AU2012203792B2 - Process for making substituted 2H-3,1-benzoxazine-2,4(1H)-diones - Google Patents

Abstract

Disclosed is a method for preparing a compound of Formula 2 by contacting a compound of Formula 4 with phosphorus tribromide. H 3 N 0 NHCO 2 R wherein R 2 is CH3 or Cl; R 3 is Ci-C 6 alkyl or C3-C 6 alkenyl, each optionally substituted 5 with up to 3 halogen and up to 1 phenyl; and X is Cl or Br.

Description

P/00/01I Regulation 3.2 AUSTRALIA Patents Act 1990 COMPLETE SPECIFICATION FOR A DIVISIONAL PATENT ORIGINAL Name of Applicant: E. I. DU PONT DE NEMOURS AND COMPANY Actual Inventors: DAVIS, Richard Frank SHAPIRO, Rafael TAYLOR, Eric Deguyon Address for Service: Houlihan 2, Level 1, 70 Doncaster Road, Balwyn North, Victoria 3104, Australia Invention Title: PROCESS FOR MAKING SUBSTITUTED 2H-3,1 BENZOXAZINE-2,4(1H)-DIONES The following statement is a full description of this invention, including the best method of performing it known to the Applicant:- 2 TITLE PROCESS FOR MAKING SUBSTITUTED 2H-3,1-BENZOXAZINE-2,4(1H)-DIONES The present application is a divisional application from Australian patent application 5 number 2007275836. The entire disclosures of Australian patent application number 2007275836 and its corresponding International application, PCT/US2007/014972, are incorporated herein by reference. SUMMARY OF THE INVENTION 10 This invention provides a method for preparing a compound of Formula 2 R 2 H N O X 0 2 0 wherein R 2 is CH 3 or Cl; and X is Cl or Br; comprising contacting a compound of Formula 4 R 2

NHCO

2

R

3 X

CO

2 H 4 15 wherein R 2 is CH 3 or Cl; R 3 is CI-C 6 alkyl or C 3

-C

6 alkenyl, each optionally substituted with up to 3 halogen and up to 1 phenyl; and X is Cl or Br; with phosphorus tribromide. 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 20 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 25 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).

3 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 5 plural unless the number is obviously meant to be singular. The term "optionally substituted" in the definition of a radical (e.g., alkyl or alkenyl) means that the radical is unsubstituted or is substituted with one or more substituents up to any stated limit of number of substituents. As "optionally substituted" includes the option of no substitution, the phrase "each optionally substituted with 1-3 substituents" means that 10 optionally 0, 1, 2 or 3 substituents are present. Therefore "each optionally substituted with 1-3 substituents" is synonymous with "each optionally substituted with 0-3 substituents" and with "each optionally substituted with up to 3 substituents". Related phrases reciting "optionally substituted" are defined analogously. As further examples, "each optionally substituted with up to 3 halogen" is synonymous with "each optionally substituted with 1-3 15 halogen", and "each optionally substituted with up to 1 phenyl" is synonymous with "each optionally substituted with 0-1 phenyl". When "halogen" is recited in the context of a range that includes 1 or more than one (e.g., "up to 3 halogen"), the singular word form "halogen" means "halogens" or "halogen atoms" when more than one halogen atom is present. When more than one substituent is present, each substitution is independent of the other. For 20 example, when two or more halogens are present as substituents, each of the halogen atoms can be the same or different halogens. Ratios are generally recited herein as single numbers, which are relative to the number 1; for example, a ratio of 4 means 4: 1. As referred to in the present disclosure and claims, the term "carboxylic acid" means 25 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 30 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 35 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".

4 The compounds of Formula 2 can be used with a compound of Formula 3 R -NH 2 wherein R 1 is H, CI-C 4 alkyl, cyclopropyl, cyclopropylmethyl or methylcyclopropyl; 5 in the presence of a carboxylic acid to prepare a compound of Formula 1 R 2

NH

2 X C(O)NHR 1 which are useful starting materials for preparing arthropodicidal diamides of 10 anthranilic acids. The compounds of Formula 2 can be used to prepare a compound of Formula 5 which is an insecticide. R'~ N R5 NH z 5 15 x C(O)NHR R6 wherein X is Cl or Br; Z is CR 7 or N;

R

1 is H, CI-C 4 alkyl, cyclopropyl, cyclopropylmethyl or methylcyclopropyl; 20 R 2 is CH 3 or Cl;

R

4 is Cl, Br, CF 3 , OCF 2 H or OCH 2

CF

3 ;

R

5 is F, Cl or Br;

R

6 is H, F or Cl; and

R

7 is H, F, Cl or Br. 25 Embodiments of the present invention include: 5 Embodiment 1. The method described in the Summary of the Invention for preparing a compound of Formula 2 comprising contacting a compound of Formula 4 with phosphorus tribromide. Embodiment 2. The method of Embodiment 1 wherein R 3 is Ci-C 4 alkyl. 5 Embodiment 3. The method of Embodiment 2 wherein R 3 is unbranched at the carbon atom of R 3 bonded to oxygen. Embodiment 4. The method of Embodiment 3 wherein R 3 is methyl or ethyl. Embodiment 5. The method of Embodiment 1 wherein the compound of Formula 4 is contacted with the phosphorus tribromide in the presence of a suitable organic solvent. 10 Embodiment 6. The method of Embodiment 1 wherein the organic solvent comprise one or more solvents selected from esters, nitriles, hydrocarbons and halogenated hydrocarbons. Embodiment 6a. The method of Embodiment 6 wherein the organic solvent comprises one or more solvents selected from esters, nitriles, haloalkanes, and halogenated and 15 nonhalogenated aromatic hydrocarbons. Embodiment 7. The method of Embodiment 6a wherein the organic solvent comprises one or more solvents selected from haloalkanes, and halogenated and nonhalogenated aromatic hydrocarbons. Embodiment 8. The method of Embodiment 7 wherein the organic solvent comprises 20 one or more solvents selected from 1,2-dichloroethane, benzene, toluene, xylene and chlorobenzene. Embodiment 9. The method of Embodiment 8 wherein the organic solvent comprises toluene. Embodiment 10. The method of any one of Embodiments 1 to 9 wherein R 2 is methyl. 25 Embodiment 11. The method of any one of Embodiments 1 to 10 wherein X is Cl. Embodiment 12. The method of any one of Embodiments 1 to 11 wherein R 2 is CH 3 and X is Cl. Embodiment 13. The method of any one of Embodiments 1 to 11 wherein X is Br. Embodiments of this invention can be combined in any manner. 30 The present methods and intermediate are described in further detail below. In the following Schemes the definitions of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , X and Z are as defined above unless otherwise stated. As shown in Scheme 1, a substituted anthranilamide of Formula 1 can be prepared by contacting from a substituted isatoic anhydride of Formula 2 with an amine of Formula 3 in 35 the presence of a carboxylic acid.

6 Scheme 1 R 2 H R 2 N,, + RINH 2 carboxylic acid

NH

2 X 0 1 X C(O)NHR 2 1 As amines such as the compound of Formula 3 are bases, in the absence of the carboxylic acid the mixture of the compounds of Formulae 2 and 3 would be basic (e.g., 5 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. 10 Carboxylic acids include, for example, formic 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. 15 The combination of the carboxylic acid with the basic amine of Formula 3 forms an amine salt of the carboxylic acid. This amine salt can be preformed before addition of the isatoic anhydride compound of Formula 2, or the amine salt can be generated in situ by metering the amine of Formula 3 into a mixture of the compound of Formula 2 and the carboxylic acid. For either mode of addition, it is best carried out by maintaining the 20 effective pH of the mixture during the reaction between about 3 and about 7. As the effective pH of the mixture results from the buffering effect of the carboxylic acid in combination with the amine of Formula 3, the effective pH can be adjusted according to the effective pKa of the carboxylic acid by adjusting the molar ratio of carboxylic acid to amine of Formula 3. Typically the molar amounts of the amine of Formula 3 to carboxylic 25 acid are in the range from about 0.6 to about 3, more typically from about 0.8 to about 3. More particularly, when the mode of combination involves metering the amine of Formula 3 into a mixture of the isatoic anhydride compound of Formula 2 and carboxylic acid, the molar ratio of Formula 3 amine to carboxylic acid is preferably from about 0.85 to about 3. When the mode of combination involves forming the amine salt before addition of the 30 compound of Formula 2 the molar ratio of Formula 3 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 3 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 7 2. For optimal conversions, the molar ratio of amine of Formula 3 to isatoic anhydride compound of Formula 2 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 economy, regardless of how the components are mixed. The molar amount of amine of Formula 3 relative to compound of 5 Formula 2 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. The method of Scheme 1 typically achieves the highest product yield and purity when the reaction medium is substantially anhydrous. The reaction medium is thus typically formed from substantially anhydrous compounds of Formula 2 and 3 and carboxylic acid. 10 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 1 is typically conducted in a liquid phase. In many cases the reaction can be carried out without solvent other than the compounds of Formulae 1, 2 and 3 15 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. 20 The weight ratio of solvent to the compound of Formula 2 is typically from about 1 to about 20, and preferably about 5 for reasons of efficiency and economy. The method of Scheme 1 forms carbon dioxide as a byproduct. As the method is typically conducted, most of the carbon dioxide formed evolves from the reaction medium as a gas. The addition of the compound of Formula 2 into reaction medium containing the 25 amine of Formula 3 or the addition of the amine of Formula 3 into the reaction medium containing the compound of Formula 2 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 60 'C. 30 The product of Formula 1 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 the to starting compound of Formula 2, 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 35 be optionally separated, and most of the organic solvent can be removed by distillation or evaporation at reduced pressure. As the compounds of Formula 1 are typically crystalline solids at ambient temperature, they are generally most easily isolated by filtration, optionally followed by washing with water and then drying. Typically no pH adjustment is needed 8 during workup, and water is a useful crystallization medium for the products of Formula 1. Therefore a particularly convenient procedure is to dilute the reaction medium with water, remove most of the organic solvent by distillation at atmospheric pressure, and then cool the aqueous mixture to crystallize the product, which then can be collected by filtration. The 5 method of Scheme 1 is illustrated by Reference Examples 2-5 below. As shown in Scheme 2, a substituted isatoic anhydride of Formula 2 is prepared by contacting a compound of Formula 4 with phosphorus tribromide. Scheme 2 R 2 R 2

NHCO

2

R

3 + PBr 3 O X CO 2 H X 4 2 10 Without being bound by any particular theory, phosphorus tribromide is believed to react with a compound of Formula 4 to produce a compound of Formula 10 as shown in Exhibit 1 as an intermediate along with hydrogen bromide, which subsequently react to form the compound of Formula 2 and R 3 Br as the ultimate byproduct. Exhibit 1 R 2 N OR 3 0 X 15 10 0 In the method of Scheme 2 the stoichiometric amount of phosphorus tribromide needed to obtain complete conversion of the compound of Formula 4 to the compound of Formula 2 is one-third molar equivalent. Typically the amount of phosphorus tribromide used is between about 0.3 and 3 molar equivalents, with about 0.33 to about 0.4 equivalents 20 being preferred for reason of economy. The method of Scheme 2 is typically conducted in a liquid phase, usually comprising a solvent to at least partially dissolve the compound of Formula 4. The solvent must be inert to phosphorus tribromide and preferably has a normal boiling point higher than 50 'C, preferably greater than 70 'C, to accommodate the reaction temperature. Examples of 25 solvents suitable for this reaction are hydrocarbons (e.g., cyclohexane, benzene, toluene), halogenated hydrocarbons (e.g., 1-chlorobutane, 1,2-dichloroethane, chlorobenzene, o-dichlorobenzene), esters (e.g., n-butyl acetate) or nitriles (e.g., acetonitrile, benzonitrile).

9 The method of Scheme 2 can be conveniently carried out by diluting a compound of Formula 4 with a solvent and then adding phosphorus tribromide. Typically the phosphorus tribromide is added to the reaction mixture comprising the Formula 4 compound at such a rate that the temperature of the reaction mixture is maintained in the range between about 50 5 and 80 'C. Preferably the rate of addition of phosphorus tribromide is selected to maintain the temperature of the reaction mixture in the range between about 60 and 75 'C, as this controls the exothermic reaction and maximizes the purity of the product. After completion of the reaction the product of Formula 2 can be isolated by standard techniques known in the art, including sparging, pH adjustment, extraction, evaporation, 10 crystallization and chromatography. Much of the R 3 Br byproduct and hydrogen bromide remaining in the reaction mixture can be removed by sparging with air or a gas such as nitrogen. Compounds of Formula 2 are generally crystalline solids; on cooling the reaction mixture, the product usually crystallizes as a solid that can be collected by filtration, washed with water to remove residual phosphorous acid and hydrogen bromide, and dried. The 15 method of Scheme 2 is illustrated by Example 1. Compounds of Formula 4 can be prepared by general methods known in the art, including, for example halogenation of corresponding compounds of Formula 11 with chlorine or bromine as shown in Scheme 3. Scheme 3 R 2 R 2

NHCO

2

R

3 halogenation NHCO 2

R

3

CO

2 H X CO 2 H 20 11 Particularly useful for the halogenation of Scheme 3 is nascent chlorine or bromine generated by contact of aqueous hydrochloric acid or hydrobromic acid with hydrogen peroxide according to the general method of German Patent Publication DE 2750292-Al. This method is illustrated by Reference Example 1 for X being chlorine. Corresponding 25 compounds can be prepared by this procedure by substituting hydrobromic acid for hydrochloric acid. 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 30 way whatsoever. Percentages are by weight except for chromatographic solvent mixtures or where otherwise indicated. Parts and percentages for chromatographic solvent mixtures are by volume unless otherwise indicated. Purity of products containing 2-amino-5-chloro-N,3 dimethylbenzamide was determined by Reverse Phase HPLC using an Ace C4 Column 10 (Advanced Chromatography Technologies, Aberdeen, Scotland) and an acetonitrile/water gradient containing 0.005 M NaH 2

PO

4

/H

2 0 buffer adjusted to pH 3 with H 3

PO

4

.

1 H NMR spectra are reported in ppm downfield from tetramethylsilane; "s" means singlet, "d" means doublet, "t" means triplet, "q" means quartet, "m" means multiplet, "dd" means doublet of 5 doublets, "dt" means doublet of triplets, "br s" means broad singlet, and "br m" means broad multiplet. REFERENCE EXAMPLE 1 Preparation of 5-Chloro-2-[(ethoxycarbonyl)amino]-3-methylbenzoic acid (a compound of Formula 4) 10 A 2-L reactor equipped with overhead stirrer and thermocouple was charged with 150 g (0.672 mol) of 2- [(ethoxycarbonyl)amino]-3-methylbenzoic acid (ca. 98% purity) and acetic acid (500 g). The resulting slurry was heated to 35-40 'C to give a solution, which was cooled to 30 'C, and then hydrochloric acid (37%, 150 g, 1.5 mol, 2.2 eq) was added. The mixture was maintained at 30 'C while aqueous hydrogen peroxide (30%, 96 g, 0.85 15 mol, 1.25 eq) was added over about 1 h. The mixture was then warmed to 35 'C and held at that temperature for about 1 h. About 600 mL of water was metered in over about 30 minutes, while maintaining the temperature at 30-35 'C. The mixture was cooled to 10 'C, and the product was collected by filtration, and the wet cake was washed with water (3 x 100 mL); the third wash tested negative with KI-starch paper. The wet cake was dried to 20 constant weight in a vacuum oven at 50 'C. The crude yield was about 150 g (about 84% based on an estimated purity of 2-[(ethoxycarbonyl)amino]-3-methylbenzoic acid of 98% and estimated product purity of 95%). A portion of the crude product was first recrystallized from toluene and then recrystallized from aqueous methanol to give an analytical sample melting at 124-126 'C. 25 1 H NMR (DMSO-d 6 ) 6 1.19 (t, 3H), 2.22 (s, 3H), 4.05 (q, 2H), 7.54 (m, 2H), 8.9 (br s, 1H), 13.1 (br s, 1H). EXAMPLE 1 Preparation of 6-Chloro-8-methyl-2H-3,1-benzoxazine-2,4(1H)-dione (a compound of Formula 2) 30 A 1-L, three-necked flask equipped with an addition funnel, thermometer, condenser, nitrogen bubbler, and caustic scrubber was charged with 5-chloro-2-[(ethoxy carbonyl)amino]-3-methylbenzoic acid (i.e. the product of Reference Example 1) (74.0 g, 0.288 mol) and toluene (300 mL). The mixture was heated at 60-65 'C while phosphorus tribromide (39 g, 0.144 mol) was added over about 60 minutes. The mixture was heated at 35 65 'C for about 30 minutes, which resulted in no more than 0.2% of the intermediate 6-chloro-2-ethoxy-8-methyl-4H-3,1-benzoxazin-4-one remaining according to HPLC analysis. The mixture was sparged with nitrogen to remove hydrogen bromide and ethyl 11 bromide, and then cooled to 20 'C. The product was collected under filtration, and the filter cake was successively washed with toluene (30 mL) and water (2 x 100 mL), and then suction dried. Drying the collected solid in a vacuum oven to constant weight provided the title compound (59 g, about 97% purity by HPLC analysis). A portion of the dried product 5 was recrystallized by dissolving in N,N-dimethylformamide (4 volumes) at 60 'C and cooling to 20 'C to provide a sample of 99% purity melting at >250 'C. 1 H NMR (DMSO-d 6 ) 6 2.33 (s, 3H), 7.67 (dd, 1H, J= 2.5 and 0.6 Hz), 7.72 (d, 1H, J= 2.4 Hz), 11.2 (br s, 1H). REFERENCE EXAMPLE 2 10 Preparation of 2-Amino-5-chloro-N,3-dimethylbenzamide (a compound of Formula 1) A 300-mL flask equipped with a thermometer and nitrogen bubbler was charged with ethyl acetate (100 mL) and 12.6 g (0.21 mol) of acetic acid. Anhydrous methylamine (6.3 g, 0.20 mol) was added below the surface of the liquid mixture, which was cooled to maintain the temperature below 35 'C. Then 6-chloro-8-methyl-2H-3,1-benzoxazine-2,4(1H)-dione 15 (21 g, 0.10 mol) (i.e. the product of Example 1) was added in portions while maintaining the reaction mixture at 35-40 'C. After completion of the addition of the 6-chloro-8-methyl 2H-3,1-benzoxazine-2,4(1H)-dione the temperature was maintained at 40-45 'C, and the progress of the reaction was monitored by HPLC analysis. After about 20 minutes, when no more than 0.5% 6-chloro-8-methyl-2H-3,1-benzoxazine-2,4(1H)-dione remained, water (50 20 mL) was added. A distillation head was attached, moderate vacuum was applied, and ethyl acetate was distilled out at an internal temperature of about 46-60 'C and pressure of about 30 to 50 kPa. To replace the ethyl acetate removed by distillation, water was added to maintain the original liquid volume in the reactor. When a significant amount of water began to distill, the aqueous slurry was cooled to 10 'C. The solid was collected by filtration 25 and dried at 60 OC and 13.3 kPa to afford the title compound as a white crystalline solid (19 g, ca. 95% yield, >98% purity by peak area in HPLC analysis). REFERENCE EXAMPLE 3 A Second Preparation of 2-Amino-5-chloro-N,3-dimethylbenzamide A 250-mL flask equipped with a thermometer and nitrogen bubbler was charged with 30 6-chloro-8-methyl-2H-3,1-benzoxazine-2,4(1H)-dione (9.0 g, 43 mmol) (i.e. the product of Example 1), ethyl acetate (50 mL), and acetic acid (3.8 g, 63 mmol). The mixture was heated to 50 'C, and anhydrous methylamine (1.6 g, 50 mmol) was added below the surface of the mixture while maintaining the temperature at 48-52 'C. The mixture was held for 1 h at 50 'C, then water (65 mL) was added, and the ethyl acetate was removed by distillation. 35 When the pot temperature reached 83 'C, the solution was seeded, and the product slurry was cooled over 3 h to 10 'C. The solid was collected by filtration and dried to afford the 12 title compound as a white crystalline solid (7.94 g, > 98.5 wt. % purity by HPLC assay, 93% yield) melting at 143-145 0 C. 1 H NMR (DMSO-d 6 ) 6 2.08 (s, 3H), 2.72 (d, 3H, J= 4.5 Hz), 6.36 (s, 2H), 7.13 (d, 1H, J 2.1 Hz), 7.40 (d, 1H, J= 2.1 Hz), 8.33 (q, 1H, J= 4.5 hz). 5 REFERENCE EXAMPLE 4 A Third Preparation of 2-Amino-5-chloro-N,3-dimethylbenzamide A 250-mL flask equipped with thermometer and nitrogen bubbler was charged with 6-chloro-8-methyl-2H-3,1-benzoxazine-2,4(1H)-dione (21.0 g, 0.099 mol) (i.e. the product of Example 1), ethyl acetate (100 mL), and acetic acid (12.6 g, 0.21 mol). The mixture was 10 stirred at 22 'C, and anhydrous methylamine (4.3 g, 0.14 mol) was added below the surface of the mixture in portions over 45 minutes while maintaining the temperature at 22-41 'C. The mixture was held for 2 h at 40 'C, then water (150 mL) was added, and the ethyl acetate was removed by distillation. When the pot temperature reached 83 'C, the solution was seeded, and the product slurry was cooled over about 2 h to 10 'C. The solid was collected 15 by filtration, washed with water and dried to afford the title compound as a white crystalline solid (18.38 g, > 97.4 wt. % purity by HPLC, 94% yield) melting at 143-145 'C. REFERENCE EXAMPLE 5 Preparation of 2-Amino-5-chloro-N,3-dimethylbenzamide Using Aqueous Methylamine The procedure of Reference Example 3 was modified by using aqueous methylamine 20 (40% solution, 10.75 g, 0.138 mol) instead of anhydrous methylamine. Obtained after collection of solid and drying was 18.57 g of crude product, which HPLC showed containing the title compound in only 92.4 wt. % purity, thus corresponding to 87.3% yield. HPLC showed the crude product also containing about 3.4 wt. % of 6-chloro-3,8-dimethyl 2,4(1H,3H)-quinazolinedione derived from cyclization of the 5-chloro-3-methyl-2-[[(methyl 25 amino)carbonyl]amino]benzoic acid by-product, and about 1.7% of the hydrolysis product 2 amino-5-chloro-3-methylbenzoic acid. This Example demonstrates that water has a detrimental effect on the yield and purity of the product. Table 1 illustrates particular transformations to prepare compounds of Formula 1. For these transformations, the carboxylic acid is most conveniently acetic acid. In Table 1 and 30 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-PrCH 2 " means cyclopropylmethyl.

13 TABLE 1 R 2 H R 2 H N,, 1+ RNH 2 carboxylic acid

NH

2 x 0 X C(O)NHR 2 1 X RI R 2 X RI R 2 X RI R 2 Cl H Me Cl c-PrCH 2 Me Cl i-Pr Cl Br H Me Br c-PrCH 2 Me Br i-Pr Cl Cl Me Me Cl 1-CH 3 -c-Pr Me Cl t-Bu Cl Br Me Me Br 1-CH 3 -c-Pr Me Br t-Bu Cl Cl Et Me Cl 2-CH 3 -c-Pr Me Cl c-Pr Cl Br Et Me Br 2-CH 3 -c-Pr Me Br c-Pr Cl Cl i-Pr Me Cl H Cl Cl c-PrCH 2 Cl Br i-Pr Me Br H Cl Br c-PrCH 2 Cl Cl t-Bu Me Cl Me Cl Cl 1-CH 3 -c-Pr Cl Br t-Bu Me Br Me Cl Br 1-CH 3 -c-Pr Cl Cl c-Pr Me Cl Et Cl Cl 2-CH 3 -c-Pr Cl Br c-Pr Me Br Et Cl Br 2-CH 3 -c-Pr Cl Table 2 illustrates particular transformations to prepare compounds of Formula 2 according to a method of the present invention. 5 TABLE2 R 2 R2 NC23 H N H C 2 R + P B r 30 1N y 0 X CO 2 H X 42 X R2 R3 X R2 R3 X R2 R3 Cl Me Et Cl Cl benzyl Cl Cl Me Br Me Et Br Cl benzyl Br Cl Me Cl Me i-Pr Cl Cl n-Bu Cl Cl Et Br Me i-Pr Br Me i-Bu Br Cl Et Cl Me Me Cl Cl i-Bu Cl Me n-hexyl Br Me Me Br Me n-Bu Br Me n-hexyl Cl Cl n-Pr Cl Me benzyl Cl Me 2-Ci-Et 14 Br Me allyl Br Me benzyl Br Me 2-Ci-Et By the methods and procedures described herein together with methods known in the art, the compounds of Formula 4 listed in Table 3 can be prepared. In particular, these compounds are useful intermediates that can be made by the method of Scheme 3 and are starting materials for preparing compounds of Formula 2 according to the method of Scheme 5 2. TABLE 3 R 2

NHCO

2

R

3 X

CO

2 H 4 X R2 R3 X R2 R3 X R2 R3 Cl Me Et Cl Cl benzyl Cl Cl Me Br Me Et Br Cl benzyl Br Cl Me Cl Me i-Pr Cl Cl n-Bu Cl Cl Et Br Me i-Pr Br Me i-Bu Br Cl Et Cl Me Me Cl Cl i-Bu Cl Me n-hexyl Br Me Me Br Me n-Bu Br Me n-hexyl Cl Cl n-Pr Cl Me benzyl Cl Me 2-Ci-Et Br Me allyl Br Me benzyl Br Me 2-Ci-Et Compounds of Formula 1 prepared by the present method of Scheme 1 are useful intermediates for preparing compounds of Formula 5. R R2 N R NH z 5 10X C(O)NHR R 6 wherein X is Cl or Br; Z is CR 7 or N;

R

1 is H, Ci-C 4 alkyl, cyclopropyl, cyclopropylmethyl or methylcyclopropyl; 15 R 2 is CH 3 or Cl; 15

R

4 is Cl, Br, CF 3 , OCF 2 H or OCH 2

CF

3 ;

R

5 is F, Cl or Br;

R

6 is H, F or Cl; and

R

7 is H, F, Cl or Br. 5 Compounds of Formula 5 are useful as insecticides, as described, for example in PCT Patent Publications WO 2003/015518 and WO 2006/055922. A variety of routes are possible for preparing a compound of Formula 5 from a compound of Formula 1. In one method shown in Scheme 4, a compound of Formula 5 is prepared by combining a compound of Formula 1, a carboxylic acid compound of Formula 6 and sulfonyl chloride 10 according to the general method taught in PCT Patent Publication WO 2006/062978, which is hereby incorporated herein in its entirety by reference. Scheme 4 R4 R4 R2 O I N

NH

2 N R 5 sulfonyl 2 5 2 +Oc h lo r id e +| OH Z NH Z X C(O)NHRI 1 X C(O)NHR R 6 5 As described in WO 2006/062978 a variety of reaction conditions are possible for this 15 method. Typically a sulfonyl chloride is added to a mixture of the compounds of Formulae 1 and 6 in the presence of a solvent and a base. Sulfonyl chlorides are generally of the formula

RS(O)

2 C1 wherein R is a carbon-based radical. Typically for this method R is CI-C 4 alkyl, Ci-C 2 haloalkyl, or phenyl optionally substituted with 1-3 substituents selected from the group consisting of halogen, CI-C 3 alkyl and nitro. Commercially available sulfonyl 20 chlorides include methanesulfonyl chloride (R is CH 3 ), propanesulfonyl chloride (R is (CH2) 2

CH

3 ), 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 6 is stoichiometrically needed for complete conversion. 25 Typically the molar ratio of sulfonyl chloride to the compound of Formula 6 is no more than about 2.5, more typically no more than about 1.4. The compound of Formula 5 is formed when the starting compounds of Formulae 1 and 6 and the sulfonyl chloride are contacted with each other in a combined liquid phase, in which each is at least partially soluble. Particularly as the starting materials of Formulae 1 16 and 6 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 6 may have only slight solubility but its salt with added base may 5 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, 10 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 solvent is acetonitrile, as it often provides products in superior yield and/or purity. 15 As the reaction generates hydrogen chloride as a byproduct, which would otherwise bind to basic centers on the compounds of Formulae 1, 5 and 6, 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 6 20 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 25 not used as solvent the nominal mole ratio of the base charged to the sulfonyl chloride charged is typically from about 2.0 to 2.2, and is preferably from about 2.1 to 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 base is 3-picoline, as its salts with carboxylic acids of Formula 6 are often highly soluble in solvents such as 30 acetonitrile. The product N-phenylpyrazole-1-carboxamide compounds of Formula 5 can be isolated from the reaction mixtures by methods known to those skilled in the art, including crystallization, filtration, and extraction. WO 2006/062978 discloses specific examples relevant to the method of Scheme 4. 35 Pyrazolecarboxylic acid compounds of Formula 6 can be prepared using methods of heterocyclic synthesis known in the literature, including PCT Patent Publications WO 1998/57397, WO 2003/015519, WO 2006/055922 and WO 2006/062978 and references found in the following compendia: Rodd's Chemistry of Chemistry of Carbon Compounds, 17 Vol. IVa to IVI, S. Coffey editor, Elsevier Scientific Publishing, New York, 1973; Comprehensive Heterocyclic Chemistry, Vol. 1-7, A. R. Katritzky and C. W. Rees editors, Pergamon Press, New York, 1984; Comprehensive Heterocyclic Chemistry II, Vol. 1-9, A. R. Katritzky, C. W. Rees, and E. F. Scriven editors, Pergamon Press, New York, 1996; and 5 the series, The Chemistry of Heterocyclic Compounds, E. C. Taylor, editor, Wiley, New York. The method of Scheme 4 is illustrative of just one of many methods for converting an amine compound of Formula 1 to the corresponding carboxamide compound of Formula 5. A wide variety of general methods known in the art for preparing carboxamides from 10 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 1 with a compound of Formula 6 in the presence of a dehydrating coupling agent such as 1,3-dicyclo hexylcarbodiimide, 1,1'-carbonyldiimidazole, bis(2-oxo-3-oxazolidinyl)phosphinic chloride or benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate, or a 15 polymer-bound analogous reagent such as polymer-bound dicyclohexylcarbodiimide, typically in an inert solvent such as dichloromethane or NN-dimethylformamide, as is generally disclosed in PCT Patent Publication WO 2003/15518. Also disclosed by the reference is the alternative of preparing an acyl chloride counterpart of the compound of Formula 6, such as by contact with thionyl chloride or oxalyl chloride in the presence of a 20 catalytic amount of NN-dimethylformamide, and then contacting the derived acyl chloride with the compound of Formula 1 in the presence of an acid scavenger, such as an amine base (e.g., triethylamine, NN-diisopropylethylamine, pyridine, and polymer- supported analogs) or a hydroxide or carbonate (e.g., NaOH, KOH, Na 2

CO

3 , K 2

CO

3 ), typically in an inert solvent such as tetrahydrofuran, 1,4-dioxane, ethyl ether or dichloromethane. The product 25 compounds of Formula 5 can be isolated from the reaction mixtures by methods known to those skilled in the art, including crystallization, filtration, and extraction. Table 4 illustrates particular transformations to prepare compounds of Formula 5 from compounds of Formulae 2 and 3. The conversion of the compound of Formula 1 to the compound of Formula 5 can, for example, be accomplished according to the method of 30 Scheme 4 using a sulfonyl chloride such as methanesulfonyl chloride in the presence of a solvent such as acetonitrile and a base such as 3-picoline.

18 TABLE 4 R 2 H R 2 H N 0 carboxylic NH ~1+1H acid 2 + R NH2 a O X 3 X C(O)NHR 2 0 1 / R R 2 N R5 NH X C(O)NHR R6 5

R

6 is H. R 6 is H. X RI R2 R4 R5 Z X RI R2 R4 R5 Z Cl H Me CF 3 F N Cl Me Cl CF 3 F N Cl Et Me CF 3 F N Cl i-Pr Cl CF 3 F N Cl t-Bu Me CF 3 F N Cl c-Pr Cl CF 3 F N Cl c-PrCH 2 Me CF 3 F N Cl 1-CH 3 -c-Pr Cl CF 3 F N Cl Me Me CF 3 Cl N Cl H Cl CF 3 Cl N Cl i-Pr Me CF 3 Cl N Cl Et Cl CF 3 Cl N Cl c-Pr Me CF 3 Cl N Cl t-Bu Cl CF 3 Cl N Cl 1-CH 3 -c-Pr Me CF 3 Cl N Cl c-PrCH 2 Cl CF 3 Cl N Cl 2-CH 3 -c-Pr Me CF 3 Cl N Cl Me Cl CF 3 Br N Cl H Me CF 3 Br N Cl i-Pr Cl CF 3 Br N Cl Et Me CF 3 Br N Cl c-Pr CH 3

CF

3 Br N Cl t-Bu Me CF 3 Br N Cl 1-CH 3 -c-Pr CH 3

CF

3 Br N Cl c-PrCH 2 Me CF 3 Br N Cl H Cl Cl F N Cl H Me Cl F N Cl Me Cl Cl F N Cl Me Me Cl F N Cl Et Cl Cl F N Cl Et Me Cl F N Cl i-Pr Cl Cl F N Cl i-Pr Me Cl F N Cl t-Bu Cl Cl F N Cl t-Bu Me Cl F N Cl c-Pr Cl Cl F N Cl c-Pr Me Cl F N Cl c-PrCH 2 Cl Cl F N Cl c-PrCH 2 Me Cl F N Cl 1-CH 3 -c-Pr Cl Cl F N Cl 1-CH 3 -c-Pr Me Cl F N Cl H Cl Cl Cl N Cl H Me Cl Cl N Cl Me Cl Cl Cl N 19

R

6 is H. R 6 is H. X R1 R2 R4 R5 Z X R1 R2 R4 R5 Z Cl Me Me Cl Cl N Cl Et Cl Cl Cl N Cl Et Me Cl Cl N Cl i-Pr Cl Cl Cl N Cl i-Pr Me Cl Cl N Cl t-Bu Cl Cl Cl N Cl t-Bu Me Cl Cl N Cl c-Pr Cl Cl Cl N Cl c-Pr Me Cl Cl N Cl c-PrCH 2 Cl Cl Cl N Cl c-PrCH 2 Me Cl Cl N Cl 1-CH 3 -c-Pr Cl Cl Cl N Cl 1-CH 3 -c-Pr Me Cl Cl N Cl H Cl Cl Br N Cl 2-CH 3 -c-Pr Me Cl Cl N Cl Me Cl Cl Br N Cl H Me Cl Br N Cl Et Cl Cl Br N Cl Me Me Cl Br N Cl i-Pr Cl Cl Br N Cl Et Me Cl Br N Cl t-Bu Cl Cl Br N Cl i-Pr Me Cl Br N Cl c-Pr Cl Cl Br N Cl t-Bu Me Cl Br N Cl c-PrCH 2 Cl Cl Br N Cl c-Pr Me Cl Br N Cl 1-CH 3 -c-Pr Cl Cl Br N Cl c-PrCH 2 Me Cl Br N Cl H Cl Br F N Cl 1-CH 3 -c-Pr Me Cl Br N Cl Me Cl Br F N Cl H Me Br F N Cl Et Cl Br F N Cl Me Me Br F N Cl i-Pr Cl Br F N Cl Et Me Br F N Cl t-Bu Cl Br F N Cl i-Pr Me Br F N Cl c-Pr Cl Br F N Cl t-Bu Me Br F N Cl c-PrCH 2 Cl Br F N Cl c-Pr Me Br F N Cl 1-CH 3 -c-Pr Cl Br F N Cl c-PrCH 2 Me Br F N Cl H Cl Br Cl N Cl 1-CH 3 -c-Pr Me Br F N Cl Me Cl Br Cl N Cl H Me Br Cl N Cl Et Cl Br Cl N Cl Me Me Br Cl N Cl i-Pr Cl Br Cl N Cl Et Me Br Cl N Cl t-Bu Cl Br Cl N Cl i-Pr Me Br Cl N Cl c-Pr Cl Br Cl N Cl t-Bu Me Br Cl N Cl c-PrCH 2 Cl Br Cl N Cl c-Pr Me Br Cl N Cl 1-CH 3 -c-Pr Cl Br Cl N Cl c-PrCH 2 Me Br Cl N Cl H Cl Br Br N Cl 1-CH 3 -c-Pr Me Br Cl N Cl Me Cl Br Br N Cl 2-CH 3 -c-Pr Me Br Cl N Cl Et Cl Br Br N Cl H Me Br Br N Cl i-Pr Cl Br Br N Cl Me Me Br Br N Cl t-Bu Cl Br Br N Cl Et Me Br Br N Cl c-Pr Cl Br Br N 20

R

6 is H. R 6 is H. X R1 R2 R4 R5 Z X R1 R2 R4 R5 Z Cl i-Pr Me Br Br N Cl c-PrCH 2 Cl Br Br N Cl t-Bu Me Br Br N Cl 1-CH 3 -c-Pr Cl Br Br N Cl c-Pr Me Br Br N Cl Me Cl OCH 2

CF

3 F N Cl c-PrCH 2 Me Br Br N Cl i-Pr Cl OCH 2

CF

3 F N Cl 1-CH 3 -c-Pr Me Br Br N Cl H Cl OCH 2

CF

3 Cl N Cl H Me OCH 2

CF

3 F N Cl Et Cl OCH 2

CF

3 Cl N Cl Et Me OCH 2

CF

3 F N Cl t-Bu Cl OCH 2

CF

3 Cl N Cl t-Bu Me OCH 2

CF

3 F N Cl H Cl OCH 2

CF

3 Br N Cl Me Me OCH 2

CF

3 Cl N Cl Et Cl OCH 2

CF

3 Br N Cl i-Pr Me OCH 2

CF

3 Cl N Cl t-Bu Cl OCH 2

CF

3 Br N Cl Me Me OCH 2

CF

3 Br N Br Me Cl CF 3 F N Cl i-Pr Me OCH 2

CF

3 Br N Br i-Pr Cl CF 3 F N Cl 1-CH 3 -c-Pr Me OCH 2

CF

3 Br N Br c-Pr Cl CF 3 F N Br H Me CF 3 F N Br 1-CH 3 -c-Pr Cl CF 3 F N Br Et Me CF 3 F N Br H Cl CF 3 Cl N Br t-Bu Me CF 3 F N Br Et Cl CF 3 Cl N Br c-PrCH 2 Me CF 3 F N Br t-Bu Cl CF 3 Cl N Br Me Me CF 3 Cl N Br c-PrCH 2 Cl CF 3 Cl N Br i-Pr Me CF 3 Cl N Br H Cl CF 3 Br N Br c-Pr Me CF 3 Cl N Br Me Cl CF 3 Br N Br 1-CH 3 -c-Pr Me CF 3 Cl N Br i-Pr Cl CF 3 Br N Br Et Me CF 3 Br N Br c-Pr Cl CF 3 Br N Br t-Bu Me CF 3 Br N Br 1-CH 3 -c-Pr Cl CF 3 Br N Br c-PrCH 2 Me CF 3 Br N Br H Cl Cl F N Br H Me Cl F N Br Me Cl Cl F N Br Me Me Cl F N Br Et Cl Cl F N Br Et Me Cl F N Br i-Pr Cl Cl F N Br i-Pr Me Cl F N Br t-Bu Cl Cl F N Br t-Bu Me Cl F N Br c-Pr Cl Cl F N Br c-Pr Me Cl F N Br c-PrCH 2 Cl Cl F N Br c-PrCH 2 Me Cl F N Br 1-CH 3 -c-Pr Cl Cl F N Br 1-CH 3 -c-Pr Me Cl F N Br H Cl Cl Cl N Br H Me Cl Cl N Br Me Cl Cl Cl N Br Me Me Cl Cl N Br Et Cl Cl Cl N Br Et Me Cl Cl N Br i-Pr Cl Cl Cl N Br i-Pr Me Cl Cl N Br t-Bu Cl Cl Cl N 21

R

6 is H. R 6 is H. X R1 R2 R4 R5 Z X R1 R2 R4 R5 Z Br t-Bu Me Cl Cl N Br c-Pr Cl Cl Cl N Br c-Pr Me Cl Cl N Br c-PrCH 2 Cl Cl Cl N Br c-PrCH 2 Me Cl Cl N Br 1-CH 3 -c-Pr Cl Cl Cl N Br 1-CH 3 -c-Pr Me Cl Cl N Br H Cl Cl Br N Br H Me Cl Br N Br Me Cl Cl Br N Br Me Me Cl Br N Br Et Cl Cl Br N Br Et Me Cl Br N Br i-Pr Cl Cl Br N Br i-Pr Me Cl Br N Br t-Bu Cl Cl Br N Br t-Bu Me Cl Br N Br c-Pr Cl Cl Br N Br c-Pr Me Cl Br N Br c-PrCH 2 Cl Cl Br N Br c-PrCH 2 Me Cl Br N Br 1-CH 3 -c-Pr Cl Cl Br N Br 1-CH 3 -c-Pr Me Cl Br N Br H Cl Br F N Br H Me Br F N Br Me Cl Br F N Br Me Me Br F N Br Et Cl Br F N Br Et Me Br F N Br i-Pr Cl Br F N Br i-Pr Me Br F N Br t-Bu Cl Br F N Br t-Bu Me Br F N Br c-Pr Cl Br F N Br c-Pr Me Br F N Br c-PrCH 2 Cl Br F N Br c-PrCH 2 Me Br F N Br 1-CH 3 -c-Pr Cl Br F N Br 1-CH 3 -c-Pr Me Br F N Br H Cl Br Cl N Br H Me Br Cl N Br Me Cl Br Cl N Br Me Me Br Cl N Br Et Cl Br Cl N Br Et Me Br Cl N Br i-Pr Cl Br Cl N Br i-Pr Me Br Cl N Br t-Bu Cl Br Cl N Br t-Bu Me Br Cl N Br c-Pr Cl Br Cl N Br c-Pr Me Br Cl N Br c-PrCH 2 Cl Br Cl N Br c-PrCH 2 Me Br Cl N Br 1-CH 3 -c-Pr Cl Br Cl N Br 1-CH 3 -c-Pr Me Br Cl N Br H Cl Br Br N Br H Me Br Br N Br Me Cl Br Br N Br Me Me Br Br N Br Et Cl Br Br N Br Et Me Br Br N Br i-Pr Cl Br Br N Br i-Pr Me Br Br N Br t-Bu Cl Br Br N Br t-Bu Me Br Br N Br c-Pr Cl Br Br N Br c-Pr Me Br Br N Br c-PrCH 2 Cl Br Br N Br c-PrCH 2 Me Br Br N Br 1-CH 3 -c-Pr Cl Br Br N Br 1-CH 3 -c-Pr Me Br Br N Br Me Cl OCH 2

CF

3 F N 22

R

6 is H. R 6 is H. X R1 R2 R4 R5 Z X R1 R2 R4 R5 Z Br H Me OCH 2

CF

3 F N Br i-Pr Cl OCH 2

CF

3 F N Br Et Me OCH 2

CF

3 F N Br H Cl OCH 2

CF

3 Cl N Br t-Bu Me OCH 2

CF

3 F N Br Et Cl OCH 2

CF

3 Cl N Br Me Me OCH 2

CF

3 Cl N Br t-Bu Cl OCH 2

CF

3 Cl N Br i-Pr Me OCH 2

CF

3 Cl N Br H Cl OCH 2

CF

3 Br N Br Me Me OCH 2

CF

3 Br N Br Et Cl OCH 2

CF

3 Br N Br i-Pr Me OCH 2

CF

3 Br N Br t-Bu Cl OCH 2

CF

3 Br N Cl H Me OCHF 2 F N Cl Me Cl OCHF 2 F N Cl Et Me OCHF 2 F N Cl i-Pr Cl OCHF 2 F N Cl t-Bu Me OCHF 2 F N Cl H Cl OCHF 2 Cl N Cl Me Me OCHF 2 Cl N Cl Et Cl OCHF 2 Cl N Cl i-Pr Me OCHF 2 Cl N Cl t-Bu Cl OCHF 2 Cl N Cl H Me OCHF 2 Br N Cl Me Cl OCHF 2 Br N Cl Et Me OCHF 2 Br N Cl i-Pr Cl OCHF 2 Br N Cl t-Bu Me OCHF 2 Br N Br H Cl OCHF 2 F N Br Me Me OCHF 2 F N Br Et Cl OCHF 2 F N Br i-Pr Me OCHF 2 F N Br t-Bu Cl OCHF 2 F N Br H Me OCHF 2 Cl N Br Me Cl OCHF 2 Cl N Br Et Me OCHF 2 Cl N Br i-Pr Cl OCHF 2 Cl N Br t-Bu Me OCHF 2 Cl N Br H Cl OCHF 2 Br N Br Me Me OCHF 2 Br N Br Et Cl OCHF 2 Br N Br i-Pr Me OCHF 2 Br N Br t-Bu Cl OCHF 2 Br N Cl H Me CF 3 F CH Cl Me Cl CF 3 F CH Cl Et Me CF 3 F CH Cl i-Pr Cl CF 3 F CH Cl t-Bu Me CF 3 F CH Cl c-Pr Cl CF 3 F CH Cl c-PrCH 2 Me CF 3 F CH Cl 1-CH 3 -c-Pr Cl CF 3 F CH Cl Me Me CF 3 Cl CH Cl H Cl CF 3 Cl CH Cl i-Pr Me CF 3 Cl CH Cl Et Cl CF 3 Cl CH Cl c-Pr Me CF 3 Cl CH Cl t-Bu Cl CF 3 Cl CH Cl 1-CH 3 -c-Pr Me CF 3 Cl CH Cl c-PrCH 2 Cl CF 3 Cl CH Cl H Me CF 3 Br CH Cl Me Cl CF 3 Br CH Cl Et Me CF 3 Br CH Cl i-Pr Cl CF 3 Br CH Cl t-Bu Me CF 3 Br CH Cl c-Pr Cl CF 3 Br CH Cl c-PrCH 2 Me CF 3 Br CH Cl 1-CH 3 -c-Pr Cl CF 3 Br CH Cl H Me Cl F CH Cl H Cl Cl F CH Cl Me Me Cl F CH Cl Me Cl Cl F CH 23

R

6 is H. R 6 is H. X R1 R2 R4 R5 Z X R1 R2 R4 R5 Z Cl Et Me Cl F CH Cl Et Cl Cl F CH Cl i-Pr Me Cl F CH Cl i-Pr Cl Cl F CH Cl t-Bu Me Cl F CH Cl t-Bu Cl Cl F CH Cl c-Pr Me Cl F CH Cl c-Pr Cl Cl F CH Cl c-PrCH 2 Me Cl F CH Cl c-PrCH 2 Cl Cl F CH Cl 1-CH 3 -c-Pr Me Cl F CH Cl 1-CH 3 -c-Pr Cl Cl F CH Cl H Me Cl Cl CH Cl H Cl Cl Cl CH Cl Me Me Cl Cl CH Cl Me Cl Cl Cl CH Cl Et Me Cl Cl CH Cl Et Cl Cl Cl CH Cl i-Pr Me Cl Cl CH Cl i-Pr Cl Cl Cl CH Cl t-Bu Me Cl Cl CH Cl t-Bu Cl Cl Cl CH Cl c-Pr Me Cl Cl CH Cl c-Pr Cl Cl Cl CH Cl c-PrCH 2 Me Cl Cl CH Cl c-PrCH 2 Cl Cl Cl CH Cl 1-CH 3 -c-Pr Me Cl Cl CH Cl 1-CH 3 -c-Pr Cl Cl Cl CH Cl H Me Cl Br CH Cl H Cl Cl Br CH Cl Me Me Cl Br CH Cl Me Cl Cl Br CH Cl Et Me Cl Br CH Cl Et Cl Cl Br CH Cl i-Pr Me Cl Br CH Cl i-Pr Cl Cl Br CH Cl t-Bu Me Cl Br CH Cl t-Bu Cl Cl Br CH Cl c-Pr Me Cl Br CH Cl c-Pr Cl Cl Br CH Cl c-PrCH 2 Me Cl Br CH Cl c-PrCH 2 Cl Cl Br CH Cl 1-CH 3 -c-Pr Me Cl Br CH Cl 1-CH 3 -c-Pr Cl Cl Br CH Cl H Me Br F CH Cl H Cl Br F CH Cl Me Me Br F CH Cl Me Cl Br F CH Cl Et Me Br F CH Cl Et Cl Br F CH Cl i-Pr Me Br F CH Cl i-Pr Cl Br F CH Cl t-Bu Me Br F CH Cl t-Bu Cl Br F CH Cl c-Pr Me Br F CH Cl c-Pr Cl Br F CH Cl c-PrCH 2 Me Br F CH Cl c-PrCH 2 Cl Br F CH Cl 1-CH 3 -c-Pr Me Br F CH Cl 1-CH 3 -c-Pr Cl Br F CH Cl H Me Br Cl CH Cl H Cl Br Cl CH Cl Me Me Br Cl CH Cl Me Cl Br Cl CH Cl Et Me Br Cl CH Cl Et Cl Br Cl CH Cl i-Pr Me Br Cl CH Cl i-Pr Cl Br Cl CH Cl t-Bu Me Br Cl CH Cl t-Bu Cl Br Cl CH Cl c-Pr Me Br Cl CH Cl c-Pr Cl Br Cl CH 24

R

6 is H. R 6 is H. X R1 R2 R4 R5 Z X R1 R2 R4 R5 Z Cl c-PrCH 2 Me Br Cl CH Cl c-PrCH 2 Cl Br Cl CH Cl 1-CH 3 -c-Pr Me Br Cl CH Cl 1-CH 3 -c-Pr Cl Br Cl CH Cl H Me Br Br CH Cl H Cl Br Br CH Cl Me Me Br Br CH Cl Me Cl Br Br CH Cl Et Me Br Br CH Cl Et Cl Br Br CH Cl i-Pr Me Br Br CH Cl i-Pr Cl Br Br CH Cl t-Bu Me Br Br CH Cl t-Bu Cl Br Br CH Cl H Me OCH 2

CF

3 F CH Cl Me Cl OCH 2

CF

3 F CH Cl Et Me OCH 2

CF

3 F CH Cl i-Pr Cl OCH 2

CF

3 F CH Cl t-Bu Me OCH 2

CF

3 F CH Cl H Cl OCH 2

CF

3 Cl CH Cl Me Me OCH 2

CF

3 Cl CH Cl Et Cl OCH 2

CF

3 Cl CH Cl i-Pr Me OCH 2

CF

3 Cl CH Cl t-Bu Cl OCH 2

CF

3 Cl CH Cl H Me OCH 2

CF

3 Br CH Cl Me Cl OCH 2

CF

3 Br CH Cl Et Me OCH 2

CF

3 Br CH Cl i-Pr Cl OCH 2

CF

3 Br CH Cl t-Bu Me OCH 2

CF

3 Br CH Br H Cl CF 3 F CH Br Me Me CF 3 F CH Br Et Cl CF 3 F CH Br i-Pr Me CF 3 F CH Br t-Bu Cl CF 3 F CH Br c-Pr Me CF 3 F CH Br c-PrCH 2 Cl CF 3 F CH Br H Me CF 3 Cl CH Br 1-CH 3 -c-Pr Cl CF 3 F CH Br Et Me CF 3 Cl CH Br Me Cl CF 3 Cl CH Br t-Bu Me CF 3 Cl CH Br i-Pr Cl CF 3 Cl CH Br c-PrCH 2 Me CF 3 Cl CH Br c-Pr Cl CF 3 Cl CH Br 1-CH 3 -c-Pr Me CF 3 Cl CH Br H Cl CF 3 Br CH Br Me Me CF 3 Br CH Br Et Cl CF 3 Br CH Br i-Pr Me CF 3 Br CH Br t-Bu Cl CF 3 Br CH Br c-Pr Me CF 3 Br CH Br c-PrCH 2 Cl CF 3 Br CH Br H Me Cl F CH Br 1-CH 3 -c-Pr Cl CF 3 Br CH Br Me Me Cl F CH Br H Cl Cl F CH Br Et Me Cl F CH Br Me Cl Cl F CH Br i-Pr Me Cl F CH Br Et Cl Cl F CH Br t-Bu Me Cl F CH Br i-Pr Cl Cl F CH Br c-Pr Me Cl F CH Br t-Bu Cl Cl F CH Br c-PrCH 2 Me Cl F CH Br c-Pr Cl Cl F CH Br 1-CH 3 -c-Pr Me Cl F CH Br c-PrCH 2 Cl Cl F CH Br H Me Cl Cl CH Br 1-CH 3 -c-Pr Cl Cl F CH Br Me Me Cl Cl CH Br H Cl Cl Cl CH 25

R

6 is H. R 6 is H. X R1 R2 R4 R5 Z X R1 R2 R4 R5 Z Br Et Me Cl Cl CH Br Me Cl Cl Cl CH Br i-Pr Me Cl Cl CH Br Et Cl Cl Cl CH Br t-Bu Me Cl Cl CH Br i-Pr Cl Cl Cl CH Br c-Pr Me Cl Cl CH Br t-Bu Cl Cl Cl CH Br c-PrCH 2 Me Cl Cl CH Br c-Pr Cl Cl Cl CH Br 1-CH 3 -c-Pr Me Cl Cl CH Br c-PrCH 2 Cl Cl Cl CH Br H Me Cl Br CH Br 1-CH 3 -c-Pr Cl Cl Cl CH Br Me Me Cl Br CH Br H Cl Cl Br CH Br Et Me Cl Br CH Br Me Cl Cl Br CH Br i-Pr Me Cl Br CH Br Et Cl Cl Br CH Br t-Bu Me Cl Br CH Br i-Pr Cl Cl Br CH Br c-Pr Me Cl Br CH Br t-Bu Cl Cl Br CH Br c-PrCH 2 Me Cl Br CH Br c-Pr Cl Cl Br CH Br 1-CH 3 -c-Pr Me Cl Br CH Br c-PrCH 2 Cl Cl Br CH Br H Me Br F CH Br 1-CH 3 -c-Pr Cl Cl Br CH Br Me Me Br F CH Br H Cl Br F CH Br Et Me Br F CH Br Me Cl Br F CH Br i-Pr Me Br F CH Br Et Cl Br F CH Br t-Bu Me Br F CH Br i-Pr Cl Br F CH Br c-Pr Me Br F CH Br t-Bu Cl Br F CH Br c-PrCH 2 Me Br F CH Br c-Pr Cl Br F CH Br 1-CH 3 -c-Pr Me Br F CH Br c-PrCH 2 Cl Br F CH Br H Me Br Cl CH Br 1-CH 3 -c-Pr Cl Br F CH Br Me Me Br Cl CH Br H Cl Br Cl CH Br Et Me Br Cl CH Br Me Cl Br Cl CH Br i-Pr Me Br Cl CH Br Et Cl Br Cl CH Br t-Bu Me Br Cl CH Br i-Pr Cl Br Cl CH Br c-Pr Me Br Cl CH Br t-Bu Cl Br Cl CH Br c-PrCH 2 Me Br Cl CH Br c-Pr Cl Br Cl CH Br 1-CH 3 -c-Pr Me Br Cl CH Br c-PrCH 2 Cl Br Cl CH Br H Me Br Br CH Br 1-CH 3 -c-Pr Cl Br Cl CH Br Me Me Br Br CH Br H Cl Br Br CH Br Et Me Br Br CH Br Me Cl Br Br CH Br i-Pr Me Br Br CH Br Et Cl Br Br CH Br t-Bu Me Br Br CH Br i-Pr Cl Br Br CH Br H Me OCH 2

CF

3 F CH Br t-Bu Cl Br Br CH 26

R

6 is H. R 6 is H. X R1 R2 R4 R5 Z X R1 R2 R4 R5 Z Br Et Me OCH 2

CF

3 F CH Br Me Cl OCH 2

CF

3 F CH Br t-Bu Me OCH 2

CF

3 F CH Br i-Pr Cl OCH 2

CF

3 F CH Br Me Me OCH 2

CF

3 Cl CH Br H Cl OCH 2

CF

3 Cl CH Br i-Pr Me OCH 2

CF

3 Cl CH Br Et Cl OCH 2

CF

3 Cl CH Br H Me OCH 2

CF

3 Br CH Br t-Bu Cl OCH 2

CF

3 Cl CH Br Et Me OCH 2

CF

3 Br CH Br Me Cl OCH 2

CF

3 Br CH Br t-Bu Me OCH 2

CF

3 Br CH Br i-Pr Cl OCH 2

CF

3 Br CH Cl Me Me OCHF 2 F CH Cl H Cl OCHF 2 F CH Cl i-Pr Me OCHF 2 F CH Cl Et Cl OCHF 2 F CH Cl H Me OCHF 2 Cl CH Cl t-Bu Cl OCHF 2 F CH Cl Et Me OCHF 2 Cl CH Cl Me Cl OCHF 2 Cl CH Cl t-Bu Me OCHF 2 Cl CH Cl i-Pr Cl OCHF 2 Cl CH Cl Me Me OCHF 2 Br CH Cl H Cl OCHF 2 Br CH Cl i-Pr Me OCHF 2 Br CH Cl Et Cl OCHF 2 Br CH Br H Me OCHF 2 F CH Cl t-Bu Cl OCHF 2 Br CH Br Et Me OCHF 2 F CH Br Me Cl OCHF 2 F CH Br t-Bu Me OCHF 2 F CH Br i-Pr Cl OCHF 2 F CH Br Me Me OCHF 2 Cl CH Br H Cl OCHF 2 Cl CH Br i-Pr Me OCHF 2 Cl CH Br Et Cl OCHF 2 Cl CH Br H Me OCHF 2 Br CH Br t-Bu Cl OCHF 2 Cl CH Br Et Me OCHF 2 Br CH Br Me Cl OCHF 2 Br CH Br t-Bu Me OCHF 2 Br CH Br i-Pr Cl OCHF 2 Br CH

R

6 is F. R 6 is F. X RI R2 R4 R5 Z X RI R2 R4 R5 Z Cl H Me CF 3 F N Br t-Bu Cl OCHF 2 Br N Cl Me Cl CF 3 Cl N Cl H Me CF 3 Cl CH Cl Et Me CF 3 Br N Cl Me Cl CF 3 Br CH Cl i-Pr Cl Cl F N Cl Et Me Cl F CH Cl t-Bu Me Cl Cl N Cl i-Pr Cl Cl Cl CH Cl c-Pr Cl Cl Br N Cl t-Bu Me Cl Br CH Cl c-PrCH 2 Me Br F N Cl c-Pr Cl Br F CH Cl 1-CH 3 -c-Pr Cl Br Cl N Cl c-PrCH 2 Me Br Cl CH Cl H Me OCH 2

CF

3 F N Cl H Cl OCH 2

CF

3 F CH Cl Me Cl OCH 2

CF

3 Cl N Cl Me Me OCH 2

CF

3 Cl CH Cl Et Me OCH 2

CF

3 Br N Cl Et Cl OCH 2

CF

3 Br CH 27

R

6 is F. R 6 is F. X R1 R2 R4 R5 Z X R1 R2 R4 R5 Z Br i-Pr Cl CF 3 F N Br i-Pr Me CF 3 F CH Br t-Bu Me CF 3 Cl N Br t-Bu Cl Cl F CH Br c-Pr Cl CF 3 Br N Br c-Pr Me Cl Cl CH Br c-PrCH 2 Me Cl F N Br c-PrCH 2 Cl Cl Br CH Br 1-CH 3 -c-Pr Cl Cl Cl N Br 1-CH 3 -c-Pr Me Br F CH Br H Me Br Cl N Br H Cl Br Br CH Br Me Cl Br Br N Br Me Me OCH 2

CF

3 F CH Br Et Me OCH 2

CF

3 F N Br Et Cl OCH 2

CF

3 Cl CH Br i-Pr Cl OCH 2

CF

3 Cl N Br i-Pr Me OCH 2

CF

3 Br CH Br t-Bu Me OCH 2

CF

3 Br N Cl t-Bu Cl OCHF 2 F CH Cl H Cl OCHF 2 Cl N Cl H Me OCHF 2 Br CH Cl Me Me OCHF 2 Br N Br Me Cl OCHF 2 F CH Br Et Cl OCHF 2 F N Br Et Me OCHF 2 Cl CH Br i-Pr Me OCHF 2 Cl N Br i-Pr Cl OCHF 2 Br CH

R

6 is Cl. R 6 is Cl. X RI R2 R4 R5 Z X RI R2 R4 R5 Z Cl H Me CF 3 F N Br t-Bu Cl OCHF 2 Br N Cl Me Cl CF 3 Cl N Cl H Me CF 3 Cl CH Cl Et Me CF 3 Br N Cl Me Cl CF 3 Br CH Cl i-Pr Cl Cl F N Cl Et Me Cl F CH Cl t-Bu Me Cl Cl N Cl i-Pr Cl Cl Cl CH Cl c-Pr Cl Cl Br N Cl t-Bu Me Cl Br CH Cl c-PrCH 2 Me Br F N Cl c-Pr Cl Br F CH Cl 1-CH 3 -c-Pr Cl Br Cl N Cl c-PrCH 2 Me Br Cl CH Cl H Me OCH 2

CF

3 F N Cl H Cl OCH 2

CF

3 F CH Cl Me Cl OCH 2

CF

3 Cl N Cl Me Me OCH 2

CF

3 Cl CH Cl Et Me OCH 2

CF

3 Br N Cl Et Cl OCH 2

CF

3 Br CH Br i-Pr Cl CF 3 F N Br i-Pr Me CF 3 F CH Br t-Bu Me CF 3 Cl N Br t-Bu Cl Cl F CH Br c-Pr Cl CF 3 Br N Br c-Pr Me Cl Cl CH Br c-PrCH 2 Me Cl F N Br c-PrCH 2 Cl Cl Br CH Br 1-CH 3 -c-Pr Cl Cl Cl N Br 1-CH 3 -c-Pr Me Br F CH Br H Me Br Cl N Br H Cl Br Br CH Br Me Cl Br Br N Br Me Me OCH 2

CF

3 F CH Br Et Me OCH 2

CF

3 F N Br Et Cl OCH 2

CF

3 Cl CH 28

R

6 is Cl. R 6 is Cl. X R1 R2 R4 R5 Z X R1 R2 R4 R5 Z Br i-Pr Cl OCH 2

CF

3 Cl N Br i-Pr Me OCH 2

CF

3 Br CH Br t-Bu Me OCH 2

CF

3 Br N Cl t-Bu Cl OCHF 2 F CH Cl H Cl OCHF 2 Cl N Cl H Me OCHF 2 Br CH Cl Me Me OCHF 2 Br N Br Me Cl OCHF 2 F CH Br Et Cl OCHF 2 F N Br Et Me OCHF 2 Cl CH Br i-Pr Me OCHF 2 Cl N Br i-Pr Cl OCHF 2 Br CH Further, any prior art reference or statement provided in the specification is not to be taken as an admission that such art constitutes, or is to be understood as constituting, part of the common general knowledge in Australia.

Claims (14)

1. A method for preparing a compound of Formula

2 R 2 H N O X 0 2 0 wherein R 2 is CH 3 or Cl; and X is Cl or Br; comprising: 5 contacting a compound of Formula 4 R 2 NHCO 2 R 3 X CO 2 H 4 wherein R 2 is CH 3 or Cl; R 3 is CI-C 6 alkyl or C 3 -C 6 alkenyl, each optionally substituted with up to 3 halogen and up to 1 phenyl; and X is Cl or Br; with phosphorus tribromide. 10 2. The method of Claim 1 wherein R 3 is CI-C 4 alkyl.

3. The method of Claim 1 or 2 wherein R 3 is unbranched at the carbon atom of R 3 bonded to oxygen.

4. The method of any one of Claims 1 to 3 wherein R 3 is methyl or ethyl.

5. The method of any one of Claims 1 to 4 wherein the compound of Formula 4 is 15 contacted with the phosphorus tribromide in the presence of a suitable organic solvent.

6. The method of Claim 5 wherein the organic solvent comprises one or more solvents selected from esters, nitrites, hydrocarbons and halogenated hydrocarbons.

7. The method of Claim 6 wherein the organic solvent comprises one or more solvents selected from esters, nitrites, haloalkanes, and halogenated and nonhalogenated 20 aromatic hydrocarbons.

8. The method of Claim 7 wherein the organic solvent comprises one or more solvents selected from haloalkanes, and halogenated and nonhalogenated aromatic hydrocarbons.

9. The method of Claim 8 wherein the organic solvent comprises one or more 25 solvents selected from 1,2-dichloroethane, benzene, toluene, xylene and chlorobenzene. 30

10. The method of Claim 9 wherein the organic solvent comprises toluene.

11. The method of any one of Claims 1 to 10 wherein R 2 is methyl.

12. The method of any one of Claims 1 to 11 wherein X is Cl.

13. The method of any one of Claims 1 to 12 wherein R 2 is CH 3 and X is Cl. 5

14. The method of any one of Claims 1 to 11 wherein X is Br.