CN112961083A - Synthesis method of clethodim impurities - Google Patents
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Abstract
The invention provides a method for synthesizing clethodim impurities, which comprises the following steps: dissolving methyl crotonate in DMF, sequentially adding ethanethiol and potassium carbonate, heating, and reacting in a stirring process to obtain an ethylsulfanylmethyl ester compound; reacting an ethylthio methyl ester compound with lithium hydroxide monohydrate to obtain ethylthio acid; reacting ethyl sulfo acid with dichloromethane to obtain ethyl sulfo acyl chloride; slowly dripping ethylsulfonyl chloride into reaction liquid of n-butyl lithium, THF and triketone compound to react to obtain diketone; and oxidizing the diketone with hydrogen peroxide and reacting with chloramine to generate the clethodim impurity. The synthesis method of clethodim impurities provided by the invention can conveniently obtain a large amount of clethodim impurities, avoids huge workload of extracting impurities from production samples, plays a promoting role in preparation of impurity standard products and quality control of clethodim products, and can be popularized in a large scale.
Description
Technical Field
The invention relates to the technical field of medicine synthesis, and particularly relates to a method for synthesizing clethodim impurities.
Background
Clethodim with molecular formula C17H26ClNO3S is a broad-spectrum post-emergence herbicide for preventing and killing gramineous weeds in broad-leaved crops, which is proposed by Chevren chemical company in the United states, has excellent selectivity, has strong killing effect on various annual and perennial weeds, and is safe to dicotyledonous crops. The clethodim is quickly absorbed by leaves after stem and leaf treatment and is conducted to meristematic tissue, and the clethodim acts in sensitive plants by inhibiting the biosynthesis of branched chain fatty acid and flavonoid compounds, so that the division of plant cells is damaged, the activity of plant meristematic tissue is inhibited, and the growth of plants is delayed.
The clethodim impurity (the structural formula is shown in the formula I) is an impurity which cannot be avoided in the clethodim production process, is difficult to control in the reaction process, and finally remains in the clethodim product to influence the product quality, so that the clethodim impurity does not meet the international requirement on the limit of pesticide impurities. No literature report is available on a synthetic method of clethodim impurities, and the impurities are mainly obtained by an extraction method in the market and are expensive. Therefore, the method for synthesizing the clethodim impurity has important significance for preparing the impurity standard substance and controlling the quality of the clethodim product.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides a method for synthesizing clethodim impurities, by adopting the method, a large amount of clethodim impurities can be conveniently obtained, the huge workload of extracting the impurities from a production sample is avoided, and good technical support is provided for the production of clethodim.
In order to achieve the purpose, the invention adopts the following technical scheme:
the invention provides a method for synthesizing clethodim impurities, which comprises the following steps:
dissolving methyl crotonate in N, N-Dimethylformamide (DMF), sequentially adding ethanethiol and potassium carbonate, heating, and reacting in a stirring process; after the reaction is finished, cooling, pouring the reaction liquid with the residual ethanethiol removed into a hydrochloric acid solution, extracting, washing and drying to obtain an intermediate product 2 (an ethylthio methyl ester compound);
step two, mixing the intermediate product 2 with Tetrahydrofuran (THF) and methanol to obtain a mixed solution; dissolving lithium hydroxide monohydrate in water, dropwise adding the solution into the mixed solution, and reacting at room temperature for 1.5 to 3 hours to obtain an intermediate product 3 (ethyl amino acid);
step three, mixing the intermediate product 3 with Dichloromethane (DCM), sequentially adding DMF and thionyl chloride, and stirring under reflux to obtain an intermediate product 4 (ethylsulfonyl chloride);
step four, mixing N-butyllithium and THF, slowly adding a triketone compound, stirring for a period of time, slowly dropwise adding the intermediate product 4, reacting under stirring, adding a saturated ammonium chloride aqueous solution, slowly adding 1N HCl, adjusting the pH value to 3-5, extracting the water phase with MTBE for three times, combining the organic phases, drying with anhydrous sodium sulfate, spin-drying, and separating by column chromatography to obtain an intermediate product 5;
step five, dissolving the intermediate product 5 in acetonitrile, cooling to below 0 ℃, slowly adding hydrogen peroxide, stirring at room temperature, and reacting for 16-19 hours to obtain an intermediate product 6;
and step six, dissolving the intermediate product 6, cooling to below-40 ℃, slowly dropwise adding chloramine dissolved in methanol, stirring, heating, and after the reaction is finished, performing column chromatography separation to obtain the clethodim impurity.
Further, the molar ratio of the methyl crotonate to the ethanethiol to the potassium carbonate in the first step is 1:1: 0.1.
Further, in the step one, the temperature is heated to 60-70 ℃, and the reaction time is 16-20 hours; preferably, the heating is to 70 ℃ and the reaction time is 18 hours.
Further, in step one, after the reaction is completed, the temperature is reduced, the water pump is used for reducing the pressure and evaporating the residual ethanethiol at 60 ℃, the reaction solution is poured into 1N HCl, the pH value is measured to be 1-2, the water phase is extracted twice by methyl tert-butyl ether (MTBE), the organic phase is washed four times, dried by anhydrous sodium sulfate and dried in a rotary manner to obtain an intermediate product 2.
Further, in the second step, the molar ratio of the intermediate product 2 to the lithium hydroxide monohydrate is 1: (2.5-3.5), preferably 1: 3.
Furthermore, in the third step, the molar ratio of the intermediate product 3, DMF and thionyl chloride is 1:0.05: 2.
Further, the stirring time in the third step is 1 to 3 hours, preferably 2 hours.
Furthermore, in the fourth step, the molar using ratio of the n-butyl lithium to the triketone compound to the intermediate product 4 is 3:1: 1.
Further, in the fifth step, the concentration of the hydrogen peroxide is 30%, and the addition amount of the hydrogen peroxide enables the intermediate product 5 and H in the reaction to be2O2Preferably such that the molar ratio of intermediate 5 to H in the reaction is 1 (2.5-4)2O2In a molar ratio of 1: 3.
Further, in the sixth step, the molar ratio of the intermediate product 6 to the chloramine is 1:1-1.5, preferably 1: 1.1.
Further, in the sixth step, the temperature is increased to 30-50 ℃, preferably to 40 ℃; the reaction time is 4 to 6 hours, preferably 5 hours.
By adopting the technical scheme, compared with the prior art, the invention has the following technical effects:
the synthesis method of clethodim impurities provided by the invention can conveniently obtain a large amount of clethodim impurities, avoids huge workload of extracting impurities from production samples, plays a promoting role in preparation of impurity standard products and quality control of clethodim products, and can be popularized in a large scale.
Drawings
Figure 1 is a HNMR map of the impurity synthesized in one embodiment of the present invention.
Detailed Description
The invention provides a method for synthesizing clethodim impurities, which comprises the following steps:
step one, dissolving methyl crotonate in DMF, then sequentially adding ethanethiol and potassium carbonate, heating, and reacting in a stirring process; after the reaction is finished, cooling, pouring the reaction liquid with the residual ethanethiol removed into a hydrochloric acid solution, extracting, washing and drying to obtain an intermediate product 2 (an ethylthio methyl ester compound);
step two, mixing the intermediate product 2 with THF and methanol to obtain a mixed solution; dissolving lithium hydroxide monohydrate in water, dropwise adding the solution into the mixed solution, and reacting at room temperature for 1.5 to 3 hours to obtain an intermediate product 3 (ethyl amino acid);
step three, mixing the intermediate product 3 with DCM, then adding DMF and thionyl chloride in sequence, and stirring under reflux to obtain an intermediate product 4 (ethylsulfonyl chloride);
step four, mixing N-butyllithium and THF, slowly adding a triketone compound, stirring for a period of time, slowly dropwise adding the intermediate product 4, reacting under stirring, adding a saturated ammonium chloride aqueous solution, slowly adding 1N HCl, adjusting the pH value to 3-5, extracting the water phase with MTBE for three times, combining the organic phases, drying with anhydrous sodium sulfate, spin-drying, and separating by column chromatography to obtain an intermediate product 5;
step five, dissolving the intermediate product 5 in acetonitrile, cooling to below 0 ℃, slowly adding hydrogen peroxide, stirring at room temperature, and reacting for 16-19 hours to obtain an intermediate product 6;
and step six, dissolving the intermediate product 6, cooling to below-40 ℃, slowly dropwise adding chloramine dissolved in methanol, stirring, heating, and after the reaction is finished, performing column chromatography separation to obtain the clethodim impurity.
In a preferred embodiment of the present invention, the molar ratio of methyl crotonate, ethanethiol and potassium carbonate in step one is 1:1: 0.1.
In a preferred embodiment of the invention, in step one, the temperature is heated to 60-70 ℃ and the reaction time is 16-20 hours; more preferably, the heating is to 70 ℃ and the reaction time is 18 hours.
In a preferred embodiment of the present invention, in step one, after the reaction is completed, the temperature is reduced, the water pump is depressurized to 60 ℃ to evaporate the residual ethanethiol, the reaction solution is poured into 1N HCl, the pH is measured to be 1-2, the aqueous phase is extracted twice with methyl tert-butyl ether (MTBE), the organic phase is washed four times with water, dried over anhydrous sodium sulfate, and spun to obtain intermediate product 2.
In a preferred embodiment of the present invention, in step two, the molar ratio of the intermediate product 2 to the lithium hydroxide monohydrate is 1: (2.5-3.5), more preferably 1: 3.
In a preferred embodiment of the present invention, in step three, the molar ratio of the intermediate product 3, DMF and thionyl chloride is 1:0.05: 2.
In a preferred embodiment of the present invention, the stirring time in step three is 1 to 3 hours, more preferably 2 hours.
In a preferred embodiment of the present invention, in step four, the molar ratio of n-butyllithium, the triketone compound and the intermediate 4 is 3:1: 1.
In a preferred embodiment of the present invention, in the fifth step, the concentration of the hydrogen peroxide solution is 30%, and the hydrogen peroxide solution is added in an amount such that the intermediate product 5 and H in the reaction are reacted2O2Is 1:2.5-4, more preferably so that intermediate 5 and H are reacted in the reaction2O2In a molar ratio of 1: 3.
In a preferred embodiment of the present invention, in step six, the molar ratio of intermediate product 6 to chloramine is 1:1-1.5, more preferably 1: 1.1.
In a preferred embodiment of the invention, the temperature in step six is raised to 30-50 ℃, preferably to 40 ℃; the reaction time is 4 to 6 hours, more preferably 5 hours.
The present invention will be described in detail and specifically with reference to the following examples and drawings so as to provide a better understanding of the invention, but the following examples do not limit the scope of the invention.
In the examples, the conventional methods were used unless otherwise specified, and reagents used were those conventionally commercially available or formulated according to the conventional methods without specifically specified.
Example 1
This example provides a method for synthesizing clethodim impurities, which includes the following steps:
step one, synthesizing intermediate product 2-ethylthio methyl ester compound
In a 500ml three-necked flask, 81.9g of methyl crotonate (818mmol,1.0eq) and DMF (82ml) were mixed, followed by addition of 50.8g of ethanethiol (818mmol,1.0eq) and 11.3g of potassium carbonate (81.8mmol,0.1eq), heating to about 70 ℃ and stirring for 18 hours. Cooling, reducing pressure by a water pump, steaming residual ethanethiol at 60 ℃, pouring the reaction liquid into 1N HCl, measuring the pH value to be 1-2, extracting the water phase twice by MTBE, washing the organic phase four times by water, drying by anhydrous sodium sulfate, and spin-drying to obtain an intermediate product 2 which is yellow liquid: 106g, yield: 80 percent.
1H NMR(300MHz,CDCl3)δ1.26(t,J＝7.4Hz,3H),1.33(d,J＝6.9Hz,3H),2.28-2.73(m,4H),3.08-3.31(m,1H),3.70(s,3H).
MS(ESI+)m/z 185(M+23).
Step two, synthesizing an intermediate product 3-ethylsulfanyl acid
In a 500ml three-necked flask, 13.5g of ethylthiomethyl ester compound (83mmol,1.0eq), THF (135ml) and MeOH (135ml) were mixed, and 10.48g of lithium hydroxide monohydrate (249mmol,3.0eq) was dissolved in water (80ml) and added dropwise to the reaction solution, and the mixture was stirred at room temperature for 2 hours. The reaction was poured into 1N HCl, pH 1-2 was measured, the aqueous phase was extracted twice with MTBE, dried over anhydrous sodium sulfate, and spin dried to give intermediate 3 as a yellow liquid: 12.15g, yield: 98 percent.
1H NMR(300MHz,CDCl3)δ1.26(t,J＝7.4Hz,3H),1.35(d,J＝6.9Hz,3H),2.39-2.80(m,4H),3.09-3.34(m,1H)，7.95-10.00(brs,1H).
MS(ESI+)m/z 193(M+55).
Step three, synthesizing intermediate product 4-ethylthio acyl chloride
In a 50ml single neck flask, cooled by an ice salt bath, 6g of ethyl sulfanate (40mmol,1.0eq) and DCM (30ml) were mixed, 148mg of DMF (2mmol, 0.05eq) was added, 5.9ml of thionyl chloride (81mmol,2eq) were added slowly and stirred under reflux for 2 hours. And (3) cooling, namely firstly evaporating the solvent by rotary evaporation, then carrying out rotary drying on the residual thionyl chloride carried by the DCE to obtain an intermediate product 4, and directly feeding the intermediate product 4 into the next step.
1H NMR(300MHz,CDCl3)δ1.27(t,J＝7.4Hz,3H),1.36(d,J＝6.8Hz,3H),2.59(q J＝7.4Hz,2H),2.94-3.10(m,1H),3.12-3.34(m,2H).
Step four, synthesizing an intermediate product 5-diketone
In a 250ml three-necked flask, n-butyllithium (2.5M, 43.6ml, 109mmol,3.0eq) and THF (80ml) were mixed under cooling with dry ice, cooled to-60 ℃ or below, 5.67g of the triketone compound (36mmol, diluted with 20ml of THF) was slowly added, stirred at-60 ℃ for 20 minutes, warmed to room temperature, stirred for 15 minutes, cooled to-60 ℃ or below, the ethylthio acyl chloride (6.06g, 36mmol, 1.0eq) obtained in one step was slowly added dropwise, stirred at-60 ℃ for 1 hour, and then stirred at room temperature for 1 hour.
Adding saturated ammonium chloride aqueous solution, slowly adding 1N HCl, adjusting pH to about 3, extracting the water phase with MTBE for three times, combining the organic phases, drying with anhydrous sodium sulfate, spin-drying, and separating by column chromatography to obtain an intermediate product 5 which is yellow liquid: 800mg, yield: 8 percent.
1H NMR(300MHz,CDCl3)δ1.14(t,J＝7.4Hz,3H),1.22-1.32(m,4H),1.33-1.42(m,3H),1.69-1.93(m,2H),2.44-3.13(m,9H),18.23-18.36(m,1H).
MS(ESI+)m/z 309(M+23).
Step five, synthesizing intermediate product 6-sulfoxide
In a 50ml three-necked flask, the substrate diketone (800mg, 2.79mmol) was dissolved in 10ml acetonitrile, the temperature in a salt bath was cooled to 0 ℃ or lower, 30% hydrogen peroxide (950mg, 3.0eq) was slowly added thereto, and the mixture was stirred at room temperature and reacted for 18 hours.
Cooling the ice salt bath to below 0 ℃, slowly dropwise adding an aqueous solution of sodium bisulfite, acidifying with 2N HCl, adjusting the pH to about 1-2, extracting the aqueous phase four times with MTBE, drying over anhydrous sodium sulfate, spin-drying, and separating by column chromatography (DCM/MeOH 200:1,100:1,50:1) to obtain intermediate 6 as a yellow liquid: 186mg, yield: 32 percent.
1H NMR(300MHz,DMSO-d6)δ1.04(t,J＝7.3,3H),1.13-1.30(m,9H),1.44-1.60(m,1H),1.79-2.33(m,2H),2.52-2.79(m,4H),2.90-3.18(m,4H),5.17(s,1H),18.10(s,1H).
Step six, synthesizing clethodim impurities
In a 100ml three-necked flask, the substrate sulfoxide (361mg, 1.19mmol) was dissolved in 45ml of methanol, the mixture was cooled to-40 ℃ with dry ice, chloroamine (141 mg, 1.1eq in 5ml of methanol) was slowly added dropwise, the mixture was stirred at room temperature for 1 hour after the addition, and then the temperature was raised to 40 ℃ for 5 hours. Work-up was carried out by direct column chromatography (DCM/MeOH ═ 100:1,80:1,50:1) to give the final product as a yellow liquid: 235mg, yield: 50 percent; the nuclear magnetic hydrogen spectrum of clethodim impurity is shown in figure 1.
The embodiments of the present invention have been described in detail, but the embodiments are merely examples, and the present invention is not limited to the embodiments described above. Any equivalent modifications and substitutions to those skilled in the art are also within the scope of the present invention. Accordingly, equivalent changes and modifications made without departing from the spirit and scope of the present invention should be covered by the present invention.
Claims (10)
1. A method for synthesizing clethodim impurities is characterized by comprising the following steps:
step one, dissolving methyl crotonate in DMF, then sequentially adding ethanethiol and potassium carbonate, heating, and reacting in a stirring process; after the reaction is finished, cooling, pouring the reaction liquid with the residual ethanethiol removed into a hydrochloric acid solution, extracting, washing and drying to obtain an intermediate product 2;
step two, mixing the intermediate product 2 with THF and methanol to obtain a mixed solution; dissolving lithium hydroxide monohydrate in water, dropwise adding the solution into the mixed solution, and reacting at room temperature for 1.5-3 hours to obtain an intermediate product 3;
step three, mixing the intermediate product 3 with DCM, sequentially adding DMF and thionyl chloride, and stirring under reflux to obtain an intermediate product 4;
step four, mixing N-butyllithium and THF, slowly adding a triketone compound, stirring for a period of time, slowly dropwise adding the intermediate product 4, reacting under stirring, adding a saturated ammonium chloride aqueous solution, slowly adding 1N HCl, adjusting the pH value to 3-5, extracting the water phase with MTBE for three times, combining the organic phases, drying with anhydrous sodium sulfate, spin-drying, and separating by column chromatography to obtain an intermediate product 5;
dissolving the intermediate product 5 in acetonitrile, cooling to below 0 ℃, slowly adding hydrogen peroxide, stirring at room temperature, and reacting for 16-19 hours to obtain an intermediate product 6;
and step six, dissolving the intermediate product 6, cooling to below-40 ℃, slowly dropwise adding chloramine dissolved in methanol, stirring, heating, and after the reaction is finished, performing column chromatography separation to obtain the clethodim impurity.
2. The method of claim 1, wherein the molar ratio of methyl crotonate, ethanethiol, and potassium carbonate in step one is 1:1: 0.1.
3. The method of claim 1, wherein the heating to 60-70 ℃ in step one, and the reaction time is 16-20 hours.
4. The process of claim 1, wherein in step one, after the reaction is completed, the temperature is reduced, the water pump is used for decompressing 60 ℃ to evaporate the residual ethanethiol, the reaction solution is poured into 1N HCl, the pH value is measured to be 1-2, the water phase is extracted twice by MTBE, the organic phase is washed four times by water, dried by anhydrous sodium sulfate and dried by spinning to obtain the intermediate product 2.
5. The method according to claim 1, wherein in step two, the molar ratio of the intermediate product 2 to the lithium hydroxide monohydrate is 1: (2.5-3.5).
6. The method of claim 1, wherein in step three, the molar ratio of the intermediate product 3 to DMF to thionyl chloride is 1:0.05: 2.
7. The method of claim 1, wherein the stirring time in step three is 1-3 hours.
8. The method according to claim 1, wherein in step four, the molar ratio of n-butyllithium to the triketone compound to the intermediate 4 is 3:1: 1.
9. The method according to claim 1, wherein in the fifth step, the concentration of the hydrogen peroxide is 30%, and the addition amount of the hydrogen peroxide is such that the intermediate product 5 and H in the reaction are2O2The molar ratio of (1) to (2.5-4).
10. The method according to claim 1, wherein in step six, the molar ratio of the intermediate product 6 to the chloramine is 1: 1-1.5.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE19859224A1 (en) * | 1998-12-21 | 1999-05-06 | Novartis Ag | Synergistic herbicidal composition for selective weed control |
| CN106187841A (en) * | 2016-07-08 | 2016-12-07 | 山东润博生物科技有限公司 | A kind of industrialized process for preparing of clethodim |
| CN112225682A (en) * | 2020-10-19 | 2021-01-15 | 中国科学院大连化学物理研究所 | Method for improving reaction speed of synthesizing clethodim |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE19859224A1 (en) * | 1998-12-21 | 1999-05-06 | Novartis Ag | Synergistic herbicidal composition for selective weed control |
| CN106187841A (en) * | 2016-07-08 | 2016-12-07 | 山东润博生物科技有限公司 | A kind of industrialized process for preparing of clethodim |
| CN112225682A (en) * | 2020-10-19 | 2021-01-15 | 中国科学院大连化学物理研究所 | Method for improving reaction speed of synthesizing clethodim |
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