CN116041256A - Purification method and preparation method of alkyl picolinate - Google Patents
Purification method and preparation method of alkyl picolinate Download PDFInfo
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
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Abstract
The present invention relates to a process for removing a pyridone impurity of formula III from a mixture comprising an alkyl picolinate of formula II and the pyridone impurity of formula III,
wherein X each independently represents hydrogen or halogen, Y represents hydrogen, halogen or C 1 ‑C 6 Alkyl, R 1 Represent C 1 ‑C 6 An alkyl group, the method comprising: adding a pyridone impurity remover to the mixture; the pyridone impurity remover is selected from the group consisting of organic peroxides, inorganic peroxides, haloacids, hypohalous acids, perhalous acids, halous acid salts, hypohalous acid salts, perhalous acid salts, and persulfates. The invention also relates to a preparation method of the compound shown in the formula II.
Description
Technical Field
The invention relates to a purification method and a preparation method of alkyl picolinate.
Background
Triclopyr ethyl ester is an important intermediate for synthesizing triclopyr or triclopyr butoxyethyl ester, and has the following structure:
in the prior art, the triclopyr is generally obtained by reacting sodium triclopyr alkoxide with ethyl chloroacetate in an organic solvent in the presence of a catalyst, and in the method, a large amount of organic solvent is used, the content of byproducts is high, and the purification steps are more. In particular, pyridone impurities are generated during the preparation of ethyl triclopyr, the presence of which affects the quality of the final product, but the purification process is complicated.
Triclopyr-2-butoxyethyl ester, also known as triclopyr-2-butoxyethyl ester, is a herbicide having the following formula:
in the prior art, the preparation method of the triclopyr-2-butoxyethyl ester can adopt the reaction of triclopyr ethyl ester with ethylene glycol butyl ether in an organic solvent in the presence of a catalyst. In these prior art methods, a large amount of organic solvents are used and the purification steps are complicated.
Disclosure of Invention
In view of the above problems, the present inventors have found that by adding a specific pyridone impurity remover, the pyridone impurity content can be significantly reduced without adversely affecting the alkyl picolinate.
Thus, a first aspect of the present invention provides a process for removing a pyridone impurity of formula III from a mixture comprising an alkyl picolinate of formula II and a pyridone impurity of formula III,
wherein X each independently represents hydrogen or halogen,
y represents hydrogen, halogen or C 1 -C 6 An alkyl group, a hydroxyl group,
R 1 represent C 1 -C 6 An alkyl group, a hydroxyl group,
the method comprises the following steps: adding a pyridone impurity remover to the mixture; the pyridone impurity remover is selected from the group consisting of organic peroxides, inorganic peroxides, haloacids, hypohalous acids, perhalous acids, halous acid salts, hypohalous acid salts, perhalous acid salts, and persulfates.
The second aspect of the present invention relates to a process for the preparation of alkyl picolinate of formula II.
The purification method is simple and easy to operate, and the preparation method can reduce the dosage of the organic solvent in the process, is environment-friendly and has high yield, so that the overall process cost is reduced.
Drawings
Fig. 1 and 2 are nuclear magnetic resonance spectra and mass spectra of pyridone impurities.
Detailed Description
All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety to the same extent as if each individual publication, patent application, patent, and other reference was specifically and individually indicated to be incorporated by reference in its entirety.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In case of conflict, the present specification, including definitions, will control.
All percentages, parts, ratios, etc. are by weight unless otherwise specified.
When an amount, concentration, or other value or parameter is expressed as a range, preferred range, or preferred or exemplary value, this is to be understood as equivalent to any range specifically disclosed by combining any pair of upper and lower range limits or preferred or exemplary values. Unless otherwise indicated, the numerical ranges set forth herein are intended to include the endpoints of the ranges, and all integers and fractions within the range.
The materials, methods, and examples of the present invention are illustrative only and not intended to be limiting unless otherwise specified.
When the term "about" is used to describe an end point of a value or range, it should be understood to include within 10%, more preferably 5%, more preferably 3%, more preferably 1% of the particular value or end point involved.
First aspect
A first aspect of the invention relates to a process for removing a pyridone impurity of formula III from a mixture comprising an alkyl picolinate of formula II and a pyridone impurity of formula III,
wherein X each independently represents hydrogen or halogen, e.g., fluorine, chlorine, bromine or iodine, preferably chlorine, more preferably all X are chlorine,
y represents hydrogen, halogen or C 1 -C 6 An alkyl group, preferably hydrogen,
R 1 represent C 1 -C 6 Alkyl, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl, preferably ethyl,
the method comprises the following steps: adding a pyridone impurity remover to the mixture; the pyridone impurity remover is selected from the group consisting of organic peroxides, inorganic peroxides, haloacids, hypohalous acids, perhalous acids, halous acid salts, hypohalous acid salts, perhalous acid salts, and persulfates.
Preferably, the pyridone impurity remover is selected from H 2 O 2 Sodium hypochlorite, sodium chlorite, sodium chlorate, sodium perchlorate, hypochlorous acid, chlorous acid, chloric acid, perchloric acid, m-chloroperoxybenzoic acid, peroxyacetic acid, sodium persulfate, potassium persulfate, and ammonium persulfate.
The inventors have unexpectedly found that the addition of the above specific pyridone impurity removal agents to the mixture can reduce the pyridone impurity content therein without affecting the alkyl picolinate.
The form of addition of the pyridone impurity remover is not particularly limited, and for example, may be added in the form of an aqueous solution or may be added in its own inherent form.
The amount of the pyridone impurity remover is not particularly limited, and may be adjusted as needed according to the difference in impurity content. For example, the content of the pyridone impurity of formula III in the mixture may be detected first, and then the pyridone impurity remover may be added in a molar ratio of the pyridone impurity of formula III to the pyridone impurity remover of 2:1 to 24:1. For example, the molar ratio of pyridone impurity to pyridone impurity scavenger of formula III may be 3:1,4:1,5:1,7:1,9:1,10:1,12:1,15:1,17:1,20:1,22:1.
The reaction for removing impurities by adding the pyridone impurity remover may be carried out at a temperature in the range of 0 to 100 ℃, preferably at a temperature in the range of 50 to 70 ℃, for example, at a temperature of 25 ℃,30 ℃,35 ℃, 40 ℃, 45 ℃, 50 ℃, 55 ℃,60 ℃, 65 ℃, 70 ℃,75 ℃,80 ℃, 85 ℃, 90 ℃, 95 ℃.
After the pyridone impurity removal agent reaction, alkyl picolinate of formula II having significantly reduced pyridone impurity content of formula III can be obtained by thermal phase separation, which can be used for further purification or other reactions, as required by the process.
Particularly advantageousAlternatively, the alkyl picolinate of formula II is ethyl triclopyr:
particularly preferably, the pyridone impurity of formula III is:
second aspect
A second aspect of the invention relates to a process for preparing alkyl picolinate of formula II, wherein the process comprises:
step 1: combining a compound of formula I with a compound of formula X' -CH in the presence of a phase transfer catalyst 2 -C(＝O)-O-R 1 The compounds of formula (I) are reacted in water or an aqueous alkali metal salt solution, and thermal phase separation is carried out after the reaction to obtain a first organic phase containing alkyl picolinate of formula (II) and pyridone impurities of formula (III);
wherein M is sodium or potassium;
x each independently represents hydrogen or halogen, e.g., fluorine, chlorine, bromine or iodine, preferably chlorine, more preferably all X are chlorine,
y represents hydrogen, halogen or C 1 -C 6 An alkyl group, preferably hydrogen,
R 1 represent C 1 -C 6 Alkyl, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl, preferably ethyl,
x' represents halogen, for example fluorine, chlorine, bromine or iodine, preferably chlorine,
step 2: adding a pyridone impurity remover into the first organic phase, and thermally separating the phase again after the reaction to obtain a second organic phase containing alkyl picolinate of the formula II; the pyridone impurity remover is selected from the group consisting of organic peroxides, inorganic peroxides, haloacids, hypohalous acids, perhalous acids, halous acid salts, hypohalous acid salts, perhalous acid salts, and persulfates.
Preferably, the pyridone impurity remover is selected from H 2 O 2 Sodium hypochlorite, sodium chlorite, sodium chlorate, sodium perchlorate, hypochlorous acid, chlorous acid, chloric acid, perchloric acid, m-chloroperoxybenzoic acid, peroxyacetic acid, sodium persulfate, potassium persulfate, and ammonium persulfate.
Step 1
For compounds of formula I, sodium or potassium triclopyridyl alkoxides are preferred:
wherein M is sodium or potassium.
For alkyl picolinates of formula II, ethyl triclopyr is preferred:
for X' -CH 2 -C(＝O)-O-R 1 Preferably ethyl chloroacetate: cl-CH 2 -C(＝O)-O-CH 2 -CH 3 。
For pyridone impurities of formula III, preference is given to:
capable of catalyzing a compound of formula I with a compound of formula X' -CH 2 -C(＝O)-O-R 1 Catalysts which are capable of catalyzing the reaction of sodium or potassium trichloropyridine alkoxides with ethyl chloroacetate to the corresponding esters may be used in step 1 of the present invention. Preferably, the phase transfer catalyst may be selected from the group consisting of tetrabutylammonium bromide, tetraethylammonium bromide, benzyltriethylammonium bromide, sodium dodecyl sulfate, sodium dodecylbenzenesulfonate, benzyltriethylammonium chloride, tetrabutylammonium chloride, trioctylmethylammonium chloride, dodecyltrimethylammonium chloride, polyethylene glycol, 18 crown ether 6, and any combination thereof.
The expression "in water" may refer to the addition of water as a solvent in this step, or may refer to the addition of water by the reactants rather than in addition to this step.
The aqueous alkali metal salt solution is preferably selected from the group consisting of aqueous sodium chloride, aqueous potassium chloride, aqueous sodium carbonate, aqueous potassium carbonate, aqueous sodium bicarbonate, aqueous potassium bicarbonate, aqueous sodium phosphate, aqueous potassium phosphate, aqueous sodium hydrogen phosphate, aqueous potassium hydrogen phosphate, or any combination thereof.
The concentration of the aqueous alkali metal salt solution is not particularly limited, and a dilute salt solution to a saturated salt solution may be used.
The amount of the alkali metal salt is not particularly limited, and for example, the mass ratio of the compound of formula I (e.g., sodium or potassium triclopyridyl alkoxide) to the alkali metal salt (e.g., naCl) may be 1:0.05 to 1:2.
In theory, step 1 may be carried out at any reaction temperature that enables the reaction to proceed. Preferably, the reaction of step 1 is carried out at a temperature in the range of 20-100 ℃, more preferably at a temperature in the range of 40-80 ℃, for example at a temperature of 25 ℃,30 ℃,35 ℃, 40 ℃, 45 ℃, 50 ℃, 55 ℃,60 ℃, 65 ℃, 70 ℃,75 ℃,80 ℃, 85 ℃, 90 ℃, 95 ℃.
The reaction time in step 1 is not particularly limited and may be theoretically set up until the reaction is completed, but in the actual production process, the reaction time may be selected as required. The reaction time varies with the reaction temperature employed.
The reaction of step 1 is preferably carried out under stirring.
Compounds of formula I and formula X' -CH 2 -C(＝O)-O-R 1 The molar ratio of the compounds of (2) is preferably from 1:1 to 1:2, for example, 1:1.1,1:1.2,1:1.3,1:1.4,1:1.5,1:1.6,1:1.7,1:1.8,1:1.9.
The amount of the phase transfer catalyst is not particularly limited and may be a catalytic amount. For example, the molar ratio of the compound of formula I to the phase transfer catalyst is preferably from 1:0.01 to 1:0.5, for example, 1:0.02,1:0.03,1:0.04,1:0.05,1:0.06,1:0.07,1:0.08,1:0.09,1:0.1,1:0.2,1:0.3,1:0.4.
Step 2
Adding a pyridone impurity remover into the first organic phase, and thermally separating the phase again after the reaction to obtain a second organic phase containing the alkyl picolinate of the formula II.
The pyridone impurity remover and the reaction conditions are as described above with reference to the first aspect, all of which are defined for step 2.
The content of pyridone impurities of formula III in the first organic phase obtained by step 1 above is generally not high, for example not higher than 8% by weight. Because, in order to facilitate the addition in the actual production, the molar ratio of the pyridone impurity scavenger to the starting compound of formula I may be in the range of (0.05-1.5): 1, for example, 0.05:1,0.08:1,0.1:1,0.2:1,0.3:1,0.4:1,0.5:1,0.6:1,0.7:1,0.8:1,0.9:1,1.0:1,1.1:1,1.2:1,1.3:1,1.4:1. The amount of the pyridone impurity remover means an effective amount of the pyridone impurity remover.
After the pyridone impurity remover reaction is completed, the phase separation is again performed thermally to obtain a second organic phase containing the alkyl picolinate of formula II. In the second organic phase, the pyridone impurity content of formula III is significantly reduced.
The second organic phase may be further used to react with ethylene glycol monobutyl ether to produce butoxyalkyl picolinate corresponding to formula II, such as 2-butoxyethyl triclopyr. For ease of labeling, this further reaction is referred to in this context as "step 3".
Step 3
The second organic phase obtained in the step 2 can be subjected to a step of distilling to remove water, or can be directly mixed with ethylene glycol monobutyl ether to react without the step of distilling to remove water.
Preferably, after mixing the second organic phase with ethylene glycol monobutyl ether, the residual moisture is removed as much as possible by distillation under reduced pressure.
Adding a catalyst to the mixture of the second organic phase and ethylene glycol monobutyl ether, and reacting at a temperature in the range of 110-170 ℃ to obtain butoxyalkyl picolinate corresponding to formula II, e.g., a compound of formula IV
The reaction temperature in step 3 is preferably in the range of 120-160℃and, for example, is at a temperature of 115℃125℃130℃135℃140℃145℃150℃155℃160℃165 ℃.
Catalysts capable of catalyzing the transesterification of alkyl picolinate and monobutyl ether of formula II may be used in this step, and in particular, catalysts capable of catalyzing the transesterification of ethyl triclopyr and monobutyl ether of ethylene glycol may be used in this step. Preferably, the catalyst is selected from the group consisting of monobutyl tin oxide, concentrated sulfuric acid, and p-toluene sulfonic acid. The amount of the catalyst to be used is not particularly limited, and is a conventional amount in transesterification.
Examples
The technical scheme of the present invention will be further described with reference to specific examples, but the present invention is not limited to the following examples.
Example 1
Step 1
To a three-necked flask, 60g of sodium trichloropyridine alkoxide (88% by weight) (0.399 mol,1.0 eq) was added, 150g of a saturated aqueous sodium chloride solution, 6.0g of tetrabutylammonium bromide (0.0186 mol,0.078 eq) was stirred at 60℃and 32.2g of ethyl chloroacetate (0.263 mol,1.1 eq) was slowly added dropwise, the reaction was continued for about 6 hours at the temperature after the completion of the dropwise addition, and then the temperature was raised to 80℃for the reaction, and the reaction was completed by High Performance Liquid Chromatography (HPLC) detection, followed by thermal phase separation to obtain a first organic phase.
Step 1, component detection: the first organic phase was checked by HPLC at 221nm and normalized to give a relative content of 94.5% for ethyl triclopyr and 3.5% for the impurity pyridone.
The nuclear magnetic resonance data of the pyridone impurity is as follows, and is shown in fig. 1.
1 H-NMR(400MHz,CDCl 3 )：δ7.65(s,1H),5.08(s,2H),4.27(q,J＝7.1Hz,2H),1.31(t,J＝7.1Hz,3H)。
Step 2
40g of 30 wt% hydrogen peroxide solution (0.353 mol,1.48 eq) was slowly dropped at 65℃into the first organic phase obtained in step 1, and after the completion of the reaction, thermal phase separation was performed to obtain 70.8g of a second organic phase.
And 2, component detection: the second organic phase was checked by HPLC at 221nm and normalized to give a relative content of ethyl triclopyr of 98.3% and the impurity pyridone of 0.1%. In addition, the absolute content of ethyl triclopyr in the second organic phase was 92.3 wt.% as determined by HPLC standard curve method. The yield of ethyl triclopyr was 96.1% calculated as 68.0g of theoretical yield.
Step 3
The second organic phase obtained in step 2 was mixed with 150g of ethylene glycol monobutyl ether and distilled under reduced pressure to remove water until the water content was less than 0.3% by weight. Then, 0.5g of monobutyl tin oxide was added, and the reaction was carried out at 150℃under a slight negative pressure while removing low boiling substances, and the disappearance of the starting material was monitored by HPLC and distilled under reduced pressure to give 79.3g of a product.
And 3, component detection: HPLC is carried out at 221nm to detect the product, and the relative content of the triclopyr-2-butoxyethyl ester is 99.1% by normalization method. In addition, the absolute content of 2-butoxyethyl triclopyr was 98.2% by weight as determined by HPLC standard curve method. The total yield of 2-butoxyethyl trichloropicolinate in the two-step reaction was 93.1% calculated as 85.2g of theoretical yield.
Example 2
Step 1 is the same as in example 1.
Step 2
180g of sodium hypochlorite solution (content: 10%,0.242mol,1.01 eq) was slowly dropped at 65℃into the first organic phase obtained in step 1, and thermal phase separation was performed at the end of the reaction to obtain 71.2g of a second organic phase.
And 2, component detection: the second organic phase had a relative content of ethyl triclopyr of 98.1% and a relative content of pyridone impurity of 0.2% as determined by the assay method of example 1. The absolute content of ethyl triclopyr was 90.7% by weight. The yield of ethyl triclopyr was 95.1% calculated as 68.0g of theoretical yield.
Step 3
The second organic phase obtained in step 2 was mixed with 150g of ethylene glycol monobutyl ether and distilled under reduced pressure to remove water until the water content was less than 0.3% by weight. Then, 0.5g of monobutyl tin oxide was added, and the reaction was carried out at 150℃under a slight negative pressure while removing low boiling substances, and the disappearance of the starting material was monitored by HPLC and distilled under reduced pressure to give 78.8g of a product.
And 3, component detection: the relative content of 2-butoxyethyl trichloropicolinate in the product was 99.3% and the absolute content was 98.4% as determined by the method of detection in example 1. The total yield of 2-butoxyethyl trichloropicolinate in the two-step reaction was 92.5% calculated as 85.2g of theoretical yield.
Example 3
Step 1 is the same as in example 1.
Step 2
60g of water and 3.0g of 80% sodium chlorite (0.0265 mol,0.11 eq) were added to the first organic phase obtained in step 1, heated to 65℃and stirred, and thermal phase separation was performed after the reaction was completed to obtain 71.5g of a second organic phase.
And 2, component detection: the second organic phase had a relative content of ethyl triclopyr of 98.4% and a relative content of pyridone impurity of 0.1% as determined by the assay method of example 1. The absolute content of ethyl triclopyr was 90.7% by weight. The yield of ethyl triclopyr was 95.4% calculated as 68.0g of theoretical yield.
Example 4
Step 1 is the same as in example 1.
Step 2
60g of water and 1.3g of sodium chlorate (0.0122 mol,0.05 eq) were added to the first organic phase obtained in step 1, the temperature was raised to 65℃and stirred, and thermal phase separation was carried out after the reaction was completed, yielding 71.0g of a second organic phase.
And 2, component detection: the second organic phase had a relative content of ethyl triclopyr of 98.2% and a relative content of pyridone impurity of 0.3% as determined by the assay method of example 1. The absolute content of ethyl triclopyr was 89.7 wt.%. The yield of ethyl triclopyr was 93.7% calculated as 68.0g of theoretical yield.
Example 5
Step 1 is the same as in example 1.
Step 2
2.5g of m-chloroperoxybenzoic acid (0.0145 mol,0.06 eq) was added dropwise to the first organic phase obtained in step 1 at 65℃and the reaction was completed with thermal phase separation to obtain 71.5g of a second organic phase.
And 2, component detection: the relative content of ethyl triclopyr in the second organic phase was 97.3% and the relative content of pyridone impurity was 0.4% as determined by the assay method of example 1. The absolute content of ethyl triclopyr was 90.1 wt.%. The yield of ethyl triclopyr was 94.7% calculated as 68.0g of theoretical yield.
Step 3
The second organic phase obtained in step 2 was mixed with 150g of ethylene glycol monobutyl ether and distilled under reduced pressure to remove water until the water content was less than 0.3% by weight. Then, 0.5g of monobutyl tin oxide was added, and the reaction was carried out at 150℃under a slight negative pressure while removing low boiling substances, and the disappearance of the starting material was monitored by HPLC and distilled under reduced pressure to obtain 77.0g of a product.
And 3, component detection: the relative content of 2-butoxyethyl trichloropicolinate in the product was 98.7% and the absolute content was 98.0% as determined by the method of detection in example 1. The total yield of 2-butoxyethyl trichloropicolinate in the two-step reaction was 90.4% calculated as 85.2g of theoretical yield.
Example 6
Step 1 is the same as in example 1.
Step 2
1.1g of peracetic acid (0.0145 mol,0.06 eq) was added dropwise to the first organic phase obtained in step 1 at 65℃and the reaction was ended with thermal phase separation to obtain 69.6g of a second organic phase.
And 2, component detection: the second organic phase had a relative content of ethyl triclopyr of 98.4% and a relative content of pyridone impurity of 0.2% as determined by the assay method of example 1. The absolute content of ethyl triclopyr was 92.9% by weight. The yield of ethyl triclopyr was 95.1% calculated as 68.0g of theoretical yield.
Step 3
The second organic phase obtained in step 2 was mixed with 150g of ethylene glycol monobutyl ether and distilled under reduced pressure to remove water until the water content was less than 0.3% by weight. Then, 0.5g of monobutyl tin oxide was added, and the reaction was carried out at 150℃under a slight negative pressure while removing low boiling substances, and the disappearance of the starting material was monitored by HPLC and distilled under reduced pressure to give 79.7g of a product.
And 3, component detection: the relative content of 2-butoxyethyl trichloropicolinate in the product was 99.4% and the absolute content was 98.4% as determined by the method of detection in example 1. The total yield of 2-butoxyethyl trichloropicolinate in the two-step reaction was 93.5% calculated as 85.2g of theoretical yield.
Example 7
Step 1 is the same as in example 1.
Step 2
60g of water and 3.7g of potassium persulfate (0.0137 mol,0.06 eq) were added to the first organic phase obtained in the step 1, heated to 65℃and stirred, and thermal phase separation was performed at the end of the reaction to obtain 67.6g of a second organic phase.
And 2, component detection: the second organic phase had a relative content of ethyl triclopyr of 98.1% and a relative content of pyridone impurity of 0.3% as determined by the assay method of example 1. The absolute content of ethyl triclopyr was 91.7 wt.%. The yield of ethyl triclopyr was 91.2% calculated as 68.0g of theoretical yield.
Example 8
Step 1: the same as in example 1.
Step 2
60g of water and 3.5g of sodium persulfate (0147 mol,0.06 eq) were added to the first organic phase obtained in step 1, heated to 65℃and stirred, and thermal phase separation was performed after the reaction was completed, to obtain 67.3g of a second organic phase.
And 2, component detection: the relative content of ethyl triclopyr in the second organic phase was 97.5% and the relative content of pyridone impurity was 0.5% as determined by the assay method of example 1.
Comparative example 1
Step 1 is the same as in example 1.
Step 2
60g of water and 2.1g of potassium permanganate (0.0126 mol,0.05 eq) were added to the first organic phase obtained in step 1, heated to 65℃and stirred, and the reaction was completed with thermal phase separation to obtain 61.2g of a second organic phase.
And 2, component detection: the relative content of ethyl triclopyr in the second organic phase was 87.2% and the relative content of pyridone impurity was 0.01% as determined by the assay method of example 1. The absolute content of ethyl triclopyr was 75.3 wt.%. The yield of ethyl triclopyr was 68.7% calculated as 68.0g of theoretical yield.
Comparative example 2
Step 1 is the same as in example 1.
Step 2
60g of water and 3.0g of potassium dichromate (0.010mol, 0.04 eq) were added to the first organic phase obtained in step 1, heated to 65℃and stirred, and thermal phase separation was performed after the reaction was completed, to obtain 62.8g of a second organic phase.
And 2, component detection: the second organic phase had a relative content of ethyl triclopyr of 83.2% and a relative content of pyridone impurity of 0.01% as determined by the assay method of example 1.
Comparative example 3
Step 1 is the same as in example 1.
Step 2
60g of water and 2.2g of ferric trichloride (0.0136 mol,0.06 eq) were added to the first organic phase obtained in step 1, the temperature was raised to 65℃and stirred, and thermal phase separation was carried out after the reaction was completed, to obtain 72.2g of a second organic phase.
And 2, component detection: the second organic phase had a relative content of ethyl triclopyr of 94.0% and a relative content of pyridone impurity of 3.3% as determined by the assay method of example 1. The absolute content of ethyl triclopyr was 87.9% by weight. The yield of ethyl triclopyr was 93.3% calculated as 68.0g of theoretical yield.
Comparative example 4
Step 1 is the same as in example 1.
Step 2
60g of water and 1.9g of copper chloride (0.0141 mol,0.06 eq) were added to the first organic phase obtained in step 1, the temperature was raised to 65℃and stirred, and thermal phase separation was carried out after the reaction was completed, to obtain 73.2g of a second organic phase.
And (3) component detection: the second organic phase had a relative content of 93.6% ethyl triclopyr and 3.7% pyridone impurity as measured by the assay method of example 1. The absolute content of ethyl triclopyr was 86.5 wt.%. The yield of ethyl triclopyr was 93.1% calculated as 68.0g of theoretical yield.
Example 9 (without solvent)
Step 1
To a three-necked flask was added 60g of sodium trichloropyridinol (88% by weight) (0.239 mol,1.0 eq), 35.1g of ethyl chloroacetate (0.287 mol,1.2 eq), 6.0g of tetrabutylammonium bromide (0.0186 mol,0.078 eq), stirred at 75℃and the reaction was complete as determined by HPLC, and the first organic phase was obtained by thermal phase separation.
Step 1, component detection: the relative content of ethyl triclopyr in the first organic phase was 92.8% and the relative content of the impurity pyridone was 5.4% as determined by the assay method of example 1.
Step 2
3.6g of m-chloroperoxybenzoic acid (0.0209 mol,0.09 eq) were added to the first organic phase at 65℃and the reaction was thermally split to give 69.3g of a second organic phase.
And 2, component detection: the second organic phase had a relative content of ethyl triclopyr of 98.3% and a relative content of pyridone impurity of 0.3% as determined by the assay method of example 1. The absolute content of ethyl triclopyr was 91.6 wt.%. The yield of ethyl triclopyr was 93.4% calculated as 68.0g of theoretical yield.
Step 3
Mixing the second organic phase obtained in the step 2 with 150g of ethylene glycol monobutyl ether, distilling under reduced pressure to remove water until the water content in the reaction liquid is less than 0.3 weight percent, adding 0.5g of monobutyl tin oxide, reacting under a slight negative pressure at 150 ℃ while removing low-boiling substances, monitoring the disappearance of raw materials by HPLC, and distilling under reduced pressure to obtain 78.0g of product.
And 3, component detection: the relative content of 2-butoxyethyl trichloropicolinate in the product was 98.8% as determined by the test method in example 1. The total yield of 2-butoxyethyl trichloropicolinate in the two-step reaction was 91.6% calculated as 85.2g of theoretical yield.
Example 10 (Potassium alkoxide)
Step 1
To a three-necked flask, 65.0g of potassium trichloropyridine (weight content: 87%) (0.399 mol,1.0 eq), 150g of a saturated aqueous potassium chloride solution, 6.0g of tetrabutylammonium bromide (0.0186 mol,0.078 eq), and 32.2g of ethyl chloroacetate (0.263 mol,1.1 eq) were added dropwise with stirring at 60℃and the reaction was continued for about 6 hours after the completion of the dropwise addition, and then the temperature was raised to 80℃for the reaction, and the reaction was completed by HPLC detection and thermal phase separation to obtain a first organic phase.
Step 1, component detection: the relative content of ethyl triclopyr in the first organic phase was 95.4% and the relative content of the impurity pyridone was 2.4% as determined by the procedure of example 1.
Step 2
40g of 30% hydrogen peroxide solution (0.353 mol,1.48 eq) was slowly dropped into the first organic phase obtained in step 1 at 65℃and thermal phase separation was performed at the end of the dropping, to obtain 72.1g of a second organic phase.
And 2, component detection: the relative content of ethyl triclopyr in the second organic phase was 98.9% and the relative content of the impurity pyridone was 0.1% as determined by the procedure of example 1. The absolute content of ethyl triclopyr in the second organic phase was 91.3 wt.%. The yield of ethyl triclopyr was 96.8% calculated as 68.0g of theoretical yield.
Step 3
Mixing the second organic phase obtained in the step 2 with 150g of ethylene glycol monobutyl ether, distilling under reduced pressure to remove water until the water content in the reaction liquid is less than 0.3%, adding 0.5g of monobutyl tin oxide, reacting under a slight negative pressure at 150 ℃ while removing low-boiling substances, monitoring the disappearance of raw materials by HPLC, and distilling under reduced pressure to obtain 80.0g of product.
And 3, component detection: the relative content of 2-butoxyethyl trichloropicolinate in the product was 99.1% and the absolute content was 98.0% as determined by the method of detection in example 1. The total yield of 2-butoxyethyl trichloropicolinate in the two-step reaction was 93.9% calculated as 85.2g of theoretical yield.
Example 11 (Potassium alkoxide)
Step 1
To a three-necked flask, 65.0g of potassium trichloropyridine (weight content: 87%) (0.399 mol,1.0 eq), 150g of a saturated aqueous potassium chloride solution, 6.0g of tetrabutylammonium bromide (0.0186 mol,0.078 eq), and 32.2g of ethyl chloroacetate (0.263 mol,1.1 eq) were added dropwise with stirring at 60℃and the reaction was continued for about 6 hours after the completion of the dropwise addition, and then the temperature was raised to 80℃for the reaction, and the reaction was completed by HPLC detection and thermal phase separation to obtain a first organic phase.
Step 1, component detection: the relative content of ethyl triclopyr in the first organic phase was 95.6% and the relative content of the impurity pyridone was 2.5% as determined by the procedure of example 1.
Step 2
120g of sodium hypochlorite (content: 10%,0.161mol,0.67 eq) was slowly added dropwise to the first organic phase obtained in step 1 at 65℃and thermal phase separation was carried out at the end of the addition to obtain 72.3g of a second organic phase.
And 2, component detection: the relative content of ethyl triclopyr in the second organic phase was 99.1% and the relative content of the impurity pyridone was 0.07% as measured in example 1. The absolute content of ethyl triclopyr in the second organic phase was 91.0 wt.%. The yield of ethyl triclopyr was 96.8% calculated as 68.0g of theoretical yield.
Example 12
Step 1 is the same as in example 1.
Step 2
The first organic phase obtained in step 1 was mixed with 120g of acetonitrile, 120g of an aqueous sodium hypochlorite solution (content: 10%,0.161mol,0.67 eq) was slowly added dropwise at 0℃and stirred at 0℃for about 4 hours after the completion of the addition, to obtain 230g of a reaction solution.
And 2, component detection: the relative content of ethyl triclopyr in the reaction solution was 98.0% and the relative content of pyridone impurity was 0.2% as measured by the method of example 1. The absolute content of the triclopyr ethyl ester is 27.7 percent. The yield of ethyl triclopyr was 93.8% calculated as 68.0g of theoretical yield.
At low temperature, the triclopyr ethyl ester is solid, acetonitrile is added as a solvent to dissolve the triclopyr ethyl ester, and other solvents with dissolving effect are also suitable. At higher temperatures, no solvent is required.
Example 13
Step 1 is the same as in example 1.
Step 2
The first organic phase obtained in step 1 was mixed with 120g of acetonitrile, 120g of an aqueous sodium hypochlorite solution (content: 10%,0.161mol,0.67 eq) was slowly added dropwise at 30℃and stirred at 30℃for about 4 hours after the completion of the addition, to obtain 234g of a reaction solution.
And 2, component detection: the relative content of ethyl triclopyr in the reaction solution was 98.1% and the relative content of pyridone impurity was 0.1% as measured by the method of example 1. The absolute content of the triclopyr ethyl ester is 27.3 percent. The yield of ethyl triclopyr was 93.9% calculated as 68.0g of theoretical yield.
Example 14
Step 1 is the same as in example 1.
Step 2
120g of an aqueous sodium hypochlorite solution (content: 10%,0.161mol,0.67 eq) was slowly dropped into the first organic phase obtained in step 1 at 60℃and stirred at 60℃for about 4 hours after the end of the dropping, followed by thermal phase separation to obtain 67.9g of a second organic phase.
And 2, component detection: the second organic phase had a relative content of ethyl triclopyr of 98.3% and a relative content of pyridone impurity of 0.1% as determined by the assay method of example 1. The absolute content of ethyl triclopyr was 93.3 wt.%. The yield of ethyl triclopyr was 93.2% calculated as 68.0g of theoretical yield.
Example 15
Step 1 is the same as in example 1.
Step 2
120g of an aqueous sodium hypochlorite solution (content: 10%,0.161mol,0.67 eq) was slowly dropped into the first organic phase obtained in step 1 at 90℃and stirred at 90℃for about 4 hours after the dropping was completed, and thermal phase separation was performed to obtain 68.6g of a second organic phase.
And 2, component detection: the relative content of ethyl triclopyr in the second organic phase was 97.5% and the relative content of pyridone impurity was 0.1% as determined by the assay method of example 1. The absolute content of ethyl triclopyr was 91.5% by weight. The yield of ethyl triclopyr was 92.3% calculated as 68.0g of theoretical yield.
Example 16
Step 1
To a three-necked flask, 60g of sodium trichloropyridine alkoxide (88% by weight) (0.399 mol,1.0 eq), 150g of saturated aqueous sodium chloride solution, 6.0g of benzyltriethylammonium bromide (0.220 mol,0.09 eq) were added, and the mixture was stirred at 60℃to slowly drop 32.2g of ethyl chloroacetate (0.263 mol,1.1 eq), and the mixture was allowed to react at this temperature for about 6 hours, and then heated to 80℃to complete the reaction, followed by HPLC detection to obtain a first organic phase by thermal phase separation.
Step 1, component detection: the relative content of ethyl triclopyr in the first organic phase was 93.5% and the relative content of the impurity pyridone was 4.2% as measured by the method of example 1.
Step 2
To the first organic phase obtained in step 1, 2.5g of m-chloroperoxybenzoic acid (0.0145 mol,0.06 eq) was added at 65℃and thermal phase separation was performed at the end of the reaction to obtain 70.2g of a second organic phase.
And 2, component detection: the relative content of ethyl triclopyr in the second organic phase was 97.4% and the relative content of impurity pyridone was 0.2% as measured in example 1; the absolute content of ethyl triclopyr in the second organic phase was 91.9% by weight. The yield of ethyl triclopyr was 94.9% calculated as 68.0g of theoretical yield.
Step 3
Mixing the second organic phase obtained in the step 2 with 150g of ethylene glycol monobutyl ether, distilling under reduced pressure to remove water until the water content in the reaction liquid is less than 0.3 weight percent, adding 0.5g of monobutyl tin oxide, reacting at 150 ℃ under slight negative pressure while removing low-boiling substances, monitoring the disappearance of raw materials by HPLC, and distilling under reduced pressure to obtain 77.1g of product.
And 3, component detection: the relative content of 2-butoxyethyl trichloropicolinate in the product was 98.8% and the absolute content was 98.0% as determined by the method of detection in example 1. The total yield of 2-butoxyethyl trichloropicolinate in the two-step reaction was 90.5% calculated as 85.2g of theoretical yield.
Example 17
Step 1
To a three-necked flask, 60g of sodium trichloropyridine alkoxide (88% by weight) (0.399 mol,1.0 eq), 150g of saturated aqueous sodium chloride solution, 6.0g of sodium dodecylbenzenesulfonate (0.0172 mol,0.07 eq) were added, and the mixture was stirred at 60℃to slowly drop 32.2g of ethyl chloroacetate (0.263 mol,1.1 eq) and the mixture was allowed to react at the temperature for about 6 hours after the dropping was completed, and then the temperature was raised to 80℃for complete reaction, and then the first organic phase was obtained by HPLC detection and thermal phase separation.
Step 1, component detection: the relative content of ethyl triclopyr in the first organic phase was 94.1% and the relative content of the impurity pyridone was 3.9% as determined by the procedure of example 1.
Step 2
To the first organic phase obtained in step 1, 2.5g of m-chloroperoxybenzoic acid (0.0145 mol,0.06 eq) was added at 65℃and thermal phase separation was performed at the end of the reaction to obtain 72.2g of a second organic phase.
And 2, component detection: the relative content of ethyl triclopyr in the second organic phase was 97.2% and the relative content of impurity pyridone was 0.3% as measured in example 1; the absolute content of ethyl triclopyr in the second organic phase was 89.5 wt.%. The yield of ethyl triclopyr was 95.0% calculated as 68.0g of theoretical yield.
Example 18
Step 1
To a three-necked flask, 60g of sodium trichloropyridine alkoxide (88% by weight) (0.399 mol,1.0 eq), 150g of saturated aqueous sodium chloride solution, 6.0g of polyethylene glycol (0.0966 mol, 0.4eq based on the monomer ethylene glycol), and then, 32.2g of ethyl chloroacetate (0.263 mol,1.1 eq) were added dropwise with stirring at 60℃and the reaction was allowed to continue for about 6 hours after the completion of the dropwise addition, and then, the reaction was allowed to continue at 80℃until the completion of the HPLC detection, and the first organic phase was obtained by thermal phase separation.
Step 1, component detection: the relative content of ethyl triclopyr in the first organic phase was 94.0% and the relative content of the impurity pyridone was 4.5% as determined by the procedure of example 1.
Step 2
To the first organic phase obtained in step 1, 2.5g of m-chloroperoxybenzoic acid (0.0145 mol,0.06 eq) was added at 65℃and thermal phase separation was performed at the end of the reaction to obtain 70.2g of a second organic phase.
And 2, component detection: the relative content of ethyl triclopyr in the second organic phase was 97.7% and the relative content of impurity pyridone was 0.4% as measured by the method of example 1; the absolute content of ethyl triclopyr in the second organic phase was 90.3 wt.%. The yield of ethyl triclopyr was 93.2% calculated as 68.0g of theoretical yield.
Example 19
Step 1
To a three-necked flask, 60g of sodium trichloropyridine alkoxide (88% by weight) (0.399 mol,1.0 eq), 150g of saturated aqueous sodium chloride solution, 6.0g of tetrabutylammonium bromide (0.0186 mol,0.078 eq), and then, with stirring at 30℃were added dropwise 32.2g of ethyl chloroacetate (0.263 mol,1.1 eq), the reaction was continued for about 15 hours after the completion of the dropwise addition, and the temperature was raised to 80℃for the reaction, and the reaction was completed by HPLC detection and the thermal phase separation was completed.
Step 1, component detection: the relative content of ethyl triclopyr in the first organic phase was 94.8% and the relative content of the impurity pyridone was 3.3% as measured by the method of example 1.
Step 2
To the first organic phase obtained in step 1, 2.5g of m-chloroperoxybenzoic acid (0.0145 mol,0.06 eq) was added at 65℃and thermal phase separation was performed at the end of the reaction to obtain 68.5g of a second organic phase.
And 2, component detection: the relative content of ethyl triclopyr in the second organic phase was 96.6% and the relative content of impurity pyridone was 0.2% as measured by the method of example 1; the absolute content of ethyl triclopyr in the second organic phase was 92.1 wt.%. The yield of ethyl triclopyr was 92.8% calculated as 68.0g of theoretical yield.
Step 3
Mixing the second organic phase obtained in the step 2 with 150g of ethylene glycol monobutyl ether, distilling under reduced pressure to remove water until the water content in the reaction liquid is less than 0.3 weight percent, adding 0.5g of monobutyl tin oxide, reacting at 150 ℃ under slight negative pressure while removing low-boiling substances, monitoring the disappearance of raw materials by HPLC, and distilling under reduced pressure to obtain 75.9g of product.
And 3, component detection: the relative content of 2-butoxyethyl ester of triclopyr in the product was 98.2% and the absolute content was 98.0% as determined by the detection method in example 1. The total yield of 2-butoxyethyl trichloropicolinate in the two-step reaction was 89.1% calculated as 85.2g of theoretical yield.
Example 20
Step 1
To a three-necked flask, 60g of sodium trichloropyridine alkoxide (88% by weight) (0.399 mol,1.0 eq), 150g of saturated aqueous sodium chloride solution, 6.0g of tetrabutylammonium bromide (0.0186 mol,0.078 eq) were added, and the mixture was stirred at 80℃to slowly drop 32.2g of ethyl chloroacetate (0.263 mol,1.1 eq), the dropping was completed, the temperature reaction was maintained, and the reaction was completed by HPLC detection, and the first organic phase was obtained by thermal phase separation.
Step 1, component detection: the relative content of ethyl triclopyr in the first organic phase was 94.0% and the relative content of the impurity pyridone was 3.9% as determined by the procedure of example 1.
Step 2
To the first organic phase obtained in step 1, 2.5g of m-chloroperoxybenzoic acid (0.0145 mol,0.06 eq) was added at 65℃and thermal phase separation was performed at the end of the reaction to obtain 69.4g of a second organic phase.
And 2, component detection: the relative content of ethyl triclopyr in the second organic phase was 96.1% and the relative content of impurity pyridone was 0.02% as measured in example 1; the absolute content of ethyl triclopyr in the second organic phase was 89.3 wt.%. The yield of ethyl triclopyr was 91.1% calculated as 68.0g of theoretical yield.
Step 3
Mixing the second organic phase obtained in the step 2 with 150g of ethylene glycol monobutyl ether, distilling under reduced pressure to remove water until the water content in the reaction liquid is less than 0.3 weight percent, adding 0.5g of monobutyl tin oxide, reacting at 150 ℃ under slight negative pressure while removing low-boiling substances, monitoring the disappearance of raw materials by HPLC, and distilling under reduced pressure to obtain 74.3g of product.
And 3, component detection: the relative content of 2-butoxyethyl trichloropicolinate in the product was 97.6% and the absolute content was 97.4% as determined by the method of detection in example 1. The total yield of 2-butoxyethyl trichloropicolinate in the two-step reaction was 87.2% calculated as 85.2g of theoretical yield.
As can be seen from examples 1 to 8 and comparative examples 1 to 4 above, the specific pyridone impurity remover can significantly reduce the content of pyridone impurities during the reaction, and as can be seen from example 9, it can be performed without additional addition of solvent in step 1, and as can be seen from examples 10 to 11, either sodium or potassium triclopyr alcohol can be used in step 1; it can be seen from examples 12 to 15 that the pyridone impurity remover can function over a wide temperature range; examples 16 to 18 verify that a variety of phase transfer catalysts can be used in step 1; examples 19 to 20 verify the different reaction temperatures of step 1.
Claims (18)
1. A method of removing a pyridone impurity of formula III from a mixture comprising an alkyl picolinate of formula II and a pyridone impurity of formula III,
wherein X each independently represents hydrogen or halogen, e.g., fluorine, chlorine, bromine or iodine, preferably chlorine, more preferably all X are chlorine,
y represents hydrogen, halogen or C 1 -C 6 An alkyl group, preferably hydrogen,
R 1 represent C 1 -C 6 Alkyl, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl, preferably ethyl,
the method comprises the following steps: adding a pyridone impurity remover to the mixture; the pyridone impurity remover is selected from the group consisting of: organic peroxides, inorganic peroxides, haloacids, hypohalous acids, halous acids, perhalous acids, halous acid salts, hypohalous acid salts, halous acid salts, perhalous acid salts, and persulfates.
2. The process of claim 1 wherein the pyridone impurity remover is added in a molar ratio of pyridone impurity to pyridone impurity remover of formula III of from 2:1 to 24:1.
3. The process of claim 1 or 2, wherein after the pyridone impurity removal agent is reacted, an organic phase comprising alkyl picolinate of formula II is obtained by thermal phase separation.
4. A process for preparing an alkyl picolinate of formula II, wherein the process comprises:
step 1: combining a compound of formula I with a compound of formula X' -CH in the presence of a phase transfer catalyst 2 -C(＝O)-O-R 1 The compounds of formula (I) are reacted in water or an aqueous alkali metal salt solution, and thermal phase separation is carried out after the reaction to obtain a first organic phase containing alkyl picolinate of formula (II) and pyridone impurities of formula (III);
wherein M is sodium or potassium;
x each independently represents hydrogen or halogen, e.g., fluorine, chlorine, bromine or iodine, preferably chlorine, more preferably all X are chlorine,
y represents hydrogen, halogen or C 1 -C 6 An alkyl group, preferably hydrogen,
R 1 represent C 1 -C 6 Alkyl, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl, preferably ethyl,
x' represents halogen, for example fluorine, chlorine, bromine or iodine, preferably chlorine,
step 2: adding a pyridone impurity remover into the first organic phase, and thermally separating the phase again after the reaction to obtain a second organic phase containing alkyl picolinate of the formula II; the pyridone impurity remover is selected from the group consisting of: organic peroxides, inorganic peroxides, haloacids, hypohalous acids, halous acids, perhalous acids, halous acid salts, hypohalous acid salts, halous acid salts, perhalous acid salts, and persulfates.
5. The process of claim 4 wherein the second organic phase is used to react with ethylene glycol monobutyl ether to produce a compound of formula IV,
6. the process of any one of claims 1 to 5, wherein the pyridone impurity remover is selected from the group consisting of: h 2 O 2 Sodium hypochlorite, sodium chlorite, sodium chlorate, sodium perchlorate, hypochlorous acid, chlorous acid, chloric acid, perchloric acid, m-chloroperoxybenzoic acid, peroxyacetic acid, sodium persulfate, potassium persulfate and ammonium persulfate, preferably sodium hypochlorite.
7. The process of any one of claims 1 to 6, wherein the alkyl picolinate of formula II is ethyl triclopyr:
and/or
Wherein the pyridone impurity of formula III is:
8. the process of any one of claims 1 to 7, wherein the pyridone impurity remover is reacted at a temperature in the range of 0-100 ℃, preferably at a temperature in the range of 50-70 ℃.
9. The method of any one of claims 4 to 8, wherein the compound of formula I is:
wherein M is sodium or potassium.
10. The method of any one of claims 4 to 9, wherein the formula X' -CH 2 -C(＝O)-O-R 1 The compound of (2) is ethyl chloroacetate: cl-CH 2 -C(＝O)-O-CH 2 -CH 3 。
11. The method of any one of claims 4 to 10, wherein the aqueous alkali metal salt solution is selected from the group consisting of aqueous sodium chloride, aqueous potassium chloride, aqueous sodium carbonate, aqueous potassium carbonate, aqueous sodium bicarbonate, aqueous potassium bicarbonate, aqueous sodium phosphate, aqueous potassium phosphate, aqueous sodium hydrogen phosphate, aqueous potassium hydrogen phosphate, or any combination thereof.
12. The process of any one of claims 4 to 11, wherein the reaction of step 1 is carried out at a temperature in the range of 20-100 ℃, preferably at a temperature in the range of 40-80 ℃.
13. The process of any one of claims 4 to 12, wherein the phase transfer catalyst in step 1 is selected from the group consisting of tetrabutylammonium bromide, tetraethylammonium bromide, benzyltriethylammonium bromide, sodium dodecyl sulfate, sodium dodecylbenzenesulfonate, benzyltriethylammonium chloride, tetrabutylammonium chloride, trioctylmethylammonium chloride, dodecyltrimethylammonium chloride, polyethylene glycol, 18-crown-6, and any combination thereof.
14. The method of any one of claims 4 to 13, wherein the compound of formula I in step 1 is reacted with a compound of formula X' -CH 2 -C(＝O)-O-R 1 The molar ratio of the compounds is 1:1 to 1:2.
15. The process of any one of claims 4-14, wherein the molar ratio of the compound of formula I to the phase transfer catalyst in step 1 is from 1:0.01 to 1:0.5; and/or the number of the groups of groups,
wherein the mass ratio of the compound of formula I to the alkali metal salt in step 1 is 1:0.05 to 1:2.
16. The process of any one of claims 4 to 15, wherein the pyridone impurity remover is used in a molar ratio to the starting compound of formula I of from (0.05 to 1.5): 1.
17. The process of claim 5, wherein the reaction of the second organic phase with ethylene glycol monobutyl ether is carried out at a temperature in the range of 110-170 ℃, preferably 120-160 ℃.
18. The process of claim 17 wherein the catalyst that catalyzes the reaction of the second organic phase with ethylene glycol monobutyl ether is selected from the group consisting of monobutyl tin oxide, sulfuric acid, p-toluene sulfonic acid.
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