CN113024411A - Preparation method of tralkoxydim - Google Patents
Preparation method of tralkoxydim Download PDFInfo
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- CN113024411A CN113024411A CN201911350659.9A CN201911350659A CN113024411A CN 113024411 A CN113024411 A CN 113024411A CN 201911350659 A CN201911350659 A CN 201911350659A CN 113024411 A CN113024411 A CN 113024411A
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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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- C07C45/61—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 by using 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 separation or purification treatment is performed after said preparing the first intermediate and before said preparing tralkoxydim. The invention 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 multiple separation, purification, transfer, feeding and the like in the existing preparation method, saves time and labor, reduces the consumption of reagents, saves a large amount of cost, and solves the problems of complicated steps, lower 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 C20H27NO3Structural formula is
Belongs to oxime herbicides.
At present, the method for preparing the tralkoxydim basically comprises the steps of firstly condensing 2,4, 6-trimethylbenzaldehyde and acetone to obtain 1- (2,4, 6-trimethylphenyl) -1-buten-3-one, then separating a product, reacting the product with diethyl malonate, hydrolyzing, cyclizing and decarboxylating to obtain 3-hydroxy-5- (2,4, 6-trimethylphenyl) -cyclohex-2-en-1-one, separating the product again, then reacting with propionic anhydride to obtain 3-hydroxy-5- (2,4, 6-trimethylphenyl) -2-propionyl-cyclohex-2-en-1-one, and finally reacting with ethoxyamine hydrochloride to obtain the tralkoxydim.
The above synthesis process generally needs to be carried out by steps of product separation, purification, transfer, feeding and the like for many times, the steps are complicated, material loss is caused in the processes of product separation, purification and transfer for many times, and 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 a relatively serious layering emulsification phenomenon is easy to occur. 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 the second intermediate.
In order to solve the technical problem, the present invention provides a method for preparing tralkoxydim, which comprises:
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:
optionally, the step of S1 includes: reacting 2,4, 6-trimethylbenzaldehyde with acetone under basic conditions to prepare a first intermediate;
the step of S2 includes: without separating or purifying the product obtained in the step S1 in advance, 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 of S3 includes: without separating or purifying the product obtained in step S2 in advance, reacting the second intermediate with an ethoxyamine solution to prepare a crude tralkoxydim technical product;
the method further comprises the following steps:
s4, recrystallizing the crude technical product of the tralkoxydim without separating or purifying the product obtained in the step S3 in advance, and preparing the refined technical product of the tralkoxydim.
Optionally, the step of S1 includes:
putting 2,4, 6-trimethyl benzaldehyde, acetone, water and a 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 of reflux; and 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 step of S2 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 while stirring, and keeping the temperature at over 66 ℃ for reflux for 1 h; 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 step of S3 includes:
the product obtained in the step S2 is not required 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 increased 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 of S4 includes:
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.
Optionally, the concentration of the 2,4, 6-trimethylbenzaldehyde and acetone is 99% m/m, the concentration of the sodium hydroxide solution is 30% m/m, and the weight ratio of the 2,4, 6-trimethylbenzaldehyde to acetone to the sodium hydroxide solution to water is 18: 100: 1: 60.
optionally, in the step S2, the concentrations of the diethyl malonate, the sodium methoxide solution and the propionyl chloride are 98% m/m, 20% m/m and 98% m/m, respectively, and the weight ratio of the diethyl malonate, the sodium methoxide solution and the propionyl chloride is 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 0.9 g.
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 drug substance to the isopropanol is 1: 2.
Compared with the prior art, the invention has the following advantages:
in the preparation method of the tralkoxydim, condensation and rearrangement reactions are carried out simultaneously 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 invention1H NMR detection result chart;
FIG. 4 shows a refined bulk drug of tralkoxydim in example one of the present invention1H NMR detection result chart.
Detailed Description
As described in the background art, in the methods for preparing tralkoxydim in the prior art, 2,4, 6-trimethylbenzaldehyde is used as a starting material, and the tralkoxydim is prepared by reacting with acetone, diethyl malonate, propionic anhydride, ethoxyamine and the like through operations of product separation, purification, transfer, feeding and the like for many times. 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 process for 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 raw material, acetone, diethyl malonate, propionyl chloride, ethoxyamine and the like are added into the starting raw 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 of S1 includes: reacting 2,4, 6-trimethylbenzaldehyde with acetone under basic conditions to prepare a first intermediate;
the step of S2 includes: without separating or purifying the product obtained in the step S1 in advance, 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 of S3 includes: without separating or purifying the product obtained in step S2 in advance, reacting the second intermediate with an ethoxyamine solution to prepare a crude tralkoxydim technical product;
the method further comprises the following steps:
s4, recrystallizing the crude technical product of the tralkoxydim without separating or purifying the product obtained in the step S3 in advance, and preparing the refined technical product of the tralkoxydim.
In step S2 of the embodiment of the present invention, 4-dimethylaminopyridine and propionyl chloride are added simultaneously, so as to ensure that a rearrangement reaction catalyzed by 4-dimethylaminopyridine is performed while a condensation reaction is performed with propionyl chloride, and to ensure that the condensation and rearrangement reactions are performed simultaneously during the synthesis of the second intermediate. Solves the problems of complicated method steps, low 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 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 may 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 step of S1 includes:
putting 2,4, 6-trimethyl benzaldehyde, acetone, water and a 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 of reflux; and 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 step of S2 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 while stirring, and keeping the temperature at over 66 ℃ for reflux for 1 h; 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 not directly washed, and the problem of serious layering emulsification phenomenon easily caused by water washing after propionyl chloride is added in the process of synthesizing the second intermediate is effectively solved through multiple layering, moisture removal and addition of organic solvent petroleum ether.
In some embodiments, the step of S3 includes:
the product obtained in the step S2 is not required 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 increased 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.
In some embodiments, the step of S4 includes:
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.
In some embodiments, in the step S1, the concentrations of the 2,4, 6-trimethylbenzaldehyde and acetone are 99% m/m, the concentration of the sodium hydroxide solution is 30% m/m, and the weight ratio of the 2,4, 6-trimethylbenzaldehyde to acetone to the sodium hydroxide solution to water is 18: 100: 1: 60.
in some embodiments, in the step S2, the concentrations of the diethyl malonate, the sodium methoxide solution and the propionyl chloride are 98% m/m, 20% m/m and 98% m/m, respectively, and the weight ratio of the diethyl malonate, the sodium methoxide solution and the propionyl chloride is 21.2: 36.2: 12.6.
in some embodiments, 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.
in some embodiments, the 4-dimethylaminopyridine is present at a concentration of 99% m/m and the 4-dimethylaminopyridine is added in an amount of 0.9 g.
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: 2.
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:
first intermediate body
TABLE 1 first intermediate Synthesis feeding Table
The method comprises the following operation steps:
adding 2,4, 6-trimethylbenzaldehyde, acetone, water and a 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 synthetic feed table for the second intermediate
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 1 h; 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, and adding 4-Dimethylaminopyridine (DMAP) and propionyl chlorideHeating to 90 ℃, and keeping the temperature for 8 hours; 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 84-86 ℃ for backflow 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 backflow, keeping the temperature at 60 ℃ for backflow 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).1H NMR analysis to determine the structure, FIG. 3 for the second intermediate1H NMR detection 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 hydrochloric acid of about 2g, 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: 1), and drying to obtain a crude raw pesticide of the tralkoxydim. 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 (the synthesis of the tralkoxydim) for recrystallization, wherein the weight ratio of the crude drug to the isopropanol is 1:2, heating to 60 ℃, dissolving, cooling to-10 ℃, preserving heat for more than 4 hours, and filtering to obtain the refined tralkoxydim drug. The yield of the refined raw medicine is 95 percent, and the content is more than 98 percent.1H NMR analysis to determine its structure, and FIG. 4 shows the structure of refined bulk drug of tralkoxydim1H 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 therein by one skilled in the art without departing from the spirit and scope of the invention as defined in the appended claims.
Claims (12)
1. A process for preparing tralkoxydim, 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:
2. the method of claim 1,
the step of S1 includes: reacting 2,4, 6-trimethylbenzaldehyde with acetone under basic conditions to prepare a first intermediate;
the step of S2 includes: without separating or purifying the product obtained in the step S1 in advance, 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 of S3 includes: without separating or purifying the product obtained in step S2 in advance, reacting the second intermediate with an ethoxyamine solution to prepare a crude tralkoxydim technical product;
the method further comprises the following steps:
s4, recrystallizing the crude technical product of the tralkoxydim without separating or purifying the product obtained in the step S3 in advance, and preparing the refined technical product of the tralkoxydim.
3. The method according to claim 1 or 2, wherein the step S1 includes:
putting 2,4, 6-trimethyl benzaldehyde, acetone, water and a 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 of reflux; and 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. The method according to claim 1 or 2, wherein the step S2 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 while stirring, and keeping the temperature at over 66 ℃ for reflux for 1 h; 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.
5. The method according to claim 1 or 2, wherein the step S3 includes:
the product obtained in the step S2 is not required 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 increased 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.
6. The method of claim 2, wherein the step of S4 includes:
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.
7. The method according to claim 3, wherein the concentrations of the 2,4, 6-trimethylbenzaldehyde and acetone are 99% m/m, the concentration of the sodium hydroxide solution is 30% m/m, and the weight ratio of the 2,4, 6-trimethylbenzaldehyde to acetone to sodium hydroxide solution to water is 18: 100: 1: 60.
8. the method according to claim 2, wherein in the step S2, the concentrations of the diethyl malonate, the sodium methoxide solution and the propionyl chloride are respectively 98% m/m, 20% m/m and 98% m/m, and the weight ratio of the diethyl malonate, the sodium methoxide solution and the propionyl chloride is 21.2: 36.2: 12.6.
9. the method as claimed in claim 2, wherein 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.
10. the method of claim 2, wherein the concentration of the 4-dimethylaminopyridine is 99% m/m and the 4-dimethylaminopyridine is added in an amount of 0.9 g.
11. The method according to claim 5, 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.
12. the method of claim 6, wherein the weight ratio of the crude drug substance to the isopropanol is 1: 2.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2124198A (en) * | 1982-06-18 | 1984-02-15 | Ici Plc | Plant growth regulating method |
| EP0128642A1 (en) * | 1983-05-18 | 1984-12-19 | Imperial Chemical Industries Plc | Herbicidal compositions |
| US4717418A (en) * | 1981-11-20 | 1988-01-05 | Ici Australia Limited | Herbicidal cyclohexane-1,3-dione derivatives |
-
2019
- 2019-12-24 CN CN201911350659.9A patent/CN113024411B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| EP0128642A1 (en) * | 1983-05-18 | 1984-12-19 | Imperial Chemical Industries Plc | Herbicidal compositions |
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| CN116041156A (en) * | 2023-01-29 | 2023-05-02 | 南京合创药业有限公司 | Synthesis method of 5- (2, 4, 6-trimethyl phenyl) -2-propionyl-3-hydroxy-2-cyclohexene-1-one |
| CN116041156B (en) * | 2023-01-29 | 2024-04-05 | 南京合创药业有限公司 | Synthesis method of 5- (2, 4, 6-trimethyl phenyl) -2-propionyl-3-hydroxy-2-cyclohexene-1-one |
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