CN113024411B - Preparation method of tralkoxydim - Google Patents
Preparation method of tralkoxydim Download PDFInfo
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- CN113024411B CN113024411B CN201911350659.9A CN201911350659A CN113024411B CN 113024411 B CN113024411 B CN 113024411B CN 201911350659 A CN201911350659 A CN 201911350659A CN 113024411 B CN113024411 B CN 113024411B
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- C07C249/00—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton
- C07C249/04—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton of oximes
- C07C249/08—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton of oximes by reaction of hydroxylamines with carbonyl compounds
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- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
- C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
- C07C45/72—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction of compounds containing >C = O groups with the same or other compounds containing >C = O groups
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- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
- C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
- C07C45/72—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction of compounds containing >C = O groups with the same or other compounds containing >C = O groups
- C07C45/74—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction of compounds containing >C = O groups with the same or other compounds containing >C = O groups combined with dehydration
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Abstract
The invention discloses a method for preparing tralkoxydim, which comprises the following steps: preparing a first intermediate from 2,4, 6-trimethylbenzaldehyde and acetone; preparing a second intermediate by using the first intermediate, diethyl malonate and propionyl chloride; preparing the tralkoxydim by utilizing the second intermediate and the ethoxyamine; in the process of preparing the second intermediate, condensation and rearrangement reactions are carried out simultaneously; no isolation or purification treatment is performed after said preparing the first intermediate and before said preparing tralkoxydim. The method prepares the tralkoxydim by simultaneously carrying out condensation and rearrangement reactions and not carrying out separation or purification processes in the reaction process, saves the steps of repeated separation, purification, transfer, feeding and the like in the conventional preparation method, saves time and labor, reduces the consumption of reagents, saves a large amount of cost, and solves the problems of complicated steps, low product yield and serious layering and emulsification in the esterification reaction process of the preparation method of the tralkoxydim in the prior art.
Description
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to a preparation method of tralkoxydim.
Background
Tralkoxydim of formula C 20 H 27 NO 3 Structural formula is
Belongs to oxime herbicides.
At present, the method for preparing the tralkoxydim is basically that 2,4, 6-trimethylbenzaldehyde and acetone are condensed to obtain 1- (2, 4, 6-trimethylphenyl) -1-buten-3-one, then the product is separated, reacted with diethyl malonate, hydrolyzed, cyclized and decarboxylated to obtain 3-hydroxy-5- (2, 4, 6-trimethylphenyl) -cyclohex-2-en-1-one, the product is separated again, then reacted with propionic anhydride to obtain 3-hydroxy-5- (2, 4, 6-trimethylphenyl) -2-propionyl-cyclohex-2-en-1-one, and finally reacted with ethoxyamine hydrochloride to obtain the tralkoxydim.
The synthesis process generally needs to be carried out through steps of product separation, purification, transfer, feeding and the like for multiple times, the steps are complex, material loss is caused in the processes of product separation, purification and transfer for multiple times, especially in large-scale production, time and labor are consumed, material waste is caused, and the product yield is low. In addition, in the conventional process for synthesizing the second intermediate (3-hydroxy-5- (2, 4, 6-trimethylphenyl) -2-propionyl-cyclohex-2-en-1-one) described in the application, after the first intermediate (1- (2, 4, 6-trimethylphenyl) -1-buten-3-one) reacts with diethyl malonate, propionyl chloride is added and then the mixture is washed with water, so that the relatively serious phenomenon of layering and emulsification easily occurs. At present, no report for solving the above problems is found.
Disclosure of Invention
The invention aims to solve the technical problems that the preparation method of the tralkoxydim in the prior art has complex steps and low product yield, and the serious layering emulsification phenomenon is easy to occur after propionyl chloride is added and washed in the process of synthesizing a second intermediate.
In order to solve the technical problems, the invention provides a method for preparing tralkoxydim, which comprises the following steps:
s1, preparing a first intermediate by using 2,4, 6-trimethyl benzaldehyde and acetone;
s2, preparing a second intermediate by using the first intermediate, diethyl malonate and propionyl chloride;
s3, preparing the tralkoxydim by utilizing the second intermediate and the ethoxyamine;
in the process of preparing the second intermediate, condensation and rearrangement reactions are carried out simultaneously; (ii) no isolation or purification treatment is performed after said preparing the first intermediate and before said preparing tralkoxydim;
wherein the structural formula of the first intermediate is as follows:
the structural formula of the second intermediate is as follows:
the structural formula of the tralkoxydim is as follows:
optionally, the step S1 includes: reacting 2,4, 6-trimethylbenzaldehyde with acetone under basic conditions to prepare a first intermediate;
the step S2 comprises the following steps: the product obtained in the step S1 does not need to be separated or purified in advance, and the first intermediate is firstly reacted with diethyl malonate and sodium methoxide solution; then simultaneously adding 4-dimethylamino pyridine and propionyl chloride to perform condensation and rearrangement reactions, and adding acid and alkali after the reactions to prepare a second intermediate;
the step S3 comprises the following steps: the product obtained in the step S2 does not need to be separated or purified in advance, and the second intermediate is reacted with an ethoxyamine solution to prepare a crude raw trimethylbenzene clomazone;
the method further comprises the following steps:
and S4, recrystallizing the crude tralkoxydim technical product without separating or purifying the product obtained in the step S3 in advance to prepare the refined tralkoxydim technical product.
Optionally, the step S1 includes:
2,4, 6-trimethyl benzaldehyde, acetone, water and sodium hydroxide solution are put into a four-mouth bottle, the temperature is raised to reflux under stirring, and the reflux is kept for 4 hours within the range of 72 to 76 ℃; removing the solvent at normal pressure, cooling to below 70 ℃, adding toluene, layering, refluxing and dewatering the toluene layer, and cooling to 25-30 ℃ to obtain a toluene solution of the first intermediate.
Optionally, the S2 step includes:
without separating or purifying the product obtained in the step S1 in advance, sequentially adding the toluene solution of the first intermediate obtained in the step S1, diethyl malonate and sodium methoxide into a four-mouth bottle, slowly heating to reflux under stirring, and keeping the temperature at over 66 ℃ for reflux for 1h; after the solvent is removed to 110 ℃, keeping reflux for 30min, synchronously adding toluene with the same volume as the solvent, if the temperature is reduced, continuously removing the solvent to 110 ℃, and if the temperature is constant, finishing the desolventizing; cooling to below 50 deg.C, adding 4-dimethylaminopyridine and propionyl chloride, heating to 90 deg.C, and keeping the temperature for 8 hr; cooling to 50 ℃, adding water, layering, removing a water layer, adding liquid alkali and water into a toluene layer, keeping the temperature within the range of 84-86 ℃ for backflow for 4h, cooling to below 50 ℃, layering, removing an organic phase, adding petroleum ether and hydrochloric acid with the temperature of 60-90 ℃ into a water phase, slowly heating to backflow, keeping the temperature at 60 ℃ for backflow 2h, cooling to 55-60 ℃, thermally layering, removing the water phase, washing the organic phase with water, and adding a small amount of alkali to adjust the pH to 6-7 to obtain a petroleum ether solution of a second intermediate.
Optionally, the S3 step includes:
the product obtained in the step S2 does not need to be separated or purified in advance, the petroleum ether solution of the second intermediate obtained in the step S2 and the ethoxyamine are put into a four-mouth bottle, the temperature is raised to 50 ℃, the temperature is kept for 4 hours, and the sample is taken until the product is qualified, namely, the content of the second intermediate is less than 1 percent in the content determination of the liquid chromatography normalization method; adjusting pH to 4-5, removing water phase by layering, removing solvent from organic phase at normal pressure, concentrating, cooling to below 10 deg.C, and filtering; and continuously washing the obtained material twice by using a mixed solution of petroleum ether and acetone, and drying to obtain a crude drug of the tralkoxydim.
Optionally, the step S4 includes:
and (4) adding isopropanol into the crude drug for recrystallization without separating or purifying the product obtained in the step S3 in advance, heating to 60 ℃ for dissolution, cooling to-10 ℃, preserving heat for more than 4 hours, and filtering to obtain the refined bulk drug of the tralkoxydim.
Optionally, the concentrations of said 2,4, 6-trimethylbenzaldehyde and acetone are each 99% m/m, the concentration of said sodium hydroxide solution is 30% m/m, the weight ratio of said 2,4, 6-trimethylbenzaldehyde, acetone, sodium hydroxide solution, water is 18:100:1:60.
optionally, in the S2 step, the concentrations of the diethyl malonate, sodium methoxide solution, propionyl chloride are respectively 98%/m, 20% m/m, 98%/m, the weight ratio of the diethyl malonate, sodium methoxide solution, propionyl chloride being 21.2:36.2:12.6.
optionally, in the step S3, the concentration of the ethoxyamine solution is 25% m/m, and the weight ratio of the product obtained in the step S2 to the ethoxyamine solution is 74:13.9.
alternatively, the concentration of the 4-dimethylaminopyridine is 99% m/m, and the 4-dimethylaminopyridine is added in an amount of 0.9g.
Optionally, the weight ratio of the petroleum ether to the acetone in the mixed solution of the petroleum ether and the acetone is 14:1.
optionally, the weight ratio of the crude technical material to isopropanol is 1.
Compared with the prior art, the invention has the following advantages:
in the preparation method of the tralkoxydim, condensation and rearrangement reactions are simultaneously carried out in the process of preparing the second intermediate; after the first intermediate is prepared and before the tralkoxydim is prepared, separation or purification treatment is not carried out, so that the steps of multiple separation, purification, transfer, feeding and the like in the conventional preparation method are omitted, time and labor are saved, a large amount of materials are saved, the consumption of reagents is reduced, and a large amount of cost is saved.
Furthermore, the preparation method of the invention increases the reaction speed, avoids the generation of byproducts in the reaction process and increases the content of products by selecting proper solvents and strictly executing the sequence of adding materials.
Furthermore, in the process of synthesizing the second intermediate, after propionyl chloride is added, water is not directly washed, water is removed through multiple times of layering, and petroleum ether serving as an organic solvent is added, so that the problem that the serious layering emulsification phenomenon is easy to occur in the process of water washing after the propionyl chloride is added in the process of synthesizing the second intermediate is effectively solved.
In addition, experiments show that by adopting the preparation method, the yield of crude drug is 90%, the content of the crude drug is about 90%, the yield of refined drug is 95%, the content is more than 98%, and the product quality is high, so that the preparation method is suitable for large-scale production.
Drawings
FIG. 1 is a process flow diagram of a process for preparing tralkoxydim in an embodiment of the present invention;
FIG. 2 is a process flow diagram of a process for preparing tralkoxydim according to another embodiment of the present invention;
FIG. 3 is a diagram of a second intermediate in accordance with example one of the present invention 1 H NMR detection result chart;
FIG. 4 shows a refined bulk drug of tralkoxydim in example one of the present invention 1 H NMR detection result chart.
Detailed Description
As described in the background art, the methods for preparing tralkoxydim in the prior art all use 2,4, 6-trimethylbenzaldehyde as a starting material, and the tralkoxydim is prepared by reacting the starting material with acetone, diethyl malonate, propionic anhydride, ethoxyamine and the like through multiple operations of product separation, purification, transfer, feeding and the like. The synthesis process generally needs to be carried out through the steps of separation, purification, transfer, feeding and the like for many times, the steps are complicated, material loss is caused in the processes of separation, purification and transfer of products for many times, and particularly in large-scale production, time and labor are consumed, material waste is caused, and the product yield is low.
The process of the invention has a number of advantages. In the process of preparing the second intermediate, condensation and rearrangement reactions are carried out simultaneously; after the first intermediate is prepared and before the tralkoxydim is prepared, separation or purification treatment is not carried out, so that the steps of multiple separation, purification, transfer, feeding and the like in the conventional preparation method are omitted, time and labor are saved, a large amount of materials are saved, the consumption of reagents is reduced, and a large amount of cost is saved.
In order to make the aforementioned objects, features and advantages of the present invention comprehensible, embodiments accompanied with figures are described in detail below.
The source of the reagent used in the present invention is not particularly limited unless otherwise specified, and may be commercially available, for example.
FIG. 1 is a process flow diagram of a method of preparing tralkoxydim in an embodiment of the present invention. The preparation method provided by the embodiment of the invention can be applied to preparation of the tralkoxydim, and the preparation method is the steps in fig. 1.
The invention shown in figure 1 provides a process for preparing tralkoxydim, the process comprising:
s1, preparing a first intermediate by using 2,4, 6-trimethyl benzaldehyde and acetone;
s2, preparing a second intermediate by using the first intermediate, diethyl malonate and propionyl chloride;
s3, preparing the tralkoxydim by utilizing the second intermediate and the ethoxyamine;
in the process of preparing the second intermediate, condensation and rearrangement reactions are carried out simultaneously; (ii) no separation or purification treatment is performed after said preparing the first intermediate and before said preparing tralkoxydim;
wherein the structural formula of the first intermediate is as follows:
the structural formula of the second intermediate is as follows:
the structural formula of the tralkoxydim is as follows:
the method for preparing the tralkoxydim provided by the invention takes 2,4, 6-trimethylbenzaldehyde as a starting material, acetone, diethyl malonate, propionyl chloride, ethoxyamine and the like are added into the starting material according to a certain proportion to prepare the tralkoxydim, condensation and rearrangement reactions are carried out simultaneously in the process of preparing a second intermediate, components in a reaction container are identified after the tralkoxydim is prepared, separation or purification treatment is not carried out after the first intermediate is prepared and before the tralkoxydim is prepared, the reaction container is not replaced (one-pot method), the steps of multiple separation, purification, transfer and charging in the existing preparation method are omitted, time and labor are saved, a large number of materials are saved, the consumption of reagents is reduced, and a large number of costs are saved.
Referring to fig. 2, fig. 2 is a process flow diagram of a process for preparing tralkoxydim according to an embodiment of the present invention. In some embodiments of the present invention, the,
the step S1 comprises the following steps: reacting 2,4, 6-trimethylbenzaldehyde with acetone under basic conditions to prepare a first intermediate;
the step S2 comprises the following steps: the product obtained in the step S1 does not need to be separated or purified in advance, and the first intermediate is firstly reacted with diethyl malonate and sodium methoxide solution; then simultaneously adding 4-dimethylamino pyridine and propionyl chloride for condensation and rearrangement reaction, and adding acid and alkali after the reaction to prepare a second intermediate;
the step S3 comprises the following steps: the product obtained in the step S2 does not need to be separated or purified in advance, and the second intermediate is reacted with an ethoxyamine solution to prepare a crude raw trimethylbenzene clomazone;
the method further comprises the following steps:
and S4, recrystallizing the crude technical product of the tralkoxydim without separating or purifying the product obtained in the step S3 in advance to prepare the refined technical product of the tralkoxydim.
In the step S2 of the embodiment of the present invention, 4-dimethylaminopyridine and propionyl chloride are added simultaneously, so as to ensure that the rearrangement reaction catalyzed by 4-dimethylaminopyridine is performed while the condensation reaction is performed with propionyl chloride, and ensure that the condensation reaction and the rearrangement reaction are performed simultaneously in the process of synthesizing the second intermediate. Solves the problems of complex method steps, lower product yield, time and labor consumption caused by step-by-step reaction in the existing preparation method.
The alkaline condition in step S1 of the embodiment of the present invention may be adding sodium hydroxide or potassium hydroxide; the sodium methoxide solution in the S2 is a methanol solution of sodium methoxide; the acid can be hydrochloric acid or sulfuric acid, and the alkali can be sodium hydroxide or potassium hydroxide; the ethoxyamine solution in the step S3 can be an aqueous solution of ethoxyamine, or a dichloromethane solution of ethoxyamine, or a dichloroethane solution of ethoxyamine; the solvent selected for recrystallization in S4 may be isopropanol, n-propanol, methanol, or ethanol.
In some embodiments, the S1 step includes:
putting 2,4, 6-trimethyl benzaldehyde, acetone, water and sodium hydroxide solution into a four-mouth bottle, heating to reflux while stirring, and keeping the temperature within the range of 72-76 ℃ for 4 hours; removing the solvent at normal pressure, cooling to below 70 ℃, adding toluene, layering, refluxing and dewatering the toluene layer, and cooling to 25-30 ℃ to obtain a toluene solution of the first intermediate.
In some embodiments, the S2 step includes:
without separating or purifying the product obtained in the step S1 in advance, sequentially adding a toluene solution of the first intermediate obtained in the step S1, diethyl malonate and sodium methoxide into a four-mouth bottle, slowly heating to reflux while stirring, and keeping the temperature above 66 ℃ for reflux for 1h; after the solvent is removed to 110 ℃, keeping reflux for 30min, synchronously adding toluene with the same volume as the solvent, if the temperature is reduced, continuously removing the solvent to 110 ℃, and if the temperature is constant, finishing the desolventizing; cooling to below 50 deg.C, adding 4-dimethylaminopyridine and propionyl chloride, heating to 90 deg.C, and keeping the temperature for 8 hr; cooling to 50 ℃, adding water, layering, removing a water layer, adding liquid alkali and water into a toluene layer, keeping the temperature within the range of 84-86 ℃ for refluxing for 4h, cooling to below 50 ℃, layering, removing an organic phase, adding petroleum ether and hydrochloric acid with the temperature of 60-90 ℃ into a water phase, slowly heating to reflux, keeping the temperature at 60 ℃ for refluxing for 2h, cooling to 55-60 ℃, thermally layering, removing the water phase, washing the organic phase with water, and adding a small amount of alkali to adjust the pH to 6-7 to obtain a petroleum ether solution of a second intermediate.
According to the embodiment of the invention, after propionyl chloride is added in the process of synthesizing the second intermediate, water is removed through multiple layering instead of direct water washing, and organic solvent petroleum ether is added, so that the problem that the water washing is easy to generate a serious layering emulsification phenomenon after propionyl chloride is added in the process of synthesizing the second intermediate is effectively solved.
In some embodiments, the S3 step includes:
the product obtained in the step S2 does not need to be separated or purified in advance, petroleum ether solution and ethoxyamine of the second intermediate obtained in the step S2 are put into a four-mouth bottle, the temperature is raised to 50 ℃, the temperature is kept for 4 hours, and the sample is taken until the sample is qualified, namely, the content of the second intermediate is less than 1 percent in the content determination of the liquid chromatography normalization method; adjusting pH to 4-5, removing water phase by layering, removing solvent from organic phase under normal pressure, concentrating, cooling to below 10 deg.C, and filtering; and continuously washing the obtained material twice by using a mixed solution of petroleum ether and acetone, and drying to obtain a crude product of the tralkoxydim.
In some embodiments, the S4 step includes:
and (4) adding isopropanol into the crude drug for recrystallization without separating or purifying the product obtained in the step S3 in advance, heating to 60 ℃ for dissolution, cooling to-10 ℃, preserving heat for more than 4 hours, and filtering to obtain the refined bulk drug of the tralkoxydim.
In some embodiments, in said S1 step, the concentrations of said 2,4, 6-trimethylbenzaldehyde and acetone are each 99% m/m, the concentration of the sodium hydroxide solution is 30% m/m, the weight ratio of said 2,4, 6-trimethylbenzaldehyde, acetone, sodium hydroxide solution, water is 18:100:1:60.
in some embodiments, in the S2 step, the concentrations of diethyl malonate, sodium methoxide solution, propionyl chloride are respectively 98% m/m, 20% m/m, 98% m/m, the weight ratio of diethyl malonate, sodium methoxide solution, propionyl chloride being 21.2:36.2:12.6.
in some embodiments, the concentration of the ethoxyamine solution in the S3 step is 25%: 13.9.
in some embodiments, the concentration of the 4-dimethylaminopyridine is 99% m/m, and the 4-dimethylaminopyridine is added in an amount of 0.9g.
In some embodiments, the weight ratio of the petroleum ether to the acetone in the mixed solution of petroleum ether and acetone is 14:1.
in some embodiments, the weight ratio of the crude drug substance to isopropanol is 1.
According to the preparation method disclosed by the embodiment of the invention, by selecting a proper solvent and strictly executing the sequence of adding materials, the reaction speed is increased, the generation of byproducts in the reaction process is avoided, and the content of the product is increased.
To further illustrate the present invention, the following examples are given to illustrate the above embodiments more specifically for the purpose of further understanding by those skilled in the art.
Example one
In this example, the one-pot process was used to prepare tralkoxydim, with the following steps being performed without prior separation or purification of the product from the previous step.
1. Synthesis of the first intermediate
The synthetic route of the first intermediate is as follows:
TABLE 1 first intermediate Synthesis feeding Table
The operation steps are as follows:
adding 2,4, 6-trimethylbenzaldehyde, acetone, water and sodium hydroxide solution into a four-mouth bottle according to the actual adding amount shown in the table 1, heating to reflux under stirring, and keeping the temperature within the range of 72-76 ℃ for refluxing for 4 hours; removing about 90mL of solvent at normal pressure, cooling to below 70 ℃, adding toluene, layering, refluxing and dewatering the toluene layer, and cooling to 25-30 ℃ to obtain a toluene solution of the first intermediate.
2. Synthesis of the second intermediate
The synthetic route of the second intermediate is as follows:
TABLE 2 Synthesis of the second intermediate feeding Table
The method comprises the following operation steps:
sequentially adding the toluene solution of the first intermediate obtained in the step 1 (synthesis of the first intermediate), diethyl malonate and sodium methoxide into a four-necked flask according to the actual adding amount shown in table 2, slowly heating to reflux while stirring, and keeping the temperature at 66 ℃ or higher for reflux for 1h; after the solvent is removed to 110 ℃, keeping reflux for 30min, synchronously adding toluene with the same volume as the solvent, if the temperature is reduced, continuously removing the solvent to 110 ℃, and if the temperature is constant, finishing the desolventizing; cooling to below 50 deg.C, adding 4-Dimethylaminopyridine (DMAP) and propionyl chloride, heating to 90 deg.C, and keeping the temperature for 8 hr; cooling to 50 ℃, adding 100g of water, layering, removing a water layer, adding 75mL of liquid caustic soda and water into a toluene layer, keeping the temperature within the range of 84-86 ℃ for refluxing for 4h, cooling to below 50 ℃, layering, removing an organic phase, adding 60-90 ℃ petroleum ether and hydrochloric acid into a water phase, slowly heating to reflux, keeping the temperature at 60 ℃ for refluxing for 2h, cooling to 55-60 ℃, thermally layering, removing the water phase, washing the organic phase with water, and adding a small amount of sodium hydroxide to adjust the pH to 6-7 to obtain a petroleum ether solution of a second intermediate. The content of the second intermediate was about 10%, and the yield was 80% (based on trimesic aldehyde). 1 H NMR analysis to determine the structure, FIG. 3 for the second intermediate 1 H NMR result chart.
3. Synthesis of tralkoxydim
The synthetic route of the tralkoxydim is as follows:
table 3 table for synthetic feeding of raw drugs
The method comprises the following operation steps:
adding the petroleum ether solution of the second intermediate obtained in the step 2 (synthesis of the second intermediate) and an ethanolamine aqueous solution into a four-mouth bottle according to the actual adding amount shown in the table 3, heating to 50 ℃, keeping the temperature for 4 hours, and sampling until the second intermediate is qualified, namely, the content of the second intermediate is less than 1% in the content determination of the liquid chromatography normalization method; after the reaction is finished, adding water and about 2g of hydrochloric acid, adjusting the pH to 4-5, removing a water phase by layering, removing a solvent from an organic phase at normal pressure, concentrating, cooling to below 10 ℃, and filtering; and continuously washing the obtained material twice by using 20mL of mixed solution of petroleum ether and acetone (the weight ratio of the petroleum ether to the acetone is 14. Quantitative determination by an external standard method, wherein the yield of crude drug is 90%, and the content of crude drug is about 90%.
4. Refining crude drug
Adding isopropanol into the crude drug obtained in the step 3 (synthesis of the tralkoxydim) for recrystallization, wherein the weight ratio of the crude drug to the isopropanol is 1. The yield of the refined raw medicine is 95 percent, and the content is more than 98 percent. 1 H NMR analysis to determine its structure, and FIG. 4 shows the crude Tritoxylzone 1 H NMR detection result chart.
Although the present invention is disclosed above, the present invention is not limited thereto. Various changes and modifications may be effected by one skilled in the art without departing from the spirit and scope of the invention, as defined in the appended claims.
Claims (11)
1. A process for preparing tralkoxydim, comprising:
s1, preparing a first intermediate by using 2,4, 6-trimethyl benzaldehyde and acetone;
s2, without separating or purifying the product obtained in the step S1 in advance, sequentially adding the toluene solution of the first intermediate obtained in the step S1, diethyl malonate and sodium methoxide into a four-mouth bottle, slowly heating to reflux while stirring, and keeping the temperature above 66 ℃ for reflux for 1h; after the solvent is removed to 110 ℃, keeping reflux for 30min, synchronously adding toluene with the same volume as the solvent, if the temperature is reduced, continuously removing the solvent to 110 ℃, and if the temperature is constant, finishing the desolventizing; cooling to below 50 deg.C, adding 4-dimethylaminopyridine and propionyl chloride, heating to 90 deg.C, and keeping the temperature for 8h; cooling to 50 ℃, adding water, layering, removing a water layer, adding liquid alkali and water into a toluene layer, keeping the temperature within 84-86 ℃ for reflux for 4 hours, cooling to below 50 ℃, layering, removing an organic phase, adding petroleum ether and hydrochloric acid with the temperature of 60-90 ℃ into a water phase, slowly heating to reflux, keeping the temperature at 60 ℃ for reflux for 2 hours, cooling to 55-60 ℃, thermally layering, removing the water phase, washing the organic phase with water, and adding a small amount of alkali to adjust the pH to 6-7 to obtain a petroleum ether solution of a second intermediate;
s3, preparing the tralkoxydim by utilizing the second intermediate and the ethoxyamine;
in the process of preparing the second intermediate, condensation and rearrangement reactions are carried out simultaneously; (ii) no separation or purification treatment is performed after said preparing the first intermediate and before said preparing tralkoxydim;
wherein the structural formula of the first intermediate is as follows:
the structural formula of the second intermediate is as follows:
the structural formula of the tralkoxydim is as follows:
2. the method of claim 1,
the step S1 comprises the following steps: reacting 2,4, 6-trimethylbenzaldehyde with acetone under basic conditions to prepare a first intermediate;
the step S3 comprises the following steps: the second intermediate reacts with the ethoxyamine solution without separating or purifying the product obtained in the step S2 in advance to prepare a crude trimethylbenzene clomazone;
the method further comprises the following steps:
and S4, recrystallizing the crude tralkoxydim technical product without separating or purifying the product obtained in the step S3 in advance to prepare the refined tralkoxydim technical product.
3. Method according to claim 1 or 2, characterized in that said S1 step comprises:
2,4, 6-trimethyl benzaldehyde, acetone, water and sodium hydroxide solution are put into a four-mouth bottle, the temperature is raised to reflux under stirring, and the reflux is kept for 4 hours within the range of 72 to 76 ℃; removing the solvent at normal pressure, cooling to below 70 ℃, adding toluene, layering, refluxing and dewatering the toluene layer, and cooling to 25-30 ℃ to obtain a toluene solution of the first intermediate.
4. Method according to claim 1 or 2, characterized in that said step S3 comprises:
the product obtained in the step S2 does not need to be separated or purified in advance, the petroleum ether solution of the second intermediate obtained in the step S2 and the ethoxyamine are put into a four-mouth bottle, the temperature is raised to 50 ℃, the temperature is kept for 4 hours, and the sample is taken until the product is qualified, namely, the content of the second intermediate is less than 1 percent in the content determination of the liquid chromatography normalization method; adjusting pH to 4-5, removing water phase by layering, removing solvent from organic phase at normal pressure, concentrating, cooling to below 10 deg.C, and filtering; and continuously washing the obtained material twice by using a mixed solution of petroleum ether and acetone, and drying to obtain a crude drug of the tralkoxydim.
5. The method of claim 2, wherein the step S4 comprises:
and (3) adding isopropanol into the crude drug for recrystallization without separating or purifying the product obtained in the step S3 in advance, heating to 60 ℃ for dissolution, cooling to-10 ℃, preserving heat for more than 4 hours, and filtering to obtain the refined pseudocumene hydroperoxide crude drug.
6. The method according to claim 3, wherein the concentrations of said 2,4, 6-trimethylbenzaldehyde and acetone are each 99% m/m, the concentration of said sodium hydroxide solution is 30% m/m, said 2,
the weight ratio of 4, 6-trimethyl benzaldehyde to acetone to sodium hydroxide solution to water is 18:100:1:60.
7. the method according to claim 1, wherein in the step S2, the concentrations of said diethyl malonate, sodium methoxide solution and propionyl chloride are respectively 98% m/m, 20% m/m, 98% in a weight ratio of 21.2:36.2:12.6.
8. the method of claim 2, wherein the concentration of the ethoxyamine solution in step S3 is 25% m/m, and the weight ratio of the product from step S2 to the ethoxyamine solution is 74:13.9.
9. the method according to claim 1, wherein the concentration of 4-dimethylaminopyridine is 99% m/m, the amount of 4-dimethylaminopyridine added being 0.9g.
10. The method according to claim 4, wherein the weight ratio of the petroleum ether to the acetone in the mixed solution of the petroleum ether and the acetone is 14:1.
11. the method of claim 5, wherein the weight ratio of the crude drug substance to the isopropanol is 1.
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| US4717418A (en) * | 1981-11-20 | 1988-01-05 | Ici Australia Limited | Herbicidal cyclohexane-1,3-dione derivatives |
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| US4717418A (en) * | 1981-11-20 | 1988-01-05 | Ici Australia Limited | Herbicidal cyclohexane-1,3-dione derivatives |
| GB2124198A (en) * | 1982-06-18 | 1984-02-15 | Ici Plc | Plant growth regulating method |
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