CN110669041B - Synthetic method of flumioxazin - Google Patents
Synthetic method of flumioxazin Download PDFInfo
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Abstract
The invention discloses flumioxazin which has a structure shown in a formula I and is characterized in that: reacting 6-amino-7-fluoro-4-propynyl-1, 4-benzoxazine-3 (4H) -ketone shown in a formula II with 3,4,5, 6-tetrahydrophthalic anhydride shown in a formula III in a solvent, wherein the solvent is hydrous acetic acid, and the water content in the hydrous acetic acid is 5-50%. The method provided by the invention can be used for directly feeding phthalic anhydride and 3,4,5, 6-tetrahydrophthalic anhydride with higher 2,3,4, 5-tetrahydrophthalic anhydride content as raw materials under the condition of no purification, and can be in contact reaction with 6-amino-7-fluoro-4-propynyl-1, 4-benzoxazine-3 (4H) -one without purification, so that the generation of two impurities difficult to remove, namely M354-delta 2 and M350, can be effectively avoided, the content of the two impurities in the flumioxazin crude product is controlled to be below 0.1%, and the flumioxazin product is ensured to meet the requirement of quality standard.
Description
Technical Field
The invention relates to a synthetic method of flumioxazin, belonging to the technical field of chemical synthesis.
Background
Flumioxazin (quick harvest) is an N-phenyl o-aminomethephon imine herbicide which is produced and developed by Sumitomo chemical industry Co., Ltd, is absorbed by sprouts and leaves, can effectively prevent and kill 1-year-old broadleaf weeds and partial gramineous weeds when used for soil treatment, is easy to degrade in the environment, and is safe for the next crop. The soybean and the peanut have good drug resistance. The herbicide has moderate tolerance to corn, wheat, barley and rice, so the herbicide has wide application in agricultural production and has great economic market value.
There are various synthetic methods for the synthesis of flumioxazin, such as Lyga, Jo flumioxazin synthetic method n W. et al in Pesticide Science; vol.55; nb.3; (1999) (ii) a p.281-287 for a review of the synthesis of flumioxazin; flumioxazin can be prepared by reacting 6-amino-7-fluoro-4-propynyl-1, 4-benzoxazin-3 (4H) -one with 3,4,5, 6-tetrahydrophthalic anhydride as described in US 5108488 and US 4640707. 2011 Liuanchang et al published a synthesis study of a novel herbicide flumioxazin on world pesticides (world pesticides, 2011,33(2), 27-29). Liwenan et al reported the synthesis of the highly effective herbicide flumioxazin on the 93 rd academic meeting discourse collection of the national institute of Industrial and Industrial science (pages 220 and 222) of the Chinese chemical society. JP patent JP propyzamide synthesis method 0597848 issued by Sumitomo chemical industry Co., Ltd., Japan describes that 1, 3-dimethylbutenylamino) -7-fluoro-4- (2-propargyl) -1, 4-benzoxazine-3 (4-propyzamide synthesis method) -one reacts with 3,4,5, 6-tetrahydrophthalic anhydride to produce propyzamide with a yield of 95% and a content of 99%.
Chinese patent CN105061416B previously filed by this company has provided a method for preparing high content flumioxazin, that is, 6-amino-7-fluoro-4-propynyl-1, 4-benzoxazine-3 (4H) -one is contacted with 3,4,5, 6-tetrahydrophthalic anhydride in solvent in the presence of catalyst; the catalyst is an alkaline nitrogen-containing organic matter or a mixture of an organic acid and the alkaline nitrogen-containing organic matter, and the solvent is a solvent capable of azeotropically removing water. The yield of the flumioxazin product prepared by the method can reach more than 90%, the purity can reach more than 99% by weight, and the content of organic impurities is lower than 0.1% by weight. However, the method has high requirements on raw materials, and if the purity of the 6-amino-7-fluoro-4-propynyl-1, 4-benzoxazine-3 (4H) -one and the 3,4,5, 6-tetrahydrophthalic anhydride is low, the impurity content of the flumioxazin product is increased, so that the flumioxazin product needs to be further purified, or the two raw materials are pre-purified and then fed.
Since the impurities in the starting material 3,4,5, 6-tetrahydrophthalic anhydride are mostly anhydrides having very similar properties, such as 1,2,3, 6-tetrahydrophthalic anhydride, 1,2,3, 4-tetrahydrophthalic anhydride, 2,3,4, 5-tetrahydrophthalic anhydride, phthalic anhydride and hexahydrophthalic anhydride, these impurities, if not removed, react with 6-amino-7-fluoro-4-propynyl-1, 4-benzoxazin-3 (4H) -one to cause impurities; in particular, M350 produced by the reaction of phthalic anhydride with 6-amino-7-fluoro-4-propynyl-1, 4-benzoxazin-3 (4H) -one, and M354- Δ 2 produced by the reaction of 2,3,4, 5-tetrahydrophthalic anhydride (. DELTA.2-tetrahydrophthalic anhydride) with 6-amino-7-fluoro-4-propynyl-1, 4-benzoxazin-3 (4H) -one are very difficult to remove during purification. If the content of the two impurities in the flumioxazin crude product is more than 0.1%, the content can not be reduced to below 0.1% by adopting a conventional purification method (such as recrystallization, pulping and the like); if the content of other impurities (e.g., M262, M220, M316, M356, M350, M336, M354-. DELTA.3) is more than 0.1%, they can be removed by a conventional purification method.
Chinese patent CN105061416B provides another method using a solvent capable of azeotropic dehydration and acetic acid/organic base catalysis, and although it is not necessary to purify 3,4,5, 6-tetrahydrophthalic anhydride, we have found through experiments that once the content of Δ 2-tetrahydrophthalic anhydride in 3,4,5, 6-tetrahydrophthalic anhydride is greater than 0.3%, this synthetic method cannot ensure that the content of M354- Δ 2 impurity in flumioxazin is less than 0.1%.
The largest 3,4,5, 6-tetrahydrophthalic anhydride manufacturer in China is Puyang-Hecheng electronic materials, Inc., from which 3,4,5, 6-tetrahydrophthalic anhydride used by my company is mostly purchased. Before 2016, the company has a 3,4,5, 6-tetrahydrophthalic anhydride product with a main content of not less than 96.0%, a phthalic anhydride content of more than 0.4%, and a 2,3,4, 5-tetrahydrophthalic anhydride (delta 2-tetrahydrophthalic anhydride) content of not more than 0.3%. However, from 2016, the content of 2,3,4, 5-tetrahydrophthalic anhydride (delta 2-tetrahydrophthalic anhydride) in 3,4,5, 6-tetrahydrophthalic anhydride products is higher than 0.3%, even reaches 0.6% in some batches, and the content of phthalic anhydride is still higher than 0.05% with slight decrease. Directly feeding a 3,4,5, 6-tetrahydrophthalic anhydride product after 2016 years of use, wherein the contents of impurities M354-delta 2 and M350 are both higher than 0.1%; therefore, the 3,4,5, 6-tetrahydrophthalic anhydride must be purified in advance before being fed, which not only increases the loss of raw materials and the production cost, but also increases the difficulty of industrial operation.
Disclosure of Invention
The invention aims to provide a synthetic method of flumioxazin aiming at the defects and shortcomings of the prior art, the method is simple in process and convenient for industrial operation, can effectively avoid the generation of two impurities of M354-delta 2 and M350, and ensures the product quality of the flumioxazin.
In order to achieve the purpose, the invention adopts the technical scheme that:
a synthetic method of flumioxazin with a structure shown as a formula I comprises the following steps: reacting 6-amino-7-fluoro-4-propynyl-1, 4-benzoxazin-3 (4H) -one of formula II with 3,4,5, 6-tetrahydrophthalic anhydride of formula III in a solvent, which is aqueous acetic acid,
the synthesis method comprises the following specific steps:
step A, putting aqueous acetic acid and 3,4,5, 6-tetrahydrophthalic anhydride into a reactor for pre-reaction, and then cooling to room temperature;
step B, putting 6-amino-7-fluoro-4-propynyl-1, 4-benzoxazine-3 (4H) -ketone into a reactor for reaction, and cooling to room temperature after the reaction is finished;
and C, filtering and drying to obtain the high-purity flumioxazin.
In the above synthesis method, the water content in the aqueous acetic acid is 5% to 50%, more preferably 10% to 30%. The volume amount of the aqueous acetic acid is 1-8 times, and more preferably 3-5 times of the weight of 6-amino-7-fluoro-4-propynyl-1, 4-benzoxazine-3 (4H) -ketone. The feeding molar ratio of the 6-amino-7-fluoro-4-propynyl-1, 4-benzoxazine-3 (4H) -ketone to the 3,4,5, 6-tetrahydrophthalic anhydride is 1: 1-2, more preferably 1: 1.05 to 1.1.
In the step A, the reaction temperature is 60-reflux temperature, preferably 90-100 ℃; the reaction time is 0.1 to 5 hours, preferably 0.5 to 2 hours.
In the step B, the reaction temperature is 60-reflux temperature, preferably 90-100 ℃; the reaction time is 1-12 h, preferably 2-5 h, and more preferably 3-4 h.
And C, filtering at room temperature, pulping the filter cake with 95% ethanol at room temperature, filtering, and drying. The volume of the 95% ethanol is 3-10 times, preferably 5-8 times of the mass of 6-amino-7-fluoro-4-propynyl-1, 4-benzoxazine-3 (4H) -ketone.
If the main content of the flumioxazin obtained in the step C is more than 99.5 percent and the single impurity content is less than 0.1 percent, the flumioxazin can be directly used as a finished product for treatment; and D, if the main content of the flumioxazin obtained in the step C is less than 99.5 percent or the single impurity content is higher than 0.1 percent, refining the crude product, namely the step D.
The specific step of the step D is to perform recrystallization by using any system of acetic acid/ethanol, acetic acid/methanol or dichloromethane/isopropanol. The refining adopts a conventional method: heating and dissolving the flumioxazin crude product in a first solvent, dripping a second solvent for recrystallization, and filtering to obtain the flumioxazin finished product.
Due to the adoption of the technical scheme, the invention has the beneficial effects that:
the invention provides a synthetic method of flumioxazin shown in formula I, aiming at 3,4,5, 6-tetrahydrophthalic anhydride which is a raw material with higher content of phthalic anhydride and 2,3,4, 5-tetrahydrophthalic anhydride, the raw material can be directly fed under the condition of no purification and can be in contact reaction with 6-amino-7-fluoro-4-propynyl-1, 4-benzoxazine-3 (4H) -ketone which is not purified, so that the generation of two impurities which are difficult to remove, namely M354-delta 2 and M350, can be effectively avoided, the content of the two impurities in a flumioxazin crude product is controlled below 0.1 percent, and the flumioxazin product can meet the requirement of quality standard.
The method has the advantages of simple reaction, mild conditions, high reaction yield, high product content, conventional and few reaction equipment, and is convenient for industrial large-scale production expansion. The yield of the flumioxazin product prepared by the method can reach 88-92% (mother liquor is not used indiscriminately), and the yield can reach 93-95% under the condition of indiscriminate use of the mother liquor; the content of the flumioxazin product can easily reach the quality control requirement of 99.2 percent.
Drawings
FIG. 1 is a liquid phase diagram of the product of example 1 of the present invention;
FIG. 2 is a liquid phase diagram of a comparative example 1 product of the present invention;
FIG. 3 is a liquid phase diagram of a comparative example 3 product of the present invention.
Detailed Description
The present invention will be described in detail with reference to examples. It should be understood that the detailed description and specific examples, while indicating the present invention, are given by way of illustration and explanation only, not limitation.
Chinese patent CN105061416B previously filed by this company has provided a method for preparing high content flumioxazin, that is, 6-amino-7-fluoro-4-propynyl-1, 4-benzoxazine-3 (4H) -one is contacted with 3,4,5, 6-tetrahydrophthalic anhydride in solvent in the presence of catalyst; the catalyst is an alkaline nitrogen-containing organic matter or a mixture of an organic acid and the alkaline nitrogen-containing organic matter, and the solvent is a solvent capable of azeotropically removing water. The main chemical reactions of the method are as follows:
one of raw materials used in the reaction is 3,4,5, 6-tetrahydrophthalic anhydride, the content of the 3,4,5, 6-tetrahydrophthalic anhydride which is commercialized at home and can be supplied in a ton grade at present is about 96 percent, and the main impurities of the 3,4,5, 6-tetrahydrophthalic anhydride comprise the following substances:
since 2016, the impurity 2,3,4, 5-tetrahydrophthalic anhydride (Δ 2-tetrahydrophthalic anhydride) content in the sample provided by Puyang Pucheng electronics materials GmbH, the largest domestic 3,4,5, 6-tetrahydrophthalic anhydride manufacturer, has been high. The results of the gas phase analysis as shown in the table below show that the manufacturer provided less than 0.3% 2,3,4, 5-tetrahydrophthalic anhydride (Δ 2-tetrahydrophthalic anhydride) in 2015, while the manufacturer provided more than 0.3% 2,3,4, 5-tetrahydrophthalic anhydride (Δ 2-tetrahydrophthalic anhydride) in 2017, and even some batches up to 0.6%.
Note: in the table, M148 is phthalic anhydride, M152-. DELTA.1 is 3,4,5, 6-tetrahydrophthalic anhydride, M152-. DELTA.2 is 2,3,4, 5-tetrahydrophthalic anhydride, M152-. DELTA.3 is 1,2,3, 4-tetrahydrophthalic anhydride, M152-. DELTA.4 is 1,2,3, 6-tetrahydrophthalic anhydride, and M154 is hexahydrophthalic anhydride.
As the impurities in the 3,4,5, 6-tetrahydrophthalic anhydride are all anhydrides with similar structures to the 3,4,5, 6-tetrahydrophthalic anhydride, the impurities can react with the 6-amino-7-fluoro-4-propynyl-1, 4-benzoxazine-3 (4H) -ketone to generate corresponding impurities, and the impurities have similar properties to the flumioxazin and are difficult to remove, which is the biggest obstacle for improving the content of the flumioxazin, and particularly, the single impurity content in the product is reduced to be less than 0.1 percent, so that great difficulty exists.
At present, the compounds contained in the flumioxazin products mainly comprise the following compounds:
according to the product specification requirement of flumioxazin, the content of the main component is not less than 99.2%.
Intensive research results show that most of impurities (such as M262, M220, M316, M354-delta 3, M356, M350 and M336) in a series of impurities mixed with flumioxazin can be removed by recrystallization in a single or mixed solvent (such as ethanol, methanol and the like), but two impurities (such as M350 and M354-delta 2) are difficult to remove, and the content of the two impurities is slightly changed before and after purification. After analyzing the impurity structure, the two difficultly removed impurities are generated by respectively reacting phthalic anhydride and 2,3,4, 5-tetrahydrophthalic anhydride (delta 2-tetrahydrophthalic anhydride), which are impurities contained in tetrahydrophthalic anhydride, with 6-amino-7-fluoro-4-propynyl-1, 4-benzoxazine-3 (4H) -one.
Repeated experiments confirm that the two impurities of M350 and M354-delta 2 can be controlled only through reaction, and are extremely difficult to remove after the reaction, wherein the impurities are included in the flumioxazin. If the content of M350 and M354-delta 2 in the flumioxazin crude product is more than 0.1%, the content of single impurity of the flumioxazin cannot meet the quality control standard of less than 0.1% inevitably; if the content of M350 and M354-delta 2 is too large, the content of the flumioxazin can even be less than 99 percent. In other words, when 3,4,5, 6-tetrahydrophthalic anhydride, which is currently sold by Puyang-Hecheng electronic materials, GmbH, is used as a raw material to synthesize flumioxazin, the content of M350 and M354-Delta 2 in the obtained flumioxazin crude product is more than 0.1%, and even if the flumioxazin product is recrystallized and purified, other impurities can be removed, but the content of M350 and M354-Delta 2 cannot be reduced to be less than 0.1%.
In order to solve the problems, the invention provides a synthetic method of flumioxazin, which has a structure shown in formula I, and the synthetic method comprises the following steps: reacting 6-amino-7-fluoro-4-propynyl-1, 4-benzoxazin-3 (4H) -one of formula II with 3,4,5, 6-tetrahydrophthalic anhydride of formula III in a solvent, which is aqueous acetic acid,
the main chemical reactions of the method are as follows:
the method comprises the following specific steps:
step A, putting aqueous acetic acid and 3,4,5, 6-tetrahydrophthalic anhydride into a reactor for pre-reaction, and then cooling to room temperature;
step B, putting 6-amino-7-fluoro-4-propynyl-1, 4-benzoxazine-3 (4H) -ketone into a reactor for reaction, and cooling to room temperature after the reaction is finished;
c, filtering and drying to obtain flumioxazin;
d, if the main content of the flumioxazin obtained in the step C is more than 99.5 percent and the single impurity content is less than 0.1 percent, directly processing the flumioxazin into a finished product; and (C) if the main content of the flumioxazin obtained in the step C is less than 99.5% or the single impurity content is higher than 0.1%, refining the crude product. Recrystallizing with acetic acid/ethanol, acetic acid/methanol or dichloromethane/isopropanol according to conventional method; heating and dissolving the flumioxazin crude product in a first solvent, then cooling, dropwise adding a second solvent to separate out the product, growing crystals, and filtering to obtain the flumioxazin finished product.
During industrial production, a plurality of batches of flumioxazin products can be uniformly mixed; if the main content and the single impurity content after mixing reach the quality standard, refining treatment can be omitted; if the mixed materials do not reach the standard, the materials can be refined with large feeding amount, and the refining loss is reduced.
In the above synthesis method, the water content in the aqueous acetic acid is 5% to 50%, more preferably 10% to 30%. The volume amount of the aqueous acetic acid is 1-8 times, and more preferably 3-5 times of the weight of 6-amino-7-fluoro-4-propynyl-1, 4-benzoxazine-3 (4H) -ketone. The feeding molar ratio of the 6-amino-7-fluoro-4-propynyl-1, 4-benzoxazine-3 (4H) -ketone to the 3,4,5, 6-tetrahydrophthalic anhydride is 1: 1-2, more preferably 1: 1.05 to 1.1.
In the step A, the reaction temperature is 60-reflux temperature, preferably 90-100 ℃; the reaction time is 0.1 to 5 hours, preferably 0.5 to 2 hours.
In the step B, the reaction temperature is 60-reflux temperature, preferably 90-100 ℃; the reaction time is 1-12 h, preferably 2-5 h, and more preferably 3-4 h.
And C, filtering at room temperature, pulping the filter cake with 95% ethanol at room temperature, filtering, and drying. The volume of the 95% ethanol is 3-10 times, preferably 5-8 times of the mass of 6-amino-7-fluoro-4-propynyl-1, 4-benzoxazine-3 (4H) -ketone.
Tetrahydrophthalic anhydride is a relatively reactive anhydride which, in the general chemical knowledge, decomposes with water. At first, the inventor is limited by the common knowledge, and cannot try to use the aqueous acetic acid as a solvent to synthesize the flumioxazin, and even the acetic acid is recovered as the solvent and is purposely used after being removed of water. Later, the acetic acid containing water is not obviously decomposed in the process of applying the acetic acid solution. Especially, in the reaction monitoring, the 3,4,5, 6-tetrahydrophthalic anhydride is not excessive, and liquid phase detection is carried out after the reaction is finished, so that the residual is remained. Based on this finding, we made destructive tests to find that 3,4,5, 6-tetrahydrophthalic anhydride is not easily hydrolyzed, or only a small portion of the hydrolysis is performed, in the acetic acid/water system. Hydrolysis and cyclization are in equilibrium. The invention unexpectedly solves the problem of impurities caused by the high content of 2,3,4, 5-tetrahydrophthalic anhydride (delta 2-tetrahydrophthalic anhydride) by using an acetic acid/water system as a solvent, and simultaneously greatly reduces the generation of another impurity, namely an acetylation byproduct (M262). As for the reaction mechanism, we guess that the presence of a proper amount of water makes other impurity acid anhydrides easy to hydrolyze and not easy to cyclize, thereby achieving the effect of in-situ purification.
The present invention will be described with reference to examples.
In the following examples of the present invention,
purity (% by weight) was measured using Agilent HPLC 1200;
the yield (%) was calculated as: yield (%) — actual yield (g) × purity (% by weight) ÷ theoretical yield (g) × 100%.
In the following examples, the starting materials used were:
example 1
Step A: placing 14.6g of 3,4,5, 6-tetrahydrophthalic anhydride (M152-delta 2 content is 0.4% -0.6%) with content more than 97% into a reaction bottle, adding 80mL of acetic acid and 20mL of water, stirring and heating to 95-100 ℃, preserving heat for reaction for 2 hours, and cooling to room temperature;
and B: adding 20.8g of 6-amino-7-fluoro-4-propynyl-1, 4-benzoxazine-3 (4H) -ketone (content 92.17%) into a reaction bottle, heating to 95-100 ℃, preserving heat for reaction for 3-4 hours, after the central control detection reaction (HPLC method) is finished, cooling to room temperature;
and C: filtering, pulping with 80mL of 95% ethanol at room temperature, filtering, and drying to obtain 27.86g of a crude flumioxazin product;
through detection, the content of the obtained flumioxazin crude product is 99.34%, the content of M354-delta 2 is 0.00%, and the content of M350 is 0.08%, which are all less than 0.1%. The calculated yield was 89.72%.
Step D: refining the flumioxazin crude product by using acetic acid/ethanol to obtain the high-purity flumioxazin with single impurity content of less than 0.1%.
Examples 2 to 7
Examples 2 to 7 were repeated for the stability test of example 1, using the same starting materials and reaction parameters as in example 1. The content of the flumioxazin crude products obtained in examples 1 to 7 is detected, and the analysis results are shown in the following table:
| examples | 1 | 2 | 3 | 4 | 5 | 6 | 7 |
| M262 | 0.02 | 0.00 | 0.02 | 0.02 | 0.02 | 0.00 | 0.00 |
| M220 | 0.00 | 0.00 | 0.00 | 0.03 | 0.00 | 0.00 | 0.00 |
| M316 | 0.00 | 0.08 | 0.10 | 0.09 | 0.07 | 0.11 | 0.13 |
| M354-Δ2 | 0.00 | 0.00 | 0.00 | 0.03 | 0.04 | 0.00 | 0.00 |
| M354-Δ3 | 0.14 | 0.21 | 0.22 | 0.23 | 0.16 | 0.23 | 0.18 |
| M356 | 0.02 | 0.00 | 0.00 | 0.03 | 0.00 | 0.00 | 0.00 |
| M350 | 0.08 | 0.06 | 0.06 | 0.07 | 0.08 | 0.06 | 0.06 |
| M336 | 0.06 | 0.07 | 0.00 | 0.09 | 0.06 | 0.08 | 0.00 |
| M354-Δ1 | 99.66 | 99.50 | 99.54 | 99.37 | 99.34 | 99.39 | 99.39 |
From the data, the content of the flumioxazin crude product prepared by the method is not less than 99.3%, the content of two impurities M354-delta 2 and M350 which are difficult to purify are both less than 0.1%, and the content of M354-delta 2 can even be as low as 0.00%.
Example 8
Step A: placing 14.6g of 3,4,5, 6-tetrahydrophthalic anhydride (M152-delta 2 content is 0.4% -0.6%) with content more than 97% into a reaction bottle, adding 80mL of acetic acid and 20mL of water, stirring and heating to 95-100 ℃, keeping the temperature for reaction for 0.5 hour, and cooling to room temperature;
and B: adding 6-amino-7-fluoro-4-propynyl-1, 4-benzoxazine-3 (4H) -ketone (content is 96%) into a reaction bottle, heating to 95-100 ℃, keeping the temperature, reacting for 3-4 hours, and cooling to room temperature after the reaction of the central control detection (HPLC method);
and C: filtering, pulping with 80mL of 95% ethanol at room temperature, filtering, and drying to obtain 28.68g of a crude flumioxazin product;
through detection, the content of the obtained crude product is 99.22%, and the contents of impurities M262, M316, M220, M354-delta 2, M354-delta 3, M356, M336 and M350 are all less than 0.1%. Can be directly used as a finished product without refining.
The yield of this example was calculated to be 92.12%.
Example 9
Step A: placing 14.6g of 3,4,5, 6-tetrahydrophthalic anhydride (M152-delta 2 content is 0.4% -0.6%) with content more than 97% into a reaction bottle, adding 90mL of acetic acid and 10mL of water, stirring and heating to 95-100 ℃, preserving heat for reaction for 2 hours, and cooling to room temperature;
and B: adding 20.0g of 6-amino-7-fluoro-4-propynyl-1, 4-benzoxazine-3 (4H) -ketone (the content is 96%) into a reaction bottle, heating to 95-100 ℃, preserving heat for reaction for 3-4 hours, after the reaction of the central control detection (HPLC method), cooling to room temperature;
and C: filtering, pulping with 80mL of 95% ethanol at room temperature, filtering, and drying to obtain 26.58g of a crude flumioxazin product;
through detection, the content of the crude product is 99.65%, and the contents of impurities M262, M316, M220, M354-delta 2, M354-delta 3, M356, M336 and M350 are all less than 0.1%. Can be directly used as a finished product without refining.
The yield of this example was calculated to be 85.92%.
Example 10
Step A: placing 14.6g of 3,4,5, 6-tetrahydrophthalic anhydride (M152-delta 2 content is 0.4% -0.6%) with content more than 97% into a reaction bottle, adding 70mL of acetic acid and 30mL of water, stirring and heating to 95-100 ℃, preserving heat for reaction for 2 hours, and cooling to room temperature;
and B: adding 20.0g of 6-amino-7-fluoro-4-propynyl-1, 4-benzoxazine-3 (4H) -ketone (the content is 96%) into a reaction bottle, heating to 95-100 ℃, preserving heat for reaction for 3-4 hours, after the reaction of the central control detection (HPLC method), cooling to room temperature;
and C: filtering, pulping with 80mL of 95% ethanol at room temperature, filtering, and drying to obtain 29.68g of a crude flumioxazin product;
through detection, the content of the crude product is 96.92%, and the content of impurities M354-delta 2 and M350 which are difficult to purify is less than 0.1%. The crude yield was calculated to be 93.3%.
Step D: refining the flumioxazin crude product by using acetic acid/ethanol, dissolving the flumioxazin crude product by using acetic acid at high temperature, and adding absolute ethanol for recrystallization to obtain high-purity flumioxazin; the content is more than 99.6 percent, the content of single impurity is less than 0.1 percent, and the refining loss rate is about 5 percent.
Example 11
Step A: placing 14.6g of 3,4,5, 6-tetrahydrophthalic anhydride (M152-delta 2 content is 0.4% -0.6%) with content more than 97% into a reaction bottle, adding 60mL of acetic acid and 40mL of water, stirring and heating to 95-100 ℃, preserving heat for reaction for 2 hours, and cooling to room temperature;
and B: adding 20.0g of 6-amino-7-fluoro-4-propynyl-1, 4-benzoxazine-3 (4H) -ketone (the content is 96%) into a reaction bottle, heating to 95-100 ℃, preserving heat for reaction for 3-4 hours, after the reaction of the central control detection (HPLC method), cooling to room temperature;
and C: filtering, pulping with 80mL of 95% ethanol at room temperature, filtering, and drying to obtain 30.24g of a crude flumioxazin product; the detection shows that the content of the product is 95.33 percent, and the content of impurities (M354-delta 2 and M350) which are difficult to purify is less than 0.1 percent. The crude yield was calculated to be 93.5%.
Step D: refining the flumioxazin crude product by using acetic acid/methanol, dissolving the flumioxazin crude product by using acetic acid at high temperature, and adding anhydrous methanol for recrystallization to obtain high-purity flumioxazin; the content is more than 99.5 percent, the content of single impurity is less than 0.1 percent, and the refining loss rate is about 5 percent.
Example 12
Step A: placing 14.6g of 3,4,5, 6-tetrahydrophthalic anhydride (M152-delta 2 content is 0.4% -0.6%) with content more than 97% into a reaction bottle, adding 50mL of acetic acid and 50mL of water, stirring and heating to 95-100 ℃, preserving heat for reaction for 2 hours, and cooling to room temperature;
and B: adding 20.0g of 6-amino-7-fluoro-4-propynyl-1, 4-benzoxazine-3 (4H) -ketone (the content is 96%) into a reaction bottle, heating to 95-100 ℃, preserving heat for reaction for 3-4 hours, after the reaction of the central control detection (HPLC method), cooling to room temperature;
and C: filtering, pulping with 80mL of 95% ethanol at room temperature, filtering, and drying to obtain 31.13g of a crude flumioxazin product;
the detection shows that the content of the crude product is 93.17 percent, and the content of impurities (M354-delta 2 and M350) which are difficult to purify is less than 0.1 percent. The crude yield was calculated to be 94.1%.
Step D: refining the flumioxazin crude product by adopting dichloromethane/isopropanol, refluxing and dissolving the flumioxazin crude product in dichloromethane, and adding isopropanol for recrystallization to obtain high-purity flumioxazin; the content is more than 99.2 percent, the content of single impurity is less than 0.1 percent, and the refining loss rate is about 3 percent.
Example 13
Step A: placing 14.6g of 3,4,5, 6-tetrahydrophthalic anhydride (M152-delta 2 content is 0.4% -0.6%) with content more than 97% into a reaction bottle, adding 80mL of acetic acid and 20mL of water, stirring and heating to 90-95 ℃, keeping the temperature for reaction for 0.5 hour, and cooling to room temperature;
and B: adding 20.0g of 6-amino-7-fluoro-4-propynyl-1, 4-benzoxazine-3 (4H) -ketone (the content is 96%) into a reaction bottle, heating to 95-100 ℃, preserving heat for reaction for 3-4 hours, after the reaction of the central control detection (HPLC method), cooling to room temperature;
and C: filtering, pulping with 80mL of 95% ethanol at room temperature, filtering and drying to obtain 27.66g of crude flumioxazin.
Through detection, the content of the crude product is 99.28%, and the content of impurities M354-delta 2 and M350 which are difficult to purify is less than 0.1%; the yield of this example was calculated to be 89.09%.
Step D: refining the flumioxazin crude product by using acetic acid/methanol, heating and dissolving the flumioxazin crude product in acetic acid, and adding anhydrous methanol for recrystallization to obtain high-purity flumioxazin; the content is more than 99.7 percent, the content of single impurities is less than 0.1 percent, and the refining loss rate is about 3 percent.
Example 14
Step A: placing 14.6g of 3,4,5, 6-tetrahydrophthalic anhydride (M152-delta 2 content is 0.4% -0.6%) with content more than 97% into a reaction bottle, adding 80mL of acetic acid and 20mL of water, stirring and heating to 80-85 ℃, keeping the temperature for reaction for 2 hours, and cooling to room temperature;
and B: adding 20.0g of 6-amino-7-fluoro-4-propynyl-1, 4-benzoxazine-3 (4H) -ketone (the content is 96%) into a reaction bottle, heating to 99-104 ℃, preserving heat, reacting for 3-4 hours, after the reaction of the central control detection (HPLC method), cooling to room temperature;
and C: filtering, pulping with 80mL of 95% ethanol at room temperature, filtering, and drying to obtain 27.46g of crude flumioxazin; through detection, the content of the crude product is 99.12%, and the contents of impurities M262, M316, M220, M354-delta 2, M354-delta 3, M356, M336 and M350 are all less than 0.1%. Can be directly used as a finished product without refining.
The yield of this example was calculated to be 88.29%.
Comparative example 1
In the comparative example, 6-amino-7-fluoro-4-propynyl-1, 4-benzoxazine-3 (4H) -one, 3,4,5, 6-tetrahydrophthalic anhydride (2017 tetrahydrophthalic anhydride, main content > 97%, M152-delta 2 content 0.4% -0.6%, M148 content 0.05%) and aqueous acetic acid were directly reacted after being mixed, and the reaction process of 3,4,5, 6-tetrahydrophthalic anhydride and aqueous acetic acid was removed.
The reaction comprises the following specific steps:
step A: placing 14.6g of 3,4,5, 6-tetrahydrophthalic anhydride and 20.0g of 6-amino-7-fluoro-4-propynyl-1, 4-benzoxazine-3 (4H) -ketone (the content is 96%) in a reaction bottle, adding 80mL of acetic acid and 20mL of water, heating to 95-100 ℃, keeping the temperature and reacting for about 3-4 hours, and cooling to room temperature after the central control detection reaction is finished;
and B: filtering, pulping with 80mL of 95% ethanol at room temperature, filtering and drying to obtain 27.58g of flumioxazin.
The product was subjected to HPLC, and the HPLC spectrum and the content table are shown in FIG. 2. As can be seen from the figure, the main content of the product is 98.8%, the content of difficult-to-purify impurities M354-delta 2 is 0.22%, the content of M350 is 0.13%, and the content of the two impurities is greatly higher than the control limit of 0.1%.
Comparative example 2
This comparative example directly mixes 6-amino-7-fluoro-4-propynyl-1, 4-benzoxazin-3 (4H) -one, 3,4,5, 6-tetrahydrophthalic anhydride (2015 tetrahydrophthalic anhydride, main content > 97%, M152-. DELTA.2 content 0.27%, M148 content 0.13%), and aqueous acetic acid and then reacts, and the reaction process of 3,4,5, 6-tetrahydrophthalic anhydride and aqueous acetic acid is eliminated.
The reaction comprises the following specific steps:
step A: placing 14.6g of 3,4,5, 6-tetrahydrophthalic anhydride and 20.0g of 6-amino-7-fluoro-4-propynyl-1, 4-benzoxazine-3 (4H) -ketone (the content is 96%) in a reaction bottle, adding 80mL of acetic acid and 20mL of water, heating to 95-100 ℃, keeping the temperature and reacting for about 3-4 hours, and cooling to room temperature after the central control detection reaction is finished;
and B: filtering, pulping with 80mL of 95% ethanol at room temperature, filtering and drying to obtain 27.21g of flumioxazin.
HPLC detection is carried out on the product, the content of the main product is 99.15%, the content of M354-delta 2 which is an impurity difficult to purify is 0.18%, the content of M350 is 0.25%, and the content of the two impurities is greatly higher than the control limit of 0.1%.
Comparative example 3
This comparative example was conducted by mixing 6-amino-7-fluoro-4-propynyl-1, 4-benzoxazin-3 (4H) -one, 3,4,5, 6-tetrahydrophthalic anhydride and a solvent, followed by reaction, and was substantially the same as in comparative example 1; the differences are as follows: acetic acid containing no water was used as a solvent.
The method comprises the following specific steps:
step A: placing 14.6g of 3,4,5, 6-tetrahydrophthalic anhydride (M152-delta 2 is 0.4% -0.6%) with the content of more than 97% and 20.0g of 6-amino-7-fluoro-4-propynyl-1, 4-benzoxazine-3 (4H) -ketone (with the content of 96%) in a reaction bottle, adding 100mL of acetic acid, heating to 95-100 ℃, carrying out heat preservation reaction for about 3-4 hours, after the central control detection reaction is finished, cooling to room temperature;
and B: filtering, pulping with 80mL of 95% ethanol at room temperature, filtering and drying to obtain 24.54g of flumioxazin.
The product was subjected to HPLC analysis, and the HPLC spectrum and the content table are shown in FIG. 3 (slightly different from the mobile phase of the liquid phase of comparative example 1, resulting in different retention times). As can be seen from the figure, the content of the product is 98.69%, the content of M354-Delta 2 which is an impurity difficult to purify is 0.47%, the content of M350 is 0.14%, and the content of the two impurities is greatly higher than the control limit of 0.1%.
Comparative example 4
Step A: placing 14.6g of 3,4,5, 6-tetrahydrophthalic anhydride (M152-delta 2 content is 0.4% -0.6%) with content more than 97% in a reaction bottle, adding 100mL of anhydrous acetic acid, stirring and heating to 95-100 ℃, preserving heat for reaction for 2 hours, and cooling to room temperature;
and B: adding 20.8g of 6-amino-7-fluoro-4-propynyl-1, 4-benzoxazine-3 (4H) -ketone (content 92.17%) into a reaction bottle, heating to 95-100 ℃, preserving heat for reaction for 3-4 hours, after the central control detection reaction (HPLC method) is finished, cooling to room temperature;
and C: filtering, pulping with 80mL of 95% ethanol at room temperature, filtering and drying to obtain 25.34g of flumioxazin.
Through detection, the content of the product is 98.91%, the content of the impurity M354-delta 2 difficult to purify is 0.13%, and the content of M350 is 0.15%.
In the above comparative examples, both comparative example 1 and comparative example 2 used aqueous acetic acid as the reaction solvent, eliminating the pre-reaction of 3,4,5, 6-tetrahydrophthalic anhydride with aqueous acetic acid given in step A of the process of the present invention; comparative example 1 used 3,4,5, 6-tetrahydrophthalic anhydride produced by Puyang-forming electronic materials, Inc. in 2017 as a raw material, and comparative example 2 used 3,4,5, 6-tetrahydrophthalic anhydride produced by the company in 2015 as a raw material. From the data of these two comparative examples it can be seen that the content of the two difficult impurities M354-. DELTA.2 and M350 cannot be controlled without pre-reacting the 3,4,5, 6-tetrahydrophthalic anhydride with aqueous acetic acid, irrespective of which starting material is used.
Comparative example 3 and comparative example 4 both used anhydrous acetic acid as a reaction solvent, wherein the reaction process of comparative example 3 was substantially the same as that of comparative example 1 except that the anhydrous acetic acid was replaced with the aqueous acetic acid in comparative example 1, and 3,4,5, 6-tetrahydrophthalic anhydride and 6-amino-7-fluoro-4-propynyl-1, 4-benzoxazin-3 (4H) -one were directly reacted; the reaction procedure of comparative example 4 was substantially the same as that of example 1 except that the reaction solvent was replaced. As can be seen from the reaction data of comparative example 3 and comparative example 4, the contents of the two difficult-to-purify impurities M354-Delta 2 and M350 are high, and the control limit of less than 0.1 percent cannot be reached.
The above description is only for the purpose of illustrating the technical solutions of the present invention and not for the purpose of limiting the same, and other modifications or equivalent substitutions made by those skilled in the art to the technical solutions of the present invention should be covered within the scope of the claims of the present invention without departing from the spirit and scope of the technical solutions of the present invention.
Claims (8)
1. A synthetic method of flumioxazin has a structure shown in a formula I, and is characterized in that: reacting 6-amino-7-fluoro-4-propynyl-1, 4-benzoxazine-3 (4H) -ketone shown in a formula II with 3,4,5, 6-tetrahydrophthalic anhydride shown in a formula III in a solvent, wherein the solvent is aqueous acetic acid, the water content of the aqueous acetic acid is 10-50%,
the method comprises the following specific steps:
step A, putting aqueous acetic acid and 3,4,5, 6-tetrahydrophthalic anhydride into a reactor for pre-reaction, and then cooling to room temperature;
step B, putting 6-amino-7-fluoro-4-propynyl-1, 4-benzoxazine-3 (4H) -ketone into a reactor for reaction, and cooling to room temperature after the reaction is finished;
and C, filtering and drying to obtain the high-purity flumioxazin.
2. The method for synthesizing flumioxazin as claimed in claim 1, which is characterized in that: the volume amount of the aqueous acetic acid is 1-8 times of the weight of 6-amino-7-fluoro-4-propynyl-1, 4-benzoxazine-3 (4H) -ketone.
3. The method for synthesizing flumioxazin as claimed in claim 1, which is characterized in that: the feeding molar ratio of the 6-amino-7-fluoro-4-propynyl-1, 4-benzoxazine-3 (4H) -ketone to the 3,4,5, 6-tetrahydrophthalic anhydride is 1: 1 to 2.
4. The method for synthesizing flumioxazin as claimed in claim 1, which is characterized in that: the reaction temperature of the step A is 60-reflux temperature, and the reaction time is 0.1-5 h.
5. The method for synthesizing flumioxazin as claimed in claim 1, which is characterized in that: the reaction temperature of the step B is 60-reflux temperature, and the reaction time is 1-12 h.
6. The method for synthesizing flumioxazin as claimed in claim 1, which is characterized in that: the concrete step of the step C is that the filtration is carried out at room temperature, then 95 percent ethanol is used for beating the filter cake at room temperature, and then the filtration and the drying are carried out; the volume of the 95% ethanol is 3-10 times of the mass of 6-amino-7-fluoro-4-propynyl-1, 4-benzoxazine-3 (4H) -ketone.
7. The method for synthesizing flumioxazin as claimed in claim 1, which is characterized in that: when the main content of the flumioxazin product obtained in the step C is less than 99.5 percent or the single impurity content is more than 0.1 percent, the refining process of the step D is also included.
8. The method for synthesizing flumioxazin as claimed in claim 7, which is characterized in that: the specific step of the step D is to perform recrystallization by using any system of acetic acid/ethanol, acetic acid/methanol or dichloromethane/isopropanol.
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| CN105061416A (en) * | 2015-07-16 | 2015-11-18 | 北京颖泰嘉和生物科技股份有限公司 | Method for preparing flumioxazin |
| CN105399699A (en) * | 2015-11-02 | 2016-03-16 | 迈克斯(如东)化工有限公司 | Preparation method and application of N-propinyl benzolactam compound |
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| CN104610186A (en) * | 2015-02-05 | 2015-05-13 | 北京颖泰嘉和生物科技有限公司 | Method for purifying amino benzoxazinone crude product and preparation method of flumioxazin |
| CN105061416A (en) * | 2015-07-16 | 2015-11-18 | 北京颖泰嘉和生物科技股份有限公司 | Method for preparing flumioxazin |
| CN105399699A (en) * | 2015-11-02 | 2016-03-16 | 迈克斯(如东)化工有限公司 | Preparation method and application of N-propinyl benzolactam compound |
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