CN111233828A - Preparation method of imazethapyr with stable crystal form - Google Patents
Preparation method of imazethapyr with stable crystal form Download PDFInfo
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- CN111233828A CN111233828A CN201811440518.1A CN201811440518A CN111233828A CN 111233828 A CN111233828 A CN 111233828A CN 201811440518 A CN201811440518 A CN 201811440518A CN 111233828 A CN111233828 A CN 111233828A
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Abstract
The specific embodiment of the invention provides a preparation method of imazethapyr with stable crystal form, which comprises the steps of adding acid into an aqueous solution of imazethapyr salt containing a crystallization modifier for precipitation to obtain imazethapyr crystals; the crystallization denaturant is benzene, alkylbenzene or halogenated alkane, and the preparation method has the advantages of high conversion rate of stable crystal forms and simple preparation process.
Description
Technical Field
The invention belongs to the field of organic purification of compounds, and particularly relates to a method for preparing imazethapyr with a stable crystal form.
Background
Imazethapyr (imazethapyr), also known as imazethapyr, belongs to an imidazolinone herbicide, and is a high-efficiency, low-toxicity and broad-spectrum herbicide for soybean fields developed by cyanamide company in the 80 s of the 20 th century. The chemical name of the imazethapyr is (RS) -5-ethyl-2- (4-isopropyl-4-methyl-5-oxo-2-imidazoline-2-yl) nicotinic acid, and the structural formula is as follows:
imazethapyr is known to form two different forms of crystals, and the two forms of crystals have significant differences in appearance and size, infrared spectrogram analysis, X-ray diffraction analysis and 13C nuclear magnetic resonance analysis. The two different types of imazethapyr crystals are respectively a stable crystal form (called crystal form I for short) and a metastable crystal form (called crystal form II for short). The I form is a crystalline form of the current commercial product, and the II form is not only thermodynamically unstable, but also has very fine crystal particles and is difficult to filter in the production process.
At present, the imazethapyr product with the crystal form I sold in the market is mainly prepared in the following way, in the synthesis production process of the imazethapyr, an alkaline imazethapyr aqueous solution (sodium salt or sylvite aqueous solution) is finally formed, and after acidification crystallization, temperature reduction and filtration, ethanol recrystallization is adopted, or a gradient temperature reduction way is adopted to obtain the imazethapyr. For the method, ethanol is adopted for recrystallization, the yield is low, the loss is large, a large amount of non-biochemically-processable imazethapyr is remained in the ethanol, the wastewater amount is large and does not meet the environmental protection requirement, if a gradient cooling mode is adopted, the cooling period is long, the energy consumption is large, the existence proportion of the crystal form II in the product is still large, the crystal form separated by crystallization is unstable, and the turbidity fluctuation of the product is large.
Disclosure of Invention
The invention aims to provide a preparation method of imazethapyr in a stable crystal form, which has high conversion rate of the stable crystal form and simple preparation process, and the specific scheme is as follows:
a method for preparing imazethapyr in stable crystal form comprises adding acid into aqueous solution of imazethapyr salt containing crystallization modifier to precipitate to obtain imazethapyr crystal; wherein, the crystallization denaturant is one or more of benzene, alkylbenzene or halogenated alkane.
Optionally, the alkylbenzene is toluene or xylene.
Optionally, the halogenated alkane is dichloromethane, dichloroethane or trichloromethane.
Optionally, the addition amount of the crystallization denaturant is 0.05-5% by weight of the total weight of the imazethapyr aqueous solution.
Optionally, the pH value after the acid addition is 2-3.
Optionally, the imazethapyr aqueous solution is an imazethapyr aqueous solution to be acidified and crystallized in the synthetic preparation process of imazethapyr or an imazethapyr aqueous solution formed by alkalizing imazethapyr containing a metastable crystal form.
Compared with the existing recrystallization and slow gradient cooling, the preparation method of the stable crystal form imazethapyr has the advantages that the imazethapyr aqueous solution is added with the crystallization denaturant and then is acidified and crystallized, the preparation process is simple, the crystallization preparation time is greatly shortened, and the conversion rate of the stable crystal form is high.
Detailed Description
The specific embodiment of the invention provides a preparation method of imazethapyr with stable crystal form, which comprises the steps of adding acid into an aqueous solution of imazethapyr salt containing a crystallization modifier for precipitation to obtain imazethapyr crystals; wherein, the crystallization denaturant is one or more of benzene, alkylbenzene or halogenated alkane.
In the embodiment of the present invention, the inventors have found through studies that conversion of imazethapyr crystals into a stable crystal form can be promoted by adding a crystallization modifier, benzene, an alkylbenzene or a halogenated alkane, which is a halogenated C1-C4 alkane, more preferably dichloromethane, dichloroethane or trichloromethane, to an aqueous imazethapyr salt solution and precipitating by adding an acid, wherein the alkylbenzene is preferably a C1-C4 alkylbenzene, more preferably toluene or xylene, and the halogenated alkane is preferably a halogenated C1-C4 alkane.
In a specific embodiment of the present invention, the pH after the acid addition is preferably 2 to 3, and the amount of the crystallization modifier is preferably 0.05 to 5% by weight, preferably 0.5 to 1.5% by weight, and may be selected from 0.6%, 0.8%, 1%, 1.2%, 1.4% by weight, and the like, based on the total weight of the imazethapyr aqueous solution.
In a particular embodiment of the present invention, the imazethapyr salt is preferably a sodium or potassium imazethapyr salt, which is commonly used.
In a specific embodiment of the present invention, the imazethapyr aqueous solution may be formed by salifying imazethapyr containing a metastable crystal form (crystal form II) and dissolving the salt in water to prepare an imazethapyr aqueous solution, or may be an imazethapyr aqueous solution to be acidified and crystallized in the synthetic preparation of imazethapyr, preferably an imazethapyr aqueous solution to be acidified and crystallized in the synthetic preparation of imazethapyr, and thus may be directly performed in the post-treatment process of the synthesis.
In a specific embodiment of the present invention, the aqueous solution of imazethapyr to be acidified and crystallized obtained in the preparation of the synthesis of imazethapyr is not limited to the synthesis as long as the aqueous solution of imazethapyr to be acidified and crystallized can be obtained in the preparation, and for example, may be an aqueous solution of imazethapyr formed in the synthesis as described in patent application CN 102453022A.
In a specific embodiment of the present invention, in order to facilitate precipitation, it is preferable that the temperature of the solution is reduced during the precipitation by adding acid or after the completion of the addition of acid, the temperature of the aqueous imazethapyr salt solution before the addition of acid is preferably 30 to 50 ℃, and the temperature of the solution after the reduction is preferably 10 to 25 ℃.
Examples
Description of raw materials:
table of sources for each raw material (purchased) in examples:
description of the test:
testing the content of imazethapyr: tested according to the method of line HT/T4810-2015.
And (3) yield test: the number of moles of the product obtained by the actual reaction was determined by a standard sample using liquid chromatography, and the yield was calculated using the following formula.
Turbidity test:
the measurement was carried out by a turbidimeter using 17mL of deionized water, adding 2mL of 29% ammonia water, weighing 4.5g of imazethapyr sample, adding the obtained mixture thereto, dissolving the mixture by stirring, and adjusting the pH to 10 with ammonia water. The sample was loaded into a sample cell, placed in a turbidimeter and read after 30 seconds.
Example 1
40.2g (0.2mol, 97%) of 5-ethylpyridine dicarboxylic acid, 23g (0.22mol, 97.6%) of acetic anhydride and 160g of xylene are added into a 500ml reaction bottle, the temperature is increased and the reflux reaction is carried out for 0.5h, the temperature is reduced to 25 to 30 ℃, 26g (0.22mol, 95%) of 2-amino-2, 3-dimethylbutyranitrile is added dropwise, the temperature is kept for 1h at 8 to 12 ℃ after the dropwise addition is finished, the xylene is removed by desolventization under reduced pressure, the temperature is reduced to separate out a solid, and the solid is filtered and dried to obtain 50.2g of 2- [ (1-nitrile-1, 2-dimethylpropyl) -formamido ] -5-ethylnicotinic acid with the content of 97% and the yield of 87.
Adding 50.2g of 2- [ (1-nitrile-1, 2-dimethylpropyl) -formamido ] -5-ethyl nicotinic acid into a 500ml reaction bottle, dissolving in 106.7g (0.8mol, 30%) of NaOH aqueous solution, stirring for 10min, dropwise adding 40.8g (0.3mol, 25%) of hydrogen peroxide at room temperature of 20-25 ℃, after dropwise adding, preserving heat for 2h at 20-25 ℃, then heating to 70 ℃, preserving heat for 2h, and then heating to 90 ℃, preserving heat for 20 min. Then cooling to 30-40 ℃, adding 1.5g of crystallization denaturant xylene, dropwise adding 8-10% hydrochloric acid until the pH value is 2-3, and keeping for 20 min; then cooling to 10 deg.C, filtering. Washing with 50g water, and oven drying to obtain imazethapyr 56.2g, content 98.7%, yield 96%, and turbidity 15 NTU.
Example 2
30g of raw imazethapyr in the mixed crystal form I and II is added into a 500ml reaction bottle, the pH is adjusted to be approximately equal to 8.5 by 14g of 30 percent liquid alkali, and the imazethapyr is completely dissolved in salt. Then adding 0.4g of crystallization denaturant dichloroethane with the weight of about 1 percent of the total weight, dropwise adding 8-10 percent hydrochloric acid at the temperature of 30-50 ℃ until the pH value is approximately equal to 2-3, and cooling to 20-25 ℃. Filtering and washing with quantitative water to obtain the imazethapyr original drug. 29.7g of imazethapyr is obtained, the content is 99.3 percent, the yield is 98.31 percent, and the turbidity is 20 NTU.
Example 3
30g of raw imazethapyr in the mixed crystal form I and II is added into a 500ml reaction bottle, the pH is adjusted to be approximately equal to 8.5 by 14g of 30 percent liquid alkali, and the imazethapyr is completely dissolved in salt. Then 0.4g of crystallization denaturant xylene with the total weight of about 1 percent is added, 8 to 10 percent hydrochloric acid is dripped at the temperature of 30 to 50 ℃ until the pH value is approximately equal to 2 to 3, and the temperature is reduced to 20 to 25 ℃. Filtering and washing with quantitative water to obtain the imazethapyr original drug. 29.5g of imazethapyr is obtained, the content is 99 percent, the yield is 97.4 percent, and the turbidity is 15 NTU.
Example 4
30g of raw imazethapyr in the mixed crystal form I and II is added into a 500ml reaction bottle, the pH is adjusted to be approximately equal to 8.5 by 14g of 30 percent liquid alkali, and the imazethapyr is completely dissolved in salt. Then 0.4g of crystallization denaturant toluene with the total weight of about 1 percent is added, 8-10 percent hydrochloric acid is dripped at the temperature of 30-50 ℃ until the pH value is approximately equal to 2-3, and the temperature is reduced to 20-25 ℃. Filtering and washing with quantitative water to obtain the imazethapyr original drug. 29.2g of imazethapyr is obtained, the content is 99.5 percent, the yield is 96.8 percent, and the turbidity is 15 NTU.
Example 5
30g of raw imazethapyr in the mixed crystal form I and II is added into a 500ml reaction bottle, the pH is adjusted to be approximately equal to 8.5 by 14g of 30 percent liquid alkali, and the imazethapyr is completely dissolved in salt. Then 0.4g of crystallization denaturant dichloromethane accounting for 1 percent of the total weight is added, 8-10 percent hydrochloric acid is dripped at the temperature of 30-50 ℃ until the pH value is approximately equal to 2-3, and the temperature is reduced to 20-25 ℃. Filtering and washing with quantitative water to obtain the imazethapyr original drug. 29.5g of imazethapyr is obtained, the content is 99.5 percent, the yield is 97.8 percent, and the turbidity is 15 NTU.
Comparative example 1
30g of raw imazethapyr I and II mixed crystal form is added into a 500ml reaction bottle, the pH value is adjusted to be approximately equal to 8.5 by 30% liquid alkali, and the imazethapyr is completely dissolved in salt. Dripping 15% hydrochloric acid at the temperature of 25-45 ℃ until the pH value is approximately equal to 2-3, and cooling to 20-25 ℃. Filtering and washing with quantitative water to obtain the imazethapyr original drug. 29.5g of imazethapyr is obtained, the content is 99 percent, the yield is 97.35 percent, and the turbidity is more than 800 NTU.
Comparative example 2
50g of intermediate 2- [ (1-nitrile-1, 2-dimethylpropyl) -formamido ] -5-ethyl nicotinic acid is synthesized according to the synthesis method of example 1, added into a 500ml reaction bottle, added with 106.7g (0.8mol, 30%) of NaOH aqueous solution, stirred for 10min, added with 40.8g (0.3mol, 25%) of hydrogen peroxide dropwise at room temperature of 20-25 ℃, kept at 20-25 ℃ for 2h after dropwise addition, then heated to 70 ℃ for 2h, and then heated to 90 ℃ for 20 min. Then cooling to 30-40 ℃, dropwise adding 15% hydrochloric acid until the pH value is 2-3, and keeping for 20 min; then cooling to 10 deg.C, filtering. Washing with 50g of water, and drying to obtain 56g of imazethapyr with the content of 98%, the yield of 95% and the turbidity of 120 NTU.
Although the present invention is disclosed above, the present invention is not limited thereto. Various changes and modifications may be effected therein by one skilled in the art without departing from the spirit and scope of the invention as defined in the appended claims.
Claims (6)
1. A method for producing imazethapyr in a stable crystal form, characterized by comprising the steps of adding an acid to an aqueous solution of imazethapyr containing a crystallization modifier to precipitate imazethapyr crystals; wherein, the crystallization denaturant is one or more of benzene, alkylbenzene or halogenated alkane.
2. The method according to claim 1, wherein the alkylbenzene is toluene or xylene.
3. The method of claim 1, wherein the halogenated alkane is dichloromethane, dichloroethane, or chloroform.
4. The method according to claim 1, wherein the crystallization denaturant is added in an amount of 0.05 to 5% by weight based on the total weight of the imazethapyr aqueous solution.
5. The method according to claim 1, wherein the pH after the addition of the acid is 2 to 3.
6. The process according to claim 1, wherein the aqueous imazethapyr salt solution is an aqueous imazethapyr salt solution to be acidified and crystallized in the process of synthesizing imazethapyr or an aqueous imazethapyr salt solution formed by alkalifying imazethapyr containing a metastable crystal form.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN118063430A (en) * | 2024-04-25 | 2024-05-24 | 内蒙古新农基科技有限公司 | Method and equipment for purifying imazethapyr |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4638068A (en) * | 1981-04-09 | 1987-01-20 | American Cyanamid Company | 2-(2-imidazolin-2-yl)-pyridines and quinolines, process and intermediates for the preparation thereof, and use of said compounds as herbicidal agents |
| CN102453022A (en) * | 2010-10-27 | 2012-05-16 | 中国中化股份有限公司 | Method for preparing imazethapyr |
| CN103524485A (en) * | 2013-09-10 | 2014-01-22 | 江苏长青农化股份有限公司 | Method for continuously synthesizing imazethapyr |
-
2018
- 2018-11-28 CN CN201811440518.1A patent/CN111233828A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4638068A (en) * | 1981-04-09 | 1987-01-20 | American Cyanamid Company | 2-(2-imidazolin-2-yl)-pyridines and quinolines, process and intermediates for the preparation thereof, and use of said compounds as herbicidal agents |
| CN102453022A (en) * | 2010-10-27 | 2012-05-16 | 中国中化股份有限公司 | Method for preparing imazethapyr |
| CN103524485A (en) * | 2013-09-10 | 2014-01-22 | 江苏长青农化股份有限公司 | Method for continuously synthesizing imazethapyr |
Non-Patent Citations (3)
| Title |
|---|
| PETER WEPPLO: ""Imidazolinone Herbicides: Synthesis and Novel Chemistry"", 《PESTIC. SCI.》 * |
| 程志明: ""咪唑啉酮类除草剂的工业化合成方法"", 《上海化工》 * |
| 程志明等: ""咪哇琳酮类除草剂—咪草烟的合成"", 《农药》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN118063430A (en) * | 2024-04-25 | 2024-05-24 | 内蒙古新农基科技有限公司 | Method and equipment for purifying imazethapyr |
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