# Patent

## Title
Process for preparing 2-amino-5-cyanobenzoic acid derivatives

## Abstract

Disclosed is a method for preparing a compound of Formula 1 comprising contacting a compound of Formula 2 with a metal cyanide reagent, a copper(I) salt reagent, an iodide salt reagent and at least one compound of Formula 3




wherein R1 is NHR3 or OR4; R2 is CH3 or Cl; R3 is H, C1-C4 alkyl, cyclopropyl, cyclopropylcyclopropyl, cyclopropylmethyl or methylcyclopropyl; R4 is H or C1-C4 alkyl; X is Br or Cl; and R5, R6, R7, R8 and R9 are as defined in the disclosure.

Also disclosed is a method for preparing a compound of Formula 4 wherein R12, R13, R14 and Z are as defined in the disclosure, using a compound of Formula 1 characterized by preparing the compound of Formula 1 by the method disclosed above or using a compound of Formula 1 prepared by the method disclosed above.

## Background
FIELD OF THE INVENTION
The present invention pertains to a method for the preparation of 3-substituted 2-amino-5-cyanobenzoic acids and derivatives.
BACKGROUND OF THE INVENTION
Preparation of certain 2-amino-5-cyanobenzoic acids and their utility as intermediates for preparing corresponding insecticidal cyanoanthranilic diamides has been disclosed (see e.g., Scheme 9 in PCT Patent Publication WO 2004/067528; Scheme 9 and Example 2, Step A in PCT Patent Publication WO 2006/068669; and Scheme 15 and Example 6, Step B in PCT Patent Publication WO 2006/062978).
However, the need continues for new or improved methods suitable for rapidly and economically providing 2-amino-5-cyanobenzoic acids and derivatives.
SUMMARY OF THE INVENTION
The present invention is directed to a method for preparing a compound of Formula 1




wherein

    
    
        R1 is NHR3 or OR4;
        R2 is CH3 or Cl;
        R3 is H, C1-C4 alkyl, cyclopropyl, cyclopropylcyclopropyl, cyclopropylmethyl or methylcyclopropyl; and
        R4 is H or C1-C4 alkyl;

comprising contacting (1) a compound of Formula 2

    
    






wherein X is Br or Cl;

with (2) a metal cyanide reagent, (3) a copper(I) salt reagent, (4) an iodide salt reagent and (5) at least one compound of Formula 3





wherein

    
    
        each R5, R6, R7, R8 and R9 is independently H, C1-C12 alkyl, C1-C6 alkoxy or NR10R11;
        each R10 and R11 is independently H or C1-C6 alkyl; or
        a pair of R10 and R11 attached to the same nitrogen are taken together as —CH2CH2CH2—, —CH2CH2CH2CH2—, —CH2(CH2)3CH2—, —CH2CH2OCH2CH2—, —CH2CH2N(R16)CH2CH2— or —CH2CH2S(O)nCH2CH2—, each optionally substituted with up to 4 substituents independently selected from C1-C4 alkyl;
        each R16 is independently H or C1-C12 alkyl; and
        each n is independently 0, 1 or 2;

provided that when X is Cl, then R2 is methyl.

    
    


This invention also provides a method for preparing a compound of Formula 4




wherein

    
    
        R2 is CH3 or Cl;
        R3 is H, C1-C4 alkyl, cyclopropyl, cyclopropylcyclopropyl, cyclopropylmethyl or methylcyclopropyl;
        Z is CR15 or N;
        R12 is Cl, Br, CF3, OCF2H or OCH2CF3;
        R13 is F, Cl or Br;
        R14 is H, F or Cl; and
        R15 is H, F, Cl or Br;

using a compound of Formula 1. The method is characterized by (a) preparing the compound of Formula 1 from the compound of Formula 2 by the method disclosed above, or (b) using as said compound of Formula 1 a compound of Formula 1 prepared by the method disclosed above.

    
    


Further related aspects of the present invention pertain to combinations of the aforedescribed methods, including a method for preparing a compound of Formula 4 comprising preparing a compound of Formula 1 from a compound of Formula 2 as described above, and then preparing the compound of Formula 4 using the compound of Formula 1.


DETAILS OF THE INVENTION
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. Further, unless expressly stated to the contrary, “or” refers to an inclusive or and not to an exclusive or. For example, a condition A or B is satisfied by any one of the following: A is true (or present) and B is false (or not present), A is false (or not present) and B is true (or present), and both A and B are true (or present).
Also, the indefinite articles “a” and “an” preceding an element or component of the invention are intended to be nonrestrictive regarding the number of instances (i.e. occurrences) of the element or component. Therefore “a” or “an” should be read to include one or at least one, and the singular word form of the element or component also includes the plural unless the number is obviously meant to be singular.
In the above recitations, the term “alkyl”, used either alone or in compound words such as “haloalkyl” includes straight-chain or branched alkyl, such as, methyl, ethyl, n-propyl, i-propyl, or the different butyl, pentyl or hexyl isomers.
The term “cyclopropylcyclopropyl,” denotes cyclopropyl substitution on another cyclopropyl ring. Examples of “cyclopropylcyclopropyl,” include 1,1′-bicyclopropyl-1-yl, 1,1′-bicyclopropyl-2-yl and the different cis- and trans-cyclopropylcyclopropyl isomers such as (1R,2S)-1,1′-bicyclopropyl-2-yl and (1R,2R)-1,1′-bicyclopropyl-2-yl.
“Alkoxy” includes, for example, methoxy, ethoxy, n-propyloxy, isopropyloxy and the different butoxy, pentoxy and hexyloxy isomers.
The term “halogen”, either alone or in compound words such as “haloalkyl”, includes fluorine, chlorine, bromine or iodine. Furthermore, when used in compound words such as “haloalkyl”, said alkyl may be partially or fully substituted with halogen atoms which may be the same or different. Examples of “haloalkyl” include F3C, ClCH2, CF3CH2 and CF3CCl2.
In the present invention, ratios are generally recited as single numbers, which are relative to the number 1; for example, a ratio of 4 means 4:1.
As used herein, the term “cyanide equivalent” when referring to a compound comprising one or more cyanide groups, relates to the number of cyanide ions (CN−) per mole of the cyanide-containing compound. For example, a hexacyanoferrate(II) reagent has six cyanide ions per mole; therefore, if the cyanide equivalent ratio of a hexacyanoferrate(II) reagent relative to another reagent is 1:1, then the mole ratio would be 0.167:1.
As used herein, the term “ligand” refers to an organic molecule comprising at least one pair of electrons available for coordination with a metal atom (in this case a copper atom). Ligands in general can be neutral or charged, and can be unidentate, bidentate or higher.
Carbon-based radical refers to a monovalent molecular component comprising a carbon atom that connects the radical to the remainder of the chemical structure through a single bond. Carbon-based radicals can optionally comprise saturated, unsaturated and aromatic groups, chains, rings and ring systems, and heteroatoms. Although carbon-based radicals are not subject to any particular limit in size, in the context of the present invention they typically comprise 1 to 16 carbon atoms and 0 to 3 heteroatoms. Of note are carbon-based radicals selected from C1-C4 alkyl, C1-C2 haloalkyl and phenyl optionally substituted with 1-3 substituents selected from C1-C3 alkyl, halogen and nitro.
The method of the present invention involves reagent (2) (i.e. a metal cyanide reagent), reagent (3) (i.e. a copper(I) salt reagent), and reagent (4) (i.e. an iodide salt reagent). Reagent (2) is alternatively and equivalently described as at lease one metal cyanide, because a metal cyanide reagent contains one or more metal cyanides. Reagent (3) is alternatively and equivalently described as at least one copper(I) salt, because a copper(I) salt reagent contains one or more copper(I) salts. Reagent (4) is alternatively and equivalently described as at least one iodide salt, because an iodide salt reagent contains one or more iodide salts. Furthermore the number of moles of a metal cyanide reagent refers to the number of moles of cyanide contained in the reagent. The number of moles of a copper(I) salt reagent refers to the number of moles of copper(I) contained in the reagent. The number of moles of an iodide salt reagent refers to the number of moles of iodide contained in the reagent.
As referred to in the present disclosure, the term “carboxylic acid” means an organic chemical compound comprising at least one carboxylic acid functional group (i.e. —C(O)OH). The term “carboxylic acid” does not include the compound carbonic acid (i.e. HOC(O)OH). Carboxylic acids include, for example, formic acid, acetic acid, propionic acid, chloroacetic acid, benzoic acid, maleic acid, and citric acid. The term “effective pKa” refers to the pKa of the carboxylic acid functional group, or if the compound has more than one carboxylic acid functional group, “effective pKa” refers to the pKa of the most acidic carboxylic acid functional group. As referred to herein, the “effective pH” of a nonaqueous substance or mixture, such as a reaction mixture, is determined by mixing an aliquot of the substance or mixture with about 5 to 20 volumes of water and then measuring the pH of the resulting aqueous mixture (e.g., with a pH meter). As referred to herein, a “substantially anhydrous” substance means the substance contains no more than about 1% water by weight. The chemical name “isatoic anhydride” is another name corresponding to the current Chemical Abstracts name “2H-3,1-benzoxazine-2,4(1H)-dione”.
Embodiments of the present invention include:
Embodiment A1. The method described in the Summary of the Invention for preparing a compound of Formula 1 comprising contacting reagent (1) (i.e. a compound of Formula 2) with reagent (2) (i.e. a metal cyanide reagent), reagent (3) (i.e. a copper(I) salt reagent), reagent (4) (i.e. an iodide salt reagent) and reagent (5) (i.e. at least one compound of Formula 3).
Embodiment A2. The method of Embodiment A1 wherein R1 is NHR3.
Embodiment A3. The method of Embodiment A1 or A2 wherein R3 is C1-C4 alkyl, cyclopropyl, cyclopropylcyclopropyl, cyclopropylmethyl or methylcyclopropyl.
Embodiment A4. The method of Embodiment A3 wherein R3 is C1-C4 alkyl or cyclopropylmethyl.
Embodiment A4a. The method of Embodiment A4 wherein R3 is methyl.
Embodiment A5. The method of any one of Embodiments A1 through A4a wherein R2 is methyl.
Embodiment A6. The method of any one of Embodiments A1 through A5 wherein X is Br.
Embodiment A7. The method of any one of Embodiments A1 through A6 wherein reagent (2) comprises one or more compounds selected from the group consisting of alkali metal cyanides and alkali metal hexacyanoferrates(II).
Embodiment A8. The method of Embodiment A7 wherein reagent (2) comprises at one or more compounds selected from the group consisting of sodium cyanide, potassium cyanide, potassium hexacyanoferrate(II) and sodium hexacyanoferrate(II).
Embodiment A9. The method of Embodiment A8 wherein reagent (2) comprises at one or more compounds selected from the group consisting of sodium cyanide, potassium cyanide and potassium hexacyanoferrate(II).
Embodiment A10. The method of Embodiment A9 wherein reagent (2) comprises sodium cyanide or potassium hexacyanoferrate(II).
Embodiment A11. The method of Embodiment A10 wherein reagent (2) comprises sodium cyanide.
Embodiment A12. The method of any one of Embodiments A1 through A11 wherein the cyanide equivalent ratio of reagent (2) to reagent (1) is at least about 1.
Embodiment A13. The method of Embodiment A12 wherein the cyanide equivalent ratio of reagent (2) to reagent (1) is at least about 1.15.
Embodiment A14. The method of any one of Embodiments A1 through A13 wherein the cyanide equivalent ratio of reagent (2) to reagent (1) is not larger than about 2.1.
Embodiment A15. The method of Embodiment A14 wherein the cyanide equivalent ratio of reagent (2) to reagent (1) is not larger than about 1.7.
Embodiment A16. The method of Embodiment A15 wherein the cyanide equivalent ratio of reagent (2) to reagent (1) is not larger than about 1.5.
Embodiment A17. The method of Embodiment A16 wherein the cyanide equivalent ratio of reagent (2) to reagent (1) is not larger than about 1.4.
Embodiment A17a. The method of Embodiment A11 wherein the cyanide equivalent ratio of reagent (2) to reagent (1) is not larger than about 1.25.
Embodiment A18. The method of any one of Embodiments A1 through A11 wherein each R5 and R9 is independently H or C1-C4 alkyl.
Embodiment A19. The method of Embodiment A18 wherein each R5 and R9 is independently H or methyl.
Embodiment A20. The method of any one of Embodiments A1 through A19 wherein each R6 and R8 is independently H or C1-C4 alkyl.
Embodiment A21. The method of Embodiment A20 wherein each R6 and R8 is independently H or methyl.
Embodiment A22. The method of any one of Embodiments A1 through A21 wherein R7 is H, C1-C4 alkyl, C1-C4 alkoxy or NR10R11.
Embodiment A23. The method of Embodiment A22 wherein R7 is C1-C4 alkyl, C1-C4 alkoxy or NR10R11.
Embodiment A24. The method of Embodiment A23 wherein R7 is methyl or methoxy.
Embodiment A24a. The method of Embodiment A24 wherein R7 is methyl.
Embodiment A25. The method of any one of Embodiments A1 through A24a wherein each R10 and R11 is independently C1-C4 alkyl or a pair of R10 and R11 are taken together as —CH2CH2CH2CH2—.
Embodiment A25a. The method of Embodiment 25 wherein each R10 and R11 is methyl.
Embodiment A26. The method of any one of Embodiments A1 through A22 wherein reagent (5) comprises one or more compounds selected from the group consisting of pyridine, 3-methylpyridine (also known as 3-picoline), 4-methylpyridine (also known as 4-picoline), 4-ethylpyridine, 4-(1,1-dimethylethyl)pyridine (also known as 4-tert-butylpyridine), 3,4-dimethylpyridine (also known as 3,4-lutidine), 3,5-dimethylpyridine (also known as 3,5-lutidine), 4-methoxypyridine, N,N-dimethyl-4-pyridinamine (also known as 4-(dimethylamino)pyridine), N,N-diethyl-4-pyridinamine (also known as 4-(diethylamino)pyridine), 4-(1-pyrrolidinyl)pyridine (also known as 4-pyrrolidinopyridine) and 4-(4-pyridinyl)morpholine (also known as 4-morpholinopyridine).
Embodiment A26a. The method of Embodiment A26 wherein reagent (5) comprises one or more compounds selected from the group consisting of pyridine, 4-methylpyridine (also known as 4-picoline), 4-ethylpyridine, N,N-dimethyl-4-pyridinamine (also known as 4-(dimethylamino)pyridine), N,N-diethyl-4-pyridinamine (also known as 4-(diethylamino)pyridine), 4-(1-pyrrolidinyl)pyridine (also known as 4-pyrrolidinopyridine) and 4-(4-pyridinyl)morpholine (also known as 4-morpholinopyridine).
Embodiment A27. The method of Embodiment A26a wherein reagent (5) comprises one or more compounds selected from the group consisting of pyridine, 4-picoline, 3-picoline, 3,4-lutidine, 3,5-lutidine and N,N-dimethyl-4-pyridinamine.
Embodiment A27a. The method of Embodiment A27 wherein reagent (5) comprises one or more compounds selected from the group consisting of pyridine, 4-picoline and N,N-dimethyl-4-pyridinamine.
Embodiment A28. The method of Embodiment A27a wherein reagent (5) comprises one or more compounds selected from the group consisting 4-picoline, 3-picoline, 3,4-lutidine and 3,5-lutidine.
Embodiment A29. The method of Embodiment A28 wherein reagent (5) comprises 4-picoline.
Embodiment A30. The method of any one of Embodiments A1 through A29 wherein the mole ratio of reagent (5) to reagent (3) (based on copper(I) content) is at least about 1.
Embodiment A30a. The method of any one of Embodiment A30 wherein the mole ratio of reagent (5) to reagent (3) (based on copper(I) content) is at least about 1.2.
Embodiment A31. The method of Embodiment A30a wherein the mole ratio of reagent (5) to reagent (3) is at least about 2.
Embodiment A32. The method of Embodiment A31 wherein the mole ratio of reagent (5) to reagent (3) is at least about 2.4.
Embodiment A33. The method of Embodiment A32 wherein the mole ratio of reagent (5) to reagent (3) is at least about 3.
Embodiment A34. The method of Embodiment A33 wherein the mole ratio of reagent (5) to reagent (3) is at least about 4.
Embodiment A35. The method of any one of Embodiments A1 through A34 wherein the mole ratio of reagent (5) to reagent (3) (based on copper(I) content) is not larger than about 10.
Embodiment A36. The method of Embodiment A35 wherein the mole ratio of reagent (5) to reagent (3) is not larger than about 6.
Embodiment A37. The method of Embodiment A36 wherein the mole ratio of reagent (5) to reagent (3) is not larger than about 5.7.
Embodiment A38. The method of Embodiment A37 wherein the mole ratio of reagent (5) to reagent (3) is not larger than about 5.
Embodiment A39. The method of any one of Embodiments A1 through A38 wherein the mole ratio of reagent (3) (based on copper(I) content) to reagent (1) is at least about 0.01.
Embodiment A40. The method of Embodiment A39 wherein the mole ratio of reagent (3) to reagent (1) is at least about 0.1.
Embodiment A41. The method of Embodiment A40 wherein the mole ratio of reagent (3) to reagent (1) is at least about 0.15.
Embodiment A41a. The method of Embodiment A40 wherein when X is Cl then the mole ratio of reagent (3) to reagent (1) is at least about 0.3.
Embodiment A42. The method of any one of Embodiments A1 through A41a wherein the mole ratio of reagent (3) (based on copper(I) content) to reagent (1) is less than about 1.
Embodiment A43. The method of any one of Embodiments A1 through A42 wherein the mole ratio of reagent (3) (based on copper(I) content) to reagent (1) is not larger than about 0.99.
Embodiment A44. The method of Embodiment A43 wherein the mole ratio of reagent (3) to reagent (1) is not larger than about 0.5.
Embodiment A45. The method of Embodiment A44 wherein the mole ratio of reagent (3) to reagent (1) is not larger than about 0.4.
Embodiment A46. The method of Embodiment A45 wherein when X is Br then the mole ratio of reagent (3) to reagent (1) is not larger than about 0.3.
Embodiment A47. The method of Embodiment A46 wherein when X is Br then the mole ratio of reagent (3) to reagent (1) is not larger than about 0.25.
Embodiment A48. The method of Embodiment A47 wherein when X is Br then the mole ratio of reagent (3) to reagent (1) is not larger than about 0.2.
Embodiment A49. The method of any one of Embodiments A1 through A48 wherein the mole ratio of reagent (4) (based on the iodide content) to reagent (1) is at least about 0.001.
Embodiment A50. The method of Embodiment A49 wherein the mole ratio of reagent (4) to reagent (1) is at least about 0.01.
Embodiment A50a. The method of Embodiment A50 wherein the mole ratio of reagent (4) to reagent (1) is at least about 0.1.
Embodiment A51. The method of Embodiment A50a wherein the mole ratio of reagent (4) to reagent (1) is at least about 0.15.
Embodiment A52. The method of any one of Embodiments A1 through A51 wherein the mole ratio of reagent (4) (based on the iodide content) to reagent (1) is less than about 1.
Embodiment A52a. The method of any one of Embodiments A1 through A52 wherein the mole ratio of reagent (4) (based on the iodide content) to reagent (1) is not larger than about 0.99.
Embodiment A53. The method of Embodiment A52a wherein the mole ratio of reagent (4) to reagent (1) is not larger than about 0.5.
Embodiment A54. The method of Embodiment A53 wherein mole ratio of reagent (4) to reagent (1) is not larger than about 0.4.
Embodiment A55. The method of Embodiment A54 wherein mole ratio of reagent (4) to reagent (1) is not larger than about 0.3.
Embodiment A56. The method of Embodiment A55 wherein the mole ratio of reagent (4) to reagent (1) is not larger than about 0.25.
Embodiment A57. The method of Embodiment A56 wherein mole ratio of reagent (4) to reagent (1) is not larger than about 0.2.
Embodiment A58. The method of any one of Embodiments A1 through A57 wherein reagent (3) and reagent (4) comprise copper(I) iodide.
Embodiment A59. The method of any one of Embodiments A1 through A58 wherein reagent (1), reagent (2), reagent (3), reagent (4) and reagent (5) are contacted in the presence of a suitable organic solvent.
Embodiment A59a. The method of any one of Embodiments A1 through A59 wherein reagent (1), reagent (2), reagent (3), reagent (4) and reagent (5) are contacted in the presence of a suitable organic solvent wherein the mole ratio of reagent (5) to reagent (3) is between about 1:1 and about 1:3.
Embodiment A60. The method of any one of Embodiments A1 through A59a wherein reagent (1) is contacted with a suitable organic solvent to form a mixture, and then reagent (2), reagent (3), reagent (4) and reagent (5) are sequentially added to the mixture.
Embodiment A61. The method of any one of Embodiments A59 through A60 wherein the suitable organic solvent comprises one or more solvents selected from the group consisting of halogenated and nonhalogenated aliphatic and aromatic hydrocarbons.
Embodiment A62. The method of Embodiment A61 wherein the suitable organic solvent comprises one or more solvents selected from the group consisting of xylenes, toluene, chlorobenzene, methoxybenzene (also known as anisole), 1,2,4-trimethylbenzene, 1,3,5-trimethylbenzene (also known as mesitylene), ethylbenzene, (1-methylethyl)benzene (also known as cumene), C1-C3 alkyl-substituted naphthalenes (e.g., 1-methylnaphthalene, 2-methylnaphthalene, 1,5-dimethylnaphthalene, 2,6-dimethylnaphthalene and 1,3-dimethylnaphthalene), ShellSol A100 (mixture of C9-C10 aromatic hydrocarbons) and ShellSol A150 (mixture of C10-C11 aromatic hydrocarbons).
Embodiment A63. The method of Embodiment A62 wherein the suitable organic solvent comprises one or more solvents selected from the group consisting of xylenes, toluene, anisole, 1,2,4-trimethylbenzene, 1,3,5-trimethylbenzene, 1-methylnaphthalene, ShellSol A100 (aromatic C9-C10 hydrocarbon solvent) and ShellSol A150 (aromatic C10-C11 hydrocarbon solvent).
Embodiment A63a. The method of Embodiment A62 wherein the suitable organic solvent comprises one or more solvents selected from the group consisting of xylenes, toluene, chlorobenzene, anisole, 1,2,4-trimethylbenzene, 1,3,5-trimethylbenzene, ethylbenzene, cumene and 1-methylnaphthalene.
Embodiment A63b. The method of Embodiment A63a wherein the suitable organic solvent comprises one or more solvents selected from the group consisting of xylenes, toluene, anisole, 1,2,4-trimethylbenzene, 1,3,5-trimethylbenzene and 1-methylnaphthalene.
Embodiment A63c. The method of Embodiment A63b wherein the suitable organic solvent comprises one or more solvents selected from the group consisting of xylenes, toluene and anisole.
Embodiment A64. The method of Embodiment A63 wherein and the suitable organic solvent comprises 1-methylnaphthalene or anisole.
Embodiment A66. The method of any one of Embodiments A59 through A65 wherein the ratio of the volume of the suitable solvent to the weight of reagent (1) is at least about 1.5 mL/g.
Embodiment A67. The method of Embodiment A66 wherein the ratio of the volume of the suitable solvent to the weight of reagent (1) is at least about 2 mL/g.
Embodiment A68. The method of Embodiment A67 wherein the ratio of the volume of the suitable solvent to the weight of reagent (1) is at least about 3 mL/g.
Embodiment A69. The method of any one of Embodiments A59 through A68 wherein the ratio of the volume of the suitable solvent to the weight of reagent (1) is not larger than about 10 mL/g.
Embodiment A69a. The method of Embodiment A69 wherein the ratio of the volume of the suitable solvent to the weight of reagent (1) is not larger than about 5 mL/g.
Embodiment A70. The method of Embodiment A69a wherein the ratio of the volume of the suitable solvent to the weight of reagent (1) is not larger than about 4 mL/g.
Embodiment A71. The method of any one of Embodiments A1 through A70 wherein reagent (1), reagent (2), reagent (3), reagent (4) and reagent (5) are contacted in the presence of a suitable organic solvent to form a mixture, the pressure above the mixture is increased above atmospheric pressure and the temperature of the mixture is increased above the normal boiling point of the solvent (i.e. boiling point at 100 kPa pressure).
Embodiment A71a. The method of Embodiment A71 wherein the suitable organic solvent comprises xylenes, toluene or anisole.
Embodiment A72. The method of any one of Embodiments A1 through A71a wherein reagent (1), reagent (2), reagent (3), reagent (4) and reagent (5) are contacted with a suitable organic solvent at a temperature not greater than about 200° C.
Embodiment A73. The method of Embodiment A72 wherein reagent (1), reagent (2), reagent (3), reagent (4) and reagent (5) are contacted with a suitable organic solvent at a temperature not greater than about 180° C.
Embodiment A74. The method of Embodiment A73 wherein reagent (1), reagent (2), reagent (3), reagent (4) and reagent (5) are contacted with a suitable organic solvent at a temperature not greater than about 170° C.
Embodiment A75. The method of Embodiment A74 wherein reagent (1), reagent (2), reagent (3), reagent (4) and reagent (5) are contacted with a suitable organic solvent at a temperature not greater than about 160° C.
Embodiment A76. The method of any one of Embodiments A1 through A75 wherein reagent (1), reagent (2), reagent (3), reagent (4) and reagent (5) are contacted with a suitable organic solvent at a temperature greater than about 115° C.
Embodiment A77. The method of Embodiment A76 wherein reagent (1), reagent (2), reagent (3), reagent (4) and reagent (5) are contacted with a suitable organic solvent at a temperature greater than about 145° C.
Embodiment A78. The method of Embodiment A77 wherein reagent (1), reagent (2), reagent (3), reagent (4) and reagent (5) are contacted with a suitable organic solvent at a temperature greater than about 155° C.
Embodiment A79. The method of Embodiment A1 wherein X is Br and the compound of Formula 1 is prepared as a solid, comprising contacting reagent (1) with a suitable organic solvent to form a mixture, and then sequentially adding reagent (2), reagent (3), reagent (4) and reagent (5) to the mixture, maintaining the temperature of the mixture between about 145 and 180° C. for about 6 to about 12 h, cooling the mixture to between about 0 and 50° C., adding water to the mixture, optionally adding a copper-coordinating agent to the mixture, optionally stirring for about 1 to about 2 h, and then recovering a compound of Formula 1 as a solid from the mixture.
Embodiment A80. The method of Embodiment A1 wherein X is Cl and the compound of Formula 1 is prepared as a solid, comprising contacting reagent (1) with a suitable organic solvent to form a mixture, and then sequentially adding reagent (2), reagent (3), reagent (4) and reagent (5) to the mixture, maintaining the temperature of the mixture between about 160 and 200° C. for about 6 to about 24 h, cooling the mixture to about 0 to 50° C., adding water to the mixture, optionally adding a copper-coordinating agent to the mixture, optionally stirring for about 1 to about 2 h, and then recovering a compound of Formula 1 as a solid from the mixture.
Embodiment B1. The method described in the Summary of the Invention for preparing a compound of Formula 4 using a compound of Formula 1 prepared from a compound of Formula 2.
Embodiment B2. The method of Embodiment B1 wherein the compound of Formula 1 is prepared from a compound of Formula 2 by the method of any one of Embodiments A1 through A80.
Embodiment B3. The method of Embodiment B1 or B2 wherein Z is N.
Embodiment B4. The method of Embodiment B1 or B2 wherein Z is CH.
Embodiment B5. The method of any one of Embodiments B1 through B4 wherein R12 is Br.
Embodiment B6. The method of any one of Embodiments B1 through B5 wherein R13 is Cl.
Embodiment B7. The method of any one of Embodiments B1 through B6 wherein R14 is H.
Embodiment B8. The method of any one of Embodiments A1 through A80 or B1 through B7 wherein the compound of Formula 1 is 2-amino-5-cyano-N,3-dimethylbenzamide.
Embodiment C1. A method described in the Summary of the Invention or any one of Embodiments A1 through A80 or B1 through B8 wherein each R5, R6, R7, R8 and R9 is independently H, C1-C12 alkyl or NR10R11, unless a narrower definition is specified.
Embodiment C2. The method described in the Summary of the Invention or any one of Embodiments A1 through A80, B1 through B8 or C1 wherein reagent (2) is a metal cyanide reagent, reagent (3) is a copper(I) salt reagent and reagent (4) is an iodide salt reagent, unless a narrower definition is specified.
Embodiment C2. The method described in the Summary of the Invention or any one of Embodiments A1 through A80, B1 through B8 or C1 through C2 wherein a pair of R10 and R11 are taken together as —CH2CH2CH2—, —CH2CH2CH2CH2—, —CH2(CH2)3CH2— or —CH2CH2OCH2CH2—, each optionally substituted with up to 4 substituents independently selected from C1-C4 alkyl, unless a narrower definition is specified.
Embodiments of this invention can be combined in any manner. Of note is the method of any one of Embodiments A1-A79 or B1-B8 wherein X is Br. Also of note is the method of any one of Embodiments A1-A5, A7-A78, A80 or B1-B8 wherein X is Cl.
Also of interest is a method for preparing a compound of Formula 1 from a compound of Formula 2 by the method disclosed above using a compound of Formula 3 wherein R5 and R6 or R6 and R7 are taken together as —CH═CH—CH═CH—.
In the following Schemes 1-8 the definitions of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, X and Z in the compounds of Formulae 1 through 10 are as defined above in the Summary of the Invention and description of Embodiments unless otherwise indicated. Formulae 1a, 1b and 1c are subsets of Formula 1. Formula 2a is a subset of Formula 2.
As shown in Scheme 1, in a method of the present invention a compound of Formula 1 is prepared by contacting a compound of Formula 2 with at least one metal cyanide (i.e. a metal cyanide reagent), at least one copper(I) salt (i.e a copper(I) salt reagent), at least one iodide salt (i.e. an iodide salt reagent) and at least one compound of Formula 3.




In the present method the metal cyanide reagent particularly comprises at least one compound selected from the group consisting of alkali metal cyanides and alkali metal hexacyanoferrates(II). Suitable alkali metal cyanides include compounds of the formula M1CN wherein M1 is an alkali metal such as sodium or potassium. Suitable alkali metal hexacyanoferrates(II) include, for example, potassium hexacyanoferrate(II) and sodium hexacyanoferrate(II), both of which are commercially available at low cost, are non-toxic, easy to handle, and have six cyanide ions available for transfer to compounds of Formula 2. Highest yields of Formula 1 compounds are usually achieved when using a metal cyanide reagent comprising sodium cyanide. Typically the cyanide equivalent ratio of the metal cyanide reagent relative to the compound of Formula 2 is from about 1 to about 1.5, and more typically from about 1.15 to about 1.25. However, the use of larger amounts of the metal cyanide reagent can be advantageous for removing copper during isolation of compounds of Formula 1. Alkali metal cyanides such as sodium cyanide are particularly useful as copper-coordinating agents for facilitating the removal of copper during isolation of compounds of Formula 1. When additional amounts of a metal cyanide reagent comprising an alkali metal cyanide (e.g., sodium cyanide) are included in the reaction mixture to facilitate later removal of copper, the total equivalent ratio (i.e. an amount sufficient for both the cyanation step and removal of copper) of metal cyanide reagent relative to the compound of Formula 2 is typically from about 1.4 to about 2.1 or even higher. When using an alkali metal cyanide it may be beneficial to reduce the particle size of the alkali metal cyanide by standard means, such as grinding or milling, before adding the alkyl metal cyanide to the reaction mixture, although the benefit is influenced by the reaction conditions. Typically an alkali metal cyanide that has been ground or milled is particularly advantageous when using only a stoichiometric amount or slightly more of the alkali metal cyanide. In contrast, when an alkali metal cyanide is used in large excess, such as an amount sufficient for not only the cyanation step but also later removal of copper from the reaction mixture (i.e. about 1.4 to 2.1 relative to Formula 2), grinding or milling the alkali metal cyanide may provide little benefit or even inferior results compared to using the alkali metal cyanide not ground or milled before addition to the reaction mixture.
In the method of Scheme 1, the copper(I) salt reagent is believed to act as a source of a chemical species which catalyzes the conversion of Formula 2 compounds to Formula 1. Suitable copper(I) salt reagents comprise one or more compounds selected from the group consisting of copper(I) salts, such as copper(I) iodide, copper(I) bromide, copper(I) chloride, copper(I) cyanide and copper(I) triflate (CuOSO2CF3). The mole ratio of the copper(I) salt reagent (based on Cu(I)) to the compound of Formula 2 is from about 0.01 to about 1, and typically from about 0.1 to about 0.99, and more typically from about 0.1 to about 0.4. When X is Br, optimal results are typically obtained from mole ratios from about 0.1 to about 0.3 of the copper(I) salt reagent to the compound of Formula 2. Because compounds of Formula 2 wherein X is Cl are generally less reactive than corresponding compounds of Formula 2 in the reaction of Scheme 1, greater amounts of copper(I) are typically used to promote the reaction when X is Cl. Therefore when X is Cl, mole ratios from about 0.3 to about 0.4 of the copper(I) salt reagent to the compound of Formula 2 are typically used.
Without being bound by any particular theory, it is believed under the conditions of the present method a 5-(bromo or chloro) derivative of Formula 2 is at least partially converted to the corresponding 5-iodo derivative in the presence of an iodide salt. Suitable iodide salt reagents comprise one or more compounds selected from the group consisting of quaternary ammonium, alkali and alkaline earth metal iodide salts such as copper(I) iodide, sodium iodide, potassium iodide, zinc iodide, lithium iodide, calcium iodide, tetrabutylammonium iodide and tetramethylammonium iodide. The mole ratio of the iodide salt to the compound of Formula 2 is from about 0.001 to about 1, and typically from about 0.01 to about 0.4, and more typically from about 0.1 to about 0.4.
In the method of Scheme 1 highest yields of Formula 1 compounds with optimal reaction rates are often obtained when copper(I) iodide (CuI) is used as the source of the copper(I) salt reagent and the iodide salt reagent. When copper(I) iodide (CuI) is used in the present method typically the mole ratio is from about 0.1 to about 0.4 relative to the compound of Formula 2. In some cases it can be beneficial to use copper(I) iodide in combination with another iodide salt reagent, such as sodium iodide, potassium iodide, zinc iodide, tetrabutylammonium iodide or tetramethylammonium iodide. The usefulness of combining copper(I) iodide with another iodide salt reagent depends on the specific reaction conditions and substrate. Typically optimal yields of Formula 1 compounds can be obtained from the present process simply by using copper(I) iodide as the only source of iodide salt reagent.
Compounds of Formula 3 act as ligands in the method of Scheme 1. Both mono- and polydentate chelating ligands comprising an amine-type binding site(s) can be used. These ligands have been found to accelerate the rate of conversion of compounds of Formula 2 to Formula 1. Not being bound by any particular theory, it is believed the ligands facilitate the reaction by increasing the solubility, reactivity and/or stability of the active copper(I) catalytic species via the formation of a copper-ligand complex. Formula 3 compounds including pyridine and a wide variety pyridine-substituted derivatives are useful as ligands in the present method. Typically ligands of Formula 3 include compounds wherein R5, R6, R7 R8 and R9 are independently H or C1-C4 alkyl, such as of pyridine, 3-methylpyridine (also known as 3-picoline), 4-methylpyridine (also known as 4-picoline), 4-ethylpyridine, 4-(1,1-dimethylethyl)pyridine (also known as 4-tert-butylpyridine), 3,4-dimethylpyridine (also known as 3,4-lutidine), 3,5-dimethylpyridine (also known as 3,5-lutidine), 4-methoxypyridine, N,N-dimethyl-4-pyridinamine (also known as 4-(dimethylamino)pyridine), N,N-diethyl-4-pyridinamine (also known as 4-(diethylamino)pyridine), 4-(1-pyrrolidinyl)pyridine (also known as 4-pyrrolidinopyridine), 4-(4-pyridinyl)morpholine (also known as 4-morpholinopyridine), and mixtures thereof. In the method of Scheme 1 typically the highest yields of Formula 1 compounds and the most favorable reaction rates are achieved with the use of one or more of the following commercially available ligands: pyridine, 4-picoline, 3-picoline, 3,4-lutidine, 3,5-lutidine and 4-(dimethylamino)pyridine; more typical is the use of 4-picoline, 3,4-lutidine and 3,5-lutidine, and most typical is the use of 4-picoline. The mole ratio of Formula 3 compounds to the copper(I) salt reagent is typically from about 1 to about 10. As mole ratios greater than 1 can often accelerate the reaction while ratios above 6 generally offer little additional benefit while increasing cost, the ratio is preferably from about 1 to about 6. Ligand compounds of Formula 3 which are liquids having boiling points consistent with the reaction of Scheme 1 (e.g., pyridine) can often be used to form the reaction solvent as well as serving as the ligand. Typically the reaction solvent contains mostly organic solvents other than compounds of Formula 3. However, when the reaction solvent contains substantial amounts of one or more ligand compounds of Formula 3, the ligand is generally in correspondingly large stoichiometric excess relative to the copper(I) salt reagent.
The reaction of Scheme 1 is typically conducted in a suitable organic solvent. A variety of solvents can be used to form the suitable solvent for this method. Typically, the method is most satisfactorily conducted using solvents in which compounds of Formula 2 are preferably completely or at least substantially soluble and the metal cyanide reagent has a low solubility in the volume of solvents used and at reaction temperatures. Although the suitable organic solvent for the reaction of Scheme 1 can comprise or even consist essentially of one or more ligand compounds of Formula 3, typically the reaction solvent comprises one or more organic solvents other than the compounds of Formula 3 and, at most, the compounds of Formula 3 are minor (i.e. in total less than about 20% by weight) components of the reaction solvent. Examples of suitable solvents include halogenated and nonhalogenated aliphatic and aromatic hydrocarbons such as xylenes, toluene, chlorobenzene, methoxybenzene (also known as anisole), 1,2,4-trimethylbenzene, 1,3,5-trimethylbenzene (also known as mesitylene), ethylbenzene, (1-methylethyl)benzene (also known as cumene), C1-C3 alkyl-substituted naphthalenes (e.g., 1-methylnaphthalene, 2-methylnaphthalene, 1,5-dimethylnaphthalene, 2,6-dimethylnaphthalene and 1,3-dimethylnaphthalene) and aromatic solvent mixtures which are sold, for example, by Shell Chemical under the trade name ShellSol, in particular ShellSol A100 (mixture of C9-C10 aromatic hydrocarbons) and ShellSol A150 (mixture of C10-C11 aromatic hydrocarbons), including mixtures of the foregoing solvents. The method is most satisfactorily conducted using a solvent that allows for reaction temperatures between about 155 and 180° C. This can be accomplished by using a solvent with a normal boiling point (i.e. boiling point at 100 kPa pressure) within or above this range or by operating at elevated pressure with a lower boiling solvent such as anisole, xylenes or toluene. The solvents anisole, xylenes or toluene are useful solvents as high yields of Formula 1 compounds are typically obtained when using these solvents, particularly when the present method is run at elevated pressure. The volume of the organic solvent relative to the weight of the compound of Formula 2 is typically between about 1.5 mL/g and about 10 mL/g. Amounts of solvent greater than 1.5 mL/g can facilitate stirring the reaction mixture, but larger amounts of solvent can slow the reaction as well as increase cost; therefore typically the volume of solvent to the weight of the compound Formula 2 is between about 2 mL/g and about 5 mL/g, and more typically between about 2 mL/g and 4 mL/g.
In the present method, the order in which the reactants are combined is not critical to the outcome of the reaction. One order of combination, for example, involves combining the compound of Formula 2 with the suitable organic solvent to form a mixture, and then sequentially adding the metal cyanide reagent, the copper(I) salt reagent, the iodide salt reagent and at least one compound of Formula 3 to the mixture. Alternatively, in some cases it is advantageous to dissolve at least one compound of Formula 3 and the copper(I) salt reagent in the suitable organic solvent and add this solution to a mixture comprising the compound of Formula 2, metal cyanide reagent, iodide salt reagent and suitable organic solvent. For this mode of addition, typically the suitable organic solvent (i.e. solvent compound or mixture of solvent compounds) used to dissolve the compound(s) of Formula 3 and copper(I) salt reagent is the same suitable organic solvent used to form the mixture comprising the compound of Formula 2, the metal cyanide reagent and the iodide salt reagent. A variety of other orders of addition are also useful for the present method.
The method of Scheme 1 is preferably conducted in an oxygen-free environment, although this is not essential for the successful outcome of the reaction. Reducing the presence of atmospheric oxygen in the reaction vessel prior to and during the addition of the reagents and maintaining an oxygen-free environment during the course of the reaction has been found to be advantageous. Standard techniques for obtaining an oxygen-free environment can be used including, for example, evacuating the reaction vessel using a vacuum pump and then repressurizing to atmospheric pressure with an inert gas (e.g., nitrogen or argon). This method can be repeated two or more times to further reduce the oxygen present in the reaction vessel. Alternatively, the reaction vessel can be purged with an inert gas and then a positive pressure of inert gas can be maintained throughout the reaction.
The reaction of Scheme 1 according to the present method is typically conducted at temperatures between about 115 and 200° C. and more typically between about 145 and 180° C. Temperatures between about 155 and 170° C. often achieve the highest product yield and purity with the most favorable reaction rates; for example, in most cases compounds of Formula 1 are obtained in greater than 95% yields in about 6 to about 12 h.
The product of Formula 1 can be isolated by standard techniques known in the art, including filtration, extraction, evaporation and crystallization. For example, the reaction medium can be diluted with about 2 to 8 parts by weight of water relative to the compound of Formula 2 to dissolve inorganic salts that are present in the reaction medium. As the compounds of Formula 1 are typically solids at ambient temperature and generally sparingly soluble in the reaction solvent, they are most easily isolated by filtration, followed by washing with water and optionally an organic solvent (e.g., xylenes or toluene). If the compounds of Formula 1 are soluble in the reaction solvent, they are most conveniently isolated by diluting the reaction medium with water to dissolve inorganic salts, then separating the organic phase, optionally followed by washing with water, to remove residual amounts of salts and/or metal cyanides, and then removing of the solvent by distillation or evaporation at reduced pressure. In some cases it may be advantageous to add a water-soluble copper-coordinating agent to optimize the removal of copper prior to isolating compounds of Formula 1. Useful copper-coordinating agents include, for example, 2,2′-thiodiethanol, ethylenediamine, N,N-dimethylethylenediamine and alkali metal cyanides. As discussed above, particularly useful for the removal of copper are alkali metal cyanides, such as sodium cyanide. If an alkali metal cyanide (e.g., sodium cyanide) is used in the present method as a copper-coordinating agent typically about 0.4 to about 0.6 moles relative to the compounds of Formula 2 is useful for reducing the amount of residual copper in compounds of Formula 1. This amount of sodium cyanide can be added when the metal cyanide reagent is added (i.e. during the cyanation reaction as discussed above) or at the completion of the reaction and prior to isolating compounds of Formula 1. For the first mode of addition the alkali metal cyanide is added in anhydrous form and for the second it is added either in anhydrous form or as an aqueous solution. Compounds of Formula 1 can be further purified by recrystallization from an appropriate organic solvent. Examples of appropriate solvents include alcohols, such as methanol. The method of Scheme 1 is illustrated in Examples 1-11 below. Example 3 illustrates the method of Scheme 1 including the treatment of the reaction mixture with an aqueous sodium cyanide solution prior to isolation of the compound of Formula 1.
The features of the present method provide an efficient means using inexpensive reagents to produce 3-substituted 2-amino-5-cyanobenzoic acid derivatives of Formula 1 in high yields (typically 95% or greater based on the moles of Formula 2 compound used) in 6 to 12 h. Of particular note is that the present method can be used to provide remarkably high yields of the compounds of Formula 1 in excellent purity even though these compounds as well as the starting compounds of Formula 2 contain amino substituents and in some cases amide substituents that can potentially participate in side reactions.
Starting compounds of Formula 2 can be made by a number of methods known in the art. As shown in Scheme 2, according to one method compounds of Formula 2 can be prepared by halogenation of a compound of Formula 5 using a variety of reagents known in the literature including bromine, chlorine, sulfuryl chloride, N-chlorosuccinimide (NCS), N-bromosuccinimide (NBS) and halogenating reagents such as mixtures comprising hydrogen peroxide and a hydrogen halide. For leading references describing these methods, see PCT Patent Publications WO 1998/16503 (Scheme 4 and Example 132), WO 2006/068669 (Scheme 11), WO 2003/015519 (Scheme 4 and Example 1, Step A) and WO 2006/062978 (Scheme 15; Example 4, Step B and Example 5, Step B).




Another method for preparing compounds of Formula 2 wherein X is Br and R1 is NHR3 involves bromination of compounds of Formula 5 by treatment with a gas containing bromine, as illustrated by the procedure of Reference Example 1 (Reference Example 1 is also found in PCT Patent Publication WO 2008/082502).
Compounds of Formula 2 wherein R1 is NHR3 can also be prepared by contacting an isatoic anhydride of Formula 6 with an alkyl amine of Formula 7 in the presence of a carboxylic acid as illustrated in Scheme 3.




As amines such as the compound of Formula 7 are bases, in the absence of the carboxylic acid, the mixture of the compounds of Formulae 6 and 7 would be basic (i.e. effective pH>7). The carboxylic acid acts as a buffer to reduce the effective pH of the reaction mixture. A wide variety of carboxylic acids are useful, as the only requirement is for at least one carboxylic acid group to impart acidity. Other functional groups can be present, and more than one carboxylic acid group can be present on the carboxylic acid molecule. Typically the carboxylic acid has an effective pKa in the range of about 2 to about 5. Carboxylic acids include, for example, formic acid, acetic acid, propionic acid, chloroacetic acid, benzoic acid, phthalic acid, maleic acid, tartaric acid and citric acid. For reason of cost, inexpensive carboxylic acids such as formic acid, acetic acid, propionic acid and benzoic acid are preferred. Acetic acid, which is commercially available at low cost in its anhydrous form (known as “glacial acetic acid”) is particularly preferred.
The combination of the carboxylic acid with the basic amine of Formula 7 forms an amine salt of the carboxylic acid. This amine salt can be preformed before addition of the isatoic anhydride compound of Formula 6, or the amine salt can be generated in situ by metering the amine of Formula 7 into a mixture of the compound of Formula 6 and the carboxylic acid. For either mode of addition, maintaining the effective pH of the mixture during the reaction between about 3 and about 7 is generally optimal.
As the effective pH of the mixture results from the buffering effect of the carboxylic acid in combination with the amine of Formula 7, the effective pH can be adjusted according to the effective pKa of the carboxylic acid by adjusting the molar ratio of carboxylic acid to the amine of Formula 7. Typically the molar amounts of the amine of Formula 7 to carboxylic acid are in the range from about 0.8 to about 3. More particularly, when the mode of combination involves metering the amine of Formula 7 into a mixture of the isatoic anhydride compound of Formula 6 and carboxylic acid, the molar ratio of Formula 7 amine to carboxylic acid is preferably from about 0.95 to about 3. When the mode of combination involves forming the amine salt before addition of the compound of Formula 6 the molar ratio of Formula 7 amine to carboxylic acid is preferably from about 0.8 to about 1.05; as long as a nearly equimolar ratio (e.g., about 0.95 to about 1.05) of Formula 7 amine to carboxylic acid is used, the amine salt thus formed is typically used in a ratio of about 1.1 to about 5 molar equivalents relative to the compound of Formula 6. For optimal conversions, the molar ratio of amine of Formula 7 to isatoic anhydride compound of Formula 6 should be at least 1.0, although the molar ratio is preferred to be from about 1.1 to about 1.5 for reasons of efficiency and of economy, regardless of how the components are mixed. The molar amount of amine of Formula 7 relative to compound of Formula 6 can be substantially greater than 1.5, particularly when a nearly equimolar ratio (e.g., about 0.95 to about 1.05) of amine to acid is used.
Highest product yield and purity is achieved when the reaction medium is substantially anhydrous. The reaction medium is thus typically formed from substantially anhydrous compounds of Formulae 6 and 7 and carboxylic acid. Preferably the reaction medium and forming materials contain about 5% or less, more preferably about 1% or less, and most preferably about 0.1% water or less (by weight). If the carboxylic acid is acetic acid, it is preferably in the form of glacial acetic acid.
The reaction of Scheme 3 is typically conducted in a liquid phase. In many cases the reaction can be carried out without solvent other than the compounds of Formulae 2, 6 and 7 and the carboxylic acid. But a preferred procedure involves use of a solvent that can suspend and at least partially dissolve the reactants. Preferred solvents are those which are non-reactive with the reaction components and have a dielectric constant of about 5 or greater, such as alkyl nitriles, esters, ethers, or ketones. Preferably the solvent should be substantially anhydrous to facilitate achieving a substantially anhydrous reaction medium. The weight ratio of solvent to the compound of Formula 6 is typically from about 1 to about 20, and preferably about 5 for reasons of efficiency and economy.
Carbon dioxide forms as a byproduct of the reaction of Scheme 3. Most of the carbon dioxide formed evolves from the reaction medium as a gas. The addition of the compound of Formula 6 into reaction medium containing the amine of Formula 7 or the addition of the amine of Formula 7 into the reaction medium containing the compound of Formula 6 is preferably conducted at such a rate and temperature as to facilitate controlling the evolution of carbon dioxide. The temperature of the reaction medium is typically between about 5 and 75° C., more typically between about 35 and 55° C.
The product of Formula 2 can be isolated by standard techniques known in the art, including pH adjustment, extraction, evaporation, crystallization and chromatography. For example, the reaction medium can be diluted with about 3 to 15 parts by weight of water relative to the starting compound of Formula 6, the pH can be optionally adjusted with either acid or base to optimize the removal of either acidic or basic impurities, the water phase can be optionally separated, and most of the organic solvent can be removed by distillation or evaporation at reduced pressure. As the compounds of Formula 2 are typically crystalline solids at ambient temperature, they are generally most easily isolated by filtration, optionally followed by washing with water and then drying.
As shown in Scheme 4, isatoic anhydrides of Formula 6 can be prepared from anthranilic acids of Formula 2a (Formula 2 wherein R1 is OR4 and R4 is H) via a cyclization reaction involving treatment of the anthranilic acids with phosgene or a phosgene equivalent such as triphosgene or an alkyl chloroformate (e.g., methyl chloroformate) in a suitable solvent such as toluene or tetrahydrofuran. The method is described in PCT Patent Publication WO 2006/068669, including a specific example relevant to Scheme 4. Also see Coppola, Synthesis 1980, 505 and Fabis et al., Tetrahedron 1998, 10789.




In another aspect of the present invention, compounds of the Formula 1 prepared by the method of Scheme 1 are useful as intermediates for preparing compounds of Formula 4. Compounds of Formula 4 are useful as insecticides, as described, for example in PCT Patent Publications WO 2003/015518 and WO 2006/055922.




wherein

    
    
        R2 is CH3 or Cl;
        R3 is H, C1-C4 alkyl, cyclopropyl, cyclopropylcyclopropyl, cyclopropylmethyl or methylcyclopropyl;
        Z is CR15 or N;
        R12 is Cl, Br, CF3, OCF2H or OCH2CF3;
        R13 is F, Cl or Br;
        R14 is H, F or Cl; and
        R15 is H, F, Cl or Br;
    
    


A variety of routes are possible for the preparation of a compound of Formula 4 from a compound of Formula 1. As outlined in Scheme 5, one such method involves the coupling of a compound of Formula 1a (Formula 1 wherein R1 is OR4 and R4 is H) with a pyrazole-5-carboxylic acid of Formula 8, resulting in a cyanobenzoxazinone of Formula 9. Subsequent reaction of the cyanobenzoxazinone with an amine of Formula 7 provides a compound of Formula 4. Conditions for the first step involve sequential addition of methanesulfonyl chloride in the presence of a tertiary amine such as triethylamine or pyridine to a pyrazole of Formula 8, followed by the addition of a compound of Formula 1a, followed by a second addition of tertiary amine and methanesulfonyl chloride. The reaction can be run neat or in a variety of suitable solvents including tetrahydrofuran, diethyl ether, dioxane, toluene, dichloromethane or chloroform with optimum temperatures ranging from room temperature to the reflux temperature of the solvent. The second step, reaction of benzoxazinones with amines to produce anthranilamides, is well documented in the chemical literature. For a general review of benzoxazinone chemistry see Jakobsen et al., Biorganic and Medicinal Chemistry 2000, 8, 2095-2103 and references cited within, and G. M. Coppola, J. Heterocyclic Chemistry 1999, 36, 563-588. Also see PCT Patent Publication WO 2004/067528, which teaches the general method shown in Scheme 5, including experimental examples relevant to Scheme 5.




Another method of preparing compounds of Formula 4 is shown in Scheme 6. In this method a compound of Formula 4 is prepared by combining a compound of Formula 1b (Formula 1 wherein R1 is NHR3), a pyrazole of Formula 8 and sulfonyl chloride according to the general method taught in PCT Patent Publication WO 2006/062978, which is hereby incorporated herein in its entirety by reference.




As described in WO 2006/062978, a variety of reaction conditions are possible for this transformation. Typically a sulfonyl chloride is added to a mixture of the compounds of Formulae 1b and 8 in the presence of a solvent and a base. Sulfonyl chlorides are generally of the formula RS(O)2C1 wherein R is a carbon-based radical. Usually for this method R is C1-C4 alkyl, C1-C2 haloalkyl, or phenyl optionally substituted with 1-3 substituents independently selected from the group consisting of halogen, C1-C3 alkyl and nitro. Commercially available sulfonyl chlorides include methanesulfonyl chloride (R is CH3), propanesulfonyl chloride (R is (CH2)2CH3), benzenesulfonyl chloride (R is phenyl), and p-toluenesulfonyl chloride (R is 4-methylphenyl). Methanesulfonyl chloride is of note for reasons of lower cost, ease of addition and/or less waste. At least one molar equivalent of the sulfonyl chloride per mole of the compound of Formula 8 is stoichiometrically needed for complete conversion. Typically the molar ratio of sulfonyl chloride to the compound of Formula 8 is no more than about 2.5, more typically no more than about 1.4.
The compound of Formula 4 is formed when the starting compounds of Formulae 1b, 8 and the sulfonyl chloride are contacted with each other in a combined liquid phase, in which each is at least partially soluble. Since the starting materials of Formulae 1b and 8 are typically solids at ordinary ambient temperatures, the method is most satisfactorily conducted using a solvent in which the starting compounds have significant solubility. Thus typically the method is conducted in a liquid phase comprising a solvent. In some cases the carboxylic acid of Formula 8 may have only slight solubility, but its salt with added base may have more solubility in the solvent. Suitable solvents for this method include nitriles such as acetonitrile and propionitrile; esters such as methyl acetate, ethyl acetate, and butyl acetate; ketones such as acetone, methyl ethyl ketone (MEK), and methyl butyl ketone; haloalkanes such as dichloromethane and trichloromethane; ethers such as ethyl ether, methyl tert-butyl ether, tetrahydrofuran (THF), and p-dioxane; aromatic hydrocarbons such as benzene, toluene, chlorobenzene, and dichlorobenzene; tertiary amines such as trialkylamines, dialkylanilines, and optionally substituted pyridines; and mixtures of the foregoing. Solvents of note include acetonitrile, propionitrile, ethyl acetate, acetone, MEK, dichloromethane, methyl tert-butyl ether, THF, p-dioxane, toluene, and chlorobenzene. Of particular note as the solvent is acetonitrile, as it often provides products in superior yield and/or purity.
As the reaction of the present method generates hydrogen chloride as a byproduct, which would otherwise bind to basic centers on the compounds of Formulae 1b, 4 and 8, the method is most satisfactorily conducted in the presence of at least one added base. The base can also facilitate constructive interaction of the carboxylic acid with the sulfonyl chloride compound and the anthranilamide. Reaction of an added base with the carboxylic acid of Formula 8 forms a salt, which may have greater solubility than the carboxylic acid in the reaction medium. Although the base may be added at the same time, in alternation, or even after the addition of the sulfonyl chloride, the base is typically added before the addition of the sulfonyl chloride. Some solvents such as tertiary amines also serve as bases, and when these are used as solvents they will be in large stoichiometric excess as bases. When the base is not used as the solvent the nominal mole ratio of the base to the sulfonyl chloride is typically from about 2.0 to about 2.2, and is preferably from about 2.1 to about 2.2. Preferred bases are tertiary amines, including substituted pyridines. More preferred bases include 2-picoline, 3-picoline, 2,6-lutidine, and pyridine. Of particular note as the base is 3-picoline, as its salts with carboxylic acids of Formula 8 are often highly soluble in solvents such as acetonitrile.
The compounds of Formula 4 can be isolated from the reaction mixtures by methods known to those skilled in the art, including crystallization, filtration and extraction. As disclosed in WO 2006/062978, in some cases under the coupling reaction conditions of Scheme 6 compounds of Formula 4 can partially cyclize to form iminobenzoxazine derivatives of Formula 10, as shown below in Scheme 7.




As discussed in WO 2006/062978, in these cases it is often advantageous to convert the iminobenzoxazine compounds of Formula 10 back to the amides of Formula 4 prior to isolation. This conversion can be accomplished by treatment of the reaction mixture with an aqueous acid solution (e.g., aqueous hydrochloric acid); or by isolating the mixture of Formula 10 and Formula 4 compounds, and then treating the mixture with an aqueous acid solution, optionally in the presence of a suitable organic solvent (e.g., acetonitrile). WO 2006/062978 discloses specific examples relevant to the method of Scheme 6, including examples illustrating treatment of the reaction mixture with an aqueous acid solution prior to isolating compounds of Formula 4.
Alternatively, compounds of Formula 10 can be converted back to compounds of Formula 4 prior to isolation by contacting the reaction mixture with water and heating. Typically, the conversion of Formula 10 compounds to Formula 4 compounds can be achieved by adding between about 2 to 6 parts by weight of water relative to the weight of the starting compound of Formula 1 and then heating to between about 45 and about 65° C. The conversion of the compound of Formula 10 to the compound of Formula 4 is usually complete in 1 h or less. Reference Example 2 below illustrates the method of Scheme 6 including the treatment of the reaction mixture with water and heating prior to isolating the compound of Formula 4.
Pyrazole-5-carboxylic acids of Formula 8 can be prepared from 5-oxo-3-pyrazolidinecarboxylates by treatment with a halogenating agent to give 3-halo-4,5-dihydro-1H-pyrazole-5-carboxylates, which can subsequently be treated with an oxidizing agent to provide esters of Formula 8. The esters can then be converted to the acids (i.e. Formula 8). Halogenating agents that can be used include, for example, phosphorus oxyhalides, phosphorus trihalides, phosphorus pentahalides, thionyl chloride, dihalotrialkylphosphoranes, dihalodiphenylphosphoranes, oxalyl chloride and phosgene. The oxidizing agents can be, for example, hydrogen peroxide, organic peroxides, potassium persulfate, sodium persulfate, ammonium persulfate, potassium monopersulfate (e.g., Oxone®) or potassium permanganate. See PCT Patent Publications WO 2003/016283, WO 2004/087689 and WO 2004/011453 for a description of the halogenation and oxidation methods, and a procedure for preparing the starting 5-oxo-3-pyrazolidinecarboxylates. To convert the esters to carboxylic acids a variety of methods reported in the chemical literature can be used, including nucleophilic cleavage under anhydrous conditions or hydrolysis involving the use of either acids or bases (see T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2nd ed., John Wiley & Sons, Inc., New York, 1991, pp. 224-269 for a review of methods). Base-catalyzed hydrolytic methods are preferred to prepare the carboxylic acids of Formula 8 from the corresponding esters. Suitable bases include alkali metal hydroxides (such as lithium, sodium, or potassium hydroxides). For example, the esters can be dissolved in a mixture of water and alcohol such as methanol. Upon treatment with sodium hydroxide or potassium hydroxide, the esters saponify to provide the sodium or potassium salt of the carboxylic acid. Acidification with a strong acid, such as hydrochloric acid or sulfuric acid, gives the carboxylic acids. PCT Patent Publication WO 2003/016283 provides a relevant experimental example illustrating the base-catalyzed hydrolysis method for the conversion of an ester to an acid.
Alternatively, pyrazole-5-carboxylic acids of Formula 8 can be prepared from 4,5-dihydro-5-hydroxy-1H-pyrazole-5-carboxylates via an acid-catalyzed dehydration reaction to give esters, which can then be converted to acids of Formula 8. Typical reaction conditions involve treatment of 4,5-dihydro-5-hydroxy-1H-pyrazole-5-carboxylates with an acid, for example, sulfuric acid, in an organic solvent, such as acetic acid, at temperatures between about 0 and 100° C. The method is described PCT Patent Publication WO 2003/016282. Conversion of the esters to acids can be done using the methods described above. Also, WO 2003/016282 provides a relevant experimental example for the conversion of an ester to an acid.
Anthranilic amides of Formula 1b can also be prepared from the corresponding acids or esters of Formula 1c (Formula 1 wherein R1 is OR4) wherein R4 is H or C1-C4 alkyl as shown below in Scheme 8. Forming amides from carboxylic acids typically involves addition of a coupling agent (e.g., silicon tetrachloride, or alternatively dicyclohexylcarbodiimide or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide often in the presence of 1-hydroxy-benzotriazole). Preparation of anthranilic amides from anthranilic acids is disclosed in M. J. Kornet, Journal of Heterocyclic Chemistry 1992, 29(1), 103-5; PCT Publication WO 01/66519-A2; T. Asano et al., Bioorganic & Medicinal Chemistry Letters 2004, 14(9), 2299-2302; H. L. Birch et al., Bioorganic & Medicinal Chemistry Letters 2005, 15(23), 5335-5339; and D. Kim et al., Bioorganic & Medicinal Chemistry Letters 2005, 15(8), 2129-2134. Also T. Asano et al. reports preparation of an anthranilic amide from an anthranilic acid through an N-protected aniline intermediate or through a 4H-3,1-benzoxazine-2,4(1H)-dione (isatoic anhydride) intermediate. Forming amides from esters often involves heating the ester with the appropriate amine in a polar solvent such as ethylene glycol. A procedure useful for conversion of anthranilic esters to anthranilic amides is described in PCT Patent Publication WO 2006/062978. Also, E. B. Skibo et al., Journal of Medicinal Chemistry 2002, 45(25), 5543-5555 discloses preparation of an anthranilic amide from the corresponding anthranilic ester using sodium cyanide catalyst.




The methods of Schemes 5 and 6 are illustrative of just two of many methods for converting a compound of Formula 1 to the carboxamide compound of Formula 4. A wide variety of general methods known in the art for preparing carboxamides from carboxylic acids and amines. For a general review, see M. North, Contemporary Org. Synth. 1995, 2, 269-287. Particular methods include contacting a compound of Formula 1b with a compound of Formula 8 in the presence of a dehydrating coupling agent such as 1,1′-carbonyldiimidazole, bis(2-oxo-3-oxazolidinyl)phosphinic chloride or benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate, or a polymer-bound analogous reagent such as polymer-bound dicyclohexylcarbodiimide, typically in an inert solvent such as dichloromethane or N,N-dimethylformamide, as is generally disclosed in PCT Patent Publication WO 2003/15518. Also disclosed in WO 2003/15518 is a method of preparing an acyl chloride counterpart of the compound of Formula 8, such as by contact with thionyl chloride or oxalyl chloride in the presence of a catalytic amount of N,N-dimethylformamide, and then contacting the derived acyl chloride with the compound of Formula 1b in the presence of an acid scavenger, such as an amine base (e.g., triethylamine, N,N-diisopropylethylamine, pyridine, and polymer-supported analogs) or a hydroxide or carbonate (e.g., NaOH, KOH, Na2CO3, K2CO3), typically in an inert solvent such as tetrahydrofuran, 1,4-dioxane, ethyl ether or dichloromethane. The product compounds of Formula 4 can be isolated from the reaction mixtures by methods known to those skilled in the art, including crystallization, filtration, and extraction.
Without further elaboration, it is believed that one skilled in the art using the preceding description can utilize the present invention to its fullest extent. The following Examples are, therefore, to be construed as merely illustrative, and not limiting of the disclosure in any way whatsoever. Steps in the following Examples illustrate a procedure for each step in an overall synthetic transformation, and the starting material for each step may not have necessarily been prepared by a particular preparative run whose procedure is described in other Examples or Steps. As used in the following Examples, the term “oxygen-free” refers to a solvent or reagent in which atmospheric oxygen was removed before use by distilling in an inert atmosphere in the presence of calcium hydride. In Examples 8 and 9 the reaction mixtures were analyzed by reversed phase HPLC (HP Zorbax® Eclipse XDB-C8, manufactured by Agilent Technologies, 5 μm, 4.6 mm×75 mm). The solvent system was solvent A: water with 0.1% by volume trifluoroacetic acid, and solvent B: acetonitrile with 0.1% by volume trifluoroacetic acid (gradient started at 0 minutes with 95% solvent A and 5% solvent B, and solvent B was increased to 95% over 8 minutes, flow was 1 mL/minute). In Example 11 the reaction mixture was analyzed by reversed phase HPLC (HP Zorbax® SB-Phenyl, manufactured by Agilent Technologies, 3.5 μm, 4.6 mm×15 cm). The solvent system was solvent A: water with the pH adjusted to 3.0 by the addition of phosphoric acid, and solvent B: acetonitrile (gradient started at 0 minutes with 83% solvent A and 17% solvent B, and solvent B was increased to 95% over 15 minutes, flow was 1.5 mL/minute). 1H NMR and 31P NMR spectra are reported in ppm downfield from tetramethylsilane and phosphoric acid, respectively; s means singlet, d means doublet, m means multiplet, br s means broad singlet and br d means broad doublet.
REFERENCE EXAMPLE 1
Preparation of 2-amino-5-bromo-N,3-dimethylbenzamide (a compound of Formula 2)
A 1000-mL flask equipped with a mechanical stirrer, thermocouple, condenser and Teflon® fluoropolymer tubing ( 1/16′′ (0.16) cm I.D.×1⁄8′′ (0.32 cm) O.D.) (positioned such that the end of the tubing was submerged below the surface of the reaction mixture) was charged with acetic acid (226 mL). A solution of aqueous sodium hydroxide (50%, 25 g) in water (85 g) was added over 15 minutes, and then 2-amino-N,3-dimethylbenzamide (50 g, 0.305 mol) (see PCT Patent Publication WO 2006/062978 for a method of preparation) was added and the mixture was heated at 55° C. A two-necked 200-mL flask fitted on one neck with a Teflon® tubing dip tube was charged with liquid bromine (50.1 g), and the other neck was connected to the Teflon® tubing on the 1000-mL flask. Nitrogen gas was then flowed through the dip tube below the surface of the liquid bromine at a rate of about 0.012 m3 (0.4 cu ft) per h for 2.5 h, during which time all of the bromine evaporated and the bromine vapor entrained in the nitrogen gas flowed out of the two-necked 200-mL flask and entered the reaction mixture through the Teflon® tubing. The reaction temperature was held at about 55° C. during the bromine vapor addition and for 30 minutes thereafter, and then cooled to 45° C. and stirred overnight. A solution of aqueous sodium hydroxide (50%, 52 g) in water (88 mL) was added to the reaction mixture at a rate of 0.8 mL/minute. After about 10% of the total volume of the sodium hydroxide solution had been added, the addition was stopped and the reaction mixture was stirred for 1 h at 45° C. After 1 h the remaining sodium hydroxide solution was added at a rate of 0.8 mL/minute. After the addition was complete, the reaction was stirred for 30 minutes at 45° C., and then cooled to 10° C. and stirred for 1 h. The mixture was filtered and the solid collected was washed with methanol (130 mL) and water (260 mL), and then dried to a constant weight in a vacuum-oven at 45° C. to give the title compound as a solid (67 g, 99.4 area % purity by HPLC, 90% yield) melting at 133-135° C.
1H NMR (DMSO-d6) δ 8.30 (m, 1H), 7.49 (d, 1H), 7.22 (d, 1H), 6.35 (br s, 2H), 2.70 (d, 3H), 2.06 (s, 3H).
EXAMPLE 1
Preparation of 2-amino-5-cyano-N,3-dimethylbenzamide (a compound of Formula 1)
A 100-mL, three-necked flask equipped with a mechanical stirrer, thermometer and condenser was charged with 2-amino-5-bromo-N,3-dimethylbenzamide (prepared by the method of Reference Example 1) (5.0 g, 0.020 mol, 99.1% purity) and 1-methylnaphthalene (20 g) while maintaining a flow of nitrogen through a gas inlet line connected to the condenser. The reaction mixture was stirred at room temperature, and powdered sodium cyanide (powdered just prior to use) (1.25 g, 0.024 mol, assuming 95% purity), copper(I) iodide (0.57 g, 0.0030 mol) and 4-picoline (1.60 g, 0.017 mol) were added. The mixture was heated at 158 to 162° C. for 6 h, and then transferred to a 200-mL flask and allowed to cool overnight. Water (20 mL) was added dropwise to the reaction mixture over 5 minutes while stirring. After stirring for an additional 2 h, the reaction mixture was filtered, and the solid collected was washed with water (3×10 mL) and xylenes (10 mL), and then dried to a constant weight in a vacuum-oven at 50° C. to give the title compound as a light brown solid (2.8 g).
1H NMR (DMSO-d6) δ 8.44 (br d, 1H), 7.83 (br d, 1H), 7.44 (br s, 1H), 7.18 (br s, 2H), 2.75 (d, 3H), 2.10 (s, 3H).
EXAMPLE 2
A Second Preparation of 2-amino-5-cyano-N,3-dimethylbenzamide
A 100-mL, three-necked flask equipped with a mechanical stirrer, thermometer and condenser was charged with 2-amino-5-bromo-N,3-dimethylbenzamide (prepared by the method of Reference Example 1) (5.0 g, 0.020 mol, 99.1% purity) and 1-methylnaphthalene (20 g) while maintaining a flow of nitrogen through a gas inlet line connected to the condenser. The reaction mixture was stirred at room temperature, and powdered sodium cyanide (powdered just prior to use) (1.25 g, 0.024 mol, assuming 95% purity), copper(I) iodide (0.57 g, 0.0030 mol) and 4-(dimethylamino)pyridine (2.10 g, 0.017 mol) were added. The mixture was heated at 160 to 165° C. for 4.25 h and then allowed to cool to 25° C. Water (20 mL) was added dropwise to the reaction mixture over 5 minutes while stirring. After stirring for an additional 30 minutes, the reaction mixture was filtered, and the solid collected was washed with water (3×10 mL) and xylenes (10 mL), and then dried to a constant weight in a vacuum-oven at 50° C. to give the title compound as a light brown solid (3.9 g).
1H NMR (DMSO-d6) δ 8.44 (br d, 1H), 7.83 (br d, 1H), 7.44 (br s, 1H), 7.18 (br s, 2H), 2.75 (d, 3H), 2.10 (s, 3H).
EXAMPLE 3
A Third Preparation of 2-amino-5-cyano-N,3-dimethylbenzamide
A 100-mL, four-necked flask equipped with a magnetic stirrer, thermocouple and condenser was charged with copper(I) iodide (1.01 g, 5.3 mmol), 2-amino-5-bromo-N,3-dimethylbenzamide (prepared by the method of Reference Example 1) (5.00 g, 20.6 mmol), powdered sodium cyanide (1.27 g, 25.1 mmol, 97% purity), oxygen-free 4-picoline (1.92 g, 20.6 mmol) and oxygen-free anisole (10 mL) under a nitrogen atmosphere in a glovebox. The reaction mixture was heated at about 153° C. for 12 h and allowed to cool to room temperature overnight. The solid reaction mixture was then heated at 125° C. and more anisole (10 mL) was added. A solution of sodium cyanide (0.505 g, 10.0 mmol) in water (20 mL) was added to the reaction mixture at about 105° C., and then the mixture was taken out of the glovebox and allowed to cool to room temperature while stirring. The reaction mixture was filtered, and the solid collected was washed with water (2×10 mL, 1×5 mL) and toluene (2×10 mL), and then dried in a vacuum-oven at 55° C. to give the title compound as an off-white solid (3.66 g).
1H NMR (DMSO-d6) δ 8.44 (br d, 1H), 7.82 (d, 1H), 7.44 (s, 1H) 7.18 (br s, 2H), 2.74 (d, 3H), 2.10 (s, 3H).
EXAMPLE 4
A Fourth Preparation of 2-amino-5-cyano-N,3-dimethylbenzamide
A 100-mL, four-necked flask equipped with a magnetic stirrer, thermocouple and condenser was charged with copper(I) iodide (0.88 g, 4.6 mmol), powdered sodium cyanide (1.87 g, 37.0 mmol, 97% purity), 2-amino-5-bromo-N,3-dimethylbenzamide (prepared by the method of Reference Example 1) (7.50 g, 30.9 mmol), oxygen-free 4-methoxypyridine (0.505 g, 4.6 mmol) and oxygen-free anisole (15 mL) under a nitrogen atmosphere in a glovebox. The reaction mixture was heated at about 155° C. for 12 h and then allowed to cool to room temperature overnight. The solid reaction mixture was then heated at 155° C., and then more copper iodide (0.588 g. 4.6 mmol) was added. After about 3 h, more anisole (15 mL) and powdered sodium cyanide (0.779 g, 15.4 mmol) were added to the reaction mixture, the mixture was cooled to 110° C., and then water (30 mL) was added. The reaction mixture was taken out of the glovebox, allowed to cool to room temperature and filtered. The solid collected was washed with water (3×15 mL) and toluene (2×15 mL), and then dried in a vacuum-oven at 55° C. to give the title compound as an off-white solid (5.22 g).
1H NMR (DMSO-d6) δ 8.43 (br m, 1H), 7.81 (s, 1H), 7.44 (s, 1H) 7.17 (br s, 2H), 2.74 (d, 3H), 2.10 (s, 3H).
EXAMPLE 5
A Fifth Preparation of 2-amino-5-cyano-N,3-dimethylbenzamide
A 100-mL, four-necked flask equipped with a magnetic stirrer, thermocouple and condenser was charged with copper(I) iodide (1.47 g, 7.7 mmol), powdered sodium cyanide (1.87 g, 37.0 mmol, 97% purity), 2-amino-5-bromo-N,3-dimethylbenzamide (prepared by the method of Reference Example 1) (7.50 g, 30.9 mmol), oxygen-free 3,5-lutidine (1.98 g, 18.5 mmol) and oxygen-free anisole (15 mL) under a nitrogen atmosphere in a glovebox. The reaction mixture was heated at about 155° C. for 12 h and allowed to cool to room temperature overnight. The solid reaction mixture was heated at 155° C. for 2 h, and then more anisole (15 mL) and powdered sodium cyanide (0.779 g, 15.4 mmol) were added to the mixture. The reaction mixture was taken out of the glovebox, heated at about 115° C. and water (45 mL) was added over 5 minutes. After cooling to room temperature, the reaction mixture was filtered. The solid collected was washed with water (2×15 mL) and toluene (2×15 mL), and then dried in a vacuum-oven at 40° C. to give the title compound as an off-white solid (5.53 g).
1H NMR (DMSO-d6) δ 8.44 (br d, 1H), 7.82 (d, 1H), 7.44 (s, 1H) 7.18 (br s, 2H), 2.74 (d, 3H), 2.10 (s, 3H).
EXAMPLE 6
A Sixth Preparation of 2-amino-5-cyano-N,3-dimethylbenzamide
The title compound was obtained as an off-white solid (5.47 g) by the procedure of Example 5 with the exception that oxygen-free 3,4-lutidine (1.98 g, 18.5 mmol) was used in place of 3,5-lutidine and the temperature in the vacuum-oven was 55° C. instead of 40° C.
1H NMR (DMSO-d6) δ 8.44 (br d, 1H), 7.82 (d, 1H), 7.44 (s, 1H) 7.18 (br s, 2H), 2.74 (d, 3H), 2.10 (s, 3H).
EXAMPLE 7
A Seventh Preparation of 2-amino-5-cyano-N,3-dimethylbenzamide
The title compound was obtained as an tan solid (5.45 g) by the procedure of Example 5 with the exception that oxygen-free 3-picoline (1.72 g, 18.5 mmol) was used in place of 3,5-lutidine and the reaction mixture was allowed to slowly cool to room temperature before adding the water. Also, the temperature in the vacuum-oven was 55° C. instead of 40° C.
1H NMR (DMSO-d6) δ 8.44 (br d, 1H), 7.82 (s, 1H), 7.44 (s, 1H) 7.18 (br s, 2H), 2.74 (d, 3H), 2.10 (s, 3H).
EXAMPLE 8
An Eighth Preparation of 2-amino-5-cyano-N,3-dimethylbenzamide
The title compound was prepared by the procedure of Example 5 with the exception that oxygen-free 2,4-lutidine (1.98 g, 18.5 mmol) was used in place of 3,5-lutidine, and after heating the reaction mixture at 155° C. for 12 h the reaction mixture was analyzed by HPLC, which showed 80% conversion of the 2-amino-5-bromo-N,3-dimethylbenzamide with 2-amino-5-cyano-N,3-dimethylbenzamide being the major product, and 2-amino-5-iodo-N,3-dimethylbenzamide and 2-amino-N,3-dimethylbenzamide being minor products (molar ratio 72 to 7 to 1).
EXAMPLE 9
A Ninth Preparation of 2-amino-5-cyano-N,3-dimethylbenzamide
A 100-mL, four-necked flask equipped with a magnetic stirrer, thermocouple and condenser was charged with copper(I) iodide (0.881 g, 4.63 mmol), powdered sodium cyanide (97% purity, 1.87 g, 37.0 mmol), 2-amino-5-bromo-N,3-dimethylbenzamide (prepared by the method of Reference Example 1) (7.50 g, 30.9 mmol), 4-tert-butylpyridine (1.67 g, 12.3 mmol) and oxygen-free anisole (15 mL) under a nitrogen atmosphere in a glovebox. The reaction mixture was at heated at 155° C. for 12 h and then allowed to cool to room temperature overnight. Analysis of the reaction mixture by HPLC indicated 33% conversion of the 2-amino-5-bromo-N,3-dimethylbenzamide with 2-amino-5-cyano-N,3-dimethylbenzamide being the major product and 2-amino-5-iodo-N,3-dimethylbenzamide and 2-amino-N,3-dimethylbenzamide the minor products (molar ratio 23 to 9 to 1).
EXAMPLE 10
A Tenth Preparation of 2-amino-5-cyano-N,3-dimethylbenzamide
A 250-mL, four-necked flask equipped with a mechanical stirrer and condenser was charged with copper(I) iodide (1.97 g, 10.3 mmol), sodium cyanide (95% purity, 3.30 g, 64.0 mmol), 2-amino-5-bromo-N,3-dimethylbenzamide (prepared by the method of Reference Example 1) (10.0 g, 40.9 mmol), 4-picoline (distilled prior to use) (1.16 g, 12.5 mmol) and oxygen-free anisole (20 mL), and then purged with nitrogen, after which time the reaction mixture was maintained under a nitrogen atmosphere. The reaction mixture was heated at about 155° C. for 12 h and then allowed to cool to room temperature overnight. Toluene (20 mL) was added to the solid-containing reaction mixture, the mixture was heated at about 100° C., and then water (60 mL) was added over 20 minutes with stirring. The reaction mixture was stirred for 1 h at 85° C., cooled to room temperature, and then filtered. The solid collected was washed with water (3×mL) and toluene (1×20 mL), and then dried in a vacuum-oven at 55° C. to give the title compound as an off-white solid (7.34 g).
1H NMR (DMSO-d6) δ 8.43 (br d, 1H), 7.82 (s, 1H), 7.44 (s, 1H) 7.17 (br s, 2H), 2.74 (d, 3H), 2.10 (s, 3H).
EXAMPLE 11
An Eleventh Preparation of 2-amino-5-cyano-N,3-dimethylbenzamide
A 100 mL reactor (HP autoMATE high pressure reactor system constructed of Hastelloy® C and produced by HEL, Inc.) was equipped with a mechanical stirrer (constructed of Hastelloy® C) with a twin turbine agitator (bottom turbine pumping up and top turbine pumping down). The reactor was purged with nitrogen, then maintained under a nitrogen atmosphere, and charged successively with 2-amino-5-bromo-N,3-dimethylbenzamide (99% purity, 12.3 g, 0.05 mol), powder sodium cyanide (CyPlus®, 3.9 g, 0.075 mol), copper(I) iodide (98% purity, 2.4 g, 0.0125 mol) and xylenes (20 g). The reactor was pressurized to 345 kPa (50 psia) with nitrogen and then vented. The nitrogen pressurization/venting procedure was repeated two times. Stirring was started at 300 rpm and the reactor then leak tested by pressurization to 690 kPa (100 psia) for 20 minutes. The reactor was then vented to atmospheric pressure and a solution of 4-picoline (98% purity, 1.4 g, 0.015 mol) in of xylenes (5.0 g) was added to the reaction mixture. The reactor was pressurized to 345 kPa (50 psia) with nitrogen and then vented. The nitrogen pressurization/venting procedure was repeated two times. The reactor vent was closed and the mixture heated at 170° C. for 6 h. The reaction mixture was cooled to between 20 and 25° C. and vented. After standing overnight, the reaction mixture was diluted with dimethylformamide to a total weight of 166.6 g. Analysis of this mixture by HPLC showed 99% conversion of the 2-amino-5-bromo-N,3-dimethylbenzamide with 2-amino-5-cyano-N,3-dimethylbenzamide being the major product.
REFERENCE EXAMPLE 2
Preparation of 3-bromo-1-(3-chloro-2-pyridinyl)-N-[4-cyano-2-methyl-6-[(methylamino)carbonyl]phenyl]-1H-pyrazole-5-carboxamide (a compound of Formula 4)
To a mixture of 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid (see PCT Patent Publication WO 2003/015519 for a method of preparation) (97.4% purity, 15 g, 0.049 mol) and 2-amino-5-cyano-N,3-dimethylbenzamide (see PCT Patent Publication 2006/62978 for a method of preparation) (10.0 g, 0.0525 mol) in acetonitrile (80 mL) was added 3-picoline (13.9 g, 0.148 mol). The mixture was cooled to 15 to 20° C., and then methanesulfonyl chloride (8.2 g, 0.071 mol) was added dropwise. After 1 h, water (37.3 g) was added dropwise to the reaction mixture while maintaining the temperature at 15 to 20° C. The mixture was heated at 45 to 50° C. for 30 minutes, and then cooled to 15 to 25° C. for 1 h. The mixture was filtered, and the solid collected was washed with acetonitrile-water (approximately a 5:1 mixture, 2×10 mL) and acetonitrile (2×10 mL), and then dried under nitrogen to afford the title compound as an off-white solid (24.0 g, 93.6% corrected yield based on an assay of 91.6%).
1H NMR (DMSO-d6) δ 10.53 (br s, 1H) 8.49 (dd, 1H), 8.36 (m, 1H), 8.16 (dd, 1H), 7.87 (d, 1H), 7.76 (d, 1H), 7.60 (m, 1H), 7.41 (s, 1H), 2.67 (d, 3H), 2.21 (s, 3H).
Table 1 illustrates the particular transformations to prepare compounds of Formula 1 according to a method of the present invention. For these transformations, the copper(I) salt reagent and the iodide salt reagent are copper(I) iodide. In Table 1 and the following tables: t means tertiary, s means secondary, n means normal, i means iso, c means cyclo, Me means methyl, Et means ethyl, Pr means propyl, and Bu means butyl. Concatenations of groups are abbreviated similarly; for example, “c-PrCH2” means cyclopropylmethyl.







TABLE 1
























R2
R3
R5
R6
R7
R8
R9










R1 is NHR3, X is Br, and the metal cyanide reagent is sodium cyanide.













Me
H
H
H
Me
H
H


Me
Me
H
H
Me
H
H


Me
Et
H
H
Me
H
H


Me
n-Pr
H
H
Me
H
H


Me
i-Pr
H
H
Me
H
H


Me
n-Bu
H
H
Me
H
H


Me
i-Bu
H
H
Me
H
H


Me
s-Bu
H
H
Me
H
H


Me
t-Bu
H
H
Me
H
H


Me
c-Pr
H
H
Me
H
H


Me
c-PrCH2
H
H
Me
H
H


Me
1-CH3-c-Pr
H
H
Me
H
H


Me
2-CH3-c-Pr
H
H
Me
H
H


Me
1,1′-bicyclopropyl-2-yl
H
H
Me
H
H


Me
1,1′-bicyclopropyl-1-yl
H
H
Me
H
H


Me
(1R,2S)-1,1′-bicyclopropyl-2-yl
H
H
Me
H
H







R1 is NHR3, X is Br, and the metal cyanide reagent is potassium cyanide.













Me
H
H
H
Me
H
H


Me
Me
H
H
Me
H
H


Me
Et
H
H
Me
H
H


Me
n-Pr
H
H
Me
H
H


Me
i-Pr
H
H
Me
H
H


Me
n-Bu
H
H
Me
H
H


Me
i-Bu
H
H
Me
H
H


Me
s-Bu
H
H
Me
H
H


Me
t-Bu
H
H
Me
H
H


Me
c-Pr
H
H
Me
H
H







R1 is NHR3, X is Br, and the metal cyanide reagent is potassium hexacyanoferrate(II).













Me
H
H
H
Me
H
H


Me
Me
H
H
Me
H
H


Me
Et
H
H
Me
H
H


Me
n-Pr
H
H
Me
H
H


Me
i-Pr
H
H
Me
H
H


Me
n-Bu
H
H
Me
H
H


Me
i-Bu
H
H
Me
H
H


Me
s-Bu
H
H
Me
H
H


Me
t-Bu
H
H
Me
H
H


Me
c-Pr
H
H
Me
H
H


Me
c-PrCH2
H
H
Me
H
H


Me
1-CH3-c-Pr
H
H
Me
H
H


Me
2-CH3-c-Pr
H
H
Me
H
H


Me
1,1′-bicyclopropyl-2-yl
H
H
Me
H
H


Me
1,1′-bicyclopropyl-1-yl
H
H
Me
H
H


Me
(1R,2S)-1,1′-bicyclopropyl-2-yl
H
H
Me
H
H







R1 is NHR3, X is Br, and the metal cyanide reagent is sodium cyanide.













Me
H
H
H
NMe2
H
H


Me
Me
H
H
NMe2
H
H


Me
Et
H
H
NMe2
H
H


Me
n-Pr
H
H
NMe2
H
H


Me
i-Pr
H
H
NMe2
H
H


Me
n-Bu
H
H
NMe2
H
H


Me
i-Bu
H
H
NMe2
H
H


Me
s-Bu
H
H
NMe2
H
H


Me
t-Bu
H
H
NMe2
H
H


Me
c-Pr
H
H
NMe2
H
H


Me
c-PrCH2
H
H
NMe2
H
H


Me
1-CH3-c-Pr
H
H
NMe2
H
H


Me
2-CH3-c-Pr
H
H
NMe2
H
H


Me
1,1′-bicyclopropyl-2-yl
H
H
NMe2
H
H


Me
1,1′-bicyclopropyl-1-yl
H
H
NMe2
H
H


Me
(1R,2S)-1,1′-bicyclopropyl-2-yl
H
H
NMe2
H
H







R1 is NHR3, X is Br, and the metal cyanide reagent is potassium cyanide.













Me
H
H
H
NMe2
H
H


Me
Me
H
H
NMe2
H
H


Me
Et
H
H
NMe2
H
H


Me
n-Pr
H
H
NMe2
H
H


Me
i-Pr
H
H
NMe2
H
H


Me
n-Bu
H
H
NMe2
H
H


Me
i-Bu
H
H
NMe2
H
H


Me
s-Bu
H
H
NMe2
H
H


Me
t-Bu
H
H
NMe2
H
H


Me
c-Pr
H
H
NMe2
H
H







R1 is NHR3, X is Br, and the metal cyanide reagent is potassium hexacyanoferrate(II).













Me
H
H
H
NMe2
H
H


Me
Me
H
H
NMe2
H
H


Me
Et
H
H
NMe2
H
H


Me
n-Pr
H
H
NMe2
H
H


Me
i-Pr
H
H
NMe2
H
H


Me
n-Bu
H
H
NMe2
H
H


Me
i-Bu
H
H
NMe2
H
H


Me
s-Bu
H
H
NMe2
H
H


Me
t-Bu
H
H
NMe2
H
H


Me
c-Pr
H
H
NMe2
H
H


Me
c-PrCH2
H
H
NMe2
H
H


Me
1-CH3-c-Pr
H
H
NMe2
H
H


Me
2-CH3-c-Pr
H
H
NMe2
H
H


Me
1,1′-bicyclopropyl-2-yl
H
H
NMe2
H
H


Me
1,1′-bicyclopropyl-1-yl
H
H
NMe2
H
H


Me
(1R,2S)-1,1′-bicyclopropyl-2-yl
H
H
NMe2
H
H







R1 is NHR3, X is Br, and the metal cyanide reagent is sodium cyanide.













Me
H
H
H
NEt2
H
H


Me
Me
H
H
NEt2
H
H


Me
Et
H
H
NEt2
H
H


Me
n-Pr
H
H
NEt2
H
H


Me
i-Pr
H
H
NEt2
H
H


Me
n-Bu
H
H
NEt2
H
H


Me
i-Bu
H
H
NEt2
H
H


Me
s-Bu
H
H
NEt2
H
H


Me
t-Bu
H
H
NEt2
H
H


Me
c-Pr
H
H
NEt2
H
H


Me
c-PrCH2
H
H
NEt2
H
H


Me
1-CH3-c-Pr
H
H
NEt2
H
H


Me
2-CH3-c-Pr
H
H
NEt2
H
H


Me
1,1′-bicyclopropyl-2-yl
H
H
NEt2
H
H


Me
1,1′-bicyclopropyl-1-yl
H
H
NEt2
H
H


Me
(1R,2S)-1,1′-bicyclopropyl-2-yl
H
H
NEt2
H
H


Me
H
H
H
1-pyrrolidinyl
H
H


Me
Me
H
H
1-pyrrolidinyl
H
H


Me
Et
H
H
1-pyrrolidinyl
H
H


Me
n-Pr
H
H
1-pyrrolidinyl
H
H


Me
i-Pr
H
H
1-pyrrolidinyl
H
H


Me
n-Bu
H
H
1-pyrrolidinyl
H
H


Me
i-Bu
H
H
1-pyrrolidinyl
H
H


Me
s-Bu
H
H
1-pyrrolidinyl
H
H


Me
t-Bu
H
H
1-pyrrolidinyl
H
H


Me
c-Pr
H
H
1-pyrrolidinyl
H
H







R1 is NHR3, X is Br, and the metal cyanide reagent is potassium hexacyanoferrate(II).













Me
H
H
H
1-pyrrolidinyl
H
H


Me
Me
H
H
1-pyrrolidinyl
H
H


Me
Et
H
H
1-pyrrolidinyl
H
H


Me
n-Pr
H
H
1-pyrrolidinyl
H
H


Me
i-Pr
H
H
1-pyrrolidinyl
H
H


Me
n-Bu
H
H
1-pyrrolidinyl
H
H


Me
i-Bu
H
H
1-pyrrolidinyl
H
H


Me
s-Bu
H
H
1-pyrrolidinyl
H
H


Me
t-Bu
H
H
1-pyrrolidinyl
H
H


Me
c-Pr
H
H
1-pyrrolidinyl
H
H







R1 is NHR3, X is Br, and the metal cyanide reagent is sodium cyanide.













Me
Me
H
H
H
H
H


Me
Me
H
Me
Me
H
H


Me
Me
H
Me
H
H
H


Me
Me
H
Me
H
Me
H


Me
Me
Me
H
H
H
H


Me
Me
Me
Me
H
H
H


Me
Me
Me
H
Me
H
H


Me
Me
Me
H
H
Me
H


Me
Me
Me
H
H
H
Me


Me
Me
H
H
1-piperidinyl
H
H


Me
Me
H
H
4-morpholinyl 
H
H


Me
Me
Et
H
H
H
H


Me
Me
H
Et
H
H
H


Me
Me
H
H
Et
H
H


Me
i-Pr
H
Me
Me
H
H


Me
i-Pr
H
Me
H
H
H


Me
i-Pr
H
H
H
H
H







R1 is NHR3, X is Cl, and the metal cyanide reagent is sodium cyanide.













Me
Me
H
H
Me
H
H


Me
Me
H
H
NMe2
H
H


Me
Me
H
H
NEt2
H
H


Me
Me
H
H
1-pyrrolidinyl
H
H


Me
Me
H
H
H
H
H


Me
Me
H
Me
Me
H
H


Me
Me
H
Me
H
H
H


Me
Me
H
Me
H
Me
H


Me
Me
Me
H
H
H
H


Me
Me
Me
Me
H
H
H


Me
Me
Me
H
Me
H
H


Me
Me
Me
H
H
Me
H


Me
Me
Me
H
H
H
Me


Me
Me
H
H
1-piperidinyl
H
H


Me
Me
H
H
4-morpholinyl 
H
H


Me
Me
Et
H
H
H
H


Me
Me
H
Et
H
H
H


Me
Me
H
H
Et
H
H


Me
i-Pr
H
Me
Me
H
H


Me
i-Pr
H
Me
H
H
H


Me
i-Pr
H
H
H
H
H







R1 is NHR3, X is Br, and the metal cyanide reagent is sodium cyanide.













Cl
Me
H
H
Me
H
H


Cl
Me
H
H
NMe2
H
H


Cl
Me
H
H
NEt2
H
H


Cl
Me
H
H
1-pyrrolidinyl
H
H


Cl
Me
H
H
H
H
H


Cl
Me
H
Me
Me
H
H


Cl
Me
H
Me
H
H
H


Cl
Me
H
Me
H
Me
H


Cl
Me
Me
H
H
H
H


Cl
Me
Me
Me
H
H
H


Cl
Me
Me
H
Me
H
H


Cl
Me
Me
H
H
Me
H


Cl
Me
Me
H
H
H
Me


Cl
Me
H
H
1-piperidinyl
H
H


Cl
Me
H
H
4-morpholinyl 
H
H


Cl
Me
Et
H
H
H
H


Cl
Me
H
Et
H
H
H


Cl
Me
H
H
Et
H
H


Cl
i-Pr
H
Me
Me
H
H


Cl
i-Pr
H
Me
H
H
H


Cl
i-Pr
H
H
H
H
H







R1 is OR4, X is Br, and the metal cyanide reagent is sodium cyanide.













Me
H
H
H
Me
H
H


Me
Me
H
H
Me
H
H


Me
Et
H
H
Me
H
H


Me
n-Pr
H
H
Me
H
H


Me
i-Pr
H
H
Me
H
H


Me
n-Bu
H
H
Me
H
H


Me
i-Bu
H
H
Me
H
H


Me
s-Bu
H
H
Me
H
H


Me
t-Bu
H
H
Me
H
H


Cl
H
H
H
Me
H
H


Cl
Me
H
H
Me
H
H


Cl
Et
H
H
Me
H
H







R1 is OR4, X is Br, and the metal cyanide reagent is sodium cyanide.













Me
H
H
H
1-pyrrolidinyl
H
H


Me
Me
H
H
1-pyrrolidinyl
H
H


Me
Et
H
H
1-pyrrolidinyl
H
H


Me
n-Pr
H
H
1-pyrrolidinyl
H
H


Me
i-Pr
H
H
1-pyrrolidinyl
H
H


Me
H
H
H
NMe2
H
H


Me
Me
H
H
NMe2
H
H


Me
Et
H
H
NMe2
H
H


Me
n-Pr
H
H
NMe2
H
H


Me
i-Pr
H
H
NMe2
H
H


Me
H
H
H
NEt2
H
H


Me
Me
H
H
NEt2
H
H


Me
Et
H
H
NEt2
H
H


Me
n-Pr
H
H
NEt2
H
H


Me
i-Pr
H
H
NEt2
H
H


Me
H
H
H
Me
H
H


Me
Me
H
H
H
H
H


Me
Et
H
Me
Me
H
H


Me
n-Pr
H
Me
H
H
H


Me
i-Pr
H
Me
H
Me
H


Me
H
Me
H
H
H
H


Me
Me
Me
Me
H
H
H


Me
Et
Me
H
Me
H
H


Me
n-Pr
Me
H
H
Me
H


Me
i-Pr
Me
H
H
H
Me


Me
H
H
H
1-piperidinyl 
H
H


Me
H
H
H
4-morpholinyl 
H
H


Me
Me
Et
H
H
H
H


Me
Et
H
Et
H
H
H


Me
n-Pr
H
H
Et
H
H









Table 2 illustrates particular transformations to prepare compounds of Formula 4 from compounds of Formula 2 according to a method of the present invention. Conversion of the compound of Formula 1 to the compound of Formula 4 can, for example, be accomplished according to the method of Scheme 6 using a sulfonyl chloride such as methanesulfonyl chloride in the presence of a solvent such as acetonitrile and a base such as 3-picoline. For these transformations, the metal cyanide reagent is sodium cyanide, the copper(I) salt reagent and the iodide salt reagent are copper(I) iodide, and the compound of Formula 5 is 4-picoline (i.e. R5, R6, R8 and R9 are H, and R7 is methyl).







TABLE 2













 









R3
R12
R13










R2 is Me, X is Br, R14 is H and Z is N.









H
Br
F


Me
Br
F


Et
Br
F


n-Pr
Br
F


i-Pr
Br
F


n-Bu
Br
F


i-Bu
Br
F


s-Bu
Br
F


t-Bu
Br
F


c-Pr
Br
F


c-PrCH2
Br
F


1-CH3-c-Pr
Br
F


2-CH3-c-Pr
Br
F


1,1′-bicyclopropyl-2-yl
Br
F


1,1′-bicyclopropyl-1-yl
Br
F


(1R,2S)-1,1′-bicyclopropyl-2-yl
Br
F


H
Br
Cl


Me
Br
Cl


Et
Br
Cl


n-Pr
Br
Cl


i-Pr
Br
Cl


n-Bu
Br
Cl


i-Bu
Br
Cl


s-Bu
Br
Cl


t-Bu
Br
Cl


c-Pr
Br
Cl


c-PrCH2
Br
Cl


1-CH3-c-Pr
Br
Cl


2-CH3-c-Pr
Br
Cl


1,1′-bicyclopropyl-2-yl
Br
Cl


1,1′-bicyclopropyl-1-yl
Br
Cl


(1R,2R)-1,1′-bicyclopropyl-2-yl 
Br
Cl


H
Br
Br


Me
Br
Br


Et
Br
Br


n-Pr
Br
Br


i-Pr
Br
Br


n-Bu
Br
Br


i-Bu
Br
Br


s-Bu
Br
Br


t-Bu
Br
Br


c-Pr
Br
Br


c-PrCH2
Br
Br


1-CH3-c-Pr
Br
Br


2-CH3-c-Pr
Br
Br


1,1′-bicyclopropyl-2-yl
Br
Br


1,1′-bicyclopropyl-1-yl
Br
Br


H
Cl
F


Me
Cl
F


Et
Cl
F


n-Pr
Cl
F


i-Pr
Cl
F


n-Bu
Cl
F


i-Bu
Cl
F


s-Bu
Cl
F


t-Bu
Cl
F


c-Pr
Cl
F


c-PrCH2
Cl
F


1-CH3-c-Pr
Cl
F


2-CH3-c-Pr
Cl
F


1,1′-bicyclopropyl-2-yl
Cl
F


1,1′-bicyclopropyl-1-yl
Cl
F


(1S,2R)-1,1′-bicyclopropyl-2-yl
Cl
F


H
Cl
Cl


Me
Cl
Cl


Et
Cl
Cl


n-Pr
Cl
Cl


i-Pr
Cl
Cl


n-Bu
Cl
Cl


i-Bu
Cl
Cl


s-Bu
Cl
Cl


t-Bu
Cl
Cl


c-Pr
Cl
Cl


c-PrCH2
Cl
Cl


1-CH3-c-Pr
Cl
Cl


2-CH3-c-Pr
Cl
Cl


1,1′-bicyclopropyl-2-yl
Cl
Cl


1,1′-bicyclopropyl-1-yl
Cl
Cl


(1R,2R)-1,1′-bicyclopropyl-2-yl
Cl
Cl


H
Cl
Br


Me
Cl
Br


Et
Cl
Br


n-Pr
Cl
Br


i-Pr
Cl
Br


n-Bu
Cl
Br


i-Bu
Cl
Br


s-Bu
Cl
Br


t-Bu
Cl
Br


c-Pr
Cl
Br


c-PrCH2
Cl
Br


1-CH3-c-Pr
Cl
Br


2-CH3-c-Pr
Cl
Br


1,1′-bicyclopropyl-2-yl
Cl
Br


1,1′-bicyclopropyl-1-yl
Cl
Br


H
CF3
F


Me
CF3
F


t-Bu
CF3
F


1-CH3-c-Pr
CF3
F


2-CH3-c-Pr
CF3
F


1,1′-bicyclopropyl-1-yl
CF3
F


(1R,2S)-1,1′-bicyclopropyl-2-yl
CF3
F


H
CF3
Cl


Me
CF3
Cl


t-Bu
CF3
Cl


1-CH3-c-Pr
CF3
Cl


2-CH3-c-Pr
CF3
Cl


1,1′-bicyclopropyl-2-yl
CF3
Cl


1,1′-bicyclopropyl-1-yl
CF3
Cl


H
CF3
Br


Me
CF3
Br


t-Bu
CF3
Br


1-CH3-c-Pr
CF3
Br


2-CH3-c-Pr
CF3
Br


1,1′-bicyclopropyl-2-yl
CF3
Br


H
OCH2CF3
F


Me
OCH2CF3
F


t-Bu
OCH2CF3
F


1,1′-bicyclopropyl-1-yl
OCH2CF3
F


H
OCH2CF3
Cl


Me
OCH2CF3
Cl


t-Bu
OCH2CF3
Cl


1,1′-bicyclopropyl-1-yl
OCH2CF3
Cl


H
OCH2CF3
Br


Me
OCH2CF3
Br


t-Bu
OCH2CF3
Br


1,1′-bicyclopropyl-1-yl
OCH2CF3
Br


H
OCF2H
F


Me
OCF2H
F


t-Bu
OCF2H
F


1,1′-bicyclopropyl-2-yl
OCF2H
F


H
OCF2H
Cl


Me
OCF2H
Cl


t-Bu
OCF2H
Cl


1,1′-bicyclopropyl-1-yl
OCF2H
Cl


H
OCF2H
Br


Me
OCF2H
Br


t-Bu
OCF2H
Br







R2 is Me, X is Br, R14 is H and Z is CH.









H
Br
F


Me
Br
F


t-Bu
Br
F


c-Pr
Br
F


c-PrCH2
Br
F


1,1′-bicyclopropyl-2-yl
Br
F


1,1′-bicyclopropyl-1-yl
Br
F


(1R,2S)-1,1′-bicyclopropyl-2-yl 
Br
F


(1R,2R)-1,1′-bicyclopropyl-2-yl
Br
F


H
Br
Cl


Me
Br
Cl


t-Bu
Br
Cl


c-Pr
Br
Cl


c-PrCH2
Br
Cl


1,1′-bicyclopropyl-2-yl
Br
Cl


1,1′-bicyclopropyl-1-yl
Br
Cl


H
Br
Br


Me
Br
Br


t-Bu
Br
Br


c-Pr
Br
Br


c-PrCH2
Br
Br


1,1′-bicyclopropyl-2-yl
Br
Br


1,1′-bicyclopropyl-1-yl
Br
Br


H
Cl
F


Me
Cl
F


t-Bu
Cl
F


c-Pr
Cl
F


c-PrCH2
Cl
F


1,1′-bicyclopropyl-2-yl
Cl
F


1,1′-bicyclopropyl-1-yl
Cl
F


(1R,2R)-1,1′-bicyclopropyl-2-yl 
Cl
F


H
Cl
Cl


Me
Cl
Cl


t-Bu
Cl
Cl


c-Pr
Cl
Cl


c-PrCH2
Cl
Cl


1,1′-bicyclopropyl-2-yl
Cl
Cl


1,1′-bicyclopropyl-1-yl
Cl
Cl


(1S,2R)-1,1′-bicyclopropyl-2-yl
Cl
Cl


H
Cl
Br


Me
Cl
Br


t-Bu
Cl
Br


c-Pr
Cl
Br


c-PrCH2
Cl
Br


1,1′-bicyclopropyl-2-yl
Cl
Br


1,1′-bicyclopropyl-1-yl
Cl
Br


H
CF3
F


Me
CF3
F


t-Bu
CF3
F


2-CH3-c-Pr
CF3
F 


1,1′-bicyclopropyl-2-yl
CF3
F


H
CF3
Cl


Me
CF3
Cl


t-Bu
CF3
Cl


Me
CF3
Cl


Et
CF3
Br


c-Pr
CF3
Br


c-PrCH2
CF3
Br


1,1′-bicyclopropyl-2-yl
CF3
Br


Me
OCH2CF3
F


Et
OCH2CF3
F


c-Pr
OCH2CF3
F


c-PrCH2
OCH2CF3
Cl


1,1′-bicyclopropyl-2-yl
OCH2CF3
Cl


Me
OCH2CF3
Br


Et
OCH2CF3
Br


Me
OCF2H
F


Et
OCF2H
F


c-Pr
OCF2H
Cl


c-PrCH2
OCF2H
Cl


1,1′-bicyclopropyl-2-yl
OCF2H
Cl


Me
OCF2H
Br


Et
OCF2H
Br







R2 is Me, X is Br, R14 is F and Z is N.









H
Br
F


Me
Br
F


t-Bu
Br
F


c-Pr
Br
F


c-PrCH2
Br
F


1,1′-bicyclopropyl-2-yl
Br
F


1,1′-bicyclopropyl-1-yl
Br
F


H
Br
Cl


Me
Br
Cl


t-Bu
Br
Cl


c-Pr
Br
Cl


c-PrCH2
Br
Cl


1,1′-bicyclopropyl-1-yl
Br
Cl


H
Br
Br


Me
Br
Br


t-Bu
Br
Br


c-Pr
Br
Br


c-PrCH2
Br
Br


1,1′-bicyclopropyl-1-yl
Br
Br


(1R,2S)-1,1′-bicyclopropyl-2-yl 
Br
Br


H
Cl
F


Me
Cl
F


t-Bu
Cl
F


c-Pr
Cl
F


c-PrCH2
Cl
F


1,1′-bicyclopropyl-2-yl
Cl
F


H
Cl
Cl


Me
Cl
Cl


t-Bu
Cl
Cl


c-Pr
Cl
Cl


c-PrCH2
Cl
Cl


1,1′-bicyclopropyl-1-yl
Cl
Cl


H
Cl
Br


Me
Cl
Br


t-Bu
Cl
Br


c-Pr
Cl
Br


c-PrCH2
Cl
Br


1,1′-bicyclopropyl-2-yl
Cl
Br


1,1′-bicyclopropyl-1-yl
Cl
Br


H
CF3
F


Me
CF3
F


t-Bu
CF3
F


2-CH3-c-Pr
CF3
F 


1,1′-bicyclopropyl-2-yl
CF3
F


H
CF3
Cl


Me
CF3
Cl


t-Bu
CF3
Cl


Me
CF3
Br


Et
CF3
Br


c-Pr
CF3
Br


c-PrCH2
CF3
Br


1,1′-bicyclopropyl-2-yl
CF3
Br


Me
OCH2CF3
F


Et
OCH2CF3
F


c-Pr
OCH2CF3
Cl


c-PrCH2
OCH2CF3
Cl


1,1′-bicyclopropyl-1-yl
OCH2CF3
Cl


Me
OCH2CF3
Br


Et
OCH2CF3
Br


Me
OCF2H
F


Et
OCF2H
F


c-Pr
OCF2H
Cl


c-PrCH2
OCF2H
Cl


1,1′-bicyclopropyl-1-yl
OCF2H
Cl


Me
OCF2H
Br


Et
OCF2H
Br







R2 is Me, X is Br, R14 is Cl and Z is N.









H
Br
F


Me
Br
F


t-Bu
Br
F


c-Pr
Br
F


c-PrCH2
Br
F


1,1′-bicyclopropyl-2-yl
Br
F


1,1′-bicyclopropyl-1-yl
Br
F


H
Br
Cl


Me
Br
Cl


t-Bu
Br
Cl


c-Pr
Br
Cl


c-PrCH2
Br
Cl


1,1′-bicyclopropyl-2-yl
Br
Cl


(1R,2S)-1,1′-bicyclopropyl-2-yl
Br
Cl


H
Br
Br


Me
Br
Br


t-Bu
Br
Br


c-Pr
Br
Br


c-PrCH2
Br
Br


1,1′-bicyclopropyl-1-yl
Br
Br


(1R,2R)-1,1′-bicyclopropyl-2-yl
Br
Br


H
Cl
F


Me
Cl
F


t-Bu
Cl
F


c-Pr
Cl
F


c-PrCH2
Cl
F


1,1′-bicyclopropyl-2-yl
Cl
F


H
Cl
Cl


Me
Cl
Cl


t-Bu
Cl
Cl


c-Pr
Cl
Cl


c-PrCH2
Cl
Cl


1,1′-bicyclopropyl-2-yl
Cl
Cl


1,1′-bicyclopropyl-1-yl
Cl
Cl


H
Cl
Br


Me
Cl
Br


t-Bu
Cl
Br


c-Pr
Cl
Br


c-PrCH2
Cl
Br


1,1′-bicyclopropyl-2-yl
Cl
Br


1,1′-bicyclopropyl-1-yl
Cl
Br


H
CF3
F


Me
CF3
F


t-Bu
CF3
F


2-CH3-c-Pr
CF3
F


1,1′-bicyclopropyl-2-yl
CF3
F


1,1′-bicyclopropyl-1-yl
CF3
F


H
CF3
Cl


Me
CF3
Cl


t-Bu
CF3
Cl


Me
CF3
Br


Et
CF3
Br


c-Pr
CF3
Br


c-PrCH2
CF3
Br


1,1′-bicyclopropyl-2-yl
CF3
Br


Me
OCH2CF3
F


Et
OCH2CF3
F


c-Pr
OCH2CF3
Cl


c-PrCH2
OCH2CF3
Cl


1,1′-bicyclopropyl-1-yl
OCH2CF3
Cl


Me
OCH2CF3
Br


Et
OCH2CF3
Br


Me
OCF2H
F


Et
OCF2H
F


c-Pr
OCF2H
Cl


c-PrCH2
OCF2H
Cl


1,1′-bicyclopropyl-2-yl 
OCF2H
F


Me
OCF2H
Br


Et
OCF2H
Br







R2 is Me, X is Cl, R14 is H and Z is N.









H
Br
F


Me
Br
F


Et
Br
F


n-Pr
Br
F


i-Pr
Br
F


n-Bu
Br
F


i-Bu
Br
F


s-Bu
Br
F


t-Bu
Br
F


c-Pr
Br
F


c-PrCH2
Br
F


1-CH3-c-Pr
Br
F


2-CH3-c-Pr
Br
F


1,1′-bicyclopropyl-2-yl
Br
F


1,1′-bicyclopropyl-1-yl
Br
F


(1R,2S)-1,1′-bicyclopropyl-2-yl 
Br
F


H
Br
Br


Me
Br
Br


Et
Br
Br


n-Pr
Br
Br


i-Pr
Br
Br


n-Bu
Br
Br


i-Bu
Br
Br


s-Bu
Br
Br


t-Bu
Br
Br


c-Pr
Br
Br


c-PrCH2
Br
Br


1-CH3-c-Pr
Br
Br


2-CH3-c-Pr
Br
Br


1,1′-bicyclopropyl-2-yl
Br
Br


1,1′-bicyclopropyl-1-yl
Br
Br


(1S,2R)-1,1′-bicyclopropyl-2-yl
Br
Br


H
Cl
Cl


Me
Cl
Cl


Et
Cl
Cl


n-Pr
Cl
Cl


i-Pr
Cl
Cl


n-Bu
Cl
Cl


i-Bu
Cl
Cl


s-Bu
Cl
Cl


t-Bu
Cl
Cl


c-Pr
Cl
Cl


c-PrCH2
Cl
Cl


1-CH3-c-Pr
Cl
Cl


2-CH3-c-Pr
Cl
Cl


1,1′-bicyclopropyl-2-yl
Cl
Cl


1,1′-bicyclopropyl-1-yl
Cl
Cl


(1R,2R)-1,1′-bicyclopropyl-2-yl
Cl
Cl


H
CF3
F


Me
CF3
F


t-Bu
CF3
F


1-CH3-c-Pr
CF3
F


2-CH3-c-Pr
CF3
F


1,1′-bicyclopropyl-1-yl
CF3
F


(1R,2S)-1,1′-bicyclopropyl-2-yl
CF3
F


H
CF3
Br


Me
CF3
Br


t-Bu
CF3
Br


1-CH3-c-Pr
CF3
Br


2-CH3-c-Pr
CF3
Br


1,1′-bicyclopropyl-1-yl
CF3
Br


H
OCF2H
F


Me
OCF2H
F


t-Bu
OCF2H
F


1,1′-bicyclopropyl-1-yl
OCF2H
F


H
OCF2H
Cl


Me
OCF2H
Cl


t-Bu
OCF2H
Cl


1,1′-bicyclopropyl-2-yl
OCF2H
Cl


H
OCF2H
Br


Me
OCF2H
Br







R2 is Me, X is Cl, R14 is H and Z is CH.









H
Br
F


Me
Br
F


t-Bu
Br
F


c-Pr
Br
F


c-PrCH2
Br
F


1,1′-bicyclopropyl-2-yl
Br
F


1,1′-bicyclopropyl-1-yl
Br
F


(1R,2S)-1,1′-bicyclopropyl-2-yl
Br
F


(1R,2R)-1,1′-bicyclopropyl-2-yl
Br
F


H
Br
Br


Me
Br
Br


t-Bu
Br
Br


c-Pr
Br
Br


c-PrCH2
Br
Br


1,1′-bicyclopropyl-2-yl
Br
Br


1,1′-bicyclopropyl-1-yl
Br
Br


(1R,2R)-1,1′-bicyclopropyl-2-yl
Br
Br


H
Cl
Cl


Me
Cl
Cl


t-Bu
Cl
Cl


c-Pr
Cl
Cl


c-PrCH2
Cl
Cl


1,1′-bicyclopropyl-2-yl
Cl
Cl


1,1′-bicyclopropyl-1-yl
Cl
Cl


(1S,2R)-1,1′-bicyclopropyl-2-yl 
Cl
Cl


H
CF3
F


Me
CF3
F


t-Bu
CF3
F


2-CH3-c-Pr
CF3
F


1,1′-bicyclopropyl-2-yl
CF3
F


Me
OCH2CF3
F


Et
OCH2CF3
F


c-Pr
OCH2CF3
F


Me
OCH2CF3
Cl


c-PrCH2
OCH2CF3
Cl


1,1′-bicyclopropyl-1-yl
OCH2CF3
Cl


Me
OCH2CF3
Br


Et
OCH2CF3
Br


Et
OCH2CF3
Br


c-Pr
OCH2CF3
Br







R2 is Me, X is Cl, R14 is F and Z is N.









H
Br
F


Me
Br
F


t-Bu
Br
F


c-Pr
Br
F


c-PrCH2
Br
F


1,1′-bicyclopropyl-2-yl
Br
F


1,1′-bicyclopropyl-1-yl
Br
F


H
Br
Br


Me
Br
Br


t-Bu
Br
Br


c-Pr
Br
Br


c-PrCH2
Br
Br


1,1′-bicyclopropyl-2-yl
Br
Br


(1R,2S)-1,1′-bicyclopropyl-2-yl
Br
Br


H
Cl
Cl


Me
Cl
Cl


t-Bu
Cl
Cl


c-Pr
Cl
Cl


c-PrCH2
Cl
Cl


1,1′-bicyclopropyl-2-yl
Cl
Cl


1,1′-bicyclopropyl-1-yl
Cl
Cl


H
CF3
F


Me
CF3
F


t-Bu
CF3
F


2-CH3-c-Pr
CF3
F


1,1′-bicyclopropyl-2-yl
CF3
F


H
CF3
Cl


Me
CF3
Cl


t-Bu
CF3
Cl


c-Pr
CF3
Cl


Me
CF3
Br


Et
CF3
Br


c-Pr
CF3
Br


c-PrCH2
CF3
Br


1,1′-bicyclopropyl-1-yl
CF3
Br







R2 is Me, X is Cl, R14 is Cl and Z is N.









H
Br
F


Me
Br
F


t-Bu
Br
F


c-Pr
Br
F


c-PrCH2
Br
F


1,1′-bicyclopropyl-2-yl
Br
F


1,1′-bicyclopropyl-1-yl
Br
F


H
Br
Br


Me
Br
Br


t-Bu
Br
Br


c-Pr
Br
Br


c-PrCH2
Br
Br


1,1′-bicyclopropyl-1-yl
Br
Br


(1R,2R)-1,1′-bicyclopropyl-2-yl
Br
Br


H
Cl
Br


Me
Cl
Br


t-Bu
Cl
Br


c-Pr
Cl
Br


c-PrCH2
Cl
Br


1,1′-bicyclopropyl-2-yl
Cl
Br


1,1′-bicyclopropyl-1-yl
Cl
Br


H
CF3
F


Me
CF3
F


t-Bu
CF3
F


2-CH3-c-Pr
CF3
F


1,1′-bicyclopropyl-2-yl
CF3
F


1,1′-bicyclopropyl-1-yl
CF3
F


H
CF3
Cl


Me
CF3
Cl


t-Bu
CF3
Cl


Me
CF3
Br


Et
CF3
Br


c-Pr
CF3
Br


c-PrCH2
CF3
Br


1,1′-bicyclopropyl-1-yl
CF3
Br







R2 is Cl, X is Br, R14 is H and Z is N.









H
Br
F


Me
Br
F


Et
Br
F


n-Pr
Br
F


i-Pr
Br
F


n-Bu
Br
F


i-Bu
Br
F


s-Bu
Br
F


t-Bu
Br
F


c-Pr
Br
F


c-PrCH2
Br
F


1-CH3-c-Pr
Br
F


2-CH3-c-Pr
Br
F


1,1′-bicyclopropyl-2-yl
Br
F


1,1′-bicyclopropyl-1-yl
Br
F


(1R,2S)-1,1′-bicyclopropyl-2-yl
Br
F


H
Br
Cl


Me
Br
Cl


Et
Br
Cl


n-Pr
Br
Cl


i-Pr
Br
Cl


n-Bu
Br
Cl


i-Bu
Br
Cl


s-Bu
Br
Cl


t-Bu
Br
Cl


c-Pr
Br
Cl


c-PrCH2
Br
Cl


1-CH3-c-Pr
Br
Cl


2-CH3-c-Pr
Br
Cl


1,1′-bicyclopropyl-2-yl
Br
Cl


1,1′-bicyclopropyl-1-yl
Br
Cl


(1R,2R)-1,1′-bicyclopropyl-2-yl 
Br
Cl


H
Br
Br


Me
Br
Br


Et
Br
Br


n-Pr
Br
Br


i-Pr
Br
Br


n-Bu
Br
Br


i-Bu
Br
Br


s-Bu
Br
Br


t-Bu
Br
Br


c-Pr
Br
Br


c-PrCH2
Br
Br


1-CH3-c-Pr
Br
Br


2-CH3-c-Pr
Br
Br


1,1′-bicyclopropyl-2-yl
Br
Br


1,1′-bicyclopropyl-1-yl
Br
Br


H
Cl
F


Me
Cl
F


Et
Cl
F


n-Pr
Cl
F


i-Pr
Cl
F


n-Bu
Cl
F


i-Bu
Cl
F


s-Bu
Cl
F


t-Bu
Cl
F


c-Pr
Cl
F


c-PrCH2
Cl
F


1-CH3-c-Pr
Cl
F


2-CH3-c-Pr
Cl
F


1,1′-bicyclopropyl-2-yl
Cl
F


1,1′-bicyclopropyl-1-yl
Cl
F


(1S,2R)-1,1′-bicyclopropyl-2-yl
Cl
F


H
Cl
Cl


Me
Cl
Cl


Et
Cl
Cl


n-Pr
Cl
Cl


i-Pr
Cl
Cl


n-Bu
Cl
Cl


i-Bu
Cl
Cl


s-Bu
Cl
Cl


t-Bu
Cl
Cl


c-Pr
Cl
Cl


c-PrCH2
Cl
Cl


1-CH3-c-Pr
Cl
Cl


2-CH3-c-Pr
Cl
Cl


1,1′-bicyclopropyl-2-yl
Cl
Cl


1,1′-bicyclopropyl-1-yl
Cl
Cl


(1R,2R)-1,1′-bicyclopropyl-2-yl
Cl
Cl


H
Cl
Br


Me
Cl
Br


Et
Cl
Br


n-Pr
Cl
Br


i-Pr
Cl
Br


n-Bu
Cl
Br


i-Bu
Cl
Br


s-Bu
Cl
Br


t-Bu
Cl
Br


c-Pr
Cl
Br


c-PrCH2
Cl
Br


1-CH3-c-Pr
Cl
Br


2-CH3-c-Pr
Cl
Br


1,1′-bicyclopropyl-2-yl
Cl
Br


1,1′-bicyclopropyl-1-yl
Cl
Br


H
CF3
F


Me
CF3
F


t-Bu
CF3
F


1-CH3-c-Pr
CF3
F


2-CH3-c-Pr
CF3
F


1,1′-bicyclopropyl-1-yl
CF3
F


(1R,2S)-1,1′-bicyclopropyl-2-yl
CF3
F


H
CF3
Cl


Me
CF3
Cl


t-Bu
CF3
Cl


1-CH3-c-Pr
CF3
Cl


2-CH3-c-Pr
CF3
Cl


1,1′-bicyclopropyl-2-yl
CF3
Cl


1,1′-bicyclopropyl-1-yl
CF3
Cl


H
CF3
Br


Me
CF3
Br


t-Bu
CF3
Br


1-CH3-c-Pr
CF3
Br


2-CH3-c-Pr
CF3
Br


1,1′-bicyclopropyl-2-yl
CF3
Br


H
OCH2CF3
F


Me
OCH2CF3
F


t-Bu
OCH2CF3
F


1,1′-bicyclopropyl-1-yl
OCH2CF3
F


H
OCH2CF3
Cl


Me
OCH2CF3
Cl


t-Bu
OCH2CF3
Cl


1,1′-bicyclopropyl-1-yl
OCH2CF3
Cl


H
OCH2CF3
Br


Me
OCH2CF3
Br


t-Bu
OCH2CF3
Br


1,1′-bicyclopropyl-1-yl
OCH2CF3
Br


H
OCF2H
F


Me
OCF2H
F


t-Bu
OCF2H
F


1,1′-bicyclopropyl-2-yl
OCF2H
F


H
OCF2H
Cl


Me
OCF2H
Cl


t-Bu
OCF2H
Cl


1,1′-bicyclopropyl-1-yl
OCF2H
Cl


H
OCF2H
Br


Me
OCF2H
Br


t-Bu
OCF2H
Br







R2 is Cl, X is Br, R14 is H and Z is CH.









H
Br
F


Me
Br
F


t-Bu
Br
F


c-Pr
Br
F


c-PrCH2
Br
F


1,1′-bicyclopropyl-2-yl
Br
F


1,1′-bicyclopropyl-1-yl
Br
F


(1R,2S)-1,1′-bicyclopropyl-2-yl 
Br
F


(1R,2R)-1,1′-bicyclopropyl-2-yl
Br
F


H
Br
Cl


Me
Br
Cl


t-Bu
Br
Cl


c-Pr
Br
Cl


c-PrCH2
Br
Cl


1,1′-bicyclopropyl-2-yl
Br
Cl


1,1′-bicyclopropyl-1-yl
Br
Cl


H
Br
Br


Me
Br
Br


t-Bu
Br
Br


c-Pr
Br
Br


c-PrCH2
Br
Br


1,1′-bicyclopropyl-2-yl
Br
Br


1,1′-bicyclopropyl-1-yl
Br
Br


H
Cl
F


Me
Cl
F


t-Bu
Cl
F


c-Pr
Cl
F


c-PrCH2
Cl
F


1,1′-bicyclopropyl-2-yl
Cl
F


1,1′-bicyclopropyl-1-yl
Cl
F


(1R,2R)-1,1′-bicyclopropyl-2-yl 
Cl
F


H
Cl
Cl


Me
Cl
Cl


t-Bu
Cl
Cl


c-Pr
Cl
Cl


c-PrCH2
Cl
Cl


1,1′-bicyclopropyl-2-yl
Cl
Cl


1,1′-bicyclopropyl-1-yl
Cl
Cl


(1S,2R)-1,1′-bicyclopropyl-2-yl
Cl
Cl


H
Cl
Br


Me
Cl
Br


t-Bu
Cl
Br


c-Pr
Cl
Br


c-PrCH2
Cl
Br


1,1′-bicyclopropyl-2-yl
Cl
Br


1,1′-bicyclopropyl-1-yl
Cl
Br


H
CF3
F


Me
CF3
F


t-Bu
CF3
F


c-Pr
CF3
F 


1,1′-bicyclopropyl-2-yl
CF3
F


H
CF3
Cl


Me
CF3
Cl


t-Bu
CF3
Cl


Me
CF3
Cl


Et
CF3
Br


c-Pr
CF3
Br


c-PrCH2
CF3
Br


1,1′-bicyclopropyl-2-yl
CF3
Br


Me
OCH2CF3
F


Et
OCH2CF3
F


c-Pr
OCH2CF3
F


c-PrCH2
OCH2CF3
Cl


1,1′-bicyclopropyl-2-yl
OCH2CF3
Cl


Me
OCH2CF3
Br


Et
OCH2CF3
Br


Me
OCF2H
F


Et
OCF2H
F


c-Pr
OCF2H
Cl


c-PrCH2
OCF2H
Cl


1,1′-bicyclopropyl-2-yl
OCF2H
Cl


Me
OCF2H
Br


Et
OCF2H
Br







R2 is Cl, X is Br, R14 is F and Z is N.









H
Br
F


Me
Br
F


t-Bu
Br
F


c-Pr
Br
F


c-PrCH2
Br
F


1,1′-bicyclopropyl-2-yl
Br
F


1,1′-bicyclopropyl-1-yl
Br
F


H
Br
Cl


Me
Br
Cl


t-Bu
Br
Cl


c-Pr
Br
Cl


c-PrCH2
Br
Cl


1,1′-bicyclopropyl-1-yl
Br
Cl


H
Br
Br


Me
Br
Br


t-Bu
Br
Br


c-Pr
Br
Br


c-PrCH2
Br
Br


1,1′-bicyclopropyl-1-yl
Br
Br


(1R,2S)-1,1′-bicyclopropyl-2-yl 
Br
Br


H
Cl
F


Me
Cl
F


t-Bu
Cl
F


c-Pr
Cl
F


c-PrCH2
Cl
F


1,1′-bicyclopropyl-2-yl
Cl
F


H
Cl
Cl


Me
Cl
Cl


t-Bu
Cl
Cl


c-Pr
Cl
Cl


c-PrCH2
Cl
Cl


1,1′-bicyclopropyl-1-yl
Cl
Cl


H
Cl
Br


Me
Cl
Br


t-Bu
Cl
Br


c-Pr
Cl
Br


c-PrCH2
Cl
Br


1,1′-bicyclopropyl-2-yl
Cl
Br


1,1′-bicyclopropyl-1-yl
Cl
Br


H
CF3
F


Me
CF3
F


t-Bu
CF3
F


c-Pr
CF3
F 


1,1′-bicyclopropyl-2-yl
CF3
F


H
CF3
Cl


Me
CF3
Cl


t-Bu
CF3
Cl


Me
CF3
Br


Et
CF3
Br


c-Pr
CF3
Br


c-PrCH2
CF3
Br


1,1′-bicyclopropyl-2-yl
CF3
Br


Me
OCH2CF3
F


Et
OCH2CF3
F


c-Pr
OCH2CF3
Cl


c-PrCH2
OCH2CF3
Cl


1,1′-bicyclopropyl-1-yl
OCH2CF3
Cl


Me
OCH2CF3
Br


Et
OCH2CF3
Br


Me
OCF2H
F


Et
OCF2H
F


c-Pr
OCF2H
Cl


c-PrCH2
OCF2H
Cl


1,1′-bicyclopropyl-1-yl
OCF2H
Cl


Me
OCF2H
Br


Et
OCF2H
Br







R2 is Cl, X is Br, R14 is Cl and Z is N.









H
Br
F


Me
Br
F


t-Bu
Br
F


c-Pr
Br
F


c-PrCH2
Br
F


1,1′-bicyclopropyl-2-yl
Br
F


1,1′-bicyclopropyl-1-yl
Br
F


H
Br
Cl


Me
Br
Cl


t-Bu
Br
Cl


c-Pr
Br
Cl


c-PrCH2
Br
Cl


1,1′-bicyclopropyl-2-yl
Br
Cl


(1R,2S)-1,1′-bicyclopropyl-2-yl
Br
Cl


H
Br
Br


Me
Br
Br


t-Bu
Br
Br


c-Pr
Br
Br


c-PrCH2
Br
Br


1,1′-bicyclopropyl-1-yl
Br
Br


(1R,2R)-1,1′-bicyclopropyl-2-yl
Br
Br


H
Cl
F


Me
Cl
F


t-Bu
Cl
F


c-Pr
Cl
F


c-PrCH2
Cl
F


1,1′-bicyclopropyl-2-yl
Cl
F


H
Cl
Cl


Me
Cl
Cl


t-Bu
Cl
Cl


c-Pr
Cl
Cl


c-PrCH2
Cl
Cl


1,1′-bicyclopropyl-2-yl
Cl
Cl


1,1′-bicyclopropyl-1-yl
Cl
Cl


H
Cl
Br


Me
Cl
Br


t-Bu
Cl
Br


c-Pr
Cl
Br


c-PrCH2
Cl
Br


1,1′-bicyclopropyl-2-yl
Cl
Br


1,1′-bicyclopropyl-1-yl
Cl
Br


H
CF3
F


Me
CF3
F


t-Bu
CF3
F


c-Pr
CF3
F


1,1′-bicyclopropyl-2-yl
CF3
F


1,1′-bicyclopropyl-1-yl
CF3
F


H
CF3
Cl


Me
CF3
Cl


t-Bu
CF3
Cl


Me
CF3
Br


Et
CF3
Br


c-Pr
CF3
Br


c-PrCH2
CF3
Br


1,1′-bicyclopropyl-2-yl
CF3
Br


Me
OCH2CF3
F


Et
OCH2CF3
F


c-Pr
OCH2CF3
Cl


c-PrCH2
OCH2CF3
Cl


1,1′-bicyclopropyl-1-yl
OCH2CF3
Cl


Me
OCH2CF3
Br


Et
OCH2CF3
Br


Me
OCF2H
F


Et
OCF2H
F


c-Pr
OCF2H
Cl


c-PrCH2
OCF2H
Cl


1,1′-bicyclopropyl-2-yl 
OCF2H
F


Me
OCF2H
Br


Et
OCF2H
Br







R2 is Me, X is Cl, R14 is H and Z is N.









H
Br
Cl


Me
Br
Cl


Et
Br
Cl


n-Pr
Br
Cl


i-Pr
Br
Cl


n-Bu
Br
Cl


i-Bu
Br
Cl


s-Bu
Br
Cl


t-Bu
Br
Cl


c-Pr
Br
Cl


c-PrCH2
Br
Cl


1-CH3-c-Pr
Br
Cl


2-CH3-c-Pr
Br
Cl


1,1′-bicyclopropyl-2-yl
Br
Cl


1,1′-bicyclopropyl-1-yl
Br
Cl


(1R,2R)-1,1′-bicyclopropyl-2-yl 
Br
Cl


H
Cl
F


Me
Cl
F


Et
Cl
F


n-Pr
Cl
F


i-Pr
Cl
F


n-Bu
Cl
F


i-Bu
Cl
F


s-Bu
Cl
F


t-Bu
Cl
F


c-Pr
Cl
F


c-PrCH2
Cl
F


1-CH3-c-Pr
Cl
F


2-CH3-c-Pr
Cl
F


1,1′-bicyclopropyl-2-yl
Cl
F


1,1′-bicyclopropyl-1-yl
Cl
F


(1S,2R)-1,1′-bicyclopropyl-2-yl
Cl
F


H
Cl
Br


Me
Cl
Br


Et
Cl
Br


n-Pr
Cl
Br


i-Pr
Cl
Br


n-Bu
Cl
Br


i-Bu
Cl
Br


s-Bu
Cl
Br


t-Bu
Cl
Br


c-Pr
Cl
Br


c-PrCH2
Cl
Br


1-CH3-c-Pr
Cl
Br


2-CH3-c-Pr
Cl
Br


1,1′-bicyclopropyl-2-yl
Cl
Br


1,1′-bicyclopropyl-1-yl
Cl
Br


(1R,2R)-1,1′-bicyclopropyl-2-yl
Cl
Br


H
CF3
Cl


Me
CF3
Cl


t-Bu
CF3
Cl


1-CH3-c-Pr
CF3
Cl


2-CH3-c-Pr
CF3
Cl


1,1′-bicyclopropyl-2-yl
CF3
Cl


1,1′-bicyclopropyl-1-yl
CF3
Cl


H
OCH2CF3
F


Me
OCH2CF3
F


t-Bu
OCH2CF3
F


1-CH3-c-Pr
OCH2CF3
F


1,1′-bicyclopropyl-1-yl
OCH2CF3
F


H
OCH2CF3
Cl


Me
OCH2CF3
Cl


t-Bu
OCH2CF3
Cl


2-CH3-c-Pr
OCH2CF3
Cl


1,1′-bicyclopropyl-1-yl
OCH2CF3
Cl


H
OCH2CF3
Br


Me
OCH2CF3
Br


t-Bu
OCH2CF3
Br


1-CH3-c-Pr
OCH2CF3
Br


1,1′-bicyclopropyl-2-yl
OCH2CF3
Br


t-Bu
OCF2H
Br







R2 is Me, X is Cl, R14 is H and Z is CH.









H
Br
Cl


Me
Br
Cl


t-Bu
Br
Cl


c-Pr
Br
Cl


c-PrCH2
Br
Cl


1,1′-bicyclopropyl-2-yl
Br
Cl


1,1′-bicyclopropyl-1-yl
Br
Cl


(1R,2S)-1,1′-bicyclopropyl-2-yl
Br
Cl


(1R,2R)-1,1′-bicyclopropyl-2-yl
Br
Cl


H
Cl
F


Me
Cl
F


t-Bu
Cl
F


c-Pr
Cl
F


c-PrCH2
Cl
F


1,1′-bicyclopropyl-2-yl
Cl
F


1,1′-bicyclopropyl-1-yl
Cl
F


(1R,2R)-1,1′-bicyclopropyl-2-yl
Cl
F


H
Cl
Br


Me
Cl
Br


t-Bu
Cl
Br


c-Pr
Cl
Br


c-PrCH2
Cl
Br


1,1′-bicyclopropyl-2-yl
Cl
Br


1,1′-bicyclopropyl-1-yl
Cl
Br


(1S,2R)-1,1′-bicyclopropyl-2-yl 
Cl
Br


H
CF3
Cl


Me
CF3
Cl


t-Bu
CF3
Cl


Me
CF3
Cl


Et
CF3
Br


c-Pr
CF3
Br


c-PrCH2
CF3
Br


1,1′-bicyclopropyl-1-yl
CF3
Br


Me
OCF2H
F


Et
OCF2H
F


c-Pr
OCF2H
Cl


c-PrCH2
OCF2H
Cl


1,1′-bicyclopropyl-1-yl
OCF2H
Cl


Me
OCF2H
Br


Et
OCF2H
Br







R2 is Me, X is Cl, R14 is F and Z is N.









H
Br
Cl


Me
Br
Cl


t-Bu
Br
Cl


c-Pr
Br
Cl


c-PrCH2
Br
Cl


1,1′-bicyclopropyl-2-yl
Br
Cl


1,1′-bicyclopropyl-1-yl
Br
Cl


H
Cl
F


Me
Cl
F


t-Bu
Cl
F


c-Pr
Cl
F


c-PrCH2
Cl
F


1,1′-bicyclopropyl-1-yl
Cl
F


(1R,2S)-1,1′-bicyclopropyl-2-yl
Cl
F


H
Cl
Br


Me
Cl
Br


t-Bu
Cl
Br


c-Pr
Cl
Br


c-PrCH2
Cl
Br


1,1′-bicyclopropyl-2-yl
Cl
Br


1,1′-bicyclopropyl-1-yl
Cl
Br


Me
OCH2CF3
F


Et
OCH2CF3
F


c-Pr
OCH2CF3
Cl


c-PrCH2
OCH2CF3
Cl


1,1′-bicyclopropyl-1-yl
OCH2CF3
Cl


Me
OCH2CF3
Br


Et
OCH2CF3
Br


Me
OCF2H
F


Et
OCF2H
F


c-Pr
OCF2H
Cl


c-PrCH2
OCF2H
Cl


1,1′-bicyclopropyl-2-yl
OCF2H
Cl


Me
OCF2H
Br


Et
OCF2H
Br







R2 is Me, X is Cl, R14 is Cl and Z is N.









H
Br
Cl


Me
Br
Cl


t-Bu
Br
Cl


c-Pr
Br
Cl


c-PrCH2
Br
Cl


1,1′-bicyclopropyl-2-yl
Br
Cl


(1R,2S)-1,1′-bicyclopropyl-2-yl
Br
Cl


H
Cl
F


Me
Cl
F


t-Bu
Cl
F


c-Pr
Cl
F


c-PrCH2
Cl
F


1,1′-bicyclopropyl-2-yl
Cl
F


(1R,2R)-1,1′-bicyclopropyl-2-yl
Cl
F


H
Cl
Cl


Me
Cl
Cl


t-Bu
Cl
Cl


c-Pr
Cl
Cl


c-PrCH2
Cl
Cl


1,1′-bicyclopropyl-2-yl
Cl
Cl


1,1′-bicyclopropyl-1-yl
Cl
Cl


Me
OCH2CF3
F


Et
OCH2CF3
F


c-Pr
OCH2CF3
Cl


c-PrCH2
OCH2CF3
Cl


1,1′-bicyclopropyl-1-yl
OCH2CF3
Cl


Me
OCH2CF3
Br


Et
OCH2CF3
Br


Me
OCF2H
F


Et
OCF2H
F


c-Pr
OCF2H
Cl


c-PrCH2
OCF2H
Cl


1,1′-bicyclopropyl-2-yl
OCF2H
F


Me
OCF2H
Br


Et
OCF2H
Br

## Claims

1. A method for preparing a compound of Formula 1




wherein
R1 is NHR3;
R2 is CH3 or Cl; and
R3 is H, C1-C4 alkyl, cyclopropyl, cyclopropylcyclopropyl, cyclopropylmethyl or methylcyclopropyl;

comprising contacting (1) a compound of Formula 2




wherein X is Br or Cl;
with (2) a metal cyanide reagent, (3) a copper(I) salt reagent, (4) an iodide salt reagent and (5) at least one compound of Formula 3




wherein
each R5, R6, R7, R8 and R9 is independently H, C1-C12 alkyl, C1-C6 alkoxy or NR10R11; and
each R10 and R11 is independently H or C1-C6 alkyl; or
a pair of R10 and R11 attached to the same nitrogen are taken together as —CH2CH2CH2—, —CH2CH2CH2CH2—, —CH2(CH2)3 CH2—, —CH2CH2OCH2CH2—, —CH2CH2N(R16)CH2CH2— or —CH2CH2S(O)nCH2CH2—, each optionally substituted with up to 4 substituents independently selected from C1-C4 alkyl;
each R16 is independently H or C1-C12 alkyl; and
each n is independently 0, 1 or 2;

provided that when X is Cl , then R2 is methyl.

2. The method of claim 1 wherein the copper(I) salt reagent and the iodide salt reagent comprise copper(I) iodide.

3. The method of claim 1 wherein the at least one compound of Formula 3 comprises one or more compounds selected from the group consisting of pyridine, 3-picoline, 4-picoline, 4-ethylpyridine, 4-tert-butylpyridine, 3,4-lutidine, 3,5-lutidine, 4-methoxypyridine, 4-(dimethylamino)pyridine, 4-(diethylamino)pyridine, 4-pyrrolidinopyridine and 4-morpholinopyridine.

4. The method of claim 3 wherein the at least one compound of Formula 3 comprises one or more compounds selected from the group consisting of pyridine, 4-picoline, 3-picoline, 3,4-lutidine, 3,5-lutidine and N,N-dimethyl-4-pyridinamine.

5. The method of claim 4 wherein the at least one compound of Formula 3 comprises 4-picoline.

6. The method of claim 1 wherein the compound of Formula 2, the metal cyanide reagent, the copper(I) salt reagent, the iodide salt reagent and the at least one compound of Formula 3 are contacted in the presence of a suitable organic solvent; and wherein the mole ratio of the Formula 3 component to the copper(I) salt reagent component is between about 1:1 and about 1:3.

7. The method of claim 1 wherein the compound of Formula 2 is contacted with a suitable organic solvent to form a mixture, and then the metal cyanide reagent, the copper(I) salt reagent, the iodide salt reagent and the at least one compound of Formula 3 are sequentially added to the mixture.

8. The method of claim 1 wherein a compound of Formula 2, the metal cyanide reagent, the copper(I) salt reagent, the iodide salt reagent and the at least one compound of Formula 3 are contacted in the presence of a suitable organic solvent to form a mixture, and the temperature of the mixture is between about 155 and 200° C.

9. The method of claim 1 wherein the compound of Formula 2, the metal cyanide reagent, the copper(I) salt reagent, the iodide salt reagent and the at least one compound of Formula 3 are contacted in the presence of a suitable organic solvent comprising one or more solvents selected from the group consisting of xylenes, toluene, chlorobenzene, anisole, 1,2,4-trimethylbenzene, 1,3,5-trimethylbenzene, ethylbenzene, (1-methylethyl)benzene and 1-methylnaphthalene.

10. The method of claim 9 wherein the suitable organic solvent comprises one or more solvents selected from the group consisting of xylenes, toluene, anisole, 1,2,4-trimethylbenzene, 1,3,5-trimethylbenzene and 1-methylnaphthalene.

11. The method of claim 10 wherein the suitable organic solvent comprises xylenes, toluene or anisole.

12. The method of claim 1 wherein the metal cyanide reagent comprises one or more compounds selected from the group consisting of alkali metal cyanides and alkali metal hexacyanoferrates(II).

13. The method of claim 12 wherein the metal cyanide reagent comprises one or more compounds selected from the group consisting of sodium cyanide, potassium cyanide, sodium hexacyanoferrate(II) and potassium hexacyanoferrate(II).

14. The method of claim 13 wherein the metal cyanide comprises sodium cyanide.

15. The method of claim 1 wherein X is Br and the compound of Formula 1 is prepared as a solid comprising: contacting a compound of Formula 2 with a suitable organic solvent to form a mixture, and then sequentially adding the metal cyanide reagent, the copper(I) salt reagent, the iodide salt reagent and the compound or compounds of Formula 3, maintaining the temperature of the mixture between about 145 and 180° C. for about 6 to about 12 h, cooling the mixture to between about 0 and 50° C., adding water to the mixture, optionally stirring for about 1 to about 2 h, and then recovering a compound of Formula 1 as a solid from the mixture.

16. The method of claim 1 wherein the compound of Formula 1 is 2-amino-5-cyano-N,3-dimethylbenzamide.