A process for the preparation of 3-chloro-n-hydroxy-2-oxo-propionimidoyl chloride
By using diketene as a raw material and combining chlorination, hydrolysis, and oxime steps, the problems of difficult raw material availability and large waste acid production in existing technologies have been solved, achieving efficient preparation of 3-chloro-N-hydroxy-2-oxo-propaneimine chloride, which is suitable for industrial applications.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- JINGBO AGROCHEM TECH CO LTD
- Filing Date
- 2024-11-29
- Publication Date
- 2026-05-29
AI Technical Summary
Existing methods for synthesizing 3-chloro-N-hydroxy-2-oxo-propanediol chloride suffer from problems such as numerous byproducts, difficulty in obtaining raw materials, and large amounts of waste acid, making them unsuitable for industrial production.
3-Chloro-N-hydroxy-2-oxo-propanediol chloride was prepared from diketene via chlorination, hydrolysis, oxime reaction, and chlorination steps. This method avoids the use of expensive 1,3-dichloroacetone or ethyl 4-chloroacetoacetate and uses sodium nitrite instead of nitrite esters, simplifying the post-processing.
It reduces raw material costs, improves process safety, reduces waste emissions, simplifies post-processing operations, and is suitable for industrial production.
Smart Images
Figure CN122102945A_ABST
Abstract
Description
Technical Field
[0001] This invention relates to the field of organic synthesis, specifically to a method for preparing 3-chloro-N-hydroxy-2-oxo-propaneimine chloride. Background Technology
[0002] Fluoxazopyrone is a novel fungicide developed by DuPont (now Corteva) to control oomycete pathogens. It is highly effective against downy mildew and late blight, exhibiting both protective and curative activity. This product is rapidly absorbed by waxy layers, resistant to rain washout, and features systemic and acrotropic translocation, protecting newly formed tissues. It is suitable for various economic crops and demonstrates excellent control of oomycete diseases.
[0003] Bis-difluorooxazolidinone is an OSBP fungicide developed by Bayer Crop Science in 2012. It has a chemical structure similar to fluthiazopyrone and exhibits excellent inhibitory activity against the plant pathogenic oomycetes Phytophthora capsici and Phytophthora virosa.
[0004] 3-Chloro-N-hydroxy-2-oxo-propaneimine chloride is an important intermediate in the synthesis of fluoxapiprolin and fluoxapiprolin. Existing literature reports two main methods for its synthesis. Route one, reported in patent CN101888843B, uses 1,3-dichloroacetone as a starting material, which is oximated by tert-butyl nitrite. However, Route one has poor selectivity during oximation and easily generates dinitration byproducts. Furthermore, 1,3-dichloroacetone is a controlled substance, expensive and difficult to procure. Route two, reported in patent CN106414417A, uses ethyl 4-chloroacetoacetate as a starting material, synthesizing it in three steps: hydrolysis, oximation, and chlorination. Route two uses a large amount of concentrated hydrochloric acid for hydrolysis, generating a large amount of waste acid that pollutes the environment. Moreover, the post-treatment requires distilling the hydrochloric acid at a low temperature (40°C), placing high demands on the equipment. Summary of the Invention
[0005] To address the technical problems of byproducts, difficulty in obtaining raw materials, and large waste acid production in existing synthesis methods of 3-chloro-N-hydroxy-2-oxo-propaneimine chloride, this invention provides a method for preparing 3-chloro-N-hydroxy-2-oxo-propaneimine chloride, thus solving the aforementioned problems. This invention uses diketene as a raw material and prepares 3-chloro-N-hydroxy-2-oxo-propaneimine chloride through steps including chlorination addition, hydrolysis, oxime conversion, and chlorination. The preparation method of this invention solves the problems of difficult-to-obtain raw materials and large waste acid production in the original route, making it suitable for industrial production.
[0006] The technical solution of the present invention is as follows: A method for preparing 3-chloro-N-hydroxy-2-oxo-propanediol chloride includes the following steps: (1) reacting diketene with chlorine to obtain 4-chloro-3-oxobutyryl chloride; then hydrolyzing to obtain 4-chloro-3-oxobutyric acid; (2) oximation to obtain 1-chloro-3-(hydroxyimino)acetone; (3) chlorination to obtain 3-chloro-N-hydroxy-2-oxo-propanediol chloride. The synthetic route is shown below: .
[0007] Further, step (1) is as follows: diketene is dissolved in solvent one, chlorine gas is introduced at a controlled temperature of -25~40℃ to react, water is added after the gas phase monitoring shows that the reaction of the raw materials is complete, and 4-chloro-3-oxobutyric acid is obtained by filtration after the reaction is completed.
[0008] Furthermore, in step (1), the molar ratio of diketene to chlorine is 1:1 to 2; preferably 1:1 to 1.5.
[0009] Further, step (2) is as follows: after mixing solvent one, water, hydrochloric acid and 4-chloro-3-oxobutyric acid, the mixture is cooled down, and sodium nitrite aqueous solution is added. During the addition process, the temperature of the reaction system is kept at 0~5℃. After the addition is completed, the reaction is kept at 0~25℃. After the reaction is completed, the mixture is separated and the organic phase is concentrated to obtain 1-chloro-3-(hydroxyimino)acetone.
[0010] Furthermore, in step (2), the molar ratio of 4-chloro-3-oxobutyric acid to sodium nitrite is 1:1~2, preferably 1:1~1.3.
[0011] Furthermore, the temperature of the heat preservation reaction in step (2) is preferably 0~10℃.
[0012] Further, step (3) is as follows: 1-chloro-3-(hydroxyimino)acetone is dissolved in solvent one, the temperature is controlled at -25~40℃, chlorine gas is introduced to react, and after the reaction is completed, solvent is added to crystallize and obtain 3-chloro-N-hydroxy-2-oxo-propaneimino chloride.
[0013] Furthermore, in step (3), the reaction temperature for introducing chlorine gas is -15~25℃.
[0014] Furthermore, in step (3), the molar ratio of 1-chloro-3-(hydroxyimino)acetone to chlorine is 1:1~2, preferably 1:1~1.5.
[0015] Furthermore, the solvent is one of dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene, ethyl acetate, propyl acetate, isopropyl acetate, diethyl ether, isopropyl ether, or methyl tert-butyl ether.
[0016] Furthermore, the solvent two is 1-chlorobutane or carbon tetrachloride.
[0017] The beneficial effects of this invention are as follows: This invention uses diketene as a raw material, avoiding the use of expensive controlled substances such as 1,3-dichloroacetone or ethyl 4-chloroacetoacetate, thus reducing the availability and cost of raw materials. Compared to existing synthesis methods, this invention offers milder reaction conditions, and uses sodium nitrite instead of nitrite esters for oxime oxidization, improving process safety. It avoids the low-temperature distillation of concentrated hydrochloric acid in post-processing, reducing equipment corrosion and making it suitable for scale-up production. Furthermore, this invention generates minimal waste and does not produce organic byproducts such as tert-butanol or ethanol, making it environmentally friendly. The byproducts of this invention are HCl and CO2, which are easily separated from the products, simplifying post-processing operations. Attached Figure Description
[0018] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, for those skilled in the art, other drawings can be obtained based on these drawings without creative effort.
[0019] Figure 1 This is the HNMR spectrum of 4-chloro-3-oxobutyric acid prepared in Example 1.
[0020] Figure 2 This is the HNMR spectrum of 4-chloro-3-oxobutyric acid prepared in Example 3.
[0021] Figure 3 The image shows the 1H NMR spectrum of 3-chloro-N-hydroxy-2-oxo-propaneimine chloride prepared in Example 5. Detailed Implementation
[0022] To enable those skilled in the art to better understand the technical solutions of this invention, the technical solutions of the embodiments of this invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of this invention, and not all embodiments. Based on the embodiments of this invention, all other embodiments obtained by those skilled in the art without creative effort should fall within the scope of protection of this invention.
[0023] Example 1 Preparation of 4-chloro-3-oxobutyric acid Add 840 ml of carbon tetrachloride and 168.0 g (2.0 mol) of diketene to a 2000 ml four-necked reaction flask with stirring, and cool to -25 °C. Maintain the temperature at -25 to -20 °C, then introduce 156.2 g (2.2 mol) of chlorine gas. After the gas introduction is complete, continue stirring at this temperature for 30 min, and gas chromatography analysis confirms complete reaction of the starting materials. Maintain the temperature at -25 to -20 °C, then add 36 g (2.0 mol) of water dropwise to the system. After the addition is complete, continue stirring at this temperature for 1 h. Filter, wash the filter cake with 100 ml of carbon tetrachloride at -25 °C, and dry to obtain 229.4 g of product, yield: 79.9%. HPLC analysis shows the product purity to be 95.1%.
[0024] The product was analyzed by HNMR, and the detection data are as follows: 1 ¹H NMR (400MHz, DMSO-d6): δ 12.53–13.20 (b, 1.12H), 5.35 (s, 0.09H enol form), 4.60 (s, 2H), 4.27 (s, 0.17H enol form), 3.59 (s, 2H). Example 2 Preparation of 4-chloro-3-oxobutyric acid Add 840 ml of dichloromethane and 168.0 g (2.0 mol) of diketene to a 2000 ml four-necked reaction flask with stirring, and cool to -25 °C. Maintain the temperature at -25 to -20 °C and introduce 156.2 g (2.2 mol) of chlorine gas. After the gas introduction is complete, continue stirring at this temperature for 30 min, and gas phase detection indicates complete reaction of the starting materials. Maintain the temperature at -25 to -20 °C and add 36 g (2.0 mol) of water dropwise to the system. After the addition is complete, continue stirring at this temperature for 1 h. No solid precipitates in the system. Maintain the temperature below 20 °C and remove dichloromethane under reduced pressure. After the dichloromethane is removed, add 600 ml of carbon tetrachloride to the system, cool to -25 °C, and maintain this temperature for 1 h. Filter, wash the filter cake with 100 ml of carbon tetrachloride at -25 °C, and dry to obtain 234.4 g of product, yield: 80.9%. The product was analyzed by HPLC and the purity was 94.3%.
[0025] Example 3 Preparation of 1-chloro-3-(hydroxyimino)acetone Add 207 ml of water and 124.2 g (1.8 mol) of sodium nitrite to a 1000 ml flask while stirring. After the sodium nitrite has completely dissolved, cool to 0 °C and set aside.
[0026] Under stirring, 1020 ml of diethyl ether, 313.5 ml of water, 184.5 g of hydrochloric acid (30%), and 215.3 g (1.5 mol) of 4-chloro-3-oxobutyric acid (95.1%) were added sequentially to a 3000 ml four-necked reaction flask. The mixture was then cooled to 0 °C. The prepared sodium nitrite aqueous solution was added dropwise to the system, maintaining the reaction temperature between 0 and 5 °C during the addition. After the addition was complete, the mixture was stirred and kept at 0–5 °C for 30 min, and then separated. The aqueous phase was extracted with diethyl ether (300 ml × 2), and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate and then dissolved. The crude product was crystallized from carbon tetrachloride to obtain 179.0 g of product, with a yield of 95.4%. HPLC analysis showed the product purity to be 97.2%.
[0027] The product was analyzed by HNMR, and the detection data are as follows: 1 H NMR (400MHz, DMSO-d6): δ 12.86(s, 1H), 7.63(s, 1H), 4.82(s, 2H). Example 4 Preparation of 1-chloro-3-(hydroxyimino)acetone Add 207 ml of water and 124.2 g (1.8 mol) of sodium nitrite to a 1000 ml flask while stirring. After the sodium nitrite has completely dissolved, cool to 0 °C and set aside.
[0028] Under stirring, 1020 ml of dichloromethane, 313.5 ml of water, 184.5 g of hydrochloric acid (30%), and 215.3 g (1.5 mol) of 4-chloro-3-oxobutyric acid (95.1%) were added sequentially to a 3000 ml four-necked reaction flask. The mixture was then cooled to 0 °C. The prepared sodium nitrite aqueous solution was added dropwise to the system, maintaining the reaction temperature between 0 and 5 °C during the addition. After the addition was complete, the mixture was stirred and kept at 0–5 °C for 30 min, and then separated. The aqueous phase was extracted with dichloromethane (300 ml × 2). The organic phases were combined, dried over anhydrous sodium sulfate, and then dissolved. The crude product was crystallized from carbon tetrachloride to obtain 179.4 g of the product, with a yield of 95.6%. HPLC analysis showed a purity of 97.1%.
[0029] Example 5 Preparation of 3-chloro-N-hydroxy-2-oxo-propaneimine chloride Add 600 ml of dichloromethane and 125.0 g (1.0 mol) of 1-chloro-3-(hydroxyimino)acetone (purity 97.2%) to a 1000 ml four-necked reaction flask with stirring, and cool to 15 °C. Maintain the temperature at 15–20 °C and purge with 106.5 g (1.5 mol) of chlorine gas. After the purging is complete, continue stirring at this temperature for 30 min. Remove dichloromethane under reduced pressure (maintaining the temperature below 20 °C), add 900 ml of 1-chlorobutane to the residue, cool to -5–0 °C, and stir at this temperature for 24 h. Filter, place the filter cake in a vacuum desiccator, and dry the residual solvent under negative pressure to obtain 146.0 g of product, yield: 89.3%. HPLC analysis showed the product purity to be 95.4%.
[0030] The product was analyzed by HNMR, and the detection data are as follows: 1 H NMR (400MHz, DMSO-d6): δ 13.77(s, 1H), 4.96(s, 2H). Example 6 Preparation of 3-chloro-N-hydroxy-2-oxo-propaneimine chloride Add 600 ml of dichloromethane and 125.0 g (1.0 mol) of 1-chloro-3-(hydroxyimino)acetone (purity 97.2%) to a 1000 ml four-necked reaction flask with stirring, and cool to 15 °C. Maintain the temperature at 15–20 °C and purge with 106.5 g (1.5 mol) of chlorine gas. After the purging is complete, continue stirring at this temperature for 30 min. Remove dichloromethane under reduced pressure (maintaining the temperature below 20 °C). Add 900 ml of carbon tetrachloride to the residue, cool to -5–0 °C, and stir at this temperature for 24 h. Filter, place the filter cake in a vacuum desiccator, and dry the residual solvent under negative pressure to obtain 147.2 g of product, yield: 89.6%. HPLC analysis showed the product purity to be 94.9%.
[0031] Comparative Example 1 Add 400 ml of 2M diethyl ether hydrochloride solution to a 1000 ml four-necked reaction flask with stirring. Cool to 14 °C, add 100 g (0.79 mol) of 1,3-dichloroacetone, and maintain the reaction temperature at 14–16 °C. Add 55 g (0.53 mol) of tert-butyl nitrite dropwise over a period of no more than 10 min. After the addition is complete, maintain the temperature at 14–16 °C and continue stirring for 30 min. Desolventize the reaction solution under reduced pressure to a semi-solid state, then add 400 ml of 1-chlorobutane and stir at room temperature for 2 h. Filter, place the filter cake in a vacuum desiccator, and remove the residual solvent under negative pressure to obtain 67.3 g of product. Further concentrate the filtrate under reduced pressure to a semi-solid residue, add another 60 ml of 1-chlorobutane, and continue stirring at room temperature for 2 h. Filter, place the filter cake in a vacuum desiccator, and remove the residual solvent under negative pressure to obtain 8.1 g of product. Yield: 57.3%. The product was analyzed by HPLC and the purity was 93.4%.
[0032] As can be seen from the method in Comparative Example 1, the yield and content of 3-chloro-N-hydroxy-2-oxo-propaneimine chloride were significantly reduced when using 1,3-dichloroacetone as a raw material. This is mainly because the method generates dinitration byproducts. To avoid excessive dinitration byproducts, the amount of oxime reagent used was only 0.67 eq; otherwise, the dinitration byproducts would exceed 3%, making purification difficult.
[0033] Comparative Example 2 92 g (0.56 mol) of ethyl 4-chloroacetoacetate and 542 g of 37% hydrochloric acid were added to a 2000 ml four-necked flask with stirring, and the mixture was reacted at 25 °C for 24 h. Then, the mixture was concentrated under vacuum to 320 g at 40 °C, and the residue was cooled to 5 °C. 215 g of 20% sodium hydroxide solution was slowly added dropwise to the residue, keeping the system temperature below 10 °C throughout the addition. After the sodium hydroxide addition was complete, the mixture was cooled to 0 °C, and 159 g (0.46 mol) of 20% sodium nitrite solution was added over 15 minutes. At this point, gas was released from the reaction system, and finally, 1-chloro-3-(hydroxyimino)acetone precipitated. After stirring at 0°C for 30 minutes, the mixture was extracted with 360 ml of ethyl acetate. The aqueous phase was further extracted twice with ethyl acetate (120 ml × 2). The organic phases were combined, and 51 g of sodium bicarbonate and 29 g of water were added. The mixture was cooled to 0°C and maintained at 0–5°C. 37.6 g (0.53 mol) of chlorine gas was bubbled through the mixture over 30 minutes. After the bubbling was complete, the mixture was stirred for another 30 minutes at 0–5°C. The mixture was filtered, and the aqueous phase was separated from the filtrate. The organic phase was desolvated under reduced pressure to obtain 37.2 g of the product. Yield: 40.1%. The purity of the product was 94.1% as determined by HPLC.
[0034] As can be seen from the method in Comparative Example 2, the yield of the above method is significantly lower than that of the present invention. The main reason is that the above method is cumbersome and difficult to control during the preparation process. In addition, during the evaporation of hydrochloric acid, the intermediate 4-chloro-3-oxobutyric acid will slowly decompose, and the addition of sodium bicarbonate and water during chlorination will also cause the product to decompose, thereby reducing the product yield.
[0035] Although the present invention has been described in detail with reference to the accompanying drawings and preferred embodiments, the present invention is not limited thereto. Various equivalent modifications or substitutions can be made to the embodiments of the present invention by those skilled in the art without departing from the spirit and essence of the invention, and such modifications or substitutions should all be within the scope of the present invention. Any variations or substitutions that can be easily conceived by those skilled in the art within the technical scope disclosed in the present invention should also be covered within the protection scope of the present invention.
Claims
1. A method for preparing 3-chloro-N-hydroxy-2-oxo-propaneimine chloride, characterized in that, The synthesis route is shown below: ； The process includes the following steps: (1) using diketene as a raw material, reacting it with chlorine to obtain 4-chloro-3-oxobutyryl chloride; then hydrolyzing it to obtain 4-chloro-3-oxobutyric acid; (2) oximation to obtain 1-chloro-3-(hydroxyimino)propanone; (3) chlorination to obtain 3-chloro-N-hydroxy-2-oxo-propaneimino chloride.
2. The method for preparing 3-chloro-N-hydroxy-2-oxo-propanediol chloride as described in claim 1, characterized in that, Step (1) is as follows: Diketene is dissolved in solvent one, chlorine gas is introduced at a controlled temperature of -25~40℃ to react, water is added after the gas phase monitoring shows that the reaction of the raw materials is complete, and 4-chloro-3-oxobutyric acid is obtained by filtration after the reaction is completed.
3. The method for preparing 3-chloro-N-hydroxy-2-oxo-propanediol chloride as described in claim 2, characterized in that, In step (1), the molar ratio of diketene to chlorine is 1:1~2.
4. The method for preparing 3-chloro-N-hydroxy-2-oxo-propanediol chloride as described in claim 1, characterized in that, Step (2) is as follows: Mix solvent 1, water, hydrochloric acid and 4-chloro-3-oxobutyric acid and cool down, add sodium nitrite aqueous solution, keep the reaction system temperature at 0~5℃ during the addition process, and keep the reaction at 0~25℃ after the addition is completed; after the reaction is completed, separate the liquid and concentrate the organic phase to obtain 1-chloro-3-(hydroxyimino)acetone.
5. The method for preparing 3-chloro-N-hydroxy-2-oxo-propanediol chloride as described in claim 4, characterized in that, The molar ratio of 4-chloro-3-oxobutyric acid to sodium nitrite is 1:1~2.
6. The method for preparing 3-chloro-N-hydroxy-2-oxo-propanediol chloride as described in claim 1, characterized in that, Step (3) is as follows: Dissolve 1-chloro-3-(hydroxyimino)acetone in solvent one, control the temperature at -25~40℃, introduce chlorine gas to react, and after the reaction is completed, add solvent to crystallize and obtain 3-chloro-N-hydroxy-2-oxo-propaneimino chloride.
7. The method for preparing 3-chloro-N-hydroxy-2-oxo-propanediol chloride as described in claim 6, characterized in that, In step (3), the reaction temperature for introducing chlorine gas is -15~25℃.
8. The method for preparing 3-chloro-N-hydroxy-2-oxo-propanediol chloride as described in claim 6, characterized in that, In step (3), the molar ratio of 1-chloro-3-(hydroxyimino)acetone to chlorine is 1:1~2.
9. The method for preparing 3-chloro-N-hydroxy-2-oxo-propanediol chloride according to any one of claims 2-8, characterized in that, The solvent is one of dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene, ethyl acetate, propyl acetate, isopropyl acetate, diethyl ether, isopropyl ether, or methyl tert-butyl ether.
10. The method for preparing 3-chloro-N-hydroxy-2-oxo-propanediol chloride as described in claim 6, characterized in that, The second solvent is 1-chlorobutane or carbon tetrachloride.