Method for the preparation of 5-chloro-2-((ETHOXYCARBONYL)amino)-3-methylbenzoic acid

Abstract

Disclosed herein are methods for the synthesis of 5-chloro-2-((ethoxycarbonyl)amino)-3-methylbenzoic acid and its derivatives.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 63 / 330,813, filed April 14, 2022.

[0002] The present disclosure relates to methods for the synthesis of 5-chloro-2-((ethoxycarbonyl)amino)-3-methylbenzoic acid and its derivatives. Compounds prepared by the methods disclosed herein are particularly useful for the preparation of certain anthranilamide compounds of interest as pesticides, such as, for example, the pesticides chlorantraniliprole and cyantraniliprole. [Background technology]

[0003] The present disclosure provides novel methods useful for the preparation of 5-chloro-2-((ethoxycarbonyl)amino)-3-methylbenzoic acid and its derivatives. Methods for preparing 5-chloro-2-((ethoxycarbonyl)amino)-3-methylbenzoic acid are known in the art, such as those described in U.S. Patent Application No. 8,153,844. However, these known methods are costly and inefficient.

[0004] In this known process, chlorine is generated in situ with 30% hydrogen peroxide and 37% hydrochloric acid. The reaction rate is controlled by the feed rate of hydrogen peroxide. Typically, the reaction is carried out in acetic acid solution at 30-35°C for 3-5 hours. After the reaction, the product is obtained by sufficient dilution of the reaction mixture with water, thereby generating a lot of wastewater. The acetic acid remains in the wastewater and is difficult to recover.

[0005] The advantages of the disclosed methods compared to conventional processes are numerous, including waste remediation, solvent recovery and / or recycling, and cost savings. Summary of the Invention [Means for solving the problem]

[0006] In one aspect, a compound of formula (II) [ka] (In the formula, R 3 is CH3 or Cl; R 4 is C1-C6 alkyl or C3-C6 alkenyl, each of which is optionally substituted with up to three halogens and up to one phenyl; and X is Cl or Br. 1. A method for preparing a composition comprising: (I) Below: A) A compound of formula (I) [ka] (In the formula, R 1 is CH3 or Cl; R 2 is C1-C6 alkyl or C3-C6 alkenyl, each of which is optionally substituted with up to three halogens and up to one phenyl; and B) Aqueous solvents present at a concentration of about 90% v / v or less forming a mixture comprising (II) introducing a halogenating agent to said mixture; (III) removing the halogenating agent from the mixture; and (IV) optionally, cooling the mixture to a temperature in the range of about 0° C. to about 5° C. is provided. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0007] Disclosed herein are methods for the synthesis of 5-chloro-2-((ethoxycarbonyl)amino)-3-methylbenzoic acid and its derivatives.

[0008] Embodiments of the present disclosure include the following.

[0009] Embodiment 1. Compound of Formula (II) [ka] (In the formula, R 3 is CH3 or Cl; R 4 is C1-C6 alkyl or C3-C6 alkenyl, each of which is optionally substituted with up to three halogens and up to one phenyl; and X is Cl or Br. 1. A method for preparing a composition comprising: (I) Below: A) A compound of formula (I) [ka] (In the formula, R 1 is CH3 or Cl; R 2 is C1-C6 alkyl or C3-C6 alkenyl, each of which is optionally substituted with up to three halogens and up to one phenyl; and B) Aqueous solvents present at a concentration of about 90% v / v or less forming a mixture comprising (II) introducing a halogenating agent to said mixture; (III) removing the halogenating agent from the mixture; and (IV) optionally, cooling the mixture to a temperature in the range of about 0° C. to about 5° C.

[0010] Embodiment 2.R 3 and X are each Cl.

[0011] Embodiment 3.R 3 3. The method of any one of the preceding embodiments, wherein is CH3 and X is Cl.

[0012] Embodiment 4.R 4 The method of any one of embodiments 1 to 3, wherein is C1 to C2 alkyl.

[0013] Embodiment 5.R 1 The method of any one of embodiments 1-4, wherein is CH3.

[0014] Embodiment 6.R 2 The method of any one of the preceding embodiments, wherein is C1-C2 alkyl.

[0015] Embodiment 7.R 3 is CH3, X is Cl, and R 4 The method of any one of embodiments 1-6, wherein is ethyl.

[0016] Embodiment 8. The method of any one of embodiments 1-7, wherein the aqueous solvent is present at a concentration of about 85% v / v or less.

[0017] Embodiment 9. The method of any one of embodiments 1-8, wherein the aqueous solvent is present at a concentration of about 80% v / v or less.

[0018] Embodiment 10. The method of any one of embodiments 1 to 9, wherein the aqueous solvent is an aqueous solution of acetic acid.

[0019] Embodiment 11. The method of any one of embodiments 1 to 10, wherein the aqueous solvent does not contain hydrogen peroxide.

[0020] Embodiment 12. The method of any one of embodiments 1 to 11, wherein the aqueous solvent comprises recovered and / or recycled aqueous solvent.

[0021] Embodiment 13. The method of any one of embodiments 1 to 12, wherein the halogenating agent is a chlorinating agent or a brominating agent.

[0022] Embodiment 14. The method of any one of embodiments 1 to 13, wherein the halogenating agent is selected from the group consisting of Cl2, Br2, and combinations thereof.

[0023] Embodiment 15. The method of any one of embodiments 1 to 14, wherein the method step of introducing the halogenating agent to the mixture comprises introducing the halogenating agent to the mixture at a temperature in the range of from about 0° C. to about 35° C.

[0024] Embodiment 16. The method of any one of embodiments 1 to 15, wherein the method step of removing the halogenating agent from the mixture comprises bubbling N2 through the mixture.

[0025] Embodiment 17. The method of any one of embodiments 1 to 16, further comprising the method steps of producing a solid product and filtering and / or washing said solid product.

[0026] Embodiment 18. The method of any one of embodiments 1 to 18, further comprising the method step of recovering and / or recycling the aqueous solvent.

[0027] Embodiment 19. The method of embodiment 19, wherein the method step of recovering and / or recycling the aqueous solvent recovers and / or recycles at least 50% v / v of the aqueous solvent.

[0028] Embodiment 20. The method of embodiment 18, wherein the method step of recovering and / or recycling the aqueous solvent recovers and / or recycles at least 75% v / v of the aqueous solvent.

[0029] Embodiment 21. The method of any one of embodiments 1 to 20, further comprising the step of recovering and / or recycling the mother liquor.

[0030] Embodiment 22. The method of embodiment 21, wherein the method step of recovering and / or recycling the mother liquor recovers and / or recycles at least 50% v / v of the mother liquor.

[0031] Embodiment 23. The method of embodiment 21, wherein the method step of recovering and / or recycling the mother liquor recovers and / or recycles at least 80% v / v of the mother liquor.

[0032] In one aspect, 5-chloro-2-((ethoxycarbonyl)amino)-3-methylbenzoic acid is prepared according to the method represented by Scheme 1. [ka]

[0033] In one aspect, compounds of formula II are prepared according to the method depicted by Scheme 2. The R groups and X are as defined elsewhere in this disclosure. [ka]

[0034] This aspect includes forming a mixture including a compound of formula I and an aqueous solvent, introducing a halogenating agent to the mixture, optionally removing the halogenating agent from the mixture, and optionally cooling the mixture to a temperature in the range of about 0° C. to about 5° C.

[0035] In some embodiments, the reaction of the mixture is complete after the completion of the reaction time.

[0036] In some embodiments, the aqueous solvent is an aqueous solution of acetic acid. In some embodiments, the aqueous solvent does not include hydrogen peroxide. In some embodiments, the aqueous solvent comprises recovered and / or recycled aqueous solvent.

[0037] Generally, any suitable amount of acetic acid can be used in the solvent, in many embodiments, the amount and / or concentration of acetic acid is relatively low to reduce the use of acetic acid and waste products.

[0038] In some embodiments, the aqueous solvent is a mother liquor. In some embodiments, the aqueous solvent is a recovered and / or recycled mother liquor. In these embodiments, the mother liquor is a mixture of the aqueous solvent, any residual products from previous reactions, and any impurities from previous reactions. In many embodiments, recovering the mother liquor from previous reactions and recycling it as an aqueous solvent in subsequent reactions allows for reduced waste and increased yields.

[0039] In some embodiments, the aqueous solvent is present at a concentration of about 90% v / v, about 85% v / v, or less than about 80% v / v, hi some embodiments, the aqueous solvent is present at a concentration ranging from about 80% v / v to about 85% v / v.

[0040] In some embodiments, the aqueous solvent is present in the mother liquor at a concentration of about 90% v / v, about 85% v / v, or about 80% v / v or less, hi some embodiments, the aqueous solvent is present in the mother liquor at a concentration ranging from about 80% v / v to about 85% v / v.

[0041] In some embodiments, the halogenating agent is a chlorinating agent or a brominating agent. In some embodiments, the halogenating agent is a gaseous halogenating agent. In some embodiments, the halogenating agent is a gaseous chlorinating agent or a gaseous brominating agent. In some embodiments, the halogenating agent is selected from the group consisting of gaseous Cl2, gaseous Br2, liquid Br2, and combinations thereof. In some embodiments, the gaseous halogenating agent is bubbled into the mixture. In some embodiments, the gaseous halogenating agent is bubbled into the mixture for a period of about 1, 2, 3, 4, 5, or 6 hours. In some embodiments, the gaseous halogenating agent is bubbled into the mixture for a period of about 1-6, 2-5, or 2-4 hours. In some embodiments, the halogenating agent is selected from the group consisting of gaseous Cl2, gaseous Br2, or combinations thereof, and is bubbled into the mixture. In some embodiments, the gaseous halogenating agent is bubbled into the mixture for a period of about 2 hours.

[0042] In some embodiments, when the halogenating agent is a liquid halogenating agent, the liquid halogenating agent is added to the mixture by dropwise addition.

[0043] In some embodiments, the halogenating agent does not include hydrochloric acid. In some embodiments, the halogenating agent does not include concentrated hydrochloric acid.

[0044] In some embodiments, the method step of introducing a halogenating agent to the mixture comprises introducing the halogenating agent to the mixture at a temperature in the range of about 0°C to about 35°C.

[0045] In some embodiments, the method step of removing the halogenating agent from the mixture comprises bubbling an inert gas through the mixture. In some embodiments, the method step of removing the halogenating agent from the mixture comprises bubbling N2 through the mixture.

[0046] In some embodiments, the method produces a solid product and the method further comprises the method step of filtering and / or washing the solid product. In some embodiments, the method step of filtering and / or washing the solid product comprises washing the solid product with a solution comprising acetic acid and / or water.

[0047] In some embodiments, the method further comprises the process step of recovering and / or recycling the aqueous solvent, hi some embodiments, the process step of recovering and / or recycling the aqueous solvent recovers and / or recycles at least about 50% v / v, at least about 55% v / v, at least about 60% v / v, at least about 65% v / v, at least about 70% v / v, at least about 75% v / v, at least about 80% v / v, at least about 85% v / v, at least about 90% v / v, at least about 95% v / v, or about 100% v / v of the aqueous solvent.

[0048] In some embodiments, the method further comprises a step of recovering and / or recycling the mother liquor. In some embodiments, the method step of recovering and / or recycling the mother liquor recovers and / or recycles at least about 50% v / v, at least about 55% v / v, at least about 60% v / v, at least about 65% v / v, at least about 70% v / v, at least about 75% v / v, at least about 80% v / v, at least about 85% v / v, at least about 90% v / v, at least about 95% v / v, or about 100% v / v of the mother liquor.

[0049] In some embodiments, the method includes forming a mixture comprising a compound of formula I and an optionally recycled aqueous solvent, the aqueous solvent being present at a concentration of about 90% v / v or less, introducing a gaseous halogenating agent into the mixture, reacting the mixture at a temperature in the range of about 20 to about 35° C., cooling the mixture to a temperature in the range of about 0° C. to about 5° C., filtering and washing the mixture, and recovering the compound of formula II in the form of a wet cake. After the filtering and washing steps, a small portion of the mother liquor may be subjected to a stripping step to recover acetic acid. The recovered acetic acid may be recycled in further reactions. Also, after the filtering and washing steps, a majority of the mother liquor may be recycled in further reactions.

[0050] In some embodiments, the method includes forming a mixture comprising a compound of formula I and an optionally recycled aqueous solvent, the aqueous solvent being present at a concentration of about 90% v / v or less, introducing a gaseous halogenating agent into the mixture, reacting the mixture at a temperature ranging from about 20 to about 35° C., removing the gaseous halogenating agent from the mixture by bubbling N2 through the mixture, cooling the mixture to a temperature ranging from about 0° C. to about 5° C., filtering and washing the mixture, and recovering the compound of formula II in the form of a wet cake. After the filtering and washing steps, the cake is optionally subjected to a slurry wash with water to obtain a first portion of wet cake. Also, after the filtering and washing steps, the mother liquor is optionally subjected to a stripping step at −20 to 60° C. to recover acetic acid, followed by cooling and filtering and washing steps to further recover acetic acid to obtain a second portion of wet cake. The recovered acetic acid may be recycled in further reactions. The first portion of wet cake and the second portion of wet cake may be combined. EXAMPLES

[0051] Without further elaboration, it is believed that one skilled in the art using the preceding description can utilize the present invention to its fullest extent. Thus, the following examples are merely intended to be illustrative and are not intended to limit the present disclosure in any way. The starting materials in the following examples may not necessarily have been prepared by the specific preparation procedures whose procedures are described in other examples. Also, any numerical range recited herein is understood to include all values ​​from the lower value to the upper value. For example, if a range is recited as 10-50, it is intended that values ​​such as 12-30, 20-40, or 30-50 are expressly recited herein. These are merely examples of what is specifically intended, and all possible combinations of numerical values ​​between the lowest and highest values ​​recited should be considered as expressly stated in this application.

[0052] Comparative Example 1. Chlorination with hydrochloric acid In a 1 L flask equipped with a condenser, thermometer and dropping funnel, 120 g of dry 2-((ethoxycarbonyl)amino)-3-methylbenzoic acid and 420 g of acetic acid are added. The mixture is stirred and heated to 35-40 °C until all solids are dissolved. The mixture is then cooled to about 30 °C. Next, 124 g of 37% hydrochloric acid is added to the mixture and 77 g of 30% hydrogen peroxide solution is fed in a period of 3 hours. After the addition, the mixture is stirred for another 2 hours until the reaction is complete. 1000 g of water is added dropwise to the mixture at 30-35 °C over a period of 2 hours, during the addition of water the product appears as white crystals. The mixture is cooled to 20-25 °C and the product is obtained by filtration and subsequent water washing. About 124 g of 5-chloro-2-((ethoxycarbonyl)amino)-3-methylbenzoic acid product is obtained in about 90% yield.

[0053] Example 1. Chlorination with chlorine gas 120 g of 2-((ethoxycarbonyl)amino)-3-methylbenzoic acid and 465 g of about 83% acetic acid are added to a 1 L flask equipped with a condenser, a thermometer and a gas inlet tube. Chlorine gas is bubbled slowly into the mixture at 0-35°C for a period of 2 hours, and the solid disappears during the gas bubbling step as the temperature increases. At the end of the gas bubbling stage, some product appears as white crystals. After the reaction is completed, the reaction mixture is bubbled with nitrogen to remove excess chlorine. The reaction mixture is cooled to 0-5°C and stirred for another 2 hours. The first portion of product is obtained by filtration and subsequent 80% acetic acid washing and water washing. The filtrate is concentrated to about 20% volume under reduced pressure at 40-50°C. The remaining solution is cooled again to 0-5°C, and then the second portion of product is obtained by filtration, subsequent 80% acetic acid washing and water washing. The overall yield of the 5-chloro-2-((ethoxycarbonyl)amino)-3-methylbenzoic acid product is about 92%.

[0054] Example 2. Chlorination with chlorine gas and recycling In a 1 L flask equipped with a condenser, a thermometer and a gas inlet tube, 120 g of 2-((ethoxycarbonyl)amino)-3-methylbenzoic acid and 465 g of about 83% acetic acid are added at room temperature. Chlorine gas is bubbled into the mixture at 0-35°C for a period of 2 hours, and the solid disappears during the gas bubbling process as the temperature increases. At the end of the gas bubbling stage, some product appears as white crystals. After the reaction is completed, the reaction mixture is bubbled with nitrogen to remove excess chlorine. The reaction mixture is cooled to 0-5°C and stirred for another 2 hours. The first portion of product is obtained by filtration and subsequent 80% acetic acid washing and water washing. The yield of 5-chloro-2-((ethoxycarbonyl)amino)-3-methylbenzoic acid product in the first batch product is about 80%.

[0055] The filtrate is treated as the solvent for the next batch, and after the same reaction and recrystallization process on the same scale as above, more product is obtained in the second batch. The yield of 5-chloro-2-((ethoxycarbonyl)amino)-3-methylbenzoic acid product in the second batch product is about 95%.

[0056] The filtrate of the second batch can also be recycled to the third, fourth, and fifth batches. The average yield of the first to fifth batches is about 90-91%.

[0057] The disclosed method reduces the volume of wastewater by about 80%. The disclosed method also reduces the amount of acetic acid used by about 80-85%. Therefore, the disclosed method is particularly beneficial in reducing costs and waste.

[0058] This specification uses examples to illustrate the disclosure, including the best mode, and to enable those skilled in the art to practice the disclosure, including making and using any devices or systems and performing any incorporated methods. The patentable scope of the disclosure is defined by the claims, and may include other examples that occur to those skilled in the art. Such other examples are intended to be within the scope of the claims if they have structural elements that do not differ from the literal language of the claims, or if they include equivalent structural elements that do not differ substantially from the literal language of the claims.

[0059] As used herein, the terms "comprises," "comprising," "includes," "including," "has," "having," "contains," "containing," "characterized by," or any other variations thereof, are intended to cover a non-exclusive inclusion, subject to any limitations expressly stated. For example, a composition, mixture, process, or method that includes a list of elements is not necessarily limited to only those elements but may include other elements not expressly listed or inherent to such composition, mixture, process, or method.

[0060] The transitional phrase "consisting of" excludes any unspecified element, step, or ingredient. In a claim, when the claim is closed to include substances different from those recited, apart from impurities, it is usually related thereto. When the phrase "consisting of" appears in a clause in the body of a claim rather than immediately following a preamble, it limits only the elements recited in that clause; other elements are not excluded from the claim as a whole.

[0061] The transitional phrase "consisting essentially of" is used to define compositions or methods that include materials, steps, configurations, ingredients, or elements in addition to those literally disclosed, provided that these additional materials, steps, configurations, ingredients, or elements do not materially affect the basic and novel characteristics of the claimed invention. The term "consisting essentially of" occupies a middle ground between "comprising" and "consisting of."

[0062] It should be readily understood that where the invention or portions thereof are defined in open-ended terms such as "comprising," the statement should be construed as also describing such inventions using the terms "consisting essentially of" or "consisting of" (unless otherwise stated).

[0063] Further, unless expressly stated to the contrary, "or" refers to an inclusive "or" and not an exclusive "or." For example, a condition A or B is satisfied by any one of the following: A is true (or exists) and B is false (or does not exist), A is false (or does not exist) and B is true (or exists), and both A and B are true (or exist).

[0064] Furthermore, the indefinite articles "a" and "an" preceding an element or component of the invention are intended to be open-ended regarding the number of instances (i.e., occurrences) of that element or component. Thus, "a" or "an" should be read to include one or at least one, and such singular form of the element or component also includes the plural, unless it is clear that the number is intended to be singular.

[0065] As used herein, the term "about" means ±10% of a value.

[0066] The term "alkyl", used alone or in compound words such as "alkylthio" or "haloalkyl", includes straight-chain or branched alkyl, for example, methyl, ethyl, n-propyl, i-propyl, or the different butyl, pentyl or hexyl isomers.

[0067] The term "alkenyl" includes straight-chain or branched alkenes, such as 1 propenyl, 2 propenyl, and the different butenyl, pentenyl, and hexenyl isomers. "Alkenyl" also includes polyenes, such as 1,2 propadienyl and 2,4 hexadienyl.

[0068] The term "halogen", either alone or in compound words such as "haloalkyl", includes fluorine, chlorine, bromine or iodine.

[0069] The total number of carbon atoms in a substituent is indicated by the prefix "Ci-Cj", where i and j are numbers from 1 to 8. For example, C1-C3 alkylsulfonyl refers to methylsulfonyl through propylsulfonyl.

[0070] A group may have a substituent which may be hydrogen, e.g. R 4 and this substituent is then taken to be hydrogen, this is considered to be equivalent to said group being unsubstituted.

[0071] Certain compounds of the present invention may exist as one or more stereoisomers. The various stereoisomers include enantiomers, diastereomers, atropisomers, and geometric isomers. As will be well understood by those skilled in the art, one stereoisomer may be more active and / or exhibit advantageous effects when enriched or separated from other stereoisomers. In addition, those skilled in the art know how to separate, enrich, and / or selectively prepare stereoisomers.

Claims

1. Compound of formula (II) 【Chemistry 1】 (In the formula, R 3 CH 3 or Cl; R 4 Each of these C atoms is optionally substituted with up to three halogens and up to one phenyl molecule. 1 ~C 6 Alkyl or C 3 ~C 6 It is an alkenyl; and X is either Cl or Br. A method for preparing: (I) Below: A) Compound of formula (I) 【Chemistry 2】 (wherein, R 1 is CH 3 or Cl; R 2 Each of these C atoms is optionally substituted with up to three halogens and up to one phenyl molecule. 1 ~C 6 Alkyl or C 3 ~C 6 (is an alkenyl); and B) Aqueous solvent present at a concentration of approximately 90% v / v or less Forming a mixture containing; (II) Introducing a halogenating agent into the mixture; (III) Removing the halogenating agent from the mixture as appropriate; (IV) In some cases, introducing a strong base into the mixture; and (V) A method comprising, optionally, cooling the mixture to a temperature in the range of about 0°C to about 5°C.

2. R 3 The method according to claim 1, wherein X and X are each Cl.

3. R 3 ga CH 3 The method according to claim 1 or 2, wherein X is Cl.

4. R 4 C 1 ~C 2 The method according to claim 1, wherein the alkyl group is alkyl.

5. R 1 ga CH 3 The method according to claim 1.

6. R 2 C 1 ~C 2 The method according to claim 1, wherein the alkyl group is alkyl.

7. R 3 ga CH 3 And X is Cl, R 4 The method according to claim 1, wherein is ethyl.

8. The method according to claim 1, wherein the aqueous solvent is present at a concentration of about 85% v / v or less.

9. The method according to claim 1, wherein the aqueous solvent is present at a concentration of about 80% v / v or less.

10. The method according to claim 1, wherein the aqueous solvent is an aqueous solution of acetic acid.

11. The method according to claim 1, wherein the aqueous solvent does not contain hydrogen peroxide.

12. The method according to claim 1, wherein the aqueous solvent includes a recovered and / or recycled aqueous solvent.

13. The method according to claim 1, wherein the halogenating agent is a chlorinating agent or a brominating agent.

14. The halogenating agent is Cl 2 , Br 2 The method according to claim 1, selected from and combinations thereof.

15. The method step of introducing the halogenating agent into the mixture involves heating the halogenating agent at approximately 0°C to approximately 35°C. The method according to claim 1, comprising introducing into the mixture at a temperature in the range of °C.

16. The method step of removing the halogenating agent from the mixture is performed by adding N to the mixture. 2 The method according to claim 1, comprising bubbling.

17. The method according to claim 1, wherein the strong base is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, and combinations thereof.

18. The method according to claim 1, further comprising the steps of generating a solid product and filtering and / or washing the solid product.

19. The method according to claim 1, further comprising a step of recovering and / or recycling the aqueous solvent.

20. The method according to claim 19, wherein the step of recovering and / or recycling the aqueous solvent recovers and / or recycles at least 50% v / v of the aqueous solvent.

21. The method according to claim 19, wherein the step of recovering and / or recycling the aqueous solvent recovers and / or recycles at least 75% v / v of the aqueous solvent.

22. The method according to claim 1, further comprising a step of recovering and / or recycling the mother liquor.

23. The method according to claim 22, wherein the step of recovering and / or recycling the mother liquor recovers and / or recycles at least 50% v / v of the mother liquor.

24. The method according to claim 22, wherein the step of recovering and / or recycling the mother liquor recovers and / or recycles at least 80% v / v of the mother liquor.

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