Compositions and methods for preparing N-phenylpyrazole-1-carboxamide

Abstract

An improved method is disclosed for preparing an organic biocidal agent having formula 4-A from a composition comprising (1) the following: (a) crystallizing the organic biocidal agent; (b and c) compounds having formula 1 and formula 2; (d) an amine base and (e) an aprotic solvent; (2) reacting with a sulfonyl chloride having formula 3; and (3) allowing the mixture to further form an organic biocidal agent having formula 4-A. Wherein R 1 R 2 R 3 R 4 R 5 R 6 R 7 and R 8 As defined in this disclosure.

Description

[0001] Cross-references to related applications

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 055443, filed July 23, 2020, and U.S. Provisional Application No. 63 / 144115, filed February 1, 2021, the entire contents of which are incorporated herein by reference. Technical Field

[0003] This disclosure relates to novel compositions and improved methods for preparing N-phenylpyrazole-1-carboxamide. Background Technology

[0004] Conventional methods for producing an-aminobenzoic acid diamide have several industrial challenges, including processability, environmental hazards, high costs, reagent reactivity, the need for specialized equipment, and limitations in commercial-scale operation. New methods are needed to produce high-purity an-aminobenzoic acid diamide at a higher commercial scale.

[0005] This disclosure provides novel methods for the preparation of brofentanil, chlorantraniliprole, and their derivatives. The benefits of the method disclosed herein compared to previous methods include significant improvements in operating the method on a commercial scale by eliminating the formation of viscous reaction mixtures and the need for time-consuming batch-by-batch reactor cleaning. Summary of the Invention

[0006] In one respect, this disclosure relates to a composition comprising:

[0007] (a) Crystallized organic biocides.

[0008] (b) Carboxylic acid compounds having Formula 1,

[0009]

[0010] in

[0011] R 4 It is Cl, Br, CF3, OCF2H, or OCH2CF3;

[0012] R 5 It is F, Cl, or Br;

[0013] R 6 It is H, F, or Cl;

[0014] Z is CR 7 Or N; and

[0015] R 7 It is H, F, Cl, or Br;

[0016] (c) Aniline compounds having formula 2,

[0017]

[0018] in

[0019] R 1 It is CH3 or Cl;

[0020] R 2 It is Br, Cl, I or CN;

[0021] R 3 It is an H or C1-C4 alkyl group;

[0022] (d) amine bases, and

[0023] (e) Aprotic solvents.

[0024] On the other hand, this disclosure provides a method for preparing compounds having formula 4-A.

[0025]

[0026] in

[0027] R 1 It is CH3 or Cl;

[0028] R 2 It is Br, Cl, I or CN;

[0029] R 3 It is an H or C1-C4 alkyl group;

[0030] R 4 It is Cl, Br, CF3, OCF2H, or OCH2CF3;

[0031] R 5 It is F, Cl, or Br;

[0032] R 6 It is H, F, or Cl;

[0033] Z is CR 7 Or N; and

[0034] R 7 Is it H, F, Cl or Br?

[0035] The method includes the following steps:

[0036] (1) Forming the composition as described above;

[0037] (2) React the composition with a sulfonyl chloride compound having formula 3,

[0038] R 8S(O)2Cl 3

[0040] in

[0041] R 8 It is a carbon-based group; and

[0042] (3) Allow acid-activated mixtures to couple to form compounds having formula 4-A.

[0043] On the other hand, this disclosure provides an organic pest control agent having formula 4-A formed using the composition described above. Detailed Implementation

[0044] As used herein, the terms “comprises,” “comprising,” “includes,” “including,” “has,” “having,” “contains,” “containing,” “characterized by,” or any other variation thereof, are intended to cover non-exclusive inclusion, subject to any expressly indicated limitations. For example, a composition, mixture, process, or method that comprises a list of elements is not necessarily limited to those elements, but may include other elements not expressly listed or other elements inherent to such compositions, mixtures, processes, or methods.

[0045] The connecting phrase "consisting of..." excludes any unspecified element, step, or component. If in a claim, this phrase makes the claim closed, excluding material other than those expressly listed, except for impurities typically associated with it. When the phrase "consisting of..." appears in a clause of the body of a claim rather than immediately following the preamble, the phrase only limits the element set forth in that clause; the claim as a whole does not exclude other elements.

[0046] The connecting phrase "substantially constitutes..." is used to define a composition, process, or method that includes materials, steps, features, components, or elements in addition to those explicitly disclosed, provided that such additional materials, steps, features, components, or elements do not materially affect the essential and novel characteristics of this disclosure. The term "substantially constitutes..." falls between "comprising" and "consisting of...".

[0047] When the applicant has defined an embodiment or a portion thereof using open-ended terms such as “comprising,” it should be readily understood (unless otherwise stated) that the specification should be interpreted as also using the terms “substantially constitutes” or “composes of” to describe the embodiment.

[0048] Furthermore, unless explicitly stated to the contrary, "or" refers to an inclusive "or" rather than an exclusive "or". For example, conditions A or B are satisfied by any 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).

[0049] Similarly, the indefinite article “a / an” preceding any element or component in this disclosure is intended to be non-limiting in terms of the number of examples (i.e., occurrences) of the element or component. Thus, “a / an” should be understood to include one or more, and the singular word form of an element or component also includes the plural, unless the number clearly indicates the singular.

[0050] As used herein, “amine base” refers to organic bases and their salts, including primary, secondary, and tertiary amines. Suitable amine bases include, but are not limited to, substituted amines, cyclic amines, and naturally occurring amines, such as pyridine bases (e.g., 3-methylpyridine), N,N′-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, isopropylamine, morpholine, piperazine, piperidine, triethylamine, trimethylamine, tripropylamine, thiocyanate, etc.

[0051] As used herein, “aprotic solvent” means any solvent that does not have the ability to donate protons. Examples include, but are not limited to, acetonitrile, 2-methyltetrahydrofuran, tetrahydrofuran, ethyl acetate, propyl acetate (e.g., isopropyl acetate), acetone, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, hexamethylphosphoramide, and propylene carbonate.

[0052] As used herein, the term "polar aprotic solvent" refers to an aprotic solvent that is a polar solvent. Examples include, but are not limited to, acetonitrile and N,N-dimethylformamide.

[0053] As used herein, the term "acid activator" refers to a reactant that promotes the coupling of a carboxylic acid compound with aniline. Examples include, but are not limited to, reactants having the general formula R. 8 A compound of S(O)₂Cl (Formula 3), wherein R 8 It is a carbon-based group. Examples include, but are not limited to, methanesulfonyl chloride, propanesulfonyl chloride, benzenesulfonyl chloride, and p-toluenesulfonyl chloride. Methanesulfonyl chloride is preferred due to its lower cost, ease of addition, and / or less waste.

[0054] A carbon-based group is a monovalent molecular component containing a carbon atom that is linked to the rest of the chemical structure by a single bond. Carbon-based groups may optionally contain saturated, unsaturated, and aromatic groups, chains, rings, and cyclic systems, as well as heteroatoms. While there are no particular limitations on the size of carbon-based groups, in the context of this disclosure, they typically contain 1 to 16 carbon atoms and 0 to 3 heteroatoms. Notably, carbon-based groups are selected from C1-C6 alkyl groups, C1-C4 haloalkyl groups, and phenyl groups optionally substituted with 1 to 3 substituents selected from C1-C3 alkyl groups, halogens, and nitro groups.

[0055] As used herein, the term "C1-C6 alkyl" includes straight-chain or branched alkyl groups having one to four carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, or various butyl, pentyl, or hexyl isomers. As used herein, the term "halogen" includes fluorine, chlorine, bromine, and iodine. The term "halogen," alone or in compound terms such as "halogenated alkyl," includes fluorine, chlorine, bromine, or iodine. Furthermore, when used in compound terms such as "halogenated alkyl," the alkyl group may be partially or completely substituted with the same or different halogen atoms. Examples of "halogenated alkyl" include F3C, ClCH2, CF3CH2, and CF3CCl2.

[0056] As used herein, the term “suitable” indicates that the entity so described is well-suited for use in the indicated conditions or environment. The terms “reaction” and the like refer to the addition, contact, or mixing of two or more reagents under suitable conditions to produce the indicated and / or desired product. It should be understood that a reaction producing the indicated and / or desired product does not necessarily arise directly from the combination of the two initially added reagents; one or more intermediates may be generated in the mixture that ultimately leads to the formation of the indicated and / or desired product. Reactions can be carried out in the presence or absence of a solvent, at temperatures above or below room temperature, under an inert atmosphere, etc.

[0057] The term “optionally” as used herein means that optional conditions may or may not be present. For example, when a reaction is optionally carried out in the presence of a solvent, that solvent may or may not be present.

[0058] The term "optionally substituted" refers to a group that is unsubstituted or has at least one non-hydrogen substituent that does not eliminate the chemical or biological activity of the unsubstituted analogue. As used herein, unless otherwise specified, the following definitions shall apply. The term "optionally substituted" is used interchangeably with the phrase "unsubstituted or substituted" or with the term "(un)substituted". Unless otherwise specified, an optionally substituted group may have substituents at each substituted position of the group, and each substitution is independent of the others.

[0059] The embodiments disclosed herein include:

[0060] Example C1. A composition as described in the invention, comprising (a) a crystalline organic biocide; (b) a carboxylic acid having formula 1; (c) an aniline having formula 2; (d) an amine base; and (e) an aprotic solvent.

[0061] Example C2. The composition as described in Example C1, wherein R 5 It is Cl.

[0062] Example C3. The composition as described in any one of Examples C1 to C2, wherein R 1 It is CH3.

[0063] Example C4. The composition as described in any one of Examples C1 to C3, wherein Z is N.

[0064] Example C5. The composition as described in any one of Examples C1 to C4, wherein R 4 It is Cl, Br, or CF3.

[0065] Example C6. The composition as described in any one of Examples C1 to C5, wherein R 2 It is either Cl or CN.

[0066] Example C7. The composition as described in any one of Examples C1 to C6, wherein R 4 It is CH3, R 5 It is Cl, R 6 It is CH3, R 1 It is Br, R 2 It is Cl, R 3 H is H, and Z is N.

[0067] Example C8. The composition as described in any one of Examples C1 to C6, wherein R 4 It is CH3, R 5 It is CN, R 6 It is CH3, R 1 It is Br, R 2 It is Cl, R 3 H is H, and Z is N.

[0068] Example C9. A composition as described in any one of Examples C1 to C8, wherein the molar ratio of the compound having Formula 1 to the compound having Formula 2 is from about 1.2:1 to about 1:1.2.

[0069] Example C10. A composition as described in any one of Examples C1 to C9, wherein the molar ratio of the compound having Formula 1 to the compound having Formula 2 is from about 1:1 to about 1:1.2.

[0070] Example C11. The composition as described in any one of Examples C1 to C10, wherein the molar ratio of the compound having Formula 1 to the compound having Formula 2 is about 1:1.1.

[0071] Example C12. The composition as described in any one of Examples C1 to C11, wherein the molar ratio of the sulfonyl chloride to the compound having Formula 1 is at least about 1:1.

[0072] Example C13. The composition as described in any one of Examples C1 to C12, wherein the molar ratio of the sulfonyl chloride to the compound having Formula 1 is from about 1:1 to about 2.5:1.

[0073] Example C14. The composition as described in any one of Examples C1 to C13, wherein the molar ratio of the sulfonyl chloride to the compound having Formula 1 is from about 1.1:1 to about 1.4:1.

[0074] Example C15. The composition as described in any one of Examples C1 to C14, wherein the amount of the amine base is at least about 2 equivalents relative to the sulfonyl chloride having Formula 3.

[0075] Example C16. The composition as described in any one of Examples C1 to C15, wherein the amount of the amine base is at least about 2.1 equivalents relative to the sulfonyl chloride having Formula 3.

[0076] Example C17. The composition as described in any one of Examples C1 to C16, wherein the amount of the amine base is from about 2.1 to 2.2 equivalents relative to the sulfonyl chloride having Formula 3.

[0077] Example C18. A composition as described in any one of Examples C1 to C17, wherein the amine base is selected from tertiary amines (including optionally substituted pyridines).

[0078] Example C19. A composition as described in any one of Examples C1 to C18, wherein the amine base is selected from optionally substituted pyridines and mixtures thereof.

[0079] Example C20. A composition as described in any one of Examples C1 to C19, wherein the amine base is selected from 2-methylpyridine, 3-methylpyridine, 2,6-dimethylpyridine, pyridine, and mixtures thereof.

[0080] Example C21. The composition as described in any one of Examples C1 to C20, wherein the amine base is 3-methylpyridine.

[0081] Example C22. A composition as described in any one of Examples C1 to C21, wherein the aprotic solvent is selected from nitrile (e.g., acetonitrile, propionitrile), ester (e.g., methyl acetate, ethyl acetate, butyl acetate), ketone (e.g., acetone, methyl ethyl ketone, methyl butyl ketone), haloalkanes (e.g., dichloromethane, trichloromethane), ethers (e.g., diethyl ether, methyl tert-butyl ether, tetrahydrofuran, p-dioxane), aromatic hydrocarbons (e.g., benzene, toluene, chlorobenzene, dichlorobenzene), tertiary amines (e.g., trialkylamine, dialkylaniline, optionally substituted pyridine), and mixtures thereof.

[0082] Example C23. The composition as described in Example C22, wherein the aprotic solvent is selected from tertiary amines (e.g., trialkylamines, dialkylanilines, optionally substituted pyridines) and mixtures thereof.

[0083] Example C24. The composition as described in Example C22, wherein the solvent is selected from nitrile (e.g., acetonitrile, propionitrile), ester (e.g., methyl acetate, ethyl acetate, butyl acetate), ketone (e.g., acetone, methyl ethyl ketone, methyl butyl ketone), haloalkanes (e.g., dichloromethane, trichloromethane), ethers (e.g., diethyl ether, methyl tert-butyl ether, tetrahydrofuran, p-dioxane), aromatic hydrocarbons (e.g., benzene, toluene, chlorobenzene, dichlorobenzene), and mixtures thereof.

[0084] Example C25. The composition as described in Example C22, wherein the solvent is acetonitrile.

[0085] Example C26. The composition as described in any one of Examples C1 to C25, wherein the molar ratio of the crystalline organic biocide to the compound having Formula 1 is greater than 0.001:1.

[0086] Example C27. The composition as described in any one of Examples C1 to C26, wherein the molar ratio of the crystalline organic biocide to the compound having Formula 1 is greater than 0.01:1.

[0087] Example C28. The composition as described in any one of Examples C1 to C25, wherein the molar ratio of the crystalline organic biocide to the compound having Formula 1 is between about 0.001:1 and 0.25:1.

[0088] Example C29. The composition as described in any one of Examples C1 to C26, wherein the molar ratio of the crystalline organic biocide to the compound having Formula 1 is between about 0.01:1 and 0.2:1.

[0089] Example C30. The composition as described in any one of Examples C1 to C29, wherein the molar ratio of the crystalline organic biocide to the compound having Formula 1 is between about 0.05:1 and 0.2:1.

[0090] Example C31. The composition as described in any one of Examples C1 to C27, wherein the molar ratio of the crystalline organic biocide to the compound having Formula 1 is greater than 0.09:1.

[0091] Example C32. The composition as described in any one of Examples C1 to C31, wherein the molar ratio of the crystalline organic biocide to the compound having Formula 1 is between about 0.10:1 and 0.25:1.

[0092] Example C32a. The composition as described in any one of Examples C1 to C32, wherein the molar ratio of the crystalline organic biocide to the compound having Formula 1 is between about 0.1:1 and 0.2:1.

[0093] Example C33. The composition as described in any one of Examples C1 to C32a, wherein the molar ratio of the crystalline organic biocide to the compound having Formula 1 is about 0.1:1.

[0094] Example C34. The composition as described in any one of Examples C1 to C32a, wherein the molar ratio of the crystalline organic biocide to the compound having Formula 1 is about 0.125:1.

[0095] Example C34a. The composition as described in any one of Examples C1 to C32a, wherein the molar ratio of the crystalline organic biocide to the compound having Formula 1 is about 0.15:1.

[0096] Example C35. The composition as described in any one of Examples C1 to C32a, wherein the molar ratio of the crystalline organic pesticide to the compound having Formula 1 is about 0.20:1. Example C36. The composition as described in any one of Examples C1 to C35, wherein the crystalline organic pesticide is a fungicide.

[0097] Example C37. The composition as described in any one of Examples C1 to C35, wherein the crystalline organic biocide is a bactericide.

[0098] Example C38. The composition as described in any one of Examples C1 to C35, wherein the crystalline organic pest control agent is a herbicide.

[0099] Example C39. The composition as described in any one of Examples C1 to C35, wherein the crystalline organic pesticide is a nematicide.

[0100] Example C40. The composition as described in any one of Examples C1 to C35, wherein the crystalline organic pesticide is an insecticide.

[0101] Example C41. The composition as described in any one of Examples C1 to C35, wherein the crystalline organic biocide is selected from chlorantraniliprole, bromocyanamide, fenpyroxen, indoxacarb, imidacloprid, fludioxonil, and combinations thereof.

[0102] Example C42. The composition as described in any one of Examples C1 to C35, wherein the organic biocide is anthranilic acid diamide having formula 4.

[0103]

[0104] Example C43. The composition as described in any one of Examples C1 to C35, wherein the crystalline organic biocide is selected from chlorantraniliprole and bromocyanamide.

[0105] Example C44. The composition as described in any one of Examples C1 to C35, wherein the crystalline organic biocide is chlorantraniliprole.

[0106] Example C45. The composition as described in any one of Examples C1 to C35, wherein the crystalline organic biocide is bromocyanamide.

[0107] Example M1. A method for preparing a compound having formula 4-A as described in the present invention, the method comprising the steps of: (1) forming a composition as described in any one of Examples C1 to C45; (2) reacting the composition with a sulfonyl chloride compound having formula 3; and (3) allowing the activated mixture to form a compound having formula 4-A.

[0108] Example M2. The method as described in Example M1, wherein the molar ratio of the sulfonyl chloride having Formula 3 to the compound having Formula 1 is at least about 1:1.

[0109] Example M3. The method as described in any one of Examples M1 to M2, wherein the molar ratio of the sulfonyl chloride having Formula 3 to the compound having Formula 1 is from about 1:1 to about 2.5:1.

[0110] Example M4. The method as described in any one of Examples M1 to M3, wherein the molar ratio of the sulfonyl chloride having Formula 3 to the compound having Formula 1 is from about 1.1:1 to about 1.4:1.

[0111] Example M5. The method as described in any one of Examples M1 to M4, wherein when R 2When the sulfonyl chloride is Br, Cl or I, the molar ratio of the sulfonyl chloride having formula 3 to the compound having formula 1 is about 1.2:1.

[0112] Example M6. The method as described in any one of Examples M1 to M4, wherein when R 2 When CN is present, the molar ratio of the sulfonyl chloride having formula 3 to the compound having formula 1 is approximately 1.3:1.

[0113] Example M7. The method as described in any one of Examples M1 to M6, wherein R 8 It is a C1-C4 alkyl, C1-C2 haloalkyl, or optionally substituted with 1-3 substituents selected from the group consisting of halogen, C1-C3 alkyl and nitro groups.

[0114] Example M8. The method as described in any one of Examples M1 to M7, wherein R 8 It is a C1-C2 alkyl, CF3, phenyl, or 4-methylphenyl.

[0115] Example M9. The method as described in any one of Examples M1 to M8, wherein R 8 It is a C1-C2 alkyl, phenyl, or 4-methylphenyl.

[0116] Example M10. The method as described in any one of Examples M1 to M9, wherein R 8 It is CH3.

[0117] Example M11. The method as described in any one of Examples M1 to M10, wherein the temperature of the composition is between about -70°C and 100°C prior to reaction with the sulfonyl chloride having Formula 3.

[0118] Example M12. The method as described in any one of Examples M1 to M11, wherein the temperature of the composition is between about -10°C and 50°C.

[0119] Example M13. The method as described in any one of Examples M1 to M11, wherein the temperature of the composition is between about 10°C and 40°C.

[0120] Example M14. The method as described in any one of Examples M1 to M11, wherein the temperature is about 20°C.

[0121] Example M15. The method of any one of Examples M1 to M14, further comprising the step of: (4) adding water to the reaction.

[0122] Example M16. The method as described in Example M15, wherein the molar ratio of water to the compound having Formula 1 is at least 1:1.

[0123] Example M17. The method as described in Example M15, wherein the molar ratio of water to the compound having Formula 1 is from about 1:1 to about 100:1.

[0124] Example M18. The method as described in Example M15, wherein the molar ratio of water to the compound having Formula 1 is from about 10:1 to about 50:1.

[0125] Example M19. The method as described in Example M15, wherein the molar ratio of water to the compound having Formula 1 is from about 15:1 to about 40:1.

[0126] Example M20. The method as described in Example M15, wherein the molar ratio of water to the compound having Formula 1 is from about 20:1 to about 35:1.

[0127] Example M21. The method as described in any one of Examples M15 to M20, wherein the temperature during the addition of water is between about -70°C and 100°C.

[0128] Example M22. The method as described in any one of Examples M15 to M20, wherein the temperature during the water addition is between about 0°C and 80°C.

[0129] Example M23. The method as described in any one of Examples M15 to M20, wherein the temperature during the addition of water is between about 15°C and 75°C.

[0130] Example M24. The method as described in any one of Examples M15 to M20, wherein the temperature during the addition of water is between about 20°C and 65°C.

[0131] Example M25. The method as described in any one of Examples M15 to M20, wherein the temperature during the addition of water is between about 40°C and 60°C.

[0132] Example M26. The method as described in any one of Examples M15 to M20, wherein the temperature during the addition of water is at least 50°C.

[0133] Example M27. The method as described in any one of Examples M15 to M20, wherein the temperature during the addition of water is about 65°C.

[0134] Example F1. A compound having formula 4-A prepared by any one of Examples M1 to M27.

[0135] Example F2. The composition as described in Example F1, wherein R 5 It is Cl.

[0136] Example F3. The composition as described in any one of Examples F1 to F2, wherein R1 It is CH3.

[0137] Example F4. The composition as described in any one of Examples F1 to F3, wherein Z is N.

[0138] Example F5. The composition as described in any one of Examples F1 to F4, wherein R 4 It is Cl, Br, or CF3.

[0139] Example F6. The composition as described in any one of Examples F1 to F5, wherein R 2 It is either Cl or CN.

[0140] Example F7. The composition as described in any one of Examples F1 to F6, wherein R 4 It is CH3, R 5 It is Cl, R 6 It is CH3, R 1 It is Br, R 2 It is Cl, R 3 H is H, and Z is N.

[0141] Example F8. The composition as described in any one of Examples F1 to F6, wherein R 4 It is CH3, R 5 It is CN, R 6 It is CH3, R 1 It is Br, R 2 It is Cl, R 3 H is H, and Z is N.

[0142] Examples C1 to C45; M1 to M27; F1 to F8; and any other one or more examples described herein may be combined in any way, and the description of variables in the examples relates not only to diamides of o-aminobenzoic acid having formula 4 and having 4-A, but also to starting intermediate compounds having formula 1, having formula 2 and having formula 3 that can be used to prepare organic biocides.

[0143] Of particular note is that the method disclosed herein prevents the formation of a highly viscous suspension prior to reaction with sulfonyl chloride having formula 3. Those skilled in the art will recognize that a viscous suspension hinders stirring, which leads to reduced control over heat transfer and reagent mixing. Those skilled in the art will further recognize that reactor capacity and production scale are limited because further solvent addition is necessary to maintain reaction control, resulting in increased production costs and waste. Compared to previously known methods for producing organic biocides (such as anthranilamide having formula 4-A), the method of the present invention features a free-flowing reaction suspension that is easily stirred throughout and allows for convenient control of the coupling process. In some embodiments of the method of the present invention, increased production capacity of organic biocides is provided due to the benefits of improved stirring, heat transfer, and reaction control.

[0144] In some embodiments, crystallized organic biocides can act as a nucleation source during the crystallization of organic biocides. In some embodiments, crystallized organic biocides can produce improved solid-state properties with respect to larger crystals having a more uniform crystal size distribution, thereby significantly reducing filtration time and significantly reducing the need for time-consuming batch-by-batch reactor cleaning when operating the method on a commercial scale.

[0145] In various embodiments, up to about 10 mol% of the crystalline organic biocide is part of the composition in step (1), and additional crystalline organic biocide may be added in step (2) after the addition of a portion of an acid activator (such as at least about 5 mol% of an acid activator, or about 10 mol% to about 20 mol% of an activator, or about 15 mol% to about 20 mol% of an activator). Alternatively, in step (1), a reactor that has already produced the crystalline organic biocide may be used instead of the crystalline organic biocide.

[0146] In various embodiments, the methods disclosed herein can be carried out over a wide temperature range, but typically within a range from -70°C to 100°C, or from 0°C to reflux, or from 10°C to 70°C. In some embodiments, the reaction is carried out at a temperature of about 20°C. Those skilled in the art will recognize that the temperature of the disclosed exothermic reaction can be readily controlled by simply controlling the rate of addition of the sulfonyl chloride compound.

[0147] The crystalline organic pest control agents used in the compositions disclosed herein are biologically active compounds or reagents, including crystalline insecticides, fungicides, nematicides, bactericides, acaricides, herbicides, herbicides safeners, growth regulators such as insect molting inhibitors and rooting stimulants, chemical sterilizers, chemical pheromones, insect repellents, attractants, pheromones, feeding stimulants, and other biologically active compounds or insect pathogenic bacteria, insect pathogenic viruses, or insect pathogenic fungi.

[0148] Examples of the organic pest control agents disclosed herein that can be used in the disclosed compositions are insecticides such as abamectin, acephate, miticide, acetamiprid, flufenoxuron, acynonapyr, tebufenozide ([(3S,4R,4aR,6S,6aS,12R,12aS,12bS)-3-[(cyclopropylcarbonyl)oxy]-1,3,4,4a,5,6,6a,12,12a,12b-decahydro-6,12-dihydroxy-4,6a,12b-trimethyl-11-oxo-9-(3-pyridyl)-2H,11H-naphtho[2,1-b]pyrano[3,4-e]pyran-4-yl]methylcyclopropanecarbamate), sulfadiazine, and amitraz. Abamectin, azadirachtin, phosmet, carbofuran, chlorpyrifos, benzpyrimoxan, bifenthrin, κ-bifenthrin, bifenazate, bispyribac-methyl, borate, broflanilide, thiamethoxam, thionylphos, carbofuran, carbofuran, pyridaben, chlorantraniliprole, brofenoxuron, flufenoxuron, chloroprallethrin, chlorpyrifos-e, methyl chlorpyrifos, cyclofenazate, tetradifon, chloroprallethrin, thiamethoxam, brofenoxuron (3-bromo-1-(3-) 3-chloro-2-pyridyl)-N-[4-cyano-2-methyl-6-[(methylamino)carbonyl]phenyl]-1H-pyrazole-5-carboxamide), cyclobromofenac (3-bromo-N-[2-bromo-4-chloro-6-[[(1-cyclopropylethyl)amino]carbonyl]phenyl]-1-(3-chloro-2-pyridyl)-1H-pyrazole-5-carboxamide), cypermethrin, cyclopyridinium ((5S,8R)-1-[(6-chloro-3-pyridyl)methyl]-2,3,5,6,7,8-hexahydro-9-nitro-5,8-epoxy-1H-imidazo[1,2-a]azapyr), pyridaben, cypermethrin, deltamethrin, cypermethrin, β-cypermethrin, cypermethrin, trifluralin, and high-efficiency cypermethrin Pyrethrin (gamma-cyhalothrin), lambda-cyhalothrin, cypermethrin, cis-cypermethrin, ζ-cypermethrin, cyromazine, deltamethrin, difenoconazole, diazinon, dichlorvos, dieldrin, diflubenzuron, tetrafluoromethrin, cartap, dimethoate, fenpropathrin, fipronil, benzyl ether, emamectin, emamectin benzoate, endosulfan, fenvalerate, acetamiprid, fenpropathrin, ε-methoxybenzylflumethrin, etoxazole, fenbutatin, fenitrothion, fenthiocarb, fenoxycarb, cypermethrin, fenvalerate, fipronil, fometoquin (2-ethyl-3,7-Dimethyl-6-[4-(trifluoromethoxy)phenoxy]-4-quinolinylmethyl carbonate), flupyradifurone, trifluralinamide, flufenoxuron, cypermethrin, pyrimethanil, flufenoxuron, methyl 2-(αE)-2-[[2-chloro-4-(trifluoromethyl)phenoxy]methyl]-α-(methoxymethylene)phenylacetate), sulfadiazine (5-chloro-2-[(3,4,4-trifluoro-3-buten-1-yl)sulfonyl]thiazole), fluhexafon, flupyradifurone, flupiprole (1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-5-[(2-methyl-2-propene)] -1-yl)amino]-4-[(trifluoromethyl)sulfinyl]-1H-pyrazole-3-carboxylon, flupyrfuranone (4-[[(6-chloro-3-pyridyl)methyl](2,2-difluoroethyl)amino]-2(5H)-furanone), flupyrimin, cypermethrin, flufenoxuron, chlorfenapyr, thiamethoxam, thiamethoxam, gamma-cyhalothrin, chlorfenapyr, heptamethrin ([2,3,5,6-tetrafluoro-4-(methoxymethyl)phenyl]methyl 2,2-dimethyl-3-[(1Z)-3,3,3-trifluoro-1-propen-1 [2,3,5,6-tetrafluoro-4-(methoxymethyl)phenyl]methyl(1R,3S)-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane carboxylate, cyhalothrin, flufenoxuron, thiamethoxam, chlorpyrifos, methoxyfenozide, chlorpyrifos, methoxyfenozide, chlorpyrifos, methoxyfenozide, methomyl, chlorpyrifos, methoxyfenozide, methoxyfenozide, ε-methoxyfenozide, ε-cyhalothrin fluorothrin), phosmet, pyrethrin ([2,3,5,6-tetrafluoro-4-(methoxymethyl)phenyl]methyl 3-(2-cyano-1-propen-1-yl)-2,2-dimethylcyclopropane carboxylate), nicotine, acetamiprid, nitenpyram, flufenoxuron, polyfluorourea, chlorpyrifos, oxazosulfyl, parathion, methyl parathion, permethrin, phorate, phosmet, phosmet, pymetrozine, propargite, propargite, propargite, propargite, pyrethrin, pyrethroid (1,3,5-trimethyl-N-(2-methyl-1-oxypropyl)-N-[3-(2-methylpropyl)-4-[2,2,2-Trifluoro-1-methoxy-1-(trifluoromethyl)ethyl]phenyl]-1H-pyrazole-4-carboxamide), pymetrozine, pyridaben, pyrethroid, pyridaben, acetamiprid, pyrifluquinazon, pyrimethanil ((αE)-2-[[[2-[(2,4-dichlorophenyl)amino]-6-(trifluoromethyl)-4-pyrimidinyl]oxy]methyl]-α-(methoxymethylene)phenylacetic acid methyl ester), pyrazole, pyriproxyfen, rotenone, lanyl alkaloid, flusilazole, ethyl spinosad, spinosad, spirodiclofen, spiropidion, spirodiclofen, thiophanate-methyl, flonicamid (N-[methyloxy[1-[6-(trifluoromethyl)-3-pyridinyl]ethyl]-λ, 4 [-sulfanilic acid] cyanamide), tebufenozide, pyridaben, flufenoxuron, heptafluthrin, κ-heptafluthrin, terbufos, tetrachlorfenapyr, chlorfenapyr, pyrethroid, pyrethroid, tetrafluoro-4-(methoxymethyl)phenyl]methyl 2,2,3,3-tetramethylcyclopropane carboxylate, tetrazolium, thiamethoxam, thiamethoxam, thiamethoxam, thiamethoxam, thiazoxfen (3-phenyl-5-(2-thienyl)-1,2,4-oxadiazole), tebufenozide Tetrabromopyrethrin, azoxystrobin, trichlorfon, trifluralin (2,4-dioxo-1-(5-pyrimidinylmethyl)-3-[3-(trifluoromethyl)phenyl]-2H-pyrido[1,2-a]pyrimidinyl endosalate), chlorfenapyr, tyclopyrazoflor, zeta-cypermethrin, Bacillus thuringiensis δ-endotoxin, entomopathogenic bacteria, entomopathogenic viruses, or entomopathogenic fungi.

[0149] Further examples of the organic pest control agents disclosed herein that can be used in the disclosed compositions are: fungicides, such as acibenzolar-S-methyl, aldimorph, azoxystrobin, aminopyrifen, indoxamyl, fenbendazole, azaconazole, pyraclostrobin, benalaxyl (including benalaxyl-M), fenbendazole, benthiamethoxam, benthiavalicarb (including benthiavalicarb-isopropyl), benzovindiflubenzuron, bethoxazin, chlorfenapyr, biphenyl, bifenthrin, bifenpyroxenamide, blasticidin-S, boscalid, furazolidone, bupirimate, thiophanate-methyl, carbendazim, cyclopropionimide, captan, thiophanate-methyl, carbendazim, and difenoconazole. Chloroneb, Chlozolinate, Copper hydroxide, Copper oxychloride, Copper sulfate, Syringepyridaben, Cyazofamid, Cyflumetazone, Cycloconazole, Azoxystrobin, Dichlorobenzylazox, Diclofenac, Diclocymet, Diclomezine, Dicloran, Dietofencarb, Diflumetorim, Dimethirimol, Dimethomorph, Diclofenac, Diconazole (including Diconazole-M), Dipymetitrone, Dithianon, Dithiocarbamate, Dodecylmorph, Polyoxin, Econazole, Etiazole, Klebsiella pneumoniae, EnoxastrobinAlso known as enestroburin, flutriafol, ethaboxam, ethirimol, etridiazole, oxadiazon, fenamidone, enestroburin, chlorpyrifos, fenhexamide, fenoxanil, seed dressing agent, fenpicoxamid, fenpropidine, butylmorpholine, amidopyrone, triphenyltin acetate, triphenylhydrochloride Tin oxide, ferram, ferimzone, flumectin, pyridaben, fluazinam, fluazinam, fludioxonil, flufenoxuron, fluindapyr, flumorpholine, fluopicolide, fluopicolide, fluoxapiprolin, fluazinam, fluquinazole, flusilazole, flusulfamide, flutianil, flutolanil, fenpyroxacin, fluazinam, captan, fthalideAlso known as phthalide, wheat-spinning agent, furaxyl, furazolidone, hexaconazole, hymexazole, guazatine, imidazolium, iminoctadine albesilate, iminoctadine triacetate, inpyrfluxam, thiamethoxam, tebuconazole, ipfentrifluconazole, ipflufenoquin, iprobenfos, isopyrazine, propineb, isoflurane, isopyrazine, isopyrazine, and pyraclostrobin. Am), isothiazine, kasugamycin, azoxystrobin, lancotrione, mancozeb, mandipropamid, mandestrobin, mancozeb, mapanipyrin, chlorfluazuron, chlorfenapyr, meptyldinocap, metalaxyl (including high-efficiency metalaxyl-M / mefenoxam), tebuconazole, methisulfuron-methyl, mancozeb, phenoxybenzamide Metyltetraprole, benomyl, cyproconazole, naftitine, ferric methylarsonia arsonate, fluphenylpyrimidinol, octathione, furfuramide, oxadixyl, oxathiapiprolin, oxopropyl acid, oxpoconazole, oxytetracycline, tebuconazole, pencycuron, fluopyram, pyrimethanil Penthiopyrad, perfurazoate, phosphorous acid (including its salts, e.g., fosetyl-aluminum), azoxystrobin, piperalin, polyoxin, thiabendazole, prochloraz, procymidone, propamocarb, propiconazole, zinc methyl thiophanate, proquinazid, prothiocarb, and fluopyram. Azoxystrobin, pyrapropoyne, azoxystrobin, pyraziflumid, pyrafos, pyrabencarb, pyributacarb, pyridachlometyl, pyrifenox, pyriofenone, perisoxazole, pyrimethanil, pyrrolnitrin, pyroquilon, fluquinazole, quinmethionate, quinofolin Inofumelin), Quinoxazone, Pentachloronitrobenzene, Silthiofam, Sedaxane, Simeconazole, Spirocyclohexane, Streptomycin, Thiophanate, Tebufloquin, Teclofthalam, Teclodil, Tetrachloronitrobenzene, Terbinafine, Flufenoxuron, Thibendazole, Thifluzamide, Thiabenzin, Thiazidophos, Thiazidophos, Tolprocarb, Tolflunamide, Triadimefon, Triazole, Azoxystrobin, Triazol, Triazoxane, Triazol, Basic Copper Sulfate, Chlorpyrifos, Tridemorph, Azoxystrobin, Fluopyram, Trimoprhamide Tricyclazole, azoxystrobin, cyproconazole, tebuconazole, uniconazole, fenpropathrin, valifenalate (also known as valifenal), vinclozoline, zineb, thiram, zoxamide, and 1-[4-[4-[5-(2,6-difluorophenyl)-4,5-dihydro-3-isoxazolyl]-2-thiazolyl]-1-piperidinyl]-2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl] acetone; nematicides Insecticides, such as fluopyram, spirotetramat, thiamethoxam, thiazophos, abamectin, iprodione, sulfadiazine, dimethyl disulfide, thiazoxafen, 1,3-dichloropropene (1,3-D), methyl parathion (sodium and potassium), dazomet, chloropicrin, fenamiphos, ethoprophos, cadusaphos, terbufos, imidacloprid, carbofuran, tioxazafen, Bacillus thuringiensis, and Pasteurianishizawae; bactericides, such as streptomycin;Acaricides, such as amitraz, dicofol, ethyl ester, cyhexatin, trichlorfon, chlorpyrifos, etoxazole, quinclorac, fenbutatin, cypermethrin, azoxystrobin, thiamethoxam, dicofol, pyridaben, and pyridaben.

[0150] General references for organic pesticides (i.e., insecticides, fungicides, nematicides, acaricides, herbicides, and biopesticides) include The Pesticide Manual, 13th edition, edited by CDSTomlin, British Crop Protection Council, Farnham, Surrey, UK, 2003, and The BioPesticide Manual, 2nd edition, edited by LGCopping, British Crop Protection Council, Farnham, Surrey, UK, 2001.

[0151] In some embodiments, materials having a crystal structure similar to or with similar crystal structure properties to compounds having Formula 4-A can be used as heterogeneous nucleation sources to form and grow desired product crystals. Materials having a crystal structure similar to compounds having Formula 4-A can also be used to induce beneficial polymorphic properties, thereby improving chemical reaction processes.

[0152] When starting compounds having formula 1, formula 2, and formula 3 are contacted with each other in a combined liquid phase (where each is at least partially soluble), an organic biocide having formula 4-A is formed. In particular, since the starting materials having formula 1 and formula 2 are typically solids at normal ambient temperatures, this method is most satisfactory when using solvents in which the starting compounds have significant solubility. Therefore, this method is typically carried out in a liquid phase containing a solvent. In some cases, a carboxylic acid having formula 1 may have only weak solubility, but its base-added salt may have greater solubility in the solvent. Suitable solvents for this method include nitriles, such as acetonitrile and propionitrile; esters, such as methyl acetate, ethyl acetate, and butyl acetate; ketones, such as acetone, methyl ethyl ketone (MEK), and methyl butyl ketone; haloalkanes, such as dichloromethane and trichloromethane; ethers, such as diethyl ether, methyl tert-butyl ether, tetrahydrofuran (THF), and p-dioxane; aromatic hydrocarbons, such as benzene, toluene, chlorobenzene, and dichlorobenzene; tertiary amines, such as trialkylamines, dialkylaniline, and optionally substituted pyridines; and mixtures of the foregoing. Notable solvents include acetonitrile, propionitrile, ethyl acetate, acetone, MEK, dichloromethane, methyl tert-butyl ether, THF, p-dioxane, toluene, and chlorobenzene. Acetonitrile is particularly noteworthy as a solvent because it typically provides products with superior yields and / or purity.

[0153] Because the reaction of the method of the present invention produces hydrogen chloride as a byproduct (which would otherwise bind to the basic centers of compounds having formula 1, formula 2, and formula 4), the method is most satisfactorily carried out in the presence of at least one added base. The base can also promote beneficial interactions between carboxylic acids and sulfonyl chloride compounds and o-aminobenzamide. The added base reacts with the carboxylic acid having formula 1 to form a salt that can have greater solubility in the reaction medium than the carboxylic acid. Although the base can be added simultaneously, alternately, or even after the addition of the sulfonyl chloride, it is typically added before the addition of the sulfonyl chloride. Some solvents, such as tertiary amines, also act as bases, and when these are used as solvents, they will be in large stoichiometric excess as bases. When no base is used as a solvent, the nominal molar ratio of the base to the sulfonyl chloride is typically from about 2.0 to 2.2, and preferably from about 2.1 to 2.2. Preferred bases are tertiary amines, including substituted pyridines. More preferred bases include 2-methylpyridine, 3-methylpyridine, 2,6-dimethylpyridine, and pyridine. 3-Methylpyridine is particularly noteworthy as a base because it is generally highly soluble in solvents such as acetonitrile when it comes to salts of carboxylic acids having Formula 1.

[0154] Typically, more than one solid form can be present in the production of anthranilic diamide having formula 4 and formula 4-A. Therefore, anthranilic diamide having formula 4 and formula 4-A includes all crystalline and amorphous forms of anthranilic diamide in the classes represented by formula 4 and formula 4-A. Amorphous forms include examples that are solids (such as waxes and gums) and examples that are liquids (such as solutions and melts). Crystalline forms include examples representing substantially single-crystal types and examples representing mixtures of polymorphs (i.e., different crystal types). The term "polymorph" refers to a specific crystalline form of a compound that can crystallize in different crystal forms, having different molecular arrangements and / or conformations in the crystal lattice. While polymorphs may have the same chemical composition, they can also differ in composition due to the presence or absence of co-crystallization water or other molecules, which may be weakly or strongly bonded within the crystal lattice. Polymorphs can differ in these chemical, physical, and biological properties, such as crystal shape, density, hardness, color, chemical stability, melting point, hygroscopicity, suspendability, dissolution rate, and bioavailability.

[0155] Those skilled in the art will understand that polymorphs of various an-aminobenzoic acid diamides having formula 4 and formula 4-A can exhibit beneficial effects (e.g., suitability for improved stirring, heat transfer, and filtration) relative to other polymorphs or mixtures of the same an-aminobenzoic acid diamide having formula 4 and formula 4-A. The preparation and separation of specific polymorphs of an-aminobenzoic acid diamide having formula 4 and formula 4-A can be achieved by methods known to those skilled in the art, including, for example, crystallization using selected solvents and temperatures. For a comprehensive discussion of polymorphism, see R. Hilfiker (ed.), *Polymorphism in the Pharmaceutical Industry*, Wiley-VCH, Weinheim, 2006.

[0156] No further detailed explanation is required, and it is believed that those skilled in the art will utilize this disclosure to its fullest extent using the foregoing description. Therefore, the following examples should be interpreted as illustrative only and do not limit this disclosure in any way. The steps in the following examples illustrate the procedure for each step in the overall synthetic transformation, and the starting materials used for each step are not necessarily prepared by the specific preparation experiments described in other examples or steps. Ambient temperature or room temperature is defined as about 20°C–25°C. Percentages are by weight unless otherwise specified. All patents and publications cited herein are incorporated in their entirety by reference.

[0157] Example 1

[0158] 3-Bromo-1-(3-chloro-2-pyridyl)-N-[4-cyano-2-methyl-6-[(methylamino)carbonyl]phenyl]-1H-pyrazole

[0159] Preparation of 5-formamide (bromnipotentiamide)

[0160] At 20°C, acetonitrile (123.5 g, 3.01 mol) was added to a mixture of crystalline 3-bromo-1-(3-chloro-2-pyridyl)-N-[4-cyano-2-methyl-6-[(methylamino)carbonyl]phenyl]-1H-pyrazole-5-carboxamide (10.3 g, 0.020 mol), 3-bromo-1-(3-chloro-2-pyridyl)-1H-pyrazole-5-carboxylic acid (preparation of which is described in PCT Patent Publication WO 03 / 015519) (40.0 g, 0.132 mol) and 2-amino-5-cyano-N,3-dimethylbenzamide (preparation of which is described in PCT Patent Publication WO 03 / 015519) (27.5 g, 0.142 mol) and stirred. 3-methylpyridine (34.5 g, 0.367 mol) was added over 5 min. Methanesulfonyl chloride (19.6 g, 0.171 mol) was added linearly over 1.5 h. The mixture was stirred for 2 h. Water (76.2 g, 4.23 mol) was added linearly over 1.2 h. The pH was adjusted to 1.1 with concentrated hydrochloric acid (4.37 g, 0.043 mol) and the mixture was stirred for 1 h. The pH was then adjusted to 3.3 with sodium hydroxide (4.34 g, 0.027 mol) and the mixture was stirred for 15 min. The mixture was filtered and the resulting material was washed with an aqueous acetonitrile solution (84% w / w, 43.0 g), then with acetonitrile (83.2 g), and dried to obtain the title compound.

[0161] Separation yield: 95% (seed-modified, based on 3-bromo-l-(3-chloro-2-pyridyl)-1H-pyrazole-5-carboxylic acid) Crystal size distribution: D[4,3] values ​​in the range of 50-65 μm, containing a small amount of fine powder Example 2

[0162] 3-Bromo-1-(3-chloro-2-pyridyl)-N-[4-cyano-2-methyl-6-[(methylamino)carbonyl]phenyl]-1H-pyrazole

[0163] Preparation of 5-formamide (bromnipotentiamide)

[0164] Experiments 1-10 and Experiments A-F used the parameters in Tables A, B, and C as in the preparation of bromocyanamide in Example 1. Experiments 1-10 were conducted on a scale of 100 g of 3-bromo-1-(3-chloro-2-pyridyl)-1H-pyrazole-5-carboxylic acid. Experiments A-F were conducted on a scale of 40 g of 3-bromo-1-(3-chloro-2-pyridyl)-1H-pyrazole-5-carboxylic acid. Experiments A-F were conducted using a 5 cm diameter Buchner funnel fitted with a Grade GF / B unadhesive-free glass fiber filter to filter and wash the resulting material.

[0165] The observations in Tables A and B were made after the addition of 3-methylpyridine and before the addition of methanesulfonyl chloride. In Experiments 1–4, the stirring rate at which adequate mixing was achieved was measured after the reactants had thickened.

[0166] As can be observed in Tables A and B, the addition of a crystalline organic biocide to the reagent resulted in improved reaction suspension characteristics. These improved characteristics reduce the stirring rate required for thorough mixing. They also allow for stirring at lower solvent concentrations (i.e., higher reaction concentrations).

[0167] As can be observed in Table C, due to the use of less solvent, a greater amount of crystalline organic biocide is required to control crystallization. The degree of crystallization control is indicated by the correlation between a larger D10 value and improved solid-state quality (i.e., faster filtration and washing times). A D10 value indicates that 10% of the samples contain particles of that size or smaller. A D50 value indicates that 50% of the samples contain particles of that size or smaller. A D90 value indicates that 90% of the samples contain particles of that size or smaller.

[0168] The abbreviation "Exp." stands for "experiment." The abbreviation "rpm." stands for revolutions per minute.

[0169] Table A

[0170]

[0171] Table B

[0172]

[0173] Table C

[0174]

[0175]

[0176] Example 3

[0177] Preparation of 3-bromo-1-(3-chloro-2-pyridyl)-N-[4-cyano-2-methyl-6-[(methylamino)carbonyl]phenyl]-1H-pyrazole-5-carboxamide (bromnipotentilamide)

[0178] Crystallized 3-bromo-1-(3-chloro-2-pyridyl)-N-[4-cyano-2-methyl-6-[(methylamino)carbonyl]phenyl]-1H-pyrazole-5-carboxamide (22.8 g, 0.043 mol), 3-bromo-1-(3-chloro-2-pyridyl)-1H-pyrazole-5-carboxylic acid (for its preparation, see PCT patent publication WO 03 / 015519) (65.0 g, 0.214 mol), 2-amino-5-cyano-N,3-dimethylbenzamide (for its preparation, see PCT patent publication WO 03 / 015519) (42.7 g, 0.221 mol), and acetonitrile (85.0 g, 2.07 mol) were loaded into a 400 mL temperature-controlled jacketed reactor equipped with a thermometer, an anchor mechanical stirrer, a syringe pump, and a reflux condenser. The mixture was stirred at 250 rpm and the temperature was adjusted to 20 °C. 3-Methylpyridine (56.1 g, 0.596 mol) was added over 5 min. Methanesulfonyl chloride (31.8 g, 0.278 mol) was loaded into a syringe and linearly added to the reaction mixture over 4.0 h. After the addition of methanesulfonyl chloride was complete, the reaction mixture was linearly heated to 50 °C over 2 h. Water (128.3 g, 7.12 mol) was added over 146.5 min according to the following dosage profile.

[0179]

[0180]

[0181] After the water addition was complete, the reaction mixture was linearly cooled to 20°C over 30 min. The mixture was filtered, and the resulting material was washed with an aqueous acetonitrile solution (84% w / w, 140.0 g), then with acetonitrile (135.0 g), and dried to obtain the title compound.

[0182] Separation yield: 95% (seed-modified, based on 3-bromo-l-(3-chloro-2-pyridyl)-1H-pyrazole-5-carboxylic acid) Crystal particle size distribution: D[4,3] values ​​in the range of 50-65 μm, containing a small amount of fine powder.

Claims

1. A composition comprising essentially the following substances: (a) A crystalline organic biocide, wherein the crystalline organic biocide is a crystalline compound having Formula 4. in R 1 It is CH3; R 2 It is CN; R 3 It is CH3; R 4 It is Br; R 5 It is Cl; R 6 It is H; and Z is N; (b) Carboxylic acid compounds having Formula 1, in R 4 It is Br; R 5 It is Cl; R 6 It is H; and Z is N; (c) Aniline compounds having formula 2, in R 1 It is CH3; R 2 It is CN; and R 3 It is CH3; (d) 3-methylpyridine; and (e) Acetonitrile; The molar ratio of the crystalline compound having Formula 4 to the carboxylic acid compound having Formula 1 is from 0.10:1 to 0.25:

1.

2. The composition of claim 1, wherein the amount of acetonitrile is selected from 1200 or 1000 mL / mol of the carboxylic acid compound having formula 1.

3. A method for preparing a compound having formula 4-A, in R 1 It is CH3; R 2 It is CN; R 3 It is CH3; R 4 It is Br; R 5 It is Cl; R 6 It is H; and Z is N; The method includes the following steps: (1) Formation of a composition consisting essentially of the following substances: (a) A crystalline organic biocide, wherein the crystalline organic biocide is a crystalline compound having Formula 4. in R 1 It is CH3; R 2 It is CN; R 3 It is CH3; R 4 It is Br; R 5 It is Cl; R 6 It is H; and Z is N; (b) Carboxylic acid compounds having Formula 1, in R 4 It is Br; R 5 It is Cl; R 6 It is H; and Z is N; (c) Aniline compounds having formula 2, in R 1 It is CH3; R 2 It is CN; and R 3 It is CH3; (d) 3-methylpyridine; and (e) Acetonitrile; The molar ratio of the crystalline compound having Formula 4 to the carboxylic acid compound having Formula 1 is 0.10:1 to 0.25:1, and the temperature of the composition is 10 to 40°C. (2) React the composition with methanesulfonyl chloride; (3) Allowing acid-activated mixtures to couple to form compounds having formula 4-A; and (4) Add water to the reaction.

4. The method of claim 3, wherein the temperature of the composition is 20°C.

5. The method of claim 3, wherein the amount of acetonitrile is selected from 1200 or 1000 mL / mol of the carboxylic acid compound having formula 1.

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