WO2002056681A2

WO2002056681A2 - Novel intermediates and process to pyrimidinedione herbicides

Info

Publication number: WO2002056681A2
Application number: PCT/US2001/050000
Authority: WO
Inventors: Jaidev S. Goudar; Guozhi Wang
Original assignee: Fmc Corporation
Priority date: 2000-10-25
Filing date: 2001-10-19
Publication date: 2002-07-25
Also published as: AU2002246798A1; WO2002056681A3

Abstract

A class of novel intermediates is described that have utility in processes for preparing uracil herbicides; wherein the novel intermediates are compounds of formula (A) which are cyclized with at least one cyclizing agent of formula (B) to provide a penultimate intermediate to, or a uracil herbicide, both of formula (I) where (X)n, Y, Z, R, R?1, R5, R7, and R8¿ are fully described herein. Preferred are those where Y and Z taken together are -N=C(R2)-NR3-, (X)¿n? is 4-fluoro-6-chloro; R is hydrogen and methyl; R?1 and R2¿ are trifluoromethyl, and R3 is hydrogen.

Description

Novel Intermediates and Process to Pyrimidinedione Herbicides

FIELD OF THE INVENTION The present invention relates generally to the field of organic chemical synthesis. In particular, it pertains to novel intermediates useful in a process for preparing pyrimidinedione herbicides.

BACKGROUND OF THE INVENTION The compound 3-(2-trifluoromethyl-4-chloro-6-fluorobenzimidazol-7-yl)-

1 -methyl-6-trifluoromethyl-2,4( 1 H,3H)pyrimidinedione (termed "uracil herbicide") is a potentially commercial herbicide that provides control of broad- leaf weeds which would otherwise cause significant damage to grasseous crops, such as corn and wheat. For example, US Patent 6,077,812 discloses a class of herbicides that includes the aforementioned uracil herbicide, compositions containing them, and methods for their use in controlling weeds. Additionally, US Patent 6,077,812 discloses a method to prepare the uracil herbicide in which the uracil moiety is formed early in the reaction sequence, prior to forming the benzimidazole moiety of the molecule. The disclosed method reacts an ethyl N- (substituted-2-fluorophenyl)carbamate with the cyclizing agent ethyl 3-amino- 4,4,4-trifluoro-2-butenoate, to obtain a 3-(substituted-2-fluorophenyl)-6- trifluoromethyl-2,4(lH,3H)pyrimidinedione. The so-formed pyrimidinedione is then subjected to a series of at least five more reactive steps of diminishing overall yield in which the benzimidazole is formed from the substituted 2-fluorophenyl moiety, providing the aforementioned uracil herbicide.

Cyclizing agents, such as ethyl 3-amino-4,4,4-trifluoro-2-butenoate and ethyl 3-methylamino-4,4,4-trifluoro-2-butenoate, are relatively expensive. In a process to prepare commercial quantities of the uracil herbicide, it is therefore economically unfeasible, at least by methods disclosed in US Patent 6,077,812, to prepare the uracil moiety early in the reaction sequence and subject it to reactive steps of diminishing overall yield to obtain the uracil herbicide. Accordingly, it would be desirable to have a process in which the uracil moiety is formed in the ultimate step, or the penultimate step in the process to prepare the aforementioned uracil herbicide.

SUMMARY OF THE INVENTION

Accordingly, the objects of the present invention include the following: 1) a class of novel intermediates with utility in processes, to prepare uracil herbicides; and 2) a process, in which the novel intermediates are used to prepare uracil herbicides wherein the ultimate, or penultimate step is the formation of the uracil moiety.

By bringing the expensive cyclizing agent into the reaction sequence late, subsequent to forming the benzimidazole moiety of the molecule, the methods of the present invention offer a more cost-effective approach to preparing a uracil herbicide by optimizing the required amount of cyclizing agent. Accordingly, one embodiment of the present invention is the novel intermediates, which are compounds of formula A, of the following structure:

A wherein n is 0-3;

X is selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, cyano, nitro, and amino, and is the same or different when n is 2 or 3; Y is selected from the group consisting of hydrogen, nitro, amino, and

-NHC(O)-R²; and Z is selected from the group consisting of hydrogen, nitro, amino, -

NHC(O)-R², and -NHCO₂R⁴, or

Y and Z taken together are -N=C(R²)-NR³- where; 2 R is hydrogen, hydroxy, thiol, straight or branched chain alkyl, cycloalkyl, alkoxy, aryl, heteroaryl, alkenyl, haloalkyl, hydroxyalkyl, haloaryl, alkoxyaryl, arylalkyl, aryloxyalkyl, haloarylalkyl, alkylthio, heterocyclyl, alkoxyalkyl, alkoxyalkyloxyalkyl, alkylcarbonyloxyalkyl, arylcarbonyloxyalkyl, aminocarbonyloxyalkyl, aminoalkyl, cyanoalkyl, aminoalkenyl, carboxy, carboxyalkyl, alkylcarboxy, alkylcarboxyalkyl, formyl, aminocarbonyl, amino, oxygen, cyano, nitro, alkylsulfonyl, aminosulfonyl, alkylsulfonylamino, alkoxycarbonyloxyalkyl, alkylcarboxylalkoxy, alkoxycarbonylamino, alkoxycarbonylalkylaminoalkyl, aryliminoalkyl, (aryl)(alkoxy)alkyl, (aryl)(alkylcarbonyloxy)alkyl, arylalkoxyalkyl, cyanoalkylthio, alkynylalkylthio, arylalkylthio, cyanothio, cyanothioalkyl, alkoxycarbonylalkylthio, aminocarbonylalkylthio, alkenylalkylthio, haloalkylalkynylalkylthio, aminocarbonyloxyalkyl, arylalkylcarbonylaminoalkyl, (hydroxy)(aryl)alkyl, alkylcarbonylaminoalkyl, alkylsulfonylaminoalkyl, aminocarbonylalkyl, alkoxycarbonyl, and alkenyloxy, where the amino group may be substituted with one or two substituents independently selected from alkyl, hydroxy, alkoxy, carboxy, aryl, alkylsulfonyl, or haloalkylsulfonyl;

3 R is hydrogen, alkyl, haloalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, carboxyalkyl, alkoxyalkyl,

4 alkylsulfonyl, alkenyl, alkynyl, or -CO₂R ; and,

R is hydrogen, or -CO2R , where R and R are independently Ci to C12 straight or branched chain alkyl; with the proviso that when Y is hydrogen, nitro, or amino, Z and R are other than hydrogen.

A second embodiment of the present invention is a process in which the novel intermediates of formula A have utility in preparing a uracil herbicide or the penultimate compound, namely in the case of the uracil herbicide identified above, 3-(2-trifluoromethyl-4-cUoro-6-fluorobenzimidazol-7-yl)-6-trifluoromethyl- 2,4(lH,3H)pyrimidinedione (both uracil herbicide and penultimate compound hereinafter termed "compound or compounds of formula I"). Said process, as set forth below, is one wherein a compound of formula I:

I is prepared from a compound of formula A:

where R is selected from the group consisting of hydrogen, alkyl, haloalkyl, cyanoalkyl, alkenyl, alkynyl, alkoxycarbonylalkyl, alkoxyalkyl, and amino; R is selected from the group consisting of alkyl and haloalkyl; Y and Z taken together are -N=C(R )-N(R )-; and n, X, R -R are as described above; which process comprises cyclizing a compound of formula A with at least one cyclizing agent of formula B:

B wherein

1 8 9 7

R and R are described above; R is hydrogen, and -CO2R where R and

9 R are independently Ci to C12 straight or branched chain alkyl. Other aspects of the invention will also be apparent. DETAILED DESCRIPTION OF THE INVENTION A class of novel intermediates has now been found that has utility in a process to prepare a uracil herbicide. The process in which the novel intermediates find utility lead to formation of a uracil herbicide wherein the ultimate, or penultimate step is the formation of the uracil moiety.

The first embodiment of the present invention is the novel intermediates, a compound of formula A:

A wherein n is 0-3;

X is selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, cyano, nitro, and amino, and is the same or different when n is 2 or 3;

Y is selected from the group consisting of hydrogen, nitro, amino, and -NHC(O)-R²; and

Z is selected from the group consisting of hydrogen, nitro, amino, -NHC(O)-R², and -NHCO₂R⁴, or

Y and Z taken together are -N=C(R²)-NR³-,

2 where R is hydrogen, hydroxy, thiol, straight or branched chain alkyl, cycloalkyl, alkoxy, aryl, heteroaryl, alkenyl, haloalkyl, hydroxyalkyl, haloaryl, alkoxyaryl, arylalkyl, aryloxyalkyl, haloarylalkyl, alkylthio, heterocyclyl, alkoxyalkyl, alkoxyalkyloxyalkyl, alkylcarbonyloxyalkyl, arylcarbonyloxyalkyl, aminocarbonyloxyalkyl, aminoalkyl, cyanoalkyl, aminoalkenyl, carboxy, carboxyalkyl, alkylcarboxy, alkylcarboxyalkyl, formyl, aminocarbonyl, amino, oxygen, cyano, nitro, alkylsulfonyl, aminosulfonyl, alkylsulfonylamino, alkoxycarbonyloxyalkyl, alkylcarboxylalkoxy, alkoxycarbonylamino, alkoxycarbonylalkylaminoalkyl, aryliminoalkyl, (aryl)(alkoxy)alkyl,

(aryl)(alkylcarbonyloxy)alkyl, arylalkoxyalkyl, cyanoalkylthio, alkynylalkylthio, arylalkylthio, cyanothio, cyanothioalkyl, alkoxycarbonylalkylthio, aminocarbonylalkylthio, alkenylalkylthio, haloalkylalkynylalkylthio, aminocarbonyloxyalkyl, arylalkylcarbonylaminoalkyl, (hydroxy)(aryl)alkyl, alkylcarbonylaminoalkyl, alkylsulfonylaminoalkyl, aminocarbonylalkyl, alkoxycarbonyl, and alkenyloxy, where the amino group may be substituted with one or two substituents independently selected from alkyl, hydroxy, alkoxy, carboxy, aryl, alkylsulfonyl, or haloalkylsulfonyl;

4 alkylsulfonyl, alkenyl, alkynyl, or -CO₂R ; and,

Preferred compounds of formula A are those wherein n is 1, or 2; X is

2 halogen; R is alkyl, hydroxyalkyl, haloalkyl, cyanoalkyl, alkoxycarbonylalkyl,

3 alkylcarbonyloxyalkyl, or alkylsulfonylaminoalkyl; R is hydrogen, alkyl, haloalkyl, or

4 4 6

-CO₂R , where R and R are independently Ci to C straight or branched chain alkyl. More preferred compounds of formula A are those wherein n is 1 and X is

2 3 fluoro, and n is 2 and X is fluoro and chloro; R is trifluoromethyl; R is hydrogen,

4 4 6 and -CO₂R , where R and R are independently methyl, ethyl, and straight or branched chain propyl and butyl.

Within the class of compounds of formula A, most preferred are those i) wherein n is 2; X is 4-fluoro-6-chloro; Y is hydrogen; Z is nitro; and R is - CO2R , where R is ethyl; ii) wherein n is 2; X is 4-fluoro-6-chloro; Y is hydrogen; Z is amino; and R is -CO2 , where R is ethyl; iii) wherein n is 2; X is 4-fluoro-6-chloro; Y is

0 0 ^ f hydrogen; Z is -NHC(O)R , where R is trifluoromethyl; and R is -CO2R , where R is ethyl;

2 2 iv) wherein n is 2; X is 4-fluoro-6-chloro; Y is nitro; Z is -NHC(O)R , where R is trifluoromethyl; and

is ethyl; v) wherein n is 1; X is 4-

2 2 5 fluoro; Y is -NHC(O)R , where R is trifluoromethyl; and Z and R are hydrogen;

2 2 vi) wherein n is 1; X is 4-fluoro; Y is -NHC(O)R , where R is trifluoromethyl; Z is hydrogen; and R is

-CO2R , where R is ethyl; vii) wherein n is 2; X is 4-fluoro-6-chloro; Y is -

0 0 ^ f NHC(O)R , where R is trifluoromethyl; Z is hydrogen; and R is -CO2R , where

R is ethyl;

2 2 viii) wherein n is 2; X is 4-fluoro-6-chloro; Y is -NHC(O)R , where R is

trifluoromethyl; Z is nitro; and R is -CO2 , where is ethyl; ix) wherein n is

2 2

2; X is 4-fluoro-6-chloro; Y is -NHC(O)R , where R is trifluoromethyl; Z is

amino; and

, where is ethyl; x) wherein n is 2; X is 4-fluoro-6- chloro; Y is -NHC(O)R², where R² is trifluoromethyl; Z is -NHCO₂R⁴, where R⁴ c f_\ f_t is n-butyl; and R is -CO2R , where R is ethyl; xi) wherein n is 2; X is 4-fluoro-

6-chloro; Y is nitro; Z is amino; and R is -CO2

is ethyl; xii) wherein n is 2; X is 4-fluoro-6-chloro; Y and Z are amino; and R is -CO

is ethyl; xiii) wherein n is 2; X is 4-fluoro-6-chloro; Y and Z taken together are -

N=C

, where R is ethyl; xiv) wherein n is 2; X is 4-fluoro-6-chloro; Y and Z taken

2 3 2 3 together are -N=C(R )-NR -, where R is trifluoromethyl; R is 4 4 5 6 6

-CO2R , where R is n-butyl; and R is -CO2R , where R is ethyl; and xv),

2 3 wherein n is 2; X is 4-fluoro-6-chloro; Y and Z taken together are -N=C(R )-NR -

2 3 5

, where R is trifluoromethyl; and R and R are hydrogen.

In one aspect of the present invention, certain compounds of formula A, for example, Compounds 26, 27, 28, and 29 described in detail below, were prepared in a step-wise manner from 2,4-dinitrofluorobenzene by methods known to one skilled in the art, as depicted in Scheme 1, presented below:

Scheme 1 Compounds of Formula A Derived From 2.4-Dinitrofluorobenzene

a: 3-N0₂ to -NHR⁵ where R⁵ is H (Cmpd 8) b: R⁵ is H to -C0₂R⁶ where R⁶ is -C₂H₅ (Cmpd 9) c: Y is -N0₂ to -NH₂ (Cmpd 10) d: Y is -NH₂ to -NHC(0)R² where R² is -CF₃ (Cmpd 13)

Compound of Formula A Cmpd 26 Compound of Formula A Cmpd 27

a) H₂/Pd on C/Fe/EtOH/AcOH; b) EtOCOCl/Na₂C0₃; c) H₂/Pd on C; d) (CF₃CO)₂0/CH₂Cl2; e) H₂/Pd on C/V₂O_s; f) CF₃C0₂Ph/Et₃N/DMF; g) EtOCOCl/DMF; h) CI2/CH3CN; i) 70% HN0₃/85% H₃P0₄/95% H₂S0₄; j) Pd on C/V₂0₅/Fe/AcOH/ pressure; k) aq. 10% Na₂C0₃/(n-Bu)4NBr/EtOAc; 1) H₂/Pt onC/V₂0₅/conc. HCl/EtOAc; m) BuOCOCl/aq. 10% Na₂C0₃/EtOAc; o) heat; p) NaOH/H₂0/heat

Intermediate Compound 13, for example, was prepared in a step-wise manner from 2,4-dinitrofluorobenzene. The selective hydrogenation of the 2-nitro moiety of 2,4-dinitrofluorobenzene in the presence of 5% palladium on carbon and acetic acid in a solvent, such as ethyl acetate, yielded the corresponding 2-fluoro-5- nitroaniline (Compound 8). Compound 8, was in turn reacted with ethyl chloroformate under basic conditions, affording ethyl N-(2-fiuoro-4- nitrophenyl)carbamate (Compound 9); which was then reduced by hydrogenation of the 4-nitro moiety, under conditions previously described, to yield the corresponding 3-ethylcarbamoyl-4-fluoroaniline (Compound 10). Compound 10 was then treated with trifluoroacetic acid in a solvent, such as methylene chloride, yielding 3-ethylcarbamoyl-4-fluoro- , , -trifluoroacetanilide (Compound 13).

In an alternate method utilizing 2,4-dinitrofluorobenzene, intermediate Compound 13 was prepared by, first, hydrogenation of the 2,4- dinitrofluorobenzene to afford the corresponding 4-fluoro-l,3-benzenediamine (Compound 11). Compound 11 was then reacted with phenyl trifluoroacetate under basic conditions in a solvent, such as DMF, yielding 3-amino-4-fluoro- r,r, r-trifluoroacetanilide (Compound 12); which was in turn reacted with ethyl chloroformate, yielding Compound 13.

Intermediate Compound 13 was then chlorinated at reduced temperature with chlorine gas in a solvent, such as acetonitrile, yielding the corresponding 6- chloro-3-ethylcarbamoyl-4-fluoro-l ',1 ',1 '-trifluoroacetanilide (Compound 14), which, in turn, was nitrated with 70% nitric acid under strongly acidic conditions, affording 6-chloro-3 -ethylcarbamoyl-4-fluoro-2-nitro- 1 ' , 1 ' , 1 ' -trifluoroacetanilide (Compound 15). Compound 15 was then reduced with vanadium(V) oxide, 5% palladium on carbon, iron powder, and hydrogen gas to 100 psig at elevated temperature, to form the corresponding benzimidazole derivative, namely, ethyl N- (2-trifluoromethyl-4-chloro-6-fluorobenzimidazol-7-yl)carbamate (Compound 26). Example 1, presented below, provides a detailed method by which Compound 26 was prepared from Compounds 10 and 11.

In an alternative method, Compound 15 was reduced by hydrogenation in the presence of 5% platinum on carbon, vanadium(V) oxide, and concentrated hydrochloric acid in a solvent, such as ethyl acetate, yielding the corresponding amino derivative, 2-amino-6-chloro-3 -ethylcarbamoyl-4-fluoro- 1 ' , 1 ' , 1 ' - trifluoroacetanilide (Compound 16). Compound 16 was then reacted with an alkyl chloroformate, such as ethyl or butyl chloroformate, in aqueous 10% sodium bicarbonate, yielding, for example, 2-butylcarbamoyl-6-chloro-3-ethylcarbamoyl- 4-fluoro- 1 ' , 1 ' , 1 ' -trifluoroacetanilide (Compound 17). Compound 17 was, in turn, cyclized with heat under gas chromatographic conditions to form the corresponding benzimidazole, namely, ethyl N-(l-butoxycarbonyl-2- trifluoromethyl-4-chloro-6-fluorobenzimidazol-7-yl)carbamate (Compound 27) . Example 3, presented below, provides a detailed method by which Compound 27 was prepared from Compound 15.

Compound 26 can be reacted directly with a cyclizing agent of formula B to obtain compounds of formula I, or it can be further reacted to prepare additional compounds of formula A. Compound 26, for example, was reacted with an alkyl chloroformate, for example, ethyl or butyl chloroformate, in the presence of tetrabutlyammonium bromide and aqueous 10% sodium bicarbonate in a solvent, such as ethyl acetate, yielding ethyl N-(l-butoxycarbonyl-2-trifluoromethyl-4- chloro-6-fluorobenzimidazol-7-y)carbamate (Compound 27), a compound of formula A. Example 2, presented below, provides a detailed method by which Compound 27 was prepared from Compound 26. Compound 26, for example, also can be reacted with aqueous sodium hydroxide at elevated temperature, affording the free amino derivative, namely, 7- amino-4-chloro-6-fluoro-2-trifluoromethylbenzimidazole (Compound 29), a compound of formula A. Example 4, presented below, provides a detailed method by which Compound 29 can be prepared from Compound 26. In another aspect of the present invention, certain compounds of formula A, namely, Compound 26, was prepared in a step-wise manner from either 2- fluoroaniline or from 2,6-difluoroaniline by methods known to one skilled in the art, as depicted in Scheme 2, presented below:

Scheme 2 Compounds of Formula A Derived From 2-Fluoroaniline or 2.6-Difluoroaniline

Compound of Formula A Cmpd 26

la) EtOCOCl/DMF; lb) C1₂/ CH₃CN; lc) 70% HNOs/conc. H₂S0₄; Id) Fe/AcOH/H 0; le) (CF₃C0)₂0/CH₂C1₂; If) 70% HN0₃/conc. H₂S0₄; lg) NCS/CH₂C1₂; lh) EtOCOCl/

DMF; li) 70% HNOs/conc. H₂S0₄; lj) NH₃/ l,4-dioxane/heat; Ik) (CF₃CO)2θ/CH₂Cl2; lm) Fe/AcOH/H₂0; lo) Fe/AcOH/H₂0; lp) CF3CO2H. Intermediate Compound 7, for example, was prepared in a step-wise manner from either 2-fluoroaniline (Compound 1) or from 2,6-difluoroaniline (Compound 19).

2-Fluoroaniline was reacted with ethyl chloroformate in a solvent, such as DMF, yielding the corresponding ethyl N-(2-fluorophenyl)carbamate (Compound 2), which was, in turn, chlorinated with chlorine gas in a solvent, such as methylene chloride, affording ethyl N-(4-chloro-2-fluorophenyl)carbamate. (Compound 3). Compound 3 was, in turn, nitrated with 70% nitric acid under strongly acidic conditions, yielding the corresponding ethyl N-(4-chloro-2-fluoro- 6-nitrophenyl)carbamate (Compound 4), which was then reduced with iron powder in acetic acid and water, providing ethyl N-(6-amino-4-chloro-2- fluorophenyι)carbamate. (Compound 5). Compound 5 was further reacted with acetic anhydride in a solvent, such as methylene chloride, yielding 5-chloro-2- ethylcarbamoy 1-3 -fluoro- l',r,l '-trifluoroacetanilide (Compound 6), which was then nitrated with 70% nitric acid under strongly acidic conditions, affording 5- chloro-2-ethylcarbamoyl-3 -fluoro-6-nitro- 1 ' , 1 ' , 1 ' -trifluoroacetanilide (Compound 7). Example 5, Reactions lc-lf, presented below, provide a detailed method by which Compound 7 was prepared from 2-fluoroaniline.

2,6-Difluoroaniline was chlorinated with N-chlorosuccinimide in a solvent, such as methylene chloride, yielding the corresponding 4-chloro-2,6- difluoroaniline (Compound 20). Compound 20 was, in turn, reacted with ethyl chloroformate in a solvent, such as DMF, affording ethyl N-(4-chloro-2,6- difluorophenyl)carbamate (Compound 21), which was then nitrated with 70% nitric acid under strongly acidic conditions, affording the corresponding ethyl N- (4-chloro-2,6-difluoro-5-nitrophenyl)carbamate (Compound 22). Compound 22 was then reduced under pressure with excess gaseous ammonia in a solvent, such as 1,4-dioxane, at elevated temperature, affording the corresponding ethyl N-(6- amino-4-chloro-2-fluoro-5-nitrophenyl)carbamate (Compound 23). Compound 23 was, in turn, reacted with trifluoroacetic anhydride, in a solvent, such as methylene chloride, yielding Compound 7, named above. Example 6, Reactions lj and Ik, presented below, provide a detailed method by which Compound 7 was prepared from 2,6-difluoroaniline.

Intermediate Compound 7, prepared either from 2-fluoroaniline or from 2,6-difluoroaniline, was then reduced with acetic acid and iron powder in water, at low temperature, yielding Compound 26, previously described. Example 5, Reaction lm, presented below, provides a detailed method by which Compound 26 was prepared from Compound 7.

In an alternate method, Compound 26 was prepared from Compound 23, described above, by first reducing Compound 23 with iron powder in acetic acid

10 and water, affording ethyl N-(4-chloro-2-fluoro-5,6-diaminophenyl)carbamate (Compound 24), then reacting Compound 24 with trifluoroacetic acid, yielding Compound 26. Example 7, presented below, provides a detailed method by which Compound 26 was prepared from Compound 23.

Table 1, presented below, sets forth compounds of formula A that are

15 useful in the step-wise preparation of compounds of formula I:

Table 1

Compounds of Formula A Useful In

Preparation of Compounds of Formula I

20

Cmpd.

No. n X Y Z R² R⁴ R⁵ R⁶

1 1 4-F H H .... H

2 1 4-F H H — — -C0₂R⁶ -C₂H₅

3 2 4-F, 6-C1 H H — — -C0₂R⁶ -C₂H₅

4 2 4-F, 6-C1 H -N0₂ — — -C0₂R⁶ -C₂H₅

5 2 4-F, 6-C1 H -NH₂ — — -C0₂R⁶ -C₂H₅

6 2 4-F, 6-C1 H -NHC(0)R² -CF₃ — -C0₂R⁶ -C₂H₅

7 2 4-F, 6-C1 -N0₂ -NHC(0)R² -CF₃ — -C0₂R⁶ -C₂H₅

8 4-F -N0₂ H — — H —

9 4-F -N0₂ H — — -C0₂R⁶ -Q₂H₅

10 4-F -NH₂ H — — -C0₂R⁶ -C₂H₅

11 4-F -NH₂ H — — H —

12 4-F -NHC(0)R² H -CF₃ — H — Cmpd.

No. X R" R⁴ R⁵ R⁶

13 1 4-F -NHC(0)R² H -CF₃ -C0₂R⁶ -C₂Hs

14 2 4-F, 6-C1 -NHC(0)R² H -CF₃ -C0₂R⁶ -C₂H₅

15 2 4-F, 6-C1 -NHC(0)R² -N0₂ -CF₃ -C0₂R⁶ -C₂H₅

16 2 4-F, 6-C1 -NHC(0)R² -NH₂ -CF₃ — -C0₂R⁶ -C₂H₅

17 2 4-F, 6-C1 -NHC(0)R² -NHC0₂R⁴ -CF₃ 11-C4H₉ -C0₂R⁶ -C₂H₅

18 2 4-F, 6-C1 -NHC(0)R² -NHC0₂R⁴ -CF₃ -C₂H₅ -C0₂R⁶ -C₂H₅

19 1 4-F H F — — H —

20 2 4-F, 6-C1 H F — — H —

21 2 4-F, 6-C1 H F — — -C0₂R⁶ -C₂H₅

22 2 4-F, 6-C1 -N0₂ F — — -C0₂R⁶ -C₂H₅

23 2 4-F, 6-C1 -N0₂ -NH₂ — -C0₂R⁶ -C₂H₅

24 2 4-F, 6-C1 -NH₂ -NH₂ — — -C0₂R⁶ -C₂H₅

25 2 4-F, 6-C1 H H — — H —

Where Y and Z taken together are

-N=C(R²)-NR³-, and R²andR³ are:

Cmpd.

No. n X R² R³ R⁴ R⁵ R⁶

26 2 4-F, 6-C1 -CF₃ H ____ -C0₂R⁶ -C₂H₅

27 2 4-F, 6-C1 -CF₃ -C0₂R⁴ n -C₄H₉ -C0₂R⁶ -C₂Hs

28 2 4-F, 6-C1 -CF₃ -C0₂R⁴ C₂H₅ -C0₂R⁶ -C₂H₅

29 2 4-F, 6-C1 -CF₃ H H

The second embodiment of the present invention is a process for preparing 5 a compound of formula I:

_I from a compound of formula A:

wherein, R is selected from the group consisting of hydrogen, alkyl, haloalkyl, cyanoalkyl, alkenyl, alkynyl, alkoxycarbonylalkyl, alkoxyalkyl, and amino;

R is selected from the group consisting of alkyl and haloalkyl n is 0-3; X is selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, cyano, nitro, and amino, and is the same of different when n is 2 or 3;

Y and Z taken together are -N=C(R²)-N(R³)-, where

2 R is hydrogen, hydroxy, thiol, straight or branched chain alkyl, cycloalkyl, alkoxy, aryl, heteroaryl, alkenyl, haloalkyl, hydroxyalkyl, haloaryl, alkoxyaryl, arylalkyl, aryloxyalkyl, haloarylalkyl, alkylthio, heterocyclyl, alkoxyalkyl, alkoxyalkyloxyalkyl, alkylcarbonyloxyalkyl, arylcarbonyloxyalkyl, aminocarbonyloxyalkyl, aminoalkyl, cyanoalkyl, aminoalkenyl, carboxy, carboxyalkyl, alkylcarboxy, alkylcarboxyalkyl, formyl, aminocarbonyl, amino, oxygen, cyano, nitro, alkylsulfonyl, aminosulfonyl, alkylsulfonylamino, alkoxycarbonyloxyalkyl, alkylcarboxylalkoxy, alkoxycarbonylamino, alkoxycarbonylalkylaminoalkyl, aryliminoalkyl, (aryl)(alkoxy)alkyl,

(aryI)(alkylcarbonyloxy)alkyl, arylalkoxyalkyl, cyanoalkylthio, alkynylalkylthio, arylalkylthio, cyanothio, cyanothioalkyl, alkoxycarbonylalkylthio, aminocarbonylalkylthio, alkenylalkylthio, haloalkylalkynylalkylthio, aminocarbonyloxyalkyl, arylalkylcarbonylaminoalkyl, (hydroxy)(aryl)alkyl, alkylcarbonylaminoalkyl, alkylsulfonylaminoalkyl, aminocarbonylalkyl, alkoxycarbonyl, and alkenyloxy, where the amino group may be substituted with one or two substituents independently selected from alkyl, hydroxy, alkoxy, carboxy, aryl, alkylsulfonyl, or haloalkylsulfonyl;

4 alkylsulfonyl, alkenyl, alkynyl, or -CO₂R ; and,

R is hydrogen, or -CO2R , where R and R are independently C1 to Cι straight or branched chain alkyl, which comprises cyclizing a compound of formula A with at least one cyclizing agent of formula B:

R¹- -C0₂R⁷

z^N-R⁸ R B wherein

8 9 7 9

R is hydrogen, or -CO2R where R and R are independently C\ to C 12 straight or branched chain alkyl.

A preferred process of the present invention includes those compounds of formula A, formula B, and formula I, wherein n is 1, or 2; X is halogen; R is

1 2 hydrogen, alkyl, or amino; R is haloalkyl; R is alkyl, hydroxyalkyl, haloalkyl, cyanoalkyl, alkoxycarbonylalkyl, alkylcarbonyloxyalkyl, or

3 4 s alkylsulfonylaminoalkyl; R is hydrogen, alkyl, haloalkyl, or -CO R ; and R is

₆ 4 6 7 9 hydrogen, and -CO₂R , where R , R , R and R are independently Cj to C straight or branched chain alkyl.

A more preferred process includes those compounds of formula A, formula

B, and formula I wherein n is 1 and X is fluoro, and n is 2 and X is fluoro and

1 2 3 chloro; R is hydrogen and methyl; R and R are trifluoromethyl; R is hydrogen,

4 _{5 6} 4 6 7 9 and -CO₂R ; and R is hydrogen, and -CO₂R , where R , R R and R are independently methyl, ethyl, and straight or branched chain propyl and butyl.

A most preferred process of the present invention is wherein i) the compound of formula I is where n is 2; X is 4-fluoro-6-chloro; R is hydrogen and

1 2 3 methyl; R is trifluoromethyl; Y and Z taken together are -N=C(R )-NR -, where

2 3

R is trifluoromethyl; and R is hydrogen; ii) the compound of formula A is where

2 3 n is 2; X is 4-fluoro-6-chloro; Y and Z taken together are -N=C(R )-NR -, where

2 3 4 4 5

R is trifluoromethyl; R is hydrogen and -CO₂R , where R is n-butyl; and R is -CO2R , where R is ethyl; iii) and the at least one cyclizing agent of formula B is

1 7 8 where R is hydrogen and methyl; R is trifluoromethyl; R is ethyl; and R is hydrogen; and alternatively, wherein iv) the compound of formula A is where n is

2 3 2

2; X is 4-fluoro-6-chloro; Y and Z taken together are -N=C(R )-NR -, where R is

3 5 trifluoromethyl; and R and R are hydrogen; v) and the at least one cyclizing

1 8 9 agent of formula B is where R is methyl; R is trifluoromethyl; and R is -CO2R

7 9 where R and R are ethyl.

In a process for cyclizing a compound of formula A with at least one cyclizing agent of formula B to obtain compounds of formula I, the use of at least one suitable organic solvent is preferably employed.

Preferred organic solvents, both polar and apolar, useful in the process of the present invention include halogenated solvents, for example, such as, without limitation, chlorobenzene, carbon tetrachloride, bromodichloromethane, dibromochloromethane, bromoform, chloroform, bromochloromethane, butyl chloride, dichloromethane, tetrachloroethylene, trichloroethylene, 1,1,1- trichloroethane, 1,1,2-trichloroethane, 1,1-dichloroefhane, 2-chloropropane, hexafluorobenzene, 1,2,4-trichlorobenzene, 1,2-dichlorobenzene, fluorobenzene and other halogenated solvents known in the art.

Preferred polar organic solvents include ethers, for example, such as, without limitation, dimethoxymethane, THF, 1,3-dioxane, 1,4-dioxane, furan, diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, tert. -butyl ethyl ether, tert. -butyl methyl ether and other ether solvents known in the art. Other polar organic solvents useful in the context of the present invention include, for example, without limitation, propionitrile, ethyl formate, methyl acetate, hexachloroacetone, acetone, ethyl methyl ketone, ethyl acetate, nitromethane, nitrobenzene, glymes, and other polar solvents known in the art.

Other organic solvents useful herein include polar aprotic solvents, for example, such as, without limitation, DMF, DMAC, DMPU, l,3-dimethyl-2- imidazolidinone, N-methylpyrrolidinone, formamide,, N-methylacetamide, N- methylformamide, acetonitrile, dimethyl sulfoxide, sulfolane, N,N- dimethylpropionamide, TMU, hexamethylphosphoramide and other polar aprotic solvents known in the art. Yet other organic solvents useful for implementation of the present invention include protic solvents, for example, such as, without limitation, water, methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroefhanol, ethylene glycol, 1-propanol, 2-propanol, 2-methoxyethanol, 1-butanol, 2-butanol, isobutanol, tert.-butanol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3-pentanol, 2,2-dimethyl-l-propanol, tert.-pentanol, cyclohexanol, anisole, benzyl alcohol, glycerol and other protic solvents known in the art.

Further organic solvents useful in the present invention include: acidic solvents, for example, such as, without limitation, trifluoroacetic acid, acetic acid, formic acid and other acidic solvents known in the art; basic solvents, for example, such as, without limitation, 2-, 3-, or 4-picoline, pyrrole, pyrrolidine, morpholine, pyridine, piperidine, triethylamine, and other basic solvents known in the art; and hydrocarbon solvents, for example, such as, without limitation, benzene, cyclohexane, pentane, hexane, toluene, cycloheptane, methylcyclohexane, heptane, ethylbenzene, ortho-, meta-, or para-xylene, octane, indane, nonane, naphthaline and other hydrocarbon solvents known in the art.

Organic solvents most suitable for cyclizing a compound of formula A with at least one cyclizing agent of formula B to obtain compounds of formula I are those that are low cost, best enhance the solubility of the starting materials to promote rate of reaction, and offer minimum solvent decomposition. Accordingly, preferred organic solvents include DMF, DMPU, TMU, and glymes.

In the course of conducting chemical reactions, especially large scale organic chemical reactions yielding commercial quantities of desired product, a balance must be met between having to handle too much solvent and yet provide sufficient solvent to afford optimum reaction conditions. A preferable ratio of solvent to compound of formula A to afford optimum reaction conditions is in the range of about 2.5/1 to about 20/1 wt/wt. In order to form a compound of formula I, a compound of formula A is cyclized with at least one cyclizing agent. Compounds of formula B represent useful cyclizing agents:

^•CO,R⁷

R¹-^

N- »_R»

R

B

where R is selected from the group consisting of hydrogen, alkyl, haloalkyl, cyanoalkyl, alkenyl, alkynyl, alkoxycarbonylalkyl, alkoxyalkyl, and amino; R is selected from the group consisting of alkyl and haloalkyl, R is hydrogen, and -

9 7 9

CO2R where R and R are independently Ci to C12 straight or branched chain alkyl. Preferred cyclizing agents of formula B are those wherein R is hydrogen,

1 8 9 7 9 alkyl, or amino; R is haloalkyl; and R is hydrogen, or -CO₂R , where R and R are independently Ci to C straight or branched chain alkyl. More preferred cyclizing agents of formula B are those wherein R is hydrogen or methyl; R is

8 9 7 9 trifluoromethyl; and R is hydrogen, or -CO₂R , where R and R are independently methyl, ethyl, and straight or branched chain propyl and butyl, most

1 7 preferably where R is hydrogen or methyl; R is trifluoromethyl; R is ethyl; and

8 1 7

R is hydrogen; or where R is hydrogen or methyl; R is trifluoromethyl; R is

8 9 9 ethyl; and R is -CO₂R , where R is ethyl. Such cyclizing agents include, without limitation, ethyl 3-amino-4,4,4-trifluoro-2-butenoate, ethyl 3- methylamino-4,4,4-trifluoro-2-butenoate, and ethyl 3-

(ethoxycarbonyl)(methyl)amino-4,4,4-trifluoro-2-butenoate.

Preferably, the cyclization of a compound of formula A with at least one cyclizing agent of formula B to obtain compounds of formula I is conducted under acidic or basic conditions. An acid useful in the present invention can be a protic (Brontsted) acid or an electron pair-accepting (Lewis) acid. Such acids include, for example, mineral, organic, inorganic, and organometallic acids. Preferred acids include, but are not limited to, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, perchloric acid, acetic acid, trifluoroacetic acid, trifluoromefhanesulfonic acid, chlorosulfonic acid, methanesulfonic acid, >αra-toluenesulfonic acid, camphorsulfonic acid, benzenesulfonic acid, boron trifluoride, boron trifluoride etherate, aluminium chloride, zinc chloride, and lanthanum series trifluoromethanesulfonates such as the trifluoromethanesulfonates of scandium, praseodymium, and ytterbium, and other acids known in the art.

Preferred bases include, but are not limited to, alkali metal, alkaline earth metal, and transition metal halides, hydrides, hydroxides, bicarbonates, carbonates, and the like. Metal halides useful in the present invention include, but are not limited to, lithium chloride, lithium fluoride, lithium bromide, lithium iodide, sodium chloride, sodium fluoride, sodium bromide, sodium iodide, potassium chloride, potassium fluoride, potassium bromide, potassium iodide, magnesium chloride, magnesium fluoride, magnesium bromide, magnesium iodide, calcium chloride, calcium fluoride, calcium bromide, calcium iodide, silver bromide, and silver iodide. Metal hydrides useful in the present invention include, but are not limited to, lithium hydride, sodium hydride, potassium hydride, magnesium hydride, calcium hydride, and barium hydride. Metal hydroxides useful in the present invention include, but are not limited to, lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide, and barium hydroxide. Metal bicarbonates useful in the present invention include, but are not limited to, sodium bicarbonate, and potassium bicarbonate. Metal carbonates useful in the present invention include, but are not limited to, sodium carbonate and potassium carbonate. One of ordinary skill, upon receipt of the teachings hereof, may select other alkali metal, alkaline earth metal, and transition metal halides, hydrides, hydroxides, bicarbonates, and carbonates known in the art as bases.

Useful bases also include alkali metal alkoxides, such as, without limitation, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, potassium tert.-butoxide, and other alkali metal alkoxides known in the art. Other useful bases include organic alkyl amines and cyclic amines, for example, but are not limited to methylamine, ethylamine, dimethylamine, diethylamine, trimethylamine, triethylamine, ethyldiisopropylamine, butylamine, pyridine, DMAP, 2,6-dimethylpyridine, piperidine, piperazine, morpholine, quinoline, DBN, DBU, and other alkyl amines and cyclic amines known in the art. Preferably, the acid or base is present in a mole ratio of acid or base to compound of formula A in a range of about 0.01/1 to about 5/1. Additional amounts of acid or base can be added if necessary to drive the reaction to completion, for example.

The cyclization of a compound of formula A with at least one cyclizing agent of formula B to obtain compounds of formula I can be conducted in the presence of at least one catalyst. The catalyst need not be present in order to form a compound of formula I; however, its presence will generally accelerate the formation of a compound of formula I. Whether or not a catalyst is preferably present may depend upon the compound of formula I being formed, the compounds of formulae A and B being used as the reactants, the catalyst, the desired reaction time, and the reaction temperature, which one of ordinary skill in the art can readily determine based on general knowledge and this disclosure. Such catalysts can readily be selected from one or more of the acids and bases set forth above, or from other catalysts known in the art.

Preferably, the catalyst, if it is present, is in a mole ratio of catalyst to compound of formula A in a range of about 0.0001/1 to about 1/1. Additional amounts of catalyst can be added if necessary to drive the reaction faster, for example.

The temperature at which and the period for which a chemical reaction, such as the cyclization of a compound of formula A with a compound of formula B to obtain a compound of formula I, is conducted will vary according to, among other things, the solvent or solvents in which the reaction is conducted, the reaction format (e.g., batch, semi-batch, or continuous), the cyclizing agent of formula B, and/or the compound of formula A, the acid or base present, and whether or not a catalyst is used. The cyclization of a compound of formula A with a compound of formula B to obtain a compound of formula I as set forth herein is generally conducted at a temperature in the range of about 0° C to about 240° C for a period of time of up to about 20 hours.

Generally, in a process for cyclizing a compound of formula A with at least one cyclizing agent of formula B to obtain compounds of formula I, a compound of formula A, for example Compound 26 or 27, is dissolved in an organic solvent, such as DMF, TMU, diglyme, xylene, or combinations thereof, in the presence of a base, such as sodium hydride or lithium hydride. The compound of formula A is then treated with the cyclizing agent of formula B, yielding the corresponding compound of formula I. Compounds of formula I, described in detail presented below,, were prepared as depicted in Scheme 3, presented below,.

Scheme 3 Compounds of Formula I Derived From Compounds of Formula A

2a) 50% NaH/DMF/heat; 2b) 50% NaH/DMF/heat; 2c) LiH/TMU/xylene 2d) NaOH/H_zO/heat; 2e) 60% NaH/diglyme/heat

The compound of formula I formed depends upon which compounds of formulae A and B reacted to obtain the compound of formula I. For example, when the process of the present invention is the ultimate step, the compound of

« formula I that is formed by the cyclizing of a compound of formula A with at least one cyclizing agent of formula B is the uracil herbicide, namely, 3-(2- frifluoromethyl-4-chloro-6-fluorobenzimidazol-7-yl)-l-methyl-6-trifluoromethyl- 2,4(lH,3H)pyrimidinedione. Examples 9, 10, and 11, presented below, provide detailed methods for the preparation of a compound of formula I that is the aforementioned uracil herbicide.

When the process of the present invention is the penultimate step, the compound of formula I that is formed by the cyclizing of a compound of formula A with at least one cyclizing agent of formula B is an intermediate, namely, 3-(2- trifluoromethyl-4-chloro-6-fluorobenzimidazol-7-yl)-6-trifluoromethyl- 2,4(lH,3H)pyrimidinedione. Example 8, presented below, provides a detailed method for the preparation of a compound of formula I that is the aforementioned intermediate. The intermediate compound of formula I is readily converted to the uracil herbicide by methods set forth in Step E of Example 4 in US Patent 6,077,812. The modifier "about" is used herein to indicate that certain preferred operating ranges, such as ranges for molar ratios for reactants, material amounts, and temperature, are not fixedly determined. The meaning will often be apparent to one of ordinary skill. For example, a recitation of a temperature range of about 120° C to about 135° C in reference to, for example, an organic chemical reaction would be interpreted to include other like temperatures that can be expected to favor a useful reaction rate for the reaction, such as 105° C or 150° C. Where guidance from the experience of those of ordinary skill is lacking, guidance from the context is lacking, and where a more specific rule is not recited presented below,, the "about" range shall be not more than 10% of the absolute value of an end point or 10% of the range recited, whichever is less.

As used in this specification and unless otherwise indicated the substituent terms "alkyl", "alkoxy", and "haloalkyl", used alone or as part of a larger moiety, includes straight or branched chains of at least one or two carbon atoms, as appropriate to the substituent, and preferably up to 12 carbon atoms, more preferably up to ten carbon atoms, most preferably up to seven carbon atoms. The term "aryl" refers to phenyl or naphthyl optionally substituted with one or more halogen, alkyl, alkoxy, or haloalkyl. "Halogen" or "halo" refers to fluorine, bromine, iodine, or chlorine. The term "ambient temperature" refers to a temperature in the range of about 20° C to about 30° C. Certain solvents, catalysts, and the like are known by their acronyms. These include the acronyms "DMAC" meaning N,N-dimethylacetamide, "DMF" meaning N,N-dimethylformamide, "THF" meaning tetrahydrofuran, "DMAP" meaning 4-dimethylaminopyridine, "TMU" meaning 1,1,3,3-tetramethylurea, "DBN" meaning 1,5- diazabicyclo[4.3.0]non-5-ene, "DBU" meaning l,8-diazabicyclo[5.4.0]undec-7- ene and "DMPU" meaning l,3-dimethyl-3,4,5,6-tetrahydro-2(lH)-pyrimidinone. The term "glymes" refers to a class of solvents comprised of monoglyme, diglyme, triglyme, tetraglyme, and polyglyme. The term "GC" refers to gas chromatography or gas chromatographic methods of analyses, whereas the term "MS" refers to mass spectroscopy or mass spectrographic methods of analysis.

The present invention is now described in more detail by reference to the following examples, but it should be understood that the invention is not construed as being limited thereto. Unless indicated otherwise, all parts, percentages, and the like are by weight.

EXAMPLE 1 Synthesis of a Compound Of Formula A Ethyl N- [2-Trifluoromethyl-4-Chloro-6-Fluorobenzimidazol-7- yl)carbamate (Compound 26) from 2,4-Dinitrofluorobenzene

Reaction d Synthesis of 3 -ethylcarbamoyl-4-fluoro- 1 ' , 1 ' , 1 ' -trifluoroacetanilide (Compound 13)

A solution of 1.0 gram (0.005 mole) of 3-ethylcarbamoyl-4-fluoroaniline

(Compound 10, a known composition of matter derived from 2,4- dinitrofluorobenzene by Reactions a, b, and c of Scheme 1) in 50 mL of methylene chloride was stirred, and 1.3 grams (0.006 mole) of trifluoroacetic anhydride was added dropwise. Upon completion of addition, the reaction mixture was stirred at ambient temperature for about 18 hours. The reaction mixture was then washed with one 50 mL portion of aqueous sodium bicarbonate, and dried with magnesium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure, yielding 1.3 grams of Compound 13. The NMR spectrum was consistent with the proposed structure. The reaction was repeated to obtain additional amounts of Compound 13.

An Alternate Synthesis Of 3-Ethylcarbamoyl-4-Fluoro-l', , - Trifluoroacetanilide (Compound 13)

Reaction f Synthesis of 3 -amino-4-fluoro- 1 ' , 1 ' , 1 ' ,-trifluoroacetanilide (Compound 12) A stirred solution of 6.1 grams (0.048 mole) of 4-fluoro- 1,3- benzenediamine (Compound 11, a known composition of matter derived from 2,4- dinitrofluorobenzene by Reaction e of Scheme 1) in about 60 grams of N,N- dimethylformamide (DMF) was cooled to 0-5 °C, and 10.0 grams (0.097 mole) of triethylamine was added slowly. Upon completion of addition, 9.4 grams (0.048 mole) of phenyl trifluoroacetate was added dropwise while maintaining the reaction mixture temperature presented below, 5 °C. The reaction mixture was then stirred at 0-5 °C for about 18 hours under a nitrogen atmosphere. After this time, the reaction mixture was subjected to gas chromatographic (GC) analysis, which indicated 100% conversion of Compound 11 to Compound 12. The theoretical yield of 10.8 grams was assumed.

Reaction g Synthesis of 3 -ethylcarbamoyl-4-fluoro- 1 ' , 1 ' , 1 ' -trifluoroacetanilide (Compound 13)

The stirred DMF solution containing the 10.8 grams (0.048 mole) of

Compound 12 was cooled to about 0 °C, and 6.0 grams (0.053 mole) of ethyl chloroformate was added dropwise at a rate of addition to maintain the reaction mixture temperature at 0 °C. Upon completion of addition, the reaction mixture was allowed to warm to ambient temperature where it stirred for about 22 hours. After this time, the reaction mixture was subjected to GC analysis, which indicated about 6.4% conversion of Compound 12 to Compound 13.

Reaction h Synthesis of 6-chloro-3-ethylcarbamoyl-4-fluoro- , , - trifluoroacetanilide (Compound 14) A stirred solution of 22.8 grams (0.076 mole) of Compound 13 in 262 mL of acetonitrile was cooled to about -2 °C to 0 °C, and 6.5 grams (0.092 mole) of chlorine gas was bubbled into the reaction mixture while maintaining the reaction mixture temperature presented below, 0 °C. Upon completion of addition, GC analysis of the reaction mixture indicated 100% conversion of Compound 13 to Compound 14. The reaction mixture was concentrated under reduced pressure, yielding 23.2 grams of Compound 14 that was, by GC analysis, 90% pure (83.6% yield). The NMR spectrum was consistent with the proposed structure.

Reaction i Synthesis of 6-chloro-3 -ethylcarbamoyl-4-fluoro-2-nitro- 1 ' , 1 ' , 1 ' - trifluoroacetanilide (Compound 15)

A solution of 3.3 grams (0.010 mole) of Compound 14 in 18 grams of 95% sulfuric acid was stirred, and 1.0 gram of 85% phosphoric acid was added in one portion. Upon completion of addition, 1.1 grams of 70% nitric acid was added dropwise, which resulted in the formation of a red precipitate. Upon completion of addition, the reaction mixture was poured into ice-water. A yellow solid was collected by filtration, washed with water and dried, yielding 3.1 grams of Compound 15. The NMR spectrum was consistent with the proposed structure.

Reaction j Synthesis of ethyl N-(2-trifluoromethyl-4-chloro-6- fluorobenzimidazol-7-yl)carbamate (Compound 26)

A 300 mL stainless steel autoclave was charged with 4.98 grams (0.013 mole) of Compound 15, 0.25 gram (0.0014 mole) of vanadium(V) oxide, 0.24 gram of 5% palladium on carbon catalyst, 0.23 gram (0.004 mole) of iron powder, and 100 mL of acetic acid. The reaction mixture was stirred and heated to about 100 °C, then pressurized with hydrogen gas to about 100 psig. The pressure and temperature in the autoclave were maintained during a five hour period before cooling to ambient temperature and venting to atmospheric pressure. After this time, the reaction mixture was filtered to remove the catalyst, and the filtrate was concentrated under reduced pressure to a residue. The residue was dissolved in ethyl acetate and washed with one 40 mL portion of aqueous sodium bicarbonate solution. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding 4.2 grams (99% yield) of

Compound 26. The NMR spectrum was consistent with the proposed structure. EXAMPLE 2

Synthesis of a Compound of Formula A

Ethyl N-( 1 -butoxycarbonyl-2-trifluoromethyl-4-chloro-6-fluorobenzimidazol-7- yl)carbamate (Compound 27) from Compound 26

Reaction k Synthesis of ethyl N-(l-butoxycarbonyl-2-trifluoromethyl-4-chloro- 6-fluorobenzimidazol-7-y)carbamate (Compound 27)

A solution of 32.0 grams (0.098 mole) of Compound 26 (prepared as set forth in Example 1, Reaction j above) and 3.0 grams (0.009 mole) of terfrabutylammonium bromide in 100 mL of ethyl acetate and 50 mL of aqueous 10% sodium bicarbonate was stirred, and 27.2 grams (0.199 mole) of butyl chloroformate was added dropwise. Upon completion of addition, the reaction mixture stirred until the reaction stopped at about 50% formation of compound 27, as monitored by liquid chromatography (LC). The organic layer was separated and washed sequentially with two portions of aqueous IN sodium hydroxide, one portion of aqueous IN hydrochloric acid, and one portion of water. The organic layer was dried and concentrated under reduced pressure, yielding 16 grams of Compound 27 (37% yield). The NMR spectrum was consistent with the proposed structure.

EXAMPLE 3

Synthesis of a Compound of Formula A

Ethyl N-( 1 -butoxycarbonyl-2-trifluoromethyl-4-chloro-6-fluorobenzimidazol-7- yl)carbamate (Compound 27) from Compound 15

Reaction 1 Synthesis of 2-amino-6-chloro-3 -ethylcarbamoyl-4-fluoro- 1 ' , 1 ' , 1 ' - trifluoroacetanilide (Compound 16)

A suspension of 10.0 grams (0.027 mole) of Compound 15 (prepared as set forth in Example 1 , Reaction i above), 0.2 gram of 5% platinum on carbon catalyst,

0.002 gram of vanadium(N) oxide catalyst, and 1 mL of concentrated hydrochloric acid in 100 mL of ethyl acetate was shaken in a Parr hydrogenator at 48 psi for about two hours. Upon uptake of the theoretical amount of hydrogen gas, the reaction mixture was filtered through diatomaceous earth, yielding a solution of Compound 16. The theoretical yield of 9.3 grams was assumed.

Reaction m Synthesis of 2-butylcarbamoyl-6-chloro-3-ethylcarbamoyl-4-fluoro- 1' , 1 ' , 1 ' -trifluoroacetanilide (Compound 17)

The stirred ethyl acetate solution from Reaction 1 containing 9.3 grams (0.027 mole) of Compound 16 was treated with 10 mL of aqueous 10% sodium carbonate, then 2.6 grams (0.019 mole) of butyl chloroformate was added. Upon completion of addition, the reaction mixture was stirred at ambient temperature for about 14 hours. After this time the organic layer was separated from the reaction mixture and washed with one portion of aqueous IN sodium hydroxide. The organic layer was concentrated to a volume of about 15 mL and about 50 mL of toluene was added. The resultant precipitate was collected by filtration, washed with about 5 mL of toluene, and dried, yielding 7.0 grams (60% yield) of Compound 17.

Reaction o Synthesis of ethyl N-(l-butoxycarbonyl-2-trifluoromefhyl-4-chloro- 6-fluorobenzimidazol-7-yl)carbamate (Compound 27)

A sample of Compound 17 was injected into a Hewlett-Packard HP6890 Series Gas Chromatography System (injection temperature: 250 °C; column temperature: 150-270 °C; rate of column temperature change: 10 °C/minute; column: DP-1), and Compound 27 was formed instantaneously. Analysis by mass spectroscopy (MS) of Compound 27 prepared by the method of Example 3 indicated it to be the same molecule as Compound 27 prepared by the method of Example 2.

EXAMPLE 4

Synthesis of a Compound of Formula A

7-Amino-4-Chloro-6-Fluoro-2-trifluoromethylbenzimidazole

(Compound 29) From Compound 26 Reaction p Synthesis of 7-amino-4-chloro-6-fluoro-2- trifluoromethylbenzimidazole (Compound 29)

A stirred solution of 3.3 grams (0.010 mole) of Compound 26 (prepared as set forth in Example 1, Reaction j above) and 0.4 gram (0.010 mole) of sodium hydroxide in about 10 mL of water is heated at 100 °C for about five hours. The reaction mixture is cooled to ambient temperature and acidified with concentrated hydrochloric acid. The mixture is extracted with ethyl acetate, and the extract is dried with magnesium sulfate. The mixture is filtered and the filtrate is concentrated under reduced pressure, yielding Compound 29.

EXAMPLE 5 Synthesis of a Compound of Formula A Ethyl N-(2-Trifluoromethyl-4-Chloro-6-Fluorobenzimidazol-7- yl)carbamate (Compound 26) from 2-Fluoroaniline

Reaction lc Synthesis of ethyl N-(4-chloro-2-fluoro-6-nitrophenyl)carbamate (Compound 4)

Stirred concentrated sulfuric acid, 160 mL, was cooled in an ice-water bath, and 60 grams (0.276 mole) of ethyl N-(4-chloro-2-fluoro-phenyl)carbamate (Compound 3, a known composition of matter derived from 2-fluoroaniline by Reactions la and lb of Schema 2) was added portionwise. Upon completion of addition, the reaction mixture was stirred until homogeneous, then 24.8 grams (0.276 mole) of 70% nitric acid was added portionwise while maintaining the reaction mixture temperature at about 5 °C to 8 °C. Upon completion of addition, the reaction mixture was stirred for about two hours, while warming to ambient temperature. After this time, the reaction mixture was poured into ice-water. The mixture was stirred until the ice melted, and the resultant precipitate was collected by filtration. The filter cake was washed with water and dried, yielding 71.7 grams (99% yield) of Compound 4.

Reaction 1 d Synthesis of ethyl N-(6-amino-4-chloro-2-fluorophenyl)carbamate (Compound 5) A mixture of 25.0 grams (0.095 mole) of Compound 4 and 8.4 grams (0.150 g-atom) of iron powder in 500 mL of 3/2 parts by volume of acetic acid and water was stirred at ambient temperature for about 5 hours. After this time, an additional 7.6 grams (0.136 g-atoms) of iron powder was added. The reaction mixture was then stirred at ambient temperature for about an additional 18 hours. The reaction mixture was filtered through diatomaceous earth, and the filtrate was washed with multiple portions of ethyl acetate. The combined extracts were dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a viscous residue. The residue was re-dissolved in ethyl acetate and washed with multiple portions of an aqueous solution saturated with potassium carbonate. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a solid residue. The residue was dried, yielding 21.3 grams (96% yield) of Compound 5.

Reaction le Synthesis of 5 -cHoro-2-ethylcarbamoyl-3 -fluoro- r,l',l'- trifluoroacetanilide (Compound 6)

A stirred solution of 5.0 grams (0.022 mole) of Compound 5 in 100 mL of methylene chloride was cooled in an ice-water bath, and a solution of 6.8 grams

(0.032 mole) of acetic anhydride in 20 mL of methylene chloride was added dropwise. Upon completion of addition, the reaction mixture was stirred for 45 minutes. A solution of 4.5 grams of potassium carbonate in 100 mL of water was then added to the reaction mixture, and stirring was continued for about an additional ten minutes. The water layer was then separated from the organic layer and washed with one 30 mL portion of methylene chloride. The wash was combined with the organic layer, and the combination was washed with one 25 mL portion of water. The organic layer was dried with magnesium sulfate and filtered.

The filtrate was concentrated under reduced pressure, yielding 6.7 grams (95.5% yield) of Compound 6. The NMR spectrum was consistent with the proposed structure. Reaction If Synthesis of 5-chloro-2-ethylcarbamoyl-3-fluoro-6-nitro- , , - trifluoroacetanilide (Compound 7)

Stirred concentrated sulfuric acid, 10 mL, was cooled in an ice- water bath, and 1.0 gram (0.003 mole) of Compound 6 was added. The mixture was stirred until solution was complete, then 0.27 gram (0.003 mole) of 70% nitric acid was added dropwise while maintaining the reaction mixture temperature presented below, 20 °C. Upon completion of addition, the reaction mixture was stirred for an additional 20 minutes, then it was poured into ice-water. The mixture was stirred until the ice melted, at which time a solid precipitate was collected by filtration. The solid was washed with 25 mL of water and dried, yielding 1.01 grams (94.2% yield) of Compound 7. The NMR spectrum was consistent with the proposed structure. The reaction was repeated to obtain additional amounts of Compound 7.

Reaction lm Synthesis of Ethyl N-(2-trifluoromethyl-4-chloro-6- fluorobenzimidazol-7-yl)carbamate (Compound 26)

A stirred solution of 11.5 grams (0.031 mole) of Compound 7 in 60 mL of 3/2 parts by volume of acetic acid and water was cooled in an ice-water bath, and 5.3 grams (0.092 gram-atoms) of iron powder was added portionwise. Upon completion of addition, the reaction mixture was stirred for about two hours. Thin layer chromatographic (TLC) analysis of the reaction mixture at two hours indicated reaction was complete. The reaction mixture was filtered through diatomaceous earth to remove excess iron powder. The filter cake was washed with ethyl acetate, and the combined filtrate and wash was concentrated under reduced pressure to remove some of the acetic acid. The residue was extracted with ethyl acetate, and the extract was concentrated under reduced pressure to a residue. The residue was dissolved in 100 mL of aqueous 10% sodium hydroxide, and the pH of the solution was adjusted to 5 with hydrochloric acid. The mixture was stirred for about 10 minutes, diluted with water, and the resultant solid precipitate collected by filtration. The solid was dried, yielding about 9.1 grams (90% yield) of Compound 26. The NMR spectrum was consistent with the proposed structure. EXAMPLE 6 Synthesis of a Compound of Formula A Ethyl N-(2-Trifluoromethyl-4-Chloro-6-Fluorobenzimidazol-7- yl)carbamate (Compound 26), from 2,6-Difluoroaniline

Reaction lj Synthesis of ethyl N-(6-amino-4-chloro-2-fluoro-5- nitrophenyl)carbamate (Compound 23)

In a pressure bottle, a solution of 5.0 grams (0.018 mole) of ethyl N-(4- chloro-2,6-difluoro-5-nitrophenyl)carbamate (Compound 22, a known composition of matter derived from 2,6-difluoroaniline by reactions lg, lh, and li of Scheme 2 ) in 20 mL of 1,4-dioxane was stirred, and excess ammonia gas was bubbled into the reaction mixture. The pressure bottle was sealed, and the reaction mixture was heated to about 70 °C where it was maintained for about two hours. After this time, the reaction mixture was cooled and filtered to remove solid by-products. The filtrate was concentrated under reduced pressure to a residual oil. The oil was stirred with about 20 mL of water, and the resultant solid material was collected by filtration. The solid was dried, yielding 4.8 grams (92.5% yield) of Compound 23. The NMR spectrum was consistent with the proposed structure. The reaction was repeated to obtain additional amounts of Compound 23.

Reaction Ik Synthesis of 5-cMoro-2-ethylcarbamoyl-3-fluoro-6-nitro-l', , - trifluoroacetanilide (Compound 7)

A solution of 5.0 grams (0.018 mole) of Compound 23 in 30 mL of methylene chloride was stirred, and 7.6 grams (0.036 mole) of trifluoroacetic anhydride was added. Upon completion of addition, the reaction mixture was stirred for 1.5 hours at ambient temperature. After this time, the reaction mixture was concentrated under reduced pressure to a solid residue. The solid was slurried in 30 mL of water and collected by filtration. The solid was washed with 15 mL of water and dried, yielding 6.5 grams (97% yield) of Compound 7. The NMR spectrum was consistent with the proposed structure. Compound 7 was then converted to Compound 26 by the method of Reaction lm, as set forth in Example 5 above.

EXAMPLE 7 Synthesis of a Compound of Formula A

Ethyl N-(2-Trifluoromethyl-4-Chloro-6-Fluorobenzimidazol-7- yl)carbamate (Compound 26) from Compound 23

Reaction lo Synthesis of ethyl N-(4-chloro-2-fluoro-5,6- diaminophenyl)carbamate (Compound 24)

A solution of 4.0 grams (0.028 mole) of Compound 23 (prepared as set forth in Reaction lj of Example 6 above) in 20 mL of three parts of acetic acid and two parts of water was stirred, and 1.6 grams (0.028 g-atoms) of iron powder was added. Upon completion of addition, the reaction mixture was stirred at ambient temperature for about three hours, after which time (TLC) analysis indicated the reaction to be complete. The reaction mixture was filtered through diatomaceous earth, and the filtrate was extracted with one 25 mL portion of ethyl acetate. The organic layer was washed with one 15 mL portion of water and dried with magnesium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure, yielding 3.2 grams (90.6% yield) of Compound 24. The NMR spectrum was consistent with the proposed structure.

Reaction lp Synthesis of ethyl N-(2-trifluoromethyl-4-chloro-6- fluorobenzimidazol-7-yl)carbamate (Compound 26)

A solution of 1.0 gram (0.004 mole) of Compound 24 in 10 mL of trifluoroacetic acid was stirred at reflux for about two hours, after which time TLC analysis of the reaction mixture indicated the reaction was complete. The reaction mixture was concentrated under reduced pressure, yielding 1.3 grams (93.5% yield) of Compound 26. The NMR spectrum was consistent with the proposed structure.

EXAMPLE 8 Synthesis of a Compound of Formula I 3-(2-Trifluoromethyl-4-Chloro-6-Fluorobenzimidazol-7-yl)-6-Trifluoromethyl- 2,4(lH,3H)pyrimidinedione from Compound 26

Reaction 2a Synthesis of 3-(2-trifluoromethyl-4-chloro-6-fluorobenzimidazol- 7-yl)-6-Trifluoromethyl-2,4(lH,3H)pyrimidinedione

A stirred solution of 1.0 gram (0.003 mole) of Compound 26 in about 8 mL of DMF was cooled in an ice-water bath, and 0.37 gram (0.008 mole) of 50% sodium hydride was added portionwise. Upon completion of addition, the reaction mixture was stirred for about 10 minutes, and 0.67 gram (0.004 mole) of ethyl 3- amino-4,4,4-trifluoro-2-butenoate (a cyclizing agent of formula B) was added portionwise. Upon completion of addition, the reaction mixture was allowed to warm to ambient temperature where it stirred for about 20 minutes. The reaction mixture was then heated at reflux under a nitrogen atmosphere for 3.5 hours. After this time, the reaction mixture was cooled to ambient temperature and concentrated under reduced pressure to a residue. The residue was dissolved in 20 mL of ethyl acetate, and the solution was washed with 15 mL of water. The ethyl acetate solution was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residual solid. Trituration of the solid with 20 mL of hexane yielded 0.96 gram (77.4% yield) of the subject Compound of Formula I. The NMR spectrum was consistent with the proposed structure.

EXAMPLE 9 Synthesis of a Compound of Formula I 3-(2-Trifluoromethyl-4-Chloro-6-Fluorobenzimidazol-7-yl)-l-Methyl-6-

Trifluoromethyl-2,4(lH,3H)pyrimidinedione from Compound 26

Reaction 2b Synthesis of 3-(2-trifluoromethyl-4-chloro-6-fluorobenzimidazol- 7-yl)-l-methyl-6-trifluoromethyl-2,4(lH,3H)pyrimidinedione

This Compound of Formula I was prepared in a manner analogous to that of Reaction 2a of Example 8, from 0.6 gram (0.0018 mole) of Compound 26, 0.44 gram (0.0022 mole) of ethyl 3-methylamino-4,4,4-trifluoro-2-butenoate (a cyclizing agent of formula B), and 0.11 gram (0.0046 mole) of 50% sodium hydride in about 6 mL of DMF. After about five hours of heating at reflux, GC analysis of the reaction mixture indicated the presence of about 23% of the proposed subject Compound of Formula I, and amine by-products. After this time, the reaction mixture was cooled to ambient temperature and concentrated under reduced pressure to a residue. The residue was slurried with about 15 mL of water and the mixture was extracted with three 15 mL portions of ethyl acetate. The combined extracts were dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. Analysis of the residue by NMR confirmed formation of the subject Compound of Formula I, and amine byproducts.

EXAMPLE 10

Synthesis of a Compound of Formula I

3 -(2-Trifluoromethyl-4-Chloro-6-Fluorobenzimidazol-7-yl)- 1 -Methyl-6-

Trifluoromethyl-2,4(lH,3H)pyrimidinedione from Compound 27

Reaction 2c Synthesis of 3-(2-trifluoromethyl-4-chloro-6-fluorobenzimidazol- 7-yl)-l-Methyl-6-Trifluoromethyl-2,4(lH,3H)pyrimidinedione

A solution of 4.3 grams (0.010 mole) of Compound 27 and 2.0 grams (0.010 mole) of ethyl 3-methylamino-4,4,4-trifluoro-2-butanoate (a cyclizing agent of formula B) is dissolved in an appropriate amount of a mixture of 1/3 parts by volume of 1,1,3,3-tetramethylurea and xylene is stirred, and 0.12 gram (0.015 mole) of lithium hydride is added portionwise. After hydrogen by-product evolution subsides, the reaction mixture is heated to about 140 °C where it is maintained for about 2 hours, yielding the subject Compound of Formula I.

EXAMPLE 11 Synthesis of a Compound of Formula I 3 -(2-Trifluoromethyl-4-Chloro-6-Fluorobenzimidazol-7-yl)- 1 -Methyl-6- Trifluoromethyl-2,4(lH,3H)pyrimidinedione from Compound 29

Reaction 2d Synthesis of a Compound of Formula A: 7-Amino-4-Chloro-6- Fluoro-2-trifluoromethylbenzimidazole (Compound 29) From A Compound of Formula I For purposes of obtaining a quantity of Compound 29 for experimentation, a Compound of Formula I, namely, 3-(2-trifluoromethyl-4-chloro-6- fluorobenzimidazol-7-yl)-l-methyl-6-trifluoromethyl-2,4(lH,3H)pyrimidinedione was reduced to the its free amine, 7-amino-4-chloro-6-fluoro-2- trifluoromethylbenzimidazole (Compound 29). The reaction to obtain Compound 29 was conducted as set forth presented below,.

A solution of 80.0 grams (2.0 moles) of sodium hydroxide in 1000 mL of water was stirred, and 43.2 grams (0.10 mole) of 3-(2-trifluoromethyl-4-chloro-6- fluorobenzimidazol-7-yl)- 1 -methyl-6-trifluoromethyl-2,4( 1 H,3H)pyrimidinedione was added. Upon completion of addition, the reaction mixture was stirred at ambient temperature for about 48 hours. The reaction mixture was warmed to 60- 65 °C, where it stirred for about eight hours. GC analysis at that time indicated about a 10% conversion of the pyrimidinedione to Compound 29. The reaction mixture was allowed to cool as it stood for about 18 hours, then it was warmed to 80-95 °C where it stirred for about six hours. GC analysis at that time indicated about a 50% conversion of the pyrimidinedione to Compound 29. The reaction mixture was again allowed to cool as it stood for about 18 hours, then it was warmed to 95-100 °C where it stirred for about eight hours. GC analysis at that time indicated about a 90% conversion of the pyrimidinedione to Compound 29. After this time, the reaction mixture was acidified with concentrated hydrochloric acid until a solid precipitate formed. The precipitate was collected by filtration and dried, yielding 14.1 grams of 88% pure (48.8% yield) of Compound 29. The NMR spectrum was consistent with the proposed structure.

Reaction 2e Synthesis of 3-(2-trifluoromethyl-4-chloro-6-fluorobenzimidazol-

7-yl)- 1 -methyl-6-trifluoromethyl-2,4(l H,3H)pyrimidinedione

A solution of 0.20 gram (0.001 mole) of ethyl 3-methylamino-4,4,4- trifluoro-2-butanoate in 5 mL of dioxane was stirred, and 0.11 gram (0.001 mole) of ethyl chloroformate was added. The resultant reaction produced ethyl 3-

(ethoxycarbonyl)(methyl)amino-4,4,4-trifluoro-2-butenoate (a cyclizing agent of formula B) in quantitative yield. To this was then added 0.12 gram (0.003 mole) of 60% sodium hydride, 0.33 gram (0.010 mole) of Compound 29, and 10 mL of diglyme. Upon completion of addition, the reaction mixture was warmed to about 60 °C, where it stirred for about 30 minutes. GC analysis of the reaction mixture indicated about 70% conversion to 3-(2-trifluoromethyl-4-chloro-6- fluorobenzimidazol-7-yl)-l-methyl-6-trifluoromethyl-2,4(lH,3H)pyrimidinedione. While the invention has been described in detail with reference to specific embodiments, it will be apparent to one of ordinary skill in the art that various changes and modifications can be made therein without departing from the spirit and scope thereof.

Claims

What is claimed is:

1. A compound of formula A:

A wherein n is 0-3;

Y is selected from the group consisting of hydrogen, nitro, amino, and -

NHC(O)-R²; and

Z is selected from the group consisting of hydrogen, nitro, amino,

-NHC(O)-R², and -NHCO₂R⁴' or

Y and Z taken together are -N=C(R²)-NR³- where;

4 alkylsulfonyl, alkenyl, alkynyl, or -CO₂R ; and,

R is hydrogen, or -CO2R , where R and R are independently Ci to C12 straight or branched chain alkyl; wwiitthh tthhee pprroo'viso that when Y is hydrogen, nitro, or amino, Z and R are other than hydrogen,

2 2. The compound according to claim 1, wherein n is 1, or 2; X is halogen; R is alkyl, hydroxyalkyl, haloalkyl, cyanoalkyl, alkoxycarbonylalkyl,

3 alkylcarbonyloxyalkyl, or alkylsulfonylaminoalkyl; R is hydrogen, alkyl,

4 4 6 haloalkyl, or -CO₂R , where R and R are independently Ci to Cf, straight or branched chain alkyl.

3. The compound according to claim 2, wherein n is 1 and X is fluoro, and n is 2 and X is fluoro and chloro; R is trifluoromethyl; R is hydrogen, and -CO₂R ,

4 6 where R and R are independently methyl, ethyl, and straight or branched chain propyl and butyl.

4. The compound according to claim 3, wherein n is 2; X is 4-fluoro-6-chloro;

2 2

Y is hydrogen, nitro, or amino; Z is nitro, amino or -NHC(O)R , where R is

S 6 6 trifluoromethyl; and R is -CO₂R , where R is ethyl.

5. The compound according to claim 3, wherein n is 1 ; X is 4-fluoro; Y is

2 2 5

-NHC(O)R , where R is trifluoromethyl; Z is hydrogen; and R is hydrogen, or

-CO2 , where is ethyl.

6. The compound according to claim 3, wherein n is 2; X is 4-fluoro-6-chloro;

Y is

2 2

-NHC(O)R , where R is trifluoromethyl; Z is hydrogen, nitro, amino, or -

NHCO₂R⁴, where R⁴ is n-butyl; and R⁵ is -CO₂R⁶, where R⁶ is ethyl.

7. The compound according to claim 3, wherein n is 2; X is 4-fluoro-6-chloro;

2 3 2 3

Y and Z taken together are -N=C(R )-NR -, where R is trifluoromethyl; R is

hydrogen; and R is

where is ethyl.

8. The compound according to claim 3, wherein n is 2; X is 4-fluoro-6-chloro;

2 3 2 3

Y and Z taken together are -N=C(R )-NR -, where R is trifluoromethyl; R is

4 4 5 6 6

CO2R , where R is n-butyl; and R is -CO2R , where R is ethyl.

9. The compound according to claim 3, wherein n is 2; X is 4-fluoro-6-chloro;

2 3 2 3

Y and Z taken together are -N=C(R )-NR -, where R is trifluoromethyl; and R and R are hydrogen.

10. A process for preparing a compound of formula I:

from a compound of formula A:

A wherein

R is selected from the group consisting of hydrogen, alkyl, haloalkyl, cyanoalkyl, alkenyl, alkynyl, alkoxycarbonylalkyl, alkoxyalkyl, and amino;

R is selected from the group consisting of alkyl and haloalkyl n is 0-3;

X is selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, cyano, nitro, and amino, and is the same of different when n is 2 or 3;

Y and Z taken together are -N=C(R²)-N(R³)-, where

(aryl)(alkylcarbonyloxy)alkyl, arylalkoxyalkyl, cyanoalkylthio, alkynylalkylthio, arylalkylthio, cyanothio, cyanothioalkyl, alkoxycarbonylalkylthio, aminocarbonylalkylthio, alkenylalkylthio, haloalkylalkynylalkylthio, aminocarbonyloxyalkyl, arylalkylcarbonylaminoalkyl, (hydroxy)(aryι)alkyl, alkylcarbonylaminoalkyl, alkylsulfonylaminoalkyl, aminocarbonylalkyl, alkoxycarbonyl, and alkenyloxy, where the amino group may be substituted with with one or two substituents independently selected from alkyl, hydroxy, alkoxy, carboxy, aryl, alkylsulfonyl, or haloalkylsulfonyl;

4 alkylsulfonyl, alkenyl, alkynyl, or -CO₂R ; and,

R is hydrogen, or -CO2R , where R and R are independently Ci to C12 straight or branched chain alkyl, which comprises cyclizing a compound of formula A with at least one cyclizing agent of formula B:

B wherein

8 9 7 9

R is hydrogen, or -CO2R where R and R are independently C to C12 straight or branched chain alkyl.

11. The process according to claim 10, wherein n is 1, or 2; X is halogen; R is

1 2 hydrogen, alkyl, or amino; R is haloalkyl; R is alkyl, hydroxyalkyl, haloalkyl, cyanoalkyl, alkoxycarbonylalkyl, alkylcarbonyloxyalkyl, or alkylsulfonylaminoalkyl; R 3 is hydrogen, alkyl, haloalkyl, or -CO₂R 4 ; and R s is hydrogen, and -CO₂R⁶, where R , R , R and R are independently Ci to C straight or branched chain alkyl.

12. The process according to claim 11, wherein n is 1 and X is fluoro, and n is

1 2

2 and X is fluoro and chloro; R is hydrogen and methyl; R and R are

3 4 , , trifluoromethyl; R is hydrogen, and -CO₂R ; and R is hydrogen, and -CO₂R ,

4 .6 O _^77 , „9 y where R , R R and R are independently methyl, ethyl, and straight or branched chain propyl and butyl.

13. The process according to claim 12, wherein the compound of formula I is where n is 2; X is 4-fluoro-6-chloro; R is hydrogen and methyl; R is

2 3 2 trifluoromethyl; Y and Z taken together are -N=C(R )-NR -, where R is

3 trifluoromethyl; and R is hydrogen: the compound of formula A is where n is 2; X

2 3 2 is 4-fluoro-6-chloro; Y and Z taken together are -N=C(R )-NR -, where R is

3 4 ₄ 5 trifluoromethyl; R is hydrogen and -CO2R , where R is n-butyl; and R is -

CO2 , where

is ethyl: and the at least one cyclizing agent of formula B is

1 7 8 where R is hydrogen and methyl; R is trifluoromethyl; R is ethyl; and R is hydrogen.

14. The process according to claim 12, wherein the compound of formula I is where n is 2; X is 4-fluoro-6-chloro; R is hydrogen and methyl; R is

2 3 2 trifluoromethyl; Y and Z taken together are -N=C(R )-NR -, where R is

3 5 trifluoromethyl; and R and R are hydrogen: and the at least one cyclizing agent

1 8 9 of formula B is where R is methyl; R is trifluoromethyl; and R is -CO2R where

7 9

R and R are ethyl.