CN112047897A - Preparation method of 3-aminoisoxazole - Google Patents
Preparation method of 3-aminoisoxazole Download PDFInfo
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- CN112047897A CN112047897A CN202011109306.2A CN202011109306A CN112047897A CN 112047897 A CN112047897 A CN 112047897A CN 202011109306 A CN202011109306 A CN 202011109306A CN 112047897 A CN112047897 A CN 112047897A
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- aminoisoxazole
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
- C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
- C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
- C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
The invention belongs to the technical field of medicines, and particularly relates to a preparation method of 3-aminoisoxazole, which comprises the following steps: (1) preparation of 2, 3-dichloropropionitrile: adding acrylonitrile, N-dimethylformamide and pyridine into a reaction container, cooling to 5-15 ℃, introducing chlorine into the reaction container, and keeping the reaction temperature at 10-20 ℃; controlling the temperature to be 15-25 ℃ and stirring for 5 hours after the chlorine gas is introduced; blowing out excessive chlorine until the reaction solution is yellowish or colorless and transparent to obtain 2, 3-dichloropropionitrile; (2) preparation of 3-aminoisoxazole: under the alkaline condition, hydroxyurea and 2, 3-dichloropropionitrile are taken as raw materials, N, N-dimethylformamide is taken as a catalyst, and the 3-aminoisoxazole is synthesized. The invention is used for solving the technical problems of easy material flushing and high process risk caused by adopting a 2, 3-dibromopropionitrile intermediate in the existing preparation of 3-aminoisoxazole.
Description
Technical Field
The invention belongs to the technical field of medicines, and relates to a preparation method of 3-aminoisoxazole.
Background
The traditional process for preparing 3-aminoisoxazole needs to use 2, 3-dibromopropionitrile, but the preparation of 2, 3-dibromopropionitrile has the following problems:
firstly, aggregation and rapid heat release can occur in the process of adding bromine dropwise, so that the process is extremely easy to flush, has high process risk and is not beneficial to industrial production.
Secondly, the liquid bromine has high price, large molecular weight and large raw material consumption, and further increases the raw material cost.
Thirdly, 2, 3-dibromopropionitrile is used for preparing 3-aminoisoxazole, liquid bromine is contained in the product, the product is added into pyridine for heating reflux, and the 3-aminoisoxazole which is colorless and does not contain bromine can be obtained by distilling after the pyridine is evaporated.
Disclosure of Invention
The invention aims to provide a preparation method of 3-aminoisoxazole, which aims to solve the technical problems of high possibility of material flushing, high process risk and high cost caused by the adoption of a 2, 3-dibromopropionitrile intermediate in the conventional preparation of 3-aminoisoxazole.
In order to solve the technical problems, the invention adopts the following technical scheme that the preparation method of the 3-aminoisoxazole comprises the following steps:
(1) preparation of 2, 3-dichloropropionitrile: adding acrylonitrile, N-dimethylformamide and pyridine into a reaction container; cooling the materials in the reaction bottle to 5-15 ℃, slowly introducing chlorine gas into the reaction bottle, and keeping the reaction temperature at 10-20 ℃; controlling the temperature to be 15-25 ℃ and stirring for 5 hours after the ventilation is finished; blowing out redundant chlorine by a nitrogen drum until the reaction solution is yellowish or colorless and transparent to obtain 2, 3-dichloropropionitrile;
(2) preparation of 3-aminoisoxazole: under the alkaline condition, hydroxyurea and 2, 3-dichloropropionitrile are taken as raw materials, N, N-dimethylformamide is taken as a catalyst, and the 3-aminoisoxazole is synthesized.
Compared with the prior art, the invention has the following beneficial effects:
(1) the chlorine gas is not aggregated in the process of introducing the chlorine gas, so that the phenomenon of quick heat release is avoided, the phenomenon of extremely easy material flushing is avoided, the process danger is greatly reduced, and the industrial production is facilitated; the invention selects 2, 3-dichloropropionitrile as a raw material instead of 2, 3-dibromopropionitrile, so that the production process is safer and more efficient, and the operation is safer and more environment-friendly. In the double bond addition process, the activity of chlorine is greater than that of liquid bromine. In the process of adding liquid bromine and acrylonitrile, Br-Br is polarized and then broken, and then one end with positive electricity is close to a pi bond of olefin; the lone pair of electrons on the bromine then combines with the carbenium ion to form a cyclobromonium ion, and then Br "binds another carbon from the other side. When chlorine gas and olefin are added, pi bonds in the olefin are firstly broken to form positive carbon ions, chlorine forms negative ions, the positive carbon ions and the negative chlorine ions form ion pairs, and then the chlorine ions are combined with the positive carbon ions. When liquid bromine and acrylonitrile are added, the addition reaction is carried out only when the liquid bromine and the acrylonitrile reach a certain concentration, and a large amount of heat is released after the reaction is carried out, so that the risk of material flushing is caused; and chlorine gas is introduced into acrylonitrile, and electrophilic addition reaction is carried out under the action of an alkaline catalyst and at a lower concentration, the temperature is well controlled, and the reaction is relatively stable.
(2) The price of the chlorine is far lower than that of the liquid bromine, the molecular weight of the chlorine is smaller than that of the liquid bromine, the 3-aminoisoxazole with the same weight is prepared, the weight of the chlorine is obviously smaller than that of the liquid bromine, and the cost of using the chlorine is lower than that of the liquid bromine.
In order to solve the technical problem of how to specifically prepare the 3-aminoisoxazole, the invention adopts the following technical scheme, and the preparation method of the 3-aminoisoxazole in the step (2) comprises the following steps:
(2-1) putting liquid alkali, hydroxyurea and N, N-dimethylformamide into a reaction vessel; 2, 3-dichloropropionitrile is dripped; stirring after the dropwise addition is finished;
(2-2) after the reaction in the step (2-1) is finished, adjusting the pH value to 8-9, and performing suction filtration; extracting mother liquor, drying extract liquor, decolorizing and filtering, desolventizing the extract liquor to obtain light yellow oily matter, and then distilling under reduced pressure to obtain colorless oily matter, namely 3-aminoisoxazole.
The method for preparing 3-aminoisoxazole from 2, 3-dichloropropionitrile has the advantages of simple process steps and simple operation, the byproducts of the process are sodium chloride and sodium carbonate (the byproduct in the prior art is sodium bromide), the environmental pollution is less, the product purity is higher, the yield is obviously improved, and the method can be used for industrial production.
After the reaction is finished, only the PH is required to be adjusted to 8-9, the extraction is carried out, the mother liquor is extracted, the extract liquor is dried, decolorization and filtration are carried out, the extract liquor is desolventized to obtain a light yellow oily substance, and the light yellow oily substance, namely 3-aminoisoxazole, is obtained by reduced pressure distillation, so that the process steps are simpler to operate. The 3-aminoisoxazole is prepared by using 2, 3-dichloropropionitrile, and the colorless and bromine-free 3-aminoisoxazole can be obtained without adding a product into pyridine, heating and refluxing, evaporating the pyridine and then distilling.
In order to solve the technical problem of low yield of the existing preparation method, the invention adopts the following technical scheme that the molar ratio of the hydroxyurea, the 2, 3-dichloropropionitrile and the sodium hydroxide is 1: 1: (3-4).
In order to solve the technical problem of low yield of the existing preparation method, the invention adopts the following technical scheme that the weight ratio of the hydroxyurea to the N, N-dimethylformamide is as follows: 1: (0.05-0.10).
In order to solve the technical problem of insufficient reaction of the 2, 3-dichloropropionitrile, the invention adopts the following technical scheme that the dropping temperature of the 2, 3-dichloropropionitrile is controlled to be 10-20 ℃.
In order to solve the technical problem of insufficient reaction of the 2, 3-dichloropropionitrile, the invention adopts the following technical scheme that the 2, 3-dichloropropionitrile is stirred after being dropwise added, the stirring temperature is 10-30 ℃, and the stirring time is 4 hours.
In order to solve the technical problem of irrational extraction effect of an extraction solvent, the invention adopts the following technical scheme that the extraction solvent used in the extraction mother liquor is methyl isobutyl ketone.
In order to solve the technical problem that the PH adjusting effect is not ideal, the invention adopts the following technical scheme that the PH is adjusted to 8-9 by introducing carbon dioxide.
In order to solve the technical problem that the drying effect of the extraction liquid is not ideal, the invention adopts the following technical scheme that the drying extraction liquid adopts anhydrous sodium sulfate.
In order to solve the technical problem that the decolorizing and filtering effect is not ideal, the invention adopts the following technical scheme that the decolorizing and filtering are realized by adopting activated carbon.
In order to solve the technical problem of simple reaction vessel, the invention adopts the following technical scheme that the reaction vessel is a reaction kettle.
In order to solve the technical problem of how to further improve the yield of the 2, 3-dichloropropionitrile, the invention adopts the following technical scheme that the mass ratio of the acrylonitrile to the N, N-dimethylformamide to the pyridine is 1000: 10: 1.
in order to solve the technical problem of how to further improve the yield of the 2, 3-dichloropropionitrile, the invention adopts the following technical scheme that the molar weight of the introduced chlorine gas is 1.05-1.1 times of that of the acrylonitrile.
Detailed Description
The present invention will be further described with reference to the following examples.
A preparation method of 3-aminoisoxazole comprises the following reaction route:
the method comprises the following specific steps:
adding liquid alkali, hydroxyurea and N, N-dimethylformamide into a reaction kettle; controlling the temperature to be 10-20 ℃, and dropwise adding 2, 3-dichloropropionitrile; and stirring for 4 hours at 10-30 ℃ after the dropwise addition. After the reaction is finished, introducing carbon dioxide, adjusting the pH value to 8-9, and performing suction filtration; extracting the mother liquid with methyl isobutyl ketone, drying the extract with anhydrous sodium sulfate, decolorizing with activated carbon, filtering, desolventizing the extract to obtain yellowish oily matter, and distilling under reduced pressure to obtain colorless oily matter.
The mol ratio of the hydroxyurea to the 2, 3-dichloropropionitrile to the sodium hydroxide is as follows: 1: 1: 3 to 4.
The weight ratio of the hydroxyurea to the N, N-dimethylformamide is as follows: 1: 0.05 to 0.10.
After the dropwise addition of the 2, 3-dichloropropionitrile is finished, stirring and reacting at the temperature of 10-30 ℃.
The extraction solvent is methyl isobutyl ketone.
Example 1:
preparation of 2, 3-dichloropropionitrile: adding 130g of acrylonitrile into a 500ml reaction kettle, and starting stirring; sequentially adding 1.3g of N, N-dimethylformamide and 0.13g of pyridine; cooling the materials in the reaction bottle to 5-15 ℃, slowly introducing chlorine gas into the reaction bottle, and keeping the reaction temperature not to exceed 20 ℃; weighing, wherein the introduced gas molar weight is 1.05-1.1 times of the acrylonitrile molar weight, and finishing the gas introduction; controlling the temperature to be 15-25 ℃ and stirring for more than 5 hours.
And blowing out redundant chlorine gas by a nitrogen gas drum until the reaction solution is yellowish or colorless and transparent.
Preparation of 3-aminoisoxazole: adding 600g of liquid caustic soda with mass concentration of 20% into a 2L reaction kettle, and starting stirring; then 76g of hydroxyurea and 7.6g of N, N-dimethylformamide are added in sequence, and the temperature is reduced; beginning to add 126.7g of 2, 3-dichloropropionitrile dropwise at the temperature of below 15 ℃; and keeping the temperature at 10-20 ℃ in the dropping process, wherein the dropping time is about 2 hours. After the dropwise addition, stirring for 4 hours at the temperature of 15 +/-3 ℃.
And (3) after the reaction is finished, introducing carbon dioxide, adjusting the pH to be 8-9, and performing suction filtration to remove salt. Extracting the mother liquor with methyl isobutyl ketone for 3 times, each time using 200ml, combining the extracts, drying with anhydrous sodium sulfate, decolorizing with 12g of active carbon, and filtering. The filtrate was desolventized to give 75.3g of a pale yellow oil, which was then distilled under reduced pressure using an oil pump (high vacuum below 50 Pa) to give 71.4g of a colorless oil, 85.0% yield and 98.3% purity.
Example 2:
preparation of 2, 3-dichloropropionitrile: 1.30kg of acrylonitrile is put into a 2000ml reaction kettle, and stirring is started; 13g of N, N-dimethylformamide and 1.3g of pyridine are sequentially added; cooling the materials in the reaction bottle to 5-15 ℃, slowly introducing chlorine gas into the reaction bottle, and keeping the reaction temperature not to exceed 20 ℃; weighing, wherein the introduced gas molar weight is 1.05-1.1 times of the acrylonitrile molar weight, and finishing the gas introduction; controlling the temperature to be 15-25 ℃ and stirring for more than 5 hours.
Preparation of 3-aminoisoxazole: adding 6.0kg of liquid caustic soda with the mass concentration of 20% into a 20L reaction kettle, and starting stirring; 760g of hydroxyurea and 57g of N, N-dimethylformamide are sequentially added, and the temperature is reduced; dropping 1.27kg of 2, 3-dichloropropionitrile below 15 ℃; and keeping the temperature at 10-20 ℃ in the dropping process, wherein the dropping time is about 2 hours. After the dropwise addition, stirring for 4 hours at the temperature of 25 +/-3 ℃.
And (3) after the reaction is finished, introducing carbon dioxide, adjusting the pH to be 8-9, and performing suction filtration to remove salt. Extracting the mother liquor with methyl isobutyl ketone for 3 times, wherein the dosage is 2L each time, combining the extract, drying with anhydrous sodium sulfate, decoloring with 120g of activated carbon, filtering, and desolventizing the filtrate to obtain 755g of light yellow oily substance. The oil was further subjected to vacuum distillation using an oil pump (high vacuum 50Pa or less) to give 738g of a colorless oil, yield 87.8%, and purity 98.5%.
Example 3:
preparation of 2, 3-dichloropropionitrile: 2.60kg of acrylonitrile is put into a 5000ml reaction kettle, and stirring is started; then, 26g of N, N-dimethylformamide and 2.6g of pyridine are sequentially added; cooling the materials in the reaction bottle to 5-15 ℃, slowly introducing chlorine gas into the reaction bottle, and keeping the reaction temperature not to exceed 20 ℃; weighing, wherein the introduced gas molar weight is 1.05-1.1 times of the acrylonitrile molar weight, and finishing the gas introduction; controlling the temperature to be 15-25 ℃ and stirring for more than 5 hours.
Preparation of 3-aminoisoxazole: adding 12.0kg of liquid caustic soda with the mass concentration of 20% into a 20L reaction kettle, and starting stirring; 1520g of hydroxyurea and 76g of N, N-dimethylformamide are sequentially added, and the temperature is reduced; 2.54kg of 2, 3-dichloropropionitrile is started to be dripped below 15 ℃; and keeping the temperature at 10-20 ℃ in the dropping process, wherein the dropping time is about 2 hours. After the dropwise addition, stirring for 4 hours at the temperature of 20 +/-3 ℃.
And (3) after the reaction is finished, introducing carbon dioxide, adjusting the pH to be 8-9, and performing suction filtration to remove salt. Extracting the mother liquor with methyl isobutyl ketone for 3 times, wherein the dosage is 4L each time, combining the extracts, drying with anhydrous sodium sulfate, decoloring with 240g of activated carbon, and filtering. The filtrate was desolventized to give 1.53kg of a pale yellow oil, which was then distilled under reduced pressure using an oil pump (high vacuum below 50 Pa) to give 1.47kg of a colorless oil, 87.5% yield and 98.6% purity.
Comparative example:
preparation of 2, 3-dibromopropionitrile: 26.5g of acrylonitrile is added into a 500ml four-neck flask, and the temperature is reduced to 10 ℃; dripping 20g of liquid bromine, controlling the temperature to be below 20 ℃, and dripping for 1 hour; after the dripping, stirring the mixture at room temperature until the color becomes light, wherein the temperature is not obviously changed and is about 1 to 2 hours; continuously dripping 20g of liquid bromine, controlling the temperature to be below 20 ℃, and dripping for 1 hour; after the dripping, stirring the mixture at room temperature until the color becomes light, wherein the temperature is not obviously changed and is about 1 to 2 hours; continuously dripping 20g of liquid bromine, controlling the temperature to be below 20 ℃, and dripping for 1 hour; after the dripping, stirring the mixture at room temperature until the color becomes light, wherein the temperature is not obviously changed and is about 1 to 2 hours; continuously dripping 20g of liquid bromine, controlling the temperature to be below 20 ℃, and dripping for 1 hour; after the dripping, stirring the mixture at room temperature until the color becomes light, wherein the temperature is not obviously changed and is about 1 to 2 hours; 106g of yellow liquid are obtained.
Preparation of 3-aminoisoxazole (2, 3-dibromopropionitrile intermediate method): adding 160g of liquid caustic soda with the mass concentration of 20% into a 1L reaction kettle, and starting stirring; then 20g of hydroxyurea and 2g of N, N-dimethylformamide are added in sequence, and the temperature is reduced; dripping 56g of 2, 3-dibromopropionitrile below 15 ℃; and keeping the temperature at 10-20 ℃ in the dropping process, wherein the dropping time is about 2 hours. After the dropwise addition, stirring for 4 hours at the temperature of 15 +/-3 ℃.
And (3) after the reaction is finished, introducing carbon dioxide, adjusting the pH to be 8-9, and performing suction filtration to remove salt. Extracting the mother liquor with methyl isobutyl ketone for 3 times, each time using 100ml, combining the extracts, drying with anhydrous sodium sulfate, decolorizing with 6g of active carbon, and filtering. The filtrate was desolventized to give 40.8g of a pale yellow oil, which was then distilled under reduced pressure using an oil pump (high vacuum below 50 Pa) to give 34.9g of a yellowish oil with a yield of 79.0% and a purity of 95.8%. Adding 34.9g of the yellowish oily matter and 30mL of pyridine into a 250mL flask, heating and refluxing for 1h, and then distilling the pyridine under reduced pressure; after the pyridine was distilled off, 33.4g of colorless 3-aminoisoxazole was continuously distilled under reduced pressure, the total yield was 75.6%, and the purity was 98.4%.
Claims (10)
1. A preparation method of 3-aminoisoxazole is characterized by comprising the following steps:
(1) preparation of 2, 3-dichloropropionitrile: adding acrylonitrile, N-dimethylformamide and pyridine into a reaction container, cooling to 5-15 ℃, introducing chlorine into the reaction container, and keeping the reaction temperature at 10-20 ℃; controlling the temperature to be 15-25 ℃ and stirring for 5 hours after the chlorine gas is introduced; blowing out excessive chlorine until the reaction solution is yellowish or colorless and transparent to obtain 2, 3-dichloropropionitrile;
(2) preparation of 3-aminoisoxazole: under the alkaline condition, synthesizing and obtaining 3-aminoisoxazole by taking hydroxyurea and 2, 3-dichloropropionitrile as raw materials and N, N-dimethylformamide as a catalyst;
the reaction route is as follows:
2. the process for producing 3-aminoisoxazole according to claim 1, wherein the production of 3-aminoisoxazole of the step (2) comprises the steps of:
(2-1) putting liquid alkali, hydroxyurea and N, N-dimethylformamide into a reaction vessel; 2, 3-dichloropropionitrile is dripped; stirring after the dropwise addition is finished;
(2-2) after the reaction in the step (2-1) is finished, adjusting the pH value to 8-9, and performing suction filtration; extracting mother liquor, drying extract liquor, decolorizing and filtering, desolventizing the extract liquor to obtain light yellow oily matter, and then distilling under reduced pressure to obtain colorless oily matter, namely 3-aminoisoxazole.
3. The process for producing 3-aminoisoxazole according to claim 2 wherein the liquid base is sodium hydroxide.
4. The process for preparing 3-aminoisoxazole according to claim 3, characterized in that the molar ratio of hydroxyurea, 2, 3-dichloropropionitrile and sodium hydroxide is: 1: 1: (3-4).
5. The process for the preparation of 3-aminoisoxazole according to claim 2, characterized in that the weight ratio between hydroxyurea and N, N-dimethylformamide is: 1: (0.05-0.10).
6. The preparation method of 3-aminoisoxazole according to claim 2, wherein the dropping temperature of the 2, 3-dichloropropionitrile is controlled to be 10-20 ℃.
7. The process for producing 3-aminoisoxazole according to claim 2, wherein the 2, 3-dichloropropionitrile is stirred after the dropwise addition, the stirring temperature is 10 to 30 ℃, and the stirring time is 4 hours.
8. The process for preparing 3-aminoisoxazole according to claim 2, characterized in that the extraction solvent used in the extraction mother liquor is methyl isobutyl ketone.
9. The process for preparing 3-aminoisoxazole according to claim 2 wherein the adjustment of the pH to 8 to 9 is carried out by feeding carbon dioxide.
10. The process for producing 3-aminoisoxazole according to claim 2, wherein the dried extract is anhydrous sodium sulfate.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115219640A (en) * | 2022-07-15 | 2022-10-21 | 天和药业股份有限公司 | 3-aminoisoxazole purity detection method |
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| US5679826A (en) * | 1995-10-30 | 1997-10-21 | Bayer Aktiengesellschaft | Process for the preparation of 2-chloroacrylonitrile |
| CN105073719A (en) * | 2012-12-07 | 2015-11-18 | 拜耳作物科学股份公司 | N-(isoxazol-3-yl)-aryl-carboxylic acid amides and use thereof as herbicides |
| CN109369553A (en) * | 2018-10-22 | 2019-02-22 | 上海凌凯医药科技有限公司 | A method of efficiently synthesizing N-3- isoxazole t-butyl carbamate |
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2020
- 2020-10-16 CN CN202011109306.2A patent/CN112047897A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5679826A (en) * | 1995-10-30 | 1997-10-21 | Bayer Aktiengesellschaft | Process for the preparation of 2-chloroacrylonitrile |
| CN105073719A (en) * | 2012-12-07 | 2015-11-18 | 拜耳作物科学股份公司 | N-(isoxazol-3-yl)-aryl-carboxylic acid amides and use thereof as herbicides |
| CN109369553A (en) * | 2018-10-22 | 2019-02-22 | 上海凌凯医药科技有限公司 | A method of efficiently synthesizing N-3- isoxazole t-butyl carbamate |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN115219640A (en) * | 2022-07-15 | 2022-10-21 | 天和药业股份有限公司 | 3-aminoisoxazole purity detection method |
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