A METHOD FOR THE SYNTHESIS OF ANTHRANILIC AMIDE COMPOUNDS AND INTERMEDIATES THEREOF

FIELD OF THE INVENTION:

The present invention relates to a method for synthesis of a compound of formula (V) or salt thereof. Further, the present invention comprises a method for the synthesis of anthranilic diamides of formula (Z) from substituted anilines of formula (I) making use of compound of formula (VII).

BACKGROUND OF THE INVENTION:

W02003015518, W02003015519, W02004067528, W02005077934,

W020100069502 and W02019150220 disclose the use of anthranilic acid diamides for controlling invertebrate pests such as arthropods.

Several patent documents, for example W02004011447, W02004111030, W02006062978, W02008010897, WO2012103436 and W02020170092 disclose methods for preparing anthranilic diamides and suitable intermediates.

WO2022064454 discloses the synthesis of a diamide compound, particularly anthranilic amides through an isatin intermediate wherein the isatin intermediate is obtained from the corresponding oxime which in turn is prepared by reacting the corresponding aniline derivative with a chloral reagent to obtain a chloroacetamide. However, this approach on a production scale was not found to be economical.

Tetrahedron Letters, 2005, vol. 46, # 50, p. 8719 - 8721 discloses the synthesis of such an oxime intermediate. However, the approach described in the article is not feasible on an industrial scale because of high volume of solvents and reagents that are required for this method.

N-substituted anthranilic amides with desired substitution patterns being suitable as advanced intermediates for the preparation of anthranilic acid diamides of formula (Z), are not easily available, and methods mentioned in the literatures to synthesize them lack from selectivity as well as from scalability. Therefore, there is a need to find a simple, efficient and industrially economical method for the preparation of anthranilic acid diamides of formula (Z) from N-substituted anthranilic amides of formula (V) as well as for N-substituted anthranilic amides of formula (V) themselves. This need is addressed by the present invention.

OBJECTIVE OF THE INVENTION:

The objective of the presented invention is to provide a method for the synthesis of N-substituted anthranilic amides of formula (V).

Another objective of the present invention is to provide a method for the synthesis of compounds of formula (III) and compounds of formula (II).

Yet another objective of the present invention is to provide a simple, environmentfriendly and cost-effective method for the synthesis of anthranilic diamides of formula (Z), based on readily available starting materials.

SUMMARY OF THE INVENTION:

It is the objective of the present invention to provide an industrially amenable and convenient method for the preparation of anthranilic amides of formula (V).

Surprisingly, the present invention provides a solution to this objective by providing a novel method that allows the preparation of anthranilic amides, overcoming at least one of the shortcomings of the methods described in the prior art.

Accordingly,

In a first aspect, the present invention provides a method for preparing a compound of formula (V), wherein

R ¹ is selected from the group comprising of halogen, C1-C4 alkyl, C1-C4 haloalkyl and C3-C4-cycloalkyl;

R ² is selected from the group comprising of hydrogen, halogen, cyano, C1-C4 alkyl and C3-C4-cycloalkyl;

R ³ is selected from the group comprising of hydrogen, halogen, cyano, C1-C4 haloalkyl or C3-C6 cycloalkyl;

R ^4a and R ^4b are independently selected from the group comprising of hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl-Ci-C4 alkyl; or NR ^4a R ^4b represents -N=S(R ⁷ R ⁸ )=(O) _n ; wherein R ⁷ and R ⁸ are independently selected from the group comprising of C1-C4 alkyl, C1-C4 haloalkyl C3-C6 cycloalkyl or C3-C6 cycloalkyl C1-C4 alkyl; comprising the steps of: a) reacting a compound of formula (I) with a compound of formula (VII), optionally isolating a compound of formula (Y) to afford a compound of formula (II), optionally in the presence of a suitable base and a solvent; wherein, R ¹ , R ² and R ³ have the same meaning as define above; b) reacting the compound of formula (II) with a dehydrating agent to obtain an isatin of formula (III), optionally in the presence of a suitable solvent; wherein, R ¹ , R ² and R ³ have the same meaning as define above; c) oxidizing the isatin of formula (III) to obtain an isatoic anhydride of formula (IV) in the presence of a suitable oxidizing agent and optionally in the presence of a suitable solvent; wherein, R ¹ , R ² , and R ³ have the same meaning as defined above; d) reacting the compound of formula (IV) with a compound of formula (VIII), to obtain a compound of formula (V), optionally in the presence of a suitable acid and a suitable solvent; as shown in the following scheme: wherein R ¹ , R ² , R ³ , R ^4a and R ^4b have same meaning as define above.

In another aspect, the present invention provides a method for the synthesis of anthranilic diamides of formula (Z), wherein,

R ¹ is selected from the group comprising of halogen, C1-C4 alkyl, C1-C4 haloalkyl and C3-C4-cycloalkyl; R ² is selected from the group comprising of hydrogen, halogen, cyano, C1-C4 alkyl and C3-C4-cycloalkyl;

R ³ is selected from the group comprising of hydrogen, halogen, cyano, C1-C4 haloalkyl or C3-C6 cycloalkyl;

R ^4a and R ^4b are independently selected from the group comprising of hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl-Ci-C4 alkyl; or NR ^4a R ^4b represents -N=S(R ⁷ R ⁸ )=(O) _n ; wherein R ⁷ and R ⁸ are independently selected from the group comprising of C1-C4 alkyl, C1-C4 haloalkyl C3-C6 cycloalkyl or C3-C6 cycloalkyl C1-C4 alkyl; n represents an integer from 0-1;

R ⁵ is selected from the group comprising of halogen, C1-C4 alkyl, C1-C4 haloalkyl, CHF ₂ , CF ₃ , C1-C4 alkoxy; OCF ₂ H, OCH2CF3, or -A-C3-C5 heterocyclyl; wherein -A- is selected from the group comprising of direct bond, CHR ⁶ , -O- or -S-; and said heterocyclyl may optionally be substituted with one or more groups selected from hydrogen, halogen, cyano, C1-C4 alkyl or C1-C4 haloalkyl;

R ⁶ is selected from the group comprising of hydrogen, halogen, cyano, C1-C4 alkyl or C1-C4 haloalkyl;

X is halogen; from a substituted aniline of formula (I); wherein,

R ¹ is selected from the group comprising of halogen, C1-C4 alkyl, C1-C4 haloalkyl and C3-C4-cycloalkyl;

R ² is selected from the group comprising of hydrogen, halogen, cyano, C1-C4 alkyl and C3-C4-cycloalkyl; R ³ is selected from the group comprising of hydrogen, halogen, cyano, C1-C4 haloalkyl or C3-C6 cycloalkyl; according to the reaction scheme as depicted below, wherein,

W is OH, Cl, O-C1-C4 alkyl, O-C(O)Ci-C4 alkyl or imidazolyl;

R ⁵ is selected from the group comprising of halogen, C1-C4 alkyl, C1-C4 haloalkyl, CHF ₂ , CF ₃ , C1-C4 alkoxy, OCF ₂ H, OCH2CF3, or -A-C3-C5 heterocyclyl; wherein -A- is selected from the group comprising of direct bond, CHR ⁶ , -O- or -S-; and said heterocyclyl may optionally be substituted with one or more groups selected from hydrogen, halogen, cyano, C1-C4 alkyl or C1-C4 haloalkyl;

R ⁶ is selected from the group comprising of hydrogen, halogen, cyano, C1-C4 alkyl or C1-C4 haloalkyl and X represents halogen;

R ¹ , R ² , R ³ , R ^4a and R ^4b have the same meaning as defined above.

DETAILED DESCRIPTION OF THE INVENTION:

GENERAL DEFINITIONS

The definitions provided herein for the terminologies used in the present disclosure are for illustrative purpose only and in no manner limit the scope of the present invention disclosed in the present disclosure.

As used herein, the terms “comprises”, “comprising”, “includes”, “including”, “has”, “having”, “contains”, “containing”, “characterized by” or any other variation thereof, are intended to cover a non-exclusive inclusion, subject to any limitation explicitly indicated. For example, a composition, mixture, method or method 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, mixture, process or method.

The transitional phrase “consisting of’ excludes any element, step or ingredient not specified. If in the claim, such would close the claim to the inclusion of materials other than those recited except for impurities ordinarily associated therewith. When the phrase “consisting of’ appears in a clause of the body of a claim, rather than immediately following the preamble, it limits only the element set forth in that clause; other elements are not excluded from the claim as a whole.

The transitional phrase “consisting essentially of’ is used to define a composition or method that includes materials, steps, features, components or elements, in addition to those literally disclosed, provided that these additional materials, steps, features, components or elements do not materially affect the basic and novel characteristic(s) of the claimed invention. The term “consisting essentially of’ occupies a middle ground between “comprising” and “consisting of’.

Further, unless expressly stated to the contrary, “or” refers to an inclusive “or” and not to an exclusive “or”. For example, a condition A “or” B is satisfied by any one of the following: A is true (or present) and B is false (or not present), A is false (or not present) and B is true (or present), and both A and B are true (or present).

Also, the indefinite articles “a” and “an” preceding an element or component of the present invention are intended to be non-restrictive regarding the number of instances (i.e. occurrences) of the element or component. Therefore “a” or “an” should be read to include one or at least one, and the singular word form of the element or component also includes the plural unless the number is obviously meant to be singular.

Carbon-based radical refers to a monovalent molecular component comprising a carbon atom that connects the radical to the remainder of the chemical structure through a single bond. Carbon-based radicals can optionally comprise saturated, unsaturated and aromatic groups, chains, rings and ring systems, and heteroatoms. Although carbon-based radicals are not subject to any particular limit in size, in the context of the present invention they typically comprise 1 to 16 carbon atoms and o to 3 heteroatoms. Of note are carbon-based radicals selected from Ci-Ce alkyl, Ci-C ₆ haloalkyl and phenyl optionally substituted with 1-3 substituents selected from C1-C3 alkyl, halogen and nitro.

The meaning of various terms used in the description shall now be illustrated.

The term “alkyl”, used either alone or in compound words such as “alkylthio” or “haloalkyl” or -N(alkyl) or alkylcarbonylalkyl or alkylsuphonylamino includes straight-chain or branched Ci to Cf> alkyl. Representative examples of alkyl include methyl, ethyl, propyl, 1 -methylethyl, butyl, 1 -methylpropyl, 2-methylpropyl, 1,1- dimethylethyl, pentyl, 1 -methylbutyl, 2-methylbutyl, 3 -methylbutyl, 2,2- dimethylpropyl, 1 -ethylpropyl, hexyl, 1,1 -dimethylpropyl, 1,2-dimethylpropyl, 1- methylpentyl, 2-methylpentyl, 3 -methylpentyl, 4-methylpentyl, 1,1 -dimethylbutyl, 1,2-dimethylbutyl, 1,3 -dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3- dimethylbutyl, 1 -ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2- trimethylpropyl, 1 -ethyl- 1 -methylpropyl and l-ethyl-2-methylpropyl or the different isomers. If the alkyl is at the end of a composite substituent, as, for example, in alkylcycloalkyl, the part of the composite substituent at the start, for example the cycloalkyl, may be mono- or polysubstituted identically or differently and independently by alkyl. The same also applies to composite substituents in which other radicals, for example alkenyl, alkynyl, hydroxyl, halogen, carbonyl, carbonyloxy and the like, are at the end.

The term “cycloalkyl” means alkyl closed to form a ring. Representative examples include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. This definition also applies to cycloalkyl as a part of a composite substituent, for example cycloalkylalkyl etc., unless specifically defined elsewhere.

The term "alkoxy" used either alone or in compound words included Ci to Cf> alkoxy. Non limiting examplesof alkoxy include methoxy, ethoxy, propoxy, 1- methylethoxy, butoxy, 1 -methylpropoxy, 2-methylpropoxy, 1,1 -dimethylethoxy, pentoxy, 1 -methylbutoxy, 2 -methylbutoxy, 3 -methylbutoxy, 2,2-dimethylpropoxy, 1 -ethylpropoxy, hexoxy, 1,1 -dimethylpropoxy, 1,2-dimethylpropoxy, 1- methylpentoxy, 2-methylpentoxy, 3 -methylpentoxy, 4-methylpentoxy, 1,1- dimethylbutoxy, 1,2-dimethylbutoxy, 1,3 -dimethylbutoxy, 2,2-dimethylbutoxy, 2, 3 -dimethylbutoxy, 3, 3 -dimethylbutoxy, 1 -ethylbutoxy, 2-ethylbutoxy, 1,1,2- trimethylpropoxy, 1,2,2-trimethylpropoxy, 1 -ethyl- 1 -methylpropoxy and l-ethyl-2- methylpropoxy and the different isomers. This definition also applies to alkoxy as a part of a composite substituent, for example haloalkoxy, alkynylalkoxy, etc., unless specifically defined elsewhere.

The term "hydroxy" means -OH.

The term "halogen", either alone or in compound words such as "haloalkyl", includes fluorine, chlorine, bromine or iodine. Further, when used in compound words such as "haloalkyl", said alkyl may be partially or fully substituted with halogen atoms which may be the same or different. Non-limiting examples of "haloalkyl" include chloromethyl, bromomethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, 1 -chloroethyl, 1 -bromoethyl, 1- fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2- fluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2,2- trichloroethyl, pentafluoroethyl, l,l-dichloro-2,2,2-trifluoroethyl, and 1,1,1- trifluoroprop-2-yl. This definition also applies to haloalkyl as a part of a composite substituent, unless specifically defined elsewhere.

The term "hetero" in connection with rings refers to a ring in which at least one ring atom is not carbon and which can contain 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur, provided that each ring contains no more than 4 nitrogen, no more than 2 oxygen and no more than 2 sulfur.

The term "aromatic" indicates that the Huckel rule is satisfied and the term "nonaromatic" indicates that the Huckel rule is not satisfied. The term "heterocycle" or "heterocyclic" or "heterocyclyl" includes "aromatic heterocycle" or "heteroaryl bicyclic ring system" and "nonaromatic heterocycle " or polycyclic or bicyclic (spiro, fused, bridged, non-fused) ring compounds in which ring may be aromatic or non-aromatic, wherein the heterocycle ring contains at least one heteroatom selected from N, O, S(0)o-2, and/or C ring member of the heterocycle may be replaced by C(=O) and C(=S).

The term "non-aromatic heterocycle" or "non-aromatic heterocyclic" means three- to ten-membered, preferably three- to six-membered, saturated or partially unsaturated heterocycle containing one to four heteroatoms, selected from the group of oxygen, nitrogen and sulphur; mono, bi- or tricyclic heterocycles which contain, in addition to carbon ring members, one to three nitrogen atoms and/or one oxygen or sulphur atom or one or two oxygen and/or sulphur atoms; if the ring contains more than one oxygen atom, they are not directly adjacent; for example (but not limited to) oxetanyl, thietanyl, thietanyl 1 -oxide, thietanyl 1,1 -dioxide, oxiranyl, aziridinyl, azetidinyl, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, oxadiazolidinyl, thiadiazolidinyl, triazolidinyl, dihydrofuryl, dihydrothienyl, pyrrolinyl, isoxazolinyl, isothiazolinyl, dihydropyrazolyl, dihydrooxazolyl, dihydrothiazolyl, piperidinyl, pyrazynyl, morpholinyl, thiomorphlinyl, 1,3-dioxany, tetrahydropyranyl, tetrahydro thienyl; wherein these rings are attached to the skeleton via one of the carbon or nitrogen of said rings. This definition also applies to heterocyclyl as a part of a composite substituent, for example heterocyclylalkyl etc., unless specifically defined elsewhere.

The term "heteroaryl" or "aromatic heterocyclic" means 5-membered, fully unsaturated monocyclic ring system containing one to four heteroatoms selected from the group of oxygen, nitrogen and sulphur; if the ring contains more than one oxygen atom, they are not directly adjacent; 5 -membered heteroaryl containing one to four nitrogen atoms or one to three nitrogen atoms and one sulphur or oxygen atom; 5-membered heteroaryl groups which, in addition to carbon atoms, may contain one to four nitrogen atoms or one to three nitrogen atoms and one sulphur or oxygen atom as ring members, for example (but not limited thereto) furyl, thienyl, pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl; wherein these rings are attached to the skeleton via one of the carbon or nitrogen of said rings.

As used herein, the term “optionally’ means that the subsequently described event(s) may or may not occur, and includes both event(s) that occur and events that do not occur.

In a first aspect, the present invention provides a method for preparing a compound of formula (V), wherein

R ¹ is selected from the group comprising of halogen, C1-C4 alkyl, C1-C4 haloalkyl and C3-C4-cycloalkyl;

R ² is selected from the group comprising of hydrogen, halogen, cyano, C1-C4 alkyl and C3-C4-cycloalkyl;

R ³ is selected from the group comprising of hydrogen, halogen, cyano, C1-C4 haloalkyl or C3-C6 cycloalkyl;

R ^4a and R ^4b are independently selected from the group comprising of hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl-Ci-C4 alkyl; or NR ^4a R ^4b represents -N=S(R ⁷ R ⁸ )=(O) _n ; wherein R ⁷ and R ⁸ are independently selected from the group comprising of C1-C4 alkyl, C1-C4 haloalkyl C3-C6 cycloalkyl or C3-C6 cycloalkyl C1-C4 alkyl;

X is halogen; comprising the steps of: a) reacting a compound of formula (I) with a compound of formula (VII), optionally isolating a compound of formula (Y) to afford a compound of formula (II), optionally in the presence of a suitable base and a solvent; wherein, R ¹ , R ² and R ³ have the same meaning as define above; b) reacting the compound of formula (II) with a dehydrating agent to obtain an isatin of formula (III), optionally in the presence of a suitable solvent; wherein, R ¹ , R ² and R ³ have the same meaning as define above; c) oxidizing the isatin of formula (III) to obtain an isatoic anhydride of formula (IV) in the presence of a suitable oxidizing agent and optionally in the presence of a suitable solvent; wherein, R ¹ , R ² , and R ³ have the same meaning as defined above; d) reacting the compound of formula (IV) with a compound of formula (VIII), to obtain a compound of Formula (V), optionally in the presence of a suitable acid and a suitable solvent; as shown in the following scheme: wherein R ¹ , R ² , R ³ , R ^4a and R ^4b have same meaning as define above.

In a second aspect, the present invention provides a method for the synthesis of anthranilic diamides of formula (Z),

Formula (Z) wherein,

R ¹ is selected from the group comprising of halogen, C1-C4 alkyl, C1-C4 haloalkyl and C3-C4-cycloalkyl;

R ² is selected from the group comprising of hydrogen, halogen, cyano, C1-C4 alkyl and C3-C4-cycloalkyl;

R ³ is selected from the group comprising of hydrogen, halogen, cyano, C1-C4 haloalkyl or C3-C6 cycloalkyl;

R ^4a and R ^4b are independently selected from the group comprising of hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl-Ci-C4 alkyl; or NR ^4a R ^4b represents -N=S(R ⁷ R ⁸ )=(O) _n ; wherein R ⁷ and R ⁸ are independently selected from the group comprising of C1-C4 alkyl, C1-C4 haloalkyl C3-C6 cycloalkyl or C3-C6 cycloalkyl C1-C4 alkyl; n represents an integer from 0-1; R ⁵ is selected from the group comprising of halogen, C1-C4 alkyl, C1-C4 haloalkyl, CHF ₂ , CF ₃ , C1-C4 alkoxy; OCF ₂ H, OCH2CF3, or -A-C3-C5 heterocyclyl; wherein -A- is selected from the group comprising of direct bond, CHR ⁶ , -O- or -S-; and said heterocyclyl may optionally be substituted with one or more groups selected from hydrogen, halogen, cyano, C1-C4 alkyl or C1-C4 haloalkyl;

R ⁶ is selected from the group comprising of hydrogen, halogen, cyano, C1-C4 alkyl or C1-C4 haloalkyl;

X is halogen; from a substituted aniline of formula (I); wherein,

R ¹ is selected from the group comprising of halogen, C1-C4 alkyl, C1-C4 haloalkyl and C3-C4-cycloalkyl;

R ² is selected from the group comprising of hydrogen, halogen, cyano, C1-C4 alkyl and C3-C4-cycloalkyl;

R ³ is selected from the group comprising of hydrogen, halogen, cyano, C1-C4 haloalkyl or C3-C6 cycloalkyl; comprising the steps of: a) reacting the compound of formula (I) with the compound of formula (VII), optionally isolating the intermediate compound of formula (Y) to afford a compound of formula (II), optionally in the presence of a suitable base and a suitable solvent; wherein, R ¹ , R ² and R ³ have the same meaning as define above; b) reacting the compound of formula (II) with a dehydrating agent to obtain an isatin of formula (V), optionally in the presence of a suitable solvent; wherein, R ¹ , R ² and R ³ have the same meaning as define above; c) oxidizing the isatin of formula (III) to obtain an isatoic anhydride of formula (IV) using a suitable oxidizing agent; wherein, R ¹ , R ² , and R ³ have the same meaning as defined above; d) reacting the compound of formula (IV) with a compound of formula (VIII), to obtain a compound of formula (V), optionally in the presence of a suitable acid and a suitable solvent; as shown in the following scheme: wherein R ¹ , R ² , R ³ , R ^4a and R ^4b have the same meaning as define above; e) reacting the compound of formula (V) with a compound of formula (IX), to obtain a compound of formula (Z), optionally in the presence of a suitable reagent and a suitable solvent; as shown in the following scheme: wherein,

W is OH, Cl, O-C1-C4 alkyl, O-C(O)Ci-C4 alkyl or imidazolyl;

R ⁵ is selected from the group comprising of halogen, C1-C4 alkyl, Ci- C ₄ haloalkyl, CHF ₂ , CF ₃ , C1-C4 alkoxy, OCF ₂ H, OCH2CF3, or -A-C3- C5 heterocyclyl; wherein -A- is selected from the group comprising of direct bond, CHR ⁶ , -O- or -S-; and said heterocyclyl may optionally be substituted with one or more group selected from hydrogen, halogen, cyano, Ci- C4 alkyl or C1-C4 haloalkyl;

R ⁶ is selected from the group comprising of hydrogen, halogen, cyano, C1-C4 alkyl or C1-C4 haloalkyl and X represents halogen;

R ¹ , R ² , R ³ , R ^4a and R ^4b have the same meaning as defined above.

In a third aspect, the present invention provides a method for preparing a compound of formula (III),

wherein,

R ¹ is selected from the group comprising of halogen, C1-C4 alkyl, C1-C4 haloalkyl and C3-C4-cycloalkyl; R ² is selected from the group comprising of hydrogen, halogen, C1-C4 alkyl and C3-C4-cycloalkyl;

R ³ is selected from the group comprising of hydrogen, halogen, C1-C4 haloalkyl or C3-C6 cycloalkyl; comprising the steps of: i. reacting glyoxalic acid with acetic anhydride at a temperature of 80-

130 °C optionally isolating the intermediate (2) which was further reacting with thionyl chloride to obtain a compound of formula (VII); a) reacting a compound of formula (I) with the compound of formula (VII), optionally isolating the intermediately formed compound of formula (Y), to afford a compound of formula (II), optionally in the presence of a suitable base and a suitable solvent; wherein, R ¹ , R ² and R ³ have same meaning as define above; b) reacting the compound of formula (II) with a dehydrating agent to obtain an isatin of formula (V), optionally in the presence of a suitable solvent; wherein, R ¹ , R ² and R ³ have the same meaning as defined above.

In fourth aspect, the present invention provides a method for the synthesis of compounds of formula (II) wherein,

R ¹ is selected from the group comprising of Cl or methyl

R ² is selected from the group comprising of hydrogen or F;

R ³ is selected from the group comprising of hydrogen, halogen; comprising the steps of: i. reacting glyoxalic acid with acetic anhydride at a temperature of 80- 130 °C optionally isolating the intermediate (2) which was further reacting with thionyl chloride to obtain a compound of formula (VII) as shown in below scheme; a) reacting a compound of formula (I) with a compound of formula (VII), optionally isolating the intermediately formed compound of formula (Y) to afford a compound of formula (II), optionally in the presence of a suitable base and a suitable solvent; wherein, R ¹ , R ² and R ³ have the same meaning as defined above.

In particular, the present invention provides a method for preparing a compound of formula (V),

V wherein

R ¹ is selected from the group comprising of F, Cl, Br, CH3 and CF3;

R ² is selected from the group comprising of hydrogen and halogen;

R ³ is selected from the group comprising of hydrogen, F, Cl, Br, CH3 and CF ₃ ;

R ^4a is selected from the group comprising of hydrogen, Ci-Ce alkyl and C3- Ce cycloalkyl;

R ^4a and R ^4b are independently selected from the group comprising of hydrogen, Ci-Cs alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl-Ci-C4 alkyl.

Embodiment-A: The present invention provides a method for obtaining the compounds of formula (V) wherein R ³ represents halogen, by this specification representing compounds of formula (Va), from compounds of formula (I) wherein R ³ represents hydrogen, by this specification representing compounds of formula (la), comprising the steps of: a) reacting the compound of formula (la) with the compound of formula (VII), optionally isolating the intermediately formed compound of formula (Ya), to afford a compound of formula (Ila), optionally in the presence of a suitable base and a suitable solvent; wherein, R ¹ , R ² and R ³ have the same meaning as define above; b) reacting the compound of formula (Ila) with a dehydrating agent to obtain an isatin of formula (Illa), optionally in the presence of a suitable solvent; and then further converting the isatin with formula (Illa) to a compound of formula (Illb) using a suitable halogenating reagent. wherein, R ¹ , R ² and Xhave the same meaning as define above; c) oxidizing the isatin of formula (Illb) to obtain an isatoic anhydride of formula (IV a) using a suitable oxidizing agent, preferably in the absence of a solvent; wherein, R ¹ , R ² , and R ³ have the same meaning as defined above; d) reacting the compound of formula (IVa) with a compound of formula (VIII), to obtain a compound of Formula (Va), optionally in the presence of a suitable acid and a suitable solvent; as shown in the following scheme:

IVa Va wherein R ¹ , R ² , X, R ^4a and R ^4b have the same meaning as define above.

Embodiment-B : According to embodiment-B, the preferred compounds of formula (Illa) are converted to compounds of formula (Illb) by reacting them with an appropriate halogenating agent as described in table- 1:

Table-1:

Embodiment-C: According to the embodiment-C, the compounds of formula (Illaa), (Iliac), (Iliad) and (Illae) are converted to corresponding compounds of formula (Illba), (Illbc), (Illbd) and (Illbe) by reacting them with an appropriate halogenating agent, preferably the applied halogenating agent for this purpose is chlorine gas.

Embodiment-D: According to the embodiment-D, the present invention provides a method for in situ preparation of compounds of formula (V) from compounds of formula (III) as shown in below scheme: wherein R ¹ , R ² , R ³ , R ^4a and R ^4b have the same meaning as define above.

Embodiment-E: According to the embodiment-E, the present invention provides a method for in situ preparation of compounds of formula (IVa) from compounds of formula (Illa) as shown in below scheme: wherein R ¹ , R ² , X, R ^4a and R ^4b have the same meaning as define above.

Embodiment-F: According to the embodiment-F, the present invention provides a method for obtaining the compound of formula (IV) from a compound of formula (III) as described in step-c of the first aspect of the present invention using a suitable oxidising agent and optionally in the presence of a suitable catalyst. wherein, R ¹ , R ² , and R ³ have the same meaning as defined above. Embodiment-G: According to the embodiment-G, the present invention provides a method for obtaining the compound of formula (III) from a compound of formula (II) as described in step-b of the first aspect of the present invention using a suitable dehydrating agent preferably in absence of a solvent.

Embodiment-H: According to the embodiment-H, the present invention provides a method for the synthesis of a compound of formula (VII) comprising the step: i. reacting glyoxalic acid with acetic anhydride at a temperature of 80-130 °C optionally isolating intermediate (2) which was further reacting with thionyl chloride to obtain a compound of formula (VII).

Embodiment-I: According to the embodiment-I, the present invention provides a method for obtaining compounds of formula (V) wherein R ³ represents halogen, by this specification representing compounds of formula (Va), from compounds of formula (I) wherein R ³ represents hydrogen, by this specification representing compounds of formula (la), comprising the steps of: i. reacting glyoxalic acid with acetic anhydride at a temperature of 80- 130 °C optionally isolating the intermediate (2) which was further reacting with thionyl chloride to obtain a compound of formula (VII); a) reacting the compound of formula (la) with the compound of formula

(VII), optionally isolating the intermediately formed compound of formula (Ya), to afford a compound of formula (Ila), optionally in the presence of a suitable base and a suitable solvent; wherein, R ¹ , R ² and R ³ have the same meaning as define above; b) reacting the compound of formula (Ila) with a dehydrating agent to obtain an isatin of formula (Illa), optionally in the presence of a suitable solvent; and then further converting the isatin of formula (Illa) to a compound of formula (Illb) using a suitable halogenating reagent. wherein, R ¹ , R ² and R ³ have the same meaning as define above; c) oxidizing the isatin of formula (Illb) to obtain an isatoic anhydride of formula (IVa) using a suitable oxidizing agent, preferably in the absence of a solvent; wherein, R ¹ , R ² , and R ³ have the same meaning as defined above; d) reacting the compound of formula (IVa) with a compound of formula (VIII), to obtain a compound of formula (Va), optionally in the presence of a suitable acid and a suitable solvent; as shown in the following scheme: wherein R ¹ , R ² , R ³ , R ^4a and R ^4b have the same meaning as define above.

The cyanation of the isatin of formula (III) or of the isatoic anhydride of formula (IV) or of the compounds of formula (V) can be carried out according to methods reported in W02008010897, W02008070158, W02009085816, W02009061991, W02009006061 and W02008082502.

In a preferred embodiment, the compound of formula (Va) is converted to a compound of formula (Vb) using a suitable cyanating reagent and a suitable solvent as shown in below scheme: wherein R ¹ , R ² , R ³ , R ^4a and R ^4b have the same meaning as define above.

The cyanation, as described in the present invention, is carried out in the presence of a suitable cyanating reagent which includes metal cyanides that are selected from sodium cyanide, cuprous cyanide, zinc cyanide, nickel cyanide, iron (III) cyanide, potassium cyanide, sodium hexacyanoferrate(II) and potassium hexacyanoferrate(II). More preferably, the appropriate metal cyanide reagent is selected from sodium cyanide or cuprous cyanide.

The compounds of formula (IX) can be obtained by either one of the methods disclosed in W02003015518, W020030155519, WO2011157664 and W02013030100. The compound of Formula (Z) can be obtained by reacting compound of formula (V) obtained according to present invention with compound of formula (IX) according to any of the method disclosed in W02003015518, W020030155519, WO201 1157664 or W02013030100.

The halogenation reactions as described in the present invention are carried out in the presence of suitable halogenating reagents which include, but are not limited to, HX, NaX, KX, CuX ₂ , MgX ₂ , CsX, ZnX ₂ , SOC1 ₂ , SO ₂ C1 ₂ , COC1 ₂ , X ₂ , C(=O)(OC13) ₂ , NaOCl, Chloramine-T, -halosuccinamides, methane sulfonyl chloride, POX3, PX3, PX5 or metal halides; wherein X is Cl, Br, I or F. The chlorination itself may be conducted in the presence of a suitable catalyst.

The suitable oxidizing agents as described in the present invention include, but are not limited to, hydrogen peroxide, oxone, hydrogen peroxide, t-butyl- hydroperoxide, tungstic peroxide, m-chloroperbenzoic acid, benzoyl peroxide, hypohalogeneous acids, ceric ammonium nitrate, hypoceric ammonium nitrate, oxone, periodic acid, peracetic acid, performic acid, and hydrogen peroxide urea- adduct, sodium perborate, pyridinium chlorochromate, pyridinium dichromate, ruthenium(II) oxide, manganese(II) oxide, copper(II) acetate / O ₂ , dimethyl sulfoxide and the like. Preferably the suitable oxidizing agent is hydrogen peroxide and formic acid.

The halogenating reagents useful for converting the isatin of formula (Illa) into the compounds of formula (Illb) are selected from, but are not limited to, HX, CuX ₂ , MgX ₂ , FeCl ₃ , CsX, ZnX ₂ , SOC1 ₂ , SO ₂ C1 ₂ , COC1 ₂ , X ₂ , C(=O)(OC1 ₃ ) ₂ , t-BuOCl, NaOCl, Chloramine-T, N-halosuccinimides, methane sulfonyl chloride, POX3, PX3, PX5 or suitable other metal halides; wherein X is Cl, Br, I or F.

Preferably, the halogenating reagents useful for converting the isatin of formula (Illa) into the compounds of formula (Illb) are selected from, HX+H ₂ O ₂ , SOC1 ₂ , SO ₂ C1 ₂ .COC1 ₂ , X ₂ , NaOCl, N-halosuccinimides, methane sulfonyl chloride, POX3, PX3 suitable other metal halides; wherein X is Cl, or Br. More preferably, the halogenating reagents useful for converting the isatin of formula (Illa) into the compounds of formula (Illb) are selected from, HX+H2O2, SO ₂ C12, C1 ₂ , or Br ₂ .

The oxidizing agents useful for converting the isatin of formula (III) into the isatoic anhydrides of formula (IV) are selected from, but are not limited to, hydrogen peroxide, t-butyl-hydroperoxide, tungstic peroxide, m-chloroperbenzoic acid, benzoyl peroxide, hypohalogeneous acids, ceric ammonium nitrate, oxone, periodic acid, peracetic acid, performic acid hydrogen peroxide urea-adduct, sodium perborate, pyridinium chlorochromate, pyridinium dichromate, ruthenium(II) oxide, manganese(II) oxide, copper(II) acetate / O2 and dimethyl sulfoxide. Preferably the suitable oxidizing agent is hydrogen peroxide and formic acid.

The dehydrating agent used in the present invention is selected from sulfuric acid, formic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, p- toluenesulfonic acid, polyphosphoric acid phosphorus pentaoxide (P2O5), an acidic ion-exchange resin, an acidic form of a zeolithe, or mixtures thereof.

Preferably, the suitable dehydrating agent for converting compounds of formula (II) into isatins of formula (III) is sulphuric acid.

The suitable acid used for the conversion of substituted isatoic anhydrides of formula (IV) to substituted anthranilic amides of formula (V) is selected from weak acids such as acetic acid, toluenesulfonic acid (pTSA) and the like.

The solvents useful in carrying out the reaction steps mentioned in the present invention are selected from aliphatic hydrocarbons such as hexane, heptane, octane, nonane, decane, dodecane, decaline and the like; alicyclic hydrocarbons such as cycloalkanes: cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, and the like; aromatic hydrocarbons such as toluene, xylene, mesitylene, benzene and the like; halogenated aromatic hydrocarbons as chlorobenzene, 1,2- dichlorobenzene, 1,3 -dichlorobenzene and the like; ethers such as diisopropyl ether, t-butyl methyl ether, tetrahydrofuran, 2 -methyl tetrahydrofuran, dioxane, monoglyme, diglyme, methoxy-methane, methoxy-ethane, ethoxy-ethane, di- methoxyethane, di-ethoxyethane and the like; alcohols such as methanol, ethanol, n- or i-propanol, n-, i-, sec- or tert-butanol, ethanediol, propane- 1,2-diol, ethoxyethanol, methoxyethanol, ketones such as acetone, ethyl methyl ketone, esters such as ethyl acetate and methyl acetate; halogenated hydrocarbons such as dichloromethane, chloroform, dichloroethane and the like; nitriles, such as acetonitrile, propionitrile; polar aprotic solvents such as V,V-di met hy formamide, dimethyl sulfoxide, V-mcthyl-2-pyrrolidonc, l,3-dimethyl-3,4,5,6-tetrahydro- 2(lH)-pyrimidinone, hexamethylphosphortriamide, l,3-dimethyl-2- imidazolidinone; acetic acid and the like; water or mixtures thereof.

The preferred solvents useful in carrying out the oxime formation reaction mentioned in the present invention are selected from alcohols such as methanol, ethanol, n- or i-propanol, n-, i-, sec- or tert-butanol, ethanediol, as ethanol, n- or i- propanol, n-, i-, sec- or tert-butanol and ethanediol; more preferably a mixture of ethanol and water perceived as useful.

The preferred solvent useful in carrying out the isatin compound (III) formation from oxime derivative (step-b) is selected from dichloroethane toluene, xylene, chlorobenzene or 1,2 -dichlorobenzene.

The preferred solvent useful in carrying out the isotoic anhydride compound (IV) formation from isatin derivative (III) (step-c) is selected from dichloroethane, acetic acid or ethyl acetate.

The preferred solvent useful in carrying out the compound (V) formation from isotoic anhydride compound (IV) (step-d) is selected from dichloroethane, toluene, xylene, chlorobenzene, acetonitrile, toluene or ethyl acetate.

The reaction steps mentioned in the present invention can also be carried out in the absence of solvents.

The oximes of formula (II) are converted to the isatins of formula (III) by using mineral acids selected from, but not limited to, sulfuric acid, hydrochloric acid and nitric acid, preferably sulfuric acid; usually under stirring or other means of mixing within a temperature ranging from 0 °C to 150 °C.

The obtained isatins of formula (III) are converted into isatoic anhydrides of formula (IV) using a suitable oxidizing agent and one or more suitable solvents at a temperature ranging from 0 °C to 250 °C, preferably from 25 °C to 150 °C.

The compounds of formula (Z) are obtained by reacting the compounds of formula (V) with the compounds of formula (IX), wherein W is OH, using a suitable reagent such as SOCh, SO2CI2, COCI2, X2, C(=O)(OC1 ₃ )2, chloramine-T, methane sulfonyl chloride, POX3, PX3, PX5 FeCh or metal halides; wherein X is Cl, Br.

The compounds of formula (Z) are obtained by reacting the compounds of formula (V) with the compounds of formula (IX), wherein W is Cl or O-C1-C4 alkyl, optionally using suitable reagents such as triethylamine, diisopropylamine, diisopropyl ethyl amine, pyridine, alkylated and dialkylated pyridines, dimethylamino pyridine, and the like, or of mixtures thereof.

Inorganic bases are preferably selected in a not limiting way from the group comprising of alkali or alkaline earth metal hydroxide, carbonate, bicarbonate and the like, wherein the alkali and alkaline earth metals are selected from the group comprising of lithium, sodium, potassium, rubidium, caesium, calcium, magnesium, barium and the like or from mixtures thereof.

The organic bases are preferably selected in a not limiting way from the group comprising of amines as methylamine, dimethyl amine, diethyl amine, triethylamine, diisopropylamine, diisopropyl ethyl amine, pyridine, alkylated and dialkylated pyridines, dimethylamino pyridine, piperidine, and the like or from mixtures thereof.

An embodiment of the present invention provides the compounds of formula (VII), wherein, R ^4a and R ^4b are independently selected from hydrogen, methyl, ethyl, isopropyl, t-butyl, methyl cyclopropyl or ethyl cyclopropyl. A preferred embodiment of the present invention provides the compound of formula (VII), wherein, R ^4a is hydrogen and R ^4b are independently selected from methyl, ethyl, isopropyl, t-butyl, methyl cyclopropyl or ethyl cyclopropyl ( ).

Yet another embodiment provides the compound of formula (IX), wherein, R ⁵ is selected from the group comprising of bromo, chloro,

In one embodiment, the compounds of formula (Z) comprise chlorantraniliprole, cyantraniliprole, cyclaniliprole, tetraniliprole, tetra-chlorantraniliprole or fluchlordiniliprole .

Any person skilled in the art knows the best work-up of the reaction mixtures after the end of the respective reactions. In one embodiment, the work-up is usually carried out by isolation of the product by filtration, and optionally washing with solvent, further optionally drying of the product if required.

The method steps according to the invention are generally carried out under atmospheric pressure. Alternatively, however, it is also possible to work under increased or reduced pressure.

The methods as disclosed in the present invention are preferably carried out batch- wise. However, semi-continuous or continuous reaction passages are also possible.

Without further elaboration, it is reasonable to believe that any person skilled in the art who is using the preceding description can utilize the present invention to its fullest extent. The following examples are therefore to be interpreted as merely illustrative and not limiting of the disclosure in any way whatever.

Examples:

Scheme- 1

Example-1: Synthesis of 2-chloro-2-oxoethane-l,l-diyl diacetate

Preparation of 2,2-diacetoxyacetic acid (2)

Method 1: To a solution of 2,2-dihydroxyacetic acid (monohydrate (95%)) (18.4 g, 190 mmol) in acetic acid (30 mL, 1.6 Vol.), acetic anhydride (126 mL, 1329 mmol, 7 eq.) was added at room temperature and heated to reflux for 2 hours at 120 °C. After completion of the reaction, the volatiles were removed via an azeotropic distillation with toluene (20 mL) and concentrated under reduced pressure to obtain 2,2-diacetoxyacetic acid (2) as a light brown oil which was used for the next step without purification.

Method 2: To a solution of 2,2-dihydroxyacetic acid (50% glyoxalic acid was concentrated to an extent of 80-85%) (25 g, 272 mmol) in acetic acid (40 mL, 1.6 Vol.), acetic anhydride (77 mL, 815 mmol, 3 eq.) was added at room temperature and heated to reflux for 2 hours at 120 °C. After completion of the reaction, the volatiles were removed via an azeotropic distillation with toluene (25 mL) and concentrated under reduced pressure to obtain 2,2-diacetoxyacetic acid (2) as a light brown oil which was used for the next step without purification.

'H-NMR (400 MHz, DMSO-D6) 8 6.667 (s, 1H) ppm

Preparation of 2-chloro-2-oxoethane- 1,1 -diyl diacetate (3)

To a solution of 2,2-diacetoxyacetic acid (110.936 g, 630 mmol) in toluene (348 mL), thionyl chloride (115 mL, 1575 mmol, 2.5 eq.) was added and heated to reflux for 1 hour. After completion of the reaction, the volatiles were removed via an azeotropic distillation with toluene (2x230 mL) and concentrated under reduced pressure to obtain 2-chloro-2-oxoethane- 1,1 -diyl diacetate (3) (136.88 g, 703.511 mmol) as a brown sticky oil and was used for the next step without further purification.

Example-2: Synthesis of 2-((4-chloro-2-methylphenyl)amino)-2-oxoethane- 1,1-diyl diacetate / N-(4-cyano-2-methylphenyl)-2-(hydroxyimino)acetamide

To an ice-cooled stirred solution of aniline (4a) (1.0 eq.) in DCE (6 vol.), sodium bicarbonate (3.75 eq.) was added under nitrogen atmosphere. To this reaction mass, a solution of 2-chloro-2-oxoethane- 1,1 -diyl diacetate (1.2 eq.) in DCE (2 vol.) was added dropwise maintaining the temperature below 5 °C. The resulting reaction mixture was stirred at 25 °C for 1.5 hours. After completion of the reaction, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure to obtain the diacetate (5a) as a sticky brown oil. To a stirred solution of the diacetate (5a) in a solvent mixture of ethanokwater (2:1), hydroxylamine hydrochloride (1.5 eq.) was added at room temperature. The reaction mass was gradually heated up to 95 °C and maintained at the same temperature for 2 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and the majority of the solvent was removed under reduced pressure. Water was added until a precipitate appeared, which was filtered, washed with water and dried under reduced pressure to obtain the oxime (6a) as a beige powder (78%). The oximes (6b-e) were obtained in an analogous manner.

Example-3: Isatin formation

To an ice-cold stirred solution of the oxime (6a-e) (1 g), in DCE (4 volume), cone, sulfuric acid (98%, 7 eq.) was added dropwise maintaining the temperature below 10 °C. After complete addition, the temperature of the reaction mass was gradually raised to 50 °C and continued to stir at the same temperature for 12 hours. After completion of the reaction, the reaction mass was cooled to 0-5 °C and chilled water (10 Vol.) was added slowly under stirring to obtain an orange precipitate. The temperature of the reaction mass was again raised to 50 °C and kept under stirring for 1 hour. After Ihour, the solid was collected via filtration followed by drying under reduced pressure to obtain the oximes (7a-e) (65-96% yield) as an orange fine powder.

Example-4:

To a stirred solution of 7-methylindoline-2,3-dione (20 g, 118 mmol) in acetic acid (200 mL, 10 vol.) at 50°C, chlorine gas was purged for 3 hours. After completion of the reaction, the reaction mass was cooled to room temperature, filtered, washed with acetic acid (1 vol.) and dried under reduced pressure to obtain 5-chloro-7- methylindoline-2, 3-dione (19 g, 74.15%, q-NMR: 90%) as a reddish orange solid. ^X H-NMR (DMSO-D6, 400 MHz) 8 11.19 (s, 1H), 7.50 (s, 1H), 7.36 (s, 1H), 2.17 (s, 3H);

¹³ C-NMR (DMSO-D6,100 MHz,) 8 183.7, 159.7, 148.0, 138.0, 126.6, 123.9, 121.3, 118.6, 15.2;

Example-5:

To a stirred solution of 5-chloro-7-methylindoline-2, 3-dione (25 g, 113 mmol) in formic acid (125 mL, 5 vol.), hydrogen peroxide (50% aq, 3 eq.) was added dropwise over a period of 1 hour at 45 °C. After complete addition, the reaction mass was stirred at 50 °C for 12 hours. After completion of the reaction, the reaction mass was cooled to room temperature, filtered, washed with hexane and dried under reduced pressure to obtain 6-chloro-8-methyl-2H-benzo[d][l,3]oxazine-2,4(lH)- dione (23 g, 95%).

^X H-NMR (DMS0-D6, 400 MHz) 8 (ppm): 2.33 (3H, s), 7.69 (IH, d, J=2Hz), 7.73 (IH, d, J=2Hz), 11.18 (IH, s).

Example-6: To a suspension of 7-methylindoline-2, 3-dione (25 g, 132 mmol) and acetic acid (250 ml), hydrogen peroxide (81 ml, 791 mmol) was added at 25 °C. The reaction mixture was cooled to 15-20 °C followed by the addition of hydrobromic acid (14.79 ml, 125 mmol) over a period of 1 hour. The reaction mixture was then warmed to 25 °C and continued to stir for 2 hours at the same temperature. To this reaction mixture, H2SO4 (0.351 ml, 6.59 mmol) was added and the reaction mass was heated to 45-50 °C under stirring for 8 hours. The temperature was slowly raised to 70-75 °C and stirred further for 2 hours. After completion of the reaction, the reaction mixture was cooled to 25 °C and poured slowly over crushed icewater mixture (250 g) under constant stirring. The solid obtained was filtered, washed with cold water (100 g) and dried under reduced pressure to obtain 6- bromo-8-methyl-2H-benzo[d][l,3]oxazine-2,4(lH)-dione (25.5 g, 75.5% yield) ^X H-NMR (DMSO-D6, 400 MHz) d 11.16 (s, 1H), 7.83 (d, J = 2.4 Hz, 1H), 7.78 (d, J = 2.4 Hz, 1H), 2.31 (s, 3H).

LCMS: m/z = 254 [M-2H],

Example-7

To a stirred solution of 6-chloro-8-methyl-2H-benzo[d][l,3]oxazine-2,4(lH)-dione (15 g, 65.7 mmol) in acetonitrile (130 mL), acetic acid (1.2 eq, 4.51 mL) was added and heated to 50 °C. tert-Butylamine (2.2 eq, 15.32 mL) was added dropwise over a period of 1 hour at 50 °C. After complete addition, the reaction mass was stirred at 50 °C for 12 hours. After completion of the reaction, the reaction mass was cooled to room temperature, filtered, washed with hexane and dried under reduced pressure to obtain 2-amino-N-(tert-butyl)-5-chloro-3-methylbenzamide.

^X H-NMR (400 MHz, DMSO-d ₆ ) 6 7.70 (s, 1H), 7.32 (d, J = 2.8 Hz, 1H), 7.08 (d, J= 0.8 Hz, 1H), 6.05 (bs, 2H), 2.06 (s, 3H), 1.32 (s, 9H). Having described the invention with reference to certain preferred embodiments, other embodiments will become apparent to one skilled in the art from consideration of the specification. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention.