Process for preparing N-phenylpyrazole-1-carboxamide

Abstract

A method for making a compound of formula 1 by combining compounds of formulas 2 and 3 and a sulfonyl chloride in a continuous process is disclosed. [Formula 1] TIFF2022513703000046.tif65169

Description

[Technical field]

[0001] The present disclosure relates to a method for producing N-phenylpyrazole-1-carboxamides or N-pyridinylpyrazole-1-carboxamides by coupling a carboxylic acid with an anthranilamide in a continuous process. [Background technology]

[0002] US Pat. No. 5,399,633 discloses the utility of N-acyl anthranilic acid derivatives of formula i as arthropodicides. [ka] wherein A and B are independently O or S; R 1 is H;R 2 is H, C1-C6 alkyl, C2-C6 alkoxycarbonyl or C2-C6 alkylcarbonyl; R 3 is especially H or C1-C6 alkyl; R 4 is especially H or C1-C6 alkyl; R 5 is H, C1-C6 alkyl or halogen; R 6 is H, C1-C6 alkyl, C1-C6 haloalkyl, halogen, CN, C1-C4 alkoxy or C1-C4 haloalkoxy; R 7 is especially a phenyl ring, a benzyl ring, a 5- or 6-membered heteroaromatic ring, a naphthyl ring system, each ring or ring system optionally substituted with 1 to 3 substituents; R 8 is especially H.

[0003] US Patent No. 5,399,663 discloses a method for preparing N-phenylpyrazole-1-carboxamides or N-pyridinylpyrazole-1-carboxamides by coupling a carboxylic acid with an anthranilamide. See also US Patent No. 5,499,663, US Patent No. 5,499,673, US Patent No. 5,499,685, US Patent No. 5,599,703, US Patent No. 5,599,826, and US Patent No. 5,699,832.

[0004] Although the methods disclosed in the above references are capable of providing the desired compounds, continuous improvements are required, particularly in the development of methods to provide materials on a commercial scale. Thus, there remains a need for new methods that are cheaper, more efficient, more flexible, or more convenient to operate. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] International Publication No. 2003 / 015518 [Patent Document 2] International Publication No. 2006 / 062978 [Patent Document 3] International Publication No. 2003 / 016283 [Patent Document 4] International Publication No. 2004 / 011453 [Patent Document 5] International Publication No. 2005 / 077934 [Patent Document 6] International Publication No. 2007 / 144100 [Patent Document 7] International Publication No. 2008 / 072745 [Patent Document 8] International Publication No. 2010 / 069502 Summary of the Invention [Means for solving the problem]

[0006] The present disclosure relates to methods of making compounds of formula 1 (including all stereoisomers and N-oxides of such compounds, and salts of such compounds): [ka] (In the formula, X is O or S; Z is CR 7 or N; R 1 is H, CH3, Cl or Br; R2 is H, Br, Cl or CN; R 3 is H, C1-C4 alkyl or C4-C 10 cycloalkylalkyl; R 4 is Cl, Br, OCF2H, OCH2CF3; or C1-C4 alkyl optionally substituted with halogen; or C1-C4 alkyl substituted with Q; R 5 is F, Cl or Br; R 6 is H, F or Cl; R 7 is H, F, Cl or Br; Q is a 5- or 6-membered aromatic heterocyclic ring optionally substituted with one or more substituents independently selected from the group consisting of halogen, C1-C6 alkyl, C3-C6 cycloalkyl, and C1-C6 haloalkyl; This method:

[0007] (1) Carboxylic acid compound of formula 2 [ka] (In the formula, Z, R 4 , R 5 , R 6 , R 7 and Q is as defined for compounds of formula 1;

[0008] (2) Aniline compound of formula 3 [ka] (In the formula, X, R 1 , R 2 and R 3 is as defined for compounds of formula 1); and (3) Sulfonyl chloride to form a compound of Formula 1; wherein the method comprises a continuous process. [Brief description of the drawings]

[0009] [Figure 1] FIG. 1 shows a flow chart illustrating a continuous process for producing a compound of Formula 1, which includes sequentially charging a compound of Formula 2, a compound of Formula 3, a sulfonyl chloride, an optional base, and an optional solvent to a reaction zone; transferring the resulting mixture containing the compound of Formula 1 to a quench zone where an anti-solvent is introduced; and transferring the quenched mixture containing the compound of Formula 1 to an isolation zone where the anti-solvent, optional solvent, and optional base are removed. [Diagram 2] FIG. 2 shows a schematic diagram of a series of reactors, such as a reaction CSTR and a quench CSTR, suitable for producing the compound of Formula 1 by the continuous process of the present disclosure. [Diagram 3] FIG. 3 shows a schematic diagram of a multiple batch mixing tank suitable for mixing a compound of Formula 2, a compound of Formula 3, a solvent, and a base for introduction into the reaction zone of a continuous process of the present disclosure. [Figure 4] FIG. 4 shows a schematic diagram of a loading system suitable for powder mixing of a compound of Formula 2, a compound of Formula 3, a solvent, and a base for introduction into the reaction zone of a continuous process of the present disclosure. [Diagram 5] FIG. 5 shows a schematic diagram of the reaction zone of the continuous process of the present disclosure, said reaction zone comprising a series of two continuous stirred tank reactors (CSTRs) providing a combination of a first reaction subzone in a first CSTR where a mixture of a compound of Formula 2, a compound of Formula 3, a solvent and a base is introduced and where a sulfonyl chloride, e.g., methanesulfonyl chloride (MSC), is introduced, and a second reaction subzone in a second CSTR where the reaction of the mixture and MSC is terminated. [Figure 6] FIG. 6 shows a schematic diagram of the reaction zone of the continuous process of the present disclosure, which comprises a combination of a plug flow reactor and a continuous stirred tank reactor to provide a first reaction subzone in the plug flow reactor where a mixture of the compound of Formula 2, the compound of Formula 3, a solvent and a base is introduced and where a sulfonyl chloride, such as methanesulfonyl chloride (MSC), is introduced, and a second reaction subzone in the continuous stirred tank reactor where the reaction of the mixture and the MSC is terminated. [Figure 7]FIG. 7 shows a schematic of the reaction zone of the continuous process of the present disclosure, which comprises two continuous stirred tank reactors (CSTRs) in series providing a combination of a first reaction subzone in a first CSTR into which a mixture of the compound of Formula 2, the compound of Formula 3, a solvent and a base is introduced, and methylsulfonyl chloride (MSC) is introduced, and a second reaction subzone in a second CSTR with an additional methylsulfonyl chloride feed stream. [Figure 8] FIG. 8 shows a schematic diagram of an apparatus useful in the process of the present disclosure, which includes a continuous stirred tank reactor combined with a solids concentrator (e.g., a hydrocyclone) that allows for removal of solids to a quench zone and recycling of the reaction solution back to the continuous stirred tank reactor. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0010] As used herein, the words "comprise," "include," "contain," "contains," "having," "having" or any variations thereof are intended to encompass inclusive inclusions. For example, a composition, process, method, article, or device 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, process, method, article, or device. Furthermore, unless otherwise specified, "or" means an inclusive "or" and not an exclusive "or." For example, a condition A or B is satisfied by any one of: A is true (or present) and B is false (or absent), A is false (or absent) and B is true (or present), and both A and B are true (or present).

[0011] Also, 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 understood to include one or at least one, and singular word forms of the element or component also include the plural, unless the number clearly indicates the singular.

[0012] Combining chemicals refers to bringing the chemicals into contact with each other.

[0013] A "carbon-based group" refers to a monovalent molecular moiety that includes a carbon atom that connects the group to the remainder of the chemical structure through a single bond. Carbon-based groups can optionally include saturated, unsaturated, and aromatic groups, chains, rings, and ring systems, as well as heteroatoms. Carbon-based groups are not particularly limited in size, but typically contain 1-16 carbon atoms and 0-3 heteroatoms for the purposes of this disclosure. Of note are carbon-based groups selected from C1-C6 alkyl, C1-C4 haloalkyl, and phenyl, optionally substituted with 1-3 substituents selected from C1-C3 alkyl, halogen, and nitro.

[0014] In this specification, the abbreviation "Ph" means phenyl. Alkyl can be straight-chained or branched. "Cycloalkyl" includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. The term "cycloalkylalkyl" refers to cycloalkyl substitution on an alkyl moiety. Examples of "cycloalkylalkyl" include cyclopropylmethyl, cyclopropylethyl, cyclopentylethyl, and other cycloalkyl moieties attached to straight-chain or branched alkyl groups. The term "halogen", whether alone or in compound terms such as "haloalkyl", includes fluorine, chlorine, bromine, or iodine. Additionally, when used in compound terms such as "haloalkyl", the alkyl may be partially or fully substituted with halogen atoms, which may be the same or different. Examples of "haloalkyl" include F3C, ClCH2, BrCH2, CF3CH2, and CF3CCl2.

[0015] As stated above, Q is a 5- or 6-membered aromatic heterocyclic ring, optionally substituted with one or more substituents selected from the group of substituents defined in the Summary of the Invention. When Q is a 5- or 6-membered nitrogen-containing heterocyclic ring, it may be attached to the remainder of Formula 1 through any available carbon or nitrogen ring atom, unless otherwise stated. Examples of 5- or 6-membered aromatic heterocyclic rings, optionally substituted with one or more substituents, include rings U-2 through U-63 shown in Example Table 1 below, where R v is any of the substituents defined in the Summary of the Invention for Q, and r is an integer from 0 to 4 limited by the number of available positions on each U group. Since U-29, U-30, U-36, U-37, U-38, U-39, U-40, U-41, U-42, U-43, U-49, and U-50 have only one available position, r is limited to the integer 0 or 1 for these U groups, where r is 0 means that the U group is unsubstituted and (R v ) r means that a hydrogen is present at the position indicated.

[0016] [ka] [ka]

[0017] In various embodiments, Q groups include U-49 and U-50. In various embodiments, U-49 groups include U-49 substituted with tert-butyl, cyclopropyl, CF2H, CF3, CF2CF3, CF2CF2CF3, or CF(CF3)2. In various embodiments, U-50 groups include U-50 substituted with CF2H, CF3, CF2CF3, or CF(CF3)2. In some embodiments, Q groups are U-49 substituted with CF3.

[0018] The use of a continuous process to produce N-phenylpyrazole-1-carboxamides offers many advantages over the batch process carried out in WO 2006 / 062978. Running continuously allows for faster throughput in a given reactor and helps improve the safety of the process by minimizing the amount of reactive chemicals that can cause runaway reactions. Although not all processes can be run in a continuous mode, for example due to impurity generation or handling issues, it has been discovered that the process described herein can be run in a continuous process with high yields and without forming new impurities, which has implications for meeting current global pesticide registration requirements.

[0019] In addition, it has been discovered that running in a continuous mode can be beneficial to the particle size of the final product, especially when feeding the partially converted material into the reaction zone, which improves its ease of filtration and the concentration of the product. In a typical batch process, it is desirable to run with a high concentration of starting material, which often produces undissolved starting material solids that affect the crystallization of the final product, resulting in small, difficult-to-filter particles of the product. By running the partially converted material into the reaction zone continuously, these solid starting materials dissolve quickly upon entering the reaction zone, essentially eliminating their effect on crystallization. It has also been discovered that the final product has a higher solubility in the reaction medium with increasing levels of conversion to the compound of formula 1, which also benefits crystallization and particle size by reducing the amount of supersaturation during crystallization.

[0020] The embodiments of the present disclosure include the following.

[0021] Embodiment M1.(a) combining a compound of formula 2 with a compound of formula 3 and a sulfonyl chloride; (b) isolating the compound of formula 1 wherein the combining step (a) is performed in a continuous process.

[0022] Embodiment M1a. The method of Embodiment M1 wherein combining the compound of Formula 2 with the compound of Formula 3 and the sulfonyl chloride is carried out in the presence of a base and / or a solvent.

[0023] Embodiment M2. The method of Embodiment M1 wherein in the combining step (a), the compound of Formula 2, the compound of Formula 3 and the sulfonyl chloride are continuously charged to the reaction zone; and the isolating step (b) comprises continuously removing the compound of Formula 1 from the reaction zone after it is formed.

[0024] Embodiment M2a. The method of embodiment M2 wherein the optional solvent and / or base are also continuously charged to the reaction zone.

[0025] Embodiment M3. The method of Embodiment M1 or Embodiment M2 wherein the rates of charging the compound of Formula 2, the compound of Formula 3 and the sulfonyl chloride and the rate of removal of the compound of Formula 1 are adjusted to provide an average residence time in the reaction zone of 2 hours or less.

[0026] The method of embodiment M3 wherein any solvent and / or base are continuously charged to and removed from the reaction zone at rates adjusted to provide an average residence time in the reaction zone of 2 hours or less.

[0027] Embodiment M4. The method of Embodiment M3 or Embodiment 3a, wherein the average residence time in the reaction zone is about 15 minutes or less.

[0028] Embodiment M5. The method of any of Embodiments M1-M4 wherein at least a portion of the compound of Formula 1 is isolated from the process medium.

[0029] Embodiment M6. The method of any of Embodiments M1-M5, wherein the isolating step comprises (b1) quenching the reaction of the compound of Formula 2, 3 with a sulfonyl chloride to precipitate the compound of Formula 1, and (b2) filtering the compound of Formula 1 from the process medium.

[0030] Embodiment M7. The method of Embodiment M6 wherein the quenching step (b1) is carried out by adding an anti-solvent, such as water, to the reaction stream in the quenching zone.

[0031] Embodiment M8. The method of embodiment M7, wherein the added water is characterized by a neutral, acidic, or basic pH value, or is present sequentially at different pH values ​​in a plurality of separate quenching zones.

[0032] Embodiment M9. The method of any one of Embodiments M1 through M8 further comprising drying the compound of Formula 1.

[0033] Embodiment M10. The method of any one of Embodiments M1 through M9 wherein the combining step (a) is carried out in an inert atmosphere at atmospheric pressure.

[0034] Embodiment M11. The method of any one of Embodiments M1-M10, wherein the reaction zone comprises a single reaction vessel.

[0035] Embodiment M12. The method of any of Embodiments M1-M10, wherein the reaction zone comprises multiple reaction subzones having independent average residence times and temperatures for each subzone.

[0036] Embodiment M13. The method of M12, wherein the reaction zone comprises a first reaction vessel and a second reaction vessel.

[0037] Embodiment M14. The method of any one of Embodiments M1 through M13, wherein the reaction zone comprises a plug flow reactor, a continuous stirred tank reactor, or a combination thereof.

[0038] Embodiment M15. The method of any one of Embodiments M1 through M14, wherein the molar ratio of the compound of Formula 2 to the compound of Formula 3 is from about 1.2:1 to about 1:1.2.

[0039] Embodiment M16. The method of Embodiment M15 wherein the molar ratio of the compound of Formula 2 to the compound of Formula 3 is from about 1:1 to about 1:1.2.

[0040] Embodiment M17. The method of Embodiment M15 wherein the molar ratio of the compound of Formula 2 to the compound of Formula 3 is about 1:1.1.

[0041] Embodiment M18. The method of any one of Embodiments M1 through M17 wherein the molar ratio of the sulfonyl chloride to the compound of Formula 2 is at least about 1:1.

[0042] Embodiment M19. The method of Embodiment M18 wherein the molar ratio of the sulfonyl chloride to the compound of Formula 2 is from about 1:1 to about 2.5:1.

[0043] Embodiment M20. The method of Embodiment M19 wherein the molar ratio of the sulfonyl chloride to the compound of Formula 2 is from about 1.1:1 to about 1.4:1.

[0044] Embodiment M21.R 2 The method of any one of Embodiments M1 through M18, wherein when is Br or Cl, the molar ratio of sulfonyl chloride to the compound of Formula 2 is about 1.2:1.

[0045] Embodiment M22.R 2 The method of any one of Embodiments M1 through M18, wherein when is CN, the molar ratio of sulfonyl chloride to the compound of Formula 2 is about 1.4:1.

[0046] Embodiment M23. The sulfonyl chloride is of Formula 4 [ka] R in the formula 8 The method of any of embodiments M1 through M22, wherein is a carbon-based group.

[0047] Embodiment M24.R 8 The method of embodiment M23, wherein is C1-C4 alkyl, C1-C2 haloalkyl, or phenyl, optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, C1-C3 alkyl, and nitro.

[0048] Embodiment M25.R8 The method of embodiment M24, wherein is C1-C2 alkyl, CF3, phenyl, or 4-methylphenyl.

[0049] Embodiment M26.R 8 The method of embodiment M25, wherein is C1-C2 alkyl, phenyl, or 4-methylphenyl.

[0050] Embodiment M27.R 8 The method of embodiment M26, wherein is CH3.

[0051] Embodiment M28. The method of any one of Embodiments M1 through M27 wherein the carboxylic acid of Formula 2, the aniline of Formula 3 and the sulfonyl chloride are combined at a temperature of from about -70 to about 100°C.

[0052] The method of embodiment M28 wherein the temperature is from about -20 to about 40°C.

[0053] The method of embodiment M26, wherein the temperature is from about -10 to about 30°C.

[0054] Embodiment M31. The method of any one of Embodiments M1 through M30 wherein a carboxylic acid of Formula 2 is combined with an aniline of Formula 3 to form a mixture, and then the mixture is combined with a sulfonyl chloride.

[0055] Embodiment M32. The method of any one of Embodiments M1 through M31 wherein a base is combined with the compounds of Formulae 2 and 3 and a sulfonyl chloride.

[0056] Embodiment M33. The method of embodiment M32 wherein a base is combined with the mixture either before or after it is combined with the sulfonyl chloride.

[0057] Embodiment M34. The method of embodiment M33 wherein the base is combined with the compounds of Formulae 2 and 3 to form a mixture before being combined with the sulfonyl chloride.

[0058] Embodiment M35. The method of any of Embodiments M32-M34 wherein the amount of base is at least about 2 equivalents relative to the sulfonyl chloride.

[0059] Embodiment M36. The method of Embodiment M35 wherein the amount of base is at least about 2.1 equivalents relative to the sulfonyl chloride.

[0060] Embodiment M37. The method of Embodiment M36 wherein the amount of base is about 2.1 to 2.2 equivalents relative to the sulfonyl chloride.

[0061] Embodiment M38. The method of any one of Embodiments M32 through M37 wherein the base is selected from tertiary amines, including optionally substituted pyridines.

[0062] Embodiment M39. The method of embodiment M38 wherein the base is selected from optionally substituted pyridines and mixtures thereof.

[0063] Embodiment M40. The method of embodiment M39 wherein the base is selected from 2-picoline, 3-picoline, 2,6-lutidine, pyridine and mixtures of the foregoing.

[0064] Embodiment M41. The method of embodiment M40, wherein the base is 3-picoline.

[0065] Embodiment M42. The method of any one of Embodiments M1 through M41 wherein a solvent is combined with the compounds of Formulae 2 and 3 and a sulfonyl chloride.

[0066] Embodiment M43. The method of embodiment M42 wherein the solvent is combined with the compounds of Formulae 2 and 3 to form a mixture before being combined with the sulfonyl chloride.

[0067] Embodiment M44. The method of embodiment M43 wherein the base is combined with the compounds of Formulae 2 and 3 and the solvent and heated to form a solution before being combined with the sulfonyl chloride.

[0068] Embodiment M45. The method of Embodiment M43 wherein the base is combined with the compounds of Formulae 2 and 3 and the solvent to form a slurry before being combined with the sulfonyl chloride.

[0069] Embodiment M46. The method of any one of Embodiments M42-M45, wherein the solvent is selected from nitriles (e.g., acetonitrile, propionitrile), esters (e.g., methyl acetate, ethyl acetate, butyl acetate), ketones (e.g., acetone, methyl ethyl ketone, methyl butyl ketone, haloalkanes (e.g., dichloromethane, trichloromethane), ethers (e.g., ethyl ether, methyl tert-butyl ether, tetrahydrofuran, p-dioxane), aromatic hydrocarbons (e.g., benzene, toluene, chlorobenzene, dichlorobenzene), tertiary amines (e.g., trialkylamines, dialkylanthranilamides, optionally substituted pyridines), and mixtures thereof.

[0070] Embodiment M47. The method of Embodiment M46 wherein the solvent is selected from tertiary amines (eg, trialkylamines, dialkylanthranilamides, optionally substituted pyridines) and mixtures thereof.

[0071] Embodiment M48. The method of embodiment M46, wherein the solvent is selected from nitriles (e.g., acetonitrile, propionitrile), esters (e.g., methyl acetate, ethyl acetate, butyl acetate), ketones (e.g., acetone, methyl ethyl ketone, methyl butyl ketone, haloalkanes (e.g., dichloromethane, trichloromethane), ethers (e.g., ethyl ether, methyl tert-butyl ether, tetrahydrofuran, p-dioxane), aromatic hydrocarbons (e.g., benzene, toluene, chlorobenzene, dichlorobenzene), and mixtures thereof.

[0072] Embodiment M49. The method of embodiment M48, wherein the solvent is acetonitrile.

[0073] Further, in the embodiment M50, R 1Compounds of formula 1, where R is H, can be treated with a halogenating agent to form 1 The method of any one of embodiments M1 through M49 comprising providing a compound of Formula 1 where is Cl or Br.

[0074] Further, embodiment M51. R 2 Compounds of formula 1, where R is H, can be treated with a halogenating agent to form 2 The method of any one of embodiments M1 through M49 comprising providing a compound of Formula 1 where is Cl or Br.

[0075] In various embodiments, the methods of the disclosure can be used to prepare compounds of formula 1. Accordingly, the present invention includes the following embodiments.

[0076] The method of any of Embodiments M1 through M51 used to prepare a compound of Formula 1. [ka] During the ceremony, X is O or S; Z is CR 7 or N; R 1 is H, CH3, Cl or Br; R 2 is H, Br, Cl or CN; R 3 is H, C1-C4 alkyl or C4-C 10 cycloalkylalkyl; R 4 is Cl, Br, OCF2H, OCH2CF3; or C1-C4 alkyl optionally substituted with halogen; or C1-C4 alkyl substituted with Q; R 5 is F, Cl or Br; R 6 is H, F or Cl; R 7 is H, F, Cl or Br; Q is a 5- or 6-membered aromatic heterocyclic ring optionally substituted with one or more substituents independently selected from the group consisting of halogen, C1-C6 alkyl, C3-C6 cycloalkyl, and C1-C6 haloalkyl.

[0077] Embodiment C2. The method of any one of Embodiments M1 through M51, wherein in the compound of Formula 3, X is O.

[0078] Embodiment C3. The method of any one of Embodiments M1 through M51 wherein, in the compound of Formula 3, X is S.

[0079] Embodiment C4. In a compound of Formula 3, R 1 The method of any one of embodiments C1 through C3, wherein is Cl.

[0080] Embodiment C5. In a compound of Formula 3, R 1 The method of any one of embodiments C1 through C3, wherein is Br.

[0081] Embodiment C6. In a compound of Formula 3, R 1 The method of any one of embodiments C1-C3, wherein

[0082] Embodiment C7. In a compound of Formula 3, R 2 The method of any one of embodiments C1 through C6, wherein is Br or Cl.

[0083] Embodiment C8. In a compound of Formula 3, R 2 The method of any one of embodiments C1 through C6, wherein

[0084] Embodiment C9. In a compound of Formula 3, R 2 The method of any one of embodiments C1-C6, wherein is CN.

[0085] Embodiment C10. In a compound of Formula 3, R 3 The method of any one of embodiments C1 through C9, wherein is C1-C4 alkyl.

[0086] Embodiment C11.R 3 The method of embodiment C10, wherein is methyl.

[0087] Embodiment C12.R 3 The method of embodiment C10, wherein is ethyl.

[0088] Embodiment C13.R 3 The method of embodiment C10, wherein is isopropyl.

[0089] Embodiment C14. In a compound of Formula 3, R 3 C4~C 10 The method of any one of embodiments C1 through C9 wherein is cycloalkylalkyl.

[0090] Embodiment C15.R 3 The method of embodiment C14, wherein is 1-(cyclopropyl)ethyl.

[0091] Embodiment C16. The method of any one of Embodiments C1 through C15, wherein in the compound of Formula 2, Z is N.

[0092] Embodiment C17. In a compound of Formula 2, R 4 The method of any one of embodiments C1 through C16, wherein is Cl or Br.

[0093] Embodiment C18. In the compound of Formula 2, R 4 The method of any one of Embodiments C1 through C16, wherein is C1-C4 alkyl optionally substituted with halogen or C1-C4 alkyl substituted with Q.

[0094] Embodiment C19.R 4 is C1-C4 alkyl.

[0095] Embodiment C20.R 4 is methyl.

[0096] Embodiment C21.R 4is a C1-C4 alkyl substituted with halogen.

[0097] Embodiment C22.R 4 is CF3, C21 method.

[0098] Embodiment C23.R 4 is CH2Br.

[0099] Embodiment C24.R 4 is C1-C4 alkyl optionally substituted with a 5-membered aromatic heterocycle, optionally substituted with one or more substituents independently selected from the group consisting of halogen, C1-C6 alkyl, C3-C6 cycloalkyl, and C1-C6 haloalkyl.

[0100] Embodiment C25.R 4 The method of C24, wherein is 5-(trifluoromethyl)-2H-tetrazol-2-ylmethyl.

[0101] Embodiment C26. In a compound of Formula 2, R 5 The method of any one of embodiments C1 through C25, wherein is Cl.

[0102] Embodiment C27. In a compound of Formula 2, R 6 The method of any one of embodiments C1 through C26, wherein

[0103] Embodiment C28. In a compound of Formula 2, R 6 The method of any one of embodiments C1 through C27, wherein is Cl.

[0104] Embodiment C29. The method of C1 wherein, in the compound of Formula 1, X is O.

[0105] The method of C1 wherein, in the compound of Formula 1, X is S.

[0106] Embodiment C31. In a compound of Formula 1, R 1The method of any one of embodiments C29-C30, wherein is Cl.

[0107] Embodiment C32. In a compound of Formula 1, R 1 The method of any one of embodiments C29-C30, wherein is Br.

[0108] Embodiment C33. In a compound of Formula 1, R 1 The method of any one of embodiments C29-C30, wherein

[0109] Embodiment C34. In a compound of Formula 1, R 2 The method of any one of embodiments C29-C33, wherein is Br or Cl.

[0110] Embodiment C35. In a compound of Formula 1, R 2 The method of any one of embodiments C29-C33, wherein

[0111] Embodiment C36. In a compound of Formula 1, R 2 The method of any one of embodiments C29-C33, wherein is CN.

[0112] Embodiment C37. In a compound of Formula 1, R 3 The method of any one of embodiments C29-C36, wherein is C1-C4 alkyl.

[0113] Embodiment C38.R 3 The method of embodiment C37, wherein is methyl.

[0114] Embodiment C39.R 3 The method of embodiment C37, wherein is ethyl.

[0115] Embodiment C40.R 3 The method of embodiment C37, wherein is isopropyl.

[0116] Embodiment C41. In a compound of Formula 1, R 3 C4~C 10The method of any one of embodiments C29-C36, wherein is cycloalkylalkyl.

[0117] Embodiment C42.R 3 The method of embodiment C41, wherein is 1-(cyclopropyl)ethyl.

[0118] Embodiment C43. The method of any one of Embodiments C29 through C42 wherein, in the compound of Formula 1, Z is N.

[0119] Embodiment C44. In a compound of Formula 1, R 4 The method of any one of embodiments C29 through C43, wherein is Cl or Br.

[0120] Embodiment C45. In a compound of Formula 1, R 4 The method of any one of Embodiments C29-C43, wherein is C1-C4 alkyl optionally substituted with halogen or C1-C4 alkyl substituted with a 5- or 6-membered aromatic heterocycle optionally substituted with C1-C2 haloalkyl.

[0121] Embodiment C46.R 4 is C1-C4 alkyl.

[0122] Embodiment C47.R 4 is methyl.

[0123] Embodiment C48.R 4 is a C1-C4 alkyl substituted with halogen.

[0124] Embodiment C49.R 4 is CF3, C48 method.

[0125] Embodiment C50.R 4 is CH2Br.

[0126] Embodiment C51.R 4is C1-C4 alkyl substituted with a 5-membered aromatic heterocycle optionally substituted with C1-C2 haloalkyl.

[0127] Embodiment C52.R 4 The method of C51, wherein is 5-(trifluoromethyl)-2H-tetrazol-2-ylmethyl.

[0128] Embodiment C53. In a compound of Formula 1, R 5 The method of any one of embodiments C29-C52, wherein is Cl.

[0129] Embodiment C54. In a compound of Formula 1, R 6 The method of any one of embodiments C29 through C53, wherein

[0130] Embodiment C55. In a compound of Formula 1, R 6 The method of any one of embodiments C29-C53, wherein is Cl.

[0131] The embodiments of the invention, including the above embodiments M1-M51 and C1-C55 as well as any other embodiment described herein, may be combined in any manner, and the descriptions of the variables of the embodiments relate not only to compounds of formula 1, but also to starting compounds and intermediate compounds useful for making compounds of formula 1, including compounds of formulas 2, 3, and 4. Additionally, the embodiments of the invention, including the above embodiments M1-M51 and C1-C55 as well as any other embodiment described herein, as well as any combination thereof, relate to the compositions and methods of the invention.

[0132] Embodiment A1. X is O; R 1 is CH3; R 2 is H, Cl, Br or CN; R 3 The method of any one of embodiments M1 through M51 comprising a compound of formula 3, wherein is CH3 or CH2CH3.

[0133] Embodiment A2. X is O; R 1is CH3; R 2 is Cl or CN; R 3 The method of embodiment A1 comprising a compound of Formula 3, wherein is CH3.

[0134] Embodiment A3. X is O; R 1 is CH3; R 2 is H or Br; R 3 The method of embodiment A1 comprising a compound of formula 3, wherein is CH3 or CH2CH3.

[0135] Embodiment A4. X is O or S; R 1 is Cl; R 2 is Cl; R 3 The method of any one of embodiments M1 through M51 comprising a compound of formula 3, wherein is CH(CH3)2.

[0136] Embodiment A5. X is O; R 1 is H or Br; R 2 is Cl; R 3 The method of any one of Embodiments M1 through M51 comprising a compound of Formula 3, wherein is 1-(cyclopropyl)ethyl.

[0137] Embodiment A6. Z is N; R 4 is Br;R 5 is Cl; R 6 The method of any one of embodiments M1 through M51 comprising a compound of formula 2, wherein is H or Cl.

[0138] Embodiment A7. Z is N; R 3 is CH3, CH2Br or 5-(trifluoromethyl)-2H-tetrazol-2-ylmethyl; R 5 is Cl; R 6 The method of any one of embodiments M1 through M51 comprising a compound of formula 2, wherein is H.

[0139] Embodiment A8. X is O; R 1 is CH3; R 2 is H, Cl, Br or CN; R 3The method of any one of embodiments M1 through M51 comprising a compound of formula 1 wherein is CH3 or CH2CH3.

[0140] Embodiment A9. X is O; R 1 is CH3; R 2 is Cl or CN; R 3 The method of embodiment A8 comprising a compound of Formula 1 wherein is CH3.

[0141] Embodiment A10. X is O; R 1 is CH3; R 2 is H or Br; R 3 The method of embodiment A8 comprising a compound of Formula 1 wherein is CH3 or CH2CH3.

[0142] Embodiment A11. X is O or S; R 1 is Cl; R 2 is Cl; R 3 The method of any one of embodiments M1 through M51 comprising a compound of Formula 1, wherein is CH(CH3)2.

[0143] Embodiment A12. X is O; R 1 is H or Br; R 2 is Cl; R 3 The method of any one of Embodiments M1 through M51 comprising a compound of Formula 1 wherein is 1-(cyclopropyl)ethyl.

[0144] Embodiment A13. Z is N; R 4 is Br; R 5 is Cl; R 6 The method of any one of embodiments M1 through M51 comprising a compound of formula 1 wherein is H or Cl.

[0145] Embodiment A14. Z is N; R 3 is CH3, CH2Br or 5-(trifluoromethyl)-2H-tetrazol-2-ylmethyl; R 5 is Cl; R 6 The method of any one of embodiments M1 through M51 comprising a compound of Formula 1 wherein is H.

[0146] Embodiment A15. X is O; Z is N; R 1 is CH3; R 2 is H, Cl, Br or CN; R 3 is CH3 or CH2CH3; R 4 is Br; R 5 is Cl; R 6 The method of any one of embodiments M1 through M51 comprising a compound of Formula 1 wherein is H.

[0147] Embodiment A16. X is O or S; Z is N; R 1 is Cl; R 2 is Cl; R 3 is CH3 or CH(CH3)2; R 4 is Br; R 5 is Cl; R 6 The method of any one of embodiments M1 through M51 comprising a compound of formula 1 wherein is H or Cl.

[0148] Particular embodiments of the present invention include: 3-Bromo-N-[4-chloro-2-methyl-6-[(methylamino)carbonyl]phenyl]-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxamide (also known as chlorantraniliprole), 3-Bromo-1-(3-chloro-2-pyridinyl)-N-[4-cyano-2-methyl-6-[(methylamino)carbonyl]phenyl]-1H-pyrazole-5-carboxamide (also known as cyantraniliprole), 1-(3-chloro-2-pyridinyl)-N-[4-cyano-2-methyl-6-[(methylamino)carbonyl]phenyl]-3-[[5-(trifluoromethyl)-2H-tetrazol-2-yl]methyl]-1H-pyrazole-5-carboxamide (also known as tetraniliprole), and 3-Bromo-N-[2-bromo-4-chloro-6-[[(1-cyclopropylethyl)amino]carbonyl]phenyl]-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxamide (also known as cyclaniliprole) The process of any one of embodiments M1-M51, C1-C55, and A1-A16 is used to prepare a compound of Formula 1 selected from the group consisting of:

[0149] In the following scheme, Q, X, Z, and R in the compounds of the following formulas 1 to 41 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are as defined above in the Summary of the Invention and the Description of the Preferred Embodiments unless otherwise indicated. Compounds of formulas 2a-2f are a subset of formula 2, and compounds of formulas 3a-3c are a subset of formula 3.

[0150] As shown in Scheme 1, the present disclosure relates to a method for preparing a compound of formula 1 by coupling a carboxylic acid of formula 2 with an aniline of formula 3 using a sulfonyl chloride, typically in the presence of a base and a solvent.

[0151] [ka]

[0152] Thus, in the present method, a pyrazole carboxylic acid of formula 2, an aniline of formula 3 and a sulfonyl chloride are combined (ie, contacted) in a continuous process to provide the corresponding N-phenylpyrazole-1-carboxamide of formula 1.

[0153] As shown in Figure 1, the continuous process 100 involves continuously charging a compound of Formula 2, a compound of Formula 3, and a sulfonyl chloride to a reaction zone 110 where they can be combined to provide the corresponding compound of Formula 1. As used herein, the term "reaction zone" refers to a location where the compound of Formula 2, the compound of Formula 3, the sulfonyl chloride, and / or any moieties derived therefrom are in sufficient proximity to each other so that they can contact and combine to form the compound of Formula 1. As described in more detail below, an optional solvent and / or an optional base may also be continuously charged to the reaction zone to facilitate the reaction.

[0154] In various embodiments, at least a portion of the compound of Formula 1 is then continuously removed from reaction zone 110 to quench zone 120 where it is contacted with an anti-solvent as described in more detail below. Suitable anti-solvents include any solvent capable of precipitating the compound of Formula 1. In some embodiments, a suitable anti-solvent is water. After quenching, the compound of Formula 1 is isolated from the liquid process components and water-soluble reaction by-products in isolation step 130, for example by crystallization and / or filtration.

[0155] In other embodiments, at least a portion of the compound of formula 1 can be isolated directly using any suitable isolation technique known to those of skill in the art, such as crystallization or filtration, thereby bypassing any quenching step.

[0156] A simplified schematic of a method system 200 suitable for carrying out the continuous process 100 shown in FIG. 1 is shown in FIG. 2. The method system 200 includes a series of three continuous stirred tank reactors (CSTRs) 210, 220, 230. In various embodiments, a CSTR is defined as a reactor in which the reactor contents are generally well mixed (e.g., by stirring, agitation, gassed mixing, or fluid impingement), but may range from "highly mixed," where substantially no changes in chemical concentrations and temperatures within the reactor are observable, to a mixing level approaching "nonmixed," meaning that large fluctuations in local concentrations and temperatures may occur. The first CSTR 2 10 includes a batch mixing zone 211 where the compound of Formula 2, the compound of Formula 3, the solvent, and the base are mixed. The compounds of Formula 2 and Formula 3 are generally solids and are added neat by well-known powder addition methods such as hopper and / or metering screw feeding. Alternatively, one or both may be dissolved in the solvent prior to introduction to the mixing zone. In some embodiments, the batch mixture may be optionally heated if necessary to provide a solution in which the base, the compound of Formula 2, and the compound of Formula 3 are all dissolved in the solvent. In other embodiments, one or more of the base, the compound of Formula 2, and the compound of Formula 3 remain as suspended solids in the solvent to provide a slurry.

[0157] After mixing, the solution or slurry is passed through a second CSTR having a reaction zone 221. 2 20, and a sulfonyl chloride, such as methylsulfonyl chloride (MSC), is continuously added to the mixture in reaction zone 221. 2 At 20, the sulfonyl chloride, the compound of Formula 2, and the compound of Formula 3 combine to form the compound of Formula 1. In various embodiments, substantially all of the compound of Formula 2 and the compound of Formula 3 are consumed to form the compound of Formula 1. In some embodiments, at least a portion of the compound of Formula 1 may precipitate from the reaction mixture after its formation. In various embodiments, the compound of Formula 1 is continuously removed from the reaction zone, for example as a slurry in a solvent, and quenched in a third CSTR comprising a quench zone 231. 2The compound of Formula 1 is then transferred to a separation device 240, such as a centrifuge or continuous filter, and dried in a drying zone 250, such as a continuous dryer.

[0158] After an initial start-up period in which the reaction zone reactor is filled to a desired volume, the rates of introduction and removal may be substantially constant or variable (e.g., introduction and / or removal may be intermittent), but are balanced to achieve, on average, a desired residence time in the reaction zone. For example, the rates of introduction and removal are not simultaneously zero during a continuous process. Alternatively, intermittent introduction and / or removal may be useful to couple a continuous process with upstream (e.g., batch loading of one or more reactants) or downstream batch processing equipment and / or steps. Desirably, the rates of introduction of the compounds of formulas 2 and 3 into the reaction zone and removal of the compound of formula 1 are adjusted so that the moieties derived from the compounds of formulas 2 and 3 and incorporated into the compound of formula 1 have an average residence time in the reaction zone of sufficient duration to provide a conversion of greater than about 85, 90, 95, or 98%. For example, the average residence time in the reaction zone can range from about 15 minutes to about 2 hours, e.g., about 2 hours or less, or about 1 hour or less, about 30 minutes or less, or about 15 minutes or less. The average residence time is defined as the average amount of time a given molecule spends in the reaction zone (or quench zone, described below). Although the distribution of residence times can be very broad (i.e., some molecules can exit the reaction zone quickly while others in the same reaction zone remain for a longer period of time), the average residence time is generally defined as the volume of the reactor in the reaction zone (or quench zone) divided by the average flow rate of the feed stream. Although the reaction of the compounds of formulas 2 and 3 with the sulfonyl chloride is relatively rapid, in some embodiments, it may be desirable to have an average residence time longer than required to achieve a desired conversion level, for example, to provide reduced equipment clogging, improved interface with other processes, improved crystal properties that allow for more efficient recovery of the resulting compound of formula 1, or for other reasons. In various embodiments, each reactor within a reaction zone operates at an independent residence time and temperature.

[0159] A wide range of equipment can be used to carry out continuous reactions. These methods include, but are not limited to, the use of: continuous stirred tank reactors (CSTRs), plug flow reactors (PFRs), fluidized bed reactors, packed bed reactors, continuous crystallizers, static mixers, reactive distillation columns, and any combination of these. Examples of CSTRs can be anything from a traditional stirred tank to the pumping zone of a centrifugal pump. A plug flow reactor (PFR) can be as simple as flow through a pipe or more complex, for example a shell-and-tube heat exchanger or a plate and frame exchanger. In general, a PFR has a distinct difference in concentration between the inlet and outlet of the reactor.

[0160] As already discussed in connection with Figure 2, the compounds of formulas 2 and 3 are optionally mixed with a solvent and / or base prior to introduction into the reaction zone. Figure 3 shows a schematic diagram of a multiple batch mixing tank 300 suitable for mixing a compound of formula 2, a compound of formula 3, a solvent and a base for introduction into the reaction zone of a continuous process of the present disclosure. The multiple batch mixing tanks 300 allow a first batch mixing tank 310 to be loaded and optionally heated to provide a first batch mixture 311 for introduction into the reaction zone. While the contents of the first batch mixing tank are being pumped into the reaction zone, a second batch mixing tank 320 can be loaded and optionally heated to produce a second batch mixture 321 for subsequent introduction into the reaction zone.

[0161] FIG. 4 shows a schematic diagram of an alternative loading system 400 suitable for powder mixing of compounds of formula 2, formula 3, solvent and base for introduction into the reaction zone of the continuous process of the present disclosure. In this embodiment, the base is introduced into the solvent stream 401 through the process equipment, followed by the compound of formula 2, which is substantially continuously fed into the solvent stream 401 from a first solids hopper 410 downstream (e.g., from a metering screw feed). Similarly, the compound of formula 3 is fed into the solvent stream 401 from a second solids hopper 420 downstream of the first solids hopper 410 and then into the reaction zone 430. There, a sulfonyl chloride is fed into the solvent stream and can react with the compound of formula 2 to form an intermediate, which reacts with the compound of formula 3 to provide the compound of formula 1. In various embodiments, the base can also be added to the solvent stream at a point further downstream and also directly into the reaction zone 430. The compound of formula 1 is then transferred from the reaction zone 430 to a quench zone 440.

[0162] FIG. 5 shows a schematic diagram of two continuous stirred tank reactors 500 in series providing a combination of a first reaction subzone 510 and a second reaction subzone 520, each of which comprises a continuous stirred tank reactor within the reaction zone of the continuous process of the present disclosure. As used herein, the term "subzone" refers to a location (such as a vessel) within a reaction zone or quench zone (see below where a given set of process parameters apply). In the first reaction subzone 510, all components of the reaction mixture are introduced, mixed, and at least partially reacted. In the second reaction subzone 520, the reaction proceeds to completion (i.e., a desired level of conversion) and can provide the compound of formula 1 in a form that facilitates its isolation, for example, the formation of crystal sizes that provide for rapid filtration. For this reason, the second reaction subzone 520 is also referred to as a finishing zone. The volume, average residence time, temperature, mixing, and / or other process parameters can be the same or different in the first and second reaction subzones 510, 520. For example, the temperature in the first reaction subzone 510 may be hotter than in the second reaction subzone 520 .

[0163] Figure 6 shows a schematic diagram of a combination of a first reaction subzone 610 comprising a plug flow reactor 611 and a second reaction subzone 620 comprising a continuous stirred tank reactor 621 in a reaction zone 600 of a continuous process of the present disclosure. As discussed with reference to Figure 5, the first reaction subzone 610 provides mixing and at least partial conversion of the process components, while the second reaction subzone 620 can provide finishing conditions.

[0164] 7 shows a schematic diagram of two continuous stirred tank reactors 700 in series to provide a combination of a first reaction subzone 710 containing a continuous stirred tank reactor 711 and a second reaction subzone 720 containing a continuous stirred tank reactor 721 in the reaction zone of a continuous process of the present disclosure, along with an additional sulfonyl chloride feed stream 730. This allows for a more controlled addition of sulfonyl chloride. It also allows for the addition of additional sulfonyl chloride in case some is consumed in the formation of cyclo-1 compounds (see below).

[0165] In any combination of first and second reaction subzones, transfer between the zones allows for in-line monitoring of the reaction progress (not shown in Figures 5, 6, or 7) and also allows for adjustment of process parameters in the second subzone.

[0166] 8 shows a schematic diagram of a continuous stirred tank reactor equipped with a solids concentrator 820 (e.g., a hydrocyclone) that sends a recycle stream 820 of the reaction solution back to the reaction zone 810 of the continuous stirred tank reactor while allowing preferential removal of solids (e.g., compounds of Formula 1) to the quench zone. This recycle loop allows the reaction to be run at lower reactant concentrations without the loss of yield associated with running at lean conditions, which may be advantageous for reaction selectivity, crystal formation, and slurry handling. It may also allow for in-line monitoring of the reaction.

[0167] Although a wide range of reactant ratios are possible, the nominal molar ratio of the compound of formula 3 to the compound of formula 2 is typically about 0.9 to 1.1, or about 1.0, and both compounds are completely consumed. The process can be carried out at a wide range of temperatures, for example, from -70°C to +100°C, or from -20°C to +40°C, or from -10°C to +30°C, for reasons of convenient operation, favorable reaction rate and selectivity, and high process yield. In some embodiments, the temperature is from 30°C to 60°C.

[0168] Sulfonyl chloride compounds are used as reactants to facilitate the coupling of carboxylic acids of formula 2 with anilines of formula 3 to form N-phenylpyrazole-1-carboxamides of formula 1. The nominal molar ratio of sulfonyl chloride to compound of formula 2 is typically about 1.0-2.5, or about 1.1-1.4, with the assumption that the cyclization side reaction described below occurs to no more than a small extent (i.e., 0-10%). The sulfonyl chloride is generally represented by the formula R 8 is a carbon-based group of the formula R 8 S(O)2Cl (Formula 4). Typically, in this method, R 8 is C1-C4 alkyl, C1-C2 haloalkyl, or phenyl optionally substituted with 1-3 substituents selected from the group consisting of halogen, C1-C3 alkyl, and nitro. Sulfonyl chloride compounds suitable for the present process due to their commercial availability include methanesulfonyl chloride (R 8 is CH3), propanesulfonyl chloride (R 8 (CH2)2CH3), benzenesulfonyl chloride (R 8 Ph), and p-toluenesulfonyl chloride (R 8 In some embodiments, methanesulfonyl chloride is used because of its lower cost, ease of addition, and / or less waste.

[0169] In the method, a sulfonyl chloride is combined with a pyrazole carboxylic acid of formula 2 and an aniline of formula 3. The reactants can be combined in various orders, for example, the sulfonyl chloride can be combined with a carboxylic acid of formula 2 to form a mixture, and then the mixture can be combined with an aniline of formula 3. However, in various embodiments to prepare a particular N-phenylpyrazole-1-carboxamide of formula 1, the order of combination includes combining a carboxylic acid of formula 2 with an aniline of formula 3 to form a mixture, and then combining a sulfonyl chloride with the mixture (e.g., adding the sulfonyl chloride to a mixture of compounds of formulas 2 and 3). This order of addition allows for convenient control of the coupling process. The rate of reaction is easily controlled by controlling the rate of addition of the sulfonyl chloride compound. Thus, one embodiment of the method includes the sequential steps of (1) combining a carboxylic acid of formula 2 and an aniline of formula 3 to form a mixture, and (2) then combining the mixture with a sulfonyl chloride. Although the addition of a sulfonyl chloride to a mixture containing the aniline of formula 2 can potentially result in undesirable side reactions, the stereoelectronic profile of the compounds of formulas 2 and 3 facilitates obtaining significantly higher yields of the compound of formula 1 using the present method.

[0170] The compound of formula 1 is formed when the starting compounds of formulas 2 and 3 and the sulfonyl chloride are contacted with each other in a mixed liquid phase in which each is at least partially soluble. Since the starting materials of formulas 2 and 3 are typically solids at normal ambient temperatures, the process is most satisfactorily carried out using a solvent in which the starting compounds have significant solubility. Thus, the process is typically carried out in a liquid phase containing a solvent. In some cases, the carboxylic acid of formula 2 may be only sparingly soluble, but its salt with the added base may be more soluble in the solvent. Suitable solvents for this process 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 ethyl ether, methyl tert-butyl ether, tetrahydrofuran (THF), and p-dioxane; aromatic hydrocarbons such as benzene, toluene, chlorobenzene, and dichlorobenzene; tertiary amines such as trialkylamines, dialkylanilines, and optionally substituted pyridines; and mixtures of the above. Solvents of note include acetonitrile, propionitrile, ethyl acetate, acetone, MEK, dichloromethane, methyl tert-butyl ether, THF, p-dioxane, toluene, and chlorobenzene. Acetonitrile is a particularly noteworthy solvent as it often provides products in excellent yield and / or purity.

[0171] Since the reaction of the present process would otherwise produce hydrogen chloride as a by-product that binds to the basic center of the compounds of formulas 1, 2 and 3, the process is most satisfactorily carried out in the presence of at least one added base. The base also facilitates the constitutive interaction of the carboxylic acid with the sulfonyl chloride compound and the aniline. The reaction of the added base with the carboxylic acid of formula 2 forms a salt, which is more soluble in the reaction medium than the carboxylic acid. The base is typically added prior to the addition of the sulfonyl chloride, although the base may be added simultaneously, alternately, or even after the addition of the sulfonyl chloride. Some solvents, such as tertiary amines, also serve as bases and are in large stoichiometric excess as base when used as a solvent. The nominal molar ratio of charged base to charged sulfonyl chloride when no base is used as a solvent is typically about 2.0 to 2.2, or about 2.1 to 2.2. Suitable bases include tertiary amines, including substituted pyridines. In various embodiments, suitable bases include 2-picoline, 3-picoline, 2,6-lutidine, and pyridine. In one embodiment, a suitable base is 3-picoline, since salts with carboxylic acids of formula 2 are often highly soluble in solvents such as acetonitrile.

[0172] The features of the present process provide for efficient preparation of N-phenylpyrazole-1-carboxamides of formula 1, while limiting the amount of carboxylic acid, sulfonyl chloride and aniline consumed during the production of N-phenylpyrazole-1-carboxamide and reducing waste products. The present process allows for convenient control of the coupling process and provides a process involving fewer and simpler operations compared to previously known methods for preparing N-phenylpyrazole-1-carboxamides such as formula 1.

[0173] In one embodiment of the method, a pyrazole carboxylic acid of formula 2, an amide of formula 3, and a suitable base are combined in a suitable solvent, followed by the addition of a sulfonyl chloride compound (alone or mixed with a suitable solvent).

[0174] Following the reaction of formula 2 and formula 3 to form the compound of formula 1, the reaction mixture is quenched in a quenching zone by the addition of an anti-solvent such as water. The water converts any unconsumed sulfonyl chloride to its corresponding acid or salt with any excess base present. The addition of water also promotes the complete precipitation of formula 1 from the reaction medium. The quench water may be neutral, acidic or basic. In some embodiments, the quench water may comprise portions of water having different pH values ​​added sequentially to multiple separate quenching subzones. As described in more detail below, adjusting the pH of the quench water minimizes the amount of formula cyclo-1 recovered from the process.

[0175] The rate of introduction and / or removal of the compound of formula 1 into and / or from the quench zone may be substantially constant or variable (e.g., introduction and / or removal may be intermittent), but is balanced to achieve, on average, a desired residence time in the quench zone. For example, the rates of introduction and removal are not simultaneously zero during a continuous process. Alternatively, intermittent introduction and / or removal may be useful for coupling a continuous process to upstream or downstream batch processing equipment and / or steps (e.g., batch filtration). For example, the average residence time in the quench zone may range from about 15 minutes to about 2 hours, e.g., 2 hours or less, 1 hour or less, 30 minutes or less, or 15 minutes or less. Although quenching of the reaction is relatively rapid, in some embodiments, a longer average residence time may be desirable to provide reduced equipment clogging, improved interfaces with other processes, crystal properties that allow for more efficient recovery of the compound of formula 1, or for other reasons. For example, a longer residence time in the quench zone may be desirable to provide an average crystal size suitable for efficient filtration of the compound of Formula 1.

[0176] The product N-phenylpyrazole-1-carboxamide of formula 1 can be isolated from the reaction mixture by methods known to those skilled in the art, including crystallization, filtration, and extraction. As shown in Figures 2 and 8, isolation of the compound of formula 1 as a solid can be accomplished in a wide variety of process equipment, including, but not limited to, solids concentrators, centrifuges, hydrocyclones, continuous filters, dryers, and the like. After isolation, the compound of formula 1 may be further processed, including, but not limited to, washing with solvents and / or water, recrystallization, conversion of the cyclo-1 compound, if present (see below), to the compound of formula 1, and the like. The compound of formula 1 can be combined with additional materials, including other active ingredients and / or formulation aids, for use as a pesticide.

[0177] As shown in Scheme 2, in some cases partial cyclization of amide 1 to an iminobenzoxazine of formula cyclo-1 occurs under the conditions of the coupling reaction.

[0178] [ka]

[0179] In these cases, it is often advantageous to convert the compound of formula cyclo-1 back to the amide of formula 1 prior to isolation of the reaction product. This can be accomplished by treatment of the reaction mixture with aqueous acid. Treatment of the reaction mixture with aqueous acid can be carried out by quenching the reaction mixture with dilute aqueous acid or by adding acid to the process stream after quenching. Alternatively, the mixture of the iminobenzoxazine of formula cyclo-1 and the amide of formula 1 can be isolated and then this mixture can be converted to the amide of formula 1, for example, by treatment with dilute aqueous acid, optionally in the presence of a suitable organic solvent.

[0180] In various embodiments of the process conditions, there is usually little, if any, side cyclization reaction converting the desired product of formula 1 to a compound of formula cyclo-1, in which case the appropriate ratio of sulfonyl chloride to base is sufficient to complete the coupling reaction. However, the pyrazole carboxylic acid of formula 2, the anthranilic acid of formula 3 (e.g., R 2 Depending on the reaction conditions (e.g., when R is CN) and the use of a sterically hindered substituted pyridine such as 2,6-lutidine as the base), the conversion of the desired product of formula 1 to the compound of formula cyclo-1 may occur to a more significant extent or may be the predominant reaction. In these cases, the use of a larger ratio of sulfonyl chloride to base can promote completion of the coupling reaction. The cyclization side reaction stoichiometrically consumes an equivalent of sulfonyl chloride in addition to the equivalent of sulfonyl chloride consumed in the coupling reaction. Thus, if 100% cyclization is to occur, a molar ratio of 2:1 sulfonyl chloride to compound of formula 2 would be stoichiometrically required to achieve complete consumption of the starting material. (R 2 A molar ratio of about 1.4:1 of sulfonyl chloride to compound of formula 2, when cyclization occurs to the extent of only 5-10% (as is typical for most bases when R is CN), and when the cyclization side reaction is negligible (R 2 Typically, up to about a 2.5:1 molar ratio of sulfonyl chloride to compound of formula 2 will be used, as opposed to about a 1.2:1 molar ratio of sulfonyl chloride to compound of formula 2, which is typical for most bases when is Br, Cl, or H. If the cyclization reaction is observed to be occurring, additional amounts of sulfonyl chloride and base can be added as the reaction progresses.

[0181] The above illustrates a beneficial feature of this continuous process, i.e., any component of the process can be added continuously in the additional amount needed to complete the conversion. Completion of the coupling of the compound of formula 2 with the compound of formula 3 to form the compound of formula 1 can be detected by analysis of the reaction mixture using any of a variety of methods well known and available, such as FTIR, HPLC and NMR. Analysis can be performed by taking the reaction mixture or a portion thereof passing through the reaction zone or a sampling loop. The ratio of the components of the mixture can be corrected by adjusting the amount of the appropriate component introduced into the reaction mixture by adjusting the concentration of the component in the reaction stream or by adjusting the flow rate of its introduction.

[0182] Once the rate of combining a particular compound of Formula 2 with a particular compound of Formula 3 has been optimized to form a particular compound of Formula 1 in high yield and / or purity, the rates of introduction of the compound of Formula 2, the compound of Formula 3, the sulfonyl chloride, and any solvent and / or any base (if present), and the rate of removal of the compound of Formula 1 from the reaction zone are kept substantially constant for the duration of the run of the continuous process. It will be understood that the rates of introduction and removal may differ when different compounds of Formula 1 are produced.

[0183] R 1 Compounds of formula 1, where R is H, can be treated with a halogenating agent to form 1 The reaction can provide a compound of formula 1 in which R 1The halogenation is carried out by treating the compound of formula 1, where is H, with a halogenating agent such as chlorine or bromine, usually in the presence of a base and a solvent. The base is selected from metal hydroxides such as sodium hydroxide, lithium hydroxide, potassium hydroxide and calcium hydroxide, alkali metal hydrides such as sodium hydride and potassium hydride, and alkali metal alkoxides such as sodium methoxide, sodium ethoxide and potassium tert-butoxide. The base can be used in an amount of 0.8 to 5 molar equivalents, or 1 to 3.5 molar equivalents, relative to the compound of formula 1. The solvent is selected from ethers such as diethyl ether, butyl methyl ether, tetrahydrofuran, dioxane and dimethoxyethane; halogenated hydrocarbons such as chlorobenzene, dichlorobenzene, dichloromethane, chloroform, carbon tetrachloride, dichloroethane, trichloroethane and dichloroethylene; aromatic hydrocarbons such as benzene, toluene and xylene; aliphatic hydrocarbons such as pentane, hexane, heptane, octane and cyclohexane; esters such as methyl acetate, ethyl acetate and propyl acetate; ketones such as acetone, methyl ethyl ketone and cyclohexene; and polar aprotic solvents such as acetonitrile, propionitrile, N,N-dimethylformamide, dimethylsulfoxide, hexamethylphosphoric triamide, sulfolane, dimethylacetamide and N-methylpyrrolidone. The reaction can be carried out at temperatures of -20 to 120°C, or 0 to 80°C, and the reaction time is usually about 0.5 to about 48 hours, or about 1 to about 24 hours. Exemplary halogenations are described in WO 2008 / 072745. Similarly, R 2 Compounds of formula 1, where R is H, are treated with a halogenating agent to give 2 Compounds of formula 1 can be provided in which is Cl or Br.

[0184] The pyrazole carboxylic acids of formula 2 can be prepared using heterocyclic synthetic methods known in the literature, including references found in the following abstracts: Rodd's Chemistry of Chemistry of Carbon Compounds, Vol. IVa to IVl, S. Coffey editor, Elsevier Scientific Publishing, New York, 1973; Comprehensive Heterocyclic Chemistry, Vol. 1-7, AR Katritzky and CW Rees editors, Pergamon Press, New York, 1984; Comprehensive Heterocyclic Chemistry II, Vol. 1-9, AR Katritzky, CW Rees, and EF Scriven editors, Pergamon Press, New York, 1996; and the series, The Chemistry of Heterocyclic Compounds, EC Taylor, editor, Wiley, New York. A variety of heterocyclic acids, including pyrazole carboxylic acids, and general methods for their synthesis can be found in WO 98 / 57397.

[0185] One embodiment of a procedure for preparing pyrazole carboxylic acids of formula 2a is shown in Scheme 3.

[0186] [ka]

[0187] Reaction of pyrazoles of formula 6 with 2-halopyridines of formula 7 gives good yields of 1-pyridinylpyrazoles of formula 8 with good specificity for the desired regiochemistry. Metallation of compounds of formula 8 with lithium diisopropylamide (LDA) and quenching of the lithium salt with carbon dioxide gives the 1-(2-pyridinyl)pyrazole carboxylic acids of formula 2a. See WO 03 / 015519 for the primary reference for this method.

[0188] As shown in Scheme 4, pyrazole carboxylic acids of formula 2b can be prepared via a 3+2 cycloaddition of an appropriately substituted iminohalide of formula 9 with a substituted propiolate of formula 10 or an acrylate of formula 11.

[0189] [ka]

[0190] Cycloaddition with acrylates requires additional oxidation of the intermediate pyrazoline to a pyrazole. Hydrolysis of the ester of formula 12 gives the pyrazole carboxylic acid of formula 2b. Suitable iminohalides for this reaction include trifluoromethyliminochloride of formula 9a and iminodibromide of formula 9b. Compounds such as formula 9a are known (J. Heterocycl. Chem. 1985, 22(2), 565-8). Other compounds of formula 9, such as formula 9b, are available by known methods (Tetrahedron Letters 1999, 40, 2605).

[0191] An alternative method for preparing pyrazole carboxylic acids of formula 2b is shown in Scheme 5.

[0192] [ka]

[0193] Pyrazoles of formula 13 can be condensed with aryl iodides using methods such as those reported in A. Klapars, JC Antilla, X. Huang and SL Buchwald, J. Am. Chem. Soc. 2001, 123, 7727-7729, or with aryl boronic acids using methods such as those reported in PYS Lam, CG Clark, S. Saubern, J. Adams, MP Winters, DMT Chan and A. Combs, Tetrahedron Lett. 1998, 39, 2941-2944. The resulting adducts of formula 15 can be oxidized with an oxidizing agent such as potassium permanganate to give pyrazole carboxylic acids of formula 2b.

[0194] The starting pyrazoles of formula 6 and 13 are known compounds or can be prepared according to known methods. For example, the pyrazole of formula 6a (R 4 Compounds of formula 6, where R is CF3, can be prepared by literature procedures (J. Fluorine Chem. 1991, 53(1), 61-70). Pyrazoles of formula 6b, where R is CF3, can be prepared by literature procedures (J. Fluorine Chem. 1991, 53(1), 61-70). 4 Compounds of formula 6, in which is Cl or Br, can be prepared by the procedure described in Chem. Ber. 1966, 99(10), 3350-7.

[0195] A useful alternative method for the preparation of compounds of formula 6b is depicted in Scheme 6.

[0196] [ka]

[0197] Metallation of the sulfamoylpyrazole of formula 16 with n-butyllithium and subsequent decomposition of the anion into hexachloroethane (R 4 is Cl) or 1,2-dibromotetrachloroethane (R 4Direct halogenation with either 1,2-difluorophenyl or 1,3-difluorophenyl (Br) affords the halogenated derivatives of formula 17a. Removal of the sulfamoyl group with trifluoroacetic acid (TFA) at room temperature proceeds easily and in good yield to afford the pyrazoles of formula 6c. Those skilled in the art will recognize that formula 6c is a tautomer of formula 6b.

[0198] Pyrazole carboxylic acids 2 can also be prepared by oxidation of pyrazolines of formula 18 to give pyrazoles of formula 19, followed by hydrolysis to the carboxylic acids as shown in Scheme 7.

[0199] [ka]

[0200] The oxidizing agent can be hydrogen peroxide, an organic peroxide, potassium persulfate, sodium persulfate, ammonium persulfate, potassium monopersulfate (e.g., Oxone®), or potassium permanganate. The oxidation can be carried out in the presence of a solvent, including ethers such as tetrahydrofuran, p-dioxane, and the like, organic esters such as ethyl acetate, dimethyl carbonate, and the like, or polar aprotic organics such as N,N-dimethylformamide, acetonitrile, and the like.

[0201] R 4 Halopyrazolines 18, where is Cl or Br, can be prepared from pyrazolones of formula 20 by treatment with an appropriate halogenating agent as shown in Scheme 8.

[0202] [ka]

[0203] The halogenation reagents that can be used include phosphorus oxyhalides, phosphorus trihalides, phosphorus pentahalides, thionyl chloride, dihalotrialkylphosphoranes, dihalotriphenylphosphoranes, oxalyl chloride, and phosgene. In various embodiments, the halogenation reagents are phosphorus oxyhalides and phosphorus pentahalides. Typical solvents for this halogenation include halogenated alkanes such as dichloromethane, chloroform, chlorobutane, etc., aromatic solvents such as benzene, xylene, chlorobenzene, etc., ethers such as tetrahydrofuran, p-dioxane, diethyl ether, etc., and polar aprotic solvents such as acetonitrile, N,N-dimethylformamide, etc. Optionally, an organic base such as triethylamine, pyridine, N,N-dimethylaniline, etc. can be added. Addition of a catalyst such as N,N-dimethylformamide is also an option.

[0204] Or, R 4 Compounds of formula 18 where R is a halogen are 4 Different halogens (e.g., R 4 Formula 18, in which R is Br, Cl, or a sulfonate group such as methanesulfonate, benzenesulfonate, or p-toluenesulfonate, can be prepared by treating the corresponding compound of formula 18 with hydrogen bromide or hydrogen chloride, respectively. 4 The halogen or sulfonate substituents are replaced by Br or Cl, derived from hydrogen bromide or hydrogen chloride, respectively. 4 Starting compounds of formula 18, where R is Cl or Br, can be prepared from the corresponding compounds of formula 20 as previously described. 4 Starting compounds of formula 18, where is a sulfonate group, can similarly be prepared from the corresponding compounds of formula 20 by standard methods such as treatment with a sulfonyl chloride (e.g., methanesulfonyl chloride, benzenesulfonyl chloride, or p-toluenesulfonyl chloride) and a base such as a tertiary amine (e.g., triethylamine) in a suitable solvent such as dichloromethane.

[0205] R 4 Pyrazole carboxylic acids of formula 2c, where is OCHF2 or OCH2CF3, can be prepared by the method outlined in Scheme 9.

[0206] [ka]

[0207] In this method, instead of halogenation as shown in Scheme 8, the compound of formula 20 is oxidized to a compound of formula 21. The reaction conditions for this oxidation are as already described for the conversion of a compound of formula 18 to a compound of formula 19 in Scheme 7. The compound of formula 21 is then alkylated by contact with a difluorocarbene, prepared in situ from CHClF2, in the presence of a base to form a compound of formula 22. The compound of formula 21 can also be alkylated by contact with an alkylating agent, CF3CH2Lg, in the presence of a base to form a compound of formula 24. The alkylation reaction is generally carried out in a solvent, which can include ethers such as tetrahydrofuran or dioxane, and polar aprotic solvents such as acetonitrile, N,N-dimethylformamide, and the like. The base can be selected from inorganic bases such as potassium carbonate, sodium hydroxide, or sodium hydride. In various embodiments, the reaction is carried out using potassium carbonate with N,N-dimethylformamide or acetonitrile as the solvent. The alkylating agent CF3CH2Lg, where Lg is a nucleolytic (i.e., leaving group) such as a halogen (e.g., Br, I), OS(O)2CH3 (methanesulfonate), OS(O)2CF3, OS(O)2Ph-p-CH3 (p-toluenesulfonate), and the like. The product of formula 22 can be isolated by conventional techniques such as extraction. The ester can then be converted to the carboxylic acid of formula 2c by the methods already described for the conversion of formula 12 to formula 2b in Scheme 4.

[0208] Compounds of formula 20 can be prepared from compounds of formula 25 as outlined in Scheme 10.

[0209] [ka]

[0210] In this method, the hydrazine compound of formula 25 is contacted with the compound of formula 26 (fumaric acid ester or maleic acid ester or mixtures thereof are used) in the presence of a base and a solvent. The base is typically a metal alkoxide salt such as sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, potassium tert-butoxide, lithium tert-butoxide, and the like. Polar protic and polar aprotic organic solvents such as alcohol, acetonitrile, tetrahydrofuran, N,N-dimethylformamide, dimethylsulfoxide, and the like can be used. In various embodiments, the solvent is an alcohol such as methanol and ethanol. In other embodiments, the alcohol corresponds to (i.e., is the same as that which constitutes) the fumaric or maleic acid ester and the alkoxide base. Depending on the reaction conditions and the means of isolation, the -CO2R functionality on the compound of formula 20 is hydrolyzed to -CO2H; for example, the presence of water in the reaction mixture can facilitate such hydrolysis. Once the carboxylic acid (-COH) is formed, it can be converted back to -COR, where R is C1-C4 alkyl, using esterification methods well known in the art. The desired product, a compound of formula 20, can be isolated by methods known to those skilled in the art, such as crystallization, extraction, or distillation.

[0211] R 4 Compounds of formula 2d, where R is a C1-C4 alkyl substituted with a 5- or 6-membered aromatic heterocycle substituted with Q, can be prepared according to the methods described in WO 2007 / 144100. 4Compounds of formula 2e, where is C1-C4 alkyl substituted with tetrazole, optionally substituted with one or more substituents independently selected from the group consisting of halogen, C1-C6 alkyl, C3-C6 cycloalkyl and C1-C6 haloalkyl, can be prepared according to the methods described in WO 2010 / 069502.

[0212] As shown in Scheme 11, compounds of formula 2e can be prepared, for example, by combining Q, R 5 and R 6 has the above meaning, R represents C1-C4 alkyl, R 8 The pyrazole carboxylates of formula 27, in which Q, R, R are H or C1-C3 alkyl, can be prepared by reaction with an alkali metal hydroxide, such as sodium hydroxide or potassium hydroxide, in the presence of an inert diluent, such as dioxane / water or ethanol / water, followed by acidification. 5 and R 6The pyrazole carboxylate derivatives of formula 28, in which Z has the above-mentioned meaning and Z is chlorine, bromine, iodine, methylsulfonyl or toluenesulfonyl, can be prepared by reacting them with tetrazoles of formula 29, in which Q has the above-mentioned meaning, in the presence of a base, for example sodium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate, sodium methoxide, triethylamine or sodium hydride, in the presence of a solvent, for example tetrahydrofuran, toluene, acetone, acetonitrile, methanol, dimethylformamide or dioxane. A typical procedure is disclosed in WO 2010 / 069502. Tetrazoles of formula 29 are known and commercially available or can be prepared by known methods (see, for example, WO 2004 / 020445; William P. Norris, J. Org. Chem., 1962, 27 (9), 3248-3251; Henry C. Brown, Robert J. Kassal, J. Org. Chem., 1967, 32 (6), 1871-1873; Dennis P. Curran, Sabine Hadida, Sun-Young Kim, Tetrahedron, 1999, 55 (29), 8997-9006; LD Hansen, EJ Baca, P. Scheiner, Journal of Heterocyclic Chemistry, 1970, 7, 991-996). Alternatively, compounds of formula 28a can be prepared from compounds of formula 28 where Z is H by bromination or chlorination with active halogen compounds such as N-chlorosuccinimide or N-bromosuccinimide in the presence of a radical initiator such as benzoyl peroxide or AIBN. Exemplary procedures are disclosed in WO2016014463, WO2012112946 and WO2016023832. Compounds of formula 2f can be prepared from compounds of formula 28a where Z is a halogen by treatment with an alkali metal hydroxide (e.g., sodium hydroxide or potassium hydroxide) in the presence of an inert diluent (e.g., dioxane / water or ethanol / water).

[0213] [ka]

[0214] As shown in Scheme 12, the pyrazole carboxylate of formula 28 can be prepared by, for example, reacting R, R 5 , R 6 and R 8 where R, R have the above meaning, can be prepared by reacting the alcohol derivative of formula 30 with a sulfonyl chloride (e.g. methylsulfonyl chloride or toluenesulfonyl chloride) or a halogenating agent (e.g. thionyl chloride), if appropriate in the presence of a solvent (e.g. dichloromethane) and if appropriate in the presence of a base (e.g. triethylamine or pyridine). 5 , R 6 and R 8 The ketone derivatives of formula 31, in which R, R have the above meanings, can be prepared by reacting them with a suitable reducing agent (e.g., sodium borohydride) in the presence of a solvent (e.g., ethanol). The ketone derivatives of formula 31 can be prepared, for example, by reacting R, R 5 and R 6 has the above meaning and Y represents chlorine or bromine, 9 is H or C1-C2-alkyl in the presence of a transition metal (e.g. tetrakis(triphenylphosphine)palladium(0)) and a salt (e.g. lithium chloride) in the presence of a solvent (e.g. tetrahydrofuran). Tin derivatives of formula 33 are known and / or commercially available. Pyrazole derivatives of formula 32 are known or can be obtained by known methods (see, for example, WO 2004 / 033468, WO 2003 / 015518 and WO 2003 / 016283).

[0215] [ka]

[0216] Anilines of formula 3a can be prepared by reaction of isatoic anhydrides of formula 34 with ammonia or alkylamines of formula 35 as shown in Scheme 13 by procedures such as those described in L.H. Sternbach et al., J. Org. Chem. 1971, 36, 777-781.

[0217] [ka]

[0218] Isatoic anhydrides of formula 34 can be made by a variety of known methods well documented in the chemical literature. For example, isatoic anhydrides are available from the corresponding anthranilic acids by cyclization involving reaction of anthranilic acid with phosgene or a phosgene equivalent. For primary methodological references, see Coppola, Synthesis 1980, 505 and Fabis et al., Tetrahedron, 1998, 10789.

[0219] The synthesis of isatoic anhydrides of formula 34 can also be accomplished from isatins of formula 37 as outlined in Scheme 14.

[0220] [ka]

[0221] Isatins of formula 37 are accessible from aniline derivatives of formula 36 following literature procedures such as FD Popp, Adv. Heterocycl. Chem. 1975, 18, 1-58 and JFM Da Silva et al., Journal of the Brazilian Chemical Society 2001, 12(3), 273-324. Oxidation of isatins 30 with hydrogen peroxide generally gives good yields of the corresponding isatoic anhydrides 28 (G. Reissenweber and D. Mangold, Angew. Chem. Int. Ed. Engl. 1980, 19, 222-223).

[0222] As shown in Scheme 15, R 2 Isatins of formula 37, where R is Cl, Br or I, can also be obtained from the 5-unsubstituted isatins of formula 38 by halogenation. Cyanide displacement then gives isatins of formula 37a (R 2 isatin of formula 37) where is CN.

[0223] [ka]

[0224] Halogenation reactions can be carried out using a number of reagents and techniques known in the literature. Suitable reagents include halogenating agents such as elemental halogens (chlorine, bromine, or iodine), "positive halogen" agents such as trichloroisocyanuric acid, N-chlorosuccinimide (NCS), N-bromosuccinimide (NBS) or N-iodosuccinimide (NIS), and mixtures containing hydrogen peroxide and hydrogen halides. 2The halogen at the 5-position of isatins of formula 37, where is Cl, Br or I, can be displaced by cyanide using methods known in the literature. These methods involve the use of cyanide salts, usually metal compounds, often in the presence of ligands such as substituted phosphines or substituted bisphosphinoalkanes. Suitable methods include those using palladium compounds as described in PE Maligres et al., Tetrahedron Letters 1999, 40, 8193-8195, and M. Beller et al., Chem. Eur. J. 2003, 9(8), 1828-1836; those using copper compounds as described in SL Buchwald in J. Am. Chem. Soc. 2003, 125, 2890-2891; and those using nickel compounds as described in European Patent No. 384392, and K. Sasaki in Bull. Chem. Soc. Japan 2004, 77, 1013-1019, and RK Arvela and NE Leadbeater in J. Org. Chem. 2003, 68, 9122-9125. As will be appreciated by those skilled in the art, R 1 When R is Cl, R in formula 27 is used to obtain selectivity in cyanation (i.e., replacement of halogen with cyanide). 2 can be Br or I.

[0225] As shown in Scheme 16, anilines of formula 3a are typically available from the corresponding 2-nitrobenzoic acids (or esters) of formula 32 by catalytic hydrogenation of the nitro group followed by reaction of anthranilic acid esters of formula 33 with ammonia or alkylamines.

[0226] [ka]

[0227] Typical reduction procedures include reduction with hydrogen in the presence of a metal catalyst such as palladium on carbon or platinum oxide in hydroxylic solvents such as ethanol and isopropanol. Reduction can also be carried out in the presence of zinc in acetic acid. These methods for reducing nitro groups are well described in the chemical literature. Many methods for the interconversion of carboxylic acids, esters, and amides are also well described in the chemical literature.

[0228] As shown in Scheme 17, the anilines of formula 3a are also available from the 5-unsubstituted anilines of formula 41 by halogenation, R 2 is Br, Cl or I, and optionally by cyanide displacement, anilines of formula 3c (R 2 provides an aniline of formula 3) in which

[0229] [ka]

[0230] Suitable methods and procedures are known in the literature and are similar to those described for the halogenation and cyanide substitution depicted in Scheme 13. As will be appreciated by those skilled in the art, halogenation and cyanation can also be carried out at other stages in the preparation of anilines of formula 3.

[0231] Thioamides of formula 3c can be prepared by vulcanization of their amide analogs 3a (Scheme 18). Methods can be classified as proceeding either by direct treatment of the amide with a vulcanization reagent or by preactivation of the amide with an electrophilic reagent. Methods using the former strategy are similar to P4S with or without additives. 10These include treatment of the amide with dimethylaminoethyl ether, and the use of diethylthiocarbamoyl chloride, ethylaluminum sulfide, boron sulfide, or Lawesson's reagent. Recently, polymer-supported vulcanizing reagents prepared from commercially available diamine resins and ethyl dichlorothiophosphate have also been disclosed, along with techniques involving microwave irradiation. Methods that proceed via preactivation of the amide include the reaction of the pyridinium salt resulting from the combination of oxalyl chloride or phosphorus oxychloride with benzyltriethylammonium tetrathiomolybdate, phosphorus oxychloride with hexamethyldisilathiane, and trialkyloxonium tetrafluoroborate with sodium hydrosulfide, as well as aqueous ammonium sulfide and treatment of the amide with pyridine and triflic anhydride. Brillon, D. Sulfur Rep. 1992, 12, 297; Hartke, K.; Gerber, H.-DJ Prakt. Chem. 1996, 338, 763; Raucher, S.; Klein, PJ Org. Chem. 1981, 46, 3558; Scheeren, JW; Ooms, PHJ; Nivard, RJF Synthesis 1973, 149; Brillon, D. Synth. Commun. 1990, 20, 3085; Goel, OP; Krolls, U. Synthesis 1987, 162; Curphey, TJJ Org. Chem. 2002, 67, 6461; Ogata, M.; Matsumoto, H. Heterocycles 1978, 11, 139; Hirabayashi, T.; Inoue, K.; Yokota, KJ Organomet. Chem. 1975, 92, 139; Steliou, K.; Mrani, MJ Am. Chem. Soc. 1982, 104, 3104; Wojtkowski, PW; Dolfini, JE; Kocy, O.; Cimarusti, CMJ Am. 1975, 97, 5628; Cava, MP; Levinson, MITetrahedron 1985, 41, 5061; Ley, SV; Leach, AG; Storer, RIJ Chem. Soc., Perkin Trans. 1 2001, 358; Varma, RS; Kumar, D. Org. Lett. 1999, 1, 697; Ilankumaran, P.; Ramesha, AR; Chandrasekaran, S. Tetrahedron Lett. 1995, 36, 8311; Smith, DC; Lee, SW; Fuchs, PLJ Org. Chem. 1994, 59, 348; Bodine, JJ, Kaloustian, M. Synth. Commun. 1982, 12, 787 and Charette, AB, Grenon, M., J. Org. Chem. 2003, 68, See 5792-5794.

[0232] [ka]

[0233] R 4 CH2R 8 (R 4 The subset of is C1-C4 alkyl. Compounds of formula 1a can be prepared by a continuous process using R 4 CH2R 8 and R 8 can be prepared from a compound of formula 2, as defined above, and an appropriate compound of formula 3. As shown in Scheme 19, a compound of formula 1a can be converted to a compound of 1b by halogenation as described above for a compound of formula 28a. Alternatively, a compound of formula 28b, where R is H and Z is Cl or Br, can be combined with a compound of formula 2 using a sequential process to provide a compound of formula 1b. A compound of formula 1b can be treated with a tetrazole of formula 29 to provide a compound of formula 1c.

[0234] [ka]

[0235] It is recognized that some of the reagents and reaction conditions described above for preparing compounds of formulas 2 and 3 may not be compatible with some functional groups present in the intermediates. In these cases, the incorporation of a protection / deprotection sequence or functional group interconversion into the synthesis will help to obtain the desired product. The use and selection of protecting groups will be apparent to those skilled in chemical synthesis (see, for example, Greene, TW; Wuts, PGM Protective Groups in Organic Synthesis, 2nd ed.; Wiley: New York, 1991). As will be recognized by those skilled in the art, in some cases, after the introduction of a given reagent as shown in the individual schemes, it may be necessary to carry out additional routine synthetic steps not described in detail in order to complete the synthesis of compounds of formulas 2 and 3. It will also be recognized by those skilled in the art that it may be necessary to carry out combinations of steps shown in the above schemes in an order other than that shown by the specific sequences presented to prepare compounds of formulas 2 and 3. Those of skill in the art will also recognize that the compounds of formulas 2 and 3 and intermediates described herein can be subjected to a variety of electrophilic, nucleophilic, radical, organometallic, oxidative, and reductive reactions to add substituents or modify existing substituents.

[0236] Without further elaboration, it is believed that one skilled in the art can utilize the method of the present disclosure to its fullest extent based on the above description. Therefore, the following examples are merely illustrative and should not be construed as limiting the present disclosure in any way. The steps in the following examples show the sequence of each step in the total synthetic transformation, and the starting materials of each step may not necessarily be prepared in the practice of a particular preparation by the sequence described in other examples or steps. Percentages are by weight unless otherwise indicated for chromatographic solvent mixtures or otherwise. Parts and percentages for chromatographic solvent mixtures are by volume unless otherwise indicated. 1H NMR spectra are expressed in ppm downfield from tetramethylsilane, where s is singlet, d is doublet, and m is multiplet. Quantitative HPLC of products was performed using Ace C18 or C4 Ultra Inert® chromatography columns (reverse phase columns from MacMod Analytical Inc., Chadds Ford, PA 19317) (3 μm particle size, 4.6 mm × 15 cm, eluent 5-80% acetonitrile in pH 3 phosphate buffer). EXAMPLES

[0237] Preparation of 3-bromo-N-[4-chloro-2-methyl-6-[(methylamino)carbonyl]phenyl]-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxamide using a two-stage CSTR reaction zone followed by a one-stage CSTR quench zone at room temperature Acetonitrile (262 g), 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid (230 g, 0.8 mol), prepared similarly to WO 2003 / 015519, and 2-amino-5-chloro-N,3-dimethylbenzamide (152 g, 0.77 mol), prepared similarly to WO 2006 / 062978, and 3-picoline (180 g, 2 mol) were mixed together in a jacketed stirred tank. The mixture was heated until all solids were dissolved. This solution was then pumped continuously into reactor 1 (reaction zone 1), a 200 mL jacketed stirred tank, at a rate of 1.7 g / min. Additionally, methanesulfonyl chloride was pumped into reactor 1 at a rate of 0.21 g / min. The volume level in reactor 1 was controlled at 100 mL and the temperature was maintained at 25° C. The contents of reactor 1 were fed to reactor 2 (reaction zone 2) at an average rate of 1.9 g / min. Reactor 2 was a 200 mL jacketed stirred tank maintained at a temperature of 25° C. and a level controlled at 100 mL. Material from reactor 2 was pumped to reactor 3 (quench zone) at an average rate of 1.9 g / min, and water was also pumped to reactor 3 at an average rate of 0.23 g / min. Reactor 3 was a 200 mL jacketed stirred tank maintained at a temperature of 25° C. and a level of 100 mL. Product was removed from reactor 3 at a continuous rate and filtered. The recovered solids were washed with 5:1 acetonitrile:water, then acetonitrile, and dried under nitrogen to give the title compound as a light brown powder. The purity of the product was 98.6 wt % and the yield was greater than 90%. The total cake resistance was 15.9×10 for a typical batch process. 8 6.7 x 10 compared to ft / lb 8 It was ft / lb. 1 H NMR (CDCl3) δ 2.18 (s, 3H), 2.95 (s, 3H), 6.21 (m, 1H), 7.10 (s, 1H), 7.24 (m, 2H), 7.39 (m, 1H), 7.80 (d, 1H), 8.45 (d, 1H). EXAMPLES

[0238] Preparation of 3-bromo-N-[4-chloro-2-methyl-6-[(methylamino)carbonyl]phenyl]-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxamide using two CSTRs with different reaction zone temperatures followed by a single CSTR quench zone Acetonitrile (420 g), 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid (249 g, 0.82 mol) prepared as in WO 2003 / 015519, and 2-amino-5-chloro-N,3-dimethylbenzamide (168 g, 0.85 mol) prepared as in WO 2006 / 062978, and 3-picoline (200 g, 2.14 mol) were mixed together in a jacketed stirred tank. The mixture was heated until all solids were dissolved. This solution was then continuously pumped at a rate of 1.4 g / min into reactor 1 (reaction zone 1), a 200 mL jacketed stirred tank. Additionally, methanesulfonyl chloride was pumped into reactor 1 at a rate of 0.15 g / min. The volume level in reactor 1 was controlled at 100 mL and the temperature was maintained at 50° C. The contents of reactor 1 were fed to reactor 2 (reaction zone 1) at an average rate of 1.55 g / min. Reactor 2 was a 200 mL jacketed stirred tank with a temperature maintained at 25° C. and a level controlled at 100 mL. Material from reactor 2 was pumped to reactor 3 (quench zone) at an average rate of 1.55 g / min and water was also pumped to reactor 3 at an average rate of 0.17-g / min. Reactor 3 was a 200 mL jacketed stirred tank with a temperature maintained at 25° C. and a level maintained at 100 mL. Product was removed from reactor 3 at a continuous rate and filtered. The recovered solids were washed with 5:1 acetonitrile:water, then acetonitrile and dried under nitrogen to give the title compound as a light brown powder. The purity of the product was 98.8 wt% and the yield was over 90%. The total cake resistance was 15.9 × 10 8 7.0 x 10 compared to ft / lb 8 It was ft / lb. 1H NMR (CDCl3) δ 2.18 (s, 3H), 2.95 (s, 3H), 6.21 (m, 1H), 7.10 (s, 1H), 7.24 (m, 2H), 7.39 (m, 1H), 7.80 (d, 1H), 8.45 (d, 1H). EXAMPLES

[0239] Preparation of 3-bromo-N-[4-chloro-2-methyl-6-[(methylamino)carbonyl]phenyl]-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxamide using two CSTR reaction zones with 12 min residence time followed by a single CSTR quench zone Acetonitrile (532 g), 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid (79 g, 0.26 mol), prepared similarly to WO 2003 / 015519, and 2-amino-5-chloro-N,3-dimethylbenzamide (53 g, 0.27 mol), prepared similarly to WO 2006 / 062978, and 3-picoline (63 g, 68 mol) were mixed together in a jacketed stirred tank. The mixture was heated until all solids were dissolved. This solution was then continuously pumped at a rate of 8.09 g / min into reactor 1 (reaction zone 1), a 200 mL jacketed stirred tank. Additionally, methanesulfonyl chloride was pumped into reactor 1 at a rate of 0.40 g / min. The volume level in reactor 1 was controlled at 100 mL and the temperature was maintained at 25° C. The contents of reactor 1 were fed to reactor 2 (reaction zone 1) at an average rate of 8.49 g / min. Reactor 2 was a 200 mL jacketed stirred tank, the temperature was maintained at 25° C., and the level was controlled at 100 mL. Material from reactor 2 was pumped to reactor 3 (quench zone) at an average rate of 8.49 g / min, and water was also pumped to reactor 3 at an average rate of 3.19 g / min. Reactor 3 was a 200 mL jacketed stirred tank, the temperature was maintained at 25° C., and the level was 150 mL. Product was removed from reactor 3 at a continuous rate and filtered. The recovered solids were washed with 5:1 acetonitrile:water, then acetonitrile, and dried under nitrogen to give the title compound as a light brown powder. Product purity was 98.5 wt % and yield was greater than 90%. 1 H NMR (CDCl3) δ 2.18 (s, 3H), 2.95 (s, 3H), 6.21 (m, 1H), 7.10 (s, 1H), 7.24 (m, 2H), 7.39 (m, 1H), 7.80 (d, 1H), 8.45 (d, 1H). EXAMPLES

[0240] Preparation of 3-bromo-N-[4-chloro-2-methyl-6-[(methylamino)carbonyl]phenyl]-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxamide using two CSTR reaction zones with a 2.5 minute residence time followed by a single CSTR quench zone Acetonitrile (1506 g), 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid (175 g, 0.58 mol), prepared similarly to WO 2003 / 015519, and 2-amino-5-chloro-N,3-dimethylbenzamide (119 g, 0.60 mol), prepared similarly to WO 2006 / 062978, and 3-picoline (140 g, 1.51 mol) were mixed together in a jacketed stirred tank. The mixture was heated until all solids were dissolved. This solution was then continuously pumped at a rate of 32 g / min into reactor 1 (reaction zone 1), a 200 mL jacketed stirred tank. Additionally, methanesulfonyl chloride was pumped into reactor 1 at a rate of 1.6 g / min. The volume level in reactor 1 was controlled at 100 mL and the temperature was maintained at 35° C. The contents of reactor 1 were fed to reactor 2 (reaction zone 1) at an average rate of 51 g / min. Reactor 2 was a 200 mL jacketed stirred tank with a temperature maintained at 25° C. and a level controlled at 100 mL. Material from reactor 2 was pumped to reactor 3 (quench zone) at an average rate of 51 g / min, and water was also pumped to reactor 3 at an average rate of 13-g / min. Reactor 3 was a 200 mL jacketed stirred tank with a temperature maintained at 25° C. and a level of 150 mL. Product was removed from reactor 3 at a continuous rate and filtered. The recovered solids were washed with 5:1 acetonitrile:water, then acetonitrile, and dried under nitrogen to give the title compound as a light brown powder. Product purity was 98.56 wt%. 1 H NMR (CDCl3) δ 2.18 (s, 3H), 2.95 (s, 3H), 6.21 (m, 1H), 7.10 (s, 1H), 7.24 (m, 2H), 7.39 (m, 1H), 7.80 (d, 1H), 8.45 (d, 1H). EXAMPLES

[0241] Preparation of 3-bromo-1-(3-chloro-2-pyridinyl)-N-[4-cyano-2-methyl-6-[(methylamino)carbonyl]phenyl]-1H-pyrazole-5-carboxamide using two CSTR reaction zones followed by a single CSTR quench zone Acetonitrile (609 g), 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid (36 g, 0.12 mol), prepared as in WO 2003 / 015519, and 2-amino-5-cyano-N,3-dimethylbenzamide (24 g, 0.13 mol), and 3-picoline (33 g, 0.36 mol) were mixed together in a jacketed stirred tank. The mixture was heated until all solids were dissolved. This solution was then continuously pumped at a rate of 2.0 g / min into reactor 1 (reaction zone 1), a 200 mL jacketed stirred tank. Additionally, methanesulfonyl chloride was pumped into reactor 1 at a rate of 0.05 g / min. The volume level in reactor 1 was controlled at 130 mL and the temperature was maintained at 25° C. The contents of reactor 1 were fed to reactor 2 (reaction zone 1) at an average rate of 2.1 g / min. Reactor 2 was a 200 mL jacketed stirred tank with a temperature maintained at 25° C. and a level controlled at 130 mL. Material from reactor 2 was pumped to reactor 3 (quench zone) at an average rate of 2.1 g / min, and acid water was also pumped to reactor 3 at an average rate of 0.21-g / min. Reactor 3 was a 200 mL jacketed stirred tank with a temperature maintained at 25° C. and a level of 170 mL. Product was removed from reactor 3 at a continuous rate, neutralized with sodium hydroxide, and filtered. The recovered solids were washed with 5:1 acetonitrile:water, then acetonitrile, and dried under nitrogen to give the title compound as a light brown powder. Product purity was 94.7 area %. EXAMPLES

[0242] Production of 3-bromo-N-[4-chloro-2-methyl-6-[(methylamino)carbonyl]phenyl]-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxamide: Two CSTR reaction zones with two MSC feeds followed by a slurry feed using a single CSTR quench zone Acetonitrile (420 g), 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid (249 g, 0.82 mol) prepared similarly to WO 2003 / 015519, and 2-amino-5-chloro-N,3-dimethylbenzamide (168 g, 0.85 mol) prepared similarly to WO 2006 / 062978, and 3-picoline (200 g, 2.14 mol) were mixed together in a jacketed stirred tank at room temperature. This slurry was then continuously pumped at a rate of 1.4 g / min into reactor 1 (reaction zone 1), a 200 mL jacketed stirred tank. Additionally, methanesulfonyl chloride was pumped into reactor 1 at a rate of 0.08 g / min. The volume level in reactor 1 was controlled at 100 mL and the temperature was maintained at 25° C. The contents of reactor 1 were fed to reactor 2 (reaction zone 1) at an average rate of 1.48 g / min. Additionally, a stream of methanesulfonyl chloride was pumped to reactor 2 at a rate of 0.07-g / min. Reactor 2 was a 200 mL jacketed stirred tank with a temperature maintained at 25° C. and a level controlled at 200 mL. Material from reactor 2 was pumped to reactor 3 (quench zone) at an average rate of 1.55 g / min, and water was also pumped to reactor 3 at an average rate of 0.17-g / min. Reactor 3 was a 200 mL jacketed stirred tank with a temperature maintained at 25° C. and a level of 50 mL. Product was removed from reactor 3 at a continuous rate and filtered. The recovered solids were washed with 5:1 acetonitrile:water, then acetonitrile, and dried under nitrogen to give the title compound as a light brown powder. EXAMPLES

[0243] Preparation of 3-bromo-N-[4-chloro-2-methyl-6-[(methylamino)carbonyl]phenyl]-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxamide: Using a combined PFR and CSTR reaction zone followed by a single CSTR quench zone Acetonitrile (420 g), 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid (249 g, 0.82 mol) prepared similarly to WO 2003 / 015519, and 2-amino-5-chloro-N,3-dimethylbenzamide (168 g, 0.85 mol) prepared similarly to WO 2006 / 062978, and 3-picoline (200 g, 2.14 mol) were mixed together in a jacketed stirred tank at room temperature. This slurry was then continuously pumped into reactor 1 (reaction zone 1), a 17 mL jacketed plug flow reactor with an internal mixing zone, at a rate of 4.2 g / min. Additionally, methanesulfonyl chloride was co-fed into reactor 1 at a rate of 0.45 g / min. The temperature of reactor 1 was maintained at 70° C. and the reactor outlet was fed to reactor 2 (reaction zone 2) at an average rate of 4.65 g / min. Reactor 2 was a 200 mL jacketed stirred tank with a temperature maintained at 50° C. and a level controlled at 50 mL. Material from reactor 2 was pumped to reactor 3 (quench zone) at an average rate of 4.65 g / min and water was also pumped to reactor 3 at an average rate of 0.61-g / min. Reactor 3 was a 200 mL jacketed stirred tank with a temperature maintained at 25° C. and a level of 200 mL. Product was removed from reactor 3 at a continuous rate and filtered. The recovered solids were washed with 5:1 acetonitrile:water, then acetonitrile and dried under nitrogen to give the title compound as a light brown powder. EXAMPLES

[0244] Preparation of 3-bromo-N-[4-chloro-2-methyl-6-[(methylamino)carbonyl]phenyl]-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxamide: using a single CSTR reaction zone followed by a single CSTR quench zone Acetonitrile (420 g), 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid (249 g, 0.82 mol) prepared similarly to WO 2003 / 015519, and 2-amino-5-chloro-N,3-dimethylbenzamide (168 g, 0.85 mol) prepared similarly to WO 2006 / 062978, and 3-picoline (200 g, 2.14 mol) were mixed together in a jacketed stirred tank at room temperature. This slurry was then continuously pumped at a rate of 1.4 g / min into reactor 1 (reaction zone), a 200 mL jacketed stirred tank. Additionally, methanesulfonyl chloride was pumped into reactor 1 at a rate of 0.15 g / min. The volume level in reactor 1 was controlled at 100 mL and the temperature was maintained at 25° C. The contents of Reactor 1 were fed to Reactor 2 (the quench zone) at an average rate of 1.55 g / min, and water was also pumped into Reactor 2 at an average rate of 0.17-g / min. Reactor 2 was a 200 mL jacketed stirred tank maintained at a temperature of 10° C. and a level of 100 mL. Product was removed from Reactor 2 at a continuous rate and filtered. The recovered solids were washed with 5:1 acetonitrile:water, then acetonitrile, and dried under nitrogen to give the title compound as a light brown powder.

[0245] Using procedures similar to those in Examples 1 to 8, a compound in which Z is N and R 4 is CH2(5-CF3-2H-tetrazol-2-yl), and R 5 is Cl, and R 6 is H, and compounds of formula 2 where X is O and R 1 is CH3 and R 2 is CN and R 3 is methyl, and 1 is CH3 and R 2 is CN and R 3 is methyl and R 4 is CH2(5-CF3-2H-tetrazol-2-yl), and R 5 is Cl, and R 6is H (i.e., 1-(3-chloro-2-pyridinyl)-N-[4-cyano-2-methyl-6-[(methylamino)carbonyl]phenyl]-3-[[5-(trifluoromethyl)-2H-tetrazol-2-yl]methyl]-1H-pyrazole-5-carboxamide).

[0246] Using procedures similar to those in Examples 1 to 8, a compound in which Z is N and R 4 is Br and R 5 is Cl, and R 6 is H, and compounds of formula 2 where X is O and R 1 is Br and R 2 is Cl, and R 3 is 1-cyclopropylethyl in a continuous process to form a compound of formula 3, 1 is Br and R 2 is Cl, and R 3 is 1-cyclopropylethyl, R 4 is Br and R 5 is Cl, and R 6 is H (i.e., 3-bromo-N-[2-bromo-4-chloro-6-[[(1-cyclopropylethyl]amino]carbonyl]phenyl]-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxamide).

[0247] By the procedures described herein, together with methods known in the art, the compounds in Tables 1-227 below can be made and used in the methods of the disclosure. The following abbreviations are used in the tables below: t means tertiary, s means secondary, n means normal, i means iso, Me means methyl, Et means ethyl, Pr means propyl, i-Pr means isopropyl, c-Pr means cyclopropyl, and Bu means butyl.

[0248] [Table 1-1] [Table 1-2]

[0249] The present disclosure also includes Table 2, which is constructed similarly to Table 1 above, except that formula 3a is replaced with formula 3c, shown below. For example, the first entry in Table 2 is R 1 is CH3 and R 2 is Cl, and R 3 is H.

[0250] [ka]

[0251] [Table 2-1] [Table 2-2]

[0252] The disclosure also includes Tables 4-7, each of which is structured similarly to Table 3 above, except that the top line of Table 3 (i.e., Z is N) is replaced in Tables 4-7 with the respective top lines shown below. For example, the first of Table 4 is 7 and R 7 is H and R 4 is CF3, and R 5 is F and R 6 is H. Tables 5-7 are similarly structured.

[0253] [Table 3]

[0254] Table 8 shows specific transformations to prepare compounds of formula 1 according to the methods of the present disclosure.

[0255] [Table 4-1] [Table 4-2]

[0256] The disclosure also includes Tables 9-227, each of which is structured similarly to Table 8 above, except that the top row of Table 8 (i.e., X is O, Z is N, and R 1 is CH3 and R 2 is Cl, R 3 is H, and ) is replaced in Tables 9-227 with the top line of each of the following: For example, the first in Table 9 is where X is O, Z is N, and R is 1 is CH3 and R 2 is Cl, and R 3 is H and R 4 is CF3, and R 5 is F and R 6 is H. Tables 10-227 are similarly structured.

[0257] [Table 5-1] [Table 5-2] [Table 5-3] [Table 5-4] [Table 5-5]

Claims

1. Formula 1 [Formula 1] [In the formula, X is O; Z is N; R 1 is H, CH 3 , Cl or Br; R 2 is H, Br, Cl or CN; R 3 is H, C 1 ~C 4 Alkyl or C 4 ~C 10 cycloalkylalkyl; R 4 is C substituted with Cl, Br or Q 1 ~C 4 is alkyl; R 5 is F, Cl or Br; R 6 is H, F or Cl; Q is a 5 or 6 atom bonded to the remainder of formula 1 through any available carbon or nitrogen ring atom. a 5-membered aromatic heterocyclic ring.

1. A method for producing a compound of the formula: (1) Formula 2 [chemical 2] [In the formula, Z, R 4 , R 5 , R 6 , R 7 and Q is as defined for compounds of formula 1. and (2) Formula 3 [C3] [wherein, X, R 1 , R 2 and R 3 is as defined for compounds of formula 1; (3) Sulfonyl chloride Including; The method comprises a continuous process comprising continuously combining a compound of Formula 2, a compound of Formula 3 and a sulfonyl chloride in a reaction zone; and continuously removing a compound of Formula 1 in an isolation step, further comprising: the reaction zone comprising one or more continuous reaction vessels, and the isolation step comprising: quenching the reaction mass containing the compound of formula 1 obtained from the reaction zone in a quench zone to precipitate the compound of formula 1; separating said compound of Formula 1 from the quenched reaction mass by filtration to form a collected solid compound of Formula 1, and quenching the reaction mass comprises continuously adding an anti-solvent to said reaction mass in said quench zone.

2. The method according to claim 1 , further comprising the step of carrying out the reaction in the presence of a base or a solvent.

3. Q is halogen, C 1 ~C 6 Alkyl, C 3 ~C 6 Cycloalkyl and C 1 ~C 6 10. The method of claim 1, wherein the alkyl group is substituted with one or more substituents independently selected from the group consisting of haloalkyl.

4. Sulfonyl chlorides are represented by the formula 4 [C4] [In the formula, R 8 is C 1 ~C 4 Alkyl, C 1 ~C 2 haloalkyl, or optionally halogen, C 1 ~C 3 and phenyl, optionally substituted with 1 to 3 substituents selected from the group consisting of alkyl and nitro. The method of claim 1, wherein

5. The process according to any one of claims 1 to 4, wherein the sulfonyl chloride is methanesulfonyl chloride.

6. 6. The process of any one of claims 1 to 5, wherein a carboxylic acid of formula 2 is combined with an aniline of formula 3 to form a mixture, and then the mixture is combined with a sulfonyl chloride.

7. 7. The method of any one of claims 1 to 6, further comprising combining a base with the compounds of formulas 2 and 3 to form a mixture prior to combining with the sulfonyl chloride.

8. The method of claim 7, wherein the base is a tertiary amine.

9. 9. The method of claim 8, wherein the base is an optionally substituted pyridine.

10. The method of claim 9, wherein the base is selected from 2-picoline, 3-picoline, 2,6-lutidine and pyridine.

11. The method of any one of claims 1 to 10, further comprising a solvent, said solvent being combined with the compounds of formulas 2 and 3 and the sulfonyl chloride.

12. The method of claim 11 , wherein the solvent is acetonitrile.

13. X is O; R 1 is CH 3 and R 2 is H, Cl, Br or CN; R 3 is CH 3 or CH 2 CH 3 The method according to any one of claims 1 to 11, wherein

14. X is O; R 1 is CH 3 and R 2 is Cl or CN; R 3 is CH 3 The method according to any one of claims 1 to 11, wherein

15. X is O; R 1 is CH 3 and R 2is H or Br; R 3 is CH 3 or CH 2 CH 3 The method according to any one of claims 1 to 11, wherein

16. X is O or S; R 1 is Cl; R 2 is Cl; R 3 is CH(CH 3 ) 2 The method according to any one of claims 1 to 11, wherein

17. X is O; R 1 is H or Br; R 2 is Cl; R 3 The method of any one of claims 1 to 11, wherein is 1-(cyclopropyl)ethyl.

18. Z is N; R 4 is Br; R 5 is Cl; R 6 The method according to any one of claims 1 to 11, wherein is H or Cl.

19. Z is N; R 3 is CH 3 , C.H. 2 Br or 5-(trifluoromethyl)-2H-tetrafluoroethylene trazol-2-ylmethyl; R 4 is Cl; R 6 The method of any one of claims 1 to 11, wherein

20. X is O; R 1 is CH 3 and R 2 is H, Cl, Br or CN; R 3 is CH 3 or CH 2 CH 3 The method according to any one of claims 1 to 11, wherein

21. X is O; R 1 is CH 3and R 2 is Cl or CN; R 3 is CH 3 The method according to any one of claims 1 to 11, wherein

22. X is O; R 1 is CH 3 and R 2 is H or Br; R 3 is CH 3 or CH 2 CH 3 The method according to any one of claims 1 to 11, wherein

23. X is O or S; R 1 is Cl; R 2 is Cl; R 3 is CH(CH 3 ) 2 The method according to any one of claims 1 to 11, wherein

24. X is O; R 1 is H or Br; R 2 is Cl; R 3 The method of any one of claims 1 to 11, wherein is 1-(cyclopropyl)ethyl.

25. Z is N; R 4 is Br; R 5 is Cl; R 6 The method according to any one of claims 1 to 11, wherein is H or Cl.

26. Z is N; R 3 is CH 3 , C.H. 2 Br or 5-(trifluoromethyl)-2H-tetrazol-2-ylmethyl; R 5 is Cl; R 6 The method of any one of claims 1 to 11, wherein

27. X is O; Z is N; R 1 is CH 3 and R 2is H, Cl, Br or CN; R 3 is CH 3 or CH 2 CH 3 and R 4 is Br; R 5 is Cl; R 6 The method of any one of claims 1 to 11, wherein

28. X is O or S; Z is N; R 1 is Cl; R 2 is Cl; R 3 is CH 3 or CH (CH 3 ) 2 and R 4 is Br; R 5 is Cl; R 6 The method according to any one of claims 1 to 11, wherein is H or Cl.

29. A compound of formula 1 is prepared, the compound being: 3-bromo-N-[4-chloro-2-methyl-6-[(methylamino)carbonyl]phenyl]-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxamide, 3-bromo-1-(3-chloro-2-pyridinyl)-N-[4-cyano-2-methyl-6-[(methylamino)carbonyl]phenyl]-1H-pyrazole-5-carboxamide, 1-(3-chloro-2-pyridinyl)-N-[4-cyano-2-methyl-6-[(methylamino)carbonyl]phenyl]-3-[[5-(trifluoromethyl)-2H-tetrazol-2-yl]methyl]-1H-pyrazole-5-carboxamide, and 3-Bromo-N-[2-bromo-4-chloro-6-[[(1-cyclopropylethyl)amino]carbonyl]phenyl]-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxamide The method of claim 1 , wherein the compound is selected from the group consisting of:

30. The process of any one of claims 1 to 29, wherein the reaction vessel is selected from the group consisting of a continuous stirred tank reactor, a plug flow reactor, and combinations thereof.

31. The process of any one of claims 1 to 29, wherein the reaction zone comprises two consecutive reaction vessels in series.

32. The process of any one of claims 1 to 29, wherein the reaction zone comprises one continuous reaction vessel.

33. The process of any one of claims 1 to 31, wherein the one or more reaction vessels within the reaction zone are each operated at an independent residence time and temperature.

34. 34. The process of claim 33, wherein the average residence time for portions of each reaction vessel within the reaction zone is 2 hours or less.

35. 34. The method of claim 33, wherein the average residence time is 15 minutes or less.

36. The method of claim 1 , wherein the anti-solvent is water.

37. 10. The process of claim 1, wherein the quench zone comprises one or more successive quench vessels.

38. 10. The method of claim 1, wherein the antisolvent added in the quench zone has a pH selected from the group consisting of neutral pH, acidic pH, and basic pH.

39. 39. The process of any one of claims 1 to 38, wherein the anti-solvent added to the quench zone has the same or a different pH in each of the one or more successive quench vessels.

40. A process according to any one of claims 1 to 39, wherein the isolation step produces a filtrate which is recycled back to the reaction zone.

41. 41. The method of claim 40, wherein the filtrate is purified or unpurified.

42. The process of any one of claims 1 to 41, wherein each reaction vessel within the reaction zone contains one or more independent feed streams.

43. 43. The process of any one of claims 1 to 42, wherein the molar ratio of the compound of formula 2 to the compound of formula 3 is from 1.2:1 to 1:1.

2.

44. 44. The process of any one of claims 1 to 43, wherein the carboxylic acid compound of formula 2, the aniline compound of formula 3 and the sulfonyl chloride are combined at a temperature of from -70 to 100°C.

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