hydrotalcite was 2:1, and the other pretreatment and reaction conditions were the same as in Example 1.

[0054] Comparative Example 2

[0055] The Mg / Al molar ratio of the magnesium aluminum hydrotalcite was 5:1, and the other pretreatment and reaction conditions were the same as in Example 1.

[0056] Comparative Example 3

[0057] Uncalcined raw magnesium aluminum hydrotalcite was used directly, and the remaining reaction conditions were the same as in Example 1.

[0058] Comparative Example 4

[0059] The magnesium-aluminum hydrotalcite was calcined at 300°C, and the other conditions were the same as in Example 1.

[0060] Comparative Example 5

[0061] The magnesium-aluminum hydrotalcite was calcined at 600°C, and the other conditions were the same as in Example 1.

[0062] Comparative Example 6: Traditional Aluminum Isopropoxide Process

[0063] Add 1200L of toluene, 161kg of indeneamine, and 101kg of dicyandiamide to the drying reactor, purge with nitrogen three times, and raise the temperature to 60℃;

[0064] 245 kg of aluminum isopropoxide (1.2 equivalents) was added dropwise. After the addition was complete, the temperature was raised to 80°C and the reaction was carried out for 6 hours. The residual amount of indeneamine was 0.4%.

[0065] 139 kg of methyl R-2-fluoropropionate (1.3 equivalents) was added dropwise, and the mixture was heated to 100°C and reacted for 8 hours. The residual amount of biguanide was 0.8%.

[0066] After the reaction solution was cooled, 10% dilute hydrochloric acid was added to quench it. After standing and separating the layers, the organic phase was washed with water three times to remove aluminum salts, and toluene was recovered by vacuum distillation.

[0067] The crude product was recrystallized three times with ethanol and dried under vacuum at 80°C to obtain indazine-flufenoxam.

[0068] The total yield, purity of technical grade of indazine-flufenazate, total reaction time, and number of times magnesium aluminum hydrotalcite were statistically analyzed for the above examples and comparative examples.

[0069] in,

[0070] The overall yield is calculated based on the initial amount of chiral indeneamine, using the molar yield from the mass of qualified technical material obtained after recrystallization. The formula is as follows:

[0071]

[0072] When calculating, only the quality of qualified raw materials with a purity of ≥98% is counted; qualified products after recrystallization of unqualified crude products can be included.

[0073] The product recovered from recrystallization mother liquor should also be included in the total yield (the data in the example already includes the average yield of 3 mother liquor reuses).

[0074] The experiment should be conducted in three parallel trials, and the average value should be taken as the final yield data. The relative deviation should be ≤1%.

[0075] The purity of the active ingredient, i.e., the purity of indazine-fluoxam, was determined by high performance liquid chromatography area normalization method.

[0076] The reaction time begins from the completion of substrate feeding and ends when the reaction endpoint is determined, and the entire process is automatically recorded by an online monitoring system.

[0077] Biguanide synthesis reaction time: from the start of heating to the reaction temperature after the addition of indane to the end of HPLC detection of indane residual amount <0.5%;

[0078] The ring-closing reaction time is from the start of heating to the reaction temperature after the addition of methyl R-2-fluoropropionate until the residual amount of biguanide intermediate is <1% as detected by HPLC.

[0079] Total reaction time = Biguanide reaction time + Ring-closing reaction time (Pretreatment and post-treatment times are not included in the reaction time statistics)

[0080] The hydrotalcite is used in a batch reactor, and the process is exactly the same each time it is used:

[0081] Hydrotalcite recovery: After the biguanide synthesis reaction reaches its endpoint, the reaction solution is filtered while hot at 110°C to recover the filter cake (i.e., hydrotalcite). The filter cake is washed twice with toluene at 100°C to remove adsorbed organic impurities.

[0082] Activity correction: After each recovery, weigh the hydrotalcite mass and replenish it with 10% of the lost amount of fresh activated hydrotalcite (there will be a small amount of loss during filtration in the production process; after correction, ensure that the amount of hydrotalcite used in each reaction is consistent with the first time).

[0083] Repeated reaction: The recovered hydrotalcite is fed into the next batch of reaction, and all reaction parameters (feed ratio, temperature, time) are exactly the same as the first reaction;

[0084] Data recording: After each batch of reaction was completed, three core indicators were tested: biguanide synthesis selectivity, total yield of indazine-flufenoxam, and purity of technical grade drug.

[0085] When any of the indicators in Table 1 fails to meet the standard, the catalyst is deemed to have reached its service life, and the application experiment is terminated. The previous consecutive application batches are considered the number of stable application cycles for the catalyst.

[0086] Table 1:

[0087]

[0088] If two consecutive batches fail to meet the required standards, the catalyst is deemed to be completely deactivated to avoid the impact of occasional errors on the results.

[0089] The statistical results are shown in Table 2.

[0090] Table 2:

[0091]

[0092] As can be seen from Table 2, Example 6 with added tetrabutylammonium bromide exhibited the best performance, with a total yield of 85.1% and a total reaction time of only 7.5 hours, representing a 113% improvement in efficiency compared to the traditional process.

[0093] The Mg / Al molar ratio of 3:1 to 4:1 and the calcination temperature range of 400 to 500°C specified in this application are necessary conditions for achieving high performance. Performance deteriorates significantly when the range is exceeded.

[0094] The effect of deviation from the Mg / Al ratio range (Comparative Examples 1 and 2)

[0095] When the Mg / Al ratio is 2:1, the overall yield drops to 68.7%, which is 14.5 percentage points lower than the average level of the optimal range. The purity of the original drug is only 95.2%, requiring two additional recrystallization steps.

[0096] When the Mg / Al ratio is 5:1, the number of times the hydrotalcite is applied decreases to 14 times, which is 30% lower than the optimal range, and the structural stability is significantly reduced.

[0097] The effect of calcination temperature deviation from the range (Comparative Examples 3, 4, and 5)

[0098] The overall yield of uncalcined hydrotalcite catalysis was only 56.2%, and the total reaction time was as long as 24 hours, with the most significant performance degradation.

[0099] The total yields of calcination at 300℃ and calcination at 600℃ decreased to 70.1% and 73.5% respectively, which is 10 to 13 percentage points lower than the optimal range, and the reaction time is extended by more than 50%.

[0100] The above experimental results demonstrate that the preparation method of indazine-flutamide in this application, by adding magnesium aluminum hydrotalcite as a catalyst to replace aluminum isopropoxide, and by calcining the magnesium aluminum hydrotalcite at a set temperature according to the set magnesium-aluminum ratio, can significantly improve the yield and purity of indazine-flutamide, reduce the reaction time, and increase the service life of magnesium aluminum hydrotalcite.

[0101] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of this application, and are not intended to limit them. Although this application has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some or all of the technical features therein. Such modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of this application.

Claims

1. A method for preparing indazine-flufenoxam, characterized in that: Using indaneamine and dicyandiamide as reactants and magnesium aluminum hydrotalcite as catalyst, a biguanide intermediate was obtained by reaction in an organic solvent. The Mg / Al molar ratio of the magnesium aluminum hydrotalcite was 3:1 to 4:1, and the magnesium aluminum hydrotalcite was activated by calcination at 400 to 500 °C. The structural formula of the indanamine is: The biguanide intermediate then reacts with methyl R-2-fluoropropionate to generate indazine-fluoxane.

2. The method for preparing indazine-flufenoxam according to claim 1, characterized in that: The specific calcination and activation process of the magnesium-aluminum hydrotalcite is as follows: Magnesium aluminum hydrotalcite powder was placed in a muffle furnace and heated to 400–500°C at a rate of 4–7°C / min. It was then calcined at a constant temperature for 3.5–4.5 hours to remove interlayer water of crystallization and some carbonate ions, forming a magnesium aluminum composite oxide with a mesoporous structure. The powder was then cooled to room temperature.

3. The method for preparing indazine-fluoxadecan as described in claim 1, characterized in that: The specific surface area of ​​the magnesium-aluminum hydrotalcite is greater than 15 m². 2 / g.

4. The method for preparing indazine-flufenoxam according to claim 1, characterized in that: The average particle size of the magnesium-aluminum hydrotalcite is 200–300 nm.

5. The method for preparing indazine-flufenoxam according to claim 1, characterized in that: The amount of magnesium aluminum hydrotalcite used is 30% to 35% of the mass of indaneamine.

6. The method for preparing indazine-flufenoxam according to claim 1, characterized in that: The organic solvent is toluene and isopropanol, and the volume ratio of toluene to isopropanol is 4:1 to 3.5:

1.

7. The method for preparing indazine-flufenoxam according to claim 1, characterized in that: The preparation process of indazine-flufenoxam is as follows: The toluene / isopropanol mixed solvent, magnesium aluminum hydrotalcite, and dicyandiamide were premixed to ensure uniform dispersion of the magnesium aluminum hydrotalcite. Add indeneamine dropwise, and after the addition is complete, raise the temperature to 110-120°C and react for 4-4.5 hours. Terminate the reaction when the residual amount of indeneamine is <0.5%, and filter to obtain the biguanide reaction solution. Add methyl R-2-fluoropropionate dropwise to the biguanide reaction solution, react at a temperature of 70-80℃ for a time of less than 1 hour, and maintain a volume ratio of biguanide reaction solution to methyl R-2-fluoropropionate of 1:1.15-1:1.

25. After the addition is complete, the temperature is raised to 130-135℃ and kept at this temperature for 4.5-5 hours. The reaction is terminated when the residual amount of biguanide intermediate is <1%. Distillation separates the toluene / isopropanol mixed solvent and the reaction solution. Add dilute hydrochloric acid to the reaction solution, stir to neutralize the residual alkaline impurities, let stand to separate the layers, and separate the aqueous phase. The organic phase was washed with a saturated sodium chloride aqueous solution until neutral, dried with anhydrous sodium sulfate, and then toluene was recovered by vacuum distillation to obtain indazine-flufenoxam.

8. The method for preparing indazine-fluoxadecan as described in claim 1, characterized in that: When the biguanide intermediate reacts with methyl R-2-fluoropropionate, 0.5% to 0.6% of tetrabutylammonium bromide is added to the solvent to shorten the reaction time.

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