CN116693549A

CN116693549A - Improved process for preparing pinoxaden

Info

Publication number: CN116693549A
Application number: CN202210179138.7A
Authority: CN
Inventors: 王欣; 韩明轩; 程柯; 左翔
Original assignee: Lier Chemical Co Ltd
Current assignee: Lier Chemical Co Ltd
Priority date: 2022-02-25
Filing date: 2022-02-25
Publication date: 2023-09-05

Abstract

The invention relates to the field of chemical synthesis, in particular to an improved process for preparing pinoxaden. The method comprises two steps of deamination and acylation, and an intermediate treatment step. In the process method, inorganic alkali is used as an acid binding agent, so that the use of triethylamine is avoided, the recovery procedure is reduced, continuous production is facilitated, the color state of the product is met, and a decoloring process is avoided. Meanwhile, the process method greatly improves the reaction yield and the product purity, the total reaction yield can reach 95%, the product purity can reach 99%, the operation is simple, no special reagent is used, the cost is low, and the process method is green and environment-friendly and is suitable for industrial scale-up production.

Description

Improved process for preparing pinoxaden

Technical Field

The invention relates to the field of chemical synthesis, in particular to an improved process for preparing pinoxaden.

Background

Pinoxaden (Pinoxaden) was developed by the company n-da, marketed in 2006, and belongs to a new class of phenylpyrazoline herbicides, as well as to acetyl-coa carboxylase inhibitor herbicides. The pinoxaden is a selective and systemic conductive post-emergent gramineous weed herbicide, can effectively prevent and remove annual gramineous weeds in wheat and barley fields, and is very suitable for spring grains. The herbicide has good control effect on grassy weeds such as wild oat, ryegrass, green bristlegrass, hard grass, crowndaisy chrysanthemum, japanese wheat grass, club head grass and the like, and particularly has control effect close to 100% on malignant grassy weeds such as wild oat, ryegrass, hard grass and crowndaisy chrysanthemum. It has the characteristics of high efficiency, broad spectrum, high safety, wide application period, rain wash resistance and the like, and the plant-type water-soluble organic compound fertilizer is fast in degradation in animals, plants, soil and environment, does not stay and accumulate, and cannot be leached into underground water. Compared with other wheat field herbicides, the pinoxaden has great development potential and market competitiveness.

The general synthetic method of pinoxaden is that the compound of formula I and the compound of formula II are subjected to deamination reaction to synthesize the compound of formula III, and then the compound of formula III is reacted with pivaloyl chloride under the action of alkali (organic alkali), and triethylamine is generally adopted as the organic alkali to synthesize the pinoxaden of formula IV.

Triethylamine is colorless or pale yellow transparent liquid, has smelly ammonia smell, has the chemical property of tertiary amine, is alkaline, and has strong irritation to skin and mucous membrane. Triethylamine is widely used as an acid binding agent (a trapping agent of hydrogen chloride) in the acylation reaction of acyl chloride, and the solid byproduct triethylamine hydrochloride is generated by the reaction, the solid byproduct triethylamine hydrochloride is easy to dissolve in water, and water extraction is adopted for post-treatment, so that wastewater containing triethylamine hydrochloride is obtained. Triethylamine is expensive and toxic, so that the waste water containing triethylamine hydrochloride needs to be recovered.

Patent application CN106928253a discloses a preparation method of pinoxaden, the synthetic route is as follows, wherein the compound of formula I and 1-oxa-4, 5-diazacycloheptane (compound of formula II) hydrobromide undergo deamination reaction to generate compound of formula III, and then undergo acylation reaction with pivaloyl chloride to generate pinoxaden. Triethylamine was used in both reactions, with a total amount of triethylamine of approximately 7 equivalents (relative to the compound of formula I) and the yields in both steps were 76.3%, 80% and the total yield was only 61%.

Patent CN1140528C discloses a method for preparing herbicide derivative, wherein the preparation method of pinoxaden is a one-pot method, the compound of formula I, 1-oxa-4, 5-diazacycloheptane hydrobromide and 4 equivalent triethylamine are refluxed in xylene to generate the compound of formula III, and then cooled and reacted with pivaloyl chloride to generate pinoxaden. The method is simple in steps, but triethylamine is used in the same way, and the total yield is 62%.

Patent CN112028906B discloses a method for preparing pinoxaden by a one-pot method, which is similar to the method of patent CN1140528C, a catalyst is added, the amount of triethylamine is reduced to 2 equivalents, but the yield is only 72% at the highest, and recovery of triethylamine is still a problem to be solved in the process.

In summary, in the prior art, triethylamine is generally used as an acid binding agent, however, the post-treatment of triethylamine is very complex, and a special triethylamine recovery device is required to be equipped, which clearly increases the investment cost of equipment and the complexity of the process, and the yield of pinoxaden does not reach a higher level. In addition, the organic base such as triethylamine is adopted to prepare pinoxaden, and the final product is darker in color and often needs further decolorization treatment. Therefore, there is a need to develop a process for preparing pinoxaden with higher reaction yield and product purity without using triethylamine.

Disclosure of Invention

Problems to be solved by the invention

In order to avoid using triethylamine and improve the reaction yield and the product purity, the invention provides an improved process for preparing pinoxaden.

Solution for solving the problem

The invention provides an improved process for preparing pinoxaden, which comprises the following steps:

(1) Deamination reaction: reacting a compound of formula I with a compound of formula II in the presence of a water-immiscible organic solvent A to obtain a solution containing a compound of formula III;

(2) Intermediate treatment steps: contacting the solution containing the compound of formula III obtained in step (1) with an aqueous solution of an inorganic base to obtain a two-phase mixture;

(3) Acylation reaction: and (3) reacting the two-phase mixture obtained in the step (2) with pivaloyl chloride under the condition of full mixing, and performing aftertreatment to obtain pinoxaden.

Preferably, the inorganic base in step (2) is sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate or lithium carbonate.

More preferably, the inorganic base in step (2) is sodium hydroxide or potassium hydroxide.

Preferably, in step (2), a halide salt is added to the two-phase mixture.

Preferably, the halide salt is sodium chloride, potassium chloride, lithium chloride, sodium bromide, potassium bromide or lithium bromide.

More preferably, the halide salt is sodium chloride or potassium chloride.

Preferably, the water-immiscible organic solvent a in step (1) is chlorobenzene, xylene or dichlorobenzene.

More preferably, the water-immiscible organic solvent a in step (1) is chlorobenzene.

Preferably, the aqueous phase of the two-phase mixture in step (2) has a mass concentration of alkali metal ions of 7% to 30%.

In a preferred embodiment, in step (2), the solution containing the compound of formula III obtained in step (1) is contacted with an aqueous solution of an inorganic base, the phases are separated by extraction, and the aqueous phase is contacted with a water-immiscible organic solvent B to obtain a two-phase mixture.

Preferably, the water-immiscible organic solvent B in step (2) is 1, 2-dichloroethane, dichloromethane, ethyl acetate or sec-butyl acetate.

More preferably, the water-immiscible organic solvent B in step (2) is 1, 2-dichloroethane or ethyl acetate.

Further preferably, the water-immiscible organic solvent B in step (2) is 1, 2-dichloroethane.

Preferably, in the above preferred embodiment the mass concentration of alkali metal ions in the aqueous phase of the two-phase mixture in step (2) is 2% -30%.

Preferably, a phase transfer catalyst is added to the two-phase mixture in step (2) above.

Preferably, the phase transfer catalyst is a quaternary ammonium salt or a crown ether.

More preferably, the phase transfer catalyst is tetrabutylammonium chloride, tetramethylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium bisulfate, or benzyltriethylammonium chloride.

Further preferably, the phase transfer catalyst is tetrabutylammonium chloride or tetramethylammonium chloride.

Preferably, the molar ratio of the phase transfer catalyst to the compound of formula I is from 0.001 to 0.02:1.

more preferably, the molar ratio of the phase transfer catalyst to the compound of formula I is 0.01:1.

in a preferred embodiment, in step (2), the solution containing the compound of formula III obtained in step (1) is contacted with an aqueous solution of an inorganic base, the aqueous solution of the compound of formula III and an acid are contacted, the phase is separated by extraction, and the organic phase is contacted with the aqueous solution of an inorganic base.

Preferably, the acid in step (2) is an inorganic acid or an organic acid.

More preferably, the acid in step (2) is hydrochloric acid, sulfuric acid or acetic acid.

Further preferably, the acid in step (2) is hydrochloric acid.

Preferably, the aqueous acid solution in step (2) has a mass concentration of 2wt% to 20wt%.

More preferably, the aqueous acid solution in step (2) has a mass concentration of 10wt%.

Preferably, the molar ratio of acid to compound of formula I in step (2) is from 0.2 to 5:1.

more preferably, the molar ratio of acid to compound of formula I in step (2) is 2:1.

preferably, the molar ratio of the compound of formula II to the compound of formula I in step (1) is from 1 to 5:1.

more preferably, the molar ratio of the compound of formula II to the compound of formula I in step (1) is 1:1.

preferably, the mass ratio of the water-immiscible organic solvent a and the compound of formula I in step (1) is 1-10:1.

more preferably, the mass ratio of the water-immiscible organic solvent a and the compound of formula I in step (1) is 3-4:1.

preferably, the temperature of the reaction in step (1) is from 100 ℃ to 140 ℃.

Preferably, the reaction time in step (1) is the time required to achieve at least 90% purity of the compound of formula III in the solution containing the compound of formula III.

More preferably, the reaction time in step (1) is the time required to achieve at least 96% purity of the compound of formula III in the solution containing the compound of formula III.

Further preferably, the reaction time in step (1) is the time required to achieve at least 98% purity of the compound of formula III in the solution containing the compound of formula III.

Preferably, the temperature is reduced after the reaction in step (1) is completed.

Preferably, the temperature of the cooling is 20 ℃ to 100 ℃.

Preferably, the mass concentration of the aqueous solution of the inorganic base in the step (2) is 1wt% to 50wt%.

More preferably, the aqueous solution of the inorganic base in step (2) has a mass concentration of 3wt% to 40wt%.

It is further preferred that the aqueous solution of the inorganic base in step (2) has a mass concentration of 3wt% to 30wt%.

Preferably, the molar ratio of the inorganic base to the compound of formula I in step (2) is from 1 to 3:1.

more preferably, the molar ratio of the inorganic base to the compound of formula I in step (2) is from 1.2 to 2:1.

preferably, the mass ratio of the water-immiscible organic solvent B and the compound of formula I in step (2) is 1-10:1.

more preferably, the mass ratio of the water-immiscible organic solvent B and the compound of formula I in step (2) is 3-5:1.

preferably, the molar ratio of pivaloyl chloride to the compound of formula I in step (3) is from 1 to 3:1.

more preferably, the molar ratio of pivaloyl chloride to the compound of formula I in step (3) is 1:1.

preferably, the reaction in step (3) is controlled by temperature.

Preferably, the temperature of the temperature control in step (3) is from 0 ℃ to 25 ℃.

More preferably, the temperature controlled in step (3) is from 0 ℃ to 20 ℃.

Further preferably, the temperature controlled in step (3) is from 0 ℃ to 10 ℃.

Preferably, the reaction time in step (3) is the time required to fully react the compound of formula III.

Preferably, the post-treatment in step (3) is: and (3) phase separation is carried out after the reaction is finished, and the organic phase is concentrated and crystallized after water washing, so as to obtain the pinoxaden.

Preferably, the solvent for crystallization in step (3) is n-hexane, cyclohexane, methylcyclohexane, n-heptane, n-octane or petroleum ether.

More preferably, the crystallization solvent in step (3) is n-hexane.

Preferably, the mass ratio of the crystallization solvent to the compound of formula I is from 1 to 10:1.

more preferably, the mass ratio of the crystallization solvent to the compound of formula I is 3-5:1.

ADVANTAGEOUS EFFECTS OF INVENTION

The improved process for preparing pinoxaden provided by the invention changes the acid binding agent in the prior art from organic base to inorganic base, avoids the use of triethylamine, reduces the recovery procedure, is convenient for continuous industrial production, meets the color state of the product, and avoids the decolorization process. The process method comprises two steps of deamination and acylation and an intermediate treatment step, wherein the separation and purification step is not needed after the deamination reaction, the intermediate treatment step is simple to operate, and the complex operation procedure is not increased. Compared with the prior art, the process method greatly improves the reaction yield and the product purity, is simple to operate, reduces the filtering flow, does not use special reagents, has low cost, is environment-friendly, and is suitable for industrial scale-up production.

Detailed Description

Definition of terms

The "acid-binding agent" in the present invention means a reagent that traps hydrogen ions in an acylation reaction to accelerate the rate of the acylation reaction and prevent the formation of byproducts, typically an alkaline reagent.

The phase transfer catalyst in the invention is a catalyst which can help the transfer of reactants from one phase to another phase capable of reacting, thereby accelerating the reaction rate of a heterogeneous system and overcoming the defects of slow reaction rate, low yield, incomplete reaction and the like of heterogeneous organic systems. The phase transfer catalysts commonly used in organic synthesis are quaternary ammonium salts such as tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium bisulfate, tetramethylammonium chloride, benzyltriethylammonium chloride, and the like.

"purity" in the present invention means HPLC purity measured by peak area normalization.

The term "equivalent" in the present invention refers to the amount of the reagent used in the reaction, specifically the molar ratio of the reagent to the compound of formula I, abbreviated as "eq".

Abbreviations in the context of the present invention have the following meanings:

abbreviations (abbreviations)	Meaning of
		eq	Equivalent weight
DCE	1, 2-dichloroethane
		DCM	Dichloromethane (dichloromethane)
HPLC	High performance liquid chromatography

Synthesis process

In the existing synthetic process method of the pinoxaden, triethylamine is generally adopted as an acid binding agent, the aftertreatment of the triethylamine is quite complex, and the yield of the pinoxaden is low. In addition, the organic base such as triethylamine is adopted to prepare pinoxaden, and the final product is darker in color and often needs further decolorization treatment. In order to solve the problems, the inventor tries to use inorganic alkali as an acid binding agent, optimizes various technological parameters through a great deal of experimental study, and finally improves the reaction yield and the purity of the product on the premise of not using organic alkali. The specific synthesis steps are as follows:

In one embodiment, the inorganic base in step (2) is sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, or lithium carbonate.

In a preferred embodiment, the inorganic base in step (2) is sodium hydroxide or potassium hydroxide.

In one embodiment, in step (2), a halide salt is added to the two-phase mixture.

In one embodiment, the halide salt is sodium chloride, potassium chloride, lithium chloride, sodium bromide, potassium bromide, or lithium bromide.

In a preferred embodiment, the halide salt is sodium chloride or potassium chloride.

In one embodiment, the water-immiscible organic solvent a in step (1) is chlorobenzene, xylene or dichlorobenzene.

In a preferred embodiment, the water-immiscible organic solvent a in step (1) is chlorobenzene.

In one embodiment, the aqueous phase of the two-phase mixture in step (2) has a mass concentration of alkali metal ions of 7% to 30%.

In one embodiment, in step (2), the solution containing the compound of formula III obtained in step (1) is contacted with an aqueous solution of an inorganic base, the extraction phase is separated, and the aqueous phase is contacted with a water-immiscible organic solvent B to obtain a two-phase mixture.

In one embodiment, the water-immiscible organic solvent B in step (2) is 1, 2-dichloroethane, dichloromethane, ethyl acetate or sec-butyl acetate.

In a preferred embodiment, the water-immiscible organic solvent B in step (2) is 1, 2-dichloroethane or ethyl acetate.

In a more preferred embodiment, the water-immiscible organic solvent B in step (2) is 1, 2-dichloroethane.

In the above embodiment, the mass concentration of alkali metal ions in the aqueous phase of the two-phase mixture in step (2) is 2% -30%.

In one embodiment, a phase transfer catalyst is added to the two-phase mixture in step (2) above.

In one embodiment, the phase transfer catalyst is a quaternary ammonium salt or a crown ether.

In a preferred embodiment, the phase transfer catalyst is tetrabutylammonium chloride, tetramethylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium bisulfate or benzyltriethylammonium chloride.

In a more preferred embodiment, the phase transfer catalyst is tetrabutylammonium chloride or tetramethylammonium chloride.

In one embodiment, the molar ratio of the phase transfer catalyst to the compound of formula I is from 0.001 to 0.02:1.

in a preferred embodiment, the molar ratio of the phase transfer catalyst to the compound of formula I is 0.01:1.

in one embodiment, in step (2), the solution containing the compound of formula III obtained in step (1) is contacted with an aqueous solution of an inorganic base prior to contacting the solution containing the compound of formula III with an aqueous solution of an acid, the phase is separated by extraction, and the organic phase is contacted with an aqueous solution of the inorganic base. The aqueous solution of acid is added for extraction phase separation, and the residual compound of the formula II and black tar generated by the reaction can be removed, thereby improving the product quality.

In one embodiment, the acid in step (2) is an inorganic acid or an organic acid.

In a preferred embodiment, the acid in step (2) is hydrochloric acid, sulfuric acid or acetic acid.

In a more preferred embodiment, the acid in step (2) is hydrochloric acid.

In one embodiment, the aqueous acid solution in step (2) has a mass concentration of 2wt% to 20wt%.

In a preferred embodiment, the aqueous acid solution in step (2) has a mass concentration of 10wt%.

In one embodiment, the molar ratio of the acid to the compound of formula I in step (2) is from 0.2 to 5:1.

in a preferred embodiment, the molar ratio of the acid to the compound of formula I in step (2) is 2:1.

in one embodiment, the molar ratio of the compound of formula II to the compound of formula I in step (1) is from 1 to 5:1.

in a preferred embodiment, the molar ratio of the compound of formula II to the compound of formula I in step (1) is 1:1.

in one embodiment, the mass ratio of the water-immiscible organic solvent a and the compound of formula I in step (1) is from 1 to 10:1.

in a preferred embodiment, the mass ratio of the water-immiscible organic solvent a and the compound of formula I in step (1) is 3 to 4:1.

in one embodiment, the temperature of the reaction in step (1) is from 100 ℃ to 140 ℃.

In one embodiment, the reaction time in step (1) is the time required to achieve at least 90% purity of the compound of formula III in the solution containing the compound of formula III.

In a preferred embodiment, the reaction time in step (1) is the time required to achieve at least 96% purity of the compound of formula III in the solution containing the compound of formula III.

In a more preferred embodiment, the reaction time in step (1) is the time required to achieve at least 98% purity of the compound of formula III in the solution containing the compound of formula III.

In one embodiment, the temperature is reduced after the reaction in step (1) is completed.

In one embodiment, the reduced temperature is from 20 ℃ to 100 ℃.

In one embodiment, the aqueous solution of inorganic base in step (2) has a mass concentration of 1wt% to 50wt%.

In a preferred embodiment, the aqueous solution of the inorganic base in step (2) has a mass concentration of 3wt% to 40wt%.

In a more preferred embodiment, the aqueous solution of inorganic base in step (2) has a mass concentration of 3wt% to 30wt%.

In one embodiment, the molar ratio of the inorganic base to the compound of formula I in step (2) is from 1 to 3:1.

in a preferred embodiment, the molar ratio of the inorganic base to the compound of formula I in step (2) is from 1.2 to 2:1.

in one embodiment, the mass ratio of the water-immiscible organic solvent B and the compound of formula I in step (2) is from 1 to 10:1.

in a preferred embodiment, the mass ratio of the water-immiscible organic solvent B and the compound of formula I in step (2) is 3-5:1.

in one embodiment, the molar ratio of pivaloyl chloride to the compound of formula I in step (3) is from 1 to 3:1.

in a preferred embodiment, the molar ratio of pivaloyl chloride to the compound of formula I in step (3) is 1:1.

in one embodiment, the reaction in step (3) is controlled.

In one embodiment, the temperature controlled in step (3) is from 0 ℃ to 25 ℃.

In a preferred embodiment, the temperature controlled in step (3) is in the range of 0 ℃ to 20 ℃.

In a more preferred embodiment, the temperature controlled in step (3) is in the range of 0 ℃ to 10 ℃.

In one embodiment, the reaction time in step (3) is the time required to fully react the compound of formula III.

In one embodiment, the post-treatment in step (3) is: and (3) phase separation is carried out after the reaction is finished, and the organic phase is concentrated and crystallized after water washing, so as to obtain the pinoxaden.

In one embodiment, the crystallization solvent in step (3) is n-hexane, cyclohexane, methylcyclohexane, n-heptane, n-octane or petroleum ether.

In a preferred embodiment, the crystallization solvent in step (3) is n-hexane.

In one embodiment, the mass ratio of the crystallization solvent to the compound of formula I is from 1 to 10:1.

in a preferred embodiment, the mass ratio of the crystallization solvent to the compound of formula I is from 3 to 5:1.

the technical scheme of the invention is further described below by combining examples. It should be understood that the following examples are illustrative and not intended to limit the scope of the present invention. The instruments, materials, reagents, etc. used in the following examples are all available by conventional commercial means unless otherwise indicated.

Examples

Example 1

The compound of formula II (9.8 g,0.096 mol), the compound of formula I (23.8 g,0.096 mol) and chlorobenzene (80 g) are weighed into a 250mL three-necked flask, heating is started, the reaction temperature is maintained at 126 ℃, stirring reaction is carried out for 5 hours, the reaction is stopped, the relative content is detected by HPLC and is cooled to room temperature (25 ℃), 10wt% of aqueous sodium hydroxide solution (46.08 g,0.1152 mol) is added, phase separation is carried out by extraction, water phase is collected, organic solvent DCE (96 g) is added into the water phase, pivaloyl chloride (11.52 g,0.096 mol) is slowly added dropwise, the internal temperature is maintained at 10 ℃, stirring is carried out for 10 minutes, the organic phase is taken for analysis, the relative content of HPLC is detected to be 92%, and the raw material reaction is complete. Standing for phase separation, collecting organic phase, washing the organic phase with 50g of water, phase separation, concentrating to remove DCE, adding n-hexane (100 g) for crystallization, and filtering to obtain the product (product HPLC purity is 99%, based on total yield of the compound of formula II is 92.5%, product color is yellow).

Example 2

The compound of formula II (9.8 g,0.096 mol), the compound of formula I (23.8 g,0.096 mol) and chlorobenzene (80 g) were weighed into a 250mL three-necked flask, heating was started, the reaction temperature was maintained at 126℃and after stirring for 5 hours, the reaction was stopped, the relative content was detected by HPLC and cooled to room temperature (25 ℃), 10wt% aqueous hydrochloric acid solution (70 g,0.192 mol) was added for extraction, phase separation was performed, the organic phase was collected, 10wt% aqueous sodium hydroxide solution (46.08 g,0.1152 mol) was added for extraction, phase separation was performed, the aqueous phase was collected, the organic solvent DCE (96 g) was added to the aqueous phase, the inner temperature was maintained at 10℃and stirring was continued for 10 minutes, the relative content by HPLC was detected by sampling analysis and 98% for complete reaction of the raw materials. The organic phase was collected by phase separation, washed with 50g of water, concentrated to remove DCE, crystallized with n-hexane (100 g) and filtered to give the product (product HPLC purity 99%, 95% based on total yield of the compound of formula II) as white.

Examples 3 to 15

The concentration or the amount of the aqueous sodium hydroxide solution, the kind of the organic solvent to be added, the temperature of the acylation reaction, and the addition of the catalyst were adjusted in the same manner as in example 2, and the experimental results are shown in Table 1. Wherein "NaOH amount" is an equivalent calculated based on the equivalent of the compound of formula I; "conversion" means the proportion of reacted compound of formula III to the starting material of the compound of formula III fed to indicate the extent to which the reaction has proceeded; the HPLC relative content refers to the HPLC purity of the pinoxaden in the reaction solution after the reaction is finished according to the area normalization calculation; total yield refers to the product yield based on the compound of formula II.

TABLE 1

Conclusion: as shown in Table 1, the reaction can be carried out when the organic solvent is DCE, toluene, o-xylene, dichloropropane, tetrachloroethylene, ethyl acetate, sec-butyl acetate and DCM, wherein when DCE, DCM, ethyl acetate and sec-butyl acetate are selected, the total reaction yield is high and can reach more than 90%; the reaction effect is also better when the mass concentration of the sodium hydroxide solution is lower (5 wt%), namely, the sodium ion concentration is 2.9%; the acylation reaction temperature is controlled to be between 0 and 10 ℃; as is evident from the comparison of example 10 and example 12, the addition of the phase transfer catalyst further improved the reaction yield.

Example 16

The compound of formula II (9.8 g,0.096 mol), the compound of formula I (23.8 g,0.096 mol) and chlorobenzene (80 g) were weighed into a 250mL three-necked flask, heating was started, the reaction temperature was maintained at 126℃and after stirring for 5 hours, the reaction was stopped, the relative content was detected by HPLC and was cooled to room temperature (25 ℃), 10wt% aqueous hydrochloric acid solution (70 g,0.192 mol) was added for extraction, phase separation was performed, the organic phase was collected, 20wt% aqueous sodium hydroxide solution (23 g,0.1152 mol) was added to the organic phase at one time, tetrabutylammonium chloride (0.2668 g,0.00096 96 mol) was further added as a phase transfer catalyst, and pivaloyl chloride (11.52 g,0.096 mol) was slowly added dropwise after completion of the dropwise addition, stirring was performed for 10 minutes, the relative content by HPLC was detected by sampling analysis and the content was 98% by sampling analysis was detected, and the reaction of the raw material was completed. The organic phase was collected by phase separation, washed with water, concentrated to remove the organic solvent chlorobenzene, crystallized by addition of n-hexane (100 g), and filtered to give the product (product HPLC purity 98.5%, 95% based on total yield of the compound of formula II) as white.

Examples 17 to 22

The concentration of the aqueous sodium hydroxide solution and the conditions (including temperature and catalyst) of the acylation reaction were adjusted in the same manner as in example 16, and the experimental results are shown in Table 2.

TABLE 2

Remarks:

(1)Na ⁺ the mass concentration is calculated, and the specific calculation method is as follows:

(2)OH ^- the mass concentration is calculated, and the specific calculation method is as follows:

conclusion: comparing example 17 with example 18, example 20 and example 16, it can be seen that increasing the mass concentration of NaOH solution (Na ⁺ The mass concentration is correspondingly increased) can obviously improve the reaction conversion rate and the total yield; acylation reactionThe effect is better when the temperature is controlled at 0-20 ℃, and the lower the temperature is, the higher the yield is.

Example 23

The intermediate of the compound of formula II (9.8 g,0.096 mol), the intermediate of the compound of formula I (23.8 g,0.096 mol) and chlorobenzene (80 g) are weighed into a 250mL three-necked flask, heating is started, the reaction temperature is maintained at 126 ℃, after stirring for 5 hours, the reaction is stopped, the relative content of the compound is 98% by HPLC, the temperature is reduced to room temperature (25 ℃), 10wt% aqueous hydrochloric acid solution (70 g,0.192 mol) is added for extraction, phase separation is carried out, an organic phase is collected, 10wt% aqueous sodium hydroxide solution (46.08 g,0.1152 mol) is added to the organic phase at one time, tetrabutylammonium chloride (0.2668 g,0.00096 mol) and sodium chloride solid (6.73 g,0.1152 mol) are added, the temperature is reduced to 0 ℃, after the dropwise addition of the pivaloyl chloride (11.52 g,0.096 mol) is slowly dropped, stirring is carried out for 10 minutes, the relative content of the compound of formula II is 97% after sampling analysis, and the reaction of the raw material is completed. The organic phase was collected by phase separation, washed with water, concentrated to remove the organic solvent chlorobenzene, crystallized by addition of n-hexane (100 g), and filtered to give the product (product HPLC purity 99%, total yield 93% based on the compound of formula II) as white.

Examples 24 to 25

The concentration of the aqueous sodium hydroxide solution and the conditions (including temperature and sodium chloride amount) of the acylation reaction were adjusted in the same manner as in example 23, and the experimental results are shown in Table 3.

TABLE 3 Table 3

Remarks:

(1)Na ⁺ the mass concentration is calculated, and the added sodium chloride is calculated by adding sodium chloride into aqueous phase NaOH solution, and the specific calculation method is as follows:

(2)OH ^- the mass concentration is calculated by a specific calculation method such asThe following steps:

conclusion: as can be seen from the comparison of the example 23 and the example 20, under the condition that the concentration and the dosage of NaOH are the same, the conversion rate and the total yield of the reaction can be obviously improved by adding NaCl; na (Na) ⁺ The mass concentration has larger influence on the reaction, when Na ⁺ When the mass concentration is 7.0% -11.4%, the reaction effect is better.

Examples 26 to 28

The intermediate (9.8 g,0.096 mol) of the compound of formula II, the intermediate (23.8 g,0.096 mol) of the compound of formula I and chlorobenzene (80 g) are weighed into a 250mL three-necked flask, heating is started, the reaction temperature is maintained at 126 ℃, after stirring for 5 hours, the reaction is stopped, the relative content is detected by HPLC and is 98%, the temperature is reduced to room temperature (25 ℃), 10wt% of aqueous hydrochloric acid solution (70 g,0.192 mol) is added for extraction, phase separation is carried out, an organic phase is collected, an aqueous potassium hydroxide solution is added into the organic phase at one time, a phase transfer catalyst tetrabutylammonium chloride (0.2668 g,0.00096 mol) is added, potassium chloride is added or not added, the temperature is reduced to 0 ℃, and after the dropwise addition, pivaloyl chloride (11.52 g,0.096 mol) is slowly added, stirring is carried out for 10 minutes, and the relative content of HPLC is detected by sampling analysis. The organic phase was collected by phase separation, washed with water, concentrated to remove the organic solvent chlorobenzene, crystallized by the addition of n-hexane (100 g), and filtered to give the product (white).

The concentration of the aqueous potassium hydroxide solution and the amount of potassium chloride were adjusted, and the specific conditions and results are shown in Table 4:

TABLE 4 Table 4

Conclusion: as can be seen from the results of the examples in Table 4, K ⁺ When the mass concentration is 13.9% -20.8%, the reaction conversion rate and the total yield are higher.

Example 29

The compound of formula II (9.8 g,0.096 mol), the compound of formula I (23.8 g,0.096 mol) and chlorobenzene (80 g) were weighed into a 250mL three-necked flask, heating was started, the reaction temperature was maintained at 126℃and stirred for 5 hours, the reaction was stopped, the relative content was detected by HPLC and cooled to room temperature (25 ℃), 10% by weight aqueous sodium hydroxide solution (46.08 g,0.1152 mol) and tetrabutylammonium chloride (0.2668 g,0.00096 mol) were added, the internal temperature was maintained at 10℃or below, pivaloyl chloride (11.52 g,0.096 mol) was slowly added dropwise, the internal temperature was maintained at 10℃and stirred for 10 minutes, the organic phase was taken for analysis, and the relative content by HPLC was detected by sampling analysis and found 68% of the raw material was not reacted completely. Pivaloyl chloride (2.3 g,0.0192 mol) was added, the organic phase was analyzed, the relative content of HPLC was found to be 71% by sampling analysis, 26% of the starting material was unreacted, the phase was separated by complete standing, the organic phase was collected, the organic phase was washed with 50g of water, separated, chlorobenzene was removed by concentration, n-hexane (100 g) was added for crystallization, and the product was obtained by filtration (product HPLC purity was 96%, total yield was 69%).

Example 30

The compound of formula II (9.8 g,0.096 mol), the compound of formula I (23.8 g,0.096 mol) and chlorobenzene (80 g) were weighed into a 250mL three-necked flask, heated, kept at a reaction temperature of 126℃and stirred for 5 hours, stopped, the relative content detected by HPLC was 98%, cooled to room temperature (25 ℃), 20wt% aqueous sodium hydroxide solution (23 g,0.1152 mol) and tetrabutylammonium chloride (0.2668 g,0.00096 mol) were added, kept at an internal temperature of 10℃or less, pivaloyl chloride (11.52 g,0.096 mol) was slowly added dropwise, kept at an internal temperature of 10℃and stirred for 10 minutes, and the organic phase was taken for analysis, and the relative content by HPLC was 94% and 4% of the raw materials were not reacted completely. The organic phase was analyzed and sampled to detect that the HPLC relative content was 98%, the reaction of the raw materials was complete, the phase was separated by complete standing, the organic phase was collected, washed with 50g of water, separated, concentrated to remove chlorobenzene, crystallized with n-hexane (100 g), and filtered to give the product (product HPLC purity 98.1%, total yield 94.5%).

Claims

1. An improved process for preparing pinoxaden, comprising the steps of:

2. The improved process for preparing pinoxaden according to claim 1, characterized in that:

the inorganic base in the step (2) is sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate or lithium carbonate, preferably sodium hydroxide or potassium hydroxide.

3. The process improvement for preparing pinoxaden according to claim 1 or 2, characterized in that:

in step (2), a halide salt is added to the two-phase mixture;

the halide salt is sodium chloride, potassium chloride, lithium chloride, sodium bromide, potassium bromide or lithium bromide, preferably sodium chloride or potassium chloride.

4. A process improvement for the preparation of pinoxaden according to any of claims 1-3, characterized in that:

the water-immiscible organic solvent A in step (1) is chlorobenzene, xylene or dichlorobenzene, preferably chlorobenzene.

5. The improved process for preparing pinoxaden according to any of claims 1-4, characterized in that:

the aqueous phase of the two-phase mixture in step (2) has a mass concentration of alkali metal ions of 7% to 30%.

6. The improved process for preparing pinoxaden according to any of claims 1-4, characterized in that:

in the step (2), the solution containing the compound of formula III obtained in the step (1) is contacted with an aqueous solution of an inorganic base, the phase is separated by extraction, and the aqueous phase is contacted with an organic solvent B which is not miscible with water, to obtain a two-phase mixture.

7. The improved process for preparing pinoxaden according to claim 6, characterized in that:

the water-immiscible organic solvent B in step (2) is 1, 2-dichloroethane, dichloromethane, ethyl acetate or sec-butyl acetate, preferably 1, 2-dichloroethane or ethyl acetate, more preferably 1, 2-dichloroethane.

8. The improved process for preparing pinoxaden according to claim 6 or 7, characterized in that:

the aqueous phase of the two-phase mixture in step (2) has a mass concentration of alkali metal ions of 2% to 30%.

9. The improved process for preparing pinoxaden according to any of claims 1-8, characterized in that:

in step (2), adding a phase transfer catalyst to the two-phase mixture;

the phase transfer catalyst is a quaternary ammonium salt or crown ether, preferably tetrabutylammonium chloride, tetramethyl ammonium chloride, tetrabutylammonium bromide, tetrabutylammonium bisulfate or benzyl triethyl ammonium chloride, more preferably tetrabutylammonium chloride or tetramethyl ammonium chloride;

the molar ratio of the phase transfer catalyst to the compound of formula I is 0.001-0.02:1, preferably 0.01:1.

10. the improved process for preparing pinoxaden according to any of claims 1-9, characterized in that:

in the step (2), before the solution containing the compound of formula III obtained in the step (1) is brought into contact with an aqueous solution of an inorganic base, the solution containing the compound of formula III is brought into contact with an aqueous solution of an acid, phase separation is performed by extraction, and then an organic phase is brought into contact with the aqueous solution of an inorganic base.

11. The improved process for preparing pinoxaden according to claim 10, characterized in that:

the acid in step (2) is an inorganic or organic acid, preferably hydrochloric acid, sulfuric acid or acetic acid, more preferably hydrochloric acid;

the aqueous acid solution in step (2) has a mass concentration of 2wt% to 20wt%, preferably 10wt%;

the molar ratio of acid to compound of formula I in step (2) is from 0.2 to 5:1, preferably 2:1.

12. the improved process for preparing pinoxaden according to any of claims 1-11, characterized in that:

the molar ratio of the compound of formula II to the compound of formula I in step (1) is 1-5:1, preferably 1:1, a step of;

the mass ratio of the organic solvent A which is not mutually soluble with water to the compound of the formula I in the step (1) is 1-10:1, preferably 3-4:1, a step of;

the temperature of the reaction in the step (1) is 100-140 ℃;

the molar ratio of pivaloyl chloride to the compound of formula I in step (3) is 1-3:1, preferably 1:1, a step of;

controlling the temperature in the reaction in the step (3), wherein the temperature is 0-25 ℃, preferably 0-20 ℃, more preferably 0-10 ℃.