CN1344260A - Process for prepn. of 6-(perfluoroalkyl) uracil compounds from urea compounds - Google Patents

Abstract

An improved process for the preparation of 6-(perfluoroalkyl) uracil compounds having structural formula (I) from urea compounds having structural formula (II).

Description

Process for preparing 6-(perfluoroalkyl)uracil compounds from urea compounds

Background of the invention

6-(Perfluoroalkyl)uracil compounds are useful as herbicides and their preparation is known in the prior art. 6-(perfluoroalkyl)uracil compounds can be prepared by reacting 2-(N,N-disubstituted)amino-4-(perfluoroalkyl)-1,3-oxazin-6-ones with amine compounds .

Bull.Soc.Chem.Belg., 101(4), pages 313-321 (1992) disclose 2-(N,N-dialkyl)amino-4-(trifluoromethyl)-1,3-oxo The azin-6-one compound is prepared by reacting ethyl 3-amino-4,4,4-trifluorocrotonate with a phosgene iminium chloride compound. However, this method is not entirely satisfactory because the required phosgene imine chloride compound is difficult and expensive to handle. Therefore, there is still a need to avoid the use of 2-(N, N-disubstituted) amino-4-(perfluoroalkyl)-1,3-oxazin-6-one compounds for the preparation of 6-( Improved methods for perfluoroalkyl)uracil compounds.

Therefore, it is an object of the present invention to provide a method for the preparation of 6-(perfluoro Improved methods for alkyl)uracil compounds.

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

Summary of the invention

The present invention provides a new method for preparing 6-(perfluoroalkyl)uracil compounds of structural formula I where n is an integer of 1, 2, 3, 4, 5 or 6;

Y is hydrogen or C ₁ -C ₆ alkyl; and

Q is C ₁ -C ₆ alkyl or optionally substituted phenyl, benzyl, heteroaryl or methylene heteroaryl, the method comprising:

(a) make the urea compound of structural formula II in

Z and Z ₁ are each independently C ₁ -C ₈ alkyl or Z and Z ₁ may be joined together with the atoms to which they are attached to form a 4- to 7-membered ring, wherein ZZ ₁ is formed by -(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, the latter is optionally replaced by any group selected from 1-3 halogen, C ₁ -C ₄ alkyl or C ₁ -C ₄ haloalkyl on the phenyl ring group group replaced;

and n are as described above, with the amine compound of formula III

QNH ₂

(III) wherein Q is as described above, reacted in the presence of an acid or base to form a 6-(perfluoroalkyl)uracil compound of general formula I wherein Y is hydrogen; and

(b) optionally alkylating a compound of formula I wherein Y is hydrogen to form a compound of formula I wherein Y is C ₁ -C ₆ alkyl.

Detailed Description of the Invention

In a preferred embodiment of the present invention, the 6-(perfluoroalkyl)uracil compound of general formula I wherein Y is hydrogen is prepared from the urea compound of general formula II and the amine compound of general formula III and acid or base It is prepared by reacting in the presence of a solvent, preferably at a temperature ranging from about 20°C to 150°C.

In another preferred embodiment of the invention, the double bond in the compound of general formula II assumes predominantly the (Z)-configuration.

The present invention advantageously provides a method that avoids the use of 2-(N,N-disubstituted)amino-4-(perfluoroalkyl)-1,3-oxazin-6-one compounds for the preparation of 6-(perfluoroalkyl)urea Improved methods for pyrimidine compounds.

The product compound of general formula I can be isolated using conventional isolation methods, such as diluting the reaction mixture with water and isolating or extracting the product with a suitable extraction solvent. In the separation step, common extraction solvents such as diethyl ether, ethyl acetate, toluene, dichloromethane, etc., and mixtures thereof can be used.

Acids suitable for use in the present invention include organic acids, which include but are not limited to C ₁ -C ₆ alkanoic acids such as formic acid, acetic acid, propionic acid, etc.; and inorganic acids, which include but are not limited to hydrochloric acid, sulfuric acid, phosphoric acid wait. A preferred acid is acetic acid.

Bases suitable for use in the process of the invention include, but are not limited to, tri(C ₁ -C ₆ -alkyl)amines such as trimethylamine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine Amines, etc.; heterocyclic tertiary amines such as 1,8-diaza-bicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo-[4.3.0]nona- 5-ene (DBN), 1,4-diazabicyclo[2.2.2]octane, pyridine, substituted pyridine, quinoline, substituted quinoline, etc.; and alkali metal C ₁ -C ₆ alkoxylates such as tertiary Potassium butoxide, sodium tert-butoxide, etc. Preferred bases include 1,8-diazabicyclo-[5.4.0]undec-7-ene and 1,5-diazabicyclo[4.3.0]non-5-ene.

Solvents suitable for use in step (a) of the method of the present invention include, but are not limited to, carboxylic acid amides such as N, N-dimethylformamide, N, N-dimethylacetamide, etc.; dialkyl sulfoxides such as di Methyl sulfoxide, etc.; aromatic hydrocarbons such as toluene, benzene, xylene, mesitylene, etc.; halogenated aromatic hydrocarbons such as chlorobenzene, fluorobenzene, etc.; aliphatic hydrocarbons such as pentane, hexane, heptane, etc.; halogenated aliphatic Hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, etc.; alcohols such as methanol, ethanol, n-propanol, sec-propanol, etc.; alkanoic acids such as formic acid, acetic acid, propionic acid etc.; ketones such as acetone, butanone, etc.; ethers such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, etc.; nitriles such as acetonitrile, propionitrile, etc.; and water; and mixtures thereof. It should be understood that solvents can be selected that do not react with acids or bases. In particular, alkanoic acids are generally not suitable solvents when bases are used.

Alkylation methods suitable for use in the present invention include conventional methods known in the art. In a preferred embodiment of the present invention, the step (b) alkylation process comprises allowing the compound of general formula I wherein Y is hydrogen to have the alkyl halide of structural formula IV or the dialkyl sulfate with structural formula V in base Reaction XY(IV) in the presence of or

wherein X is chlorine, bromine or iodine, and Y is C ₁ -C ₆ alkyl.

Bases suitable for use in the alkylation process of the present invention include common bases known in the art, which include but are not limited to alkali metal hydrides such as sodium hydride, etc.; alkali metal C ₁ -C ₆ alkoxylates Such as potassium tert-butoxide, sodium tert-butoxide, etc.; alkali metal hydroxides such as potassium hydroxide, sodium hydroxide, etc.; alkali metal carbonates such as sodium carbonate, potassium carbonate, etc.; alkaline earth metal hydroxides such as calcium hydroxide, etc. ; and alkaline earth metal carbonates such as calcium carbonate and the like.

Preferred compounds of general formula II for use in the method of the invention are those in which

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

Z ₂ is C ₁ -C ₄ alkyl; and

n is 1.

More preferred urea compounds of general formula II for use in the method of the invention are those in which

Z and _Z are identical and represent methyl or ethyl;

_Z is methyl or ethyl; and

n is 1.

Preferred compounds of general formula I prepared by the process of the invention are those in which

n is 1;

G是CH₂或键；Y is hydrogen or C ₁ -C ₄ alkyl; Q is

G is _CH2 or a bond;

G ₁ is CX ₅ or N;

G ₂ is CX ₄ or N; X ₁ is hydrogen, halogen or C ₁ -C ₆ alkyl optionally substituted by an 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 ,

_{CH2O - NCO2R16} ,

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

ring,

1,3-dioxa optionally substituted by one C ₁ -C ₆ alkoxy or one or two C ₁ -C ₄ alkyl

cyclopentenone, or

C ₁ -C ₄ alkyl optionally substituted by a CO ₂ R ₂ group and a halogen atom, and 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 when X ₁ and X ₂ are joined together with the carbon atom to which they are attached, they form a five- or six-membered

ring, wherein X ₁ X ₂ or X ₂ X ₁ is represented by the following formula:

-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 when X ₂ and X ₃ are joined together with the carbon atoms to which they are attached, they form five or six

ring, wherein X ₂ X ₃ or X ₃ X ₂ is represented by the following formula:

-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 O-, -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 alkyne radical, phenyl or benzyl; R ₁ is hydrogen, SOR ₅₀ , C(O)R ₅₁ , amino or C ₁ -C ₄ alkyl optionally substituted by 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 ₈ alkynyl, phenyl, benzyl, furfuryl, pyridyl, thienyl,

C ₁ -C ₈ alkyl optionally substituted by CO ₂ R ₅₄ , morpholine or C(O)R ₅₅ , or an 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 is 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 C ₁ - optionally substituted by cyano or C(O)R ₆₂ C ₄ alkyl; 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 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, each of which is optionally substituted by any combination of the following groups: 1-3 C ₁ -C ₁₀ -Alkoxy, 1 or 2 C ₁ -C ₆ haloalkoxy groups, 1 or 2 NR ₇₀ R ₇₁ groups, 1 or 2 S(O)qR ₇₂ groups, 1 or 2 cyano, 1 or 2 C ₃ -C ₇ cycloalkyl groups, 1 OSO ₂ R ₇₃ group, 1 or 2 C(O)R ₇₄ groups, 1 or 2 COR ₇₅ groups, 1 or 2 C(O)SR ₇₆ groups, 1 or 2 C(O)NR ₇₇ R ₇₈ groups, 1-3 OR ₇₉ groups, 1 or 2 P(O)(OR ₈₀ ) ₂ groups, 1 optionally substituted by 1-3 C ₁ -C ₄ alkyl 1,3-dioxolane, or 1 optionally substituted by 1-3 C ₁ -C ₄ alkyl Substituted 1,3-dioxolane,

or

Phenyl or benzyl optionally substituted by any combination of the following groups: 1-3 halogen atoms, 1-3 C ₁ -C ₆ alkyl, 1-3 C ₁ -C ₆ alkoxy, 1 C ₃ -C ₇ cycloalkyl, 1 C ₁ -C ₄ haloalkyl, 1 C ₁ -C ₄ alkylthio, 1 cyano, 1 nitro, 1 C(O)R ₈₁ group, 1 CO ₂ R ₈₂ group, 1 OR ₈₃ group, 1 SR ₈₄ group, 1 C ₁ -C ₆ alkoxymethyl group, 1 hydroxymethyl group, 1 C ₃ - C ₈ alkenyloxymethyl, or 1 C ₁ -C ₈ haloalkoxymethyl; R ₄₃ 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 can be linked together with the carbon atoms to which they are attached Form C ₃ -C ₇ cycloalkyl; 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 alkenes 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 ₈₂ are each independently hydrogen, C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl, C ₁ -C ₆ haloalkyl, C ₃ -C ₆ chain 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 optionally replaced by a 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)NR ₉₁ R ₉₂ or C ₁ -C ₁₀ alkyl substituted by cyano ; R ₉₃ and R ₉₄ are each independently hydrogen, C ₁ -C ₄ haloalkyl, C ₂ -C ₆ alkenyl, C ₃ -C ₈ cycloalkyl, optionally replaced by 1 or 2 C ₁ -C C ₁ -C ₈ alkyl substituted by ₄ alkoxy or 1 cyanoalkyl, or benzyl or phenyl optionally substituted by any combination of the following groups: 1-3 halogen atoms, 1-3 C ₁ -C ₄ alkyl, 1-3 C ₁ -C ₄ haloalkyl, 1-3 C ₁ -C ₄ alkoxy, 1-3 C ₁ -C ₄ haloalkoxy, 1 cyano group or a nitro group, and when R ₉₃ and R ₉₄ are joined together with the carbon atom to which they are attached, they form a 5- to 12-membered monocyclic or fused bicyclic ring, optionally selected from halogen, cyano radical, nitro, amino, hydroxyl, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkoxy and C ₁ -C ₄ haloalkyl a heterocyclic ring substituted with one or more groups of sulfonyl; and p and q are each independently 0, 1 or 2; and optical isomers, diastereomers and/or tautomers thereof.

More preferred herbicides of general formula I which can be prepared by the process of the invention are those in which

n is 1;

Y is hydrogen or methyl; Q is 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 C ₁ -C ₃ alkyl optionally substituted by an 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 )=NOR15, CH ₂ O-NCO ₂ R ₁₆ , optionally replaced by one C ₁ -C ₆ alkoxy group or one or two 1,3-dioxolane substituted by C ₁ -C ₄ alkyl, 1,3-dioxo optionally substituted by one C ₁ -C ₆ alkoxy or one or two C ₁ -C ₄ alkyl Holocyclopentenone, or

C ₁ -C ₄ alkyl optionally substituted by a CO ₂ R ₂ group and a halogen atom, and X ₃ is hydrogen, halogen, C ₁ -C ₄ haloalkyl, CO ₂ R ₁ , cyano, C ₁ -C ₄ haloalkoxy, OR ₁₈ or C ₁ -C ₄ alkyl, or when X ₁ and X ₂ are joined together with the carbon atoms to which they are attached, they will form a five-membered or six-membered ring, wherein X ₁ X ₂ or X ₂ X ₁ is represented by the following groups:

-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

When _X2 and _X3 are joined together with the carbon atom to which they are attached, they will form a five- _membered or six-membered ring, wherein _X2X3 or _X3X2 is represented by the following groups _:

-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 O-, -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( _R47 )(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 is 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 optionally substituted by CO ₂ R ₅₂ or C(O)R ₅₃ C ₁ -C ₄ alkyl; R ₂ , R ₁₆ , R ₁₇ , R ₂₆ , R ₃₀ , R ₆₈ , R ₇₅ , R ₇₆ , R ₈₂ and R ₈₉ are each independently hydrogen, C ₃ -C ₆ chain Alkenyl or C ₁ -C ₄ alkyl optionally substituted by CO ₂ R ₅₄ , morpholine 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 alkynyl; 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 , _R45 ,

R ₄₆ and R ₈₀ are each independently hydrogen or _methyl ; R ₇ is C ₁ -C 4 alkyl optionally substituted by cyano or C(O)R ₆₂ ; R ₈ is hydrogen or C ₁ -C ₄ alkane Oxygen; 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 optionally substituted by any combination of the following groups: 1 or 2 halogen atoms, 1 or 2 C ₁ -C ₃ alkoxy groups, 1 or 2 C ₁ - C ₃ haloalkoxy, 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 C(O)R ₇₄ group, 1 CO ₂ R ₇₅ group, 1 C(O)SR ₇₆ group, 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 1 1,3-dioxane group; or optionally replaced by 1 halogen atom, 1 or 2 A phenyl group substituted by any combination of methyl, 1 methoxy group, 1 halomethyl group or 1 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 are linked together with the carbon atoms to which they are attached to 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 optionally substituted by one OC(O)R ₈₇ , CO ₂ R ₈₈ , C(O ₎ R ₈₉ , C(OR ₉₀ ) ₂ or cyano; _{R 93 and} Each R ₉₄ is independently hydrogen or C ₁ -C ₈ alkyl;

and p is 0, 1 or 2.

The process of the invention is especially useful for the preparation of 6-(trifluoromethyl)uracil compounds of formula VI

in

Y is hydrogen or methyl;

_X is hydrogen or halogen;

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

C ₁ -C ₃ alkyl optionally substituted by any combination of the following groups: 1 or 2 halogen atoms, 1 or 2 C ₁ -C ₃ alkoxy groups, 1 or 2 C ₁ - C ₃ haloalkoxy, 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 group, a P(O)(OR ₈₀ ) ₂ group, a 1,3-dioxolane group or a 1,3-dioxane group, or optionally replaced by a halogen atom , 1 or 2 methyl groups, 1 methoxy group, 1 halomethyl group or 1 OR ₈₃ substituted phenyl 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 optionally replaced by CO ₂ R ₅₄ , morpholine or C ₁ -C ₄ alkyl substituted by 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 alkane or C ₁ -C ₄ haloalkyl; R ₇₂ is NR ₆₀ R ₆₁ or indole; R ₇₉ and R ₈₃ are each independently hydrogen, C(O)R ₈₅ , SO ₂ R ₈₆ , C ₁ -C ₄ haloalkane C ₃ -C ₄ alkenyl or C 1 -C ₃ optionally substituted by one OC(O)R ₈₇ , CO _{2 R 88} , C(O)R ₈₉ , C(OR ₉₀ ) ₂ or cyano Alkyl; R ₈₀ is hydrogen or methyl; and R ₉₀ is C ₁ -C ₄ alkyl.

Examples of the aforementioned halogen 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 defined as methyl, C ₁ -C ₄ alkyl, C ₁ -C ₈ alkyl, C ₁ -C ₃ alkoxy substituted by one or more halogen atoms group, C ₁ -C ₄ alkoxy or C ₁ -C ₈ alkoxymethyl. In Formula I above, alkali metals include sodium, potassium, and lithium, and alkaline earth metals include calcium and magnesium. Organoammonium cations useful in the present invention include, but are not limited to, positively charged nitrogen atoms to which 1-4 aliphatic groups (each containing 1-16 carbon atoms) are attached.

In the above general formula I, 5- to 12-membered monocyclic or fused bicyclic, heterocyclic rings include, but are not limited to, benzimidazole, imidazole, imidazoline-2-thione, indole, isatoic anhydride, mol line, piperazine, piperidine, purine, pyrazole, pyrrole, pyrrolidine and 1,2,4-triazole rings, wherein each ring is optionally independently selected from halogen, cyano, nitro, amino, hydroxyl, One or more groups of C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkoxy or C ₁ -C ₄ haloalkylsulfonyl replaced.

The starting structure formula II urea compound can be obtained by making the β-amino-β-(perfluoroalkyl) acrylate compound of general formula VII

wherein n and _Z are prepared as defined above by reaction with a base and a carbamoyl chloride compound of formula VIII,

wherein Z and _Z1 are as defined above.

β-Amino-β-(perfluoroalkyl)acrylate compounds of general formula VII are known in the prior art and can be described according to US 5,777,154; Journal of Heterocyclic Chemistry (Heterocyclic Chemistry Journal), 9, pp. 513-522 (1972); and Institute of Chemistry, Ural Science Center, Academy of Sciences of the USSR, Sverdlovsk, 1442-1447 pages (1987)-Zhurnal OrganicheskoiKhimii's English translation, 22 (8), the method described in 1603-1609 pages (1986) to prepare .

Carbamoyl chloride compounds of general formula VIII are known in the prior art and can be prepared by conventional methods. Additionally, certain carbamoyl chloride compounds of general formula VIII are commercially available.

Amine compounds of formula IIIa

具有该结构式IIIb的起始胺化合物其中X₁，X₅和R₄₁如以上所定义，可以通过，按反应历程II中所示，通式XI的酮与羟胺盐酸盐任选在乙酸钠存在下进行反应形成通式XII的肟，用碱如氢氧化钾将通式XII化合物加以环化而形成通式XIII的硝基苯并异噁唑，和使用普通的还原剂如在乙酸中的氯化亚铁(II)还原通式XIII化合物来制备。反应历程II

wherein X ₁ , X ₅ and R ₄₀ are as defined above, the nitro group of general formula X can be formed by cyclizing the ketone of general formula IX with sulfur and ammonium hydroxide or ammonia gas as shown in reaction scheme I Benzisothiazoles, and are prepared by reducing the compound of general formula X using a common reducing agent such as iron in acetic acid. Reaction Process I

The starting amine compound having the structural formula IIIb wherein X ₁ , X ₅ and R ₄₁ are as defined above, an oxime of general formula XII can be formed by, as shown in Reaction Scheme II, reacting a ketone of general formula XI with hydroxylamine hydrochloride, optionally in the presence of sodium acetate , the compound of general formula XII is cyclized with a base such as potassium hydroxide to form nitrobenzisoxazole of general formula XIII, and the general reducing agent such as iron(II) chloride in acetic acid is used to reduce the general formula XIII compound to prepare. Reaction Process II

Alternatively, nitrobenzisoxazole compounds of general formula XIII can form oximes of general formula XV by reacting ketones of XIV with hydroxylamine hydrochloride, optionally in the presence of a base such as sodium acetate, as shown in Scheme III, Cyclization of compounds of general formula XV with 1,1'-carbonyl-diimidazole in the presence of a base such as triethylamine to form benzisoxazoles of general formula XVI, and using common methods such as nitric/sulfuric acid mixtures will Compounds of formula XVI are prepared by nitration.

Reaction Scheme III

Intermediate compounds of general formula X and XIII wherein R ₄₀ and R ₄₁ are OR ₆₅ can be passed through, as shown in reaction scheme IV, the benzisoxazole of general formula XVII is reacted with common nitrating agent such as nitric acid/sulfuric acid mixture -3-ol or benzisothiazol-3-ol is nitrated to form 5-nitrobenzisoxazol-3-alcohol or 5-nitrobenzisothiazol-3-alcohol of general formula XVIII, and then in It is prepared by reacting a compound of general formula XVIII with an electrophile of general formula XIX in the presence of a base such as potassium carbonate.

Reaction Scheme IV

Wherein R ₄₀ and R ₄₁ are Cl or Br The intermediate compounds of general formula X and XIII can be passed, as shown in reaction scheme V, from 5-nitrobenzisoxazol-3-alcohol of general formula XVIII or 5 -Nitrobenzisothiazol-3-alcohol reacts with phosphorus oxychloride, phosphorus oxybromide or phosphorus pentabromide to prepare.

Reaction history V

Further methods of preparing amine compounds of general formula IIIa and IIIb will be apparent from the examples given below. Additionally, certain compounds of general formula IIIa, IIIb, X and XIII can be converted into other compounds of general formula IIIa, IIIb, X and XIII by using those common methods known to those skilled in the art.

Other amine compounds of general formula III are known in the prior art and can be prepared according to the methods described in the following patent documents: 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; 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 96/28442; WO 96/34859; WO 96/35679; WO 97/01541; WO 97/01542; WO 97/05118; WO 97/07105; WO 97/08170; WO 97/12884; WO 97/12886; WO 97/29094; WO 97/29105; WO 97/34484; WO 98/02422; WO 98/06706; WO 98/08824; WO 98/27057; WO 98/27067; WO 98/27082;

In order to facilitate a further understanding of the present invention, the following examples are given mainly to illustrate more specific details of the present invention. The scope of the present invention should not be considered limited to the examples but includes the whole point defined in the claims.

Example 1

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

Ethyl 3-amino-4,4,4-trifluorocrotonate (18.4 g, 100 mmol) was added to sodium hydride (60% solution in mineral oil, 9.6 g, 250 mmol) in a stirred solution in N,N-dimethyl-formamide (60 ml). The reaction mixture was allowed to warm to room temperature and held at room temperature for 15 minutes, cooled to 5°C, and treated with dimethylcarbamoyl chloride (21.6 g, 200 mmol) for 60 minutes. The resulting solution was then warmed to room temperature and kept at room temperature for 2 hours, diluted with water (150ml), and extracted with ethyl acetate (2 x 150ml). The combined organic layers were dried, filtered and concentrated, and the mineral oil layer was removed to give a residue. Flash column chromatography of the residue on silica gel using 85:15 hexane/ethyl acetate solution gave the title product (18.1 g, 71% yield) as a yellow liquid: ¹ H NMR (DMSO-d ₆ ) δ9. 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 procedure, the following compounds were obtained:

(Z)-configuration

Z Z ₁ Z ₂ mp(℃) Yield(%)

C ₂ H ₅ C ₂ H ₅ C ₂ H ₅ Yellow oil 88

-(CH ₂ ) ₄ -C ₂ H ₅ 54-57 37

CH ₃ CH ₃ CH ₃

C ₂ H ₅ C ₂ H ₅ CH ₃

-(CH ₂ ) ₄ - CH ₃

Preparation of Example 23-(3-methyl-1,2-benzisothiazol-5-yl)-6-(trifluoromethyl)-2,4-(1H,4H)-pyrimidinedione

(Z)-3-[(N,N-Dimethylcarbamoyl)-amino]-4,4,4-trifluoroethyl crotonate (1.15 g, 4.5 mmol) and 5-amino-3-methanol A solution of 1,2-benzisothiazole (0.75 g, 4.5 mmol) in glacial acetic acid (7 mL) was maintained at gentle reflux for 1 hour, cooled, and diluted with water. The resulting aqueous mixture was filtered to obtain a solid. The solid was washed with water and dried to give the title product (1.3 g, 88% yield), which was confirmed by ¹ H and ¹⁹ F NMR spectral analysis.

Z      Z₁                Q                  酸/碱         溶剂          颜色/状态/mp(℃)    收率(％)CH₃   CH₃    

   CH₃CO₂H    CH₃CO₂H    ＞250                88C₂H₅ C₂H₅   

       CH₃CO₂H    CH₃CO₂H    白色固体             92

Z       Z₁             Q                      酸/碱         溶剂          颜色/状态/mp(℃)    收率(％)CH₃   CH₃    

     CH₃CO₂H    CH₃CO₂H    ＞250                88C₂H₅ C₂H₅   

          CH₃CO₂H    CH₃CO₂H    白色固体            92实施例32’-氯-2-甲氧基-5-甲基-5’-硝基二苯甲酮的制备

Following essentially the same procedure, but using appropriate reagents, the following compounds were obtained:

Z Z ₁ Q Acid/base Solvent Color/State/mp(℃) Yield(%)CH ₃ CH ₃

CH ₃ CO ₂ H CH ₃ CO ₂ H >250 88C ₂ H ₅ C ₂ H ₅

CH ₃ CO ₂ H CH ₃ CO ₂ H White solid 92

Z Z ₁ Q Acid/base Solvent Color/State/mp(℃) Yield(%)CH ₃ CH ₃

CH ₃ CO ₂ H CH ₃ CO ₂ H >250 88C ₂ H ₅ C ₂ H ₅

CH ₃ CO ₂ H CH ₃ CO ₂ H white solid 92 Example 3 Preparation of 2'-chloro-2-methoxy-5-methyl-5'-nitrobenzophenone

A mixture of aluminum chloride (33.3 g, 25.0 mmol) in dichloromethane was cooled to about 5 °C and treated with p-methylanisole (31.6 g, 25.0 mmol) for 1 hour while maintaining the temperature of the reaction mixture at 10 °C Next, treat with a solution of 2-chloro-5-nitrobenzoyl chloride (50.0 g, 22.7 mmol) in dichloromethane for 20 minutes while keeping the temperature of the reaction mixture below 10° C., warm to room temperature, and Stir for 60 minutes, then pour onto ice. The resulting aqueous mixture was treated with concentrated hydrochloric acid (50ml) and extracted with dichloromethane. The organic extracts were dried over anhydrous magnesium sulfate and concentrated in vacuo to give a yellow solid. After placing the solid in a Kugelrohr apparatus at 40° C. to remove residual p-methylanisole, the title product was obtained as a light brown solid (68.8 g, 99.1%), which was confirmed by NMR spectral analysis.

Using essentially the same procedure, the following compounds were obtained: X ₃ X ₅ W W ₁ W ₂ W ₃ W ₄ mp°C Cl HCl H H I H H OCH ₃ 115-116.5Cl H H H CH ₃ H OCH ₃ Cl H H H C ₂ H ₅ H HCl H H CH ₃ CH ₃ H OCH ₃ Cl H H H OCH ₃ H H 108 -112Cl H H C ₂ H ₅ H H OCH ₃ 98-99.5Cl H H H OCH ₃ H CH ₃ 91-92Cl H H H CH ₃ H H 95.5-96.5Cl H H H SCH ₃ H H 127-128Cl H H H CH ₃ HO OCH ₃ 91-92.5Cl H H H C ₂ H ₅ H HCl H H H Cl H H 88.5-90.5Cl H H H F H H 68-69.5Cl H H Cl H HOCH ₃ 124-126Cl HHOCH ₃ HHOCH ₃ 71-73Cl H H H OCH ₃ HOCH ₃ 98-100Cl HH CH ₃ CH ₃ HOCH ₃ 127 -129Cl H H H Cl H OCH ₃ 96-99Cl H CH ₃ H CH ₃ H OCH ₃ 108.5-110Cl H H H H CH ₃ OCH ₃ 71-74X ₃ X ₅ W W ₁ W ₂ W ₃ W ₁ mp°C Cl H H H N(CH ₃ )- H H

SO _{2 CH 3} Cl H H CH ₃ Cl HOCH ₃ 126-128Cl H H CH ₃ H CH _{3 OCH 3 110-112Cl H CH 3 CH 3 CH 3 HOCH 3} 104-106Cl H H CH(CH ₃ ) ₂ H H OCH ₃ 69 -71Cl H H CH ₃ H H HCl H H H H H CNCl H H H H H OCH ₃ Cl H H OCH ₃ H H HCl H H F H H OCH ₃ Cl H H H F H OCH ₃ Cl H H H H H H SCH ₃ Cl H H H H H CH ₃ Cl H H H H H FCl H H H SCH ₃ H H HCl H H H OCH ₃ H HCl H H -(CH ₂ ) ₃ -HOCH ₃ Cl F H H H H HF F H CH ₃ H H OCH ₃ Example 43-(6-methoxy-m-tolyl)-5-nitro-1,2-benzisothiazole preparation

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

W    W₁      W₂            W₃   W₄      mp℃H    H        CH₃           H      OCH₃   201-203H    CH₃     CH₃           H      OCH₃   199-200H    CH₃     H              H      H        116.5-117.5H    H        Cl             H      OCH₃    229-231H    H        H              CH₃   OCH₃    134-136H    H        H              H      CN       187.5-189H    H        H              H      OCH₃    193-198H    H        OCH₃          H      H        201-203H    OCH₃    H              H      H        174-175H    F        H              H      OCH₃    224-226H    C₂H₅   H             H      OCH₃    153-154.5H    H        CH₃           H      H        188-189H    H    N(CH₃)SO₂CH₃   H      HH    CH₃     Cl             H      OCH₃    230-234H    I        H              H      OCH₃H    H        SCH₃          H      H        177.5-178.5H    H        OCH₃          H      CH₃     131-135H    H        F              H      H         226-228H    H        Cl             H      H         217.5-219H    H        F              H      OCH₃     224-225H    H        H              H      SCH₃     114.5-115.5H    H        CH₃           H      OCH₃     201-203H    OCH₃    H              H      OCH₃     195-196H    H        H              H      CH₃      145-146H    H        H              H      F         181-182H    H        OCH₃          H      OCH₃     171-172.5H    SCH₃    H              H      H         139-140.5H    CH₃     H              CH₃   OCH₃   CH₃ CH₃       CH₃   H    OCH₃ Using essentially the same procedure, the following compounds were obtained:

W W ₁ W ₂ W ₃ W ₄ mp°CH H CH ₃ H OCH ₃ 201-203H CH ₃ CH ₃ H OCH ₃ 199-200H CH ₃ H H H 116.5-117.5H H Cl H OCH ₃ 229-231H H H CH ₃ OCH ₃ 134- _{( _ _ _ _ _ _ _} CH ₃ )SO ₂ CH ₃ H HH CH ₃ Cl H OCH ₃ 230-234H I H H OCH ₃ H H SCH ₃ H H 177.5-178.5H H OCH ₃ H CH ₃ 131-135H H F H H 226-228H H Cl H H 217.5-219H H F H OCH ₃ 224-225H H H H SCH ₃ 114.5-115.5H H CH ₃ H OCH ₃ 201-203H OCH ₃ H H OCH ₃ 195-196H H H H CH ₃ 145-146H H H H F 181-182H H OCH ₃ HOCH ₃ 171-172.5H SCH ₃₃₉ H H H 1 -140.5H CH ₃ H CH ₃ OCH ₃ CH ₃ CH ₃ CH ₃ H OCH ₃

H CH(CH ₃ ) ₂ H H OCH ₃

H H CH ₃ CH ₃ OCH ₃

H -(CH ₂ ) ₃ -HOCH ₃

The preparation of embodiment 53-methyl-5-nitro-1,2-benzisothiazole

Ammonia (45 g, 2,642 mmol) was bubbled through methanol form in a steel autoclave at -40 °C. Sulfur (30.5 g, 95.0 mmol) and 2'-chloro-5'-nitroacetophenone (19 g, 95.0 mmol) were then added. The autoclave was sealed and heated overnight at approximately 90°C. After cooling, the reaction mixture was removed from the autoclave and concentrated in vacuo to obtain a residue. The residue was diluted with dichloromethane, passed through a pad of silica gel and concentrated in vacuo to give the title product (12.0 g) as an orange solid, which was confirmed by NMR spectral analysis.

实施例65-氨基-3-(6-甲氧基-间甲苯基)-1，2-苯并异噻唑的制备 Using essentially the same procedure, the following compounds were obtained:

The preparation of embodiment 65-amino-3-(6-methoxy-m-tolyl)-1,2-benzisothiazole

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

X₅       R₄₀             mp℃H         HH         CN               118.5-120H         CH₃             112-113.5H         C₂H₅H        179-181H         90-91X₅         R₄₀          mp℃F     

H   

      130-130.5H         152-153H     

        121.5-123H     

        108.5-109.5H     

        158.5-161H     

         101.5-102.5H     

         104-105X₅         R₄₀               mp℃H     

     191-192.5H     

H     

H     

        128-129H     

H     

             64H     

       108.5-109.5H               133-134H                114.5-115X₅        R₄₀              mp℃H          152-153.5H               146-147H    

          60-65H    

         143-145H                   100-101H    

H             125-127X₅          R₄₀             mp℃H     

       172-174H                  146-147H  

     161-162H   

     173-175H     

H     

H     

X₅  R₁₀                               mp℃H    

F    CH₃F    

H    CH₂CO₂C₂H₅H    C(CH₃)₂CO₂C₂H₅H    OCH₂CNH    OCH₃H    OCH(CH₃)₂H    OCCHCH＝CH₂H    OCH₂C≡CHH    OCH₂CO₂CH₃ Using essentially the same procedure, the following compounds were obtained:

X ₅ R ₄₀ mp °C CH HH CN 118.5-120H CH ₃ 112-113.5H C ₂ H ₅ H 179-181H 90-91X ₅ R ₄₀ mp°C F

h

130-130.5H 152-153H

121.5-123H

108.5-109.5H

158.5-161H

101.5-102.5H

104-105X ₅ R ₄₀ mp°C

191-192.5H

h

h

128-129H

h

64H

108.5-109.5H 133-134H 114.5-115X ₅ R ₄₀ mp°C 152-153.5H 146-147H

60-65H

143-145H 100-101H

h 125-127X ₅ R ₄₀ mp°C

172-174H 146-147H

161-162H

173-175H

h

h

X ₅ R ₁₀ mp°C CH

F CH ₃ F

H CH ₂ CO ₂ C ₂ H ₅ H C(CH ₃ ) ₂ CO ₂ C ₂ H ₅ H OCH ₂ CNH OCH ₃ H OCH(CH ₃ ) ₂ H OCCHCH=CH ₂ H OCH ₂ C≡CHH OCH ₂ CO ₂ CH ₃

Example 72-Chloro-2'-methoxy-5'-methyl-5-nitrobenzophenone, preparation of oxime

A mixture of 2-chloro-2-methoxy-5'-methyl-5-nitro-benzophenone (90.0 g, 0.294 mol) in ethanol was treated with hydroxylamine hydrochloride (102.3 g, 1.47 mol) in water The solution was refluxed overnight and poured onto ice. The resulting aqueous mixture was filtered to obtain a solid. The solid was washed with water and dried overnight in a hot vacuum oven to give the title product (84.2 g) as a white solid, confirmed ^by1H NMR spectral analysis.

mp 165-167℃Using essentially the same procedure, the following compounds were obtained: X ₅ W W ₂ W ₃ mp °C H OCH ₃ H H 173-178H H H H 143-145H H OCH ₃ H 191-192.5H OCH ₃ H FH H OCH ₂ CO ₂ CH ₃ H 150-155H OCH ₃ H CH ₃ 185.5-186.5 F OCH ₃ H CH ₃ and

mp 165-167°C

Preparation of Example 83-(6-methoxy-m-tolyl)-5-nitro-1,2-benzisoxazole

A mixture of 2-chloro-2'-methoxy-5'-methyl-5-nitro-benzophenone oxime (84.0g, 0.262mol) in ethanol was warmed to 65°C, and 150ml of 10% hydrogen The potassium oxide solution was treated for 25 minutes, heated to 78°C over one hour, cooled, and poured onto ice. The resulting mixture was filtered to obtain a solid. The solid was washed with water, dried, recrystallized from N,N-dimethylformamide, washed successively with N,N-dimethylformamide and ethanol, and dried in a vacuum oven at 80°C to obtain The title product was a solid (mp 225-226°C) and was confirmed ^by1H NMR spectral analysis.

X₅  W     W₁   W₂    mp℃H   OCH₃  H     H     170-171H    H     H     H     138-139H    H     H    OCH₃  205-207F   OCH₃ CH₃  HUsing essentially the same procedure, the following compounds were obtained:

X ₅ W W ₁ W ₂ mp °C CH OCH ₃ H H 170-171H H H H 138-139H H H OCH ₃ 205-207F OCH ₃ CH ₃ H

and

mp 84.5-86.5℃

Example 9

5-amino-3-(6-methylhydro-m-tolyl)-1,2-benzisoxazole and 5-amino-4-chloro-3-(6-methoxy-m-tolyl)- 1, the preparation of 2-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 wash with stannous chloride Warm solution of (II) (47.4g, 0.210mol) in concentrated hydrochloric acid (110ml), refluxed for 1 hour, cooled to 10°C, and concentrated in vacuo gave a gum. The gum was added to water and stirred to obtain a slurry. The slurry was treated with 80 g of 50% sodium hydroxide solution, stirred at 60-80°C for 1 hour, cooled, and decanted to obtain a residue. A mixture of the residue in ethanol was 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 was diluted with ethyl acetate and filtered. The filtrate was concentrated in vacuo and chromatographed using silica gel and 2% ethyl acetate in dichloromethane to afford the title product as a semi-solid, confirmed by elemental and mass spectral analyses.

Using essentially the same procedure, the following compounds were obtained: X ₅ R ₄₁ H H CH ₃ H ClH OCH ₂ CO ₂ CH ₃ H OCH(CH ₃ ) ₂ H OCH(CH ₃ )CO ₂ CH ₃ F OCH ₂ CO ₂ CH ₃ H OCH ₃

The preparation of embodiment 10 m-fluorophenyl acetate

A solution of 3-fluorophenol (100g, 0.890mol) in dichloromethane was cooled to 0°C-5°C, treated with pyridine (75.0ml, 0.930mol), stirred for a few minutes, and acetyl chloride (66.0ml, 0.930mol) was added dropwise ) for treatment while keeping the temperature of the reaction mixture below 17° C., stirring for two hours at ice bath temperature, warming to room temperature, and pouring into an ice-water mixture. The organic phase was separated, washed with brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to give the title product as a yellow oil, confirmed by ¹ H NMR spectral analysis.

Example 11

Preparation of 4'-fluoro-2'-hydroxyacetophenone

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

Example 12

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 nmol) in methanol was refluxed for 1 hour, then poured in ice-water mixture. The resulting aqueous mixture was filtered to obtain a solid. The solid was dissolved in dichloromethane and the resulting organic solution was dried over anhydrous magnesium sulfate, concentrated in vacuo, diluted with hexanes, and filtered to give the title product (55.0 g, mp 112-114°C) as a solid, and Confirmed by ¹ H NMR spectral analysis.

Example 13

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

Heat a mixture of 4'-fluoro-2'-hydroxyacetophenone oxime (47.0 g, 0.278 mol) in tetrahydrofuran just to reflux, and add 1,1'-carbonyl-diimidazole (55.0 g, 0.340 mol) and three A solution of ethylamine (39.0 g, 0.390 mol) in tetrahydrofuran was treated, refluxed for 1 hour, cooled, concentrated in vacuo, and poured into an ice-water mixture. The resulting aqueous mixture was extracted with ether. The organic extracts were combined, washed successively with saturated ammonium chloride solution and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain an oil. Column chromatography of the oil using silica gel and dichloromethane/hexane solution (1:1) gave the title product as a yellow oil and was confirmed ^by1H NMR spectral analysis.

Example 14

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 was cooled in an ice bath, and treated dropwise with 90% nitric acid (8.5 ml) while keeping The reaction mixture was kept below 15°C, stirred for 1 hour at ice bath temperature, treated with additional 90% nitric acid (5.80 mL), allowed to warm to room temperature, and stirred at room temperature overnight before pouring onto ice. The resulting aqueous mixture was filtered to obtain a solid. The solid was air dried and dissolved in dichloromethane. The resulting organic solution was dried over anhydrous magnesium sulfate, diluted with hexanes, and filtered to give the title product as a purple solid, confirmed by ¹ H NMR spectral analysis.

Using essentially the same procedure, the following compounds were obtained: The preparation of X ₅ HClF embodiment 15 acetate [(5-nitro-1,2-benzisoxazol-3-yl) oxygen] methyl ester

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, treat with methyl bromoacetate (3.96 g, 0.0260 mol), stir overnight at room temperature, and pour into an acidic mixture of ice and water. The resulting aqueous mixture was extracted with ethyl acetate. The organic extracts were combined, washed successively with water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain a yellow oil. Column chromatography of the oil using silica gel and a gradient of (1:1)-(4:1) dichloromethane/hexanes gave the title product (2.80 g, mp 72-73.5°C) as a white solid, which was analyzed by ¹ H NMR. Spectral analysis was confirmed.

X₅       R₁₁           mp℃H      OCH(CH₃)₂      81-83H     OCH₂CH＝CH₂     70-72H         OCH₃         101.5-103Cl  OCH(CH₃)CO₂CH₃   98-100F     OCH₂CO₂CH₃     104-106实施例163-氯-5-硝基-1，2-苯并异噁唑的制备 Using essentially the same procedure, the following compounds were obtained:

X ₅ R ₁₁ mp°CH OCH(CH ₃ ) ₂ 81-83H OCH ₂ CH=CH ₂ 70-72H OCH ₃ 101.5-103Cl OCH(CH ₃ )CO ₂ CH ₃ 98-100F OCH ₂ CO ₂ CH ₃ 104- Preparation of 106 Example 163-chloro-5-nitro-1,2-benzisoxazole

A mixture of 5-nitro-1,2-benzisoxazol-3-ol (4.00g, 0.0220mol) and phosphorus oxychloride (40.0ml, 65.8g, 0.429mol) was placed in a glass reactor, Heat at 150-155°C for 2 hours, cool overnight, concentrate in vacuo, dilute with dichloromethane, and adjust to pH about 8 with sodium bicarbonate solution. The phases were separated. The organic phase was washed successively with water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain a residue. Column chromatography of the residue using silica gel and dichloromethane/hexane solution (1:1) gave the title product as an amber oil and was confirmed ^by1H NMR spectral analysis.

Example 17

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

A solution of 2-bromoanisole (27.9g, 145mmol) in diethyl ether was cooled to -70°C, treated with butyl lithium (64.0ml, 160mmol), stirred at -70°C for 1 hour, and washed with 0.5M chloride Treatment with a solution of zinc in tetrahydrofuran (320 mL, 160 mmol), stirring at -70°C for 1 hour, warming to about 0°C, and concentration in vacuo gave a yellow-green oil. A solution of the oil in THF was sequentially treated with a solution of tetrakis(triphenylphosphine)palladium(0) (5.00 g, 4.35 mmol) and 2-chloro-5-nitrobenzoyl chloride (35.0 g, 159 mmol) in THF. Treated, stirred for 3 days, then poured into 10% hydrochloric acid. The resulting aqueous mixture was extracted with dichloromethane. The organic extracts were combined, washed sequentially with water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain a semi-solid. Trituration of this solid with diethyl ether afforded the title product as a yellow solid, confirmed by NMR spectral analysis.

W₁    W₂   W₃   W₄      mp℃H      Cl     H     OCH₃    96-99H      H     CH₃  OCH₃    71-74F      H      H    OCH₃Cl     H      H    OCH₃    124-126OCH₃   H      H    OCH₃    71-73H     OCH₃   H    OCH₃    98-100H      F      H    OCH₃H      H     CH₃   H       65-66.5H      H     SCH₃  H       87-88H      H      H     F       118-120H      H      H    CH₃     78-79.5H      H      H    SCH₃   123-124.5H      F      H     HH      H     OCH₃  HH      H      H    OCH₃H     CH₃   CH₃ OCH₃实施例182-氯-2’-甲氧基-5-硝基二苯基甲醇的制备

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

W ₁ W ₂ W ₃ W ₄ mp °C CH Cl HO CH ₃ 96-99H H CH ₃ OCH ₃ 71-74F H H OCH ₃ Cl H HOCH ₃ 124-126OCH ₃ H H OCH ₃ 71-73H OCH ₃ H OCH ₃ 98- 100H F H OCH ₃ H H CH ₃ H 65-66.5H H SCH ₃ H 87-88H H H F 118-120H H H CH ₃ 78-79.5H H H SCH ₃ 123-124.5H F H HH H OCH ₃ HH H H OCH ₃ H CH ₃ CH ₃ OCH ₃ The preparation of embodiment 182-chloro-2'-methoxy-5-nitrobenzylmethanol

W     W₃   W₄OCH₃  H    OCH₃CH₃   H    OCH₃F     H    OCH₃H    OCH₃  H实施例192-氯-2’-甲氧基-5-硝基二苯甲酮的制备

A solution of 2-bromoanisole (50.0 g, 0.267 mol) in ether was added portionwise to a mixture of magnesium (7.10 g, 0.293 mol) in ether. After the addition was complete, the reaction mixture was heated at reflux for 1 h, diluted with ether, cooled to 0 °C, treated with a solution of 2-chloro-5-nitrobenzaldehyde (39.0 g, 0.210 mol) in THF, and warmed to room temperature and diluted with an ice-water mixture. After acidifying the aqueous mixture (pH2-pH3) with brine, the organic phase was separated and the aqueous phase was extracted with ether. The organic extracts were combined, washed successively with 10% sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to give the title product as a brown gum. Using essentially the same procedure, the following compounds were obtained:

W W ₃ W ₄ OCH ₃ H OCH ₃ CH ₃ H OCH ₃ F H OCH ₃ H OCH ₃ H Example 19 Preparation of 2-chloro-2'-methoxy-5-nitrobenzophenone

A solution of chromium(VI) dioxide (91.0 g, 0.919 mol) in water/acetic acid solution (1:4) was added in portions to 2-chloro-2'-methoxy-5-nitrobenzylmethanol (64.2 g, 0.219 mol) while maintaining the temperature of the reaction mixture at 25-35°C. The reaction mixture was then stirred at 25-35°C for 1 hour, cooled, diluted with water, and concentrated in vacuo to obtain a residue. The residue was diluted with water and extracted with dichloromethane. The organic extracts were combined, dried over anhydrous sodium sulfate, mixed with silica gel (10 g), and filtered. The filtrate was concentrated in vacuo to give an oil. A solution of the oil in methanol/water was decolorized with charcoal and concentrated in vacuo to give a residue. Column chromatography of the residue using silica gel and dichloromethane/hexane solution gave the title product as a white solid.

W₁    W₃   W₄     mp℃OCH₃   H    OCH₃CH₃    H    OCH₃    109-111F      H    OCH₃    94-95H     OCH₃  H       79-81Using essentially the same procedure, the following compounds were obtained:

W ₁ W ₃ W ₄ mp°COCH ₃ H OCH ₃ CH ₃ H OCH ₃ 109-111F H OCH ₃ 94-95H OCH ₃ H 79-81

Example 20

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

A mixture of 2-chloro-4-fluoro-5-nitrobenzoic acid (50.0g, 0.228mol) and N,N-dimethylformamide (5 drops) in 1,2-dichloroethane was added dropwise to grass Acyl chloride (30.8 mL, 0.353 mol), refluxed for 3 hours, cooled, and concentrated in vacuo to afford the title product as an orange solid, confirmed by NMR spectral analysis.

Following essentially the same procedure, but using 2,4-difluoro-5-nitrobenzoic acid, 2,4-difluoro-5-nitrobenzoyl chloride was obtained as a brown oil.

Example 21

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

A 2M solution of methylzinc chloride in tetrahydrofuran (5.00ml, 10.1mol) was treated dropwise with a solution of 2-chloro-4-fluoro-5-nitrobenzoyl chloride (2.00g, 8.40mmol) in tetrahydrofuran, Treat with tetrakis(triphenylphosphine)palladium(0) (0.400 g, 0.350 mmol), stir at room temperature for 1 hour, then pour into 3N hydrochloric acid. The resulting aqueous mixture was extracted with ethyl acetate. The organic extracts were combined, washed sequentially with water and saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain a dark liquid. Flash column chromatography of this liquid using silica gel and dichloromethane in hexane (6:4) gave the title product (mp 66-68°C) as an off-white solid, confirmed by NMR spectral analysis.

Example 22

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

2'-chloro-4'-fluoro-5'-nitroacetophenone (12.0g, 0.0552mol), sulfur (1.77g, 0.0552mol), 30% ammonium hydroxide solution (100ml, 0.856mol) and methanol The mixture was charged to a steel reaction kettle, heated at 85°C overnight, cooled, treated with additional sulfur (0.270g) and 30% ammonium hydroxide solution (50ml), heated at 85°C overnight, cooled, Filter to remove solids, and extract with ethyl acetate. The organic extracts were combined, washed sequentially with water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain a solid. Flash column chromatography of this solid using silica gel and 0%, 1%, and 2% diethyl ether in dichloromethane gave the title product (4.19 g, mp 189-191 °C) as an orange solid, which was detected by NMR Spectral analysis was confirmed.

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

Example 23

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

A mixture of tert-butyl nitrite (3.30ml, 0.0278mol) and copper(II) chloride (2.98g, 0.0222mol) in acetonitrile was heated to 65°C and treated with 6-amino-3-methyl-5-nitrate Base-1,2-benzisothiazole (3.88g, 0.0185mol) was treated in batches, stirred at 65°C, cooled to room temperature, and poured into 20% hydrochloric acid. The resulting aqueous mixture was extracted with ethyl acetate. The organic extracts were combined, washed with 20% hydrochloric acid, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain a solid. Flash column chromatography of this solid using silica gel and dichloromethane/hexane solutions (1:1 and 3:1) gave the title product (2.54 g, mp 156-158°C) as a light yellow solid, which was analyzed by NMR spectroscopy. Analysis is OK.

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

Example 24

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 ether were heated in a sealed tube -6 (1.50 g, 5.70 mmol) in acetonitrile for 29 days, filtered to remove solids, and partially concentrated in vacuo to give a liquid. The liquid was diluted with ethyl acetate, washed successively with water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain a dark brown solid. Flash column chromatography of the yellow oil using silica gel and a gradient of 10-50% ethyl acetate in hexanes gave a yellow solid containing two components. Flash column chromatography of the yellow solid using silica gel and a gradient of 50-70% dichloromethane in hexanes gave the title product (0.870 g, mp 118-119° C.) as a light yellow solid, confirmed by NMR spectral analysis .

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

Example 25

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

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

Example 26

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

A mixture of 2,2'-dithiobis[5-nitrobenzoic acid] (44.6g, 0.113mol) and thionyl chloride (49.0ml, 0.670mol) in dichloromethane was treated with N,N-dimethyl Treated with formamide (0.800ml), refluxed overnight, concentrated in vacuo, and diluted with 1,2-dichloroethane. The resulting organic solution was 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 obtain a residue. A solution of the residue in 1,2-dichloroethane was cooled in an ice-water bath, treated with concentrated aqueous 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 was stirred at room temperature for 1 hour and filtered to obtain a solid. The solid was washed with water and air dried to give the title product as a yellow solid, confirmed by NMR spectral analysis.

The preparation of embodiment 273-chloro-5-nitro-1,2-benzisothiazole

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

Example 28

Preparation of ethyl α-cyano-5-nitro-1.2-benzisothiazole-3-acetate

Sodium ethoxide solution (prepared with ethanol and sodium (1.00 g, 0.0430 mol)) was cooled with an ice-acetone bath, treated in batches with ethyl cyanoacetate (4.51 g, 0.0398 mol), stirred at room temperature for 30 minutes, and washed with 3-Chloro-5-nitro-1,2-benzisothiazole (4.27 g, 0.0199 mol) was treated, stirred at room temperature overnight, cooled to 0°C, and 10% hydrochloric acid (15.0 ml) was added dropwise to deal with. The resulting aqueous mixture was stirred at room temperature for 1 hour and filtered to obtain a solid. The solid was washed with ethanol and air dried to give the title product as a yellow solid, confirmed by NMR spectral analysis.

Example 29

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) was added to a solution of acetyl chloride (67.0 mL) in ethanol. The reaction mixture was refluxed overnight, cooled, and filtered to remove solids. The resulting filtrate was concentrated in vacuo to obtain a brown semi-solid. A mixture of the semi-solid in diethyl ether was stirred for 2 hours and filtered to obtain a solid. The solid was washed with diethyl ether and air dried to give the title product (1.04g, mp 91-92°C) as yellow crystals.

Example 30

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

A mixture of ethyl 5-nitro-1,2-benzisothiazole-3-acetate (5.00g, 17.2mmol), water (1.00ml) and dimethylsulfoxide (35.0ml) was stirred at 107°C for 24 hours , stirred at room temperature for 2 days, and poured into an ice-water mixture. The resulting aqueous mixture was stirred for two hours and filtered to obtain a solid. The solid was washed with water and air dried to give the title product as a tan solid.

Example 31

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

A mixture of 5-nitro-1,2-benzisothiazole-3-acetonitrile (1.29g, 5.89mmol) in N,N-dimethylformamide was cooled to -9°C, and sodium hydride (1.00g Dispersion in oil) was treated at -3°C for 20 minutes, treated with iodomethane (5.00 mL), stirred at room temperature for 4 hours, and poured onto ice. The resulting aqueous mixture was treated with 10% hydrochloric acid, and extracted with dichloromethane. The combined organic extracts were washed successively with water, saturated sodium bicarbonate solution and water, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain a solid. Column chromatography of this solid using silica gel and dichloromethane gave the title product as a yellow solid, which was confirmed by NMR spectral analysis.

Example 32

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

Make α, α-dimethyl-5-nitro-1,2-benzisothiazole-3-acetonitrile (0.913g, 3.69mmol), water (0.450ml), concentrated sulfuric acid (4.55ml) and ethanol (9.10 ml) was refluxed for 1 hour, cooled, and poured onto ice. The resulting aqueous mixture was neutralized with saturated sodium bicarbonate solution, and extracted with dichloromethane. The organic extracts were washed with water, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain a solid. Column chromatography of this solid using silica gel and dichloromethane gave the title product as pale yellow crystals and was confirmed by spectral analysis.

Example 33

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), heated to reflux, Water (8.00ml) was added dropwise, refluxed for 35 minutes, cooled to room temperature and filtered through celite. The resulting filtrate was concentrated in vacuo to obtain a residue. Flash column chromatography of the residue using silica gel and ethyl acetate/hexane solution (1:1) gave the title product.

Example 34

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

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

R₄₀          mp℃OCH₃        108-109OCH(CH₃)₂OCH₂CH＝CH₂OCH₂C≡CH   115-117OCH₂CO₂CH₃ Using essentially the same procedure, the following compounds were obtained:

R ₄₀ mp °COCH ₃ 108-109OCH(CH ₃ ) ₂ OCH ₂ CH=CH ₂ OCH ₂ C≡CH 115-117OCH ₂ CO ₂ CH ₃

The preparation of embodiment 355-nitro-1,2-benzisothiazole

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

Following essentially the same procedure, but using 2'-chloro-5'-nitro-2-methyl-2-ethoxycarbonylphenyl ethyl ketone, α,α-dimethyl - Ethyl 5-nitro-1,2-benzisothiazole-3-acetate (mP75-77°C).

Example 36

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 was heated to 80°C to form a solution. The heat was removed and chlorine gas was added continuously at 70-80°C over 6 hours until saturation of the mixture occurred. The mixture was chlorine-gassed to room temperature and stirred overnight. Filtration gave the title compound (237 g, 73.6%) as a yellow crystalline solid, which was confirmed by NMR spectral analysis.

Example 37

Preparation of 2'-chloro-2-methyl-2-ethoxycarbonylphenyl ethyl ketone

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

Example 38

Preparation of 2'-chloro-5'-nitro-2-methyl-2-ethoxycarbonylphenyl ethyl ketone

Add 2'-chloro-2-methyl-2-ethoxycarbonylphenyl ethyl ketone (4.00g, 0.01570mol) to concentrated sulfuric acid (15.0ml) at 5°C, then add concentrated nitric acid (90%, 0.740mol) dropwise ml, 0.0204mol). After stirring for 5 minutes, the mixture was 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 give the title compound (3.90 g, 83.0%) as a yellow oil, which was confirmed by NMR spectral analysis.

Example 39

Preparation of 1-benzothiophene-2,3-dione

To a solution of thiophenol (100 g, 0.907 mol) in ether was added dropwise a solution of oxalyl chloride (175 g, 1.38 mol) in ether. The mixture was stirred at reflux for 2 hours and concentrated in vacuo. The residue was dissolved in dichloromethane and cooled to 0°C. Aluminum chloride (145 g, 1.09 mol) was added in portions such that the temperature did not exceed 25°C. The resulting mixture was 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 an orange solid, which was recrystallized from dichloromethane:hexanes to afford the title compound (102 g, 69.0% ), and was confirmed by NMR spectral analysis.

Example 40

Preparation of 1,2-benzisothiazole-3-carboxamide

To ammonium hydroxide (1.781) was added 1-benzothiophene-2,3-dione (87.0 g, 0.530 mol) at 5-10 °C followed by hydrogen peroxide (30% in water, 178 ml). The resulting mixture was filtered to give a yellow oil which was dried (77.0 g, 81.7%) and was identified as the title compound by NMR and IR spectral analysis.

Example 41

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

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

Example 42

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

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

Example 43

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

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

Example 44

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 (7.30g, 0.0218mol), potassium fluoride (6.33g, 0.109mol), The mixture of 18-crown-6 (2.31 g, 0.0872 mol) and sulfolane was stirred at 154°C for 19 hours, cooled to room temperature, and poured into ice water. The resulting solid was filtered and chromatographed on dichloromethane and silica gel to give a solid which was recrystallized from acetonitrile to give a tan powder. The powder was recrystallized from ethyl acetate to give the title compound (2.09 g, 29.9%) as a tan solid, which was confirmed by NMR spectral analysis.

Example 45

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

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

Claims (14)

1. the method for preparing 6-(perfluoroalkyl) uracil compound of following structural formula I

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

Y is hydrogen or C ₁-C ₆Alkyl; With

Q is C ₁-C ₆Alkyl or optional phenyl, benzyl, heteroaryl or the methylene radical heteroaryl that replaces, this method comprises:

(b) make the carbamide compound of structural formula II

Wherein

Z and Z ₁Be C independently of one another ₁-C ₈Alkyl or Z and Z ₁Can connect together with the atom that they are connected and form 4-to 7-joint ring, wherein ZZ ₁Be by-(CH ₂) ₂O (CH ₂) ₂-or-(CH ₂) m-represents that wherein m is 3,4,5 or 6 integer;

Z ₂Be C ₁-C ₆Alkyl or benzyl, the latter chooses wantonly on benzyl ring by 1-3 halogen, C ₁-C ₄Alkyl or C ₁-C ₄Any moiety combinations of haloalkyl replaces;

With n be as mentioned above, with the amine compound of structural formula II I

QNH ₂

(III)

Wherein Q is as mentioned above, reacts in the presence of acid or alkali, and Y is 6-(perfluoroalkyl) uracil compound of the general formula I of hydrogen to form wherein; With

(b) optional wherein Y is the compound of Formula I alkylation of hydrogen, and Y is C to form wherein ₁-C ₆The compound of Formula I of alkyl.

2. according to the process of claim 1 wherein that the two keys in general formula I I compound mainly are in (Z)-configuration.

3. according to the process of claim 1 wherein that the reaction in the step (a) carries out in the presence of acid.

4. according to the method for claim 3, wherein this acid is selected from C ₁-C ₆Paraffinic acid, hydrochloric acid, sulfuric acid and phosphoric acid.

5. according to the method for claim 3, wherein this acid is acetate.

6. according to the process of claim 1 wherein that this alkali is selected from three (C ₁-C ₆Alkyl) amine, heterocycle tertiary amine and basic metal C ₁-C ₆Alkoxide.

7. according to the method for claim 6, wherein this alkali is selected from 1,8-diazabicyclo [5.4.0] 11 carbon-7-alkene and 1,5-diazabicyclo [4.3.0] ninth of the ten Heavenly Stems-5-alkene.

8. according to the process of claim 1 wherein that this carbamide compound and amine compound react in the presence of solvent.

9. method according to Claim 8, wherein this solvent is selected from carboxylic acid amide, dialkyl sulfoxide, aromatic hydrocarbon, halogenated aromatic hydrocarbon, aliphatic hydrocrbon, halogenation aliphatic hydrocrbon, alcohol, paraffinic acid, ketone, ether, nitrile and water and their mixture.

10. according to the process of claim 1 wherein that this carbamide compound and amine compound react under about 20 ℃ to 150 ℃ temperature.

11. according to the process of claim 1 wherein step (b) comprise make Y wherein be compound of Formula I and the sulfuric acid dialkyl that has the alkylogen of general formula I V or have a structural formula V of hydrogen in the presence of alkali, react XY (IV) or

Wherein X is that chlorine, bromine or iodine and Y are C ₁-C ₆Alkyl.

12. according to the method for claim 1, n is 1; Y is hydrogen or C ₁-C ₄Alkyl; Q is

G is CH ₂Or key;

G ₁Be CX ₅Or N;

G ₂Be CX ₄Or N; X ₁Be hydrogen, halogen or the optional C that is replaced by an epoxy group(ing) ₁-C ₆Alkyl, X ₂Be hydrogen, halogen, NRR ₁, CO ₂R ₂, C (O) R ₃, OR ₄, SO ₂R ₅, SO ₂NR ₆R ₇, C (R ₈) (OR ₉) ₂, C (R ₁₀)=NOR ₁₁, C (R ₁₂)=C (R ₁₃)-C (OR ₁₄)=NOR ₁₅, CH ₂O-NCO ₂R ₁₆,

Optional by a C ₁-C ₆Alkoxyl group or one or two C ₁-C ₄1 of alkyl replacement, the 3-dioxolane,

Optional by a C ₁-C ₆Alkoxyl group or one or two C ₁-C ₄1 of alkyl replacement, the 3-dioxolone, or

Optional by a CO ₂R ₂Group and the C that halogen atom replaces ₁-C ₄Alkyl, and X ₃Be hydrogen, halogen, C ₁-C ₄Haloalkyl, CO ₂R ₁₇, cyano group, C ₁-C ₄Halogenated alkoxy, OR ₁₈Or C ₁-C ₄Alkyl, or work as X ₁And X ₂When the carbon atom that is connected with them connected together, they had formed five joint or six-membered ring, wherein X ₁X ₂Or X ₂X ₁Be expressed from the next:

-OC (R ₂₀) (R ₂₁) O-,-CH ₂S (O) _pN (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 ₂R ₂₆)=C (R ₂₇)-,-NC (R ₂₈)=C (SR ₂₉)-,-CH=C (CO ₂R ₃₀) O-,-CH ₂CH (R ₃₁) O-or-OC (R ₃₂) (R ₃₃) C (O)-, or work as X ₂And X ₃When the carbon atom that is connected with them connected together, they had formed five joint or six joints

Ring, wherein X ₂X ₃Or X ₃X ₂Be expressed from the next:

-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 ₂O-，-N(R ₃₉)C(O)CH＝CH-，-S-N＝C(R ₄₀)-，

-O-N=C (R ₄₁)-,-N=N-N (R ₄₂)-,-C (R ₄₃) (R ₄₄) C (O) N (R ₄₅)-or

-N (R ₄₆) C (O) C (R ₄₇) (R ₄₈)-; X ₄Be hydrogen, halogen or OR ₁₉X ₅It is hydrogen or halogen; R, R ₅₆, R ₆₄, R ₆₉, R ₇₀, R ₇₇And R ₉₁Be hydrogen, SO independently of one another ₂R ₄₉, C ₁-C ₄Alkyl, C ₃-C ₇Cycloalkyl, C ₃-C ₆Alkenyl, C ₃-C ₆Alkynyl, phenyl or benzyl; R ₁Be hydrogen, SOR ₅₀, C (O) R ₅₁, amino or optional by CO ₂R ₅₂Or C (O) R ₅₃The C that replaces ₁-C ₄Alkyl; R ₂, R ₁₆, R ₁₇, R ₂₆, R ₃₀, R ₆₈, R ₇₅, R ₇₆, R ₈₂And R ₈₈Be independently of one another hydrogen,

C ₁-C ₈Haloalkyl, C ₃-C ₈Alkenyl, C ₃-C ₈Alkynyl, phenyl, benzyl, furfuryl group, pyrrole

Pyridine base, thienyl,

Optional by CO ₂R ₅₄, morpholine or C (O) R ₅₅The C that replaces ₁-C ₈Alkyl, or

Basic metal, alkaline-earth metal, ammonium or organic ammonium positively charged ion; R ₃, R ₆₆, R ₆₇, R ₈₁, R ₈₅And R ₈₉Be independently of one another hydrogen,

C ₁-C ₆Alkyl, C ₃-C ₆Alkenyl, C ₃-C ₆Alkynyl, NR ₅₆R ₅₇, phenyl or benzyl; R ₄, R ₁₈, R ₁₉And R ₆₅Be hydrogen, C independently of one another ₁-C ₆Alkyl, C ₃-C ₆Alkenyl, C ₃-C ₆

Alkynyl, C ₁-C ₄Haloalkyl, C (O) R ₅₈, C (S) R ₅₉Or benzyl; R ₅And R ₇₂Be C independently of one another ₁-C ₆Alkyl, C ₁-C ₆Haloalkyl, NR ₆₀R ₆₁, imidazoles 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 ₆₃And R ₈₀Be hydrogen or C independently of one another ₁-C ₄Alkyl; R ₇Be hydrogen, C ₃-C ₆Alkenyl, C ₃-C ₆Alkynyl, benzyl or optional by cyano group or C (O) R ₆₂Replace

C ₁-C ₄Alkyl; R ₈And R ₂₇Be hydrogen, C independently of one another ₁-C ₄Alkyl or C ₁-C ₄Alkoxyl group; R ₉And R ₉₀Be C independently of one another ₁-C ₆Alkyl; R ₁₀Be hydrogen, C ₁-C ₆Alkyl, phenyl or benzyl; R ₁₃, R ₂₄And R ₃₆Be hydrogen, C independently of one another ₁-C ₆Alkyl or halogen; R ₂₃Be hydrogen or NR ₆₃R ₆₄R ₃₄Be hydrogen, C ₁-C ₄Alkyl or C ₁-C ₄Haloalkyl; R ₃₇Be hydrogen, C ₁-C ₄Alkyl or C ₂-C ₈Alkoxyalkyl; R ₃₈And R ₃₉Be hydrogen, C independently of one another ₁-C ₄Alkyl, C ₁-C ₄Haloalkyl, C ₃-C ₆Alkenyl or C ₃-C ₆Alkynyl; R ₄₀, R ₄₁And R ₄₂Be hydrogen, halogen, cyano group, OR independently of one another ₆₅, C (O) R ₆₆, C (S) R ₆₇, CO ₂R ₆₈, C (=NOR ₆₉), C ₁-C ₈Alkyl, C ₃-C ₇Cycloalkyl, C ₂-C ₈Alkenyl or C ₂-C ₈Alkynyl, wherein each group is optional is replaced by following any moiety combinations: 1-3 C ₁-C ₁₀-alkoxyl group, 1 or 2 C ₁-C ₆Halogenated alkoxy, 1 or 2 NR ₇₀R ₇₁Group, 1 or 2 S (O) qR ₇₂Group, 1 or 2 cyano group, 1 or 2 C ₃-C ₇Cycloalkyl, 1 OSO ₂R ₇₃Group, 1 or 2 C (O) R ₇₄Group, 1 or 2 COR ₇₅Group, 1 or 2 C (O) SR ₇₆Group, 1 or 2 C (O) NR ₇₇R ₇₈Group, 1-3 OR ₇₉Group, 1 or 2 P (O) (OR ₈₀) ₂Group, 1 optional by 1-3 C ₁-C ₄Alkyl replace 1,3-dioxolane, or 1 optional by 1-3 C ₁-C ₄1 of alkyl replacement, the 3-dioxolane,

Or

Optional by following phenyl that any moiety combinations replaced or benzyl: 1-3 halogen atom, 1-3 C ₁-C ₆Alkyl, 1-3 C ₁-C ₆Alkoxyl group, 1 C ₃-C ₇Cycloalkyl, 1 C ₁-C ₄Haloalkyl, 1 C ₁-C ₄Alkylthio, 1 cyano group, 1 nitro, 1 C (O) R ₈₁Group, 1 CO ₂R ₈₂Group, 1 OR ₈₃Group, 1 SR ₈₄Group, 1 C ₁-C ₆Alkoxy methyl, 1 methylol, 1 C ₃-C ₈Alkenyl oxy methyl, or 1 C ₁-C ₈The haloalkoxy ylmethyl; R ₄₃And R ₄₈Be hydrogen, C independently of one another ₁-C ₄Alkyl, C ₁-C ₄Haloalkyl, C ₃-C ₆Alkenyl, C ₃-C ₆Alkynyl or C ₃-C ₇Cycloalkyl, or R ₄₃And R ₄₄Or R ₄₇And R ₄₈Can connect together with the carbon atom that they are connected and form C ₃-C ₇Cycloalkyl; R ₄₉, R ₅₀And R ₈₆Be C independently of one another ₁-C ₆Alkyl, NR ₉₃R ₉₄, C ₁-C ₄Haloalkyl, C ₃-C ₆Alkenyl, C ₃-C ₆Alkynyl 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 ₈₇And R ₈₂Be hydrogen, C independently of one another ₁-C ₆Alkyl, C ₃-C ₇Cycloalkyl, C ₁-C ₆Haloalkyl, C ₃-C ₆Alkenyl, C ₃-C ₆Alkynyl, phenyl or benzyl; R ₇₉, R ₈₃And R ₈₄Be hydrogen, C (O) R independently of one another ₈₅, SO ₂R ₈₆, C ₁-C ₆Haloalkyl, C ₂-C ₆Alkenyl, C ₅-C ₈Cycloalkenyl, C ₂-C ₆Alkynyl, phenyl, benzyl, or optional by a hydroxyl, benzyloxy, OC (O) R ₈₇, C ₁-C ₆Alkoxyl group, CO ₂R ₈₈, C (O) R ₈₉, C (OR ₉₀) ₂, C (O) N ₉₁R ₉₂Or the C of cyano group replacement ₁-C ₁₀Alkyl; R ₉₃And R ₉₄Be hydrogen, C independently of one another ₁-C ₄Haloalkyl, C ₂-C ₆Alkenyl, C ₃-C ₈Cycloalkyl, optional by 1 or 2 C ₁-C ₄Alkoxyl group or 1 C that the cyano group alkyl replaces ₁-C ₈Alkyl, or

Optional by following benzyl that any moiety combinations replaced or phenyl: 1-3 halogen atom, 1-3 C ₁-C ₄Alkyl, 1-3 C ₁-C ₄Haloalkyl, 1-3 C ₁-C ₄Alkoxyl group, 1-3 C ₁-C ₄Halogenated alkoxy, 1 cyano group or 1 nitro and

Work as R ₉₃And R ₉₄When the carbon atom that is connected with them connected together, they had formed 5-to 12-joint monocycle or condensed-bicyclic, and optional quilt is selected from halogen, cyano group, nitro, amino, hydroxyl, C ₁-C ₄Alkyl, C ₁-C ₄Haloalkyl, C ₁-C ₄Alkoxyl group, C ₁-C ₄Halogenated alkoxy and C ₁-C ₄The heterocycle that one or more groups of halogenated alkyl sulfonyl replace; With

P and q are 0,1 or 2 independently of one another; With

Z and Z ₁Be C independently of one another ₁-C ₆Alkyl; With

Z ₂Be C ₁-C ₄Alkyl.

13, according to the method for claim 12, wherein Y is hydrogen or methyl; X ₁Be hydrogen, fluorine or the optional C that is replaced by an epoxy group(ing) ₁-C ₃Alkyl; X ₂Be hydrogen, halogen, NRR ₁, CO ₂R ₂, C (O) R ₃, OR ₄, SO ₂R ₅, SO ₂N ₆R ₇, C (R ₈) (OR ₉) ₂, C (R ₁₀)=NOR ₁₁, C (R ₁₂)=C (R ₁₃)-C (OR ₁₄)=NOR ₁₅, CH ₂O-NCO ₂R ₁₆,

Optional by a C ₁-C ₆Alkoxyl group or one or two C ₁-C ₄1 of alkyl replacement, 3-dioxy penta

Ring,

Optional by a C ₁-C ₆Alkoxyl group or one or two C ₁-C ₄1 of alkyl replacement, 3-two oxa-s

Cyclopentenone, or

Optional by a CO ₂R ₂Group and the C that halogen atom replaces ₁-C ₄Alkyl, and X ₃Be hydrogen, halogen, C ₁-C ₄Haloalkyl, CO ₂R ₁, cyano group, C ₁-C ₄Halogenated alkoxy, OR ₁₈Or C ₁-C ₄Alkyl, or work as X ₁And X ₂When the carbon atom that is connected with them connects together, they will form five joint or six-membered ring, wherein X ₁X ₂Or X ₂X ₁Represent by following group:

-OC(R ₂₀)(R ₂₁)O-，-CH ₂S(O) _pN(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 ₂R ₂₆)＝CH-，-NC(R ₂₈)＝C(SR ₂₉)-，-CH＝C(CO ₂R ₃₀)O-，

-CH ₂CH (R ₃₁) O-or-OC (R ₃₂) (R ₃₃) C (O)-, or work as X ₂And X ₃When the carbon atom that is connected with them connects together, they will form five joint or six-ring, wherein X ₂X ₃Or X ₃X ₂Represent by following group:

-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 ₂O-，-N(R ₃₉)C(O)CH＝CH-，-S-N＝C(R ₄₀)-，

-O-N=C (R ₄₁)-,-N=N-N (R ₄₂)-,-C (R ₄₃) (R ₄₄) C (O) N (R ₄₅)-or

-N (R ₄₆) C (O) C (R ₄₇) (R ₄₈)-; X ₄Be hydrogen, halogen or OR ₁₉X ₅It is hydrogen or halogen; R, R ₆₄, R ₆₉And R ₇₇Be hydrogen independently of one another, SO ₂R ₄₉Or C ₁-C ₄Alkyl; R ₁Be hydrogen, SO ₂R ₅₀, C (O) R ₅₁, amino or optional by CO ₂R ₅₂Or C (O) R ₅₃The C that replaces ₁-C ₄Alkyl; R ₂, R ₁₆, R ₁₇, R ₂₆, R ₃₀, R ₆₈, R ₇₅, R ₇₆, R ₈₂And R ₈₉Be hydrogen independently of one another, C ₃-C ₆Alkenyl or optional by CO ₂R ₅₄, morpholine or C (O) R ₅₅The C that replaces ₁-C ₄Alkyl; R ₃, R ₆₆, R ₆₇, R ₈₅And R ₈₉Be hydrogen independently of one another, C ₁-C ₄Alkyl or NR ₅₆R ₅₇R ₄, R ₁₈And R ₁₉Be hydrogen independently of one another, C ₁-C ₄Alkyl, C ₁-C ₄Haloalkyl, C (O) R ₅₈, C ₃-C ₄Alkenyl or C ₃-C ₄Alkynyl; R ₅₆Be SO ₂R ₄₉R ₅₇Be hydrogen or C ₁-C ₄Alkyl; R ₅And R ₇₂Be NR independently of one another ₆₀R ₆₁Or 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 ₄₆And R ₈₀Be hydrogen or methyl independently of one another; R ₇Be optional by cyano group or C (O) R ₆₂The C that replaces ₁-C ₄Alkyl; R ₈Be hydrogen or C ₁-C ₄Alkoxyl group; R ₉And R ₉₀Be C independently of one another ₁-C ₄Alkyl; R ₁₀Be hydrogen or C ₁-C ₃Alkyl; R ₁₃, R ₂₄And R ₃₆Be hydrogen or chlorine independently of one another; R ₂₃Be NR ₆₃R ₆₄R ₃₄Be C ₁-C ₃Haloalkyl; R ₃₇Be C ₂-C ₄Alkoxyalkyl; R ₃₈And R ₃₉Be C independently of one another ₁-C ₃Haloalkyl, C ₁-C ₃Alkyl or propargyl; R ₄₀, R ₄₁And R ₄₂Be hydrogen independently of one another, C (O) R ₆₆, C (S) R ₆₇, CO ₂R ₆₈, C (=NOR ₆₉),

Optional by the following C that any moiety combinations replaced ₁-C ₃Alkyl: 1 or 2 halogen atoms, 1 or 2 C ₁-C ₃Alkoxyl group, 1 or 2 C ₁-C ₃Halogenated alkoxy, 1 SO ₂R ₇₂Group, 1 or 2 cyano group, 1 C ₃-C ₅Cycloalkyl, 1 OSO ₂R ₇₃Group, 1 C (O) R ₇₄Group, 1 CO ₂R ₇₅Group, 1 C (O) SR ₇₆Group, 1 C (O) NR ₇₇R ₇₈Group, 1 or 2 OR ₇₉Group, 1 P (O) (OR ₈₀) ₂Group, 11,3-dioxolane group or 11,3-diox group; Or it is optional by 1 halogen atom, 1 or 2 methyl, 1 methoxyl group, 1 monochloromethyl or 1 OR ₈₃The phenyl that any moiety combinations replaced in the group; R ₄₃, R ₄₄, R ₄₇And R ₄₈Be hydrogen or methyl independently of one another, or R ₄₃And R ₄₄Or R ₄₇And R ₄₈The carbon atom that is connected with them the formation cyclopropyl that connects together; R ₄₉, R ₅₀And R ₈₆Be C independently of one another ₁-C ₄Alkyl or NR ₉₃R ₉₄R ₅₁, R ₅₂, R ₅₃, R ₅₄, R ₅₅, R ₅₈, R ₆₀, R ₆₁, R ₆₂, R ₇₃, R ₇₄, R ₇₈And R ₈₇Be hydrogen, C independently of one another ₁-C ₄Alkyl or C ₁-C ₄Haloalkyl; R ₇₉And R ₈₃Be hydrogen, C (O) R independently of one another ₈₅, SO ₂R ₈₆, C ₁-C ₄Haloalkyl, C ₃-C ₄Alkenyl or optional by an OC (O) R ₈₇, CO ₂R ₈₈, C (O) R ₈₉, C (OR ₉₀) ₂Or the C of cyano group replacement ₁-C ₃Alkyl; R ₉₃And R ₉₄Be hydrogen or C independently of one another ₁-C ₈Alkyl;

With p be 0,1 or 2;

Z and Z ₁Be identical and expression methyl or ethyl; With

Z ₂Be methyl or ethyl.

14. have the method for 6-(trifluoromethyl) uracil compound of structural formula VI according to the preparation of claim 1,

Wherein

Y is hydrogen or methyl;

X ₅It is hydrogen or halogen;

R ₄₀Be hydrogen, C (O) R ₆₆, C (S) R ₆₇, CO ₂R ₆₈,

Optional by the following C that any moiety combinations replaced ₁-C ₃Alkyl: 1 or 2 halogen atoms, 1 or 2 C ₁-C ₃Alkoxyl group, 1 or 2 C ₁-C ₃Halogenated alkoxy, 1 SO ₂R ₇₂Group, 1 or 2 cyano group, 1 C ₃-C ₅Cycloalkyl, 1 OSO ₂R ₇₃Group, 1 or 2 OR ₇₉Group, 1 P (O) (OR ₈₀) ₂Group, 11,3-dioxolane group or 11,3-diox group, or optional by 1 halogen atom, 1 or 2 methyl, 1 methoxyl group, 1 monochloromethyl or 1 OR ₈₃The phenyl that group replaces; R ₆₆, R ₆₇, R ₈₅And R ₈₉Be hydrogen independently of one another, C ₁-C ₄Alkyl or NR ₅₆R ₅₇R ₅₆Be SO ₂R ₄₉R ₅₇Be hydrogen or C ₁-C ₄Alkyl; R ₄₉And R ₈₆Be C independently of one another ₁-C ₄Alkyl or NR ₉₃R ₉₄R ₉₃And R ₉₄Be hydrogen or C independently of one another ₁-C ₈Alkyl; R ₆₈And R ₈₈Be hydrogen independently of one another, C ₃-C ₆Alkenyl or optional by CO ₂R ₅₄, morpholine or C (O) R ₅₅The C that replaces ₁-C ₄Alkyl; R ₅₄, R ₅₅, R ₆₀, R ₆₁, R ₇₃And R ₈₇Be hydrogen, C independently of one another ₁-C ₄Alkyl or C ₁-C ₄Haloalkyl; R ₇₂Be NR ₆₀R ₆₁Or indoles; R ₇₉And R ₈₃Be hydrogen, C (O) R independently of one another ₈₅, SO ₂R ₈₆, C ₁-C ₄Haloalkyl, C ₃-C ₄Alkenyl or optional by an OC (O) R ₈₇, CO ₂R ₈₈, C (O) R ₈₉, C (OR ₉₀) ₂Or the C of cyano group replacement ₁-C ₃Alkyl; R ₈₀Be hydrogen or methyl; And R ₉₀Be C ₁-C ₄Alkyl.