Preparation method of N-phenylpyrazole-1-carboxamide

Abstract

The present invention discloses a method for preparing a compound of Formula 1 by combining compounds of Formula 2 and Formula 3 with sulfonyl chloride in a continuous process.

Description

Technical Field

[0001] The present disclosure relates to a method for preparing N-phenylpyrazole-1-carboxamide or N-pyridylpyrazole-1-carboxamide by coupling a carboxylic acid with anthranilamide in a continuous process. Background Art

[0002] PCT Patent Publication WO 2003 / 015518 discloses the use of N-acyl anthranilic acid derivatives of formula (i) as arthropodicides.

[0003]

[0004] Wherein A and B are independently O or S; R 1 H; R 2 is H, C1-C6 alkyl, C2-C6 alkoxycarbonyl or C2-C6 alkylcarbonyl; R 3 is H or C1-C6 alkyl; R 4 is 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 a phenyl ring, a benzyl ring, a 5-membered or 6-membered heteroaromatic ring, or a naphthyl ring system, each ring or ring system being optionally substituted with 1 to 3 substituents; and R 8 For H.

[0005] WO 2006 / 062978 discloses a process for preparing N-phenylpyrazole-1-carboxamide or N-pyridylpyrazole-1-carboxamide by coupling a carboxylic acid with anthranilamide. See also WO 2003 / 016283, WO 2004 / 011453, WO 2005 / 077934, WO 2007 / 144100, WO 2008 / 072745 and WO 2010 / 069502.

[0006] Although the methods disclosed in the aforementioned references can provide the desired compounds, continuous improvements are still being sought, particularly in developing methods that provide materials on a commercial scale. Therefore, there is a continuous need for new methods that are less expensive, more efficient, more flexible, or easier to operate. Summary of the invention

[0007] The present disclosure relates to a method for preparing a compound of Formula 1 (including all stereoisomers and N-oxides of such compounds, and salts of such compounds):

[0008]

[0009] in

[0010] X is O or S;

[0011] Z is CR 7 or N;

[0012] R 1 is H, CH3, Cl or Br;

[0013] R 2 is H, Br, Cl or CN;

[0014] R 3 is H, C1-C4 alkyl or C4-C 10 Cycloalkylalkyl;

[0015] R 4 is Cl, Br, OCF2H, OCH2CF3; or C1-C4 alkyl optionally substituted by halogen; or C1-C4 alkyl substituted by Q;

[0016] R 5 is F, Cl or Br;

[0017] R 6 is H, F or Cl;

[0018] R 7 is H, F, Cl or Br; and

[0019] Q is a 5-membered or 6-membered aromatic heterocyclic ring, which is optionally substituted with one or more substituents independently selected from halogen, C1-C6 alkyl, C3-C6 cycloalkyl and C1-C6 haloalkyl;

[0020] The method comprises:

[0021] Combining (1) a carboxylic acid compound of Formula 2, (2) an aniline compound of Formula 3, and (3) a sulfonyl chloride to form a compound of Formula 1; wherein the method comprises a continuous process,

[0022]

[0023] Among them, Z, R 4 , R 5 , R 6 , R 7 and Q is as defined for the compound of Formula 1;

[0024]

[0025] Among them, X, R 1 , R 2 and R 3 As defined for compounds of formula 1. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 A flow chart illustrating a continuous process for preparing a compound of Formula 1 is shown, the continuous process comprising continuously adding 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 comprising the compound of Formula 1 to a quenching zone, wherein an anti-solvent is introduced; and transferring the quenched mixture comprising the compound of Formula 1 to a separation zone, wherein the anti-solvent, the optional solvent, and the optional base are removed.

[0027] Figure 2 A schematic diagram of a series of reactors, such as a reaction CSTR and a quenching CSTR, suitable for preparing the compound of Formula 1 by the continuous process of the present disclosure is shown.

[0028] Figure 3 A schematic diagram of a plurality of intermittent mixing tanks suitable for mixing the compound of Formula 2, the compound of Formula 3, a solvent, and a base for introduction into the reaction zone of the continuous process of the present disclosure is shown.

[0029] Figure 4 A schematic diagram of a feeding system suitable for powder mixing of a compound of Formula 2, a compound of Formula 3, a solvent and a base for introduction into a reaction zone of a continuous process of the present disclosure is shown.

[0030] Figure 5 A schematic diagram of a reaction zone of a continuous process of the present invention is shown, wherein the reaction zone includes a series of two continuously stirred tank reactors (CSTRs), which provide a combination of a first reaction sub-zone within the first CSTR and a second reaction sub-zone within the second CSTR, a mixture of a compound of Formula 2, a compound of Formula 3, a solvent and a base is introduced into the first reaction sub-zone, and a sulfonyl chloride such as methanesulfonyl chloride (MSC) is introduced into the first reaction sub-zone, and a reaction of the mixture with MSC is completed in the second reaction sub-zone.

[0031] Figure 6 A schematic diagram of a reaction zone of a continuous process of the present invention is shown, wherein the reaction zone comprises a combination of a plug flow reactor and a continuous stirred tank reactor, wherein a first reaction sub-zone is provided in the plug flow reactor, into which a mixture of a compound of Formula 2, a compound of Formula 3, a solvent and a base is introduced, and into which a sulfonyl chloride such as methanesulfonyl chloride (MSC) is introduced, and a second reaction sub-zone is provided in the continuous stirred tank reactor, in which a reaction of the mixture with MSC is completed.

[0032] Figure 7A schematic diagram of a reaction zone of a continuous process of the present disclosure is shown, the reaction zone comprising a series of two continuously stirred tank reactors (CSTRs) providing a combination of a first reaction sub-zone within the first CSTR and a second reaction sub-zone within the second CSTR, a mixture of a compound of Formula 2, a compound of Formula 3, a solvent and a base being introduced into the first reaction sub-zone, and methanesulfonyl chloride (MSC) being introduced into the first reaction sub-zone, with an additional methanesulfonyl chloride feed stream in the second reaction sub-zone.

[0033] Figure 8 A schematic diagram of an apparatus that can be used for the process of the present disclosure is shown, comprising a continuous stirred tank reactor combined with a solids concentrator (e.g., a hydrocyclone) that allows solids to be removed to a quenching zone and the reaction solution to be recycled to the continuous stirred tank reactor. DETAILED DESCRIPTION

[0034] As used herein, the terms "comprises," "comprising," "includes," "including," "has," "having," or any other variation thereof, are intended to cover a non-exclusive inclusion. For example, a composition, process, method, article, or apparatus that comprises 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 apparatus. In addition, unless expressly stated to the contrary, "or" refers to an inclusive "or" and not an exclusive "or." For example, any of the following satisfies condition A or B: A is true (or exists) and B is false (or does not exist); A is false (or does not exist) and B is true (or exists); and both A and B are true (or exist).

[0035] Moreover, the indefinite articles "a" and "an" before an element or component of the present invention are intended to be non-restrictive in terms of the number of instances (i.e., occurrences) of the element or component. Therefore, "a" and "an" should be understood to include one or at least one, and the singular form of an element or component also includes the plural form, unless the number obviously refers to the singular.

[0036] Combining chemicals means bringing the chemicals into contact with each other.

[0037] "Carbonyl group" refers to a monovalent molecular component comprising a carbon atom that connects the group to the rest of the chemical structure via a single bond.Carbonyl groups may optionally include saturated, unsaturated and aromatic groups, chains, rings and ring systems and heteroatoms. Although the size of the carbonyl group is not subject to any specific restrictions, in the context of the present disclosure, they typically include 1 to 16 carbon atoms and 0 to 3 heteroatoms. It is noteworthy that the carbonyl group is selected from C1-C6 alkyl, C1-C4 haloalkyl and phenyl groups optionally substituted by 1-3 substituents selected from C1-C3 alkyl, halogen and nitro.

[0038] In the description of this article, the abbreviation "Ph" refers to phenyl. Alkyl can be straight or branched. "Cycloalkyl" includes, for example, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The term "cycloalkylalkyl" represents that the cycloalkyl on the alkyl part replaces. Examples of "cycloalkylalkyl" include cyclopropylmethyl, cyclopropylethyl, cyclopentylethyl and other cycloalkyl parts bonded to straight or branched alkyl. Whether used alone or in compound words such as "haloalkyl", the term "halogen" includes fluorine, chlorine, bromine or iodine. In addition, when used in compound words such as "haloalkyl", the alkyl can be partially or completely replaced by halogen atoms, which can be the same or different. Examples of "haloalkyl" include F3C, ClCH2, BrCH2, CF3CH2 and CF3CCl2.

[0039] As described above, Q is a 5-membered or 6-membered aromatic heterocyclic ring, which is optionally substituted with one or more substituents selected from the substituents defined in the "Summary of the Invention". When Q is a 5-membered or 6-membered nitrogen-containing heterocyclic ring, it can be attached to the remainder of Formula 1 via any available carbon or nitrogen ring atom, unless otherwise specified. Examples of 5-membered or 6-membered aromatic heterocyclic rings optionally substituted with one or more substituents include rings U-2 to U-63 as shown below, wherein R V is any substituent as defined for Q in the Summary of the Invention, and r is an integer from 0 to 4, limited by the number of available positions on each U group. Since there is only one available position for 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, for these U groups, r is limited to an integer of 0 or 1, and r being 0 means that the U group is unsubstituted and hydrogen is present in the residue represented by (R v ) r At the indicated location.

[0040]

[0041]

[0042] In various embodiments, the Q group includes U-49 and U-50. In various embodiments, the U-49 group includes U-49 substituted with tert-butyl, cyclopropyl, CF2H, CF3, CF2CF3, CF2CF2CF3, or CF(CF3)2. In various embodiments, the U-50 group includes U-50 substituted with CF2H, CF3, CF2CF3, or CF(CF3)2. In some embodiments, the Q group is U-49 substituted with CF3.

[0043] There are several advantages to producing N-phenylpyrazole-1-carboxamide using a continuous process compared to the batch process implemented in WO 2006 / 062978. Continuous operation allows faster output from a given reactor and helps improve the safety of the process by minimizing the amount of reactive chemicals that may cause difficult to control reactions. Not all processes can be run in a continuous mode due to impurity formation or handling issues, for example, it has been found that the process described herein can be run in a continuous process at high yields without forming new impurities, which is of great significance for meeting current global pesticide registration requirements.

[0044] In addition, it is also found that, especially when feeding to the reaction zone of the partially converted material, running in a continuous mode may be beneficial to the final product particle size, which improves the convenience of its filtration and product concentration. In a typical batch process, it is necessary to use a high concentration of starting materials to run, which usually leads to the production of undissolved raw material solids, which will affect the crystallization of the final product, resulting in small and difficult to filter particles of the product. By continuously entering the reaction zone of the partially converted material, these solid raw materials are rapidly dissolved when entering the reaction zone, substantially eliminating their effect on crystallization. It is also found that as the conversion level to the compound of Formula 1 increases, the final product has a higher solubility in the reaction medium, which is also beneficial to crystallization and particle size by reducing the amount of supersaturation during crystallization.

[0045] Embodiments of the present disclosure may include the following embodiments.

[0046] Embodiment M1. The method comprises:

[0047] (a) combining a compound of Formula 2 with a compound of Formula 3 and a sulfonyl chloride; and

[0048] (b) isolating the compound of Formula 1, wherein the combining step (a) is performed in a continuous process.

[0049] Embodiment M1a. The method of Embodiment M1 wherein combining the compound of Formula 2 with the compound of Formula 3 and the sulfonyl chloride can be performed in the presence of a base and / or a solvent.

[0050] 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 can be continuously added to the reaction zone; and the separation step (b) can include continuously removing the compound of Formula 1 from the reaction zone after the compound of Formula 1 is formed.

[0051] Embodiment M2a. The process of Embodiment M2 wherein optionally a solvent and / or a base may also be added continuously to the reaction zone.

[0052] Embodiment M3. The method of Embodiment M1 or Embodiment M2, wherein the feed rate of the compound of Formula 2, the compound of Formula 3, and the sulfonyl chloride and the removal rate of the compound of Formula 1 can be adjusted to provide an average residence time in the reaction zone of two hours or less.

[0053] Embodiment M3a. The process of Embodiment M3 wherein the optional solvent and / or base are continuously added to and removed from the reaction zone at a rate adjusted to provide an average residence time in the reaction zone of two hours or less.

[0054] 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.

[0055] Embodiment M5. The method of any of Embodiments M1 to M4, wherein at least a portion of the compound of Formula 1 can be separated from the process medium.

[0056] Embodiment M6. The method of any of Embodiments M1 to M5, wherein the separation step can include (b1) quenching the reaction of the compound of Formula 2, 3 with the sulfonyl chloride to precipitate the compound of Formula 1, and (b2) filtering the compound of Formula 1 from the process medium.

[0057] Embodiment M7. The method of Embodiment M6, wherein the quenching step (b1) can be performed by adding an anti-solvent such as water to the reaction stream in the quenching zone.

[0058] Embodiment M8. The method of Embodiment M7, wherein the added water can be characterized by a neutral, acidic, or basic pH, or the added water can be present sequentially at different pH values ​​in multiple separate quenching zones.

[0059] Embodiment M9. The method of any one of Embodiments M1 to M8, further comprising drying the compound of Formula 1.

[0060] Embodiment M10. The method of any one of Embodiments M1 to M9, wherein the combining step (a) can be performed in an inert atmosphere at atmospheric pressure.

[0061] Embodiment M11. The method of any of Embodiments M1 to M10, wherein the reaction zone can comprise a single reactor vessel.

[0062] Embodiment M12. The method of any one of Embodiments M1 to M10, wherein the reaction zone comprises a plurality of reaction subzones, each subzone having an independent average residence time and temperature.

[0063] Embodiment M13. The method of Embodiment M12, wherein the reaction zone comprises a first reactor vessel and a second reactor vessel.

[0064] Embodiment M14. The method of any of Embodiments M1 to M13, wherein the reaction zone comprises a plug flow reactor, a continuous stirred tank reactor, or a combination thereof.

[0065] Embodiment M15. The method of any one of Embodiments M1 to 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.

[0066] 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.

[0067] 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.

[0068] 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.

[0069] Embodiment M19. The method of Embodiment M18 wherein the molar ratio of sulfonyl chloride to the compound of Formula 2 is from about 1:1 to about 2.5:1.

[0070] Embodiment M20. The method of Embodiment M19 wherein the molar ratio of sulfonyl chloride to the compound of Formula 2 is from about 1.1:1 to about 1.4:1.

[0071] Embodiment M21. The method of any one of Embodiments M1 to M18, wherein when R2 is Br or Cl, then the molar ratio of sulfonyl chloride to the compound of Formula 2 is about 1.2:1.

[0072] Embodiment M22. The method of any one of Embodiments M1 to M18, wherein when R2 is CN, the molar ratio of sulfonyl chloride to the compound of Formula 2 is about 1.4:1.

[0073] Embodiment M23. The method of any one of Embodiments M1 to M22, wherein the sulfonyl chloride has Formula 4:

[0074] R8 S(O)2Cl 4

[0076] Where R 8 A carbon-based group.

[0077] Embodiment M24. The method of Embodiment M23, wherein R 8 is C1-C4 alkyl, C1-C2 haloalkyl or phenyl optionally substituted by 1 to 3 substituents selected from halogen, C1-C3 alkyl and nitro.

[0078] Embodiment M25. The method of Embodiment M24, wherein R 8 It is C1-C2 alkyl, CF3, phenyl or 4-methylphenyl.

[0079] Embodiment M26. The method of Embodiment M25, wherein R 8 It is C1-C2 alkyl, phenyl or 4-methylphenyl.

[0080] Embodiment M27. The method of Embodiment M26, wherein R 8 For CH3.

[0081] 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 about -70 to about 100 °C.

[0082] Embodiment M29. The method of Embodiment M28, wherein the temperature is from about -20 to about 40°C.

[0083] Embodiment M30. The method of Embodiment M26, wherein the temperature is from about -10 to about 30°C.

[0084] Embodiment M31. The method of any of Embodiments M1 through M30, wherein the carboxylic acid of Formula 2 can be combined with the aniline of Formula 3 to form a mixture, which is then combined with the sulfonyl chloride.

[0085] Embodiment M32. The method of any of Embodiments M1 to M31, wherein a base can be combined with the compound of Formula 2 and Formula 3 and the sulfonyl chloride.

[0086] Embodiment M33. The method of Embodiment M32 wherein the base can be combined with the mixture before or after combining with the sulfonyl chloride.

[0087] Embodiment M34. The method of Embodiment M33 wherein a base can be combined with the compounds of Formula 2 and Formula 3 to form a mixture and then combined with the sulfonyl chloride.

[0088] Embodiment M35. The method of any one of Embodiments M32 to M34, wherein the amount of the base is at least about 2 equivalents relative to the sulfonyl chloride.

[0089] Embodiment M36. The method of Embodiment M35 wherein the amount of base is at least about 2.1 equivalents relative to the sulfonyl chloride.

[0090] Embodiment M37. The method of Embodiment M36 wherein the amount of the base is about 2.1 to 2.2 equivalents relative to the sulfonyl chloride.

[0091] Embodiment M38. The method of any one of Embodiments M32 to M37 wherein the base is selected from tertiary amines, including optionally substituted pyridines.

[0092] Embodiment M39. The method of Embodiment M38 wherein the base is selected from optionally substituted pyridines and mixtures thereof.

[0093] Embodiment M40. The method of Embodiment M39 wherein the base is selected from the group consisting of 2-picoline, 3-picoline, 2,6-lutidine, pyridine, and mixtures thereof.

[0094] Embodiment M41. The method of Embodiment M40 wherein the base is 3-methylpyridine.

[0095] Embodiment M42. The method of any of Embodiments M1 through M41, wherein a solvent can be combined with the compounds of Formula 2 and Formula 3 and the sulfonyl chloride.

[0096] Embodiment M43. The method of Embodiment M42 wherein a solvent is combined with the compounds of Formula 2 and Formula 3 to form a mixture prior to combining with the sulfonyl chloride.

[0097] Embodiment M44. The method of Embodiment M43 wherein the base is combined with the compound of Formula 2 and Formula 3 and a solvent and heated to form a solution prior to combining with the sulfonyl chloride.

[0098] Embodiment M45. The method of Embodiment M43, wherein the base is mixed with the compounds of Formula 2 and Formula 3 and a solvent to form a slurry and then combined with the sulfonyl chloride.

[0099] Embodiment M46. The method of any one of Embodiments M42 to M45, wherein the solvent can be 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), halogenated alkanes (e.g., dichloromethane, chloroform), 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, dialkyl o-aminobenzamides, optionally substituted pyridines), and mixtures thereof.

[0100] Embodiment M47. The method of Embodiment M46 wherein the solvent is selected from tertiary amines (eg, trialkylamines, dialkyl anthranilamides, optionally substituted pyridines), and mixtures thereof.

[0101] 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), halogenated alkanes (e.g., dichloromethane, chloroform), ethers (e.g., diethyl ether, methyl tert-butyl ether, tetrahydrofuran, p-dioxane), aromatic hydrocarbons (e.g., benzene, toluene, chlorobenzene, dichlorobenzene) and mixtures thereof.

[0102] Embodiment M49. The method of Embodiment M48 wherein the solvent is acetonitrile.

[0103] Embodiment M50. The method of any one of Embodiments M1 to M49 further comprising treating a compound of Formula 1 with a halogenating agent, wherein R 1 is H, to provide a compound of Formula 1, wherein R 1 It is Cl or Br.

[0104] Embodiment M51. The method of any one of Embodiments M1 to M49, further comprising treating a compound of Formula 1 with a halogenating agent, wherein R 2 is H, to provide a compound of Formula 1, wherein R 2 It is Cl or Br.

[0105] In various embodiments, the methods of the present disclosure can be used to prepare compounds of Formula 1. Accordingly, the present invention includes the following embodiments.

[0106] Embodiment C1. Methods of Embodiments M1 to M51 for preparing compounds of Formula 1,

[0107]

[0108] in

[0109] X is O or S;

[0110] Z is CR 7 or N;

[0111] R 1 is H, CH3, Cl or Br;

[0112] R 2 is H, Br, Cl or CN;

[0113] R 3 is H, C1-C4 alkyl or C4-C 10 Cycloalkylalkyl;

[0114] R 4 is Cl, Br, OCF2H, OCH2CF3; or C1-C4 alkyl optionally substituted by halogen; or C1-C4 alkyl substituted by Q;

[0115] R 5 is F, Cl or Br;

[0116] R 6 is H, F or C1;

[0117] R 7 is H, F, Cl or Br; and

[0118] Q is a 5-membered or 6-membered aromatic heterocyclic ring optionally substituted with one or more substituents independently selected from halogen, C1-C6 alkyl, C3-C6 cycloalkyl and C1-C6 haloalkyl.

[0119] Embodiment C2. The method of any one of Embodiments M1 to M51 wherein in the compound of Formula 3, X is O.

[0120] Embodiment C3. The method of any one of Embodiments M1 to M51 wherein in the compound of Formula 3, X is S.

[0121] Embodiment C4. The method of any one of Embodiments C1 to C3, wherein in the compound of Formula 3, R 1 For Cl.

[0122] Embodiment C5. The method of any one of Embodiments C1 to C3, wherein in the compound of Formula 3, R 1 For Br.

[0123] Embodiment C6. The method of any one of Embodiments C1 to C3, wherein in the compound of Formula 3, R 1 For H.

[0124] Embodiment C7. The method of any one of Embodiments C1 to C6, wherein in the compound of Formula 3, R 2 It is Br or Cl.

[0125] Embodiment C8. The method of any one of Embodiments C1 to C6, wherein in the compound of Formula 3, R 2 For H.

[0126] Embodiment C9. The method of any one of Embodiments C1 to C6, wherein in the compound of Formula 3, R 2 For CN.

[0127] Embodiment C10. The method of any one of Embodiments C1 to C9, wherein in the compound of Formula 3, R 3 It is a C1-C4 alkyl group.

[0128] Embodiment C11. The method of Embodiment C10, wherein R 3 It is methyl.

[0129] Embodiment C12. The method of Embodiment C10, wherein R 3 It is ethyl.

[0130] Embodiment C13. The method of Embodiment C10, wherein R 3 It is isopropyl.

[0131] Embodiment C14. The method of any one of Embodiments C1 to C9, wherein in the compound of Formula 3, R 3 C4-C 10 Cycloalkylalkyl.

[0132] Embodiment C15. The method of Embodiment C14, wherein R 3 It is 1-(cyclopropyl)ethyl.

[0133] Embodiment C16. The method of any one of Embodiments C1 to C15, wherein in the compound of Formula 2, Z is N.

[0134] Embodiment C17. The method of any one of Embodiments C1 to C16, wherein in the compound of Formula 2, R 4 It is Cl or Br.

[0135] Embodiment C18. The method of any one of Embodiments C1 to C16, wherein in the compound of Formula 2, R 4 is C1-C4 alkyl optionally substituted by halogen or C1-C4 alkyl substituted by Q.

[0136] Embodiment C19. The method of Embodiment C18, wherein R 4 It is a C1-C4 alkyl group.

[0137] Embodiment C20. The method of Embodiment C19, wherein R 4It is methyl.

[0138] Embodiment C21. The method of Embodiment C18, wherein R 4 It is a C1-C4 alkyl group substituted by halogen.

[0139] Embodiment C22. The method of Embodiment C21, wherein R 4 It is CF3.

[0140] Embodiment C23. The method of Embodiment C21, wherein R 4 It is CH2Br.

[0141] Embodiment C24. The method of Embodiment C18, wherein R 4 is a C1-C4 alkyl group substituted by a 5-membered aromatic heterocyclic ring, wherein the 5-membered aromatic heterocyclic ring is optionally substituted by one or more substituents independently selected from halogen, C1-C6 alkyl, C3-C6 cycloalkyl and C1-C6 haloalkyl.

[0142] Embodiment C25. The method of Embodiment C24, wherein R 4 It is 5-(trifluoromethyl)-2H-tetrazol-2-ylmethyl.

[0143] Embodiment C26. The method of any one of Embodiments C1 to C25, wherein in the compound of Formula 2, R 5 For Cl.

[0144] Embodiment C27. The method of any one of Embodiments C1 to C26, wherein in the compound of Formula 2, R 6 For H.

[0145] Embodiment C28. The method of any one of Embodiments C1 to C27, wherein in the compound of Formula 2, R 6 For Cl.

[0146] Embodiment C29. The method of Embodiment C1 wherein in the compound of Formula 1, X is O.

[0147] Embodiment C30. The method of Embodiment C1 wherein in the compound of Formula 1, X is S.

[0148] Embodiment C31. The method of any one of Embodiments C29 to C30, wherein in the compound of Formula 1, R 1 For Cl.

[0149] Embodiment C32. The method of any one of Embodiments C29 to C30, wherein in the compound of Formula 1, R 1 For Br.

[0150] Embodiment C33. The method of any one of Embodiments C29 to C30, wherein in the compound of Formula 1, R 1 For H.

[0151] Embodiment C34. The method of any one of Embodiments C29 to C33, wherein in the compound of Formula 1, R 2 is Br or Cl.

[0152] Embodiment C35. The method of any one of Embodiments C29 to C33, wherein in the compound of Formula 1, R 2 For H.

[0153] Embodiment C36. The method of any one of Embodiments C29 to C33, wherein in the compound of Formula 1, R 2 For CN.

[0154] Embodiment C37. The method of any one of Embodiments C29 to C36, wherein in the compound of Formula 1, R 3 It is a C1-C4 alkyl group.

[0155] Embodiment C38. The method of Embodiment C37, wherein R 3 It is methyl.

[0156] Embodiment C39. The method of Embodiment C37, wherein R 3 It is ethyl.

[0157] Embodiment C40. The method of Embodiment C37, wherein R 3 It is isopropyl.

[0158] Embodiment C41. The method of any one of Embodiments C29 to C36, wherein in the compound of Formula 1, R 3 C4-C 10 Cycloalkylalkyl.

[0159] Embodiment C42. The method of Embodiment C41, wherein R 3 It is 1-(cyclopropyl)ethyl.

[0160] Embodiment C43. The method of any one of Embodiments C29 to C42, wherein in the compound of Formula 1, Z is N.

[0161] Embodiment C44. The method of any one of Embodiments C29 to C43, wherein in the compound of Formula 1, R 4 It is Cl or Br.

[0162] Embodiment C45. The method of any one of Embodiments C29 to C43, wherein in the compound of Formula 1, R 4It is a C1-C4 alkyl group optionally substituted by halogen, or a C1-C4 alkyl group substituted by a 5-membered or 6-membered aromatic heterocyclic ring optionally substituted by a C1-C2 haloalkyl group.

[0163] Embodiment C46. The method of Embodiment C45, wherein R 4 It is a C1-C4 alkyl group.

[0164] Embodiment C47. The method of Embodiment C46, ​​wherein R 4 It is methyl.

[0165] Embodiment C48. The method of Embodiment C45, wherein R 4 It is a C1-C4 alkyl group substituted by halogen.

[0166] Embodiment C49. The method of Embodiment C48, wherein R 4 It is CF3.

[0167] Embodiment C50. The method of Embodiment C48, wherein R 4 It is CH2Br.

[0168] Embodiment C51. The method of Embodiment C45, wherein R 4 is a C1-C4 alkyl group substituted by a 5-membered aromatic heterocyclic ring, and the 5-membered aromatic heterocyclic ring is optionally substituted by a C1-C2 haloalkyl group.

[0169] Embodiment C52. The method of Embodiment C51, wherein R 4 It is 5-(trifluoromethyl)-2H-tetrazol-2-ylmethyl.

[0170] Embodiment C53. The method of any one of Embodiments C29 to C52, wherein in the compound of Formula 1, R 5 For Cl.

[0171] Embodiment C54. The method of any one of Embodiments C29 to C53, wherein in the compound of Formula 1, R 6 For H.

[0172] Embodiment C55. The method of any one of Embodiments C29 to C53, wherein in the compound of Formula 1, R 6 For Cl.

[0173] Embodiments of the present invention, including the above-mentioned embodiments M1 to M51 and C1 to C55 and any other embodiments described herein, can be combined in any manner, and the description of the variables in the embodiments relates not only to the compound of Formula 1, but also to the starting compounds and intermediate compounds used to prepare the compound of Formula 1, including compounds of Formulas 2, 3 and 4. In addition, embodiments of the present invention, including the above-mentioned embodiments M1 to M51 and C1 to C55 and any other embodiments described herein, and any combination thereof, relate to the compositions and methods of the present invention.

[0174] Embodiment A1. The method of any one of Embodiments M1 to M51, comprising a compound of Formula 3, wherein X is O; R 1 CH3; R 2 is H, Cl, Br or CN; and R 3 It is CH3 or CH2CH3.

[0175] Embodiment A2. The method of Embodiment A1, comprising a compound of Formula 3, wherein X is O; R 1 CH3; R 2 is Cl or CN; and R 3 For CH3.

[0176] Embodiment A3. The method of Embodiment A1, comprising a compound of Formula 3, wherein X is O; R 1 CH3; R 2 is H or Br; and R 3 It is CH3 or CH2CH3.

[0177] Embodiment A4. The method of any one of Embodiments M1 to M51, comprising a compound of Formula 3, wherein X is O or S; R 1 Cl; R 2 is Cl; and R 3 It is CH(CH3)2.

[0178] Embodiment A5. The method of any one of Embodiments M1 to M51, comprising a compound of Formula 3, wherein X is O; R 1 is H or Br; R 2 is Cl; and R 3 It is 1-(cyclopropyl)ethyl.

[0179] Embodiment A6. The method of any one of Embodiments M1 to M51, comprising a compound of Formula 2, wherein Z is N; R 4 Br; R 5 is Cl; and R 6 is H or Cl.

[0180] Embodiment A7. The method of any one of Embodiments M1 to M51, comprising a compound of Formula 2, wherein Z is N; R 3 is CH3, CH2Br or 5-(trifluoromethyl)-2H-tetrazolyl-2-ylmethyl; R 5 is Cl; and R 6 For H.

[0181] Embodiment A8. The method of any one of Embodiments M1 to M51, comprising a compound of Formula 1, wherein X is O; R 1 CH3; R 2 is H, Cl, Br or CN; and R 3 It is CH3 or CH2CH3.

[0182] Embodiment A9. The method of Embodiment A8, comprising a compound of Formula 1, wherein X is O; R 1 CH3; R 2 is Cl or CN; and R 3 For CH3.

[0183] Embodiment A10. The method of Embodiment A8, comprising a compound of Formula 1, wherein X is O; R 1 CH3; R 2 is H or Br; and R 3 It is CH3 or CH2CH3.

[0184] Embodiment A11. The method of any one of Embodiments M1 to M51, comprising a compound of Formula 1, wherein X is O or S; R 1 Cl; R 2 Cl; R 3 It is CH(CH3)2.

[0185] Embodiment A12. The method of any one of Embodiments M1 to M51, comprising a compound of Formula 1, wherein X is O; R 1 is H or Br; R 2 is Cl; and R 3 It is 1-(cyclopropyl)-ethyl.

[0186] Embodiment A13. The method of any one of Embodiments M1 to M51, comprising a compound of Formula 1, wherein Z is N; R 4 Br; R 5 is Cl; and R 6 is H or Cl.

[0187] Embodiment A14. The method of any one of Embodiments M1 to M51, comprising a compound of Formula 1, wherein Z is N; R 3is CH3, CH2Br or 5(trifluoromethyl)-2H-tetrazolyl-2-ylmethyl; R 5 is Cl; and R 6 For H.

[0188] Embodiment A15. The method of any one of Embodiments M1 to M51, comprising a compound of Formula 1, wherein X is O; Z is N; R 1 CH3; R 2 is H, Cl, Br or CN; R 3 is CH3 or CH2CH3; R 4 Br; R 5 is Cl; and R 6 For H.

[0189] Embodiment A16. The method of any one of Embodiments M1 to M51, comprising a compound of Formula 1, wherein X is O or S; Z is N; R 1 Cl; R 2 Cl; R 3 is CH3 or CH(CH3)2; R 4 Br; R 5 is Cl; and R 6 is H or Cl.

[0190] Specific embodiments of the present invention include the method of any one of embodiments M1 to M51, C1 to C55 and A1 to A16 for preparing a compound of Formula 1 selected from the following:

[0191] 3-bromo-N-[4-chloro-2-methyl-6-[(methylamino)carbonyl]phenyl]-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxamide (also known as chlorantraniliprole),

[0192] 3-bromo-1-(3-chloro-2-pyridinyl)-N-[4-cyano-2-methyl-6-[(methylamino)carbonyl]phenyl]-1H-pyrazole-5-carboxamide (also known as cyantraniliprole),

[0193] 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

[0194] 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).

[0195] In the following schemes, unless otherwise indicated, in the compounds of the following formulae 1 to 41, Q, X, Z, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 The definition of is as defined above in the Summary of the Invention and the description of the embodiments. The compounds of Formulae 2a to 2f are a subset of Formula 2, and the compounds of Formulae 3a to 3c are a subset of Formula 3.

[0196] As shown in Scheme 1, the present disclosure relates to a process for preparing compounds 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.

[0197] Solution 1

[0198]

[0199] Thus, in the present method, a pyrazolecarboxylic 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.

[0200] like Figure 1 As shown, the continuous process 100 includes continuously adding a compound of Formula 2, a compound of Formula 3, and a sulfonyl chloride to a reaction zone 110, where they can combine to provide the corresponding compound of Formula 1. As used herein, the term "reaction zone" refers to a location in a continuous process stream where the compound of Formula 2, the compound of Formula 3, the sulfonyl chloride, and / or any moiety derived therefrom are sufficiently close that they can contact each other and combine to form a compound of Formula 1. As described in more detail below, an optional solvent and / or an optional base can also be continuously added to the reaction zone to promote the reaction.

[0201] In various embodiments, at least a portion of the compound of Formula 1 can then be continuously removed from reaction zone 110 to quenching zone 120, where it is contacted with an anti-solvent, which is described in more detail below. Suitable anti-solvents can include any solvent capable of precipitating the compound of Formula 1. In some embodiments, suitable anti-solvents include water. After quenching, the compound of Formula 1 can be separated from liquid process components and water-soluble reaction byproducts in separation step 130 by, for example, crystallization and / or filtration.

[0202] In other embodiments, at least a portion of the compound of Formula 1 can be isolated directly using any suitable separation technique known to those skilled in the art, such as crystallization or filtration, avoiding any quenching step.

[0203] Suitable for Figure 1 A simplified schematic diagram of a processing system 200 for the continuous process 100 is shown in Figure 2 The treatment system 200 includes a series of three continuously stirred tank reactors (CSTRs) 210, 220, 230. In various embodiments, a CSTR is defined as a reactor in which the contents of the reactor are generally well mixed (e.g., by stirring, agitation, aeration mixing, or fluid impact), but can range from "high mixing" (at which point the chemical concentration and temperature observed in the reactor are substantially unchanged) to a mixing level close to "non-mixing" (which means that local concentrations and temperatures may vary greatly). The first CSTR 210 includes an intermittent mixing zone 211, in which 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 solid and can be added as is by well-known powder addition methods such as from a hopper and / or via a metering screw feed. Alternatively, one or both of the compounds of Formula 2 and Formula 3 can be dissolved in a solvent before being introduced into the mixing zone. In some embodiments, if desired, the batch mixture can be optionally heated to provide a solution in which the base, the compound of Formula 2, and the compound of Formula 3 are all dissolved in a solvent. In other embodiments, one or more of the base, the compound of Formula 2, and the compound of Formula 3 remain as solids suspended in a solvent, thereby providing a slurry.

[0204] After mixing, the solution or slurry is continuously pumped to a second CSTR 220 having a reaction zone 221, including a reaction zone 221 in which a sulfonyl chloride such as methylsulfonyl chloride (MSC) is continuously added to the mixture. In the second CSTR 220, sulfonyl chloride, a compound of formula 2, and a compound of formula 3 are combined to form a compound of formula 1. In various embodiments, substantially all compounds of formula 2 and compounds of formula 3 are consumed to form a compound of formula 1. In some embodiments, at least a portion of the compound of formula 1 can be precipitated from the reaction mixture after its formation. In various embodiments, the compound of formula 1 can be continuously removed from the reaction zone, such as in the form of a slurry in a solvent, and continuously added to a third CSTR 230 including a quenching zone 231. The compound of formula 1 can then be transferred to a separation device 240 such as a centrifuge or a continuous filter and dried in a drying zone 250 such as a continuous dryer.

[0205] After the initial startup period in which the reaction zone reactor is filled to the desired volume, the introduction and removal rates may be substantially constant or variable (e.g., introduction and / or removal may be intermittent), but the average balance is to reach the desired residence time in the reaction zone. For example, the rates of introduction and removal during a continuous process are not zero at the same time. Alternatively, intermittent introduction and / or removal may be used to connect a continuous process to an upstream (e.g., intermittent feeding of one or more reactants) or downstream intermittent processing equipment and / or steps. Desirably, the rate at which compounds of Formula 2 and Formula 3 are introduced into the reaction zone and the compounds of Formula 1 are removed may be adjusted so that the average residence time in the reaction zone of the compound derived from Formula 2 and Formula 3 and incorporated into the compound of Formula 1 is long enough to provide a conversion rate greater than about 85, 90, 95, or 98%. For example, the average residence time in the reaction zone may be from about 15 minutes to about 2 hours, such as from about two hours or less, or from about one hour or less, from about 30 minutes or less, or from about 15 minutes or less. Mean residence time is defined as the average amount of time a given molecule spends in a reaction zone (or quenching zone as discussed below). Although residence time distribution may be wide (i.e., some molecules can leave the reaction zone quickly, while other molecules remain longer in the same reaction zone), mean residence time is generally defined as the reactor volume in the reaction zone (or quenching zone) divided by the average flow rate of the feed stream. Although the reaction of the compound of Formula 2 and Formula 3 with sulfonyl chloride is relatively fast, in some embodiments, it may be necessary to have a mean residence time longer than the mean residence time required to achieve the desired conversion level, to reduce equipment fouling, improve the interface with other methods, improve crystal properties, for example, allow more effective recovery of the compound of obtained Formula 1, or for other reasons. In various embodiments, each reactor in the reaction zone operates at an independent residence time and temperature.

[0206] Various equipment can be used to carry out the continuous reaction. The process can include, but is not limited to, the use of: a continuous stirred tank reactor (CSTR), a plug flow reactor (PFR), a fluidized bed reactor, a packed bed reactor, a continuous crystallizer, a static mixer, a reactive distillation column, and any combination of these. Examples of CSTRs can be anything from a conventional stirred vessel to the pumping zone of a centrifugal pump. A plug flow reactor (PFR) can be as simple as a flow through a pipe, or more complex, such as a shell and tube exchanger or a plate and frame exchanger. Typically, a PFR has a significant difference between the inlet and outlet concentrations of the reactor.

[0207] As referenced above Figure 2 As discussed, the compounds of Formula 2 and Formula 3 may be mixed, optionally with a solvent and / or a base, prior to introducing them into the reaction zone. Figure 3A schematic diagram of multiple intermittent mixing tanks 300 suitable for mixing a compound of Formula 2, a compound of Formula 3, a solvent, and a base for introduction into a reaction zone of a continuous process of the present disclosure is shown. The multiple intermittent mixing tanks 300 allow a first intermittent mixing tank 310 to be charged and optionally heated to provide a first batch of mixture 311 introduced into the reaction zone. When the contents of the first intermittent mixing tank are discharged into the reaction zone, a second intermittent mixing tank 320 can be charged and optionally heated to prepare a second batch of mixture 321 subsequently introduced into the reaction zone.

[0208] Figure 4 A schematic diagram of an alternative feeding system 400 suitable for powder mixing of a compound of Formula 2, a compound of Formula 3, a solvent, and a base for introduction into a reaction zone of a continuous process of the present disclosure is shown. In this embodiment, the base is introduced into a solvent stream 401 passing through a process apparatus, and then the compound of Formula 2 is introduced downstream, which is substantially continuously fed (e.g., fed from a metering screw) from a first solid hopper 410 into the solvent stream 401. Similarly, the compound of Formula 3 is fed from a second solid hopper 420 into the solvent stream 401 downstream of the first solid hopper 410 before entering the reaction zone 430. There, a sulfonyl chloride is fed into the solvent stream, where it can react with the compound of Formula 2 to form an intermediate, which reacts with the compound of Formula 3 to provide a compound of Formula 1. In various embodiments, the base can also be added at more points downstream in the solvent stream, as well as directly into the reaction zone 430. The compound of Formula 1 can then be transferred from the reaction zone 430 to the quenching zone 440.

[0209] Figure 5 A schematic diagram of a series of two continuous stirred tank reactors 500 is shown, which provides a combination of a first reaction sub-zone 510 and a second reaction sub-zone 520 in the reaction zone of the continuous process of the present disclosure, and each reaction sub-zone includes a continuous stirred tank reactor. As used herein, the term "sub-zone" refers to a place (such as a container) in a reaction zone or a quenching zone (see below, wherein a set of given process parameters are adopted). In the first reaction sub-zone 510, all components of the reaction mixture are introduced, mixed and reacted at least partially. In the second reaction sub-zone 520, the reaction can be carried out to complete (i.e., reaching the desired conversion level) and provide a compound of formula 1 in a form that promotes its separation, such as forming a crystal size that is convenient for rapid filtration. Therefore, the second reaction sub-zone 520 can also be referred to as a completion zone. The volume, average residence time, temperature, mixing and / or other process parameters in the first and second reaction sub-zones 510, 520 may be the same or different. For example, the temperature in the first reaction sub-zone 510 may be higher than the temperature in the second reaction sub-zone 520.

[0210] Figure 6A schematic diagram showing a combination of a first reaction sub-zone 610 including a plug flow reactor 611 and a second reaction sub-zone 620 including a continuous stirred tank reactor 621 in a reaction zone 600 of a continuous process of the present disclosure is shown. Figure 5 As discussed, the first reaction sub-zone 610 provides mixing and at least partial conversion of the components of the process, while the second reaction sub-zone 620 can provide finishing conditions.

[0211] Figure 7 A schematic diagram of a series of two continuous stirred tank reactors 700 is shown to provide a combination of a first reaction sub-zone 710 including a continuous stirred tank reactor 711 and a second reaction sub-zone 720 including a continuous stirred tank reactor 721 with an additional sulfonyl chloride feed stream 730 in the reaction zone of the continuous process of the present disclosure. This can allow for a more controlled addition of sulfonyl chloride. It can also allow for the addition of additional sulfonyl chloride if some of the sulfonyl chloride is consumed in the formation of the cyclo-1 compound (see below).

[0212] In any combination of first and second reaction sub-zones, transfer between zones can allow online monitoring ( Figure 5 , 6 or 7) reaction progress and allows adjustment of process parameters in the second reaction sub-zone.

[0213] Figure 8 A schematic diagram of a continuous stirred tank reactor with a solid concentrator 820 (e.g., a hydrocyclone) is shown, which allows solids (e.g., compounds of Formula 1) to be preferentially removed to the quenching zone while a recycle stream 820 of the reaction solution is sent back to the continuous stirred tank reactor reaction zone 810. This circulation loop can allow the reaction to be carried out at lower reactant concentrations without the yield loss associated with operating under dilute conditions, which is advantageous for reaction selectivity, crystal formation, and slurry handling. It can also allow online monitoring of the reaction.

[0214] Although a wide range of reactant ratios is possible, the nominal molar ratio of the compound of Formula 3 to the compound of Formula 2 is generally about 0.9 to 1.1, or about 1.0, so that both compounds can be fully consumed. The process can be carried out over a wide range of temperatures, for example, in the temperature range of -70°C to +100°C, or -20°C to +40°C or -10°C to +30°C for reasons of ease of operation, favorable reaction rates and selectivity, high process yields, etc. In some embodiments, the temperature is 30°C to 60°C.

[0215] The sulfonyl chloride compound is used as a reactant to promote the coupling of the carboxylic acid of Formula 2 with the aniline of Formula 3 to form the N-phenylpyrazole-1-carboxamide of Formula 1. When the cyclization side reaction described below occurs to no more than a small extent (i.e., 0-10%), the nominal molar ratio of the sulfonyl chloride to the compound of Formula 2 is generally about 1.0 to 2.5, or about 1.1 to 1.4. The sulfonyl chloride generally has the formula R 8 S(O)2Cl (Formula 4), where R 8 For this method, usually R 8 is C1-C4 alkyl, C1-C2 haloalkyl or phenyl optionally substituted by 1-3 substituents selected from the group consisting of halogen, C1-C3 alkyl and nitro. Sulfonyl chloride compounds suitable for use in the present method because they are commercially available include methanesulfonyl chloride (R 8 =CH3), propanesulfonyl chloride (R 8 (CH2)2CH3), benzenesulfonyl chloride (R 8 is Ph) and p-toluenesulfonyl chloride (R 8 In some embodiments, methanesulfonyl chloride is used for reasons of reduced cost, ease of addition, and / or reduced waste.

[0216] In the present method, sulfonyl chloride is combined with pyrazole carboxylic acid of formula 2 and aniline of formula 3. The reactants can be combined in various orders, such as combining sulfonyl chloride with carboxylic acid of formula 2 to form a mixture, and then combining the mixture with aniline of formula 3. However, in various embodiments for preparing a specific N-phenylpyrazole-1-carboxamide of formula 1, the order of combination can include combining carboxylic acid of formula 2 with aniline of formula 3 to form a mixture, and then combining sulfonyl chloride with the mixture (e.g., adding sulfonyl chloride to a mixture of compounds of formula 2 and formula 3), because this order of addition allows for convenient control of the coupling process. The reaction rate can be easily controlled by controlling the addition rate of the sulfonyl chloride compound. Therefore, one embodiment of the present method includes the following sequential steps: (1) combining carboxylic acid of formula 2 with aniline of formula 3 to form a mixture, and (2) then combining the mixture with sulfonyl chloride. Although adding sulfonyl chloride to a mixture containing aniline of formula 2 may result in undesirable side reactions, the stereoelectronic distribution of compounds of formula 2 and formula 3 helps to obtain compounds of formula 1 in significantly high yields using the present method.

[0217] When the starting compound of formula 2 and formula 3 and sulfonyl chloride contact each other in the combined liquid phase, the compound of formula 1 is formed, wherein in the combined liquid phase, each of the starting compound of formula 2 and formula 3 and sulfonyl chloride is at least partially soluble. In particular, because the raw materials of formula 2 and formula 3 are generally solid at ordinary ambient temperatures, the method is most satisfactorily carried out using a solvent in which the starting compound has significant solubility. Therefore, the method is usually carried out in a liquid phase comprising a solvent. In some cases, the carboxylic acid of formula 2 may have only a slight solubility, but the salt thereof and the added alkali may have a greater solubility in a solvent. Solvents suitable for use in the 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), methyl butyl ketone; halogenated alkanes such as dichloromethane and chloroform; ethers such as diethyl ether, methyl tert-butyl ether, tetrahydrofuran (THF) and p-dioxane; aromatic hydrocarbons such as benzene, toluene, chlorobenzene and dichlorobenzene; tertiary amines such as trialkylamines, dialkylanilines and optionally substituted pyridines; and mixtures thereof. Notable solvents include acetonitrile, propionitrile, ethyl acetate, acetone, MEK, dichloromethane, methyl tert-butyl ether, THF, p-dioxane, toluene and chlorobenzene. Acetonitrile is a particularly notable solvent because it can generally provide the product in excellent yield and / or purity.

[0218] Since the reaction of the present method produces hydrogen chloride as a byproduct, which would otherwise bind to the basic centers of the compounds of formulas 1, 2, and 3, it is most desirable that the method be carried out in the presence of at least one added base. The base can also promote the beneficial 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 may have a greater solubility in the reaction medium than the carboxylic acid. Although the base can be added at the same time as the addition of the sulfonyl chloride, alternately with the sulfonyl chloride, or even after the addition of the sulfonyl chloride, the base is usually added before the addition of the sulfonyl chloride. Some solvents such as tertiary amines are also used as bases, and when these substances are used as solvents, they are used as bases in large stoichiometric excess. When the base is not used as a solvent, the nominal molar ratio of the added base to the added sulfonyl chloride is generally 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-methylpyridine, 3-methylpyridine, 2,6-lutidine, and pyridine. In one embodiment, a suitable base is 3-methylpyridine, since its salt with the carboxylic acid of Formula 2 is generally highly soluble in solvents such as acetonitrile.

[0219] The features of the present method provide efficient production of N-phenylpyrazole-1-carboxamide of formula 1 while limiting the amount of carboxylic acid, sulfonyl chloride and aniline consumed during the formation of N-phenylpyrazole-1-carboxamide and reducing waste. The present method allows convenient control of the coupling process and provides a method involving fewer and simpler operations than previously known methods for producing N-phenylpyrazole-1-carboxamide compounds (such as formula 1).

[0220] In one embodiment of the present method, the pyrazolecarboxylic acid of Formula 2, the amide of Formula 3 and a suitable base can be combined in a suitable solvent, followed by the addition of the sulfonyl chloride compound (alone or mixed with a suitable solvent).

[0221] After the compounds of formula 2 and formula 3 react to form the compound of formula 1, the reaction mixture can be quenched by adding an antisolvent such as water in the quenching zone. Water converts any unconsumed sulfonyl chloride into the corresponding acid or salt with any excess base present. The addition of water also promotes the complete precipitation of the compound of formula 1 from the reaction medium. The quenching water can be neutral, acidic or alkaline. In some embodiments, the quenching water can include multiple portions of water with different pH values ​​and sequentially added in multiple separate quenching sub-zones. As discussed in more detail below, adjusting the pH of the quenching water will minimize the amount of the compound of formula cyclo-1 recovered from the process.

[0222] The rate at which the compound of Formula 1 is introduced into the quenching zone and / or removed from the quenching zone may be substantially constant or variable (e.g., introduction and / or removal may be intermittent), but on average balanced to achieve the desired residence time in the quenching zone. For example, the rate of introduction and removal during the continuous process is not zero at the same time. Alternatively, intermittent introduction and / or removal may be used to connect the continuous process with upstream or downstream intermittent processing equipment and / or steps (e.g., batch filtration). For example, the average residence time in the quenching zone may be about 15 minutes to about 2 hours, such as two hours or less, one hour or less, 30 minutes or less, or 15 minutes or less. Although the quenching of the reaction is relatively fast, in some embodiments, it may be necessary to have a longer average residence time to provide reduced equipment fouling, an improved interface with other processes, a crystal performance of the compound of Formula 1 that allows for more effective recovery, or other reasons. For example, it may be necessary to have a longer residence time in the quenching zone to provide an average crystal size suitable for effective filtration of the compound of Formula 1.

[0223] The product of Formula 1, N-phenylpyrazole-1-carboxamide, can be isolated from the reaction mixture by methods known to those skilled in the art, including crystallization, filtration and extraction. Figure 2 and 8As shown, the isolation of the compound of Formula 1 as a solid can be accomplished using a variety of process equipment, including, for example, but not limited to, solid concentrators, centrifuges, hydrocyclones, continuous filters, dryers, etc. After isolation, the compound of Formula 1 can be further processed, such as, but not limited to, washing with solvents and / or water, recrystallization, and converting the cyclo-1 compound (if present) (see below) to the compound of Formula 1. The compound of Formula 1 can be used as a pesticide in combination with additional materials including other active ingredients and / or formulation adjuvants.

[0224] As shown in Scheme 2, in certain cases, under the coupling reaction conditions, partial cyclization of the amide 1 to the iminobenzoxazine of formula cyclo-1 occurs.

[0225] Solution 2

[0226]

[0227] In these cases, it is often advantageous to convert the compound of formula cyclo-1 back to the amide of formula 1 prior to isolating the reaction product. Such conversion can be accomplished by treating the reaction mixture with an aqueous acid. Treating the reaction mixture with an aqueous acid can be performed by quenching the reaction mixture with a dilute aqueous acid or adding the acid to the process stream after quenching. Alternatively, a mixture of the iminobenzoxazine of formula cyclo-1 and the amide of formula 1 can be isolated and the mixture can then be converted to the amide of formula 1, for example by treating with a dilute aqueous acid, optionally in the presence of a suitable organic solvent.

[0228] In various embodiments of the process conditions, the cyclization side reaction that converts the desired product of Formula 1 to the compound of Formula cyclo-1, if any, generally occurs only to a minor extent, in which case a suitable ratio of sulfonyl chloride to base is sufficient to complete the coupling reaction. However, for some pyrazolecarboxylic acids of Formula 2, anthranilic acids of Formula 3 (such as when R 2 , CN) and reaction conditions (e.g., using a sterically hindered substituted pyridine such as 2,6-lutidine as a base), the conversion of the desired product of Formula 1 to the compound of Formula cyclo-1 can occur to a more significant extent or can be the predominant reaction. In these cases, the use of a larger ratio of sulfonyl chloride to base can facilitate the completion of the coupling reaction. In addition to the equivalents of sulfonyl chloride consumed in the coupling reaction, the cyclization side reaction stoichiometrically consumes equivalents of sulfonyl chloride. Thus, if 100% cyclization is to occur, a 2:1 molar ratio of sulfonyl chloride to the compound of Formula 2 is stoichiometrically required to achieve complete consumption of the starting material, and a molar ratio of sulfonyl chloride to the compound of Formula 2 of no more than about 2.5:1 will generally be used, compared to when the extent of cyclization is only 5-10% (when R 2When the sulfonyl chloride is CN, which is typical for most bases, the molar ratio of sulfonyl chloride to the compound of formula 2 is about 1.4:1; when the cyclization side reaction is negligible (when R 2 When Br, Cl or H is present, which is typical for most bases, the molar ratio of sulfonyl chloride to compound of Formula 2 is about 1.2:1. If cyclization is observed, additional amounts of sulfonyl chloride and base may be added while the reaction proceeds.

[0229] The valuable feature of the continuous process is described above, that is, any component of the process of additional amount can be continuously added as needed to complete the conversion. The completion of the compound of formula 1 formed by coupling the compound of formula 2 and the compound of formula 3 can be detected by using any of the commonly known and available multiple methods. These methods include FTIR, HPLC and NMR. When the reaction mixture or its part passes through the reaction zone or sampling loop, it can be analyzed by sampling it. By adjusting the concentration of the component in the reaction stream or by adjusting its introduction flow rate, the amount of the appropriate component introduced into the reaction mixture is regulated, so that the ratio of the component of the mixture can be corrected.

[0230] Once the ratio of the combination of a specific compound of Formula 2 and a specific compound of Formula 3 is optimized to form a specific compound of Formula 1 with high yield and / or purity, the rate of introduction of the compound of Formula 2, the compound of Formula 3, the sulfonyl chloride and the optional solvent and / or the optional base (if present) and the rate of removal of the compound of Formula 1 from the reaction zone can be kept substantially constant during the duration of the continuous process operation. It will be appreciated that the rates of introduction and removal may be different when different compounds of Formula 1 are prepared.

[0231] The R 1 is H, to provide a compound of formula 1 wherein R 1 The compound of formula 1 wherein R is Cl or Br. The compound wherein R is Cl or Br can be treated with a halogenating agent such as chlorine or bromine, usually in the presence of a base and a solvent. 1The reaction is carried out by using a compound of formula 1 wherein the base is H. The base may be 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 amount of the base may be 0.8 to 5 times (by mole) of the compound of formula 1, or 1 to 3.5 times (by mole). The solvent may be selected from ethers such as 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 cyclohexanone; and polar aprotic solvents such as acetonitrile, propionitrile, N,N-dimethylformamide, dimethyl sulfoxide, hexamethylphosphoric acid triamide, cyclopentane, dimethylacetamide and N-methylpyrrolidone. The reaction may be generally carried out at -20 to 120°C or 0 to 80°C, and the reaction time is generally about 0.5 to about 48 hours, or about 1 to about 24 hours. Representative halogenation reactions are described in WO 2008 / 072745. Similarly, compounds of Formula 1 wherein R2 is H may be treated with a halogenating agent to provide compounds wherein R 2 The compound of formula 1 wherein R is Cl or Br.

[0232] Pyrazolecarboxylic acids of Formula 2 can be prepared using heterocyclic synthesis methods known in the literature, including references found in the following compendiums: Rodd's Chemistry of Chemistry of Carbon Compounds, Volumes Iva to IV1, edited by S. Coffey, Elsevier Scientific Publishing, New York, 1973; Comprehensive Heterocyclic Chemistry, Volumes 1-7, edited by AR Katritzky and C W Rees, Pergamon Press, New York, 1984; Comprehensive Heterocyclic Chemistry II, Volumes 7-9, edited by AR Katritzky, C W Rees and E F Scriven, Pergamon Press, New York, 1996; and The Chemistry of Heterocyclic Compounds series, edited by EC Taylor, Wiley, New York. General methods for the synthesis of a variety of heterocyclic acids, including pyrazolecarboxylic acids, and thereof can be found in PCT Patent Publication WO 98 / 57397.

[0233] One embodiment of a process for preparing pyrazole carboxylic acids of Formula 2a is shown in Scheme 3.

[0234] Solution 3

[0235]

[0236] The reaction of pyrazoles of formula 6 with 2-halopyridines of formula 7 provides good yields of 1-pyridylpyrazoles of formula 8 with good desired regiochemical specificity. Metalation of compounds of formula 8 with lithium diisopropylamide (LDA) followed by quenching of the lithium salt with carbon dioxide affords 1-(2-pyridyl)pyrazolecarboxylic acid of formula 2a. The primary reference for this method is PCT patent publication WO 03 / 015519.

[0237] As shown in Scheme 4, pyrazole carboxylic acids of Formula 2b can be prepared via the 3+2 cycloaddition of an appropriately substituted imino halide of Formula 9 with a substituted propiolate of Formula 10 or an acrylate of Formula 11.

[0238] Solution 4

[0239]

[0240] Cycloaddition with acrylate requires additional oxidation of the intermediate pyrazoline to pyrazole. Hydrolysis of the ester of formula 12 yields the pyrazolecarboxylic acid of formula 2b. Suitable imino halides for this reaction include trifluoromethylimino chloride of formula 9a and imino dibromide 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 can be obtained by known methods (Tetrahedron Letters 1999, 40, 2605).

[0241] Another method for preparing pyrazolecarboxylic acids of Formula 2b is shown in Scheme 5.

[0242] Solution 5

[0243]

[0244] Pyrazoles of formula 13 can be condensed with aryl iodides using methods such as those reported by A. Klapars, JC Antilla, X. Huang and SL Buchwald, J. Am. Chem. Soc. 2001, 123, 7727-7729, or pyrazoles of formula 13 can be condensed with aryl boronic acids using methods such as those reported by PYS Lam, CG Clark, S. Saubern, J. Adams, MP Winters, DM T Chan and A. Combs, Tetrahedron Lett. 1998, 39, 2941-2944. The resulting adduct of formula 15 can be oxidized with an oxidizing agent such as potassium permanganate to provide pyrazolecarboxylic acids of formula 2b.

[0245] 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 (compound of formula 6, wherein R 4 The pyrazole of formula 6b (compound of formula 6, wherein R is CF3) can be prepared by the process described in Chem. Ber. 1966, 99(10), 3350-7. 4 is Cl or Br).

[0246] An alternative method that can be used to prepare compounds of Formula 6b is depicted in Scheme 6.

[0247] Solution 6

[0248]

[0249] The sulfamoylpyrazole of formula 16 is metallated with n-butyl lithium followed by hexachloroethane (for R 4 for Cl) or 1,2-dibromotetrachloroethane (for R 4 Direct halogenation of the anion with Br) affords the halogenated derivative of Formula 17a. Removal of the sulfamoyl group with trifluoroacetic acid (TFA) at room temperature affords the pyrazole of Formula 6c in complete and good yields. One of ordinary skill in the art will recognize that Formula 6c is a tautomer of Formula 6b.

[0250] Pyrazole carboxylic acids 2 can also be prepared as shown in Scheme 7 by oxidation of pyrazolines of formula 18 to give pyrazoles of formula 19 followed by hydrolysis to carboxylic acids.

[0251] Solution 7

[0252]

[0253] The oxidizing agent may be hydrogen peroxide, an organic peroxide, potassium persulfate, sodium persulfate, ammonium persulfate, potassium monopersulfate (e.g., ) or potassium permanganate. The oxidation can be carried out in the presence of a solvent, including ethers such as tetrahydrofuran, p-dioxane, etc.; organic esters such as ethyl acetate, dimethyl carbonate, etc.; or polar aprotic organic substances such as N,N-dimethylformamide, acetonitrile, etc.

[0254] As shown in Scheme 8, pyrazolone compounds of formula 20, wherein R 4 The halogenated pyrazoline 18 is Cl or Br.

[0255] Solution 8

[0256] R 4 Cl or Br

[0257] Halogenating agents that can be used include phosphoryl halides, phosphorus trihalides, phosphorus pentahalides, thionyl chloride, dihalotrialkylphosphanes, dihalotriphenylphosphanes, oxalyl chloride, and phosgene. In various embodiments, the halogenating agents are phosphoryl halides and phosphorus pentahalides. Typical solvents for such 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. Adding a catalyst such as N, N-dimethylformamide is also an option.

[0258] Alternatively, the compounds wherein R4 is a different halogen (e.g., for the preparation of compounds wherein R 4 is a compound of formula 18 wherein R is Cl) or a sulfonate group such as mesylate, benzenesulfonate or p-toluenesulfonate to prepare a corresponding compound of formula 18 wherein R 4 By this method, R on the starting compound of formula 18 4 The halogen or sulfonate substituent is replaced by Br or Cl from hydrogen bromide or hydrogen chloride, respectively. Starting compounds of formula 18 wherein R4 is Cl or Br can be prepared from the corresponding compounds of formula 20 as already described. Starting compounds of formula 18 wherein R4 is a sulfonate group can also 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.

[0259] The method described in Scheme 9 can be used to prepare4 The pyrazole carboxylic acid of formula 2c is OCHF2 or OCH2CF3.

[0260] Solution 9

[0261]

[0262] In this method, the compound of formula 20 is oxidized to a compound of formula 21, rather than halogenated as shown in Scheme 8. The reaction conditions of the oxidation are as described in Scheme 7 for converting a compound of formula 18 to a compound of formula 19. The compound of formula 21 can then be alkylated to form a compound of formula 22 by contacting with difluorocarbene, which is prepared in situ by CHClF2 in the presence of a base. The compound of formula 21 can also be alkylated to form a compound of formula 24 by contacting with an alkylating agent CF3CH2Lg in the presence of a base. The alkylation reaction is typically carried out in a solvent, which may include ethers, such as tetrahydrofuran or dioxane, and polar aprotic solvents, such as acetonitrile, N, N-dimethylformamide, etc. The base may be selected from an inorganic base, such as potassium carbonate, sodium hydroxide, or sodium hydride. In various embodiments, potassium carbonate and N, N-dimethylformamide or acetonitrile as a solvent are used to react. In the alkylating agent CF3CH2Lg, Lg is a nucleofugal agent (i.e., a leaving group) such as a halogen (e.g., Br, I), OS(O)2CH3 (mesylate), OS(O)2CF3, OS(O)2Ph-p-CH3 (p-toluenesulfonate), etc. The product of formula 22 can be isolated by conventional techniques such as extraction. The ester can then be converted to a carboxylic acid of formula 2c by the method already described in Scheme 4 for converting formula 12 to formula 2b.

[0263] Compounds of Formula 20 can be prepared from compounds of Formula 25 as described in Scheme 10.

[0264] Solution 10

[0265]

[0266] In this method, a hydrazine compound of formula 25 is contacted with a compound of formula 26 (a fumarate or maleate or a mixture thereof may be used) in the presence of a base and a solvent. The base is generally a metal alkoxide, such as sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, potassium tert-butoxide, lithium tert-butoxide, etc. Polar protons and polar aprotic organic solvents such as alcohols, acetonitrile, tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide, etc. may be used. In various embodiments, the solvent is an alcohol, such as methanol and ethanol. In other embodiments, the alcohol corresponds to (i.e., constitutes) a fumarate or maleate and an alkoxide base (the same alcohol). Depending on the reaction conditions and the separation method, the -CO2R functional group on the compound of formula 20 may be hydrolyzed to -CO2H; for example, the presence of water in the reaction mixture may promote such hydrolysis. If a carboxylic acid (-CO2H) is formed, it may be converted back to -CO2R using esterification methods well known in the art, wherein R is a C1-C4 alkyl. The desired product, ie, the compound of formula 20, can be isolated by methods known to those skilled in the art such as crystallization, extraction or distillation.

[0267] The compound of formula 2d, wherein R 4 is a C1-C4 alkyl group substituted by a 5-membered or 6-membered aromatic heterocycle substituted by Q. The compound of formula 2e, wherein R 4 is a C1-C4 alkyl substituted by tetrazole, said tetrazole being optionally substituted by one or more substituents independently selected from halogen, C1-C6 alkyl, C3-C6 cycloalkyl and C1-C6 haloalkyl.

[0268] As shown in Scheme 11, for example, a pyrazole carboxylate of formula 27 (wherein Q, R 5 and R 6 has the above meanings, R represents a C1-C4 alkyl group and R 8 The compound of formula 2e can be prepared, for example, by reacting a pyrazole carboxylic acid ester derivative of formula 28 (wherein Q, R, R 5 and R 6has the above meaning and Z represents chloro, bromo, iodo, mesyl or tosyl) with a tetrazole of formula 29 (wherein Q has the above meaning) to prepare pyrazole carboxylates of formula 27. Representative schemes are disclosed in WO2010 / 069502. Tetrazoles of formula 29 are known, 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 using an active halogen compound such as N-chlorosuccinimide or N-bromosuccinimide in the presence of a free radical initiator such as benzoyl peroxide or AIBN. Representative schemes are disclosed in WO 2016014463, WO 2012112946, and WO2016023832. Compounds of formula 2f can be prepared from compounds of formula 28a where Z is halogen by treatment 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.

[0269] Solution 11

[0270]

[0271] As shown in Scheme 12, the following can be accomplished, for example, by reacting a 3-hydroxy-2-nitropropene ether in the presence of a solvent (if appropriate) such as dichloromethane and a base (if appropriate) such as triethylamine or pyridine: 5 , R 6 and R 8 The alcohol derivative of formula 30 having the above meaning is reacted with a sulfonyl chloride (e.g., methanesulfonyl chloride or toluenesulfonyl chloride) or a halogenating agent (e.g., thionyl chloride) to prepare a pyrazole carboxylic acid ester of formula 28. For example, in the presence of a solvent (e.g., ethanol), R, R 5 , R 6 and R 8The alcohol derivative of formula 30 can be prepared by reacting a ketone derivative of formula 31 having the above meaning with a suitable reducing agent (e.g. sodium borohydride). For example, the alcohol derivative of formula 30 can be prepared by reacting a ketone derivative of formula 31 with a suitable reducing agent (e.g. sodium borohydride). 5 and R 6 A pyrazole derivative of formula 32 having the above meanings and wherein Y represents chlorine or bromine and wherein R 9 The ketone derivatives of formula 31 are prepared by reacting a tin derivative of formula 33 representing H or C1-C2-alkyl. The tin derivatives of formula 33 are known and / or commercially available. The 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).

[0272] Solution 12

[0273]

[0274] As shown in Scheme 13, anilines of formula 3a can be prepared by reaction of isatoic anhydrides of formula 34 with ammonia or an alkylamine of formula 35 using a procedure such as that described by LH Sternbach et al., J. Org. Chem. 1971, 36, 777-781.

[0275] Solution 13

[0276]

[0277] Isatoic anhydride of formula 34 can be prepared by a variety of known methods well documented in the chemical literature. For example, isatoic anhydride can be obtained from the corresponding anthranilic acid via a cyclization reaction involving the reaction of anthranilic acid with phosgene or a phosgene equivalent. For the main references to these methods, see Coppola, Synthesis 1980, 505 and Fabis et al., Tetrahedron, 1998, 10789.

[0278] The synthesis of isatoic anhydride of Formula 34 can also be achieved from isatoins of Formula 37 as outlined in Scheme 14.

[0279] Solution 14

[0280]

[0281] Isotins of formula 37 can be obtained from aniline derivatives of formula 36 according to the procedures of literature such as FD Popp, Adv. Heterocycl. Chem. 1975, 18, 1-58 and JFM DaSilva et al., Journal of the Brazilian Chemical Society 2001, 12(3), 273-324. Oxidation of isotins 30 with hydrogen peroxide usually gives the corresponding isatoic anhydride 28 in good yields (G. Reissenweber and D. Mangold, Angew. Chem. Int. Ed. Engl. 1980, 19, 222-223).

[0282] As shown in Scheme 15, the unsubstituted isatin at the 5-position of Formula 38 can also be obtained by halogenation to obtain the compound R 2 is an isatin of formula 37 wherein R is Cl, Br or I. Displacement of the cyano group can then provide an isatin of formula 37a (Formula 37, wherein R 2 for CN).

[0283] Solution 15

[0284]

[0285] Halogenation reactions can be carried out using many reagents and processes known in the literature. Suitable reagents include elemental halogens (chlorine, bromine or iodine); "positive-halogen" reagents such as trichloroisocyanuric acid, N-chlorosuccinimide (NCS), N-bromosuccinimide (NBS) or N-iodosuccinimide (NIS); and halogenating agents such as mixtures containing hydrogen peroxide and hydrogen halides. Methods known in the literature can be used to replace the halogen at the 5-position of the indigo of formula 37 where R2 is Cl, Br or I with cyanide. These methods include the use of cyanide salts, typically using metal compounds, and typically in the presence of ligands such as substituted phosphine or substituted bisphosphinoalkanes. Suitable methods include those using palladium compounds, such as those described by 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, such as those described by SL Buchwald in J. Am. Chem. Soc. 2003, 125, 2890-2891; and those using nickel compounds, such as those described in European Patent 384392 and by K. Sasaki in Bull. Chem. Soc. Japan 2004, 77, 1013-1019 and by RK Arvela and NE Leadbeater in J. Org. Chem. 2003, 68, 9122-9125. Those skilled in the art will appreciate that when R 1 When Cl is used, R 2 It can be Br or I to obtain selectivity in cyanation (ie, replacement of the halogen with cyanide).

[0286] As shown in Scheme 16, anilines of Formula 3a can generally be obtained from the corresponding 2-nitrobenzoic acid (or ester) of Formula 32 via catalytic hydrogenation of the nitro group and then via reaction of an anthranilate of Formula 33 with ammonia or an alkylamine.

[0287] Scheme 16

[0288]

[0289] Typical reduction procedures involve reduction with hydrogen in the presence of a metal catalyst such as palladium on carbon or platinum oxide in a hydroxyl-based solvent such as ethanol and isopropanol. Reduction can also be performed in acetic acid in the presence of zinc. These methods for reducing the nitro group are well documented in the chemical literature. Many methods for the interconversion of carboxylic acids, esters, and amides are also well documented in the chemical literature.

[0290] As shown in Scheme 17, 5-unsubstituted anilines of Formula 41 can also be halogenated to provide anilines of Formula 3a, wherein R 2 is Br, Cl or I, optionally followed by cyanide displacement to provide aniline of Formula 3c (Formula 3, wherein R 2 is CN), to obtain the aniline of formula 3a.

[0291] Solution 17

[0292]

[0293] Suitable methods and procedures are known in the literature and are similar to those described for the halogenation and cyano displacement shown in Scheme 13. One skilled in the art will recognize that halogenation and cyanation can also be performed at other stages in the preparation of anilines of Formula 3.

[0294] Thioamides of formula 3c can be prepared by thiolation of their amide analogs 3a (Scheme 18). Methods can be divided into two categories: by direct treatment of the amide with a thiolation agent, or by pre-activation of the amide with an electrophilic reagent. Methods employing the former strategy include the use of P4S with or without additives. 10The amide is treated and diethylthiocarbamoyl chloride, ethylaluminum sulfide, boron sulfide or Lawesson's reagent is used. Polymer-supported sulfurizing agents prepared from commercially available diamine resins and ethyl dichlorothiophosphate and processes involving microwave irradiation have also been recently disclosed. Methods that proceed by prior activation of the amide include combinations of oxalyl chloride or phosphorus oxychloride with benzyltriethylammonium tetrathiomolybdate, phosphorus oxychloride with hexamethyldisilathiane, and trialkyloxonium tetrafluoroborates with sodium hydrosulfide, and reactions of aqueous ammonium sulfide solutions with pyridinium salts (from treatment of the amide with pyridine and trifluoromethanesulfonic anhydride).See Brillon, D. Sulfur Rep. 1992, 12, 297; Hartke, K.; Gerber, H.-D. J. Prakt. Chem. 1996, 338, 763; Raucher, S.; Klein, P. J. Org. Chem. 1981, 46, 3558; Scheeren, J. W.; Ooms, P. H. J.; Nivard, R. J. F. Synthesis 1973, 149; Brillon, D. Synth. Commun. 1990, 20, 3085; Goel, O. P.; Krolls, U. Synthesis 1987, 162; Curphey, T. J. J. Org. Chem. 2002, 67, 6461; Ogata, M.; Matsumoto, H. Heterocycles 1978, 11, 139; Hirabayashi, T.; Inoue, K.; Yokota, K. J. Organomet. Chem. 1975, 92, 139; Steliou, K.; Mrani, M. J. Am. Chem. Soc. 1982, 104, 3104; Wojtkowski, P. W.; Dolfini, J. E.; Kocy, O.; Cimarusti, C. M. J. Am. Chem. Soc. 1975, 97, 5628; Cava, M. P.; Levinson, M. I. Tetrahedron 1985, 41, 5061; Ley, S. V.; Leach, A. G.; Storer, R. I. J. Chem. Soc., Perkin Trans. 1 2001, 358; Varma, R. S.; Kumar, D. Org. Lett. 1999, 1, 697; Ilankumaran, P.; Ramesha, A. R.; Chandrasekaran, S. Tetrahedron Lett. 1995, 36, 8311; Smith, D. C.; Lee, S. W.; Fuchs, P. L. J. Org. Chem. 1994, 59, 348; Bodine, J. J., Kaloustian, M. S. Synth. Commun. 1982, 12, 787 and Charette, A. B.,. Grenon , M., J. Org. Chem. 2003, 68, 5792 - 5794.

[0295] Scheme 18

[0296]

[0297] A continuous process can be used, where R 4 For CH2R 8 The compound of formula 2 is prepared wherein R 4 For CH2R 8 (R 4 The subset of which is C1-C4 alkyl) is a compound of formula 1a, wherein R 8 As previously defined for suitable compounds of Formula 3. As shown in Scheme 19, compounds of Formula 1a can be converted to compounds of Formula 1b by halogenation as described above for compounds of Formula 28a. Alternatively, a continuous process can be used to combine compounds of Formula 28b, wherein R is H and Z is Cl or Br, with compounds of Formula 2 to provide compounds of Formula 1b. Compounds of Formula 1b can be treated with tetrazoles of Formula 29 to provide compounds of Formula 1c.

[0298] Solution 19

[0299]

[0300] It should be recognized that some of the reagents and reaction conditions used to prepare the compounds of formula 2 and formula 3 described above may be incompatible with certain functional groups present in the intermediates. In these cases, the protection / deprotection sequence or functional group interconversion is incorporated into the synthesis, which will help to obtain the desired product. The use and selection of protecting groups are obvious to those skilled in the art of chemical synthesis (see, for example, Greene, TW; Wuts, PGM Protective Groups in Organic Synthesis, 2nd Edition; Wiley: New York, 1991). Those skilled in the art will recognize that in some cases, after introducing a given reagent as described in any corresponding scheme, additional conventional synthesis steps not described in detail may be required to complete the synthesis of compounds of formula 2 and formula 3. Those skilled in the art will also recognize that it may be necessary to perform the combination of the steps shown in the above scheme in an order different from that implied by the specific order of the compounds of formula 2 and formula 3 presented. Those skilled in the art will also recognize that the compounds of formula 2 and formula 3 and the intermediates described herein can undergo various electrophilic, nucleophilic, free radical, organometallic, oxidation and reduction reactions to add substituents or modify existing substituents.

[0301] Without further elaboration, it is believed that using the above description, those skilled in the art can make the most of the methods disclosed herein. Therefore, the following examples should be interpreted as being merely illustrative and not limiting the disclosure in any way. The steps in the following examples illustrate the flow of each step in the entire synthetic transformation, and the raw materials of each step may not necessarily be prepared by specific preparative operations, the flow of which is described in other embodiments or steps. Unless otherwise stated, the percentages except for the chromatographic solvent mixture are by weight. Unless otherwise stated, the parts and percentages of the chromatographic solvent mixture are by volume. 1 H NMR spectra are reported as downfield shifts from tetramethylsilane in ppm; s is a singlet, d is a doublet, and m is a multiplet. Quantitative HPLC of the product was performed using a chromatographic column (reverse phase column, manufactured by MacMod Analytical Inc., Chadds Ford, PA 19317) (3 μm particle size, 4.6 mm×15 cm, eluent 5-80% acetonitrile / pH 3 phosphate buffer).

[0302] Example 1

[0303] Preparation of 3-bromo-N-[4-chloro-2-methyl-6-[(methylamino)carbonyl]phenyl]-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxamide using a 2-stage CSTR reaction zone followed by a 1-stage CSTR quench zone at room temperature

[0304] Acetonitrile (262 g), 3-bromo-1-(3-chloro-2-pyridyl)-1H-pyrazole-5-carboxylic acid (230 g, 0.8 mol) (prepared as in PCT Patent Publication WO 2003 / 015519) and 2-amino-5-chloro-N,3-dimethylbenzamide (152 g, 0.77 mol) (prepared as in PCT Patent Publication WO 2006 / 062978) were mixed together with 3-picoline (180 g, 2 mol) in a jacketed stirred vessel. The mixture was heated until all solids dissolved. The solution was then continuously pumped into Reactor 1 (Reaction Zone 1), which was a 200 mL jacketed stirred vessel, at a rate of 1.7 g / min. In addition, 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 vessel in which the temperature was maintained at 25°C and the volume level was controlled at 100 mL. The material from Reactor 2 was pumped into Reactor 3 (Quenching Zone) at an average rate of 1.9 g / min, and water was also pumped into Reactor 3 at an average rate of 0.23 g / min. Reactor 3 was a 200 mL jacketed stirred vessel in which the temperature was maintained at 25°C and the volume level was controlled at 100 mL. The product was removed from Reactor 3 at a continuous rate where it was filtered. The recovered solid was washed with 5:1 acetonitrile:water, then washed with acetonitrile, and dried under nitrogen to obtain 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 overall cake resistance was 6.7 x 10 8 ft / lbs, while a typical batch process is 15.9x10 8 ft. / lbs.

[0305] 1 H NMR (CDCl3) δ2.18 (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).

[0306] Example 2

[0307] Preparation of 3-bromo-N-[4-chloro-2-methyl-6-[(methylamino)carbonyl]phenyl]-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxamide using 2 CSTRs at different temperatures as reaction zones followed by a single CSTR quench zone

[0308] Acetonitrile (420 g), 3-bromo-1-(3-chloro-2-pyridyl)-1H-pyrazole-5-carboxylic acid (249 g, 0.82 mol) (prepared as in PCT Patent Publication WO 2003 / 015519) and 2-amino-5-chloro-N,3-dimethylbenzamide (168 g, 0.85 mol) (prepared as in PCT Patent Publication WO 2006 / 062978) were mixed together with 3-picoline (200 g, 2.14 mol) in a jacketed stirred vessel. The mixture was heated until all solids dissolved. The solution was then continuously pumped into Reactor 1 (Reaction Zone 1), which was a 200 mL jacketed stirred vessel, at a rate of 1.4 g / min. In addition, 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 into reactor 2 (reaction zone 1) at an average rate of 1.55 g / min. Reactor 2 was a 200 mL jacketed stirred vessel in which the temperature was maintained at 25° C. and the volume level was controlled at 100 mL. The material from reactor 2 was pumped into reactor 3 (quenching zone) at an average rate of 1.55 g / min, and water was also pumped into reactor 3 at an average rate of 0.17 g / min. Reactor 3 was a 200 mL jacketed stirred vessel in which the temperature was maintained at 25° C. and the volume level was maintained at 100 mL. The product was taken out from reactor 3 at a continuous rate and filtered there. The recovered solids were washed with 5:1 acetonitrile: water, then washed with acetonitrile, and dried under nitrogen to obtain the title compound as a light brown powder. The purity of the product was 98.8% by weight and the yield was greater than 90%. The overall anti-caking property was 7.0x10 8 ft / lbs, while a typical batch process is 15.9x10 8 ft. / lbs.

[0309] 1 H NMR (CDCl3) δ2.18 (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).

[0310] Example 3

[0311] 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 residence time of 12 minutes followed by a single CSTR quench zone

[0312] Acetonitrile (532 g), 3-bromo-1-(3-chloro-2-pyridyl)-1H-pyrazole-5-carboxylic acid (79 g, 0.26 mol) (prepared as in PCT Patent Publication WO 2003 / 015519) and 2-amino-5-chloro-N,3-dimethylbenzamide (53 g, 0.27 mol) (i.e., prepared as in PCT Patent Publication WO 2006 / 062978) were mixed with 3-picoline (63 g, 0.68 mol) in a jacketed stirred vessel. The mixture was heated until all solids dissolved. The solution was then continuously pumped into Reactor 1 (Reaction Zone 1), which was a 200 mL jacketed stirred vessel, at a rate of 8.09 g / min. In addition, 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 vessel in which the temperature was maintained at 25°C and the volume level was controlled at 100 mL. Material from Reactor 2 was pumped into Reactor 3 (Quenching Zone) at an average rate of 8.49 g / min and water was also pumped into Reactor 3 at an average rate of 3.19 g / min. Reactor 3 was a 200 mL jacketed stirred vessel in which the temperature was maintained at 25°C and the volume level was maintained at 150 mL. Product was removed from Reactor 3 at a continuous rate where it was filtered. The recovered solid was washed with 5:1 acetonitrile:water, then with acetonitrile, and dried under nitrogen to give the title compound as a light brown powder. The product purity was 98.5 wt % and the yield was greater than 90%.

[0313] 1 H NMR (CDCl3) δ2.18 (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).

[0314] Example 4

[0315] 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 residence time of 2.5 minutes followed by a single CSTR quench zone

[0316] Acetonitrile (1506 g), 3-bromo-1-(3-chloro-2-pyridyl)-1H-pyrazole-5-carboxylic acid (175 g, 0.58 mol) (prepared as in PCT Patent Publication WO 2003 / 015519) and 2-amino-5-chloro-N,3-dimethylbenzamide (119 g, 0.60 mol) (prepared as in PCT Patent Publication WO 2006 / 062978) were mixed together with 3-picoline (140 g, 1.51 mol) in a jacketed stirred vessel. The mixture was heated until all solids dissolved. The solution was then continuously pumped into Reactor 1 (Reaction Zone 1), which was a 200 mL jacketed stirred vessel, at a rate of 32 g / min. In addition, 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 vessel in which the temperature was maintained at 25°C and the volume level was controlled at 100 mL. Material from Reactor 2 was pumped into Reactor 3 (Quenching Zone) at an average rate of 51 g / min, and water was also pumped into Reactor 3 at an average rate of 13 g / min. Reactor 3 was a 200 mL jacketed stirred vessel in which the temperature was maintained at 25°C and the volume level was maintained at 150 mL. The product was removed from Reactor 3 at a continuous rate where it was filtered. The recovered solid was washed with 5:1 acetonitrile:water, then with acetonitrile, and dried under nitrogen to obtain the title compound as a light brown powder. The product purity was 98.56% by weight.

[0317] 1 H NMR (CDCl3) δ2.18 (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).

[0318] Example 5

[0319] Preparation of 3-bromo-1-(3-chloro-2-pyridinyl)-N-[4-cyano-2-methyl-6-[(methylamino)carbonyl]phenyl]-1H-pyrazole-5-carboxamide using 2 CSTR reaction zones followed by a single CSTR quench zone

[0320] Acetonitrile (609 g), 3-bromo-1-(3-chloro-2-pyridyl)-1H-pyrazole-5-carboxylic acid (36 g, 0.12 mol) (prepared as described in PCT Patent Publication WO 2003 / 015519) and 2-amino-5-cyano-N,3-dimethylbenzamide (24 g, 0.13 mol) were mixed together with 3-methylpyridine (33 g, 0.36 mol) in a jacketed stirred vessel. The mixture was heated until all solids were dissolved. The solution was then continuously pumped into Reactor 1 (reaction zone 1), which was a 200 mL jacketed stirred vessel, at a rate of 2.0 g / min. In addition, 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 into Reactor 2 (reaction zone 1) at an average rate of 2.1 g / min. Reactor 2 was a 200 mL jacketed stirred vessel in which the temperature was maintained at 25°C and the volume level was controlled at 130 mL. Material from Reactor 2 was pumped into Reactor 3 (quenching zone) at an average rate of 2.1 g / min and acidic water was also pumped into Reactor 3 at an average rate of 0.21 g / min. Reactor 3 was a 200 mL jacketed stirred vessel in which the temperature was maintained at 25°C and the volume level was maintained at 170 mL. The product was removed from Reactor 3 at a continuous rate where it was neutralized with sodium hydroxide and filtered. The recovered solid was washed with 5:1 acetonitrile:water, then with acetonitrile, and dried under nitrogen to give the title compound as a light brown powder. The product purity was 94.7 area %.

[0321] Example 6

[0322] Preparation of 3-bromo-N-[4-chloro-2-methyl-6-[(methylamino)carbonyl]phenyl]-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxamide using 2 CSTR reaction zones slurry feed with two methanesulfonyl chloride (MSC) feeds followed by a single CSTR quench zone

[0323] Acetonitrile (420 g), 3-bromo-1-(3-chloro-2-pyridyl)-1H-pyrazole-5-carboxylic acid (249 g, 0.82 mol) (prepared as in PCT Patent Publication WO 2003 / 015519) and 2-amino-5-chloro-N,3-dimethylbenzamide (168 g, 0.85 mol) (prepared as in PCT Patent Publication WO 2006 / 062978) were mixed with 3-picoline (200 g, 2.14 mol) in a jacketed stirred vessel at room temperature. The slurry was then continuously pumped into Reactor 1 (Reaction Zone 1), which was a 200 mL jacketed stirred vessel, at a rate of 1.4 g / min. In addition, 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. In addition, a stream of methanesulfonyl chloride was pumped into Reactor 2 at a rate of 0.07 g / min. Reactor 2 was a 200 mL jacketed stirred vessel in which the temperature was maintained at 25° C. and the volume level was controlled at 200 mL. Material from Reactor 2 was pumped into Reactor 3 (quenching zone) at an average rate of 1.55 g / min, and water was also pumped into Reactor 3 at an average rate of 0.17 g / min. Reactor 3 was a 200 mL jacketed stirred vessel in which the temperature was maintained at 25° C. and the volume level was maintained at 50 mL. Product was removed from Reactor 3 at a continuous rate where it was filtered. The recovered solid was washed with 5:1 acetonitrile:water, then washed with acetonitrile, and dried under nitrogen to give the title compound as a light brown powder.

[0324] Example 7

[0325] 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

[0326] Acetonitrile (420 g), 3-bromo-1-(3-chloro-2-pyridyl)-1H-pyrazole-5-carboxylic acid (249 g, 0.82 mol) (prepared as in PCT Patent Publication WO 2003 / 015519) and 2-amino-5-chloro-N,3-dimethylbenzamide (168 g, 0.85 mol) (prepared as in PCT Patent Publication WO 2006 / 062978) were mixed with 3-picoline (200 g, 2.14 mol) in a jacketed stirred vessel at room temperature. The slurry was then continuously pumped into Reactor 1 (Reaction Zone 1) at a rate of 4.2 g / min, which was a 17 mL jacketed plug flow reactor with an internal mixing zone. In addition, 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 vessel in which the temperature was maintained at 50°C and the volume level was controlled at 50 mL. Material from Reactor 2 was pumped into Reactor 3 (Quenching Zone) at an average rate of 4.65 g / min and water was also pumped into Reactor 3 at an average rate of 0.61 g / min. Reactor 3 was a 200 mL jacketed stirred vessel in which the temperature was maintained at 25°C and the volume level was maintained at 200 mL. Product was removed from Reactor 3 at a continuous rate where it was filtered. The recovered solid was washed with 5:1 acetonitrile:water, then washed with acetonitrile, and dried under nitrogen to give the title compound as a light brown powder.

[0327] Example 8

[0328] 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

[0329] Acetonitrile (420 g), 3-bromo-1-(3-chloro-2-pyridyl)-1H-pyrazole-5-carboxylic acid (249 g, 0.82 mol) (prepared as in PCT Patent Publication WO 2003 / 015519) and 2-amino-5-chloro-N,3-dimethylbenzamide (168 g, 0.85 mol) (prepared as in PCT Patent Publication WO 2006 / 062978) were mixed with 3-picoline (200 g, 2.14 mol) in a jacketed stirred vessel at room temperature. The slurry was then continuously pumped into Reactor 1 (reaction zone), which was a 200 mL jacketed stirred vessel, at a rate of 1.4 g / min. In addition, 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 (quenching 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 vessel in which the temperature was maintained at 10° C. and the volume level was maintained at 100 mL. The product was removed from Reactor 2 at a continuous rate where it was filtered. The recovered solid was washed with 5:1 acetonitrile:water, then with acetonitrile, and dried under nitrogen to give the title compound as a light brown powder.

[0330] Using procedures similar to those in Examples 1-8, a compound of Formula 2 (wherein Z is N, R 4 is CH2(5-CF3-2H-tetrazolyl-2-yl), R 5 C1 and R 6 H) and compounds of formula 3 (wherein X is O, R 1 For CH3, R 2 CN and R 3 is methyl) are combined in a continuous process to prepare a compound of formula 1 (wherein X is O, Z is N, R 1 For CH3, R 2 CN and R 3 is methyl, R 4 is CH2(5-CF3-2H-tetrazolyl-2-yl), R 5 is Cl and R 6 is H), that is, 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.

[0331] Using procedures similar to those in Examples 1-8, a compound of Formula 2 (wherein Z is N, R 4 Br, R 5 is Cl and R6 H) and compounds of formula 3 (wherein X is O, R 1 Br, R 2 for Cl and R 3 is 1-cyclopropylethyl) in a continuous process to prepare a compound of formula 1 (wherein X is O, Z is N, R 1 Br, R 2 Cl, R 3 is 1-cyclopropylethyl, R 4 Br, R 5 is Cl and R 6 is H), that is, 3-bromo-N-[2-bromo-4-chloro-6-[[(1-cyclopropylethyl]amino]carbonyl]phenyl]-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxamide.

[0332] The following compounds of Tables 1 to 227 can be prepared and used in the methods of the present disclosure by the schemes described herein and methods known in the art. The following abbreviations are used in the following tables: t represents tertiary, s represents secondary, n represents normal, i represents iso, Me represents methyl, Et represents ethyl, Pr represents propyl, i-Pr represents isopropyl, c-Pr represents cyclopropyl and Bu represents butyl.

[0333] Table 1

[0334]

[0335]

[0336] The present disclosure also includes Table 2, which is constructed the same as Table 1 above, except that Formula 3a is replaced with Formula 3c shown below. For example, the first item in Table 2 is a compound of Formula 3c, wherein R 1 For CH3, R 2 is Cl and R 3 For H.

[0337]

[0338] Table 3

[0339]

[0340] where Z is N and

[0341]

[0342]

[0343] The present disclosure also includes Tables 4 to 7, each of which is constructed the same as Table 3 above, except that the header row in Table 3 (i.e., Z is N and) is replaced with the corresponding header row shown in Tables 4 to 7 below. For example, the first entry in Table 4 is a compound of Formula 2, wherein Z is CR 7 , R 7 For H, R 4 For CF3, R 5 is F and R 6 is H. Tables 5 to 7 are constructed similarly.

[0344]

[0345] Table 8 illustrates specific transformations for preparing compounds of Formula 1 according to the methods of the present disclosure.

[0346] Table 8

[0347]

[0348] in

[0349] X is O, Z is N, R is 1 For CH3, R 2 Cl, R 3 is H and

[0350]

[0351]

[0352] The present disclosure also includes Tables 9 to 227, each of which is constructed the same as Table 8 above, except that the header row in Table 8 (i.e., X is O, Z is N, R is 1 For CH3, R 2 For C1, R 3 is H and) is replaced with the corresponding heading row shown in Tables 9 to 227 below. For example, the first entry in Table 9 is a compound of Formula 1, wherein X is O, Z is N, R 1 For CH3, R 2 Cl, R 3 For H, R 4 For CF3, R 5 is F and R 6 is H. Tables 10 to 227 are constructed similarly.

[0353]

[0354]

[0355]

[0356]

[0357]

[0358]

[0359]

Claims

1. Method for preparing the compound of formula 1 in X is O; Z is 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; or a C1-C4 alkyl group substituted by Q; R 5 is F, Cl or Br; R 6 is H, F or Cl; Q is a 5- or 6-membered aromatic heterocyclic ring connected to the remainder of Formula 1 through any available carbon or nitrogen ring atom, wherein said Q is optionally substituted with one or more substituents independently selected from halogen, C1-C6 alkyl, C3-C6 cycloalkyl, and C1-C6 haloalkyl; The method comprises: Combining (1) a carboxylic acid compound of Formula 2, (2) an aniline compound of Formula 3, and (3) a sulfonyl chloride to form a compound of Formula 1, wherein one or both of the compound of Formula 2 and the compound of Formula 3 are dissolved in a solvent before the combination; wherein the method comprises a continuous process comprising continuously combining the compound of Formula 2, the compound of Formula 3 and the sulfonyl chloride in a reaction zone; and wherein the compound of Formula 1 is continuously removed in a separation step, and wherein the reaction zone comprises one or more continuous reactors, Among them, Z, R 4 , R 5 , R 6 and Q is as defined for the compound of Formula 1; Among them, X, R 1 , R 2 and R 3 As defined for compounds of formula 1.

2. The method according to claim 1, further comprising a base or a solvent.

3. The method according to claim 1, wherein Q is substituted by one or more substituents independently selected from halogen, C1-C6 alkyl, C3-C6 cycloalkyl and C1-C6 haloalkyl.

4. The method according to claim 1, wherein the sulfonyl chloride has formula 4: R 8 S(O)2Cl 4 Where R 8 is C1-C4 alkyl, C1-C2 haloalkyl, or phenyl optionally substituted by 1 to 3 substituents selected from halogen, C1-C3 alkyl and nitro.

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

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

7. The method of any one of claims 1 to 6, further comprising a base, wherein the base is combined with the compounds of Formula 2 and Formula 3 to form the mixture and then combined with the sulfonyl chloride.

8. The process according to claim 7, wherein the base is a tertiary amine.

9. The process according to claim 8, wherein the base is an optionally substituted pyridine.

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

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

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

13. The method according to any one of claims 1 to 12, wherein X is O; R 1 CH3; R 2 is H, Cl, Br or CN; and R 3 It is CH3 or CH2CH3.

14. The method according to any one of claims 1 to 12, wherein X is O; R 1 CH3; R 2 is Cl or CN; and R 3 For CH3.

15. The method according to any one of claims 1 to 12, wherein X is O; R 1 CH3; R 2 is H or Br; and R 3 It is CH3 or CH2CH3.

16. The method according to any one of claims 1 to 12, wherein X is O or S; R 1 Cl; R 2 is Cl; and R 3 It is CH(CH3)2.

17. The method according to any one of claims 1 to 12, wherein X is O; R 1 is H or Br; R 2 is Cl; and R 3 It is 1-(cyclopropyl)ethyl.

18. The method according to any one of claims 1 to 17, wherein Z is N; R 4 Br; R 5 is Cl; and R 6 is H or Cl.

19. The method according to any one of claims 1 to 17, wherein Z is N; R 3 is CH3, CH2Br or 5-(trifluoromethyl)-2H-tetrazolyl-2-ylmethyl; R 4 is Cl; and R 6 For H.

20. The method according to any one of claims 1 to 12, wherein X is O; R 1 CH3; R 2 is H, Cl, Br or CN; and R 3 It is CH3 or CH2CH3.

21. The method according to any one of claims 1 to 12, wherein X is O; R 1 CH3; R 2 is Cl or CN; and R 3 For CH3.

22. The method according to any one of claims 1 to 12, wherein X is O; R 1 CH3; R 2 is H or Br; and R 3 It is CH3 or CH2CH3.

23. The method according to any one of claims 1 to 12, wherein X is O or S; R 1 Cl; R 2 is Cl; and R 3 It is CH(CH3)2.

24. The method according to any one of claims 1 to 12, wherein X is O; R 1 is H or Br; R 2 is Cl; and R 3 It is 1-(cyclopropyl)ethyl.

25. The method according to any one of claims 1 to 12, wherein Z is N; R 4 Br; R 5 is Cl; and R 6 is H or Cl.

26. The method according to any one of claims 1 to 12, wherein Z is N; R 3 is CH3, CH2Br or 5-(trifluoromethyl)-2H-tetrazolyl-2-ylmethyl; R 5 is Cl; and R 6 For H.

27. The method according to any one of claims 1 to 12, wherein X is O; Z is N; R 1 CH3; R 2 is H, Cl, Br or CN; R 3 is CH3 or CH2CH3; R 4 Br; R 5 is Cl; and R 6 For H.

28. The method according to any one of claims 1 to 12, wherein X is O or S; Z is N; R 1 Cl; R 2 Cl; R 3 is CH3 or CH(CH3)2; R 4 Br; R 5 Cl; R 6 is H or Cl.

29. The method according to claim 1, wherein a compound of formula 1 is prepared and the compound is selected from: 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.

30. The process of any one of claims 1-29, wherein the reactor 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 1-29, wherein the reaction zone comprises two continuous reactors connected in series.

32. The process of any one of claims 1-29, wherein the reaction zone comprises a continuous reactor.

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

34. The process of claim 33 wherein the average residence time of each portion in each reactor in the reaction zone is 2 hours or less.

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

36. The method of any one of claims 1-35, wherein the separating step comprises: quenching the reaction mass comprising the compound of Formula 1 obtained from the reaction zone in a quenching zone to precipitate the compound of Formula 1; and The compound of Formula 1 is separated from the quenched reaction mass by filtration to form a collected solid compound of Formula 1.

37. The method of claim 36, wherein quenching the reaction mass comprises continuously adding an anti-solvent to the reaction mass in the quenching zone.

38. The method of claim 37, wherein the anti-solvent is water.

39. The method of any one of claims 36-38, wherein the quenching zone consists of one or more consecutive quenching vessels.

40. The method of any one of claims 37-39, wherein the antisolvent added to the quenching zone has a pH selected from neutral pH, acidic pH, and basic pH.

41. The method of any one of claims 37-40, wherein the antisolvent added to the quenching zone has the same or different pH in each of the one or more consecutive quenching vessels.

42. The process of any one of claims 1-41, wherein the separating step produces a filtrate, and wherein the filtrate is recycled to the reaction zone.

43. The method of claim 42, wherein the filtrate is refined or unrefined.

44. The process of any one of claims 1-43, wherein each reactor in the reaction zone comprises one or more independent feed streams.

45. The method of any one of claims 1 to 44, wherein the molar ratio of the compound of Formula 2 to the compound of Formula 3 is 1.2:1 to 1:1.

2.

46. ​​The method of any one of claims 1 to 45, wherein the carboxylic acid compound of Formula 2, the aniline compound of Formula 3, and sulfonyl chloride are combined at a temperature of -70 to 100°C.

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