Preparation process of Propaquizaphop

Abstract

Preparation process of Propaquizaphop This invention relates to a process for preparing propaquiza fop. The process of this invention is carried out under mild reaction conditions. Furthermore, the process of this invention is a single synthesis procedure. Moreover, the process of this invention is simple, cost-effective, environmentally friendly, and provides propaquiza fop with relatively improved purity and yield.

Description

Technical Field

[0001] The present invention relates to a preparation process of propaquizafop.

Background Art

[0002] The following background information relates to the present invention and is not necessarily related to the prior art.

[0003] Propaquizafop is an aryloxyphenoxypropionate herbicide mainly used for germinated weeds. The mode of action of propaquizafop is to inhibit plastid acetyl-CoA carboxylase (ACCase), which is a major enzyme in fatty acid biosynthesis. Propaquizafop is used for selective weed control for many broad-leaved crops such as sugar beet, rapeseed, soybean, sunflower, vegetables, fruit trees, vineyards for wine, forestry, etc. Propaquizafop is immediately absorbed from the leaves and transported from the whole leaves of the sprayed weeds to the growing points of each leaf and root. This substance is environmentally friendly and safe for beneficial insects and mammals. The chemical name of propaquizafop is (R)-2-((propan-2-ylideneamino)oxy)ethyl 2-(4-((6-chloroquinoxalin-2-yl)oxy)phenoxy)propanoate. Propaquizafop has the following structure:

Chemical Formula

Summary of the Invention

Problems to be Solved by the Invention

[0004] According to the conventional preparation method of propaquizafop, there are disadvantages such as impurities and low product yield. In the conventional process, expensive reagents are required, and further purification is needed, which is uneconomical. The impurities in the final product may have an adverse effect on the efficacy, safety and stability of the final product.

[0005] Therefore, there is a recognized need to provide a preparation process for propaquizafop that eliminates the aforementioned disadvantages and provides at least a useful alternative.

[0006] Purpose of the invention Some of the objectives of the present invention can be adequately expressed by at least one example described herein, which is as follows:

[0007] The object of the present invention is to improve one or more of the underlying problems or to provide at least a useful alternative.

[0008] Another objective of the present invention is to provide a process for preparing propaquizaphop.

[0009] Another objective of the present invention is to provide a one-step preparation process for propaquizafop.

[0010] Another objective of the present invention is to provide a process for preparing propaquizafop with relatively good purity and yield.

[0011] Another objective of the present invention is to provide a simple and cost-effective preparation process for propaquizaphop.

[0012] Another objective of the present invention is to provide an environmentally friendly and commercially scalable preparation process for propaquizaphop.

[0013] Other objectives and advantages of the present invention will become even clearer from the following description, which is not intended to limit the scope of the invention. [Means for solving the problem]

[0014] The present invention relates to a process for preparing propaquizafop. This process consists of mixing a predetermined amount of alkyl(2R)-2-[4-(6-chloroquinoxaline-2-yl)oxyphenoxy]propanoate in a liquid medium while stirring at a first predetermined temperature to obtain a first mixture. A predetermined amount of catalyst is added to the first mixture while stirring at a first predetermined temperature to obtain a second mixture. A predetermined amount of 2-[(isopropylideneamino)oxy]ethanol is added to the second mixture while stirring at a first predetermined temperature, and stirring is continued for a first predetermined period to obtain a reaction product. The reaction product is heated to a second predetermined temperature over a second predetermined period while stirring to obtain a product compound consisting of propaquizafop.

[0015] Alkyl(2R)-2-[4-(6-chloroquinoxalin-2-yl)oxyphenoxy]propanoate is selected from methyl(2R)-2-[4-(6-chloroquinoxalin-2-yl)oxyphenoxy]propanoate and ethyl(2R)-2-[4-(6-chloroquinoxalin-2-yl)oxyphenoxy]propanoate.

[0016] The liquid medium is selected from the group consisting of toluene, mesitylene, mixed xylene, o-xylene, p-xylene, and m-xylene.

[0017] The catalyst is selected from the group consisting of titanium(IV) isopropoxide, aluminum chloride, and titanium chloride.

[0018] In one embodiment of the present invention, the molar ratio of alkyl(2R)-2-[4-(6-chloroquinoxaline-2-yl)oxyphenoxy]propanoate to the catalyst is in the range of 1:0.05 to 1:0.5.

[0019] In one embodiment of the present invention, the molar ratio of alkyl(2R)-2-[4-(6-chloroquinoxaline-2-yl)oxyphenoxy]propanoate to 2-[(isopropylideneamino)oxy]ethanol is in the range of 1:1 to 1:5.

[0020] The first predetermined temperature ranges from 20 °C to 50 °C.

[0021] The first predetermined period ranges from 5 minutes to 30 minutes.

[0022] The second predetermined temperature ranges from 120 °C to 160 °C.

[0023] The second predetermined period ranges from 10 hours to 30 hours.

[0024] In one embodiment of the present invention, the yield of propaquizafop ranges from 82% to 90%, and the purity ranges from 98% to 99.5%.

[0025] In one embodiment of the present invention, after cooling the product compound to the range of 25 °C to 35 °C, a predetermined amount of inorganic acid is dropped while stirring at the third predetermined temperature for the third predetermined time, and the resulting reaction product is filtered to obtain a filtrate containing propaquizafop.

[0026] The third predetermined period ranges from 20 minutes to 40 minutes.

[0027] The third predetermined temperature ranges from 5 °C to 20 °C.

[0028] The mineral acid is selected from the group consisting of hydrochloric acid and sulfuric acid.

Embodiments for Carrying Out the Invention

[0029] The present invention relates to a preparation process of propaquizafop.

[0030] Embodiments of the present invention are described below. With the embodiments described herein, a person skilled in the art will be able to fully and completely grasp the scope of the present invention. Numerous details relating to specific components are described to fully understand the embodiments of the present invention. It will be clear to a person skilled in the art that the details described in the embodiments cannot be interpreted as limiting the scope of the present invention. Some embodiments do not describe in detail well-known processes, well-known apparatus structures, or well-known techniques.

[0031] In this invention, the terms used herein are used solely to describe specific embodiments and should not be construed as limiting the scope of the invention. Nouns used herein include multiple things unless the context requires them to be treated as singular. Terms such as "consisting of," "including," "composed of," and "consisting of" are transitional phrases that may include other things and thus define the existence of functions, features, integers, procedures, operations, elements, modules, units, or components described herein, but do not exclude the existence or addition of other functions, integers, procedures, operations, elements, components, or groups of components. The order of specific procedures disclosed in the methods and processes of this invention should be interpreted as meaning that the performance described or illustrated is not necessarily an essential element. It should also be understood that additional or alternative procedures may be used.

[0032] As used herein, the term "or" includes one or any combination of the relevant list elements.

[0033] The terms "first," "second," "third," etc., can only be used to distinguish one element or component, region, layer, or section from other components, regions, layers, or sections, and therefore cannot be construed as limiting the scope of the invention. Unless expressly indicated in the invention, the terms "first," "second," "third," etc., do not imply any particular permutation or order.

[0034] Conventional preparation methods for propaquiza fop have disadvantages such as impurities and low product yield. Conventional processes require uneconomical subsequent purification. Impurities in the final product can adversely affect its efficacy, safety, and stability.

[0035] This invention provides an improved preparation process for propaquizaphop.

[0036] The process of the present invention is simple, environmentally friendly, economical, and yields high-purity propaquizafop with improved yield.

[0037] The preparation process for propaquizaphop according to the present invention consists of the following steps: a) A predetermined amount of alkyl(2R)-2-[4-(6-chloroquinoxaline-2-yl)oxyphenoxy]propanoate is mixed in a liquid medium with stirring at a first predetermined temperature to obtain a first mixture. b) Add a predetermined amount of catalyst to the first mixture while stirring at a first predetermined temperature to obtain a second mixture. c) Add a predetermined amount of 2-[(isopropylideneamino)oxy]ethanol to the second mixture while stirring at a predetermined temperature for a predetermined period of time to obtain the reaction product, and further, d) The reaction product is heated to a second predetermined temperature for a second predetermined period while stirring to obtain a product compound consisting of propaquizafop.

[0038] The preparation process for propaquizaphop is described in detail below.

[0039] In the first step, a predetermined amount of alkyl(2R)-2-[4-(6-chloroquinoxaline-2-yl)oxyphenoxy]propanoate is mixed with a liquid medium while stirring at a predetermined temperature to obtain the first mixture.

[0040] In one embodiment of the present invention, alkyl(2R)-2-[4-(6-chloroquinoxalin-2-yl)oxyphenoxy]propanoate is selected from methyl(2R)-2-[4-(6-chloroquinoxalin-2-yl)oxyphenoxy]propanoate and ethyl(2R)-2-[4-(6-chloroquinoxalin-2-yl)oxyphenoxy]propanoate. In one example of the present invention, alkyl(2R)-2-[4-(6-chloroquinoxalin-2-yl)oxyphenoxy]propanoate is ethyl(2R)-2-[4-(6-chloroquinoxalin-2-yl)oxyphenoxy]propanoate (quizalophop-P-ethyl).

[0041] The liquid medium is selected from the group consisting of toluene, mesitylene, mixed xylene, o-xylene, p-xylene, and m-xylene. In one embodiment of the present invention, the liquid medium is mixed xylene.

[0042] The first predetermined temperature is in the range of 20°C to 50°C. In one embodiment of the present invention, the first predetermined temperature is 30°C. In the second step, a predetermined amount of catalyst is added to the first mixture while stirring at the first predetermined temperature to obtain the second mixture.

[0043] The catalyst is selected from the group consisting of titanium(IV) isopropoxide, aluminum chloride, and titanium chloride. In one embodiment of the present invention, the catalyst is titanium(IV) isopropoxide.

[0044] In one embodiment of the present invention, the molar ratio of alkyl(2R)-2-[4-(6-chloroquinoxalin-2-yl)oxyphenoxy]propanoate to the catalyst is in the range of 1:0.05 to 1:0.5. In one example of the present invention, the molar ratio of alkyl(2R)-2-[4-(6-chloroquinoxalin-2-yl)oxyphenoxy]propanoate to the catalyst is 1:0.1.

[0045] In the third step, a predetermined amount of 2-[(isopropylideneamino)oxy]ethanol is added to the second mixture while stirring at a first predetermined temperature over a first predetermined period of time to obtain the reaction product.

[0046] The first predetermined period is in the range of 5 to 30 minutes. In one embodiment of the present invention, the first predetermined period is 10 minutes.

[0047] In one embodiment of the present invention, the molar ratio of alkyl(2R)-2-[4-(6-chloroquinoxalin-2-yl)oxyphenoxy]propanoate to 2-[(isopropyrideneamino)oxy]ethanol is in the range of 1:1 to 1:5. In one example of the present invention, the molar ratio of alkyl(2R)-2-[4-(6-chloroquinoxalin-2-yl)oxyphenoxy]propanoate to 2-[(isopropyrideneamino)oxy]ethanol is 1:1.3.

[0048] In the fourth step, the reaction product is heated to a second predetermined temperature while being stirred for a second predetermined period of time to obtain a product compound containing propaquizafop.

[0049] The second predetermined temperature is in the range of 120°C to 160°C. In one embodiment of the present invention, the second predetermined temperature is 140°C.

[0050] The second predetermined period is in the range of 10 to 30 hours. In one embodiment of the present invention, the second predetermined period is 16 hours.

[0051] In one embodiment of the present invention, as the reaction proceeds, by-products such as ethanol, methanol, titanium hydroxide or titanium dioxide, S-isomers of propaquizahop, quizahop-(p)-isopropyl ester, and quizahop-(p)-methyl ester are formed.

[0052] In one embodiment of the present invention, the product compound is cooled to a temperature range of 25°C to 35°C, and then a predetermined amount of mineral acid is added dropwise over a third predetermined period of time while stirring at a third predetermined temperature to obtain a reaction product. The reaction product is filtered to obtain a filtrate consisting of propaquiza fop.

[0053] The third predetermined period is in the range of 20 to 40 minutes. In one embodiment of the present invention, the third predetermined period is 30 minutes.

[0054] The third predetermined temperature is in the range of 5°C to 20°C. In one embodiment of the present invention, the third predetermined temperature is 10°C.

[0055] The mineral acid is selected from the group consisting of hydrochloric acid and sulfuric acid. In one embodiment of the present invention, the mineral acid is hydrochloric acid.

[0056] In one embodiment of the present invention, the filtrate is allowed to settle for 20 to 40 minutes, and the two layers are separated to obtain an organic layer and an aqueous layer.

[0057] In one embodiment of the present invention, the organic layer is separated, washed with a 10% NaHCO3 solution, and then washed with water to obtain the washed organic layer. This washed organic layer is distilled under reduced pressure at a temperature range of 80 °C to 95 °C to obtain the crude solid product propaquiza fop. Isopropanol is added to this crude propaquiza fop and stirred for a time range of 20 to 40 minutes, and then filtered to obtain propaquiza fop.

[0058] According to the process of the present invention, the propaquiza fop obtained by the above procedure has a yield range of 82% to 90% and a purity range of 98% to 99.5%. In one embodiment of the present invention, the yield of the propaquiza fop is 88% and the purity is 99%.

[0059] A conceptual diagram of the preparation of propaquizaphop according to one embodiment of the present invention is illustrated in the following schema I: [ka] Here, R is selected from methyl and ethyl.

[0060] This invention provides a simple, environmentally friendly, and economical process for propaquisafop with relatively improved yield and purity.

[0061] The foregoing description of embodiments is for illustrative purposes only and is not intended to limit the scope of the invention to that description alone. Individual components of a particular embodiment are generally not limited to that particular embodiment and are interchangeable. Such variations cannot be considered different from the invention, and all such variations are considered to be within the scope of the invention.

[0062] The present invention will be further illustrated by the following non-limiting embodiments. However, the following examples are provided for illustrative purposes only and should not be construed as limiting the scope of the invention. The following experiments can be scaled up to an industrial / commercial scale, and the results can be extrapolated to an industrial scale. Experimental Content

[0063] Example 1: Preparation of propaquizaphop according to the present invention from ethyl(2R)-2-[4-(6-chloroquinoxaline-2-yl)oxyphenoxy]propanoate

[0064] 700 g (3 parts) of mixed xylene was placed in the reactor, and then 100 g of ethyl(2R)-2-[4-(6-chloroquinoxaline-2-yl)oxyphenoxy]propanoate was added with stirring at 30 °C to obtain the first mixture. 7.6 g of titanium(IV) isopropoxide was added to the first mixture with stirring at 30 °C to obtain the second mixture. 40.85 g of 2-[(isopropylideneamino)oxy]ethanol (IPAE) was added to the second mixture with stirring at 30 °C, and the reaction product was obtained by stirring for 10 minutes at 30 °C. The reaction product was heated to 140 °C with stirring and maintained at this temperature for 16 hours to obtain the product compound consisting of propaquizafop. Ethanol (by-product) was collected in a receiving container during the reaction. The progress of the reaction was tracked by HPLC / TLC.

[0065] The product compound consisting of propaquiza fop was cooled to 25 °C while stirring, and the cooled mass was obtained. 35% HCl was added dropwise to the cooled mass over 30 minutes at 10 °C to obtain the reaction product. The reaction product was filtered through a Celite layer to obtain a filtrate containing propaquiza fop. The filtrate was allowed to settle over 30 minutes, and the two layers were separated to obtain an organic layer and an aqueous layer. The organic layer was washed with a 10% NaHCO3 solution, and then washed with water to obtain the washed organic layer. This washed organic layer was distilled under reduced pressure at 90 °C to obtain the crude solid product propaquiza fop.

[0066] 40 ml of isopropanol was added to crude propaquiza fop, stirred at 30°C for 30 minutes, then filtered to obtain pure propaquiza fop, which was washed with isopropanol and then washed at 50°C for 5 hours to obtain propaquiza fop (yield: 88%, purity: 99%). Comparative example:

[0067] Comparative Example 1 (Conventional preparation process for Propaquizaphop): In the first step, (S)-2-(4-((6-chloroquinoxalin-2-yl)oxy)phenoxy)propionic acid is chlorinated in thionyl chloride / dichloromethane solution (MDC) at 40 °C to obtain (S)-2-(4-((6-chloroquinoxalin-2-yl)oxy)phenoxy)propanoyl chloride.

[0068] In the second step, (S)-2-(4-((6-chloroquinoxaline-2-yl)oxy)phenoxy)propanoyl chloride is used as a base with potassium carbonate and reacted with propan-2-one O-(2-hydroxyethyl)oxime in mixed xylene at 140 °C to obtain propaquizafop with a yield of 80% and purity of 95%.

[0069] Schema II below schematically represents the preparation of propaquizaphop according to Comparative Example 1: [ka]

[0070] Comparative Example 2 (Conventional preparation process for Propaquizaphop):

[0071] In the first step, 4-methylbenzene-1-sulfonyl chloride is reacted with propan-2-one-O-(2-hydroxyethyl)oxime in the presence of tetrabutylammonium bromide (TBAB) to obtain 2-((propan-2-ylideneamino)oxy)ethyl 4-methylbenzenesulfonate.

[0072] In the second step, potassium carbonate is used as the base to react 2-((propane-2-ylideneamino)oxy)ethyl 4-methylbenzene sulfonate with (S)-2-(4-((6-chloroquinoxalin-2-yl)oxy)phenoxy)propionic acid in a mixed xylene at 140 °C to obtain propaquizafop with a yield of 75% and purity of 95%.

[0073] Schema III below schematically represents the preparation of propaquizaphop according to Comparative Example 2: [ka]

[0074] Based on Example 1 and Comparative Examples 1 and 2, the preparation process of propaquiza fop according to the present invention is a single-reactor process (catalytic amount only) using a minimum amount of reagent, and the yield of the final product propaquiza fop obtained is relatively good, with fewer by-products and higher purity. Furthermore, the reaction operation in the process of the present invention is simple, and product separation is possible in a single operation step. In addition, the liquid medium used in the process of the present invention can be recovered and reused in subsequent batches.

[0075] In ethyl(2R)-2-[4-(6-chloroquinoxaline-2-yl)oxyphenoxy]propanoate, (2R) represents the R enantiomer, and also, In (S)-2-(4-((6-chloroquinoxaline-2-yl)oxy)phenoxy)propionic acid, (S) represents the S enantiomer.

[0076] The R / S system is a naming convention for enantiomers. In the R / S naming convention, each chiral center is assigned either an R or S configuration based on its substituents (R and S are Latin for right and left, meaning rectus and sinister, respectively). According to this naming convention, each substituent on the chiral center is assigned a priority order based on its atomic number, following the Kahn-Ingold-Prelogue priority rule. A clockwise arrow indicates an R configuration. A clockwise arrow indicates an S configuration. Technological advancements

[0077] The present invention described above has several technical advantages, including, but is not limited to, the preparation of process propaquiza fop that achieves the following: • Conducted under mild reaction conditions, • Synthesized in a single process, • Simple, cost-effective, and environmentally friendly. • Relatively high purity and high yield of propaquiza fop can be obtained.

[0078] The embodiments disclosed herein and their various features and advantages are described below with reference to non-limiting embodiments. Descriptions of established existing components and processing techniques are omitted to avoid unnecessarily complicating the understanding of the embodiments of the present invention. The experiments used in the present invention are solely for the purpose of facilitating the understanding of how to make the embodiments of the present invention practical and enabling those skilled in the art to carry out the embodiments of the present invention. Therefore, they should not be construed as limiting the scope of the embodiments of the present invention by convention.

[0079] The descriptions of the above-mentioned specific embodiments sufficiently clarify the general nature of the embodiments of the present invention. Therefore, by applying the existing knowledge, the above-mentioned specific embodiments can be modified or adapted for different uses without deviating from the above-mentioned general concepts. Accordingly, any adaptation / modification should and is intended to be understood as equivalent to and within the scope of the embodiments of the present invention. The usage of phrases and terms used herein is for illustrative purposes only and not for limitation. Accordingly, the embodiments described herein are based on preferred embodiments, and it is recognized that the embodiments described herein can be modified within the intent and scope of the embodiments described herein.

[0080] The use of the phrases "at least" or "at least one" implies the use of one or more elements, components, or quantities, as they may be used in the embodiments of the invention to obtain one or more target substances or results. Although several embodiments of the invention have been described, these embodiments are provided only as examples and are not intended to limit the scope of the invention. Formulations or modifications relating to the manufacture of the invention may be immediately possible for a person skilled in the art upon consideration of the invention, provided they remain within the scope of the invention. Such variations and modifications are within the intended scope of the invention.

[0081] Any discussion of documents, acts, materials, devices, products or similar items included herein is provided solely for the purpose of creating the context for the disclosure of the present invention. Nothing or all of the above shall be construed as an endorsement that any or all of the above constitutes part of the basis of known inventive art or is common knowledge in the art relevant to the present invention that existed anywhere prior to the priority date of this application.

[0082] Numerical values ​​representing different physical parameters, dimensions, or quantities are approximate, and values ​​higher than those substituted for physical parameters, dimensions, or quantities are intended to fall within the scope of the present invention, unless otherwise stated in the specification.

[0083] While certain features of the present invention have been considerably emphasized, different modifications are possible, and many additions can be made to the preferred embodiments without deviating from the principles of the invention. It will be obvious to those with expertise in the art that the features of the present invention or the preferred embodiments can be modified, and it is important to understand that the above description is merely for illustrative purposes and should not be interpreted as limiting.

Claims

1. The preparation process for propaquizaphop consists of the following steps: a) A predetermined amount of alkyl(2R)-2-[4-(6-chloroquinoxaline-2-yl)oxyphenoxy]propanoate is mixed in a liquid medium while stirring at a first predetermined temperature to obtain the first mixture. b) Add a predetermined amount of catalyst to the first mixture while stirring at the first predetermined temperature to obtain a second mixture. c) Add a predetermined amount of 2-[(isopropylideneamino)oxy]ethanol to the second mixture while stirring at the first predetermined temperature, continue stirring for the first predetermined period, and obtain the reaction product. d) The reaction product is heated to a second predetermined temperature for a second predetermined period while stirring to obtain a product compound consisting of propaquizafop.

2. A process according to claim 1, wherein the alkyl(2R)-2-[4-(6-chloroquinoxalin-2-yl)oxyphenoxy]propanoate is selected from methyl(2R)-2-[4-(6-chloroquinoxalin-2-yl)oxyphenoxy]propanoate and ethyl(2R)-2-[4-(6-chloroquinoxalin-2-yl)oxyphenoxy]propanoate.

3. A process according to claim 1, wherein the liquid medium is selected from the group consisting of toluene, mesitylene, mixed xylene, o-xylene, p-xylene, and m-xylene.

4. A process according to claim 1, wherein the catalyst is selected from the group consisting of titanium(IV) isopropoxide, aluminum chloride, and titanium chloride.

5. A process according to claim 1, wherein the molar ratio of the alkyl(2R)-2-[4-(6-chloroquinoxaline-2-yl)oxyphenoxy]propanoate to the catalyst is in the range of 1:0.05 to 1:0.

5.

6. A process according to claim 1, wherein the molar ratio of alkyl(2R)-2-[4-(6-chloroquinoxaline-2-yl)oxyphenoxy]propanoate to 2-[(isopropylideneamino)oxy]ethanol is in the range of 1:1 to 1:

5.

7. A process according to claim 1, wherein the first predetermined temperature is in the range of 20°C to 50°C.

8. A process as claimed in claim 1, wherein the first predetermined period is in the range of 5 minutes to 30 minutes.

9. A process according to claim 1, wherein the second predetermined temperature is in the range of 120°C to 160°C.

10. A process as claimed in claim 1, wherein the second predetermined period is in the range of 10 to 30 hours.

11. A process according to claim 1, wherein the yield of propaquizafop is in the range of 82% to 90% and the purity is in the range of 98% to 99.5%.

12. A process according to claim 1, wherein the product compound is cooled to a temperature range of 25°C to 35°C, a predetermined amount of mineral acid is added dropwise at a third predetermined temperature for a third predetermined period while stirring to obtain a reaction product, and the reaction product is filtered to obtain a filtrate containing propaquiza fop.

13. A process according to claim 12, wherein the third predetermined period is in the range of 20 to 40 minutes.

14. A process according to claim 12, wherein the third predetermined temperature is in the range of 5°C to 20°C.

15. A process according to claim 12, wherein a selection is made from the group consisting of mineral acid salts and sulfuric acid.

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