KR20020000140A - Processes And Intermediates For The Preparation Of 1,3-Oxazin-6-ones And Uracils - Google Patents

Abstract

Improved methods and intermediates for the preparation of 2- (N, N-2 substituted) amino-4- (perfluoro-alkyl) -1,3-oxazin-6-one compounds having Formula I, and Improved method for preparing 6- (perfluoroalkyl) uracil compound having V.

Description

Processes and Intermediates For The Preparation Of 1,3-Oxazin-6-ones And Uracils

Background of the Invention

6- (perfluoroalkyl) uracil compounds are useful as herbicides and their preparation is known. 6- (perfluoroalkyl) uracil compounds react 2- (N, N-2 substituted) amino-4- (perfluoroalkyl) -1,3-oxazin-6-one compounds with amine compounds Can be prepared.

Bull. Soc. Chem. Belg., 101 (4), pages 313-321 (1992), reacted with ethyl-3-amino-4,4,4-trifluorocrotonate and phosgene iminium chloride compounds to give 2- (N The preparation of, N-dialkyl) amino-4- (trifluoromethyl) -1,3-oxazin-6-one compounds is disclosed. However, this method was not entirely satisfactory for preparing 2- (N, N-2 substituted) amino-4- (perfluoroalkyl) -1,3-oxazin-6-one compounds, because This is because phosgene iminium chloride compounds are difficult to handle and relatively expensive. Thus, in the art, preparation of 2- (N, N-2 substituted) amino-4- (perfluoroalkyl) -1,3-oxazin-6-one compounds without using phosgene iminium chloride compounds A method is required.

It is therefore an object of the present invention to provide an improved process for the preparation of 2- (N, N-2 substituted) amino-4- (perfluoroalkyl) -1,3-oxazin-6-one compounds.

It is also an object of the present invention to provide intermediate compounds useful for the preparation of 2- (N, N-2 substituted) amino-4- (perfluoroalkyl) -1,3-oxazin-6-one compounds. .

It is further an object of the present invention to provide an improved process for the preparation of 6- (perfluoroalkyl) uracil compounds.

Other objects and advantages of the invention will be apparent to those skilled in the art from the following detailed description and the appended claims.

Summary of the Invention

The present invention

(a) reacting a β-amino-β- (perfluoroalkyl) acrylate compound having formula II with a carbamoyl chloride compound having formula III and a base to form a urea compound having formula IV ; And

(b) reacting the urea of Formula IV with phosphorus pentahalide or oxalyl halide,

Provided is a novel process for the preparation of 2- (N, N-2 substituted) amino-4- (perfluoroalkyl) -1,3-oxazin-6-one compounds having the general formula:

Where

Z and Z ₁ are each independently C ₁ -C ₈ alkyl, or Z and Z ₁ together with the atoms to which they are attached may form a 4 to 7 membered ring, wherein ZZ ₁ is — (CH ₂ ) ₂ O (CH ₂ ) ₂ -or-(CH ₂ ) _m , where m is an integer of 3, 4, 5 or 6;

n is an integer of 1, 2, 3, 4, 5 or 6;

Wherein n is as defined above and Z ₂ is optionally selected from any combination of C ₁ -C ₆ alkyl or benzyl [1 to 3 halogen, C ₁ -C ₄ alkyl or C ₁ -C ₄ haloalkyl groups Substituted on a phenyl ring;

Wherein Z and Z ₁ are as defined above;

;

In addition, the present invention

(a) reacting a urea compound having formula IV with phosphorus pentahalide or oxalyl chloride to yield 2- (N, N-2 substituted) amino-4- (perfluoroalkyl) -1 having formula I, Preparing a 3-oxazine-6-one compound;

(b) reacting the 2- (N, N-2 substituted) amino-4 (perfluoroalkyl) -1,3-oxazin-6-one with an amine compound of formula VI in the presence of an acid or a base to Forming a 6- (perfluoroalkyl) uracil compound of formula V wherein ₃ is hydrogen; And

(c) optionally, alkylating a compound of Formula V wherein Z ₃ is hydrogen,

Provided is a process for preparing a 6- (perfluoroalkyl) uracil compound having the formula (V):

Wherein n is an integer of 1, 2, 3, 4, 5 or 6;

Z ₃ is hydrogen or C ₁ -C ₆ alkyl;

Q is a C ₁ -C ₆ alkyl group or an optionally substituted phenyl, benzyl, heteroaryl or methyleneheteroaryl group.

<Formula IV>

Wherein Z and Z ₁ are each independently C ₁ -C ₈ alkyl, or Z and Z ₁ together with the atoms to which they are attached may form a 4 to 7 membered ring, wherein ZZ ₁ is — (CH ₂ ) ₂ O (CH ₂ ) ₂ -or-(CH ₂ ) _m , where m is an integer of 3, 4, 5 or 6;

Z ₂ is C ₁ -C ₆ alkyl or benzyl [optionally substituted on any phenyl ring with any combination of one to three halogen, C ₁ -C ₄ alkyl or C ₁ -C ₄ haloalkyl groups];

n is an integer of 1, 2, 3, 4, 5 or 6.

<Formula I>

QNH ₂ (where Q is as defined above)

The invention also relates to novel urea compounds of formula IV.

<Formula IV>

Wherein Z and Z ₁ are each independently C ₁ -C ₈ alkyl, or Z and Z ₁ together with the atoms to which they are attached may form a 4 to 7 membered ring, wherein ZZ ₁ is — (CH ₂ ) ₂ O (CH ₂ ) ₂ -or-(CH ₂ ) _m , where m is an integer of 3, 4, 5 or 6;

n is an integer of 1, 2, 3, 4, 5 or 6;

Z ₂ is C ₁ -C ₆ alkyl or benzyl [optionally substituted on any phenyl ring with any combination of one to three halogen, C ₁ -C ₄ alkyl or C ₁ -C ₄ haloalkyl groups].

Detailed description of the invention

In a preferred embodiment of the invention, the 2- (N, N-2 substituted) amino-4- (perfluoroalkyl) -1,3-oxazin-6-one compound of formula (I) In the presence, the β-amino-β- (perfluoroalkyl) acrylate compound of formula II is preferably prepared at a temperature ranging from about -20 ° C to 80 ° C, more preferably from about 0 ° C to 50 ° C. Reacting with the carbamoyl chloride compound of III to form a urea compound of formula IV; Optionally in the presence of a second solvent, preferably at a temperature in the range of about 0 ° C. to 100 ° C., more preferably at about 20 ° C. to 50 ° C., the urea compound of formula IV is combined with phosphorus pentahalide or It is prepared by the step of reacting.

The present invention also provides a process for the preparation of 2- (N, N-2 substituted) amino-4- (perfluoroalkyl) -1,3-oxazin-6-one compound of formula (I) Optionally in the presence of a second solvent, preferably at a temperature in the range of about 0 ° C. to 100 ° C., more preferably at about 20 ° C. to 50 ° C., the urea compound of Formula IV is combined with phosphorus pentahalide or oxalyl halide Reacting.

Advantageously, the present invention relates to a 2- (N, N-2 substituted) amino-4- (perfluoroalkyl) -1,3-oxazin-6-one compound that does not use a phosgene iminium chloride compound. It provides a manufacturing method.

The present invention further relates to urea compounds of formula IV for use in the process of the invention.

<Formula IV>

Where

Z and Z ₁ are each independently C ₁ -C ₈ alkyl, or Z and Z ₁ together with the atoms to which they are attached may form a 4 to 7 membered ring, wherein ZZ ₁ is — (CH ₂ ) ₂ O (CH ₂ ) ₂ -or-(CH ₂ ) _m , where m is an integer of 3, 4, 5 or 6;

n is an integer of 1, 2, 3, 4, 5 or 6,

Z ₂ is C ₁ -C ₆ alkyl or benzyl [optionally substituted on any phenyl ring with any combination of one to three halogen, C ₁ -C ₄ alkyl or C ₁ -C ₄ haloalkyl groups].

Preferred compounds of formula IV are

Z and Z ₁ are each independently C ₁ -C ₆ alkyl,

Z ₂ is C ₁ -C ₄ alkyl,

n is 1 compounds.

More preferred urea compounds of formula IV of the present invention are

Z and Z ₁ are the same and are methyl or ethyl;

Z ₂ is methyl or ethyl;

n is 1 compounds.

Representative examples of compounds of formula IV that are particularly useful in the methods of the present invention include, among others:

Ethyl 3-[(N, N-dimethylcarbamoyl) amino] -4,4,4-trifluorocrotonate, (Z)-;

Methyl 3-[(N, N-dimethylcarbamoyl) amino] -4,4,4-trifluorocrotonate, (Z)-;

Ethyl 3-[(N, N-diethylcarbamoyl) amino] -4,4,4-trifluorocrotonate, (Z)-;

Methyl 3-[(N, N-diethylcarbamoyl) amino] -4,4,4-trifluorocrotonate, (Z)-;

Ethyl 3-[(N-pyrrolodinecarbonyl) amino] -4,4,4-trifluorocrotonate, (Z)-; And

Methyl 3-[(N-pyrrolodinecarbonyl) amino] -4,4,4-trifluorocrotonate, (Z)-.

In a preferred embodiment of the invention, the double bonds of the compounds of formulas (II) and (IV) are predominantly (Z) -positioned.

The compounds of formula (I) can be isolated by diluting the reaction mixture with water and extracting the product with a suitable extraction solvent. In the isolation procedure, conventional extraction solvents may be used, such as diethyl ether, ethyl acetate, toluene, methylene chloride and the like and mixtures thereof.

Suitable bases for use in the preparation of the urea compounds of formula IV include, but are not limited to:

Alkali metal hydrides such as sodium hydride and the like; Alkali metal C ₁ -C ₆ alkoxides (eg potassium tert-butoxide, sodium tert-butoxide, etc.); Alkali metal hydroxides (eg potassium hydroxide, sodium hydroxide, etc.); Alkali metal carbonates such as sodium carbonate, potassium carbonate and the like; Alkaline earth metal hydroxides (eg calcium hydroxide); Alkaline earth metal carbonates (such as calcium carbonate); And lithium bases such as alkyllithium (e.g., n-butyllithium, sec-butyllithium, tert-butyllithium, methyllithium, etc.), lithium dialkylamides (e.g., lithium diisopropylamide, etc.), and lithium cyclic Amides such as lithium tetramethylpiperidine and the like]. Preferred first bases include alkali metal hydrides and alkali metal C ₁ -C ₆ alkoxides.

Phosphorus pentahalides suitable for use in the process of the invention include phosphorus pentachloride, phosphorus pentabromide and phosphorus pentaiodide, and phosphorus pentachloride is preferred. Oxalyl halides suitable for use in the present invention include oxalyl chloride, oxalyl bromide and oxalyl iodide, with oxalyl chloride being preferred.

Suitable first solvents in the present invention include, but are not limited to:

Carboxylic acid amides such as N, N-dimethylformamide, N, N-dimethylacetamide and the like; Ethers such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane and the like; Nitriles such as acetonitrile, propionitrile and the like; Dialkyl sulfoxides such as dimethyl sulfoxide and the like; And mixtures thereof. Preferred first solvent is N, N-dimethylformamide.

Secondary solvents suitable for use in the present invention include, but are not limited to:

Phosphorus oxyhalides such as phosphorus oxychloride and the like; Aromatic hydrocarbons such as toluene, benzene, xylene, mesitylene and the like; Halogenated aromatic hydrocarbons such as chlorobenzene, fluorobenzene, etc .; Carboxylic acid amides such as N, N-dimethylformamide, N, N-dimethylacetamide and the like; Aliphatic hydrocarbons such as pentane, hexane, heptane, etc .; Halogenated aliphatic hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane and the like; And mixtures thereof. Preferred second solvent is phosphorus oxychloride.

Preferred compounds of formula (I) which can be prepared according to the process of the invention are those in which Z and Z ₁ are each independently C ₁ -C ₆ alkyl; n is 1 compounds.

The methods of the present invention also show that Z and Z ₁ are the same and are methyl or ethyl; Preference is given to the preparation of compounds of formula (I) wherein n is one.

2- (N, N-2 substituted) amino-4- (perfluoroalkyl) -1,3-oxazin-6-one compounds of formula (I) are herbicidal 6- (perfluoroalkyl) of formula (V). Useful for the preparation of uracil compounds:

<Formula V>

Where

n is an integer of 1, 2, 3, 4, 5 or 6;

Z ₃ is hydrogen or C ₁ -C ₆ alkyl;

Q is a C ₁ -C ₆ alkyl group or an optionally substituted phenyl, benzyl, heteroaryl or methylenehetero aryl group.

Advantageously, 6- (perfluoroalkyl) uracil compounds of formula V can be prepared by a process comprising the following steps:

(a) reacting a urea compound having formula IV with phosphorus pentahalide or oxalyl halide to yield 2- (N, N-2 substituted) amino-4- (perfluoroalkyl) -1 having formula I, Preparing a 3-oxazine-6-one compound;

<Formula IV>

In the above formula

Z and Z ₁ are each independently C ₁ -C ₈ alkyl, or Z and Z ₁ together with the atoms to which they are attached may form a 4 to 7 membered ring, wherein ZZ ₁ is — (CH ₂ ) ₂ O (CH ₂ ) ₂ -or-(CH ₂ ) _m , where m is an integer of 3, 4, 5 or 6;

Z ₂ is C ₁ -C ₆ alkyl or benzyl [optionally substituted on any phenyl ring with any combination of one to three halogen, C ₁ -C ₄ alkyl or C ₁ -C ₄ haloalkyl groups];

n is as defined above;

<Formula I>

(b) reacting the 2- (N, N-2 substituted) amino-4 (perfluoroalkyl) -1,3-oxazin-6-one with an amine compound of formula VI in the presence of an acid or a base to Forming a 6- (perfluoroalkyl) uracil compound of formula V wherein ₃ is hydrogen; And

<Formula VI>

QNH ₂ (where Q is as defined above)

(c) optionally, alkylating the compound of Formula V wherein Z ₃ is hydrogen.

Acids suitable for use in the preparation of compounds of Formula V include, but are not limited to, organic acids; C ₁ -C ₆ alkano acids (eg, formic acid, acetic acid, propionic acid, etc.) and mineral acids (including but not limited to; Eg hydrochloric acid, sulfuric acid, phosphoric acid, etc.]. Preferred acids are acetic acid.

Suitable bases for use in the preparation of the compound of formula V include, but are not limited to:

Tri (C ₁ -C ₆ alkyl) amines such as trimethylamine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine and the like; Heterocyclic tert-amines such as 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), 1,5-diazabicyclo [4.3.0] non-5-ene (DBN) , 1,4-diazabicyclo [2.2.2] octane, pyridine, substituted pyridine, quinoline, substituted quinoline and the like); And alkali metal C ₁ -C ₆ alkoxides such as potassium tert-butoxide, sodium tert-butoxide and the like.

Preferred second bases are 1,8-diazabicyclo [5.4.0] -undec-7-ene and 1,5-diazabicyclo [4.3.0] non-5-ene.

In a preferred embodiment of the invention, preferably 2- (N, N-2 substituted) amino-4- (perfluoroalkyl)-in the presence of a third solvent, in the temperature range of about 20 ° C to 150 ° C. 1,3-oxazin-6-one is reacted with the amine and the acid. Suitable third solvents for use in this reaction include, but are not limited to:

Carboxylic acid amides such as N, N-dimethylformamide, N, N-dimethylacetamide and the like; Dialkyl sulfoxides such as dimethyl sulfoxide and the like; Aromatic hydrocarbons such as toluene, benzene, xylene, mesitylene and the like; Halogenated aromatic hydrocarbons such as chlorobenzene, fluorobenzene, etc .; Aliphatic hydrocarbons such as pentane, hexane, heptane, etc .; Halogenated aliphatic hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane and the like; Alkano acids (eg, formic acid, acetic acid, propionic acid, etc.); Ketones (eg acetone, methyl ethyl ketone, etc.); Ethers such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane and the like; Nitriles such as acetonitrile, propionitrile and the like; And water; And mixtures thereof.

Suitable alkylation methods for use in the present invention include conventional methods known in the art. In a preferred embodiment of the present invention, the alkylation process comprises reacting a compound of formula V wherein Z ₃ is hydrogen in the presence of a base with an alkyl halide of formula VII or a dialkylsulfate ester of formula VIII.

XZ ₃

Wherein X is chlorine, bromine or iodine and Z ₃ is C ₁ -C ₆ alkyl.

Suitable bases for use in the alkylation process of the invention include, but are not limited to, conventional bases known in the art as follows:

Alkali metal hydrides such as sodium hydride and the like; Alkali metal C ₁ -C ₆ alkoxides (eg potassium tert-butoxide, sodium tert-butoxide, etc.); Alkali metal hydroxides (eg potassium hydroxide, sodium hydroxide, etc.); Alkali metal carbonates such as sodium carbonate, potassium carbonate and the like; Alkaline earth metal hydroxides (eg calcium hydroxide); And alkaline earth metal carbonates such as calcium carbonate and the like.

Preferred compounds of formula V, which may be prepared by the process of the invention,

n is 1;

Z ₃ is hydrogen or C ₁ -C ₄ alkyl;

Q is ego;

G is CH ₂ or a bond;

G ₁ is CX ₅ or N;

G ₂ is CX ₄ or N;

X ₁ is hydrogen, halogen, or a C ₁ -C ₆ alkyl group optionally substituted with one epoxy group;

X ₂ is hydrogen, halogen NRR ₁ , CO ₂ R ₂ , C (O) R ₃ , OR ₄ , SO ₂ R ₅ , SO ₂ NR ₆ R ₇ , C (R ₈ ) (OR ₉ ) ₂ , C (R ₁₀ ) = NOR ₁₁ , C (R ₁₂ ) = C (R ₁₃ ) -C (OR ₁₄ ) = NOR ₁₅ , CH ₂ O-NCO ₂ R ₁₆ ,

1,3-dioxolane optionally substituted with one C ₁ -C ₆ alkoxy group or one or two C ₁ -C ₄ alkyl groups,

1, 3-dioxolinone, optionally substituted with one C ₁ -C ₆ alkoxy group or one or two C ₁ -C ₄ alkyl groups,

Or C ₁ -C ₄ alkyl optionally substituted with one CO ₂ R ₂ group and one halogen atom;

X ₃ is hydrogen, halogen, C ₁ -C ₄ haloalkyl, CO ₂ R ₁₇ , cyano, C ₁ -C ₄ haloalkoxy, OR ₁₈ or C ₁ -C ₄ alkyl, or

X ₁ and X ₂ together with the atoms to which they are attached may form a five or six membered ring, wherein X ₁ X ₂ or X ₂ X ₁ is represented as follows: —OC (R ₂₀₎ (R _21- O-, -CH ₂ S (O) _p N (R ₂₂ )-, -SC (R ₂₃ ) = N-, -CH = CH-CH (R ₁₁ ) O-, -OC (O) N- , -SC (R ₂₄ ) = N-, -ON (R ₂₅ ) C (O)-, -OC (CO ₂ R ₂₆ ) = C (R ₂₇ )-, -NC (R ₂₈ ) = C (SR ₂₉ )-, -CH = C (CO ₂ R ₃₀ ) O-, -CH ₂ CH (R ₃₁ ) O- or -OC (R ₃₂ ) (R ₃₃ ) C (O)-], or

X ₂ and X ₃ together with the atoms to which they are attached may form a five or six membered ring, where X ₂ X ₃ or X ₃ X ₂ is represented as: -NC (R ₃₄ ) = NC (S)-, -N (R ₃₅ ) N = C (R ₃₆ )-, -N (R ₃₇ ) C (R ₃₈ ) = N-, -N (R ₃₈ ) C (O) CH ₂ 0-, -N (R ₃₉ ) C (O) CH = CH-, -SN = C (R ₄₀ )-, -ON = C (R ₄₁ )-, -N = NN (R ₄₂ )-, -C (R ₄₃ ) (R ₄₄ ) C (O) N (R ₄₅ )-or -N (R ₄₆ ) C (O) C (R ₄₇ ) (R ₄₈ )-];

X ₄ is hydrogen, halogen or OR ₁₉ ;

X ₅ is hydrogen or halogen;

R, R ₅₆ , R ₆₄ , R ₆₉ , R ₇₀ , R ₇₇ and R ₉₁ are each independently hydrogen, SO ₂ R ₄₉ , C ₁ -C ₄ alkyl, C ₃ -C ₇ cycloalkyl, C ₃ -C ₆ Alkenyl, C ₃ -C ₆ alkynyl, phenyl or benzyl;

R ₁ is hydrogen, SO ₂ R ₅₀ , C (O) R ₅₁ , amino or C ₁ -C ₄ alkyl optionally substituted with CO ₂ R ₅₂ or C (O) R ₅₃ ;

R ₂ , R ₁₆ , R ₁₇ , R ₂₆ , R ₃₀ , R ₆₈ , R ₇₅ , R ₇₆ , R ₈₂ and R ₈₈ are each independently hydrogen, C ₁ -C ₈ haloalkyl, C ₃ -C ₈ alkenyl , C ₃ -C ₆ alkynyl, phenyl, benzyl, furfuryl, pyridyl, thienyl,

C ₁ -C ₈ alkyl optionally substituted with CO ₂ R ₅₄ , morpholine or C (O) R ₅₅ , or

Alkali metal, alkaline earth metal, ammonium or organic ammonium cation;

R ₃ , R ₆₆ , R ₆₇ , R ₈₁ , R ₈₅ and R ₈₉ are each independently hydrogen, C ₁ -C ₆ alkyl, C ₃ -C ₆ alkenyl, C ₃ -C ₆ alkynyl, NR ₅₆ R ₅₇ , Phenyl or benzyl;

R ₄ , R ₁₈ , R ₁₉ and R ₆₅ are each independently hydrogen, C ₁ -C ₆ alkyl, C ₃ -C ₆ alkenyl, C ₃ -C ₆ alkynyl, C ₁ -C ₄ haloalkyl, C ( O) R ₅₈ , C (S) R ₅₉ or benzyl;

R ₅ and R ₇₂ are each independently C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, NR ₆₀ R ₆₁ , imidazole or indazole;

R ₆ , R ₁₁ , R ₁₂ , R ₁₄ , R ₁₅ , R ₂₀ , R ₂₁ , R ₂₂ , R ₂₅ , R ₂₈ , R ₂₉ , R ₃₁ , R ₃₂ , R ₃₃ , R ₃₅ , R ₄₅ , R ₄₆ , R ₆₃ and R ₈₀ are each independently hydrogen or C ₁ -C ₄ alkyl;

R ₇ is hydrogen, C ₃ -C ₆ alkenyl, C ₃ -C ₆ alkynyl, benzyl, or cyano or C ₁ -C ₄ alkyl optionally substituted with C (O) R ₆₂ ;

R ₈ and R ₂₇ are each independently hydrogen, C ₁ -C ₄ alkyl or C ₁ -C ₄ alkoxy;

R ₉ and R ₉₀ are each independently C ₁ -C ₆ alkyl;

R ₁₀ is hydrogen, C ₁ -C ₆ alkyl, phenyl or benzyl;

R ₁₃ , R ₂₄ and R ₃₆ are each independently hydrogen, C ₁ -C ₆ alkyl or halogen;

R ₂₃ is hydrogen or NR ₆₃ R ₆₄ ;

R ₃₄ is hydrogen, C ₁ -C ₄ alkyl or C ₁ -C ₄ haloalkyl;

R ₃₇ is hydrogen, C ₁ -C ₄ alkyl or C ₂ -C ₈ alkoxyalkyl;

R ₃₈ and R ₃₉ are each independently hydrogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₃ -C ₆ alkenyl or C ₃ -C ₆ alkynyl;

R ₄₀ , R ₄₁ and R ₄₂ are each independently hydrogen, halogen, cyano, OR ₆₅ , C (O) R ₆₆ , C (S) R ₆₇ , CO ₂ R ₆₈ , C (= NOR ₆₉ ),

C ₁ -C ₈ alkyl, C ₃ -C ₇ cycloalkyl, C ₂ -C ₈ alkenyl or C ₂ -C ₈ alkynyl groups, wherein each group is 1 to 6 halogen atoms, 1 to 3 C _1- C ₁₀ -alkoxy group, 1 or 2 C ₁ -C ₆ haloalkoxy groups, 1 or 2 NR ₇₀ R ₇₁ groups, 1 or 2 S (0) _q R ₇₂ groups, 1 or 2 cyano groups, 1 or 2 C ₃ -C ₇ cycloalkyl groups, 1 OSO ₂ R ₇₃ groups, 1 or 2 C (O) R ₇₄ groups, 1 or 2 CO ₂ R ₇₅ groups, 1 or 2 C (O ) SR ₇₆ groups, 1 or 2 C (O) NR ₇₇ R ₇₈ groups, 1 to 3 OR ₇₉ groups, 1 or 2 P (O) (OR ₈₀ ) ₂ groups, 1 1,3-dioxolane Optionally substituted with one to three C ₁ -C ₄ alkyl groups, or any combination of one 1,3-dioxane (optionally substituted with one to three C ₁ -C ₄ alkyl groups) Is substituted with; or

Phenyl or benzyl, wherein each has 1 to 3 halogen atoms, 1 to 3 C ₁ -C ₆ alkyl groups, 1 to 3 C ₁ -C ₆ alkoxy groups, 1 C ₃ -C ₇ cycloalkyl group, 1 1 C ₁ -C ₄ haloalkyl group, 1 C ₁ -C ₄ alkylthio group, 1 cyano group, 1 nitro group, 1 C (O) R _8l group, 1 CO ₂ R ₈₂ group, 1 OR ₈₃ group, 1 SR ₉₄ group, 1 C ₁ -C ₆ alkoxymethyl group, 1 hydroxymethyl group, 1 C ₃ -C ₈ alkenyloxymethyl group, or 1 C ₁ -C _Is optionally substituted with any combination of ₈ haloalkoxymethyl groups;

R ₄₃ , R ₄₄ , R ₄₇ and R ₄₈ are each independently hydrogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₃ -C ₆ alkenyl, C ₃ -C ₆ alkynyl or C ₃ -C ₇ cycloalkyl, or

R ₄₃ and R ₄₄ or R ₄₇ and R ₄₈ together with the atoms to which they are attached form a C ₃ -C ₇ cycloalkyl group;

R ₄₉ , R ₅₀ and R ₈₆ are each independently C ₁ -C ₆ alkyl, NR ₉₃ R ₉₄ , C ₁ -C ₄ haloalkyl, C ₃ -C ₆ alkenyl, C ₃ -C ₆ alkynyl or benzyl ;

R ₅₁ , R ₅₂ , R ₅₃ , R ₅₄ , R ₅₅ , R ₅₇ , R ₅₈ , R ₅₉ , R ₆₀ , R ₆₁ , R ₆₂ , R ₇₁ , R ₇₃ , R ₇₄ , R ₇₈ , R ₈₇ and R ₉₂ Are each independently hydrogen, C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl, C ₁ -C ₆ haloalkyl, C ₃ -C ₆ alkenyl, C ₃ -C ₆ alkynyl, phenyl or benzyl;

R ₇₉ , R ₈₃ and R ₈₄ are each independently hydrogen, C (O) R ₈₅ , SO ₂ R ₈₆ , C ₁ -C ₆ haloalkyl, C ₂ -C ₆ alkenyl, C ₅ -C ₈ cycloalkenyl , C ₂ -C ₆ alkynyl, phenyl, benzyl, or

C ₁ -C ₁₀ alkyl [1 hydroxyl, benzyloxy, OC (O) R ₈₇ , C ₁ -C ₆ alkoxy, CO ₂ R ₈₈ , C (O) R ₈₉ , C (OR ₉₀ ) ₂ , C ( O) is optionally substituted with NR ₉₁ R ₉₂ or a cyano group;

R ₉₃ and R ₉₄ are each independently hydrogen, C ₁ -C ₄ haloalkyl, C ₂ -C ₆ alkenyl, C ₃ -C ₈ cycloalkyl,

C ₁ -C ₈ alkyl [optionally substituted with one or two C ₁ -C ₄ alkoxy groups or one cyanoalkyl group], or

Benzyl or phenyl [1 to 3 halogen atoms, 1 to 3 C ₁ -C ₄ alkyl groups, 1 to 3 C ₁ -C ₄ haloalkyl groups, 1 to 3 C ₁ -C ₄ alkoxy groups, 1 to 3 Optionally substituted with any combination of three C ₁ -C ₄ haloalkoxy groups, one cyano group, or one nitro group;

R ₉₃ and R ₉₄ are 5-12 membered monocyclic or fused bicyclic, heterocyclic rings when taken together with the atoms to which they are attached [halogen, cyano, nitro, amino, hydroxyl, C ₁ -C Optionally substituted with one or more groups independently selected from ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkoxy and C ₁ -C ₄ haloalkylsulfonyl groups; To form;

p and q are each independently 0, 1 or 2 and their optical isomers, diastereomers and / or tautomers.

More preferred herbicides of formula V that can be prepared by the process of the invention

n is 1;

Z ₃ is hydrogen or methyl;

Q is ego;

G is CH ₂ or a bond;

G ₁ is CX ₅ or N;

G ₂ is CX ₄ or N;

X ₁ is hydrogen, fluorine or a C ₁ -C ₃ alkyl group optionally substituted with one epoxy group;

X ₂ is hydrogen, halogen NRR ₁ , CO ₂ R ₂ , C (O) R ₃ , OR ₄ , SO ₂ R ₅ , SO ₂ NR ₆ R ₇ , C (R ₈ ) (OR ₉ ) ₂ , C (R ₁₀ ) = NOR ₁₁ , C (R ₁₂ ) = C (R ₁₃ ) -C (OR ₁₄ ) = NOR ₁₅ , CH ₂ O-NCO ₂ R ₁₆ ,

1,3-dioxolane optionally substituted with one C ₁ -C ₆ alkoxy group or one or two C ₁ -C ₄ alkyl groups,

1, 3-dioxolinone, optionally substituted with one C ₁ -C ₆ alkoxy group or one or two C ₁ -C ₄ alkyl groups,

Or C ₁ -C ₄ alkyl optionally substituted with one CO ₂ R ₂ group and one halogen atom;

X ₃ is hydrogen, halogen, C ₁ -C ₄ haloalkyl, CO ₂ R ₁₇ cyano, C ₁ -C ₄ haloalkoxy, OR ₁₈ or C ₁ -C ₄ alkyl, or

X ₁ and X ₂ together with the atoms to which they are attached may form a five or six membered ring, wherein X ₁ X ₂ or X ₂ X ₁ is represented as follows: —OC (R ₂₀₎ (R _21- O-, -CH ₂ S (O) _p N (R ₂₂ )-, -SC (R ₂₃ ) = N-, -CH = CH-CH (R ₁₁ ) O-, -OC (O) N- , -SC (R ₂₄ ) = N-, -ON (R ₂₅ ) C (O)-, -OC (CO ₂ R ₂₆ ) = CH-, -NC (R ₂₈ ) = C (SR ₂₉ )-,- CH = C (CO ₂ R ₃₀ ) O-, -CH ₂ CH (R ₃₁ ) O- or -OC (R ₃₂ ) (R ₃₃ ) C (O)-], or

X ₂ and X ₃ together with the atoms to which they are attached may form a five or six membered ring, where X ₂ X ₃ or X ₃ X ₂ is represented as: -NC (R ₃₄ ) = NC (S)-, -N (R ₃₅ ) N = C (R ₃₆ )-, -N (R ₃₇ ) C (R ₃₈ ) = N-, -N (R ₃₈ ) C (O) CH ₂ 0-, -N (R ₃₉ ) C (O) CH = CH-, -SN = C (R ₄₀ )-, -ON = C (R ₄₁ )-, -N = NN (R ₄₂ )-, -C (R ₄₃ ) (R ₄₄ ) C (O) N (R ₄₅ )-or -N (R ₄₆ ) C (O) C (R ₄₇ ) (R ₄₈ )-];

X ₄ is hydrogen, halogen or OR ₁₉ ;

X ₅ is hydrogen or halogen;

R, R ₆₄ , R ₆₉ , and R ₇₇ are each independently hydrogen, SO ₂ R ₄₉ or C ₁ -C ₄ alkyl;

R ₁ is hydrogen, SO ₂ R ₅₀ , C (O) R ₅₁ , amino, or C ₁ -C ₄ alkyl optionally substituted with CO ₂ R ₅₂ or C (O) R ₅₃ ;

R ₂ , R ₁₆ , R ₁₇ , R ₂₆ , R ₃₀ , R ₆₈ , R ₇₅ , R ₇₆ , R ₈₂ and R ₈₈ are each independently hydrogen, C ₃ -C ₆ alkenyl, or CO ₂ R ₅₄ , mor C ₁ -C ₄ alkyl optionally substituted with Pauline or C (O) R ₅₅ ;

R ₃ , R ₆₆ , R ₆₇ , R ₈₅ and R ₈₉ are each independently hydrogen, C ₁ -C ₄ alkyl or NR ₅₆ R ₅₇ ;

R ₄ , R ₁₈ and R ₁₉ are each independently hydrogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C (O) R ₅₈ , C ₃ -C ₄ alkenyl or C ₃ -C ₄ alkoxy Nil;

R ₅₆ is SO ₂ R ₄₉ ;

R ₅₇ is hydrogen or C ₁ -C ₄ alkyl;

R ₅ and R ₇₂ are each independently NR ₆₀ R ₆₁ or indazole;

R ₆ , R ₁₁ , R ₁₂ , R ₁₄ , R ₁₅ , R ₂₀ , R ₂₁ , R ₂₂ , R ₂₅ , R ₂₈ , R ₂₉ , R ₃₁ , R ₃₂ , R ₃₃ , R ₃₅ , R ₄₅ , R ₄₆ And R ₈₀ are each independently hydrogen or methyl;

R ₇ is cyano or C ₁ -C ₄ alkyl optionally substituted with C (O) R ₆₂ ;

R ₈ is hydrogen or C ₁ -C ₄ alkoxy;

R ₉ and R ₉₀ are each independently C ₁ -C ₄ alkyl;

R ₁₀ is hydrogen or C ₁ -C ₃ alkyl;

R ₁₃ , R ₂₄ and R ₃₆ are each independently hydrogen or chlorine;

R ₂₃ is NR ₆₃ R ₆₄ ;

R ₃₄ is C ₁ -C ₃ haloalkyl;

R ₃₇ is C ₂ -C ₄ alkoxyalkyl;

R ₃₈ and R ₃₉ are each independently C ₁ -C ₃ haloalkyl, C ₁ -C ₃ alkyl, or propargyl;

R ₄₀ , R ₄₁ and R ₄₂ are each independently hydrogen, C (O) R ₆₆ , C (S) R ₆₇ , CO ₂ R ₆₈ , C (= NOR ₆₉ ),

C ₁ -C ₃ alkyl group [1 or 2 halogen atoms, 1 or 2 C ₁ -C ₃ alkoxy groups, 1 or 2 C ₁ -C ₃ haloalkoxy groups, 1 S (0) ₂ R ₇₂ group , 1 or 2 cyano groups, 1 C ₃ -C ₅ cycloalkyl group, 1 OSO ₂ R ₇₃ group, 1 C (O) R ₇₄ group, 1 CO ₂ R ₇₅ group, 1 C ( O) SR ₇₆ groups, 1 C (O) NR ₇₇ R ₇₈ group, 1 or 2 OR ₇₉ groups, 1 P (O) (OR ₈₀ ) ₂ groups, 1 1,3-dioxolane group, or Optionally substituted with any combination of one 1,3-dioxane group], or

Phenyl [optionally substituted with any combination of one halogen atom, one or two methyl groups, one methoxy group, one halomethyl group or one OR ₈₃ group];

R ₄₃ , R ₄₄ , R ₄₇ and R ₄₈ are each independently hydrogen or methyl, or

R ₄₃ and R ₄₄ or R ₄₇ and R ₄₈ together with the atoms to which they are attached form a cyclopropyl group;

R ₄₉ , R ₅₀ and R ₈₆ are each independently C ₁ -C ₄ alkyl or NR ₉₃ R ₉₄ ;

R ₅₁ , R ₅₂ , R ₅₃ , R ₅₄ , R ₅₅ , R ₅₈ , R ₆₀ , R ₆₁ , R ₆₂ , R ₇₃ , R ₇₄ , R ₇₈ , and R ₈₇ are each independently hydrogen, C ₁ -C ₄ Alkyl or C ₁ -C ₄ haloalkyl;

R ₇₉ and R ₈₃ are each independently hydrogen, C (O) R ₈₅ , SO ₂ R ₈₆ , C ₁ -C ₄ haloalkyl, C ₃ -C ₄ alkenyl or

C ₁ -C ₃ alkyl substituted with one OC (O) R ₈₇ , CO ₂ R ₈₈ , C (O) R ₈₉ , C (OR ₉₀ ) ₂ or cyano group;

R ₉₃ and R ₉₄ are each independently hydrogen or C ₁ -C ₈ alkyl;

p is a compound that is 0, 1 or 2.

The process of the invention is particularly useful for the preparation of 6- (trifluoromethyl) uracil compounds of the general formula (IX).

Where

Z ₃ is hydrogen or methyl;

X ₅ is hydrogen or halogen;

R ₄₀ is hydrogen, C (0) R ₆₆ , C (S) R ₆₇ , CO ₂ R ₆₈ ,

C ₁ -C ₃ alkyl [1 or 2 halogen atoms, 1 or 2 C ₁ -C ₃ alkoxy groups, 1 or 2 C ₁ -C ₃ haloalkoxy groups, 1 SO ₂ R ₇₂ group, 1 or 2 Cyano groups, 1 C ₃ -C ₅ cycloalkyl group, 1 OSO ₂ R ₇₃ group, 1 or 2 OR ₇₉ groups, 1 P (O) (OR ₈₀ ) ₂ groups, 1 1,3 Optionally substituted with a dioxolane group or any combination of one 1,3-dioxane group], or

Phenyl [optionally substituted with any combination of one halogen atom, one or two methyl groups, one methoxy group, one halomethyl group or one OR ₈₃ group];

R ₆₆ , R ₆₇ , R ₈₅ and R ₈₉ are each independently hydrogen, C ₁ -C ₄ alkyl or NR ₅₆ R ₅₇ ;

R ₅₆ is SO ₂ R ₄₉ ;

R ₅₇ is hydrogen or C ₁ -C ₄ alkyl;

R ₄₉ and R ₈₆ are each independently C ₁ -C ₄ alkyl or NR ₉₃ R ₉₄ ;

R ₉₃ and R ₉₄ are each independently hydrogen or C ₁ -C ₈ alkyl;

R ₆₈ and R ₈₈ are each independently hydrogen, C ₃ -C ₆ alkenyl or

C ₁ -C ₄ alkyl [optionally substituted with CO ₂ R ₅₄ , morpholine or C (O) R ₅₅ ];

R ₅₄ , R ₅₅ , R ₆₀ , R ₆₁ , R ₇₃ and R ₈₇ are each independently hydrogen, C ₁ -C ₄ alkyl or C ₁ -C ₄ haloalkyl;

R ₇₂ is NR ₆₀ R ₆₁ or indazole;

R ₇₉ and R ₈₃ are each independently hydrogen C (O) R ₈₅ , SO 2 R ₈₆ , C ₁ -C ₄ haloalkyl, C ₃ -C ₄ alkenyl or

C ₁ -C ₃ alkyl [substituted with one OC (O) R ₈₇ , CO 2 R ₈₈ , C (0) R ₈₉ , C (OR ₉₀ ) ₂ or cyano group];

R ₈₀ is hydrogen or methyl; And

R ₉₀ is C ₁ -C ₄ alkyl.

Examples of such halogens are fluorine, chlorine, bromine and iodine. The terms "halomethyl", "C ₁ -C ₄ haloalkyl", "C ₁ -C ₈ haloalkyl", "C ₁ -C ₃ haloalkoxy", "C ₁ -C ₄ haloalkoxy", and "C ₁ -C ₈ haloalkoxymethyl "is methyl, C ₁ -C ₄ alkyl, C ₁ -C ₈ alkyl, C ₁ -C ₃ alkoxy, C ₁ -C ₄ alkoxy or C ₁ -substituted with one or more halogen atoms It is defined as a C ₈ alkoxymethyl group. In formula (V), alkali metals include sodium, potassium, and lithium, and alkaline earth metals include calcium and magnesium. Organic ammonium cations suitable for use in the present invention include, but are not limited to, groups consisting of nitrogen atoms charged in an amount bonded to 1 to 4 aliphatic groups, each containing 1 to 16 carbon atoms.

In formula (V), the 5-12 membered monocyclic or fused bicyclic, heterocyclic rings are benzimidazole, imidazole, imidazoline-2-thione, indole, isato acid anhydride, morpholine, piperazine , Piperidine, purine, pyrazole, pyrrole, pyrrolidine and 1,2,4-triazole rings, wherein each ring is halogen, cyano, nitro, amino, hydroxyl, C ₁ -C ₄ alkyl, Optionally substituted with one or more groups independently selected from C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkoxy, or C ₁ -C ₄ haloalkylsulfonyl groups; It is not limited to this.

The starting compounds β-amino-β- (perfluoroalkyl) -acrylate compounds of formula II are known in the art and described in US Pat. No. 5,777,154 and Journal of heterocyclic Chemistry, 9, pages 513-522 (1972); And Institute of Chemistry, Urals Scientific Center, Academy of Sciences of the USSR, Sverdlovsk, pages 1442-1447 (1987) -English translation of Zhurnal Organicheskoi Khimii, 22 (8), pages 1603-1609 (1986). Thus it can be produced.

Carbamoyl chloride compounds of formula III are known in the art and can be prepared by conventional methods. In addition, certain carbamoyl chloride compounds of formula III are commercially available.

An amine compound having formula VIa is prepared by cyclizing a ketone of formula X with sulfur and ammonium hydroxide or ammonia, as shown in Scheme I, to produce nitrobenzisothiazole of formula XI and the compound of formula XI in It can be prepared by the step of reducing using a conventional reducing agent such as iron.

Wherein X ₁ , X ₅ and R ₄₀ are as defined above.

The amine compound having the formula VIb as the starting compound is prepared by reacting a ketone of formula XII with hydroxylamine hydrochloride, optionally in the presence of sodium acetate, to produce an oxime of formula XIII, as disclosed in Scheme II, By cyclizing a compound of to a base such as potassium hydroxide to produce nitrobenzisoxazole of formula XIV and reducing the compound of formula XIV using a conventional reducing agent such as tin (II) chloride in acetic acid It can manufacture.

Wherein X ₁ , X ₅ and R ₄₁ are as defined above.

Alternatively, the nitrobenzisoxazole compound of formula (XIV) is prepared by reacting a ketone of formula (XV) with hydroxylamine hydrochloride, optionally in the presence of a base, such as sodium acetate, as shown in Scheme III to prepare an oxime of formula (XVI). Cyclizing a compound of formula (XVI) with 1,1'-carbonyl-diimidazole to produce benzisoxazole of formula (XVII), and a nitric acid / sulfuric acid mixture It can be prepared by the step of nitriding the compound of formula (XVII) using the same conventional method.

Intermediate compounds of Formulas (XI) and (XIV), wherein R ₄₀ and R ₄₁ are OR ₆₅ , are represented by the following formula (IV): benzisoxazol-3-ol or benzisothiazol-3-ol nitric acid / sulfuric acid mixture Nitriding with a conventional nitriding agent such as preparing 5-nitrobenzisoxazol-3-ol or 5-nitrobenzisothiazol-3-ol of formula (XIX), and in the presence of a base such as potassium carbonate It may be prepared by the step of reacting with an electron affinity of formula (XX).

Intermediate compounds of Formulas (XI) and (XIV), wherein R ₄₀ and R ₄₁ are Cl or Br, 5-nitrobenzisoxazol-3-ol or 5-nitrobenzisothiazole-3 of Formula (XIX) as shown in Scheme V -Ols can be prepared by reacting with phosphorus oxychloride, phosphorus oxybromide or phosphorus pentabromide.

Other methods for preparing amine compounds of formula VIa and VIb will be apparent from the examples described below. In addition, certain compounds of formulas VIa, VIb, XI and XIV can be converted to other compounds of formulas VIa, VIb, XI and XIV by conventional procedures known to those skilled in the art.

Other amine compounds of formula VI are known in the art and can be prepared according to the procedures disclosed in the following documents, among others:

EP 561319-A; EP 540023-A; EP 545206-A;

EP 542685-A; EP 473551-A; EP 476697-A; EP 489480-A;

EP 496595-A; EP 420194-A; EP 648749-A; EP 705829-A;

EP 714602-A; JP 9241245; JP 9301973; U.S. 5,169,430;

U.S. 5,310,723; U.S. 5,324,854; U.S. 5,391,541;

U.S. 5,399,543; U.S. 5,484,763; U.S. 5,523,278;

U.S. 5,602,077; U.S. 5,661,108; WO 93/14073; WO 94/10155;

WO 94/24128; WO 91/07393; WO 91/107392; WO 95/04461;

WO 95/05079; WO 95/05080; WO 95/17096; WO 95/25725;

WO 95/29168; WO 95/32952; WO 95/33746; WO 96/02518;

WO 96/08151; WO 96/14315; WO 96/28442; WO 96/34859;

WO 96/35679; WO 97/01541; WO 97/01542; WO 97/05118;

WO 97/07105; WO 97/08170; WO 97/08171; WO 97/08953;

WO 97/12884; WO 97/12886; WO 97/29094; WO 97/29105;

WO 97/34484; WO 97/35845; WO 97/42176; WO 97/42188;

WO 97/45418; WO 97/47607; WO 98/02422; WO 98/06706;

WO 98/08824; WO 98/27057; WO 98/27067; WO 98/27082; And

WO 98/27088.

The following examples are set forth in order to provide a better understanding of the present invention. The following examples are merely to illustrate the invention in more detail. Accordingly, the scope of the present invention should not be deemed to be limited by the embodiments, but encompasses the entire claim as defined in the claims.

Example 1

Preparation of ethyl 3-[(N, N-dimethylcarbamoyl) amino] -4,4,4-trifluorocrotonate, (Z)-

Sodium hydride (60% in mineral oil, 9.6 g in mineral oil) in N, N-dimethylformamide (60 mL) with ethyl 3-amino-4,4,4-trifluorocrotonate (18.4 g, 100 mmol) at 5 ° C. nitrogen. , 250 mmol) was added over 60 minutes. The temperature of the reaction mixture is allowed to rise to room temperature, held at room temperature for 15 minutes, cooled to 5 ° C. and treated with dimethylcarbamoylchloride (21.6 g, 200 mmol) for 60 minutes. The resulting solution is then allowed to rise to room temperature, held at room temperature for 2 hours, diluted with water (150 mL) and extracted with ethyl acetate (2 × 150 mL). The combined organic layers are dried, filtered and concentrated and the mineral oil layer is removed to give a residue. The residue was flash column chromatography on silica gel using 85:15 hexanes / ethyl acetate solution to give the title compound as a yellow liquid (18.1 g, 71% yield): ¹ H NMR (DMSO-d ₆ ) δ 9.18 ( s, 1H), 5.85 (s, 1H), 4.20 (q, 2H), 2.89 (s, 6H), 1.18 (t, 3H); ¹⁹ F NMR δ −65.7 (s).

Using essentially the same method, the following compounds are obtained:

Example 2

Preparation of 2-dimethylamino-4- (trifluoromethyl) -6H-1,3-oxazin-6-one

A solution of ethyl 3- [N- (N, N-dimethylcarbamoyl) amino] -4,4,4-trifluorocrotonate (5.08 g, 0.02 mol) in phosphorus oxytrichloride (3 mL), Treat with phosphorus pentachloride (4.16 g, 0.02 mol) (divided into three portions at 15 minute intervals), stir for 30 minutes, and quench with ice water. The resulting aqueous mixture is extracted with ethyl acetate. The organic layer was washed sequentially with saturated sodium bicarbonate and water and evaporated to afford the title compound as a white solid (3.9 g, 93.8% yield), which was determined by ¹ H and ¹⁹ F NMR, according to the procedure in the literature [ Bull. Soc. Chem. Belg. 101,313, 1992]. The title compound is further purified by crystallization from heptane (74.5% crystallization yield).

3- [N- (N, N-dimethylcarbamoyl) amino] -4,4,4-trifluorocrotonate 3- [N- (N, N-diethylcarbamoyl) amino] -4 2-diethylamino-4- (trifluoromethyl) -6H-1,3-oxazine-6 using essentially the same procedure except for replacing with 4,4-trifluorocrotonate Obtain the warm in oil form (86%. Crude yield, 65% purification yield).

Example 3

Preparation of 3-isopropyl-6- (trifluoromethyl) -2,4 (1H, 3H) -pyrimidinedione

Isopropylamine (1.2 g, 20.3 mmol) and 1,8-diazabicyclo [5,4,0] undec-7-ene (DBU, 6 mL) were added 2-dimethylamino-4- in xylene (34 mL). To a solution of trifluoromethyl-6H-1,3oxazin-6-one (4.0 g, 19.2 mmol). The resulting reaction mixture is kept at 100 ° C. for 3 hours, cooled, washed with 5% by weight HCl (40 mL) and extracted with ethyl acetate. The combined organic extracts are concentrated and triturated with heptane. The solid was filtered and dried to give the title compound as a yellow powder (2.3 g, 54% yield, mp 127-129 ° C.) which was confirmed by ¹ H NMR:

¹ H NMR (DMSO-d ₆ ) δ 6.11 (1H, s), 4.96 (1H, sp), 1.35 (6H, d); And ¹⁹ F NMR δ -68.9 (s).

Using essentially the same method, except using the appropriate amine, the following compounds are obtained:

Example 4

Preparation of 2'-chloro-2-methoxy-5-methyl-5'-nitrobenzophenone

The mixture of aluminum chloride (33.3 g, 25.0 mmol) in methylene chloride is cooled to about 5 ° C. and treated with p-methylanisole (31.6 g, 25.0 mmol) over 1 hour, at which time the temperature of the reaction mixture is 10 ° C. And a solution of 2-chloro-5-nitrobenzoyl chloride (50.0 g, 22.7 mmol) in methylene chloride over 20 minutes (wherein the temperature of the reaction mixture is kept below 10 ° C), Warm to room temperature and stir for 60 minutes at room temperature, pour over ice. The resulting aqueous mixture is treated with concentrated hydrochloric acid (50 mL) and extracted with methylene chloride. The organic extract is dried over anhydrous magnesium sulfate and concentrated in vacuo to yield a yellow solid. After the solid is placed in a Kugelrohr apparatus at 40 ° C. to remove residual p-methylanisole, the title compound is obtained as a beige solid (68.8 g, 99.1%) which is confirmed by NMR spectral analysis.

Using essentially the same method, the following compounds are obtained:

Example 5

Preparation of 3- (6-methoxy-m-tolyl) -5-nitro-1,2-benzisothiazole

Ammonium hydroxide (350 mL of 30% solution, 270 mmol) was dissolved in 2'-chloro-2-methoxy-5-methyl-5'-nitrobenzophenone (68.7 g, 22.5 mmol) and sulfur in N, N-dimethylformamide. (7.57 g, 23.6 mmol) is added to the mixture. The resulting reaction mixture is stirred at 80 ° C. for 19.5 hours, cooled to 40 ° C., treated with additional ammonium hydroxide (50 mL of 30% solution), stirred at 80 ° C. for 25 hours, cooled and poured onto ice . The resulting aqueous mixture is filtered to give the title compound as a yellow solid (63.5 g, 93.9%) which is confirmed by NMR spectral analysis.

Using essentially the same method, the following compounds are obtained:

Example 6

Preparation of 3-methyl-5-nitro-1,2-benzisothiazole

Ammonia (45 g, 2,642 mmol) is bubbled into methanol at -40 ° C. in a steel bomb. Sulfur (30.5 g, 95.0 mmol) and 2'-chloro-5'-nitroacetophenone (19 g, 95.0 mmol) are then added. The bomb is sealed and heated at about 90 ° C. overnight. After cooling, the reaction mixture is removed from the bomb and concentrated in vacuo to give a residue. This residue is diluted with methylene chloride, passed through a silica gel plug and concentrated in vacuo to give the title compound as an orange solid (12.0 g) which is confirmed by NMR spectral analysis.

Using essentially the same method, the following compounds are obtained:

Example 7

Preparation of 5-amino-3- (6-methoxy-m-tolyl) -1,2-benzisothiazole

3- (6-methoxy-m-tolyl) -5-nitro-1,2-benzisothiazole (63.0 g, 0.210 mol), 5% acetic acid (1.52 L, 1.21 mol) and ethyl acetate (975 mL ) Is heated to 65 ° C. and treated in part with iron powder (58.6 g, 1.05 mol), stirred at 65 ° C. and filtered with quartz filter paper. The filtrate phases are separated and the aqueous phase is extracted with ethyl acetate. The organic phases and extracts were combined, washed sequentially with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to afford the title compound as an orange oil (55.7 g, 98.1%) which was confirmed by NMR spectral analysis. .

Using essentially the same method, the following compounds are obtained:

Example 8

3- [3- (6-methoxy-3,4-xylyl) -1,2-benzisothiazol-5-yl] -6- (trifluoromethyl) -2,4 (1H, 3H) Preparation of Pyrimidinedione

5-amino-3- (6-methoxy-3,4-xylyl) -1,2-benzisothiazole (8.53 g, 30.0 mmol), 2-dimethylamino-4- (trifluoromethyl)- A mixture of 6H-1,3-oxazine-6-one (6.87 g, 33.0 mmol) and acetic acid is refluxed for 2 hours, cooled and poured into water. The resulting aqueous mixture is filtered to give a solid. The solution of said solid in methylene chloride is washed sequentially with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to give an oil. Using 5% diethyl ether solution in silica gel and methylene chloride, the oil is column chromatographed to give the title compound as a yellow foam (8.37 g, 62.0%) which is confirmed by NMR spectral analysis.

Using essentially the same method, the following compounds are obtained:

Example 9

3- [3- (6-methoxy-m-tolyl) -1,2-benzisothiazol-5-yl] -1-methyl-6- (trifluoromethyl) -2,4 (1H, 3H Preparation of Pyrimidinedione

3- [3- (6-methoxy-m-tolyl) -1,2-benzisothiazol-5-yl] -6- (trifluoromethyl) -2,4 in N, N-dimethylformamide A mixture of (1H, 3H) -pyrimidinedione (160 g, 0.369 mol), potassium carbonate (76.6 g, 0.554 mol) and methane iodide (34.5 mL, 0.554 mol) is stirred at room temperature for 4 hours and poured into ice . The resulting aqueous mixture is extracted with methylene chloride. The organic extract is diluted with hexane, washed with water, dried over anhydrous magnesium sulfate and concentrated in vacuo to give the title compound as an orange foam (163 g, 98.8%) which is confirmed by NMR spectral analysis.

Using essentially the same method, the following compounds are obtained:

Example 10

Preparation of 2-chloro-2'-methoxy-5'-methyl-5-nitrobenzophenone, oxime

Treatment of a mixture of 2-chloro-2'-methoxy-5'-methyl-5-nitro-benzophenone (90.0 g, 0.294 mol) in ethanol with a solution of hydroxylamine hydrochloride (102.3 g, 1.47 mol) in water Reflux overnight, pour on ice. The resulting aqueous mixture is filtered to give a solid. The solid is washed with water and dried overnight in a hot vacuum oven to give the title compound as a white solid (84.2 g) which is confirmed by ¹ H NMR spectral analysis.

Using essentially the same method, the following compounds are obtained:

Example 11

Preparation of 3- (6-methoxy-m-tolyl) -5-nitro-1,2-benzisoxazole

A mixture of 2-chloro-2'-methoxy-5'-methyl-5-nitro-benzophenone, oxime (84.0 g, 0.262 mol) in ethanol is warmed to 65 ° C. and 150 mL of 10% over 25 minutes. Treat with potassium hydroxide solution, heat to 78 ° C. over 1 hour, cool and pour on ice. The resulting aqueous mixture is filtered to give a solid. The solid is washed with water, dried, recrystallized from N, N-dimethylformamide, washed sequentially with N, N-dimethylformamide and ethanol and dried in a vacuum oven at 80 ° C. to give the title compound as a solid. (mp 225-226 ° C.), which is confirmed by ¹ H NMR spectral analysis.

Using essentially the same method, the following compounds are obtained:

Example 12

5-amino-3- (6-methoxy-m-tolyl) -1,2-benzisoxazole and 5-amino-4-chloro-3- (6-methoxy-m-tolyl) -1,2- Preparation of Benzisoxazole

Warm a mixture of 3- (6-methoxy-m-tolyl) -5-nitro-1,2-benzisoxazole (20.0 g, 0.0703 mol) in acetic acid (380 mL) and concentrated hydrochloric acid (110 mL) Treated with a warm solution of tin (II) chloride dihydrate (47.4 g, 0.210 mol) in, refluxed for 1 hour, cooled to 10 ° C. and concentrated in vacuo to give a gum. The gum is added to water with stirring to obtain a slurry. The slurry is treated with 80 g of 50% sodium hydroxide solution, stirred at 60 ° C. to 80 ° C. over 1 hour, cooled and decanted to give a residue. The residue mixture in ethanol is treated with potassium hydroxide (10 g), heated overnight, cooled to room temperature, neutralized with hydrochloric acid and concentrated in vacuo to give a residue. The residue is diluted with ethyl acetate and filtered. The filtrate is concentrated in vacuo and chromatographed using a 2% ethyl acetate solution in silica gel and methylene chloride to give the title compound in a semisolid state, which is confirmed by elemental and mass spectral analysis.

The essentially same procedure is followed, except that 3- (6methoxy-m-tolyl) -5-nitro-1,2-benzisoxazole is replaced by 5-nitro-3-phenyl-1,2-benzisoxazole To obtain 5-amino-3-phenyl-1,2-benzisoxazole.

Example 13

3- [3- (6-methoxy-m-tolyl) -1,2-benzisoxazol-5-yl] -6- (trifluoromethyl) -2,4 (1H, 3H) -pyrimidinedione Manufacture

5-amino-3- (6-methoxy-m-tolyl) -1,2-benzisoxazole (8.40 g, 0.033 mol), 2-dimethylamino-4- (trifluoromethyl) -6H-1, The mixture of 3-oxazine-6-one (7.60 g, 0.036 mol), and acetic acid is refluxed for 3 hours, cooled, poured into ice and diluted with water. The resulting aqueous mixture is filtered to give a solid. The solid is washed with water and dried to give the title compound as a pink solid which is confirmed by NMR spectral analysis.

Using essentially the same method, the following compounds are obtained:

Example 14

3- [3- (6-methoxy-m-tolyl) -1,2-benzisoxazol-5-yl] -1-methyl-6- (trifluoromethyl) -2,4 (1H, 3H) Preparation of Pyrimidinedione

3- [3- (6-methoxy-m-tolyl) -1,2-benzisoxazol-5-yl] -6- (trifluoromethyl) -2,4 in N, N-dimethylformamide A mixture of 1H, 3H) -pyrimidinedione (10.5 g, 0.0255 mol) and potassium carbonate (7.04 g, 0.051 mol) is stirred for 15 minutes, treated with methyl iodide (7.24 g, 0.051 mol) and overnight Stir and pour on ice. The resulting aqueous mixture is extracted with methylene chloride. The organic extracts are combined, washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo to give a brown glass. The glass was dried by column chromatography using silica gel and hexane / ethyl acetate solution (3: 1) to give the title compound as an off-white solid which was confirmed by NMR spectral analysis.

Using essentially the same method, the following compounds are obtained:

Example 15

Preparation of m-fluorophenyl acetate

A solution of 3-fluorophenol (100 g, 0.890 mol) in methylene chloride is cooled to 0 ° C. to 5 ° C., treated with pyridine (75.0 mL, 0.930 mol), stirred for several minutes, and dropwise acetyl chloride (66.0 mL, 0.930 mol) (at which time the temperature of the reaction mixture was kept at 17 ° C. or lower), stirred at ice bath temperature for 2 hours, warmed to room temperature and poured into ice water. The organic phase is separated, washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to afford the title compound as a yellow oil which is confirmed by ¹ H NMR spectral analysis.

Example 16

Preparation of 4'-fluoro-2'-hydroxyacetophenone

m-fluorophenyl acetate (123 g, 0.798 mol) is cooled in an ice bath, treated in part with aluminum chloride (150 g, 1.12 mol), stirred at 190 ° C. for 1 hour and cooled to obtain a solid. A mixture of ice, water and hydrochloric acid, and methylene chloride are added to the solid. The resulting mixture is stirred for a few minutes and the phases are separated. The organic phase is washed sequentially with water, saturated sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to give the title compound (99.0 g), which is confirmed by ¹ H NMR spectral analysis. .

Example 17

Preparation of 4'-fluoro-2'-hydroxyacetophenone, oxime

A mixture of 4'-fluoro-2'-hydroxyacetophenone (99.0 g, 0.640 mol), hydroxylamine hydrochloride (89.0 g, 1.28 mol) and sodium acetate (79.0 g, 0.960 mol) in methanol was refluxed for 1 hour. And pour into ice water. The resulting aqueous mixture is filtered to give a solid. The solid is dissolved in methylene chloride and the resulting organic solution is dried over anhydrous magnesium sulfate, concentrated in vacuo, diluted with hexanes and filtered to give the title compound as a solid (55.0 g, mp 112-114 ° C.). This is confirmed by ¹ H NMR spectral analysis.

Example 18

Preparation of 6-fluoro-3-methyl-1,2-benzisoxazole

A mixture of 4'-fluoro-2'-hydroxyacetophenone, oxime (47.0 g, 0.278 mol) in tetrahydrofuran is heated to precise reflux and 1,1'-carbonyl-diimine in tetrahydrofuran Treat with a solution of dozol (55.0 g, 0.340 mol) and triethylamine (39.0 g, 0.390 mol), reflux for 1 hour, cool, concentrate in vacuo and pour into ice water. The resulting aqueous mixture is extracted with ether. The organic extracts are combined, washed sequentially with saturated ammonium chloride solution and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to give an oil. The oil is column chromatographed using silica gel and methylene chloride / hexane solution (1: 1) to afford the title compound as a yellow oil, which is confirmed by ¹ H NMR spectral analysis.

Example 19

Preparation of 6-fluoro-3-methyl-5-nitro-1,2-benzisoxazole

A mixture of 6-fluoro-3-methyl-1,2-benzisoxazole (23.5 g, 0.156 mol) in concentrated sulfuric acid is cooled in an ice bath and treated dropwise with 90% nitric acid (8.50 mL) (wherein The temperature of the reaction mixture is kept below 15 ° C.), stirred at ice bath temperature for 1 hour, treated with additional 90% nitric acid (5.80 mL), warmed to room temperature, stirred at room temperature overnight and poured on ice. The resulting aqueous mixture is filtered to give a solid. The solid is dried with air and dissolved in methylene chloride. The resulting organic solution is dried over anhydrous magnesium sulfate, diluted with hexanes and filtered to give the title compound as a purple solid, which is confirmed by ¹ H NMR spectral analysis.

Example 20

Preparation of 5-amino-6-fluoro-3-methyl-1,2-benzisoxazole and 5-amino-4-chloro-6-fluoro-3-methyl-1,2-benzisoxazole

A mixture of 6-fluoro-3-methyl-5-nitro-1,2-benzisoxazole (3.00 g, 0.0153 mol) and acetic acid (85.0 mL) was heated to 40 ° C. and tin (II) chloride dihydrate (9.70 g, 0.0430 mol) and concentrated hydrochloric acid (45.0 mL) are treated, refluxed for 90 minutes, concentrated in vacuo, neutralized with 2N sodium hydroxide solution and filtered to give a solid. Using silica gel and methylene chloride, the solid is column chromatographed to give the title compound as a solid, which is confirmed by NMR spectral analysis.

Using essentially the same procedure, except using an ethyl acetate / ethanol mixture instead of acetic acid, the following compounds are obtained:

Example 21

Preparation of 3- (6-fluoro-3-methyl-1,2-benzisoxazol-5-yl) -6- (trifluoromethyl) -2,4 (1H, 3H) -pyrimidinedione

5-amino-6-fluoro-3-methyl-1,2-benzisoxazole (4.85 g, 0.029 mol) in acetic acid and 2-dimethylamino-4- (trifluoromethyl) -6H-1,3 The mixture of oxazine-6-one (6.70 g, 0.0320 mol) is refluxed for 90 minutes, cooled to room temperature and poured into ice water. The resulting aqueous mixture is filtered to give a solid. The solid is dried with air and dissolved in ethyl acetate. The resulting organic solution is washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to afford the title compound as a yellow solid (7.00 g, mp 235-237 ° C.) which is confirmed by NMR spectral analysis.

Using essentially the same method, the following compounds are obtained:

Example 22

3- (6-fluoro-3-methyl-1,2-benzisoxazol-5-yl) -1-methyl-6- (trifluoromethyl) -2,4 (1H, 3H) pyrimidinedione Produce

3- (6-Fluoro-3-methyl-1,2-benzisoxazol-5-yl) -6- (trifluoromethyl) -2,4 (1H, 3H) in N, N-dimethylformamide A mixture of pyrimidinedione (3.00 g, 9.12 mmol) and potassium carbonate (2.52 g, 18.2 mmol) was stirred for 15 minutes, treated with methyl iodide (2.58 g, 18.2 mmol) and stirred overnight at room temperature , Pour in ice water. The resulting aqueous mixture is filtered to give a solid which is recrystallized from methylene chloride / hexane solution to give the title compound as a white solid (mp 158-159 ° C.) which is confirmed by NMR spectral analysis.

Using essentially the same method, the following compounds are obtained:

Example 23

Preparation of 2'-chloro-5'-nitroacetophenone, oxime

A mixture of 2'-chloro-5'-nitroacetophenone (50.0 g, 0.250 mol) in ethanol is treated with a solution of hydroxylamine hydrochloride (83.0 g, 1.19 mol) in water, refluxed overnight, cooled to room temperature, Filtration affords the title compound as a solid (mp 165-167 ° C.) which is confirmed by NMR spectral analysis.

Example 24

Preparation of 3-methyl-5-nitro-1,2-benzisoxazole

A mixture of 2'-chloro-5'-nitroacetophenone, oxime (30.0 g, 0.140 mol) in ethanol was treated dropwise with 10% potassium hydroxide solution (7.86 g KOH), stirred at room temperature for 1 hour, and overnight Reflux, cool, pour into water. The resulting aqueous mixture is filtered to give a solid. Using silica gel and methylene chloride, the solid is column chromatographed to give the title compound as a yellow solid (mp 84.5-86.5 ° C.) which is confirmed by NMR spectral analysis.

Example 25

Preparation of 5-nitro-1,2-benzisoxazol-3-ol

1,2-benzisoxazol-3-ol (19.7 g, 0.146 mol) is added in portions to concentrated sulfuric acid. The resulting reaction mixture is treated dropwise with 70% nitric acid (11.3 mL), stirred for 90 minutes and poured onto ice. The resulting aqueous mixture is filtered to give a waxy paste. The paste is recrystallized from a methanol / water mixture to give the title compound as a solid which is confirmed by ¹ H NMR spectral analysis.

Using essentially the same method, the following compounds are obtained:

Example 26

Preparation of Methyl [(5-nitro-1,2-benzisoxazol-3-yl) oxy] acetate

A mixture of 5-nitro-1,2-benzisoxazol-3-ol (3.90 g, 0.0220 mol) and potassium carbonate (4.17 g, 0.0300 mol) in N, N-dimethylformamide was stirred for 30 minutes and methyl bromine Treat with moacetate (3.96 g, 0.0260 mol), stir overnight at room temperature and pour into acidic ice water. The resulting aqueous mixture is extracted with ethyl acetate. The organic extracts are combined, washed sequentially with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to yield a yellow oil. Column chromatography of the oil using silica gel and (1: 1) to (4: 1) methylene chloride / hexane gradients gave the title compound as a white solid (2.80 g, mp 72-73.5 ° C). Confirm by analysis.

Using essentially the same method, the following compounds are obtained:

Example 27

Preparation of 3-chloro-5-nitro-1,2-benzisoxazole

A mixture of 5-nitro-1,2-benzisoxazol-3-ol (4.00 g, 0.0220 mol) and phosphorus oxychloride (40.0 mL, 65.8 g, 0.429 mol) is placed in a glass cylinder and at 150-155 ° C. Heat for 2 hours, cool overnight, concentrate in vacuo, dilute with methylene chloride and bring to pH about 8 with sodium hydrogen carbonate solution. The phases are separated and the organic phase is washed sequentially with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to give a residue. The residue is column chromatographed using silica gel and methylene chloride / hexane solution (1: 1) to give the title compound as an amber oil, which is confirmed by NMR spectral analysis.

Example 28

Preparation of 2-chloro-2'-methoxy-5-nitrobenzophenone

A solution of 2-bromoanisole (27.9 g, 145 mmol) in diethyl ether was cooled to -70 ° C, treated with butyllithium (64.0 mL, 160 mmol), stirred at -70 ° C for 1 hour, Treat with a 0.5 M solution of zinc chloride in tetrahydrofuran (320 mL, 160 mmol), stir at −70 ° C. for 1 hour, warm to about 0 ° C. and concentrate in vacuo to give an yellowish green oil. A solution of this oil in tetrahydrofuran was sequentially followed by a solution of tetrakis (triphenylphosphine) palladium (0) (5.00 g, 4.35 mmol) and 2-chloro-5-nitrobenzoyl chloride in tetrahydrofuran (35.0 g, 159 mmol), stirred for 3 days, and poured into 10% hydrochloric acid. The resulting aqueous mixture is extracted with methylene chloride. The organic extracts are combined, washed sequentially with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to give a semisolid. Triturate the solid with diethyl ether to give the title compound as a yellow solid, which is confirmed by NMR spectral analysis.

Using essentially the same method, the following compounds are obtained:

Example 29

Preparation of 2-chloro-2'-methoxy-5-nitrobenzhydrol

A solution of 2-bromoanisole (50.0 g, 0.267 mol) in ether is added in portions to the magnesium mixture in ether (7.10 g, 0.293 mol). After the addition was complete, the reaction mixture was heated at reflux for 1 hour, diluted with ether, cooled to 0 ° C. and a solution of 2-chloro-5-nitrobenzaldehyde (39.0 g, 0.210 mol) in tetrahydrofuran Treat to, warm to room temperature and dilute with ice water. After acidifying the aqueous mixture with hydrochloric acid (pH 2-pH 3), the organic phase is separated and the aqueous phase is extracted with ether. The organic extracts are combined, washed sequentially with 10% sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford the title compound as a brown gum.

Using essentially the same method, the following compounds are obtained:

Example 30

Preparation of 2-chloro-2'-methoxy-5-nitrobenzophenone

A portion of chromium oxide (VI) (91.0 g, 0.919 mol) in water / acetic acid solution (1: 4) was added portionwise to 2-chloro-2'-methoxy-5-nitrobenzhydrol (64.2 g, 0.219 mol) ), Wherein the temperature of the reaction mixture is maintained at 25 ° C to 35 ° C. The reaction mixture is then stirred at 25 ° C. to 35 ° C. for 1 hour, cooled, diluted with water and concentrated in vacuo to give a residue. The residue is diluted with water and extracted with methylene chloride. The organic extracts are combined, dried over anhydrous sodium sulfate, mixed with silica gel (10 g) and filtered. The filtrate is concentrated in vacuo to give an oil. A solution of this oil in a methanol / water solution is decolorized using charcoal and concentrated in vacuo to give a residue. The residue is column chromatographed using silica gel and methylene chloride / hexane solution to afford the title compound as a white solid.

Using essentially the same method, the following compounds are obtained:

Example 31

2-chloro-4-fluoro-5-nitrobenzoyl chloride

A mixture of 2-chloro-4-fluoro-5-nitrobenzoic acid (50.0 g, 0.228 mol) and N, N-dimethylformamide (5 drops) in 1,2-dichloroethane was added dropwise to oxalyl chloride (30.8 mL, 0.353 mol), reflux for 3 hours, cool and concentrate in vacuo to afford the title compound as an orange solid, which is confirmed by NMR spectral analysis.

Example 32

Preparation of 2'-chloro-4'-fluoro-5'-nitroacetophenone

Treat the methyl zinc chloride 2 M solution (5.00 mL, 10.1 mmol) in tetrahydrofuran dropwise with a solution of 2-chloro-4-fluoro-5-nitrobenzoyl chloride (2.00 g, 8.40 mmol) in tetrahydrofuran, Treat with tetrakis (triphenylphosphine) palladium (0) (0.400 g, 0.350 mmol), stir at room temperature for 1 hour and pour into 3 N hydrochloric acid. The resulting aqueous mixture is extracted with ethyl acetate. The organic extracts are combined, washed sequentially with water and saturated sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate and concentrated in vacuo to give a dingy liquid. Flash column chromatography of the liquid using silica gel and methylene chloride solution (4: 6) in hexanes gave the title compound as a gray solid (mp 66-68 ° C.) which was confirmed by NMR spectral analysis.

Example 33

Preparation of 6-amino-3-methyl-5-nitro-1,2-benzisothiazole

A mixture of 2'-chloro-4'-fluoro-5'-nitroacetophenone (12.0 g, 0.0552 mol), sulfur (1.77 g, 0.0552 mol), 30% ammonium hydroxide solution (100 mL, 0.856 mol) and methanol Into a steel cylinder, heated at 85 ° C. overnight, cooled, treated with additional sulfur (0.270 g) and 30% ammonium hydroxide solution (50 mL), heated at 85 ° C. overnight, cooled and filtered to give a solid Are removed and extracted with ethyl acetate. The organic extracts are combined, washed sequentially with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to give a solid. Flash column chromatography of the solid using silica gel and 0%, 1% and 2% solutions of diethyl ether in methylene chloride gave the title compound as an orange solid (4.19 g, mp 189-191 ° C.). Confirm by spectral analysis.

Using essentially the same method, the following compounds are obtained:

Example 34

Preparation of 6-chloro-3-methyl-5-nitro-1,2-benzisothiazole

A mixture of tert-butyl nitrite (3.30 mL, 0.0278 mol) and copper (II) chloride (2.98 g, 0.0222 mol) in acetonitrile was heated to 65 ° C. and partly 6-amino-3-methyl-5-nitro- Treat with 1,2-benzisothiazole (3.88 g, 0.0185 mol), stir at 65 ° C., cool to room temperature and pour into 20% hydrochloric acid. The resulting aqueous mixture is extracted with ethyl acetate. The organic extracts are combined, washed with 20% hydrochloric acid, dried over anhydrous magnesium sulfate and concentrated in vacuo to give a solid. Flash column chromatography of the solid using silica gel and methylene chloride / hexane solution S (1: 1 and 3: 1) gave the title compound as a pale yellow solid (2.54 g, mp 156-158 ° C.). Confirm by analysis.

Using essentially the same procedure, the following compounds are obtained:

Example 35

Preparation of 6-fluoro-3-methyl-5-nitro-1,2-benzisothiazole

6-chloro-3-methyl-5-nitro-1,2-benzisothiazole (2.25 g, 9.80 mmol), potassium fluoride (2.85 g, 49.0 mmol), and 18-crown-6 (1.50 g) in acetonitrile , 5.70 mmol) is heated in a sealed tube for 29 days, filtered to remove solids and partially concentrated in vacuo to give a liquid. The liquid is diluted with ethyl acetate, washed sequentially with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to give a dark brown solid. Flash column chromatography of the solids using silica gel and 10% to 50% ethyl acetate gradient in hexanes yields a yellow solid containing two components. Flash column chromatography of the yellow solid using silica gel and 50% to 70% methylene chloride gradient in hexanes gave the title compound as a pale yellow solid (0.870 g, mp 118-119 ° C.). Check it.

Using essentially the same procedure, the following compounds are obtained:

Example 36

Preparation of 5-amino-6-fluoro-3-methyl-1,2-benzisothiazole

A solution of 6-fluoro-3-methyl-5-nitro-1,2-benzisothiazole (0.740 g, 3.50 mmol), 5% acetic acid (25.0 mL) and ethyl acetate was heated to 65 ° C. and iron Treat with powder (0.980 g, 17.5 mmol), stir at 65 ° C. for 1 h, cool to rt and filter to remove solids. The organic phase was separated, washed sequentially with water, saturated sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to afford the title compound as an orange solid (0.610 g) which was analyzed by NMR spectral analysis. Check it.

Using essentially the same procedure, the following compounds are obtained:

Example 37

Preparation of 2-chloro-4-fluoro-5-nitrobenzophenone

A solution of 2-chloro-4-fluoro-5-nitrobenzoyl chloride (26.7 g, 0.112 mol) and benzene (12.0 mL, 0.134 mol) in 1,1,2,2-tetrachloroethane was heated to 0 ° C to 5 ° C. Cooled to, treated with aluminum chloride (18.1 g, 0.136 mol), stirred at about 8 ° C. for 15 minutes, heated to 50 ° C. and stirred at 50 ° C. for 1 hour, cooled to room temperature, ice water and Dilute with concentrated hydrochloric acid. The organic phase is separated, washed sequentially with water and saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate and concentrated in vacuo to give a solid. Flash column chromatography of the solid using silica gel and methylene chloride gives the title compound as an orange solid (30.8 g) which is confirmed by NMR spectral analysis.

Example 38

Preparation of 2,2'-dithiobis [5-nitrobenzoic acid]

The mixture of 2-chloro-5-nitrobenzoic acid (100 g, 0.496 mol) in ethanol was treated in portions with potassium tert-butoxide (55.5 g, 0.495 mol), diluted with additional ethanol and heated to reflux. Treated in portions with a solution prepared from sodium sulfide hexahydrate (60.0 g, 0.249 mol), sulfur (8.80 g, 0.274 mol) and water, refluxed for 2 hours, cooled to room temperature and treated with concentrated hydrochloric acid do. The resulting acid mixture is stirred for 1 hour and filtered to give a solid. The solid is washed with water and dried with air to give the title compound as a yellow powder, which is confirmed by NMR spectral analysis.

Example 39

Preparation of 5-nitro-1,2-benzisothiazol-3 (2H) -one

Mixture of 2,2'-dithiobis [5-nitrobenzoic acid] (44.6 g, 0.113 mol) and thionyl chloride (49.0 mL, 0.670 mol) in methylene chloride with N, N-dimethylformamide (0.800 mL) Treat, reflux overnight, concentrate in vacuo and dilute with 1,2-dichloroethane. The resulting organic solution is treated with bromine (22.5 mL, 0.436 mol), stirred at room temperature for 20 minutes, refluxed for 3.5 hours and concentrated in vacuo to give a residue. The solution of the residue in 1,2-dichloroethane is cooled in an ice-water bath, treated with concentrated ammonia (112 mL) for 15 minutes, stirred at room temperature for 16 hours, cooled in an ice-water bath and treated with concentrated hydrochloric acid. . The resulting aqueous mixture is stirred at room temperature for 1 hour and filtered to give a solid. The solid is washed with water and dried with air to give the title compound as a yellow solid, which is confirmed by NMR spectral analysis.

Example 40

Preparation of 3-chloro-5-nitro-1,2-benzisothiazole

5-nitro-1,2-benzisothiazol-3 (2H) -one (10.0 g, 0.0510 mol), phosphorus oxychloride (40.0 mL, 0.429 mol) and tributylamine (12.0 mL, 0.050 mol) The mixture is heated at 103-115 ° C. for 6 hours, stirred overnight at room temperature and poured into ice water. The resulting aqueous mixture is extracted with methylene chloride. The combined organic extracts are washed sequentially with water and saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate and concentrated in vacuo to give a gum. Column chromatography of the gum using silica gel and methylene chloride gave the title compound as an orange-yellow solid, which was confirmed by NMR spectral analysis.

Example 41

Preparation of ethyl α-cyano-5-nitro-1,2-benzisothiazole-3-acetate

Sodium ethoxide solution (previously prepared from ethanol and sodium (1.00 g, 0.0430 mol)) is cooled in an ice-acetone bath, treated in portions with ethyl cyanoacetate (4.51 g, 0.0398 mol), and at room temperature 30 Stir for minutes, treat with 3-chloro-5-nitro-1,2-benzisothiazole (4.27 g, 0.0199 mol), stir overnight at room temperature, cool to 0 ° C, drop by drop 10% hydrochloric acid ( 15.0 mL). The resulting aqueous mixture is stirred at room temperature for 1 hour and filtered to give a solid. The solid is washed with ethanol and dried with air to give the title compound as a yellow solid, which is confirmed by NMR spectral analysis.

Example 42

Preparation of ethyl 5-nitro-1,2-benzisothiazole-3-acetate

Ethyl α-cyano-5-nitro-1,2-benzisothiazole-3-acetate (6.67 g, 0.0229 mol) is added to a solution of acetyl chloride (67.0 mL) in ethanol. The reaction mixture is refluxed overnight, cooled and filtered to remove solids. The resulting filtrate is concentrated in vacuo to give a brown semisolid. The mixture of said semisolids in diethyl ether is stirred for 2 hours and filtered to give a solid. The solid is dried with diethyl ether and air to give the title compound as yellow crystals (1.04 g, mp 91-92 ° C.).

Example 43

Preparation of ethyl 5-amino-1,2-benzisothiazole-3-acetate

10% acetic acid solution (31.0 mL) was stirred at 50 ° C., treated with iron powder (0.656 g), and dropwise, ethyl 5-nitro-1,2-benzisothiazole-3-acetate (1.03) in ethyl acetate. g, 3.88 mmol), stirred at 50 ° C. for 2 hours, treated with additional iron powder (0.305 g), stirred at 50 ° C. for 15 minutes, and poured into saturated sodium bicarbonate solution. The resulting aqueous mixture is extracted with ethyl acetate. The combined organic extracts are washed sequentially with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give an oil. Using silica gel and methylene chloride, the oil is column chromatographed to give the title compound as a yellow oil.

Example 44

Of ethyl 5- [3,6-dihydro-2,6-dioxo-4- (trifluoromethyl) -1 (2H) -pyrimidinyl] -1,2-benzisothiazole-3-acetate Produce

Ethyl 5-amino-1,2-benzisothiazole-3-acetate (0.748 g, 3.16 mmol) and 2-dimethylamino-4- (trifluoromethyl) -6H-1,3-oxazine in acetic acid A mixture of -6-one (0.660 g, 3.17 mmol) is refluxed for 3 hours, concentrated in vacuo and diluted with saturated sodium bicarbonate solution. The resulting mixture is extracted with methylene chloride. The combined organic extracts are washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo to afford the title compound as a light brown (light brown) solid, which is confirmed by NMR spectral analysis.

Example 45

Ethyl 5- [3,6-dihydro-3-methyl-2,6-dioxo-4- (trifluoromethyl) -1 (2H) -pyrimidinyl] -1,2-benzisothiazole- Preparation of 3-acetate

Ethyl 5- [3,6-dihydro-2,6-dioxo-4- (trifluoromethyl) -1 (2H) -pyrimidinyl] -1,2-benz in N, N-dimethylformamide A mixture of isothiazole-3-acetate (0.643 g, 0.00160 mol) and potassium carbonate (0.243 g, 0.00170 mol) is stirred at room temperature for 90 minutes, treated with methane iodide (0.320 mL, 0.00500 mol) and at room temperature Stir overnight and dilute with water. The resulting aqueous mixture is extracted with methylene chloride. The organic extract is washed with water, dried over anhydrous magnesium sulfate and concentrated in vacuo to give a brown oil. The oil is column chromatographed using silica gel and a 10% solution of ethyl acetate in hexanes to afford the title compound as a pale brown solid (0.362 g, mp 150-152 ° C.).

Example 46

Preparation of 5-nitro-1,2-benzisothiazole-3-acetonitrile

A mixture of ethyl 5-nitro-1,2-benzisothiazole-3-acetate (5.00 g, 17.2 mmol), water (1.00 mL), and methyl sulfoxide (35.0 mL) was stirred at 107 ° C for 24 h and Stir for 2 days at room temperature and pour in ice water. The resulting aqueous mixture is stirred for 2 hours and filtered to give a solid. The solid is washed with water and dried with air to afford the title compound as a pale brown solid.

Example 47

Preparation of α, α-dimethyl-5-nitro-1,2-benzisothiazole-3-acetonitrile

A mixture of 5-nitro-1,2-benzisothiazole-3-acetonitrile (1.29 g, 5.89 mmol) in N, N-dimethylformamide is cooled to -9 ° C and sodium hydride (60% dispersion in oil) 1.00 g), stirred at −3 ° C. for 20 minutes, treated with methane iodide (5.00 mL), stirred at room temperature for 4 hours, and poured onto ice. The resulting aqueous mixture is treated with 10% hydrochloric acid and extracted with methylene chloride. The combined organic extracts are washed sequentially with water, saturated sodium bicarbonate solution and water, dried over anhydrous sodium sulfate and concentrated in vacuo to give a solid. Using silica gel and methylene chloride, the solid is column chromatographed to give the title compound as a yellow solid, which is confirmed by NMR spectral analysis.

Example 48

Preparation of ethyl α, α-dimethyl-5-nitro-1,2-benz-isothiazole-3-acetate

a mixture of α, α-dimethyl-5-nitro-1,2-benzisothiazole-3-acetonitrile (0.913 g, 3.69 mmol), water (0.450 mL), concentrated sulfuric acid (4.55 mL) and ethanol (9.10 mL) Reflux for 1 h, cool and pour on ice. The resulting aqueous mixture is neutralized with saturated sodium bicarbonate solution and extracted with methylene chloride. The organic extract is washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo to give a solid. Using silica gel and methylene chloride, the solid is column chromatographed to give the title compound as pale yellow crystals.

Example 49

Preparation of ethyl 5-amino-α, α-dimethyl-1,2-benzisothiazole-3-acetate

Ethyl α, α-dimethyl-5-nitro-1,2-benzisothiazole-3-acetate (0.714 g, 2.42 mmol), iron powder (0.500 g), 10% acetic acid (23.0 mL) and ethyl acetate ( 23.0 mL) is stirred at 54-58 ° C. for 1 hour, cooled and poured into saturated sodium hydrogen carbonate solution. The resulting aqueous mixture is extracted with ethyl acetate. The combined organic extracts are washed sequentially with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give a yellow oil. Using a 10% solution of ethyl acetate in silica gel and methylene chloride, the oil is column chromatographed to give the title compound as a light brown oil, which is confirmed by NMR spectral analysis.

Example 50

Ethyl 5- [3,6-dihydro-3-methyl-2,6-dioxo-4- (trifluoromethyl) -1 (2H) -pyrimidinyl] -α, α-dimethyl-1,2 Preparation of Benzisothiazole-3-acetate

Ethyl 5-amino-α, α-dimethyl-1,2-benzisothiazole-3-acetate (0.546 g, 2.06 mmol) and 2-dimethylamino-4- (trifluoromethyl) -6H- in acetic acid A mixture of 1,3-oxazin-6-one (0.430 g, 2.06 mmol) is refluxed for 4.5 h, concentrated in vacuo and diluted with saturated sodium hydrogen carbonate solution. The resulting aqueous mixture is extracted with methylene chloride. The combined organic extracts are washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo to give a brown foam. The solution of the foam in N, N-dimethylformamide was treated with potassium carbonate (0.312 g, 2.25 mmol), stirred for 1 hour, treated with methane iodide (0.420 mL, 6.70 mmol) and stirred overnight at room temperature Pour into iced water containing 20 mL of concentrated hydrochloric acid. The resulting aqueous mixture is extracted with methylene chloride. The combined organic extracts are washed sequentially with 10% hydrochloric acid, water, saturated sodium bicarbonate solution and water, dried over anhydrous sodium sulfate and concentrated in vacuo to give a brown oil. The oil is column chromatographed using a 33% solution of ethyl acetate in silica gel and methylene chloride to give a pink foam which is recrystallized from ethanol to give the title compound as pink crystals. mp 164-167 ° C.

Example 51

Preparation of 5-amino-3-chloro-1,2-benzisothiazole

A solution of 3-chloro-5-nitro-1,2-benzisothiazole (2.00 g) in toluene was treated with iron powder (8.40 g, 325 mesh) and concentrated hydrochloric acid (8 drops) and heated to reflux, Treat dropwise with water (8.00 mL), reflux for 35 minutes, cool to room temperature and filter through diatomaceous earth. The resulting filtrate is concentrated in vacuo to give a residue. The residue is flash column chromatographed using silica gel and ethyl acetate / hexane solution (1: 1) to afford the title compound.

Example 52

3- (3-Chloro-1,2-benzisothiazol-5-yl) -6- (trifluoromethyl) -2,4 (1H, 3H) -pyrimidinedione

5-amino-3-chloro-1,2-benzisothiazole (1.10 g) and 2-dimethylamino-4- (trifluoromethyl) -6H-1,3-oxazine in acetic acid (15.1 mL) The mixture of -6-one (1.38 g) is stirred at 90-105 ° C for 2 hours, cooled to room temperature and filtered to give 0.500 g of the title compound as a solid. The resulting filtrate is diluted with water and filtered to afford 1.11 g of additional title compound.

Example 53

Preparation of 3- (3-chloro-1,2-benzisothiazol-5-yl) -1-methyl-6- (trifluoromethyl) -2,4 (1H, 3H) -pyrimidinedione

3- (3-Chloro-1,2-benzisothiazol-5-yl) -6- (trifluoromethyl) -2,4 (1H, 3H) -pyrimidinedione in N, N-dimethylformamide (1.06 g), a mixture of potassium carbonate (0.470 g) and methane iodide (0.500 mL) was stirred at room temperature for 90 minutes, treated with additional methane iodide (0.500 mL), stirred at room temperature for 15 minutes, and with water Dilute. The resulting aqueous mixture is filtered to give a solid. The solid is washed with water and dried in a vacuum oven at room temperature to give the title compound as a solid, which is confirmed by NMR spectral analysis.

Example 54

Preparation of [(5-nitro-1,2-benzisothiazol-3-yl) -oxy] acetonitrile

A mixture of 5-nitro-1,2-benzisothiazol-3 (2H) -one (17.5 g, 89.2 mmol) in N, N-dimethylformamide was treated with potassium carbonate (18.5 g, 134 mmol), Stir at room temperature for 30 minutes, treat with bromoacetonitrile (16.0 g, 133 mmol), stir overnight at room temperature and pour on ice. The resulting aqueous mixture is acidified with hydrochloric acid to pH 3 and extracted with ethyl acetate. The combined organic extracts are washed sequentially with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to give a solid. Column chromatography on the solid using silica gel and methylene chloride gives the title compound as a yellow solid (15.0 g, mp 123-124.5 ° C.).

Using essentially the same method, the following compounds are obtained:

Example 55

Preparation of [(5-amino-1,2-benzisothiazol-3-yl) -oxy] acetonitrile

A mixture of iron powder (13.0 g, 0.233 mol) in 5% acetic acid solution (65.0 mL) was heated to 50 ° C. and partially [(5-nitro-1,2-benzisothiazol-3-yl) oxy ] Treat with a mixture of acetonitrile (11.0 g, 0.047 mol), acetic acid (100 mL) and ethyl acetate (65.0 mL), reflux for 2 hours, cool to 40 ° C. and filter to remove solids. The phases are separated and the aqueous phase is extracted with ethyl acetate. The organic phase and the organic extracts are combined, washed sequentially with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to afford the title compound as an oil, which is confirmed by NMR spectral analysis.

Using essentially the same method, the following compounds are obtained:

Example 56

{{5- [3,6-dihydro-2,6-dioxo-4- (trifluoromethyl) -1 (2H) -pyrimidinyl] -1,2-benzisothiazol-3-yl } Oxy} Preparation of Acetonitrile

[(5-amino-1,2-benzisothiazol-3-yl) oxy] -acetonitrile (4.30 g, 21.0 mmol) and 2-dimethylamino-4- (trifluoromethyl) -6H in acetic acid A mixture of -1,3-oxazine-6-one (4.37 g, 21.0 mmol) is refluxed for 3 hours, stirred overnight at room temperature and poured into ice water. The resulting aqueous mixture is filtered to give a solid. The solid is washed with water and dried overnight in a vacuum oven at 55 ° C. to afford the title compound as a brown solid (2.63 g, mp 254-258 ° C.).

Using essentially the same method, the following compounds are obtained:

Example 57

{{5- [3,6-Dihydro-3-methyl-2,6-dioxo-4- (trifluoromethyl) -1 (2H) -pyrimidinyl] -1,2-benzisothiazole Preparation of -3-yl} oxy} acetonitrile

{{5- [3,6-dihydro-2,6-dioxo-4- (trifluoromethyl) -1 (2H) -pyrimidinyl] -1,2- in N, N-dimethylformamide A mixture of benzisothiazol-3-yl} oxy} acetonitrile (2.63 g, 7.15 mmol) and potassium carbonate (1.97 g, 14.3 mmol) is stirred for 30 minutes and treated with methane iodide (2.03 g, 14.3 mmol) The mixture is stirred overnight at room temperature and poured into ice water. The resulting aqueous mixture is filtered to give a solid. The solid is dissolved in ethyl acetate and the resulting solution is washed sequentially with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to give a brown solid. The silica is column chromatographed using silica gel and methylene chloride to give a yellow solid. The yellow solid is recrystallized from methylene chloride / hexane solution to give the title compound as a gray solid, mp 265-266 ° C.

Using essentially the same method, the following compounds are obtained:

Example 58

Preparation of 5-nitro-1,2-benzisothiazole

To a mixture of ammonium hydroxide (1000 ml) and N, N-dimethylformamide is added 2-chloro-5-nitrobenz-aldehyde (300 g, 1.62 mol) and sulfur (54.4 g, 1.70 mol). The mixture is slowly heated to 90 ° C., stirred at 90 ° C. for 1 hour, cooled to room temperature, poured into ice and diluted with water. Filtration affords the title compound as a yellow solid (277.1 g, 94.9%).

Example 59

Preparation of 3-chloro-5-nitro-1,2-benzisothiazole

A suspension of 5-nitro-1,2-benzisothiazole (271 g, 1.50 mol) in acetic acid is heated to 80 ° C. to make a solution. The heat source is removed and chlorine gas is continuously added at 70-80 ° C. over 6 hours until the mixture is saturated. The mixture is cooled to room temperature and stirred overnight. Filtration affords the title compound as a yellow crystalline solid (237 g, 73.6%) which is confirmed by NMR spectral analysis.

Example 60

2'-chloro-2-methyl-2-carboethoxy propiophenone

A mixture of 2-chlorobenzoyl chloride (52.2 g, 0.298 mol), ethyl 2-bromoisobutyrate (58.2 g, 0.298 mol) and ether is added in portions to zinc foil (19.5 g, 0.298 mol), The resulting mixture is stirred for 3 hours while refluxing and overnight at room temperature. The mixture is poured into cold, diluted sulfuric acid and the organic layer is washed with saturated sodium bicarbonate and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to give a yellow oil. Chromatography the oil with silica gel and hexanes: ethyl acetate to afford the title compound as a colorless oil (41.8 g, 55.1%).

Example 61

Preparation of 2'-chloro-5'-nitro-2-methyl-2-carboethoxypropiophenone

2'-Chloro-2-methyl-2-carboethoxypropiophenone (4.00 g, 0.01570 mol) was added to concentrated sulfuric acid (15.0 ml) at 5 ° C, followed by concentrated nitric acid (90%, 0.740 ml, 0.0204 mol). Add drop by drop. After stirring for 5 minutes, the mixture is poured onto ice and extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford the title compound as a yellow oil (3.90 g, 83.0%) which was analyzed by NMR spectrum Confirm with

Example 62

Preparation of ethyl α, α-dimethyl-5-nitro-1,2-benzisothiazole-3-acetate

A mixture of 2'-chloro-5'-nitro-2-methyl-2-carboethoxypropiophenone (3.24 g, 0.00108 mol), N, N-dimethylformamide and sulfur (0.350 g, 0.00109 mol) Treat dropwise with ammonium hydroxide (9 mL), heat to 70-80 ° C. and stir at that temperature for 2 hours, cool to room temperature and dilute with water. Filtration affords the title compound as a solid (2.49 g, 78.3%, mp 75-77 ° C.). This is confirmed by NMR spectral analysis.

Example 63

Preparation of 1-benzothiophene-2,3-dione

To a solution of thiophenol (100 g, 0.907 mol) in ether is added dropwise to a solution of oxalyl chloride (175 g, 1.38 mol) in ether. The mixture is stirred under reflux for 2 hours and concentrated in vacuo. The residue is transferred into methylene chloride and cooled to 0 ° C. Aluminum chloride (145 g, 1.09 mol) is added in portions so that the temperature does not exceed 25 ° C. The resulting mixture is stirred at reflux for 30 minutes, cooled to room temperature and poured into ice water with stirring. The organic layer was washed with saturated sodium bicarbonate, water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give an orange solid which was recrystallized from methylene chloride: hexane to give the title compound (102 g, 69.0%) and confirmed by NMR spectral analysis.

Example 64

Preparation of 1,2-benzisothiazole-3-carboxamide

At 5-10 ° C., 1-benzothiophene-2,3-dione (87.0 g, 0.530 mol) is added to ammonium hydroxide (1.78 l) followed by hydrogen peroxide (30% aqueous solution, 178 ml). The resulting mixture is filtered to give a yellow solid which is dried (77.0 g, 81.7%) and identified as the title compound by NMR and IR spectral analysis.

Example 65

Preparation of 3-cyano-5-nitro-1,2-benzisothiazole

A solution of 1,2-benzisothiazole-3-carboxamide (12.0 g, 0.0674 mol) in concentrated sulfuric acid was added dropwise at 0-5 ° C. so that the temperature did not exceed 10 ° C. (90%, 4.12 mL). Treatment, stirred at 5 ° C. for 1 hour, and poured into ice water with vigorous stirring. The resulting suspension is filtered to give a solid. The solid is dried and recrystallized from acetonitrile to give a white solid (10.0 g) which is treated with phosphorus oxychloride (60.0 mL). The resulting mixture is stirred at 90-100 ° C. for 90 minutes, cooled to room temperature, slowly poured into ice water with stirring and filtered to give a solid. Recrystallization of the solid from methylene chloride: hexanes affords the title compound as an orange solid (8.00 g, 87.9%, mp 168-170 ° C.) which is confirmed by NMR and IR spectral analysis.

Example 66

Preparation of 2,4-difluoro-5-nitrobenzoyl chloride

A mixture of 2,4-difluoro-5-nitrobenzoic acid (100.0 g, 0.492 mol), methylene chloride and N, N-dimethylformamide (0.600 ml) dropwise to oxalyl chloride (94.0 g, 0.739 mol) Add to The resulting mixture was stirred at reflux for 3.25 h, cooled to rt and concentrated in vacuo to afford the title compound as a brown oil (111 g, 95.2%).

Example 67

Preparation of 2 ', 4'-difluoro-2-methoxy-5-methyl-5'-nitrobenzophenone

A mixture of aluminum chloride (62.3 g, 0.467 mol) and methylene chloride is cooled to -20 ° C to -10 ° C, treated with 4-methylanisole (60.1 g, 0.492 mol), dropwise over 10 minutes, 2, Treat with a mixture of 4-difluoro-5-nitrobenzoyl chloride (111 g, 0.468 mol) and methylene chloride, warm to 0 ° C, stir overnight at ambient temperature, pour slowly on ice with stirring, and with methylene chloride Dilute. The organic layer is washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to give a solid. The solid is recrystallized from acetonitrile to give the title compound as a yellow solid (82.1 g, 54.0%) which is confirmed by NMR spectral analysis.

Example 68

Preparation of 3- (6-methoxy-m-tolyl) -6-amino-5-nitro-1,2-benzisothiazole

Ammonium hydroxide (330 mL) was added to 2 ', 4'-difluoro-2-methoxy-5-methyl-5'-nitrobenzophenone (60.0 g, 0.186 mol), sulfur (6.25 g, 0.195 mol) on an ice bath. ) And N, N-dimethylformamide. The resulting mixture is warmed to 35 ° C. and slowly heated to 81 ° C. over 2 hours, cooled to room temperature and poured into water. The resulting solid is taken up in ethyl acetate and N, N-dimethylformamide and washed with water. The organic layer is concentrated in vacuo to afford the title compound, which is confirmed by NMR spectral analysis.

Example 69

Preparation of 3- (6-methoxy-m-tolyl) -6-chloro-5-nitro-1,2-benzisothiazole

A mixture of tert-butyl nitrite (5.90 g, 0.0571 mol), copper chloride (6.20 g, 0.0457 mol) and acetonitrile was heated to 65-75 ° C. and 3- (6-methoxy-m-tolyl over 10 minutes ) -6-amino-5-nitro-1,2-benzisothiazole (12.0 g, 0.0381 mol), stirred at 67-75 ° C. for 2 hours, tert-butyl nitrite (1.50 mL) and chloride Treat with copper (1.00 g), stir for 40 minutes at 67-75 ° C., cool to room temperature and dilute with ethyl acetate. The organic layer is washed with 10% hydrochloric acid and filtered. The filtrate is washed with water and concentrated in vacuo to give the title compound as a solid (10.6 g, 83.1%), which is confirmed by NMR and IR spectral analysis.

Example 70

Preparation of 3- (6-methoxy-m-tolyl) -6-fluoro-5-nitro-1,2-benzisothiazole

3- (6-methoxy-m-tolyl) -6-chloro-5-nitro-1,2-benzisothiazole (7.30 g, 0.0218 mol), potassium fluoride (6.33 g, 0.109 mol), 18-crown The mixture of -6 (2.31 g, 0.0872 mol) and sulfolane is stirred at 154 ° C. for 19 hours, cooled to room temperature and poured into ice water. The resulting solid is filtered and chromatographed with methylene chloride on silica gel to give a solid which is recrystallized from acetonitrile to give a pale brown powder. The powder is recrystallized from ethyl acetate to give the title compound as a light brown solid (2.09 g, 29.9%) which is confirmed by NMR spectral analysis.

Example 71

Preparation of 5-amino-4-bromo-6-fluoro-3-methyl-1,2-benzisothiazole

N-bromosuccinimide (0.586 g, 0.00329) in a solution of 5-amino-6-fluoro-3-methyl-1,2-benzisothiazole (0.600 g, 0.00329 mol) in 1,2-dichloroethane mol) is added followed by 1,1'-azobis (cyclohexanecarbonitrile) (0.0200 g). The mixture is stirred at 70 ° C. for 2 hours, additional N-bromosuccinimide (0.240 g, 0.00135 mol) is added and the mixture is stirred at 70 ° C. for 40 minutes. The mixture is then cooled to room temperature, filtered and concentrated in vacuo to give a residue. The residue is chromatographed on silica gel to give the title compound (0.870 g, 100%) which is confirmed by NMR spectral analysis.

Claims (42)

(a) reacting a β-amino-β- (perfluoroalkyl) acrylate compound having formula II with a carbamoyl chloride compound having formula III and a base to form a urea compound having formula IV ; And (b) reacting the urea of Formula IV with phosphorus pentahalide or oxalyl halide, Process for preparing 2- (N, N-2 substituted) amino-4- (perfluoroalkyl) -1,3-oxazin-6-one compound having formula (I) <Formula I> Where Z and Z ₁ are each independently C ₁ -C ₈ alkyl, or Z and Z ₁ together with the atoms to which they are attached may form a 4 to 7 membered ring, wherein ZZ ₁ is — (CH ₂ ) ₂ O (CH ₂ ) ₂ -or-(CH ₂ ) _m , where m is an integer of 3, 4, 5 or 6; n is an integer of 1, 2, 3, 4, 5 or 6, <Formula II> Wherein n is as defined above and Z ₂ is optionally selected from any combination of C ₁ -C ₆ alkyl or benzyl [1 to 3 halogen, C ₁ -C ₄ alkyl or C ₁ -C ₄ haloalkyl groups Substituted on a phenyl ring; <Formula III> Wherein Z and Z ₁ are as defined above; <Formula IV> . The method of claim 1, wherein the double bond of the compounds of Formula II and IV is mainly in the (Z) type configuration. The method of claim 1, wherein the base is composed of alkali metal hydride, alkali metal C ₁ -C ₆ alkoxide, alkali metal hydroxide, alkali metal carbonate, alkaline earth metal hydroxide, alkaline earth metal carbonate and lithium base Selected from the group consisting of: The method of claim 3, wherein the base is selected from the group consisting of alkali metal hydrides and alkali metal C ₁ -C ₆ alkoxides. The method of claim 4, wherein the base is selected from the group consisting of sodium hydride, sodium tert-butoxide and potassium tert-butoxide. The method of claim 1 wherein said phosphorus pentahalide is phosphorus pentachloride and said oxalyl halide is oxalyl chloride. The method of claim 1, wherein the β-amino-β- (perfluoroalkyl) acrylate is reacted with the base and carbamoyl chloride in the presence of a first solvent, and the urea is in the presence of a second solvent, Reacting with said phosphorus pentahalide or oxalyl halide. 8. The process of claim 7, wherein the first solvent is selected from the group consisting of carboxylic acid amides, ethers, nitriles and dialkyl sulfoxides and mixtures thereof; Said second solvent is selected from the group consisting of phosphorus oxyhalides, aromatic hydrocarbons, halogenated aromatic hydrocarbons, carboxylic acid amides, aliphatic hydrocarbons and halogenated aliphatic hydrocarbons and mixtures thereof. The method of claim 8, wherein the first solvent is N, N-dimethylformamide. The method of claim 1, wherein the β-amino-β- (perfluoroalkyl) acrylate is reacted with the base and carbamoyl chloride at a temperature of about −20 ° C. to 80 ° C. and the urea is about 0 ° C. to about Reacting with said phosphorus pentahalide or oxalyl halide at a temperature of 100 ° C. The method of claim 10, wherein the β-amino-β- (perfluoroalkyl) acrylate is reacted with the base and carbamoyl chloride at a temperature of about 0 ° C. to 50 ° C., and the urea is between about 20 ° C. and about Reacting with said phosphorus pentahalide or oxalyl halide at a temperature of 50 ° C. The compound of claim 1, wherein Z and Z ₁ are each independently C ₁ -C ₆ alkyl; Z ₂ is C ₁ -C ₄ alkyl; n is one. The compound of claim 12, wherein Z and Z ₁ are the same and are methyl or ethyl; Z ₂ is methyl or ethyl; n is one. 2- (N, N-2 substituted) amino-4- (perfluoroalkyl) having the formula (I) which comprises reacting a urea compound having the formula (IV) with phosphorus pentahalide or oxalyl chloride Process for the preparation of -1,3-oxazine-6-one compound: <Formula I> Where Z and Z ₁ are each independently C ₁ -C ₈ alkyl, or Z and Z ₁ together with the atoms to which they are attached may form a 4 to 7 membered ring, wherein ZZ ₁ is — (CH ₂ ) ₂ O (CH ₂ ) ₂ -or-(CH ₂ ) _m , where m is an integer of 3, 4, 5 or 6; n is an integer of 1, 2, 3, 4, 5 or 6; <Formula IV> Wherein Z and Z ₁ are as previously described and Z ₂ is any of C ₁ -C ₆ alkyl or benzyl [1 to 3 halogen, C ₁ -C ₄ alkyl or C ₁ -C ₄ haloalkyl groups And optionally substituted on a phenyl ring. The method of claim 14, wherein the double bond of the compound of formula IV is mainly in the (Z) type configuration. 15. The method of claim 14, wherein said phosphorus pentahalide is phosphorus pentachloride and said oxalyl halide is oxalyl chloride. The method of claim 14, wherein said urea is reacted with said phosphorus pentahalide or oxalyl halide in the presence of a solvent. 18. The method of claim 17, wherein the solvent is selected from the group consisting of phosphorus oxyhalides, aromatic hydrocarbons, halogenated aromatic hydrocarbons, carboxylic acid amides, aliphatic hydrocarbons and halogenated aliphatic hydrocarbons and mixtures thereof. The method of claim 14, wherein said urea is reacted with said phosphorus pentahalide or oxalyl chloride at a temperature of about 0 ° C. to 100 ° C. 16. 20. The method of claim 19, wherein the urea is reacted with the phosphorus pentahalide or oxalyl chloride at a temperature of about 20 ° C to 50 ° C. The compound of claim 14, wherein Z and Z ₁ are each independently C ₁ -C ₆ alkyl; Z ₂ is C ₁ -C ₄ alkyl; n is one. The compound of claim 21, wherein Z and Z ₁ are the same and are methyl or ethyl; Z ₂ is methyl or ethyl; n is one. Urea compounds having Formula IV: <Formula IV> Wherein Z and Z ₁ are each independently C ₁ -C ₈ alkyl, or Z and Z ₁ together with the atoms to which they are attached may form a 4 to 7 membered ring, wherein ZZ ₁ is — (CH ₂ ) ₂ O (CH ₂ ) ₂ -or-(CH ₂ ) _m , where m is an integer of 3, 4, 5 or 6; n is an integer of 1, 2, 3, 4, 5 or 6; Z ₂ is C ₁ -C ₆ alkyl or benzyl [optionally substituted on any phenyl ring with any combination of one to three halogen, C ₁ -C ₄ alkyl or C ₁ -C ₄ haloalkyl groups]. 24. The compound of claim 23, wherein said double bond is primarily a (Z) type coordination. The compound of claim 23, wherein Z and Z ₁ are each independently C ₁ -C ₆ alkyl; Z ₂ is C ₁ -C ₄ alkyl; n is 1; The compound of claim 25, wherein Z and Z ₁ are the same and are methyl or ethyl; Z ₂ is methyl or ethyl. The compound of claim 23 selected from the group consisting of: Ethyl 3-[(N, N-dimethylcarbamoyl) amino] -4,4,4-trifluorocrotonate, (Z)-; Methyl 3-[(N, N-dimethylcarbamoyl) amino] -4,4,4-trifluorocrotonate, (Z)-; Ethyl 3-[(N, N-diethylcarbamoyl) amino] -4,4,4-trifluorocrotonate, (Z)-; Methyl 3-[(N, N-diethylcarbamoyl) amino] -4,4,4-trifluorocrotonate, (Z)-; Ethyl 3-[(N-pyrrolodinecarbonyl) amino] -4,4,4-trifluorocrotonate, (Z)-; And Methyl 3-[(N-pyrrolodinecarbonyl) amino] -4,4,4-trifluorocrotonate, (Z)-. (a) reacting a urea compound having formula IV with phosphorus pentahalide or oxalyl halide to yield 2- (N, N-2 substituted) amino-4- (perfluoroalkyl) -1 having formula I, Preparing a 3-oxazine-6-one compound; (b) reacting the 2- (N, N-2 substituted) amino-4 (perfluoroalkyl) -1,3-oxazin-6-one with an amine compound of formula VI in the presence of an acid or a base to Forming a 6- (perfluoroalkyl) uracil compound of formula V wherein ₃ is hydrogen; And (c) optionally, alkylating a compound of Formula V wherein Z ₃ is hydrogen, Process for preparing 6- (perfluoroalkyl) uracil compound having formula <Formula V> Wherein n is an integer of 1, 2, 3, 4, 5 or 6; Z ₃ is hydrogen or C ₁ -C ₆ alkyl; Q is a C ₁ -C ₆ alkyl group or an optionally substituted phenyl, benzyl, heteroaryl or methyleneheteroaryl group, <Formula IV> Wherein Z and Z ₁ are each independently C ₁ -C ₈ alkyl, or Z and Z ₁ together with the atoms to which they are attached may form a 4 to 7 membered ring, wherein ZZ ₁ is — (CH ₂ ) ₂ O (CH ₂ ) ₂ -or-(CH ₂ ) _m , where m is an integer of 3, 4, 5 or 6; Z ₂ is C ₁ -C ₆ alkyl or benzyl [optionally substituted on any phenyl ring with any combination of one to three halogen, C ₁ -C ₄ alkyl or C ₁ -C ₄ haloalkyl groups]; n is as described above; <Formula I> ; <Formula VI> QNH ₂ , where Q is as defined above. 29. The method of claim 28, wherein the double bond of the compound of formula IV is primarily in the (Z) type configuration. 29. The method of claim 28, wherein said phosphorus pentahalide is phosphorus pentachloride and said oxalyl halide is oxalyl chloride. 29. The method of claim 28, wherein said acid is selected from the group consisting of organic acids and mineral acids. 32. The method of claim 31, wherein the organic acid is C ₁ -C ₆ alkanoic acid and the mineral acid is selected from the group consisting of hydrochloric acid, sulfuric acid and phosphoric acid. 32. The method of claim 31, wherein said acid is acetic acid. The method of claim 28, wherein said base is selected from the group consisting of tri (C ₁ -C ₆ alkyl) amines, heterocyclic tert-amines and alkali metal C ₁ -C ₆ alkoxides. The method of claim 34, wherein the base is selected from the group consisting of 1,8-diazabicyclo [5.4.0] undec-7-ene and 1,5-diazabicyclo [4.3.0] non-5-ene How to be. The method of claim 28, wherein the urea is reacted with the phosphorus pentahalide or oxalyl halide, optionally in the presence of a first solvent, and the 2- (N, N-2 substituted) amino-4- (perfluoro Alkyl) -1,3-oxazin-6-one is reacted with the amine and the acid in the presence of a second solvent. 37. The method of claim 36, wherein the first solvent is selected from the group consisting of phosphorus oxyhalides, aromatic hydrocarbons, halogenated aromatic hydrocarbons, carboxylic acid amides, aliphatic hydrocarbons and halogenated aliphatic hydrocarbons and mixtures thereof; The second solvent is selected from the group consisting of carboxylic acid amides, dialkyl sulfoxides, aromatic hydrocarbons, halogenated aromatic hydrocarbons, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons, alkanoic acids, ketones, ethers, nitriles and water and mixtures thereof How to be. The method of claim 28, wherein the urea is reacted with the phosphorus pentahalide or oxalyl chloride at a temperature of about 0 ° C. to 100 ° C .; Reacting the 2- (N, N-2 substituted) amino-4- (perfluoroalkyl) -1,3-oxazin-6-one with the amine and the acid at a temperature of about 20 ° C. to 150 ° C. How to. The method of claim 28, wherein step (c) comprises reacting a compound of formula V wherein Z ₃ is hydrogen with an alkyl halide of formula VII or a dialkylsulfate ester of formula VIII in the presence of a base. <Formula VII> XZ ₃ <Formula VIII> Wherein X is chlorine, bromine or iodine and Z ₃ is C ₁ -C ₆ alkyl. The method of claim 28, n is 1; Z ₃ is hydrogen or C ₁ -C ₄ alkyl; Q is ego; G is CH ₂ or a bond; G ₁ is CX ₅ or N; G ₂ is CX ₄ or N; X ₁ is a C ₁ -C ₆ alkyl group optionally substituted with hydrogen, halogen or one epoxy group; X ₂ is hydrogen, halogen NRR ₁ , CO ₂ R ₂ , C (O) R ₃ , OR ₄ , SO ₂ R ₅ , SO ₂ NR ₆ R ₇ , C (R ₈ ) (OR ₉ ) ₂ , C (R ₁₀ ) = NOR ₁₁ , C (R ₁₂ ) = C (R ₁₃ ) -C (OR ₁₄ ) = NOR ₁₅ , CH ₂ O-NCO ₂ R ₁₆ , 1,3-dioxolane optionally substituted with one C ₁ -C ₆ alkoxy group or one or two C ₁ -C ₄ alkyl groups, 1, 3-dioxolinone, optionally substituted with one C ₁ -C ₆ alkoxy group or one or two C ₁ -C ₄ alkyl groups, Or C ₁ -C ₄ alkyl optionally substituted with one CO ₂ R ₂ group and one halogen atom; X ₃ is hydrogen, halogen, C ₁ -C ₄ haloalkyl, CO ₂ R ₁₇ , cyano, C ₁ -C ₄ haloalkoxy, OR ₁₈ or C ₁ -C ₄ alkyl, or X ₁ and X ₂ together with the atoms to which they are attached may form a five or six membered ring, wherein X ₁ X ₂ or X ₂ X ₁ is represented as follows: —OC (R ₂₀₎ (R _21- O-, -CH ₂ S (O) _p N (R ₂₂ )-, -SC (R ₂₃ ) = N-, -CH = CH-CH (R ₁₁ ) O-, -OC (O) N- , -SC (R ₂₄ ) = N-, -ON (R ₂₅ ) C (O)-, -OC (CO ₂ R ₂₆ ) = C (R ₂₇ )-, -NC (R ₂₈ ) = C (SR ₂₉ )-, -CH = C (CO ₂ R ₃₀ ) O-, -CH ₂ CH (R ₃₁ ) O- or -OC (R ₃₂ ) (R ₃₃ ) C (O)-], or X ₂ and X ₃ together with the atoms to which they are attached may form a five or six membered ring, where X ₂ X ₃ or X ₃ X ₂ is represented as: -NC (R ₃₄ ) = NC (S)-, -N (R ₃₅ ) N = C (R ₃₆ )-, -N (R ₃₇ ) C (R ₃₈ ) = N-, -N (R ₃₈ ) C (O) CH ₂ 0-, -N (R ₃₉ ) C (O) CH = CH-, -SN = C (R ₄₀ )-, -ON = C (R ₄₁ )-, -N = NN (R ₄₂ )-, -C (R ₄₃ ) (R ₄₄ ) C (O) N (R ₄₅ )-or -N (R ₄₆ ) C (O) C (R ₄₇ ) (R ₄₈ )-]; X ₄ is hydrogen, halogen or OR ₁₉ ; X ₅ is hydrogen or halogen; R, R ₅₆ , R ₆₄ , R ₆₉ , R ₇₀ , R ₇₇ and R ₉₁ are each independently hydrogen, SO ₂ R ₄₉ , C ₁ -C ₄ alkyl, C ₃ -C ₇ cycloalkyl, C ₃ -C ₆ Alkenyl, C ₃ -C ₆ alkynyl, phenyl or benzyl; R ₁ is hydrogen, SO ₂ R ₅₀ , C (O) R ₅₁ , amino, or C ₁ -C ₄ alkyl optionally substituted with CO ₂ R ₅₂ or C (O) R ₅₃ ; R ₂ , R ₁₆ , R ₁₇ , R ₂₆ , R ₃₀ , R ₆₈ , R ₇₅ , R ₇₆ , R ₈₂ and R ₈₈ are each independently hydrogen, C ₁ -C ₈ haloalkyl, C ₃ -C ₈ alkenyl , C ₃ -C ₆ alkynyl, phenyl, benzyl, furfuryl, pyridyl, thienyl, C ₁ -C ₈ alkyl optionally substituted with CO ₂ R ₅₄ , morpholine or C (O) R ₅₅ , or Alkali metal, alkaline earth metal, ammonium or organic ammonium cation; R ₃ , R ₆₆ , R ₆₇ , R ₈₁ , R ₈₅ and R ₈₉ are each independently hydrogen, C ₁ -C ₆ alkyl, C ₃ -C ₆ alkenyl, C ₃ -C ₆ alkynyl, NR ₅₆ R ₅₇ , Phenyl or benzyl; R ₄ , R ₁₈ , R ₁₉ and R ₆₅ are each independently hydrogen, C ₁ -C ₆ alkyl, C ₃ -C ₆ alkenyl, C ₃ -C ₆ alkynyl, C ₁ -C ₄ haloalkyl, C ( O) R ₅₈ , C (S) R ₅₉ or benzyl; R ₅ and R ₇₂ are each independently C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, NR ₆₀ R ₆₁ , imidazole or indazole; R ₆ , R ₁₁ , R ₁₂ , R ₁₄ , R ₁₅ , R ₂₀ , R ₂₁ , R ₂₂ , R ₂₅ , R ₂₈ , R ₂₉ , R ₃₁ , R ₃₂ , R ₃₃ , R ₃₅ , R ₄₅ , R ₄₆ , R ₆₃ and R ₈₀ are each independently hydrogen or C ₁ -C ₄ alkyl; R ₇ is hydrogen, C ₃ -C ₆ alkenyl, C ₃ -C ₆ alkynyl, benzyl, or cyano or C ₁ -C ₄ alkyl optionally substituted with C (O) R ₆₂ ; R ₈ and R ₂₇ are each independently hydrogen, C ₁ -C ₄ alkyl or C ₁ -C ₄ alkoxy; R ₉ and R ₉₀ are each independently C ₁ -C ₆ alkyl; R ₁₀ is hydrogen, C ₁ -C ₆ alkyl, phenyl or benzyl; R ₁₃ , R ₂₄ and R ₃₆ are each independently hydrogen, C ₁ -C ₆ alkyl or halogen; R ₂₃ is hydrogen or NR ₆₃ R ₆₄ ; R ₃₄ is hydrogen, C ₁ -C ₄ alkyl or C ₁ -C ₄ haloalkyl; R ₃₇ is hydrogen, C ₁ -C ₄ alkyl or C ₂ -C ₈ alkoxyalkyl; R ₃₈ and R ₃₉ are each independently hydrogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₃ -C ₆ alkenyl or C ₃ -C ₆ alkynyl; R ₄₀ , R ₄₁ and R ₄₂ are each independently hydrogen, halogen, cyano, OR ₆₅ , C (O) R ₆₆ , C (S) R ₆₇ , CO ₂ R ₆₈ , C (= NOR ₆₉ ), C ₁ -C ₈ alkyl, C ₃ -C ₇ cycloalkyl, C ₂ -C ₈ alkenyl or C ₂ -C ₈ alkynyl groups, wherein each group is 1 to 6 halogen atoms, 1 to 3 C _1- C ₁₀ -alkoxy group, 1 or 2 C ₁ -C ₆ haloalkoxy groups, 1 or 2 NR ₇₀ R ₇₁ groups, 1 or 2 S (0) _q R ₇₂ groups, 1 or 2 cyano groups, 1 or 2 C ₃ -C ₇ cycloalkyl groups, 1 OSO ₂ R ₇₃ groups, 1 or 2 C (O) R ₇₄ groups, 1 or 2 CO ₂ R ₇₅ groups, 1 or 2 C (O ) SR ₇₆ groups, 1 or 2 C (O) NR ₇₇ R ₇₈ groups, 1 to 3 OR ₇₉ groups, 1 or 2 P (O) (OR ₈₀ ) ₂ groups, 1 1,3-dioxolane Optionally substituted with one to three C ₁ -C ₄ alkyl groups, or any combination of one 1,3-dioxane (optionally substituted with one to three C ₁ -C ₄ alkyl groups) Is substituted with; or Phenyl or benzyl, wherein each has 1 to 3 halogen atoms, 1 to 3 C ₁ -C ₆ alkyl groups, 1 to 3 C ₁ -C ₆ alkoxy groups, 1 C ₃ -C ₇ cycloalkyl group, 1 1 C ₁ -C ₄ haloalkyl group, 1 C ₁ -C ₄ alkylthio group, 1 cyano group, 1 nitro group, 1 C (O) R _8l group, 1 CO ₂ R ₈₂ group, 1 OR ₈₃ group, 1 SR ₉₄ group, 1 C ₁ -C ₆ alkoxymethyl group, 1 hydroxymethyl group, 1 C ₃ -C ₈ alkenyloxymethyl group, or 1 C ₁ -C _Is optionally substituted with any combination of ₈ haloalkoxymethyl groups; R ₄₃ , R ₄₄ , R ₄₇ and R ₄₈ are each independently hydrogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₃ -C ₆ alkenyl, C ₃ -C ₆ alkynyl or C ₃ -C ₇ cycloalkyl, or R ₄₃ and R ₄₄ or R ₄₇ and R ₄₈ together with the atoms to which they are attached form a C ₃ -C ₇ cycloalkyl group; R ₄₉ , R ₅₀ and R ₈₆ are each independently C ₁ -C ₆ alkyl, NR ₉₃ R ₉₄ , C ₁ -C ₄ haloalkyl, C ₃ -C ₆ alkenyl, C ₃ -C ₆ alkynyl or benzyl ; R ₅₁ , R ₅₂ , R ₅₃ , R ₅₄ , R ₅₅ , R ₅₇ , R ₅₈ , R ₅₉ , R ₆₀ , R ₆₁ , R ₆₂ , R ₇₁ , R ₇₃ , R ₇₄ , R ₇₈ , R ₈₇ and R ₉₂ Are each independently hydrogen, C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl, C ₁ -C ₆ haloalkyl, C ₃ -C ₆ alkenyl, C ₃ -C ₆ alkynyl, phenyl or benzyl; R ₇₉ , R ₈₃ and R ₈₄ are each independently hydrogen, C (O) R ₈₅ , SO ₂ R ₈₆ , C ₁ -C ₆ haloalkyl, C ₂ -C ₆ alkenyl, C ₅ -C ₈ cycloalkenyl , C ₂ -C ₆ alkynyl, phenyl, benzyl, or C ₁ -C ₁₀ alkyl [1 hydroxyl, benzyloxy, OC (O) R ₈₇ , C ₁ -C ₆ alkoxy, CO ₂ R ₈₈ , C (O) R ₈₉ , C (OR ₉₀ ) ₂ , C ( O) is optionally substituted with NR ₉₁ R ₉₂ or a cyano group; R ₉₃ and R ₉₄ are each independently hydrogen, C ₁ -C ₄ haloalkyl, C ₂ -C ₆ alkenyl, C ₃ -C ₈ cycloalkyl, C ₁ -C ₈ alkyl [optionally substituted with one or two C ₁ -C ₄ alkoxy groups or one cyanoalkyl group], or Benzyl or phenyl, each having 1 to 3 halogen atoms, 1 to 3 C ₁ -C ₄ alkyl groups, 1 to 3 C ₁ -C ₄ haloalkyl groups, 1 to 3 C ₁ -C ₄ alkoxy groups , Optionally substituted with any combination of 1 to 3 C ₁ -C ₄ haloalkoxy groups, 1 cyano group, or 1 nitro group; R ₉₃ and R ₉₄ are 5-12 membered monocyclic or fused bicyclic, heterocyclic rings when taken together with the atoms to which they are attached [halogen, cyano, nitro, amino, hydroxyl, C ₁ -C Optionally substituted with one or more groups independently selected from ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkoxy and C ₁ -C ₄ haloalkylsulfonyl groups; To form; p and q are each independently 0, 1 or 2; Z and Z ₁ are each independently C ₁ -C ₈ alkyl; Z ₂ is C ₁ -C ₄ alkyl. The method of claim 40, Z ₃ is hydrogen or methyl; X ₁ is hydrogen, fluorine or a C ₁ -C ₃ alkyl group (optionally substituted with one epoxy group); X ₂ is hydrogen, halogen NRR ₁ , CO ₂ R ₂ , C (O) R ₃ , OR ₄ , SO ₂ R ₅ , SO ₂ NR ₆ R ₇ , C (R ₈ ) (OR ₉ ) ₂ , C (R ₁₀ ) = NOR ₁₁ , C (R ₁₂ ) = C (R ₁₃ ) -C (OR ₁₄ ) = NOR ₁₅ , CH ₂ O-NCO ₂ R ₁₆ , 1,3-dioxolane optionally substituted with one C ₁ -C ₆ alkoxy group or one or two C ₁ -C ₄ alkyl groups, 1,3-dioxolinone optionally substituted with one C ₁ -C ₆ alkoxy group or one or two C ₁ -C ₄ alkyl groups, Or C ₁ -C ₄ alkyl optionally substituted with one CO ₂ R ₂ group and one halogen atom; X ₃ is hydrogen, halogen, C ₁ -C ₄ haloalkyl, CO ₂ R ₁₇ cyano, C ₁ -C ₄ haloalkoxy, OR ₁₈ or C ₁ -C ₄ alkyl, or X ₁ and X ₂ together with the atoms to which they are attached may form a five or six membered ring, wherein X ₁ X ₂ or X ₂ X ₁ is represented as follows: —OC (R ₂₀₎ (R _21- O-, -CH ₂ S (O) _p N (R ₂₂ )-, -SC (R ₂₃ ) = N-, -CH = CH-CH (R ₁₁ ) O-, -OC (O) N- , -SC (R ₂₄ ) = N-, -ON (R ₂₅ ) C (O)-, -OC (CO ₂ R ₂₆ ) = CH-, -NC (R ₂₈ ) = C (SR ₂₉ )-,- CH = C (CO ₂ R ₃₀ ) O-, -CH ₂ CH (R ₃₁ ) O- or -OC (R ₃₂ ) (R ₃₃ ) C (O)-], or X ₂ and X ₃ together with the atoms to which they are attached may form a five or six membered ring, where X ₂ X ₃ or X ₃ X ₂ is represented as: -NC (R ₃₄ ) = NC (S)-, -N (R ₃₅ ) N = C (R ₃₆ )-, -N (R ₃₇ ) C (R ₃₈ ) = N-, -N (R ₃₈ ) C (O) CH ₂ 0-, -N (R ₃₉ ) C (O) CH = CH-, -SN = C (R ₄₀ )-, -ON = C (R ₄₁ )-, -N = NN (R ₄₂ )-, -C (R ₄₃ ) (R ₄₄ ) C (O) N (R ₄₅ )-or -N (R ₄₆ ) C (O) C (R ₄₇ ) (R ₄₈ )-]; X ₄ is hydrogen, halogen or OR ₁₉ ; X ₅ is hydrogen or halogen; R, R ₆₄ , R ₆₉ , and R ₇₇ are each independently hydrogen, SO ₂ R ₄₉ or C ₁ -C ₄ alkyl; R ₁ is hydrogen, SO ₂ R ₅₀ , C (O) R ₅₁ , amino or C ₁ -C ₄ alkyl optionally substituted with CO ₂ R ₅₂ or C (O) R ₅₃ ; R ₂ , R ₁₆ , R ₁₇ , R ₂₆ , R ₃₀ , R ₆₈ , R ₇₅ , R ₇₆ , R ₈₂ and R ₈₈ are each independently hydrogen, C ₃ -C ₆ alkenyl, or CO ₂ R ₅₄ , mor C ₁ -C ₄ alkyl optionally substituted with Pauline or C (O) R ₅₅ ; R ₃ , R ₆₆ , R ₆₇ , R ₈₅ and R ₈₉ are each independently hydrogen, C ₁ -C ₄ alkyl or NR ₅₆ R ₅₇ ; R ₄ , R ₁₈ and R ₁₉ are each independently hydrogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C (O) R ₅₈ , C ₃ -C ₄ alkenyl or C ₃ -C ₄ alkoxy Nil; R ₅₆ is SO ₂ R ₄₉ ; R ₅₇ is hydrogen or C ₁ -C ₄ alkyl; R ₅ and R ₇₂ are each independently NR ₆₀ R ₆₁ or indazole; R ₆ , R ₁₁ , R ₁₂ , R ₁₄ , R ₁₅ , R ₂₀ , R ₂₁ , R ₂₂ , R ₂₅ , R ₂₈ , R ₂₉ , R ₃₁ , R ₃₂ , R ₃₃ , R ₃₅ , R ₄₅ , R ₄₆ And R ₈₀ are each independently hydrogen or methyl; R ₇ is cyano or C ₁ -C ₄ alkyl optionally substituted with C (O) R ₆₂ ; R ₈ is hydrogen or C ₁ -C ₄ alkoxy; R ₉ and R ₉₀ are each independently C ₁ -C ₄ alkyl; R ₁₀ is hydrogen or C ₁ -C ₃ alkyl; R ₁₃ , R ₂₄ and R ₃₆ are each independently hydrogen or chlorine; R ₂₃ is NR ₆₃ R ₆₄ ; R ₃₄ is C ₁ -C ₃ haloalkyl; R ₃₇ is C ₂ -C ₄ alkoxyalkyl; R ₃₈ and R ₃₉ are each independently C ₁ -C ₃ haloalkyl, C ₁ -C ₃ alkyl, or propargyl; R ₄₀ , R ₄₁ and R ₄₂ are each independently hydrogen, C (O) R ₆₆ , C (S) R ₆₇ , CO ₂ R ₆₈ , C (= NOR ₆₉ ), C ₁ -C ₃ alkyl group [1 or 2 halogen atoms, 1 or 2 C ₁ -C ₃ alkoxy groups, 1 or 2 C ₁ -C ₃ haloalkoxy groups, 1 S (0) ₂ R ₇₂ group , 1 or 2 cyano groups, 1 C ₃ -C ₅ cycloalkyl group, 1 OSO ₂ R ₇₃ group, 1 C (O) R ₇₄ group, 1 CO ₂ R ₇₅ group, 1 C ( O) SR ₇₆ groups, 1 C (O) NR ₇₇ R ₇₈ group, 1 or 2 OR ₇₉ groups, 1 P (O) (OR ₈₀ ) ₂ groups, 1 1,3-dioxolane group, or Optionally substituted with any combination of one 1,3-dioxane group], or Phenyl [optionally substituted with any combination of one halogen atom, one or two methyl groups, one methoxy group, one halomethyl group or one OR ₈₃ group]; R ₄₃ , R ₄₄ , R ₄₇ and R ₄₈ are each independently hydrogen or methyl, or R ₄₃ and R ₄₄ or R ₄₇ and R ₄₈ together with the atoms to which they are attached form a cyclopropyl group; R ₄₉ , R ₅₀ and R ₈₆ are each independently C ₁ -C ₄ alkyl or NR ₉₃ R ₉₄ ; R ₅₁ , R ₅₂ , R ₅₃ , R ₅₄ , R ₅₅ , R ₅₈ , R ₆₀ , R ₆₁ , R ₆₂ , R ₇₃ , R ₇₄ , R ₇₈ , and R ₈₇ are each independently hydrogen, C ₁ -C ₄ Alkyl or C ₁ -C ₄ haloalkyl; R ₇₉ and R ₈₃ are each independently hydrogen, C (O) R ₈₅ , SO ₂ R ₈₆ , C ₁ -C ₄ haloalkyl, C ₃ -C ₄ alkenyl or C ₁ -C ₃ alkyl substituted with one OC (O) R ₈₇ , CO ₂ R ₈₈ , C (O) R ₈₉ , C (OR ₉₀ ) ₂ or cyano group; R ₉₃ and R ₉₄ are each independently hydrogen or C ₁ -C ₈ alkyl; p is 0, 1 or 2; Z and Z ₁ are the same and are methyl or ethyl; Z ₂ is methyl or ethyl. The method of claim 28, wherein the 6- (trifluoromethyl) uracil compound has the formula <Formula IX> Where Z ₃ is hydrogen or methyl; X ₅ is hydrogen or halogen; R ₄₀ is hydrogen, C (0) R ₆₆ , C (S) R ₆₇ , CO ₂ R ₆₈ , C ₁ -C ₃ alkyl [1 or 2 halogen atoms, 1 or 2 C ₁ -C ₃ alkoxy groups, 1 or 2 C ₁ -C ₃ haloalkoxy groups, 1 SO ₂ R ₇₂ group, 1 or 2 Cyano groups, 1 C ₃ -C ₅ cycloalkyl group, 1 OSO ₂ R ₇₃ group, 1 or 2 OR ₇₉ groups, 1 P (O) (OR ₈₀ ) ₂ groups, 1 1,3 Optionally substituted with a dioxolane group or any combination of one 1,3-dioxane group], or Phenyl [optionally substituted with any combination of one halogen atom, one or two methyl groups, one methoxy group, one halomethyl group or one OR ₈₃ group]; R ₆₆ , R ₆₇ , R ₈₅ and R ₈₉ are each independently hydrogen, C ₁ -C ₄ alkyl or NR ₅₆ R ₅₇ ; R ₅₆ is SO ₂ R ₄₉ ; R ₅₇ is hydrogen or C ₁ -C ₄ alkyl; R ₄₉ and R ₈₆ are each independently C ₁ -C ₄ alkyl or NR ₉₃ R ₉₄ ; R ₉₃ and R ₉₄ are each independently hydrogen or C ₁ -C ₈ alkyl; R ₆₈ and R ₈₈ are each independently hydrogen, C ₃ -C ₆ alkenyl or C ₁ -C ₄ alkyl [optionally substituted with CO ₂ R ₅₄ , morpholine or C (O) R ₅₅ ]; R ₅₄ , R ₅₅ , R ₆₀ , R ₆₁ , R ₇₃ and R ₈₇ are each independently hydrogen, C ₁ -C ₄ alkyl or C ₁ -C ₄ haloalkyl; R ₇₂ is NR ₆₀ R ₆₁ or indazole; R ₇₉ and R ₈₃ are each independently hydrogen C (O) R ₈₅ , SO 2 R ₈₆ , C ₁ -C ₄ haloalkyl, C ₃ -C ₄ alkenyl or C ₁ -C ₃ alkyl [substituted with one OC (O) R ₈₇ , CO 2 R ₈₈ , C (0) R ₈₉ , C (OR ₉₀ ) ₂ or cyano group]; R ₈₀ is hydrogen or methyl; And R ₉₀ is C ₁ -C ₄ alkyl.